VOL. LX • NO. 5 • 2019

VOLUME LX • NO. 5 • 2019

Wonderful Father's Day or graduation gift idea for anyone in medicine!

Pickup in Ridgeland for $49.95 or $57.95 includes shipping.

Order three or more to receive a discount at: http://tinyurl.com/yb7ab974 “ Images In Mississippi Medicine by Dr. Luke Lampton and Karen Evers is a handsome and impressive book, filled with stories and scenes ranging from primitive operating rooms and rows of hospitalized tornado victims a century ago to the new teaching complex at the University of Mississippi Medical Center with its modern breakthroughs.

The volume is a piece of our history that every Mississippian can appreciate.”

– Curtis Wilkie, journalist, author, and professor at Ole Miss

Images in Mississippi Medicine: A Photographic History of Medicine in Mississippi; MSMA; Jackson, MS: 2018.

VOL. LX • NO. 5 • MAY 2019

SPECIAL ARTICLES

EDITOR Lucius M. Lampton, MD ASSOCIATE EDITORS D. Stanley Hartness, MD Philip T. Merideth, MD, JD

THE ASSOCIATION President Michael Mansour, MD President-Elect J. Clay Hays, Jr., MD

MANAGING EDITOR Karen A. Evers

Secretary-Treasurer W. Mark Horne, MD

PUBLICATIONS COMMITTEE Dwalia S. South, MD Chair Richard D. deShazo, MD Sheila Bouldin, MD Wesley Youngblood, M3 and the Editors

Speaker Geri Lee Weiland, MD Vice Speaker Jeffrey A. Morris, MD Executive Director Claude D. Brunson, MD

JOURNAL OF THE MISSISSIPPI STATE MEDICAL ASSOCIATION (ISSN 0026-6396) is owned and published monthly by the Mississippi State Medical Association, founded 1856, located at 408 West Parkway Place, Ridgeland, Mississippi 39158-2548. (ISSN# 0026-6396 as mandated by section E211.10, Domestic Mail Manual). Periodicals postage paid at Jackson, MS and at additional mailing offices.

CORRESPONDENCE: Journal MSMA, Managing Editor, Karen A. Evers, P.O. Box 2548, Ridgeland, MS 39158-2548, Ph.: 601-853-6733, Fax: 601-853-6746, www.MSMAonline.com.

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The views expressed in this publication reflect the opinions of the authors and do not necessarily state the opinions or policies of the Mississippi State Medical Association.

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Official Publication

MSMA • Since 1959

Top 10 Facts You Need to Know about Musculoskeletal Ultrasound Luciano De Lima Villarinho, MD; Kathryn M. Nutter, MD

168

Dementia Facts: Distinguishing the Differential Diagnosis Netrali Patel, MD; Lilian E. Massihi, MD; Ashishkumar Patel, MD; Andrew Majeste, BSN, RN

172

Autoimmune Hepatitis (AIH) – A Case Report and Review of Literature Tobe Momah, MD ; Rachel Yi, M4; Will Payne, MD; David Green, MD; Alana Persanti, MD; Matthew Meece, DO

177

Ten Examples of How Evolutionary Medicine Can Furnish Ideas for 180

Clinical Research and Improve Medical Practice Mary C. Bailey, M1; Piyush S. Borse, M1; Nicholas A. Bosworth, M1;

Nicholas H. Brewer, M1; Nelson P. Douglass, M1; Rosario K. Guastella, M1;

Ghali G. Haddad, M1; Mary M. Haire, M1; Kelly G. Hill, M1; Alan D. Penman, MD

Autologous Bone Marrow Transplantation for Multiple Myeloma: 185 An Analysis of Risk Factors that Affected Patient Outcomes at the University of Mississippi Medical Center

Doris K. Hansen, MD; Thomas Williamson, MD; Johann Hsu, MD; Tondre Buck, MD; Carter P. Milner, MD DEPARTMENTS From the Editor – “Mens Sana” In A World Of Rising Suicide Lucius M. Lampton, MD

166

President’s Page – The Past is Prologue; Keeping the Patient First – Remembering James C. Waites, MD, MSMA President 1991-1992 Michael Mansour, MD

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Letters

190

New Members

196

Images in Medicine – The Turner Hospital, Meridian, 1910 Lucius M. Lampton, MD

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Poetry and Medicine – Killed in Mississippi Hotel Fire; Greenville, March 4 195 Merrill Moore, MD

RELATED ORGANIZATIONS Mississippi Department of Health

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Mississippi Rural Physicians Scholarship Program

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ABOUT THE COVER "Red Snapper Catch" – Hattiesburg nephrologist Dr. Brian Rifkin caught

the cover catch on an annual family fishing trip out of “the world’s luckiest fishing village,” Destin, Florida. Located next to the East Pass, within minutes of the Gulf of Mexico and the Choctawhatchee Bay, the area offers both inshore and deep sea fishing. The 100 fathom curve draws closer to Destin than any other spot in Florida providing the speediest deep-water access on the Gulf. Anglers only need to travel 23 miles offshore to reach the edge of the continental shelf, aka “The Edge” which is home to huge grouper, red snapper, and amberjack, as well as pelagic fish like mahi-mahi, tuna, wahoo, and even billfish. Red snapper season varies among Gulf states. Dr. Rifkin said, “Catching is fun, but catching and eating is even better.”

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“Mens Sana” In A World Of Rising Suicide

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nthony Bourdain’s suicide last June surprised me. The tattooed culinary legend possessed a charmed life, traveling the world filming an award-winning television program that my sons and I loved to watch together (a rare and treasured experience for a parent to find a program or book you are able to enjoy mutually with your children!). The gracious Bourdain, lacking hubris, called himself a cook, not a chef, and he Lucius M. Lampton, MD seemed emotionally well-grounded.

Editor There were hints of past struggles with addiction, but he appeared beyond it.

However, despite these apparent triumphs, he hanged himself in his hotel room in France while filming his “Parts Unknown” series. I could imagine his early death occurring by skydiving in Peru or bungee jumping in Greece or snorkeling underwater in Indonesia.

But suicide in a hotel room?

A few days before Bourdain’s death, fashion designer Kate Spade committed suicide in New York. Widespread media coverage of these

suicides coincided with a Centers for Disease Control and Prevention report revealing suicide rates have increased markedly in the US over the past two decades. Looking at the CDC data, middle-aged adults have the highest number of suicides and the largest rate increases.

Many who committed suicide also had no known mental illness. A writer for The New York Times asserted that the deaths of Bourdain and Spade “were not simply pop culture tragedies. They were the latest markers of an intractable public health crisis that has been unfolding in slow motion for a generation.”

The goal of public health and medicine has long been “mens sana in corpore sano,” Latin for “a healthy mind in a healthy body.” As physicians, we often concentrate more on the importance of a healthy body than a healthy mind, but the reverse is just as critical: psychological well-being is absolutely essential for physical health.

Better recognition of those at risk of suicide as well as increased access to treatment are necessary for suicide prevention. We as healers need to focus intensely on improving the mental health of our patients in order to stem this tragic upsurge of suicides. n Contact me at lukelampton@cableone.net.

— Lucius M. Lampton, MD, Editor

JOURNAL EDITORIAL ADVISORY BOARD ADDICTION MEDICINE Scott L. Hambleton, MD

EMERGENCY MEDICINE Philip Levin, MD

INTERNAL MEDICINE/EPIDEMIOLOGY Thomas E. Dobbs, MD

ALLERGY/IMMUNOLOGY Stephen B. LeBlanc, MD Patricia H. Stewart, MD

FAMILY MEDICINE Tim J. Alford, MD Diane K. Beebe, MD Jennifer J. Bryan, MD J. Edward Hill, MD Ben Earl Kitchens, MD

MEDICAL STUDENT John F. G. Bobo, M3

GASTROENTEROLOGY James Q. Sones, MD

OBSTETRICS & GYNECOLOGY Sidney W. Bondurant, MD Sheila Bouldin, MD Darden H. North, MD

ANESTHESIOLOGY Douglas R. Bacon, MD John W. Bethea, Jr., MD CARDIOVASCULAR DISEASE Thad F. Waites, MD CHILD & ADOLESCENT PSYCHIATRY John Elgin Wilkaitis, MD CLINICAL NEUROPHYSIOLOGY Alan R. Moore, MD DERMATOLOGY Robert T. Brodell, MD Adam C. Byrd, MD

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GENERAL SURGERY Andrew C. Mallette, MD HEMATOLOGY Carter Milner, MD INFECTIOUS DISEASE Rathel "Skip" Nolen, III, MD INTERNAL MEDICINE Daniel P. Edney, MD Daniel W. Jones, MD Brett C. Lampton, MD Kelly J. Wilkinson, MD

NEPHROLOGY Harvey A. Gersh, MD Sohail Abdul Salim, MD

ORTHOPEDIC SURGERY Chris E. Wiggins, MD OTOLARYNGOLOGY Bradford J. Dye, III, MD PEDIATRIC OTOLARYNGOLOGY Jeffrey D. Carron, MD PEDIATRICS Michael Artigues, MD Owen B. Evans, MD

PLASTIC SURGERY William C. Lineaweaver, MD Chair, Journal Editorial Advisory Board PSYCHIATRY Beverly J. Bryant, MD June A. Powell, MD PUBLIC HEALTH Mary Margaret Currier, MD, MPH PULMONARY DISEASE Sharon P. Douglas, MD John R. Spurzem, MD RADIOLOGY P. H. (Hal) Moore, Jr., MD RESIDENT / FELLOW Cesar Cardenas, MD UROLOGY W. Lamar Weems, MD VASCULAR SURGERY Taimur Saleem, MD

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Top 10 Facts You Need to Know about Musculoskeletal Ultrasound LUCIANO DE LIMA VILLARINHO, MD; KATHRYN M. NUTTER, MD

Ultrasound is a widely available imaging modality in most hospitals, clinics and outpatient imaging facilities. Diagnostic ultrasound, also called sonography, is an imaging method that uses high-frequency sound waves to produce images of structures within the body.

Utilization of ultrasound in the investigation of complaints in the musculoskeletal system has been gaining in popularity in the United States in the last decade, lagging somewhat behind its widespread use across Europe and South America. The reasons for this increase in ultrasound use include technological advancements allowing optimal imaging of superficial structures and small parts as well as the continued movement in medicine toward means of diagnosis with improved cost efficiency and availability for patients. The European Society of Musculoskeletal Radiology (ESSR) first released technical guidelines for image optimization and scanning protocols to standardize the practice of musculoskeletal ultrasound in 2004.1 Radiology training programs are now incorporating ultrasound instruction into musculoskeletal curricula in addition to the traditional role of ultrasound in body imaging for residents. Radiography remains the first line evaluation for nearly every musculoskeletal system query.

Computed tomography (CT) also provides superior visualization of osseous structures, and CT generated 3D renditions of complex fractures have become a valuable preoperative planning tool for orthopedic surgeons. However, there is more to the musculoskeletal system than just osseous elements, and ultrasound has proven valuable for both diagnosis and guidance of therapeutic interventions in a myriad of joint and soft tissue indications. Without question, magnetic resonance imaging (MRI) remains the preferred choice for investigation of complex joint injuries and optimal preoperative and postoperative analysis of neoplastic lesions of the musculoskeletal system. However, the relative affordability and accessibility of ultrasound compared with magnetic resonance imaging (MRI) and the lack of ionizing radiation intrinsic to radiography and computed tomography (CT) has led to the increasing utilization of ultrasound.

Ultrasound exams are fast and accessible. Ultrasound is a widely available imaging modality in most hospitals, clinics and outpatient imaging facilities. Average ultrasound examination time is only approximately 10-15 minutes. Therefore, a patient often can be evaluated almost immediately with this modality with infrequent need for distant scheduling or a return visit for the exam. Formal interpretation of an ultrasound exam by the radiologist, accordingly, often takes no more than 5-10 minutes. Ultrasound may provide the 168 VOL. 60 • NO. 5 • 2019

answer to the clinical concern or may serve to redirect further workup by excluding some diagnoses. In this respect, ultrasound should be added to the musculoskeletal imaging toolbox as a complement to the existing effective tools of radiography, CT and MRI.2 Ultrasound examination is cheaper than CT or MRI. As the waistline on America’s health care costs bulges, so does the belt tighten. We as physicians are charged to pursue more cost-effective means of diagnosis and treatment of disease or injury.

Using data from the most current Centers for Medicare and Medicaid Services’ Physician Fee Schedule, the average reimbursement for ultrasound extremity joint CPT code 76881 is approximately $130-145, compared with $305-340 for MRI lower extremity joint without dye CPT code 73721.3 As well, ultrasound units are relatively inexpensive to obtain in the range of $50-150,000, relative to cost of CT or MRI units. Multichannel CT unit may cost $400-800,000, and MRI units will start around $1,000,000.

Ultrasound utilizes no ionizing radiation. Ultrasound utilizes high-frequency sound waves which cause no ill effects to fetus or children in diagnostic doses.4 Radiation dose estimated for an extremity X-ray is 0.001 mSv (comparable to 3h background radiation) and for a CT Abdomen is 8 mSv (comparable to 8-16 months of background radiation or similar effective dose to 400 chest X-rays).5,6 Ultrasound is useful in patients that have a contraindication to MRI. Although MRI is the exam of choice in many musculoskeletal conditions, patients with contraindications to MRI including certain incompatible implanted devices or patients with severe claustrophobia can often benefit from an ultrasound. Also, pediatric patients, patients unable to hold still or those with limited positioning such as those confined to a wheelchair or with a fixed deformity can be scanned without difficulty or even at bedside.7 Ultrasound is a dynamic exam. Tendons, muscles and joints can be evaluated at real time during gentle motion guided by the imager. For example, dynamic ultrasound evaluation can distinguish between partial and complete tear of a tendon that is more apparent with stress on that tendon.7 This can be seen with evaluation of the Achilles tendon with foot dorsiflexed or plantarflexed relative to neutral

position. As well, the relation of a mass or fluid collection to a tendon or tendon sheath in a digit can be better determined by manipulation of the affected digit at real-time ultrasound evaluation. In many cases, a contralateral anatomic comparison can be easily obtained as needed.

