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■■GI Illness in Older Adults ■■Physical Activity and HCC Risk ■■Maternal Hyperglycemia ■■WHO Top Health Threat FEATURE

Health Literacy and the Older Adult: A Persistent and Widespread Problem LEGAL ADVISOR

NP Testifies in a Rape Case


Lower Extremity Swelling and Rash


Evolution of the Intestinal Microbiome


MARCH 2019



Insights Into the Diagnosis and Treatment of OpioidInduced Constipation Constipation is one of the most common adverse effects of chronic opioid therapy.

Vice president, content, medical communications, editor Kathleen Walsh Tulley 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 @ Associate account manager Michael Deverin, 732.343.4921 Publisher Kathleen Hiltz, 201.774.1078 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 3, 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. 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.


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@ 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.


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 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.


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 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.





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


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.





MBER 2015

Abimbo la Farinde

, PhD,

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

• www.Clinic



Laura A.


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

Abby A.


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

.indd 62


2:44 PM




10 Maternal Weight and Pregnancy

Newsline ■■Maternal Weight Linked to Pregnancy Complications ■■Statin Therapy Often Not Initiated Before First ACS Event ■■Increase in GI Illness, Hospitalization Among Older Adults ■■Physical Activity Associated With Reduced Risk for HCC ■■Aspirin for CVD Prevention Tied to Major Bleeding ■■Effects of Hyperglycemia During Pregnancy on Offspring ■■WHO Names Anti-Vaccine Top Health Threat


29 Overcoming Low Health Literacy

14 Insights Into the Diagnosis and Treatment of Opioid-Induced Constipation As opioid-induced constipation can have a significant impact on quality of life, prevention is the cornerstone of management. 20 CME Evolution of the Intestinal Microbiome: Laying the Foundation for Child Health Expert faculty discuss key issues regard­ing the importance of the infant gut microbiome. 27 CME Feature Posttest

35 Itchy, Scaly Rash on the Back

Continues on page 6

44 NP Testifies in a Rape Case

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FEATURES (cont’d) Health Literacy and the Older Adult: A Persistent and Widespread Problem Strategies for overcoming low health literacy can improve clinician-patient communication and patient outcomes.



■ GI Illness in Older Adults ■ Physical Activity and HCC Risk ■ Maternal Hyperglycemia ■ WHO Top Health Threat


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



Health Literacy and the Older Adult: A Persistent and Widespread Problem

Lower Extremity Swelling and Rash


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


An Incidental Finding of Hypercalcemia

Constipation is

Human Immunodeficiencyone of theLEGAL most ADVISOR Virus (HIV) Fired for Refusing a Flu Shot common adverse LEGAL ADVISOR

effects of chronic opioid therapy. CONFERENCE ROUNDUP

To Question, or Not to Question a Supervisor

SABCS 2018


Erythematous, Scaly Scalp Lesions

Hyperkeratotic Plaques in the Axilla



Evolution of the Intestinal Microbiome

Public Health Implications of Drugs of Misuse and Abuse

WGS analyzes the AKs are one of entire genomic the most common DNA sequence of lesions seen in an organism. dermatology practice.



Irritable Bowel Syndrome and Vitamin D


Web Roundup A summary of our most recent opinion, news, and multimedia content from



Dermatology Clinic ■ Bumpy, Itchy Rash on the Extremities ■ Itchy, Scaly Rash on the Back



Dermatologic Look-Alikes Lower Extremity Swelling and Rash


Legal Advisor Clinician Testimony in a Rape Case




Clinical Pearls


NP Testifies in a Rape Case





Advances in Management Actinic Keratoses: Insights Into the Diagnosis of Breast Field Cancerization andCancer With and Treatment of OpioidGenome Sequencing Therapy Induced ConstipationPhotodynamicWhole

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Opioid-Free Pain Management Following Cesarean Delivery

Brady Pregerson, MD Shoulder Injury Following a Biking Accident A 41-year-old man is brought to the emergency department for evaluation of a shoulder injury sustained as the result of a fall from his road bike. He denies loss of consciousness, headache, neck or back pain, or other injury, and he reports that he was wearing a helmet. The triage nurse comments that the shoulder looks dislocated and asks if procedural sedation is needed. Read the full case here: CaseBikingAccident

A quality improvement intervention aimed at eliminating routine oral opioid prescription following cesarean delivery was found to reduce opioid consumption without jeopardizing pain control or patient satisfaction.

Hormone Therapy May Affect Cardiovascular Profiles in Transgender Persons In transgender individuals undergoing hormone therapy, testosterone was found to have a negative effect on lipids and lipoprotein concentrations, whereas estrogen plus cyproterone acetate was associated with more favorable lipid profi les.


Official Blog of The Clinical Advisor

Transvaginal Mesh Sling Complications and Risk of Psychiatric Illness

Jim Anderson, MPAS, PA-C, DFAAPA When Opioid Prescribing Guidelines Become Rules Understanding the current opioid prescribing rules is necessary for clinicians to safely and effectively treat patients with chronic pain conditions.

Women with incontinence who require surgical intervention following complications from a midurethral mesh sling procedure are at significantly increased risk for depression and self-harm.

Do School Report Cards Serve as a Precipitant to Child Physical Abuse?

Results of a recent study reveal an increased rate of calls to a state child abuse hotline resulting in verif ied reports of child physical abuse on the day following report card release.

Struggles in Managing Iatrogenic Polypharmacy: Case Study The presentation of an elderly patient receiving polypharmacy with development of new neurologic symptoms raises concern that iatrogenic polypharmacy may obscure the presence of a disease and delay appropriate diagnosis and treatment.



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 Check out some of our latest cases below!


Swollen Lesion on the Lower Lip A 63-year-old man presents for evaluation of a 5-day history of painful swelling affecting his lower lip. He denies antecedent trauma to the site. He does not have diabetes. He is a nonsmoker and drinks alcohol in moderation. Examination reveals an erythematous, 1.5cm nodule that is tender to palpation. Cervical and submandibular lymph nodes are not palpable. CAN YOU DIAGNOSE THIS CONDITION?

• Bacterial abscess • Squamous cell carcinoma

• Actinomycosis • Mucocele

● See the full case at

In partnership with


Journal of Orthopedics for Physician Assistants

How Would You Treat This Ulnar Styloid Fracture? A 28-year-old man presents to the office with left wrist pain after he fell on his outstretched hand. Anteroposterior and lateral radiographs show a displaced distal radius and ulnar styloid fracture. The distal radius fracture is treated with open reduction and internal fixation. HOW SHOULD THE ULNAR STYLOID FRACTURE BE TREATED?

• Observation • Percutaneous pinning • Open reduction and internal fixation • Excision of the styloid fragment ● See the full case at • THE CLINICAL ADVISOR • MARCH 2019 9



Women were recruited before 15 weeks’ gestation.

Maternal Weight Linked to Pregnancy Complications WOMEN WHO WERE born at a low birth weight and currently are overweight or obese were found to be at increased risk for complications of pregnancy, including preeclampsia, gestational hypertension, and gestational diabetes mellitus (GDM), according to a study published in Obesity. Researchers recruited women from the Screening for Pregnancy Endpoints (SCOPE) study to examine the influence of maternal birth weight on the risk of developing complications during pregnancy. Nulliparous women were recruited before 15 weeks’ gestation; participants were interviewed at 15 ± 1 and 20 ± 1 weeks’ gestation by SCOPE research midwives.The birth weights of 5327 women from the study were confirmed through clinical records or birth registries. All participants were followed after delivery; pregnancy outcome data and infant measurements were recorded within 72 hours of birth. Women with birth weights of 3000 g to 3499 g were

considered the reference group. Complications of pregnancy identified for the study included gestational hypertension, preeclampsia, small for gestational age (SGA) pregnancy, spontaneous preterm birth (sPTB), and GDM. Gestational hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg on 2 or more measurements 6 hours apart at 20 weeks’ gestation. Preeclampsia was defined as gestational hypertension or postpartum hypertension with proteinuria or any multisystem complication of preeclampsia or uteroplacental dysfunction. SGA diagnosis included a birth weight below the tenth customized centile adjusted for maternal height, weight, parity and ethnicity, gestational age at delivery, and infant sex. The definition of sPTB was spontaneous preterm labor or preterm rupture of membranes resulting in a preterm birth at <37 weeks. GDM was defined as fasting glucose ≥5.1 mmol/L or a 2-hour level of ≥8.5 mmol/L following an


oral glucose tolerance test. Any pregnancy that was uncomplicated was defined as a pregnancy with no antenatal, medical, or obstetric complications and resulted in the delivery of a healthy baby at 37 weeks’ gestation or later. Among the women eligible for the study, 60.1% had uncomplicated pregnan­ cies, 6.7% had gestational hyperten­sion, 6.5% had preeclampsia, 8.1% had SGA, 4.1% had sPTB, 3.1% had GDM, and 26.7% had other medical or obstetric compli­cations. After adjusting for confounders, birth weight <2500 g was associated with increased risk of developing preeclampsia, gesta­tional hypertension, SGA, and GDM com­pared with women in the reference group. Based on body mass index (BMI), women were classified into 4 groups: group 1 included those with a birth weight ≥2500 g and remained lean throughout life (BMI <25 kg/m2 at the 15-week visit); group 2 were those with a birth weight ≥2500 g and were either overweight or obese (BMI >25 kg/m2); group 3 included those who had a birth weight <2500 g and remained lean (BMI <25 kg/m2); group 4 were women who had a birth weight <2500 g and were overweight or obese (BMI >25 kg/m2). After adjusting for confounders, women in group 2 were at increased risk for preeclampsia and gestational hypertension, those in group 3 were at increased risk for gestational hypertension, and those in group 4 were at increased risk for preeclampsia, gestational hypertension, and GDM. “The main finding of this study is that women with a low birth weight and subsequently developed overweight or were diagnosed with obesity appear to be at increased risk for developing gestational hypertension, preeclampsia, and GDM,” the authors concluded.

Statin Therapy Often Not Initiated Before First ACS Event INTENSITY OF STATIN therapy for primary prevention has increased since the release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines; however, the change in the percentage of patients appropriately placed on statin therapy has been insignificant, according to a study published in The American Journal of Cardiology. A team of researchers from Illinois and California conducted a retrospective primary and sensitivity analysis to determine the effects of the 2013 ACC/ AHA guidelines on statin use for primary prevention in patients with first-time acute coronary syndrome (ACS). The 10-year predicted atherosclerotic cardiovascular disease (10yASCVD) risk score was calculated in 1265 patients aged 40 to 75 years (mean age, 58.29; 63.64% men) who presented with ACS and no

previous ASCVD.The 10yASCVD calculation included an ambulatory systolic blood pressure (SBP); a linear regression model was used to predict SBP for patients without known ambulatory SBP.

therapy prior to the 2013 guideline compared with 42.9% after the 2013 guideline publication; 33.6% of patients with predicted SBP with 10yASCVD ≥7.5% were on statins before 2013 compared

The investigators found that a significant number of patients with an ACS would have qualified for statin therapy per 2013 ACC/AHA guidelines before their event. Outcomes measured included statin status and statin intensity (high, medium, or low), which was subcategorized by ACS event type and date of left heart catheterization. The investigators defined agreement between 10yASCVD and statin status as 10yASCVD ≥7.5% on statin therapy and 10yASCVD <5% not on statins (not including patients with diabetes). Primary analysis resulted in 41% of patients with 10yASCVD ≥7.5% on statin

with 35.9% after the guideline release. In addition, 79.3% of patients with 10yASCVD ≥7.5% who were on statin therapy before the 2013 guidelines were administered high- or medium-intensity statins compared with 89.6% following the guideline release. Similar results were reported in the sensitivity analysis. The investigators conclude “… our data may help clinicians … understand the potential value of guideline adherence.”


Increase in GI Illness, Hospitalization Among Older Adults ALTHOUGH SEVERE gastrointestinal illness and related hospitalization is more common in older adults, the number of individuals who report symptoms associated with enteric infections decreases with age, according to a study published in Clinical Infectious Diseases. A team of researchers used data from surveillance and epidemiologic studies to determine age-specific clinical characteristics among subjects with laboratory-confirmed Campylobacter infection, nontyphoidal Salmonella infections, and acute gastroenteritis. Illness characteristics, including percentage reporting bloody diarrhea, fever, vomiting, abdominal pain, number of hospitalizations, duration of hospitalization, and duration of illness, among adults ≥65 years of age were compared with

adults aged 25 to 64 years, children aged <5 years, and subjects aged 5 to 24 years. The investigators reported a signifi­cant negative correlation among age groups and all symptoms, excluding bloody diarrhea, among patients with acute gastroenteritis.

Complaints of GI infection symptoms decrease with age.

In adults aged ≥85 years, only 9% and 4% reported bloody diarrhea associated with nontyphoidal Salmonella and Campylobacter infection compared with 59% and 55% of children <5 years, respectively. In contrast, the proportion of adults aged ≥65 years who reported being hospitalized was greater than in all younger groups. “… [I]t is important to understand the clinical presentation of gastrointestinal illness in older adults to prioritize early recognition and rapid treatment to prevent hospitalizations and poor outcomes,” the authors wrote.“This study highlights the importance and challenges of early clinical detection of gastrointestinal illness in older adults and the need for research on age-specific risk factors, symptoms, and severity indicators associated with gastrointestinal illness.” • THE CLINICAL ADVISOR • MARCH 2019 11



Physical Activity Associated With Reduced Risk for HCC

Time spent participating in physical activity was captured.

