• Allergy & Immunology
    • 1

      Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

      By Steven K. Lundy, PhD; Alison Gizinski, MD; David A. Fox, MD
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      Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

      • STEVEN K. LUNDY, PHDResearch Assistant Professor, Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
      • ALISON GIZINSKI, MDAssistant Professor, Division of Rheumatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
      • DAVID A. FOX, MDProfessor, Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School and Health System, Ann Arbor, MI

      The immune system is a complex network of cells and mediators that must balance the task of protecting the host from invasive threats. From a clinical perspective, many diseases and conditions have an obvious link to improper functioning of the immune system, and insufficient immune responses can lead to uncontrolled acute and chronic infections. The immune system may also be important in tumor surveillance and control, cardiovascular disease, health complications related to obesity, neuromuscular diseases, depression, and dementia. Thus, a working knowledge of the role of immunity in disease processes is becoming increasingly important in almost all aspects of clinical practice. This review provides an overview of the immune response and discusses immune cell populations and major branches of immunity, compartmentalization and specialized immune niches, antigen recognition in innate and adaptive immunity, immune tolerance toward self antigens, inflammation and innate immune responses, adaptive immune responses and helper T (Th) cell subsets, components of the immune response that are important targets of treatment in autoimmune diseases, mechanisms of action of biologics used to treat autoimmune diseases and their approved uses, and mechanisms of other drugs commonly used in the treatment of autoimmune diseases. Figures show the development of erythrocytes, platelets, lymphocytes, and other immune system cells originating from hematopoietic stem cells that first reside in the fetal liver and later migrate to the bone marrow, antigen–major histocompatibility complex recognition by T cell receptor control of T cell survival and activation, and Th cells as central determinants of the adaptive immune response toward different stimuli. Tables list cell populations involved in innate and adaptive immunity, pattern recognition receptors with known ligands, autoantibody-mediated human diseases: examples of pathogenic mechanisms, selected Food and Drug Administration–approved autoimmune disease indications for biologics, and mechanism of action of biologics used to treat autoimmune diseases.

       

      This review contains 3 highly rendered figures, 5 tables, and 64 references.

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    • 2

      Deficiencies of Innate and Adaptive Immunity

      By Soma Jyonouchi, MD; Kathleen E Sullivan, MD, PhD
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      Deficiencies of Innate and Adaptive Immunity

      • SOMA JYONOUCHI, MDInstructor, Department of Pediatrics, Division of Allergy/Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA
      • KATHLEEN E SULLIVAN, MD, PHDProfessor of Pediatrics, University of Pennsylvania School of Medicine, Chief, Division of Allergy/Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA

      Defects in B cell function, T cell function, and innate immunity comprise the majority of primary immune deficiencies. Each compartment has a characteristic set of archetypical features. Defects in B cell function are characterized by poor immunoglobulin production, which, in turn, leads to recurrent sinopulmonary infections. Defects in T cell function are characterized by delayed clearance of viruses, susceptibility to opportunistic infections, and a high rate of autoimmune disease. Defects of innate immunity are typically associated with early-onset, severe infections. This chapter describes defects in immunoglobulin production or function, T cell disorders, defects in Toll-like receptor (TLR) signaling, defects in the interleukin-12 (IL-12)/interferon-gamma signaling pathway, and defects of T helper type 17 (Th17) immunity. Tables outline specific pathogens that should alert the clinician to potential immune deficiency, provide a comparison of immunoglobulin production defects, and describe severe combined immune deficiency types. Figures include schematic representations of the TLR signaling pathway, the IL-12/interferon-gamma signaling pathway, and the Th17 immune response.

      This chapter contains 3 highly rendered figures, 3 tables, 72 references, and 5 MCQs.

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    • 3

      Allergic Response

      By Joud Hajjar, MD; Lawrence B Schwartz, MD, PhD
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      Allergic Response

      • JOUD HAJJAR, MDAllergy and Immunology Fellow, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA
      • LAWRENCE B SCHWARTZ, MD, PHDCharles & Evelyn Thomas Professor of Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA

      This chapter begins with a definition of allergic response and a discussion of the epidemiology of atopic disorders, as well as the development of IgE-mediated hypersensitivity. Subjects covered in a section on humoral and cellular mechanisms of allergic sensitization include antigen-presenting cells and sensitization, T cells, and IgE and IgE receptors. A discussion of mast cells and basophils includes information on mediators, biomarkers, eosinophils, and eosinophil mediators. Therapy of atopic disorders is also discussed. Figures depict inflammatory mechanisms in allergic inflammation, microscopy of a mast cell before and after the introduction of antigen, and mediators released by activated human mast cells. Tables outline selected cytokines and chemokines involved in IgE-mediated allergic inflammation, serum tryptase levels, examples of patterns of serum total tryptase elevations and interpretations, and a summary of therapeutic interventions for allergic diseases.
      This chapter contains 3 highly rendered figures, 4 tables, 84 references, 1 teaching slide set, and 5 MCQs.

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    • 4

      Allergic Rhinitis, Conjunctivitis, and Sinusitis

      By Robert Naclerio, MD
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      Allergic Rhinitis, Conjunctivitis, and Sinusitis

      • ROBERT NACLERIO, MDProfessor and Chief, Department of Surgery, Section of Otolaryngology, Head and Neck Surgery, University of Chicago, Chicago, IL

      Allergic rhinitis is an immunoglobulin E–mediated inflammatory response in the nose to foreign substances known as allergens. Allergic conjunctivitis is the ocular counterpart of allergic rhinitis, and the two often occur together. Sinusitis refers to inflammation of the sinuses, although the term rhinosinusitis is more accurate than the term sinusitis for the following reasons: sinusitis without rhinitis is rare; the mucosa of the nose and sinuses is contiguous, and most sinusitis starts in the lateral wall of the nose; and the symptoms of both entities overlap. This review details the epidemiology, etiology and pathophysiology, diagnosis, differential diagnosis, and management of allergic rhinitis, allergic conjunctivitis, and sinusitis. Figures show the paranasal sinuses, and computed tomography scans show an acute exacerbation of chronic sinusitis, an example of a unilateral right maxillary sinusitis that was caused by a sinus lift prior to a dental implant, a case of allergic fungal sinusitis, and a unilateral nasal polyp and opacification of the left maxillary sinus. Tables list a guideline for primary care physicians seeing a new rhinitis patient, combinations for added-on therapy of allergic rhinitis, considerations to review before applying guidelines for the treatment of allergic rhinitis, factors predisposing to sinusitis, and warning signs on physical examination.

      This review contains 5 highly rendered figures, 5 tables, and 51 references.

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    • 5

      Diagnostic and Therapeutic Principles in Allergy

      By Jonathan Tam, MD; Dorothy S Cheung, MD; Mitchell H. Grayson, MD
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      Diagnostic and Therapeutic Principles in Allergy

      • JONATHAN TAM, MDInstructor, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
      • DOROTHY S CHEUNG, MDAssistant Professor of Pediatrics and Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
      • MITCHELL H. GRAYSON, MDAssociate Professor of Pediatrics, Medicine, Department of Pediatrics, Microbiology and Molecular Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

      By definition, allergy is an untoward physiologic event mediated by immune mechanisms, usually involving the interaction of an allergen with the allergic antibody, immunoglobulin E (IgE). This chapter begins with a brief description of the so-called “hygiene hypothesis,” which posits that greater exposure to infectious agents (bacterial endotoxins in particular) early in life reduces the likelihood of subsequent allergy. A section on the importance of a careful and thorough medical history follows, with a table presenting inhaled aeroallergens that cause rhinitis, conjunctivitis, and asthma. The physical examination of a patient with a suspected allergic illness is reviewed. A section on assays of IgE includes skin testing (i.e., epicutaneous and intradermal testing, with photographs, videos, and a table outlining the time before skin testing to stop antihistamines), serum-specific IgE testing (with a figure illustrating the test), basophil histamine release assay, and the interpretation of IgE test results. A section on treatment discusses environmental control; a table presents concepts on environmental control for allergy management. A discussion of pharmacologic agents begins with a figure illustrating mechanisms of action of medications used in allergic diseases and covers antihistamines and decongestants, anti-IgE therapy with bronchodilators, corticosteroids, inhaled corticosteroid/long-acting bronchodilator combinations, leukotriene antagonists, and theophylline. Information on immunotherapy is also presented.
      This chapter contains 4 highly rendered figures, 4 videos, 3 tables, 28 references, and 5 MCQs.

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    • 6

      Urticaria and Angioedema

      By Justin R Chen, MD; David A. Khan, MD
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      Urticaria and Angioedema

      • JUSTIN R CHEN, MDFellow Physician, Division of Allergy & Immunology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
      • DAVID A. KHAN, MDProfessor of Internal Medicine and Pediatrics, Division of Allergy & Immunology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX

      Urticaria and angioedema are common diseases with diverse origins that constitute a substantial component of medical practice. Urticaria, or hives, refers to one or more areas of intensely pruritic papules or plaques with swelling of the superficial dermis (wheal) surrounded by local erythema (flare). Angioedema refers to deep dermal subcutaneous swelling that may manifest as swelling of the mucosa of the face, tongue, pharynx, larynx, or intestines that can be alarming and, in some cases, life threatening. These conditions are heterogeneous in their presentation and chronicity. Although allergies are responsible for some cases, autoimmunity and dysregulation of the bradykinin system often play a significant role, leading to challenging diagnostic and therapeutic dilemmas. This review discusses the epidemiology, natural history, pathophysiology, diagnosis, and treatment of acute and chronic urticaria and angioedema. Emphasis is placed on physical triggers, the role of proper laboratory testing, and alternative agents for refractory cases. Emerging therapies for hereditary and acquired angioedema syndromes are also covered. Tables list the causes of acute and chronic urticaria, an escalating treatment approach for difficult cases, and a comparison of available parenteral therapies specific to bradykinin-mediated angioedema. Figures illustrate the mechanisms of urticaria, photographs of typical presentations, and an evidence-based diagnostic algorithm for clinicians. 

       

      This review contains 9 highly rendered figures, 5 tables, and 100 references.

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    • 7

      Anaphylaxis

      By Cem Akin, MD, PhD
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      Anaphylaxis

      • CEM AKIN, MD, PHDAssociate Physician, Harvard Medical School, Brigham and Women’s Hospital, Department of Rheumatology, Immunology, and Allergy, Boston, MA

      Anaphylaxis, a serious allergic reaction, is rapid in onset and marked by flushing, urticaria, angioedema, pruritus, bronchospasm, and abdominal cramping with nausea, vomiting, and diarrhea. It is not uncommon; approximate lifetime prevalence of anaphylaxis was estimated to be 0.5 to 2% or possibly higher due to the common academic belief that the incidence of anaphylactic reactions is underreported. Rarely, anaphylaxis may cause death, most commonly from drugs, foods, and insect stings. This review covers the epidemiology, etiology, pathogenesis, diagnosis, clinical manifestations, treatment, and prognosis. Figures show inflammatory pathways in allergic inflammation and mast cell degranulation and pathways of activation. Tables list the diagnostic criteria, selected mast cell activators of possible clinical relevance, signs and symptoms that may be encountered according to tissue site, and common considerations in the differential diagnosis.

      This review contains ­2 highly rendered figures, 4 tables, and 73 references.

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    • 8

      Food Allergies

      By Matthew Greenhawt, MD, MBA, MSc
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      Food Allergies

      • MATTHEW GREENHAWT, MD, MBA, MSCAssistant Professor, Division of Allergy and Clinical Immunology, University of Michigan Medical School, University of Michigan Health System, Ann Arbor, MI

      Food allergy represents a rapidly growing public health problem in the United States and other westernized nations. Adverse reactions to foods are categorized as either immunologic or nonimmunologic reactions. This distinction is highly important but often confusing to patients and physicians unfamiliar with allergy, who may simply describe any adverse reaction to a food as an “allergy.” A food allergy is an immune-mediated, adverse reaction to one or more protein allergens in a particular food item involving recognition of that protein by specifically targeted IgE or allergen-specific T cells. This chapter discusses the definition, pathophysiology, epidemiology, testing, management, prognosis, and natural history of food allergy. Clinical manifestations are systematically covered, including cutaneous, respiratory, cardiovascular, and gastrointestinal reactions, as well as eosinophilic esophagitis, food protein–induced enterocolitis syndrome, and oral allergy syndrome. Emerging treatments such as food oral immunotherapy are also reviewed. Tables outline signs and symptoms of immediate hypersensitivity reactions to food, the prevalence of major food allergens in the United States, common patterns of cross-reactivity among foods, clinical criteria for the diagnosis of anaphylaxis, and clinical studies involving treatment for food allergies. Figures illustrate the classification of adverse reactions to food, esophageal histology, visual and radiographic features of eosinophilic esophagitis, and a food allergy action plan.
      This chapter contains 4 highly rendered figures, 5 tables, 82 references, and 5 MCQs.

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    • 9

      Drug Allergies

      By James L Baldwin, MD; Aimee L. Speck, MD
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      Drug Allergies

      • JAMES L BALDWIN, MDDivision Chief, Division of Allergy and Clinical Immunology, Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI
      • AIMEE L. SPECK, MDFellow, Division of Allergy and Clinical Immunology, University of Michigan School of Medicine, Ann Arbor, MI

      Adverse drug reactions (ADRs) are an important public health problem. An ADR is defined by the World Health Organization as an unintended, noxious response to a drug that occurs at a dose usually tolerated by normal subjects. The classification of ADRs by Rawlins and Thompson divides ADRs into two major subtypes: (1) type A reactions, which are dose dependent and predictable, and (2) type B reactions, which are uncommon and unpredictable. The majority of ADRs are type A reactions, which include four subtypes: overdosage or toxicity, side effects, secondary effects, and interactions. Type B reactions constitute approximately 10 to 15% of all ADRs and include four subtypes: drug intolerance, idiosyncratic reactions, pseudoallergic reactions, and drug hypersensitivity reactions. This chapter reviews the epidemiology of ADRs, risk factors for drug hypersensitivity reactions, the classification of drug reactions, diagnostic tests, reactions to specific drugs, and management of the patient with drug allergy. Figures illustrate drugs as haptens and prohaptens, the Gell and Coombs system, the four basic immunologic mechanisms for drug reactions, the chemical structure of different β-lactam antibiotics, penicillin skin testing, sulfonamide metabolism and haptenation, nonsteroidal antiinflammatory drug effects, and patient management. Tables outline the classification of ADRs, drugs frequently implicated in allergic drug reactions, and reagents and concentrations recommended for prick and intradermal skin testing.

      This review contains 8 highly rendered figures, 3 tables, and 83 references.

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    • 10

      Allergic Reactions to Hymenoptera

      By David B. K. Golden, MD, FACP
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      Allergic Reactions to Hymenoptera

      • DAVID B. K. GOLDEN, MD, FACPAssociate Professor of Medicine, Division of Allergy-Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD

      Allergic reactions to insect venom can occur in individuals of all ages and may be preceded by a number of uneventful stings. These allergic reactions can be fatal. In the United States, at least 40 deaths due to insect stings occur each year; this number may be higher as some unexplained deaths may be caused by insect stings. This review details the epidemiology, etiology, pathogenesis, diagnosis, differential diagnosis, and acute and preventive treatment for allergic reactions to Hymenoptera. Figures show the honeybee, the European hornet, the Eastern yellow jacket, the red imported fire ant, the paper wasp, and the appearance of a pustule resulting from the sting of a fire ant. Tables list the risk of systemic reactions and clinical recommendations based on reaction to previous stings and venom skin test or serum immunoglobulin E test results, stinging insects of the order Hymenoptera, risk factors for severe reactions to stings, and risk factors for relapse after discontinuing venom immunotherapy.

      This review contains 6 highly rendered figures, 4 tables, and 62 references.

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    • 11

      Igg4-related Disease and Retroperitoneal Fibrosis

      By John H. Stone, MD, MPH
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      Igg4-related Disease and Retroperitoneal Fibrosis

      • JOHN H. STONE, MD, MPHDirector, Clinical Rheumatology, Massachusetts General Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

      IgG4-related disease (IgG4-RD) has been observed to affect almost every organ system, with consistent histopathologic findings across systems. IgG4-RD can mimic malignant, infectious, and inflammatory disorders; accordingly, consideration of the histopathologic features of tissue biopsies and rigorous clinicopathologic correlations are essential to avoid misdiagnosis. Since the early 2000s, IgG4-RD has increasingly been recognized as a cause of what was previously referred to as “idiopathic” retroperitoneal fibrosis (RPF), and this IgG4-related RPF is now considered to comprise an important subset of IgG4-RD. This review includes an overview of IgG4-RD and discusses the pathology, pathophysiology, and clinical manifestations of IgG4. IgG4-related RPF is also discussed in this review, with topics including IgG4-related RPF versus RPF of other causes, the differences between RPF and other subsets of IgG4-RD, and treatment of both IgG4-RD and IgG4-related RPF. Figures show the histopathology features of IgG4-RD, immunostaining of tissue for IgG4, IgG4-related RPF and chronic periaortitis, “Mikulicz disease”, IgG4-RD of the lung, IgG4-related renal disease, and type 1 (IgG4-related) pancreatitis. The table lists conditions known previously by other names that often fall within the spectrum of IgG4-RD.

      This review contains 7 highly rendered figures, 1 table, and 66 references.

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    • 12

      Disorders of Macrophages and Dendritic Cells

      By Alexei A. Grom, MD; Michael B Jordan, MD, PhD; Jun Qin Mo, MD
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      Disorders of Macrophages and Dendritic Cells

      • ALEXEI A. GROM, MDAssociate Professor of Pediatrics, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
      • MICHAEL B JORDAN, MD, PHDAssistant Professor of Pediatrics, Divisions of Immunobiology and Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
      • JUN QIN MO, MDAssociate Professor of Pediatrics, Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

      The mononuclear phagocytic system consists of dendritic cells (DCs) and monocytes/macrophages, historically referred to as histiocytes. The macrophages exhibit varying degrees of phagocytic activity. DCs typically have dendritic morphology. Their phagocytic activity is limited. Instead, they play a key role in antigen presentation to lymphocytes. The various populations of macrophages and DCs (such as Langerhans cells [LCs] and dermal dendrocytes) are usually distinguished based on characteristic morphology and patterns of expression of specific cell surface and intracellular markers. Abnormal accumulation and behavior of these cells may lead to the development of a spectrum of diseases collectively known as the histiocytoses. Clinically, histiocytic disorders comprise a wide variety of conditions that affect both children and adults and range from benign skin lesions to rapidly progressive life-threatening systemic disorders. LCs play a pivotal role in the development of Langerhans cell histiocytosis, dermal dendrocytes are the predominant cell population in the lesionsof juvenile xanthogranuloma, and macrophages are central to the pathogenesis of hemophagocytic lymphohistiocytosis and related disorders.

      This review contains 5 figures, 3 tables, and 77 references.

      Key words: dendritic cells, dermal dendrocytes, hemophagocytic lymphohistiocytosis, histiocytes, juvenile xanthogranuloma, Langerhans cell histiocytosis, Langerhans cells, macrophage activation syndrome,macrophages 

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    • 13

      Transplant Immunology: Basic Immunology and Clinical Practice

      By Lung-Yi Lee, MD; David P Foley, MD
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      Transplant Immunology: Basic Immunology and Clinical Practice

      • LUNG-YI LEE, MDDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • DAVID P FOLEY, MDDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, and Veterans Administration Surgical Services, William S. Middleton Veterans Hospital, Madison, WI

      Engraftment of a transplanted organ into an allogeneic host triggers a cascade of immunologic responses in the host that are designed to facilitate graft rejection. Modern donor-to-host matching techniques and immunosuppression protocols have successfully tempered this natural immune response so that graft survival has dramatically improved. However, optimizing graft survival by precisely downregulating the host response to graft rejection while preserving host immune defenses against pathologic and infectious agents remains poorly understood and elusive in current clinical practice. This review discusses transplant immunology with respect to host versus graft and the basis of allorecognition, as well as clinical management of the transplanted allograft. Figures show human leukocyte antigen (HLA), direct allorecognition, T cell receptor and CD3, T cell–associated second messenger signaling pathway, CD8 molecules directly ligating class I HLAs and CD4 molecules directly binding HLA class II, detection of alloantibodies by enzyme-linked immunosorbent assay or flow cytometry, recipient-donor crossmatch, histopathology of kidney allograft with antibody-mediated rejection, and an algorithm for assessment and management of renal allograft rejection. Tables list costimulatory molecules and ABO blood group compatibility for solid-organ transplantation.

      This review contains 9 highly rendered figures, 2 tables, and 65 references.

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    • 14

      Pediatric Rashes

      By Summer Stears-Ellis, MD
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      Pediatric Rashes

      • SUMMER STEARS-ELLIS, MDClinical Instructor, Emergency Ultrasound Fellow, Department of Emergency Medicine, University of Arizona, Tucson, AZ.

      Pediatric rashes are a common chief complaint in the emergency department (ED) and a source of anxiety for both parents and providers. Many of these rashes will not require intervention aside from symptomatic relief and parental reassurance. However, there is a subset of rashes that are the result of underlying life-threatening conditions that will warrant immediate intervention and treatment to prevent further deterioration and possible death. This review focuses on outlining the pathology of seven potentially deadly pediatric rashes that ED physicians are likely to encounter, how they present, and how to treat and manage them according to the most recent available guidelines. Figures show primary lesions, pattern of lesions, and distribution of rash associated with bacterial meningitis, toxic shock syndrome (TSS), Rocky Mountain spotted fever, Stevens-Johnson syndrome/toxic epidermal necrolysis, erythema multiforme minor and major, necrotizing fasciitis, and Henoch-Schönlein purpura. Tables list bacterial meningitis antibiotic treatment, Centers for Disease Control and Prevention clinical and laboratory criteria for TSS, TSS antibiotic treatment regimens, scoring systems for toxic epidermal necrolysis and necrotizing fasciitis, and the latest guidelines as of June 2017.

      This review contains 9 figures, 6 tables, and 50 references.

      Key words: Pediatric rash, toxic shock syndrome, skin rash, rash distribution, Rocky Mountain spotted fever, Stevens-Johnson syndrome, toxic epidermal necrolysis,  necrotizing fasciitis, Henoch-Schönlein purpura

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  • Cardiovascular Medicine
    • 1

      Approach to the Cardiovascular Patient

      By Catherine M. Otto, MD; David M Shavelle, MD
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      Approach to the Cardiovascular Patient

      • CATHERINE M. OTTO, MDJ. Ward Kennedy-Hamilton Endowed Chair in Cardiology, Professor of Medicine, Departmentof Medicine, Division of Cardiology, University of Washington School of Medicine, Seattle, WA
      • DAVID M SHAVELLE, MDAssociate Clinical Professor of Medicine, Keck School of Medicine at USC, Director, Interventional Cardiology Fellowship, Director, Cardiac Catheterization Laboratories, USC Medical Center, Los Angeles County, Los Angeles, CA

      The complete evaluation of the cardiovascular patient begins with a thorough history and a detailed physical examination. These two initial steps will often lead to the correct diagnosis and assist in excluding life-threatening conditions. The history and physical examination findings should be assessed in the overall clinical status of the patient, including the patient's specific complaints, lifestyle, comorbidities, and treatment expectations. This chapter discusses the cardiovascular conditions that frequently require evaluation: chest pain, dyspnea, palpitations, syncope, claudication, and cardiac murmurs; and reviews the background, history and physical examination, and diagnostic tests available for each. Diagnostic algorithms are provided, and the appropriate use of invasive and noninvasive cardiac testing for each condition is discussed.

      This review contains 8 highly rendered figures, 12 tables, and 52 references.

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    • 2

      Cardiovascular Biomarkers

      By Parul U Gandhi, MD; James L Januzzi Jr, MD
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      Cardiovascular Biomarkers

      • PARUL U GANDHI, MDClinical and Research Fellow, Department of Medicine, Cardiology Division, Massachusetts General Hospital, Boston, MA
      • JAMES L JANUZZI JR, MDRoman W. DeSanctis Endowed Clinical Scholar, Department of Medicine, Cardiology Division, Massachusetts General Hospital, Hutter Family Professor of Medicine, Harvard Medical School, Boston, MA

      The value of circulating biomarkers to care for patients with cardiovascular disease has grown significantly over the last few decades. The majority of clinical data focus on the use of natriuretic peptides (NPs) for the diagnosis, prognosis, and management of patients with heart failure (HF) and troponin measurements in patients with suspected or proven acute coronary syndrome (ACS). Part of the reason for the slow adoption of biomarkers beyond these two classes has been limitation in the optimal modes of application of new assays. Future studies are needed to clarify the use of biomarkers, with the ultimate goal of simplifying the diagnosis, prognosis, and patient care of complex cardiovascular conditions. This chapter reviews the use of established biomarkers for HF, ACS, and atrial fibrillation (AF). Tables include a summary of emerging and established cardiovascular biomarkers, characteristics of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide, cutoff points for NP measurement, differential diagnosis of elevated NP concentrations, biomarkers in HF with preserved ejection fraction, summary of NP management trials, third universal definition of myocardial infarction, and guidelines for recommendations of biomarkers in HF. Figures depict the various causes of NP release, the complex mechanism of troponin release in patients with HF, the ischemic and nonischemic etiologies of troponin release, timing of biomarker release during myocardial infarction, and the biomarkers involved in the pathogenesis of AF. Algorithms demonstrate evaluating outpatients with dyspnea in the clinic using NPs in their workup and the use of troponin to assist with determining an appropriate management strategy for a patient with ACS.

      This review contains 7 highly rendered figures, 8 tables, and 202 references.

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    • 3

      Cardiac Catheterization and Intervention

      By Dharam J. Kumbhani, MD, SM, MRCP, FACC; Deepak L Bhatt, MD, MPH, FACP
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      Cardiac Catheterization and Intervention

      • DHARAM J. KUMBHANI, MD, SM, MRCP, FACCAssistant Professor of Medicine, Division of Cardiology, University of Texas Southwestern Medical School, Dallas, TX
      • DEEPAK L BHATT, MD, MPH, FACPExecutive Director of Interventional Cardiovascular Programs, Brigham and Womens Hospital Heart & Vascular Center, Professor of Medicine, Harvard Medical School, Boston, MA

      Cardiac catheterization involves the insertion of a catheter (hollow polymer-coated tubing) into a blood vessel of the heart or into one of its chambers. Cardiac catheterization procedures are one of the most commonly performed cardiac procedures today. This review outlines the basics of angiography and coronary anatomy, the technical details of cardiac catheterizations, preferred access sites, and hemodynamic measurements. The basic steps in coronary intervention are listed. Common indications and contraindications for cardiac catheterization and intervention are described, as are appropriate use criteria for diagnostic catheterization and coronary intervention, fractional flow reserve (FFR) and intravascular ultrasonography, and complications of cardiac catheterization and percutaneous coronary intervention. Future directions in the field are discussed. Tables describe normal hemodynamic measurements, derived measurements during right heart catheterization, coronary artery disease prognostic index for medically managed patients, American College of Cardiology (ACC)/American Heart Association (AHA) guidelines regarding indications for coronary angiography, ACC/AHA appropriate use criteria for diagnostic catheterization, common indications for FFR, and risk of cardiac catheterization and coronary angiography. Figures include an overview of coronary anatomy, angiograms of the coronary arteries, images of a normal cardiac cycle and hemodynamic waveforms, the design of a stent, FFR evaluation, basic intravascular ultrasonography measurements, and coronary imaging with an optical coherence tomography system.

      This review contains 7 highly rendered figures, 8 tables, and 62 references.

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    • 4

      Chronic Stable Angina

      By Benjamin J Scirica, MD, MPH; J. Antonio T. Gutierrez, MD
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      Chronic Stable Angina

      • BENJAMIN J SCIRICA, MD, MPHSenior Investigator, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, MA
      • J. ANTONIO T. GUTIERREZ, MDCardiovascular Medicine Fellow, Brigham and Women's Hospital, Boston, MA

      By definition, chronic stable angina is angina that has been stable with regard to frequency and severity for at least 2 months. Chronic stable angina is the initial manifestation of coronary heart disease in approximately 50% of patients. Typically, this type of angina occurs in the setting of atherosclerotic coronary arterial narrowing, although other causes are possible. This review covers the epidemiology, pathophysiology, initial evaluation, differential diagnosis, management, and treatment of patients with chronic stable angina. Figures show noninvasive testing and the probability of coronary artery disease; diagnosis of patients with suspected ischemic heart disease; probability of severe coronary artery disease; coronary outcomes for high- versus low-intensity statin therapy; optimal medical therapy (OMT) versus OMT and percutaneous coronary intervention for chronic angina; OMT versus percutaneous coronary intervention for stable coronary heart disease; and coronary artery bypass grafting versus percutaneous coronary intervention for diabetes and coronary artery disease. Tables list the grading of angina pectoris by the Canadian Cardiovascular Society classification system, the differential diagnosis of chest pain, conditions promoting myocardial oxygen supply and demand mismatch, the features of typical angina, the classification of chest pain, a comparison of the pretest likelihood of coronary heart disease (CHD) in low-risk and high-risk symptomatic patients, the posttest probability of significant CHD based on pretest probabilities of CHD and normal or abnormal results of noninvasive studies, survival according to risk groups based on Duke treadmill scores, high- and moderate-intensity statin therapy, revascularization to improve survival compared with medical therapy, revascularization to improve symptoms with significant anatomic (≥ 50% left main or ≥ 70% nonleft main coronary artery disease) or physiologic (fractional flow reserve ≤ 0.80) coronary artery stenoses, and questions recommended by an expert panel for patients with chronic stable angina at follow-up visits.

      This review contains 7 highly rendered figures, 13 tables, and 109 references.

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    • 5

      Unstable Angina and Other Acute Coronary Syndromes

      By R Scott Wright, MD, FACC, FESC, FAHA; Joseph G Murphy, MD, FACC, FESC
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      Unstable Angina and Other Acute Coronary Syndromes

      • R SCOTT WRIGHT, MD, FACC, FESC, FAHAProfessor of Medicine, Consultant in Cardiology and the Coronary Care Unit, Mayo Clinic, Rochester, MN
      • JOSEPH G MURPHY, MD, FACC, FESCProfessor of Medicine, Consultant in Cardiology and the Coronary Care Unit, Chair, Section of Scientific Publications, Mayo Clinic, Rochester, MN

      Patients with coronary artery disease (CAD) present clinically when their disease enters an unstable phase known as an acute coronary syndrome (ACS), in which the cap of a previously stable atheromatous coronary plaque ruptures or erodes, which in turn activates a thrombotic cascade that may lead to coronary artery occlusion, myocardial infarction (MI), cardiogenic shock, and patient death. There are nearly 2 million episodes of ACS in the United States annually; it is the most common reason for hospitalization with CAD and is the leading cause of death in the developed world. ACS patients include those with unstable angina (UA), non–ST segment elevation myocardial infarction (non-STEMI), and ST segment elevation myocardial infarction (STEMI) and patients who die suddenly of an arrhythmia precipitated by coronary occlusion. The distinction among various ACS subgroups reflects varying characteristics of clinical presentation (presence or absence of elevated cardiac biomarkers) and the type of electrocardiographic (ECG) changes manifested on the initial ECG at the time of hospitalization. This chapter focuses on UA and non-STEMI. A graph outlines mortality risks faced by patients with varying degrees of renal insufficiency. An algorithm describes the suggested management of patients admitted with UA or non-STEMI. Tables describe the risk stratification of the patient with chest pain, categories of Killip class, examination findings of a patient with high-risk ACS, diagnosis of MI, causes of troponin elevation other than ischemic heart disease, initial risk stratification of ACS patients, and long-term medical therapies and goals in ACS patients.

      This review contains 2 highly rendered figures, 11 tables, and 76 references.

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    • 6

      St-segment Elevation Myocardial Infarction

      By Grant William Reed, MD; Christopher Paul Cannon, MD
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      St-segment Elevation Myocardial Infarction

      • GRANT WILLIAM REED, MDFellow, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH
      • CHRISTOPHER PAUL CANNON, MD Cardiovascular Division, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Executive Director of Cardiometabolic Trials, Harvard Clinical Research Institute, Boston, MA

      Patients with acute coronary syndrome fall into two groups: those with unstable angina or non—ST segment elevation (formerly non—Q wave) myocardial infarction (NSTEMI) and those with acute ST segment elevation (formerly Q wave) myocardial infarction (STEMI). STEMI is the focus of this chapter. The epidemiology, pathophysiology, diagnosis, differential diagnosis, and complications of STEMI are elaborated. Reperfusion therapy (including time to reperfusion; diagnostic coronary angiography; primary, facilitated, rescue, and late percutaneous coronary intervention [PCI]; thrombolytic therapy and choice of thrombolytic agent; early invasive strategy; coronary artery bypass grafting; and therapeutic hypothermia), medical therapy (including aspirin, P2Y12 inhibitors, glycoprotein IIb/IIIa inhibitors, anticoagulants, nitrates, beta blockers, inhibition of the renin-angiotensin-aldosterone system, oxygen, analgesia, lipid-lowering therapy, prophylactic antiarrhythmics, and magnesium), risk stratification, secondary prevention, and post-STEMI care are also covered. Tables delineate classifications of MI as defined by proximal cause of myocardial ischemia, Killip classification of acute MI and mortality rates, differential diagnosis of ST segment elevation, contraindications for administering thrombolytic agents, and major recommendations for antithrombotic therapy in patients with STEMI treated with primary PCI and thrombolysis. Algorithms indicate a diagnostic approach to acute coronary syndromes and corresponding pathology and reperfusion strategies. Electrocardiogram changes in STEMI and corresponding territory of myocardium are depicted. A variety of graphs are included.

      This review contains 11 highly rendered figures, 7 tables, and 151 references.

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    • 7

      Heart Failure

      By Sachin P Shah, MD; Mandeep R. Mehra, MD
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      Heart Failure

      • SACHIN P SHAH, MDCenter for Advanced Heart Disease, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, Director, Cardiovascular Intensive Care Unit, Lahey Hospital and Medical Center, Burlington, MA
      • MANDEEP R. MEHRA, MDMedical Director, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA

      Heart failure is a syndrome related to abnormal cardiac performance with a consequence of impaired cardiac output at rest or with exertion and/or congestion, which usually leads to symptoms of fatigue, dyspnea, and edema. The syndrome is characterized by various phenotypes related to a vast array of etiologies with diverse management targets. The current broad categorization of heart failure separates patients based on ejection fraction. Further description of the phenotype beyond ejection fraction is imperative to correctly identify the etiology of heart failure and, ultimately, to choose medical, device, and surgical therapies appropriately. This review covers the epidemiology of heart failure, defining the phenotype and etiology of heart failure, recognition and management of acute decompensated heart failure, management of chronic heart failure with a reduced ejection fraction, implantable cardioverter-defibrillators in heart failure with a reduced ejection fraction, management of heart failure with a preserved ejection fraction, and advanced heart failure. Figures show the evolution of therapy in chronic heart failure from the symptom-directed model, the complex pathophysiology and principal aberrations underlying heart failure with preserved ejection fraction, and concepts underlying surgical therapy in advanced heart failure using Laplace’s law. Tables list various etiologies of heart failure; sensitivity and specificity of clinical, biomarker, and radiographic data in the diagnosis of acute decompensated heart failure; drugs and devices with a demonstrated survival benefit in heart failure with a reduced ejection fraction; neurohormonal antagonist dosing in heart failure with a reduced ejection fraction; randomized, placebo-controlled trials in heart failure with a preserved ejection fraction; categorization of heart failure according to American Heart Association/American College of Cardiology heart failure stage, New York Heart Association functional class, and Interagency Registry for Mechanically Assisted Circulatory Support level; and poor prognostic indicators in heart failure.

      This review contains 3 highly rendered figures, 7 tables, and 113 references.

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    • 8

      Heart Transplantation

      By Michael M. Givertz, MD
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      Heart Transplantation

      • MICHAEL M. GIVERTZ, MDMedical Director, Heart Transplant and Circulatory Assist, Brigham and Women's Hospital, Associate Professor, Harvard Medical School, Boston, MA

      Heart failure is a major public health problem with significant associated morbidity and mortality. Heart transplantation remains the standard of care for highly selected patients with end-stage heart failure and absence of contraindications to transplantation. This chapter discusses indications and contraindications for transplantation; recipient evaluation, selection, and management; donor selection; timing of the procedure and surgical technique; medical management, including immunosuppression, prevention and treatment of infections, and other standard or preventive therapy; late complications; and functional status and long-term survival. Tables describe patient referral to a specialized center for heart transplantations; guidelines of indications for cardiac transplantation; organ dysfunction; pretransplantation evaluation; waiting lists; therapeutic options for patients with advanced or refractory heart failure; treating highly sensitized patients; suggested vaccinations; guidelines for donor hearts with severe infection; high-risk donor behavior; hemodynamic effect of commonly used parenteral agents; frequency of follow-up evaluations; revised International Society for Heart and Lung Transplantation (ISHLT) formulation for diagnosis of cardiac allograft rejection and suggested treatment; function of immunosuppressive agents; administration, dosing, monitoring, and adverse effects of commonly used immunosuppressants; common agents that interfere with tacrolimus and cyclosporine; cytomegalovirus prophylaxis and valganciclovir based on estimated renal function; cumulative morbidity rates in adult heart transplant survivors; and therapies to prevent and treat osteoporosis posttransplantation. Figures depict the progression of heart failure; change in functional status over time in patients with chronic heart failure; US heart transplantations in 2012; percentage of US adult wait-listed patients who received a donor heart transplant within a year and donation rates by state; bicaval surgical technique; endomyocardial biopsies; timeline of infection following solid-organ transplantation; cardiac allograft vasculopathy; and squamous cell carcinomas in a heart transplant patient. Graphs show adult worldwide heart transplantation volume from 1982 to 2010; changing characteristics of US adult heart transplant recipients; relative risk of death and development of cardiac allograft vasculopathy; posttransplantation immunosuppression at 1 and 5 years in the ISHLT Registry; older donor age and risk of developing cardiac allograft vasculopathy; freedom from malignancy in the ISHLT Registry; employment status of adult heart transplant recipients; adult heart transplant survival; and patient survival among US heart transplant recipients by gender and race.

      This review contains 18 highly rendered figures, 20 tables, and 109 references.

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    • 9

      Supraventricular Tachycardia

      By Saurabh Kumar, BSc(Med)/MBBS, PhD; Laurence M. Epstein, MD
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      Supraventricular Tachycardia

      • SAURABH KUMAR, BSC(MED)/MBBS, PHDAdvanced Clinical Electrophysiology Fellow, Cardiac Arrhythmia Service, Brigham and Woman’s Hospital, Boston, MA
      • LAURENCE M. EPSTEIN, MDChief, Cardiac Arrhythmia Service, Associate Professor of Medicine, Harvard Medical School, Cardiac Arrhythmia Service, Brigham and Women’s Hospital, Boston, MA

      Supraventricular tachycardias (SVTs) comprise a group of usually benign arrhythmias that originate from cardiac tissue at or above the His bundle. SVTs include inappropriate sinus tachycardia, atrial tachycardias (ATs), atrial flutter (AFL), junctional tachycardia, atrioventricular nodal reentrant tachycardia (AVNRT), and forms of accessory pathway–mediated reentrant tachycardias (atrioventricular reentrant tachycardia [AVRT]). Although mostly benign, symptoms can be debilitating, in the form of palpitations, shortness of breath, chest discomfort, dizziness, and/or syncope; rarely, SVTs can result in cardiomyopathy due to incessant arrhythmia. This review covers the epidemiology, diagnosis, management, and classification of SVTs. Figures show differential diagnosis for wide (> 120 ms) QRS complex tachycardia, differential diagnosis for narrow QRS complex tachycardia, method for assessing RP interval during SVT, example of a short RP tachycardia with a positive deflection at the end of the QRS complex in lead V1 and a pseudo S wave in lead III, example of a short RP tachycardia with an RP greater than 70 ms, example of a long RP tachycardia, example of preexcited atrial fibrillation in a 17-year-old man, the utility of the response to intravenous adenosine in determining the cause of tachycardia, mechanism of AVNRT, accessory pathway conduction, mechanism of orthodromic and antidromic AVRT, distribution of focal ATs, a schematic showing the different types of AFL circuits, and an electrocardiogram (ECG) example of typical AFL. Tables list a summary of mechanism and definition of SVTs, ECG criteria to differentiate ventricular tachycardia from SVT in wide-complex tachycardia, and drugs used to maintain sinus rhythm in patients with SVT.

       

      This review contains 14 highly rendered figures, 3 tables, and 74 references.

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    • 10

      Atrial Fibrillation

      By Roy M. John, MD, PhD; Gregory F. Michaud, MD
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      Atrial Fibrillation

      • ROY M. JOHN, MD, PHDAssociate Director EP Laboratory, Director, Experimental Research, Cardiac Arrhythmia Service, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MA
      • GREGORY F. MICHAUD, MDDirector, Center for the Advanced Management of Atrial Fibrillation, Brigham and Women’s, Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MD

      Atrial fibrillation (AF) is an abnormal rhythm characterized by chaotic atrial electrical activity resulting in loss of atrial contraction, an irregular and unpredictable heart rate, and a tendency for thrombus formation. The prevalence of AF is estimated at 1 to 2%, but it’s likely higher than that because one-third of patients may have no symptoms and might never seek medical attention. Data suggest that 1 in 4 people over the age of 40 will develop AF in their lifetime. About 10% of patients over age 80 have experienced the arrhythmia, and some estimates predict the prevalence will double in the next 50 years. This chapter discusses the pathophysiology, genetics, diagnosis, classification, and treatment of AF. Figures show atrial fibrillation and coarse atrial fibrillation plus common right atrial flutter. One algorithm is for oral anticoagulation therapy, and a second shows a recommended hierarchical choice of antiarrhythmic therapies versus catheter ablation for recurrent symptomatic atrial fibrillation. Tables list classification, diagnostic evaluation of, clinical consequences of, and conditions often associated with atrial fibrillation. Three scoring systems are included: 1) for congestive heart failure, hypertension, diabetes, stroke, and transient ischemic attack; 2) to assess the risk of bleeding with oral anticoagulation, and 3) data and proportion of patients from the Euro Heart Survey. Other tables include long-term anticoagulation guidelines for atrial fibrillation, intravenous drugs used for acute rate control, oral drugs used for chronic rate control, and antiarrhythmic drugs for conversion of atrial fibrillation and/or maintenance of sinus rhythm. In addition, there’s a summary of randomized trials weighing rate control and rhythm control strategies, plus schemes for categorizing thromboembolism risk.

      This review contains 4 highly rendered figures, 14 tables, and 129 references.

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    • 11

      Ventricular Arrhythmias

      By Roy M. John, MD, PhD; William G Stevenson, MD
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      Ventricular Arrhythmias

      • ROY M. JOHN, MD, PHDAssociate Director EP Laboratory, Director, Experimental Research, Cardiac Arrhythmia Service, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MA
      • WILLIAM G STEVENSON, MDDirector, Clinical Cardiac Electrophysiology, Brigham and Women’s Hospital, Boston, MA

      Ventricular arrhythmias are common in all forms of heart disease and are an important cause of cardiac arrest and sudden death. Many ventricular arrhythmias are benign but may serve as a marker for underlying disease or its severity. Others are life threatening. The significance of an arrhythmia is determined by the specific characteristics of the arrhythmia and the associated heart disease, and these features guide evaluation and therapy. This review discusses various mechanisms and types of ventricular arrhythmias and management based on clinical presentation (including patients with symptomatic arrhythmia and increased risk of sudden death without arrhythmia symptoms). Genetic arrhythmia syndromes, such as abnormalities of repolarization and the QT interval, catecholaminergic polymorphic ventricular tachycardia (VT), and inherited cardiomyopathies, are discussed in depth. Under the rubric of management of ventricular arrhythmias, drug therapy for ventricular arrhythmias, implantable cardioverter-defibrillators (ICDs), and catheter ablation for VT are also covered. Tables chart out guideline recommendations for ICD therapy, drugs for the management of ventricular arrhythmias, and indications and contraindications for catheter ablation of ventricular arrhythmias. Electrocardiograms are provided, as well as management algorithms for ventricular arrhythmias based on patient presentation, and an algorithm for identifying patients with systolic heart failure and left ventricular ejection less than or equal to 35% who are candidates for consideration of an ICD for primary prevention of sudden cardiac death.

      This review contains 5 highly rendered figures, 3 tables, and 60 references.

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    • 12

      Pacemaker Therapy

      By Shamai A. Grossman, MD, MS
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      Pacemaker Therapy

      • SHAMAI A. GROSSMAN, MD, MSAssociate Professor of Emergency Medicine, Harvard Medical School, Vice Chair for Health Care Quality, Harvard Medical Faculty Physicians, Beth Israel Deaconess Medical Center, Boston, MA

      The number of permanent pacemakers implanted per year increased by 55.6% between 1993 and 2009, and is continuing to rise. Accordingly, the number of patients treated in the emergency department who have permanent pacemakers is increasing, and it is important for physicians in the emergency department to be familiar with the operation and potential complications of these devices. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for patients with pacemakers presenting to the emergency department. Figures show examples of dual chamber pulse generators from four major pacemaker manufacturers, VVI pacing with a lower rate limit of 60 beats per minute,  DDD pacing with a lower rate limit of 60 beats per minute and an upper rate limit of 120 beats per minute, a 12-lead electrocardiogram with bifascicular block, a proprietary algorithm (Managed Ventricular Pacing, Medtronic Inc.) aimed at reducing ventricular pacing, and an example of a pacemaker pocket infection. Tables list North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group generic five-position code for antibradycardia pacing, and Levels of Evidence and Society Guideline Recommendations for Selected Pacing Indications.

      This review contains 6 highly rendered figures, 2 tables, and 27 references.

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    • 13

      Valvular Heart Disease

      By Miriam S. Jacob, MD; Brian P Griffin, MD
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      Valvular Heart Disease

      • MIRIAM S. JACOB, MDAdvanced Fellow in Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland OH
      • BRIAN P GRIFFIN, MDJohn and Rosemary Brown Chair in Cardiovascular Medicine, Cleveland Clinic, Cleveland OH

      Valvular heart disease is an important cause of cardiac morbidity in developed countries despite a decline in the prevalence of rheumatic disease in those countries. This chapter discusses the many etiologies of valvular heart disease and presents methods for assessment and management. Specific valvular lesions discussed include mitral stenosis, mitral regurgitation, mitral valve prolapse, aortic stenosis, aortic regurgitation, and tricuspid and pulmonary disease. The section on tricuspid disease includes a discussion of mechanical prostheses (ball-in-cage and tilting-disk) and biologic prostheses (xenografts, allografts, and autografts) and their complications. The chapter concludes with a discussion of anorexiant-induced valvular disorder. Figures include color photographs of pathologic specimens, numerous echocardiographic images of valvular lesions, plus fluoroscopies of a percutaneous mitral valve repair and a transcatheter aortic valve replacement. Tables include causes of specific valvular lesions, assessment of patients with valvular heart disease, auscultatory findings associated with common valvular problems, risk factors for severe adverse outcomes with infective endocarditis, and American Heart Association recommendations for endocarditis prophylaxis.

      This review contains 11 highly rendered figures, 5 tables, and 153 references.

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    • 14

      Congenital Heart Disease in Adults

      By Luke J Lamers, MD; Heather L. Bartlett, MD; Susan E. Haynes, MD; David J Skorton, MD
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      Congenital Heart Disease in Adults

      • LUKE J LAMERS, MDAssistant Professor, Department of Pediatrics, Director, Pediatric Cardiac Catheterization Laboratory, University of Wisconsin, Madison, WI
      • HEATHER L. BARTLETT, MDAssistant Professor, Department of Pediatrics, Director, Adult Congenital Heart Disease Program, University of Iowa Children’s Hospital, Iowa City, IA
      • SUSAN E. HAYNES, MDAssociate Professor, Department of Pediatrics, University of Iowa Children’s Hospital, Iowa City, IA
      • DAVID J SKORTON, MDProfessor, Departments of Medicine and Pediatrics, Weill Cornell Medical College, New York, NY and Department of Biomedical Engineering, Cornell University, Ithaca, NY

      With advances in medical and surgical care, an increasing number of children with congenital diseases of the heart and vasculature now survive to adulthood. The proportion of adults who are affected by congenital heart disease is expected to continue to increase. Thus, it is important for clinicians to be knowledgeable about the care of these patients. This review examines acyanotic disorders (shunts and valvular lesions), vascular anomalies, cyanotic disorders, and women’s health issues. Figures show the anatomy of atrial septal defects, transcatheter closure of atrial septal defects, an anatomic cross section showing the atrioventricular septum, the anatomic positions of ventricular septal defects, a computed tomography scan of aortic coarctation, angiogram of a persistent left superior vena cava draining into the right atrium, systemic artery-to-pulmonary artery shunts, magnetic resonance image of a patient with repaired tetralogy of Fallot and long-standing pulmonary valve insufficiency, treatment of pulmonary valve regurgitation with a transcatheter pulmonary valve, computed tomographic images of a patient with atrial switch palliation of transposition of the great arteries and multiple baffle obstructions, stages in the repair of functional single ventricles, and echocardiograms of a patient with Ebstein anomaly. Tables list recommendations for pulmonary valve replacement in repaired tetralogy of Fallot, conditions in which pregnancy is high risk, and cardiac indications for fetal echocardiography.

      This review contains 12 highly rendered figures, 4 tables, and 62 references.

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    • 15

      Hypertension

      By Marc P Bonaca, MD, MPH
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      Hypertension

      • MARC P BONACA, MD, MPHVascular Section, Cardiovascular Division, Brigham and Women’s Hospital, Assistant Professor, Harvard Medical School, Boston, MA

      Hypertension is a common chronic disorder with an increasing prevalence in the context of an aging population. Patients with hypertension are at risk for adverse cardiovascular, renal, and neurologic outcomes. Treatment of hypertension reduces this associated risk; therefore, early diagnosis and systematic management are critical in reducing morbidity and mortality. Although hypertension is multifactorial, a large component is related to lifestyle, including excess sodium intake, lack of physical activity, and obesity. Lifestyle intervention and education, therefore, are critical to both prevention and treatment of hypertension. Patients diagnosed with hypertension should be evaluated for their overall risk, with specific therapies and treatment targets guided by their characteristics and comorbidities. Several professional and guideline societies have published recommendations with regard to the diagnosis and treatment of hypertension, which have many similarities but also several areas of discussion and ongoing debate. Recent evolutions in the field include the expanded indications for home-based and ambulatory blood pressure monitoring and outcomes trials, which add important data regarding optimal treatment targets. These evolutions are likely to be addressed in ongoing guideline updates.

      Key words: ambulatory blood pressure monitoring, antihypertensive therapy, blood pressure, blood pressure targets, cardiovascular risk, high blood pressure, home blood pressure monitoring, hypertension, screening, secondary hypertension

      This review contains 9 figures, 13 tables, and 65 references.

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    • 16

      Diseases of the Aorta

      By Anna M Booher, MD; Kim A Eagle, MD
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      Diseases of the Aorta

      • ANNA M BOOHER, MDClinical Assistant Professor, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI
      • KIM A EAGLE, MDAlbion Walter Hewlett Professor of Internal Medicine, Chief of Clinical Cardiology, Clinical Director, Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI

      This review covers the major presentations affecting the aorta: aortic aneurysms (abdominal aortic aneurysms and thoracic aortic aneurysms), acute aortic syndromes (including aortic dissection, intramural hematoma, and penetrating atherosclerotic ulcer), other nonacute aortic processes, and traumatic disease of the aorta. The section on abdominal aortic aneurysms covers screening, clinical presentation, diagnostic evaluation, management to reduce the risk of aneurysm rupture, open surgical treatment and endovascular aortic repair, and the role of medical therapy. The section on thoracic aortic aneurysms also covers pathophysiology, etiology, and inherited and inflammatory conditions. Aortic dissections affect either the ascending aorta (type A) or the descending aorta (type B) and may be classified as acute or chronic. The discussion of aortic dissection describes the clinical presentation, diagnostic steps and decisions, and treatment for both type A and type B dissections. The figures include two algorithms: a potential management strategy for patients with thoracic aortic aneurysm and a logical procedure for the evaluation and treatment of a suspected aortic dissection. Figures also include illustrations, computed tomographic images, and echocardiograms of various aortic presentations. Tables list normal aortic dimensions by computed tomographic angiography and echocardiography, etiology and associated factors in diseases of the aorta, revised Ghent criteria for the diagnosis of Marfan syndrome, size criteria for elective surgical intervention in thoracic aortic aneurysm, and independent predictors of in-hospital death. Also included is a follow-up imaging timeline for acute aortic syndromes.

      This review contains 9 figures, 6 tables, and 132 references.

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    • 17

      Peripheral Artery Diseases

      By Mark A Creager, MD
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      Peripheral Artery Diseases

      • MARK A CREAGER, MD Professor of Medicine, Harvard Medical School, Director, Vascular Center, Head, Vascular Medicine Section, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA

      Peripheral arterial diseases (PADs) compromise blood flow to the limbs. Common causes of arterial obstruction include atherosclerosis, thrombus, embolism, vasculitis, arterial entrapment, adventitial cysts, fibromuscular dysplasia, arterial dissection, trauma, and vasospasm. The most frequently encountered cause of PAD is peripheral atherosclerosis. This chapter considers its epidemiology and risk factors, as well as its diagnosis, including clinical presentation and noninvasive diagnostic tests. This chapter also discusses acute arterial occlusion, atheroembolism, popliteal artery entrapment, thromboangiitis obliterans, and acrocyanosis, as well as the etiology, diagnosis, and treatment of Raynaud phenomenon. The chapter contains 4 tables and 7 figures. Tables describe the Fontaine classification and clinical categories of chronic limb ischemia, provide examples of leg segmental pressure measurements in a patient with calf claudication and foot pain, and summarize secondary causes of Raynaud phenomenon. Figures include a photograph of an ischemic foot demonstrating dependent rubor, measurement of the ankle:brachial index, ultrasonography of a stenosis of the right common femoral artery, magnetic resonance angiograms of patients with calf claudication, arteriograms of critical ischemia of the foot and of disabling claudication of the leg, and ischemia of the toes caused by atheroemboli. This chapter contains 80 references.

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    • 18

      Venous Thromboembolism

      By Samuel Z. Goldhaber, MD
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      Venous Thromboembolism

      • SAMUEL Z. GOLDHABER, MDProfessor of Medicine, Harvard Medical School Director, Venous Thromboembolism Research Group

      Venous thromboembolism, which involves venous thrombosis and pulmonary embolism, is a leading cause of morbidity and mortality in hospitalized patients and is being seen with increasing frequency in outpatients. This chapter discusses the risk factors, etiology, classification, pathophysiology, natural history, prognosis, diagnosis (including venous thrombosis, recurrent venous thrombosis, and pulmonary embolism), prophylaxis, and treatment of venous thromboembolism (including the pharmacology of antithrombotic agents), as well as venous thromboembolism in pregnancy and miscellaneous thromboembolic disorders (including thrombosis of unusual sites). Tables in the chapter present a model for determining clinical suspicion of deep vein thrombosis, test results that effectively confirm or exclude deep vein thrombosis, a model for determining a clinical suspicion of pulmonary embolism, test results that effectively confirm or exclude pulmonary embolism, drug and food interactions with warfarin by level of supporting evidence and direction of interaction, risk categories for venous thromboembolism, and recommendations for prophylaxis. Figures include a venogram illustrating thrombi in the left iliac vein, perfusion scans showing multiple perfusion defects, a computed tomographic pulmonary angiogram demonstrating intraluminal filling defects, a diagnostic approach for suspected pulmonary embolism, and an algorithm for selecting duration of anticoagulation after venous thromboembolism. There are 105 references in this chapter.

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    • 19

      Diseases of the Pericardium, Cardiac Tumors, and Cardiac Trauma

      By Terrence D. Welch, MD; Kyle W Klarich, MD; Jae K. Oh, MD
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      Diseases of the Pericardium, Cardiac Tumors, and Cardiac Trauma

      • TERRENCE D. WELCH, MDAssistant Professor of Medicine, Section of Cardiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH
      • KYLE W KLARICH, MDProfessor of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
      • JAE K. OH, MDSamsung Professor of Cardiovascular Diseases, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

      The pericardium consists of a fibrous sac and a serous membrane. Because of its simple structure, the clinical syndromes involving the pericardium are relatively few but vary substantially in severity. Cardiac tumors may be either primary or secondary and either benign or malignant, with attachment sites throughout the endocardium. Cardiovascular trauma should be suspected in all patients with chest injuries or severe generalized trauma. Cardiovascular injury may be either blunt or penetrating. This review covers pericardial disease, cardiac tumors, and cardiovascular trauma. Figures show an electrocardiogram in acute pericarditis; acute pericarditis with delayed gadolinium enhancement of the pericardium shown with cardiac magnetic resonance imaging; underlying cause of pericardial effusion requiring pericardiocentesis; pericardial pressure-volume curves; large pericardial effusion with swinging motion of the heart resulting in electrical alternans; typical pulsed-wave Doppler pattern of tamponade; underlying causes of constrictive pericarditis in patients undergoing pericardiectomy; pericardial calcification seen on a chest radiograph; thickened pericardium; typical pulsed-wave Doppler pattern of constrictive pericarditis; typical mitral annular tissue velocities in constrictive pericarditis; a diagnostic algorithm for the echocardiographic diagnosis of constrictive pericarditis; simultaneous right ventricular and left ventricular pressure tracings in restrictive cardiomyopathy; computed tomographic scan showing inflammatory constrictive pericarditis; systolic and diastolic transesophageal echocardiographic images of a large left atrial myxoma attached to the atrial septum; a decision tree of management options for patients with suspected papillary; transesophageal echocardiographic examples of aortic valve, mitral valve, left ventricular outflow tract, and tricuspid valve papillary fibroelastomas; and transesophageal short-axis view of the descending thoracic aorta in a hypotensive patient after a motor vehicle accident. The table lists tamponade versus constriction versus restrictive cardiomyopathy.

      This review contains 18 highly rendered figures, 1 table, and 77 references.

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  • Competency-based Patient Care
    • 1

      On Being a Physician

      By Elizabeth G Nabel, MD, FACP
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      On Being a Physician

      • ELIZABETH G NABEL, MD, FACPPresident, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

      The role of a physician as healer has grown more complex, and emphasis will increasingly be on patient and family-centric care. Physicians must provide compassionate, appropriate, and effective patient care by demonstrating competence in the attributes that are essential to successful medical practice. Beyond simply gaining medical knowledge, modern physicians embrace lifelong learning and need effective interpersonal and communication skills. Medical professionalism encompasses multiple attributes, and physicians are increasingly becoming part of a larger health care team. To ensure that physicians are trained in an environment that fosters innovation and alleviates administrative burdens, the Accreditation Council for Graduate Medical Education has recently revamped the standards of accreditation for today’s more than 130 specialties and subspecialties.

      This review contains six references.

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    • 2

      Ethical and Social Issues in Medicine

      By Roberta Springer Loewy, PhD (PHIL, ETHICS); Erich H. Loewy, MD, FACP (deceased); Faith T. Fitzgerald, MD, MACP
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      Ethical and Social Issues in Medicine

      • ROBERTA SPRINGER LOEWY, PHD (PHIL, ETHICS)Professor and Bioethics Education Consultant, VCF, University of California, Davis, Sacramento, CA
      • ERICH H. LOEWY, MD, FACP (DECEASED)Professor and Founding Chair of the Bioethics Program (Emeritus), University of California, Davis, Sacramento, CA
      • FAITH T. FITZGERALD, MD, MACPProfessor of Internal Medicine, University of California, Davis, Sacramento, CA

      So rapidly has the field of health care ethics continued to grow that, when recently “googled,” the term produced 28.2 million hits. The challenge is to address the ethical and social issues in medicine in this very limited article space. It remains an impossible task to present more than a superficial discussion of these complex issues and the complicated cases in which they are to be found. Like good medicine, good ethics cannot be practiced by algorithm. The authors have opted to provide an operational guide to help clinicians sort through the ethical and social quandaries they must face on a daily basis. To that end, the authors have chosen to divide this chapter into the following sections:
      1. A brief description of the biopsychosocial nature of ethics and how it differs from personal morality
      2. A method for identifying and dealing with ethical issues
      3. A discussion of the role of bioethicists and ethics committees
      4. The professional fiduciary role of clinicians
      5. Listings of some of the common key bioethical and legal terms (online access only)
      6. A very brief discussion of the terms cited in the above listings (online access only)

      This reviews contains 2 tables (common bioethical concepts and legal concepts), 6 references, 1 appendix, and 24 additional readings.

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    • 3

      Principles of Neurologic Ethics

      By Thomas I. Cochrane, MD, MBA
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      Principles of Neurologic Ethics

      • THOMAS I. COCHRANE, MD, MBAAssociate Neurologist, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Assistant Professor of Neurology, Harvard Medical School, Boston, MA

      Many neurologic diseases affect the brain and thus cognition and personality. Many people consider some neurologic conditions “worse than death” and would prefer not to be kept alive using medical technology if there is no reasonable chance of recovery. The clinician caring for patients with neurologic disease will frequently be confronted with decisions about whether to initiate or continue life-sustaining therapies. And because neurologic disease often impairs the ability to understand and to decide, clinicians are more often called on to make decisions for patients who cannot decide for themselves. This chapter covers general principles, including respect for autonomy, beneficence, nonmaleficence, justice, informed consent, and implied consent. Discussion about making decisions for others includes competence and decision-making capacity, advance directives (powers of attorney and living wills), substituted judgment, and best interests. Decisions about life-sustaining treatment include withholding versus withdrawing, acts versus omissions, and limiting life-sustaining treatment for the patient with no surrogate. Also covered are decisions in the face of prognostic uncertainty, and futility, as well as commonly encountered problems such as states of severely disordered consciousness, coma, vegetative state, minimally conscious state, and brain death (including ethical controversies). Organ donation after both brain death and cardiac death is discussed. The section on dementia covers feeding tubes for patients with advanced dementia, the locked-in state, and neuroenhancement. Tables include elements of informed consent, elements of competence, assumed ethical priority of potential surrogates, steps that aid decision making in the face of prognostic uncertainty, and the American Academy of Neurology’s criteria for determination of brain death. This chapter includes 23 references.