Ultrasound can distinguish between cystic or solid mass.

Ultrasound is recommended as the initial imaging evaluation of a superficial palpable soft tissue mass in current American College of Radiology (ACR) Appropriateness Criteria®.8 The same reference emphasizes ultrasound is not as useful for evaluating a deeper, nonpalpable lesion or mass with spontaneous hemorrhage or suspected vascular mass. In these instances, and if initial imaging evaluation with ultrasound is not diagnostic, then MRI with and without contrast is recommended. Ultrasound has proven to be most useful when applied to the evaluation of small superficial lesions, typically those superficial to the deep fascia. For example, ultrasound would be quite useful for imaging of an indicated palpable lesion suspected to be a ganglion cyst at wrist or ankle (Figure 1).

Ultrasound accurately demonstrates the architecture and quality of tendons. Ultrasound can demonstrate the expected linear, fibrillar architecture of densely packed collagen fibrils in a tendon. Accordingly, alterations in this appearance that may indicate tendinosis or tear are well demonstrated. This makes ultrasound useful for evaluation of commonly injured and overused tendons including those of the rotator cuff, extensor complex at knee, biceps, Achilles, and distal extremities (Figure 2). Ultrasound has been reported to demonstrate accuracies in detection of rotator cuff abnormalities equivalent to MRI10 (Figure 3, Figure 4).

Figure 2. Normal Tendon Longitudinal static ultrasound image of long head of biceps tendon in upper arm demonstrating normal tendon architecture by sonography (arrows). Note underlying curvilinear echogenic structure which is the humeral cortex.

Figure 1. Cyst Image obtained in investigation of palpable suspected cyst along margin of young girl’s ankle demonstrates a lobular wellmarginated lesion with very limited internal echoes and increased through transmission of sound typical for cystic nature of lesion.

Figure 3. Supraspinatus tendon Longitudinal ultrasound image of normal appearing supraspinatus tendon attachment on the humeral head (arrows).

The underlying linear white echogenic line is the humeral head surface.

Ultrasound is most useful for targeted evaluation of a specific structure. Ultrasound is typically not considered adequate for whole joint evaluation due to small focal zone or “field of view” with ultrasound which limits overview or visualization of structures such as ligaments in entirety. MRI is superior for evaluation of entirety of a joint and surrounding structures and is indicated if clinical history is such as “acute traumatic knee pain, twisting injury, internal derangement suspected” in which case the ACR Appropriateness Criteria rates ultrasound as a “1= usually not appropriate” compared with the rating of “9 = usually appropriate” for MRI.9 But, in cases where an isolated quadriceps or patellar tendon injury is suspected clinically, ultrasound can be a quick and inexpensive way to answer a direct clinical question. Then, if clinical concern is not adequately resolved, MRI could be pursued accordingly.

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Figure 4. Longitudinal ultrasound image of tear in the supraspinatus tendon at humeral attachment denoted by calipers as hypoechoic defect in normal expected fibrillar structure of the tendon.

Ultrasound can demonstrate irregularity of bony surfaces but should NOT be used for evaluation of bone. Underlying bony landmarks are often utilized in ultrasound for orientation, particularly in documenting images of pathology (Figure 3). The surface of the bone is visible, but bone does not allow sound wave transmission. The superficial cortical margin is visible as echogenic linear structure but with shadowing or obscuration of remainder of bone and any deeper structures beyond the bone (Figure 5, Figure 6).

Therefore, ultrasound should not be utilized to attempt characterizing a bone lesion or deep soft tissue lesion that could potentially be deep to bone. As well, on an MRI, rotator cuff tendons can be visualized deep to the acromioclavicular joint. However, given the inability of sound waves to penetrate bone in ultrasound imaging, provocative positioning of the patient’s arm is required for ultrasound imaging of the rotator cuff that will adequately displace the tendons from under the bones for optimal visualization.11,12

Figure 5. Acromioclavicular joint Ultrasound image of acromioclavicular joint demonstrating fairly smooth contour of osseous margins of acromion process of scapula and distal clavicle visible as opposing curvilinear echogenic margins with minimal intervening joint effusion.

Figure 6. Acromioclavicular joint osteoarthritis Acromioclavicular joint osteoarthritis. Acromioclavicular joint ultrasound image demonstrating more advanced osteoarthritic changes with greater bony hypertrophic changes in the adjacent osseous margins which appear more irregular than in Figure 2.

Ultrasound can be used for detection of suspected inflammatory arthritis in superficial joints if initial radiographs are normal. The presence of even small joint effusions or excessive fluid accumulation in tendon sheaths can be easily detected by conventional gray-scale ultrasound. As well, Doppler ultrasound imaging can demonstrate hypervascularity about joints which may also be expected with inflammatory arthritis.13 In the same way, in characterizing a small superficial soft tissue mass thought clinically to be a lipoma, the detection of hypervascularity/hyperemia

by Doppler ultrasound within and adjacent to lesion would raise concern for potential neoplastic instead of benign etiology and warrant further imaging with MRI and, likely, biopsy.

Ultrasound is indicated for use in the imaging investigation of many common musculoskeletal complaints. This modality is cost effective and widely available. Ultrasound may answer the clinical question or, at the very least, direct the next course of action. n References 1. Beggs I, Bianchi S, Bueno A, et al. Musculoskeletal ultrasound technical guidelines shoulder. ESSR website. https://essr.org/content-essr/uploads/2016/10/ shoulder.pdf. Accessed June 26, 2018.

2. Rogers, LF. The sound of bones: sonography of the musculoskeletal system. AJR Am Roentgenol. 2000;175(3):573.

3. Medicare Physician Fee Schedule. Centers for Medicare & Medicaid Services website. https://www.cms.gov/apps/physician-fee-schedule/overview.aspx.

Accessed June 19, 2018.

4. AIUM Official Statement Prudent Use and Clinical Safety. American Institute of Ultrasound in Medicine website. https://www.aium.org/officialStatements/34.

Accessed June 26, 2018.

5. Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging website. https://www.fda.gov/radiation-emittingproducts/radiationsafety/ radiationdosereduction/default.htm February 2010. U.S. Food & Drug Administration Center for Devices and Radiological Health. Accessed March 25, 2019.

6. Amis ES, Butler PF, Applegate KE, et al. American College of Radiology white paper on radiation dose in medicine. J Am Coll Radiol 2007;4(5):272-284.

7. Nazarian LN. The top 10 reasons musculoskeletal sonography is an important

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complementary or alternative technique to MRI. AJR Am J Roentgenol. 2008;190(6): 1621-1626.

8. Kransdorf MJ, Murphey MD, Wessell DE, et al. ACR Appropriateness Criteria® Soft Tissue Masses. Soft-tissue mass. Superficial or palpable. Initial imaging study.

American College of Radiology website. https://acsearch.acr.org/docs/69434/ Narrative/. Accessed June 27, 2018.

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9. Tuite MJ, Kransdorf MJ, Beaman, FD, et al. ACR Appropriateness Criteria® Acute Trauma to the Knee. American College of Radiology website. https://acsearch.acr. org/docs/69419/Narrative/. Accessed June 30, 2018.

10. Small KM, Adler RS, Shah SH, et al. ACR Appropriateness Criteria® Shoulder Pain– Atraumatic. American College of Radiology website. https://acsearch.acr.org/ docs/3101482/Narrative/. Accessed June 27, 2018.

11. Morrison WB, Weissman BN, Kransdorf MJ, et al. ACR Appropriateness Criteria® Primary Bone Tumors. American College of Radiology website. https://acsearch. acr.org/docs/69421/Narrative/. Accessed June 25, 2018.

12. AIUM Practice Parameter for the Performance of a Musculoskeletal Ultrasound Examination. American Institute for Ultrasound in Medicine website. https://www. aium.org/resources/guidelines/musculoskeletal.pdf. Accessed June 25, 2018.

13. Jacobson JA, Roberts CC, Bencardino JT, et al. ACR Appropriateness Criteria® Chronic Extremity Joint Pain-Suspected Inflammatory Arthritis. American College of Radiology website. https://acsearch.acr.org/docs/3097211/Narrative/. Accessed June 30, 2018.

Author Information Author Information: Radiology resident, University of Mississippi Medical Center (UMMC) (Villarinho). Assistant Professor of Radiology with sub-specialization in musculoskeletal radiology, UMMC (Nutter). Conflicts of interest: None.

318 Howard St reet • Greenwood, Mississippi 662 .453. 2114 • thealluvian.com

Corresponding Author: Kathryn Nutter, MD, Department of Radiology, UMMC, 2500 North State St., Jackson, MS 39216.

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Dementia Facts: Distinguishing the Differential Diagnosis NETRALI PATEL, MD; LILIAN E. MASSIHI, MD; ASHISHKUMAR PATEL, MD; ANDREW MAJESTE, BSN, RN Introduction Dementia is characterized by chronic, global, irreversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired in persons with dementia. Over 5.8 million Americans are currently living with Alzheimer’s disease (AD), and this number is expected to increase to nearly fourteen million by the year 2050. 1 More than 55,000 Mississippians aged 65 and older have Alzheimer’s disease.2 There is a growing need for early detection and diagnosis of AD and other types of dementia.

A dementia evaluation consists of cognitive evaluation, a complete history, physical and neurological exam, neurocognitive testing, and depression screening. Diagnostic laboratory and imaging studies, as well as pharmacological and behavioral therapies, are offered when Table 1. Dementia Syndromes

Table 1. Dementia Syndromes Demen�a Syndromes:

Mild1.Cogni�ve Table DementiaImpairment Syndromes Alzheimer’s Disease

Dementia Syndromes: Lewy Body Demen�a MCI Frontotemporal Alzheimer’s Disease Demen�a Lewy Body Dementia Pseudodemen�a Frontotemporal DementiaDemen�a Parkinson’s Disease Pseudodementia Parkinson’s Disease Dementia

indicated. Careful evaluation to exclude reversible causes of cognitive impairment is significant. Patients with early dementia may benefit from formal neuropsychological testing and further imaging for uncertain diagnosis. This article is intended to be used as a guide to help providers evaluate suspected dementia and differentiate between the various types. The dementia syndromes discussed in this paper are outlined in Table 1.

What Are Common Risk Factors for AD? 3 When thinking about risk factors associated with the development of AD, the literature suggests that family history does play a role.

Genetic testing is not indicated in the clinical workup, but research has found genetic correlations between the early and late onset of AD. Early onset is defined as the development of AD prior to age 65 and is associated with genetic mutations of Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). Late onset is defined as the development of AD after age 65 and is associated with genetic mutations to the apolipoprotein E (APOE) gene including APOE ε2, APOE ε3, and APOE ε4. Other risk factors are associated with comorbidities including the history of head trauma, hyperlipidemia, hypertension, and diabetes. Psychosocial risk factors for the development of AD include low education level and depression.

Table 2 outlines the differences between normal aging and early signs of dementia.

The normal aging process is associated with declines in certain cognitive abilities. These changes are small and should not result in impairment in function. New learning is slower, yet still occurs. It Table 2. Signs Early of Alzheimer’s Dementia Aging 4,5 is important to detect these changes early. Participation in certain Table 2. Early of Signs Alzheimer’s Dementia vs Normal Aging 4,5 vs Normal 4,5 Table 2. Early Signs of Alzheimer’s Dementia vs Normal Aging activities, building cognitive reserve, and engaging in cognitive Normal Aging Early Signs of ADretraining may all be approaches Normal Aging Early Signs of AD to achieving successful cognitive aging.toMost Forge�ng the names of people they rarely see Forge�ng names of people close themadults over the age Forgetting the names of people they rarely see Forgetting names of people close to them of 65 will not develop dementia Briefly forgetting part of part an experience more often than more they used to than Briefly forge�ng of an experience Forgetting things Forge�ng things o�en to Impairment or they Mild used Cognitive (MCI), and more work is Not putting things away properly Repeating phrases or stories needed to understand better Not pu�ng things away properly Repea�ng phrases or stories in the same conversation how we can maximize cognitive in the same conversa�on function and quality of life for Mood changes in response to an appropriate cause Unpredictable mood changes these individuals.6 Early signs of Mood changes in response to an appropriate cause Unpredictable mood changes AD are more pronounced and Changes in their interests Decreased interest in activities and difficulty making choices persistent, worsening over time Changes in their interests Decreased interest in ac�vi�es

and difficulty making choices

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Diagnosis Figure 1. Algorithm to Determine What Steps Must Be Taken Next in Differentiating the Dementia Diagnosis Suspected Cogni�ve Decline

↓ Evaluate ADLS and Mental Status

↓↓ Normal ADLS with Impaired Mental Status

↓

Mild Cognitive Impairment (MCI)

Abnormal ADLS with Normal Mental Status

Abnormal ADLS with Impaired Mental Status

Normal ADLS and Normal Mental Status

Consider Depression or Frontotemporal Dementia

Dementia

Cognitively Intact

↓

↓

↓

↓ Evaluate for treatable causes with laboratory tes�ng and neuroimaging

← (Abnormal) ↓

↓

Treat the underlying issue (Subdural hematoma, normal pressure hydrocephalus, brain tumor, metabolic a�er encephali�s)

(Normal)

→

Temporal link to stroke?

