Showing papers by "Heidelberg University published in 2014"
University of Washington1, Sapienza University of Rome2, Mekelle University3, University of Texas at San Antonio4, King Saud bin Abdulaziz University for Health Sciences5, Debre markos University6, Emory University7, University of Oxford8, University of Cartagena9, United Nations Population Fund10, University of Birmingham11, Stanford University12, Aga Khan University13, University of Melbourne14, National Taiwan University15, University of Cambridge16, University of California, San Diego17, Public Health Foundation of India18, Public Health England19, University of Peradeniya20, Harvard University21, National Institutes of Health22, Tehran University of Medical Sciences23, Auckland University of Technology24, University of Sheffield25, University of Western Australia26, Karolinska Institutet27, Birzeit University28, Brandeis University29, American Cancer Society30, Ochsner Medical Center31, Yonsei University32, University of Bristol33, Heidelberg University34, Vanderbilt University35, South African Medical Research Council36, Jordan University of Science and Technology37, New Generation University College38, Northeastern University39, Simmons College40, Norwegian Institute of Public Health41, Boston University42, Chinese Center for Disease Control and Prevention43, University of Bari44, University of São Paulo45, University of Otago46, University of Crete47, International Centre for Diarrhoeal Disease Research, Bangladesh48, Fred Hutchinson Cancer Research Center49, Teikyo University50, Bhabha Atomic Research Centre51, University of Tokyo52, Finnish Institute of Occupational Health53, Heriot-Watt University54, University of Alabama at Birmingham55, Griffith University56, National Center for Disease Control and Public Health57, University of California, Irvine58, Johns Hopkins University59, New York University60, University of Queensland61, Universidade Federal de Minas Gerais62, National Research University – Higher School of Economics63, University of Bergen64, Columbia University65, Shandong University66, University of North Carolina at Chapel Hill67, Fujita Health University68, Korea University69, Chongqing Medical University70, Zhejiang University71
TL;DR: The global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013 is estimated using a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs).
9,180 citations
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
St. Jude Children's Research Hospital1, University of Edinburgh2, Singapore Immunology Network3, New York University4, University College London5, Heidelberg University6, University of Oxford7, Royal Melbourne Hospital8, Hospital for Special Surgery9, University of Milan10, Aix-Marseille University11, University of Maryland, College Park12, European Institute of Oncology13, Massachusetts Institute of Technology14, University of Bonn15, University of Maryland, Baltimore16, University of Eastern Piedmont17, University of Louisville18, Vrije Universiteit Brussel19, National Institutes of Health20
TL;DR: A set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation are described with the goal of unifying experimental standards for diverse experimental scenarios.
4,287 citations
Eric A. Collisson1, Joshua D. Campbell2, Angela N. Brooks2, Angela N. Brooks3 +315 more•Institutions (41)
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
4,104 citations
Mayo Clinic1, National and Kapodistrian University of Athens2, University of Turin3, Heidelberg University4, Harvard University5, Memorial Sloan Kettering Cancer Center6, University of Navarra7, University of Pennsylvania8, VU University Medical Center9, Emory University10, University of Bologna11, Mount Sinai Hospital12, Memorial Hospital of South Bend13, Karolinska University Hospital14, Carolinas Healthcare System15, Aalborg University16, Ankara University17, Cedars-Sinai Medical Center18
TL;DR: The disease definition of multiple myeloma is updated to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions), and specific metrics that new biomarkers should meet for inclusion in the disease definition are provided.
Abstract: This International Myeloma Working Group consensus updates the disease defi nition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identifi cation of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfi l the criteria for the presence of myeloma-defi ning CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specifi c metrics that new biomarkers should meet for inclusion in the disease defi nition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any diff erences in outcome that might occur as a result of the new disease defi nition.
3,049 citations
TL;DR: The Illustris Project as mentioned in this paper is a series of large-scale hydrodynamical simulations of galaxy formation, which includes primordial and metal-line cooling with self-shielding corrections, stellar evolution, stellar feedback, gas recycling, chemical enrichment, supermassive black hole growth, and feedback from active galactic nuclei.