HIGHER TOTAL PHYSICAL activity, including vigorous physical activity, was found to be associated with a reduced risk of hepatocellular carcinoma (HCC), according to a study published in the Journal of Hepatology. Researchers used the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, a multinational prospective study that analyzes the link between diet, lifestyle, and environmental factors with cancer risk and chronic diseases, to identify the relationship between physical activity and hepatobiliary cancer risk. From 1992 to 2000, men and women aged 25 to 70 years (n = 467,336) were recruited from 23 European centers; patient data on physical activity, education, smoking, alcohol consumption, coffee intake, anthropometric measurements, and medical history were collected at baseline. Of these patients, 275 were identified with HCC, 93 with intrahepatic bile duct cancers (IHBC), and 164 with nongallbladder extrahepatic bile duct cancers (NGBC). The EPIC physical activity questionnaire was used to assess recreational, household, and occupational physical activity. Recreational activities such as

cycling and physical exercises were calculated by the amount of time — in hours per week — spent performing these activities and summarized into 4 categories: inactive, moderately inactive, moderately active, and active. Occupational physical therapy was patient reported as either sedentary, standing, manual, or heavy manual work. Patients were also asked whether engaging in household or physical activity caused increased sweating or heart rate and, if so, how many hours per week they dedicated to vigorous physical activities. Patient mean age was 51.3 years; 70.2% were women. Follow-up occurred at 14.9 years or 6,508,182 person-years. Comparing active and inactive individuals resulted in an adjusted hazard ratio (HR) for HCC of 0.55. For HCC risk with >2 h/wk of vigorous activity vs no vigorous activity, the adjusted HR was 0.50. These outcomes were not modified by sex, age, waist circumference, body mass index (BMI), smoking, current alcohol consumption, or lifetime alcohol consumption.Total and vigorous physical activity were unrelated to IHBC or NGBC risk. In the analysis of the associations with HCC that were mediated by waist circumference, BMI, and diabetes, waist circumference explained 40% and BMI explained 30% of the association of total physical activity and HCC. Of the total effect of vigorous physical activity on HCC mediated by waist circumference and BMI, the proportions were 17% and 12%, respectively. Diabetes did not mediate the associations. “Studies with more detailed and objectively measured physical activity assessed at multiple time points throughout the life course are warranted to confirm our findings and may help establish the optimal dose, type, intensity, and timing of physical activity that is needed to prevent HCC,” the authors concluded.


Aspirin for CVD Prevention Tied to Major Bleeding THE USE OF ASPIRIN in individuals without cardiovascular disease (CVD) was found to be linked to a reduced risk of cardiovascular events and an increased risk for major bleeding, according to a study published in JAMA. Researchers from London, United Kingdom, conducted a meta-analysis of 13 randomized clinical trials to determine the effects of aspirin for primary prevention of cardiovascular events. The main cardiovascular outcome was the combination of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. The main bleeding outcome was any major bleeding as defined by each study. Eligible studies in the meta-analysis compared aspirin use with either placebo or no treatment; follow-up of ≥12 months was required, and participants could not have known CVD. A total of 164,225 individuals (median age, 62 years; 53% women) with 1,050,511 participant-years of follow-up were included in the analysis; 19% of participants had diabetes. The risk of the primary cardiovascular outcome ranged from 2.6% to 15.9%, with a median baseline of 9.2%. Aspirin use was found to be significantly associated with a reduced risk of composite cardiovascular outcomes compared with no aspirin use (hazard ratio [HR], 0.89; absolute risk reduction, 0.38%). In addition, aspirin use was linked to an increased risk of major bleeding events compared with no aspirin use (HR, 1.43; absolute risk increase, 0.47%).

Effects of Hyperglycemia During Pregnancy on Offspring DURING PREGNANCY, across the maternal glucose spectrum, higher glucose levels are significantly linked to childhood glucose and insulin resistance in offspring regardless of family history of diabetes and maternal and childhood body mass index (BMI), according to a study published in Diabetes Care. A team of international researchers analyzed maternal glycemia during pregnancy and childhood glucose outcomes from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, an observational, population-based study that identified a link between maternal glucose and adverse perinatal outcomes. The investigators invited 4832 children aged 10 to 14 years whose mothers had a 75-g oral glucose tolerate test at or near 28 weeks’ gestation to participate in the study; 4160 children were evaluated for glucose outcomes.

Maternal glycemia may contribute to type 2 diabetes in children.

Primary outcomes were impaired glucose tolerance and impaired fasting glucose among children. Secondary outcomes included glucose-related measures using plasma glucose, glycated hemoglobin (HbA1c), and C-peptide from child oral glucose tolerance tests to determine

insulin sensitivity.The disposition index, which is a measure of pancreatic β-cell function, was also calculated. Maternal fasting plasma glucose measurements were positively associated with fasting plasma glucose and HbA1c levels in children; 1-hour and 2-hour maternal plasma glucose levels were linked to 30-minute, 1-hour, and 2-hour plasma glucose and HbA1c levels in children. Maternal fasting plasma glucose and 1-hour and 2-hour plasma glucose levels were inversely related to insulin sensitivity.Additionally, 1-hour and 2-hour plasma glucose measurements were inversely related to the disposition index. Maternal fasting glucose levels were associated with child impaired fasting glucose levels, and 1-hour and 2-hour plasma glucose levels were associated with impaired glucose tolerance. These associations were independent of maternal and child BMI.


WHO Names Anti-Vaccine Top Health Threat THE WORLD Health Organization (WHO) named vaccine hesitancy one of the top 10 threats to global health in 2019. “Vaccine hesitancy  —  the reluctance or refusal to vaccinate despite the availability of vaccines  —  threatens to reverse progress made in tackling ­vaccine-preventable diseases.” Although the vast majority of parents vaccinate their children according to the immunization schedule recommended by the Centers for Disease Control and Prevention, the percentage of children who have not undergone any of the 14 recommended vaccinations has more than quadrupled from 0.3% to 1.3% since 2001. WHO points to a “3Cs” model  — complacency, convenience, and confidence  —  to explain why people refuse to vaccinate. Complacency occurs when

the perceived risks of disease are low and vaccination is deemed unnecessary. Convenience is measured by the extent to which availability, affordability, willingness to pay, health literacy, and other potential obstacles prevent vaccination. Confidence

Hysteresis describes how a system is dependent on its history and how the impacts of a force can persist well after the initial force has been altered or eliminated.This phenomenon can be seen in many physical systems but also in society. In the context

Hysteresis describes how a system is depen­dent on its history and how the impacts of a force can persist well after the initial force has been altered or eliminated. refers to distrust in the safety and efficacy of the vaccines, the system that delivers them, and the motivations of policymakers who decide which vaccines are necessary. In a study published in Proceedings of the Royal Society B, Dartmouth College researchers explained that hysteresis may describe persistent vaccine skepticism.

of vaccines, it prevents an increase in vaccination levels even after negative objections have been debunked. As a result, society is more vulnerable to outbreaks of disease. “Hysteresis is a powerful force that is difficult to break at a societal level,” concluded Feng Fu, assistant professor of mathematics at Dartmouth College. ■ • THE CLINICAL ADVISOR • MARCH 2019 13


Insights Into the Diagnosis and Treatment of OpioidInduced Constipation Treatment of OIC includes modalities that address non-opioid-related constipation as well as those that target the OIC mechanism of action.



Constipation is one of the most common adverse effects of chronic opioid therapy.

pioid-induced constipation (OIC) is a condition whereby patients experience constipation in the setting of opioid therapy.1 It is estimated that more than 100 million adults live with chronic nonmalignant pain, and between 6% and 33% of patients seen in the primary care setting have chronic pain.2,3 According to the US Centers for Disease Control and Prevention, 191 million prescriptions for opioids were written in 2017, and it is estimated that 4% of US adults are receiving chronic opioid therapy (COT).4,5 One study of the adverse effects of COT concluded that 41% of individuals taking opioids chronically experience constipation, making constipation one of the most common adverse effects for those using COT.6 Furthermore, OIC has a significant impact on quality of life.A study conducted on the burden of OIC concluded that “[p]atients have reported that they would rather suffer pain than constipation.”7 Because OIC is one of the most frequently reported side effects of COT, and opioid use is so common, clinicians must be cognizant of this issue and be comfortable with its diagnosis and management. In 2018, the American Gastroenterological Association (AGA) issued new guidelines for the management of OIC.8 The approach to treatment of OIC includes the use of modalities that address non-opioid-related constipation as well as several relatively new medications that specifically target the OIC mechanism of action.1 Continues on page 16


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Approximately 40% of chronic opiate users experience opioid-induced constipation, which has a significant impact on quality of life. Pathophysiology

Opioids affect the gastrointestinal (GI) system by binding to 3 types of receptors: delta (δ), kappa (κ), and mu (μ) receptors; of these, μ receptors are primarily responsible for the gastrointestinal adverse effects associated with opioids including constipation, nausea, and vomiting.9 When opioids bind to μ receptors in the gut, they inhibit the enteric neural system by blocking adenylate cyclase, thereby reducing acetylcholine release, which decreases smooth muscle contraction.9,10 In addition, opioids cause increased water reabsorption in the gut leading to firm, dry stool.9,11 OIC is unique because unlike other GI-related adverse effects of opioids, patients do not develop tolerance to the constipation, making the need for further intervention necessary.10 Clinical Presentation and Diagnosis

Patients who develop OIC present similarly to patients with chronic idiopathic constipation; however, the symptoms begin following the initiation of opioid therapy. It is important for clinicians to conduct a thorough medication history when evaluating new-onset constipation. The risk of developing constipation in the setting of opioids increases with a longer duration of use; however, patients can still develop symptoms when opioids are used for a short period of time.12 As defined by the Rome IV criteria, diagnostic criteria for OIC include new or worsening symptoms of constipation when initiating, changing, or increasing opioid therapy.13 Symptoms must include 2 or more of the following: fewer than 3 spontaneous bowel movements per week, straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, or manual maneuvers to facilitate defecation during more than 25% of bowel movements.13 Other symptoms of OIC may include abdominal pain or distention, gas or bloating, and nausea.6 Clinicians must evaluate for red flag signs and symptoms such as weight loss, loss of appetite, blood in the stool, severe symptoms, failure to respond to therapy, or iron deficiency anemia that may warrant further evaluation before making a diagnosis. Additionally, a thorough physical examination including full abdominal and rectal examinations should be performed to rule out alarm features of more severe bowel pathology. It is also important to evaluate for comorbid conditions or concurrent medications that may cause or exacerbate constipation. Once a diagnosis of OIC is made, clinicians should monitor for the development of fecal impaction or ileus. Challenges to making the diagnosis of OIC have been identified and include a lack of awareness of OIC, lack of proactive

questioning on the part of clinicians about OIC, and patient discomfort in initiating a conversation about constipation.1 Nevertheless, it is important for patients and clinicians to recognize symptoms of OIC early and treat appropriately in an effort to improve patient satisfaction and adherence to therapy. Management

The AGA published updated treatment guidelines for OIC in October of 2018 recommending the use of both lifestyle modifications as well as pharmacologic therapies.8 Prevention is a cornerstone of OIC management. Patient education focused on the potential constipating side effects of opioids at the onset of therapy can help to ensure that constipation is recognized and treated early in an effort to prevent treatment nonadherence, severe symptoms, and eventual fecal impaction or ileus.A bowel regimen can be initiated in patients who require opioids to prevent severe constipation before symptoms develop.12 In addition, clinicians should only prescribe opioids for the shortest timeframe needed to accomplish the clinician-patient agreed-upon goals of treatment.4 Once OIC is diagnosed, regardless of which treatment modality is chosen, it is essential to emphasize the importance of adherence to and consistency with the treatment. Understanding the patient’s baseline bowel movements prior to initiation of opioid therapy will help to identify the development of constipating side effects.This not only allows for easier recognition of OIC, but it also helps set goals for treatment. Lifestyle modifications. The AGA guidelines recommend the use of nonpharmacologic lifestyle interventions in addition to pharmacologic agents when treating OIC. Lifestyle modifications include such behaviors as increasing fluid intake, implementation of a toilet schedule, taking in adequate fiber, and engaging in regular physical activity.8 Pharmacologic therapy. The AGA guidelines recommend the use of laxatives as first-line agents for OIC due to their general safety, availability, and low cost.8,14 For laxativerefractory OIC, which is defined as persistent constipation despite the scheduled use of 2 laxatives from 2 different classes for at least 2 weeks, the AGA recommends initiating targeted opioid antagonists.8 Four therapies are approved by the US Food and Drug Administration (FDA) for the treatment of mild to moderate OIC: lubiprostone, methylnaltrexone, naloxegol, and naldemedine (Table). Laxatives. Two open-label studies have evaluated the efficacy of laxatives in OIC.15,16 Twycross et al demonstrated a 75% response rate to a stimulant laxative in cancer patients with constipation due to morphine therapy.15 Wirz et al


A detailed history and physical exam are crucial for identifying the underlying cause of constipation and excluding the presence of alarm features. compared the efficacy of polyethylene glycol (PEG), lactulose, and a stimulant laxative in treating OIC, with findings suggesting improvement in symptoms with the use of PEG or a stimulant laxative over lactulose.16 In a randomized control trial comparing the efficacy of PEG or lactulose to placebo for the treatment of OIC, a reduction in constipation symptoms was noted in patients who received either lactulose or PEG with no statistically significant difference between the 2 treatment arms.17 In addition to safety, availability, and cost, the AGA also considered that most OIC clinical trials offer laxatives as rescue

agents to patients not responding to therapy and therefore recommends laxatives as first-line agents in OIC.8 Options for treatment include stimulant laxatives such as senna and bisacodyl, stool softeners such as docusate, and osmotic laxatives such as PEG, lactulose, sorbitol, milk of magnesia, and magnesium. Clinicians should use caution when considering magnesium-containing therapies for patients with renal disease. Peripherally acting mu-opioid antagonists (PAMORA). PAMORAs indicated for the treatment of OIC include naloxegol, naldemedine, and methylnatrexone. These agents are opioid antagonists selective to peripheral μ-receptors and

TABLE. FDA-Approved Treatment Options for Opioid-Induced Constipation* Drug

Dosage/Administration Common Adverse Effects†



Known or suspected mechanical bowel obstruction or increased risk for recurrent bowel obstruction

Dose adjustment needed for renal and hepatic impairment

PERIPHERAL OPIOID ANTAGONISTS Methylnaltrexone 0.15 mcg/kg every other day subcutaneously

Abdominal pain, diarrhea, nausea, flatulence, headache, hyperhidrosis, hot flush, tremor, chills, dizziness

250 mg/d orally

Abdominal pain, diarrhea, headaches, abdominal distention, vomiting, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, chills


