მთავარი Davidson S Principles and Practice of M
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07 May 2021 (08:09)
ok s e. re sf ok m co m e. co m co e. re sf sf re ok ok ks oo eb m co e. fre ok s eb o m m m co e. ks fre oo eb m co m e. re ks f oo eb m sf ks oo eb m oo k eb m .c om m e. co re e fre ks oo eb m m e. co fre eb oo ks m ks oo eb m co m fre e. ks oo eb m m e. co e. co m fre oo ks eb m ks fre oo eb m ks oo eb m e. co m om fre e. c fre ks oo eb m ok s eb o m m e. co re ks f oo eb m fre fre e. c eb m fre e. co m e. co m fre oo eb m m m eb eb oo ks ks oo ks oo eb m oo oo eb m m m e. co ks fre Activate the eBook version of this title at no additional charge. ks ks ok s eb o oo eb m e. co m om m e. co re ks f Any screen. Any time. Anywhere. om re e 6 Go to “My Library” m m co e. ok s fre ks fre Place Peel Off Sticker Here m m m eb eb o oo eb eb m eb eb m co e. e. oo ks f It’s that easy! m e. co e. co co m m For technical assistance: email firstname.lastname@example.org call 1-800-401-9962 (inside the US) call +1-314-447-8200 (outside the US) e. ks Log in or Sign up oo 5 re sf ok sf re ok ok sf re Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on studentconsult.inkling.com. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at studentconsult.inkling.com and may not be transferred to another party by resale, lending, or other means. 2015v1.0 ok s Click “Redeem” co m 4 m m 3 Type code into “Enter Code” box oo oo k oo eb Scratch off your code re m 2 Scan this QR code to redeem your eBook through your mobile device: ks eb oo ks 1 Visit studentconsult.inkling.com/redeem ks sf fre fre Unlock your eBook today. .c e. co e. co m m Student Consult eBooks give you the power to browse and find content, view enhanced images, share notes and high; lights—both online and offline. ok s e. re sf ok m co m e. co m co e. re sf sf re ok ok ks oo eb m co e. fre ok s eb o m m m co e. ks fre oo eb m co m e. re ks f oo eb m sf ks oo eb m oo k eb m .c m om e. co re e fre ks oo eb m m e. co fre eb oo ks m ks oo eb m ks oo eb m m e. co e. co m fre oo ks eb m ks fre oo eb m Medicine co m fre e. Davidson’s Principles and Practice of ks oo eb m e. co m om fre e. c fre ks oo eb m ok s eb o m m e. co re ks f oo eb m fre e. c ks oo ks ks oo eb m m co e. fre oo ks ok s eb eb o m m m m ok s ok sf re e. co e. co sf re ok oo m om .c re e sf oo k eb m m co e. ks fre oo eb m m co e. re eb eb m m e. co fre ks oo eb m co m e. re ks f oo eb sf m oo ks fre e. co m e. co m fre oo ks eb m m e. co fre eb oo ks m m ok eb eb m m m e. co ks fre oo eb fre oo ks ok s This famous textbook was the brainchild of one of the great Professors of Medicine of the 20th century. Stanley Davidson was born in Sri Lanka and began his medical undergraduate training at Trinity College, Cambridge; this was interrupted by World War I and later resumed in Edinburgh. He was seriously wounded in battle, and the carnage and shocking waste of young life that he encountered at that time had a profound effect on his subsequent attitudes and values. In 1930 Stanley Davidson was appointed Professor of Medicine at the University of Aberdeen, one of the first full-time Chairs of Medicine anywhere and the first in Scotland. In 1938 he took up the Chair of Medicine at Edinburgh and was to remain in this post until retirement in 1959. He was a renowned educator and a particularly gifted teacher at the bedside, where he taught that everything had to be questioned and explained. He himself gave most of the systematic lectures in Medicine, which were made available as typewritten notes that emphasised the essentials and far surpassed any textbook available at the time. Principles and Practice of Medicine was conceived in the late 1940s with its origins in those lecture notes. The first edition, published in 1952, was a masterpiece of clarity and uniformity of style. It was of modest size and price, but sufficiently comprehensive and up to date to provide students with the main elements of sound medical practice. Although the format and presentation have seen many changes in 22 subsequent editions, Sir Stanley’s original vision and objectives remain. More than half a century after its first publication, his book continues to inform and educate students, doctors and health professionals all over the world. eb o oo eb m m e. co m om m e. co ks f re Sir Stanley Davidson (1894–1981) fre fre e. c m fre e. co m e. co m fre m om .c re e m m co e. fre ks m co e. Sydney 2018 ok s sf St Louis ok sf re ok oo m m m e. co co e. re sf ok Philadelphia eb eb o oo eb m m Illustrations by Robert Britton re Consultant Microbiologist, Harrogate and District NHS Foundation Trust; Honorary Senior Lecturer, University of Leeds, UK oo eb ok s ks f Richard P Hobson LLM, PhD, MRCP(UK), FRCPath m oo eb eb m m ks fre re e. e. co Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh; Honorary Professor, University of Edinburgh, UK Oxford ks sf oo k ks oo eb m co m Mark WJ Strachan BSc(Hons), MD, FRCPE New York ks eb eb m m e. co fre fre eb oo ks m Consultant Gastroenterologist, Royal Infirmary of Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK London oo oo ks oo ks eb m m e. co Arthritis Research UK Professor of Rheumatology, University of Edinburgh; Honorary Consultant Rheumatologist, Western General Hospital, Edinburgh, UK Ian D Penman BSc(Hons), MD, FRCPE ks eb eb m m m e. co ks fre oo Stuart H Ralston MD, FRCP, FMedSci, FRSE, FFPM(Hon) Edinburgh oo oo ks ok s eb o oo eb m eb Edited by Medicine 23rd Edition m e. co m om m e. co re ks f Davidson’s Principles and Practice of oo eb m m m eb eb o oo ks ks ok s fre fre e. c e. co m om m e. co re ks f oo eb m © 2018 Elsevier Ltd. All rights reserved. co m e. co m m Illustrations and boxes in Chapter 8 © Julian White. fre e. oo oo eb eb m m om m re e .c e. co ks oo eb m ok s sf re e. co Content Strategist: Laurence Hunter Content Development Specialist: Wendy Lee Content Coordinator: Susan Jansons Project Manager: Louisa Talbott Designer: Miles Hitchen ok 3 2 1 m m e. co 5 4 sf re 6 ok 8 7 oo m e. ok s eb o m m fre ks fre oo eb The publisher’s policy is to use paper manufactured from sustainable forests m co e. re sf ok m co co e. e. re ks f oo eb m Printed in China Last digit is the print number: 9 ks sf eb m co m m m m eb oo oo k ks eb oo ks fre fre Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. eb e. co ISBN 978-0-7020-7028-0 International ISBN 978-0-7020-7027-3 ks ks oo ks Seventeenth edition 1995 Eighteenth edition 1999 Nineteenth edition 2002 Twentieth edition 2006 Twenty-first edition 2010 Twenty-second edition 2014 Twenty-third edition 2018 eb Ninth edition 1968 Tenth edition 1971 Eleventh edition 1974 Twelfth edition 1977 Thirteenth edition 1981 Fourteenth edition 1984 Fifteenth edition 1987 Sixteenth edition 1991 m First edition 1952 Second edition 1954 Third edition 1956 Fourth edition 1958 Fifth edition 1960 Sixth edition 1962 Seventh edition 1964 Eighth edition 1966 m m eb oo fre ks fre e. co No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the publisher (other than as may be noted herein). ks oo eb m om .c re e ks eb oo sf m m co e. fre Envenomation ks oo eb m m m m SHL Thomas 8. 131 eb o oo eb Poisoning 99 131 ok s ks fre ks f eb 7. eb co m fre e. ks oo m m co e. co m re e. 91 EMERGENCY AND CRITICAL CARE MEDICINE oo PART 2 61 Principles of infectious disease JAT Sandoe, DH Dockrell 1 37 Population health and epidemiology H Campbell, DA McAllister 1 13 eb eb m m Clinical immunology SE Marshall, SL Johnston 6. xix oo k Clinical genetics K Tatton-Brown, DR FitzPatrick 5. xvii m fre Clinical therapeutics and good prescribing oo eb oo ks e. co Clinical decision-making N Cooper, AL Cracknell ks m e. co fre FUNDAMENTALS OF MEDICINE SRJ Maxwell 4. xi xv m m m Introduction 3. ix eb Acknowledgements 2. m m e. co m fre oo ks eb eb International Advisory Board 1. oo oo eb eb o m m e. co ks fre oo Contributors ks ks ok s fre fre e. c e. co m om m e. co re ks f oo eb m Preface PART 1 Contents 151 J White m m co e. co 173 ok sf re e. Acute medicine and critical illness VR Tallentire, MJ MacMahon 163 ok s M Byers sf re 10. Environmental medicine ok ok sf re e. co m 9. e. co m fre eb m ks oo eb ks oo eb m m co e. fre ks eb m m m co e. 1269 ok s re sf ok sf re L Mackillop, FEM Neuberger e. co Maternal medicine ok co e. re sf m .c re e oo k 1209 m Dermatology SH Ibbotson 30. 1179 m RM Steel, SM Lawrie 29. 1061 1163 eb o Medical psychiatry m eb 28. oo Medical ophthalmology J Olson 981 1147 ok s Stroke medicine P Langhorne 27. m ks fre 26. e. Neurology JP Leach, RJ Davenport eb oo ks f re e. 25. co GPR Clunie, SH Ralston 911 m Rheumatology and bone disease co m 24. eb Haematology and transfusion medicine m m 23. eb QM Anstee, DEJ Jones 719 845 m Hepatology oo 22. HG Watson, DJ Culligan, LM Manson ok om m e. co E El-Omar, MH McLean 691 763 sf Gastroenterology ks 21. Diabetes mellitus ER Pearson, RJ McCrimmon fre e. co fre 20. AG Shand, JPH Wilding oo Nutritional factors in disease m 19. 629 m MWJ Strachan, JDC Newell-Price 381 545 eb eb Endocrinology m eb 18. eb oo ks co m oo Respiratory medicine PT Reid, JA Innes 345 441 ks Cardiology fre B Conway, PJ Phelan, GD Stewart DE Newby, NR Grubb 17. m fre e. Nephrology and urology ks ks A Mather, L Burnett, DR Sullivan, P Stewart oo ks 16. e. co m Clinical biochemistry and metabolic medicine m e. co oo ks fre 15. 329 m GR Scott 14. 305 eb Sexually transmitted infections m m 13. 215 oo HIV infection and AIDS G Maartens 215 oo fre e. c ok s Infectious disease DH Dockrell, S Sundar, BJ Angus 12. eb om m 11. CLINICAL MEDICINE eb o oo ks f re PART 3 e. co vi • Contents m co ks oo eb m co e. fre m om ks oo eb m Laboratory reference ranges ks oo eb m .c re e co m fre e. ks eb m 1313 1301 ks oo fre ks oo om e. co m fre e. c Adolescent and transition medicine ok s e. re sf oo Pain and palliative care m eb Oncology sf oo k eb m Index ok s eb m m ok s Ageing and disease eb o m m SJ Jenks e. co m GG Dark eb o m m e. co re ks f R Mann ok m e. co 35. fre oo ks eb m m e. co 34. co e. fre ks oo eb m m e. co fre ks fre oo eb m 33. e. co ks fre oo eb m co m e. re ks f oo eb m MD Witham sf re m co e. re sf oo eb oo ks m 32. ok ok eb m 31. Contents • vii 1287 1337 LA Colvin, M Fallon 1357 1365 ok s e. re sf ok m co m e. co m co e. re sf sf re ok ok ks oo eb m co e. fre ok s eb o m m m co e. ks fre oo eb m co m e. re ks f oo eb m sf ks oo eb m oo k eb m .c om m e. co re e fre ks oo eb m m e. co fre eb oo ks m ks oo eb m co m fre e. ks oo eb m m e. co e. co m fre oo ks eb m ks fre oo eb m ks oo eb m e. co m om fre e. c fre ks oo eb m ok s eb o m m e. co re ks f oo eb m This page intentionally left blank fre fre e. c eb m co m fre e. ks oo eb m m co e. eb oo ks fre ok s eb o m m m m SHR, IDP, MWJS, RPH Edinburgh 2018 ok s ok sf re e. co e. co sf re ok oo eb m om .c re e sf oo k eb m co e. ks fre oo eb m m co ks ks oo eb m m m ks oo eb m co m e. e. re sf the core principles behind clinical decision-making and good prescribing. Subsequent chapters discuss medical emergencies in poisoning, envenomation and environmental medicine, while a new chapter explores common presentations in acute medicine, as well as the recognition and management of the critically ill. The disease-specific chapters that follow cover the major medical specialties, each one thoroughly revised and updated to ensure that readers have access to the ‘cutting edge’ of medical knowledge and practice. Two new chapters on maternal and adolescent/transition medicine now complement the one on ageing and disease, addressing particular problems encountered at key stages of patients’ lives. Medical ophthalmology is also now included as a direct response to readers’ requests. The innovations introduced in recent editions have been maintained and, in many cases, developed. The highly popular ‘Clinical Examination’ overviews have been extended to the biochemistry, nutrition and dermatology chapters. The ‘Presenting Problems’ sections continue to provide an invaluable overview of the most common presentations