Abstract: We introduce the Illustris Project, a series of large-scale hydrodynamical simulations of galaxy formation. The highest resolution simulation, Illustris-1, covers a volume of (106.5 Mpc)^3, has a dark mass resolution of 6.26 × 10^6 M_⊙, and an initial baryonic matter mass resolution of 1.26 × 10^6 M_⊙. At z = 0 gravitational forces are softened on scales of 710 pc, and the smallest hydrodynamical gas cells have an extent of 48 pc. We follow the dynamical evolution of 2 × 1820^3 resolution elements and in addition passively evolve 1820^3 Monte Carlo tracer particles reaching a total particle count of more than 18 billion. The galaxy formation model includes: primordial and metal-line cooling with self-shielding corrections, stellar evolution, stellar feedback, gas recycling, chemical enrichment, supermassive black hole growth, and feedback from active galactic nuclei. Here we describe the simulation suite, and contrast basic predictions of our model for the present-day galaxy population with observations of the local universe. At z = 0 our simulation volume contains about 40 000 well-resolved galaxies covering a diverse range of morphologies and colours including early-type, late-type and irregular galaxies. The simulation reproduces reasonably well the cosmic star formation rate density, the galaxy luminosity function, and baryon conversion efficiency at z = 0. It also qualitatively captures the impact of galaxy environment on the red fractions of galaxies. The internal velocity structure of selected well-resolved disc galaxies obeys the stellar and baryonic Tully–Fisher relation together with flat circular velocity curves. In the well-resolved regime, the simulation reproduces the observed mix of early-type and late-type galaxies. Our model predicts a halo mass dependent impact of baryonic effects on the halo mass function and the masses of haloes caused by feedback from supernova and active galactic nuclei.
2,012 citations
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
Clinical Trial Service Unit1, University of Glasgow2, Cedars-Sinai Medical Center3, Stanford University4, Boehringer Ingelheim5, Mayo Clinic6, University of Edinburgh7, University of Melbourne8, Florey Institute of Neuroscience and Mental Health9, University of Texas Health Science Center at Houston10, University of Alabama at Birmingham11, Helsinki University Central Hospital12, The George Institute for Global Health13, University of Newcastle14, Sapienza University of Rome15, Karolinska Institutet16, University of Washington17, Heidelberg University18
TL;DR: In this paper, a pre-specifi ed meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control was conducted.
1,773 citations
TL;DR: The European Space Agency's Planck satellite, dedicated to studying the early Universe and its subsequent evolution, was launched 14 May 2009 and has been scanning the microwave and submillimetre sky continuously since 12 August 2009 as discussed by the authors.
Abstract: The European Space Agency’s Planck satellite, dedicated to studying the early Universe and its subsequent evolution, was launched 14 May 2009 and has been scanning the microwave and submillimetre sky continuously since 12 August 2009. In March 2013, ESA and the Planck Collaboration released the initial cosmology products based on the first 15.5 months of Planck data, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the mission and its performance, the processing, analysis, and characteristics of the data, the scientific results, and the science data products and papers in the release. The science products include maps of the cosmic microwave background (CMB) and diffuse extragalactic foregrounds, a catalogue of compact Galactic and extragalactic sources, and a list of sources detected through the Sunyaev-Zeldovich effect. The likelihood code used to assess cosmological models against the Planck data and a lensing likelihood are described. Scientific results include robust support for the standard six-parameter ΛCDM model of cosmology and improved measurements of its parameters, including a highly significant deviation from scale invariance of the primordial power spectrum. The Planck values for these parameters and others derived from them are significantly different from those previously determined. Several large-scale anomalies in the temperature distribution of the CMB, first detected by WMAP, are confirmed with higher confidence. Planck sets new limits on the number and mass of neutrinos, and has measured gravitational lensing of CMB anisotropies at greater than 25σ. Planck finds no evidence for non-Gaussianity in the CMB. Planck’s results agree well with results from the measurements of baryon acoustic oscillations. Planck finds a lower Hubble constant than found in some more local measures. Some tension is also present between the amplitude of matter fluctuations (σ8) derived from CMB data and that derived from Sunyaev-Zeldovich data. The Planck and WMAP power spectra are offset from each other by an average level of about 2% around the first acoustic peak. Analysis of Planck polarization data is not yet mature, therefore polarization results are not released, although the robust detection of E-mode polarization around CMB hot and cold spots is shown graphically.
