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<br /> EUROPEAN MEDICAL JOURNAL<br /> ISSN 2397-6764 Vol 1.3 • August 2016 • emjreviews.com<br /> CONTENTS<br /> EDITORIAL BOARD...................................................................................................................................... 4<br /> FEATURES<br /> • ETHICAL ISSUES ON AWAKE THORACIC SURGERY FOR SERIOUSLY CHRONICALLY<br /> ILL PATIENTS............................................................................................................................................ 12<br /> Gabor Kiss<br /> • ENDOSCOPIC MANAGEMENT OF SESSILE SERRATED POLYPS OF THE COLON.................. 16<br /> Karen Ma, Joshua Melson<br /> SYMPOSIUM REVIEWS<br /> • REGORAFENIB IN ADVANCED AND REFRACTORY GASTROINTESTINAL CANCERS.......... 21<br /> • OPTIMISING CANCER IMMUNOTHERAPY: CHALLENGES AND OPPORTUNITIES.................. 26<br /> • CHALLENGES A<a title="EMJ 1.3 2016 page 1" href="http://viewer.zmags.com/publication/981085ef?page=1"> EUROPEAN MEDICAL JOURNAL ISSN 2397-6764 </a> <a title="EMJ 1.3 2016 page 2" href="http://viewer.zmags.com/publication/981085ef?page=2"> CONTENTS EDITORIAL BOARD.......................</a> <a title="EMJ 1.3 2016 page 3" href="http://viewer.zmags.com/publication/981085ef?page=3"> EUROPEAN MEDICAL JOURNAL • THE EVOLVING BIOSIMI</a> <a title="EMJ 1.3 2016 page 4" href="http://viewer.zmags.com/publication/981085ef?page=4"> Editorial Board Editor-in-Chief: Prof Markus P</a> <a title="EMJ 1.3 2016 page 5" href="http://viewer.zmags.com/publication/981085ef?page=5"> European Medical Journal Prof Robert Dellaval</a> <a title="EMJ 1.3 2016 page 6" href="http://viewer.zmags.com/publication/981085ef?page=6"> SUBSCRIBE TOTHEEMJ NEWSLETTER NwEwwW.newSs.eLmjEr</a> <a title="EMJ 1.3 2016 page 7" href="http://viewer.zmags.com/publication/981085ef?page=7"> Welcome Welcome to the third edition of </a> <a title="EMJ 1.3 2016 page 8" href="http://viewer.zmags.com/publication/981085ef?page=8"> In asthma and COPD </a> <a title="EMJ 1.3 2016 page 9" href="http://viewer.zmags.com/publication/981085ef?page=9"> Foreword Dr Harry Thirkettle BSc Hons MBCh</a> <a title="EMJ 1.3 2016 page 10" href="http://viewer.zmags.com/publication/981085ef?page=10"> Information reflects UK marketing authorisation </a> <a title="EMJ 1.3 2016 page 11" href="http://viewer.zmags.com/publication/981085ef?page=11"> Now, when you want to give 50% them more help f</a> <a title="EMJ 1.3 2016 page 12" href="http://viewer.zmags.com/publication/981085ef?page=12"> ETHICAL ISSUES ON AWAKE THORACIC SURGERY FOR SERI</a> <a title="EMJ 1.3 2016 page 13" href="http://viewer.zmags.com/publication/981085ef?page=13"> hospital stays, leading to quick discharge </a> <a title="EMJ 1.3 2016 page 14" href="http://viewer.zmags.com/publication/981085ef?page=14"> process and its combination with a higher risk of</a> <a title="EMJ 1.3 2016 page 15" href="http://viewer.zmags.com/publication/981085ef?page=15"> A A A U U U S S S T T T R R VI VI VI </a> <a title="EMJ 1.3 2016 page 16" href="http://viewer.zmags.com/publication/981085ef?page=16"> ENDOSCOPIC MANAGEMENT OF SESSILE SERRATED POLYPS </a> <a title="EMJ 1.3 2016 page 17" href="http://viewer.zmags.com/publication/981085ef?page=17"> found in the proximal colon. Macroscopically thes</a> <a title="EMJ 1.3 2016 page 18" href="http://viewer.zmags.com/publication/981085ef?page=18"> mucosal resection (EMR) has become the widely ado</a> <a title="EMJ 1.3 2016 page 