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    • 4

      Quality of Care: Performance Measurement and Quality Improvement in Clinical Practice

      By Sonali P. Desai, MD, MPH; Allen Kachalia, MD, JD
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      Quality of Care: Performance Measurement and Quality Improvement in Clinical Practice

      • SONALI P. DESAI, MD, MPHAmbulatory Director, Patient Safety, Center for Clinical Excellence, Associate Director of Quality, Department of Medicine, Division of Rheumatology, Brigham and Women's Hospital, Boston, MA
      • ALLEN KACHALIA, MD, JDAssociate Chief Quality Officer, Co-Director, Center for Clinical Excellence, Brigham and Women's Hospital, Boston, MA

      Attention to the quality of care within the United States health care system has grown tremendously over the past decade. We have witnessed a significant change in how quality improvement and clinical performance measurement are approached. The current focus on quality and safety stems in part from the increasingly clear realization that more services and technological advancement are not automatically equivalent to high-quality care. Much of the discussion about cost and quality in health care is shifting towards the concept of value. Value is defined as health outcomes achieved per dollar spent (in other words, an assessment of the quality of care per cost). This chapter reviews the current state of quality improvement in health care and, because improvement cannot be determined without measurement, reviews several aspects of effective clinical performance measurement. Since many measures are already in place, the chapter describes some of the organizations involved in quality measurement and improvement, as well the approaches they utilize. It looks at the multiple strategies in place to improve quality, from process management to collaboration, from financial incentives to transparency, and reviews newer models of care delivery that may materialize in the near future. Tables list types of quality measures, characteristics to consider when developing a quality measure, and organizations involved in quality improvement and performance measurement. A figure shows strategies used by the federal government to spur performance measurement and quality improvement.

      This review contains 1 highly rendered figure, 3 tables, and 56 references.

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    • 5

      Practicing Evidence-based Medicine

      By Michael Barnett, MD; Niteesh Choudhry, MD, PhD
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      Practicing Evidence-based Medicine

      • MICHAEL BARNETT, MDFellow in General Internal Medicine, Division of General Internal Medicine and Primary Care, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
      • NITEESH CHOUDHRY, MD, PHDAssociate Professor, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

      Today, a plethora of resources for evidence-based medicine (EBM) are available via alert services, compendia, and more. In theory, a clinician researching a topic or looking for information regarding a clinical decision should easily find the literature or synopses needed. However, the real challenge lies in recognizing which resources (out of hundreds or possibly thousands) present the best and most reliable evidence. As well, evidence from research is only part of the decision calculus, and the clinician, not the evidence, makes the final decisions. Medical decision analysis attempts to formalize the process and reduce it to algebra, but it is difficult or impossible to represent all the components of a decision mathematically and validly let alone do so in “real time” for individual patients. This review discusses these challenges and more, including how to ask answerable questions, understand the hierarchy for evidence-based information resources, critically appraise evidence, and apply research results to patient care. Figures show the total number of new articles in Medline from 1965 to 2012, a “4S” hierarchy of preappraised medicine, percentage of physician and medical student respondents with a correct or incorrect answer to a question about calculating the positive predictive value of a hypothetical screening test, a nomogram for Bayes’s rule, an example of nomogram use for pulmonary embolism, and a model for evidence-informed clinical decisions. Tables list selected barriers to the implementation of EBM; Patient, Intervention, Comparison, and Outcome (PICO) framework for formulating clinical questions; guides for assessing medical texts for evidence-based features; clinically useful measures of disease frequency and statistical significance and precision; definitions of clinically useful measures of diagnostic test performance and interpretation; definitions of clinically useful measures of treatment effects from clinical trials; summary of results and derived calculations from the North American Symptomatic Carotid Endarterectomy Trial (NASCET); and selected number needed to treat values for common therapies.

      This review contains 6 highly rendered figures, 9 tables, and 28 references.

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    • 6

      Medical Evaluation of the Surgical Patient

      By Marie Gerhard-Herman, MD; Jonathan Gates, MD
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      Medical Evaluation of the Surgical Patient

      • MARIE GERHARD-HERMAN, MDDepartment of Medicine, Cardiovascular Division, Brigham and Womens Hospital, Boston, MA
      • JONATHAN GATES, MDDirector of the Burn and Trauma Unit, Department of Surgery, Brigham and Womens Hospital, Boston, MA

      Medical evaluation prior to surgery includes risk assessment and the institution of therapies to decrease perioperative morbidity and mortality to improve patient outcomes. The most effective medical consultation for surgical patients begins with an assessment of the individual patient and knowledge of the planned surgery and anesthesia followed by clear communication of a concise and specific recommended plan of perioperative care to the surgical team. This chapter describes anesthetic, cardiac, pulmonary, hepatic, nutritional, and endocrine risk assessment. Perioperative thrombotic management and postoperative care and complications, including fluid management; pulmonary, cardiac, renal complications; and delirium are discussed. Tables outline the American Society of Anesthesiologists class and perioperative mortality risk, a comparison of the Revised Cardiac Risk Index and National Surgery Quality Improvement Program, Duke Activity Status Index, high-risk stress test findings, markers for increased perioperative risk in pulmonary hypertension, aortic stenosis and nonemergent noncardiac surgery, risk factors for pulmonary complications in noncardiac surgery, the Model for End-Stage Liver Disease score to predict postoperative mortality, venous thromboembolism risk factors and options for pharmacologic prophylactic regimens, perioperative management of warfarin, and Brigham and Women’s Hospital guidelines for postoperative blood product replacement. Figures include a care algorithm for noncardiac surgery, an illustration of types of myocardial infarction, and an algorithm for the treatment of postoperative delirium.

      This chapter contains 3 highly rendered figures, 12 tables, 68 references, and 5 MCQs.

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  • Dermatology
    • 1

      Approach to the Diagnosis of Skin Disease

      By Robert T Brodell, MD; Lindsey B Dolohanty, MD; Stephen E Helms, MD
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      Approach to the Diagnosis of Skin Disease

      • ROBERT T BRODELL, MDProfessor and Chair, Department of Dermatology and Professor of Pathology, University of Mississippi Medical School, Jackson, MI, Instructor in Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY
      • LINDSEY B DOLOHANTY, MDAssistant Professor, Department of Dermatology, University of Rochester School of Medicine, Rochester, NY
      • STEPHEN E HELMS, MDAssociate Professor of Internal Medicine, Dermatology Section, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, Assistant Clinical Professor of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio, Professor of Dermatology, University of Mississippi Medical School, Jackson, MI

      The diagnosis of skin disease is not something that changes radically year to year. In fact, for hundreds of years physicians have been assessing the skin to diagnose and treat skin diseases and  to “view” internal diseases. The latest edition of this review provides several updates that enhance our approach to the diagnosis of skin disease with active links to updated digital references and atlases. These will be valuable to students, residents, and physicians interested in improving their dermatologic diagnostic skills. A new algorithm highlights our suggested approach to cutaneous diagnoses. It is our hope that readers will begin to “think like dermatologists” as they digest the contents of this review. 

      Key words: Macule, papule, vesicle, bulla, plaque, excoriation, scale, ulceration, diagnosis, errors

      This review contains 13 figures, 5 tables, 17 references, and 7 additional readings.

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    • 2

      Papulosquamous Disorders

      By Elizabeth A Abel, MD
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      Papulosquamous Disorders

      • ELIZABETH A ABEL, MDAdjunct Clinical Professor of Dermatology, Stanford University School of Medicine, Stanford, CA, Private Practice, California Skin Institute, Mountain View, CA

      Papulosquamous disorders comprise a group of dermatoses that have distinct morphologic features. The characteristic primary lesion of these disorders is a papule, usually erythematous, that has a variable amount of scaling on the surface. Plaques or patches form through coalescence of the primary lesions. Some common papulosquamous dermatoses are pityriasis rosea, lichen planus, seborrheic dermatitis, tinea corporis, pityriasis rubra pilaris, psoriasis, and parapsoriasis. The etiology, diagnosis, and treatment of pityriasis rosea, lichen planus, and seborrheic dermatitis (including seborrheic dermatitis associated with AIDS) are discussed in this chapter. Also discussed are the diagnosis and treatment of pityriasis rubra, parapsoriasis (pityriasis lichenoides and small- and large-plaque parapsoriasis), and erythroderma. This chapter includes color photographs of the aforementioned dermatoses plus the Koebner phenomenon, lichen planus of the mucous membranes, and erythroderma in Sézary syndrome.

      This review contains 11 highly rendered figures and 79 references.

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    • 3

      Psoriasis

      By Elizabeth A Abel, MD; Mark Lebwohl, MD
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      Psoriasis

      • ELIZABETH A ABEL, MDAdjunct Clinical Professor of Dermatology, Stanford University School of Medicine, Stanford, CA, Private Practice, California Skin Institute, Mountain View, CA
      • MARK LEBWOHL, MDSol and Clara Kest Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York City, NY

      Psoriasis is an immune-mediated inflammatory skin disorder characterized by chronic, scaling, erythematous patches and plaques of skin. This chapter discusses the epidemiology and pathogenesis of psoriasis, as well as the role of genetic factors, psychological stress, climate, concurrent infection, and drugs in the etiology of the disorder. A diagnostic summary highlights histopathologic features and reviews clinical variants, including plaque-type, guttate, erythrodermic, and pustular psoriasis, and special presentations, such as nail psoriasis and psoriatic arthritis. The chapter details various treatments and their indications and side effects; a discussion of topical therapies addresses topical corticosteroids, vitamin D analogues, tazarotene, tars, and anthralin. Phototherapy with ultraviolet B light (UVB); photochemotherapy with psoralen plus ultraviolet A light (PUVA); and systemic therapies such as methotrexate, acitretin, cyclosporine, tacrolimus, hydroxyurea, sulfasalazine, combination therapy, and other systemic therapies are reviewed. The chapter also highlights the current status of biologic therapies, including alefacept, etanercept, infliximab, adalimumab, and ustekinumab, plus some newer agents. The chapter includes 1 table and 21 figures, with the table ranking topical steroids by potency. Figures include various images of plaque psoriasis, psoriasis of the palms, scaling plaques on the feet, inverse psoriasis of the vulva and inguinal folds, guttate psoriasis, erythrodermic psoriasis, pustular psoriasis, psoriasis involving the fingernails and toenails, plus psoriasis in a child before and after phototherapy.

      This review contains 12 highly rendered figures, 1 table, and 142 references.

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    • 4

      Eczematous Disorders, Atopic Dermatitis, and Ichthyoses

      By Seth R Stevens, MD
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      Eczematous Disorders, Atopic Dermatitis, and Ichthyoses

      • SETH R STEVENS, MDPartner Physician, Southern California Permanente Medical Group, Woodland Hills, CA, and Assistant Clinical Professor, Case Medical School, Cleveland, OH

      This review describes eczematous dermatitis, or eczema, a skin disease that is characterized by erythematous vesicular, weeping, and crusting patches; atopic dermatitis, a common chronic inflammatory dermatosis that generally begins in infancy; and the ichthyoses, a group of diseases of cornification that are characterized by excessive scaling. The purpose of this review is to examine the major variants, epidemiology, etiology, diagnosis, differential diagnosis, and treatment of these dermatologic diseases. Figures depict chronic eczematous dermatitis, allergic contact dermatitis to poison ivy, seborrheic dermatitis, nummular eczema, acute eczematous patches, lichenified patches that appear after chronic rubbing of eczematous patches, erythroderma (total body erythema), and marked scaling (acquired ichthyosis). Tables list the diagnostic criteria for atopic dermatitis and the differential diagnosis of atopic dermatitis.

      This review contains 9 highly rendered figures, 2 tables, and 88 references.

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    • 5

      Contact Dermatitis and Related Disorders

      By Savina Aneja, BA; James S Taylor, MD
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      Contact Dermatitis and Related Disorders

      • SAVINA ANEJA, BACase Western Reserve University School of Medicine, Cleveland, OH
      • JAMES S TAYLOR, MDDepartment of Dermatology, Dermatology-Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH

      Contact dermatitis is an acute or chronic skin inflammation resulting from interaction with a chemical, biologic, or physical agent. This chapter discusses the major types of contact dermatitis, including irritant contact dermatitis and allergic contact dermatitis (ACD), and their predisposing factors, pathogenesis, diagnosis, risk reduction, and treatment. Also reviewed are specific etiologic forms of contact dermatitis (including topical medication allergy dermatitis, systemic contact dermatitis, clothing, textile and shoe dermatitis, and occupational contact dermatitis) as well as subtypes of contact dermatitis (including photosensitivity and latex allergy dermatitis). Figures show different types of dermatitis (such as chronic eczematous dermatitis, acute and ACD, and photocontact dermatitis), along with specific reactions from causes such as wearing a bib, a leather hatband, or sandals and from poison oak, glyceryl thioglycolate, tosylamide formaldehyde resin, rosin applied to a violin bow, bacitracin, and powdered natural rubber latex gloves. Tables list body sites affected by contact allergens, misconceptions about ACD, criteria for determining who should be given a patch test, key points in diagnosis of ACD, North America patch-test results from 2003 through 2004, topical sensitizers and potential systemic cross-reactants, substances that may cause systemic contact dermatitis, clinical features of systemic contact dermatitis, criteria for establishing occupational causation of contact dermatitis, topical and systemic photosensitizers, and distinguishing features of phototoxic versus photoallergic contact dermatitis. A sidebar lists Internet resources on contact dermatitis.

      This review contains 12 highly rendered figures, 11 tables, and 160 references.

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    • 6

      Cutaneous Adverse Drug Reactions

      By Neil H. Shear, MD, FRCPC; Sandra Knowles, BScPhm; Lori Shapiro, MD, FRCPC
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      Cutaneous Adverse Drug Reactions

      • NEIL H. SHEAR, MD, FRCPCProfessor and Chief of Dermatology, Department of Medicine, Divisions of Dermatology and Clinical Pharmacology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, CA
      • SANDRA KNOWLES, BSCPHMAssistant Professor (Status Only), Department of Pharmacy, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, CA
      • LORI SHAPIRO, MD, FRCPCAssistant Professor of Medicine, Department of Medicine, Division of Dermatology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, CA

      An adverse drug reaction is defined as any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. A cutaneous eruption is one of the most common manifestations of an adverse drug reaction. This chapter reviews the epidemiology, etiology, diagnosis, clinical manifestations, and differential diagnosis of adverse drug reactions, as well as laboratory tests for them. Also discussed are the types of cutaneous eruption: exanthematous eruption, urticarial eruption, blistering eruption, pustular eruption, and others. The simple and complex forms of each type of eruption are reviewed. The chapter includes 4 tables and 12 figures. Tables present the warning signs of a serious drug eruption, clinical features of hypersensitivity syndrome reaction and serum sickness-like reaction, characteristics of Stevens-Johnson Syndrome and toxic epidermal necrolysis, and clinical pearls to identify anticoagulant-induced skin necrosis. Figures illustrate hypersensitivity syndrome reaction, a fixed drug eruption from tetracycline, pseudoporphyria from naproxen, linear immunoglobulin A disease induced by vancomycin, pemphigus foliaceus from taking enalapril, pemphigus vulgaris from taking penicillamine, toxic epidermal necrolysis after starting phenytoin therapy, acneiform drug eruption due to gefitinib, acute generalized exanthematous pustulosis from cloxacillin, coumarin-induced skin necrosis, a lichenoid drug eruption associated with ramipril, and leukocytoclastic vasculitis from hydrochlorothiazide. This chapter contains 106 references.

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    • 7

      Fungal, Bacterial, and Viral Infections of the Skin

      By Jan V. Hirschmann, MD
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      Fungal, Bacterial, and Viral Infections of the Skin

      • JAN V. HIRSCHMANN, MDProfessor of Medicine, University of Washington School of Medicine, Staff Physician, Puget Sound VA Medical Center, Seattle, WA

      The skin can become infected by viruses, fungi, and bacteria, including some that ordinarily are harmless colonizing organisms. The most common fungal infections are caused by dermatophytes, which can involve the hair, nails, and skin. Potassium hydroxide (KOH) preparations of specimens from affected areas typically demonstrate hyphae, and either topical or systemic antifungal therapy usually cures or controls the process. The most common bacterial pathogens are Staphylococcus aureus and group A streptococci, which, alone or together, can cause a wide variety of disorders, including impetigo, ecthyma, and cellulitis. Topical antibiotics may suffice for impetigo, but ecthyma and cellulitis require systemic treatment. S. aureus, including methicillin-resistant strains, can also cause furuncles, carbuncles, and cutaneous abscesses. For these infections, incision and drainage without antibiotics are usually curative. Warts are the most common cutaneous viral infection, and eradication can be difficult, especially where the skin is thick, such as the palms and soles, or the patient is immunocompromised. Most therapies consist of trying to destroy the viruses by mechanical, chemical, or immune mechanisms. This review covers dermatophyte infections, yeast infections, bacterial infections, and viral infections of the skin. Figures show the classic annular lesion of tinea corporis, a typical kerion presenting as a zoophilic Microsporum canis infection of the scalp (tinea capitis), tinea corporis, tinea barbae, tinea pedis between and under the toes and on the plantar surface, inflammatory tinea pedis, tinea unguium, tinea manuum, angular cheilitis, prominent satellite lesions of discrete vesicles associated with candidiasis, facial candidiasis, Candida paronychia, tinea versicolor, nonbullous impetigo, bullous impetigo, ecthyma, leg cellulitis, erythema and edema on the cheeks, eyelids, and nose, furuncle, carbuncle, nasal folliculitis, pitted keratolysis, trichomycosis axillaris, necrotizing fasciitis, Fournier gangrene, folliculitis, plantar wart, condyloma acuminatum, and benign lesions of bowenoid papulosis. Tables list dermatophyte species, terminology of dermatophyte infections, topical agents for dermatophyte infections, treatment options for impetigo (adult doses), and treatment options for erythrasma.

       

      This review contains 28 highly rendered figures, 5 tables, and 33 references

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    • 8

      Infestations

      By Dirk Elston, MD
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      Infestations

      • DIRK ELSTON, MDDirector, Ackerman Academy of Dermatopathology, New York, NY

      This review looks at parasitic diseases of the skin. Scabies, caused by the human itch mite (Sarcoptes scabiei), and pediculosis, caused by the bloodsucking louse, are the most prevalent parasitic diseases in temperate regions. For treatment of scabies, ivermectin is suitable for mass drug administration during severe outbreaks, although patients with heavy scabies infestation may exhibit Mazzotti reactions during treatment with oral ivermectin. Another promising scabicide is Tinospora cordifolia lotion. The increase in global travel has also meant a worldwide increase in parasitic disorders endemic to tropical regions; these disorders include cutaneous larva migrans, pyodermas, arthropod-reactive dermatitis, myiasis, tungiasis, urticaria, and cutaneous and mucocutaneous leishmaniasis. Finally, patients with delusional parasitosis will express the belief that parasitical organisms are infesting their skin. Pimozide, an antipsychotic, has been successfully used to treat delusional parasitosis.

      This module contains 16 highly rendered figures, 2 tables, 15 references, and 5 MCQs.

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    • 9

      Vesiculobullous Diseases

      By Jacob Levitt, MD, FAAD; Annette Czernik, MD, FAAD; Bonnie Koo, MD
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      Vesiculobullous Diseases

      • JACOB LEVITT, MD, FAADVice Chairman, Residency Director, and Associate Professor, The Mount Sinai School of Medicine, New York, NY
      • ANNETTE CZERNIK, MD, FAADAssistant Professor, The Mount Sinai School of Medicine, New York, NY
      • BONNIE KOO, MDUniversity of California, Irvine, Irvine, CA

      Vesiculobullous diseases can be characterized most easily by the anatomic location of the blister cleft, which can result from autoimmune-mediated adhesion protein dysfunction, genetically faulty proteins, drug-induced keratinocyte necrosis, and infectious or traumatic causes. This chapter discusses several paradigmatic vesiculobullous diseases: pemphigus (including pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and Hailey-Hailey disease), bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, linear IgA bullous dermatosis, epidermolysis bullosa, and various infectious vesiculobullous diseases. Clinical presentation, diagnosis and monitoring, and treatment of these diseases are provided. Tables list systemic drugs used for treating pemphigus; the diseases and disease subtypes, protein defects, inheritance patterns, and clinical features of epidermolysis bullosa; and blister planes for various diseases. Figures (30 in all) illustrate presentations of vesiculobullous diseases.

      This review contains 30 figures, 3 tables, and 137 references.

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    • 10

      Malignant Cutaneous Tumors

      By Allan C Halpern, MD; Patricia L. Myskowski, MD
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      Malignant Cutaneous Tumors

      • ALLAN C HALPERN, MDChief, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
      • PATRICIA L. MYSKOWSKI, MDAttending Physician, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY

      This chapter reviews the most common malignant cutaneous tumors. The section on malignant tumors of the epidermis discusses nonmelanoma skin cancer (i.e., basal cell carcinoma and squamous cell carcinoma) and malignant melanoma. The section on malignant tumors of the dermis covers metastatic tumors, primary tumors (Merkel cell carcinoma, Paget disease, extramammary Paget disease, angiosarcoma, and dermatofibrosarcoma protuberans), and Kaposi sarcoma (i.e., classic Kaposi sarcoma, African Kaposi sarcoma, organ-transplant Kaposi sarcoma, and HIV-associated Kaposi sarcoma). The final section covers cutaneous lymphomas. The coverage of each disease includes a discussion of epidemiology, etiology, diagnosis, differential diagnosis, treatment, and prognosis. Tables provide the adjusted estimated relative risks of melanoma by nevus type and number, the American Joint Committee on Cancer (AJCC) TNM classification and staging system, the estimated probability of 10-year survival in patients with primary cutaneous melanoma, and an overview of overview of therapy for cutaneous T cell lymphoma. Figures illustrate the presentation of many malignant cutaneous tumors.

      This review contains 10 highly rendered figures, 5 tables, and 105 references.

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    • 11

      Benign Cutaneous Tumors

      By Elizabeth A Abel, MD
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      Benign Cutaneous Tumors

      • ELIZABETH A ABEL, MDAdjunct Clinical Professor of Dermatology, Stanford University School of Medicine, Stanford, CA, Private Practice, California Skin Institute, Mountain View, CA

      Tumors of the cutaneous surface may arise from the epidermis, dermis, or subcutaneous tissue or from any of the specialized cell types in the skin or its appendages. Broad categories include tumors derived from epithelial, melanocytic, or connective tissue structures. Within each location or cell type, lesions are classified as benign, malignant, or, in certain cases, premalignant. Benign epithelial tumors include tumors of the surface epidermis that form keratin, tumors of the epidermal appendages, and cysts of the skin. Melanocytic (pigment-forming) lesions are very common. One of the most frequently encountered forms is the nevus cell nevus. Tumors that are derived from connective tissue include fibromas, histiocytomas, lipomas, leiomyomas, and hemangiomas. This chapter provides an overview of each type of tumor, including sections on epithelial tumors, tumors of the epidermal appendages, familial tumor syndromes, melanocytic tumors, neural tumors, connective tissue tumors, vascular birthmarks, acquired vascular disorders, Kimura disease, lipoma, leiomyoma, and lymphangioma circumscriptum. The sections discuss various forms and their diagnosis, differential diagnosis, and treatment. Figures accompany the descriptions.

      This chapter contains 83 references, 26 highly rendered figures, and 5 MCQs.

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    • 12

      Acne Vulgaris and Rosacea

      By James Q Del Rosso, DO
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      Acne Vulgaris and Rosacea

      • JAMES Q DEL ROSSO, DOAdjunct Clinical Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, NV

      Acne vulgaris is the most common disorder seen in general dermatology practice, accounting for approximately 10% of visits each year. Both sexes and all ethnicities are affected, usually in the late preteenage or early teenage years. Both inflammatory and comedonal lesions of acne vulgaris characteristically involve the face, but truncal involvement is also relatively common. Multiple clinical presentations may be observed, with severity often progressing over time during adolescence. Severe forms of acne vulgaris can be especially disfiguring and debilitating, and are more likely to lead to permanent scarring. Therapeutic options are chosen primarily on the basis of clinical severity, with adjustments in treatment made on the basis of response or disease progression. Rosacea begins in adulthood, usually in the third decade of life or later. The disorder predominantly affects the central face in fair-skinned people, mostly those of northern European ancestry, although individuals of any race may be affected. Rosacea may present as one or more of a variety of clinical phenotypes (subtypes); it is a chronic disorder characterized by periods of exacerbation and remission. Fortunately, rosacea is not associated with scarring, although a subset of patients may develop localized proliferations of sebaceous and fibrous tissue called a phyma. Like acne vulgaris, rosacea may also adversely impact quality of life. Figures in this chapter illustrate acne vulgaris and inflammatory papules. Tables detail laboratory evaluation for women with acne vulgaris and hyperandrogenism, surgical/physical modality options for specific acne lesions and acne scars, major topical therapies for acne vulgaris, and commonly prescribed systemic therapies for acne. This chapter contains 50 references.

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    • 13

      Disorders of Hair

      By James Q Del Rosso, DO
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      Disorders of Hair

      • JAMES Q DEL ROSSO, DOAdjunct Clinical Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, NV

      A basic knowledge of the hair growth cycle is needed to evaluate disorders of hair growth. This chapter presents a broad overview of the physiology and evaluation of hair growth, as well as discussions of specific types of alopecia. The epidemiology, pathogenesis, diagnosis, and treatment of androgenetic alopecia, the most common type of nonscarring hair loss, are covered. Diffuse hair shedding is generalized hair loss over the entire scalp. Diagnosis and treatment of telogen effluvium, anagen arrest (anagen effluvium), and other causes of diffuse hair shedding are covered in detail. Alopecia areata, typically characterized by patchy hair loss; cicatricial alopecia, which results from permanent scarring of the hair follicles; and miscellaneous causes of hair loss are also discussed. Tables list the causes of diffuse and cicatricial alopecia, telogen effluvium, and miscellaneous chemicals and categories of drugs that can cause alopecia, as well as miscellaneous causes of hair loss. Included is an algorithm outlining the approach to diagnosing nonscarring alopecia, as well as a variety of clinical photographs.

      This review contains 9 highly rendered figures, 6 tables, and 42 references.

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    • 14

      Diseases of the Nail Unit

      By Jennifer Nguyen, MD; George Cotserelis, MD
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      Diseases of the Nail Unit

      • JENNIFER NGUYEN, MDAssistant Professor of Dermatology, Department of Dermatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA
      • GEORGE COTSERELIS, MDMilton Bixler Hartzell Professor of Dermatology, Department of Dermatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA

      The human nail is a complex unit that includes five major modified cutaneous structures: the nail matrix, nail bed, nail plate, nail folds, and cuticle (eponychium). This chapter discusses the function and structure of the five nail components and the pathophysiology affecting each. Also reviewed are nail findings associated with underlying systemic and dermatologic conditions: splinter hemorrhages, koilonychia, transverse nail-plate depressions (Beau’s lines), onycholysis, leukonychia, clubbing, nail-plate pitting, and longitudinal pigmented bands. Infections of the nail are discussed, which include bacterial paronychia, chronic paronychia, and onychomycosis. Figures illustrate the longitudinal section of the fingernail, multiple pigmented longitudinal bands, psoriasis involving the fingernail, late-stage lichen planus of the fingernail, transverse linear grooves, Pseudomonas aeruginosa causing a green nail, psoriasis of the nail, melanonychia striata, and a nail specimen for potassium hydroxide preparation. Tables describe antifungal treatment for toenail onychomycosis as well as selected dermatologic disorders that affect the nail unit. This chapter contains 50 references.

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    • 15

      Disorders of Pigmentation

      By Pearl E. Grimes, MD
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      Disorders of Pigmentation

      • PEARL E. GRIMES, MDClinical Professor of Dermatology, Division of Dermatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA; Director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, CA

      The disorders of skin pigmentation discussed in this chapter fall into two categories: disorders of hyperpigmentation (melasma, postinflammatory hyperpigmentation, drug-induced hyperpigmentation, erythema dyschromicum perstans, lentigines, confluent and reticulated papillomatosis of Gougerot and Carteaud, and Dowling-Degos disease) and disorders of hypopigmentation (vitiligo, albinism, piebaldism, and idiopathic guttate hypomelanosis). The definition, epidemiology, etiology and pathogenesis, diagnosis, differential diagnosis, and treatment are discussed for each condition. Figures show examples of melasma, hyperpigmentation secondary to acne, vitiligo and its response to treatment with tacrolimus and with narrow-band ultraviolet B (UVB) light, Vogt-Koyanagi-Harada syndrome, and piebaldism. A table lists therapeutic approaches to vitiligo. This chapter contains 182 references.

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    • 16

      Pruritus

      By Hong-Liang Tey, MRCP(UK); Gil Yosipovitch, MD; Jeffrey D Bernhard, MD, FRCP(Edin)
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      Pruritus

      • HONG-LIANG TEY, MRCP(UK)Consultant, National Skin Centre, Singapore
      • GIL YOSIPOVITCH, MDProfessor and Chair, Department of Dermatology and Itch Center, Temple University School of Medicine, Philadelphia, PA
      • JEFFREY D BERNHARD, MD, FRCP(EDIN)Editor Emeritus, Journal of the American Academy of Dermatology, Professor Emeritus, University of Massachusetts Medical School, MA

      Pruritus, or itch, can be defined as a sensation that elicits the desire to scratch. Normal physiologic "acute" itch occurs daily and can usually be abolished by scratching the affected area. On the other hand, chronic itch (defined as itch that persists for 6 weeks or more) is often made worse by scratching and is associated with significant morbidity. The focus of this chapter is on chronic pruritus. Discussion includes causes, clinical evaluation, investigation of, and treatment for chronic pruritus. Tables cover the etiologic classification of chronic pruritus, a morphologic approach to typically pruritic dermatoses and their classic distribution (with illustrative images), systemic diseases and associated clinical signs, localized pruritus and underlying neuropathy, screening tests for pruritus, further investigations following results of clinical findings and screening tests, general measures for patients managing pruritus, topical treatment, topical calcineurin inhibitors, systemic therapies, recommended stepwise treatment options, and phototherapy. Also included are a patient history checklist, an algorithm outlining the approach to chronic pruritus, and images depicting various forms of pruritus.

      This review contains 16 highly rendered figures (including table images), 13 tables, and 41 references.

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    • 17

      Cutaneous Manifestations of Systemic Diseases

      By Mark Lebwohl, MD
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      Cutaneous Manifestations of Systemic Diseases

      • MARK LEBWOHL, MDSol and Clara Kest Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York City, NY

      This chapter reviews key cutaneous manifestations of systemic diseases that should be recognized by most physicians and highlights recent developments in the diagnosis and management of those disorders. In many of the disorders presented, workup and therapy of the underlying systemic condition are essential to a favorable outcome. Cardiopulmonary, vascular, endocrinologic, gastrointestinal, hematologic, immunodeficiency, infectious, neurologic, renal, and rheumatologic diseases are discussed. Many of the syndromes characterized by physical symptoms are accompanied by photographs demonstrating the manifestations for the reader's reference.

      This review contains 28 figures and 104 references.

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  • Endocrinology & Metabolism
    • 1

      Approach to the Patient With Endocrine Disorders

      By Graham T McMahon, MD, MMSc; Robert G. Dluhy, MD
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      Approach to the Patient With Endocrine Disorders

      • GRAHAM T MCMAHON, MD, MMSCAssociate Professor of Medicine, Harvard Medical School, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA
      • ROBERT G. DLUHY, MDProfessor of Medicine, Harvard Medical School, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA

      The distribution of hormones throughout the human body results in presentations of endocrine disease that are diffuse and variable. Although some endocrine syndromes result in characteristic sets of symptoms and features, most patients experience a limited number of components of the syndrome and may note symptoms that are not typically syndromic. This review discusses presentations of endocrine diseases and the endocrine patient. Specific attention is given to endocrine testing, which can be achieved by measuring the hormone itself, stimulating or suppressing a hormone feedback loop, or measuring peripheral hormone receptor function. The chronic care relationship is explored as many patients with endocrine diseases require extended chronic care to achieve control of abnormal hormonal systems. The dependency on chronic care necessitates that endocrinologists develop particular expertise in managing illnesses over the long term. Tables list hormones and their associated syndromes, clusters of contrasting symptoms and signs of over- and underactivity of the thyroid and adrenal glands, approaches to endocrine testing and treatment, and variability in selected hormone concentrations over time. Figures show diagnostic criteria related to hypercalcemia, growth hormone deficiency, acromegaly, and adrenal incidentaloma. The chronic care model is also represented.

      This review contains 4 highly rendered figures, 4 tables, and 12 references.

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    • 2

      Adrenal Insufficiency

      By D. Lynn Loriaux, MD, PhD, MACP
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      Adrenal Insufficiency

      • D. LYNN LORIAUX, MD, PHD, MACPProfessor of Medicine and Chief, Division of Endocrinology and Metabolism, Oregon Health and Science University, Portland, OR

      Adrenal insufficiency (Addison disease) can be categorized as primary or secondary; the former results from adrenal cortex destruction, whereas the latter is caused by disruption of pituitary secretion of adrenocorticotropic hormone. The clinical pictures are the same, and their signs can be differentiated only by the presence of hyperpigmentation and vitiligo in autoimmune disease. Diagnosing both chronic and acute syndromes requires laboratory confirmation; however, the only available diagnostic test for adrenal insufficiency is cosyntropin stimulation. Relative adrenal insufficiency is a hypothetical situation stemming from misinterpretation of this test, and there is no pathophysiologic evidence of its existence. The most common form of congenital adrenal hyperplasia is the 21-hydroxylase deficiency syndrome.

      This module contains 1 highly rendered figure, 2 tables, 4 references, and 5 MCQs.

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    • 3

      Cushing Syndrome

      By Lynnette Nieman, MD
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      Cushing Syndrome

      • LYNNETTE NIEMAN, MDProgram on Adult and Reproductive Endocrinology, National Institutes of Health, Bethesda, MD

      Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed.

      This chapter contains 5 highly rendered figures, 6 tables, 49 references, and 5 MCQs.

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    • 4

      Adrenal Hypertension

      By Naomi D.L. Fisher, MD; Gail K Adler, MD, PhD
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      Adrenal Hypertension

      • NAOMI D.L. FISHER, MDDivision of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, MA
      • GAIL K ADLER, MD, PHDDivision of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Boston, MA

      The secondary causes of hypertension are associated with the excess of the principal hormones produced by the adrenal glands: cortisol, epinephrine, and aldosterone. Excess aldosterone production is recognized as primary hyperaldosteronism, or primary aldosteronism (PA). Individuals with PA are at increased risk for a variety of disorders, including atrial fibrillation, coronary artery disease, myocardial infarction, and stroke. Pheochromocytoma is a very rare tumor (accounting for fewer than one in 10,000 hypertension cases) and is marked by high secretions of catecholamines, mostly epinephrine as well as norepinephrine. Cushing disease and Cushing syndrome are addressed in a separate review.

      This review contains 5 highly rendered figures, 4 tables, and 39 references.

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    • 5

      Adrenal Neoplasia

      By Anand Vaidya, MD, MMSc
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      Adrenal Neoplasia

      • ANAND VAIDYA, MD, MMSCDirector, Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

      The adrenal glands are composed of two distinct tissue types: the cortex, which serves as a factory for adrenal steroidogenesis, and the medulla, which produces catecholamines as a neuroendocrine organ. Neoplasia of the adrenal is approached by considering both whether the tumor is benign or malignant and whether it may represent a hormonally active tumor that can contribute to cardiometabolic disease or a hormonally silent tumor. Adrenal neoplasia is rarely malignant. This module discusses the approach to an incidentally discovered adrenal mass, with emphasis on the clinical determination as to whether it is benign or malignant and hormonally functional or nonfunctional. The pathogenesis and genetics of hyperaldosteronism and pheochromocytoma-paraganglioma are reviewed, as are the pathogenesis and management of adrenocortical carcinoma. Tables describe the differential diagnosis and diagnostic approach for an incidentally discovered adrenal mass; suggested biochemical screening tests for incidentally discovered adrenal masses; radiographic features of adrenal masses to determine benign or malignant potential; and the genetics of primary hyperaldosteronism, pheochromocytoma, and paraganglioma syndromes. A drawing shows the genetic mechanisms of hyperaldosteronism in familial hyperaldosteronism type III. Algorithms outline the suggested management approach for the incidentally discovered adrenal mass, genetic counseling and testing for patients with pheochromocytoma or paraganglioma, testing for family members of patients with pheochromocytoma and positive genetic testing, patients with stage I–III adrenocortical carcinoma, and patients with advanced adrenocortical carcinoma.

      This module contains 6 highly rendered figures, 6 tables, 55 references, and 5 MCQs.

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    • 6

      The Pituitary

      By Shlomo Melmed, MD, FACP
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      The Pituitary

      • SHLOMO MELMED, MD, FACPSenior Vice President, Academic Affairs, Dean of Medical Faculty, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048

      The pituitary gland plays a prominent role in regulating the critical hormonal functions of growth, development, reproduction, stress homeostasis, and metabolic control; for this reason, the pituitary has been termed the master gland. The anterior pituitary synthesizes and secretes adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The posterior pituitary secretes vasopressin (also known as antidiuretic hormone [ADH]) and oxytocin, which are synthesized in the hypothalamus. This chapter describes genetic syndromes associated with pituitary tumors, including multiple endocrine neoplasia type 1. Information is provided on the diagnosis and treatment of disorders associated with the underproduction and hypersecretion of pituitary hormones, including Cushing syndrome, pituitary mass effects, and pituitary failure. Figures illustrate pituitary anatomy and physiology and management of prolactinoma. Tables describe hypothalamic and related pituitary hormones; pituitary hormones, their mediators, and their effects; effects of pituitary adenomas; causes of hyperprolactinemia; dopamine agonists in the treatment of prolactinomas; findings in adult GH deficiency; causes and features of acromegaly; clinical features of Cushing syndrome; causes of pituitary failure; and replacement therapy for hypopituitarism in adults.

      This review contains 4 references, 11 tables, and 43 references.

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    • 7

      The Thyroid

      By Paul W. Ladenson, MD
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      The Thyroid

      • PAUL W. LADENSON, MDJohn Eager Howard Professor of Endocrinology & Metabolism, Professor of Medicine, Pathology, Oncology, Radiology & Radiological Sciences, and International Health, University Distinguished Service Professor, Director, Division of Endocrinology & Metabolism, Johns Hopkins Medical Institutions, Baltimore, Maryland

      Thyroid disorders are the most common endocrine conditions encountered in clinical practice and can range from clinically obvious to clinically silent. This review provides the definition and epidemiology of the conditions of hypothyroidism and hyperthyroidism. Hypothyroidism can be congenital or acquired, and its pathogenesis, diagnosis, and management are presented. The three most common disorders of thyrotoxicosis (diffuse toxic goiter [Graves disease], toxic nodular goiter, and iatrogenic thyrotoxicosis in thyroid hormone–treated patients are addressed, as well as the many diseases in each of these categories. This review also discusses thyroiditis, goiter, thyroid nodules, and thyroid cancer. Tables list the causes of elevated serum thyroid-stimulating hormone (TSH) levels, the etiologic classification of thyrotoxicosis, characteristic features of thyroiditis, and causes of elevated serum total thyroxine levels. Figures show the prevalence of abnormalities in thyroid function tests in different populations, certain forms of hyperthyroidism that result from pathophysiologic activation of the TSH receptor, and inflammation of thyroid tissue in acute thyroiditis.

      This review contains 3 highly rendered figures, 4 tables, and 126 references.

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    • 8

      Diseases of Calcium Metabolism and Metabolic Bone Disease

      By Carolyn Becker, MD
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      Diseases of Calcium Metabolism and Metabolic Bone Disease

      • CAROLYN BECKER, MDAssociate Professor, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

      Hypercalcemia and hypocalcemia are common metabolic disturbances affecting a wide range of patients. Metabolic bone disease is more common in the older population and places enormous burdens on both patients and the population at large; hip fractures carry the highest morbidity and mortality of all fractures, and death can occur from associated complications, such as pulmonary embolism or pneumonia. This review discusses the role of body calcium stores and how depletion can manifest as abnormalities of bone turnover, architecture, mineralization, density, and strength. The clinical manifestations, history and physical examination, laboratory studies, differential diagnoses, and treatment of hypercalcemia, hypocalcemia, and metabolic bone disease, including osteoporosis, osteomalacia, and Paget disease, are discussed. Emphasis is placed on mitigation of risk factors. Emerging therapies for osteoporosis are also covered. Tables include the differential diagnoses of hypercalcemia and hypocalcemia, guidelines on follow-up testing for patients with hyperparathyroidism without surgery, and risk factors and therapies for osteoporosis. Figures illustrate circulating concentrations of ionized calcium in the body, how osteoclast precursors mature into multinucleated cells, and radiographs of typical fractures. 

      This review contains 5 highly rendered figures, 9 tables, 114 references, and a list of internet resources for osteoporosis and bone metabolism.

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    • 9

      Testes and Testicular Disorders

      By Elizabeth G Nabel, MD, FACP
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      Testes and Testicular Disorders

      • ELIZABETH G NABEL, MD, FACPPresident, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

      The testes begin to function in utero and continue to function into senescence, with the major roles of testosterone secretion and sperm production. This review discusses how testicular function can be affected by diseases of the hypothalamus and pituitary, as well as by diseases of the testes themselves. These diseases may be either congenital or acquired. The clinical manifestation, history and physical examination, laboratory studies, diagnoses, and treatment of these diseases, as well as other conditions, including gynecomastia and erectile dysfunction, are discussed. Specific therapies, such as the off-label use of tamoxifen (gynecomastia) and the various oral phosphodiesterase inhibitors (for erectile dysfunction), are also covered. Tables list the causes of primary and secondary hypogonadism. Figures illustrate the serum concentration of testosterone in healthy men and how concentrations differ during the course of long-term administration of three different testosterone preparations for hypogonadal men.

      This review contains 2 highly rendered figures, 2 tables, and 62 references.

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    • 10

      Type 1 Diabetes Mellitus

      By Joseph I. Wolfsdorf, MB, BCh; Katharine Garvey, MD, MPH
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      Type 1 Diabetes Mellitus

      • JOSEPH I. WOLFSDORF, MB, BCHProfessor of Pediatrics, Harvard Medical School, Boston, MA
      • KATHARINE GARVEY, MD, MPHInstructor of Pediatrics, Harvard Medical School, Boston, MA

      Type 1 diabetes mellitus is a heterogeneous metabolic disease characterized by destruction of the pancreatic beta cells resulting in an absolute deficiency of insulin secretion with subsequent hyperglycemia. This review details the definition and classification, epidemiology, pathophysiology, pathogenesis, prevention, diagnosis, and management of type 1 diabetes mellitus. Figures show the opposing actions of insulin and glucagon, particularly within the liver, on substrate flow and plasma levels; plasma glucose, insulin and C-peptide levels; the structure of human proinsulin; the cellular actions of insulin; measurement of insulin levels after the administration of glucose; the pathways that lead from insulin deficiency to the major clinical manifestations of type 1 diabetes mellitus; the pathogenesis of type 1 autoimmune diabetes mellitus; the relationship between hemoglobin A1C and calculated average glucose level; basal-bolus and insulin pump regimens; and management of diabetic ketoacidosis. Tables list the etiologic classification of diabetes mellitus, criteria for the diagnosis of diabetes, American Diabetes Association standards for glycemic control in diabetes mellitus, insulin preparations, potential advantages of continuous subcutaneous insulin infusion compared with multiple daily injections, cardiovascular risk factor screening and treatment, and typical admission laboratory findings and monitoring in diabetic ketoacidosis.

      This review contains 10 highly rendered figures, 7 tables, and 66 references.

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    • 11

      Hypoglycemia

      By F John Service, MD, PhD; Adrian Vella, MD
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      Hypoglycemia

      • F JOHN SERVICE, MD, PHDEmeritus Professor of Medicine, Mayo Clinic College of Medicine, Rochester, MN
      • ADRIAN VELLA, MDProfessor of Medicine, Mayo Clinic College of Medicine, Rochester, MN

      Hypoglycemia is a clinical syndrome that has diverse causes and is characterized by episodes of low blood glucose and typically marked by autonomic and neuroglycopenic manifestations. This review discusses the classification, etiology, and diagnosis for hypoglycemia, including the Whipple triad, and the classic diagnostic test, the prolonged (72-hour) fast. Specific attention is given to the conditions that cause hypoglycemia, including insulinomas, factitious hypoglycemia, insulin autoimmune hypoglycemia, and post–gastric bypass hypoglycemia, as well as the diagnosis and management of these conditions. Tables show the clinical classification of hypoglycemic disorders and the protocol for prolonged supervised fast. Figures illustrate levels of serum glucose compared with serum levels of insulin during a 72-hour fast and pancreatic ducts revealing nesidioblastosis.

      This review contains 2 highly rendered figures, 2 tables, and 43 references.

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    • 12

      Type 2 Diabetes Mellitus

      By Matthew C. Riddle, MD; Saul Genuth, MD, FACP
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      Type 2 Diabetes Mellitus

      • MATTHEW C. RIDDLE, MDProfessor, Department of Medicine, and Head, Section of Diabetes, Oregon Health & Sciences University, Portland, OR
      • SAUL GENUTH, MD, FACPProfessor, Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, OH

      Type 2 diabetes mellitus (DM) is defined by high levels of plasma glucose and is associated with many long-term complications caused or enhanced by hyperglycemia and related metabolic abnormalities. This chapter discusses prediabetes; the metabolic syndrome; and the epidemiology, risk factors, pathophysiology, pathogenesis, prevention, screening, diagnosis, and management of type 2 DM. Figures illustrate the age-related prevalence of diabetes in the United States; insulin response to a graded infusion of glucose; insulin resistance in lean and obese diabetic and nondiabetic persons; plasma glucose, insulin, and glucagon responses to glucose ingestion in patients with type 2 DM; typical 24-hour glucose and insulin patterns in patients with type 2 DM; and the prevalence of retinopathy before and after the diagnosis of DM. Tables list American Diabetes Association diagnostic criteria for impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM; and formulations and properties of oral and parenteral drugs commonly used for type 2 DM. This chapter contains 113 references.

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    • 13

      Gestational Diabetes Mellitus

      By Ellen W. Seely, MD; Chloe A. Zera, MD, MPH
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      Gestational Diabetes Mellitus

      • ELLEN W. SEELY, MDDirector of Clinical Research, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
      • CHLOE A. ZERA, MD, MPHDivision of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

      Gestational diabetes mellitus (GDM) has historically been defined as glucose intolerance first identified during pregnancy. The definition fails to distinguish overt (pre-gestational) diabetes diagnosed during pregnancy from glucose intolerance induced by pregnancy. Recently, the recognition that overt diabetes may first be identified in pregnancy has led to the recommendation that diabetes diagnosed in the first trimester should be termed type 2 diabetes (T2DM) rather than GDM , a clinically relevant difference in terminology as the outcomes and management of T2DM in pregnancy are distinct from outcomes and management of GDM. This chapter discusses the epidemiology, pathophysiology, screening, diagnosis, treatment and impact of GDM, as well as the obstetric management of GDM and management of GDM after pregnancy. Tables describe the risk factors for, and complications of, GDM; the diagnosis of pregestational (overt) diabetes; a comparison of third-trimester GDM diagnostic strategies; and Institute of Medicine gestational weight gain guidelines. A figure shows the cumulative incidence of type 2 diabetes following GDM pregnancy. This chapter contains 57 references.

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    • 14

      Complications of Diabetes Mellitus

      By Samuel Dagogo-Jack, MD, MBBS, FRCP, FACP
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      Complications of Diabetes Mellitus

      • SAMUEL DAGOGO-JACK, MD, MBBS, FRCP, FACPA. C. Mullins Professor & Chief, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, TN

      The long-term complications of diabetes mellitus include microvascular, neuropathic, and macrovascular complications. Due to the long period of asymptomatic or undiagnosed diabetes, up to 25% of type 2 diabetes patients have already developed one or more microvascular complication by the time of diagnosis. This review covers microvascular complications, nephropathy, neuropathy, and macrovascular complications of diabetes mellitus. Figures show the pathways linking high blood glucose levels to the microvascular and neuropathic complications of diabetes, fundus photographs of both nonproliferative (or background) and proliferative retinopathy, the natural history of nephropathy in type 1 diabetes, data on the cumulative incidence of the first cardiovascular event and first nonfatal myocardial infarction, stroke, or death from the Diabetes Control and Complications Trial. Tables list screening for diabetes complications in adults, foot care recommendations for patients with diabetes, comparison of major trials of intensive glucose control and CVD outcomes, cardiovascular outcome studies with newer classes of antidiabetes agents, American Diabetes Association treatment recommendations for dyslipidemia in patients with diabetes, and targets of intervention for CVD risk reduction in diabetes,

       This review contains 8 highly rendered figures, 6 tables, and 120 references.

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    • 15

      Secondary Forms of Diabetes Mellitus

      By Ildiko Lingvay, MD, MPH, MSCS; Philip Raskin, MD, FACP
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      Secondary Forms of Diabetes Mellitus

      • ILDIKO LINGVAY, MD, MPH, MSCSAssistant Professor, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
      • PHILIP RASKIN, MD, FACPProfessor of Medicine, Clifton and Betsy Robinson Chair in Biomedical Research, University of Texas Southwestern Medical Center at Dallas, Director, University Diabetic Treatment Center, Parkland Memorial Hospital, Dallas, TX

      Secondary forms of diabetes mellitus are those cases of diabetes mellitus that have a specific identifiable cause and do not meet the diagnostic criteria for type 1, type 2, or gestational diabetes. This review discusses the etiology, pathogenesis, diagnosis, management, complications, and prognosis of these forms, which include diabetes mellitus occurring as a result of pancreatic disorders; endocrinopathies; drugs, chemical agents, or toxins; and genetic mutations or syndromes. Tables list the endocrinopathies; the drug, chemicals, and toxins; and the genetic disorders causing secondary forms of diabetes mellitus.

      This review contains 3 tables and 15 references.

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    • 16

      Obesity

      By Jonathan Q. Purnell, MD
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      Obesity

      • JONATHAN Q. PURNELL, MDAssociate Professor, Department of Medicine, and Medical Director, Multidisciplinary Obesity Clinic, Oregon Health & Science University, Portland, OR

      Obesity and its associated disorders are leading causes of morbidity and premature mortality around the world, and in the United States, the prevalence of overweight and obese adults has increased over the past several decades. This review discusses how identifying factors contributing to obesity can result from not only establishing the patient’s dietary and activity habits but also from assessing for secondary causes of obesity. Comorbid conditions as a result of obesity are discussed; these can be severe and include hypertension, impaired glucose tolerance or diabetes, hyperlipidemia, heart disease, pulmonary disease, gastroesophageal reflux, and sleep apnea. Treatment modalities, in addition to lifestyle changes, are presented and include pharmacologic agents with one of the Food and Drug Administration (FDA)-approved medications or with surgical options (laparoscopic gastric banding, biliopancreatic diversion, and Roux-en-Y gastric bypass). Tables include the classification of weight and risk for comorbid conditions, the criteria for metabolic syndrome, the medications commonly associated with weight gain and obesity, FDA-approved medications for obesity treatment, and the most commonly used bariatric procedures. Figures show body mass index representations of both overweight and obese; a feedback model for body weight regulation in humans based on data from animal models; and the evaluation, laboratory testing, and treatment of overweight and obese patients.

      This review contains 3 highly rendered figures, 5 tables, and 172 references.

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    • 17

      Diagnosis and Treatment of Dyslipidemia

      By John D. Brunzell, MD, FACP; R Alan Failor, MD
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      Diagnosis and Treatment of Dyslipidemia

      • JOHN D. BRUNZELL, MD, FACPProfessor Emeritus, Active, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98195
      • R ALAN FAILOR, MDClinical Professor, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98195

      Disorders of lipoprotein metabolism in conjunction with the prevalence of high-fat diets, obesity, and physical inactivity have resulted in an epidemic of atherosclerotic disease in the United States and other developed countries. The interaction of genetic disorders with these adverse environmental factors leads to the premature development of atherosclerosis. This chapter discusses lipoprotein composition and metabolism and the genetic and environmental defects that can lead to dyslipidemias. Primary disorders of dyslipidemia discussed include the metabolic syndrome, familial combined hyperlipidemia, familial hypertriglyceridemia, familial hypercholesterolemia (both heterozygous and homozygous), familial defective apolipoprotein B-100, a disorder causing increased levels of lipoprotein(a), and remnant removal disease. Secondary disorders discussed include those caused by endocrine disorders, renal disorders, and gastrointestinal disorders. The clinical manifestations of hyperlipidemia and how they correspond to specific lipid disorders are presented, including abnormal levels of lipoproteins, cutaneous manifestations (e.g., xanthomas), signs and symptoms that constitute the chylomicronemia syndrome, and nonalcoholic fatty liver disease. Management principles, including diet and exercise modification and drug therapy, are discussed for patients with elevated cholesterol levels, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol, and atherosclerosis accompanied by normal lipid levels. Primary and secondary prevention of coronary artery disease using statins, bile-acid sequestrants, fibrates, and niacin are covered. Management recommendations for patients of varied age groups are reviewed, including screening for hypercholesterolemia in children, the management of dyslipidemia in women, and the management of dyslipidemia in older patients. The eight tables present the major apolipoproteins and their functions, the Adult Treatment Panel III (ATP-III) classifications of the various lipid levels, the effects of selected drugs on lipoprotein levels, the clinical features of the metabolic syndrome, the ATP-III low-density lipoprotein (LDL) cholesterol goals and cutpoints for therapeutic lifestyle changes and drug therapy in different risk categories, ATP-III major risk factors that modify LDL cholesterol goals, drug treatment for lipid disorders, and doses of statins required to achieve a 30% to 40% reduction of LDL cholesterol levels. The six figures illustrate aspects of lipid metabolism. This chapter contains 108 references.

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    • 18

      Metabolic Disorders: Inborn Errors of Carbohydrate Metabolism

      By Sameer S Chopra, MD, PhD; Gerald T Berry, MD
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      Metabolic Disorders: Inborn Errors of Carbohydrate Metabolism

      • SAMEER S CHOPRA, MD, PHDClinical Fellow in Medicine, Dana-Farber Cancer Institute, Boston, MA
      • GERALD T BERRY, MDDirector, Metabolism Program, Division of Genetics and Genomics, Boston's Children's Hospital, Boston, MA

      The small-molecule diseases include inborn errors of carbohydrate metabolism, ammonia, amino acid, organic acid, and fatty acid metabolism. Many of these entities are now routinely detected through newborn screening in most states in the United States. Although several of these diseases have effective therapies that largely eliminate the signs and symptoms, in many, the disease process is without an effective treatment or may be brought under control but not corrected. Newborn screening and/or the implementation of effective therapy in infancy and childhood are now allowing patients to survive into adulthood. Many variant or hypomorphic gene mutations are now being detected, and the affected patients are not manifesting clinical disease until late adolescence or adulthood. This chapter reviews the essential features of the diagnosis, treatment, and, where appropriate, natural history of inborn errors of carbohydrate metabolism, including the glycogen storage diseases with primary hepatic involvement and fasting hypoglycemia. The inborn errors of amino acids, ammonia, organic acid, and fatty acid metabolism are reviewed. A figure shows the process of galactose metabolism.

      This chapter contains 1 highly rendered figure, 7 references, 9 suggested readings, and 5 MCQs.

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    • 19

      Metabolic Disorders: Inborn Errors of Amino Acid, Ammonia, Organic Acid, and Fatty Acid Metabolism

      By Sameer S Chopra, MD, PhD; Gerard T Berry, MD
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      Metabolic Disorders: Inborn Errors of Amino Acid, Ammonia, Organic Acid, and Fatty Acid Metabolism

      • SAMEER S CHOPRA, MD, PHDClinical Fellow in Medicine, Dana-Farber Cancer Institute, Boston, MA
      • GERARD T BERRY, MDDirector, Metabolism Program, Division of Genetics and Genomics, Boston's Children's Hospital, Boston, MA

      The small molecule diseases include inborn errors of carbohydrate, ammonia, amino acid, organic acid, and fatty acid metabolism. They are central among the biochemical genetic disorders that may present with life-threatening illnesses during infancy and childhood. Many of these disorders are now detected through routine newborn screening. Internists should be familiar with small molecule metabolic disorders as early diagnosis and therapy may enable many patients to survive into adulthood. Additionally, because some patients may not manifest symptoms until late adolescence or adulthood, recognition of the possibility of an inborn error of metabolism in a patient with unusual signs or symptoms may lead to referral to a metabolic specialist and timely diagnosis and treatment. This module reviews the diagnosis, treatment, and natural history of disorders of amino acid, ammonia, organic acid, and fatty acid metabolism. Figures show the methionine-homocysteine-cysteine pathway and branched-chain amino acid metabolism.

      This module contains 2 highly rendered figures, 18 references, 53 recommended readings, and 5 MCQs.

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    • 20

      The Porphyrias

      By Karl E Anderson, MD, FACP; Attallah Kappas, MD
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      The Porphyrias

      • KARL E ANDERSON, MD, FACPProfessor, Departments of Preventive Medicine and Community Health, Internal Medicine, and Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX
      • ATTALLAH KAPPAS, MDSherman Fairchild Professor, Physician-in-Chief, Emeritus, The Rockefeller University, Attending Physician, Rockefeller University Hospital, New York, NY

      The porphyrias are uncommon disorders caused by deficiencies in the activities of enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias are inherited, with the exception of porphyria cutanea tarda, which is primarily acquired. In all porphyrias, there is significant interplay between genetic traits and acquired or environmental factors in the expression of clinical symptoms. This review discusses the classification, pathophysiology, and clinical presentations of the porphyrias. These include those associated with neurovisceral attacks (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase [alad] deficiency porphyria) and the porphyrias associated with cutaneous photosensitivity (porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, and congenital erythropoietic porphyria). Specific emphasis on the epidemiology, molecular defects and pathophysiology, clinical features, diagnosis, and treatment are discussed for each of these disorders.A table lists the safe and unsafe drugs for patients with porphyrias. Figures illustrate the genetic pathways of the disorders and the activities of enzymes of the heme biosynthetic pathway.

      This review contains 2 highly rendered figures, 1 table, and 96 references.

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  • Ethics & Professionalism
    • 1

      Management of Psychosocial Issues in Terminal Illness

      By Jane DeLima Thomas, MD; Eva Reitschuler-Cross, MD; Susan D Block, MD
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      Management of Psychosocial Issues in Terminal Illness

      • JANE DELIMA THOMAS, MDAttending Physician, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Instructor in Medicine, Harvard Medical School, Boston, MA
      • EVA REITSCHULER-CROSS, MDClinical Assistant Professor of Medicine, University of Pittsburgh, Section of Palliative Care and Medical Ethics, University of Pittsburgh Medical Center, Pittsburgh, PA
      • SUSAN D BLOCK, MDChair, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute and Brigham and Women’s Hospital Co-Director, HMS Center for Palliative Care, Professor of Psychiatry and Medicine, Harvard Medical School, Boston, MA

      Patients facing serious or life-threatening illness experience challenges to their psychological, social, and spiritual lives as well as to their physical function and comfort. Physicians may be accustomed to focusing on the biomedical aspects of illness, but they have a critical role in assessing the patient's psychosocial issues to identify sources of distress and help implement a plan for mitigating them. An appropriate psychosocial assessment requires a methodical and rigorous approach and includes assessment of any psychosocial issue affected by or affecting a patient's experience of illness. This chapter outlines a structured approach to addressing psychosocial issues by discussing (1) the doctor-patient relationship; (2) coping with illness; (3) family dynamics and caregiving; (4) ethnic and cultural issues; (5) religious, spiritual, and existential issues; (6) mental health issues, including adjustment disorder, depression, anxiety, personality disorders, aberrant drug behaviors, and major mental health issues; and (7) grief and bereavement. Tables outline psychosocial assessment questions, factors predisposing patients with serious illness to depression, risk factors for suicide in patients with terminal illness, and classes of antidepressants, anxiolytics, and sedatives. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire is provided, as well as a list of Web sites with further resources about psychosocial issues in serious illness.

      This review contains 1 highly rendered figure, 6 tables, and 216 references.

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    • 2

      Brain Death and Organ Donation

      By Thomas I. Cochrane, MD, MBA
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      Brain Death and Organ Donation

      • THOMAS I. COCHRANE, MD, MBAAssociate Neurologist, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Assistant Professor of Neurology, Harvard Medical School, Boston, MA

      Brain death is the state of irreversible loss of the clinical functions of the brain. A patient must meet strict criteria to be declared brain dead. They must have suffered a known and demonstrably irreversible brain injury and must not have a condition that could render neurologic testing unreliable. If the patient meets these criteria, a formal brain death examination can be performed. The three findings in brain death are coma or unresponsiveness, absence of brainstem reflexes, and apnea. Brain death is closely tied to organ donation, because brain-dead patients represent approximately 90% of deceased donors and thus a large majority of donated organs. This review details a definition and overview of brain death, determination of brain death, and controversy over brain death, as well as the types of organ donation (living donation versus deceased donation), donation after brain death, and donation after cardiac death. A figure presents a comparison of organ donation after brain death and after cardiac death, and a table lists the American Academy of Neurology Criteria for Determination of Brain Death.

      This review contains 1 highly rendered figure, 3 table, and 20 references.

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    • 3

      Advance Care Planning

      By Lauren Jodi Van Scoy, MD; Michael Green, MD, MS; Benjamin Levi, MD, PhD
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      Advance Care Planning

      • LAUREN JODI VAN SCOY, MDAssistant Professor, Departments of Medicine and Humanities, Penn State College of Medicine, Hershey, PA
      • MICHAEL GREEN, MD, MSProfessor, Departments of Humanities and Medicine, Penn State College of Medicine, Hershey, PA
      • BENJAMIN LEVI, MD, PHDProfessor, Departments of Humanities and Pediatrics, Penn State College of Medicine, Hershey, PA

      Advance care planning (ACP) is defined by the Institute of Medicine as an iterative process that involves discussing end-of-life issues, clarifying relevant values and goals of care, and embodying preferences through written documents and medical orders. ACP is predicated on the principle of respect for autonomy, which recognizes an individual’s right to accept or decline medical therapies. With the development of medical technologies that can sustain life (including mere physiologic existence), effective ACP has become a critical yet underused process for patients, their families, and clinicians. This review discusses the emergence of ACP, promises and pitfalls of advance directives, and promising approaches, including ACP interventions and research, as well as a focus on public engagement and future directions. Figures show a timeline of important advances in ACP since 1990, key features of the comprehensive ACP process, the three core aspects or pillars for implementation of ACP, stages of change for ACP behaviors, and two commercially available end-of-life games. Tables list theoretical pros and cons of advance directives, ACP resources, examples of recent research studies on ACP interventions, types and examples of ACP resources, and public engagement campaigns.

       

      This review contains 5 highly rendered figures, 5 tables, and 100 references.