1,719 citations
University of Sydney1, National and Kapodistrian University of Athens2, The Royal Marsden NHS Foundation Trust3, University of Tübingen4, University of Duisburg-Essen5, University of Kiel6, Aix-Marseille University7, University of Paris8, University of Barcelona9, Netherlands Cancer Institute10, Karolinska Institutet11, Heidelberg University12, Mount Vernon Hospital13, Institut Gustave Roussy14, University of California, Los Angeles15, GlaxoSmithKline16, Harvard University17
TL;DR: A combination of dabraenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.
Abstract: BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib–trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib–trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib–trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib–trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib–trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib–trametinib group. CONCLUSIONS A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.)
1,501 citations
TL;DR: In this article, the authors present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey.
Abstract: We present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey, which includes more than twice the integration time of the nominal survey used for the 2013 release papers. The Planck full mission temperature data and a first release of polarization data on large angular scales measure the spectral index of curvature perturbations to be ns = 0.968 ± 0.006 and tightly constrain its scale dependence to dns/ dlnk = −0.003 ± 0.007 when combined with the Planck lensing likelihood. When the Planck high-l polarization data are included, the results are consistent and uncertainties are further reduced. The upper bound on the tensor-to-scalar ratio is r0.002< 0.11 (95% CL). This upper limit is consistent with the B-mode polarization constraint r< 0.12 (95% CL) obtained from a joint analysis of the BICEP2/Keck Array and Planck data. These results imply that V(φ) ∝ φ2 and natural inflation are now disfavoured compared to models predicting a smaller tensor-to-scalar ratio, such as R2 inflation. We search for several physically motivated deviations from a simple power-law spectrum of curvature perturbations, including those motivated by a reconstruction of the inflaton potential not relying on the slow-roll approximation. We find that such models are not preferred, either according to a Bayesian model comparison or according to a frequentist simulation-based analysis. Three independent methods reconstructing the primordial power spectrum consistently recover a featureless and smooth over the range of scales 0.008 Mpc-1 ≲ k ≲ 0.1 Mpc-1. At large scales, each method finds deviations from a power law, connected to a deficit at multipoles l ≈ 20−40 in the temperature power spectrum, but at an uncompelling statistical significance owing to the large cosmic variance present at these multipoles. By combining power spectrum and non-Gaussianity bounds, we constrain models with generalized Lagrangians, including Galileon models and axion monodromy models. The Planck data are consistent with adiabatic primordial perturbations, and the estimated values for the parameters of the base Λ cold dark matter (ΛCDM) model are not significantly altered when more general initial conditions are admitted. In correlated mixed adiabatic and isocurvature models, the 95% CL upper bound for the non-adiabatic contribution to the observed CMB temperature variance is | αnon - adi | < 1.9%, 4.0%, and 2.9% for CDM, neutrino density, and neutrino velocity isocurvature modes, respectively. We have tested inflationary models producing an anisotropic modulation of the primordial curvature power spectrum findingthat the dipolar modulation in the CMB temperature field induced by a CDM isocurvature perturbation is not preferred at a statistically significant level. We also establish tight constraints on a possible quadrupolar modulation of the curvature perturbation. These results are consistent with the Planck 2013 analysis based on the nominal mission data and further constrain slow-roll single-field inflationary models, as expected from the increased precision of Planck data using the full set of observations.
