Harrison 's Principles of Internal Medic - Harrison

Cover Preface: Harrison's Principles ofInternal Medicine, 18e Copyright: Harrison's Principlesof Internal Medicine, 18e Contributors: Harrison'sPrinciples of Internal Medicine,18e Part 1. Introduction to ClinicalMedicine Chapter 1. The Practice ofMedicine Chapter 2. Global Issues in

Medicine Chapter 3. Decision-Making inClinical Medicine Chapter 4. Screening andPrevention of Disease Chapter 5. Principles of ClinicalPharmacology Chapter 6. Women's Health Chapter 7. Medical DisordersDuring Pregnancy Chapter 8. Medical Evaluationof the Surgical Patient Chapter 9. Palliative and End-of-Life Care

Chapter 10. The Safety andQuality of Health Care Chapter e1. Primary Care inLow- and Middle-IncomeCountries Chapter e2. Complementary,Alternative, and IntegrativeMedicine Chapter e3. The Economics ofMedical Care Chapter e4. Racial and EthnicDisparities in Health Care Chapter e5. Ethical Issues inClinical Medicine

Chapter e6. Neoplasia DuringPregnancy Part 2. Cardinal Manifestationsand Presentation of Diseases Section 1. Pain Chapter 11. Pain:Pathophysiology andManagement Chapter 12. Chest Discomfort Chapter 13. Abdominal Pain Chapter 14. Headache Chapter 15. Back and NeckPain Section 2. Alterations in Body

Temperature Chapter 16. Fever andHyperthermia Chapter 17. Fever and Rash Chapter e7. Atlas of RashesAssociated With Fever Chapter 18. Fever of UnknownOrigin Chapter 19. Hypothermia andFrostbite Section 3. Nervous SystemDysfunction Chapter 20. Syncope Chapter 21. Dizziness and

Vertigo Chapter 22. Weakness andParalysis Chapter 23. Numbness,Tingling, and Sensory Loss Chapter 24. Gait and BalanceDisorders Chapter e8. Video Library ofGait Disorders Chapter 25. Confusion andDelirium Chapter 26. Aphasia, MemoryLoss, and Other Focal CerebralDisorders

Chapter e9. Memory Loss Chapter e10. PrimaryProgressive Aphasia, MemoryLoss, and Other Focal CerebralDisorders Chapter 27. Sleep Disorders Section 4. Disorders of Eyes,Ears, Nose, and Throat Chapter 28. Disorders of theEye Chapter e11. Video Library ofNeuro-Ophthalmology Chapter 29. Disorders of Smelland Taste

Chapter 30. Disorders ofHearing Chapter 31. Pharyngitis,Sinusitis, Otitis, and OtherUpper Respiratory TractInfections Chapter 32. Oral Manifestationsof Disease Chapter e12. Atlas of OralManifestations of Disease Section 5. Alterations inCirculatory and RespiratoryFunctions Chapter 33. Dyspnea

Chapter 34. Cough andHemoptysis Chapter 35. Hypoxia andCyanosis Chapter 36. Edema Chapter e13. Approach to thePatient with a Heart Murmur Chapter 37. Palpitations Section 6. Alterations inGastrointestinal Function Chapter 38. Dysphagia Chapter 39. Nausea, Vomiting,and Indigestion Chapter 40. Diarrhea and

Constipation Chapter 41. GastrointestinalBleeding Chapter 42. Jaundice Chapter 43. AbdominalSwelling and Ascites Section 7. Alterations in Renaland Urinary Tract Function Chapter 44. Azotemia andUrinary Abnormalities Chapter e14. Atlas of UrinarySediments and Renal Biopsies Chapter 45. Fluid andElectrolyte Disturbances

Chapter e15. Fluid andElectrolyte Imbalances andAcid-Base Disturbances: CaseExamples Chapter 46. Hypercalcemia andHypocalcemia Chapter 47. Acidosis andAlkalosis Section 8. Alterations in SexualFunction and Reproduction Chapter 48. Sexual DysfunctionChapter 49. Hirsutism andVirilization Chapter 50. Menstrual

Disorders and Pelvic Pain Section 9. Alterations in theSkin Chapter 51. Approach to thePatient with a Skin Disorder Chapter 52. Eczema, Psoriasis,Cutaneous Infections, Acne,and Other Common SkinDisorders Chapter 53. Skin Manifestationsof Internal Disease Chapter 54. ImmunologicallyMediated Skin Diseases Chapter 55. Cutaneous Drug

Reactions Chapter 56. Photosensitivityand Other Reactions to Light Chapter e16. Atlas of SkinManifestations of InternalDisease Section 10. HematologicAlterations Chapter 57. Anemia andPolycythemia Chapter 58. Bleeding andThrombosis Chapter 59. Enlargement ofLymph Nodes and Spleen

Chapter 60. Disorders ofGranulocytes and Monocytes Chapter e17. Atlas ofHematology and Analysis ofPeripheral Blood Smears Part 3. Genes, the Environment,and Disease Chapter 61. Principles ofHuman Genetics Chapter 62. ChromosomeDisorders Chapter 63. The Practice ofGenetics in Clinical Medicine Chapter e18. Mitochondrial

DNA and Heritable Traits andDiseases Chapter 64. The HumanMicrobiome Chapter e19. Systems Biologyin Health and Disease Part 4. Regenerative Medicine Chapter 65. Stem Cell Biology Chapter 66. HematopoieticStem Cells Chapter 67. Applications ofStem Cell Biology in ClinicalMedicine Chapter 68. Gene Therapy in

Clinical Medicine Chapter 69. Tissue Engineering Part 5. Aging Chapter 70. WorldDemography of Aging Chapter 71. The Biology ofAging Chapter 72. Clinical Problemsof Aging Part 6. Nutrition Chapter 73. NutrientRequirements and DietaryAssessment Chapter 74. Vitamin and Trace

Mineral Deficiency and Excess Chapter 75. Malnutrition andNutritional Assessment Chapter 76. Enteral andParenteral Nutrition Therapy Chapter 77. Biology of Obesity Chapter 78. Evaluation andManagement of Obesity Chapter 79. Eating Disorders Chapter 80. Involuntary WeightLoss Part 7. Oncology andHematology Section 1. Neoplastic Disorders

Chapter 81. Approach to thePatient with Cancer Chapter 82. Prevention andEarly Detection of Cancer Chapter 83. Cancer Genetics Chapter 84. Cancer CellBiology and Angiogenesis Chapter 85. Principles ofCancer Treatment Chapter 86. Infections inPatients with Cancer Chapter 87. Cancer of the Skin Chapter 88. Head and NeckCancer

Chapter 89. Neoplasms of theLung Chapter 90. Breast Cancer Chapter 91. GastrointestinalTract Cancer Chapter 92. Tumors of theLiver and Biliary Tree Chapter 93. Pancreatic Cancer Chapter 94. Bladder and RenalCell Carcinomas Chapter 95. Benign andMalignant Diseases of theProstate Chapter 96. Testicular Cancer

Chapter 97. GynecologicMalignancies Chapter 98. Soft Tissue andBone Sarcomas and BoneMetastases Chapter 99. Carcinoma ofUnknown Primary Chapter 100. ParaneoplasticSyndromes- Endocrinologic-Hematologic Chapter 101. ParaneoplasticNeurologic Syndromes Chapter e20. Thymoma Chapter 102. Late

Consequences of Cancer andIts Treatment Section 2. HematopoieticDisorders Chapter 103. Iron Deficiencyand Other HypoproliferativeAnemias Chapter 104. Disorders ofHemoglobin Chapter 105. MegaloblasticAnemias Chapter 106. HemolyticAnemias and Anemia Due toAcute Blood Loss

Chapter 107. Aplastic Anemia,Myelodysplasia, and RelatedBone Marrow FailureSyndromes Chapter 108. PolycythemiaVera and OtherMyeloproliferative Diseases Chapter 109. Acute andChronic Myeloid Leukemia Chapter 110. Malignancies ofLymphoid Cells Chapter e21. Less CommonHematologic Malignancies Chapter 111. Plasma Cell

Disorders Chapter 112. Amyloidosis Chapter 113. TransfusionBiology and Therapy Chapter 114. HematopoieticCell Transplantation Section 3. Disorders ofHemostasis Chapter 115. Disorders ofPlatelets and Vessel Wall Chapter 116. CoagulationDisorders Chapter 117. Arterial andVenous Thrombosis

Chapter 118. Antiplatelet,Anticoagulant, and FibrinolyticDrugs Part 8. Infectious Diseases Section 1. Basic Considerationsin Infectious Diseases Chapter 119. Introduction toInfectious Diseases; Host-Pathogen Interactions Chapter 120. MolecularMechanisms of MicrobialPathogenesis Chapter 121. Approach to theAcutely Ill Infected Febrile

Patient Chapter 122. ImmunizationPrinciples and Vaccine Use Chapter 123. HealthRecommendations forInternational Travel Chapter e22. LaboratoryDiagnosis of Infectious DiseasesSection 2. Clinical Syndromes:Community-Acquired InfectionsChapter 124. InfectiveEndocarditis Chapter 125. Infections of theSkin, Muscles, and Soft Tissues

Chapter 126. Osteomyelitis Chapter 127. IntraabdominalInfections and Abscesses Chapter 128. Acute InfectiousDiarrheal Diseases andBacterial Food Poisoning Chapter 129. ClostridiumDifficile Infection, IncludingPseudomembranous Colitis Chapter 130. SexuallyTransmitted Infections;Overview and ClinicalApproach Chapter e23. Infectious

Complications of Burns Chapter e24. InfectiousComplications of Bites Section 3. Clinical Syndromes:Health Care-AssociatedInfections Chapter 131. Health Care-Associated Infections Chapter 132. Infections inTransplant Recipients Section 4. Approach to Therapyfor Bacterial Diseases Chapter 134. PneumococcalInfections

Section 5. Diseases Caused byGram-Positive Bacteria Chapter 134. PneumococcalInfections Chapter 135. StaphylococcalInfections Chapter 136. StreptococcalInfections Chapter 137. EnterococcalInfections Chapter 138. Diphtheria andOther Infections Caused byCorynebacteria and RelatedSpecies

Chapter 139. ListeriaMonocytogenes Infections Chapter 140. Tetanus Chapter 141. Botulism Chapter 142. Gas Gangrene andOther Clostridial Infections Section 6. Diseases Caused byGram-Negative Bacteria Chapter 143. MeningococcalInfections Chapter 144. GonococcalInfections Chapter 145. Haemophilus andMoraxella Infections

Chapter 146. Infections Due tothe HACEK Group andMiscellaneous Gram-NegativeBacteria Chapter 147. LegionellaInfections Chapter 148. Pertussis andOther Bordetella Infections Chapter 149. Diseases Causedby Gram-Negative EntericBacilli Chapter 150. AcinetobacterInfections Chapter 151. Helicobacter

pylori Infections Chapter 152. Infections Due toPseudomonas Species andRelated Organisms Chapter 153. Salmonellosis Chapter 154. Shigellosis Chapter 155. Infections Due toCampylobacter and RelatedOrganisms Chapter 156. Cholera andOther Vibrioses Chapter 157. Brucellosis Chapter 158. Tularemia Chapter 159. Plague and Other

Yersinia Infections Chapter 160. BartonellaInfections, Including Cat-Scratch Disease Chapter 161. Donovanosis Section 7. MiscellaneousBacterial Infections Chapter 162. Nocardiosis Chapter 163. Actinomycosis Chapter 164. Infections Due toMixed Anaerobic Organisms Section 8. MycobacterialDiseases Chapter 165. Tuberculosis

Chapter 166. Leprosy Chapter 167. NontuberculousMycobacterial Infections Chapter 168. AntimycobacterialAgents Section 9. Spirochetal Diseases Chapter 169. Syphilis Chapter 170. EndemicTreponematoses Chapter 171. Leptospirosis Chapter 172. Relapsing Fever Chapter 173. Lyme Borreliosis Section 10. Diseases Caused byRickettsiae, Mycoplasmas, and

Chlamydiae Chapter 174. RickettsialDiseases Chapter 175. Infections Due toMycoplasmas Chapter 176. ChlamydialInfections Section 11. Viral Diseases:General Considerations Chapter 177. Medical Virology Chapter 178. AntiviralChemotherapy, ExcludingAntiretroviral Drugs Section 12. Infections Due to

DNA Viruses Chapter 179. Herpes SimplexVirus Infections Chapter 180. Varicella-ZosterVirus Infections Chapter 181. Epstein-BarrVirus Infections, IncludingInfectious Mononucleosis Chapter 182. Cytomegalovirusand Human Herpesvirus Types6, 7, and 8 Chapter 183. MolluscumContagiosum, Monkeypox, andOther Poxvirus Infections

Chapter 184. ParvovirusInfections Chapter 185. HumanPapillomavirus Infections Section 13. Infections Due toDNA and RNA RespiratoryViruses Chapter 186. Common ViralRespiratory Infections Chapter 187. Influenza Section 14. Infections Due toHuman ImmunodeficiencyVirus and Other HumanRetroviruses

Chapter 188. The HumanRetroviruses Chapter 189. HumanImmunodeficiency VirusDisease: AIDS and RelatedDisorders Section 15. Infections Due toRNA Viruses Chapter 190. ViralGastroenteritis Chapter 191. Enteroviruses andReoviruses Chapter 192. Measles(Rubeola)

Chapter 193. Rubella (GermanMeasles) Chapter 194. Mumps Chapter 195. Rabies and OtherRhabdovirus Infections Chapter 196. Infections Causedby Arthropod- and Rodent-Borne Viruses Chapter 197. Ebola andMarburg Viruses Section 16. Fungal Infections Chapter 198. Diagnosis andTreatment of Fungal Infections Chapter 199. Histoplasmosis

Chapter 200.Coccidioidomycosis Chapter 201. Blastomycosis Chapter 202. Cryptococcosis Chapter 203. Candidiasis Chapter 204. Aspergillosis Chapter 205. Mucormycosis Chapter 206. SuperficialMycoses and Less CommonSystemic Mycoses Chapter 207. PneumocystisInfections Section 17. Protozoal andHelminthic Infections: General

Considerations Chapter e25. LaboratoryDiagnosis of Parasitic InfectionsChapter 208. Agents Used toTreat Parasitic Infections Chapter e26. Pharmacology ofAgents Used to Treat ParasiticInfections Section 18. Protozoal InfectionsChapter 209. Amebiasis andInfection with Free-LivingAmebas Chapter 210. Malaria Chapter 211. Babesiosis

Chapter e27. Atlas of BloodSmears of Malaria andBabesiosis Chapter 212. Leishmaniasis Chapter 213. Chagas' Diseaseand Trypanosomiasis Chapter 214. ToxoplasmaInfections Chapter 215. ProtozoalIntestinal Infections andTrichomoniasis Section 19. HelminthicInfections Chapter 216. Trichinellosis and

Other Tissue NematodeInfections Chapter 217. IntestinalNematode Infections Chapter 218. Filarial andRelated Infections Chapter 219. Schistosomiasisand Other Trematode InfectionsChapter 220. Cestode InfectionsPart 9. Terrorism and ClinicalMedicine Chapter 221. MicrobialBioterrorism Chapter 222. Chemical

Terrorism Chapter 223. RadiationTerrorism Part 10. Disorders of theCardiovascular System Section 1. Introduction toCardiovascular Disorders Chapter 224. Basic Biology ofthe Cardiovascular System Chapter 225. Epidemiology ofCardiovascular Disease Chapter 226. Approach to thePatient with PossibleCardiovascular Disease

Section 2. Diagnosis ofCardiovascular Disorders Chapter 227. PhysicalExamination of theCardiovascular System Chapter 228.Electrocardiography Chapter e28. Atlas ofElectrocardiography Chapter 229. NoninvasiveCardiac Imaging:Echocardiography, NuclearCardiology, and MRI/CTImaging

Chapter e29. Atlas ofNoninvasive Cardiac Imaging Chapter 230. DiagnosticCardiac Catheterization andCoronary Angiography Section 3. Disorders of RhythmChapter 231. Principles ofElectrophysiology Chapter 232. TheBradyarrhythmias Chapter 233. TheTachyarrhythmias Chapter e30. Atlas of CardiacArrhythmias

Section 4. Disorders of theHeart Chapter 234. Heart Failure andCor Pulmonale Chapter 235. CardiacTransplantation and ProlongedAssisted Circulation Chapter 236. Congenital HeartDisease in the Adult Chapter 237. Valvular HeartDisease Chapter 238. Cardiomyopathyand Myocarditis Chapter 239. Pericardial

Disease Chapter 240. Tumors andTrauma of the Heart Chapter e31. CardiacManifestations of SystemicDisease Section 5. Vascular Disease Chapter 241. The Pathogenesis,Prevention, and Treatment ofAtherosclerosis Chapter e32. Atlas ofAtherosclerosis Chapter 242. The MetabolicSyndrome

Chapter 243. Ischemic HeartDisease Chapter 244. Unstable Anginaand Non-ST-Segment ElevationMyocardial Infarction Chapter 245. ST-SegmentElevation Myocardial InfarctionChapter 246. PercutaneousCoronary Interventions andOther Interventional ProceduresChapter e33. Atlas ofPercutaneous RevascularizationChapter 247. HypertensiveVascular Disease

Chapter 248. Diseases of theAorta Chapter 249. Vascular Diseasesof the Extremities Chapter 250. PulmonaryHypertension Part 11. Disorders of theRespiratory System Section 1. Diagnosis ofRespiratory Disorders Chapter 251. Approach to thePatient with Disease of theRespiratory System Chapter 252. Disturbances of

Respiratory Function Chapter 253. DiagnosticProcedures in RespiratoryDisease Chapter e34. Atlas of ChestImaging Section 2. Diseases of theRespiratory System Chapter 254. Asthma Chapter 255. HypersensitivityPneumonitis and PulmonaryInfiltrates with Eosinophilia Chapter 256. Occupational andEnvironmental Lung Disease

Chapter 257. Pneumonia Chapter 258. Bronchiectasisand Lung Abscess Chapter 259. Cystic Fibrosis Chapter 260. ChronicObstructive Pulmonary Disease Chapter 261. Interstitial LungDiseases Chapter 262. Deep VenousThrombosis and PulmonaryThromboembolism Chapter 263. Disorders of thePleura and Mediastinum Chapter 264. Disorders of

Ventilation Chapter 265. Sleep Apnea Chapter 266. LungTransplantation Part 12. Critical Care Medicine Section 1. Respiratory CriticalCare Chapter 267. Approach to thePatient with Critical Illness Chapter 268. Acute RespiratoryDistress Syndrome Chapter 269. MechanicalVentilatory Support Section 2. Shock and Cardiac

Arrest Chapter 270. Approach to thePatient with Shock Chapter 271. Severe Sepsis andSeptic Shock Chapter 272. CardiogenicShock and Pulmonary Edema Chapter 273. CardiovascularCollapse, Cardiac Arrest, andSudden Cardiac Death Section 3. Neurologic CriticalCare Chapter 274. Coma Chapter 275. Neurologic

Critical Care, IncludingHypoxic-IschemicEncephalopathy, andSubarachnoid Hemorrhage Section 4. OncologicEmergencies Chapter 276. OncologicEmergencies Part 13. Disorders of theKidney and Urinary Tract Chapter 277. Cellular andMolecular Biology of theKidney Chapter 278. Adaption of the

Kidney to Renal Injury Chapter 279. Acute KidneyInjury Chapter 280. Chronic KidneyDisease Chapter 281. Dialysis in theTreatment of Renal Failure Chapter 282. Transplantation inthe Treatment of Renal Failure Chapter 283. GlomerularDiseases Chapter 284. Polycystic KidneyDisease and Other InheritedTubular Disorders

Chapter 285. TubulointerstitialDiseases of the Kidney Chapter 286. Vascular Injury tothe Kidney Chapter 287. Nephrolithiasis Chapter 288. Urinary TractInfections, Pyelonephritis, andProstatitis Chapter e35. InterstitialCystitis-Painful BladderSyndrome Chapter 289. Urinary TractObstruction Part 14. Disorders of the

Gastrointestinal System Section 1. Disorders of theAlimentary Tract Chapter 290. Approach to thePatient with GastrointestinalDisease Chapter 291. GastrointestinalEndoscopy Chapter e36. Video Atlas ofGastrointestinal Endoscopy Chapter 292. Diseases of theEsophagus Chapter 293. Peptic UlcerDisease and Related Disorders

Chapter 294. Disorders ofAbsorption Chapter e37. The Schilling TestChapter 295. InflammatoryBowel Disease Chapter 296. Irritable BowelSyndrome Chapter 297. DiverticularDisease and CommonAnorectal Disorders Chapter 298. MesentericVascular Insufficiency Chapter 299. Acute IntestinalObstruction

Chapter 300. AcuteAppendicitis and Peritonitis Section 2. Liver and BiliaryTract Disease Chapter 301. Approach to thePatient with Liver Disease Chapter 302. Evaluation ofLiver Function Chapter 303. TheHyperbilirubinemias Chapter 304. Acute ViralHepatitis Chapter 305. Toxic and Drug-Induced Hepatitis

Chapter 306. Chronic Hepatitis Chapter 307. Alcoholic LiverDisease Chapter 308. Cirrhosis and ItsComplications Chapter e38. Atlas of LiverBiopsies Chapter 309. Genetic,Metabolic, and InfiltrativeDiseases Affecting the Liver Chapter 310. LiverTransplantation Chapter 311. Diseases of theGallbladder and Bile Ducts

Section 3. Disorders of thePancreas Chapter 312. Approach to thePatient with Pancreatic Disease Chapter 313. Acute andChronic Pancreatitis Part 15. Disorders of the Jointsand Adjacent Tissues Section 1. The Immune Systemin Health and Disease Chapter 314. Introduction to theImmune System Chapter 315. The MajorHistocompatibility Complex

Chapter 316. Primary ImmuneDeficiency Diseases Chapter e39. PrimaryImmunodeficiencies Associatedwith (or Secondary to) OtherDiseases Section 2. Disorders ofImmune-Mediated Injury Chapter 317. Allergies,Anaphylaxis, and SystemicMastocytosis Chapter 318. Autoimmunityand Autoimmune Diseases Chapter 319. Systemic Lupus

Erythematosus Chapter 320. AntiphospholipidAntibody Syndrome Chapter 321. RheumatoidArthritis Chapter 322. Acute RheumaticFever Chapter 323. Systemic Sclerosis(Scleroderma) and RelatedDisorders Chapter 324. Sjögren'sSyndrome Chapter 325. TheSpondyloarthritides

Chapter 326. The VasculitisSyndromes Chapter e40. Atlas of theVasculitic Syndromes Chapter 327. Behçet'sSyndrome Chapter 328. RelapsingPolychondritis Chapter 329. Sarcoidosis Chapter 330. FamilialMediterranean Fever and OtherHereditary Recurrent Fevers Section 3. Disorders of theJoints and Adjacent Tissues

Chapter 331. Approach toArticular and MusculoskeletalDisorders Chapter 332. Osteoarthritis Chapter 333. Gout and OtherCrystal-AssociatedArthropathies Chapter 334. InfectiousArthritis Chapter 335. Fibromyalgia Chapter 336. ArthritisAssociated with SystemicDisease, and Other Arthritides Chapter 337. Periarticular

Disorders of the Extremities Part 16. Endocrinology andMetabolism Section 1. Endocrinology Chapter 338. Principles ofEndocrinology Chapter 339. Disorders of theAnterior Pituitary andHypothalamus Chapter 340. Disorders of theNeurohypophysis Chapter 341. Disorders of theThyroid Gland Chapter 342. Disorders of the

Adrenal Cortex Chapter 343.Pheochromocytoma Chapter 344. Diabetes Mellitus Chapter 345. Hypoglycemia Chapter 346. Disorders of theTestes and Male ReproductiveSystem Chapter 347. The FemaleReproductive System,Infertility, and Contraception Chapter 348. The MenopauseTransition and PostmenopausalHormone Therapy

Chapter 349. Disorders of SexDevelopment Chapter 350. EndocrineTumors of the GastrointestinalTract and Pancreas Chapter 351. DisordersAffecting Multiple EndocrineSystems Section 2. Disorders of Boneand Mineral Metabolism Chapter 352. Bone and MineralMetabolism in Health andDisease Chapter 353. Disorders of the

Parathyroid Gland and CalciumHomeostasis Chapter 354. Osteoporosis Chapter 355. Paget's Diseaseand Other Dysplasias of Bone Section 3. Disorders ofIntermediary Metabolism Chapter 356. Disorders ofLipoprotein Metabolism Chapter 357. HemochromatosisChapter 358. The Porphyrias Chapter 359. Disorders ofPurine and PyrimidineMetabolism

Chapter 360. Wilson's Disease Chapter 361. LysosomalStorage Diseases Chapter 362. Glycogen StorageDiseases and Other InheritedDisorders of CarbohydrateMetabolism Chapter 363. HeritableDisorders of Connective Tissue Chapter 364. InheritedDisorders of Amino AcidMetabolism in Adults Chapter 365. Inherited Defectsof Membrane Transport

Chapter e41. Atlas of ClinicalManifestations of MetabolicDiseases Part 17. Neurologic Disorders Section 1. Diagnosis ofNeurologic Disorders Chapter 366. Biology ofNeurologic Diseases Chapter 367. Approach to thePatient with Neurologic DiseaseChapter e42. The NeurologicScreening Exam Chapter e43. Video Atlas of theDetailed Neurologic

Examination Chapter 368. Neuroimaging inNeurologic Disorders Chapter e44. Atlas ofNeuroimaging Chapter e45. ElectrodiagnosticStudies of Nervous SystemDisorders- EEG, EvokedPotentials, and EMG Chapter e46. Technique ofLumbar Puncture Section 2. Diseases of theCentral Nervous System Chapter 369. Seizures and

Epilepsy Chapter 370. CerebrovascularDiseases Chapter 371. Dementia Chapter 372. Parkinson'sDisease and Other MovementDisorders Chapter 373. Ataxic Disorders Chapter 374. AmyotrophicLateral Sclerosis and OtherMotor Neuron Diseases Chapter 375. Disorders of theAutonomic Nervous System Chapter 376. Trigeminal

Neuralgia, Bell's Palsy, andOther Cranial Nerve Disorders Chapter 377. Diseases of theSpinal Cord Chapter 378. Concussion andOther Head Injuries Chapter 379. Primary andMetastatic Tumors of theNervous System Chapter 380. Multiple Sclerosisand Other DemyelinatingDiseases Chapter 381. Meningitis,Encephalitis, Brain Abscess,

and Empyema Chapter 382. Chronic andRecurrent Meningitis Chapter 383. Prion Diseases Section 3. Nerve and MuscleDisorders Chapter 384. PeripheralNeuropathy Chapter 385. Guillain-BarreSyndrome and Other Immune-Mediated Neuropathies Chapter 386. Myasthenia Gravisand Other Diseases of theNeuromuscular Junction

Chapter 387. MuscularDystrophies and Other MuscleDiseases Chapter 388. Polymyositis,Dermatomyositis, and InclusionBody Myositis Chapter e47. Special Issues inInpatient NeurologicConsultation Section 4. Chronic FatigueSyndrome Chapter 389. Chronic FatigueSyndrome Section 5. Psychiatric Disorders

Chapter 390. Biology ofPsychiatric Disorders Chapter 391. Mental Disorders Section 6. Alcoholism and DrugDependency Chapter 392. Alcohol andAlcoholism Chapter 393. Opioid DrugAbuse and Dependence Chapter 394. Cocaine andOther Commonly AbusedDrugs Chapter 395. NicotineAddiction

Chapter e48. NeuropsychiatricIllnesses in War Veterans Part 18. Poisoning, DrugOverdose, and Envenomation Chapter e49. Heavy MetalPoisoning Chapter e50. Poisoning andDrug Overdosage Chapter 396. Disorders Causedby Venomous Snakebites andMarine Animal Exposures Chapter 397. EctoparasiteInfestations and ArthropodBites and Stings

Part 19. High-Altitude andDecompression Sickness Chapter e51. Altitude Illness Chapter e52. Hyperbaric andDiving Medicine Appendix: Laboratory Valuesof Clinical Importance Chapter e53. The ClinicalLaboratory in Modern HealthCare

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Preface

Welcome to the 18th editionof Harrison's Principles ofInternal Medicine. In the 62years since the first editionof this textbook waspublished, virtually everyarea of medicine hasevolved substantially andmany new areas haveemerged. In 1949, when thefirst edition appeared, pepticulcer disease was thought tobe caused by stress, nearly

every tumor that was notresected resulted in death,rheumatic heart disease waswidely prevalent, andhepatitis B and HIV infectionwere unknown. In theintervening years, both theinfectious cause of and thecure for peptic ulcer diseasewere identified; advances indiagnosis and treatmentmade it possible to curetwo-thirds of cancers;rheumatic heart diseasevirtually disappeared;atherosclerotic coronaryartery disease waxed andthen—at least in part

through management ofmodifiable risk factors—began to wane; hepatitis Band its consequences,cirrhosis and hepatocellularcarcinoma, becamepreventable by a vaccine;and HIV, first viewed as auniformly fatal worldwidescourge, became a treatablechronic disease. During thissame period, the amount ofinformation required for theeffective practice ofmedicine grew unabated,and learning options forstudents, residents, andpracticing physicians also

burgeoned to includemultiple sources ofinformation in print andelectronic formats.