NO↓ YES↓

YES↓ Lewy Body Demen�a

and adversely affecting activities of daily living.

The Dementia Work-Up3

↓

NO↓ Alzheimer’s Demen�a, Frontotemporal Demen�a, or Primary Progressive Aphasia

from either MCI or AD. Image on left: PET scan showing normal level of glucose metabolism (indicated in yellow and red; middle: MCI; and right: Alzheimer’s disease. The levels of glucose metabolism in the Figure 2. Brain Changes- Radiological imagining available can help providers distinguish between a brain are decreased in patients with MCI and with Alzheimer’s dementia,

normal brain and one suffering from either MCI or AD. Left: PET scan showing normal level of The American Geriatrics Society recommends several specificcontrol glucose andwith red) MCI and Alzheimer’s disease:(indicated The levels ofin glucose butmetabolism there is (indicated a greaterin yellow decline Alzheimer’s dementia laboratory and radiologic tests in the evaluation of patients withmetabolism in the brain are decreased in patients with MCI and with Alzheimer’s dementia, but there is yellow and red). suspected dementia. Laboratory tests are directed at excluding reversiblea greater decline with Alzheimer’s dementia (indicated in yellow and red). causes of dementia which include CBC, Folate, TSH, and Vitamin B12. There are certain laboratory tests to consider when specific risk factors are present including CSF analysis, HIV test, Lyme titers and Rapid Plasma Reagin (RPR) test. A CT Brain or MRI Brain should be considered if there is an abrupt or rapid decline in cognition, there are focal deficits, or there are predisposing conditions. The clinician should consider an Amyloid PET Scan (Figure 2) or Metabolic Brain PET Scan if definitive diagnosis changes the management of patients.

Figure 2. Radiological imaging can help providers evaluate brain

changes and distinguish between a normal brain and one suffering Figure 3. Normal vs. Alzheimer’s Brain Radiological imagining available that can help providers distinguish between a control normal brain and one suffering from AD. Alzheimer’s: Marked dilation of MAYloss, • JOURNAL MSMA 173 the sulci and fissures, diffuse atrophy with volume ventricular enlargement.

An Algorithm for Diagnosis The dementia workup is vital in differentiating the type of dementia and the plan of care needed for patient treatment. When there is suspected cognitive decline, the clinician should evaluate both mental status and activities of daily living (ADLs). Depending on what deficits are present, the clinician can utilize the algorithm in Figure 1 to determine what next steps must be taken in differentiating the dementia diagnosis.

Mild Cognitive Impairment (MCI)3

Treatment for AD is often focused on symptoms management and behavioral modifications. Behavioral methods should be attempted first before considering antipsychotic medication. Reassurance, referral to adult day care, caregiver support groups, psychoeducation, distraction, redirection, and a structured environment can be beneficial.3 The use of cholinesterase inhibitors, particularly Donepezil is indicated for all stages of AD. When patients advance to the mild to moderate stages of AD, Galantamine (Razadyne) and Rivastigmine (Exelon) are indicated. As the disease progresses to the moderate-tosevere stage the addition of Memantine (Namenda) is indicated.

The clinical course of MCI is usually gradual and is primarily caused byFigure 3. Normal vs. Alzheimer’s Brain Radiological imagining available that can help p Figure between 3. Radiological is available to help a controlimagining normal brain and one suffering fromproviders AD. Alzheimer’s: M an abnormal amyloid deposition. The cognitive symptom associateddistinguish sulci and fissures, diffuse atrophy withbrain volume enlargement. between a control normal andloss, oneventricular suffering from AD. with MCI is memory impairment; however, symptoms do not preventthe distinguish The AD brains shows marked dilation of the sulci and fissures, diffuse patients from performing daily activities and are not as severe as those of AD. Clinically a patient will score 24-26 on the Mini-Mental Status atrophy with volume loss, ventricular enlargement.

Exam (MMSE) with functional status intact.7 The progression of MCI is unknown, but approximately 12% of MCI cases progress to AD within one year. There are currently no medications approved by the FDA to treat MCI. Treatment is focused on reduction in risk factors associated with MCI including increased physical activity, controlling cardiovascular risk factors and participating in mentally stimulating and socially engaging activities to help sustain brain activity.7 Presently Recognized Forms of Dementia Alzheimer’s Dementia Alzheimer’s dementia has a gradual onset with a progressive decline in cognitive functioning. The etiology behind AD is currently debated across the literature. The primary hypothesis is that AD is caused by amyloid plaques and oligomers or tau neurofibrillary tangles (or both).

The accumulation of these proteins or protein aggregates within the brain affect neuronal function and ultimately cell death.3 AD is the most common type of dementia, accounting for approximately twothirds of all cases and affecting 6%–8% of those ≥65 years old. The disease prevalence doubles every 5 years after age 60; an estimated 45% or more of those who are ≥85 years old have AD.3 Memory impairment is often a core symptom of any dementia, but in AD it is typically the core feature present in the earliest stages. Typically, AD patients demonstrate difficulty learning and retaining new information.

In later disease stages, their ability to learn and retrieve information is compromised even more, and patients are unable to access older, more distant memories.3 MMSE score is <24 accompanied by impaired functional status. The primary neurological symptoms associated with AD are aphasia, apraxia, disorientation, visuospatial dysfunction, impaired judgment, and executive dysfunction.

In AD there may be structural and functional imaging findings on an MRI, CT, and FDG-PET scan. On an MRI there is possible global atrophy, small hippocampal volumes, hippocampal atrophy, and volume loss. On a CT there may be diffuse cortical atrophy with disproportionate volume loss in the medial temporal lobe structures.3 A FDG-PET scan may be useful, but not required for diagnosis of AD. This scan will show hypo-metabolism in bilateral parietal and temporal lobes.3 174 VOL. 60 • NO. 5 • 2019

Lewy Body Dementia The clinical course of Lewy body dementia (LBD) is gradual. Etiology of LBD is characterized by Parkinson dementia and the abnormal buildup of alpha-synuclein inclusion bodies. The clinical presentation and features include deficits in memory, visuospatial, hallucinations and Parkinsonian features.8 The diagnostic criteria include progressive cognitive decline, dementia (required) plus core features (2 required for probable LBD) including recurrent, detailed, fluctuations (change in alertness, attention), visual hallucinations, and early parkinsonism.

Suggestive features include REM Sleep Disorder (acting out dreams), severe neuroleptic sensitivity (motor, consciousness, NMS, autonomic dysfuntion) and low dopamine transporter uptake in BG. Supportive features include repeated falls, syncope, transient loss of consciousness and low uptake with reduced occipital activity PET/SPEC. MRI reveals less atrophy of the hippocampus and other medial temporal lobe structures relative to patients with AD; more atrophy seen in cortical and subcortical structures such as striatum, substantia innominata, hypothalamus and dorsal midbrain.9 FDGPET reveals hypometabolism in parietal and occipital regions with relatively preserved metabolism in temporal lobes. Treatment consists of cholinesterase inhibitors +/- carbidopa/levodopa for movement.8 Vascular Dementia The clinical course of vascular dementia (VD) is sudden and thought to cause an estimated 15%–20% of cases. It often coexists with AD pathology, i.e., so-called “mixed dementia.” The etiology is related to

reduced blood flow to the brain, damaging and killing brain cells. Motor and cognitive symptoms depend on the location of ischemia. There is a gradual or stepwise progression of the disease as ischemia worsens.

Cortical or subcortical changes, however, may be seen. Cholinesterase inhibitors are used for memory deficit only. Widespread use in VD is not recommended.3 Frontotemporal Dementia The course of symptoms in patients who have frontotemporal dementia begins at >50 years of age with a younger age of onset than seen in other dementias. It is the most common cause of young-onset dementia (i.e., dementia developing in midlife or earlier). The estimated point prevalence is 15–22/100,000, and incidence 2.7–4.1/100,000.

Twenty-five percent are late-life onset cases.10 The etiology reveals the accumulation of tau or ubiquitin proteins. Patients experience primarily cognitive symptoms, such as problems with executive function, hyperorality, personality changes, preservation of visual-spatial skills.3 The progression is gradual but faster than that of Alzheimer’s disease.

FDG-PET scan reveals hypometabolism in frontal and temporal regions. Currently there is no treatment approved by the FDA.11

body and brain active (trying new activities, working crossword puzzles or word finding and math puzzles, exercising 30-45 minutes/day, playing a musical instrument and enjoying leisure activities) are some ways of slowing down memory loss. Also, following good health strategies including controlling blood pressure and cholesterol, preventing or managing diabetes, maintaining a healthy weight, drinking alcohol in moderation, avoiding smoking and eating a well-balanced, heart-healthy diet can be effective ways to better manage these diseases. n About the MIND Center A visit to The Memory Impairment and Neurodegenerative Dementia (MIND) Center Clinic includes a comprehensive 90-minute evaluation consisting of a cognitive evaluation, a complete history, physical and neurological exam, neurocognitive testing, and depression screening. Patients are encouraged to bring a family caregiver who can report on memory and cognitive changes they may have observed. Diagnostic labs and imaging studies, as well as pharmacological and behavioral therapies, are ordered when indicated. Ongoing care includes continued monitoring of disease progression, medication management, and communication with primary care providers to determine the best treatment options for each patient.

The course of symptoms is short and abrupt in onset with depression being the etiology. Cognitive symptoms are temporary and dementialike. Motor symptoms include delayed motor response. Lab tests, imaging (i.e., MRI & CT) and the neurological exam are normal.

PHQ-2, PHQ-9 and GDS results, however, may likely be abnormal.

Treatment is based on treating underlying depression (SSRIs/SNRIs/ MAOIs/Psychotherapy).

The MIND Center Clinic offers counseling, education, and support for caregivers to better manage disease symptoms as well as caregiver burden. In addition, MIND providers offer guidance on difficult issues such as assisted living, skilled nursing or home health placement, as well as legal considerations.

Once a treatment plan is established, the patient is seen in the MIND Center Clinic every six months for dementia management and instructed to followup with their local physician for all other medical needs. Visits to the MIND Center Clinic are reimbursed by Medicare and other payers in the same manner as other outpatient or ambulatory visits. The patient is responsible for paying a standard copay.

Parkinson’s Disease Dementia

References

Pseudodementia

Parkinson’s Disease Dementia develops in the setting of established Parkinson’s disease (PD).12 PD can be caused by mutations in the SNCA gene. Alpha-synuclein is the protein that is the main component of Lewy bodies which accumulate in the brain in PD patients.1 Prevalence and incidence increase with age and is slightly higher in men than in women.14 Executive dysfunction is present early in the disease and manifests in deficiencies in set shifting, attention and planning. Tests of face recognition, a measure of visuospatial function, are impaired early.15 Motor symptoms include tremor, rigidity, bradykinesia, and postural instability.16 The neurocognitive exam is congruent with parkinsonian symptoms. MRI reveals global atrophy and enlarged ventricles (AD findings). White matter hyperintensities are found in PDD.17 Treatment includes Levodopa, dopamine agonists, anticholinergic inhibitors.18 Slowing Progression of Memory Loss

3

While dementia is never 100% preventable, there are changes that can be incorporated in the everyday routine to slow down memory loss and improve overall cognitive functioning. For example, stimulating one’s senses (i.e. involving as many senses as possible such as, vision, sound, touch, smell and taste), writing things down i.e. making lists, keeping calendars, following a routine, maintaining associations, repeating names, running through the alphabet, and and keeping one’s

1. L atest Alzheimer’s Facts and Figures. Alzheimer’s Association website. https:// www.alz.org/alzheimers-dementia/facts-figures. Accessed April 26, 2019.

2. Mississippi Alzheimer’s State Fact Sheet. Alzheimer’s Association website. https:// www.alz.org/getmedia/0fd6858b-fae4-489c-95ed-e63dc6743861/mississippialzheimers-facts-figures-2019. Accessed April 26, 2019.

3. A merican Geriatrics Society. A guide to dementia diagnosis and treatment. http://unmfm.pbworks.com/f/American+Geriatric+Society+Dementia+Diagnosis+ 03-09-11.pdf/Accessed May 8, 2019.

4. K nopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.

2001;56(9):1143–1153.

5. Dementia and Memory Loss. http://www.psychiatry24x7.com/bgdisplay. jhtml?itemname=dementia_memoryloss. Accessed on April 02, 2018.

6. Harada, CN, Love, MC, Triebel, K. Normal cognitive aging. Clin Geriatr Med. 2013;29(4):737-752.

7. Russ TC, Morling, JR. Cholinesterase inhibitors for mild cognitive impairment.

Cochrane Database Syst Rev. 2012;(9):CD009132.

8. Zupancic, M, Mahajan, A, Handa, K. Dementia with Lewy bodies: diagnosis and management for primary care providers. Prim Care Companion CNS Disord. 2011;13(5) doi: 10.4088/PCC.11r01190.

9. B onifacio G, Zamboni G. Brain imaging in dementia. Postgrad Med J. 2016;92(1088):333-340.

10. Onyike, C. Diehl-Schmid, J. The epidemiology of frontotemporal dementia. Int Rev Psychiatry. 2013;25(2):130-137.

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11. B oxer, Adam L, Boeve, B. Frontotemporal dementia treatment: current symptomatic therapies and implications of recent genetic, biochemical and neuroimaging slides. Alzheimer Dis Assoc Disord. 2007;21(4):S79-87.

12. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the Movement Disorder Society Task Force.

Mov Disord. 2007;22(16):2314-2324.

