February 2019 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■IUS Safe and Effective ■■ Genetic Counseling in Ovarian Cancer ■■Improving TG, Cholesterol ADVISOR FORUM

Clinical Pearls STAT CONSULT

Human Immunodeficiency Virus (HIV) LEGAL ADVISOR

To Question, or Not to Question a Supervisor

DERMATOLOGY CLINIC

Hyperkeratotic Plaques in the Axilla

FREE CME COURSE

Public Health Implications of Drugs of Misuse and Abuse

FEBRUARY 2019

| www.ClinicalAdvisor.com

DERMATOLOGY

Actinic Keratoses: Field Cancerization and Photodynamic Therapy AKs are one of the most common lesions seen in dermatology practice.

Vice president, content, medical communications, editor Kathleen Walsh Tulley editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Senior production manager Krassi Varbanov Assistant manager, audience development Ashley Noelle Director of audience insights Paul Silver National sales manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Associate account manager Michael Deverin, 732.343.4921 michael.deverin@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317),Volume 22, Number 2, Published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2019

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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecUniversity of Pennsylvania School Physicians Dermatology blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision•on It p recurr•ent 44 THE ADVISOR AUGUST 2015 www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that enter infections. for glycemic impede the recept into There or blockers control in ability to cleans this decisio adults are FDA-appr n. Poor hygien are with diet and should the e and quell oved child have exercise, but with type 2 diabet e may appro phimosis, simpl infection potential. es appropriate the in ved for use in conjun 2:38 PM FDA has Moreover, AdvisorForum_CA0815.indd urine 44 e cathet patients with stated that 9/29/15ction culture can ketoacidosi steroid cream they are not type be a challenge. erization to obtain s, or those may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

OUR CO

NSULTA

PEARLS

NTS

VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

CAL ADVI

AdvisorForum_

CA0915

SOR • SEPTE

MBER 2015

Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

alAdvisor.c

Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

E-MAIL editor@clinicaladvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 1

CONTENTS FEBRUARY 2019

NEWS 8

Newsline ■■Intrauterine Levonorgestrel System Safe, Effective for

Pregnancy Prevention ■■Genetic Counseling Referral for Ovarian Cancer Survivors ■■No Benefit With Omega-3, Aspirin for Colorectal Adenoma ■■Cottonseed vs Olive Oil for Improving Cholesterol,

8 IUS Safe, Effective

Triglyceride Levels ■■Postmenopausal Fat and Increased Breast Cancer Risk ■■And more

FEATURES

35 Asymptomatic Trunk Nodules

16 CME Emerging Drugs of Misuse and Their Public Health Implications Given the increasing numbers of deaths associated with opioid overdose, major initiatives are underway in an effort to decrease the morbidity and mortality associated with the misuse and abuse of these drugs. 22 CME Feature Posttest

40 Human Immunodeficiency Virus (HIV)

24 Actinic Keratoses: Field Cancerization and Photodynamic Therapy Predicting the clinical course of actinic keratoses can be challenging, and no method exists for identifying lesions that will evolve into invasive squamous cell carcinoma. Continues on page 4

46 To Question, or Not to Question

Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App

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CONTENTS FEBRUARY 2019

DEPARTMENTS Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ IUS Safe and Effective ■ Genetic Counseling in Ovarian Cancer ■ Improving TG, Cholesterol ADVISOR FORUM

Clinical Pearls

THE CLINICAL ADVISOR • DECEMBER 2018

A PEER-REVIEWED| FORUM FOR NURSE PRACTITIONERS | DECEMBER 2018 FEBRUARY A PEER-REVIEWED 2019 | www.ClinicalAdvisor.com FORUM FOR NURSE PRACTITIONERS JANUARY 2019 | www.ClinicalAdvisor.com

NEWSLINE DERMATOLOGY

■ NICU Nursing Workload and Missed Care ■ Probiotic for Infant Colic ■ Digital Obesity Treatment

LEGAL ADVISOR

CONFERENCE ROUNDUP

To Question, or Not to Question a Supervisor

SABCS 2018

DERMATOLOGY CLINIC

Erythematous, Scaly Scalp Lesions

Hyperkeratotic Plaques in the Axilla

FREE CME COURSE

Public Health Implications of Drugs of Misuse and Abuse

Dermatologic Look-Alikes Small, Asymptomatic Nodules

Stat Consult Human Immunodeficiency Virus (HIV)

Evidence-Based Medicine ■ Physical Therapy vs Surgery for Meniscal Tears ■ GLP-1 Reduces Major CV Events in Patients With T2D, CVD ■ Assessment of Dual Antiplatelet Therapy After Stroke, TIA ■ Apixaban in Patients With ESRD and Atrial Fibrillation

Legal Advisor To Question, or Not to Question Your Supervisor

ADVISOR FORUM 39

Clinical Pearls Diabetic foot ulcers, dressing changes, nasogastric tube insertion, glucose testing, and more.

WGS analyzes the AKs are one of CASE PEDIATRICS entireSTUDY: genomic the most common

ADNA Casesequence of Floppy of Baby Fired for Refusing a Flu Shot lesions seen in an organism. Syndrome dermatology practice.

DERMATOLOGY CLINIC

FEATURE

Irritable Bowel Syndrome and Vitamin D

ADPKD can have a devastating effect on patients.

LEGAL ADVISOR

Terminated for Taking FMLA?

DERMATOLOGY CLINIC

Pigmented Growth on the Upper Back

VOLUME 21, NUMBER 12

Dermatology Clinic ■ Hyperkeratotic Plaques in the Axilla ■ Violaceous Flat-Topped Papules and Plaques

Guidance for Antibiotic Use in Myasthenia Gravis

An Incidental Finding of Hypercalcemia LEGAL ADVISOR

■ HBV Guideline Adherence ■ Ovarian Cancer Screening ■ Cesarean Delivery Rates

FEATURE

CASE STUDY

STAT CONSULT

Human Immunodeficiency Virus (HIV)

| www.ClinicalAdvisor.com

NEWSLINE CME: CASE STUDY CME: GENOMIC MEDICINE ■ Flu Vaccine in Pregnancy

ADPKD: Promising Actinic Keratoses: Advances in Management Treatment for a Rare, of Breast Cancer With Field Cancerization and Sequencing Inherited Disorder Photodynamic TherapyWhole Genome

FEATURE

Effect of Artificial Sweeteners on Obesity Risk in Children

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“If you must know, a pterodactyl brought you.”

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

CASE STUDY Clinical Advisor.com/CaseStudy Brady Pregerson, MD Case Study: Fever and Headache in an Adolescent Boy A 13-year-old adolescent is sent to the emergency department by his pediatrician for evaluation of fever and a frontal headache, both of which have been present for 6 to 7 days. The pediatrician had prescribed a 5-day course of amoxicillin for a diagnosis of sinusitis; however, the patient’s symptoms have not improved. The boy denies current nasal discharge but did have a cold about 3 weeks ago. Read the full case here: ClinicalAdvisor.com/ CaseFeverHeadache

Uterine Transplant From Deceased Donor Results in Successful Childbirth A successful live birth was reported in a patient with congenital uterine absence following uterus transplantation from a deceased donor, establishing proofof-concept for treating infertility with transplantation from deceased donors.

Food Deprivation During Fetal Development Linked to Early Menopause, Premature Ovarian Failure Compared with women not exposed to famine during fetal development, those who were exposed were found to be at higher risk of developing premature ovarian failure; a trend toward higher risk of early menopause was also noted in this group.

Negative Colonoscopy Findings Linked to Lower Risk of Colorectal Cancer, Related Deaths Colonoscopy with normal findings in patients with average risk of colorectal cancer was linked to decreased risk of colorectal cancer and associated mortality for more than 12 years.

ACC, AHA Publish Appropriate Use Criteria Guidelines for Peripheral Artery Intervention In publishing updated appropriate use criteria, the organizations hope to provide guidance to clinicians who may refer patients for revascularization therapy.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Is Bed Rest Necessary in Pregnancy? Although bed rest was once frequently advised in pregnancy, clinicians today routinely warn against bed rest for most pregnant patients due to potential negative effects.

MY PRACTICE ClinicalAdvisor.com/MyPractice Physician Responsibility to Combat “Fake News” in Medicine Now more than ever, healthcare professionals must be thoughtful when correcting false harmful misinformation for their patients.

6 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Check out some of our latest cases below!

DERM DX

Asymptomatic Blisters on a Child’s Upper Leg A 7-year-old boy presents with 2 asymptomatic blisters that developed acutely on his upper thigh. The lesions began as reddened patches less than 48 hours earlier. Needle puncture of the lesions resulted in drainage of a serosanguineous fluid with slight purulence. CAN YOU DIAGNOSE THIS CONDITION

• Cigarette burn • Erythema multiforme

• Bullous impetigo • Bullous pemphigoid

● See the full case at ClinicalAdvisor.com/DermDx_Feb19

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Assessing Flexion and Extension During Total Knee Arthroplasty A 74-year-old woman is referred for right total knee arthroplasty. AP radiograph shows arthritis with the knee in varus alignment. During surgery, femoral and tibial cuts are made, and trial implants are inserted. On movement with the trial implants, the knee is stable in flexion but does not fully extend. WHICH OF THE FOLLOWING APPROACHES WOULD MOST LIKELY BALANCE THE KNEE?

• Resect more distal femur • Decrease the polyethylene • Resect more proximal tibia liner thickness • Resect more posterior femur ● See the full case at ClinicalAdvisor.com/OrthoDx_Feb19

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 7

Newsline Intrauterine Levonorgestrel System Safe, Effective for Pregnancy Prevention

A LEVONORGESTREL 52-mg intrauterine system (IUS) was found to be safe and effective for pregnancy prevention, according to a study published in Obstetrics & Gynecology. Researchers assessed the efficacy and safety of a levonorgestrel 52-mg IUS in 1011 nulliparous and 438 parous women aged 16 to 45 years. Participants were healthy, sexually active (≥4 times per month), and had regular menstrual cycles (21-35 days without additional hormone use). Participants had scheduled follow-up visits with IUS presence confirmed by palpation or direct visualization of the strings; participants with unidentifiable strings underwent transvaginal ultrasonography at that visit and at subsequent annual visits. Participants also completed a diary for the first 2 years for daily recording of other contraceptive use and amount of bleeding per day.

Efficacy and safety data were collected through September 8, 2017; pregnancy rates were evaluated in women aged 16 to 35 years at study entry with successful IUS insertion who had at least 1 followup contact during IUS use. The 5-year life-table pregnancy rate was 0.92% (95% CI, 0.46%-1.82%). Nine pregnancies occurred in 4 nulliparous and 5 parous women, indicating life-table pregnancy rates of 0.83% (95% CI, 0.28%-2.50%) and 1.26% (95% CI, 0.51%-3.10%), respectively. Six (67%) pregnancies were ectopic, resulting in an ectopic pregnancy rate of 0.13 per 100 woman-years. Approximately half of patients experienced amenorrhea or spotting only during the last 90 days of the first year of IUS insertion, and 80% experienced amenorrhea, spotting, or light bleeding only. For participants who reported heavy menstrual flow at baseline, 53 of 145 (36.6%), 53 of 122 (43.4%), and 52

The IUS system is inserted into the uterus to prevent pregnancy.

8 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

of 102 (51.0%) reported amenorrhea or spotting only at 1, 2, and 3 years, respectively. Similarly, for participants who reported severe menstrual cramping, 26 of 62 (41.9%), 25 of 52 (48.1%), and 21 of 44 (47.7%) reported none or mild cramping at 1, 2, and 3 years, respectively. Overall, 1041 (66.4%) participants aged 16 to 35 years and 69 (47.3%) participants aged 36 to 45 years discontinued study participation, most frequently for an adverse event (n=293 [18.3%] and n=29 [19.2%], respectively), desire for pregnancy (n=228 [14.5%] and n=4 [2.6%], respectively), lost to follow-up or withdrawal of consent (n=226 [14.1%] and n=16 [10.6%], respectively), or relocation from a study site (n=102 [6.5%] and n=4 [2.6%], respectively).At least 1 adverse event was noted in 1438 (89.9%) participants aged 16 to 35 years and 136 (90.1%) participants aged 36 to 45 years; of these, 73 (4.2%) were serious, including ectopic pregnancies and 1 ovarian cyst surgical treatment. Overall, 322 (18.8%) of patients discontinued treatment due to an adverse event. Bleeding symptoms were the most frequent nonadverse events that resulted in IUS discontinuation; however, only 39 (2.2%) reported experiencing bleeding symptoms. Rates of discontinuation for bleeding events were low: 17 of 1714 (1.0%) participants in the first year, 13 of 1401 (0.9%) in the second, 5 of 1149 (0.4%) in the third, 2 of 965 (0.2%) in the fourth, and 2 of 819 (0.2%) participants in the fifth.A total of 7 (0.04%) participants attributed vaginal infection to the IUS and requested removal.

Genetic Counseling Referral for Ovarian Cancer Survivors TWO CASE-FINDING strategies for women with a history of ovarian cancer for referral for genetic counseling and DNA testing (GCT) showed promise, according to a study published in the British Journal of General Practice. A team of researchers from the Netherlands conducted a nonrandomized study to compare the efficacy of 2 pilot strategies targeted to find ovarian cancer survivors for GCT referral by their primary care providers. The first strategy (strategy A) required the clinicians to determine and refer eligible patients with a history of ovarian cancer without the support of additional communication technology; the second strategy (strategy B) required clinicians to identify patients electronically using information and communication technology (ICT). The percentages of patients who were contacted, referred by a clinician for GCT, and seen by a clinical geneticist were used to measure

Genetic counseling can inform decisionmaking in patients at risk for cancer.

the efficacy of each strategy. In addition, clinician and patient questionnaires were used to assess the acceptance of each strategy. Nineteen of 30 patients identified by strategy A and 39 of 94 identified by

strategy B were eligible for GCT referral by clinicians; 8 patients from each strategy were referred, and 5 were seen for GCT. Eleven of 36 patients approached clinical practices for strategy A and 21 of 46 did for strategy B. Reasons for desirability of the strategies were “clinical relevance of case finding and referral,” “easy to perform,” “[clinician was] the right person for case finding,” and “workability of the strategies”; these reasons were similar in both groups. Technical aspects of the strategies such as “too much work,”“ICT support should improve,” and “no ICT support required” were among the most common reasons for opposing desirability. Of 15 patients who used the opportunity to report on desirability of case findings, 13 patients claimed case findings by the clinician for referral for GCT were desirable predominantly because “knowing the increased risk is important for offspring.”

