Author: "Martin, James A." / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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1. A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance

Author: Martin, James K, Sheehan, Joseph P, Bratton, Benjamin P, Moore, Gabriel M, Mateus, André, Li, Sophia Hsin-Jung, Kim, Hahn, Rabinowitz, Joshua D, Typas, Athanasios, Savitski, Mikhail M, Wilson, Maxwell Z, and Gitai, Zemer
Subjects: Biodefense, Antimicrobial Resistance, Prevention, Emerging Infectious Diseases, Infectious Diseases, Vaccine Related, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.2 Factors relating to the physical environment, Aetiology, Infection, Animals, Anti-Bacterial Agents, Cell Membrane, Drug Resistance, Bacterial, Female, Folic Acid, Gram-Negative Bacteria, Gram-Positive Bacteria, HEK293 Cells, Humans, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Ovariectomy, Proteomics, Pseudomonas aeruginosa, Pyrroles, Quinazolines, Acinetobacter baumannii, Gram-negative pathogens, Neisseria gonorrhoeae, antibiotics, broad spectrum, dual-target drugs, folate metabolism, membrane disrupting, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.
Published: 2020

2. Aligning Practice to Policies: Changing the Culture to Recognize and Reward Teaching at Research Universities

Author: Dennin, Michael, Schultz, Zachary D, Feig, Andrew, Finkelstein, Noah, Greenhoot, Andrea Follmer, Hildreth, Michael, Leibovich, Adam K, Martin, James D, Moldwin, Mark B, O’Dowd, Diane K, Posey, Lynmarie A, Smith, Tobin L, and Miller, Emily R
Subjects: Education Policy, Sociology and Philosophy, Education Systems, Education, Quality Education, Culture, Curriculum, Female, Humans, Male, Models, Educational, Policy, Research, Reward, Students, Teaching, Universities, Curriculum and Pedagogy, Curriculum and pedagogy
Abstract: Recent calls for improvement in undergraduate education within STEM (science, technology, engineering, and mathematics) disciplines are hampered by the methods used to evaluate teaching effectiveness. Faculty members at research universities are commonly assessed and promoted mainly on the basis of research success. To improve the quality of undergraduate teaching across all disciplines, not only STEM fields, requires creating an environment wherein continuous improvement of teaching is valued, assessed, and rewarded at various stages of a faculty member's career. This requires consistent application of policies that reflect well-established best practices for evaluating teaching at the department, college, and university levels. Evidence shows most teaching evaluation practices do not reflect stated policies, even when the policies specifically espouse teaching as a value. Thus, alignment of practice to policy is a major barrier to establishing a culture in which teaching is valued. Situated in the context of current national efforts to improve undergraduate STEM education, including the Association of American Universities Undergraduate STEM Education Initiative, this essay discusses four guiding principles for aligning practice with stated priorities in formal policies: 1) enhancing the role of deans and chairs; 2) effectively using the hiring process; 3) improving communication; and 4) improving the understanding of teaching as a scholarly activity. In addition, three specific examples of efforts to improve the practice of evaluating teaching are presented as examples: 1) Three Bucket Model of merit review at the University of California, Irvine; (2) Evaluation of Teaching Rubric, University of Kansas; and (3) Teaching Quality Framework, University of Colorado, Boulder. These examples provide flexible criteria to holistically evaluate and improve the quality of teaching across the diverse institutions comprising modern higher education.
Published: 2017

3. Cardiomyocyte Regeneration

Author: Eschenhagen, Thomas, Bolli, Roberto, Braun, Thomas, Field, Loren J, Fleischmann, Bernd K, Frisén, Jonas, Giacca, Mauro, Hare, Joshua M, Houser, Steven, Lee, Richard T, Marbán, Eduardo, Martin, James F, Molkentin, Jeffery D, Murry, Charles E, Riley, Paul R, Ruiz-Lozano, Pilar, Sadek, Hesham A, Sussman, Mark A, and Hill, Joseph A
Subjects: Animals, Cardiology, Cell Proliferation, Consensus, Heart Diseases, Humans, Myocytes, Cardiac, Recovery of Function, Regeneration, Regenerative Medicine, Stem Cell Transplantation, Treatment Outcome, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Published: 2017

4. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals

Author: Di Renzo, Gian Carlo, Conry, Jeanne A, Blake, Jennifer, DeFrancesco, Mark S, DeNicola, Nathaniel, Martin, James N, McCue, Kelly A, Richmond, David, Shah, Abid, Sutton, Patrice, Woodruff, Tracey J, van der Poel, Sheryl Ziemin, and Giudice, Linda C
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Contraception/Reproduction, Nutrition, Patient Safety, Prevention, 2.1 Biological and endogenous factors, Aetiology, 2.2 Factors relating to the physical environment, Reproductive health and childbirth, Good Health and Well Being, Breast Feeding, Cost of Illness, Environmental Exposure, Environmental Monitoring, Environmental Pollutants, Female, Global Health, Humans, International Agencies, Pregnancy, Prenatal Exposure Delayed Effects, Reproduction, Risk Factors, Socioeconomic Factors, Developmental health, Environmental chemicals, Reproductive environmental health, Toxic chemicals, Women's health, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract: Exposure to toxic environmental chemicals during pregnancy and breastfeeding is ubiquitous and is a threat to healthy human reproduction. There are tens of thousands of chemicals in global commerce, and even small exposures to toxic chemicals during pregnancy can trigger adverse health consequences. Exposure to toxic environmental chemicals and related health outcomes are inequitably distributed within and between countries; universally, the consequences of exposure are disproportionately borne by people with low incomes. Discrimination, other social factors, economic factors, and occupation impact risk of exposure and harm. Documented links between prenatal exposure to environmental chemicals and adverse health outcomes span the life course and include impacts on fertility and pregnancy, neurodevelopment, and cancer. The global health and economic burden related to toxic environmental chemicals is in excess of millions of deaths and billions of dollars every year. On the basis of accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals, the International Federation of Gynecology and Obstetrics (FIGO) joins other leading reproductive health professional societies in calling for timely action to prevent harm. FIGO recommends that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice.
Published: 2015

5. An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between Asthma in the Workplace and Non–Work-related Asthma

Author: Malo, Jean-Luc, Tarlo, Susan M, Sastre, Joaquin, Martin, James, Jeebhay, Mohamed F, Le Moual, Nicole, Heederik, Dick, Platts-Mills, Thomas, Blanc, Paul D, Vandenplas, Olivier, Moscato, Gianna, de Blay, Frédéric, and Cartier, André
Subjects: Asthma, Lung, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Allergens, Asthma, Occupational, Canada, Congresses as Topic, Humans, Immunoglobulin E, Occupational Diseases, Occupational Exposure, Risk Factors, Societies, Medical, Workplace, ATS ad hoc committee on Asthma in the Workplace, Clinical Sciences, Respiratory System
Abstract: The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non-work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home.
Published: 2015

6. Towards comprehensive syntactic and semantic annotations of the clinical narrative

Author: Albright, Daniel, Lanfranchi, Arrick, Fredriksen, Anwen, Styler, William F, Warner, Colin, Hwang, Jena D, Choi, Jinho D, Dligach, Dmitriy, Nielsen, Rodney D, Martin, James, Ward, Wayne, Palmer, Martha, and Savova, Guergana K
Subjects: Data Management and Data Science, Information and Computing Sciences, Artificial Intelligence, Networking and Information Technology R&D (NITRD), Electronic Health Records, Humans, Linguistics, Narration, Natural Language Processing, Semantics, Gold Standard Annotations, UMLS, Treebank, Propbank, cTAKES, Engineering, Medical and Health Sciences, Medical Informatics, Biomedical and clinical sciences, Health sciences, Information and computing sciences
Abstract: ObjectiveTo create annotated clinical narratives with layers of syntactic and semantic labels to facilitate advances in clinical natural language processing (NLP). To develop NLP algorithms and open source components.MethodsManual annotation of a clinical narrative corpus of 127 606 tokens following the Treebank schema for syntactic information, PropBank schema for predicate-argument structures, and the Unified Medical Language System (UMLS) schema for semantic information. NLP components were developed.ResultsThe final corpus consists of 13 091 sentences containing 1772 distinct predicate lemmas. Of the 766 newly created PropBank frames, 74 are verbs. There are 28 539 named entity (NE) annotations spread over 15 UMLS semantic groups, one UMLS semantic type, and the Person semantic category. The most frequent annotations belong to the UMLS semantic groups of Procedures (15.71%), Disorders (14.74%), Concepts and Ideas (15.10%), Anatomy (12.80%), Chemicals and Drugs (7.49%), and the UMLS semantic type of Sign or Symptom (12.46%). Inter-annotator agreement results: Treebank (0.926), PropBank (0.891-0.931), NE (0.697-0.750). The part-of-speech tagger, constituency parser, dependency parser, and semantic role labeler are built from the corpus and released open source. A significant limitation uncovered by this project is the need for the NLP community to develop a widely agreed-upon schema for the annotation of clinical concepts and their relations.ConclusionsThis project takes a foundational step towards bringing the field of clinical NLP up to par with NLP in the general domain. The corpus creation and NLP components provide a resource for research and application development that would have been previously impossible.
Published: 2013

7. Use of Clinical Pathway Simulation and Machine Learning to Identify Key Levers for Maximizing the Benefit of Intravenous Thrombolysis in Acute Stroke

Author: Michael Allen, Charlotte James, Julia Frost, Kristin Liabo, Kerry Pearn, Thomas Monks, Richard Everson, Ken Stein, and Martin James
Subjects: Machine Learning, Stroke, Advanced and Specialized Nursing, Fibrinolytic Agents, Critical Pathways, Humans, Administration, Intravenous, Thrombolytic Therapy, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract: Background: Expert opinion is that about 20% of emergency stroke patients should receive thrombolysis. Currently, 11% to 12% of patients in England and Wales receive thrombolysis, ranging from 2% to 24% between hospitals. The aim of this study was to assess how much variation is due to differences in local patient populations, and how much is due to differences in clinical decision-making and stroke pathway performance, while estimating a realistic target thrombolysis use. Methods: Anonymised data for 246 676 emergency stroke admissions to 132 acute hospitals in England and Wales between 2016 and 2018 was obtained from the Sentinel Stroke National Audit Programme data. We used machine learning to learn decisions on who to give thrombolysis to at each hospital. We used clinical pathway simulation to model effects of changing pathway performance. Qualitative research was used to assess clinician attitudes to these methods. Three changes were modeled: (1) arrival-to-treatment in 30 minutes, (2) proportion of patients with determined stroke onset times set to at least the national upper quartile, (3) thrombolysis decisions made based on majority vote of a benchmark set of hospitals. Results: Of the modeled changes, any single change was predicted to increase national thrombolysis use from 11.6% to between 12.3% to 14.5% (clinical decision-making having the most effect). Combined, these changes would be expected to increase thrombolysis to 18.3%, but there would still be significant variation between hospitals depending on local patient population. Clinicians engaged well with the modeling, but those from hospitals with lower thrombolysis use were most cautious about the methods. Conclusions: Machine learning and clinical pathway simulation may be applied at scale to national stroke audit data, allowing extended use and analysis of audit data. Stroke thrombolysis rates of at least 18% look achievable in England and Wales, but each hospital should have its own target.
Published: 2022
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8. SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

Author: Karen A. Maegley, Kephart Susan Elizabeth, Christopher P. Dillon, Manli Shi, Kristen Jensen-Pergakes, Prakash B. Palde, Ya-Li Deng, Chi-Yeh Chung, Natalie Miller, John Sherrill, Wei Liu, Ryan L. Patman, Shinji Yamazaki, Tao Xie, Fen Wang, Hieu Lam, Eleanore Hendrickson, John F. Braganza, Yuli Wang, Robert Arnold Kumpf, Shannon Karlicek Bryant, Thomas A Paul, Noah Spiegel, Martin James Wythes, Amy Nemeth, Stephanie Scales, Elizabeth A. McMillan, Michelle Tran-Dubé, Alexei Brooun, Vesta Goshtasbi, Eugene Rui, Michele McTigue, Indrawan James Mcalpine, and Tatlock John H
Subjects: Protein-Arginine N-Methyltransferases, S-Adenosylmethionine, Cancer Research, Cell signaling, Spliceosome, Lung Neoplasms, Chemistry, Cellular differentiation, Protein arginine methyltransferase 5, Alternative splicing, Drug Resistance, Apoptosis, Cell cycle, Mice, Oncology, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, RNA splicing, Cancer cell, Cancer research, Animals, Humans, Female, Cell Proliferation
Abstract: Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non–small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.
Published: 2022
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9. 3D printing of inorganic-biopolymer composites for bone regeneration

Author: Daphne van der Heide, Gianluca Cidonio, Martin James Stoddart, and Matteo D’Este
Subjects: Calcium Phosphates, Tissue Engineering, Tissue Scaffolds, Biomedical Engineering, Biocompatible Materials, Bioengineering, General Medicine, 3D printing, Biochemistry, Biomaterials, Biopolymers, bone regeneration, Bone Substitutes, Printing, Three-Dimensional, Humans, composite biomaterial-ink, Biotechnology
Abstract: In most cases, bone injuries heal without complications, however, there is an increasing number of instances where bone healing needs major clinical intervention. Available treatment options have severe drawbacks, such as donor site morbidity and limited availability for autografting. Bone graft substitutes containing growth factors would be a viable alternative, however they have been associated with dose-related safety concerns and lack control over spatial architecture to anatomically match bone defect sites. A 3D printing offers a solution to produce patient specific bone graft substitutes that are customized to the patient bone defect with temporal control over the incorporated therapeutics to maximize their efficacy. Inspired by the natural constitution of bone tissue, composites made of inorganic phases, such as nanosilicate particles, calcium phosphate, and bioactive glasses, combined with biopolymer matrices have been investigated as building blocks for the biofabrication of bone constructs. Besides capturing elements of the bone physiological structure, these inorganic/organic composites can be designed for specific cohesivity, rheological and mechanical properties, while both inorganic and organic constituents contribute to the composite bioactivity. This review provides an overview of 3D printed composite biomaterial-inks for bone tissue engineering. Furthermore, key aspects in biomaterial-ink design, 3D printing techniques, and the building blocks for composite biomaterial-inks are summarized., Biofabrication, 14 (4), ISSN:1758-5082, ISSN:1758-5090
Published: 2022

10. Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis

Author: Dominique Lambin, Katja Conrath, Tom De Munck, Ann De Blieck, Hans Kelgtermans, Steven Emiel Van Der Plas, Marlon D. Cowart, Christel Jeanne Marie Menet, Sebastien Dropsit, Caroline Joannesse, Oscar Mammoliti, Sebastien Laurent Xavier Martina, Maarten Gees, Giovanni Tricarico, Martin James Inglis Andrews, and Anne-Sophie Wesse
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis, Pyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Gating, Computational biology, 01 natural sciences, Cystic fibrosis, Ivacaftor, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, biology, Drug discovery, Lumacaftor, Potentiator, medicine.disease, Small molecule, Cystic fibrosis transmembrane conductance regulator, Rats, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, biology.protein, Molecular Medicine, medicine.drug
Abstract: Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.
Published: 2021
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11. Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial

Author: Jonathan G, Best, Liz, Arram, Norin, Ahmed, Maryam, Balogun, Kate, Bennett, Ekaterina, Bordea, Marta G, Campos, Emilia, Caverly, Marisa, Chau, Hannah, Cohen, Hakim-Moulay, Dehbi, Caroline J, Doré, Stefan T, Engelter, Robert, Fenner, Nick, Freemantle, Rachael, Hunter, Martin, James, Gregory Yh, Lip, Macey L, Murray, Bo, Norrving, Nikola, Sprigg, Roland, Veltkamp, Iwona, Zaczyk, and David J, Werring
Subjects: acute ischemic stroke, DOAC, Administration, Oral, Anticoagulants, Atrial fibrillation, Brain Ischemia, Stroke, Intracranial Hemorrhages/drug therapy, Brain Ischemia/complications, Treatment Outcome, Neurology, Anticoagulants/therapeutic use, Risk Factors, Atrial Fibrillation, timing, Quality of Life, Humans, Multicenter Studies as Topic, anticoagulation, Atrial Fibrillation/complications, Intracranial Hemorrhages, Stroke/complications, Ischemic Stroke, Randomized Controlled Trials as Topic
Abstract: Rationale Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. Aim Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. Methods and design OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. Study outcomes The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. Sample size target A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. Discussion OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke. Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938
Published: 2022
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12. Evaluation of microalbuminuria as a prognostic indicator after a TIA or minor stroke in an outpatient setting: the prognostic role of microalbuminuria in TIA evolution (ProMOTE) study

Author: Angela C. Shore, William Henley, Nicola Wedge, W. David Strain, Luke T. A. Mounce, Martin James, and Salim Elyas
Subjects: medicine.medical_specialty, Urinary system, Population, Transient ischaemic attacks, risk management, Risk Factors, Internal medicine, Outpatients, medicine, Humans, Myocardial infarction, cardiovascular diseases, education, Stroke, Aged, 80 and over, education.field_of_study, Framingham Risk Score, business.industry, General Medicine, medicine.disease, Prognosis, Medical Management, Ischemic Attack, Transient, stroke medicine, Medicine, Microalbuminuria, business, Mace
Abstract: ObjectiveTransient ischaemic attacks (TIA) and minor strokes are important risk factors for further vascular events. We explored the role of albumin creatinine ratio (ACR) in improving risk prediction after a first event.SettingRapid access stroke clinics in the UK.Participants2202 patients attending with TIA or minor stroke diagnosed by the attending stroke physician, able to provide a urine sample to evaluate ACR using a near-patient testing device.Primary and secondary outcomesPrimary outcome was major adverse cardiac events (MACE: recurrent stroke, myocardial infarction or cardiovascular death) at 90 days. The key secondary outcome was to determine whether urinary ACR could contribute to a risk prediction tool for use in a clinic setting.Results151 MACE occurred in 144 participants within 90 days. Participants with MACE had higher ACR than those without. A composite score awarding a point each for age >80 years, previous stroke/TIA and presence of microalbuminuria identified those at low risk and high risk. 90% of patients were at low risk (scoring 0 or 1). Their 90-day risk of MACE was 5.7%. Of the remaining ‘high-risk’ population (scoring 2 or 3) 12.4% experienced MACE over 90 days (pConclusionA risk score comprising age, previous stroke/TIA and microalbuminuria predicts future MACE while identifying those at low risk of a recurrent event. This tool shows promise in the risk stratification of patients to avoid the admission of low-risk patients.
Published: 2021

13. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Author: Patrick A Flume, Reta Fischer Biner, Damian G Downey, Cynthia Brown, Manu Jain, Rainald Fischer, Kris De Boeck, Gregory S Sawicki, Philip Chang, Hildegarde Paz-Diaz, Jaime L Rubin, Yoojung Yang, Xingdi Hu, David J Pasta, Stefanie J Millar, Daniel Campbell, Xin Wang, Neil Ahluwalia, Caroline A Owen, Claire E Wainwright, Ronald L. Gibson, Steven M. Rowe, Noah Lechtzin, Richard C. Ahrens, Karen S. McCoy, Moira Aitken, Scott H. Donaldson, Kimberly Ann McBennett, Joseph M. Pilewski, Joanne Billings, Carlos Milla, Ronald Rubenstein, Daniel Brian Rosenbluth, Rachel Linnemann, Michael R. Powers, Christopher Fortner, Carla Anne Frederick, Theodore G. Liou, Philip Black, Janice Wang, John L. Colombo, Maria Berdella, Maria Veronica Indihar, Cynthia D. Brown, Michael Anstead, Lara Bilodeau, Leonard Sicilian, James Jerome Tolle, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, Tara Lynn Barto, Nicholas Antos, John S. Rogers, Bryon Quick, Henry R. Thompson, Gregory Sawicki, Bruce Barnett, Robert L. Zanni, Thomas C. Smith, Karen D. Schultz, Claire Keating, Patrick Flume, Gregory J. Omlor, Alix Ashare, Karen Voter, Nighat Mehdi, Maria Gabriela Tupayachi Ortiz, Tonia E. Gardner, Steven R. Boas, Barbara Messore, Edith Zemanick, Raksha Jain, Michael McCarthy, Dana G. Kissner, Kapilkumar Patel, John McNamara, Julie Philley, Ariel Berlinski, Francisco J. Calimano, Terry Chin, Douglas Conrad, Cori Daines, Hengameh H. Raissy, Thomas G. Keens, Jorge E. Lascano, Bennie McWilliams, Brian Morrissey, Santiago Reyes, Subramanyam Chittivelu, Sabiha Hussain, Arvey Stone, James Wallace, Ross Klingsberg, Julie A. Biller, Stephanie Bui, Olaf Sommerburg, Elisabetta Bignamini, Mirella Collura, Alexander Moller, Donatello Salvatore, Chantal Belleguic, Lea Bentur, Ori Efrati, Eitan Kerem, Dario Prais, Esther Quintana Gallego, Peter Barry, Galit Livnat-Levanon, Jose Ramon Villa Asensi, David Stuart Armstrong, Oscar Asensio de la Cruz, Francis Gilchrist, Diana Elizabeth Tullis, Bradley Quon, Larry C. Lands, Nancy Morrison, Annick Lavoie, Barry Linnane, Okan Elidemir, Felix Ringshausen, Matthias Kappler, Helge Hebestreit, Jochen Mainz, Alexander Kiefer, Cordula Koerner-Rettberg, Doris Staab, Wolfgang Gleiber, Tacjana Pressler, Florian Stehling, Andreas Hector, Sivagurunathan Sutharsan, Lutz Naehrlich, Damian Downey, Jane Carolyn Davies, Robert Ian Ketchell, Mary Patricia Carroll, Simon Doe, Gordon MacGregor, Edward Fairbairn Nash, Nicholas Withers, Daniel Gavin Peckham, Martin James Ledson, Sonal Kansra, Timothy William Rayner Lee, Bertrand Delaisi, Gilles Rault, Jean Le Bihan, Dominique Hubert, Isabelle Fajac, Isabelle Sermet-Gaudelus, Marleen Bakker, Bert Arets, Christiane De Boeck, Raphael Chiron, Philippe Reix, Catherine Mainguy, Eva van Braeckel, Anne Malfroot, Isabelle Durieu, Nadine Desmazes Dufeu, Anne Prevotat, Renske van der Meer, Petrus Merkus, E.J.M. Weersink, Isabel Barrio Gomez-Aguero, Silvia Gartner, Amparo Sole Jover, Antonio Alvarez Fernandez, Desmond William Cox, Edward F. McKone, Barry James Plant, Hiranjan Selvadurai, Simon David Bowler, Claire Elizabeth Wainwright, Daniel Smith, Peter Gordon Middleton, John William Wilson, Sonia Volpi, Carla Colombo, Benedetta Fabrizzi, Vincenzina Lucidi, Federico Cresta, Salvatore Cucchiara, Ernst Eber, Helmut Ellemunter, Isidor Huttegger, Lena Hjelte, Christina Krantz, Marita Gilljam, and Pulmonology
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Indoles, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Cystic fibrosis, Time, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Clinical endpoint, Humans, Benzodioxoles, 030212 general & internal medicine, Israel, biology, business.industry, Australia, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Discontinuation, Europe, Drug Combinations, Treatment Outcome, Clinical research, 030228 respiratory system, Tolerability, Mutation, North America, biology.protein, Female, business, medicine.drug
Abstract: Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.
Published: 2021
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14. Estimating the effectiveness and cost-effectiveness of establishing additional endovascular Thrombectomy stroke Centres in England: a discrete event simulation