13. L esage S, Brice A. Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum. Mol. Genet.. 2009;18(R1):R48-59 14. de Lau, LM, Breteler, MM. Epidemiology of Parkinson’s disease. Lancet Neurol.

2006;5:525- 535.

15. R askin SA, Borod JC, Tweedy J. Neuropsychological aspects of Parkinson's disease.

Neuropsychol Rev. 1990;1(3):185.

16. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol.

2006;5(1):75.

Helping you build a more secure future.

We invest our own money alongside yours, so we are invested in your success.

17. Lee SJ, Kim JS, Yoo JY, et al. Influence of white matter hyperintensities on the cognition of patients with Parkinson disease. Alzheimer Dis Assoc Disord.

2010;24(3):227–233.

18. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review.

JAMA. 2014;311(16):1670-1683.

Author Information Author Information: Prior Clinical Director of the MIND Center; Assistant Professor, Departments of Medicine and Family Medicine at the University of Mississippi Medical Center (UMMC), Jackson, MS (N Patel). Family medicine resident, UMMC (Massihi). Third-year pediatric cardiology Fellow in the Department of Pediatrics, UMMC (A Patel). Clinical research nurse, MIND Center and Department of Neurology, UMMC (Majeste). Conflicts of interest: None.

MEDLEY & BROWN F I N A N C I A L

601-982-4123

A D V I S O R S

medleybrown.com

Corresponding Author: Andrew Majeste, BSN, RN, MIND Center, Johns A2Z Ad 4.25x5.5.pdf 1 6/28/18 10:25 AM 2500 North State Street, Jackson, MS 39216. Ph: (601) 984-5490 (acmajeste@umc.edu).

M&B MSMA 4'17'17.indd 1

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601-540-2864 jonm9564@gmail.com 2125 TV Road • Jackson, MS 39204 www.a2zprinting.net

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Autoimmune Hepatitis (AIH): A Case Report and Review of Literature TOBE MOMAH, MD; RACHEL YI, M4; WILL PAYNE, MD; DAVID GREEN, MD; ALANA PERSANTI, MD; MATTHEW MEECE, DO A 74-year-old Caucasian female with a past medical history of hypertension and a 30-pack-year history of nicotine dependence (who quit two years prior) presented to the emergency room (ER) of a local hospital complaining of worsening shortness of breath (SOB) for three weeks. She had been seen by a local physician and started on longacting corticosteroid metered dose inhalers (including also albuterol and umeclidinium/vilanterol). When she did not improve, he added oral furosemide, but the patient’s shortness of breath only worsened.

Our patient denied any history of coughing, chest pain or syncope.

The patient’s daughter, who accompanied her to the ER, stated that in addition to the patient’s other symptoms she had noticed her increased forgetfulness and frequent falls.

A computed tomography (CT) of the chest with contrast was done in the ER to evaluate for pulmonary embolus. It revealed a large right pleural effusion with consolidating atelectasis but no visualized pulmonary embolus (Figure 1). As a result of the partial visualization of the liver by the CT Chest, a diagnosis of new-onset liver cirrhosis and cholelithiasis were made. Our patient subsequently underwent a thoracentesis by interventional radiology which drained 1400 mls of pleural fluid. A paracentesis was not done because our patient did not exhibit any signs of ascites at the time. After the procedure, the patient developed tachypnea and was placed on BIPAP in the progressive care unit (PCU) for respiratory status monitoring.

In PCU, the patient was started on IV antibiotics, including ceftriaxone and azithromycin, and her home medication of amlodipine was held secondary to the decreased blood pressure of 100/51 mmHg. Other vital signs, including oxygen saturation, were within normal limits. Her laboratory values were significant for an elevated lactic acid level (> 8.0 meq/l), a decreased platelet count (68 K/ul), elevated liver enzymes (including alanine and aspartate transaminases above 100 U/l) and decreased albumin levels (2.2 g/dl). Also, the patient’s pro-BNP, white blood cell count and neutrophil shift were within normal limits.

Two days after admission, the patient’s respiratory status declined further, and she was transferred to the Intensive Care Unit (ICU) of the hospital. After further laboratory and radiological evaluations including a CT abdomen and pelvis, it was determined that the patient had re-

accumulated a massive amount of right-sided pleural fluid (within 24 hours). Studies from the earlier thoracentesis showed a pleural protein of 1.5 gm/dl, lactate dehydrogenase of 110 gm/dl and a pleural fluid dominated by lymphocytes on cell count.

Figure 1. Chest XR with Right Pleural Effusion Figure 1. Chest XR with Right Pleural Effusion

Based on these calculations, the patient was determined to have transudate-derived pleural fluid (as pleural/serum protein ratio was < 0.2), and a hepatic hydrothorax secondary to cirrhosis as a possible cause. Even though tumor markers including alpha-fetoprotein (11.9 ng/mL), CA 125 (297.0) and carcinoembryonic antigen (14.2 ng/ mL) were elevated, her CT abdomen and pelvis with contrast did not reveal any obvious malignancy or metastatic lesion. Also, the patient had an anti-nuclear antibody (ANA) titer of 1:320 and a positive antismooth muscle antibody (SMA) test.

A bedside thoracoscopy was subsequently performed which withdrew more than four liters of serosanguinous fluid withdrawn from the right pleural cavity. Gastrointestinal service was consulted because of increased coagulopathy (INR > 4), increased ammonia levels (68 mmol/l), worsening hyponatremia (115 mmol/l), and patient’s persistent state of confusion. The patient was diagnosed with cirrhosis

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of unknown etiology leading to portal-systemic encephalopathy. She was started on oral rifaximin, lactulose, spironolactone and furosemide and prepared for a liver biopsy. After being given two units of fresh frozen plasma (FFP) and three units of cryoprecipitate and normalizing the INR, a percutaneous ultrasound-guided liver biopsy was done.

Histopathology revealed chronic hepatitis with bridging fibrosis and plasma cells consistent with AIH (Figure 2). The patient was started on high dose oral prednisone of 30mg daily and discharged with expectations to follow up as an outpatient with a hepatologist. She returned to the hospital two months later with findings consistent with respiratory pneumonia. After three days in the hospital on IV antibiotics, she was discharged home in stable condition.

Figure Figure 2. CT Chest of Right Pleural Effusion 2. CT Chest of Right Pleural Effusion

The patient eventually started Imuran 200 mg as an outpatient and two weeks after commencement presented to the ER in a state of confusion. Her labs showed a sodium of 117 mmol/l, potassium of 7.4 meq/l and creatinine of 3.7 mg/dl. She was started on intravenous (IV) solumedrol, IV antibiotics including vancomycin and cefepime, bicarbonate infusion, and treatment for elevated potassium including calcium gluconate and insulin with D50 injections. She tolerated these interventions well but quickly became thrombocytopenic with platelet counts as low as 25 K/ul, and LFTs and coagulation profile were rising to total bilirubin count of 22 mg/ml and INR greater than 3.5 respectively.

With a Model for End-stage Liver Disease (MELD) score of more than fifty, the patient’s family was notified of the high risk of mortality (>50%) and the low likelihood of successfully undergoing a liver transplant procedure. She was diagnosed with hepatorenal syndrome and started on octreotide and albumin infusion. They were offered a transfer to the only transplant center in the state for a possible liver transplant, but the daughter declined and chose hospice care instead.

The patient was discharged home with a home hospice group with prescriptions given for pain medications. The patient died peacefully at

178 VOL. 60 • NO. 5 • 2019

home the next day surrounded by her family. It had been 3 months after her initial diagnosis with AIH. Discussion AIH is a relatively rare condition. It has an estimated prevalence rate of 4 to 42.9 cases per 100,000 persons with reported annual incidence rates of 0.67 to 2.23 cases per 100,000 persons.1 It is more common in Caucasian females with a peak age of occurrence between 50 and 60 years of age.2 The etiology of AIH is still unknown and consists of type 1 and type 2 AIH. Type 1 AIH is more common in adults with positive ANA (anti-nuclear antibody) serology and/or smooth muscle antibodies (SMA) while type 2 AIH is rarely seen in adults and is more common in juvenile AIH (where it makes up more than 30% of cases).3 New diagnostic guidelines published by the International Autoimmune Hepatitis Group (IAIHG) in 2008 have simplified the diagnosis of AIH.4 Instead of complex diagnostic modalities based on clinical, laboratory and histological diagnoses that were formulated in 19995, the updated IAIHG diagnostic guidelines are based on four parameters: presence and titer of autoantibodies detected by Immunofluorescence (IFL) or Enzyme Linked Immuno Sorbent assay (ELISA) for anti-soluble liver antigen/liver pancreas, serum IgG concentration, presence of typical or compatible histology, and absence of viral hepatitis markers (Table).

This recommendation was followed by clinical practice guidelines published in 2015 by the European Association for the Study of the Liver (EASL) to establish comprehensive guidelines for diagnostic, clinical, and immunological tests in the treatment and long-term survival strategies for AIH patients.6 Table.Diagnostic DiagnosticCriteria CriteriaofofInternational InternationalAutoimmune AutoimmuneHepatitis HepatitisGroup Group Table.

Feature/Parameter

Cutoff

Points

ANA or SMA+

≥1:40

+1

≥1:80

+2

or LKM+

≥1:40

+2

or SLA/LP+

Any titer

+2

IgG or γ-globulins level

> upper limit of normal

+1

> 1.1x upper limit

+2

Liver histology

Compatible with AIH

+1

(evidence of hepatitis is necessary condition)

Typical AIH

+2

Absence of viral hepatitis

No

0

Yes

1

The various international hepatology associations agree on the importance of obtaining a histopathological specimen from the liver

and using immunosuppressive therapy for the diagnosis and treatment of AIH. They are, however, not in total agreement with the preferred diagnostic guidelines to use. While the updated 2008 International Autoimmune Hepatitis Group (IAIHG) guidelines are considered more specific (90%) and accurate (92%) than the 1999 IAIHG guidelines (with 73% sensitivity and 90% accuracy), some in the European Association for the Study of the Liver (EASL) consider the latter a better research test for atypical cases as it has higher sensitivity (100%) than the former at 95%.7 In terms of treatment, AIH is very responsive to immunosuppressive therapy. This includes oral prednisolone between 0.5 to 1 mg/kg/ day or budesonide at 9 mg/day till tapered off and after two weeks adding azathioprine (AZA) at a dose of 1-1.5 mg/kg/day.8 The 2-week delay is to avoid confusion between non-responsiveness to primary immunosuppressive therapy and AZA-induced hepatotoxicity in cases of AIH with persistently elevated liver enzymes. More than 80% of AIH patients respond to immunosuppressive treatment with biochemical remission in the form of normalized transaminase, bilirubin and IgG levels noted within three years.

To assess the efficacy of AZA, there should be a monitoring period of at least eight weeks. Some patients unfortunately do not tolerate this medication. Other medications that can be used as second-line maintenance therapy include mycophenolate and methotrexate. The latter is affordable and readily available, but the former is expensive and not widely used. Along with these two, other substitutes to firstline immunosuppressive treatment include cyclosporine A, rituximab, tacrolimus, sirolimus, everolimus, infliximab, and the thiopurines.9 Our patient was a relatively elderly patient with a diagnosis of cirrhosis and hydrothorax at presentation. Unlike the 80% of AIH patients who readily responded to immunosuppressive therapy, our patient had an impaired functional status coupled with a long history of smoking cigarettes and cirrhosis and was, therefore, a prognostically poor patient from the onset.10 Eventually, with poor tolerance to AZA and fulminant-looking hepatic failure, her prognosis became even direr.

She may have benefited from a replacement of her immunosuppressive therapy to mycophenolate or methotrexate, but with a MELD score of 50, she was considered a poor therapeutic candidate for any immunosuppressive medication or intervention.

Even though a large number of AIH patients recover and go into remission on immunosuppressive therapy, patients such as ours that do not tolerate first-line medications and are more vulnerable due to age or co-morbidities are documented to have a five-year mortality rate above 75%.11 The option of hospice, in the absence of long term beneficial treatment, must always be considered and made an option for the family. The argument may be made that the absence of a dedicated transplant and hepatology team in the local hospital our patient was

admitted to may have contributed to the tenuous diagnosis, rapid decline and non-introduction of a more viable second-line medication for our patient. Eventually, however, the hospice option chosen by the family must be respected and abided by. n References 1.

Van Gerven N, Verwer B, Witte B, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol. 2014; 49(10):1245-1254.

2. Kim B, Choi H, Ki M, Kim K, Jang E, Jeong S. Population-based prevalence, incidence, and disease burden of auto-immune hepatitis in South Korea. PLoS One. 2017;12(8):e0182391.

3. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterology. 2017;23(33):6030-6048.

4. Hennes E, Zeniya M, Czaja A, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatol. 2008;48:169-176.

5.

Alvarez F, Berg P, Bianchi F, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol.1999;31(5):929-938.

6. European Association for the Study of the Liver. EASL clinical practice guidelines for autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004.

7. Qui D, Wang Q, Wang H, et al. Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J Hepatol. 2011;54(2):340-347.

8. Liwinski T, Schramm C. Autoimmune hepatitis â&#x20AC;&#x201C; update on clinical management in 2017. Clin Res Hepatol Gastroenterol. 2017;41(6); 6017-6025.

9. Pieseler M, Liebsecher T, Sebode M, et al. Efficacy and limitations of Budesonide as a second-line treatment for patients with autoimmune hepatitis. Clin Gastroenterol Hepatol. 2018;16(2):260-267.e1. doi: 10.1016/j.cgh.2016.12.040.

Epub 2017 Jan 23.

10. Wong GW, Yeong T, Lawrence D, Yeoman A, Verma S, Heneghan MA. Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long-term outcomes. Liver Int. 2017;37(3):449457.