Nicholas J Kassebaum1, Amelia Bertozzi-Villa1, Megan Coggeshall1, Katya Anne Shackelford1 +349 more•Institutions (179)
TL;DR: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015, with evidence of continued acceleration in the MMR, and MMR was highest in the oldest age groups in both 1990 and 2013.
Harvard University1, Seoul National University2, Fox Chase Cancer Center3, Agency for Science, Technology and Research4, Autonomous University of Barcelona5, University of Washington6, University of Colorado Denver7, Katholieke Universiteit Leuven8, University of Utah9, Memorial Sloan Kettering Cancer Center10, Peter MacCallum Cancer Centre11, University of Cologne12, Heidelberg University13, German Cancer Research Center14, University of Duisburg-Essen15, Princess Margaret Cancer Centre16, Novartis17
TL;DR: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.
Abstract: BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-l...
TL;DR: A simulation that starts 12 million years after the Big Bang, and traces 13 billion years of cosmic evolution with 12 billion resolution elements in a cube of 106.5 megaparsecs a side yields a reasonable population of ellipticals and spirals, reproduces the observed distribution of galaxies in clusters and characteristics of hydrogen on large scales, and at the same time matches the ‘metal’ and hydrogen content of galaxies on small scales.
Abstract: Previous simulations of the growth of cosmic structures have broadly reproduced the ‘cosmic web’ of galaxies that we see in the Universe, but failed to create a mixed population of elliptical and spiral galaxies, because of numerical inaccuracies and incomplete physical models. Moreover, they were unable to track the small-scale evolution of gas and stars to the present epoch within a representative portion of the Universe. Here we report a simulation that starts 12 million years after the Big Bang, and traces 13 billion years of cosmic evolution with 12 billion resolution elements in a cube of 106.5 megaparsecs a side. It yields a reasonable population of ellipticals and spirals, reproduces the observed distribution of galaxies in clusters and characteristics of hydrogen on large scales, and at the same time matches the ‘metal’ and hydrogen content of galaxies on small scales. A simulation that starts 12 million years after the Big Bang and traces 13 billion years of cosmic evolution yields a reasonable population of elliptical and spiral galaxies, reproduces the observed distribution of galaxies in clusters and the characteristics of hydrogen on large scales, and at the same time matches the ‘metal’ and hydrogen content of galaxies on small scales. Established cosmological models of galaxy formation and evolution have achieved limited success, failing to create the mixed population of elliptical and spiral galaxies that we observe. A new simulation that makes full use of the latest advances in computing power and algorithmic developments successfully recreates a population of ellipticals and spirals, reproduces the observed distribution of galaxies in clusters, the evolution of dark and visible matter and the characteristics of hydrogen on large scales, at the same time matching the metal (heavier than helium) and hydrogen content of galaxies on small scales. The calculation tracks the build-up of galaxies at unprecedented precision from shortly after the Big Bang until the present day, spanning more than 13 billion years of cosmic evolution.
TL;DR: The open-source C++ software package qpOASES is described, which implements a parametric active-set method in a reliable and efficient way and can be used to compute critical points of nonconvex QP problems.
Abstract: Many practical applications lead to optimization problems that can either be stated as quadratic programming (QP) problems or require the solution of QP problems on a lower algorithmic level. One relatively recent approach to solve QP problems are parametric active-set methods that are based on tracing the solution along a linear homotopy between a QP problem with known solution and the QP problem to be solved. This approach seems to make them particularly suited for applications where a-priori information can be used to speed-up the QP solution or where high solution accuracy is required. In this paper we describe the open-source C++ software package qpOASES, which implements a parametric active-set method in a reliable and efficient way. Numerical tests show that qpOASES can outperform other popular academic and commercial QP solvers on small- to medium-scale convex test examples of the Maros-Meszaros QP collection. Moreover, various interfaces to third-party software packages make it easy to use, even on embedded computer hardware. Finally, we describe how qpOASES can be used to compute critical points of nonconvex QP problems.
TL;DR: The value of the ratio of branching fractions for the dilepton invariant mass squared range 1 < q(2) < 6 GeV(2)/c(4) is measured to be 0.745(-0.074)(+0.090)(stat) ± 0.036(syst).