in each disease area. The ‘Emergency’ and ‘Practice Point’ boxes have been retained along with the ‘In Old Age’, ‘In Pregnancy’ and ‘In Adolescence’ boxes, which emphasise key practical points in the presentation and management of the elderly, women with medical disorders who are pregnant or planning pregnancy, and teenagers transitioning between paediatric and adult services. Education is achieved by assimilating information from many sources and readers of this book can enhance their learning experience by using several complementary resources. We are delighted to have a new self-testing companion book entitled Davidson’s Assessment in Medicine, containing over 1250 multiple choice questions specifically tailored to the contents of Davidson’s. The long-standing association of Davidson’s with its sister books, Macleod’s Clinical Examination (now in its 14th Edition) and Principles and Practice of Surgery (7th Edition), still holds good. Our ‘family’ has also expanded with the publication of Davidson’s Essentials of Medicine, a long-requested pocket-sized version of the main text; Davidson’s 100 Clinical Cases, which contains scenarios directly based on our ‘Presenting Problems’; and Macleod’s Clinical Diagnosis, which describes a systematic approach to the differential diagnosis of symptoms and signs. We congratulate the editors and authors of these books for continuing the tradition of easily digested and expertly illustrated texts. We all take immense pride in continuing the great tradition first established by Sir Stanley Davidson and in producing an outstanding book for the next generation of doctors. e. co fre fre re ks f oo ok oo oo eb m e. co m fre oo ks e. co m m eb oo eb ks ks ok s eb o m m e. co ks fre Well over two million copies of Davidson’s Principles and Practice of Medicine have been sold since it was first published in 1952. Now in its 23rd Edition, Davidson’s is regarded as a ‘must-have’ textbook for thousands of medical students, doctors and health professionals across the world, describing the pathophysiology and clinical features of the most important conditions encountered in the major specialties of adult medicine and explaining how to investigate, diagnose and manage them. The book is the winner of numerous prizes and awards and has been translated into many languages. Taking its origins from Sir Stanley Davidson’s much-admired lecture notes, the book has endured because it continues to keep pace with how modern medicine is taught and to provide a wealth of information in an easy-to-read, concise and beautifully illustrated format. Davidson’s strives to ensure that readers can not only recognise the clinical features of a disease but also understand the underlying causes. To achieve this, each chapter begins with a summary of the relevant pre-clinical science, linking pathophysiology with clinical presentation and treatment so that students can use the book from the outset of their medical studies right through to their final examinations and beyond. The regular introduction of new authors and editors is important for maintaining freshness. On this occasion, Professor Mark Strachan and Dr Richard Hobson have come on board as editors, and 26 new authors have joined our existing contributors to make up an outstanding team of authorities in their respective fields. As well as recruiting authors from around the globe, particularly for topics such as infectious diseases, HIV and envenomation, we welcome members from 17 countries on to our International Advisory Board. These leading experts provide detailed comments that are crucial to our revision of each new edition. A particularly important aspect in planning the revision is for the editors to meet students and faculty in medical schools in those countries where the book is most widely read, so that we can respond to the feedback of our global readership and their tutors. We use this feedback, along with the information we gather via detailed student reviews and surveys, to craft each edition. The authors, editors and publishing team aim to ensure that readers all over the world are best served by a book that integrates medical science with clinical medicine to convey key knowledge and practical advice in an accessible and readable format. The amount of detail is tailored to the needs of medical students working towards their final examinations, as well as candidates preparing for Membership of the Royal Colleges of Physicians (MRCP) or its equivalent. With this new edition we have introduced several changes in both structure and content. The opening six chapters provide an account of the principles of genetics, immunology, infectious diseases and population health, along with a discussion of eb oo ks eb e. co m om m e. co re ks f oo eb m m m m Preface ok s e. re sf ok m co m e. co m co e. re sf sf re ok ok ks oo eb m co e. fre ok s eb o m m m co e. ks fre oo eb m co m e. re ks f oo eb m sf ks oo eb m oo k eb m .c om m e. co re e fre ks oo eb m m e. co fre eb oo ks m ks oo eb m co m fre e. ks oo eb m m e. co e. co m fre oo ks eb m ks fre oo eb m ks oo eb m e. co m om fre e. c fre ks oo eb m ok s eb o m m e. co re ks f oo eb m This page intentionally left blank fre fre e. c eb m co m ks ks oo eb m m m Marie Fallon MD, FRCP St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, UK co e. oo eb m m Neil R Grubb MD, FRCP Consultant in Cardiology, Royal Infirmary of Edinburgh; Honorary Senior Lecturer in Cardiovascular Sciences, University of Edinburgh, UK ks fre eb o ok s David R FitzPatrick MD, FMedSci Professor, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK Sally H Ibbotson BSc(Hons), MD, FRCPE Professor of Photodermatology, University of Dundee; Honorary Consultant Dermatologist and Head of Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK m co e. ok s re sf ok ok sf re e. oo .c re e sf oo k eb m Emad El-Omar BSc(Hons), MD(Hons), FRCPE, FRSE, FRACP Professor of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia e. co co Nicola Cooper FAcadMEd, FRCPE, FRACP Consultant Physician, Derby Teaching Hospitals NHS Foundation Trust, Derby; Honorary Clinical Associate Professor, Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, UK eb m om m David H Dockrell MD, FRCPI, FRCPG, FACP Professor of Infection Medicine, Medical Research Council/ University of Edinburgh Centre for Inflammation Research, University of Edinburgh, UK m ks fre oo eb m m Bryan Conway MB, MRCP, PhD Senior Lecturer, Centre for Cardiovascular Science, University of Edinburgh; Honorary Consultant Nephrologist, Royal Infirmary of Edinburgh, UK re Richard J Davenport DM, FRCPE, BMedSci Consultant Neurologist, Royal Infirmary of Edinburgh and Western General Hospital, Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK co e. e. re oo ks f Lesley A Colvin BSc, FRCA, PhD, FRCPE, FFPMRCA Consultant, Department of Anaesthesia, Critical Care and Pain Medicine, Western General Hospital, Edinburgh; Honorary Professor in Anaesthesia and Pain Medicine, University of Edinburgh, UK sf Graham G Dark FRCP, FHEA Senior Lecturer in Medical Oncology and Cancer Education, Newcastle University, Newcastle upon Tyne, UK e. co fre ks oo eb m co m Gavin PR Clunie BSc, MD, FRCP Consultant Rheumatologist and Metabolic Bone Physician, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK ok fre e. ks oo eb m m m e. co fre eb oo ks Harry Campbell MD, FRCPE, FFPH, FRSE Professor of Genetic Epidemiology and Public Health, Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK eb oo oo eb m e. co m fre oo ks Dominic J Culligan BSc, MD, FRCP, FRCPath Consultant Haematologist, Aberdeen Royal Infirmary; Honorary Senior Lecturer, University of Aberdeen, UK eb Quentin M Anstee BSc(Hons), PhD, FRCP Professor of Experimental Hepatology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne; Honorary Consultant Hepatologist, Freeman Hospital, Newcastle upon Tyne, UK Mark Byers OBE, FRCGP, FFSEM, FIMC, MRCEM Consultant in Pre-Hospital Emergency Medicine, Institute of Pre-Hospital Care, London, UK m ks ks ok s eb o m m e. co ks fre oo eb m Alison L Cracknell FRCP Consultant, Medicine for Older People, Leeds Teaching Hospitals NHS Trust, Leeds; Honorary Clinical Associate Professor, University of Leeds, UK Leslie Burnett MBBS, PhD, FRCPA, FHGSA Chief Medical Officer, Genome.One, Garvan Institute of Medical Research, Sydney; Conjoint Professor, St Vincent’s Clinical School, UNSW; Honorary Professor in Pathology and Genetic Medicine, Sydney Medical School, University of Sydney, Australia m e. co m om m e. co re ks f oo eb m Brian J Angus BSc(Hons), DTM&H, FRCP, MD, FFTM(Glas) Associate Professor, Nuffield Department of Medicine, University of Oxford, UK Contributors fre e. c fre Michael J MacMahon FRCA, FICM, EDIC Consultant in Anaesthesia and Intensive Care, Victoria Hospital, Kirkcaldy, UK ks oo ks m om re e ks sf m eb oo oo k m co e. eb oo ks fre ok s eb o m m Peter T Reid MD, FRCPE Consultant Physician, Respiratory Medicine, Lothian University Hospitals, Edinburgh, UK m co ok s sf re e. Jonathan AT Sandoe PhD, FRCPath Associate Clinical Professor, University of Leeds; Consultant Microbiologist, Leeds Teaching Hospitals NHS Trust, UK ok ok sf re e. re Stuart H Ralston MD, FRCP, FMedSci, FRSE, FFPM(Hon) Arthritis Research UK Professor of Rheumatology, University of Edinburgh; Honorary Consultant Rheumatologist, Western General Hospital, Edinburgh, UK e. co co m Amanda Mather MBBS, FRACP, PhD Consultant Nephrologist, Department of Renal Medicine, Royal North Shore Hospital, Sydney; Conjoint Senior Lecturer, Faculty of Medicine, University of Sydney, Australia Paul J Phelan MD, FRCPE Consultant Nephrologist and Renal Transplant Physician, Royal Infirmary of Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK m oo eb m Sara E Marshall FRCP, FRCPath, PhD Professor of Clinical Immunology, Medical Research Institute, University of Dundee, UK sf eb m co e. ks fre ks f oo Lynn M Manson MD, FRCPE, FRCPath Consultant Haematologist, Scottish National Blood Transfusion Service, Department of Transfusion Medicine, Royal Infirmary of Edinburgh, UK ok John Olson MD, FRPCE, FRCOphth Consultant Ophthalmic Physician, Aberdeen Royal Infirmary; Honorary Reader, University of Aberdeen, UK Ewan R Pearson MA, PhD, FRCPE Professor of Diabetic Medicine, University of Dundee, UK co m re e. Rebecca Mann BMedSci, MRCP, FRCPCh Consultant Paediatrician, Taunton and Somerset NHS Foundation Trust, Taunton, UK John DC Newell-Price MA, PhD, FRCP Professor of Endocrinology and Consultant Endocrinologist, Department of Oncology and Metabolism, University of Sheffield, UK m m eb oo Lucy Mackillop MA(Oxon), FRCP Consultant Obstetric Physician, Oxford University Hospitals NHS Foundation Trust, Oxford; Honorary Senior Clinical Lecturer, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, UK .c e. co fre ks eb oo ks David E Newby BA, BSc(Hons), PhD, BM DM DSc, FMedSci, FRSE, FESC, FACC British Heart Foundation John Wheatley Professor of Cardiology, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, UK m m e. co fre Gary Maartens MBChB, FCP(SA), MMed Professor of Clinical Pharmacology, University of Cape Town, South Africa eb eb m m Francesca EM Neuberger MRCP(UK) Consultant Physician in Acute Medicine and Obstetric Medicine, Southmead Hospital, Bristol, UK oo oo ks oo ks eb Stephen M Lawrie MD(Hons), FRCPsych, FRCPE(Hon) Professor of Psychiatry, University of Edinburgh, UK John Paul Leach MD, FRCPG, FRCPE Consultant Neurologist, Institute of Neuroscience, Queen Elizabeth University Hospital, Glasgow; Head of Undergraduate Medicine and Honorary Associate Clinical Professor, University of Glasgow, UK eb co m ks fre Mairi H McLean BSc(Hons), MRCP, PhD Senior Clinical Lecturer in Gastroenterology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen; Honorary Consultant Gastroenterologist, Aberdeen Royal Infirmary, UK fre e. Rory J McCrimmon MD, FRCPE Professor of Experimental Diabetes and Metabolism, University of Dundee, UK e. co David EJ Jones MA, BM, PhD, FRCP Professor