19" href="http://viewer.zmags.com/publication/981085ef?page=19"> Given the above findings, the US Multi-Society Tas</a> <a title="EMJ 1.3 2016 page 20" href="http://viewer.zmags.com/publication/981085ef?page=20"> 19. Kahi CJ et al. High colonoscopic preval</a> <a title="EMJ 1.3 2016 page 21" href="http://viewer.zmags.com/publication/981085ef?page=21"> REGORAFENIB IN ADVANCED AND REFRACTORY </a> <a title="EMJ 1.3 2016 page 22" href="http://viewer.zmags.com/publication/981085ef?page=22"> contribute to the efficacy and side effect profile</a> <a title="EMJ 1.3 2016 page 23" href="http://viewer.zmags.com/publication/981085ef?page=23"> 70 60 50 40 Proportion of patients (%) 30 2</a> <a title="EMJ 1.3 2016 page 24" href="http://viewer.zmags.com/publication/981085ef?page=24"> patients with mCRC in their clinics. The v</a> <a title="EMJ 1.3 2016 page 25" href="http://viewer.zmags.com/publication/981085ef?page=25"> Regorafenib in Metastatic Colorectal Cancer in </a> <a title="EMJ 1.3 2016 page 26" href="http://viewer.zmags.com/publication/981085ef?page=26"> OPTIMISING CANCER IMMUNOTHERAPY: CHALLENGES A</a> <a title="EMJ 1.3 2016 page 27" href="http://viewer.zmags.com/publication/981085ef?page=27"> Squibb, Celgene, GlaxoSmithKline, IQWig, Lilly, N</a> <a title="EMJ 1.3 2016 page 28" href="http://viewer.zmags.com/publication/981085ef?page=28"> assess T cell reactivity.6 This type of informati</a> <a title="EMJ 1.3 2016 page 29" href="http://viewer.zmags.com/publication/981085ef?page=29"> to overall response rate (ORR) and median p</a> <a title="EMJ 1.3 2016 page 30" href="http://viewer.zmags.com/publication/981085ef?page=30"> This calls into question the approach of one-size</a> <a title="EMJ 1.3 2016 page 31" href="http://viewer.zmags.com/publication/981085ef?page=31"> antiangiogenic therapy.39 Nivolumab significant</a> <a title="EMJ 1.3 2016 page 32" href="http://viewer.zmags.com/publication/981085ef?page=32"> PD-L1 testing has several technical challenges an</a> <a title="EMJ 1.3 2016 page 33" href="http://viewer.zmags.com/publication/981085ef?page=33"> patients with melanoma were representative of the</a> <a title="EMJ 1.3 2016 page 34" href="http://viewer.zmags.com/publication/981085ef?page=34"> MEDI6469, MEDI6383, MEDI0562, MOXR0916, PF</a> <a title="EMJ 1.3 2016 page 35" href="http://viewer.zmags.com/publication/981085ef?page=35"> cell tumour infiltration, total lymphocyte co</a> <a title="EMJ 1.3 2016 page 36" href="http://viewer.zmags.com/publication/981085ef?page=36"> PD-1/PD-L1 blockade can then be combined with blo</a> <a title="EMJ 1.3 2016 page 37" href="http://viewer.zmags.com/publication/981085ef?page=37"> a humanised murine model has been developed that </a> <a title="EMJ 1.3 2016 page 38" href="http://viewer.zmags.com/publication/981085ef?page=38"> into an immunogenic tumour to maximise the anti- </a> <a title="EMJ 1.3 2016 page 39" href="http://viewer.zmags.com/publication/981085ef?page=39"> Table 1 continued. Combination approach Targe</a> <a title="EMJ 1.3 2016 page 40" href="http://viewer.zmags.com/publication/981085ef?page=40"> Atezolizumab is being investigated in combination</a> <a title="EMJ 1.3 2016 page 41" href="http://viewer.zmags.com/publication/981085ef?page=41"> Science. 2015;348(6230):69-74. 