Author: Darren Flynn, Hannah Lumley, Martin James, Peter McMeekin, David Burgess, Joyce S. Balami, Diarmuid Coughlan, Michael Allen, Ken Stein, Phil White, and Gary A. Ford
Subjects: Budgets, Male, medicine.medical_specialty, Cost effectiveness, Cost-Benefit Analysis, Ambulatory Care Facilities, B700, State Medicine, Health administration, Time-to-Treatment, Predictive models, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Medicine, Humans, Acute stroke, 030212 general & internal medicine, Discrete event simulation, Stroke, Aged, Thrombectomy, Health economics, business.industry, Health Policy, Incidence (epidemiology), lcsh:Public aspects of medicine, Endovascular Procedures, lcsh:RA1-1270, Middle Aged, medicine.disease, Hospitals, B900, Hospitalization, Treatment Outcome, England, Emergency medicine, Female, Quality-Adjusted Life Years, business, Delivery of Health Care, 030217 neurology & neurosurgery, Research Article
Abstract: Background We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30. Methods We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30. Results Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters ( Conclusion Changes in acute stroke service configuration will produce clinical and cost benefits when the time taken for patients to receive treatment is reduced. Benefits are highly likely to be cost saving over 5 years before any capital investment above £8 million is required.
Published: 2019
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15. External Validation Of The Updated ADO Score In COPD Patients From The Birmingham COPD Cohort

Author: Keene, Spencer J, Jordan, Rachel E, Franssen, Frits ME, de Vries, Frank, Martin, James, Sitch, Alice, Turner, Alice Margaret, Dickens, Andrew P, Fitzmaurice, David, Adab, Peymane, Pulmonologie, RS: NUTRIM - R3 - Respiratory & Age-related Health, MUMC+: DA KFT Medische Staf (9), Farmacologie en Toxicologie, RS: CAPHRI - R5 - Optimising Patient Care, Afd Pharmacoepi & Clinical Pharmacology, and Pharmacoepidemiology and Clinical Pharmacology
Subjects: Adult, Male, Time Factors, PREDICTION, MODELS, Vital Capacity, International Journal of Chronic Obstructive Pulmonary Disease, OBSTRUCTIVE PULMONARY-DISEASE, Risk Assessment, Decision Support Techniques, Pulmonary Disease, Chronic Obstructive, Predictive Value of Tests, Risk Factors, Forced Expiratory Volume, Prevalence, Humans, Registries, Lung, INDEX, Original Research, pulmonary disease, validation studies, Aged, Aged, 80 and over, chronic obstructive, Primary Health Care, DEATH, Age Factors, Reproducibility of Results, Middle Aged, Prognosis, mortality, Dyspnea, England, Female, prognosis
Abstract: Spencer J Keene,1–3 Rachel E Jordan,1 Frits ME Franssen,3,4 Frank de Vries,2,5 James Martin,1 Alice Sitch,1,6 Alice Margaret Turner,1 Andrew P Dickens,1 David Fitzmaurice,7 Peymane Adab1 1Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; 2Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands; 3Ciro, Horn, the Netherlands; 4Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands; 5Utrecht Institute for Pharmaceutical Sciences Utrecht University, Utrecht, The Netherlands; 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK; 7Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UKCorrespondence: Rachel E JordanInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UKTel +44 0121 414 6775Email r.e.jordan@bham.ac.ukBackground: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation.Objectives: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods.Patients and methods: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots.Results: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69–0.79). Similar performance was foundfor 1- (AUC= 0.73; 0.66–0.80) and 2-year mortality (0.72; 0.67–0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70–1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45–1.13) and 2-year (0.79; 0.57–1.01) mortality.Discussion: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks.Keywords: pulmonary disease, chronic obstructive, mortality, prognosis, validation studies
Published: 2019