12.5 mg/d to 25 mg/d orally

Abdominal pain, diarrhea, nausea, flatulence, headache

• Known or suspected mechanical bowel obstruction or increased risk for recurrent bowel obstruction • Those taking CYP 3A4 inhibitors

• Start at 12.5 mg/d and titrate up, as needed • Dose adjustment in renal impairment • Avoid in severe hepatic failure


0.2 mg/d orally

Abdominal pain, diarrhea, nausea, vomiting, gastroenteritis

Known or suspected mechanical bowel obstruction or increased risk for recurrent bowel obstruction

• Patient receiving opioids for <4 weeks may be less responsive • Avoid in severe hepatic impairment • No dose adjustment required in mild or moderate impairment

Nausea, diarrhea, syncope, hypotension, dyspnea, bowel obstruction

Known or suspected mechanical bowel obstruction or increased risk for recurrent bowel obstruction

Dose adjustment needed for hepatic impairment


24 mcg twice daily orally

* See package inserts for complete prescribing details. † For all drugs, monitor for opioid withdrawal symptoms, severe abdominal pain/diarrhea, GI perforation. ‡ Not recommended in the AGA 2018 OIC treatment algorithm. Data adapted from: • THE CLINICAL ADVISOR • MARCH 2019 17


POLL POSITION Opioids affect the gastrointestinal system by binding to all but which of the following receptors? 5.21% ■ Beta (β) receptors


■ Delta (δ) receptors ■ Kappa (κ) receptors ■ Mu (μ) receptors

48.96% 31.25%

For more polls, visit

are unable to cross the blood-brain barrier.18,19 Of note, oral naloxone, a systemic opioid antagonist used to treat opioid addiction, has been shown to be effective in treating the symptoms of OIC; however, it is a nonselective opioid antagonist and therefore may reduce analgesic effects and is not routinely used in clinical practice to treat OIC.20 Naloxegol blocks peripheral μ receptors and includes a PEG component to limit the ability to cross the blood-brain barrier.21,22 Between 2011 and 2012, two identical multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 studies were conducted in the United States and Europe.19 Patients were randomly assigned in a 1:1:1 ratio to receive naloxegol 25 mg vs naloxegol 12.5 mg vs placebo with a primary end point of achieving spontaneous bowel movements without the use of rescue laxatives over a 12-week treatment period. Response rates were greatest in patients who received naloxegol 25 mg compared with those receiving placebo (in one study: 44.4 % vs 29.4 %, P =.001; in the second study: 39.7% vs 29.3%, P =.02), without significant pain score or daily opioid dose requirement.19 Naldemedine is the latest PAMORA to be approved by the FDA, receiving approval for treatment of OIC in March 2017, and is structurally similar to naltrexone.8 Four randomized control trials enrolling more than 2400 patients combined investigated the efficacy of naldemedine compared with placebo.23-25 Across all studies, 52% of patients receiving naldemedine achieved at least 3 spontaneous bowel movements per week compared with 35% in the placebo arm.8 One of these studies also investigated the safety of long-term use of naldemedine with patients enrolled for 52 weeks.24 Treatment-emergent adverse effects in the naldemedine arm

were 68% compared with 72.1% in the placebo group with a difference of -3.6% (95% CI, -8.7 to 1.5).24 Further, sustained improvement in bowel movements and overall quality of life was observed in the naldemedine arm compared with placebo at all time points throughout the study (P< .0001).24 The inability of methylnaltrexone to cross the blood-brain barrier is due to an added quaternary functional group, which inhibits the constipating effects of opioids without effecting analgesia.18,26 In a double-blinded, randomized, placebo-controlled study conducted between 2004 and 2005, 133 patients with OIC were randomly assigned to receive methylnaltrexone subcutaneously or placebo every other day. Primary outcomes of this study included laxation within 4 hours of the first dose and laxation without rescue laxatives after 2 or more doses. Of the patients who received methylnaltrexone, 48% achieved laxation within 4 hours and 52% achieved laxation within 4 hours after 2 or more doses without the use of a rescue laxative compared with 15% and 8% in the placebo group, respectively (P <.001).27 An oral formulation of methylnaltrexone is also available.A randomized, double-blinded study was conducted between 2010 and 2011 with a primary end point of achieving rescue-free bowel movements.28 The response rate of patients who received oral methylnaltrexone 300 mg/d or 450 mg/d was significantly greater than that seen in patients administered placebo.28 Chloride channel activators. Lubiprostone is an oral chloride channel activator that increases intestinal fluid secretion. By selectively activating chloride channel 2, fluid is secreted into the lumen of the gut without disturbing serum electrolyte levels.29 A randomized, double-blind, placebo-controlled, parallel-group phase 3 study was conducted between 2010 and 2011 in patients receiving COT for chronic nonmalignant pain with OIC.30 Patients were randomly assigned to receive lubiprostone 24 mcg or placebo twice daily.The primary end point was overall spontaneous bowel movement response rate based on constipation events recorded daily in a patient diary. Overall spontaneous bowel movement response rates were found to be improved in patients treated with lubiprostone vs placebo (27.1% vs 18.9%, respectively; P =.03).30 Although approved by the FDA for use in OIC, the AGA currently makes no recommendation for the use of lubiprostone in OIC due to poor quality of evidence; this is therefore identified as a research gap.8 Conclusion

OIC is a common side effect of opioid treatment but is often undertreated by clinicians. Identification of OIC can be challenging as it presents similarly to functional constipation; however, it is important to distinguish between the two as clinical course and treatment options differ. A detailed history and physical examination are crucial for identifying the underlying cause of constipation and excluding the presence


of alarm features. Prevention is the foundation of management, which includes taking the time to discuss constipation as well as starting a bowel regimen when initiating opioid treatment. The newly issued AGA guidelines recommend laxatives as first-line agents for treating OIC, with PAMORAs the recommended class of pharmacologic agents for laxativeresistant OIC. Further research is ongoing to identify newer agents that may be effective in treating OIC. ■

picosulfate in opioid-induced constipation: results of an open-label, prospective, dose-ranging study. Palliat Med. 2006;20(4):419-423. 16. Wirz S, Nadstawek J, Elsen C, Junker U, Wartenberg HC. Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care (Engl). 2012;21(1):131-140. 17. Freedman MD, Schwartz HJ, Roby R, Fleisher S. Tolerance and efficacy of polyethylene glycol 3350/electrolyte solution versus lactulose in relieving opiate induced constipation: a double-blinded placebo-controlled trial. J Clin

Frank R. Giannelli, MS, PA-C, and Sarah Patel, MS, PA-C, MBA, are RBHS Lecturers at Rutgers School of Health Professions, in Newark, New Jersey, and practice at the Hope Clinic in Plainfield, New Jersey.

Pharmacol. 1997;37(10):904-907. 18. Yuan CS, Foss JF, OConnor M,Toledano A, Roizen MF, Moss J. Methyl­ naltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin


Pharmacol Ther. 1996;59(4):469-475.

1. Gaertner J, Siemens W, Camilleri M, et al. Definitions and outcome

19. Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J.

measures of clinical trials regarding opioid-induced constipation: a systematic

Naloxegol for opioid-induced constipation in patients with noncancer pain.

review. J Clin Gastroenterol. 2015;49(1):9-16.

New Engl J Med. 2014;370(25):2387-2396.

2. Nahin RL. Estimates of pain prevalence and severity in adults: United States,

20. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced

2012. J Pain. 2015;16(8):769-780.

constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48-53.

3. Use of opioids for the treatment of chronic pain. 2009. http://

21. Webster L, Dhar S, Eldon M, Masuoka L, Lappalainen J, Sostek M. A phase

2, double-blind, randomized, placebo-controlled, dose-escalation study to

therapy-cncp.pdf. Accessed December 6, 2018.

evaluate the efficacy, safety, and tolerability of naloxegol in patients with

4. Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids

opioid-induced constipation. Pain. 2013;154(9):1542-1550.

for chronic pain — United States. MMWR Recomm Rep. 2016;65(1):1-49.

22. Camilleri M. Opioid-induced constipation: challenges and therapeutic

5. Centers for Disease Control and Prevention. US Opioid Prescribing Rate

opportunities. Am J Gastroenterol. 2011;106(5):835-842; quiz 843.

Maps. 2018. Accessed January 11, 2019, 2019.

23. Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. Naldemedine versus

6. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer

placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2):

pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380.

two multicentre, phase 3, double-blind, randomised, parallel-group trials.

7. Panchal SJ, Müller-Schwefe P,Wurzelmann JI. Opioid-induced bowel dysfunction:

Lancet Gastroenterol Hepatol. 2017;2(8):555-564.

prevalence, pathophysiology and burden. Int J Clin Pract. 2007;61(7):1181-1187.

24. Webster LR, Nalamachu S, Morlion B, et al. Long-term use of naldemedine

8. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological

in the treatment of opioid-induced constipation in patients with chronic non-

Association Institute guideline on the medical management of opioid-induced

cancer pain: a randomized, double-blind, placebo-controlled phase 3 study.

constipation. Gastroenterology. 2019;156(1):218-226.

Pain. 2018;159(5):987-994.

9. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and

25. Webster LR, Yamada T, Arjona Ferreira JC. A phase 2b, randomized,

potential new therapies. Drugs. 2003;63(7):649-671.

double-blind placebo-controlled study to evaluate the efficacy and safety of

10. Nelson AD, Camilleri M. Chronic opioid induced constipation in

naldemedine for the treatment of opioid-induced constipation in patients

patients with nonmalignant pain: challenges and opportunities. Therap Adv

with chronic noncancer pain. Pain Med. 2017;18(12):2350-2360.

Gastroenterol. 2015;8(4):206-220.

26. Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. Antagonism of gut, but

11. Pappagallo M. Incidence, prevalence, and management of opioid bowel

not central effects of morphine with quaternary narcotic antagonists. Eur J

dysfunction. Am J Surg. 2001;182(5A Suppl):11S-18S.

Pharmacol. 1982;78(3):255-261.

12. Camilleri M, Drossman DA, Becker G, Webster LR, Davies AN, Mawe GM.

27. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced

Emerging treatments in neurogastroenterology: a multidisciplinary working

constipation in advanced illness. New Engl J Med. 2008;358(22):2332-2343.

group consensus statement on opioid-induced constipation. Neurogastroent

28. Rauck R, Slatkin NE, Stambler N, Harper JR, Israel RJ. Randomized, double-

Motil. 2014;26(10):1386-1395.

blind trial of oral methylnaltrexone for the treatment of opioid-induced consti-

13. Drossman DA, Chang LC, Kellow WJ, Tack J, Whitehead WE. ROME IV

pation in patients with chronic noncancer pain. Pain Pract. 2017;17(6):820-828.

Diagnostic Algorithms for Common GI Symptoms. Raleigh, North Carolina: The

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ROME Foundation; 2016.

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14. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology,

30. Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-

clinical consequences, and management. Gastroenterol Res Pract. 2014;2014:141737.

controlled trial of lubiprostone for opioid-induced constipation in chronic

15. Twycross RG, McNamara P, Schuijt C, Kamm MA, Jordan C. Sodium

noncancer pain. Am J Gastroenterol. 2015;110(5):725-732. • THE CLINICAL ADVISOR • MARCH 2019 19

CME FEATURED COURSE LEARNING OBJECTIVES After completing this activity, the participant should be better able to: • Describe the intestinal microbiome and the role of pre- and probiotics in pediatric health and development of the immune system • Identify factors, including vaginal birth and breastfeeding, that promote healthful microbial colonization of the infant gut • Recommend evidencebased strategies for using probiotics in the management of pediatric diarrhea and colic • Advise parents about the evolving understanding of the benefits of human milk oligosaccharides (HMOs) added to infant formula COMPLETE THE POSTTEST: Page 27

Release Date: March 15, 2019 Expiration Date: March 15, 2020 Estimated Time to Complete: 60 minutes Maximum Credits: 1.0 AMA PRA Category 1 Credit(s)TM Accredited Provider: This activity is provided by Haymarket Medical Education. Commercial Supporter Statement: Supported by an educational grant from Nestlé Nutrition Institute. Program Description: The potential for prebiotics and probiotics to prevent the development of allergies as well as to prevent and/or treat gastrointestinal disorders such as diarrhea and colic in infants has been the subject of increased attention in the media, but not all of the information parents of infants and young children get from the lay media is accurate or reliable. Pediatricians and other clinicians who advise parents about infant and child nutrition are challenged to provide parents with up-to-date information about this rapidly evolving field of study. In this article, expert faculty discuss key issues regarding the importance of the infant gut microbiome and our still-evolving understanding of its critical role in the development of a healthy immune system, as well as its direct effects in the gastrointestinal tract. Topics include the safe and efficacious use of prebiotics, probiotics, and human milk oligosaccharides that are being made commercially available in infant formulas. Intended Audience: This activity has been designed to meet the educational needs of pediatricians, family physicians, pediatric and family nurse practitioners (NPs) and physician assistants (PAs), dietitians, and other clinicians who advise parents about the nutritional needs of infants and children. 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 Michael D. Cabana, MD, MPH - Chair Professor of Pediatrics, Epidemiology & Biostatistics Chief, Division of General Pediatrics University of California, San Francisco San Francisco, CA Dr Cabana discloses that he is a consultant for BioGaia, Genentech, Inc., Nestlé Nutrition, and Novartis Pharmaceuticals Corporation. He is also on the speakers’ bureau for Merck & Co, Inc. Ardythe L. Morrow, PhD Director, Human Milk Research Laboratory Professor, Departments of Environmental Health, Pediatrics, and Nutrition University of Cincinnati Cincinnati, OH Dr Morrow has no relevant financial relationships to disclose.

