THE NEXUS OF NASH AND T2DM

This activity is to be held in conjunction with the American Diabetes Association’s 78th Scientific Sessions.

Jointly provided by Postgraduate Institute for Medicine and Integritas Communications.

This activity is supported by an independent educational grant from Gilead Sciences, Inc.

MEDICAL COMMUNICATIONS INQUIRIES info@integritasgrp.com integritasgrp.com

KENNETH CUSI, MD, FACP, FACE Chair

FACULTY

FACULTY

Professor of Medicine Chief, Division of Endocrinology, Diabetes and Metabolism The University of Florida Gainesville, Florida

Dr. Kenneth Cusi serves as Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida. He received his medical degree in Argentina from the University of Buenos Aires School of Medicine and is board certified in both Internal Medicine and Endocrinology, Diabetes & Metabolism. He completed his residency at the Center of Medical Education & Clinical Research (CEMIC) in Buenos Aires, Argentina, and a clinical fellowship at Baylor College of Medicine in Houston, Texas. Prior to joining the University of Florida, Dr. Cusi was a faculty member for over 15 years in the Diabetes Division at the University of Texas Health Science Center at San Antonio and the Veterans Health Administration System in Texas, which is one of the leading diabetes programs in the country.

Dr. Cusi is a fellow of the American College of Physicians and the American Association of Clinical Endocrinologists (AACE). He has actively participated in many clinical diabetes programs and in the training of many young researchers and clinicians. He is the principal investigator of various ongoing clinical translational research projects in obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease.

3

STEPHEN A. HARRISON, MD FACULTY

Medical Director Pinnacle Clinical Research San Antonio, Texas

Dr. Stephen Harrison is the Medical Director of Pinnacle Clinical Research. He earned his medical degree from the University of Mississippi School of Medicine. He completed his Internal Medicine residency and Gastroenterology fellowship at Brooke Army Medical Center and a 4th year advanced liver disease fellowship at Saint Louis University. He is board certified in both Internal Medicine and Gastroenterology. Dr. Harrison served as a Professor of Medicine at the Uniformed Services University of the Health Sciences and is currently a Visiting Professor of Hepatology at the Radcliffe College of Medicine, University of Oxford. He is a past Associate Editor for Hepatology and is currently an Associate Editor for Alimentary Pharmacology and Therapeutics. He is a peer reviewer for over 20 medical journals and internationally known for studies in hepatitis C and nonalcoholic fatty liver disease with over 180 peer-reviewed publications in these fields.

Dr. Harrison most recently served as a Colonel in the United States Army. Retiring in 2016, he concluded 20 years of dedicated service to his country. During his army tenure, he served as the Director of Graduate Medical Education at Brooke Army Medical Center, Associate Dean for the San Antonio Uniformed Services Health Education Consortium, and Gastroenterology Consultant to the Army Surgeon General.

4

ARUN J. SANYAL, MBBS, MD, FAASLD FACULTY

Professor of Medicine, Physiology and Molecular Pathology Virginia Commonwealth University Richmond, Virginia

Dr. Arun Sanyal is Professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University (VCU). He has been a physician-scientist for 25 years. His research spans the spectrum of translational science from basic discovery to first in humans and advanced phase clinical trials and regulatory aspects of drug development. These studies revolve around cirrhosis and its complications and nonalcoholic fatty liver disease, a major complication of obesity.

He chaired the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) nonalcoholic steatohepatitis (NASH) clinical research network, which has played a transformational role in the field. As chair, he gained extensive experience in team science that he further applied to alcoholic liver disease as leader of several specific efforts in the National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded TREAT (Translational Research and Evolving Alcoholic Hepatitis Treatment) consortium. Over the last 2 years, he established the Liver Forum, which provides a neutral platform for the US Food and Drug Administration, European Medicines Agency, and other stakeholders in fatty liver disorders to work collaboratively on the regulatory science needed to accelerate drug development in liver disease.