of Liver Immunology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne; Consultant Hepatologist, Freeman Hospital, Newcastle upon Tyne, UK oo eb m m m e. co m m m Sarah L Johnston FCRP, FRCPath Consultant Immunologist, Department of Immunology and Immunogenetics, North Bristol NHS Trust, Bristol, UK eb eb David A McAllister MSc, MD, MRCP, MFPH Wellcome Trust Intermediate Clinical Fellow and Beit Fellow, Senior Clinical Lecturer in Epidemiology, and Honorary Consultant in Public Health Medicine, University of Glasgow, UK Peter Langhorne PhD, FRCPG, FRCPI Professor of Stroke Care, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK m fre ks eb o oo Sara J Jenks BSc(Hons), MRCP, FRCPath Consultant in Metabolic Medicine, Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, UK oo eb m Simon RJ Maxwell BSc, MD, PhD, FRCP, FRCPE, FBPhS, FHEA Professor of Student Learning – Clinical Pharmacology and Prescribing, and Medical Director, UK Prescribing Safety Assessment, Clinical Pharmacology Unit, University of Edinburgh, UK ok s ks f re J Alastair Innes BSc, PhD, FRCPE Consultant, Respiratory Unit, Western General Hospital, Edinburgh; Honorary Reader in Respiratory Medicine, University of Edinburgh, UK m e. co m om m e. co xii • Contributors ks oo ks oo m m co e. fre oo ks ok s eb eb o m m m m ok s ok sf re e. co e. co sf re ok oo eb eb eb m m co e. ks fre oo eb m m co e. re eb .c re e oo oo k ks sf Miles D Witham PhD, FRCPE Clinical Reader in Ageing and Health, University of Dundee, UK eb co m e. re ks f oo eb m sf m om John PH Wilding DM, FRCP Professor of Medicine, Obesity and Endocrinology, University of Liverpool, UK m m m co m Julian White MB, BS, MD, FACTM Head of Toxinology, Women’s and Children’s Hospital, North Adelaide; Professor, University of Adelaide, Australia e. co fre fre David R Sullivan MBBS, FRACP, FRCPA, FCSANZ Clinical Associate Professor, Faculty of Medicine, University of Sydney; Physician and Chemical Pathologist, Department of Chemical Pathology, Royal Prince Alfred Hospital, Sydney, Australia ok fre e. ks eb oo Henry G Watson MD, FRCPE, FRCPath Consultant Haematologist, Aberdeen Royal Infirmary; Honorary Professor of Medicine, University of Aberdeen, UK m eb m e. co m Mark WJ Strachan BSc(Hons), MD, FRCPE Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh; Honorary Professor, University of Edinburgh, UK Simon HL Thomas MD, FRCP, FRCPE Professor of Clinical Pharmacology and Therapeutics, Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, UK m fre oo ks oo Peter Stewart MBBS, FRACP, FRCPA, MBA Associate Professor in Chemical Pathology, University of Sydney; Area Director of Clinical Biochemistry and Head of the Biochemistry Department, Royal Prince Alfred and Liverpool Hospitals, Sydney, Australia ks ks oo eb m Katrina Tatton-Brown BA, MD, FRCP Consultant in Clinical Genetics, South West Thames Regional Genetics Service, St George’s Universities NHS Foundation Trust, London; Reader in Clinical Genetics and Genomic Education, St George’s University, London, UK e. co m m ks fre e. co Grant D Stewart BSc(Hons), FRCSEd(Urol), PhD University Lecturer in Urological Surgery, Academic Urology Group, University of Cambridge; Honorary Consultant Urological Surgeon, Department of Urology, Addenbrooke’s Hospital, Cambridge; Honorary Senior Clinical Lecturer, University of Edinburgh, UK eb fre fre e. c ok s eb o Robby M Steel MA, MD, FRCPsych Consultant Liaison Psychiatrist, Department of Psychological Medicine, Royal Infirmary of Edinburgh; Honorary (Clinical) Senior Lecturer, Department of Psychiatry, University of Edinburgh, UK eb oo ks Shyam Sundar MD, FRCP(London), FAMS, FNASc, FASc, FNA Professor of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Victoria R Tallentire BSc(Hons), MD, FRCPE Consultant Physician, Western General Hospital, Edinburgh; Honorary Clinical Senior Lecturer, University of Edinburgh, UK m m eb oo Alan G Shand MD, FRCPE Consultant Gastroenterologist, Western General Hospital, Edinburgh, UK m e. co m om m e. co ks f re Gordon R Scott BSc, FRCP Consultant in Genitourinary Medicine, Chalmers Sexual Health Centre, Edinburgh, UK Contributors • xiii ok s e. re sf ok m co m e. co m co e. re sf sf re ok ok ks oo eb m co e. fre ok s eb o m m m co e. ks fre oo eb m co m e. re ks f oo eb m sf ks oo eb m oo k eb m .c om m e. co re e fre ks oo eb m m e. co fre eb oo ks m ks oo eb m co m fre e. ks oo eb m m e. co e. co m fre oo ks eb m ks fre oo eb m ks oo eb m e. co m om fre e. c fre ks oo eb m ok s eb o m m e. co re ks f oo eb m This page intentionally left blank oo eb m m m eb eb o oo ks ks ok s fre fre e. c e. co m om m e. co re ks f oo eb m co m fre e. ks oo eb m om .c re e eb oo ks sf oo k eb m m m m co e. ks m m eb Piotr Kuna Professor of Medicine; Chairman, 2nd Department of Medicine; Head of Division of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Poland oo eb o ok s fre Vasantha Kamath Senior Professor, Department of Internal Medicine, MVJ Medical College and Research Hospital, Bengaluru, Karnataka, India Pravin Manga Emeritus Professor of Medicine, Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa m co e. ok s re sf ok ok sf re e. re AL Kakrani Professor and Head, Department of Medicine, Dr DY Patil Medical College, Hospital and Research Centre; Dean, Faculty of Medicine, Dr DY Patil Vidyapeeth Deemed University, Pimpri, Pune, India e. co co m Tarun Kumar Dutta Professor of Medicine and Clinical Hematology, Mahatma Gandhi Medical College and Research Institute, Puducherry, India sf Saroj Jayasinghe Chair Professor of Medicine, Faculty of Medicine, University of Colombo; Honorary Consultant Physician, National Hospital of Sri Lanka, Colombo, Sri Lanka co e. m eb oo oo Sydney C D’Souza Professor of Medicine, AJ Institute of Medical Science, Mangalore; Former Head, Department of Medicine, Kasturba Medical College Mangalore, Manipal University, India M Abul Faiz Professor of Medicine (Retired), Sir Salimullah Medical College, Mitford, Dhaka, Bangladesh Rajiva Gupta Director and Head, Rheumatology and Clinical Immunology, Medanta – The Medicity, Gurgaon, India m ks f ks fre re e. D Dalus Professor and Head, Department of Internal Medicine, Medical College and Hospital, Trivandrum, India ok m e. co fre ks oo eb m co m MK Daga Director Professor of Medicine, and In-Charge Intensive Care Unit and Center for Occupational and Environment Medicine, Maulana Azad Medical College, New Delhi, India eb m m e. co fre eb oo ks Arnold Cohen Clinical Professor of Medicine, Elson S. Floyd College of Medicine at Washington State University, Spokane, Washington; Associate Clinical Professor, University of Washington School of Medicine; Gastroenterologist, Spokane Digestive Disease Center, Washington, USA m ks Hadi A Goubran Haematologist, Saskatoon Cancer Centre and Adjunct Professor, College of Medicine, University of Saskatchewan, Canada; Professor of Medicine and Haematology (Sabbatical), Cairo University, Egypt eb Matthew A Brown Professor and Director of Genomics, Queensland University of Technology, Brisbane, Australia eb Sujoy Ghosh Associate Professor, Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, India Khalid I Bzeizi Senior Consultant and Head of Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia m AG Frauman Professor of Clinical Pharmacology and Therapeutics, University of Melbourne, Australia Ragavendra Bhat Professor of Internal Medicine, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates m m eb oo oo ks fre ks fre Amitesh Aggarwal Associate Professor, Department of Medicine, University College of Medical Sciences and GTB Hospital, Delhi, India oo e. co e. co m m International Advisory Board fre e. c ks ks oo eb m om ks oo eb m m co e. fre oo ks ok s eb eb o m m m m ok s ok sf re e. co e. co sf re ok oo co m .c m m co e. ks fre oo eb m m co e. re re e sf oo k eb fre ks oo eb Josanne Vassallo Professor of Medicine, Faculty of Medicine and Surgery, University of Malta; Consultant Endocrinologist, Division of Endocrinology, Mater Dei Hospital, Msida, Malta m co m e. re ks f oo eb m sf fre e. ks oo eb m SG Siva Chidambaram Professor of Medicine, Dean/SPL Officer, Perambalur Government Medical College and GHQ, Perambalur, India e. co e. co fre Ian J Simpson Emeritus Professor of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand Arvind K Vaish Professor and Head, Department of Medicine, Hind Institute of Medical Sciences, Lucknow; Ex-Professor and Head of Medicine, KG Medical University, Lucknow, India NR Rau Consultant Physician, Anugraha Medical Centre and Adarsha Hospital, Udupi, Karnataka; Former Professor and Head, Department of Medicine, Kasturba Medical College, Manipal University, Karnataka, India ok m m fre oo ks eb m m Ami Prakashvir Parikh Consultant Physician, Sheth VS General Hospital, Ellisbridge, Ahmedabad; Professor of Medicine and Head of Department of Medicine, NHL Municipal Medical College, Ahmedabad, India Medha Y Rao Professor of Internal Medicine, Principal and Dean, MS Ramaiah Medical College, Bangalore, India Ibrahim Sherif Emeritus Professor of Medicine, Tripoli University; Consultant Endocrinologist, Alafia Clinic, Tripoli, Libya m e. co ks fre eb oo Tommy Olsson Professor of Medicine, Department of Medicine, Umeå University Hospital, Sweden eb oo ks Surendra K Sharma Adjunct Professor, Department of Molecular Medicine, Jamia Hamdard Institute of Molecular Medicine, Hamdard University, Delhi; Director of Research and Adjunct Professor, Departments of General Medicine and Pulmonary Medicine, JNMC, Datta Meghe Institute of Medical Sciences, Sawangi (M), Wardha Maharashtra, India e. co m m m Matthew Ng Honorary Clinical Professor, University of Hong Kong, Tung Wah Hospital, Hong Kong eb eb eb o oo KR Sethuraman Vice-Chancellor, Sri Balaji Vidyapeeth University, Pondicherry, India Moffat Nyirenda Professor of Medicine (Global Non-Communicable Diseases), London School of Hygiene and Tropical Medicine, UK; Honorary Professor of Research, College of Medicine, University of Malawi m fre ks Milind Nadkar Professor of Medicine and Chief of Rheumatology and Emergency Medicine, Seth GS Medical College and KEM Hospital, Mumbai, India oo eb m Nirmalendu Sarkar Professor and Head (Retired), Department of Medicine, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, India ok s ks f re Ammar F Mubaidin Professor of Neurology, Jordan University Hospital, Khalidi Medical Center, Amman, Jordan m e. co m om m e. co xvi • International Advisory Board fre fre e. c eb m fre e. ks oo eb m m co e. eb oo ks fre ok s eb o m m m m ok s ok sf re e. co e. co sf re ok oo eb m om .c re e sf oo k eb m co e. ks fre oo eb m m co ks ks oo eb m m m ks oo eb m co m e. e. re sf Avin Aggarwal, Dorothy Agrapidis, Sakir Ahmed, Iman Akhtar, Muhammad Faizan Ali, Syeda A Rfa Ali, M Amogh, Ramprasath Anbazhagan, Anju George C, Vamseedhar Annam, Muhammad Ehtisham Ansar, David C Antoney, Hina Arif, Sriharsha Athota, Muhammed Ali Azher, Bilal Al Azzawi, Janak Bahirwani, Devyani Bahl, Mohammed Naseem Baig, Deepak Kumar Bandari, Sagnik Banerjee, Tapastanu Banerjee, Kieran Bannerman, Emily Bart, Suranjana Basak, Saravana Bavan, Mark Beeston, Andrew Beverstock, Jeetendra Bhandari, Navin Bhatt, Soumyadeep Bhaumik, Rajrsh Bhawani, Kriti Bhayana, Praveen Bhugra, Amit Bisht, Rahul Bisht, Rudradeep Biswas, Tamoghna Biswas, Moira Bradfield, S Charles Bronson, Rosie Jane Campbell, Anup Chalise, Subhankar Chatterjee, Chiranjivi Chaudhari, Lok Bandhu Chaudhary, Muhammad Hamid Chaudhary, Umar Iftikhar Chaudhry, Himshree Gaurang Chhaya, Smitha Chirayil, Alexandra Choa, Rahul Choudhary, Guy Conlon, Gabriel MetcalfCuenca, Jack Cuningham, Gopal Dabade, Saraswata Das, Rahul Dev, Muinul Islam Dewan, Sree Divya, Muhammad Dizayee, Lucy Drummond, Simon Dryden, Fiona Drysdale, Kaitlin Duell, Gemma Dwyer, Md Khader Faheem N, Mahedi Hasan Faisal, Ali Mokhtari Farivar, Mohammed Omar Farooq, Ten Fu Fatt, Muhammad Zubair Fazal, Rebecca Ferris, Rebecca Fisher, Kartik Nimish Gandhi, Vibhav Gandhi, James Gao, Ella Gardner, Ankit Kumar