While retaining the foundinggoals of Harrison's, thisedition has been modifiedextensively in light of thevaried needs of the book'sreaders and the diversemethods and formats bywhich information is nowacquired. The print versionof the 18th edition is morereader-friendly in severalrespects: the book is printedin type that is easier to read

than prior editions, thegraphics and tables havebeen enhanced for ease ofinterpretation, and morethan 300 new figures areincluded. This improvedformat requires publicationof the print edition in twovolumes convenientlydivided by subject matter. ADVD accompanies the bookand contains additional e-chapters, videos, andatlases; its image bankincludes figures andphotographs from the bookthat can be incorporatedinto slide presentations. All

chapters have beenextensively updated byexperts in the field. Inaddition, this editionincludes 25 new chaptersand more than 100 newauthors. Thepathophysiologic approachto evaluating patients onthe basis of theirpresentation continues toreceive emphasis in anenriched section on thecardinal manifestations ofdisease. A new sectionfocuses on aging, itsdemographics and biology,and distinctive clinical

issues affecting olderpatients. The e-chaptershave increased in numberfrom 39 to 57 and include anew video atlas of neuro-ophthalmology, an audio-enhanced chapter on theapproach to a patient with aheart murmur, a case-basedteaching exercise in fluidand electrolyte imbalancesand acid-base disturbances,and explorations ofinfectious complications ofburns and bites. New videosdemonstrate the neurologicexamination and severalcommonly performed

medical procedures. A newchapter focuses onneuropsychiatric problemsamong war veterans. E-chapters on altitudesickness and hyperbaric anddiving medicine form a newsection on medical effects ofchanges in environmentalpressure.

For readers who wish tocontinue using Harrison's ina single-volume format, weare pleased to offer two neweBook versions of the 18thedition: a traditional eBook,with text and illustrations

from the new editionincluded for reading on aportable e-reader or on adesktop, and an enhancedeBook developed especiallyfor new tablet devices (e.g.,iPad, Galaxy, Playbook,Nook) that offer high-definition resolution ofmultimedia content andinteractive features. TheHarrison's 18th editionenhanced eBook will containextensive embedded videofootage, including all of thenew clinical proceduralvideos; the wonderfulneurologic examination

videos from Samuels andLowenstein; examples ofcardiovascular imaging andassessment; and high-resolution versions of morethan 2000 color imagesfrom the book and theHarrison's atlases on thecompanion DVD. Along withother social media features,the enhanced eBook offersusers the opportunity totake and share notes fromlectures and their ownreading. Additionalresources include Harrison'sOnline, a continuouslyupdated electronic resource

that highlights andsummarizes newly publishedarticles on significantmedical findings andadvances. Harrison's Self-Assessment and BoardReview, a useful study guidefor board review based oninformation in the 18thedition, will soon beproduced. Harrison's Manualof Medicine, a pocketversion of Harrison'sPrinciples of InternalMedicine, is available inboth print and electronicformats.

We have many people tothank for their efforts inproducing this book. First,the authors have done asuperb job of producingauthoritative chapters thatsynthesize vast amounts ofscientific and clinical data tocreate state-of-the-artdescriptions of medicaldisorders encompassed byinternal medicine. In today'sinformation-rich, rapidlyevolving environment, theyhave ensured that thisinformation is current.Helpful suggestions andcritical input have been

provided by a number ofcolleagues; particularlynotable was the advice ofChung Owyang on theGastroenterology Section.We are most grateful to ourcolleagues in each of oureditorial offices who havekept track of the work in itsvarious phases andfacilitated communicationwith the authors, with theMcGraw-Hill staff, andamong the editors: PatriciaConrad, Emily Cowan,Patricia L. Duffey, GregoryK. Folkers, Julie B. McCoy,Elizabeth Robbins, Kristine

Shontz, and StephanieTribuna.

The staff at McGraw-Hill hasbeen a constant source ofsupport and expertise.James Shanahan, Editor-in-Chief, Internal Medicine, forMcGraw-Hill's ProfessionalPublishing Division, hasbeen a superb and insightfulpartner to the editors,guiding the development ofthe book and its relatedproducts in new formats.Kim Davis seamlesslystepped into the position ofAssociate Managing Editor,

ensuring that the complexproduction of this multi-authored textbookproceeded in an efficientfashion. Paula Torres,Dominik Pucek, and MichaelCrumsho oversaw theproduction of the newprocedural and neurologyvideos. Phil Galea againserved as ProductionDirector on this, his finaledition, and did so with apeak performance. Mary A.Murray, Director,International Rights, isretiring from McGraw Hill in2012, after 50 years with

the company. Mary joinedthe Blakiston Division ofMcGraw Hill in 1961, whenTinsley Harrison was stillthe editor of the book. Herfirst assignment was todistribute reprints ofHarrison's chapters to theeditors and contributors. Forthe next 23 years, Marycontinued to be involved inthe editorial process ofHarrison's. In the early1990s, she was givenresponsibility for licensingMcGraw-Hill's medical titles;making use of her manycordial connections in global

medical publishing, shelicensed translations ofHarrison's into 19languages. We areextremely grateful to Maryfor her manyaccomplishments in supportof the book through 13editions.

We are privileged to havecompiled this 18th editionand are enthusiastic aboutall that it offers our readers.We learned much in theprocess of editing Harrison'sand hope that you will findthis edition a uniquely

valuable educationalresource.

The Editors

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CopyrightInformation

Harrison's™PRINCIPLES OFINTERNAL MEDICINEEighteenth Edition

Note: Dr. Fauci's work aseditor and author wasperformed outside the scopeof his employment as a U.S.government employee. Thiswork represents hispersonal and professional

views and not necessarilythose of the U.S.government.

Copyright © 2012, 2008,2005, 2001, 1998, 1994,1991, 1987, 1983, 1980,1977, 1974, 1970, 1966,1962, 1958 by The McGraw-Hill Companies, Inc. Allrights reserved. Printed inthe United States ofAmerica. Except aspermitted under the UnitedStates Copyright Act of1976, no part of thispublication may bereproduced or distributed in

any form or by any means,or stored in a data base orretrieval system, withoutthe prior written permissionof the publisher.

Harrison's™ is a trademarkof The McGraw-HillCompanies, Inc.

Two Volume Set ISBN 978-0-07174889-6; MHID 0-07-174889-XVolume 1 ISBN 978-0-07-163244-7; MHID 0-07-163244-1Volume 2 ISBN 978-0-07-

174887-2; MHID 0-07-174887-3DVD ISBN 978-0-07-174888-9; MHID 0-07-174888-1

Notice

Medicine is an ever-changing science. As newresearch and clinicalexperience broaden ourknowledge, changes intreatment and drug therapyare required. The authorsand the publisher of thiswork have checked withsources believed to be

reliable in their efforts toprovide information that iscomplete and generally inaccord with the standardsaccepted at the time ofpublication. However, inview of the possibility ofhuman error or changes inmedical sciences, neitherthe authors nor thepublisher nor any otherparty who has beeninvolved in the preparationor publication of this workwarrants that theinformation containedherein is in every respectaccurate or complete, and

they disclaim allresponsibility for any errorsor omissions or for theresults obtained from use ofthe information contained inthis work. Readers areencouraged to confirm theinformation containedherein with other sources.For example and inparticular, readers areadvised to check the productinformation sheet includedin the package of each drugthey plan to administer tobe certain that theinformation contained inthis work is accurate and

that changes have not beenmade in the recommendeddose or in thecontraindications foradministration. Thisrecommendation is ofparticular importance inconnection with new orinfrequently used drugs.

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Contributors

Editors

Dan L. Longo, MDLecturer, Department ofMedicine, Harvard MedicalSchool; Senior Physician,Brigham and Women'sHospital; Deputy Editor,New England Journal ofMedicine, Boston,Massachusetts; AdjunctInvestigator, NationalInstitute on Aging, National

Institutes of Health,Baltimore, Maryland

Dennis L. Kasper, MDWilliam Ellery ChanningProfessor of Medicine,Professor of Microbiologyand Molecular Genetics,Harvard Medical School;Director, ChanningLaboratory, Department ofMedicine, Brigham andWomen's Hospital, Boston,Massachusetts

J. Larry Jameson, MD,PhDRobert G. Dunlop Professor

of Medicine; Dean,University of PennsylvaniaSchool of Medicine;Executive Vice-President ofthe University ofPennsylvania for the HealthSystem, Philadelphia,Pennsylvania

Anthony S. Fauci, MDChief, Laboratory ofImmunoregulation;Director, National Instituteof Allergy and InfectiousDiseases, National Institutesof Health, Bethesda,Maryland

Stephen L. Hauser, MDRobert A. FishmanDistinguished Professor andChairman, Department ofNeurology, University ofCalifornia, San Francisco,San Francisco, California

Joseph Loscalzo, MD,PhDHersey Professor of theTheory and Practice ofMedicine, Harvard MedicalSchool; Chairman,Department of Medicine;Physician-in-Chief, Brighamand Women's Hospital,Boston, Massachusetts

Contributors

James L. Abbruzzese, MDProfessor and Chair,Department of GI MedicalOncology; M.G. and LillieJohnson Chair for CancerTreatment and Research,University of Texas, MDAnderson Cancer Center,Houston, Texas [99]

Jamil Aboulhosn, MDAssistant Professor,Departments of Medicineand Pediatrics, David GeffenSchool of Medicine,University of California, Los

Angeles, Los Angeles,California [236]

John C. Achermann, MD,PhDWellcome Trust SeniorFellow, UCL Institute ofChild Health, UniversityCollege London, London,United Kingdom [349]

John W. Adamson, MDClinical Professor ofMedicine, Department ofHematology/Oncology,University of California, SanDiego, San Diego, California[57, 103]

Anthony A. Amato, MDProfessor of Neurology,Harvard Medical School;Department of Neurology,Brigham and Women'sHospital, Boston,Massachusetts [384, 385,387]

Michael J. Aminoff, MD,DScProfessor of Neurology,University of California, SanFrancisco School ofMedicine, San Francisco,California [22, 23, e45]

Neil M. Ampel, MDProfessor of Medicine,University of Arizona,Tucson, Arizona [200]

Kenneth C. Anderson, MDKraft Family Professor ofMedicine, Harvard MedicalSchool; Chief, JeromeLipper Multiple MyelomaCenter, Dana-Farber CancerInstitute, Boston,Massachusetts [111, 113]

Elliott M. Antman, MDProfessor of Medicine,Harvard Medical School;Brigham and Women's

Hospital; Boston,Massachusetts [243, 245]

Frederick R. Appelbaum,MDDirector, Division of ClinicalResearch, Fred HutchinsonCancer Research Center,Seattle, Washington [114]

Gordon L. Archer, MDProfessor of Medicine andMicrobiology/Immunology;Senior Associate Dean forResearch and ResearchTraining, VirginiaCommonwealth UniversitySchool of Medicine,

Richmond, Virginia [133]

Cesar A. Arias, MD, PhDAssistant Professor,University of Texas MedicalSchool, Houston, Texas;Director, Molecular Geneticsand AntimicrobialResistance Unit, UniversidadEl Bosque, Bogotá, Colombia[137]

Wiebke Arlt, MD, DSc,FRCP, FMedSciProfessor of Medicine,Centre for Endocrinology,Diabetes and Metabolism,School of Clinical and

Experimental Medicine,University of Birmingham;Consultant Endocrinologist,University HospitalBirmingham, Birmingham,United Kingdom [342]

Valder R. Arruda, MD,PhDAssociate Professor ofPediatrics, University ofPennsylvania School ofMedicine; Division ofHematology, The Children'sHospital of Philadelphia,Philadelphia, Pennsylvania[116]

Arthur K. Asbury, MD,FRCPVan Meter ProfessorEmeritus of Neurology,University of PennsylvaniaSchool of Medicine,Philadelphia, Pennsylvania[23]

John R. Asplin, MDMedical Director, LitholinkCorporation; Chicago,Illinois [287]

John C. Atherton, MD,FRCPNottingham DigestiveDiseases Centre Biomedical

Research Unit (NDDC BRU),University of Nottinghamand Nottingham UniversityHospitals NHS Trust,Nottingham, UnitedKingdom [151]

Evelyn Attia, MDProfessor of ClinicalPsychiatry, ColumbiaCollege of Physicians andSurgeons; Weill CornellMedical College, New York,New York [79]

Paul S. Auerbach, MD, MSRedlich Family Professor,Department of Surgery,

Division of EmergencyMedicine, StanfordUniversity School ofMedicine, Palo Alto,California [396]

K. Frank Austen, MDAstraZeneca Professor ofRespiratory andInflammatory Diseases;Director, Inflammation andAllergic Diseases ResearchSection, Harvard MedicalSchool; Brigham andWomen's Hospital, Boston,Massachusetts [317]

Eric H. Awtry, MD

Assistant Professor ofMedicine, Boston UniversitySchool of Medicine;Inpatient Clinical Director,Section of Cardiology,Boston Medical CenterBoston, Massachusetts [240,e31]

Bruce R. Bacon, MDJames F. King, MD EndowedChair in Gastroenterology;Professor of InternalMedicine, St. LouisUniversity Liver Center, St.Louis University School ofMedicine, St. Louis, Missouri[308, 309]

Lindsey R. Baden, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Dana-Farber CancerInstitute, Brigham andWomen's Hospital, Boston,Massachusetts [178]

John R. Balmes, MDProfessor of Medicine, SanFrancisco General Hospital,San Francisco, California[256]

Manisha Balwani, MD, MSAssistant Professor,Department of Genetics and

Genomic Sciences, MountSinai School of Medicine ofNew York University, NewYork, New York [358]

Peter A. Banks, MDProfessor of Medicine,Harvard Medical School;Senior Physician, Division ofGastroenterology, Brighamand Women's Hospital,Boston, Massachusetts [312,313]

Robert L. Barbieri, MDKate Macy Ladd Professor ofObstetrics, Gynecology andReproductive Biology,

Harvard Medical School;Chairperson, Department ofObstetrics and Gynecology,Brigham and Women'sHospital, Boston,Massachusetts [7]

Joanne M. Bargman, MD,FRCPCProfessor of Medicine,University of Toronto; StaffNephrologist, UniversityHealth Network; Director,Home Peritoneal DialysisUnit and Co-Director, RenalRheumatology Lupus Clinic,University Health Network,Toronto, Ontario, Canada

[280]

Tamar F. Barlam, MDAssociate Professor ofMedicine, Boston UniversitySchool of Medicine, Boston,Massachusetts [121, 146]

Peter J. Barnes, DM, DSc,FMedSci, FRSHead of RespiratoryMedicine, Imperial College,London, United Kingdom[254]

Richard J. Barohn, MDChairman, Department ofNeurology; Gertrude and

Dewey Ziegler Professor ofNeurology, University ofKansas Medical Center,Kansas City, Kansas [384]

Miriam J. Baron, MDAssistant Professor ofMedicine, Harvard MedicalSchool; Associate Physician,Brigham and Women'sHospital, Boston,Massachusetts [127]

Rebecca M. Baron, MDAssistant Professor, HarvardMedical School; AssociatePhysician, Department ofPulmonary and Critical Care

Medicine, Brigham andWomen's Hospital, Boston,Massachusetts [258]

John G. Bartlett, MDProfessor of Medicine andChief, Division of InfectiousDiseases, Department ofMedicine, Johns HopkinsSchool of Medicine,Baltimore, Maryland [258]

Robert C. Basner, MDProfessor of ClinicalMedicine, Division ofPulmonary, Allergy, andCritical Care Medicine,Columbia University College

of Physicians and Surgeons,New York, New York[Appendix]

Buddha Basnyat, MD,MSc, FACP, FRCP(E)Principal Investigator,Oxford University ClinicalResearch Unit-PatanAcademy of HealthSciences; Medical Director,Nepal International Clinic,Kathmandu, Nepal [e51]

Shari S. Bassuk, ScDEpidemiologist, Division ofPreventive Medicine,Brigham and Women's

Hospital, Boston,Massachusetts [348]

John F. Bateman, PhDDirector, Cell Biology,Development and Disease,Murdoch Childrens ResearchInstitute, Parkville, Victoria,Australia [363]

David W. Bates, MD, MScProfessor of Medicine,Harvard Medical School;Chief, General InternalMedicine and Primary CareDivision, Brigham andWomen's Hospital; MedicalDirector, Clinical and

Quality Analysis, PartnersHealthCare System, Inc.,Boston, Massachusetts [10]

Robert P. Baughman, MDDepartment of InternalMedicine, University ofCincinnati Medical Center,Cincinnati, Ohio [329]

M. Flint Beal, MDChairman of Neurology andNeuroscience; Neurologist-in-Chief, New YorkPresbyterian Hospital; WeillCornell Medical College,New York, New York [366,376]

Laurence H. Beck, Jr.,MD, PhDAssistant Professor ofMedicine, Boston UniversitySchool of Medicine, Boston,Massachusetts [285]

Nicholas J. Beeching, MA,BM BCh, FRCP, FRACP,FFTM RCPS (Glasg), DCH,DTM&HSenior Lecturer (Clinical) inInfectious Diseases,Liverpool School of TropicalMedicine; Clinical Lead,Tropical and InfectiousDisease Unit, Royal

Liverpool UniversityHospital; HonoraryConsultant, HealthProtection Agency;Honorary CivilianConsultant in InfectiousDiseases, Army MedicalDirectorate, Liverpool,United Kingdom [157]

Robert S. Benjamin, MDP.H. and Fay E. RobinsonDistinguished Professor andChair, Department ofSarcoma Medical Oncology,University of Texas MDAnderson Cancer Center,Houston, Texas [98]

Michael H. Bennett, MD,MBBSConjoint Associate Professorin Anesthesia andHyperbaric Medicine;Faculty of Medicine,University of New SouthWales; Senior StaffSpecialist, Department ofDiving and HyperbaricMedicine, Prince of WalesHospital, Sydney, Australia[e52]

Edward J. Benz, Jr., MDRichard and Susan SmithProfessor of Medicine,

Professor of Pediatrics,Professor of Genetics,Harvard Medical School;President and CEO, Dana-Farber Cancer Institute;Director, Dana-Farber/Harvard CancerCenter (DF/HCC), Boston,Massachusetts [104]

Jean Bergounioux, MD,PhDPediatric Intensive CareUnit, Hôpital Necker-EnfantsMalades, Paris, France [154]

Joseph R. Betancourt,MD, MPH

Associate Professor ofMedicine, Harvard MedicalSchool; Director, TheDisparities Solutions Center,Massachusetts GeneralHospital, Boston,Massachusetts [e4]

Atul K. Bhan, MBBS, MDProfessor of Pathology,Harvard Medical School;Director ofImmunopathology,Department of Pathology,Massachusetts GeneralHospital, Boston,Massachusetts [e38]

Shalender Bhasin, MDProfessor of Medicine;Section Chief, Division ofEndocrinology, Diabetes andNutrition, Boston UniversitySchool of Medicine, Boston,Massachusetts [346]

Deepak L. Bhatt, MD,MPHAssociate Professor ofMedicine, Harvard MedicalSchool; Chief of Cardiology,VA Boston HealthcareSystem; Director,Integrated InterventionalCardiovascular Program,Brigham and Women's

Hospital and VA BostonHealthcare System; SeniorInvestigator, TIMI StudyGroup, Boston,Massachusetts [246, e33]

David R. Bickers, MDCarl Truman NelsonProfessor and Chair,Department of Dermatology,College of Physicians andSurgeons, ColumbiaUniversity Medical Center;Dermatologist-in-Chief, NewYork Presbyterian Hospital,New York, New York [56]

Henry J. Binder, MD

Professor Emeritus ofMedicine; Senior ResearchScientist, Yale University,New Haven, Connecticut[294, e37]

William R. Bishai, MD,PhDProfessor and Co-Director,Center for TuberculosisResearch, Department ofMedicine, Division ofInfectious Diseases, JohnsHopkins University School ofMedicine, Baltimore,Maryland [138]

Bruce R. Bistrian, MD,

PhDProfessor of Medicine,Harvard Medical School;Chief, Clinical Nutrition,Beth Israel DeaconessMedical Center, Boston,Massachusetts [76]

Martin J. Blaser, MDFrederick H. King Professorof Internal Medicine; Chair,Department of Medicine;Professor of Microbiology,New York University Schoolof Medicine, New York, NewYork [151, 155]

Gijs Bleijenberg, PhD

Professor; Head, ExpertCentre for Chronic Fatigue,Radboud UniversityNijmegen Medical Centre,Nijmegen, Netherlands[389]

Clara D. Bloomfield, MDDistinguished UniversityProfessor; William G. Pace,III Professor of CancerResearch; Cancer Scholarand Senior Advisor, TheOhio State UniversityComprehensive CancerCenter; Arthur G. JamesCancer Hospital and RichardJ. Solove Research Institute,

Columbus, Ohio [109]

Richard S. Blumberg, MDChief, Division ofGastroenterology, Brighamand Women's Hospital,Boston, Massachusetts[295]

Jean L. Bolognia, MDProfessor of Dermatology,Yale University School ofMedicine, New Haven,Connecticut [53]

Joseph V. Bonventre, MD,PhDSamuel A. Levine Professor

of Medicine, HarvardMedical School; Chief, RenalDivision; Chief, BWH HSTDivision of Bioengineering,Brigham and Women'sHospital, Boston,Massachusetts [279]

George J. Bosl, MDProfessor of Medicine, WeillCornell Medical College;Chair, Department ofMedicine; Patrick M. ByrneChair in Clinical Oncology,Memorial Sloan-KetteringCancer Center, New York,New York [96]

Richard C. Boucher, MDKenan Professor ofMedicine, Pulmonary andCritical Care Medicine;Director, CysticFibrosis/Pulmonary Reseachand Treatment Center,University of North Carolinaat Chapel Hill, Chapel Hill,North Carolina [259]

Eugene Braunwald, MD,MA (Hon), ScD (Hon)FRCPDistinguished HerseyProfessor of Medicine,Harvard Medical School;Founding Chairman, TIMI

Study Group, Brigham andWomen's Hospital, Boston,Massachusetts [36, 239,244]

Irwin M. Braverman, MDProfessor of Dermatology,Yale University School ofMedicine, New Haven,Connecticut [53]

Otis W. Brawley, MDChief Medical Officer,American Cancer SocietyProfessor of Hematology,Oncology, Medicine, andEpidemiology, EmoryUniversity, Atlanta, Georgia

[82]

Joel G. Breman, MD,DTPHScientist Emeritus, FogartyInternational Center,National Institutes ofHealth, Bethesda, Maryland[210, e27]

George J. Brewer, MDMorton S. and Henrietta K.Sellner Professor Emeritusof Human Genetics;Emeritus Professor ofInternal Medicine,University of MichiganMedical School, Senior Vice

President for Research andDevelopment, AdeonaPharmaceuticals, Inc., AnnArbor, Michigan [360]

Josephine P. Briggs, MDDirector, National Center forComplementary andAlternative Medicine,National Institutes ofHealth, Bethesda, Maryland[e2]

F. Richard Bringhurst, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Physician,Massachusetts General

Hospital, Boston,Massachusetts [352]

Steven M. Bromley, MDClinical Assistant Professorof Neurology, Department ofMedicine, New Jersey Schoolof Medicine and Dentistry–Robert Wood JohnsonMedical School, Camden,New Jersey [29]

Kevin E. Brown, MD,MRCP, FRCPathConsultant MedicalVirologist, Virus ReferenceDepartment, HealthProtection Agency, London,

United Kingdom [184]

Robert H. Brown, Jr., MD,PhDChairman, Department ofNeurology, University ofMassachusetts MedicalSchool, Worchester,Massachusetts [374, 387]

Amy E. Bryant, PhDResearch Scientist, VeteransAffairs Medical Center,Boise, Idaho; AffiliateAssistant Professor,University of WashingtonSchool of Medicine, Seattle,Washington [142]

Christopher M. Burns, MDAssistant Professor,Department of Medicine,Section of Rheumatology,Dartmouth Medical School;Dartmouth HitchcockMedical Center, Lebanon,New Hampshire [359]

David M. Burns, MDProfessor Emeritus,Department of Family andPreventive Medicine,University of California, SanDiego School of Medicine,San Diego, California [395]

Stephen B. Calderwood,MDMorton Swartz MD AcademyProfessor of Medicine(Microbiology and MolecularGenetics), Harvard MedicalSchool; Chief, Division ofInfectious Diseases,Massachusetts GeneralHospital, Boston,Massachusetts [128]

Michael V. Callahan, MD,DTM&H (UK), MSPHClinical Associate Physician,Division of InfectiousDiseases, MassachusettsGeneral Hospital, Boston,

Massachusetts; ProgramManager, Biodefense,Defense Advanced ResearchProject Agency (DARPA),United States Department ofDefense, Washington, DC[18]

Michael Camilleri, MDAtherton and Winifred W.Bean Professor; Professor ofMedicine and Physiology,Mayo Clinic College ofMedicine, Rochester,Minnesota [40]

Christopher P. Cannon,MD

Associate Professor ofMedicine, Harvard MedicalSchool; Senior Investigator,TIMI Study Group, Brighamand Women's Hospital,Boston, Massachusetts[244]

Jonathan Carapetis, PhD,MBBS, FRACP, FAFPHMDirector, Menzies School ofHealth Research, CharlesDarwin University, Darwin,Australia [322]

Kathryn M. Carbone, MDDeputy Scientific Director,Division of Intramural

Research, National Instituteof Dental and CraniofacialResearch, Bethesda,Maryland [194]

Brian I. Carr, MD, PhD,FRCPProfessor of Oncology andHepatology, IRCCS De BellisMedical Research Institute,Castellana Grotte, Italy [92]

Arturo Casadevall, MD,PhDChair, Department ofMicrobiology andImmunology, Albert EinsteinCollege of Medicine, Bronx,

New York [202]

Agustin Castellanos, MDProfessor of Medicine, andDirector, ClinicalElectrophysiology, Divisionof Cardiology, University ofMiami Miller School ofMedicine, Miami, Florida[273]

Bartolome R. Celli, MDLecturer on Medicine,Harvard Medical School;Staff Physician, Division ofPulmonary and Critical CareMedicine, Brigham andWomen's Hospital, Boston,

Massachusetts [269]

Murali Chakinala, MDAssociate Professor ofMedicine, Division ofPulmonary and Critical CareMedicine, WashingtonUniversity School ofMedicine, St. Louis, Missouri[234]

Anil Chandraker, MD,FASN, FRCPAssociate Professor ofMedicine, Harvard MedicalSchool; Medical Director ofKidney and PancreasTransplantation; Assistant

Director, Schuster FamilyTransplantation ResearchCenter, Brigham andWomen's Hospital;Children's Hospital, Boston,Massachusetts [282]

Stanley W. Chapman, MDProfessor of Medicine,University of MississippiMedical Center, Jackson,Mississippi [201]

PanithayaChareonthaitawee, MDAssociate Professor ofMedicine, Mayo ClinicCollege of Medicine,

Rochester, Minnesota [229,e29]

Lan X. Chen, MD, PhDPenn Presbyterian MedicalCenter, Philadelphia,Pennsylvania [333]

Yuan-Tsong Chen, MD,PhDDistinguished ResearchFellow, Institute ofBiomedical Sciences,Academia Sinica, Taiwan[362]

Glenn M. Chertow, MD,MPH

Norman S. Coplon/SatelliteHealthcare Professor ofMedicine; Chief, Division ofNephrology, StanfordUniversity School ofMedicine, Palo Alto,California [281]

John S. Child, MD, FACC,FAHA, FASEStreisand Professor ofMedicine and Cardiology,Geffen School of Medicine,University of California, LosAngeles (UCLA); Director,Ahmanson-UCLA AdultCongenital Heart DiseaseCenter; Director, UCLA

Adult NoninvasiveCardiodiagnosticsLaboratory, Ronald Reagan-UCLA Medical Center; LosAngeles, California [236]

Augustine M. K. Choi, MDParker B. Francis Professorof Medicine, HarvardMedical School; Chief,Division of Pulmonary andCritical Care Medicine,Brigham and Women'sHospital, Boston,Massachusetts [251, 253,268]