He translated his own research into several patents and patent applications that have led to a spinoff company (Sanyal Biotechnologies) from VCU. He served as chair of the National Institutes of Health (NIH) hepatobiliary study section and chair of the Division of Gastroenterology at VCU. He was the Director of the Gastroenterology and then the Advanced Hepatology fellowship programs at VCU. He has trained/mentored over 50 such fellows. He has directed an NIDDK-funded T32 training program, competitively renewed in 2014, for over 15 years. He served on the Hepatology board of the American Board of Internal Medicine.

5

ZOBAIR M. YOUNOSSI, MD, MPH, FACP, FACG, AGAF, FAASLD FACULTY

Chairman, Department of Medicine Professor of Medicine Inova Fairfax Medical Campus Falls Church, Virginia

Dr. Zobair Younossi is the Chairman of the Department of Medicine at Inova Fairfax Hospital as well as Professor of Medicine at Virginia Commonwealth University, Inova Campus, and Affiliate Professor of Biomedical Sciences at George Mason University. He earned his medical degree from the University of Rochester School of Medicine and Dentistry in Rochester, New York (Alpha Omega Alpha, 1989), and completed his residency in internal medicine as well as a fellowship in gastroenterology and hepatology at Scripps Clinic and Research Foundation in La Jolla, California.

During his residency and fellowship, he earned his Master of Public Health degree from San Diego State University School of Public Health in San Diego, California, where he earned the Hanlon Award and Outstanding Student Award. He then served as the Staff Hepatologist and Senior Researcher at the Cleveland Clinic Foundation, Cleveland, Ohio (1995-2000).

Dr. Younossi specializes in hepatology and gastroenterology and has authored over 400 articles and 12 book chapters in this field. He has also presented over 600 abstracts at international meetings and over 300 faculty lectures. His experience in scientific publishing includes being associate editor for Evidence Based Gastroenterology, former associate editor of Liver International, and editorial board member and reviewer for Hepatology. He has also worked with many other journals in the areas of hepatology, gastroenterology, and internal medicine with prominent publications such as The American Journal of Medicine and the Journal of the American Medical Association.

6

TARGET AUDIENCE This activity is intended for endocrinologists, diabetologists, diabetes nurse specialists, and diabetes educators engaged in the care of patients with type 2 diabetes mellitus (T2DM) and attendant increased risks of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

NAFLD is a spectrum of potentially progressive liver disorders, ranging from simple hepatic steatosis to such severe forms as NASH, fibrosis, and cirrhosis.1 The prevalence rates of both NAFLD and NASH have been steadily trending upwards for years, mirroring the rapid and well-documented expansions of patient populations with obesity and/or T2DM.2-4 Thus, in the coming decade, burdens associated with this under-recognized epidemic are likely to increase exponentially for patients, clinicians, and health care systems.2-4 Of note, NAFLD is extremely common in individuals with T2DM, and the presence of both disorders significantly increases the likelihood that steatohepatitis and cirrhosis will develop compared with NAFLD cohorts without persistent hyperglycemia.4,5 Thus, endocrinologists and other clinicians with a focus on diabetes management are essential to accelerating the identification of patients with NAFLD. Importantly, however, appropriate diagnostic and management approaches for patients with T2DM who have advanced fibrosis markedly differ from those for patients who have received an NAFLD diagnosis, and bestpractice strategies are quickly evolving.5 During this Interactive Exchange™ program, expert faculty will highlight epidemiologic and pathophysiologic relationships between NASH and T2DM, review recommendations for disease diagnosis and patient referral, and discuss current management options and the latest evidence for emerging NASH therapies.

REFERENCES 1. Haas JT, et al. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol.

2016;78:181-205.

2. Hassan K, et al. Nonalcoholic fatty liver disease: a comprehensive review of a growing epidemic. World J Gastroenterol. 2014;20(34):12082-12101.

3. Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133.

4. Calzadilla Bertot L, Adams LA. The natural course of non-alcoholic fatty liver disease. Int J Mol Sci. 2016;17(5):774.