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    • 4

      Clinical Trial Design and Statistics

      By Samantha M. Thomas, MS; April K.S. Salama, MD; Julie Ann Sosa, MA, MD, FACS
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      Clinical Trial Design and Statistics

      • SAMANTHA M. THOMAS, MSBiostatistician, Department of Biostatistics & Bioinformatics, Duke Cancer Institute, Durham, NC
      • APRIL K.S. SALAMA, MDAssistant Professor of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC
      • JULIE ANN SOSA, MA, MD, FACSAssociate Professor of Surgery, Divisions of Endocrine Surgery and Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, CT

      A clinical trial is a planned experiment designed to prospectively measure the efficacy or effectiveness of an intervention by comparing outcomes in a group of subjects treated with the test intervention with those observed in one or more comparable group(s) of subjects receiving another intervention.  Historically, the gold standard for a clinical trial has been a prospective, randomized, double-blind study, but it is sometimes impractical or unethical to conduct such in clinical medicine and surgery. Conventional outcomes have traditionally been clinical end points; with the rise of new technologies, however, they are increasingly being supplemented and/or replaced by surrogate end points, such as serum biomarkers. Because patients are involved, safety considerations and ethical principles must be incorporated into all phases of clinical trial design, conduct, data analysis, and presentation. This review covers the history of clinical trials, clinical trial phases, ethical issues, implementing the study, basic biostatistics for data analysis, and other resources. Figures show drug development and clinical trial process, and type I and II error. Tables list Food and Drug Administration new drug application types, and types of missing data in clinical trials.

      This review contains 2 highly rendered figures, 2 tables, and 38 references

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    • 5

      Withdrawing Life Support and Medical Futility

      By David Oxman, MD
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      Withdrawing Life Support and Medical Futility

      • DAVID OXMAN, MD

      Life support technologies have the potential to save many lives. However, in some cases – particularly when disease is advanced or incurable – the use of these interventions may simply prolong the dying process while causing significant pain and suffering. The ethical basis for withdraw of life support has been clearly elucidated in medical ethics and the law, but given the emotions surrounding these issues, it is not surprising that controversy still exists.  This review discusses withdrawal of life support and withdrawal of artificial nutrition. Additionally, this review explores medical futility, including the historical background, futility and the law, focus on process: hospital futility policies and ethics committees, and current practice and the future of medical futility. Illustrative case reports are presented. The table lists some examples of responding to requests for non-beneficial care from patients or surrogates.

      This review contains 1 figure, 3 tables, and 27 references.

      Key Words: Withdrawal of life support; Withdrawal of care; Medical futility  

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    • 6

      Preparing for the Ethical Practice of Precision Medicine

      By Megan A Allyse, PhD; Richard R Sharp, PhD
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      Preparing for the Ethical Practice of Precision Medicine

      • MEGAN A ALLYSE, PHD
      • RICHARD R SHARP, PHD

      The role of genetics in medicine is changing quickly. New discoveries are rapidly bridging the chasm from bench to bedside, and in addition to medical advances, thousands of people are exploring their genetic traits and ancestry through direct-to-consumer companies. Staying abreast of these changes and their potential implications for patient care can be difficult. To help, we suggest several high-level points of reference regarding the current state of genomic medicine, with a focus on the ethical and social issues raised by these technologies. This review covers the rise of genomic medicine, information overload, direct access to genetic information, genetic discrimination, and informed consent. Tables list the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings in clinical exome and genome sequencing, an excerpt from the Genetic Information Nondiscrimination Act, and genetics education resources for physicians.

      This review contains 3 tables, and 44 references.

      Key words: Genomic medicine, genetic medicine, medical genetics, genetic testing, direct-to-consumer genetics, genetic discrimination

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  • Gastroenterology
    • 1

      Esophageal Disorders

      By Michael F. Vaezi, MD, PhD, MSc (EPI)
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      Esophageal Disorders

      • MICHAEL F. VAEZI, MD, PHD, MSC (EPI)Professor of Medicine, Clinical Director of Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN

      Typically, symptoms that may indicate the presence of an esophageal disorder include heartburn, dysphagia, odynophagia, and regurgitation. Endoscopy is the technique of choice to evaluate the mucosa of the esophagus and to detect structural abnormalities, whereas esophageal manometry is the standard test to diagnose motor disorders of the esophageal body and the lower esophageal sphincter. This review examines normal esophageal anatomy and physiology, the diagnosis of esophageal disorders, disease states causing dysphagia, and gastroesophageal reflux disease. Figures show the cross-sectional anatomy of the esophagus; an algorithm for the evaluation of dysphagia; the anatomy of the gastroesophageal junction; esophagograms of patients with achalasia, late-stage achalasia, and diffuse esophageal spasm; endoscopic views of esophageal strictures; a proximal esophageal web on barium swallow in a patient with Plummer-Vinson syndrome; an endoscopic view of the esophagus of a 25-year-old man with a 3-year history of severe dysphagia; photographs of midesophageal traction diverticulum, multiple epiphrenic diverticula, long-segment Barrett esophagus, and severe Candida esophagitis; and a treatment algorithm for extraesophageal manifestations of gastroesophageal reflux disease. Tables list the high-resolution manometry classification of esophageal motility disorders, causes of esophageal strictures, classic endoscopic findings in patients with eosinophilic esophagitis, the Los Angeles classification of erosive esophagitis, categories of dysplasia, surveillance of Barrett metaplasia, medications implicated in pill-induced esophagitis, and classification of caustic esophageal injury.

      This review contains 13 highly rendered figures, 8 tables, and 111 references.

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    • 2

      Eosinophilic Esophagitis in Children and Adolescents

      By Elizabeth J Hait, MD, MPH
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      Eosinophilic Esophagitis in Children and Adolescents

      • ELIZABETH J HAIT, MD, MPHAssistant Professor, Department of Pediatrics, Harvard Medical School, Attending Physician, Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, MA

      Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus characterized by symptoms of esophageal dysfunction in association with histologic evidence of eosinophilic infiltration of the esophageal mucosa. The diagnosis is based on esophageal biopsies showing more than 15 eosinophils per high-power field in the absence of pathologic gastroesophageal reflux. It can present with a wide array of upper gastrointestinal tract symptoms. Babies and toddlers typically present with feeding intolerance or refusal, vomiting, and failure to thrive. Older children often present with abdominal pain and reflux symptoms, whereas adolescents and adults typically present with solid-food dysphagia and/or food impaction. Diagnosis is also supported by a family history of EoE and other allergy-based disorders, such as asthma, seasonal allergies, and atopy. Topical corticosteroids and dietary elimination are acceptable first-line treatment approaches.

      This review contains 7 figures, 5 tables, and 51 references.

      Key words: dysphagia, elimination diets, endoscopic dilation, eosinophilic esophagitis, eotaxin-3, feeding dysfunction, interleukin-5, proton pump inhibitor–responsive esophageal eosinophilia, swallowed fluticasone, viscous budesonide

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    • 3

      Gastrointestinal Bleeding

      By Deepak Agrawal, MD; Don C Rockey, MD
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      Gastrointestinal Bleeding

      • DEEPAK AGRAWAL, MDDirector, Endoscopy, Parkland Memorial Hospital, Assistant Professor of Medicine, University of Texas Southwestern, Dallas, TX
      • DON C ROCKEY, MDChief, Division of Digestive and Liver Diseases, Professor of Medicine, University of Texas Southwestern, Dallas, TX

      Gastrointestinal bleeding (GIB) is commonly encountered in clinical practice, in both outpatient and inpatient settings. Minor bleeding, such as from hemorrhoids, is exceedingly common. Major bleeding requiring a high level of care results in approximately 1 million hospital admissions in the United States every year. Approximately 50% of these admissions are for upper gastrointestinal bleeding (UGIB), 40% for lower gastrointestinal bleeding (LGIB), and 10% for obscure GIB. This chapter discusses acute gastrointestinal bleeding covering history, physical examination, and laboratory studies, as well as endoscopic management and radiologic imaging. A section on UGIB covers endoscopic management, medical management, and radiologic and surgical management, variceal bleeding, Mallory-Weiss tear, Dieulafoy’s lesions, Cameron’s lesions, gastric antral vascular ectasia (GAVE), and portal hypertensive gastropathy. A section on LGIB covers diverticulosis, hemorrhoids, angiodysplasia, rectal ulcers, radiation proctitis, ischemic colitis, rectal varices, postpolypectomy bleeding, anal fissures, cancer, and polyps. Obscure GIB includes Meckel’s diverticulum, small intestinal diverticula, small intestine neoplasms, small intestine Dieulafoy’s lesion, non-steroidal antiinflammatory drug–induced small intestine erosions, and blue rubber bleb nevus syndrome. Figures include various bleeding ulcers, the wireless capsule, the bleeding vessel, a duodenal bulbar ulcer, treatment of a high-risk gastric ulcer, formation of varices, varices with a spurting lesion, various treatments for esophageal varices, a Mallory-Weiss tear, a Dieulafoy lesion in the rectum, severe portal hypertensive gastropathy, vascular ectasia, and ischemic colitis, plus an algorithm for obscure GIB. Tables cover major causes, terms and their definitions, clinical high-risk criteria for rebleeding and mortality, endoscopic high-risk stigmata for rebleeding and indications for endoscopic therapy, differentiation of portal hypertensive gastropathy and GAVE, and uncommon causes of obscure GIB.

      This chapter contains 21 highly rendered figures, 6 tables, 110 references, 5 MCQs.

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    • 4

      Gastrointestinal Motility and Functional Disorders

      By Adil E Bharucha, MBBS, MD
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      Gastrointestinal Motility and Functional Disorders

      • ADIL E BHARUCHA, MBBS, MDProfessor of Medicine, Director, Motility Interest Group, Mayo Clinic, Rochester, MN

      Gastrointestinal (GI) motility disorders represent diseases characterized by abnormal, predominantly impaired, sometimes exaggerated, movement of contents through the GI tract due to neuromuscular dysfunctions in the absence of mucosal disease and mechanical causes of impaired passage. By contrast, functional GI disorders represent illnesses, defined only by GI symptoms, which occur in the absence of mucosal or structural abnormality or of known biochemical or metabolic disorders. The first section of this chapter discusses the enteric and extrinsic neural regulation of GI sensorimotor functions and normal GI motility in humans. Disorders such as gastroparesis (including diabetic gastroparesis, idiopathic gastroparesis, and postsurgical gastroparesis), dumping syndrome, intestinal pseudo-obstruction, small intestinal bacterial overgrowth, megacolon (including Hirschsprung disease, toxic megacolon, and colonic pseudo-obstruction), chronic constipation (including defecatory disorders, normal transit constipation, and slow transit constipation), functional dyspepsia, functional diarrhea and irritable bowel syndrome, and fecal incontinence are then discussed in depth. Tables present a comparison of GI motility and functional disorders, the causes of gastroparesis, the etiology of intestinal pseudo-obstruction and fecal incontinence, common medical conditions and medications associated with constipation, and the symptom severity scale in fecal incontinence. Illustrations, graphs, magnetic resonance images, and algorithms are provided.
      This chapter contains 10 highly rendered figures, 6 tables, 92 references, and 5 MCQs.

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    • 5

      Diseases Producing Malabsorption and Maldigestion

      By Rupa Mukherjee, MD; Ciarán P Kelly, MD
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      Diseases Producing Malabsorption and Maldigestion

      • RUPA MUKHERJEE, MDClinical Instructor in Medicine, Department of Gastroenterology, The Celiac Center, Harvard Medical School, Boston, MA
      • CIARÁN P KELLY, MDProfessor of Medicine, Medical Director of The Celiac Center, Director of Gastroenterology Fellowship Training Program, Harvard Medical School, Boston, MA

      Malabsorption refers to the impaired intestinal absorption of nutrients. It can result from congenital defects in absorption and the transport of ions and nutrients, defects in hydrolysis within the intestinal lumen, acquired defects in the intestinal absorptive cells that line the surface of the intestine, impaired bile production, or interruption of enterohepatic circulation or secondary to pancreatic insufficiency. Maldigestion, another factor in nutrient absorption, refers to the impaired digestion of nutrients within the intestinal lumen or at the terminal digestive site of the brush border membrane of mucosal epithelial cells. Although malabsorption and maldigestion are pathophysiologically distinct, they are interdependent, and in clinical practice, malabsorption has come to signify derangements in either or both processes. This chapter discusses the clinical manifestations of malabsorption and tests for suspected malabsorption. The diseases that can cause malabsorption, their diagnosis, and treatment recommendations are included. Figures illustrate the diagnosis and management of celiac disease; an approach to gluten challenge for the diagnosis or exclusion of celiac disease in patients maintained on a gluten-free diet without previous definitive diagnostic testing; and the histologic features of celiac disease, Crohn disease, collagenous sprue, autoimmune enteropathy, eosinophilic gastritis, and intestinal lymphangiectasia. Tables list causes of malabsorptive syndromes and tests of digestive-absorptive function.
      This chapter contains 9 highly rendered figures, 2 tables, 139 references, 1 teaching slide set, and 5 MCQs.

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    • 6

      Peptic Ulcer Diseases

      By Edward A Lew, MD, MPH
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      Peptic Ulcer Diseases

      • EDWARD A LEW, MD, MPHStaff Gastroenterologist, VA Boston Healthcare System, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MA

      Peptic ulcers are defects or breaks in the inner lining of the gastrointestinal (GI) tract. Although the pathogenesis is multifactorial they tend to arise when there is an imbalance between protective and aggressive factors, such as when GI mucosal defense mechanisms are impaired in the presence of gastric acid and pepsin. Peptic ulcers extend through the mucosa and the muscularis mucosae, a thin layer of smooth muscle separating the mucosa from the deeper submucosa, muscularis propria, and serosa. Peptic ulcer disease affects up to 10% of men and 4% of women in Western countries at some time in their lives. This chapter discusses the pathogenesis of peptic ulcer disease and the etiologic contribution of Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs, and gastrinoma or other hypersecretory states. Also addressed are rare and unusual causes for ulcers and GI bleeding. A section on the diagnosis of peptic ulcers discusses clinical manifestations, physical examination findings, laboratory and imaging studies, and surgical diagnosis. Differential diagnosis is also reviewed. Tests to establish the etiology of peptic ulcer disease include endoscopy, quantitative serologic tests, the urea breath test, and the fecal antigen test. Discussed separately are treatments for uncomplicated duodenal ulcers, uncomplicated gastric ulcers, intractable duodenal or gastric ulcers, complicated peptic ulcers (bleeding ulcers, acute stress ulcers, perforated ulcers, obstructing ulcers, fistulizing ulcers, and Cameron ulcers), H. pylori ulcers, and gastric cancer. Figures illustrate the etiopathogenesis of peptic ulcers, prevalence of H. pylori infection in duodenal and gastric ulcer patients compared with normal controls, the approach to a patient with new and undiagnosed ulcerlike symptoms refractory to antisecretory therapy, an upper GI series showing an uncomplicated duodenal ulcer, a chest x-ray showing pneumoperitoneum from a perforated duodenal ulcer, gastric biopsy samples showing H. pylori organisms, and the approach to treatment and follow-up in patients with either complicated or uncomplicated duodenal or gastric ulcer. Tables list differential diagnoses of peptic ulcer disease, commonly used regimens to eradicate H. pylori, additional antimicrobial agents with activity against H. pylori, and FDA-approved antisecretory drugs for active peptic ulcer disease. This chapter contains 76 references.

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    • 7

      Gastrointestinal Tract Infections

      By Molly Paras, MD; Marcia B Goldberg, MD
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      Gastrointestinal Tract Infections

      • MOLLY PARAS, MDDivision of Infectious Diseases, Department of Medicine
      • MARCIA B GOLDBERG, MDAssociate Professor of Medicine, Division of Infectious Diseases, Harvard Medical School, and Physician, Massachusetts General Hospital, Boston, MA

      Gastrointestinal infections, which present with acute diarrhea, sometimes accompanied by vomiting, are an extremely common medical complaint, with an annual incidence of 0.6 illnesses per person. Transmission can occur from animals to person, from person to person, or by the ingestion of contaminated foodstuffs. In the United States, more than 90% of cases are caused by viruses, with norovirus being by far the most common. Common among bacterial causes of acute gastrointestinal infection are Salmonella, Campylobacter, Shigella, Shiga toxin–producing Escherichia coli, Vibrio,Yersinia, and Clostridium difficile. These infections are typically self-limited, but depending on the etiologic agent and characteristics of the host, antibiotic therapy may be indicated. Certain gastrointestinal infections are associated with significant complications, including reactive arthritis, Guillain-Barré syndrome, or septicemia.

      This review contains 4 figures, 7 tables, and 60 references.

      Key words: Campylobacter, Escherichia coli, Guillain-Barré syndrome,reactive arthritis, Shiga toxin, Shigella, Vibrio, Yersinia

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    • 8

      Diverticulosis, Diverticulitis, and Appendicitis

      By William V. Harford, MD, FACP
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      Diverticulosis, Diverticulitis, and Appendicitis

      • WILLIAM V. HARFORD, MD, FACPProfessor, Internal Medicine, University of Texas Southwestern Medical Center, Director, GI Endoscopy, VA Medical Center, Dallas, TX

      Colonic diverticula are herniations of colonic mucosa and submucosa through the muscularis propria. They occur where perforating arteries traverse the circular muscle layer, in parallel rows between the mesenteric and antimesenteric taenia. Colonic diverticular disease may present as diverticulosis, diverticulitis, or diverticular bleeding. Of patients with known diverticulosis, only 10% to 20% will develop diverticulitis. Diverticulitis varies in presentation and severity. This chapter discusses the diagnosis, differential diagnosis, and management of diverticulitis and its complications. Appendicitis is generally caused by obstruction of the lumen of the appendix, followed by infection. In the United States, the lifetime risk of appendicitis is about 9% for males and 7% for females. This chapter also discusses the diagnosis of appendicitis (including typical and atypical presentations and appendicitis as it presents in special groups of patients) and its management. Figures illustrate imaging study findings in diverticulitis and appendicitis. Tables describe the modified Hinchey classification of acute diverticulitis, the differential diagnosis of acute diverticulosis, and the differential diagnosis of appendicitis. This chapter contains 92 references.

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    • 9

      Appendicitis

      By James Creswell Simpson, MD; Sarah Sebbag, MD, CM, CCFP(EM)
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      Appendicitis

      • JAMES CRESWELL SIMPSON, MDResident Physician, Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA
      • SARAH SEBBAG, MD, CM, CCFP(EM)Director, Emergency Ultrasound, Ochsner Health System, Department of Emergency Medicine, New Orleans, LA

      Appendicitis is defined as inflammation of the vermiform appendix. It is the most common abdominal surgical emergency and occurs at an annual rate of approximately one in 10,000 in the United States. The lifetime risk of appendicitis is about 9% for males and 7% for females; approximately 80% of cases occur before 45 years of age. Appendicitis rarely occurs in infants; it increases in frequency between 2 and 4 years of age and reaches a peak between the ages of 10 and 19 years. However, clinicians must maintain a high index of suspicion in patients of all age groups. This review covers the pathophysiology, stabilization and assessment, and diagnosis and treatment of complicated and uncomplicated appendicitis. The disposition and outcomes are also reviewed. Figures show an image of appendicitis on a bedside sonogram, and a computed tomographic image of appendicitis. Tables list likelihood ratios of signs and symptoms of appendicitis, the sonographic appearance of appendicitis, the Alvarado scoring system, and the differential diagnosis of appendicitis.

      Key words: appendicitis, obstructed appendiceal lumen, rebound abdomen, right lower quadrant pain, ruptured appendix

      This review contains 2 highly rendered figures, 4 tables, and 33 references.

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    • 10

      Peritonitis and Intra-abdominal Abscesses

      By W. Conrad Liles, MD, PhD; E Patchen Dellinger, MD
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      Peritonitis and Intra-abdominal Abscesses

      • W. CONRAD LILES, MD, PHDProfessor and Vice-Chair of Medicine, Director, Division of Infectious Diseases, University of Toronto, Toronto, ON
      • E PATCHEN DELLINGER, MDProfessor and Vice-Chair, Department of Surgery, University of Washington, Chief, Division of General Surgery, University of Washington Medical Center, Seattle, WA

      Peritonitis is a diffuse or localized inflammatory process affecting the peritoneal lining. Peritonitis has acute and chronic forms and may have a variety of causes. The etiology, epidemiology, diagnosis, and treatment of acute peritonitis caused by bacteria or fungi, including primary and secondary peritonitis, are discussed in this chapter. Primary or spontaneous peritonitis has no underlying intra-abdominal disorder as a direct cause of the infection but usually involves an underlying disorder that inhibits normal host defenses in the peritoneal cavity. Secondary peritonitis has an intra-abdominal focus that initiates the infection. Tertiary peritonitis is a relatively new term that refers to the persistence of intra-abdominal infection after the initial treatment of secondary peritonitis. Peritonitis in dialysis patients is also discussed. Intra-abdominal abscesses may present as complications of abdominal surgery, intra-abdominal conditions (e.g., diverticulitis, appendicitis, biliary tract disease, pancreatitis, perforated viscus), or penetrating abdominal trauma; as fever of obscure origin; or as dysfunction of neighboring organs (e.g., so-called lower lobe pneumonia related to a subphrenic abscess). Intra-abdominal abscesses are classified according to the anatomic location in which they occur: intraperitoneal, retroperitoneal, or visceral. Discussion of the different intra-abdominal abscesses in this chapter includes their diagnosis, bacteriology, and treatment. A figure shows CT scans before and after treatment of a multilobular liver abscess. This chapter contains 101 references.

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    • 11

      Enteral and Parenteral Nutrition

      By Kris M. Mogensen, MS, RD, LDN, CNSC; Malcolm K. Robinson, MD
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      Enteral and Parenteral Nutrition

      • KRIS M. MOGENSEN, MS, RD, LDN, CNSCTeam Leader Dietitian, Department of Nutrition, Brigham and Women’s Hospital, Boston, MA
      • MALCOLM K. ROBINSON, MDDirector, Nutrition Support Service, Brigham and Women’s Hospital, Assistant Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, MA

      Alternative routes of nutrient administration are available for patients who are unable to eat or digest sufficient food to prevent malnutrition. These routes include enteral (administered through the gastrointestinal tract) and parenteral (administered intravenously). This review details the clinical consequences of malnutrition, nutritional assessment, the benefits of nutrition support therapy,  determining the nutrient prescription, special considerations in nutrition support therapy, aspects of obtaining enteral or parenteral access, monitoring of patients receiving nutrition support therapy, and complications and ethical issues associated with enteral and parenteral nutrition. Figures include algorithms showing the identification of malnutrition, the nutrition support decision process, and the approach to gastric residual monitoring; nasogastric tube displacement leading to pneumothorax; proper placement of a long or “midline” catheter versus a peripherally inserted central catheter; and photographs of a 43-year-old man with Crohn disease complicated by enterocutaneous fistula formation, distal small bowel obstruction, and evisceration of the small bowel after developing a pelvic abscess. Tables list acute illness- or injury-related malnutrition; chronic disease−related malnutrition; social or environmental circumstances−related malnutrition; indications and contraindications to enteral and parenteral nutrition; selected examples of predictive equations; electrolyte provision in parenteral nutrition; parenteral vitamin and trace element requirements; complications associated with enteral and parenteral nutrition; and indications, contraindications, and complications of gastrostomy tube placement.

      This review contains 6 highly rendered figures, 11 tables, and 167 references.

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    • 12

      Diseases of the Pancreas

      By Sunil Sheth, MD; Gyanprakash Ketwaroo, MD, MSc; Steven Freedman, MD, PhD
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      Diseases of the Pancreas

      • SUNIL SHETH, MDCo-Director, The Pancreas Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
      • GYANPRAKASH KETWAROO, MD, MSCClinical Fellow, The Pancreas Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
      • STEVEN FREEDMAN, MD, PHDDirector, The Pancreas Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA

      Acute pancreatitis is characterized by an acute inflamatory process of the pancreas associated with abdominal pain and elevations in serum levels of pancreatic enzymes. The acute inflammation usually completely resolves with restoration of normal pancreatic architecture and function. By contrast, chronic pancreatitis is characterized by the presence of ongoing inflammation and irreversible damage to the gland. Recurrent attacks of acute pancreatitis may lead to chronic pancreatitis over time. This chapter discusses the epidemiology, etiology, pathogenesis, diagnosis, and treatment of acute and chronic pancreatitis. Figures illustrate findings on imaging studies in patients with pancreatic disorders. Tables list causes and complications of acute pancreatitis, nonpancreatic causes of elevated amylase and lipase levels, and diagnostic tests for chronic pancreatitis.

      This chapter contains 6 figures, 4 tables, 115 references, and 5 Board-styled MCQs.

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    • 13

      Gallstones and Biliary Tract Disease

      By Vinay Chandrasekhara, MD; Gregory G. Ginsberg, MD
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      Gallstones and Biliary Tract Disease

      • VINAY CHANDRASEKHARA, MDInstructor of Medicine, Gastroenterology Division, Penn Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
      • GREGORY G. GINSBERG, MDProfessor of Medicine, Gastroenterology Division, Director of Endoscopic Services, Penn Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

      Gallstones (cholelithiasis) are hardened deposits of digestive fluid that can form in the gallbladder and bile ducts. Gallstones range in size from as small as a grain of sand to as large as a billiard ball. Some people develop a single gallstone, whereas others develop many. Gallstone disease or disorders may encompass biliary pain, acute and chronic cholecystitis, choledocholithiasis, and gallstone pancreatitis. Gallstones (cholelithiasis) and biliary tract diseases constitute a common and costly health problem in the United States. This chapter reviews the formation of the two principal types of stone, the cholesterol stone and the pigment stone, that form in the gallbladder and biliary tract. The prevention of gallstones is discussed. The diagnosis, differential diagnosis, treatment, and complications of acute cholecystitis are presented. Diagnosis and treatment of chronic cholecystitis, asymptomatic cholelithiasis, choledocholithiasis, Mirizzi syndrome, and gallbladder polyps are also discussed. Common bile duct stricture, primary sclerosing cholangitis, recurrent pyogenic cholangitis, choledochal cyst, and sphincter of Oddi dysfunction are summarized. Figures illustrate the mechanism of gallstone formation and imaging study results in a variety of biliary tract disorders. Tables list risk factors for cholesterol and pigment gallstone formation, a modified classification system for choledochal cysts and surgical procedure of choice, and a clinical classification system for biliary-specific abdominal pain associated with sphincter of Oddi dysfunction.
      This chapter contains 6 highly rendered figures, 3 tables, 122 references, 1 teaching slide set, and 5 MCQs.

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    • 14

      Pancreatic, Gastric, and Other Gastrointestinal Cancers

      By Vinay Chandrasekhara, MD; Gregory G. Ginsberg, MD
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      Pancreatic, Gastric, and Other Gastrointestinal Cancers

      • VINAY CHANDRASEKHARA, MDInstructor of Medicine, Gastroenterology Division, Penn Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
      • GREGORY G. GINSBERG, MDProfessor of Medicine, Gastroenterology Division, Director of Endoscopic Services, Penn Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

      According to 2009 estimates from the American Cancer Society, cancers originating in the gastrointestinal tract rank second in both incidence and cancer-related deaths. One in four deaths in the United States is caused by cancer, with 25% of cancer-related deaths caused by gastrointestinal (GI) malignancies; more than 50% of these deaths are caused by cancer of the pancreas, stomach, esophagus, liver, or biliary tract. Recent advances in molecular biology, medical genetics, and imaging and endoscopic techniques, as well as the development of antitumor agents, have significantly altered the approaches to the prevention, diagnosis, and treatment of GI cancers. The chapter covers esophageal, gastric, pancreatic, hepatocellular, biliary tract, and anal cancers, as well as GI stromal tumors and gastric lymphoma. Coverage of all cancers includes diagnosis and treatment; various sections include information on epidemiology, etiology, risk factors, screening and prevention, molecular mutations, pathogenesis, and/or metastatic disease. Figures depict a barium esophagogram showing squamous cell carcinoma; imaging of esophageal cancer, gastric cancer, and pancreatic cancer; a pedigree of a family with inactivation of germline mutation of E-cadherin; hereditary gastric cancer; gastric cancer survival rates after gastrectomy; axial T1-weighted magnetic resonance imaging (MRI) showing cancer of the pancreatic head; and T1- and T2-weighted MRIs of intrahepatic bile duct carcinoma. Tables provide information on new cases and mortality from GI cancer in 2009; guidelines for diagnosis and surveillance of Barrett esophagus; the declining incidence of gastric cancer in Japan, Slovenia, and the United States; TNM staging of gastric cancer, pancreatic cancer, and hepatocellular carcinoma; the incidence of familial pancreatic carcinoma; molecular mutations involved in pancreatic cancer; staging of pancreatic intraepithelial neoplasia; and the Chinese University Prognostic Index. This chapter contains 235 references.

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    • 15

      Pathophysiology and Diagnosis of Ulcerative Colitis and Crohn Disease

      By Julia B. Greer, MD, MPH; Miguel D. Regueiro, MD
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      Pathophysiology and Diagnosis of Ulcerative Colitis and Crohn Disease

      • JULIA B. GREER, MD, MPHAssistant Professor of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA
      • MIGUEL D. REGUEIRO, MDProfessor of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Co-Director, Inflammatory Bowel Disease Center, University of Pittsburgh Medical Center, Pittsburgh, PA

      Inflammatory bowel disease (IBD) encompasses both ulcerative colitis and Crohn disease, and is characterized by recurrent bouts of inflammation of the gastrointestinal tract. IBD affects approximately 4 million people worldwide, and rates are gradually increasing. This review covers the etiology, epidemiology, definition and pathophysiology, extraintestinal manifestations, and other disease-related complications of IBD. Figures show the distribution of ulcerative colitis and Crohn disease by location, several colonoscopic photographs of patients with ulcerative colitis as well as those with Crohn disease, computed tomography images of patients with Crohn disease, small bowel follow-through and fluoroscopic spot images of a patient with chronic structuring Crohn disease, and a computed tomographic scan showing extraenteric manifestations of Crohn disease. Tables list the differential diagnosis of ulcerative colitis, types of infectious colitis, complications of IBD, diagnostic criteria of toxic colitis, physical signs of Crohn disease, differences between Crohn disease and ulcerative colitis, and common extraintestinal manifestations of IBD.

      This review contains 11 highly rendered figures, 7 tables, and 63 references.

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    • 16

      Management of Ulcerative Colitis and Crohn Disease

      By Julia B. Greer, MD, MPH; Miguel D. Regueiro, MD
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      Management of Ulcerative Colitis and Crohn Disease

      • JULIA B. GREER, MD, MPHAssistant Professor of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA
      • MIGUEL D. REGUEIRO, MDProfessor of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Co-Director, Inflammatory Bowel Disease Center, University of Pittsburgh Medical Center, Pittsburgh, PA

      There have been considerable advances in the treatment of inflammatory bowel disease (IBD) since the 20th century, and there are multiple options available to the clinician. The management of IBD depends on the location of disease, as well as its clinical, endoscopic and histologic severity. The field is currently undergoing a paradigm shift from a step-up approach (starting treatment with a “milder” medication and, if this treatment fails, moving on to a more powerful medication) to a top-down approach (in which stronger medications are given earlier in the disease course). This review details the medications used to treat IBD, nutrition in IBD patients, and surgical treatment of IBD. Figures show step-up therapy, top-down therapy, strictureplasty technique, gross pathology image of a patient with Crohn disease and previous ileocecal resection, and ileal pouch anal anastomosis surgery. Tables list 5-aminosalicylic acid medications, antibiotics, corticosteroids, immunomodulators, and biologic medications used to treat IBD, as well as causes of nutritional deficiencies in IBD patients.

      This review contains 5 highly rendered figures, 6 tables, and 96 references.

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    • 17

      Constipation in the Emergency Department

      By Jamie Santistevan, MD; Mary C. Westergaard, MD, FACEP; Ciara J. Barclay-Buchanan, MD, FACEP
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      Constipation in the Emergency Department

      • JAMIE SANTISTEVAN, MDResident Physician, Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • MARY C. WESTERGAARD, MD, FACEPResidency Program Director, Assistant Professor (Clinical Health Sciences), Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • CIARA J. BARCLAY-BUCHANAN, MD, FACEPAssociate Residency Program Director, Assistant Professor (Clinical Health Sciences), Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI

      Constipation can be classified as either primary constipation or secondary constipation. Constipation can be distressing to patients and can lead to serious complications, including bowel obstruction, perforation, volvulus, and proctitis. Emergency physicians should be aware of the evaluation, diagnosis, and management of patients presenting with the chief complaint of constipation. This review covers the risk factors, pathophysiology, assessment, diagnosis and treatment, and disposition and outcomes for patients presenting to the emergency department with constipation. Figures show radiographic and schematic images of several diagnoses which may present with the chief complaint of constipation. Tables list the primary and secondary causes of constipation, the criteria for the diagnosis of irritable bowel syndrome, and the mechanism of action of common medications used to treat constipation.

      This review contains 6 highly rendered figures, 5 tables, and 66 references.

      Key words:  bowel obstruction, constipation, 

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    • 18

      Hernias in the Emergency Department

      By Daniel Berhanu, MD; Ciara J. Barclay-Buchanan, MD, FACEP; Mary C. Westergaard, MD, FACEP
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      Hernias in the Emergency Department

      • DANIEL BERHANU, MDResident Physician, Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • CIARA J. BARCLAY-BUCHANAN, MD, FACEPAssociate Residency Program Director, Assistant Professor (Clinical Health Sciences), Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • MARY C. WESTERGAARD, MD, FACEPResidency Program Director, Assistant Professor (Clinical Health Sciences), Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI

      Hernia is defined as an abnormal protrusion of an organ or tissue through a pathologic defect in its surrounding wall. Overall, hernia is common and is generally believed to be a benign condition associated with some morbidity, although it is not thought to be associated with significant mortality. Between 2001 and 2010, 2.3 million inpatient abdominal hernia repairs were performed in the United States, of which 567,000 were performed emergently. In some cases, a hernia can be a deadly condition. In 2002, hernia was listed as the cause of death for 1,595 US citizens. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of hernia. Figures show anatomic locations of the various abdominal wall, groin, lumbar, and pelvic floor hernias; a direct inguinal hernia; an indirect inguinal hernia; point-of-care sonograms showing a ventral wall hernia and an abdominal wall hernia; and the differential diagnosis of an abdominal mass based on anatomic location. Tables list risk factors for the development of inguinal hernia, sex-based differences in inguinal hernia development, risk factors for the development of incisional hernia, factors to consider when assessing the patient for a hernia, and factors associated with the highest rates of incarceration in patients with groin hernia.
       

      Key words: emergent hernia, hernia incarceration, incisional hernia, inguinal hernia, strangulated hernia

      This review contains 6 highly rendered figures, 5 tables, and 66 references.

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    • 19

      Mesenteric Ischemia

      By Ugo A. Ezenkwele, MD, MPH
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      Mesenteric Ischemia

      • UGO A. EZENKWELE, MD, MPHChief, Emergency Department, Mount Sinai Queens, Associate Professor, Department of Emergency Medicine, Icahn Mount Sinai School of Medicine, New York, NY

      Acute mesenteric ischemia is interruption of intestinal blood flow by embolism, thrombosis, or a low-flow state. Bowel infarction is the end result of a process initiated by mediator release and inflammation. On clinical assessment, the early hallmark is severe abdominal pain but minimal physical findings. The abdomen remains soft, with little or no tenderness. Mild tachycardia may be present. Early diagnosis is difficult, but selective mesenteric angiography and computed tomographic angiography have the most sensitivity; other imaging studies and serum markers can show abnormalities but lack sensitivity and specificity early in the course of the disease, when diagnosis is most critical. Treatment is by embolectomy, anticoagulation, revascularization of viable segments, or resection; sometimes vasodilator therapy is successful. If diagnosis and treatment take place before infarction occurs, mortality is low; after intestinal infarction, mortality approaches 30 to 70%. For this reason, in the emergency department, clinical diagnosis should supersede diagnostic tests, which may delay treatment.

      This review contains 6 highly rendered figures, 4 tables, and 33 references.

      Key words: acute mesenteric ischemia; bowel necrosis; chronic mesenteric ischemia; mesenteric occlusive disease; mesenteric venous thrombosis; nonocclusive mesenteric ischemia; postprandial abdominal pain; superior mesenteric artery thromboembolism

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    • 20

      Infections Due to Salmonella

      By Molly Paras, MD; Marcia B Goldberg, MD
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      Infections Due to Salmonella

      • MOLLY PARAS, MDDivision of Infectious Diseases, Department of Medicine
      • MARCIA B GOLDBERG, MDAssociate Professor of Medicine, Division of Infectious Diseases, Harvard Medical School, and Physician, Massachusetts General Hospital, Boston, MA

      Salmonella, which is acquired via ingestion, is classified as nontyphoidal or typhoidal disease. Typhoidal disease is caused by S typhi or S paratyphi,and nontyphoidal disease is caused by all other serovars. Salmonella causes a range of infectious syndromes that include gastroenteritis, bacteremia, endovascular infections, and enteric fever. For immunocompromised hosts or patients with extraintestinal disease, antibiotic therapy should be provided. Effective agents often include third-generation cephalosporins and fluoroquinolones, although rates of resistance of Salmonella isolates to many antibiotics are increasing. A carrier state exists whereby patients may shed bacteria despite being asymptomatic. To eradicate the carrier state, longer courses of antibiotics and, in rare instances, surgical removal of the reservoir, which is most commonly the gallbladder, may be required. 

      This review contains 2 figures, 4 tables, and 20 references.

      Key Words: Salmonella, typhoidal, non-typhoidal, enteric fever, endovascular infection, gastroenteritis, carrier, food-borne, antibiotic resistance

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    • 21

      Nutritional Management of Celiac Disease

      By Mariana Urquiaga, MD; Ciarán P Kelly, MD; Satya Kurada, MD
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      Nutritional Management of Celiac Disease

      • MARIANA URQUIAGA, MD
      • CIARÁN P KELLY, MDProfessor of Medicine, Medical Director of The Celiac Center, Director of Gastroenterology Fellowship Training Program, Harvard Medical School, Boston, MA
      • SATYA KURADA, MD

      Celiac disease (CD) is an autoimmune disorder characterized by an immune response to gluten peptides in wheat, barley, and rye. The diagnosis of celiac disease is confirmed by three important characteristics: consistent symptoms, positive celiac-specific serology, and small intestinal biopsy findings of inflammation, crypt hyperplasia, and villous atrophy. CD may present with overt gastrointestinal symptoms, including diarrhea (or constipation), weight loss, and abdominal bloating and discomfort, or covertly with micronutrient deficiencies such as iron deficiency with anemia. A gluten-free diet (GFD) remains the mainstay of treatment. The aim of this review is to highlight the pathogenesis of CD, concepts and challenges associated with a GFD, and nutritional management of CD applicable in clinical practice to internists, gastroenterologists, and dietitians. Patients should be referred to an expert celiac dietitian for education on adherence to a GFD to address gluten contamination in the diet, the psychosocial implications of following a GFD, and macro- and micronutrient disequilibria arising from celiac disease and the GFD. Several novel therapeutics are on the horizon in various stages of development, including glutenases, antigliadin antibodies, tight junction regulators, modulation of the immune response to gliadin, and efforts to engineer less toxic gluten-containing foodstuffs.

      This review contains 3 figures, 5 tables, and 61 references.

      Key words: celiac disease, genetic engineering, food engineering, gluten, glutenases, gluten-free diet, oats, IgY, nutrition, tight junction regulators, wheat

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    • 22

      Overview of Enteral Nutrition

      By Erin Sisk, MS, RD, LDN, CNSC; Rebecca Lynch, MS, RD, LDN, CNSC
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      Overview of Enteral Nutrition

      • ERIN SISK, MS, RD, LDN, CNSC
      • REBECCA LYNCH, MS, RD, LDN, CNSC

      Enteral nutrition (EN) is recognized as a medical nutrition therapy for patients with a functional gastrointestinal tract who are unable to maintain their weight and health by oral intake alone either due to a highly catabolic medical condition or a functional limitation. EN support provides calories and protein to help improve or maintain adequate weight, lean body mass, and overall nutritional status. EN also provides nonnutritive benefits such as maintaining intestinal integrity, supporting the immune system, and preventing infection. EN support can be tailored to a patient’s nutrient needs, and there are various formulas that vary in composition of macronutrients, concentration, and electrolytes for specific disease processes or conditions that may help with tolerance and absorption. EN support complications include issues with access, diarrhea, constipation, electrolyte abnormalities, hyperglycemia, and dehydration/overhydration. Generally, EN is well tolerated. While a patient is on this type of nutrition support, it is important to closely monitor tolerance, weight, laboratory values if indicated, and overall clinical progress, with adjustment to the regimen as needed.

      This review contains 1 figure, 4 tables, and 48 references.

      Key words: enteral access, enteral formula, enteral nutrition support, gastric residuals, gastrointestinal tract, immunonutrition, malnutrition, medical nutrition therapy, tube feed formula, tube feed tolerance, tube feeding, volume-based feeding

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    • 23

      Endoscopic Techniques for Obtaining Enteral Access

      By Sanjay Salgado, MD; Marvin Ryou, MD
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      Endoscopic Techniques for Obtaining Enteral Access

      • SANJAY SALGADO, MD
      • MARVIN RYOU, MDAssociate Staff Physician, Brigham and Women’s Hospital, Boston, MA

      In the absence of contraindications, enteral feeding is recommended for patients who are expected to be intolerant of oral feedings beyond 7 days. Enteral access can be accomplished by a variety of means, including surgical, endoscopic, or radiographic methods. This review focuses on endoscopy-guided options for enteral access. These methods include gastric feeding, which can be accomplished by orogastric, nasogastric, or percutaneous endoscopic gastrostomy tube placement, and postpyloric feeding, accessed through oral or nasal jejunal tubes, percutaneous gastrostomy with a jejunal extension, or direct percutaneous jejunostomy. The indications, techniques, complications, and comparative data of these placement options are outlined, and special clinical considerations (including establishing access in patients with dementia or cirrhosis and those on anticoagulation) are discussed.

      This review contains 5 figures, 1 table, and 33 references.

      Key words: direct percutaneous jejunostomy, endoscopy, enteral access in cirrhosis, enteral access in dementia, enteral feeding, enteric access, nasogastric feeding tubes, percutaneous endoscopic gastrojejunostomy tubes, percutaneous endoscopic gastrostomy tubes

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  • Geriatric Medicine
    • 1

      Approach to the Geriatric Patient

      By Tia Kostas, MD; Mark Simone, MD; James L Rudolph, MD, SM
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      Approach to the Geriatric Patient

      • TIA KOSTAS, MDAssistant Professor of Medicine, Section of Geriatrics & Palliative Medicine, Department of Medicine, University of Chicago, Chicago, IL
      • MARK SIMONE, MDInstructor of Medicine, Harvard Medical School, Associate Program Director-Primary Care, Mount auburn Hospital Internal Medicine Residency, Director, Quality Improvement, Division of Geriatric Medicine, Department of Medicine, Mount Auburn Hospital, Cambridge, MA
      • JAMES L RUDOLPH, MD, SMAssociate Professor of Medicine, Harvard Medical School, Chief (Interim) Geriatrics and Palliative Care, Director, Boston, GRECC, VA Boston Healthcare System, Jamaica Plain, MA, Acting Clinical Chief, Associate Epidemiologist, Division of Aging, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

      As of 2012, over one in eight Americans is over the age of 65, and this number is rising, particularly in the 85+ age group. This segment of the population has a rate of hospitalization three times higher than that for persons of all ages. General internists and family medicine physicians provide a large portion of care for this age group and should therefore be comfortable using a comprehensive approach to geriatric assessment. This review describes general considerations regarding geriatric care, including the process of taking a functional history and clinical implications of geriatric care. The geriatric assessment process is discussed in terms of physical, cognitive, social, and medical domains. The benefits of geriatric assessment in primary care, specialty care, and hospitalized patients are described. Tables outline activities of daily living, sensory changes with aging, major causes of visual impairment in the geriatric population, major neurocognitive disorder diagnostic criteria, medications to avoid or use with caution based on Beers criteria and Screening Tool of Older individuals’ Potentially inappropriate Prescriptions criteria, U.S. Preventive Services Task Force–recommended services relevant to older adults, and vaccinations in older adults. Figures illustrate the key vulnerabilities of older adults; outcomes linked to functional dependence; common disorders associated with cognitive concerns; domains of cognition and examples of impairment in theDiagnostic and Statistical Manual of Mental Disorders, fifth edition; the social and medical domains of geriatric assessment; barriers to medication adherence in older patients; and resources for medication appropriateness in older adults.

      This review contains 8 highly rendered figures, 8 tables, 110 references, and 5 MCQs.

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    • 2

      Assessment and Management of the Geriatric Patient

      By Tia Kostas, MD; Mark Simone, MD; James L Rudolph, MD, SM
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      Assessment and Management of the Geriatric Patient

      • TIA KOSTAS, MDAssistant Professor of Medicine, Section of Geriatrics & Palliative Medicine, Department of Medicine, University of Chicago, Chicago, IL
      • MARK SIMONE, MDInstructor of Medicine, Harvard Medical School, Associate Program Director-Primary Care, Mount auburn Hospital Internal Medicine Residency, Director, Quality Improvement, Division of Geriatric Medicine, Department of Medicine, Mount Auburn Hospital, Cambridge, MA
      • JAMES L RUDOLPH, MD, SMAssociate Professor of Medicine, Harvard Medical School, Chief (Interim) Geriatrics and Palliative Care, Director, Boston, GRECC, VA Boston Healthcare System, Jamaica Plain, MA, Acting Clinical Chief, Associate Epidemiologist, Division of Aging, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

      Adults age 65 years and older make up an increasing percentage of the patient population. Physicians should recognize predisposing factors in their assessment of the geriatric patient, looking out for conditions such as homeostatic failure, multimorbidity, and functional disability, as well as clinical disorders that do not fit into discrete disease or organ system categories and are often described as geriatric syndrome. Through this and other strategies, such as evaluating patients at risk and implementing evidence-based therapy, physicians can substantially improve the well-being, functional independence, and quality of life of older adults. This review addresses the assessment and management of several geriatric syndromes, detailing cognitive impairment, falls and gait disturbances, malnutrition and weight loss, and pressure ulcers. Figures show types of dementia, nonpharmacologic interventions for cognitive impairment, a checklist for assessment of a delirious patient, nonpharmacologic management of delirium, the Timed Up and Go test, modifiable fall risk factors, and etiologies and management of weight loss. Tables list cognitive screens, cognition enhancers, delirium prevalence, confusion assessment method for diagnosis of delirium, differential features of delirium and dementia, common causes of unintentional weight loss in older adults, appetite enhancers and side effects, extrinsic forces involved in creating pressure ulcers, National Pressure Ulcer Advisory Panel staging system for pressure ulcers, specialty mattresses for pressure relief, and pressure ulcer dressings.

      This review contains 8 highly rendered figures, 11 tables, and 84 references.

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    • 3

      Rehabilitation of Geriatric Patients

      By Stephanie Studenski, MD, MPH; Cynthia R. Brown, MD, MSPH; Susan E. Hardy, MD, PhD
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      Rehabilitation of Geriatric Patients

      • STEPHANIE STUDENSKI, MD, MPHProfessor, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
      • CYNTHIA R. BROWN, MD, MSPHAssistant Professor, Division of Geriatrics, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
      • SUSAN E. HARDY, MD, PHD

      Primary care physicians play an important role in the rehabilitation of geriatric patients: they must be able to assess rehabilitation potential, determine specific patient needs, and then determine the appropriate setting to optimize patient care. Rehabilitation service planning is usually based on a different model of diagnosis and treatment than traditional medical care. This chapter describes the key aspects of rehabilitation planning for stroke, amputation and peripheral vascular disease, hip fracture, rheumatoid arthritis, and arthroplasty. The revised World Health Organization International Classification of Functioning, Disability and Health (ICIDH-2), included in a figure, can be used to assess the causes of disability, plan treatment approaches, and determine the outcomes of care. Tables describe selected results of the neurologic examination of a patient with stroke, assessment and management of complications of stroke and other disabling conditions, and pharmacologic therapy for poststroke depression. An algorithm shows the selection of the appropriate setting for rehabilitation after hospitalization for acute stroke. The Orpington Prognostic Scale for estimating stroke recovery is provided, as is a list of current Internet resources pertaining to geriatric care. This chapter contains 96 references.

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    • 4

      Mistreatment of Elders

      By Emily I Gorman, MD; Judith Linden, MD
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      Mistreatment of Elders

      • EMILY I GORMAN, MDDepartment of Emergency Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA
      • JUDITH LINDEN, MDAssociate Professor and Vice Chair for Education, Department of Emergency Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA

      Elder mistreatment affects a considerable proportion of individuals older than 60 to 65 years of age and may include intentional abuse (physical, sexual, emotional, or financial) and neglect. As the proportion of the population that is older than 65 years of age increases, elder mistreatment will become an increasingly common issue. Only a minority of cases of elder abuse are reported; thus, an interview with the patient should be conducted in private if elder mistreatment is suspected. Patient risk factors for elder mistreatment include cognitive or behavioral impairment, poor physical health, and poor social supports. This review examines the approach to the patient, as well as definitive treatment, disposition, and outcomes for victims of elder abuse. The figure shows an algorithm for elder abuse assessment and intervention. Tables list types of elder abuse, factors predisposing to elder mistreatment, indicators of abuse, and the Elder Abuse Suspicion Index.

      This review contains 1 highly rendered figure, 4 tables, and 42 references.

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  • Hematology
    • Hematologic Malignancies
      • 1

        Acute Leukemia

        By Richard A. Larson, MD; Roland B Walter, MD, PhD, MS
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        Acute Leukemia

        • RICHARD A. LARSON, MDProfessor of Medicine, Pritzker School of Medicine, University of Chicago. Chicago, IL
        • ROLAND B WALTER, MD, PHD, MSAssistant Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, Associate Professor of Medicine, Division of Hematology/Department of Medicine, University of Washington, Seattle, WA

        The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia.

        This review contains 1 highly rendered figure, 9 tables, and 117 references.

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      • 2

        Essential Thrombocythemia and Myelofibrosis

        By Srdan Verstovsek, MD, PhD; Hagop M. Kantarjian, MD
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        Essential Thrombocythemia and Myelofibrosis

        • SRDAN VERSTOVSEK, MD, PHDProfessor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
        • HAGOP M. KANTARJIAN, MDProfessor and Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

        This review details two major clonal stem cell disorders: essential thrombocythemia (ET) and myelofibrosis (MF). ET is distinguished by a sustained proliferation of megakaryocytes that results in peripheral blood thrombocytosis. Primary myelofibrosis (PMF) is associated with extramedullary hematopoiesis, splenomegaly, a leukoerythroblastic blood picture, and varying degrees of marrow fibrosis with marked megakaryocyte hyperplasia and atypia. The epidemiology, etiology/genetics, pathogenesis, diagnosis (including clinical manifestations and laboratory tests), differentials, management, and prognosis of each disorder are examined. Also included is the evaluation of treatment options for MF, including interferon alfa, JAK inhibitors, and allogeneic stem cell transplantation, the latter of which is still the only curative treatment for MF. Figures show treatment algorithms for ET and MF. Tables list the current criteria for the diagnosis of ET and PMF via the World Health Organization (WHO), the guidelines for diagnosis of post-ET MF via the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT), prognostic factors in the International Prognostic Score for ET (IPSET) and IPSET-thrombosis, prognostic scoring systems for MF, and the clinical activity of JAK2 inhibitors.

        This review contains ­2 highly rendered figures, 6 tables, and 60 references. 

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      • 3

        Chronic Myeloid Leukemia

        By Elias Jabbour, MD; Susan O'Brien, MD
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        Chronic Myeloid Leukemia

        • ELIAS JABBOUR, MDAssociate Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
        • SUSAN O'BRIEN, MDProfessor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

        Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, chronic myelocytic leukemia, and chronic granulocytic leukemia, is characterized by the expansion of myeloid progenitor cells at various stages of maturation, their premature release into the circulation, and a tendency to home to extramedullary sites. Symptoms at presentation reflect the increase in mass and turnover of the leukemic cells, although as many as 50% of patients are asymptomatic at diagnosis and come to attention through unexpected findings on routine blood tests. In treatment, the ongoing development of established and novel tyrosine kinase inhibitors (TKIs) has made for closer to normal life spans in patients diagnosed with CML. This review serves as an overview of CML, detailing its epidemiology and etiology, pathophysiology, diagnosis, treatment (including an assessment of the latest clinical trials involving TKIs), and management of patients with advanced phases. Figures show BCR-ABL signaling pathways and mechanisms of resistance to imatinib. Tables list stages of CML, differential diagnosis of CML and Philadelphia chromosome–negative myeloproliferative disorders, a summary of pivotal phase III trials of approved TKIs for the treatment of front-line or relapsed CML, response evaluation to TKIs used as first-line therapy, and a summary of important phase II trials of second- and third-generation TKIs after previous TKI failure.

        This review contains 2 highly rendered figures, 5 tables, and 87 references.

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      • 4

        Chronic Lymphocytic Leukemia and Other Chronic Lymphoid Leukemias

        By Tait D. Shanafelt, MD
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        Chronic Lymphocytic Leukemia and Other Chronic Lymphoid Leukemias

        • TAIT D. SHANAFELT, MDProfessor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN

        The chronic lymphoid leukemias are a group of generally indolent B cell malignancies that include chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, hairy cell leukemia, and large granular lymphocyte leukemia. The unique aspects of diagnosis and management for each condition are discussed separately, with the primary focus being on CLL, the most common form of leukemia in most Western countries. Charts show the percentages of CLL patients’ survival divided into Rai risk category, treatment-free survival, and overall survival, and an algorithm displays approaches to selecting therapy for CLL patients. Tables list how CLL and other B cell lymphoproliferative disorders can be distinguished using immunophenotyping, chromosome categories by fluorescence in situ hybridization for predicting CLL patient survival, criteria indications for the initiation of therapy from the International Workshop on CLL and the National Cancer Institute CLL Working Group, and criteria for high-risk CLL disease.

        This review contains ­4 highly rendered figures, 4 tables, and 172 references. 

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      • 5

        Plasma Cell Disorders

        By Morie A. Gertz, MD, MACP
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        Plasma Cell Disorders

        • MORIE A. GERTZ, MD, MACPChair, Department of Medicine, Roland Seidler Junior Professor of the Art of Medicine, Mayo Clinic, Rochester, MN

        Multiple myeloma represents 1.4% of all new patients with cancer and will result in an estimated 11,090 deaths in 2014. It is twice as common in black men as in white men and 2.5 times more common in black women than in white women. Myeloma is the 14th most common cause of cancer in the United States, with a median age at diagnosis of 69 years. Multiple myeloma is defined by the presence of a clonal growth of plasma cells, usually in the bone marrow, but patients may also present with extramedullary disease. Anemia and bone disease are common in patients with multiple myeloma. Multiple myeloma cells display multiple genetic abnormalities, with no one specific genetic lesion common to a majority of patients. This module describes the immunologic profile of multiple myeloma and its diagnosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, plasmacytoma, plasma cell leukemia, the clinical presentation of multiple myeloma bone disease, anemia, renal impairment, hypercalcemia, and neurologic symptoms associated with multiple myeloma. Therapy for transplantation-eligible and non–transplantation-eligible patients, maintenance treatment for multiple myeloma, Waldenström macroglobulinemia, and amyloidosis are also discussed. Tables outline the risk of monoclonal gammopathy of undetermined significance evolution, the myeloma staging system, recommended diagnostic testing and uniform response criteria for myeloma, and commonly used regimens in the treatment of myeloma. Figures include a magnetic resonance image showing multiple plasmacytomas, tibial lytic lesion from myeloma, calvarial lytic lesions, a positron emission tomographic scan in a myeloma patient, and hyperviscosity causing retinal hemorrhages.

        This review contains 5 highly rendered figures, 5 tables, and 149 references.

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      • 6

        Lymphomas

        By Kieron Dunleavy, MD; Wyndham H Wilson, MD, PhD
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        Lymphomas

        • KIERON DUNLEAVY, MDAttending Physician/Investigator, Lymphoma Therapeutics Section, Metabolism Branch, National Cancer Institute, Bethesoa, Maryland
        • WYNDHAM H WILSON, MD, PHDSenior Investigator, Chief, Lymphoma Therapeutics Section, Metabolism Branch, National Cancer Institute, Bethesoa, Maryland

        Lymphoma is the fifth most common type of cancer in the United States, with 74,490 new cases estimated in 2009. Approximately 15% of patients with lymphoma have Hodgkin lymphoma; the remainder have one of the non-Hodgkin lymphomas. The incidence of non-Hodgkin lymphoma has increased steadily over recent decades. This chapter reviews the epidemiology, classification, clinical features, pathology, diagnostic evaluation, staging and prognosis, and treatment of Hodgkin and non-Hodgkin lymphoma. Other topics discussed include the acute and chronic effects of therapy for Hodgkin disease, as well as the subtypes of non-Hodgkin lymphomas, including indolent B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal-zone lymphoma, diffuse large B cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), Burkitt lymphoma, and HIV-related non-Hodgkin lymphoma. Figures illustrate the cellular appearance of Hodgkin lymphoma subtypes and DLBCL, diagnosis of DLBCL subtypes by gene expression, computed tomography and plain chest film in primary mediastinal cell lymphoma, MRI of the brain in PCNSL, and gene expression and gene expression predictors of survival among patients with DLBCL treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone (R-CHOP). Tables describe the Ann Arbor classification and the Cotswold modification for staging of lymphoma; the International Prognostic Score for advanced Hodgkin lymphoma; the World Health Organization classification of hematopoietic neoplasms; chromosomal translocations in non-Hodgkin lymphoma; the Eastern Cooperative Oncology Group performance scale; the International Prognostic Index for aggressive non-Hodgkin lymphoma; and the Follicular Lymphoma International Prognostic Index. This chapter has 185 references.

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    • Principles of Nonmalignant Hematology
      • 1

        Approach to the Patient With Benign Hematologic Disorders

        By J Mark Sloan, MD; David C Seldin, MD, PhD
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        Approach to the Patient With Benign Hematologic Disorders

        • J MARK SLOAN, MDAssistant Professor of Medicine, Boston Univeristy School of Medicine, Boston, MA
        • DAVID C SELDIN, MD, PHDChief, Section of Hematology-Oncology, Professor of Medicine and Microbiology, Boston University School of Medicine, Boston, MA

        Hematology principally concerns the function and disorders of the formed elements of the blood—red blood cells (RBCs), white blood cells (WBCs), and platelets—as well as those factors governing hemostasis. Hematologists have been a powerful force in basic biomedical and translational research. Their work, propelled partly by the ease of collection of blood and bone marrow for study, has enabled an understanding of many blood disorders at a fundamental molecular level. Techniques developed for the study of hematology are often adopted by other disciplines. This chapter discusses the anatomy of the hematopoietic system, hematopoiesis and the bone marrow, physical examination of the hematology patient, evaluation of the complete blood count (CBC) and peripheral blood smear, and coagulation. Tables delineate CBC parameters with normal ranges; peripheral smear findings, descriptions, and RBC indices and significance; laboratory findings in erythrocytosis; diseases commonly associated with eosinophilia and useful workup; common medications strongly associated with thrombocytopenia; and the 4Ts score for determining pretest probability of heparin-induced thrombocytopenia. Figures depict the three fractions of centrifuged blood, the lymph node, hematopoietic stem cells, bone marrow aspirate and biopsy procedure, architecture of the bone marrow microenvironment, petechiae, WBC types found in the smear of peripheral blood, the direct antiglobulin test, myeloid cells, and the coagulation system.

        This review contains 10 highly rendered figures, 6 tables, and 40 references.

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      • 2

        Red Blood Cell Function and Disorders of Iron Metabolism

        By Robert T. Means Jr, MD, FACP
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        Red Blood Cell Function and Disorders of Iron Metabolism

        • ROBERT T. MEANS JR, MD, FACPDean of Medicine, Professor of Internal Medicine, Office of the Dean, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN

        The red blood cell, or erythrocyte, is an anucleate biconcave disk, approximately 7 µm in diameter. The principal function of the red blood cell is to exchange carbon dioxide for oxygen while in the pulmonary circulation, exchange that oxygen for carbon dioxide in the peripheral tissue, and carry that carbon dioxide back to the lungs. The physicochemical composition of the red cell is aligned to optimize that function. The state of tissue oxygenation, in turn, regulates the production of red cells. This review covers red blood cell function, iron metabolism, iron deficiency, iron overload, and primary iron overload. Figures show a model of the hemoglobin molecule showing the relative alignment of the α chains and β chains; the normal oxygen-hemoglobin dissociation curve shifted by changes in temperature, pH, and the intracellular concentration of 2,3-diphosphoglycerate; body iron supply and storage; regulation of hepcidin expression and its role in disease; blood smear from a patient with iron deficiency; and mechanisms contributing to iron overload in iron-loading anemias. Tables list laboratory results associated with decreased iron balance, causes of iron deficiency, oral iron replacement therapy, parenteral iron replacement therapy, primary iron overload syndromes, secondary iron overload syndromes, laboratory results associated with increased iron stores, and other rare disorders of iron overload.

        This review contains 6 highly rendered figures, 8 tables, and 108 references.

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      • 3

        Transfusion Medicine

        By Harvey G Klein, MD
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        Transfusion Medicine

        • HARVEY G KLEIN, MDThe Department of Transfusion Medicine is at the National Institutes of Health (NIH). I am Chief, Department of Transfusion Medicine. I also hold Professorships in both the Departments of Medicine and Pathology at the Johns Hopkins School of Medicine

        Transfusion medicine has advanced to a laboratory-based clinical discipline because of key discoveries and technical advances. These include the discovery of blood group antigens and the understanding of the host immune response to these antigens, development of methods of anticoagulation and storage of blood, and creation of plastic bags that allow sterile fractionation of whole blood into components. The potential of blood to act as an agent of disease transmission has heavily shaped both the donation process and transfusion practice. This chapter offers information to help the physician decide whether to transfuse. It includes sections on blood donation (autologous and directed), on postdonation screening procedures for the presence of viral agents (e.g., hepatitis, retrovirus, and emerging infectious pathogens), on pretransfusion testing (i.e., antigen phenotyping and testing for the presence of antibodies), and on blood components. Sections give specific information on transfusion of red cells, platelets, fresh frozen plasma, and recombinant clotting factors. Indications and complications of apheresis are described. Complications of transfusions are discussed, as are future prospects for transfusion therapy. Tables detail the advantages and disadvantages of autologous donation, estimated risks of blood transfusion, characteristics of blood products and indications for their use, plasma and recombinant clotting factors, indications for recombinant factor VIIa therapy, indications for the use of irradiated blood products, indications for the use of cytomegalovirus-negative blood products, and recommendations for therapeutic apheresis. This chapter contains 154 references.

