Showing papers by "University of Toronto published in 2009"
Dissertation•
01 Jan 2009TL;DR: In this paper, the authors describe how to train a multi-layer generative model of natural images, using a dataset of millions of tiny colour images, described in the next section.
Abstract: In this work we describe how to train a multi-layer generative model of natural images. We use a dataset of millions of tiny colour images, described in the next section. This has been attempted by several groups but without success. The models on which we focus are RBMs (Restricted Boltzmann Machines) and DBNs (Deep Belief Networks). These models learn interesting-looking filters, which we show are more useful to a classifier than the raw pixels. We train the classifier on a labeled subset that we have collected and call the CIFAR-10 dataset.
15,005 citations
TL;DR: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage.
Abstract: Background Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Methods In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Results Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P = 0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P = 0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P = 0.13) and 3.64% per year with 150 mg of dabigatran (P = 0.051). Conclusions In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)
9,676 citations
University Hospital of Lausanne1, University of Toronto2, Erasmus University Rotterdam3, University Medical Center Utrecht4, Queen's University5, European Organisation for Research and Treatment of Cancer6, University of Western Ontario7, Medical University of Vienna8, French Institute of Health and Medical Research9, National Institutes of Health10, University of Tübingen11, University of Calgary12
TL;DR: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up, and a benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years.
Abstract: BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.
6,161 citations
TL;DR: In this article, the Wilkinson Microwave Anisotropy Probe (WMAP) 5-year data were used to constrain the physics of cosmic inflation via Gaussianity, adiabaticity, the power spectrum of primordial fluctuations, gravitational waves, and spatial curvature.
Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP) 5-year data provide stringent limits on deviations from the minimal, six-parameter Λ cold dark matter model. We report these limits and use them to constrain the physics of cosmic inflation via Gaussianity, adiabaticity, the power spectrum of primordial fluctuations, gravitational waves, and spatial curvature. We also constrain models of dark energy via its equation of state, parity-violating interaction, and neutrino properties, such as mass and the number of species. We detect no convincing deviations from the minimal model. The six parameters and the corresponding 68% uncertainties, derived from the WMAP data combined with the distance measurements from the Type Ia supernovae (SN) and the Baryon Acoustic Oscillations (BAO) in the distribution of galaxies, are: Ω b h 2 = 0.02267+0.00058 –0.00059, Ω c h 2 = 0.1131 ± 0.0034, ΩΛ = 0.726 ± 0.015, ns = 0.960 ± 0.013, τ = 0.084 ± 0.016, and at k = 0.002 Mpc-1. From these, we derive σ8 = 0.812 ± 0.026, H 0 = 70.5 ± 1.3 km s-1 Mpc–1, Ω b = 0.0456 ± 0.0015, Ω c = 0.228 ± 0.013, Ω m h 2 = 0.1358+0.0037 –0.0036, z reion = 10.9 ± 1.4, and t 0 = 13.72 ± 0.12 Gyr. With the WMAP data combined with BAO and SN, we find the limit on the tensor-to-scalar ratio of r 1 is disfavored even when gravitational waves are included, which constrains the models of inflation that can produce significant gravitational waves, such as chaotic or power-law inflation models, or a blue spectrum, such as hybrid inflation models. We obtain tight, simultaneous limits on the (constant) equation of state of dark energy and the spatial curvature of the universe: –0.14 < 1 + w < 0.12(95%CL) and –0.0179 < Ω k < 0.0081(95%CL). We provide a set of WMAP distance priors, to test a variety of dark energy models with spatial curvature. We test a time-dependent w with a present value constrained as –0.33 < 1 + w 0 < 0.21 (95% CL). Temperature and dark matter fluctuations are found to obey the adiabatic relation to within 8.9% and 2.1% for the axion-type and curvaton-type dark matter, respectively. The power spectra of TB and EB correlations constrain a parity-violating interaction, which rotates the polarization angle and converts E to B. The polarization angle could not be rotated more than –59 < Δα < 24 (95% CL) between the decoupling and the present epoch. We find the limit on the total mass of massive neutrinos of ∑m ν < 0.67 eV(95%CL), which is free from the uncertainty in the normalization of the large-scale structure data. The number of relativistic degrees of freedom (dof), expressed in units of the effective number of neutrino species, is constrained as N eff = 4.4 ± 1.5 (68%), consistent with the standard value of 3.04. Finally, quantitative limits on physically-motivated primordial non-Gaussianity parameters are –9 < f local NL < 111 (95% CL) and –151 < f equil NL < 253 (95% CL) for the local and equilateral models, respectively.