5. Singh A, et al. Prevalence of non-alchologic fatty liver disease and advanced fibrosis in type-2 diabetic patients via non-invasive methods. J Hepatol. 2017;66(suppl 1):S150.

7

PREAMBLE

STATEMENT of NEED/PROGRAM OVERVIEW

EDUCATIONAL OBJECTIVES

PREAMBLE

After completing this activity, the participant should be better able to: • Describe pathophysiologic mechanisms linking obesity, T2DM, and NASH • Evaluate patients with prediabetes or T2DM to appropriately screen for NAFLD/NASH and monitor disease progression • Discuss the mechanisms of action and clinical trial data for current and emerging NASH therapies • Implement best practices for multidisciplinary management of NASH in the endocrinology/ diabetes setting

PROGRAM AGENDA 6:30 pm–7:00 pm

Registration and Dinner

7:00 pm–7:05 pm

Introductions and Preactivity Questionnaire

7:05 pm–7:15 pm

NASH & T2DM: Introduction to Disease Mechanisms

7:15 pm–7:30 pm

NAFLD & NASH—New Concerns for the Diabetologist

7:30 pm–7:50 pm

Multifaceted Pathogenesis of Fatty Liver and T2DM

7:50 pm–8:10 pm

Disease Recognition and Specialist Referral

8:10 pm–8:30 pm

NASH Management—Today and Tomorrow

8:30 pm–8:45 pm

Build-a-Case™: Audience-Selected Case Studies

8:45 pm–9:00 pm

Postactivity Questionnaire and Question & Answer Session

JOINT ACCREDITATION STATEMENT In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and Integritas Communications. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the health care team.

8

PHYSICIAN CONTINUING MEDICAL EDUCATION The Postgraduate Institute for Medicine designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CONTINUING NURSING EDUCATION DISCLOSURE OF CONFLICTS OF INTEREST Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest.

Faculty Kenneth Cusi, MD, FACP, FACE Nothing to disclose Stephen A. Harrison, MD

Consulting Fees: AbbVie Inc., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb, Cirius Therapeutics, Civ., Corcept Therapeutics Incorporated, CymaBay Therapeutics, Echosens, Gilead Sciences, Inc., Histoindex Pte. Ltd., Innovate Biopharmaceuticals Inc., IQVIA, Madrigal Pharmaceuticals, Inc., Medpace, Inc., Metacrine, Inc., NGM Biopharmaceuticals, Inc., Novartis International AG, Novo Nordisk Inc., Perspectum Diagnostics Ltd., Pfizer Inc., The Pharmaceutical Product Development, LLC, Prometheus Laboratories Inc., Shenzhen Hightide Biopharmaceutical Ltd; Contracted Research: Bristol-Myers Squibb, Cirius Therapeutics, Inc., Conatus Pharmaceuticals Inc., CymaBay Therapeutics, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Inc., Pfizer Inc; Ownership Interest: Cirius Therapeutics, GENFIT, Madrigal Pharmaceuticals, Metacrine, Inc.

9

PREAMBLE

The maximum number of hours awarded for this Continuing Nursing Education activity is 2.0 contact hours. Pharmacotherapy contact hours for Advance Practice Registered Nurses to be determined.

PREAMBLE

Arun J. Sanyal, MBBS, MD, FAASLD

Consulting Fees: Ardelyx, Inc., Eli Lilly and Company, Gilead Sciences, Inc., HemoShear Therapeutics, LLC, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, LLC, Nitto Denko Technical Corporation, Pfizer Inc., Salix Pharmaceuticals, Sanyal Biotechnology; Contracted Research: Bristol-Myers Squibb, Conatus Pharmaceuticals Inc., Galectin Therapeutics, Inc., Gilead Sciences, Inc., Mallinckrodt Pharmaceuticals, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Salix Pharmaceuticals, Sequana Medical AG; Salary: Sanyal Biotechnology; Ownership Interest: Akarna Therapeutics Ltd., GENFIT SA, Natural Shield, NewCo LLC, Tiziana Life Sciences plc

Zobair M. Younossi, MD, MPH, Consulting Fees: Bristol-Myers Squibb, Conatus Pharmaceuticals Inc., Enterome Bioscience, Gilead Sciences, Inc., Intercept FACG, AGAF, FAASLD Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Salix Pharmaceuticals, Vertex Pharmaceuticals Incorporated

Planners and Managers The PIM planners and managers have nothing to disclose. The Integritas Communications planner and manager, Jim Kappler, PhD, has nothing to disclose.

DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and Integritas Communications do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER Participants have an implied responsibility to use newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions, possible contraindications, dangers of use, review of applicable manufacturer’s product information, and comparison with recommendations of other authorities.

10

SLIDES

11

SLIDES

12

SLIDES

13

SLIDES

14

SLIDES

15

SLIDES

16

SLIDES

17

SLIDES

18

SLIDES

19

SLIDES

20

SLIDES

21

SLIDES

22

SLIDES

23

SLIDES

24

SLIDES

25

SLIDES

26

SLIDES

27

SLIDES

28

SLIDES

29

SLIDES

30

SLIDES

31

SLIDES

32

SLIDES

33

SLIDES

34

SLIDES

35

SLIDES

36

SLIDES

37

SLIDES

38

SLIDES

39

SLIDES

40

SLIDES

41

SLIDES

42

SLIDES

43

SLIDES

44

SLIDES

45

SLIDES

46

SLIDES

47

SLIDES

48

SLIDES

49

SLIDES

50

SLIDES

51

SLIDES

52

SLIDES

53

SLIDES

54

NOTES

55

CLINICAL PRACTICE GUIDELINES »»The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

Chalasani N, et al. Hepatology. 2018;67(1):328-357. http://onlinelibrary.wiley.com/doi/10.1002/hep.29367/epdf

»» EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO). J Hepatol. 2016;64(6):1388-1402. http://www.journal-of-hepatology.eu/article/S0168-8278(15)00734-5/pdf

CLINICAL RESOURCES »» Histological Scoring System for Nonalcoholic Fatty Liver Disease.

Transplant Pathology Internet Services, 2009. http://tpis.upmc.com/changebody.cfm?url=/tpis/schema/NAFLD2006.jsp

»» MELD Score (Model for End-Stage Liver Disease) (12 and older).

MD+CALC online calculator, 2016. https://www.mdcalc.com/meld-score-model-end-stage-liver-disease-12-older

»» NAFLD (Non-Alcoholic Fatty Liver Disease) Fibrosis Score.

RESOURCE CENTER

MD+CALC online calculator. https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score

PATIENT RESOURCES »» American College of Gastroenterology (ACG) Patient Education and Resource Center.

The ACG website provides a basic overview of NAFLD and includes patientcentered podcasts. http://patients.gi.org/topics/fatty-liver-disease-nafld/

56

»» American Liver Foundation.

The American Liver Foundation website offers broad-based information and links to additional educational resources and support services for patients living with liver disease. http://www.liverfoundation.org

»» National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Health Information Center.

The NIDDK website for NAFLD and NASH provides comprehensive patient-centered information and resources, including an overview of clinical trial participation. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash

SUGGESTED READING »» Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

Armstrong MJ, et al. Lancet. 2016;387(10019):679-690. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00803-X/fulltext

»» Non-alcoholic fatty liver disease: an expanded review.

Benedict M, Zhang X. World J Hepatol. 2017;9(16):715-732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468341/

»» Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action.

Bril F, Cusi K. Diabetes Care. 2017;40(3):419-430. http://care.diabetesjournals.org/content/40/3/419.long

»» NAFLD: a multisystem disease.

»» Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.

Cusi K, et al. Ann Intern Med. 2016;165(5):305-315. https://www.ncbi.nlm.nih.gov/pubmed/27322798

»» Effect of canagliflozin treatment on intrahepatic triglycerides and insulin action in patients with type 2 diabetes (T2DM).