6. Kvistborg P et </a> <a title="EMJ 1.3 2016 page 42" href="http://viewer.zmags.com/publication/981085ef?page=42"> versus everolimus in advanced renal- cell ca</a> <a title="EMJ 1.3 2016 page 43" href="http://viewer.zmags.com/publication/981085ef?page=43"> advanced solid tumors. Abstract TPS3107. ASCO Ann</a> <a title="EMJ 1.3 2016 page 44" href="http://viewer.zmags.com/publication/981085ef?page=44"> CHALLENGES AND CONSIDERATIONS IN THE MANAGEME</a> <a title="EMJ 1.3 2016 page 45" href="http://viewer.zmags.com/publication/981085ef?page=45"> Pathophysiology and Risk of Hyperkalaemia</a> <a title="EMJ 1.3 2016 page 46" href="http://viewer.zmags.com/publication/981085ef?page=46"> (i.e. low glomerular filtration rate [GFR]/protein</a> <a title="EMJ 1.3 2016 page 47" href="http://viewer.zmags.com/publication/981085ef?page=47"> alternative (CPS) available in some countries, wh</a> <a title="EMJ 1.3 2016 page 48" href="http://viewer.zmags.com/publication/981085ef?page=48"> With regards to the excretion of potassium,</a> <a title="EMJ 1.3 2016 page 49" href="http://viewer.zmags.com/publication/981085ef?page=49"> Safety data from the two ZS-9 studies indicated t</a> <a title="EMJ 1.3 2016 page 50" href="http://viewer.zmags.com/publication/981085ef?page=50"> cardiovascular risk, and effects of an ACE inhibi</a> <a title="EMJ 1.3 2016 page 51" href="http://viewer.zmags.com/publication/981085ef?page=51"> EDITOR’S PICK In t</a> <a title="EMJ 1.3 2016 page 52" href="http://viewer.zmags.com/publication/981085ef?page=52"> (FM), chronic fatigue syndrome (CFS), chroni</a> <a title="EMJ 1.3 2016 page 53" href="http://viewer.zmags.com/publication/981085ef?page=53"> Table 1: Features of central sensitisation.10,21-</a> <a title="EMJ 1.3 2016 page 54" href="http://viewer.zmags.com/publication/981085ef?page=54"> The current hypothesis is that the continuum of C</a> <a title="EMJ 1.3 2016 page 55" href="http://viewer.zmags.com/publication/981085ef?page=55"> Consequently, patients with organic rheumatologic</a> <a title="EMJ 1.3 2016 page 56" href="http://viewer.zmags.com/publication/981085ef?page=56"> The fibromyalgia/polysymptomatic distress visit In</a> <a title="EMJ 1.3 2016 page 57" href="http://viewer.zmags.com/publication/981085ef?page=57"> Table 2: Mayo Clinic fibromyalgia self-management </a> <a title="EMJ 1.3 2016 page 58" href="http://viewer.zmags.com/publication/981085ef?page=58"> Table 3: Central sensitisation: Multifactorial ae</a> <a title="EMJ 1.3 2016 page 59" href="http://viewer.zmags.com/publication/981085ef?page=59"> age U.S. adults. J Manag Care Pharm. 2012;18(6):4</a> <a title="EMJ 1.3 2016 page 60" href="http://viewer.zmags.com/publication/981085ef?page=60"> Outcome. 2014;12:128. 54. Pollard L et al</a> <a title="EMJ 1.3 2016 page 61" href="http://viewer.zmags.com/publication/981085ef?page=61"> AVANAFIL: THE SECOND-GENERATION TREATMENT OF</a> <a title="EMJ 1.3 2016 page 62" href="http://viewer.zmags.com/publication/981085ef?page=62"> colour Doppler ultrasound, is associated wit</a> <a title="EMJ 1.3 2016 page 63" href="http://viewer.zmags.com/publication/981085ef?page=63"> present in the heart), PDE-6 (120-fold, pre</a> <a title="EMJ 1.3 2016 page 64" href="http://viewer.zmags.com/publication/981085ef?page=64"> Table 2: Efficacy and safety parameters for avana</a> <a title="EMJ 1.3 2016 page 65" href="http://viewer.zmags.com/publication/981085ef?page=65"> Of note, the efficacy of the 100 mg dosage was lo</a> <a title="EMJ 1.3 2016 page 66" href="http://viewer.zmags.com/publication/981085ef?page=66"> which is of particular interest for couples seeki</a> <a title="EMJ 1.3 2016 page 67" href="http://viewer.zmags.com/publication/981085ef?page=67"> instrument to detect psychological componen</a> <a title="EMJ 1.3 2016 page 