Department of Family and Community Medicine University of California, San Francisco School of Medicine presents

Annual Review in Family Medicine: Controversies and Challenges in Primary Care

December 15-16, 2014 Parc 55 Hotel San Francisco, California

Course Chairs: Shira Shavit, MD Ronald Goldschmidt, MD University of California, San Francisco

University of California, San Francisco School of Medicine

1 Exhibitors

Learners Digest

UCSF Physician Liaison Service

2

University of California, San Francisco School of Medicine Presents

Annual Review in Family Medicine: Controversies and Challenges in Primary Care

Overview

Presented by the Department of Family and Community Medicine, University of California, San Francisco, School of Medicine, the Annual Review in Family Medicine is designed to update primary care clinicians in controversial and rapidly changing areas. The emphasis is on practical and useful information for clinical practice. The discussions will also be extremely valuable in preparation for the board examination of the American Board of Family Medicine.

Target Audience

This course is intended for family medicine and other primary care providers including internists, pediatricians, gynecologists, nurse practitioners, physician assistants, nurses, and other health care professionals.

Educational Objectives

Upon completion of this course, participants will have improved skills and strategies to:

• Appropriately identify and initiate treatment of patients with hypo- and hyperthyroidism; • Appropriately evaluate and diagnose rheumatologic disorders; • Employ effective and practical strategies in management of Hepatitis C; • Address effective prevention and treatment of common oral health diseases.

Accreditation

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this live activity for a maximum of 13.5 Category 1 Credits™ toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

This Live activity, Annual Review in Family Medicine, with a beginning date of 12/15/2014, has been reviewed and is acceptable for up to 13.50 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 General Information

Attendance Verification/ Sign-In Sheet/ Electronic CME Certificate Claiming Please remember to sign-in on the sign-in sheet when you check in at the UCSF Registration Desk on your first day. You only need to sign-in once for the course, when you first check in.

After the meeting, please visit this website to complete the Electronic CME Certificate Claiming: http://www.ucsfcme.com/evaluation

Upon completing the Electronic CME Certificate Claiming, your CME certificate will be automatically generated to print.

Evaluation The speaker evaluation is the hand-out you received when you checked in. Please complete this during the meeting and turn it in to the registration staff at the end of the course.

The overall course evaluation is online and part of the Electronic CME Certificate Claiming at: http://www.ucsfcme.com/evaluation

Please complete the Electronic CME Certificate Claiming within 30 days of the conference in order to receive your CME certificate through this format; if you do not, you will need to certify your hours with the registration office at [email protected]

Security We urge caution with regard to your personal belongings and syllabus books. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during lunch or breaks or overnight.

Final Presentations A link to PDF versions of the final presentations will be sent via e-mail approximately 3 – 4 weeks post course. Only presentations that have been authorized for inclusion by the presenter will be included.

4

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.

HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .

As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.

Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.

A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non- emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

5 In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.

The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.

It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

6 Course Chairs:

Shira Shavit, MD Associate Clinical Professor of Family and Community Medicine; Director, Transitions Clinic

Ronald H. Goldschmidt, MD Professor of Family and Community Medicine; Vice-Chair, Department of Family and Community Medicine

Faculty (University of California, San Francisco unless indicated)

Kevin Barrows, MD Professor of Family and Community Medicine

Quynh Bui, MD, MPH Associate Professor of Family and Community Medicine

Diana Coffa, MD Assistant Professor of Family and Community Medicine Director, Family Medicine Residency Program

Stephanie Cohen, MD Assistant Professor of Medicine

Susan Fisher-Owens, MD, MPH Associate Professor of Pediatrics

Jonathan Graf, MD Associate Professor of Medicine, Division of Rheumatology

Annie Luetkemeyer, MD Associate Professor of Medicine

Anthony Luke, MD, MPH Professor of Orthopaedic Surgery and of Family and Community Medicine Director, Primary Care Sports Medicine

Andrea Marmor, MD Associate Professor of Pediatrics

Ina Park, MD, MS Assistant Professor of Family and Community Medicine

Christine Pecci, MD Associate Professor of Family and Community Medicine

David M. Schneider, MD Faculty Physician, Santa Rosa Family Medicine Residency Professor of Family and Community Medicine

7

Matt Tierney, NP Assistant Clinical Professor, School of Nursing

Lisa Winston, MD Professor of Medicine, Division of Infectious Diseases Vice Chief, Inpatient Medical Services and Hospital Epidemiologist San Francisco General Hospital

Eve Zaritsky, MD Assistant Professor of ObGyn and Reproductive Sciences

8 Disclosures

The following faculty speakers, moderators, and planning committee members have disclosed they have no financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Kevin Barrows, MD Christine Pecci, MD Quynh Bui, MD David Schneider, MD Diana Coffa, MD Shira Shavit, MD Ronald Goldschmidt, MD Matt Tierney, MD Jonathan Graf, MD Lisa Winston, MD Andrea Marmor, MD Eve Zaritsky, MD Ina Park, MD

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

Stephanie Cohen, MD Grant/Research Support Gilead

Susan A. Fisher-Owens, MD, MPH Grant/Research Support Western Dental

Annie Luetkemeyer, MD Grant/Research Support Abbvie , Bristol Myers Squibb (BMS), Gilead, Pfizer, Merck, ACTG (NIH)

Anthony Luke, MD Grant/Research Support Sanofi

Board Member, Stock SPORTZPEAK Inc Shareholder (excluding mutual funds), Holder of Intellectual Property Rights

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced.

This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

9 MONDAY, DECEMBER 15, 2014

7:00 am Registration and Continental Breakfast

8:00 Introduction and Welcome

8:10 G Musculoskeletal Twists and Turns: Getting the Diagnosis and Treatment Right 12 Anthony Luke, MD, MPH

9:00 Practical Guidance for Managing and Curing Hepatitis C in Primary Care 39 Annie Luetkemeyer, MD

9:50 Break

10:10 G Testing for Rheumatologic Disease: A Common Sense Approach for Primary Care 51 Jonathan Graf, MD

11:00 The Science of Burnout: What is It, What Causes It, and What Makes It Go Away 67 Diana Coffa, MD

11:50 Lunch on your own

1:30 pm Pre-exposure Prophylaxis: The HIV Prevention Revolution 74 Stephanie Cohen, MD

2:20 Influenza Update 87 Lisa Winston, MD

3:10 Break

3:30 Postpartum Care: The Beginning, Not the End 97 Christine Pecci, MD

4:20 Updates in the Primary Care Management of Fibroids 108 Eve Zaritsky, MD

5:10 Adjourn

TUESDAY, DECEMBER 16, 2014

7:30 am Continental Breakfast

8:15 Introduction

8:20 Assessing and Treating Substance Use Disorders in Primary Care 117 Matt Tierney, NP

9:10 Mind-Body Medicine: Evidence and Practice for Primary Care 133 Kevin Barrows, MD

10:00 Break

10 10:20 G Hypertension Management: JNC 8’s Evidence and Recommendations 143 Quynh Bui, MD

11:10 G Primary Care Management of Hypo- and Hyperthyroidism 154 David Schneider, MD

12:00 pm Lunch on your own

1:20 STI Update: What’s New in the 2014 CDC STD Treatment Guidelines 177 Ina Park, MD

2:10 Oral Health: The Fluoride Fallacy and Other Clinical Controversies Susan Fisher-Owens, MD

3:00 Break

3:20 Evaluation of the Febrile Infant 191 Andrea Marmor, MD

4:10 Primary Care in the Palm of Your Hand: Efficient Use of Clinical Internet Resources 202 Shira Shavit, MD

5:00 Adjourn

G Geriatric credit

11 Common Orthopaedic and Sports Disclosures Medicine Problems • Founder, RunSafe™ Crash Course • Founder & CEO, SportZPeak Inc.

• Sanofi, Investigator initiated grant A n t h o n y L u k e MD, MPH, CAQ (Sport Med) University of California, San Francisco FP Board Review 2015

Overview History is Key Who? • Quick approach to What? MSK problems Pain • Highlight common presentations • Joint by joint Instability Dysfunction • Discuss basics of conservative and surgical management • Numbness • Fever

12 1 History is Key Red Flag Symptoms

When? • Severe disability • Acute vs Chronic (2 weeks? 6 weeks?) • Numbness and tingling Where? • Night pain • Think anatomy • Constitutional symptoms (fever, wt loss) • One finger test • Swelling with no injury How? • Systemic illness • Mechanism of injury • Multiple joint injury

Treatment Options

Intrinsic Risk Factors Extrinsic Risk Factors Conservative Surgery •Growth • Training • MICE (Modified activity, • Reconstruction • Anatomy • Technique Ice, Compression, • Repair • Muscle/Tendon • Footwear Elevation) • Re-align imbalance •Surface • Medications/Analgesia • Remove internal • Illness • Occupation • Rehabilitation therapy derangement • Nutrition • Casting/ Braces / • Conditioning • TO PREVENT Orthoses • Psychology INJURIES!! • Crutches

13 2 Ankle Sprains Physical Exam

Mechanism Symptoms LOOK • Inversion, • Localized pain usually • Swelling/bruising plantarflexion (most over the lateral aspect laterally common injury) FEEL Anterior of the ankle talofibular • Eversion (Pronation) • Difficulty weight • Point of maximal ligament bearing, limping tenderness usually ATF Calcaneo • May feel unstable in MOVE fibular the ankle ligament • Limited motion due to swelling

Special Tests Anterior Drawer Subtalar Tilt Test Test • Normal ~ 3 mm • Foot in neutral • Foot in neutral position position • Fix tibia • Fix tibia • Invert or tilt • Draw calcaneus calcaneus forward •Tests • Tests ATF ligament Calcaneofibular ligament Sens = 80% Spec = 74% No Sens / Spec PPV = 91% Data NPV = 52% van Dijk et al. J Bone Joint Surg-Br, 1996; 78B: 958-962

14 3 Subtalar Tilt test Grading Ankle Sprains Grade Drawer/Tilt Pathology Functional Test results Recovery in weeks 1 Drawer and Mild stretch 2 – 4 tilt negative, with no but tender instability 2 Drawer lax, ATFL torn, CFL 4 – 6 tilt with good and PTFL end point intact 3 Drawer and ATFL and CFL 6 – 12 tilt lax injured/torn

Ottawa Ankle Rules Treatment of Ankle Sprains

• Inability to weight bear immediately and in the Acute Physical Therapy emergency / office (4 steps) • Rest or modified •ROM activities • Strengthening • Bone tenderness at the posterior edge of the • Ice, Compression, medial or lateral malleolus (Obtain Ankle Series) Elevation •Stretching • Bone tenderness over the navicular or base of • Crutches PRN • Proprioception / the fifth metatarsal (Obtain Foot Series) • Bracing (Grade 2 and Balance exercises 3) (i.e. Wobble Board) • Sens 97%, Spec 31-63%, NPV 99%, PPV <20% • Early Motion is (Am J Emerg Med 1998; 16: 564-67) essential

15 4 Not Always Only a “Sprain” “High Ankle” Sprains

Ligaments Bone Mechanism • Osteochondral talus • Subtalar joint sprain injury • Dorsiflexion, eversion • Sinus tarsi syndrome • Lateral talar process injury • Syndesmotic sprain fracture • Disruption of the • Posterior impingement Syndesmotic ligaments, • Deltoid sprain (os trigonum) most commonly the • Lisfranc injury • Fracture at the base of Tendons the fifth metatarsal anterior tibiofibular ligament • Posterior tibial tendon • Jones fracture strain • Salter fracture (fibula) • R/O Proximal fibular • Ankle fractures • Peroneal tendon fracture subluxation

External Rotation Stress Test Squeeze test

•Fix tibia • Hold leg at mid calf • Foot in neutral level • Dorsiflex and • Squeeze tibia and externally fibula together rotate ankle • Pain located over anterior tibiofibular ligament area No Sens/ Spec Data Kappa = 0.75

Alonso et al. J Orthop Sports Phys Ther, 1998; 27: 276-284

16 5 Treatment for Syndesmosis Injury Ankle Sprain Prevention

Conservative Surgery • Ankle braces, tape and proprioceptive training • Cast or walking boot • May needs ORIF if help reduce the risk of lateral ankle sprains • Protected unstable Verhagen EALM, van Mechelen W, de Vente weightbearing with W. Clin J Sport Med, 2000 crutches must be painfree • Significant reduction in the number of ankle •PT sprains in people allocated to an external ankle support (RR 0.53, 95% CI 0.40 to 0.69). Handoll et al. Cochrane Database Rev, 2005 Maisonneuve Fracture

Acute Hemarthrosis Emergencies

1) ACL (almost 50% in children, >70% in 1. Neurovascular injury adults) 2. Knee Dislocation 2) Fracture (Patella, tibial plateau, Femoral – Associated with multiple ligament injuries supracondylar, Physeal) (posterolateral) 3) Patellar dislocation – High risk of popliteal artery injury – Needs arteriogram • Unlikely meniscal lesions 3. Fractures (open, unstable) 4. Septic Arthritis

17 6 Anterior Cruciate Ligament (ACL) Urgent Orthopedic Referral Tear •Fracture Mechanism • Patellar Dislocation • Landing from a “ ” jump, pivoting or • Locked Joint - unable to fully extend the decelerating knee (OCD or Meniscal tear) suddenly • Tumor • Foot fixed, valgus stress

Anterior Cruciate Ligament (ACL) ACL physical exam Tear LOOK Mechanism • Effusion (if acute)

• Landing from a jump, FEEL pivoting or decelerating • “O’Donaghue’s Unhappy Triad” suddenly = Medial meniscus tear, MCL • Foot fixed, valgus stress injury, ACL tear • Lateral meniscus tears more Symptoms common than medial • Audible pop heard or felt • Lateral joint line tender - femoral condyle bone bruise • Pain and tense swelling in minutes after injury MOVE • Feels unstable (bones Double fist sign • Maybe limited due to effusion shifting or giving way) or other internal derangement

18 7 Special Tests ACL X-ray

• Lachman's test – test at 20° • Usually non- Sens 81.8%, Spec 96.8% diagnostic • Anterior drawer – test at 90° • Can help rule in or Sens 22 - 41%, Spec 97%* out injuries • Pivot shift Sens 35 - 98.4%*, Spec 98%* • Segond fracture – Malanga GA, Nadler SF. Musculoskeletal Physical avulsion over Examination, Mosby, 2006 lateral tibial plateau * - denotes under anesthesia

MRI MRI

• Sens 94%, Spec 84% • Sens 94%, Spec 84% for ACL tear for ACL tear ACL tear signs ACL tear signs • Fibers not seen in • Lateral femoral corner continuity bone bruise on T2 • Edema on T2 films • May have meniscal • PCL – kinked or tear (Lateral > medial) Question mark sign

19 8 Initial Treatment ACL Tear Treatment

• Referral to Orthopaedics/Sports Medicine Conservative Surgery • Consider bracing, crutches • No reconstruction • Reconstruction • Physical therapy • Depends on activity • Begin early Physical Therapy • Hamstring demands strengthening  Reconstruction allows • Analgesia usually NSAIDs • Proprioceptive training better return to sports • ACL bracing  Reduce chance of symptomatic meniscal controversial tear • Patient should be  Less giving way asymptomatic with symptoms ADL’s • Recovery ~ 6 months

Special Tests: Meniscus Meniscus Tear Fowler PJ, Lubliner JA. Arthroscopy 1989; 5(3): 184-186. Mechanism Symptoms Test Sensitivity Specificity • Occurs after twisting •Catching Joint line tender 85.5% 29.4% injury or deep squat • Medial or lateral knee Hyperflexion 50% 68.2% • Patient may not recall pain specific injury • Usually posterior Extension block 84.7% 43.75% aspects of joint line McMurray Classic 28.75% 95.3% • Swelling (Med Thud) McMurray Classic (Lat 50% 29% pain) Appley (Comp/Dist) 16% / 5%

20 9 Modified McMurray Testing X-ray

• Flex hip to 90 degrees • May show joint space • Flex knee narrowing and early • Internally or externally osteoarthritis changes rotate lower leg with rotation of knee • Rule out loose bodies • Fully flex the knee with rotations

Courtesy of Keegan Duchicella MD

MRI Meniscal Tear Treatment

Conservative Surgery • MRI for specific exam • Often if degenerative • Operate if internal tear in older patient derangement • Similar treatment to symptoms • Look for fluid (linear mild knee bright signal on T2) osteoarthritis • Meniscal repair if possible into the meniscus • Analgesia • Physical therapy • General Leg Strengthening

21 10 Medial Collateral Ligament (MCL) Medial Collateral Ligament (MCL) Injury Injury Mechanism Symptoms Physical Exam • Valgus stress to • Pain medially • Tender medially over partially flexed knee • May feel unstable MCL (often • Blow to lateral leg with valgus proximally) • May lack ROM “pseudolocking” • Valgus stress test

MRI MCL Treatment

Conservative Surgery • X-ray non-diagnostic • Analgesia • Rarely needs surgery (rarely avulsion) • Protected motion • MRI not usually +/- hinged brace necessary +/- crutches • Rule out meniscal • Early physical therapy tear

22 11 Posterior Cruciate Ligament (PCL) Posterior Cruciate Ligament (PCL) Injury Injury Mechanism Symptoms Physical Exam • Sag sign • Fall directly on knee • Pain with activities with foot plantarflexed • “Disability” > Sens 79%, Spec 100% • “Dashboard injury” “Instability” • Posterior drawer test

Sens 90%, Spec 99%

Rubenstein et al., Am J Sports Med, 1994; 22: 550-557

X-ray- often non-diagnostic

MRI is test of choice

PCL Treatment Patellofemoral Pain

Conservative Surgery • Excessive Symptoms • Acute: hinged • May require surgery compressive forces • Anterior knee pain post-op brace in if complete Grade 3 over articulating • Worse with bending surfaces of PFP joint extension (0-10° tear and symptomatic (5x body wt), stairs flexion) (3x body wt) Mechanism • Crepitus under • Crutches • Needs urgent surgery • Too kneecap • Early physical if lateral side is loose/hypermobile • May sublux if loose therapy unstable  postero- • Too tight – XS lateral corner injury pressure

Early and urgent referral!!

23 12 PFP Syndrome Treatment Options

• Tender over facets of Too Loose/Weak Surgical (RARE) patella • Strengthen quads (Vastus Medialis Obliquus) • Last resort • Apprehension sign • Correct alignment (+/-orthotics) • Lateral release suggests possible • Support (McConnell Taping, • Patellar instability Bracing) realignment Too Tight • Stretch hamstring, quadriceps, • X-rays may show hip flexor lateral deviation or tilt • Strengthen quads, hip abductors • Correct alignment (+/-orthotics)

What’s Hip? Shoulder Impingement Syndrome

Mechanism Symptoms • Impingement under • Pain with acromion with flexion – Overhead activities and internal rotation – Sleep (Internal of the shoulder rotation) • Rotator cuff, – Putting on a jacket subacromial bursa and biceps tendon

24 13 Shoulder Pain Differential Shoulder Impingement Syndrome Diagnosis • Rotator cuff tendinopathy LOOK • Rotator cuff tears • May have posterior shoulder atrophy if • SLAP Lesion chronic or RC tear • Calcific tendinopathy • Poor posture • “Frozen” shoulder (adhesive capsulitis) FEEL • Tender over anterolateral • Acromioclavicular joint problems shoulder structures • Scapular weakness MOVE • Cervical radiculopathy • May lack full active ROM

Rotator Cuff strength Shoulder Impingement Syndrome testing LOOK Supraspinatus 30° • May have posterior •Empty can shoulder atrophy if • Thumbs down abducted chronic or RC tear to 90º • Poor posture • Horizontally adduct to 30º FEEL • Tender over anterolateral For tendonitis shoulder structures Sens = 77 % MOVE Spec = 38 % • May lack full active ROM For tears, Sens = 19 % Naredo et al. Ann Rheum Dis, 2002; Spec = 100 % 61: 132‐136.

25 14 Rotator Cuff strength testing Rotator Cuff strength testing

Infraspinatus/teres minor - Subscapularis – Internal External rotation rotation / Lift-off test • Keep elbows at 90º • Patte’s test at 90º For lesions, shoulder abduction Sens = 50 % For tendonitis, Spec = 84 % Sens = 57 % For tears, Spec = 71 % Sens = 50 % For tears, Spec = 95 % Sens = 36 % Spec = 95 %

Naredo et al. Ann Rheum Dis, Naredo et al. Ann Rheum Dis, 2002; 61: 132-136. 2002; 61: 132-136.

Impingement Signs Impingement Signs

Neer Hawkin’s test • Passive full flexion • Flex shoulder to 90º • Positive is • Flex elbow to 90º reproduction of • Internally rotate shoulder pain • Positive - reproduce Sens = 83 % shoulder pain Spec = 51 % Sens = 88 % PPV = 40 % Spec = 43 % NPV = 89 % PPV = 38 % MacDonald et al. J Shoulder Elbow Surg, 2000; 9: 299-301. NPV = 90 % MacDonald et al. J Shoulder Elbow Surg, 2000; 9: 299-301.

26 15 Impingement Signs X-ray AP Scapula

• Spurling’s test for • Avulsion cervical radiculopathy • Calcific tendinosis Sens = 64% • Enthesopathy Spec = 95% (traction spurs) PPV = 58% • Alignment NPV = 96%

X-ray Lateral Scapula Ultrasound

• Dynamic test • Operator dependent • Areas of tendinosis hypoechoic • Tears

Normal Large acromial spur

27 16 MRI SIS Treatment

• MRI not needed for Conservative Surgery conservative treatment • Education • If patient fails • Use it to rule out • Modify Activities conservative treatment for > 6-12 months significant pathology • Alter Biomechanics / Decrease tendon load • If rotator cuff tear > 1 cm How good for full • Ice/NSAIDs (no evidence) thickness tears? • Eccentric exercise • Subacromial • 69 to 100 percent programs decompression sensitive • Steroid injection +/- bursectomy • 88 to 100 percent – slightly better than placebo +/- rotator cuff repair specific (Cochrane Database, 2004

Adhesive Capsulitis Frozen Shoulder “Frozen Shoulder” • Women greater than • Gradual loss of range of men (70%) motion • Age > 40 years • May have had initial trauma • Affects 2-5 % of • Pain at the extremes of population motion • 20-30% develop symptoms in opposite • May have history of shoulder diabetes, hypothyroidism, rheumatoid arthritis

28 17 Diagnosis Natural History

• Limited range of • 0-3 months “gradual onset” - painful motion (usually lose • 2-9 months “ freezing” external rotation, abduction and flexion) • 4-12 months “ frozen” • 5-26 months “thawing” • Investigations (X-ray, Ultrasound) usually negative • Usually self-limited Hannafin & Chiaia, Clin Orthop Rel Res, 2000

Treatment Shoulder Dislocation

• Pain management (+/- sling) Mechanism • Education and reassurance Anterior (>95%) • Active home stretching • Force applied with program shoulder in external rotation/ abduction • Physiotherapy • Oral NSAIDs (or steroids) • Glenohumeral injection capsular distension • Rarely needs surgery (examination under anesthesia or Arthroscopic release)

29 18 Shoulder Dislocation Diagnosis

Mechanism Physical Exam Anterior (>95%) • Tender anterior • Force applied with shoulder shoulder in external rotation/ abduction • May have decreased Posterior (<5%) sensation to army • Posterior force with patch (axillary nerve) shoulder in internal • Apprehension test rotation/ adduction • Sulcus sign (MDI) • EtOH (alcohol), Electrocution, Epilepsy

X-ray and MRI Complications after Dislocation

Acute rotator cuff tear • 40 to 60% incidence of in patients > 40 years old Frozen shoulder • Older the patient the stiffer they get mobilize early within 2-3 weeks Recurrent dislocation • >90% recurrence < 20 years; 14% > 40 yrs Rowe CR. Prognosis in dislocation of the shoulder. J Bone Joint Surg Am, 1956. • Early surgical stabilization still controversial Hill Sachs Lesion – compression Bankart Lesion – Avulsion of fracture of posterior humerus capsular attachment to the glenoid

30 19 Initial Treatment Treatment for Shoulder Instability

• Sling x 2-4 weeks • T – Traumatic • A – Atraumatic with pendulum • U – Unilateral • M – Multidirectional exercises • Early physical therapy • B – Bankart lesion • B – Bilateral • Modification of • S – Surgical • R – Rehabilitation activities treatment • I – Inferior capsular (refer for consultation) shift

Acromioclavicular Joint Diagnosis “Separation” Mechanism Symptoms Physical Exam • Direct fall on the • Pain directly over AC • Swelling, tenderness shoulder joint +/- step deformity • Common biking, • Difficulty lifting over AC joint contact sports (hockey, weights • Early limited motion football etc.) • Difficulty reaching actively due to pain • May tear #1 overhead and across • Cross over sign + acromioclavicular body ligament; #2 coracoclavicular ligament

31 20 Investigations Classifying AC Separations

•AC joint views Type Ligaments affected Exam • Weighted views rarely 1 Acromioclavicular (AC) lig Tender over AC ordered strain; joint, no step Coracoclavicular (CC) lig OK 2 AC lig torn Mild step < width CC lig partially torn of clavicle

3 AC and CC ligs torn Obvious step => width of clavicle

Treatment Refer to Surgery

Conservative • Type 4 – Posterior dislocation • Type 5 – High riding distal clavicle (tenting • Sling as good as figure eight the skin) • Physiotherapy – taping, restore ROM, • Type 6 – Posterior-inferior dislocation maintain strength • Modify activities

32 21 Lateral and Medial Epicondylitis Clinical Diagnosis

Mechanism Symptoms Physical Exam • Repetitive overuse • Pain shaking hands, causing microtrauma lifting objects • Tender almost directly over the epicondyle at the tendon • Lateral – pain reproduced with resisted insertion Lateral wrist extension and third digit extension • Lateral epicondylitis • Tennis, using • Medial – pain reproduced with resisted  wrist extensors “ ” computer mouse wrist flexion and wrist pronation • Medial epicondylitis Medial  wrist flexors and • Check ulnar nerve (posteromedial elbow) pronator teres • Golf, turning hand over Investigations usually unnecessary

Causes of Back Pain Epicondylitis Treatment (Micheli, Wood. Arch Pediatr Adolesc Med 1995; 149:15- 18.) Conservative Aggressive (Step 3) Step 1 • Extracorporeal Lesion Youth Adult P value • Education Shockwave therapy (no clear evidence) • Activity modification! Discogenic 11 48 0.05 • Stretching and • Surgical debridement strengthening exercises Spondylolytic lesion 47 50.05 • Counterforce brace (no evidence) Lumbosacral strain 6 27 0.05 Step 2 • Physiotherapy in Hyperlordotic 26 0 persistent cases mechanical back pain • Steroid injection Osteoarthritis 04

33 22 Disk Herniation Treatment • Education Mechanism Symptoms • Activity modifications • L5-S1 most common • Acute herniation •Physical Therapy 90% usually 30-50 years • Compression of • Pain worse with • Medications neural structures such flexion – NSAIDs should be recommended (Strength: Strong) as sciatic nerve • May have “Sciatica” – Opioids may be considered but should be avoided if causes radicular pain – Pain with sitting too possible (Strength: Weak) • Compression of long (i.e. driving) – Antidepressants should not be routinely used cauda equina = • Rule out bowel or (Strength: Strong) EMERGENCY bladder symptoms White et al. Spine, 2011

Surgery better than Non‐operative Treatment Mean differences Reported (SPORT) –Disk (SE: A) • Medications •In patients with a herniated disk confirmed by – Corticosteroids pooled results of two trials (overall imaging and leg symptoms persisting for at and leg pain -12.2, 95% C.I. -20.9 to -3.4) least six weeks, surgery was superior to non‐ – Single trial of gabapentin (pain -26.6, -38.3 to -14.9) but only short term benefits operative treatment in relieving symptoms Pinto et al. BMJ, 2012 (15.0 (95% C.I.’s, 11.8 ‐ 18.1)) and improving – Epidural corticosteroid injections vs placebo for leg function (14.9 (95% C.I.’s, 12.0 ‐ 17.8)) pain (mean difference, -6.2 [95% CI, -9.4 to -3.0]) and also for disability (-3.1 [CI, -5.0 to -1.2]) in the •4‐year rate of reoperation was 10% short term Pinto et al. Ann Intern Med, 2012 Weinstein et al., Spine, 2008

34 23 Spinal Stenosis Physical Exam

Mechanism Symptoms • Assess if pain reproduced by flexion vs • Osteoarthritis causes • Usually older patients extension narrowing of spinal canal • Pain worse with • Perform neurological exam • Large disk herniation can extension also cause stenosis • “Neurogenic Criteria for Acute Disk herniation • Can compress neural claudication” 1. Leg symptoms dominant (Leg > back) structures – Reproducible leg • Can cause compression symptoms worse with 2. Pain in dermatomal distribution walking of spinal artery 3. Positive straight leg raise – Relieved by sitting • Rule out bowel or bladder 4. Neurologic signs symptoms

Diagnosis Conservative Treatment

X-ray • Assess alignment (scoliosis, • Modified activities lordosis) • NSAID and other analgesics • Disk space narrowing • Osteoarthritis • Physical therapy – core stabilization • Spondylolisthesis (translation of vertebral bodies) exercises, McKenzie exercises CT Scan • Can assess disk and bony • Others: Traction, braces structures MRI • Can assess soft tissue • Consider spinal injections structures, bone and nerves

35 24 Surgical Treatment Concussion Update

• Cauda equina needs emergency decompression

Surgical Indications • Sufficient morbidity • Failure of conservative treatment • Anatomic lesion that can be corrected • Complications usually neurologic

Concussion 2013 Symptoms & Signs

• Concussion is defined as a traumatically 1. Symptoms - somatic (e.g. headache), cognitive induced transient disturbance of brain (e.g. feeling like in a fog) and/or emotional function and involves a complex symptoms (e.g. lability) pathophysiological process. 2. Physical signs (e.g. loss of consciousness, amnesia) • Concussion is a subset of mild traumatic 3. Behavioural changes (e.g. irritablity) brain injury (MTBI) which is generally self- 4. Cognitive impairment (e.g. slowed reaction limited and at the less-severe end of the times) brain injury spectrum. 5. Sleep disturbance (e.g. drowsiness) AMSSM Position Statement, Br J Sports Med, 2013

36 25 Physical Examination Diagnostic Imaging

• Use the SCAT3 card (free on the web) Neuroimaging (CT, MRI) • Clear C-spine • Most patients do not require imaging • Rule out soft tissue and bony injury to • Use when suspicion of intracerebral head structural lesion exists: • Balance Error Scoring System – prolonged loss of consciousness • Mental status testing – focal neurologic deficit • Orientation – worsening symptoms • Concentration (numbers backwards) – Deterioration in conscious state • Short and long term memory

Symptom resolution after sport Management concussion

• 7-10 days avg. symptom resolution (3rd International • All student athletes need to have an MD or Conference on Concussion in Sport (2008). Clin J Sport Med, 2009.) qualified health professional to clear to play • 50% recovered and returned to play in 1 week; • School-aged athletes will be out at least 1 week 90% in 3 weeks (Collins et al. Neurosurgery, 2006.) most likely 2 (check your area for legal • High schoolers take longer to recover based on requirements) neuropsychological testing compared to college • Check new guidelines for returning to learn – athletes (Field et al, J Pediatr, 2003.) cognitive rest recommended for students • Use SCAT 3 as a good simple evaluation (on line)

37 26 Can the Athlete Play Safely?