Irene Chong, MRCP, FRCR

Clinical Research Fellow,Royal Marsden NHSFoundation Trust, Londonand Sutton, United Kingdom[93]

Raymond T. Chung, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Director ofHepatology; Vice Chief,Gastrointestinal Unit,Massachusetts GeneralHospital, Boston,Massachusetts [310]

Fredric L. Coe, MDProfessor of Medicine,

University of Chicago,Chicago, Illinois [287]

Jeffrey I. Cohen, MDChief, Medical VirologySection, Laboratory ofClinical Infectious Diseases,National Institutes ofHealth, Bethesda, Maryland[181, 191]

Ronit Cohen-Poradosu,MDSenior Physician,Department of ClinicalMicrobiology and InfectiousDiseases, Hadassah HebrewMedical Center, Jerusalem,

Israel [164]

Francis S. Collins, MD,PhDDirector, National Institutesof Health, Bethesda,Maryland [83]

Wilson S. Colucci, MDThomas J. Ryan Professor ofMedicine, Boston UniversitySchool of Medicine; Chief ofCardiovascular Medicine,Boston Medical Center,Boston, Massachusetts [240,e31]

Darwin L. Conwell, MD

Associate Professor ofMedicine, Harvard MedicalSchool; Associate Physician,Division ofGastroenterology, Brighamand Women's Hospital,Boston, Massachusetts [312,313]

Michael J. Corbel, PhD,DSc, FRCPathHead, Division ofBacteriology, NationalInstitute for BiologicalStandards and Control,Hertfordshire, UnitedKingdom [157]

William EdwardCorcoran, V, MDClinical Instructor, HarvardMedical School;Cardiothoracic Fellow,Department ofAnesthesiology,Perioperative, and PainMedicine, Brigham andWomen's Hospital, Boston,Massachusetts [e54]

Kathleen E. Corey, MD,MPHClinical and ResearchFellow, Harvard MedicalSchool; Fellow,Gastrointestinal Unit,

Massachusetts GeneralHospital, Boston,Massachusetts [43]

Lawrence Corey, MDProfessor of Medicine andLaboratory Medicine andHead, Virology Division,Department of LaboratoryMedicine, University ofWashington; Head, Programin Infectious Diseases, FredHutchinson Cancer ResearchCenter, Seattle, Washington[179]

Felicia Cosman, MDProfessor of Clinical

Medicine, ColumbiaUniversity College ofPhysicians and Surgeons,New York [354]

Mark A. Creager, MDProfessor of Medicine,Harvard Medical School;Simon C. Fireman Scholarin Cardiovascular Medicine;Director, Vascular Center,Brigham and Women'sHospital, Boston,Massachusetts [248, 249]

Leslie J. Crofford, MDGloria W. SingletaryProfessor of Internal

Medicine; Chief, Division ofRheumatology, University ofKentucky, Lexington,Kentucky [335]

Jennifer M. Croswell, MD,MPHActing Director, Office ofMedical Applications ofResearch, NationalInstitutes of Health,Bethesda, Maryland [82]

Philip E. Cryer, MDIrene E. and Michael M. KarlProfessor of Endocrinologyand Metabolism in Medicine,Washington University

School of Medicine;Physician, Barnes-JewishHospital, St. Louis, Missouri[345]

David Cunningham, MD,FRCPProfessor of CancerMedicine, Royal MarsdenNHS Foundation Trust,London and Sutton, UnitedKingdom [93]

John J. Cush, MDDirector of ClinicalRheumatology, BaylorResearch Institute, Dallas,Texas [331]

Charles A. Czeisler, MD,PhD, FRCPBaldino Professor of SleepMedicine; Director, Divisionof Sleep Medicine, HarvardMedical School; Chief,Division of Sleep Medicine,Department of Medicine,Brigham and Women'sHospital, Boston,Massachusetts [27]

Marinos C. Dalakas, MD,FAANProfessor of Neurology,Department ofPathophysiology, National

University of Athens MedicalSchool, Athens, Greece[388]

Josep Dalmau, MD, PhDICREA Research Professor,Institute for BiomedicalInvestigations, August Pi iSunyer (IDIBAPS)/HospitalClinic, Department ofNeurology, University ofBarcelona, Barcelona,Spain; Adjunct Professor ofNeurology University ofPennsylvania, Philadelphia,Pennsylvania [101]

Daniel F. Danzl, MD

University of Louisville,Department of EmergencyMedicine, Louisville,Kentucky [19]

Robert B. Daroff, MDProfessor and ChairEmeritus, Department ofNeurology, Case WesternReserve University Schoolof Medicine; UniversityHospitals–Case MedicalCenter, Cleveland, Ohio[21]

Charles E. Davis, MDProfessor of Pathology andMedicine, Emeritus,

University of California, SanDiego School of Medicine;Director Emeritus,Microbiology, University ofCalifornia, San DiegoMedical Center, San Diego,California [e25]

Stephen N. Davis, MBBS,FRCPTheodore E. WoodwardProfessor and Chairman,Department of Medicine,University of MarylandSchool of Medicine;Physician-in-Chief,University of MarylandMedical Center, Baltimore,

Maryland [345]

Lisa M. DeAngelis, MDProfessor of Neurology,Weill Cornell MedicalCollege; Chair, Departmentof Neurology, MemorialSloan-Kettering CancerCenter, New York, New York[379]

John Del Valle, MDProfessor and SeniorAssociate Chair of Medicine,Department of InternalMedicine, University ofMichigan School ofMedicine, Ann Arbor,

Michigan [293]

Marie B. Demay, MDProfessor of Medicine,Harvard Medical School;Physician, MassachusettsGeneral Hospital, Boston,Massachusetts [352]

Bradley M. Denker, MDAssociate Professor, HarvardMedical School; Physician,Department of Medicine,Brigham and Women'sHospital; Chief ofNephrology, HarvardVanguard MedicalAssociates, Boston,

Massachusetts [44]

David W. Denning, MBBS, FRCP, FRCPathProfessor of Medicine andMedical Mycology; Director,National AspergillosisCentre, The University ofManchester andWythenshawe Hospital,Manchester, UnitedKingdom [204]

Robert J. Desnick, MD,PhDDean for Genetics andGenomics; Professor andChairman, Department of

Genetics and GenomicSciences, Mount SinaiSchool of Medicine of NewYork University, New York,New York [358]

Richard A. Deyo, MD,MPHKaiser PermanenteProfessor of Evidence-BasedFamily Medicine,Department of FamilyMedicine, Department ofMedicine, Department ofPublic Health andPreventive Medicine, Centerfor Research in Occupationaland Environmental

Toxicology, Oregon Healthand Science University;Clinical Investigator, KaiserPermanente Center forHealth Research, Portland,Oregon [15]

Betty Diamond, MDThe Feinstein Institute forMedical Research, NorthShore LIJ Health System;Center for Autoimmunityand MusculoskeletalDiseases, Manhasset, NewYork [318]

Jules L. Dienstag, MDCarl W. Walter Professor of

Medicine and Dean forMedical Education, HarvardMedical School; Physician,Gastrointestinal Unit,Department of Medicine,Massachusetts GeneralHospital, Boston,Massachusetts [304, 305,306, 310, e38]

William P. Dillon, MDElizabeth GuillauminProfessor of Radiology,Neurology andNeurosurgery; ExecutiveVice-Chair, Department ofRadiology and BiomedicalImaging, University of

California, San Francisco,San Francisco, California[368, e44]

Charles A. Dinarello, MDProfessor of Medicine,Division of InfectiousDiseases, University ofColorado School ofMedicine, Aurora, Colorado[16]

Raphael Dolin, MDMaxwell Finland Professor ofMedicine (Microbiology andMolecular Genetics),Harvard Medical School;Beth Israel Deaconess

Medical Center; Brighamand Women's Hospital,Boston, Massachusetts [178,186, 187]

Richard L. Doty, PhDProfessor, Department ofOtorhinolaryngology: Headand Neck Surgery; Director,Smell and Taste Center,University of PennsylvaniaSchool of Medicine,Philadelphia, Pennsylvania[29]

Neil J. Douglas, MD, MBChB, DSc, Hon MD, FRCPEProfessor of Respiratory and

Sleep Medicine, Universityof Edinburgh, Edinburgh,Scotland, United Kingdom[265]

Daniel B. Drachman, MDProfessor of Neurology andNeuroscience, W. W. SmithCharitable Trust Professor ofNeuroimmunology,Department of Neurology,Johns Hopkins School ofMedicine, Baltimore,Maryland [386]

David F. Driscoll, PhDAssociate Professor ofMedicine, University of

Massachusetts MedicalSchool, Worchester,Massachusetts [76]

Thomas D. DuBose, Jr.,MD, MACPTinsley R. HarrisonProfessor and Chair,Internal Medicine; Professorof Physiology andPharmacology, Departmentof Internal Medicine, WakeForest University School ofMedicine, Winston-Salem,North Carolina [47, e15]

J. Stephen Dumler, MDProfessor, Division of

Medical Microbiology,Department of Pathology,Johns Hopkins UniversitySchool of Medicine,Baltimore, Maryland [174]

Andrea Dunaif, MDCharles F. KetteringProfessor of Endocrinologyand Metabolism; Vice-Chairfor Research, Department ofMedicine, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, Illinois[6]

Samuel C. Durso, MD,MBA

Mason F. Lord Professor ofMedicine; Director, Divisionof Geriatric Medicine andGerontology, Johns HopkinsUniversity School ofMedicine, Baltimore,Maryland [32, e12]

Janice Dutcher, MDDepartment of Oncology,New York Medical College,Montefiore, Bronx, NewYork [276]

Mark S. Dworkin, MD,MPH&TMAssociate Professor, Divisionof Epidemiology and

Biostatistics, University ofIllinois at Chicago School ofPublic Health, Chicago,Illinois [172]

Johanna Dwyer, DSc, RDProfessor of Medicine(Nutrition), FriedmanSchool of Nutrition Scienceand Policy, Tufts UniversitySchool of Medicine;Director, Frances SternNutrition Center, TuftsMedical Center, Boston,Massachusetts [73]

Jeffery S. Dzieczkowski,MD

Physician, St. AlphonsusRegional Medical Center;Medical Director,Coagulation Clinic, SaintAlphonsus Medical Group,International Medicine andTravel Medicine, Boise,Idaho [113]

Kim A. Eagle, MDAlbion Walter HewlettProfessor of InternalMedicine; Director,Cardiovascular Center,University of MichiganHealth System, Ann Arbor,Michigan [8]

Robert H. Eckel, MDProfessor of Medicine,Division of Endocrinology,Metabolism and Diabetes,Division of Cardiology;Professor of Physiology andBiophysics, Charles A.Boettcher, II Chair inAtherosclerosis, Universityof Colorado School ofMedicine, Anschutz MedicalCampus, Director LipidClinic, University ofColorado Hospital, Aurora,Colorado [242]

John E. Edwards, Jr,. MDChief, Division of Infectious

Diseases, Harbor/Universityof California, Los Angeles(UCLA) Medical Center,Torrance, California;Professor of Medicine, DavidGeffen School of Medicine atUCLA, Los Angeles,California [198, 203]

David A. Ehrmann, MDProfessor of Medicine, TheUniversity of Chicago,Chicago, Illinois [49]

Andrew J. Einstein, MD,PhDAssistant Professor ofClinical Medicine, Columbia

University College ofPhysicians and Surgeons;Department of Medicine,Division of Cardiology,Department of Radiology,Columbia University MedicalCenter and New York-Presbyterian Hospital, NewYork, New York [Appendix]

Ezekiel J. Emanuel, MD,PhDChief, Department ofClinical Bioethics, NationalInstitutes of Health,Bethesda, Maryland [9]

Joey D. English, MD

Assistant Clinical Professor,Department of Neurology,Univeristy of California, SanFrancisco, San Francisco,California [370]

John W. Engstrom, MDBetty Anker FifeDistinguished Professor ofNeurology; NeurologyResidency Program Director;Clinical Chief of Service,University of California, SanFrancisco, San Francisco,California [15, 375]

Moshe Ephros, MDSenior Lecturer, Faculty of

Medicine, Technion—IsraelInstitute of Technology;Pediatric Infectious DiseaseUnit, Carmel MedicalCenter; Haifa, Israel [160]

Jonathan A. Epstein, MD,DTMHWilliam Wikoff SmithProfessor of Medicine;Chairman, Department ofCell and DevelopmentalBiology; Scientific Director,Cardiovascular Institute,University of Pennsylvania,Philadelphia, Pennsylvania[224]

Tim Evans, MD, PhDAssistant Director-General,Information, Evidence, andResearch, World HealthOrganization, Geneva,Switzerland [e1]

Christopher Fanta, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Member, Pulmonaryand Critical Care Division,Brigham and Women'sHospital, Boston,Massachusetts [34]

Paul Farmer, MD, PhDKolokotrones University

Professor, HarvardUniversity; Chair,Department of Global Healthand Social Medicine,Harvard Medical School;Chief, Division of GlobalHealth Equity, Brigham andWomen's Hospital; Co-Founder, Partners in Health,Boston, Massachusetts [2]

Anthony S. Fauci, MD,DSc (Hon), DM&S (Hon),DHL (Hon), DPS (Hon),DLM (Hon), DMS (Hon)Chief, Laboratory ofImmunoregulation;Director, National Institute

of Allergy and InfectiousDiseases, National Institutesof Health, Bethesda,Maryland [1, 188, 189, 221,314, 326, e40]

Murray J. Favus, MDProfessor, Department ofMedicine, Section ofEndocrinology, Diabetes andMetabolism, Director BoneProgram, University ofChicago Pritzker School ofMedicine, Chicago, Illinois[287, 355]

David P. Faxon, MDSenior Lecturer, Harvard

Medical School; Vice Chairof Medicine for StrategicPlanning, Department ofMedicine, Brigham andWomen's Hospital, Boston,Massachusetts [230, 246,e33]

David T. Felson, MD, MPHProfessor of Medicine andEpidemiology; Chair,Clinical Epidemiology Unit,Boston University School ofMedicine, Boston,Massachusetts [332]

Luigi Ferrucci, MD, PhDDirector, Baltimore

Longitudinal Study of AgingNational Institute of Health,Baltimore, Maryland [72]

Howard L. Fields, MD,PhDProfessor of Neurology,University of California, SanFrancisco, San Francisco,California [11]

Gregory A. Filice, MDProfessor of Medicine,University of Minnesota;Chief, Infectious DiseaseSection, Veterans AffairsMedical Center, Minneapolis,Minnesota [162]

Robert Finberg, MDChair, Department ofMedicine, University ofMassachusetts MedicalSchool, Worcester,Massachusetts [86, 132]

Joyce Fingeroth, MDAssociate Professor ofMedicine, Harvard MedicalSchool, Boston,Massachusetts [132]

Alain Fischer, MD, PhDUniversity Paris Descartes,Inserm Unit 768;Immunology and Pediatric

Hematology Unit, NeckerChildren's Hospital, Paris,France [316, e39]

Jeffrey S. Flier, MDCaroline Shields WalkerProfessor of Medicine andDean, Harvard MedicalSchool, Boston,Massachusetts [77]

Agnes B. Fogo, MDJohn L. Shapiro Professor ofPathology; Professor ofMedicine and Pediatrics,Vanderbilt UniversityMedical Center, Nashville,Tennessee [e14]

Larry C. Ford, MDAssociate Researcher,Divisions of ClinicalEpidemiology and InfectiousDiseases, University ofUtah, Salt Lake City, Utah[31]

Jane E. Freedman, MDProfessor, Department ofMedicine, University ofMassachusetts MedicalSchool, Worcester,Massachusetts [117]

Roy Freeman, MBCHBProfessor of Neurology,

Harvard Medical School,Boston, Massachusetts [20]

Gyorgy Frendl, MD, PhDAssistant Professor ofAnesthesia and CriticalCare, Harvard MedicalSchool; Director ofResearch, Surgical CriticalCare, Brigham and Women'sHospital, Boston,Massachusetts [e54]

Carl E. Freter, MD, PhDProfessor, Department ofInternal Medicine, Divisionof Hematology/MedicalOncology, University of

Missouri; Ellis FischelCancer Center, Columbia,Missouri [102]

Lawrence S. Friedman,MDProfessor of Medicine,Harvard Medical School;Professor of Medicine, TuftsUniversity School ofMedicine; Assistant Chief ofMedicine, MassachusettsGeneral Hospital, Boston,Massachusetts; Chair,Department of Medicine,Newton-Wellesley Hospital,Newton, Massachusetts [43]

Sonia Friedman, MDAssistant Professor ofMedicine, Harvard MedicalSchool, Boston,Massachusetts [295]

Anne L. Fuhlbrigge, MD,MSAssistant Professor, HarvardMedical School; Pulmonaryand Critical Care Division,Brigham and Women'sHospital, Boston,Massachusetts [253]

Andre Furtado, MDAssociate Specialist at theDepartment of Radiology,

Neuroradiology Section,University of California, SanFrancisco, San Francisco,California [e44]

Robert F. Gagel, MDProfessor of Medicine andHead, Division of InternalMedicine, University ofTexas MD Anderson CancerCenter, Houston, Texas[351]

Nicholas B. Galifianakis,MD, MPHAssistant Clinical Professor,Surgical MovementDisorders Center,

Department of Neurology,University of California, SanFrancisco, San Francisco,California [e8]

John I. Gallin, MDDirector, Clinical Center,National Institutes ofHealth, Bethesda, Maryland[60]

Charlotte A. Gaydos,DrPh, MPH, MSProfessor of Medicine, JohnsHopkins University School ofMedicine, Baltimore,Maryland [176]

J. Michael Gaziano, MD,MPHProfessor of Medicine,Harvard Medical School;Chief, Division of Aging,Brigham and Women'sHospital; Director,Massachusetts VeteransEpidemiology Center,Boston VA HealthcareSystem, Boston,Massachusetts [225]

Thomas A. Gaziano, MD,MScAssistant Professor, HarvardMedical School; AssistantProfessor, Health Policy and

Management, Center forHealth Decision Sciences,Harvard School of PublicHealth; Associate Physicianin Cardiovascular Medicine,Department of Cardiology,Brigham and Women'sHospital, Boston,Massachusetts [225]

Susan L. Gearhart, MDAssistant Professor ofColorectal Surgery andOncology, The JohnsHopkins University School ofMedicine, Baltimore,Maryland [297, 298]

Robert H. Gelber, MDClinical Professor ofMedicine and Dermatology,University of California, SanFrancisco, San Francisco,California [166]

Jeffrey A. Gelfand, MDClinical Professor ofMedicine, Harvard MedicalSchool; Physician,Massachusetts GeneralHospital, Boston,Massachusetts [18, 211]

Alfred L. George, Jr., MDProfessor of Medicine andPharmacology; Chief,

Division of GeneticMedicine, VanderbiltUniversity School ofMedicine, Nashville,Tennessee [277]

Dale N. Gerding, MDProfessor of Medicine,Loyola University ChicagoStritch School of Medicine;Associate Chief of Staff forResearch and Development,Edward Hines, Jr. VAHospital, Hines, Illinois[129]

Alicia K. Gerke, MDAssociate, Division of

Pulmonary and Critical CareMedicine, University ofIowa, Iowa City, Iowa [255]

Michael Geschwind, MD,PhDAssociate Professor ofNeurology, Memory andAging Center, University ofCalifornia, San Francisco,School of Medicine, SanFrancisco, California [e8]

Marc G. Ghany, MD, MHScStaff Physician, LiverDiseases Branch, NationalInstitute of Diabetes andDigestive and Kidney

Diseases, National Institutesof Health, Bethesda,Maryland [301]

Michael Giladi, MD, MScAssociate Professor ofMedicine, Faculty ofMedicine, Tel AvivUniversity, Tel Aviv, Israel[160]

Bruce C. Gilliland,† MDProfessor of Medicine andLaboratory Medicine,University of WashingtonSchool of Medicine, Seattle,Washington [337]

Roger I. Glass, MD, PhDDirector, FogartyInternational Center,Bethesda, Maryland [190]

Eli Glatstein, MDProfessor and ViceChairman, Department ofRadiation Oncology, Hospitalof the University ofPennsylvania, Philadelphia,Pennsylvania [223]

Peter J. Goadsby, MD,PhD, DSc, FRACP FRCPProfessor of Neurology,University of California, SanFrancisco, California;

Honorary ConsultantNeurologist, Hospital forSick Children, London,United Kingdom [14]

Ary L. Goldberger, MDProfessor of Medicine,Harvard Medical School;Wyss Institute forBiologically InspiredEngineering, HarvardUniversity; Beth IsraelDeaconess Medical Center,Boston, Massachusetts [228,e28, e30]

David Goldblatt, PhD,MBChB, FRCP, FRCPCH

Professor of Vaccinology andImmunology; Consultant inPaediatric Immunology;Director of Clinical Researchand Development; Director,NIHR Biomedical ResearchCentre, Institute of ChildHealth; University CollegeLondon; Great OrmondStreet Hospital for ChildrenNHS Trust, London, UnitedKingdom [134]

Samuel Z. Goldhaber, MDProfessor of Medicine,Harvard Medical School;Director, VenousThromboembolism Research

Group, CardiovascularDivision, Brigham andWomen's Hospital, Boston,Massachusetts [262]

Ralph Gonzales, MD,MSPHProfessor of Medicine,University of California, SanFrancisco, San Francisco,California [31]

Douglas S. Goodin, MDProfessor of Neurology,University of California, SanFrancisco School ofMedicine, San Francisco,California [380]

Craig E. Gordon, MD, MSAssistant Professor ofMedicine, Boston UniversitySchool of Medicine;Attending, Section ofNephrology, Boston MedicalCenter, Boston,Massachusetts [284]

Jeffrey I. Gordon, MDDr. Robert J. GlaserDistinguished UniversityProfessor; Director, Centerfor Genome Sciences,Washington UniversitySchool of Medicine, St.Louis, Missouri [64]

Maria Luisa Gorno-Tempini, MD, PhDAssociate Professor ofNeurology, Memory andAging Center, University ofCalifornia, San Francisco,San Francisco, California[e10]

Gregory A. Grabowski,MDProfessor, Departments ofPediatrics, and MolecularGenetics, Biochemistry, andMicrobiology; University ofCincinnati College ofMedicine, A. Graeme

Mitchell Chair in HumanGenetics; Director, Divisionof Human Genetics,Cincinnati Children'sHosptial Medical Center,Cincinnati, Ohio [361]

Alexander R. Green, MD,MPHAssistant Professor ofMedicine, Harvard MedicalSchool; Associate Director,The Disparities SolutionsCenter, MassachusettsGeneral Hospital, Boston,Massachusetts [e4]

Norton J. Greenberger,

MDClinical Professor ofMedicine, Harvard MedicalSchool; Senior Physician,Division ofGastroenterology, Brighamand Women's Hospital,Boston, Massachusetts [311,312, 313]

Daryl R. Gress, MD,FAAN, FCCMProfessor of NeurocriticalCare and Stroke; Professorof Neurology, University ofCalifornia, San Francisco,San Francisco, California[275]

Rasim Gucalp, MDProfessor of ClinicalMedicine, Albert EinsteinCollege of Medicine;Associate Chairman forEducational Programs,Department of Oncology;Director,Hematology/OncologyFellowship, MontefioreMedical Center, Bronx, NewYork [276]

Kalpana Gupta, MD, MPHAssociate Professor,Department of Medicine,Boston University School of

Medicine; Chief, Section ofInfectious Diseases, VABoston Healthcare System,Boston, Massachusetts[288]

John G. Haaga, MDDeputy Associate Director,Behavioral and SocialResearch Program, NationalInstitute on Aging, NationalInstitutes of Health,Bethesda, Maryland [70]

Chadi A. Hage, MDAssistant Professor ofMedicine, Pulmonary–Critical Care and Infectious

Diseases, Roudebush VAMedical Center; IndianaUniversity, Indianapolis,Indiana [199]

Bevra Hannahs Hahn, MDProfessor of Medicine,University of California, LosAngeles, David GeffenSchool of Medicine, LosAngeles, California [319]

Janet E. Hall, MD, MScProfessor of Medicine,Harvard Medical School;Associate Physician,Massachusetts GeneralHospital, Boston,

Massachusetts [50, 347]

Jesse B. Hall, MD, FCCPProfessor of Medicine,Anesthesia and CriticalCare; Chief, Section ofPulmonary and Critical CareMedicine, University ofChicago, Chicago, Illinois[267]

Scott A. Halperin, MDProfessor of Pediatrics andMicrobiology andImmunology; CIHR/WyethChair in Clinical VaccineResearch; Head, PediatricInfectious Diseases;

Director, Canadian Centerfor Vaccinology, DalhousieUniversity, Halifax, NovaScotia, Canada [148]

R. Doug Hardy, MDAssociate Professor ofInternal Medicine andPediatrics, University ofTexas Southwestern MedicalCenter, Dallas, Texas [175]

Raymond C. Harris, MDAnn and Roscoe R. RobinsonProfessor of Medicine; Chief,Division of Nephrology,Vanderbilt University Schoolof Medicine, Nashville,

Tennessee [278]

William L. Hasler, MDProfessor of InternalMedicine, Division ofGastroenterology,University of MichiganHealth System, Ann Arbor,Michigan [39, 290]

Terry Hassold, PhDEastlick DistinguishedProfessor; Director, Centerfor Reproductive Biology,Washington State UniversitySchool of MolecularBiosciences, Pullman,Washington [62]

Stephen L. Hauser, MDRobert A. FishmanDistinguished Professor andChairman, Department ofNeurology, University ofCalifornia, San Francisco,San Francisco, California [1,366, 367, 376, 377, 380,385, e46]

Barton F. Haynes, MDFrederic M. Hanes Professorof Medicine andImmunology, Departmentsof Medicine andImmunology; Director, DukeHuman Vaccine Institute,

Duke University School ofMedicine, Durham, NorthCarolina [314]

Douglas C. Heimburger,MD, MSProfessor of Medicine;Associate Director forEducation and Training,Vanderbilt Institute forGlobal Health, VanderbiltUniversity School ofMedicine, Nashville,Tennessee [75]

J. Claude Hemphill, III,MD, MASProfessor of Clinical

Neurology and NeurologicalSurgery, Department ofNeurology, University ofCalifornia, San Francisco;Director of NeurocriticalCare, San Francisco GeneralHospital, San Francisco,California [275]

Patrick H. Henry, MDClinical Adjunct Professor ofMedicine, University ofIowa, Iowa City, Iowa [59]

Katherine A. High, MDInvestigator, HowardHughes Medical Institute;William H. Bennett

Professor of Pediatrics,University of PennsylvaniaSchool of Medicine;Director, Center for Cellularand Molecular Therapeutics,Children's Hospital ofPhiladelphia, Philadelphia,Pennsylvania [68, 116]

Ikuo Hirano, MDProfessor of Medicine,Division of Gastroenterologyand Hepatology,Department of Medicine,Northwestern UniversityFeinberg School of Medicine,Chicago, Illinois [38, 292]

Martin S. Hirsch, MDProfessor of Medicine,Harvard Medical School;Professor of Immunologyand Infectious Diseases,Harvard School of PublicHealth; Physician,Massachusetts GeneralHospital, Cambridge,Massachusetts [182]

Helen H. Hobbs, MDProfessor of InternalMedicine and MolecularGenetics, University ofTexas Southwestern MedicalCenter, Dallas, Texas;Investigator, Howard

Hughes Medical Institute,Chevy Chase, Maryland[356]

Judith S. Hochman, MDHarold Snyder FamilyProfessor of Cardiology;Clinical Chief, Leon CharneyDivision of Cardiology; Co-Director, NYU-HHC Clinicaland Translational ScienceInstitute; Director,Cardiovascular ClinicalResearch Center, New YorkUniversity School ofMedicine, New York, NewYork [272]

A. Victor Hoffbrand, DMProfessor Emeritus ofHaematology, UniversityCollege, London; HonoraryConsultant Haematologist,Royal Free Hospital, London,United Kingdom [105]

David M. Hoganson, MDLaboratory for TissueEngineering and OrganFabrication Center forRegenerative Medicine,Department of Surgery,Massachusetts GeneralHospital, Boston,Massachusetts [69]

Charles W. Hoge, MDSenior Scientist and StaffPsychiatrist, Center forPsychiatry andNeuroscience, Walter ReedArmy Institute of Researchand Water Reed ArmyMedical Center, SilverSpring, Maryland [e48]

Elizabeth L. Hohmann,MDAssociate Professor ofMedicine and InfectiousDiseases, Harvard MedicalSchool; MassachusettsGeneral Hospital, Boston,Massachusetts [139]