Abstract: A measurement of the ratio of the branching fractions of the B+→K+μ+μ− and B+→K+e+e− decays is presented using proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb−1, recorded with the LHCb experiment at center-of-mass energies of 7 and 8 TeV. The value of the ratio of branching fractions for the dilepton invariant mass squared range 1
TL;DR: The PLATO 2.0 mission as discussed by the authors has been selected for ESA's M3 launch opportunity (2022/24) to provide accurate key planet parameters (radius, mass, density and age) in statistical numbers.
Abstract: PLATO 2.0 has recently been selected for ESA’s M3 launch opportunity (2022/24). Providing accurate key planet parameters (radius, mass, density and age) in statistical numbers, it addresses fundamental questions such as: How do planetary systems form and evolve? Are there other systems with planets like ours, including potentially habitable planets? The PLATO 2.0 instrument consists of 34 small aperture telescopes (32 with 25 s readout cadence and 2 with 2.5 s candence) providing a wide field-of-view (2232 deg 2) and a large photometric magnitude range (4–16 mag). It focusses on bright (4–11 mag) stars in wide fields to detect and characterize planets down to Earth-size by photometric transits, whose masses can then be determined by ground-based radial-velocity follow-up measurements. Asteroseismology will be performed for these bright stars to obtain highly accurate stellar parameters, including masses and ages. The combination of bright targets and asteroseismology results in high accuracy for the bulk planet parameters: 2 %, 4–10 % and 10 % for planet radii, masses and ages, respectively. The planned baseline observing strategy includes two long pointings (2–3 years) to detect and bulk characterize planets reaching into the habitable zone (HZ) of solar-like stars and an additional step-and-stare phase to cover in total about 50 % of the sky. PLATO 2.0 will observe up to 1,000,000 stars and detect and characterize hundreds of small planets, and thousands of planets in the Neptune to gas giant regime out to the HZ. It will therefore provide the first large-scale catalogue of bulk characterized planets with accurate radii, masses, mean densities and ages. This catalogue will include terrestrial planets at intermediate orbital distances, where surface temperatures are moderate. Coverage of this parameter range with statistical numbers of bulk characterized planets is unique to PLATO 2.0. The PLATO 2.0 catalogue allows us to e.g.: - complete our knowledge of planet diversity for low-mass objects, - correlate the planet mean density-orbital distance distribution with predictions from planet formation theories,- constrain the influence of planet migration and scattering on the architecture of multiple systems, and - specify how planet and system parameters change with host star characteristics, such as type, metallicity and age. The catalogue will allow us to study planets and planetary systems at different evolutionary phases. It will further provide a census for small, low-mass planets. This will serve to identify objects which retained their primordial hydrogen atmosphere and in general the typical characteristics of planets in such low-mass, low-density range. Planets detected by PLATO 2.0 will orbit bright stars and many of them will be targets for future atmosphere spectroscopy exploring their atmosphere. Furthermore, the mission has the potential to detect exomoons, planetary rings, binary and Trojan planets. The planetary science possible with PLATO 2.0 is complemented by its impact on stellar and galactic science via asteroseismology as well as light curves of all kinds of variable stars, together with observations of stellar clusters of different ages. This will allow us to improve stellar models and study stellar activity. A large number of well-known ages from red giant stars will probe the structure and evolution of our Galaxy. Asteroseismic ages of bright stars for different phases of stellar evolution allow calibrating stellar age-rotation relationships. Together with the results of ESA’s Gaia mission, the results of PLATO 2.0 will provide a huge legacy to planetary, stellar and galactic science.
TL;DR: In this article, the authors present an overview of galaxy evolution across cosmic time in the Illustris Simulation, an N-body/hydrodynamical simulation that evolves 2*1820^3 resolution elements in a (106.5Mpc)^3 box from cosmological initial conditions down to z=0 using the AREPO moving-mesh code.