5,904 citations
TL;DR: This revision of the consensus algorithm for the medical management of type 2 diabetes focuses on the new classes of medications that now have more clinical data and experience and addresses safety issues surrounding the thiazolidinediones.
Abstract: The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.
3,807 citations
TL;DR: The burden of mortality and disease attributable to alcohol, both globally and for ten large countries, is quantified and concludes that alcohol consumption is one of the major avoidable risk factors, and actions to reduce burden and costs associated with alcohol should be urgently increased.
3,123 citations
TL;DR: Examination of US data on risk factor exposures and disease-specific mortality finds that smoking and hypertension, which both have effective interventions, are responsible for the largest number of deaths.
Abstract: Background: Knowledge of the number of deaths caused by risk factors is needed for health policy and priority setting. Our aim was to estimate the mortality effects of the following 12 modifiable dietary, lifestyle, and metabolic risk factors in the United States (US) using consistent and comparable methods: high blood glucose, low-density lipoprotein (LDL) cholesterol, and blood pressure; overweight–obesity; high dietary trans fatty acids and salt; low dietary polyunsaturated fatty acids, omega-3 fatty acids (seafood), and fruits and vegetables; physical inactivity; alcohol use; and tobacco smoking. Methods and Findings: We used data on risk factor exposures in the US population from nationally representative health surveys and disease-specific mortality statistics from the National Center for Health Statistics. We obtained the etiological effects of risk factors on disease-specific mortality, by age, from systematic reviews and meta-analyses of epidemiological studies that had adjusted (i) for major potential confounders, and (ii) where possible for regression dilution bias. We estimated the number of disease-specific deaths attributable to all non-optimal levels of each risk factor exposure, by age and sex. In 2005, tobacco smoking and high blood pressure were responsible for an estimated 467,000 (95% confidence interval [CI] 436,000–500,000) and 395,000 (372,000–414,000) deaths, accounting for about one in five or six deaths in US adults. Overweight–obesity (216,000; 188,000–237,000) and physical inactivity (191,000; 164,000–222,000) were each responsible for nearly 1 in 10 deaths. High dietary salt (102,000; 97,000–107,000), low dietary omega-3 fatty acids (84,000; 72,000–96,000), and high dietary trans fatty acids (82,000; 63,000–97,000) were the dietary risks with the largest mortality effects. Although 26,000 (23,000–40,000) deaths from ischemic heart disease, ischemic stroke, and diabetes were averted by current alcohol use, they were outweighed by 90,000 (88,000–94,000) deaths from other cardiovascular diseases, cancers, liver cirrhosis, pancreatitis, alcohol use disorders, road traffic and other injuries, and violence. Conclusions: Smoking and high blood pressure, which both have effective interventions, are responsible for the largest number of deaths in the US. Other dietary, lifestyle, and metabolic risk factors for chronic diseases also cause a substantial number of deaths in the US. Please see later in the article for the Editors’ Summary.
2,751 citations
TL;DR: In this large cohort, infection was independently associated with an increased risk of hospital death and risk of infection increases with duration of ICU stay.
Abstract: Context Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. Objective To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. Design, Setting, and Patients The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14 414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13 796 adult (>18 years) patients. Results On the day of the study, 7087 of 13 796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P Conclusions Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.