68" href="http://viewer.zmags.com/publication/981085ef?page=68"> the safety and efficacy of avanafil in subje</a> <a title="EMJ 1.3 2016 page 69" href="http://viewer.zmags.com/publication/981085ef?page=69"> dysfunction: a systematic review and meta-ana</a> <a title="EMJ 1.3 2016 page 70" href="http://viewer.zmags.com/publication/981085ef?page=70"> NEW EVIDENCE FOR EXOGENOUS GLYCO</a> <a title="EMJ 1.3 2016 page 71" href="http://viewer.zmags.com/publication/981085ef?page=71"> (cystitis). Exogenous restoration of the GAG laye</a> <a title="EMJ 1.3 2016 page 72" href="http://viewer.zmags.com/publication/981085ef?page=72"> treatment include the adverse effects associated </a> <a title="EMJ 1.3 2016 page 73" href="http://viewer.zmags.com/publication/981085ef?page=73"> Steinhoff et al.25 investigated the exogenous CS </a> <a title="EMJ 1.3 2016 page 74" href="http://viewer.zmags.com/publication/981085ef?page=74"> in men with post-radiation bladder pain following</a> <a title="EMJ 1.3 2016 page 75" href="http://viewer.zmags.com/publication/981085ef?page=75"> Urology. 1996;48(5):817-21. 8. Maggi CA, Meli A. </a> <a title="EMJ 1.3 2016 page 76" href="http://viewer.zmags.com/publication/981085ef?page=76"> THE EVOLVING BIOSIMILAR LANDSCAPE: APPROVAL OF TH</a> <a title="EMJ 1.3 2016 page 77" href="http://viewer.zmags.com/publication/981085ef?page=77"> INTRODUCTION In 2013, the European Commission (EC</a> <a title="EMJ 1.3 2016 page 78" href="http://viewer.zmags.com/publication/981085ef?page=78"> Box 1: How are biosimilars defined? Key characteri</a> <a title="EMJ 1.3 2016 page 79" href="http://viewer.zmags.com/publication/981085ef?page=79"> is highly similar for all critical quality attrib</a> <a title="EMJ 1.3 2016 page 80" href="http://viewer.zmags.com/publication/981085ef?page=80"> Analytics Physicochemical characterisation </a> <a title="EMJ 1.3 2016 page 81" href="http://viewer.zmags.com/publication/981085ef?page=81"> Table 3: European Medicines Agency Guidelines rel</a> <a title="EMJ 1.3 2016 page 82" href="http://viewer.zmags.com/publication/981085ef?page=82"> and a prospective observational study to assess t</a> <a title="EMJ 1.3 2016 page 83" href="http://viewer.zmags.com/publication/981085ef?page=83"> Immunogenicity is a crucial issue for all biologi</a> <a title="EMJ 1.3 2016 page 84" href="http://viewer.zmags.com/publication/981085ef?page=84"> REFERENCES 1. European Medicines Agency. Summary</a> <a title="EMJ 1.3 2016 page 85" href="http://viewer.zmags.com/publication/981085ef?page=85"> LATE AND VERY LATE STENT THROMBOSIS IN THE ERA </a> <a title="EMJ 1.3 2016 page 86" href="http://viewer.zmags.com/publication/981085ef?page=86"> syndrome), ‘probable’ (any unexplained death ≤30 </a> <a title="EMJ 1.3 2016 page 87" href="http://viewer.zmags.com/publication/981085ef?page=87"> response.7,15-17 In an autopsy study consisting o</a> <a title="EMJ 1.3 2016 page 88" href="http://viewer.zmags.com/publication/981085ef?page=88"> (e, f): a 60-year-old man who received a </a> <a title="EMJ 1.3 2016 page 89" href="http://viewer.zmags.com/publication/981085ef?page=89"> Zotarolimus is a semisynthetic derivative</a> <a title="EMJ 1.3 2016 page 90" href="http://viewer.zmags.com/publication/981085ef?page=90"> stent thrombosis compared with BMSs (OR: 0.27, 95</a> <a title="EMJ 1.3 2016 page 91" href="http://viewer.zmags.com/publication/981085ef?page=91"> However, it is important to note that these trial</a> <a title="EMJ 1.3 2016 page 92" href="http://viewer.zmags.com/publication/981085ef?page=92"> limit