Stern Expert Report Publicly Filed

IN THE CIRCUIT COURT FOR SULLIVAN COUNTY
AT KINGSPORT, TENNESSEE
BARRY STAUBUS, in his official capacity as the District )

Attorney General for the Second Judicial District and on behalf )
of all political subdivisions therein, including SULLIVAN )
COUNTY, CITY OF BLUFF, CITY OF BRISTOL, CITY OF ) JURY DEMAND
KINGSPORT; ) Case No. C-41916
STATE OF TENNESSEE ex rel. BARRY STAUBUS;
TONY CLARK, in his official capacity as the District Attorney
) Division C
General for the First Judicial District and on behalf of all political )
subdivisions therein, including CARTER COUNTY, CITY OF )
ELIZABETHTON, CITY OF WATAUGA, JOHNSON )
COUNTY, CITY OF MOUNTAIN CITY, UNICOI COUNTY, )
TOWN OF UNICOI, TOWN OF ERWIN, WASHINGTON )
COUNTY, CITY OF JOHNSON CITY, TOWN OF )
JONESBOROUGH; )
STATE OF TENNESSEE ex rel. TONY CLARK; )
DAN ARMSTRONG, in his official capacity as the District )
Attorney General for the Third Judicial District and on behalf of
)
all politic al subdivisions therein, including GREENE COUNTY,
CITY OF TUSCULUM, TOWN OF BAILEYTON, TOWN OF
)
GREENVILLE, TOWN OF MOSHEIM, HAMBLEN COUNTY, )
CITY OF MORRISTOWN, HANCOCK COUNTY, TOWN OF )
SNEEDVILLE; HAWKINS COUNTY; CITY OF CHURCH )
HILL; TOWN OF BULLS GAP; TOWN OF MOUNT )
CARMEL, TOWN OF ROGERSVILLE, TOWN OF )
SURGOINSVILLE; )
STATE OF TENNESSEE ex rel. DAN ARMSTRONG; )
and BABY DOE, by and through his Guardian Ad Litem, )
)
Plaintiffs,
)
v.
)
)
PURDUE PHARMA, L.P.; PURDUE PHARMA, INC.; THE )
PURDUE FREDERICK COMPANY; MALLINCKRODT LLC; )
ENDO HEALTH SOLUTIONS, INC; ENDO )
PHARMACEUTICALS, INC; ELIZABETH ANN BOWERS )
CAMPBELL; PAMELA MOORE; and ABDELRAHMAN )
HASSABU MOHAMED, )
)
Defendants.
EXPERT REPORT OF DAVID M. STERN, M.D.

Table of Contents
I. Qualifications........................................................................................................................ 1
II. Assignment and Summary of Conclusions ........................................................................ 4
III. Opioid Epidemic in Northeast Tennessee .......................................................................... 5
A. Hancock County Case Study .............................................................................................. 5
B. Opioid Addiction, Abuse, Diversion, Overdose, and Death ............................................... 7
C. The Opioid Epidemic’s Impact on Infants, Children, Families, and the
Community ....................................................................................................................... 11
IV. Opioid Use Disorder .......................................................................................................... 15
A. Addiction, Opioids and the Underlying Neurobiology ..................................................... 15
B. A Chronic, Relapsing Condition ....................................................................................... 18
V. Treatment Principles ......................................................................................................... 20
A. A Chronic Care Model ...................................................................................................... 20
B. Medication Assisted Treatment and Abstinence............................................................... 22
C. Long-Term Care................................................................................................................ 25
D. A Continuum of Care ........................................................................................................ 27
E. Psychosocial Treatment .................................................................................................... 29
F. Recovery Support Services ............................................................................................... 29
VI. Barriers to Care and “The Treatment Gap” ................................................................... 30
VII. Assets of the Region ........................................................................................................... 33
VIII. Tennessee Recovery Enhanced Addiction Treatment (TREAT)................................... 34
A. Approach ........................................................................................................................... 34
B. Development ..................................................................................................................... 36
C. Goals ................................................................................................................................. 38
D. Key Elements .................................................................................................................... 40
1. The Node ........................................................................................................................ 41
2. Node Team Members ..................................................................................................... 43
E. Mobile Community Health Team ..................................................................................... 55
F. Emergency Consult Line for Healthcare Providers .......................................................... 57
G. Telemedicine ..................................................................................................................... 58
H. Residential Treatment Centers .......................................................................................... 60
I. Recovery Housing ............................................................................................................. 63
J. Continuity of Care & Clinical Pathways .......................................................................... 66
i
K. Patient Capacity & Distribution of Patients ...................................................................... 69
L. Infrastructure for Data Collection and Evaluation of Clinical Outcomes......................... 72
X. Appendix ............................................................................................................................. 77
ii
I. Qualifications
1. I have a career in academic medicine spanning over four decades during which I
have been a physician scientist at the College of Physicians & Surgeons of Columbia University
(until 2002), and then a leader of medical schools and healthcare organizations in Georgia,
Cincinnati and, most recently, Tennessee. My work has achieved national recognition based on
my publications and presentations.
2. At Columbia, I founded and directed the Center for Vascular and Lung
Pathobiology, one of the leading centers in this field. I was the Gerald and Janet Carrus
Endowed Professor, and my work on properties of blood vessels was widely known through over
350 publications, over a dozen patents and multiple peer-reviewed grants from the National
Institutes of Health and other organizations (MERIT award, program project awards, center
grants, Juvenile Diabetes Research Foundation, American Heart Association, LeDucq
Foundation, etc.). My research group occupied a floor of the medical center and was a place of
innovation and training. Many postdoctoral fellows and junior faculty received their research
training in my vascular biology laboratory.
3. As a leader of academic health centers, I am known for my emphasis on

addressing pressing health problems in the community and establishing a culture of excellence in
medical institutions so that care is of the highest quality. For example, shortly after coming to
Tennessee in 2011, I recognized the importance of stroke as a cause of morbidity and mortality
for the communities the University of Tennessee Health Science Center was involved in serving.
Moving patients quickly and efficiently to the hospital so treatment could be initiated was one of
the barriers. For this reason, I established a mobile stroke unit for the Shelby County area. At
that time, it was one of three such units in the world and the only one in the mid-South. The
mobile stroke unit is dispatched by 911 to the site of a suspected stroke patient, and it carries a
hospital-grade CT scanner, along with medical personnel, to make a diagnosis of stroke. Once
the diagnosis of stroke is made and confirmed, treatment begins immediately. This is often
within minutes. Since delay in stroke treatment results in loss of brain cells, the goal of the
mobile stroke unit is to “save brain” and, thereby, to minimize a patient’s disability after a
stroke. Recently, a Delta flight was diverted to Memphis because a patient onboard was believed
Expert Report of David M. Stern, M.D.

Page 1
to be having a stroke. The mobile stroke unit was dispatched to the airport and efficiently
provided the first step in the patient’s stroke care. I also founded a free clinic, The Stress and
Wellness Clinic in Oakhaven, an underserved area, on the grounds of the Healing Center Baptist
Church. The goal of this clinic has been to bring community medicine to a vulnerable
community.
4. I came to Tennessee in 2011 from the University of Cincinnati (where I was Dean
and Vice President for Health Sciences). I was Executive Dean and Vice-Chancellor for Health
Affairs at the University of Tennessee Health Science Center until 2017, when I undertook a
one-year term as Vice-Chancellor for Health Affairs for Statewide Initiatives. As of this
summer, I have become CEO of Integrated Addiction Care, a venture I started with two partners
this spring, that offers integrated addiction care to patients in West Tennessee and beyond.
During my time in Georgia, I was Dean of the College of Medicine and Chief Clinical Officer at
the Medical College of Georgia.
5. My focus on addiction medicine started with a personal tragedy with my younger

son Alan who passed in 2008. In Tennessee, I founded the Center for Addiction Science and
instituted the multidisciplinary integrated model of care at the University of Tennessee. This led
to my being invited to the White House (2016) to present this model, and the designation of the
Center as an official “Center of Excellence” by The Addiction Medicine Foundation
(Washington DC). I served on the Governor’s Commission on Pain and Addiction Medicine
Education (2018) and the Shelby County Opioid Taskforce (2018) among other groups working
in the area of substance use disorder locally and nationally. I am a frequent invited speaker at
national and local events such as the Senate President’s Forum, Medicine Responds to Addiction
II, State Government Affairs Council, TennCare Health Plan meeting, South Central Telehealth
Forum and others.
6. Making a positive impact on the epidemic of opioid use disorder in Tennessee has
become a consuming activity for me. In particular, I am focused on implementing models of
integrated care for patients with opioid/substance use disorder and charting outcomes to achieve
the most effective means of helping patients move into treatment and durable recovery. In my
current position as CEO of Integrated Addiction Care, I am deeply involved in organizing care
for patients with opioid use disorder. For example, the practice employs telemedicine in order to

Page 2
make care delivery more accessible for patients. Once an in-person relationship has been
established with a particular patient, if it is more convenient for the patient to have telemedicine
visits, this approach is employed. Telemedicine visits can then take place at a time and place
that minimally disrupts the patient’s life. Visits can often be conducted with the patient at home
and during the evening.
7. In addition, I have established with Baptist Memorial Health Care, a major health
system in the mid-South, a Center of Excellence in Addiction Medicine. Together the two
organizations provide an inpatient service for addiction medicine as well as referral pathways for
outpatients and the emergency room. In the emergency room, via telemedicine and an
emergency consult line, the expertise of Integrated Addiction Care is leveraged for the benefit of
patients in real-time.
8. Because of the scarcity of addiction medicine specialists, Integrated Addiction

Care, working with Baptist, has created an addiction medicine fellowship which is the first such
fellowship accredited by the Accreditation Council for Graduate Medical Education (ACGME)
in Tennessee and the region (there is another program in Lexington, Kentucky). The purpose of
this program is to provide an intensive one-year fellowship experience that produces experts in
addiction medicine to care for patients with substance/alcohol use disorder in the region.
Graduates of this program will be the kind of individuals that could potentially be recruited to the
region under consideration in this litigation in Northeast Tennessee to lead and staff the “nodes”
of addiction medicine expertise.
9. I have seen first-hand the devastation of the opioid epidemic in Northeast and
West Tennessee. I would like to be a part of changing the trajectory of the region so that people
with addiction can achieve durable recovery and go about their lives in a manner that allows
them to achieve their aspirations. The program described herein has that goal.

Page 3
II. Assignment and Summary of Conclusions
10. I was asked to determine the nature and intensity of the local response needed in a
nine-county area in Northeast Tennessee (“Northeast Tennessee”)1 to treat, rehabilitate, and
support individuals suffering from opioid use disorder and the opioid epidemic. My goal is to
treat as many individuals suffering from the effects of opioid use disorder as possible over an
extended period of time and actively recruit and engage a greater number of people in durable
recovery.
11. Opioid use disorder is associated with increased risk for both fatal and nonfatal
overdoses, infectious disease transmission, job loss and work-related injury, homelessness, and a
host of other health and social costs. Furthermore, opioid misuse or abuse can lead to physical
dependence in as little as days to weeks. People living with opioid use disorder often lose
control of their lives as opioids alter brain function, including clouding judgment. The chemical
dependence contributes to individuals sacrificing social, educational, and economic opportunities
in pursuit of drugs to achieve a temporary “high” early during drug use and avoid dreaded
withdrawal later in the course of drug use.
12. Most individuals living with opioid use disorder require treatment in order to
diminish withdrawal symptoms and transition to healthier lifestyles which no longer include
opioid abuse. However, treatment is not a static process; instead, it is dynamic and moves from
induction to stabilization and ultimately recovery. Induction denotes that a course of treatment
has begun, and stabilization means that the precarious state of illicit drug use has been replaced
by a degree of physical and emotional normalcy. This is the context in which recovery can
begin, a condition in which patients regain their independence from opioid dependency and
embark on a path to realize their personal potential.
13. In order to obtain this outcome, attention needs to be focused in several inter-
related areas: treatment for the opioid addiction; treatment and management of any underlying
physical health needs; treatment and therapy for co-occurring mental health issues; and provision
of resources that address additional social determinants of health challenges (e.g., housing,
1
The nine counties in the Judicial Districts at issue in this litigation are Carter County, Greene County, Hamblen
County, Hancock County, Hawkins County, Johnson County, Sullivan County, Unicoi County and Washington
County.

Page 4
employment, legal and others). During recovery (also referred to as maintenance of physiologic
functions to denote that addiction is a chronic disease and often requires long-term therapy and
support), people accumulate personal capital in key domains: medical (health & well-being
improvements), social (stable housing and interpersonal relationships (re)form) and financial
stability (maintaining a job leading to greater financial independence). This “recovery capital” is
a deterrent to relapse, in which patients enter the maelstrom of addiction once again. One of the
challenges of this scenario is that relapse is an ever-lurking threat because of the persistence of
the chronic brain condition that characterizes addiction, described in greater detail herein, and
the ever-present physical, mental, social and economic costs of prolonged addiction to opioids.
14. This document provides a roadmap for transitioning individuals with opioid use
disorder in Northeast Tennessee into treatment, and, from there, into durable recovery. The
program outlined in Section VIII seeks to maximize the number of people who can be brought
into treatment and transitioned to recovery.
15. I reserve the right to supplement my opinions to the extent new information
becomes available.
16. My rate for work in this matter is $500 per hour and $1,000 per hour of testimony.
My compensation does not depend on the outcome of this litigation.
III. Opioid Epidemic in Northeast Tennessee
A. Hancock County Case Study
17. The Northeast Tennessee setting poses significant challenges for its residents on
many levels. To highlight an extreme example, 25 percent of the population of one of the
subject counties, Hancock County (population 6,549; 223 square miles), live below the state
poverty line.2 The unemployment rate in Hancock County is 10 percent; however, only 46.7
percent of the non-institutionalized (e.g., non-incarcerated) population over the age of 16 is
2
American Community Survey 2017, Hancock County (https://factfinder.census.gov/faces/tableservices/
jsf/pages/productview.xhtml?src=bkmk).

Page 5
currently employed, indicating that significant numbers of the population are no longer searching
for work.3
18. The opioid epidemic has contributed to many of these challenges in Hancock
County by destroying the fabric of families, disrupting the integrity of the workforce,
diminishing educational preparedness of young people, and degrading the overall health of the
community. Hancock County ranks as the number one county in the state (number 13
nationally) at-risk for HIV and Hepatitis C outbreaks as a result of the opioid epidemic.4 Current
estimates suggest a rate of over 30 drug overdose deaths per 100,000 residents in Hancock
County, placing it amongst the highest rates in the state.5 In 2016, Hancock County had the
highest county level incidence rate of neonatal abstinence syndrome (“NAS”) with 180.3 per
1,000 live infants, greater than 15 percent.6 In 2018, 240 patients in Hancock county had a
buprenorphine prescription filled for medication-assisted treatment (MAT).7 On July 22, 2019,
an undercover drug operation yielded 110 indictments for 45 defendants in Hancock County
related, in part, to diversion of prescription opioids.8 The operation was code-named, “Taking
Back Hancock County.”9
3
Ibid.
4
M. Van Handel, et al., “County-level Vulnerability Assessment for Rapid Dissemination of HIV or HCV Infects
among Persons who Inject Drugs, United States,” Journal of Acquired Immune Deficiency Syndromes, 73(3), 2016,
pp. 323-331; Centers for Disease Control and Prevention (CDC), “Vulnerable Counties and Jurisdictions
Experiencing or At-Risk of Outbreaks,” last updated July 19, 2018, https://www.cdc.gov/pwid/vulnerable-counties-
data.html.
5
CDC, “Opioid Overdose Death Rates,” https://www.cdc.gov/drugoverdose/
data/prescribing/overdose-death-maps.html.
6
Tennessee Division of Tenncare, “Neonatal Abstinence Syndrome Among Tenncare Enrollees - 2016 data,” 2018
(https://www.tn.gov/content/dam/tn/tenncare/documents/TennCareNASData2016.pdf).
7
Tennessee Department of Health, “Data Dashboard,” Sept 19, 2019 (https://www.tn.gov/health/health-program-
areas/pdo/pdo/data-dashboard.html).
8
“110 indictments on 45 people in largest drug round-up in Hancock County history,” WATE, July 28, 2019
(https://www.wate.com/news/110-indictments-on-45-people-in-drug-round-up-dubbed-taking-back-hancock-
county/); Robert Moore, “Taking Back Hancock County nets 31 suspects,” Citizen Tribune, Jul 27, 2019,
https://www.citizentribune.com/news/local/taking-back-hancock-county-nets-suspects/article_f399a672-b0e0-11e9-
9398-cfed839a5c21.html; Citizen Tribune, “Three more nabbed in Hancock County round up,” from Staff Reports,
Jul 31, 2019, https://www.citizentribune.com/news/local/three-more-nabbed-in-hancock-county-round-
up/article_3c8e517c-b3af-11e9-9da0-bf6ddddb15bb.html; Tommy Campbell, :Taking Back Hancock County:
Sheriff Brewer announces major drug indictments,” The Rogersville Review, Jul 29, 2019,
http://www.therogersvillereview.com/rogersville/article_9a0720ad-70ab-50fe-9562-9cd3211e12c3.html
9
Ibid.

Page 6
19. As in Hancock County, Northeast Tennessee is facing a systemic crisis as a result
of the health challenges, including disability and death, that opioid addiction has created. This
has had a severely detrimental effect on the quality of life in these counties. In view of the
central role of opioids in bringing about this situation, I have concluded that a long-term, system-
coordinated treatment plan targeting opioid addiction is needed to address this hopelessness in a
meaningful way.
B. Opioid Addiction, Abuse, Diversion, Overdose, and Death
20. The opioid epidemic in Northeast Tennessee is similar to the epidemic throughout
Appalachia. The mistaken view of physicians, instilled by pharmaceutical company promotional
efforts,10 that agents such as OxyContin were not addictive, resulted in indiscriminate
prescribing. By 2012, opioids were among the most prescribed drugs, and approximately 90
percent of prescription opioids were given for chronic pain conditions, and only 10 percent of
prescription opioids were dispensed for post-surgical, palliative, and cancer pain treatments.11
Such prescribing patterns were detrimental, since chronic opioid administration has not been
shown to be effective for longstanding management of pain, and the propensity for chemical
dependency to lead to abuse is very real.12 Indeed, this was the fate of many patients.
21. The 2016 CDC Guidelines make clear that there is “insufficient evidence to
determine the long-term benefits of opioid therapy for chronic pain[.]”13 The CDC found that
“[n]o evidence shows a long-term benefit of opioids in pain and function versus no opioids for
chronic pain with outcomes examined at least 1 year later (with most placebo-controlled
randomized trials ≤ 6 weeks in duration.”14 The CDC warned that “for the vast majority of
A. Van Zee, “The Promotion and Marketing of OxyContin: Commercial Triumph, Public Health Tragedy,”
10
American Journal of Public Health, 99(2), 2009, pp. 221-227.

11
L. Manchikanti, et al., “Opioid Epidemic in the United States,” Pain Physician, ES9- ES38, 2012.
12
N.D. Volkow, “Opioid abuse in chronic pain – Misconceptions and mitigation strategies,” New England Journal
of Medicine, 374, 2016, pp. 1253–1263.
13
CDC, “Guideline for Prescribing Opioids for Chronic Pain - United States, 2016,” CDC Recommendations and
Reports, 2016 (https://www.cdc.gov/drugoverdose/prescribing/guideline.html) (hereafter, “CDC Guideline”), at pp.
2, 20, 25. (confirming, based on existing research and evidence, that opioid use presents a “serious risk” of
addiction, use for three months or more “substantially increases” that risk, and there never has been “good evidence
that opioids improve pain or function with long-term use”).
14
Ibid.

Page 7
patients, the known, serious, and too-often-fatal risks far outweigh the unproven and transient
benefits [of opioids for chronic pain].”15
22. Some addicts began with a legal opioid prescription from their doctor or by taking
pills from a bottle belonging to a family member or friend.16 Individuals who developed opioid
use disorder while taking legally prescribed opioids often move to procuring the drugs illegally.
Once a patient becomes addicted to opioids, the only question for that individual is how to
continue obtaining the drug. Legal use of prescription opioids often moves to misuse of opioid
drugs as patients illicitly obtain additional opioids. This ranges from stealing supplies of opiates
that family/friends have in medicine chests to purchasing pain killers illicitly. When the price of
opioid prescriptions increases and/or their availability decreases, heroin and fentanyl (and, to the
extent cheaper and more readily available, even the non-opioid methamphetamine) become the
drug of choice.
23. Tennessee has consistently had one of the highest per capita opioid prescribing
rates in the country. In 2013, Tennessee was ranked third in the country for number of
prescriptions filled per capita; in 2014, fourth; and from 2015 - 2017, third.17 Within Tennessee,
the nine counties located in Northeast Tennessee have consistently been among the highest in the
state. For example, in Hamblen County there were 289.3 prescriptions per 100 residents in 2007,
or 2.89 prescriptions per person. Hancock County filled 177.6 prescriptions per 100 residents in
2013. Sullivan County peaked in 2011 with 240.6 prescriptions per 100 residents. Overall, the
average rate of opioid prescription per 100 residents, between 2006 and 2015, of the nine
counties of Northeast Tennessee (i.e., Carter, Greene, Hamblen, Hancock, Hawkins, Johnson,
Sullivan, Unicoi, and Washington) was 170.2, or 1.7 prescription per person.18
15
T. Frieden, et al., “Reducing the Risks of Relief—The CDC Opioid Prescribing Guideline,” New England Journal
of Medicine, 374, 2016, pp. 1501 - 1503.
16
N. Volkow, et al., “‘All Scientific Hands On Deck’ to End the Opioid Crisis,” National Institute on Drug Abuse,
2017 (https://www.drugabuse.gov/about-nida/norasblog/2017/05/all-scientific-hands-deck-to-end-opioid-crisis)
(“While there were nearly 20,000 overdoses in 2015 due to heroin or fentanyl, the trajectory of opioid addiction
usually begins with prescription opioid misuse. Some people with opioid addiction began by taking diverted pills
from friends and family members, but others began with an opioid prescription of their own”).
17
CDC, “Opioid Prescribing Rate Maps” (https://www.cdc.gov/drugoverdose/maps/rxrate-maps.html.).
18
Ibid.

Page 8
24. The Medical Director for the Northeast Tennessee Regional Health Office, Dr.
David Kirschke, pointed to Tennessee’s prescribing rates as the cause of the overdose deaths:
“The primary driver for the epidemic has been the large number of prescriptions for opioids in
our region …We had among the highest number of prescriptions for opioids in East Tennessee
compared to the rest of the state for a long time so that’s resulted in higher numbers of people
that are addicted to opioids so that’s resulted in higher numbers of people that are overdosing on
opioids.”19
25. Tennessee is consistently ranked among the top 15 states in the country for opioid
overdose deaths.20 In 2017, there were 1,269 opioid overdose deaths in Tennessee – a rate of
19.3 deaths per 100,000 persons, which is higher than the national rate of 14.6 deaths per
100,000 persons.21 Northeast Tennessee, exacerbated by the regional crisis, experienced
significantly higher rates: Carter County (24-25.9 deaths per 100,000); Greene County (24-25.9
deaths per 100,000); Hamblen County (26-27.9 deaths per 100,000), Hawkins County (26-27.9
deaths per 100,000), Sullivan County (24-25.9 deaths per 100,000); Washington County (22-23.9
deaths per 100,000) and Unicoi County (30+ deaths per 100,000).22 From 2013-2016, between
41 percent and 58 percent of those who died from a prescription opioid overdose did not fill an
opioid prescription in the 60 days prior to death, 23 indicating an illicit source of drug.
26. Since 2012, there have been over 500 overdose deaths in Northeast Tennessee.24
The number is likely underreported because counties are unable to cover the costs of performing
autopsies for every death.25 The 2017 Annual Report of the Office of the State Chief Medical
19
J. Soto, “Opioid epidemic by the numbers in Northeast Tennessee,” WJHL, Nov. 15, 2018
(https://www.wjhl.com/news/local/opioid-epidemic-by-the-numbers-in-northeast-tennessee/).
CDC, “Opioid Overdose Death Maps” (https://www.cdc.gov/drugoverdose/data/prescribing/overdose-death-
20
maps.html).
21
Ibid.
CDC, “Opioid Overdose Death Maps” (https://www.cdc.gov/drugoverdose/data/prescribing/overdose-death-
22
maps.html).
23
Tennessee Department of Health, “Prescription Drug Overdose Program 2018 Report: Understanding and
responding to the opioid epidemic in Tennessee using Mortality, Morbidity, and Prescription Data,” February 6,
2018 (https://www.tn.gov/content/dam/tn/health/documents/pdo/PDO_2018_Report_02.06.18.pdf), at p. 57.
24
Ibid.
25
A. Wadhwani, “Investigation: How many lives are lost to opioids? No one knows,” USA Today Network, August
25, 2017; R. Houk, “Covering the Cost of Autopsies,” Johnson City Press, May 20, 2018

Page 9
Examiner states, “The current opioid epidemic has increased the number of deaths that must be
investigated by county medical examiners and made it necessary for the regional forensic centers
to perform more autopsies. The financial and workload burden continues to overwhelm the
system.”26
27. As Volkow observed, although overprescription of opioid medications triggered

the opioid crisis, improving opioid prescription practices for pain management, important for
addressing the opioid crisis, is no longer sufficient.27 While other states have seen overdose rates
decline, Tennesseans continue to have statistically significant increases in the number of
overdoses each year and expect overdose rates to continue to increase due to heroin and
fentanyl.28 As depicted in Figure 1, Tennessee’s rates of opioid-related inpatient stays, opioid-
related emergency department visits, and neonatal abstinence syndrome cases have increased
alongside its overdose deaths.29
(https://www.johnsoncitypress.com/Government/2018/05/20/Controlling-the-cost-of-autopsies); 2017 Annual

Report of Medical Examiner Death Investigations; Office of the State Chief Medical Examiner, “Tennessee 2017
Annual Report of Medical Examiner Death Investigations”; J. Lurie, “We’re Undercounting Opioid Overdoses by
Thousands”, Mother Jones, September 15, 2017.
26
Ibid.
27
N.D. Volkow, et al., “Prevention and Treatment of Opioid Misuse and Addiction: A Review,” JAMA Psychiatry,
76(2), 2018, pp. 208–216.
28
M. Osborne, “TBI Director: Expect Tenn. drug overdose deaths to keep climbing,” WMOT Roots Radio, August
6, 2019 (https://www.wmot.org/post/tbi-director-expect-tenn-drug-overdose-deaths-keep-climbing#stream/0); Brett
Kelman, “Tennessee has deadliest year yet for drug overdoses, as nearby states improve,” Nashville Tennessean,
July 19, 2019, https://www.tennessean.com/story/news/health/2019/07/19/opioid-crisis-tennessee-overdose-deaths-
climbing-heroin-fentanyl-meth/1550137001/.
29
Sycamore Institute, “The Opioid Epidemic in Tennessee, 2018 Update on Indicators of Progress,” August 9, 2018
(https://www.sycamoreinstitutetn.org/wp-content/uploads/2018/08/2018.08.09-FINAL-Opioids-in-Tennessee-2018-
Indicators-Update.pdf).

Page 10
Figure 1
C. The Opioid Epidemic’s Impact on Infants, Children, Families, and the

Community
28. In the United States, the number of children born with neonatal abstinence
syndrome (NAS) has quadrupled over the past 15 years.30 Appalachia is considered “ground
zero for the NAS epidemic,”31 and over the past decade, the number of NAS births in Tennessee
has increased 15-fold.32 From 2013 to 2018, there were 6,113 babies diagnosed with NAS in
Tennessee.33 The highest NAS rates in the state have consistently been found in Northeast
Tennessee, as shown in Figure 2.
30
H. Rappleye, et al., “Born addicted: The number of opioid-addicted babies is soaring,” Today, October 9, 2017.
31
P. Erwin, et al., “Neonatal Abstinence Syndrome in East Tennessee: Characteristics and Risk Factors among
Mothers and Infants in One Area of Appalachia,” Journal of Health Care for the Poor and Underserved, 28(4),
2017, pp, 1393–1408.
32
A. Culver, “October is Neonatal Abstinence Syndrome Awareness Month,” WATE, 2016
(https://www.wate.com/news/local-news/october-is-neonatal-abstinence-syndrome-awareness-month/).
33
Tennessee Department of Health, “Neonatal Abstinence Syndrome Surveillance Annual Report 2018,” 2019
(https://www.tn.gov/content/dam/tn/health/documents/nas/NAS percent20Annual percent20Report percent202018
percent20FINAL.pdf).

Page 11
Figure 2
29. These high rates of NAS births in Northeast Tennessee are consistent with other
indicators of opioid misuse and abuse in Tennessee, including opioid prescriptions and overdose
deaths.34
30. Babies born with NAS experience some of the same symptoms as adult opioid
abusers including tremors and seizures.35 Research indicates that children born with NAS may
experience developmental delays, behavioral disorders, and are more likely to end up in foster
care.36 The full impact of neonatal abstinence syndrome on a child’s long-term development is
34
CDC, “Implementation of a Statewide Surveillance System for Neonatal Abstinence Syndrome – Tennessee,
2013,” Morbidity and Mortality Weekly Report, 64(125), 2015, pp. 125-128.
35
“Addicted at Birth: Full Series,” Herald Courier, September 13, 2017 (https://www.heraldcourier.com/addicted-
at-birth-full-series/collection_9dc2e12e-98b8-11 percente2 percent80 percenta6/); see also, Rappleye, et al., op. cit.
36
Rappleye, et al., op. cit.; M. Fill, “Educational Disabilities Among Children Born With Neonatal Abstinence
Syndrome,” Pediatrics, 142(3), 2018, pp. 1-8.

Page 12
not yet known, but teachers in Northeast Tennessee are reporting behavioral problems in children
born with NAS, including, according to one local teacher, “impulsivity and lack of cooperation,”
trouble sitting down to complete a task, hyperactivity, and trouble paying attention.37 A Johnson
City pediatric occupational therapist stated that schools will soon need to prepare for students
entering with the effects of NAS, saying that it won’t be “more than five years for teachers to be
able to identify which kids had been drug-exposed at birth…I was talking with teachers at a
lunch for a pre-three school, and they made statements like ‘We know’ or ‘We know we’re
getting more of these kids,’ so it’s happening.”38
31. In addition to addressing the needs of children born with neonatal abstinence
syndrome, Northeast Tennessee schools are faced with other consequences of the opioid
epidemic, including parental opioid abuse, opioid-related adverse childhood experiences and
trauma, opioid-related overdoses in families and in the community, and adolescent opioid abuse.
In Unicoi County, a survey of school students found that the average age of the first use of a
prescription drug not prescribed to them is 13 years old.39 While discussing a drastic increase in
opioid prescribing rates, Tommy Farmer, an assistant special agent in charge of the Tennessee
Bureau of Investigation stated: “We're in jeopardy of losing an entire generation of our youth to
addiction if we don't get a grip on this…I mean that sincerely.”40
32. Other school measures show that the opioid epidemic is always at the forefront of
school concerns. Sullivan County Schools have begun stocking naloxone, and the Sullivan
County Children’s Advocacy Center is preparing to host a seminar in October called, “Impact of
the Innocent: The Lasting Effect of the Opioid Crisis on Our Youth.”41 Johnson City Mayor
Jenny Block recently announced the “Healthy Tennessee Challenge,” which invites high school
37
J. Nocera, “Local Schools Don’t Have NAS Diagnosis as Priority,” Bristol Herald Courier, September 7, 2017.
38
Ibid.
39
K. Groner, “‘Addiction can last a lifetime’: Officials discuss opioid crisis at community forum,” Erwin Record,
May 4, 2018 (https://www.erwinrecord.net/featured-news/addiction-can-last-lifetime-officials-discuss-opioid-crisis-
community-forum/?_sf_s=opioid).
40
“Report: Pill Prescriptions surging in Tennessee” TN Ledger, May 18, 2012 (https://www.tnledger.com/
editorial/article.aspx?id=59373).
41
L. Spell, “Sullivan County Schools to Stock Opioid Antidote Narcan”, Bristol Herald Courier, September 8, 2018
(http://cacsctn.org/events/fall19/); Children's Advocacy Center of Sullivan County, 2019 Fall Seminar: “Impact on
the innocent: The lasting effect of the opioid crisis on our youth,” http://cacsctn.org/events/fall19/.

Page 13
students to design their own plan to educate people about the dangers of opioid abuse.42 Carter
County school children decorated 12 houses to spotlight the 12 overdoses in the county and the
impact of overdose on families, while school students in Unicoi County participated in an art
competition to design anti-drug billboards. The winning billboard is now on display in Erwin,
Tennessee.
33. The opioid crisis is having a severe economic impact as well. The University of
Tennessee has recently issued a study indicating that “[p]rescription opioids may explain up to
half of the decline in labor force participation since 2000.”43 Dr. Jon Smith, director of East
Tennessee State University’s Bureau of Business and Economic Research, stated:
We frequently think about this opioid epidemic in terms of lives shattered, which
is, of course, the most important thing…But, the impact this has on communities,
especially rural communities like ours, it’s just horrific. It not only affects the
people who are condemned by addiction, but it has a serious impact on the ability
of our economy to produce wealth and make lives better.44
Washington County, Tennessee, Mayor Dan Eldridge reported that when companies consider
locating to his county, they often ask specifically if the workforce can routinely pass drug tests.45
Employers in the area report that job interviews sometimes end abruptly when a drug test is
mentioned. Many employers attend seminars regarding opioid use disorder in the workplace and
change company policies to allow for opioid use disorder.46
B. Paykamian, “Mayor Encourages Youth to Take Leadership in Fighting Opioid Crisis,” Johnson City Press,
42
Mar 8, 2019.
43
“High Rates of Opioid Prescriptions May Be Linked to Poor Labor Force Participation,” University of Tennessee,
Press Release, January 28, 2019 (https://news.utk.edu/2019/01/28/high-rates-of-opioid-prescriptions-may-be-linked-
to-poor-labor-force-participation/).
44
“Another Reason Opioids Are Killing Americans,” Johnson City Press, February 6, 2019
(https://www.johnsoncitypress.com/Editorial/2019/02/06/Another-reason-opioids-are-killing-
America.html?ci=content&lp=4&p=1).
45
Statement of Earl Gohl Federal Co-Chair, Appalachian Regional Commission, Before the House Subcommittee
on Economic Development, Public Buildings and Emergency Management, House Committee on Transportation
and Infrastructure, December 12, 2017,
http://www.arc.gov/images/newsroom/testimony/FederalCoChairEarlGohlTestimonyOnOpioids12-11-2017.pdf.
46
See e.g., D. McGee, “Firms Address Their Response to Opioids in the Workplace,” Bristol Herald Courier, April
11, 2019 (https://www.heraldcourier.com/news/firms-address-their-response-to-opioids-in-the-
workplace/article_9b381f6d-6d52-5708-870a-02ce1ac19423.html); J. McGee, “Opioid Epidemic’s ‘Collateral
Damage’: When a Drug-Free Workplace Doesn’t Exist,” The Tennessean, December 21, 2017.