No Benefit With Omega-3, Aspirin for Colorectal Adenoma THE OMEGA-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin, in combination and separately, did not significantly reduce the proportion of individuals with at least 1 colorectal adenoma (polyp) in a population identified as being at high risk for colon cancer, according to a study published in the Lancet. A UK-based team of researchers assessed the effect of EPA and aspirin, either separately or in combination, on patients with sporadic colorectal neoplasia. The main outcome was the proportion of patients with 1 or more colorectal adenomas identified at surveillance colonoscopy.The patients (N = 709) were randomly assigned to 1 of 4 treatments: EPA-free fatty acid 2 g/d

(n=179), aspirin 300 mg/d (n=177), both treatments (n=177), or placebo (n=176) for 12 months. Of the participants with available adenoma outcomes, adenoma detection rates for the placebo, EPA, aspirin, and

adverse events were reported among 44% of participants in the placebo group, 46% in the EPA group, 39% in the aspirin group, and 45% in the combination treatment group.A total of 146 gastrointestinal (GI) adverse events were reported

A UK-based team of researchers assessed the effect of EPA and aspirin, either separately or in combination, on patients with sporadic colorectal neoplasia. combination groups were 61%, 63%, 61%, and 61%, respectively.There was no evidence for an effect for EPA or aspirin (risk ratios, 0.98 and 0.99, respectively). The majority of participants tolerated the EPA and aspirin. One or more

in the EPA group, while the placebo, aspirin, and combination groups each had 85, 86, and 68, respectively; 2 upper GI bleeding events were reported in the EPA group, 3 in the aspirin group, and 1 in the placebo group.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 9

Newsline

Cottonseed vs Olive Oil for Improving Cholesterol, Triglyceride Levels

Cottonseed oil has been linked to lower cholesterol levels.

A 5-DAY DIET regimen rich in cottonseed oil (CSO) was associated with improvements in cholesterol and triglyceride levels in healthy men compared with a diet rich in olive oil (OO), according to a study published in Nutrition Research. Researchers assessed the effect of a 5-day diet rich in either CSO or OO on fasting and postprandial lipid profiles in healthy-weight men (n = 15) between the ages of 18 and 45 years. During the baseline visit, height, weight, and body composition measurements were recorded, followed by indirect calorimetry to measure resting metabolic weight. Participants were then provided with a lead-in diet (50% carbohydrate, 35% fat, and 15% protein intake) that they were to complete for 3 days prior to the prediet testing visit. Participants recorded their food and beverage intake on a document that was later collected for evaluation. Following the lead-in diet, the researchers evaluated patient anthropometric measurements and extracted a 15-mL blood sample to assess total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Participants were then

provided with a high-fat liquid meal rich in either CSO or OO, following which blood samples were obtained; this process was then repeated. Participants then began the 5-day outpatient feeding trial of either CSO or OO, during which they consumed food prepared by the researchers and documented food intake for diet adherence. Total cholesterol was higher prediet vs postdiet in the CSO group (148.40 ± 6.39 vs 135.93 ± 6.31 mg/dL, respectively), whereas no differences were found in the OO diet (149.71 ± 6.38 vs 140.93 ± 6.92 mg /dL, prediet vs postdiet, respectively). Fasting HDL-C was lower prediet vs postdiet in the CSO group (46.67 ± 2.41 vs 50.24 ± 2.20 mg/dL, respectively); no significant change was found in the OO group (48.92 ± 2.44 vs 48.21 ± 1.92 mg/ dL). Fasting LDL-C was higher prediet vs postdiet in the CSO intervention (92.20 ± 5.57 vs 78.13 ± 5.60 mg/dL, respectively) but not in the OO intervention (91.14 ± 6.87 vs 85.64 ± 6.29 mg/dL, respectively). Fasting TG levels were significantly higher prediet vs postdiet in the CSO intervention (80.11 ± 4.91 vs 56.37 ± 5.46 mg/ dL, respectively), and there was a trend toward a significant difference in TG levels for the OO diet (74.51 ± 8.38 vs 64.08 ± 6.87 mg/dL, respectively). Postdiet comparisons revealed lower LDL-C levels after the CSO diet compared with the OO diet (78.13 ± 5.60 mg/dL vs 85.64 ± 6.29 mg/dL), as well as lower TG levels (56.37 ± 5.46 mg/dL vs 64.08 ± 6.87 mg/dL). “The results of this study reveal significant improvements in cholesterol profiles and both fasting and postprandial TG levels after a 5-day [high-fat] diet rich in CSO,” the authors concluded. “Conversely, the 5-day [high-fat] diet rich in OO did not change either cholesterol profiles or TG levels significantly.”

Cesarean Delivery Outcomes May Influence Early Childhood Weight MATERNAL DELIVERY choice may affect the risk of being overweight in early childhood, according to research published in JAMA Network Open. A team of researchers compiled data from the Growing Up in Singapore Toward Healthy Outcomes study, a prospective mother-child birth cohort study, to determine whether elective or emergency cesarean delivery was linked to risk of early childhood overweight. Elective and emergency cesarean delivery were analyzed separately against vaginal delivery. At 12 months, body mass index (BMI)-for-age z scores were calculated; BMI status was defined as z-score standard deviations of more than 1 and less than or equal to 2 for at risk of overweight and more than 2 for overweight. Of the 1237 recruited mother-child pairs, 727 (372 male newborns) were included in the primary study; 222 infants were born via cesarean delivery, of which 74 deliveries were elective. At age 12 months, 89 infants were at risk of being overweight, and 17 infants were overweight. After statistical adjustment, the investigators noted a significant link between elective cesarean delivery and risk of being overweight at 12 months (odds ratio [OR], 2.05). The association between emergency cesarean delivery and childhood overweight was unremarkable. Clinicians may be encouraged to discuss potential long-term implications of elective [cesarean delivery] on child metabolic outcomes with patients who intend to have children,” the authors noted.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 13

Newsline Postmenopausal Fat and Increased Breast Cancer Risk ELEVATED LEVELS of body fat in postmenopausal women was associated with an increased risk of invasive breast cancer, despite the presence of a normal body mass index (BMI), according to research published in JAMA Oncology. A team of US-based investigators conducted a long-term prospective study to determine whether there was a link between elevated body fat level and risk of breast cancer in women with normal BMIs. Demographic information, medical history, and lifestyle factors were recorded at the start of the analysis and body fat levels of eligible participants were measured with dual-energy x-ray absorptiometry (DXA) at baseline and 1, 3, 6, and 9 years. Review of medical records confirmed invasive breast cancer cases. A total of 3460 postmenopausal women with BMI varying between

18.5 mg/kg2 and 24.9 mg/kg2 underwent DXA measurements with a median follow-up of 16 years (range, 9-20 y); 182 breast cancer cases were reported and 146 were estrogen-receptor positive. For the highest quartile of whole-body fat and trunk fat mass, multivariable-adjusted

insulin, C-reactive protein, interleukin 6, leptin, and triglycerides, and lower levels of high-density lipoprotein cholesterol and sex hormone-binding globulin. “When considering an individual’s health, physicians generally assess BMI by absolute categorical levels,” the authors

A team of US-based investigators conducted a long-term prospective study in an ad hoc secondary analysis of the Women’s Health Initiative. hazard ratios for risk of invasive breast cancer were 1.89 and 1.88, respectively. For estrogen-receptor positive breast cancer, adjusted hazard ratios were 2.21 and 1.98 for whole-body fat and trunk fat mass, respectively. Women in the highest quartile of trunk fat mass had elevated circulating levels of

wrote. “As such, increased adiposity in an individual categorized as having normal BMI is likely to remain clinically unrecognized,” they continued.“Future studies are needed to determine whether interventions that reduce fat mass... might lower the elevated risk of breast cancer in this population with normal BMI.”

Persistence of Low-Value Colorectal Cancer Screening

PATIENTS WHO HAD undergone colorectal cancer screening reported being skeptical about physician-recommended cessation of such screening, even though the testing has not been found to be significantly beneficial for all patients, according to a study published in JAMA Network Open.

Patients are hesitant to discontinue screening despite lack of significant benefit.

A group of US-based researchers deployed a survey to patients in theVeterans Affairs health system to determine how older patients felt about discontinuing lowvalue colorectal cancer screening, defined as having small benefit based on quantitative estimates from hypothetical risk calculators. The primary outcome measured was response to the survey question, “If you personally had serious health problems that were likely to shorten your life, and your doctor did not think screening would be of much benefit based on the calculator, how comfortable would you be with not getting any more screening colonoscopies?” A total of 332 participants believed that life expectancy calculators were not at all reasonable tools to guide such decisions; 255 participants expressed that it was not at all reasonable to use colorectal cancer risk calculators to

14 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

guide screening-cessation decisions. The investigators calculated the odds ratio (OR) of factors linked to comfort with screening discontinuation including higher trust in physician (OR, 1.19), higher perceived health status (OR, 1.41), and higher barriers to screening (OR, 1.20). Greater perceived effectiveness of screening (OR, 0.86) and greater perceived threat of colorectal cancer (OR, 0.81) were factors linked to less comfort with discontinued screening. “The findings suggest that many veterans have strong preferences against screening cessation, even when given detailed information about why the benefit may be low,” the authors concluded. “Efforts to tailor screening recommendations ... [should be] accompanied by efforts to address underlying perceptions about the benefit of screening.” ■

CME FEATURED COURSE LEARNING OBJECTIVES After completing this activity, the participant should be better able to: • Identify emerging drugs of abuse, including natural opioids and synthetic opioids, synthetic cannabinoids, synthetic cathinones, and new and upcoming designer drugs  • Recognize the potential signs and symptoms associated with these emerging substances COMPLETE THE POSTTEST: Page 22

Shalon R. Buchs, MHS, PA-C Associate Director UF School of Physician Assistant Studies University of Florida Health Gainesville, Florida

Release Date: February 15, 2019 Expiration Date: February 15, 2020 Estimated Time to Complete: 45 minutes Maximum Credits: 0.75 AMA PRA Category 1 Credit(s)TM Accredited Provider: This activity is provided by Haymarket Medical Education. Program Description: Substance use, misuse, abuse, and diversion is a growing public health concern in the United States.  It is therefore important for healthcare providers to maintain a level of awareness in terms of current and emerging drugs of abuse. Although these substances contribute to the broad picture of substance-related morbidity and mortality and cost burden, regulation of these drugs remains an ongoing challenge. The purpose of this article is to educate and inform primary care clinicians of the potential signs and symptoms associated with these emerging substances so that they may be equipped to provide optimal care for their patients exposed to these drugs. Intended Audience: This activity has been designed to meet the educational needs of primary care health care professionals who will manage patients who may be exposed to drugs with potential for misuse. Conflict of Interest Disclosure Policies: In accordance with the ACCME Standards for Commercial Support, Haymarket Medical Education (HME) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. Faculty David W. Indarawis, MPAS, PA-C Director of Clinical Studies UF School of Physician Assistant Studies University of Florida Health Gainesville, Florida

All faculty have no relevant financial relationships to disclose. Nick Zittell Director, Grant and Content Development Haymarket Medical Education Paramus, NJ Mr. Zittell has no financial relationships with commercial interest(s). HME staff involved in the review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

Provided by

CME FEATURED COURSE: DAVID W. INDARAWIS, MPAS, PA-C; SHALON BUCHS, MHS, PA-C

Emerging Drugs of Misuse and Their Public Health Implications A growing number of prescription drug fatalities in the United States are occurring as a result of substance use, misuse, and abuse.

Substance misuse and abuse has become a public health crisis.

ubstance use, misuse, abuse, and diversion has become a leading public health concern in the United States.The American Public Health Association estimated that 15,000 Americans died from prescription drug overdose in 2015 alone.1 However, by 2016 the number of prescription drug fatalities had increased exponentially, with the US Department of Health and Human Services (DHHS) reporting 42,249 deaths that year from an opioid overdose.2 The Centers for Disease Control and Prevention (CDC), using data collected from the National Center for Health Statistics (NHS) during the Wide-ranging Online Data for Epidemiologic Research (WONDER) evaluation, found that 63,632 drug overdose deaths occurred in 2016, reflecting a 21.4% increase from 2015.3,4 Even more concerning was that the number of opioid overdoses increased 30% from July 2016 through September 2017 in 52 areas in 45 states; midwestern regions witnessed a 70% increase in opioid overdoses from July 2016 through September 2017, and a 54% increase in opioid overdoses was seen in large cities in 16 different states. In light of these harrowing statistics, the DHHS had declared in 2017 that the misuse and abuse of opioids has become a national public health epidemic.5 Substance misuse also harms our economy. The National Institute on Drug Abuse (NIDA) estimates that substance misuse and abuse cost the United States $232 billion in health care and $740 billion in overall expenditures to the economy.1 One of the goals of Healthy People

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CME FEATURED COURSE

Although many clinicians are informed about opioid abuse and its related morbidity and mortality, ongoing patient education is necessary. 2020 is to “reduce substance abuse to protect the health, safety and quality of life for all, especially children.”6 In the 1990s, pharmaceutical companies that were massproducing prescription opioids had assured medical providers that patients would not become addicted to prescribed opioids, leading to increased comfort of providers to prescribe these drugs at greater rates. This high rate of opioid prescription led to extensive misuse of both prescription and synthetic opioids before providers were aware that these medications could undeniably be highly addictive.5 Defining “Misuse” and “Abuse”

An expert panel from the Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) partnership conducted a systematic literature review in 2015 to identify how the words “misuse” and “abuse” should be used to guide prescription drug postmarketing adverse event surveillance.7 The ACTTION panel identified limitations to the tenth revision of the International Classification of Diseases (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision (DSM-IV-TR) definitions of misuse and abuse.7 Thus, standardization of these definitions was needed. According to Cheatle and colleagues from the panel, misuse is now defined as an “intentional therapeutic use of a drug in an inappropriate way.”Abuse is defined as “an intentional, nontherapeutic use of a drug or substance for the purpose of achieving a desirable psychological or physiological effect.”7 In 2013, the updated fifth edition of the DSM (DSM-5) listed several major changes, mainly combining abuse and dependence into a single category, substance use disorders (SUD).8 Although the DSM-5 changed the diagnostic terminology to SUD, the terms “abuse” and “misuse” largely continue to be used interchangeably because they have been adopted by national and federal authorities on the topic, including the US Food & Drug Administration (FDA), the Drug Enforcement Agency (DEA), and NIDA.6,9,10 Apart from the difficulty of incorporating the term SUD — and, more importantly, reducing the morbidity and mortality associated with prescription drug abuse — there is a need to develop a better understanding of the emerging drugs of abuse. As such, the focus is on natural and synthetic opioids, synthetic cannabinoids (K2/Spice), synthetic cathinones (“bath salts”), and new designer drugs, such as kratom and flakka. Natural and Synthetic Opioids

Today, the terms narcotic and opioid are used interchangeably; however, according to the DEA, currently the term opioid has

replaced narcotic because its meaning and the drug origin are less ambiguous. According to NIDA, the “opioid effect” is due to the binding of the drug to opioid receptors in the central nervous system (CNS), causing inhibition of ascending pain pathways, which alters the perception of and response to pain. Opioids produce generalized depression of the CNS, resulting in euphoria, decreased tension, and decreased anxiety. Opioids also are accompanied by a variety of undesired effects such as inability to concentrate, drowsiness, and apathy. Two types of opiates exist: those that occur naturally (opiates) and those that are synthetically derived.11 Opiates come from dried milk of the poppy plant, Papaver somniferum, and include opium, morphine, and codeine. Heroin is an opioid that is cultivated from the opium resin of morphine.11 Semisynthetic opioids are made from naturally occurring opium, such as morphine and codeine, and include heroin, oxycodone, hydrocodone, and hydromorphone.11 Synthetic opioids, alternatively, are fabricated in a laboratory and are commonly used to treat chronic, malignant, or severe pain. Examples of synthetic opioids include meperidine, fentanyl, and methadone.11 Opioids are available as tablets, capsules, patches, powders, and chunks; in liquid form for oral use in syrups or for injection; and as suppositories and lollipops.This class of drugs can be swallowed, crushed and sniffed, smoked, or injected.11 Kratom