their widespread usage. Future stent design</a> <a title="EMJ 1.3 2016 page 93" href="http://viewer.zmags.com/publication/981085ef?page=93"> (EXAMINATION): 1 year results of a randomise</a> <a title="EMJ 1.3 2016 page 94" href="http://viewer.zmags.com/publication/981085ef?page=94"> Have you read the previous editions of the Europe</a> <a title="EMJ 1.3 2016 page 95" href="http://viewer.zmags.com/publication/981085ef?page=95"> uropean Medical Journal which are available now t</a> <a title="EMJ 1.3 2016 page 96" href="http://viewer.zmags.com/publication/981085ef?page=96"> SPONDYLOARTHRITIS: PATHOGENESIS, CLINICAL MANIFES</a> <a title="EMJ 1.3 2016 page 97" href="http://viewer.zmags.com/publication/981085ef?page=97"> ethnicity, and geographical distribution of </a> <a title="EMJ 1.3 2016 page 98" href="http://viewer.zmags.com/publication/981085ef?page=98"> Arthritis, enthesitis, or dactylitis plus ≥1 of: </a> <a title="EMJ 1.3 2016 page 99" href="http://viewer.zmags.com/publication/981085ef?page=99"> level, there is evidence with TNF and IL23/IL17. </a> <a title="EMJ 1.3 2016 page 100" href="http://viewer.zmags.com/publication/981085ef?page=100"> HLA-B27 positivity is an excellent predictor</a> <a title="EMJ 1.3 2016 page 101" href="http://viewer.zmags.com/publication/981085ef?page=101"> TREATMENT The main goal of SpA management is to </a> <a title="EMJ 1.3 2016 page 102" href="http://viewer.zmags.com/publication/981085ef?page=102"> Immunol Rev. 2010;233(1):162-80. 7. Brown MA e</a> <a title="EMJ 1.3 2016 page 103" href="http://viewer.zmags.com/publication/981085ef?page=103"> EVALUATION OF STRESS URINARY INCONTINENCE: </a> <a title="EMJ 1.3 2016 page 104" href="http://viewer.zmags.com/publication/981085ef?page=104"> Table 1: Features of urethral biology contributin</a> <a title="EMJ 1.3 2016 page 105" href="http://viewer.zmags.com/publication/981085ef?page=105"> Table 3: Preoperative evaluation. History • On</a> <a title="EMJ 1.3 2016 page 106" href="http://viewer.zmags.com/publication/981085ef?page=106"> Recently, the American College of Obstetricians a</a> <a title="EMJ 1.3 2016 page 107" href="http://viewer.zmags.com/publication/981085ef?page=107"> testing with CST and prolapse reduction alone is </a> <a title="EMJ 1.3 2016 page 108" href="http://viewer.zmags.com/publication/981085ef?page=108"> or ‘very much better’. At 12 months, treatment su</a> <a title="EMJ 1.3 2016 page 109" href="http://viewer.zmags.com/publication/981085ef?page=109"> 5. Clinicians should perform stress testing with</a> <a title="EMJ 1.3 2016 page 110" href="http://viewer.zmags.com/publication/981085ef?page=110"> slingplasty (IVS): an ambulatory surgical procedu</a> <a title="EMJ 1.3 2016 page 111" href="http://viewer.zmags.com/publication/981085ef?page=111"> CIRRHOSIS: REVIEWING THE LITERATURE A</a> <a title="EMJ 1.3 2016 page 112" href="http://viewer.zmags.com/publication/981085ef?page=112"> East Asia and Sub-Saharan Africa. According to th</a> <a title="EMJ 1.3 2016 page 113" href="http://viewer.zmags.com/publication/981085ef?page=113"> PSC or PBC.20 Gamma-glutamyl transpeptidase l</a> <a title="EMJ 1.3 2016 page 114" href="http://viewer.zmags.com/publication/981085ef?page=114"> gradient to >5 mmHg.38 The haemodynamic</a> <a title="EMJ 1.3 2016 page 115" href="http://viewer.zmags.com/publication/981085ef?page=115"> In a study, it was demonstrated that in patients </a> <a title="EMJ 1.3 2016 page 116" href="http://viewer.zmags.com/publication/981085ef?page=116"> fumarate for up