Page 14
34. The opioid epidemic often seems to dominate public debate. Every newspaper in
Northeast Tennessee has featured numerous stories regarding the opioid epidemic, and every
county has held a town hall or public forum to discuss the opioid epidemic.47 Local politicians
have detailed positions on the opioid situation, and state politicians regularly single out the
region as the area most affected by the opioid epidemic in Tennessee.
IV. Opioid Use Disorder
A. Addiction, Opioids and the Underlying Neurobiology
35. The American Society of Addiction Medicine defines addiction as follows:
Addiction is a primary, chronic disease of brain reward, motivation, memory and

related circuitry. Dysfunction in these circuits leads to characteristic biological,
psychological, social and spiritual manifestations. This is reflected in an
individual pathologically pursuing reward and/or relief by substance use and other
behaviors. Addiction is characterized by inability to consistently abstain,
impairment in behavioral control, craving, diminished recognition of significant
problems with one’s behaviors and interpersonal relationships, and a
dysfunctional emotional response. Like other chronic diseases, addiction often
involves cycles of relapse and remission. Without treatment or engagement in
recovery activities, addiction is progressive and can result in disability or
premature death.48
36. Important elements of this definition are that addiction is a chronic, relapsing
disorder and that the addicted individual demonstrates pathological pursuit of a reward caused by
use of the “substance” even though such behavior appears contrary to that person’s own interest.
This indicates that judgment has been suspended. A logical question to ask is: how could this
situation come about?
47
See e.g., B. Bailey, “Two Tennessee counties to host anti-drug forums,” WYCB, April 23, 2019
(https://wcyb.com/news/local/two-tennessee-counties-to-host-anti-drug-forums); M. Ward, “ACTION Coalition
hosts Town Hall on opioids abuse,” The Tomahawk, September 12, 2018 (https://www.thetomahawk.com/featured-
news/action-coalition-hosts-town-hall-on-opioids-abuse/); “Confronting Carter County’s Opioid Crisis,” The
Elizabethton Star, August 7, 2017 (https://www.elizabethton.com/2017/08/07/confronting-carter-countys-opioid-
crisis/).
48
American Society of Addiction Medicine (ASAM), “Public Policy Statement: Definition of Addiction,”
(https://www.asam.org/docs/default-source/public-policy-statements/1definition_of_addiction_long_4-
11.pdf?sfvrsn=a8f64512_4. )

Page 15
37. Opioids are compounds (derived from natural substances or synthetic processes)
which exert effects throughout the body, but especially in the brain that impact behavior and
cognition. Heroin and morphine are examples of compounds called opiates (which are opioids
derived from natural substances). OxyContin is a synthetically produced opioid that has similar
properties to heroin and morphine. A list of opiates and opioids that have been used for
medicinal and illicit purposes is below:
Opiates
• Naturally occurring substances from opium poppy

• Morphine, codeine, heroin, opium
Opioids
• Synthetic or partly synthetic compounds mimicking structure of opiates

• Methadone
• Percocet, Percodan, OxyContin (oxycodone)
• Vicodin, Lorcet, Lortab (hydrocodone)
• Demerol (pethidine)
• Dilaudid (hydromorphone)
• Duragesic (fentanyl)
38. What do these molecules have in common? Heroin, morphine and OxyContin
exert their influence by binding to molecules on the surface of cells in the body called receptors.
Receptors are acceptor sites for signals from the internal or external environment that change
cellular properties by triggering intracellular signal transduction mechanisms. These changes
result in cellular activation/perturbation with release of mediators systemically as well as local
neurotransmitters that allow the body to respond to environmental stimuli.
39. In the case of opioids, there are specific receptors that bind and are activated by
this class of molecules (opioids). These receptors are broadly distributed in neuronal tissues,
both in the central (brain and spinal cord) and peripheral nervous systems. Opioid receptors
come in several types, delta, kappa, mu (classical receptors), and ORL-1 (nonclassical). When
an opioid ligand occupies an opioid receptor, cellular activation takes place via a group of
intracellular proteins call G-proteins. G-proteins function as signal transducers that translate the
signal of receptor occupancy at the cell surface (an opioid has “landed” on the receptor) into a
change in cellular behavior.

Page 16
40. Of course, the opioid–opioid receptor system has not evolved solely to interact
with illicit drugs. Rather, there is an endogenous opioid system that mediates complex social
behavior such as formation of stable, emotionally committed relationships. In order for this to
occur, the body produces a variety of endogenous opioids: dynorphins, enkephalins, endorphins,
endomorphins and nociception. Thus, taking opioid drugs hijacks an endogenous system in the
body that was designed for a quite different purpose; subtle modulation of complex behaviors.
41. The mu opioid receptor is the primary molecular target for heroin, morphine and
other opioids in vivo. It mediates both the apparently beneficial and adverse effects of the most
broadly used opiates. It also appears to mediate the rewarding properties of certain nonopioid
drugs of abuse such as cannabinoids, alcohol and nicotine, as well as natural reinforcers, such as
social interactions. Thus, the mu opioid receptor represents a key molecular trigger for reward
and most likely contributes to the initiation of addictive behaviors.
42. Drugs of addiction affect the “reward circuit” in the brain by flooding it with
dopamine. In the case of opiates, this occurs especially via the mu opioid receptor. In the case
of stimulants such as methamphetamine, dopamine is also released, but using different molecular
mechanisms. Overstimulation with dopamine is responsible for the “high” leading to repetitive
drug intake. Over time, cells in the midbrain and striatum (brain subregions) adjust to the excess
dopamine by reducing response of cells in the reward circuit. This leads to tolerance. In the
clinical setting, this leads patients to seek increased amount of drug intake in order to stimulate
activity of cells in the reward circuit. Brain imaging has shown profound alterations in
expression of opioid receptors and distribution of dopamine.
43. At the core of these changes in brain function is the concept of synaptic plasticity.
Synapses are interconnections among neurons (brain cells) that lead to rapid cell-cell
communication and eventual remodeling of synaptic connections and activity in response to
stimulation. These changes have an important impact on learning, memory, behavior, etc.
Synaptic plasticity has been defined as “the ability of synapses to strengthen or weaken over
time, in response to increases or decreases in their activity.”49
49
J. Hughes, "Post-tetanic Potentiation," Physiological Reviews, 38 (1), 1958, pp. 91–113.

Page 17
44. Opioids and opiates stimulate synaptic activity through activation of the mu
opioid receptor, and, thus, synaptic plasticity is an important part of the evolving response.
45. There are no specific receptors or pathways that have been “designed” for these
drugs, but there are natural mechanisms that they interact with and modulate, significantly
altering normal physiology of multiple systems. Thus, opioid drugs (illicit or obtained
legitimately) hijack an endogenous system in the body created for a quite different purpose, as
mentioned previously.
46. The next logical question is: what happens when an individual ceases to take
opioids? Does brain chemistry and circuity go back to what it was before exposure to these
agents? Unfortunately, the answer to this question is not known definitively for any given
individual. Since the extent of changes induced by opioids in neurons is not fully understood, it
is difficult to be certain that full reversibility of these changes has occurred. Furthermore, the
issue with regard to the duration of the effects caused by opioids is similarly vague when it
comes to individuals. From a behavioral standpoint, there appear to be longstanding changes,
and these are, undoubtedly, associated with long-term changes in brain function. This
supposition is supported by the results of brain imaging studies. This is the reason that opioid
use disorder is considered a chronic disease.
47. It is also for this reason that efforts to curb opioid prescriptions carried out in the
absence of efforts to expand access to treatment do not result in amelioration of morbidity and
mortality of opioid use disorder, though the number of prescriptions does decrease. It is because
patients addicted to opioids will seek out the drug regardless of where and how they get it.
Furthermore, treatment for opioid use disorder must be long-term, as the changes in brain and
behavior are likely long-term as well.
B. A Chronic, Relapsing Condition
48. Addiction is a chronic, relapsing disorder characterized by compulsive drug

seeking, continued use despite harmful consequences, and long-lasting changes in the brain.50
50
See A.T. McLellan, et al., “Drug Dependence, a Chronic Medical Illness: Implications for Treatment, Insurance,
and Outcomes Evaluation,” JAMA, 284(13), 2000, pp.1689–1695.

Page 18
While certain factors predispose a person to addiction, it is widely agreed that “anyone who takes
prescription opioids can become addicted to them.”51
49. Relapses, periods in which a patient returns to elicit drug use and
ceases treatment, can be devastating for the individual because the loss of “capital” accumulated
in several domains (health and well-being, social, financial, legal), as mentioned
previously. However, following a period of relapse a patient can often be drawn back into
treatment by the same persuasive approach used for the initial treatment. Relapse must be
considered because it can occur frequently, and the risk of relapse remains for many years.
50. In patients in treatment with either buprenorphine or methadone medication-

assisted treatment, attrition is steepest in the first nine months with about 35-40 percent relapsing
in the methadone group and 55-60 percent relapsing in the buprenorphine group.52 However,
from months 11 to 60, the two groups become indistinguishable with about a 50 percent relapse
rate.53 When the data is analyzed differently, assessing days of illicit use per month, it
appeared that patients treated with buprenorphine-medication-assisted treatment had more
days of illicit opioid use per month (7-12 days per month) during months 4-20 of treatment than
those with methadone-medication-assisted treatment.54 However, by month 22, the groups
were indistinguishable through the remainder of the study, 60 months.55 Another study
compared patients on buprenorphine-medication-assisted treatment at three different doses, low
(<16 mg) medium >16 and <24 mg) and high (>24 mg).56 Individuals on low
dose buprenorphine had the greatest number of relapses (which occurred at the highest level in
year 1), and those on the highest dose consistently had the least relapses.57 These data
demonstrate a constant risk of relapse, even if it is lower in patients treated with medication-
assisted treatment.
51
CDC, “Opioid Overdose” (https://www.cdc.gov/drugoverdose/opioids/
prescribed.html).
Y. Hser, et al., “Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a
52
multi-site trial,” Addiction, 111(4), 2016, pp. 695–705.

53
Ibid.
54
Ibid.
55
Ibid.
56
Ibid.
57
Ibid.

Page 19
V. Treatment Principles
A. A Chronic Care Model
51. Despite all the hallmarks of a chronic disease, addiction has been removed from
typical medical practice and confined to “treatment programs.” A 2014 National Institute on
Drug Abuse Consensus Group summarized the issue as follows:
Addictions have historically been misunderstood by the public as a bad habit,

hedonism or a moral failing—not as an acquired health condition. Evidence of
genetic vulnerability to nicotine, alcohol, opioid and other substance addictions;
and persistent brain changes following heavy use of many substances have
suggested that many addictions are best considered as acquired illnesses. In turn,
because there is now evidence that long-term treatments can be effective in
managing—but not curing—addictions, it is reasonable to think of these
as chronic illnesses.
But addictions have never been treated, insured or evaluated like other chronic
illnesses. Since the late 1960s, addictions have been treated as acute conditions, in
specialty addiction treatment programs which are segregated geographically,
financially and culturally from the rest of general healthcare. This segregation has
contributed to willful inattention by physicians to the pervasive substance use
problems that occur in every medical setting. Addictions occur in eight to 11
percent of the general United States adult population, but are found in 20 percent
of patients in US primary care settings and over 50 percent of patients in US
hospital, emergency room and trauma centers.58
52. Based on the scientific conceptualization of addiction, the Institute of Medicine

and leading addiction researchers have called for a shift in the treatment of substance use
disorders from the prevalent acute care model to a continuum of care model akin to that used in
other chronic conditions.59 A Chronic Care Model is “a patient-centered model of care that
involves longitudinal care delivery; integrated, and coordinated primary medical and specialty
care; patient and clinician education; explicit evidence-based care plans; and expert care
availability” and incorporates mental health and specialty addiction care.60 The core elements of
58
A.T. McLellan, et al., “Can Substance Use Disorders be Managed Using the Chronic Care Model? Review and
Recommendations from a NIDA Consensus Group,” Public Health Reviews, 35(2), 2014.
59
K. Humphreys, et al., “Toward more responsive and effective intervention systems for alcohol-related problems,”
Addiction, 97, 2002, pp.126-132.
60
R. Saitz, et al., “The case for chronic disease management for addiction,” Journal of Addiction Medicine, 2(2),
2008, pp. 55–65.

Page 20
the Chronic Care Model are healthcare delivery system design, expert-informed decision
support; clinical information systems; and self-management support.61
53. Delivery system design refers to the use of multidisciplinary teams, patient
reminders, on-site service delivery of care, and collaboration between addiction, medical, and
psychiatric providers.62 This element includes use of multidisciplinary teams, including a nurse
care manager, a social worker, and clinicians with expertise in the disease of interest and
common comorbidities. These team members can spend time with the patient, coordinate with
primary care physicians (PCPs), address necessary releases of information, facilitate specialist
referrals, provide access to community resources, implement evidence-based protocols,
encourage self-management, and be proactive about follow-up.63
54. Expert-informed decision support to primary care teams can include provider
education, facilitated expert consultation, standardized assessment tools, and evidence-based
treatment algorithms.64 These decision supports are used by primary care teams in cardiology,
oncology and diabetes care and are likely more important in the addiction context, where non-
addiction specialists are ill-equipped to handle patients with active addiction.65
55. Clinical information sharing across team members, primary care clinicians, and
specialists can be achieved by using electronic records creating virtual colocation of care even
when clinicians are in separate physical locations. This same information, when aggregated in a
registry, can support the attention of the team to individual patients who have not received
needed care and to clinical outcomes. Proactive engagement through electronic (message, text)
or voice (phone) reminders and follow-up contacts, has produced improved patient retention,
care participation and lower relapse rates among out-patients in substance abuse treatment.66
61
Ibid.; McLellan, et al. (2014), op. cit.
62
Ibid.
63
Ibid.
64
McLellan, et al. (2014), op. cit.
65
Ibid.
J.R. McKay et al., “The Effectiveness of Telephone Based Continuing Care for Alcohol and Cocaine
66
Dependence: 24 Month Outcomes,” Archives of Geneneral Psychiatry, 62, 2005, pp. 199–207.

Page 21
56. Clinical techniques such as Motivational Interviewing – an empathic, respectful,
collaborative approach to promoting behavior change – have reliably produced significant and
long-lasting reductions in substance use and related unhealthy behaviors. Psychosocial treatment
falls under this category as well.
B. Medication Assisted Treatment and Abstinence
57. There are four treatments that have been utilized for treating patients with opioid
use disorder or addiction to opioids:
58. Abstinence. The patient takes no opioid of any kind. Abstinence-based therapy
is associated with a higher relapse rate than medication-assisted treatment. There is an 80
percent relapse rate within a month after discharge from a detoxification program. Even
enriched detoxification programs fail to improve outcomes compared to medication-assisted
treatment. In certain limited populations, such as addicted physicians and airline pilots (where
revocation of a professional license is a consequence of relapse and strong support systems and
resources tend to be present), there is a higher probability of success: a 79 percent abstinence rate
at 5 years is reported.
59. Medication-assisted treatment. The patient takes one of three medicines below
and is closely monitored. Often, provision of the medicine is accompanied by
counseling. Ideally, the patient is evaluated simultaneously for physical health, mental health,
addiction issues and social determinants of health (housing, family issues, workforce
preparedness/job placement, benefits eligibility, legal issues). Addressing this constellation of
issues constitutes a “wraparound” or “integrated” model of holistic care. I utilize this model of
integrated care in my clinic because I believe that it provides the greatest opportunity for patients
to enter treatment and achieve durable recovery.
a. Methadone. According to this approach, the patient takes the drug

methadone and, often, receives it with some (but not all) of the
components of integrated care. Methadone is distributed only in specially
licensed centers. The drug is closely regulated by the DEA. Methadone
fully stimulates the opioid receptor (thus, methadone is an opioid), and
taking a high enough dose can result in a “high,” as occurs with

Page 22
heroin. Methadone dispensed from a methadone program is legal and
therapy can be long-term resulting in a stable life, from the perspective of
the workplace, housing, family, etc. This is the most longstanding opioid
agonist therapy and was introduced in the 1960s. The main disadvantage
of methadone is the need to come to a clinic for daily dosing early in the
course of treatment. As one might imagine, this is very
inconvenient. Over time, patients are given doses of methadone to take
home, and they do not need to return as frequently.
b. Buprenorphine. According to this treatment, the patient takes the drug

buprenorphine and often receives it with some (but not all) of the
components of integrated care. Buprenorphine (and related
buprenorphine-containing products) partially stimulates the mu opioid
receptor (it is called a partial agonist). While it controls craving and
prevents withdrawal symptoms, it does not normally produce the “high”
associated with heroin, as it is only a partial stimulator of the mu opioid
receptor. Since buprenorphine does stimulate the opioid receptor (though
less effectively than heroin or methadone), it is an opioid. Long-term
treatment with buprenorphine can result in a stable life, as with
methadone. Buprenorphine is more easily available than methadone, as
any licensed physician can take a short course, lasting eight hours, on-line,
that allows her/him to prescribe buprenorphine. Buprenorphine was
introduced in 2002, so the clinical experience with this therapy is shorter
than with methadone.
c. Naltrexone. According to this treatment, the patient takes the drug

naltrexone and, often receives it with some (but not all) of the components
of integrated care. Naltrexone is an antagonist (a blocker) of the mu
opioid receptor. Therefore, naltrexone prevents activation of the
receptor by opioids (and the patient cannot get “high”). If a patient is
taking opioids and receives naltrexone, she/he will be thrown into
withdrawal. This is why patients are not given naltrexone until a
significant period after the last possible use of an opioid. Naltrexone is

Page 23
not an opioid. Any physician can prescribe naltrexone. It is generally
given by injection once per month. One important caveat with naltrexone
is that if the patient stops the medicine, that individual is very vulnerable
to relapse. The reason for this is that the patient has not been exposed to
an opioid during the time on naltrexone and has lost previously acquired
tolerance to an opioid such as heroin. Thus, taking the “old” dose of
opioid could result in a fatal overdose.
60. In general, it is difficult to determine which treatment will be optimal for a

particular patient. For example, a patient may elect to try abstinence and find that multiple
relapses occur. Following that, the patient may desire medication-assisted
treatment. Medication-assisted treatment could be done with either methadone, buprenorphine
or naltrexone. Patient preference is important in determining the choice for the same reason: a
priori, the physician will not know the best drug for medication-assisted treatment for that
patient. Sometimes, a patient may opt for one drug and then, after a time, desire to switch to
another agent. That is perfectly reasonable and occurs with regularity.
61. In sum, there are strong advantages of medication-assisted treatment for patients
undergoing this therapy versus abstinence/no therapy:
 Decreased opioid use,
 Decreased opioid-related overdose deaths,
 Decreased criminal activity – decreased contact with the criminal justice system,
 Decreased infectious disease transmission (HIV, hepatitis C, bacterial

endocarditis, osteomyelitis, etc.),
 Increased social functioning,
 Retention in treatment, and

Page 24
 Decreased occurrence of neonatal abstinence syndrome and decreased length of stay for
newborns in the neonatal intensive care unit.67
62. Accordingly, leading medical and public health organizations support medication-
assisted treatment for treatment of opioid use disorder, including the American Medical
Association; American Academy of Family Physicians; American Society of Addiction
Medicine; National Institute on Drug Abuse; National Academies of Sciences and Engineering;
CDC; the Food and Drug Administration (FDA); and the Substance Abuse and Mental Health
Services Administration (SAMHSA).68
C. Long-Term Care
63. The fundamental reason why short-term care for patients with opioid use disorder
is inadequate derives from the chronic nature of the underlying changes in brain function
consequent to exposure to opioids. These changes in brain function lead to the continued
dependence on opioids, including intravenously administered heroin, and multiple
medical/mental health complications that result in a complex clinical course for patients. Since
there is no consistent data on the time required for a given person to “recover” from the chronic
brain disease of opioid use disorder, it has become clear that treatment needs to be long-term. In
many cases it is likely to be required for the duration of an individual’s life. Some patients may
be able to successfully stop treatment and remain free of illicit drug use, but for others achieving
sustained sobriety is a continual challenge. For example, if one asks an individual who has been
in recovery for 10 years or more if the challenge of addiction is still with her/him, the answer
67
P. Schwartz, et al., “Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995-2009,”
American Journal of Public Health, 103(5), 2013, pp. 917–922; R.P. Mattick, et al., “Methadone maintenance therapy
versus no opioid replacement therapy for opioid dependence,” Cochrane Database of Systematic Reviews, 3, 2009.
68
See American Academy of Family Physicians and American Medical Association (AMA), “The AMA and AAFP
Urge Removing All Barriers toTreatment for Substance Use Disorder”
(https://www.aafp.org/dam/AAFP/documents/advocacy/prevention/risk/BKG-AMA-AAFP-MAT.pdf); AMA,
“With opioid deaths increasing, AMA urges expansion of proven treatment” (https://www.ama-assn.org/press-
center/press-releases/opioid-deaths-increasing-ama-urges-expansion-proven-treatment); ASAM, “The ASAM
National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use,” 2015
(http://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-
guideline-supplement.pdf?sfvrsn=24); and U.S. Department of Health and Human Services, “Addressing
Prescription Drug Abuse in the United States: Current Activities and Future Opportunities,” 2013
(https://www.cdc.gov/drugoverdose/pdf/ hhs_prescription_drug_abuse_report_09.2013.pdf); NIDA, “Effective
Treatments for Opioid Addiction,” 2016 (https://www.drugabuse.gov/effective-treatments-opioid-addiction-0).

Page 25
will most likely be, “I have been in recovery for 11 years, 3 months and 2 days. Every day is a
challenge not to ‘use,’ but I meet that challenge and have achieved a good life for myself and
loved ones.”
64. The National Academies of Sciences, Engineering & Medicine (NASEM),

observed:
[M]ultiple studies with longer-term follow-up indicate that extending treatment

for years allows individuals to increase their opportunities to return to work, to
regain their health, to avoid involvement with the criminal justice system, and to
establish supportive networks of non-drug-using individuals.69
65. The National Institute on Drug Abuse (NIDA) states:
Individuals progress through drug addiction treatment at various rates, so there is

no predetermined length of treatment. However, research has shown
unequivocally that good outcomes are contingent on adequate treatment length.
Generally, for residential or outpatient treatment, participation for less than 90
days is of limited effectiveness, and treatment lasting significantly longer is
recommended for maintaining positive outcomes. For methadone maintenance, 12
months is considered the minimum, and some opioid-addicted individuals
continue to benefit from methadone maintenance for many years.70
66. Citing the National Institute of Health’s National Consensus Development Panel
on Effective Medical Treatment of Opiate Addiction, Facing Addiction in America: The Surgeon
General’s Spotlight on Opioids states:
MAT patients with an opioid use disorder must be delivered for an adequate
duration in order to be effective. Patients who receive MAT for fewer than 90
days have not shown improved outcomes. One study suggested that individuals
who receive MAT for fewer than 3 years are more likely to relapse than those
who are in treatment for 3 or more years.71
67. Though long-term treatment is widely acknowledged to be the appropriate course

for individuals suffering from opioid addiction, individuals are regularly treated by a short-term
program of 30 days or less.
69
National Academies of Sciences, Engineering, and Medicine, Medications for opioid use disorder save lives,
National Academies Press: Washington, D.C., 2019.
70
NIDA, “Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition),” January 2018
(https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition).
71
U.S. Department of Health and Human Services, Office of the Surgeon General, “Facing Addiction in America:
The Surgeon General’s Spotlight on Opioids,” September 2018.

Page 26
D. A Continuum of Care
68. Treatment according to the Chronic Care Model includes routine assessment and
treatment customized to the needs and preferences of the individual patient. The patient’s status
and risk of relapse is monitored systematically and longitudinally, and the intensity of treatment
is adjusted as the addiction presents over time. There are multiple, well-established guidelines
that assist practitioners in determining the level of care for patients. The most-frequently used
guidelines were developed by the American Society of Addiction Medicine (“ASAM”). The
guidelines describe treatment for opioid use disorder as a continuum marked by four broad levels
of services and an early intervention level.72
69. The treatment setting described as level 1 may be a general outpatient location
such as a clinician's practice site. General outpatient treatment involves less than nine hours of
service per week for adults or less than six hours per week for adolescents. Opioid treatment
programs (“OTPs”) offer daily supervised dosing of methadone, and increasingly buprenorphine
is offered as well. In accordance with the Federal law (21 CFR § 1306.07), office-based opioid
treatment (“OBOT”), which provides medication on a prescribed weekly or monthly basis, is
limited to buprenorphine. Naltrexone can be prescribed in any setting by any clinician with the
authority to prescribe any medication.
70. The setting described as level 2 in the ASAM Criteria may be an intensive
outpatient treatment (“IOP”) or partial hospitalization program (“PHP”) housed in a specialty
addiction treatment facility, a community mental health center, or another setting. IOP involves
at least nine hours of services per week for adults or a minimum of six hours a week for
adolescents. PHP involves 20 or more hours of services per week, but 24-hour care is not
required.
71. The ASAM Criteria describes level 3 or level 4, respectively, at a residential

addiction treatment facility or hospital. Residential treatment involves 24-hour care at a facility
with professionally trained counselors. Services during residential treatment may be less
intensive, but more environmentally controlled and opportunities for group therapy and
discussion provides the assistance needed for some patients. Factors influencing whether
72
ASAM, “What are the ASAM Levels of Care?” ASAM Continuum, 2015. (https://www.asamcontinuum.org/
knowledgebase/what-are-the-asam-levelsof-care).

Page 27
patients need longer-term residential treatment include the presence of a psychiatric dual
diagnosis, more extensive morbidity from the opioid use disorder, a lack of stable sober support
in the community, and the degree to which the opiate use disorder has progressed in severity.
72. Residential treatment can be short-term (less than 30 days) or long-term (more
than 90 days). In practice, the terms of residential treatment are dictated by what insurance will
cover, which, in Northeast Tennessee, usually means short-term treatment. Practitioners
generally agree that the 28-day treatment model is ineffective and not based on scientific
evidence.73 Kimberly Johnson, former director of SAMHSA’s Center for Substance Abuse
Treatment stated: “As far as I know, there’s nothing magical about 28 days.”74 Residential
treatment centers were created to treat alcohol addiction and employed a protocol known as the
“Minnesota Model,” which involved four weeks of stabilization and abstinence.75 Though
residential treatment facilities have long been used to treat a variety of other substance use
disorders, this approach has continued to be the norm despite evidence that opioid use disorder
requires more intensive medical, psychological, and social support services over a longer period
of time than alcohol use disorder.76 Residential treatment can be a valuable part of the
continuum of care for opioid use disorder; however, in most residential treatment settings,
medication-assisted treatment has been viewed as incompatible with this traditionally abstinence-
based approach, causing the two treatment models to develop and operate separately from one
another.77 Over time, the benefits of medication-assisted treatment have prompted efforts to
integrate these approaches, and some residential treatment programs have revised their practices
to accommodate evidence-based treatment and patients’ preference.78
73
See, e.g., S. Roan, “The 30-Day Myth,” LA Times, November 10, 2008 (https://www.latimes.com/archives/la-
xpm-2008-nov-10-he-addiction10-story.html); B. Allen, “Rehab for Addiction Usually Lasts 28 Days. But Why?”
NPR, October 7, 2016 (https://www.npr.org/sections/health-shots/2016/10/01/495031077/how-we-got-here-treating-
addiction-in-28-days).
74
Allen, op. cit.
75
Ibid; J. Spicer, The Minnesota Model: The Evolution of the Interdisciplinary Approach to Addiction Recovery,
Center City, MN: Hazelden Educational Materials, 1993.
76
L. Hoffman et al., “Recovery from Opioid Problems in the US Population.” Journal of Addiction Medicine, 2019.
T. Chen, et al., “Residential Treatment Modifications: Adjunctive Services to Accommodate Clients on
77
Methadone,” American Journal of Drug and Alcohol Abuse, 35, 2009; pp. 91–94.
Ibid.; B. Greenberg, et al., “Methadone Maintenance Therapy in Residential Therapeutic Community Settings:
78
Challenges and Promise,” Journal of Psychoactive Drugs, 39(3), 2007, pp. 203-10; J.L. Sorensen, et al.,

Page 28
E. Psychosocial Treatment
73. Because OTP and OBOT regulations require some level of psychosocial treatment
alongside medication-assisted treatment, many researchers have studied the effect of
psychosocial treatment on outcomes. The most recent comprehensive systematic review of
findings on the role of psychosocial interventions in medication-assisted treatment concluded:
“The results generally support the efficacy of providing psychosocial interventions in
combination with medications to treat opioid addictions, although the incremental utility varied
across studies, outcomes, medications, and interventions.”79 Because people with opioid use
disorder have differing levels of severity and complexity and different backgrounds and
environmental stressors, psychosocial treatment should be flexible and tailored to each patient,
and it should embrace a “whole-person” approach. In addition, trauma-informed care, which
takes into account the patient’s ACE (adverse childhood experience) score, has proven value.80
F. Recovery Support Services
74. A recovery-oriented system of care is “a coordinated network of community-

based services and supports that is person-centered and builds on the strengths and resiliencies of
individuals, families, and communities to achieve abstinence and improved health, wellness, and
quality of life for those with or at risk” of substance use disorder.81
75. Recovery support services are nonclinical services that assist individuals and
families to recover from opioid use disorder, including social support, linkage to and
coordination among allied service providers, and a full range of human services that facilitate
“Methadone Patients in the Therapeutic Community: A Test Of Equivalency,” Drug and Alcohol Dependence,
100(1-2), 2009, pp.100–106.
K. Dugosh, et al., “A Systematic Review on the Use of Psychosocial Interventions in Conjunction with
79
Medications for the Treatment of Opioid Addiction,” Journal of Addiction Medicine, 10(2), 2016, pp. 93–103.
80
See, e.g., K. Quinn, et al., “The relationship of childhood trauma and adult prescription pain reliever misuse and
injection drug use,” Drug and Alcohol Dependence, 169, 2016, pp.190-198; R.A. Sansone, et al., “The Prevalence
of Childhood Trauma Among Those Seeking Buprenorphine Treatment,” Journal of Addictive Diseases, 28(1),
2009, pp. 64-67; E Davids, et al., “Childhood Trauma and Later Opioid Dependence,” Krankenhauspsychiatrie,
17(3), 2006, pp. 92-95.
81
SAMHSA, “Recovery-Oriented Systems of Care Resource Guide,” 2010 (https://www.samhsa.gov/sites/
default/files/rosc_resource_guide_book.pdf).

Page 29
recovery and wellness contributing to an improved quality of life.82 Recovery support services
may include: employment services and job training; case management and individual services
coordination, such as social services, legal issues, driver’s license procurement, and benefits;
housing assistance; child care; transportation to and from treatment; peer services; self-help and
support groups; life skills training; and education.83 Recovery support services are often
accessed by the case manager on behalf of the patient. The case manager is, in a sense, a
navigator for the patient in accessing the different services that help to rebuild a life and create a
foundation of durable recovery.
76. Case management is an important aspect of care for the patient with opioid use
disorder.84 Often a patient has “reached bottom” when the individual comes into treatment. This
is often characterized by loss of family, housing, work, financial independence and anything else
that an individual might value. When a person reaches this state, the case manager reconstructs
each aspect of the individual’s life in multiple domains in a very concrete way. For example, the
case manager can be actively engaged in assisting a patient to secure housing, a new job, a
driver’s license, benefits, or other services. Intensive case management has resulted in
significantly higher levels of substance abuse treatment initiation, engagement and retention
compared with usual care.85
VI. Barriers to Care and “The Treatment Gap”
77. In Northeast Tennessee, the treatment gap for patients with opioid use disorder is
enormous. The reasons for this gap are several:
L. Kaplan, “The Role of Recovery Support Services in Recovery-Oriented Systems of Care,” SAMHSA, 2008,
82
DHHS Publication No. (SMA) 08-4315.

83
Ibid.
84
See, e.g., W. Vanderplasschen, et al., “A Meta-Analysis of the Efficacy of Case Management for Substance Use
Disorders: A Recovery Perspective,” Frontiers in Psychiatry, 10(186), 2019.
85
J. Morgenstern, et al., “Effectiveness of Intensive Case Management for Substance-Dependent Women Receiving
Temporary Assistance For Needy Families.” American Journal of Public Health, 96(11), 2006, pp. 2016–2023.

Page 30
78. Lack of capacity. There is only one Opioid Treatment Program serving the
entire Northeast Tennessee region.86 Individuals in Northeast Tennessee report that some people
in the most rural parts of the state are travelling across state lines to Boone, North Carolina to
procure treatment.87 Some counties in Northeast Tennessee do not have a single buprenorphine-
waivered physician listed on SAMHSA’s website.88 Residential treatment facilities and recovery
housing options are extremely limited.
79. Accessibility of care. Providers in the market often will not accept new patients
or will only provide services on a cash basis, which makes them out of reach for many
individuals. The latter practice actually fuels the epidemic of opioid use disorder as it
contributes to a culture in which there is a lack of accountability for both patient and
provider. This is a situation in which a patient may use buprenorphine during the week and take
illicit drugs on the weekend. It also creates obstacles for low-income and/or uninsured patients
who are open to treatment. The most-accepted and evidence-based treatment, medication-
assisted treatment, is not widely accepted in Tennessee and the mid-South. For rural
populations, pregnant women, and those in jails and prisons, access to MAT is extremely limited.
80. Lack of expertise in addiction medicine in the medical profession. Much of

the care given by physicians is not evidence-based and is not oriented towards seeking a solution
for each patient they serve, and for the appropriate amount of time (which varies for each
person). In other words, care of poor quality leads to patients prematurely dropping out before
they derive maximum benefit. In many parts of the country, including Northeast Tennessee,
there are few board-certified addiction medicine specialist physicians offering medication-
assisted treatment with wraparound therapy, and access to them is limited. Furthermore, their
distribution is often limited to metropolitan areas with few addiction medicine specialists in rural
areas.
86
Tennessee Department of Mental Health and Substance Abuse Services (TDMHSAS), “Tennessee Opioid
Treatment Clinics,” February 2019, available at https://www.tn.gov/content/dam/tn/mentalhealth/
documents/Opioid%20Clinic%20Map%20Feb%202019.pdf
87
Personal conversation with Dr. Pack.
88
SAMHSA, Buprenorphine Provider Locator, https://www.samhsa.gov/medication-assisted-treatment/practitioner-
program-data/treatment-practitioner-locator?field_bup_physician_us_state_value=TN.

