Showing papers by "University of Florida published in 2014"
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Massachusetts Institute of Technology1, Harvard University2, Princeton University3, University of Chicago4, Las Cumbres Observatory Global Telescope Network5, University of Copenhagen6, Arizona State University7, Carnegie Institution for Science8, University of Birmingham9, Aarhus University10, Goddard Space Flight Center11, University of Maryland, College Park12, Vanderbilt University13, Northern Kentucky University14, Lowell Observatory15, University of Texas at Austin16, University of Florida17, Max Planck Society18, Tokyo Institute of Technology19, University of California, Berkeley20, University of California, Santa Cruz21, Space Telescope Science Institute22, Johns Hopkins University23, Spanish National Research Council24, Lehigh University25, INAF26, Fisk University27
TL;DR: The Transiting Exoplanet Survey Satellite (TESS) as discussed by the authors will search for planets transiting bright and nearby stars using four wide-field optical charge-coupled device cameras to monitor at least 200,000 main-sequence dwarf stars.
Abstract: The Transiting Exoplanet Survey Satellite (TESS) will search for planets transiting bright and nearby stars. TESS has been selected by NASA for launch in 2017 as an Astrophysics Explorer mission. The spacecraft will be placed into a highly elliptical 13.7-day orbit around the Earth. During its 2-year mission, TESS will employ four wide-field optical charge-coupled device cameras to monitor at least 200,000 main-sequence dwarf stars with I C â4â13 for temporary drops in brightness caused by planetary transits. Each star will be observed for an interval ranging from 1 month to 1 year, depending mainly on the starâs ecliptic latitude. The longest observing intervals will be for stars near the ecliptic poles, which are the optimal locations for follow-up observations with the James Webb Space Telescope. Brightness measurements of preselected target stars will be recorded every 2 min, and full frame images will be recorded every 30 min. TESS stars will be 10 to 100 times brighter than those surveyed by the pioneering Kepler mission. This will make TESS planets easier to characterize with follow-up observations. TESS is expected to find more than a thousand planets smaller than Neptune, including dozens that are comparable in size to the Earth. Public data releases will occur every 4 months, inviting immediate community-wide efforts to study the new planets. The TESS legacy will be a catalog of the nearest and brightest stars hosting transiting planets, which will endure as highly favorable targets for detailed investigations.
2,604Â citations
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American Museum of Natural History1, University of Tartu2, University of Colombo3, Royal Netherlands Academy of Arts and Sciences4, University of Florida5, University of Palermo6, Goethe University Frankfurt7, Hobart Corporation8, Nakhon Phanom University9, University of Bamenda10, University of Gothenburg11, Naturalis12, Swedish University of Agricultural Sciences13, Royal Botanic Gardens14, Universiti Malaysia Sabah15, United States Department of Agriculture16, Forest Research Institute Malaysia17, Humboldt State University18, Chinese Academy of Sciences19, Landcare Research20, University of Western Australia21, Estonian University of Life Sciences22, University of Southern Queensland23, Botanic Garden Meise24, Manchester Metropolitan University25, James Cook University26
TL;DR: Diversity of most fungal groups peaked in tropical ecosystems, but ectomycorrhizal fungi and several fungal classes were most diverse in temperate or boreal ecosystems, and manyfungal groups exhibited distinct preferences for specific edaphic conditions (such as pH, calcium, or phosphorus).
Abstract: Fungi play major roles in ecosystem processes, but the determinants of fungal diversity and biogeographic patterns remain poorly understood. Using DNA metabarcoding data from hundreds of globally distributed soil samples, we demonstrate that fungal richness is decoupled from plant diversity. The plant-to-fungus richness ratio declines exponentially toward the poles. Climatic factors, followed by edaphic and spatial variables, constitute the best predictors of fungal richness and community composition at the global scale. Fungi show similar latitudinal diversity gradients to other organisms, with several notable exceptions. These findings advance our understanding of global fungal diversity patterns and permit integration of fungi into a general macroecological framework.
2,346Â citations
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TL;DR: The tunnelling-assisted interlayer recombination of the majority carriers is responsible for the tunability of the electronic and optoelectronic processes in atomically thin p-n heterojunctions fabricated using van der Waals assembly of transition-metal dichalcogenides.