Philip M. Sherman, MD, FRCPC Hospital for Sick Children Staff Gastroenterologist Gastroenterology, Hepatology, and Nutrition Professor of Paediatrics, Microbiology, Nutritional Sciences, and Dentistry University of Toronto Toronto, Ontario, Canada Dr Sherman discloses that he is on the speakers’ bureaus for Mead Johnson Nutrition and Nestlé Nutrition. Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content 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 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physician Assistant Continuing Education: AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. PAs may receive a maximum of 1.0 Category 1 Credits for completing this activity. Nurse Practitioner Continuing Education: The American Academy of Nurse Practitioners Certification Program (AANPCP) accepts certificates of participation for education activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME. Individuals are responsible for checking with the AANPCP for further guidelines. 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. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education or Nestlé Nutrition Institute. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

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Evolution of the Intestinal Microbiome: Laying the Foundation for Child Health Experts discuss the infant gut microbiome and our still-evolving understanding of its critical role in the development of a healthy immune system.


n this roundtable discussion, key issues regarding the importance of the infant gut microbiome, its critical role in the development of a healthy immune system, as well as its direct effects in the gastrointestinal (GI) tract are addressed by a panel of experts.


MICHAEL D. CABANA, MD, MPH: It seems like in the last 10 or 15 years, the topic of the gut microbiome has really exploded. Why is that? PHILIP SHERMAN, MD, FRCPC: There has been a huge advance in our understanding of the gut microbiome and a lot of that relates to technology. There have been advances in genomics, transcriptomics and proteomics, which together tell us what is colonizing the gut. And there’s been a global 10-year study to understand the composition of the intestinal microbiome, including bacteria, viruses, phages, fungi, and proteas. Now we’re moving to knowing the functional consequences of the microbiome in both health and in the disease state.

Breast milk contains staphylococci, streptococci, and lactic acid bacteria that are found in the infant gut.

DR CABANA: I know there has been some work associating the microbiome with outcomes such as eczema, allergies, and asthma. DR SHERMAN: Precisely. An interesting part of that work is it’s not just the microbiome that you have today, but the microbiome that you • THE CLINICAL ADVISOR • MARCH 2019 21


“Clinicians are challenged to provide parents with up-to-date information about the use of prebiotics and probiotics in GI disorders.” were born with and that developed during that first year of life has a huge impact on you and your innate and adaptive immune systems and how it functions later in life in both health and in disease states. ARDYTHE L. MORROW, PHD: And it’s not only atopic disease, but also infectious disease and neurologic-associated diseases that are being described. DR CABANA: What factors influence the composition and function of the gut microbiome? DR SHERMAN: These would include where you were born geographically, who you were born to, whether you were born in a hospital or outside of a hospital, and very importantly whether or not you’ve been exposed to antibiotics. The genes of the mother and the baby have an impact on the composition and function of the microbiome. The mode of delivery — cesarean vs vaginal delivery — also has a huge impact on whether an infant has a skin-predominant microbiome or the maternal microbiome. Born premature vs term also has an impact, and in the short-term for sure, breastfeeding vs formula feeding does affect the composition and probably the function of the gut microbiome. DR CABANA: So when a baby is born vaginally, there is a benefit from being exposed to the mother’s vaginal microbiota? DR MORROW: Yes, and that’s where the evidence is tying the idea of the baby born via cesarean delivery to having higher risk of allergic disease later, and that this may well be differences in microbial colonization. DR SHERMAN: Babies born by cesarean delivery do have a skin-predominant microflora. DR CABANA: How you feed your baby is another way you can potentially influence his or her microbiota. DR MORROW:Yes. One of the things we want to encourage is feeding with mother’s milk from the earliest time. Breastfeeding initiation rates worldwide have been increasing, and there is evidence that it protects against a number of infectious diseases, including various respiratory infections, gastroenteritis or diarrheal disease, and protection against necrotizing enterocolitis in the preterm infant.There is also evidence of reduced atopic

dermatitis and some other things that were initially surprising, such as childhood leukemia and type 1 and type 2 diabetes. DR CABANA: Can you discuss the link between breastfeeding and the development of the microbiota? DR MORROW: A mother has this incredibly complex array of sophisticated structures in her milk that help do a series of things. One is what I call pathogen-binding inhibition. Two, it has a prebiotic effect that helps change bacterial metabolism in a healthy way and grow healthy microbes. And three, it provides immune-system modulation, as well. In addition, preclinical studies and a few clinical studies suggest that this results in lowering infection rates. Human milk has many different components that help shape a healthy microbiota, including antipathogenic components that help us to survive.What has been shown is that the microbiota disadvantage for a baby born via cesarean delivery or who has potentially received an antibiotic seems to even out when the baby is also breastfed. Oligosaccharide is one of the more recently studied components of human breast milk. It appears that this is one of the most abundant components of human milk after lactose and lipid, and is very similar in concentration to protein. It appears that its functionalities include helping to manage the microbial world in various ways, to help grow beneficial organisms such as Bifidobacteria, and to blunt the edge of pathogens. Lactose is the core molecule in milk.The disaccharide, the lactose, and glucose in combination represent the core of what oligosaccharides are. Different enzymes go into building from 3 up to 32 sugars in the link.When you add things like fructose or sialic acid you get more of a set. I like to think of it like tinker toys. You’re adding on complexities over time. These structures are very similar to those found in the infant gut. So this is a pairing between what the mother provides and what the baby has endogenously. It’s a beautiful example of systems biology. Mothers have different combinations of oligosaccharides in their milk; but they’re all healthy and beneficial. DR CABANA: So if you took 100 different mothers, you would have 100 different combinations of oligosaccharides? DR MORROW:Yes. I like to say the simplest ones are 3-sugar combinations, so trisaccharide, building on lactose, and the most complex ones are 32-sugar combinations. And we’re just beginning to really understand what each one of them does.


“There is evidence that breastfeeding provides protection against not only infectious disease but immune disorders of various kinds.” DR CABANA: Clinicians might be familiar with fructooligosaccharides (FOS) or galactooligosaccharides (GOS).Those are different than what you’re describing here, correct?

DR CABANA: So if a baby were born to a mother who didn’t have 2’-FL in her breast milk, there would be no harm to receiving 2’-FL?

DR MORROW:Yes. FOS and GOS are substitute structures that were made to be as similar to human milk oligosaccharide as industry was able to make. What’s so interesting is that it was so complex to make human milk oligosaccharide. Once they were discovered, industry began making a substitute in order to be able to put them in infant foods and to give babies a chance to have something that I think of as a health food with a prebiotic effect.And now there is a pipeline basically of a number of different companies and groups that are working on making human milk oligosaccharides. The first to come out commercially was something called 2’-FL, or 2’-fucosyllactose, which is just a simple trisaccharide. But it’s a very abundant one, and there is the most evidence around that one compared with any other.

DR MORROW: That’s correct. Mothers are variable. Some mothers, sometimes called secretors, have an abundance of 2’-FL. But there are approximately one-quarter of mothers who don’t have this. It’s fine to have mothers with different oligosaccharides in them. But it is, regardless, a very important component of human milk. I think that the oligosaccharide fraction, including 2’-FL and other oligosaccharides, have a way of helping shape a healthy microbiota toward Bifidobacteria and other healthy microbes as a community, but also of inhibiting pathogens so they don’t. Oligosaccharides don’t support the growth of disease-causing organisms.They also help modulate the immune system toward an immune system that has positive benefits of short-chain fatty acids and small organic acids.

DR SHERMAN: I think it’s important to remind people that these important human milk oligosaccharides are not normally present in cow’s milk–based formula or soy-based formulas. They are added so the product can be closer to human breast milk.

DR CABANA: Well, it’s certainly an exciting development to go from FOS and GOS, which seem like very nonspecific substances, to human milk oligosaccharides. It’s interesting to think also about what 2’-FL or human milk oligosaccharides are doing in the gut.What do we know about how these are working?

DR MORROW: Yes, cow’s milk has only trace amounts. DR CABANA: Might one way to look at human milk oligosaccharides be to compare it to different blood types? DR MORROW: Yes. Many of us may not be aware that our blood-group types are actually sugars.There are oligosaccharides, too, on the surface of our red blood cells, but they’re not only on our red blood cells. In fact, Landsteiner, who discovered the ABO blood-group system, discovered these structures in secretions, of which milk is a major secretion. Milk is the equivalent of an O blood group. It’s like universal donor.That means a woman can give milk to her infant regardless of her baby’s type, if you will, and this applies to donor milk banks or pooling milk from multiple mothers. It’s all safe. DR SHERMAN: To carry on that theme, in donor milk banks, some of the bioactive compounds in the milk are degraded as a result of pasteurization. But the milk oligosaccharides are not and they stay intact from the donor to the recipient.

DR SHERMAN: Well, there has been great interest in understanding shaping of the innate and adaptive arms of the host immune system. There is increasing evidence that the composition of the microbiome early in life affects the immune system for the rest of one’s life. Some of those very powerful studies in animal models, rodent models in particular, support that, but there are 2 human studies looking at the microbiome composition at 3 months of age and then again at 6 years of age. It turns out the biodiversity of the microbiome at 3 months of age can predict those children who will have a reactive airway disease like asthma. A less-pronounced diversity was seen in those who developed asthma later in life, whereas the microbiome at the time of illness at 6 years of age wasn’t different. So there’s something about that early composition and why the issue about the impact of antibiotics and breastfeeding early in life on the immune system isn’t just for the time of exposure, but it’s probably for the rest of one’s life. DR CABANA: It seems like it’s a combination of 3 different things: your genetic susceptibility, having the right exposure, • THE CLINICAL ADVISOR • MARCH 2019 23


“Human milk has many different components that help shape a healthy microbiota, including antipathogenic components that help us to survive.” and also the timing of the exposure — at least in the study you mentioned— within this 3-month window. DR MORROW: I would also emphasize one thing about pathogen-binding inhibition, which has been a focus of my research. An incoming pathogen might want to attach to that gut-carbohydrate receptor, but instead with mother’s milk having this abundant source of oligosaccharide, if it’s in the gut lumen then it can instead attach to the mother’s milk oligosaccharide structure and blunt the edge of whatever would have attached at the gut surface. DR CABANA: Are there specific pathogens that it’s protecting against? Or is this nonspecific? DR MORROW: For 2’-FL, which is the oligosaccharide that I’ve done the most work on and the first one to come out commercially, we found that to be important in terms of enteric infection or diarrheal disease. Moderate to severe diarrheal disease seemed to be reduced by having an abundance of that structure or related structures, and then specifically Campylobacter diarrhea, norovirus diarrhea, and potentially rotavirus.


Birth mode


Geography Aging

Exercise Drugs


FIGURE. Factors influencing the composition and function of the gut microbiome.

There has also been preclinical work that indicates mechanisms besides pathogen-binding inhibition that are immunerelated. So it’s a very sophisticated, multidimensional system. DR CABANA: And moving on from that, one of the other ways to potentially influence the microbiome is through probiotics or probiotic interventions. And probiotics are defined by the World Health Organization as live microorganisms that when ingested in adequate amounts confer a beneficial effect to the host. Probiotics encompass many different types of strains and many different types of mechanisms. How do probiotics work? DR SHERMAN: Well, as we heard about human milk oligosaccharides, life is complicated. Probiotics is an inclusive term for a lot of different organisms that work in a lot of different ways. Beneficial microbes, mostly gram-positive bacteria but also gram-negative bacteria and some yeast, work in multiple different ways to have different effects. And it’s very strain-specific. So, for example, there are some bacteria that work like Ardythe just described for milk oligosaccharides, where there’s competition for receptor-binding sites, which is known as colonization resistance — when one beneficial microbe outcompetes a pathogen, for example. Other probiotic strains that don’t have that effect have an impact on human health by promoting the immune system. Some organisms secrete IgA, for example. Other organisms increase goblet-cell mucin and innate trefoil factors. Other organisms tighten up the epithelial barrier in the gut, making it more resistant to macromolecular uptake, and other organisms — such as inflammatory cells in the lamina propria underlying the gut epithelia — affect more distal sites in the immune system. So it might be that one strain does all of those effects, but it’s much more likely that you need multiple strains or that you target for an anti-inflammatory disease a probiotic strain that has anti-inflammatory effects. For an antipathogenic effect, you would use a probiotic strain that’s selective for antipathogenic effects. DR CABANA: One of the concepts in this idea of bacterial diversity is dysbiosis. Is it possible to address dysbiosis with one specific intervention? DR MORROW: Dysbiosis means the idea of imbalance in the microbial community, as well as an influence on the functionality of that microbial community.


“The microbiome that you were born with and that developed during the first year of your life has a huge impact on your immune system.” DR CABANA: So, a probiotic intervention can address bacterial diversity or an imbalance? DR SHERMAN: Yes; it is part of a therapeutic armamentarium that’s available to us. DR MORROW: I was struck by the concept that years ago microbes were considered bad. Now we’re tending to transition to thinking, “Well, microbes are good.” I think what we have instead is the idea of trying to understand the balance between what human beings need to thrive and a healthy microbial community, because there are certainly still pathogens, and we don’t really know what all of these organisms, phages, or fungi might actually be doing. So this is why, in my opinion, we have to be careful with things like fecal transplant because we don’t yet know all of the ramifications. Might we talk about synbiotics? Human milk, for example, has been proposed as a model: that it’s the combination of the carbohydrates that help feed the beneficial microbes and the microbes themselves. DR SHERMAN: The definition of a synbiotic is the combination of a live organism and a probiotic plus either a human milk oligosaccharide or a prebiotic (a synthetic oligosaccharide). There is much less evidence out there, but there is increasing evidence that synbiotics may be the way to go. For the practitioner, more evidence is still required before we go that route, but it’s certainly on the radar for evaluation. DR CABANA: We’ve talked about specific strains used in specific situations at specific doses. The literature is growing quickly, clinical trials are now being published, and there is some indication that we have good evidence for probiotic interventions. DR SHERMAN: There are many areas that are evolving right now, but we can chose a few to focus on. One example is the issue of colic. Although it hasn’t been evaluated in great numbers, there is a dysbiosis, an altered composition in babies with colic compared to age-matched controls in the same community who were fed the same diet. There are a number of studies looking at an active probiotic agent against placebo, showing that as treatment strategy, the probiotic is more effective in reducing irritability in those babies.