• Make a working diagnosis • Is there potential for worsening injury? AVOID STRESS A new secondary injury? • MD or trainer decides: CAN THE ATHLETE PLAY SAFELY ? 9th UCSF Primary Care Sports • Coach and MD decide: Can the athlete Medicine Conference play effectively? San Francisco, Dec 5-6, 2014 • Player, coach and MD decide: Can the Hotel Intercontinental athlete play pain free? San Francisco

38 27 Disclosures

I have received research grant support to UCSF related to HCV from the following: 2014 Update on HCV • Abbvie management & treatment in • Bristol Myers Squibb (BMS) Primary care • Gilead •Pfizer Annie Luetkemeyer •Merck HIV Division •ACTG (NIH) San Francisco General Hospital

What role does the Family Practice Outline Provider play in HCV care in 2014?

• HCV screening & diagnosis of all HCV cases • Brief overview of HCV diagnosis, fibrosis • Staging of disease & appropriate management evaluation, and cirrhosis management of cirrhosis •Whom should we treat • Prioritizing HCV treatments with patients • How should we treat • Where will HCV be treated? • Addressing the treatment price tag – Hepatotology • HCV treatment and the primary care HIV – Infectious Disease/HIV provider – Primary care • Treatment shorter, less toxic, more effective • Excellent platform to engage and support patients through treatment

39 1 Our case

• 55 year old man, transferring to your clinic • As part of your intake evaluation, you offer him HCV antibody testing • Never had HCV testing and is surprised by your offer

“Why do I need to be tested, Doc? I never shot drugs and don’t know anyone with HCV”

HCV treatment Cascade 2003-13 Screening Recommendations

Yehia PLOS One 2014 • CDC 2012 recommendations: test at least once:

• Up to 50% of American with HCV – All baby-boomers (birth 1945-1965) unaware of their infection –HIV+ • 45% with HCV report no known risk factor –IDU • 75% of US HCV infections are in – Hemodialysis “Baby Boomers” born 1945-1965 MMWR 2012: 61(4) – Organ transplant or blood transfusion before 1992 – People with exposure to HCV infected blood: health care workers and children born to HCV+ mothers • HCV RNA testing to diagnose HCV – If acute HCV suspected – In advanced immunocompromise ( including HIV with low CD4+)

40 2 HCV Ab+: next steps HCV Genotype

To his surprise, his HCV Antibody test comes back positive • Confirm viremia with HCV RNA • Screen and vaccinate if indicated for HAV & HBV • Genotypes 1-6 • Reduce alcohol consumption • Can impact disease progression • Reduce forward transmission risk – Genotype 3: associated with steatohepatitis – Drug use – avoid sharing needles or nasal straws • Impacts selection and response to therapy – Sexual counseling: MSM or HIV infected partner – Household precautions: no shared toothbrushes or razor – Easiest to Cure: 2>3>4≥1 (1b>1a) • Genotype 1: most common in US (70%) •Send genotype if considering HCV treatment

Fibrosis Evaluation Fibrosis assessment • Serologic markers • Key to assess for advanced fibrosis – Platelets, INR, Albumin – Impacts decision to screen for HCC and varices – Serologic tests: Fibrosure/test, APRI – Informs risk of decompensation and mortality • Physical Exam – Affects HCV treatment response, choice & – Palmar erythema, telangectasia, gynecomastia, splenomegaly duration of therapy, and treatment initiation • Imaging: Ultrasound reasonable first step timeline – CT and MRI usually unnecessary- would avoid radiation and save as follow-on tests • If initial evaluation does not show fibrosis, • Elastography: Fibroscan suggest repeat imaging in 3-5 years – Excellent option when available: now FDA approved • Biopsy: rarely necessary

41 3 When cirrhosis is present Back to the Case • Hepatocellular carcinoma screening – Imaging q 6 months • Physical exam: no physical stigmata cirrhosis – U/S recommended initial screening, will need f/u • Laboratory evaluation with CT or MRI for some – HCV RNA 458,000 IU/ml – AFP no longer routinely recommended – HCV Genotype 1a • Variceal screening and prophylaxis – HAV total Ab + – EGD recommended to screen for varices – Hep B S ab+, S ag-, Core ab- – Nonselective beta-blocker if large varices or small • Ultrasound: “Coarse liver”, no clear varices (particularly if higher risk of bleeding) indication of cirrhosis • Discuss risk of decompensation and current What should I do, Doc? Do I need to be barriers to transplantation treated? What are my chances of cure?

Benefits of HCV treatment Back to the case: Treat now or wait? • Reduction in fibrosis progression and decompensation – Some cirrhotics will have regression with HCV cure – Still are at risk for HCC and should undergo continued screening “Evidence clearly supports treatment in • Decrease in all cause mortality, including non- all HCV-infected persons except those liver related with limited life expectancy (less than 12 • May impact non-hepatic complications of HCV: months) due to non liver related – Diabetes - Risk of fracture comorbid conditions” – Neurocognitive impairment - Lymphoproliferative – Increased risk of CV events disease www.hcvguidelines.org – Renal disease

42 4 Priority for HCV therapy HIGHEST PRIORTY • Advanced Fibrosis (F3) or compensated cirrhosis (F4) AASLD Position on Treating Patient with HCV : “Our Guidance is not intended to be used by payers to • Cryoglobulinemia with end organ manifestations deny access to treatment. In no way does this position • Renal complications of HCV infection contradict the evidence evaluated to produce the Guidance and the recommendation made in the HIGH PRIORITY Guidance to treat the sickest first, but recognizes need to treat all.” • Fibrosis (F2) • Debilitating Fatigue • HIV Coinfection • Diabetes • Porphyria cutanea Tarda • HBV Coinfection • HIGH HCV Transmission http://www.aasld.org/aboutus/publicpolicy/Pages/aasldhcvposition.aspx • Other liver disease (e.g. NASH) Risk (includes MSM, IDU)

HCV Treatment Cost

• Sofosbuvir: 1000.00 pill, $84,000/12 weeks of therapy • Even though many HCV Arsenal & analyses project HCV cure cost effective in the Principals of therapy long run, initial costs overwhelming • Many plans current restrict access to those with advance fibrosis

43 5 Assaleh Liver Int 2013: The HCV Future is here!

• Most HCV patients now curable in 12 weeks or less • Majority can receive all-oral therapy without the side effects of injectable interferon • Hard to treat patients including cirrhotics, decompensated liver disease and those with prior treatment failure can now be cured

Assaleh Liver Int 2013

NS5B Polymerase inhibitors: “‐BUVIRs”: Nucleoside inhibitors: ex. Sofosbuvir Non‐ Nucleoside Protease inhibitors inhibitors: (NNI): ex. “‐PREVIRs” eg. Dasabuvir simeprevir

44 6 Current DAA combinations

• NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2nd class

NS5a SOFOSBUVIR Protease inhibitor

Ribavirin

NS5A Inhibitors: • Triple therapy without a NS5b Nuke “‐ASVIRs” e.g Daclatasvir NS5a NS5b Non-Nuke Protease inhibitor Ledipasvir Ombitasvir • Other approaches Protease inhibitor NS5a

Current DAA combinations I am confused already…

• http://www.hcvguidelines.org • NS5b Nucleotide based therapy NS5b Nuke Backbone One drug from 2nd class

NS5a SOFOSBUVIR Protease inhibitor

Ribavirin • http://www.hep‐druginteractions.org • Triple therapy without a NS5b Nuke – Free downloadable app NS5a NS5b Non-Nuke Protease inhibitor • www.hcvadvocate.org • Other approaches – great patient information Protease inhibitor NS5a

45 7 Genotype 1: Current Standard of Care Sofosbuvir/Ledipasvir • Sofosbuvir: NS5b nucleotide inhibitor, plusLedipasvir: NS5a inhibitor • Co-formulated as “Harvoni”: one pill/daily • Side Effects: headache, fatigue, nausea • Cannot be given at creatinine clearance < 30 ml/min • Drug interactions: – If taking PPI, must dose at same time, not prior to Harvoni – Use lowest dose of statin – Ok to coadminister with methadone – Avoid with HIV protease inhibitor + tenofovir Sulkowski IAS 2014

Sofosbuvir/Ledipasvir

Sulkowski IAS 2014

46 8 Sofosbuvir/Ledipasvir SOF/LED in Cirrhosis

ION-1Treatment Naïve Cirrhotics: ION-2Treatment Experienced Cirrhotics • 12 weeks 94% cure w/o RBV • 86% SVR ( 19/22) with 12 weeks • No benefit to 24 weeks • 100% SVR (22/22) with 24 weeks • No clear benefit of RBV • No clear benefit of RBV

Sulkowski IAS 2014 Sulkowski IAS 2014, IDSA 2014

Sofosbuvir/Ledispasvir Indications SOF/LED in Decompensated Cirrhotics • SOLAR: 12 weeks SOF/LED/RBV in CPT‐B & C Genotype 1 Patient Cirrhotic? Duration Treatment naïve, HCV Non‐cirrhotic 8 weeks RNA < 6 million Treatment Naïve, HCV> 6 Non‐cirrhotic million Treatment Naïve Cirrhotic 12 weeks

Treatment Experienced Non‐cirrhotic

Treatment Experienced Cirrhotic 24 weeks

Flamm AASLD #239

47 9 SOF/LED to retreat Cirrhotics • SIRIUS : cirrhotics with prior PEG/RBV and PEG/RBV/PI failure (no sosfosbuvir or NS5a failures) Non Genotype 1

Bouliere AASLD 2014 Abstract # LB-6

Genotype 2: Sofosbuvir/Ribavirin Genotype 3: Sofosbuvir/Ribavirin

Cirrhotic? Duration Cirrhotic? Duration Non-cirrhotic Non-cirrhotic Treatment naïve & 24 weeks Treatment naïve & 12 weeks Cirrhotic Cirrhotic Treatment Experienced Non-Cirrhotic 24 weeks Treatment Experienced Non-Cirrhotic 12 weeks 24 weeks Treatment-Experienced Cirrhotic CONSIDER Treatment-Experienced Cirrhotic 16 weeks SOF/PEG/RBV Better treatment options coming for Genotype 3 • Daclastasvir (NS5a) • Merck Pangenotypic Combination (PI+NS5a)

48 10 Monitoring on and after treatmetn Reinfection: Achilles heel of Cure

12 weeks after Before 4 Every 4 End of therapy therapy therapy weeks weeks completed HCV x Genotype Fibrosis x Staging HCV RNA x x x x CBC* x x x LFTS/Renal xx x

*More Frequent CBC monitoring if Ribavirin-containing regimen Cirrhotic patients need continued HCC surveillance after cure Hill AASLD 2014 Abstract 44

Conclusions “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. ” Winston Churchill • We finally have to tools to cure HCV in the majority of HCV patients Thank you!! • This is the beginning: Future regimens will be even shorter (and hopefully cheaper) and address remaining gaps (such as treatment in ESRD and Genotype 3) • While we need to prioritize treatment of those with most advanced disease, all benefit from HCV cure • In order realize the tremendous potential of HCV DAAs, we will need large cadre of HCV treaters, including primary care based

49 11 Resources References

• AASLD/IDSA HCV Guidelines: 1. Yehia, B.R., et al., The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One, 2014. 9(7): p. http://www.hcvguidelines.org e101554. 2. Smith, B.D., et al., Recommendations for the identification of chronic hepatitis C • University of Liverpool HCV Drug interaction virus infection among persons born during 1945-1965. MMWR. Recommendations and database: http://www.hep-druginteractions.org reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, 2012. 61(RR-4): p. 1-32. • Patient education resource HCV Advocate: 3. Asselah, T. and P. Marcellin, Interferon free therapy with direct acting antivirals for HCV. Liver international : official journal of the International Association for the Study www.hcvadvoate.org of the Liver, 2013. 33 Suppl 1: p. 93-104. 4. Ditah, I., et al., The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. Journal of Hepatology, 2014. 60(4): p. 691-8.

References

1. Yehia, B.R., et al., The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One, 2014. 9(7): p. e101554. 2. Smith, B.D., et al., Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, 2012. 61(RR-4): p. 1-32. 3. Asselah, T. and P. Marcellin, Interferon free therapy with direct acting antivirals for HCV. Liver international : official journal of the International Association for the Study of the Liver, 2013. 33 Suppl 1: p. 93-104. 4. Ditah, I., et al., The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. Journal of Hepatology, 2014. 60(4): p. 691-8. 5. http://www.hcvguidelines.org 6. http://www.hep-druginteractions.org

50 12 Staring down a black hole: A primary care perspective of rheumatologic lab testing

A Primary Care Primer to Interpreting Rheumatologic Lab Tests

Annual Review Family Medicine 2014 Jonathan Graf, M.D. Associate Professor of Clinical Medicine University of California, San Francisco Division of Rheumatology San Francisco General Hospital

Demystifying Rheumatology Lab Sample ABIM question Tests • Understand basic principles of how given test is performed Typical ABIM Board Examination Question On Rheumatology Lab Testing – What type of test is it? – What does the test measure? No Idea – What are the test’s limitations? Rh. Factor • Know the patients being tested ANA – Pretest likelihood that they have disease for ANCA which they are being tested?

51 1 Sedimentation Rate Sedimentation Rate

• Sample question: What is the highest • Sample question: What is the highest Erythrocyte sedimentation rate ever recorded? Erythrocyte sedimentation rate ever recorded?

• 100 • 100 • 200 • 200 • 400 • 400 • I have no Idea!!!!! • I have no Idea!!!!!

•Answer: – Technically speaking: 200 MM/hr – Practically speaking: About 150

ESR: Technique

• Aspirating the diluted EDTA- blood (in citrate) to the 200 mm mark of a Westergren tube

• Placing the tube in a vertical position in a Westergren rack in a location that is free of vibration and that is not exposed to direct sunlight.

• After exactly one hour, reading the distance the erythrocytes have fallen.

52 2 What does an ESR Measure? Causes of Elevated ESR’s

• Measures Acute Phase Proteins • Pregnancy (increased Fib levels) – Fibrinogen most common • Anemia (Plasma counter flow altered) – Produced in liver as part of an inflammatory response under control of cytokines like Il-6, Il-1, TNF • Macrocytosis (cells fall faster) • Diabetes • RBC’s serve as proxy for fibrinogen levels • End Stage Renal Failure – Fibrinogen interacts with RBC to make them sediment faster • Malignancy • Infections • Many other factors that affect serum fibrinogen • Autoimmune inflammatory diseases levels or RBC morphology can affect the ESR – Especially Vasculitis, PMR, RA

ESR - Tidbits C Reactive Protein

• Women generally have slightly higher ESRs then Men • What is it? – Acute phase protein produced by the liver • ESRs rise with age: ESR < Age/2 (+5 in women) • How is it measured? • ESRs can be affected by room temperature and – Directly via an ELISA or nephelometrey (unlike ESR) laboratory technique • Advantages • Although ESRs are non-specific….. – Rises and falls more rapidly in association with acute phase response – ESRs part of diagnostic criteria for Polymyalgia Rheumatica & – Not affected by anemia, renal failure, or other Giant Cell Arteritis conditions that affect ESR – Unclear if always more sensitive than ESR for various – ESRs can be useful in following disease activity or response to CVD’s therapy for rheumatoid arthritis and osteomyelitis

53 3 Measuring the Acute Phase Timing of CRP vs. ESR Response Response Directly

Autoantibodies: Target self-antigens Comparison Between ESR & CRP Self Antigens: Components of cells

ESR CRP Complex Organelles

1,000’s of proteins Results affected by Gender Yes No Age Yes No Complex Ribonuclear Proteins Pregnancy Yes No Temperature Yes No Nucleic Acids Drugs (eg. steroids, salicylates) Yes No Phospholipids Smoking Yes No

- CRP and ESR measure somewhat different aspects of inflammatory response. - They usually but not always correlate with each other.

54 4 Examples of Autoantibodies What is an Anti-Nuclear Antibody?

PM • Autoabs directed specifically against intra-nuclear antigens

Plasma Membrane Antiphospholipid • Most commonly (not always) detected by immunofluorecence on intact cells Cytoplasm Antimitochondrial

Nucleolus Anti Topoisomerase I

Neutrophilic Cytoplasm Anti Pr3 (ANCA) • If an ANA is detected, the specific antigen may or may not Nucleus Anti dsDNA be known (most ANA’s aren’t known – only detected by fluorescence inside of an intact nucleus)

• When an ANA screen is positive, one then uses more specific tests against known antigens to determine if that ANA is relevant to medical disease (Subserology)

How is an ANA Performed?? ANA Patterns

• Hep-2 cells fixed to slide • Depends upon what & permeabolized molecule(s) are • Incubated in patient recognized by patient serum antibodies • Washed vigorously to – DNA is remove serum homogeneously distributed • Fluorescently labeled Anti-hum Ig secondary Ab – Centromeres seen in dividing cells • Wash again – Extractable nuclear • Detect florescence of antigens are speckled bound secondary Ab throughout cell

55 5 ANA Patterns: Homogeneous ANA Patterns: Speckled

ANA Patterns: Nucleolar Testing for Anti-Nuclear Abs

• General screening test for antibodies against most nuclear antigens

• Most of the other specific antibody tests for SLE are test for ANA’s

• If ANA negative, with few exceptions (SSA), No need to test for other antibodies

• Newest generation of IIF ANA’s, use human cell lines, are 95-99% sensitive for SLE

• ANA negative SLE is rare

56 6 More ANA Facts Antinuclear Antibodies and SLE • Only one of eleven ACR classification criteria for • ANA is not nearly as specific for SLE as it is SLE sensitive – 2/11 criteria………………..50% Specificity – Autoimmune thyroid disease – 3/11 criteria………………..75% Specificity – Other Collagen-Vascular diseases (>90% of SSc) – 4/11 criteria………………..95% Specificity – Medications – Malignancies • When working up SLE, the ANA should only be – Infections (viral) ordered with good pretest, clinical suspicion for SLE – Normal people (especially low titers) – In a patient with arthritis, ANA is no better than coin flip

• If ANA negative, no need to check ANA “panel.”

ABIM Choosing Wisely Campaign 2013 http://www.choosingwisely.org/ When the ANA is Positive

• “An initiative of the ABIM Foundation…specialty societies have • Further differentiating the specific target may created lists of “Things Physicians and Patients Should Question” — be of use, in the right clinical context evidence-based recommendations that should be discussed to help make wise decisions about the most appropriate care based on a patients’ individual situation.” • Most tests/sub-serologies are done by specific ELISA or immunoblot – Patient serum is incubated with target antigen – Antibodies remaining bound to the target antigen are detected with labeled antisera

• If detected, the specific target of the ANA, with the right clinical picture, can help clarify a diagnosis and/or serve a predictive role

57 7 Homogeneous Patterns: Anti- Anti-Histone Antibodies (Histones dsDNA Abs are bound to DNA) • 50-60% sensitive for SLE • Diected against one or more proteins or protein- • 90-95% specific for SLE DNA complexes in nucleosome (histone + • 1/11 SLE “criteria” dsDNA) • Presence and titer can • Can be seen in SLE and Drug-induced LE correlate with – Not specific for Drug-LE renal/systemic disease – Very Sensitive (practically required to even consider flares the diagnosis of drug-induced LE) • Possible direct implication • Strong negative predictive value (not positive) Homogeneous Pattern • Can be seen with or without disease, with other diseases in GN (SLE) • 95% cases of procainamide LE • Hydralazine, INH, Aldomet, Dilantin, Tegretol

Speckled: Extractable Nuclear U1snRNP Particle Antigens • Acid extractable • Complex nuclear antigens macromolecule of – U1SNRnP RNA and proteins • Anti-Smith • Anti-RNP • Includes target sites – SSA (RO) for both anti-Smith – SSB (La) and anti-RNP Abs Speckled Particles • Helps explain why many SLE patients have antibodies to both Smith and RNP

58 8 Anti-Smith Antibodies Anti-RNP Antibodies

• Poor sensitivity for SLE (20-30%) • 100% sensitivity for patients with MCTD (diagnostic criterion) • Very high Specificity for SLE (95-99%) • 40-60% patients with SLE – More raynaud’s phenomenon, less renal involvement, “less severe disease” • May identify a subset of patients with more – More interstitial lung disease severe disease and/or renal involvement – Features of myositis, scleroderma, and arthritis

Anti-SSA (Ro) and SSB (La) Anti-Ro (SSA) Skin Disease Key Associations You Have to Know Subacute cutaneous lupus erythematosus

• Sjogren’s syndome – 88-96% of patients with primary SS have SSA – 70-80% with primary SS have SSB – Much lower percentage for secondary SS pts. – Primary SS usually dual Ab positive • Increased incidence of vasculitis, purpura, lymphoma, etc… • Associated with neonatal lupus – Implicated in pathogenesis, although not only factor – Mothers with SLE, Sjogren’s, or asymptomatic – Rash and congenital heart block Papulosquamous Annular

Courtesy ACR Image Bank

59 9 Anti-Centromere Antibodies Anti-Centromere Antibodies

• Newer ANA assays use a cell line that rapidly divides • Classically associated with Limited Scleroderma “CREST” syndrome (60-80%) • ANA’s may recognize • Diagnostic/ prognostic significance: components of mitotic spindle – Isolated Raynaud’s 25% (? Predict future?)

• Most IIF can detect Anti- – Pulmonary HTN Centromere Abs now – Incomplete “CREST” features – Progressive Systemic Sclerosis continuum • Any doubt, order specific ELISA

Nucleolar ANA’s: Systemic Sclerosis and Idiopathic Inflammatory Myopathies Not all antigens are in the Nucleus

• ANA is also 90-95 % sensitive for • Sometimes IIF fails to stain progressive systemic sclerosis the nucleus, but stains the – Not just a test for SLE cytoplasm instead – ANA negative PSS is relatively rare • TRNA synthestases: Most • Anti-Topoisomerase I (SCL-70) clinically relevant myositis – 25% sensitivity – Jo-1 (histadyl TRNA synthetase) – 90+% specificity – Anti Jo-1 syndrome – Risk for more sub-acute, progressive, and systemic organ – Myositis, Raynaud’s, Arthritis, Nucleaolar Pattern involvement (renal crisis, ILD, GI) ILD (prognosis) 20 TRNA synthtases: each charges a separate TRNA molecule with a specific amino acid for its RNA codon • Mitochondria (primary biliary cirrhosis)

60 10 Features of Anti-Jo1 Growing list of Anti-synthetase antibody associated diseases (synthetase) Syndrome

Solomon et al. J. bras. Pneumol;37:1 Jan./Feb. 2011

Solomon et al. J. bras. Pneumol;37:1 Jan./Feb. 2011

Rheumatoid Factor Rheumatoid Factor

• Usually IgM directed • In collagen vascular disease and RA, higher titer against Fc domain of RF with stronger affinity for IgG one’s own IgG

• RF may be natural • Present in 1-5% of normal population response of body to downregulate normal antibody responses • Incidence increases with age – 10% prevalence over age 65 • Usually low titer, low affinity, more transient • Association with rheumatoid arthritis, but hardly antibodies exclusive to RA

61 11 Rheumatoid Factor and Non-Rheumatic Rheumatoid Factor – but not RA! Diseases • Collagen Vascular Diseases Preval. • Overriding principle: Chronic antigenemia can lead to rheumatoid factor production – Sjogren’s Syndrome 20-30% – SLE 15-35% • Chronic Infections – Cryoglobulinemia 40-100% – Chronic infections elicit chronic immune responses, – Scleroderma 20-30% including rheumatoid factor – Poly/Dermatomyositis 5-10% – Includes: hepatitis C, endocarditis, osteomyelitis, syphillis – Antigen-antibody complexes usually contain RF All rheumatoid factor positive arthritis is NOT rheumatoid arthritis!!! • IPF, cirrhosis, sarcoid, etc…

Antibodies to Citrullinated Rheumatoid Factor and RA Proteins • Prevalence increases with disease duration • Originally identified over 40 years ago when rheumatoid arthritis patients were found to have antibodies to – 33-50% positive at disease onset something in epidermal (skin) cells – perhaps keratin. – 75% positive after one year – 80+% positive at 18 months • For decades, the finding not definitively confirmed, and so it was largely ignored

• Prognostic significance • Fast forward to late 1990’s – Actual target later identified as filaggrin, a form of keratin where – More severe, erosive, difficult to treat, and extra the amino acid arginine has been modified into citrulline articular disease – RA patients make antibodies not only to filaggrin, but to many – Titers not usually followed (only occasionally correlate proteins that contain citrulline with dz activity) – Specific target of anti-citrullinated protein antibodies is not known

62 12 Anti-CCP antibody test Citrulline

• Because the actual citrullinated protein target(s) • Not one of 20 AA’s coded for in DNA/RNA for these antibodies is not known, the anti-cyclic citrullinated protein test was developed • Mamalians possess – Synthetically constructed peptides Peptidyl Arginine – Circularized for maximal sensitivity and specificity Deiminase that can – Different diagnostic companies market their own convert arginine residues proprietary “cocktail” of artificial CCPs within proteins to citrulline. – Attempts to recognize the diversity of antibodies to Deiminase removes amino group citrullinated proteins found in RA patients • May create new targets for autoimmunity

RA-associated autoantibodies that Anti-CCP Antibodies and RA recognize peptides containing citrulline Girbal-Neuhauser et al J Immunol 162: 585, 1999 • 70-80% Sensitivity for RA • 90-95% Specificity for RA Peptide sequence Antibody recognition

ESSRDGSRHPRSHD No • Help distinguish RA from other diseases

PADI • Presence can antedate and predict development of disease in undifferentiated individuals ESSRDGScitHPRSHD Yes

Actual inciting citrullinated antigen is not known • Highly correlated with more severe and erosive disease

63 13 Diagnosis of early RA by ACR criteria Factors predictive of progression van Gaalen et al Arth Rheum 50: 709, 2004 from undifferentiated arthritis to RA van Gaalen et al Arth Rheum 50: 709, 2004 936 patients with early inflammatory arthritis At initial evaluation OR (95% CI) Initial evaluation After 3 years Positive rheumatoid factor 1.7 (0.5-5.6) Positive anti-CCP antibody 38.6 (9.9-151.0) 205 RA by ACR criteria

936 318 “undifferentiated 127 RA arthritis”

413 other diagnoses

Anti-Neutrophil Cytoplasmic ANCA Immunoflorescence Patterns Antibodies (ANCA) • Antibodies directed against neutrophilic antigens • C-ANCA – Associated most commonly with – Neutrophils chock full of proteases Granulomatosis with Polyangiitis (Wegeners) – >90% sensitive and specific • Detected by immunoflorescence performed on – Titers may correlate with neutrophils fixed to slide disease, but unreliable Cytoplasmic Staining • P-ANCA – Analogous to ANA’s, except uses a neutrophil cell line – Microscopic Polyangiitis – Detects neutrophil-specific antigens in cytoplasm – Churg-Strauss –IBD – Drugs • Unknown if ANCA are directly pathogenic or – Not commonly PAN epiphenomenon of disease Perinuclear Staining

64 14 Predictive Value and Testing for Specific Targets of ANCAs Rheumatic Diseases • Sensitivity and Specificity are intrinsic properties of a given diagnostic test – Never changes depending upon who/what is being screened

• We now know specific antigens that stain in these – ANCA’s revolutionized diagnosis of vasculitis patterns and how they correlate with specific diseases because of their high sensitivity and specificity – C-ANCA is Proteinase 3 and correlates with WG – P-ANCA is usually myeloperoxidase and correlates with MPA – Also created huge problems in interpretation – Some P-ANCA not MPO = “atypical” • VERY POOR PREDICTIVE VALUE!!!!! – Although one can order ELISAs directly, some advocate ordering both IIF and ELISAs to enhance sensitivity, specificity and interpretation of all ANCAs

False positives are a problem when testing Predictive Value for rare diseases

• Describes the usefulness of a positive or • For a given rare disease that affects less than 0.01% negative test in ruling in or out a given disease general population (100/1,000,000)

• Even with an ANCA-like specificity of 95%, if 1,000,000 • Takes into account not only test’s sensitivity and people were randomly screened, 5% false positives = specificity, but also disease prevalence 50,000/1,000,000

• True positives = 100, False positives = 50,000 • PPV = True positives/Total positives • With a test that is 100% sensitive, 95% specific, PPV • Total positives = True Pos + FALSE POS!! only roughly 100/50,100 = 0.2%!!!!