11. Kirk AP. Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut. 1980;21(1):78-83.

Author Information Author Information: Assistant Professor, Department of Family Medicine, UMMC (Momah). Fourth-year medical student, University of Mississippi Medical Center (UMMC), Jackson (Yi). Pathologist, Mississippi Baptist Hospital Services, Jackson (Payne). PGY-2, Department of Family Medicine, UMMC (Green, Persanti). PGY3, Department of Family Medicine, UMMC (Meece).

Corresponding Author: Tobe Momah, MD, Assistant Professor, Department of Family Medicine, UMMC, 2500 North State Street, Jackson, MS 39216 (tmomah@umc.edu). Ph: (601)815-4778; Fax: (601)984-5420.

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Ten Examples of How Evolutionary Medicine Can Furnish Ideas for Clinical Research and Improve Medical Practice MARY C. BAILEY, M1; PIYUSH S. BORSE, M1; NICHOLAS A. BOSWORTH, M1; NICHOLAS H. BREWER, M1; NELSON P. DOUGLASS, M1; ROSARIO K. GUASTELLA, M1; GHALI G. HADDAD, M1; MARY M. HAIRE, M1; KELLY G. HILL, M1; ALAN D. PENMAN, MD Abstract There is a good case for making evolutionary medicine (“Darwinian medicine”) a core preclinical subject in the medical curriculum though some question its value. Ten examples are presented here of how evolutionary medicine can increase understanding of disease origins and characteristics. These examples are just a few of many that could have been given to demonstrate the relevance of concepts and principles from human evolution to medical practice and research.

Evolutionary knowledge gives a deeper understanding of health and disease in human populations.

Key Words: Evolutionary medicine; human evolution; natural selection Introduction Evolutionary medicine is the application of modern evolutionary theory to understanding health and disease. The discipline has grown rapidly in the past 30 years, and the case has been made that it should be a core preclinical subject in the medical curriculum – indeed, that it is medicine’s theoretical foundation.1 Some, however, question its value.

In this article, 10 examples are presented of how evolutionary medicine can increase understanding of disease origins and characteristics and, by doing so, can furnish ideas for clinical research and improve medical practice.

Methods Online search using the terms “Old Friends hypothesis”, “hygiene hypothesis”, “microbiome”, “malaria”, “malaria hypothesis”, “genetic polymorphisms”, “human trypanosomiasis”, “APOL1”, “chronic kidney disease”, “Alzheimer’s disease”, “Apolipoprotein E-ε4 allele”, “p53”, “meat-adaptive genes”, and “cereals” AND “human evolution”, “natural selection”, “selection pressure”, “adaptation”, and “genetic variation”; review of published reviews, reports, and texts.

Results The following examples are presented and briefly described: 1. The “Old Friends” (Hygiene) Hypothesis 2. Evolution of the Human Microbiome 3. Infectious Diseases and Natural Selection 180 VOL. 60 • NO. 5 • 2019

4. Malaria and Human Genetic Polymorphisms 5. Human Trypanosomiasis, APOL1, and Chronic Kidney Disease 6. Alzheimer’s Disease and APOE 7. Meat: Good or Bad for Us? 8. Cereals: a Double-Edged Sword?

9. Physical Activity in Human Evolution 10. Cancer and P53: Why Elephants Don’t Get Cancer The “Old Friends” (Hygiene) Hypothesis The “Old Friends” hypothesis (formerly known as the hygiene hypothesis) postulates that the recent increases in allergic and autoimmune diseases are attributable to the decline in childhood exposure to microorganisms, resulting in immunodysregulation.2 Studies have shown associations between both allergies and autoimmune diseases and lack of exposure to microorganisms in the environment. For example, children living on farms who had more exposure to a greater variety of microorganisms had a lower prevalence of asthma and atopy than those living in urban areas.3 Compared to children from Hutterite communities (practicing modern industrialized farming), the prevalence of asthma and allergic sensitization was 4 and 6 times as low, respectively, in children from Amish communities (following traditional farming practices). Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes, and median endotoxin levels in Amish house dust was 6.8 times as high.4 Children living in homes that wash dishes with a machine, rather than hand washing, have a higher allergy prevalence than those who do not.5 These concepts are now being tested in clinical trials of specific microorganisms, probiotics, and immune regulatory agents.

Evolution of the Human Microbiome The composition of the human gut microbiome reflects a threeway interaction between human genetics, diet, and the microbiota.

Compared to wild apes, human microbiomes have lost ancestral microbial diversity while becoming specialized for animal-based diets.6 Comparative studies between unindustrialized rural communities in Africa and South America and industrialized western communities in

Europe and North America have revealed specific adaptations in gut microbiota. For example, the Hadza hunter-gatherers of Tanzania have higher levels of microbial richness and biodiversity than Italian urban controls.7 A further change occurred in the Neolithic period (beginning about 10,200 BC and ending between 4500 and 2000 BC) with the shift in diet to more high-starch plant foods and dairy products; dense acellular carbohydrates promote an inflammatory microbiota and may be the primary dietary cause of leptin resistance and obesity.8,9 There is also increasing evidence for the role of the microbiome in colorectal cancer, atherosclerosis, allergy and asthma, and autism, raising the possibility of using specific commensals as potential preventive or therapeutic agents.10 Infectious Diseases and Natural Selection Throughout human evolution, infectious diseases such as smallpox, cholera, tuberculosis, leprosy, bubonic plague, and (in Africa) yellow fever and Lassa hemorrhagic fever have exerted some of the strongest selection pressures on human populations, allowing resistance alleles to emerge and spread. Increasingly, novel methods of genomic analysis have been able to detect genetic signatures of these natural selection pressures.11-13 The oldest and best-known example of human adaptation to infectious disease is malaria and sickle cell disease described later.

Some other examples, taken from Table 1 in Withrock et al.,14 are: 1. Cystic fibrosis and cholera Cystic fibrosis (CF) is marked by frequent lung and sinus infections, poor growth, fatty stool, and infertility in most males. It results from a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The mutation is inherited in an autosomal recessive manner. Homozygotes develop CF, but most heterozygotes are asymptomatic. Such mutations may have conferred a survival advantage to carriers in situations where gastrointestinal infections such as cholera were common and widespread. Researchers are studying whether pharmacologic inhibition of the CFTR chloride channel can prevent the gastrointestinal fluid loss associated with cholera.

2. Tay-Sachs disease and tuberculosis Tay-Sachs disease usually develops in infancy; affected children exhibit mental and physical disabilities leading to early death.

The disease results from a mutation in the gene encoding α-hexosaminidase, a lysosomal enzyme, leading to accumulation of neuronal lipids. Like CF, Tay-Sachs is inherited in an autosomal recessive manner. It has been hypothesized that carriers of the mutation had a degree of relative protection against Mycobacterium tuberculosis infection in ancestral populations with high rates of TB. Research is ongoing to develop drugs that up-regulate or maintain α-hexosaminidase activity and have mycobactericidal effects.

3. Congenital disorder of glycosylation IIb and viral infections Congenital disorders of glycosylation are a family of rare inborn errors of metabolism. Congenital disorder of glycosylation IIb (CDG-IIb) comprises developmental disorder, hypotonia, hypoglycemia, and protein-losing enteropathy and is inherited in an autosomal recessive manner. It results from a mutation in the gene encoding mannosyl-oligosaccharide glucosidase (MOGS). Certain enveloped viruses (such as HIV-1, dengue, HSV-2, hepatitis C, and

influenza) are dependent on proper host cell glycosylation, and the defective host cell glycosylation in CDG-IIb disrupts cell entry/ egress and replication of the virus. This may have given carriers a survival advantage in the past. Researchers are working to determine the efficacy of MOGS inhibitors or other glycosylation inhibitors against viral infections.

Further research into resistance and susceptibility alleles may identify mechanisms that lead to novel treatments and vaccines against other infectious diseases.

Malaria and Human Genetic Polymorphisms Malaria and humans have coevolved for thousands of years, allowing malaria to exert influence over the evolution of the human genome.15 The selection pressure exerted by malaria has been strong and relatively recent: resistance alleles date to the past 5,000 years.16 In the mid-1900s it was observed that the sickle cell mutation (HbS allele) provided heterozygotes with increased resistance to malaria in malaria-endemic areas of Africa. Although sickle cell is perhaps the best known of the blood disorders associated with malaria, many others have been identified: the thalassemias, G6PD deficiency, HbC, HbE, ovalocytosis, and Duffy antigen negativity.17 The Duffy antigen may provide an even more compelling argument for human adaptation in response to pressures applied by infectious disease. The Duffy antigen (FY) gene regulates the production of a protein necessary for the parasitic invasion of red blood cells, thus protecting the individual from malaria infection. Uniquely, this variant maintains a prevalence of 100% in sub-Saharan Africa yet is essentially non-existent elsewhere. A better understanding of the mechanisms by which this and other genetic variants confer resistance to malaria has important implications for the design of future malaria vaccines.

Human Trypanosomiasis, APOL1, and Chronic Kidney Disease Trypanosomes are a group of protozoan parasites that emerged roughly 300 million years ago and have co-evolved with wild animals (game) – which act as reservoirs in some cases – primates, and hominins. All humans possess natural resistance to Trypanosoma b. brucei through a serum lytic complex (based on apolipoprotein L1 (APOL1))18 but are susceptible to two other variants, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which can cause fatal African sleeping sickness. Selection pressure on the parasite has selected for resistance in T.b.rhodesiense, mediated by serum resistance-associated (SRA) protein which neutralizes the APOL1 lytic protein.19 In turn, three genetic variants of APOL1 (G1, G2, G3) have been selected for in humans which prevent SRA binding – a perfect example of an evolutionary “arms race” between trypanosomes and humans.20 However, the price paid for restoring resistance to T.b.rhodesiense appears to be susceptibility to kidney disease. African Americans suffer from kidney failure at high rates compared with individuals without recent African ancestry. Specifically, African Americans have increased susceptibility to focal segmental glomerulosclerosis (FSGS) and hypertensionattributed end-stage kidney disease (H-ESKD).21 FSGS and H-ESKD are associated with two of the independent sequence variants (G1, G2) in the APOL1 gene on chromosome 22.22 Researchers are working to develop APOL1 variants that could be used as new therapeutic tools to cure sleeping sickness, even at the late stages of infection.

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Alzheimer’s Disease and APOE Apolipoprotein E (APOE) is important in managing the breakdown of dietary triglyceride-rich lipoproteins by way of chylomicrons. APOE is produced by the liver and macrophages as well as by astrocytes in the CNS that control the distribution of cholesterol to neurons and brain. Humans have evolved several isoforms (APOE-ε2, APOE-ε3, and APOE-ε4); APOE-ε4 is probably the ancestral form.23 Brazilian researchers studying Bolivian Tsimane hunter-gatherers have found that older adult APOE-ε4 carriers with high parasite burdens either maintained or showed slight improvements in cognitive performance, whereas non-carriers with a high parasite burden showed reduced cognitive performance.24 They hypothesize that the APOE-ε4 variant has a protective role against cerebral parasitic infections. The APOE-ε4 gene’s protective functions may also extend to enhancing cognition and development in children suffering from persistent diarrhea.25 The downside is that in contemporary populations in industrialized countries APOE-ε4 is associated with a number of health risks such as atherosclerosis and cardiovascular disease, Alzheimer's disease, impaired cognitive function, reduced hippocampal volume, and accelerated telomere shortening.26 Interestingly the APOE-ε4 frequency has declined over time. Currently, the prevalence is about 14%. The dominant variant at present is APOE-ε3, with a prevalence of 79%.27 The APOE-ε3 allele has been associated with a reduced risk for Alzheimer’s and vascular disease; it also has a beneficial influence on inflammation, infection, and neuronal growth. This change in allele frequency is hypothesized to have resulted from a shift in diet to one focused on meat with its associated risks of diet-induced hypercholesterolemia and cerebral infections.28 It has also been hypothesized that the emergence of grandparenting in H. sapiens has selected for a switch from APOE-ε4 to APOE-ε3.29 During early human evolution, the postnatal maturation phase was increased by five or more years, placing an additional burden on mothers. Grandmothers would have played an increasingly important role in the survival of infants and young children, but any selective advantage would also require that age-related declines in mental and physical health be delayed. The advantages of grandmothers who are mentally and physically fit by the minimization of cardiovascular disease and Alzheimer's disease would select for the spread of the APOE-ε3 allele.

Meat: Good or Bad for Us? The diet of the earliest hominins was most likely omnivorous with large quantities of fruit, leaves, flowers, seeds, nuts, and underground storage organs such as roots and tubers, supplemented by insects and occasional meat.30 However, around 2.6 million years ago, many hominins began consuming meat and marrow regularly. Around 1.7 million years ago, this increased meat consumption became especially significant during the transition from H. habilis to H. erectus in Africa.31 Research shows that total energy expenditure greatly increased with the emergence of H. erectus and was due largely in part to an increased activity level and body size.32 After this increase in meat consumption, there was likely an initial spurt in brain growth with a subsequent synergistic interaction between diet and brain expansion, leading to further shifts in foraging tactics and use of more sophisticated tools for hunting and removing animal flesh.32 This high reliance upon animalbased foods also led to several health benefits, including an increased 182 VOL. 60 • NO. 5 • 2019

life expectancy, but likely did not increase blood lipid levels due to the low omega-6:omega-3 fatty acid ratio in wild game.33 It has been hypothesized that this dietary shift selected for “meat-adaptive” genes, including APOE-ε4, a cholesterol transporting gene.28 Cereals: a Double-Edged Sword?