Page 31
81. Transportation. Transportation is regularly cited as one of the barriers to opioid
use disorder treatment. A small survey of Vermont OTP patients found that 23 percent missed at
least one visit due to lack of transportation and 8 percent due to transportation costs.89
Additionally, 22 percent reported that travel time to their OTP interfered with their ability to
maintain employment.90 Though TennCare Rides is technically available throughout Tennessee,
Northeast Tennessee residents report that the service is extremely unreliable and, when it does
arrive in a timely fashion, it can take a patient’s entire day to travel to and from their
appointment due to the large number of people it serves.91
82. Cost of treatment. In 2016, 19.9 million adults needed substance use treatment
but only 10.8 percent received specialty treatment; 26.9 percent of those who did not receive
specialty treatment, but perceived that they needed it, cited lack of healthcare coverage and
inability to afford the cost of treatment as reasons for non-treatment.92
83. Stigma. An individual’s stigma with regard to their OUD is fueled by four
factors: (1) public misperception of OUD as a moral and/or affirmative choice; (2) clinicians’
imperfect understanding of OUD and how it differs from other SUDs; (3) the pejorative language
used to describe OUD treatments; and (4) the criminal justice system’s failure to defer to medical
judgment regarding treatment.93 When health care providers and the general public manifest a
stigma against patients with addiction (i.e., “weak morals,” “lazy and unethical people”) this
serves as a barrier for patients seeking care. Patients who are attempting to hide their addiction
from loved ones or employers may fear entry into treatment, as it increases the likelihood that
people become aware of their disease.
84. Self-reliance or “I can handle this problem myself.” This attitude does not
recognize the chronic and profound nature of the disease that characterizes opioid use
89
S.C. Sigmon, “Access to Treatment for Opioid Dependence in Rural America: Challenges and Future Directions,”
JAMA Psychiatry, 71(4), 2014, pp. 359–360.
90
Ibid.
91
Based on my conversations with Northeast Tennessee residents.
92
E. Park-Lee,, et al., “Receipt of services for substance use and mental health issues among adults: Results from
the 2016 National Survey on Drug Use and Health,” NSDUH Data Review, September 2017, retrieved from
https://www.samhsa.gov/data/.
93
Y. Olsen and J.M. Sharfstein, “Confronting the Stigma of Opioid Use Disorder – and Its Treatment,” JAMA.
311(14), 2014, pp. 1393–1394.

Page 32
disorder. However, it is a part of the self-reliant character of people in the Appalachian region.
One fallacy of the “I can handle this problem myself” attitude is that it leads people to only
seek help when the situation spirals out of their control. For example, a small focus of cellulitis
can often be ignored and may resolve spontaneously. The same is not true of a blood-borne
infection due to contaminated needles introducing microbes into the general circulation, which
have the potential to seed a heart valve. The resulting endocarditis is a complex and expensive
medical/surgical problem in personal and economic terms. The same is true of an unintentional
overdose. It may at first appear to be a situation that can be handled by friends in the
community with a quick dose of naloxone, but suppression of respiration can quickly lead to a
critical “life or death” situation.
85. This is why emergency departments are focal points for care of patients with
opioid use disorder. The emergency department is an “equalizer” in that it treats all segments of
the opioid use disorder (and general) population without regard to insurance status, race,
ethnicity, gender, etc. Although the stigmatization of opioid use disorder makes patients harder
to identify, when they need the emergency department, there is no substitute and they appear for
treatment. It is for this reason that I consider the emergency department a vital space in which
individuals living with opioid use disorder could connect to key resources to begin their journey
towards treatment/recovery.
VII. Assets of the Region
86. Despite the foregoing, in preparing this plan, I found that the Northeast Tennessee
region has a number of assets that will facilitate implementation of a system-wide plan to combat
the opioid epidemic. Local communities are said to be on the “front lines” of the opioid
epidemic, in which case Northeast Tennessee has an impressive set of “foot soldiers.” Many
residents have taken initiative and created successful programs, and the area has implemented
evidence-based practices. These endeavors are inadequately funded and mostly on a small scale,
but they provide an infrastructure and could be extended and scaled up with additional funding.
87. Despite long-held beliefs about the nature of addiction in the region, many
officials are pragmatic and acknowledge that the traditional approach to addiction simply has not

Page 33
been effective. Officials are open to learning about proven methods from other regions and want
to actively address the problem.
88. Treatment and community-based resource services, to the extent available, are
siloed and not coordinated across counties and providers. However, key stakeholders in the
region already know each other and regularly meet, discuss solutions, and engage in healthy
debate. This cross-communication will assist in creating a systemic strategy to address the crisis.
VIII. Tennessee Recovery Enhanced Addiction Treatment (TREAT)
A. Approach
89. My approach “meets patients where they are” and brings individuals into an
environment that supports recovery. It is long-term and inclusive, as opioid use disorder is a
chronic brain disease that can be relapsing. Though medication-assisted treatment is an
important component, this plan is not yet another attempt to “sell” medication-assisted treatment
as the cure for addiction; rather, it represents a comprehensive, holistic approach that has a much
greater probability of success in the current Northeast Tennessee environment. In the words of
the project manager for a Johnson City sober living facility, “we are all about recycling and
repurposing so people can achieve their long-term goals for years.” This plan will allow people
the opportunity to reinvent themselves and achieve a quality of life that permits them to be
productive members of their communities.
90. Removing the most frequent barriers to recovery, the plan’s recovery support
services bring together: colleagues/friends, navigators/health advocates, mental and physical
healthcare providers, and case managers who attend to housing, transportation, legal issues, job
placement, and other key social problems. Housing and other support must be long-term so that
the individual builds “recovery capital” allowing fulfillment of aspirations and obligations. Easy
access to care is essential. Clients must be able to receive services in a timely manner,
administered by caregivers who understand opioid use disorder in addition to physical and
mental health issues. Adherence to this principle is absolutely necessary and a focal point of this
plan.

Page 34
91. The plan uses an integrated, “no-wrong-door” approach, which minimizes the
need to refer patients to care outside the program. This prevents opioid use disorder patients
with more complicated needs from becoming discouraged and giving up. Medication-assisted
treatment providers who cannot address underlying mental health conditions or polysubstance
abuse, which so often accompanies opioid use disorder, do patients a disservice by supplying
them with yet another phone number and appointment that needs to be made.
92. Treatment alone (including medication-assisted treatment) will not rebuild a life
that has been shattered by addiction. In the words of a patient in Johnson City, “you can’t cure
addiction with a pill.” Treatment is necessary but not sufficient to achieve recovery. A patient
prescribed medicine for addiction may no longer need to spend large sums of money and time
seeking out illicit drugs on a daily basis, but this hardly addresses all the challenges faced by
patients that can prevent long-term recovery. There are broken personal relationships to be
rebuilt. There are consequences of physical and emotional stress imposed by activities inherent
in “using.” There are financial realities that may result in garnishment of wages for a period of
time. One patient said to me, “your past stays with you when you are in treatment and
recovery.” The question is: can a long-term and future-oriented vision of recovery overcome the
issues facing individuals with opioid use disorder? A peer in long-term recovery from Northeast
Tennessee put it very well during our discussion: “when the pain of staying the same becomes
greater than the pain of change, then change will occur.” This inner voice motivating change
needs to grow within each individual moving out of illicit drug use, but without basic human
needs met, relapse and a return to old habits are more likely. Our approach emphasizes
providing tools to build a life in recovery.
93. Thus, medication-assisted treatment is an important tool, not a “be-all, end-all”

solution to the complicated, pervasive, and deeply entrenched Northeast Tennessee opioid
crisis. In fact, the region’s ongoing experience of pill mills facilitating the flood of prescription
opioids informs my approach to supplying medication-assisted treatment. Using a
buprenorphine waiver, secured from SAMHSA in an appropriate manner, some providers are
reportedly “selling” buprenorphine to patients with barely a cursory consideration of their
medical/mental health condition. As a result, medication-assisted treatment in many places in
Northeast Tennessee is not considered a therapy but a “pill for a pill.” A local law enforcement
official said, “Do you see [that operation] labelled ‘medication-assisted treatment clinic?’ Those

Page 35
docs are drug dealers.” My approach not only discourages this practice, but actively seeks to win
market share from such “cash clinics.” Eventually, I anticipate that this plan will displace them.
94. The plan is called the Tennessee Recovery Enhanced Addiction Treatment (or
“TREAT”) because the emphasis is on treating the whole patient to achieve long-term recovery.
It is much more than simply dispensing a medicine and sending a patient to therapy.
B. Development
95. This plan was developed after review of evidence-based practices and proven
models implemented in other regions and careful consideration of the current treatment
landscape in Northeast Tennessee. I selected and tailored best practices and approaches as
needed to fit the region’s opioid crisis. For example, Vermont’s “Hub and Spoke” system has
shown the necessity of system-wide coordination and continuity of care.94 Vermont has
achieved a high rate of treatment – 21.7 people per 1000 in treatment between the ages of 18 and
64, while providing comprehensive, long-term care.95 The Massachusetts care model has
expanded access to treatment through use of nurse care managers, and provides integrated,
coordinated care.96 I have incorporated a similar nursing program in the Northeast Tennessee
plan to provide more supportive, fully-integrated care.
96. Further, every aspect of the plan is designed to align with the elements of the
Chronic Care Model for addiction. Expert-informed decision support for providers is a core
94
J.R. Brooklyn and S.C. Sigmon, “Vermont Hub-and-Spoke Model of Care for Opioid Use Disorder:
Development, Implementation, and Impact,” Journal of Addiction Medicine, 11(4), 2017, pp. 286–292; R.A.
Rawson, et al., “Vermont Hub-and-Spoke Model of Care for Opioid Use Disorders: An Evaluation,” for the
Vermont Center on Behavior and Health, the University of Vermont, December 2017.
95
Vermont Department of Health, Opioids Scorecard, available at https://www.healthvermont.gov/scorecard-
opioids.
96
See C.T. LaBelle, et al., “Office-Based Opioid Treatment with Buprenorphine (OBOT-B): Statewide
Implementation of the Massachusetts Collaborative Care Model in Community Health Centers,” Journal of
Substance Abuse Treatment, 60, 2016, pp. 6–13; D.P. Alford, et al. “Collaborative care of opioid-addicted patients
in primary care using buprenorphine: five-year experience,” Archives of Internal Medicine, 171(5), 2011, pp. 425–
431.

Page 36
element of the Chronic Care Model, as are electronic medicine, psychosocial treatment, case
management, connection to community resources, and multidisciplinary teams.97
97. I studied efforts to engage individuals with opioid use disorder through (1)
primary care providers, OB/GYNs, hospitals, and emergency departments; (2) courts, jails, and
prisons; and (3) schools, churches, and employers. For example, initiation of buprenorphine in
emergency departments has proven successful, not only as a life-saving measure but a way to
begin treatment at a critical time for the individual.98 Similarly, “sequential intercept mapping”
is an effective way for communities to coordinate treatment and support services for the
individuals with opioid use disorder at each of five “intercept points.”99
98. Mobile health and telemedicine have proven effective and are widely regarded as
an important approach in addressing the opioid epidemic in rural areas and among underserved
populations.100 The US Department of Agriculture has provided mobile health and telemedicine
grants to assist parts of Appalachian Kentucky, Tennessee, and Virginia.101 Agriculture
Secretary Tom Vilsack explained that “[b]ecause addiction treatment is often out of reach for
many in rural America, expanding access to telemedicine is an important step towards making
sure rural communities have the tools they need to fight the opioid epidemic.”102 Rhode Island
97
A.T. McLellan, et al., “Can Substance Use Disorders be Managed Using the Chronic Care Model? Review and
Recommendations from a NIDA Consensus Group,” Public Health Reviews, 35(2), 2014,
http://www.journalindex.net/visit.php?j=6676.
98
G. D'Onofrio, “Emergency Department-Initiated Buprenorphine for Opioid Dependence with Continuation in
Primary Care: Outcomes During and After Intervention,” Journal of General Internal Medicine, 32(6), 2017, pp.
660–666.
99
See N. Bonfine, M.R. Munetz, and R.H. Simera, “Sequential Intercept Mapping: Developing Systems-Level
Solutions for the Opioid Epidemic,” Psychiatric Services, 69(11), 2018, pp. 1124-1126.
100
See e.g. S. Yu, et al., “The scope and impact of mobile health clinics in the United States: a literature review,”
International Journal for Equity in Health, 16(178), 2017, pp. 1-12; J.C. Fortney, et al., “Practice-based versus
telemedicine-based collaborative care for depression in rural federally qualified health centers: a pragmatic
randomized comparative effectiveness trial,” American Journal of Psychiatry, 170(4), 2013 pp. 414–425; Y. Yang,
E. Weintraub, and R.L. Haffajee, “Telemedicine's Role in Addressing the Opioid Epidemic” Mayo Clinic
Proceedings, 93(9), 2018, pp. 1177–1180.
101
U.S. Department of Agriculture, Rural Development, “USDA Announces Telemedicine Funding to Address
Opioid Epidemic in Appalachia,” June 30, 2016 (https://www.rd.usda.gov/newsroom/news-release/usda-announces-
telemedicine-funding-address-opioid-epidemic-appalachia-); E. Wicklund, “USDA Telemedicine Grants Target
Opioid Abuse,” mHealth, June 30, 2016, (https://mhealthintelligence.com/news/usda-telemedicine-grants-target-
opioid-abuse).
102
Ibid.

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and many other states (including Tennessee) and regions are using Recovery Navigators, and
peer recovery support specialists generally, with great success.103
99. I reviewed other states’ experiences in transitioning traditionally abstinence-only

programs to allow for medication-assisted treatment when indicated. Specifically, I evaluated
Ohio’s endeavors to expand recovery housing104 and accommodate patients with medication-
assisted treatment and California’s approach to incorporating medication-assisted treatment into
residential treatment centers.105
100. To gain insight into conditions “on the ground” in the nine counties that are the
subject of this litigation, I met with stakeholders in the community, including peers, patients,
healthcare providers and administrators, law enforcement, judges, East Tennessee State
University (“ETSU”) faculty, prevention/anti-drug coalition leaders, departments of public
health, citizens and others. From the first meeting, it was clear that addiction and the opioid
epidemic, in particular, have the attention of every group and that they are poised to move
forward towards a solution. For example, a nurse in the emergency room in Sneedville said, “in
the past 5 years, we have seen 20 young people die of overdoses in our emergency room. This
never happened before. Almost every emergency room visit involves a drug-related incident.”
Similarly, the Sheriff in Sullivan County indicated that almost everyone in their jail was
incarcerated for a drug-related offense. The bottom line was, “we need a solution to this problem
that is wrecking our community.”
C. Goals
101. The key goals of the plan are:
103
Addiction Policy Forum, “Spotlight: AnchorED Rhode Island,” Spotlight Series, February 2017, available at
(https://cdn2.hubspot.net/hubfs/4132958/bfe1ed_72e4bcbf11de4f15b80e46684854e543.pdf); TDMHSAS,
“Tennessee Recovery Navigators” (https://www.tn.gov/behavioral-health/substance-abuse-services/treatment---
recovery/treatment---recovery/tennessee-recovery-navigators.html).
104
Ohio Council of Behavioral Health and Family Services Providers, “Recovery Housing in the State of Ohio:
Findings and Recommendations from an Environmental Scan,” June 2013 9https://obc.memberclicks.net/assets/
OHRecoveryHousing/ohiorecoveryhousingjune2013 percent20final.pdf0; Government Accountability Office,
“Substance Use Disorder, Information on Recovery Housing Prevalence, Selected States’ Oversight, and Funding,”
March 2018 (https://www.gao.gov/assets/700/691302.pdf).
105
California Department of Health Care Services, “Training & Resources,” 2019 (https://www.dhcs.ca.gov/
provgovpart/Pages/Training-and-Resources.aspx).

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• Create a coordinated, collaborative system to engage a substantial number of patients
in evidence-based opioid use disorder treatment over a reasonable period of time,
reaching full capacity in 5 years.
• Achieve outcome measures including reductions in all-cause mortality, overdose

mortality, emergency room visits and hospitalizations, violent criminal offenses,
stable work and housing status, and stable social relationships, allowing patients to
move out of the maelstrom of addiction (specific metrics are in Section VIII Clinical
Outcomes below).
• Develop a culture in which addiction is viewed as a chronic brain disorder that can be
treated and should not be the subject of stigma. An organized group of health
advocates/navigators will work to permeate the community with this viewpoint
through their actions in support of patients.
• Move individuals towards durable recovery in which patients maximize their

functionality in terms of realization of personal goals as reflected by accumulation of
capital in social (for example, stable family and friends), medical (health & well-
being) and financial (independence) terms girding against relapse.

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102. Figure 3 below is a schematic depiction of the plan underlying TREAT.
Figure 3
Schematic Depiction of the Plan Underlying TREAT
D. Key Elements
103. The key elements of the plan are:
• Sites (or “Nodes”) with a concentration of specialized services for patients with
opioid use disorder offering multidisciplinary, coordinated and integrated care that
engages the patient in wraparound services (addressing social and mental health
issues is an important component), increasing access to high-quality care in a timely
manner. This is intended as a one-stop shop for opioid use disorder patients. The
Node provides expert decision-support to other providers in the area, improving care
and moving addiction treatment into mainstream medical practice.
• Effective outreach from the Nodes to rural, underserved, and vulnerable populations
(criminal justice system, women with substance-exposed pregnancies, those just
discharged from residential treatment centers, etc.), reaching people who have not
been engaged in treatment.

Page 40
• Work with and coordinate the efforts of community partners to leverage their
strengths and recruit additional talent where there are gaps.
• Adopt a long-term approach that views opioid use disorder as a chronic brain disorder
that requires the availability of long-term sober living facilities and support services
including mental and physical health, and case management/social work.
104. Each element of TREAT is described in greater detail below.
1. The Node
105. The Node described herein is a special case of Office-Based Opioid Treatment (an
“OBOT”), which most often utilizes medication-assisted treatment with buprenorphine-
containing formulations or naltrexone (less often) to treat patients with opioid use disorder. The
features which distinguish the Node from the OBOT found in most settings are:
• Integration of care with contributions from the whole provider team,
• Intensive case management (in-depth examination of social determinants of health),
• Several mechanisms to ensure effective outreach. The latter include:
o Mobile community health teams (based in one of the Nodes that travels to
rural areas),
o Telemedicine,
o Emergency consult line available at all times (for time-sensitive clinical
matters that local providers have questions about), and
o Organized group of navigators/community health advocates. I anticipate that
the latter individuals will have an important role in changing the culture of
opioid use disorder from one of shame and stigma to acceptance of treatment
for a chronic brain disease. The goal is to educate and demonstrate that
treatment can lead to recovery in which the patient achieves a high level of
functionality.
106. As mentioned above, the purpose of the Node is to provide a “one-stop shop”
supporting the goal of recovery for patients with opioid use disorder. The Node will be co-
directed by one administrative and one medical leader. The number of patients cared for by a
Node will vary depending on staffing of the Node and the population served (the Node is
designed to care for up to 1200 patients). A description of each node team member and how
she/he interacts to provide integrated care is below. It is essential to point out that the model of

Page 41
care is one in which addiction, mental and physical health, as well as intensive case management
focusing on social determinants of health (housing, transportation, food, job placement,
legal issues), are addressed in a coordinated manner by the interdisciplinary team.
107. In contrast to collocated care, in which different medical professionals work in

physical proximity but do not interact closely, integrated care features prominently the
development of collaborative care pathways with input from each of the disciplines. The
treatment team functions as a unit and the nurse care manager often serves as the integrator by
analogy with the “Massachusetts model.”106 In Northeast Tennessee, it is essential to employ an
integrated-wraparound model to counter elements in the environment that favor patient isolation
and relapse.
108. In view of the devastation of Northeast Tennessee by the opioid epidemic, an

OBOT that strongly targets outreach to communities it serves is required to effectively draw
people into treatment. This is community medicine that needs to be done by reaching into the
community.
Figure 4
106
LaBelle, et al., op. cit.; Alford, et al., op. cit.

Page 42
109. Like the “Hub” in the Vermont Hub-and-Spoke model, the Node will house a
concentration of specialized services to care for more complex and unstable patients, and to
serve as a focal point for community interactions. Staffing would ideally consist of physicians
boarded in addiction medicine (subspecialty) and family or internal medicine (primary specialty),
therapists (LCSW, LPC, Psychologist), case managers-social workers (MSW) and nurse care
managers (RN). Administrative support includes an office manager for patient flow and
financial issues, and assistant for handling scheduling, telephone, and issues arising.
110. The Node will be linked to the network in the nine-county area by a common
outpatient Electronic Medical Record (“EMR”). An example of such an EMR would
be AdvancedMD, an IT platform that consists of an EMR, telemedicine, and practice
management/billing. There are multiple other examples of outpatient EMRs that could be
utilized as well. EMRs allow clinical information sharing across team members, primary care
clinicians, and other specialists, creating a “virtual colocation of care even when clinicians are in
separate physical locations.”107
2. Node Team Members
a) Addiction Medicine Physician
111. The addiction medicine physician is board-certified in addiction medicine, is

expected to have a buprenorphine waiver allowing treatment of 275 patients and will also
serve as the medical director of the OBOT. The situation with regard to distribution of
methadone is described below. Most often, the addiction medicine physician will also be
boarded in family medicine so that she/he will be qualified to evaluate physical, as well as most
mental health issues (except severe mental illness – psychoses – which require a psychiatrist, see
below).
112. This addiction specialist is responsible for (1) developing evidence-based

treatment protocols for the Node and (2) leading the care team according to the integrated care
model that is inclusive of the input from other providers. In many instances, there will be a
107
R. Saitz, M.J. Larson, C. Labelle, J. Richardson, and J.H. Samet, “The case for chronic disease management for
addiction,” Journal of Addiction Medicine, 2(2), 2008, 55–65.

Page 43
group of physicians that form the Node’s medical team. This depends on the acuity and number
of patients seen in the Node. Each additional physician might have the same qualifications as the
medical director or might be a family medicine physician (or other primary care physician) with
a buprenorphine waiver for 275 patients and significant experience in addiction medicine. It will
also be essential to have several addiction psychiatrists as a part of the medical staff of Nodes for
dealing with patients with addiction and serious mental illness (psychoses). At the outset,
TREAT will seek to recruit three addiction psychiatrists to spread over the Nodes (spending a
portion of their time at different Nodes).
113. Overmountain Recovery, a collaboration of Ballad Health and ETSU, is the only
OTP that is authorized to dispense methadone in Northeast Tennessee. Patients from this part of
Tennessee are reported to leave the state to obtain methadone, since the Overmountain
Recovery’s clinic opened recently. The medical director, Tim Smyth, MD, has indicated that the
number of patients they see is growing, and that they would be open to collaborating with
TREAT.108
114. The most common co-occurring conditions with opioid use disorder are mental
illnesses. In one study, while 40 percent of patients with opioid use disorder had no mental
illness, 36 percent had mild-moderate mental illness and 24 percent had severe mental illness.109
According to the 2017 National Survey on Drug Use and Health, 27.6% adults aged 18 and older
who had a substance use disorder also had a serious mental illness.110 These ranges vary
considerably from practice-to-practice. In general, addiction medicine specialists, especially
those with a background in family medicine, are comfortable treating mental health conditions of
average acuity, which represents about 90 percent of the patients seen in a practice. However,
patients of high acuity with regard to mental health conditions are referred to an addiction
108
As TREAT expands, I anticipate collaborating with Overmountain Recovery and applying for CON’s for new OTP
as it becomes clear that the need for such facilities is necessary.
109
P. Novak, et al., “Behavioral health treatment utilization among individuals with co-occurring opioid use disorder
and mental illness: Evidence from a national survey,” Journal of Substance Abuse Treatment, 98, 2019, pp. 47 – 52.
110
SAMHSA, “Key substance use and mental health indicators in the United States: Results from the 2017 National
Survey on Drug Use and Health,” 201, retrieved from https://www.samhsa.gov/data/sites/default/files/cbhsq-
reports/NSDUHFFR2017/NSDUHFFR2017.pdf.

Page 44
psychiatrist. The presence of addiction psychiatrists rotating through the Nodes to address issues
in patients with severe mental illness is a part of TREAT.111
115. Physician recruitment. Because of the need for addiction medicine physicians
given their important role in leading evidence-based care for patients with opioid use disorder, it
is essential to consider recruitment issues. There are several strategies which should be utilized
in tandem:
• Recruitment of individuals graduating from addiction medicine fellowships. On

average, the debt load of physicians finishing addiction medicine fellowship is about
$200,000 each. This is a major burden. A carefully structured program that offers
fair market value compensation in addition to loan repayment at a rate of about
$50,000 per year over 4 years would be a strong recruitment stimulus. The agreement
would stipulate that the individual must stay in the program for a minimum of four
years, and that if a person left early, repayment would be required. Another stimulus
for recruitment would be joining a comprehensive program such as TREAT where
there will be many like-minded colleagues. I anticipate TREAT will be a well-funded
program that provides an ideal working environment where the physician can “make
a difference” and be part of an innovative team. This is the reason that
many physicians are now choosing to go into addiction medicine.
• Identify physicians with primary care training (especially family medicine and
general internal medicine) and an interest in addiction medicine. In this case, one
would recruit these trainees to addiction medicine fellowships (1-year training period)
and provide a stipend (about $30,000) that makes the fellowship year easier on
families.
• These individuals would also be offered fair market value compensation at TREAT in
addition to loan repayment after completion of the fellowship. There are three
addiction medicine fellowship programs in Tennessee which would be likely to
cooperate with this plan.112
111
Based on my discussions with Frontier Health (the major mental health provider in the region), they would be
open to collaborating with TREAT in meeting mental health needs of the opioid use disorder population.
112
ETSU, Meharry, and Baptist Memorial Healthcare have addiction medicine fellowships.

Page 45
• Utilize a search firm to identify addiction medicine physicians. Although the scarcity
of addiction medicine physicians makes this approach a challenge, I have had success
identifying strong candidates in the recent past using particular search firms. The key
to success with this approach is offering a strong economic incentive (loan
repayment) and the chance to join an innovative program, as suggested above.
• If one considers the distribution of physicians with buprenorphine waivers in

the nine-county area, it is clear there are physicians who could, potentially, participate
in TREAT: Carter (3 buprenorphine waivers), Greene (11), Hamblen (7), Hancock
(0), Hawkins (2), Johnson (0), Sullivan (33), Unicoi (1) and Washington
(70). Existing providers in the region can potentially be a valuable resource for
TREAT.
• In the short-term, it might be necessary to utilize a vendor who provides staffing of

medication-assisted treatment clinics.
116. I estimate that this approach would provide seven to ten addiction medicine
physicians per year to staff TREAT. These addiction medicine physicians will be a combination
of individuals boarded in addiction medicine and a limited number of physicians with
buprenorphine waivers who are not boarded. The latter will be supervised by the boarded and
fellowship trained physicians. It is important to note that a certain number of addiction
psychiatrists (see below) will also be hired in the pool of addiction medicine physicians. At the
outset, I estimate three psychiatrists distributed over the Nodes described above. This number
will need to be adjusted based on the patients actually seen at each Node.
b) Nurse Care Manager
117. A nurse care manager is an experienced nurse who has worked with patients with
addiction. This individual will be trained according to the model developed at Boston Medical
Center and will have an important role in initial patient assessment (at the point of intake) and
working with the team to develop the integrated treatment plan.113 The nurse care manager
also tracks the number of patients on each of the physician’s buprenorphine waivers to assure
113

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compliance with federal guidelines. A nurse care manager has the capacity to participate in care
for 100-150 patients, depending on the acuity of patients and the infrastructure of the practice.
Higher acuity patients and an environment without wraparound services places the burden of
organizing these functions on the nurse care manager requiring her/him to spend more time with
each patient.
c) Addiction Psychiatrist
118. Addiction Psychiatrists care for those with co-occurring serious/severe mental
illness (major depression, schizophrenia, bipolar disorder and other psychoses) and opioid use
disorder. Serious or severe mental illness is defined at the federal level as “having within the
past year, a diagnosable mental, behavior or emotional disorder that cause serious functional
impairment that substantially interferes with or limits one or more major life activities.”114 This
is the patient group that the addiction psychiatrist focuses on. At the outset, I anticipate
recruiting in a stepwise manner three addiction psychiatrists (i.e., physicians boarded in
psychiatry and addiction medicine) to care for these patients. These are included in the physician
recruits described in the table accompanying this report. Depending on the actual number of
patients with serious mental illness and addiction, the number of addiction psychiatrists could be
expanded or diminished.
d) Therapist
119. The therapist is the behavioral health specialist and treats about 90 percent of the
patients with co-occurring disorders (anxiety, depression, stable bipolar disease/mood disorders)
but not unstable patients with serious mental illness (psychoses). The latter patients are referred
to addiction psychiatrists who will be part of the care team (see above). The therapist is director
of the Node’s Intensive Outpatient Program (IOP). The training of this individual will be either
LPC, LCSW, or clinical psychologist, and this individual will have significant experience
working with patients with opioid use disorder. The caseload of this individual depends on the
acuity of mental health conditions in the patient population.
114
SAMHSA, “Mental Health and Substance Use Disorders,” last updated April 13, 2019
(https://www.samhsa.gov/find-help/disorders).

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e) Case Manager
120. A case manager is a social worker with the role of addressing social determinants
of health. Patients will be evaluated according to the Arizona Self-Sufficiency Matrix,115 and
attention will be focused on domains with deficiencies. The term “social determinants of health”
applies to those social activities and needs that enable the individual to live a fulfilling life.
These needs are inherent to the human experience. Abraham Maslow first coined his Hierarchy
of Human Needs theoretical model in 1943. Often, clients with opioid use disorder are trapped
at the first tier of this theoretical model (physiological needs: air, water, food, shelter, sleep,
housing). Their needs, such as not having food, safety, and proper clothing, take priority
over higher level needs such as supportive friends or gainful employment. Many opioid use
disorder clients do not have their basic needs met and lack the social support structure integral to
the nourishment of their long-term recovery. An important goal of the case manager is to
develop that supportive social structure around each patient.
121. A problem-based approach to case management will be carried out according to

the following problems to be addressed in each stage of treatment (induction: beginning of
medication-assisted treatment, the first 1-3 months of treatment; stabilization: intermediate
period of medication-assisted treatment and the next 4-8 months after induction;
maintenance: long-term phase of medication-assisted treatment and commencing at about 9
months after starting medication-assisted treatment and continuing as long as a patient
participates in medication-assisted treatment). Issues addressed during these phases include:
• Induction Phase with associated social issue addressed with client: insurance,
healthcare, housing, food, clothing, license, resume.
• Stabilization Phase with associated social issue addressed with client: stable
employment, safe housing, reliable transportation, schooling, workforce
preparedness.
• Maintenance Phase with associated social issue addressed with client: healthy social
support network, hobbies, career fulfillment, community involvement.
115
Abt, “Arizona Self-Sufficiency Matrix,”
https://wthn.communityos.org/cms/files/os007/p/Arizona%20Matrix.pdf.

Page 48
122. All of these issues involve extensive interaction between the case manager and the
client. The load of a case manager, like that of a therapist, depends on the needs of patients.
f) Recovery Navigators
123. Recovery Navigators (or “Navigators”) are an essential element of the response to
the opioid epidemic in Northeast Tennessee. Tennessee has already embraced Recovery
Navigators to a limited extent, funding a handful in all of Northeast Tennessee.116 It also funds
the Lifeline Peer Project.117 The Lifeline Peer Project provides peer recovery specialists who
serve as navigators and patient liaisons/support coaches for patients with opioid use disorder.118
Along with other peers (for both substance use disorder and mental illness), Recovery Navigators
are trained in a program called Certified Peer Recovery Specialists (CPRS) that is offered several
times a year throughout the state.119 While these programs are certainly a sound approach to
dealing with opioid use disorder, they would benefit enormously from the strong
treatment/recovery infrastructure and program proposed herein. There appears to be only one
Lifeliner in Northeast Tennessee , and there are only 19 Recovery Navigators in the state.120
124. Other states, regions, and programs have reported impressive outcomes. A 2016
review found that most of the studies analyzed reported statistically significant improvements in
substance use, a range of recovery outcomes, or both, among participants receiving the peer
intervention.121 In Rhode Island, any person who presents at an emergency department due to an
opioid-related overdose is provided the opportunity to meet with a peer recovery coach before
leaving the hospital.122 In the first 29 months of the program, over 1,400 people met with a peer
116
TDMHSAS, “Tennessee Recovery Navigators,” (https://www.tn.gov/behavioral-health/substance-abuse-
services/treatment---recovery/treatment---recovery/tennessee-recovery-Navigators.html).
117
Appalachian Regional Commission, Issue Brief, Health Disparities Related to Opioid Misuse in Appalachia.
118
TDMHSAS, “Lifeline Peer Project” (https://www.tn.gov/behavioral-health/substance-abuse-
services/prevention/prevention/lifeline-peer-project.html).
119
Ibid.
TDMHSAS, “Lifeline Peer Project Regions,” (https://www.tn.gov/content/dam/tn/mentalhealth/
120
documents/Lifeline_Contacts_8-5-19.pdf).
E.L. Bassuk, et al., “Peer-Delivered Recovery Support Services for Addictions in the United States: A Systematic
121
Review,” Journal of Substance Abuse Treatment, 63, 2016, pp. 1-9.

122
“Spotlight: AnchorED Rhode Island,” op. cit.

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recovery coach, and of those, more than 80 percent engaged in recovery support services upon
discharge.123 SAMHSA reported that peer recovery services are “proving to be very adaptable,
operating within diverse populations, stages of recovery, pathways to recovery, service settings,
and organizational contexts” and that they “build on resources that already exist in the
community, including diverse communities of recovering people who wish to be of service.”124 I
recommend not only significantly increasing the number of Navigators in Northeast Tennessee
but also expanding the scope of their role in combatting the opioid epidemic.
125. In Northeast Tennessee, Navigators’ efforts should be directed at making linkage

to critical addiction, mental health, physical health and social services a reality. This will include
assistance with transportation, support in complex social situations, providing the means for
women with substance-exposed pregnancies to attend prenatal care visits (potentially, this could
involve providing baby-sitting services for pregnant women’s other young children). For
example, if a patient does not have transportation to attend a job interview or a support group
meeting, the Navigator would assume the responsibility of finding/providing transportation for
the client. This is especially important in remote parts of Northeast Tennessee, as taxi service,
including Uber, is not always available. This is like the model employed successfully by Mental
Health Cooperative (Nashville), whose patient population includes many with addiction and
mental health issues. As a result of the efforts of their Navigators, patients reach a higher level
of function. The program will provide vehicles to Navigators in certain cases, for
example for longer trips to remote areas, and reimburse Navigators for mileage traveled in
others.
126. Navigators are key elements of the plan to provide a support network for patients
with opioid use disorder. Because of the importance of Navigators, below is a more
comprehensive outline of their recruitment, training and activities.
127. The pool of Navigators will be selected from two groups of individuals: those
with a history of addiction and at least five years of sobriety, and individuals in the
123
Ibid.
124
SAMHSA, “What Are Peer Recovery Support Services?” 2019.

Page 50
community (without a history of addiction) who express a willingness to support patients with
addiction.
128. A training curriculum will be developed for Navigators using well-accepted,

evidence-based references on trauma-informed care using Seeking Safety and other materials, as
well as instruction in specific areas relevant to opioid use disorder, including harm reduction,
healthcare literacy, case management, overdose recognition/management, medication-assisted
treatment, Screening, Brief Intervention and Referral to Treatment (“SBIRT”), motivational
interviewing, and community navigation (from drawing overdose patients in hospital ER’s into
treatment, to visiting sites of “risky substance use” in the community). The training curriculum
would be anticipated to last about 6 weeks. Ideally, it would include didactic/role-playing
exercises for 4 weeks and experiential learning (in the clinical setting) for 2 weeks. It
would conclude with a certifying exercise resulting in the designation of “Navigator.”
129. A unique feature of the Navigator program will be to develop virtual meetings
among front-line responders who serve patients with opioid use disorder. Front-
line responders to opioid use disorder crisis situations include certified peer recovery specialists
(CPRS), emergency medical service (EMS) personnel, law enforcement and other
concerned members of the community. Navigators that will have multiple interactions
with these individuals as a part of moving patients into treatment. In order to develop
camaraderie and constructive interactions among this group, as well as delineating roles and
protocols, there will be a biweekly “zoom meeting.” Clinical situations will be discussed in a de-
identified manner so that no personal health information is revealed. Sessions will be taped, and
a summary provided along with editing to develop protocols for different clinical
situations. This approach is analogous to Extension for Community Healthcare Outcomes
(“ECHO”), and the proposed program could join ECHO (formally registered with the ECHO
Institute of the University of New Mexico) to gain access to their library of clinical scenarios and
didactic programs.125 That will be decided by the group in the future. Each zoom session will be
led by a “lead Navigator in the Node,” and participants will also include the Node case managers
and therapists. The addiction medicine physician is a key consultant to this group. This group
125
University of New Mexico, “Project ECHO: A revolution in medical education and care delivery”
(https://echo.unm.edu/; Project ECHO, Research, retrieved from: https://echo.unm.edu/about-echo/research).