Kratom (Mitragyna speciosa) is a tropical tree found in Southeast Asia, the leaves of which contain a psychoactive ingredient. The leaves are typically crushed and smoked, brewed with tea, or made into gel capsules.10 Two compounds in kratom leaves, mitragynine and 7-α-hydroxymitragynine, interact with opioid receptors, producing euphoria and sedation, and possibly decreasing pain.10 Kratom is known on the street as “Thang,” “Kakuam,”“Thom,”“Ketom,” or “Biak.” In the United States, the abuse and misuse of kratom have significantly increased in the last several years; however, according to NIDA and the DEA, this drug is currently not considered illegal. Kratom produces varied physiologic effects, including stimulant effects in low doses and sedative effects in high doses. Recently, the FDA commissioner, Scott Gottlieb, MD, published a statement on the scientific evidence related to opioidlike compounds found in kratom, emphasizing its potential for abuse.9 The FDA has identified the chemical constituents of substances at a molecular level by using 3-dimensional computer technology with PHASE (Public Health Assessment via Structural Evaluation) methodology.With PHASE, the FDA

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Although emerging drugs of abuse contribute to morbidity, mortality, and cost burden, regulation of these drugs remains an ongoing challenge. evaluates the molecular structure of a compound to predict how it can affect physiologic functions in the brain and body. During computational modeling, FDA scientists analyzed 25 of the most prevalent compounds in kratom and discovered that 22 of them bind strongly to mu-opioid receptors, in a manner similar to that of scheduled opioid drugs such as morphine derivates.12 What is the public health dilemma with a drug with which many providers may be completely unfamiliar? In May 2018, the CDC issued a national notification of a multistate (41) outbreak of Salmonella infection associated with kratom.13 At that time, 199 cases of people infected with an outbreak strain of Salmonella in kratom had been reported.13 Proponents of the herb say that kratom provides relief from pain, depression, and anxiety. Some scientists believe that it may hold the key to treating chronic pain and might become a tool to combat opioid addictions.12 In August 2016, the DEA announced that it would make kratom a Schedule 1 drug (like lysergic acid diethylamide [LSD] and heroin). The decision was deferred after Congress urged delay of the ban to give the public a chance to discuss and comment. Nationally, as of March 2018, the FDA had confirmed 44 reported deaths associated with the use of kratom, reflecting an increase from the 36 deaths reported in November of 2017.9 Synthetic Cannabinoids

Synthetic cannabinoids (SCBs), referred to as Spice and K2, are often considered a “legal high” and an alternative to marijuana, particularly because of their ability to escape detection on standard drug screening tests.14 SCBs have been manufactured to mimic classic marijuana but are much more potent.15 The greater potency can be attributed to many factors including variations in individual metabolism and a strong affinity of SCB for both CB1 and CB2 receptors.16 Various formulations of SCBs have been available to the public without age restrictions on the internet, in convenience stores, and in head shops. Many chemical and herbal combinations have been marketed as incense and air fresheners and are specifically labeled as not for human consumption, yet SCBs are increasingly common drugs of abuse and a cause of emergency department visits.15 Although some countries have been successful in identifying and categorizing SCBs as controlled substances, frequent structural modification makes maintaining control difficult.14 Symptoms and sequelae of SCB use include nausea, vomiting, dyspnea, hypertension, supraventricular tachycardia, syncope, acute kidney injury, hypokalemia, insomnia, agitation, suicidal

ideation, seizures, and cognitive impairment.17 Newer adverse effects related to SCB use include severe bleeding thought to be a consequence of lacing the synthetic drug with lethal vitamin K antagonist anticoagulants.18 Residual effects of SCBs are not well known.14,16 Synthetic Cathinones

Synthetic cathinones, more commonly referred to as bath salts, also stimulate the CNS and simulate effects of other drugs such as cocaine, methamphetamines, and ecstasy. In an effort to avoid regulation by the Federal Analogue Act (a section of the US Controlled Substances Act), manufacturers will market these drugs as bath salts, research chemicals, plant food, or glass cleaner, with direction that these substances are not for human consumption.19 Bath salts and other synthetic cathinones are typically manufactured in East Asia and sold wholesale in North America in places such as smoke shops, gas stations, and head shops.19 According to the DEA, common street names of these drugs are bliss, blue silk, cloud nine, and white lightning. Bath salts are usually sniffed, snorted, ingested, smoked, or injected intravenously, and they are also available in compressed gelatin-form capsules.20 The desired effects of these drugs include a state of euphoria and alertness; however, negative effects such as agitation, confusion, combativeness, and psychosis have also been reported.The physiologic effects — such as mydriasis, hypertension, tachycardia, and diaphoresis — mirror those of sympathomimetics.20 In July 2012, Congress passed the Synthetic Drug Abuse Prevention Act (SDAPA), which categorized a number of synthetic cathinones under Schedule 1 of the Controlled Substances Act. SDAPA successfully placed these substances under the most restraining category of controlled substances.20 Cannabimimetic agents — which include 15 synthetic cannabinoid compounds, 2 synthetic cathinones (mephedrone and methylenedioxypyrovalerone [MDPV]), and 9 synthetic hallucinogens — are now regulated by the Controlled Substances Act.20 In addition, another 10 synthetic cathinones are subject to temporary control. Purveyors of additional emerging synthetic cathinones may also be subject to prosecution under the Controlled Substance Analogue Enforcement Act, which allows these harmful street drugs also to be treated as Schedule 1 controlled substances.20 Flakka

Flakka (alpha-pyrrolidinovalerophenone [alpha-PVP]) is a synthetic drug that is chemically similar to MDPV.21 The low cost of flakka and its ability to produce euphoric highs are well known.22 Other street names for flakka include “insanity”

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TABLE. Drug Slang Code Words for Synthetic Cannabinoids and Synthetic Cathinones Synthetic Cannabinoids 4-20

Devil's Venom

Red Magic

Abyss

Dr Feel Good

Kaos

Rewind

Ace of Spades

Dragon Eye

Karma

Scooby Snax

AK-47

Earth Blend

Kong

Sexy

Amnesia

Exodus

Krazy Kandy

Sky High

Atomic Blast

Extreme

Kryp2nite

Snake Bite

Big Bang

Fake Bake

Kush

Spice

Blaze

Fruit Candy Flavors

Layer Cake

Spike Diamond

Black Magic Smoke

Funky Buddha

Limitless

Storm

Black Mamba

Funky Monkey

Mad Hatter

Sweet Leaf

Blaze

G-Force

Mile High

Synthetic Marijuana

Blue Cheese

GI Joe

Mystique

Time Traveler

Brain Freeze

Green Dream

Ninja

Top Gear

Buzz Haze

Green Peace

Odyssey

Train Wreck

Cherry Bomb

Hammer Head

OMG

Ultimate

Chill

Helix

Pandora's Box

Viper

Chrome

Hipster

Phoenix

Voodoo Child

Clockwork Orange

Hysteria

Pineapple Express

Wazabi

Cloud 10

Ice Dragon

Posh

Wicked Wizard

Cowboy Kush

Juicy Leaf

Potpourri

Xtreme

Crystal Skull

Jungle Juice

Pow

Zero Gravity

Dead Man

Just Chill

Rapture

Zombie

Bath Salts

Flakka (Alpha-PVP)

Phone Screen Cleaner

Vanilla Sky

Bliss

Gravel (Alpha-PVP)

Plant Food

White Dove

Bloom

Insect Repellant

Pure Ivory

White Knight

Blow

Ivory Wave

Purple Wave

White Lightening

Blue Silk

Jewelry Cleaner

Recharge

White Magic

Cloud 9

Lunar Wave

Red Dove

Zoom

Drone

M-Cat

Scarface

Energy-1

Meow-Meow

Snow Leopard

Explosion

Ocean Burst

Stardust

Synthetic Cathinones

From the DEA Intelligence Report. Drug Slang Code Words. Publication No. DEA-HOU_DIR-020-17; May 2017.

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and “grave.” Flakka can be taken orally, snorted, injected, or smoked/vaped. It is considered part of the cathinone class; cathinones affect the CNS by increasing the release of dopamine and inhibiting its reuptake. Similarly, the drug inhibits reuptake of norepinephrine and serotonin.23 The onset of action of flakka is more rapid than that of methamphetamine, and it has a longer duration of activity. It is considered more potent than cocaine and methamphetamine and is extremely addictive.23 The development of tolerance and compulsive redosing are common.22 Alpha-PVP also has been noted to have an unpleasant “come-down” effect. As with MDPV, users experience anxiety, appetite suppression, dysphoria, cognitive fatigue, motivation suppression, irritability, and wakefulness as they come off the drug.22 The onset of symptoms resulting from flakka use is generally abrupt. It has been known to cause a multitude of signs and symptoms including bizarre behavior, agitation, altered mental status, violent outbursts, seizures, tachycardia, hypertension, hyperthermia, and mydriasis.21 Pulmonary congestion, rhabdomyolysis, kidney failure,21 dehydration, jaw clenching, and pupillary dilation22 also may occur. Several case reports indicate that behavioral signs and symptoms may last for days, and patients may not return to baseline even with the use of traditional benzodiazepines. The drug has the potential to produce an excited delirium.21,22 This state is characterized by fearfulness and hyperactivity, the latter often compounded by superhuman strength. Patients in an excited delirium can become acidotic and experience cardiopulmonary collapse and/or severe renal injury. It is important to employ extreme caution when interacting with these individuals; sedation will be necessary, but restraints should be used with caution.21 Although the drug is not tracked independently in current epidemiologic surveys, recent data have shown disturbing trends. Over a 1-year period in Florida, rates of seizure secondary to flakka use tripled.22 A large spike in flakka use for one particular Florida county resulted in 40 deaths associated with the drug during a 1-year period.23 Although only a handful of substances were covered in this review, it is important to consider how healthcare providers can have a positive effect on patients who struggle with SUD. Appropriate education related to substances of abuse followed by a heightened index of suspicion for SUD and ongoing patient education can have a tremendous impact on this public health crisis. Many healthcare providers are well informed regarding opioid abuse and its related morbidity and mortality. Given the increasing numbers of deaths associated with opioid overdose, major initiatives by DHHS and NIH are underway in an effort to decrease the morbidity and mortality associated with opioids. The DHHS is responding to the opioid epidemic by focusing its efforts in 5 major areas5:

1. Increasing entry to treatment and recovery facilities; 2. Supporting the use of overdose-reversal drugs; 3. Reinforcing knowledge of the epidemic through better public health monitoring; 4. Supporting innovative research on pain and addiction; and 5. Advancing best practice for pain management. The NIH is also working on innovative measures to prevent opioid misuse, treat opioid-related disorders, and manage pain more effectively. In 2017, representatives from the NIH met with pharmaceutical companies and academic research centers to discuss safer and nonaddictive strategies to manage chronic pain, innovative medications to treat opioid-use disorders, and improvements in opioid reversal agents.6 Lastly, in April 2018, at the National Rx Drug Abuse & Heroin Summit, NIH Director Francis S. Collins, MD, PhD, publicized promotion of the HEAL (Helping to End Addiction Long-term) initiative, a trans-agency effort established to increase scientific solutions to curtail the national opioid public health epidemic. Conclusion

As control of SUD becomes a public health imperative in the United States, it is increasingly important for healthcare providers to maintain a level of awareness in terms of current and emerging drugs of abuse. Although these substances contribute to the broad picture of substance-related morbidity and mortality and cost burden, regulation of these drugs remains an ongoing challenge. Consequently, providers must continue to be mindful of the fact that these drugs are not easily identified with traditional drug screens and may cause significant symptomology in patients who have ingested them. Knowledge of the potential signs and symptoms associated with these emerging substances is therefore vital. ■ References 1. Prescription drug overdose. American Public Health Association website. https://www.apha.org/topics-and-issues/prescription-drug-overdose. January, 2018. Accessed December 4, 2018. 2. Drug overdose death data. Centers for Disease Control and Prevention website. https://www.cdc.gov/drugoverdose/data/statedeaths.html. Updated December 19, 2017. Accessed December 4, 2018. 3. Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999-2016. NCHS data brief, no 294. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics; 2017. https://www.cdc.gov/nchs/data/databriefs/db294.pdf. Accessed December 6, 2018. 4. CDC WONDER (Wide-Ranging Online Data for Epidemiologic Research). Centers for Disease Control and Prevention website. https://wonder.cdc.gov. Accessed December 6, 2018. 5. What is the U.S. Opioid Epidemic? U.S. Department of Health and Human Services website. https://www.hhs.gov/opioids/about-the-epidemic/. Reviewed September 2018. Accessed December 6, 2018.

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6. Emerging trends and alerts. National Institute on Drug Abuse website.

15. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harm-

https://www.drugabuse.gov/drugs-abuse/emerging-trends-alerts. Accessed

less herbal blends: a review of the pharmacology and toxicology of synthetic

December 6, 2018.

cannabinoids. Prog Neuro Psychopharmacol Biol Psychiatry. 2012;39(2):234-243.

7. Cheatle MD. Prescription opioid misuse, abuse, morbidity, and mortality:

16. Patton AL, Seely KA, Yarbrough AL, et al. Altered metabolism of synthetic

balancing effective pain management and safety. Pain Med. 2015;16(1):S3-S8.

cannabinoid JWH-018 by human cytochrome P450 2C9 and variants.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental

Biochem Biophys Res Communications. 2018;498(3):597-602.

Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

17. Bush DM, Woodwell DA. Update: Drug-related emergency department

9. Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s

visits involving synthetic cannabinoids. The CBHSQ Report. 2013:1-10.

scientific evidence on the presence of opioid compounds in kratom, under-

18. Brooks M. Severe bleeding tied to synthetic cannabinoids, CDC warns.

scoring its potential for abuse. U.S. Food and Drug Administration web-

Medscape website. May 25, 2018. 2018. https://www.medscape.com/viewartic

site. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/

le/897268?nlid=122791_3901&src=wnl_newsalrt_18055_MSCPEDIT&uac=

ucm595622.htm. February 6, 2018. Accessed December 6, 2018.

244969HV&impID=1642568&faf=1. Accessed December 6, 2019.

10. Kratom. National Institute on Drug Abuse website. https://www.drugabuse.gov/

19. Synthetic cathinones (bath salts). National Institute on Drug Abuse web-

publications/drugfacts/kratom. September 20, 2018. Accessed December 6, 2018.

site. https://www.drugabuse.gov/drugs-abuse/synthetic-cathinones-bath-salts.

11. Prescription opioids. National Institute on Drug Abuse website. https://

December 13, 2014. Accessed December 8, 2018.

www.drugabuse.gov/publications/drugfacts/prescription-opioids. June 17, 2018.

20. Bath salts or designer cathinones. Drug Enforcement Agency website.

Accessed December 6, 2018.

https://www.dea.gov/documents/2017/06/15/drugs-abuse. June 15, 2017.