Steven M. Holland, MDChief, Laboratory of ClinicalInfectious Diseases,National Institute of Allergyand Infectious Diseases,National Institutes ofHealth, Bethesda, Maryland[60, 167]

King K. Holmes, MD, PhDChair, Global Health;Professor of Medicine andGlobal Health; AdjunctProfessor, Epidemiology;Director, Center for AIDSand STD; University ofWashington School of

Medicine; Head, InfectiousDiseases Section,Harborview Medical Center,Seattle, Washington [130]

Jay H. Hoofnagle, MDDirector, Liver DiseasesResearch Branch, NationalInstitute of Diabetes,Digestive and KidneyDiseases, National Institutesof Health, Bethesda,Maryland [301]

Robert Hopkin, MDAssociate Professor ofClinical Pediatrics,University of Cincinnati

College of Medicine;Division of Human Genetics,Cincinnati Children'sHospital Medical Center,Cincinnati, Ohio [361]

Leora Horn, MD, MScDivision of Hematology andMedical Oncology,Vanderbilt University Schoolof Medicine, Nashville,Tennessee [89]

Jonathan C. Horton, MD,PhDWilliam F. Hoyt Professor ofNeuro-ophthalmology,Professor of Ophthalmology,

Neurology and Physiology,University of California, SanFrancisco School ofMedicine, San Francisco,California [28]

Howard Hu, MDEnvironmental HealthSciences, University ofMichigan Schools of PublicHealth and Medicine, AnnArbor, Michigan [e49]

Gary W. Hunninghake,MDProfessor, Division ofPulmonary and Critical CareMedicine, University of

Iowa, Iowa City, Iowa [255]

Sharon A. Hunt, MD,FACCProfessor, Division ofCardiovascular Medicine,Stanford University, PaloAlto, California [235]

Charles G. Hurst, MDChief, Chemical CasualtyCare Division, United StatesMedical Research Instituteof Chemical Defense, APG-Edgewood Area, Maryland[222]

Ashraf S. Ibrahim, PhD

Associate Professor ofMedicine, Geffen School ofMedicine, University ofCalifornia, Los Angeles(UCLA); Division ofInfectious Diseases, LosAngeles BiomedicalResearch Institute atHarbor–UCLA MedicalCenter, Torrance, California[205]

David H. Ingbar, MDProfessor of Medicine,Pediatrics, and Physiology;Director, Pulmonary Allergy,Critical Care and SleepDivision, University of

Minnesota School ofMedicine, Minneapolis,Minnesota [272]

Alan C. Jackson, MD,FRCPCProfessor of Medicine(Neurology) and MedicalMicrobiology, University ofManitoba; Section Head ofNeurology, WinnipegRegional Health Authority,Winnipeg, Manitoba, Canada[195]

Lisa A. Jackson, MD, MPHSenior Investigator, GroupHealth Research Institute;

Research Professor,Department ofEpidemiology; AdjunctProfessor, Department ofMedicine, University ofWashington, Seattle,Washington [122]

Richard F. Jacobs, MDRobert H. Fiser, Jr., MDEndowed Chair in Pediatrics;Professor and Chairman,Department of Pediatrics,University of Arkansas forMedical Sciences; President,Arkansas Children's HospitalResearch Institute, LittleRock, Arkansas [158]

J. Larry Jameson, MD,PhDRobert G. Dunlop Professorof Medicine; Dean,University of PennsylvaniaSchool of Medicine;Executive Vice President ofthe University ofPennsylvania for the HealthSystem, Philadelphia,Pennsylvania [1, 61, 63, 80,100, 338, 339, 341, 346,349, e41]

Robert T. Jensen, MDDigestive Diseases Branch,National Institute of

Diabetes; Digestive andKidney Diseases, NationalInstitutes of Health,Bethesda, Maryland [350]

David H. Johnson, MD,FACPDonald W. SeldinDistinguished Chair inInternal Medicine; Professorand Chairman, Departmentof Internal Medicine,University of TexasSouthwestern MedicalSchool, Dallas, Texas [89]

James R. Johnson, MDProfessor of Medicine,

University of Minnesota,Minneapolis, Minnesota[149]

Stuart Johnson, MDAssociate Professor ofMedicine, Loyola UniversityChicago Stritch School ofMedicine; Staff Physician,Edward Hines, Jr. VAHospital, Hines, Illinois[129]

S. Claiborne Johnston,MD, PhDProfessor of Neurology andEpidemiology, University ofCalifornia, San Francisco

School of Medicine, SanFrancisco, California [370]

S. Andrew Josephson, MDAssociate Professor,Department of Neurology;Director, NeurohospitalistProgram, University ofCalifornia, San Francisco,San Francisco, California[25, e47]

Harald Jüppner, MDProfessor of Pediatrics,Endocrine Unit and PediatricNephrology Unit,Massachusetts GeneralHospital, Boston,

Massachusetts [353]

Peter J. Kahrilas, MDGilbert H. MarquardtProfessor in Medicine,Division ofGastroenterology,Department of Medicine,Northwestern UniversityFeinberg School of Medicine,Chicago, Illinois [38, 292]

Gail Kang, MDAssistant Clinical Professorof Neurology, Memory andAging Center, University ofCalifornia, San Francisco,San Francisco, California

[e8]

Marshall M. Kaplan, MDProfessor of Medicine, TuftsUniversity School ofMedicine, Boston,Massachusetts [42, 302]

Adolf W. Karchmer, MDProfessor of Medicine,Harvard Medical School;Division of InfectiousDiseases, Beth IsraelDeaconess Medical Center,Boston, Massachusetts[124]

Dennis L. Kasper, MD, MA

(Hon)William Ellery ChanningProfessor of Medicine andProfessor of Microbiologyand Molecular Genetics,Harvard Medical School;Director, ChanningLaboratory, Department ofMedicine, Brigham andWomen's Hospital, Boston,Massachusetts [1, 119, 121,127, 146, 164]

Lloyd H. Kasper, MDProfessor of Medicine(Neurology) andMicrobiology andImmunology, Dartmouth

Medical School, Lebanon,New Hampshire [214]

Daniel L. Kastner, MD,PhDScientific Director, NationalHuman Genome ResearchInstitute, National Institutesof Health, Bethesda,Maryland [330]

Carol A. Kauffman, MDProfessor of InternalMedicine, University ofMichigan Medical School;Chief, Infectious DiseasesSection, Veterans AffairsAnn Arbor Healthcare

System, Ann Arbor,Michigan [206]

Elaine T. Kaye, MDAssistant Clinical Professorof Dermatology, HarvardMedical School, Boston,Massachusetts [17, e7]

Kenneth M. Kaye, MDAssociate Professor ofMedicine, Harvard MedicalSchool, Boston,Massachusetts [17, e7]

John A. Kessler, MDProfessor and Chair,Department of Neurology,

Northwestern UniversityFeinberg School of Medicine,Chicago, Illinois [67]

Jay S. Keystone, MD,FRCPC, MSc (CTM)Professor of Medicine,University of Toronto,Toronto, Ontario, Canada[123]

Sundeep Khosla, MDProfessor of Medicine andPhysiology, College ofMedicine, Mayo Clinic,Rochester, Minnesota [46]

Elliott Kieff, MD, PhD

Harriet Ryan AlbeeProfessor, Harvard MedicalSchool; Chief, InfectiousDiseases Division, Brighamand Women's Hospital,Boston, Massachusetts[177]

Anthony A. Killeen, MD,PhDAssociate Professor;Director of ClinicalLaboratories, University ofMinnesota Medical Center,Minneapolis, Minnesota[e53]

Jim Yong Kim, MD, PhD

Chair, Department of GlobalHealth and Social Medicine,Harvard Medical School;Director, François-XavierBagnoud Center for Healthand Human Rights, HarvardSchool of Public Health;Chief, Division of GlobalHealth Equity, Brigham andWomen's Hospital, Boston,Massachusetts [2]

Kami Kim, MDProfessor of Medicine(Infectious Diseases) and ofMicrobiology andImmunology, Albert EinsteinCollege of Medicine, Bronx,

New York [214]

Lindsay King, MDClinical and ResearchFellow, Department ofMedicine, GastrointestinalUnit, Massachusetts GeneralHospital, Boston,Massachusetts [e56]

Talmadge E. King, Jr., MDJulius R. KrevansDistinguished Professor inInternal Medicine; Chair,Department of Medicine,University of California, SanFrancisco, San Francisco,California [261]

Louis V. Kirchhoff, MD,MPHProfessor of InternalMedicine (InfectiousDiseases) and Epidemiology,Department of InternalMedicine, The University ofIowa, Iowa City, Iowa [213]

Priya S. Kishnani, MDProfessor of Pediatrics, DukeUniversity Medical Center,Durham, North Carolina[362]

Rob Knight, PhDAssistant Professor,

Department of Chemistryand Biochemistry,University of Colorado,Boulder, Colorado [64]

Minoru S. H. Ko, MD, PhDSenior Investigator andChief, DevelopmentalGenomics and AgingSection, Laboratory ofGenetics, National Instituteon Aging, National Institutesof Health, Baltimore,Maryland [65]

Barbara Konkle, MDProfessor of Medicine,Hematology, University of

Washington; Director,Translational Research,Puget Sound Blood Center,Seattle, Washington [58,115]

Peter Kopp, MDAssociate Professor, Divisionof Endocrinology,Metabolism and MolecularScience, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, Illinois[61]

Walter J. Koroshetz, MDNational Institute ofNeurological Disorders and

Stroke, National Institutesof Health, Bethesda,Maryland [382]

Thomas R. Kosten, MDBaylor College of Medicine;Veteran's AdministrationMedical Center, Houston,Texas [393]

Theodore A. Kotchen, MDProfessor Emeritus,Department of Medicine;Associate Dean for ClinicalResearch, Medical College ofWisconsin, Milwaukee,Wisconsin [247]

Phyllis E. Kozarsky, MDProfessor of Medicine andInfectious Diseases, EmoryUniversity School ofMedicine, Atlanta, Georgia[123]

Barnett S. Kramer, MD,MPHAssociate Director forDisease Prevention, Officeof Disease Prevention,National Institutes ofHealth, Bethesda, Maryland[82]

Joel Kramer, PsyDClinical Professor of

Neuropsychology inNeurology; Director ofNeuropsychology, Memoryand Aging Center,University of California, SanFrancisco, San Francisco,California [e10]

Stephen M. Krane, MDPersis, Cyrus and Marlow B.Harrison DistinguishedProfessor of Medicine,Harvard Medical School;Massachusetts GeneralHospital, Boston,Massachusetts [352]

Alexander Kratz, MD,

PhD, MPHAssociate Professor ofPathology and Cell Biology,Columbia University Collegeof Physicians and Surgeons;Director, Core Laboratory,Columbia University MedicalCenter, New York, New York[Appendix]

John P. Kress, MDAssociate Professor ofMedicine, Section ofPulmonary and CriticalCare, University of Chicago,Chicago, Illinois [267]

Patricia Kritek, MD, EdM

Associate Professor, Divisionof Pulmonary and CriticalCare Medicine, University ofWashington, Seattle,Washington [34, 251, e34]

Henry M. Kronenberg, MDProfessor of Medicine,Harvard Medical School;Chief, Endocrine Unit,Massachusetts GeneralHospital, Boston,Massachusetts [352]

Robert F. Kushner, MD,MSProfessor of Medicine,Northwestern University

Feinberg School of Medicine,Chicago, Illinois [78]

Loren Laine, MDProfessor of Medicine,University of SouthernCalifornia Keck School ofMedicine, Los Angeles,California [41]

Anil K. Lalwani, MDProfessor, Departments ofOtolaryngology, Pediatrics,and Physiology andNeuroscience, New YorkUniversity School ofMedicine, New York, NewYork [30]

H. Clifford Lane, MDClinical Director; Director,Division of ClinicalResearch; Deputy Director,Clinical Research andSpecial Projects; Chief,Clinical and MolecularRetrovirology Section,Laboratory ofImmunoregulation, NationalInstitute of Allergy andInfectious Diseases,National Institutes ofHealth, Bethesda, Maryland[189, 221]

Carol A. Langford, MD,

MHSDirector, Center forVasculitis Care andResearch, Department ofRheumatic and ImmunologicDiseases, Cleveland Clinic,Cleveland, Ohio [326, 328,336, 337, e40]

Regina C. LaRocque, MDAssistant Professor ofMedicine, Harvard MedicalSchool; Assistant Physician,Massachusetts GeneralHospital, Boston,Massachusetts [128]

Wei C. Lau, MD

Associate Professor, MedicalDirector, CardiovascularCenter Operating Rooms;Director, AdultCardiovascular and ThoracicAnesthesiology, Universityof Michigan Health System,Ann Arbor, Michigan [8]

Leslie P. Lawley, MDAssistant Professor,Department of Dermatology,School of Medicine, EmoryUniversity, Atlanta, Georgia[52]

Thomas J. Lawley, MDWilliam P. Timmie Professor

of Dermatology, Dean,Emory University School ofMedicine, Atlanta, Georgia[51, 52, 54, e16]

Thomas H. Lee, MD, MScProfessor of Medicine,Harvard Medical School;Network President, PartnersHealthcare System, Boston,Massachusetts [12]

Jane A. Leopold, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Brigham andWomen's Hospital, Boston,Massachusetts [230, e33]

Nelson Leung, MDAssociate Professor ofMedicine, Department ofNephrology andHypertension, Division ofHematology, Mayo Clinic,Rochester, Minnesota [286]

Bruce D. Levy, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Pulmonary andCritical Care Medicine,Brigham and Women'sHospital, Boston,Massachusetts [268]

Julia B. Lewis, MDProfessor, Department ofMedicine, Division ofNephrology, VanderbiltUniversity Medical Center,Nashville, Tennessee [283]

Peter Libby, MDMallinckrodt Professor ofMedicine, Harvard MedicalSchool; Chief,Cardiovascular Medicine,Brigham and Women'sHospital, Boston,Massachusetts [224, 241,e32]

Richard W. Light, MD

Professor of Medicine,Division of Allergy,Pulmonary, and CriticalCare Medicine, VanderbiltUniversity, Nashville,Tennessee [263]

Julie Lin, MD, MPHAssistant Professor ofMedicine, Harvard MedicalSchool, Boston,Massachusetts [44]

Robert Lindsay, MD, PhDChief, Internal Medicine;Professor of ClinicalMedicine, Helen HayesHospital, West Haverstraw,

New York [354]

Marc E. Lippman, MD,MACPKathleen and Stanley GlaserProfessor; Chairman,Department of Medicine,Deputy Director, SylvesterComprehensive CancerCenter, University of MiamiMiller School of Medicine,Miami, Florida [90]

Peter E. Lipsky, MDCharlottesville, Virginia[318, 331]

Kathleen D. Liu, MD, PhD,

MASAssistant Professor,Divisions of Nephrology andCritical Care Medicine,Departments of Medicineand Anesthesia, Universityof California, San Francisco,San Francisco, California[281]

Bernard Lo, MDProfessor of Medicine;Director, Program in MedicalEthics, University ofCalifornia, San Francisco,San Francisco, California[e5]

Dan L. Longo, MDLecturer, Department ofMedicine, Harvard MedicalSchool; Senior Physician,Brigham and Women'sHospital; Deputy Editor,New England Journal ofMedicine, Boston,Massachusetts; AdjunctInvestigator, NationalInstitute on Aging, NationalInstitutes of Health,Baltimore, Maryland [1, 57,59, 66, 81, 84, 85, 100,102, 110, 111, 188, e6,e17, e20, e21]

Nicola Longo, MD, PhD,

MACPProfessor of Pediatrics;Chief, Division of MedicalGenetics, Department ofPediatrics, University ofUtah, Salt Lake City, Utah[364, 365]

Joseph Loscalzo, MD,PhDHersey Professor of theTheory and Practice ofMedicine, Harvard MedicalSchool; Chairman,Department of Medicine;Physician-in-Chief, Brighamand Women's Hospital,Boston, Massachusetts [1,

35, 36, 37, 117, 224, 226,227, 237, 238, 243, 245,248, 249, e13, e19]

Phillip A. Low, MDRobert D. and Patricia E.Kern Professor ofNeurology, Mayo ClinicCollege of Medicine,Rochester, Minnesota [375]

Daniel H. Lowenstein, MDDr. Robert B. and Mrs.Ellinor Aird Professor ofNeurology; Director,Epilepsy Center, Universityof California, San Francisco,San Francisco, California

[367, 369, e42]

Elyse E. Lower, MDMedical Oncology andHematology, University ofCincinnati; OncologyHematology Care, Inc.,Cincinnati, Ohio [329]

Franklin D. Lowy, MDProfessor of Medicine andPathology, ColumbiaUniversity College ofPhysicians and Surgeons,New York, New York [135]

Sheila A. Lukehart, PhDProfessor, Departments of

Medicine and Global Health,University of Washington,Seattle, Washington [169,170]

Lucio Luzzatto, MD,FRCP, FRCPathProfessor of Haematology,University of Genova,Scientific Director IstitutoToscano Tumori, Italy [106]

Lawrence C. Madoff, MDProfessor of Medicine,University of MassachusettsMedical School, Worcester,Massachusetts; Director,Division of Epidemiology

and Immunization,Massachusetts Departmentof Public Health, JamaicaPlain, Massachusetts [119,334, e23, e24]

Emily Nelson Maher, MDClinical Instructor,Department ofAnesthesiology, HarvardMedical School; Brighamand Women's Hospital,Boston, Massachusetts[e57]

Adel A. F. Mahmoud, MD,PhDProfessor, Department of

Molecular Biology and theWoodrow Wilson School ofPublic and InternationalAffairs, PrincetonUniversity, Princeton, NewJersey [219]

Ronald V. Maier, MDJane and Donald D. TrunkeyProfessor and Vice-Chair,Surgery, University ofWashington; Surgeon-in-Chief, Harborview MedicalCenter, Seattle, Washington[270]

Mark E. Mailliard, MDFrederick F. Paustian

Professor; Chief, Division ofGastroenterology andHepatology, Department ofInternal Medicine,University of NebraskaCollege of Medicine, Omaha,Nebraska [307]

Hari R. Mallidi, MDAssistant Professor ofCardiothoracic Surgery;Director of MechanicalCirculatory Support,Stanford University MedicalCenter, Stanford, California[235]

Hanna Mandel, MD

Director, Pediatric MetabolicDisorders, Rambam HealthCare Campus, Haifa, Israel[e18]

Brian F. Mandell, MD,PhD, MACP, FACRProfessor and Chairman ofMedicine, Cleveland ClinicLerner College of Medicine;Department of Rheumaticand Immunologic Disease,Cleveland Clinic, Cleveland,Ohio [336]

Lionel A. Mandell, MD,FRCP(C), FRCP(LOND)Professor of Medicine,

McMaster University,Hamilton, Ontario, Canada[257]

Douglas L. Mann, MDLewin Chair and Chief,Cardiovascular Division;Professor of Medicine, CellBiology and Physiology,Washington UniversitySchool of Medicine, St.Louis, Missouri [234]

JoAnn E. Manson, MD,DrPHProfessor of Medicine andthe Michael and Lee BellProfessor of Women's

Health, Harvard MedicalSchool; Chief, Division ofPreventive Medicine,Brigham and Women'sHospital, Boston,Massachusetts [348]

Eleftheria Maratos-Flier,MDAssociate Professor ofMedicine, Harvard MedicalSchool; Division ofEndocrinology, Beth IsraelDeaconess Medical Center,Boston, Massachusetts [77]

Francis Marchlinski, MDProfessor of Medicine;

Director, CardiacElectrophysiology,University of PennsylvaniaHealth System,Philadelphia, Pennsylvania[233]

Guido Marcucci, MDProfessor of Medicine; JohnB. and Jane T. McCoy Chairin Cancer Research;Associate Director ofTranslational Research,Comprehensive CancerCenter, The Ohio StateUniversity College ofMedicine, Columbus, Ohio[109]

Daniel B. Mark, MD, MPHProfessor of Medicine, DukeUniversity Medical Center;Director, OutcomesResearch, Duke ClinicalResearch Institute, Durham,North Carolina [3]

Alexander G. Marneros,MD, PhDAssistant Professor,Department of Dermatology,Harvard Medical SchoolBoston, Massachusetts;Cutaneous Biology ResearchCenter, MassachusettsGeneral Hospital,

Charlestown, Massachusetts[56]

Jeanne M. Marrazzo, MD,MPHAssociate Professor ofMedicine, Division ofInfectious Diseases,Harborview Medical Center,Seattle, Washington [130]

Thomas Marrie, MDDean, Faculty of Medicine,Dalhousie University,Halifax, Nova Scotia,Canada [174]

Gary J. Martin, MD

Raymond J. Langenbach, MDProfessor of Medicine; ViceChairman for FacultyAffairs, Department ofMedicine, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, Illinois[4]

George M. Martin, MDProfessor of PathologyEmeritus, Adjunct Professorof Genome Sciences(Retired), University ofWashington, Seattle,Washington; VisitingScholar, Molecular BiologyInstitute, University of

California at Los Angeles,Los Angeles, California [71]

Joseph B. Martin, MD,PhDEdward R. and Anne G.Lefler Professor,Department ofNeurobiology, HarvardMedical School, Boston,Massachusetts [367]

Matthew Martinez, MDLehigh Valley PhysicianGroup, Lehigh Valley HeartSpecialists, Allentown,Pennsylvania [229, e29]

Susan Maslanka, PhDEnteric Diseases LaboratoryBranch, Centers for DiseaseControl and Prevention,Atlanta, Georgia [141]

Robert J. Mayer, MDStephen B. Kay FamilyProfessor of Medicine,Harvard Medical School,Boston, Massachusetts [91]

Alexander J. McAdam,MD, PhDAssistant Professor ofPathology, Harvard MedicalSchool, Children's Hospital,Boston, Massachusetts

[e22]

Calvin O. McCall, MDAssociate Professor,Department of Dermatology,Virginia CommonwealthUniversity Medical Center;Chief, Dermatology Section,Hunter Holmes McGuireVeterans Affairs MedicalCenter, Richmond, Virginia[52]

John F. McConville, MDAssistant Professor ofMedicine, University ofChicago, Chicago, Illinois[264]

Kevin T. McVary, MD,FACSProfessor of Urology,Department of Urology,Northwestern UniversityFeinberg School of Medicine,Chicago, Illinois [48]

Nancy K. Mello, PhDProfessor of Psychology(Neuroscience), HarvardMedical School, Boston,Massachusetts; Director,Alcohol and Drug AbuseResearch Center, McLeanHospital, Belmont,Massachusetts [394]

Shlomo Melmed, MDSenior Vice President andDean of the Medical Faculty,Cedars-Sinai MedicalCenter, Los Angeles,California [339]

Jack H. Mendelson,† MDProfessor of Psychiatry(Neuroscience), HarvardMedical School, Belmont,Massachusetts [394]

Robert O. Messing, MDProfessor, Department ofNeurology; Senior AssociateDirector, Ernest Gallo Clinic

and Research Center,University of California, SanFrancisco, San Francisco,California [390]

M.-Marsel Mesulam, MDProfessor of Neurology,Psychiatry and Psychology,Cognitive Neurology andAlzheimer's Disease Center,Northwestern UniversityFeinberg School of Medicine,Chicago, Illinois [26]

Susan Miesfeldt, MDMercy Hospital, MaineCenters for CancerMedicine, Scarbrough,

Maine [63]

Edgar L. Milford, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Director, TissueTyping Laboratory, Brighamand Women's Hospital,Boston, Massachusetts[282]

Bruce L. Miller, MDAW and Mary MargaretClausen DistinguishedProfessor of Neurology,University of California, SanFrancisco School ofMedicine, San Francisco,

California [25, 371, 383,e9, e10]

Samuel I. Miller, MDProfessor of GenomeSciences, Medicine, andMicrobiology, University ofWashington, Seattle,Washington [153]

Simon J. Mitchell, MBChB, PhDAssociate Professor inAnesthesiology, Diving andHyperbaric Medicine,Faculty of Medical andHealth Sciences, Universityof Auckland; Consultant

Anesthetist, Auckland CityHospital, Auckland, NewZealand [e52]

Thomas A. Moore, MD,FACP, FIDSAChairman, Department ofInfectious Diseases, OchsnerHealth System, NewOrleans, Louisiana [208,e26]

Pat J. Morin, PhDSenior Investigator,Laboratory of MolecularBiology and Immunology,National Institute on Aging,National Institutes of

Health, Baltimore, Maryland[83]

Charles A. Morris, MD,MPHInstructor in Medicine,Harvard Medical School;Associate Physician,Brigham and Women'sHospital, Boston,Massachusetts [e55, e57]

William J. Moss, MD, MPHAssociate Professor,Departments ofEpidemiology, InternationalHealth, and MolecularMicrobiology and

Immunology, Johns HopkinsBloomberg School of PublicHealth, Baltimore, Maryland[192]

Robert J. Motzer, MDProfessor of Medicine, WeillCornell Medical College;Attending Physician,Genitourinary OncologyService, Memorial Sloan-Kettering Cancer Center,New York, New York [94,96]

David B. Mount, MD,FRCPCAssistant Professor of

Medicine, Harvard MedicalSchool, Renal Division, VABoston Healthcare System;Brigham and Women'sHospital, Boston,Massachusetts [45, e15]

Haralampos M.Moutsopoulos, MD, FACP,FRCP, Master ACRProfessor and Director,Department ofPathophysiology, MedicalSchool, National Universityof Athens, Athens, Greece[320, 324, 327]

Robert S. Munford, MD

Bethesda, Maryland [271]

Nikhil C. Munshi, MDAssociate Professor ofMedicine, Harvard MedicalSchool; Associate Director,Jerome Lipper MultipleMyeloma Center, DanaFarber Cancer Institute,Boston, Massachusetts[111]

John R. Murphy, PhDProfessor of Medicine andMicrobiology, BostonUniversity School ofMedicine, Boston,Massachusetts [138]

Timothy F. Murphy, MDUB Distinguished Professorof Medicine andMicrobiology, University ofBuffalo, State University ofNew York, Buffalo, New York[145]

Barbara E. Murray, MDJ. Ralph Meadows Professorand Director, Division ofInfectious Diseases,University of Texas MedicalSchool, Houston, Texas[137]

Joseph A. Murray, MD

Professor of Medicine,Departments of InternalMedicine and Immunology,Mayo Clinic, Rochester,Minnesota [40]

Mark B. Mycyk, MDAssociate Professor,Department of EmergencyMedicine, Boston UniversitySchool of Medicine;Associate Professor,Department of EmergencyMedicine; Rush UniversitySchool of Medicine,Research Director, Divisionof Toxicology, Cook CountyHospital, Chicago, Illinois

[e50]

Robert J. Myerburg, MDProfessor, Departments ofMedicine and Physiology,Division of Cardiology; AHAChair in CardiovascularResearch, University ofMiami Miller School ofMedicine, Miami, Florida[273]

Hari Nadiminti, MDClinical Instructor,Department of Dermatology,Emory University School ofMedicine, Atlanta, Georgia[87]

Edward T. Naureckas, MDAssociate Professor ofMedicine, Section ofPulmonary and Critical CareMedicine, University ofChicago, Chicago, Illinois[252]

Eric G. Neilson, MDThomas Fearn Frist SeniorProfessor of Medicine andCell and DevelopmentalBiology, VanderbiltUniversity School ofMedicine, Nashville,Tennessee [277, 278, 283,e14]

Gerald T. Nepom, MD,PhDDirector, Benaroya ResearchInstitute at Virginia Mason;Director, Immune ToleranceNetwork; Professor,University of WashingtonSchool of Medicine, Seattle,Washington [315]

Eric J. Nestler, MD, PhDNash Family Professor andChair, Department ofNeuroscience; Director,Friedman Brain Institute,Mount Sinai School ofMedicine, New York, New

York [390]

Hartmut P. H. Neumann,MDHead, Section PreventativeMedicine, Department ofNephrology and GeneralMedicine, Albert-Ludwigs-University of Freiburg,Germany [343]

Joseph P. Newhouse,PhDJohn D. MacArthur Professorof Health Policy andManagement, Department ofHealth Care Policy, HarvardMedical School; Department

of Health Policy andManagement, HarvardSchool of Public Health,Harvard Kennedy School;Faculty of Arts andSciences, HarvardUniversity, Boston,Massachusetts [e3]

Jonathan Newmark, MDColonel, Medical Corps, USArmy; Deputy Joint ProgramExecutive Officer, MedicalSystems, Joint ProgramExecutive Office forChemical/BiologicalDefense, US Department ofDefense, Falls Church,

Virginia; Chemical CasualtyCare Consultant to the USArmy Surgeon General;Adjunct Professor ofNeurology, F. EdwardHebert School of Medicine,Uniformed ServicesUniversity of the HealthSciences, Bethesda,Maryland [222]