Page 51
will make outreach more adaptable and responsive to input from patients and the community. An
expected benefit of this approach is the development of esprit de corps among the Navigators.
130. Navigators will be deployed throughout the community and will represent the
Node on many levels. The time of Navigators will be divided among the following activities:
a. Navigators will work with law enforcement and EMS, as well as other
front-line responders. They will:
i. Function as patient advocates for individuals opioid use disorder

patients who are nonviolent offenders and willing to accept
treatment. Initially, police will identify such individuals, and
Navigators will meet them, work to develop relationships and
encourage them to enter treatment. This is analogous to Seattle’s
Law Enforcement Assisted Diversion (“LEAD”) and programs in
other cities that seek to move patients ready for treatment in the
latter direction rather than into the criminal justice
system.126 Tennessee approved such a program in 2018. These
programs have had success in decreasing re-arrests of drug-abusing
individuals. I have spoken with sheriffs and a judge in the area,
both of whom expressed interest in participating in such a
program. I think it is likely that other police departments and
judges will be similarly interested.
ii. Work with front-line responders using ODMAP and other “real-
time” GIS mapping tools to identify hot spots at high-risk for
overdoses. Navigators (in cooperation with police, as appropriate)
will educate people in these areas as to the risks of drug use and
distribute naloxone.
126
National Institute of Justice, “Program Profile: Law Enforcement Assisted Diversion (LEAD) Program (Seattle,
Washington),” CrimeSolutions.gov, July 11, 2016 (https://www.crimesolutions.gov/ProgramDetails.aspx?ID=477);
S.E. Collins, et al., University of Washington, “LEAD Program Evaluation: Recidivism Report,” 2015
(http://static1.1.sqspcdn.com/static/f/1185392/26121870/1428513375150/LEAD_EVALUATION_4-7-15.pdf);
TDMHSAS, “Pre-Arrest Diversion Infrastructure Program” (https://www.tn.gov/behavioral-health/mental-health-
services/mental-health-services-for-adults0/pre-arrest-diversion-infrastructure-program.html).

Page 52
b. Navigators will, to the extent permitted, follow-up with patients who were
seen in the Emergency Room, seek to develop a relationship with the
patient and then, when the patient feels ready, accompany the individual to
treatment. Such engagement by Navigators/healthcare advocates has been
shown to increase the number of individuals who enter treatment programs
by up to 80 percent.127
c. Navigators will work with jails and prisons to engage inmates close to
their release dates. The goal of the Navigator in this situation will be to
form a relationship with the inmate and serve as a conduit for follow-up
wraparound care after incarceration. It will be essential that Navigators
contact program staff in the jail or prison facility, including therapists and
case managers, to provide continuity. By offering long-term support to
former inmates, it is anticipated that Navigators will become a positive
factor in the lives of these individuals. Namely, they will become
“someone who cares.”
d. Navigators will also be deployed to residential treatment centers to

coordinate follow-up care after discharge. As the immediate discharge
period is one of vulnerability to relapse and overdose, Navigators will
have an important role in the safety and continuity of care for these
individuals.
e. Women with substance-exposed pregnancies are an important group in

need of supportive services for prenatal visits, nutrition, living conditions,
etc. Navigators will interact with this population at obstetrics clinics in
the community and at doctors’ offices.
f. Navigators will go to sites in the community, such as churches and

schools, to be available to meet with individuals referred by these
organizations as a result of screening. The role of the Navigator will be to
discuss with the individual the advantages of entering a treatment program
127
“Spotlight: AnchorED Rhode Island,” op. cit.

Page 53
and making that opportunity available. In many cases, it is likely that
people will not feel ready to join treatment, and the information discussed
will be principally for educational purposes. Nonetheless, it is likely that
the potential patient will return to this discussion over time as the
possibility of treatment is raised again.
g. Individuals in treatment will also require, from time-to-time, additional

support to remain engaged in treatment. Each patient will be assigned a
Navigator as a support person to monitor progression of the patient
throughout the treatment/recovery process. For Navigators to be optimally
effective, they will need to supply transportation to themselves and clients,
as their work will carry them throughout the community. In most cases, I
anticipate Navigators using their personal vehicles and reimbursing for
mileage (according to a standard rate). In certain cases, especially longer
trips to remote areas, it may be necessary to supply vehicles, which could
be rented or provided by local government.
131. Navigators will be on-call for the activities cited above for 12-hour shifts
(40 hrs/week). Once a Navigator gains the agreement of a prospective participant to accept a
referral treatment, then other staff at the Node will conduct medical and psychosocial
evaluations, and the treatment process will begin immediately if the patient agrees. It is expected
that whereas some patients will have fewer needs that the Navigator can help with, others will
consume a larger amount of the Navigator’s effort. I anticipate employing a number of
Navigators per Node, depending on the number of clients to be served and their level of acuity.
A social worker experienced in working with patients with opioid use disorder will be appointed
Director of the Navigator Service. This individual will lead the tele-education sessions, career
development and assignment of responsibilities/scheduling for the Navigators. In addition to
providing an important service for clients, the plan should draw talented individuals who are not
currently in the workforce into Navigator positions resulting in opportunities for employment
and career advancement.

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E. Mobile Community Health Team
132. Mobile health is well-supported in the literature, and it is regularly recommended

as a way to reach rural areas and other underserved populations.128 It has also been shown to
improve retention.129 The Mobile Community Health Team (or “Mobile Team”) derives from
experience in Vermont with “Medication-Assisted Treatment Teams” and the “Massachusetts
model.”130 In each case, the goal was to increase accessibility and quality of care for opioid use
disorder patients by providing additional resources to local practices. In Vermont, each “spoke”
has a dedicated Medication-Assisted Treatment Team comprised of one registered nurse and one
licensed behavioral health provider for every 100 Medicaid patients prescribed buprenorphine.131
Mobile teams in Massachusetts generally consisted of a nurse care manager and other providers,
and delivered care to about 100-125 patients in partnership with local practitioners and treatment
centers.132 In Pennsylvania, the “Addiction Recovery Mobile Outreach Team” provides case
management and recovery support services.133
133. I have adapted these concepts by taking into account the rurality of the region,
lack of physicians with buprenorphine waivers/expertise in addiction medicine, and the need for
Mobile Teams to also function as an emergency response team when situations arise such as a
tainted shipment of illicit drugs that results in overdose/toxic deaths. Thus, in certain cases, the
Mobile Team will become the “Node” for a remote/rural community. For this reason, the
composition of the Mobile Team will include: a nurse care manager (always present), a therapist
(always present), a case manager–social worker (always present), and a physician (sometimes
present). The responsibilities of member of the team are described below.
128
Yu, et al., op. cit.; G. Hall, et al. “Mobile opioid agonist treatment and public funding expands treatment for
disenfranchised opioid-dependent individuals,” Journal of Substance Abuse Treatment, 46(4), pp. 511 – 515.
129
L. Greenfield, et al, “Patient retention in mobile and fixed-site methadone maintenance treatment,” Drug and
Alcohol Dependence, 42(2), 1996, pp. 125-131.
130
Personal Communication Dr. John Brooklyn 2017; E. Post, “Inventing the Wheel,” Vermont Medicine Magazine,
(http://www.med.uvm.edu/vtmedicine/inventing-the-wheel); LaBelle, et al., op. cit.; Alford, et al., op. cit.
131
Post, op. cit.
132
133
Rural Health Information Hub, “Addiction Recovery Mobile Outreach Team (ARMOT)”
(https://www.ruralhealthinfo.org/project-examples/940).

Page 55
a. The nurse care manager is the leader of the team and provides expertise in
patient assessment, management (especially with regard to induction of
medication-assisted treatment), development and implementation of
treatment plans and tracking provider prescriptions for buprenorphine.
The nurse care manager in the Node will train nurse care managers for
Mobile Teams selected from a pool of interested nurses from Northeast
TN.
b. The case manager has an essential role on the Mobile Team, as most rural
practices are not staffed to deal with social service needs of patients and
access to social services is very limited in certain areas. The key task of
the case manager will be to understand social issues of patients with
opioid use disorder and be knowledgeable with regard to
community/regional resources. For example, the case manager in my
current practice is a peer recovery specialist (>10 years of sobriety) who
resonates with opioid use disorder patients and through experience in
Memphis can navigate governmental and nongovernmental service
agencies on behalf of patients. The case manager in the Node will be
selected for experience in this area, and one of her/his duties will be to
train case managers who join Mobile Teams.
c. The therapist provides mental health care for most patients except those
with unstable/serious mental illness. In the latter case, the Mobile Team
staff will include an addiction psychiatrist who can provide the appropriate
level of care. For the great majority of patients, the therapist provides the
link to behavioral health therapy that is often missing from the primary
care provider’s office. As with the case manager, the presence of the
therapist adds essential infrastructure to local care that is often missing
especially in more rural settings.
d. The presence of an addiction medicine physician on the Mobile Team

indicates that an area is being covered where there are otherwise no
physicians available to care for patients with opioid use disorder. Another

Page 56
situation in which a physician is on the Mobile Team is when the team
will include an addiction psychiatrist who can provide care that would
otherwise not be available. Not every Mobile Team will have a
physician. This will depend on the needs of the region and the specific
group of patients that the team is caring for. Addiction medicine
physicians will rotate among the Mobile Teams.
134. The number of Mobile Teams will depend on the population to be

served. Interactions with opioid use disorder patients could occur in a “low visibility” manner at
community sites selected in each area by patients (churches, schools, community centers).
Coordination with the community and input from local officials would be essential. The goal
will be to provide service and avoid exacerbating the stigma of opioid use disorder prevalent in
Northeast Tennessee. It is anticipated that three Mobile Teams will be launched over the first
three years to be certain there is coverage of the nine-county area with addiction medicine
services. Depending on the need for the Mobile Team’s services, the number of teams could be
expanded in future years. Personnel for the Mobile Teams will be recruited specifically for this
purpose. The Mobile Teams are designed to reach those patients who would ordinarily not
access care. They are part of the initiative to meaningfully increase access of the opioid use
disorder community to the kind of wraparound care needed to build sustainable recovery.
F. Emergency Consult Line for Healthcare Providers
135. An emergency consult line available to every level of healthcare provider is an

important way for the Node’s addiction specialists to improve care for patients with opioid use
disorder throughout the region and engage greater numbers of patients in treatment. Each of the
healthcare system’s interactions with an individual suffering from opioid use disorder presents an
opportunity to engage that individual in treatment, and a patient’s encounter with a healthcare
provider lacking expertise and experience in addiction medicine is a missed opportunity. The
plan addresses this problem by providing real-time expert consultation, when needed, through a
round-the-clock emergency consult line for every level of healthcare providers. This consult line
will be offered in addition to the teleconsultation services described in Section D.
136. This hotline will be staffed by nurse care managers (hired specifically for this
purpose) and consulting addiction medicine specialists (the latter drawn from the Nodes), who

Page 57
have expertise in handling opioid use disorder problems and will be able to provide on-the-spot
answers 24-7-365. There are multiple situations in which this emergency line could be
used. For example, an emergency room physician in a remote area may want to share ideas
about how to treat a patient with a history of addiction and an intervening episode of acute pain
due to an accident. Another consult might involve management of an unstable opioid use
disorder patient who could benefit from rapid induction with buprenorphine in the emergency
room. The emergency consult line will be staffed by five nurses, two alternate nurses to fill slots
during vacations and other absences of staff, and two consulting addiction medicine physicians.
G. Telemedicine
137. Telemedicine will also be offered by the Node. In terms of teleconsultation with
hospitals (ERs or inpatient services), there are a number of technical issues that need to be
addressed, such as medical staff privileges and the mechanics of telemedicine (IT compatibility,
confidentiality, institutional firewalls). In view of there being one major health system (Ballad)
in the region, these limitations could potentially be overcome at an administrative
level. Teleconsultation delivered to doctors’ offices and telemedicine delivered to patients at
home or in another private place can be offered on any secure internet-enabled device with
current technology. One system that provides a HIPAA/cfr part II compliant system for
telemedicine, as well as other features such as an electronic medical record and practice
management module, is available for AdvancedMD and works well in outpatient settings.
138. Telepsychiatry is a setting in which telemedicine has been used for years and
produced results comparable to in-person psychiatry.134 As a form of contingency management,
patients who are compliant with their course of treatment for opioid use disorder will be
permitted to conduct therapy sessions via telemedicine.
W. Zheng, et al., „Treatment Outcome Comparison Between Telepsychiatry and Face-to-face Buprenorphine
134
Medication-assisted Treatment for Opioid Use Disorder: A 2-Year Retrospective Data Analysis,” Journal of
Addiction Medicine, 11(2), 2017, pp. 138–144.

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Figure 3
139. Figure 3, repeasted above, displays a series of green circles which represent key
areas for outreach of TREAT services. An example of the depth and breadth of these
interactions is illustrated by the level of interaction I envision between TREAT and local
emergency rooms, which are a focus of care for patients with opioid use disorder:
• Medical professionals, including those who staff emergency rooms, will be provided
with the emergency consult line which is available 24-7-365. Telemedicine will also
be a part of the service so addiction medicine specialists in the Node can evaluate
patients directly.
• Case managers and caregivers in the emergency room can provide a warm handoff to
TREAT Navigators in order to guide follow-up care at the level of medical, mental
health and social services.
• Provision of free transportation from the emergency room to the next step in the
journey of care is an essential part of “retaining the patient,” especially at an early
“pre-contemplative” stage, before the patient is fully committed to treatment (and the

Page 59
pull back towards illicit drug use is strong). Navigators from TREAT will make and
implement transportation arrangements.
140. I envision that these multiple levels of support for ERs in the region will make the
experience for opioid use disorder patients more effective with respect to care offered in the ER
and provision of follow-up services. Our goal is to draw virtually every opioid use disorder
patient who presents in the ER into TREAT for long-term services.
H. Residential Treatment Centers
141. The roots of opioid use disorder derive from an individual’s past (as impacted, in
part, by adverse childhood experiences or “ACE” scores), genetic/environmental interactions (at
the level of particular genes and epigenetic changes), and the microcosm in which the person
lives. When a patient presents for evaluation, that indicates the individual is seeking change.
Even if there is ambivalence (in terms of the “stages of change”), there is a recognition that the
current trajectory is destroying a life. While one cannot change an ACE score (though one can
provide trauma-informed care) or genetic factors, altering the patient’s environment is something
that can be accomplished. A police captain of narcotics and organized crime and a deputy sheriff
said, “you are no use to us as providers if you cannot find a place for people to reside outside of
the environment that has fostered their current behavior.” Without a major change in venue for
the patient, law enforcement was confident the person would turn up night after night with the
same issues until catastrophe ensued.
142. Providing a safe place for patients who are seeking to change their behavior is
critical for many patients, especially those living with/among people who encourage use of illicit
drugs. This “protective residence” also potentially serves as an important bridge to the
beginning long-term treatment. Thus, at the outset, residential treatment potentially makes a
critical contribution to the treatment of individuals with opioid use disorder. Adding greater
value, studies have shown that “therapeutic community” programs, which are typically features
of residential treatment, to be effective, with participants who showed improved behavior after 1
year continuing to show improvements after 5 years.135
135
National Institute on Drug Abuse, “Therapeutic Communities,” Research Report Series, 2015
(https://www.drugabuse.gov/publications/research-reports/therapeutic-communities/are-therapeutic-communities-
effective), at section entitled “Are Therapeutic Communities Effective?”.

Page 60
143. Most residential treatment centers in Tennessee (and Northeast Tennessee),
including those accepting public funding and private facilities, have counselors, therapists and
often social workers on their staffs. There is also a medical doctor/medical director who is
present in name but, in most cases, is largely absent. These facilities do not provide medication-
assisted treatment.
144. This presents a conundrum: residential treatment centers, by providing a

protected environment with counseling and therapy, can make a major contribution to recovery;
however, by not carrying out or endorsing (in many cases) medication-assisted treatment, they
are not providing the best for their patients in terms of evidence-based care. By supporting
abstinence-only treatment for all patients, many residential treatment centers return patients to
the community vulnerable to opioid overdoses with potentially lethal consequences. The rate of
relapse for a client with opioid use disorder who receives treatment in a residential facility
without MAT approaches 80 percent within two years.136 This is exacerbated by the fact that the
patient often reenters the environment that contributed to the addiction in the first place. Thus,
rather than functioning as a bridge to long-term care for opioid use disorder, residential treatment
centers are, in large part, setting their patients up for failure by pushing abstinence despite the
knowledge that it will not be a successful approach for many of their clients.
145. Residential treatment centers should permit residents to be prescribed medication-

assisted treatment in coordination with addiction medicine specialists. In Vermont, residential
treatment centers continue to serve a function and provide medication-assisted treatment.137
California has created the “MAT in Residential Facilities Toolkit” to assist residential facilities
comply with recent state legislation preventing them from denying patients admittance due to
medication-assisted treatment.138
146. Under this plan, residential treatment facilities should provide access to
medication-assisted treatment for their clients, either within the facility or in the community
through relationships with local providers like the Nodes. Patients with opioid use disorder
136
G. Bart, “Maintenance Medication for Opiate Addiction: The Foundation of Recovery,” Journal of Addictive
Diseases, 31(3), 2012, pp. 207-225.
137
Brooklyn and Sigmon, op. cit.
138
California Department of Health Services, op. cit.

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referred to residential treatment will have their care overseen by addiction medicine specialists
employed by the Node. This will entail TREAT physicians being credentialed at the residential
treatment centers. Continuation or initiation of buprenorphine as a part of medication-assisted
treatment is likely to be a part of the treatment program for patients referred by TREAT.
TREAT physicians will prescribe the appropriate medication(s) and oversee induction and
stabilization (the maintenance phase is likely to take place after discharge from the facility). For
patients in residential treatment centers previously on methadone, arrangements will be made
with Overmountain Recovery.139
147. Working with the residential treatment center, TREAT will assist them in meeting
the requirements to procure and/or dispense buprenorphine or methadone. Utilizing this
approach, the much-needed counseling and therapy offered by residential treatment centers is
joined to evidence-based treatment for opioid use disorder using medication-assisted treatment.
148. Furthermore, as a part of TREAT, when patients are discharged from a residential
treatment facility, which is likely to occur in under 90 days, they are already a part of the opioid
use disorder treatment/recovery program of TREAT so that long-term follow-up is in place.
Since opioid use disorder is a chronic disease, this type of long-term approach to treatment is
essential. In this context, residential treatment has a role in the initial phase of treatment as well
as relapses.
149. Though there are some barriers, California and other states have in place or are
creating the regulatory framework for residential treatment centers to deliver medication-assisted
treatment. Dealing with the financial hurdles will also need to be addressed. Estimating the
demand for residential treatment is difficult because of the combination of public and private
facilities (the latter are hard to track) and the varying occupancy of these facilities.
150. Moving forward, the role of residential treatment facilities should be contributing
positively in the short and intermediate term to the continuum of care needed for a patient with
opioid use disorder to remain in treatment and achieve recovery. In order to maximize this
139
The latter facility is very cooperative and collaborative with regard to expanding methadone-medication-assisted
treatment for appropriate patients (personal communication to D. Stern, MD).

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contribution, these facilities must transition to delivering or supporting medication-assisted
treatment as an integral part of their programs.
I. Recovery Housing
151. While it is widely recognized that opioid use disorder is a chronic disease and safe
and stable housing is integral to durable recovery, nearly a third of individuals (32 percent)
entering substance abuse treatment report being marginally housed in the 30 days prior to
treatment entry.140 Numerous individuals I interviewed in Northeast Tennessee mentioned the
importance of long-term housing and the extreme lack of recovery housing options in the region.
152. Recovery housing can range along a continuum of four non-linear levels
described by the National Association of Recovery Residences (NARR), ranging from peer-run
establishments like Oxford Houses (level I), to monitored sober living homes (level II), to
supervised housing (level III), and residential treatment housing (level IV).141 Aside from these
levels, there are two general approaches to sober housing that depend on the relationship to a
treatment program: in one case, the house is directly connected to a treatment program in which
the residents participate. Alternatively, the house is independent of a treatment program, but
mandates a certain number of support group meetings (especially at the outset), such as
Alcoholics Anonymous or Narcotics Anonymous, that individuals need to attend. In the latter
category, some houses have more oversight of resident activities (Options Recovery Services,
ORS- linked to a treatment program) where others are less engaged with treatment for each
resident (Clean and Sober Transitional Living and Oxford Houses).
153. Analyzing outcomes from two sober living models (more and less engaged in
each patient’s recovery), the following was observed: clients resided on average 254 days in the
house linked to a treatment program versus 166 days in the independent house.142 At 18 months,
K.M. Eyrich-Garg, et al., “Individual characteristics of the literally homeless, marginally housed, and
140
impoverished in a US substance abuse treatment-seeking sample,” Social Psychiatry Psychiatry Epidemiology, 43,
2008, pp. 831-842.
141
National Association of Recovery Residences (NARR), “Primer on Recovery Residences,” 2012, at pp. 20-24
(https://narronline.org/wp-content/uploads/2014/06/Primer-on-Recovery-Residences-09-20-2012a.pdf).
142
D. Polcin, et al., “What did we learn from our study on sober living houses and where do we go from here?”
Journal of Psychoactive Drugs, 42(4), 2011, pp. 425–433.

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abstinence rates were similar in residents at the two types of houses (treatment-linked house at
46 percent abstinent vs independent house at 42 percent).143 Both of these numbers were
substantially above baseline when individuals moved into the house (11 percent for treatment-
linked house and 20 percent for independent house). In both types of houses, there was an
improvement in terms of employment (increased) and arrests (decreased).144 For example, in the
model linked to treatment, arrests were reduced by 80 percent at 6 months and even more at 12
and 18 months, compared with baseline.145
154. Many recovery housing operators are innovating to meet the significant demand
and unmet need for safe, supportive housing among people in recovery from opioid use disorder.
A growing number of mission-driven recovery housing operators are adapting policies,
procedures and programs to build proficiency in supporting residents who use medication-
assisted treatment. Key considerations include how homes screen and support residents, prepare
and train staff, ensure safety and prevent diversion of medications, coordinate with prescribing
physicians, and foster a culture inclusive of medication-assisted treatment pathways. NARR, in
collaboration with the National Council for Behavioral Health, recently released a guide for
recovery residence operators.146 Recovery housing providers may need support in developing
capacity and safety and security procedures to house residents who are using medication-assisted
treatment.
155. The current situation in the Johnson City area is that there are two types of sober
living houses currently in operation in the nine-county area. The larger group of sober living
facilities is Oxford Houses. They are part of a national umbrella organization (501c3) that
provides start-up costs for the houses. There are eleven Oxford Houses in the Johnson City Area
and none elsewhere in Northeast Tennessee.147 These houses accommodate 6-12 residents and
143
Ibid.
144
Ibid.
145
Ibid.
146
NARR, “MAT-Capable Recovery Residences: How State Policymakers Can Enhance and Expand Capacity to
Adequately Support Medication-Assisted Recovery,” August 2018 (https://narronline.org/wp-
content/uploads/2018/09/NARR_MAT_guide_for_state_agencies.pdf).
147
TDMHSAS, “Oxford Houses of Tennessee,” Directory as of September 19, 2019
(http://www.oxfordhouse.org/pdf/tn_directory_listing.pdf).

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have a total of 118 beds. The second group is run by Fairview Housing Corp and includes
Manna House (24 beds) and Bristol Lifestyle Recovery (which anticipates opening in the near
future with 240 beds). Neither Oxford Houses nor Manna House has a direct link to a treatment
program.148
156. Oxford Houses are run by the residents of the house. There are rules – for
example, the home (and occupants) must be free of alcohol and drug use, residents must attend
support meetings, contribute to their share of chores and pay appropriate fees – but the basic
approach is that the residents run the house via a democratic process. The advantage of this
approach is of the same as for any participatory democratic structure. But that is also the
disadvantage, as many Oxford Houses do not accept patients on medication-assisted treatment,
and “majority rule” by committee can be a barrier to medication-assisted treatment.
157. The approach of Fairview Housing is different: a house manager runs the facility,
and there are weekly meetings with residents to discuss every aspect of house operations. In a
study that Fairview Housing commissioned to estimate demand for beds in the Bristol Lifestyle
Recovery Facility, it was estimated that 1,706 referrals would be available annually.149 This
number of potential admissions is considerable, and draws from a fairly wide area as the hospital
discharges, re-entry and state-level corrections include people living in other parts of the state.
Nonetheless, these numbers emphasize the potential need for recovery housing.
158. The view that a significant increase in recovery housing will be needed as the
treatment population increases is supported by a study of patients with alcohol/other drug
problems who had successfully resolved their use disorder issues.150 The menu of “recovery
choices” indicates that 8.5 percent of former patients utilized sober living as a recovery support
pathway. For this reason, I estimated that as more individuals in Northeast Tennessee engage in
treatment/recovery, there will be a significant need for more recovery housing. Medications can
be self-managed by the resident, managed by a licensed 3rd party provider, or in the case of
Level IV Recovery Housing, managed by licensed staff of the facility.
148
Based on personal communication with Bob Garrett.
149
Province Evaluation, Bristol Lifestyle Recovery Statistics, May 1, 2018.
J.F. Kelly, et al., “Prevalence and pathways of recovery from drug and alcohol problems in the United States
150
population: Implications for practice, research, and policy,” Drug and Alcohol Dependence, 181, 2017, pp. 162–169.

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J. Continuity of Care & Clinical Pathways
159. Continuity of care is an element that is almost universally lacking for patients
with opioid use disorder. In this case, continuity of care means that an individual or
team assumes responsibility for care of a patient with opioid use disorder wherever she/he may
be. Thus, TREAT providers will direct and track the patient’s treatment through the levels of
care/different facilities and community-based recovery support services.
160. The team of physicians, therapists, case managers, and navigators in the Node is
designed to facilitate continuity of care. This would occur via:
• Mobile community health teams.
• TREAT personnel strategically positioned to oversee care in a residential treatment or

skilled nursing facility.
• Telemedicine in which TREAT care providers reach out to patients in the facility and
implement treatment plans. This could occur wherever the patients are located.
• Navigators who will provide support for patients that will guide them on their
care/living pathways with continuous positive reinforcement.
161. One of the issues that confounds efforts to help those with opioid use disorder is
the difficulty in engaging potential patients such that they see the advantages of treatment. Thus,
one of the key challenges in combatting the opioid epidemic is identifying patients, intervening,
and then encouraging them to enter and be retained in treatment. Hospitals and emergency
departments are a key part of the strategy to intervene and engage individuals with opioid use
disorder in treatment.
162. The complexity of the disease process and its chronicity have not been matched
by a well-planned response to the epidemic of opioid use disorder. This is illustrated by the
situation that most often plays out in emergency departments. Patients who present the
emergency department with opioid use disorder receive treatment to stabilize their condition,
followed by disposition to another setting, hopefully one that will support recovery, though this
is relatively rare. For example, Naeger et al. (2016) found that only 17 percent of privately
insured patients who presented at the hospital for an opioid-related problem engaged in post-
discharge SUD (substance use disorder)/opioid use disorder services within 30 days of their

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discharge.151 Another study of referral sources for prescription opioid treatment concluded that
less than 10 percent of referrals to treatment from 2006-2009 came from healthcare
professionals.152 A survey of 1,261 ER physicians indicated that about 92 percent of their ER
departments did not offer medication-assisted treatment to patients with opioid use
disorder.153 Furthermore, data on follow-up after an ER visit for alcohol or other drug
dependence (including opioids) within the 30-day range for adults from a sample of large health
plans of between 5-14 percent.154 This indicates that most people do not receive ANY follow-up
care for opioid use disorder after an ER visit, even though it is well-recognized that opioid use
disorder is a chronic disease. This is an untenable situation in terms of combatting the epidemic
of opioid use disorder.
163. For those patients with an opioid use disorder presenting in the ER who become
hospitalized for medical complications related to opioid use disorder or are sent to a residential
treatment center, care is often far from optimal, as many caregivers are not versed in addiction
medicine. For example, a patient who has endocarditis from injection drug use will get treatment
for the infectious cause of bacterial endocarditis but the patient is not placed in an addiction
treatment program and is released back into an unsafe environment where they might be
injecting illicit drugs with contaminated needles. Such an approach not uncommonly produces
an outcome in which the patient returns for future medical care with additional complications of
IV drug use.
151
S. Naeger, et al., “Post-Discharge Treatment Engagement Among Patients with an Opioid-Use Disorder,”
Journal of Substance Abuse Treatment, 69, 2016, pp. 64-71.
152
B. St. Marie, E. Sahker, and S. Arndt, “Referrals and Treatment Completion for Prescription Opioid Admissions:
Five Years of National Data,” Journal of Substance Abuse Treatment, 59, 2015, pp. 109–114.
153
https://www.emergencyphysicians.org/press-releases/2017/10-30-2017--oct-30-2017-research-offers-new-
insights-into-the-opioid-crisis.
154
There are likely well over 20,000 persons with opioid use disorder in Northeast Tennessee. According to a study
evaluating the number of opioid use disorder sufferers in Massachusetts, a state that in the aggregate is likely less
impacted by the opioid crisis that Northeast Tennessee, over 4% of the Massachusetts population has OUD. This is
likely applicable to Northeast Tennessee, but likely understates the problem. Tennessee Department of Health
records show that over 11,000 persons in the nine counties at issue have obtained prescriptions for Buprenorphine.
Given that most opioid use disorder goes untreated, it is reasonable to estimate that well over twice that number of
persons have the disorder. Joshua A. Barocas, Laura F. White, Jianing Wang, Alexander Y. Walley, Marc R.
LaRochelle, Dana Bernson, Thomas Land, Jake R. Morgan, Jeffrey H. Samet, and Benjamin P. Linas,
2018:Estimated Prevalence of Opioid Use Disorder in Massachusetts, 2011–2015: A Capture–Recapture Analysis,
American Journal of Public Health 108, 1675_1681, https://doi.org/10.2105/AJPH.2018.304673.

Page 67
164. Another group of patients presenting in the ER with opioid use disorder come
from an environment not conducive to sobriety/recovery (i.e., one which encourages
relapse). For example, family and friends might include multiple individuals who use illicit
drugs. In addition, the patient’s willingness/readiness to change might be suboptimal along with
emotional and behavioral problems, and an inability to deal with physical problems that are
associated with withdrawal. These patients are often referred to residential treatment centers
which provide short-term housing for the individual along with therapy and, sometimes, social
work. Unfortunately, many of these treatment centers do not offer medication-assisted
treatment. Thus, the immediate need for housing is met by a residential treatment center, but the
equally important requirement of evidence-based treatment is not addressed. In this plan, long-
term state-of-the-art care for patients with opioid use disorder is an important goal.
165. The disposition of most opioid use disorder patients who come to the ER
is “routine discharge,” meaning that they return to the community. The key issue is their ability
and/or desire to access follow-up opioid use disorder care of high-quality care. These patients
will often have a place to live, some level of family/social support and, potentially, some level of
willingness to enter treatment. The problem is that without considerably more effort on behalf of
the general system of health care, a small percentage of these people enter treatment.
166. The above summary of care for patients with opioid use disorder indicates that
coordination between acute health care settings and medium- and longer-term treatment sites
remains elusive. Any plan to reduce opioid use disorder and its consequences in Northeast
Tennessee must necessarily provide for coordination of services to ensure consistency and
continuity of care to the extent possible.
167. Representative care pathways are shown in Figure 5 below.

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Figure 5
168. The TREAT team (physicians, therapists, case managers, Navigators) will
participate and oversee care at all sites. TREAT has the goal of moving patients to and having
them remain in outpatient therapy on medication-assisted treatment as long as indicated. This
will be facilitated by the model of wraparound services that is the foundation of this treatment
plan.
K. Patient Capacity & Distribution of Patients
169. In determining the recommended capacity of the plan described herein, I

considered the following:
1. The current treatment landscape in Northeast Tennessee, detailed throughout this

report.
2. Statistics concerning community sites where underserved populations with high opioid
use disorder rates can be accessed and engaged in treatment.
3. The rate at which patients have been recruited, engaged, and retained in other states
and regions, as well as the outcomes of other evidence-based practices.

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4. The staffing and recruitment needs and processes based on my own experience, input
from local stakeholders, and standards that are regularly used in the field.
5. The range of estimates of the prevalence of opioid use disorder in Northeast Tennessee
and other anecdotal and statistical data regarding the severity of the opioid epidemic in
the region.
6. The number of patients that would need to be comprehensively treated in order to make
substantial progress in combatting the opioid epidemic.
7. The extent to which patients will cycle in and out of treatment multiple times and the
treatment population will constantly change due to the chronic, often relapsing nature
of addiction.
170. Based on the foregoing, I have determined that, at full capacity, this plan should
be able to treat 10,000 individuals suffering from opioid use disorder at any given time and
continue providing care at this capacity until substantial progress is made. Given the prevalence
of opioid use disorder in Northeast Tennessee, the ability of TREAT to eliminate existing
financial and structural barriers to treatment, and the attractive, high-quality service that TREAT
promises to offer, I estimate that TREAT will have no difficulty attracting at least 10,000
persons to its system of treatment after its initial ramp-up period. I estimate that capacity will
start at 2,000 patients in 2020 and be increased by 1,600 each year until 10,000 is reached at the
end of Year 5. The distribution of patients along the continuum of care will be as outlined in
Figure 6 below. In the current system of short-term residential treatment and long-term sober-
living houses, MAT is not permitted or administered. However, I estimate that MAT-friendly
facilities can be ramped up to accommodate the need of patients within this system.

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Figure 6
171. Most of the care provided under the plan falls into the “outpatient” category,
which includes intensive outpatient, moderate intensity outpatient, and maintenance, and will be
administered by the Nodes or coordinated with well-supported primary care physicians. The
majority of patients will receive medication-assisted treatment.
172. At any given time, residential treatment facilities that allow medication-assisted
treatment will accommodate around 15 percent of the patients treated under the plan. These
facilities serve as a valuable option for patients with opioid use disorder, though I anticipate that
an emphasis on high-quality outpatient care and long-term recovery housing will decrease the
level of relapses and the need for multiple stays in residential treatment facilities.
173. The number of inpatient admissions will also decrease as a result of better
outpatient care. However, there will always be a need for a certain level inpatient care due to co-
occurring, severe mental illnesses and patients presenting with polysubstance use who must be
stabilized before treatment can begin. It will be essential that inpatient care includes treatment
for the underlying addiction and a “warm” handoff to a Node as patients reach discharge.
174. In addition to residential treatment facilities, Recovery Housing that integrates

evidence-based treatment should be available to 10 percent of patients with opioid use disorder.