Garg, Vibhuti Garg, Vishal Garg, Rakesh Garlapati, Partha Sarathi Ghosh, Prattay Ghosh, Muhammad Umer Gill, Madelaine Gimzewska, Nikolaos D Giotis, Evan Goh, Iain Gow, Bharatiram Guduri, Aantriksha Gupta, Shiwam Kumar Gupta, Michael Hagarty, Md Rashid Haider, Iqra Haq, Abdalla A Hassan, Fatima Hemani, Bianca Honnekeri, Prerana Huddar, Sandip Hulke, Mohammed Laique Hussain, Syahir Ibrahim, Victor Ilubaera, Sushrut Ingawale, Aroobah Iqbal, Tooba Irshad, Nagib Ul-Islam, Sehra Jabeen, Jeevan Jacob, Samreen Jaffar, Ankita Jain, Anukriti Jain, Ghazfa Jamil, Karan Jatwani, Surani Dilhani Jayawickrema, Per-Kristian Jensen, Love Kapil, Ishwor Karki, Ewan D Kennedy, Amit Keshri, Haider Ali Khalid, Ali Khaliq, Hina Khan, Md Taha Ali Khan, Raazia Khan, Priya Khetarpal, Robert Kimmitt, Navneet Kishore, Narendranath Reddy Konda, Kirsten Kramers, Ajay Kumar, Gaurav Kumar, Karun Kumar, Mudit Kumar, Sathish Kumar A, Sonu Kumar, Ramasamy Shakthi Kumaran, Joachim Langhans, Keith Leung, Ang Li, Lai Nai Lim (Jeremiah), Marlene Da Vitoria Lobo, Bo Løfgren, Sham Kumar Lulla, Apurva Lunia, Arslan Luqman, Faizan Luqman, Mithilesh Chandra Malviya, Sudhir Mane, Sachin Mangal, G. Manju, Adupa Manupranay, Ussama Maqbool, Zahid Marwat, Ronny John Mathew, Ross Mclaren, Lucy Mcnally, Varshil Mehta, Kamran Younis Memon, Nisha Menon, Varun Menon P, Jessica Mills, Asim Abid Minhas, e. co fre fre re ks f oo ok co m e. co m fre oo ks e. co m m eb oo eb oo oo eb m m m e. co ks fre Following the publication of the 22nd edition of Davidson’s, Professor Brian Walker and Dr Nicki Colledge retired as editors. We would like to express our gratitude for the immense contribution they both made to the continuing success of this textbook. The current editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition would not have been possible. In particular we are indebted to those former authors who step down with the arrival of this new edition. They include Assistant Professor Albiruni Ryan Abdul-Razak, Professor Andrew Bradbury, Dr Jenny Craig, Professor Allan Cumming, Dr Robert Dawe, Emeritus Professor Michael Field, Dr Jane Goddard, Professor Philip Hanlon, Dr Charlie Lees, Dr Helen Macdonald, Professor Iain McInnes, Dr Graham Nimmo, Dr Simon Noble, Dr David Oxenham, Professor Jonathan Seckl, Professor Michael Sharpe, Professor Neil Turner, Dr Simon Walker and Professor Timothy Walsh. We are grateful to members of the International Advisory Board, all of whom provided detailed suggestions that have improved the book. Several members have now retired from the Board and we are grateful for their support during the preparation of previous editions. They include Professor OC Abraham, Professor Tofayel Ahmed, Professor Samar Banerjee, Professor Tapas Das, Professor Tsuguya Fukui, Professor Saman Gunatilake, Professor Wasim Jafri, Professor Saraladevi Naicker, Professor Nardeep Naithani, Professor Prem Pais, Professor A Ramachandran, the late Professor (Mrs) Harsha R Salkar and Professor Subhash Varma. Detailed chapter reviews were commissioned to help plan this new edition and we are grateful to all those who assisted, including Professor Rustam Al-Shahi, Dr David Enoch, Dr Colin Forfar, Dr Richard Herriot and Dr Robert Lindsay. The Editors and Publisher would like to thank all those who have provided valuable feedback on this textbook and whose comments have helped shape this new edition. We would particularly like to extend our thanks to the many readers who contact us with suggestions for improvements. This input has been invaluable and is much appreciated; we regret the names are too numerous to mention individually. As part of the Publisher’s review, 360 readers from over 200 universities and colleges around the world supplied many innovative ideas on how to enhance the book. We are deeply indebted to the following for their enthusiastic support and we trust we have listed all those who contributed; we apologise if any names have been accidentally omitted. Rabab Hasan Abbasi, Ayesha Abdul Aziz, Ahmed Al Abdullah, Osama Abuzagaia, Humaira Achakzai, Sajan Acharya, Anurag Adhikari, Esha Agarwal, eb oo ks eb ks ks ok s eb o oo eb m m m m e. co m om m e. co re ks f Acknowledgements fre e. c ks ks oo ks sf oo oo k eb eb m m m m co co e. e. fre oo ks ok s eb eb o m m m m ok s ok sf re e. co e. co sf re ok oo eb eb om re e .c e. co fre ks ks fre oo eb m m co e. re m m m SHR, IDP, MWJS, RPH Edinburgh 2018 oo eb m co m e. re ks f oo eb sf m eb oo ks fre e. co m e. co m fre oo ks eb m m e. co fre eb oo ks m m ok fre ks oo eb eb o m m e. co ks fre oo eb Prince Singh, Rajshree Singh, Shruti Singh, Vikas Singh, Yogita Singh, Ayush Keshav Singhal, Dattatreya Sitaram, Brooke Smith, Yeshwanth Sonnathi, Soundarya Soundararajan, Nicola Stuber, Maleeha Subhan, Udayasree Sagar Surampally, Monika Surana, Jason Suresh, Salman Ali Syed, Mohammad Hasnain Tahir, Syeda Sara Tamkanath, Areeba Tariq, Saipriya Tatineni, Ghias Un Nabi Tayyab, Arul Qubert Thaya, Jolley Thomas, Stephanie Tristram, Neelanchal Trivedi, Vaibhav Trivedi, Kriti Upadhyay, Sanjaya Kumar Upadhyaya, Rukhsar Vankani, Rajkumar Krishnan Vasanthi, D Vijayaraju, R Vinayak, Neelakantan Viswanathan, Joarder Wakil, Syed Hamza Bin Waqar, Waiz A Wasey, William Wasif, Kiran Wasti, Donald Waters, Katherine Weir, Clinton White, Aalok Yadav, Loong Yee Yew, Shahwar Yousuf, Amal Yusof and Hassam Zulfiqar. The authors of Chapter 20 would like to thank Dr Drew Henderson, who reviewed the ‘Diabetic nephropathy’ section. Two short sections in Chapter 3 on array comparative genomic hybridisation and single-molecule sequencing are adapted from Dr K Tatton-Brown’s Massive Open Online Course for FutureLearn. We would like to thank the Open University and St George’s, University of London, for permission to use this material. We are especially grateful to all those working for Elsevier, in particular Laurence Hunter, Wendy Lee and Robert Britton, for their endless support and expertise in the shaping, collation and illustration of this edition. m ok s ks f re Mohd Nasir Mohiuddin, Matshidiso Mokgwathi, Kristin Monk, Joseph Raja Mony, Sudeb Mukherjee, Sadaf Nadeem, Huda Naim, B Abhilash Nair, Ramya Narasimhan, Rahul Navani, Ayesha Nazir, Prakhar Nigam, Sripriya Nopany, Prakash Raj Oli, Chieh Yin Ooi, Muhammad Osama, Kate O’Sullivan, Hajer Oun, Ashwin Pachat, Akshay Pachyala, Kannan Padma, Gregory Page, Vishal Krishna Pai, Dhiman Pal, Vidit Panchal, Madhav Pandey, Ambikapathi Panneerselvam, Rakesh Singh Panwar, Prakash Parida, Ashwin Singh Parihar, Kunal Parwani, Riya Patel, Himanshu Pathak, Prathamesh Pathrikar, Samanvith Patlori, Gary Paul, Harris Penman, Lydia B Peters, Kausthubha Puttalingaiah, Muneeb Qureshi, Sidra Qureshi, Varun Venkat Raghavan MS, Raghavendra MS, Abdur Rahaman, Ajmal Rahman Km, SM Tajdit Rahman, Ankit Raj, Solai Raj, Namita Raja, Revathi Rajagopal, Aswathy Raju B, Nagarajan Raju, Al-Amin Hossain Rakib, Abhiraj Ramchandani, Varun Ramchandani, Viviktha Ramesh, Jai Ranjan, Ganga Raghava Rao, Gomathi Ravula, Aneeqa Abdul Rehman, Neeha Abdul Rehman, Varun Bhaktarahalli Renukappa, Rosalind Revans, Madina Riaz, Lachlan Rodd, Jan Ross, Pritam Roy, Jazeel Sa, Iqra Saeed, Israel Safiriyu, Partha Saha, Mohammed Sulaiman Sait J, Ribha Salman, Souvik Samaddar, Juliane Rf Sanner, Abhinav Sathe, Smarter Sawant, Jeff Schwartz, Somanshi Sehgal, Arbind Shah, Basit Shah, Rakesh Kumar Shah, Mohith Shamdas, Abhishek Sharma, Anmol Sharma, Deepak Sharma, Pawan Kumar Sharma, Nisha Sharoff, Alsba Sheikh, Haris Sheikh, Nujood Al Shirawi, William Shomali, Pratima Shrestha, Suhana Shrestha, Ajay Shukla, Prithiv Siddharth, Arpit Sikri, Ankita Singh, Avinash Singh, Deepali Singh, Jeevika Singh, oo eb m m e. co m om m e. co xviii • Acknowledgements fre fre e. c eb m ks ks m m Emergency e. co m m eb eb There are many practical skills that students and doctors must master. These vary from inserting a nasogastric tube to reading an ECG or X-ray, or interpreting investigations such as arterial blood gases or thyroid function tests. ‘Practice Point’ boxes provide straightforward guidance on how these and many other skills can be acquired and applied. oo oo k Practice Point ks oo m m m m eb eb o In many countries, older people comprise 20% of the population and are the chief users of health care. While they contract the same diseases as those who are younger, there are often important differences in the way they present and how they are best managed. Chapter 32, ‘Ageing and disease’, concentrates on the principles of managing the frailest group who suffer from multiple comorbidity and disability, and who tend to present with non-specific problems such as falls or delirium. Many older people, though, also suffer from specific single-organ pathology. ‘In Old Age’ boxes are thus included in each chapter and describe common presentations, implications of physiological changes of ageing, effects of age on investigations, problems of co e. re sf ok ok s In Old Age fre These boxes describe the management of many of the most common emergencies in medicine. e. co sf re ok oo eb m om .c re e sf These include causes, clinical features, investigations, treatments and other useful information. co e. General Information ok s fre ks fre oo eb m m co re e. Medical students and junior doctors must not only assimilate a great many facts about various disorders but also develop an analytical approach to formulating a differential diagnosis sf co m m e. co m Boxes are a popular way of presenting information and are particularly useful for revision. They are classified by the type of information they contain, using specific symbols. ks oo re ks f oo Presenting problems fre e. ks oo Boxes eb eb eb m co m e. The value of good clinical skills is highlighted by a two-page overview of the important elements of the clinical examination at the beginning of most chapters. The left-hand page includes a mannikin to illustrate key steps in examination of the relevant system, beginning with simple observations and progressing in a logical sequence around the body. The right-hand page expands on selected themes and includes tips on examination technique and interpretation of physical signs. These overviews are intended to act as an aide-mémoire and not as a replacement for a detailed text on clinical examination, as provided in our sister title, Macleod’s Clinical Examination. ok oo oo eb m e. co m fre oo ks and a plan of investigation for patients who present with particular symptoms or signs. In Davidson’s this is addressed by incorporating a ‘Presenting Problems’ section into all relevant chapters. Nearly 250 presentations are included, which represent the most common reasons for referral to each medical specialty. m m e. co fre eb oo ks eb ks ks ok s eb o m m e. co ks fre oo eb m m e. co m om m e. co re ks f oo eb m The opening six chapters of the book, making up Part 1 on ‘Fundamentals of Medicine’, provide an account of the principles of genetics, immunology, infectious diseases and population health, along with a discussion of the core principles behind clinical decision-making and good prescribing. Subsequent chapters in Part 2, ‘Emergency and Critical Care Medicine’, discuss medical emergencies in poisoning, envenomation and environmental medicine, while a new chapter explores common presentations in acute medicine, as well as the recognition and management of the critically ill. The third part, ‘Clinical Medicine’, is devoted to the major medical specialties. Each chapter has been written by experts in the field to provide the level of detail expected of trainees in their discipline. To maintain the book’s virtue of being concise, care has been taken to avoid unnecessary duplication between chapters. The system-based chapters in Part 3 follow a standard format, beginning with an overview of the relevant aspects of clinical examination, followed by an account of functional anatomy, physiology and investigations, then the common presentations of disease, and details of the individual diseases and treatments relevant