Showing papers by "Sunnybrook Health Sciences Centre published in 2018"
University of Las Palmas de Gran Canaria1, Sunnybrook Health Sciences Centre2, Autonomous University of Barcelona3, Sanford Health4, Tel Aviv University5, University of Turin6, University of California, Los Angeles7, Kansai Medical University8, Epworth Hospital9, University of Sydney10, University of South Florida11, Merck & Co.12
TL;DR: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum‐based drug resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone.
Abstract: Background First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. Methods In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy...
4,102 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
TL;DR: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression, and both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles.
590 citations
TL;DR: The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer’s disease and show that the procedure is safe.
Abstract: Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood–brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer’s disease. Here, we used focused ultrasound to open the blood–brain barrier in five patients with early to moderate Alzheimer’s disease in a phase I safety trial. In all patients, the blood–brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood–brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer’s disease. Magnetic resonance-guided focused ultrasound with injected microbubbles has been used to temporarily open the blood–brain barrier (BBB) in animal models of Alzheimer's disease (AD). Here, the authors use this technology to non-invasively open the BBB in 5 patients with mild-to-moderate AD in a phase I trial, and show that the procedure is safe.
551 citations
University of Queensland1, Royal Brisbane and Women's Hospital2, Princess Alexandra Hospital3, National University of Singapore4, Tan Tock Seng Hospital5, Nanyang Technological University6, Istanbul Medipol University7, King Saud bin Abdulaziz University for Health Sciences8, Sapienza University of Rome9, University of Udine10, Monash University11, American University of Beirut12, North Shore Hospital13, University of Sydney14, Westmead Hospital15, University of Cape Town16, Wollongong Hospital17, University of Wollongong18, Illawarra Health & Medical Research Institute19, Middlemore Hospital20, King Fahad Specialist Hospital21, St. Vincent's Health System22, University of Western Australia23, Fiona Stanley Hospital24, Sunnybrook Health Sciences Centre25, QIMR Berghofer Medical Research Institute26, Mater Health Services27, Deakin University28, Monash University, Clayton campus29
TL;DR: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality, and findings do not support use of piperACillin- tazobactsam in this setting.
Abstract: Importance Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers. Objectives To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae . Design, Setting, and Participants Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration anzctr.org.au Identifiers:ACTRN12613000532707andACTRN12615000403538and ClinicalTrials.gov Identifier:NCT02176122
487 citations
TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.
444 citations
St. Vincent's Health System1, University of Melbourne2, Mayo Clinic3, University of Florida4, University of Copenhagen5, Johns Hopkins University School of Medicine6, Brigham and Women's Hospital7, Duke University8, University of Pennsylvania9, Rutgers University10, Harvard University11, Icahn School of Medicine at Mount Sinai12, Utrecht University13, Karolinska University Hospital14, University of California, San Diego15, University of Wisconsin-Madison16, Beth Israel Deaconess Medical Center17, Johns Hopkins University18, University of California, San Francisco19, Sunnybrook Health Sciences Centre20, University of Florida College of Public Health and Health Professions21, University of New South Wales22, Oregon Health & Science University23, Johns Hopkins Bayview Medical Center24, Indiana University25, Columbia University26
TL;DR: The working group recommends that ‘perioperative neurocognitive disorders’ be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period as well as two major classification guidelines used outside of anaesthesia and surgery.
Abstract: Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).
413 citations
University of Western Ontario1, University of Alberta2, Université du Québec à Trois-Rivières3, Queen's University4, Children's Hospital of Eastern Ontario5, University of Ottawa6, Technical University of Madrid7, University of Saskatchewan8, Sunnybrook Health Sciences Centre9, University of Toronto10, Camosun College11
TL;DR: These guidelines provided guidance for pregnant women and obstetric care and exercise professionals on prenatal physical activity and the majority of stakeholders and end users indicated that following these recommendations would be feasible, acceptable and equitable.
Abstract: The objective is to provide guidance for pregnant women and obstetric care and exercise professionals on prenatal physical activity. The outcomes evaluated were maternal, fetal or neonatal morbidity, or fetal mortality during and following pregnancy. Literature was retrieved through searches of MEDLINE, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science Core Collection, CINAHL Plus with Full Text, Child Development & Adolescent Studies, Education Resources Information Center, SPORTDiscus, ClinicalTrials.gov and the Trip Database from inception up to 6 January 2017. Primary studies of any design were eligible, except case studies. Results were limited to English-language, Spanish-language or French-language materials. Articles related to maternal physical activity during pregnancy reporting on maternal, fetal or neonatal morbidity, or fetal mortality were eligible for inclusion. The quality of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation methodology. The Guidelines Consensus Panel solicited feedback from end users (obstetric care providers, exercise professionals, researchers, policy organisations, and pregnant and postpartum women). The development of these guidelines followed the Appraisal of Guidelines for Research and Evaluation II instrument. The benefits of prenatal physical activity are moderate and no harms were identified; therefore, the difference between desirable and undesirable consequences (net benefit) is expected to be moderate. The majority of stakeholders and end users indicated that following these recommendations would be feasible, acceptable and equitable. Following these recommendations is likely to require minimal resources from both individual and health systems perspectives.