Abstract: We present an overview of galaxy evolution across cosmic time in the Illustris Simulation. Illustris is an N-body/hydrodynamical simulation that evolves 2*1820^3 resolution elements in a (106.5Mpc)^3 box from cosmological initial conditions down to z=0 using the AREPO moving-mesh code. The simulation uses a state-of-the-art set of physical models for galaxy formation that was tuned to reproduce the z=0 stellar mass function and the history of the cosmic star-formation rate density. We find that Illustris successfully reproduces a plethora of observations of galaxy populations at various redshifts, for which no tuning was performed, and provide predictions for future observations. In particular, we discuss (a) the buildup of galactic mass, showing stellar mass functions and the relations between stellar mass and halo mass from z=7 to z=0, (b) galaxy number density profiles around massive central galaxies out to z=4, (c) the gas and total baryon content of both galaxies and their halos for different redshifts, and as a function of mass and radius, and (d) the evolution of galaxy specific star-formation rates up to z=8. In addition, we (i) present a qualitative analysis of galaxy morphologies from z=5 to z=0, for the stellar as well as the gaseous components, and their appearance in HST mock observations, (ii) follow galaxies selected at z=2 to their z=0 descendants, and quantify their growth and merger histories, and (iii) track massive z=0 galaxies to high redshift and study their joint evolution in star-formation activity and compactness. We conclude with a discussion of several disagreements with observations, and lay out possible directions for future research.
Christopher J L Murray1, Katrina F Ortblad1, Caterina Guinovart1, Stephen S Lim1 +367 more•Institutions (179)
TL;DR: The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.
TL;DR: The results indicate that serum-derived exosomes can be used to determine genomic DNA mutations for cancer prediction, treatment, and therapy resistance.
TL;DR: 68Ga-PSMA PET/CT can detect lesions characteristic for PC with improved contrast when compared to standard 18F-fluoromethylcholine PET/ CT, especially at low PSA levels.
Abstract: Purpose
Positron emission tomography (PET) with choline tracers has found widespread use for the diagnosis of prostate cancer (PC). However, choline metabolism is not increased in a considerable number of cases, whereas prostate-specific membrane antigen (PSMA) is overexpressed in most PCs. Therefore, a 68Ga-labelled PSMA ligand could be superior to choline tracers by obtaining a high contrast. The aim of this study was to compare such a novel tracer with standard choline-based PET/CT.
TL;DR: A large number of patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled and the proportion of patients who achieved a pathological complete response to carboplatin was analyzed.
Abstract: Summary Background Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. Methods Patients with previously untreated, non-metastatic, stage II–III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m 2 once a week) and non-pegylated liposomal doxorubicin (20 mg/m 2 once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. Findings 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1–49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3–42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96–1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4–60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4–44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0–40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7–44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [ vs one [ vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. Interpretation The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. Funding GlaxoSmithKline, Roche, and Teva.
St. Paul's Hospital1, MedStar Washington Hospital Center2, Columbia University Medical Center3, McGill University Health Centre4, Odense University Hospital5, Heidelberg University6, University Hospital of Lausanne7, Sheba Medical Center8, Leiden University Medical Center9, University of Bern10, University of Padua11, St George's Hospital12, Rabin Medical Center13
TL;DR: The survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves was determined and stenosis was worse than regurgitation among patients with structural valve deterioration.
Abstract: Importance Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. Objective To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. Design, Setting, and Participants Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and Main Outcomes and Measures Survival, stroke, and New York Heart Association functional class. Results Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) ( P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) ( P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). Conclusions and Relevance In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.
University College London1, Royal Free Hospital2, Heidelberg University3, University of Notre Dame4, Sir Charles Gairdner Hospital5, University of Copenhagen6, University of California, San Francisco7, University of Western Australia8, Ninewells Hospital9, Technische Universität München10, East Carolina University11, National Cancer Research Institute12
TL;DR: 5-year results for local recurrence and the first analysis of overall survival are reported and complications and mortality were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT.