DR CABANA: So this is treatment, not prevention, of colic. DR SHERMAN: The multiple studies that have been done are treatment strategies.There is an additional study undertaken in Italy using the same probiotic strain and the same doses as a prevention strategy; it is also showing a beneficial effect. I think there is more room to work in this area to show that it is effective in both prevention and treatment. And, you may ask, how does it work? It might be working through altering the microbiome. But the interesting thing is that this probiotic strain, in particular, has other direct effects on nerve channels that relate to visceral hyperalgesia. Those pain channels are turned from the open state to the closed state by probiotics, and culture supernatant is secreted out from the probiotic strain that directly affect the local milieu. In addition, there is evidence accumulating that those effects of probiotics are not only local in the gut, but also distant in the brain. DR CABANA: So there is a gut-to-brain axis. DR SHERMAN: And it’s a bidirectional brain-to-gut axis and gut-to-brain axis. It is mediated hormonally and probably neurally. We know this from animal models where transecting the vagus nerve abolishes the beneficial effects distally of probiotics locally. A recently published paper has shown that there is a new cell type, an enteroendocrine cell called a neuropod, which senses microbial products and transmits them to nerves that go up to your brain. So there is now a biologic explanation for the microbial gut-brain axis. DR MORROW: Are there any negatives to taking probiotics? I have often heard on the adult side that some people take it and say that they feel more GI disturbance than they do without. DR SHERMAN: It might relate to dose, or it might relate to the sugar content in the case of a synbiotic. Many of the studies that have been done so far in humans are limited in numbers and quite short-term. In the doses taken in foods and in food supplements, there is a long history showing them to be safe with very few side effects. In the larger concentrations of single strains that are used in human subjects as therapeutics, short-term we think they’re safe; but we need to follow those people long-term, especially when these are given to babies. Short-term, I think we would say it’s safe in otherwise healthy individuals. Because probiotics are viable organisms, there is some concern in very immunosuppressed individuals. • THE CLINICAL ADVISOR • MARCH 2019 25


Evidence to date suggests it’s probably safe, and single strains and lower doses are probably safer than high strains delivered locally into the gut. DR CABANA: What has been your experience with probiotics for the treatment of infectious diarrhea?

to that normal growth pattern. For the formulations in the United States, the Food and Drug Administration makes sure that growth would be appropriate and equivalent to a breastfed baby. But they certainly should be at least as good as formulations without oligosaccharide in them. We would look at tolerance and, as Phil mentioned, colic.

DR SHERMAN: There have been numerous meta-analyses looking at trials assessing the effects of various strains of probiotics as interventions to reduce the duration of diarrhea.The interesting thing for me is that it doesn’t matter which probiotic strain is used; they all show the same results.The summary of all of these meta-analyses is that you reduce the duration of diarrhea by about a day, which is statistically significant. What’s interesting is how the experts in the field can look at that and have completely different interpretations of what that data mean. In the global context, it’s been said that 1 day isn’t good enough. It distracts from the important primary therapeutic intervention, which is oral rehydration therapy, which saves lives for severe diarrheal disease. So, probiotics have not been added as an adjunct to manage diarrheal disease in the global setting. However, if you have a child who you want to get back in daycare and he or she is not allowed to go back until the diarrhea is settled, 1 day can make a difference. So there is a difference of opinion when evaluating the same data.

DR CABANA: This discussion has certainly reinforced for me why it’s so difficult to do some of these clinical trials because there are so many factors that affect the microbiome. However, simple things like what we choose to do — such as how and what we feed our infants — and what we choose not to do — for example, antibiotic exposure — can have a significant impact. ■

DR CABANA: The other issue is probiotics for antibioticassociated diarrhea.The evidence is actually pretty good that probiotics can reduce the risk of antibiotic-associated diarrhea. However, every time you complicate a regimen — such as going from 1 therapy to 2 therapies — potential adherence to the regimen decreases.You also want to be able to work with parents to make sure that it is something they can manage. Are there any potential side effects with too much prebiotics?

• Harb T, Matsuyama M, David M, Hill RJ. Infant colic-what works: a systematic

References • Abrahamsson TR, Wu RY, Sherman PM. Microbiota in functional gastrointestinal disorders in infancy: implications for management. Nestle Nutr Inst Workshop Ser. 2017;88:107-115. • Allen SJ, Okoko B, Martinez E, Gregorio G, Dans LF. Probiotics for treating infectious diarrhoea. Cochrane Database Syst Rev. 2004;(2):CD003048. • Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008;138:1796S-1800S. • Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971-11975. review of interventions for breastfed infants. J Pediatr Gastroenterol Nutr. 2016;62(5):668-686. • Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efficacy of probiotic use in acute diarrhea in children: a meta-analysis. Dig Dis Sci. 2002;47(11):2625-2634. • Huurre A, Kalliomäki M, Rautava S, Rinne M, Salminen S, Iolauri E. Mode of delivery – effects on gut microbiota and humoral immunity. Neonatology. 2008;93:236-240. • Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the

DR MORROW: When we’re starting to give human milk oligosaccharide structures in formula, they have to be tested. So far, there have been a lot of safety tests conducted preclinically.There have been 2 trials in which the formula was tested and they have also shown safety. So given the studies that have been done so far, all is looking quite good. But it’s also about dose; dose should always be considered and not getting above what would have been given in human milk.

human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev. 2017;81(4):e00036-17. • Morrow AL, Ruiz-Palacios GM, Altaye M, et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004;145(3):297-303. • Quigley EMM. Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet? Nat Rev Gastroenterol Hepatol. 2017;14(5):315-320. • Ruiz-Palacios GM, Cervantes LE, Ramos P, Chavez-Munguia B, Newburg DS.

DR CABANA: Is there anything that you’d be looking for as far as safety issues are concerned?

Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem. 2003;278(16):14112-14120.

DR MORROW: Growth is a big one, of course.You would look at the growth curves and be alert to anything anomalous

• Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of action of probiotics. Nutr Clin Pract. 2009:24(1):10-14.


• Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention

• Weichert S, Jennewein S, Hufner E, et al. Bioengineered 2’-fucosyllactose

of acute infectious diarrhea in infants and children: a systematic review

and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and

of published randomized, double-blind, placebo-controlled trials. J Pediatr

enteric pathogens to human intestinal and respiratory cell lines. Nutr Res.

Gastroenterol Nutr. 2001;33(suppl 2):S17-S25.


• Thomas DW, Greer FR; Committee on Nutrition, Section on

• Weichert S, Koromyslova A, Singh BK, et al. Structural basis for norovirus

Gastroenterology, Hepatology, and Nutrition. Probiotics and prebiotics in pediatrics. Pediatrics. 2010;126(6):1217-1231.

inhibition by human milk oligosaccharides. J Virol. 2016;90(9):4843-4848. • Xu M, Wang J, Wang N, Sun F, Wang L, Liu X-H. The efficacy and safety

• Van Neil CW, Feudtner C, Garrison MM, Christakis DA. Lactobacillus

of the probiotic bacterium Lactobacillus reuteri DSM 17938 for infan-

therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics.

tile colic: a meta-analysis of randomized controlled trials PLoS One.




POSTTEST Expiration date: March 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 CREDITS: 1.0 | Evolution of the Intestinal Microbiome: Laying the Foundation for Child Health

1. Which of the following best promotes healthful microbial colonization of the infant gut? a. Vaginal delivery and formula feeding b. Cesarean delivery and formula feeding c. Vaginal delivery and breast milk feeding d. Vaginal delivery, breast milk feeding, and avoidance of antibiotics 2. Which of the following statements about human milk oligosaccharides (HMOs) most accurately describes these components of breast milk and their role in developing a healthy microbiota? a. Though only a small component of breast milk, HMOs act as prebiotics (ie, they help grow beneficial organisms), inhibit the activity of pathogens, and act as anti-inflammatory agents. b. One of the largest components of breast milk, HMOs act as prebiotics, inhibit the activity of pathogens, and act as anti-inflammatory agents. c. Available in most formulas as well as in breast milk, HMOs act as prebiotics, inhibit the activity of pathogens, and act as anti-inflammatory agents. d. Each mother has a different combination of HMOs in her milk, and not all of them are beneficial.

3. Which of the following statements most accurately describes the status of industry-replicated HMOs for use in infant formulas? a. Formula manufacturers have so far made no effort to replicate HMOs. b. Of the more than 200 HMOs, formula manufacturers have selected a dozen of the most prominent to study and to develop for use in formula. c. The most studied HMO is 2’-fucosyllactose (2’-FL), which is identical in structure to the 2’-FL found abundantly in human milk. d. Fructooligosaccharides occur naturally in human breast milk. 4. Which of the following statements best describes the mechanism(s) of action of probiotics? a. Probiotics function primarily by beating out pathogens in the competition for receptor binding sites (colonization resistance). b. Probiotics work in a variety of ways, including supporting epithelial barrier function, increasing mucin production, and reducing macromolecular permeability. c. How a probiotic works depends on the particular strain of the organism. d. How probiotics work is not yet understood.


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Health Literacy and the Older Adult: A Persistent and Widespread Problem Every day, low health literacy results in patients’ misunderstanding the instructions of their clinicians, sometimes with very serious consequences. Mr C, a 72-year-old patient with type 2 diabetes, is brought to the emergency department comatose with a blood sugar of 29 mg/dL.When seen in his primary care provider’s office the previous day, his blood sugar was 456 mg/dL; he was prescribed fast-acting insulin with meals in addition to an increase in his insulin glargine.



n this brief case vignette, the patient experienced an avoidable health crisis. Mr C did not understand his clinician’s verbal and written instructions and took too much fast-acting insulin at breakfast. An estimated 90 million people in the United States have low basic literacy skills, with the average adult reading at an eighth-grade level.1 Almost 20% of American adults cannot read and almost 30% do not read well, representing a significant segment of society who have some difficulty reading at even a fifth-grade level. This group of Americans with limited reading skills comprises several demographic groups, including older adults, Latinos,African Americans,American Indians, and Alaskan natives.1

Health Literacy

Poor health literacy places a financial burden on a healthcare system.

This low basic literacy is compounded by the widespread illiteracy associated with health information. Health literacy is multifaceted and includes printed literature, oral communication, and numeracy. Printed literature requires reading and writing ability, while oral literacy requires the ability to listen and speak. Many older adults have • THE CLINICAL ADVISOR • MARCH 2019 29


An estimated 90 million people in the United States have low basic literacy skills, with the average adult reading at an eighth-grade level. vision and/or hearing loss that represent additional obstacles to health literacy. Numeracy — the ability to understand and use numbers — is especially important with respect to medication dosages. Even people with high basic literacy skills can have low health literacy, and medical jargon can seem like a foreign language to many people. The most widely used definition for health literacy is “the ability to obtain, process, and understand basic health information and services needed to make appropriate healthcare decisions and follow instructions for treatment.”2 Poor health literacy among Americans has been an area of focus for several federal agencies for more than a decade. The Institute of Medicine first described the problem in a 2004 report titled, “Health Literacy: A Prescription to End Confusion.”3 The Joint Commission addressed the issue in a 2007 white paper titled, “What Did the Doctor Say? Improving Health Literacy to Protect Patient Safety.”4 In 2010, the United States Department of Health and Human Services suggested solutions in its “National Action Plan to Improve Health Literacy” and included a health literacy goal to improve communication in the Healthy People 2010 10-year national health objectives.5,6 The objective has also been included in the Healthy People 2020 agenda for improving health among Americans.7 Despite publication of ample literature on health literacy since Ratzen and Parker2 first defined the issue, health literacy remains a widespread problem among older adults. Why Does It Matter?

The Agency for Healthcare Research and Quality (AHRQ) reported that low health literacy is associated with more emergency department visits and hospital readmissions, less preventive care, and poor medication administration skills.8 Older adults with poor health literacy were found to have overall poorer health status and higher mortality than those who possessed adequate health literacy skills.8 In addition to poor patient outcomes, low health literacy is a financial burden on our healthcare system with costs reaching $92 billion annually in the United States.9 A Veterans Health Administration study indicated that low health literacy was a significant factor in higher healthcare costs.10 Hitting closer to home, many payers are penalizing healthcare practitioners who have poor patient outcomes. Older Adult Learning Theory

Before we can address best practices to overcome low health literacy, we need to understand how older adults learn and

factors that could impede older adult learning. Geragogy involves the principles of older adult learning theory. Factors affecting learning can be physical functions such as vision, hearing, and mobility.11,12 Increasing age can be associated with a decrease in vision and hearing, as well as slower psychomotor abilities. Adjustments in teaching will need to be made when educating these patients. Cognitive factors need to be considered. Older adults may have decreased short-term memory and a tendency to be distracted.11 Repetition is a key element in teaching the older adult. Elliot identified the following principles of older adult learning11: • “Approach the older adult in a way that communicates respect, acceptance, and support. Create a learning environment in which the patient can feel comfortable when expressing what is and is not understood.” • “Schedule teaching sessions in mid-morning when energy levels are usually highest for the older adult. Conduct several brief sessions over different days rather than one long session, which may cause fatigue.” • “Provide more time for the older adult to process new information.” • “Link new knowledge to past experiences. Reminiscing helps the older adult reconnect with lived experiences.” • “Keep the content practical and relevant to the older adult’s daily activities, social structure, and physical function. Older adults tend to be more motivated when the information is perceived as a way to address a current problem.” • “Minimize distractions.” • “Speak slowly, but not so slowly that the patient becomes bored or distracted.” • “Use terminology that is familiar to the older adult.” • “Give older adults written material that reinforces the major points of teaching. Use a large font.” • “Use visuals that portray older adults in a positive manner.” • “Encourage patients to keep written information easily accessible such as near a phone, bed table, or on the refrigerator.” • “Use concrete terms and avoid abstract terminology.” • “Encourage older adults to be actively involved in their teaching.” • “Encourage family members to actively participate in the educational sessions.” Many of the principles of geragogy are also recommendations for low health literacy, which are discussed later in this article.