340 citations
Mount Sinai Hospital, Toronto1, University of Toronto2, Sunnybrook Health Sciences Centre3, University of New South Wales4, University of Manitoba5, University of Western Ontario6, Dalhousie University7, Alberta Children's Hospital8, University of Calgary9, Boston Children's Hospital10, University of Sydney11
TL;DR: FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care.
287 citations
Duminda N. Wijeysundera, Rupert M Pearse1, Mark A Shulman2, Mark A Shulman3 +177 more•Institutions (8)
TL;DR: Subjective assessment of functional capacity should not be used for preoperative risk evaluation, and Clinicians should instead consider a measure such as DASI for cardiac risk assessment.
284 citations
National and Kapodistrian University of Athens1, University of Tennessee Health Science Center2, German National Metrology Institute3, Ruhr University Bochum4, GE Healthcare5, Omron6, Stanford University7, National Institute for Health Research8, Green Templeton College9, Newcastle University10, Sunnybrook Health Sciences Centre11, University of Padua12, University of Milano-Bicocca13, St Thomas' Hospital14, Shanghai Jiao Tong University15, National Institutes of Health16, University College Dublin17
TL;DR: The AAMI/ESH/ISO standard as mentioned in this paper was developed by the International Organization for Standardization (ISO) and developed by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation.
Abstract: Copyright © 2018 Wolters Kluwer Health, Inc., and American Heart Association, Inc. This article has been copublished in Hypertension. In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.
Comprehensive Epilepsy Center1, Université libre de Bruxelles2, University of Kiel3, Necker-Enfants Malades Hospital4, Boston Children's Hospital5, University of Paris6, Katholieke Universiteit Leuven7, University of Lausanne8, Mayo Clinic9, University of Western Ontario10, Children's Hospital of Philadelphia11, University of Toronto12, Sunnybrook Health Sciences Centre13, Goethe University Frankfurt14, Paracelsus Private Medical University of Salzburg15
TL;DR: An international group of experts were convened to standardize definitions of New‐Onset Refractory Status Epilepticus (NORSE), Febrile Infection‐Related Epilepsy Syndrome (FIRES), and related conditions to enable improved communication for investigators, physicians, families, patients, and other caregivers.
Abstract: We convened an international group of experts to standardize definitions of New-Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in-person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion-Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super-refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.
Heart and Stroke Foundation of Canada1, Halifax2, Sunnybrook Health Sciences Centre3, Dalhousie University4, Vancouver General Hospital5, Northern Ontario School of Medicine6, University of Calgary7, Laval University8, Kelowna General Hospital9, University of Alberta10, Canadian Association of Emergency Physicians11, University of British Columbia12, Ottawa Hospital13, Montreal Neurological Institute and Hospital14, McMaster University15, University Health Network16, Vancouver Island Health Authority17, Université de Montréal18, University of Saskatchewan19, Alberta Health Services20, University of Manitoba21, Royal University Hospital22, St. John's University23
TL;DR: The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack.
Abstract: The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for ...
TL;DR: Two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy were tested.
Abstract: Background Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. Methods We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. Results A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphoterici...
University College London1, UCL Institute of Neurology2, King's College London3, Erasmus University Rotterdam4, University of Brescia5, University of Milan6, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico7, Sunnybrook Health Sciences Centre8, University of Toronto9, University of Cambridge10, Karolinska Institutet11, University of Geneva12, Laval University13, University of Western Ontario14, University of Lisbon15, University of Florence16
TL;DR: A machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies is introduced, using two neurodegenerative disease cohorts.
Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.
TL;DR: The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission.
Abstract: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-β1b (IFN-β1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-β1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. ClinicalTrials.gov, ID: NCT02845843. Registered on 27 July 2016.