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      • 4

        Hematopoietic Cell Transplantation

        By Fred Appelbaum, MD
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        Hematopoietic Cell Transplantation

        • FRED APPELBAUM, MDExecutive Vice President and Deputy Director, Fred Hutchinson Cancer Research Center, Professor, Division of Medical Oncology, University of Washington School of Medicine, Seattle, WA

        Hematopoietic cell transplantation (HCT) can replace abnormal nonmalignant hematopoietic stem cells with cells from a healthy donor, making transplantation a potential cure for a variety of nonmalignant and malignant diseases. This review discusses the indications for HCT, source of stem cells, preparative regimen, engraftment, complications, late effects and long-term survivorship, and treatment of post-transplantation relapse. Figures show the estimated total numbers of allogeneic and autologous HCTs performed in the United States, the major histocompatibility loci on chromosome 6, an approximation of the relative intensities of various preparative regimens, the typical patterns of myeloid recovery after HCT, the description  and timing of major syndromes complicating allogeneic HCT, and erythema and desquamation associated with cutaneous acute graft versus host  disease (GVHD). Tables list estimated 3-year survival rates following HCT, probability of finding a donor for HCT, clinical staging and grading of acute GVHD, National Institutes of Health global severity score of chronic GVHD, typical approach to infection prophylaxis in allogeneic transplant recipients, and summary of Centers for Disease Control and Prevention HCT vaccine guidelines.

        Key words: Hematopoietic cell transplantation; HCT; Allogeneic HCT; Hematopoietic stem cell transplantation; HSCT; Diseases of the lymphohematopoietic system; Autologous HCT; Hematopoietic stem cells

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    • Nonmalignant Hematologic Disorders
      • 1

        Anemia: Production Defects Generally Associated With a Normal or Largely Normal Bone Marrow

        By John M Gansner, MD, PhD; Nancy Berliner, MD
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        Anemia: Production Defects Generally Associated With a Normal or Largely Normal Bone Marrow

        • JOHN M GANSNER, MD, PHDInstructor in Medicine (Hematology), Harvard Medical School, Boston, MA
        • NANCY BERLINER, MDProfessor of Medicine (Hematology), Harvard Medical School, Boston, MA

        This review focuses on anemia resulting from production defects generally associated with a normal or largely normal bone marrow. The definition, epidemiology, etiology, pathogenesis, diagnosis, differential diagnosis, management, complications, and prognosis of the following production defects are discussed: Anemia of inflammation (AI; formerly known as anemia of chronic disease), and anemia in kidney disease, as well as anemia secondary to other conditions such as alchohol abuse and starvation. Iron deficiency anemia (IDA) is discussed elsewhere in this publication.  A figure depicts peripheral smear changes in the size and shape of red blood cells seen in starvation. A table lists the differential diagnoses of hypochromic anemias.

        1 figure; 1 table; 79 references

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      • 2

        Anemia: Production Defects Generally Associated With Marrow Aplasia or Replacement

        By John M Gansner, MD, PhD; Nancy Berliner, MD
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        Anemia: Production Defects Generally Associated With Marrow Aplasia or Replacement

        • JOHN M GANSNER, MD, PHDInstructor in Medicine (Hematology), Harvard Medical School, Boston, MA
        • NANCY BERLINER, MDProfessor of Medicine (Hematology), Harvard Medical School, Boston, MA

        This review focuses on anemia resulting from production defects generally associated with marrow aplasia or replacement. The definition, epidemiology, etiology, pathogenesis, diagnosis, differential diagnosis, management, complications, and prognosis of the following production defects are discussed: Acquired aplastic anemia and acquired pure red cell aplasia. Figures depict a leukoerythroblastic blood smear, a biopsy comparing normal bone marrow and bone marrow showing almost complete aplasia, and a marrow smear. A table lists the causes of aplastic anemia.

        3 figures; 1 table; 108 references.

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      • 3

        Anemia: Production Defects Generally Associated With Marrow Erythroid Hyperplasia and Ineffective Erythropoiesis

        By John M Gansner, MD, PhD; Nancy Berliner, MD
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        Anemia: Production Defects Generally Associated With Marrow Erythroid Hyperplasia and Ineffective Erythropoiesis

        • JOHN M GANSNER, MD, PHDInstructor in Medicine (Hematology), Harvard Medical School, Boston, MA
        • NANCY BERLINER, MDProfessor of Medicine (Hematology), Harvard Medical School, Boston, MA

        This review focuses on anemia resulting from production defects generally associated with marrow erythroid hyperplasia and ineffective erythropoiesis. The definition, epidemiology, etiology, pathogenesis, diagnosis, differential diagnosis, management, complications, and prognosis of the following production defects are discussed: Megaloblastic anemias, megaloblastic anemia caused by cobalamin deficiency, megaloblastic anemia caused by folic acid deficiency, copper deficiency, and sideroblastic anemias. Figures depict intracellular interdependent cofactor activity of cobalamin and folic acid, synthesis of succinyl–coenzyme A from methylmalonyl–coenzyme A, folic acid functions as a coenzyme in single-carbon transfer reactions, cobalamin assimilation, peripheral blood smear in folic acid or cobalamin deficiency, and a Prussian blue stain showing ring sideroblasts. Tables list causes of cobalamin deficiency and folic acid deficiency.

        5 figures; 2 tables; 95 references.

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      • 4

        Hemoglobinopathies and Hemolytic Anemias

        By Stavrula Otis, MD; Elizabeth A. Price, MD, MPH
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        Hemoglobinopathies and Hemolytic Anemias

        • STAVRULA OTIS, MDClinical Instructor in Medicine, Stanford University, Stanford, CA
        • ELIZABETH A. PRICE, MD, MPHAssistant Professor in Medicine (Hematology), Stanford University, Stanford, CA

        Alteration of the erythrocyte membrane usually signals the reticuloendothelial macrophages to remove the damaged red blood cell (RBC) from the circulation. In extraordinary circumstances, however, the damage to the membrane is so great that the erythrocyte undergoes hemolysis, and its intracellular contents, including hemoglobin, are liberated into the plasma. This chapter describes the structural and functional features of normal erythrocytes and diseases involving membrane architecture, RBC proteins, and extracorpuscular factors that can lead to shortened RBC survival. The chapter contains major discussions of sickle cell disease and the thalassemias. Included are tables providing information on erythrocyte metabolism and etiologies of hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency; figures illustrating histologic features of abnormal erythrocytes and sickle cells are also provided.

        This review contains 7 figures, 2 tables, and 243 references.

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      • 5

        Polycythemias

        By Virginia C Broudy, MD
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        Polycythemias

        • VIRGINIA C BROUDY, MDProfessor of Medicine and Vice Chair, Department of Medicine, University of Washington School of Medicine, Seattle, WA

        Polycythemia, also called erythrocytosis, is an increase in the number of circulating red blood cells per volume of blood, as reflected by an elevated hematocrit or hemoglobin level. The three major categories of polycythemia are relative polycythemia, secondary polycythemia, and polycythemia vera. Included in this chapter are discussions on initial evaluation; familial polycythemia; and polycythemia caused by renal and hepatic disorders, drug use, and appropriate increases in erythropoietin production. A flowchart depicts an approach to the evaluation of a patient with polycythemia. Other figures depict the oxygen-hemoglobin dissociation curve characteristic of various polycythemias and a gene mutation associated with familial polycythemia.

        This review contains 3 highly rendered figures and 27 references.

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      • 6

        Nonmalignant Disorders of Leukocytes

        By Andrew A Lane, MD, PhD; Nancy Berliner, MD
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        Nonmalignant Disorders of Leukocytes

        • ANDREW A LANE, MD, PHDFellow, Hematology-Oncology, Dana-Farber/Partners, Boston, MA
        • NANCY BERLINER, MDProfessor of Medicine (Hematology), Harvard Medical School, Boston, MA

        Leukocytes are white blood cells; they protect the body against infections and participate in many types of immunologic and inflammatory responses. The two types of leukocytes are lymphocytes and phagocytes (which include neutrophils, monocytes, macrophages, and eosinophils). This chapter discusses each type of leukocyte separately, focusing on physiology and then specific disorders. Tables present normal leukocyte values in peripheral blood, drugs associated with neutropenia, intrinsic disorders of neutrophils that cause neutropenia, guidelines for management and prevention of febrile neutropenia, selected disorders of neutrophil function, diagnostic criteria for hemophagocytic lymphohistiocytosis, causes of eosinophilia, and causes of lymphocytosis. Figures include electron micrographs of a neutrophil, monocyte, and eosinophil; a graph showing the maturation process of neutrophils; where body neutrophils are found in the normal state; a diagram of the neutrophil response to bacterial invasion; where neutrophils in the peripheral blood exist; and an algorithm presenting the evaluation steps in a patient with recurrent infections from a phagocytic disorder.

        This review contains 6 highly rendered figures, 9 tables, and 79 references.

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      • 7

        Hemostasis and Its Regulation

        By Lawrence L K Leung, MD
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        Hemostasis and Its Regulation

        • LAWRENCE L K LEUNG, MDChief of Staff, Maureen Lyles D’Ambrogio Professor of Medicine, Stanford University School of Medicine, Chief of Staff, Veterans Affairs Palo Alto Health Care System, Stanford, CA

        Hemostasis, the process of blood clot formation, is a coordinated series of responses to vessel injury. It requires complex interactions between platelets, the clotting cascade, blood flow and shear, endothelial cells, and fibrinolysis. This review covers platelet plug formation, clotting cascade, initiation and propagation of blood clot formation, control mechanisms, overview of blood coagulation, blood coagulation as part of the host defense system, heterogeneity of endothelial cells and vascular bed–specific hemostasis, platelet production and thrombopoietin, and coagulation tests and their use. Figures show activated platelets, platelet aggregation, the classic and revised view of the clotting cascade, the inhibition of thrombin by antithrombin, the protein C/protein S pathway, the synergism between nitric oxide (NO) and prostacyclin (PGI2), tissue-type plasminogen activator, the transformation of fibrinogen to fibrin, activated protein C (APC) and carboxypeptidase B-2 (CPB-2) at the site of vascular injury, and an algorithm detailing the exposure of tissue factor at a vascular wound that initiates the clotting cascade. The table lists natural antithrombotic mechanisms of endothelial cells.

        This review contains 10 highly rendered figures, 1 table, and 45 references.

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      • 8

        Platelet Disorders

        By James L. Zehnder, MD; Lawrence L K Leung, MD
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        Platelet Disorders

        • JAMES L. ZEHNDER, MDProfessor of Pathology and Medicine (Hematology), Departments of Pathology and Medicine, Stanford University School of Medicine, Stanford, CA
        • LAWRENCE L K LEUNG, MDChief of Staff, Maureen Lyles D’Ambrogio Professor of Medicine, Stanford University School of Medicine, Chief of Staff, Veterans Affairs Palo Alto Health Care System, Stanford, CA

        A bleeding disorder may be suspected when a patient reports spontaneous or excessive bleeding or bruising, often secondary to trauma. Possible causes can vary between abnormal platelet number or function, abnormal vascular integrity, coagulation defects, fibrinolysis, or a combination thereof. This review addresses hemorrhagic disorders associated with quantitative or qualitative platelet abnormalities, such as thrombocytopenia, platelet function disorders, thrombocytosis and thrombocythemia, and vascular purpuras. Hemorrhagic dis­orders associated with abnormalities in coagulation (e.g., von Willebrand disease and hemophilia) are not covered. An algorithm shows evidence-based practice guidelines for the management of immune thrombocytopenic purpura. Tables list questions regarding bleeding and bruising to ask patients, clinical manifestations of hemorrhagic disorders, typical results of tests for hemostatic function in bleeding disorders, causes of thrombocytopenia, other forms of drug-induced thrombocytopenia, classification of platelet function disorders, and selected platelet-modifying agents.

        This review contains ­1 highly rendered figure, 7 tables, and 82 references. 

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      • 9

        Microangiopathic and Vascular Disorders

        By Nathan T. Connell, MD, MPH
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        Microangiopathic and Vascular Disorders

        • NATHAN T. CONNELL, MD, MPHInstructor in Medicine, Department of Medicine, Harvard Medical School, Associate Physician, Hematology Division, Brigham and Women’s Hospital, Boston, MA

        The thrombotic microangiopathies are characterized by microangiopathic hemolytic anemia and thrombocytopenia and can be classified as autoimmune, drug induced, complement mediated, and infectious/other. Reaching a definitive diagnosis for these disorders can be challenging due to the similarity of presenting symptoms and laboratory findings. Specific disorders described in this review include thrombotic thrombocytopenic purpura, the hemolytic-uremic syndrome, thrombotic microangiopathies of pregnancy (including preeclampsia and HELLP syndrome), disseminated intravascular coagulation, and antiphospholipid syndrome. Vascular disorders that lead to hematologic abnormalities are also discussed. Figures show the major classifications of the thrombotic microangiopathies; ADAMTS13 activity in normal and thrombotic thrombocytopenic purpura plasma; a fragmented red blood cell (arrow), also known as a schistocyte or helmet cell; major considerations in the initial treatment of thrombotic thrombocytopenic purpura and options for refractory patients as well as treatment considerations after discontinuation of plasma exchange; and a diagram of the complement pathway showing regulatory proteins as well as the site of action for the monoclonal antibody eculizumab. Tables list medications associated with thrombotic thrombocytopenia purpura, diagnostic criteria for HELLP, major classifications and examples of the causes of disseminated intravascular coagulation, diagnostic criteria for the antiphospholipid syndrome, vascular purpuras, and criteria for diagnosing hereditary hemorrhagic telangiectasia.

        This review contains 5 highly rendered figures, 6 tables, and 69 references.

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      • 10

        Thrombotic Disorders

        By Lawrence L K Leung, MD
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        Thrombotic Disorders

        • LAWRENCE L K LEUNG, MDChief of Staff, Maureen Lyles D’Ambrogio Professor of Medicine, Stanford University School of Medicine, Chief of Staff, Veterans Affairs Palo Alto Health Care System, Stanford, CA

        The three main elements in the pathophysiology of thrombosis are endothelial injury, a decrease in blood flow, and an imbalance between procoagulant and anticoagulant factors. The latter element can be either hereditary (e.g., antithrombin deficiency) or acquired (e.g., antiphospholipid syndrome). This review details the assessment of patients with thrombotic disorders, hereditary and acquired hypercoagulable states, and the management of venous thromboembolism. Figures show how the degradation of thrombin-activated factor V Leiden by activated protein C (APC) is significantly slower than that of normal activated factor V (factor Va), leading to enhanced thrombin generation; how normal factor V serves as a cofactor of APC in the inhibition of factor VIIIa, whereas factor V Leiden has a poor cofactor function; and how IgG antibodies recognize platelet factor 4–heparin complexes in heparin-induced thrombocytopenia. Tables list inherited and acquired hypercoagulable states, questions for assessing thrombosis, screening tests for patients with suspected hypercoagulable states, clinical features that suggest thrombophilia, frequency and relative risk of venous thrombosis in selected hypercoagulable states, proposed clinical and laboratory criteria for antiphospholipid syndrome, the classification of antiphospholipid antibodies, the 4Ts scoring system for heparin-induced thrombocytopenia, and general guidelines for the management of patients with venous thromboembolism.

        This review contains 2 highly rendered figures, 9 tables, and 168 references.

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      • 11

        Hemophilia

        By Aric Parnes, MD; Lisa Rotenstein, MD, MBA
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        Hemophilia

        • ARIC PARNES, MDHematology Division, Instructor in Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
        • LISA ROTENSTEIN, MD, MBAHarvard Medical School, Brigham and Women’s Hospital, Boston, MA

        Hemophilia is a family of rare bleeding disorders characterized by deficiency of clotting factors. Hemophilia A is an inherited deficiency of factor VIII, whereas hemophilia B (Christmas disease) represents a deficiency of factor IX. Both hemophilia A and B are X-linked diseases, with hemophilia A accounting for 80 to 85% of cases and hemophilia B 15 to 20%. Although hemophilia has historically referred to deficiencies of factors VIII and IX, it is important to recognize that similar bleeding disorders can occur with other missing clotting factors, although this is far more rare. This review covers the definition, history, epidemiology, biology/genetics, clinical manifestations, diagnosis, differential diagnosis, treatment, complications, measures of quality of care, and prognosis of hemophilia, as well as future directions. Figures show the clotting cascade, the genetic makeup of severe hemophilia A, an algorithm for diagnosing hemophilia, and hemophilic arthropathy in a patient’s knees. Tables list severity in hemophilia A and B, treatment of acute bleeding in hemophilia A and B, frequency of dosing in acute bleeding, and treatment of acute bleeding with inhibitors.

        This review contains 4 highly rendered figures, 4 tables, and 59 references.

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      • 12

        Von Willebrand Disease

        By Meghan Campo, MD; Elisabeth M. Battinelli, MD, PhD
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        Von Willebrand Disease

        • MEGHAN CAMPO, MDInstructor in Medicine, Department of Hematology Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
        • ELISABETH M. BATTINELLI, MD, PHDAssistant Professor of Medicine, Associate Physician, Department of Hematology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

        Von Willebrand disease is the most common hereditary bleeding disorder. The disease is caused by inherited defects in the concentration, structure, or function of von Willebrand protein, a multimeric protein that mediates the initial adhesion of platelets at sites of vascular injury and binds and stabilizes blood clotting factor VIII in plasma. Defects in von Willebrand factor concentration, structure, or function that were not inherited can also occur; this is termed acquired von Willebrand syndrome. These defects occur as a consequence of other medical disorders (valvular heart disease, thrombocythemia, malignant neoplasms, and myeloproliferative and autoimmune diseases). This review examines the laboratory evaluation, clinical variants, and treatment of von Willebrand disease. Figures show the initial assessment of von Willebrand disease, and a treatment algorithm for von Willebrand disease. Tables list types of von Willebrand disease and medications used to treat von Willebrand disease.

        This review contains 2 highly rendered figures, 2 tables, and 10 references.

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  • Hepatology
    • 1

      Evaluating the Patient With Liver Disease

      By Andrew J Muir, MD, MHS
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      Evaluating the Patient With Liver Disease

      • ANDREW J MUIR, MD, MHSClinical Director of Hepatology, Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC

      Until the advanced stages of cirrhosis, the identification of liver disease can be challenging for clinicians. In the earlier stages of the condition, most forms of chronic liver disease are asymptomatic or associated with vague and rather nonspecific complaints, such as fatigue. Even in the setting of cirrhosis, liver enzymes may be normal or mildly elevated. Patients with liver disease are currently recognized through a variety of routes, including screening programs, routine laboratory testing, and imaging performed for other complaints. This chapter discusses the approach to the evaluation of patients identified with liver disease, including the role of the history, physical examination, and diagnostic studies. In addition to understanding the etiology of the liver disease, understanding the severity and the risk of liver failure is critical to the evaluation process. Specific sections discuss mild elevation in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), elevated alkaline phosphatase, elevated bilirubin, severe elevation in AST/ALT, and liver lesions. Figures include algorithms for the initial evaluation of patients with abnormal liver tests and the natural history of chronic liver disease; a breakdown of the etiology of liver disease among patients waiting for liver transplantation in the United States in 2012; and illustrations of the West Haven criteria for hepatic encephalopathy and the initial approach to patients with liver masses. Tables show the groups at risk for hepatitis C, hepatitis B, and nonalcoholic fatty liver disease; common patterns of drug-induced liver injury; common laboratory tests for the etiology of patients with liver disease; the Child-Pugh score for patients with cirrhosis; and the etiologies of, and diagnostic tests for, acute liver failure. This chapter contains 5 highly rendered figures, 5 tables, 75 references, 5 MCQs.

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    • 2

      Viral Hepatitis

      By Esperance A K Schaefer, MD, MPH; Jules L Dienstag, MD
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      Viral Hepatitis

      • ESPERANCE A K SCHAEFER, MD, MPHResearch fellow, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
      • JULES L DIENSTAG, MDCarl W. Walter Professor of Medicine and Dean for Medical, Education, Harvard Medical School and Professor of Medicine, Massachusetts General Hospital, Boston, MA

      Despite a common tropism for the liver, the hepatitis viruses encompass a heterogeneous group of diseases with varying modes of acquisition, symptoms, chronicity, and complications. The five major hepatitis viruses, hepatitis A, B, C, D, and E, can be categorized by their modes of acquisition (parenteral versus enteral) and by their risk of chronicity. Beginning with the approach to the patient with viral hepatitis, this chapter reviews both the acute and chronic clinical features, diagnoses, and treatment options for hepatitis A, B, C, D, and E. Nonhepatotropic viruses that may cause liver inflammation are covered as well: herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human parvovirus B19, adenovirus, yellow fever, rubella (German measles) and rubeola (measles), and coxsackievirus B. Treatment options are covered and listed in depth and details. Tables include characteristics of types of viral hepatitis, differential diagnosis of acute hepatitis, and treatment guidelines for hepatitis B.

      This review contains 4 highly rendered figures, 12 tables, and 145 references.

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    • 3

      Viral Hepatitis Other Than A, B, or C

      By Nadeem Anwar, MD ; Kenneth E. Sherman, MD, PhD
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      Viral Hepatitis Other Than A, B, or C

      • NADEEM ANWAR, MD University of Cincinnati College of Medicine, Cincinnati, OH
      • KENNETH E. SHERMAN, MD, PHD University of Cincinnati College of Medicine, Cincinnati, OH

      Viral hepatitis is a global, although variably distributed, health problem associated with significant morbidity and mortality. Infection with a hepatitis virus leads to acute inflammation and liver cell damage (hepatocyte injury). Such infection may be symptomatic or subclinical and may result in disease resolution, death from fulminant hepatic failure, or development of  a chronic disease state. Whereas the chronic infection with hepatitis B and C accounts for a global burden of more than 500,000,000 cases, the global death rate from all types of hepatitis is approximately 1 million people annually. This review focuses on the virology, epidemiology, clinical features, diagnosis, treatment, and prevention of hepatitis D and hepatitis E, as well as other viruses associated with hepatitis. Figures show the global distribution of hepatitis D infection, elevation of anti–hepatitis D virus antibodies in hepatitis B/hepatitis D virus coinfection, geographic distribution of hepatitis E virus by genotype, factors significant in the pathogenesis of hepatitis E, and pattern of antibody elevation in hepatitis E. The table lists proposed diagnostic criteria for hepatitis E virus.

      This review contains 5 highly rendered figures, 1 table, and 42 references.

      Key words: hepatitis D, hepatitis D virus, hepatitis E, hepatitis E virus, non-A hepatitis, non-B hepatitis, non-C hepatitis, viral hepatitis 

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    • 4

      Chronic Liver Diseases

      By Sandra Ciesek, MD; Michael P Manns, MD
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      Chronic Liver Diseases

      • SANDRA CIESEK, MDDepartment of Gastroenterology, Hepatology, and Enterology, The Hannover Medical School, Hannover, Germany
      • MICHAEL P MANNS, MDProfessor and Chairman, Department of Gastroenterology, Hepatology, and Enterology, The Hannover Medical School, Hannover, Germany

      The term chronic hepatitis encompasses many distinct clinical and pathologic diseases affecting the liver, the most important of which are autoimmune hepatitis (AIH), chronic hepatitis B with or without hepatitis D, and chronic hepatitis C caused by hepatitis C virus (HCV). The standard treatment of AIH is immunosuppressive therapy either with prednisolone alone or in combination with azathioprine. Although mycophenolate mofetil or cyclosporine can be used for retherapy in the case of treatment failure, controlled clinical trials are missing for these immunosuppressive drugs; thus, they are not part of the American Association for the Study of Liver Diseases (AASLD) practice guidelines for AIH.

      Chronic hepatitis B is a major global health care problem as 5% of the world’s population, or approximately 350 million persons, is chronically infected. Anti–hepatitis B virus (HBV) drugs can be divided into three classes: alfa interferons, nucleoside analogue (lamivudine, entecavir, telbivudine), and nucleotide analogue (adefovir dipivoxil, tenofovir dipivoxil). Interferon alfa has a number of potential side effects, and careful consideration must be given to its use. Tenofovir, which falls under the nucleotide analogue class, was approved by the Food and Drug Administration in 2008 and has been shown in clinical trials to have more potent activity in serum-suppressing HBV DNA levels than the comparable adefovir.

      More prevalent than chronic hepatitis B is chronic hepatitis C due to the high chronicity rate of HCV infection (approximately 160 million people are chronically infected with HCV worldwide). Until 2011, the only treatment for chronic HCV was a combination therapy of pegylated interferon alfa and ribavirin (RBV); however, new treatments for chronic hepatitis C include the directly acting antivirals (DAAs) sofosbuvir and simeprevir, although host-targeting agents are also being developed. The side effects of pegylated interferon/RBV therapy and DAAs should be considered, of which only sofosbuvir has shown no specific side effects so far in clinical studies.

      This module contains 5 highly rendered figures, 6 tables, 61 references, and 5 MCQs.

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    • 5

      Hereditary Hemochromatosis

      By Matthew S Chang, MD; Benjamin N Smith, MD
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      Hereditary Hemochromatosis

      • MATTHEW S CHANG, MDResearch/Clinical Fellow, Division of Gastroenterology, Hepatology & Endoscopy, Brigham & Women’s Hospital, Boston, MA
      • BENJAMIN N SMITH, MDLecturer on Medicine, Division of Gastroenterology, Hepatology & Endoscopy, Brigham and Women’s Faulkner Hospital, Jamaica Plain, MA

      Hereditary hemochromatosis is an inherited iron overload disorder that can result in liver and other end-organ involvement and injury. The phenotypic expression ranges from asymptomatic to end-stage liver disease and can be separated into three stages. This review covers the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, treatment, complications, and prognosis of hereditary hemochromatosis. Figures show the fraction of patients with mutations for hemochromatosis and clinical manifestations, the regulation of iron by hepcidin, physical examination findings in hemochromatosis, a diagnostic algorithm for hemochromatosis, and a treatment algorithm for hemochromatosis. Tables list hemochromatosis disease stage according to the European Association for the Study of the Liver, genetic mutations in hemochromatosis, secondary (non-hemochromatosis-related) causes of iron overload, indications for liver biopsy in patients with hemochromatosis, and clinical manifestations in hemochromatosis.

      This review contains 5 highly rendered figures, 5 tables, and 32 references

      Key words: Hemochromatosis; Hereditary hemochromatosis; Iron overload; Iron regulatory pathways; Hepatic  iron; Hepcidin

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    • 6

      Liver and Pancreas Transplantation

      By Julie A Thompson, MD; Aleksandra Kukla, MD
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      Liver and Pancreas Transplantation

      • JULIE A THOMPSON, MDAssistant Professor, Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN
      • ALEKSANDRA KUKLA, MDAssistant Professor of Medicine, Medical Director of Pancreas Transplant Program, Division of Renal Diseases and Hypertension, University of Minnesota, Minneapolis, MN

      More than 6,000 liver transplantations are performed annually in the United States. Enhancements in patient selection and surgical technique and the availability of more powerful immunosuppressive agents have resulted in steady improvement in patient survival. As a result, liver transplantation has been accepted as the standard of care for patients with severe acute or chronic liver disease in whom conventional modalities of therapy have failed. The major obstacle to patients receiving the procedure is the critical shortage of donor organs. Many more recipients of liver transplantation are now receiving the bulk of their care from general internists, gastroenterologists, and primary care physicians. As a result, recognition of potential long-term complications and the need for appropriate immunizations and regular screening visits have become increasingly important. This chapter discusses who qualifies as a candidate for liver transplantation, contraindications to transplantation, timing of transplantation, operative procedures, complications of transplantation (e.g., perioperative and surgical complications, immunologic complications, infectious complications, complications of medical and immunosuppressive therapy, and disease-specific complications), and transplantation outcome. Pancreas transplantation, which aims at providing physiologic insulin replacement, is a therapy that reliably achieves euglycemia in patients with type 1 diabetes mellitus. The discussion of pancreas transplantation focuses on topics such as evaluation of candidates for transplantation (including islet transplantation); contraindications to transplantation; operative procedures; outcome survival; and the effect of transplantation on disorders associated with type 1 diabetes mellitus. The figures show estimated 3-month survival as a function of the Model for End-Stage Liver Disease (MELD) score, the sections of the liver that can be used for transplantation, an algorithm for evaluation of patients with type 1 diabetes mellitus being considered for pancreas transplantation, and an illustration of enteric drainage technique used in whole pancreas transplantation. The tables provide the common indications for liver transplantation, the scoring system for the Child-Turcotte-Pugh classification of liver disease severity, drug interactions with immunosuppressants, and immunization recommendations for liver transplant patients. 
      This chapter contains 4 highly rendered figures, 4 tables, 101 references, 5 MCQs, and 1 teaching slide set.

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    • 7

      Cirrhosis and Complications of Portal Hypertension

      By Andres Cardenas, MD; Isabel Graupera, MD; Elsa Sola, MD; Pere Ginès, MD, PhD
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      Cirrhosis and Complications of Portal Hypertension

      • ANDRES CARDENAS, MDGI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer, Ciber de Enfermedades Hepaticas y Digestivas, Instituto Reina Sofía de Investigación Nefrológica, Barcelona, Spain
      • ISABEL GRAUPERA, MDLiver Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer, Ciber de Enfermedades Hepaticas y Digestivas, Instituto Reina Sofía de Investigación Nefrológica, Barcelona, Spain
      • ELSA SOLA, MDLiver Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer, Ciber de Enfermedades Hepaticas y Digestivas, Instituto Reina Sofía de Investigación Nefrológica, Barcelona, Spain
      • PERE GINÈS, MD, PHDChairman, Liver Unit, Hospital Clínic, Professor of Medicine, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer, Ciber de Enfermedades Hepaticas y Digestivas, Instituto Reina Sofía de Investigación Nefrológica, Barcelona, Spain

      Cirrhosis is the most advanced stage of all the different types of chronic liver diseases. It is defined as a diffuse disorganization of normal hepatic structure by extensive fibrosis associated with regenerative nodules. Hepatic fibrosis is potentially reversible if the causative agent is removed. However, advanced cirrhosis leads to major alterations in the hepatic vascular bed and is usually irreversible. Cirrhosis is a progressive and severe clinical condition associated with considerable morbidity and high mortality. It leads to a wide spectrum of characteristic clinical manifestations, mainly attributable to hepatic insufficiency and portal hypertension. Major complications of portal hypertension include ascites, gastrointestinal (GI) variceal bleeding, hepatic encephalopathy (HE), renal failure, and bacterial infections. In recent years, major advances in the understanding of the natural history and pathophysiology of cirrhosis and the treatment of its complications have led to improved management, quality of life, and life expectancy of patients with this disease. Cirrhosis is also a risk factor for developing hepatocellular carcinoma (HCC). Decompensated cirrhosis carries a poor short-term prognosis; thus, orthotopic liver transplantation (OLT) should always be considered in suitable candidates. This chapter describes the epidemiology, etiology and genetic factors, pathogenesis, diagnosis, general management, and treatment of cirrhosis. Complications of cirrhosis are discussed, including ascites, spontaneous bacterial peritonitis, dilutional hyponatremia, hepatorenal syndrome, variceal bleeding, hepatopulmonary syndrome and postpulmonary hypertension, HE, and HCC. Indications and contraindications for liver transplantation are described. Figures show liver biopsy results and ultrasound images in cirrhosis from hepatitis C, a patient with tense ascites, transjugular intrahepatic portosystemic shunting (TIPS), large esophageal varices with red spots, and HCC. Tables outline the main causes of cirrhosis and the diagnostic methods for identifying them, the Child-Pugh score, diagnostic criteria for hepatorenal syndrome, grades of HE, and indications for liver transplantation.
      This chapter contains 6 highly rendered figures, 8 tables, 73 references.

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    • 8

      Parenteral Nutrition Associated Liver Toxicity: Prevention, Diagnosis and Management

      By Meredith A. Baker, MD; Lorenzo Anez-Bustillos, MD; Duy T. Dao, MD; Gillian L. Fell, MD; Kathleen M. Gura, PharmD; Mark Puder, MD, PhD
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      Parenteral Nutrition Associated Liver Toxicity: Prevention, Diagnosis and Management

      • MEREDITH A. BAKER, MD
      • LORENZO ANEZ-BUSTILLOS, MD
      • DUY T. DAO, MD
      • GILLIAN L. FELL, MD
      • KATHLEEN M. GURA, PHARMD
      • MARK PUDER, MD, PHD

      Long-term parenteral nutrition (PN) treatment is limited by parenteral nutrition–associated liver disease (PNALD), which is characterized initially by intrahepatic cholestasis, typically defined as a direct bilirubin greater than 2 mg/dL in the absence of other causes of liver disease. PNALD is typically less common and less severe and progresses more slowly in older children and adults than in infants. The etiology of PNALD is multifactorial. Key factors include immature liver function, sepsis, and a lack of enteral nutrition. Additionally, nearly every component of PN has been attributed to or exacerbated hepatotoxicity. PN preparations must be carefully individualized and monitored to minimize hepatotoxicity from its various components. Although many hepatotoxic components or imbalances have been recognized, soybean oil–based lipid emulsions continue to be widely used as they are the only lipid emulsions currently approved for PN by the Food and Drug Administration. Fish oil–based lipid emulsions have been shown to reverse PNALD, with an associated decrease in mortality. As such, fish oil therapy should be considered early once biochemical cholestasis is detected in PN-dependent patients. Studies investigating the use of novel lipid emulsions for prevention and treatment of PNALD are ongoing.  

      This review contains 5 figures, 5 tables, and  114 references.

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  • Human Genetics
    • 1

      Genomics Overview

      By W Gregory Feero, MD, PhD
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      Genomics Overview

      • W GREGORY FEERO, MD, PHDSpecial Advisor to the Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, Faculty, Maine-Dartmouth Family Medicine Residency, Augusta, ME

      New genomic applications are affecting internal medicine subspecialties and will soon affect the practices of all physicians. This chapter discusses the fields of genetics versus genomics and details the fundamentals of a genomic approach to health care. It includes special considerations such as the intersection between genomics and evidence-based medicine, genetic discrimination, the regulation of genetic testing, and the marketing of genetic testing directly to consumers. The chapter looks at genome-wide association studies and clinical care, as well as sequencing technologies. Tables offer examples of patterns of inheritance, clinical recommendations and red flags raised by family history, and intended uses for genetic tests. One figure shows an example pedigree obtained by using the US surgeon general's My Family Health Portrait family history tool, while the other shows the chromosomal locations of genetic markers associated with disease risk discovered in genome-wide association studies between 2005 and 2009. This chapter contains 41 references.

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    • 2

      Practice of Genetics in Clinical Medicine

      By Bruce R Korf, MD, PhD, FACMG; Carlos Gallego, MD
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      Practice of Genetics in Clinical Medicine

      • BRUCE R KORF, MD, PHD, FACMGProfessor and Chair, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
      • CARLOS GALLEGO, MDInternist Geneticist, Huntsville Hospital

      This review provides a general overview of the genetic approach in medical practice, discusses the principles of genetic testing, including interpretation of genetic tests and direct-to-consumer genomic testing, and looks at genetic counseling and approaches to treatment. The internist should become familiar with genetic disorders such as those associated with mutations in single genes or changes in chromosome number or structure. This is the traditional area of focus for medical geneticists and is likely to remain so. The internist should be familiar with basic principles of care for individuals with the more common of these conditions and needs to recognize clues that suggest the presence of these disorders, especially in family history. The section on genetics of common disorders focuses on pharmacogenetics, risk assessment, and prevention. Figures illustrate commonly used standard pedigree symbols and examples of autosomal recessive, autosomal dominant, X-linked recessive, and maternal inheritance. Tables offer different forms of genetic testing and types of gene mutations at genome and DNA levels.

      This review contains 2 figures, 2 tables, and 83 references.

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  • Infectious Diseases
    • Overview of Infectious Diseases
      • 1

        Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

        By Steven K. Lundy, PhD; Alison Gizinski, MD; David A. Fox, MD
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        Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

        • STEVEN K. LUNDY, PHDResearch Assistant Professor, Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
        • ALISON GIZINSKI, MDAssistant Professor, Division of Rheumatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
        • DAVID A. FOX, MDProfessor, Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School and Health System, Ann Arbor, MI

        The immune system is a complex network of cells and mediators that must balance the task of protecting the host from invasive threats. From a clinical perspective, many diseases and conditions have an obvious link to improper functioning of the immune system, and insufficient immune responses can lead to uncontrolled acute and chronic infections. The immune system may also be important in tumor surveillance and control, cardiovascular disease, health complications related to obesity, neuromuscular diseases, depression, and dementia. Thus, a working knowledge of the role of immunity in disease processes is becoming increasingly important in almost all aspects of clinical practice. This review provides an overview of the immune response and discusses immune cell populations and major branches of immunity, compartmentalization and specialized immune niches, antigen recognition in innate and adaptive immunity, immune tolerance toward self antigens, inflammation and innate immune responses, adaptive immune responses and helper T (Th) cell subsets, components of the immune response that are important targets of treatment in autoimmune diseases, mechanisms of action of biologics used to treat autoimmune diseases and their approved uses, and mechanisms of other drugs commonly used in the treatment of autoimmune diseases. Figures show the development of erythrocytes, platelets, lymphocytes, and other immune system cells originating from hematopoietic stem cells that first reside in the fetal liver and later migrate to the bone marrow, antigen–major histocompatibility complex recognition by T cell receptor control of T cell survival and activation, and Th cells as central determinants of the adaptive immune response toward different stimuli. Tables list cell populations involved in innate and adaptive immunity, pattern recognition receptors with known ligands, autoantibody-mediated human diseases: examples of pathogenic mechanisms, selected Food and Drug Administration–approved autoimmune disease indications for biologics, and mechanism of action of biologics used to treat autoimmune diseases.

         

        This review contains 3 highly rendered figures, 5 tables, and 64 references.

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      • 2

        Vaccines and Vaccination

        By Lindsey Obradovich, PharmD, MSc; Nicholas C Issa, MD
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        Vaccines and Vaccination

        • LINDSEY OBRADOVICH, PHARMD, MSCSenior Research Pharmacist, Investigational Drug Service, Brigham and Women’s Hospital, Boston, MA
        • NICHOLAS C ISSA, MDAssistant Professor of Medicine, Harvard Medical School, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA

        The advent of vaccination began a new era in the world and in medicine. From the eradication of smallpox and near-eradication of polio to the significant reduction in many childhood diseases, vaccination has saved countless lives. Progress continues today in the form of safer and more effective vaccines, along with new vaccines against old and emerging pathogens that threaten worldwide pandemics. Several vaccines have been approved recently by the Food and Drug Administration, including a more immunogenic pneumococcal vaccine, new meningococcal serotype B vaccines, a 9-valent HPV vaccine, and the first adjuvanted influenza vaccine. Additional advancement with improved vaccines against herpes zoster and novel vaccines against emerging pathogens (Ebola and Zika viruses) is on the horizon. In this review, we discuss the immune mechanisms by which vaccines induce protection, the different types of vaccines, and the most recent recommendations by the Advisory Committee on Immunization Practices for vaccination schedules in adults. Key information for the general practitioner is presented in a concise and easy-to-read format, summarized in tables whenever possible. Vaccination in special populations, such as pregnant women, immunocompromised patients, international travelers, and health care workers, is also included in this review. A list of guidelines is also included.

        Key words: immunocompromised host, postexposure prophylaxis, travel, vaccination, vaccine

        This review contains 7 highly rendered figures, 12 tables, and 57 references.

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      • 3

        General Principles of Antibiotic Therapy

        By Alyssa R. Letourneau, MD, MPH; Michael S. Calderwood, MD, MPH
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        General Principles of Antibiotic Therapy

        • ALYSSA R. LETOURNEAU, MD, MPHDepartment of Medicine , Harvard Medical School, Assistant Director, Antimicrobial Stewardship Program, Massachusetts General Hospital, Boston, MA
        • MICHAEL S. CALDERWOOD, MD, MPHAssistant Professor, Department of Medicine, Harvard Medical School, Assistant Hospital Epidemiologist/Associate Director, Antimicrobial Stewardship, Brigham and Women’s Hospital, Boston, MA

        The essential feature of effective antibiotic agents is the ability to inhibit the growth of microorganisms at concentrations tolerated by the host. Antibiotic agents generally target anatomic structures or biosynthetic pathways unique to bacteria. The appropriate choice of an antibiotic for an infection depends on the following: clinician’s level of suspicion; the infecting organism and its antibiotic susceptibilities; the type of infection; factors associated with specific antibiotic agents; host factors; and public health considerations. This review provides an overview of antibiotic therapy and covers identifying the cause of an infection, determination of bacterial susceptibility to specific drugs, site of infection and ancillary therapy, antibiotic drug targets, pharmacodynamic parameters, factors affecting dosage and route of administration, host factors, complications of antibiotic therapy, Clostridium difficile infection, and antimicrobial resistance. Figures show sites of action for major antibiotic classes and pharmacodynamic parameters determining antibiotic efficacy. Tables list pharmacodynamic parameters predictive of outcome, antibiotics with equivalent oral and intravenous bioavailability, and direct drug toxicity of the major antibiotic classes.

         

        This review contains 2 highly rendered figures, 3 tables, and 43 references.

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      • 4

        Specific Antibiotic Agents

        By Alyssa R. Letourneau, MD, MPH; Michael S. Calderwood, MD, MPH
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        Specific Antibiotic Agents

        • ALYSSA R. LETOURNEAU, MD, MPHDepartment of Medicine , Harvard Medical School, Assistant Director, Antimicrobial Stewardship Program, Massachusetts General Hospital, Boston, MA
        • MICHAEL S. CALDERWOOD, MD, MPHAssistant Professor, Department of Medicine, Harvard Medical School, Assistant Hospital Epidemiologist/Associate Director, Antimicrobial Stewardship, Brigham and Women’s Hospital, Boston, MA

        The simultaneous use of multiple antibiotics in a shotgun fashion should be avoided because of the problems of drug toxicity and hypersensitivity reactions, microbial superinfections, and antagonisms between certain agents. Most bacterial infections can be treated satisfactorily with a single antibiotic agent. There are a limited number of situations, however, in which the simultaneous administration of different antibiotics is warranted. This review covers specific antimicrobial agents, including β-lactam antibiotics, aminoglycosides, polymyxins, tetracyclines, macrolides, clindamycin, nitroimidazoles, chloramphenicol, vancomycin, lipoglycopeptides, oxazolidinones, daptomycin, streptogramins, sulfonamides and trimethoprim, fluoroquinolones, nitrofurantoin, fosfomycin, rifamycins, and fidaxomicin, and provides empirical therapy recommendations. Figures show an overview of penicillin antibiotics, an overview of β-lactam/β-lactamase inhibitor combinations, and a positive D-zone test for inducible clindamycin resistance. Tables list antibacterial guidelines for initial inpatient empirical therapy and empirical sepsis guidelines.

         

        This review contains 3 highly rendered figures, 2 tables, and 78 references.

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      • 5

        Antimicrobial Resistance in Enteric Gram-negative Organisms

        By Allison Mah, MD, FRCPC; Inna Sekirov, MD, PhD; Theodore S Steiner, MD, FRCPC
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        Antimicrobial Resistance in Enteric Gram-negative Organisms

        • ALLISON MAH, MD, FRCPCPostgraduate Year 6, Division of Infectious Diseases, Department of Internal Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, BC
        • INNA SEKIROV, MD, PHDPostgraduate Year 5, Division of Medical Microbiology, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver General Hospital , Vancouver, BC
        • THEODORE S STEINER, MD, FRCPCProfessor and Associate Head, Division of Infectious Diseases, Department of Internal Medicine, Associate Member, Department of Microbiology and Immunology, University of British Columbia , Vancouver General Hospital , Vancouver, BC

        Antimicrobial resistance is a phenomenon that predates the introduction of antibiotics into clinical practice and has become an exponentially growing problem worldwide, leading to increased mortality and increased costs of health care use. Among the many organisms with ever-worsening resistance profiles, Escherichia coli and other Enterobacteriaceae species are significant pathogens, both in terms of numbers and the severity of the infections they cause. The purpose of this review is to examine the emerging concern of antimicrobial resistance and the approach to treatment in the setting of infection with resistant organisms. We will focus on the resistance mechanisms of Enterobacteriaceae to select antimicrobial classes, briefly discuss the epidemiology of resistance, and discuss current treatment strategies. The specific epidemiology, clinical manifestations, and treatment of individual members of the Enterobacteriaceae are discussed in the review “Infections Due to Escherichia coli and Other Enteric Gram-Negative Bacilli,” found elsewhere in this publication. Figures illustrate the mechanisms of antimicrobial resitance in Enterobacteriaceae. Tables list the Ambler classification of ESBL/AmpC and carbapenemase enzymes, and antibiotics with activity against carbapenem-resistant enterobacteriaceae.

        This review contains 4 highly rendered figures, 2 tables, and 27 references.

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    • Infectious Syndromes
      • 1

        Hyperthermia, Fever, and Fever of Undetermined Origin

        By Harvey B Simon, MD, FACP
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        Hyperthermia, Fever, and Fever of Undetermined Origin

        • HARVEY B SIMON, MD, FACPAssociate Professor of Medicine, Harvard Medical School, Health, Sciences, Technology Faculty, Massachusetts Institute of Technology, Physician, Massachusetts General Hospital, Boston, MA

        Abnormal elevation of body temperature, or pyrexia, can occur in one of two ways: hyperthermia or fever. In hyperthermia, thermal control mechanisms fail, so that heat production exceeds heat dissipation. In contrast, in fever, the hypothalamic thermal set point rises, and intact thermal control mechanisms are brought into play to bring body temperature up to the new set point. The distinction between fever and hyperthermia is more than academic: hyperthermia is best treated with drugs that lower the thermal set point, such as aspirin, other cyclooxygenase inhibitors, or acetaminophen. Fever of undetermined origin (FUO) presents one of the most challenging and perplexing problems in clinical medicine. Such fevers may persist for weeks or months in the absence of characteristic clinical findings or clues. Ultimately, most such obscure fevers prove to be caused by common diseases presenting in an atypical fashion rather than by rare and exotic illnesses. This chapter discusses fever and hyperthermia and further clarifies the distinction between fever and hyperthermia. The section on hyperthermia discusses the etiology of hyperthermia; the epidemiology, pathophysiology, diagnosis, differential diagnosis, treatment, and prevention of heatstroke; and the diagnosis and treatment of neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia of anesthesia. The section on fever discusses the pathogenesis, diagnosis, and treatment of fever, as well as the possible benefits and complications of elevated body temperature. The section on FUO presents the defining criteria of FUO; the etiologic classification of FUO, including the infections and neoplasms possibly responsible; and the diagnosis of FUO, including laboratory and radiologic studies, biopsies, and the role of exploratory laparotomy. Tables describe the causes of hyperthermia; the causes of FUO as reported in various studies over five decades; and a comprehensive list of causes of FUO. An algorithm depicts the progressive steps in the pathogenesis of fever and hyperthermia.

        This review contains 1 highly rendered figure, 3 tables, and 107 references.

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      • 2

        Sepsis

        By Steven P LaRosa, MD; Steven M. Opal, MD
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        Sepsis

        • STEVEN P LAROSA, MDStaff Physician, Infectious Disease Division, Beverly Hospital/Lahey Health System, Beverly, MA
        • STEVEN M. OPAL, MDChief, Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, RI

        Sepsis, along with the multiorgan failure that often accompanies the systemic inflammatory response syndrome (SIRS), is a leading cause of mortality in the intensive care unit. Although modest improvements in the prognosis have been made over the past two decades and promising new therapies continue to be investigated, innovations in the management of septic shock are still required. This chapter discusses the definitions, epidemiology, and pathogenesis (including microbial factors, host-derived mediators, and organ dysfunction) relating to sepsis. Management of severe sepsis and septic shock is also described. Tables outline the terminology of sepsis, the PIRO classification system, host-derived inflammatory mediators in septic shock, standard laboratory values in sepsis, multiple organ dysfunction syndrome in severe sepsis, hemodynamic findings, suggested empirical antibiotic choices, and current experimental therapies in the treatment of septic shock. Graphs show trends in sepsis cases and mortality rates in septic shock patients and patients with acute respiratory distress syndrome. Illustrations demonstrate the interaction between bacterial endotoxin and bacterial superantigens and neutrophil–endothelial cell interactions in sepsis.

        This review contains 5 highly rendered figures, 8 tables, and 143 references.

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      • 3

        Pneumonia and Other Pulmonary Infections

        By Joel T. Katz, MD, FACP
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        Pneumonia and Other Pulmonary Infections

        • JOEL T. KATZ, MD, FACPMedicine Education Office, Brigham and Woman’s Hospital, Boston, MA

        Pulmonary infections span a wide spectrum, ranging from self-limited to life-threatening and from acute to chronic. Although overall hospitalization rates are declining, hospitalizations for acute lower respiratory tract infections have increased steadily since 1980, particularly in the elderly. Taken together, pneumonia and influenza rank as the sixth leading cause of death in the United States and the leading infectious cause of death in the United States and the world. This chapter details the pathophysiology, epidemiology, general features, and treatment of pulmonary infections, particularly bacterial pneumonia. The chapter includes a Pneumonia Severity Index calculator. Tables list the major causes of pulmonary infection, host defense mechanisms against pulmonary infection, initial empirical antibiotic therapy in patients with suspected community-acquired pneumonia, initial antibiotic therapy for community-acquired pneumonia in outpatients and in patients who require hospitalization, and antibiotic choices for aspiration pneumonia. This chapter contains 105 references.

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      • 4

        Bacterial Infections of the Adult Upper Respiratory Tract

        By Laura K Certain, MD, PhD; Miriam B Barshak, MD, PhD
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        Bacterial Infections of the Adult Upper Respiratory Tract

        • LAURA K CERTAIN, MD, PHDInstructor, Harvard Medical School, Assistant in Medicine, Massachusetts General Hospital, Boston, MA
        • MIRIAM B BARSHAK, MD, PHDAssistant Professor, Harvard Medical School, Attending Physician, Massachusetts General Hospital, Clinical Associate, Massachusetts Eye and Ear Infirmary, Boston, MA

        Sore throat, sinus congestion, earaches, and dental pain are among the most common reasons for which adults seek medical care. Although most of these complaints are self-limited, there are life-threatening complications as well. Accurate diagnosis and recognition of when to use antibiotics are critical, especially given increasing concerns about the effects of antibiotic overuse on the healthy microbiome and in promoting antibiotic resistance. Recent data suggest that (1) the pattern and duration of symptoms should guide the decision about whether sinus symptoms should be treated with antibiotics; patients who do not respond to first-line treatment with amoxicillin or amoxicillin-clavulanic acid should have cultures collected before receiving alternative antibiotics; (2) Fusobacterium necrophorum is an important consideration in young adults with pharyngitis; (3) most cases of otitis externa should be treated with topical, not oral, antibiotics; (4) malignant otitis externa should always be considered in an immunocompromised or diabetic patient with ear pain and drainage; (5) dental abscesses should be managed with urgent referral for drainage; and (6) antibiotic coverage for macrolide- and clindamycin-resistant streptococcal species should be considered in β-lactam-allergic patients with complicated dental or pharyngeal infections.

        This review contains 5 figures, 4 tables, and 84 references.

        Key words: Sinusitis, Pharyngitis, Otitis, Peritonsillar Abscess, Epiglottitis, Dental Abscess, Streptococci

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      • 5

        Respiratory Viral Infections

        By Michael G. Ison, MD, MSc
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        Respiratory Viral Infections

        • MICHAEL G. ISON, MD, MSCAssociate Professor, Divisions of Infectious Diseases & Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL

        The respiratory tract can be infected by a diverse group of viruses that produce syndromes ranging in severity from mild colds to fulminant pneumonias. Respiratory viral infections are a leading cause of morbidity, hospitalization, and mortality throughout the world; influenza and pneumonia were the most prevalent infectious causes of death during the 20th century in the United States. Respiratory viral infections are also a common cause of acute illness and physician visits in the United States. This chapter discusses the etiology, pathophysiology, and approach to the diagnosis of respiratory viral infections, as well as common syndromes, including common colds, pharyngitis and laryngitis, acute bronchitis, influenza syndrome, croup, bronchiolitis, reactive airway disease exacerbation, and pneumonia. The chapter also describes infections caused by specific agents, such as adenoviruses; human and zoonotic coronaviruses, including the MERS-CoV, which has emerged as a newly recognized pathogen causing severe respiratory viral infections; human metapneumovirus (hMPV); influenza virus; parainfluenza viruses; respiratory syncytial virus (RSV); and rhinovirus. The discussion of these infections includes classification and pathogenesis, epidemiology and transmission, diagnosis, complications, treatment, and prevention. Most notably, the emergence of the 2009 pandemic influenza A/H1N1 virus has enhanced our understanding of the pathogenesis and management of influenza. The chapter notes several novel antivirals, including DAS181, CMX001 (brincidofovir), and ALN-RSV01, that hold promise as future therapies against common respiratory viruses.

        Tables describe epidemiologic features of principal human respiratory viruses, laboratory methods for diagnosis of respiratory viral infections, and agents used to prevent and treat influenza. A sidebar lists Internet resources for respiratory viral infections. The chapter is also enhanced by a graph, numerous depictions of the viruses discussed, and a chest radiograph of a patient infected with influenza.

        This review contains 10 highly rendered figures, 3 tables, and 109 references.

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      • 6

        Acute Bacterial Meningitis

        By Karen L. Roos, MD
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        Acute Bacterial Meningitis

        • KAREN L. ROOS, MDJohn and Nancy Nelson Professor of Neurology and Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN

        Acute bacterial meningitis is a life-threatening infection. By definition, meningitis is an infection of the meninges and the subarachnoid space. Bacterial meningitis is associated with an inflammatory response that involves the meninges, the subarachnoid space, the brain parenchyma, and the cerebral arteries and veins. As such, bacterial meningoencephalitis is the more accurate descriptive term. This chapter discusses the epidemiology, etiology, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of the disease. The discussion of diagnosis covers clinical manifestations, physical examination findings, laboratory tests, and imaging studies. The discussion of treatment covers empirical therapy, specific antimicrobial therapy, and dexamethasone therapy. Graphs compare causative organisms and clinical manifestations of community-acquired meningitis. Illustrations depict proper patient positioning for detecting nuchal rigidity, Kernig sign, Brudzinski sign, and lumbar puncture, as well as a sagittal view of a lumbar puncture needle as it is advanced into the subarachnoid space. An algorithm delineates the approach to the patient with symptoms and signs of bacterial meningitis. Tables outline bacterial pathogens based on predisposing and associated conditions, cerebrospinal fluid diagnostic studies for meningitis, the appearance of the organism on a Gram stain, empirical antimicrobial therapy based on predisposing and associated conditions, recommendations for specific antibiotic therapy in bacterial meningitis, and recommended doses for antibiotics commonly used in the treatment of bacterial meningitis.

         

        This review contains 8 highly rendered figures, 6 tables, and 75 references.

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      • 7

        Acute Viral Meningitis

        By Jared R. Brosch, MD; Karen L. Roos, MD
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        Acute Viral Meningitis

        • JARED R. BROSCH, MDDeptment of Neurology, Assistant Professor of Neurology, Indiana University School of Medicine, Indianapolis, IN
        • KAREN L. ROOS, MDJohn and Nancy Nelson Professor of Neurology and Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN

        Acute viral meningitis refers to inflammation of the meninges of the brain in response to a viral pathogen. Viruses cause meningitis, encephalitis, myelitis, or a combination of these, meningoencephalitis or encephalomyelitis. Viral meningitis is typically a self-limited disorder with no permanent neurologic sequelae. This chapter reviews the epidemiology, etiology, diagnosis, differential diagnosis, treatment, complications, and prognosis. Tables describe Wallgren’s criteria for aseptic meningitis, important arboviral infections found in North America, herpes family viruses and meningitis, classic cerebrospinal fluid (CSF) abnormalities with viral meningitis, Centers for Disease Control and Prevention criteria for confirming arboviral meningitis, basic CSF studies for viral meningitis, and etiology of CSF pleocytosis. Figures depict common causes of viral meningitis, nuchal rigidity, examination for Kernig sign, and Brudzinski sign for meningeal irritation.

        This review contains 4 highly rendered figures, 7 tables, and 16 references.

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      • 8

        Brain and Spinal Abscesses

        By Allan R Tunkel, MD, PhD; W Michael Scheld, MD
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        Brain and Spinal Abscesses

        • ALLAN R TUNKEL, MD, PHDProfessor of Medicine, Drexel University College of Medicine, Philadelphia, PA, Chair, Department of Medicine, Monmouth Medical Center, Long Branch, NJ
        • W MICHAEL SCHELD, MDProfessor of Medicine and Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA

        Brain and spinal abscesses are focal infections of the central nervous system that are often associated with significant morbidity and mortality if not recognized early and managed in a timely manner. In patients with brain abscess, the clinical manifestations run the gamut from indolent to fulminant; most are related to the size and location of the space-occupying lesion within the brain and the virulence of the infecting organism. Untreated spinal epidural abscess usually progresses through four stages: backache and focal vertebral pain, nerve root pain, spinal cord dysfunction, and complete paralysis. Magnetic resonance imaging is the diagnostic neuroimaging procedure of choice in patients with brain and spinal abscesses; on diffusion-weighted images, restricted diffusion may be seen and may help distinguish abscesses from necrotic neoplasms. Aspiration of the abscess is important to facilitate microbiologic diagnosis; after aspiration and submission of specimens for special stains, histopathologic examination, and culture, empirical antimicrobial therapy should be initiated based on stains of the aspirated specimen and the probable pathogenesis of infection. Once the infecting pathogen is isolated, antimicrobial therapy can be modified for optimal treatment. Surgical therapy is often required for the optimal approach to patients with brain and spinal abscesses.

        This review contains 6 figures, 5 tables, and 72 references.

        Key words: antimicrobial therapy for central nervous system infections, brain abscess, epidural abscess, focal intracranial infections, head trauma, infections in immunocompromised hosts, spine infections, subdural empyema, toxoplasmosis 

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      • 9

        Septic Arthritis, Septic Bursitis, and Osteomyelitis

        By Cameron Ashbaugh, MD
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        Septic Arthritis, Septic Bursitis, and Osteomyelitis

        • CAMERON ASHBAUGH, MDAssistant Professor of Medicine, Harvard Medical School, Associate Physician, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA

        Infections of joints and bones are important causes of morbidity due to the potential for permanent injury to structures necessary for mechanical support and useful motion. The spectrum of disease is broad, with host factors, pathogen, site of infection, and comorbidities all influencing outcome. In some cases of bone infection, cure may not be possible, and the therapeutic goal becomes control. This review details the epidemiology, pathogenesis, diagnosis, differential diagnosis, treatment, and prognosis of septic arthritis, septic bursitis, vertebral body osteomyelitis, pedal osteomyelitis in association with diabetes, and chronic posttraumatic osteomyelitis with union or malunion.

        Figures include algorithms for the initial evaluation and management of a suspected septic joint, suspected vertebral body osteomyelitis, osteomyelitis in diabetic patients with neuropathic ulcers, and chronic posttraumatic osteomyelitis; pathophysiology of bone infection; magnetic resonance imaging (MRI) of vertebral body osteomyelitis; probe-to-bone test for diagnosing osteomyelitis in the diabetic foot; MRI of diabetic foot infection with osteomyelitis; nonsurgical treatment of osteomyelitis of the foot in a patient with diabetes; cutaneous sinus; a healed tibial fracture with malunion and chronic osteomyelitis; and a sequestrum associated with chronic tibial osteomyelitis. Tables describe representative studies with likelihood ratios for diagnostic tests used in the evaluation of native joint septic arthritis and diabetic pedal osteomyelitis; risk factors for the development of septic arthritis in patients with underlying joint disease; microbiology in septic arthritis, vertebral body osteomyelitis, and diabetic pedal osteomyelitis; empirical antibiotic therapy for septic arthritis; suggested tests and test frequencies to monitor for antibiotic toxicity; the two most commonly referenced classification schemes for osteomyelitis; supportive findings for diagnosis of chronic osteomyelitis; antibiotic therapy for vertebral osteomyelitis awaiting culture results and with unknown or established microbiology; International Working Group on the Diabetic Foot approach to diagnosis and management of diabetic pedal osteomyelitis; antibiotic therapy for diabetic pedal osteomyelitis with unknown or established microbiology; and antibiotic duration for diabetic pedal osteomyelitis. 

        This review contains 13 highly rendered figures, 15 tables, and 187 references.

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      • 10

        Infective Endocarditis

        By Patrick T. O'Gara, MD, FACC, FAHA, FACP
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        Infective Endocarditis

        • PATRICK T. O'GARA, MD, FACC, FAHA, FACPDirector, Clinical Cardiology, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

        Infective endocarditis is a microbial infection of a cardiac valve or the mural endocardium caused by bacteria or fungi. Forms of this infection include subacute bacterial endocarditis (SBE) and acute bacterial endocarditis (ABE). Etiology and epidemiology are discussed. There is a section on pathogenesis followed by specific clinical presentations, including endocarditis associated with parenteral drug abuse as well as prosthetic valve endocarditis (PVE). Diagnosis and cardiac complications of endocarditis, treatment, recommendations for prophylaxis, and prognosis are addressed. There are several figures showing manifestations and anatomic relations from the infection. Tables describe microorganisms that cause native valve endocarditis, the etiology of PVE, the Duke criteria for diagnosis of infective endocarditis, antimicrobial therapy for endocarditis in adults, guidelines to prevent endocarditis, and recommendations and regimens for endocarditis prophylaxis. This chapter contains 99 references.

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      • 11

        Vaginitis and Sexually Transmitted Diseases

        By Joel T. Katz, MD, FACP
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        Vaginitis and Sexually Transmitted Diseases

        • JOEL T. KATZ, MD, FACPMedicine Education Office, Brigham and Woman’s Hospital, Boston, MA

        Sexually transmitted diseases (STDs) are among the most common causes of infectious illness worldwide, and therefore, familiarity with the recognition and management of these infectious pathogens is critical for physicians. This chapter reviews the epidemiology and transmission of STDs and describes the principles of taking a sexual history, reporting STDs, and screening for them. Urethritis, vulvovaginitis, mucopurulent cervicitis, pelvic inflammatory disease (PID), and genital ulcer disease are discussed. STDs in men who have sex with men is discussed, as is anorectal STDs in women. One figure shows a Gram stain in gonorrhea; the other shows ectopic pregnancy and tubal infertility in PID. Tables cover recommended STD screening; clinical features and management of vulvovaginitis; Amsel criteria for the diagnosis of bacterial vaginosis; treatment regimens for PID; clinical features, laboratory diagnosis, and treatment of genital ulcers; and treatment of genital herpes in immunocompetent patients. This chapter contains 106 references.