Abstract: In heterostructures of the transition metal dichalcogenides MoS2 and WSe2, atomically thin pân junctions are created that show gate-tunable rectifying and photovoltaic behaviour mediated by tunnelling-assisted interlayer recombination. Semiconductor pân junctions are essential building blocks for electronic and optoelectronic devices1,2. In conventional pân junctions, regions depleted of free charge carriers form on either side of the junction, generating built-in potentials associated with uncompensated dopant atoms. Carrier transport across the junction occurs by diffusion and drift processes influenced by the spatial extent of this depletion region. With the advent of atomically thin van der Waals materials and their heterostructures, it is now possible to realize a pân junction at the ultimate thickness limit3,4,5,6,7,8,9,10. Van der Waals junctions composed of p- and n-type semiconductorsâeach just one unit cell thickâare predicted to exhibit completely different charge transport characteristics than bulk heterojunctions10,11,12. Here, we report the characterization of the electronic and optoelectronic properties of atomically thin pân heterojunctions fabricated using van der Waals assembly of transition-metal dichalcogenides. We observe gate-tunable diode-like current rectification and a photovoltaic response across the pân interface. We find that the tunnelling-assisted interlayer recombination of the majority carriers is responsible for the tunability of the electronic and optoelectronic processes. Sandwiching an atomic pân junction between graphene layers enhances the collection of the photoexcited carriers. The atomically scaled van der Waals pân heterostructures presented here constitute the ultimate functional unit for nanoscale electronic and optoelectronic devices.
1,953Â citations
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TL;DR: Current progress in epidemiology, pathology, diagnosis, and treatment of type 1 diabetes, and prospects for an improved future for individuals with this disease are discussed.
1,881Â citations
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Goddard Institute for Space Studies1, Columbia University2, University of Chicago3, University of East Anglia4, Potsdam Institute for Climate Impact Research5, Karlsruhe Institute of Technology6, University of Florida7, Swiss Federal Institute of Aquatic Science and Technology8, International Institute for Applied Systems Analysis9, Netherlands Environmental Assessment Agency10, University of Natural Resources and Life Sciences, Vienna11
TL;DR: Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies.
Abstract: Here we present the results from an intercomparison of multiple global gridded crop models (GGCMs) within the framework of the Agricultural Model Intercomparison and Improvement Project and the Inter-Sectoral Impacts Model Intercomparison Project. Results indicate strong negative effects of climate change, especially at higher levels of warming and at low latitudes; models that include explicit nitrogen stress project more severe impacts. Across seven GGCMs, five global climate models, and four representative concentration pathways, model agreement on direction of yield changes is found in many major agricultural regions at both low and high latitudes; however, reducing uncertainty in sign of response in mid-latitude regions remains a challenge. Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies.
1,704Â citations
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Duke University1, University of Texas at Austin2, Heidelberg Institute for Theoretical Studies3, American Museum of Natural History4, Beijing Genomics Institute5, Xi'an Jiaotong University6, New Mexico State University7, University of Sydney8, University of California9, Uppsala University10, University of Copenhagen11, Okinawa Institute of Science and Technology12, University of Georgia13, Griffith University14, Catalan Institution for Research and Advanced Studies15, Joint Institute for Nuclear Research16, Oak Ridge National Laboratory17, Aarhus University18, Washington University in St. Louis19, University of California, Santa Cruz20, Cardiff University21, Kunming Institute of Zoology22, China Agricultural University23, Tulane University24, Louisiana State University25, Copenhagen Zoo26, Oregon Health & Science University27, Federal University of ParĂĄ28, Technical University of Denmark29, Canterbury Museum30, Curtin University31, Novosibirsk State University32, Smithsonian Institution33, National University of Singapore34, National Museum of Natural History35, Nova Southeastern University36, Occidental College37, University of Edinburgh38, Harvard University39, University of California, San Francisco40, University of Florida41, University of Illinois at UrbanaâChampaign42
TL;DR: A genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves recovered a highly resolved tree that confirms previously controversial sister or close relationships and identifies the first divergence in Neoaves, two groups the authors named Passerea and Columbea.
Abstract: To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
1,624Â citations
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TL;DR: It is demonstrated that trackers can be evaluated objectively by survival curves, Kaplan Meier statistics, and Grubs testing, and it is found that in the evaluation practice the F-score is as effective as the object tracking accuracy (OTA) score.