Rick A. Nishimura, MD,FACC, FACPJudd and Mary MorrisLeighton Professor ofCardiovascular Diseases;Professor of Medicine;Consultant, Division of

Cardiovascular Diseases andInternal Medicine, MayoClinic College of Medicine,Rochester, Minnesota [229,e29]

Robert L. Norris, MDProfessor, Department ofSurgery, Division ofEmergency Medicine,Stanford University Schoolof Medicine, Palo Alto,California [396]

Thomas B. Nutman, MDHead, Helminth ImmunologySection; Head, ClinicalParasitology Unit,

Laboratory of ParasiticDiseases, National Institutesof Health, Bethesda,Maryland [217, 218]

Katherine L. O'Brien,MDCM, MPH, FRCPCAssociate Professor, Centerfor American Indian Health;Departments ofInternational Health andEpidemiology, JohnsHopkins Bloomberg Schoolof Public Health, Baltimore,Maryland [134]

Richard J. O'Brien, MDHead, Product Evaluation

and Demonstration,Foundation for Innovativeand New Diagnostics (FIND),Geneva, Switzerland [165]

Max R. O'Donnell, MDAssistant Professor ofMedicine, Albert EinsteinCollege of Medicine, Bronx,New York [168]

Nigel O'Farrell, MSc, MD,FRCPEaling Hospital, London,United Kingdom [161]

Jennifer Ogar, MSSpeech Pathologist, Memory

and Aging Center,University of California, SanFrancisco, San Francisco,California; Acting Chief ofSpeech Pathology at theDepartment of VeteransAffairs, Martinez, California[e10]

Patrick T. O'Gara, MDProfessor of Medicine,Harvard Medical School;Director, Clinical Cardiology,Brigham and Women'sHospital, Boston,Massachusetts [227, 237,e13]

C. Warren Olanow MD,FRCPCDepartment of Neurologyand Neuroscience, MountSinai School of Medicine,New York, New York [372]

Andrew B. Onderdonk,PhDProfessor of Pathology,Harvard Medical School;Brigham and Women'sHospital, Boston,Massachusetts [e22]

Chung Owyang, MDH. Marvin Pollard Professorof Internal Medicine; Chief,

Division ofGastroenterology,University of MichiganHealth System, Ann Arbor,Michigan [290, 296]

William Pao, MD, PhDAssociate Professor ofMedicine, Cancer Biology,and Pathology, Division ofHematology and MedicalOncology, VanderbiltUniversity School ofMedicine, Nashville,Tennessee [89]

Umesh D. Parashar,MBBS, MPH

Lead, Viral GastroenteritisEpidemiology Team, Divisionof Viral Diseases, NationalCenter for Immunizationand Respiratory Diseases,Centers for Disease Controland Prevention, Atlanta,Georgia [190]

Shreyaskumar R. Patel,MDCenter Medical Director,Sarcoma Center; Professorof Medicine; DeputyChairman, Department ofSarcoma Medical Oncology,MD Anderson CancerCenter, Houston, Texas [98]

David L. Paterson, MD,PhDProfessor of Medicine,University of QueenslandCentre for ClinicalResearch; Royal Brisbaneand Women's Hospital,Brisbane, Australia [150]

Gustav Paumgartner, MDProfessor Emeritus ofMedicine, University ofMunich, Munich, Germany[311]

David A. Pegues, MDHospital Epidemiologist,

David Geffen School ofMedicine, University ofCalifornia, Los Angeles, LosAngeles, California [153]

Anton Y. Peleg, MBBS,PhD, MPH, FRACPInfectious DiseasesPhysician, Senior Lecturer,and NHMRC BiomedicalFellow, Department ofInfectious Diseases andMicrobiology, The AlfredHospital and MonashUniversity, Melbourne,Victoria, Australia [150]

Florencia Pereyra, MD

Assistant Professor ofMedicine, Harvard MedicalSchool; Associate Physician,Infectious Disease Division,Brigham and Women'sHospital, Boston,Massachusetts [e23, e24]

Michael A. Pesce, PhDProfessor Emeritus ofPathology and Cell Biology,Columbia University Collegeof Physicians and Surgeons;Columbia University MedicalCenter, New York, New York[Appendix]

Clarence J. Peters, MD

John Sealy DistinguishedUniversity Chair in Tropicaland Emerging Virology;Professor, Department ofMirobiology andImmunology; Department ofPathology; Director forBiodefense, Center forBiodefense and EmergingInfectious Diseases,University of Texas MedicalBranch, Galveston, Texas[196, 197]

Gerald B. Pier, PhDProfessor of Medicine(Microbiology and MolecularGenetics), Harvard Medical

School; Microbiologist,Brigham and Women'sHospital, Boston,Massachusetts [120]

Ronald E. Polk, PharmDProfessor of Pharmacy andMedicine; Chairman,Department of Pharmacy,School of Pharmacy,Virginia CommonwealthUniversity/Medical Collegeof Virginia Campus,Richmond, Virginia [133]

Richard J. Pollack, PhDResearch AssociateProfessor, Department of

Biology, Boston University;Research Associate,Department of Immunologyand Infectious Diseases,Harvard School of PublicHealth, Boston,Massachusetts [397]

Andrew J. Pollard, PhD,FRCPCHProfessor of PediatricInfection and Immunity;Director of the OxfordVaccine Group, Departmentof Pediatrics, University ofOxford, Oxford, UnitedKingdom [143]

Reuven Porat, MDInternal MedicineDepartment, Tel-AvivSourasky Medical Centre;Sackler Faculty of Medicine,Tel-Aviv University, Tel-Aviv, Israel [16]

Daniel A. Portnoy, PhDProfessor of Biochemistryand Molecular Biology,Department of Molecularand Cell Biology, The Schoolof Public Health, Universityof California, Berkeley,Berkeley, California [139]

John T. Potts, Jr., MD

Director of Research,Massachusetts GeneralHospital, Boston,Massachusetts [353]

Lawrie W. Powell, MD,PhDProfessor of Medicine;Director, Centre for theAdvancement of ClinicalResearch, Royal Brisbaneand Women's Hospital,Brisbane, Australia [357]

Alvin C. Powers, MDJoe C. Davis Chair inBiomedical Science;Professor of Medicine,

Molecular Physiology, andBiophysics; Director,Vanderbilt Diabetes Center;Chief, Division of Diabetes,Endocrinology, andMetabolism, VanderbiltUniversity School ofMedicine, Nashville,Tennessee [344]

Daniel S. Pratt, MDAssistant Professor ofMedicine, Harvard MedicalSchool; MassachusettsGeneral Hospital, Boston,Massachusetts [42, 302]

Michael B. Prentice, MB

ChB, PhD, MRCP(UK),FRCPath, FFPRCPIProfessor of MedicalMicrobiology, Department ofMicrobiology, UniversityCollege Cork, Cork, Ireland[159]

Darwin J. Prockop, MD,PhDDirector and Professor,Institute for RegenerativeMedicine, Texas A&M HealthScience Center College ofMedicine at Scott & White,Temple, Texas [363]

Stanley B. Prusiner, MD

Director, Institute forNeurodegenerativeDiseases; Professor,Department of Neurology,University of California, SanFrancisco, San Francisco,California [383]

Howard I. Pryor, II, MDLaboratory for TissueEngineering and OrganFabrication, Center forRegenerative Medicine,Department of Surgery,Massachusetts GeneralHospital, Boston,Massachusetts [69]

Thomas C. Quinn, MDProfessor of Medicine, JohnsHopkins University,Baltimore, Maryland; SeniorInvestigator, NationalInstitute of Allergy andInfectious Diseases,National Institutes ofHealth, Bethesda, Maryland[176]

Gil Rabinovici, MDAttending Neurologist,Memory and Aging Center,University of California, SanFrancisco, San Francisco,California [e10]

Daniel J. Rader, MDCooper-McClure Professor ofMedicine and Pharmacology,University of PennsylvaniaSchool of Medicine,Philadelphia, Pennsylvania[356]

Sanjay Ram, MDAssociate Professor ofMedicine, Division ofInfectious Diseases andImmunology, University ofMassachusetts MedicalSchool, Worcester,Massachusetts [144]

Reuben Ramphal, MD

Professor of Medicine,Molecular Genetics andMicrobiology, University ofFlorida College of Medicine,Gainesville, Florida [152]

Kumanan Rasanathan,MBChB, MPH, FAFPHMTechnical Officer,Department of Ethics,Equity, Trade, and HumanRights, World HealthOrganization, Geneva,Switzerland [e1]

Neil H. Raskin, MDDepartment of Neurology,University of California, San

Francisco, San Francisco,San Francisco, California[14]

Anis Rassi, Jr., MD, PhD,FACC, FACP, FAHAScientific Director, AnisRassi Hospital, Goiânia,Brazil [213]

James P. Rathmell, MDAssociate Professor ofAnesthesia, Harvard MedicalSchool; Chief, Division ofPain Medicine,Massachusetts GeneralHospital, Boston,Massachusetts [11]

Mario C. Raviglione, MDDirector, Stop TBDepartment, World HealthOrganization, Geneva,Switzerland [165]

Sharon L. Reed, MDProfessor of Pathology andMedicine; Director,Microbiology and VirologyLaboratories, University ofCalifornia, San DiegoMedical Center, San Diego,California [e25]

Susan E. Reef, MDMedical Epidemiologist,

Centers for Disease Controland Prevention, Atlanta,Georgia [193]

Richard C. Reichman, MDProfessor of Medicine and ofMicrobiology andImmunology, University ofRochester School ofMedicine and Dentistry,Rochester, New York [185]

John J. Reilly, Jr., MDExecutive Vice Chairman;Department of Medicine;Professor of Medicine,University of Pittsburgh,Pittsburgh, Pennsylvania

[260, e34]

John T. Repke, MDUniversity Professor andChairman, Department ofObstetrics and Gynecology,Pennsylvania StateUniversity College ofMedicine, Obstetrician-Gynecologist-in-Chief, TheMilton S. Hershey MedicalCenter, Hershey,Pennsylvania [7]

Victor I. Reus, MD,DFAPA, FACPDepartment of Psychiatry,University of California, San

Francisco School ofMedicine; Langley PorterNeuropsychiatric Institute,San Francisco, SanFrancisco, California [391]

Joseph Rhatigan, MDAssistant Professor ofMedicine, Harvard MedicalSchool; Assistant Professor,Harvard School of PublicHealth; Brigham andWomen's Hospital, Boston,Massachusetts [2]

Peter A. Rice, MDProfessor of Medicine,Division of Infectious

Diseases and Immunology,University of MassachusettsMedical School, Worcester,Massachusetts [144]

Stuart Rich, MDProfessor of Medicine,Department of Medicine,Section of Cardiology,University of Chicago,Chicago, Illinois [250]

Gary S. Richardson, MDSenior Research Scientistand Staff Physician, HenryFord Hospital, Detroit,Michigan [27]

Elizabeth Robbins, MDClinical Professor ofPediatrics, University ofCalifornia, San Francisco,San Francisco, California[e46]

Gary L. Robertson, MDEmeritus Professor ofMedicine, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, Illinois[340]

Russell G. Robertson, MDVice President for MedicalAffairs, Rosalind FranklinUniversity of Medicine and

Science; Dean, ChicagoMedical School, Chicago,Illinois [80]

Dan M. Roden, MDWilliam Stokes Professor ofExperimental Therapeutics;Assistant Vice-Chancellorfor Personalized Medicine,Vanderbilt University Schoolof Medicine, Nashville,Tennessee [5]

James A. Romano, Jr.,PhD, DABTSenior Principal LifeScientist and TechnicalFellow, Science Applications

International Corporation,Frederick, Maryland [222]

Karen L. Roos, MDJohn and Nancy NelsonProfessor of Neurology andProfessor of NeurologicalSurgery, Indiana UniversitySchool of Medicine,Indianapolis, Indiana [381]

Allan H. Ropper, MDProfessor of Neurology,Harvard Medical School;Executive Vice Chair ofNeurology, Raymond D.Adams DistinguishedClinician, Brigham and

Women's Hospital, Boston,Massachusetts [274, 377,378]

Roger N. Rosenberg, MDZale Distinguished Chairand Professor of Neurology,Department of Neurology,University of TexasSouthwestern MedicalCenter, Dallas, Texas [373]

Myrna R. Rosenfeld, MD,PhDProfessor of Neurology andChief, Division of Neuro-oncology, University ofPennsylvania, Philadelphia,

Pennsylvania [101]

John H. Rubenstein, MD,PhDNina Ireland DistinguishedProfessor in ChildPsychiatry, Center forNeurobiology andPsychiatry, Department ofPsychiatry, University ofCalifornia, San Francisco,San Francisco, California[390]

Michael A. Rubin, MD,PhDAssistant Professor ofMedicine, University of Utah

School of Medicine, SaltLake City, Utah [31]

Steven Rubin, MSActing PrincipalInvestigator, Center forBiologics Evaluation andResearch, Food and DrugAdministration, Bethesda,Maryland [194]

Robert M. Russell, MDProfessor Emeritus ofMedicine and Nutrition,Tufts University, Boston,Massachusetts; Office ofDietary Supplements,National Institutes of

Health, Bethesda, Maryland[74]

Thomas A. Russo, MD,CM, FIDSAProfessor of Medicine andMicrobiology andImmunology; Chief, Divisionof Infectious Diseases,University at Buffalo, StateUniversity of New York,Buffalo, New York [149,163]

Anna Rutherford, MD,MPHInstructor in Medicine,Harvard Medical School;

Associate Physician, Divisionof Gastroenterology,Hepatology and Endoscopy,Brigham and Women'sHospital, Boston,Massachusetts [e56]

Edward T. Ryan, MD,DTM&HAssociate Professor ofMedicine, Harvard MedicalSchool; Associate Professorof Immunology andInfectious Diseases, HarvardSchool of Public Health;Director, Tropical andGeographic Medicine,Massachusetts General

Hospital, Boston,Massachusetts [128, 156]

Miguel Sabria, MDProfessor of Medicine,Autonomous University ofBarcelona; Chief, InfectiousDiseases Section, GermansTrias I Pujl Hospital,Barcelona, Spain [147]

David J. Salant, MDProfessor of Medicine,Boston University School ofMedicine; Chief, Section ofNephrology, Boston MedicalCenter, Boston,Massachusetts [284, 285]

Martin A. Samuels, MD,DSc(hon), FAAN, MACP,FRCPProfessor of Neurology,Harvard Medical School;Chairman, Department ofNeurology, Brigham andWomen's Hospital, Boston,Massachusetts [e43, e47]

Philippe Sansonetti, MD,MSProfessor, Collège deFrance; Institut Pasteur,Paris, France [154]

Jussi J. Saukkonen, MD

Associate Professor ofMedicine, Section ofPulmonary, Allergy, andCritical Care Medicine,Boston University School ofMedicine, Boston,Massachusetts [168]

Edward A. Sausville, MD,PhDProfessor, Department ofMedicine, University ofMaryland School ofMedicine; Deputy Directorand Associate Director forClinical Research, Universityof Maryland Marlene andStewart Greenebaum

Cancer Center, Baltimore,Maryland [85]

Mohamed H. Sayegh, MDRaja N. Khuri Dean, Facultyof Medicine; Professor ofMedicine and Immunology;Vice President of MedicalAffairs, American Universityof Beirut, Beirut, Lebanon;Visiting Professor ofMedicine and Pediatrics,Harvard Medical School;Director, Schuster FamilyTransplantation ResearchCenter, Brigham andWomen's Hospital;Children's Hospital, Boston,

Massachusetts [282]

David T. Scadden, MDGerald and Darlene JordanProfessor of Medicine,Harvard Stem Cell Institute,Harvard Medical School;Department of Stem Celland Regenerative Biology,Massachusetts GeneralHospital, Boston,Massachusetts [66]

Anthony H. V. Schapira,DSc, MD, FRCP, FMedSciUniversity Department ofClinical Neurosciences,University College London;

National Hospital forNeurology andNeurosurgery, Queen'sSquare, London, UnitedKingdom [372]

Howard I. Scher, MDProfessor of Medicine, WeillCornell Medical College; D.Wayne Calloway Chair inUrologic Oncology; Chief,Genitourinary OncologyService, Department ofMedicine, Memorial Sloan-Kettering Cancer Center,New York, New York [94,95]

Anne Schuchat, MDDirector, National Center forImmunization andRespiratory Diseases,Centers for Disease Controland Prevention, Atlanta,Georgia [122]

Marc A. Schuckit, MDDistinguished Professor ofPsychiatry, University ofCalifornia, San Diego Schoolof Medicine, La Jolla,California [392]

H. Ralph Schumacher, MDProfessor of Medicine,Division of Rheumatology,

University of Pennsylvania,School of Medicine,Philadelphia, Pennsylvania[333]

Gordon E. Schutze, MDProfessor of Pediatrics,Section of Retrovirology;Vice President, BaylorInternational Pediatric AIDSInitiative at Texas Children'sHospital, Baylor College ofMedicine, Houston, Texas[158]

Stuart Schwartz, PhDProfessor of HumanGenetics, Medicine and

Pathology, University ofChicago, Chicago, Illinois[62]

Richard M.Schwartzstein, MDEllen and Melvin GordonProfessor of Medicine andMedical Education;Associate Chief, Division ofPulmonary, Critical Care,and Sleep Medicine, BethIsrael Deaconess MedicalCenter, Harvard MedicalSchool, Boston,Massachusetts [33]

William W. Seeley, MD

Associate Professor ofNeurology, Memory andAging Center, University ofCalifornia, San Francisco,San Francisco, California[371]

Michael V. Seiden, MD,PhDProfessor of Medicine;President and CEO, FoxChase Cancer Center,Philadelphia, Pennsylvania[97]

Julian L. Seifter, MDAssociate Professor ofMedicine, Harvard Medical

School; Brigham andWomen's Hospital, Boston,Massachusetts [289]

David C. Seldin, MD, PhDChief, Section ofHematology-Oncology,Department of Medicine;Director, Amyloid Treatmentand Research Program,Boston University School ofMedicine; Boston MedicalCenter, Boston,Massachusetts [112]

Andrew P. Selwyn, MD,MBCHBProfessor of Medicine

Brigham and Women'sHospital, Boston,Massachusetts [243]

Ankoor Shah, MDDepartment of Medicine,Division of Rheumatologyand Immunology, DukeUniversity Medical Center,Durham, North Carolina[321]

Steven D. Shapiro, MDJack D. Myers Professor andChair, Department ofMedicine, University ofPittsburgh, Pittsburgh,Pennsylvania [260]

Kanade Shinkai, MD, PhDAssistant Professor,Department of Dermatology,University of California, SanFrancisco, San Francisco,California [55]

William Silen, MDJohnson and JohnsonProfessor Emeritus ofSurgery, Harvard MedicalSchool, Auburndale,Massachusetts [13, 299,300]

Edwin K. Silverman, MD,PhD

Associate Professor ofMedicine, Harvard MedicalSchool; ChanningLaboratory, Pulmonary andCritical Care Division,Department of Medicine,Brigham and Women'sHospital, Boston,Massachusetts [260]

Martha Skinner, MDProfessor, Department ofMedicine, Boston UniversitySchool of Medicine, Boston,Massachusetts [112]

Karl Skorecki, MD,FRCP(C), FASN

Annie Chutick Professor inMedicine (Nephrology);Director, RappaportResearch Institute, Technion– Israel Institute ofTechnology; Director,Medical and ResearchDevelopment, RambamHealth Care Campus, Haifa,Israel [280, e18]

Wade S. Smith, MD, PhDProfessor of Neurology,Daryl R. Gress EndowedChair of Neurocritical Careand Stroke; Director,University of California, SanFrancisco Neurovascular

Service, San Francisco, SanFrancisco, California [275,370]

A. George Smulian,MBBChAssociate Professor ofMedicine, University ofCincinnati College ofMedicine; Chief, InfectiousDisease Section, CincinnatiVA Medical Center,Cincinnati, Ohio [207]

Jeremy Sobel, MD, MPHMedical Officer, Office ofGlobal Health, Centers forDisease Control and

Prevention, Atlanta, Georgia[141]

Kelly A. Soderberg, PhD,MPHDirector, ProgramManagement, Duke HumanVaccine Institute, DukeUniversity School ofMedicine, Durham, NorthCarolina [314]

Julian Solway, MDWalter L. PalmerDistinguished ServiceProfessor of Medicine andPediatrics; Associate Deanfor Translational Medicine,

Biological Sciences Division;Vice Chair for Research,Department of Medicine;Chair, Committee onMolecular Medicine,University of Chicago,Chicago, Illinois [252, 264]

Michael F. Sorrell, MDRobert L. Grissom Professorof Medicine, University ofNebraska Medical Center,Omaha, Nebraska [307]

Frank E. Speizer, MDE. H. Kass DistinguishedProfessor of Medicine,Channing Laboratory,

Harvard Medical School;Professor of EnvironmentalScience, Harvard School ofPublic Health, Boston,Massachusetts [256]

Brad Spellberg, MDAssociate Professor ofMedicine, Geffen School ofMedicine, University ofCalifornia, Los Angeles(UCLA); Divisions ofGeneral Internal Medicineand Infectious Diseases, LosAngeles BiomedicalResearch Institute atHarbor–UCLA MedicalCenter, Torrance, California

[205]

Jerry L. Spivak, MDProfessor of Medicine andOncology, HematologyDivision, Johns HopkinsUniversity School ofMedicine, Baltimore,Maryland [108]

David D. Spragg, MDAssistant Professor ofMedicine, Johns HopkinsUniversity, Baltimore,Maryland [231, 232]

Samuel L. Stanley, Jr.,MD

President, Stony BrookUniversity, Stony Brook,New York [209]

E. William St. Clair, MDDepartment of Medicine,Division of Rheumatologyand Immunology, DukeUniversity Medical Center,Durham, North Carolina[321]

Allen C. Steere, MDProfessor of Medicine,Harvard Medical School;Massachusetts GeneralHospital, Boston,Massachusetts [173]

Robert S. Stern, MDCarl J. Herzog Professor ofDermatology, HarvardMedical School; Chair,Department of Dermatology,Beth Israel DeaconessMedical Center, Boston,Massachusetts [55]

Dennis L. Stevens, MD,PhDProfessor of Medicine,University of WashingtonSchool of Medicine, Seattle,Washington; Chief,Infectious Disease Section,Veterans Affairs Medical

Center, Boise, Idaho [125,142]

Lynne Warner Stevenson,MDProfessor of Medicine,Harvard Medical School;Director, Heart FailureProgram, Brigham andWomen's Hospital, Boston,Massachusetts [238]

Stephen E. Straus,† MDNational Institute of Allergyand Infectious Diseases,Bethesda, Maryland [e2]

Stephanie Studenski, MD,

MPHProfessor of GeriatricMedicine, Department ofMedicine, University ofPittsburgh School ofMedicine; Staff Physician,VA Pittsburgh GeriatricResearch Education andClinical Center, Pittsburgh,Pennsylvania [72]

Lewis Sudarsky, MDAssociate Professor ofNeurology, Harvard MedicalSchool; Director ofMovement Disorders,Brigham and Women'sHospital, Boston,

Massachusetts [24]

Donna C. Sullivan, PhDProfessor, Department ofMedicine, Division ofInfectious Diseases,University of MississippiMedical School, Jackson,Mississippi [201]

Shyam Sundar, MDProfessor of Medicine,Institute of MedicalSciences, Banaras HinduUniversity, Varanasi, India[212]

Paolo M. Suter, MD, MS

Professor, Clinic andPoliclinic of InternalMedicine, UniversityHospital, Zurich,Switzerland [74]

Richard Suzman, PhDDirector, Behavioral andSocial Research Program,National Institute on Aging,National Institutes ofHealth, Chevy Chase,Maryland [70]

Morton N. Swartz, MDProfessor of Medicine,Harvard Medical School;Chief, Jackson Firm Medical

Service and InfectiousDisease Unit, MassachusettsGeneral Hospital, Boston,Massachusetts [382]

Robert A. Swerlick, MDAlicia Leizman StonecipherProfessor and Chair ofDermatology, EmoryUniversity School ofMedicine, Atlanta, Georgia[e16]

Geoffrey Tabin, MDProfessor of Ophthalmologyand Visual Sciences,University of Utah School ofMedicine; Director,

InternationalOphthalmology Division,John A. Moran Eye Center;Director, HimalayanCataract Project, Salt LakeCity, Utah [e51]

Maria Carmela Tartaglia,MD, FRCPCClinical Instructor ofNeurology, Memory andAging Center, University ofCalifornia, San Francisco,San Francisco, California[e10]

Joel D. Taurog, MDProfessor of Internal

Medicine, RheumaticDiseases Division,University of TexasSouthwestern MedicalCenter, Dallas, Texas [325]

Stephen C. Textor, MDProfessor of Medicine,Division of Nephrology andHypertension, Mayo Clinic,Rochester, Minnesota [286]

C. Louise Thwaites, MD,MBBSMusculoskeletal Physician,Horsham, West Sussex;Oxford University ClinicalResearch Unit, Hospital for

Tropical Diseases, Ho ChiMinh City, Vietnam [140]

Alan D. Tice, MD, FACPInfections Limited Hawaii;John A. Burns School ofMedicine, University ofHawaii, Honolulu, Hawaii[126]

Zelig A. Tochner, MDProfessor of RadiationOncology, University ofPennsylvania School ofMedicine; Medical Director,Proton Therapy Center,Philadelphia, Pennsylvania[223]

Gordon F. Tomaselli, MDMichel Mirowski, MDProfessor of Cardiology;Professor of Medicine andCellular and MolecularMedicine; Chief, Division ofCardiology, Johns HopkinsUniversity, Baltimore,Maryland [231, 232]

Mark Topazian, MDProfessor of Medicine, MayoClinic, Rochester, Minnesota[291, e36]

Barbara W. Trautner, MD,PhD

Assistant Professor, Sectionof Infectious Diseases,Baylor College of Medicine;The Michael E. DeBakeyVeterans Affairs MedicalCenter, Houston VA HealthServices Research andDevelopment Center ofExcellence, Houston, Texas[288]

Jeffrey M. Trent, PhD,FACMGPresident and ResearchDirector, TranslationalGenomics ResearchInstitute, Phoenix, Arizona;Van Andel Research

Institute, Grand Rapids,Michigan [83]

Elbert P. Trulock, MDRosemary and I. JeromeFlance Professor inPulmonary Medicine,Washington UniversitySchool of Medicine, St.Louis, Missouri [266]

Kenneth L. Tyler, MDReuler-Lewin FamilyProfessor and Chair,Department of Neurology;Professor of Medicine andMicrobiology, University ofColorado School of

Medicine, Denver, Colorado;Chief of Neurology,University of ColoradoHospital, Aurora, Colorado[381]

Athanasios G. Tzioufas,MDProfessor, Department ofPathophysiology, NationalUniversity of Athens Schoolof Medicine, Athens, Greece[324]

Walter J. Urba, MD, PhDDirector of Cancer Research,Robert W. Franz CancerResearch Center,

Providence Portland MedicalCenter, Portland, Oregon[87]

Joseph P. Vacanti, MDJohn Homans Professor ofSurgery, Harvard MedicalSchool; Surgeon-in-Chief,Massachusetts GeneralHospital for Children;Deputy Director, Center forRegenerative Medicine,Massachusetts GeneralHospital, Boston,Massachusetts [69]

Jos W. M. van der Meer,MD, PhD

Professor of Medicine; Head,Department of GeneralInternal Medicine, RadboudUniversity, NijmegenMedical Centre, Nijmegen,Netherlands [389]

Edouard Vannier, PhD,PharmDAssistant Professor, Divisionof Geographic Medicine andInfectious Diseases, TuftsUniversity School ofMedicine; Tufts MedicalCenter, Boston,Massachusetts [211]

Gauri R. Varadhachary,

MDAssociate Professor,Department ofGastrointestinal MedicalOncology, University ofTexas MD Anderson CancerCenter, Houston, Texas [99]

John Varga, MDJohn Hughes Professor ofMedicine, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, Illinois[323]

Camilo Jimenez Vasquez,MDAssistant Professor,

Department of EndocrineNeoplasia and HormonalDisorders, Division ofInternal Medicine,University of Texas MDAnderson Cancer Center,Houston, Texas [351]

Joseph M. Vinetz, MDProfessor of Medicine,Division of InfectiousDiseases, Department ofMedicine, University ofCalifornia, San Diego, SanDiego, California [171]

Indre V. Viskontas, PhDVisiting Scholar, Memory

and Aging Center,University of California, SanFrancisco, San Francisco,California [e9]