to 5 years. Hepatol Int. 2015;9(2</a> <a title="EMJ 1.3 2016 page 117" href="http://viewer.zmags.com/publication/981085ef?page=117"> 49. Mathurin P, Bataller R. Trends in the managem</a> <a title="EMJ 1.3 2016 page 118" href="http://viewer.zmags.com/publication/981085ef?page=118"> IN-STENT RESTENOSIS AFTER CAROTID ARTERY S</a> <a title="EMJ 1.3 2016 page 119" href="http://viewer.zmags.com/publication/981085ef?page=119"> IN-STENT RESTENOSIS: INCIDENCE AND PATHOPHYSIOLOG</a> <a title="EMJ 1.3 2016 page 120" href="http://viewer.zmags.com/publication/981085ef?page=120"> are the most common parameters used for ste</a> <a title="EMJ 1.3 2016 page 121" href="http://viewer.zmags.com/publication/981085ef?page=121"> Table 1: Comparison of parameters for defining ste</a> <a title="EMJ 1.3 2016 page 122" href="http://viewer.zmags.com/publication/981085ef?page=122"> of HbA1c should be a strong recommendation to the</a> <a title="EMJ 1.3 2016 page 123" href="http://viewer.zmags.com/publication/981085ef?page=123"> and stent removal; primary closure of </a> <a title="EMJ 1.3 2016 page 124" href="http://viewer.zmags.com/publication/981085ef?page=124"> 17. Wasser K et al. Clinical impact and predictor</a> <a title="EMJ 1.3 2016 page 125" href="http://viewer.zmags.com/publication/981085ef?page=125"> EUROPEAN MEDICAL JOURNAL provides influential arti</a> <a title="EMJ 1.3 2016 page 126" href="http://viewer.zmags.com/publication/981085ef?page=126"> HEPATITIS C: IS REGRESSION OF ADVANCED FIBROSI</a> <a title="EMJ 1.3 2016 page 127" href="http://viewer.zmags.com/publication/981085ef?page=127"> the extracellular matrix and the progre</a> <a title="EMJ 1.3 2016 page 128" href="http://viewer.zmags.com/publication/981085ef?page=128"> Table 1: Rates of cirrhosis regression measured b</a> <a title="EMJ 1.3 2016 page 129" href="http://viewer.zmags.com/publication/981085ef?page=129"> regression of cirrhosis was assessed by performin</a> <a title="EMJ 1.3 2016 page 130" href="http://viewer.zmags.com/publication/981085ef?page=130"> 70 60 50 40 30 Number of patients 20 10 </a> <a title="EMJ 1.3 2016 page 131" href="http://viewer.zmags.com/publication/981085ef?page=131"> In cirrhotic patients, SVR improves prognosi</a> <a title="EMJ 1.3 2016 page 132" href="http://viewer.zmags.com/publication/981085ef?page=132"> Hepatol. 2013;59(4):675-83. 8. Bruno S et al. Is </a> <a title="EMJ 1.3 2016 page 133" href="http://viewer.zmags.com/publication/981085ef?page=133"> CHRONIC TOTAL OCCLUSION IN PATIENTS AFTER </a> <a title="EMJ 1.3 2016 page 134" href="http://viewer.zmags.com/publication/981085ef?page=134"> significantly and are carried out in 3% of </a> <a title="EMJ 1.3 2016 page 135" href="http://viewer.zmags.com/publication/981085ef?page=135"> compared with the CTOs without a CABG and severe </a> <a title="EMJ 1.3 2016 page 136" href="http://viewer.zmags.com/publication/981085ef?page=136"> Currently, the retrograde approach can </a> <a title="EMJ 1.3 2016 page 137" href="http://viewer.zmags.com/publication/981085ef?page=137"> the patient experienced angina, particularly duri</a> <a title="EMJ 1.3 2016 page 138" href="http://viewer.zmags.com/publication/981085ef?page=138"> CONCLUSION • CTOs after a CABG have worse lesi</a> <a title="EMJ 1.3 2016 page 139" href="http://viewer.zmags.com/publication/981085ef?page=139"> equipment delivery from target lesion</a> <a title="EMJ 1.3 2016 page 140" href="http://viewer.zmags.com/publication/981085ef?page=140"> SUBSCRIBE TO RECEIVE THE LATEST PUBLICATIONS, NE</a>