University of Edinburgh1, University of Cambridge2, Cedars-Sinai Medical Center3, Harvard University4, Henry Ford Health System5, University Hospital Heidelberg6, The George Institute for Global Health7, Niigata University8, Santa Maria Nuova Hospital9, Ottawa Hospital Research Institute10, Autonomous University of Barcelona11, Catholic University of Korea12, University of Santiago de Compostela13, Shanghai Jiao Tong University14, Columbia University15, University of Erlangen-Nuremberg16, University of Bern17, Jichi Medical University18, Chongqing Medical University19, University of Cincinnati20, University of Texas Health Science Center at Houston21, University of Alberta22, Stanford University23, Washington University in St. Louis24, Tokyo Medical University25, Hannover Medical School26, Johns Hopkins University School of Medicine27, Foothills Medical Centre28, Sunnybrook Health Sciences Centre29, Nippon Medical School30, Mayo Clinic31, Memorial Hermann Healthcare System32, Beth Israel Deaconess Medical Center33, University of Calgary34
TL;DR: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination and could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Abstract: Summary Background Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. Methods In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. Findings Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p Interpretation In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. Funding UK Medical Research Council and British Heart Foundation.
TL;DR: It is found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth, and the highly expressed circular RNA circ-Nmt1 could bind to and regulate oncogenic proteins in breast cancer cells.
Abstract: Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research.
TL;DR: Basics of nuclear Overhauser enhancement (NOE) and chemical exchange saturation transfer (CEST) and comprehensive description of the features of the endogenous saturation spectrum (Z‐spectrum) in MRI are described.
University Hospital of North Tees1, Newcastle University2, National Health Service3, National Taiwan University4, University of California, San Francisco5, University of Barcelona6, Karolinska Institutet7, Salisbury University8, University of Bremen9, Curie Institute10, Netherlands Cancer Institute11, Utrecht University12, St James's University Hospital13, University College London14, University of Toronto15, Veterans Health Administration16, Dartmouth College17, University of Pittsburgh18, University of Manitoba19, Sunnybrook Health Sciences Centre20, Flinders University21, Maastricht University22
TL;DR: An international team of gastroenterologists, pathologists, and epidemiologists met to formulate a series of recommendations, standardize definitions and categories, develop an algorithm to determine most-plausible etiologies, and develop standardized methodology to calculate rates of PCCRC and PICRC.
TL;DR: Antenatal anxiety is associated with multiple adverse perinatal outcomes and is not benign and the impact of treating anxiety on these associations is unknown.
Abstract: OBJECTIVE This systematic review and meta-analysis examined the association between maternal antenatal anxiety (AA) and a range of perinatal outcomes. DATA SOURCES Ovid MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, PsycINFO, CINAHL, Embase, and the Cochrane Library were searched to May 31, 2016, using controlled vocabulary and keywords (eg, prenatal, anxiety, preterm). STUDY SELECTION Perinatal outcomes of women with and without AA (diagnosed or self-reported using validated scale) derived from English language, prospectively collected data were included. 1,458 abstracts were reviewed, 306 articles were retrieved, and 29 articles were included. DATA EXTRACTION Two independent reviewers extracted data and assessed quality. Random-effects models were utilized for outcomes (≥ 3 studies). Subanalyses examined potential effect moderators including study quality and diagnostic versus self-reported anxiety among others. RESULTS Antenatal anxiety was associated with increased odds for preterm birth (pooled odds ratio [OR] = 1.54; 95% confidence interval [CI], 1.39 to 1.70, 16 studies) and spontaneous preterm birth (OR = 1.41; 95% CI, 1.13 to 1.75), lower mean birth weight (mean difference = -55.96 g; 95% CI, -93.62 to -18.31 g), increased odds for low birth weight (OR = 1.80; 95% CI, 1.48 to 2.18), earlier gestational age (mean difference = -0.13 wk; 95% CI, -0.22 to -0.04 wk), increased odds for being small for gestational age (OR = 1.48; 95% CI, 1.26 to 1.74), and smaller head circumference (mean difference = -0.25 cm; 95% CI, -0.45 to -0.06 cm). Heterogeneity between studies was not significant for most outcomes. Subanalyses for birth weight found women with diagnosed anxiety had infants with significantly lower birth weight (P < .03) compared to those identified with rating scales (although both subanalyses were significant [P < .01]). Associations between anxiety and preeclampsia, cesarean delivery, and Apgar scores were nonsignificant. CONCLUSIONS Antenatal anxiety is associated with multiple adverse perinatal outcomes and is not benign. The impact of treating anxiety on these associations is unknown.
University of Cagliari1, University of Washington2, Johns Hopkins University3, Walter Reed National Military Medical Center4, Ludwig Maximilian University of Munich5, Sunnybrook Health Sciences Centre6, Cedars-Sinai Medical Center7, Yale University8, University College London9, Maastricht University10, University of California, San Francisco11, Stanford University12, University Health Network13
TL;DR: The goal of this article is to present the perspective of the ASNR Vessel Wall Imaging Study Group as it relates to the current status of arterial wall imaging in carotid artery disease.