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      • 12

        Diseases Due to Chlamydiaceae

        By Walter E Stamm, MD, FACP (deceased)
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        Diseases Due to Chlamydiaceae

        • WALTER E STAMM, MD, FACP (DECEASED)

        The Chlamydiaceae are obligate intracellular bacteria that produce a wide variety of infections in many mammalian and avian species. Three species belonging to two genera of Chlamydiaceae infect humans: Chlamydia trachomatis, Chlamydophila psittaci, and Chlamydophila pneumoniae. C. trachomatis is exclusively a human pathogen and is transmitted from person to person via sexual contact, perinatal transmission, or close contact in households. C. psittaci, in contrast, is more widely distributed in nature, producing genital, conjunctival, intestinal, or respiratory infections in many avian and mammalian species. C. pneumoniae is a fastidious organism that produces upper respiratory tract infection and pneumonitis in both children and adults. This chapter details the epidemiology, pathogenesis, diagnosis, and treatment of chlamydial diseases. Sexually transmitted diseases, perinatal infections, adult inclusion conjunctivitis, trachoma, and psittacosis are covered. The chapter also includes tables outlining comparative features of the three species and treatment of sexually transmitted diseases caused by C. trachomatis, as well as a figure illustrating the life cycle of Chlamydiaceae. 

        This review contains 1 highly rendered figure, 2 tables, and 87 references.

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      • 13

        Syphilis and the Nonvenereal Treponematoses

        By Michael Augenbraun, MD, FACP
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        Syphilis and the Nonvenereal Treponematoses

        • MICHAEL AUGENBRAUN, MD, FACPAssociate Professor of Medicine, State University of New York Downstate Medical Center, New York, NY

        Syphilis is an infectious disease with complex acute and chronic manifestations that is transmitted primarily through sexual contact. The disease has been recognized for many centuries, although its origin remains unknown. This chapter’s discussion of the epidemiology of syphilis includes figures illustrating the rate of syphilis in the United States by state and county and the rate of syphilis in the United States from 1941 to 2009. The etiology, pathogenesis and disease course, diagnosis, differential diagnosis, treatment, and complications of syphilis are discussed. Special cases of syphilis—in pregnant women, in children, in HIV-infected patients, and congenital syphilis—are also considered. Illustrations include a dark-field microphotograph of treponemes and photographs of a syphilitic chancre, the classic aculopapular rash from spirochetemia, condylomata lata, and a gumma. Tables outline the clinical manifestations of syphilis in adults and the treatment of syphilis. The nonvenereal treponematoses—yaws, endemic syphilis, and pinta—are a group of infections distributed throughout tropical and semitropical areas of the world. They are primarily noted to cause a variety of skin and skeletal lesions. There is little biologic difference between the treponemes that cause these conditions. The epidemiology, pathogenesis, diagnosis, differential diagnosis, and treatment of the nonvenereal treponematoses are discussed.

        This review contains 7 highly rendered figures, 2 tables, and 60 references.

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      • 14

        Urinary Tract Infections

        By Sigal Yawetz, MD
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        Urinary Tract Infections

        • SIGAL YAWETZ, MDAssociate Physician, Brigham and Women’s Hospital, Boston, MA; Assistant Professor of Medicine, Harvard Medical School, Boston, MA

        Urinary tract infection (UTI) is the most common bacterial infection, affecting women far more than men. Aerobic gram-negative bacteria are the most common uropathogens causing UTI, with Escherichia coli remaining the most predominant organism in complicated infections. UTI can result in a variety of infections and inflammations, from asymptomatic bacteriuria to typical symptomatic cystitis to acute pyelonephritis, as well as bacterial prostatitis in men.

        In general, antimicrobial therapy is warranted for any symptomatic infection of the urinary tract. However, new consensus treatment guidelines for uncomplicated UTI in women, set by the Infectious Diseases Society of America and the European Society for Microbiology of Infection Diseases in 2010, account for the increasing antimicrobial resistance of pathogens and focus on first-line empirical treatment regimens. To reduce the use of antibiotics, treatment and prevention of recurrent UTI may involve several strategies on varying levels of effectiveness; some of the more well-tested options include probiotics, antiseptics, and topical estrogen. Antimicrobial approaches should be reserved for women in whom these options prove to be ineffective.

        This review contains 7 highly rendered figures, 7 tables, and 120 references.

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      • 15

        Gastrointestinal Tract Infections

        By Molly Paras, MD; Marcia B Goldberg, MD
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        Gastrointestinal Tract Infections

        • MOLLY PARAS, MDDivision of Infectious Diseases, Department of Medicine
        • MARCIA B GOLDBERG, MDAssociate Professor of Medicine, Division of Infectious Diseases, Harvard Medical School, and Physician, Massachusetts General Hospital, Boston, MA

        Gastrointestinal infections, which present with acute diarrhea, sometimes accompanied by vomiting, are an extremely common medical complaint, with an annual incidence of 0.6 illnesses per person. Transmission can occur from animals to person, from person to person, or by the ingestion of contaminated foodstuffs. In the United States, more than 90% of cases are caused by viruses, with norovirus being by far the most common. Common among bacterial causes of acute gastrointestinal infection are SalmonellaCampylobacterShigella, Shiga toxin–producing Escherichia coliVibrio, Yersinia, and Clostridium difficile. These infections are typically self-limited, but depending on the etiologic agent and characteristics of the host, antibiotic therapy may be indicated. Certain gastrointestinal infections are associated with significant complications, including reactive arthritis, Guillain-Barré syndrome, or septicemia.

        This review contains 4 figures, 7 tables, and 60 references.

        Key words: CampylobacterEscherichia coli, Guillain-Barré syndrome, reactive arthritis, Shiga toxin, ShigellaVibrioYersinia

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      • 16

        Peritonitis and Intra-abdominal Abscesses

        By W. Conrad Liles, MD, PhD; E Patchen Dellinger, MD
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        Peritonitis and Intra-abdominal Abscesses

        • W. CONRAD LILES, MD, PHDProfessor and Vice-Chair of Medicine, Director, Division of Infectious Diseases, University of Toronto, Toronto, ON
        • E PATCHEN DELLINGER, MDProfessor and Vice-Chair, Department of Surgery, University of Washington, Chief, Division of General Surgery, University of Washington Medical Center, Seattle, WA

        Peritonitis is a diffuse or localized inflammatory process affecting the peritoneal lining. Peritonitis has acute and chronic forms and may have a variety of causes. The etiology, epidemiology, diagnosis, and treatment of acute peritonitis caused by bacteria or fungi, including primary and secondary peritonitis, are discussed in this chapter. Primary or spontaneous peritonitis has no underlying intra-abdominal disorder as a direct cause of the infection but usually involves an underlying disorder that inhibits normal host defenses in the peritoneal cavity. Secondary peritonitis has an intra-abdominal focus that initiates the infection. Tertiary peritonitis is a relatively new term that refers to the persistence of intra-abdominal infection after the initial treatment of secondary peritonitis. Peritonitis in dialysis patients is also discussed. Intra-abdominal abscesses may present as complications of abdominal surgery, intra-abdominal conditions (e.g., diverticulitis, appendicitis, biliary tract disease, pancreatitis, perforated viscus), or penetrating abdominal trauma; as fever of obscure origin; or as dysfunction of neighboring organs (e.g., so-called lower lobe pneumonia related to a subphrenic abscess). Intra-abdominal abscesses are classified according to the anatomic location in which they occur: intraperitoneal, retroperitoneal, or visceral. Discussion of the different intra-abdominal abscesses in this chapter includes their diagnosis, bacteriology, and treatment. A figure shows CT scans before and after treatment of a multilobular liver abscess. This chapter contains 101 references.

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    • Infectious Pathogens
      • 1

        Herpesvirus Infections

        By Martin S. Hirsch, MD
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        Herpesvirus Infections

        • MARTIN S. HIRSCH, MDProfessor of Medicine, Harvard Medical School, Boston, MA

        The herpes group of viruses is composed of at least eight human viruses and numerous animal viruses. The human herpesviruses include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus types 6 (HHV-6), 7 (HHV-7), and 8 (HHV-8, also known as Kaposi sarcoma–associated herpesvirus). Human herpesviruses share the properties of latency and reactivation. Members of the group can cause productive lytic infections, in which infectious virus is produced and cells are killed, or nonproductive lytic infections, in which viral DNA persists but complete replication does not occur and cells survive. After acute lytic infections, herpesviruses often persist in a latent form for years; periodic reactivations are followed by recurrent lytic infections. Sites of latency vary: HSV and VZV persist in neural ganglion cells, EBV persists in B cells, and CMV probably remains latent in many cell types. The sites of latency for HHV-6 and HHV-7 have not been identified, although both herpesviruses have been detected in salivary glands. All human herpesviruses have a worldwide distribution. Considerable efforts are being directed toward the development of vaccines and antiviral agents that will be active against herpesviruses. This chapter discusses the epidemiology, pathogenesis, diagnosis, prevention, and treatment of herpes simplex virus and varicella-zoster virus and their clinical syndromes. The descriptions of the clinical syndromes include complications and clinical features, as well as descriptions of symptoms. Tables provide information on chemotherapy for primary genital and mucocutaneous herpes infection, suppression of severe and recurring genital herpes infection, and varicella-zoster infection. Figures provide photographic illustrations of the various clinical syndromes. A sidebar about herpesvirus information on the Internet provides further detail.

        This review contains 123 references, 4 tables, and 6 highly rendered figures.

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      • 2

        Viral Hepatitis

        By Esperance A K Schaefer, MD, MPH; Jules L Dienstag, MD
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        Viral Hepatitis

        • ESPERANCE A K SCHAEFER, MD, MPHResearch fellow, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
        • JULES L DIENSTAG, MDCarl W. Walter Professor of Medicine and Dean for Medical, Education, Harvard Medical School and Professor of Medicine, Massachusetts General Hospital, Boston, MA

        Despite a common tropism for the liver, the hepatitis viruses encompass a heterogeneous group of diseases with varying modes of acquisition, symptoms, chronicity, and complications. The five major hepatitis viruses, hepatitis A, B, C, D, and E, can be categorized by their modes of acquisition (parenteral versus enteral) and by their risk of chronicity. Beginning with the approach to the patient with viral hepatitis, this chapter reviews both the acute and chronic clinical features, diagnoses, and treatment options for hepatitis A, B, C, D, and E. Nonhepatotropic viruses that may cause liver inflammation are covered as well: herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human parvovirus B19, adenovirus, yellow fever, rubella (German measles) and rubeola (measles), and coxsackievirus B. Treatment options are covered and listed in depth and details. Tables include characteristics of types of viral hepatitis, differential diagnosis of acute hepatitis, and treatment guidelines for hepatitis B.

        This review contains 4 highly rendered figures, 12 tables, and 145 references.

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      • 3

        Viral Zoonoses

        By Lyle R Petersen, MD, MPH; Duane J. Gubler, ScD
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        Viral Zoonoses

        • LYLE R PETERSEN, MD, MPHDirector, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, CO
        • DUANE J. GUBLER, SCDProfessor, Program on Emerging Infectious Diseases, DUKE-NUS Graduate Medical School, Singapore

        Human infection by zoonotic viruses—pathogens that normally infect animals—may result in no obvious illness, a nonspecific viral syndrome, or more severe illness typically characterized by hemorrhagic fever, encephalitis, or rash arthralgia. Transmission usually occurs by direct contact with or a bite from an infected animal or arthropod. Viral families discussed include Flaviviridae, Bunyaviridae, Arenaviridae, Filoviridae, Togaviridae, Rhabdoviridae, Paramyxoviridae, and Reoviridae, with consideration given to the epidemiology, diagnosis, treatment, and prevention of specific viruses. Hemorrhagic fevers addressed include dengue fever, dengue hemorrhagic fever, yellow fever, Crimean-Congo hemorrhagic fever, and Rift Valley fever; hantavirus infections; and the Marburg and Ebola viruses. Encephalitic fever–causing viruses discussed include La Crosse; Japanese; Murray Valley; St. Louis; tick-borne; West Nile; Powassan; eastern, western, and Venezuelan equine; rabies; Nipah; Barmah Forest; and Colorado tick fever. Rash arthralgia may be caused by the Barmah Forest, Chikungunya, Mayaro, O’nyong-nyong, Ross River, and dengue viruses. Other viral zoonoses considered include monkey B virus, ruminant and primate poxvirus, Newcastle, and foot-and-mouth diseases, as well as vesicular stomatitis virus infection. A diagram depicts the generalized arbovirus maintenance cycle. Tables list the important viral zoonoses that cause human disease, the principal hantaviruses that cause human disease, the arenaviruses that cause significant human illness, and the viral zoonoses endemic in the United States. 

        This review contains 1 highly rendered figure, 4 tables, and 81 references.

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      • 4

        HIV and AIDS

        By Daniel R. Kuritzkes, MD, FACP
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        HIV and AIDS

        • DANIEL R. KURITZKES, MD, FACP

        In the quarter-century since the first report of AIDS in the United States, HIV infection has spread throughout the population, disproportionately affecting black women, Hispanic women, and men who have sex with men. The prognosis for persons infected with HIV has improved dramatically with the introduction and evolution of highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requires different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. The prospect that currently available antiretroviral therapy (ART) regimens may suppress HIV replication indefinitely provides the hope that infected patients will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and management of short- and long-term complications of HIV, ART toxicities, and aging. This chapter describes the epidemiology, pathophysiology and pathogenesis, prevention, diagnosis, and management of acute and chronic HIV infection and AIDS, with figures and tables illustrating each chapter section.


        This review contains 9 highly rendered figures, 22 tables, and 248 references.

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      • 5

        Infections Due to Gram-positive Cocci

        By Dennis L. Stevens, PhD, MD, FACP, FIDSA
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        Infections Due to Gram-positive Cocci

        • DENNIS L. STEVENS, PHD, MD, FACP, FIDSAChief Infectious Diseases, Veterans Affairs Medical Center, Boise, ID, Professor of Medicine, University of Washington School of Medicine, Seattle, WA

        The gram-positive cocci that produce infection include pneumococci, group A streptococci, non?group A streptococci (including groups B, C, D, G, and nongroupable streptococci), anaerobic streptococci, enterococci, and staphylococci. This chapter discusses the pathogenesis, diagnosis, and treatment of infections associated with each of these gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). The clinical infections caused by each of these organisms are reviewed. Tables describe the incidence of pneumococcal disease according to age and underlying disease, factors associated with adverse outcomes in pneumococcal pneumonia; medically important streptococci and enterococci; antibiotic treatment for penicillin-resistant Streptococcus pneumoniae, enterococcal infections, and staphylococcal infections; laboratory tests for streptococcal pharyngitis; clinical manifestations and antibiotic treatment for staphylococcal toxic-shock syndrome (TSS); revised Jones criteria for the diagnosis of acute rheumatic fever, and drug treatment of acute rheumatic fever.

        This review contains 105 references.

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      • 6

        Infections Due to Escherichia Coli and Other Enteric Gram-negative Bacilli

        By Allison Mah, MD, FRCPC; Inna Sekirov, MD, PhD; Theodore S Steiner, MD, FRCPC
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        Infections Due to Escherichia Coli and Other Enteric Gram-negative Bacilli

        • ALLISON MAH, MD, FRCPCPostgraduate Year 6, Division of Infectious Diseases, Department of Internal Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, BC
        • INNA SEKIROV, MD, PHDPostgraduate Year 5, Division of Medical Microbiology, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver General Hospital , Vancouver, BC
        • THEODORE S STEINER, MD, FRCPCProfessor and Associate Head, Division of Infectious Diseases, Department of Internal Medicine, Associate Member, Department of Microbiology and Immunology, University of British Columbia , Vancouver General Hospital , Vancouver, BC

        This review describes infections caused by Escherichia coli and related members of the family Enterobacteriaceae, excluding other genera that principally cause enteric infections. Infections caused by Salmonella, Shigella, and Yersinia are described in the review “Gastrointestinal Tract Infections," found elsewhere in this publication. The purpose of this review is to examine the specific epidemiology, clinical manifestations, and treatment of individual members of the Enterobacteriaceae. The emerging concern of antimicrobial resistance amongst enteric gram-negative organisms and the approach to treatment in the setting of infection with these resistant organisms are discussed in the review “Antimicrobial Resistance in Enteric Gram-Negative Organisms,” found elsewhere in this publication. Figures illustrate the mechanisms of antimicrobial resistance in Enterobacteriaceae. A table lists the clinical, epidemiologic, pathogenetic, and therapeutic aspects of infection with various pathotypes of Escherichia coli.

        This review contains 6 highly rendered figures, 1 table, and 79 references.

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      • 7

        Infections Due to Brucella, Francisella, Yersinia Pestis, and Bartonella

        By W. Conrad Liles, MD, PhD
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        Infections Due to Brucella, Francisella, Yersinia Pestis, and Bartonella

        • W. CONRAD LILES, MD, PHDProfessor and Vice-Chair of Medicine, Director, Division of Infectious Diseases, University of Toronto, Toronto, ON

        Brucellosis, tularemia, (bubonic) plague, and bartonellosis are zoonoses (i.e., infectious diseases that can be transmitted from animals to humans) caused by gram-negative bacilli. The causative agents of these diseases are Brucella species, Francisella tularensis, Yersinia pestis, and Bartonella species, respectively. Infected arthropods, such as ticks or fleas, can serve as vectors for the transmission of tularemia, (bubonic) plague, and bartonellosis. In general, the diagnosis of these zoonoses requires the physician to consider the clinical presentation (which is not always distinctive) in light of the epidemiology of these diseases. This chapter contains discussions of epidemiology, etiology, pathogenesis, diagnosis and differential diagnosis, treatment, complications, and prognosis of brucellosis, tularemia, plague, and Bartonella infections (including trench fever, cat-scratch disease, and bacillary angiomatosis). Also included are tables outlining diagnosis and treatment and a figure showing the distribution of tularemia in the United States from 1990 to 2000. 

        This review contains 1 highly rendered figure, 2 tables, and 81 references.

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      • 8

        Anaerobic Infections

        By Itzhak Brook, MD; Ellie JC Goldstein, MD, FIDSA, FSHEA
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        Anaerobic Infections

        • ITZHAK BROOK, MDProfessor of Pediatrics at Georgetown University, Washington, DC.
        • ELLIE JC GOLDSTEIN, MD, FIDSA, FSHEAClinical Professor of Medicine at the David Geffen School of Medicine, UCLA; Director of the R. M. Alden Research Laboratory

        Anaerobes are the most predominant components of the bacterial flora of normal human skin and mucous membranes and are a frequent cause of endogenous bacterial infections. Anaerobic infections can occur in all body locations: the central nervous system, oral cavity, head and neck, chest, abdomen, pelvis, skin, and soft tissues. Treatment of anaerobic infection is complicated by the slow growth of anaerobes in culture, by their polymicrobial nature, and by their growing resistance to antimicrobials. Antimicrobial therapy is frequently the only form of therapy needed, whereas in some patients it is an important adjunct to drainage and surgery. Because anaerobes are generally isolated mixed with aerobes, the antimicrobial chosen should provide for adequate coverage of both. The most effective antimicrobials against anaerobes are metronidazole, the carbapenems (imipenem, meropenem, doripenem, ertapenem), chloramphenicol, the combination of a penicillin and a β-lactamase inhibitors (ampicillin or ticarcillin plus clavulanate, amoxicillin plus sulbactam, piperacillin plus tazobactam), tigecycline, cefoxitin, and clindamycin.

        This review contains 4 figures, 9 tables, and 150 references.

        Key words: anaerobic bacteria, antibiotics, antimicrobial resistance, Bacteroides fragilis, Clostridium spp, Fusobacterium spp, infection, Peptostreptococcus spp  

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      • 9

        Lyme Disease and Other Spirochetal Zoonoses

        By David C Tompkins, MD; Benjamin J Luft, MD, FACP
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        Lyme Disease and Other Spirochetal Zoonoses

        • DAVID C TOMPKINS, MDVice Chairman, Department of Medicine, Head, Division of Infectious Diseases, Lutheran Medical Center, Brooklyn, NY
        • BENJAMIN J LUFT, MD, FACPEdmund D. Pellegrino Professor, Division of Infectious Diseases, Department of Medicine, SUNY at Stony Brook, Stony Brook, NY

        This review discusses the epidemiology, pathology, clinical features, laboratory findings, and treatment for Lyme disease, leptospirosis, relapsing fever, and rat-bite fever. Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. Lyme disease is a progressive infectious disease with a wide array of clinical manifestations. In most persons, the initial sign of infection is the development of erythema migrans. In general, three stages of the illness can be distinguished: early localized disease, early disseminated disease, and persisting late disease. A photograph shows an erythema migrans lesion, and an algorithm for diagnosis of Lyme disease is provided. A table lists the antibiotic regimens used for the different stages and manifestations of Lyme disease. Leptospirosis is a worldwide zoonosis caused by spirochetes from the genus Leptospira; these spirochetes are shown in a photomicrograph. The disease is acquired by contact with infected animals or exposure to contaminated soil or freshwater and can cause illness ranging from asymptomatic infection to severe multisystem disease with a significant mortality. Relapsing fever is an acute louse-borne or tick-borne infection caused by spirochetes of the genus Borrelia and is characterized by recurrent febrile episodes separated by asymptomatic intervals. Rat-bite fever is infection caused by Streptobacillus moniliformis in the United States and Europe or by Spirillum minus in Asia. A table details the differing characteristics of rat-bite fever from these two organisms.

        This review has 124 references.

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      • 10

        Infections Due to Rickettsia and Related Organisms

        By Lucas S Blanton, MD
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        Infections Due to Rickettsia and Related Organisms

        • LUCAS S BLANTON, MDAssistant Professor, Division of Infectious Diseases, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX

        Infections caused by organisms of the genus Rickettsia, Orientia, Ehrlichia, Anaplasma, and Coxiella occur throughout the world and are important, yet often overlooked, causes of febrile illness. They are transmitted by ticks, lice, mites, fleas, and, in the case of Coxiella, infected aerosols. Some are considered emerging and reemerging infectious diseases, as exemplified by the emergence of Rocky Mountain spotted fever in the American Southwest and Mexico; the reemergence of murine typhus in parts of Texas; and the discovery of new pathogens, such as Ehrlichia muris–like agent. Manifestations are usually of an acute undifferentiated febrile illness, with associated headache, malaise, myalgias, and varying frequency of rash. Since confirmation of diagnosis is often retrospective, requiring the dynamic change in antibody titers from acute and convalescent phase sera, clinical recognition for empirical treatment is imperative. Indeed, timely treatment is effective at abating symptoms and preventing complications. This review discusses important aspects of the epidemiology, clinical manifestations, diagnostic methods, and treatment of infections caused by Rickettsia and related organisms. 

        This review contains 5 figures, 9 tables, and 50 references.

        Key words: anaplasmosis, ehrlichiosis, Q fever, Rocky Mountain spotted fever, scrub typhus, spotted fever group rickettsioses, typhus group rickettsioses

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      • 11

        Mycoplasma Infections

        By R. Doug Hardy, MD
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        Mycoplasma Infections

        • R. DOUG HARDY, MD

        Mycoplasmas are the smallest known free-living organisms. Their size-150 to 350 nm-is closer to that of viruses than of bacteria. Mycoplasmas, however, are able to grow in cell-free media and possess both RNA and DNA. Notably, they lack a cell wall and are bound by a cell membrane. The absence of a rigid cell wall explains many of the biologic properties of mycoplasmas, including resistance to beta-lactam antibiotics and marked pleomorphism among individual cells. At least 13 Mycoplasma species, two Acholeplasma species, and one Ureaplasma species have been isolated from humans with varying frequency; most of these species are thought to be normal inhabitants of oral and urogenital mucous membranes. Only four species, M. pneumoniae, M. hominis, U. urealyticum, and U. urealyticum, have been shown conclusively to be pathogenic in humans. This chapter covers the epidemiology, pathogenesis, pathology, immunology, diagnosis, and treatment of infections caused by mycoplasmas. Pneumonia and genitourinary tract infections (including nongonococcal urethritis and pelvic inflammatory disease) are discussed in major sections. Tables list the accuracy of diagnostic tests for M. pneumoniae and the antimicrobial drugs and doses used in the treatment of mycoplasma infections. A figure illustrates the spread of M. pneumoniaewithin a family. This chapter contains 122 references.

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      • 12

        Tuberculosis

        By Jonathan B. Parr, MD, MPH; Michael K Leonard Jr, MD; Henry M Blumberg, MD, FACP
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        Tuberculosis

        • JONATHAN B. PARR, MD, MPHClinical Instructor, Division of Global Health Equity, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
        • MICHAEL K LEONARD JR, MDID Consultants, Charlotte, NC
        • HENRY M BLUMBERG, MD, FACPProfessor of Medicine, Epidemiology, and Global Health, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA

        Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis, a relatively slow-growing, aerobic, acid-fast bacillus. Classically, tuberculosis is a pulmonary disease, but disseminated and extrapulmonary disease may also occur, especially in immunocompromised persons. Tuberculosis is transmitted person to person and is usually contracted by inhalation of M. tuberculosis carried in droplets coughed out by an infectious person. After M. tuberculosis enters the body, the host’s cell-mediated immunity may contain the organism but not eradicate all the bacilli, resulting in latent tuberculosis infection (LTBI). M. tuberculosis can remain dormant and persist (e.g., within macrophages), and in such cases, persons are at risk for reactivation and development of active tuberculosis. This review discusses the epidemiology, genetics, pathogenesis, diagnosis, and treatment of tuberculosis in its various forms, as well as screening for latent tuberculosis. Figures illustrate the global incidence of tuberculosis, the numbers of cases in the United States from 1992 through 2011, the natural history of tuberculosis, atypical findings in HIV-infected patients, findings of vertebral tuberculosis, treatment completion rates for pulmonary tuberculosis, and treatment of drug-susceptible pulmonary tuberculosis. Tables show the criteria for a positive tuberculin skin test by risk group, recommended doses and adverse effects of antituberculosis medications for adults, treatment guidelines for drug-susceptible pulmonary tuberculosis in adults, evidence-based guidelines for duration of therapy for drug-susceptible extrapulmonary tuberculosis and adjunctive use of corticosteroids, potential regimens for the treatment of drug-resistant tuberculosis, and guidelines for the treatment of latent tuberculosis in adults.

        This review contains 7 highly rendered figures, 6 tables, and 144 references.

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      • 13

        Infections Due to Mycobacterium Leprae and Nontuberculous Mycobacteria

        By Carlos Franco-Paredes, MD, MPH; Michael K Leonard Jr, MD; Henry M Blumberg, MD, FACP
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        Infections Due to Mycobacterium Leprae and Nontuberculous Mycobacteria

        • CARLOS FRANCO-PAREDES, MD, MPHDirector, Clinical and Translational Research Training Programs
        • MICHAEL K LEONARD JR, MDID Consultants, Charlotte, NC
        • HENRY M BLUMBERG, MD, FACPProfessor of Medicine, Epidemiology, and Global Health, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA

        Mycobacterium leprae infection (i.e., leprosy) is a disease that has been recognized—and often misunderstood—since ancient times. The emergence of HIV/AIDS and the development of newer culture methodologies and molecular diagnostic tools have brought about increased interest in the epidemiology, diagnosis, and treatment of human infections from nontuberculous mycobacteria (NTM). More than 140 species of NTM have been identified; approximately 50 of these may be pathogenic for humans, causing a broad spectrum of disease. This chapter covers both M. leprae and selected NTM organisms, including M. avium complex; M. kansasiiM. marinum; and rapidly growing mycobacteria such as M. chelonaeM. fortuitum, and M. abscessus. The section on leprosy encompasses subsections on diagnosis, clinical manifestations and classification, laboratory studies, treatment, and leprosy reactions. Treatments for nontuberculous mycobacteria infections are also covered. Figures include a natural history of leprosy, tuberculoid leprosy, lepromatous leprosy, and various forms of borderline leprosy, as well as type 1 and type 2 leprosy reaction. Tables include the Ridley-Jopling classification of leprosy, recommendations for treatment of leprosy, clinical characteristics and treatment of leprosy, major clinical syndromes associated with nontuberculous mycobacterial infections, diagnosing nontuberculous mycobacterial lung disease, a listing of slow and rapidly growing mycobacteria that are human pathogens, plus treatment regimens for selected nontuberculous mycobacterial infections in adults.

        This review contains 59 references.

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      • 14

        Mycotic Infections

        By Carol A Kauffman, MD, FACP
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        Mycotic Infections

        • CAROL A KAUFFMAN, MD, FACPChief, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Professor, Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

        Endemic mycoses are caused by fungi that share several important characteristics but differ greatly in other respects. They include histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis. Discussions on their epidemiology, pathogenesis, clinical presentation, diagnosis, differential diagnosis, treatment, and prognosis are included. A section on antifungal therapy is included, discussing the use of azoles and amphotericin B. Figures show photomicrographs of biopsy samples from patients with histoplasmosis, blastomycosis, and coccidioidomycosis. Tables list selected drugs that may interact with azoles to change serum levels and information on the administration of amphotericin B for treatment of endemic mycoses.

        This review contains 3 highly rendered figures, 3 tables, and 71 references.

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      • 15

        Mycotic Infections in the Compromised Host

        By Jo-Anne H. Young, MD, FACP
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        Mycotic Infections in the Compromised Host

        • JO-ANNE H. YOUNG, MD, FACP

        Opportunistic fungal infections have become increasingly important over the past several decades, paradoxically because advances in medical practice have improved the survival of debilitated and immunosuppressed patients. The mycotic infections that appear in the compromised host are candidiasis, cryptococcosis, pneumocystosis, aspergillosis, zygomycosis, and fusariosis. The aspergillosis section addresses allergic bronchopulmonary aspergillosis and invasive aspergillosis separately. Timely diagnosis of opportunistic fungal infection depends on understanding host characteristics, environmental risk factors, clinical presentation, and diagnostic testing, which each section covers. There is also a section on infection by dematiaceous fungi. Figures illustrate the cysts of Pneumocystis and the bimodal distribution of Aspergillus infection after bone marrow transplantation. Tables describe the desensitization of adult patients with sulfa allergy; the stages of allergic bronchopulmonary aspergillosis; the treatment of infections caused by Candida, Cryptococcus, Aspergillus, and Fusarium species; and the treatment and prophylaxis of Pneumocystis jiroveci pneumonia. 

        This review contains 2 highly rendered figures, 7 tables, and 108 references.

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      • 16

        Infections Due to Salmonella

        By Marcia B Goldberg, MD; Molly Paras, MD
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        Infections Due to Salmonella

        • MARCIA B GOLDBERG, MDAssociate Professor of Medicine, Division of Infectious Diseases, Harvard Medical School, and Physician, Massachusetts General Hospital, Boston, MA
        • MOLLY PARAS, MDDivision of Infectious Diseases, Department of Medicine

        Salmonella, which is acquired via ingestion, is classified as nontyphoidal or typhoidal disease. Typhoidal disease is caused by S typhi or S paratyphi,and nontyphoidal disease is caused by all other serovars. Salmonella causes a range of infectious syndromes that include gastroenteritis, bacteremia, endovascular infections, and enteric fever. For immunocompromised hosts or patients with extraintestinal disease, antibiotic therapy should be provided. Effective agents often include third-generation cephalosporins and fluoroquinolones, although rates of resistance of Salmonella isolates to many antibiotics are increasing. A carrier state exists whereby patients may shed bacteria despite being asymptomatic. To eradicate the carrier state, longer courses of antibiotics and, in rare instances, surgical removal of the reservoir, which is most commonly the gallbladder, may be required. 

        This review contains 2 figures, 4 tables, and 20 references.

        Key Words: Salmonella, typhoidal, non-typhoidal, enteric fever, endovascular infection, gastroenteritis, carrier, food-borne, antibiotic resistance

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      • 17

        Protozoan Infections

        By Wesley C Van Voorhis, MD, PhD, FACP
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        Protozoan Infections

        • WESLEY C VAN VOORHIS, MD, PHD, FACPProfessor of Medicine and Adjunct Professor of Pathobiology, Head Allergy and Infections Diseases Division, Department of Medicine, University of Washington School of Medicine, Attending Physician, Infectious Diseases & Tropical Medicine Clinic, University of Washington Medical Center, Seattle, WA

        Protozoans cause a number of important infectious diseases. This chapter discusses malaria, babesiosis, toxoplasmosis, trichomoniasis, leishmaniasis, and trypanosomiasis; in addition, the chapter describes the intestinal protozoan infections caused by Giardia lamblia; Dientamoeba fragilis; Entamoeba histolytica; Blastocystis hominis; the coccidial organisms Cystoisospora belli, Cryptosporidium, and Cyclospora cayetanensis; Balantidium coli; and microsporidia. Figures illustrate the taxonomy of pathogenic protozoans; the life cycle of malaria; identification of species of malaria based on forms seen on blood smears; Babesia parasites in erythrocytes; the life cycle, tachyzoites, and tissue cysts ofToxoplasma gondii; G. lamblia trophozoites and cysts; a D. fragilis trophozoite; E. histolytica cyst and trophozoite forms; Entamoeba coli; clinical involvement in amebiasis; B. hominis; cysts of Cryptosporidium, Cyclospora, and Cystoisospora; Acanthamoeba polyphaga cyst and histopathologic features; histopathology of Naeglaria meningoencephalitis;Leishmania (Viannia) braziliensis cutaneous infection; amastigotes of Old World leishmaniasis; the insect vector for Chagas disease; Romaña sign in acute Chagas disease;Trypanosoma cruzi, and T. brucei. Tables list the differentiating features of Plasmodium species that cause malaria; dosages, principal side effects, and main limitations of antimalarial drugs; and forms of New World leishmaniasis. A sidebar provides Internet links on protozoan infection. 

        This review contains 22 highly rendered figures, 3 tables, and 121 references.

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      • 18

        Helminthic Infections

        By Wesley C Van Voorhis, MD, PhD, FACP
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        Helminthic Infections

        • WESLEY C VAN VOORHIS, MD, PHD, FACPProfessor of Medicine and Adjunct Professor of Pathobiology, Head Allergy and Infections Diseases Division, Department of Medicine, University of Washington School of Medicine, Attending Physician, Infectious Diseases & Tropical Medicine Clinic, University of Washington Medical Center, Seattle, WA

        Helminthic parasites are multicellular worms that possess differentiated organ systems. They (with a few exceptions) do not replicate in the human host, and they tend to elicit eosinophilia within the tissues and blood of infected humans. Helminthic parasites include nematodes (roundworms), cestodes (tapeworms), and trematodes (flukes). The major intestinal nematodes are roundworm, pinworm, hookworm, whipworm, and Strongyloides stercoralis. Trichinellosis is caused by five species of the nematode Trichinella and develops after ingestion of infected meat, usually pork or the meat of certain carnivores. Nematode infections of the major tissue are anisakiasis, visceral larva migrans,Angiostrongylus cantonensis infection, mammomonogamosis (syngamosis), gnathostomiasis, dracunculiasis, and filariasis. Trematode and cestode infections are also described in this chapter, including infections by fish, beef, and pork tapeworms, as well as cysticercosis. Disease from ParagonimusClonorchisFasciolaFasciolopsis, and Schistosoma is covered. Echinococcus infection and hydatid cyst disease are discussed. Tables describe intestinal nematode infection and treatment and filarial parasites of humans. Figures illustrate a variety of helminthic parasites and their life cycles.

        This review contains 136 references.

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      • 19

        Infections Due to Staphylococci

        By Sarah E Hobdey, PhD; Dennis L. Stevens, PhD, MD, FACP, FIDSA
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        Infections Due to Staphylococci

        • SARAH E HOBDEY, PHDResearch Scientist, Veterans Affairs Medical Center, Boise, ID
        • DENNIS L. STEVENS, PHD, MD, FACP, FIDSAChief Infectious Diseases, Veterans Affairs Medical Center, Boise, ID, Professor of Medicine, University of Washington School of Medicine, Seattle, WA

        Staphylococci are nonsporulating, nonmotile, gram-positive cocci that have an average diameter of 1 µm. Microscopically, staphylococci tend to be larger and rounder than streptococci. Because cell division occurs on three planes, these organisms are typically found in grapelike clusters and tetrads, as well as in pairs and sometimes in short chains. Staphylococci are very hardy organisms and can withstand much more physical and chemical stress than pneumococci and streptococci. Because staphylococci are facultative anaerobes, they will grow in the presence or absence of oxygen. Staphylococci are catalase positive. Of the species of staphylococci, Staphylococcus aureus is by far the most important human pathogen. This review covers the epidemiology and pathogenesis of S. aureus, clinical infections associated with S. aureus, treatment of staphylococcal infections, and staphylococcal toxic shock syndrome. Clinically important coagulase-negative staphylococci such as S. epidermidis and S. saprophyticus are also discussed. Tables list antibiotic treatment for staphylococcal infections, clinical manifestations of staphylococcal toxic shock syndrome, and antibiotic treatment for staphylococcal toxic shock syndrome.

        This review contains 3 figures, 3 tables, and 52 references.

        Key words: Staphylococcus aureus;Staphylococcal infections;Coagulase-negative staphylococci; Skin and soft tissue infections; S. aureus bacteremia; MRSA; Methicillin-resistant S. aureus; Toxic shock syndrome

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      • 20

        Infections Due to Streptococcus Pneumoniae

        By Sarah E Hobdey, PhD; Dennis L. Stevens, PhD, MD, FACP, FIDSA
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        Infections Due to Streptococcus Pneumoniae

        • SARAH E HOBDEY, PHDResearch Scientist, Veterans Affairs Medical Center, Boise, ID
        • DENNIS L. STEVENS, PHD, MD, FACP, FIDSAChief Infectious Diseases, Veterans Affairs Medical Center, Boise, ID, Professor of Medicine, University of Washington School of Medicine, Seattle, WA

        Pneumococci, or Streptococcus pneumoniae, are gram-positive, lancet-shaped diplococci but may also grow in short chains. The polysaccharide polymer that forms the outer capsule of S pneumoniae is chemically and antigenically unique and is crucial to virulence. There are at least 90 distinct serotypes. The capsule allows the bacteria to resist phagocytosis by leukocytes unless the organisms have been opsonized by antibody or serum complement components. Certain pneumococcal serotypes, such as the heavily encapsulated type 3 pneumococcus, are particularly virulent. In fact, only 23 serotypes account for 80% of bacteremic pneumococcal infections in the United States; capsular polysaccharides from these 23 serotypes are incorporated into the polyvalent polysaccharide pneumococcal vaccine (PPSV23), which has been available since 1983. This review covers the epidemiology and pathogenesis of pneumococcal infections, clinical pneumococcal infections, and prevention of pneumococcal infections. Adverse outcomes in pneumococcal pneumonia, antibiotic treatment for penicillin-resistant S pneumoniae, and Centers for Disease Control and Prevention child and adolescent immunization schedules are discussed.

        This review contains 1 figure, 3 tables, and 38 references. 

        Key words: bacterial pneumonia, PCV13, penicillin-resistant Streptococcus pneumoniae, pneumococcal pneumonia, pneumococcus, PPSV23, pneumonia vaccine, Streptococcus pneumoniae

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      • 21

        Infections Due to Candida, Cryptococcus, Other Yeasts, and Pneumocystis

        By Jo-Anne H. Young, MD, FACP; Jaime S Green, MD
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        Infections Due to Candida, Cryptococcus, Other Yeasts, and Pneumocystis

        • JO-ANNE H. YOUNG, MD, FACP
        • JAIME S GREEN, MDAssistant Professor, Division of Infectious Disease and International Medicine, Department of Medicine, Assistant Director, Program in Adult Transplant Infectious Disease, University of Minnesota, Minneapolis, MN

        Yeast-based fungal infections have become increasingly important over several decades, paradoxically because advances in medical practice have allowed patients with chronic medical conditions to live longer and have more productive lives. Many of these yeast infections are superficial in nature, such as thrush and candidal vaginitis among persons treated with antibiotics or with short courses of steroids. A minority of the yeast infections are associated with significant morbidity and mortality, generally among debilitated or otherwise immunosuppressed patients who have survived major surgeries or extensive chemotherapy regimens. These opportunistic yeast pathogens may originate as human commensals (e.g., Candida albicans) or have an environmental reservoir (e.g., Cryptococcus neoformans). Opportunistic Pneumocystis infections are inhaled. Knowledge of the host characteristics associated with specific infections will allow high suspicion for the type of yeast infection that may be occurring. Standard methods for making a diagnosis have included antigen testing, culture, and cytology. Newer methods for making the diagnosis include nucleic acid testing and nanotechnology. There are three general classes of antifungal agents. Treatment with antifungal agents for the most serious of these infections requires source control for cure. In addition, correction of predisposing conditions will also assist with prevention of recurrence. Immunocompromised patients require either prophylaxis or early empirical treatment during high-risk periods.

        This review contains 1 figure, 4 tables, and 74 references.

        Key words: Candida, Candidiasis, Cryptococcus, Malassezia, Trichosporon, Pneumocystis

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      • 22

        HIV Prevention

        By Jennifer A Johnson, MD; Daniel R Kuritzkes, MD, FACP
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        HIV Prevention

        • JENNIFER A JOHNSON, MDAssociate Physician, Division of Infectious Diseases, Brigham and Women’s Hospital; Assistant Professor of Medicine, Harvard Medical School, Boston, MA
        • DANIEL R KURITZKES, MD, FACPChief, Division of Infectious Diseases, Brigham and Women's Hospital; Professor of Medicine, Harvard Medical School, Boston, MA

        Although risk reduction counseling and barrier protection remain important strategies for prevention of HIV acquisition and other sexually transmitted infections, there have been significant advances in medication-based prevention strategies in recent years following advances in HIV treatment. There are now many safe and highly effective methods for HIV prevention, components of a prevention toolkit that clinicians may choose from or use in combination as appropriate for each patient. Treatment of HIV-infected individuals to achieve virologic suppression prevents transmission to others in nearly all cases. Treatment of HIV-infected pregnant women with combination antiretroviral therapy also prevents transmission to the infant in nearly all cases. Treating HIV-uninfected individuals with antiretroviral agents either before or after possible exposure has also been shown to be effective in significantly reducing the risk of HIV acquisition. Clinicians should use these effective tools to compose an HIV prevention strategy that is individualized to each patient. 

        This review contains 1 figure, and 34 references.

        Key words: circumcision, dolutegravir, emtricitabine, needle exchange, preexposure prophylaxis, prevention of mother-to-child transmission, postexposure prophylaxis, raltegravir, tenofovir, treatment as prevention

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    • Special Hosts and Exposures
      • 1

        Fever in Returning Travelers

        By Mary E Wilson, MD; Lin H Chen, MD
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        Fever in Returning Travelers

        • MARY E WILSON, MDVisiting Professor of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, CA; Adjunct Professor of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA
        • LIN H CHEN, MDDirector, Travel Medicine Center, Mount Auburn Hospital, Cambridge, MA; Associate Professor of Medicine, Harvard Medical School, Boston, MA

        Fevers in individuals with recent tropical travel require rapid assessment because many of the potential causes are treatable and/or have important public health implications. History and clinical findings are essential to identify the likely causes of the fever and, thus, recognize those that require urgent intervention.This review outlines obtaining the travel history, incubation periods, undifferentiated fever, and evaluation based on syndromes. Figures show the most common diagnoses and range of incubation periods; the top specific diagnoses in febrile returned travelers by geographic region; countries/areas at risk for dengue transmission; images of Aedes aegypti and Aedes albopictus, vectors of dengue virus and chikungunya virus; countries and territories where chikungunya cases have been reported (as of March 10, 2015), excluding where imported cases only are documented; cases of Ebola virus disease in Africa, 1976–2015, by species and size; and an algorithm for approach to workup. Tables list Web sites and resources for travel medicine; the epidemiology of fever in travelers; key areas of exposure queries in returned travelers; obtaining exposure history in febrile returned travelers; estimated protective effect of previous vaccination; common posttravel infections, by incubation period; guiding principles for care of febrile patients returning from tropical travel; common clinical findings and associated infections; key cannot-miss diagnoses with fever; malaria antigens; fever syndromes, diagnoses, and diagnostic tests to be considered; and major hemorrhagic fevers and their distribution based on world regions.

        This review contains 7 highly rendered figures, 12 tables, and 151 references.

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      • 2

        Infections in Cancer Patients

        By Gowri Satyanarayana, MD; Sarah P. Hammond, MD
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        Infections in Cancer Patients

        • GOWRI SATYANARAYANA, MDAssistant Professor of Internal Medicine, Division of Infectious Diseases, Department of Medicine, Vanderbilt University, Nashville, TN
        • SARAH P. HAMMOND, MDAssistant Professor of Medicine, Harvard Medical School, Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

        Infection is a common complication in cancer patients who receive cytotoxic chemotherapy and other targeted therapies. A clear understanding of the underlying host risk factors, the immunologic effects of specific cancer therapies, and the anatomic location of the tumor and its impact on surrounding structures helps predict the types of infection to which the host is most vulnerable. This review covers fever in the setting of neutropenia, infection risk with biological and targeted cancer therapy, and infections in patients with solid tumors. Figures show risk for fever and neutropenia, and empirical antibiotic algorithm for initial management of febrile neutropenia in patients at high risk for complications, radiographic findings associated with invasive fungal disease, a schematic of hepatitis B virus infection and reactivation after anti-CD20 therapy, and management of nonpurulent cellulitis in cancer patients. Tables list the Multinational Association of Supportive Care in Cancer (MASCC) risk index score, the Clinical Index of Stable Febrile Neutropenia (CISNE) scoring system, common bacterial pathogens that cause infection in neutropenic patients, assessment of specific signs and symptoms during febrile neutropenia, empirical antibiotic management of febrile neutropenia, criteria for addition of vancomycin to empirical antibiotic regimen for febrile neutropenia, and biological and targeted agents commonly used to treat hematologic malignancy and associated infections.

         

        This review contains 5 highly rendered figures, 7 tables, and 107 references

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  • Interdisciplinary Medicine
    • 1

      Adult Preventive Health Care

      By Jennifer S Haas, MD, MSc
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      Adult Preventive Health Care

      • JENNIFER S HAAS, MD, MSCProfessor of Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

      Over the past quarter century, prevention has become a major activity in primary care. During a typical day, primary care clinicians spend much of their time managing asymptomatic conditions in which the main goal is to prevent death or complications (e.g., hypertension, hyperlipidemia, osteoporosis). This chapter focuses primarily on preventive screening recommendations from the United States Preventive Services Task Force (USPSTF). The rationale and evolution of preventive care guidelines are discussed. Advantages and disadvantages of cervical, colorectal, breast, prostate, ovarian and lung cancer screening are explained, along with recommendations regarding behavioral counseling, especially for smoking cessation and alcohol use. Graphs are included. Tables delineate major causes of death in the United States, criteria for evaluating a screening program, sample board examination questions about screening, government-sponsored preventive guidelines programs, the USPSTF grading system, strongly recommended noncancer preventive services in adults, the recommended adult immunization schedule, recommended and strongly recommended measures for cancer prevention, recommended preventive noncancer screening measures, and selected recommendations for counseling and patient education.

      This review contains 5 figures, 10 tables, and 77 references.

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    • 2

      Diet

      By Elizabeth G Nabel, MD, FACP
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      Diet

      • ELIZABETH G NABEL, MD, FACPPresident, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

      An unhealthy diet is a major risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and conditions related to obesity. In the 20th century, the average American diet shifted from one based on fresh, minimally processed vegetable foods to one based on animal products and highly refined, processed foods, leading to an increased consumption of calories, fat, cholesterol, refined sugar, animal protein, sodium, and alcohol and far less fiber and starch than was healthful. As a result, more than one third of US adults are obese, with an estimated medical cost of $147 billion. Physicians have an important role in educating patients about healthful nutrition and in providing dietary guidelines. This module discusses the role of energy in weight loss; the structure of fat and cholesterol, their effects on blood lipid levels and cardiovascular risk, and related dietary recommendations; carbohydrates; dietary fiber; proteins; vitamin and mineral consumption; water and food consumption; and the relationship between diet and health. Tables review the principles of a healthy diet; recommended daily intake of fat and other nutrients; types of dietary fiber and representative food sources; types of vitamins; essential minerals and trace elements; and dietary guidelines for healthy people. Figures include a graph showing the percentage of adults who are healthy weight, overweight, and obese and the structure of fat and cholesterol.

      This review contains 2 highly rendered figures, 6 tables, and 37 references.

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    • 3

      Exercise

      By Elizabeth G Nabel, MD, FACP
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      Exercise

      • ELIZABETH G NABEL, MD, FACPPresident, Brigham and Women’s Hospital, Professor of Medicine, Harvard Medical School, Boston, MA

      Numerous observational studies have demonstrated an inverse relationship between physical activity and risk of many chronic illnesses. The protective effect of exercise is strongest against coronary artery disease, hypertension, stroke, type 2 diabetes mellitus, obesity, anxiety, depression, osteoporosis, and cancers of the colon and breast. Despite these proven benefits, only 25% of adults in the United States exercise at recommended levels. Globally, physical inactivity is the fourth leading risk factor for death, followed by overweight and obesity. This module describes exercise physiology, including cardiovascular response to dynamic exercise, pulmonary response, musculoskeletal response, metabolic effects, effects on blood lipid levels, hematologic effects, effects on vascular inflammation, effects on body fluids, and psychological effects. Exercise and the elderly and the relationship between exercise and longevity are reviewed. Prescribing exercise and complications of exercise are also discussed. Tables describe the categories of patients screened for possible coronary artery disease, exercise time required to consume 2,000 kcal, and exercise advice for patients. Figures include a graph showing the number of adults who met the federal physical activity guidelines criteria, the top 10 global risk factors for death in 2004, the process of providing energy for the muscle, and trends in physician prescriptions for exercise.

      This module contains 4 highly rendered figures, 3 tables, 35 references, and 5 MCQs.

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    • 4

      Nutritional Support

      By Rindi Uhlich, MD; Parker Hu, MD; Patrick L Bosarge, MD, FACS, FCCM
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      Nutritional Support

      • RINDI UHLICH, MDResident, General Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
      • PARKER HU, MDFellow, Surgery Critical Care, Division of Acute Care Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
      • PATRICK L BOSARGE, MD, FACS, FCCMAssociate Professor of Surgery, Division of Acute Care Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL

      Nutritional optimization of the critically ill patient remains a cornerstone of perioperative care. Significant effort and scrutiny are routinely directed to the field as it has the potential to improve outcomes, limit infectious complications, and decrease hospital length of stay and mortality. As such, previously identified cornerstones of care have been called into question. The timing, route, and intensity of nutritional supplementation remain the subject of controversy in an ever-evolving field. Previous methods of nutritional assessment, such as albumin and transthyretin, have proved unreliable, and their use is no longer recommended. In their place, new scoring systems are available to risk assess patients for malnutrition. We review the most pressing changes and assess the landscape of the field today.

      Key words: critical illness, enteral, glutamine, malnutrition, nutrition, outcomes, parenteral, protein

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    • 5

      Reducing the Risk of Injury and Disease

      By Harold C. Sox, MD, MACP
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      Reducing the Risk of Injury and Disease

      • HAROLD C. SOX, MD, MACPEditor, Annals of Internal Medicine, Philadelphia, PA

      Public interest in disease and injury prevention is very high, driven by a steady accumulation of high-quality evidence that preventive interventions do reduce cause-specific death rates. The purpose of these interventions is to eliminate the root causes of diseases that precede death (e.g., heart disease, cancer, and stroke). This chapter presents a review of health risks posed by substance abuse (tobacco, alcohol, and drugs), accidents (e.g., from motor vehicles, accidental poisoning, falling, fire, drowning, and firearms), and domestic violence. The physician’s role in prevention is to identify risk factors for disease and injury and counsel patients about modifying potentially harmful behaviors. Figures illustrate the life expectancy of men and women, and years of potential life lost from various causes, in the United States. Tables list recommendations of the United States Preventive Services Task Force (USPSTF), years of smoking abstinence needed to reduce the risk of disease, elements of a successful smoking cessation strategy, stages of readiness for smoking cessation, the test performance of screening questionnaires for alcohol abuse, the CAGE questionnaire, unintentional and undetermined poisoning deaths in 11 states, and risk factors for falls among the elderly. A sidebar provides links to domestic violence information on the Internet.

      This review contains 3 highly rendered figures, 9 tables, and 87 references.

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    • 6

      Complementary, Alternative, and Integrative Medicine

      By Helene M. Langevin, MD
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      Complementary, Alternative, and Integrative Medicine

      • HELENE M. LANGEVIN, MDDirector, Osher Center for Integrative Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

      Complementary and alternative medicine (CAM) refers to a group of diverse medical and health care systems, practices, and products that are not considered to be part of conventional or allopathic medicine. Common CAM practices (e.g., acupuncture, meditation, and therapeutic massage) are gradually becoming incorporated into conventional care in response to patients looking to alternative sources for information and advice about health matters and increased understanding of various CAM methods through evidence-based testing. However, although the claims of some methods are supported with academic research, well-founded concerns remain in many popularized CAM practices regarding the lack of evidence and placebo effects. It is thus imperative for physicians to be comfortable in discussing CAM-related topics with patients and be able to appropriately and informatively guide them in a way that harnesses potential benefits and avoids potential harm. In this review, the major CAM therapies in the United States are examined, including the settings in which they are being used, evidence base status, and efficacy of some of the most commonly used modalities. Figures show percentages of use for various CAM approaches. Tables show major CAM health practices, CAM therapies with significant increases between 2002 and 2007, Internet sources for evidence-based information and tools for patient education, sources for health care provider information, and resources to assess dietary supplement–drug interactions.

      This review contains 5 highly rendered figures, 5 tables, and 155 references.

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    • 7

      Occupational Medicine

      By Tee L. Guidotti, MD, MPH, FACP, DABT, QEP (Air Quality), FRCPC, FCBOM, FFOM
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      Occupational Medicine

      • TEE L. GUIDOTTI, MD, MPH, FACP, DABT, QEP (AIR QUALITY), FRCPC, FCBOM, FFOMVice President for Health/Safety/Environment & Sustainability, Medical Advisory Services, Rockville, Maryland

      Occupational medicine concerns keeping workers healthy, screening for early signs of health problems, and promoting good health through workplace initiatives. According to recent estimates, 55,000 deaths and 3.8 million disabling injuries per year result from occupational illness at a cost of $125 to $155 billion. This chapter covers the basic principles and clinical evaluation of occupational disease, guidelines for taking a patient’s occupational history, and exposure assessment. Major occupational disorders in developed countries are discussed, including respiratory tract disorders, skin disorders, disorders of the kidneys, liver disease, central and peripheral nervous systems, organs of sensation, occupational cancer, musculoskeletal disorders, hematologic disorders, endocrine and reproductive effects, stress and psychogenic effects, and nonspecific illness. Tables outline critical dimensions of occupational medicine, the conceptual approach to a patient with a suspected workplace injury or illness, common hazards with widely available tests for exposure, historically common occupational disorders, and established occupational carcinogens. Figures includes a chest film of asbestosis, a sample occupational and environmental history questionnaire, lungs in various states of pneumoconiosis, a photograph of contact dermatitis, and a graph showing hearing decline at 4,000 Hz frequency. Illustrations demonstrate the impact of occupational exposure on the kidneys and liver and the anatomy of the hearing mechanism.

      This review contains 9 highly rendered figures, 5 tables, and 112 references.

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    • 8

      Medical Evaluation of the Surgical Patient

      By Marie Gerhard-Herman, MD; Jonathan Gates, MD
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      Medical Evaluation of the Surgical Patient

      • MARIE GERHARD-HERMAN, MDDepartment of Medicine, Cardiovascular Division, Brigham and Womens Hospital, Boston, MA
      • JONATHAN GATES, MDDirector of the Burn and Trauma Unit, Department of Surgery, Brigham and Womens Hospital, Boston, MA

      Medical evaluation prior to surgery includes risk assessment and the institution of therapies to decrease perioperative morbidity and mortality to improve patient outcomes. The most effective medical consultation for surgical patients begins with an assessment of the individual patient and knowledge of the planned surgery and anesthesia followed by clear communication of a concise and specific recommended plan of perioperative care to the surgical team. This chapter describes anesthetic, cardiac, pulmonary, hepatic, nutritional, and endocrine risk assessment. Perioperative thrombotic management and postoperative care and complications, including fluid management; pulmonary, cardiac, renal complications; and delirium are discussed. Tables outline the American Society of Anesthesiologists class and perioperative mortality risk, a comparison of the Revised Cardiac Risk Index and National Surgery Quality Improvement Program, Duke Activity Status Index, high-risk stress test findings, markers for increased perioperative risk in pulmonary hypertension, aortic stenosis and nonemergent noncardiac surgery, risk factors for pulmonary complications in noncardiac surgery, the Model for End-Stage Liver Disease score to predict postoperative mortality, venous thromboembolism risk factors and options for pharmacologic prophylactic regimens, perioperative management of warfarin, and Brigham and Women’s Hospital guidelines for postoperative blood product replacement. Figures include a care algorithm for noncardiac surgery, an illustration of types of myocardial infarction, and an algorithm for the treatment of postoperative delirium.

      This review contains 3 highly rendered figures, 12 tables, and 68 references.

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    • 9

      Bioterrorism

      By Jeffrey Duchin, MD; John D Malone, MD, MPH
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      Bioterrorism

      • JEFFREY DUCHIN, MDAssociate Professor of Medicine, Division of Allergy and Infectious Disease, University of Washington School of Medicine, Seattle, WA
      • JOHN D MALONE, MD, MPHAdjunct Professor of Medicine, Center for Disaster and Humanitarian Assistance Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; National Naval Medical Center, Bethesda, MD

      Well before the 2001 anthrax outbreak, public health and government leaders in the United States recognized the need for increased preparedness to detect and respond to acts of biologic terrorism. In April 2000, the Centers for Disease Control and Prevention (CDC) published a strategic plan for preparedness and response to biologic and chemical terrorism. This chapter describes the clinician's role in recognizing potential bioterrorism agents and responding accordingly, as presented in the CDC plan. It also reviews data analyses arising from the United States military and civilian smallpox vaccination programs of 2002 to 2004. The critical biologic agent categories for public health preparedness are presented in a table. Current information is provided on the diagnosis and management of the following agents of bioterrorism: smallpox, anthrax, plague, botulism, tularemia, and hemorrhagic fever viruses. A sidebar provides Internet resources for authoritative information and guidelines related to bioterrorism. This chapter contains 169 references.

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    • 10

      The Future of Transplant Biology and Surgery

      By Marc Colaco, MD, MBA; Anthony Atala, MD
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      The Future of Transplant Biology and Surgery

      • MARC COLACO, MD, MBAResident, Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC
      • ANTHONY ATALA, MDDirector, Wake Forest Institute for Regenerative Medicine, and W.H. Boyce Professor and Chair, Department of Urology, Wake Forest University, Winston-Salem, NC

      Although organ transplantation remains the mainstay of treatment for patients with severely compromised organ function, with the growing number of patients in need of treatment and the lack of organ supply, medical scientists have begun seeking out alternatives. In the last two decades, researchers have attempted to grow native and stem cells, engineer tissues, and design treatment modalities using regenerative medicine techniques for almost every tissue of the human body. This chapter discusses the basics of tissue engineering, including cell isolation and biomaterial selection. It then outlines specific advances and potential surgical uses.

      This review contains 9 figures, 2 tables, and 135 references.

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    • 11

      Management of Poisoning and Drug Overdose

      By Timothy J Wiegand, MD; Manish M Patel, MD; Kent R. Olson, MD, FACEP, FAACT, FACMT
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      Management of Poisoning and Drug Overdose

      • TIMOTHY J WIEGAND, MDAssistant Adjunct Professor of Medicine, University of California, San Francisco, CA
      • MANISH M PATEL, MDAssistant Professor, Emory University School of Medicine, Atlanta, GA
      • KENT R. OLSON, MD, FACEP, FAACT, FACMTClinical Professor of Medicine, Pediatrics and Pharmacy, University of California, San Francisco, San Francisco, CA

      Drug overdose and poisoning are leading causes of emergency department visits and hospital admissions in the United States, accounting for more than 500,000 emergency department visits and 11,000 deaths each year. This chapter discusses the approach to the patient with poisoning or drug overdose, beginning with the initial stabilization period in which the physician proceeds through the ABCDs (airway, breathing, circulation, dextrose, decontamination) of stabilization. The management of some of the more common complications of poisoning and drug overdose are summarized and include coma, hypotension and cardiac dysrhythmias, hypertension, seizures, hyperthermia, hypothermia, and rhabdomyolysis. The physician should also perform a careful diagnostic evaluation that includes a directed history, physical examination, and the appropriate laboratory tests. The next step is to prevent further absorption of the drug or poison by decontaminating the skin or gastrointestinal tract and, possibly, by administering antidotes and performing other measures that enhance elimination of the drug from the body. The diagnosis and treatment of overdoses of a number of specific drugs and poisons that a physician may encounter, as well as food poisoning and smoke inhalation, are discussed. Tables present the ABCDs of initial stabilization of the poisoned patient; mechanisms of drug-induced hypotension; causes of cardiac disturbances; drug-induced seizures; drug-induced hyperthermia; autonomic syndromes induced by drugs or poison; the use of the clinical laboratory in the initial diagnosis of poisoning; methods of gastrointestinal decontamination; methods of and indications for enhanced drug removal; toxicity of common beta blockers; common stimulant drugs; corrosive agents; dosing of digoxin-specific antibodies; poisoning with ethylene glycol or methanol; manifestations of excessive acetylcholine activity; common tricyclic and other antidepressants; seafood poisonings; drugs or classes that require activated charcoal treatment; and special circumstances for use of activated charcoal.

      This review contains 3 highly rendered figures, 17 tables, and 193 references.

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    • 12

      Venomous Bites and Stings

      By J Patrick Walker, MD, FACS
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      Venomous Bites and Stings

      • J PATRICK WALKER, MD, FACSChief of Surgery, ETMC, Crockett, TX, Houston County Surgical Associates, Crockett, TX

      Approximately 8000 persons are bitten by venomous snakes in the US each year.  Mortality is low (4 to 6/yr), but morbidity can be significant, treatment costly. Overuse of surgery and antivenom is common. Simply cutting the wound with attempted aspiration is not indicated. Fasciotomy should only be used for patients with elevated compartment pressures. CroFab is a highly effective (but expensive) treatment useful for serious envenomation. Antivenom should be used in patients with life-threatening symptoms (hypotension, clinical coagulopathy) or rapid advancement of local signs, and to reduce compartment pressures to avoid fasciotomy. The most significant morbidity from insect envenomation is secondary to anaphylaxis. A bite from the black widow spider can induce abdominal cramping and pain that can mimics an acute abdomen. Brown recluse envenomation can produce tissue necrosis and long-term complications. Most events are seen rarely by the average physician; this review can be a useful guide in management. 