Abstract: There is a large variety of trackers, which have been proposed in the literature during the last two decades with some mixed success. Object tracking in realistic scenarios is a difficult problem, therefore, it remains a most active area of research in computer vision. A good tracker should perform well in a large number of videos involving illumination changes, occlusion, clutter, camera motion, low contrast, specularities, and at least six more aspects. However, the performance of proposed trackers have been evaluated typically on less than ten videos, or on the special purpose datasets. In this paper, we aim to evaluate trackers systematically and experimentally on 315 video fragments covering above aspects. We selected a set of nineteen trackers to include a wide variety of algorithms often cited in literature, supplemented with trackers appearing in 2010 and 2011 for which the code was publicly available. We demonstrate that trackers can be evaluated objectively by survival curves, Kaplan Meier statistics, and Grubs testing. We find that in the evaluation practice the F-score is as effective as the object tracking accuracy (OTA) score. The analysis under a large variety of circumstances provides objective insight into the strengths and weaknesses of trackers.
1,604Â citations
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Pennsylvania State University1, University of California, San Diego2, Stanford University3, University of Washington4, University of Michigan5, New College of Florida6, Florida State University7, Cold Spring Harbor Laboratory8, California Institute of Technology9, University of Vienna10, Emory University11, Fred Hutchinson Cancer Research Center12, Massachusetts Institute of Technology13, Broad Institute14, University of California, Irvine15, University of California, Santa Cruz16, University of California, San Francisco17, Yale University18, University of Florida19, Johns Hopkins University20, University College London21, University of Oxford22, Cornell University23, Memorial Sloan Kettering Cancer Center24, Harvard University25, University of Iowa26, Yeshiva University27, University of Pennsylvania28, Washington University in St. Louis29, National Institutes of Health30, University of North Carolina at Chapel Hill31
TL;DR: The mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types as mentioned in this paper.
Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases
1,335Â citations
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University of Illinois at UrbanaâChampaign1, Massachusetts Institute of Technology2, Harvard University3, Stanford University4, Rensselaer Polytechnic Institute5, Pennsylvania State University6, University of California, Berkeley7, Brown University8, University of Florida9, University of Texas at Austin10
TL;DR: In this article, a review of thermal transport at the nanoscale is presented, emphasizing developments in experiment, theory, and computation in the past ten years and summarizes the present status of the field.
Abstract: A diverse spectrum of technology drivers such as improved thermal barriers, higher efficiency thermoelectric energy conversion, phase-change memory, heat-assisted magnetic recording, thermal management of nanoscale electronics, and nanoparticles for thermal medical therapies are motivating studies of the applied physics of thermal transport at the nanoscale. This review emphasizes developments in experiment, theory, and computation in the past ten years and summarizes the present status of the field. Interfaces become increasingly important on small length scales. Research during the past decade has extended studies of interfaces between simple metals and inorganic crystals to interfaces with molecular materials and liquids with systematic control of interface chemistry and physics. At separations on the order of âŒ1 nm, the science of radiative transport through nanoscale gaps overlaps with thermal conduction by the coupling of electronic and vibrational excitations across weakly bonded or rough interface...
1,307Â citations
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Harvard University1, University of Pennsylvania2, University of Florida3, University of Texas Health Science Center at San Antonio4, Henry Ford Health System5, University of Miami6, Scripps Health7, Saint Louis University8, University of New Mexico9, Duke University10, Johns Hopkins University11, Indiana University12
TL;DR: Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologyic response to prior interferon-based treatment.
Abstract: Background Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. Methods We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvirâsofosbuvir plus ribavirin for 12 weeks, ledipasvirâsofosbuvir for 24 weeks, or ledipasvirâsofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of ...
1,258Â citations
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George Washington University1, University of Idaho2, University of New South Wales3, University of Michigan4, University of British Columbia5, Utah State University6, University of Tennessee7, University of Western Sydney8, Wesleyan University9, University of Florida10, University of Missouri11, Macquarie University12, Queen's University13, College of the Holy Cross14, Royal Botanic Gardens15, Polish Academy of Sciences16, Michigan State University17
TL;DR: It is shown that woody clades successfully moved into freezing-prone environments by either possessing transport networks of small safe conduits and/or shutting down hydraulic function by dropping leaves during freezing.