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This estimate of the number who would be likely to seek such accommodations for a period of
one year or longer is based on the literature.155
L. Infrastructure for Data Collection and Evaluation of Clinical Outcomes.
175. It will be essential to develop an infrastructure that tracks outcomes (both process
and impact outcomes) in order to continuously evaluate and improve the level of service to
opioid use disorder patients. There are three components that comprise TREAT infrastructure
for this purpose:
1. An IT platform that includes an electronic medical record (EMR), and telemedicine,

billing/revenue cycle and practice management modules to capture the data.
2. Outcomes coordinators who will be charged with overseeing data collection and
compliance, as well as protection of human subjects. These individuals will be
placed in each node and function analogous to a research nurse about the integrity of
the data.
3. Outcomes evaluators who will be analytics experts. They will run reports on
outcomes data, establish trends and statistically significant results, and draw
conclusions. These conclusions will be used to evaluate the effectiveness of the
program in real-time, and guide performance improvement projects. Outcomes
evaluators will be located centrally as well as traveling node-to-node.
176. I have divided my evaluation of clinical results into process and impact
outcomes. My most important initial process outcome is the referral of patients to TREAT
providers resulting in those individuals entering and being retained in TREAT’s long-term and
wraparound brand of medication-assisted treatment.
177. The population that I have targeted to move into treatment includes a total of
10,000 patients over 5 years. I anticipate 2000 patients will be referred to TREAT by the end of
Year 1, and 2000 additional referrals each year up to Year 5 (see Table 1). At Year 5, this would
mean that a substantial number of those with opioid use disorder in the nine-county region would
be in TREAT wraparound programs. Our key targets by year 5 are indicated in Table 1 below.
155
Kelly, et al., op. cit.

Page 72
Particularly noteworthy is that, following referral (I anticipate that 10,000 patients will be
referred by the end of year 5), I anticipate that patients can be engaged in TREAT protocols (90
percent) and that they will be adherent and retained on these treatment protocols (>80 percent).
Note that adherence and retention on TREAT protocols (80 percent and >80 percent in years 4
and 5, respectively) would be outstanding at a national level based on today’s benchmarks (see
references below and https://doi.org/10.1016/j.drugalcdep.2015.02.030).
Table 1
Process outcomes in a patient population of 10,000
Year
1 2 3 4 5
a
Percent patients referred 20 40 60 80 100
percent percent percent percent percent
Percent referred patients on protocol 15 40 60 80 90
percent percent percent percent percent
Percent patients experiencing 50 60 70 80 >80
adherence and retention on medical percent percent percent percent percent
protocol
a
Referral is defined as a referral from an outside agency (Ballad, Frontier, treatment center,
jail/prison, etc.) that results in the patient coming to TREAT for service. Though this may seem
like a simple process, it proves to be a very difficult issue to address. A recent study shows that only
10 percent of patients who misuse opioids are referred to substance abuse treatment by a health care
professional. Very few patients with substance/alcohol use disorder or “chemical dependency”
follow-up on these referrals for care. This includes the population with opioid use disorder. Our
approach to improving the effectiveness of referral is interposing Navigators to discuss the referral
process and advantages of treatment, and to have them facilitate transportation to TREAT. In many
ways, the Navigators will be the community face of our program.
178. In Table 2 below are the impact outcomes that will be tracked in TREAT on an
annual basis.

Page 73
Table 2
The estimated effect of TREAT on impact outcomes
within the entire patient population of opioid misusers
(N = 10,000)
Impact outcomes Year

1 2 3 4 5
a
All-cause mortality -1 percent -7 percent -17 percent -31 percent -52 percent
Overdose b -1 percent -8 percent -20 percent -36 percent -61 percent
ED Admissions c -1 percent -6 percent -17 percent -29 percent -51 percent
Hospital Admissions d -1 percent -7 percent -20 percent -35 percent -69 percent
Work Status e 1 percent 6 percent 15 percent 23 percent 39 percent
Stable Housing f 0 percent 1 percent 2 percent 3 percent 6 percent
Stable Family g 1 percent 6 percent 15 percent 23 percent 40 percent
Contact with the 0 percent -3 percent -9 percent -15 percent -26 percent
criminal justice system h
a
All-cause mortality data will be obtained by reviewing death certificates and coroner files (if
needed; Sordo et al., 2017).
b
Overdose data will be obtained by examining police records, medical records, autopsy results,
and toxicological results. Intoxication death will be defined according to two criteria: (1) the drug
was mentioned as the cause of death, or (2) the determined cause of death used non-specific terms
such as “drug intoxication” or “narcotic intoxication” and the toxicological analysis indicated the
presence of the drug(s) (Schwartz et al., 2013).
c
Emergency department visits will be measured as the proportion of people who had at least 1
emergency department (ED) admission with any diagnosis related to opioid or other drug use.
Data will be obtained by reviewing medical records. (London, Utter, Battistella, & Wisner, 2009;
Ronquest, Willson, Montejano, Nadipelli, & Wollschlaeger, 2018).
d
Hospital admissions visits will be measured as the proportion of people who had at least 1
inpatient admission with any diagnosis related to opioid use. Data will be obtained by reviewing
medical records (London et al., 2009; Ronquest et al., 2018).
e
Work status will be measured as stable employment, which will be defined as working at the
same place of employment for one year. Data will be obtained from self-report (Gerra et al.,
2003).
f
Stable housing will be defined as reporting two consecutive “stable housing” designations (i.e.,
living in an apartment or house) during the follow-up period. Data will be obtained through
medical records or self-report (Palepu, Marshall, Lai, Wood, & Kerr, 2010).
g
Stable family will be defined as the quality of interpersonal relationships. Data will be obtained
through self-report by developing a visual analog scale (0-100 slider) where people rate the quality
of their interpersonal relationships. Bad relationships will be defined as having no affective
relationship with family members or friends (scores less than 30), good relationships will be
defined as having close affective relationships with family members or friends (scores more than
70), and maintained relationships will be relationships that exist but have many difficulties (scores
between 31 and 70; Gerra et al., 2003b).
h
Contact with the criminal justice system will be defined as the total number of violent and
nonviolent crimes committed. Criminal offenses will be obtained by accessing criminal records (if
available) or through self-report (Russolillo, Moniruzzaman, McCandless, Patterson, & Somers,
2018).

Page 74
How to interpret the outcomes in Table 2
179. The correct interpretation of the outcomes in Table 2 is illustrated by the

following two examples:
a. Example 1: By Year 3, TREAT is expected to reduce hospital admissions

by 20 percent among the entire opioid use disorder patient population
b. Example 2: By Year 3, TREAT is expected to improve stable employment

(e.g., working at the same company during the year and regularly paying
taxes) by 15 percent among the entire opioid use disorder patient
population.
180. Another way to assess the same outcomes is by comparison with the population of
patients who are engaged in TREAT (rather than the whole population with opioid use disorder).
That method was used to create Table 3 below.
Table 3
Estimated impact of TREAT on impact outcomes among patients
receiving treatment for opioid use disorder (and are in the TREAT program)
Impact outcomes Year

1 2 3 4 5
All-cause mortality -34 percent -41 percent -48 percent -55 percent -62 percent
Overdose -40 percent -48 percent -56 percent -64 percent -72 percent
ED Admissions -33 percent -40 percent -46 percent -53 percent -60 percent
Hospital Admissions -39 percent -47 percent -55 percent -62 percent -70 percent
Work Status 29 percent 35 percent 41 percent 47 percent 52 percent
Stable Housing 4 percent 5 percent 6 percent 6 percent 7 percent
Stable Family 30 percent 35 percent 41 percent 47 percent 53 percent
Contact with the -17 percent -21 percent -34 percent -34 percent -34 percent
criminal justice system
How to interpret these outcomes:
181. The correct interpretation of the outcomes in Table 3 is illustrated by the

following two examples:
a. Example 1: By Year 3, TREAT is expected to reduce hospital admissions

by 55 percent among patients who are within TREAT and are adherent to
MAT.

Page 75
b. Example 2: By Year 3, TREAT is expected to improve stable employment
(e.g., working at the same company during the year and regularly paying
taxes) by 41 percent among patients who are within TREAT and are
adherent to MAT.
References for Tables Above

Gerra, G., Ferri, M., Polidori, E., Santoro, G., Zaimovic, A., & Sternieri, E. (2003). Long-term
methadone maintenance effectiveness: psychosocial and pharmacological variables. Journal
of Substance Abuse Treatment, 25(1), 1–8. https://doi.org/10.1016/S0740-5472(03)00031-X
London, J. A., Utter, G. H., Battistella, F., & Wisner, D. (2009). Methamphetamine Use is
Associated With Increased Hospital Resource Consumption Among Minimally Injured
Trauma Patients. The Journal of Trauma: Injury, Infection, and Critical Care, 66(2), 485–
490. https://doi.org/10.1097/TA.0b013e318160e1db
Marie, B. St., Sahker, E., & Arndt, S. (2015). Referrals and Treatment Completion for
Prescription Opioid Admissions: Five Years of National Data. Journal of Substance Abuse
Treatment, 59, 109–114. https://doi.org/10.1016/j.jsat.2015.07.010
Palepu, A., Marshall, B. D. L., Lai, C., Wood, E., & Kerr, T. (2010). Addiction Treatment and
Stable Housing among a Cohort of Injection Drug Users. PLoS ONE, 5(7), e11697.
https://doi.org/10.1371/journal.pone.0011697
Ronquest, N., Willson, T., Montejano, L., Nadipelli, V., & Wollschlaeger, B. (2018).
Relationship between buprenorphine adherence and relapse, health care utilization and costs
in privately and publicly insured patients with opioid use disorder. Substance Abuse and
Rehabilitation, Volume 9, 59–78. https://doi.org/10.2147/SAR.S150253
Russolillo, A., Moniruzzaman, A., McCandless, L. C., Patterson, M., & Somers, J. M. (2018).
Associations between methadone maintenance treatment and crime: a 17-year longitudinal
cohort study of Canadian provincial offenders. Addiction, 113(4), 656–667.
https://doi.org/10.1111/add.14059
Schwartz, R. P., Gryczynski, J., O’Grady, K. E., Sharfstein, J. M., Warren, G., Olsen, Y., …
Jaffe, J. H. (2013). Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore,
Maryland, 1995–2009. American Journal of Public Health, 103(5), 917–922.
https://doi.org/10.2105/AJPH.2012.301049
Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., … Pastor-
Barriuso, R. (2017). Mortality risk during and after opioid substitution treatment: systematic
review and meta-analysis of cohort studies. BMJ, j1550. https://doi.org/10.1136/bmj.j1550
182. Attached to this report is a table that provides additional costs.

Page 76
X. Appendix
Supplemental Table
Estimated impact of medication-assisted treatment on proposed process measures
Impact outcomes Adherent Non-adherent

1. All-cause mortality rate (per 1000 person-years) 11 36
2. Overdose mortality (per 1000 person-years) 3 13
3. ED visits (percent with at least 1 emergency
department visit) 4 percent 11 percent
4. Hospital admissions (percent with at least 1 hospital

admission) 4 percent 17 percent
5. Number of violent criminal offenses (per 100 person-

years) 7 11
6. Number of nonviolent offenses (per 100 person-years) 69 106

7. Work status (percent with stable job) 45 percent 28 percent
8. Interpersonal relationship quality (percent with good
relationships) 64 percent 40 percent
9. Stable housing (percent living in an apartment or a

house over two consecutive interviews during the 23 percent 21 percent
follow-up period)
The above information provides the lower (population with opioid/substance use disorder that is
nonadherent to therapy) and upper (population with opioid/substance use disorder that is adherent
to therapy) limits for the impact outcomes that TREAT proposes to track.
1. All-cause mortality rates are based on 122,885 people treated with methadone over 1.3–13.9 years.
These estimates compare crude mortality rates per 1000 years based on people in and outside of
methadone treatment (Sordo et al., 2017). Because of the long-time over which methadone
treatment has been available (since the 1960s) compared with buprenorphine (approved by the
FDA for treatment of addiction in 2002), these kinds of long-term outcomes data are mainly
available for the population with opioid use disorder treated with methadone. At present, I am
assuming that outcomes with methadone/medication-assisted treatment will be roughly
comparable to the combination of buprenorphine/medication-assisted treatment,
methadone/medication-assisted treatment and naltrexone/medication-assisted treatment that will
be offered by TREAT. However, it is expected that outcomes backed up by studies in many
patients over longer times will be available with buprenorphine/medication-assisted treatment
during our program. Based on these emerging data, TREAT outcome expectations may be
modified accordingly.
2. Over-dose mortality rates are based on 122,885 people treated with methadone over 1.3–13.9
years. These estimates compare crude mortality rates per 1000 years based on people in and
outside of methadone treatment (Sordo et al., 2017). Please note the comment above regarding
methadone/medication-assisted treatment versus medication-assisted treatment offered in TREAT
(methadone/buprenorphine/naltrexone-medication assisted treatment).

Page 77
3. Emergency department admissions are based on 16,085 commercially insured patients and 5,688
Medicaid patients. Buprenorphine MAT adherence was measured using the proportion of days
covered (PDC) by buprenorphine in the 12 months following treatment initiation. Adherent people
spent 80 percent or more days covered by Buprenorphine and non-adherent people spent less than
20 percent of days covered by Buprenorphine (Ronquest et al., 2018).
4. Hospital admissions are based on 16,085 commercially insured patients and 5,688 Medicaid
patients. Buprenorphine MAT adherence was measured using the proportion of days covered
(PDC) by buprenorphine in the 12 months following treatment initiation. Adherent people spent
80 percent or more days covered by Buprenorphine and non-adherent people spent less than 20
percent of days covered by Buprenorphine (Ronquest et al., 2018).
5. Total crime (violent crime + non-violent crime) estimates are based on the linkage of population-
level administrative data (health and justice) for all individuals (n=14,530) in British Columbia,
Canada with a history of conviction and who filled a methadone prescription between 1 January
1998 and 31 March 2015. Estimates for adherence are based on when methadone was dispensed,
and non-adherence was based on when methadone was not dispensed (Russolillo et al., 2018).
6. Work status and interpersonal relationship quality estimates are based on 265 heroin-dependent
patients in long-term methadone maintenance treatment. Adherence estimates are based on
individuals who had negative results on more than 50 percent of urine tests, and non-adherence
estimates were based on individuals who completed 1 or fewer urine tests or tested positive for
illicit drugs in 50 percent or more of the urine tests (Gerra et al., 2003).
7. No studies indicated that MAT improved housing stability. Entering MAT treatment seems to be
associated with increased housing instability, but this association may just reflect how volatile
clients are when they enter MAT treatment (Palepu et al., 2010). Because the estimated impact of
MAT on housing may be null or negative, these estimates are based on the base rate of housing
stability among persons who had injected illicit drugs at least once in the previous six months.
Therefore, 21.30 percent represent the actual percentage of people who can reside in a home or
apartment for two consecutive survey periods (Palepu et al., 2010), and this number was used as a
placeholder for non-adherence. The adherence estimate is arbitrary, but a small and nonsignificant
impact is expected given the lack of good evidence.
NOTE: References are the same as those listed for Table 2.

Page 78
David M. Stern, M.D.
September 20, 2019

Page 79
Attachment A
CURRICULUM VITAE
DAVID MARK STERN

CEO and cofounder
Integrated Addiction Care Inc.
Telephone: (901) 598 0982

E-mail: dstern@integratedaddictioncare.com
Education: Yale University, New Haven Connecticut, B.S.

Chemistry (Magna) 1973
Columbia University, New York, Chemistry, 1973-1974
Harvard Medical School, Boston, Massachusetts, M.D., 1978
Executive Development Seminar for Deans, Council of Deans

of AAMC, Washington DC, 2002
Course for Leaders in Medical Education, Harvard/Macy

Institute, Harvard Medical/Business School, Boston
Massachusetts, 2002
Research and/or Professional Experience:
2019 - CEO and cofounder, Integrated Addiction Care Inc.
2018 Member, Tennessee Governor’s Commission on Pain and

Addiction Medicine Education
2017 – 2018 Vice-Chancellor for Health Affairs for Statewide Initiatives,

University of Tennessee Health Science Center, Memphis,
TN
2013 – 2019 Board Member, Medical Education and Research Institute,

Memphis, TN
2012 – 2017 Member of Board, Board of Directors, Methodist LeBonheur

Healthcare, Memphis, TN
2012 – 2016 Executive Vice-President of Medical Affairs, Methodist

LeBonheur Healthcare, Memphis, TN (position assigned to
my designee on December 31, 2016)
Stern, David M., MD
Curriculum Vitae
2012 - 2013 Chair of Research Council, University of Tennessee Health

Science Center
2012 – 2019 Professor of Medicine and Physiology, University of

Tennessee Health Science Center (tenured, 2012)
2011 - 2012 interim Vice-Chancellor for Research, University of

Tennessee Health Science Center, Memphis, Tennessee
2011 – 2017 Chairman of the Board, University of Tennessee Medical

Group (renamed University Clinical Health in 2016 as part of
rebranding campaign), Memphis, Tennessee
2011 – 2017 Co-chair of the Board, University-LeBonheur Pediatric

Specialists
2011 - 2017 Robert J. Kaplan Executive Dean and Vice-Chancellor for

Health Affairs, University of Tennessee Health Sciences
Center
2010 – 2016 Consulting physician, FTI Healthcare Consulting, Inc.
2009 – 2010 Health Alliance Board of Trustees, Cincinnati, OH
2009 – 2010 Co-Chair, Health Affairs Subcommittee, Board of Trustees

University of Cincinnati, Cincinnati, OH
2008 - 2010 Vice-President for Health Affairs, University of Cincinnati,

Cincinnati, OH
2008 - 2010 Member, Executive Committee, University of Cincinnati;

member, President’s Cabinet, University of Cincinnati,
Cincinnati, OH
2007 - 2010 President, University of Cincinnati Physicians (faculty practice

group), Cincinnati, OH
2007 - 2009 Chair, Council of Ohio Medical School Deans
2006 - 2010 Member, Research and Education Subcommittee of the

Board of Trustees of Cincinnati Children’s Hospital Medical
Center
2006 - 2010 Member, Board of Directors (and Executive Committee),

Craig and Frances Lindner Center of HOPE (new mental
health hospital), Mason, OH
2
Stern, David M., MD
Curriculum Vitae
2005 - 2010 Christian R. Holmes Professor and Dean, College of

Medicine, University of Cincinnati, Cincinnati, OH
2005 - 2010 Member, Board of Directors, the University Hospital,

Cincinnati, OH
2005 - 2010 Professor, Departments of Internal Medicine and Molecular

and Cellular Physiology, College of Medicine, University of
Cincinnati, Cincinnati, OH
2005 - 2010 Chairman of the Board, University of Cincinnati Physicians,

Cincinnati, OH
2005 - 2009 Interim Cancer Center Director, College of Medicine,

University of Cincinnati, Cincinnati, OH
2002 - 2005 Director, Board of Directors, MCG Health, Inc., Augusta, GA
2002 - 2005 Dean, School of Medicine, Medical College of Georgia,

Augusta, GA
1/03 - 2005 Chief Clinical Officer, Medical College of Georgia, Augusta,

GA
4/02 - 1/03 Senior Vice-President for Clinical Activities, Medical College

of Georgia, Augusta, GA
2002 – 2005 Professor of Medicine and Physiology, Medical College of

Georgia, Augusta, GA
2000 - 2002 Director, Center for Vascular and Lung Pathobiology,

College of Physicians & Surgeons of Columbia University,
New York, NY
2000 - 2002 Director, Juvenile Diabetes Research Foundation Center on

the Vascular Complications of Diabetes, Columbia University
New York, NY
2000 - 2002 Chief, Division of Surgical Science, Department of Surgery,

New York, NY
1998 - 2002 Gerald and Janet Carrus Professor of Surgical Sciences and
of Physiology and Cellular Biophysics, Faculty of Medicine,
New York, NY
3
Stern, David M., MD
Curriculum Vitae
1996 - 1998 Professor, Department of Physiology and Cellular Biophysics

(in Surgery), College of Physicians & Surgeons of Columbia
University, New York, NY
1987 - 1996 Associate Professor, Department of Physiology and Cellular

Biophysics, College of Physicians & Surgeons of Columbia
University, New York, NY (tenure, 1994)
1986 - 1987 Associate Member, Thrombosis/Hematology Research

Program, Oklahoma Medical Research Foundation,
Oklahoma City, OK
1985 - 1986 Assistant Member, Thrombosis/Hematology Research

Program, Oklahoma Medical Research Foundation,
Oklahoma City, OK
1983 - 1985 Assistant Professor, Department of Medicine, College of

Physicians & Surgeons of Columbia University, New York,
NY
1981 - 1983 Fellow, Hematology Division, College of Physicians &

Surgeons of Columbia University, New York, NY
1978 - 1981 Resident in Medicine, Columbia Presbyterian Medical Center,

New York, NY
Certification: Diplomate American Board of Internal Medicine, 1981
Licensure: Ohio, 35-087438

Georgia, 051557
New York, 141478-1
Tennessee, 047378
Awards and Honors:
Clinician Scientist Award, American Heart Association, #83-419
Young Investigator Award, Oklahoma Affiliate, American Heart Association
Merrick Award, Oklahoma Medical Research Foundation, 1986
Finalist, Sanofi Thrombosis Research Foundation's International Award on

Thrombosis, Brussels, 1987
Established Investigator Award, American Heart Association (Awarded 11/87)
4
Stern, David M., MD
Curriculum Vitae
Fellow of the Council on Arteriosclerosis, American Heart Association, 1/92
Special Lecturer, 10th Japanese Society on Thrombosis and Hemostasis,

December, 1987
Co-chairman, Gordon Conference on Vascular Cell Biology (elected 1990 to run

the 1992 meeting)
Borun Visiting Professor, Cardiology Division, Dept. of Medicine, UCLA (8/92)
Special Invited Lecturer, Third Symposium on Diabetes, Osaka, Japan, 3/93
Board of Scientific Advisors, Sterling Winthrop, 1992-1996
Visiting Professor, University of Hong Kong, 1997
Merit Award, NIH-NHLBI, 2000 (related to HL63967)
Fellow of the American Heart Association (2/01)
Eli Lilly Visiting Professor, Division of Endocrinology, University of Colorado

School of Medicine, Denver, CO (4/02)
Co-Chair, Diabetes Summit at National AHA meeting, Chicago, IL (2002)
Scientific Advisory Board, Atherogenics, 2003-2005
Visiting Professor, Department of Medicine, UCLA, 2004
Elected to Alpha Omega Alpha (medical honor society), 2004
United States Department of Veterans Affairs Blue Ribbon Panel on VA-Medical

School Affiliations, 2006-2009
Special Recognition Award, University Hospital, 2009
Health Care Heroes Award (category: administrative excellence), Memphis

Business Journal, Memphis, TN, August, 2016 – annual award for physicians and
administrators
“10 to Watch” designation for University of Tennessee College of Medicine (2016)

by Chamber of Commerce and described in Memphis Crossroads magazine in
2016
5
Stern, David M., MD
Curriculum Vitae
Invited plenary speaker, Medicine Responds to Addiction II, White House,

October 2016, Washington DC: Centers of Excellence in Addiction Medicine and
Practice.
Invited speaker, TennCare Health Plan Meeting (the managed care companies
that manage Medicaid in Tennessee): UT-Memphis: community engagement
and the academic health center, February, 2017
Secured designation for University of Tennessee Health Science Center of

“Center of Excellence” for the Center for Addiction Science, 2016
Secured for placement at University of Tennessee Health Science Center –
College of Medicine of the National Research Center of The Addiction Medicine
Foundation (TAMF), presentation by Dr. D. Stern and subsequent affirmative vote
at 3/9/17 meeting of Board of TAMF
Invited speaker, TN Governor’s Subcabinet meeting on opioid epidemic: Plan for

Western TN to halt the epidemic of substance use disorder. Nashville, TN, 2018
Invited speaker, Sixth Judicial Circuit Conference

Plenary session: Reentry Court
Breakout: Opioid litigation and conference
Nashville, TN, 2018
Invited panelist, SAMHSA, meeting on Serious mental illness and substance use
disorder: Integrated care for substance use disorder in Western Tennessee.
August, 2018, Rockville, MD
Invited speaker, Senate President’s Forum: Combating the opioid epidemic: it

takes a village. September, 2018, Nashville, TN
Invited speaker Council of State Governments annual meeting: the opioid

epidemic, education and treatment. November, 2018, Covington, KY
Invited speaker, TennCare Health Plan annual planning meeting, Q source

1) Program in Addiction Medicine
2) Free Clinic for the Underserved in South Memphis
June, 2019, Nashville, TN
Invited speaker and moderator, Opioids – using telemedicine to win the war.
South Central Telehealth Forum, Nashville TN, August, 2019
Fellowships and Memberships in Scientific Societies:
American Society of Clinical Investigation

Association of American Physicians
American Society of Biochemistry and Molecular Biology
American Society of Hematology
6
Stern, David M., MD
Curriculum Vitae
American Society of Cell Biology

Councils on Thrombosis and Basic Sciences of the American Heart Association
American Association of Pathologists
American Federation of Clinical Research
Harvey Society
International Society on Thrombosis and Hemostasis
Grant/Contract Support (during my tenure as Vice Chancellor for Health Affairs

for Statewide Initiatives and Executive Director of Center for Addiction Science at
UTHSC the followed grants-contracts-gifts have been secured and/or are
pending)
Awarded
State Allocation for Center for Addiction Science - $2 million: for Dr. Stern to grow
the Center for Addiction science in the clinical, research and educational
missions. There is an emphasis on creating addiction medicine services that
make the Center a statewide resource
The Addiction Medicine Foundation- total of $150,000 over three years (P.I., D.
Stern). This establishes the Center for Addiction Science as the National
Research Center for The Addiction Medicine Foundation (Washington DC)
Assisi Foundation, $1.5 M, PI, D. Stern
Shelby County Contract – $2 million; PI, D. Stern. Create an addiction medicine

network (hub and spoke) for Shelby County
BOJA (with Shelby County Dept of Community Services as the submitting

organization)- $500,000, application formulated by D. Stern, MD
SAMHSA (with First Step Recovery as submitting organization):

$900,000, application formulated by D. Stern, MD
Pending:
Rural Addiction medicine network-

Title: Combating the opioid epidemic in rural America: demonstration project in
Western TN
Submitted to USDA: $3.6 million per year x 2 years
Bequest:
Chris and Watty Hall: $3 million to Center for Addiction Science (donors
cultivated by D. Stern)
7
Stern, David M., MD
Curriculum Vitae
Past grant support:

Active grant support at the time Dr. Stern (then at Columbia University, College of
Physicians & Surgeons) became Dean and Senior Vice-President for Clinical
Activities at Medical College of Georgia (4/02). Dr. Stern’s formal role in these
projects terminated when he moved to Georgia.
1PO1 HL60901 3/1/99-2/29-04

NIH PPG P.I., D. Stern $700,000(direct)/year
Grant title: RAGE and mechanisms of vascular and monocyte dysfunction
1PO1 AG17490 8/1/00-6/30/05

NIH PPG P.I., D. Stern $1,050,000(direct)/year
Grant title: Cellular cofactors, neuronal stress & rescue, aging and AD
1R37 HL63967 3/1/99-2/29/04

NIH MERIT Award, P.I., D. Stern $190,000(direct)/year
Grant title: Modulation of vascular function by hypoxemia/ischemia
1PO1 AG512807 3/1/99-2/29/04

NIH PPG P.I., B. Zlokovic (subcontract to D. Stern at Columbia)
Grant title: The aging brain: cerebrovascular mechanisms and amyloid-beta
Project title (for subcontract): Chronic cerebrovascular perturbation: role of
RAGE
Subcontract $130,000(direct)/year
T32 HL07854 7/1/96-6/30/02

NIH Training grant, P.I., D. Stern $185,000(direct)/year
Grant title: Postdoctoral training in cardiovascular biology
Competitive renewal was successful and funding was in place to start 7/1/02
through 6/30/06 at a level of $285,000/year.
Juvenile Diabetes Research Foundation (JDRF) Center on Diabetic Complications

(at Columbia) 8/1/00-7/31/03
P.I., D. Stern $1,100,000/year
Grant title: RAGE, a central receptor in the pathogenesis of diabetic
complications
LeDucq Foundation 7/1/00-6/30/03

Mechanisms of vascular dysfunction $500,000/year
Trans Tech Pharma, Inc. 7/1/00-6/30/05

Industrial contract P.I., D. Stern $500,000/year
8
Stern, David M., MD
Curriculum Vitae
Grant Activity in Georgia

Georgia Cancer Coalition 7/1/04-6/30/07
Center of Excellence:
Georgia Cancer Research Center, P.I., D. Stern
This grant application led to MCG receiving the Georgia Cancer Coalition
designation as the second Center of Excellence in Georgia. Dr. Stern’s role in
this project terminated on leaving Georgia in 7/05.
BIBLIOGRAPHY
I. Peer-Reviewed
1. Stern, D., Nossel, H.L., and Owens, J. Acquired antibody to factor XI in a

patient with congenital factor XI deficiency. J. Clin. Invest. 69:1270-1276,
1982.
2. Stern, D.M., Drillings, M., Nossel, H.L., Hurlet-Jensen, A., LaGamma, K.

and Owen, J., Binding of factors IX and IXa to cultured vascular
endothelial cells. Proc. Natl. Acad. Sci. USA 80:4119-4123, 1983.
3. Stern, D.M., Drillings, M., Kisiel, W., Nawroth, P., Nossel, H.L. and
LaGamma K.S., Activation of factor IX bound to cultured bovine aortic
endothelial cells. Proc. Natl. Acad. Sci., USA 81:913-917, 1984.
4. Nawroth, P., Stern, D.M., Kaplan, K.L. and Nossel, H.L. Prostacyclin
production by perturbed bovine aortic endothelial cells in culture. Blood
64:801-806, 1984.
5. Stern, D.M., Nawroth, P., Kisiel, W., Handley, D., Drillings, M. and Bartos,
J. A coagulation pathway on bovine aortic segments leading to generation
of factor Xa and thrombin. J. Clin. Invest. 74:1910-1921, 1984.
6. Stern, D.M., Nawroth, P., Marcum, J., Handley, D., Kisiel, W., Rosenberg,
R. and Stern, K. Interaction of antithrombin III with bovine aortic segments.
J. Clin. Invest. 75:272-277, 1985.
7. Stern, D.M., Nawroth, P., Handley, D. and Kisiel, W. An endothelial cell-

dependent pathway of coagulation. Proc. Natl. Acad. Sci. USA 82:2523-
2527, 1985.
8. Nawroth, P.P., Stern, D.M. and Dietrich, M. Thromboxane production by

perturbed bovine aortic endothelial cells in culture. Blut 50:7-11, 1985.
9. Stern, D.M., Nawroth, P.P., Kisiel, W., Vehar, G. and Esmon, C.T. The
binding of factor IXa to cultured bovine aortic endothelial cells: induction of
9
Stern, David M., MD
Curriculum Vitae
a specific site in the presence of factors VIII and X. J. Biol. Chem.

260:6717-6722, 1985.
10. Nawroth, P., McCarthy, D., Kisiel, W., Handley, D. and Stern, M.D. Cellular
processing of bovine factors X and Xa by cultured bovine aortic endothelial
cells. J. Exp. Med. 162:559-572, 1985.
11. Stern, D.M., Bank, I., Nawroth, P.P., Cassimeris, J., Kisiel, W., Fenton,
J.W., Dinarello, C., Jaffe, E.A. and Chess L. Self-regulation of
procoagulant events on the endothelial surface. J. Exp. Med. 162:1223-
1235, 1985.
12. Nawroth, P., Stern, D.M., Kisiel, W. and Bach, R. Cellular requirements for
tissue factor generation by perturbed bovine aortic endothelial cells in
culture. Thromb. Res. 40:677-691, 1985.
13. Nawroth, P., Stern, D.M., Kisiel, W. and Dietrich, M. A coagulation

pathway on cultured capillary endothelium. Br. J. Haematol. 63:309-320,
1986.
14. Nawroth, P.P., Handley, D., Esmon, C.T. and Stern, D. Interleukin 1
induces endothelial cell procoagulant while suppressing cell surface
anticoagulant activity. Proc. Natl. Acad. Sci. USA 83:3460-3464, 1986.
15. Stern, D.M., Nawroth, P.P., Harris, K. and Esmon, C.T. Cultured bovine
aortic endothelial cells promote activated protein C/protein S-mediated
inactivation of factor Va. J. Biol. Chem. 261:713-718, 1986.
16. Nawroth, P.P. and Stern, D.M. Modulation of endothelial cell hemostatic
properties by tumor necrosis factor. J. Exp. Med. 163:740-745, 1986.
17. Stern, D.M., Brett, J., Harris, K. and Nawroth, P.P. Participation of
endothelial cells in the protein C-protein S anticoagulant pathway: the
synthesis and release of protein S. J. Cell Biol. 102:1971-1978, 1986.
18. Marcum, J.A., Atha, D.H., Fritze, L.M.S., Nawroth, P., Stern, D.M. and
Rosenberg, R.D. Cloned bovine aortic endothelial cells synthesize
anticoagulant active heparan sulfate proteoglycan. J. Biol. Chem.
261:7507-7517, 1986.
19. Nawroth, P., Bank, I., Handley, D., Cassimeris, J., Chess, L. and Stern, D.
Tumor necrosis factor/cachectin interacts with endothelial cell receptors to
induce release of interleukin 1. J. Exp. Med. 163:1363-1375, 1985.
10
Stern, David M., MD
Curriculum Vitae
20. Gajdusek, C., Carbon, S., Ross, R., Nawroth, P.P. and Stern, D.M.
Activation of coagulation releases endothelial cell mitogens. J. Cell Biol.
103:419-428, 1986.
21. Levin, E.G., Stern, D.M., Nawroth, P.P., Marlar, R.A., Fair, D.S., Fenton,
J.W. II and Harker, L.A. Specificity of the thrombin-induced release of
tissue plasminogen activator from cultured human endothelial cells.
Thromb. and Haemost. 56:115-119, 1986.
22. Nawroth, P.P., Kisiel, W. and Stern, D.M. Anticoagulant and antithrombotic
properties of a gamma-carboxyglutamic acid-rich peptide derived from the
light chain of blood coagulation factor X. Thromb. Res. 44:625-637, 1986.
23. Stern, D.M., Knitter, G., Kisiel, W., Nawroth, P.P. In vivo evidence of
intravascular binding sites for coagulation factor IX. Brit. J. Haematol.
66:227-232, 1987.
24. Rimon, S., Melamed, R., Savion, N., Nawroth, P. and Stern, D.M.
Identification of a factor IX/IXa binding protein on the endothelial cell
surface. J. Biol. Chem. 262:6023-6031, 1987.
25. de Groot, P.G., Verweij, C., Nawroth, P.P., de Boer, H., Stern, D.M. and
Sixma, J.J. Interleukin-1 inhibits the synthesis of von Willebrand factor in
endothelial cells which results in a decreased reactivity of their matrix
towards platelets. Arteriosclerosis, 7:605-611, 1987.
26. Brett, J.G, Steinberg, S.F., deGroot, P.G., Nawroth, P.P. and Stern, D.M.
Norepinephrine down-regulates the activity of protein S on endothelial
cells. J. Cell Biol. 106:2109-2119, 1988.
27. Cozzolino, F., Torcia, M., Miliani, A., Carossino, A., Giordani, R., Cinotti, S.,
Filimberti, E., Saccardi, R., Bernabei, P., Guidi, G., Guglielmo, R., Pistola,
V., Ferrarini, M., Nawroth, P. and Stern, D.M. Potential role of Interleukin 1
as the trigger for diffuse intravascular coagulation in acute non-
lymphoblastic leukemia. Am. J. Med., 84:240-250, 1988.
28. Nawroth, P.P., Handley, D., Matsueda, G., deWaal, R., Gerlach, H., Blohm,
D., Stern, D.M. Tumor necrosis factor/cachectin-induced intravascular
fibrin formation in meth A fibrosarcomas. J. Exp. Med, 168:637-647, 1988.
29. Brett, J., Gerlach, H., Nawroth, P., Steinberg, S., Godman, G., and Stern,
D. Tumor necrosis factor/cachectin increases permeability of endothelial
cell monolayers by a mechanism involving regulatory G proteins. J. Exp.
Med. 169:1977-1991, 1989.
30. May, L., Torcia G., Cozzolino F., Ray A., Tatter S., Santhanam U., Sehgal,
P., and Stern, D. Interleukin-6 gene expression in human endothelial cells:
11
Stern, David M., MD
Curriculum Vitae
RNA start sites, multiple IL-6 proteins and inhibition of proliferation.