Cusi K, et al. Endocrine Society 2018. March 17-20, 2018; Chicago, IL. Abstract OR05-3. http://www.abstractsonline.com/pp8/#!/4482/presentation/6412

57

RESOURCE CENTER

Byrne CD, Targher G. J Hepatol. 2015;62(suppl 1):S47-S64. http://www.journal-of-hepatology.eu/article/S0168-8278(14)00933-7/fulltext

»» Glucagon like peptide-1 receptor agonists for the management of obesity and nonalcoholic fatty liver disease: a novel therapeutic option.

Dhir G, Cusi K. J Investig Med. 2018;66(1):7-10. http://jim.bmj.com/content/66/1/7.long

»» Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.

Dulai PS, et al. Hepatology. 2017;65(5):1557-1565. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397356/

»» Algorithm to identify patients with an activity grade > 2 in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD)—development in a large prospective multicenter UK study.

Eddowes P, et al. J Hepatol. 2018;68(suppl 1): S552. Abstract Fri-424. https://ilc-congress.eu/wp-content/uploads/2018/04/Abstract-book-2018EASL_14.04.2018.pdf

»» A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.

Friedman SL, et al. Hepatology. 2018;67(5):1754-1767. http://onlinelibrary.wiley.com/doi/10.1002/hep.29477/pdf

»» Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD).

Golabi P, et al. Medicine (Baltimore). 2018;97(13):e0214. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895395/

»» Recent advances in nonalcholic fatty liver disease.

RESOURCE CENTER

Greenfield V, et al. Curr Opin Gastroenterol. 2008;24(3):320-327. https://insights.ovid.com/pubmed?pmid=18408460

»» Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Hannah WN Jr, Harrison SA. Hepatology. 2016;64(6):2234-2243. https://www.ncbi.nlm.nih.gov/pubmed/27338123

»» Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study.

Koehler EM, et al. Hepatology. 2016;63(1):138-147. https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.27981

58

»» The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial.

Loomba R, et al. Hepatology. 2018;67(2):549-559. http://onlinelibrary.wiley.com/doi/10.1002/hep.29514/epdf

»» Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.

Neuschwander-Tetri BA, et al. Lancet. 2015;385(9972):956-965. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447192/pdf/nihms672595.pdf

»» Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.

Ratziu V, et al. Gastroenterology. 2016;150(5):1147-1159. http://www.gastrojournal.org/article/S0016-5085(16)00140-2/pdf

»» Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.

Ratziu V, et al. Hepatology. 2010;51(2):445-453. http://onlinelibrary.wiley.com/doi/10.1002/hep.23270/epdf

»» Management of NAFLD: a stage-based approach.

Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016;13(4):196-205. https://www.ncbi.nlm.nih.gov/pubmed/26907882

»» Treatment of NAFLD with diet, physical activity and exercise.

Romero-Gómez M, et al. J Hepatol. 2017;67(4):829-846. https://www.journal-of-hepatology.eu/article/S0168-8278(17)32052-4/fulltext

»» The performance of vibration controlled transient elastography in a US cohort of patients with non-alcoholic fatty liver disease.

RESOURCE CENTER

Tapper EB, et al. Am J Gastroenterol. 2016;111(5):677-684. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860094/

»» Noninvasive imaging biomarker assessment of liver fibrosis by elastography in NAFLD. Tapper EB, Loomba R. Nat Rev Gastroenterol Hepatol. 2018;15(5):274-282. https://www.nature.com/articles/nrgastro.2018.10

59

»» Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients.

Targher G, et al. Diabetes. 2005;54(12):3541-3546. http://diabetes.diabetesjournals.org/content/54/12/3541

»» Extrahepatic manifestations of nonalcoholic fatty liver disease.

RESOURCE CENTER

VanWagner LB, Rinella ME. Curr Hepatol Rep. 2016;15(2):75- 85. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874648/pdf/nihms-773290.pdf

60

NOTES

61

NOTES

62

Please visit the CLINICAL RESOURCE CENTER for additional information and resources

ExchangeCME.com/NASHResources18

Š 2018 Postgraduate Institute for Medicine and Integritas Communications. All rights reserved.

No part of this syllabus may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embedded in articles or reviews.