Abstract: Early flowering plants are thought to have been woody species restricted to warm habitats 1â3 . This lineage has since radiated into almost every climate, with manifold growth forms 4 . As angiosperms spread and climate changed, they evolved mechanisms to cope with episodic freezing. To explore the evolution of traits underpinning the ability to persist in freezing conditions, we assembled a large species-level database of growth habit (woody or herbaceous; 49,064 species), as well as leaf phenology (evergreen or deciduous), diameter of hydraulic conduits (that is, xylem vessels and tracheids) and climate occupancies (exposure to freezing). To model the evolution of speciesâ traits and climate occupancies, we combined these data with an unparalleled dated molecular phylogeny (32,223 species) for land plants. Here we show that woody clades successfully move di nto freezingprone environments by either possessing transport networks of small
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Christopher P. Ahn1, Rachael M. Alexandroff2, Carlos Allende Prieto3, Carlos Allende Prieto4Â +272 moreâąInstitutions (69)
TL;DR: The 10th public data release (DR10) from the Sloan Digital Sky Survey (SDSS-III) was released in 2013 as mentioned in this paper, which includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopy data from Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July.
Abstract: The Sloan Digital Sky Survey (SDSS) has been in operation since 2000 April. This paper presents the Tenth Public Data Release (DR10) from its current incarnation, SDSS-III. This data release includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July. The APOGEE instrument is a near-infrared R ~ 22,500 300 fiber spectrograph covering 1.514-1.696 ÎŒm. The APOGEE survey is studying the chemical abundances and radial velocities of roughly 100,000 red giant star candidates in the bulge, bar, disk, and halo of the Milky Way. DR10 includes 178,397 spectra of 57,454 stars, each typically observed three or more times, from APOGEE. Derived quantities from these spectra (radial velocities, effective temperatures, surface gravities, and metallicities) are also included. DR10 also roughly doubles the number of BOSS spectra over those included in the Ninth Data Release. DR10 includes a total of 1,507,954 BOSS spectra comprising 927,844 galaxy spectra, 182,009 quasar spectra, and 159,327 stellar spectra selected over 6373.2 deg2.
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Stockholm University1, Alfred Wegener Institute for Polar and Marine Research2, University of Hamburg3, United States Geological Survey4, University of Florida5, Northern Arizona University6, University of Alaska Fairbanks7, Lawrence Berkeley National Laboratory8, National Park Service9, University of Copenhagen10, Argonne National Laboratory11, Bowdoin College12, Lehigh University13
TL;DR: In this article, the authors presented revised estimates of permafrost organic carbon stocks, including quantitative uncertainty estimates, in the 0-3 m depth range in soils as well as for sediments deeper than 3 m in deltaic deposits of major rivers and in the Yedoma region of Siberia and Alaska.
Abstract: Soils and other unconsolidated deposits in the northern circumpolar permafrost region store large amounts of soil organic carbon (SOC). This SOC is potentially vulnerable to remobilization following soil warming and permafrost thaw, but SOC stock estimates were poorly constrained and quantitative error estimates were lacking. This study presents revised estimates of permafrost SOC stocks, including quantitative uncertainty estimates, in the 0â3 m depth range in soils as well as for sediments deeper than 3 m in deltaic deposits of major rivers and in the Yedoma region of Siberia and Alaska. Revised estimates are based on significantly larger databases compared to previous studies. Despite this there is evidence of significant remaining regional data gaps. Estimates remain particularly poorly constrained for soils in the High Arctic region and physiographic regions with thin sedimentary overburden (mountains, highlands and plateaus) as well as for deposits below 3 m depth in deltas and the Yedoma region. While some components of the revised SOC stocks are similar in magnitude to those previously reported for this region, there are substantial differences in other components, including the fraction of perennially frozen SOC. Upscaled based on regional soil maps, estimated permafrost region SOC stocks are 217 ± 12 and 472 ± 27 Pg for the 0â0.3 and 0â1 m soil depths, respectively (±95% confidence intervals). Storage of SOC in 0â3 m of soils is estimated to 1035 ± 150 Pg. Of this, 34 ± 16 Pg C is stored in poorly developed soils of the High Arctic. Based on generalized calculations, storage of SOC below 3 m of surface soils in deltaic alluvium of major Arctic rivers is estimated as 91 ± 52 Pg. In the Yedoma region, estimated SOC stocks below 3 m depth are 181 ± 54 Pg, of which 74 ± 20 Pg is stored in intact Yedoma (late Pleistocene ice- and organic-rich silty sediments) with the remainder in refrozen thermokarst deposits. Total estimated SOC storage for the permafrost region is âŒ1300 Pg with an uncertainty range of âŒ1100 to 1500 Pg. Of this, âŒ500 Pg is in non-permafrost soils, seasonally thawed in the active layer or in deeper taliks, while âŒ800 Pg is perennially frozen. This represents a substantial âŒ300 Pg lowering of the estimated perennially frozen SOC stock compared to previous estimates.