Biochem. Biophys. Res. Comm.159:991-998, 1989.
31. Gerlach, H., Liebermann, H., Brett, J., Bach, R., Godman, G. and Stern, D.
Growing/motile endothelium shows enhanced responsiveness to tumor
necrosis factor/cachectin. J. Exp. Med 170:913-931, 1989.
32. Esposito, C., Gerlach, H., Brett, J., Stern, D. and Vlassara, H. Endothelial
receptor-mediated binding of glucose-modified albumin is associated with
increased monolayer permeability and modulation of cell surface coagulant
properties. J. Exp. Med.170:1387-1407, 1989.
33. Cozzolino, F., Torcia, M., Aldinucci, D., Ziche, M., Almerigogna, F., Bani,
D., and Stern, D. M. Interleukin 1 is an autocrine regulator of human
endothelial cell growth. PNAS(USA), 87:6487-6491, 1990.
34. Ogawa, S., Gerlach, H., Esposito, C., Pasagian-Macaulay A., Brett J., and
Stern, D. Hypoxia modulates the barrier and coagulant function of cultured
bovine endothelium: increased monolayer permeability and induction of
procoagulant properties. J. Clin. Invest. 85:1090-1098, 1990.
35. Ryan, J., Wolitzky, B., Heimer, E., Lambrose, T., Felix, A., Huang, L., Tam,
J., Nawroth, P., Wilner, G., Kisiel, W., Nelsestuen, G., and Stern, D.
Structural determinants of the Factor IX molecule mediating interaction with
the endothelial cell binding site are distinct from those involved in
phospholipid binding. J. Biol. Chem. 264:20283-20287, 1989.
36. Schwalbe, R., Ryan, J., Stern, D., Kisiel, W., Dahlback, B., and Nelsestuen,
G. Protein structural requirements and properties of membrane binding by
gamma-carboxyglutamic acid-containing plasma proteins and peptides. J.
Biol. Chem. 264:20288-20296, 1989.
37. Clauss, M., Murray, C., Vianna, M., deWaal, R., Thurston, G., Nawroth, P.,
Gerlach, H., Bach, R., Familletti, P., and Stern, D. A polypeptide factor
produced by fibrosarcoma cells that induces endothelial tissue factor and
enhances the procoagulant response to tumor necrosis factor/cachectin. J.
Biol. Chem. 265:7078-7083, 1990.
38. Ogawa, S., Shreeniwas, R., Brett, J., Clauss, M., Furie, M., and Stern, D.
The effect of hypoxia on capillary endothelial cell function: modulation of
barrier and coagulant function. Brit. J. Haematol. 75:517-524, 1990.
39. Kirstein, M., Brett, J., Radoff, S., Stern, D., and Vlassara, H. Advanced
glycosylation endproducts induce selective monocyte migration across
endothelium, and elaboration of growth factors. PNAS(USA) 87: 9010-
9014, 1990.
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40. Clauss, M., Gerlach, M., Gerlach, H., Brett, J., Wang, F., Pan, P.-C.,
Familletti, P., Olander, J., Connolly, D., and Stern, D. Vascular
permeability factor: a tumor-derived polypeptide which induces endothelial
cell and monocyte procoagulant activity, and promotes monocyte
migration. J. Exp. Med. 172:1535-1545, 1990.
41. Ogawa, S., Shreeniwas, R., Clauss, M., and Stern, D. Hypoxia induces
endothelial cell synthesis of membrane-associated proteins. PNAS(USA)
88:9897-9901, 1991.
42. Shreeniwas, R., Ogawa, S., Cozzolino, F., Torcia, G., Braunstein, N.,
Butura, C., Brett, J., Lieberman, H. B., Furie, M. B., and Stern, D. M.
Macrovascular and microvascular endothelium during long-term exposure
to hypoxia: alterations in cell growth, monolayer permeability and cell
surface coagulant properties. J. Cell. Physiol. 146:8-17, 1991.
43. Murray, J., Smith, K., and Stern, D. Flavone acetic acid and tumour
necrosis factor act synergistically to promote endothelial procoagulant
activity in vitro and inhibit tumour growth in vivo. Eur. J. Cancer. 27:765-
770, 1991.
44. Steinberg, S., Robinson, R., Lieberman, H., Stern, D., and Rosen, M.
Thrombin modulates phosphoinositide metabolism, cytosolic calcium and
impulse initiation in the heart. Circulation Res. 68:1216-1239, 1991.
45. Tijburg, P., Ryan, J., Stern, D., Wolitzky, B., Rimon, S., Rimon, B.,
Handley, D., Nawroth, P., Sixma, J., and deGroot, P. Activation of the
coagulation mechanism on TNF-stimulated cultured endothelial cells and
their extracellular matrix: the role of flow and factor IX/IXa. J. Biol. Chem.
266:12067-12074, 1991.
46. Benedict, C., Ryan J., Wolitzky, B., Ramos, R., Gerlach, M., Tijburg, P.,
and Stern, D. Active site-blocked factor IXa prevents intravascular
thrombus formation in the coronary vasculature without inhibiting
extravascular coagulation in a canine thrombosis model. J. Clin. Invest.
88:1760-1765, 1991.
47. Murray, J., Clauss, M., Thurston, G., and Stern, D. Tumour-derived factors
which induce endothelial tissue factor and enhance the procoagulant
response to TNF. Int. J. Radiat. Biol, 60:273-277, 1991.
48. Murray, J., Clauss, M., Denekamp, J., and Stern, D. Selective induction of
endothelial cell tissue factor in the presence of a tumour-derived mediator:
a potential mechanism of flavone acetic acid action in tumour vasculature.
Int. J. Cancer 49:254-259, 1991.
13
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Curriculum Vitae
49. Loike, J., Cao, L., Brett, J., Ogawa, S., Silverstein, S. C., and Stern, D.
Induction of glucose transporters in hypoxic cultured endothelial cells. Am.
J. Physiol., 263 (Cell Physiol.32): C3226-C333, 1992.
50. Ogawa, S., Koga, S., Kuwabara, K., Morrow, B., Morris, S., Bilezikian, J.,
Silverstein, S. C., and Stern, D. Hypoxia-induced increased permeability of
cultured bovine pulmonary and aortic endothelial monolayers occurs
through lowering of cellular cAMP levels and is modulated by
glucocorticoids. Am. J. Physiol. 262 (Cell Physiol. 31): C546-554, 1992.
51. Ryan, J., Brett, J., Tijburg, P., Bach, R., Kisiel, W., and Stern, D. Tumor
necrosis factor-induced endothelial tissue factor is associated with
subendothelial matrix vesicles but is not expressed on the apical surface.
Blood 80:966-974, 1992.
52. Koga, S., Ogawa, S., Kuwabara, K., Brett, J., Leavy, J., Ryan, J., Koga, Y.,
Plocinski J., Benjamin, W., Burns, D., and Stern, D. Synthesis and release
of Interleukin 1 by reoxygenated human mononuclear phagocytes. J. Clin.
Invest. 90:1007-1015, 1992.
53. Schmidt, A-M., Vianna, M., Gerlach, M., Brett, J., Ryan, J., Kao, J.,
Esposito, C., Hegarty, H., Hurley, W., Clauss, M., Wang, F., Pan, Y-C.,
Tsang, T.C., and Stern, D. Isolation and characterization of binding
proteins for advanced glycosylation end products from lung tissue which
are present on the endothelial cell surface. J. Biol Chem. 267:14987-
14997, 1992.
54. Neeper, M., Schmidt, A-M., Brett, J., Yan, S-D., Wang, F., Pan, Y-C.,
Elliston, K., Stern, D., and Shaw A. Cloning and expression of RAGE: a
cell surface receptor for advanced glycosylation end products of proteins.
J. Biol. Chem. 267:14998-15004, 1992.
55. Kao, J., Brett, J., Godman, G., Chen, J., Familletti, P., Wang, J., Pan, Y-C.,
Stern, D., and Clauss, M. Endothelial-monocyte activating polypeptide II: a
novel tumor derived polypeptide which activates host-response
mechanisms. J. Biol. Chem. 267:20239-20247, 1992.
56. Shreeniwas, R., Koga, S., Pinsky, D., Kaiser, E., Brett, J., Wolitzky, D.,
Norton, C., Plocinski, J., Benjamin, W., Burns, D., Goldstein, A., and Stern,
D. Hypoxia-mediated induction of endothelial cell Interleukin 1 alpha: an
autocrine mechanism promoting expression of leukocyte adhesion
molecules on the vessel surface. J. Clin. Invest. 90:2333-2339, 1992.
57. Schmidt, A-M., Yan, S.D., Brett, J., Mora, R., Nowygrod, R., and Stern, D.
Regulation of mononuclear phagocyte migration by cell surface binding
14
Stern, David M., MD
Curriculum Vitae
proteins for advanced glycosylation endproducts. J. Clin. Invest. 92:2155-

2168, 1993.
58. Benedict, C., Ryan, J., Todd, J., Kuwabara, K., Tijburg, P., Cartwright, J.,
and Stern, D. Active site-blocked Factor Xa prevents intravascular
thrombus formation in the coronary vasculature in parallel with inhibition of
extravascular coagulation in a canine thrombosis model. Blood 81:2059-
2066, 1993.
59. Shen, H., Clauss, M., Kao, J., Ryan, J., Schmidt, A-M., Tijburg, P., Borden,
L., and Stern, D. Characterization of vascular permeability factor/vascular
endothelial growth factor receptors on mononuclear phagocytes. Blood
81:2767-2773, 1993.
60. Cozzolino, F., Torcia, M., Lucibello, M., Ziche, M., Platt, J., Brett, J., and
Stern, D. Cytokine-mediated control of endothelial cell growth: interferon-
alpha and interleukin-2 synergistically enhance basic fibroblast growth
factor synthesis and induce release promoting cell growth in vitro and in
vivo. J. Clin. Invest., 91:2504-2512, 1993.
61. Yuzawa, Y., Brentjens, J., Brett, J., Caldwell, P., Esposito, C., Fukatsu, A.,
Godman, G., Stern, D., and Andres, G. Antibody-mediated redistribution of
endothelial antigens in the rabbit. J. of Immunol. 150:5633-5646, 1993.
62. Oz, M., Pinsky, D., Koga, S., Liao, H., Marboe, C., Han, D., Kline, R.,
Jeevanandam, V., Williams, M., Morales, A., Popilskis, S., Nowygrod, R.,
Stern, D., Rose, E., and Michler, R. Novel preservation solution permits 24
hr preservation in a rat and baboon cardiac transplant model. Circulation
88 (part 2):291-297, 1993.
63. Pinsky, D., Oz, M., Morris, S., Liao, H., Brett, J., Morales, A., Karakurum,
M., Van Lookeren Campagne, M., Platt, J., Nowygrod, R., Koga, S., and
Stern, D. Restoration of the cAMP second messenger pathway enhances
cardiac preservation for transplantation in a heterotopic rat model. J. Clin.
Invest. 92:2994-3002, 1993.
64. Brett, J., Schmidt, A-M.,Zou, Y-S., Yan, S-D., Weidman, E., Pinsky, D.,
Neeper, M., Przysiecki, M., Shaw, A., Migheli, A., and Stern, D. Tissue
distribution of the receptor for advanced glycation endproducts (RAGE):
expression in smooth muscle, cardiac myocytes, and neural tissue in
addition to the vasculature. Am. J. Pathol.143:1699-1712, 1993.
65. Lupu, F., Moldovan, N., Ryan, J., and Stern, D. Intrinsic procoagulant
surface induced by hypercholesterolemia on rabbit aortic endothelium.
Blood Coagul. Fibrinol. 4:743-752, 1993.
15
Stern, David M., MD
Curriculum Vitae
66. Hori, O., Matsumoto, M., Maeda, Y., Ueda, H., Ohtsuki, T., Stern, D.,
Kinoshita, T., Ogawa, S., and Kamada, T. Metabolic and biosynthetic
alterations in cultured astrocytes exposed to hypoxia/reoxygenation. J. of
Neurochemistry 62:1489-1495, 1994.
67. Zhang, Y., Deng, Y., Luther, T., Stern, D., Ziegler, R., Waldherr, R.,
Nathans, D., and Nawroth, P. Role of tissue factor in growth of solid
tumors. J. Clin. Invest. 94:1320-1327, 1994.
68. Smith, M., Kutty, R., Richey, P., Yan, S-D., Stern, D., Chader, G., Wiggert,
B., Petersen, R., and Perry, G. Heme oxygenase-1 is associated with the
neurofibrillary pathology of Alzheimer disease. Am. J. Pathol. 145:42-47,
1994.
69. Karakurum, M., Shreeniwas, R., Chen, J., Sunouchi, J., Hamilton, T.,
Anderson, M., Kuwabara, K., Rot, A., Nowygrod, R., and Stern, D. Hypoxic
induction of Interleukin-8 gene expression in endothelial cells. J. Clin.
Invest. 93:1564-1570, 1994.
70. Smith, M., Taneda, S., Richey, P., Miyata, S., Yan, S-D., Stern, D.,
Monnier, V., and Perry, G. Advanced maillard reaction endproducts are
associated with Alzheimer disease pathology. PNAS(USA) 91:5710-5714,
1994.
71. Pinsky, D., Oz, M., Koga, S., Taha, Z., Broekman, J., Marcus, A., Cannon,
P., Nowygrod, R., Malinski, T., and Stern. D., Augmentation of the nitric
oxide pathway enhances cardiac preservation for transplantation. J. Clin.
Invest. 93:2291-2297, 1994.
72. Schmidt, A-M., Mora, R., Cao, R., Yan, S-D., Brett, J., Ramakrishnan, R.,
Tsang, T-C., Simionescu M., and Stern, D. The endothelial cell binding site
for advanced glycation endproducts consists of a complex: an integral
membrane protein and a lactoferrin-like polypeptide. J. Biol. Chem.
269:9882-9888, 1994.
73. Yan, S-D., Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S.,
Pinsky, D., and Stern, D. Enhanced cellular oxidant stress by the
interaction of advanced glycation endproducts with their receptors/binding
proteins. J. Biol. Chem. 269:9889-9897, 1994.
74. Kao, J., Y-G. Fan, I. Haehnel, J. Brett, S. Greenberg, M. Clauss, M.

Kayton, K. Houck, W. Kisiel, J. Burnier, and D. Stern. A peptide derived
from the amino terminus of endothelial-monocyte activating polypeptide II
(EMAP II) modulates mononuclear and polymorphonuclear leukocyte
functions, defines an apparently novel cellular interaction site, and induces
an acute inflammatory response. J. Biol. Chem. 269:9774-9782, 1994.
16
Stern, David M., MD
Curriculum Vitae
75. Schmidt, A-M., Hasu, M., Popov, D., Zhang, J-H., Yan, S-D., Brett, J., Cao,
R., Kuwabara, K., Costache, G., Simionescu, N., Simionescu, M., and
Stern, D. The receptor for Advanced Glycation Endproducts (AGEs) has a
central role in vessel wall interactions and gene activation in response to
AGEs in the intravascular space. PNAS(USA) 91:8807-8811, 1994.
76. Koppelman, S., Koedam, J., van Wijnen, M., Stern, D., Nawroth, P., Sixma,
J., and Bouma. B., Von Willebrand Factor as a regulator of intrinsic Factor
X Activation. J. Lab. Clin. Med. 123:585-93, 1994.
77. Wautier, J-L., Wautier, M-P., Schmidt, A-M., Anderson, G.M., Zoukourian,
C., Capron, L., Chappey, O., Yan, S-D., Brett, J., Guillausseau, P-J., and
Stern. D., Advanced glycation endproducts (AGEs) on the surface of
diabetic red cells bind to the vessel wall via a specific receptor inducing
oxidant stress in the vasculature: a link between surface-associated AGEs
and diabetic complications. PNAS(USA) 91:7742-7746, 1994.
78. Pinsky, D., Y. Naka, N. Chowdhury, H. Lao, M. Oz, R. Michler, and D.

Stern. The nitric oxide/cGMP pathway: central role in lung preservation for
transplantation. PNAS (USA) 91:12086-12090, 1994.
79. Chowdhury, N., Naka, Y., Pinsky, D., Yano, O., Smith, C., Rose, E., Stern,
D., Michler, R., and Oz. M., Novel technique of orthotopic lung
transplantation in rats in which survival and hemodynamic assessment can
be measured independent of the native lung. Surgical Forum 45:268-270,
1994.
80. Kao, J., Houck, K., Fan, Y., Brett, J., Haehnel, I., Kayton, M., Grickscheit,
T., Libutti, S., Chabot, J., Nowygrod, R., Greenberg, S., Kuang, W-J.,
Leung, D., Kisiel, W., Heath, M., and Stern, D., Characterization of a novel
tumor-derived cytokine: Endothelial-Monocyte Activation Polypeptide II
(EMAP II). J. Biol. Chem. 269:25106-25119, 1994.
81. Yan, S-D., Chen, X., Schmidt, A-M., Brett, J., Godman, G., Scott, C.W.,
Caputo, C., Frappier, T., Yen, S-H., and Stern, D. The presence of glycated
tau in Alzheimer’s disease: a mechanism for induction of oxidant stress.
PNAS(USA) 91:7787-7791, 1994.
82. Maeda, Y.,Matsumoto, M., Hori, O., Ogawa, S., Ohtsuki, T., Kinoshita, T.,
Kamada, T., and Stern, D. Hypoxia/reoxygenation-mediated induction of
astrocyte Interleukin 6 in cell culture and Interleukin 6 expression in
ischemic gerbil brain: a paracrine mechanism potentially enhancing
neuron survival. J. Exp. Med. 180:2297-2308, 1994.
83. Kuwabara, K., Ogawa, S., Matsumoto, M., Koga, S., Clauss, M., Pinsky,
D., Witte, L., Joseph-Silverstein, J., Furie, M., Torcia, G., Cozzolino, F.,
17
Stern, David M., MD
Curriculum Vitae
Kamada, T., and Stern, D. Hypoxia-mediated induction of acidic/basic

fibroblast growth factor and platelet-derived growth factor in mononculear
phagocytes stimulates growth of hypoxic endothelial cells. PNAS(USA)
92:4606-4610, 1995.
84. Naka, Y., Chowdhury, N., Oz, M., Smith, C., Yano, O., Michler, R., Stern,
D., and Pinsky, D. Nitroglycerin maintains graft vascular homeostasis and
enhances preservation in an orthotopic rat lung transplant model. J.
Thoracic and Cardiovascular Surg. 109:206-211, 1995.
85. Kuwabara, K., Pinsky, D., Schmidt, A-M., Benedict, C., Brett, J., Ogawa,
S., Broekman, M., Marcus, A., Sciacca, R., Michalak, M., Wang, F., Pan, Y-
C., Grunfeld, S., Patton, S., Malinski, T., Stern, D., and Ryan, J.
Calreticulin, an antithrombotic agent which binds vitamin K-dependent
coagulation factors, stimulates endothelial nitric oxide production, and limits
thrombosis in canine coronary arteries. J. Biol. Chem.270:8179-8187,
1995.
86. Koga, S., Morris, S., Ogawa, S., Liao, H., Bilezikian, J., Chen, G.,
Thompson, W., Ashikaga, T., Brett, J., and Stern, D. Tumor necrosis factor
increases endothelial cell monolayer permeability through activation of
cyclic nucleotide phosphodiesterase and decreased intracellular cyclic
AMP. Am. J. Physiol. 268:C1104-1113, 1995.
87. Ritthaler, U., Deng, Y., Zhang, Y., Greten, J., Abel, M., Allenberg, J., Otto,
G., Roth, H., Bierhaus, A., Ziegler, R., Schmidt, A-M., Waldherr, R., Wahl,
P., Stern, D., and Nawroth, P. Expression of receptors for advanced
glycation endproducts in peripheral occlusive vascular disease. Am. J.
Pathol. 146:688-694, 1995.
88. Lawson, C., Smerling, A., Naka, Y., Burkhoff, D., Dickstein, M., Stern, D.,
and Pinsky, D. Inhalation of cGMP analogs selectively reduces pulmonary
vascular resistance in porcine models of pulmonary hypertension. Am. J.
Physiol. 268:H2056-H2062, 1995.
89. Yuzawa, Y., Brett, J., Fukatsu, A., Matsuo, S., Caldwell, P., Godman, G.,
Stern, D., and Andres, G. Interaction of antibody with Forssman antigen in
guinea pigs: a mechanism of adaptation to antibody- and complement-
mediated injury. Am. J. Pathol. 146:1260-1272, 1995.
90. Yan, S-F., Tritto, I., Pinsky, D., Liao, H., Huang, J., Fuller, G., Brett, J.,
May, L., and Stern, D. Induction of Interleukin 6 by hypoxia in vascular
cells: central role of the binding site for nuclear factor-Interleukin 6. J. Biol.
Chem. 270:11463-11471, 1995.
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91. Abel, M., Ritthaler, U., Zhang, Y., Deng, Y., Greten, J., Sernau, Th.,
Ziegler, R., Wahl, P., Andrassy, K., Ritz, R., Waldherr, R., Schmidt, A-M.,
Stern, D., and Nawroth, P. Expression of receptors for advanced glycation
endproducts in renal disease. Nephrology, Dialysis, Transplantation
10:1662-1667, 1995.
92. Yan, S-D., Yan, S-F., Chen, X., Fu, J., Chen, M., Kuppusamy, P., Smith,
M., Perry, G., Godman, G., Nawroth, P., and Stern, D. Nonenzymatically
glycated tau in Alzheimer’s disease induces neuronal oxidant stress
resulting in cytokine gene expression and release of amyloid-ß peptide.
Nature Medicine 1:693-699, 1995.
93. Schmidt, A-M., Hori, O., Chen, J., Crandall, J., Zhang, J., Cao, R., Yan,
SD., Brett J., and Stern, D. Advanced glycation endproducts interacting
with their endothelial receptor induce expression of vascular cell adhesion
molecule-1 (VCAM-1): a potential mechanism for the accelerated
vasculopathy of diabetes. J. Clin. Invest. 96:1395-1403, 1995.
94. Connolly, E., Winfree, C., Stern, D., Solomon, R., and Pinsky, D.
Procedural and strain-related variables significantly affect outcome in a
murine model of focal cerebral ischemia. Neurosurgery 38:523-532, 1996.
95. Oz, M., Liao, H., Naka, Y., Eldomridge, A., Becker, D., Michler, R., Smith,
C., Rose, E., Stern, D., and Pinsky, D. Ischemia-induced Interleukin 8
release following human heart transplantation: a potential role for
endothelial cells. Circ.92 (suppl. II): II-428-II-432, 1995.
96. Naka, Y., Roy, D., Smerling, A., Michler, R., Smith, C., Stern, D., Oz, M.,
and Pinsky, D. Inhaled nitric oxide fails to confer the pulmonary protection
provided by distal stimulation of the nitric oxide pathway at the level of
cGMP. J. Thorac. and Cardiovasc. Surgery 110:1434-1441, 1995.
97. Yellin, M., Brett, J., Baum, D., Matsushima, A., Szabolcs, M., Stern, D., and
Chess, L. Functional interactions of T cells with endothelial cells: the role of
C40L-CD40 mediated signals. J. Exp. Med. 182:1857-1864, 1995.
98. Hori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J., Nagashima, M.,
Lundh, E., Vijay, S., Nitecki, D., and Stern, D. The Receptor for Advanced
Glycation Endproducts (RAGE) is a cellular binding site for amphoterin:
mediation of neurite outgrowth and co-expression of RAGE and amphoterin
in the developing nervous system. J. Biol. Chem. 270:25752-25761, 1995.
99. Saadi S., Holzknecht, R., Patte, C., Stern, D., and Platt, J. Complement-
mediated enhancement of the coagulant properties of endothelium. J. Exp.
Med. 182:1807-1814, 1995.
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100. Bierhaus, A., Zhang, Y., Deng, Y., Mackman, N., Quehenberger, S.,
Haase, M., Greten, J., Muller, M., Bohrer, H., Gretens, J., Stern, D., and
Nawroth, P. Mechanism of the tumor necrosis factor alpha-mediated
induction of endothelial tissue factor. J. Biol. Chem. 270:26419-26432,
1995.
101. Matsuo N., Ogawa, S., Imai, Y., Takagi, T., Kinoshita, T., Tohyama, M.,
Stern, D., and Wanaka, A. Cloning of a novel RNA binding polypeptide,
RAO310, induced by hypoxia. J. Biol. Chem. 270:28216-28222, 1995.
102. Connolly, E., Winfree, C., Springer, T., Gutierrez-Ramos, J-C., Naka, Y.,
Liao, H., Yan, S-D., Stern, D., Solomon, R., and Pinsky, D.
Cerebroprotection in homozygous null ICAM-1 mice following middle
cerebral artery occlusion: role of neutrophil adhesion in the pathogenesis
of stroke. J. Clin Invest. 97:209-216, 1996.
103. Wautier, J-L., Zoukourian, C., Chappey, O., Wautier, M-P., Guillausseau,
P-J., Cao, R., Hori, O., Stern, D., and Schmidt, A-M. Receptor-mediated
endothelial cell dysfunction in diabetic vasculopathy: soluble receptor for
advanced glycation endproducts blocks hyperpermeability. J. Clin. Invest.
97:238-243, 1996.
104. Hori, O., Matsumoto, M., Maeda, Y., Kuwabara, K., Ueda, H., Ohtsuki, T.,
Kinoshita, T., Ogawa, S., Stern, D., and Kamada, T. Exposure of cultured
primary rat astrocytes to hypoxia/reoxygenation results in intracellular
glucose depletion and leads to induction of glucose-regulated proteins
(GRP): GRP78 maintains astrocyte glutamate uptake during oxygen
deprivation. J. Neurochem. 66:973-979, 1996.
105. Pinsky, D., Naka, Y., Liao, H., Oz, M., Wagner, D., Hynes, R., Mayadas, T.,
Heath, M., Lawson, C., and Stern, D. Hypoxia-induced exocytosis of
endothelial cell Weibel-Palade bodies: a mechanism for rapid neutrophil
recruitment following cardiac preservation. J. Clin. Invest. 97:493-500,
1996.
106. Simionescu, M., Popov, D., Sima, A., Hasu, M., Costache, G., Faitar, S.,
Vulpanovici, A., Stancu, C., Stern, D., and Simionescu, N.
Pathobiochemistry of combined diabetes and atherosclerosis studied in a
novel animal model: the hyperlipemic hyperglycemic hamster. Am. J.
Pathol. 148:997-1014, 1996.
107. Kuwabara, K., Matsumoto, M., Ikeda, J., Ogawa, S., Maeda, Y., Kitagawa,
K., Imuta, N., Kinoshita, T., Stern, D., Yangi, H., and Kamada, T.
Purification and characterization of a novel stress protein, the 150 kDa
oxygen regulated protein (ORP150), from cultured rat astrocytes and its
expression in ischemic gerbil brain. J. Biol. Chem. 271:5025-5032, 1996.
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108. Zhang, Y., Deng, Y., Wendt, T., Liliensiek, B., Bierhaus, A., Greten, J., He,
W., Chen, B., Hac-Wunderle, V., Waldherr, R., Ziegler, R., Mannel, D.,
Stern, D. M., and Nawroth, P.M. Intravenous somatic gene transfer with
antisense tissue factor restores blood flow by reducing tumor necrosis
factor-induced tissue factor expression and fibrin deposition in mouse meth
A sarcomas. J. Clin. Invest. 97:2213-2224, 1996.
109. Marvin, M., Libutti, S., Kayton, M., Kao, J., Hayward, J., Grikscheit, T.,
Fan, Y., Brett, J., Weinberg, A., Nowygrod, R., LoGerfo, P., Feind, C.,
Hansen, K., Schwarz, M., Stern, D., and Chabot, J. A novel tumor-derived
mediator which sensitizes cytokine-resistant tumors to tumor necrosis
factor. J. Surg. Res. 243:255-262, 1996.
110. Spanier, T., Oz, M., Levin, H., Weinberg, A., Stamatis, K., Stern, D., Rose,
E., and Schimdt, A-M. Activation of coagulation and fibrinolysis in patients
with left ventricular assist devices. J. Thoracic and Cardiovascular Surgery
112:1090-1097, 1996.
111. Popov, D., Sima, A., Stern, D., Simionescu, M. The pathomorphological
alterations of endocardial endothelium in experimental diabetes and
diabetes associated with hyperlipidemia. Acta Diabetol. 33:41-47, 1996.
112. Zoukourian, C., Wautier, M., Chappey, O., Dosquet, C., Rohban, T.,
Schmidt, A-M., Stern, D., and Wautier, J-L. Endothelial cell dysfunction
secondary to the adhesion of diabetic erythrocytes. Modulation by iloprost.
International Angiology 15:195-200, 1996.
113. Yan, S-D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T.,
Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D.,
and Schmidt, A-M. RAGE in Alzheimer’s disease: a receptor mediating
amyloid-ß peptide-induced oxidant stress and neurotoxicity, and microglial
activation. Nature 382:685-691, 1996.
114. Tsukamoto, Y., Kuwabara, K., Hirota, S., Ikeda, J., Stern, D., Yanagi, H.,
Matsumoto, M., Ogawa, S., and Kitamura, Y. Expression of the 150 kDa
oxygen regulated protein (ORP150) in vascular cells of human
atherosclerotic plaques. J. Clin. Invest. 98:1930-1941, 1996.
115. Yan, S-F., Zou, Y-S., Mendelsohn, M., Gao, Y., Naka, Y., Du, Y-S., Pinsky,
D., and Stern, D. Nuclear factor Interleukin 6 motifs mediate tissue specific
activation and suppression of gene transcription in hypoxia. J. Biol. Chem
272:4287-4294, 1997.
116. Lawson, C., Liao, H., Yan, S-D., Yan, S-F., Sobel, J., Kisiel, W., Stern, D.,
and Pinsky,D. Hypoxia-mediated fibrin deposition in lung vasculature. J.
Clin. Invest. 99:1729-1738, 1997.
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117. Al-Mohanna, F., Collison, K., Parhar, R., Kwaasi, A., Meyer, B., Saleh, S.,
Allen, S., Al-Sedairy, S., Stern, D. and Yacoub, M. Activation of naive
xenogeneic but not allogeneic endothelial cells by human naive
neutrophils. Am. J. Pathol. 151:111-120, 1997.
118. Yan, S-D., Zhu, H., Fu, J., Yan, S-F., Roher, A., Tourtellotte, W.,
Rajavashisth, T., Chen, X., Godman, G., Stern, D. and Schmidt, A-M.
Amyloid-beta peptide-RAGE interaction elicits neuronal expression of M-
CSF: a proinflammatory pathway in Alzheimer’s disease. PNAS(USA)
94:5296-5301, 1997.
119. Spanier, T., Oz, M., Madigan, J., Rose, E., Stern, D., Nowygrod, R., and
Schmidt, A-M. Active site blocked Factor IXa: a novel selective
anticoagulant for use in cardiopulmonary bypass. Surg. Forum.
XLVIII:259-261, 1997.
120. Matsuo, N., Ogawa, S., Takagi, T., Wanaka, A., Mori, T., Matsuyama, T.,
Pinsky, D., Stern, D., and Tohyama, M. Cloning of a novel vesicle transport
related protein, RA410: role in the neurotrophic response of astrocytes
subject to hypoxia/reoxygenation. J. Biol. Chem. 272:16438-16444, 1997.
121. Bohrer, H., Qiu, F., Zimmermann, T., Zhang, Y., Luther, T., Mannel, D.,
Stern, D., Waldherr, R., Muller, M., Seege, D., Ziegler, R., Bierhaus, A.,
Martin, E., and Nawroth, P. Role of members of the bZIP and NF-kB family
in the lethality of septicemia. J. Clin. Invest. 100:972-985, 1997.
122. Sima, A., Popov, D., Starodub, O., Stancu, C., Cristea, C., Stern, D., and
Simionescu, M. Pathobiology of the heart in experimental diabetes:
immunolocalization of lipoproteins, immunoglobulin G and AGE proteins in
diabetic and/or hyperlipidemic hamster. Lab. Invest. 77:3-18, 1997.
123. Spanier, T., Oz, M., Madigan, J., Rose, E., Stern, D., Nowygrod, R., and
Schmidt, A. Selective anticoagulation with active site-blocked Factor IXa in
synthetic patch vascular repair results in decreased blood loss and
operative time. ASAIO J. 43:M526-530, 1997.
124. Yan, S-D., Fu, J., Soto, C., Chen, X., Al-Mohanna, F., Collison, K., Zhu, A.,
Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A., and Stern, D.
ERAB: a novel intracellular amyloid-beta peptide binding protein and
neurotoxicity in Alzheimer’s disease. Nature 389:689-695, 1997.
125. Spanier, T., Chen, J., Oz, M., Edwards, N., Kisiel, W., Stern, D., Rose, E.,
and Schmidt, A-M. Selective anticoagulation with active site-blocked Factor
IXa suggests separate roles for intrinsic and extrinsic coagulation pathways
in cardiopulmonary bypass. J. Thoracic and Cardiovascular Surgery
116:860-869, 1998.
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126. Zhang, Y., Weiler-Guettler, H., Welhelm, O. Deng, Y., Qiu, F., Nakagawa,
K., Klevesth, M., Welhelm, S., Dittman, W., Stern, D., Rosenberg, R.,
Ziegler, R., and Nawroth, P. Thrombomodulin controls growth of cells. J.
Clin. Invest. 101:1301-1309, 1998.
127. Tsukamoto, Y., Hirota, S., Kuwabara, K., Kawano, K., Yoshikawa, K.,
Ozawa, K., Kobayashi, T., Yanagi, H., Stern, D., Kitamura, Y., Tohyama,
M., and Ogawa, S. Expression of the 150 kDa oxygen-regulated protein
(ORP150) in human breast cancer. Lab Invest. 78:699-706, 1998.
128. Yan, S-F., Zou, Y-S., Gao, Y., Zhai, C., Mackmann, N., Lee, S., Milbrandt,
J., Pinsky, D., Kisiel, W., and Stern, D. Tissue factor transcription driven by
Egr-1 is a critical mechanism of thrombosis in hypoxia. PNAS(USA)
95:8298-8303, 1998.
129. Mackic, J., Stins, M., McComb, J., Calero, M., Ghiso, J., Kim, K., Yan, S-
D., Stern, D., Schmidt, A-M., Frangione, B., and Zlokovic, B. Human blood-
brain barrier receptors for Alzheimer’s amyloid-beta 1-40. J. Clin. Invest.
102:734-743, 1998.
130. Pinsky, D., Lawson, C., Liao, H., Yan, S-F., Carmeliet, P., Loskutoff, D.,
and Stern, D. Hypoxia-mediated suppression of fibrinolysis enhances
pulmonary vascular fibrin deposition. J. Clin. Invest. 102:919-928, 1998.
131. Park, L., Raman, K., Lee, K., Lu, Y., Ferran, L., Chow, W., Stern, D. and
Schmidt, A-M. Suppression of accelerated diabetic atherosclerosis by
soluble receptor for AGE (sRAGE). Nature Medicine 4:1025-1031, 1998.
132. Spanier, T., Oz, M., Minanov, O., Simantov, R., Kisiel, W., Stern, D., Rose,
E., and Schmidt, A-M. Heparinless cardiopulmonary bypass with active
site-blocked Factor IXa: a preliminary study on the dog. J. Thorac.
Cardiovasc. Surg. 115:1179-1188, 1998.
133. Yan, S.D., Stern, D., Kane, M.D., Kuo, Y.M., Lampert, H.C., Roher, A.E.
RAGE-AB Interactions in the pathophysiology of alzheimer’s disease.
Restor Neurol Neurosci. 12(2,3):167-173, 1998.
134. Yan, S-D., Shi, Y., Zhu, A., Zhu, H., Zhu, Y., Gibson, L., Collison, K., Al-
Mohanna, F., Ogawa, S., Roher, A., Clarke, S., and Stern, D.
ERAB/mitochondrial L-3-hydroxyacyl-coenzyme A dehydrogenase type II:
central role of ERAB enzymatic activity in amyloid beta-peptide-induced
cytotoxicity. J. Biol. Chem. 274:2145-2156, 1999.
135. Schwarz, M., Lee, M., Zhang, F., Zhao, J., Jin, Y., Smith, S., Bhuva, J.,
Stern, D., Warburton, D., and Starnes, V. EMAP II: a modulator of
neovascularization in the developing lung. Am. J. Physiol. 276:L365-L375,
1999.
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136. Ozawa, K., Kuwabara, K., Tamatani, M., Tsukamoto, Y., Kobayashi, T.,
Yanagi, H., Stern, D., Ogawa, S., and Tohyama, M. ORP150 suppresses
hypoxia-induced apoptotic cell death. J. Biol. Chem. 274:6397-6404, 1999.
137. Feng, L., Stern, D., and Pile-Spellman, J. In situ endothelial cell biopsy
during invasive radiological procedures. Radiology 212:655-664, 1999.
138. Yan, S-F., Lu, J., Zou, Y-S., Cohen, D., Buttrich, P., Steinberg, S., Pinsky,
D., and Stern, D. Activation of Protein kinase C-ßII isoform links
hypoxia/hypoxemia and induction of tissue factor via Egr-1. J. Biol. Chem.
274:15030-15040, 1999.
139. Hofmann, M., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., Avila, C.,
Kambhan, N., Bierhaus, A., Nawroth, M., Slattery, T., Beach, D., McClary,
J., Nagashima, M., Morser, J., Stern, D., and Schmidt, A-M. RAGE
mediates a novel proinflammatory axis: the cell surface receptor for
S100/calgranulin polypeptides. Cell 97:889-901, 1999.
140. Spanier, T., Chen, J., Oz, M., Stern, D. Rose, E., and Schmidt, A-M. Time-
dependent cellular population of textured-surface left ventricular assist
devices contributes to the development of a biphasic systemic
procoagulant response. J. Thorac. Cardiovasc. Surg. 118:404-413, 1999.
141. Maruyama, S., Cantu, E., Pernis, B., Galili, U., Godman, G., Stern, D., and
Andres, G. Alpha-galactosyl antibody redistributes alpha-galactosyl at the
surface of pig blood and endothelial cells. Transplant Immunol. 7:101-106,
1999.
142. Maruyama, S., Cantu, E., DeMartino, C., Vladutiu, A., Caldwell, P., Wang,
C., D’Agati, V., Godman, G. Stern, D., and Andres, A. Membranous
glomerulonephritis induced in the pig by antibody to angiotensin-converting
enzyme: considerations on its relevance to the pathogenesis of human
idiopathic membranous glomerulonephritis. J. Am. Soc. Nephrology
10:2102-2108, 1999.
143. Maruyama, S., Cantu, E., DeMartino, C., Yang, C., Chen, J., Al-Mohanna,
F., Nakeeb, S., D’Agati, V., Pernis, B., Galili, U., Godman, G., Stern, D.,
and Andres, G. Interaction of baboon anti-alpha-galactosyl antibody with
pig tissues. Am. J. Pathol. 155:1635-1649, 1999.
144. Kislinger, T., Fu, C., Huber, B., Qu, W., Du, YS., Hofmann, M., Yan, S-F.,
Pischetsrider, M., Stern, D., and Schmidt, A-M. N(epsilon)-
(carboxymethyl)lysine adducts of proteins are ligands for RAGE that
activate cell signalling pathways and modulate gene expression. J. Biol.
Chem. 274:31740-31749, 1999.
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145. Schwarz, M., Kandel, J., Brett, J., Li, J., Hayward, J., Schwarz, R.,
Chappey, O., Wautier, J-L., Chabot, J., LoGerfo, P., and Stern, D.
Endothelial-monocyte activating polypeptide II, a novel anti-tumor cytokine
that suppresses primary and metastatic tumor growth, and induces
apoptosis in growing endothelial cells. J. Exp. Med. 190:341-353, 1999.
146. Yamaguchi, A., Hori, O., Stern, D., Hartmann, E., Ogawa, S., and
Tohyama, M. SERP1/RAMP4 stabilizes membrane proteins during stress
and facilitates subsequent glycosylation. J. Cell Biol. 147:1195-1204, 1999.
147. Maruyama, S., Cantu, E., Galili, U., D’Agati, V., Godman, G., Stern, D., and
Andres, G. Alpha-galactosyl epitopes on glycoproteins of porcine renal
extra-cellular matrix. Kidney International 57:655-663, 2000.
148. Yan, S-F., Lu, J., Zou, Y-S., Kisiel, W., Mackman, N., Leitges, M.,
Steinberg, S., Pinsky, D., and Stern, D. Protein kinase C-ß and oxygen
deprivation: a novel Egr-1-dependent pathway for fibrin deposition in
hypoxemic vasculature. J. Biol. Chem. 275:11921-11928, 2000.
149. Lalla, E., Lamster, I., Huang, L., Spessot, A., Qu, W., Kislinger, T., Lu, Y.,
Stern, D. M., and Schmidt, A-M. Blockade of RAGE suppresses
periodontitis-associated alveolar bone loss in diabetic mice. J. Clin. Invest.
105:1117-1124, 2000.
150. Tanji, N., Markowitz, G., Fu, C., Kislinger, T., Taguchi, A., Pischetstrieder,
M., Stern, D., Schmidt, A-M., and D’Agati, V. Expression of advanced
glycation endproducts and their cellular receptor RAGE in diabetic
nephropathy and nondiabetic renal disease. J. Am. Soc. Nephrol. 11:1656-
1666, 2000.
151. Taguchi, A., Blood, D., delToro, G., Canet, A., Lee, D., Tanji, N., Lu, Y.,
Ingram, M., Lalla, E., Hofmann, M., Fu, C., Kislinger, T., Lu, A., Stern, D.,
and Schmidt, A-M. Blockade of RAGE/amphoterin axis suppresses tumor
growth and metastases. Nature 405:354-360, 2000.
152. Yan, S-D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto,
C., Schmidt, A-M., Stern, D., and Kindy, M. Receptor-dependent cell stress
and amyloid accumulation in systemic amyloidosis. Nature Medicine 6:643-
651, 2000.
153. Yan, S-F., Lu, J., Xu, L., Zou, Y-S., Tongers, J., Kisiel, W., Mackman, N.,
Pinsky, D., and Stern, D. M. Pulmonary expression of Egr-1: biphasic time
course and effect of oxygen concentration. J. Appl. Physiol. 88:2303-2309,
2000.
154. Berger, A., Alexander, H., Tang, G., Wu, P., Hewitt, S., Turner, E., Kruger,
E., Figg, W., Grove, A., Kohn, E., Stern, D., and Libutti, S. EMAP II induces
25
Stern, David M., MD
Curriculum Vitae
endothelial cell apoptosis and may inhibit tumor angiogenesis. Microvasc.