TL;DR: In this article, the statistical isotropy and Gaussianity of the cosmic microwave background (CMB) anisotropies using observations made by the Planck satellite were investigated.
Abstract: We test the statistical isotropy and Gaussianity of the cosmic microwave background (CMB) anisotropies using observations made by the Planck satellite. Our results are based mainly on the full Planck mission for temperature, but also include some polarization measurements. In particular, we consider the CMB anisotropy maps derived from the multi-frequency Planck data by several component-separation methods. For the temperature anisotropies, we find excellent agreement between results based on these sky maps over both a very large fraction of the sky and a broad range of angular scales, establishing that potential foreground residuals do not affect our studies. Tests of skewness, kurtosis, multi-normality, N-point functions, and Minkowski functionals indicate consistency with Gaussianity, while a power deficit at large angular scales is manifested in several ways, for example low map variance. The results of a peak statistics analysis are consistent with the expectations of a Gaussian random field. The “Cold Spot” is detected with several methods, including map kurtosis, peak statistics, and mean temperature profile. We thoroughly probe the large-scale dipolar power asymmetry, detecting it with several independent tests, and address the subject of a posteriori correction. Tests of directionality suggest the presence of angular clustering from large to small scales, but at a significance that is dependent on the details of the approach. We perform the first examination of polarization data, finding the morphology of stacked peaks to be consistent with the expectations of statistically isotropic simulations. Where they overlap, these results are consistent with the Planck 2013 analysis based on the nominal mission data and provide our most thorough view of the statistics of the CMB fluctuations to date.
TL;DR: The ENIGMA Consortium has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected.
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
Betty Abelev1, Luke David Hanratty2, M. Esposito3, Edmundo Javier Garcia-Solis4 +940 more•Institutions (90)
TL;DR: The ALICE experiment at the CERN Large Hadron Collider as mentioned in this paper continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams.
Abstract: ALICE is the heavy-ion experiment at the CERN Large Hadron Collider. The experiment continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams. In this paper we describe the running environment and the data handling procedures, and discuss the performance of the ALICE detectors and analysis methods for various physics observables.
University of Glasgow1, University of Belgrade2, Karolinska University Hospital3, Mayo Clinic4, University of Verona5, Heidelberg University6, Freeman Hospital7, Trinity College, Dublin8, University of Barcelona9, Technische Universität München10, University of Amsterdam11, Harvard University12, University of Milan13, University of Liverpool14, Kyoto University15, Hospital of the University of Pennsylvania16, Thomas Jefferson University17
TL;DR: Current evidence justifies portomesenteric venous resection in patients with BRPC, and a new classification of extrahepatic mesentericoportal ven Mous resections is proposed by the ISGPS.
TL;DR: Five miRNA binding site SNPs associated significantly with breast cancer risk are located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively, which belongs to miRNA machinery genes and has a central role in initial miRNA processing.
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
TL;DR: Examination of patterns of 25-hydroxyvitamin D levels worldwide and differences by age, sex and region suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values.
Abstract: Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD. Despite these numerous potential health effects, data on vitamin D status at the population level and within key subgroups are limited. The aims of the present study were to examine patterns of 25-hydroxyvitamin D (25(OH)D) levels worldwide and to assess differences by age, sex and region. In a systematic literature review using the Medline and EMBASE databases, we identified 195 studies conducted in forty-four countries involving more than 168 000 participants. Mean population-level 25(OH)D values varied considerably across the studies (range 4·9-136·2 nmol/l), with 37·3 % of the studies reporting mean values below 50 nmol/l. The highest 25(OH)D values were observed in North America. Although age-related differences were observed in the Asia/Pacific and Middle East/Africa regions, they were not observed elsewhere and sex-related differences were not observed in any region. Substantial heterogeneity between the studies precluded drawing conclusions on overall vitamin D status at the population level. Exploratory analyses, however, suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values. Substantial details on worldwide patterns of vitamin D status at the population level and within key subgroups are needed to inform public health policy development to reduce risk for potential health consequences of an inadequate vitamin D status.