2,710 citations
TL;DR: Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
Abstract: Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
2,446 citations
TL;DR: PYR/PYLs are ABA receptors functioning at the apex of a negative regulatory pathway that controls ABA signaling by inhibiting PP2Cs, illustrating the power of the chemical genetic approach for sidestepping genetic redundancy.
Abstract: Type 2C protein phosphatases (PP2Cs) are vitally involved in abscisic acid (ABA) signaling. Here, we show that a synthetic growth inhibitor called pyrabactin functions as a selective ABA agonist. Pyrabactin acts through PYRABACTIN RESISTANCE 1 (PYR1), the founding member of a family of START proteins called PYR/PYLs, which are necessary for both pyrabactin and ABA signaling in vivo. We show that ABA binds to PYR1, which in turn binds to and inhibits PP2Cs. We conclude that PYR/PYLs are ABA receptors functioning at the apex of a negative regulatory pathway that controls ABA signaling by inhibiting PP2Cs. Our results illustrate the power of the chemical genetic approach for sidestepping genetic redundancy.
2,336 citations
Royal Botanic Garden Edinburgh1, National Institutes of Health2, University of Guelph3, University of Johannesburg4, Royal Botanic Gardens5, Smithsonian Institution6, University of British Columbia7, Natural History Museum8, Korea University9, University of Toronto10, State University of Feira de Santana11, University of Costa Rica12, Columbus State University13, New York Botanical Garden14, University of Wisconsin-Madison15, University of the Andes16, University of Cape Town17, Seoul National University18, Hallym University19, National Autonomous University of Mexico20, Imperial College London21
TL;DR: The 2-locus combination of rbcL+matK will provide a universal framework for the routine use of DNA sequence data to identify specimens and contribute toward the discovery of overlooked species of land plants.
Abstract: DNA barcoding involves sequencing a standard region of DNA as a tool for species identification. However, there has been no agreement on which region(s) should be used for barcoding land plants. To provide a community recommendation on a standard plant barcode, we have compared the performance of 7 leading candidate plastid DNA regions (atpF–atpH spacer, matK gene, rbcL gene, rpoB gene, rpoC1 gene, psbK–psbI spacer, and trnH–psbA spacer). Based on assessments of recoverability, sequence quality, and levels of species discrimination, we recommend the 2-locus combination of rbcL+matK as the plant barcode. This core 2-locus barcode will provide a universal framework for the routine use of DNA sequence data to identify specimens and contribute toward the discovery of overlooked species of land plants.
Proceedings Article•
15 Apr 2009TL;DR: A new learning algorithm for Boltzmann machines that contain many layers of hidden variables that is made more efficient by using a layer-by-layer “pre-training” phase that allows variational inference to be initialized with a single bottomup pass.
Abstract: We present a new learning algorithm for Boltzmann machines that contain many layers of hidden variables Data-dependent expectations are estimated using a variational approximation that tends to focus on a single mode, and dataindependent expectations are approximated using persistent Markov chains The use of two quite different techniques for estimating the two types of expectation that enter into the gradient of the log-likelihood makes it practical to learn Boltzmann machines with multiple hidden layers and millions of parameters The learning can be made more efficient by using a layer-by-layer “pre-training” phase that allows variational inference to be initialized with a single bottomup pass We present results on the MNIST and NORB datasets showing that deep Boltzmann machines learn good generative models and perform well on handwritten digit and visual object recognition tasks
University of Washington1, University of Paris2, Queen Mary University of London3, McMaster University4, Cornell University5, University of Pennsylvania6, University of New South Wales7, Medical University of Vienna8, Sapienza University of Rome9, Scripps Research Institute10, Boston Children's Hospital11, University of Toronto12, University of Oklahoma Health Sciences Center13
TL;DR: An International Working Group of recognized expert clinicians convened a 2-day structured meeting to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response.
TL;DR: It is shown that the individual PB insertions can be removed from established iPS cell lines, providing an invaluable tool for discovery, and the traceless removal of reprogramming factors joined with viral 2A sequences delivered by a single transposon from murine iPS lines is demonstrated.