The consumption of cereal grains is relatively new in the existence of the human species.34 It was not until roughly 10,000-20,000 years ago that humans began to utilize grains as the main food source. This transition in diet and subsequent development of an agricultural society created a dependence upon cereal grains which have now become a major constituent of the global food supply. The utilization of grains and the growth of urbanization paralleled growth in the human population. The early human diet consisted mostly of a high protein/low carbohydrate diet, but with the switch to grain consumption, an overall decline in quality of life ensued. Societies with a higher grain consumption exhibited a marked reduction in stature and reduction in life span, attributed to an increased incidence of infectious diseases as well as an increase in infant mortality.35 With the majority of human protein coming from grains, deficiencies in iron and vitamin B12 (previously provided by meat) increased markedly.35 Also, the incidence of dental (enamel) defects paralleled the increase in grain consumption.35 High dietary grain consumption has been linked to two gluten-related disorders, celiac disease and non-gluten (or wheat) sensitivity; both are associated with a wide range of other disorders such as dermatitis herpetiformis, gluten ataxia and type 1 diabetes.36 The explosion of grain consumption in the past 10,000 years appears to have played a role in the manifestation of many modern diseases and insufficiencies.

Physical Activity in Human Evolution Evolutionary history and metabolic biology suggest that humans are generally adapted to be physically active. However, differences between Westerners and our hunter-gatherer ancestors are not as great as was once thought. Physical activity levels were greater among traditional Hadza foragers in Tanzania than among Westerners, but the average daily energy expenditure of the foragers was no different from that of Westerners after controlling for body size.37 The Tsimane hunter-gatherers of Bolivia displayed relatively high physical activity levels typical of other subsistence populations but of moderate intensity and not outside the range of Western populations.38 Over the course of human evolution, fluctuations in resource availability and energy requirements have required adaptations favoring both sedentary and active physical behavior patterns variable over the life span.39 In other words, “move when you have to, rest when you can.”

Official recommendations for physical activity need to incorporate insights from evolutionary studies. Humans are genetically adapted for a pattern of exercise that involves a diversity of activities performed intermittently, at moderate intensities and moderate durations.39 Cancer and P53: Why Elephants Don’t Get Cancer In multicellular organisms, there is likely an inherent basal rate of random mutations that eventually give rise to tumors. It follows that large-bodied or older animals should possess more random mutations predisposing them to cancer than smaller or younger animals as their cells have divided many more times. However, Peto and others

noted that cancer risk does not appear to scale with size in the animal kingdom (the Peto paradox).40 For example, aging elephants appear to have low cancer rates. Cell proliferation and turnover need to be taken into account, not simply the steady-state number of cells. The most important consideration is the total numbers of proliferating stem cells and progenitor cells over a lifetime. The progressive increase in the complexity, size, and longevity of animals over millions of years must have provided selective pressure for cancer-suppressing adaptations to restrain cancer risk. The p53 tumor suppressor protein has a prominent role in cancer suppression and is often termed the “guardian of the genome.” When activated, p53 triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation. Elephants have multiple copies (at least 20) of TP53 of which 19 have been found to be pseudogenes or retrogenes which appear to produce a functional protein.41 Elephant cells are very sensitive to DNA damage; when damaged, their cells die without attempt to repair.42 Transgenic mice with increased numbers of p53 become tumor resistant, 43 an interesting discovery that could lead to better cancer treatments. The downside to having cancersuppressing adaptations is that both apoptosis and cellular senescence processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Thus, there are likely to be significant costs or trade-offs, notably in attrition of stem cells, accelerated aging, and decreased longevity.

Conclusion These examples are just a few of many that could have been given to demonstrate the relevance of concepts and principles from human evolution to medical practice and research. Evolutionary knowledge gives a deeper understanding of health and disease in human populations. n References 1. Labov JB. Evolutionary medicine and the medical school curriculum: meeting students along their paths to medical school. Evo Edu Outreach. 2011;4(4):561-566.

2. Rook GAW. A Darwinian view of the hygiene or “old friends” hypothesis. Microbe.

2012;7(4):173-180.

3. Ege MJ, Mayer M, Normand AC, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011;364(8):701-709.

4. Stein MM, Hrusch CL, Gozdz J, et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med. 2016;375(5):411-421.

11. Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat Rev Genet. 2001;2(12):967-977.

12. Novembre J, Han E. Human population structure and the adaptive response to pathogen-induced selection pressures. Philos Trans R Soc Lond B Biol Sci. 2012;367(1590):878-886.

13. Karlsson EK, Kwiatkowski DP, Sabeti PC. Natural selection and infectious disease in human populations. Nat Rev Genet. 2014;15(6):379-393.

14. Withrock IC, Anderson SJ, Jefferson MA, et al. Genetic diseases conferring resistance to infectious diseases. Genes Dis. 2015;2(3):247-254.

15. Carter R, Mendis KN. Evolutionary and historical aspects of the burden of malaria.

Clin Microbiol Rev. 2002;15(4):564-594.

16. Hedrick PW. Resistance to malaria in humans: the impact of strong, recent selection. Malar J. 2012;11:349.

17. Bauduer F. Red cell polymorphisms and malaria: an evolutionary approach. Bull.

Mém. Soc. Anthropol. 2013;25:55-64.

18. Pays E, Vanhollebeke B. Human innate immunity against African trypanosomes.

Curr Opin Immunol. 2009;21(5):493-498.

19. Gibson WC. The SRA gene: the key to understanding the nature of Trypanosoma brucei rhodesiense. Parasitology. 2005;131(Pt 2):143-50.

20. Pays E, Vanhollebeke B, Uzureau P, Lecordier L, Pérez-Morga D. The molecular arms race between African trypanosomes and humans. Nat Rev Microbiol.

2014;12(8):575-584.

21. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841-845.

22. Parsa A, Kao WH, Xie D, et al. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med. 2013;369(23):2183-2196.

23. Mahley RW, Rall SC Jr. Is ε4 the ancestral human apoE allele? Neurobiol Aging.

1999;20(4):429-430.

24. Trumble BC, Stieglitz J, Blackwell AD, et al. Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden. FASEB J. 2017;31(4):1508-1515.

25. Oria RB, Patrick PD, Zhang H, et al. APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil. Pediatr Res. 2005;57(2):310–316.

26. Wikipedia contributors. (2018, May 1). Apolipoprotein E. In Wikipedia, The Free Encyclopedia. https://en.wikipedia.org/wiki/Apolipoprotein_E. Accessed June 19, 2018.

27. Eisenberg DT, Kuzawa CW, Hayes MG. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history.

Am J Phys Anthropol. 2010;143(1):100-111.

28. Finch CE, Stanford CB. Meat-adaptive genes and the evolution of slower aging in humans. Q Rev Biol. 2004;79(1):3-50.

29. Finch CE, Sapolsky RM. The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms. Neurobiol Aging. 1999;20(4):407-428.

30. Eaton SB. The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition? Proc Nutr Soc. 2006;65(1):1-6.

31. Eaton SB. Humans, lipids and evolution. Lipids. 1992;27(10):814-820.

5. Hesselmar B, Hicke-Roberts A, Wennergren G. Allergy in children in hand versus machine dishwashing. Pediatrics. 2015;135(3):e590-597.

32. Leonard WR. Food for thought. Dietary change was a driving force in human evolution. Sci Am. 2002;287(6):106-115.

6. Moeller AH, Li Y, Mpoudi Ngole E, et al. Rapid changes in the gut microbiome during human evolution. Proc Natl Acad Sci USA. 2014;111(46):16431-16435.

33. Cordain L, Eaton SB, Miller JB, Mann N, Hill K. The paradoxical nature of huntergatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr. 2002;56(Suppl 1):S42-S52.

7. Schnorr SL, Candela M, Rampelli S, et al. Gut microbiome of the Hadza huntergatherers. Nat Commun. 2014;5:3654.

8.

Spreadbury I. Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Diabetes Metab Syndr Obes.

2012;5:175-189.

9. Walter J, Ley R. The human gut microbiome: ecology and recent evolutionary changes. Annu Rev Microbiol. 2011;65:411-429.

10. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369-2379.

34. Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283-289.

35. Cordain L. Cereal grains: humanity’s double-edged sword. World Rev Nutr Diet.

1999;84:19-73.

36. Bathrellou E, Kontogianni MD, Panagiotakos DB. Celiac disease and non-celiac gluten or wheat sensitivity and health in later life: a review. Maturitas. 2018;112:29-33.

37. Pontzer H, Raichlen DA, Wood BM, Mabulla AZ, Racette SB, Marlowe FW. Hunter-gatherer energetics and human obesity. PLoS One. 2012;7(7):e40503.

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38. Gurven M, Jaeggi AV, Kaplan H, Cummings D. Physical activity and modernization among Bolivian Amerindians. PLoS One. 2013;8(1):e55679.

39. O'Keefe JH, Vogel R, Lavie CJ, Cordain L. Achieving hunter-gatherer fitness in the 21(st) century: back to the future. Am J Med. 2010;123(12):1082-1086.

40. Peto R. Quantitative implications of the approximate irrelevance of mammalian body size and lifespan to lifelong cancer risk. Philos Trans R Soc Lond B Biol Sci. 2015;370(1673).

41. Abegglen LM, Caulin AF, Chan A, et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA. 2015;314(17):1850-1860.

42. Sulak M, Fong L, Mika K, et al. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife. 2016;5:e11994.

43. García-Cao I, García-Cao M, Martín-Caballero J, et al. ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 2002;21(22): 6225–6235.

Author Information

Author Information: First-year medical student, University of Mississippi Medical Center (UMMC) School of Medicine, Jackson, MS (Bailey, Bosworth, Brewer, Douglass, Guastella, Haddad, Haire, Hill). Professor, Departments of Preventive Medicine and Ophthalmology, John D. Bower School of Population Health, UMMC, Jackson, MS (Penman). Conflicts of Interest: None Corresponding Author: Alan D. Penman, Department of Preventive Medicine, John D. Bower School of Population Health, UMMC, 2500 N. State Street, Jackson, MS, 39216.

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Autologous Bone Marrow Transplantation for Multiple Myeloma: An Analysis of Risk Factors that Affected Patient Outcomes at the University of Mississippi Medical Center DORIS K. HANSEN, MD; THOMAS WILLIAMSON, MD; JOHANN HSU, MD; TONDRE BUCK, MD; CARTER P. MILNER, MD Abstract Objectives: To examine prognostic factors that affected Mississippian outcomes in autologous hematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) as opposed to historical cohorts.

To implement institutional changes for MM patients undergoing HSCT at the University of Mississippi Medical Center (UMMC) based on our study results.

Methods: This retrospective chart review included 128 patients with MM who received autologous HSCT at UMMC from 2009 to 2014. IRB approval was obtained. Nine parameters were evaluated including age, sex, ethnicity, time of diagnosis to transplantation, disease status at the time of transplantation and day + 100, DurieSalmon stage at diagnosis, type of induction chemotherapy received, Karnofsky performance status, cytogenetics, and post-transplantation maintenance therapy.

Results: Median age of our patients was 57 years with the majority being African American (54%) and female (52%). The majority of patients had IgG kappa MM (41%), with stage 3A, and a Karnofsky score > 80%. Induction chemotherapy received was either revlimid/ dexamethasone (RD 27%) or revlimid/velcade/dexamethasone (RVD 20%). Sixty percent of patients underwent maintenance therapy after HSCT while 33% were observed. Disease status at HSCT was a partial response (40%), very good partial response (23%) or complete response (20%). Thirty-seven percent of patients had a complete response at day 100 following HSCT. Most patients underwent HSCT 6 months from initial diagnosis. Median time to disease progression was approximately 24 months. There were statistical differences observed for higher Karnofsky scores (p=0.004), disease status at transplant (p<0.01), disease status at day 100 (p<0.01) with improved progression-free survival (PFS) in patients with a complete response.

There was a trend toward improved overall survival (OS) with earlier HSCT (p=0.38), earlier stage disease (p=0.14) and low-risk cytogenetics (p=0.09) but our study was underpowered to show these differences definitively.

Conclusion: MM remains an incurable malignancy. However, there are several prognostic factors that can affect patient survival. We recommend using a 3-drug induction chemotherapy regimen such as RVD rather than RD, earlier transplantation and standard maintenance chemotherapy for all multiple myeloma patients following HSCT. Furthermore, we need to ensure that cytogenetics are obtained in

all MM patients as they are prognostic of survival benefit. While a few areas of improvement are needed and currently in the process of being implemented, our institution appears to be at par with national standards regarding disease PFS despite healthcare disparity in the state of Mississippi.

Introduction Multiple myeloma is an incurable malignant plasma cell disorder characterized by hypercalcemia, renal insufficiency, anemia, and osteolytic bone lesions that accounts for 10-15% of hematologic malignancies.3 Average survival rates have increased up to 80% with the use of autologous stem cell transplantation.5-6 Although there are generally accepted factors that improve outcomes in patients who receive transplantation (<1 year from time of diagnosis, complete response with induction chemotherapy, standard risk cytogenetics and a higher Karnofsky performance status), uncertainties still exist as to the relationship of other factors and outcomes.2-4 Moreover, there have been few studies to examine how these accepted prognostic factors apply to bone marrow transplantation patients in the state of Mississippi, a state among the lowest in the United States in terms of overall health and access to health care.

It is assumed that patient outcomes in Mississippi are similar to historical cohorts, but this review will seek to identify if there are any factors that are more likely to predict improved transplantation outcomes.