16. Depression and Incidence of Frailty in Older People From Six Latin American Countries

Author: Prina, Matthew, Stubbs, Brendon, Veronese, Nicola, Guerra, Mariella, Kralj, Carolina, Llibre Rodriguez, Juan, Prince, Martin James, Wu, Yu-Tzu, Prina, A.M., Stubbs, B., Veronese, N., Guerra, M., Kralj, C., Llibre Rodriguez, J.J., Prince, M., and Wu, Y.-T.
Subjects: Male, Aged, 80 and over, Internationality, Frailty, Depression, Frail Elderly, Incidence, frailty, Article, Latin America, Socioeconomic Factors, older age, Humans, Dementia, Female, epidemiology, low- and middle-income countries, Developing Countries, Geriatric Assessment, Aged
Abstract: ObjectiveFrailty and depression are highly comorbid conditions, but the casual direction is unclear and has not been explored in low- and middle-income countries. The aim of this study was to investigate the potential impact of depression on incident frailty in older people living in Latin America.MethodsThis study was based on a population-based cohort of 12,844 people aged 65 or older from six Latin American countries (Cuba, Dominican Republic, Mexico, Venezuela, Puerto Rico, and Peru), part of the 10/66 cohort study. Two types of frailty measures were used: a modified Fried frailty phenotype and a multidimensional frailty criterion, which included measures from cognition, sensory, nutrition, and physical dimensions. Depression was assessed using EURO-D and International Classification of Diseases, Tenth Revision criteria. A competing risk model was used to examine the associations between baseline depression and incidence of frailty in the 3–5 years of follow-up, accounting for sociodemographic and health factors and the competing event of frailty-free death.ResultsDepression was associated with a 59% increased hazard of developing frailty using the modified Fried phenotype (subdistribution hazard ratio [SHR]: 1.59; 95% confidence interval [CI]: 1.40, 1.80) and 19% for multidimensional frailty (SHR: 1.19; 95% CI: 1.06, 1.33) after adjusting for sociodemographic factors, physical impairments, and dementia. The associations between depression and the multidimensional frailty criteria were homogenous across all the sites (Higgins I2 = 0%).ConclusionDepression may play a key role in the development of frailty. Pathways addressing the association between physical and mental health in older people need to be further investigated in future research.
Published: 2019
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17. Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Author: George Ntaios, Menno V. Huisman, Hans-Christoph Diener, Jonathan L. Halperin, Christine Teutsch, Sabrina Marler, Venkatesh K. Gurusamy, Milla Thompson, Gregory Y.H. Lip, Brian Olshansky, Dzifa Wosornu Abban, Nasser Abdul, Atilio Marcelo Abud, Fran Adams, Srinivas Addala, Pedro Adragão, Walter Ageno, Rajesh Aggarwal, Sergio Agosti, Piergiuseppe Agostoni, Francisco Aguilar, Julio Aguilar Linares, Luis Aguinaga, Jameel Ahmed, Allessandro Aiello, Paul Ainsworth, Jorge Roberto Aiub, Raed Al-Dallow, Lisa Alderson, Jorge Antonio Aldrete Velasco, Dimitrios Alexopoulos, Fernando Alfonso Manterola, Pareed Aliyar, David Alonso, Fernando Augusto Alves da Costa, José Amado, Walid Amara, Mathieu Amelot, Nima Amjadi, Fabrizio Ammirati, Marianna Andrade, Nabil Andrawis, Giorgio Annoni, Gerardo Ansalone, M.Kevin Ariani, Juan Carlos Arias, Sébastien Armero, Chander Arora, Muhammad Shakil Aslam, M. Asselman, Philippe Audouin, Charles Augenbraun, S. Aydin, Ivaneta Ayryanova, Emad Aziz, Luciano Marcelo Backes, E. Badings, Ermentina Bagni, Seth H. Baker, Richard Bala, Antonio Baldi, Shigenobu Bando, Subhash Banerjee, Alan Bank, Gonzalo Barón Esquivias, Craig Barr, Maria Bartlett, Vanja Basic Kes, Giovanni Baula, Steffen Behrens, Alan Bell, Raffaella Benedetti, Juan Benezet Mazuecos, Bouziane Benhalima, Jutta Bergler-Klein, Jean-Baptiste Berneau, Richard A. Bernstein, Percy Berrospi, Sergio Berti, Andrea Berz, Elizabeth Best, Paulo Bettencourt, Robert Betzu, Ravi Bhagwat, Luna Bhatta, Francesco Biscione, Giovanni BISIGNANI, Toby Black, Michael J. Bloch, Stephen Bloom, Edwin Blumberg, Mario Bo, Ellen Bøhmer, Andreas Bollmann, Maria Grazia Bongiorni, Giuseppe Boriani, D.J. Boswijk, Jochen Bott, Edo Bottacchi, Marica Bracic Kalan, Drew Bradman, Donald Brautigam, Nicolas Breton, P.J.A.M. Brouwers, Kevin Browne, Jordi Bruguera Cortada, A. Bruni, Claude Brunschwig, Hervé Buathier, Aurélie Buhl, John Bullinga, Jose Walter Cabrera, Alberto Caccavo, Shanglang Cai, Sarah Caine, Leonardo Calò, Valeria Calvi, Mauricio Camarillo Sánchez, Rui Candeias, Vincenzo Capuano, Alessandro Capucci, Ronald Caputo, Tatiana Cárdenas Rizo, Francisco Cardona, Francisco Carlos da Costa Darrieux, Yan Carlos Duarte Vera, Antonio Carolei, Susana Carreño, Paula Carvalho, Susanna Cary, Gavino Casu, Claudio Cavallini, Guillaume Cayla, Aldo Celentano, Tae-Joon Cha, Kwang Soo Cha, Jei Keon Chae, Kathrine Chalamidas, Krishnan Challappa, Sunil Prakash Chand, Harinath Chandrashekar, Ludovic Chartier, Kausik Chatterjee, Carlos Antero Chavez Ayala, Aamir Cheema, Amjad Cheema, Lin Chen, Shih-Ann Chen, Jyh Hong Chen, Fu-Tien Chiang, Francesco Chiarella, Lin Chih-Chan, Yong Keun Cho, Jong-Il Choi, Dong Ju Choi, Guy Chouinard, Danny Hoi-Fan Chow, Dimitrios Chrysos, Galina Chumakova, Eduardo Julián José Roberto Chuquiure Valenzuela, Nicoleta Cindea Nica, David J. Cislowski, Anthony Clay, Piers Clifford, Andrew Cohen, Michael Cohen, Serge Cohen, Furio Colivicchi, Ronan Collins, Paolo Colonna, Steve Compton, Derek Connolly, Alberto Conti, Gabriel Contreras Buenostro, Gregg Coodley, Martin Cooper, Julian Coronel, Giovanni Corso, Juan Cosín Sales, Yves Cottin, John Covalesky, Aurel Cracan, Filippo Crea, Peter Crean, James Crenshaw, Tina Cullen, Harald Darius, Patrick Dary, Olivier Dascotte, Ira Dauber, Vicente Davalos, Ruth Davies, Gershan Davis, Jean-Marc Davy, Mark Dayer, Marzia De Biasio, Silvana De Bonis, Raffaele De Caterina, Teresiano De Franceschi, J.R. de Groot, José De Horta, Axel De La Briolle, Gilberto de la Pena Topete, Angelo Amato Vicenzo de Paola, Weimar de Souza, A. de Veer, Luc De Wolf, Eric Decoulx, Sasalu Deepak, Pascal Defaye, Freddy Del-Carpio Munoz, Diana Delic Brkljacic, N. Joseph Deumite, Silvia Di Legge, Igor Diemberger, Denise Dietz, Pedro Dionísio, Qiang Dong, Fabio Rossi dos Santos, Elena Dotcheva, Rami Doukky, Anthony D'Souza, Simon Dubrey, Xavier Ducrocq, Dmitry Dupljakov, Mauricio Duque, Dipankar Dutta, Nathalie Duvilla, A. Duygun, Rainer Dziewas, Charles B. Eaton, William Eaves, L.A. Ebels-Tuinbeek, Clifford Ehrlich, Sabine Eichinger-Hasenauer, Steven J. Eisenberg, Adnan El Jabali, Mahfouz El Shahawy, Mauro Esteves Hernandes, Ana Etxeberria Izal, Rudolph Evonich, Oksana Evseeva, Andrey Ezhov, Raed Fahmy, Quan Fang, Ramin Farsad, Laurent Fauchier, Stefano Favale, Maxime Fayard, Jose Luis Fedele, Francesco Fedele, Olga Fedorishina, Steven R. Fera, Luis Gustavo Gomes Ferreira, Jorge Ferreira, Claudio Ferri, Anna Ferrier, Hugo Ferro, Alexandra Finsen, Brian First, Stuart Fischer, Catarina Fonseca, Luísa Fonseca Almeida, Steven Forman, Brad Frandsen, William French, Keith Friedman, Athena Friese, Ana Gabriela Fruntelata, Shigeru Fujii, Stefano Fumagalli, Marta Fundamenski, Yutaka Furukawa, Matthias Gabelmann, Nashwa Gabra, Niels Gadsbøll, Michel Galinier, Anders Gammelgaard, Priya Ganeshkumar, Christopher Gans, Antonio Garcia Quintana, Olivier Gartenlaub, Achille Gaspardone, Conrad Genz, Frédéric Georger, Jean-Louis Georges, Steven Georgeson, Evaldas Giedrimas, Mariusz Gierba, Ignacio Gil Ortega, Eve Gillespie, Alberto Giniger, Michael C. Giudici, Alexandros Gkotsis, Taya V. Glotzer, Joachim Gmehling, Jacek Gniot, Peter Goethals, Seth Goldbarg, Ronald Goldberg, Britta Goldmann, Sergey Golitsyn, Silvia Gómez, Juan Gomez Mesa, Vicente Bertomeu Gonzalez, Jesus Antonio Gonzalez Hermosillo, Víctor Manuel González López, Hervé Gorka, Charles Gornick, Diana Gorog, Venkat Gottipaty, Pascal Goube, Ioannis Goudevenos, Brett Graham, G. Stephen Greer, Uwe Gremmler, Paul G. Grena, Martin Grond, Edoardo Gronda, Gerian Grönefeld, Xiang Gu, Ivett Guadalupe Torres Torres, Gabriele Guardigli, Carolina Guevara, Alexandre Guignier, Michele Gulizia, Michael Gumbley, Albrecht Günther, Andrew Ha, Georgios Hahalis, Joseph Hakas, Christian Hall, Bing Han, Seongwook Han, Joe Hargrove, David Hargroves, Kenneth B. Harris, Tetsuya Haruna, Emil Hayek, Jeff Healey, Steven Hearne, Michael Heffernan, Geir Heggelund, J.A. Heijmeriks, Maarten Hemels, I. Hendriks, Sam Henein, Sung-Ho Her, Paul Hermany, Jorge Eduardo Hernández Del Río, Yorihiko Higashino, Michael Hill, Tetsuo Hisadome, Eiji Hishida, Etienne Hoffer, Matthew Hoghton, Kui Hong, Suk keun Hong, Stevie Horbach, Masataka Horiuchi, Yinglong Hou, Jeff Hsing, Chi-Hung Huang, David Huckins, null kathy Hughes, A. Huizinga, E.L. Hulsman, Kuo-Chun Hung, Gyo-Seung Hwang, Margaret Ikpoh, Davide Imberti, Hüseyin Ince, Ciro Indolfi, Shujiro Inoue, Didier Irles, Harukazu Iseki, C. Noah Israel, Bruce Iteld, Venkat Iyer, Ewart Jackson-Voyzey, Naseem Jaffrani, Frank Jäger, Martin James, Sung-Won Jang, Nicolas Jaramillo, Nabil Jarmukli, Robert J. Jeanfreau, Ronald D. Jenkins, Carlos Jerjes Sánchez, Javier Jimenez, Robert Jobe, Tomas Joen-Jakobsen, Nicholas Jones, Jose Carlos Moura Jorge, Bernard Jouve, Byung Chun Jung, Kyung Tae Jung, Werner Jung, Mikhail Kachkovskiy, Krystallenia Kafkala, Larisa Kalinina, Bernd Kallmünzer, Farzan Kamali, Takehiro Kamo, Priit Kampus, Hisham Kashou, Andreas Kastrup, Apostolos Katsivas, Elizabeth Kaufman, Kazuya Kawai, Kenji Kawajiri, John F. Kazmierski, P. Keeling, José Francisco Kerr Saraiva, Galina Ketova, AJIT Singh Khaira, Aleksey Khripun, Doo-Il Kim, Young Hoon Kim, Nam Ho Kim, Dae Kyeong Kim, Jeong Su Kim, June Soo Kim, Ki Seok Kim, Jin bae Kim, Elena Kinova, Alexander Klein, James J. Kmetzo, G. Larsen Kneller, Aleksandar Knezevic, Su Mei Angela Koh, Shunichi Koide, Anastasios Kollias, J.A. Kooistra, Jay Koons, Martin Koschutnik, William J. Kostis, Dragan Kovacic, Jacek Kowalczyk, Natalya Koziolova, Peter Kraft, Johannes A. Kragten, Mori Krantz, Lars Krause, B.J. Krenning, F. Krikke, Z. Kromhout, Waldemar Krysiak, Priya Kumar, Thomas Kümler, Malte Kuniss, Jen-Yuan Kuo, Achim Küppers, Karla Kurrelmeyer, Choong Hwan Kwak, Bénédicte Laboulle, Arthur Labovitz, Wen Ter Lai, Andy Lam, Yat Yin Lam, Fernando Lanas Zanetti, Charles Landau, Giancarlo Landini, Estêvão Lanna Figueiredo, Torben Larsen, Karine Lavandier, Jessica LeBlanc, Moon Hyoung Lee, Chang-Hoon Lee, John Lehman, Ana Leitão, Nicolas Lellouche, Malgorzata Lelonek, Radoslaw Lenarczyk, T. Lenderink, Salvador León González, Peter Leong-Sit, Matthias Leschke, Nicolas Ley, Zhanquan Li, Xiaodong Li, Weihua Li, Xiaoming Li, Christhoh Lichy, Ira Lieber, Ramon Horacio Limon Rodriguez, Hailong Lin, Feng Liu, Hengliang Liu, Guillermo Llamas Esperon, Nassip Llerena Navarro, Eric Lo, Sergiy Lokshyn, Amador López, José Luís López-Sendón, Adalberto Menezes Lorga Filho, Richard S. Lorraine, Carlos Alberto Luengas, Robert Luke, Ming Luo, Steven Lupovitch, Philippe Lyrer, Changsheng Ma, Genshan Ma, Irene Madariaga, Koji Maeno, Dominique Magnin, Gustavo Maid, Sumeet K. Mainigi, Konstantinos Makaritsis, Rohit Malhotra, Rickey Manning, Athanasios Manolis, Helard Andres Manrique Hurtado, Ioannis Mantas, Fernando Manzur Jattin, Vicky Maqueda, Niccolo Marchionni, Francisco Marin Ortuno, Antonio Martín Santana, Jorge Martinez, Petra Maskova, Norberto Matadamas Hernandez, Katsuhiro Matsuda, Tillmann Maurer, Ciro Mauro, Erik May, Nolan Mayer, John McClure, Terry McCormack, William McGarity, Hugh McIntyre, Brent McLaurin, Feliz Alvaro Medina Palomino, Francesco Melandri, Hiroshi Meno, Dhananjai Menzies, Marco Mercader, Christian Meyer, Beat j. Meyer, Jacek Miarka, Frank Mibach, Dominik Michalski, Patrik Michel, Rami Mihail Chreih, Ghiath Mikdadi, Milan Mikus, Davor Milicic, Constantin Militaru, Sedi Minaie, Bogdan Minescu, Iveta Mintale, Tristan Mirault, Michael J. Mirro, Dinesh Mistry, Nicoleta Violeta Miu, Naomasa Miyamoto, Tiziano Moccetti, Akber Mohammed, Azlisham Mohd Nor, Michael Mollerus, Giulio Molon, Sergio Mondillo, Patrícia Moniz, Lluis Mont, Vicente Montagud, Oscar Montaña, Cristina Monti, Luciano Moretti, Kiyoo Mori, Andrew Moriarty, Jacek Morka, Luigi Moschini, Nikitas Moschos, Andreas Mügge, Thomas J. Mulhearn, Carmen Muresan, Michela Muriago, Wlodzimierz Musial, Carl W. Musser, Francesco Musumeci, Thuraia Nageh, Hidemitsu Nakagawa, Yuichiro Nakamura, Toru Nakayama, Gi-Byoung Nam, Michele Nanna, Indira Natarajan, Hemal M. Nayak, Stefan Naydenov, Jurica Nazli, Alexandru Cristian Nechita, Libor Nechvatal, Sandra Adela Negron, James Neiman, Fernando Carvalho Neuenschwander, David Neves, Anna Neykova, Ricardo Nicolás Miguel, George Nijmeh, Alexey Nizov, Rodrigo Noronha Campos, Janko Nossan, Tatiana Novikova, Ewa Nowalany-Kozielska, Emmanuel Nsah, Juan Carlos Nunez Fragoso, Svetlana Nurgalieva, Dieter Nuyens, Ole Nyvad, Manuel Odin de Los Rios Ibarra, Philip O'Donnell, Martin O'Donnell, Seil Oh, Yong Seog Oh, Dongjin Oh, Gilles O'Hara, Kostas Oikonomou, Claudia Olivares, Richard Oliver, Rafael Olvera Ruiz, Christoforos Olympios, null Anna omaszuk-Kazberuk, Joaquín Osca Asensi, null eena Padayattil jose, Francisco Gerardo Padilla Padilla, Victoria Padilla Rios, Giuseppe Pajes, A. Shekhar Pandey, Gaetano Paparella, F. Paris, Hyung Wook Park, Jong Sung Park, Fragkiskos Parthenakis, Enrico Passamonti, Rajesh J. Patel, Jaydutt Patel, Mehool Patel, Janice Patrick, Ricardo Pavón Jimenez, Analía Paz, Vittorio Pengo, William Pentz, Beatriz Pérez, Alma Minerva Pérez Ríos, Alejandro Pérez-Cabezas, Richard Perlman, Viktor Persic, Francesco Perticone, Terri K. Peters, Sanjiv Petkar, Luis Felipe Pezo, Christian Pflücke, David N. Pham, Roland T. Phillips, Stephen Phlaum, Denis Pieters, Julien Pineau, Arnold Pinter, Fausto Pinto, R. Pisters, Nediljko Pivac, Darko Pocanic, Cristian Podoleanu, Alessandro Politano, Zdravka Poljakovic, Stewart Pollock, Jose Polo Garcéa, Holger Poppert, Maurizio Porcu, Antonio Pose Reino, Neeraj Prasad, Dalton Bertolim Précoma, Alessandro Prelle, John Prodafikas, Konstantin Protasov, Maurice Pye, Zhaohui Qiu, Jean-Michel Quedillac, Dimitar Raev, Carlos Antonio Raffo Grado, Sidiqullah Rahimi, Arturo Raisaro, Bhola Rama, Ricardo Ramos, Maria Ranieri, Nuno Raposo, Eric Rashba, Ursula Rauch-Kroehnert, Ramakota Reddy, Giulia Renda, Shabbir Reza, Luigi Ria, Dimitrios Richter, Hans Rickli, Werner Rieker, Tomas Ripolil Vera, Luiz Eduardo Ritt, Douglas Roberts, Ignacio Rodriguez Briones, Aldo Edwin Rodriguez Escudero, Carlos Rodríguez Pascual, Mark Roman, Francesco Romeo, E. Ronner, Jean-Francois Roux, Nadezda Rozkova, Miroslav Rubacek, Frank Rubalcava, Andrea M. Russo, Matthieu Pierre Rutgers, Karin Rybak, Samir Said, Tamotsu Sakamoto, Abraham Salacata, Adrien Salem, Rafael Salguero Bodes, Marco A. Saltzman, Alessandro Salvioni, Gregorio Sanchez Vallejo, Marcelo Sanmartín Fernández, Wladmir Faustino Saporito, Kesari Sarikonda, Taishi Sasaoka, Hamdi Sati, Irina Savelieva, Pierre-Jean Scala, Peter Schellinger, Carlos Scherr, Lisa Schmitz, Karl-Heinz Schmitz, Bettina Schmitz, Teresa Schnabel, Steffen Schnupp, Peter Schoeniger, Norbert Schön, Peter Schwimmbeck, Clare Seamark, Greg Searles, Karl-Heinz Seidl, Barry Seidman, Jaroslaw Sek, Lakshmanan Sekaran, Carlo SERRATI, Neerav Shah, Vinay Shah, Anil Shah, Shujahat Shah, Vijay Kumar Sharma, Louise Shaw, Khalid H. Sheikh, Naruhito Shimizu, Hideki Shimomura, Dong-Gu Shin, Eun-Seok Shin, Junya Shite, Gerolamo Sibilio, Frank Silver, Iveta Sime, Tim A. Simmers, Narendra Singh, Peter Siostrzonek, Didier Smadja, David W. Smith, Marcelo Snitman, Dario Sobral Filho, Hassan Soda, Carl Sofley, Adam Sokal, Yannie Soo Oi Yan, Rodolfo Sotolongo, Olga Ferreira de Souza, Jon Arne Sparby, Jindrich Spinar, David Sprigings, Alex C. Spyropoulos, Dimitrios Stakos, Clemens Steinwender, George Stergiou, Ian Stiell, Marcus Stoddard, Anastas Stoikov, Witold Streb, Ioannis Styliadis, Guohai Su, Xi Su, Wanda Sudnik, Kai Sukles, Xiaofei Sun, H. Swart, Janko Szavits-Nossan, Jens Taggeselle, Yuichiro Takagi, Amrit Pal Singh Takhar, Angelika Tamm, Katsumi Tanaka, Tanyanan Tanawuttiwat, Sherman Tang, Aylmer Tang, Giovanni Tarsi, Tiziana Tassinari, Ashis Tayal, Muzahir Tayebjee, J.M. ten Berg, Dan Tesloianu, Salem H.K. The, Dierk Thomas, Serge Timsit, Tetsuya Tobaru, Andrzej R. Tomasik, Mikhail Torosoff, Emmanuel Touze, Elina Trendafilova, W. Kevin Tsai, Hung Fat Tse, Hiroshi Tsutsui, Tian Ming Tu, Ype Tuininga, Minang Turakhia, Samir Turk, Wayne Tcurner, Arnljot Tveit, Richard Tytus, C. Valadão, P.F.M.M. van Bergen, Philippe van de Borne, B.J. van den Berg, C. van der Zwaan, M. Van Eck, Peter Vanacker, Dimo Vasilev, Vasileios Vasilikos, Maxim Vasilyev, Srikar Veerareddy, Mario Vega Miño, Asok Venkataraman, Paolo Verdecchia, Francesco Versaci, Ernst Günter Vester, Hubert Vial, Jason Victory, Alejandro Villamil, Marc Vincent, Anthony Vlastaris, Jürgen vom Dahl, Kishor Vora, Robert B. Vranian, Paul Wakefield, Ningfu Wang, Mingsheng Wang, Xinhua Wang, Feng Wang, Tian Wang, Alberta L. Warner, Kouki Watanabe, Jeanne Wei, Christian Weimar, Stanislav Weiner, Renate Weinrich, Ming-Shien Wen, Marcus Wiemer, Preben Wiggers, Andreas Wilke, David Williams, Marcus L. Williams, Bernhard Witzenbichler, Brian Wong, Ka Sing Lawrence Wong, Beata Wozakowska-Kaplon, Shulin Wu, Richard C. Wu, Silke Wunderlich, Nell Wyatt, John (Jack) Wylie, Yong Xu, Xiangdong Xu, Hiroki Yamanoue, Takeshi Yamashita, Ping Yen Bryan Yan, Tianlun Yang, Jing Yao, Kuo-Ho Yeh, Wei Hsian Yin, Yoto Yotov, Ralf Zahn, Stuart Zarich, Sergei Zenin, Elisabeth Louise Zeuthen, Huanyi Zhang, Donghui Zhang, Xingwei Zhang, Ping Zhang, Jun Zhang, Shui Ping Zhao, Yujie Zhao, Zhichen Zhao, Yang Zheng, Jing Zhou, Sergio Zimmermann, Andrea Zini, Steven Zizzo, Wenxia Zong, L Steven Zukerman, Cardiology, ACS - Heart failure & arrhythmias, Ntaios G., Huisman M.V., Diener H.-C., Halperin J.L., Teutsch C., Marler S., Gurusamy V.K., Thompson M., Lip G.Y.H., Olshansky B., Abban D.W., Abdul N., Abud A.M., Adams F., Addala S., Adragao P., Ageno W., Aggarwal R., Agosti S., Agostoni P., Aguilar F., Linares J.A., Aguinaga L., Ahmed J., Aiello A., Ainsworth P., Aiub J.R., Al-Dallow R., Alderson L., Aldrete Velasco J.A., Alexopoulos D., Manterola F.A., Aliyar P., Alonso D., Alves da Costa F.A., Amado J., Amara W., Amelot M., Amjadi N., Ammirati F., Andrade M., Andrawis N., Annoni G., Ansalone G., Ariani M.K., Arias J.C., Armero S., Arora C., Aslam M.S., Asselman M., Audouin P., Augenbraun C., Aydin S., Ayryanova I., Aziz E., Backes L.M., Badings E., Bagni E., Baker S.H., Bala R., Baldi A., Bando S., Banerjee S., Bank A., Esquivias G.B., Barr C., Bartlett M., Kes V.B., Baula G., Behrens S., Bell A., Benedetti R., Mazuecos J.B., Benhalima B., Bergler-Klein J., Berneau J.-B., Bernstein R.A., Berrospi P., Berti S., Berz A., Best E., Bettencourt P., Betzu R., Bhagwat R., Bhatta L., Biscione F., BISIGNANI G., Black T., Bloch M.J., Bloom S., Blumberg E., Bo M., Bohmer E., Bollmann A., Bongiorni M.G., Boriani G., Boswijk D.J., Bott J., Bottacchi E., Kalan M.B., Bradman D., Brautigam D., Breton N., Brouwers P.J.A.M., Browne K., Cortada J.B., Bruni A., Brunschwig C., Buathier H., Buhl A., Bullinga J., Cabrera J.W., Caccavo A., Cai S., Caine S., Calo L., Calvi V., Sanchez M.C., Candeias R., Capuano V., Capucci A., Caputo R., Rizo T.C., Cardona F., Carlos da Costa Darrieux F., Duarte Vera Y.C., Carolei A., Carreno S., Carvalho P., Cary S., Casu G., Cavallini C., Cayla G., Celentano A., Cha T.-J., Cha K.S., Chae J.K., Chalamidas K., Challappa K., Chand S.P., Chandrashekar H., Chartier L., Chatterjee K., Chavez Ayala C.A., Cheema A., Chen L., Chen S.-A., Chen J.H., Chiang F.-T., Chiarella F., Chih-Chan L., Cho Y.K., Choi J.-I., Choi D.J., Chouinard G., Hoi-Fan Chow D., Chrysos D., Chumakova G., Jose Roberto Chuquiure Valenzuela E.J., Nica N.C., Cislowski D.J., Clay A., Clifford P., Cohen A., Cohen M., Cohen S., Colivicchi F., Collins R., Colonna P., Compton S., Connolly D., Conti A., Buenostro G.C., Coodley G., Cooper M., Coronel J., Corso G., Sales J.C., Cottin Y., Covalesky J., Cracan A., Crea F., Crean P., Crenshaw J., Cullen T., Darius H., Dary P., Dascotte O., Dauber I., Davalos V., Davies R., Davis G., Davy J.-M., Dayer M., De Biasio M., De Bonis S., De Caterina R., De Franceschi T., de Groot J.R., De Horta J., De La Briolle A., Topete G.D.L.P., Vicenzo de Paola A.A., de Souza W., de Veer A., De Wolf L., Decoulx E., Deepak S., Defaye P., Del-Carpio Munoz F., Brkljacic D.D., Deumite N.J., Di Legge S., Diemberger I., Dietz D., Dionisio P., Dong Q., Rossi dos Santos F., Dotcheva E., Doukky R., D'Souza A., Dubrey S., Ducrocq X., Dupljakov D., Duque M., Dutta D., Duvilla N., Duygun A., Dziewas R., Eaton C.B., Eaves W., Ebels-Tuinbeek L.A., Ehrlich C., Eichinger-Hasenauer S., Eisenberg S.J., El Jabali A., El Shahawy M., Hernandes M.E., Izal A.E., Evonich R., Evseeva O., Ezhov A., Fahmy R., Fang Q., Farsad R., Fauchier L., Favale S., Fayard M., Fedele J.L., Fedele F., Fedorishina O., Fera S.R., Gomes Ferreira L.G., Ferreira J., Ferri C., Ferrier A., Ferro H., Finsen A., First B., Fischer S., Fonseca C., Almeida L.F., Forman S., Frandsen B., French W., Friedman K., Friese A., Fruntelata A.G., Fujii S., Fumagalli S., Fundamenski M., Furukawa Y., Gabelmann M., Gabra N., Gadsboll N., Galinier M., Gammelgaard A., Ganeshkumar P., Gans C., Quintana A.G., Gartenlaub O., Gaspardone A., Genz C., Georger F., Georges J.-L., Georgeson S., Giedrimas E., Gierba M., Ortega I.G., Gillespie E., Giniger A., Giudici M.C., Gkotsis A., Glotzer T.V., Gmehling J., Gniot J., Goethals P., Goldbarg S., Goldberg R., Goldmann B., Golitsyn S., Gomez S., Mesa J.G., Gonzalez V.B., Gonzalez Hermosillo J.A., Gonzalez Lopez V.M., Gorka H., Gornick C., Gorog D., Gottipaty V., Goube P., Goudevenos I., Graham B., Greer G.S., Gremmler U., Grena P.G., Grond M., Gronda E., Gronefeld G., Gu X., Torres Torres I.G., Guardigli G., Guevara C., Guignier A., Gulizia M., Gumbley M., Gunther A., Ha A., Hahalis G., Hakas J., Hall C., Han B., Han S., Hargrove J., Hargroves D., Harris K.B., Haruna T., Hayek E., Healey J., Hearne S., Heffernan M., Heggelund G., Heijmeriks J.A., Hemels M., Hendriks I., Henein S., Her S.-H., Hermany P., Hernandez Del Rio J.E., Higashino Y., Hill M., Hisadome T., Hishida E., Hoffer E., Hoghton M., Hong K., Hong S.K., Horbach S., Horiuchi M., Hou Y., Hsing J., Huang C.-H., Huckins D., kathy Hughe, Huizinga A., Hulsman E.L., Hung K.-C., Hwang G.-S., Ikpoh M., Imberti D., Ince H., Indolfi C., Inoue S., Irles D., Iseki H., Israel C.N., Iteld B., Iyer V., Jackson-Voyzey E., Jaffrani N., Jager F., James M., Jang S.-W., Jaramillo N., Jarmukli N., Jeanfreau R.J., Jenkins R.D., Sanchez C.J., Jimenez J., Jobe R., Joen-Jakobsen T., Jones N., Moura Jorge J.C., Jouve B., Jung B.C., Jung K.T., Jung W., Kachkovskiy M., Kafkala K., Kalinina L., Kallmunzer B., Kamali F., Kamo T., Kampus P., Kashou H., Kastrup A., Katsivas A., Kaufman E., Kawai K., Kawajiri K., Kazmierski J.F., Keeling P., Kerr Saraiva J.F., Ketova G., Khaira A.S., Khripun A., Kim D.-I., Kim Y.H., Kim N.H., Kim D.K., Kim J.S., Kim K.S., Kim J.B., Kinova E., Klein A., Kmetzo J.J., Kneller G.L., Knezevic A., Angela Koh S.M., Koide S., Kollias A., Kooistra J.A., Koons J., Koschutnik M., Kostis W.J., Kovacic D., Kowalczyk J., Koziolova N., Kraft P., Kragten J.A., Krantz M., Krause L., Krenning B.J., Krikke F., Kromhout Z., Krysiak W., Kumar P., Kumler T., Kuniss M., Kuo J.-Y., Kuppers A., Kurrelmeyer K., Kwak C.H., Laboulle B., Labovitz A., Lai W.T., Lam A., Lam Y.Y., Zanetti F.L., Landau C., Landini G., Figueiredo E.L., Larsen T., Lavandier K., LeBlanc J., Lee M.H., Lee C.-H., Lehman J., Leitao A., Lellouche N., Lelonek M., Lenarczyk R., Lenderink T., Gonzalez S.L., Leong-Sit P., Leschke M., Ley N., Li Z., Li X., Li W., Lichy C., Lieber I., Limon Rodriguez R.H., Lin H., Liu F., Liu H., Esperon G.L., Navarro N.L., Lo E., Lokshyn S., Lopez A., Lopez-Sendon J.L., Lorga Filho A.M., Lorraine R.S., Luengas C.A., Luke R., Luo M., Lupovitch S., Lyrer P., Ma C., Ma G., Madariaga I., Maeno K., Magnin D., Maid G., Mainigi S.K., Makaritsis K., Malhotra R., Manning R., Manolis A., Manrique Hurtado H.A., Mantas I., Jattin F.M., Maqueda V., Marchionni N., Ortuno F.M., Santana A.M., Martinez J., Maskova P., Hernandez N.M., Matsuda K., Maurer T., Mauro C., May E., Mayer N., McClure J., McCormack T., McGarity W., McIntyre H., McLaurin B., Medina Palomino F.A., Melandri F., Meno H., Menzies D., Mercader M., Meyer C., Meyer B.J., Miarka J., Mibach F., Michalski D., Michel P., Chreih R.M., Mikdadi G., Mikus M., Milicic D., Militaru C., Minaie S., Minescu B., Mintale I., Mirault T., Mirro M.J., Mistry D., Miu N.V., Miyamoto N., Moccetti T., Mohammed A., Nor A.M., Mollerus M., Molon G., Mondillo S., Moniz P., Mont L., Montagud V., Montana O., Monti C., Moretti L., Mori K., Moriarty A., Morka J., Moschini L., Moschos N., Mugge A., Mulhearn T.J., Muresan C., Muriago M., Musial W., Musser C.W., Musumeci F., Nageh T., Nakagawa H., Nakamura Y., Nakayama T., Nam G.-B., Nanna M., Natarajan I., Nayak H.M., Naydenov S., Nazli J., Nechita A.C., Nechvatal L., Negron S.A., Neiman J., Neuenschwander F.C., Neves D., Neykova A., Miguel R.N., Nijmeh G., Nizov A., Campos R.N., Nossan J., Novikova T., Nowalany-Kozielska E., Nsah E., Nunez Fragoso J.C., Nurgalieva S., Nuyens D., Nyvad O., Odin de Los Rios Ibarra M., O'Donnell P., O'Donnell M., Oh S., Oh Y.S., Oh D., O'Hara G., Oikonomou K., Olivares C., Oliver R., Ruiz R.O., Olympios C., Anna omaszuk-Kazberuk, Asensi J.O., eena Padayattil jose, Padilla Padilla F.G., Rios V.P., Pajes G., Pandey A.S., Paparella G., Paris F., Park H.W., Park J.S., Parthenakis F., Passamonti E., Patel R.J., Patel J., Patel M., Patrick J., Jimenez R.P., Paz A., Pengo V., Pentz W., Perez B., Perez Rios A.M., Perez-Cabezas A., Perlman R., Persic V., Perticone F., Peters T.K., Petkar S., Pezo L.F., Pflucke C., Pham D.N., Phillips R.T., Phlaum S., Pieters D., Pineau J., Pinter A., Pinto F., Pisters R., Pivac N., Pocanic D., Podoleanu C., Politano A., Poljakovic Z., Pollock S., Garcea J.P., Poppert H., Porcu M., Reino A.P., Prasad N., Precoma D.B., Prelle A., Prodafikas J., Protasov K., Pye M., Qiu Z., Quedillac J.-M., Raev D., Raffo Grado C.A., Rahimi S., Raisaro A., Rama B., Ramos R., Ranieri M., Raposo N., Rashba E., Rauch-Kroehnert U., Reddy R., Renda G., Reza S., Ria L., Richter D., Rickli H., Rieker W., Vera T.R., Ritt L.E., Roberts D., Briones I.R., Rodriguez Escudero A.E., Pascual C.R., Roman M., Romeo F., Ronner E., Roux J.-F., Rozkova N., Rubacek M., Rubalcava F., Russo A.M., Rutgers M.P., Rybak K., Said S., Sakamoto T., Salacata A., Salem A., Bodes R.S., Saltzman M.A., Salvioni A., Vallejo G.S., Fernandez M.S., Saporito W.F., Sarikonda K., Sasaoka T., Sati H., Savelieva I., Scala P.-J., Schellinger P., Scherr C., Schmitz L., Schmitz K.-H., Schmitz B., Schnabel T., Schnupp S., Schoeniger P., Schon N., Schwimmbeck P., Seamark C., Searles G., Seidl K.-H., Seidman B., Sek J., Sekaran L., SERRATI C., Shah N., Shah V., Shah A., Shah S., Sharma V.K., Shaw L., Sheikh K.H., Shimizu N., Shimomura H., Shin D.-G., Shin E.-S., Shite J., Sibilio G., Silver F., Sime I., Simmers T.A., Singh N., Siostrzonek P., Smadja D., Smith D.W., Snitman M., Filho D.S., Soda H., Sofley C., Sokal A., Oi Yan Y.S., Sotolongo R., Ferreira de Souza O., Sparby J.A., Spinar J., Sprigings D., Spyropoulos A.C., Stakos D., Steinwender C., Stergiou G., Stiell I., Stoddard M., Stoikov A., Streb W., Styliadis I., Su G., Su X., Sudnik W., Sukles K., Sun X., Swart H., Szavits-Nossan J., Taggeselle J., Takagi Y., Singh Takhar A.P., Tamm A., Tanaka K., Tanawuttiwat T., Tang S., Tang A., Tarsi G., Tassinari T., Tayal A., Tayebjee M., Berg J.M.T., Tesloianu D., The S.H.K., Thomas D., Timsit S., Tobaru T., Tomasik A.R., Torosoff M., Touze E., Trendafilova E., Tsai W.K., Tse H.F., Tsutsui H., Tu T.M., Tuininga Y., Turakhia M., Turk S., Tcurner W., Tveit A., Tytus R., Valadao C., van Bergen P.F.M.M., van de Borne P., van den Berg B.J., van der Zwaan C., Van Eck M., Vanacker P., Vasilev D., Vasilikos V., Vasilyev M., Veerareddy S., Mino M.V., Venkataraman A., Verdecchia P., Versaci F., Vester E.G., Vial H., Victory J., Villamil A., Vincent M., Vlastaris A., Dahl J.V., Vora K., Vranian R.B., Wakefield P., Wang N., Wang M., Wang X., Wang F., Wang T., Warner A.L., Watanabe K., Wei J., Weimar C., Weiner S., Weinrich R., Wen M.-S., Wiemer M., Wiggers P., Wilke A., Williams D., Williams M.L., Witzenbichler B., Wong B., Lawrence Wong K.S., Wozakowska-Kaplon B., Wu S., Wu R.C., Wunderlich S., Wyatt N., Wylie J.J., Xu Y., Xu X., Yamanoue H., Yamashita T., Bryan Yan P.Y., Yang T., Yao J., Yeh K.-H., Yin W.H., Yotov Y., Zahn R., Zarich S., Zenin S., Zeuthen E.L., Zhang H., Zhang D., Zhang X., Zhang P., Zhang J., Zhao S.P., Zhao Y., Zhao Z., Zheng Y., Zhou J., Zimmermann S., Zini A., Zizzo S., Zong W., and Zukerman L.S.
Subjects: Oral, medicine.medical_specialty, anticoagulants, Vitamin K, medicine.drug_class, Medizin, Administration, Oral, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, Antithrombotic treatment, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, Internal medicine, Antithrombotic, medicine, non-vitamin-K antagonist oral anticoagulant, Diseases of the circulatory (Cardiovascular) system, Humans, SAMe-TT2R2, In patient, atrial fibrillation, 030212 general & internal medicine, Prospective Studies, Registries, Medical prescription, business.industry, Anticoagulant, non-vitamin-K antagonist oral, Atrial fibrillation, medicine.disease, non-vitamin-K antagonist oral anticoagulants, Clinical trial, Stroke, Treatment Outcome, SAMe-TT, RC666-701, 2, R, vitamin-K-antagonist oral anticoagulants, Administration, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, SAMe-TT R, Cardiology and Cardiovascular Medicine, business
Abstract: CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology
Published: 2021