Abstract: Transgenic expression of just four defined transcription factors (c-Myc, Klf4, Oct4 and Sox2) is sufficient to reprogram somatic cells to a pluripotent state. The resulting induced pluripotent stem (iPS) cells resemble embryonic stem cells in their properties and potential to differentiate into a spectrum of adult cell types. Current reprogramming strategies involve retroviral, lentiviral, adenoviral and plasmid transfection to deliver reprogramming factor transgenes. Although the latter two methods are transient and minimize the potential for insertion mutagenesis, they are currently limited by diminished reprogramming efficiencies. piggyBac (PB) transposition is host-factor independent, and has recently been demonstrated to be functional in various human and mouse cell lines. The PB transposon/transposase system requires only the inverted terminal repeats flanking a transgene and transient expression of the transposase enzyme to catalyse insertion or excision events. Here we demonstrate successful and efficient reprogramming of murine and human embryonic fibroblasts using doxycycline-inducible transcription factors delivered by PB transposition. Stable iPS cells thus generated express characteristic pluripotency markers and succeed in a series of rigorous differentiation assays. By taking advantage of the natural propensity of the PB system for seamless excision, we show that the individual PB insertions can be removed from established iPS cell lines, providing an invaluable tool for discovery. In addition, we have demonstrated the traceless removal of reprogramming factors joined with viral 2A sequences delivered by a single transposon from murine iPS lines. We anticipate that the unique properties of this virus-independent simplification of iPS cell production will accelerate this field further towards full exploration of the reprogramming process and future cell-based therapies.
TL;DR: The Wilkinson Microwave Anisotropy Probe (WMAP) is a medium-class Explorer (MIDEX) satellite aimed at elucidating cosmology through full-sky observations of the cosmic microwave background (CMB) as mentioned in this paper.
Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP) is a Medium-Class Explorer (MIDEX) satellite aimed at elucidating cosmology through full-sky observations of the cosmic microwave background (CMB). The WMAP full-sky maps of the temperature and polarization anisotropy in five frequency bands provide our most accurate view to date of conditions in the early universe. The multi-frequency data facilitate the separation of the CMB signal from foreground emission arising both from our Galaxy and from extragalactic sources. The CMB angular power spectrum derived from these maps exhibits a highly coherent acoustic peak structure which makes it possible to extract a wealth of information about the composition and history of the universe. as well as the processes that seeded the fluctuations. WMAP data have played a key role in establishing ACDM as the new standard model of cosmology (Bennett et al. 2003: Spergel et al. 2003; Hinshaw et al. 2007: Spergel et al. 2007): a flat universe dominated by dark energy, supplemented by dark matter and atoms with density fluctuations seeded by a Gaussian, adiabatic, nearly scale invariant process. The basic properties of this universe are determined by five numbers: the density of matter, the density of atoms. the age of the universe (or equivalently, the Hubble constant today), the amplitude of the initial fluctuations, and their scale dependence. By accurately measuring the first few peaks in the angular power spectrum, WMAP data have enabled the following accomplishments: Showing the dark matter must be non-baryonic and interact only weakly with atoms and radiation. The WMAP measurement of the dark matter density puts important constraints on supersymmetric dark matter models and on the properties of other dark matter candidates. With five years of data and a better determination of our beam response, this measurement has been significantly improved. Precise determination of the density of atoms in the universe. The agreement between the atomic density derived from WMAP and the density inferred from the deuterium abundance is an important test of the standard big bang model. Determination of the acoustic scale at redshift z = 1090. Similarly, the recent measurement of baryon acoustic oscillations (BAO) in the galaxy power spectrum (Eisenstein et al. 2005) has determined the acoustic scale at redshift z approx. 0.35. When combined, these standard rulers accurately measure the geometry of the universe and the properties of the dark energy. These data require a nearly flat universe dominated by dark energy consistent with a cosmological constant. Precise determination of the Hubble Constant, in conjunction with BAO observations. Even when allowing curvature (Omega(sub 0) does not equal 1) and a free dark energy equation of state (w does not equal -1), the acoustic data determine the Hubble constant to within 3%. The measured value is in excellent agreement with independent results from the Hubble Key Project (Freedman et al. 2001), providing yet another important consistency test for the standard model. Significant constraint of the basic properties of the primordial fluctuations. The anti-correlation seen in the temperature/polarization (TE) correlation spectrum on 4deg scales implies that the fluctuations are primarily adiabatic and rule out defect models and isocurvature models as the primary source of fluctuations (Peiris et al. 2003).