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Even people with high basic literacy skills can have low health literacy, and medical jargon can seem like a foreign language to many people. Include Family Members. As Jones, Treiber, and Jones state,“it takes a village” to assist a patient who has low health literacy.13 Not only do the various members of the healthcare team serve in important roles in the process, the family also plays a key role in overcoming low health literacy. The patient’s spouse can assist in reinforcing patient education and adherence to treatment regimens. Ideally, a family member who has a higher level of basic and health literacy should be recruited, but realistically this may be difficult to accomplish. Slow Down. Communication can be greatly improved simply by speaking more slowly, as older adults have slower processing speeds.14 If rushed, older adults can feel frustrated and exhibit unwillingness to learn due to fear of shame or failure.11 Although time is often limited during patient visits, which makes it difficult to slow down, the additional time allocated may contribute to better patient outcomes. Use Plain, Nonmedical Language. Clinicians can improve patient understanding by adopting simple speech patterns, such as using words with no more than 2 syllables (Table). Communication with patients with low health literacy can be TABLE. Recommended Diabetes Nonmedical Terms for Patients Medical Term

Nonmedical Term


Problem with too much blood sugar


Diabetes doctor


Low blood sugar


Too much blood sugar


Low blood pressure


High blood pressure




As you need it


Nerve problem

improved by asking colleagues to listen to patient encounters and give feedback, or by role playing with nonmedical friends and family members. Show or Draw Pictures. Simple pictures can be used to help patients better recall important health information.The pictures do not need to be detailed, although the use of color can make them more appealing to the eye. In a pilot study of a narrative- and pictured-based health literacy intervention for older adults, pictures were found to be appealing and comprehensible.15 Limit the Volume of Information at Each Encounter. As older adults may have difficulty multitasking and dividing their attention, each encounter should be limited to 1 or 2 key pieces of important information.11 Practitioners may overwhelm patients with information during a single encounter, which can lead to confusion and poor understanding. Patients with low health literacy may benefit from longer appointments, more frequent visits, or both. Teach Back. Instructing patients to repeat back the information provided can serve to confirm their understanding. If the patient repeats information incorrectly, the clinician can clarify the information to ensure patient comprehension.The following is an example of a dialogue using the teach-back method: Clinician: The sugar in your blood is high, so I want you to take 1 more unit of your insulin glargine every 2 days until your morning blood sugar is 80 to 110. I want to make sure you understand what I just said, so can you tell me what you’re going to do? Mr C: I’m going to take 1 extra unit of insulin glargine every 2 days until my blood sugar is 80 to 110. Clinician: That’s correct. Once you have a morning blood sugar between 80 and 110, don’t increase your insulin glargine anymore. Keep taking the same dose of insulin glargine you took to reach 80 to 110. So, how much insulin glargine will you take once your blood sugar is between 80 and 110? Mr C: Once my blood sugar is 80 to 110, I won’t increase my insulin glargine anymore. I’ll keep taking the last dose of insulin glargine that I had been taking.

Create a Shame-Free Environment. The American Medical Association (AMA) created a video with actual patients who had low health literacy to demonstrate a woman describing her experience with a physician she consulted about her abnormal menses. She went to the hospital and signed consent for surgery, but she did not realize until her 6-week postoperative visit that her procedure was a hysterectomy.


Low health literacy is associated with more ED visits and hospital readmissions, less preventive care, and poor medication administration skills. The patient said she had been too ashamed to tell the physician and the admitting office that she didn’t read well, so she didn’t fully understand the papers she signed. A body part was removed, which was never her intention, as a result of her low health literacy. As the woman’s experience shows, if patients feel shamed, they are less likely to ask questions. A shame-free environment allows patients to ask important and clarifying questions about their healthcare. Clinicians can create such an environment by developing rapport with patients and approaching them with a demeanor of acceptance that encourages them to ask questions. Educate Staff. Clinicians should prioritize education on health literacy for the entire office staff. Many resources are available to assist in staff education about this important topic (see boxed information below). Use Printed Material. When selecting or creating printed patient education materials, the most effective tools for patients with low health literacy limit information to 1 or 2 objectives and use plain language, primarily 1- or 2-syllable words, bullet points, pictures, readable fonts, and more empty space on the page.16 A 12- to 14-point font size is recommended for the general population; however, a larger font size is recommended for older adults due to potential visual disturbances.11 Black font is recommended because it is

Online Health Literacy Resources • Agency for Healthcare Research and Quality. Health Literacy Universal Precautions Toolkit. quality-resources/tools/literacy-toolkit/index.html • Centers for Medicare & Medicaid Services. Toolkit for Making Written Material Clear and Effective. WrittenMaterialsToolkit/index.html • Centers for Disease Control and Prevention. Health Literacy for Public Health Professionals. • University of Michigan. Plain Language Dictionary. • Readability Calculator. and_improve.jsp

much easier for the older adult to see than other font colors such as red. Although patient education materials should be written at a third- to fifth-grade level, many are often written at higher levels.17 To ensure that written material is at an appropriate level for most patients, clinicians can use the numerous online resources available. Technology and the Older Adult

Clinicians should exhibit caution when using electronic methods to deliver patient education to the older adult. Only 42% of the US population between the ages of 55 and 74 years are regular users of computer technology.18 This gap increases with age, and women are less likely than men to have computer skills. A 2014 Pew Report states that “seniors remain unattached from online and mobile life — 41% do not use the internet at all, 53% do not have broadband access at home, and 23% do not use cell phones.”19 Although technology use among older adults is increasing, they remain slower to adopt new products or innovations. Conclusion

Older adults may have multiple medical conditions, and effective control of these conditions often begins with overcoming low health literacy. Using the recommended strategies, clinicians can improve patient communication in their day-to-day practice — particularly with older adults and other patients with lower health literacy — potentially decreasing healthcare costs and improving patient outcomes through more effective communication. ■ Gwenn Scott RN, DNP, CNS, FNP-BC, is an assistant professor in the School of Nursing Master’s Program at the University of Texas Medical Branch in Galveston. References 1. Hersh L, Salzman B, Snyderman D. Health literacy in primary care practice. Am Fam Physician. 2015;92(2):118-124. 2. Ratzan SC, Parker RM. Health literacy. National Library of Medicine website. Published 2000. Accessed October 1, 2018. 3. Health literacy: a prescription to end confusion. Institute of Medicine website. Published April 8, 2004. Accessed October 9, 2018. 4. What did the doctor say? Improving health literacy to protect patient safety. The Joint Commission website. the_doctor_say/. Published February 27, 2007. Accessed October 9, 2018. • THE CLINICAL ADVISOR • MARCH 2019 33

5. National action plan to improve health literacy. Office of Disease Prevention

13. Jones JH, Treiber LA, Jones MC. Intervening at the intersection

and Health Promotion website.

of medication adherence and health literacy. J Nurse Pract. 2014;10(8):

health-literacy-action-plan.asp. Published 2010. Accessed October 9, 2018.


6. Healthy People 2010. Centers for Disease Control and Prevention website.

14. Kobayashi LC, Wardle J, Wolf MS, von Wagner C. Aging and functional Published October, 2011.

health literacy: a systematic review and meta-analysis. J Gerontol Series B:

Accessed October 9, 2018.

Psychol Sci Social Sci. 2016;71(3):445-457.

7. Healthy People 2010. Centers for Disease Control and Prevention website.

15. Koops JR, Winter AF, Reijneveld SA, Hoeks JC, Jansen CJ. Development Accessed October 9, 2018.

of a communication intervention for older adults with limited health literacy:

8. Agency for Healthcare Research and Quality. National healthcare disparities

photo stories to support doctor-patient communication. J Health Commun.

report. Washington, DC: Government Printing Office; 2017.


9. Rasu RS, Bawa WA, Suminski R, Snella K, Warady B. Health literacy impact

16. Weiss BD. How to bridge the health literacy gap. Fam Pract Manag.

on national healthcare utilization and expenditure. Int J Health Policy Manag.



17. Bailey SC, Fang G, Annis IE, O’Conor R, Paasche-Orlow MK, Wolf MS.

10. Hahn EA, Burns JL, Jacobs EA, et al. Health literacy and patient-reported

Health literacy and 30-day hospital readmission after acute myocardial

outcomes: a cross-sectional study of underserved English- and Spanish-

infarction. BMJ Open. 2015;5(6):e006975.

speaking patients with type 2 diabetes. J Health Commun. 2015;20(Suppl 2):4-15.

18. Schmidt-Hertha B, Krasovec SJ, Formosa M (eds). Learning Across

11. Elliot RW. Educating older adults with chronic kidney disease. Nephrol

Generations in Europe. Rotterdam: Sense Publications; 2014.

Nurs J. 2014;41(5):522-526.

19. Smith A. Older adults and technology use. Pew Research Center Internet

12. Osorio AR. The learning of the elderly and the profile of the adult

& Technology website.

educator. Convergence. 2008;41(2-3):155-172.

technology-use/. Published 2014. Accessed October 9, 2018.

“Instead of hibernating, he entertained himself this winter in his man cave.” 34 THE CLINICAL ADVISOR • MARCH 2019 •

© Harley Schwadron 2019


Dermatology Clinic CASE #1


A 46-year-old woman presents to the clinic with a 6-week history of a bumpy, itchy rash on her arms and legs. She is otherwise healthy and has no known family history of skin conditions. On physical examination, symmetric urticarial plaques are identified on both knees with overlying grouped vesicles and erosions. The patient also has symmetrically grouped vesicles and erosions over the extensor surfaces of both arms. Skin biopsy reveals subepidermal vesicles filled with neutrophils and eosinophils. What is your diagnosis? Turn to page 36



A 68-year-old woman presents with an itchy, scaly red rash on her back for 9 months. She denies history of eczema, psoriasis, or other skin diseases. She smokes a half-pack of cigarettes per day but is otherwise healthy. On examination, erythematous, scaly patches, plaques, and nodules of irregular size and shape are seen on the back. She has no lymphadenopathy and no other symptoms. Skin biopsy of one plaque demonstrates neoplastic T cells with a halo appearance and Pautrier microabscesses. What is your diagnosis? Turn to page 37 • THE CLINICAL ADVISOR • MARCH 2019 35

Dermatology Clinic CASE #1

Dermatitis Herpetiformis

Dermatitis herpetiformis is a chronic skin eruption that presents as a cutaneous manifestation in patients with celiac disease, a gluten-sensitive enteropathy.The rash presents as pruritic papulovesicles in a characteristic distribution, mainly across the elbows, knees, and buttocks.1 Patients typically present with skin manifestations as the only complaint and are often unaware of the underlying small bowel disease.2 Like celiac disease, dermatitis herpetiformis is most common in individuals of European descent and can be diagnosed at any age. However, unlike celiac disease, dermatitis herpetiformis rarely presents in early childhood, with most diagnoses made in the third or fourth decades of life. While celiac disease is more common in women, studies have shown dermatitis herpetiformis to be slightly more prevalent in men.3 Dermatitis herpetiformis can be caused by genetic or environmental factors. Genetic screening has shown a strong association between dermatitis herpetiformis and HLA-DQ2 in 95% of patients.1 The rash is generated by immunocomplexes of gluten-induced IgA autoantibodies against the autoantigen, epidermal transglutaminase, accumulating in the superficial papillary dermis.4 Due to the genetic predisposition for

Dermatitis herpetiformis rarely presents in early childhood, with most diagnoses made in the third or fourth decades of life. both dermatitis herpetiformis and celiac disease, screening close family members for the presence of antibodies against transglutaminases is indicated to identify forms of gluten sensitivity. Dietary gluten is the main environmental cause of the immunologic reaction; however, exposure to iodine can also precipitate severe clinical manifestations.1 Dermatitis herpetiformis can be diagnosed clinically if the typical distribution pattern of grouped papulovesicles on an erythematous base is seen across the elbows, knees, buttocks, shoulders, and scalp. While not always present, petechiae may be observed on the fingertips and toes.5 The diagnosis is confirmed with histopathologic examination of the skin and direct immunofluorescence. Histopathology

reveals subepidermal blister formation with accumulations of neutrophils and scant eosinophils at the papillary tips. Immunopathology can reveal granular deposits of IgA in the papillary dermis, the basement membrane, or a combination of both.6 The most sensitive diagnostic marker, serologic testing, can be performed to detect the presence of IgA antibodies against transglutaminases.1 Small bowel biopsy is unnecessary but may serve as additional evidence of celiac disease if the characteristic villous atrophy is seen on microscopic examination. While dermatitis herpetiformis is the best characterized extraintestinal manifestation of celiac disease, other mucocutaneous symptoms associated with celiac disease — such as urticaria, atopic dermatitis, psoriasis, or rosacea — may present similarly.7 The differential diagnosis may also include scabies, impetigo, or bullous pemphigoid. Therefore, the characteristic distribution pattern in addition to histopathology and direct immunofluorescence are used to differentiate dermatitis herpetiformis from similar presentations.6 Because patients typically present in the absence of gastrointestinal symptoms, identifying these skin manifestations may lead to a diagnosis of latent or silent celiac disease. The treatment associated with the best prognosis and eventual remission is a strict gluten-free diet. The gastrointestinal symptoms are relieved more rapidly than the skin manifestations, which require an average of 2 years to resolve completely. Patients may also take oral dapsone to alleviate pruritus and inflammation in the period before improvements are seen as a result of a gluten-free diet. Sulfasalazine, sulfamethoxypyridazine, or potent topical steroids can be used as second-line treatment for alleviating symptoms if the desired effects are not achieved with dapsone therapy.6 After initiating a gluten-free diet and observing its effects, following up with patients can allow for confirmation of the diagnosis and prevention of other related comorbidities. In order to ensure adherence to a gluten-free diet, patients must be monitored regularly and consult with dietitians. Strict adherence to a gluten-free diet has shown a reduction in the risk for developing B-cell or T-cell lymphomas associated with dermatitis herpetiformis.8 Additionally, monitoring is advised as patients with dermatitis herpetiformis are at risk of developing other autoimmune diseases, such as type I diabetes, vitiligo, pernicious anemia, and alopecia areata, as well as disorders related to malabsorption, such as microcytic or megaloblastic anemias.1 Patients receiving dapsone therapy require regular blood monitoring in the early stages due to possible hematologic adverse effects, such as hemolytic anemia or methemoglobinemia.6 The patient in the case above adhered to a strict glutenfree diet and received 25 mg oral dapsone daily. At 6-month follow-up, dramatic regression of her skin lesions was noted.