The results of this review will be used to guide future autologous transplantation among multiple myeloma patients at UMMC. Materials and Methods This retrospective chart review included 128 patients with multiple myeloma who received autologous bone marrow transplantation at UMMC from 2009 to 2014. IRB approval was obtained to conduct a review of patient charts. Nine parameters were evaluated including age, sex, ethnicity, time of diagnosis to transplantation (< 6 months vs. 6 months to 1 year vs. > 1 year), disease status at the time of transplantation and at day + 100, Durie-Salmon stage at diagnosis, type of induction chemotherapy received, Karnofsky performance status, cytogenetics/ FISH and post-transplantation therapy (observation vs. maintenance chemotherapy). Information on cytogenetics is very limited as this was not standard of care at our institution prior to 2010. Disease status at transplantation was reported based on response criteria as defined by the International Myeloma Working Group (IMWG).15 The IMWG

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Table 1. Disease Characteristics Table 1. Disease characteristics

Table 2. Patient characteristics Table 2. Patient characteristics and andMM MMtherapy therapy

MM Subtype

IgG Kappa

41% (53)

Age

Mean

57 (33-77)

IgG Lambda

20% (25)

Race

Black

54% (69)

IgA Kappa

10% (13)

Sex

Female

52% (67)

IgA Lambda

7%(9)

Karnofsky

60

1%(1)

Kappa alone

13% (17)

70

4%(5)

Lambda alone

5% (6)

34%(43)

Unknown

3% (4)

80

90

52%(66)

Other

1% (1)

100

10(13)

Durie‐Salmon Stage

1A

13% (17)

VD

17%(22)

1B

1% (1)

Chemotherapy

VAD

9%(12)

2A

23% (29)

RVD

20%(26)

2B

3% (4)

3A

48% (62)

3B

9% (11)

Unknown

3% (4)

Cytogenetics

Standard

45%(61)

Intermediate

3%(4)

High

5%(6)

Unknown

48%(61)

Disease Status: HSCT

sCR

13%(17)

CR

20% (25)

VGPR

23%(29)

PR

40%(51)

SD

1%(1)

PD

3%(4)

Unknown

1%(1)

Disease Status: Day 100

sCR

11%(14)

CR

37% (47)

VGPR

29%(37)

PR

9%(11)

SD

2%(3)

PD

5%(6)

Unknown

8%(10)

Time to HSCT

<6 Months

9%(12)

6-12 mo

39%(50)

>12 months

38%(49)

Unknown

13%(17)

response criteria defined response to chemotherapy as complete, stringent complete, very good partial, partial response and progressive disease.

An exploratory analysis using Cox proportional hazards model evaluated time to progression and survival with variables listed. The Wilcoxon test was used to compare survivor functions.

Results Patient and disease characteristics are shown in Tables 1 and 2. Median age of our patients was 57 years (range, 33-77 years) with the majority being African American (54%) and female (52%). The majority of patients had IgG Kappa (41%) disease, with stage 3A, and a Karnofsky score > 80%. Cytogenetics were unknown for 48% of our patients but with 45% having standard cytogenetics. Induction chemotherapy consisted of either revlimid/dexamethasone (RD 27%) or revlimid/ velcade/dexamethasone (RVD 20%). Sixty percent of patients received maintenance chemotherapy after HSCT while 33% were

186 VOL. 60 • NO. 5 • 2019

and MM therapy Table 2. Patient characteristics RD 27%(34)

TD

8%(10)

Age

Mean Other/Combo

57 (33-77) 18%(23)

Race

Black Unknown

1%(1) 54% (69)

Post‐HSCT Therapy Sex

Observation Female

33%(42) 52% (67)

Karnofsky

Maintenance 60

60%(76) 1%(1)

Progression 70

Unknown 80

5%(7) 4%(5) 2%(3) 34%(43)

52%(66) observed.

Disease status at time90of transplantation was partial response

100 10(13) (40%), very good partial response (23%), or complete response Figure 1. Kaplan‐Meier curve: Karnofsky performance status. Note(20%). an improved PFS Thirty-seven percent of patients Chemotherapy VD had a complete response 17%(22) at day 100 better Karnofsky performance status. after HSCT. Most patients underwent transplantation six months from VAD 9%(12) diagnosis.

RVD

20%(26)

Median months. There was time to progression was RDapproximately 24 27%(34) a trend toward improved PFS again with earlier transplant

TD 8%(10) (p=0.38), earlier stage (p=0.14), and low-risk cytogenetics (p=0.09).

There were

Other/Combo 18%(23) statistical differences noted for higher Karnofsky scores (p=0.004), status at transplant (p<0.01), Unknown disease disease status at1%(1) Day 100 (p<0.01) Observation 33%(42) withPost‐HSCT Therapy improved survival with sCR and CR.

Maintenance

60%(76)

Median time to death was approximately 30 months (range 3-70

Progression 5%(7) months). Again noted, there was statistical improvement in survival Unknown with higher performance status (p<0.01), sCR 2%(3) or CR at time of transplantation (p=0.04) and at Day 100 (p<0.01). There was a trend toward earlier transplantation leading to better survival but our study Kaplan‐Meier curve: Karnofsky performance status.

Note an impro wasFigure 1. underpowered to definitely show this difference. There were also better Karnofsky performance status.

Figure 1. Kaplan-Meier curve: Karnofsky performance status. Note an improved PFS in patients with a better Karnofsky performance status.

Figure 2. Kaplan‐Meier curve: Disease status at diagnosis. Patients with a complete response had a better PFS.

2. Kaplan-Meier curve: Disease status at diagnosis.

Figure 2. Kaplan‐Meier curve: Disease status at diagnosis.

Patients withwith a complete response had a Figure Patients a Figure 4. Kaplan-Meier curve: Transplant timing. Earlier Figure 4. Kaplan‐Meier curve: Transplant timing.

Earliertransplantation transplantation allowe better response PFS. complete had a better PFS. allowed in PFS and a trendintoward improvement in OS. PFS for andimprovement a trend toward improvement OS.

our patient population, while underpowered, the median time to

approximately 24 months which is significantly better Standardrisk risk cytogenetics cytogenetics lead improvementwas in PFS Figure 3. Kaplan-Meier curve: Cytogenetics. Standard leadto anprogression Figure 3. Kaplan‐Meier curve: Cytogenetics. than 9-12 months reported in the literature. Furthermore, treatmentwith earlier HSCT. improvement in PFS with earlier HSCT. to an

mortality Standard risk cytogenetics lead to an related improvement in PFS remains very low and transplants are now being Figure 3. Kaplan‐Meier curve: Cytogenetics. performed entirely on an outpatient basis on selected patients at our with earlier HSCT.

institution and nationwide. The addition of new monoclonal antibodies

in relapsed disease has shown significant clinical activity and promise in the long-term management of this disease.11-14

While a few areas of improvement are needed and currently in the process of being implemented, our institution appears to be at par with national standards despite healthcare disparity in the state of Mississippi. n References 1. Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88(4):360.

trends with lower stage (p=0.054) and standard-risk cytogenetics toward improved survival (p=0.43). There was no difference between sex and overall survival (p=0.15).

Discussion Multiple myeloma remains an incurable malignancy. However, there are several prognostic factors that can affect patient survival.2 As expected, our study demonstrated a trend toward improved survival with a better performance status, sCR or CR at transplantation and at day 100 post-transplantation, lower-stage disease and standard risk cytogenetics. We suspect that there was no difference between sex and overall survival secondary to an underpowered study. Historical cohort comparisons would indicate a worse progression-free survival and overall survival in African American males. We recommend using a 3 drug induction chemotherapy regimen such as RVD rather than RD, earlier transplantation and standard maintenance chemotherapy for all patients with MM following autologous stem cell transplantation.6-9 Furthermore, we need to ensure that cytogenetics are obtained in all multiple myeloma patients at our institution as they are prognostic of survival benefit. 1 While autologous stem cell transplant is not curative for multiple myeloma, it prolongs median survival by at least 12 months.2,10 In

2. Rajkumar SV, Merlini G, San Miguel JF. Haematological cancer: redefining myeloma. Nat Rev Clin Oncol. 2012;9(9):494.

3. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. 2012;87(1):78.

4.

Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol. 2011;8(8):479.

5. Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617-1629.

6. Palumbo, A, Cavallo, F, Gay, F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895-905.

7. Jagannath, S, Abonour R, Durie BGM, et al. Impact of post-ASCT maintenance therapy on outcomes in patients with newly diagnosed multiple myeloma in Connect MM. Blood Adv. 2018;2(13):1608-1615.

8. Shah, N, Callander N, Ganguly S, et al. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(7):1155-1166.

9. Roussel, M, Lauwere-Cances, V, Gentil C, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712-2717.

10. Attal, M, Lauwers-Cances, V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320.

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11. Abramson, HN. Monoclonal antibodies for the treatment of multiple myeloma: an update. Int J Mol Sci. 2018;19(12) pii: E3924

“Team Walker are an amazing Realtor couple and did an incredible job selling our home! Their attention to details and knowledge of the market helps on reducing your homework and saves precious time. They have done an incredible job in finding homes for our incoming faculty and family. They find homes that meet your needs and individual personality.

12. Jullien, M, Trusel, S, Tessoulin, B, et al. Single-agent daratumumab in very advanced relapsed and refractory multiple myeloma patients: a real-life singlecenter retrospective study. Ann Hematol. 2019; Mar 14. doi: 10.1007/s00277019-03655-5. Epub ahead of print.

13. Jelinek, T, Mihályová J, Hájek R, et al. CD38 targeted treatment for multiple myeloma. Vnitr Lek. 2018;64(10):939-948.

14. Franssen, LE, et al. Immunotherapy in myeloma: how far have we come? Ther Adv Hematol. 2019;10:2040620718822660. Published online 2019 Jan 18. doi: 10.1177/2040620718822660.

15. Kumar, S,. Paiva B, Anderson KC, et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346.

Author Information Author Information: Fellow, Hematology/Oncology, Division of Hematology and Oncology, University of Mississippi Medical Center (UMMC) (Hansen). Internal medicine resident, UMMC (Williamson). Fellow, Hematology/Oncology, Division of Hematology and Oncology (Hsu). Former Assistant Professor, Division of Hematology and Oncology, UMMC (Buck). Assistant Professor, Division of Hematology and Oncology, UMMC (Milner).

Conflicts of Interest: None.

Corresponding Author: Carter Milner, MD, Assistant Professor, Division of Hematology and Oncology, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216. Ph:(601)9845616 (capayne@umc.edu).

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188 VOL. 60 • NO. 5 • 2019

M I S S I S S I P P I

S T A T E

D E P A R T M E N T

O F

H E A L T H

Mississippi Mississippi Provisional ReportableDisease DiseaseStatistics* Statistics Provisional Reportable February 2019

February 2019

*Monthly statistics are provisional. Disease totals may change depending on additional reporting from healthcare providers and public health investigation. These numbers do not *Monthly statistics are provisional. totals may change depending on additional reflect the finalDisease case counts. reporting from healthcare providers and public health investigation. These numbers do not reflect the final case counts.

Public Health District

Sexually Transmitted Diseases

Primary & Secondary Syphilis Early Latent Syphilis Gonorrhea Chlamydia HIV Disease Mycobacterial Diseases

Pulmonary Tuberculosis (TB) Extrapulmonary TB Mycobacteria Other Than TB Diphtheria Pertussis

Vaccine Preventable Diseases

Tetanus Poliomyelitis Measles Mumps Hepatitis B (acute) Invasive H. influenzae disease Invasive Meningococcal disease Hepatitis A (acute) Enteric Diseases

Salmonellosis Shigellosis Campylobacteriosis

Zoonotic Diseases

E. coli O157:H7/STEC/HUS Animal Rabies (bats) Lyme disease Rocky Mountain spotted fever

State Totals*

I

II

III

IV

V

VI

VII

VIII

IX

4

4

2

1

3

4

3

8

4

4

6

4

2

22

74

81

58

50

177

0

0

1

0

1

236 161 191 118 417 0 0 2 0 0 0 0 0 2 0 2 0 0 0 0 3 0 0 0 0

1 0 2 0 1 0 0 0 0 0 1 0 0 3 1 8 0 0 0 1

5 0 0 0 0 0 0 0 0 0 0 0 0 3 0 1 0 0 0 0

3 0 3 0 0 0 0 0 0 0 0 0 0 3 1

11 0 6 0 0 0 0 0 0 0 4 0 0 3 6

5

24

0

0

0 0 0

0 0 1

6

0

74

34

0

0

155 110 3 0 2 0 1 0 0 0 0 0 0 0 0 3 1 6 4 0 1 0

2 0 1 0 0 0 0 0 0 0 1 0 0 2 0 1 0 0 0 1

3

72

167

10

Feb 2019

Feb 2018

YTD 2019

YTD 2018

33

26

74

52

57

87

707

0

2

37

5

10

31

0

0

0

1

3

0

1

0 1 0 0 0 0 0 0 0 1 0 4 0 0 1 0 0 2

149

115

706

1825

1572

5

3

9

207 1,762 1,725 4,120 3,585 8

4

57

0

1

0

0

0

0

0

0

0

0

0

2

0

0

1

9

5

26

1

6

2

7

0

9

3

51

0

1

0

0

0 0 0 0 0 0 0 0 0 0 West Nile virus *Totals include reports from Department of Corrections and those not reported from a specific District.