Panayiotis G.Vlachoyiannopoulos, MDAssociate Professor ofMedicine-Immunology,Department ofPathophysiology, MedicalSchool, National Universityof Athens, Athens, Greece[320]

Bert Vogelstein, MDProfessor of Oncology andPathology; Investigator,

Howard Hughes MedicalInstitute; Sidney KimmelComprehensive CancerCenter; Johns HopkinsUniversity School ofMedicine, Baltimore,Maryland [83]

Everett E. Vokes, MDJohn E. Ultmann Professorand Chairman, Departmentof Medicine; Physician-in-Chief, University of ChicagoMedical Center, Chicago,Illinois [88]

Tamara J. Vokes, MD,FACP

Professor, Department ofMedicine, Section ofEndocrinology, University ofChicago, Chicago, Illinois[355]

Sushrut S. Waikar, MD,MPHAssistant Professor ofMedicine, Harvard MedicalSchool; Brigham andWomen's Hospital, Boston,Massachusetts [279]

Matthew K. Waldor, MD,PhDEdward H. Kass Professor ofMedicine, Channing

Laboratory, Brigham andWomen's Hospital; HarvardMedical School and HowardHughes Medical Institute,Boston, Massachusetts[156]

David H. Walker, MDThe Carmage and MarthaWalls DistinguishedUniversity Chair in TropicalDiseases; Professor andChairman, Department ofPathology; ExecutiveDirector, Center forBiodefense and EmergingInfectious Diseases,University of Texas Medical

Branch, Galveston, Texas[174]

Mark F. Walker, MDAssociate Professor,Department of Neurology,Case Western ReserveUniversity School ofMedicine; Daroff-Dell' OssoOcular Motility Laboratory,Louis Stokes ClevelandDepartment of VeteransAffairs Medical Center,Cleveland, Ohio [21]

B. Timothy Walsh, MDProfessor, Department ofPsychiatry, College of

Physicians and Surgeons,Columbia University; NewYork State PsychiatricInstitute, New York, NewYork [79]

Peter D. Walzer, MD, MScProfessor of Medicine,University of CincinnatiCollege of Medicine;Associate Chief of Staff forResearch, Cincinnati VAMedical Center, Cincinnati,Ohio [207]

Fred Wang, MDProfessor of Medicine,Harvard Medical School;

Brigham and Women'sHospital, Boston,Massachusetts [177, 183]

John W. Warren, MDProfessor of Medicine,University of MarylandSchool of Medicine,Baltimore, Maryland [e35]

Carl V. Washington, MDAssociate Professor ofDermatology, WinshipCancer Center, EmoryUniversity School ofMedicine, Atlanta, Georgia[87]

Anthony P. Weetman, MDUniversity of SheffieldSchool of Medicine,Sheffield, United Kingdom[341]

Robert A. Weinstein, MDThe C Anderson Hedberg MDProfessor of InternalMedicine, Rush MedicalCollege; Interim Chairman,Department of Medicine,John Stroger Hospital,Chicago, Illinois [131]

Jeffrey I. Weitz, MD,FRCP(C), FACPProfessor of Medicine and

Biochemistry; ExecutiveDirector, Thrombosis andAtherosclerosis ResearchInstitute; HSFO/J. F.Mustard Chair inCardiovascular Research,Canada Research Chair (Tier1) in Thrombosis, McMasterUniversity, Hamilton,Ontario, Canada [118]

Peter F. Weller, MDChief, Infectious DiseaseDivision; Chief, Allergy andInflammation Division, BethIsrael Deaconess MedicalCenter, Boston,Massachusetts [215-218,

220]

Patrick Y. Wen, MDProfessor of Neurology,Harvard Medical School;Dana-Farber CancerInstitute, Boston,Massachusetts [379]

Michael R. Wessels, MDJohn F. Enders Professor ofPediatrics; Professor ofMedicine, Harvard MedicalSchool; Chief, Division ofInfectious Diseases,Children's Hospital, Boston,Massachusetts [136]

Meir Wetzler, MD, FACPProfessor of Medicine,Roswell Park CancerInstitute, Buffalo, New York[109]

L. Joseph Wheat, MDMiraVista Diagnostics andMiraBella Technologies,Indianapolis, Indiana [199]

A. Clinton White, Jr., MDDirector, Infectious DiseaseDivision, Department ofInternal Medicine,University of Texas MedicalBranch, Galveston, Texas[220]

Nicholas J. White, MD,DSc, FRCP, F Med Sci,FRSProfessor of TropicalMedicine, Faculty of TropicalMedicine, MahidolUniversity, Bangkok,Thailand [210, e27]

Richard J. Whitley, MDDistinguished Professor ofPediatrics, Loeb EminentScholar Chair in Pediatrics;Professor of Pediatrics,Microbiology, Medicine, andNeurosurgery, University ofAlabama at Birmingham,

Birmingham, Alabama [180]

John W. Winkelman, MD,PhDAssociate Professor ofPsychiatry, Harvard MedicalSchool; Medical Director,Sleep Health Centers,Brigham and Women'sHospital, Boston,Massachusetts [27]

Bruce U. Wintroub, MDProfessor and Chair,Department of Dermatology,University of California, SanFrancisco, San Francisco,California [55]

Andrea Wolf, MD, MPHInstructor in Surgery,Harvard Medical School;Chief Resident inCardiothoracic Surgery,Division of ThoracicSurgery, Brigham andWomen's Hospital, Boston,Massachusetts [e55]

Allan W. Wolkoff, MDProfessor of Medicine andAnatomy and StructuralBiology; Associate Chair ofMedicine for Research;Chief, Division ofGastroenterology and Liver

Diseases, Albert EinsteinCollege of Medicine andMontefiore Medical Center,Bronx, New York [303]

John B. Wong, MDProfessor of Medicine, TuftsUniversity School ofMedicine; Chief, Division ofClinical Decision Making,Department of Medicine,Tufts Medical Center,Boston, Massachusetts [3]

Louis Michel Wong KeeSong, MDAssociate Professor, Divisionof Gastroenterology and

Hepatology, Mayo Clinic,Rochester, Minnesota [291,e36]

Robert L. Wortman, MD,FACP, MACRProfessor, Department ofMedicine, DartmouthMedical School andDartmouth HitchcockMedical Center, Lebanon,New Hampshire [359]

Shirley H. Wray, MB, ChB,PhD, FRCPProfessor of Neurology,Harvard Medical School;Department of Neurology,

Massachusetts GeneralHospital, Boston,Massachusetts [e11]

Bechien U. Wu, MDInstructor of Medicine,Harvard Medical School;Associate Physician, Divisionof Gastroenterology,Brigham and Women'sHospital, Boston,Massachusetts [313]

Richard Wunderink, MDProfessor of Medicine,Division of Pulmonary andCritical Care, NorthwesternUniversity Feinberg School

of Medicine, Chicago, Illinois[257]

Kim B. Yancey, MDProfessor and Chair,Department of Dermatology,University of TexasSouthwestern MedicalCenter, Dallas, Texas [51,54]

Janet A. Yellowitz, DMD,MPHAssociate Professor;Director, Geriatric Dentistry,University of MarylandDental School, Baltimore,Maryland [e12]

Lam Minh Yen, MDDirector, Tetanus IntensiveCare Unit, Hospital forTropical Diseases, Ho ChiMinh City, Vietnam [140]

Maria A. Yialamas, MDInstructor, Harvard MedicalSchool; Associate ProgramDirector, Internal MedicineResidency, Brigham andWomen's Hospital, Boston,Massachusetts [e54, e56]

Neal S. Young, MDChief, Hematology Branch,National Heart, Lung and

Blood Institute, NationalInstitutes of Health,Bethesda, Maryland [107]

Victor L. Yu, MDProfessor of Medicine,Department of Medicine,University of PittsburghMedical Center, Pittsburgh,Pennsylvania [147]

Laura A. Zimmerman,MPHEpidemiologist, Centers forDisease Control andPrevention, Atlanta, Georgia[193]

†Deceased

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Harrison's Online > Appendix: Laboratory Values of Clinical Importance >

APPENDIX: LABORATORY VALUES OFCLINICAL IMPORTANCEThis Appendix contains tables of reference values forlaboratory tests, special analytes, and special functiontests. A variety of factors can Such variables include the population duration and means of specimen transport, laboratorymethods and instrumentation, and even the type ofcontainer used for the collection of the specimen. The

reference or "normal" ranges given in therefore not be appropriate for all laboratories, andthese values should only be used as general guidelines.Whenever possible, reference values provided by thelaboratory performing the interpretation of laboratory data. Appendix reflect typical reference ranges in Pediatric reference ranges may vary significantly fromadult values.In preparing the Appendix, the authors have taken intoaccount the fact that the system système international d'unités) is used in and in some medical journals. However, clinicallaboratories may continue to report values in "traditional"or conventional units. Therefore, both systems are

provided in the Appendix. The dual system is also used inthe text except for (1) those numbers remain the same but only the terminology changed (mmol/L for meq/L or IU/L for mIU/mL), whenonly the SI units are given; and (2) most pressuremeasurements (e.g., blood and pressures), when the traditional units (mmHg, mmHare used. In all other instances in the text the SI unit isfollowed by the traditional unit in parentheses.REFERENCE VALUES FOR LABORATORYTESTS

Table 1 Hematology and Coagulation

Analyte Specimen

Activated clottingtime

WB

Activated proteinC resistance(factor V Leiden)

P

ADAMTS13activity P

ADAMTS13inhibitor activity P

ADAMTS13antibody P

Alpha2antiplasmin

P

Antiphospholipid

antibody panel PTT-LA (lupusanticoagulantscreen)

P

Plateletneutralizationprocedure

P

Dilute vipervenom screen P

Anticardiolipinantibody S

IgG

IgM

Antithrombin III P

Antigenic

Functional

Anti-Xa assay(heparin assay) P

Unfractionatedheparin

Low-molecular-weight heparin

Danaparoid(Orgaran)

Autohemolysistest WB

Autohemolysistest with glucose WB

Bleeding time(adult)

Bone marrow:See Table 7

Clot retraction WB

Cryofibrinogen P

D-dimer P

Differential blood Relative counts:

count Neutrophils Bands Lymphocytes Monocytes Eosinophils Basophils Absolute counts:

Neutrophils

Bands

Lymphocytes

Monocytes

Eosinophils

Basophils WB

Erythrocyte count WB

Adult males

Adult females

Erythrocyte lifespan WB

Normal survival Chromiumlabeled, half-life(t1/2)

Erythrocytesedimentationrate

WB

Females Males Euglobulin lysistime P

Factor II,prothrombin P

Factor V PFactor VII PFactor VIII PFactor IX PFactor X PFactor XI PFactor XII P

Factor XIII screen P

Factor inhibitorassay P

Fibrin(ogen)degradationproducts

P

Fibrinogen P

Glucose-6-phosphatedehydrogenase(erythrocyte)

WB

Ham's test (acidserum) WB

Hematocrit WB

Adult males

Adult females

Hemoglobin Plasma P Whole blood: WB

Adult males

Adult females

Hemoglobinelectrophoresis WB

Hemoglobin A

Hemoglobin A2

Hemoglobin F Hemoglobinsother than A, A2,or F

Heparin-inducedthrombocytopeniaantibody

P

Immature plateletfraction (IPF) WB

Joint fluid crystal JF

Joint fluid mucin JFLeukocytes Alkalinephosphatase(LAP)

WB

Count (WBC) WB

Mean corpuscularhemoglobin(MCH)

WB

Mean corpuscularhemoglobinconcentration(MCHC)

WB

Mean corpuscularhemoglobin ofreticulocytes (CH)

WB

Mean corpuscularvolume (MCV) WB

Mean plateletvolume (MPV) WB

Osmotic fragilityof erythrocytes WB

Direct

Indirect

Partial

thromboplastintime, activated

PPlasminogen p

Antigen

Functional Plasminogenactivator inhibitor1

P

Plateletaggregation PRP

Platelet count WB

Platelet, meanvolume WB

Prekallikreinassay P

Prekallikreinscreen P

Protein C P Total antigen

Functional Protein S P Total antigen Functional Free antigen P Prothrombin genemutationG20210A

WB

Prothrombin time P

Protoporphyrin,free erythrocyte WB

Red celldistribution width WB

Reptilase time PReticulocytecount WB

Adult males

Adult females

Reticulocytehemoglobincontent

WB

Ristocetincofactor(functional von P

Willebrand factor) Blood group O

Blood group A

Blood group B

Blood group AB P

Serotonin releaseassay S

Sickle cell test WBSucrosehemolysis WB

Thrombin time P

Total eosinophils WB

Transferrinreceptor S, P

Viscosity P Plasma p Serum Svon Willebrandfactor (vWF)antigen (factorVIII:R antigen)

Blood group O

Blood group A

Blood group B

Blood group AB P

von Willebrandfactor multimers P

White blood cells:see "Leukocytes"

Abbreviations:JF, joint fluid; P, plasma; PRP, platelet-rich plasma; S, serum; WB, whole blood.

Table 2 Clinical Chemistry and Immunology

Analyte Specimen*

SI Units

Acetoacetate P 49–294 Adrenocorticotropin(ACTH)

P 1.3–16.7 pmol/L

Alanineaminotransferase (ALT,SGPT)

S 0.12–0.70

Albumin S 40–50 g/LAldolase S 26–138 nkat/LAldosterone (adult) Supine, normal sodiumdiet

S, P <443 pmol/L

Upright, normal S, P 111–858 pmol/LAlpha fetoprotein (adult) S 0–8.5 Alpha1 antitrypsin

S 1.0–2.0 g/L

Ammonia, as NH3

P 11–35

Amylase (methodS 0.34–1.6

dependent)Androstendione (adult) S Males 0.81–3.1 nmol/L Females Premenopausal 0.91–7.5 nmol/L Postmenopausal 0.46–2.9 nmol/LAngiotensin-convertingenzyme (ACE)

S 0.15–1.1

Anion gap S 7–16 mmol/LApolipoprotein A-1

Male

Female

S0.94–1.78 g/L

1.01–1.99 g/L

Apolipoprotein B

Male

Female

S0.55–1.40 g/L

0.55–1.25 g/L

Arterial blood gases

[HCO3–]

PCO2 WB

22–30 mmol/L

4.3–6.0 kPa

pH

PO2

7.35–7.45

9.6–13.8 kPa

Aspartateaminotransferase (AST,SGOT)

S 0.20–0.65

Autoantibodies

Anti-centromereantibody IgG

Anti-double-strand(native) DNA

Anti-glomerularbasement membraneantibodies

Qualitative IgG, IgA

Quantitative IgGantibody

Anti-histone antibodies

Anti-Jo-1 antibody

Anti-mitochondrial

29 AU/mL

<25 IU/L

Negative

19 AU/mL

<1.0 U

>29 AU/mL

Not applicable

antibody

Anti-neutrophilcytoplasmicautoantibodies

Serine proteinase 3antibodies

Myeloperoxidaseantibodies

Antinuclear antibody

Anti-parietal cellantibody

Anti-RNP antibody

Anti-Scl 70 antibody

Anti-Smith antibody

Anti–smooth muscleantibody

Anti-SSA antibody

Anti-SSB antibody

S

Not applicable

>19 AU/mL

>19 AU/mL

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

<40 KIU/L

<35 KIU/L

Anti-thyroglobulinantibody

Anti-thyroid peroxidaseantibodyB-type natriureticpeptide (BNP)

PAge and gender specific:<100 ng/L

Bence Jones protein,serum qualitative

S Not applicable

Bence Jones protein,serum quantitative

Free kappa

Free lambda

K/L ratio

S

3.3–19.4 mg/L

5.7–26.3 mg/L

0.26–1.65

Beta-2-microglobulin S 1.1–2.4 mg/LBilirubin

Total

Direct

Indirect

S

5.1–22

1.7–6.8

3.4–15.2

C peptide S 0.27–1.19 nmol/L

C1-esterase-inhibitorprotein

S 210–390 mg/L

CA 125 S <35 kU/LCA 19-9 S <37 kU/LCA 15-3 S <33 kU/LCA 27-29 S 0–40 kU/LCalcitonin

Male

Female

S0–7.5 ng/L

0–5.1 ng/L

Calcium S 2.2–2.6 mmol/LCalcium, ionized WB 1.12–1.32 mmol/LCarbon dioxide content(TCO2)

P (sealevel)

22–30 mmol/L

Carboxyhemoglobin(carbon monoxidecontent)

Nonsmokers

SmokersWB

0.0–0.015

0.04–0.09

>0.50

Loss of consciousnessand deathCarcinoembryonicantigen (CEA)

Nonsmokers

Smokers

S0.0–3.0

0.0–5.0

Ceruloplasmin S 250–630 mg/LChloride S 102–109 mmol/LCholesterol: see Table 5 Cholinesterase S 5–12 kU/LChromogranin A S 0–50 Complement

C3

C4

Complement total

S

0.83–1.77 g/L

0.16–0.47 g/L

60–144 CAE units

Cortisol

Fasting, 8 A.M.–12noon

S

138–690 nmol/L

138–414 nmol/L

12 noon–8 P.M.

8 P.M.–8 A.M.

0–276 nmol/L

C-reactive protein S <10 mg/L

C-reactive protein, highsensitivity

S

Cardiac risk

Low: <1.0 mg/L

Average: 1.0–3.0 mg/L

High: >3.0 mg/L

Creatine kinase (total)

Females

Males

S0.66–4.0

0.87 5.0

Creatine kinase-MB

Mass

Fraction of total activity(by electrophoresis)

S0.0–5.5

0–0.04

Creatinine

Female

Male

S44–80

53>106

Cryoglobulins S Not applicableCystatin C S 0.5–1.0 mg/LDehydroepiandrosterone(DHEA) (adult)

Male

Female

S6.2–43.4 nmol/L

4.5–34.0 nmol/L

Dehydroepiandrosterone(DHEA) sulfate

Male (adult)

Female (adult,premenopausal)

Female (adult,postmenopausal)

S

100–6190

120–5350

300–2600

11-Deoxycortisol (adult)(compound S)

S 0.34–4.56 nmol/L

Dihydrotestosterone

Male

Female

S, P1.03–2.92 nmol/L

0.14–0.76 nmol/L

Dopamine P 0–130 pmol/LEpinephrine

Supine (30 min)

Sitting

Standing (30 min)

P

<273 pmol/L

<328 pmol/L

<491pmol/L

Erythropoietin S 4–27 U/LEstradiol

Female

Menstruating:

Follicular phase

Midcycle peak

Luteal phase

Postmenopausal

Male

S, P

74–532 pmol/L

411–1626 pmol/L

74–885 pmol/L

217 pmol/L

74 pmol/L

Estrone

Female<555 pmol/L

Menstruating:

Follicular phase

Luteal phase

Postmenopausal

Male

S, P<740 pmol/L

11–118 pmol/L

33–133 pmol/L

Fatty acids, free(nonesterified)

P 0.1–0.6 mmol/L

Ferritin

Female

Male

S10–150

29 248

Follicle-stimulatinghormone (FSH)

Female

Menstruating

Follicular phase

Ovulatory phase

Luteal phase

S, P

3.0–20.0 IU/L

9.0–26.0 IU/L

1.0–12.0 IU/L

18.0–153.0 IU/L

1.0–12.0 IU/L

Postmenopausal

MaleFructosamine S <285 umol/LGammaglutamyltransferase

S 0.15–0.99

Gastrin S <100 ng/LGlucagon P 40–130 ng/L

Glucose

Glucose (fasting)

Normal

Increased risk fordiabetes

Diabetes mellitus

WB

P

3.6–5.3 mmol/L

4.2–5.6 mmol/L

5.6–6.9 mmol/L

Fasting >7.0 mmol/L

A 2-hour level of >11.1mmol/L during an oralglucose tolerance test

A random glucose level of>11.1 mmol/L in patientswith symptoms ofhyperglycemia

Growth hormone S 0–5

Hemoglobin Alc

Pre-diabetes

Diabetes mellitus

WB

0.04–0.06 HgB fraction

0.057-0.064 HgB fraction

A hemoglobin A>0.065 Hgb fraction assuggested by the AmericanDiabetes Association

Hemoglobin A1c withestimated averageglucose (eAg)

WBeAg mmoL/L = 1.592.59

High-density lipoprotein(HDL) (see Table 5)

Homocysteine P 4.4–10.8 Human chorionicgonadotropin (HCG)

Nonpregnant female

1–2 weekspostconception

2–3 weekspostconception

<5 IU/L

9–130 IU/L

75–2600 IU/L

850–20,800 IU/L

3–4 weekspostconception

4–5 weekspostconception

5–10 weekspostconception

10–14 weeks postconception

Second trimester

Third trimester

S4000–100,200 IU/L

11,500–289,000 IU/L

18,300–137,000 IU/L

1400–53,000 IU/L

940–60,000 IU/L

>-Hydroxybutyrate P 60–170 17-Hydroxyprogesterone(adult)

Male

Female

Follicular phase

Luteal phase

S

<4.17 nmol/L

0.45–2.1 nmol/L

1.05–8.7 nmol/L

Immunofixation S Not applicable

Immunoglobulin,quantitation (adult)

IgA

IgD

IgE

IgG

IgG1

IgG2

IgG3

IgG4

IgM

S

S

S

S

S

S

S

S

S

0.70–3.50 g/L

0–140 mg/L

1–87 KIU/L

7.0–17.0 g/L

2.7–17.4 g/L

0.3–6.3 g/L

0.13–3.2 g/L

0.11–6.2 g/L

0.50–3.0 g/L

Insulin S, P 14.35–143.5 pmol/LIron S 7–25 Iron-binding capacity S 45–73 Iron-binding capacitysaturation

S 0.16–0.35

Ischemia modifiedalbumin

S <85 KU/L

Joint fluid crystal JF Not applicableJoint fluid mucin JF Not applicableKetone (acetone) S Negative

LactateP, arterial

P, venous

0.5–1.6 mmol/L

0.5–2.2 mmol/L

Lactate dehydrogenase S 2.0–3.8 Lipase S 0.51–0.73 Lipids: see Table 5 Lipoprotein (a) S 0–300 mg/LLow-density lipoprotein(LDL) (see Table 5)

Luteinizing hormone(LH)

Female

Menstruating

Follicular phase

Ovulatory phase

Luteal phase

S, P

2.0–15.0 U/L

22.0–105.0 U/L

0.6–19.0 U/L

16.0–64.0 U/L

2.0–12.0 U/L

Postmenopausal

MaleMagnesium S 0.62–0.95 mmol/L

Metanephrine P<0.5 nmol/L

<100 pg/mL

Methemoglobin WB 0.0–0.01Myoglobin

Male

Female

S20>71

25>58

Norepinephrine

Supine (30 min)

Sitting

Standing (30 min)

P

650–2423 pmol/L

709–4019 pmol/L

739–4137 pmol/L

N-telopeptide (cross-linked), NTx

Female, premenopausal

MaleS

6.2–19.0 nmol BCE

5.4–24.2 nmol BCE

BCE = bone collagenequivalent

NT-Pro BNP S, P<125 ng/L up to 75 years

<450 ng/L >75 years

5> Nucleotidase S 0.00–0.19

Osmolality P275–295 mOsmol/kg serumwater

Osteocalcin S 11–50 Oxygen content

Arterial (sea level)

Venous (sea level)

WB17–21

10–16

Oxygen saturation (sealevel)

Arterial

Venous, arm

WB

Fraction:

0.94–1.0

0.60–0.85

Parathyroid hormone(intact)

S 8–51 ng/L

Phosphatase, alkaline S 0.56–1.63 Phosphorus, inorganic S 0.81–1.4 mmol/LPotassium S 3.5–5.0 mmol/LPrealbumin S 170–340 mg/LProcalcitonin S <0.1 Progesterone

Female: Follicular

Midluteal

Male

S, P

<3.18 nmol/L

9.54–63.6 nmol/L

<3.18 nmol/L

Prolactin

Male

Female

S53–360 mIU/L

40–530 mIU/L

Prostate-specific antigen(PSA)

S 0.0–4.0

Prostate-specific

With total PSA between 4 and10 g/L and when the freePSA is:

>0.25 decreased risk of

antigen, free S prostate cancer

<0.10 increased risk ofprostate cancer

Protein fractions:

Albumin

Globulin

Alpha1

Alpha2

Beta

Gamma

S

35–55 g/L

20–35 g/L

2–4 g/L

5–9 g/L

6–11 g/L

7–17 g/L

Protein, total S 67–86 g/LPyruvate P 40–130 Rheumatoid factor S <15 kIU/LSerotonin WB 0.28–1.14 umol/LSerum proteinelectrophoresis

S Not applicable

Sex hormone–binding

globulin (adult)

Male

Female

S 11–80 nmol/L

30–135 nmol/L

Sodium S 136–146 mmol/LSomatomedin-C (IGF-1)(adult)

16 years

17 years

18 years

19 years

20 years

S

226–903

193–731

163–584

141–483

127–424

21–25 years

26–30 years

31–35 years

36–40 years

41–45 years

46–50 years

116–358

117–329

115–307

119–204

101–267

94–252

51–55 years

56–60 years

61–65 years

66–70 years

71–75 years

76–80 years

81–85 years

87–238

81–225

75–212

69–200

64–188

59–177

55–166

Somatostatin P <25 ng/LTestosterone, free

Female, adult

Male, adult

S10.4–65.9 pmol/L

312–1041 pmol/L

Testosterone, total,

Female

Male

S0.21–2.98 nmol/L

9.36–37.10 nmol/L

Thyroglobulin S 1.3>31.8Thyroid-binding globulin S 13–30 mg/L

Thyroid-stimulatinghormone

S 0.34–4.25 mIU/L

Thyroxine, free (fT4) S 9.0–16 pmol/LThyroxine, total (T4) S 70–151 nmol/LThyroxine index (free) S 6.7–10.9Transferrin S 2.0–4.0 g/LTriglycerides (see Table5)

S 0.34–2.26 mmol/L

Triiodothyronine, free(fT3)

S 3.7–6.5 pmol/L

Triiodothyronine, total(T3)

S 1.2–2.1 nmol/L

Troponin I (methoddependent)

99th percentile of ahealthy population

S,P 0–0.04

Troponin T

99th percentile of ahealthy population

S,P 0–0.01

Urea nitrogen S 2.5–7.1 mmol/LUric acid

Females

MalesS

0.15–0.33 mmol/L

0.18–0.41 mmol/L

Vasoactive intestinalpolypeptide

P 0–60 ng/L

Zinc protoporphyrin WB 0–400 Zinc protoporphyrin(ZPP)-to-heme ratio

WB 0–69

Abbreviations:P, plasma; S, serum; WB, whole blood.