Abstract: Identification of carotid artery atherosclerosis is conventionally based on measurements of luminal stenosis and surface irregularities using in vivo imaging techniques including sonography, CT and MR angiography, and digital subtraction angiography. However, histopathologic studies demonstrate considerable differences between plaques with identical degrees of stenosis and indicate that certain plaque features are associated with increased risk for ischemic events. The ability to look beyond the lumen using highly developed vessel wall imaging methods to identify plaque vulnerable to disruption has prompted an active debate as to whether a paradigm shift is needed to move away from relying on measurements of luminal stenosis for gauging the risk of ischemic injury. Further evaluation in randomized clinical trials will help to better define the exact role of plaque imaging in clinical decision-making. However, current carotid vessel wall imaging techniques can be informative. The goal of this article is to present the perspective of the ASNR Vessel Wall Imaging Study Group as it relates to the current status of arterial wall imaging in carotid artery disease.
TL;DR: This guideline aims to promptly and transparently translate potentially practice-changing evidence to usable recommendations for clinicians and patients.
Abstract: ### What you need to know
What is the best way to use oxygen therapy for patients with an acute medical illness? A systematic review published in the Lancet in April 2018 found that supplemental oxygen in inpatients with normal oxygen saturation increases mortality.1 Its authors concluded that oxygen should be administered conservatively, but they did not make specific recommendations on how to do it. An international expert panel used that review to inform this guideline. It aims to promptly and transparently translate potentially practice-changing evidence to usable recommendations for clinicians and patients.2 The panel used the GRADE framework and following standards for trustworthy guidelines.3
The panel asked;
The panel makes a strong recommendation for maintaining an oxygen saturation of no more than 96% in acutely ill medical patients (upper limit). The panel did not make a recommendation on when to start (the lower limit) for …
University of British Columbia1, Libin Cardiovascular Institute of Alberta2, Dalhousie University3, University Health Network4, Sunnybrook Health Sciences Centre5, McMaster University6, University of Toronto7, University of Alberta8, University of Ottawa9, McGill University Health Centre10, University of Western Ontario11, Montreal Heart Institute12
TL;DR: The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management.
TL;DR: A potential role for a specific IM community and functional profile in the pathogenesis of NAFLD is suggested, independent of BMI and IR.
Abstract: This study aimed to determine if there is an association between dysbiosis and nonalcoholic fatty liver disease (NAFLD) independent of obesity and insulin resistance (IR). This is a prospective cross-sectional study assessing the intestinal microbiome (IM) of 39 adults with biopsy-proven NAFLD (15 simple steatosis [SS]; 24 nonalcoholic steatohepatitis [NASH]) and 28 healthy controls (HC). IM composition (llumina MiSeq Platform) in NAFLD patients compared to HC were identified by two statistical methods (Metastats, Wilcoxon). Selected taxa was validated using quantitative PCR (qPCR). Metabolites in feces and serum were also analyzed. In NAFLD, 8 operational taxonomic units, 6 genera, 6 families and 2 phyla (Bacteroidetes, Firmicutes) were less abundant and; 1 genus (Lactobacillus) and 1 family (Lactobacillaceae) were more abundant compared to HC. Lower abundance in both NASH and SS patients compared to HC were confirmed by qPCR for Ruminococcus, Faecalibacterium prausnitzii and Coprococcus. No difference was found between NASH and SS. This lower abundance in NAFLD (NASH+SS) was independent of BMI and IR. NAFLD patients had higher concentrations of fecal propionate and isobutyric acid and serum 2-hydroxybutyrate and L-lactic acid. These findings suggest a potential role for a specific IM community and functional profile in the pathogenesis of NAFLD.
TL;DR: Single fraction and multiple fraction radiation treatment regimens continue to demonstrate similar outcomes in pain control and toxicities, but re-treatment is more common for single fraction treatment patients.
TL;DR: In patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive strategy for red‐cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis at 6 months after surgery.
Abstract: Background We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. Methods We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any c...
McGill University1, Montreal General Hospital2, Heart and Stroke Foundation of Canada3, University of Western Ontario4, University of Alberta5, Dalhousie University6, Valley Regional Hospital7, McMaster University8, Kelowna General Hospital9, University of British Columbia10, Université de Montréal11, University of Toronto12, Thunder Bay Regional Health Sciences Centre13, University of Ottawa14, Boston Children's Hospital15, University of Manitoba16, Population Health Research Institute17, Sunnybrook Health Sciences Centre18
TL;DR: The 2017 update of The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke is a collection of current evidence-based recommendations intended for use by clinicians across a wide range of settings to provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors.