12. Hemby SE, McIntosh S, Leon F, Cutler SJ, McCurdy CR. Abuse liability and

Accessed December 6, 2018.

therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine

21. Crespi C. Flakka-induced prolonged psychosis. Case Rep Psychiatr.

and 7‐hydroxymitragynine [published online June 27, 2018]. Addict Biol. doi:

2016;3460849.

10.1111/adb.12639

22. Stanciu CN, Penders TM, Gnanasegaram SA., Pirapakaran E, Padda JS,

13. Multistate outbreak of Salmonella infections linked to kratom (final updat-

Padda JS. The behavioral profile of methylenedioxypyrovalerone (MDPV) and

ed). CDC website. https://www.cdc.gov/salmonella/kratom-02-18/index.html .

α-pyrrolidinopentiophenone (PVP): a systematic review [published online

Updated May 24, 2018. Accessed December 6, 2018.

March 21, 2017]. Curr Drug Abuse Rev. doi: 10.2174/1874473710666170321122226

14. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S,

23. Cherry SV, Rodriguez YF. Synthetic stimulant reaching epidemic propor-

Huestis M. Synthetic cannabinoids: epidemiology, pharmacodynamics, and

tions: flakka-induced ST-elevation myocardial infarction with intracardiac

clinical implications. Drug Alcohol Depend. 2014;144:12-41.

thrombi. J Cardiothorac Vasc Anesth. 2017;31(1):e13-e14.

CME

POSTTEST Expiration date: February 15, 2020

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Feb19feature. CREDITS: 0.75 | Emerging Drugs of Misuse and Their Public Health Implications

1. Which of the following is a naturally occurring opiate product? a. Fentanyl c. Meperidine b. Methadone d. Morphine

3. Which of the following is not a sequelae associated with ingestion of synthetic cannabinoids? a. Cognitive impairment c. Psychosis b. Hypersomnia d. Seizure

2. Synthetic cathinones are commonly referred to by which street name? a. Bath salts c. Ecstasy b. Catnip d. Flakka

4. Which of the following is not a typical route of delivery of kratom? a. Beverage c. Inhalation b. Capsule d. Injection

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Feb19feature

22 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

For first-line constipation therapy, stick with the leader

The AGA recommends PEG laxatives (like MiraLAX) as a first-line constipation treatment1

✔ 96% patient satisfaction rate* ✔ #1 GI-recommended laxative for over 10 years Start with MiraLAX for proven relief of occasional constipation. *Survey of 300 consumers, 2017. Use as directed on product labeling or as directed by your doctor. Reference: 1. Clinical decision support tools. American Gastroenterological Association website. http://campaigns.gastro.org/algorithms/constipation/index.html. Accessed May 12, 2017. Bayer, the Bayer Cross, and MiraLAX are trademarks of Bayer. © 2017 Bayer May 2017 68522-PP-MLX-BASE-US-0328

1003669ha_a.indd 1

Doctor recommended, patient approved

6/2/17 10:21 AM

FEATURE: AMY J. BRONSON, EDD, PA-C; NIKKI WILLIAMS, MSPAS, PA-C; DR STEVEN R. MURRAY

Actinic Keratoses: Field Cancerization and Photodynamic Therapy Early treatment can eliminate the potential for malignant transformation of AK and decrease the burden of cutaneous squamous cell carcinoma.

ctinic keratoses (AKs) are one of the most frequently encountered skin lesions in clinical practice.1,2 AKs are precancerous, focal, sun-induced areas of abnormal proliferation of atypical keratinocytes confined to the lower layer of the epidermis.1,2 Often referred to as solar keratoses, these lesions commonly occur in areas with chronic and cumulative sun exposure such as the face, ears, neck, dorsal forearms, hands, and scalp.1,2 The highest incidence of AK is seen in middle-aged to elderly men with chronic and sustained ultraviolet (UV) radiation exposure over their lifetimes. AKs are more prevalent in fair-skinned individuals and those categorized as Fitzpatrick skin types I and II (Table 1)3; the Fitzpatrick phototype scale is a numerical classification used to estimate the response of different types of skin to UV light.3

Etiology/ Histology

AKs result from ultraviolet radiation exposure.

24 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

The main mechanism of AK formation is prolonged sun exposure and cumulative exposure to UV radiation.4 AKs result from the adverse effects of UV-A and UV-B light radiation on keratinocyte DNA.2,5 UV radiation induces cellular mutations and results in the formation of atypical keratinocytes.2,5 Mutations of genes may cause impaired apoptosis, uncontrolled cell proliferation, and progression to invasive squamous cell carcinoma (SCC).1,6 Although most AKs remain superficial and confined to the epidermis, some lesions will penetrate the

reticular or papillary dermis and differentiate into SCC, especially when multiple AKs are present.1,6 Clinical Presentation

The classic presentation of AKs is a gritty macule or small papule, varying in size, with an erythematous base and an overlying scaly white patch that is rough to palpation.2 Although AKs are commonly asymptomatic, patients may report occasional burning or lesion tenderness. Immunocompromised patients, specifically organ transplant recipients receiving treatment with immunosuppressive medications, are at increased risk of developing AKs.1,6 AKs may spontaneously regress, completely resolve, persist, or progress to SCC, particularly in the presence of multiple AKs.2 Clinically it is difficult to predict the course of AKs, and no method exists for predicting lesions that will evolve into invasive SCC.5 The risk of AKs transforming to SCC is minimal (1%)1; however, current guidelines suggest treating all AKs.4 Diagnosis

Diagnosis generally is made by visual inspection and palpation. Keratoacanthoma, SCC, basal cell carcinoma, and seborrheic keratosis lesions may have a similar presentation to AKs and must be considered in the differential diagnosis.2 Characteristic history and examination findings are usually adequate for diagnosing AK, but dermoscopy, if available, is recommended if the clinical exam findings are not typical of AK. A strawberry pattern, consistent with undulated vessels surrounding hair follicles filled with yellow keratotic plugs on an erythematous background, is characteristic of AK lesions on dermoscopy. Skin biopsy is performed if the clinical exam and dermoscopy findings are not typical of AK. Any clinically suspicious lesion — including lesions with increasing tenderness, rapid enlargement, or those recalcitrant to initial therapies — warrants skin biopsy for a definitive diagnosis.2 Surrounding the visible and palpable AKs lesions are skin areas prone to sun damage that are more likely to develop into clinical AKs or other sun-related cancers.5 Subclinical, nonvisible sun damage is known as field cancerization.5 Determining the severity of AKs and the extent of surrounding field damage can be challenging. Many AK grading tools use visible isolated lesion counts to assess the severity of the AKs, but they lack grading of the surrounding sun-damaged skin. The Actinic Keratosis Field Assessment Scale (AK-FAS) has been developed and tested as a relevant and reproducible assessment of AKs in clinical practice and aids in the grading of the severity of AKs and the field area damaged by UV radiation.5 Utilizing the scale can standardize a diagnosis, aid in selecting the most appropriate treatment, and provide an objective method to assess treatment response (Table 2).5

TABLE 1. Fitzpatrick Phototype Scale3 Fitzpatrick Skin Category

Sun Reactive Types

Type I

Always burns, never tans

• Skin: pale • Hair: blond or red • Eyes: blue • Other: freckles

Type II

Usually burns, tans minimally

• Skin: fair • Hair: blond or red • Eyes: blue, hazel, or green

Type III

Sometimes mild burn, tans about average

• Skin: fair; light brown pigmentation • Hair: any • Eyes: any

Type IV

Rarely burns, tans easily

• Skin: moderate brown pigmentation

Type V

Very rarely burns, tans very easily

• Skin: dark brown pigmentation

Type VI

Never burns, always tans

• Skin: deeply pigmented dark brown

Description

TABLE 2. Actinic Keratosis Field Assessment Scale5 AK Grade

III

AK Area (% area covered by AK on face or scalp)

<10

10-25

>25-50

>50

Hyperkeratosis Severity

+: >1 AK with significant hyperkeratosis >5 mm in diameter are present in the area −: no hyperkeratosis is present

Sun Damage Severity

+: moderate or severe sun damage, leading to more frequent patient follow-up −: none or mild sun damage Signs considered in the evaluation: erythema, telangiectasia, inflammation, atrophy, and pigmentation disorders

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 25

ACTINIC KERATOSES

Treatment

Various treatments are available for AKs, and the choice of treatment should be individualized. Localized or lesion-directed therapy is best for isolated solidary lesions with no surrounding field cancerization.1 Field treatments are recommended for patients with multiple diffuse AK lesions on contiguous areas of sun-damaged skin,3 and it is advantageous in the treatment of subclinical AKs and for the prevention of further AK development.3,8 Treating both visible AK lesions and the areas of subclinical, nonvisible sun-damaged skin is critical to reducing the recurrence of AKs.3 Field therapy alone or a combination of field and lesion-directed therapy achieves high rates of sustained lesion clearance.5 Patient preference, number and prevalence of hyperkeratotic and nonhyperkeratotic lesions, and consideration for the prevention of the development of more AKs must be considered when deciding on individual patient treatment strategies (Table 3).1,2,8

Initial US Food and Drug Administration clinical trials of ALA-PDT treatment of AKs on the face and scalp had a clearance rate of 85% to 90% after 2 treatment sessions (note that the treatment’s efficacy is improved with repeated PDT treatment within 30 days).8 A Cochrane review on AK treatment found PDT to be superior for eradicating lesions and resulted in preferred cosmetic outcomes, including improvement in lentigines, skin roughness, fine lines, and sallow complexion compared with cryotherapy and topical fluourouracil 5% cream (5-FU).7,8 PDT is an effective treatment with a 14% increased incidence of lesion clearance and preferred cosmetic outcomes when compared with cryosurgery on the face and scalp.7 Treatment efficacy is contingent on the proper application of the photosynthesizer.4 Cleansing the skin with acetone, chlorohexidine, or soap prior to applying ALA allows for greater photosynthesizer penetration.To increase efficacy when treating the extremities, occlusion with plastic wrap or a nonporous flexible covering enhances ALA penetration.4

Photodynamic Therapy

Photodynamic therapy (PDT) is a field treatment option with a mechanism of action driven by the interaction of light, a photosynthesizer, and oxygen.8 A low-molecular-weight photosynthesizer, 5-aminolevulinic acid (ALA), is synthesized in the porphyrin-heme pathway and converted endogenously into PpIX.8,9 ALA preferentially targets cells with a defective epidermal barrier. The light source, commonly blue light, excites PpIX, producing oxygen-free radicals that affect intracellular components, resulting in necrosis or apoptosis.9 The concentration of the PpIX in damaged cells destroys targeted cells while minimizing surrounding tissue damage.8,9

POLL POSITION Which of the following is the least effective topical therapy for actinic keratoses? 9.22% ■ Diclofenac ■ Glycolic acid ■ 5-Fluorouracil ■ Imiquimod

PDT Procedure Patients undergoing in-office treatment with PDT will have their skin cleansed with acetone and then undergo ALA application to the targeted treatment area. Incubation times will vary based on anatomical region and severity of actinic damage.8 Both the patient and light technician are required to wear a protective eye covering to ensure ocular safety during the 10 to 15 minutes of irradiation with the blue light. Patients commonly report heat but minimal pain during irradiation. PDT Postcare Immediately following PDT patients may develop erythema and mild edema that may persist for 2 to 10 days.8 Patient postprocedure counseling includes remaining indoors and at least 6 feet from any window for 36 hours following the treatment to avoid exposure to ambient light and minimize the risk of continued activation of PpIX.8,9 Discussion

13.36% 49.77% 27.65%

For more polls, visit ClinicalAdvisor.com/Polls.

The available research consistently indicates that early treatment of both visible AK lesions and nonvisible sun-damaged skin can eliminate the potential for malignant transformation and decrease the burden of cutaneous SCC.3 Treatment efficacy is dependent on patient adherence to therapy; therefore, it is important to educate patients on procedure expectations, any known adverse events, side effects, and postprocedure care to alleviate patient frustration and anxiety. Also, it is widely accepted that there is no way to clinically determine which AK lesions will transform into invasive SCC and recur after treatment.2 As a result, it is crucial to emphasize the

26 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

TABLE 3. Common Treatment Options for Actinic Keratoses2,4,6,7 Localized Lesion Treatments

Indication

Pros/Cons

Liquid Nitrogen Cryotherapy

• Most common approach to AK management and effective for thicker lesions • Used for isolated AKs; not effective as a field therapy

• No cutting or anesthesia necessary • 10-14 days postprocedure healing time • Risk of surrounding tissue hypopigmentation and scarring

Curettage

• Not recommended for first-line therapy • May be required before photodynamic therapy to remove hyperkeratotic tissue

• May require local anesthesia • Risk of hypopigmentation and scarring

Surgical Excision

• AKs are not typically excised • Solitary lesions resistant to treatment or new lesion with diagnostic uncertainty • Biopsy is recommended when clinical diagnosis is unclear

• Requires local anesthesia • Risk of hypopigmentation and scarring

Diclofenac

• 3% gel applied twice daily for 60-90 days • Nondestructive properties can be favorable for early treatment before resorting to more invasive measures4

• Long application period can result in decreased patient adherence • Less-severe cutaneous reaction • Contraindicated in patients with allergy to nonsteroidal anti-inflammatory drugs

5-Fluorouracil

• 1.0-5.0% cream applied twice daily for 2-4 weeks • Common treatment for superficial and numerous AKs

• Photosensitivity • Inflammation and skin erosions • Application frequency may be restricted due to its erosive nature • Healing typically occurs 3-4 weeks after discontinuing the medication • Efficacy of 80% reduction in lesion count for patients who can complete treatment regimen4

Imiquimod

• 2.5 or 3.75% cream applied at bedtime for 2 weeks, 2-week break, and then repeat 2-week application • Recommended for nonhyperkeratotic, nonhyper trophic AKs on face or scalp

• Contraindicated in patients with underlying autoimmune condition • May cause systemic flu-like symptoms • Hypopigmentation at treatment site

Photodynamic therapy (5-aminolevulinic acid + blue light)

• Effective for superficial and numerous confluent AKs or when significant surrounding solar damage • Recommended as first-line treatment for patients with multiple AKs4

• No sun exposure for minimum 36 hours following treatment • Quick recovery in 1-2 weeks • 2 cycles needed for best results

Ablative laser (yttrium aluminum garnet ablative fractional laser)

• Suggested resurfacing for areas of clustered AKs

• May require local anesthesia and recovery periods will vary • May need repeated application to get desired results • Added cosmetic preference for skin resurfacing

Field Treatments TOPICAL TREATMENTS

Procedural Treatments

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 27

ACTINIC KERATOSES

The main mechanism of actinic keratosis formation is prolonged sun exposure and cumulative exposure to ultraviolet radiation. importance of patient follow-up after any recommended treatment. Patient follow-up should include monitoring of treatment efficacy, tolerability, and patient adherence. The majority of studies recommend patient monitoring every 6 to 12 months, but the frequency of individual patient monitoring depends on associated malignancy and the development of new AK lesions.2,4 Patients with AKs are at increased risk for other cutaneous malignancies and should receive education on the importance of skin self-monitoring for any concerning changes such as lesions that bleed, enlarge quickly, or do not heal. In addition, management of all AKs and field cancerization should include primary prevention with patient counseling on reducing UV radiation exposure with regular use of broad-spectrum sunscreen, wearing sunprotective clothing including a wide-brimmed hat, avoiding artificial UV tanning sources, and avoiding sun exposure during peak UV hours.7

References 1. Ayer G. Photo damage and actinic keratosis: a case study approach. Derm Nurs. 2017;16(1):22-25. 2. Bolognia, JL, Schaffer, JV, Duncan KO, Ko, CJ. Dermatology Essentials. New York, New York: Elsevier Saunders; 2014. 3. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch of Derm. 1988;124(6);869-871. 4. Goldberg, G. Treatment considerations in actinic keratosis. Europ Acad Dermatol Venereol. 2017;31(2):12-16. 5. Dreno B, Cerio R, Dirschka T, et al. A novel actinic keratosis assessment scale for grading actinic keratosis disease severity. Acta Dermatol Venereol. 2017;97:1108-1113. 6. Martin MM. In-office painless aminolevulinic acid photodynamic therapy. J Clin Aesthet Dermatol: 2016;9(2):19-26. 7. Fleming P, Zhou S, Bobotsis R, et al. Comparison of the treatment guidelines for actinic keratosis: a critical appraisal and review. J Cutan Med Surg. 2017;21(5):408-417. 8. Ozog DM, Rkein AM, Fabi SG, et al. Photodynamic therapy: a clinical

Conclusion

consensus guide. Dermatol Surg. 2016;42:804-827.