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University of Rochester1, University of Texas Southwestern Medical Center2, University of North Carolina at Chapel Hill3, Thomas Jefferson University4, University of Colorado Denver5, University of Virginia6, University of Miami7, Johns Hopkins University8, University of Florida9, Harvard University10, Duke University11, Cincinnati Children's Hospital Medical Center12, Mayo Clinic13, Food and Drug Administration14, National Institutes of Health15, American Institutes for Research16
TL;DR: Hydxyurea and transfusion therapy are strongly recommended for many individuals with SCD and many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals withSCD.
Abstract: Importance Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100 000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. Objective To support and expand the number of health professionals able and willing to provide care for persons with SCD. Evidence Review Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. Findings Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (â„200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. Conclusions and Relevance Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.
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TL;DR: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir.
Abstract: Background All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. Methods In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfaâribavirin). The primary end point was a sustained virologi...
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University of Florida1, University of Maryland, Baltimore2, Wake Forest University3, University of South Carolina4, Pennington Biomedical Research Center5, United States Department of Agriculture6, Yale University7, University of California, San Diego8, Veterans Health Administration9, Stanford University10, Northwestern University11, University of Pittsburgh12
TL;DR: The findings suggest mobility benefit from a structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability.
Abstract: Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). Conclusions and Relevance A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Trial Registration clinicaltrials.gov Identifier:NCT01072500
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St. Jude Children's Research Hospital1, University of Washington2, University of New Mexico3, National Institutes of Health4, Washington University in St. Louis5, University of Florida6, Ohio State University7, New York University8, University of Alabama at Birmingham9, University of Texas Southwestern Medical Center10, University of Pennsylvania11, Royal Children's Hospital12, University of Toronto13, Texas A&M University14, University of Utah15, Emory University16, Mayo Clinic17, University of Chicago18, University of Texas Health Science Center at San Antonio19, University of Texas MD Anderson Cancer Center20, Yeshiva University21, University of California, San Francisco22, University of Colorado Denver23
TL;DR: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors.
Abstract: BACKGROUND Philadelphia chromosomeâlike acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCRâABL1âpositive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6âNTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.)
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TL;DR: A general-purpose MATLAB software program called GPOPS--II is described for solving multiple-phase optimal control problems using variable-order Gaussian quadrature collocation methods.
Abstract: A general-purpose MATLAB software program called GPOPS--II is described for solving multiple-phase optimal control problems using variable-order Gaussian quadrature collocation methods. The software employs a Legendre-Gauss-Radau quadrature orthogonal collocation method where the continuous-time optimal control problem is transcribed to a large sparse nonlinear programming problem (NLP). An adaptive mesh refinement method is implemented that determines the number of mesh intervals and the degree of the approximating polynomial within each mesh interval to achieve a specified accuracy. The software can be interfaced with either quasi-Newton (first derivative) or Newton (second derivative) NLP solvers, and all derivatives required by the NLP solver are approximated using sparse finite-differencing of the optimal control problem functions. The key components of the software are described in detail and the utility of the software is demonstrated on five optimal control problems of varying complexity. The software described in this article provides researchers a useful platform upon which to solve a wide variety of complex constrained optimal control problems.
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TL;DR: Sequence Demarcation Tool (SDT) as discussed by the authors is a free user-friendly computer program that aims to provide a robust and highly reproducible means of objectively using pairwise genetic identity calculations to classify any set of nucleotide or amino acid sequences.