TL;DR: In this paper, a core brain network has been proposed to underlie a number of different processes, including remembering, prospection, navigation, and theory of mind, which has been argued to represent self-projection.
Abstract: A core brain network has been proposed to underlie a number of different processes, including remembering, prospection, navigation, and theory of mind [Buckner, R. L., & Carroll, D. C. Self-projection and the brain. Trends in Cognitive Sciences,11, 49-57, 2007]. This purported network-medial prefrontal, medial-temporal, and medial and lateral parietal regions-is similar to that observed during default-mode processing and has been argued to represent self-projection [Buckner, R. L., & Carroll, D. C. Self-projection and the brain. Trends in Cognitive Sciences,11, 49-57, 2007] or scene-construction [Hassabis, D., & Maguire, E. A. Deconstructing episodic memory with construction. Trends in Cognitive Sciences,11, 299-306, 2007]. To date, no systematic and quantitative demonstration of evidence for this common network has been presented. Using the activation likelihood estimation (ALE) approach, we conducted four separate quantitative meta-analyses of neuroimaging studies on: (a) autobiographical memory, (b) navigation, (c) theory of mind, and (d) default mode. A conjunction analysis between these domains demonstrated a high degree of correspondence. We compared these findings to a separate ALE analysis of prospection studies and found additional correspondence. Across all domains, and consistent with the proposed network, correspondence was found within the medial-temporal lobe, precuneus, posterior cingulate, retrosplenial cortex, and the temporo-parietal junction. Additionally, this study revealed that the core network extends to lateral prefrontal and occipital cortices. Autobiographical memory, prospection, theory of mind, and default mode demonstrated further reliable involvement of the medial prefrontal cortex and lateral temporal cortices. Autobiographical memory and theory of mind, previously studied as distinct, exhibited extensive functional overlap. These findings represent quantitative evidence for a core network underlying a variety of cognitive domains.
TL;DR: It is reported that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors.
National Institutes of Health1, Norwegian University of Science and Technology2, National Research Council3, University of São Paulo4, University of Tübingen5, University of Coimbra6, University of Paris7, French Institute of Health and Medical Research8, Chang Gung University9, Columbia University10, Mayo Clinic11, Tel Aviv University12, Technion – Israel Institute of Technology13, Rambam Health Care Campus14, Tel Aviv Sourasky Medical Center15, University of Rostock16, University Health Network17, National Taiwan Normal University18, University of Washington19, University of Tokyo20, Kobe University21, Magna Græcia University22, University of Toronto23, Duke University24, Singapore General Hospital25
TL;DR: Data collected demonstrate that there is a strong association between GBA mutations and Parkinson's disease, and those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were morelikely to have atypical clinical manifestations.
Abstract: Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel–Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of p...
TL;DR: In this paper, the authors present cosmological constraints from the Wilkinson Microwave Anisotropy Probe (WMAP) alone for both the ACDM model and a set of possible extensions.
Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP), launched in 2001, has mapped out the Cosmic Microwave Background with unprecedented accuracy over the whole sky. Its observations have led to the establishment of a simple concordance cosmological model for the contents and evolution of the universe, consistent with virtually all other astronomical measurements. The WMAP first-year and three-year data have allowed us to place strong constraints on the parameters describing the ACDM model. a flat universe filled with baryons, cold dark matter, neutrinos. and a cosmological constant. with initial fluctuations described by nearly scale-invariant power law fluctuations, as well as placing limits on extensions to this simple model (Spergel et al. 2003. 2007). With all-sky measurements of the polarization anisotropy (Kogut et al. 2003; Page et al. 2007), two orders of magnitude smaller than the intensity fluctuations. WMAP has not only given us an additional picture of the universe as it transitioned from ionized to neutral at redshift z approx.1100. but also an observation of the later reionization of the universe by the first stars. In this paper we present cosmological constraints from WMAP alone. for both the ACDM model and a set of possible extensions. We also consider tlle consistency of WMAP constraints with other recent astronomical observations. This is one of seven five-year WMAP papers. Hinshaw et al. (2008) describe the data processing and basic results. Hill et al. (2008) present new beam models arid window functions, Gold et al. (2008) describe the emission from Galactic foregrounds, and Wright et al. (2008) the emission from extra-Galactic point sources. The angular power spectra are described in Nolta et al. (2008), and Komatsu et al. (2008) present and interpret cosmological constraints based on combining WMAP with other data. WMAP observations are used to produce full-sky maps of the CMB in five frequency bands centered at 23, 33, 41, 61, and 94 GHz (Hinshaw et al. 2008). With five years of data, we are now able to place better limits on the ACDM model. as well as to move beyond it to test the composition of the universe. details of reionization. sub-dominant components, characteristics of inflation, and primordial fluctuations. We have more than doubled the amount of polarized data used for cosmological analysis. allowing a better measure of the large-scale E-mode signal (Nolta et al. 2008). To this end we describe an alternative way to remove Galactic foregrounds from low resolution polarization maps in which Galactic emission is marginalized over, providing a cross-check of our results. With longer integration we also better probe the second and third acoustic peaks in the temperature angular power spectrum, and have many more year-to-year difference maps available for cross-checking systematic effects (Hinshaw et al. 2008).
Posted Content•
TL;DR: In this article, the authors overview and synthesize extant word of mouth theory and present a study of a marketing campaign in which mobile phones were seeded with prominent bloggers, revealing the complex cultural conditions through which marketing "hype" is transformed by consumers into the "honey" of relevant, shared communications.
Abstract: Word of mouth marketing — the intentional influencing of consumer-to-consumer communications — is an increasingly important technique. The authors overview and synthesize extant word of mouth theory and present a study of a marketing campaign in which mobile phones were seeded with prominent bloggers. Eighty-three blogs were followed for six months. Findings reveal the complex cultural conditions through which marketing “hype” is transformed by consumers into the “honey” of relevant, shared communications. Four word of mouth communication strategies are identified — evaluation, embracing, endorsement and explanation. Each is influenced by communicator narrative, communications forum, communal norms and the nature of the marketing promotion. An intrinsic tension between commercial and communal interests plays a prominent, normative role in message formation and reception. This “hype-to-honey” theory shows that communal word of mouth does not simply increase or amplify marketing messages. Rather, marketing messages and meanings are systematically altered in the process of embedding them. The theory has implications for how marketers should plan, target and benefit from word of mouth and how scholars should understand word of mouth in a networked world.
TL;DR: Educational meetings alone or combined with other interventions, can improve professional practice and healthcare outcomes for the patients and is most likely to be small and similar to other types of continuing medical education, such as audit and feedback, and educational outreach visits.
Abstract: Background
Educational meetings are widely used for continuing medical education. Previous reviews found that interactive workshops resulted in moderately large improvements in professional practice, whereas didactic sessions did not.
Objectives
To assess the effects of educational meetings on professional practice and healthcare outcomes.
Search methods
We updated previous searches by searching the Cochrane Effective Practice and Organisation of Care Group Trials Register and pending file, from 1999 to March 2006.
Selection criteria
Randomised controlled trials of educational meetings that reported an objective measure of professional practice or healthcare outcomes.