      Key words: antivenom, copperhead bite, CroFab, insect bite, rattlesnake bite, snakebite, water moccasin bite

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    • 13

      Toxic Gases

      By Stephanie T Weiss, MD, PhD; Kathryn W Weibrecht, MD
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      Toxic Gases

      • STEPHANIE T WEISS, MD, PHDAssociate Director, Emergency Medicine, Morton Hospital and Medical Center, Taunton, MA
      • KATHRYN W WEIBRECHT, MDAssociate Director, Emergency Medicine, Morton Hospital, Taunton, MA

      This review looks at the potential causes, diagnoses, and possible treatments for three asphyxiant gases: carbon monoxide, hydrogen cyanide, and hydrogen sulfide. Exposure to these gases can lead to central nervous system depression, unconsciousness, and death due to tissue hypoxia. These gases are among the most common causes of fatalities related to toxic gas poisoning, with carbon monoxide responsible for 36% and hydrogen sulfide 7.7%. It is necessary to remove victims affected by poisoning immediately from the source of the toxic gas, administer oxygen, and assess their stability. As symptoms of these gases can differ widely, ranging from broad and unspecific to highly morbid, and may require different levels of care, the correct diagnosis should also rely on inferences from the patient history and the context of the admission, including evidence of fire and chemical reactions. Normobaric oxygen and hyperbaric oxygen are the two main treatments for carbon monoxide, although studies have been inconclusive in regards to the effectiveness of hyperbaric oxygen. The Cyanokit (containing hydroxocobalamin) is considered to be more effective for hydrogen cyanide when compared with the Cyanide Antidote Kit due to the former’s low toxicity and high effectiveness. Hydrogen sulfide is often used as a suicide agent, the mortality of which is close to 100%. Figures show the mechanisms by which the asphyxiant gases carry out their negative effects on the human body. Tables show the half-life of carboxyhemoglobin with oxygen therapy and a comparison between the Cyanide Antidote Kit and the Cyanokit. 

      This review contains 3 highly rendered figures, 2 tables, and 43 references. 


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    • 14

      Toxic Plants and Mushrooms

      By Marie King, MD, PhD; Richard Church, MD
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      Toxic Plants and Mushrooms

      • MARIE KING, MD, PHDEmergency Physician, Harrington Hospital, Southbridge, MA
      • RICHARD CHURCH, MDAssistant Professor, Emergency Medicine and Toxicology, University of Massachusetts, Worcester, MA

      Many species of plants and mushrooms exist that, when consumed, can induce poisoning in individuals, causing a range of side effects. As the toxins do not always correspond to an antidote, it is important to have the ability to identify each harmful species to determine the appropriate treatment. This review gives an overview of some of the more prevalent toxic plants and mushrooms, detailing their principles of toxicity, recommendations for immediate stabilization, keys to proper diagnosis and definitive therapy, and patient disposition and outcomes. Figures show photographs of the various toxic plants and mushrooms featured. Tables show a list of toxic species for both plants and mushrooms, including their common names, the toxins contained within, their effects, and the corresponding antidote (if any).

      This review contains 16 highly rendered figures, 2 tables, and 44 references.

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    • 15

      Anticholinergic Toxicity

      By Jeffrey T Lai, MD; Kavita M Babu, MD
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      Anticholinergic Toxicity

      • JEFFREY T LAI, MDResident Physician, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA
      • KAVITA M BABU, MDAssociate Professor, Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA

      Anticholinergic compounds oppose the action of the endogenous neurotransmitter acetylcholine at its target receptors and are found in over-the-counter and prescription medication, natural products, and plants. Anticholinergic medications, such as atropine and scopolamine, are used for the treatment of a wide range of conditions, including bradycardia, motion sickness, and insomnia. Antihistaminergic medications, such as diphenhydramine, also possess anticholinergic activity and are used in the treatment of seasonal allergies, common cold symptoms, and allergic reactions. Other medications, such as antidepressants (especially the older tricyclic class), antipsychotics, muscle relaxants, and anticonvulsants, can act as anticholinergic agents or produce anticholinergic side effects. Toxicity can result from therapeutic misadventure, intentional overdose, recreational use, and pediatric exposures. This review covers the principles of toxicity, immediate stabilization, diagnosis and definitive therapy, and disposition and outcomes. Figures show the anticholinergic toxidrome, look-alike structures, and electrocardiographic changes in tricyclic antidepressant overdose. Tables list medications with anticholinergic activity and selected botanicals that cause anticholinergic toxicity.

      Key words: anticholinergic overdose, anticholinergic toxicity, anticholinergic toxidrome, physostigmine, tricyclic antidepressant toxicity

      This review contains 3 highly rendered figures, 2 tables, and 49 references.

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    • 16

      Cholinergic Toxicity

      By Steven B Bird, MD, FACEP, FACMT
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      Cholinergic Toxicity

      • STEVEN B BIRD, MD, FACEP, FACMTAssociate Professor of Emergency Medicine, Division of Medical Toxicology, University of Massachusetts Medical School, Worcester, MA

      Cholinergic drugs exert their functions by inhibiting acetylcholinesterase, the enzyme responsible for hydrolyzing acetylcholine and ending neuronal or neuromuscular neurotransmission. These compounds are used in clinical medicine to treat various disorders, as pesticides, and as weapons of mass destruction. This review describes the drugs that affect the cholinergic system and discusses stabilization, diagnosis and definitive therapy, principles and controversies of definitive care, and disposition and outcomes for these agents. Figures show acetylcholinesterase hydrolysis of acetylcholine, neurotransmission in the nervous system, the mechanism of inhibition of acetylcholinesterase by an organophosphorus (OP) compound, and the general chemical structure of thion OP and oxon OP agents and carbamates. Tables list OP pesticides associated with OP-induced delayed neuropathy, the effects of cholinesterase inhibition, the symptoms of cholinergic poisoning according to severity, and a treatment algorithm for acetylcholinesterase poisoning.

      This review contains 4 highly rendered figures, 4 tables, and 85 references.

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    • 17

      Caustics

      By Lynn A Farrugia, MD; Kavita Babu, MD, FACEP, FACMT
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      Caustics

      • LYNN A FARRUGIA, MDEmergency Medicine Residency Program, University of Massachusetts Medical School, Worcester, MA
      • KAVITA BABU, MD, FACEP, FACMTFellowship Director, Division of Medical Toxicology, Associate Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA

      A caustic is any substance capable of causing full-thickness damage on contact with healthy, intact tissue. Caustic agents are generally classified by pH as acids or bases. Irritants are those substances that do not produce true breakdown of tissue but cause discomfort and inflammation, such as vomiting, burning eyes, or coughing. This review covers caustic and irritant agents, dermal caustic exposure, caustic inhalation and pulmonary irritants, caustic ingestion, and ocular caustic exposure, along with special consideration of hydrofluoric acid, including hydrofluoric acid and dermal exposure, hydrofluoric acid ingestion, hydrofluoric acid inhalation, ocular hydrofluoric acid exposure, and systematic hydrofluoric acid toxicity. Figures show classification of burns; chemical burns; an autopsy specimen of the tongue, epiglottis, and esophagus after caustic ingestion; and an autopsy specimen of the stomach after caustic ingestion. Tables list common caustic and irritant agents, household products containing caustic and irritant agents, agents for which water or saline irrigation is not recommended, indications for endoscopy after caustic ingestion, ocular chemical burn management, and common chemicals and products containing fluoride.

      Key words: caustic eye injury, caustic ingestion, caustic injury, chemical burn, hydrofluoric acid, pulmonary irritants 

      This review contains 5 highly rendered figures, 6 tables, and 53 references.

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    • 18

      Drugs of Abuse

      By Matthew D Zuckerman , MD; Kavita Babu, MD, FACEP, FACMT
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      Drugs of Abuse

      • MATTHEW D ZUCKERMAN , MDAssistant Professor, Department of Emergency Medicine, Medical Toxicology, University of Colorado Anschutz Medical Campus, Aurora, CO
      • KAVITA BABU, MD, FACEP, FACMTFellowship Director, Division of Medical Toxicology, Associate Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA

      The term “drugs of abuse” lacks a formal medical definition. Historically, discussions of drugs of abuse focused on “street drugs”; however, the adverse effects of the nonmedical use of prescription medications, such as opiates, benzodiazepines, and therapeutic amphetamines, are increasingly seen. The purpose of this review is to aid the clinician in identifying and treating a broad representation of drugs of abuse, which may include those illicitly produced in laboratories (e.g., methamphetamine), diverted pharmaceuticals (oxycodone), and herbal products (marijuana). This review covers stimulants, hallucinogens, cannabinoids, and sedative-hypnotics. Figures show substances ranked according to weighted harm score on a normalized scale from 0 being no harm to 100 being extreme harm to self and others, a treatment algorithm for sympathomimetic toxicity, a treatment algorithm for sedative-hypnotic overdose, and a treatment algorithm for opioid overdose. Tables list commonly abused sympathomimetic agents, modern novel drugs of abuse, commonly abused sedative-hypnotic agents, commonly abused opiates, and pitfalls of the drug screen.

       

      This review contains 4 highly rendered figures, 5 tables, and 89 references

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    • 19

      Psychoactive Medications

      By Mark J Neavyn, MD; Kavita Babu, MD, FACEP, FACMT
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      Psychoactive Medications

      • MARK J NEAVYN, MDDirector of Medical Toxicology, Department of Emergency Medicine, Hartford Hospital, Hartford, CT
      • KAVITA BABU, MD, FACEP, FACMTFellowship Director, Division of Medical Toxicology, Associate Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA

      Psychoactive medications are defined as medications that affect the central nervous system neurotransmitter pathways with the intention to modulate mood or consciousness. This broad category of medications includes sedative-hypnotic agents such as benzodiazepines and barbiturates, antidepressants, neuroleptics, and mood stabilizers. The principal source of exposure for these medications is through prescription drug use and misuse. This review discusses the principles of toxicity, immediate stabilization, diagnosis and definitive therapy, and disposition and outcomes related to sedative-hypnotics, antidepressants, neuroleptics, and lithium. Tables include common benzodiazepine and barbiturate compounds, dosing instructions for multidose activated charcoal, flumazenil dosing recommendations, commonly available tricyclic and atypical (noncyclic) antidepressants, dosing recommendations for sodium bicarbonate in serum alkalinization, benzodiazepine dosing recommendations in serotonin syndrome, dosing recommendations for cyproheptadine, signs and symptoms that differentiate  neuroleptic malignant syndrome from serotonin syndrome, and indications for renal replacement therapy based on lithium concentration and clinical setting. Figures show action potentials in the His-Purkinje syndrome, an electrocardiogram tracing demonstrating a terminal R wave, and a QT interval nomogram.

      This review contains 2 highly rendered figures, 9 tables, and 101 references.

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  • Nephrology
    • 1

      Management of Cardiovascular Disease in Dialysis Patients

      By John P. Middleton; John K. Roberts
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      Management of Cardiovascular Disease in Dialysis Patients

      • JOHN P. MIDDLETON
      • JOHN K. ROBERTS

      Cardiovascular disease is a common cause of death and disease in patients with end-stage renal disease (ESRD). Registry data show that 41% of deaths in ESRD patients are due to a variety of cardiovascular causes, such as acute myocardial infarction, congestive heart failure, arrhythmia/sudden cardiac death, and stroke. In the general population, each of these disease entities in isolation can be effectively managed according to evidence from large clinical trials and evidence-based guidelines. However, many of these trials did not include patients with ESRD, limiting the transferability of this evidence to the care of patients on dialysis. To complicate matters, cardiovascular events in ESRD patients are likely augmented from a unique interplay of cardiac risk due to both reduced kidney function and the necessity for artificial renal replacement therapies. In this light, the patient on dialysis is subjected to a series of unique factors: the continued presence of the metabolic perturbations of uremia and the peculiar environment of the dialysis treatment itself. Since the ESRD heart is under a considerable amount of strain due to chronic volume overload, rapid electrolyte and fluid shifts, and accelerated vascular calcification, management can be complex and outcomes multifactorial. In this review, we summarize the current evidence regarding management of acute myocardial infarction, heart failure, sudden cardiac death, and atrial fibrillation. We also address modifiable risk factors related to the dialysis procedure itself and highlight recent randomized controlled trials that included dialysis patients and measured important cardiovascular outcomes. 

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    • 2

      Metabolic Acidosis

      By Lisa Cohen; Dipal Savla; Shuchi Anand
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      Metabolic Acidosis

      • LISA COHEN
      • DIPAL SAVLA
      • SHUCHI ANAND

      Metabolic acidosis is a common clinical entity that can arise from a variety of disease states, medications, and toxic ingestions. This review covers the pathophysiology, diagnosis, and management of common presentations of metabolic acidosis. We have differentiated various causes of metabolic acidosis based on the presence of a normal or elevated anion gap (AG), the sum of serum anions unaccounted for by the measurement of plasma sodium, bicarbonate, and chloride levels. Normal AG metabolic acidosis, or non-AG metabolic acidosis, arises when there is excessive loss of bicarbonate from the gastrointestinal tract or in the urine. This review covers the development and diagnosis of non-AG metabolic acidosis, including a discussion of the spectrum of renal tubular acidosis subtypes. The treatment of non-AG metabolic acidosis is reviewed. Metabolic acidosis with an elevated AG, also called AG metabolic acidosis, develops when exogenous or endogenous nonchloride acid accumulates in the body. The most common causes of AG metabolic acidosis are lactic acidosis and ketoacidosis from starvation, heavy alcohol intake, or diabetes with total body insulin depletion. Medications, toxic substances, and uremia can also lead to AG acidosis. The mechanisms and management of these causes of metabolic acidosis with high AG are covered in detail.

      Key words: anion-gap acidosis, diabetic ketoacidosis, lactic acidosis, non–anion gap acidosis

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    • 3

      Transplantation Immunobiology

      By Ilaria Gandolfini, MD; Paolo Cravedi, MD, PhD
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      Transplantation Immunobiology

      • ILARIA GANDOLFINI, MDPostdoctoral fellow, Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, Renal fellow, Renal Division, Department of Medicine, University Hospital of Parma, Parma, Italy
      • PAOLO CRAVEDI, MD, PHDAssistant Professor, Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

      The immune system has evolved to clear the host of invading microorganisms and its own cells that have become altered in some way, such as infected cells or mutated tumorigenic cells. The immune system recognizes such cells as “foreign” based on their expression of different molecules (antigens). Similarly, when organs are transplanted between genetically disparate (allogeneic) individuals, the immune system recognizes and reacts against the foreign antigens of the other individual (alloantigens) to cause rejection. The immune response to a transplanted organ is the consequence of a complex interplay between the innate and adaptive immune systems. Early ischemia-reperfusion injury to the allograft triggers an innate immune response and contributes to the activation of recipient T cells that recognize donor major and minor histocompatibility alloantigens.1 Once activated, T cells migrate into the allograft, where they mediate rejection by imposing direct cytotoxicity on allogeneic cells, or by providing help to other cells of the immune system, such as macrophages, natural killer (NK) cells, and B lymphocytes, which differentiate into antibody-producing cells. These effector cells and factors then lead to allograft injury.2 This review outlines the elements involved in the innate and adaptive immune responses to a transplant and the mechanisms of rejection.

      Key Words: Allograft injury, Allograft rejection, Alloantigen recognition, Antibody-mediated rejection, Immune response, Adaptive immunity, Innate immunity

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    • 4

      Hypertensive Disorders in Pregnancy

      By Kavitha Vellanki, MD; Susan Hou, MD
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      Hypertensive Disorders in Pregnancy

      • KAVITHA VELLANKI, MDAssociate Professor of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL.
      • SUSAN HOU, MDProfessor of Medicine, Division of Nephrology and Hypertension, Department of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL.

      Hypertensive disorders are the second leading cause of maternal mortality in the United States. Hypertension in pregnancy is defined as blood pressure greater than or equal to 140 mm Hg systolic or greater than or equal to 90 mm Hg diastolic, measured on at least two separate occasions. Preeclampsia, as per the new guidelines, is characterized by the new onset of hypertension and either proteinuria or other end-organ dysfunction, more often after 20 weeks of gestation in a previously normotensive pregnant woman. New-onset proteinuria is not required for diagnosis of preeclampsia if there is evidence of other end-organ damage—a change from previous classifications. Although no screening test has yet proven accurate enough to predict preeclampsia, the use of a combination of the serologic factors seems promising. There are few data to support any specific blood pressure target in pregnancy. Although there is a general consensus on treating severe hypertension in pregnancy, there is a difference of opinion on treating mild to moderate hypertension in pregnancy. Avoiding uteroplacental ischemia and minimizing fetal exposure to adverse effects of medications are as important as avoiding maternal complications from high blood pressure during pregnancy.

      This review contains 2 figures, 4 tables, and 73 references.

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    • 5

      Approach to the Patient With Kidney Disease

      By Ajay K Singh, MBBS, FRCP (UK), MBA; Jameela A. Kari, MD, FRCP (UK), FRCPCH
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      Approach to the Patient With Kidney Disease

      • AJAY K SINGH, MBBS, FRCP (UK), MBAAssociate Professor of Medicine, Associate Dean for Global Education and Continuing Education, Harvard Medical School, Director, Continuing Medical Education, Department of Medicine and Renal Division, Brigham and Women’s Hospital, Boston, MA
      • JAMEELA A. KARI, MD, FRCP (UK), FRCPCHProfessor of Pediatrics and Consultant Pediatric Nephrologist, King Abdulaziz University, Jeddah, Saudi Arabia

      Diseases of the kidney can present with a variety of different clinical presentations. These presentations are best considered syndromically: prerenal, renal, and postrenal. Besides this commonly used framework, kidney disease can have the kidney as the prime mover, such as with a primary glomerular disease, versus the kidney as a target of a systemic process, for example, as in the hepatorenal syndrome, where the primary abnormality physiologically is with the liver. Therefore, the most important aspect when approaching patients with kidney disease is to use a systematic framework. This framework applies regardless of whether kidney disease occurs in adults or children. This review covers determination of disease duration, assessment of kidney function, measurement of kidney function, staging of kidney disease, imaging techniques for the genitourinary system, major syndromes of kidney disease, and asymptomatic urinary sediment abnormalities. Figures show an approach to the patient with renal disease, components of urinary sediment, and an approach to the patient with hematuria. Tables list considerations for referral to nephrology, the National Kidney Foundation classification of chronic kidney disease, categories of proteinuria, correlation between dipstick positivity for protein and protein concentration in urine, causes of hematuria, and causes of hematuria by age and gender.

       

      This review contains 3 highly rendered figures, 6 tables, and 26 references.

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    • 6

      Disorders of Water and Sodium Balance

      By Richard H Sterns, MD, FACP
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      Disorders of Water and Sodium Balance

      • RICHARD H STERNS, MD, FACPProfessor of Medicine, University of Rochester School of Medicine and Dentistry, Chief of Medicine, Rochester General Hospital and the Genesee Hospital, Rochester, NY

      Water accounts for approximately half of an adult human’s body weight. Two thirds of body water is intracellular, and the remaining one third is contained in the extracellular fluid compartment, which includes intravascular (plasma) and interstitial fluid. Small amounts of water are also contained in bone, dense connective tissue, digestive secretions, and cerebrospinal fluid. To maintain the stability of the internal milieu, body fluids are processed by the kidney, guided by intricate physiologic control systems that regulate fluid volume and composition. This chapter reviews the regulation of body fluid volumes, cell volume regulation in hypotonicity and hypertonicity, disorders of water excess (hyponatremia), water deficiency (hypernatremia), water conservation (diabetes insipidus), saltwater excess (edematous states), and saltwater deficiency (volume depletion). Tables describe control of body fluid volumes, causes of nonhypotonic hyponatremia, causes and treatment of acute hyponatremia, causes of the syndrome of inappropriate release of antidiuretic hormone (SIADH), and causes of hypernatremia. Figures illustrate sodium reabsorption by the renal tubules, the relationship between plasma vasopressin levels, renal sodium handling, and dose-response curves for a loop diuretic in patients with normal and reduced renal function.

      This chapter contains 4 highly rendered figures, 5 tables, 88 references, and 5 MCQs.

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    • 7

      Drug Dosing in Acute Kidney Injury

      By Steven Gabardi, PharmD, BCPS, FAST, FCCP; Marjan Sadegh, PharmD, BCPS; Craig A Stevens, PharmD, BCPS; Jamil Azzi, MD
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      Drug Dosing in Acute Kidney Injury

      • STEVEN GABARDI, PHARMD, BCPS, FAST, FCCP
      • MARJAN SADEGH, PHARMD, BCPS
      • CRAIG A STEVENS, PHARMD, BCPS
      • JAMIL AZZI, MD

      The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. 

      Key words: acute kidney injury, drug dosing, pharmacokinetics

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    • 8

      Disorders of Acid-base and Potassium Balance

      By Stuart L Linas, MD, FACP
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      Disorders of Acid-base and Potassium Balance

      • STUART L LINAS, MD, FACPProfessor of Medicine, University of Colorado Denver, Denver, CO

      Water accounts for approximately half of an adult human's body weight. Two thirds of body water is intracellular, and the remaining one third is contained in the extracellular fluid compartment, which includes intravascular (plasma) and interstitial fluid. Small amounts of water are also contained in bone, dense connective tissue, digestive secretions, and cerebrospinal fluid. To maintain stability of the internal milieu, body fluids are processed by the kidney, guided by intricate physiologic control systems that regulate fluid volume and composition. This chapter reviews the principles of body fluid hemostasis and discusses disorders of water excess (hyponatremia), water deficiency (hypernatremia), water conservation (diabetes insipidus), saltwater excess (edematous states), and saltwater deficiency (volume depletion). Figures illustrate the relation between the plasma hydrogen ion concentration and the blood pH, proximal tubular bicarbonate reabsorption, renal secretion of hydrogen ions, renal glutamine metabolism and ammonia diffusion, metabolic alkalosis, and the electrocardiographic changes in and approach to causes of hypokalemia and hyperkalemia. Tables describe causes of metabolic acidosis with a high and a normal ion gap; causes of type 1 renal tubular acidosis; causes of type 4 renal tubular acidosis and aldosterone resistance; causes of metabolic alkalosis, respiratory acidosis, and respiratory alkalosis; evaluation of the renal defect in hyperkalemia; and treatment of hyperkalemia.

      This chapter contains 50 references.

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    • 9

      Kidney Disease in Pregnancy

      By Kavitha Vellanki, MD; Susan Hou, MD
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      Kidney Disease in Pregnancy

      • KAVITHA VELLANKI, MDAssociate Professor of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL.
      • SUSAN HOU, MDProfessor of Medicine, Division of Nephrology and Hypertension, Department of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL.

      Pregnancy-induced changes in renal hemodynamics play an important role in favorable maternal and fetal outcomes. Renal plasma flow and glomerular filtration rate (GFR) increase by approximately 50% in normal pregnancy, leading to a decrease in both blood urea nitrogen and serum creatinine when compared with prepregnancy levels. Hence, serum creatinine–based formulas are not accurate in calculating estimated GFR in pregnant patients. The most compelling risk for pregnant women with moderate to severe chronic kidney disease is the risk of rapid progression of underlying kidney disease; the mechanisms for such decline are yet to be elucidated. The rule of kidney disease not progressing when serum creatinine is less than 1.4 mg/dL does not apply to women with lupus nephritis. New-onset lupus is an indication for kidney biopsy during pregnancy because diffuse proliferative lupus nephritis requires prompt treatment and first-line treatments are teratogenic. Infertility is common in women on dialysis and is usually reversed after successful kidney transplantation. Pregnancy outcomes have improved over the years with increasing intensity of hemodialysis in end-stage kidney disease patients. Pregnancy post–kidney transplantation should be planned and teratogenic medications discontinued before conception.

      Key words: glomerular filtration rate, proliferative lupus nephritis, serum creatinine, pregnancy post–kidney transplantation, end-stage kidney disease, infertility, kidney biopsy

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    • 10

      Acute Kidney Injury in the Cancer Patient

      By Shveta Motwani, MD, MMSc, FASN; Albert Q. Lam, MD
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      Acute Kidney Injury in the Cancer Patient

      • SHVETA MOTWANI, MD, MMSC, FASNOnco-Nephrologist, Dana-Farber Cancer Institute, Associate Physician, Division of Renal Medicine, Brigham and Women’s Hospital, Instructor in Medicine, Harvard Medical School, Boston, MA.
      • ALBERT Q. LAM, MDOnco-Nephrologist, Dana-Farber Cancer Institute, Associate Physician, Division of Renal Medicine, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, MA.

      Acute kidney injury (AKI) is a problem frequently encountered in patients with cancer that significantly impacts their well-being and outcomes. In addition to the usual prerenal, intrarenal, and postrenal etiologies of AKI, patients with cancer experience unique causes of AKI. Nephrologists caring for this population must be able to identify and manage these conditions, which often require distinguishing between causes resulting from the cancer itself and those related to chemotherapeutic or other concurrent treatment, to institute appropriate preventive or therapeutic strategies. In this review, we present a suggested systematic approach to the diagnosis of AKI in patients with cancer and discuss common clinical scenarios specific to this patient population, with a special emphasis on tumor infiltration of the kidney parenchyma, myeloma-related AKI, tumor lysis syndrome, thrombotic microangiopathy, AKI in the patient with hematopoietic stem cell transplantation, and renal disease in patients with renal cell carcinoma. We cover the latest evidence-based strategies for management of these disorders in this evolving field. In addition, we provide an updated table of potentially nephrotoxic chemotherapeutic agents with their associated mechanisms of kidney injury as a reference for clinicians to build on as they encounter the ever-expanding list of oncologic agents in practice. As the subspecialty of onconephrology continues to evolve, it will be increasingly important for clinicians to have the skills to effectively diagnose and treat AKI in cancer patients to minimize morbidity and mortality, decrease the incidence of subsequent chronic kidney disease, and maintain chemotherapeutic options for these patients.

      This review contains 5 figures, 5 tables, and 61 references.

      Key words: acute kidney injury, cancer, chemotherapy, onconephrology, renal failure

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    • 11

      Glomerular Diseases

      By Ramon G.B. Bonegio, MD, PhD; David J. Salant, MD
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      Glomerular Diseases

      • RAMON G.B. BONEGIO, MD, PHDAssistant Professor of Medicine, Renal Section, Boston University School of Medicine, Boston, MA
      • DAVID J. SALANT, MDProfessor of Medicine, Boston University School of Medicine, Chief of Nephrology Section, Boston Medical Center, Boston, MA

      Some disease processes that affect the glomerulus are acute and self-limited, whereas others lead to progressive loss of renal function. Glomerular diseases cause more than half the cases of chronic kidney disease. This chapter first briefly reviews normal glomerular structure and function, clinical classifications, terminology, diagnosis, and epidemiology of glomerular disease. Pathogenesis of glomerular injury is discussed, and then more detailed approaches to diagnosis. General principles in the management of glomerular diseases are presented. Specific glomerular diseases and their management, discussed at length, are divided into nephritic, nephrotic, and nephritic-nephrotic syndromes. Figures illustrate the pathogenesis and findings on light microscopy, electron microscopy, and immunostaining of a variety of glomerular diseases, including poststreptococcal glomerulonephritis, IgA nephropathy, anti–glomerular basement membrane disease, focal and segmental glomerulosclerosis (FSGS), membranous nephropathy, and membranoproliferative glomerulonephritis (MPGN). Also illustrated are treatment algorithms for FSGS and minimal change disease. Tables list the clinical presentation and common causes of glomerular disease, diseases associated with mesangial IgA deposition, causes of FSGS, conditions associated with membranous nephropathy, diseases associated with minimal change lesions, causes of dense deposit disease, and causes of MPGN types I to III. This chapter contains 140 references.

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    • 12

      Tubulointerstitial Diseases

      By Gerald B. Appel, MD, FACP, FASN; Premila Bhat, MD; Pietro Canetta, MD
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      Tubulointerstitial Diseases

      • GERALD B. APPEL, MD, FACP, FASNProfessor of Clinical Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY
      • PREMILA BHAT, MDAtlantic Dialysis Management Services, L.L.C
      • PIETRO CANETTA, MDClinical Fellow, Division of Nephrology, Columbia University Medical Center, New York, NY

      Tubulointerstitial diseases predominantly involve the tubules and the interstitium (the space between the tubules). They may be acute or chronic. Drug-induced acute interstitial nephritis (AIN) can be caused by antibiotics or nonsteroidal anti-inflammatory drugs. Drug-induced chronic interstitial nephritis can be caused by analgesic agents, lithium, antineoplastic agents, and cyclosporine. Physical factors causing interstitial damage are obstructive nephropathy, reflux nephropathy, and radiation nephritis. Discussions of infectious tubulointerstitial nephritis, metabolic and toxic tubulointerstitial nephritis, interstitial disease associated with vascular damage, tubulointerstitial disease caused by dysproteinemias and other tumors, and cystic disease of the kidney are also included. There are 13 figures, including micrographs, CT scans, pyelograms, and photographs of gross specimens, that illustrate the clinical findings of these diseases. Tables list the etiologies of tubulointerstitial diseases and drugs associated with AIN. This chapter has 161 references.

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    • 13

      Acute Kidney Injury

      By Anupam Agarwal, MD, FASN; Paul W Sanders, MD, FACP
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      Acute Kidney Injury

      • ANUPAM AGARWAL, MD, FASNProfessor and Director, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
      • PAUL W SANDERS, MD, FACPProfessor and Director, Nephrology Research and Training Center, University of Alabama at Birmingham, Chief, Renal Section, Birmingham Veterans Affairs Medical Center, Birmingham, AL

      Acute renal failure (ARF) has been defined as a syndrome in which an abrupt decrease in renal function produces retention of nitrogenous waste products. Translating this abstract description into a clinically useful, accurate, and widely accepted definition has been challenging, in large part because of the focus on serum creatinine concentration, which is easily obtained but has the inherent limitation of poor detection of rapid or subtle, but clinically important, changes in the glomerular filtration rate (GFR). In recent years, therefore, the term acute kidney injury (AKI) has replaced ARF because AKI denotes the entire clinical spectrum from mild increases in serum creatinine to overt renal failure. AKI is defined by the Risk-Injury-Failure-Loss-ESRD (RIFLE) criteria, based on serum creatinine concentration and urine flow rate. The Acute Kidney Injury Network (AKIN) subsequently modified the definition further and divided AKI into three stages. This chapter includes discussions of the etiology and diagnosis of AKI in hospitalized patients and community-acquired AKI. The specific causes, management, and complications of AKI are also discussed. Figures illustrate the pathophysiologic classification of AKI and the effect of hyperkalemia on cardiac conduction—electrocardiogram (ECG) changes. A worksheet for following patients with AKI is provided. Tables describe the RIFLE and AKIN criteria in AKI; prevention, diagnostic evaluation, daily evaluation and management of hospitalized patients, and urinary diagnostic indices in AKI, as well as features that help differentiate between acute and chronic kidney failure; details of furosemide dosing; and treatment modalities for hyperkalemia. This chapter contains 96 references.

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    • 14

      Management of Chronic Kidney Disease and Its Complications

      By Joshua S. Hundert, MD; Ajay K Singh, MBBS, FRCP (UK), MBA
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      Management of Chronic Kidney Disease and Its Complications

      • JOSHUA S. HUNDERT, MDClinical Fellow, Department of Medicine, Division of Nephrology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
      • AJAY K SINGH, MBBS, FRCP (UK), MBAAssociate Professor of Medicine, Associate Dean for Global Education and Continuing Education, Harvard Medical School, Director, Continuing Medical Education, Department of Medicine and Renal Division, Brigham and Women’s Hospital, Boston, MA

      Management of early renal failure helps in the reduction or prevention of end-stage renal disease. The monitoring of renal function is discussed, and the chapter includes a table that shows commonly used methods for monitoring. Risk factors for chronic renal failure include stroke and cardiac disease. Risk factors for renal disease progression are diabetes mellitus, hypertension, proteinuria, smoking, protein intake, and hyperlipidemia. Complications of chronic renal failure that are addressed include sodium and water imbalance, potassium imbalance, acidosis, calcium and phosphorus imbalance, and anemia. There is also a section that discusses the case for early referral to a nephrologist. Tables present the equations used to estimate the glomerular filtration rate (GFR); stages of chronic kidney disease and the appropriate steps in their management; risk factors for chronic kidney disease in which the testing of proteinuria and estimation of GFR are indicated; appropriate diet for patients who have chronic kidney disease; and guidelines for diagnosing and treating anemia resulting from chronic kidney disease. An algorithm outlines the steps in management of calcium and phosphate in patients with kidney disease.

      This review contains 3 highly rendered figures, 6 tables, and 93 references.

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    • 15

      Chronic Kidney Failure and Dialysis

      By Raghu V Durvasula, MD; Jonathan Himmelfarb, MD
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      Chronic Kidney Failure and Dialysis

      • RAGHU V DURVASULA, MDAssistant Professor of Medicine, Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, WA
      • JONATHAN HIMMELFARB, MDDepartment of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, WA

      Chronic kidney disease (CKD) is a clinical syndrome arising from progressive kidney injury, formerly known as chronic renal failure, chronic renal disease, and chronic renal insufficiency. It is classified into five stages based primarily on glomerular filtration rate (GFR). This article discusses the epidemiology of CKD and end-stage renal disease (ESRD), as well as etiology and genetics, pathophysiology, and pathogenesis. The section on diagnosis looks at clinical manifestations and physical findings, laboratory (and other) tests, imaging studies, and biopsy. A short section on differential diagnosis is followed by a discussion of treatment, including hemodialysis and peritoneal dialysis. Long-term complications of patients on dialysis include cardiovascular disease, renal osteodystrophy, dialysis-related amyloidosis, and acquired cystic disease (renal cell carcinoma). The final section addresses prognosis and socioeconomic burden. Figures include the classification system for CKD, prevalence of CKD in the United States, rising prevalence, risk of, and leading causes of ESRD in the United States, plus the changing prevalence of ESRD over time, clinical manifestations of uremia, and an overview of hemodialysis circuit. Tables look at the burden of CKD relative to other chronic disorders, the specific hereditary causes of kidney disease, and situations when serum creatinine does not accurately predict GFR. Other tables list equations for estimating GFR, the causes of CKD without shrunken kidneys, and clinical features distinguishing chronic kidney disease from acute kidney injury. ESRD and indications for initiation of dialysis are presented, as well as typical composition of dialysate and reasons for failure of peritoneal dialysis. This chapter contains 71 references.

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    • 16

      Pharmacologic Approach to Renal Insufficiency

      By Ali J. Olyaei, PharmD; William M. Bennett, MD
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      Pharmacologic Approach to Renal Insufficiency

      • ALI J. OLYAEI, PHARMD
      • WILLIAM M. BENNETT, MDMedical Director, Legacy Transplant Services, Professor of Pharmacy Practice, Legacy Good Samaritan Medical Center, Oregon State University, Portland, OR

      Prescribing drugs in patients with kidney disease is complex: drug dosing needs to be adjusted by the stage of kidney disease (whether chronic kidney disease [CKD] stages 1 through 5 or acute kidney injury [AKI] stages 1 through 3); because potential interactions with other agents that are being used need to be considered; and because of the possibility of extracorporeal treatment that might need to be used (e.g., continuous renal replacement therapy [CRRT], peritoneal dialysis [PD], or hemodialysis [HD]). Besides this complexity, there has been an explosion in the classes of new agents and the routes of delivery of these agents. The purpose of this chapter is to review the basic pharmacokinetic and pharmacologic principles that should guide therapy and to summarize basic recommendations for patients with CKD and AKI. The general principles for drug dosing in CKD and AKI include pharmacokinetics in renal failure; bioavailability; volume of distribution; protein binding; and biotransformation. A stepwise approach to dosage adjustment is described and created as an algorithmic approach. Drug dosing considerations in dialysis patients and in AKI patients are covered as well.
      This chapter contains 2 algorithms, 7 tables, 25 references, 5 Board-styled MCQs, and 1 Teaching Slide Set.

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    • 17

      Nephrolithiasis

      By Ita Pfeferman Heilberg, MD, PhD; José Luiz Nishiura, MD, PhD
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      Nephrolithiasis

      • ITA PFEFERMAN HEILBERG, MD, PHDAssociate Professor, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
      • JOSÉ LUIZ NISHIURA, MD, PHDAssociate Researcher, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.

      Nephrolithiasis is a highly prevalent condition, but its incidence varies depending on race, gender, and geographic location. Approximately half of patients form at least one recurrent stone within 10 years of the first episode. Renal stones are usually composed of calcium salts (calcium oxalate monohydrate or dihydrate, calcium phosphate), uric acid, or, less frequently, cystine and struvite (magnesium, ammonium, and phosphate). Calcium oxalate stones, the most commonly encountered ones, may result from urinary calcium oxalate precipitation on the Randall plaque, which is a hydroxyapatite deposit in the interstitium of the kidney medulla. Uric acid nephrolithiasis, which is common among patients with metabolic syndrome or diabetes mellitus, is caused by an excessively acidic urinary pH as a renal manifestation of insulin resistance. The medical evaluation of the kidney stone patient must be focused on identifying anatomic abnormalities of the urinary tract, associated systemic diseases, use of lithogenic drugs or supplements, and, mostly, urinary risk factors such as low urine volume, hypercalciuria, hyperuricosuria, hypocitraturia, hyperoxaluria, and abnormalities in urine pH that can be affected by dietary habits, environmental factors, and genetic traits. Metabolic evaluation requires a urinalysis, stone analysis (if available), serum chemistry, and urinary parameters, preferably obtained by two nonconsecutive 24-hour urine collections under a random diet. Targeted medication and dietary advice are effective to reduce the risk of recurrence. Clinical, radiologic, and laboratory follow-ups are needed to prevent stone growth and new stone formation, to assess treatment adherence or effectiveness to dietary recommendations, and to allow adjustment of pharmacologic treatment.

      This review contains 5 highly rendered figure, 3 tables, and 105 references.

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    • 18

      Vascular Diseases of the Kidney

      By Ronald J. Falk, MD, FACP; Julieanne G McGregor, MD; Vimal K Derebail, MD, MPH; Abhijit V. Kshirsagar, MD, MPH
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      Vascular Diseases of the Kidney

      • RONALD J. FALK, MD, FACPAllan Brewster Distinguished Professor of Medicine; Chief, Division of Nephrology and Hypertension; Director, UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
      • JULIEANNE G MCGREGOR, MDAssistant Professor, Department of Medicine, Division of Nephrologyand Hypertension, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
      • VIMAL K DEREBAIL, MD, MPHAssistant Professor, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
      • ABHIJIT V. KSHIRSAGAR, MD, MPHAssociate Professor, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC

      A number of local and systemic disease processes affect the renal vascular tree. Although the underlying mechanisms may differ, vascular diseases of the kidney all characteristically cause varying degrees of vessel obstruction, eventually leading to an impairment of renal blood flow. Acute impairment in renal function occurs in most vascular diseases of the kidney. This chapter discusses the major vascular diseases of the kidney, categorized according to the size of the affected vessel. Large-vessel diseases described are renal artery stenosis from atherosclerosis and fibromuscular dysplasia, Takayasu arteritis, and renal vein thrombosis. Medium-size-vessel diseases described are polyarteritis nodosa and Kawasaki disease. Small-vessel diseases described are those traditionally associated with glomerulopathy, including rapidly progressive glomerulonephritis and Henoch-Schönlein purpura; thrombotic microangiopathy, including thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, preeclampsia, antiphospholipid syndrome, systemic sclerosis, and malignant hypertension; sickle cell disease; and atheroembolic disease. Tables describe the American College of Rheumatology classification criteria for Takayasu arteritis and induction therapy for rapidly progressive glomerulonephritis. Figures show an overview of vascular disease of the kidney; an arteriogram of renal artery stenosis demonstrating an ostial lesion; light microscopy showing typical crescentic glomerulonephritis; purpuric eruptions in small vessel vasculitides, Henoch-Schönlein purpura, hypersensitivity vasculitis, and antineutrophil cytoplasmic autoantibody–associated disease; light microscopy showing the characteristic onion-skin lesion in scleroderma renal crisis; electron microscopy showing a glomerular capillary with thrombotic thrombocytopenic purpura; injection microradioangiograms comparing the vasa recta of a normal kidney with that in a patient with sickle cell disease; and a light microscopy that reveals an atheroembolus lodged in a small renal artery and occlusion of the vascular lumen. This chapter contains 151 references.

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    • 19

      Benign Prostatic Hyperplasia

      By Michael J Barry, MD, FACP
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      Benign Prostatic Hyperplasia

      • MICHAEL J BARRY, MD, FACPPhysician Medical Services, Massachusetts General Hospital, Clinical Professor of Medicine, Harvard Medical School, Boston, MA

      Benign prostatic hyperplasia (BPH) is a common cause of morbidity in older men in developed countries. BPH causes lower urinary tract symptoms (LUTS) and occasionally results in such complications as acute urinary retention (AUR), urinary tract infection, and even obstructive uropathy. Although the development of medical treatments has reduced the role of surgery, prostatectomy remains a widely performed procedure. Epidemiology, risk factors, and pathophysiology are discussed. Diagnosis includes clinical features, history, physical examination, and laboratory testing. Management can include watchful waiting, medical treatment, surgery, and minimally invasive treatment. Management of AUR is also addressed. A table lists the alpha blockers commonly used in the treatment of men with LUTS attributed to BPH. Figures illustrate the prevalence of BPH histology with age, the anatomy of the prostate gland, the International Prostate Symptom Score (IPSS) for assessing BPH, and 4-year outcomes in men with moderate and severe LUTS attributable to BPH.

      This chapter contains 4 highly rendered figures, 1 table, 70 references, and 5 MCQs.

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    • 20

      Cardiovascular Disease in Patients With Kidney Disease

      By Ernest I Mandel, MD; David M. Charytan, MD, MSc
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      Cardiovascular Disease in Patients With Kidney Disease

      • ERNEST I MANDEL, MDClinical Fellow in Medicine, Harvard Medical School and Renal Division, Brigham and Women’s Hospital, Boston, MA
      • DAVID M. CHARYTAN, MD, MSCAssistant Professor of Medicine, Harvard Medical School, Associate Staff Physician, Renal Division, Brigham & Women’s Hospital, Boston, MA

      Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD) and is the leading cause of morbidity and mortality in dialysis patients. Clinical practice guidelines established by the National Kidney Foundation identify five stages of CKD defined by estimated glomerular filtration rate (eGFR) as determined by the abbreviated Modification of Diet in Renal Disease (MDRD) study equation. The National Health and Nutrition Epidemiology Survey (NHANES III) estimated that 13% of adults in the United States have CKD. An estimated 5 to 10% of the world's population—a staggering 300 to 600 million people—have CKD. This chapter covers the epidemiology, clinical spectrum, pathogenesis, and management of CVD in patients who have CKD. The clinical spectrum of CVD in patients with CKD is divided into four major categories: arterial disease, myocardial disease, disorders of cardiac rhythm, and valvular disease. Sections discuss some or all of the following: epidemiology/pathophysiology, diagnosis, management, risk factors, intervention, prevention. The chapter includes 4 tables and 6 figures. Figures present age-standardized rates of death, Kaplan–Meier estimates of rates of death, mortality by stage of CKD, hazard ratios and 95% confidence intervals for all-cause and cardiovascular mortality, cardio-renal syndrome pathophysiology, and ratios for actual to expected number of occurrences of sudden death. Tables list the five stages of CKD, types of CVD associated with CKD, risk factors for CVD in patients with CKD/end-stage renal disease (ESRD), and factors contributing to platelet dysfunction and enhanced bleeding risk in CKD/ESRD. This chapter contains 191 references.

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    • 21

      Kidney Transplantation 1: an Overview--recipient Evaluation and Immunosuppression

      By Jamil Azzi, MD; Belinda T. Lee, MD; Martina M McGrath, MB, BCh; Anil Chandraker, MD
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      Kidney Transplantation 1: an Overview--recipient Evaluation and Immunosuppression

      • JAMIL AZZI, MD
      • BELINDA T. LEE, MDCharles Bernard Carpenter Transplant Fellow, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
      • MARTINA M MCGRATH, MB, BCHInstructor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
      • ANIL CHANDRAKER, MDMedical Director of Kidney and Pancreas Transplantation, Associate Professor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

      Kidney transplantation remains the optimal renal replacement therapy for patients with end-stage renal disease (ESRD). A timely referral to kidney transplantation and a thorough pretransplantation evaluation ensure improvement in the morbidity and mortality of ESRD patients. Basic knowledge of immune biology and an in-depth understanding of the different induction and maintenance therapies used post kidney transplantation are imperative for optimal patient management. In this review, we discuss the multidisciplinary process of pretransplantation evaluation of kidney transplant recipients. We also discuss state-of–the-art early management post kidney transplantation with the different immunosuppressive therapies currently available.

      This review contains 3 figures, 11 tables, and 106 references.

      Key words: crossmatch, donor-specific antibody, immunosuppression, human leukocyte antigen, immunosuppression, induction, maintenance, medical evaluation, transplantation

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    • 22

      Kidney Transplantation 2: Care of the Kidney Transplant Recipient

      By Belinda T. Lee, MD; Anil Chandraker, MD; Jamil Azzi, MD; Martina M McGrath, MB, BCh
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      Kidney Transplantation 2: Care of the Kidney Transplant Recipient

      • BELINDA T. LEE, MDCharles Bernard Carpenter Transplant Fellow, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
      • ANIL CHANDRAKER, MDMedical Director of Kidney and Pancreas Transplantation, Associate Professor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
      • JAMIL AZZI, MDInstructor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
      • MARTINA M MCGRATH, MB, BCHInstructor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

      Renal transplantation is the preferred therapy for patients with end-stage kidney disease, leading to increased life expectancy, improved quality of life, and reduced health care resource use. Owing to their preexisting burden of disease, caring for renal transplant recipients is complex. Patient management following successful renal transplantation involves a multifactorial approach to cardiovascular risk factor management, along with titration of immunosuppression, management of complications related to immunosuppression, and active monitoring of allograft function. Recent advances in immunosuppressive management hold promise for improved long-term allograft survival. Finally, immune monitoring of transplant recipients is an area of considerable research, with the ultimate aim of individualized management of immunosuppression and the ability to induce transplant-specific tolerance.

      This review contains 7 figures,7 tables, and 117 references.

      Key words: cardiovascular disease, drug interactions, immunosuppression, infection, interstitial fibrosis and tubular atrophy, malignancy, rejection, tolerance

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    • 23

      Kidney Disease in the Cancer Patient

      By Colm Magee, MD, MPH, FRCPI; Lynn Redahan, MD, MRCPI
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      Kidney Disease in the Cancer Patient

      • COLM MAGEE, MD, MPH, FRCPIDepartment of Nephrology, Consultant Nephrologist and Lynn Redahan, MRCPI, Senior Registrar in Nephrology, Beaumont Hospital, Beaumont, Dublin, Ireland
      • LYNN REDAHAN, MD, MRCPIDepartment of Nephrology, Consultant Nephrologist and Lynn Redahan, MRCPI, Senior Registrar in Nephrology, Beaumont Hospital, Beaumont, Dublin, Ireland

      The spectrum of kidney disease in the cancer patient is wide. Kidney dysfunction can result from the cancer itself or its treatment. The presentation in this population is varied and may manifest as acute kidney injury (AKI) or chronic kidney disease. In addition, other manifestations of kidney disease can include proteinuria, hypertension, and electrolyte disturbances. As new cancer treatments emerge, the range of therapy-associated renal syndromes increases. This chapter deals predominantly with causes and management of renal dysfunction that are specific to the cancer patient, including those caused by hypercalcemia; hepatorenal syndrome; the use of interleukin-2 (IL-2) and bisphosphonate; glomerular, tubular, interstitial, and vascular diseases; multiple myeloma (MM); and tumor infiltration. The chapter also examines postrenal causes of AKI, electrolyte disorders, and hematopoietic stem cell transplantation (HSCT). Tables provide the features of kidney disease in the cancer patient, the pathogenesis of hypercalcemia, strategies for preventing and managing AKI with IL-2 therapy, laboratory findings with hemolytic-uremic syndrome/thrombocytopenic purpura, the causes of acute tubular necrosis in MM, a summary of electrolyte disturbances in the cancer patient, indications for HSCT, and a summary of the management of patients with post-HSCT AKI. The chapter is also enhanced by ultrasound and computed tomographic scans, histology images, and an illustration of tumor lysis syndrome.

      This chapter contains 105 references, 8 tables, 4 highly rendered figures, and 5 MCQs.

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    • 24

      Urinalysis

      By Gautam Kishore Valecha , MBBS; Rafeel Syed, MD; Amina Rehman, MBBS; Suzanne El-Sayegh, MD
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      Urinalysis

      • GAUTAM KISHORE VALECHA , MBBSResident, Department of Medicine, Staten Island University Hospital, Staten Island, NY
      • RAFEEL SYED, MDFellow, Department of Nephrology, Staten Island University Hospital, Staten Island, NY
      • AMINA REHMAN, MBBSClinical Research Volunteer, Department of Medicine, Staten Island University Hospital, Staten Island, NY
      • SUZANNE EL-SAYEGH, MDProgram Director, Department of Medicine, Staten Island University Hospital, Staten Island, NY

      Urinalysis comprises physical, chemical, and microscopic examination of urine. Although widely available, this test is often underused and misinterpreted. Urinalysis can provide helpful clues in the assessment of a variety of clinical conditions, but one must be aware of their limitations. On proper collection, the sample must be analyzed ideally within 2 hours. Dipstick urinalysis is convenient and commonly performed but provides qualitative or semiquantitative assessment only, and its results can be affected by urine discoloration and the presence of various other substances. Finally, urine microscopy is an important component of urinalysis used to identify various structures such as crystals, cells, microorganisms, and casts, which in turn helps in the assessment of the underlying disease. In this review, we discuss the clinical implications of various findings on urinalysis. Additionally, we also highlight the importance of proper sample collection and examination techniques to optimize the diagnostic yield of this invaluable test.

      This review contains 1 highly rendered figure, 5 tables, and 53 references.

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    • 25

      Hematologic Abnormalities in Chronic Kidney Disease

      By Khalid Al Talib, MD; Michael Auerbach, MD, FACP; John Anderson, MD
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      Hematologic Abnormalities in Chronic Kidney Disease

      • KHALID AL TALIB, MDMedStar Franklin Square Medical Center, Clinical Assistant Professor of Medicine, University of Maryland School of Medicine, Baltimore, MD.
      • MICHAEL AUERBACH, MD, FACPClinical Professor of Medicine, Georgetown University School of Medicine, Washington, DC
      • JOHN ANDERSON, MDAssistant Professor of Medicine, retired, Johns Hopkins School of Medicine, Baltimore, MD.

      The focus of this review is on information practical to the practicing nephrologist and internists managing patients with chronic kidney disease (CKD), with an emphasis on the quantitative aspects of risk, diagnosis, treatment, and prognosis. Consequently, anemia associated with non–dialysis-associated CKD is emphasized, with special attention to the role of erythropoiesis-stimulating agents and intravenous (IV) iron in treating the anemia of CKD, as well as sections on uremic bleeding and anticoagulation in CKD patients. Figures show a patient before and after a minor infusion reaction, an algorithm outlining grading and management of acute hypersensitivity reactions to IV iron infusions, and an algorithm for the management of uremic platelet dysfunction. Tables list Food and Drug Administration-recommended dose adjustments for novel oral anticoagulant (NOACs) in CKD patients, evidence for preprocedural withholding of NOACs, and management guidelines for anticoagulation in nonvalvular atrial fibrillation and venous thromboembolism.

      This review contains 2 highly rendered figures, 3 tables, and 101 references.

      Key words: Chronic kidney disease; CKD; Anemia of chronic kidney disease; Anemia of CKD; Uremic bleeding; Anticoagulation in CKD; Novel oral anticoagulants in CKD; NOAC CKD

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    • 26

      Respiratory Acidosis and Alkalosis

      By Horacio J Adrogué, MD; Nicolaos E Madias, MD
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      Respiratory Acidosis and Alkalosis

      • HORACIO J ADROGUÉ, MD
      • NICOLAOS E MADIAS, MD

      Respiratory acid-base disorders are those disturbances in acid-base equilibrium that are expressed by a primary change in CO2 tension (Pco2) and reflect primary changes in the body’s CO2 stores (i.e., carbonic acid). A primary increase in Pco2 (and a primary increase in the body’s CO2 stores) defines respiratory acidosis or primary hypercapnia and is characterized by acidification of the body fluids. By contrast, a primary decrease in Pco2 (and a primary decrease in the body’s CO2 stores) defines respiratory alkalosis or primary hypocapnia and is characterized by alkalinization of the body fluids. Primary changes in Pco2 elicit secondary physiologic changes in plasma [HCO3ˉ] that are directional and proportional to the primary changes and tend to minimize the impact on acidity. This review presents the pathophysiology, secondary physiologic response, causes, clinical manifestations, diagnosis, and therapeutic principles of respiratory acidosis and respiratory alkalosis. 

      This review contains 4 figures, 3 tables, and 59 references.

      Key words: Respiratory acidosis, respiratory alkalosis, primary hypercapnia, primary hypocapnia, hypoxemia, pseudorespiratory alkalosis

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    • 27

      Acute Graft Dysfunction

      By Oluwafisayo Adebiyi, MD; Alexander C. Wiseman, MD; James E. Cooper, MD
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      Acute Graft Dysfunction

      • OLUWAFISAYO ADEBIYI, MDTransplant Nephrology Fellow, Division of Renal Disease and Hypertension, Transplant Center, University of Colorado, Denver, CO
      • ALEXANDER C. WISEMAN, MDProfessor of Medicine, Division of Renal Disease and Hypertension, Transplant Center, University of Colorado, Denver, CO
      • JAMES E. COOPER, MDAssistant Professor of Medicine, Division of Renal Disease and Hypertension, Transplant Center, University of Colorado, Denver, CO

      Acute renal allograft dysfunction represents a spectrum of abnormalities that may be seen from the time of transplant surgery to eventual organ failure. Although renal allografts are often plagued by similar conditions as seen in native kidneys, they are also at risk for unique abnormalities specific to the transplant setting, such as delayed graft function (DGF), acute and chronic graft rejection, post-transplantation infections, and perinephric fluid collections.

      This review contains 5 figures, 10 tables, and 94 references.

      Keywords: Acute renal allograft dysfunction, delayed graft function, acute graft rejection, chronic graft rejection, perinephric fluid collections, post-transplantation infections

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  • Neurology
    • Neurologic Symptoms
      • 1

        Dizziness

        By Kevin A. Kerber, MD, MS; Robert W. Baloh, MD
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        Dizziness

        • KEVIN A. KERBER, MD, MSAssistant Professor, Department of Neurology, University of Michigan, Ann Arbor, MI
        • ROBERT W. BALOH, MDProfessor, Departments of Neurology and Surgery (Head and Neck), UCLA Medical Center, Reed Neurological Research Center, Los Angeles, CA

        Dizziness is the quintessential symptom presentation in all of clinical medicine. It is a common reason that patients present to a physician. This chapter provides background information about the vestibular system, then reviews key aspects of history-taking and examination of the patient, then discusses specific disorders and common presentation types. Throughout the chapter the focus is on neurologic and vestibular disorders. Normal vestibular anatomy and physiology are discussed, followed by recommendations for history-taking and the physical examination. Specific disorders that cause dizziness are explored, along with common causes of non-specific dizziness. Common presentations are discussed, including acute severe dizziness, recurrent attacks, and recurrent positional vertigo. Finally, the chapter looks at laboratory investigations in diagnosis and management. Figures include population prevalence of dizziness symptoms, the anatomy of inner structures, primary afferent vestibular nerve activity, the head thrust test, the Dix-Hallpike maneuver, the supine positional test, the canalith repositioning procedure, and the barbecue roll maneuver. Tables list physiologic properties and clinical features of the components of the peripheral vestibular system, information to be acquired from history of the present illness, common symptoms patients report as dizziness, examination components, distinguishing among common peripheral and central vertigo syndromes, common causes of nonspecific dizziness, types of dizziness presentations, relevant imaging abnormalities on neuroimaging studies, vestibular testing components, and medical therapy for symptomatic dizziness.

        This review contains 8 highly rendered figures, 11 tables, and 69 references.

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      • 2

        Headache and Facial Pain

        By Elizabeth W. Loder, MD, MPH
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        Headache and Facial Pain

        • ELIZABETH W. LODER, MD, MPHAssociate Professor of Neurology, Harvard Medical School, Chief, Division of Headache and Pain, Department of Neurology, Brigham and Women’s Hospital, Boston, MA

        Headaches are a near-universal experience, with a 1-year prevalence of 90% and a lifetime prevalence of 99%. Headaches and pain to the head account for roughly 3% of visits to US emergency departments annually, making them the fourth most common reason for seeking emergency care. There are numerous types of headaches, and although the majority are benign, types exist that may result from serious and potentially life-threatening causes. As such, it is important for the physician to consider a broad differential diagnosis for every headache patient. This review discusses the classification of headaches, identifies pain-sensitive structures in the head, discusses the history and examination in patients with headache, and describes many of the primary and secondary headaches. Figures show the areas of the brain sensitive to pain; 1-year prevalence of migraine in men, women, and children; frequency of attacks in migraineurs; prevalence of headaches by age group and in patients with cerebrovascular disorders; and symptoms of idiopathic intracranial hypertension. Tables list the major categories of headache disorders, key elements of the headache history, helpful questions to ask, features of selected primary and secondary headaches, reasons to consider neuroimaging, efficacy of selected over-the-counter medications, triptans available in the United States, medication options for urgent or emergency treatment of migraine, selected preventive medications for migraine, generally accepted indications for preventive treatment, general principles for the use of preventive medications, titration schedules for preventive medication, interval or short-term preventive treatment of menstrual migraine, strategies for managing increase in migraines in patients starting estrogen replacement therapy, transition medications for rapid, temporary suppression of headaches, medications possibly effective for cluster and hypnic headaches, differential diagnosis of the acute, severe, new-onset headache, and etiologies of papilledema and headache.

        This review contains 6 highly rendered figures, 20 tables, and 112 references.

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      • 3

        Pain Syndromes Other Than Headache

        By Edgar L. Ross, MD
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        Pain Syndromes Other Than Headache

        • EDGAR L. ROSS, MD

        Chronic pain is very common in the United States. Although effective treatments are available, pain remains poorly managed in many patients. This review covers how to assess a patient with pain; the management of acute and chronic pain; and peripheral neuropathy, complex regional pain syndrome (CRPS), fibromyalgia, myofascial pain, back and spine pain, and cancer pain. Figures show how pain transducers (nociceptors) monitor and influence tissue conditions, sensory processing in the spinal cord dorsal horn, and classification of chronic pain syndromes. Tables list the International Association for the Study of Pain’s definitions for the management of pain; differences between acute and chronic pain; physiologic mechanisms sustaining pain; pain descriptors and types of pain; distinguishing hyperalgesia and allodynia; patient classifications and group characteristics; treatments and medication classes used for acute pain as well as chronic pain; two categories of chronic pain, differences between nociceptive and neuropathic pain; behavioral and rehabilitative therapies used for chronic pain; the Budapest diagnostic criteria for CRPS; diagnostic approaches to CRPS; signs and symptoms of fibromyalgia; conditions that can mimic myofascial pain; clinical presentation of myofascial pain; differences between myofascial pain and fibromyalgia; trigger-point examination; myofascial pain treatment; diagnostic categories of spinal pain; spinal pain red flags; the Waddell criteria; and cancer pain syndromes, characteristics, treatment options, and side-effect management options.

        This review contains 3 highly rendered figures, 31 tables, and 82 references.

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      • 4

        Sleep Disorders

        By Sudhansu Chokroverty, MD, FRCP, FACP
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        Sleep Disorders

        • SUDHANSU CHOKROVERTY, MD, FRCP, FACPProfessor and Director of Sleep Research, Medical Director of Devry Technology Training Program, Co-Chair Emeritus of Neurology, Department of Neurology, JFK Neuroscience Institute, Edison, NJ, Professor of Neuroscience, Seton Hall University, South Orange, NJ, Clinical Professor of Neurology, Robert Wood Johnson Medical School, New Brunswick, NJ

        Recent research has generated an enormous fund of knowledge about the neurobiology of sleep and wakefulness. Sleeping and waking brain circuits can now be studied by sophisticated neuroimaging techniques that map different areas of the brain during different sleep states and stages. Although the exact biologic functions of sleep are not known, sleep is essential, and sleep deprivation leads to impaired attention and decreased performance. Sleep is also believed to have restorative, conservative, adaptive, thermoregulatory, and consolidative functions. This review discusses the physiology of sleep, including its two independent states, rapid eye movement (REM) and non–rapid eye movement (NREM) sleep, as well as functional neuroanatomy, physiologic changes during sleep, and circadian rhythms. The classification and diagnosis of sleep disorders are discussed generally. The diagnosis and treatment of the following disorders are described: obstructive sleep apnea syndrome, narcolepsy-cataplexy sydrome, idiopathic hypersomnia, restless legs syndrome (RLS) and periodic limb movements in sleep, circadian rhythm sleep disorders, insomnias, nocturnal frontal lobe epilepsy, and parasomnias. Sleep-related movement disorders and the relationship between sleep and psychiatric disorders are also discussed. Tables describe behavioral and physiologic characteristics of states of awareness, the international classification of sleep disorders, common sleep complaints, comorbid insomnia disorders, causes of excessive daytime somnolence, laboratory tests to assess sleep disorders, essential diagnostic criteria for RLS and Willis-Ekbom disease, and drug therapy for insomnia. Figures include polysomnographic recording showing wakefulness in an adult; stage 1, 2, and 3 NREM sleep in an adult; REM sleep in an adult; a patient with sleep apnea syndrome; a patient with Cheyne-Stokes breathing; a patient with RLS; and a patient with dream-enacting behavior; schematic sagittal section of the brainstem of the cat; schematic diagram of the McCarley-Hobson model of REM sleep mechanism; the Lu-Saper “flip-flop” model; the Luppi model to explain REM sleep mechanism; and a wrist actigraph from a man with bipolar disorder.

        This review contains 14 highly rendered figures, 8 tables, 115 references, and 5 MCQs.

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      • 5

        Migraine Epidemiology, Impact, and Pathogenesis

        By Amy A Gelfand, MD; Dawn C Buse, PhD
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        Migraine Epidemiology, Impact, and Pathogenesis

        • AMY A GELFAND, MDDirector, Pediatric Headache, Division of Child Neurology, Department of Neurology, UCSF Benioff Children’s Hospital, San Francisco, CA
        • DAWN C BUSE, PHDAssociate Professor, Department of Neurology, Albert Einstein College of Medicine of Yeshiva University, Assistant Professor, Clinical Health Psychology Doctoral Program, Ferkauf Graduate School of Psychology of Yeshiva University, Director of Behavioral Medicine, Montefiore Headache Center Bronx, NY

        Migraine is a common and often disabling neurologic disorder. No longer thought of as neurovascular in etiology, migraine is now known to be a complex disorder of the brain with strong genetic underpinnings. The impact of migraine may extend beyond the affected individual to also impact partners and children. Although many patients search to identify “triggers” of migraine, teasing out such relationships can be remarkably complex. The premonitory phase of a migraine attacks can include symptoms such as food cravings, photophobia, and increased yawning—symptoms that could, for example, lead a person to mistakenly conclude that the migraine attacks are “triggered” by eating chocolate, bright lights, or being tired. We review current evidence on the epidemiology, impact, and pathophysiology of migraine. 