Abstract: The perpetually increasing rate at which viral full-genome sequences are being determined is creating a pressing demand for computational tools that will aid the objective classification of these genome sequences. Taxonomic classification approaches that are based on pairwise genetic identity measures are potentially highly automatable and are progressively gaining favour with the International Committee on Taxonomy of Viruses (ICTV). There are, however, various issues with the calculation of such measures that could potentially undermine the accuracy and consistency with which they can be applied to virus classification. Firstly, pairwise sequence identities computed based on multiple sequence alignments rather than on multiple independent pairwise alignments can lead to the deflation of identity scores with increasing dataset sizes. Also, when gap-characters need to be introduced during sequence alignments to account for insertions and deletions, methodological variations in the way that these characters are introduced and handled during pairwise genetic identity calculations can cause high degrees of inconsistency in the way that different methods classify the same sets of sequences. Here we present Sequence Demarcation Tool (SDT), a free user-friendly computer program that aims to provide a robust and highly reproducible means of objectively using pairwise genetic identity calculations to classify any set of nucleotide or amino acid sequences. SDT can produce publication quality pairwise identity plots and colour-coded distance matrices to further aid the classification of sequences according to ICTV approved taxonomic demarcation criteria. Besides a graphical interface version of the program for Windows computers, command-line versions of the program are available for a variety of different operating systems (including a parallel version for cluster computing platforms).
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Northwestern University1, University of Texas at Austin2, University of Alberta3, University of Arizona4, University of Georgia5, University of Florida6, Eastern Kentucky University7, American Museum of Natural History8, Pennsylvania State University9, Harvard University10, University of Cologne11, University of British Columbia12, Duke University13, Spanish National Research Council14, New York Botanical Garden15, Ludwig Maximilian University of Munich16, Université de Montréal17, Centre national de la recherche scientifique18, Chinese Academy of Sciences19, University of Michigan20, Donald Danforth Plant Science Center21
TL;DR: Strong and robust support is found for a sister-group relationship between land plants and one group of streptophyte green algae, the Zygnematophyceae, and suggests that phylogenetic hypotheses used to understand the evolution of fundamental plant traits should be reevaluated.
Abstract: Reconstructing the origin and evolution of land plants and their algal relatives is a fundamental problem in plant phylogenetics, and is essential for understanding how critical adaptations arose, including the embryo, vascular tissue, seeds, and flowers. Despite advances in molecular systematics, some hypotheses of relationships remain weakly resolved. Inferring deep phylogenies with bouts of rapid diversification can be problematic; however, genome-scale data should significantly increase the number of informative characters for analyses. Recent phylogenomic reconstructions focused on the major divergences of plants have resulted in promising but inconsistent results. One limitation is sparse taxon sampling, likely resulting from the difficulty and cost of data generation. To address this limitation, transcriptome data for 92 streptophyte taxa were generated and analyzed along with 11 published plant genome sequences. Phylogenetic reconstructions were conducted using up to 852 nuclear genes and 1,701,170 aligned sites. Sixty-nine analyses were performed to test the robustness of phylogenetic inferences to permutations of the data matrix or to phylogenetic method, including supermatrix, supertree, and coalescent-based approaches, maximum-likelihood and Bayesian methods, partitioned and unpartitioned analyses, and amino acid versus DNA alignments. Among other results, we find robust support for a sister-group relationship between land plants and one group of streptophyte green algae, the Zygnematophyceae. Strong and robust support for a clade comprising liverworts and mosses is inconsistent with a widely accepted view of early land plant evolution, and suggests that phylogenetic hypotheses used to understand the evolution of fundamental plant traits should be reevaluated.
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TL;DR: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation.
Abstract: A B S T R AC T BACKGROUND The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/râombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of om bitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. RESULTS A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B. CONCLUSIONS In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/râombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.)