18. Prosthetic Rehabilitation of a Patient Diagnosed With Sarcoidosis Using Dental Implants: A Clinical Case Report

Author: Martin James, Shakeel Shahdad, and Jay Matani
Subjects: Adult, Sarcoidosis, medicine.medical_treatment, Dentistry, Prosthesis, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, medicine, Tooth loss, Maxilla, Humans, Maxillary central incisor, Dental Restoration Failure, Dental implant, Radiation treatment planning, Dental Implants, Periodontitis as a manifestation of systemic disease, business.industry, Dental Implantation, Endosseous, 030206 dentistry, Periodontium, stomatognathic diseases, Treatment Outcome, 030228 respiratory system, Dental Prosthesis Design, Female, Implant, Dental Prosthesis, Implant-Supported, Oral Surgery, medicine.symptom, business
Abstract: No previously published studies have reported on the placement and restoration of dental implants in a patient diagnosed with sarcoidosis. Patients with sarcoidosis may develop periodontitis as a manifestation of systemic disease and are therefore at increased risk of tooth loss. These patients are likely to want fixed dental prostheses, which may need to be supported by dental implants. The case presented is that of a 31-year-old female patient presenting with a missing maxillary central incisor and a sarcoidal process affecting the anterior maxilla, which had severely compromised the periodontium of the adjacent lateral incisor. The patient was successfully rehabilitated with an implant-retained prosthesis following a staged horizontal and vertical bone augmentation procedure. At the 4-year review, the implant restoration performed well with stable peri-implant bone levels. We conclude that dental implant rehabilitation in patients with sarcoidosis may be a predictable treatment option, depending on disease stability and concurrent systemic therapy, but these patients will require additional maintenance because of the possibility of an increased risk of peri-implantitis. The effects of sarcoidosis and its management on the success of dental implants are discussed to aid treatment planning for such patients.
Published: 2020

19. Rapid mobilisation of research in response to covid-19: a paradigm for the future

Author: Gary A. Ford, Rustam Al-Shahi Salman, Martin James, and Thompson G. Robinson
Subjects: 2019-20 coronavirus outbreak, medicine.medical_specialty, Biomedical Research, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, 030204 cardiovascular system & hematology, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Government regulation, Pandemic, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, Stroke, Pandemics, biology, business.industry, SARS-CoV-2, COVID-19, General Medicine, biology.organism_classification, medicine.disease, Research studies, Government Regulation, business, Coronavirus Infections
Abstract: As clinical researchers in stroke we applaud the rapid mobilisation of research into covid-19 in response to this new global threat.1 Nearly 100 urgent research studies in covid-19 have been approved over the past few weeks, many of them complex trials that would have taken months or years to start before the pandemic.2 This has been made possible, in part, by streamlined and proportionate regulation and approvals. But …
Published: 2020

20. The cost of providing mechanical thrombectomy in the UK NHS: a micro-costing study

Author: Rachael Jones, Stephen Rice, Anand Dixit, Alastair Gray, Sanjeev Nayak, Lisa Foddy, Dawn Craig, Kurdow Nader, Robert Simister, Christine Roffe, Indira Natarajan, Joyce S. Balami, Hannah Lumley, Gary A. Ford, Darren Flynn, Phil White, Don Sims, David Burgess, Ivan Wiggam, Alastair M. Buchan, Beverley Hudson, Diamuid Coughlan, Martin James, J Chembala, Yazen Sammaraiee, Emer Hopkins, Peter Flynn, and Peter McMeekin
Subjects: medicine.medical_specialty, Total cost, 030204 cardiovascular system & hematology, State Medicine, law.invention, B800, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, law, medicine, Humans, General anaesthesia, 030212 general & internal medicine, Stroke, Reimbursement, Retrospective Studies, Thrombectomy, Original Research, Inpatient care, business.industry, Retrospective cohort study, General Medicine, A300, medicine.disease, Intensive care unit, Confidence interval, United Kingdom, B900, Emergency medicine, business
Abstract: Introduction The clinical efficacy and cost-effectiveness of mechanical thrombectomy (MT) for the treatment of large vessel occlusion stroke is well established, but uncertainty remains around the true cost of delivering this treatment within the NHS. The aim of this study was to establish the cost of providing MT within the hyperacute phase of care and to explore differences in resources used and costs across different neuroscience centres in the UK. Method This was a multicentre retrospective study using micro-costing methods to enable a precise assessment of the costs of MT from an NHS perspective. Data on resources used and their costs were collected from five UK neuroscience centres between 2015 and 2018. Results Data were collected on 310 patients with acute ischaemic stroke treated with MT. The mean total cost of providing MT and inpatient care within 24 hours was £10,846 (95% confidence interval (CI) 10,527–11,165) per patient. The main driver of cost was MT procedure costs, accounting for 73% (£7,943; 95% CI 7,649–8,237) of the total 24-hour cost. Costs were higher for patients treated under general anaesthesia (£11,048; standard deviation (SD) 2,654) than for local anaesthesia (£9,978; SD 2,654), mean difference £1,070 (95% CI 381–1,759; p=0.003); admission to an intensive care unit (ICU; £12,212; SD 3,028) against for admission elsewhere (£10,179; SD 2,415), mean difference £2,032 (95% CI 1,345–2,719; p The mean cost within 72 hours was £12,440 (95% CI 10,628–14,252). The total costs for the duration of inpatient care before discharge from a thrombectomy centre was £14,362 (95% CI 13,603–15,122). Conclusions Major factors contributing to costs of MT for stroke include consumables and staff for intervention, use of general anaesthesia and ICU admissions. These findings can inform the reimbursement, provision and strategic planning of stroke services and aid future economic evaluations.
Published: 2020

21. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy

Author: Jie Guo, Li-Chin Yao, Christopher P. Dillon, Wenlin Li, Stefano Crosignani, Karen A. Maegley, Danying Cai, Reece Marillier, Sandra Cauwenberghs, Manfred Kraus, Virginie Rabolli, Valeria Fantin, Benoît Van den Eynde, Deepak Dalvie, Joseph Tumang, Derek W. Bartlett, Martin James Wythes, Vince Torti, Xianxian Zheng, Sofie Denies, Gregory Driessens, Bruno Gomes, Nichol Miller, Konstantinos Tsaparikos, Nicole Streiner, Marie-Claire Letellier, Chad Ray, and Romain Pirson
Subjects: 0301 basic medicine, Cancer Research, Indoles, T-Lymphocytes, medicine.medical_treatment, Succinimides, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, Substrate Specificity, Immune tolerance, Interferon-gamma, 03 medical and health sciences, chemistry.chemical_compound, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, CTLA-4 Antigen, Enzyme Inhibitors, Indoleamine 2,3-dioxygenase, Kynurenine, Cell Proliferation, Mice, Inbred BALB C, Tumor microenvironment, Chemistry, Antibodies, Monoclonal, FOXP3, Stereoisomerism, Immunotherapy, Immune checkpoint, Mice, Inbred C57BL, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Biocatalysis, Cancer research, Female
Abstract: Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment. This leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As a nexus for the induction of key immunosuppressive mechanisms, IDO1 represents an important immunotherapeutic target in oncology. Here, we report the identification and characterization of the novel selective, orally bioavailable IDO1 inhibitor EOS200271/PF-06840003. It reversed IDO1-induced T-cell anergy in vitro. In mice carrying syngeneic tumor grafts, PF-06840003 reduced intratumoral kynurenine levels by over 80% and inhibited tumor growth both in monotherapy and, with an increased efficacy, in combination with antibodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti–PD-L1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDO1 inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a phase I open-label, multicenter clinical study (NCT02764151) has been initiated.
Published: 2018
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22. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

Author: Barbara J Meyer, Lars Kober, Richard Haynes, Martin Craig, Tuomas Kiviniemi, Tor Ole Klemsdal, Nicholas Mills, Steen Stender, Yue Li, Pia Thisted Dinesen, Martin James, Borislava Mihaylova, Jari Laukkanen, Aldo Pietro Maggioni, Martin Landray, Christie Ballantyne, Helle Klingenberg Iversen, Annett Salzwedel, Tarek Bekfani, Henrik Vadmann, Alastair Gray, Lucy Cureton, Tim Reynolds, Karl Wallendszus, Martin Bødtker Mortensen, Eri Kato, Gunnar Gislason, Fang Chen, Jemma Hopewell, TOBIAS DANIEL TRIPPEL, Timo Strandberg, Jonathan Emberson, Christopher Bellamy, and Caitrin McDonough
Subjects: Male, 0301 basic medicine, Atorvastatin, Clinical Trial, Phase III, Coronary Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, chemistry.chemical_compound, 0302 clinical medicine, Anacetrapib, Myocardial infarction, biology, Anticholesteremic Agents, Incidence, Research Support, Non-U.S. Gov't, General Medicine, Middle Aged, Multicenter Study, Cholesterol, Randomized Controlled Trial, Cardiology, Drug Therapy, Combination, Female, lipids (amino acids, peptides, and proteins), medicine.drug, medicine.medical_specialty, Statin, medicine.drug_class, Medication Adherence, 03 medical and health sciences, Double-Blind Method, Internal medicine, Cholesterylester transfer protein, Journal Article, medicine, Humans, Oxazolidinones, Aged, business.industry, Torcetrapib, ta3121, Atherosclerosis, medicine.disease, Cholesterol Ester Transfer Proteins, 030104 developmental biology, chemistry, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Evacetrapib
Abstract: BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .).
Published: 2017
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23. Congenital pleural effusions: 15 years single-centre experience from North-East England

Author: Janet E. Berrington, Naveen Athiraman, and Benjamin Martin James Shillitoe
Subjects: Male, Pediatrics, medicine.medical_specialty, Poor prognosis, Pleural effusion, North east, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, medicine, Humans, Retrospective Studies, business.industry, Mortality rate, Infant, Newborn, Obstetrics and Gynecology, Chylothorax, Retrospective cohort study, medicine.disease, Pleural Effusion, Single centre, England, Pediatrics, Perinatology and Child Health, Female, business, Live birth, 030217 neurology & neurosurgery
Abstract: AIM The aim of this study is to add to the scant literature on congenital pleural effusions to aid counselling and clinical management decisions. METHODS Retrospective case series of 15 years of congenital pleural effusions resulting in live birth in a single tertiary foetal medicine/neonatal centre in North East England. RESULTS Data were available for 21 infants. Mortality rates were 43% overall. All spontaneous resolution occurred within 9 d, and active management was used where effusions persisted beyond this. CONCLUSION Prematurity was associated with a poor prognosis. Resolution without active management occurred before day 10 and active strategies should be considered by this time.
Published: 2017
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24. Body dysmorphic disorder and facial aesthetic treatments in dental practice

Author: Martin James, Peter Clarke, and Rebecca Darcey
Subjects: Dental practice, medicine.medical_specialty, media_common.quotation_subject, Dentists, MEDLINE, Esthetics, Dental, 03 medical and health sciences, Presentation, 0302 clinical medicine, Surveys and Questionnaires, mental disorders, medicine, Prevalence, Humans, 030212 general & internal medicine, Patient group, General Dentistry, media_common, High prevalence, Physical health, 030206 dentistry, medicine.disease, Body Dysmorphic Disorders, Mental health, Family medicine, Body dysmorphic disorder, Psychology
Abstract: There is a relatively high prevalence of body dysmorphic disorder (BDD) and it is known that this patient group regularly and frequently visit dental practitioners, especially those who advertise themselves as cosmetic or aesthetic practices. The market for facial aesthetics is hugely increasing both generally and within dental practices making it ever more likely that dentists will encounter this patient group frequently. Moreover, due to the nature of their concerns individuals within this group are likely to have contact with dentists (or other medical professionals in the physical health field) prior to any contact with mental health professionals. The aim of this paper is to give an overview of the presentation of BDD, to discuss the changing climate of facial aesthetic treatments and to highlight a care pathway for general dentists. Identification of patients with potential BDD is far more predictable with the use of a validated questionnaire, and the BDD Questionnaire and Dysmorphic Concern Questionnaire are described. A flowchart approach for the management of patients requesting aesthetic improvements is presented as the ideal method for identifying, referring and managing the aesthetic treatment desires of potential BDD patients.
Published: 2019

25. A cross sectional study of dental implant service provision in British and Irish dental hospitals

Author: Martin James and Carly Taylor
Subjects: Dental Implants, Surgical team, Cross-sectional study, business.industry, medicine.medical_treatment, Dental prosthesis, Dental Implantation, Endosseous, Dentistry, medicine.disease, Prosthodontics, United Kingdom, stomatognathic diseases, Hypodontia, Cross-Sectional Studies, medicine, Humans, Implant, Dental Prosthesis, Implant-Supported, Dental implant, business, Restorative dentistry, General Dentistry, Ireland
Abstract: Introduction There are multiple ways in which treatment using dental implants is provided in a secondary care setting, not only in terms of the groups of patients treated, but also the clinicians who provide that care.Methods An online survey was circulated to speciality registrars in restorative dentistry in all UK dental hospitals and to postgraduate students in prosthodontics in the Republic of Ireland, consisting of nine questions aimed at understanding which patient groups are treated using dental implants in a hospital setting, how cases are planned, executed and to explore the underlying reasons for each unit's method of provision.Results Completed surveys were received from 67% of dental hospitals in Britain and Ireland. Treatment planning was undertaken by the restorative team alone in 64% of units in patients with hypodontia, 57% with trauma and 71% with an atrophic edentulous ridge and by a multi-disciplinary team in 50% of units for patients with cleft lip and palate (CLP) and 45% with head and neck (H&N) cancer. The restorative team place all or most of the implant fixtures in 50% of units in patients with CLP, 71% in trauma patients, 71% in hypodontia patients, 64% in edentulous patients and 43% in H&N oncology patients. Stents are produced and used by the restorative team in 64% of units for edentulous patients, 79% of patients with hypodontia, 79% of those suffering trauma, 58% of CLP patients and 50% of patients with H&N cancer. Twenty-one percent of responding units had stents made by the restorative team and used by the surgical team. The median percentage of implant-supported restorations that are screw retained is 90% (SD: 4.93, range: 25-95%) and the median percentage of zirconia abutments being used is 22.5% (SD: 5.24, range: 0-50%). Use of zygomatic implants varies hugely between responding units with 43% of them not placing any zygomatic implants.Conclusions There is a wide range of protocols and team members involved in the provision of dental implant rehabilitations throughout the British Isles reflecting the lack of any single evidence-based approach. A multi-disciplinary team approach with the restorative dentist as a key member is likely to yield the most favourable long term outcomes.
Published: 2019

26. An update on X-Linked agammaglobulinaemia: clinical manifestations and management

Author: Benjamin Martin James Shillitoe and Andrew R. Gennery
Subjects: medicine.medical_specialty, Recurrent respiratory tract infections, Bronchiectasis, Delayed Diagnosis, Research areas, business.industry, Genetic enhancement, Immunology, MEDLINE, Immunoglobulins, Intravenous, X linked agammaglobulinaemia, Genetic Therapy, medicine.disease, X-Linked Combined Immunodeficiency Diseases, Mice, Lung disease, Agammaglobulinemia, medicine, Immunology and Allergy, Animals, Humans, Intensive care medicine, business, Cohort study
Abstract: Purpose of review X-linked agammaglobulinaemia (XLA) is a congenital defect of development of B lymphocytes leading to agammaglobulinaemia. It was one of the first primary immunodeficiencies described, but treatment has remained relatively unchanged over the last 60 years. This summary aims to outline the current outcomes, treatments and future research areas for XLA. Recent findings Immunoglobulin therapy lacks IgA and IgM, placing patients at theoretical risk of experiencing recurrent respiratory tract infections and developing bronchiectasis despite best current therapy. Recent cohort studies from Italy and the USA conform that bronchiectasis remains a major burden for this group despite best current efforts. However, gene therapy offers a potential cure for these patients with proven proof of concept murine models. Summary The potential limitations of current immunoglobulin therapy appear to be confirmed by recent cohort studies, and therefore further work in the development of gene therapy is warranted. Until this is available, clinicians should strive to reduce the diagnostic delay, regularly monitor for lung disease and individualize target immunoglobulin doses to reduce infection rates for their patients.
Published: 2019

27. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Author: Rustam Al-Shahi Salman, David P Minks, Dipayan Mitra, Mark A Rodrigues, Priya Bhatnagar, Johann C du Plessis, Yogish Joshi, Martin S Dennis, Gordon D Murray, David E Newby, Peter A G Sandercock, Nikola Sprigg, Jacqueline Stephen, Cathie L M Sudlow, David J Werring, William N Whiteley, Joanna M Wardlaw, Philip M White, Colin Baigent, Daniel Lasserson, Frank Sullivan, Johanna Carrie, Javier Rojas, Shannon Amoils, John Bamford, Jane Armitage, Gabriel Rinkel, Gordon Lowe, Jonathan Emberson, Karen Innes, Lynn Dinsmore, Jonathan Drever, Carol Williams, David Perry, Connor McGill, David Buchanan, Allan Walker, Aidan Hutchison, Christopher Matthews, Ruth Fraser, Aileen McGrath, Ann Deary, Rosemary Anderson, Pauli Walker, Christian Hansen, Richard Parker, Aryelly Rodriguez, Malcolm Macleod, Thomas Gattringer, Jeb Palmer, Eleni Sakka, Jennifer Adil-Smith, David Minks, Johannes du Plessis, Christine Lerpiniere, Richard O'Brien, Seona Burgess, Gillian Mead, Ruth Paulton, Fergus Doubal, Katrina McCormick, Neil Hunter, Pat Taylor, Ruwan Parakramawansha, Jack Perry, Gordon Blair, Allan MacRaild, Adrian Parry-Jones, Mary Johnes, Stephanie Lee, Kelly Marie Shaw, Ilse Burger, Martin Punter, Andrea Ingham, Jane Perez, Zin Naing, Jordi Morell, Tracy Marsden, Andrea Hall, Sally Marshall, Louise Harrison, Rowilson Jarapa, Edith Wood, Victoria O'Loughlin, David Cohen, Silvie Davies, Kelechi Njoku, Mushiya Mpelembue, Laura Burgess, Radim Licenik, Mmua Ngwako, Nabeela Nisar, Rangah Niranchanan, Tatjana Roganova, Rajaram Bathula, Joseph Devine, Anette David, Anne Oshodi, Fenglin Guo, Emmanuelle Owoyele, Varthi Sukdeo, Robert Ballantine, Mudhar Abbdul-saheb, Angela Chamberlain, Aberami Chandrakumar, Philip Poku, Kirsty Harkness, Catrin Blank, Emma Richards, Ali Ali, Faith Kibutu, Olesia Balitska, Kathryn Birchall, Pauline Bayliss, Clare Doyle, Kathy Stocks, Arshad Majis, Jo Howe, Christine Kamara, Luke Barron, Ahmad Maatouk, Ralf Lindert, Katy Dakin, Jessica Redgrave, Biju Bhaskaran, Isam Salih, Debs Kelly, Susan Szabo, Dawn Tomlin, Helen Bearne, Jean Buxton, Pauline Fitzell, Georgina Ayres, Afaq Saulat, Kathleen Horan, Joanne Garfield-Smith, Harbens Bhakri, Paul Guyler, Devesh Sinha, Thayalini Loganathan, Amber Siddiqui, Anwer Siddiqui, Lucy Coward, Swapna Kunhunny, Sharon Tysoe, Rajalakshmi Orath Prabakaran, Shyam Kelavkar, Sindhu Rashmi, David Ngo, Kheng Xiong Ng, Nisha Menon, Sweni Shah, Mark Barber, Derek Esson, Fiona Brodie, Talat Anjum, Mushtaq Wani, Manju Krishnan, Leanne Quinn, Jayne Spencer, Terry Jones, Helen Thompson-Jones, Lynne Dacey, Srikanth Chenna, Sharon Storton, Sarah Thomas, Teresa Beaty, Shelley Treadwell, Caroline Davies, Susan Tucker, Lynda Connor, Peter Slade, Glyn Gainard, Girish Muddegowda, Ranjan Sanyal, Alda Remegoso, Nenette Abano, Chelsea Causley, Racquel Carpio, Stephanie Stevens, Adrian Butler, Resti Varquez, Hayley Denic, Francis Alipio, Andrew Moores, Adrian Barry, Holly Maguire, Jeanette Grocott, Kay Finney, Sue Lyjko, Christine Roffe, Joanne Hiden, Phillip Ferdinand, Vera Cvoro, Khalil Ullah, Nicola Chapman, Mandy Couser, Susan Pound, Sean Mcauley, Senthil Raghunathan, Faye Shelton, Amanda Hedstrom, Margi Godfrey, Diane Havard, Amanda Buck, Kailash Krishnan, Nicola Gilzeane, Jack Roffe, Judith Clarke, Katherine Whittamore, Saima Sheikh, Rekha Keshvara, Carla Jordan, Benjamin Jackson, Gwendoline Wilkes, Jason Appleton, Zhe Law, Oliver Matias, Evangelos Vasileiadis, Cathy Mason, Anthea Parry, Geraldine Landers, Melinda Holden, Basaam Aweid, Khalid Rashed, Linda Balian, Carinna Vickers, Elizabeth Keeling, Sarah Board, Joanna Allison, Clare Buckley, Barbara Williams-Yesson, Joanne Board, Tressy Pitt-Kerby, Alfonso Tanate, Diane Wood, Manohar Kini, Dinesh Chadha, Deborah Walstow, Rosanna Fong, Robert Luder, Tolu Adesina, Jill Gallagher, Hayley Bridger, Elodie Murali, Maneesh Bhargava, Chloe van Someren, Frances Harrington, Abhijit Mate, Ali James, Gillian Courtauld, Christine Schofield, Katja Adie, Linda Lucas, Kirsty Bond, Bev Maund, Sam Ellis, Paul Mudd, Martin James, Samantha Keenan, Angela Bowring, Julie Cageao, Hayley Kingwell, Caroline Roughan, Anthony Hemsley, Jane Sword, David Strain, Keniesha Miller, Anita Goff, Karin Gupwell, Kevin Thorpe, Hedley Emsley, Shuja Punekar, Alison McLoughlin, Sulaiman Sultan, Bindu Gregory, Sonia Raj, Donna Doyle, Keith Muir, Wilma Smith, Angela Welch, Fiona Moreton, Bharath Kumar Cheripelli, Salwa El Tawil, Dheeraj Kalladka, Xuya Huang, Nicola Day, Sankaranarayanan Ramachandran, Caroline Crosbie, Jennifer Elliot, Tony Rudd, Katherine Marks, Ajay Bhalla, Jonathan Birns, Sagal Kullane, Nic Weir, Christopher Allen, Vanessa Pressly, Pam Crawford, Emma Battersby-Wood, Alex Blades, Shuna Egerton, Ashleigh Walters, Sue Evans, James Richard Marigold, Fiona Smith, Gabriella Howard, Imogen Gartrell, Simon Smith, Robyn Creeden, Chloe Cox, Cherish Boxall, Jonathan Hewitt, Claire Nott, Procter Sarah, Jessica Whiteman, Steve Buckle, Rebecca Wallace, Rina Mardania, Jane Gray, Claire Triscott, Anand Nair, Jill Greig, Pratap Rana, Matthew Robinson, Mohammad Irfan Alam, David Werring, Duncan Wilson, Caroline Watchurst, Maria Brezitski, Luci Crook, Ifan Jones, Azra Banaras, Krishna Patel, Renuka Erande, Caroline Hogan, Isabel Hostettler, Amy Ashton, Shez Feerick, Nina Francia, Nnebuife Oji, Emma Elliott, Talal Al-Mayhani, Martin Dennis, Cathie Sudlow, William Whiteley, Dipankar Dutta, Pauline Brown, Deborah Ward, Fiona Davis, Jennifer Turfrey, Chloe Hughes, Kayleigh Collins, Rehana Bakawala, Susan O'Connell, Jon Glass, David Broughton, Dinesh Tryambake, Lynn Dixon, Kath Chapman, Andrew Young, Adrian Bergin, Andrew Sigsworth, Aravind Manoj, Glyn Fletcher, Paula Lopez, Penelope Cox, Mark Wilkinson, Paul Fitzsimmons, Nikhil Sharma, James Choulerton, Denise Button, Lindsey Dow, Lukuman Gbadamoshi, Joanne Avis, Barbara Madigan, Stephanie McCann, Louise Shaw, Deborah Howcroft, Suzanne Lucas, Andrew Stone, Gillian Cluckie, Caroline Lovelock, Brian Clarke, Neha Chopra, Natasha Clarke, Bhavini Patel, Kate Kennedy, Rebecca Williams, Adrian Blight, Joanna O'Reilly, Chukwuka Orefo, Nilofer Dayal, Rita Ghatala, Temi Adedoyin, Fran Watson, Sarah Trippier, Lillian Choy, Barry Moynihan, Usman Khan, Val Jones, Naomi Jeyaraj, Lourda Kerin, Kamy Thavanesan, Divya Tiwari, Chantel Cox, Anja Ljubez, Laura Tucker, Arshi Iqbal, Caroline Bagnall, Marketa Keltos, Josh Roberts, Becky Jupp, Catherine Ovington, Emily Rogers, Owen David, Jo Bell, Barbara Longland, Gail Hann, Martin Cooper, Mohammad Nasar, Anoja Rajapakse, Inez Wynter, Ijaz Anwar, Helen Skinner, Tarn Nozedar, Damian McArdle, Balakrishna Kumar, Susan Crawford, Arunkumar Annamalai, Alex Ramshaw, Clare Holmes, Sarah Caine, Mairead Osborn, Emily Dodd, Peter Murphy, Nicola Devitt, Pauline Baker, Amy Steele, Lucy Belle Guthrie, Samantha Clarke, Ahamad Hassan, Dean Waugh, Emelda Veraque, Linetty Makawa, Mary Kambafwile, Marc Randall, Vasileios Papavasileiou, Claire Cullen, Jenny Peters, Hlaing Thant, Tanya Ingram, Mellor Zoe, Ramesh Durairaj, Melanie Harrison, Sarah Stevenson, Daniela Shackcloth, Jordan Ewing, Victoria Sutton, Mark McCarron, Jacqueline McKee, Mandy Doherty, Ferghal McVerry, Caroline Blair, Mary MacLeod, Janice Irvine, Heather Gow, Jacqueline Furnace, Anu Joyson, Baljit Jagpal, Sarah Ross, Katrina Klaasen, Sandra Nelson, Rebecca Clarke, Nichola Crouch, Beverly MacLennan, Vicky Taylor, Daniel Epstein, Avani Shukla, Vinodh Krishnamurthy, Paul Nicholas, Sammie Qureshi, Adam Webber, Justin Penge, Hawraman Ramadan, Stuart Maguire, Chris Patterson, Ruth Bellfield, Brigid Hairsine, Kelvin Stewart, Michaela Hooley, Outi Quinn, Bella Richard, Sally Moseley, Mandy Edwards, Heidi Lawson, Michelle Tayler, Yogish Pai, Mahesh Dhakal, Bernard Esisi, Sofia Dima, Gemma Marie Smith, Mark Garside, Muhammad Naeem, Vidya Baliga, Gill Rogers, Ellen Brown, David Bruce, Rachel Hayman, Susan Clayton, Ed Gamble, Rebecca Grue, Bethan Charles, Adam Hague, Sujata Blane, Caroline Lambert, Afnan Chaudhry, Thomas Harrison, Kari Saastamoinen, Dionne Hove, Laura Howaniec, Gemma Grimwood, Ozlem Redjep, Fiona Humphries, Lucia Argandona, Larissa Cuenoud, Esther Erumere, Sageet Amlani, Grace Auld, Afraim Salek-Haddadi, Ursula Schulz, James Kennedy, Gary Ford, Philip Mathieson, Ian Reckless, Rachel Teal, Giulia Lenti, George Harston, Eoin O'Brien, Joanne Mcgee, Jennifer Mitchell, Elaine Amis, Dominic Handley, Siobhan Kelly, George Zachariah, Jobbin Francis, Sarah Crisp, Juliana Sesay, Sarah Finlay, Helen Hayhoe, Niamh Hannon, Tom Hughes, Bethan Morse, Henry De Berker, Emma Tallantyre, Ahmed Osman, Susan White, Stefan Schwarz, Benjamin Jelley, Rajendra Yadava, Khalid Azhar, Julie Reddan, Mirriam Sangombe, Samantha Stafford, Ken Fotherby, Debbie Morgan, Farrukh Baig, Karla Jennings-Preece, Donna Butler, Nasar Ahmad, Angela Willberry, Angela Stevens, Baljinder Rai, Prasad Siddegowda, Peter Howard, Lisa Hyatt, Tracey Dobson, David Jarrett, Suheil Ponnambath, Jane Tandy, Yasmin Harrington-Davies, Rebecca Butler, Claire James, Stacey Valentine, Anne Suttling, Peter Langhorne, Gillian Kerr, Fiona Wright, Ruth Graham, Christine McAlpine, Mohammad Shahzad Iqbal, Louise Humphreys, Kath Pasco, Olga Balazikova, Ashraf Nasim, Cassilda Peixoto, Louise Gallagher, Shahrzad Shahmehri, Sandip Ghosh, Elizabeth Barrie, Danielle Gilmour, Margo Henry, Tom Webb, Linda Cowie, Hannah Rudenko, Shanni McDonald, Natasha Schumacher, Susannah Walker, Tracey Cosier, Anna Verrion, Eva Beranova, Audrey Thomson, Marius Venter, Arindam Kar, Sheila Mashate, Kirsten Harvey, Léjeune Gardener, Vinh Nguyen, Omid Halse, Olivia Geraghty, Beth Hazel, Peter Wilding, Victoria Tilley, Tim Cassidy, Beverley McClelland, Maria Bokhari, Timothy England, Mohana Maddula, Richard Donnelly, Paul Findlay, Ashish Macaden, Ian Shread, Charlotte Barr, Azlisham Mohd Nor, Claire Brown, Nicola Persad, Charlotte Eglinton, Marie Weinling, Benjamin Hyams, Alex Shah, John Baker, Anthony Byrne, Caroline McGhee, Amanda Smart, Claire Copeland, Michael Carpenter, Marion Walker, Richard Davey, Ann Needle, Razik Fathima, Gavin Bateman, Prabal Datta, Andrew Stanners, Linda Jackson, Julie Ball, Michelle Davis, Natalie Atkinson, Michelle Fawcett, Teresa Thompson, Helen Guy, Valerie Hogg, Carole Hays, Stephen Woodward, Mohammad Haque, Eluzai Hakim, Stuart Symonds, Mehran Maanoosi, Jane Herman, Toby Black, Skelton Miriam, Caroline Clarke, Alpha Anthony, Michele Tribbeck, Julie Cronin, Denise Mead, Ruth Fennelly, James McIlmoyle, Christina Dickinson, Carol Jeffs, Sajjad Anwar, Joanne Howard, Kirsty Jones, Saikat Dhar, Caroline Clay, Muhammad Siddiq, Simone Ivatts, Yolanda Baird, Moore Sally, Isobel Amey, Sophie Newton, Lisa Clayton-Evans, Indra Chadbourn, Rayessa Rayessa, Charde Naylor, Alicia Rodgers, Lisa Wilson, Sarah Wilson, Emma Clarkson, Ruth Davies, Paula Owings, Graeme Sangster, Valerie Gott, Victoria Little, Pauline Weir, Suja Cherian, Deepa Jose, Helen Moroney, Susan Downham, Angela Dodd, Venetia Vettimootal Johnson, Laura Codd, Naomi Robinson, Ashraf Ahmed, Mo Albazzaz, Sharon Johnson, Carol Denniss, Mishell Cunningham, Tajammal Zahoor, Timothy Webster, Sandra Leason, Syed Haider, Kausic Chatterjee, Arumugam Nallasivan, Charlotte Perkins, Samantha Seagrave, Colin Jenkins, Fiona Price, Claire Hughes, Lily Mercer, Malik Hussain, Sarah Brown, Miriam Harvey, Jane Homan, Mohammad Khan, Robert Whiting, Leanne Foote, Nicholas Hunt, Helen Durman, Lucy Brotherton, Jayne Foot, Corinne Pawley, Eliza Foster, Alison Whitcher, Kneale Metcalf, Jenny Jagger, Susan McDonald, Kelly Waterfield, Patrick Sutton, Naval Shinh, Ajmal Anversha, Garth Ravenhill, Richard Greenwood, Janak Saada, Alison Wiltshire, Rebekah Perfitt, Sreeman Andole, Naveen Gadapa, Karen Dunne, Magdalini Krommyda, Evelyne Burssens, Sam King, Catherine Plewa, Nigel Smyth, Jenny Wilson, Elio Giallombardo, Lucy Sykes, Pradeep Kumar, James Barker, Isabel Huggett, Linda Dunn, Charlotte Culmsee, Philip Thomas, Min Myint, Helen Brew, Nikhil Majmudar, Janice OConnell, George Bunea, Charlotte Fox, Diane Gulliver, Andrew Smith, Betty Mokoena, Naweed Sattar, Ramesh Krishnamurthy, Emily Osborne, David Wilson, Belinda Wroath, Kevin Dynan, Michael Power, Susan Thompson, Victoria Adell, Enoch Orugun, Una Poultney, Rachel Glover, Hannah Crowther, Sarah Thornthwaite, Ivan Wiggam, Aine Wallace, Enda Kerr, Ailsa Fulton, Annemarie Hunter, Suzanne Tauro, Sarah Cuddy, David Mangion, Anne Hardwick, Skarlet Markova, Tara Lawrence, Carmen Constantin, Jo Fletcher, Isobel Thomas, Kerry Pettitt, Lakshmanan Sekaran, Margaret Tate, Kiranjit Bharaj, Rohan Simon, Frances Justin, Sakthivel Sethuraman, Duke Phiri, Niaz Mohammed, Meena Chauhan, Khaled Elfandi, Uzma Khan, David Eveson, Amit Mistri, Lisa Manning, Shagufta Khan, Champa Patel, Mohammed Moqsith, Saira Sattar, Man Yee Lam, Kashif Musarrat, Claire Stephens, Latheef Kalathil, Richard Miller, Maqsud Salehin, Nikki Gautam, Duncan Bailey, Kelly Amor, Julie Meir, Anne Nicolson, Javed Imam, Lisa Wood, Julie White, Mahmud Sajid, George Ghaly, Margaret Ball, Rachel Gascoyne, Harald Proeschel, Simon Sharpe, Sarah Horton, Emily Beaves, Stephanie Jones, Brigitte Yip, Murdina Bell, Linda MacLiver, Brian MacInnes, Don Sims, Jennifer Hurley, Mark Willmot, Claire Sutton, Edward Littleton, Susan Maiden, Rachael Jones, James Cunningham, Carole Green, Michelle Bates, Raj Shekhar, Ellie Gilham, Iman Ahmed, Rachel Crown, Tracy Fuller, Neetish Goorah, Angela Bell, Christine Kelly, Arun Singh, Jamie Walford, Benjamin Tomlinson, Farzana Patel, Stephen Duberley, Ingrid Kane, Chakravarthi Rajkumar, Jane Gaylard, Joanna Breeds, Nicola Gainsborough, Alexandra Pitt-Ford, Emma Barbon, Laura Latter, Philip Thompson, Simon Hervey, Shrivakumar Krishnamoorthy, Joseph Vassallo, Deborah Walter, Helen Cochrane, Meena Srinivasan, Robert Campbell, Denise Donaldson, Nichola Motherwell, Frances Hurford, Indranil Mukherjee, Antony Kenton, Sheila Nyabadza, Irene Martin, Benjamin Hunt, Hardi Hassan, Sarah O'Toole, Bander Dallol, Janet Putterill, Ratneshwari Jha, Rachel Gallifent, Puneet Kakar, Aparna Pusalkar, kelly Chan, Puneet Dangri, Hannah Beadle, Angela Cook, Karen Crabtree, Santhosh Subramonian, Peter Owusu-Agyei, Natalie Temple, Nicola Butterworth-Cowin, Suzanne Ragab, Kerstin Knops, Emma Jinks, Christine Dickson, Laura Gleave, Judith Dube, Jacqui Leggett, Tatiana Garcia, Sissy Ispoglou, Rachel Evans, Sandeep Ankolekar, Anne Hayes, Hlaing Ni, Bithi Rahman, Josette Milligan, Carol Graham, Josin Jose, Breffni Keegan, Jim Kelly, Richard Dewar, James White, Kelly Thomas, Rajkumar, C, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, University of St Andrews. Pure Mathematics, University of St Andrews. School of Psychology and Neuroscience, and University of St Andrews. School of Biology
Subjects: Male, MICROBLEEDS, 030204 cardiovascular system & hematology, AMYLOID ANGIOPATHY, Brain Ischemia, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Secondary Prevention, ACUTE ISCHEMIC-STROKE, Aged, 80 and over, Aspirin, Manchester Cancer Research Centre, medicine.diagnostic_test, Hazard ratio, Brain, Magnetic Resonance Imaging, Superficial siderosis, Cerebral Small Vessel Diseases, Stroke, Treatment Outcome, Female, medicine.drug, CT, medicine.medical_specialty, ANTITHROMBOTIC THERAPY, Clinical Neurology, Neuroimaging, Subgroup analysis, 03 medical and health sciences, Internal medicine, medicine, Journal Article, Humans, Aged, Cerebral Hemorrhage, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, DAS, Magnetic resonance imaging, medicine.disease, SIGNS, ASPIRIN, Neurology (clinical), Tomography, X-Ray Computed, business, SUPERFICIAL SIDEROSIS, Platelet Aggregation Inhibitors, 030217 neurology & neurosurgery
Abstract: Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.
Published: 2019
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28. Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase

Author: Dafydd R. Owen, Aiping Dong, Martin James Wythes, Steven Kennedy, Dalia Barsyte-Lovejoy, Matthieu Schapira, Hong Wu, Rajiah Aldrin Denny, Viacheslav V. Trush, Mihir D. Parikh, Agustin Casimiro-Garcia, Renato Ferreira de Freitas, Masoud Vedadi, Magdalena Swewczyk, Hong Zeng, Tatlock John H, Fengling Li, Alexandria P. Taylor, Robert Arnold Kumpf, Peter Brown, and Cheryl H. Arrowsmith
Subjects: Models, Molecular, S-Adenosylmethionine, Methyltransferase, Lysine, 01 natural sciences, Small Molecule Libraries, 03 medical and health sciences, Structure-Activity Relationship, Drug Discovery, Structure–activity relationship, Humans, Binding site, Enzyme Inhibitors, Enhancer, Cells, Cultured, 030304 developmental biology, Cell Proliferation, chemistry.chemical_classification, 0303 health sciences, Binding Sites, Dose-Response Relationship, Drug, Molecular Structure, Substrate (chemistry), Histone-Lysine N-Methyltransferase, Small molecule, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, Biochemistry, Molecular Medicine
Abstract: The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable.
Published: 2019

29. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS) : a pragmatic, double-blind, randomised, controlled trial