Data collection and analysis
Two authors independently extracted data and assessed study quality. Studies with a low or moderate risk of bias and that reported baseline data were included in the primary analysis. They were weighted according to the number of health professionals participating. For each comparison, we calculated the risk difference (RD) for dichotomous outcomes, adjusted for baseline compliance; and for continuous outcomes the percentage change relative to the control group average after the intervention, adjusted for baseline performance. Professional and patient outcomes were analysed separately. We considered 10 factors to explain heterogeneity of effect estimates using weighted meta-regression supplemented by visual analysis of bubble and box plots.
Main results
In updating the review, 49 new studies were identified for inclusion. A total of 81 trials involving more than 11,000 health professionals are now included in the review. Based on 30 trials (36 comparisons), the median adjusted RD in compliance with desired practice was 6% (interquartile range 1.8 to 15.9) when any intervention in which educational meetings were a component was compared to no intervention. Educational meetings alone had similar effects (median adjusted RD 6%, interquartile range 2.9 to 15.3; based on 21 comparisons in 19 trials). For continuous outcomes the median adjusted percentage change relative to control was 10% (interquartile range 8 to 32%; 5 trials). For patient outcomes the median adjusted RD in achievement of treatment goals was 3.0 (interquartile range 0.1 to 4.0; 5 trials). Based on univariate meta-regression analyses of the 36 comparisons with dichotomous outcomes for professional practice, higher attendance at the educational meetings was associated with larger adjusted RDs (P < 0.01); mixed interactive and didactic education meetings (median adjusted RD 13.6) were more effective than either didactic meetings (RD 6.9) or interactive meetings (RD 3.0). Educational meetings did not appear to be effective for complex behaviours (adjusted RD -0.3) compared to less complex behaviours; they appeared to be less effective for less serious outcomes (RD 2.9) than for more serious outcomes.
Authors' conclusions
Educational meetings alone or combined with other interventions, can improve professional practice and healthcare outcomes for the patients. The effect is most likely to be small and similar to other types of continuing medical education, such as audit and feedback, and educational outreach visits. Strategies to increase attendance at educational meetings, using mixed interactive and didactic formats, and focusing on outcomes that are likely to be perceived as serious may increase the effectiveness of educational meetings. Educational meetings alone are not likely to be effective for changing complex behaviours.
TL;DR: Rather than one or two domestication events leading to the extant baker’s yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
Abstract: Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
TL;DR: It is shown that non-viral transfection of a single multiprotein expression vector, which comprises the coding sequences of c-Myc, Klf4, Oct4 and Sox2 linked with 2A peptides, can reprogram both mouse and human fibroblasts and can be removed once reprogramming has been achieved.
Abstract: Reprogramming of somatic cells to pluripotency, thereby creating induced pluripotent stem (iPS) cells, promises to transform regenerative medicine. Most instances of direct reprogramming have been achieved by forced expression of defined factors using multiple viral vectors. However, such iPS cells contain a large number of viral vector integrations, any one of which could cause unpredictable genetic dysfunction. Whereas c-Myc is dispensable for reprogramming, complete elimination of the other exogenous factors is also desired because ectopic expression of either Oct4 (also known as Pou5f1) or Klf4 can induce dysplasia. Two transient transfection-reprogramming methods have been published to address this issue. However, the efficiency of both approaches is extremely low, and neither has been applied successfully to human cells so far. Here we show that non-viral transfection of a single multiprotein expression vector, which comprises the coding sequences of c-Myc, Klf4, Oct4 and Sox2 linked with 2A peptides, can reprogram both mouse and human fibroblasts. Moreover, the transgene can be removed once reprogramming has been achieved. iPS cells produced with this non-viral vector show robust expression of pluripotency markers, indicating a reprogrammed state confirmed functionally by in vitro differentiation assays and formation of adult chimaeric mice. When the single-vector reprogramming system was combined with a piggyBac transposon, we succeeded in establishing reprogrammed human cell lines from embryonic fibroblasts with robust expression of pluripotency markers. This system minimizes genome modification in iPS cells and enables complete elimination of exogenous reprogramming factors, efficiently providing iPS cells that are applicable to regenerative medicine, drug screening and the establishment of disease models.