Res. 60:70-80, 2000.
155. Biancone, L., Cantaluppi, V., Segoloni, G., Boccellino, M., Del Sorbo, L.,
Conaldi, P-G., Tjoielker, L. Maruyama, S., Cantu, E., Stern, D., Andres, G.,
and Camussi, G. Role of platelet-activating factor in functional alterations
of porcine endothelial cells induced by xenoreactive antibodies.
Transplantation 70:1198-1205, 2000.
156. Sousa, M., Yan, S-D., Stern, D., and Saraiva, M. Interaction of RAGE with
transthyretin triggers NF-kB activation. Lab. Invest. 80:1101-1110, 2000.
157. Yan, S-D., Zhu, Y., Zhu, H., Hwang, Y., Stern, E., Hori, O., Ogawa, S.,
Frosch, M. Connolly, E., McTaggert, T., Pinsky, D., Clarke, S., Stern, D.,
Ramasamy, R. ABAD is a component of the cellular response to nutritional
stress. J. Biol. Chem. 275:27100-27109, 2000.
158. Zhang, W., Yan, S-D., Zhu, A., Zou, Y-S., Williams, M., Godman, G.,
Thomashow, B. Ginsburg, M., Stern, D., and Yan, S-F. Expression of EGR-
1 in late-stage emphysema. Am. J. Pathol. 157:1311-1320, 2000.
159. Sheikh, S., Parhar, R., Kwaasi, A., Collison, K., Yacoub, M., Stern, D., and
Al-Mohanna, F. Alpha-gal-independent dual recognition and activation of
xenogeneic endothelial cells and human naive natural killer cells.
Transplantation 70:917-928, 2000.
160. Giri, R., Sultana, C., Shen, Y., Stins, M., Yan, S-D., Schmidt, A-M., Stern,
D., Kim, K-S., Zlokovic, B., and Kalra, V. ß-Amyloid induced migration of
monocytes across human brain endothelial cells involves RAGE and
PECAM-1. Am. J. Physiol. 279:C1772-C1781, 2000.
161. Powell, A., Read, J., Banfield, M., Gunn-Moore, F., Yan, S-D., Lustbader,
J., Stern, A., Stern, D., and Brady, L. Recognition of structurally diverse
substrates by Type II 3-hydroxyacyl-CoA dehydrogenase (HADH
II)/amyloid-ß binding alcohol dehydrogenase ABAD). J. Molec. Biol.
303:311-327, 2000.
162. Yan, S-F., Fujita, T., Lu, J., Okada, K., Zou, Y-S., Machman, N., Pinsky, D.,
and Stern, D. EGR-1, a master switch coordinating upregulation of
divergent gene families underlying ischemic stress. Nature Medicine
6:1355-1361, 2000.
163. Hofmann, M., Lalla, E., Lu, Y., Gleason, M., Wolf, B., Tanji, N., Ferran, L.,
Kohl, B., Rao, V., Kisiel, W., Stern, D., and Schmidt, A-M.
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Hyperhomocysteinemia enhances vascular inflammation and accelerates

atherosclerosis in a murine model. J. Clin. Invest. 107:675-683, 2001.
164. Tamatani, M., Matsuyama, T., Yamaguchi, A., Mitsuda, N., Tsukamoto, Y.,
Taniguchi, M., Che, Y-H., Ozawa, K., Hori, O., Nishimura, H., Yamashita,
A., Okabe, M., Yanagi, H., Stern, D.M., Ogawa, S. and Tohyama, M.
ORP150 protects against hypoxia/ischemia-induced neuronal death.
Nature Medicine 7:317-323, 2001.
165. Wautier, M-P., Chappey, O., Corda, S., Stern, D., Schmidt, A-M., and
Wautier, J-L. Activation of NADPH oxidase by AGEs links oxidant stress to
altered gene expression via RAGE. Am. J. Physiol. (Endocrinol. Metab.)
280:E685-694, 2001.
166. Kislinger, T., Tanji, N., Wendt, T., Qu, W., Lu, Y., Ferrna, L., Taguchi, A.,
Olson, K., Bucciarelli, L., Goova, M., Hofmann, M., Cataldegirmen, G.,
D’Agati, V., Pischetsrieder, M., Stern, D., and Schmidt, A-M. RAGE
mediates inflammation and enhanced expression of tissue factor in the
vasculature of diabetic apolipoprotein E null mice. Athero. Thromb. Vasc.
Biol. 21:905-910, 2001.
167. Lue, L-F., Walker, D., Brachova, L., Rogers, J., Shen, YH., Schmidt, A-M.,
Stern, D. M., and Yan, S-D. Involvement of RAGE-microglia interactions in
Alzheimer’s disease: in vivo and in vitro studies. Exptl. Neurology 171:29-
45, 2001.
168. Goova, M., Li, J. Kislinger, T., Qu, W., Lu, Y., Bucciarelli, L., Nowyrod, S.,
Wolf, B., Caliste, X., Yan, S-F., Stern, D., and Schmidt, A-M. Blockade of
RAGE restores effective wound healing in diabetic mice. Am. J. Pathol.
159:513-525, 2001.
169. Guha, M., O’Connell, M., Pawlinski, R., Hollis, A., McGovern, P., Yan, S-F.,
Stern, D., and Mackman, N. LPS activation of the MEK-ERK1/2 pathway in
human monocytic cells mediates tissue factor and tumor necrosis factor-
alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression.
Blood 98:1429-1439, 2001.
170. Tsukamoto, Y., Matsuo, N., Ozawa, K., Hori, O., Higashi, T., Nishizaki, J.,
Nagata, I., Kawano, K., Yutani, C., Hirota, S., Kitamura, Y., Stern, D.M.,
and Ogawa, S. Expression of a novel RNA splicing factor,
RA301/Tra2beta, in vascular lesions and its role in smooth muscle cell
proliferation. Am. J. Pathol. 158:1685-1694, 2001.
171. Ozawa, K., Tsukamoto,Y., Hori, O., Kitao, Y., Yanagi, H., Stern, D.M., and
Ogawa, S. Regulation of tumor angiogenesis by oxygen-regulated protein
27
Stern, David M., MD
Curriculum Vitae
150, an inducible endoplasmic reticulum chaperone. Cancer Res. 61:4206-

4213, 2001.
172. Sousa, M., Yan, S-D., Fernandes, R., Guimaraes, A., Stern, D., and
Saraiva, M. Familial amyloid polyneuropathy: RAGE-dependent triggering
of neuronal inflammatory and apoptotic pathways. J. Neurosci. 21:7576-
7586, 2001.
173. Ozawa, K., Kondo, T., Hori, O., Kitao, Y., Stern, D.M., Eisenmenger, W.,
Ogawa, S., Ohshima, T. Expression of ORP150 accelerates wound healing
by modulating intracellular VEGF transport. J. Clin. Invest. 108:41-50,
2001.
174. Okada, M., Fujita, T., Sakaguchi, T., Olson, K., Collins, T., Stern, D., Yan,
S-F., and Pinsky, D. Extinguishing Egr-1-dependent inflammatory and
thrombotic cascades following lung transplantation. FASEB J. 15:2757-
2759, 2001.
175. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P.,
Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., Morcos, M., Hofmann,
M., Tritschler, H., Weigle, B., Kasper, M., Smith, M., Perry, G., Schmidt, A-
M., Stern, D., Haring, H., Schleicher, E., and Nawroth, P. Diabetes-
associated sustained activation of the transcription factor NF-kB. Diabetes
50:2792-2808, 2001.
176. Kitao, Y., Ozwa, K., Miyazaki, M., Tamatani, M., Kobayashi, T., Yanagi, H.,
Okabe, M., Ikawa, M., Yamashima, T., Stern, D., Hori, O., and Ogawa, S.
Expression of the endoplasmic reticulum molecular chaperone (ORP150)
rescues hippocampal neurons from glutamate toxicity. J. Clin. Invest.
108:1439-1450, 2001.
177. Huang, E., Carter, J., Whelan, R., Liu, Y., Rosenberg, J., Rotterdam, H.,
Schmidt, A-M., Stern, D., and Forde, K. Colonoscopy in mice. Surg.
Endosc. 16:22-24, 2002.
178. Basta, G., Lazzerini, G., Massaro, M., Simonchini, T., Tanganelli, P., Fu,
C., Kislinger, T., Stern, D., Schmidt A-M., De Caterina, R. AGEs activate
endothelium through the signal transduction receptor RAGE: a mechanism
for amplification of inflammatory responses. Circ. 105:816-822, 2002.
179. Collison, K., Parhar, R., Saleh, S., Meyer, B., Kwaasi, A., Hammami, M.,
Schmidt, A-M., Stern, D., and Al-Mohanna, F. RAGE-mediated neutrophil
dysfunction is evoked by AGEs. J. Leuk. Biol. 71:433-444, 2002.
180. Hofmann, M., Drury, S., Hudson, B., Gleason, M. Qu, W., Lu, Y., Lalla, E.,
Chitnis, S., Monteiro, J., Stickland, M. Bucciarelli, L., Moser, B., Moxley, G.,
28
Stern, David M., MD
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Itescu, S., Grant, P., Gregersen, P., Stern, D., and Schmidt, A-M. RAGE
and arthritis: the G82S polymorphism amplifies the inflammatory response.
Genes Immun. 3:123-135, 2002.
181. Hou, F., Jiang, J., Guo, J., Wang, G., Zhang, X., Stern, D., Schmidt, A-M.,
and Owen, W. RAGE on human synovial fibroblasts: role in the
pathogenesis of dialysis-related amyloidosis. J. Am. Soc. Nephrol.
13:1296-1306, 2002.
182. Giri, R., Selvaraj, S., Miller, C., Hofman, F., Yan, S-D., Stern, D., Zlokovic,
B., and Kalra, V. Effect of endothelial cell polarity on beta-amyloid-induced
migration of monocytes across cultured brain endothelial cell monolayers
from normal and Alzheimer’s disease central nervous system. Am. J. Phys.
Cell Phys. 283: C895-904, 2002.
183. Bucciarelli, L.G., Wendt, T., Qu, W., Lu, Y., Lalla, E., Rong, L.L., Goova,
M.T., Moser, B., Kislinger, T., Lee, D.C., Kashyap, Y., Stern, D.M., and
Schmidt, AM. RAGE blockade stabilizes established atherosclerosis in
diabetic apolipoprotein E-null mice. Circulation, 106(22):2827-35, 2002.
184. Morcos, M., Sayed, A., Bierhaus, A., Yard, B., Waldherr, R., Merz, W.,
Kloeting, I., Schleicher, E., Mentz, S., Abdel Baki, R., Tritschler, H., Kasper,
M., Schwenger, V., Hamann, A., Dugi, K., Schmidt, A., Stern, D., Zeigler,
R., Haering, H., Andrassy, M., van der Woude, F., and Nawroth, P.
Activation of tubular epithelial cells in diabetic nephropathy. Diabetes, 5 :
3532-44, 2002.
185. Yan, S-D., Wu, Z-Y., Zhang, H-P., Furtado, G.I., Brown, C. Stern, A.
LaFaille, J., Chess, L., Stern, D., and Jiang, H. Suppression of
Experimental autoimmune encephalitis by selective blockade of
encephalitogenic T-cell infiltration of the central nervous system. Nature
Med. 9: 287-293, 2003.
186. Zhou, A., Wang, K., Penn, M.S., Marso, S.P., Lauer, M.A., Forudi, F.,
Zhou, X., Qu, W., Lu, Y., Stern, D.M., Schmidt, A.M., Lincoff, A. M., and
Topol, E.J. Receptor for AGE (RAGE) mediates neointimal formation in
response to arterial injury. Circulation, 107(17): 2238-2243, 2003.
187. Sakaguchi, T., Yan, S.F., Yan, S.D., Belov, D., Rong, L.L., Sousa, M.,
Andrassy, M., Marso, S.P., Duda, S., Arnold, B., Liliensiek, B., Nawroth,
P.P., Stern, D.M., Schmidt, A.M., and Naka, Y. Central role of RAGE-
dependent neointimal expansion in arterial restenosis. J. Clin. Inves.,
111(7): 959-972, 2003.
188. Wendt, T.M., Tanji, N., Guo, J., Kislinger, T.R., Qu, W., Lu, Y., Bucciarelli,
L.G., Rong, L.L., Moser, B., Markowitz, G.S., Stein, G., Gierhaus, A.,
Liliensiek, B., Arnold, B., Nawroth, P.P., Stern, D.M., D’Agati, V.D., and
29
Stern, David M., MD
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Schmidt, A.M. RAGE drives the development of glomerulosclerosis and

implicates podocyte activation in the pathogenesis of diabetic nephropathy.
Am J Pathol. 162(4): 1123-1137, 2003.
189. Yan S-D., Kindy, M., Submamaryan, K.R., Jovanovic., S., LaRue, B., Hogg,
E., Welch, D., Mannes, L., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern,
A., Schmidt, A.M., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Stern,
D., and Zlokovic, B. RAGE Mediates Amyloid- Peptide Transport Across
the Blood-Brain, Suppression of Cerebral Blood Flow and Development of
Cerebral Amyloidosis. Nature Medicine, 9: 907-913, 2003.
190. Shaw S.S., Schmidt A.M., Banes A.K., Wang X., Stern D.M., and Marrero,
M.B. S100B-RAGE-mediated augmentation of angiotensin II-induced
activation of JAK2 in vascular smooth muscle cells is dependent on PLD2.
Diabetes, 52: 2381-2388, 2003.
191. Kitao Y., Hashimoto, K., Matsuyama, T., Iso, H., Tamatani, T., Hori, O.,
Stern, D.M., Kano, M., Ozawa K., and Ogawa, S. ORP150/HSP12A
regulates Purkinje cell survival: a role for ER stress in cerebellar
development. J. Neuroscience, 24; 1486-1496, 2004.
192. Liliensiek B., Weigand, M.A., Bierhaus, A., Nicklas, W., Kasper, M., Hofer,
S., Plachky, J., Gröne, H-J., Schmidt, A.M., Yan, S.D., Martin, E.,
Schleicher, E., Stern, D.M., Hämmerling, G.J., Nawroth, P.P., and Arnold,
B. Receptor for Advanced Glycation End Products (RAGE) regulating
sepsis but not the adaptive immune response. J. Clin. Invest., 113:1641-
1650, 2004.
193. Lustbader, J., Cirilli, M., Lin, C., Xu, H-W., Takuma, K., Wang, N.,
Caspersen, C., Chen, X., Pollack, S., Chaney, M., Trinchese, F., Liu, S.,
Gunn-Moore, F., Lue, L-F., Walker, D., Kuppusamy, P., Zweier, J., Arancio,
O., Stern, D., Yan, S-D., and Wu, H. Interaction with ABAD directly links
Amyloid-beta to mitochondrial toxicity in Alzheimer’s disease. Science,
304: 448-452, 2004.
194. Tieu, K., Perier, C., Vila, M., Caspersen, C., Zhang, H-P., Teismann, P.,
Jackson-Lewis, V., Stern, D.M., Yan, SD., and Przedborski, S.
Overexpression of HADH II/ABAD protects dopaminergic neurons in a
model of Parkinson’s Disease. Annals of Neurology, 56:51-60, 2004.
195. Chen, Y., Yan, S-D., Colgan, J., Zhang, H-P., Schmidt, A.M., Stern, D., and
Herold K.C. Blockade of late stages of autoimmune diabetes by inhibition
of the Receptor for Advanced Glycation Endproducts (RAGE). J.
Immunol., 173:1399-1405, 2004.
196. Taguchi, A., Matsuyama, T., Moriwaki, H., Hayashi, T., Hayashida, K.,
Nagatsuka, K., Todo, K., Mori, K., Stern, D., Soma, T., and Naritomi, H.
30
Stern, David M., MD
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Circulating CD34-positive cells provide an index of cerebrovascular

function. Circulation, 109:2972-2975, 2004.
197. Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa,
H., Tsukamoto, Y., Iso, H., Fujimori, Y., Stern, D.M., Naritomi, H., and
Matsuyama, T. Administration of CD34+ cells post-stroke enhances
angiogenesis and neurogenesis in murine model. J. Clin. Invest. 114, 330-
338, 2004.
198. Hori, O., Ichinoda, F., Yamaguchi, A., Tamatani, T., Taniguchi, M.,
Koyama, Y., Katayama, T., Tohyama, M., Stern, D.M., Ozawa, K., Kitao,
Y., and Ogawa, S. Role of Herp in the endoplasmic reticulum stress
response. Genes Cells, 9, 457-469, 2004.
199. Fujita, T., Asai, T., Andrassy, M., Stern, D.M., Pinsky, D.J., Zou, Y.S.,
Okada, M., Naka, Y., Schmidt, A.M., and Yan, S-F. PKC regulates
ischemia/reperfusion injury in the lung. J. Clin. Invest. 113:1615-1623,
2004.
200. Arancio, O., Zhang, H.P., Chen, X., Chang, L., Trinchese, F., Puzzo, D.,
Liu, S., Hegde A., Yan S-F, Stern A., Luddy, J.S., Lue, L-F, Walker, D.G.,
Roher, A., Buttini, M., Mucke, L., Li, W., Schmidt, A.M., Hyslop, P.A., Stern,
D.M., and Yan, S-D. RAGE potentiates A-induced perturbation of
neuronal function in transgenic mice. EMBO J., 13, 23:4096-105, 2004.
201. Bando, Y., Tsuamoto, Y., Katayama, T., Ozawa, K., Kitao, Y., Stern, D.,
Yamauchi, A., Ogawa, S. ORP150/HSP124A protects renal tubular
epithelium from ischemia-induced cell death. FASEB J, 18:1401-3, 2004.
202. Bierhaus, A., Haselbeck, K-M., Humpert, P.M., Liliensiek, B., Dehmer, T.,
Morcos, M., Sayed, A.A.R., Andrassy, M., Schiekofer, S., Schneider, J.G.,
Schulz, J.B., Heuss, D., Neundorfer, B., Dierl, S., Huber, J., Tritschler, H.,
Schmidt, A-M., Schwaninger, M., Haering, H-U., Schleicher, E., Kasper, M.,
Stern, D.M., Arnold, B., and Nawroth, P.P. Loss of pain perception in
diabetes is dependent on a receptor of the immunglobulin superfamily. J.
Clin. Invest. 114:1741-51, 2004.
203. Takuma, K., Yao, J., Huang, J., Luddy, J., Trillat, A-C., Andrassy, M.,
Chen, X., Stern, D.M., Arancio, O., and Yan, S-D. ABAD enhances A-
induced cell stress via mitochondrial dysfunction. FASEB J. 19:597-598,
2005.
204. Chen, J., Kasper, M., Heck, T., Nakagawa, K., Humpert, P., Bai, L., Wu,
G., Zhang, Y., Luther, T., Andrassy, M., Schiekofer, S., Hamann, A.,
Morcos, M., Chen, B., Stern, D., Nawroth, P., and Bierhaus, A. Tissue
factor as a link between wounding and tissue repair. Diabetes 54:2143-
2154, 2005.
31
Stern, David M., MD
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205. Abeyama, K., Stern, D., Ito, Y., Kawahara, KK., Yoshimoto, Y., Tanaka, M.,
Uchimura, T., Ida, N., Yamazaki, Y., Yamada, S., Yamamoto, Y.,
Yamamoto, H., Lino, S., Taniguchi, N., and Maryama, I. The N-terminal
domain of thrombomdulin sequesters high-mobility group-B1 protein, a
novel anti-inflammatory mechanism. J. Clin. Invest. 115:1267-1274, 2005.
206. Chaney, M., Stine, W., Kokjohn, T., Kuo, YM., Esh, C., Rahman, A.,
Luehrs, D., Schmidt, A., Stern, D., Yan, SD., and Roher, A. RAGE and Aβ
interactions: atomic force microscopy and molecular modeling. Biochim
Biophys Acta. 1741: 199-205, 2005.
207. Feng, L., Matsumoto, C., Schwartz, A., Schmidt, AM., Stern, D., and Pile-
Spellman, J. Chronic vascular inflammation in patients with type 2
diabetes: endothelial biopsy and RT-PCR analysis. Diabetes Care 28: 379-
84. 2005.
208. Caspersen, C., Wang, N., Sosunov, A., Yao, J., Chen, X., Lustbader, J.,
Xu, H. Stern, D., McKhann, G., and Yan, S-D. Mitochondrial amyloid-beta:
a potential focal point for neuronal metabolic dysfunctioin in Alzheimer’s
disease. FASEB J. 19:2040-1 (Epub), 2005.
209. Tawfik, A., Jin, L., Ogbi, S., Caldwell, R., Barber, D., Stern, D., Fulton, D.,
Caldwell, R.W., and Marrero, M. Hyperglycemia-induced reactive oxygen
species mediates apoptosis in aortic endothelial cells through Janus
Kinase 2. Vasc. Pharmacol. 43:320-326, 2005.
210. Ding, K., Wang, Z., Hamrick, M., Deng, Z., Zhou, L., Kang, B., Yan, S.,
She, J., Stern, D., Isales, C., and Mi, Q. Disordered osteoclast formation in
RAGE-deficient mouse establishes an essential role for RAGE in diabetes
related bone loss. Biochem. Biophys. Res. Commun. 340: 1091-1097,
2006.
211. Zhou, Z., Immel, D., Xi, C-X., Bierhaus, A., Feng, Z., Mei, L., Nawroth, P.,
Stern, D. M., and Xiong, W-C. Regulation of osteoclast function and bone
mass by RAGE. J. Exp. Med. 203:1067-1080, 2006.
212. Banes-Berceli, A., Shaw, S., Ma, G., Brands, M., Eaton, D., Stern, D.,
Fulton,D., Caldwell, R., and Marrero, M. Effect of Simvastatin on high
glucose- and angiotensin II-induced activation of the JAK/STAT pathway in
mesangial cells. Am. J. Physiol. Renal Physiol. 29:F116-121, 2006.
213. Hori, O., M. Miyazaki, T. Tamatani, K. Ozawa, K. Takano, M. Okabe, M.