65 15 Take Home Message

• Rheumatic diseases are uncommon • Even with very good testing, must know your patients in whom you order these tests (what is pre-test likelihood of disease?) • Must know the qualities of test being performed • ANA general screening test – If negative, with few exceptions, no need to hunt for other specific sub-serologies

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Roadmap

• Define burnout and discuss its impact The Science of Burnout • Describe risk factors and protective factors • Define compassion fatigue, secondary traumatic stress, and compassion satisfaction What is It, What Causes It, and What • Discuss strategies for preventing burnout and Makes It Go Away promoting compassion satisfaction

Herbert Freudenberger’s original Herbert Freudenberger’s original conception of burnout conception of burnout 1. Compulsion to prove oneself 7. Withdrawal 2. Working harder 8. Obvious behavioral changes 3. Neglecting needs 9. Depersonalization 4. Displacement of conflicts 10.Inner emptiness 5. Revision of values 11.Depression 6. Denial of emerging problems 12.Burnout syndrome—physical and emotional collapse

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The concept was refined by Christina Maslach, developer of the Maslach Impact of Burnout Burnout Inventory • 25‐75% of practicing physicians have burnout • Emotional exhaustion at any given time. • Cynicism and depersonalization • Over a career, periodic episodes of burnout are virtually inevitable • Loss of sense of efficacy

Impact of Burnout Adverse impacts spread

Increased rates of Increased • Depression • Errors, both medical and surgical • Anxiety • Patient dissatisfaction Suicidality • • Postoperative recovery times • Increased inflammatory markers • Wound infections • Possible association with cardiovascular disease • Patient nonadherance • Increased sick calls • Attrition from medicine

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Risk Factors and Protective Factors Work Related Risk Factors

Work Personal • Lack of control Risk • Heavy workload • Exposure to trauma

Protection

Risk Factors and Protective Factors Work Related Protective Factors

Work Personal • Shared mission Risk Lack of control Heavy workload • Flexible schedule Exposure to trauma • Teamwork • Work friends Protection • Supportive culture • Teaching and administrative roles – Opportunity for sense of effectiveness in the short to mid term

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Risk Factors and Protective Factors Personal Risk Factors

Work Personal • Temperament and personality features Risk Lack of control Heavy workload – Alexithymia Exposure to trauma • Life stress • Personal history of trauma Protection Shared mission Flexible schedule • Approach to work Teamwork Work friends Supportive culture Shared mission Teaching and administrative roles

Approach to work

• Surface organized – Must be “just so” • Surface disorganized – Overwhelmed • Deep approach – Interested and engaged by complexity, problem solving.

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Personal Protective Factors Risk Factors and Protective Factors

Work Personal • Relationships with patients Risk Lack of control Life stress Heavy workload Personal history of trauma • Relationships with colleagues Exposure to trauma Alexithymia Approach to work • Social support

• Empathetic concern Protection Shared mission Relationships with patients Flexible schedule Relationships with co‐workers • Openness to new experience Teamwork Social support Work friends Empathetic concern • Deep approach to work Supportive culture Openness to new experience Shared mission Approach to work Teaching and administrative roles

Self‐care practices Self‐care practices • Meditation • Meditation – Increased attentional control • Exercise – Increased ability to notice and accurately label emotions • Outside interests – Decreased impulsive reaction to negative emotion • Psychological practices – Shift from “brooding” or perseverative style to “compassionate noting” style of awareness • Therapy – Increased positive affective states Special training • Happiness, joy, love, gratitude, contentment, hope, interest, • amusement, awe • Micro‐breaks – Increased internal resources: • greater purpose in life, improved resilience, enhanced • Vacations optimism, greater mindfulness, more self‐acceptance, more hope

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Psychological Practices Micro‐breaks • Short, dispersed throughout day • Gratitude list • Work‐related • Taking in the good – Conversations with colleagues • Perspective taking • Physical • Deep breath – Walk down the hall • Visualization – Stretch • Relaxing – Deep breath – Visualization – Words

Vacations Other Models

• Reduced work related stress and burnout for Secondary 1‐2 months Traumatic Stress • Shorter if high workload upon return Compassion • Consider shorter, more frequent vacations Satisfaction Compassion Fatigue

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What is Compassion Satisfaction? The Impact of Compassion Satisfaction

The satisfaction derived from being able to help • Studies on the impact of emotional others. attunement and engagement – Higher adherence to medications and recommendations – Increased patient satisfaction – Increased placebo response

“Incentivizing with money is a self‐fulfilling prophecy of cynicism. We must promote compassion, courage, and wisdom among our physicians before we make a sordid business of this high and sacred calling.”

Describe a time when you felt Your assignment compassion satisfaction at work • Notice the moments when you experience • What were the conditions that promoted it? compassion satisfaction.

• Can you build those conditions in to your work • Feel it when it happens. more? • Look for ways to build more in.

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Disclosures

Pre‐Exposure Prophylaxis (PrEP): • The views expressed herein do not necessarily reflect the official policies of the City and The HIV Prevention Revolution County of San Francisco; nor does mention of the San Francisco Department of Public Health Stephanie E. Cohen, MD, MPH imply its endorsement. Medical Director, City Clinic San Francisco Department of Public Health • Gilead donated study drug for the PrEP Demo Assistant Clinical Professor project, but was not involved in study design University of California, San Francisco Division of Infectious Diseases or data analysis

Learning Objectives What is the state of PrEP in 2014?

• Name potential candidates for pre‐exposure • Review and update of what we know prophylaxis. – What is PrEP? • Name the tests that should be performed – Does PrEP prevent HIV acquisition? In whom? prior to initiating someone on PrEP – What about…. • Identify the monitoring that should be • Adherence conducted while someone is taking PrEP • Resistance • Increased sexual risk • Side effects and toxicities • How to provide PrEP in primary care

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Question 1 Question 2

I always take a sexual history when I am seeing a I have prescribed PrEP to a patient. patient for the first time, and at least once or twice/year after that. 1) YES

1) YES 2) NO

2) NO

Why are New HIV Prevention Tools Needed? NEW HIV INFECTIONS IN 2010

• Despite testing, counseling, condoms, and ART, 40,000‐50,000 new infections annually in the U.S. • Incidence far higher in Sub‐Saharan Africa, Eastern Europe, Southeast Asia, and in certain populations • Men who have sex with men (MSM) • Racial and ethnic minorities • Injection drug users (IDU)

CDC fact sheet

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HIV INCIDENCE BY GENDER & RACE/ETHNICITY GOOD NEWS BAD NEWS • 33% decrease in annual • MSM 13‐24 years old diagnoses

• Black Women

• MSM 45‐55 & MSM ≥55

CDC fact sheet 500,000 infections 2002‐2011

9 CDC fact sheet; Johnson et al, JAMA 2014.

Current HIV Prevention Methods: where are the gaps? What is Pre‐Exposure Prophylaxis? Method (+) (‐) • A fixed dose combination of emtricitabine 200mg plus tenofovir ‐ Knowledge of HIV +status leads ‐ Condom efficacy drops off Testing/Counseling to decrease in risk behavior quickly if not used correctly 300mg, co‐formulated as FTC/TDF, or Truvada® + ‐ Condoms: 67%‐80% efficacy if and consistently • Prescribed for daily oral use by HIV(‐) persons at increased risk Condoms used correctly and consistently ‐ Questionable efficacy of for HIV infection, in combination with other prevention methods counseling in RCTs • Regular testing for HIV, STDs, renal function Decrease in reported risk ‐Need evidence of decreased Counseling Community behavior incidence • Empowerment ‐Scalable? – Adherence Risk reduction 96% risk reduction in ‐Few MSM in the RCT – serodiscordant heterosexual ‐Does not protect partners of • Approved in July 2012 by FDA ART as Prevention couples (HPTN052) infected‐unknowns or with acute HIV Risk Evaluation and Mitigation Strategy (REMS) ‐Intermittent viremia? •Training and education program to assist prescribers in counseling individuals who are taking or considering TDF/FTC for PrEP PEP 80% risk reduction (AZT ‐Underutilized monotherapy in occupational ‐Requires initiation within 72h •Goal is to minimize risk of acquiring HIV, reduce risk of HIV resistance (Post‐exposure www.truvadapreprems.com Prophylaxis) exposure) of recognized risk

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PrEP and the test/treat model

I. Universal, accessible HIV/STI testing II. IMMEDIATE ART ‐Frequency determined by risk IF(+) •Eliminate OIs/AIDS ‐Testing for acute infection in high‐risk •↓ nonAIDS populations/settings complications •↓ transmission to IF (‐) heterosexual partners Does PrEP Work? (HPTN052) III. COMBINATION PREVENTION •?↓transmission in Efficacy Results from Randomized •Condoms MSM? •Risk Reduction: counseling/education/coaching •Substance abuse treatment Controlled Trials (RCT) •PEP for occasional exposures •PrEP for Pts with elevated risk •Rectal STIs •UAI with multiple partners or non‐ Who is PrEP for? monogamous steady partnerships •Serodiscordant partners (Off ART? On ART?) •Conception

TRIAL POPULATION LOCATION Active arm(s) EFFICACY (mITT‐ analysis) Design of PrEP RCTs iPrEx 2499 MSM and TGF South America, FTC/TDF 42% (95% CI 18‐60) USA, Thailand, 48 vs. 83 South Africa • Rapid HIV testing at enrollment TDF‐2 1219 heterosexual Botswana FTC/TDF 63% (95% CI 21‐83) • Randomized to daily drug vs. placebo men and women 9 vs. 24 Partners 4758 serodiscordant Kenya and FTC/TDF 73% (95% CI 49‐85) • Monthly follow‐up visits for rapid HIV testing, PrEP heterosexual Uganda TDF 67% (95% CI 44‐81) couples 13 FTC/TDF, 17 TDF, adherence counseling and measures, 52 placebo prevention counseling, STI testing/treatment FEM‐PrEP 2120 heterosexual Kenya, FTC/TDF No difference women Tanzania, 33 FTC/TDF vs. 35 placebo If rapid(+) at a f/u visit, HIV RNA performed Zimbabwe, • Stopped early due to lack of retrospectively on stored plasma to determine South Africa efficacy VOICE 5000 heterosexual Uganda, FTC/TDF No difference infection window women Zimbabwe, TDF TDF and gel arms stopped early • Outcomes: efficacy, safety, adherence, South Africa Vaginal TDF gel Bangkok 2413 IDU Bangkok, drug TDF 48.9% (95% CI 10‐72) behavior, resistance Tenofovir treatment 17 vs. 33 Study centers

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PrEP Efficacy PrEP Efficacy and Drug Detection

Study Efficacy overall Drug detected Risk reduction with overall drug detection

iPrEx 42% 50% 92%

Partners PrEP 67% (TDF) 82% 86% (TDF) PrEP works extremely well IF you 75% (FTC/TDF) 90% (FTC/TDF) take it TDF‐2 62% 80% 78% Fem‐PrEP Stopped early < 40% adherence too low to due to futility assess efficacy VOICE Stopped early < 30 % adherence too low to due to futility assess efficacy Bangkok IDU 49% 66% 74%

DOES ADHERENCE HAVE TO BE Adherence, Drug levels and Efficacy PERFECT?

Dosing Estimated PrEP NO infections seen Efficacy w/ ≥ 4 doses/week 2x/week 76%

4x/week 96%

Daily 99%

Anderson PL. Sci Transl Med 2012;4:1‐8. Grant et al. IAS. 2014

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PrEP Safety PrEP and Antimicrobial Resistance

Number of HIV Seroconverters on Active PrEP Arms With HIV Resistance Rates of death, serious adverse events, and laboratory • Seronegative Acute HIV Infected After HIV Infections abnormalities (including renal dysfunction) low and not significantly Trial HIV Infection at Enrollment, n/N Averted, n different between those taking PrEP and those taking placebo Enrollment, n/N iPrEx[1,2] 0/36 2/2 28 • PrEP was well tolerated Partners PrEP[3] 0/30 2/8 74 [4] – Adverse effects occurred in minority of subjects TDF2 0/10 1/1 16 – GI adverse effects (eg, nausea) more common in those receiving PrEP than placebo . Resistance was rare in clinical trials of PrEP, except for those with • Occurred in < 10% and primarily during the first month only acute infection at baseline (PrEP “start up” symptoms) . Resistance mutations seen: K65R (TDF) or M184V/I (FTC)

• PrEP associated with a small change (~ 1%) in bone mineral density 1. Liegler T, et al. CROI 2011. Abstract 97LB. 2. Grant RM, et al. N Engl J Med. 2010;363:2587‐2599. but without increased risk of fracture 3. Baeten JM, et al. N Engl J Med. 2012;[Epub ahead of print] (supplementary appendix). 4. Thigpen MC, et al. N Engl J Med. 2012;[Epub ahead of print] (supplementary appendix).

PrEP and Risk Compensation PrEP and Risk Compensation

• In the Partners PrEP Study, no increase in unprotected sex • In iPrEx, belief in receiving FTC/TDF was not associated in serodiscordant couples, STIs, or pregnancy after July with an increase in numbers of RAI sex partners or % of 2011 (when placebo stopped and all received active PrEP). condomless RAI sex partners Average frequency of unprotected sex

July 2011

Mugwanya et al., Lancet Infectious Diseases 2013 Marcus, PLOS One 2013

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Not all PrEP RCTs have shown a benefit Number Needed to Treat

• Adherence is critical • Other issues? • Drug concentration at exposure site: Rectal vs. vaginal sex • Integrity of epithelium: Other STDs, trauma, other NNT ~ baseline risk products (douching, soaps, drying product) and efficacy • Intensity of exposure: # partners, frequency of sex • Stage of infection in index partner (acute vs. chronic)

Buchbinder et al. 2014. Lancet ID

Who should get PrEP? How do I prescribe PrEP in primary care?

• Receptive anal sex w/o 1) Take a sexual history (The 5 P’s) condom: High PAF, Low NNT ‒ Partners

• Single HIV ‒ Prevention of Pregnancy positive partner: ‒ Protection from STDs Low PAF; Low NNT ‒ Practices ‒ Past history of STDs

Glidden CROI 2014 #64, Buchbinder Lancet ID 2014.

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How do I prescribe PrEP in primary Risk Calculators care? 2) Identify patients who may benefit from PrEP CDC guidelines: Sexually‐active MSM, heterosexual men and women & IDU “at substantial risk” MORE SPECIFICALLY: • MSM or transgender women ‐ condomless anal intercourse with multiple partners • MSM or transgender women ‐ syphilis or rectal STI • Commercial sex workers • Men or women in serodiscordant relationships with positive partners with detectable viral load • Peri‐conception

CDC PrEP Guidelin

3) Discuss PrEP with your patient

• What is the patient currently doing to protect himself from HIV? – Discuss condom use, role of substance use, risk perception, prevention goals • Key counseling points: – Only studies of daily dosing have proven PrEP efficacy – Important to get tested for HIV regularly (at least every 3 months) while taking PrEP – Anticipatory guidance re. “start‐up syndrome” – Discussion of how to stop and safely re‐start PrEP www.sfcityclinic.org/services/prep.asp

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Additional resources for talking to your 4) Take a Medical History and do a patient about PrEP Symptom Review www.projectinform.org/prep/ • Osteoporosis and liver disease are relative contraindications to TDF/FTC

• Moderate kidney dysfunction is an absolute contraindication

• Patients with recent symptoms of a mono‐like illness should be tested for acute HIV. Wait to start PrEP until test results are back

5) Obtain Baseline Testing 6) Discuss how patient will pay for Truvada Coverage How to access HIV Antibody test (rapid if available). Uninsured and < 500% FPL • Gilead patient assistance program (PAP) provides • TDF/FTC at no cost • Strongly suggest obtaining a viral to test for acute • Client may need to pay for office visit and labs HIV when PrEP initiated. Uninsured and > 500% FPL • Pay out of pocket ($1250/month) + office visits, lab costs • Creatinine (CrCl should be ≥ 60 ml/min) Medicaid • Covered; No prior authorization in California • HBsAg Employer‐sponsored • In general, most plans cover TDF/FTC for PrEP health insurance • Cost sharing varies; Gilead offers $300/month co‐pay • STDs assistance • Some require prior authorization, mail order Rx • Pregnancy test • Provider needs to code visit correctly or q3mo HIV testing may not be covered • Offer Hep B immunization if not immune Covered California • Bronze: High deductible, 30‐40% co‐insurance after Offer HPV immunization if <26 deductible met; TDF/FTC approx $800/mo (with co‐ • pay assistance) • Silver, Gold: Most have no cost after co‐pay card

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Common PrEP‐Related Billing Codes 7) Counseling

ICD‐9Description Risk reduction Adherence V69.2 High‐risk sexual behavior • • V01.79 Exposure to other viral diseases – Sexual and drug – PrEP basics handout V65.44 HIV Counseling using behaviors and (at PrEP initiation) ICD‐10 Description current efforts for – Discuss pill‐taking Z72.5 High‐risk sexual behavior remaining HIV Z20.82 Contact with and (suspected) exposure to experience other viral communicable diseases negative – Facilitators/barriers CPT Description How PrEP fits in with – – Strategies 99401 Preventive counseling (15 min) overall sexual health 99402 Preventive counseling (30 min) 99403 Preventive counseling (45 min) goals/plan 99404 Preventive counseling (60 min)

CDC PrEP Guidelines 2014; www.prepfacts.org

9) What if my patient has a positive 8) Ongoing Monitoring and Support HIV test? Timeframe Action • Discontinue PrEP to avoid development of 30 days after  Assess side effects and the patient’s interest in continuing initiation  Adherence counseling: reinforce importance of daily use resistance and address any challenges patient has faced. Order and document results of an HIV Every 3 months  HIV test: 4th generation preferred •  If the patient has been off PrEP form more than a week, genotype consider screening for acute HIV at time of PrEP re‐initiation  Creatinine: stop if CrCl < 60 ml/min • Ensure patient is linked to an HIV‐primary care  STD screening provider for care and possible early initiation  Pregnancy test for women; If pregnant, ensure that the of ART patient has been informed about use during pregnancy and that she discusses PrEP use with her prenatal provider. • Inform health dept  Renew prescription for 90 days only if HIV test negative  At visit: adherence and risk reduction counseling

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Serodiscordant Heterosexual Couples Additional Information

• BAPAC –Bay Area Perinatal AIDS Center – “PrEP‐ception” – PRO‐Men – Positive Reproductive Outcomes for HIV positive men

http://hiv.ucsf.edu/care/perinatal.html http://www.truvadapreprems.com/

Take Home Acknowledgements

• PrEP highly effective in preventing HIV • Al Liu acquisition, dependent on adherence • Oliver Bacon • PrEP safe and well tolerated • Jonathan Volk • Talk about sexual health with patients • Susan Buchbinder • Consider PrEP for those at elevated risk for • Bob Grant HIV • Susan Philip • Baseline and at least q3month HIV testing critical component of PrEP delivery

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Extra slides

Figure Counseling

• Deemed important by iPrEx participants in US: Nonjudgmental, open ended, data‐driven, motivational 1. Sexual behavior/HIV risk reduction – Risk assessment, probe for Pt’s knowledge of risk, prevention measures: “What’s been going on sexually in last X months?” – “What is it like disclose/ask about HIV status w partners?” – “What makes it easier/harder to use condoms?” – “What are the elements of your HIV prevention plan and how does PrEP fit into them?” 2. Adherence – Ask about pill taking several ways – What makes it easier/more difficult to take your pills daily? – What could you do to make it easier? – Offer tools: alarms, pillboxes, combining PrEP with other daily meds or activities 3. Discussion of most common side effects, mitigation strategies

– With/without food, bedtime dosing, waiting it out Source: The Lancet 2013; 381:2060‐2062 (DOI:10.1016/S0140‐6736(13)61140‐X) Terms and Conditions

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PrEP Research Agenda

• New oral agents • Other routes of delivery – HPTN 069 (NEXT‐PrEP) – Vaginal microbicides • Maraviroc + FTC – Vaginal rings • Maraviroc + TDF – Rectal microbicides Maraviroc alone • – Long acting IM • Truvada alone ‐Rilpivirine • Alternate dosing ‐GSK 1265744 ADAPT – – How to improve • Daily dosing adherence? • Time‐driven (twice weekly + dose post‐exposure) – “real time” drug levels? • Event‐driven (before and after • Provider capacitation exposure) – IPERGAY • Before and after sex

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Nothing to disclose…. Influenza Update

Lisa Winston, MD UCSF / San Francisco General Hospital Divisions of Infectious Diseases and Hospital Medicine

Influenza Biology Influenza Biology

Influenza viruses are single stranded, Influenza A enveloped RNA viruses  16 different HA subtypes  Divided into types A, B, ( C )   Influenza A viruses infect humans, pigs, horses, 9 different NA subtypes sea mammals and birds  Human influenza A viruses: H1N1,  Influenza B viruses infect humans (and seals) H1N2, H2N2, H3N2  Two surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) used to subtype influenza A viruses

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Influenza Biology Influenza Drift and Shift

Hemagglutinin attaches to cellular sialic acid receptors “Antigenic Drift” – minor changes due to Neuraminidase cleaves sialic acid releasing infectious virus particles point mutations Segmented genome with “Antigenic Shift” – major changes which 8 RNA fragments •Polymerase PB2 may be due to reassortment of RNA •Polymerase PB1 •Polymerase PA segments •Hemaglutinin  In setting of infection with 2 different •Nuclear protein •Neuraminidase viruses Trifonov et al, New Engl •Matrix proteins •Nonstructural proteins J Med, 2009;361:115-119

Pandemic Influenza

Pandemics occur when little immunity to circulating virus  Potentially due to shift, recirculation of previous virus, or direct transmission from animal to human 1918 – 1919: “Spanish flu,” 20-25 million deaths; H1N1 virus 1957-1958: “Asian flu;” H2N2 virus 1968-1969: “Hong Kong flu;” H3N2 virus 2009-2010: H1N1 virus Belshe, New Engl J Med, 2005;353: 2209 - 11

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Swine is presumed Seasonal Influenza “mixing vessel” for 2009 H1N1 Morbidity and Mortality

Pigs have Old estimate: 36,000 deaths per year in U.S. receptors for Severe disease in the elderly, very young, and those human and avian with significant comorbidities influenza A viruses  90% influenza-associated deaths occur in persons 65 and older Thompson et al, JAMA 2003;289:179-86 Revised estimates of deaths associated with seasonal influenza 1976 – 2007  Average 23,607 deaths (range 3,349 to 48,614)

Trifonov et al, New Engl  When influenza A(H3N2) prominent, death rate 2.7x higher J Med, 2009;361:115-119 MMWR August 27, 2010 / 59(33);1057-1062

Novel H1N1 vs. Seasonal Influenza Novel H1N1 Epidemiology

FIGURE. Distribution by age group of persons hospitalized with laboratory-confirmed Among person 65 years and older, influenza,* --- United States, 2007--08 winter influenza season and April 15--August 11, hospitalization rates related to novel H1N1 were 2009 less than 20% of those usually seen in the winter with seasonal influenza A About 2/3 of patients hospitalized have a known medical risk factor for severe disease (including pregnancy) Hospitalization among pregnant women is about 4 times higher than in the general population

Median age hospitalization: 20 years Obesity, especially morbid obesity, may be a Highest incidence of hospitalization children < 4 years new risk factor Median age of persons who died: 37 years MMWR, August 28, 2009;58(RR10):1-8 MMWR, August 28, 2009;58(RR10):1-8

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Current Influenza Activity

2014-15 Influenza Vaccine Influenza Vaccines (same as 2013-2014) Inactivated vaccine given by injection  Trivalent: 2 influenza A strains, 1 influenza B A/California/7/2009 (H1N1)-like strain A/Texas/50/2012 (H3N2)-like  Quadrivalent: 2 influenza A strains, 2 influenza B strains B/Massachusetts/2/2012-like (Yamagata lineage)  Few contraindications For quadrivalent vaccine add: Severe egg allergy – risk assessment, referral  B/Brisbane/60/2008-like (Victoria lineage) Severe previous reaction MMWR 2014;63:483-90 Guillain-Barre (relative contraindication) Live attenuated intranasal vaccine (FluMist) • Nationwide this season: 82% A, 18%B • A almost all H3N2  Same strains as inactivated vaccine • B split Yamagata and Victoria lineages Quadrivalent

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Newest influenza vaccines Influenza Vaccine Indications licensed in U.S.

All people older than 6 months Three quadrivalent inactivated vaccines: 2 influenza A and 2 influenza B strains; intramuscular  Unless there is a contraindication  Fluarix, FluLaval, Fluzone FluBlok: baculovirus expression system (recombinant), no exposure to eggs – age 18+ Flucelvax: cell culture derived (canine kidney cells) – age 18+ Afluria trivalent vaccine can be administered by jet injector (FDA approved August 2014 ages 18-64)

High Dose Inactivated Vaccine Intradermal Influenza Vaccine Fluzone intradermal vaccine approved by FDA Fluzone High-Dose licensed for those 65 and older in 2011 Trivalent; contains 60 g of hemagglutinin per virus strain compared with 15 g in regular dose Needle is about one-tenth of standard length Enhanced immune response in those 65 and older Contains 9 mcg hemagglutinin per strain versus with high dose vs. standard dose standard 15 mcg Local reactions (mild to moderate) more common  Dose is 0.1 mL versus standard 0.5 mL with high dose vaccine J Infect Dis 2009;200:161-3 Approved ages 18 – 64 years 2-year study with 31,989 participants randomized to Local reactions are more common high dose vs. standard dose: 1.4% vs. 1.9% with confirmed influenza (relative efficacy 24.2%) New Engl J Med 2014;371:635-45.