Treating field cancerization is a shift in the traditional paradigm of treating individual lesions. Utilizing the AK-FAS can improve identification and severity grading of AKs and skin prone to sun damage. AK grading tools that rely on lesion counts — such as the Olsen and Roewert-Huber scales — have not been reproducible when grading severity.5 Utilizing a tool for assessing the field affected by AKs, such as the AK-FAS, may lead to a more standardized approach and increase the effectiveness of AK disease management.5,9 Identifying and treating field cancerization can reduce the development of new lesions and AK recurrence.5,9 As such, individual patient factors must be evaluated in the clinical decision-making process to develop patient-centric management plans. When choosing a therapy, treatment should account for the type and severity of lesions, patient tolerance to treatment-induced skin reactions, adherence to recommended therapy, duration of treatment, and cost-related factors for the individual patient.3 ■

9. Wan MT, Lin JY. Current evidence and applications of photodynamic

Amy J. Bronson, EdD, PA-C, is assistant professor and program director for the Master of Physician Assistant Studies at Colorado Mesa University, Grand Junction; Nikki Williams, MSPAS, PA-C, is assistant professor and director of didactic education for the Master of Physician Assistant Studies at Colorado Mesa University, Grand Junction; and Dr Steven R. Murray is professor of teaching at the College of Letters & Science of the University of California, Berkeley. 28 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

“You’re calling it love, but it’s really just static electricity.”

therapy in dermatology. Clinic Cosm Invest Derm. 2014;7:145-163.

Dermatology Clinic CASE #1

Hyperkeratotic Plaques in the Axilla JESSICA PAYNE; JULIA R. NUNLEY, MD

A 50-year-old woman presents with an intensely pruritic rash in her armpits first noted 2 months ago. She changed to a more “natural” deodorant 3 months earlier having read on the internet that some deodorants could potentially cause breast cancer. The rash persisted despite frequent washing and application of petroleum jelly. On examination, a brown to erythematous hyperkeratotic plaque was present in each axilla. Her dermatologic exam was otherwise unremarkable, and her past medical history was noncontributory. What is your diagnosis? Turn to page 30

CASE #2

Violaceous FlatTopped Papules and Plaques KELVIN WANG, BSE;TALIA NOORILY, BA; CHRISTOPHER RIZK, MD

A 39-year-old African American man presents to the clinic with a 5-month history of a pruritic rash on his back. His wife noticed that he has had several purple-colored bumps on his back that appear to be growing and spreading. The patient is otherwise healthy but reports a remote history of intravenous drug use. On examination, there are multiple violaceous flat-topped papules and plaques located on the patient’s back. He does not have any other lesions on his body. What is your diagnosis? Turn to page 32 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 29

Dermatology Clinic CASE #1

Granular Parakeratosis

Histologic examination of the patient’s biopsy specimen revealed the characteristic features of granular parakeratosis (GP), a rare, benign dermatologic condition that typically develops over 1 to 12 months and classically affects intertriginous areas.Within the affected area(s), which may be unilateral or bilateral, one finds brown to erythematous hyperkeratotic papules that may be discrete, coalesced into plaques, or arranged in a reticular pattern.1 Lesions are usually pruritic and friable. At times they may become violaceous and lichenified as a result of persistent scratching.2 However, for some individuals the eruption is not bothersome beyond its appearance. Some cases of GP are precipitated by an inciting topical agent, as was the case for this patient in whom the onset correlated with a recent change in deodorant; other cases, however, occur in the absence of aggravating factors. The axillae are most commonly affected, and GP was originally named “axillary granular parakeratosis” by Northcutt and colleagues, who first described the cutaneous condition in 1991.3 The name was subsequently truncated to granular parakeratosis once numerous cases affecting other intertriginous sites — such as the inframammary folds, popliteal fossa, and groin, as well as nonintertriginous areas including the lumbosacral area and face — were reported.4,5 All ages, genders, and ethnic groups are affected by GP, but the classical presentation of the condition involves the underarms of women in the 40- to 50-year-old range.5 Although GP is considered a rare condition, with an estimated incidence of 0.005%, it is speculated that it more often goes unrecognized and undiagnosed by clinicians.1 The etiology of GP has yet to be determined but several theories and associations exist. Northcutt et al hypothesized it to be a reaction induced by contact with topical antiperspirants and deodorants.3 Since then, GP has been linked to other topical irritants as well, such as zinc oxide and benzalkonium chloride, which are agents found in dermatologic products and common household items.5,6 Other associated conditions include warm occlusive environments, increased perspiration, skin maceration, and excessive washing in children.5 However, GP has also been reported to occur in the absence of recognized triggers as well as congenitally. As such, an alternate hypothesis has been generated suggesting GP may

represent an inherited or acquired disorder of cornification capable of occurring autonomously.5 Data from a mouse study comparing normal controls with those deficient in a factor essential for a functional epidermal barrier (caspase-14) support this hypothesis as mice deficient in this protease were more prone to develop parakeratosis than controls.7 Further complicating our understanding of GP is the fact that its histologic features have been noted as incidental findings in a wide range of other entities including dermatomyositis, molluscum contagiosum, dermatophyte infection, and a variety of keratinocytic neoplasms.5 In most of these reports there was no clinical evidence of GP. Based on all of the available information, the current perception is that GP represents a reactive pattern rather than a distinct clinical entity that manifests in genetically predisposed patients in the presence of aggravating irritants, malignancies, or infections.5

Granular parakeratosis is a rare condition that often goes unrecognized and undiagnosed by clinicians. The proposed mechanism in the pathogenesis of GP is the development of an abnormal sequence of keratinocyte maturation within the upper layers of the epidermis. Filaggrin, a structural protein that binds keratin fibers, acts as an adhesion matrix for keratohyalin granules during the cornification/maturation process.2,3 Normally, keratohyalin granules are degraded in the deeper layers of the epidermis. Without functional filaggrin, keratohyalin granules are retained in the stratum granulosum and stratum corneum, causing disruption in keratinocyte maturation, leading to abnormal nuclei retention (ie, parakeratosis) and thickening of the stratum corneum.2 Northcutt et el proposed that GP could result from defective processing of filaggrin from profilaggrin.3 The absence of filaggrin in the cytoplasm of granular parakeratotic cells in GP, as evidenced using immunohistochemistry and electron microscopy techniques, supports this theory.5 Retention of the keratohyalin granules produces GP’s clinical picture of epidermal papules and plaques as well as the distinctive histologic features. Diffuse epidermal hyperplasia with or without associated papillomatosis is common. Characteristic findings include marked compact parakeratosis, hyperkeratosis, and the hallmark finding of brightly staining

30 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

Continues on page 32

Dermatology Clinic basophilic keratohyalin granules throughout the stratum corneum.1 Focal vacuolization may be seen within the stratum granulosum. A sparse lymphohistiocytic infiltrate, vascular proliferation, and capillary congestion may be observed in the papillary dermis. Cultures and periodic acid Schiff (PAS) stains are negative for bacteria and fungi.5 The differential diagnosis for GP is extensive and includes conditions that have a predilection for intertriginous areas. Common mimickers include contact dermatitis (irritant or allergic) and acanthosis nigricans.Various infectious and inflammatory conditions such as inverse psoriasis, intertrigo,

appointment, the rash had resolved and she had successfully restarted her old brand of deodorant with no recurrence. Jessica Payne is a medical student and Julia R. Nunley, MD, is a professor of dermatology at the Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond,Virginia. References 1. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005;52(5):863-867. 2. Wallace CA, Pichardo RO, Yosipovitch G, et al. Granular parakeratosis: a case report and literature review. J Cutan Pathol. 2003;30(5):332-335.

Granular parakeratosis may be precipitated by an inciting topical agent and may occur without aggravating factors.

3. Northcutt AD, Nelson DM, Tschen JA. Axillary granular parakeratosis. J Am Acad Dermatol. 1991;24(4):541-544. 4. Braun‐Falco M, Laaff H. Granular parakeratosis – a clinical‐pathological correlation of 10 cases. J Dtsch Dermatol Ges. 2009;7(4):340-344. 5. Ding CY, Liu H, Khachemoune A. Granular parakeratosis: a comprehensive review and a critical reappraisal. Am J Clin Dermatol. 2015;16(6):495-500. 6. Robinson AJ, Foster RS, Halbert AR, et al. Granular parakeratosis induced

erythrasma, and dermatophytosis should also be considered, as should the genodermatoses Hailey-Hailey and Darier diseases.5 Because the diaper area is most commonly affected in infants, the differential diagnosis in infants should also include seborrheic dermatitis, acrodermatitis enteropathica, and Langerhans cell histiocytosis.5 Fortunately, the distinct histologic features of GP, as well as other tests including cultures, can help confirm the specific diagnosis. Multiple approaches may be considered in the treatment of GP; however, to date no approach has been proven superior and success rates are variable.5 Efficacy data outside of case reports are lacking. Clearly, inciting triggers should be removed if recognized or suspected. Reducing skin maceration and minimizing moisture may also lead to improvement; however, conservative management alone is not always effective.5 Reportedly effective medical interventions include topical and oral steroids, as well as various other topical agents such as retinoids, antifungals, calcineurin inhibitors, vitamin D analogues, and ammonium lactate. Procedural and destructive approaches reported in the literature range from cryotherapy and botulinum toxin5 to yttrium aluminum garnet (YAG) and CO2 lasers and even mastopexy for a case of inframammary GP.8 However, one must remember that GP is considered a self-limited condition and may resolve spontaneously in the absence of any intervention. The patient in the case described was instructed to discontinue the new deodorant and to keep the area clean and dry. She was also prescribed a low-potency topical steroid to reduce inflammation and pruritus. At her 1-month follow-up

by benzalkonium chloride exposure from laundry rinse aids. Australas J Dermatol. 2017;58(3):e138-e140 7. Hoste E, Denecker G, Gilbert B, et al. Caspase-14-deficient mice are more prone to the development of parakeratosis. J Invest Dermatol. 2013;133(3):742-750. 8. Nelson G, Lien MH, Messina JL, et al. Submammary granular parakeratosis treated with mastopexy. J Drugs Dermatol. 2017;16(8):810-812.

CASE #2

Lichen Planus

Lichen planus (LP) is an inflammatory condition of unknown cause that primarily affects mucocutaneous surfaces. It most commonly involves the skin of the extremities (cutaneous LP) and oral mucosa (oral LP), but it is known to affect the hair, nails, and other mucous membranes including 1-3 the esophagus and genitalia. LP is estimated to affect <1% of the population and tends to present in middle age, typically between 30 and 60 years.1-3 Cutaneous LP does not have a predilection for race or sex, but oral LP appears to affect women more often than men.4 The condition rarely occurs in children, with pediatric LP accounting for only 1% to 4% of cases.5 The pathogenesis of LP is not well understood.1-7 Activated CD4+ and CD8+ T lymphocytes have been implicated in an

32 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

immune-mediated mechanism whereby they are recruited to the dermal-epidermal junction and interact with basal keratinocytes. Upregulations in intercellular adhesion molecule-1 and T-helper-1 cytokines such as interferon-γ, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ-dependent cytokines lead to basal keratinocyte apoptosis.3 Other proposed mechanisms include upregulation of matrix metalloproteases and mast cell-mediated release of chemokines that disrupt the epithelial basement membrane.6 LP is known to be associated with hepatitis C virus infection (HCV), which may play an important role in the pathogenesis of the disease. A meta-analysis of 70 studies showed that the prevalence of HCV exposure was significantly greater among patients with LP compared with control patients (odds ratio, 5.4).7 In addition, patients with HCV infection have a higher prevalence of LP than the general population.7 Therefore, clinicians should have a low threshold for suspecting LP in patients with HCV who present with clinical features suggestive of the disease. Other risk factors that have been identified in association with LP include genetic polymorphisms in interferon-α promoter and TNF-α genes.6 Exposure to certain drugs such as β-blockers, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and penicillamine can cause lichenoid drug eruptions, which resemble idiopathic LP.1,3 The clinical characteristics of LP are manifold and vary based on the site of involvement. Cutaneous LP presents with a widespread, papulosquamous eruption of erythematous to violaceous isolated, flat-topped papules and plaques that commonly involve the extremities, especially the flexor surfaces of the ankles and wrists.These findings are commonly referred to as the “6 Ps”: purple, pruritic, polygonal, planar, papules, and plaques. Koebner phenomenon due to scratching of lesions is often observed.Variants of cutaneous LP include hypertrophic LP, which is characterized by thick plaques, and bullous LP, which results in vesicles and/or bullae within the lesions.1-3 Oral LP can occur either alone or in conjunction with other forms of LP. Oral LP most frequently involves the posterior buccal mucosa, gingiva, and tongue and can be classified into 3 types: reticular, erythematous, and erosive.1,2,4 Lesions of reticular oral LP are often asymptomatic and characterized by a lacelike network of white lines known as Wickham striae on the mucosa. Erythematous LP appears as atrophic, erythematous patches. Erosive LP can result in painful, burning ulcers or rarely bullae.1-4 Nail involvement is not uncommon and occurs in 1% to 16% of patients; fingernails are more frequently affected than toenails.2 LP of the nails results in nail thinning, longitudinal ridging, and distal splitting, which leads to onycholysis and

subungual hyperkeratosis.1,3 These changes have been shown to involve the nail matrix. When the nail plate splits longitudinally, the central area is raised and the lateral edges are angled downward, resulting in an “angel wing deformity.”2 Histologic findings include thickening of the stratum corneum with focal orthokeratosis, liquefactive degeneration of the basal cell layer, irregular acanthosis, and an eosinophilic amorphous band at the basement membrane. Wickham striae appear to be due to a thickened granular cell layer.The characteristic histologic feature is a band-like inflammatory infiltrate composed of lymphocytes and histiocytes adjacent to the basal layer.1,2,4 Diagnosis of LP is based on clinical findings.1,3 A thorough physical examination should focus on all sites of potential involvement including the skin, mucosa, genital area, nails, and hair. No specific laboratory-based test exists, but screening for HCV infection is recommended.1,3,7 A careful drug history may elicit a cause for a lichenoid drug eruption.1,3 Skin biopsy and histopathology can confirm the diagnosis