Table 3 Toxicology and Therapeutic Drug Monitoring

Therapeutic

Range

Drug SI Units

Acetaminophen66–199mol/L

Amikacin

Peak

Trough

34–51 mol/L

0–17 mol/L

Amitriptyline/nortriptyline(total drug)

430–900nmol/L

Amphetamine150–220nmol/L

Bromide

Mild toxicity

Severe toxicity

Lethal

9.4–18.7mmol/L

Caffeine25.8–103mol/L

Carbamazepine 17–42 mol/LChloramphenicol

Peak31–62 mol/L

15–31 mol/L

Trough

Chlordiazepoxide 1.7–10 mol/L

Clonazepam32–240nmol/L

Clozapine0.6–2.1mol/L

Cocaine

Codeine43–110nmol/mL

Cyclosporine

Renal transplant

0–6 months

6–12 months aftertransplant

>12 months

Cardiac transplant

0–6 months

6–12 months aftertransplant

208–312nmol/L

166–250nmol/L

83–125nmol/L

208–291nmol/L

125–208nmol/L

83–125

>12 months nmol/L

Lung transplant 0–6months

Liver transplant

Initiation

Maintenance

250–374nmol/L

208–291nmol/L

83–166nmol/L

Desipramine375–1130nmol/L

Diazepam (and metabolite)

Diazepam

Nordiazepam

0.7 –3.5 mol/L

0.4– 6.6 mol/L

Digoxin0.64–2.6nmol/L

Disopyramide5.3–14.7mol/L

Doxepin and nordoxepin

Doxepin

0.36–0.98 mol/L

0.38–1.04

Nordoxepin mol/L

Ethanol

Behavioral changes

Legal limit

Critical with acute exposure

Ethylene glycol

Toxic

Lethal

Ethosuximide280–700mol/L

Everolimus3.13–8.35nmol/L

Flecainide0.5–2.4mol/L

Gentamicin

Peak

Trough

10>21mol/mL

0>4.2mol/mL

Heroin (diacetyl morphine)

Ibuprofen49–243mol/L

Imipramine (and metabolite)

Desimipramine

Total imipramine +desimipramine

375–1130nmol/L

563–1130nmol/L

Lamotrigine11.7–54.7mol/L

Lidocaine5.1–21.3 mol/L

Lithium0.5–1.3mmol/L

Methadone1.0–3.2mol/L

Methamphetamine0.07–0.34mol/L

Methanol

Methotrexate 0.01–0.1

Low-dose

High-dose (24h)

High-dose (48h)

High-dose (72h)

mol/L

<5.0 mol/L

<0.50 mol/L

<0.10 mol/L

Morphine232–286mol/L

Mycophenolic acid3.1–10.9mol/L

Nitroprusside (asthiocyanate)

103–499mol/L

Nortriptyline190–569nmol/L

Phenobarbital65–172mol/L

Phenytoin 40–79 mol/L

Phenytoin, free

% Free

4.0–7.9 g/mL

0.08–0.14

Primidone and metabolite

Primidone

Phenobarbital

23–55 mol/L

65–172 mol/L

Procainamide

Procainamide

NAPA (N-acetylprocainamide)

17–42 mol/L

22–72 mol/L

Quinidine6.2–15.4mol/L

Salicylates145–2100mol/L

Sirolimus (trough level)Kidney transplant

4.4–15.4nmol/L

Tacrolimus (FK506) (trough) Kidney and liver

Initiation

Maintenance

Heart

12–19 nmol/L

6–12 nmol/L

19–25 nmol/L

Initiation

Maintenance

6–12 nmol/L

Theophylline56–111g/mL

Thiocyanate

After nitroprusside infusion

Nonsmoker

Smoker

103–499 mol/L

17–69 mol/L

52–206 mol/L

Tobramycin

Peak

Trough

11–22 g/L

0–4.3 g/L

Valproic acid346–693mol/L

Vancomycin

Peak

Trough

14–28 mol/L

3.5–10.4mol/L

Table 4 Vitamins and Selected Trace Minerals

Specimen Analyte

Aluminum SArsenic WBCadmium WBCoenzyme Q10 (ubiquinone) P-Carotene S

Copper SFolic acid RCFolic acid SLead (adult) SMercury WBSelenium SVitamin A SVitamin B1 (thiamine) SVitamin B2 (riboflavin) SVitamin B6 P

Vitamin B12 SVitamin C (ascorbic acid) SVitamin D3,1,25-dihydroxy, total S, PVitamin D3,25-hydroxy, total PVitamin E SVitamin K SZinc S

Abbreviations: P, plasma; RC, red cells; S, serum; WB, whole blood.

Table 5 Classification of LDL, Total, and HDL Cholesterol

LDL Cholesterol <70 mg/dL Therapeutic option for very high risk patients<100 mg/dL Optimal100–129 mg/dL Near optimal/above optimal130–159 mg/dL Borderline high160–189 mg/dL High190 mg/dL Very high

Total Cholesterol <200 mg/dL Desirable200–239 mg/dL Borderline high240 mg/dL High

HDL Cholesterol <40 mg/dL Low60 mg/dL High

Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein. summary of the third report of the National Cholesterol Education Program (NCEP) expertpanel on detection, evaluation, and treatment of high blood cholesterol in adults (adulttreatment panel III). JAMA 2001; 285:2486–97. Implications of Recent National Cholesterol Education Program Adult for the Coordinating Committee of the National Cholesterol Education Program: Circulation110:227, 2004.

REFERENCE VALUES FOR SPECIFICANALYTES

Table 6 Cerebrospinal Fluida

Reference Range

Constituent SI UnitsConventionalUnits

Osmolarity 292–297 mmol/kg water292–297mOsm/L

Electrolytes

Sodium 137–145 mmol/L137–145meq/L

Potassium 2.7–3.9 mmol/L2.7–3.9meq/L

Calcium 1.0–1.5 mmol/L2.1–3.0meq/L

Magnesium 1.0–1.2 mmol/L2.0–2.5meq/L

Chloride 116–122 mmol/L116–122meq/L

CO2 content

20–24 mmol/L20–24meq/L

PCO2

6–7 kPa45–49mmHg

pH 7.31–7.34

Glucose 2.22–3.89 mmol/L 40–70mg/dL

Lactate 1–2 mmol/L10–20mg/dL

Total protein:

Lumbar 0.15–0.5 g/L15–50mg/dL

Cisternal 0.15–0.25 g/L15–25mg/dL

Ventricular 0.06–0.15 g/L 6–15 mg/dL

Albumin 0.066–0.442 g/L6.6–44.2mg/dL

IgG 0.009–0.057 g/L0.9–5.7mg/dL

IgG indexb

0.29–0.59

Oligoclonalbands (OGB)

<2 bands not present inmatched serum sample

Ammonia 15–47 mol/L 25–80

Creatinine 44–168 mol/L0.5–1.9mg/dL

Myelin basic <4 g/L

protein

CSF pressure 50–180mmH

CSF volume(adult)

150 mL

Red blood cells 0 0Leukocytes

Total0–5 mononuclear cellsper L

Differential Lymphocytes 60–70% Monocytes 30–50% Neutrophils None

aSince cerebrospinal fluid concentrations are equilibriumvalues, measurements of the same parameters inblood plasma obtained at the same time arerecommended. However, there is a time lag inattainment of equilibrium, and cerebrospinal levels ofplasma constituents that can fluctuate rapidly

plasma glucose) may not achieve stable values untilafter a significant lag phase. bIgG index = CSF IgG(mg/dL) x serum albumin (g/dL)/serum IgG (g/dL) CSF albumin (mg/dL).

Table 7a Differential Nucleated CellCountsof Bone MarrowAspiratesa(See Chaps. 57, e17)

ObservedRange (%)

95%Range(%)

Blast cells 0–3.2 0–3.0Promyelocytes 3.6–13.2 3.2–12.4Neutrophilmyelocytes

4–21.4 3.7–10.0

Eosinophil myelocytes 0–5.0 0–2.8Metamyelocytes 1–7.0 2.3–5.9Neutrophils

Males21.0–45.6

29.6–46.6

21.9–42.3

28.8–45.9

FemalesEosinophils 0.4–4.2 0.3–4.2Eosinophils pluseosinophil myelocytes

0.9–7.4 0.7–6.3

Basophils 0–0.8 0–0.4Erythroblasts

Male

Females

18.0–39.4

14.0–31.8

16.2–40.1

13.0–32.0

Lymphocytes 4.6–22.6 6.0–20.0Plasma cells 0–1.4 0–1.2Monocytes 0–3.2 0–2.6Macrophages 0–1.8 0–1.3M:E ratio

Males

Females

1.1–4.0

1.6–5.4

1.1–4.1

1.6–5.2

aBased on bone marrow aspirate from 50 healthyvolunteers (30 men, 20 women).

Abbreviation: M:E, myeloid to erythroid ratio.

Source: BJ Bain: Br J Haematol 94:206, 1996.

Table 7b Bone Marrow Cellularity

AgeObservedRange

95%Range

Under 10years

59.0–95.1% 72.9–84.7%

10–19 years 41.5–86.6% 59.2–69.4%20–29 years 32.0–83.7% 54.1–61.9%30–39 years 30.3–81.3% 41.1–54.1%40–49 years 16.3–75.1% 43.5–52.9%50–59 years 19.7–73.6% 41.2–51.4%60–69 years 16.3–65.7% 40.8–50.6%70–79 years 11.3–47.1% 22.6–35.2%

Source: From RJ Hartsock et al: Am J Clin Pathol1965; 43:326, 1965.

Table 8 Stool Analysis

ReferenceRange

SI UnitsConventionalUnits

Alpha-1-antitrypsin

>540 mg/L >54 mg/dL

Amount 0.1–0.2 kg/d 100–200 g/24 h

Coproporphyrin611–1832nmol/d

400–1200 h

Fat

Adult

Adult on fat-freediet

<7 g/d

<4 g/d

Fatty acids 0–21 mmol/d 0–6 g/24 hLeukocytes None NoneNitrogen <178 mmol/d <2.5 g/24 hpH 7.0–7.5 Potassium 14–102 mmol/L 14–102 mmol/L

Occult blood Negative Negative

Osmolality280–325mOsm

280–325 mOsm

Sodium 7–72 mmol/L 7–72 mmol/LTrypsin 20–95 U/gUrobilinogen 85–510 mol/d 50–300 mg/24 hUroporphyrins 12–48 nmol/d 10–40 Water <0.75 <75%

Source: Modified from: FT Fishbach, MB Dunning III: Manual of Laboratory and Diagnostic Tests, 7th ed.Philadelphia, Lippincott Williams & Wilkins, 2004.

Table 9 Urine Analysis and RenalFunction Tests

ReferenceRange

SI UnitsConventionalUnits

Acidity, titratable 20–40mmol/d

20–40 meq/d

Aldosterone

Normal diet:6–25 g/d

Low-salt diet:17–44 g/d

High-salt diet:0–6 g/d

Normal diet:6–25

Low-salt diet:17–44

High-salt diet:0–6

Aluminum0.19–1.11mol/L

5–30

Ammonia30–50mmol/d

30–50 meq/d

Amylase 4–400 U/LAmylase/creatinineclearance ratio[(Clam/Clcr) x 100]

1–5 1–5

Arsenic0.07–0.67mol/d

5–50

Bence Jones protein,urine, qualitative

Not applicable None detected

Bence Jones protein,urine, quantitative

Free Kappa

Free Lambda

K/L ratio

1.4–24.2mg/L

0.2–6.7 mg/L

2.04–10.37

0.14–2.42mg/dL

0.02–0.67mg/dL

2.04–10.37

Calcium (10 meq/d or200 mg/d dietarycalcium)

<7.5 mmol/d <300 mg/d

Chloride140–250mmol/d

140–250mmol/d

Citrate320–1240mg/d

320–1240mg/d

Copper <0.95 mol/d <60

Coproporphyrins(types I and III)

0–20mol/mol

creatinine

0–20mol/mol

creatinine

Cortisol, free55–193nmol/d

20–70

Creatine, as creatinine

Female<760 mol/d

<380 mol/d

<100 mg/d

<50 mg/d

Male

Creatinine8.8–14mmol/d

1.0–1.6 g/d

Dopamine392–2876nmol/d

60–440

Eosinophils<100eosinophils/mL

<100eosinophils/mL

Epinephrine0–109nmol/day

0–20

Glomerular filtrationrate

>60mL/min/1.73m2

For AfricanAmericansmultiply theresult by 1.21

>60mL/min/1.73m2

For AfricanAmericansmultiply theresult by 1.21

Glucose (glucoseoxidase method)

0.3–1.7mmol/d

50–300 mg/d

5-Hydroindoleaceticacid [5-HIAA]

0–78.8 mol/d 0–15 mg/d

Hydroxyproline 53>328 mol/d53–328

mol/dIodine, spot urine

WHO classification ofiodine deficiency:

Not iodine deficient

Mild iodine deficiency

Moderate iodinedeficiency

Severe iodinedeficiency

>100 g/L

50–100 g/L

20–49 g/L

<20 g/L

>100

50–100

20–49

<20

Ketone (acetone) Negative Negative17 Ketosteroids 3–12 mg/d 3–12 mg/dMetanephrines

Metanephrine

Normetanephrine

30–350 g/d

50–650 g/d

30–350

50–650

Microalbumin

–Normal

–Microalbuminuria

0.0–0.03 g/d

0.03–0.30 g/d

0–30 mg/d

30–300 mg/d

–Clinical albuminuria >0.3 g/d >300 mg/d

Microalbumin/creatinineratio

–Normal

–Microalbuminuria

–Clinical albuminuria

0–3.4 g/molcreatinine

3.4–34 g/molcreatinine

>34 g/molcreatinine

0–30 creatinine

30–300 creatinine

>300 creatinine

2-Microglobulin

0–160 g/L 0–160

Norepinephrine89–473nmol/d

15–80

N-telopeptide (cross-linked), NTx

–Female,premenopausal

–Female,postmenopausal

–Male

–BCE = bone collagen

17–94 nmolBCE/mmolcreatinine

26–124 nmolBCE/mmolcreatinine

21–83 nmolBCE/mmol

17–94 nmolBCE/mmolcreatinine

26–124 nmolBCE/mmolcreatinine

21–83 nmolBCE/mmol

equivalent creatinine creatinine

Osmolality500–800mOsmol/kgwater

500–800mOsmol/kgwater

Oxalate

–Male

–Female

80–500 mol/d

45–350 mol/d

7–44 mg/d

4–31 mg/d

pH 5.0–9.0 5.0–9.0Phosphate(phosphorus) (varieswith intake)

12.9–42.0mmol/d

400–1300mg/d

Porphobilinogen None NonePotassium (varies withintake)

25–100mmol/d

25–100meq/d

Protein <0.15 g/d <150 mg/d

Protein/creatinine ratio

Male: 15–68mg/g

Female: 10–107 mg/g

Male: 15–68mg/g

Female: 10–107 mg/g

Sediment

–Red blood cells

–White blood cells

–Bacteria

–Crystals

–Bladder cells

–Squamous cells

–Tubular cells

–Broad casts

–Epithelial cell casts

–Granular casts

–Hyaline casts

–Red blood cell casts

–Waxy casts

–White cell casts

0–2/high-power field

0–2/high-power field

None

None

None

None

None

None

None

None

0–5/low-power field

None

None

None

Sodium (varies with 100–260 100–260

intake) mmol/d meq/dSpecific gravity:

– After 12-h fluidrestriction

– After 12-h deliberatewater intake

>1.025

1.003

>1.025

1.003

Tubular reabsorption,phosphorus

0.79–0.94 offiltered load

79–94% offiltered load

Urea nitrogen214–607mmol/d

6–17 g/d

Uric acid (normal diet)1.49–4.76mmol/d

250–800mg/d

Vanillylmandelic acid(VMA)

<30 mol/d <6 mg/d

SPECIAL FUNCTION TESTS

Table 10 Normal Pressures in Heart and Great Vessels

Pressure (mmHg)Right Atrium Meana wave c wave x wave v wave y wave Right Ventricle Peak systolicEnd-diastolicPulmonary Artery MeanPeak systolicEnd-diastolicPulmonary Artery Wedge MeanLeft Atrium Meana wave

v wave Left Ventricle Peak systolicEnd-diastolicBrachial Artery MeanPeak systolicEnd-diastolic

Source: Reproduced from: MJ Kern The Cardiac Catheterization Handbook2003.

Table 11 Circulatory Function Tests

Test

Arteriovenous oxygen difference

Cardiac output (Fick)

Contractility indexes

Max. left ventricular dp/dt (dp/dt)

DP when DP = 5.3 kPa

(40 mmHg) (DP, developed LV pressure)

Mean normalized systolic ejection rate(angiography)

Mean velocity of circumferential fibershortening (angiography)

Ejection fraction: stroke volume/end-diastolic volume (SV/EDV)

End-diastolic volume

End-systolic volume

Left ventricular work

Stroke work index

Left ventricular minute work index

Oxygen consumption indexMaximum oxygen uptake

Pulmonary vascular resistance

Systemic vascular resistance

Source: E Braunwald et al: Heart Disease, 6th ed. Philadelphia, W.B. Saunders Co., 2001.

Table 12 Normal Echocardiographic Reference Limits and PartitionValues in Adults

WomenReferenceRange

MildlyAbnormal

ModeratelyAbnormal

Left ventriculardimensions

Septalthickness, cm

0.6–0.9 1.0–1.2 1.3–1.5

Posterior wallthickness, cm

0.6–0.9 1.0–1.2 1.3–1.5

Diastolicdiameter, cm

3.9–5.3 5.4–5.7 5.8–6.1

Diastolicdiameter/BSA,cm/m2

2.4–3.2 3.3–3.4 3.5–3.7

Diastolicdiameter/height,cm/m

2.5–3.2 3.3–3.4 3.5–3.6

Left ventricularvolumes

Diastolic, mL 56–104 105–117 118–130 Diastolic/BSA,mL/m2

35–75 76–86 87–96

Systolic, mL 19–49 50–59 60–69 Systolic/BSA,mL/m2 12–30 31–36 37–42

Left ventricularmass, 2Dmethod

Mass, g 66–150 151–171 172–182 Mass/BSA,g/m2

44–88 89–100 101–112

Left ventricularfunction

Endocardialfractionalshortening (%)?

27–45 22–26 17–21

Midwallfractionalshortening (%)

15–23 13–14 11–12

Ejectionfraction, 2Dmethod (%)

55 45–54 30–44

Right heartdimensions(cm)

Basal RV

diameter 2.0–2.8 2.9–3.3 3.4–3.8 Mid-RVdiameter

2.7–3.3 3.4–3.7 3.8–4.1

Base-to-apexlength

7.1–7.9 8.0–8.5 8.6–9.1

RVOT diameterabove aorticvalve

2.5–2.9 3.0–3.2 3.3–3.5

RVOT diameterabove pulmonicvalve

1.7–2.3 2.4–2.7 2.8–3.1

Pulmonaryartery diameterbelow pulmonicvalve

1.5–2.1 2.2–2.5 2.6–2.9

Right ventricularsize andfunction in 4-chamber view

Diastolic area,cm2

11–28 29–32 33–37

Systolic area,

cm2

7.5–16 17–19 20–22

Fractional areachange, %

32–60 25–31 18–24

Atrial sizes LA diameter,cm

2.7–3.8 3.9–4.2 4.3–4.6

LAdiameter/BSA,cm/m2

1.5–2.3 2.4–2.6 2.7–2.9

RA minor axis,cm

2.9–4.5 4.6–4.9 5.0–5.4

RA minoraxis/BSA,cm/m2

1.7–2.5 2.6–2.8 2.9–3.1

LA area, cm2

<20 20–30 30–40

LA volume, mL 22–52 53–62 63–72 LA

volume/BSA,mL/m2

16–28 29–33 34–39

Aortic stenosis,classification ofseverity

Aortic jetvelocity, m/s

2.6–2.9 3.0–4.0

Mean gradient,mmHg

<20 20–40

Valve area,cm2

>1.5

1.0–1.5<1.0

Indexed valvearea, cm2/m2

>0.85 0.60–0.85

Velocity ratio >0.50 0.25–0.50Mitral stenosis,classification ofseverity

Valve area,cm2 >1.5 1.0–1.5

Mean gradient,mmHg

<5 5–10

Pulmonaryartery pressure,mmHg

<30 30–50

Aorticregurgitation,indices ofseverity

Vena contractawidth, cm

<0.30 0.30–0.60

Jet width/LVOTwidth, %

<25 25–64

Jet CSA/LVOTCSA, %

<5 5–59

Regurgitantvolume,mL/beat

<30 30–59

Regurgitantfraction, %

<30 30–49

Effectiveregurgitant

<0.10 0.10–0.29

orifice area, cm2

Mitralregurgitation,indices ofseverity

Vena contractawidth, cm

<0.30 0.30–0.69

Regurgitantvolume,mL/beat

<30 30–59

Regurgitantfraction, %

<30 30–49

Effectiveregurgitantorifice area, cm2

<0.20 0.20–0.39

Abbreviations: BSA, body surface area; CSA, cross-sectional area; LA, left atrium; outflow tract; RA, right atrium; RV, right ventricle; RVOT, right ventricular outflow tract; 2D, 2-dimensional.Source: Values adapted from: American Society of Echocardiography, Guidelines and Standards.http://www.asecho.org/i4a/pages/index.cfm?pageid=3317

Table 13 Summary of Values Useful in Pulmonary Physiology

Symbol

Pulmonary Mechanics Spirometry—volume-time curves Forced vital capacity FVC

Forced expiratory volume in 1 sFEV1

FEV1/FVC

FEV1%

Maximal midexpiratory flow rateMMEF (FEF25–75)

Maximal expiratory flow rateMEFR (FEF200–1200)

Spirometry—flow-volume curves

Maximal expiratory flow at 50% ofexpired vital capacity

Vmax 50 (FEF50%)

Maximal expiratory flow at 75% ofexpired vital capacity

Vmax 75 (FEF75%)

Resistance to airflow:

Pulmonary resistanceRL (RL

Airway resistance Raw

Specific conductance SGaw

Pulmonary compliance

Static recoil pressure at total lungcapacity

Pst TLC

Compliance of lungs (static) CL

Compliance of lungs and thorax C(L + T)

Dynamic compliance of 20 breathsper minute

C dyn 20

Maximal static respiratory pressures:

Maximal inspiratory pressure MIP

Maximal expiratory pressure MEP

Lung Volumes Total lung capacity TLCFunctional residual capacity FRCResidual volume RVInspiratory capacity ICExpiratory reserve volume ERVVital capacity VCGas Exchange (Sea Level) Arterial O2 tension

PaO2

Arterial CO2 tension

PaCO2

Arterial O2 saturation

SaO2

Arterial blood pH pH

Arterial bicarbonate HCO3–

Base excess BEDiffusing capacity for carbonmonoxide (single breath)

DLCO

Dead space volumeVD

Physiologic dead space; dead space-tidal volume ratio

VD/VT

Rest

Exercise

Alveolar-arterial difference for O2

P(A –

Source: Based on: AH Morris et al: Clinical Pulmonary Function Testing. A Manual of Uniform LaboratoryProcedures, 2nd ed. Salt Lake City, Utah, Intermountain Thoracic Society, 1984.

Table 14 Gastrointestinal Tests

Results

Test

Absorption tests D-Xylose: after overnight fast, 25 g xylose given in oral aqueoussolution

Urine, collected for following 5 h

Serum, 2 h after dose

Vitamin A: a fasting blood specimen is obtained and 200,000 units ofvitamin A in oil is given orally

Bentiromide test (pancreatic function): 500 mg bentiromide (chymex)orally; p-aminobenzoic acid (PABA) measured Plasma

Urine

Gastric juice Volume 24 h Nocturnal Basal, fasting

Reaction pH Titratable acidity of fasting juice Acid output Basal Females (mean ± 1 SD) Males (mean ± 1 SD) Maximal (after SC histamine acid phosphate, 0.004 mg/kg bodyweight, and preceded by 50 mg promethazine, or after betazole, 1.7mg/kg body weight, or pentagastrin, 6 g/kg body weight) Females (mean ± 1 SD) Males (mean ± 1 SD) Basal acid output/maximal acid output ratioGastrin, serumSecretin test (pancreatic exocrine function): 1 unit/kg body weight, IV Volume (pancreatic juice) in 80 min Bicarbonate concentration Bicarbonate output in 30 min

MISCELLANEOUS

Table 15 Body Fluids and Other Mass Data

Reference Range SI Units

Ascitic fluid: See Chap. 43

Body fluid,

Total volume (lean) ofbody weight

Intracellular

Extracellular

50% (in obese) to70%

0.3–0.4 of bodyweight

0.2–0.3 of bodyweight

Blood Total volume

Males69 mL/kg bodyweight

Females65 mL/kg bodyweight

Plasma volume Males

39 mL/kg bodyweight

Females40 mL/kg bodyweight

Red blood cell volume

Males30 mL/kg bodyweight

Females25 mL/kg bodyweight

Body mass index 18.5–24.9 kg/m

Table 16 Radiation-Derived Units

Quantity Measures Old Unit SI Unit

ActivityRate ofradioactivedecay

curie(Ci)

Disintegrationsper second(dps)

Exposure

Amount ofionizationsproduced indry air by x-rays orgammarays, per unitof mass

roentgen(R)

Coulomb perkilogram(C/kg)

Air kerma

Sum of initialenergies ofchargedparticlesliberated byionizingradiation in

radJoule perkilogram(J/kg)

air, per unitof mass

Absorbeddose

Energydepositedper unit ofmass in amedium, e.g.anorgan/tissue

radJoule perkilogram(J/kg)

Equivalentdose

Energydepositedper unit ofmass in amedium, e.g.anorgan/tissue,weighted toreflecttype(s) ofradiation

remJoule perkilogram(J/kg)

Energydepositedper unit ofmass in a

Effectivedose

referenceindividual,doublyweighted toreflecttype(s) ofradiation andorgan(s)irradiated

remJoule perkilogram(J/kg)

ACKNOWLEDGMENTThe contributions of Drs. Daniel J. Fink,Patrick M. Sluss, James L. Januzzi, and KentB. Lewandrowski to this chapter in previouseditions are gratefully acknowledged. Wealso express our gratitude to Drs. AmudhaPalanisamy and Scott Fink for carefulreview of tables and helpful suggestions.

FURTHER READINGS

Hickman PE, Koerbin G: Methods in Clinical

Chemistry. An accessory work to the fifthedition of Kaplan and Pesce's: ClinicalChemistry: Theory, Analysis, Correlation,5th ed, LA Kaplan, AJ Pesce (eds).Philadelphia, Elsevier Mosby, 2009

Kratz A et al: Case records of theMassachusetts General Hospital. Weeklyclinicopathological exercises. Laboratoryreference values. N Engl J Med 351:1548,2004[PMID: 15470219] [Full Text]

Lehman HP, Henry JB: SI Units, in Henry'sClinical Diagnosis and Management byLaboratory Methods, 21st ed, RCMcPherson, MR Pincus (eds). Philadelphia,Elsevier Saunders, 2007, pp 1404–1418

Pesce MA: Reference ranges for laboratorytests and procedures, in Nelson's Textbookof Pediatrics, 18th ed, RM Klegman et al(eds). Philadelphia, Elsevier Saunders,2007, pp 2943–2949

Copyright © The McGraw-HillCompanies. All rights reserved.

Roberts WL et al: Reference information ofthe clinical laboratory, in Tietz Textbook ofClinical Chemistry and MolecularDiagnostics, 4th ed, CA Burtis et al (eds).Philadelphia, Elsevier Saunders, 2006, pp2251–2318

Note: Large images and tables on this page may printing in landscape mode.

Copyright © The McGraw-Hill Companies. All

Harrison's Online > Chapter e53. The Clinical Laboratory in ModernHealth Care >

THE CLINICALLABORATORY INMODERN HEALTH CARE:INTRODUCTIONModern medicine relies extensivelyon the clinical laboratory as a keycomponent of health care. It isestimated that in current practice, at

least 60–70% of all clinical decisionsrely to some extent on a laboratoryresult. For many diseases, the clinicallaboratory provides essentialdiagnostic information. As anexample, histopathologic analysisprovides basic information abouthistologic type and classification oftumors and their degree of invasioninto adjacent tissues. Microbiologictesting is required to identifyinfectious organisms and determineantibiotic susceptibility. For manycommon diseases, expert groupshave produced standard guidelines

for diagnosis that rely on definedclinical laboratory values, e.g., bloodglucose or hemoglobin A1C levelsform the basis for diagnosis ofdiabetes mellitus; the presence ofspecific serum antibodies is requiredfor diagnosis of many rheumatologicdiseases; and serum levels of cardiacmarkers are a mainstay in diagnosisof acute coronary syndromes.The ever-increasing number andscope of clinical laboratory testsprovides the clinician with a powerfulset of tools but poses the challengeof appropriate selection of clinical

laboratory tests in the most judiciousand cost-effective way to delivereffective patient care.RATIONALE FORPERFORMING CLINICALLABORATORY TESTSDiagnosis of DiseaseOne of the most frequent reasons forperforming clinical laboratory tests to support, confirm, or refute adiagnosis of disease that issuspected based on other sourcessuch as the patient's history, physicalexamination findings, and imagingstudies. The questions that need tobe considered are which clinical

laboratory tests could be of value insupporting, confirming, or excludingthe clinical impression? What is most efficient test-ordering strategy?If a test result is positive, confirm the clinical impression oreven formally establish thediagnosis? If negative, does thatdisprove the clinical suspicion, what further testing or approach isneeded? What are the known of false-positive and false-negativeresults, and how does one these?

Screening for Disease

Another reason for ordering clinicallaboratory tests is screening fordisease in asymptomatic individuals(Chap. 4). Perhaps the mostcommon examples of this are thenewborn screening programs nowbeing used in most developedcountries. Their purpose is to identifynewborns with treatable conditionsfor which early intervention, evenbefore clinical symptoms develop, isknown to be beneficial. Screening ofadults for the presence of diabetesmellitus, renal disease, prostatecancer [by testing serum prostate-

specific antigen (PSA) levels], andcolorectal cancer (by testing foroccult blood in stool) are examples ofwidely used clinical laboratoryscreening procedures that areapplied to apparently healthyindividuals on the basis that earlydiagnosis and intervention in patientswith these diseases leads toimproved long-term outcomes.