TL;DR: Interestingly, the permeation of nanoparticles within the tumor is highly dependent on the overall size of the nanoparticle, where larger nanoparticles appear to stay near the vasculature while smaller nanoparticles rapidly diffuse throughout the tumor matrix.
Abstract: Here we systematically examined the effect of nanoparticle size (10-100 nm) and surface chemistry (i.e., poly(ethylene glycol)) on passive targeting of tumors in vivo. We found that the physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their tumor accumulation capacity. Interestingly, the permeation of nanoparticles within the tumor is highly dependent on the overall size of the nanoparticle, where larger nanoparticles appear to stay near the vasculature while smaller nanoparticles rapidly diffuse throughout the tumor matrix. Our results provide design parameters for engineering nanoparticles for optimized tumor targeting of contrast agents and therapeutics.
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TL;DR: In this paper, a deep graphical model of the word-count vectors obtained from a large set of documents is proposed. But the model is restricted to the deep layer of the deep neural network and cannot handle large numbers of documents.
University of Alberta1, ExxonMobil2, University of Houston3, Louisiana State University4, Queen's University5, University of Pretoria6, University of Nebraska–Lincoln7, University of Texas at Austin8, Dalhousie University9, New Mexico State University10, University of Texas at Arlington11, University of South Carolina12, University of Toronto13, Colorado School of Mines14, Chevron Corporation15, University of Saskatchewan16, University of Fribourg17, Durham University18, Royal Dutch Shell19
TL;DR: In this paper, a model-independent framework of genetic units and bounding surfaces for sequence stratigraphy has been proposed, based on the interplay of accommodation and sedimentation (i.e., forced regressive, lowstand and highstand normal regressive), which are bounded by sequence stratigraphic surfaces.
Memorial Sloan Kettering Cancer Center1, Mayo Clinic2, University of Texas MD Anderson Cancer Center3, Harvard University4, University of Toronto5, University of British Columbia6, Fox Chase Cancer Center7, University of Colorado Denver8, Kaiser Permanente9, Washington University in St. Louis10, Duke University11
TL;DR: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.
TL;DR: Current data suggest that OSA increases the risk of developing cardiovascular diseases, and that its treatment has the potential to diminish such risk, but large-scale randomised trials are needed to determine, definitively, whether treating OSA improves cardiovascular outcomes.
University of Michigan1, University of Utah2, Washington University in St. Louis3, University of Kiel4, University of Toronto5, Memorial University of Newfoundland6, Celera Corporation7, Emory University8, Université Paris-Saclay9, University of California, San Francisco10, Baylor University Medical Center11, Veterans Health Administration12
TL;DR: The results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10−8) and suggest priority targets for study in other auto-immune disorders.
Abstract: Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.
TL;DR: The results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization ofucleosomes in vivo.
Abstract: The nucleosomes are the basic repeating units of eukaryotic chromatin, and nucleosome organization is critically important for gene regulation. Kaplan et al. tested the importance of the intrinsic DNA sequence preferences of nucleosomes by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map is remarkably similar to in vivo nucleosome maps, indicating that the organization of nucleosomes in vivo is largely governed by the underlying genomic DNA sequence. This study tests the importance of the intrinsic DNA sequence preferences of nucleosomes by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map is similar to in vivo nucleosome maps, indicating that the organization of nucleosomes in vivo is largely governed by the underlying genomic DNA sequence. Nucleosome organization is critical for gene regulation1. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers2, competition with site-specific DNA-binding proteins3, and the DNA sequence preferences of the nucleosomes themselves4,5,6,7,8. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo7,9,10,11, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for ∼40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.