Abstract: The 2017 update of The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke is a collection of current evidence-based recommendations intended for use by clinicians across a wide range of settings. The goal is to provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations include those related to diagnostic testing, diet and lifestyle, smoking, hypertension, hyperlipidemia, diabetes, antiplatelet and anticoagulant therapies, carotid artery disease, atrial fibrillation, and other cardiac conditions. Notable changes in this sixth edition include the development of core elements for delivering secondary stroke prevention services, the addition of a section on cervical artery dissection, new recommendations regarding the management of patent foramen ovale, and the removal of the recommendations on management of sleep apnea. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographic barriers to ensure equity in access within a universal health care system.
TL;DR: DSLNT content in breast milk is a potential non-invasive marker to identify infants at risk of developing NEC, and screen high-risk donor milk, and could serve as a natural template to develop novel therapeutics against this devastating disorder.
Abstract: Objective Necrotising enterocolitis (NEC) is one of the most common and often fatal intestinal disorders in preterm infants. Markers to identify at-risk infants as well as therapies to prevent and treat NEC are limited and urgently needed. NEC incidence is significantly lower in breast-fed compared with formula-fed infants. Infant formula lacks human milk oligosaccharides (HMO), such as disialyllacto-N-tetraose (DSLNT), which prevents NEC in neonatal rats. However, it is unknown if DSLNT also protects human preterm infants. Design We conducted a multicentre clinical cohort study and recruited 200 mothers and their very low birthweight infants that were predominantly human milk-fed. We analysed HMO composition in breast milk fed to infants over the first 28 days post partum, matched each NEC case with five controls and used logistic regression and generalised estimating equation to test the hypothesis that infants who develop NEC receive milk with less DSLNT than infants who do not develop NEC. Results Eight infants in the cohort developed NEC (Bell stage 2 or 3). DSLNT concentrations were significantly lower in almost all milk samples in NEC cases compared with controls, and its abundance could identify NEC cases prior to onset. Aggregate assessment of DSLNT over multiple days enhanced the separation of NEC cases and control subjects. Conclusions DSLNT content in breast milk is a potential non-invasive marker to identify infants at risk of developing NEC, and screen high-risk donor milk. In addition, DSLNT could serve as a natural template to develop novel therapeutics against this devastating disorder.
University of Ottawa1, University of Texas MD Anderson Cancer Center2, Sunnybrook Health Sciences Centre3, Veterans Health Administration4, Stanford University5, American Society for Radiation Oncology6, Vanderbilt University Medical Center7, University of Maryland, Baltimore8, Virginia Commonwealth University9, Harvard University10, Lahey Hospital & Medical Center11, Duke University12, Medical College of Wisconsin13, Wake Forest University14, University of Washington15, Cedars-Sinai Medical Center16
TL;DR: Hypofractionated radiation therapy provides important potential advantages in cost and convenience for patients, and these recommendations are intended to provide guidance on moderate hypofractionation and ultrahyp ofractionation for localized prostate cancer.
Abstract: Purpose The aim of this guideline is to present recommendations regarding moderately hypofractionated (240-340 cGy per fraction) and ultrahypofractionated (500 cGy or more per fraction) radiation therapy for localized prostate cancer. Methods and Materials The American Society for Radiation Oncology convened a task force to address 8 key questions on appropriate indications and dose-fractionation for moderately and ultrahypofractionated radiation therapy, as well as technical issues, including normal tissue dose constraints, treatment volumes, and use of image guided and intensity modulated radiation therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and Society-approved tools for grading evidence quality and recommendation strength. Results Based on high-quality evidence, strong consensus was reached for offering moderate hypofractionation across risk groups to patients choosing external beam radiation therapy. The task force conditionally recommends ultrahypofractionated radiation may be offered for low- and intermediate-risk prostate cancer but strongly encourages treatment of intermediate-risk patients on a clinical trial or multi-institutional registry. For high-risk patients, the task force conditionally recommends against routine use of ultrahypofractionated external beam radiation therapy. With any hypofractionated approach, the task force strongly recommends image guided radiation therapy and avoidance of nonmodulated 3-dimensional conformal techniques. Conclusions Hypofractionated radiation therapy provides important potential advantages in cost and convenience for patients, and these recommendations are intended to provide guidance on moderate hypofractionation and ultrahypofractionation for localized prostate cancer. The limits in the current evidentiary base—especially for ultrahypofractionation—highlight the imperative to support large-scale randomized clinical trials and underscore the importance of shared decision making between clinicians and patients.