Differential diagnosis of lichen planus includes psoriasis, pityriasis rosea, lichen nitidus, lichen striatus, and lichenoid drug eruptions. by demonstrating the lymphohistiocytic infiltrate at the dermal-epidermal junction with associated degeneration of basal keratinocytes.3 Differential diagnosis includes other papulosquamous disorders such as psoriasis, pityriasis rosea, lichen nitidus, lichen striatus, and lichenoid drug eruptions, but a careful history and clinical findings can usually differentiate between these.1,2 Genital involvement in LP resulting in desquamative vaginitis, for example, can be mistaken for lichen sclerosis or atrophic vaginitis. Oral LP may be mimicked by secondary syphilis, candidiasis, leukoplakia, or discoid lupus erythematosus. Histologically, LP is extremely difficult to differentiate from discoid lupus erythematosus, with no consensus as to the exact microscopic features to distinguish between the 2 disorders; the differentiating factors are clinical.2 LP is usually benign and self-limited, resolving within a few years.1-3 First-line treatment is high-potency topical corticosteroids, although their efficacy has not been evaluated with clinical studies.1-3,5 Intralesional corticosteroid injections can also be used in larger or hypertrophic lesions.3 Secondline therapy consists of systemic corticosteroids such as oral prednisone or intramuscular injections of triamcinolone; data

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 33

Dermatology Clinic are inconclusive regarding shorter (weeks) vs longer-course (months) treatments. Oral retinoid therapy has also been reported to successfully treat LP, but the side effects and longer length of therapy should be deliberated before beginning treatment. Phototherapy, including combined psoralen and long-wave ultraviolet A radiation (PUVA) and narrow-band UVB, can also be utilized in conjunction with other treatment modalities, but clinical trial data are still limited. Case studies also support treatments such as antihistamines, griseofulvin, dapsone, cyclosporine, and other immunomodulators.1-3,5 The patient in the case described applied 0.05% betamethasone dipropionate cream to the lesions twice daily for 1 month and dramatic regression of his cutaneous lesions was noted by 1-month follow-up. ■

References 1. Le Cleach L, Chosidow O. Clinical practice. Lichen planus. N Engl J Med. 2012;366(8):723-732. 2. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25(4):593-619. 3. Lehman JS, Tollefson MM, Gibson LE. Lichen planus. Int J Dermatol. 2009;48(7):682-694. 4. Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. 2002;46(2):207-214. 5. Pandhi D, Singal A, Bhattacharya SN. Lichen planus in childhood: a series of 316 patients. Pediatr Dermatol. 2014;31(1):59-67. 6. Roopashree MR, Gondhalekar RV, Shashikanth MC, George J, Thippeswamy SH, Shukla A. Pathogenesis of oral lichen planus—a review. J Oral Pathol Med. 2010;39(10):729-734.

Kelvin Wang, BSE, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston,Texas.

7. Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W. Hepatitis C virus and lichen planus: a reciprocal association determined by a metaanalysis. Arch Dermatol. 2009;145(9):1040-1047.

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34 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Small, Asymptomatic Nodules YELENA DOCIK, BS; ELEANOR JOHNSON, BS; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 16-year-old girl presents with a collection of bluish-gray and brown papules on her trunk; the lesions are about the size of a pin-head or match-head. She states that she first noticed these lesions several years ago.The lesions are neither pruritic nor painful, but she is bothered by their appearance. She states that the lesions have not regressed since she first discovered them. Her mother mentions that she has similar lesions on her back that presented around the same age as they did in her daughter.

A 40-year-old man presents with a small, nonpainful, mobile nodule on his left lower chest. He has worked as a farmer since the age of 18 and reports that he rarely wears sunscreen. On examination, the cyst is approximately 0.5 cm in diameter and has a central punctum. It is neither tender nor erythematous.The patient states that he does not know when it first appeared, and he only noticed it because the collar of his shirt rubs on it and occasionally causes irritation.

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Dermatologic Look-Alikes CASE #1

Vellus Hair Cysts

Eruptive vellus hair cysts were first described in 1977 by Esterly et al in the case of 2 children with a hyperpigmented monomorphous papular eruption of several years’ duration.1 Since then, various cases of vellus hair cysts, or eruptive vellus hair cysts, have been described in the literature. Eruptive vellus hair cysts are typically found in children and young adults. Males and females are equally affected, and no racial predilection exists. Eruptive vellus hair cysts may have onset in infancy, suggesting that an autosomal-dominant inheritance pattern may exist.2 Thus, cases are often familial when occurring early in life and sporadic when occurring in young adulthood. No associations between vellus hair cysts and other skin conditions have been identified, suggesting that they are usually an isolated skin finding. However, vellus hair cysts tend to arise in children with other medical conditions, such as eccrine poromas, sebaceous adenomas, anhidrotic ectodermal dysplasia, hidrotic ectodermal dysplasia, and pachyonychia congenita. As a result, physicians should include vellus hair cysts in the differential diagnosis for patients who have these conditions and are presenting with papules.3

Eruptive vellus hair cysts may have onset in infancy, suggesting that an autosomaldominant inheritance pattern may exist. When a blockage occurs at the infundibulum of a hair follicle, just below the epidermis, the hair follicle is at risk for cystic dilatation.This subsequently causes atrophy of the bulb of the hair, resulting in a vellus hair cyst.4 A hamartoma that is differentiating toward vellus hair represents another possible etiology.4 Familial cases are postulated to involve a mutation in keratin genes.4 Amid the above hypotheses, the true cause of eruptive vellus hair cysts remains unknown. Clinically, eruptive vellus hair cysts appear as a collection of discrete follicular papules, each measuring approximately 1 to 4 mm in size.The appearance of these papules varies widely from brown to gray, blue, yellow, or even erythematous in appearance. The chest, flexor and extensor surfaces of the arms and legs, and the back are the most common sites of

involvement. Rarely, the papules can be seen on the ear, face, vulvar labia, abdomen, and axilla. Most lesions are smooth, but cases of umbilication, hyperkeratosis, and epidermal elimination have been described.4 Histologically, biopsy specimens demonstrate a mid-dermal cyst that is lined with stratified squamous epithelium that is approximately 2 to 5 cells thick. Laminated keratin and multiple vellus hairs are identified within the cyst. Granulomatous inflammation may be present, especially if the vellus hairs are in contact with the cyst wall.Typically, there are no sebaceous glands in the cyst wall.5 The differential diagnosis of vellus hair cysts is relatively broad and should include steatocystoma multiplex, dermoid cysts, folliculitis, perforating folliculitis, keratosis pilaris, milia, molluscum contagiosum, acne vulgaris, trichostasis spinulosa, and syringoma, as many of these medical conditions can resemble vellus hair cysts.4,6,7 Additionally, the above lesions may often affect the chest and resemble small papules or nodules. Diagnosis of vellus hair cysts is best made via histologic analysis following punch biopsy. If the biopsy has vellus hairs, as well as other histologic characteristics mentioned above, then the diagnosis can be made.Another method for diagnosis involves puncturing the skin with a blood-collecting needle to aspirate the contents of the cyst or removing the entire cyst using forceps. Following this, a potassium hydroxide wet mount of cyst contents is analyzed, which may also reveal vellus hairs.8 Treatment of vellus hair cysts is often challenging and yields varying results. First, there is no standard treatment for eruptive vellus hair cysts. The lesions can be removed with incision and drainage using an 18-gauge needle for evacuation after the application of local and topical anesthesia. However, scarring is a potential complication of this treatment method. Topical modalities include retinoic acid (0.05%), tazarotene cream (0.1%), urea (10%), or lactic acid (12%). Dermabrasion, erbium:yttrium aluminum garnet laser ablation, and CO2 laser vaporization have shown improvement in some cases. Studies using oral isotretinoin have shown no response.Although untreated lesions generally tend to persist, they can spontaneously regress as a result of transepidermal elimination in approximately 25% of individuals.4,6 For the patient in the case described, a biopsy of one of the lesions yielded findings that were consistent with an eruptive vellus hair cyst. Since the same dermatologic manifestations were also present in the patient’s mother, the case was deemed a familial case.The patient is currently using retinoic acid as treatment, but she has not noticed results. If the lesions persist after a course of topical retinoic acid, the patient would like to try a laser treatment or incision and drainage.

36 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

CASE #2

Epidermal Inclusion Cyst

An epidermal inclusion cyst — also known as an epidermoid cyst, infundibular cyst, keratin cyst, or inclusion cyst — is the most common type of cutaneous cyst. Patients present with a nodule that is movable, firm, and generally asymptomatic unless infected. The cyst can range in size from millimeters to a few centimeters and is usually covered by shiny skin with a central punctum. Because they are filled with keratin and not sebum, epidermal inclusion cysts should not be classified as a sebaceous cyst.8,9 Men in their 20s to 40s are most commonly affected by this condition. Women are affected less commonly, with a male-to-female ratio of 2 to 1. Occurrence during puberty is uncommon and genetic conditions, such as Gardner syndrome, should be considered when epidermal inclusion cysts are present in patients in this age group.8,9 Epidermal inclusion cysts result from inflammation and irritation that cause blockage of the infundibulum.This blockage results in epidermal proliferation and the formation of a

keratin-filled cyst. A central punctum is often seen when the cyst connects to the surface of the skin. Although they can occur anywhere on the body, they are usually found on the face, head, neck, back, and scrotum.This condition is extremely common, sporadic, and generally benign.8 Rarely, malignancy is diagnosed as an incidental finding upon histologic examination of the excised cyst; this occurs in approximately 1% of cysts. Of those that progress to malignancy, squamous cell carcinoma is the most common presentation (approximately 70% of cases), followed by basal cell carcinoma.9 Currently, the mechanism of neoplastic progression is unknown, but it is hypothesized that chronic irritation plays a central role. Higher clinical suspicion of neoplasm may be warranted in cases where the cyst is associated with pain, rapid growth, or ulceration.10 Known risk factors for the development of epidermal inclusion cysts are those associated with inflammation and irritation, including chronic sun damage and acne vulgaris. BRAF inhibitors have also been studied as a potential risk factor.8 This condition is not known to be contagious, but studies have suggested an association with human papillomavirus (HPV).11 Epidermal inclusion cysts are the most common complication seen in female circumcision, a still common practice worldwide.12 If a patient presents with an epidermal inclusion cyst outside of the normal epidemiologic distribution, it is important to

TABLE. Vellus Hair Cyst vs Epidermal Inclusion Cyst Vellus Hair Cyst1-8

Epidermal Inclusion Cyst9-16

Dermatologic Presentation

• Collection of discrete follicular papules, each about 1-4 mm in size • Range in color from brown to gray, blue, yellow, or erythematous

Single, movable nodule less than a few centimeters in diameter with a visible central punctum that is compressible, asymptomatic

Associations

• Can be familial • May be pruritic or erythematous in some cases

• HPV • Acne vuglaris • Men aged 20-40, chronic sun damage

Etiology

Blockage at infundibulum of hair follicle with subsequent cystic dilatation and bulb atrophy

Most cases are sporadic and result from inflammation and irritation that causes blockage of the infundibulum and formation of keratin-filled cyst; generally benign, but rarely contain squamous cell carcinoma or basal cell carcinoma

Characteristic Location Chest or flexor and extensor surfaces of the arms and legs

Face, neck, back, or genitals

Histology

• Mid-dermal cyst lined by stratified squamous epithelium with laminated keratin and vellus hairs within cyst • Possible granulomatous inflammation

Cyst wall derived from infundibulum and cavity filled with keratin; if infected, acute inflammation and neutrophils present

Diagnosis

Histologic analysis of punch biopsy or potassium hydroxide wet mount of cyst contents, both depicting vellus hairs

History and physical examination; confirm with histology

Treatment

• Topical modalities such as retinoic acid or tazarotene cream • Incision and drainage • Dermabrasion, erbium:yttrium aluminum garnet laser, CO2 • Avoid oral isotretinoin

• Surgical removal of entire cyst with intact cyst wall; for better cosmetic results, extract via the minimal incision technique • Direct injections of triamcinolone can be used as an alternative in cases of active inflammation or patient preference

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 37

Dermatologic Look-Alikes consider genetic syndromes as a cause. The most common of these is Gardner syndrome, which is due to a mutation in the APC gene and is a subcategory of familial adenomatous polyposis. Gardner syndrome presents with numerous colonic polyps, as well as extracolonic growths, including osteomas, epidermal cysts, and fibromas. Other genetic syndromes associated with epidermal inclusion cysts include Favre-Racouchot syndrome (senile comedones, solar comedones, and nodular elastosis with cysts and comedones) and Gorlin syndrome (basal cell nevus syndrome).8 The diagnosis of epidermal inclusion cyst is made clinically with the history and physical examination findings of a small, discrete, single, freely movable cyst. If the cyst is surgically removed, histology can be used to confirm the diagnosis or confirm/rule out malignancy. Epidermal elements implanted into the dermis layer of the skin with a cystic cavity filled with laminated keratinous material should be visualized by histology. A granular layer filled with keratohyalin granules may be p resent.8

into the cyst; this reduces inflammation and infection risk, potentially to the point that surgery is no longer necessary.8 For the patient in the case described, the cyst was surgically removed using the minimal incision technique. Histologic examination of the tissue confirmed the diagnosis of epidermal inclusion cyst, and no evidence of malignancy was found.The patient required no further treatment. ■ Yelena Docik, BS, is a medical student; Eleanor Johnson, BS, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston,Texas. References 1. Esterly NB. Eruptive vellus hair cysts. Arch Dermatol. 1977;113(4):500-503. 2. Stiefler RE, Bergfeld WF. Eruptive vellus hair cysts—an inherited disorder. J Am Acad Dermatol. 1980;3(4):425-429. 3. Romiti R, Neto CF. Eruptive vellus hair cysts in a patient with ectodermal dysplasia. J Am Acad Dermatol. 1997;36(2):261-262. 4. Khatu S, Vasani R, Amin S. Eruptive vellus hair cyst presenting as asymptom-

Epidermal inclusion cysts result from inflammation and irritation that cause blockage of the infundibulum.

atic follicular papules on extremities. Ind Dermatol Online J. 2013;4(3):213. 5. Tomková H, Fujimoto W, Arata J. Expression of keratins (K10 and K17) in steatocystoma multiplex, eruptive vellus hair cysts, and epidermoid and trichilemmal cysts. Am J Dermatopathol. 1997;19(3):250-253. 6. Anand P, Sarin N, Misri R, Khurana V. Eruptive vellus hair cyst: an uncommon and underdiagnosed entity. Int J Trichol. 2018;10(1):31. 7. Karadag A, Cakir E, Pelitli A. Eruptive vellus hair cysts: an alternative diagnosing