        Key words: epidemiology, impact, migraine, pathophysiology

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      • 6

        Nerve Blocks and Neurostimulation in the Treatment of Migraine

        By Matthew S Robbins, MD
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        Nerve Blocks and Neurostimulation in the Treatment of Migraine

        • MATTHEW S ROBBINS, MDAssociate Professor of Clinical Neurology, Albert Einstein College of Medicine, Chief of Neurology, Jack D. Weiler Hospital, Montefiore Medical Center, Director of Inpatient Services, Montefiore Headache Center, Associate Program Director, Neurology Residency, Bronx, NY

        Peripheral nerve and sphenopalatine ganglion blocks are a safe, effective treatment option for headache disorders, although, despite a wealth of anecdotal experience, the evidence is conflicting for efficacy in chronic migraine prophylaxis. Neurostimulation has emerged as an effective treatment modality for migraine with both noninvasive and minimally invasive options available. Such options include transcutaneous supraorbital nerve stimulation for prophylaxis and single-pulse transcranial magnetic stimulation for the acute treatment of migraine with aura. Although occipital nerve stimulation may be effective for some patients with intractable chronic migraine, the evidence is mixed and procedure-related complications are common. Emerging treatment modalities for acute and preventive treatment of migraine include noninvasive vagus nerve stimulation and implanted sphenopalatine ganglion stimulation.

        This review contains 5 highly rendered figures, 2 tables, and 106 references.

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      • 7

        Migraine: Behavioral Treatment

        By Elizabeth K Seng, PhD
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        Migraine: Behavioral Treatment

        • ELIZABETH K SENG, PHDAssistant Professor, Ferkauf Graduate School of Psychology, Yeshiva University, New York, NY

        Behavior change is an essential component of any migraine management plan. Behavioral migraine treatments are interventions designed to change a patient’s behavior with the result of a reduction in migraine symptoms and migraine-related disability. Behavioral treatments commonly target medication adherence, behavioral and psychosocial factors known to precipitate migraine (including stress, sleep, and skipping meals), maladaptive cognitive patterns, and comorbid psychiatric symptoms (most commonly depression and anxiety). Guidelines and evidence from randomized clinical trials indicate that biofeedback, relaxation treatments, and cognitive-behavioral therapy are effective preventive migraine treatments. Patient education and self-monitoring are foundational components to any behavioral intervention for migraine. Portable personal technology is increasingly becoming an essential part of migraine patient care and provides another avenue for supporting adherence to medication and behavioral migraine management.  

        This review contains 6 highly rendered figures, 4 tables, and 50 references.

        Key words: anxiety; behavior; biofeedback; cognitive-behavioral therapy; depression; migraine; psychology; relaxation; sleep; stress

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      • 8

        Difficult to Treat (refractory) Chronic Migraine: Outpatient Approaches

        By Lawrence Robbins, MD, (retired)
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        Difficult to Treat (refractory) Chronic Migraine: Outpatient Approaches

        • LAWRENCE ROBBINS, MD, (RETIRED) Assistant Professor of Neurology, Dept. of Neurology, University of Illinois; (retired) Assistant Professor of Neurology, Dept. of Neurology, Rush Medical College, Chicago, Il

        This comprehensive review addresses the many challenges in treating refractory migraine. Issues relating to pathophysiology are covered. A unique “refractory scale for migraine patients” is introduced. The definition and role of medication overuse headache are presented with a much different perspective than is usually found. Issues outside of medication that are covered include active coping, acceptance, resilience, and catastrophizing. A number of outpatient treatments are thoroughly discussed. These include the role of onabotulinum toxin, the application of polypharmacy, when to employ sphenopalatine ganglion  blocks, the role of occipital and trigger-point injections, the implementation of long-acting opioids, the advantages of stimulants, and the possible use of monoamine oxidase inhibitors. Miscellaneous approaches include muscle relaxants, nasal or intravenous ketamine, transcranial magnetic stimulation, memantine, and ergonovine. Finally, many cutting-edge “refractory clinical pearls” are listed. 

        This review contains 8 highly rendered figures, 4 tables, and 25 references.

        Key Words: Headache, migraine, chronic, refractory, medication overuse, alternative, treatments

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      • 9

        Migraine: Psychiatric Comorbidities

        By Todd A Smitherman, PhD; Anna Katherine Black, MA; A Brooke Walters Pellegrino, PhD
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        Migraine: Psychiatric Comorbidities

        • TODD A SMITHERMAN, PHDAssociate Professor of Psychology, Department of Psychology, University of Mississippi, Oxford, MS
        • ANNA KATHERINE BLACK, MAGraduate Student, Clinical Psychology, Department of Psychology, University of Mississippi, Oxford, MS
        • A BROOKE WALTERS PELLEGRINO, PHDDirector of Behavioral Medicine, Hartford Healthcare Headache Center, West Hartford, CT

        Psychiatric disorders often co-occur with migraine, and these comorbid conditions compound disability and are risk factors for medication overuse and migraine progression. For these reasons, attention to psychiatric comorbidities in clinical practice is of paramount importance. Assessment of depression, anxiety, and sleep disorders is recommended, focusing on the core cognitive and emotional symptoms of the comorbidities and using measures validated among medical patients. Pharmacologic treatment of migraine and comorbid psychiatric conditions is challenging owing to a lack of agents with proven efficacy for both conditions, side effect profiles that may exacerbate one condition, and potential drug interactions. Existing data suggest that migraineurs with psychiatric symptomatology can obtain positive outcomes with appropriate preventive medications, behavioral interventions for headache or the comorbid condition, or a combination thereof.

        Keywords: anxiety, comorbidity, depression, insomnia, migraine, pharmacotherapy, relaxation, stress management

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    • Categories of Neurologic Diseases
      • Cognitive and Behavioral Neurology
        • 1

          Clinical Aspects of Alzheimer Disease

          By David Knopman, MD
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          Clinical Aspects of Alzheimer Disease

          • DAVID KNOPMAN, MDProfessor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN

          The clinical diagnosis of Alzheimer disease (AD) has been well established, but there is a widespread misunderstanding about the relationship between dementia (a syndrome) and AD (a cause of dementia). AD is the most common etiology that causes dementia in mid- and late life. The prototypical clinical presentation is that of a gradually worsening problem with learning new information, that is, a short-term memory deficit, accompanied by cognitive impairment in other domains, including language, spatial cognition, and executive functioning, as well as changes in personality and behavior. A key element of the diagnosis of dementia is that daily functioning is impaired. The concept of mild cognitive impairment (MCI) as the earliest symptomatic presentation of a dementing illness is now widely accepted. MCI due to AD typically presents with isolated problems with learning and memory without substantial loss of ability to function in daily life.  Less common variants of AD are now recognized and include a disorder in which spatial and visual cognitive dysfunction occurs or in which word-finding problems predominate at the onset of symptoms. Although AD as a cause of dementia is the most common among etiologies, AD often co-occurs with other neurodegenerative diseases and with cerebrovascular disease. The presence of multietiology dementia in which AD is a contributor is particularly common in the eighth decade of life and beyond. 

          Key words: Alzheimer disease, cognitive impairment, dementia, mild cognitive impairment

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        • 2

          Pathophysiology of Alzheimer Disease

          By David Knopman, MD
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          Pathophysiology of Alzheimer Disease

          • DAVID KNOPMAN, MDProfessor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN

          Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. 

          Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein 

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        • 3

          Clinical Aspects of Non-alzheimer Disease Dementias

          By David Knopman, MD
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          Clinical Aspects of Non-alzheimer Disease Dementias

          • DAVID KNOPMAN, MDProfessor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN

          There are a relatively small number of disorders that account for the majority of dementia in the elderly that is not Alzheimer disease (AD): cerebrovascular disease, Lewy body disease (α-synucleinopathies), and the frontotemporal lobar degenerations. Cerebrovascular disease and Lewy body disease account for most non-AD dementia among persons in the eighth decade of life and beyond. These two frequently co-occur with AD but can occur in their pure forms rarely (in the case of dementia associated with cerebrovascular disease) or more commonly (in the case of Lewy body disease). There is no one cognitive or behavioral syndrome associated with cerebrovascular disease; however, attempts to isolate a common theme suggest that cognitive slowing is typical of cerebrovascular contributions to cognitive impairment. Cerebrovascular pathology relevant to cognitive impairment accumulates subclinically more commonly than it causes acute, strokelike declines in cognition. Dementia with Lewy bodies is a multidimensional disorder that includes a nonamnestic dementia, Parkinson disease or at least some parkinsonian features, a disorder of sleep and wakefulness, autonomic disturbances, and depression. The disorders of sleep prominently include rapid eye movement sleep behavior disorder, excessive daytime sleepiness, visual hallucinations, and marked fluctuations in level of alertness. The frontotemporal lobar degenerations are nearly as common as causes of dementia in persons under age 65 as is AD. The group of disorders includes two cognitive syndromes (primary progressive aphasia and behavior variant frontotemporal dementia) and two neuropathologic subtypes (tauopathy and TDP43 proteinopathy) and is associated with three major autosomal dominant genetic mutations (in MAPT, GRN,and C9ORF72).

          Key words: dementia with Lewy bodies, frontotemporal lobar degenerations, vascular cognitive impairment

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        • 4

          Management and Therapeutic Issues in the Dementias

          By David Knopman, MD
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          Management and Therapeutic Issues in the Dementias

          • DAVID KNOPMAN, MDProfessor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN

          As of 2016, treatment of Alzheimer disease (AD) dementia and the principal non-AD dementias is entirely palliative. Although there are several drugs approved for the treatment of mild to moderate AD dementia, these drugs—the cholinesterase inhibitors and memantine—have rather modest benefits. In general, nonpharmacologic approaches to the management of patients with dementia emphasize support for the caregiver, attention to safety, and providing a supportive and socially enriched environment for the patient. Depression is common in dementias of diverse etiology; lower doses of later-generation antidepressants are effective in controlling depressive symptoms in patients with dementia. Agitation is not a ubiquitous occurrence in patients with dementia, but physically aggressive behavior, hallucinations, and delusions affect a sizable fraction of patients with dementia. There is much controversy regarding the appropriate medication classes to use in cases of agitation, but the antipsychotic agent quetiapine is often effective and unique among its class in not causing parkinsonism or tardive dyskinesia.

          Key words: antidepressants, antipsychotic agents, caregiver support, cholinesterase inhibitors

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        • 5

          Cognitive Disorders Other Than Alzheimer Disease

          By Seth A Gale, MD; Kirk R. Daffner, MD, FAAN
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          Cognitive Disorders Other Than Alzheimer Disease

          • SETH A GALE, MDAssociate Neurologist, Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, and Instructor of Neurology, Harvard Medical School, Boston, MA
          • KIRK R. DAFFNER, MD, FAANChief, Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, J. David and Virginia Wimberly Professor of Neurology, Harvard Medical School, Boston, MA

          Higher cognitive functions, such as abstract reasoning, complex decision making, and language, are the mental faculties that separate our species from other animals. When these faculties become impaired as a result of neurologic disease, striking and devastating behavioral changes result. Many neurologic diseases are associated with impaired cognition and behavior, and their etiologies are as varied as their clinical presentations. In this review, the focus is on dementia with Lewy bodies (DLB), the frontotemporal dementias (FTDs), and vascular cognitive impairment (VCI). The review covers the epidemiology and diagnosis of  DBB, FTDs, and VCIs, as well as the etiology and genetics. Figures show neuroimaging in DLB, management of DLB, FTLD clinical syndromes, FTLD clinicopathologic correlations: approximate distribution of pathotypes for behavioral-variant FTD and primary progressive aphasia (PPA) variants, PPA-semantic subtype, PPA-logopenic subtype, post-stroke VCI, and subcortical ischemic vascular disease subtype of VCI. Tables list diagnostic criteria for DLB; FTD genetics: gene/protein relationship, clinical syndrome, salient gestures; VCI: clinical and pathologic features of the main subtypes; summary guidance based on VCI prevention studies; and summary guidance based on VCI treatment studies.

          This review contains 8 highly rendered figures, 5 tables, and 254 references.

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        • 6

          Stroke and Other Cerebrovascular Diseases

          By Scott E. Kasner, MD, MSCE, FAHA, FAAN; Christina A Wilson, MD, PhD
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          Stroke and Other Cerebrovascular Diseases

          • SCOTT E. KASNER, MD, MSCE, FAHA, FAANProfessor, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Director, Comprehensive Stroke Center, University of Pennsylvania Health System, Philadelphia, PA
          • CHRISTINA A WILSON, MD, PHDAssistant Professor, Department of Neurology, University of Florida, Gainesville, FL

          Stroke is a leading cause of neurologic morbidity and mortality, and rapid treatment is key for a good outcome. This review addresses the epidemiology, common presenting symptoms, causes, and treatment of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Current recommendations for the emergent evaluation and treatment of an acute ischemic stroke are highlighted, including recently updated indications and contraindications for intravenous recombinant tissue plasminogen activator administration and recent guidelines for the expanded role of endovascular mechanical embolectomy for stroke due to acute large vessel occlusion. An algorithm of diagnostic evaluations to assist with identification of the cause of ischemic stroke is offered. Evidence-based primary and secondary stroke prevention is discussed, including the ideal choice of antithrombotic based on identified stroke mechanism and optimal risk factor management. Best practice supportive measures for the post-stroke patient are highlighted, including recent guidelines for the management of elevated intracranial pressure. Management of uncommon causes of ischemic stroke is also addressed. 

          Key Words: Intracerebral hemorrhage, ischemic stroke, recombinant tissue plasminogen activator, subarachnoid hemorrhage

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        • 7

          Subarachnoid Hemorrhage

          By Imoigele P Aisiku, MD, MBA
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          Subarachnoid Hemorrhage

          • IMOIGELE P AISIKU, MD, MBAAssistant Professor, Chief Division of Emergency Critical Care, Department of Emergency Medicine, Harvard University, Brigham and Women’s Hospital

          Subarachnoid hemorrhage (SAH) represents a small portion of cerebrovascular disease but a disproportionally large percentage of the morbidity and mortality. The overall prognosis depends on the volume of the initial bleeding, rebleeding, and the degree of delayed cerebral ischemia. The presence of cardiac manifestations and neurogenic pulmonary edema at the initial presentation indicates a higher degree of severity and systemic complications. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of SAH. Figures show common saccular aneurysm locations, a noncontrast head computed tomographic scan of an SAH, an angiogram and surgical clipping of a broad-based anterior communicating aneurysm, and a three-dimensional reconstruction angiogram of a complex anterior communicating aneurysm with additional imaging of endoscopic stent-assisted coiling of the same aneurysm. Tables list the natural history of unruptured aneurysms and the annual risk of rupture, common clinical features and syndromes related to aneurysm location, the World Federation of Neurologic Surgeons grading system, the Hunt and Hess grading systems, and the Fisher scale.

          This review contains 4 highly rendered figures, 5 tables, and 144 references.

          Key words: aneurysm rupture, cerebral aneurysm, cerebral vasospasm, Fisher scale, Glasgow Coma Scale assessment, Hunt and Hess grading criteria, subarachnoid hemorrhage, World Federation of Neurologic Surgeons grading scale 


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        • 8

          Multiple Sclerosis and Related Disorders

          By J William Lindsey, MD
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          Multiple Sclerosis and Related Disorders

          • J WILLIAM LINDSEY, MDProfessor, Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX

          Multiple sclerosis (MS) is a relatively common cause of neurologic symptoms and disability in young adults. The distinguishing pathologic features of MS are loss of myelin and inflammation in the central nervous system (CNS). The myelin sheath is essential for rapid conduction of nerve signals along large-diameter axons. Oligodendrocytes produce and maintain myelin in the CNS, and Schwann cells produce and maintain myelin in the peripheral nerves. In addition to MS, there are a number of related disorders causing demyelination, inflammation, or both in the CNS. This chapter discusses MS and related disorders, including neuromyelitis optica, optic neuritis, acute disseminated encephalomyelitis, transverse myelitis, Behçet syndrome, neurosarcoidosis, inherited demyelinating diseases (leukodystrophies, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), and virus-induced demyelination (progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis). The section on MS covers epidemiology, etiology/genetics, pathogenesis, diagnosis, differential diagnosis, management, and prognosis. Figures include organization of the microenvironment of larger-diameter axons, typical magnetic resonance imaging findings in MS and neuromyelitis optica, postgadolinium images of the cervical spine in MS, and an approach to treatment of relapsing-remitting MS. Tables list MS and related disorders, distribution of neurologic deficits at the onset of MS, differential diagnosis of MS, disease-modifying therapies for relapsing-remitting MS, and selected leukodystrophies, as well as diagnostic criteria and selected symptomatic therapies for MS.

          This review contains 3 highly rendered figures, 7 tables, and 82 references.

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        • 9

          Traumatic Brain and Spinal Cord Injuries

          By Mohit Datta, MD; Geoffrey S.F. Ling, MD, PhD, FAAN
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          Traumatic Brain and Spinal Cord Injuries

          • MOHIT DATTA, MD
          • GEOFFREY S.F. LING, MD, PHD, FAANUniformed Services University of the Health Sciences, Bethesda, MD

          Traumatic brain and spinal cord injuries are significant causes of permanent disability and death. In 2010, 823,000 traumatic brain injuries were reported in the United States alone; in fact, the actual number is likely considerably higher because mild traumatic brain injuries and concussions are underreported. The number of new traumatic spinal cord injuries has been estimated at 12,000 annually. Survival from these injuries has increased due to improvements in medical care. This review covers mild traumatic brain injury and concussion, moderate to severe traumatic brain injury, and traumatic spinal cord injury. Figures include computed tomography scans showing a frontal contusion, diffuse cerebral edema and intracranial air from a gunshot wound, a subdural hematoma, an epidural hematoma, a skull fracture with epidural hematoma, and a spinal fracture from a gunshot wound. Tables list requirements for players with concussion, key guidelines for prehospital management of moderate to severe traumatic brain injury, key guidelines for management of moderate to severe traumatic brain injury, brain herniation brain code, key clinical practice guidelines for managing cervical spine and spinal cord injury, and the American Spinal Injury Association’s neurologic classification of spinal cord injury.

          This review contains 6 highly rendered figures, 6 tables, and 61 references.

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        • 10

          Epilepsy and Related Disorders

          By Barbara Dworetzky, MD; Jong Woo Lee, MD, PhD
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          Epilepsy and Related Disorders

          • BARBARA DWORETZKY, MDAssociate Professor of Neurology, Harvard Medical School, Chief, Division of Epilepsy, EEG, and Sleep Neurology, Director, The Edward B. Bromfield Epilepsy Program, Brigham and Women’s Hospital, Boston, MA
          • JONG WOO LEE, MD, PHDAssistant Professor of Neurology, Harvard Medical School, Director, ICU EEG Monitoring, The Edward B. Bromfield Epilepsy Program, Brigham and Women’s Hospital, Boston, MA

          Epilepsy is a chronic disorder of the brain characterized by recurrent unprovoked seizures. A seizure is a sudden change in behavior that is accompanied by electrical discharges in the brain. Many patients presenting with a first-ever seizure are surprised to find that it is a very common event. A reversible or avoidable seizure precipitant, such as alcohol, argues against underlying epilepsy and therefore against treatment with medication. This chapter discusses the epidemiology, etiology, and classification of epilepsy and provides detailed descriptions of neonatal syndromes, syndromes of infancy and early childhood, and syndromes of late childhood and adolescence. The pathophysiology, diagnosis, and differential diagnosis are described, as are syncope, migraine, and psychogenic nonepileptic seizures. Two case histories are provided, as are sections on treatment (polytherapy, brand-name versus generic drugs, surgery, stimulation therapy, dietary treatments), complications of epilepsy and related disorders, prognosis, and quality measures. Special topics discussed are women?s issues and the elderly. Figures illustrate a left midtemporal epileptic discharge, wave activity during drowsiness, cortical dysplasias, convulsive syncope, rhythmic theta activity, right hippocamal sclerosis, and right temporal hypometabolism. Tables describe international classifications of epileptic seizures and of epilepsies, epilepsy syndromes and related seizure disorders, differential diagnosis of seizure, differentiating epileptic versus nonepileptic seizures, antiepileptic drugs, status epilepticus protocol for treatment, when to consider referral to a specialist, and quality measures in epilepsy. This chapter contains 111 references.

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      • Neuromuscular Diseases
        • 1

          Motor Neuron Diseases

          By Merit E. Cudkowicz, MD, MSc; James D Berry, MD, MPH; Elena Ratti, MD
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          Motor Neuron Diseases

          • MERIT E. CUDKOWICZ, MD, MSCChief of Neurology, Massachusetts General Hospital, Julieanne Dorn Professor of Neurology Harvard Medical School, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA
          • JAMES D BERRY, MD, MPHAssistant Professor of Neurology, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA
          • ELENA RATTI, MDClinical Research Fellow, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA

          The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This chapter contains 252 references. 

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        • 2

          Radiculopathies and Neuropathies

          By William S David, MD, PhD; Kathy Chuang, MD
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          Radiculopathies and Neuropathies

          • WILLIAM S DAVID, MD, PHDAssociate Professor of Neurology, Harvard Medical School, Director of the EMG Laboratory and Neuromuscular Diagnostic Center, Massachusetts General Hospital, 165 Cambridge Street, Suite 820, Boston, MA 02114
          • KATHY CHUANG, MDClinical Fellow in Neuromuscular Medicine, Massachusetts General Hospital and Brigham and Women’s Hospital, 165 Cambridge Street, Suite 820, Boston, MA 02114

          “Radiculopathies” are disorders of nerve roots, whereas “neuropathies” are disorders of the peripheral nerve. These disorders may involve single roots or nerves, multiple roots or nerves, and even other aspects of the nervous system. This chapter reviews the anatomy and pathophysiology of the peripheral nervous system; the general approach to radiculopathies and neuropathies, including clinical manifestations and localization, diagnostic studies, and treatment; radiculopathies, including anatomy, cervical radiculopathy, lumbosacral radiculopathy, thoracic radiculopathy, and cauda equina syndrome; and neuropathies, including  mononeuropathies and polyneuropathies. Tables describe the innervation of select nerve roots and peripheral nerves, differences between root and nerve lesions, commonly used neuropathic pain medications, distinctive patterns of neuropathy with limited differential diagnoses, differential diagnosis of demyelinating polyneuropathy, drugs that may cause polyneuropathy, and neuropathies associated with diabetes mellitus. Figures show the anatomy of a spinal segment, nerve fascicles, ultrasound images of the median nerve, magnetic resonance imaging of the lumbosacral spine, the Spurling maneuver, and physical examination maneuvers for lumbosacral radiculopathies.

          This review contains 6 highly rendered figures, 8 tables, and 77 references.

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        • 3

          Neuromuscular Junction Disorders

          By Anthony A Amato, MD; Mohammad Kian Salajegheh, MD
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          Neuromuscular Junction Disorders

          • ANTHONY A AMATO, MDChief, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Professor of Neurology, Harvard Medical School, Boston, MA
          • MOHAMMAD KIAN SALAJEGHEH, MDDirector, Peripheral Nerve Clinic, Associate Neurologist, Department of Neurology, Brigham and Women’s Hospital, Assistant Professor of Neurology, Harvard Medical School, Boston, MA

          The three main components of the neuromuscular junction (NMJ) include the presynaptic region, the synaptic cleft, and the postsynaptic region. The NMJ acts as an interface between the motor nerve and muscle by converting the motor nerve electric currents into chemical signals and then back into electric currents in the muscle. This chapter reviews electrodiagnostic testing in NMJ disorders, including repetitive nerve stimulation and single-fiber electromyography. Myasthenia gravis, congenital myasthenic syndromes, Lambert-Eaton myasthenic syndrome, botulism, and organophosphate poisoning and other toxins are discussed, including epidemiology, etiology/genetics, pathogenesis, diagnosis, differential diagnosis, management, complications, and prognosis. Tables include an overview of neuromuscular disorders, drugs with adverse effects on the NMJ, common immunomodulatory agents used for treatment of myasthenia gravis, congenital myasthenic syndromes, and toxins and venoms. Figures illustrate the NMJ structure and function, structure of the presynaptic and postsynaptic regions, electrodiagnostic studies in NMJ disorders, and dysfunction of the NMJ in acetylcholine receptor myasthenia gravis.

          This review contains 5 highly rendered figures, 5 tables, and 65 references.

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        • 4

          Myopathies

          By Anthony A Amato, MD; Thomas I. Cochrane, MD, MBA
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          Myopathies

          • ANTHONY A AMATO, MDChief, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Professor of Neurology, Harvard Medical School, Boston, MA
          • THOMAS I. COCHRANE, MD, MBAAssociate Neurologist, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Assistant Professor of Neurology, Harvard Medical School, Boston, MA

          Muscle disease (myopathy) can be acquired or hereditary. Symptoms include skeletal muscle weakness, atrophy, muscle cramps or myalgias, and impaired function of respiratory, pharyngeal, facial, or ocular muscles. Clinicians must identify treatable myopathies and initiate therapy before permanent weakness occurs. For patients with untreatable disorders, proper supportive care, rehabilitation, genetic counseling, and psychological support are critical. This chapter covers common myopathies, including muscular dystrophies; malignant hyperthermia; metabolic myopathies; mitochondrial myopathies and encephalopathies; ion channelopathies, periodic paralyses, and nondystrophic myotonias; and drug-induced myopathies. Clinical presentation, diagnosis, pathogenesis, and therapy are emphasized. Tables describe genetic classification of the limb-girdle and distal muscular dystrophies; proteins involved in myofibrillar myopathy; other distal myopathies; and antirheumatic, antiinflammatory, and immunosuppressive drug-induced myopathy. Figures show the sarcolemmal membrane and enzymatic proteins associated with muscular dystrophies, sarcomeric and nuclear proteins associated with muscular dystrophies, and major metabolic pathways used by muscle.

          This review contains 3 highly rendered figures, 4 tables, and 107 references.

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      • Movement Disorders
        • 1

          Parkinsonism and Related Disorders

          By Anthony E. Lang, MD; Elizabeth J. Slow, MD, PhD
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          Parkinsonism and Related Disorders

          • ANTHONY E. LANG, MDProfessor, Morton and Gloria Shulman Movement Disorders Clinic and The Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University of Toronto, Toronto, ON
          • ELIZABETH J. SLOW, MD, PHDAssistant Professor, Morton and Gloria Shulman Movement Disorders Clinic and The Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University of Toronto, Toronto, ON

          Parkinsonism describes the core clinical criteria of tremor, bradykinesia, rigidity, and postural instability. There is a large differential diagnosis, but the most common cause of parkinsonism is due to Parkinson disease. This review details the epidemiology, etiology/genetics, pathogenesis, diagnosis and differential diagnosis, management, and prognosis of Parkinson disease, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, vascular parkinsonism, normal pressure hydrocephalus, and drug-induced parkinsonism. Figures show Parkinson disease features; timeline of the clinical course of Parkinson disease; summary of the diagnosis, management, and prognosis of Parkinson disease; an algorithm for the treatment of tremor-predominant Parkinson disease; an algorithm for the treatment of Parkinson disease with predominance of bradykinesia and rigidity; magnetic resonance imaging changes in multiple system atrophy; magnetic resonance imaging changes in progressive supranuclear palsy; and enlarged ventricles associated with normal pressure hydrocephalus. Tables list differential diagnosis of parkinsonism; clues to alternative, non-Parkinson disease causes of parkinsonism (i.e., red flags of parkinsonism); distinguishing other diseases causing parkinsonism from Parkinson disease; treatment of motor symptoms of Parkinson disease; peripheral and central side effects of dopaminergic (dopamine agonist and levodopa) therapy; and treatment of nonmotor symptoms of Parkinson disease.

          This review contains 8 highly rendered figures, 6 tables, and 88 references.

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        • 2

          Hyperkinetic Movement Disorders

          By Devin Mackay, MD; Edison Miyawaki, MD, PhD
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          Hyperkinetic Movement Disorders

          • DEVIN MACKAY, MDClinical Fellow in Neurology, Massachusetts General Hospital and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
          • EDISON MIYAWAKI, MD, PHDAssociate Neurologist, Brigham and Women’s Hospital and Assistant Professor of Neurology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

          The hyperkinetic movement disorders include heterogeneous diseases and syndromes, all characterized by one or a variety of excessive, involuntary movements. The hyperkinetic movement disorders are heterogeneous in clinical presentation, but a rational and practical approach to diagnosis exists based on new genetic correlations and targeted laboratory investigations. Treatments informed by a still-developing picture of motor pathophysiology offer significant benefit for these disorders. This chapter discusses choreiform disorders, including patterns in choreiform diagnosis; tremor disorders; paroxysmal disorders, including tics and myoclonus; dystonias, including monogenic primary dystonias; and pathophysiology and treatment in the hyperkinetic movement disorders. Figures include clinical photos, computed tomography scans, and an algorithm representing cortical-subcortical circuitry. Tables delineate definitions, distinguishing clinical features, medications, genetics, protein products, and treatments associated with various disorders. 

          This review contains 6 figures, 12 tables, and 145 references.

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        • 3

          Myoclonus

          By Hiroshi Shibasaki, MD, PhD; Marina A J Koning-Tijssen, MD, PhD
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          Myoclonus

          • HIROSHI SHIBASAKI, MD, PHDEmeritus Professor, Department of Neurology and Human Brain Research Center, Kyoto University School of Medicine, Kyoto, Japan
          • MARINA A J KONING-TIJSSEN, MD, PHDProfessor, Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands

          Myoclonus is defined as sudden, brief, jerky, shocklike, involuntary movements involving the extremities, face, and trunk, without loss of consciousness. Myoclonus is one of the most commonly encountered involuntary movements, and it can be seen in association with a variety of conditions. This review covers  the epidemiology, classification, and diagnosis of myoclonus, as well as a thorough discussion of cortical myoclonus, myoclonus of brainstem origin, myoclonus of spinal cord origin, and myoclonus of undetermined origin. Figures show the principle of jerk-locked back-averaging, example data of jerk-lock averaging, schematic diagrams of cortical reflex myoclonus and spontaneous cortical myoclonus, a polygraphic electromyogram (EMG) recorded from a patient with postanoxic, reticular reflex myoclonus, surface negative slow electroencephalographic (EEG) potentials recorded before psychogenic jerks and voluntary movements mimicking the jerks in a patient with a diagnosis of psychogenic truncal movements, and an EEG-EMG polygraph in a patient with Creutzfeldt-Jakob disease. Tables list the classification of myoclonus based on the estimated site of origin, causes of cortical myoclonus, and causes of progressive myoclonus epilepsy and gene abnormalities.

          Key words: cortical myoclonus, EEG-EMG polygraph, epilepsy syndromes, involuntary movements, myoclonus

          This review contains 6 highly rendered figures, 3 tables, and 63 references.

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        • 4

          Ataxias

          By Hélio A G Teive, MD, PhD; Orlando G P Barsottini, MD, PhD
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          Ataxias

          • HÉLIO A G TEIVE, MD, PHDAssociate Professor of Neurology, Internal Medicine Department, Neurology Service, Ataxia Unit, Universidade Federal do Paraná
          • ORLANDO G P BARSOTTINI, MD, PHDAdjunct Professor of Neurology, Department of Neurology and Neurosurgery, Division of General Neurology and Ataxia Unit, Universidade Federal de São Paulo

          Ataxia is a disorder of balance and coordination. The most common forms are cerebellar ataxia and afferent/sensory ataxia. Ataxias can be classified as primary or secondary, as well as hereditary, nonhereditary degenerative, and sporadic. This review covers the primary (congenital, hereditary, and nonhereditary degenerative ataxias) and secondary cerebellar ataxias and afferent/sensory ataxias. Hereditary ataxias are classified as autosomal recessive cerebellar ataxias (such as Friedreich ataxia and ataxia-telangiectasia), autosomal dominant cerebellar ataxias (currently known as spinocerebellar ataxias, such as spinocerebellar ataxia type 3 or Machado-Joseph disease), episodic ataxias, X-linked cerebellar ataxias, and mitochondrial ataxias. Idiopathic degenerative cerebellar ataxias include the cerebellar form of multiple system atrophy (MSA-C) and idiopathic late-onset cerebellar ataxias. Secondary cerebellar ataxias or acquired ataxias include ataxias due to exogenous or endogenous nongenetic causes, such as toxic, paraneoplastic, immune mediated, nutritional, infectious, and secondary to focal injury to the cerebellum. Afferent/sensory ataxia represents a special group of ataxias with many possible causes and is associated with peripheral neuropathies, dorsal root ganglionopathies, sensory nerve root involvement, and posterior spinal column involvement. Figures show several clinical and radiologic (magnetic resonance imaging) signs of autosomal recessive, autosomal dominant ataxias, and multiple system atrophy (type C). Tables list the most common neurologic signs of cerebellar and afferent/sensory ataxias, the main forms of autosomal recessive and autosomal dominant cerebellar ataxias, and the most common causes of secondary cerebellar and afferent/sensory ataxias.

          Key words: afferent/sensory ataxias, ataxias, autosomal recessive cerebellar ataxias, congenital ataxias, nonhereditary degenerative ataxias, secondary cerebellar ataxias, spinocerebellar ataxias

          This review contains 5 highly rendered figures, 4 tables, and 99 references.

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        • 5

          Tremors

          By Alfonso Fasano, MD, PhD; Günther Deuschl, MD, PhD
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          Tremors

          • ALFONSO FASANO, MD, PHDAssociate Professor of Medicine, Division of Neurology, University of Toronto, Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, ON, Canada
          • GÜNTHER DEUSCHL, MD, PHDProfessor of Neurology, Department of Neurology, Christian-Albrechts-University, University-Hospital Schleswig-Holstein, Kiel, Germany

          Tremor is the most common movement disorder and denotes a rhythmic and involuntary movement of one or several regions of the body. This review covers disease definition, essential tremor, enhanced physiologic tremor, parkinsonian tremor, dystonic tremor, orthostatic tremor, cerebellar tremor, Holmes tremor, neuropathic tremor, palatal tremor, drug-induced and toxic tremors, functional tremor, rare tremor syndromes, tremorlike conditions, and treatment of tremor. Figures show action tremor assessment, the central nervous system circuits of tremor, magnetic resonance imaging findings in specific tremor conditions, general management of tremor patients, an algorithm for the treatment of parkinsonian tremor, and an algorithm for the treatment of dystonic tremor and primary writing tremor. Tables list types of tremor according to the condition of activation, tremor conditions in newborns and during childhood, clinical features of the most common tremor syndromes, motor signs other than tremor and nonmotor features of essential tremor patients, Movement Disorder Society consensus criteria for the diagnosis of essential tremor, genetic and environmental causes of essential tremor, causes of enhanced physiologic tremor, drugs and toxins known to cause tremor, paroxysmal tremors, pseudorhythmic myoclonus in the differential diagnosis of tremor, and pharmacologic management of essential tremor.

          Key words: essential tremor, movement disorder, pathologic tremor, physiologic tremor, tremor

          This review contains 6 highly rendered figures, 7 videos, 11 tables, and 163 references.

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        • 6

          Chorea: Classification, Differential Diagnosis, and Treatment

          By James P Battista, MD; Ruth H Walker, MB, ChB, PhD
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          Chorea: Classification, Differential Diagnosis, and Treatment

          • JAMES P BATTISTA, MDMovement Disorders Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY
          • RUTH H WALKER, MB, CHB, PHDMovement Disorders Clinic, Department of Neurology, James J. Peters VAMC, Bronx, NY; Movement Disorders Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY

          Chorea is a common hyperkinetic movement disorder that can have a large differential diagnosis. Causes can include genetic and sporadic etiologies, including metabolic abnormalities, autoimmune, structural, paraneoplastic, psychogenic, and iatrogenic causes. The workup can be challenging due to this large number of possible causes, and can include basic metabolic and specialized blood analysis such as genetic testing, in addition to imaging studies and cerebrospinal fluid analysis. Treatment of symptoms outside the realm of reversible causes can be challenging, and is a major focus of current research. This review covers sporadic causes, genetic causes, and management. Figures show a flowchart for evaluation of patients with chorea, a computed tomography scan of a Huntington disease patient showing caudate head atrophy, brain computed tomography scan showing calcification, and acanthocytosis. Videos show mild and moderate Huntington disease, Huntington disease-like 2,  and chorea-acanthocytosis. Tables list metabolic abnormalities that can manifest as chorea, paraneoplastic and nonparaneoplastic syndromes associated with chorea, and reported successful therapies for chorea.

          This review contains 4 highly rendered figures, 4 videos, 3 tables, and 108 references.

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        • 7

          Atypical Parkinsonian Syndromes: Tauopathies

          By Hee Kyung Park, MD, PhD; Irene Litvan, MD
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          Atypical Parkinsonian Syndromes: Tauopathies

          • HEE KYUNG PARK, MD, PHDAssistant professor in the Department of Neurology, Inje University Ilsan-Paik Hospital, Goyang, Republic of Korea.
          • IRENE LITVAN, MDTasch Endowed Professor in Parkinson Disease Research in the Department of Neurosciences, University of California San Diego, San Diego, CA

          Atypical parkinsonian disorders, which include two common proteinopathies, tauopathies and α-synucleinopathies, are clinically characterized by a progressive parkinsonism that typically does not respond to levodopa therapy and usually associates with early postural instability, falls, and other atypical features not observed in Parkinson disease. Tauopathies refer to neurodegenerative diseases in which there is an abnormal accumulation of hyperphosphorylated tau. The most frequent tauopathies are progressive supranuclear palsy and corticobasal degeneration. Better recognition of the expanding phenotypes of these disorders has led to the development of new diagnostic criteria. Furthermore, better knowledge about the pathogenesis (cell-to-cell transmission of pathologic tau) has resulted in advances in novel disease-modifying therapies that target tau. This review addresses the basic concepts of and recent issues in tauopathies, including their clinical phenotypes, genetic features, biomarkers, and novel experimental therapies. 

          Key words: atypical parkinsonian disorders, corticobasal degeneration, progressive supranuclear palsy, proteinopathies, tauopathies 

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        • 8

          Huntington Disease and Other Genetic Causes of Choreas

          By Francisco Cardoso , MD, PhD, FAAN; Ainhi Ha, MBBS, PhD, FRACP; Débora Maia, MD; Victor S C Fung, PhD, FRACP
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          Huntington Disease and Other Genetic Causes of Choreas

          • FRANCISCO CARDOSO , MD, PHD, FAANProfessor of Neurology, Movement Disorders Unit, Neurology Service, The Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
          • AINHI HA, MBBS, PHD, FRACPStaff Specialist Neurologist, Department of Neurology, Westmead Hospital, Westmead, Australia
          • DÉBORA MAIA, MDConsultant, Movement Disorders Unit, Neurology Service, The Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
          • VICTOR S C FUNG, PHD, FRACPClinical Associate Professor, Sydney Medical School, University of Sydney, & Director, Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney, Australia

          The aim of this review is to provide an overview of Huntington disease (HD) and other genetic choreas with an emphasis on clinical presentation, diagnosis, treatment, and expected outcome. Chorea is a syndrome characterized by brief, abrupt, involuntary movements resulting from a continuous flow of random muscle contractions. The first step in approaching a subject with chorea is to define the underlying etiology because the natural history and management vary accordingly. Age at onset, body distribution, other neurologic features, and family history are important in establishing the cause of chorea. HD is the most common etiology of genetic choreas worldwide. It is a progressive neurodegenerative disorder transmitted as an autosomal dominant trait characterized by a combination of movement disorders, cognitive decline, and behavioral abnormalities that causes progressive disability and death. When an HD phenotype test is negative for this condition, other causes, such as neuroacanthocytosis; spinocerebellar ataxia 17; Huntington disease–like syndrome 2, 3, or 4; benign hereditary chorea; and dentatorubral-pallidoluysian atrophy, as well as others, should be investigated. 

          This review contains 2 figures, 1 table, and 108 references.

          Key words: Huntington, movement disorders, genetic choreas, neurodegenerative disorder

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        • 9

          Tics

          By Justyna R Sarna, MD, PhD ; Tamara Pringsheim, MD, MSc
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          Tics

          • JUSTYNA R SARNA, MD, PHD Clinical Assistant Professor, Division of Neurology, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB
          • TAMARA PRINGSHEIM, MD, MSC Assistant Professor, Division of Neurology, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB

          Tourette syndrome (TS) was originally described and conceptualized by Gilles de la Tourette in 1885. Since then, our understanding of tic disorders has grown immensely and continues to evolve at a rapid pace. Tics are abrupt, usually brief and repetitive, nonrhythmic movements (motor tics) and sounds (vocal tics). Motor tics can be further subdivided into simple and complex motor tics. Simple tics are sudden, meaningless movements most commonly involving eye blinking, facial grimacing, mouth gestures, and shoulder shrugs. Complex motor tics typically involve a series of stereotyped movements that may appear to be purposeful. Vocal (also called phonic) tics are similarly subdivided into simple and complex types. This review covers disease definition/subclassification, epidemiology, etiology/genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, and treatment of tic disorders. Figures show a risperidone safety monitoring template for children, an aripiprazole safety monitoring template for children, and adult antipsychotic safety monitoring recommendations. The video shows how to perform the extrapyramidal symptom rating scale. Tables list classification of tic disorders, medication dosing suggestions, and TS deep brain stimulation guidelines.

          This review contains 3 highly rendered figures, 1 video, 3 tables, and 115 references.

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    • Neurology in General Medicine and Surgery
      • 1

        Neurologic Complications of Cancer

        By Eudocia Q Lee, MD, MPH; Soma Sengupta, MD, PhD; Patrick Y Wen, MD, PhD
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        Neurologic Complications of Cancer

        • EUDOCIA Q LEE, MD, MPHInstructor in Neurology, Harvard Medical School, Center for Neuro-Oncology, Dana-Farber Cancer Institute, and Division of Neurology, Department of Neurology, Brigham and Women’s Hospital, Boston, MA
        • SOMA SENGUPTA, MD, PHDNeuro-Oncology Fellow, Dana-Farber Cancer Institute, Boston, MA
        • PATRICK Y WEN, MD, PHDProfessor of Neurology, Harvard Medical School, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, and Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Boston, MA

        Neurologic complications from cancer and its therapies can significantly impact mortality and morbidity. Early recognition and intervention are key to preventing permanent neurologic injury. This review discusses common and uncommon neurologic complications of cancer, including central nervous system metastases, treatment-related neurotoxicities (including immunotherapies), and paraneoplastic syndromes. Workup and management of these neurologic complications are also addressed.

        Key words: cancer, chemotherapy, metastases, nervous system complications, paraneoplastic syndromes

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      • 2

        Metabolic Encephalopathy

        By Matthew McCoyd, MD; Sean Ruland, DO; José Biller, MD, FACP, FAAN, FANA, FAHA
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        Metabolic Encephalopathy

        • MATTHEW MCCOYD, MDAssistant Professor, Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153
        • SEAN RULAND, DOAssociate Professor, Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 61053
        • JOSÉ BILLER, MD, FACP, FAAN, FANA, FAHAProfessor and Chair, Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153

        Encephalopathy is a general term used to describe diffuse cerebral dysfunction and may be due to myriad primary central nervous system and systemic etiologies. Acute encephalopathy has a rapid onset between hours and days and is commonly due to toxic and metabolic factors that may lead to reversible or permanent cerebral injury. The hallmark of toxic and metabolic encephalopathies is impaired arousal (i.e., hypokinetic delirium), although occasionally an agitated delirium may manifest. Toxic and metabolic encephalopathies may range in severity from the acute confusional state to frank coma. As permanent injury may occur, an organized approach is needed to make an accurate and rapid diagnosis of potentially treatable etiologies. This chapter covers the diagnostic approach to metabolic encephalopathies, specific etiologies (including septic, toxic, and hypoxic-ischemic encephalopathy; electrolyte and acid-base disturbances; and end-organ failure), nutritional deficiencies, and encephalopathy related to endocrine disorders. Figures depict characteristic changes in the posterior brain white matter on imaging, cortical laminar necrosis after severe hypoxic-ischemic insult, osmotic demyelination syndrome of the basis pontis, triphasic frontal slowing, and necrosis of mammillary bodies in a patient with Wernicke encephalopathy. Tables outline the initial management and assessment of patients with acute encephalopathy of uncertain cause, Glasgow Coma Scale, Full Outline of Unresponsiveness (FOUR) score, and West Haven classification for severity of hepatic encephalopathy. 


        This review contains 5 highly rendered figures, 4 tables, and 50 references.

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      • 3

        Uroneurology

        By Jai H Seth, MBBS, MRCS, BSc, MSc; Jalesh N. Panicker, MBBS, MD, DM, MRCP
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        Uroneurology

        • JAI H SETH, MBBS, MRCS, BSC, MSCSpecialist Registrar and Research Fellow in Urology, Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, Institute of Neurology, London, United Kingdom
        • JALESH N. PANICKER, MBBS, MD, DM, MRCPConsultant in Uro-Neurology, Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, Institute of Neurology, London, United Kingdom

        The function of the pelvic organs, including the lower urinary tract (LUT), is controlled by a complex network of nerves. This leaves patients with neurologic disease vulnerable to LUT and pelvic organ dysfunction. Physicians often come across urogenital complaints in their patients with neurologic disease, the symptoms of which can result in significant distress and loss of dignity and quality of life. Due to the health and economic burden that accompanies neurogenic pelvic organ dysfunction, it is important for clinicians to understand the common forms of dysfunction, essential investigations, and modes of management. This chapter covers bladder dysfunction from a physician’s perspective. Topics include neurologic control of the LUT, large bowel, and sexual functions; male and female sexual response; neurogenic bladder dysfunction and its management; diagnostic evaluation; management of neurogenic sexual dysfunction; management of erectile dysfunction; ejaculatory dysfunction; sexual dysfunction in women; and fecal incontinence. Figures illustrate efferent innervation of the LUT, neurologic detrusor overactivity, a urethral pressure profile in a patient with Fowler syndrome, an example bladder diary, an example bladder scan, and normal and obstructed flow patterns. Tables list common causes of injury at the suprapontine, suprasacral, and infrasacral levels and storage and voiding systems.

        This review contains 6 highly rendered figures, 2 tables, and 53 references.

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      • Neurologic Infectious Diseases
        • 1

          Encephalitis

          By Shamik Bhattacharyya, MD; Jennifer L. Lyons, MD
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          Encephalitis

          • SHAMIK BHATTACHARYYA, MDDivision of Neurological Infections, Department of Neurology Brigham and Women’s Hospital and Harvard Medical School Boston, MA
          • JENNIFER L. LYONS, MDDivision of Neurological Infections, Department of Neurology Brigham and Women’s Hospital and Harvard Medical School Boston, MA

          In 2013, the International Encephalitis Consortium proposed clinical criteria for acute encephalitis consisting of 24 hours of altered level of consciousness, lethargy, or personality change and at least three additional supportive features. Although viruses are the most common cause of acute encephalitis, not all encephalitides are acute, viral, or even infectious. Chronic encephalitis can be pathologically similar to acute encephalitis, but the causative agents and clinical manifestations vary. Management of encephalitis is largely supportive; however, for many common encephalitides primary preventive approaches exist. This module reviews the epidemiology, manifestations, diagnosis, management, and prevention of various encephalitides, including herpes family encephalitis (herpes simplex virus, varicella-zoster virus, cytomegalovirus, human herpesvirus 6), arbovirus encephalitis (West Nile virus, eastern equine encephalitis virus, tick-borne encephalitis virus, Japanese encephalitis virus), other encephalitides associated with viruses (influenza virus, human immunodeficiency virus, John Cunningham virus, rabies virus), encephalitides associated with bacteria (Mycoplasma pneumonia, Listeria monocytogenes), and autoimmune encephalitis (acute disseminated encephalomyelitis, paraneoplastic and other autoimmune encephalitides, immune reconstitution inflammatory syndrome). Tables include the International Encephalitis Consortium’s supportive feature of encephalitis, differential diagnosis for magnetic resonance imaging (MRI) findings in the patient with suspected encephalitis, diagnostic considerations for triaging workup of infection-associated encephalitis, differential diagnosis of arboviral infections by location of travel or residence, and preventive strategies for select infectious encephalitis. Figures include MRIs showing patients with herpes simplex encephalitis, varicella-zoster virus, eastern equine encephalitis, HIV, Listeria monocytogenes, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, and immune reconstitution inflammatory syndrome.

          This review contains 8 highly rendered figures, 5 tables, and 78 references.

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        • 2

          Acute Viral Meningitis

          By Karen L. Roos, MD; Jared R. Brosch, MD
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          Acute Viral Meningitis

          • KAREN L. ROOS, MDJohn and Nancy Nelson Professor of Neurology and Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN
          • JARED R. BROSCH, MDDeptment of Neurology, Assistant Professor of Neurology, Indiana University School of Medicine, Indianapolis, IN

          Acute viral meningitis refers to inflammation of the meninges of the brain in response to a viral pathogen. Viruses cause meningitis, encephalitis, myelitis, or a combination of these, meningoencephalitis or encephalomyelitis. Viral meningitis is typically a self-limited disorder with no permanent neurologic sequelae. This chapter reviews the epidemiology, etiology, diagnosis, differential diagnosis, treatment, complications, and prognosis. Tables describe Wallgren’s criteria for aseptic meningitis, important arboviral infections found in North America, herpes family viruses and meningitis, classic cerebrospinal fluid (CSF) abnormalities with viral meningitis, Centers for Disease Control and Prevention criteria for confirming arboviral meningitis, basic CSF studies for viral meningitis, and etiology of CSF pleocytosis. Figures depict common causes of viral meningitis, nuchal rigidity, examination for Kernig sign, and Brudzinski sign for meningeal irritation.

          This review contains 4 highly rendered figures, 7 tables, and 16 references.

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        • 3

          Acute Bacterial Meningitis

          By Karen L. Roos, MD
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          Acute Bacterial Meningitis

          • KAREN L. ROOS, MDJohn and Nancy Nelson Professor of Neurology and Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN

          Acute bacterial meningitis is a life-threatening infection. By definition, meningitis is an infection of the meninges and the subarachnoid space. Bacterial meningitis is associated with an inflammatory response that involves the meninges, the subarachnoid space, the brain parenchyma, and the cerebral arteries and veins. As such, bacterial meningoencephalitis is the more accurate descriptive term. This chapter discusses the epidemiology, etiology, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of the disease. The discussion of diagnosis covers clinical manifestations, physical examination findings, laboratory tests, and imaging studies. The discussion of treatment covers empirical therapy, specific antimicrobial therapy, and dexamethasone therapy. Graphs compare causative organisms and clinical manifestations of community-acquired meningitis. Illustrations depict proper patient positioning for detecting nuchal rigidity, Kernig sign, Brudzinski sign, and lumbar puncture, as well as a sagittal view of a lumbar puncture needle as it is advanced into the subarachnoid space. An algorithm delineates the approach to the patient with symptoms and signs of bacterial meningitis. Tables outline bacterial pathogens based on predisposing and associated conditions, cerebrospinal fluid diagnostic studies for meningitis, the appearance of the organism on a Gram stain, empirical antimicrobial therapy based on predisposing and associated conditions, recommendations for specific antibiotic therapy in bacterial meningitis, and recommended doses for antibiotics commonly used in the treatment of bacterial meningitis.

           

          This review contains 8 highly rendered figures, 6 tables, and 75 references.

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        • 4

          Brain and Spinal Abscesses

          By Allan R Tunkel, MD, PhD; W Michael Scheld, MD
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          Brain and Spinal Abscesses

          • ALLAN R TUNKEL, MD, PHDProfessor of Medicine, Drexel University College of Medicine, Philadelphia, PA, Chair, Department of Medicine, Monmouth Medical Center, Long Branch, NJ
          • W MICHAEL SCHELD, MDProfessor of Medicine and Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA

          Brain and spinal abscesses are often devastating infections that can lead to substantial morbidity and mortality if not recognized and treated in a timely manner. The clinical presentation depends upon the route of spread of infection to the central nervous system, location of the lesion, and severity of increased intracranial pressure. Brain abscess is defined as a focal intracranial infection that is initiated as an area of cerebritis and evolves into a collection of pus that is surrounded by a vascularized capsule; patients most often develop brain abscess by contiguous spread, hematogenous dissemination, or trauma. This chapter discusses the epidemiology, etiology, pathogenesis, diagnosis, management, and prognosis for brain abscess. Also examined are epidemiology and pathogenesis, etiology, diagnosis, management, and prognosis for both cranial subdural empyema and epidural abscess and spinal epidural abscess and subdural empyema. Tables list predisposing conditions and likely etiologic agents in brain abscess; histopathologic findings in the stages of brain abscess formation; presenting symptoms and signs in patients with brain abscess; antimicrobial therapy of brain abscess based on isolated pathogen; predisposing conditions and empirical antimicrobial therapy in patients with presumed bacterial brain abscess; recommended dosages of antimicrobial agents in adults with brain abscess; and normal renal and hepatic function. Figures in this chapter are images of intra-axial fluid collection; a subdural fluid collection; a ring-enhancing subdural empyema; an epidural abscess; a large epidural fluid collection with midline shift; a dorsal epidural collection; and loculated ring enhancement suggesting an epidural abscess. This chapter contains 6 highly rendered figures, 6 tables, 167 references, 5 MCQs.

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        • 5

          Central Nervous System Diseases Due to Slow Viruses and Prions

          By Francisco González-Scarano, MD
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          Central Nervous System Diseases Due to Slow Viruses and Prions

          • FRANCISCO GONZÁLEZ-SCARANO, MD

          Several central nervous system diseases whose common elements include a long incubation period and a progressive clinical course were once called slow virus infections, because most of them are in fact caused by viruses. However, one group of these CNS diseases is now believed to be caused by abnormally configured proteins known as prions; rather than an etiologic designation, therefore, on the whole these diseases are better characterized by their chronicity, their transmissibility, and at this point, their inexorably deteriorating natural history. This chapter reviews the more common of these: HIV-associated dementia (HAD or HIVD), human T cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy, Creutzfeldt-Jakob disease (CJD), progressive multifocal leukoencephalopathy (PML), and subacute sclerosing encephalitis (SSPE), which is associated with a variant of measles virus. Figures illustrate the pathogenesis and the pathology of HIV dementia, propagation of scrapie prion protein (PrP) in brain neurons, and spongiform brain changes of CJD. Tables list the stages of HAD and the clinical and pathologic characteristics distinguishing classic CJD and varient CJD.

          This review contains ­5 highly rendered figures, 2 tables, and 57 references. 

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        • 6

          Primary and Metastatic Central Nervous System Malignancies

          By Fabio M. Iwamoto, MD; Howard A. Fine, MD
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          Primary and Metastatic Central Nervous System Malignancies

          • FABIO M. IWAMOTO, MDAssistant Clinical Investigator, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
          • HOWARD A. FINE, MDSenior Investigator and Chief, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

          About 13,000 deaths each year in the United States are attributed to primary central nervous system (CNS) malignancies. An estimated 20% of patients with cancer eventually develop clinically apparent CNS metastases, and an estimated 170,000 cases of brain metastases are diagnosed in the United States yearly. Autopsy studies suggest that as many as 50% of patients dying from advanced cancer may have metastasis to the CNS. This chapter provides an overview of primary and metastatic CNS malignancies with in-depth discussion of gliomas, primary CNS lymphoma, meningioma, brain metastases, leptomeningeal metastases, and metastatic epidural spinal cord compression. Discussions cover epidemiology, etiology, diagnosis, and treatment of gliomas, including surgery, radiotherapy, and chemotherapy for both newly diagnosed gliomas and recurrent gliomas. The epidemiology, diagnosis, treatment and prognosis for primary CNS lymphomas are reviewed, as well as the epidemiology, etiology, diagnosis, treatment, and prognosis for meningiomas. Epidemiology, diagnosis, and prognosis for brain metastases are briefly discussed, and the section on treatment includes surgery, stereotactic radiosurgery, and whole-brain radiotherapy for patients with three or fewer brain metastases. The sections on leptomeningeal metastases and metastatic epidural spinal cord compression cover diagnosis, treatment, and prognosis. This chapter contains 126 references.

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    • Special Topics in Neurology
      • 1

        Women's Neurology

        By M. Angela O’Neal, MD
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        Women's Neurology

        • M. ANGELA O’NEAL, MDDirector of Women’s Neurology, Department of Neurology, Brigham and Women’s Hospital, Boston, MA

        This review details some of the features important to consider in women with neurologic disease, including medication and disease effects on both reproductive health and pregnancy/fetal development, as well as hormonal effects on neurologic disease. A case-based approach is used to discuss diseases that affect women throughout their life cycle (multiple sclerosis [MS] and epilepsy), disorders that affect only women (eclampsia), and those that affect women preferentially (migraine, cerebral venous thrombosis, reversible cerebral vasospasm, and Alzheimer disease). The epidemiology, differential diagnosis, pathophysiology, management, and prognosis are reviewed for each disorder. Tables include US Food and Drug Administration pharmaceutical pregnancy categories, learning objectives, migraine with aura, alternative diagnostic criteria for migraine without aura, migraine aura versus transient ischemic attacks, red flags to secondary headache, abortive headache therapy in pregnancy, migraine preventive medications and pregnancy, MS therapies in pregnancy, pregnancy consulting points for MS patients on a disease-modifying therapy, and general recommendations for women with epilepsy and pregnancy. Figures show fluid-attenuated inversion recovery and gradient echo magnetic resonance images of the right anterior parietal region; a magnetic resonance venogram demonstrating occlusion in the superior sagittal sinus; posterior reversible encephalopathy syndrome; and computed tomographic (CT) images of a hemorrhage in the left parietal region, left frontal subarachnoid bleeding, and left middle cerebral beading.

        This review contains 5 highly rendered figures, 11 tables, and 29 references.

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      • 2

        Principles of Neurologic Ethics

        By Thomas I. Cochrane, MD, MBA
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        Principles of Neurologic Ethics

        • THOMAS I. COCHRANE, MD, MBAAssociate Neurologist, Division of Neuromuscular Disease, Department of Neurology, Brigham and Women’s Hospital, Assistant Professor of Neurology, Harvard Medical School, Boston, MA

        Many neurologic diseases affect the brain and thus cognition and personality. Many people consider some neurologic conditions “worse than death” and would prefer not to be kept alive using medical technology if there is no reasonable chance of recovery. The clinician caring for patients with neurologic disease will frequently be confronted with decisions about whether to initiate or continue life-sustaining therapies. And because neurologic disease often impairs the ability to understand and to decide, clinicians are more often called on to make decisions for patients who cannot decide for themselves. This chapter covers general principles, including respect for autonomy, beneficence, nonmaleficence, justice, informed consent, and implied consent. Discussion about making decisions for others includes competence and decision-making capacity, advance directives (powers of attorney and living wills), substituted judgment, and best interests. Decisions about life-sustaining treatment include withholding versus withdrawing, acts versus omissions, and limiting life-sustaining treatment for the patient with no surrogate. Also covered are decisions in the face of prognostic uncertainty, and futility, as well as commonly encountered problems such as states of severely disordered consciousness, coma, vegetative state, minimally conscious state, and brain death (including ethical controversies). Organ donation after both brain death and cardiac death is discussed. The section on dementia covers feeding tubes for patients with advanced dementia, the locked-in state, and neuroenhancement. Tables include elements of informed consent, elements of competence, assumed ethical priority of potential surrogates, steps that aid decision making in the face of prognostic uncertainty, and the American Academy of Neurology’s criteria for determination of brain death. This chapter includes 23 references.

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      • 3

        The Neurologic Examination

        By Nicholas J Beimer, MD; Douglas J Gelb, MD, PhD
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        The Neurologic Examination

        • NICHOLAS J BEIMER, MDClinical Instructor, Department of Neurology, University of Michigan, Ann Arbor, MI
        • DOUGLAS J GELB, MD, PHDProfessor, Department of Neurology, University of Michigan, Ann Arbor, MI

        All physicians, regardless of their medical specialty or the setting in which they treat patients, must be able to perform a neurologic examination. In the outpatient office, up to 9 to 10% of all symptoms suggest the possibility of neurologic disease and up to 5% of emergency department visits are due to primary neurologic disease. The neurologic examination is critical in triaging these patients, selecting diagnostic tests, and indicating management. This review covers how to think about the neurologic examination, the screening examination, and diagnosis-focused neurologic examinations with an emphasis on stroke, epilepsy, encephalopathy and coma, neurodegenerative diseases, neuromuscular disease, and functional disorders. The figure shows a conceptual approach to the neurologic examination. The tables list components of the screening neurologic examination, neurologic examination focus points for suspected stroke and suspected epilepsy, lateralization and localization of common seizure semiologies, and neurologic examination focus points for encephalopathy/coma, suspected neurodegenerative disease, suspected neuromuscular disease, and suspected functional neurologic disorders.

        This review contains 1 highly rendered figure, 8 tables, and 14 references.

        Key words: Neurologic examination, neurodegenerative disease, neuromuscular disease, neurologic screening

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      • 4

        Neuroimaging for the Clinician

        By Joshua P Klein, MD, PhD
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        Neuroimaging for the Clinician

        • JOSHUA P KLEIN, MD, PHDChief, Division of Hospital Neurology, Department of Neurology, Brigham and Women’s Hospital, and Assistant Professor of Neurology, Harvard Medical School, Boston, MA

        Modern neuroimaging has revolutionized the practice of neurology by allowing visualization and monitoring of evolving pathophysiologic processes. High-resolution magnetic resonance imaging (MRI) can now resolve structural abnormalities on a near-cellular level. Advances in functional imaging can assess the in vivo metabolic, vascular, and functional states of neuronal and glial populations in real time. Given the high density of data obtained from neuroimaging studies, it is essential for the clinician to take an active role in understanding the nature and significance of imaging abnormalities. This chapter reviews computed tomography and MRI techniques (including angiography and advanced sequences), specialized protocols for investigating specific diagnoses, risks associated with imaging, disease-specific imaging findings with general strategies for interpretation, and incidental findings and artifacts. Figures include computed tomography, T1- and T2-weighted signal intensity, diffusion-weighted magnetic resonance imaging, magnetic resonance spectroscopy, imaging in epilepsy and dementia, extra-axial versus intra-axial lesions, typical lesions of multiple sclerosis, spinal imaging, spinal pathology, vascular pathology, intracranial hemorrhage, and common imaging artifacts. Tables list Hounsfield units, patterns of enhancement from imaging, advanced techniques in imaging, magnetic resonance imaging sequences, and the evolution of cerebral infarction and intraparenchymal hemorrhage on magnetic resonance imaging.

        This review contains 12 figures, 6 tables, and 213 references.