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Beijing Genomics Institute1, University of Copenhagen2, Royal Veterinary College3, Seoul National University4, University of NebraskaâLincoln5, University of Porto6, University of South Carolina7, Montclair State University8, Uppsala University9, National University of Singapore10, University of California, Berkeley11, South China University of Technology12, Chinese Academy of Sciences13, Kunming Institute of Zoology14, Howard Hughes Medical Institute15, Aberystwyth University16, University of Kent17, University of California, Riverside18, Mississippi State University19, Austral University of Chile20, Swedish University of Agricultural Sciences21, China Agricultural University22, Cardiff University23, Copenhagen Zoo24, Louisiana State University25, Washington University in St. Louis26, Xi'an Jiaotong University27, University of California, Santa Cruz28, Nova Southeastern University Oceanographic Center29, Smithsonian Conservation Biology Institute30, National Museum of Natural History31, Natural History Museum32, University of California, San Francisco33, Harvard University34, University of Florida35, University of Edinburgh36, New Mexico State University37, Macau University of Science and Technology38, Curtin University39
TL;DR: This work explored bird macroevolution using full genomes from 48 avian species representing all major extant clades to reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
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Massachusetts Institute of Technology1, Harvard University2, Princeton University3, University of Chicago4, Las Cumbres Observatory Global Telescope Network5, University of Copenhagen6, Arizona State University7, Carnegie Institution for Science8, Aarhus University9, University of Birmingham10, Goddard Space Flight Center11, University of Maryland, College Park12, Vanderbilt University13, Northern Kentucky University14, Lowell Observatory15, University of Texas at Austin16, University of Florida17, Max Planck Society18, Tokyo Institute of Technology19, University of California, Berkeley20, Space Telescope Science Institute21, Johns Hopkins University22, Spanish National Research Council23, Lehigh University24, INAF25, Fisk University26
TL;DR: The Transiting Exoplanet Survey Satellite (TESS) as mentioned in this paper will discover thousands of exoplanets in orbit around the brightest stars in the sky, including Earth-sized to gas giants, around a wide range of stellar types and orbital distances.
Abstract: The Transiting Exoplanet Survey Satellite (TESS) will discover thousands of exoplanets in orbit around the brightest stars in the sky. In a two-year survey, TESS will monitor more than 500,000 stars for temporary drops in brightness caused by planetary transits. This first-ever spaceborne all-sky transit survey will identify planets ranging from Earth-sized to gas giants, around a wide range of stellar types and orbital distances. No ground-based survey can achieve this feat. A large fraction of TESS target stars will be 30-100 times brighter than those observed by Kepler satellite, and therefore TESS . planets will be far easier to characterize with follow-up observations. TESS will make it possible to study the masses, sizes, densities, orbits, and atmospheres of a large cohort of small planets, including a sample of rocky worlds in the habitable zones of their host stars. TESS will provide prime targets for observation with the James Webb Space Telescope (JWST), as well as other large ground-based and space-based telescopes of the future. TESS data will be released with minimal delay (no proprietary period), inviting immediate community-wide efforts to study the new planets. The TESS legacy will be a catalog of the very nearest and brightest main-sequence stars hosting transiting exoplanets, thus providing future observers with the most favorable targets for detailed investigations.
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TL;DR: With the rice industry consolidating in many countries, there are opportunities to fortify a significant share of rice for distribution or for use in government safety net programs that target those most in need, especially women and children.
Abstract: Rice is the staple food for over half the world's population. Approximately 480 million metric tons of milled rice is produced annually. China and India alone account for âŒ50% of the rice grown and consumed. Rice provides up to 50% of the dietary caloric supply for millions living in poverty in Asia and is, therefore, critical for food security. It is becoming an important food staple in both Latin America and Africa. Record increases in rice production have been observed since the start of the Green Revolution. However, rice remains one of the most protected food commodities in world trade. Rice is a poor source of vitamins and minerals, and losses occur during the milling process. Populations that subsist on rice are at high risk of vitamin and mineral deficiency. Improved technologies to fortify rice have the potential to address these deficiencies and their associated adverse health effects. With the rice industry consolidating in many countries, there are opportunities to fortify a significant share of rice for distribution or for use in government safety net programs that target those most in need, especially women and children. Multisectoral approaches are needed for the promotion and implementation of rice fortification in countries.
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TL;DR: It is demonstrated that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replicationdomain boundaries, largely accounting for the previously reported lack of alignment.
Abstract: Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.