to that system. In chapters that describe the immunological, cellular and molecular basis of disease, this problem-based approach brings the close links between modern medical science and clinical practice into sharp focus. The methods used to present information are described below. Clinical examination overviews m Introduction fre e. c fre ks oo eb ks oo eb m m co e. fre oo ks ok s eb eb o m m m m ok s ok sf re e. co e. co sf re ok oo eb m eb m m co e. ks fre oo eb m m co e. re m .c re e sf oo k ks oo eb co m e. re ks f oo eb sf om The Editors and Publisher hope that you will find this edition of Davidson’s informative and easy to use. We would be delighted to hear from you if you have any comments or suggestions to make for future editions of the book. Please contact us by e-mail at: davidson. email@example.com. All comments received will be much appreciated and will be considered by the editorial team. m m m ok co m m m Giving us your feedback e. co fre The recommended International Non-proprietary Names (INNs) are used for all drugs, with the exception of adrenaline and eb oo ks fre e. ks oo A contents list is given on the opening page of each chapter. In addition, the book contains numerous cross-references to help readers find their way around, along with an extensive index. A list of up-to-date reviews and useful websites with links to management guidelines appears at the end of each chapter. eb eb Finding what you are looking for m m e. co fre Terminology ks ks The International System of Units (SI units) is the recommended means of presentation for laboratory data and has been used throughout Davidson’s. We recognise, though, that many laboratories around the world continue to provide data in non-SI units, so these have been included in the text for the commonly measured analytes. Both SI and non-SI units are also given in Chapter 35, which describes the reference ranges used in Edinburgh’s laboratories. It is important to appreciate that these reference ranges may vary from those used in other laboratories. e. co m oo ks fre ks fre Although paediatric medicine is not covered in Davidson’s, many chronic disorders begin in childhood and adult physicians often contribute to multidisciplinary teams that manage young patients ‘in transition’ between paediatric and adult health-care services. This group of patients often presents a particular challenge, due to the physiological and psychological changes that occur in adolescence and which can have a major impact on the disease and its management. Adolescents can be encouraged to take over responsibility from their parents/carers in managing their disease, but are naturally rebellious and often struggle to adhere to the impositions of chronic treatment. To highlight these issues, we have introduced a new chapter on adolescent and transition medicine to accompany the ‘In Adolescence’ boxes that appear in relevant chapters. oo eb oo eb o m m e. co In Adolescence m Units of measurement eb Many conditions are different in the context of pregnancy, while some arise only during or shortly after pregnancy. Particular care must be taken with investigations (for example, to avoid radiation exposure to the fetus) and treatment (to avoid the use of drugs that harm the fetus). These issues are highlighted by ‘In Pregnancy’ boxes distributed throughout the book, which complement the new chapter on maternal medicine. oo eb m ok s ks f In Pregnancy noradrenaline. British spellings have been retained for drug classes and groups (e.g. amphetamines not amfetamines). m re treatment in old age, and the benefits and risks of intervention in older people. e. co m om m e. co xx • Introduction fre oo eb ks oo eb .c Answers to problems 12 ks oo eb m ks oo m m co e. ok s re sf ok ok sf re e. e. co co m m m m eb eb eb o oo ok s fre ks fre e. e. co co m m co m m m eb eb oo oo k ks sf fre re e e. co e. co e. re ks f oo eb re om m m Clinical decision-making: putting it all together 10 fre eb oo ks m m Patient-centred evidence-based medicine and shared decision-making 10 Dealing with uncertainty 5 sf m co m eb m m Use and interpretation of diagnostic tests 3 Normal values 3 Factors other than disease that influence test results 4 Operating characteristics 4 Sensitivity and specificity 4 Prevalence of disease 5 m ks ks ks oo Reducing errors in clinical decision-making 9 Cognitive debiasing strategies 9 Using clinical prediction rules and other decision aids 10 Effective team communication 10 eb Clinical skills and decision-making 3 fre e. fre Cognitive biases 6 Type 1 and type 2 thinking 7 Common cognitive biases in medicine 7 Human factors 9 oo ks oo Clinical reasoning: definitions 2 ok oo m e. co m m e. co ks fre The problem of diagnostic error 2 eb eb fre e. c ok s eb o m m eb Clinical decision-making Introduction 2 m 1 e. co m om m e. co re ks f oo N Cooper AL Cracknell fre e. c fre oo ks oo eb m om ks oo m e. fre m m Thinking about thinking co m m ks ok s eb o Understanding cognitive biases and human factors Patient-centred EBM e. co re medicine) e. Fig. 1.1 Elements of clinical reasoning. (EBM = evidence-based sf sf re m co m co e. oo eb m Accepting a diagnosis handed over to you without question (the ‘framing effect’) instead of asking yourself ‘What is the evidence that supports this diagnosis?’ ok sf re e. co Cognitive biases Deciding a patient has not had a stroke because his brain scan is normal – computed tomography and even magnetic resonance imaging, especially when performed early, may not identify an infarct Using and interpreting diagnostic tests Clinical reasoning m Misinterpretation of diagnostic tests ok m eb oo Telling a patient she cannot have biliary colic because she has had her gallbladder removed – gallstones can form in the bile ducts in patients who have had a cholecystectomy ok Knowledge gaps Shared decision-making ks fre Examples ks f Source of error eb m co m fre e. ks eb m m co m e. re 1.2 Reasons for errors in clinical reasoning ks ks oo oo eb oo k ks eb oo Clinical skills (history and physical examination) Adapted from Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: what’s the goal? Acad Med 2002; 77:981–992. oo Inadequate data-gathering Errors in reasoning ok s Human cognitive error eb Inadequate diagnostic support Results not available Error-prone processes Poor supervision of inexperienced staff Poor team communication sf fre System error eb Unusual presentation of a disease Missing information .c Examples No fault re e Error category fre ‘Clinical reasoning’ describes the thinking and decision-making processes associated with clinical practice. It is a clinician’s ability to make decisions (often with others) based on all the available clinical information, starting with the history and physical examination. Our understanding of clinical reasoning derives from the fields of education, cognitive psychology and studies of expertise. Figure 1.1 shows the different elements involved in clinical reasoning. Good clinical skills are fundamental, followed by understanding how to use and interpret diagnostic tests. Other essential elements include an understanding of cognitive biases and human factors, and the ability to think about one’s own thinking (which is explained in more detail later). Other key elements of clinical reasoning include patient-centred evidencebased medicine (EBM) and shared decision-making with patients and/or carers. e. co e. co 1.1 Root causes of diagnostic error in studies Clinical reasoning: definitions m m m eb eb oo oo ks fre ks fre It is estimated that diagnosis is wrong 10–15% of the time in specialties such as emergency medicine, internal medicine and general practice. Diagnostic error is associated with greater morbidity than other types of medical error, and the majority is considered to be preventable. For every diagnostic error there are a number of root causes. Studies of misdiagnosis assign three main categories, shown in Box 1.1; however, errors in clinical reasoning play a significant role in the majority of diagnostic adverse events. eb oo ks eb e. co m e. co The problem of diagnostic error m Examples of errors in these three categories are shown in Box 1.2. Clearly, clinical knowledge is required for sound clinical reasoning, and an incomplete knowledge base or inadequate experience can lead to diagnostic error. However, this chapter focuses on other elements of clinical reasoning: namely, the interpretation of diagnostic tests, cognitive biases and human factors. m eb o m m m eb oo ok s ks f A great deal of knowledge and skill is required to practise as a doctor. Physicians in the 21st century need to have a comprehensive knowledge of basic and clinical sciences, have good communication skills, be able to perform procedures, work effectively in a team and demonstrate professional and ethical behaviour. But how doctors think, reason and make decisions is arguably their most critical skill. Knowledge is necessary, but not sufficient on its own for good performance and safe care. This chapter describes the principles of clinical decision-making, or clinical reasoning. Diagnostic error has been defined as ‘a situation in which the clinician has all the information necessary to make the diagnosis but then makes the wrong diagnosis’. Why does this happen? Studies reveal three main reasons: • knowledge gaps • misinterpretation of diagnostic tests • cognitive biases. m re Introduction m e. co m om m e. co 2 • Clinical decision-making ks ks oo eb m om .c re e oo ks sf eb m m co ks oo eb m co e. ok s re sf ok sf re ok oo eb m co m fre e. ks eb e. co co e. re sf m m probability of finding in patients with disease probability of finding in patients without disease LRs are also used for diagnostic tests; here a physical examination finding can be considered a diagnostic test. Data from Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002; 35:46–52. ok m eb m oo eb m nuchal rigidity in the clinical diagnosis of meningitis. e. – 45% fre 0.1 ok s – 30% eb o 0.2 m – 15% ks fre 0.5 m No change m 1 Most tests provide quantitative results (i.e. a value on a continuous numerical scale). In order to classify quantitative results as normal or abnormal, it is necessary to define a cut-off point. Many quantitative measurements in populations have a Gaussian or ‘normal’ distribution. By convention, the normal range is defined as those values that encompass 95% of the population, or 2 standard deviations above and below the mean. This means that 2.5% of the normal population will have values above, and 2.5% will have values below the normal range. For this reason, it is more appropriate to talk about the ‘reference range’ rather than the ‘normal range’ (Fig. 1.3). Test results in abnormal populations also have a Gaussian distribution, with a different mean and standard deviation. In some diseases there is no overlap between results from the abnormal and normal population. However, in many diseases there is overlap; in these circumstances, the greater the difference between the test result and the limits of the reference range, the higher the chance that the person has a disease. However, there are also situations in medicine when ‘normal’ is abnormal and ‘abnormal’ is normal. For example, a normal PaCO2 in the context of a severe asthma attack is abnormal and means the patient has life-threatening asthma. A low ferritin in a young menstruating woman is not considered to be a disease at all. Normal, to some extent, is therefore arbitrary. co + 15% e. 2 Fig. 1.2 Likelihood ratio (LR) of Kernig’s sign, Brudzinski’s sign and LR = m oo k ks Normal values oo eb + 30% m co m e. re ks f oo + 45% 5 Zero There is no such thing as a perfect diagnostic test. Test results give us test probabilities, not real probabilities. Test results have to be interpreted because they are affected by the following: • how ‘normal’ is defined • factors other than disease • operating characteristics • sensitivity and specificity • prevalence of disease in the population. e. co fre Change in probability