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  • Oncology
    • 1

      Cervical Cancer Prevention and Screening

      By Carolyn D. Runowicz, MD; Andrew Quinn, MD
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      Cervical Cancer Prevention and Screening

      • CAROLYN D. RUNOWICZ, MDAssociate Dean for Women’s Affairs, Professor of Obstetrics and Gynecology, Florida International University, Herbert Wertheim College of Medicine, 11200 S.W. 8 Street, AHC2 693, Miami, FL
      • ANDREW QUINN, MDResident, PGY-1, Department of Obstetrics and Gynecology, New York Hospital, New York, NY

      With the advent of HPV DNA testing and the availability of HPV vaccinations, the recommendations and rationale for screening and prevention of cervical cancer and its precursors have undergone revision, reflecting this new knowledge and understanding of cervical intra-epithelial neoplasia and the role of HPV. This review incorporates the new guidelines and rationale for current screening guidelines for cervical cancer and in the management of patients with atypical or unsatisfactory cervical cytology.

      This review contains 4 figures, 2 tables, and 69 references.

      Key words: Cervical cancer, Gynecological cancer, HPV, HPV testing, HPV vaccine, Pap smear, HPV DNA, Human papillomavirus

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    • Principles of Oncology
      • 1

        Cancer Epidemiology and Prevention

        By Alfred I. Neugut, MD, PhD, FACP; David P Wu, MD
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        Cancer Epidemiology and Prevention

        • ALFRED I. NEUGUT, MD, PHD, FACPMyron Studner Professor of Cancer Research, Professor of Medicine and Public Health, Columbia University Medical Center, New York, NY
        • DAVID P WU, MDPostdoctoral Clinical Fellow in Hematology Oncology, Columbia University Medical Center, New York, NY

        Recently surpassing heart disease, cancer is now the leading cause of death (one in four) in the United States. Worldwide, cancer control is becoming increasingly important as life expectancy improves because of lower infant mortality and fewer deaths from infectious diseases. Morbidity and mortality from many forms of cancer can be controlled through primary or secondary prevention. Primary prevention can be defined as risk modification to lower cancer occurrence. Secondary prevention refers to the use of screening tests to detect cancers at early stages. Environmental carcinogens, inherited factors that predispose to cancer, and screening and early detection are covered in major sections. Also included are discussions of infectious agents, occupational carcinogens, iatrogenic causes, carcinogens affecting the reproductive system, and miscellaneous environmental causes. Tables outline established causes of human cancer, common hereditary cancers and syndromes attributable to germline mutations in predisposing genes, and the American Cancer Society’s recommendations for early detection of cancer. This chapter contains 138 references.

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      • 2

        Molecular Genetics of Cancer

        By Leif W. Ellisen, MD, PhD
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        Molecular Genetics of Cancer

        • LEIF W. ELLISEN, MD, PHDAssociate Professor of Medicine, Harvard Medical School, Boston, MA

        The uncontrolled clonal expansion of a cell, which often leads to invasion of surrounding tissues and metastatic spread, produces cancer. A clear histologic and molecular genetic evolution from precancerous lesions to frankly malignant and invasive cancer has been defined for some tumors (e.g., colon and bladder cancers). In rare cases, mutations may occur and be passed on in the germline, resulting in genetic predisposition to cancer (i.e., familial cancer syndromes). Environmental factors are also thought to contribute to the development of cancer. Interactions between environmental factors and subtle germline genetic variations that distinguish individuals may in some cases constitute an important determinant of cancer risk within the general population. Finally, viral infection has been linked to the development of specific cancers. Oncogenes and proto-oncogenes, and germline genetic analysis and cancer risk assessment are covered. Also discussed are genetic alterations and abnormalities, tumor suppressor genes, tumor progression, genetic mechanisms of treatment sensitivity and resistance, and emerging trends in cancer genomics and risk assessment. Figures illustrate activation of proto-oncogenes, the Knudsen two-hit model of tumor initiation, allelic losses in tumors, the retinoblastoma gene (RB1) cell cycle pathway, the p53 cellular stress and DNA damage response pathway, microsatellite instability and DNA mismatch repair, multiple oncogenes and tumor suppressors, tumor progression, cellular senescence and telomerase activation, tumor angiogenesis, chemotherapy drug resistance, targeting of oncogenic proteins by imatinib mesylate, analysis of expression profiles using high-density microarrays, and the spectrum of risk alleles for breast cancer predisposition. Tables outline oncogene and tumor suppressor gene mutations. This chapter contains 119 references.

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      • 3

        Principles of Cancer Treatment

        By Eric H. Rubin, MD; William N Hait, MD, PhD
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        Principles of Cancer Treatment

        • ERIC H. RUBIN, MDTherapeutic Area Head, Merck Research Laboratories, North Wales
        • WILLIAM N HAIT, MD, PHDOrtho Biotech Oncology Senior Vice President and Worldwide Head, Oncology Research and Development, Johnson & Johnson, Raritan, NJ

        This review is divided into three primary sections dealing with management of cancer patients, the specific basis of cancer treatment, and specific chemotherapeutic agents. The first section outlines the diagnosis, staging, performance status, and treatment of cancer. The discussion of the specific basis of cancer treatment describes cancer biology (including its transformation and proliferation, cell viability and cell death, and invasion and metastases) and the principles of cancer pharmacology. The discussion on pharmacology details dose response and schedule, drug resistance, combination chemotherapy, common toxicities, and pharmacokinetics and pharmacogenetics. Among the specific chemotherapeutic agents discussed are drugs that alter nucleic acid synthesis or function (including DNA alkylating and cross-linking agents, inhibitors of nucleic acid synthesis, and DNA topoisomerase inhibitors); antimicrotubule drugs (eg, vinca alkaloids, taxanes, and estramustine); drugs that affect growth factors, receptors, and signal transduction pathways; drugs that inhibit metastases or angiogenesis; gene-based therapies; and immunotherapies. Tables describe the World Health Organization Performance Scale and chemotherapeutic agents, and figures illustrate targets for new cancer therapeutics and mechanisms of chemotherapeutic drug resistance.

        This review contains 4 highly rendered figures, 2 tables, and 90 references.

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      • 4

        Emergencies in Hematology and Oncology

        By Thorvardur R. Halfdanarson, MD; William J Hogan, MBBCH; Timothy J Moynihan, MD
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        Emergencies in Hematology and Oncology

        • THORVARDUR R. HALFDANARSON, MDAssistant Professor, University of Iowa Hospitals and Clinics, Department of Internal Medicine, Division of Hemtology, Oncology and Blood & Marrow Transplantation, Iowa City, IA
        • WILLIAM J HOGAN, MBBCHAssistant Professor, Division of Hematology, Mayo Clinic, Rochester, MN
        • TIMOTHY J MOYNIHAN, MDDepartment of Oncology, Mayo Clinic, Rochester, MN

        With the rising incidence of malignancies and expanding treatment options, clinicians must learn to recognize and treat emergencies associated with them. Oncologic emergencies can be broadly classified according to organ systems, which can facilitate recognition and management. Pathophysiology, presentation, diagnosis, and treatment are discussed for complications categorized by metabolic emergencies (hypercalcemia of malignancy, tumor lysis syndrome, lactic acidosis), neurologic emergencies (malignant spinal cord compression, brain metastases, and increased intracranial pressure), cardiovascular emergencies (malignant pericardial effusion and tamponade, superior vena cava syndrome), hematologic emergencies (hyperviscosity due to monoclonal proteins, hyperleukocytosis and leukostasis), infectious emergencies (neutropenic fever, neutropenic enterocolitis, fever associated with splenectomy or functional asplenia), and pulmonary emergencies (acute airway obstruction, acute airway hemorrhage). Figures illustrate spinal cord compression, brain metastases, electrical alternans, malignant pericardial effusion, superior vena cava syndrome, hyperleukocytosis, and an algorithm for initial management of fever and neutropenia. Tables cover management of hypercalcemia of malignancy; the Cairo-Bishop definition of laboratory and clinical tumor lysis; grading, risk stratification, and management of tumor lysis syndrome; management of intracranial hypertension and seizures; infection in patients with neutropenic fever; the Multinational Association for Supportive Care in Cancer Risk Index; and indications for the addition of a gram-positive antibiotic to the initial empirical regimen. This chapter contains 181 references.

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      • 5

        Tumor Immunology

        By Bruce G Redman, DO; Alfred E Chang, MD, FACS
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        Tumor Immunology

        • BRUCE G REDMAN, DOProfessor of Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
        • ALFRED E CHANG, MD, FACSHugh Cabot Professor of Surgery, University of Michigan Medical School, Ann Arbor, MI

        The development of cancer may represent a failure of immunosurveillance—a theory founded on the premise that the immune system has the capacity to recognize tumor-associated antigens and develop specific T cell responses to those antigens. The ability to intervene and enhance the immune system to achieve a beneficial antitumor response remains an area of intense clinical research. Considerable progress has been made in expanding our knowledge of the targets for an immune response and about the full repertoire of cellular and humoral constituents involved in the generation of an effective antitumor response. Tumor cells display a variety of mechanisms by which they evade immune detection and destruction and render the immune response ineffective. With a more complete understanding of these escape mechanisms, clinical investigators are devising strategies to enhance the development of a robust immune response in the tumor-bearing host (active tumor immunity) or by the adoptive transfer of activated effector cells or tumor-specific antibodies into the tumor-bearing host (passive tumor immunity). Illustrations depict immune-mediated rejection of transplanted tumors, T cell interaction with a dendritic antigen-presenting cell (APC), interaction between APCs and T cells, and novel immunotherapies. Tables list host immune response evidence and five major cellular constituents of cellular effector response.

        This review contains 8 highly rendered figures, 2 tables, 50 references, 1 teaching slide set, and 5 MCQs.

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    • Respiratory Tract Malignancies
      • 1

        Head and Neck Cancer

        By Everett E Vokes, MD; Kevin C. Wood, MD
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        Head and Neck Cancer

        • EVERETT E VOKES, MDChairman, Department of Medicine, Deputy Director, Cancer Research Center, John E. Ultmann Professor of Medicine Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
        • KEVIN C. WOOD, MDFellow, Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL

        The vast majority of head and neck tumors arise from the mucosa of the upper aerodigestive tract and are squamous cell carcinomas. Anatomically, head and neck cancers are heterogeneous—arising from the pharynx (including the nasopharynx, oropharynx, and hypopharynx), the oral cavity, the larynx, and the cervical esophagus. The etiology, pathogenesis, genetic alterations, diagnosis, staging, and treatment of squamous cell carcinomas of the head and neck are reviewed in this chapter. Salivary gland tumors arise either from one of the three major salivary glands or from the minor salivary glands lining the mucosa of the upper aerodigestive tract. Their etiology, histology, and treatment differ from those of head and neck tumors and are briefly reviewed. Figures depict the sagittal section of the upper aerodigestive tract and the trial design for the intergroup organ preservation study in laryngeal cancer. This chapter has 83 references.

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      • 2

        Lung Cancer

        By Jeffrey Crawford, MD; John Strickler, MD
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        Lung Cancer

        • JEFFREY CRAWFORD, MDGeorge Barth Geller Professor for Research in Cancer, Chief, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, NC 27710
        • JOHN STRICKLER, MDFellow, Divisions of Hematology, Medical Oncology, and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710

        In the United States, lung cancer is the second most common cancer, surpassed only by prostate cancer in men and breast cancer in women. But lung cancer is the leading cause of cancer deaths, accounting for 29% and 26% of all cancer-related deaths in men and women, respectively. The four major pathologic cell types of lung cancer are small cell carcinoma, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Because they have overlapping clinical behaviors and responses to treatment, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are generally grouped together in the category of non–small cell lung cancer (NSCLC). This chapter discusses both NSCLC and small cell lung cancer (SCLC), including lung cancer in those who have never smoked, prevention of lung cancer, with sections on diagnosis, biomarkers, treatment, and supportive care. Tables provide further detail regarding signs and symptoms of lung cancer; prognostic biomarkers, predictive biomarkers, and therapy for NSCLC; survival benefit of adjuvant chemotherapy by stage; chemotherapy regimens for adjuvant therapy established from randomized trials; and therapy and prognosis for SCLC. Figures illustrate various cancer death rates, percentages of high school students who smoke, common causes of cancer death, differential frequencies of EGFR and K-ras mutations, a tumor-nodes-metastasis four-stage system used in clinical and surgical evaluation of lung cancer, and lymph node sites (nodal stations) in the chest. This chapter contains 181 references.

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    • Gastrointestinal Malignancies
      • 1

        Colorectal Cancer

        By Cathy Eng, MD, FACP
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        Colorectal Cancer

        • CATHY ENG, MD, FACPAssociate Professor, Associate Director of the Colorectal Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX

        Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States. Although environmental factors, including diet and lifestyle, clearly play a role in the etiology of colorectal cancer, as many as 25% of patients with colorectal cancer have a family history of the disease, which suggests the involvement of a genetic factor. Inherited colon cancers can be divided into two main types: the well-studied but rare familial adenomatous polyposis (FAP) syndrome, and the increasingly well-characterized, more common hereditary nonpolyposis colorectal cancer (HNPCC, a.k.a. Lynch Syndrome). The prevention, screening, diagnosis, and treatment of cancers of the colon and rectum are covered in this chapter. Figures illustrate various forms of adenomatous polyps, the tumor, node, metastasis (TNM) staging system for colorectal cancer, and the five-year survival rate in patients with colorectal carcinoma. Tables describe risk factors; possible chemopreventive agents; evidence supporting the effectiveness of screening tests; features and usage issues with different fecal occult blood tests; recommendations for early detection, screening, and surveillance for patients at different levels of risk; colorectal cancer staging systems; indicators of poor prognosis; and chemotherapeutic and biologic agents in the treatment of colorectal cancer. This chapter contains 197 references.

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      • 2

        Pancreatic, Gastric, and Other Gastrointestinal Cancers

        By Weijing Sun, MD; Daniel Haller, MD, FACP; Davendra Sohal, MD, MPH
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        Pancreatic, Gastric, and Other Gastrointestinal Cancers

        • WEIJING SUN, MDAssociate Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
        • DANIEL HALLER, MD, FACPProfessor of Medicine, Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
        • DAVENDRA SOHAL, MD, MPHFellow, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA

        According to 2009 estimates from the American Cancer Society, cancers originating in the gastrointestinal tract rank second in both incidence and cancer-related deaths. One in four deaths in the United States is caused by cancer, with 25% of cancer-related deaths caused by gastrointestinal (GI) malignancies; more than 50% of these deaths are caused by cancer of the pancreas, stomach, esophagus, liver, or biliary tract. Recent advances in molecular biology, medical genetics, and imaging and endoscopic techniques, as well as the development of antitumor agents, have significantly altered the approaches to the prevention, diagnosis, and treatment of GI cancers. The chapter covers esophageal, gastric, pancreatic, hepatocellular, biliary tract, and anal cancers, as well as GI stromal tumors and gastric lymphoma. Coverage of all cancers includes diagnosis and treatment; various sections include information on epidemiology, etiology, risk factors, screening and prevention, molecular mutations, pathogenesis, and/or metastatic disease. Figures depict a barium esophagogram showing squamous cell carcinoma; imaging of esophageal cancer, gastric cancer, and pancreatic cancer; a pedigree of a family with inactivation of germline mutation of E-cadherin; hereditary gastric cancer; gastric cancer survival rates after gastrectomy; axial T1-weighted magnetic resonance imaging (MRI) showing cancer of the pancreatic head; and T1- and T2-weighted MRIs of intrahepatic bile duct carcinoma. Tables provide information on new cases and mortality from GI cancer in 2009; guidelines for diagnosis and surveillance of Barrett esophagus; the declining incidence of gastric cancer in Japan, Slovenia, and the United States; TNM staging of gastric cancer, pancreatic cancer, and hepatocellular carcinoma; the incidence of familial pancreatic carcinoma; molecular mutations involved in pancreatic cancer; staging of pancreatic intraepithelial neoplasia; and the Chinese University Prognostic Index. This chapter contains 235 references.

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    • Breast, Gynecologic, and Genitourinary Malignancies
      • 1

        Breast Cancer

        By Nancy E Davidson, MD
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        Breast Cancer

        • NANCY E DAVIDSON, MDDirector, University of Pittsburgh Cancer Institute and UPMC Cancer Center, Hillman Professor of Oncology, University of Pittsburgh, Pittsburgh, PA

        Invasive breast cancer, the most common nonskin cancer in women in the United States, will be diagnosed in 235,000 women in this country in 2013 and is expected to result in approximately 40,000 deaths. Incidence and mortality reached a plateau and appear to be dropping in both the United States and parts of western Europe. This decline has been attributed to several factors, such as early detection through the use of screening mammography and appropriate use of systemic adjuvant therapy, as well as decreased use of hormone replacement therapy. However, the global burden of breast cancer remains great, and global breast cancer incidence increased from 641,000 in 1980 to 1,643,000 in 2010, an annual rate of increase of 3.1%. This chapter examines the etiology, epidemiology, prevention, screening, staging, and prognosis of breast cancer. The diagnoses and treatments of the four stages of breast cancer are also included. Figures include algorithms used for the systemic treatment of stage IV breast cancer and hormone therapy for women with stage IV breast cancer. Tables describe selected outcomes from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 chemoprevention trials, tamoxifen chemoprevention trials for breast cancer, the TNM staging system and stage groupings for breast cancer, some commonly used adjuvant chemotherapy regimens, an algorithm for suggested treatment for patients with operable breast cancer from the 2011 St. Gallen consensus conference, guidelines for surveillance of asymptomatic early breast cancer survivors from the American Society of Clinical Oncology, and newer agents for metastatic breast cancer commercially available in the United States.

        This review contains 2 highly rendered figures, 8 tables, and 108 references.

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      • 2

        Gynecologic Cancer

        By Stephen A Cannistra, MD; Christina I Herold, MD
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        Gynecologic Cancer

        • STEPHEN A CANNISTRA, MDProfessor of Medicine, Harvard Medical School, Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA
        • CHRISTINA I HEROLD, MDInstructor of Medicine, Harvard Medical School, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA

        This chapter focuses on the three types of gynecologic cancer—epithelial cancer of the ovary, cancer of the uterine cervix, and cancer of the endometrium (uterine cancer)—and reviews their epidemiology, diagnosis, differential diagnosis, surgical features, and staging, as well as their risk factors and clinical features. Also discussed are methods of treatment and the management of relapse. Epithelial ovarian cancer occurs at a mean age of 60 years in the United States and is the most lethal of gynecologic tract tumors. However, a recent trial has demonstrated a survival advantage through the use of intraperitoneal chemotherapy for appropriate patients with optimally debulked ovarian cancer.

        Invasive cervical cancer is uncommon in developed countries, partly because of the effectiveness of Pap smear screening. Nevertheless, cancer of the uterine cervix is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers in the United States. However, for women with early-stage cervical cancer, data from several randomized trials indicate an improvement in response rate and survival through the use of combination platinum-based regimens for platinum-sensitive relapse. Also noted is an improvement in survival using combined-modality chemoradiation in appropriate patients with locally advanced cervical cancer.

        Endometrial cancer is the most frequent tumor of the gynecologic tract; it is estimated that it occurred in over 46,000 women and caused more than 8,000 deaths in the United States in 2011. Recent data indicate improvement in survival using adjuvant platinum-based chemotherapy in appropriate patients with high-risk endometrial cancer.

        Tables in this chapter review the common histologic types of epithelial ovarian cancer, selected signs and symptoms of ovarian cancer, the International Federation of Gynecology and Obstetrics (FIGO) staging system for epithelial ovarian cancer, differential diagnosis of a complex cyst detected by transvaginal sonography, selected adverse prognostic factors in epithelial ovarian cancer, common chemotherapy agents used in the treatment of epithelial ovarian cancer, the FIGO surgical staging of endometrial cancer, and postoperative management considerations for patients with uterine cancer. Figures illustrate the four histologic subtypes of epithelial ovarian cancer, the intraoperative appearance of stage III epithelial ovarian cancer, and FIGO staging of cervical cancer.

        This review contains 6 highly rendered figures, 8 tables, and 150 references.

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      • 3

        Prostate Cancer

        By Jonathan E. Rosenberg, MD; Philip W Kantoff, MD
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        Prostate Cancer

        • JONATHAN E. ROSENBERG, MDAssistant Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
        • PHILIP W KANTOFF, MDProfessor of Medicine, Dana-Faber Cancer Institute, Harvard Medical School, Boston, MA

        Prostate cancer is the most commonly diagnosed noncutaneous malignancy in men in the United States. This chapter discusses the epidemiology, pathogenesis, and diagnosis of prostate cancer, as well as risk factors, the use of digital rectal examination and prostate-specific antigen measurement for screening, and staging for the disease. Also reviewed are the natural history of untreated prostate cancer; the treatment of localized and advanced prostate cancer, including prostatectomy, radiation therapy, and androgen deprivation therapy; and the prevention of prostate cancer. Figures illustrate the incidence rates of prostate cancer by race, age-adjusted and/or age-specific cancer of the prostate, the risk of a diagnosis in 20 years (based on being cancer free at certain ages), the 5-year survival rate, and the overall survival in patients with early prostate cancer treated with observation or radical prostatectomy. Tables in this chapter review the clinical staging definitions and the combined-modality staging approach to prostate cancer. This chapter contains 116 references.

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      • 4

        Management of Bladder Cancer

        By Joaquim Bellmunt, MD, PhD; Rosa Nadal, MD, PhD
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        Management of Bladder Cancer

        • JOAQUIM BELLMUNT, MD, PHDAssociate Professor of Medicine, Harvard Medical School, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
        • ROSA NADAL, MD, PHDClinical Fellow Genitourinary Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

        Bladder cancer is the fourth most common cancer in men and the tenth most common in women. Patients commonly present with painless hematuria. Urinary frequency, urinary tract infection, upper tract obstruction, and pain are also possible; however, the physical examination of the patients is often unremarkable. Clinical diagnosis depends on urine cytology, bladder ultrasonography, and office cystoscopy. This review describes the epidemiology, pathology and natural history, clinical presentation and workup, staging and grading, non–muscle-invasive bladder cancer, bladder preservation strategies, nontraditional approaches, chemotherapy for metastatic disease, immunotherapy, and predictive factors of response to chemotherapy for bladder cancer. Figures show representative images of urothelial cell carcinoma, diagrams showing a cystoscopy for a man and bladder cancer staging, urinary diversion, and computed tomographic scans of a patient with hepatic metastases from bladder cancer before and after treatment with gemcitabine-cisplatin. Tables list the tumor-node-metastasis staging system for bladder cancer, the histologic classification of tumors of the urinary tract (WHO 1973 versus WHO 2004), risk group stratification based on the European Organization for Research and Treatment of Cancer Scoring System, types of bacillus Calmette-Guérin failure/recurrence and treatment recommendations, unfavorable factors for bladder preservation chemoradiation, consensus criteria for patients unfit for cisplatin-based regimens, and first-line combination chemotherapy regimens.

        This review contains 5 highly rendered figures, 7 tables, and 80 references.

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      • 5

        Clinical Management of Renal Cell Carcinoma

        By Rana R. McKay, MD; Marina D Kaymakcalan, PharmD; Guillermo De Velasco, MD; Suzanne S Mickey, BS; Andre P Fay, MD; Toni K. Choueiri, MD
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        Clinical Management of Renal Cell Carcinoma

        • RANA R. MCKAY, MDDepartment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA
        • MARINA D KAYMAKCALAN, PHARMDDepartment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA
        • GUILLERMO DE VELASCO, MDDepartment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA
        • SUZANNE S MICKEY, BSDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, MA
        • ANDRE P FAY, MDDepartment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA
        • TONI K. CHOUEIRI, MDDepartment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA

        Renal cell carcinoma (RCC) is the most common type of kidney cancer, and its incidence has continued to increase in the United States. Well-defined risk factors include smoking, obesity, and hypertension. There have been significant developments in the management of RCC over the past decade, pertaining to both patients with localized disease and those with advanced disease. In particular, agents targeting the vascular endothelial growth factor and mammalian target of rapamycin pathways have considerably improved survival for patients with metastatic disease. This review covers the epidemiology and pathogenesis of RCC, management of both localized and advanced disease, selection and sequencing of systemic therapy, non–clear cell RCC, and new targets and future directions for RCC. Figures show the morphologic features of RCC, the pathogenesis of RCC, and a huge primary RCC occupying a substantial part of the abdominal cavity. Tables include a summary of clinical and molecular characteristics of hereditary RCC syndromes and randomized phase III trials of approved first-line treatments in metastatic RCC.

        This review contains 3 highly rendered figures, 2 tables, and 59 references.

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      • 6

        Late Stage Prostate Cancer

        By Karthik Giridhar, MD; Manish Kohli, MD
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        Late Stage Prostate Cancer

        • KARTHIK GIRIDHAR, MDOncology Fellow, Mayo Clinic, Division of Medical Oncology, Rochester, MN
        • MANISH KOHLI, MDProfessor of Oncology, Mayo Clinic, Division of Medical Oncology, Rochester, MN

        Prostate cancer remains the second leading cause of cancer death in men and encapsulates a wide spectrum of disease. This review describes recent advances in genomic sciences and summarizes the impact of emerging molecular profiling–based clinical applications in the diagnosis and management of early and advanced prostate cancer. It addresses the controversial guidelines surrounding prostate-specific antigen–based screening for prostate cancer and summarizes the recommendations from six different agencies. This review highlights landmark clinical trials in metastatic prostate cancer, focusing on developments within the last 5 years. It also summarizes the rationale for earlier use of chemotherapy for newly diagnosed prostate cancer (chemohormonal therapy) and gives an overview of ongoing research into the development of novel genome-based therapeutics.

        This review contains 4 figures, 8 tables, and 74 references.

        Key words: castration resistant, molecular profiling, prostate cancer, screening guidelines, treatment options

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    • Other Solid Tumors
      • 1

        Sarcomas of Soft Tissue and Bone

        By Adam Lerner, MD; Huihong Xu, MD; Karen H Antman, MD
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        Sarcomas of Soft Tissue and Bone

        • ADAM LERNER, MDProfessor of Medicine and Pathology, Boston University School of Medicine, Boston, MA
        • HUIHONG XU, MDAssistant Professor of Pathology, Boston University School of Medicine, Boston, MA
        • KAREN H ANTMAN, MDDean, Boston University School of Medicine, Provost, Boston University Medical School Campus, Boston, MA

        Sarcomas originate from bone or soft tissue. The most common bone sarcomas are osteosarcomas, Ewing sarcomas, and chondrosarcomas. Soft tissue sarcomas develop in fibrous tissue, fat, muscle, blood vessels, and nerves. Historically, soft tissue sarcomas of the trunk and extremities were reported separately from those of visceral organs (e.g., gastrointestinal and gynecologic sarcomas). This chapter discusses the classification, epidemiology, diagnosis, staging, and treatment of sarcomas of bone and cartilage, and classic soft tissue sarcomas. Management of Kaposi sarcoma, gastrointestinal stromal tumors (GISTs), mesothelioma, and rhabdomyosarcoma is also described. Figures include images of patients with osteosarcoma, liposarcoma, uterine leiomyosarcoma, GIST, and osteosarcoma in a patient with Paget disease of bone. Tables list epidemiologic features of sarcomas, a summary of sarcomas by histology, familial syndromes associated with increased risk of sarcoma, survival rates in sarcoma patients, staging of soft tissue sarcomas, and results of a meta-analysis of doxorubicin-based adjuvant chemotherapy for localized resectable soft tissue sarcoma. This chapter contains 126 references.

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      • 2

        Management of Gastrointestinal Stromal Tumors

        By César Serrano, MD, PhD; Suzanne George, MD
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        Management of Gastrointestinal Stromal Tumors

        • CÉSAR SERRANO, MD, PHDHead, Sarcoma Translational Research Laboratory and Sarcoma Unit, Oncology Department, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain
        • SUZANNE GEORGE, MDClinical Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA

        Gastrointestinal stromal tumors (GISTs) are the most common tumors of mesenchymal origin in the gastrointestinal tract. These tumors are believed to arise from the interstitial cells of Cajal. The oncogenic activation of KIT or platelet-derived growth factor receptor–α is common to these tumors, and GISTS are considered to be a successful model for rational development of personalized treatments against oncogenic driver mutations in cancer. This review covers the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of GISTs. Figures show KIT primary and secondary mutations, the clinical and molecular progression of GISTs, a contrast-enhanced computed tomographic scan showing a gastric GIST presenting as a huge abdominal mass, a magnetic resonance image showing a rectal GIST at baseline and responding to neoadjuvant imatinib after 8 months of treatment, and hematoxylin-eosin stain of a fusocellular and an epithelioid GIST. Tables list demographics and clinical characteristics, associated genetic syndromes, relevant differential diagnosis, risk stratification systems used in GIST, and the comparative activity of approved regimens for GIST.

        This review contains 5 highly rendered figures, 5 tables, and 74 references.

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      • 3

        Primary and Metastatic Central Nervous System Malignancies

        By Fabio M. Iwamoto, MD; Howard A. Fine, MD
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        Primary and Metastatic Central Nervous System Malignancies

        • FABIO M. IWAMOTO, MDAssistant Clinical Investigator, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
        • HOWARD A. FINE, MDSenior Investigator and Chief, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

        About 13,000 deaths each year in the United States are attributed to primary central nervous system (CNS) malignancies. An estimated 20% of patients with cancer eventually develop clinically apparent CNS metastases, and an estimated 170,000 cases of brain metastases are diagnosed in the United States yearly. Autopsy studies suggest that as many as 50% of patients dying from advanced cancer may have metastasis to the CNS. This chapter provides an overview of primary and metastatic CNS malignancies with in-depth discussion of gliomas, primary CNS lymphoma, meningioma, brain metastases, leptomeningeal metastases, and metastatic epidural spinal cord compression. Discussions cover epidemiology, etiology, diagnosis, and treatment of gliomas, including surgery, radiotherapy, and chemotherapy for both newly diagnosed gliomas and recurrent gliomas. The epidemiology, diagnosis, treatment and prognosis for primary CNS lymphomas are reviewed, as well as the epidemiology, etiology, diagnosis, treatment, and prognosis for meningiomas. Epidemiology, diagnosis, and prognosis for brain metastases are briefly discussed, and the section on treatment includes surgery, stereotactic radiosurgery, and whole-brain radiotherapy for patients with three or fewer brain metastases. The sections on leptomeningeal metastases and metastatic epidural spinal cord compression cover diagnosis, treatment, and prognosis. This chapter contains 126 references.

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  • Organ Systems: Anatomy & Physiology
    • 1

      Cardiac System

      By David C Mauchley, MD
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      Cardiac System

      • DAVID C MAUCHLEY, MD

      The circulatory system, which consists of the heart, arterial system, venous system, and lymphatics, constitutes a complicated network of vessels and ducts that are responsible for the delivery of oxygenated blood to the body and return of deoxygenated blood to the heart and lungs. The heart is at the center of the circulatory system, and its pumping mechanism provides energy and nutrition to all organs in the body. This review focuses on the anatomy and physiology of the heart and describes anatomic details that are important to the planning of many common cardiac operations.   

      This review contains 28 figures, and 25 references.

      Key words: aortic root, aortic valve, atrial septum, atrioventricular node, coronary artery, fibrous skeleton of heart, mitral valve, myocardium, pericardium, pulmonic valve, sinoatrial node, tricuspid valve, ventricular septum 

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    • 2

      The Respiratory System

      By Suresh Agarwal, MD, FACS, FCCM; Hee Soo Jung, MD; Walker Julliard, MD
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      The Respiratory System

      • SURESH AGARWAL, MD, FACS, FCCMChief, Section of Trauma, Acute Care Surgery, Burn & Surgical Critical Care, Associate Professor, Department of Surgery, University of Wisconsin, Madison, WI
      • HEE SOO JUNG, MDAssistant Professor, Department of Surgery, University of Wisconsin, Madison, WI
      • WALKER JULLIARD, MDResident, Department of Surgery, University of Wisconsin, Madison, WI

      This review discusses gas exchange and transport processes in the lungs; anatomic considerations; impact on the circulatory system (airway pressure, lung volume, regional pleural pressures); normal ventilation, including the mechanics of breathing; and pulmonary function assessment, including pulse oximetry, capnometry, pulmonary function testing, physiologic variations in respiration, perioperative physiologic changes, risk factors for and strategies to prevent postoperative pulmonary complications, initial airway/respiratory evaluation and management, mechanical ventilator strategies, oxygenation, ventilation, adjuncts and rescue therapies, and weaning from mechanical ventilation. Tables describe patient-specific risk factors for noncardiothoracic postoperative pulmonary complication, chronic obstructive lung disease optimization strategies, the Glasgow Coma Scale, and the LEMON mnemonic. Figures show gas exchange at the alveolar capillary membrane, factors affecting the oxygen dissociation curve, uneven distribution of air and blood in different zones of the lung, carbon dioxide metabolism in the lungs and periphery, the lateral wall of the right nasal cavity, sagittal section of the upper aerodigestive tract, tracheobronchial tree, diaphragmatic motion during respiration, schematic diagram of normal filtration and resorption of fluid in the pleural space, respiratory tree, neurologic control of respiration, pressure gradient between the pleural space and the airway, pressure-volume curve, the four phases of a capnogram, lung volumes and capacities, the 3-3-2 rule, evaluation of the oropharynx, transnasal introduction of a flexible bronchoscope, ventilator waveforms, and the therapeutic ladder in the management of acute respiratory distress syndrome.

      This review contains 20 highly rendered figures, 4 tables, and 113 references.

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    • 3

      The Renal System

      By Jayme E. Locke, MD, MPH, FACS; John T Killian Jr, MD
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      The Renal System

      • JAYME E. LOCKE, MD, MPH, FACSAssistant Professor of Surgery, Division of Transplantation, University of Alabama at Birmingham, Birmingham, AL
      • JOHN T KILLIAN JR, MDResident, General Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL

      This updated review on the renal system provides a concise overview of the topics most important to the general surgeon. Anatomic topics have been expanded to also include variant anatomy and surgical approaches. There is a new focus on the accuracy and utility of equations for estimating the glomerular filtration rate, as well as supplementation and pharmacology for the general surgeon with discussions of vitamin D and erythropoietin. Acute kidney injury is defined; its pathophysiology is discussed; and its management is outlined, highlighting evidence-based practice. Finally, urologic surgery is addressed with a focus on donor nephrectomy and its consequences, as well as the management of iatrogenic ureteral injuries.

      This review contains 6 highly rendered figures, 6 tables, and 68 references.

      Key words: acute kidney injury; contrast nephropathy; erythropoiesis-stimulating agents; estimated glomerular filtration rate; iatrogenic ureteral injury; laparoscopic donor nephrectomy; renal surgical anatomy; vitamin D supplementation

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    • 4

      The Esophagus

      By Michael Frank Gleason, MD; Benjamin Wei, MD
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      The Esophagus

      • MICHAEL FRANK GLEASON, MDGeneral Surgery Resident, Department of Surgery, University of Alabama-Birmingham Medical Center, Birmingham, AL
      • BENJAMIN WEI, MDAssistant Professor, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL

      The esophagus is a tubular structure spanning from the posterior pharynx, through the thorax, and terminating in the stomach. It arises from endodermal foregut tissue. Its submucosal muscular layers are initially striated, transitioning to smooth muscle in more distal areas. Due to the distance in the body it traverses, the esophagus derives its blood and nerve supply from several structures. The role as a conduit from mouth to stomach necessitates secretory and barrier functions, as well as sphincters for protection from anterograde flow. Various modalities of esophageal test exist, ranging from fluoroscopy, to invasive endoscopy capable of obtaining tissue samples, to probes that detect pH and muscle tone, all of which play roles in identifying various pathologic processes.

      This review contains 12 figures, and 22 references.

      Key words: abdomen, endoscopy, esophagography, esophagus, impedance, lower sphincter, manometry, upper sphincter

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    • 5

      The Endocrine System: Pituitary and Adrenal Glands

      By Haggi Mazeh, MD; Iddo Paldor, MD; Herbert Chen, MD, FACS
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      The Endocrine System: Pituitary and Adrenal Glands

      • HAGGI MAZEH, MDClinical Instructor, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
      • IDDO PALDOR, MDClinical Instructor, Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
      • HERBERT CHEN, MD, FACSChairman, Division of General Surgery, Layton F. Rikkers M.D. Chair in Surgical Leadership, Vice-Chair for Research, Department of Surgery, University of Wisconsin, Madison, WI

      This review presents the pituitary gland--where the neural and endocrine systems function in continuity, maintaining homeostasis of many functional elements of the human body and the adrenal glands with their two hormone-secreting organs: the cortex and the medulla. The embryology and development, anatomy, normal physiology of each gland is presented. Figures show a midsagittal view of the brain; the pituitary blood supply, venous drainage, and portal system; a summary of pituitary hormones and their main acions; the adrenal layers and hormones; the adrenal blood supply and venous drainage; synthetic pathways for adrenal steroid synthesis; and major steps in catecholamine synthesis and degradation.

      This review contains 7 highly rendered figures and 61 references.

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    • 6

      The Endocrine System: Thyroid and Parathyroid

      By David F. Schneider, MD, MS; Rebecca S. Sippel, MD, FACS
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      The Endocrine System: Thyroid and Parathyroid

      • DAVID F. SCHNEIDER, MD, MSClinical Instructor of Surgery, Department of Surgery, University of Wisconsin, Madison, WI
      • REBECCA S. SIPPEL, MD, FACSAssistant Professor Surgery, Department of Surgery, University of Wisconsin, Madison, WI

      Successful surgery of the thyroid and parathyroid glands depends on a thorough knowledge of their anatomic and developmental relations. The surgeon should understand the physiology and function of these glands. Physiology, not anatomy alone, often dictates the timing and course of thyroid or parathyroid procedures. Development, anatomy, blood supply, lymphatic drainage, histology, and physiology are covered in order for the thyroid and the parathyroid. This review contains 36 references. Seven figures of highly rendered artwork include well-illustrated anatomical position and orientation. Figure 4 illustrates thyroid hormone synthesis and secretion.

      This review contains 7 highly rendered figures and 36 references.

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    • 7

      The Liver and Portal System

      By Jared A White, MD, FACS
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      The Liver and Portal System

      • JARED A WHITE, MD, FACS

      Understanding of the anatomy and physiology of the liver and techniques for safe anatomic and nonanatomic liver resections has evolved over the past several decades. The liver is composed of a complex arterial and portal venous inflow, which has several important variants that are crucial for the surgeon to understand when planning hepatic resections, both anatomic and nonanatomic. In addition, intra- and extrahepatic biliary configurations may be encountered, and variants must be recognized to prevent complications during common surgical procedures, such as cholecystectomy and liver resection. The liver is responsible for numerous metabolic, homeostatic, and immunologic processes throughout the body. It is crucial for the practicing physician and surgeon to have a fundamental understanding of hepatic anatomy and physiology when treating patients with derangements in liver structure and function. 

      Key words: bile duct, bilirubin, bilirubin metabolism, hepatic artery, hepatic blood flow, hepatic parenchyma microstructure, liver anatomy, portal hypertension, portal vein

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    • 8

      Gallbladder and Biliary Tree

      By Stephen Gray, MD, MSPH
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      Gallbladder and Biliary Tree

      • STEPHEN GRAY, MD, MSPH

      Understanding gallbladder and biliary anatomy is paramount to the surgeon. A comprehensive understanding of the gallbladder and biliary tree is necessary to properly treat a variety of surgical pathologies. Understanding the usual anatomy and the variations will help prevent iatrogenic biliary injuries. Moreover, anatomic consideration dictates oncologic therapies for gallbladder and biliary tract malignancies. 

      Key words: bile duct, bile salts, biliary tree, cholecystectomy, gallbladder

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    • 9

      Anatomy and Physiology of the Pancreas

      By John A. Windsor, MBChB, MD, FRACS, FACS
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      Anatomy and Physiology of the Pancreas

      • JOHN A. WINDSOR, MBCHB, MD, FRACS, FACSProfessor of Surgery, Department of Surgery, University of Auckland, Auckland, New Zealand

      The pancreas is the body’s largest digestive gland, situated in the center of the body, on either side of the transpyloric plane. It is notable for its complex anatomy and the co-location of exocrine and endocrine organs. Pancreatic surgery requires a detailed understanding of the anatomy of the pancreas and its relation to adjacent vital structures. This review describes the morphology of the pancreas, its ductal system, the major duodenal papilla, arterial anatomy, venous anatomy, lymphatic draining, and nerve supply. Because managing patients with pancreatic diseases requires a detailed understanding of the physiology of the exocrine and the endocrine pancreas, both are discussed here.

      This review contains 16 highly rendered figures and 15 references.

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    • 10

      The Spleen

      By Donald P. Lesslie III, DO; Lillian S. Kao, MD, MS
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      The Spleen

      • DONALD P. LESSLIE III, DOAssistant Professor, Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX
      • LILLIAN S. KAO, MD, MSAssociate Professor, Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX

      The structure of the spleen allows it to carry out its major functions, which can be categorized as hematologic and immunologic. The importance of the spleen in the immunologic response is evidenced by the increased risk of infection in patients with congenital absence of splenic dysfunction and in splenectomized patients. The presence of one or more accessory spleens is the most common congenital abnormality related to splenic development. This review covers the history, embryology, congenital anomalies, anatomy, and histology/pathophysiology of the spleen. It is important for the student and general surgeon to understand the anatomy and physiology of the spleen to perform operative procedures on the spleen, to avoid intraoperative complications during splenectomy as well as procedures such as mobilization of the splenic flexure and distal pancreatectomy, and to care for the postoperative splenectomized patient.

      This review contains 7 highly rendered figures and 17 references.

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    • 11

      The Stomach

      By Carla N Holcomb, MD, MSPH; Britney L Corey, MD
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      The Stomach

      • CARLA N HOLCOMB, MD, MSPHResident, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
      • BRITNEY L COREY, MDAssistant Professor, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL

      This review discusses the anatomy and physiology of the stomach. The embryologic origins of the foregut are described, as well as how malformations in development lead to pathology. Color illustrations are included detailing the stomach and its surrounding attachments. The neurohormonal pathways involved in the mechanics of gastric motility and gastric acid secretion are described in detail. The biochemistry involved in the digestion of fats, carbohydrates, and proteins is explained, and a summary table of gut hormones and their source and function has been provided. Additionally, an update on how the knowledge of hormonal pathways governing appetite is being used in pharmaceuticals and bariatric surgery to treat obesity is included.  

      Key words: acid suppression, digestion, foregut, ghrelin, leptin, motility, obesity, stomach, vagus nerve

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    • 12

      The Duodenum

      By Richard A Burkhart, MD; Sean Ronnekleiv-Kelly, MD
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      The Duodenum

      • RICHARD A BURKHART, MD
      • SEAN RONNEKLEIV-KELLY, MDSurgical Resident, Section of Colon and Rectal Surgery, Department of Surgery, University of Wisconsin, Madison, WI

      The duodenum is the first part of the small intestine that arises from the embryologic foregut and midgut. With maturation, it lies mostly retroperitoneal and is intimately associated with nearby structures such as the pancreas, hepatoduodenal ligament, and transverse colon mesentery. It is well vascularized with a rich lymphatic network and supports digestive, absorptive, immune, and endocrine functions. The duodenum receives food bolus from the stomach and releases various hormones important for regulating motility and gastric acid secretion. In the duodenum, food content mixes with bile and pancreatic enzymes to continue digestion of and initiate absorption for fats, carbohydrates, proteins, and vitamins and minerals. The duodenum experiences substantial exposure to the external environment and therefore contains an extensive immune barrier, including mucosa-associated lymphoid tissue. Additionally, there is a significant neuroendocrine network within the duodenum and small intestine that possesses a variety of endocrine functions, including regulation of acid secretion, motility, pancreatic function, bile flow, and mucosal cell growth. These enterochromaffin cells are the source duodenal neuroendocrine tumors (carcinoid) and can be classified according to subtype or grade. The duodenum is a diverse component of the small intestine that is uniquely suited to its numerous functions.    

      Key words: absorption, acid secretion, anatomy, digestion, duodenum, intestinal immune system, microstructure, motility, mucosa-associated lymphoid tissue, neuroendocrine

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    • 13

      Small Bowel

      By Vincent E Mortellaro, MD
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      Small Bowel

      • VINCENT E MORTELLARO, MDAssistant Professor, Division of Pediatric Surgery, Department of General Surgery, University of Alabama at Birmingham, Birmingham, AL

      The small intestine is where multiple cell types combine to achieve the complex interaction between our bodies and ingested material from the outside world. As a highly specialized organ, the small intestine has a role in digestion, absorption of nutrients and electrolytes, and innate immunity to thwart exogenous pathogens and as host to a symbiotic environment where our immune system successfully interacts with a resident microbiome. This review covers the embryology, gross and microscopic anatomy, physiology of nutritional absorption, immune function, and advances in examining new discoveries in the interplay between the host and the resident microbiome.

      Key words: duodenum, ileum, jejunum, microbiota, midgut, migrating motor complex, nutritional absorption, villi

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    • 14

      Human Adult Reproductive System

      By Patrick Guthrie, MD; Johanna Von Hofe, MD; Rachael B Lancaster, MD
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      Human Adult Reproductive System

      • PATRICK GUTHRIE, MD
      • JOHANNA VON HOFE, MD
      • RACHAEL B LANCASTER, MD

      The human reproductive system is a unique combination of organs and endocrine components that is extremely complex and adaptive. The reproductive organs are distinct between males and females, and sexual differentiation is a result of genotype, gonadal type, and phenotype. The anatomic and physiologic system of each sex is composed with a set purpose: to propagate the human species. Linked closely to the reproductive system is the endocrine system, which provides the messengers and feedback mechanisms that allow the development, maintenance, and function of the reproductive organs. The gonads have both endocrine and exocrine functions, namely steroidogenesis and gametogenesis. This review focuses on the components of the endocrine system as well as male and female anatomy and physiology to fully grasp the human reproductive system. 

      Key words: fertility, hypothalamic-pituitary-adrenal axis, reproductive anatomy, sexual aging, sexual physiology

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    • 15

      The Colon, Appendix, Rectum, and Anus

      By Margaret M Romine, MD, MS; Daniel I. Chu, MD
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      The Colon, Appendix, Rectum, and Anus

      • MARGARET M ROMINE, MD, MS
      • DANIEL I. CHU, MDAssistant Professor of Surgery, Section of Gastrointestinal Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL

      The colon, appendix, rectum, and anus have unique anatomic features, both structural and functional, that contribute to normal and pathologic states. Structural features discussed in this review include the layers of the intestinal wall, vascular anatomy, lymphatic drainage, and innervation. Functional features highlighted include the role(s) each organ plays in immunity, nutrient absorption, electrolyte secretion, water absorption, continence, and elimination of waste. A clear understanding of these structural and functional details is the foundation on which surgical techniques and treatment strategies are based when addressing surgical pathology.

      This review contains 7 highly rendered figures, 3 tables, and 58 references.

      Key words: anus, appendix, colon, colorectal pathology, colorectal surgery, rectum

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    • 16

      The Parathyroids

      By Courtney J. Balentine, MD, MPH; C Taylor Geraldson, MD
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      The Parathyroids

      • COURTNEY J. BALENTINE, MD, MPHAssistant Professor, Section of Gastrointestinal and Endocrine Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
      • C TAYLOR GERALDSON, MDResident Physician, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL

      Successful surgery of the parathyroid glands depends on a thorough knowledge of their anatomic and developmental relations. This knowledge is crucial for locating ectopic parathyroids or preventing injury to the recurrent laryngeal nerve. In addition, the surgeon should understand the physiology and function of these glands. Unlike other conditions a surgeon might treat, physiology, and not anatomy alone, often dictates the timing and course of parathyroid procedures. This surgeon-oriented, focused review covers the development, histology, anatomy, physiology, and pathophysiology of the parathyroid. Figures show the location and frequencies of ectopic upper and lower parathyroid glands, and regulation of calcium homeostasis.

      This review contains 2 highly rendered figures, and 16 references

      Key words: calcitonin; hypercalcemia; hyperparathyroidism; multiple endocrine neoplasia; parathyroid; parathyroid hormone; primary hyperparathyroidism; secondary hyperparathyroidism; tertiary hyperparathyroidism

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    • 17

      The Endocrine System: Adrenal Glands

      By Abbas Al-Kurd, MD; Haggi Mazeh, MD, FACS
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      The Endocrine System: Adrenal Glands

      • ABBAS AL-KURD, MDClinical Instructor, Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel
      • HAGGI MAZEH, MD, FACSAssociate Professor, Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel

      The adrenal glands represent an essential component of the endocrine system, and their failure can have catastrophic consequences to several aspects of bodily homeostasis. Each adrenal gland can be divided into two different endocrine components, the cortex and the medulla, each with distinct functions. This in-depth review of normal adrenal embryology, anatomy, and physiology also emphasizes the clinical relevance of various irregularities in adrenal functioning. Every surgeon attempting to manage adrenal diseases is expected to be familiar with the detailed pathophysiology of these conditions because such an understanding is essential for sound preoperative evaluation and perioperative management of this potentially complicated patient group. 

      This review contains 4 figures, 1 table, and 70 references.

      Key words: adrenal, adrenal glands, adrenal pathophysiology, adrenal physiology, anatomy of adrenal glands, cortex, embryology, endocrine system, medulla

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  • Palliative Medicine
    • 1

      Principles and Practice of Palliative Care

      By Kristen G Schaefer, MD; Rachelle E Bernacki, MD, MS
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      Principles and Practice of Palliative Care

      • KRISTEN G SCHAEFER, MDDirector of Medical Student and Resident Education, Division of Adult Palliative Care, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Center for Palliative Care, Harvard Medical School, Division of General Internal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
      • RACHELLE E BERNACKI, MD, MSDirector of Quality Initiatives, Division of Adult Palliative Care, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Center for Palliative Care, Harvard Medical School, Division of Aging, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

      The trajectories of serious illness and dying have changed in the last century; in the past, patients lived shorter lives and often died quickly of infectious disease, whereas patients in the 21st century live longer and often with prolonged debility in the advanced stages of illness. As a result, patients with serious illness can suffer undertreated symptoms and often feel poorly prepared for the final stages of disease. With more options for advanced life support and other aggressive interventions at the end of life, patients and families face increasingly complex medical decisions in the terminal phase of illness, and the treatments they receive do not always align with their goals and values. Emerging evidence suggests that integrating palliative care into the treatment of advanced illness can improve outcomes, decrease costs, and improve both patient and family satisfaction. Consequently, patient access to high-quality specialty-level palliative care is becoming standard of care at most academic cancer centers and more available in the community. This chapter describes the practice and principles of specialty-level palliative care and outlines specific "generalist" palliative care competencies essential for all physicians caring for patients with serious illness, including prognostication, patient-centered communication, and the navigation of ethical dilemmas in the field of palliative care. Tables outline the philosophy of palliative care, domains of suffering, location of death of hospice patients, the palliative performance scale, median survival times for cancer syndromes, indicators associated with a poorer prognosis in congestive heart failure, the NURSE mnemonic for accepting and responding to emotion, palliative care communication competencies in the intensive care unit, and the SPIKES mnemonic for breaking bad news. Figures depict causes of death in 1900 versus 2010, palliative care through the trajectory of serious illness, theoretical trajectories of disease, life expectancies for women and men, mortality at 1 year post discharge, and a model for patient-centered communication.

      This review contains 6 highly rendered figures, 9 tables, and 169 references.

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    • 2

      Symptom Management in Palliative Medicine

      By Kathy J Selvaggi, MD; Janet L Abrahm, MD
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      Symptom Management in Palliative Medicine

      • KATHY J SELVAGGI, MDAssistant Professor of Medicine, Harvard Medical School, Director, Intensive Palliative Care Unit, Brigham and Women’s Hospital, Boston, MA
      • JANET L ABRAHM, MDProfessor of Medicine, Harvard Medical School, Division Chief, Adult Palliative Care, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA

      Palliative care is an interdisciplinary specialty focused on providing comfort, communication, and support for patients, families, and professional caregivers throughout the course of a life-limiting illness. This chapter discusses assessment and treatment of symptoms and disorders that commonly contribute to patient distress during these illnesses: pain, disorders of the respiratory and gastrointestinal systems, skin disorders, hot flashes, fatigue, pruritis, insomnia, and delirium. This chapter reviews care of the imminently dying patient, discusses methods for assessing patients' symptoms, and provides two examples of valid and reliable symptom measurement systems: the Edmonton Symptom Assessment Scale and the Memorial Symptom Assessment Scale. Achieving symptom control requires the physician to assess patient suffering in all dimensions: physical, psychological, social, and spiritual. The extent of the assessment may be modified, however, based on patients’ prognosis as well as their goals and the burden and benefit of the diagnostic intervention. A 10-step protocol for terminal wean is presented. Signs that patients are entering their final days and symptom management in the last hours of a patient's life are discussed. Tables list the modified Edmonton Symptom Assessment Scale; the Memorial Symptom Assessment Scale; the DOLOPLUS-2 scale (behavioral pain assessment in the elderly); relative potencies of commonly used opioids; conversions between the transdermal fentanyl patch and morphine; symptomatic treatment for dyspnea, cough, and hiccups; pharmacologic treatment of nausea and vomiting; a progressive bowel regimen for patients receiving opioid therapy; treatments for constipation; etiology-based treatment for oral problems; risk factors for pressure ulcers; and applicable medications for physical and psychological sources of distress near the end of life. This chapter contains 12 tables, 120 references, 5 MCQs.

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    • 3

      Management of Psychosocial Issues in Terminal Illness

      By Eva Reitschuler-Cross, MD; Susan D Block, MD; Jane DeLima Thomas, MD
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      Management of Psychosocial Issues in Terminal Illness

      • EVA REITSCHULER-CROSS, MDClinical Assistant Professor of Medicine, University of Pittsburgh, Section of Palliative Care and Medical Ethics, University of Pittsburgh Medical Center, Pittsburgh, PA
      • SUSAN D BLOCK, MDChair, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute and Brigham and Women’s Hospital Co-Director, HMS Center for Palliative Care, Professor of Psychiatry and Medicine, Harvard Medical School, Boston, MA
      • JANE DELIMA THOMAS, MDAttending Physician, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Instructor in Medicine, Harvard Medical School, Boston, MA

      Patients facing serious or life-threatening illness experience challenges to their psychological, social, and spiritual lives as well as to their physical function and comfort. Physicians may be accustomed to focusing on the biomedical aspects of illness, but they have a critical role in assessing the patient's psychosocial issues to identify sources of distress and help implement a plan for mitigating them. An appropriate psychosocial assessment requires a methodical and rigorous approach and includes assessment of any psychosocial issue affected by or affecting a patient's experience of illness. This chapter outlines a structured approach to addressing psychosocial issues by discussing (1) the doctor-patient relationship; (2) coping with illness; (3) family dynamics and caregiving; (4) ethnic and cultural issues; (5) religious, spiritual, and existential issues; (6) mental health issues, including adjustment disorder, depression, anxiety, personality disorders, aberrant drug behaviors, and major mental health issues; and (7) grief and bereavement. Tables outline psychosocial assessment questions, factors predisposing patients with serious illness to depression, risk factors for suicide in patients with terminal illness, and classes of antidepressants, anxiolytics, and sedatives. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire is provided, as well as a list of Web sites with further resources about psychosocial issues in serious illness.


      This chapter contains 1 highly rendered figure, 6 tables, 216 references, and 5 MCQs.

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  • Psychiatry
    • 1

      Schizophrenia

      By Gunvant K. Thaker, MD; William T Carpenter Jr, MD
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      Schizophrenia

      • GUNVANT K. THAKER, MDProfessor of Psychiatry, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
      • WILLIAM T CARPENTER JR, MDProfessor of Psychiatry and Pharmacology, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD

      Schizophrenia is a clinical syndrome probably comprising several as-yet undefined disease entities. There is substantial heterogeneity between cases, which presumably reflects multiple overlapping etiologic factors, including contributions from several genes. The presence of schizophrenia is indicated by chronic psychotic symptoms, especially hallucinations and delusions. Disorganization of thought and behavior are common and distinguish schizophrenia from the many other causes of reality-distortion symptoms (eg, psychotomimetic drugs). Diminished emotional experience and expression, low drive, and reduced speech are observed in a subgroup of patients. Most patients have subtle impairments in cognition. Cognitive impairments and the emotional and social aspects of the disease often appear early in life; the psychotic symptoms typically begin in late adolescence or early adulthood in men and a little later in women. This chapter discusses the epidemiology, etiology and genetics, and pathophysiology of schizophrenia; its clinical course; the diagnosis and differential diagnosis; and its treatment, including pharmacologic management and psychosocial interventions. A figure illustrates comparative findings on functional magnetic resonance in schizophrenic and nonschizophrenic patients. Tables list diagnostic criteria for schizophrenia; cognitive disturbances seen in schizophrenic speech; medical conditions, drugs, and medications associated with psychotic symptoms; and antipsychotic drugs used in the treatment of schizophrenia. This chapter contains 63 references.

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    • 2

      Anxiety Disorders

      By Brian M. Iacoviello, PhD; Sanjay J Mathew, MD
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      Anxiety Disorders

      • BRIAN M. IACOVIELLO, PHDPsychology Fellow, Department of Psychiatry, VA VISN3 Mental Illness Research, Education and Clinical Center (MIRECC) and Mount Sinai School of Medicine, New York, NY
      • SANJAY J MATHEW, MDDirector, Mood Disorders Center, Associate Professor of Psychaitry, Baylor College of Medicine, Medical Director, Comprehensive Mental Health Program, Michael E. Debakey VA Medical Center, Houston, TX, Menninger Department of Psychiatry and Behavioral Sciences

      Anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, acute stress disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. They all share symptoms to a great extent, but they also have distinct clinical features and typical presentations. Diagnosis for each requires the presence of specific criteria. Anxiety disorders are best managed through a systematic approach to diagnosis, treatment, and, when necessary, referral to a specialist. Treatment includes pharmacotherapy and psychotherapy, with cognitive-behavioral therapy repeatedly shown to be among the most effective. If a physician decides to refer the patient to a mental health professional, it's best to tread lightly because some patients will resist.

      This review contains 1 figure, 4 tables, and 33 references.

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    • 3

      Mood Disorders

      By Jair C Soares, MD; Hasan A Baloch, MD
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      Mood Disorders

      • JAIR C SOARES, MDProfessor and Chairman, Department of Psychiatry and Behavioral Sciences, UT Houston Medical School
      • HASAN A BALOCH, MDAssistant Professor, Department of Psychiatry, Medical Director, Pediatric Bipolar Program, CERT-BD, UNC School of Medicine, Chapel Hill, NC

      Affective disorders are among the most common disorders in psychiatry. They are generally classified according to the persistence and extent of symptoms and by the polarity of these symptoms. The two poles of the affective spectrum are mania and depression. Bipolar disorder is characterized by the presence of the mania or hypomania and often depression. Unipolar depression is defined by depression in the absence of a lifetime history of mania or hypomania. These differences are not merely categorical but have important implications for the prognosis and treatment of these conditions. Bipolar disorder, for example, is better treated using mood-stabilizing medication, whereas unipolar depression responds optimally to antidepressant medications. In addition, prognostically, unipolar depression may sometimes be limited to one episode in a lifetime, whereas bipolar disorder is typically a lifelong condition. The course of both conditions, however, is often chronic, and frequently patients can present with unipolar depression only to later develop manic symptoms. A thorough understanding of both conditions is therefore required to treat patients presenting with affective symptomatology. This chapter discusses the epidemiology, etiology and genetics, pathogenesis, diagnosis, and treatment of unipolar depression and bipolar disorder. Figures illustrate gray matter differences with lithium use and the bipolar spectrum. Tables list the pharmacokinetics of commonly used antidepressants and medications commonly used in the treatment of bipolar disorder.

      This review contains 2 figures, 2 tables, and 136 references.

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    • 4

      The Eating Disorders

      By W Stewart Agras, MD
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      The Eating Disorders

      • W STEWART AGRAS, MDProfessor of Psychiatry, Department of Psychiatry, Stanford University School of Medicine, Stanford CA

      The eating disorders–anorexia nervosa, bulimia nervosa, binge eating disorder, and night eating syndrome–tend to be chronic conditions and are frequently accompanied by depression, anxiety disorders, and personality disorders. In addition, serious medical problems are associated with anorexia nervosa (because of chronic starvation) and with binge-eating disorder (because of obesity). Eating disorders may also be associated with marked life impairment, faulty interpersonal interactions, and social withdrawal. In women, the lifetime prevalence of eating disorders that meet full diagnostic criteria is about 4%. If subclinical cases are included, the overall prevalence of eating disorders in the female population is probably between 6 and 8%. Ten percent of cases of eating disorders occur in males. This chapter discusses the epidemiology of eating disorders and reviews the genetic and cultural factors that contribute to their development. The diagnosis and treatment of each of the eating disorders are considered separately. A table lists the points to be considered for management of bulimia nervosa once the diagnosis is made, and an algorithm outlines decision points in the management of anorexia nervosa. This chapter contains 34 references.

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    • 5

      Adjustment Disorders

      By James J Strain, MD; Matthew Friedman, MD, PhD
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      Adjustment Disorders

      • JAMES J STRAIN, MDProfessor of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, NY
      • MATTHEW FRIEDMAN, MD, PHDNational Center for PTSD, US. Department of Veterans Affairs, Dartmouth Medical School, VA Medical Center, White River Junction

      The adjustment disorder (AD) diagnosis has clinical appeal to both doctors and patients. The idea of temporary emotional symptoms resulting directly from a stressful life event is viewed as a more normal human reaction than an idiopathic pathologic psychiatric state and is therefore less stigmatizing. Additionally, the disorder's more benign course (especially in adults) encourages a clinician to be more prognostically optimistic. This chapter discusses the prevalence, epidemiology, course and prognosis, and etiology of ADs. Also reviewed are AD subtypes proposed but not accepted for the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), including the acute stress disorder/posttraumatic stress disorder subtype and the bereavement-related subtype. Treatment options are covered, including psychotherapy, pharmacotherapy, and primary care. Tables outline diagnostic criteria for ADs in DSM-IV, stress-related disorders in DSM-5, DSM classifications, ADs in mental illness and medical settings, and subtypes of DSM-IV, text revision adjustment disorders. Graphs categorize patients diagnosed with ADs according to type of illness and the prognosis for recovery from ADs in adolescents and adults.
      This chapter contains 2 highly rendered figures, 6 tables, 109 references, and 5 MCQs.

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    • 6

      Management of Somatic Symptoms

      By Andreas Schröder, MD, PhD; Joel E Dimsdale, MD
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      Management of Somatic Symptoms

      • ANDREAS SCHRÖDER, MD, PHDConsultant in Psychiatry, The Research Clinic for Functional Disorders, Aarhus University Hospital, Aarhus, Denmark