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University of Florida1, University of Padua2, University of WĂŒrzburg3, Pennsylvania State University4, University of Social Sciences and Humanities5, Tilburg University6, City University of New York7, Koç University8, University of Michigan9, University of Kuala Lumpur10, Texas A&M University11, San Diego State University12, Mount Saint Vincent University13, Radboud University Nijmegen14, Virginia Commonwealth University15, Texas A&M UniversityâCommerce16, Loyola University Chicago17, Worcester Polytechnic Institute18, London School of Economics and Political Science19, James Madison University20, Occidental College21, McDaniel College22, Connecticut College23, Wilfrid Laurier University24, University of BrasĂlia25, California State University, Northridge26, University of Virginia27, Ohio State University28, University of Wisconsin-Madison29, Ithaca College30, Charles University in Prague31, Western Kentucky University32, Washington and Lee University33
TL;DR: The authors compared variation in the replicability of 13 classic and contemporary effects across 36 independent samples totaling 6,344 participants and found that the results of these experiments are more dependent on the effect itself than on the sample and setting used to investigate the effect.
Abstract: Although replication is a central tenet of science, direct replications are rare in psychology. This research tested variation in the replicability of 13 classic and contemporary effects across 36 independent samples totaling 6,344 participants. In the aggregate, 10 effects replicated consistently. One effect â imagined contact reducing prejudice â showed weak support for replicability. And two effects â flag priming influencing conservatism and currency priming influencing system justification â did not replicate. We compared whether the conditions such as lab versus online or US versus international sample predicted effect magnitudes. By and large they did not. The results of this small sample of effects suggest that replicability is more dependent on the effect itself than on the sample and setting used to investigate the effect.
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TL;DR: The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
Abstract: Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) âpositive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab i...
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University of California, Santa Cruz1, University of Chicago2, Ames Research Center3, Harvard University4, Search for extraterrestrial intelligence5, Fermilab6, Northwestern University7, University of Washington8, San Jose State University9, NASA Exoplanet Science Institute10, Pennsylvania State University11, University of Florida12, California Institute of Technology13
TL;DR: In this article, Batalha et al. report on the orbital architectures of Kepler systems having multiple-planet candidates identified in the analysis of data from the first six quarters of Kepler data and report that only two pairs of planets in these candidate systems appear to be on Hill-unstable orbits, indicating ~96% of the candidate planetary systems are correctly interpreted as true systems.
Abstract: We report on the orbital architectures of Kepler systems having multiple-planet candidates identified in the analysis of data from the first six quarters of Kepler data and reported by Batalha et al. (2013). These data show 899 transiting planet candidates in 365 multiple-planet systems and provide a powerful means to study the statistical properties of planetary systems. Using a generic massâradius relationship, we find that only two pairs of planets in these candidate systems (out of 761 pairs total) appear to be on Hill-unstable orbits, indicating ~96% of the candidate planetary systems are correctly interpreted as true systems. We find that planet pairs show little statistical preference to be near mean-motion resonances. We identify an asymmetry in the distribution of period ratios near first-order resonances (e.g., 2:1, 3:2), with an excess of planet pairs lying wide of resonance and relatively few lying narrow of resonance. Finally, based upon the transit duration ratios of adjacent planets in each system, we find that the interior planet tends to have a smaller transit impact parameter than the exterior planet does. This finding suggests that the mode of the mutual inclinations of planetary orbital planes is in the range 1°.0â2°.2, for the packed systems of small planets probed by these observations.
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TL;DR: The challenges related to patients and pathogens that contribute to inadequate antibiotic dosing are explored and how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients is discussed.
Abstract: Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
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TL;DR: B cells are identified as a cellular target of noroviruses and enteric bacteria as a stimulatory factor for norovirus infection, leading to the development of an in vitro infection model for human norovIRuses.
Abstract: The cell tropism of human noroviruses and the development of an in vitro infection model remain elusive. Although susceptibility to individual human norovirus strains correlates with an individualâs histo-blood group antigen (HBGA) profile, the biological basis of this restriction is unknown. We demonstrate that human and mouse noroviruses infected B cells in vitro and likely in vivo. Human norovirus infection of B cells required the presence of HBGA-expressing enteric bacteria. Furthermore, mouse norovirus replication was reduced in vivo when the intestinal microbiota was depleted by means of oral antibiotic administration. Thus, we have identified B cells as a cellular target of noroviruses and enteric bacteria as a stimulatory factor for norovirus infection, leading to the development of an in vitro infection model for human noroviruses.