Dermatology Clinic

Rachel Graubard, BS, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Kárpáti S. Dermatitis herpetiformis. Clin Dermatol. 2012;30(1):56-59. 2. Krishnareddy S, Lewis SK, Green PH. Dermatitis herpetiformis: clinical presentations are independent of manifestations of celiac disease. Am J Clin Dermatol. 2013;15(1):51-56. 3. Reunala T, Salmi TT, Hervonen K, Kaukinen K, Collin P. Dermatitis herpetiformis: a common extraintestinal manifestation of coeliac disease. Nutrients. 2018;10(5):602.

Some possible risk factors that have been studied include higher body mass index, cigarette smoking, eczema, and various industrial/occupational exposures.3 Classic mycosis fungoides is a slowly progressive disease. Patients can initially present with erythematous pruritic patches or plaques with scaling and variability in size and/or shape.The lesions are usually present in areas of the body that are not exposed to sunlight, including the buttocks, upper thighs, and trunk.1 Staging of mycosis fungoides ranges from I-IV, with later stages of the disease being characterized by tumors, erythroderma, invasion into peripheral lymph nodes, and visceral organ involvement.1 Folliculotropic mycosis fungoides is the most common subtype;

4. Borroni G, Biagi F, Ciocca O, et al. IgA anti-epidermal transglutaminase autoantibodies: a sensible and sensitive marker for diagnosis of ­dermatitis h­ erpetiformis in adult patients. J Eur Acad Dermatol Venereol. 2012;27(7):836-841. 5. Zaghi D, Witheiler D, Menter AM. Petechial eruption on fingers. JAMA Dermatol. 2014;150(12):1353-1354.

Mycosis fungoides generally occurs in older individuals, and the incidence of the condition increases with age.

6. Caproni M, Antiga E, Melani L, Fabbri P. Guidelines for the diagnosis and treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol. 2009;23(6):633-638. 7. Rodrigo L, Beteta-Gorriti V, Alvarez N, et al. Cutaneous and mucosal ­manifestations associated with celiac disease. Nutrients. 2018;10(7):800. 8. Hervonen K, Vornanen M, Kautiainen H, Collin P, Reunala T. Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives. Br J Dermatol. 2005;152(1):82-86.


Mycosis Fungoides

Mycosis fungoides is the most prevalent form of cutaneous T-cell lymphoma. It is classified as an indolent lymphoma and has a classical form and other variants and subtypes. Mycosis fungoides generally occurs in older individuals and incidence increases throughout age; however, pediatric cases of mycosis fungoides have been reported.1 The condition is more prevalent in men and African Americans, with mycosis fungoides developing twice as often in men as in women.1 Currently, the exact etiology of mycosis fungoides is unknown. Researchers have extensively explored possible hypotheses regarding its etiology, including an underlying viral argent or persistent antigen activation (such as Staphylococcus aureus), epigenetic alteration, and immune dysregulation.1,2

it carries a worse prognosis with lesions typically located in the head and neck regions.1 Less common subtypes include pagetoid reticulosis, which generally presents with a large, single, scaly and erythematous plaque; hypopigmented mycosis fungoides, which occurs most commonly in patients with dark skin; and granulomatous slack skin, which is characterized by granulomatous infiltrate and loss of elastic fibers.4 The patches and plaques of mycosis fungoides exhibit atypical band-like T-cell infiltrate in the upper dermis, along with neoplastic T cells with cerebriform nuclei in the epidermis. The neoplastic T cells are often described as having a halo appearance due to the surrounding clear cytoplasm. T cells can also build up in the epidermal basement membrane.1 A specific but insensitive marker in individuals with mycosis fungoides is the presence of Pautrier microabscesses, which contain Langerhans cells and malignant T cells.5 Further laboratory testing for diagnosis can include immunohistochemical staining and examining T-cell clonality. Most often, immunohistochemical staining is positive for CD4+T cells; however, there have been cases of CD8+ mycosis fungoides.6 Other findings supporting the diagnosis of mycosis fungoides can be the loss of T-cell antigens (CD2, CD3, CD7, etc).1 T-cell clonality can be used as a confirmatory diagnostic test for mycosis fungoides. Increasingly sensitive methods such as next-generation sequencing have been studied for testing T-cell clonality.7 Nextgeneration sequencing examines T-cell receptor gene arrangements and scans for an overrepresentation of a sequence. It is worthwhile to note that mycosis fungoides is often difficult to diagnose, especially in earlier stages of the disease, • THE CLINICAL ADVISOR • MARCH 2019 37

Dermatology Clinic 2. McGirt LY. Latest insights into pathogenesis of mycosis fungoides and cutaneous T-cell lymphoma. G Ital Dermatol Venereol. 2017;152(2):158-168. 3. Aschebrook-Kilfot B, Cocco P, La Vecchia C, et al. Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and Sézary syndrome: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014;2014(48):98-105. 4. Nashan D, Faulhaber D, Stander S, Luger TA, Stadler R. Mycosis fungoides: a dermatological masquerader. Brit J Dermatol. 2007;156(1):1-10. 5. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053-1063. 6. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32(10):647-674. 7. Sufficool KE, Lockwood CM, Abel HJ, et al. T-cell clonality assessment by next-generation sequencing improves detection sensitivity in mycosis fungoides. J Am Acad Dermatol. 2015;73(2):228-236. 8. Vandergriff T, Nezafati KA, Susa J, et al. Defining early mycosis fungoides: validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas. J Cutan Pathol. 2015;42(5):318-328. 9. Duvic M. Choosing a systemic treatment for advanced stage cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Hematology Am Soc Hematol Educ Program. 2015;2015(1):529-44. 10. Kim YH, Bagot M, Rook AH, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9): 1192-1204.

Annie Dai, BA, is a medical student;Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sézary syndrome. Lancet. 2008;371(9616):945-957.


“Use thy core!”

© The New Yorker Collection 2019 from All Rights Reserved.

as some histopathologic features may not be present in early patches. It resembles other common skin diseases, including eczema, psoriasis, and inflammatory dermatitis.1 Therefore, biopsy is important for diagnosis.To differentiate between the possible diagnoses, it is crucial to consider and integrate clinical, histopathologic, and laboratory findings.The International Society for Cutaneous Lymphoma has established a 4-point algorithm for helping diagnose early-stage mycosis fungoides.5 Studies have shown the algorithm to be a valid method for diagnosing the condition, but further modifications to the algorithm may be needed to improve its specificity.8 Medical treatments for mycosis fungoides focus on controlling the extent of the disease. Mycosis fungoides is characterized by a chronic relapsing course; as a result, patients frequently receive multiple rounds of therapy. Generally, treatment options for patients in earlier stages of the disease include topical treatments (ie, nitrogen mustard and topical corticosteroids or retinoids) and/or ultraviolet light-based phototherapies.9 Total body skin electron beam is effective phototherapy and is generally used for patients with increased patch/plaque coverage.9 Patients who have a later stage of mycosis fungoides or refractory, early-stage mycosis fungoides benefit from systemic therapy such as interferons, retinoids, and histone deacetylase inhibitors.9 Immunosuppressive therapies are generally avoided unless the patient has aggressive, late stages of mycosis fungoides.9 Allogeneic hematopoietic stem cell transplantation for refractory or advanced mycosis fungoides has also been reported as a treatment option.9 Targeted immunotherapy is a relatively new area of therapy that has become integrated into mycosis fungoides treatment. Currently, alemtuzumab, a monoclonal antibody against CD52, has been found to be effective for mycosis fungoides but does increase the risk of opportunistic infections.9 A recently completed phase 3 clinical trial of mogamulizumab, a promising new monoclonal antibody against CCR4, reported prolonged progression-free survival in patients with cutaneous T-cell lymphoma.10 The patient in our case was diagnosed with stage I mycosis fungoides and prescribed a high-potency topical corticosteroid to be applied twice daily to her skin lesions. At 6-month follow-up, she was found to have had complete remission. ■

Dermatologic Look-Alikes Lower Extremity Swelling and Rash MAYA FIRSOWICZ, BS; CLAIRE J. WIGGINS, BS; CHRISTOPHER RIZK, MD



A 58-year-old man with congestive heart failure presents with swelling and lesions on his lower extremities. He first noticed the swelling 2 years earlier, and several painless, wart-like lesions have developed over the past few months. He reports having had a few skin infections in the same region for which his primary care provider prescribed antibiotics. On examination, the patient has bilateral nonpitting lower extremity edema with overlying verrucous lesions. A positive Stemmer sign is noted.

A 72-year-old obese woman with hypertension and type 2 diabetes presents to the clinic with a rash on her lower extremities. She states that she has had the rash for almost a year, but it has gradually worsened with time. She is concerned because the rash is becoming increasingly pruritic, and her legs are changing color to brown. On examination, she has 2+ pitting edema of her lower extremities. Erythematous, hyperpigmented plaques are noted on the lower legs with scaling and heme crusts. • THE CLINICAL ADVISOR • MARCH 2019 39

Dermatologic Look-Alikes CASE #1

Elephantiasis Nostras Verrucosa

Elephantiasis nostras verrucosa (ENV) is a rare, disfiguring sequelae of secondary chronic lymphedema, predisposing the patient to recurrent skin infections and resulting in cobblestone-like, papulonodular warts overlying woody, edematous tissue.The term “elephantiasis” characterizes gross enlargement due to lymphatic vessel obstruction. Nostras, meaning “from our region,” was first used in 1934 by Castellani in order to distinguish ENV from elephantiasis tropica or filarial elephantiasis, both of which are caused by parasitic lymphatic obstruction.1Verrucosa describes the hyperkeratotic, wart-like appearance of the skin.2 Unlike other forms of elephantiasis, ENV is not caused by primary infection. Any condition that leads to lymphatic damage may increase a patient’s susceptibility to ENV in the future. Predisposing risk factors include lymphatic fibrosis from malignancy, radiation, or scleroderma; lymphatic obstruction from congestive heart failure or obesity; or traumatic disruption of the lymphatic system from surgery or injury.3 In a retrospective study of 21 patients with ENV, all patients were obese, with 91% morbidly obese; concurrent chronic venous insufficiency was identified in 71%, and 86% relayed a history of cellulitis or soft tissue infection on initial presentation.4 Patients who progress from chronic, noninfectious lymphedema to ENV enter a cycle of recurrent dermatologic and soft tissue infections with resulting fibrosis. In the setting of lymphatic damage, protein-rich lymph stasis results, inducing a local inflammatory response.This increases the region’s susceptibility to infections such as cellulitis, erysipelas, and lymphangitis, resulting in increased dermal fibrosis and reactive tissue edema. The overlying skin is made more vulnerable to infection in this setting as well, developing hyperkeratotic lesions over time. This pathologic progression of immune system dysfunction and infection leads to the characteristic appearance of ENV: nonpitting edema with superimposed verrucous lesions.2 Diagnosis is clinical, based on characteristic history and physical examination findings. History should include a description of the time course of symptom progression, a thorough exploration of chronic medical conditions, inquiry about a family history of lymphatic pathologies, and a travel history in order to differentiate ENV from related conditions. ENV is commonly found in gravity-dependent areas of the body such as the lower extremities and typically presents bilaterally; it often first appears on the dorsal aspect of the foot and progresses proximally. A

positive Stemmer sign, or the inability to lift the skin fold at the base of the second toe, is diagnostic for lymphedema.2 This finding is due to lymphedema-induced skin thickening and would not be present in similar conditions that do not have changes in the skin.The disease has more rarely been observed in the upper extremities, abdomen, buttocks, scrotum, and face.5,6 The wart-like lesions may be malodorous due to recurrent bacterial or fungal infection.The cause of secondary lymphedema that predispose the patient to ENV can be investigated further via skin biopsy, lymphangiography, lymphoscintigraphy, computed tomography, or magnetic resonance imaging.6 Histologic findings for ENV include enlarged lymphatic vessels, fibrotic dermal tissue with loss of dermal papillae, and a hyperkeratotic epidermis with acanthosis and papillomatosis.2 The differential diagnosis for ENV includes venous stasis dermatitis, deep venous thrombosis, filariasis, lipedema, lipodermatosclerosis, papillomatosis cutis carcinoides, pretibial myxedema, and chromoblastomycosis.2,6 Although the clinical presentation of ENV is characteristic, blood smear or similar test should be performed to rule out Wuchereria bancrofti parasite infection, and skin biopsy should be performed to definitively rule out other similar diseases, especially if history and physical examination findings are ambiguous.

Diagnosis of elephantiasis nostras verrucosa is clinical, based on characteristic history and physical examination findings. Although there is no clearly defined standard of care for ENV, treating the underlying causes is central to management. Compression stockings, massage, and medical wraps can help improve the lymphostasis. Medical treatment includes diuretics, which may help limit tissue edema; topical or systemic antibiotics and antifungals for acute infection or prophylactic purposes; as well as emollients such as salicylic or acetic acid. Systemic retinoids have also been used to help limit epidermal proliferation and inflammation, although they should be used carefully considering the drug’s teratogenic properties. Surgical options such as debridement, lymphatic transplant or anastomosis, or in severe cases amputation are also possible treatment options.2,6,7 Prognosis is dependent on the progression of ENV and underlying disease severity. When the disease is diagnosed early and the patient has regular clinical follow-up, outcomes are better.Without treatment, bacterial and fungal infections of the skin and underlying tissue can persist and spread to the


Continues on page 42

Dermatologic Look-Alikes bone or lead to sepsis. Due to the disfiguring nature of the disorder, social and psychiatric comorbidities such as anxiety and depression may have a significant impact on patient life.8 As the prevalence of chronic diseases such as congestive heart failure and obesity increases, it is likely that the incidence of ENV will also increase.Therefore, prevention of these predisposing conditions is key to preventing ENV.2 The patient in the case described above elected to treat the condition with compression stockings and topical salicylic acid emollients.