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Live Attenuated Influenza Live Attenuated Influenza Vaccine Vaccine Who should not get LAIV? Attenuated, heat sensitive and cold  Outside recommended age ranges adapted  Chronic medical conditions, including asthma Approved for healthy persons ages 2 – 49,  Pregnant women including healthcare workers and contacts  History of Guillain-Barre (relative of most high risk patients contraindication)  Severe egg allergy – risk assessment, prefer Runny/stuffy nose is common TIV  Contact with highly immunosuppressed patients, e.g. bone marrow transplant

Live Attenuated Influenza LAIV Vaccine (LAIV) Surveillance in military ages 18 – 49 over 3 influenza Efficacy seasons (2006 – 2009)  In children, 85 – 90% effective in preventing Compared influenza like illness, influenza, and influenza A compared with placebo pneumonia in those vaccinated with LAIV compared with  In children, several studies suggest better inactivated vaccine: 41,670 vaccination events efficacy than inactivated vaccine Excluded those with contraindications to LAIV  Study in adults in Michigan 2004 – 2005 Controlled for sociodemographics, occupation, influenza season: decreased efficacy compared geographic area with inactivated vaccine, especially against influenza B (poor matches for both influenza B No differences found by vaccine group and H3N2 “drifted” strain)

Ohmit et al, N Engl J Med 2006;355:2513 - 22 Clin Infect Dis 2013;56:11-19

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LAIV now preferred for some Influenza Vaccination of children Healthcare Personnel

Starting 2014-15, CDC now preferentially Many elderly, chronically ill, and recommends LAIV for healthy children immunocompromised persons do not have ages 2 – 8 years if no contraindications a robust immune response to the vaccine and vaccine is immediately available Influenza is transmitted in healthcare facilities  HCP both transmit and acquire influenza  HCP frequently work when they are ill  Influenza is shed before symptoms develop; some infections are asymptomatic MMWR 2014;63:691-7

Does Influenza Vaccination of HCP Help? Does Influenza Vaccination of HCP Help?

Based on results of double blind, RCTs: HCP influenza vaccination is associated with decreased patient mortality in long-term care Vaccination can decrease some Potter et al, J Infect Dis 1997;175:1-6 manifestations of influenza infection and Carman et al, Lancet 2000;355:93-7 absenteeism in working adults Hayward et al, BMJ 2006;333:1241 Bridges et al, JAMA 2000;284:1655-63 Lemaitre et al, J Am Geriatr Soc 2009;57:1580-6 Nichol et al, JAMA 1999;281:137-44 Note that efficacy of vaccination varies from Vaccination decreases influenza infection year-to-year and is influenced by vaccine match in HCP and may decrease absenteeism Wilde et al, JAMA 1999;281:908-13 Saxen et al, Pediatr Infect Dis J 1999;18:779-83

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Required Vaccination or Declination Influenza Antivirals Adamantanes: interfere with influenza A virus M2 ion channel protein; inhibit virus uncoating  Amantadine and rimantadine  Not used at this time due to resistance Neuraminidase inhibitors: inhibit cleavage of influenza A and B viruses from host cell surface  Zanamivir (inhaled) and oseltamivir (oral)  Peramivir (intravenous) – investigational, may not be effective when oseltamivir resistance

 Zanamivir (intravenous) – investigational, resistance  Laninamivir (inhaled) – long acting/single inhalation (Japan) (Favipiravir – experimental RNA polymerase inhibitor; interest in using for Ebola and other viruses)

All influenza antivirals… Neuraminidase inhibitors controversy When given to outpatients within 48 hours Cochrane review updated 2014 looked at of symptom onset neuraminadase inhibitors for preventing and treating influenza in healthy adults in children  Decrease viral shedding Data from published and unpublished (first time  Reduce clinical illness by about 1 day available) RCTs  Are effective for chemoprophylaxis, if they have activity against the Conclusions: virus  Small effect on reducing length of symptoms in adults  Effective for prophylaxis  Unclear whether influenza complications reduced  Concerns about side effects: nausea and vomiting, renal, and psychiatric

Jefferson et al, Cochrane Database Syst Rev 2014

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CDC response Treatment with Antivirals - CDC

No change in recommendations More severe illness, especially hospitalized Emphasis on early treatment for severely ill or at Children younger than 2 years old greatest risk for complications Adults 65 years and older Other reviews have come to different conclusions – observational data not included in Cochrane review Pregnant or post partum women Studies of healthy people underpowered to detect Significant co-morbidities predisposing to severe influenza complications influenza Meta-analysis of neuraminidase inhibitors in reducing Children receiving long-term aspirin mortality in hospitalized patients with influenza A (H1N1pdm) Residents of chronic care facilities / SNF  More than 29,000 patients > 16 years Immunosuppressed persons, including HIV  25% mortality reduction compared with no treatment American Indians/Alaskan Natives Muthuri et al, Lancet Resp Med 2014;2:395-404 Morbidly obese

Influenza Diagnosis Infection Prevention: Which Masks?

Fever and cough when influenza is circulating Influenza mostly spread by droplets are most helpful symptoms but not ideally  Controversy regarding importance of airborne sensitive or specific spread of small droplet nuclei – do you need Rapid influenza tests are not sensitive an N95 mask?  Ranged from 40 – 69% in one study using clinical Most important to recognize influenza-like specimens illness MMWR, August 7, 2009;58:826-829  Mask for the patient unless/until inpatient  Consider treatment for patients with influenza-like illness and negative rapid tests who have isolation indications for antivirals  Mask and eye protection for the provider –  More sensitive tests such as real-time reverse remember for specimen collection transcription—polymerase chain reaction (rRT- PCR) or viral culture should be prioritized for hospitalized patients

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What about H7N9?

Avian virus - poultry Human infections first reported in China in March 2013 Associated with severe respiratory illness  Death in one-third of cases Most cases associated with direct exposure to poultry or contaminated environment  Limited person-to-person spread

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Postpartum Care: No Disclosures A Beginning not The End

Christine Chang Pecci, MD Associate Clinical Professor UCSF Department of Family and Community Medicine Annual Review in Family Medicine December 2014

Who are we? So much to do!

A. I care for mothers postpartum in the hospital • Contraception B. I see mothers for the “6 wk postpartum visit” • Breastfeeding/Infant Care C. I care for women of childbearing age • Mood D. Both A and B • Medical/physical issues E. All of the above In‐hospital postpartum care often brief 6 wk postpartum visits poorly attended Focus is on the BABY

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Maximizing the Post-partum Visit What more could we be doing? • Interconception Care Project • Focus on longer term maternal health issues for California • March of Dimes and ACOG in addition to short term issues District IX Project with Preconception Health Council • Realize that postpartum care has larger of California (PHCC) implications for women and their families • Goal: Produce post-partum care guidelines for obstetric • Redefine postpartum period as the beginning providers that incorporate risk assessment based on the of interconception care previous pregnancy and develop recommendations for future care

ICPC Guidelines Content Areas Rubella • Alcohol Use • Postpartum Depression • Anemia • Preeclampsia • Do not give during pregnancy and avoid • Domestic Violence • Preterm Birth pregnancy x 28 days • Gestational Diabetes • Cesarean Section • Gonorrhea and Chlamydia •Seizure • Not an indication for termination • Hepatitis • Substance Abuse • If lab evidence of immunity, no need to repeat •HIV • Syphilis • Hypertension • Thrombocytopenia • If neg or equivocal titer after 1‐2 doses, give third • Migraine • Thyroid Disorder dose and stop checking titers • Obesity • Tobacco Use • Ok for children of pregnant women to get • Vaccinations • May give with Rhogam, check titer in 3 months

MMWR June 2013

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Varicella

• Lab evidence of immunity or • Mary is 35 yo G2P2 delivered 2 days ago via disease cesarean delivery. She had declined the Tdap • Birth in US before 1980 is not and flu shot pregnancy because she was afraid sufficient for pregnant women of it hurting the baby. Now she is willing to • Diagnosis or verification of history of varicella or zoster by accept these two immunizations if you still health care provider recommend them. She got the flu shot last – Should have link to a typical case season and got a Tdap after her last pregnancy or lab confirmation if testing done during acute infection in 2011.

What immunizations should she get? Tdap

A. Tdap only • If not given prenatally between 27‐36 weeks, B. Influenza only no need to give postpartum if up to date C. Both • Immunize other family members D. Neither

Answer B

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Short Interpregnancy Interval

• Preterm birth, SGA, LBW and perinatal death – IPI <3 months 60% LBW c/w 13‐14 months – IPI <6 months 30% LBW c/w 18‐23 months – IPI <5 mo 15% SGA c/w 12‐23 months • PPROM, cardiovascular defect, autism • Anemia, placental abruption, endometritis, placenta previa, uterine rupture

Shachar BZ, Lyell DJ. I Obstet Gynecol Surv 2012;67:584‐96 Zhu BP et al NEJM1999 Grisaru‐Granovsky S Contraception.2009

What is the causal factor? Is there an ideal IPI?

• Maternal depletion • WHO and US Agency for International – protein, macro and micronutrients Development – evidence not clear • Folate depletion – Recommend IPI >2 years after a live term birth – Low 3‐4 months PP; improve w supplementation – IPI >5 years increased risk for adverse outcomes – Strong evidence – Aligns with WHO breastfeeding recommendation • Cervical insufficiency • Studies support IPI 18‐24 months – collagen concentration in cervix not normalized until 12 months PP – birth to conception • Inflammation – 12 months for moms >35 yo

Conde‐Agudelo A, Rosas‐Bermudez A, Castano F, Norton MH. Stud Wendt A, Gibbs CM, Peters S, Hogue CJ. Paediatr Perinat Epidemiol 2012 Fam Plann 2012;43:93‐114

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California Unintended Pregnancies

Almost half of live births in California result from unintended pregnancies 70 64.8

60

49.4 50 State Total 44.6 40 37.1 33.0 30 Percent (%) Percent Black 20 Hispanic White 10 Asian/Pacific Islander

0 Black Hispanic White Asian/Pacific Islander

Percent of mothers in California with a recent live birth by race/ethnicity, 2007 Data Source: Maternal and Infant Health Assessment Survey 17

Lactation Amenorrheic Method Nonbreastfeeding

• Fully breastfeeding or nearly full breastfeeding and amenorrhea • Mean day 1st ovulation 45‐94 day – 98% effective x first 6 months • Mean 1st menstruation 45‐64 • Exclusively breastfeeding • 20‐71% first menses preceded by ovulation Total contraception x 10 weeks but more than half abnormal (30‐ – 100%)(compromised fertile) • Earliest day of ovulation day 25

Bellagio Consensus Statement: Breastfeeding as a Family Planning Method, The Lancet, 19 November 1988, reaffirmed 1988

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Not fully breastfeeding Rule of 3s

• Ovulation returns 6 wk after supplementation • Fully Breastfeeding • Half of women not fully breastfeeding resume – Initiate contraception at 3 months postpartum menses by 6 weeks • Not breastfeeding – Initiate contraception at 3 weeks postpartum

What would you offer her?

• Mary (35 yo G2P2 s/p CS) was discharged on POD #4. A. Progestin only pill (POP) because you hope She was certain she was not going to have intercourse but promised that she would use condoms if it she will go back to breastfeeding happened. She left the hospital breastfeeding and was breastfeeding well when you saw her a week later for B. POP because her risk of DVT right now is too her baby’s first visit. high postpartum to start on COC • She comes in for a 3 week postpartum visit. She found it too difficult to breastfeed with all her other C. COC because she has stopped breastfeeding responsibilities. She is interested in taking “the pill”. and it is more effective than POP She wants to wait at last 2 years before getting pregnant again. She suspects that she may be having D. Talk her into using a LARC (implant, IUD) intercourse in the next week.

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Kind of a trick question… Long acting Progestins

• Considered safe even immediately postpartum • Progestins are transferred via breastmilk • Theorectical concerns but no harms seen Answer : NOT C WHO 3 <6 weeks

US Med Eligibility Criteria 2 <1 month breast 1 No breast UK Medical Eligibility Criteria 1

OCPs and breastfeeding Initiating COC postpartum

• COCs decreases quality and quantity of • VTE risk increases by 2‐5x postpartum breastmilk but no difference in infant growth • Baseline 4‐6 weeks or supplementation in well nourished moms • Risk declines by more than half second week • COC associated with decreased rate of postpartum, returns to baseline at 4‐6 weeks breastfeeding after 6 months POP modest increase in milk production; • • Exogenous estrogens increase hepatic breastfeed longer and later time to synthesis of several clotting factors 3x‐7x supplementation

Jackson,Emily Obstet Gynec 2011

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WHO classification for COC

• No one should get COC prior to 21 days pp (4) • If risk factors, don’t start prior to 42 days (3) – Age >35, prev VTE, thrombophilia, immobility, transfusion at delivery, BMI >30, PPH , post CS, preeclampsia, smoking • If no risk factors, can start 21‐42 days (2)

MMWR July 8, 2011 60(26);878‐883

Breastfeeding – good for baby …good for mom too!

• Breastfed babies • Increased weight loss immediately PP – less otitis media, • Decreased risk of pp depression gastroenteritis, • Decreased risk of Type 2 DM atopic dermatitis • Decreased risk of breast and ovarian CA • Breastfeeding at least 3 months with lower risk of • NOT Breastfed vascular changes associated with CVD – Higher risk for • Breastfeeding for lifetime >2 years asthma, obesity, DM, – 37% lower CHD, 23% lower risk of CHD than those childhood leukemia who never BF

Godrey J and Lawrence R. JWH 19(9) 2010.

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Maternal depression and their children

• Lower on cognitive, emotional and behavioral assessments • At risk for mental health problems • Social adjustment problems • Difficulties at school • Employment and health as adults • EEG findings similar to adults with depression • Increase child’s stress response system, exposure to mat depression during infancy– higher stress hormones in adolesense

Center on the Developing Child at Harvard University (2009). Working Paper No. 8. http://www.developingchild.harvard.edu

Postpartum mood disorders Depression varies with SES

% Depression in mothers with 9 month olds Blues 30‐75% Day 3‐4, resolves Reassurance 30 within 2 weeks 25 Depression 10‐15% *Within 1st year Outpatient treatment/support 20

Psychosis 0.1‐0.2% Within 2 weeks Hospitalization 15

10 *DSM V (May 2013) 5 PP Depression=Major depression episode with 0 Poor Near‐Poor Not‐Poor onset in pregnancy or within 4 weeks Crosby, D. Early Childhood Depression Study 2006

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Screening for PP depression Screening Tests

• USPTF recommends screening for depression TEST Sensitivity Specificity SOE in adults if adequate resources in place to EDPS 80‐90% 80‐90% Mod address depression (B) PDSS 80‐90% 80‐90% Mod • Best timing for screening is unknown PHQ 975‐89% 83‐91% Low • Don’t know how to prevent PP depression PHQ 2* 100% 44‐65% Mod

*In the last two weeks how often have you Antidepressant Treatment of Depression during Pregnancy and the Postpartum Period AHRQ evidenced based practice July 2014 Felt down, depressed, or hopeless? Lost interest or pleasure in doing things? Efficacy and Safety of Screening for Postpartum Depression. Comparative Effectiveness Review AHRQ evidenced based practice April 2013

Edinburgh Depression Scale Treatment

1. I have been able to laugh and see the funny side of things • Need for further research 2. I have looked forward with enjoyment to things 3. I have blamed myself unnecessarily when things went • Extrapolate treatment for adult depression wrong Meds (SSRI) 4. I have been anxious or worried for no good reason – 5. I have felt scared or panicky for no good reason – Cognitive Behavioral Therapy 6. Things have been getting on top of me – Interpersonal Behavioral therapy 7. I have been so unhappy that I have had trouble sleeping Group psychotherapy 8. I have felt sad or miserable – 9. I have been so unhappy that I have been crying • Effect of treatment on child development? 10. The thought of harming myself has occurred to me – IPV, Anxiety, substance abuse, finances

Antidepressant Treatment of Depression during Pregnancy and the Postpartum Period AHRQ evidenced based practice July 2014

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Possibilities… 安政 ansei

• Weekly parent‐toddler psychotherapy • Education for moms • Massage therapy • Mother‐infant interaction coaching • Home visits

Summary

• Provide interconception care and educate our patient about the importance of this • Let go of the 6 week postpartum visit and provide individualized timing of care • Beware of additional risk factors for VTE • Encourage breastfeeding for mothers health • Screen and treat for postpartum depression www.everywomancalifornia.org http://www.cdc.gov/breastfeeding/resources/guide.htm

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Outline

• Clinical Manifestation of Fibroids Updates in the Primary Care • Treatment Options Management of Fibroids – Medical – Minimally Invasive Eve Zaritsky MD, FACOG – Surgical Minimally Invasive Gynecologic Specialist When to Refer to a Gynecologist Kaiser Permanente Northern California Oakland • • Case Scenarios No Disclosures

Learning Objectives Clinical Manifestation of Fibroids

At the end of this presentation you will be able to:

• Evaluate a patient with fibroids • Uterine leiomyomas are very common • Provide counseling on medical treatments • Explain minimally invasive therapies • Fibroids in up to 70% of white women and • Review surgical options >80% of black women by age 50 years • Communicate fertility sparing modalities • Know when to refer to a gynecologist • Create an individualized patient care plan

Day et al 2003

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Clinical Manifestation of Fibroids Clinical Manifestation of Fibroids

Risk Factors • Two most common symptoms for which • Race women with leiomyoma seek treatment are • Family History – Bleeding • Early Menarche – Pelvic pressure • Late or No Pregnancies • Diet and Alcohol • Great variation in size, number and location • ?Obesity

Surgical Options: Hysteroscopy

Munro MG 2010

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ACOG Treatment Options • Symptoms and treatment options are affected by the size, number, and location of • Expectant Management the leiomyomas. The lack of a simple, • Medical Therapy inexpensive, and safe long‐term medical • Minimally Invasive Modalities treatment means that most symptomatic leiomyomas are still managed surgically. • Surgical Options

ACOG Practice Bulletin 2012

Watchful Waiting : Watchful Waiting

Fibroid growth in premenopausal women • Long term Progression Hard to Predict • High variability median growth rate 9% at 6 months • Evaluate 1‐2 years pelvic exam (range –89% to +138%) • Consider Baseline Ultrasound • 1.2 cm per 2.5 years, but great variation in growth rates were noted • Management may be different for women desiring fertility • ACOG: Expectant management in an asymptomatic patient should be the norm • Expectant management if slow growing, – some instances an asymptomatic fibroids might require treatment asymptomatic or perimenopausal Peddada et al 2008 DeWaay et al 2002

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Medical Therapy: Hormonal Medical Therapy: Hormonal

• Gonadotropin agonists (Lupron) No Size Reduction but Decreases Menorrhagia – 35‐60% reduction in size within 3 months • Estrogen‐progestin contraceptives – Bridge to Menopause • Progestin implants, injections, and pills – Surgical preparation • Levonorgestrel‐ releasing IUD – Significant side effects (add back progesterone)

Medical Therapy: Medical Therapy: Hormonal Less Frequently Used or Not Used in U.S. No Size Reduction but Decreases Menorrhagia • Gonadotropin antagonists ‐daily and $$ • Antiprogestins and progesterone receptor modulators – hyperplasia risk • Antifibrinolytic agents • Mifepristone (RU‐486) * • Nonsteroidal antinflammatory drugs • Ulipristal * • Aromatase inhibitors • Danazol and gestrinone *Available dose in U.S. is an impediment to off‐label treatment

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Minimally Invasive Options Minimally Invasive Options

Uterine Artery Embolization Non Fertility‐Sparing Options • Uterine arteries embolized ‐> devascularization and involution • Uterine Artery Embolization • Volume reduction (42%) (Pron 2003) • UAE versus TAH (Emmy trial 2005) • Endometrial Ablation – Less pain, return to work , major complications similar • 5‐year follow‐up of 200 patients treated with UAE: • Myolysis – 20% reoperation rate (hysterectomy 14%, myomectomy 4%, repeat UAE 2%) MRI resonance guided focused ultrasound • – failure to control symptoms in 25% were documented (Spies 2005)

Minimally Invasive Options Minimally Invasive Options

• Endometrial Ablation • Myolysis • Laparoscopic thermal coagulation • Done alone or with hysteroscopic myomectomy • Infrequently used in current practice • Risk of a second surgery 10‐40% • ~ 50% reduction size • Outpatient • < 4 leiomyomas no larger than 10 cm in diameter • Dense adhesions

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Minimally Invasive Options Surgical Options: Fertility Sparing

• MRI resonance guided focused ultrasound Myomectomy Treatment Options: • High‐intensity ultrasound waves • Hysteroscopy • Protein denaturation, cell damage, coagulative necrosis • Laparoscopic/Robotic • Maximum size ~ 10 cm • Laparotomy • Symptom reduction 71% at 6 months 51% at 12 months

Venkatachalam 2004

Surgical Options: Hysteroscopy

• Endoscope inserted through the cervix to resect fibroid – Successful removal 85‐95% – Subsequent surgery in 5‐15% of cases (Jenkins 2006) – Success: 95% at 1 year and 76% at 5 years (Polena 2007) • Outpatient

Baggish 2007

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Surgical Options: Myomectomy Surgical Options: Definitive

• Laparotomy or Laparoscopic /Robotic Hysterectomy • Fibroid size and Surgeon skill determine Route • Vaginal I

N

• Recovery V

A

S

Fertility 3‐6 months* • I • Laparoscopic/Robotic V

E

Recurrence 59% , 26% required repeat surgery • Laparotomy (Malone 1969) •

When to Refer

• Preconception & Fertility

• Obstetrical Risk/ Benefits

• Considering Surgical Options Non Fertility

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Procedure What is it? Benefits Risks Procedure Recovery Time Time

Hysterectomy Removal of uterusWhen Definitive treatment to • ReferFertility Lost 1‐3 hours 2‐6 weeks Case Scenario • Surgical Risks • Recovery

Myomectomy Removal of fibroids Preserves Fertility and • Surgical Risks 1‐4 hours 2‐6 weeks uterus • Recovery • Recurrence

UAEE Uterine artery • Preserves uterus • Radiation 1‐2hours 7‐10 days

V blocked with small • Less invasive • Not suitable if • 36 year old gravida 2 para 0 with 16 week

I particles, starving • Recovery desires future the fibroid pregnancy S

• Recurrence preterm premature rupture of membranes A

MRgFUS Focused US waves • No incision • Size and location 3‐5 hours 1‐2 days V

to heat and destroy • No radiation • Burns (rare) and known 8 cm fibroid. Comes to you for

N fibroid with MR • Recovery • Recurrence

I guidance • Can consider pregnancy consultation: Hormone Therapy Meds that cause • Non surgical • Effective for 6‐12 Not Applicable Not Applicable fibroid shrinkage months • Symptoms return • What do you recommend? • Menopause symptoms

Watchful Waiting No treatment, • Symptoms can • Increase in growth Not Applicable Not Applicable monitoring only diminish with and symptoms menopause • May need surgery

Case Scenario Case Scenario

• 25 year old found to have a 5 cm fibroid and • 43 year old gravida 2 para 2 with 10 cm fibroid comes in to discuss birth control options and abnormal uterine bleeding. Wants to preserve her uterus, not interested in future • What would you recommend? fertility. • What do you recommend?

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Patient Handouts Learning Objectives

At the end of the presentation you can: • ACOG • Evaluate a patient with fibroids • UptoDate.com • Provide counseling on medical treatments • Explain minimally invasive therapies • Medline Plus‐ U.S. National Library of Medicine/ NIH • Review surgical options • AAFP • Communicate fertility sparing modalities • Know when to refer to a gynecologist • Personalized After Visit Summaries • Create an individualized patient care plan

Questions

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Assessing and Treating Substance Use Disorders No conflicts to report

Matthew Tierney APRN

Agenda But First…

I. Epidemiology and Context • Clinician Tools II. A Treatment Approach: SBIRT • Educator • Confidence III. Medication Assisted Treatment • Motivator • (MAT) of Substance Use Disorders Interest • Researcher • IV. Other Resources

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Cost I. EPIDEMIOLOGY $600 billion/year addiction treatment reduces health and social costs more AND CONTEXT than the cost of treatment itself less expensive than alternatives:

•1 year methadone maintenance ~$4,700/patient/yr •imprisonment ~$24,000/person/yr $1 in addiction treatment yields a return of $4 to $7 in reduced drug‐related crime, criminal justice costs, and theft

http://www.drugabuse.gov/publications/principles‐drug‐addiction‐treatment‐research‐based‐guide‐third‐ edition/frequently‐asked‐questions/drug‐addiction‐treatment‐worth‐its‐cost. Accessed 11/16/14.

Illicit drug use in the past month among individuals aged 12 or older: 2013 Aged 12 or older Aged 12 to 17 Aged 18 or older Number Number Number (in (in (in Alcohol use in the past month among individuals aged 12 or older: 2013 Substance thousands) Percent thousands) Percent thousands) Percent Illicit drug Heavy use Binge use Current use use 24,573 9.4% 2,197 8.8% 22,376 9.4% Marijuana Number Number Number and hashish 19,810 7.5% 1,762 7.1% 18,048 7.6% Age Percent of adults Percent of adults Percent of adults Cocaine 1,549 0.6% 43 0.2% 1,505 0.6% Aged 12 or 16.5 60.1 136.9 6.3% 22.9% 52.2% Inhalants 496 0.2% 121 0.5% 375 0.2% older million million million Hallucinoge Aged 12 to n 1,333 0.5% 154 0.6% 1,179 0.5% 17* 1.2% 293,000 6.2% 1.6 million 11.6% 2.9 million Heroin 289 0.1% 13 0.1% 277 0.1% Aged 18 or 16.2 58.5 134.0 NMU 6.8% 24.6% 56.4% prescription‐ 6,484 2.5% 549 2.2% 5,935 2.5% older million million million type drugs Pain 4,521 1.7% 425 1.7% 4,096 1.7% relievers http://www.samhsa.gov/data/sites/default/files/NSDUH‐SR200‐RecoveryMonth‐2014/NSDUH‐SR200‐ RecoveryMonth‐2014.htm http://www.samhsa.gov/data/sites/default/files/NSDUH‐SR200‐RecoveryMonth‐2014/NSDUH‐SR200‐ RecoveryMonth‐2014.htm

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Past Year Diagnosis of Substance Use Disorder (SUD) Unmet Treatment Need

~ 20.2 million ~10% of those people who who need needed treatment for treatment did SUDs receive not receive it* it**

*in specialty treatment centers. **at a specialty facility in the past year SAMHSA, NSDUH, 2013

Most common reasons for not receiving treatment among individuals aged 12 or older who needed and made an effort to receive treatment but did not Providers: addressing? receive treatment and felt a need for treatment: annual averages, 2010 to 2013 • Adults age 18‐39 who exceed alcohol limits Reason Percent – 49% recalled being asked about their drinking No health coverage/could not afford 37.3%

Not ready to stop using 24.5% – 14% were counseled about it

Did not know where to go for treatment 9.0% • Young adults aged 18 and 25: the most likely to exceed alcohol limits Had health coverage but did not cover treatment or cover costs 8.2% – 34% were asked about drinking by their doctors,

No transportation/inconvenient 8.0% (compared with 54 percent of adults ages 26 to 39)

Source: SAMHSA, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health (NSDUH), 2010 to 2013. Hingson et al. J Gen Intern Med. 2012 Feb;27(2):179‐84

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Provider Impediments Physician Attitudes • Don’t feel competent • Unrewarding • Treating drug and alcohol use less satisfying • Peripheral to medical matters then treating HTN • Lack of role models • Positive attitude toward treating addiction associated w/ greater professional satisfaction • Lack of skill – Confidence • Lack of education – Perceived responsibility • Lack of parity

Miller et al. Acad Med. 2001 May;76(5):410‐8. Saitz et al J Gen Intern Med. 2002 May;17(5):373‐6

Context for a Solution: Primary Care Treatment of SUDs Affordable Care Act?

• Designated SUD treatment as an • Medical treatment “essential health benefit” • Prevention • Facilitates integration • Patient advocacy • Increases access • Paradigm shift: Maintaining vs. treating • No pre‐existing exclusion addiction

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SUD Integrated with Primary Care

• Less integrated than mental health • Not due to attitudes, but training

http://www.drugabuse.gov/publications/addiction‐science/relapse/relapse‐rates‐drug‐addiction‐ are‐similar‐to‐those‐other‐well‐characterized‐chronic‐ill

20th Century Treatment Why the History Lesson?

• “The Farms” Context: • Context: Medical • Civil Commitment •Commerce 1 Programs •legal/criminal • 12 Step2 • political • Synanon Treatment settings •Patient restrictions • Setting: Medical • Others…. http://unusualkentucky.blogspot.com/2011/02/lexingt •Provider restrictions Office ons‐narcotics‐farm.html

1. SAMHSA/CSAT: http://www.ncbi.nlm.nih.gov/books/NBK64157/ 2. Narcotics Anonymous, Sixth Edition (2008) Chatsworth, CA: Narcotics Anonymous World Services, Inc., p. 5.