40 0

152 1

179 0

24

60

45

0

0

0

0 8 0 0 0 6

0 7 0 0 5 5

0

14 0 0 0 7

10

15

21

23

59

44

9

10

10

0 4

10 44 0 0 0 0

1 2

32 89 0 1

11 0

0 7

26 79 0 0 1 0

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Governor Bryant Signs MRPSP Exemption to Include a Psychiatry Option

Pictured l. to R.: Angela Ladner, Executive Director Mississippi Psychiatric Association (MPA); Senate Public Health Chairman Senator Dean Kirby; House Appropriations Committee member Representative Jim Beckett; Dr. Katherine Pannell, MSMA Trustee and MPA member; UMMC Resident Dr. Finn Perkins; Dr. John Wilkaitis, Chief Medical Officer, Brentwood Behavioral Healthcare and member of MPA and MSMA; Rural Scholar Rohan Pareek, UMMC M2; MSMA Executive Director Dr. Claude Brunson; Rural Scholar Jenni Kate Miles, UMMC M2; Rural Scholar Alex Huff, UMMC M2; Rural Scholar Weston Eldridge, UMMC M2; Senator Sally Doty, the bill’s author; Matt Howard, UMMC M2; David Roberts, MSMA Chief of Staff, Director of Government Affairs.

L

egislative leaders, MPA and MSMA members and representatives, and Mississippi Rural Physician Scholars joined Governor Phil Bryant for the signing of SB 2524 in a ceremony held April 9, 2019. The bill provides an exception for one of the 61 Mississippi Rural Physician Scholars to pursue the practice of psychiatry in rural parts of our state through the Mississippi Rural Physician Scholarship Program (MRPSP). n L E T T E R S

It is important to appreciate the privilege and joy of taking care of patients!

Dear JMSMA Editor, I was very pleased to read your editorial on the “Joy of Healing.” [Lampton L. Relish the joy of healing. J Miss State Med Assoc.

2019;60(1):2] It really is important to appreciate the privilege of taking care of patients and the joy such an activity can generate.

You get great mileage out of your half-page editorials.

William C. “Bill” Lineaweaver, MD

Jackson

Editorial hits at the reason that we are physicians!

Dear JMSMA Editor, I thought your editorial in the January issue [Lampton L. Relish the joy of healing. J Miss State Med Assoc. 2019;60(1):2] was outstanding and hits the reason that we are physicians! Very encouraging! My youngest son is a family physician in Vicksburg and has been despondent about the practice of medicine particularly about EHR. I have strongly encouraged him to read your editorial!

Thanks again!

Ron Cannon, MD, Jackson 190 VOL. 60 • NO. 5 • 2019

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P R E S I D E N T ’ S

P A G E

The Past is Prologue; Keeping the Patient First – Remembering James C. Waites, MD, MSMA President 1991-1992

I

am pleased to have the opportunity to take a look back nearly 30 years to issues of importance to physicians at that time and reflected in Dr. Jimmy Waites' monthly "President's Page" in the Journal MSMA. Dr. Thad Waites gives us an overview of that year 1991-92. It is amazing but not altogether surprising how issues evolve and how issues then and now threaten the patient-physician relationship.

Dr. Jimmy Waites was prescient in advising our profession to stand firm with the highest of ethics and always to keep the patient foremost in our thoughts.

Hopefully, we can continue to keep the patient first and not hand over the gate keys to those who would be seen as vandals at the gates of medicine. n

Michael Mansour, MD President, Mississippi State Medical Association

Dr. Jimmy Waites was a community and healthcare leader throughout his nearly 50-year career as a family physician in Laurel, Mississippi.

From the president of his University of Mississippi medical school class of 1958 to president of the Southern Medical Association and president of the Mississippi State Medical Association, he used every forum to stress the importance and obligation of physicians to keep the patient first. He was a paragon of a physician whose patients considered him not only their doctor but always their friend.

References

When I was elected MSMA's 151st president in August 2017, I predicted this job would be easy if we maintain our focus always to keep the patient’s interest first. In fact, it is becoming harder for physicians to keep the patients’ interest first with so many business interests attempting to influence the practice of medicine. Many of these issues were discussed in Jerome Arnett’s book “Vandals at the Gates of Medicine.” A recent article from the journal, Health Affairs, found that from 2007-2014 hospital prices grew substantially faster than physician prices. For inpatient care hospital prices grew 42% while physician prices increased 18%. Similarly, for hospital-based outpatient care, hospital prices increased 25% while physician prices grew 6%. Hospital consolidations and mergers were supposed to cut costs but have had the opposite effect.1

DR. THAD WAITES: Dr. James C. Waites was my brother. Known naturally as Jimmy to most everyone, but “Bubba” in the family, he was a member of MSMA throughout his career. He served as president in the 1991-1992 term. He also served in many other roles including trustee and long-term delegate to the AMA. MSMA established the Leadership Award in his name in recognition of his service to many communities including church, town, society, state, and nation. Jimmy was the perfect big brother and became to me the embodiment of what a physician should be.

When community hospitals were run by community leaders and local physicians, the goal was to provide quality healthcare, and profits were kept to a minimum. Hospital mergers have often produced entities controlled by large corporations who may be more concerned with return on investment than with the quality of care. Corporations may also promote patient care by “providers” rather than physicians as a cost-saving measure shifting more care to mid-level providers. In reality, trying to control cost without physician-led team-based care has the potential to increase cost by unnecessary testing and decreased efficiency in diagnosis and appropriate treatment.

192 VOL. 60 • NO. 5 • 2019

1. Cooper Z, Craig S, Gaymon M, et al. Health Aff (Millwood). 2019;38(2):184-189. doi: 10.1377/hlthaff.2018.05424.

Dr. James C. Waites

Dr. Lampton has asked that I remember some things regarding Jimmy’s year as president and to share this with you. I do remember much of his presidency including especially the heart attack he had early in his tenure. I do much appreciate MSMA letting me refresh that memory by allowing me to browse through the archives and especially to review all of his entries to the Journal while he was president.

In his presidency, he continued to push strongly, as did other presidents, for the unity of the society and the unity with AMA. He visited all the component societies. He was a constant and strong supporter of the Alliance. He was president when the RBRVS method of payment was launched, and he commented and advised about this on several occasions. Mainly though he spoke and constantly wrote on the core meaning and mission of our profession, the care of the patients. (continued on next page)

He wrote of the heritage and the privilege of being a doctor and of our responsibility to cherish and to maintain.

In his monthly president’s page in the Journal, he presented his thoughts on these things as well as his hopes for MSMA and its mission. To make his points, his essays are laced with aphorisms, quotes, and scriptures.

To the House of Delegates, Jimmy presented his vision for his year as president and MSMA. He used Helen Keller’s words to say it is, “worse than having no sight to have sight with no vision.” In his monthly essays, he implored the membership always to remain loyal to their heritage.

He noted that the current image of the physician was becoming tarnished and the way to change this was to keep the patient always foremost and to be active but not reactive in preserving the heritage.

In one essay titled, “What’s in a Name,” he said our title is physician, not provider, and that our business is caring for people and our profession is medicine; providers provide treatment while physicians administer care as well as treatment. In another titled “What’s a Real Doctor” he defined a real one as a healer, teacher, advocate, scientist, manager/coordinator, counselor, and mainly friend. His “Prescription for Physicians” entreated us to stand firm with the highest of ethics and to always keep our patients foremost in our thoughts. He wrote that life is a gift and it should be shared. He asked us to “share the values of our profession” while also cherishing and nourishing those values.

infarction. He was rich in possession of friends-which he wrote was much more valuable than possessing money. If you knew him, I believe you also knew him as a friend. And I avow that every patient I have ever met that said he was their doctor also said that he was their friend.

Therefore, his riches.

In his final entry as president he admonished us all with words from Paul to the Philippians: "In conclusion, my friends, fill your minds with those things that are good, and that deserve praise: things that are true, noble, right, pure, lovely, and honorable."

Thank you for allowing me to remember my brother with you.

Thad F. Waites, MD, MACC Hattiesburg Clinic/Forrest General Hospital Chair, Health Affairs Committee, American College of Cardiology Vice Chair, Mississippi State Board of Health

Dr. Lampton has asked what accomplishment Jimmy was most proud of. I believe he was most proud that he was the richest man in Mississippi, and he said so in his writing just after his myocardial

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THE TURNER HOSPITAL, MERIDIAN, 1910 – Established as a privately-owned hospital in 1910, the Turner Hospital was a 30-bed facility located on 1421 20th Avenue in Meridian, founded by surgeon Dr. Robert Lee Turner (1865-1927). A native of Jasper County, Turner graduated from Mississippi A & M and then obtained his MD from Tulane in 1891. Above are two images of the hospital from its first years of operation. With a laboratory and two operating-rooms, the facility had several physicians on staff with a half-dozen nurses and technicians. (The 1920 Census reveals six young nurses there, one patient, Dr. Turner, and his wife Bessie.) Other Meridian hospital facilities in 1910 included: Tucker's Sanatorium, Meridian Sanatorium, East Mississippi Insane Hospital, Matty Hersee Hospital, and the Masonic Home. Turner Hospital enlarged to 50 beds before Dr. Turner’s death in 1927. In his 1924 will, Turner left not only $1000 to his “faithful colored servant” Joseph Rempson (a large sum at that time!) but also $2000 to “Miss Stella Mitchell, the superintendent of my Hospital, because of her long and faithful service to me, both in time of health and in time of sickness.” In 1929, Meridian physician Dr. William Jefferson “Jeff” Anderson purchased the old Turner Hospital and renamed it Anderson Infirmary. This institution evolved into Jeff Anderson Memorial Hospital which, in 1965, opened a new stateof-the-art facility. The hospital housed 120 private acute care beds with expanded services in laboratory, X-ray, surgery, obstetrics, and emergency departments. On January, 1, 2011, Anderson took ownership of Riley Hospital. This acquisition added 140 licensed beds, making Anderson Regional a 400-bed facility – among the largest in the state and region. If you have an old or even somewhat recent photograph or image which would be of interest to Mississippi physicians, please send it to me at lukelampton@cableone.net or by snail mail to the Journal. n — Lucius M. “Luke” Lampton, MD JMSMA Editor

194 VOL. 60 • NO. 5 • 2019

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Edited by Lucius Lampton, MD; JMSMA Editor [This month, I continue a multi-issue focus on the poetry of the late physician-poet Merrill Moore, MD (1903-1957), a noted American psychiatrist and neurologist who also achieved fame as a poet and sonneteer. Born and educated in Tennessee, he received his MD from Vanderbilt School of Medicine in 1928. While always a prolific poet, he specialized in psychiatry and neurology, conducting a large psychiatric practice while teaching at Harvard Medical School and publishing research on alcoholism, addiction, suicide, and the psychoneurosis of war. “Killed in Mississippi Hotel Fire; Greenville, March 4 (It Could Be Any Year)” is a memorable poem, even if not considered among Moore’s best. I have always been attracted to it, perhaps because of the Mississippi subject matter and its line about the language of journalism he called journalese: “Print can ease but cannot really soften.” The poem is from “A Doctor’s Book of Hours, Including Some Dimensions of the Emotions” published in 1955, on page 357. I strongly recommend the book as an introduction to Moore’s poetry. Perhaps one of our Delta historians (Drs. Gamble and Trotter, get to work!) can find the “March 4” Greenville hotel fire (pre-1955) Moore is referencing. Expect more Moore sonnets in coming months. Any physician is invited to submit poems for publication in the Journal either by email at lukelampton@cableone.net or regular mail to the Journal, attention: Dr. Lampton.] — Ed.

Killed in Mississippi Hotel Fire; Greenville, March 4 (It Could Be Any Year) Firemen, who found his body on the floor,

Now newspaper-wise, the simple facts

Said the cause of death was suffocation–

In the briefest syllables are told

At first the picture was not very clear;

Hard the truth in simple journalese;

There was certain cause for speculation.

Print can ease but cannot really soften:

He was a travelling salesman, forty years old,

They said that he apparently had been

Dead when firemen broke into the room;

Smoking in his bed, one time too often.

Apparently the poor guy went to bed

— Merrill Moore, MD (1903-1957)

Unaware that he would meet his doom.

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M S M A

Welcoming Our Newest Members

ADHIKARI, SUBODH, Hattiesburg, Internal Medicine

KHADER, ASMA, Hattiesburg, Internal Medicine

ALSATLI, AMRULLAH, Hattiesburg, Internal Medicine

LIEU, SANDY, Ackerman, Family Medicine

ANINDO, MOHAMMAD, Hattiesburg, Internal Medicine

MATANI, NEDAL, Hattiesburg, Internal Medicine

ATHOTA, SRIHARSHA, Hattiesburg, Internal Medicine

MINHAS, ABDUL, Hattiesburg, Internal Medicine

BOND, AARON, Southaven, Vascular Neurology

MULLENS, JESS, Vancleave, Orthopedic Surgery

CEHAJIC, BORIS, Hattiesburg, General Surgery

NIDA, ANDREW, Hattiesburg, Otolaryngology

CHAPMAN, MARLA, Petal, Pediatrics

PATEL, CHARVI, Brandon, Family Medicine

COLEMAN, KELLY, Vancleave, Anesthesiology

RUSSELL, TORI, Columbia, Family Medicine

COX, JOSEPH, Vancleave, Orthopedic Surgery

SAMRA, MAHMUD, Hattiesburg, Internal Medicine

DERA, AKRAM, Hattiesburg, Internal Medicine

SPRUILL, KRISTEN, Hattiesburg, Anesthesiology

FISHER, JASON, Hattiesburg, Family Medicine

TAYLOR, MEAGAN, Wiggins, Family Medicine

GOMEZ POMAR, ENRIQUE, Meridian, Pediatrics

WARREN, PAULA, Hattiesburg, Neurology

GRANIERI, ELIZABETH, Southaven, Endocrinology MISSISSIPPI STATE MEDICAL ASSOCIATION MSMAonline.com 196 VOL. 60 • NO. 5 • 2019

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