Stasis Dermatitis

Stasis dermatitis, or venous eczema, is an inflammatory skin pathology that develops as a result of impaired venous drainage, most commonly in the lower limbs. Often associated with peripheral pitting edema, varicose veins, and in later stages lipodermatosclerosis and ulceration, it is a concerning and debilitating condition for many older patients.9 Stasis dermatitis occurs primarily in elderly patients, as it stems from chronic venous insufficiency that occurs at an increased rate in this population. Approximately 6.2% of individuals aged ≥65 years have been found to have chronic venous insufficiency.10,11 With advanced chronic venous insufficiency, skin findings such as stasis dermatitis and skin ulcers develop, affecting an estimated 2 to 6 million people.12 In addition to older age, other risk factors for stasis dermatitis include obesity, female gender, pregnancy, occupations involving prolonged standing, and family history of venous disease.11 Chronic venous insufficiency is principally caused by venous hypertension, which results from incompetent venous valves, valve reflux, venous outflow obstruction, and failure of the skeletal muscle pump due to prolonged immobility or obesity, all leading to impaired venous flow and a rise in venous pressure.13 Increased pressure in the venous system causes movement of fluid from the vascular space to the interstitium, leading to pitting edema in the affected extremities. Edema and subsequent activation of the inflammatory cascade for prolonged periods of time lead to skin manifestations such as stasis dermatitis and venous ulcers.13 Clinical features of stasis dermatitis include erythema, scaling, lichenification, and formation of plaques and papules, in addition to the pitting edema and prominent superficial

veins that result from the underlying venous insufficiency.9,14 Hyperpigmentation often develops in these patients as well, likely from hemosiderin deposition. Patients most frequently complain of aching, itching, cramps, and a feeling of heaviness, coinciding with symptoms associated with chronic venous insufficiency.14 If left untreated, patients may develop venous ulcers, typically at the medial malleolus, or lipodermatosclerosis.9,15 Patients may also experience increased contact sensitization, frequently to topical drugs and dressings commonly used in treatment, including antiseptics, corticosteroids, and antibiotics.16 This can make treatment of stasis dermatitis and venous stasis ulcers more challenging as patients may develop contact dermatitis concurrently with their stasis dermatitis. Histologic characterization of stasis dermatitis includes extravasated erythrocytes, perivascular lymphocytic infiltrates, dermal fibrosis, and small blood vessel proliferation, which may lead to formation of discrete papules due to the inflammatory process.17,18 Nonspecific findings including hyperkeratosis, parakeratosis, acanthosis, and spongiosis are also commonly observed.Although the hyperpigmentation of chronic venous insufficiency has historically been attributed to hemosiderin deposition from extravasated erythrocytes, some studies suggest the cause may actually be hypermelanization.19 Diagnosis of stasis dermatitis is clinical and is made by evaluation of the characteristic poorly demarcated erythematous rash with other typical features including plaques, scaling, hyperpigmentation, and edema.When diagnosis is uncertain, duplex ultrasound of venous valves can be performed to show the venous reflux or incompetent valves that contribute to this pathology.9 The

The etiology of stasis dermatitis centers on chronic venous insufficiency, which is principally caused by venous hypertension. differential diagnosis for stasis dermatitis includes lower limb cellulitis, psoriasis, allergic contact or irritant dermatitis, pigmented purpuric dermatoses, and in some cases where stasis dermatitis presents with solitary lesions, neoplastic processes, as well.9,15,20 The focus of treatment is relieving venous stasis, principally by compressive therapy. Skin care treatments for stasis dermatitis — including non-soap cleansers, emollients, and barrier preparations — are also beneficial.9 Topical antiseptics and ointments containing perfumes should be avoided, as patients with stasis dermatitis are at increased risk for contact sensitization.16 Pharmacologic therapy with venoactive drugs increases venous tone and lymphatic drainage and improves


Dermatologic Look-Alikes

TABLE. Elephantiasis Nostras Verrucosa1-8 vs Stasis Dermatitis9 Dermatologic Nonpitting edema with Presentation overlying verrucous lesions Associations


Obesity, congestive heart failure, trauma to lymphatics

References 1. Schissel DJ, Hivnor C, Elston DM. Elephantiasis nostras verrucosa. Cutis.

Poorly demarcated erythema­tous rash, plaques, pitting edema Older age, obesity, female gender, pregnancy, prolonged standing

Tissue fibrosis, epidermal Venous insufficiency leading hyperkeratosis, and local infec- to edema and inflammation tion in the setting of chronic secondary lymphedema

Characteristic Location

Gravity-dependent regions such as lower extremities and scrotum

Gravity-dependent regions such as lower extremities


Enlarged lymphatic vessels, fibrotic dermal tissue with loss of dermal papillae, and a hyperkeratotic epidermis

Dermal fibrosis, perivascular lymphocytic infiltrates, extra­ vasated erythrocytes, small blood vessel proliferation


Clinically and histopathologically

Clinically; can be confirmed by venous duplex ultrasound


Treatment of underlying cause, compression stockings, topical retinoids

Treatment of underlying venous insufficiency, compression stockings

1998;62(2):77-80. 2. Baird D, Bode D, Akers T, Deyoung Z. Elephantiasis nostras verrucosa (ENV): a complication of congestive heart failure and obesity. J Am Board Fam Med. 2010;23(3):413-417. 3. Tiwari A, Cheng KS, Button M, Myint F, Hamilton G. Differential diagnosis, inves­ti­ga­tion, and current treatment of lower limb lymphedema. Arch Surg. 2003;138(2):152-161. 4. Dean SM, Zirwas MJ, Horst AV. Elephantiasis nostras verrucosa: an institutional analysis of 21 cases. J Am Acad Dermatol. 2011;64(6):1104-1110. 5. Sarma PS, Ghorpade A. Elephantiasis nostras verrucosa on the legs and abdomen with morbid obesity in an Indian lady. Dermatol Online J. 2008;14(12):20. 6. Liaw F-Y, Huang C-F, Wu Y-C, Wu B-Y. Elephantiasis nostras verrucosa: swelling with verrucose appearance of lower limbs. Can Fam Physician. 2012;58(10):e551-e553. 7. Shimony A, Tidhar D. Lymphedema: a comprehensive review. Ann Plast Surg. 2008;60(2):228. 8. Sisto K, Khachemoune A. Elephantiasis nostras verrucosa: a review. Am J Clin Dermatol. 2008;9(3):141-146. 9. Sundaresan S, Migden MR, Silapunt S. Stasis dermatitis: pathophysiology, evaluation, and management. Am J Clin Dermatol. 2017;18(3):383. 10. Yalçin B, Tamer E, Toy GG, et al. The prevalence of skin diseases in the elderly: analysis of 4099 geriatric patients. Int J Dermatol. 2006;45(6):672-676. 11. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15(3):175-184. 12. White JV, Ryjewski C. Chronic venous insufficiency. Perspect Vase Surg

symptoms of venous insuf ­fi ciency.9 Surgical management of the underlying venous reflux is the backbone of treatment; former open surgical methods of saphenofemoral junction ligation have been replaced by less-invasive techniques, including endovenous thermal ablation and ambulatory phlebectomy.9 Prognosis depends on the progression of stasis dermatitis and severity of the underlying venous insufficiency.With early diagnosis and proper use of compression stockings or with surgical intervention to address the venous insufficiency, outcomes may be improved and patients are less likely to progress to having skin manifestations such as stasis dermatitis and associated sequelae. With the increasing aging population, chronic venous insufficiency and later development of stasis dermatitis will likely become an increasingly common problem encountered in clinical practice; therefore, early intervention and management is a key step in lessening the burden of this skin pathology. The patient in the case described above elected to treat her condition with topical petrolatum and compression stockings. ■

Endovasc Ther. 2005;17(4):319-327. 13. Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med. 2006;355:488-498. 14. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FGR. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg. 2002;36(3):520-525. 15. Weaver J, Billings SD. Initial presentation of stasis dermatitis mimicking solitary lesions: a previously unrecognized clinical scenario. J Am Acad Dermatol. 2009;61(6):1028-1032. 16. Barbaud A, Collet E, Le Coz CJ, Meaume S, Gillois P. Contact allergy in chronic leg ulcers: results of a multicentre study carried out in 423 patients and proposal for an updated series of patch tests. Contact Dermatitis. 2009; 60(5):279-287. 17. Weedon D. Stasis dermatitis. In: Weedon D (ed). Weedon’s Skin Pathology. 3rd edition. Amsterdam: Churchill Livingstone, Elsevier; 2010. 18. Rapini RP. Stasis dermatitis. In: Rapini RP (ed). Practical Dermatopathology. 2nd edition. Amsterdam: Elsevier; 2012. 19. Caggiati A, Rosi C, Franceschini M, Innocenzi D. The nature of skin pigmentations in chronic venous insufficiency: a preliminary report. Eur J Vasc

Maya Firsowicz, BS, is a medical student; Claire J. Wiggins, BS, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine in Houston,Texas.

Endovasc Surg. 2008;35:111-118. 20. Hirschmann JV, Raugi GJ. Lower limb cellulitis and its mimics: part II. Conditions that simulate lower limb cellulitis. J Am Acad Dermatol. 2012;67(2):177.e1. • THE CLINICAL ADVISOR • MARCH 2019 43



Clinician Testimony in a Rape Case Can an NP’s testimony be used after a victim changes her story?


When Ms N, a 48-year-old nurse practitioner, heard her name being paged across the hospital’s PA system, she knew why. As one of only a few clinicians on staff with experience with sexual assault victims, Ms N knew that getting paged probably meant that one was being brought in. She was correct. Two officers were standing in the emergency department with a trembling woman, helping her fill out paperwork. Ms N asked a nurse to put the patient in an examination room while she spoke with the officers. “We got a 911 call from the victim. She said she had been sexually assaulted by her husband, and that he told her he was going to kill her,” said one of the officers. “When we got there, she was barricaded in the bathroom, clearly upset, dressed only in a towel. She eventually came out but ran out of the house in below-freezing temperatures still wrapped only in a towel.We convinced her to come back inside where she began crying uncontrollably. She said that her husband had physically assaulted her, and that he had choked her with one hand while penetrating her vagina

The patient attributed her accusations against her husband to PTSD as a result of being kidnapped and sexually assaulted while fleeing the civil war in Liberia.


with the other. We have another officer at home with the husband, who has denied everything. We were also called there 2 days ago for a domestic dispute where the wife was the aggressor, so there have been issues in the past.” Ms N thanked the officer for the information and went in to see the patient, Mrs B, 31. The younger woman was still shaking. Ms N spoke to her soothingly and calmed her down enough to get her story. The patient told Ms N that she had been sleeping in her toddler’s room because she and her husband had been having some problems, but at 5 AM her husband had woken her up and told her to take a shower. “I knew what that meant,” said Mrs B. “That’s always what he makes me do first…” Her husband then ordered her out of the shower. He put his right hand against her throat and 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.

used his left hand to reach into her vaginal area to claw and scratch her. Mrs B made a hook shape with her finger and described how it felt like he was trying to “pull out” her uterus. “I felt a burning feeling … down there,” Mrs B said,“and he was choking me so I couldn’t breathe. When he stopped, he told me that if I told anyone he would kill me and the kids.” Ms N carefully noted what Mrs B told her. During the sexual assault examination, Ms N noted petechiae and red marks on Mrs B’s vagina, as well as a blood stain on her underwear. Ms N filled out the requisite paperwork for the police report, and Mrs B’s husband was subsequently arrested and charged with sexual assault. Two weeks after the incident, Mrs B wrote a letter to the prosecutor asking that the charges against her husband be dropped. In her letter, Mrs B stated that she had been diagnosed with post-traumatic stress disorder as a result of being kidnapped and sexually assaulted while fleeing the civil war in Liberia, her birth country. She had recently been having nightmares about the kidnapping, and her husband was in one of her bad dreams; that was what had caused her to call the police. She stated that her husband was a loving, nonviolent person who was innocent of the charges. The prosecutor, however, declined to drop the charges and took the case to trial. At trial, Ms N testified about her examination of Mrs B, as well as what Mrs B had told her at the time. Mrs B also took the stand and testified that she had experienced a flashback; she had confused the present with her traumatic past experience, and she stated that any injuries were self-inflicted. After all of the evidence was presented, the jury deliberated and eventually found Mr B guilty. He was sentenced to 12 years in prison. Mr B immediately appealed his conviction, arguing that the lower court had abused its discretion by admitting Mrs B’s outof-court statements to Ms N (hearsay), among other arguments.

they fall under an exception to the rule forbidding hearsay. However, the court concluded that the statements were, in fact, an exception to the hearsay rule because they were made “where the declarant knows that a false statement may cause misdiagnosis or mistreatment” and thus are credible. The court noted that Ms N had testified that she informed Mrs B that she would perform a sexual assault examination, provide medical treatment, and “care for any injuries that may have happened during the assault.” Therefore, any statements Mrs B made at that time were admissible because they are assumed to be true because they were made in the course of medical treatment. The court of appeals upheld Mr B’s conviction. Protecting Yourself

Having to testify in court is never fun, even if you are not the defendant.Attorneys from the other side will be trying to impeach your testimony, attack your credibility, and discount the importance of what you have to say. The best way to protect yourself is preparation, and that starts from the very first interaction with the patient or victim. If it is a victim, explain that the examination is for police reporting purposes and that you will be providing medical evaluation and treatment for any injuries. Take copious and detailed notes; they may become crucially important if there is a change in story later in the process. And finally, be sure that the attorney who has called you to testify has properly prepared you for what to expect. A practice run isn’t a bad idea either, especially if you aren’t comfortable with public speaking. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

Legal Background

Although it may be surprising, a prosecutor in a criminal case can press charges against a defendant even if the victim decides she no longer wants to proceed. There is a good reason for this. In domestic relations situations, in particular, there is a chance that the victim might be pressured to drop the charges. Prosecutors have responded to this issue by making their own decisions about whether a case should be prosecuted rather than letting the victim make that decision. So, even though Mrs B no longer wanted to press charges, that decision was now out of her hands. In his appeal, Mr B argued that his wife’s statement to Ms N was inadmissible hearsay. The court of appeals agreed that such statements are hearsay and thus can only be admitted if

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