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The Problem: Summary

Patients not receiving needed treatment II. AN APPROACH: for SUD

Those with SUDs have health care costs double those without SBIRT SUDs are often unaddressed in medical offices—but can be

SBIRT SBIRT

Public health model designed to provide the Screening •for everyone following in primary care and other settings: • universal screening Brief •for those at moderate to secondary prevention Intervention high risk • • early intervention Referral to •for those with severe risk • treatment or dependency Treatment Babor et al., 2007; Substance Abuse, 28(3), 7–30; http://www.samhsa.gov/sites/default/files/sbirtwhitepaper_0.pdf

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Alcohol Screening Tools

• Alcohol Use Disorders Identification Test (AUDIT) • Drug Abuse Screening Test (DAST) • Alcohol, Smoking, Substance Involvement Screening Test (ASSIST) • CAGE • Single Question: “On any single occasion during the *http://myemail.constantcontact.com/News‐from‐the‐New‐York‐State‐Office‐of‐ past 3 months, have you had 5 or more drinks Alcoholism‐and‐Substance‐Abuse‐Services‐‐OASAS‐ .html?soid=1106836389851&aid=uJW744b_r0M. Accessed 11/16/14. containing alcohol? [4 or more for women]” *2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationwide NIAAA survey of 43,093 U.S. adults aged 18 or older.

RISK INTERVENTION APPROACH LEVEL OF CARE • Hospital

Low Risk No Further Intervention • Medical‐Residential

• Residential non‐medical bio psycho Moderate Risk Brief Intervention • Medical Outpatient

• Non‐medical outpatient Moderate to High Risk Brief Treatment social spiritual • Professional

Severe Risk, Referral to Specialty Treatment • Peer Dependency *Mee‐Lee, D (Ed). The ASAM Criteria: Treatment Criteria for Addictive, Substance‐Related, and Co‐Occurring Conditions. October 24, 2013 ISBN: 978‐1‐61702‐197‐8 *http://www.communitypsychiatry.org/publications/clinical_and_administrative_tools_guidelines/LOCUS% 20Instrument%202010.pdf

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SBIRT Evidence • Best for alcohol use III. MEDICATION‐ • Depends on setting, health behavior ASSISTED –Using ASSIST and BI in urban primary care: not effective for decreasing TREATMENT (MAT) drug use1

1. ASPIRE Clinical Trial. Saitz et al. Jama 2014; 312(5):502‐13.

Accessing MAT Medication Assisted Treatment “There are many reasons why I think PCP's should • Alcohol: disulfiram; naltrexone; acamprosate prescribe SUD‐focused meds: • Opioids: methadone; buprenorphine; naltrexone …the stigma many Vets feel about coming to • Nicotine/smoking: nicotine replacement; varenicline; BH and bupropion …PCP is often in a position to recognize the • Cannabis: none FDA approved beginnings of a SUD and get things going for • Stimulants: none FDA approved the patient.” • Sedatives/Benzodiazepines: flumazenil; taper Professional Correspondence with nurse colleague at New Mexico VAMC. 11/14/14

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Medical Treatment for Alcohol Use Underutilized?

15% of individuals with “The therapeutic nihilism for alcohol abuse or treatment of alcoholism with dependence receive available psychopharmacological treatment (incl self help) agents is unfortunately high, just ALCOHOL as it is for smoking.” ‐S. Stahl

• Cohen et al(2007). Drug Alcohol Depend;86(2‐ 3):214‐21

Treatment Options Out of Favor In US Treatment Facilities*

• disulfiram (1951) • Disulfiram: 16% 1 • naltrexone • Naltrexone: 16% • Acamprosate: 17% • Oral (1994) Results • Injectable (2006) • Modest effect sizes • acamprosate (2004) • Low adherence rates

http://www.drugfree.org/wp‐ *SAMHSA. National Survey on Substance Abuse Treatment Services (n‐SSATS):2009. Data on Substance Abuse content/uploads/2010/09/alcohol11.jpg Treatment Facilities. Rochville, MA: USDHHS, publ SMA 05‐4112. 1. Mark et al. /(2003) Drug and Alcohol Dependence 71: 219‐228

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Naltrexone NTX Efficacy • 28% (NTX) vs. 43% (PCB) return to heavy etoh • 1984: FDA approved for opioid dependence • 59% (NTX) vs. 65% (PCB) return to any etoh • 1994: FDA approved for alcohol dependence • 36% NTX patients discontinued treatment before – Formulations : 12 weeks 30% of all trials show no difference between NTX • Oral (ReVia tabs) • and PCB • Depot injection (Vivitrol) ‐‐ approved in • NTX adherence associated with better outcomes 2006 Srisurapanont & Ngamwong (2005) Int J Neuropsychopharmacol 8: 267‐280.

Injectable (IM) NTX: Vivitrol IM NTX Efficacy

• IM NTX vs. placebo Same therapeutic action as oral – 32% v 11% abstinent for 24 weeks – 70% v 30% no more than 2 heavy drinking days in any 28‐day period Injectable microspheres avoid first‐pass hepatic metabolism – Median 42 days v 12 days to first drink – 181 days v 20 days to first heavy etoh use Stable plasma levels for 28 days – Fewer drinking days and fewer heavy drinking days/month

O’Malley et al (2007) J. Clin. Psychopharmacol 27: 507‐512.

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IM NTX Efficacy Summary: Naltrexone Can • Etoh use Reduce – Decreased drinks per day •Number of days spent drinking – Decreased heavy drinking days •amount of alcohol consumed – Involvement in AA and intensive outpatient etoh treatment both associated with on drinking days treatment retention •excessive and destructive

Lee et al (2010). J Subs Abuse Treatment 39:14‐21. drinking See Ciraulo et al (2008) J Clin Psychiatry 69:2.

Disulfiram Disulfiram Mechanism of Action Approved for Alcohol alcohol dependence Alcohol Dehydrogenase in 1951 Acetaldehyde

Disulfiram Acetaldehyde Dehydrogenase An aversive agent – interesting history Acetic Acid

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Disulfiram: good for highly motivated patients Acamprosate Characteristics associated with better disulfiram treatment • FDA approved for alcohol dependence in 2004 outcomes: – older than 40 • Action not fully understood – longer drinking history – Some enhancement of GABA receptors – socially stable – Partial NMDA agonist. – high motivation – Alcoholics Anonymous attendance – NMDA modulator: Regulates NMDA subunit – supervised pill taking synthesis? – cognitively intact Suh et al (2006). Clin Psychopharmacol;26:290–302 Witkiewitz et al (2012). Ther Clin Risk Manag;8:45‐53

Acamprosate Efficacy

AcamprosateV. Placebo • 9% lower risk of returning to any drinking after detoxification. NNT = 9! • 9% higher continuous abstinence duration after treatment discontinuation • No difference: – Return to heavy drinking did not change OPIOIDS

Rösner et al (2010). Cochrane Database of Systematic Reviews, Issue 9. Art. No.: CD004332. DOI: 10.1002/14651858.CD004332.pub2.

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Opioid Treatment Options Methadone

Over 1,200 methadone clinics in the USA* • Methadone Est. 270,000 patients enrolled* • Buprenorphine

• Naltrexone 1972: FDA regulations

http://www.opioids.com/jh/ Current Oversight: State laws, SAMHSA (DHHS), and DEA/DOJ.

www.aatod.org

Methadone Effectiveness Barriers and Primary Care Solutions • Reduces heroin use 1 • Reduces criminal activity 1 • Low access: promote methadone as effective tx 1 • Decreased health treatments • Medication side effect: monitor drug interactions and side 1 • Decreased hospitalization effects • Reduces risk of HIV/AIDS and viral hepatitis • Methadone “silo” and privacy protections: get ROIs, confer • Reduces risk of IDU‐related illness with other providers, use PDMPs • Maintenance associated with less drug use • “Medication only” philosophy: promote person‐centered • Reduces drug related mortality 2 treatment philosophy 1) Gerstein et al (1994). Evaluating Recovery Services: The California Drug and Alcohol Treatment Assessment (CALDATA): General Report. California Department of Alcohol and Drug Programs. 2) Clausen et al. Drug Alcohol Depend. 2008 Apr 1;94(1‐3):151‐7.

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Buprenorphine

• Semi‐synthetic derivative of thebaine (an opium alkaloid)

• Partial μ agonist, antagonizes κ receptor

• High binding affinity and slow dissociation for μ receptor

• Sigmoidal dose‐response curve: ceiling effect BUPRENORPHINE • Half life: 37 hours • Side effects: sedation, CNS depression, hypotension

Buprenorphine Prescribing Methadone and Buprenorphine Outcomes

• FDA approved in 2002 for opiate • Treatment retention: MTD > BUP1, 2 replacement, schedule III • Reduced opioid use: BUP > MTD1

2 • Requires 8 hours special training and DEA • Reduced opioid use: BUP = MTD • Retention & opiate use: MTD and BUP > placebo “waiver” (Higher dose > low dose)2 • MDs only… no mid‐levels • Adjunctive tx enhances BUP and MTD outcomes2

2 • Office‐based setting • MTD & BUP less costly than no tx 1.Saxon AJ et al. J Food Drug Anal. 2013 Dec 21(4):S69‐72. 2.Connock M et al. Health Technol Assess 2007 Mar;11(9): 1‐171, iii‐iv.

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Naltrexone Naloxone Reverses Opioid Overdose

• FDA approved for relapse prevention • reduces opiate overdose • Blocks re‐enforcing effects of other deaths, results in cost‐savings 10,171 overdose reversals 1 opioids • • APRNs can prescribe Naloxone • Eliminate a conditioned response to for their patients at risk for use opioids use after MAT opioid overdose. 1. JAMA. 2012;307(13):1358‐1364. *http://www.ama‐assn.org/ama/pub/news/news/2012‐06‐19‐ama‐adopts‐new‐policies.page • No tolerance, no dependence (accessed 4/14/14) *http://prescribetoprevent.org/ *http://store.samhsa.gov/shin/content//SMA13‐4742/Overdose_Toolkit_2014_Jan.pdf

Monitor Drug Diversion

IV. OTHER • Access the PDMP RESOURCES • Urine Drug Testing • Confer with other providers (ROIs)

http://www.deadiversion.usdoj.gov/faq/rx_monitor.htm#4

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Supplemental Treatments Patient‐Centered Care • Counseling • Case management • CBT • “I didn’t ask for this.” • Contingency Management • “I’m coming to you for • Motivational Interviewing • Peer support and mutual help:12 step help… please be kind • Relapse prevention therapy to me.” • Acupuncture

Medication‐Assisted Treatment for Opioid Addiction in Opioid Treatment Programs. Treatment Improvement Protocol (TIP) Series 43. HHS Publication No. (SMA) 12‐4214.

What Next?

• Training & Education

–MAT, Motivational Interviewing, CBT Thank You!

• Expand treatment staff and referrals

• Integrate and Research

Saitz et al. Jama 2013; 310(11): 1156‐67. The AHEAD randomized trial.

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Outline

• What is Mind‐Body Medicine? Mind‐Body Medicine • Yoga Evidence and Practice for Primary Care – Background/general – Evidence – Issues for referral Kevin Barrows, MD Osher Center for Integrative Medicine • Tai chi chuan UCSF • Mindfulness meditation • Summary

I. What is Mind‐Body Medicine? I. What is Mind‐Body Medicine?

• “the field of medicine that uses processes of • NIH the mind to influence the health of the body” “Mind‐body medicine focuses on the • mind vs. body (perpetuate duality) interactions among the brain, the rest of the • mind ↔ body (bidirectional reln) body, the mind, and behavior and the ways in which emotional, mental, social, spiritual, • think of mind/body as a single entity, with the health of one part necessarily influencing the experiential, and behavioral factors can directly health of the other. affect health.”

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I. What is Mind‐Body Medicine? II. Yoga

• meditation • Description: • guided imagery – integrated series of physical postures, breathing • biofeedback exercises and meditation • hypnosis • History: • relaxation techniques – India, ? 5,000 years old • yoga • Styles: Iyengar, Ashtanga, Bikram, Viniyoga, • tai chi Sivananda, Yin, Integrative Yoga Therapy, • qigong Kripalu, Integral • more!

II. Yoga II. Yoga Evidence: Cancer • 25 RCT’s Effects of yoga on psychological health, quality of life, and physical health of patients with cancer: a meta‐analysis. • mostly breast CA Lin KY, Hu YT, Chang KJ, Lin HF, Tsauo JY. • heterogeneous, methodological problems, higher Evid Based Complement Alternat Med. 2011 quality studies in last 4 years Yoga as an alternative and complementary treatment for cancer: a systematic review. • psychological outcomes with consistent and large Sharma M, Haider T, Knowlden AP. effect sizes J Altern Complement Med. 2013 Nov;19(11):870‐5. • physical outcomes with inconsistent and small effect sizes Effects of yoga interventions on fatigue in cancer patients and survivors: a systematic review of randomized controlled trials. • Fatigue in particular has been studied in 13 RCT’s. Sadja J, Mills PJ. – “Yoga may be beneficial for reducing cancer‐related fatigue in women Explore (NY). 2013 Jul‐Aug;9(4):232‐43. with breast cancer; however, conclusions should be interpreted with caution as a result of bias and inconsistent methods used across studies. “

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II. Yoga II. Yoga Evidence: Hypertension Evidence: CV Risk Factors • 17 RCT’s • systolic blood pressure ↓ −4.17 mmHg • 44 RCTs, n = 3,168 participants • diastolic blood pressure ↓ −3.62 mmHg • high or unclear risk of bias for most • Subgroup analyses demonstrated • improved SBP, DBP, heart rate, respiratory rate, waist – ↓ BP for intervenons incorporang all 3 basic circumference , waist/hip ratio, total cholesterol, elements of yoga practice (postures, meditation HDL, VLDL, triglycerides, HbA1c, and insulin and breathing) resistance – ↓ BP compared to no treatment but not compared to exercise. Effects of yoga on cardiovascular disease risk factors: a systematic review and meta‐analysis. Effectiveness of yoga for hypertension: systematic review and meta‐analysis. Cramer H, Lauche R, Haller H, Steckhan N, Michalsen A, Dobos G. Hagins M, States R, Selfe T, Innes K. Int J Cardiol. 2014 May 1;173(2):170‐83. Evid Based Complement Alternat Med. 2013

II. Yoga II. Yoga Evidence: Low Back Pain Evidence: CAD Prevention • 10 RCT’s, n = 967 chronic low back pain patients • Primary Prevention 8 studies had low risk of bias – No study reported cardiovascular mortality or non‐ • fatal events • strong evidence for short‐term effects on pain, long‐ • Secondary Prevention term effect on pain, back specific disability and – no eligible RCTs global improvement • moderate evidence for a long‐term effect on back‐ Yoga for the primary prevention of cardiovascular disease. specific disability Hartley L, Dyakova M, Holmes J, Clarke A, Lee MS, Ernst E, Rees K. Cochrane Database Syst Rev. 2014 May 13;5:CD010072. • no serious adverse events Yoga for secondary prevention of coronary heart disease. Lau HL, Kwong JS, Yeung F, Chau PH, Woo J. A systematic review and meta‐analysis of yoga for low back pain. Cochrane Database Syst Rev. 2012 Dec 12;12:CD009506 Cramer H, Lauche R, Haller H, Dobos G. Clin J Pain. 2013 May;29(5):450‐60.

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II. Yoga II. Yoga

Evidence: Psychiatry (anxiety and depression) Yoga for asthma: a systematic review and meta‐analysis. • Cramer H, Posadzki P, Dobos G, Langhorst J. • Evidence: Pulmonary (COPD and asthma) Ann Allergy Asthma Immunol. 2014 Jun;112(6):503‐510

A systematic review of yoga for state anxiety: considerations for occupational therapy. Chugh‐Gupta N, Baldassarre FG, Vrkljan BH. Can J Occup Ther. 2013 Jun;80(3):150‐70. Review.

Clinical Inquiry: can yoga reduce symptoms of anxiety and depression? Skowronek IB, Mounsey A, Handler L. J Fam Pract. 2014 Jul;63(7):398‐407.

Effects of yoga training in patients with chronic obstructive pulmonary disease: a systematic review and meta‐analysis. Liu XC, Pan L, Hu Q, Dong WP, Yan JH, Dong L. J Thorac Dis. 2014 Jun;6(6):795‐802.

II. Yoga II. Yoga Evidence: Adverse Events Teacher Training/Certification

• N = 76 (from 2 case series and 35 case reports) • Registered Yoga Teacher® (RYT) through Yoga Alliance • 27 (35.5%) musculoskeletal system; 14 (18.4%) the nervous system; and 9 (11.8%) the eyes. • RYT 200 • 10 with medical preconditions, mainly glaucoma and • RYT 500 (plus 100 hours teaching experience) osteopenia. • E‐RYT 200 (plus 1,000 hours teaching experience and • Headstand (10) , shoulder stand (3), lotus position has taught for at least 2 years) (3), forceful breathing (3) E‐RYT 500 (plus 2,000 hours teaching experience and • Majority of cases had full recovery • has taught for at least 5 years) Adverse events associated with yoga: a systematic review of published case reports and case series. • Look for additional degree e.g. RN, PT Cramer H, Krucoff C, Dobos G PLoS One. 2013 Oct 16;8(10)

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II. Yoga III. Tai chi Styles • Hatha (general term, focused on postures, basic) • Description: a gentle, meditative exercise that • Viniyoga (personalized) consists of flowing, movements, balance and • Yin (quiet, relaxation of muscles) weight shifting, breathing and body • Iyengar (use of props, alignment, restorative) awareness. • Integrative Yoga Therapy (medical, healing focus) • History: a martial art, exact origin obscure, • Kripalu (self‐awareness emphasis, gradual, 3 stages) centuries‐old, monastic • Ashtanga (rigorous, “power yoga”) • Bikram (“hot yoga”, rigorous) • Sivananda, Integral (cultural elements) • Key words: “restorative”, “gentle”, “therapeutic”

III. Tai chi III. Tai chi Evidence: Balance/Falls Evidence: Cognitive Function in Elders • 13 RCT’s, n = 2151 • 20 studies (11 RCT’s) • sometimes active control, sometimes not • large effect size (0.9) when compared with nonintervention controls • 11 studies on balance (9+, 2‐) moderate effect size (0.5) when compared with – Tai chi always better than no tx, but not always • better than active control exercise controls • RCTs of cognitively impaired adults (MCI and • 5 studies on falls (4+, 1‐) dementia) showed smaller (0.3) but statistically – Large effect size (.85) then wanes with time (no significant effect size when Tai Chi was compared effect at 52 weeks) with other active interventions

Tai chi as an intervention to improve balance and reduce falls in older adults: A systematic and meta‐ analytical review. Effect of tai chi on cognitive performance in older adults: systematic review and meta‐analysis. Leung DP, Chan CK, Tsang HW, Tsang WW, Jones AY. Wayne PM, Walsh JN, Taylor‐Piliae RE, Wells RE, Papp KV, Donovan NJ, Yeh GY. Altern Ther Health Med. 2011 Jan‐Feb;17(1):40‐8. J Am Geriatr Soc. 2014 Jan;62(1):25‐39.

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III. Tai chi III. Tai chi Evidence: Parkinson’s Disease Evidence: Heart Failure (EF ≤ 45%)

• 7 RCT’s and 1 non‐randomized controlled trial • 5 RCTs, 4 CCTs, n = 364 • Tai Chi showed beneficial effects in improving motor • positive effects (RCTs): exercise capacity, global function, balance and functional mobility, but not symptoms score, sleep, EF, SBP, DBP, BNP, gait velocity, step length or gait endurance baroreceptor sensitivity • no effect (RCTs): walking distance, HRV Tai Chi for improvement of motor function, balance and gait in Parkinson's disease: a systematic review and meta‐analysis. Yang Y, Li XY, Gong L, Zhu YL, Hao YL. Tai chi exercise for patients with heart disease: a systematic review of controlled clinical trials. PLoS One. 2014 Jul 21;9(7) Ng SM, Wang CW, Ho RT, Ziea TC, He J, Wong VC, Chan CL. Altern Ther Health Med. 2012 May‐Jun;18(3):16‐22.

III. Tai chi III. Tai chi Evidence: Adverse Events Referral Tips: • 50 trials included reporting of AE’s • Teacher training/certification: There is no widely • no serious AE’s recognized, standardized teacher training or • majority of trials report no AE’s at all certification • most common were minor musculoskeletal pains • Lineage of master‐to‐student most important (knees, ankles, LBP) • What are characteristics of that lineage? • 9 falls • How many years experience? • Language fluency optimal, but not critical What Do We Really Know About the Safety of Tai Chi?: A Systematic Review of Adverse Event Reports in Randomized Trials. Wayne PM, Berkowitz DL, Litrownik DE, Buring JE, Yeh GY. Arch Phys Med Rehabil. 2014 May 27.

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IV. Mindfulness Meditation IV. Mindfulness Meditation Evidence: Cancer • Description: a way of paying attention to one’s • 28 studies, 17 RCT’s with n > 2000 experience that is deliberate, sustained and • all 23 studies that measured psych outcomes showed nonjudgmental. (Goals are to ↑self‐awareness, change significant improvement (mood disturbance, anxiety, maladapve thinking, ↑ capacity for skillful response to symptoms of stress, quality of life) challenges, and ↓ suffering.) • 4 studies assessed sleep problems and all found ‐ 8‐week class: body scan, mindful movement, improvement sitting meditation • 3meta‐analyses corroborate the beneficial mental health effect of mindfulness in cancer patients. • History: 2,500 years ago, northern India, buddhism • 2other cancer studies showed that psychological – 1979 Mindfulness‐Based Stress Reduction (MBSR) benefits from MBSR were sustained at 6‐month and 12‐month follow‐up

IV. Mindfulness Meditation IV. Mindfulness Meditation

Mindfulness‐based stress reduction for integrative cancer care: a summary of evidence. Evidence: Chronic Pain Musial F, Büssing A, Heusser P, Choi KE, Ostermann T. Forsch Komplementmed. 2011;18(4):192‐202. • 18 studies, n > 1,100 all showed significant improvement in mental health The efficacy of mindfulness‐based stress reduction on mental health of breast cancer patients: a • meta‐analysis. parameters, such as quality of life, acceptance, pain Zainal NZ, Booth S, Huppert FA tolerance, and mood. Psychooncology. 2013 Jul;22(7):1457‐65. • 10 of the 16 studies examining pain intensity Mindfulness‐based stress reduction and cancer: a meta‐analysis. concluded there was significant pain reduction. Ledesma D, Kumano H. • 1 follow‐up study showed that improvements were Psychooncology. 2009 Jun;18(6):571‐9. maintained up to 4 years later.

Do mindfulness‐based interventions reduce pain intensity? A critical review of the literature. Reiner K, Tibi L, Lipsitz JD. Pain Med. 2013 Feb;14(2):230‐42.

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IV. Mindfulness Meditation IV. Mindfulness Meditation Evidence: Depression Evidence: Fibromyalgia • 5 RCT’s of MBCT on patients with major depression • 6 trials of MBSR for fibromyalgia totaling 674 – almost 50% relapse reduction in patients who patients have a history of more than two relapses. • 2013 systematic review and meta‐analysis concluded • atrial of 51 patients with treatment‐resistant that there is favorable but low quality evidence depression showed ↓ depression and anxiety levels. supporting its use and that “only a weak recommendation can be made at this point”. • MBCT recommended as tx for recurrent depression in the UK’s National Institute for Clinical Guidelines. A systematic review and meta‐analysis of mindfulness‐based stress reduction for the fibromyalgia • 3 RCT’s of MBCT for bipolar affective disorder. 2+, 1‐ syndrome. Lauche R, Cramer H, Dobos G, Langhorst J, Schmidt S. Efficacy of mindfulness‐based interventions on depressive symptoms among people with mental J Psychosom Res. 2013 Dec;75(6):500‐10. disorders: a meta‐analysis. Klainin‐Yobas P, Cho MA, Creedy D. Int J Nurs Stud. 2012 Jan;49(1):109‐21.

IV. Mindfulness Meditation IV. Mindfulness Meditation Evidence: Depression Evidence: Anxiety Disorders • a few dozen studies show benefit for depressive sxs in stressed or general popns (fibromyalgia, traumatic • diverse study popns (receiving pharmacotherapy, brain injury, DM, cancer, healthy, etc.) pregnant women, OCD, PTSD, intellectual disabilities, implanted cardiac defibrillators, coronary artery • 39 studies show mindfulness interventions are disease). superior to standard care in ↓depressive symptoms • 19 studies review and meta‐analyzed and preventing relapse with effect sizes ranging from • overall effect sizes of 1.08 for anxiety symptoms, 0.11 to 1.65. controlled studies 0.83 • effect sizes were significantly associated with the • conclusions: “MBIs are associated with robust and length of intervention sessions substantial reductions in symptoms of anxiety.”

Mindfulness‐based therapy: a comprehensive meta‐analysis. Mindfulness‐ and acceptance‐based interventions for anxiety disorders: a systematic review and Khoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, Chapleau MA, Paquin K, meta‐analysis. Hofmann SG. Vøllestad J, Nielsen MB, Nielsen GH. Clin Psychol Rev. 2013 Aug;33(6):763‐71. Br J Clin Psychol. 2012 Sep;51(3):239‐60.

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IV. Mindfulness Meditation IV. Mindfulness Meditation Evidence: Telomerase Activity Evidence: Adverse Events • 5RCT’s, n = 332 • no formal literature review on this question • meta‐analysis of 4 RCT’s (n=190) indicated that mindfulness meditation leads to increased • no adverse effects have been reported in >200 telomerase activity in peripheral blood mononuclear published trials cells. (effect size of 0.46) • meditation can allow previously subconscious, • 5th RCT (pub after meta‐analysis) is large (n = 142) distressing psychic content to come into and has large effect size consciousness. A meta‐analytic review of the effects of mindfulness meditation on telomerase activity. Schutte NS, Malouff JM. • patients with psychiatric disorders should consult Psychoneuroendocrinology. 2014 Apr;42:45‐8. with a mental health care professional before Influence of mindfulness‐based stress reduction (MBSR) on telomerase activity in women with breast cancer starting a program of meditation. (BC). Lengacher CA, Reich RR, Kip KE, Barta M, Ramesar S, Paterson CL, Moscoso MS, Carranza I, Budhrani PH, Kim SJ, Park HY, Jacobsen PB, Schell MJ, Jim HS, Post‐White J, Farias JR, Park JY. Biol Res Nurs. 2014 Oct;16(4):438‐47.

IV. Mindfulness Meditation IV. Mindfulness Meditation

Referral Tips: Teacher training • good candidate is motivated to increase self‐ certification not required to teach awareness and/or has a medical, surgical, or • psychiatric condition • several teacher trainings/certifications exist • motivation important because: 1) 28 hours of – the Center for Mindfulness at UMass classroom time required over 8 weeks (including an all‐day silent retreat) and 30+ minutes of formal CD‐ • an MBSR teacher should have a long‐standing daily guided mindfulness practice each day 2) asked to mindfulness meditation practice, a history of silent directly explore any unpleasant physical or mental meditation retreats, experience with a mindful experiences as they arise. movement practice (eg, yoga, qigong), experience • often MBSR programs offer free informational leading groups, and experience in healthcare settings sessions

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Summary • Yoga ‐ cancer ‐ anxiety ‐ HTN ‐ depression ‐ LBP ‐ COPD, asthma

• Tai Chi ‐ balance/fall prevention ‐ Parkinson’s Dz ‐ cog fx elders ‐ CHF

• Mindfulness ‐ cancer ‐ anxiety ‐ chronic pain ‐ depression

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Faculty Disclosures Annual Review in Family Medicine 2014/ San Francisco Hypertension Management:JNC 8’s Evidence and Quynh Bui Recommendations Relevant financial relationships with a commercial interest:

Quynh Bui, MD MPH Annual Review in Family Medicine I have nothing to disclose. San Francisco, CA December 16, 2014

Learning Objectives List of Abbreviations ACC American College of INVEST International Cardiology Verapamil SR Trandolapril Study • Describe the main recommendations of ACCOMPLISH Avoiding Cardiovascular ISH International Society the JNC 8 panelists’ guideline for the Events Through of Hypertension treatment of hypertension Combination NHLBI National Heart, Lung, Therapy in Patients and Blood Institute Living with Systolic NICE National Institute for • Review the rationale for the Hypertension Clinical Excellence recommendations AHA American Heart SHEP Systolic Hypertension • Review dissenting opinions about blood Association in the Elderly ASH American Society of Program pressure targets and their evidence Hypertension Syst‐Eur Systolic Hypertension in Europe Trial ESC European Society of Hypertension VALUE Valsartan Antihyperetnsive HYVET Hypertension in the Long‐Term Use Very Elderly Trial Evaluation

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Comparing JNC 8 to JNC 7 Evidence Review

Topic JNC 7JNC8 • RCTs Methodology Non‐systematic review Critical questions All available evidence Systematic review by – Hypertensive adults ≥ 18 years old methodologists Restricted to RCT – N ≥ 100

Treatment Goals Separate goals for Similar goals for all HTN – Follow up ≥ 1 year “uncomplicated HTN” vs. populations unless with comorbidities evidence supports – Health outcomes: mortality, MI, HF, CVA, ESRD otherwise

Drug Therapy 5 drug classes – favor 4 drug classes based on thiazides RCT evidence Recommended drug More clinician discretion classes by comorbidity

Guiding Questions

1. At what BP should treatment be initiated to improve outcomes? 2. What should the target BP be for those undergoing treatment? 3. Which antihypertensive medications are best to use?