of disease 1 fre oo eb m oo fre oo ks eb Use and interpretation of diagnostic tests m m e. co fre Increase probability m eb oo ks 10 Decrease probability eb Infinity LR No change Kernig’s sign Brudzinski’s sign Nuchal rigidity m value, the greater the probability). Similarly, an LR of less than 1 decreases the probability of disease. LRs are developed against a diagnostic standard (e.g. in the case of meningitis, lumbar puncture results), so do not exist for all clinical findings. LRs illustrate how an individual clinical finding changes the probability of a disease. For example, in a person presenting with headache and fever, the clinical finding of nuchal rigidity (neck stiffness) may carry little weight in deciding whether to perform a lumbar puncture because LRs do not determine the prior probability of disease; they reflect only how a single clinical finding changes it. Clinicians have to take all the available information from the history and physical examination into account. If the overall clinical probability is high to begin with, a clinical finding with an LR of around 1 does not change this. ‘Evidence-based history and examination’ is a term used to describe how clinicians incorporate knowledge about the prevalence and diagnostic weight of clinical findings into their history and physical examination. This is important because an estimate of clinical probability is vital in decision-making and the interpretation of diagnostic tests. e. co m e. co ks fre m eb oo However, the frequency with which patients present with certain features and the diagnostic weight of each feature are important in clinical reasoning. For example, many patients with meningitis do not have classical signs of meningeal irritation (Kernig’s sign, Brudzinski’s sign and nuchal rigidity). In one prospective study, they had likelihood ratios of around 1, meaning they carried little diagnostic weight (Fig. 1.2). Likelihood ratios (LR) are clinical diagnostic weights. An LR of greater than 1 increases the probability of disease (the higher the • 3 ks fre e. c eb o m m m eb oo ok s ks f Even with major advances in medical technology, the history remains the most important part of the clinical decision-making process. Studies show that physicians make a diagnosis in 70–90% of cases from the history alone. It is important to remember that a good history is gathered not only from the patient but also, if necessary (and with consent if required), from all available sources: for example, paramedic and emergency department notes, eye-witnesses, relatives and/or carers. Clinicians need to be aware of the diagnostic usefulness of clinical features in the history and examination. For example, students are taught that meningitis presents with the following features: • headache • fever • meningism (photophobia, nuchal rigidity). e. co m om m e. co re Clinical skills and decision-making Use and interpretation of diagnostic tests Examples Age Creatinine is lower in old age (due to relatively lower muscle mass) – an older person can have a significantly reduced eGFR rate with a ‘normal’ creatinine ks eb oo ks ks oo m m om .c re e oo eb m m co e. eb oo ks fre ok s eb o m m ok s ok sf re e. co e. co sf re ok ks sf oo k eb m m ks fre oo eb m m co e. re m e. e. re ks f oo sf Diagnostic tests have characteristics termed ‘sensitivity’ and ‘specificity’. Sensitivity is the ability to detect true positives; specificity is the ability to detect true negatives. Even a very good test, with 95% sensitivity, will miss 1 in 20 people with the disease. Every test therefore has ‘false positives’ and ‘false negatives’ (Box 1.4). A very sensitive test will detect most disease but generate abnormal findings in healthy people. A negative result will therefore reliably exclude disease but a positive result does not mean the disease is present – it means further evaluation is required. On the other hand, a very specific test may miss significant pathology but is likely to establish the diagnosis beyond doubt when the result is positive. All tests differ in their sensitivity and specificity, and clinicians require a working knowledge of the tests they use in this respect. In choosing how a test is used to guide decision-making there is a trade-off between sensitivity versus specificity. For example, defining an exercise electrocardiogram (p. 449) as abnormal if there is at least 0.5 mm of ST depression would ensure that very few cases of coronary artery disease are missed but would generate many false-positive results (high sensitivity, low specificity). On the other hand, a cut-off point of 2.0 mm of ST depression would detect most cases of important coronary artery disease with far fewer false positives. This trade-off is illustrated by the receiver operating characteristic curve of the test (Fig. 1.4). An extremely important concept is this: the probability that a person has a disease depends on the pre-test probability, and the sensitivity and specificity of the test. For example, imagine that an elderly lady has fallen and hurt her left hip. On examination, co co m Tests are also subject to operating characteristics. This refers to the way the test is performed. Patients need to be able to comply fully with some tests, such as spirometry (p. 569), and if they cannot, then the test result will be affected. Some tests are very dependent on the skill of the operator and are also affected by the patient’s body habitus and clinical state; ultrasound of the heart and abdomen are examples. A common mistake is when doctors refer to a test result as ‘no abnormality detected’ when, in fact, the report describes a technically difficult and incomplete scan that should more accurately be described as ‘non-diagnostic’. Some conditions are paroxysmal. For example, around half of patients with epilepsy have a normal standard electroencephalogram (EEG). A normal EEG therefore does not exclude epilepsy. On the other hand, around 10% of patients who do not have epilepsy have epileptiform discharges on their EEG. This is referred to as an ‘incidental finding’. Incidental findings are common in medicine, and are increasing in incidence with the greater availability of more sensitive tests. Test results should always be interpreted in the light of the patient’s history and physical examination. ok Sensitivity and specificity m m Operating characteristics eb A spurious high potassium is seen in haemolysis and in thrombocytosis (‘pseudohyperkalaemia’) e. co fre eb oo ks eb oo ks m Spurious (in vitro) results m m e. co fre number of factors other than disease influence test results: age ethnicity pregnancy sex spurious (in vitro) results. Box 1.3 gives some examples. m Males and females have different reference ranges for many tests, e.g. haemoglobin (ECG = electrocardiogram; eGFR = estimated glomerular filtration rate, a better estimate of renal function than creatinine) Factors other than disease that influence test results A • • • • • Sex eb eb m m eb oo oo ks fre ks fre the frequency distribution of results in the normal healthy population (red line) is a symmetrical bell-shaped curve. The mean ± 2 standard deviations (SD) encompasses 95% of the normal population and usually defines the ‘reference range’; 2.5% of the normal population have values above, and 2.5% below, this range (shaded areas). For some diseases (blue line), test results overlap with the normal population or even with the reference range. For other diseases (green line), tests may be more reliable because there is no overlap between the normal and abnormal population. fre e. Fig. 1.3 Normal distribution and reference range. For many tests, eb e. co ‘Reference range’ Several tests are affected by late pregnancy, due to the effects of a growing fetus, including: Reduced urea and creatinine (haemodilution) Iron deficiency anaemia (increased demand) Increased alkaline phosphatase (produced by the placenta) Raised D-dimer (physiological changes in the coagulation system) Mild respiratory alkalosis (physiological maternal hyperventilation) ECG changes (tachycardia, left axis deviation) co m e. co m Value Healthy people of African ancestry have lower white cell counts m m Pregnancy Mean + 2SD oo oo eb eb o Ethnicity m Mean m Mean – 2SD fre Factor ks fre e. c ok s oo 1.3 Examples of factors other than disease that influence test results Abnormal populations m eb e. co m om m re Normal population ks f Number of people having each value e. co 4 • Clinical decision-making fre ks ks oo eb ks oo eb C (False negative) e. Negative test B (False positive) fre D (True negative) oo ks ok s eb o m m eb Dealing with uncertainty m m Clinical findings are imperfect and diagnostic tests are imperfect. It is important to recognise that clinicians frequently deal with uncertainty. By expressing uncertainty as probability, new information from diagnostic tests can be incorporated more accurately. However, subjective estimates of probability can sometimes be unreliable. As the section on cognitive biases will demonstrate (see below), intuition can be a source of error. ok sf re e. co e. co sf re No disease A (True positive) ks fre oo ok oo eb m m Disease Positive test Positive predictive value = A/(A+B) × 100 Negative predictive value = D/(D+C) × 100 eb m m co e. re sf ok m m co m 1.5 Predictive values: ‘What is the probability that a person with a positive test actually has the disease?’ e. e. re ks f oo eb om re e sf oo k eb ks oo co m m eb .c e. co fre fre eb oo ks m the hip is extremely painful to move and she cannot stand. However, her hip X-rays are normal. Does she have a fracture? The sensitivity of plain X-rays of the hip performed in the emergency department for suspected hip fracture is around 95%. A small percentage of fractures are therefore missed. If our patient has (or is at risk of) osteoporosis, has severe pain on hip movement and cannot bear weight on the affected side, then the clinical probability of hip fracture is high. If, on the other hand, she is unlikely to have osteoporosis, has no pain on hip movement and is able to bear weight, then the clinical probability of hip fracture is low. Doctors are continually making judgements about whether something is true, given that something else is true. This is known as ‘conditional probability’. Bayes’ Theorem (named after English clergyman Thomas Bayes, 1702–1761) is a mathematical way to describe the post-test probability of a disease by combining pre-test probability, sensitivity and specificity. In clinical practice, doctors are not able to make complex mathematical calculations for every decision they make. In practical terms, the answer to the question of whether there is a fracture is that in a high-probability patient a normal test result does not exclude the condition, but in a low-probability patient it makes it very unlikely. This principle is illustrated in Figure 1.5. Sox and colleagues (see ‘Further information’) state a fundamental assertion, which they describe as a profound and subtle principle of clinical medicine: the interpretation of m m e. co trade-off between sensitivity and specificity for a given test. The curve is generated by ‘adjusting’ the cut-off values defining normal and abnormal results, calculating the effect on sensitivity and specificity and then plotting these against each other. The closer the curve lies to the top left-hand corner, the more useful the test. The red line illustrates a test with useful discriminant value and the green line illustrates a less useful, poorly discriminant test. co 0 Fig. 1.4 Receiver operating characteristic graph illustrating the m co m eb 0.2 m 0.6 0.4 Specificity m 0.8 fre oo ks oo ks eb eb m 0.0 1.0 m oo 0.4 ok s 0.6 ks fre Sensitivity 0.8 fre e. e. co e. co m m 1.0 0.2 Consider this problem that was posed to a group of Harvard doctors: if a test to detect a disease whose prevalence is 1 : 1000 has a false-positive rate of 5%, what is the chance that a person found to have a positive result actually has the disease, assuming you know nothing about the person’s symptoms and signs? Take a moment to work this out. In this problem, we have removed clinical probability and are only considering prevalence. The answer is at the end of the chapter. Predictive values combine sensitivity, specificity and prevalence. Sensitivity and specificity are characteristics of the test; the population does not change this. However, as doctors, we are interested in the question, ‘What is the probability that a person with a positive test actually has the disease?’ This is illustrated in Box 1.5. Post-test probability and predictive values are different. Posttest probability is the probability of a disease after taking into account new information from a test result. Bayes’ Theorem can be used to calculate post-test probability for a patient in any population. The pre-test probability of disease is decided by the doctor; it is a judgement based on information gathered prior to ordering the test. Predictive value is the proportion of patients with a test result who have the disease (or no disease) and is calculated from a table of results in a specific population (see Box 1.5). It is not possible to transfer this value to a different population. This is important to realise because published information about the performance of diagnostic tests may not apply to different populations. In deciding the pre-test probability of disease, clinicians often neglect to take prevalence into account and this distorts their estimate of probability. To estimate the probability of disease in a patient more accurately, clinicians should anchor on the prevalence of disease in the subgroup to which the patient belongs and then adjust to take the individual factors into account. m m m Sensitivity = A/(A+C) × 100 Specificity = D/(D+B) × 100 oo D (True negative) Prevalence of disease eb C (False negative) 1 ks fre e. c Negative test new information depends on what you believed beforehand. In other words, the interpretation of a test result depends on the probability of disease before the test. B (False positive) eb o A (True positive) ok s No disease Positive test eb oo ks f Disease e. co m om m e. co re 1.4 Sensitivity and specificity Dealing with uncertainty • 5 fre e. c % probability of having the disease 40 50 60 90 70 80 ks oo eb om .c 60 86.4% chance of having the disease if the test is positive 90 100 re e 50 m m m 40 e. co 30 co m ks oo eb eb m m e. co 20 oo eb m fre oo ks oo eb m Patient B 5.6% chance of having the disease if the test is negative 10 ks ks oo e. co m 98.3% chance of having the disease if the test is positive 50% chance of having the disease before the test is done 0 100 m m m e. co ks fre 80 eb eb o oo eb m Patient A 34.6% chance of having the disease if the test is negative 70 90% chance of having the disease before the test is done ok s 30 fre 20 fre e. 10 ks f re 0 e. co m om m e. co 6 • Clinical decision-making fre ks m m co ks oo m m eb eb o ok s fre e. Advances in cognitive psychology in recent decades have demonstrated that human thinking and decision-making are prone to error. Cognitive biases are subconscious errors that lead to inaccurate judgement and illogical interpretation of information. They are prevalent in everyday life; as the famous saying goes, ‘to err is human.’ Take a few moments to look at this simple puzzle. Do not try to solve it mathematically but listen to your intuition: A bat and ball cost £1.10. The bat costs £1 more than the ball. How much does the ball cost? The answer is at the end of the chapter. Most people get the answer to this puzzle wrong. Two things are going on: one is that humans have two distinct types of processes when it comes to thinking and decision-making – termed ‘type 1’ and ‘type 2’ thinking. The other is that the human brain is wired to jump to conclusions sometimes or to miss things that are obvious. British psychologist and patient safety pioneer James m ok sf re e. co e. co sf re ok oo eb eb m m Cognitive biases m e. ks fre oo eb m m co e. re sf ok an understanding of the prevalence of disease in the particular care setting or the population to which the patient belongs. co co m e. re ks f oo eb m sf oo k ks oo eb Knowing the patient’s true state is often unnecessary in clinical decision-making. Sox and colleagues (see ‘Further information’) argue that there is a difference between knowing that a disease is present and acting as if it were present. The requirement for diagnostic certainty depends on the penalty for being wrong. Different situations require different levels of certainty before starting treatment. How we communicate uncertainty to patients will be discussed later in this chapter (p. 10). The treatment threshold combines factors such as the risks of the test, and the risks versus benefits of treatment. The point at which the factors are all evenly weighed is the threshold. If a test or treatment for a disease is effective and low-risk (e.g. giving antibiotics for a suspected urinary tract infection), then there is a lower threshold for going ahead. On the other hand, if a test or treatment is less effective or high-risk (e.g. starting chemotherapy for a malignant brain tumour), then greater confidence is required in the clinical diagnosis and potential benefits of treatment first. In principle, if a diagnostic test will not change the management of the patient, then careful consideration should be given to whether it is necessary to do the test at all. In summary, test results shift our thinking, but rarely give a ‘yes’ or a ‘no’ answer in terms of a diagnosis. Sometimes tests shift the probability of disease by less than we realise. Pre-test probability is key, and this is derived from the history and physical examination, combined with a sound knowledge of medicine and m m eb oo ks being carried out has a sensitivity of 95% and a specificity of 85%. Patient A has very characteristic clinical findings, which make the pre-test probability of the condition for which the test is being used very high – estimated as 90%. Patient B has more equivocal findings, such that the pre-test probability is estimated as only 50%. If the result in Patient A is negative, there is still a significant chance that he has the condition for which he is being tested; in Patient B, however, a negative result makes the diagnosis very unlikely. ok s fre Fig. 1.5 The interpretation of a test result depends on the probability of the disease before the test is carried out. In the example shown, the test fre ks ks oo oo eb m co m fre e. ks ks Automatic, subconscious Deliberate, conscious Fast, effortless Slow, effortful om High/consistent reliability Vulnerable to error Less prone to error .c Low/variable reliability Less affected by context ks m m m m eb eb was found beside her at home. Her observations show she has a Glasgow Coma Scale score of 10/15, heart rate 100 beats/ min, blood pressure 100/60 mmHg, respiratory rate 14 breaths/ min, oxygen saturations 98% on air and temperature 37.5°C. Already your mind has reached a working diagnosis. It fits a pattern (type 1 thinking). You think she has taken an overdose. At this point you can stop to think about your thinking (rational override in Fig. 1.6): ‘What is the evidence for this diagnosis? What else could it be?’ On the other hand, imagine being asked to assess a patient who has been admitted with syncope. There are several different causes of syncope and a systematic approach is required to reach a diagnosis (type 2 thinking). However, you recently heard about a case of syncope due to a leaking abdominal aortic aneurysm. At the end of your assessment, following evidence-based guidelines, it is clear the patient can be discharged. Despite this, you decide to observe the patient overnight ‘just in case’ (irrational override in Fig. 1.6). In this example, your intuition is actually availability bias (when things are at the forefront of your mind), which has significantly distorted your estimate of probability. ks oo m m m m eb eb o ok s fre e. co co co Common cognitive biases in medicine ok s sf re e. Figure 1.7 illustrates the common cognitive biases prevalent in medical practice. Biases often work together; for example, in ok e. High scientific rigour oo k sf Low emotional involvement oo High emotional involvement re e Highly affected by context Low scientific rigour e. co sf re eb m Analytical, systematic m e. co fre ks fre ok oo oo m Type 2 Intuitive, heuristic (pattern recognition) ks oo oo eb m m co e. re sf ok eb Type 1 eb eb eb m co m e. re ks f oo eb type 2 thinking in the diagnostic process. Adapted from Croskerry P. A universal model of diagnostic reasoning. Acad Med 2009; 84:1022–1028. 1.6 Type 1 and type 2 thinking m m e. co fre Studies of cognitive psychology and functional magnetic resonance imaging demonstrate two distinct types of processes when it comes to decision-making: intuitive (type 1) and analytical (type 2). This has been termed ‘dual process theory’. Box 1.6 explains this in more detail. Psychologists estimate that we spend 95% of our daily lives engaged in type 1 thinking – the intuitive, fast, subconscious mode of decision-making. Imagine driving a car, for example; it would be impossible to function efficiently if every decision and movement were as deliberate, conscious, slow and effortful as in our first driving lesson. With experience, complex procedures become automatic, fast and effortless. The same applies to medical practice. There is evidence that expert decision-making is well served by intuitive thinking. The problem is that although intuitive processing is highly efficient in many circumstances, in others it is prone to error. Clinicians use both type 1 and type 2 thinking, and both types are important in clinical decision-making. When encountering a problem that is familiar, clinicians employ pattern recognition and reach a working diagnosis or differential diagnosis quickly (type 1 thinking). When encountering a problem that is more complicated, they use a slower, systematic approach (type 2 thinking). Both types of thinking interplay – they are not mutually exclusive in the diagnostic process. Figure 1.6 illustrates the interplay between type 1 and type 2 thinking in clinical practice. Errors can occur in both type 1 and type 2 thinking; for example, people can apply the wrong rules or make errors in their application while using type 2 thinking. However, it has been argued that the common cognitive biases encountered in medicine tend to occur when clinicians are engaged in type 1 thinking. For example, imagine being asked to see a young woman who is drowsy. She is handed over to you as a ‘probable overdose’ because she has a history of depression and a packet of painkillers eb oo ks m m oo ks Reason said that, ‘Our propensity for certain types of error is the price we pay for the brain’s remarkable ability to think and act intuitively – to sift quickly through the sensory information that constantly bombards us without wasting time trying to work through every situation anew.’ This property of human thinking is highly relevant to clinical decision-making. Type 1 and type 2 thinking m 1 Fig. 1.6 The interplay between type 1 and fre Education Training Logical competence Working diagnosis Irrational override e. co m Rational override Type 2 processes oo eb fre e. c ok s eb o ks fre e. co m Not recognised m Cognitive biases more likely Type 1 processes m Clinical presentation e. co m om m e. co re ks f oo eb m Recognised Experience Context Ambient conditions Cognitive biases • 7 fre ks oo eb m co m fre e. ks oo eb m om .c re e ks eb m m Unpacking principle Failure to ‘unpack’ all the available information may mean things are missed. For example, if a thorough history is not obtained from either the patient or carers (a common problem in geriatric medicine), diagnostic possibilities may be discounted oo oo k eb m m e. co co fre Visceral bias The influence of either negative or positive feelings towards patients, which can affect our decisionmaking ks oo m m eb eb o ok s e. ks fre Posterior probability Our estimate of the likelihood of disease may be unduly influenced by what has gone on before for a particular patient. For example, a patient who has been extensively investigated for headaches presents with a severe headache, and serious causes are discounted oo eb m Triage-cueing Triage ensures patients are sent to the right department. However, this leads to ‘geography is destiny’. For example, a diabetic ketoacidosis patient with abdominal pain and vomiting is sent to surgery. The wrong location (surgical ward) stops people thinking about medical causes of abdominal pain and vomiting sf fre ks oo eb m Overconfidence bias The tendency to believe we know more than we actually do, placing too much faith in opinion instead of gathered evidence co m e. re ks f oo eb Fig. 1.7 Common cognitive biases in medicine. Adapted from Croskerry P. Achieving quality in clinical decision-making: cognitive strategies and m co e. ok s re sf ok sf re ok sf re e. e. co co m m detection of bias. Acad Emerg Med 2002; 9:1184–1204. ok m ks eb m m e. co e. co fre eb oo ks Commission bias The tendency towards action rather than inaction, on the assumption that good can come only from doing something (rather than ‘watching and waiting’) Confirmation bias The tendency to look for confirming evidence to support a theory rather than looking for disconfirming evidence to refute it, even if the latter is clearly present. Confirmation bias is common when a patient has been seen first by another doctor Search satisficing We may stop searching because we have found something that fits or is convenient, instead of systematically looking for the best alternative, which involves more effort ks fre oo ks eb m Omission bias The tendency towards inaction, rooted in the principle of ‘first do no harm.’ Events that occur through natural progression of disease are more acceptable than those that may be attributed directly to the action of the health-care team m Base rate neglect The tendency to ignore the prevalence of a disease, which then distorts Bayesian reasoning. In some cases, clinicians do this deliberately in order to rule out an unlikely but worst-case scenario m Hindsight bias Knowing the outcome may profoundly influence the perception of past events and decision-making, preventing a realistic appraisal of what actually occurred – a major problem in learning from diagnostic error Psych-out error Psychiatric patients who present with medical problems are underassessed, under-examined and under-investigated because problems are presumed to be due to, or exacerbated by, their psychiatric condition oo e. co m m m m Framing effect How a case is presented – for example, in handover – can generate bias in the listener. This can be mitigated by always having ‘healthy scepticism’ about other people’s diagnoses e. co ks fre m eb oo Availability bias Things may be at the forefront of your mind because you have seen several cases recently or have been studying that condition in particular. For example, when one of the authors worked in an epilepsy clinic, all blackouts were possible seizures eb eb o ok s ks f oo eb m Ascertainment bias We sometimes see what we expect to see (‘self-fulfilling prophecy’). For example, a frequent self-harmer attends the emergency department with drowsiness; everyone assumes he has taken another overdose and misses a brain injury Premature closure The tendency to close the decisionmaking process prematurely and accept a diagnosis before it, and other possibilities, have been fully explored oo fre e. c Diagnostic momentum Once a diagnostic label has been attached to a patient (by the patient or other health-care professionals), it can gather momentum with each review, leading others to exclude other possibilities in their thinking re Anchoring The common human tendency to rely too heavily on the first piece of information offered (the ‘anchor’) when making decisions e. co m om m e. co 8 • Clinical decision-making eb m co m fre e. eb oo ks ks oo eb m m om m .c re e oo co Red flags and ROWS (‘rule out worst case scenario’) e. co m m m m eb eb oo k These are used frequently in medicine in order to reduce reliance on fallible human memory. ABCDE (airway, breathing, circulation, disability, exposure/examination) is probably the most successful checklist in medicine, used during the assessment and treatment of critically ill patients (ABCDE is sometimes prefixed with ‘C’ for ‘control of any obvious problem’; see p. 188). Checklists ensure that important issues have been considered and completed, especially under conditions of complexity, stress or fatigue. ks sf Mnemonics and checklists ks oo co m m m m Fig. 1.8 Factors that affect our judgement and ok sf re e. decision-making. Type 1 thinking = fast, intuitive, subconscious, low-effort. ok s External factors Interruptions Cognitive overload Time pressure Ambient conditions Insufficient data Team factors Patient factors Poor feedback eb eb o ok s fre These are strategies that force doctors to consider serious diseases that can present with common symptoms. Red flags in back pain are listed in Box 24.19 (p. 996). Considering and investigating for possible pulmonary embolism in patients who e. co sf re Error oo ks ks oo eb m Once all the available data from history, physical examination and (sometimes) initial test results are available, these need to be synthesised into a problem list. The ability to identify key clinical data and create a problem list is a key step in clinical reasoning. Some problems (e.g. low serum potassium) require action but not necessarily a differential diagnosis. Other problems (e.g. vomiting) require a differential diagnosis. The process of generating a problem list ensures nothing is missed. The process of generating a differential diagnosis works against anchoring on a particular diagnosis too early, thereby avoiding search satisficing and premature closure (see Fig. 1.7). e. co e. ks fre oo eb m Type 1 thinking/ conservation of cognitive effort Cognitive and affective biases ok m co e. re sf Problem lists and differential diagnosis fre ks oo eb m co m e. re ks f oo Internal factors Knowledge Training Beliefs and values Emotions Sleep/fatigue Stress Physical illness Personality type ok Taking a history and performing a physical examination may seem obvious, but these are sometimes carried out inadequately. This is the ‘unpacking principle’: failure to unpack all the available information means things can be missed and lead to error. fre oo ks eb m m e. co fre eb oo ks Knowledge and experience do not eliminate errors. Instead, there are a number of ways in which we can act to reduce errors in clinical decision-making. Examples are: eb There are some simple and established techniques that can be used to avoid cognitive biases and errors in clinical decision-making. e. co m m e. co ks fre oo eb m An understanding of these interactions makes it easier for health-care professionals, who are committed to ‘first do no harm,’ to work in the safest way possible. For example, performance is adversely affected by factors such as poorly designed processes and equipment, frequent interruptions and fatigue. The areas of the brain required for type 2 processing are most affected by things like fatigue and cognitive overload, and the brain reverts to type 1 processing to conserve cognitive energy. Figure 1.8 illustrates some of the internal and external factors that affect human judgement and decision-making. Various experiments demonstrate that we focus our attention to filter out distractions. This is advantageous in many situations, but in focusing on what we are trying to see we may not notice the unexpected. In a team context, what is obvious to one person may be completely missed by someone else. Safe and effective team communication therefore requires us never to assume, and to verbalise things, even though they may seem obvious. m fre fre e. c eb o m m eb oo ‘Human factors’ is the science of the limitations of human performance, and how technology, the work environment and team communication can adapt for this to reduce diagnostic and other types of error. Analysis of serious adverse events in clinical practice shows that human factors and poor team communication play a significant role when things go wrong. Research shows that many errors are beyond an individual’s conscious control and are precipitated by many factors. The discipline of human factors seeks to understand interactions between: • people and tasks or technology • people and their work environment • people in a team. 1 Cognitive debiasing strategies History and physical examination Reducing errors in clinical decision-making m • adopting ‘cognitive debiasing strategies’ • using clinical prediction rules and other decision aids • engaging in effective team communication. ok s ks f re overconfidence bias (the tendency to believe we know more than we actually do), too much faith is placed in opinion instead of gathered evidence. This bias can be augmented by the availability bias and finally by commission bias (the tendency towards action rather than inaction) – sometimes with disastrous results. The mark of a well-calibrated thinker is the ability to recognise what mode of thinking is being employed and to anticipate and recognise situations in which cognitive biases and errors are more likely to occur. Human factors e. co m om m e. co Reducing errors in clinical decision-making • 9 ks oo eb co m fre e. m m eb oo ks ks eb Please can you come and see her as soon as possible? I think she needs admission to Intensive Care. om m (NEWS = National Early Warning Score; a patient with normal vital signs scores 0) From Royal College of Physicians of London. National Early Warning Score: standardising the assessment of illness severity in the NHS. Report of a working party. RCP, July 2012; www.rcplondon.ac.uk/projects/outputs/national-earlywarning-score-news (accessed March 2016). .c re e ks oo m m m m eb eb oo k sf with dual antiplatelet therapy and low-molecular-weight heparin as recommended in clinical guidelines? As this chapter has described, clinicians frequently deal with uncertainty/probability. Clinicians need to be able to explain risks and benefits of treatment in an accurate and understandable way. Providing the relevant statistics is seldom sufficient to guide decision-making because a patient’s perception of risk may be influenced by irrational factors as well as individual values. Research evidence provides statistics but these can be confusing. Terms such as ‘common’ and ‘rare’ are nebulous. Whenever possible, clinicians should quote numerical information using consistent denominators (e.g. ‘90 out of 100 patients who have this operation feel much better, 1 will die during the operation and 2 will suffer a stroke’). Visual aids can be used to present complex statistical information (Fig. 1.9). How uncertainty is conveyed to patients is important. Many studies demonstrate a correlation between effective clinician– patient communication and improved health outcomes. If patients feel they have been listened to and understand the problem and proposed treatment plan, they are more likely to follow the plan and less likely to re-attend. co e. m m eb oo ks fre ok s eb o m m Clinical decision-making: putting it all together The following is a practical example that brings together many of the concepts outlined in this chapter: A 25-year-old woman presents with right-sided pleuritic chest pain and breathlessness. She reports that she had an upper co e. ok s re sf ok ok sf re e. re oo Recommendation e. co co m ‘Patient-centred evidence-based medicine’ refers to the application of best-available research evidence while taking individual patient factors into account; these include both clinical and non-clinical factors (e.g. the patient’s social circumstances, values and wishes). For example, a 95-year-old man with dementia and a recent gastrointestinal bleed is admitted with an inferior myocardial infa