Generally, the cysts are not infected, but in infectious cases the agent is often normal skin flora, including but not limited to Staphylococcus aureus, S epidermidis, and Propionibacterium.13 The differential diagnosis of epidermal cysts includes other types of cysts (pilar cyst, dermoid cyst, ganglion cyst, brachial cleft cyst, and pilonidal cyst), lipoma, abscess, neuroma, benign growths, skin carcinomas (squamous cell carcinoma and basal cell carcinoma), metastatic cutaneous lesions, pilomatrixoma, neurofibroma, calcinosis cutis, pachyonychia congenita, steatocystoma simplex, and steatocystoma multiplex.1,6 The punctum is a feature of epidermal cysts that distinguishes it from others in the differential diagnosis, such as a pilar cyst or a lipoma. A history of an unchanging, asymptomatic mass differentiates epidermal cyst from an abscess.14 Surgery is first-line therapy. Complete removal of the cyst is essential to prevent recurrence. It is best that the cyst be removed during a period when it is not inflamed to ensure the wall of the cyst is intact.The 2 most common surgical techniques are minimal incision and punch biopsy; the minimal incision technique provides better cosmetic results.15 Local anesthetic should be injected around, not directly into, the cyst. If cellulitis is present, oral antibiotic therapy should be included in the treatment plan. An alternative, less-invasive therapy is injecting triamcinolone

method. Ind J Dermatol Venerol Leprol. 2009;75(5):537. 8. Al-Mahmoud BE, Almaslamani HA, Al Hayki NA. Eruptive vellus hair cysts: is it a disease or a phenomenon? J Clin Cosm Dermatol. 2018;2(2). 9. Weir CB, St.Hilaire NJ. Epidermal inclusion cyst. StatPearls website. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532310/. Updated October 27, 2018. Accessed January 14, 2019. 10. Zito PM, Scharf R. Cyst, epidermoid (sebaceous cyst) StatPearls website. Available at: https://www.ncbi.nlm.nih.gov/books/NBK499974. Updated October 27, 2018. Accessed January 14, 2019. 11. Frank E, Macias D, Hondorp B, Kerstetter J, Inman JC. Incidental squamous cell carcinoma in an epidermal inclusion cyst: a case report and review of the literature. Case Rep Dermatol. 2018;10(1):61-68. 12. Lee S, Lee W, Chung S, et al. Detection of human papillomavirus 60 in epidermal cysts of nonpalmoplantar location. Am J Dermatopathol. 2003;25(3):243-247. 13. Hanly MG, Ojeda VJ. Epidermal inclusion cysts of the clitoris as a complication of female circumcision and pharaonic infibulation. Central Afr J Med. 1995;41(1):22-24 14. Shastri N, Espinosa. Epidermal inclusion cysts. Modern Medicine Network website. Available at: http://www.pediatricsconsultantlive.com/articles/epidermalinclusion-cysts. July 1, 2017. Accessed January 14, 2019. 15. Higgins JC, Maher MH, Douglas MS. Diagnosing common benign skin tumors. Am Fam Physician. 2015; 92(7):601-607. 16. Zuber TJ. Minimal excision technique for epidermoid (sebaceous) cysts. Am Fam Physician. 2002;65(7):1420.

38 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

CLINICAL PEARLS

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

PATIENTS WITH DIABETIC foot ulcer(s) with or without diabetic neuropathy should be using a strong wound cleanser, such as Dakin’s Solution quarter-strength orVashe Wound Solution, to aid in decreasing bacterial bioburden prior to applying treatment. Many of these patients are being treated as outpatients and are having home health nurses wipe with saline, which is often not an effective method for bacteria reduction, leading to failure to progress.—DESALES FOSTER, BSN, MSN, DNP, Media, Pennsylvania CHANGE YOUR TOOTHBRUSH after 24 hours of starting an antibiotic for any infection of the ears, nose, or throat. Bacteria is less virulent and you won’t give it back to yourself. Don’t swap spit for 24 hours either!—MADONNA FERRIS, BSN, MBA, MHA, MSN, Columbia, Missouri FOR INJURIES, minor abrasions, or repaired lacerations, I advise my patients to use clear zinc oxide when going out in the sun so their skin tone can maintain the same color, as before.There is no marked disparity where the scar is concerned.—RONALD SHERRY, MD, Pembroke Pines, Florida UPON DISCHARGE, surgical patients (mainly orthopedic) often want to know about dressing changes. They have a hard time understanding what to look for: what’s ok, and what’s not ok. I always advise them to treat it like a Band-Aid®. If you would change your Band Aid, then you should change your dressing. One dressing change per day is fine. If you need to change it more than once a day, that’s too much; the patient should be told to call the office to be seen in those instances.—MELISSA MCCRACKEN, MPAS Baltimore, Maryland

PRIOR TO INSERTING a nasogastric tube, pretreat the patient by using a premixed lidocaine/ surgical lubricant syringe (Uro-Jet®). Over the course of 3 to 5 minutes, gently instill the syringe contents into the nostril and ask the patient to sniff the lubricant back down the throat. Allow a minute or so for the contents to get absorbed into the mucous membranes.The lubricant will numb the base of the nostril as well as the back of the throat, making passing the tube fairly painless. I have had a very high success rate with this technique; it makes placing a nasogastric tube quick and easy.—MARY KASAVICH, MSN, APRN-CNP, Cleveland, Ohio WHEN I WAS in family practice, patients would often present with insects of various types lodged in their ear canal. If the insect was still alive, they would often relate a sensation of something moving or buzzing in the involved ear. Removal could be problematic with alligator forceps and even with irrigation. A simple solution that was often successful was to position a penlight at the external auditory meatus and turn the lights out in the examination room. The insect, attracted by the light, would often crawl out on its own, thereby avoiding the need for further interventions.—PAUL BROWN, BS (PA STUDIES), MED, Orangeburg, South Carolina GLUCOSE TESTING can lead to the development of calloused fingers and scar tissue, making it difficult to get an adequate drop of blood for glucose checks. In this case, advise the patient to use a thin rubber band as a tourniquet at the distal joint of the finger for approximately 10 seconds, then prick the finger, apply blood to the strip, and remove the rubber band. Newer meters require less blood, so this works well for a successful test almost every time.—ROBIN HENSLEY, MSN, FNP, Nashville,Tennessee

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 39

Stat Consult

A quick review of common conditions, using the best global evidence

Background

Human Immunodeficiency Virus (HIV) ALYSSA ABEBE, MPAS, PA-C; JUDY TRUSCOTT, MPAS, PA-C

Alyssa Abebe, MPAS, PA-C, is associate program director and assistant professor, and Judy Truscott, MPAS, PA-C, is program director and assistant professor in the Physician Assistant program at Chatham University, Pittsburgh, Pennsylvania.

• HIV (human immunodeficiency virus) was first discovered in 1981 in homosexual men. • HIV is a virus that leads to acquired immunodeficiency syndrome (AIDS). • HIV is transmitted through body fluids such as blood, semen/vaginal fluids, rectal fluids, and breast milk. • In the United States, HIV is most often transmitted through sexual intercourse and needle sharing. • Though the rate of new HIV infections has declined over the past decade, 1 in 7 individuals do not know they are infected. • In 2015, HIV was found to be the ninth leading cause of death in the 25 to 34 years and 35 to 44 years age groups. • Currently, 1.1 million people in the United States are living with HIV/AIDS. • Worldwide, there are 36.7 million (2.1 million younger than age 15 years) people living with HIV/AIDS. • Homosexual and bisexual men are more affected, with young African American gay men being the most affected. • Since the start of the epidemic, more than 35.0 million individuals have died of AIDSrelated illnesses; 1 million died in 2016 alone. • Zidovudine (AZT) was the first drug approved for the treatment of HIV in 1987; today, 49 single or combination drugs are approved.

Clinical Assessment

1 in 7 people with HIV are unaware of their infection status.

40 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

• The acute stage may present with flu-like illness: general fatigue, diarrhea, nausea/vomiting, generalized rash, myalgia, fever, dysphagia • Can be asymptomatic in the initial stage for up to 10 years • Later symptoms and signs may include muscle wasting/atrophy, weight loss, and signs relating to opportunistic infections Diagnosis

• Diagnosis is made by assessing either the HIV antigens, antibodies, or the actual viral load in the blood.

• A fourth-generation HIV enzyme-linked immunosorbent assay (ELISA) that detects both the HIV antigen and antibody was approved in 2011. The fourth-generation test may allow for faster diagnosis since it assesses HIV antigen and antibody as little as 2 weeks and up to 6 weeks after infection. • The Centers for Disease Control and Prevention (CDC) and US Food and Drug Administration (FDA) recommend fourth-generation screening; the US Preventive Services Task Force (USPSTF) recommends ELISA and confirmatory Western Blot. • Viral load is performed to determine the amount of virus in the bloodstream; it is also used to monitor treatment once initiated. An undetectable viral load is considered <20 copies/cells. • CD4 (T-cell lymphocyte) count indicates how well the immune system is working; those infected with HIV typically have CD4 counts <500 cells/mm3. • Phenotype and genotype testing can be performed to measure drug resistance prior to initiating HIV therapy or if there is suspicion of resistance while taking medications. Differential Diagnosis

• Influenza • Gastroenteritis • Streptococcal pharyngitis • Mononucleosis • Syphilis • Upper respiratory infection • Viral hepatitis

rates of osteoporosis, kidney disease, and cardiovascular disease (lipodystrophy), as well as an overall decreased immune system. Management

• There is growing evidence to support the benefit to starting individuals on antiretroviral therapy (ART) as soon as they are diagnosed with HIV to improve mortality rates. • There are 6 main classes of drugs used to treat HIV: nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), monoclonal antibodies, integrase inhibitors, and entry inhibitors. • Recommended therapy consists of a multidrug regimen from at least 2 different drug classes (typically an NNRTI, PI, or integrase inhibitor-based regimen). • Medication side effects are still present today, but studies indicate that <10% of ART-naive patients have treatmentlimiting adverse reactions. • Adherence is a major factor when treating individuals; lack of adherence to treatment can result in drug resistance. • When choosing HIV treatment for a patient, multiple factors may guide finding the right options: ——Drug interactions with non-HIV medications the patient may be taking ——Comorbidities ——Side effects ——Drug resistance ——Cost and adherence Prognosis

Complications

• AIDS is diagnosed when the CD4 count falls below 200 cells/mm3 or in the setting of a diagnosis of any AIDS-defining illnesses. • The CDC has identified 20 opportunistic infections, including but not limited to the following: ——Candidiasis of the esophagus, trachea, bronchi, or lungs ——Cytomegalovirus ——Toxoplasmosis ——HIV wasting syndrome ——Pneumocystis carinii pneumonia ——Lymphoma, numerous forms ——Kaposi sarcoma • Medications are available that can be taken on a regular basis to prevent opportunistic infections, depending on the individual’s CD4 count. • Studies have shown that individuals living with HIV have higher

• Abstinence is the recommended method for stopping the spread of sexually transmitted HIV/AIDS. • Without treatment, the average life span of someone living with AIDS is 3 years. • With treatment, those infected with HIV are living much longer and healthier lives. • Treatment has significantly reduced the rate of motherchild transmission when the mother is treated prenatally. • Barriers to treatment can be difficult to overcome and include cost of medication, drug adherence/resistance, and lack of medical care. Preventive Measures

• Safe-sex practices including using condoms and/or dental dams • Pre-exposure prophylaxis (PrEP) treatment has been approved by the FDA ——Consists of tenofovir (TDF) and emtricitabine (FTC) ——Needs to be taken on a regular daily schedule

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 41

Stat Consult • Post-exposure prophylaxis (PEP) is available for those who have experienced an exposure to HIV-infected fluids, such as needle sticks or unprotected sex with an HIV-positive individual. ——Needs to be initiated within 72 hours of the exposure and is taken for 4 weeks ■■ For children older than age 13 years and adults, the preferred regimen is tenofovir AND emtricitabine WITH raltegravir OR dolutegravir ■■ For those with renal dysfunction, the preferred regimen is adjusted renal dosages of zidovudine AND lamivudine WITH raltegravir OR dolutegravir ■■ For women of childbearing age who are sexually active or have been sexually assaulted and not using birth control OR for pregnant women, the recommended regimen is raltegravir, tenofovir, and emtricitabine ■■ For children aged 2 to 12 years, the preferred regimen is age- and weight-adjusted dosages of tenofovir AND emtricitabine AND raltegravir Screening

• The CDC and USPSTF recommend screening of all individuals between the ages of 15 and 65 years. Screening is also recommended for those younger than age 15 years or older than age 65 years who may be at increased risk. Also recommended is routine screening of all pregnant individuals. • The CDC recommends that patients at high risk should be screened at least annually. • Screening should be done routinely unless the patient declines the test (opt-out screening) Vaccination

Resources • Chu C, Selwyn PA. Diagnosis and initial management of acute HIV infection. Am Fam Physician. 2010;81(10): 1239-1244. • Final Recommendation Statement: Human Immunodeficiency Virus (HIV) Infection: Screening. U.S. Preventive Services Task Force w ebsite. http://www. uspreventiveservicestaskforce.org/Page/Document/ RecommendationStatementFinal/humanimmunodeficiency-virus-hiv-infection-screening. May 2015. Accessed January 16, 2019. • Guidelines for the use of antiviral agents in adults and adolescents living with HIV. AIDSinfo website. https:// aidsinfo.nih.gov/guidelines/brief-html/1/adult-andadolescent-arv/0. Accessed January 16, 2019. • HIV testing. Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/hiv/basics/ testing.html. Accessed January 16, 2019. • HIV treatment. AIDSinfo. Available at: https:// aidsinfo.nih.gov/education-materials/fact-sheets/21/51/ hiv-treatment—the-basics. Accessed January 16, 2019. • Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV—United States, 2016. Centers for Disease Control and Prevention website. Available at: https://www.cdc.gov/hiv/pdf/ programresources/cdc-hiv-npep-guidelines.pdf. Accessed January 16, 2019.