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BP Treatment Thresholds/Targets BP Treatment Thresholds/ Targets

• Age ≥ 60 • CKD, Age ≥ 18 • Emphasis on two • Everyone <60 years • SBP: 150 • SBP: 140 particular comorbidities regardless of • DBP: 90 • DBP: 90 that increase risk comorbidity and people – Diabetes ≥60 have goal <140/90 • Age < 60 • Diabetes, Age ≥ 18 – CKD • People ≥60 w/o DM/ • SBP: 140 • SBP: 140 • Thresholds/targets CKD have goal <150/90 • DBP: 90 • DBP: 90 differ by age and presence of these comorbidities

Age ≥ 60 without DM/CKD HYVET

• Evidence from 4 trials • Insufficient evidence for: • Multicenter, double blind, placebo‐controlled favoring treatment at – Reduction in all‐cause SBP≥160 mortality in people 60‐79 RCT – HYVET years old • Outcomes: Stroke, CHD, CHF – SHEP – Syst‐Eur • Sample: 3845 hypertensive patients ≥ 80 years – EWPHE (fair) • Treatment: indapamide 1.5 mg SR +/‐ • Reduces CVA morbidity and mortality perindopril vs. placebo • Reduces CHF • Stopped prematurely due to positive results • Reduces CHD for treatment group

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ITT – Summary Blood pressure separation HR 95% CI

All Stroke 15 mmHg 0.70 (0.49, 1.01) Stroke Death 0.61 (0.38, 0.99) All cause 0.79 (0.65, 0.95) mortality NCV/Unknown 0.81 (0.62, 1.06) death Median follow-up 1.8 years CV Death 0.77 (0.60, 1.01)

6 mmHg Cardiac Death 0.71 (0.42, 1.19)

Heart Failure 0.36 (0.22, 0.58)

CV events 0.66 (0.53, 0.82)

0.1 0.2 0.5 02

SHEP Multicenter, randomized, double‐blind, SHEP Format placebo‐controlled trial Treatment Chlorthalidone +/‐ Atenolol Control Placebo Low‐dose chlorthalidone aged > 60: Population 4736 Reduced incidence of total stroke by 36% Patients ≥60 yrs with SBP 160 ‐ 219 mm Inclusion criteria ‐5‐year absolute benefit of 30 events per 1000 Hg and DBP <90 mm Hg participants

Persons were excluded on the basis of Major cardiovascular events were reduced Exclusion criteria history and/or signs of specified major Reduced CHF by 49% (NNT 48) cardiovascular and other major diseases if prior MI, reduced CHF by 81% (NNT 15) Follow‐up 4.5 years average Non‐fatal MI by 33% Primary endpoint Nonfatal and fatal (total) stroke Cardiovascular and coronary morbidity CHD events by 27% Secondary endpoint(s) and mortality, all‐cause mortality, and ‐5‐year absolute benefit of 55 events per 1000. quality of life measures

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Syst‐Eur Syst‐Eur Problem Isolated systolic hypertension Format Double‐blinded multi‐center RCT Treatment Nitrendipine (+‐ enalapril +‐ hydrochlorothiazide) • Reduction in BP by 13/2 mmHg in placebo Control Placebo Population 4695 group, 23/7 mmHg in treatment group Aged > 60 Inclusion criteria BP > 160 / 95 • Stroke: ‐42% Retinal hemorrhage or papilledema, CHF, Dissecting aortic aneurysm, Serum cr ≥ 180 mol/L • Non‐fatal stroke: ‐44% History of severe epistaxis, CVA, or MI in past year Exclusion criteria Dementia, Substance abuse, Unable to sit or stand • All cardiac endpoints: ‐26% ‐ 31% Any severe concomitant cardiovascular or non‐ cardiovascular disease. • Non‐fatal cardiac endpoints: ‐33% Follow‐up Median 2 years Primary endpoint Fatal and nonfatal stroke • Cardiac mortality: ‐27% Death Retinal haemorrhage or exudates • Overall mortality: ‐14% (non‐significant) Myocardial infarction Secondary endpoint(s) Congestive heart failure Dissecting aortic aneurysm Renal insufficiency.

From: Effect of Treating Isolated Systolic Hypertension on the Risk of Developing Various Types and Subtypes of Stroke: The Systolic Hypertension in the Elderly Program (SHEP) JAMA. 2000;284(4):465-471. doi:10.1001/jama.284.4.465

Figure 2 Survival free from CV death in the active treatment and placebo groups of SHEP (A) , survival free from non-CV death in the active treatment and placebo groups of SHEP (B) , survival (all death) in b...

William J. Kostis , Javier Cabrera , Franz H. Messerli , Jerry Q. Cheng , Jeanine E. Sedjro , Nora M. Cosgrove , J... Figure Legend: Competing Cardiovascular and Noncardiovascular Risks and Longevity in the Systolic Hypertension in the Elderly Program Seventeen strokes of unknown type are omitted. Three additional strokeswere also omitted (1 for a participant in the active The American Journal of Cardiology, Volume 113, Issue 4, 2014, 676 - 681 treatment group and 2participants in the placebo group). These 3 strokes occurred after the participantshad completed 5 years in the trial. http://dx.doi.org/10.1016/j.amjcard.2013.11.013

Copyright © 2014 American Medical Date of download: 12/4/2014 Association. All rights reserved.

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Age< 60: Lack of evidence for SBP Age < 60: Evidence for DBP threshold threshold of 90 • Insufficient evidence for reduction of CVA, CHD, • Treating patients age 30‐59 at DBP of 90 mortality with starting treatment at any SBP threshold. reduces CVD morbidity and mortality, CHF, • Lack of trials meeting criteria for inclusion • Up to 6 trials included: • Oslo Study, 785 men age 40‐49 started treatment – EWPHE, HDFP, Hypertension‐Stroke Cooperative, at SBP 150 HYVET, MRC, and VA cooperative – Data was rated poor due to high crossover between treatment and control groups. – All showed reduction in CVD morbidity/ mortality – No difference in CHD events, mortality, total CVD – Consistent magnitude of effect events – Significant decrease in strokes but only 7 events.

Age < 60: Evidence for DBP threshold Age < 60: Evidence for DBP threshold of 90 of 90 • Fatal or non‐fatal stroke: ‐ 30‐45% • No qualifying study assess effect of BP • Fatal stroke: ‐ 32‐39% treatment at DBP of 90 for people< 30 years. • Non‐fatal stroke: ‐11‐49% • No benefit found to treating to lower DBP target of <85 or <80. • Fatal or non‐fatal heart failure: ‐ 64% (HYVET) – HOT trial showed no improvement in CVD events, • Overall mortality: ‐1.3% (absolute decrease) at mortality 5 years (HDFP)

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Age < 60: Evidence for DBP threshold Patients with CKD of 90 • Elevated DBP is more important • 3 trials included: AASK, MDRD, REIN‐2 cardiovascular risk factor than elevated SBP • 1 post‐hoc analysis showing possible benefit • No need to change the SBP threshold of lower target at 130/80 • 2 other primary analyses did not show significant benefit of 130/80 over 140/90 • AASK: No benefit to CHD or CVD outcomes – Follow up in cohort phase 8‐12 years did not show differences in serum cr doubling, ESRD, death

Patients with CKD Patients with DM

• No benefit of target 130/80 over 140/90 in • No RCTs to support goal of < 140/90 progression of kidney disease • Treatment at SBP of 150 resulted in decreased – No reduction in ESRD, GFR by 50%, death mortality, CVD and CHD events. – Consistent finding across all three studies • HOT trial compared DBP<80 to <90 found • Trend of benefit of lower goal for patients reduction of composite CVD outcome in post‐ with severe proteinuria (> 3 gm/ day baseline) hoc analysis of subgroup of 8% of study population

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Choosing BP medications Choosing BP medications

• First‐line and later line treatments should be: • Later‐line alternatives – Direct vasodilators – Thiazides – Beta‐blockers (hydralazine) – CCBs – Alpha‐blockers – Loop diuretics – ACEIs – Alpha1/ beta‐blockers – Aldosterone antagonists – ARBs (carvedilol) – Peripherally acting • Second‐line and third‐line: – Vasodilating beta‐ blockers (nebivolol) adrenergic antagonists – Maximize dose of initial medication – Central alpha2‐ Addition of second medication of above 4 classes – adrenergic agonists (clonidine)

From: 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) Treatment strategies JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427 • Start with one of the 4 first‐line medications • Attain goal within 1 month of treatment • If not at goal, increase dose or add second medication • Add 3rd medication if needed to reach goal • Consider specialist consultation, work up for

Table Title: secondary causes if still not at goal Evidence-Based Dosing for Antihypertensive Drugs

Copyright © 2014 American Medical Date of download: 12/2/2014 Association. All rights reserved.

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Method 1 Method 2

• Start one of the 4 classes of antihypertensives • Start one of the 4 classes of antihypertensives • If not at goal: • If not at goal, add 2nd class • Titrate to maximum effective dose • Titrate both to maximum effective dose • Add 2nd class and titrate to maximum effective • If not at goal, add 3rd class and titrate, etc. dose • Add 3rd class and titrate, etc.

Method 3 Special considerations

• Start combination therapy with 2 of the 4 • Pts of African descent should start with classes of antihypertensives thiazide or CCB • Avoid ACEI/ ARB combination • Pts of any ethnicity with CKD should use ACEIs • If not at goal, add 3rd class or ARBs initially • Titrate maximum effective dose • Do not combine ACEIs and ARBs • Use this approach for BP> 160/100 or SBP>20 • Prefer CCB and thiazides in pts >75 with renal mmHg/ DBP>10 mmHg above goal dysfunction due to risk of hyperkalemia/ further renal impairment

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From: Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years Dissenting Opinions or Older: The Minority ViewSystolic Blood Pressure Goal for Patients Aged 60 Years or Older

Ann Intern Med. 2014;160(7):499-503. doi:10.7326/M13-2981

Figure Legend: Smoothed weighted frequency distribution, median, and 90th percentile of systolic blood pressure for persons aged 60 to 74 y: United States, 1959–2010. Reproduced from Lackland and colleagues (4). NHANES = National Health and Nutrition Examination Survey; NHES = National Health Examination Survey.

Date of download: 12/5/2014 Copyright © American College of Physicians. All rights reserved.

Controversy re: SBP threshold/target Controversy re: SBP threshold/target 150 v 140 150 v 140 • > 50% of pts with hypertension are ≥ 60 • The SBP achieved by both HYVET and SHEP was closer to 140 than 150 • Trend of adequate BP control has been Trials not showing benefit were underpowered increasing over last 50 years • • FEVER trial showed 27% reduction in all CVD • Clinicians may interpret that they can be less outcomes. aggressive with treating hypertension • Strict trial inclusion criteria excluded 98% of • Pts ≥ 60 have 10 year CVD risk > 20%, higher available evidence than younger pts with diabetes. • Evidence from more recent trials indicating increased benefit with SBP threshold of 140 • May be reducing benefits of current BP goals

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Comparison of Guidelines Recommendations Table 1. Comparison of Hypertension Guidelines 2011–2014

2014 Hypertension NICE 20115 ESH/ESC 20133 ASH/ISH 20142 AHA/ACC/CDC 20134 Guidelines, US JNC 81 1.Abbreviations are listed in Table 1. Blood pressure (BP) values are expressed in mm Hg. Adapted from Lindholm LH, Carlberg B. Hypertension News 2014, Opus 35 (International Society of Hypertension). • Do not relax in treating hypertension ≥140/90 and daytime Definition of ambulatory BP (or home ≥140/90 ≥140/90 ≥140/90 Not addressed hypertension BP) ≥135/85 • Increasing evidence that 140/90 may be a Drug therapy in low‐risk patients after ≥160/100 or daytime <60 y ≥140/90 ≥140/90 ≥140/90 ≥140/90 nonpharmacologic ambulatory BP ≥150/95 ≥60 y ≥150/90 better threshold for BP treatment than 150/90 treatment β‐Blockers as first‐line No (Step 4) Yes No (Step 4) No (Step 3) No (Step 4) for people over 60. drug Thiazides, Thiazides, Thiazides, Chlorthalidone, Diuretic chlorthalidone, chlorthalidone, Thiazides chlorthalidone, indapamide indapamide indapamide indapamide • May be reasonable to use higher threshold Initiate drug therapy In patients with Not mentioned ≥160/100 ≥160/100 ≥160/100 with 2 drugs markedly elevated BP with patients over 80 <140/90 Elderly patients <80 y: <140/90 <140/90 <140/90 systolic BP <140 in “fit” Lower targets may be ≥80 y <150/90 <60 y <140/90 Lots of flexibility given for clinical judgment BP targets ≥80 y systolic BP <150 in appropriate in some • Young adults: Consider ≥60 y <150/90 <150/90 “fragile” patients, including the <130/80 if tolerated elderly ≥80 y: systolic BP elderly 140–150

BP targets in patients <140/90 Lower targets with diabetes mellitus or Not addressed <140/85 <140/90 <140/90 may be considered chronic kidney disease

Recommendations

• JNC 8 does not provide guidance for pts with HF, CAD, or multiple comorbidities • ACC/AHA guidelines – Beta blockers and ACEI for patients with stable HF, LVEF≤ 40% – Beta blockers, ACEI or ARB for patients with hx of MI/ ACS and reduced EF – Avoid non‐dihydropyridine CCBs for post‐MI pts with reduced EF – Diuretics for patients with fluid retention – Diuretic +/‐ ACEI may be helpful for secondary stroke prevention

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Disclosure Statement Hyperthyroidism and Hypothyroidism Running Hot & Cold: I have nothing to disclose but disclosure itself. Hyperthyroidism & Hypothyroidism

David M Schneider, MD Family Physician/Didactics Director Santa Rosa Family Medicine Residency Clinical Professor of Family & Community Medicine, UCSF 12/16/14

Public Domain, via Wikipedia: http://en.wikipedia.org/wiki/Franklin_D._Roosevelt's_paralytic_illness#mediaviewer/File:Rooseveltinwheelchair.jpg

Learning Objectives Fun Thyroid Facts

• An estimated 20 million Americans have some form • Perform appropriate to laboratory tests diagnose of thyroid disease. hyperthyroidism and hypothyroidism based on symptomatology. –Up to 12% will develop some form of thyroid disease • Prescribe appropriate therapy for patients with during their lifetime. hyperthyroidism and hypothyroidism symptomatology and –Up to 60% of those with thyroid disease are unaware monitor patients accordingly. of their condition. • Develop a screening protocol to identify patients with risk • Thyroid receives 2% of the cardiac output, though it factors for developing hyperthyroidism and hypothyroidism. is only ~0.03% of body mass. • Thyroid hormones affect function of virtually every organ & tissue in the body.

http://www.thyroid.org/about/pressroom.html; http://www.thyroidmanager.org/

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The 1st test(s) to order to diagnose Interpretation of TSH thyroid disorders is/are: • High TSH  hypothyroid A. High sensitivity TSH – Pituitary thinks there’s B. TSH + Free T4 insufficient thyroid hormones, so it secretes C. TSH + Free T4 + Free T3 more TSH. D. TSH + thyroid antibodies • Low TSH  hyperthyroid E. T4 + T3 assays – Pituitary thinks there is plenty of thyroid hormones, so it shuts down TSH production. • There are rare exceptions.

Used with Permission by UpToDate: http://www.uptodate.com/contents/image?imageKey=ENDO/75399&topicK ey=ENDO%2F7891&source=outline_link&search=thyroid&utdPopup=true

TSH Upper Limit of Normal Total T4 & T3

• • Most young – middle-aged euthyroid people have a Total T4 (& to a lesser extent Total T3) assays TSH below 2.5 – 3.6. are rarely clinically useful in & of themselves, • Reducing the upper limit of TSH range to 2.5 will and should generally only be ordered in likely label a sizable number of people as conjunction with an estimate of free (vs bound) “abnormal” (or subclinical hypothyroidism). hormone. – FT3 assays are less well validated  total T3 is often – “…might significantly increase the use of thyroxine used. therapy for patients in whom there is no demonstrated therapeutic benefit. – Same is NOT true for T4 – use FT4.

ClinChem 2005 Aug;51(8):1480‐6; JAMA 2003;290:3195‐6

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Free Hormone Hypothesis 99.7 – 99.97% Protein-Bound

• Only free hormone is available to be active in the body, whereas hormone bound to proteins (TBG, transthyretin, albumin) is inactive.

http://www.thyroidmanager.org/chapter/assay‐of‐thyroid‐hormones‐and‐related‐substances/ With permission, royalty‐free: http://www.featurepics.com/online/NeedleHaystackPhoto36079.aspx

Thyroid Hormone Tests Summary General Rule of Thyroid Tests

Do not interpret thyroid test results in a vacuum – • TSH is the single best thyroid test. you must look at the clinical picture! • For most ambulatory patients, your lab’s Free T4 & Free T3 assays (usually EIA or related assay) are good enough. • In most clinical situations involving discordant FT4 and TSH results, the TSH usually provides the most reliable results. –Tune in later for exceptions.

http://picasaweb.google.com/lh/photo/mKq2J2fHAoXdS0z0fbykZA http://www.thyroidmanager.org/chapter/assay‐of‐thyroid‐hormones‐and‐related‐substances/

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Case 1 42 y.o. Woman w/Fatigue

• A 42 y.o. woman presents to your clinic/office with • Physical exam: fatigue. –BP 162/74, HR 104 • History reveals: –9 # wt loss since last visit 3 months ago. –Depressive symptoms. –No exophthalmos, but when she looks down you can –Anxiety symptoms. see sclerae atop the irises. –Palpitations. –Fine tremor. –Normal appetite but ~ 10 lb wt loss over last 3 –Onycholysis of a few fingernails. months—unintentional. –Diarrhea.

Lid Lag Exophthalmos

• “…when she looks down you can see sclerae atop the irises.” • Normal: after looking up, look straight ahead  no white sclera visible above iris. • Present in “nearly all” hyperthyroid pts.

Used with permission from Sarah Chen: http://sarahachen.com/ Used with permission from EyeRounds.org and The University of Iowa

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Hyperthyroidism Diagnosis Trust the TSH

• TSH low. • Free T4 . –FT4 may be WNL early in hyperthyroidism. • Free T3  — may be ordered w/FT4. –T3 assays: generally only in hyperthyroidism. –5% of hyperthyroid pts have “T3 toxicosis,” in which FT3 is elevated while FT4 is normal. • If FT4 & FT3 remain normal while TSH remains suppressed, trust the TSH and follow, or refer.

Public Domain: http://commons.wikimedia.org/wiki/File:Modificaci%C3%B3n_humor%C3%ADstica_de_foto_de_ardillas.jpg, via Jose Martin

Which of the following is FALSE about Epidemiology of Hyperthyroidism hyperthyroidism? • Women : men = 5:1. A. It is more common in women. • Overall prevalence = 1.3%. B. It is more common in smokers. –0.7% (>1/2) mild or asymptomatic. C. It occurs in 1/250 individuals in the general • Prevalence in older women= 4 – 5%. population. –TMNG more common in older women. D. Graves’ dz is the most common cause in –Graves’ more common in younger women. younger women. • More common in smokers (OR = 2.37). E. It can be treated surgically.

NHANES III‐‐JCEM 2002;87(2):489‐99; ArchIntMed 2007;167(13):1428‐32

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Signs & Symptoms of Signs & Symptoms of Hyperthyroidism Hyperthyroidism—Short Mnemonic

•Tremor • Sweating • HR increased (tachy) • Tremor + Tachycardia • Yawning (fatigue) • Restlessness (anxiety) • Intol to heat + Irreg menses + Irritability • Oligomenorrhea/amenorrhea • Nervousness • Intolerance to heat • Goiter + GI sx (diarrhea) • Diarrhea • Irritability/Insomnia • Sweating • Muscle wasting/wt loss

Pretibial Myxedema Causes of Hyperthyroidism

• Graves dz: 80% • Lumpy. • Toxic multinodular goiter: 15% • ≤5% of Graves’ pts, up to 15% • Toxic adenoma = autonomously functioning nodule = of Graves’ w/ ophthalmopathy. hot nodule: 2% • Almost always assoc’d • Thyroiditis: 1% w/ophthalmopathy. • Iodine load (CT, diet, amiodarone): <1% • May affect ankles, knees, • Thyrotoxicosis factitia: <1% elbows, upper back. • Iatrogenic: variable

Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc. • Graves + TMNG = 95%.

Medicine (Baltimore) 1994;73(1):1‐7; BestPractResClinEndocrinolMetab 2012;26:553‐65; ClinDermatol 2008;26:283‐7 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A235

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What is the Cause of the Pt’s Graves’ Dz vs TMNG Hyperthyroidism?

• Radioiodine Uptake (RAIU) •Graves’: • Toxic Multinodular – High uptake  increased hormone synthesis. – Entire gland diffusely Goiter: • Medical treatment (antithyroid drugs) may help. enlarged. – Multiple nodules on – Low uptake  no increase in hormone synthesis in – Entire gland making thyroid. thyroid. excess thyroid hormone. – Nodules independently • Inflammation & destruction of thyroid w/release of thyroid produce excess thyroid hormones. hormone (autonomously –Antithyroid meds unlikely to help. functioning = “hot”). • Nonthyroidal source of hormone production.

DDx Hyperthyroid per RAIU Back to Case 1

• Physical exam shows normal thyroid, no masses or • High RAIU: • Low RAIU: –Graves’ dz. – Thyroiditis. asymmetry. –Toxic multinodular goiter. • Subacute granulomatous –Toxic (“hot”) nodule. (DeQuervain’s—painful). • Subacute lymphocytic (painless • Is this Graves’ dz, TMNG, or other? – Hashitoxicosis. = “Silent”). – Likely Graves’: –TSH‐secreting tumor (rare). • Amiodarone. –Germ cell tumor (mole, – Exogenous—iatrogenic, • Epidemiology (young woman). chorioCA, testicular germ factitious. • No nodules. cell). – Struma ovarii. –Iodine (contrast, –Iodine (contrast, amiodarone)—post I. amiodarone)—still ingesting I.

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Risk Factors For Graves’ Dz The G’s of Graves’

• Females : males = 7:1. • Gender (F) • Genetic – FH Graves’ or other autoimmune • Genes (FH) disorders. •Gravidity • Stressful life events – may lead to immune • Gravity of life (stress) suppression followed by rebound. • Gaspers (cigarettes) • Smoking (OR = 2). • Pregnancy/postpartum (30% of young women w/Graves’ had H/O preg w/in 12months).

© David M. Schneider

ClinEndocrinol(Oxf) 2001;55(1):15‐9; ClinEndocrinol(Oxf) 1995;42(3):303‐8; JAMA 1993;269(4):479‐82; ArchIntMed 2005;165(14):1606‐11; ActaEndocrinol(Copenh) 1987;116(3):321‐5

Routine acute management of Treatment of Hyperthyroidism hyperthyroidism includes:

A. Urgent radioablation. • Acute management: control sx. B. Use of β-blockers to reduce symptoms. –Beta blockers. C. Use of β-blockers to reduce thyroid •  thyroid increases β-receptors in many tissues. • β–blockers quickly. hyperfunction. reduce sx •Try β-1 selective if relative contraindication. D. B + C. • All equally effective. E. All of the above. • Pregnancy: wean β-blockers as soon as possible – IUGR, hypoglycemia, resp depression, bradycardia. • 1 study (1991)  5-fold  SAb rate.

EndocrRev 1983;4(4):378‐88; ActaObstetGynecolScand 1991;70(6):461‐3; NEJM 1981;305:1323

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Acute Management of Hyperthyroidism Antithyroid Drug Toxicity

• Antithyroid drugs (thionamides). • Most toxic rxns occur within 1st 3 months. –Inhibit formation of thyroid hormones. • Hepatotoxicity – rare but can be serious. –Goal: euthyroid within 8 weeks. –MMI  cholestatic picture (usu reversible). –Methimazole (MMI) is the preferred drug. –PTU  hepatocellular (may be irreversible). •  side effects,  duration of action  once daily dose • PTU-related hepatotoxicity may occur days-yrs after starting (usually). med (idiosyncratic). • 10 – 15 mg daily for milder clinical picture, vs 20 – 40 mg for • Agranulocytosis – rare, but devastating. larger goiter & more severe sx & signs (can divide bid to –Aplastic anemia may occur, and is rarer. minimize side effects). • Questionable value of routine monitoring.

JCEM 2009;94:1881‐2; JCEM 1995;80:1083‐5; Thyroid 2009;19:673‐4; AnnIntMed 2007;146(9):657‐65; AmJHematol 2003;72(4):248‐ ClinEndocrinology;49:451–7; ClinEndocrinolMetab 1986;63:125; JCEM 1993;76:1516‐21; 54; AnnIntMed 1983;98(1):26‐9; ClinEndocrinol(Oxf) 1989;30(5):525‐30; Thyroid 2008;18(10):1043‐8; ArchInternMed http://www.utdol.com/online/content/topic.do?topicKey=thyroid/5541&selectedTitle=1%7E150&source=search_result#H4 1990;150(3):621‐4

Choice of Antithyroid Drug Antithyroid Drugs: Informed Consent

• Do informed consent, or don’t Rx ATD’s. • First choice = MMI. • Only use PTU if: –Risk of liver damage – rare but can be serious. –1st trimester pregnancy. –Risk of immune suppression – very rare, but can be devastating. –Life-threatening thyroid storm. –Adverse rxn to MMI, esp if not candidate for –Call right away for any signs of infection, including radioiodine ablation or surgery. fever, sore throat, etc; stop med til CBC results. • Note: after 1st trimester, potential teratogenic risks –Periodic blood tests, though uncertain benefit and not of MMI < risk of PTU hepatotoxicity (ATA). routinely recommended.

Thyroid 2011;21:1081; JCEM 2009;94:1881‐2; Thyroid 2009;19:673‐4

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Long-term Treatment of Hyperthyroidism Antithyroid Drugs

• Antithyroid drugs • 12-18 months (up to 2 years). • Radioiodine ablation –Long-term remission rate 20 – 70+%. • Surgery –Initially monitor TSH & FT4/FT3 q 4-6 weeks. –In early phase, TSH response is delayed. –When TSH rises to normal, follow TSH alone. • Can be used for ≥10 years w/o loss of effect. • TMNG does not go into remission w/ATD’s. –ATD’s may be used either as a bridge to definitive therapy, or as a long-term therapy.

NEJM 2005;352:905‐17; JCEM 1990;71(3):764‐9; AnnIntMed 1987;107(4):510‐2; Eu JEndocrinol 2005;152(5):695‐701; JClin EndocrinolMetab 1987;64(6):1241‐5; Endocr Pract 2011;17:457‐520; http://www.uptodate.com

Radioiodine Ablation Radioiodine Ablation – 2

•Graves’ Dz: • Preferred method in US, less popular in Europe & – High-dose RAI curative in up to 90%, with 80% becoming Asia. permanently hypothyroid. • Taken orally. – May cause or worsen ophthalmopathy. • Destruction of tissue in 6-18 weeks. •TMNG • ATD’s in the week before, during, or after – Destroys primarily hyperfunctioning areas. radioiodine treatment may reduce cure rate of RAI – Some pts will remain euthyroid, though  hypothyroidism (PTU may be a worse offender). w/time.

JClinEndocrinolMetab 2002;87(3):1073‐7; Thyroid 1991;1:129‐35; ClinEndocrinol (Oxf) 2008;68:814‐20; AnnIntMed 1984;101(4):488‐90; NEJM 1994;330(24):1731‐8; ClinEndocrinol (Oxf) 2005;62(3):331‐5; Clin http://www.uptodate.com/contents/radioiodine‐in‐the‐treatment‐of‐ Endocrinol(Oxf) 2012 Feb;76:297‐303; http://www.uptodate.com/contents/radioiodine‐in‐the‐treatment‐of‐ hyperthyroidism?source=search_result&selectedTitle=5%257E150#H2; BMJ 2007;334(7592):514 hyperthyroidism?source=search_result&selectedTitle=5%257E150#H2

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Surgery for Hyperthyroidism Surgery for Hyperthyroidism – 2

• Large or obstructive goiter. • Subtotal thyroidectomy preferred. • Rapid/definitive correction needed. –25% ↓ incidence of hypothyroidism vs total. • Coexisting “cold” (nonfunctioning) nodule – surgery –Somewhat ↑ recurrence of hyperthyroidism. can give Dx & Tx. –Total thyroidectomy may be indicated w/severe • Coexisting malignancy or hyperparathyroid. disease or large goiter. • Pregnant, intol of hyperthyroidism + intol of ATD’s. • May be preferred if Graves’ ophthalmopathy. • ? more cost effective for toxic nodule < 60. • Near-total thyroidectomy in TMNG.