DIFFERENCES BETWEENSCREENING TESTS ANDCONFIRMATORY TESTSIt is important to distinguish between

clinical laboratory tests that can used for screening for disease andthose that offer a confirmatory Screening tests are generally lessexpensive and more widely than are confirmatory tests, whichoften require more specializedequipment or testing personnel. As ageneral principle, screening tests aredesigned to identify all subjects whohave the disease of interest, even ifthat means incorrectly labeling somehealthy individuals as possibly havingdisease. Stated more formally, diagnostic sensitivity of screening

tests is maximized and this comes at the expense of reduceddiagnostic specificity. Confirmatorytesting is intended to correctlyseparate those individuals disease from those who do not havedisease.As an example of these principles,when screening for hepatitis C viral(HCV) infection, a common approachis to first test for the presence ofanti-HCV antibodies in a patient'sserum. A positive result generallyindicates either a current infection ora previous infection that the

immune system has successfullycleared. In the latter situation, anti-HCV antibodies may persist and bedetectable for life. However, a smallnumber of patients will have false-positive results in the serologicscreening test for HCV. To resolvethese uncertainties, a positiveserologic screening test should befollowed by confirmatoryidentification of hepatitis C viral RNAusing molecular techniques. Thisconfirmatory testing can provideevidence of current viral infection oridentify patients who are not

infected.

Risk Assessment ofFuture DiseaseAnother reason for clinical laboratorytesting is assessing a patient's risk ofdeveloping disease in the future. Anumber of diseases are associatedwith well-established clinicallaboratory-defined risk factors,which, if present, would indicate theneed for more frequent monitoringfor disease. The need for riskassessment is even clearer if thereare also useful interventions that

decrease the risk of developingdisease. For example,hypercholesterolemia is a well-established risk factor for coronaryartery disease that may be modifiedby pharmacologic intervention (Chap.241). Many genetic mutations areknown to be associated withincreased risk of cancer, such ashereditary mutations in the and BRCA2 genes, which predisposeto breast and/or ovarian cancer.Individuals who are known to carrythese mutations require more vigilantmonitoring for early signs of cancer

and may even opt for prophylacticsurgery in an attempt to preventcancer (Chap. 63). Individuals withfactor V Leiden are at increased riskof developing deep venousthrombosis and may benefit fromprophylactic anticoagulation in theperioperative period. For example,some types of surgery, such as hipreplacement, are accompanied byprolonged immobilization, which isitself an additional risk for deepvenous thrombosis.

Monitoring Disease and

TherapyMany clinical laboratory tests offeruseful information on the progress ofdisease and the response to therapy.As an example, one might considerthe role of viral load measurementsin patients with HIV-1 infection whoare on anti-retroviral agents.According to current Centers forDisease Control (CDC) guidelines, asuccessful anti-retroviral response isdefined by a fall in plasma HIV-1levels of 0.5 log10 copies/mL, and akey goal of treatment is a reductionin the viral load to below the level of

detection, which is typically in therange of 40–75 copies/mL. Otherexamples of the use of clinicallaboratory testing for monitoringdisease include measurement oftumor markers such as PSA,especially following surgical removalof tumors. In this situation, theexpectation is that successfultreatment of a tumor will cause adecrease in the level of the tumormarker. If there is a later increase inthe level of the tumor marker, itsuggests a recurrence of the disease.Finally, the clinical laboratory offers

direct monitoring of levels of sometherapeutic agents such as drugs.This monitoring is important if a drughas a defined therapeuticconcentration range, above is toxic and below which it isineffective. Monitoring of drug in this situation facilitates optimumdosing and avoidance of toxicity.

CRITICAL VALUESClinical laboratories are required toestablish a list of "critical values."These are values of test results thatindicate an immediate risk ofjeopardy to the health or life of thepatient and therefore require communication to the patient'sphysician so that appropriate intervention may be accomplished.Critical values are reportedregardless of whether the test wasordered as a "stat" or routine test.The critical values themselves are

generally created by the clinicallaboratory medical director inconjunction with the medical staff. Arepresentative list of critical values isshown in Table e53–1.

Table e53–1 SelectedExamples of LaboratoryCritical Values

Lessthan

CHEMISTRY

Ammonia

Calcium, ionized, <3mg/dL

Calcium, total <6mg/dL

Carboxyhemoglobin Creatine kinase,total

CO2, total

<11mol/L

Digoxin

Glucose <40mg/dL

Glucose—CSF <40mg/dL

Ketone

Lithium

Magnesium

Methemoglobin

Osmolality <250mmol/L

Phosphorus <1mg/dL

pH <7.1PCO2 <20

mm HgPO2, arterial

<40mm Hg

PO2, capillary

<30mm Hg

Bicarbonate <11mol/L

Potassium <2.7mmol/L

Salicylate

Sodium <120mmol/L

Troponin HEMATOLOGY INR PTT

Hemoglobin <7g/dL

WBCs<1 x109/L

Platelets<50 x109/L

MICROBIOLOGY(any positive result

below is critical)Acid-fast culture orsmear

Blood culture CSF Gramstain/culture

CSF cryptococcalantigen

Malarial smear

Abbreviations: CO2, carbondioxide; CSF, cerebrospinal fluid;INR, international normalized ratio;PCO2, partial pressure of carbon

dioxide; PO2, partial pressure ofoxygen; PTT, partial thromboplastintime; WBCs, white blood cells.

"STAT" ORDERSTests that are ordered as "stat" receivepriority in the clinical laboratory's testingqueue, which means that other patientspecimens may be delayed while a "stat"specimen is analyzed. Ordering a test "stat"should be reserved for situations in which aresult is needed for urgent medical care;this is a judgment that must be made bythe ordering physician. "Stat" testing shouldnot be used merely for convenience ofeither the patient or the health careprovider.

SENSITIVITY ANDSPECIFICITY IN THECLINICAL LABORATORY

The commonly used metrics of a clinicallaboratory test are the diagnosticsensitivity, specificity, and positive andnegative predictive values. These conceptsare discussed in Chap. 3. In the clinicallaboratory, the terms sensitivity andspecificity have alternative meanings thatare applied to tests, and the different usesof these terms may cause confusion.Analytic sensitivity can refer to the lowestdetectable concentration of analyte that canbe measured with some defined certainty,or to the rate of change of signal intensityas analyte concentration changes. As anexample, newer "generations" of laboratoryassays frequently have improved sensitivityover earlier generations, meaning that theycan detect lower concentrations of theanalyte, which is often of value in diseasediagnosis. Analytic specificity refers to theextent to which other substances in the testsystem interfere with measurement of theanalyte of interest. This concept isfrequently applied to immunoassays, in

which a detection antibody may also bindwith compounds that have a similarstructure, e.g., immunoassays for drugsmay show cross-reactivity with drugmetabolites, and immunoassays forsteroids may show cross-reactivity withother steroids of similar structure. Certainchemical assays are also subject tononspecificity. For example, a commonchemical method used to measurecreatinine, the Jaffe reaction, showspositive interference from a number ofother compounds including glucose, certainketones, and cephalosporin antibiotics.Elevated concentrations of bilirubin, freehemoglobin, and the presence of turbidity inplasma or serum specimens may alsointerfere with some assays. The clinicallaboratory should be able to provide adviceabout the presence or magnitude of theseeffects in assays that it performs.

CLINICAL LABORATORY

DIAGNOSTIC PRINCIPLESClinical laboratory diagnosis, like alldiagnosis, is based on disease-relatedchanges from normality.

1. Tissue injury or necrosis allowsleakage of intracellular componentsinto the circulation leading todetectable rises in blood levels ofthese components. Many intracellularmolecules are common across tissuetypes, and are therefore not indicativeof injury to a specific tissue. Otherconstituents are selectively expressedin relatively high concentrations, oreven uniquely present, in certaintissues. Therefore, their presence inthe blood is evidence of injury to thattissue. This principle forms therationale for measurement of bloodlevels of, for example, liver enzymes inevaluating liver disease (Chap. 302),cardiac troponins in acute coronary

syndromes (Chap. 245), andmyoglobulin in muscle injury. Theextent of the rise in blood levels ofthese markers generally correlateswith the extent of tissue damage,although there are exceptions; forexample, liver enzyme levels may fallin end-stage liver disease.

2. An increase in blood levels of someanalytes indicates failure of normalexcretory processes. This principle isdemonstrated by, for example,elevations in conjugated bilirubin thataccompany obstruction of the biliarysystem, by elevations in ammonia thatare seen in advanced or metabolic liverdisease, by rises in creatinine andpotassium levels in renal failure, and byincreases in PCO2 in some pulmonarydiseases.

3. Increases in blood concentration oftissue-specific markers may resultfrom expansion of the total volume of

that tissue. This principle forms thebasis for the use of measurement oflevels of many tumor markers such asPSA (prostate cancer), CA-125(ovarian cancer), CEA (colon cancer),and CA-19-9 (pancreatic cancer). Inpractice, the usefulness of thesemarkers varies according to thedegree to which they are produced bya tumor and by the tumor size. Smallcolon cancers, for example, may notproduce a significant rise in CEA levelswhereas small prostate cancers oftenproduce detectable rises in PSAconcentrations.

4. Disease processes often manifestcharacteristic patterns of coincidentchanges in levels of several analytes.These patterns of change can beunderstood by consideration of theunderlying pathophysiology. Forexample, acute intravascularhemolysis is characterized by a fall inlevels of hemoglobin and haptoglobin

and by a rise in unconjugated bilirubin.In endocrine diseases, there are oftenchanges in concentrations of severalhormones because of disturbance offeedback loops. Primaryhyperthyroidism, as an example, ischaracterized by increases in thyroxine(T4), and by suppression of thyroid-stimulating hormone (TSH). In diabeticketoacidosis caused by insulindeficiency, there are concomitantelevations of plasma glucose, ketones,and frequently, potassium. In responseto the metabolic acidosis, levels ofbicarbonate are typically reduced.

5. Genetic changes underlie manydiseases, both inherited and acquired.In the era of molecular medicine, thereis increasing recognition of thecontribution of hereditary factors tomany common diseases. Often, theepidemiology of common diseasessuch as hypertension is characterizedby a minority of families that have

mutations in recognized genes,whereas in the larger population, thegenetic basis of the same diseasephenotype is unclear. The search forthe genetic factors that contribute tomany common diseases remains atopic of intense research interest. It isnow clear that essentially all tumorshave genetic abnormalities. Althoughthere is an inherited predisposition insome families, most of these geneticchanges are acquired. Identification ofthe genetic abnormalities in canceroffers new tools for clinical laboratorydiagnosis and classification of tumorsin ways that surpass traditionalhistopathology and also offers insightsinto cellular processes that may betargets for treatment.

6. Clinical laboratory results shouldalways be interpreted in the context ofthe patient's history and physicalexamination and any other relevantinformation (e.g., imaging studies);

the clinician should avoid treatinglaboratory results rather than thepatient.

7. Recommended clinical laboratory testschange with time. As new markers ofdisease emerge, they may replaceolder markers, for example,measurement of serum creatinekinase (CK) levels was introduced fordiagnosis of acute myocardialinfarction in the 1980s. Use of thecardiac-specific isoenzyme CK-MBlater became widespread in clinicalpractice. Today, cardiac troponins arereplacing CK (or CK-MB)measurements in recommendedguidelines. Many other assays havefallen out of use as better assays havebecome available. Measurement ofurine 17-ketosteroids (arising fromandrogens) and of urine 17-hydroxycorticosteroids (arising fromglucocorticoids) has been supplantedby immunoassay of specific steroid

hormones. Today, many steroidhormones are measured by massspectrometry, which often providesimproved analytic specificity overimmunoassays. As new tests areintroduced, it is essential that they beevaluated critically before adoption forclinical use. At a minimum,consideration needs to be given toquestions of clinical validation,specimen stability, diagnosticsensitivity and specificity, positive andnegative predictive values, analyticaccuracy and precision, and costs.

REFERENCE RANGESWhen interpreting clinical laboratory results,comparison is usually made to a referencerange (sometimes called a normal range)that defines the values seen in health orconsidered to be desirable for health. Severalcommon methods are used to describereference ranges in the clinical laboratory.

1. For many quantitative clinical laboratorytests, the range of observed valuesseen in a healthy population shows anapproximately Gaussian distribution.The factors that contribute to this rangeinclude the inter- and intraindividualvariation in the concentration of theanalyte, and the analytic imprecision.When there is an approximatelyGaussian distribution of values in thepopulation, the reference range iscommonly defined as being the central95% of the range of distribution ofthose values. Using this method, 2.5%of the population will have a measuredvalue that is below the reference rangefor the analyte, and 2.5% will have avalue that is above the reference range.The fact that 5% of healthy individualswill have a test value that is outside thereference range has importantimplications when ordering multipletests. If N independent tests areperformed on a specimen, then the

probability of at least one result beingoutside the reference range is (1–0.95N). The greater the number oftests that are ordered, even on ahealthy individual, the greater is thelikelihood of finding an abnormal result(Fig. e53-1). If 20 independent testsare performed on a healthy subject, theprobability of having at least oneabnormal result is almost two-thirds.

In some settings, a narrower range ofvalues is considered to be abnormal.For example, current American HeartAssociation guidelines recommend usinga serum level of cardiac troponins thatis greater than the 99th percentile ofvalues found in a healthy population asevidence of acute myocardial infarction.

2. An alternative approach to usingpopulation means and standarddeviations is to define a range ofanalyte values that is judged to beconsistent with health based on expert

consensus opinion. These ranges areoften referred to as decision limits.Examples of reference rangesestablished this way include those fortotal, high-, and low-density cholesterol(Table e53–2). Such ranges maydeviate considerably from those thatwould be established if the analyteconcentrations of the population mean± 2 standard deviations were used as abasis for establishing the referencerange. For example, the "desirable"total cholesterol value according to theNational Cholesterol Education Programis under 200 mg/dL. This value isactually very close to the meanconcentration among U.S. adults; infact, almost one-half of U.S. adultshave a total cholesterol concentrationthat is above the "desirable" range. Ifthe central 95% of cholesterolconcentrations in the population weretaken as the reference range, the upperend of that range would be

approximately 240 mg/dL, well beyondwhat is considered desirable.

Reference ranges may vary with age,gender, ethnic background, andphysiologic state (e.g., pregnancy, high-altitude adaptation). Some examples ofthese are shown in the Appendix. Theexistence of different reference rangesposes challenges for interpretation ofresults. In particular, creatinine standsout as an analyte for whichconventional reference ranges are notalways easy to apply in clinical practice.Plasma levels of creatinine vary withage, gender, and ethnic group. This factmakes it difficult in practice to use asimple reference range for this analytewhen attempting to gauge a patient'srenal function. A large decrease inglomerular filtration rate (GFR) isassociated with slight increases inplasma creatinine within the typicalreference range provided by manylaboratories (Fig. e53-2). A 60-year-

old white woman with a serumcreatinine of 1.00 mg/dL, which is wellwithin the typical reference range, hasan estimated GFR of only 57 mL/minper 1.73m2, whereas the samecreatinine concentration in a 20-year-old African-American male would beconsistent with normal renal function.To better estimate the GFR, which iswidely considered to be the most usefulindex of overall renal function, it hasbecome customary to use equationsthat incorporate plasma creatinine withother parameters. The most widelyused of these equations in currentpractice is the "4-parameter"Modification of Diet in Renal Disease(MDRD) equation that incorporatesplasma creatinine, age, gender, andethnic group (African American or notAfrican American). Recommendedclinical laboratory practice is to reportthe estimated GFR (eGFR) with allcreatinine measurements in adults. This

provides more useful information thanwould a creatinine reference rangealone.

Figure e53-1

Probability of at least one laboratoryresult being abnormal in a healthyindividual as an increasing number ofindependent tests are performed. Thereference range is the central 95% ofvalues measured in a healthy population.

Table e53–2 NationalCholesterol EducationProgram Adult TreatmentPanel III Guidelines forCholesterol

LDL Cholesterol (mg/dL)

Optimal <100Near Optimal/Above Optimal 100–129Borderline High 130–159High 160–189Very High 190Total Cholesterol (mg/dL) Desirable <200Borderline High 200–239High 240HDL Cholesterol (mg/dL) Low <40High 60

Figure e53-2

Relationship between plasma creatinineand estimated glomerular filtration rate(eGFR) using the 4-parameter Modificationof Diet in Renal Disease (MDRD) equation.IDMS, isotope dilution mass spectrometry.

SOURCES OF ERROR INCLINICAL LABORATORYTESTING

Errors can arise at all stages of the testingprocess from specimen collection to resultinterpretation. An error arising at any stagemay adversely affect patient care. In clinicallaboratory practice, it is customary to dividethe testing process into three phases:preanalytic, analytic, and postanalytic.Examples of each type of error are shownin Table e53–3. The most frequent error inthe testing process is specimen mislabeling,which involves a specimen from one patientbeing placed in a container that is labeledwith another patient's name or identifiers.Specimen mislabeling errors may result invery serious consequences for a patient.For example, if a mislabeled specimenresults in erroneous typing of a patient'sblood group followed by transfusion of amismatched unit of blood, the outcomemay be fatal. A mislabeled biopsy specimenmay lead to an erroneous diagnosis andinappropriate therapy for a patient or,alternatively, failure to make a diagnosisand institute appropriate therapy.

Table e53–3 Examples ofPreanalytic, Analytic, andPostanalytic Errors duringthe Laboratory TestingProcess

Preanalytic Sources of Error

Test selection Inappropriate test for the clinical need Lack of clinical usefulness regardless ofpossible results Test order misunderstood or notcommunicatedSpecimen collection Incorrect time of collection Patient not prepared for collection (e.g.,not fasting) Incorrect specimen type (e.g., wrong

anticoagulant, wrong tissue fixative) Use of incorrect specimen container Insufficient specimen collected Contamination of specimen by IV fluids,drugs, or bacteria Specimen mislabeled or unlabeledImportant clinical information not providedDelays in transportation to the lab leadingto alterations in specimen constituents

Analytic Sources of Error Incorrect storage conditions prior toanalysisSpecimen misidentification in thelaboratoryWrong test performedAssay interferencesAssay failure (e.g., assay out of control)Postanalytic Sources of Error Delay in communication of assay resultsResults not communicated to correctperson

Incorrect result communicatedMisinterpretation of result

In addition to errors, many preanalyticfactors can influence clinical laboratoryresults. Posture (i.e., recumbent versusupright), exercise, diet, recently ingestedfood, and use of prescribed or recreationaldrugs including tobacco, alcohol, caffeine,and herbal supplements can influence avariety of analyte concentrations. Afterblood has been collected certain analytesundergo changes in their concentrationduring storage or transportation. Glucoselevels fall as a result of red cell metabolism.Ammonia levels rise as a result of proteinbreakdown. Increasing permeability andbreakdown of red cell membranes leads toincreases in plasma potassium and freehemoglobin levels. Bacterial contaminationcan lead to overgrowth of specimens. Tominimize these precollection alterations,specimens should be processed or

transported to the clinical laboratory assoon as possible after collection. The list ofknown preanalytic variables and theireffects are extensive, and the reader isreferred to the compendium on this subjectby Young (see "Further Readings").POINT-OF-CARE TESTINGThe great majority of tests continue to beperformed in dedicated clinical laboratoryfacilities, but for several decades there hasbeen a trend toward performing point-of-care testing. This has been made possibleby the development of portable analyticdevices, which include single-purposeinstruments such as glucometers andoxygen saturation monitors, andmultifunction instruments that can performa wider variety of analyses, particularly inchemistry and hematology, but also insome areas of microbiology. The use ofthese devices is driven largely by theconvenience offered by faster resultavailability. In some settings such as ruralareas and developing countries there may

not be an easily accessible clinicallaboratory, and in such settings a point-of-care device may be the best or only optionfor testing. However, the per-specimencost of point-of-care testing both in termsof reagents and supplies and of personnel isoften greater than that offered bycentralized testing. There are also concernsabout the adequacy of personnel training toperform point-of-care testing, the quality ofthe results, and the incorporation of resultsinto the medical record.

Home Testing by PatientsOne of the largest markets for point-of-care testing is home testing by patients,which has long been an important elementin the management of patients withdiabetes who monitor their own bloodglucose levels. Over-the-counter kits forhome pregnancy testing have beenavailable for decades. More recently, kitshave become available for home testing ofthe international normalized ratio (INR) or

prothrombin time by patients on oralanticoagulants. Kits are also available forcholesterol monitoring, fecal occult blooddetection, and hemoglobin measurements.This is an area where there is often littleinformation on the quality of testperformance, the accuracy of the results, orthe correct interpretation.

ISSUES SPECIFIC TOGENETIC TESTINGThe principles of genetic medicine in clinicalpractice are discussed in Chaps. 61, 62, and63. Here we will concentrate on issuesrelated to clinical laboratory testing forgenetic disease.

The distinction between genetic testing forinherited versus acquired disorders affectsthe type of tissue that should be obtainedfor analysis. In inherited disorders, allnucleated cells are expected to carry theinherited mutation, and thus white blood

cells or buccal cells (obtained by scrapingthe inside of the cheek) are convenientsources of DNA for clinical laboratorytesting. For prenatal testing of the fetus,chorionic villi or amniocytes are commonlyused. When testing for acquired geneticdisorders such as in tumors, the tissue ofinterest that contains a suspected mutationmust be sampled to obtain suitable geneticmaterial for testing. It is often useful tocompare the tumor DNA with the patient'snormal DNA to identify acquired mutations,for example in testing for microsatelliteinstability in colorectal cancer (Chap. 83).

Informed Consent forGenetic TestingAlthough it is assumed that all clinicallaboratory testing is performed with theconsent of the patient or, in the case ofminors, the parents, there may beregulatory requirements to obtain formalwritten consent for genetic testing. Suchregulations vary between jurisdictions, and

the practicing clinician should be aware ofany local regulations. In some jurisdictionsthere are regulations on the storage anduse of genetic information and on theduration of time for which geneticspecimens may be stored.

For some late-onset genetic diseases, suchas Huntington's disease (Chap. 372),genetic testing allows for a prediction ofwhether a patient will develop the disease inthe future. The degree of certainty that ispossible from this testing surpasses thatassociated with identification of typicaldisease risk factors such as hyperlipidemiaas a risk for future myocardial infarction. Itis important when deciding to undertakepredictive genetic testing that the patientconsiders the broad implications of apositive or negative test result, is madeaware of any support and counseling that isavailable, and understands the implicationsof a result for other family members. Indealing with these issues, geneticcounselors play an important role (Chap.

63). Their expertise includes the ability toexplain genetic disorders at anunderstandable level to patients and theirfamilies, arrange for support services, andprovide genetic risk assessments tomembers of families with genetic disorders.

When testing for genetic disorders, theclinical laboratory will use different analyticapproaches according to the disease ofinterest. Some disorders, such as sickle cellanemia, are caused by single-pointmutations. Testing for these disordersinvolves merely testing for one or a fewmutations in a single gene. Other disorders(e.g., hyperphenylalaninemias) may becaused by numerous mutations in a singlegene, while others (e.g., hereditary breastcancer) may be caused by mutations inmany genes. The number of possiblemutations and genes that underlie a clinicalphenotype affects the cost and timerequired to perform clinical laboratorytesting, and the likelihood of finding adisease-causing mutation.

If a disease phenotype can be caused bymany mutations, a clinical laboratory resultthat is negative should be interpreted withcare. As an example, it is common toscreen healthy pregnant women (and theirpartners) for mutations in the CFTR gene,which is mutated in patients with cysticfibrosis (CF). The goal of this screening is toidentify women who are carriers of a CFTRmutation and therefore at increased risk ofhaving a baby with CF. Because CF is anautosomal recessive disorder, a fetus has a1:4 chance of being affected if both parentsare carriers of disease-causing CFTRmutations. The screening test approachthat is commonly used to identify mutationsin carriers detects 80–85% of all knowndisease-causing CFTR mutations in whitesand up to 97% of mutations amongAshkenazi Jewish people. A negativescreening result therefore does notcompletely eliminate the possibility that awoman (or her partner) actually has amutation. What can be inferred from a

negative test result is that the risk of havinga CF-affected baby has decreasedsignificantly to an extent that depends onher ethnic group and the mutations thatwere examined. The clinical laboratoryshould calculate and report her new risk ofbeing a carrier if the screening result isnegative.

LIMITATIONS TOMOLECULAR GENETICTESTINGGenetic testing has limitations that areoften unique to this field. Results may beinconclusive. For example, a search formutations in a gene that is suspected ofcausing a disease may fail to reveal anyknown disease-causing mutations. Amutation may be discovered that is ofunknown clinical significance. In thissituation, consideration of any change in the

amino acid sequence of the protein maysuggest a biologic effect, e.g., replacementof a charged amino acid by one of theopposite charge or by a neutral amino acid,or replacement of an amino acid by one ofa different size, or replacement of an aminoacid that is conserved across multiplespecies. Further information may beobtained by determining whether themutation is found in healthy individuals.Even with all of these considerations, it isnot uncommon that the biologic significanceof an identified mutation remains uncertain,and further research may be needed toassess its significance.

It is also important to understand thelimitations of the clinical laboratoryapproach used to detect mutations. Large-scale sequencing of DNA remains at thistime an impractical undertaking foranalyzing many genes for both technicaland financial reasons, although there are afew genes for which extensive sequenceanalysis has become the standard of care,

for example, BRCA1 and BRCA2 in assessingthe risk of breast and ovarian cancer inindividuals with a strong family history. Assequencing technologies improve andbecome less expensive, it can be expectedthat these will be more commonly used forboth identifying mutations in patients withgenetic disorders and in screeningasymptomatic individuals at risk of geneticdisease.

Another unique aspect of genetic testing isthe concern that genetic information aboutindividuals may be used to discriminateagainst them by employers or by insurancecompanies. In the United States, theGenetic Information Nondiscrimination Actof 2008 (GINA) prohibits the use of geneticinformation by employers in makingdecisions related to employment, and byhealth insurance companies in issuinginsurance policies or setting premium ratesbased on knowledge of the applicant'sgenetic status. GINA does not coverdisability insurance, long-term care

insurance, or life insurance policies.

Although the focus of public attention hasbeen most closely directed to DNA testing,it should be pointed out that other clinicallaboratory investigations, not usuallythought of as being genetic, may provideimportant genetic information about theperson being tested. For example, serumprotein electrophoresis may reveal α-1antitrypsin deficiency. Measurement ofhemoglobin A1C, commonly used forfollowing diabetes control, may, dependingon the clinical laboratory technology used,reveal a hemoglobin variant such as HbS(sickle cell). Measurement of cholesteroland triglyceride levels may reveal any oneof a number of hereditary disorders. All ofthese constitute types of geneticinformation.

REGULATION OF THECLINICAL LABORATORY

In the United States, all clinical laboratorytesting performed for clinical purposes (butnot for research purposes) is regulated bythe federal Clinical Laboratory ImprovementAmendments Act of 1988 (CLIA). Homemonitoring by patients who are testing theirown specimens is not covered by CLIA. Thestatute and the regulations, which areadministered by the Centers for Medicareand Medicaid Services (CMS), apply to alllaboratories whether they are located in aphysician's office, a large hospital, or areference laboratory; and all laboratoriesare required to hold a valid CLIA certificatethat is appropriate for the complexity levelof testing that is performed. The Food andDrug Administration is responsible forassigning the complexity level ofcommercial tests. The lowest category ofcomplexity is the "waived" category. Inorder of increasing complexity are thecategories of "provider-performedmicroscopy," "moderate complexity," and"high complexity" testing. The clinical

laboratory CLIA certificate must reflect thehighest complexity level of testing that isperformed. The category of provider-performed microscopy is used to covertests such as potassium hydroxide (KOH)preparations on skin scrapings examined forfungi, fern tests, and sperm motility tests. Itdoes not apply to histopathology that fallsinto the high complexity category. It isimportant to note that even if a clinicallaboratory is performing only testing in the"waived" category, it must still hold a validCLIA certificate. Laboratories that holdcertificates for nonwaived tests are requiredto participate in proficiency testing and areregularly inspected to monitor theirperformance.

FURTHER READINGS

BURTIS CA et al: Tietz Textbook of ClinicalChemistry and Molecular Diagnostics, 4thed. St. Louis, Elsevier Saunders, 2006

GILJOHANN DA, MIRKIN CA: Drivers ofbiodiagnostic development. Nature462:461, 2009.[PMID: 19940916] [FullText]

HUDSON KL et al: Keeping pace with thetimes. The Genetic InformationNondiscrimination Act of 2008. N Engl JMed, 358:2661, 2008[PMID: 18565857] [Full Text]

MCPHERSON RA, PINCUS MR: Henry's ClinicalDiagnosis and Management by LaboratoryMethods, 21st ed. Philadelphia, ElsevierSaunders, 2006

THYGESEN K et al: Universal definition ofmyocardial infarction. Circulation116:2634, 2007.[PMID: 17951284] [FullText]

YOUNG DS: Effects of PreanalyticalVariables on Clinical Laboratory Tests, 3rd

Copyright © The McGraw-HillCompanies. All rights reserved.

ed. Washington, DC, AACC Press, 2007