Author: Martin Dennis, Gillian Mead, John Forbes, Catriona Graham, Maree Hackett, Graeme J Hankey, Allan House, Stephanie Lewis, Erik Lundström, Peter Sandercock, Karen Innes, Carol Williams, Jonathan Drever, Aileen Mcgrath, Ann Deary, Ruth Fraser, Rosemary Anderson, Pauli Walker, David Perry, Connor Mcgill, David Buchanan, Yvonne Chun, Lynn Dinsmore, Emma Maschauer, Amanda Barugh, Shadia Mikhail, Gordon Blair, Ingrid Hoeritzauer, Maggie Scott, Greig Fraser, Katherine Lawrence, Alison Shaw, Judith Williamson, David Burgess, Malcolm Macleod, Dan Morales, Frank Sullivan, Marian Brady, Ray French, Frederike Van Wijck, Caroline Watkins, Fiona Proudfoot, Joanna Skwarski, Diane Mcgowan, Rachael Murphy, Seona Burgess, William Rutherford, Katrina Mccormick, Ruaridh Buchan, Allan Macraild, Ruth Paulton, Adnan Fazal, Pat Taylor, Ruwan Parakramawansha, Neil Hunter, Jack Perry, John Bamford, Dean Waugh, Emelda Veraque, Caroline Bedford, Mary Kambafwile, Luis Idrovo, Linetty Makawa, Paula Smalley, Marc Randall, Tharani Thirugnana-Chandran, Ahamad Hassan, Richard Vowden, Joanne Jackson, Ajay Bhalla, Anthony Rudd, Chi Kai Tam, Jonathan Birns, Charlotte Gibbs, Leonie Lee Carbon, Elizabeth Cattermole, Katherine Marks, Angela Cape, Lisa Hurley, Sagal Kullane, Nigel Smyth, Charlotte Eglinton, Jennifer Wilson, Elio Giallombardo, Angela Frith, Paul Reidy, Matthew Pitt, Lucy Sykes, Deborah Dellafera, Victoria Croome, Lauriane Kerwood, Mirea Hancevic, Christina Narh, Carley Merritt, John Duffy, Duncan Cooke, Juliet Willson, Ali Ali, Aaizza Naqvi, Christine Kamara, Helen Bowler, Simon Bell, Tracy Jackson, Kirsty Harkness, Kathy Stocks, Suzanna Duty, Clare Doyle, Geoffrey Dunn, Keith Endean, Fiona Claydon, Emma Richards, Jo Howe, Ralf Lindert, Arshad Majid, Katy Dakin, Ahmad Maatouk, Luke Barron, Madana Meegada, Pratap Rana, Anand Nair, Christine Brighouse-Johnson, Jill Greig, Myint Kyu, Sanjeev Prasad, Matthew Robinson, Irfan Alam, Belinda Mclean, Lindsay Greenhalgh, Zenab Ahmed, Christine Roffe, Susan Brammer, Carole Beardmore, Kay Finney, Adrian Barry, Paul Hollinshead, Jeanette Grocott, Holly Maguire, Indira Natarajan, Jayan Chembala, Ranjan Sanyal, Sue Lijko, Nenette Abano, Alda Remegoso, Phillip Ferdinand, Stephanie Stevens, Resti Varquez, Chelsea Causley, Adrian Butler, Philip Whitmore, Caroline Stephen, Racquel Carpio, Joanne Hiden, Girish Muddegowda, Hayley Denic, Jane Sword, Ross Curwen, Martin James, Paul Mudd, Fiona Hall, Julie Cageao, Samantha Keenan, Caroline Roughan, Hayley Kingwell, Anthony Hemsley, Christoph Lohan, Sue Davenport, Angela Bowring, Tamika Chapter, Max Hough, David Strain, Karin Gupwell, Keniesha Miller, Anita Goff, Ellie Cusack, Shirley Todd, Rebecca Partridge, Georgiana Jennings, Kevin Thorpe, Jacquelyn Stephenson, Kelly Littlewood, Mark Barber, Fiona Brodie, Steven Marshall, Derek Esson, Irene Coburn, Caroline Mcinnes, Fiona Ross, Emma Bowie, Heather Barcroft, Victoria Withers, Laura Miller, Paul Willcoxson, Michelle Donninson, Richard Evans, Di Daniel, John Coyle, Michael Keeling, Peter Wanklyn, Mark Elliott, John Wightman, Elizabeth Iveson, Natasha Dyer, Anne-Marie Porteous, Monica Haritakis, Mandy Ward, Lucy Doughty, Lisa Carr, Mark O Neill, Cosmas Anazodo, Paul Wood, Poppy Cottrell, Cheryl Donne, Romina Rodriguez, Ruhail Mir, Jax Westmoreland, Judith Bell, Christopher Emms, Lorraine Wright, Pearl Clark Brown, Elizabeth Bamford, Andrew Stanners, Mike Carpenter, Prabal Datta, Richard Davey, Ann Needle, Marjorie Jane Eastwood, Fathima Zeena Razik, Imran Ghouri, Gavin Bateman, Judy Archer, Venkatesh Balasubramanian, Richard Bowers, Julie Ball, Louise Benton, Linda Jackson, Julie Ellam, Kate Norton, Paul Guyler, Terry Dowling, Sharon Tysoe, Paula Harman, Ashish Kundu, Ololade Omodunbi, Thayalini Loganathan, Stuart Chandler, Shanas Noor, Anwer Siddiqui, Amber Siddiqui, Swapna Kunhunny, Devesh Sinha, Martin Sheppard, Sindhu Rashmi, Elena France, Rajalakshmi Orath Prabakaran, Laura Wilson, Amiirah Ropun, Shyam Kelavkar, Kheng Xiong Ng, Lucy Kamuriwo, Sweni Shah, David Mangion, Camen Constantin, Luigi De Michele Hock, Anne Hardwick, Jayne Borley, Skarlet Markova, Kimberley Netherton, Tara Lawrence, Jo Fletcher, Rebecca Spencer, Helen Palmer, Claire Cullen, Dolores Hamill, Ramesh Durairaj, Zoe Mellor, Tanya Fluskey, Diane Wood, Alison Keeling, Victoria Hankin, Jennifer Peters, Daniela Shackcloth, Thant Hlaing, Rebecca Tangney, Jordan Ewing, Melanie Harrison, Sarah Stevenson, Victoria Sutton, Mohamed Soliman, Julia Hindle, Elizabeth Watson, Claire Hewitt, Susie Butler, Ibrahim Wahishi, Sarwat Arif, Amy Fields, Jagdish Sharma, Rose Brown, Caroline Taylor, Sarah Bell, Simon Leach, Chris Patterson, Sophia Khan, Helen Wilson, Joanne Price, Hawraman Ramadan, Stuart Maguire, Ruth Bellfield, Michaela Hooley, Umair Hamid, Waqar Gaba, Robina Ghulam, Leslie Masters, Outi Quinn, Lakshmanan Sekaran, Margaret Tate, Niaz Mohammed, Kiranjit Bharaj, Frances Justin, Rajan Pattni, Lanka Alwis, Sakthivel Sethuraman, Rianne Robinson, Lianne Eldridge, Susan Mintias, Meena Chauhan, Chi-Kai Tam, Jeremias Palmones, Clare Holmes, Lucy Belle Guthrie, Mairead Osborn, Lindsay Ball, Sarah Caine, Amy Steele, Peter Murphy, Nikki Devitt, Jayne Leonard, Ronak Patel, Ian Penwarden, Emily Dodd, Amy Holloway, Pauline Baker, Samantha Clarke, Sandra Williams, Lindsey Dow, Roland Wynn-Williams, James Kennedy, Rachel Teal, Ursula Schulz, Gary Ford, Philip Mathieson, Ian Reckless, Ana Deveciana, Paige Mccann, Gillian Cluckie, Geoffrey Howell, Jonathan Ayer, Barry Moynihan, Rita Ghatala, Brian Clarke, Geoffrey Cloud, Bhavini Patel, Usman Khan, Nia Al-Samarrai, Sarah Trippier, Neha Chopra, Temi Adedoyin, Fran Watson, Val Jones, Liqun Zhang, Lillian Choy, Rebecca Williams, Natasha Clarke, Adrian Blight, Kate Kennedy, Alice Dainty, Johann Selvarajah, Dheeraj Kalladka, Bharath Cheripelli, Wilma Smith, Fiona Moreton, Angela Welch, Xuya Huang, Elizabeth Douglas, Audrey Lush, Nicola Day, Salwa El Tawil, Karen Montgomery, Helen Hamilton, Doreen Ritchie, Sankaranarayanan Ramachandra, Kirsty Mcleish, Kamy Thavanesan, Sathyabama Loganathan, Josh Roberts, Chantel Cox, Sarah Orr, Alison Hogan, Divya Tiwari, Gail Hann, Barbara Longland, Owen David, Jo Bell, Catherine Ovington, Emily Rogers, Rachel Bower, Marketa Keltos, David Cohen, Joseph Devine, Lankantha Alwis, Lucy Southworth, Laura Burgess, Matilda Lang, Bhavna Badiani, Fenglin Guo, Anne Oshodi, Emmanuelle Owoyele, Norah Epie, Anette David, Mushiya Mpelembue, Rajaram Bathula, Mudhar Abdul-Saheb, Angela Chamberlain, Varthi Sudkeo, Khalid Rashed, Barbara Williams-Yesson, Joanne Board, Sarah De Bruijn, Clare Buckley, Sarah Board, Joanna Allison, Elizabeth Keeling, Tracey Duckett, Dave Donaldson, Carinna Vickers, Claire Barron, Linda Balian, Jodhi Wilson, Adam Edwards, Timothy England, Amanda Hedstrom, Elizabeth Bedford, Margaret Harper, Elina Melikyan, Wendy Abbott, Kashmira Subramanian, Marie Goldsworthy, Meena Srinivasan, Angela Yeomans, Denise Donaldson, Frances Hurford, Riquella Chapman, Sana Shahzad, Nicki Motherwell, Louise Tonks, Rachel Young, Usman Ghani, Indranil Mukherjee, Dipankar Dutta, Mudhar Obaid, Pauline Brown, Fiona Davis, Deborah Ward, Jennifer Turfrey, Bethan Cartwright, Bilal Topia, Judith Spurway, Kayleigh Collins, Rehana Bakawala, Chloe Hughes, Susan Oconnell, Linda Hill, Kausik Chatterjee, Tim Webster, Syed Haider, Pamela Rushworth, Fiona Macleod, Arumugam Nallasivan, Charlotte Perkins, Edel Burns, Sandra Leason, Tom Carter, Samantha Seagrave, Eman Sami, Lisa Armstrong, Syed Naseem Naqvi, Muhammad Hassan, Sharron Parkinson, Samantha Mawer, Gillian Darnbrook, Carl Booth, Brigid Hairsine, Matthew Smith, Sue Williamson, Fiona Farquhar, Bernard Esisi, Tim Cassidy, Gavin Mankin, Beverley Mcclelland, Maria Bokhari, David Sproates, Elliot Epstein, Steve Hurdowar, Ruth Blackburn, Nazran Sukhdeep, Saika Razak, Khalid Osman, Amina Hashmi, Natasha Upton, Frances Harrington, Gillian Courtauld, Christine Schofield, Linda Lucas, Katja Adie, Kirsty Bond, Abhijit Mate, Jo Skewes, Ali James, Carolyn Brodie, Matthew Johnson, Linda Allsop, Emma Driver, Karina Harris, Mark Drake, Sam Ellis, Bev Maund, Emma Thomas, Kimberley Moore, Matthew Burn, Adam Hamilton, Shageetha Mahalingam, Amulya Misra, Farrah Reid, Adrienne Benford, Derek Hilton, Lorraine Hazell, Keziah Ofori, Anne Louise Thomas, Moncy Mathew, Sonia Dayal, Iona Burn, Kenneth Fotherby, Karla Jennings-Preece, Angela Willberry, Debbie Morgan, Donna Butler, Gurminder Sahota, Kelly Kauldhar, Nasar Ahmad, Angela Stevens, Saugata Das, David Bruce, Yogish Pai, Khin Nyo, Lynsey Stephenson, Richard Nendick, Gill Rogers, Mahesh Dhakal, Sofia Dima, Ellen Brown, Susan Clayton, Penny Gamble, Muhammad Naeem, Rachel Hayman, Rachel Burnip, Philip Earnshaw, David Hargroves, Barbara Ransom, Hannah Rudenko, Ibrahim Balogun, Kirsty Griffiths, Kim Mears, Tom Webb, Linda Cowie, Tessa Hammond, Audrey Thomson, Daniela Ceccarelli, Navraj Chattha, Eva Beranova, Anna Verrion, Andrew Gillian, Natasha Schumacher, Anna Bahk, Susannah Walker, Vera Cvoro, Nicola Chapman, Susan Pound, Rebecca Cain, Sean Mcauley, Mandy Couser, Maria Simpson, Athan Tachtatzis, Khalil Ullah, Don Sims, Rachael Jones, Jonathan Smith, Rebecca Tongue, Mark Willmot, Claire Sutton, Edward Littleton, Jattinder Khaira, Susan Maiden, James Cunningham, Carole Green, Yin-May Chin, Michelle Bates, Katherine Ahlquist, Ingrid Kane, Joanna Breeds, Tenesa Sargent, Laura Latter, Alexandra Pitt Ford, Nicola Gainsborough, Tom Levett, Philip Thompson, Emma Barbon, Angela Dunne, Simon Hervey, Suzanne Ragab, Tracy Sandell, Christine Dickson, Judith Dube, Sharon Power, Nick Evans, Beverley Wadams, Savina Elitova, Beth Aubrey, Tatiana Garcia, James Mcilmoyle, Carol Jeffs, Christina Dickinson, Anis Ahmed, Sanjeev Kumar, Julie Frudd, Charlotte Armer, Andrew Potter, Stacey Donaldson, Joanne Howard, Kirsty Jones, Saikat Dhar, David Collas, Saul Sundayi, Lynn Denham, Deepali Oza, Elaine Walker, Mohit Bhandari, Sissy Ispoglou, Rachel Evans, Kamel Sharobeem, Elaine Walton, Steven Shanu, Anne Hayes, Jennifer Howard-Brown, Steven Billingham, Nic Weir, Vanessa Pressly, Emma Wood, Gabriella Howard, Holly Burton, Pam Crawford, Shuna Egerton, Sue Evans, Jasmine Hakkak, Janet Andrews, Rebecca Lampard, Christopher Allen, Ashleigh Walters, Rasha Said, James Richard Marigold, Sau-Mon Tsang, Robyn Creeden, Chloe Cox, Simon Smith, Imogen Gartrell, Fiona Smith, Colin Jenkins, Joanna Pryor, Andrew Hedges, Fiona Price, Linda Moseley, Lily Mercer, Claire Hughes, Abul Azim, Julie White, Milena Krasinska-Chavez, Shaun Chaplin, James Curtis, Deepwant Singh, Javed Imam, Anne Nicolson, Sajid Alam, Simon Whitworth, Lisa Wood, Elizabeth Warburton, Siobhan Kelly, Joanne Mcgee, Hugh Markus, Denish Chandrasena, Derek Hayden, Juliana Sesay, Helen Hayhoe, Mark Bolton, Jane Macdonald, Jenny Mitchell, Charlotte Farron, Elaine Amis, Diana Day, Ainsley Culbert, Ailene Espanol, Niamh Hannon, Dominic Handley, Sarah Finlay, Sarah Crisp, Lynne Whitehead, Jobbin Francis, Janice Oconnell, Emily Osborne, Rod Beard, Ramesh Krishnamurthy, Langanani Mokoena, Naweed Sattar, Min Myint, Michelle Edwards, Andrew Smith, Paul Corrigan, Anthony Byrne, Joanne Blackburn, Caroline Mcghee, Amanda Smart, Fiona Donaldson, Claire Copeland, Jill Wilson, Rhona Scott, Paul Fitzsimmons, Paula Lopez, Mark Wilkinson, Aravindakshan Manoj, Penelope Cox, Leona Trainor, Glyn Fletcher, Lisa Denny, Karen Kavanagh, Hannah Allsop, Hedley Emsley, Sulaiman Sultan, Alison Mcloughlin, Benjamin Walmsley, Louise Hough, Shakeel Ahmed, Donna Doyle, Bindu Gregary, Sonia Raj, Kirubananthan Nagaratnam, Neelima Mannava, Nyla Haque, Norma Shields, Kate Preston, Geraldine Mason, Kirsty Short, Gemma Lumsdale, Giulia Uitenbosch, Ugnius Sukys, Stacey Valentine, David Jarrett, Kerry Dodsworth, Mary Wands, Nisa Khan, Jane Tandy, Catrin Watkinson, Wendy Golding, Rebecca Butler, Max Williams, Yasmin Davies, Keith Yip, Claire James, Anne Suttling, Aditya Maney, Giles Edward Gamble, Adam Hague, Bethan Charles, Sujata Blane, Beatriz Duran, Caroline Lambert, Katherine Stagg, Robert Whiting, Jane E Homan, Sarah Brown, Malik Hussain, Miriam Harvey, Libby Graham, Leanne Foote, Catherine Lane, Liz (Joan) Kemp, Joy Rowe, Helen Durman, Jayne Foot, Lucy Brotherton, Nicholas Hunt, Corinne Pawley, Alison Whitcher, Patrick Sutton, Susan Mcdonald, Denys Pak, Alison Wiltshire, Jennifer Jagger, Anthony K Metcalf, Gail Louise Healey, Joyce Balami, Clare Marie Self, Melissa Crofts, Annie Chakrabarti, Chit Hmu, Garth Ravenhill, Charmaine Grimmer, Thandar Soe, Jocelyn Keshet-Price, Margaret Langley, Ian Potter, Pui-Lin Tam, Mary Joan Macleod, Patricia Cooper, Michael Christie, Janice Irvine, Faye Annison, David Christie, Celia Meneses, Amber Johnson, Anu Joyson, Sandra Nelson, Vicky Taylor, John Reid, Rebecca Clarke, Jacqueline Furnace, Heather Gow, Youssif Abousleiman, Tania Beadling, Sally Collins, Stuart Jones, Jessica Purcell, Samantha Bloom, Shelly Goshawk, Marcial Landicho, Sivatharshini Sangaralingham, Yasmin Begum, Sherree Mutton, Elangovan Munuswamy Vaiyapuri, Jane Allen, Jemma Lowe, Martin Hughes, Ivan Wiggam, Sarah Cuddy, Suzanne Tauro, Brian Wells, Azlisham Mohd Nor, Nicola Persad, Maggie Kalita, Stuart Weatherby, Claire Brown, Adrian Pace, Daniel Lashley, Mike Marner, Marie Weinling, Natasha Wilmshurst, Darren Waugh, Anna Mucha, Alex Shah, John Baker, Jacqueline Westcott, Richard Cowan, Evangelos Vasileiadis, Samira Mumani, Anthea Parry, Cathy Mason, Melinda Holden, Katerina Petrides, Tomoko Nishiyama, Hina Mehta, Manju Krishnan, Dacey Lynne, Lisa Thomas, Connor Lynda, Catherine Hughes, Clare Clements, Rhys Williams, Tal Anjum, Storton Sharon, Susan Tucker, Paul Jones, Deanne Colwill, Helen Thompson Jones, Dinesh Chadha, Mark Fairweather, Deborah Walstow, Rosanna Fong, Stuart Johnston, Christine Almadenboyle, Sarah Ross, Shona Carson, Priya Nair, Emily Tenbruck, Mairi Stirling, Aparna Pusalkar, Hannah Beadle, Kelly Chan, Puneet Dangri, Asaipillai Asokanathan, Anita Rana, Sunita Gohil, Mark Massyn, Prabhu Aruldoss, Angela Cook, Karen Crabtree, Sura Dabbagh, Toby Black, Caroline Clarke, Denise Mead, Ruth Fennelly, Alpha Anthony, Linda Nardone, Victoria Dimartino, Michele Tribbeck, David Broughton, Dinesh Tryambake, Lynn Dixon, Agnieszka Skotnicka, Jane Thompson, Sarah Whitehouse, Andrew Sigsworth, Jason Wong, Arunkumar Annamalai, Julie Pagan, Brendan Affley, Caroline Sunderland, Lynda Goldenberg, Atif Khan, Peter Wilkinson, Raad Nari, Lucy Abbott, Emma Young, Amritpal Shakhon, Sally Lock, Jack Stewart, Rita Pereira, Margaret Dsouza, Sally Dunn, Anne-Marie Mckenna, Nina Cron, Michelle Kidd, Grace Hull, Kerry Bunworth, Graham Drummond, Karim Mahawish, Nicola Hayes, Lynne Connell, Jennifer Simpson, Helen Penney, Shuja Punekar, Joanne Nevinson, William Wareing, Jacqueline Ward, Richard Greenwood, Duncan Austin, Azra Banaras, Carolin Hogan, Thomas Corbett, Nnebuife Oji, Emma Elliott, Maria Brezitski, Nathalie Passeron, Laura Howaniec, Caroline Watchurst, Krishna Patel, Renuka Erande, Rahi Shah, Nabarun Sengupta, Maria Metiu, Celia Gonzalez, Sarah Funnell, Jordi Margalef, Gillian Peters, Indra Chadbourn, Ramachandran Sivakumar, Rajesh Saksena, Jane Ketley-O'donel, Richard Needle, Elaine Chinery, Alison Wright, Sue Cook, Joseph Ngeh, Harald Proeschel, Paige Cook, Pauline Ashcroft, Simon Sharpe, Stephanie Jones, Damian Jenkinson, Deborah Kelly, Holly Bray, Gunaratnam Gunathilagan, Sally Jones, Sorrell Tilbey, Saidu Abubakar, Joseph Vassallo, Dee Leonard, Lucy Orrell, Aziz Hasan, Asif Khan, Sulmaaz Qamar, Susan Graham, Emma Hewitt, Jennifer Awolesi, Muhammad Haque, Alissa Kent, Elizabeth Bradshaw, Martin Cooper, Inez Wynter, Anoja Rajapakse, Joumana Janbieh, Abu M Nasar, Lynne Wade, Linda Otter, Steve Haigh, Jamie-Rae Burgoyne, Rebecca Boulton, Andrew Boulton, Rayessa Rayessa, Emma Clarkson, Horne Rhian, Amy Fleming, Kim Mitchelson, Vicki Lowthorpe, Ahmed Abdul-Hamid, Phil Jones, Claire Duggan, Abigail Hynes, Emma Nurse, Syed Abid Raza, Sarah Jones, Udaya Pallikona, Bleddyn Edwards, Geraint Morgan, Kirsty Dennett, Helen Tench, Ronda Loosley, Toby Trugeon-Smith, Rhian Jones, Richard Williams, Donna Robson, Sunanda Mavinamane, Sanjeevi Meenakshisundaram, Lalitha Ranga, Sharon Dealing, Andrew Hill, Margaret Hargreaves, Tom Smith, Julie Bate, Linda Harrison, Ramanathan Kirthivasan, Emma Cannon, Joanne Topliffe, Rebecca Keskeys, Sarah Williams, Fiona Mcneela, Frances Cairns, Thomas James, Amanda Lyle, Sheela Shah, George Zachariah, Lauren Fergey, Susan Smolen, Lucy Cooper, Elizabeth Bohannan, Siddiq Omer, Sageet Amlani, Nadia Hunter, Melissa Hawkes-Blackburn, Giosue Gulli, Alice Peacocke, Justine Amero, Maria Burova, Ottilia Speirs, Steph Levy, Lynda Francis, Susan Holland, Sean Brotheridge, Helen Lyon, Christine Hare, Samantha Jackson, Lorraine Stephenson, Samer Al Hussayni, James Featherstone, Agness Bwalya, Arun Singh, M N Goorah, Jamie Walford, Angela Bell, Christine Kelly, Darren Rusk, Deborah Sutton, Farzana Patel, Stephen Duberley, Kathryn Hayes, Lorraine Hunt, Ahmed El Nour, Sacha Honour, Chloe Box, Simon Dyer, Lynne Brown, Kerry Elliott, Emma Temlett, John Paterson, Rosie Furness, Shelli Young, Enoch Orugun, Chris Brewer, Sarah Thornthwaite, Hannah Crowther, Rachel Glover, Moe Sein, Kashif Haque, Elspeth Gibson, Sam Wong, Karen Rotchell, Karen Burton, Lisa Brookes, Linda Bailey, Chris Lindley, Abbi Murray, Karen Waltho, Maureen Holland, Pradeep Kumar, Purnima Harlekar, Laura Booth, Charlotte Culmsee, Jade Drew, Mohammad Khan, Nicola Mackenzie, Carmel Thomas, Jane Ritchie, James Barker, Michael Haley, Donna Cotterill, Lynne Lane, Christine Little, Dawn Simmons, Glenn Saunders, Harvey Dymond, Sarah Kidd, Rachel Warinton, Yara Neves-Silva, Branimir Nevajda, Michael Villaruel, Udayaraj Umasankar, Seema Patel, Anna Man, Natasha Christmas, Ravi Rangasamy, Richard Ladner, Georgina Butt, Wilson Alvares, Narasimha Gadi, Michael Power, Belinda Wroath, Kevin Dynan, David Wilson, Sarah Crothers, Catherine Leonard, Samantha Hagan, Geraldine Douris, Djamil Vahidassr, Alastair Thompson, Brian Gallen, Shirley Mckenna, Collette Edwards, Clare Mcgoldrick, Murdi Bhattad, Khalil Kawafi, Deborah Morse, Patricia Jacob, Lisa Turner, Narayanamoorti Saravanan, Linda Johnson, Sadie Humphrey, Robert Namushi, Ramesh Patel, Jemma Mclaughlin, Paul Omahony, Esther Osikominu, Chukwuka Orefo, Chisha Mcdonald, Esther Makanju, Tabindah Khan, Grace Appiatse, Helena Stone, Martia Augustin, Alicia Wardale, Maqsud Salehin, Duncan Bailey, Luciano Garcia-Alen, Latheef Kalathil, Sarah Tinsley, Taya Jones, Kelly Amor, Andrew Ritchings, Emma Margerum, Jane Horton, Richard Miller, Nireekshana Gautam, Julie Meir, Amaryl Jones, Janet Putteril, Mirella Lepore, Rachel Gallifent, Laura-Louise Arundell, Catherine Mcredmond, Alicia Goulding, Vivek Nadarajan, Julia Laurence, Su Fung Lo, Sabina Melander, Paul Nicholas, Elizabeth Woodford, Gillian Mckenzie, Vietland Le, Jacolene Crause, Robert Luder, Maneesh Bhargava, Girish Bhome, Venetia V Johnson, Dara Chesser, Hayley Bridger, Elodie Murali, Jon Scott, Susan Morrison, Amy Burns, Julie Graham, Madeline Duffy, Khalid Ali, Emma Pitcher, Jane Gaylard, Julie Newman, Sunil Punnoose, Sarah Besley, Kirtan Purohit, Amy Rees, Mark Davy, Osman Chohan, Muhammad Fozan Khan, Rachel Walker, Vicky Murray, Charlotte Bent, Susan Oakley, Cassilda Peixoto, Suzanne Jones, Gaybrielle Livingstone, Fiona Butler, Sally Bradfield, Laura Gordon, Jenneke Schmit, Anika Wijewardane, Tineke Edmunds, Rebecca Wills, Catherine Medcalf, Lucia Argandona, Larissa Cuenoud, Hanna Hassan, Esther Erumere, Aidan Ocallaghan, Patrick Gompertz, Ozlem Redjep, Grace Auld, Anna Song, Tillana Tarkas, Hashim Kabash, Rumbi Hungwe, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, and University of St Andrews. School of Medicine
Subjects: RM, medicine.medical_specialty, Neurology, Neurologi, NDAS, 030204 cardiovascular system & hematology, Placebo, Minimisation (clinical trials), Article, B700, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Modified Rankin Scale, law, Fluoxetine, Internal medicine, Humans, Medicine, 030212 general & internal medicine, R2C, Acute stroke, business.industry, ~DC~, General Medicine, Odds ratio, RM Therapeutics. Pharmacology, Stroke, RC Internal medicine, BDC, business, Selective Serotonin Reuptake Inhibitors, RC, medicine.drug
Abstract: Background: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.Findings: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.Interpretation: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.Funding: UK Stroke Association and NIHR Health Technology Assessment Programme.
Published: 2019
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30. Effects of Pedal Speed and Crank Length on Pedaling Mechanics during Submaximal Cycling