Thyroid 2004;14(11):933‐45; http://www.uptodate.com/contents/surgery‐in‐the‐treatment‐of‐hyperthyroidism‐indications‐preoperative‐ Thyroid 2011;21(6):593‐646; AFP 2005;72:623‐630 preparation‐and‐postoperative‐follow‐up?detectedLanguage=en&source=search_result&search=surgery+for+hyperthyroidism selectedTitle=1~150&provider=noProvider

Complications of Thyroidectomy Case 2

• Hypoparathyroidism – transient or permanent. • 76 y.o. man presents with weight loss, fatigue, • Recurrent laryngeal nerve injury/vocal cord anorexia. paralysis – transient of permanent. • PMH: HTN—controlled on meds • Recurrent hyperthyroidism (~2%). • Meds: HCTZ, ASA 81 mg daily • Usual surgical risks: bleeding, infection, keloid. • FH noncontributory • SH: former smoker, 30 pack-years

Thyroid 2001;11(2):187‐92; World J Surg 2008;32(7):1278‐84

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Case 2 continued DDx

• ROS: no palpitations, no GI sx • Cancer – do you start the big search? •Exam: • HIV/AIDS • Adrenal insufficiency –By your office scale, 30# wt loss in 6 months. • Hypercalcemia – malignancy? –BP 140/82. •COPD –Pulse 90. • Advanced CHF – “cardiac cachexia” –No tremor. • Depression –No goiter. • Meds, drugs • ????????

“Apathetic Hyperthyroidism” Apathetic Hyperthyroidism – 2

• More common in the elderly (>70). • Sx that are more common in elderly: • “Apathetic”  no (or few, or overlooked) sx or –Atrial fib (35% vs 2%) signs of sympathetic overactivity. –Anorexia (32% vs 4%) –Signs of sympathetic hyperactivity were less common • 3 signs most highly associated w/hyperthyroidism in elderly (p<0.001). in elderly: –↑ DTR’s, sweating, heat intol, tremor, nervousness, –Apathy +/- fatigue (OR=14.8) polydypsia, ↑ appetite. –Tachycardia (OR=11.2) • Goiter in 50% of elderly, vs 94% <50 y.o. –Wt loss (OR=8.7) • Avg 6 clinical signs in elderly, vs 10.8 in younger –These are the only 3 sx in >50% of these pts. pts.

AnnIntMed 1970;72:679; JAmGeriatrSoc 1996;44(1):50‐3 J Am Geriatr Soc 1996;44(1):50‐3

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Case 3 Case 3 – continued

• 28 y.o. male presents to your office with fatigue for • PMH neg ~ 6 months. • No meds –No F/C. •NKA –Clothes fitting tighter, but doesn’t know if wt gain • FH/SH neg (doesn’t have a scale). • ROS as above, o/w neg –No CP, but exertional dyspnea and reduced exercise •Exam: tolerance. –BP 132/98, P 60 –+ intermittent mild constipation. –Goiter? –Endorses nonspecific arthralgias. –Something funny about his DTR’s

Lab Results Hypothyroidism—Epidemiology

•CBC WNL • Prevalence = 4.6% (4.3% subclinical  93% of all • Chem: Na 134, o/w WNL hypothyroidism!). • Lipids: TC 248, LDL 164, TG 246, HDL 35 • Up to 15% of older women (>65). • TSH: 47 • 5-8 times more common in women vs men.

JCEM 2002;87(2):489‐99; JCEM 2006;91(12):4953‐6; ClinEndocrinol(Oxf) 1995;43(1):55‐68

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Risk factors for hypothyroidism include Possible Risk Factors for Hypothyroidism all the following EXCEPT: • Previous thyroid • Age >60 years. A. PMH of thyroid problems. problems (goiter, • Pregnancy or delivery B. Turner’s syndrome. surgery). within past 6 months C. HIV/AIDS. • Family history of thyroid (esp if prior postpartum disease. D. Age under 35. thyroiditis). • Other autoimmune • Radiation treatment to E. Rheumatoid arthritis. diseases (Sjögren’s, the thyroid, neck, or pernicious anemia, DM1, chest. RA, SLE). •HIV • Women w/small body • Turner’s syndrome. size at birth &/or during childhood.

http://www.endocrine.niddk.nih.gov/pubs/Hypothyroidism/#diagnosis; JCEM 2006;91:4953‐6; ClinInfectDis (2003);37:579‐583

Symptoms of Hypothyroidism Signs of Hypothyroidism

• Metabolic slowing: • Accumulation of matrix • Metabolic slowing: – Fatigue substances: –Bradycardia – Cold intolerance − Dry skin (reduced –Slowed movement & speech sweating) – Wt gain –Delayed DTR return − Edema • Matrix accumulation: –DOE − Hoarse voice – Cognitive dysfunction • Other: –Goiter – Constipation − Arthralgias, myalgias –Coarse skin; cool & pale ( blood flow) – Growth failure/delayed − Depression –Puffy face, periorbital edema puberty in children − Menorrhagia or –Tongue enlargement oligomenorrhea –Loss of eyebrows (esp lateral 1/3) − Hearing loss http://www.uptodate.com/contents/clinical‐manifestations‐of‐ hypothyroidism?detectedLanguage=en&source=search_result&search=hypothyroidism+symptoms&selectedTitle =1~150&provider=noProvider; EndocrRev 1989;10:366

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More Signs of Hypothyroidism Hypothyroid Mnemonic—Mine

• Diastolic HTN ( PVR) • Macrocytosis • Pleural/pericardial effusions • Edema (incl orbital) • Myxedema coma ≠ pretibial myxedema • Thyroid Goiter • Anemia • Anemia • Bradycardia • Macrocytosis w/o anemia or deficiency • Obesity (wt gain) • High output CHF or angina – in CV pts • Lateral eyebrow loss • Celiac dz (4-fold incr) • Irreg menses • Carpal tunnel syndrome • Constipation • Thinning hair © David M. Schneider

Lab Abnormalities in Hypothyroidism Causes of Hypothyroidism

• Hyponatremia –  free-H2O clearance. • Hashimoto’s (chronic autoimmune thyroiditis): >90% • Hyperlipidemia –  lipid clearance  incr LDL &/or • Iatrogenic: TG’s. –Radioiodine therapy –Subtotal or total thyroidectomy –Lipids usually correct w/correction of hypothyroidism. –ATD’s –Consider TSH in pts w/hyperlipidemia. –Drugs (amiodarone, Li, interferon) • Transient  Cr (20 – 90% of pts). • Thyroiditis • Iodine deficiency/excess • Thyroid agenesis

ArchIntMed 1999;159(1):79‐82; http://www.uptodate.com/contents/ clinical‐manifestations‐of‐ http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A235; hypothyroidism?source=search_result&selectedTitle=4%257E150; MayoClinProc 1993;68(9):860‐6; http://www.utdol.com/online/content/topic.do?topicKey=thyroid/7938&selectedTitle=2%7 ArchIntMed 1995;155(14):1490‐5 E150&source=search_result

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Hashimoto’s Autoimmune Thyroiditis Thyroid Autoantibodies

• F:M = 8 – 10:1 • Anti-thyroglobulin (anti-Tg). • May begin with transient hyperthyroidism – –5-20% of general population. “Hashitoxicosis.” • Anti-thyroid peroxidase (anti-TPO). –8-27% of general population.

http://www.uptodate.com/contents/pathogenesis‐of‐hashimotos‐thyroiditis‐chronic‐ autoimmune‐thyroiditis?detectedLanguage=en&source=search_result&search=anti‐ tpo&selectedTitle=1~56&provider=noProvider

Thyroid Autoantibodies – 2 Why Get Antithyroid Ab’s?

• Hashimoto’s: • Generally unnecessary. –TPO: 90% + –If hypothyroid, 90+% Hashimoto’s. –Tg: 80-90% + –Most of the rest are thyroiditis or iatrogenic. •Graves’: –2° will still get same treatment. –TPO: 50-90% + • May provide prognostic info in pts @ high risk: –Tg: 50-70% + –Such as pregnant women w/thyroid dysfunction – • DM1: 30-40% + for each. may predict later Graves’. • Relatives of Hashimoto’s: 30-50% + for each. –May help in dx & prediction of subclinical thyroid dz.

http://www.uptodate.com/contents/pathogenesis‐of‐hashimotos‐thyroiditis‐chronic‐autoimmune‐ thyroiditis?detectedLanguage=en&source=search_result&search=anti‐ Endocr Pract 2012;18:989‐1028 tpo&selectedTitle=1~56&provider=noProvider

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All hypothyroid pts should be given a Treatment of Hypothyroidism trial of combined T4/T3 therapy. • A. True Levothyroxine (LT4). –Mean dose is 1.6-1.8 mcg/kg/day (lean body wt more B. False accurate). C. Salvador Dali. • 112-125 mcg for avg 70 kg pt. • Young & healthy: begin w/near target dose. • >50 or CV dz: start @ 25 – 50 mcg daily. –Wide variability. –Take on empty stomach. –Do not take with soy flour (soy formulas).

JCEM 2005;90(1):124-7; EndocrPract 1999;5(5):233-8; JCEM 2009;94(10):3905-12

Goals of Hypothyroidism Treatment Goals of Hypothyroidism Treatment - 2

• Goals of Tx: • Goal = TSH of 0.5 – 2.0 (or 2.5). • Resolution of sx/signs. –No outcome studies to support target level. • Normalize TSH & improve thyroid [hormones]. –ATA 2012 said normal range up to 4.12. • Avoid overtreatment, esp elderly. –ATA 2014: target TSH in lower 1/3 of age-specific range may be reasonable, but not universally endorsed.

Endocr Pract 2012;18:989-1028; http://www.thyroidmanager.org/chapter/assay-of-thyroid-hormones-and-related-substances/#toc- Endocr Pract 2012;18:989-1028; http://www.thyroidmanager.org/chapter/assay-of-thyroid-hormones-and-related-substances/#toc- 4-serum-tsh-thyroid-stimulating-hormonethyrotropin-assays; http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/; JCEM 4-serum-tsh-thyroid-stimulating-hormonethyrotropin-assays; http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/ 2002;87:489-499; JCEM 2005;90:5483-5488; JCEM 2005;90:5489-5496

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Monitoring of LT4 Treatment Evidence: T3 Doesn’t Help

• Measure TSH q 4-6 weeks after change in meds. • Neurocognitive function & psych well-being may not TSH takes 6 weeks to equilibrate (incl change in return to normal w/LT4. endogenous function). • The vast majority of studies show no advantage to • TSH once yearly when stable. T3 supplementation or partial replacement (11/13 + meta-analysis). • Risk of hyperthyroidism & long-term effects.

EurJEndol 2005;153(6):747-53; ClinEndo(Oxf) 2002;57(5):577-85; NEJM 1999;340(6):424-9; JCEM 2003;88(10):4543-50; JCEM 2003;88(10):4551-5; JAMA 2003;290:2952-8; ClinEndocrinol(Oxf) 2004;60:750-7; AnnIntMed 2005;142:412-24; JCEM 2005;90:805- http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/; Endocr Pract 2012;18:989-1028; 12; JCEM 2005;90:2666-74; JCEM 2006;91:3389-93; EndocrPract 2005;11:223-33; JCEM 2005;90:4946-54; JCEM 2006;91(7):2592- http://www.thyroidmanager.org/chapter/assay-of-thyroid-hormones-and-related-substances/#toc-4-serum-tsh-thyroid-stimulating- 9; EurJEndo 2009;161:895-902; EurJEndo 2009;161:955-9; http://www.uptodate.com/contents/treatment-of- hormonethyrotropin-assays hypothyroidism?source=search_result&selectedTitle=3%257E150

An Interesting Study Caveat and Interesting Info

• There may be a • 697 hypothyroid pts: subgroup who respond to T3 (deiodinase gene polymorphism). –Validated instruments to assess psych well-being. –Up to 16% may have a deiodinase gene –FT4 & TSH  strong correlation with psych well-being. polymorphism. Some of these pts may feel better –No correlation to psych well-being: w/appropriate T3 supplementation. • FT3 • rT3, rT3:FT4, FT3:rT3 • ??significance of T3 variation or sl ↓ [T3].

Licensed for reuse via Creative Commons: http://en.wikipedia.org/wiki/Thyroid_ hormone#mediaviewer/File:Iodothyr onine_deiodinase.png

JCEM 2006;91:3389-93; http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/ JCEM 2009;94:1623-9; AmJPhysiol 1990;258:E715-26; Thyroid 2004;14:271-5

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T4:T3 and Supplementation T3 Therapy: How Do You Do It?

• Physiologic T4:T3 ratio in humans ~ 10-14:1. • Reduce LT4 by amount of added T3. –Armour Thyroid & Thyrolar have 4:1 ratio of T4:T3. – Pt on 125 mcg LT4. –Trial of ~10:1 ratio of T4:T3 may be reasonable. –1/10 of dose = 12.5 mcg. –T3 (Cytomel™) best taken bid (or slow release – –Reduce LT4 to 112 mcg and add 12.5 mcg T3. unavailable in US). 2nd dose midday or afternoon. • ½ of 25 mcg pill = 12.5 mcg, split into am & pm doses. –Avoid overtreating to hyperthyroidism. MONITOR! • 2.5 of 5 mcg T3 bid. • If changing TO LT4 FROM Armour, assume 60 mg Armour ~ 75-100 mcg LT4 (lose T3 “buzz”—rapid action).

www.uptodate.com/contents/treatment-of-hypothyroidism; www.thyroidmanager.org/chapter/adult-hypothyroidism

2014 ATA: Routine LT3 + LT4 Unstable Control &/or TSH

• dherence. • No consistent evidence of superiority of combo tx A • rand/generic changes. over LT4 monotherapy. B –ATA & Endocrine Society recommend that pts be –Not routinely recommended. maintained on the same brand-name LT4 product. –Conflicting reports of benefits. –Brand or generic changes: check TSH in 6 weeks, –Paucity of long-term outcome data. adjust med as needed. • Pts who feel unwell on LT4 alone: insufficient • Ca++ or other food interactions. evidence to support routine combo tx. • Drug interactions. • Other Endocrine (adrenal) or other conditions.

http://www.thyroid.org/professionals/advocacy/04_12_08_thyroxine.html http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/

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Unexpectedly High LT4 Requirement Drugs That Interfere w/LT4

• Also consider: • Acid reducers (PPI, probably H2, sucralfate) –Celiac dz. • Bile acid sequestrants (cholestyramine) –Atrophic gastritis. •Ca++, Carbamazepine –H. pylori gastritis. • Dilantin, Depressants (sertraline, maybe other SSRI’s) • Estrogen derivatives (incl tamoxifen) •Fe • Check drug interactions when prescribing

© David M Schneider, MD

http://www.thyroid.org/thyroid-guidelines/hypothyroidism2014/; Thyroid 2014 (Oct 27) Epub ahead of print doi:10.1089/thy.2013.0661; JCEM 2012;97:E419-22; AmJMed 2012;125:278-82

According to USPSTF and best current Thyroid & Pregnancy evidence, who should be screened for thyroid disorders? • Women with thyroid conditions should discuss their condition with their doctor before becoming A. All adults over 60. pregnant. B. All adults over 35. • Opportunity for preconception counseling & C. Women over 50. optimizing maternal & fetal health. D. People with risk factors • Challenging to diagnose E. None of the above. • In pregnancy: It is better to be slightly hyper- than slightly hypo-thyroid.

http://www.endocrine.niddk.nih.gov/pubs/Hypothyroidism/#diagnosis

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Screening for Thyroid Disorders Risk Factors for Thyroid Dz

• American Thyroid Association (ATA): screen every 5 • Hyper-/hypo- • Hyper-: years beginning at 35. –Female gender –Smoking • USPSTF, AAFP: “evidence is insufficient to –Age, esp older women > –Life stressors (?!) recommend for or against routine screening for thyroid 60 – 65 • Hypo-: disease in [nonpregnant] adults.” –Pregnancy/postpartum –Autoimmune – No proven outcome advantage to screening. (be on the lookout for –Turner’s – No association w/function, depressive sx, disability in ADLs in sx) –Small at birth or in an elderly population. –Prior thyroid problems childhood – Subclinical hypothyroidism was assoc’d w/lower all-cause/CV –FH mortality, despite higher baseline chol(!). –Neck/chest radiation • Consider targeted screening – risk factors. –HIV

http://www.ahrq.gov/clinic/uspstf/uspsthyr.htm; AnnIntMed 2004 Jan 20;140(2):128‐41; JAMA 2004 Dec 1;292(21):2591‐9 http://www.uptodate.com/contents/disorders‐that‐cause‐hyperthyroidism?source=search_result&selectedTitle=1~150

Take-Home Points References/Suggested Reading

• Thyroid dz is common. • AACE Hyperthyroidism guideline: Endocr Pract • Diagnosis of thyroid disorders. 2011;17:457-520. • “Apathetic hyperthyroidism” of elderly. • AACE Hypothyroidism guideline: Endocr Pract • Risk factors for thyroid dz. 2012;18:989-1028. • Evaluation and management of hypo- & • www.thyroidmanager.org hyperthyroidism. • http://www.thyroid.org/thyroid- • Trial of T3 in some. guidelines/hypothyroidism2014/ -- 2014 ATA Guideline on hypothyroidism treatment (draft). • Women & thyroid—preconception counseling.

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Contact Information Supplemental Info

David M. Schneider, MD Santa Rosa Family Medicine Residency [email protected] To Your Health With Dr Dave (Facebook)

I Thought Depression Occurred in Review of Thyroid Hormones HYPOthyroidism!

• Dysphoria, emotional lability, cognitive dysfunction, • T4 = thyroxine: • T3 = triiodothyronine: & depression are also well documented in – 99.97% protein bound – 99.7% protein bound hyperthyroidism. (2 ng/dL = free). (0.4 ng/dL = free). – Produced exclusively by – 80% comes from thyroid. conversion of T4 → T3 in – Half-life ~ 1 week. peripheral tissues. – ~10 X more prevalent in – Half-life ~ 1 day. serum than T3. – 3-100 (~10) times more potent than T4.

http://www.thyroidmanager.org/chapter/assay‐of‐thyroid‐hormones‐and‐related‐substances/ SouthMedJ 2007;100(8):773‐4; AnnuRevMed 1986;37:205‐14

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Laboratory Findings in Hyperthyroidism Antibodies in Graves’ Disease

• Anemia – normochromic/normocytic. •Thyroid Stimulating Antibodies (TSAb) = Thyroid – plasma volume >  RBC mass Stimulating Immunoglobulin (TSI). • Leukocytosis. –1 of 3 types of TSH-receptor antibodies; the others (TSBAb, TBII/TBAb/TRAb) do NOT the • Elevated transaminases (aminotransferases). stimulate thyroid. • Elevated alkaline phosphatase. –TSAb/TSI sensitivity 90 – 99%, specificity 99.6% (if • Low HDL. measured by sensitive assay). • Impaired glc tolerance. –Safe in pregnancy – RAIU is NOT.

Hepatogastroenterology 1997;44:1614‐8; http://emedicine.medscape.com/article/767130‐overview JCEM 1999;84:90‐7

Iodides in Treatment of Hyperthyroidism Practice Recommendations

• Potassium iodide (SSKI), iodine-KI (Lugol’s). • Use TSH as the main lab indicator for thyroid disease. • Inhibit thyroid hormone release. • Develop selective, rather than "blind" universal, screening • Short term, rapid restoration of euthyroid: protocols for patients, based on risk factors for hypo- and hyperthyroidism. – Severe hyperthyroidism/thyroid storm. • Be aware of, understand, and know signs and symptoms of • More I  more hormone synth   hyperthyroid. "apathetic hyperthyroidism" in the elderly. - • Wait  1 hr after MMI so I not used to synthesize T4. • Understand options for treatment of patients with –Preop – thyroidectomy for Graves’. hyperthyroidism, including which patients should be referred to –After radioablation – ? normalizes function faster. another practitioner, AND what Family Physicians must know and –Adjunct to MMI in Graves’— FT4 faster. do in order to prescribe antithyroid drugs. • Esophageal or duodenal mucosa injury.

BrJSurg 1985;72:45‐7; JCEM 2007;92:2182‐9; EndocrinolMetabClinNorthAm 2006;35:663‐86; JCEM 1983;57:250‐3; ClinEndocrinol(Oxf) 2010 Jun;72:845‐50; http://www.uptodate.com/contents/iodine‐in‐the‐treatment‐of‐hyperthyroidism?source=search_result&selectedTitle=1~150; InternMed. 2010;49:759‐1

176 23 Disclosures

• None What’s New in the 2015 CDC STD Treatment Guidelines

Ina Park, MD, MS California STD/HIV Prevention Training Center UCSF Dept of Family and Community Medicine STD Control Branch California Department of Public Health

Development of CDC STD Treatment Guidelines Outline • Overview of CDC STD Treatment Guidelines Answer the “Key Development Process Enlistment of Questions” • Top 10 updates for primary care providers Subject Matter Experts – 1) Screening recommendations for women – 2) Screening for men who have sex with men Rate the quality of the evidence – 3) Recommendations for GC/CT diagnostic tests Guidelines Systematic – 4) New-ish chlamydia treatment Key Meeting, Review of – 5) Changes to gonorrhea recommended/alternative therapy Questions April 2013 Evidence Identify critical gaps – 6) Partner management guidelines in knowledge – 7) Rescreening and HIV testing after an STD (research agenda) – 8) HPV vaccine Background papers – 9) Primary HPV screening Write the Tables of evidence – 10) New STI: Mycoplasma genitalium and Bonus: ? Ebola? Guidelines document Online: www.cdc.gov/std/treatment

177 1 1) STD Screening for Women 2) STD Screening for MSM* Sexually Active adolescents & up to age 25 Routine chlamydia and gonorrhea screening At LEAST annually: Other STDs and HIV based on risk •HIV • Syphilis Women over 25 years of age (non incarcerated) • Urine GC and CT (NAAT) STD/HIV testing based on risk (new partner, multiple partners, partner w/ other partners, • Rectal GC and CT (receptive anal) transactional sex, drug use) • Pharyngeal GC (receptive oral) Pregnant women • Hep C if IDU or other risk factor Chlamydia Anal Cancer in HIV+ MSM: Annual digital rectal exam Gonorrhea (<25 years of age or risk) may be useful, some centers perform anal Pap and HRA HIV More frequent (3-6 months) if patient t or their sex partners have Syphilis serology multiple partners, uses methamphetamine, or sexual performance HepBsAg enhancing drugs Hep C (if high risk) CDC 2014 (draft recommendations) CDC 2014 STD Tx Guidelines-Draft at www.cdc.gov/std/treatment

3) Vaginal Swab is preferred specimen type for women

NAATs recommended for detection of genital tract infections in men and women – with and without symptoms - highly sensitive and specific compared to culture - less dependent on specimen collection and handling

Diagnostics for GC/CT Optimal specimen types are: First catch urine for men, swabs for rectal/pharyngeal STDs in MSM Self collected vaginal swabs from women

178 2 4) Chlamydia Treatment Chlamydia Proposed Changes • Updated estimates: 2.8 million cases in US annually Additional Alternative Regimen (non-pregnant): Satterwhite, STD 2013 Doxycycline (delayed release) 200 mg QD x 7 d • Hetero male screening: Still not routinely recommended, – Equally efficacious to BID doxy, less GI side effects certain venues only (corrections, STD clinics, etc) – More $$$$ • Addition of a new (ish) treatment regimen Recommended treatment (non-pregnant): Proposed Alternative Regimen (PREGNANCY):  Azithromycin 1 g orally in a single dose Amoxicillin 500 mg po TID x 7 days  Doxycycline 100 mg orally twice daily for 7 days - CT persistence documented in vitro after treatment prompted removal from recommended to alternate Recommended treatment (pregnant): Azithromycin 1 g orally in a single dose Amoxicillin 500 mg po TID x 7 days

Gonorrhea Treatment Pre-Antibiotics

5 weeks of rest Avoid sex Avoid alcohol Still recommended today

Urethral Dilation 2 weeks of urethral irrigation

179 3 5) Gonorrhea Dual Therapy Uncomplicated Genital, Rectal, ARS audience poll: or Pharyngeal Infections • A 25 year old MSW was treated presumptively for urethritis with Azithromycin azithromycin. 1 g orally Ceftriaxone 250 mg IM PLUS* • His GC test result returns positive 4 days in a single dose (preferred) or later, what do you do??? Doxycycline 100 – Do nothing, the azithromycin alone is good • Regardless of CT test result mg BID x 7 days enough Proposed: Move doxycycline from – Treat him with just ceftriaxone recommended to alternative for dual therapy – Treat him with ceftriaxone and azithromycin CDC 2010 STD Treatment Guidelines www.cdc.gov/std/treatment

Gonorrhea Treatment Alternatives What does dual therapy mean? Anogenital Infections

• Ceftriaxone and azithromycin ALTERNATIVE CEPHALOSPORINS: administered on the same day  Cefixime 400 mg orally once PLUS • Preferrably simultaneously and under  Dual treatment with azithromycin 1 g (preferred) or direct observation doxycycline 100 mg BID x 7 days, regardless of CT

IN CASE OF SEVERE ALLERGY: Gentamicin Azithromycin 240 mg 2IM g ororally + azithromycin once 2g PO (Caution:OR GI intolerance, emerging resistance) Gemifloxacin 320 mg orally + azithromycin 2g PO

180 4 Alternative Urogenital GC Regimens Any downside to the new  Non-comparative randomized trial in adults with urethral regimens? or cervical gonorrhea 1. Gentamicin 240 mg IM + azithromycin 2 g PO, or Nausea was common 2. Gemifloxacin 320 mg PO + azithromycin 2 g PO 27% for gentamicin + AZ,  Rationale for regimens 37% for gemifloxacin + AZ . Additive effect between gentamicin and azithromycin (in vitro) . Gemifloxacin more active against GC with known ciprofloxacin resistance 3% and 7% in each group . Drugs already available in U.S. vomited <1hr after  Per-protocol efficacy: . Gentamicin + AZ=100% (202/202) administration . Gemifloxacin + AZ=99.5% (198/199)

Kirkcaldy, CID 2014

Kirkcaldy, CID 2014

Suspected GC Treatment Failure After Cephalosporin treatment failures Recommended Dual Therapy What do I do? • Oral cephalosporin treatment failures CULTURE: if GC culture not available call your local health reported worldwide department STD controller – Japan, Hong Kong, England, Austria, Norway, France, South Africa, and Canada REPEAT TREATMENT: Gemifloxacin 320 mg + AZ 2g OR gentamicin 240 mg IM + AZ 2g • Ceftriaxone treatment failures in pharyngeal REPORT: To your local health department STD program within 24 gonorrhea and a few isolates with high-level hours, or call CDC 404-639-8659 for advice ceftriaxone resistance reported TREAT PARTNERS: Within 60 days with same regimen as patient receives

TEST OF CURE (TOC): Patient returns in 7-14 week for TOC culture and NAAT Unemo Eurosurveillance 2011 | Tapsall J Med Microbiol 2009 | Ohnishi EID 2011 | Allen JAMA 2012 * If reinfection suspected instead of treatment failure, OK to repeat treatment with CTX 250 + AZ 1g

181 5 CT/GC Partner Treatment

ARS question 6) Partner Management Recs • You diagnose a 22 yr old female with chlamydia and ask her to come in to be treated with azithromycin. She has 1 • Clinical evaluation first‐line option (but traditional male partner, who is not currently your patient. What are referral has low rates of partner treatment) the most effective ways to ensure he is treated? Concurrent patient‐partner therapy may be effective – Have her bring is him with her when she is • for patients with one partner treated. Offer Expedited Partner Therapy routinely to – Tell her to encourage her partner to see a • heterosexual pts with CT/GC if partner cannot be provider promptly treated (multiple RCTs showing efficacy) – Give her medication or a prescription for her Dual therapy (cefixime 400 mg + azithromycin 1 g) is partner without evaluating her partner – crucial if this is offered – More than one of the above

182 6 Legal Status of Expedited Partner Therapy, 9/2014 ARS question

Have you used expedited partner therapy?