• There are no current vaccines available for HIV. ■

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42 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

PHYSICAL THERAPY VS SURGERY FOR MENISCAL TEARS Level 2 [mid-level] evidence A multicenter randomized noninferiority trial in the Netherlands compared early meniscectomy to physical therapy (PT) for adults age 45 to 70 with knee pain and nonobstructive meniscal tear found on magnetic resonance imaging.1 The primary outcome was change in patientreported knee function from baseline over 24 months (included data from all interval time points) based on the Subjective Knee Form of the International Knee Documentation Committee (IKDC) with scale from 0 to 100, where 100 represented no functional limitation. Researchers randomly assigned 321 patients to either arthroscopic partial meniscectomy (APM) or sixteen 30-minute sessions of PT over 8 weeks. Patients in the APM group did

not undergo postoperative PT unless indicated by the surgeon for treatment failure or functional decline. Participants in each group were similar in age (mean 57 years), body mass index (mean 27), and comorbidities. Most had “doubtful” to “minimal” osteoarthritis on plain radiography. Loss to follow-up was lower than predicted at 10%.The crossover rate from the PT group to APM was 29% (45 of 141 patients). Both groups had an overall improvement from baseline during the 2 years of follow-up. In both the as-treated and intention-to-treat analyses, PT met the predefined noninferiority margin when data from 3, 6, 12, and 24 months were combined. However, PT did not meet the noninferiority threshold at 12 or 24 months when taken individually. It is worth pointing out that the language describing the primary outcome was changed from “change from baseline to 24-month follow-up” to “change from baseline over 24-month follow-up.” This is important because the change in knee function from baseline to 24-month follow-up did not meet noninferiority criteria for PT based on the predefined one-tailed analysis (P <.025). Rather than demonstrating overall noninferiority at 24 months as reported, these data may actually point to noninferiority only up until 6 months, which overlaps with the postoperative period of the APM group. However, even when the difference was not within the noninferiority margin, the difference was less than the prespecified minimal clinically important difference of

8 points in the IKDC score.At follow-up, the greatest within-group difference over the 24-month time interval in IKDC score was only 5.7 points. These findings are consistent with those from the METEOR2 trial that found starting with PT and having surgery only if PT failed was as effective as immediate surgery in patients with knee osteoarthritis. In addition, the FIDELITY3 trial compared arthroscopic surgery to sham surgery with exercises in both groups after the procedure and found no significant differences in outcomes at 12 months, which further questions the value of surgery. References 1. van der Graaf VA, et al. Effect of early surgery vs physical therapy on knee function among patients with nonobstructive meniscal tears: the escape randomized clinical trial. JAMA. 2018;320(13):1328-1337. 2. Katz JN, et al.The MeTeOR trial (Meniscal Tear in Osteoarthritis Research): rationale and design features. Contemp Clin Trials. 2012;33(6):1189-1196. 3. Sihvonen R, et al. Finnish Degenerative Meniscal Lesion Study (FIDELITY): a protocol for a randomised, placebo surgery controlled trial on the efficacy of arthroscopic partial meniscectomy for patients with degenerative meniscus injury with a novel ‘RCT within-a-cohort’ study design. BMJ Open. 2013;3(3).

The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 43

Evidence-Based Medicine 3. Hernandez AF, et al Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.

Lancet. 2018;392:1519-1529.

had greater weight loss (1.5 lb) and a lower likelihood of beginning insulin therapy. In each group, approximately one-quarter of participants discontinued the weekly injections, although only 2% had injection-site reactions. Rates of hypoglycemia were lower in the placebo group than in the albiglutide group. This trial demonstrates albiglutide to be safe for patients with T2D and CV disease. It is worth noting that the drug has been withdrawn from the US market, although this was not for safety reasons. Also, GLP-1 agonists have black box warnings regarding concerns about thyroid cancer risk. Albiglutide is available in other countries, and this trial may serve as an impetus for its reintroduction in the United States, particularly if follow-up results show a survival advantage with albiglutide. This trial did not find a survival benefit, but a duration of only 18 months is likely too short to reliably determine if a difference in survival exists or not. References 1. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375(4):311-322. 2. Marso SP, et al. Semaglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375(19):1834-1844.

44 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

ASSESSMENT OF DUAL ANTIPLATELET THERAPY AFTER STROKE, TIA Level 2 [mid-level] evidence Initiation of dual antiplatelet therapy (DAPT) after minor ischemic stroke or high-risk transient ischemic attack (TIA) was shown to reduce the risk of stroke without increasing hemorrhage in Chinese patients in the CHANCE1 trial. Questions about the generalizability of these data lead investigators of the POINT trial to conduct a similar study in an international population.2 They randomly assigned 4881 patients to receive either clopidogrel (600-mg loading dose followed by 75 mg daily) plus aspirin 50 mg/d to 325 mg/d or aspirin 50 mg/d to 325 mg/d alone over a 90-day period.The aspirin doses were selected by individual treating physicians, although a dosage of 162 mg/d for 5 days followed by 81 mg/d was recommended. Participants were identified and randomization occurred within 12 hours of the initial event. In both studies, minor ischemic stroke was defined as an acute ischemic stroke with a score of 3 or less on the National Institutes of Health Stroke Scale. High-risk TIA is defined as a score of 4 or more on the ABCD2 scale, which estimates the risk of recurrent stroke. The trial was stopped early when a safety signal of major hemorrhage was exceeded.After review, it was determined that at the time the trial was stopped, a treatment effect had also been reached. The primary efficacy outcome, a composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes, occurred in 121 (5.0%)

GLP-1 REDUCES MAJOR CV EVENTS IN PATIENTS WITH T2D, CVD Level 1 [likely reliable] evidence Treatment goals for patients with type 2 diabetes (T2D) traditionally focus on reducing glycated hemoglobin (HbA1c). With the advent of a number of new options, however, clinicians can now select agents shown to improve patientoriented outcomes rather than just HbA1c. Several trials have examined cardiovascular (CV) outcomes in glucagon-like peptide-1 (GLP-1) agonists. The LEADER1 trial showed that liraglutide could reduce myocardial infarctions (MIs) and all-cause mortality in patients with T2D who had increased CV risk, and the SUSTAIN-62 trial demonstrated lower rates of nonfatal MI and stroke in similar patients treated with semaglutide. A recent multicenter study examined albiglutide in a double-blinded, randomized, placebo-controlled trial with more than 9000 patients with T2D. Patients had a mean HbA1c of 8.7%, and 70% had known CV disease.3 More than 75% in each group were taking a biguanide and were receiving therapy for CV disease, including aspirin and a statin. The primary composite outcome was major CV events, which consisted of MI, stroke, and CV death. Over an average of 18 months of follow-up, there were fewer major CV events in the albiglutide group than in the placebo group, which met the noninferiority margin allowing for superiority analysis for the primary outcome (4.6 events per 100 person-years in the albiglutide group vs 5.9 events per 100 person-years in the placebo group, hazard ratio 0.78, number needed to treat = 50 over 1.6 years).This was primarily driven by a single component of the composite outcome, nonfatal and fatal MI. There was no difference in the secondary outcome of death from any cause or CV death. Patients in the albiglutide group

patients in the clopidogrel-plus-aspirin group and 160 (6.5%) in the aspirin group. This finding was driven primarily by stroke; the 2 individual outcomes that were independently significant, both favoring the combination therapy, were ischemic stroke (4.6% vs 6.3%, P =.01) and ischemic or hemorrhagic stroke (4.8% vs 6.4%, P =.01). The primary safety outcome of major hemorrhage was seen in 0.9% of patients receiving clopidogrel plus aspirin and 0.4% of patients receiving aspirin alone, driven primarily by nonfatal non-intracranial hemorrhage (P =.04). The estimated number needed to treat for DAPT over 90 days was 67 and the number needed to harm was 200. A secondary analysis of the primary efficacy and safety outcomes was performed by time period; the benefit of clopidogrel plus aspirin was greater in the first 7 days (P =.04) and in the first 30 days (P =.02) than at 90 days, and the risk of major hemorrhage was significant only after 8 days (P =.04). These data contrast with the findings of the CHANCE trial, which found reduction in ischemic stroke of 3.5% without increased risk of hemorrhage. The POINT trial adds to the evidence supporting DAPT therapy for 90 days to prevent stroke in patients with high-risk TIA or minor stroke, albeit with smaller

benefit and increased risk of nonfatal non-intracranial hemorrhage than was seen before. There is no reason to continue DAPT beyond 90 days unless a subsequent trial establishes benefit, especially given that the benefits seen here were only significant in the first 30 days. References 1. Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl

J Med. 2013;369(1):11-19. 2. Johnston SC, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl

J Med. 2018;379(3):215-225.

APIXABAN IN PATIENTS WITH ESRD AND ATRIAL FIBRILLATION Level 2 [mid-level] evidence There are limited published data on the efficacy and safety of direct-acting oral anticoagulants (DOACs) in patients with end-stage renal disease (ESRD) on dialysis and atrial fibrillation. Initial DOAC trials excluded patients with ESRD. It has been suggested that when apixaban is used in patients on hemodialysis, it should be given at a reduced dose.1 A retrospective cohort study examined data from more than 25,000 Medicare beneficiaries with ESRD who were newly prescribed an anticoagulant for atrial fibrillation or atrial flutter between October 2010 and December 2015.2 Warfarin was prescribed to 23,172 patients and 2351 patients were prescribed apixaban during the 5-year time period.The authors used Medicare inpatient claims data to determine the rates of stroke, systemic embolism, major bleeding, gastrointestinal (GI) bleeding, and intracranial hemorrhage. The apixaban and warfarin cohorts had similar baseline characteristics after prognostic-score matching. There was no difference in the rates of ischemic stroke or symptomatic embolism, intracranial

bleeding, or GI bleeding among patients prescribed apixaban compared with those prescribed warfarin. There was a statistically significant reduction in major bleeding in the apixaban group compared with the warfarin group. It is important to note that rates of major bleeding, including intracranial bleeding, were high in both the apixaban and warfarin groups compared with the rates reported in randomized clinical trials. Among patients prescribed apixaban, 44% were prescribed the standard dosage (5 mg twice a day), whereas 56% were prescribed a reduced dosage of 2.5 mg twice a day. In a subgroup analysis, the standard dose of apixaban was compared with warfarin and found to be associated with lower rates of stroke/systemic embolism (hazard ratio [HR] 0.64; 95% CI, 0.42-0.97), major bleeding (HR 0.71; 95% CI, 0.53-0.95), and death (HR 0.63; 95% CI, 0.46-0.85).At the reduced dose, only the major bleeding rate was lower compared with warfarin (HR 0.71; 95% CI, 0.56-0.91). At 12 months, 62.4% of patients in the apixaban group and 72.5% of patients in the warfarin group had discontinued therapy. In summary, standard-dose apixaban for the treatment of atrial fibrillation in patients with ESRD may result in lower rates of major bleeding, stroke, and death compared with warfarin. Reduced-dose apixaban did not appear to be effective for reducing the rate of stroke/systemic embolism. Both the high discontinuation rate and the higher intracranial bleeding rates seen in these “real-world” data should be explored in future research. ■ References 1. Mavrakanas TA, et al. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc

Nephrol. 2017;28(7):2241-2248. 2. Siontis KC, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.

Circulation. 2018;138(15):1519-1529.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 45

LEGAL ADVISOR CASE

To Question, or Not to Question An NP’s hesitancy to disagree with her supervisor results in misdiagnosis.

BY ANN W. LATNER, JD

Ms N awoke with a feeling of dread. It was the same feeling she’d had for the past 2 months, ever since the 27-year-old nurse practitioner (NP) had been assigned a new supervising physician at the hospital where she worked. Ms N had been working at the hospital for 8 months. It was her second full-time position since she graduated from her NP program; her first job had been with a solo general practitioner. While it was a good starting job and she liked the physician she worked with, Ms N eventually wanted something more challenging that offered a wider range of experience.When an NP position at the hospital became available, she jumped at the opportunity. The hospital required new NPs to work rotations in different departments during their first year. Ms N’s first rotation in the gastroenterology department was challenging but interesting. Her second, on the maternity floor, was primarily uplifting. In both cases, her supervising physicians had been kind and were generous with their advice and counsel. The physicians in both instances welcomed Ms N’s questions and encouraged her

Once an avid swimmer and swim coach, following amputation the patient feared wet surfaces due to the potential for falling and could not return to swimming.

46 THE CLINICAL ADVISOR • FEBRUARY 2019 • www.ClinicalAdvisor.com

curiosity. But her latest rotation in the emergency department (ED) was quite different. Dr D was Ms N’s supervisor in the ED. He was a brusque and short-tempered 59-year-old who had a good reputation as a physician. Ms N had initially been looking forward to working with him, as she imagined that she would learn a great deal. However, her excitement soon turned to dread as she spent more time with him.Although polite to patients, the physician was extremely short with Ms N. He made it clear by the second day that he was not interested in conversing with her, and he did not appreciate what he considered unnecessary questions.Within a few days of working with him, Ms N’s excitement had diminished, and she began feeling trepidation at work. She spoke with some coworkers about the situation and discovered that no one liked working with Dr D, and everyone knew it was better to not interrupt or question him. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

out that Ms N had included knee dislocation in her differential diagnosis, but she did not raise the issue when the patient was being diagnosed by Dr D.They argued that Ms N had failed her patient by not advocating for him with the physician. The defense tried to argue that the knee dislocation had been ruled out by the radiographs, but this was rebutted by the plaintiff ’s expert who testified that radiographs alone cannot rule out a dislocation and that a vascular assessment should have been conducted. After 1 day of deliberations, the jury came back with a verdict for the plaintiff and awarded him $5.2 million.

Regardless of whether it is unpopular to challenge a supervisor, clinicians have a duty to advocate on their patients’ behalf. Protecting Yourself

The required elements of a medical malpractice case include the following: a duty owed to the patient (this exists in any clinician/patient relationship); a breach of the duty (a clinician failing to meet the standard of care); damages (physical or emotional); and causation (the damages were caused by the breach of the duty). In this case, Ms N breached her duty to Mr G by failing to question Dr D’s diagnosis and by failing to raise the possibility of a knee dislocation. Regardless of what your supervisor’s personality is like, whether you may get on someone’s “bad” side, or whether it is “unpopular” to challenge a supervisor, you have a duty to your patients to advocate on their behalf. Had Ms N done so, she might have saved her patient’s leg. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, NY.

Legal Background

The case went to a jury trial. At trial, the plaintiff ’s attorney introduced a “day in the life of ” video showing how difficult Mr G’s life had become. Once an avid swimmer and coach for his son’s swim team, Mr G now feared wet surfaces due to the potential for falling and could not return to swimming. He was a sympathetic plaintiff in the eyes of the jury. The plaintiff’s attorneys brought in medical experts who testified that 1 in 3 knee dislocations result in an injury to the popliteal artery; if the injury is not identified within a 6- to 8-hour window, the leg will most likely require amputation.The attorneys pointed www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2019 47

As the months passed, Ms N had largely succeeded in keeping a low profile with Dr D, but she couldn’t wait to get out of the ED. One afternoon a patient was brought into the ED with a knee injury. Mr G was a 40-year-old married man with 4 small children. He was employed as an armed security guard at a federal building and sustained an injury while working. According to the account he gave to the triage nurse, Mr G had been walking over a barrier that was lying in the ground when the barrier was activated by a coworker.The barrier went up and hoisted Mr G into the air, causing his knee to twist. Mr G was then trapped in the barrier.When Ms N examined the patient, he appeared to be in a great deal of pain; however, he tried to downplay the severity of the injury. Ms N sent Mr G for a series of radiographs and established a list of differential diagnoses, including knee sprain, broken or fractured knee, and knee dislocation.When the radiograph results came back, Ms N was able to eliminate a broken or fractured knee.When Dr D came to examine the patient, he snatched the radiographs and file from Ms N and asked the patient a few questions. “Knee sprain,” the physician barked to Ms N. “Discharge him.” Ms N opened her mouth to ask about the possible diagnosis of dislocated kneecap but then changed her mind. Dr D had years of experience, had just seen the patient, and had looked at the patient’s radiographs.There was nothing she could suggest that he wouldn’t have already considered. She believed that it wasn’t worth risking his wrath for such an unlikely possibility. The patient was discharged after having spent 2 hours in the ED. Two days later, the patient returned to the ED. He was found to have no pulse in his foot and was diagnosed with a knee dislocation that caused an injury to his popliteal artery. The patient required an above-the-knee leg amputation. The patient’s family encouraged him to speak with a plaintiff ’s malpractice attorney.After looking at the medical records, the attorney agreed to take the case and sued the hospital and the treating clinicians. Ms N was horrified to learn that she was part of a lawsuit.