Author: BARRATT, PAUL RICHARD, MARTIN, JAMES C., ELMER, STEVE J., and KORFF, THOMAS
Subjects: Adult, Male, COORDINATION, Knee Joint, Applied Sciences, BIOMECHANICS, Bicycling, Biomechanical Phenomena, body regions, Young Adult, CRANK LENGTH, Athletes, Task Performance and Analysis, Exercise Test, Humans, Female, Hip Joint, Range of Motion, Articular, human activities, ENDURANCE CYCLING, Ankle Joint
Abstract: During submaximal cycling, the neuromuscular system has the freedom to select different intermuscular coordination strategies. From both a basic science and an applied perspective, it is important to understand how the central nervous system adjusts pedaling mechanics in response to changes in pedaling conditions. Purpose To determine the effect of changes in pedal speed (a marker of muscle shortening velocity) and crank length (a marker of muscle length) on pedaling mechanics during submaximal cycling. Methods Fifteen trained cyclists performed submaximal isokinetic cycling trials (90 rpm, 240 W) using pedal speeds of 1.41 to 1.61 m·s−1 and crank lengths of 150 to 190 mm. Joint powers were calculated using inverse dynamics. Results Increases in pedal speed and crank length caused large increases knee and hip angular excursions and velocities (P < 0.05), whereas ankle angular kinematics stayed relatively constant (P > 0.05). Joint moments and joint powers were less affected by changes in the independent variables, but some interesting effects and trends were observed. Most noteworthy, knee extension moments and powers tended to decrease, whereas hip extension power tended to increase with an increase in crank length. Conclusions The distribution of joint moments and powers is largely maintained across a range of pedaling conditions. The crank length induced differences in knee extension moments, and powers may represent a trade-off between the central nervous system’s attempts to simultaneously minimize muscle metabolic and mechanical stresses. These results increase our understanding of the neural and mechanical mechanisms underlying multi-joint task performance, and they have practical relevance to coaches, athletes, and clinicians.
Published: 2016

31. Commentary on: Implementing mechanical thrombectomy for acute ischaemic stroke in the UK

Author: N McConachie, Martin James, C Rowland-Hill, Philip White, Helen Rodgers, Rob Lenthall, J. Dinsmore, and Ajay Bhalla
Subjects: medicine.medical_specialty, Pediatrics, Mechanical Thrombolysis, Treatment outcome, MEDLINE, Stroke mortality, Utilization review, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Risk Factors, Ischaemic stroke, Prevalence, medicine, Humans, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Survival rate, business.industry, General Medicine, United Kingdom, Stroke, Survival Rate, Mechanical thrombectomy, Treatment Outcome, Utilization Review, Emergency medicine, business, 030217 neurology & neurosurgery
Published: 2017
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32. Associations Between 30-Day Mortality, Specialist Nursing, and Daily Physician Ward Rounds in a National Stroke Registry

Author: Alex Hoffman, Elizabeth A. Williamson, Benjamin Bray, Lizz Paley, Martin James, and Anthony Rudd
Subjects: Male, Stroke registry, medicine.medical_specialty, Original Contributions, Clinical Sciences, Stroke care, Odds, 03 medical and health sciences, 0302 clinical medicine, nursing, medicine, Humans, 030212 general & internal medicine, Registries, Mortality, National audit, Stroke, Acute stroke, Aged, Advanced and Specialized Nursing, Aged, 80 and over, Wales, business.industry, adult, Multilevel model, medicine.disease, Hospitalization, Logistic Models, England, 30 day mortality, Emergency medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Multilevel Analysis, Teaching Rounds, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, hospitals, Hospital Units, Nurse Specialists, 030217 neurology & neurosurgery
Abstract: Supplemental Digital Content is available in the text., Background and Purpose— Well-organized stroke care is associated with better patient outcomes, but the most important organizational factors are unknown. Methods— Data were extracted from the Sentinel Stroke National Audit Programme of adults with acute stroke treated in stroke hospitals in England and Wales between April 2013 and March 2015. Multilevel models with random intercepts for hospitals were used to estimate the association of each variable with 30-day mortality to estimate the impact of admission to differently organized hospitals. Results— Of the 143 578 patients with acute stroke admitted to 154 hospitals, 14.4% died within 30 days of admission. In adjusted analyses, admission to hospitals with higher ratios of nurses trained in swallow screening was associated with reduced odds of death (P=0.004), and admission to hospitals with daily physician ward rounds was associated with 10% lower odds of mortality compared with less-frequent ward rounds (95% CI, 0.82–0.98; P=0.013). Number of stroke admissions and overall ratio of registered nurses on duty at weekends were not found to be independently associated with mortality after adjustment for other factors. Conclusions— If these associations are causal, an extra 1332 deaths annually in England and Wales could be saved by hospitals providing care associated with a ratio of nurses trained in swallow screening of at least 3 per 10 beds and daily stroke physician ward rounds.
Published: 2018

33. Neurological signs as early determinants of dementia and predictors of mortality among older adults in Latin America: a 10/66 study using the NEUROEX assessment

Author: Pasquini, Lorenzo, Llibre Guerra, Jorge, Prince, Martin James, Chua, Kia-Chong, and Prina, Matthew
Subjects: Male, Aging, Epidemiology, Neurodegenerative, Basic Behavioral and Social Science, lcsh:RC346-429, Predictive Value of Tests, Clinical Research, Neurological signs, Behavioral and Social Science, Acquired Cognitive Impairment, Humans, Mortality, lcsh:Neurology. Diseases of the nervous system, Proportional Hazards Models, Aged, Neurologic Examination, Neurology & Neurosurgery, Neurosciences, Brain Disorders, Latin America, Good Health and Well Being, Neurological, Regression Analysis, Low and middle-income countries, Dementia, Female, Cognitive Sciences, Research Article
Abstract: Background Neurodegenerative processes in the elderly damage the brain, leading to progressive, incapacitating cognitive, behavioral, and motor dysfunctions which culminate in dementia. Fully manifest dementia is likely to be preceded by the presence of neurological signs, which could serve as early determinants of dementia and predictors of mortality. The aims of this study were to assess the construct validity of a neurological battery assessed among older adults living in Latin America, and to test the association of groups of neurological signs with dementia cross-sectionally, and mortality longitudinally. Methods The 10/66 Dementia Research Group collected information on neurological symptoms via the NEUROEX assessment in population based surveys of older adults living in low and middle-income countries. Data from 10,856 adults participating in the baseline assessment of the 10/66 study and living in Cuba, Dominican Republic, Peru, Venezuela and Mexico were analysed. Exploratory and confirmatory analysis were used to explore dimensionality of neurological symptoms. Poisson regression analyses were used to link groups of neurological signs with dementia at baseline. Cox hazard regression models were used to explore the predictive validity of neurological signs with mortality at follow up. Results Exploratory and confirmatory factor analyses revealed four dimensions of neurological signs, which are associated with lesions of specific brain regions. The identified factors showed consistency with groups of neurological signs such as frontal, cerebellar, extrapyramidal, and more generalized gait disturbance signs. Regression analyses revealed that all groups of neurological signs were positively associated with dementia at baseline and predicted mortality at follow up. Conclusions Our findings support the construct and predictive validity of the NEUROEX assessment, linking neurological and gait impairments with dementia at baseline, and with mortality at follow up among older adults living in five Latin American countries. Electronic supplementary material The online version of this article (10.1186/s12883-018-1167-4) contains supplementary material, which is available to authorized users.
Published: 2018
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34. Physical activity, sleep, and fatigue in community dwelling Stroke Survivors

Author: Anne Forster, Rhoda Allison, Martin James, Richard M. Pulsford, Raff Calitri, Anthony I. Shepherd, Anne Spencer, Rod S Taylor, Sarah Dean, Laura Hollands, Leon Poltawski, and Meriel Norris
Subjects: Male, medicine.medical_specialty, Time Factors, Activities of daily living, Cross-sectional study, Physical activity, lcsh:Medicine, APC-PAID, Article, 03 medical and health sciences, 0302 clinical medicine, Activities of Daily Living, Humans, Medicine, Longitudinal Studies, 030212 general & internal medicine, Stroke survivor, lcsh:Science, Exercise, Stroke, Fatigue, Aged, Multidisciplinary, business.industry, lcsh:R, Assessment scale, medicine.disease, Sleep in non-human animals, Sleep patterns, Cross-Sectional Studies, Physical therapy, Female, lcsh:Q, Independent Living, Sleep, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Stroke can lead to physiological and psychological impairments and impact individuals’ physical activity (PA), fatigue and sleep patterns. We analysed wrist-worn accelerometry data and the Fatigue Assessment Scale from 41 stroke survivors following a physical rehabilitation programme, to examine relationships between PA levels, fatigue and sleep. Validated acceleration thresholds were used to quantify time spent in each PA intensity/sleep category. Stroke survivors performed less moderate to vigorous PA (MVPA) in 10 minute bouts than the National Stroke guidelines recommend. Regression analysis revealed associations at baseline between light PA and fatigue (p = 0.02) and MVPA and sleep efficiency (p = 0.04). Light PA was positively associated with fatigue at 6 months (p = 0.03), whilst sleep efficiency and fatigue were associated at 9 months (p = 0.02). No other effects were shown at baseline, 6 or 9 months. The magnitude of these associations were small and are unlikely to be clinically meaningful. Larger trials need to examine the efficacy and utility of accelerometry to assess PA and sleep in stroke survivors Stroke Association for funding this research (TSA – 2014-03) and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust
Published: 2018
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35. Intratumor MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with CREB signaling and distinct target gene signatures

Author: Andrew H. Kaye, Stanley S. Stylli, Gulay Filiz, Paul M. Daniel, Martin James Tymms, Theo Mantamadiotis, and Robert G. Ramsay
Subjects: 0301 basic medicine, MAPK/ERK pathway, Cell signaling, MAP Kinase Signaling System, medicine.medical_treatment, Clinical Biochemistry, CREB, Pathology and Forensic Medicine, Targeted therapy, 03 medical and health sciences, Genetic Heterogeneity, Phosphatidylinositol 3-Kinases, medicine, Humans, Cyclic AMP Response Element-Binding Protein, Molecular Biology, Transcription factor, PI3K/AKT/mTOR pathway, Cell Proliferation, Regulation of gene expression, biology, Brain Neoplasms, Gene signature, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Hyaluronan Receptors, biology.protein, Cancer research, Glioblastoma, Transcriptome
Abstract: Limitations in discovering useful tumor biomarkers and drug targets is not only due to patient-to-patient differences but also due to intratumor heterogeneity. Heterogeneity arises due to the genetic and epigenetic variation of tumor cells in response to microenvironmental interactions and cytotoxic therapy. We explored specific signaling pathway activation in glioblastoma (GBM) by investigating the intratumor activation of the MAPK and PI3K pathways. We present data demonstrating a striking preponderance for mutual exclusivity of MAPK and PI3K activation in GBM tissue, where MAPK activation correlates with proliferation and transcription factor CREB activation and PI3K activation correlates with CD44 expression. Bioinformatic analysis of signaling and CREB-regulated target genes supports the immunohistochemical data, showing that the MAPK-CREB activation correlates with proliferative regions. In-silico analysis suggests that MAPK-CREB signaling activates a pro-inflammatory molecular signature and correlates with a mesenchymal GBM subtype profile, while PI3K-CREB activation correlates with the proneural GBM subtype and a tumor cell invasive gene signature. Overall, the data suggests the existence of intratumor subtype heterogeneity in GBM and that using combinations of both MAPK and PI3K drug inhibitors is necessary for effective targeted therapy.
Published: 2018

36. Socioeconomic disparities in first stroke incidence, quality of care, and survival: a nationwide registry-based cohort study of 44 million adults in England

Author: Alex Hoffman, Harry Hemingway, Lizz Paley, Anthony Rudd, Patrick Gompertz, Martin James, Charles D.A. Wolfe, and Benjamin Bray
Subjects: Adult, Male, medicine.medical_specialty, Rate ratio, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Case fatality rate, Health care, Medicine, Humans, 030212 general & internal medicine, Registries, Healthcare Disparities, Stroke, Socioeconomic status, business.industry, Proportional hazards model, Incidence (epidemiology), Incidence, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Health Status Disparities, medicine.disease, Survival Analysis, Hospitalization, England, Socioeconomic Factors, Emergency medicine, Female, business, 030217 neurology & neurosurgery, Cohort study
Abstract: Summary: Background: We aimed to estimate socioeconomic disparities in the incidence of hospitalisation for first-ever stroke, quality of care, and post-stroke survival for the adult population of England. Methods: In this cohort study, we obtained data collected by a nationwide register on patients aged 18 years or older hospitalised for first-ever acute ischaemic stroke or primary intracerebral haemorrhage in England from July 1, 2013, to March 31, 2016. We classified socioeconomic status at the level of Lower Super Output Areas using the Index of Multiple Deprivation, a neighbourhood measure of deprivation. Multivariable models were fitted to estimate the incidence of hospitalisation for first stroke (negative binomial), quality of care using 12 quality metrics (multilevel logistic), and all-cause 1 year case fatality (Cox proportional hazards). Findings: Of the 43·8 million adults in England, 145 324 were admitted to hospital with their first-ever stroke: 126 640 (87%) with ischaemic stroke, 17 233 (12%) with intracerebral haemorrhage, and 1451 (1%) with undetermined stroke type. We observed a socioeconomic gradient in the incidence of hospitalisation for ischaemic stroke (adjusted incidence rate ratio 2·0, 95% CI 1·7–2·3 for the most vs least deprived deciles) and intracerebral haemorrhage (1·6, 1·3–1·9). Patients from the lowest socioeconomic groups had first stroke a median of 7 years earlier than those from the highest (p
Published: 2018
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37. PI4KIII inhibitor enviroxime impedes the replication of the hepatitis C virus by inhibiting PI3 kinases

Author: Christian Harak, Volker Lohmann, Hayat Khan, Leen Delang, Mohammed Benkheil, Pieter Leyssen, Martin James Inglis Andrews, and Johan Neyts
Subjects: 0301 basic medicine, Microbiology (medical), Small interfering RNA, viruses, Hepatitis C virus, DNA Mutational Analysis, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Virus Replication, Antiviral Agents, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Drug Resistance, Viral, Oximes, medicine, Humans, Pharmacology (medical), LY294002, Replicon, Serial Passage, NS5A, Gene, 1-Phosphatidylinositol 4-Kinase, Subgenomic mRNA, Phosphoinositide-3 Kinase Inhibitors, Pharmacology, Sulfonamides, Chemistry, RNA, virus diseases, Virology, digestive system diseases, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, Hepatocytes, Benzimidazoles
Abstract: OBJECTIVES: Many positive-stranded RNA viruses, including HCV, drastically remodel intracellular membranes to generate specialized environments for RNA replication. Phosphatidylinositol 4-kinase III (PI4KIII)α plays an essential role in the formation of HCV replication complexes and has therefore been explored as a potential drug target. Here, we characterized the anti-HCV activity of the PI4KIII inhibitors enviroxime and BF738735 and elucidated their mechanism of action. METHODS: Antiviral assays were performed using HCV subgenomic replicons and infectious HCV. Enviroxime- and BF738735-resistant HCV replicons were generated by long-term culture with increasing compound concentrations. Intracellular localization of phosphatidylinositol 4-phosphate (PI4P) lipids was analysed by confocal microscopy. RESULTS: HCV subgenomic replicons resistant to either enviroxime or BF738735 proved cross-resistant and carried mutations in the NS3, NS4B and NS5A genes. Knockdown of PI4KIIIβ by small interfering RNA (siRNA) did not affect the replication of the HCV subgenomic replicon in this study. Furthermore, the compounds did not affect PI4P lipid levels at the replication complexes nor the phosphorylation status of NS5A, activities attributed to PI4KIIIα. Interestingly, the broad-spectrum phosphoinositide 3-kinase (PI3K) inhibitor LY294002 proved to be 10-fold less effective against the resistant replicons. In addition, enviroxime and BF738735 inhibited several PI3Ks in enzymatic assays. CONCLUSIONS: Contrary to assumptions, our data indicate that PI4KIIIα and PI4KIIIβ are not the main targets for the anti-HCV activity of enviroxime and BF738735. Instead, we demonstrated that both molecules impede HCV replication at least partially by an inhibitory effect on PI3Ks. Moreover, HCV is able to bypass PI3K inhibition by acquiring mutations in its genome. ispartof: Journal Of Antimicrobial Chemotherapy vol:73 issue:12 pages:3375-3384 ispartof: location:England status: published
Published: 2018

38. Community-based Rehabilitation Training after stroke: Results of a pilot randomised controlled trial (ReTrain) investigating acceptability and feasibility

Author: Martin James, Sarah Dean, Raff Calitri, Shirley Stevens, Anne Forster, Paolo Landa, Meriel Norris, Richard M. Pulsford, Anthony I. Shepherd, Laura Hollands, Anne Spencer, Rod S Taylor, Leon Poltawski, and Rhoda Allison
Subjects: Male, Cost-Benefit Analysis, medicine.medical_treatment, Psychological intervention, Pilot Projects, Session (web analytics), law.invention, 0302 clinical medicine, Randomized controlled trial, law, Activities of Daily Living, Outcome Assessment, Health Care, Single-Blind Method, Community Health Services, 030212 general & internal medicine, Stroke, Aged, 80 and over, Rehabilitation, Stroke Rehabilitation, rehabilitation medicine, General Medicine, Middle Aged, stroke, stroke medicine, Female, Sports and Exercise Sciences, Adult, medicine.medical_specialty, Community-based rehabilitation, Rehabilitation Medicine, 03 medical and health sciences, Physical medicine and rehabilitation, Intervention (counseling), medicine, Humans, Exercise, Aged, clinical trials, business.industry, Research, Patient Acceptance of Health Care, medicine.disease, Clinical trial, Physical Fitness, Quality of Life, Physical therapy, Feasibility Studies, business, 030217 neurology & neurosurgery, Program Evaluation
Abstract: ObjectivesTo assess acceptability and feasibility of trial processes and the Rehabilitation Training (ReTrain) intervention including an assessment of intervention fidelity.DesignA two-group, assessor-blinded, randomised controlled trial with parallel mixed methods process and economic evaluations.SettingCommunity settings across two sites in Devon.ParticipantsEligible participants were: 18 years old or over, with a diagnosis of stroke and with self-reported mobility issues, no contraindications to physical activity, discharged from National Health Service or any other formal rehabilitation programme at least 1 month before, willing to be randomised to either control or ReTrain and attend the training venue, possessing cognitive capacity and communication ability sufficient to participate. Participants were individually randomised (1:1) via a computer-generated randomisation sequence minimised for time since stroke and level of functional disability. Only outcome assessors independent of the research team were blinded to group allocation.InterventionsReTrain comprised (1) an introductory one-to-one session; (2) ten, twice-weekly group classes with up to two trainers and eight clients; (3) a closing one-to-one session, followed by three drop-in sessions over the subsequent 3 months. Participants received a bespoke home-based training programme. All participants received treatment as usual. The control group received an exercise after stroke advice booklet.Outcome measuresCandidate primary outcomes included functional mobility and physical activity.ResultsForty-five participants were randomised (ReTrain=23; Control=22); data were available from 40 participants at 6 months of follow-up (ReTrain=21; Control=19) and 41 at 9 months of follow-up (ReTrain=21; Control=20). We demonstrated ability to recruit and retain participants. Participants were not burdened by the requirements of the study. We were able to calculate sample estimates for candidate primary outcomes and test procedures for process and health economic evaluations.ConclusionsAll objectives were fulfilled and indicated that a definitive trial of ReTrain is feasible and acceptable.Trial registration numberNCT02429180; Results.
Published: 2018
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39. Catalytic metallodrugs based on the LaR2C peptide target HCV SLIV IRES RNA

Author: Martin James Ross, J. A. Cowan, and Seth Bradford
Subjects: Peptide, Hepacivirus, Plasma protein binding, Virus Replication, Article, Catalysis, Inorganic Chemistry, Start codon, Cell Line, Tumor, Humans, Amino Acid Sequence, Binding site, Peptide sequence, chemistry.chemical_classification, Chemistry, Viral translation, RNA, Phosphoproteins, Molecular biology, Kinetics, Internal ribosome entry site, Biochemistry, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Nucleic Acid Conformation, RNA, Viral, 5' Untranslated Regions, Peptides, Protein Binding
Abstract: Prior work has demonstrated the potential effectiveness of a new class of metallopeptides as catalytic metallodrugs that target HCV IRES SLIIb RNA (Cu-GGHYrFK, 1). Herein new catalytic metallodrugs (GGHKYKETDLLILFKDDYFAKKNEERK, 2; and GGHKYKETDL, 3) are described based on the LaR2C peptide that has been shown to bind to the SLIV HCV IRES domain. In vitro fluorescence assays yielded KD values ∼10 μM for both peptides and reaction of the copper derivatives with SLIV RNA demonstrated initial rates comparable across different assays as well as displaying pseudo-Michaelis-Menten behavior. The sites of reaction and cleavage mechanisms were determined by MALDI-TOF mass spectrometry. The primary site of copper-promoted SLIV cleavage is shown to occur in the vicinity of the 5'-G17C18A19C20-3' sequence that corresponds to a known binding site of the RM2 motif of the human La protein and has previously been reported to be important for viral translation. This domain also flanks the internal start codon (AUG). Both copper complexes also showed efficacy in an HCV replicon assay (IC50 = 0.75 μM for 2-Cu, and 2.17 μM for 3-Cu) and show potential for treatment of hepatitis C, complementing other marketed drugs by acting on a distinct therapeutic target by a novel mechanism of action.
Published: 2015
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40. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1 H -indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate

Author: Nichol Miller, Marie Cordonnier, Hélène Cannelle, Frederik Deroose, Joseph Tumang, James Soloweij, Bruno Gomes, Stefano Crosignani, Michel Negrerie, Patrick Bingham, Karen A. Maegley, A.E. Stewart, Sandra Cauwenberghs, Martin James Wythes, Pauline Bottemanne, Benoît Van den Eynde, Stephen E. Kaiser, Vince Torti, Manfred Kraus, Brion W. Murray, Jun Li Feng, Deepak Dalvie, Manfred Schneider, Samantha Elizabeth Greasley, iTeos Therapeutics (iTeos), Pfizer, Asclepia Outsourcing Solutions, Laboratoire d'Optique et Biosciences (LOB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X), and Université Catholique de Louvain = Catholic University of Louvain (UCL)
Subjects: 0301 basic medicine, Male, Indoles, Succinimides, Pharmacology, Crystallography, X-Ray, Pyrrolidine, Immune tolerance, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Dogs, Drug Discovery, Structure–activity relationship, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enzyme Inhibitors, Indoleamine 2,3-dioxygenase, ComputingMilieux_MISCELLANEOUS, ADME, chemistry.chemical_classification, Effector, Oxidoreductase inhibitor, 3. Good health, Rats, Molecular Docking Simulation, Macaca fascicularis, 030104 developmental biology, Enzyme, chemistry, Cancer research, Molecular Medicine
Abstract: Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure–activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16–19 h.
Published: 2017
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41. Impact of insecticide resistance in

Author: Hmooda Toto, Kafy, Bashir Adam, Ismail, Abraham Peter, Mnzava, Jonathan, Lines, Mogahid Shiekh Eldin, Abdin, Jihad Sulieman, Eltaher, Anuar Osman, Banaga, Philippa, West, John, Bradley, Jackie, Cook, Brent, Thomas, Krishanthi, Subramaniam, Janet, Hemingway, Tessa Bellamy, Knox, Elfatih M, Malik, Joshua O, Yukich, Martin James, Donnelly, and Immo, Kleinschmidt
Subjects: Male, Insecticides, Mosquito Control, Medical Sciences, pyrethroid, Incidence, Drug Resistance, Phenylcarbamates, malaria, insecticide, Biological Sciences, Sudan, resistance, PNAS Plus, Child, Preschool, parasitic diseases, Anopheles, Nitriles, Pyrethrins, Costs and Cost Analysis, Animals, Humans, Female, Malaria, Falciparum, Child
Abstract: Significance Emerging insecticide resistance in malaria vectors could presage a catastrophic rebound in malaria morbidity and mortality. In areas of moderate levels of resistance to pyrethroids, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with a carbamate insecticide were significantly more effective than IRS with pyrethroid insecticide. The impact on the effectiveness of LLINs could not be quantified. The incremental cost of using a carbamate insecticide to which vectors are susceptible was US $0.65 per person protected per year, which is considered acceptable by international standards. While the WHO recommends that different interventions, where possible, should use different insecticide classes, these data alone should not be used as the basis for a policy change in vector control interventions., Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to
Published: 2017

42. Feasibility of a hyper-acute stroke unit model of care across England: a modelling analysis

Author: Michael Allen, Emma Villeneuve, Ken Stein, Martin James, Kerry Pearn, and Thomas Monks
Subjects: medicine.medical_specialty, Time Factors, Population, Stroke care, organisation of health services, quality in health care, 03 medical and health sciences, 0302 clinical medicine, Patient Admission, medicine, Humans, Unit model, 030212 general & internal medicine, education, Stroke, Acute stroke, Stroke services, education.field_of_study, Travel, Modelling analysis, business.industry, Research, General Medicine, medicine.disease, stroke, Travel time, England, Emergency medicine, Critical Pathways, Feasibility Studies, Health Services Research, business, Hospital Units, 030217 neurology & neurosurgery, Algorithms
Abstract: ObjectivesThe policy of centralising hyperacute stroke units (HASUs) in England aims to provide stroke care in units that are both large enough to sustain expertise (>600 admissions/year) and dispersed enough to rapidly deliver time-critical treatments (DesignModelling of the effect of the national reconfiguration of stroke services. Optimal solutions were identified using a heuristic genetic algorithm.Setting127 acute stroke services in England, serving a population of 54 million people.Participants238 887 emergency admissions with acute stroke over a 3-year period (2013–2015).InterventionModelled reconfigurations of HASUs optimised for institutional size and geographical access.Main outcome measureTravel distances and times to HASUs, proportion of patients attending a HASU with at least 600 admissions per year, and minimum and maximum HASU admissions.ResultsSolutions were identified with 75–85 HASUs with annual stroke admissions in the range of 600–2000, which achieve up to 82% of patients attending a stroke unit within 30 min estimated travel time (with at least 95% and 98% of the patients being within 45 and 60 min travel time, respectively).ConclusionsThe reconfiguration of hyperacute stroke services in England could lead to all patients being treated in a HASU with between 600 and 2000 admissions per year. However, the proportion of patients within 30 min of a HASU would fall from over 90% to 80%–82%.
Published: 2017

43. The latest national clinical guideline for stroke

Author: Gavin R Young, Anthony Rudd, Martin James, and Audrey Bowen
Subjects: medicine.medical_specialty, medicine.medical_treatment, MEDLINE, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Acute care, medicine, Humans, CME Cerebrovascular disease, cardiovascular diseases, 030212 general & internal medicine, Letters to the Editor, Stroke, Guideline adherence, business.industry, Atrial fibrillation, General Medicine, Guideline, medicine.disease, Surgery, Emergency medicine, Practice Guidelines as Topic, cardiovascular system, Medical emergency, Guideline Adherence, Cardiac monitoring, business, 030217 neurology & neurosurgery
Abstract: Editor – There is lack of clarity in the latest National clinical guideline for stroke on cardiac monitoring if a cardio-embolic stroke is suspected.[1][1] It is estimated that between 25 and 60% of atrial fibrillations are paroxysmal (PAF) and approximately one third of the patients affected are
Published: 2017
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44. Critical healthcare management studies: green shoots

Author: Aoife M. McDermott, Simon Cooper, and Martin James Kitchener
Subjects: Value (ethics), Instrumentalism, media_common.quotation_subject, Health administration, 03 medical and health sciences, Originality, Reflexivity, 0502 economics and business, Health care, Mainstream, Humans, Sociology, Social science, media_common, business.industry, 030503 health policy & services, Health Policy, Communication, 05 social sciences, Business, Management and Accounting (miscellaneous), Engineering ethics, Ideology, 0305 other medical science, business, Delivery of Health Care, 050203 business & management
Abstract: Purpose While critical approaches have enriched research in proximate fields, their impact has been less marked in studies of healthcare management. In response, the 2016 Organizational Behaviour in Health Care Conference hosted its first-ever session dedicated to the emergent field of critical healthcare management studies (CHMSs). The purpose of this paper is to present five papers selected from that conference. Design/methodology/approach In this introductory paper, the authors frame the contributions as “green shoots” in a field of CHMS which contains four main furrows of activity: questioning the taken-for-granted; moving beyond instrumentalism; reflexivity and meanings in research; and challenging structures of domination (Kitchener and Thomas, 2016). The authors conclude by presenting an agenda for further cultivating the field of CHMS. Findings The papers evidence the value of CHMS, and provide insight into the benefits of broadening theoretical and methodological approaches in pursuit of critical insights. Research limitations/implications CHMS works to explicate the multiple and competing ideologies and interests inherent in healthcare. As pragmatic imperatives push the provision of health and social care out of the organisational contexts and into private space, there is a particular need to simultaneously understand, and critically interrogate, the implications of new, as well as existing, forms of care. Practical implications This paper reviews, frames and details practical next steps in developing CHMS. These include: enhanced engagement with a wider range of actors than is currently the norm in mainstream healthcare management research; a broadening of theoretical and methodological lenses; support for critical approaches among editors and reviewers; and enhanced communication of critical research via its incorporation into education and training programmes. Originality/value The paper contributes to an emerging stream of CHMS research, and works to consolidate next steps for the field.
Published: 2017

45. Derivation and External Validation of a Case Mix Model for the Standardized Reporting of 30-Day Stroke Mortality Rates

Author: Pippa J. Tyrrell, Geoffrey Cloud, Alex Hoffman, Anthony Rudd, Martin James, Benjamin Bray, Charles D.A. Wolfe, and James Campbell
Subjects: Male, medicine.medical_specialty, Longitudinal study, Population, Cohort Studies, Case mix index, medicine, Humans, Prospective Studies, cardiovascular diseases, Derivation, Mortality, education, Stroke, Generalized estimating equation, Diagnosis-Related Groups, Aged, Retrospective Studies, Aged, 80 and over, Advanced and Specialized Nursing, education.field_of_study, Wales, Receiver operating characteristic, business.industry, Middle Aged, medicine.disease, England, Emergency medicine, Female, Neurology (clinical), Medical emergency, Cardiology and Cardiovascular Medicine, business, Predictive modelling
Abstract: Background and Purpose— Case mix adjustment is required to allow valid comparison of outcomes across care providers. However, there is a lack of externally validated models suitable for use in unselected stroke admissions. We therefore aimed to develop and externally validate prediction models to enable comparison of 30-day post-stroke mortality outcomes using routine clinical data. Methods— Models were derived (n=9000 patients) and internally validated (n=18 169 patients) using data from the Sentinel Stroke National Audit Program, the national register of acute stroke in England and Wales. External validation (n=1470 patients) was performed in the South London Stroke Register, a population-based longitudinal study. Models were fitted using general estimating equations. Discrimination and calibration were assessed using receiver operating characteristic curve analysis and correlation plots. Results— Two final models were derived. Model A included age ( Conclusions— We have derived and externally validated 2 models to predict mortality in unselected patients with acute stroke using commonly collected clinical variables. In settings where the ability to record the full NIHSS on admission is limited, the level of consciousness component of the NIHSS provides a good approximation of the full NIHSS for mortality prediction.
Published: 2014
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46. Can clinical audits be enhanced by pathway simulation and machine learning? An example from the acute stroke pathway

Author: Martin James, Benjamin Bray, Andrew Salmon, Ken Stein, Kerry Pearn, Richard M. Everson, Michael Allen, and Thomas Monks
Subjects: Clinical audit, thrombolysis, Time Factors, medicine.medical_treatment, Population, Audit, Machine learning, computer.software_genre, Brain Ischemia, Time-to-Treatment, Machine Learning, Clinical pathway, Fibrinolytic Agents, medicine, Humans, Computer Simulation, Thrombolytic Therapy, alteplase, education, Set (psychology), Stroke, Original Research, education.field_of_study, Clinical Audit, business.industry, Health services research, General Medicine, Thrombolysis, simulation, medicine.disease, Hospitals, England, Tissue Plasminogen Activator, Health Services Research, Artificial intelligence, business, computer
Abstract: ObjectiveTo evaluate the application of clinical pathway simulation in machine learning, using clinical audit data, in order to identify key drivers for improving use and speed of thrombolysis at individual hospitals.DesignComputer simulation modelling and machine learning.SettingSeven acute stroke units.ParticipantsAnonymised clinical audit data for 7864 patients.ResultsThree factors were pivotal in governing thrombolysis use: (1) the proportion of patients with a known stroke onset time (range 44%–73%), (2) pathway speed (for patients arriving within 4 hours of onset: per-hospital median arrival-to-scan ranged from 11 to 56 min; median scan-to-thrombolysis ranged from 21 to 44 min) and (3) predisposition to use thrombolysis (thrombolysis use ranged from 31% to 52% for patients with stroke scanned with 30 min left to administer thrombolysis). A pathway simulation model could predict the potential benefit of improving individual stages of the clinical pathway speed, whereas a machine learning model could predict the benefit of ‘exporting’ clinical decision making from one hospital to another, while allowing for differences in patient population between hospitals. By applying pathway simulation and machine learning together, we found a realistic ceiling of 15%–25% use of thrombolysis across different hospitals and, in the seven hospitals studied, a realistic opportunity to double the number of patients with no significant disability that may be attributed to thrombolysis.ConclusionsNational clinical audit may be enhanced by a combination of pathway simulation and machine learning, which best allows for an understanding of key levers for improvement in hyperacute stroke pathways, allowing for differences between local patient populations. These models, based on standard clinical audit data, may be applied at scale while providing results at individual hospital level. The models facilitate understanding of variation and levers for improvement in stroke pathways, and help set realistic targets tailored to local populations.
Published: 2019
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47. Complementary Models of Post-traumatic Osteoarthritis Reveal Cellular Responses to Contact Stress that Damage Articular Cartilage and Present Targets for Intervention

Author: Martin, James A., Anderson, Donald D., Goetz, Jessica E., Fredericks, Douglas, Pedersen, Douglas R., Ayati, Bruce P., Marsh, J. Lawrence, and Buckwalter, Joseph A.
Subjects: Disease Models, Animal, Osteoarthritis, Animals, Humans, Wounds and Injuries, Joints, Models, Biological, Article
Abstract: Two categories of joint overloading cause post-traumatic osteoarthritis (PTOA): single acute traumatic loads/impactions and repetitive overloading due to incongruity/instability. We developed and refined three classes of complementary models to define relationships between joint overloading and progressive cartilage loss across the spectrum of acute injuries and chronic joint abnormalities: explant and whole joint models that allow probing of cellular responses to mechanical injury and contact stresses, animal models that enable study of PTOA pathways in living joints and pre-clinical testing of treatments, and patient-specific computational models that define the overloading that causes OA in humans. We coordinated methodologies across models so that results from each informed the others, maximizing the benefit of this complementary approach. We are incorporating results from these investigations into biomathematical models to provide predictions of PTOA risk and guide treatment. Each approach has limitations, but each provides opportunities to elucidate PTOA pathogenesis. Taken together, they help define levels of joint overloading that cause cartilage destruction, show that both forms of overloading can act through the same biologic pathways, and create a framework for initiating clinical interventions that decrease PTOA risk. Considered collectively, studies extending from explants to humans show that thresholds of joint overloading that cause cartilage loss can be defined, that to at least some extent both forms of joint overloading act through the same biologic pathways, and interventions that interrupt these pathways prevent cartilage damage. These observations suggest that treatments that decrease the risk of all forms of OA progression can be discovered. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:515-523, 2017.
Published: 2016

48. Angina and Future Cardiovascular Events in Stable Patients With Coronary Artery Disease: Insights From the Reduction of Atherothrombosis for Continued Health (REACH) Registry

Author: Mariana Gospodinova, Francesc Formiga, Miguel-Ángel Idoate-Gastearena, Jose Nicolau, Oksana Drapkina, Winston Bonetti Yoshida, Arintaya Phrommintikul, JIANN-SHING JENG, Thomas Frieden, Vladimir Shulman, Yook-Chin Chia, Christopher Chen, Shaiful bahari Ismail, DIMITRIOS PARISSIS, Vicente Climent, John Cooke, Tomás Segura, Enrique Rodilla, Andrey Komarov, Joseph Eickmeyer, Prof Prakash P Punjabi, Yury Grinshtein, Martin James, Muriel Sprynger, Raymond Seet, Dragos Catalin Jianu, Ricardo Mourilhe-Rocha, Chaicharn Deerochanawong, Ru San Tan, Zhanna D. Kobalava, ALVARO AVEZUM, Monica Acevedo, Prof. Abdulhalim Kinsara, Iana Orlova, Maria Teresa Zanella, ELENA BOBESCU, Vijay Sharma, Veronika Lopukhova, Catalin Adrian Buzea, Yuri Karpov, Philippe Gabriel STEG, Stephen Hillis, Ali Azman Raymond, Jonathan Maltz, Albert Galyavich, Yomar Gonzalez, Hamidon Basri, Jeong-Taek Woo, Sung-Chun Tang, Ivo Petrov, Chirk Jenn Ng, TZUNG-DAU WANG, Sergei Shalaev, Marine Tanashyan, Gyorgy Gergely, Michael Lim, Mary Joan Macleod, Raffaella Pisapia, Jean Ferrieres, Alexander Nikonenko, Viktor Tashchuk, Jean-Luc Reny, Lea Maciel, Oleg Rodnenkov, Rodica Balasa, Farzanna Haffizulla, Mikhail Statsenko, Liviu Macovei, Albert Vernon Smith, Snezhanka Tisheva, Maria Glezer, Ji Hoe Heo, Umayya Musharrafieh, Emilian Bogdan Ignat, Teguh Santoso, John Malcolm Walker, Iurii Rudyk, Kyong Soo Park, Arman Postadzhiyan, Antonio Arauz, and Veeda michelle Anlacan
Subjects: Male, MYOCARDIAL-ISCHEMIA, Cardiac & Cardiovascular Systems, SYMPTOMS, Myocardial Infarction, PECTORIS, 030204 cardiovascular system & hematology, Coronary artery disease, Angina, 0302 clinical medicine, Myocardial Revascularization, Odds Ratio, Coronary Heart Disease, 030212 general & internal medicine, Myocardial infarction, Registries, Stroke, Original Research, RISK, Framingham Risk Score, Middle Aged, Prognosis, Hospitalization, Cardiovascular Diseases, Cardiology, Female, Cardiology and Cardiovascular Medicine, OUTPATIENTS, Life Sciences & Biomedicine, coronary artery disease, medicine.medical_specialty, CLINICAL-OUTCOMES, Myocardial revascularization, SOUL, HEART-DISEASE, angina, 03 medical and health sciences, cardiovascular events, Internal medicine, medicine, Humans, cardiovascular diseases, Angina, Stable, RATES, CLARIFY REGISTRY, Aged, Proportional Hazards Models, Heart Failure, Science & Technology, REACH Registry Investigators, business.industry, Odds ratio, CORONARIOPATIA, medicine.disease, United States, Heart failure, Case-Control Studies, Emergency medicine, Cardiovascular System & Cardiology, business
Abstract: Background The extent to which angina is associated with future cardiovascular events in patients with coronary artery disease has long been debated. Methods and Results Included were outpatients with established coronary artery disease who were enrolled in the REACH registry and were followed for 4 years. Angina at baseline was defined as necessitating episodic or permanent antianginal treatment. The primary end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included heart failure, cardiovascular hospitalizations, and coronary revascularization. The independent association between angina and first/total events was examined using Cox and logistic regression models. Out of 26 159 patients with established coronary artery disease, 13 619 (52%) had angina at baseline. Compared with patients without angina, patients with angina were more likely to be older, female, and had more heart failure and polyvascular disease ( P CI 1.11–1.27, P CI 0.99–1.14, P =0.11), and total primary end‐point events (adjusted risk ratio 1.08, CI 1.01–1.16, P =0.03). Patients with angina were at increased risk for heart failure (adjusted odds ratio 1.17, CI 1.06–1.28, P =0.002), cardiovascular hospitalizations (adjusted odds ratio 1.29, CI 1.21–1.38, P CI 1.13–1.34, P Conclusions Patients with stable coronary artery disease and angina have higher rates of future cardiovascular events compared with patients without angina. After adjustment, angina was only weakly associated with cardiovascular death, myocardial infarction, or stroke, but significantly associated with heart failure, cardiovascular hospitalization, and coronary revascularization.
Published: 2016

49. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Author: Hovhannes J. Gukasyan, Michael R. Collins, Sutton Scott Channing, Kephart Susan Elizabeth, Shinji Yamazaki, Sacha Ninkovic, Simon Bergqvist, Fen Wang, Robert Arnold Kumpf, Michael Ryskin, Patrick Bingham, Pei-Pei Kung, Dominique Verhelle, Brian Yip, Karen A. Maegley, Robert A. Rollins, Peter A. Wells, Martha A. Ornelas, Buwen Huang, Valeria Fantin, Xiu Yu, Stephanie Scales, Wade Diehl, Indrawan James Mcalpine, Cody Krivacic, Mei Cui, Lisa Nguyen, Wenyue Hu, Tatlock John H, Dac M. Dinh, Martin James Wythes, Connie Fan, Gary Li, Martin Paul Edwards, Rui Eugene Yuanjin, John F. Braganza, Zehnder Luke Raymond, and Wei-Guo Zhang
Subjects: 0301 basic medicine, Models, Molecular, Lactams, Stereochemistry, Pyridones, Antineoplastic Agents, Mice, SCID, 03 medical and health sciences, chemistry.chemical_compound, Mice, In vivo, Amide, Cell Line, Tumor, Neoplasms, Drug Discovery, Potency, Moiety, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Ligand efficiency, Isoquinolines, 030104 developmental biology, chemistry, Lipophilic efficiency, Cyclization, Drug Design, Lactam, Molecular Medicine, Female, Linker
Abstract: A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.
Published: 2016

50. Weekly variation in health-care quality by day and time of admission: a nationwide, registry-based, prospective cohort study of acute stroke care

Author: Martin James, Harry Hemingway, Charles D.A. Wolfe, Benjamin Bray, Lizz Paley, Kevin Stewart, Anthony Rudd, Geoffrey Cloud, and Philippa Tyrrell
Subjects: Male, Pediatrics, medicine.medical_specialty, Speech-Language Pathology, Time Factors, Weekend effect, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Occupational Therapy, medicine, Humans, Mass Screening, Thrombolytic Therapy, Prospective Studies, Registries, 030212 general & internal medicine, Healthcare Disparities, Prospective cohort study, Stroke, Physical Therapy Modalities, Mass screening, Aged, Quality of Health Care, Aged, 80 and over, Medical Audit, Wales, business.industry, Brain, General Medicine, Odds ratio, medicine.disease, Hospitalization, Radiography, Survival Rate, England, Cohort, Female, Deglutition Disorders, business, 030217 neurology & neurosurgery, Health care quality, Cohort study
Abstract: Summary Background Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week. Methods We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week. Findings The study cohort comprised 74 307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35–66% [16/46–232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95–1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82–0·99). Interpretation The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect. Funding None.
Published: 2016
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