YES

NO

Repeat Infection is Common and Repeat Infections Dangerous . 15% of women with Or the STD CT are reinfected in . Repeat CT infection leads to higher risk of complications: PID, ectopic

pregnancy, infertility Risk Relative . Most infections are asymptomatic

Hillis SD, et al. (1997). Am J Obstet Gynecol 176(1 Pt 1): 103-7.

183 7 7) Rescreen for STDs and HIV Proposed: Women who test positive for CT/GC, or trichomonas should be rescreened three months following treatment. Men who test positive for chlamydia or gonorrhea should be HPV 101 rescreened at three months after adequate therapy. Over 170 types of HPV classified Updated incidence/prevalence estimates (CDC): All patients with a bacterial STDs or • 14 million new infections per year trichomonas should be tested for HIV • 79 million people infected in the US

deVilliers, 2013, Virology Satterwhite, 2013, STD

8) HPV Vaccines Reduction in pre-cancer endpoints Bivalent: GSK Cervarix® Nonavalent vs quadrivalent vaccine • Types 16, 18 • Prevents cervical cancer Endpoint Nonavalent Quadrivalent % reduction • FDA-approved for females 10-25 n=7099 n=7105 • 3-dose series; $365 CIN 2/3 or AIS, 1 30 96.7% Quadrivalent: Merck Gardasil® VIN2/3, VaIN 2/3 (80.9-99.8) • Types 6, 11, 16, 18 Non-inferior immunogenicity for types 6/11/16/18 • Prevents warts, cervical cancer, anal cance • FDA-approved for females and males 9-26 • 3-dose series; $375 Nonavalent: Merck V503 • Types 6, 11, 16, 18, 31, 33, 45, 52, 58 CIN = Cervical Intraepithelial Neoplasia AIS = Adenocarcinoma in situ VIN = Vulvar Intraepithelial Neoplasia VaIN = Vaginal Intraepithelial Neoplasia • FDA biologics license application Dec 2013

Merck, EUROGIN Abstract SS 8-4, Nov 2013 Gardasil PI. Cervarix PI.

184 8 Estimated HPV Vaccine Uptake*, Girls Ages 13-17 National Immunization Survey-Teen (NIS-Teen), 2007-2013. 2007 2008 2009 2010 2011 2012 2013 100 90 80 70

60 53.857.3 53 50 48.7 44.3 40 37.2

30 25.1 20

Estimated Vaccine EstimatedCoverage Vaccine (%) 10 0 13 14 15 16 17 Overall Age

* ≥ 1 dose of HPV Vaccine

MMWR: 2008 / 57(40):1100-3; 2009 / 58(36):997-1001; 2010 / 59(32):1018-23; 2011 / 60(33):1117-23; 2012 / 61(34):661-77; 2013 / 62(34):685-93; 2014 / 63(29): 620-633.

9) RIP to the PAP? 10) New bugs: Man with a “Drip”

• A 23 yo male presents for evaluation of a urethral discharge • March 2014: Roche HPV testing with 16/18 without dysuria genotyping recommended 13-0 by FDA • He has been seen in STD clinic 15 times between advisory panel 5/22/12 and 9/2/14 – Sometimes visible discharge on exam, sometimes • Would replace Pap starting at 25 years of age not • Larger FDA body agreed with advisory panel – On 9 occasions a urethral Gram stain performed • Professional societies (ASCCP, ACS, etc) • 5 times <5PMN/hpf decide whether to recommend it in national • 4 times >5PMN/hpf – GC documented 5/23/13, otherwise, tested for GC guidelines and CT at each of the 15 visits and always negative • Most recently treated with 1gm Azithromycin orally once; partner received treatment; GC and CT neg

185 9 Today he presents with thick, white ARS: What is your next step? discharge…now what? •1) Give up • 2) Give him longer course of azithromycin • 3) Get a urine culture • 4) Try a different antibiotic • 5) Get a consult from ID • 6) More than 1 of the above

Source: Diepgen TL, Yihune G et al. Dermatology Online Atlas

10) New Section: Mycoplasma M. genitalium genitalium More common than you think

Young adults 18-24 yrs1,2 STD Clinic/ED Attendees3-9

3.8% 22.4% 19.2% 19.2% 2.1% 15.2% 13.4% 1.0% 12.1% 0.6% Prevalence 7.0%

MG CT GC TV

Seattle New Cincinnati Baltimore Durham Orleans Men Women

3 4 ; 5 6 7- 1 Miller 2004; 2 Manhart 2007 Totten 2001; Mena 2002 Manhart 2003; Huppert 2008; 8Gaydos 2009a & 2009b; 9Mobley 2012 L. Manhart, with permission

186 10 M. genitalium & Reproductive Detecting MG infections? Tract Disease No FDA-approved diagnostic test • Definitely associated with NGU in men • Study of association with: • Hologic Gen-Probe TMA assay . Cervicitis – Research use only . PID . Infertility • Commercial Laboratories & PCR tests . Preterm delivery – Limited test-performance information • Summary OR = ~2.0 for all conditions . Statistically significant for all but infertility

L. Manhart, with permission Lis et al., unpublished data L. Manhart, with permission

MG cure rates MG Treatment with doxycycline and azithromycin Moxifloxacin 400mg po x 7-14d Randomized Trials Doxycycline (100mg bid x 7d) vs. Azithromycin (1g)  Highly effective for treatment failures

87% o 100% cure rates in most places 67% Doxycycline 45% Azithromycin 40%  Public health 340b pricing available 31% 30% o Usual price for 7 day course ~ $100+ Negotiated price to $1.21/pill Mena 2009 Schwebke 2011 Manhart 2013 o Microbiologic Microbiologic Cure CONCLUSION: AZM (1g) is superior to DOX (100mg bid x 7d).  Caveat: Moxifloxacin treatment failures emerging However, efficacy of AZM is not consistently high and may be (Japan, Seattle, Australia) declining L. Manhart, with permission L. Manhart, with permission

187 11 Persistent NGU Treatment (proposed) Epilogue If azithromycin NOT given for 1st episode: Azithromycin 1 g orally in a single dose • Patient takes moxifloxacin 400 mg po x 7 PLUS days. Metronidazole 2 g orally in a single dose OR • Symptoms finally resolve. Tinidazole 2 g orally in a single dose

If azithromycin given for 1st episode: • Take home point: Think about M.  Moxifloxacin 400 mg orally qd x 7d genitalium in cases of cervicitis and PLUS urethritis treatment failure. Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose

Bonus: Is Ebola an STI? Ebola updates • Story leads: ‘An Indian man who survived Ebola was quarantined when his blood tested negative but his semen tested positive.’

188 12 Ebola updates Ebola updates • Ebola has been detected in blood, and • After a negative blood test for Ebola, many body fluids: semen can test positive for up to 3 – Saliva months. – Mucus • The testes are considered –Vomit immunologically ‘privileged’ sites; easier – Feces – Sweat for virus to hide from immune system – Tears • Theoretically Ebola could be transmitted – Breast milk via semen, but there have not been any –Urine documented transmissions via this route – Semen

Want to know more about STDs? Ebola updates There’s an app for that.

CDC Treatment Guidelines App for Apple • CDC advises men who have recovered and Android from Ebola to abstain from sex (including oral sex) for three months. Available now, FREE!

• If abstinence is not possible, condoms (Search “STD TX” on app should be used. store)

189 13 Download the app now…

Any burning questions?

Thank you!!

Contact information [email protected]

190 14 12/4/2014

 Nearly 20% of febrile infants have “fever without a source” (FWS)  A few, although well‐appearing, have an occult bacterial infection: . UTI: Most common, simple to dx/treat . SBI (bacteremia/meningitis): Harder to diagnosis, worse to miss, decreasing in prevalence Andi Marmor, MD, MSEd UCSF Associate Professor, Pediatrics December, 2014

 Do all neonates need the full ROS workup?  Rhizobium (“Rizzo”) is a 15 day old boy whose  What counts as a fever “source”? mother reports that he felt warm today  If urine is +, do I need to do an LP?  The whole family has a cold, and Rizzo has  What is the role for labs –CBC, CRP, PCT? coughed a few times  When and how should fever be treated?  VS: T 37.9 (R), P 145, R 35, BP 70/40  Slightly fussy, but normal exam, feeding well

191 1 12/4/2014

 Parents better at ruling out A. Unreliable than ruling in B. As accurate as a rectal temperature . UTI/SBI more likely with C. More sensitive than specific documented fever than D. Usually due to over‐bundling with reported1  Vaccines? . One time fever . May occur 1‐3 day later

1Yarden-Bilavsky, 2010

 Neonates with FWS have high risk of bacterial infection 13‐18% 2‐3%  Occult infection: 15‐20% Better GBS screening? . ~90% of these are UTI’s . Bacteremia with UTI is common (10‐15%)  Has the epidemiology of UTI/SBI in neonates changed?

Greenhow et al, Pediatr Infect Dis J; 2014

192 2 12/4/2014

A. S. pneumo, H. influenza, N. meningitidis B. E. Coli, S. pneumo, Group B Strep C. E. Coli, Group B Strep, Listeria D. E. Coli, Group B Strep, S. aureus E. Group B Strep, S. pneumo, H. influenza

TABLE 3 . Bacterial Pathogens Detected in 129 Blood, 823 Urine and 16 CSF Cultures

 Notice anything missing?

Greenhow et al, Pediatr Infect Dis J; 2014

A. S. pneumo, H. influenza, N. meningitidis  E. Coli the most common cause of all types of B. E. Coli, S. pneumo, Group B Strep bacterial infections C. E. Coli, Group B Strep, Listeria  Staph and enterococcus are emerging D. E. Coli, Group B Strep, S. aureus pathogens E. Group B Strep, S. pneumo, H. influenza  Listeria is no longer a major player  Amp/Cefotaxime remains a good choice . Cefotaxime for broad GP and GN coverage . Amp for enterococcus (not listeria!)

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Schwartz, 2009  Clinical appearance, WBC: poor predictors • Risk of UTI/SBI decreases with age • Reliability of ill appearance increases with age Greenhow et al, Pediatr Infect Dis J; 2014

 Ill appearance/low‐risk criteria are not reliable  In general: collect urine, blood and CSF for in neonates culture, and start broad‐spectrum antibiotics  UTI is the most common bacterial infection . Ampicillin/cefotaxime  E. coli is the most common cause of ALL  Risk stratification/observation can be UTI/SBI in neonates considered in select circumstances . GBS the major cause of non‐UTI SBI . Multiple reassuring factors (eg: no documented . Enterococcus, staph are emerging pathogens fever, + viral infection AND LRC met…)

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 You decide to get a CBC and blood culture, a 1. Start antibiotics, admit cath UA/culture and a rapid flu/RSV test 2. LP, antibiotics, admit  Results: 3. No LP, no antibiotics, admit for observation . WBC 15, with 33% neutrophils overnight . CRP is 1.2 mg/dL 4. Observe clinic/ED for 12 hours for fever . Rapid viral test positive for influenza . Cath U/A negative

  Rochalimea is a 7 week old girl with cough UTI and fever for 2 days at home . Common in girls and uncircumcised boys (10‐15%)  VS: T 38.9, P 150’s, R 30’s, O2 sat 100%  SBI (1‐2%)  On exam, she is well‐appearing, lungs are . S. pneumo becomes the predominant pathogen clear, she has slight crusting at the nares, no . Significant decrease since S. pneumo vaccination other findings . Still a few cases of E. Coli, GBS, others

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A. Nasal wash for RSV  Focal bacterial infection (otitis B. Nasal wash for influenza media, cellulitis) C. Chest Xray . Consider further W/U in neonates D. CBC and blood culture  Named viral infection (bronchiolitis, croup) E. Cath urine for UA and culture OR + viral test . Infants < 3 months: still consider UTI . Infants > 3 months: SBI/UTI unlikely  Clear URI symptoms in infants > 3 mo of age

A. Nasal wash for RSV  You obtain a cath urine sample on B. Nasal wash for influenza Rochalimea C. Chest Xray . UA 2+ for LE, + nitrites D. CBC and blood culture  Due to her age, you decide to get a blood E. Cath urine for UA and culture culture and admit her for pyelo  Do you need to do an LP before starting abx?

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  Bacteremia is frequent in infants < 3 mo with Anaplasma, a 2 mo old boy, presents to the ED febrile UTI (10‐15%) with 2 days of tactile fever, no other symptoms  However, meningitis with UTI is extremely . Unimmunized rare in well‐appearing infants . Circumcised ’ . A few cases of meningitis with UTI in well‐  T= 38.9, P 150, R 40 s, BP 90/65 appearing neonates been reported . Well‐appearing, well‐hydrated  LP is not recommended routinely in infants >  UA negative 1 mo if treating for pyelo  RVT negative for influenza/RSV

Paquette, 2011

Least abnormal

 UTI: Urinalysis  Meningitis: CSF cell counts  Pneumonia: Clinical diagnosis/CXR  Bacteremia: Blood culture . The only REALLY occult SBI ! Andreola, 2007 Screening Most abnormal

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 Most useful in infants 1‐3 mo of age  You send a CBC and CRP:  Best for ruling OUT SBI in low‐moderate risk . WBC 16.7 (5‐15), CRP 5.0 mg/dL (< 3) infants  Next step?  Does NOT reliably R/O UTI ( but we have another test for that)  May have selective utility in otherwise low‐ risk neonates . Only when it will change management…

 Screen for UTI in all infants <3 mo with FWS  Screen for UTI selectively based on . If UA +, get blood culture and treat for UTI age/gender . If UA negative consider RVT . Uncircumcised boys < 6 mo of age  If UA and RVT neg, labs can help stratify risk of . Girls < 24 mo of age, if fever > 48 hrs SBI  Otherwise, infants > 3 mo are at low risk for . LOW risk for SBI if occult SBI ▪ WBC count 5‐15K . Even unvaccinated infants are protected ▪ PCT < 0.2 ng/ml . Empiric labs/antibiotics NOT recommended ▪ CRP <2.0 mg/dL

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A. Reduce discomfort/metabolic stress  Benefits of fever? B. Reduce risk of seizures . Suggested in animal C. Document fever’s response to antipyretics studies, ICU pts D. Decrease risk of brain damage  Dangers of fever? E. Help the immune system fight infection . Discomfort, increased metabolism, fluid loss . NOT febrile seizures . Fever phobia

 < 50% of parents can define fever (> 38.5 C)  Primary benefit is comfort  15‐40 % think fever can cause brain damage, . In ED: may make child easier to assess! seizure or death . Does not prevent febrile seizures!  Antipyretic dosing errors common  Ibuprofen safe, well‐tolerated and effective  Social/ethnic differences . Use acetaminophen if ibuprofen contraindicated . Latino parents: most concerned, prefer tactile . Alternating NOT recommended . AA parents: most likely to overdose antipyretics . Sponging/cooling not effective and may cause . Lower level of education = higher fever concern hypothermia

Cohee (2009), Poirier (2010)

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 Do all neonates need the full ROS workup?  Do all neonates need the full ROS workup? . While SBI less common, ill appearance/low‐risk  What counts as a fever “source”? criteria still not reliable in neonates . In infants > 1 mo, named bacterial, viral illness OR . Observation without antibiotics only in very select + RVT can be considered a source circumstances (‐UA, +RVT, well, etc)  If urine is +, do I need to do an LP?  What counts as a fever “source”?  What is the role for labs –CBC, CRP, PCT?  If urine is +, do I need to do an LP?  When and how should fever be treated?  What is the role for labs –CBC, CRP, PCT?  When and how should fever be treated?

 Do all neonates need the full ROS workup?  Do all neonates need the full ROS workup?  What counts as a fever “source”?  What counts as a fever “source”?  If urine is +, do I need to do an LP?  If urine is +, do I need to do an LP? . Not in a well‐appearing infant > 1 month  What is the role for labs (CBC, CRP, PCT)  What is the role for labs –CBC, CRP, PCT? . Infants 1‐3 mo, without viral source or UTI  When and how should fever be treated? . CRP/PCT more sensitive/specific than CBC  When and how should fever be treated?

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 Do all neonates need the full ROS workup?  Neonates  What counts as a fever “source”? . High risk of UTI/SBI, labs/clinical exam unreliable  If urine is +, do I need to do an LP? . Generally should be tested/treated/admitted  What is the role for labs –CBC, CRP, PCT?  Infants 1‐3 mo  When and how should fever be treated? . Test for UTI in all infants < 3 mo . When child is uncomfortable/distressed . If viral source and/or normal serum inflammatory . Ibuprofen preferred markers = reassuring against SBI . Educate parents on treatment/supportive care!  Infants > 3 mo . Selective testing for UTI only

201 11 PROVIDER APPS

I. DRUG REFERENCE 1. Epocrates Cost; Platforms Free ; iPhone, iPad, Android, Web • Pill ID, Drug Interactions, Drug Information, Formulary (including all Medicare Part D formularies) • Provider Directory: Access to an extensive network of over 700K U.S. physicians. 2. Micromedex Cost; Platforms $2.99 annual subscription; iPhone, iPad, or Android Features • Drug interactions, Contraindications, Dose adjustments, Mechanism of action II. MEDICAL LITERATURE 1. READ by QXMD: Cost; Platforms Free ; iPhone, iPad, Android, Windows, not web Features • Allows users to link their institutional account to the app and customize a feed of journal articles by following different journals and/or different specialties. • Annotate articles as you read, save them to come back later, send them to colleagues or yourself. 2. Docphin Cost; Platforms Free, if your institution is a member ; iPhone, iPad, Android, Windows, Web Features • Allows users to curate a feed of their favorite medical journals and news/media sources, highlighting articles related to their chosen specialties. 3. NEJM This Week Cost; Platforms Free; iPhone, iPad Features • Access NEJM recent articles, images, audio, and video III. MEDICAL CALCULATORS 1. CALCULATE by QXMD: Cost; Platforms Free ; iPhone, iPad, Android, Windows, not web Features • 150 calculations, including: o BMI and BSA o Due date and gestational age o eGFR with CKD-Epi, Cockcroft-Gault, & MDRD o Framingham and Reynolds Risk Scores o CHADS2 and CHA2DS2-VASc score • References with Pubmed Integration 2. MedCalc Cost; Platforms $4.99 ; iPhone, iPad, Android Features • +300 relevant formulas, scores, scales and calculations • Detailed bibliographic references • Customizable list of favorite equations Others Archimedes through Skyscape; MediMath; MedMath IV. GENERAL REFERENCE 1. UpToDate Cost; Platforms Free if your institution has a “UpToDate Anywhere” subscription ; $499/year for individual subscription; iPhone, iPad, Android, Windows, not web Features • Same UpToDate, in mobile app form 2. Medscape Cost; Platforms Free; iPhone, iPad, Android, Windows, not web

202 Features • Fast drug reference tools. • Evidence-based disease & condition reference. • Medical news by specialty. • Engaging continuing medical education courses. • # 1 downloaded app for medical providers 3. Essential Evidence Cost; Platforms $85/year; App through browser Features • Evidence-based clinical decision support system with access to +13,000 topics, guidelines, abstracts, and summaries • Get Daily POEMs (summaries of important peer-reviewed articles) delivered to your email • NOT a native mobile app—used through browser 4. Dynamed Cost; Platforms Variable[$99.99 Student, $149.95 Resident, $199.95 Licensed Medical Practitioner, $395 Physician]; iPhone, iPad, Android Features • Continuously updated (versus UpToDate updated quarterly) • No cellular connection required after download • Individual subscription is cheaper than UpToDate • Not as easy to use, less comprehensive IV. TREATMENT GUIDELINES 1. ACP Clinical Practice Guidelines Cost; Platforms Free; iPhone, iPad, Android Features • Access to all ACP’s evidence-based clinical practice guidelines 2. CDC STD Treatment Guidelines Cost; Platforms Free ; iPhone, iPad, Android Features • Diagnosis and treatment of 21 STDs and sexual assault. • Access to the full STD Treatment Guidelines. • "A Guide to Taking a Sexual History" 3. OB Guide – Washington University Cost; Platforms $1.99 ; iPhone, iPad, Android Features • Quick reference manual for OB. • +50 sections of various pathologies, clinical situations, calculations related to OB • Cumbersome PDFs 4. Eyes Have it Cost; Platforms $4.99; iPhone, iPad Features • Pocket reference for eye pathology in a primary care, urgent care, or ER setting. • Pictures & videos with short, concise explanations. • From University of Michigan MD 5. SAMHSA Suicide Safe: Prevention App –coming soon Cost; Platforms Most likely Free; iPhone, iPad, Android Features • Provides access to SAMHSA’s Behavioral Health Treatment Services Locator to provide timely referrals for patients. • Offers tips for talking with patients about their suicidal ideation. • Includes Suicide Assessment Five-Step Evaluation and Triage (SAFE-T) card V. SCREENING & PREVENTION 1. AHRQ EPSS Cost; Platforms Free; iPhone, iPad, Android Features • Allows targeted search for recommendations for a particular patient based on age, gender, pregnancy status, sexual activity, and tobacco use • Reviews the USPTF recommendations & the information behind recommendations

203 2. CDC Vaccine Schedules Cost; Platforms Free; iPhone, iPad, Android Features • Immunization recommendations from birth – 18, adult schedules, & catch-up schedules 2. CDC Yellow Book Cost; Platforms Full version $9.99; iPhone, iPad, Android Features • Reference for international travel vaccination recommendations VI. BILLING 1. IMO Terminology Browser Cost; Platforms Free; iPhone, iPad, Android Features • Searchable ICD-9-CM, ICD-10 (CM, CA, WHO), SNOMED CT®, MeSH, UMLS, HCPCS, CPT® 2. ICD9 Consult 2014 Cost; Platforms Free, iPhone, iPad, Android Features • Searchable Complete 2014 ICD9-CM diagnosis codes and 2008 ICD9-CM procedure codes, with all subcodes VII. CME 1. ABFM Exam Prep Cost; Platforms Free; iPhone, iPad, Android Features • Practice questions for ABFM Maintenance of Certification Exam • General info about exam 2. CME Epocrates Cost; Platforms Free; iPhone, iPad, Android Features • Mobile, easy to use, and reasonable quality CME activities • also, Medscape & MedPage offer Free CME

PATIENT APPS I. Nutrition 1. Zipongo Platforms iPhone, iPad, Android Cost Free Features • Offers meal suggestions and grocery store discounts in your GPS area 2.My Fitness Pal Platforms Free; iPhone, iPad, Android, Windows Phone, Web Cost Features • Counts calories from 2 million food choices • Tracks exercises • Syncs progress to myfitnesspal.com 3.Fooducate Cost; Platforms Free; iPhone, iPad, Android Features • Pulls up nutritional information by scanning barcodes of a food item • Grades it on A-D with simple description • Offers healthy alternatives if needed II. Addiction 1. Step Away Cost; Platforms $4.99 ; iPhone, iPad, Android Features • Personal assessment of alcohol addiction • Users select high-risk locations for relapse • Note supportive persons, who are contacted by app • Record triggers and strength of cravings &provides strategies for dealing with cravings

204 From University of Alaska, funded by NIAAA

2. Craving to Quit Cost; Platforms $1 / day; iPhone, iPad, Android Features • 21 day program to quit smoking • Interactive tools for tracking smoking • Daily guided mindfulness practices • Push reminders throughout the day of personal goals From UMass, Dr. Judson Brewer, MD Brewer, J. A., Elwafi, H. M., & Davis, J. H. (2013). Craving to quit: Psychological models and neurobiological mechanisms of mindfulness training as treatment for addictions. Psychology of Addictive Behaviors, 27(2), 366. III. Kids & Parents 1. Text4Baby Cost; Platforms Free; iPhone, iPad, Android, any SMS Features • Free text messaging service for pregnant women and new mothers and fathers with +750,000 users • 3 informational messages a week tailored to the woman’s due date or baby’s date of birth • Covers: appointment reminders safe sleep, immunizations, breastfeeding, nutrition, oral health, family violence, physical activity, safety, injury prevention, mental health, substance abuse, developmental milestones, labor & delivery, car seat safety, and exercise. • Unlike many of these apps: o Over half of survey respondents (N=943) have income <$16,000. o At enrollment, higher percentage of participants lived in impoverished zip codes compared to the overall U.S. distribution. study done by the California State University San Marcos National Latino Research Center 2. Know Bullying Cost; Platforms Free; iPhone, iPad Features Tools for parents to start conversations with their children about bullying. Describes strategies to prevent bullying Provides tips how to recognize warning signs that a child is bullying or being bullied. 3. Asthma Care Tools4U Cost; Platforms Free; iPhone, iPad Features For kids with asthma to manage their own condition. Patients input asthma triggers & meds. Provides a personalized asthma action plan. Gives daily reminders to take medicine. 4. PoopMD Cost; Platforms Free; iPhone, iPad, Android • Created by an assistant professor at Johns Hopkins in Pediatric Gastroenterology. • App analyzes pictures of newborn’s poop to tell new parents whether their child’s BM is normal or not IV. Patient Support 1. Crohnology Cost; Platforms Free; Web only Features Self-report data sharing between patients with Crohn’s disease worldwide. Patients track symptoms & treatments. Allows patients to connect & share treatments & medication experiences. 2. PatientsLikeMe Cost; Platforms Free; Web only

205 Features Self-report data sharing between patients of similar demographics & diagnoses Patients can join groups of specific diagnosis populations: ALS, MS, Parkinson’s, HIV, fibromyalgia, mood disorders, etc.

V. Wearables 1. FitBit Flex; Charge Cost; Platforms $99.95; 149.99 (version with heart rate monitor); iPhone, iPad, Android Features • Worn around the wrist • Vibrating alarms • Tracks & logs your physical activity • Toggle to signify “sleep mode” • Passive/continuous Bluetooth syncing to App • 5 day battery life • Third-party integration (with other apps like Myfitnesspal and Pact).

App: • Allows you to manually log your food intake, sleep, exercise • Sets goals & sends reminders for sleep & activity • Fitbit has stated it will never integrate with Apple HealthKit

2. JAWBONE UP24 ; JAWBONE UP3 Platforms $149; $179 (version with heart rate monitor); iPhone, iPad, Android Features • Worn around the wrist • Vibrating alarms • Tracks & logs your physical activity • Toggle to signify “sleep mode” • Passive/continuous Bluetooth syncing to App • 7 day battery life • Third-party integration (with other apps like Myfitnesspal and Pact).

App: • Allows you to manually log your food intake, sleep, exercise • Sets goals & sends reminders for sleep & activity • App integrated with Apple HealthKit (which then has potential to integrate with Epic EHRs) • Does not require wearable • Example: Oschner Health in October announced its Epic system would link to Apple HealthKit 3. Android Wear: LG G Watch R Platforms $300 Android

206 Features • Worn around the wrist as watch • Links to your Android phone and displays notifications and text messages • Tracks & logs your physical activity • Heart rate monitor & barometric altimeter built in • Passive/continuous Bluetooth syncing to App • 1-2 day battery life

App: • Allows you to manually log your food intake, sleep, exercise • Sets goals & sends reminders for sleep & activity Others • Android Wear Moto 360 • Apple iWatch forthcoming in Spring 2015 • Basis Band • Nike Fuel SE

WEBSITE FOR REVIEWING MEDICAL APPS:

http://www.imedicalapps.com/

SAFE GUARDING YOUR PATIENT’S INFORMATION:

1. Hacked Apps a. The majority of healthcare apps have been hacked. The way that these apps have mostly been hacked is by hackers recreating/repackaging the app without its safety features and with the intention of gathering patient data.i b. Recommendations from iMedicalApps rd o Do not buy apps in 3 party app stores o Warn your patients from doing this o Don’t choose same password for electronic health record and your medical apps

2. Harboring Bacteria a. 30 iPads of faculty members tested at Northwestern University (16 inpatient, 14 outpatient)ii o MRSA: 64% of in-patient & 38% of outpatient o VRE and pseudomonas on 10% total b. What to do? iii o Disinfect the iPad with Sani-Cloth CHG 2% and Clorox wipes o DISCLAIMER: Apple does not recommend disinfecting your iPad, and may in fact invalidate your warranty.

i https://www.arxan.com/assets/1/7/State_of_Mobile_App_Security_2014_final.pdf ii Hirsch EB, Raux BR, Lancaster JW, Mann RL, Leonard SN. Surface Microbiology of the iPad Tablet Computer and the Potential to Serve as a Fomite in Both Inpatient Practice Settings as Well as Outside of the Hospital Environment.PLoS One. 2014 Oct 31;9(10):e111250. http://www.ncbi.nlm.nih.gov/pubmed/25360719 iii http://www.ncbi.nlm.nih.gov/pubmed/24746231

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