Ikawa, E. Hartmann, P. Mai, D. M. Stern, Y. Kitao, and S. Ogawa. Deletion
of SERP1/RAMP4, a component of the endoplasmic reticulum (ER)
32
Stern, David M., MD
Curriculum Vitae
translocation site, leads to ER stress. Molec. Cell Biol. 26:4257-4267,

2006.
214. Takano, K., Kitao, Y., Inagi, R., Momoi, T., Matsuyama, T., Miyata, T.,
Yoneda, Y., Iso, H., Stern, D.M., Hori, O., and Ogawa, S. A rat model of
human FENIB (familial encephalopathy with neuroserpin inclusion bodies).
Biochem. Biophys. Res. Commun. 346:1040-1047, 2006.
215. Kikuchi-Taura, A., Soma, T., Matsuyama, T., Stern, D.M., and Taguchi, A.
A new protocol for quantifying CD34(+) cells in peripheral blood of patients
with cardiovascular disease. Texas Heart Institute J., 33: 427-429, 2006.
216. Andrassy, M., Igwe, J., Autschbach, F., Volz, C., Remppis, A., Neurath, M.,
Schleicher, E., Humpert, P., Wendt, T., Liliensiek, B., Morcos, M.,
Schiekofer, S., Thiele, K., Chen, J., Kientsch-Engel, R., Schmidt A.,
Stremmel, W., Stern, D. M., Katus, H., Nawroth, P. P., Bierhaus, A. Post-
translationally modified proteins as mediators of sustained intestinal
inflammation. Am. J. Pathol. 169:1223-1237, 2006.
217. Kitao, Y., Imai, Y., Ozawa, K., Kataoka, A., Ikeda, To., Soda, M.,
Nakimawa, K., Kiyama, H., Stern, D. M., Hori, O., Wakamatsu, K., Ito, S.,
Itohara, S., Takahashi, R., Ogawa, S. PAEL receptor induces death of
dopaminergic neurons in the substantia nigra via endoplasmic reticulum
stress and dopamine toxicity, which is enhanced under conditions of parkin
inactivation. Hum. Mol. Genet. 16:50-60, 2007.
218. Myojin, K., Taguchi, A., Umetani, K., Fukushima, K., Nishiura, N.,
Matsuyama, T., Himura, H., Stern, D.M., Imai, Y., and Mori, H.
Visualization of intracerebral arteries by synchrotron radiation
microangiography. Am. J. Neuroradiol. 28:953-957, 2007.
219. Taguchi, A., Wen, Z., Myojin, K., Yoshihara, T., Nakagomi, T., Nakayama,
D., Tanaka, H. Soma, T., Stern, D.M., Naritomi, H., Matsuyama, T.
Granulocyte colony-stimulating factor has a negative effect on stroke
outcome in a murine model. Eur. J. Neurosci. 26:126-133, 2007.
220. Hara, K., Yasuhara, T., Matsukawa, N., Maki, M., Masuda, T., Yu, G., Xu,
L., Tambrallo, L., Rodriguez, N., Stern, D.M., Kawase, T., Yamashima, T.,
Buccafusco, J., Hess, D. and Borlongan, C. Hippocampal CA1 cell loss in a
non-human primate model of transient global ischemia: a pilot study. Brain
Res. Bull. 74(1-3): 164-171, 2007.
221. Taguchi, A., Matsuyama, T., Nakagomi, T., Shimizu, Y., Fukunaga, R.,
Tatsumi, Y., Yoshikawa, H., Kikuchi-Taura, A., Soma, T., Moriwaki, H.,
Nagatsuka, K., Stern, D.M., and Naritomi. H. Circulating CD34-positive
cells provide a marker of vascular risk associated with cognitive
impairment. J. Cereb Blood Flow Metab. Vol 28:445-449, 2008.
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Stern, David M., MD
Curriculum Vitae
222. Yoshihara, T., Taguchi, A., Matsuyama, T., Shimizu, Y., Kikuchi-Taura, A.,
Soma, T. Stern, D.M., Yoshikawa, Y., Moriwaki, H., Nagatsuka, K.,
Naritomi, H. Increase in circulating CD34-positive cells in patients with
angiographic evidence of Moyamoya-like vessels. J. Cerebral Blood Flow &
Metab., 28:1086-89, 2008.
223. Morcos, M., Du, X., Pfisterer, F., Hutter, H., Sayed, A., Thornalley, P.,
Ahmed, N., Baynes, J., Thorpe, S., Kukudov, G., Schlotterer, A.,
Bozorgmehr, F., El Baki, R., Stern, D.M., Moehrlen, F., Hamann, A.,
Becker, C., Zeier, M., Schwenger, V., Miftari, M., Humpert, P., Hammes, H-
P., Markus, B., Bierhaus, A., Brownlee, M., Nawroth, P.P. Glyoxalase-1
prevents mitochondrial protein modification and enhances life-span in C.
elegans. Aging Cell 7:260-269, 2008.
224. Origlia, N., Righi, M., Capsoni, S., Cattaneo, A., Stern, D.M., Chen, X.,
Arancio, O., Yan, S-D., and Domenici, L. RAGE-dependent activation of
p38 MAPK contributes to Aβ-mediated cortical synaptic dysfunction. J.
Neurosci 28:3521-3530, 2008.
225. Han, J., Zhong, J., Wei, W., Wang, Y., Huang, Y., Yang, P., Purohit, S.,
Dong, Z., Wang, M., She, J., Gong, F. Stern, DM., Wang, C. Extracellular
HMGB1 acts as an innate immune-mediator to enhance autoimmune
progression onset in NOD mice. Diabetes 57:2118-27, 2008.
226. Takuma, K., Fang, F., Zhang, W., Yan, S., Fukuzaki, E., Du, H., Sosunov,
A. McKhann, G., Funatsu, Y., Nakamichi, N. Nagai, T., Mizoguchi, H. Ibi,
D., Funatsu, Y., Nakamichi, Hori, O., Ogawa, S., Stern, DM., Yamada, K.,
and Yan, S-D. RAGE-mediated signaling contributes to intraneuronal
transport of amyloid-beta and neuronal dysfunction. Proc. Natl. Acad. Sci.
(USA) 106:20021-6, 2009.
227. Taguchi, A., Nakagomi, N., Matsuyama, T., Kikuchi-Taura, A., Yoshikawa,
Y., Kasahara, Y., Hirose, H., Moriwaki, H., Nakagomi, T., Soma, T., Stern,
D.M., and Naritomi, H. Circulating CD34-positive cells have prognostic
value for neurologic function in patients with past cerebral infarction. J.
Cerebral Blood Flow & Metabolism 29:34-38, 2009.
228. Nakagomi, N., Nakagomi, T., Kubo, S., Nakano-Doi, A., Saino, O., Takata,
M., Yoshikawa, H., Stern, D., Matsuyama, T., Taguchi, A. Endothelial cells
support survival, proliferation and neuronal differentiation of transplanted
adult ischemia-induced neural stem/progenitor cells after cerebral infarction.
Stem Cells 27:2185-95 2009.
229. Hara, K., Yasuhara, T., Maki, M., Matsukawa, N., Yu, G., Xu, L., Tambrallo,
L., Rodriguez, N., Stern, D., Yamashima, T., Buccafusco, J., Kawase, T.,
Hess, D., Borlongan, C. Anomaly in aortic arch alters pathological outcome
34
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Curriculum Vitae
of transient global ischemia in Rhesus macaques. Brain Res. 1286:185-

191, 2009.
230. Nakagomi, T., Taguchi, A., Fujimori, Y., Saino, O., Nakano-Doi, A., Kubo,
S., Gotoh, A., Soma, T., Yoshikawa, H., Nishizaki, T., Nakagomi, N., Stern,
D., Matsuyama, T. Isolation and characterization of neural stem/progenitor
cells from post-stroke cerebral cortex in mice. Eur J Neurosci. 29:1842-52,
2009.
231. Sliman, S., Eubank, T., Kotha, S., Kuppusamy, M., Sherwani, S., Butler, E.,
Kuppusamy P., Roy, S., Marsh, C., Stern, D., Parinandi, N. Hyperglycemic
oxoaldehyde, glyoxal, causes barrier dysfunction, cytoskeletal alterations
and inhibition of angiogenesis in vascular endothelial cells: aminoguanidine
protection. Mol. Cell. Biochem. 333:9-26, 2009.
232. Fang, F., Lue, L., Yan, S., Xu, H., Luddy, J., Chen, D., Walker, D., Stern, D.,
Yan, S., Schmidt, A., Chen, JX., and Yan, S-D. RAGE-dependent signaling
n microglia contributes to neuroinflammation, amyloid-beta accumulation
and impaired learning/memory in a mouse model of Alzheimer’s disease.
FASEB J., 24:1043-55, 2010.
233. Nakayama, D., Matsuyama, T., Ishibashi-Ueda, H., Nakagomi, T.,

Kasahara, Y., Hirose, H., Kikuchi-Taura, A., Stern, D., Mori, H., and
Taguchi, A. Injury-induced neural stem/progenitor cells in post-stroke
human cerebral cortex. Eur. J. Neurosci. 31:90-8, 2010.
234. Kasahara, Y., Taguchi, A., Uno, H., Nakano, A., Nakagomi, T., Hirose, H.,
Stern, D., and Matsuyama, T. Telmisartan suppresses cerebral injury in a
murine model of transient focal ischemia. Brain Res. 1340:70-80, 2010
235. Rauschenberger, K., Schöler, K., Sass, J., Sauer, S., Djuric, Z., Rumig,
C., Wolf, N., Okun, J., Kölker, S., Schwarz, H., Fischer, C., Grziwa,
B., Runz, H., Nümann, A., Shafqat, N., Kavanagh, K., Hämmerling, G.,
Wanders, R., Shield, J.,Wendel, U. Stern, D.M., Nawroth, P.P., Hoffmann,
M., Bartram, C., Arnold, B., Bierhaus, A., Oppermann, U., Steinbeisser,
U.,and Zschocke, J., A non-enzymatic function of 17β-hydroxysteroid
dehydrogenase type 10 is required for mitochondrial integrity and cell
survival. EMBO Molecular Medicine 2:51-62, 2010.
236. Saino, O., Taguchi, A., Nakagomi, T., Nakano-Doi, A., Kashiwamura, S.,
Doe, N., Nakagomi, N., Soma, T., Yoshikaway, H. Stern, D.M., Okamura, H.
Matsuyama, T. Immunodeficiency reduces neural stem/progenitor cell
apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J.
Neurosci. Res. 88:2385-2397, 2010.
237. Grossin, N., Wautier, M-P., Picot, J., Stern, D.M. and Wautier, J-L.
Differential effect of plasma or erythrocyte AGE-ligands of RAGE on
35
Stern, David M., MD
Curriculum Vitae
expression of transcripts for receptor isoforms. Diabetes Metab. 35:410-

417, 2009.
238. Taguchi, A., Kasahara, Y., Nakagomi, T., Stern, D.M., Fukunaga, M.,
Ishikawa, M., and Matsuyama, T., A reproducible and simple model of
permanent cerebral ischemia in CB-17 and SCID mice. J. Exp. Stroke
Transl. Med. 3:28-33, 2010.
239. Taguchi, A., Zhu, P., Cao, F., Kikuchi-Taura, A., Kasahara, Y., Stern, D.M.,
Soma, T., Matsuyama, T., and Hata, R. Reduced ischemic brain injury by
partial rejuvenation of bone marrow cells in aged rats. J. Cereb. Blood Flow
Metab. 31:855-867, 2011.
240. Yao, J., Du, H., Yan, S. Fang, F., Wang, C., Lue L., Guo, L., Chen, D.,
Stern, D.M., Gunn-Moore, F., Xi., Chen, J., Arancio, O., Yan, S. Inhibition
of amyloid-beta peptide binding alcohol dehydrogenase interaction reduces
amyloid-beta accumulation and improves mitochondrial function in a mouse
model of Alzheimer's Disease. J. Neurosci. 31: 2313-2320, 2011.
241. Kasahara, Y., Nakagorni, T., Matsuyama, T., Stern, D., and Taguchi, A.
Cilostazol reduces the risk of hemorrhagic infarction after administration of
tissue-type plasminogen activator in a murine stroke model. Stroke 43:
499-506, 2012.
242. Kikuchi-Taura, A., Taguchi, A., Kanda, T., Inoue, T., Kasahara, Y., Hirose,
H., Sato, I., Matsuyama, T., Nakagomi, T., Yanahara, K., Stern, D., Ogawa,
H., and Soma, T. Human umbilical cord provides a significant source of
unexpanded mesenchymal stromal cells. Cytotherapy 14:441-450, 2012.
243. Bierhaus, A., Fleming, T., Stoyanov, S., Leffler, A., Babes, A., Neacsu, C.,
Sauer, S., Eberhardt, M., Schnolzer, M., Lasischka, F., Neuhuber, W.,
Kichko, T., Konrade, I. Elvert, R., Mier, W., Pirags, V., Lukic, I., Morcos, M.,
Dehmer, T., Rabbani, N., Thornalley, P. Edelstein, D., Nau, C., Forbes, J.,
Humpert, P., Schwaninger, M., Ziegler, D., Stern, D.M., Cooper, M.,
Haberkorn, U., Brownlee, M., Reeh, P., Nawroth, P.P. Methylglyoxal
modification of Na(v)1.8 facilitates nociceptive neuron firing and causes
hyperalgesia in diabetic neuropathy. Nature Med. 18:926-933, 2012.
244. VonBauer, R., Oikonomou, D., Sulaj, A., Mohammed, S., Hotz-Wagenblatt,
A., Grone, J., Falk, A., Luethje, D., Erhardt, A., Stern, D.M., Bierhaus, A.,
and Nawroth, P.P. CD166/ALCAM mediates proinflammatory effects of
S100B in delayed-type hypersensitivity. J. Immunol. 191:369-377, 2013.
245. Kasahara, Y., Ihara, M., Nakagomi, T., Momota, Y., Stern, D.M.,
Matsuyama, T., and Taguchi, A. A highly reproducible model of cerebral
ischemia/reperfusion with extended survival in CB-17 mice. Neurosci. Res.
76:163-8, 2013.
36
Stern, David M., MD
Curriculum Vitae
246. Taguchi, A, Sakai, C., Soma, T., Kasahara, Y., Stern, D.M., Kajimoto, K.,
Ihara, M., Daimon, T., Yamahara, K., Doi, K., Kohara, N., Nishimura, H.,
Matsuyama, T., Naritomi, H., Sakai, N., and Nagatsuki, K. Intravenous
autologous bone marrow mononuclear cell transplantation for stroke:
phase 1/2a clinical trial in a homogeneous group of stroke patients. Stem
Cells Dev. 24:2207-2218, 2015.
247. Kennel, S., Williams, A., Stuckey, A., Richey, T., Wooliver, C., Chazin, W.,
Stern, D., Martin E., and Wall, J. The pattern recognition reagents RAGE
VC1 and peptide p5 share common binding sites and exhibit specific
reactivity with AA amyloid in mice. Amyloid 23:8-16, 2016.
248. Kasahara, Y., Yamahara, K., Soma, T., Stern, D.M., Nakagomi, T.,
Matsuyama, T., and Taguchi, A., Transplantation of hematopoietic stem
cells: intra-arterial versus intravenous administration. Transl. Res.
16:S1931-5244, 2016.
II. Invited Articles/Chapters
1. Nawroth, P.P. and Stern, D.M. A pathway of coagulation on endothelial

cells. J. Cell Biochem. 28:253-264, 1985.
2. Nawroth, P., and Stern, D.M. Endothelial cells as active participants in

procoagulant reactions. In: Vascular Endothelium in Hemostasis and
Thrombosis (Contemporary Issues in Haemostasis and Thrombosis)(M.
Gimbrone, ed.) Churchill and Livingstone. pp.14-39, 1986.
3. Nawroth, P.P., Kisiel, W. and Stern, D.M. The role of endothelium in the
homeostatic balance of hemostasis. In: Clinics in Haematology,
Coagulation Disorders (ed. C. Ruggeri) 14:531-546, 1985.
4. Nawroth, P.P., Handley, D., and Stern, D.M. The multiple levels of
endothelial cell-coagulation factor interactions. In: Clinics in Haematology,
Thrombosis and the Vessel Wall (ed. Colin Chesterman), W.B. Saunders
Co. Ltd. 15:(2)293-321, 1986.
5. Nawroth, P.P., Fenton, J.W., and Stern, D.M. Implications of thrombin

formation on the endothelial cell surface. Semin. Thromb. Haemost.
12:197-199, 1986.
6. Stern, D.M., Carpenter, B., and Nawroth, P.P. Endothelium and the
regulation of coagulation. Pathol. and Immunopathol. Res. 5:29-36, 1986.
37
Stern, David M., MD
Curriculum Vitae
7. Stern, D.M., and Nawroth, P.P. Modulation of endothelial cell coagulant

properties. In: Endothelial Cells, Volume I, (U.S. Ryan, ed.), CRC Press,
Inc. Boca Raton, FL. 1987. pp 149-163.
8. Stern, D.M., Handley, D.A., and Nawroth, P.P. Endothelium and the
regulation of coagulation. In: Endothelial Cell Biology (eds. N. Simionescu
and M. Simionescu), Plenum Pub. Corp., New York, NY. pp. 275-305,
1988.
9. Nawroth, P.P., and Stern, D.M. Tumor necrosis factor/cachectin-induced

modulation of endothelial cells hemostatic properties. Beitrage zur
Onkologie 10:254-258, 1987.
10. Esmon, C.T., Harris, K.W., Comp, P.C., Esmon, N.L., Nawroth, P.P., and
Stern, D.M. Regulation of natural anticoagulant pathways of blood
coagulation. Proceedings of Lilly-UCLA Symposium: Proteases in
Biological Control and Biotechnology. Eds. D. Cunningham and G. Long,
Vol. 57, pp 229-234, Liss, New York, 1987.
11. Stern, D.M., and Nawroth, P.P. Modulation of endothelial cell coagulant
properties. Proceedings of 13th International Congress on Clinical
Chemistry Congress of Clin. Chem., Ed. N. denBoer, pp. 217-220, Plenum,
New York, 1989.
12. Stern, D.M., and Nawroth, P.P. Coagulant properties of endothelium.

Seminars in Thrombosis and Hemostasis. 13:391-397, 1987.
13. Stern, D.M., Handley, D., and Nawroth, P.P. Endothelial cell regulation of
coagulation. In: The Molecular and Cellular Biology of Wound Repair (eds.
PM Henson and RA Clark), Plenum Pub. Co. pp. 87-114, 1988.
14. Nawroth, P.P., and Stern, D.M. A pathway of coagulation on endothelial

cells. In: Perspectives in Inflammation, Neoplasia, and Vascular Cell
Biology. UCLA Symposium on Molecular and Cellular Biology. New
Series, Volume 37, Alan R. Liss, Inc. New York. pp. 1-12, 1987.
15. Stern, D.M. and Nawroth, P.P. Tumor necrosis factor/cachectin and the
modulation of endothelial cell coagulant properties. In "Molecular Biology
of the Arterial Wall," Ed. G. Schettler, Springer-Verlag, Berlin/New York, pp
145-147, 1987.
16. Stern, D.M., Kaiser, E., and Nawroth, P.P. Regulation of the Coagulation
System by Vascular Endothelial Cells. Haemostasis 18:202-214, 1988.
17. Stern, D.M., Esposito, C., Gerlach, H., Gerlach, M., Ryan, J., Handley, D.
and Nawroth, P.P. Endothelium and the regulation of coagulation.
Diabetes Care 14:160-166, 1991.
38
Stern, David M., MD
Curriculum Vitae
18. Nawroth, P.P., and Stern, D.M. Tumor Nekrose Faktor-ein Regulator der
Gerinnung am Endothel. Proceedings of the Hamburger Gerinnungstage,
1988.
19. Nawroth, P.P., and Stern, D.M. Interaction of Vitamin K-Dependent

Coagulation Factors and the Endothelium. Cardiovascular Drugs and
Therapy 3:117-119, 1989.
20. Nawroth, P., and Stern, D. Regulation of coagulation by endothelial cells.

Zeitschrift fur Kardiologie 78 (Suppl. 6):16-24, 1989.
21. Gerlach, H., Esposito, C., and Stern, D. M. Modulation of endothelial

hemostatic properties: an active role in the host response. Annual
Reviews of Medicine 41:15-24, 1990.
22. Ogawa, S., Shreeniwas, R., Butura, C., Brett, J., and Stern, D. Modulation
of endothelial function by hypoxia: perturbation of barrier and
anticoagulant function, and induction of a novel Factor X activator.
Advances in Experimental Medicine and Biology, Volume 281:303-312,
Plenum Press 1991. (Proceedings of Thrombosis meeting in Taipei).
23. Gerlach, H., Clauss, M., Ogawa, S., and Stern, D.M. Perturbation of
endothelial barrier and coagulant properties by environmental factors. In:
Endothelial Cell Dysfunction. Eds. N. Simionescu and M. Simionescu,
Plenum Corp., New York, New York, pp. 525-545, 1991.
24. Nawroth, P., Stern, D., Bierhaus, A., Clauss, M., Gerlach, H., Stilgenbauer,
and Ziegler, R. Cytokine-induced stimulation of endothelial cells in vitro. In
New Trends in Haemostasis, Eds. Harenberg, J., Heene, D., Stehle, G.,
and Schettler, G. pp.103-106. Springer-Verlag, Berlin, 1990.
25. Ogawa, S., Matsumoto, M., Brett, J., and Stern, D. Modulation of
endothelial cell function by hypoxia: perturbation of barrier and
anticoagulant function, and induction of a novel procoagulant activity. In
New Trends in Haemostasis, Eds. Harenberg, J., Heene, D., Stehle, G.,
and Schettler, G. pp. 66-77. Springer-Verlag, Berlin, 1990.
26. Esposito, C., Vlassara, H., Brett, J., and Stern, D. Modulation of endothelial
functions by advanced glycosylation endproducts. In New Trends in
Haemostasis, Eds. Harenberg, J., Heene, D., Stehle, G., and Schettler, G.
pp. 89-96. Springer-Verlag, Berlin, 1990.
27. Ogawa, S., Matsumoto, M., Butura, C., and Stern, D. Hypoxia and
endothelial properties. Proceedings of First Altschul Symposium on
Atherosclerosis, 1990.
39
Stern, David M., MD
Curriculum Vitae
28. Ogawa, S., Matsumoto, M., Esposito, C., and Stern, D. Modulation of
endothelial barrier and coagulant properties by hypoxia. Proceedings of
International Society of Nephrology, 1990.
29. Matsumoto, M., Ogawa, S., Kogas, S., Cozzolino, F., Torcia, G.,
Shreeniwas, R., Kamada T., and Stern, D. Microvascular endothelium
during long-term exposure to hypoxia: alterations in cell growth, monolayer
permeability and cell surface coagulant properties. Proceedings of Osaka
Symposium of Endothelial Cell Biology, 1991.
30. Clauss, M., Ogawa, S., and Stern, D. Modulation of endothelium and
monocytes by tumor-derived factors. Progress in Leukocyte Biology, Vol:
II, 177-182. Cellular and Cytokine Networks in Tissue Immunity.
Proceedings of International Reticuloendothelial Cell Society. Wiley-Liss,
1991.
31. Clauss, M., Ryan, J., and Stern, D. Modulation of endothelial hemostatic
properties by tumor necrosis factor/cachectin: insights into the role of
endothelium in the host response to inflammatory stimuli. In, Biology of the
Tumor Necrosis Factors, Raven Press, 1991.
32. Gerlach, H., Clauss, M., Ogawa, S., Kao, J., Ryan, J., and Stern, D.
Cytokines and coagulation. pp. 293-300. In, Clinical Applications of
Cytokines: Role in Pathogenesis, diagnosis and Therapy, Eds. Gearing,
A., Rossio, J., and Oppenheim, J.,1993. Oxford University Press.
33. Schmidt, A-M., Esposito, C., Brett, J., Ogawa, S., Clauss, M., Kirstein, M.,
Radoff, S., Vlassara, H., and Stern, D. Modulation of endothelial function
and endothelial-monocyte interaction by advanced glycosylated end
products of proteins. In Mononuclear Phagocytes, Ed. R. van Furth, Kluwer
Academic Publishers (Dordrecht) pp. 202-207 1992.
34. Tijburg, P., Kuwabara, K., and Stern, D. Interaction of coagulation factors
with the vessel wall. Thrombosis and Hemorrhage, Editors Loscalzo and
Schaefer, pp. 331-338. Blackwell Scientific Publications 1994.
35. Kao, J., Fan, Y-G., Haehnel, I., and Stern, D. Endothelial-monocyte
polypeptides (EMAPs): tumor mediators which activate the host
inflammatory response. The Vascular Endothelium in Inflammation,
Behring Institue Mitteilungen, Behring Institute Research Communications
92: 92-106, 1993.
36. Pinsky, D., and Stern, D. Hypoxia-induced modulation of endothelial cell

function. In, Reperfusion Injury and Clinical Capillary Leak. Editors, Zikria,
B., Oz, M., and Carlson, R. pp. 31-56, Futura Publishing Co., Armonk, NY,
1994.
40
Stern, David M., MD
Curriculum Vitae
37. Schmidt, A-M., and Stern, D. Cellular receptors for advanced glycation
endproducts. Proceedings of the 5th International Symposium on the
Maillard Reaction. 1995.
38. Ryan, J., Brett, J., Kuwabara, K., Benedict, C., and Stern, D. Endothelial
cell coagulant function and its regulation by cyokines. Today’s Life Science
6: 18-22, 1994.
39. Schmidt, A-M., Hori, O., Brett, J., Yan, S-D., Wautier, S-D., and Stern, D.
Cellular receptors for advanced glycation endproducts: implications for
induction of oxidant stress and cellular dysfunction in the pathogenesis of
vascular lesions. Arterioscl. and Thromb. 14:1521-1528, 1994.
40. Hori, O., Yan, S-D., Ogawa, S., Matsumoto, M., Stern,D., and Schmidt, A-
M. Role of cellular receptors for advanced glycation endproducts: from
atherosclerosis to Alzheimer’s Disease. In, ‘94 International Symposium
on Aging and Health, pp. 152-154, 1994.
41. Simionescu, M., Popov, D., Sima, A., Hasu, M., Costache, G., Faitar, S.,
Vulpanovici, A., Stancu, C., Stern, D., and Simionescu, N. The
hyperlipidemic and diabetic hamster, a novel animal model. In
Atherosclerosis X. Eds. Woodford, F., Davignon, D., and Sniderman, A.
Elsevier B. V. Amsterdam. pp. 105-110, 1995.
42. Pinsky, D., Yan, S-F., Lawson, C., Naka, Y., Connolly, E.S., and Stern, D.
Hypoxia and modification of the endothelium: implications for regulation of
vascular homeostatic properties. Seminars in Cell Biology 5:283-294, 1995.
43. Schmidt, A-M., Yan, S-D., and Stern, D. The Dark Side of Glucose (News
and Views) Nature Medicine 1:1002-1004, 1995.
44. Yen, S., Liu, W., Hall, F., Yan, S-D., Stern, D., and Dickson, D. Alzheimer
neurofibrillary lesions: molecular nature and potential roles of different
components. Neurobiol. Aging 16:381-387, 1995.
45. Pinsky, D., Kuwabara, K., Schmidt, A-M., Lawson, C., Benedict, C.,
Broekman, M., Marcus, A., Malinski, T., Ryan, J., and Stern, D. Calreticulin
and thrombosis. In Calreticulin (Ed. M. Michalak); R.G. Landes Co., Austin
TX, Chapter 10:157-170, 1995.
46. Schmidt, A-M., Pinsky, D., Kao, J., Yan, S-D., Ogawa, S., Wautier, J-L.,
and Stern, D. Environmental perturbations of endothelium: modulation of
vascular properties by hypoxia, by hyperglycemia and by tumor-derived
cytokines. In Vascular Control of Hemostasis (ed. V. van Hinsbergh); part
of series Advances in Vascular Biology (eds. Vadas M., and Harlan, J).
Harwood Academic Publishers, Australia. pp.257-279 , 1996.
41
Stern, David M., MD
Curriculum Vitae
47. Naka, Y., Stern, D., and Pinsky, D. The pathophysiology and biochemistry
of myocardial ischemia, necrosis and reperfusion. In Atherosclerosis and
Coronary Artery Disease, V. Fuster, R. Ross, and E. Topol, Eds. Raven-
Lipincott (Philadelphia) 807-817, 1996.
48. Schmidt, A-M., Hori, O., Yan, S-D., and Stern, D. Advanced glycation
endproducts interacting with their cellular receptor induce oxidant stress:
implications for the pathogenesis of vascular disease in aging diabetes. In
Coronary Restenosis: From Genetics to Therapeutics. Ed. G. Feuerstein.
Marcel Dekker, New York. pp. 85-98, 1996.
49. Hori, O., Yan, S-D., Ogawa, S., Kuwabara, K., Matsumoto, M., Stern, D.,
and Schmidt, A-M. The receptor for advanced glycation endproducts has a
central role in mediating the effects of advanced glycation endproduucts on
the development of vascular disease in diabetes. Nephrology, Dialysis,
Transplantation 11 (Suppl. 5), 13-16 (1996).
50. Schmidt, A-M., Hori, O., Cao, R., Yan, S-D., Brett, J., Wautier, J-L., Ogawa,
S., Kuwabara, K., Matsumoto, M., and Stern, D. RAGE: a novel cellular
receptor for advanced glycation endproducts. Diabetes 45(Supplement 3):
S77-S80, 1996.
51. Andres, G., Yamaguchi, N., Brett, J., Caldwell, P., Godman, G., and Stern,
D. Cellular mechanisms of adaptation of grafts to antibody. Transplant
Immunol. 4: 1-17, 1996.
52. Yan, S-F., Ogawa, S., Stern, D. and Pinsky, D. Hypoxia-induced

modulation of endothelial cell properties: regulation of barrier function and
expression of Interleukin 6. Kidney International 51: 419-425, 1997.
53. Schmidt, A-M., Stern, D., and Yan, S-D. What’s the RAGE? European J.
Clinical Investigation 27: 179-180, 1997.
54. Schmidt, A-M., Wautier, J-L., Stern, D., and Yan, S-D. RAGE: implications
for the pathogenesis of diabetic complications. Hormones and Signalling
Volume 1, Editor, B. Mahley, pp. 41-63, 1997 (Academic Press).
55. Schmidt, A-M., Pinsky, D., Lawson, C., Tijburg, P., and Stern, D.
Interaction of coagulation proteins with the vessel wall. Thrombosis and
Hemorrhage. Editors, J. Loscalzo and J. Schafer, Williams and Wilkins. (for
second edition) Chapter 17 pp.365-371, 1998.
56. Roher, A., Kuo, Y-M., Lampert, H., Stern, D., and Yan, S-D. RAGE-Aß
interactions in the pathophysiology of Alzheimer’s disease. Restorative
Neurology and Neuroscience 12: 167-173, 1998.
42
Stern, David M., MD
Curriculum Vitae
57. Cines, D.B., Pollak, E., Buck, C. Loscalzo, J., Zimmerman, G., McEver, R.,
Pober, J., Wick, T., Konkle, B., Schwartz, B., Barnathan, E., McCrae, K.,
Schmidt, A-M., and Stern, D. Endothelial cells in physiology and in the
pathophysiology of vascular disorders. Blood 91: 3527-3561, 1998.
58. Pinsky, D., Oz, M., Naka, Y., and Stern, D. Nitric oxide and tissue
preservation in transplantation. In Nitric Oxide and the Cardiovascular
System, Editors, Loscalzo, J., and Vita, J., from Contemporary Cardiology,
Vol 4. Humana Press Inc., 1999.
59. Schmidt, A-M., Yan, S-D., Wautier, J-L., and Stern, D. Activation of RAGE:
a mechanism for chronic dysfunction in diabetic vasculopathy and
atherosclerosis. Circ. Res. 84: 489-497, 1999.
60. Yan, S-F., Mackman, N., Kisiel, W., Stern, D., and Pinsky, D.
Hypoxia/hypoxemia-induced activation of the procoagulant pathways and
the pathogenesis of ischemia-associated thrombosis. Athero. Thromb.
Vasc. Biol. 19: 2029-2035, 1999.
61. Schmidt, A-M., Rose, E., and Stern, D. Cardiopulmonary bypass: to clot or
not to clot, that is the problem. J. Thorac. Cardiovasc. Surg. 118:429-431,
1999.
62. Yan, S-D., Schmidt, A-M., and Stern, D. Cellular cofactors for amyloid beta-
peptide-induced cell stress: moving from cell culture to in vivo. Am. J.
Pathol. 155:1403-1411, 1999 (invited commentary).
63. Schmidt, A-M., and Stern, D.M. Emerging therapeutic targets in diabetic
vascular disease. Emerging Therapeutic Targets 3:483-493, 1999.
64. Yan, S-D., Roher, A., Chaney, M., Zlokovic, B., Schmidt, A-M, and Stern,
D.M.. Cellular cofactors potentiating induction of stress and cytotoxicity by
amyloid beta-peptide. Biochim. Biophys. Acta. 1502:145-157, 2000.
65. Yan, S-F., Pinsky, D., and Stern, D. A pathway leading to hypoxia-induced
vascular fibrin deposition. Seminars in Thrombosis and Hemostasis
26:479-483, 2000.
66. Schmidt, A-M., Hofmann, M., Taguchi, A., Yan, S-D., and Stern, D. RAGE:
a multiligand receptor contributing to the cellular response in diabetic
vasculopathy and inflammation. Seminars in Thrombosis and Hemostasis
26:485-493, 2000.
67. Yan, S-F., Pinsky, D., and Stern, D. Egr-1: Is it all immediate and early? J.
Clin. Invest.105:553-554 (Commentary), 2000.
43
Stern, David M., MD
Curriculum Vitae
68. Schmidt, A-M., and Stern, D.M. Atherosclerosis and diabetes: the RAGE
connection. Current Sci. 2:430-436, 2000.
69. Schmidt, A-M., and Stern, D.M. A radical approach to the pathogenesis of
diabetic complications. Trends in Pharmacological Sciences 21:367-369,
2000.
70. Schmidt, A-M., and Stern, D.M. RAGE and the complications of diabetes.
Trends in Endocrinology and Metabolism 11:368-375, 2000.
71. Schmidt, A-M., Yan, S-D., and Stern, D.M. The biology of RAGE and its
ligands. Biochimica Biophysica Acta 1498:99-111, 2000.
72. Yan, S-F., Pinsky, D., and Stern, D.M. Hypoxia-induced activation of Egr-1:
a novel pathway mediating the vascular response to oxygen deprivation.
Interactions of Blood and the Pulmonary Circulation, Eds., Weir, S., Reeve,
H., and Reeves, J., Futura Publishing Co., Chapter 22, pp 369-379, 2002.
73. Schmidt, A-M., and Stern, D. M. Rise of the chemokines: JE/MCP-1 and
restenosis (editorial). Atheroscler. Thromb. Vasc. Biol.21:297-299, 2001.
74. Yan, S-D., Roher, A., Soto, C., Al-Mohanna, F., Collison, K., Schmidt, A-
M., Stern, D. Cellular targets of amyloid-beta peptide: potential roles in
neuronal cell stress and toxicity. Neurobiology of Alzheimer’s Diseases,
second edition; editors Dawbarn, D., and Allen, S. In the Molecular and
Cellular Neurobiology Series; Series Advisors, Davies, R., Collingridge, G.,
and Hunt, S. pp. 252-269. Oxford University Press, 2001.
75. Wyss-Coray, T., McConlogue, L., Kindy, M., Schmidt, A-M., Yan, S-D., and
Stern, D. Key signaling pathways regulate the biological activities and
accumulation of Aß. Neurobiology of Aging. Neurobiol. Aging 22:967-973,
2001.
76. Yan, S-D., Schmidt, A-M., and Stern, D. Alzheimer’s disease: inside,
outside, upside down. Biochemical Society Symposium 67:15-22, 2001.
Symposium volume title: Neuronal Signal Transduction and Alzheimer’s
Disease. Edited by O’Neill, C., and Anderton, B. Published by The
Biochemical Society, London.
77. Rogers, J., Lue, L-F., Walker, D., Yan, S-D., Stern, D., Strohmeyer, R., and
Kovelowski, C. Elucidating molecular mechanisms of Alzheimer’s disease
in microglial cultures. Ernst Schering Research Foundation Workshop 39,
eds. H. Ketterman, Burton, G.A. U.1. Moenning, series editors, Stock, G.,
and Lessl, M., Springer-Verlag, Berlin Heidelberg, Germany, 25-44, 2002.
44
Stern, David M., MD
Curriculum Vitae
78. Stern, D., Yan, S-D., Yan, S-F., and Schmidt, A-M. Receptor for Advanced
Glycation Endproducts (RAGE) and the Complications of Diabetes. Aging
Research Reviews 1:1-15,2002.
79. Schmidt, A-M., Yan, S-D., Yan, S-F., and Stern, D. RAGE: a multiligand
receptor serving as a progression factor amplifying the
immune/inflammatory response. J. Clin. Invest. 108 (Perspective):949-955,
2001.
80. Krieger, M., and Stern, D. M. Multiligand receptors and human disease
(Introduction to the Perspective series). J. Clin. Invest. 108: 645-647, 2001.
81. Stern, D. Summary of the 6th EASD/JDRF Oxford workshop held at Keble
College, Oxford, August 4-6, 2001, on molecular and genetic aspects of
vascular complications of diabetes. Diabetologia 44:49-51, 2001.
82. Chen, J., Bierhaus, A., Schiekofer, S., Andrassy, M., Chen, B., Stern, D.M.,
and Nawroth, P.P. Tissue factor- a receptor involved in the control of
cellular properties, including angiogenesis. Thromb. Haemost. 86:334-345,
2001.
83. Schmidt, A-M., and Stern, D. RAGE is a gene within the MHC class II
region: implications for host response mechanisms in homeostasis and
chronic disease. Front. Biosci. 6:D1151-D1160, 2001.
84. Stern, D., Yan, S-D., Yan, S-F., and Schmidt, A-M. RAGE: a multiligand
receptor magnifying cell stress in diverse pathologic settings. Advanced
Drug Delivery Reviews- special issue, “Current treatments and therapeutic
targets in Alzheimer’s disease.” Advanced Drug Delivery Reviews,
54:1615-1625, 2002.
85. Bucciarelli, L.G., Wendt, T., Rong, L., Lalla, E., Hofmann, M.A., Goova,
M.T., Taguchi, A., Yan, S.F., Yan, S.D., Stern, D.M., and Schmidt, A-M.
RAGE is a multiligand receptor of the immunoglobulin superfamily:
implications for homeostasis and chronic disease. Cell. Mol. Life Sci.
59:1117-1128, 2002.
86. Lalla, E., Lamster, I., Stern, D., M., and Schmidt, A-M. RAGE, inflammation
and accelerated periodontal disease in diabetes: mechanisms and insights
into therapeutic modalities. Ann. Periodontal. 6:113-118, 2001.
87. Wendt ,T., Bucciarelli, L., Qu, W., Lu, Y., Yan, S-F., Stern, D.M., and
Schmidt, A-M. Receptor for Advanced Glycation Endproducts (RAGE) and
vascular inflammation: insights into the pathogenesis of macrovascular
complications in diabetes. Curr Atheroscler Rep. 4:228-37, 2002.
45
Stern, David M., MD
Curriculum Vitae
88. Rogers, J., Lue, L-F., Walker, D., Yan, S-D., Stern, D., Strohmeyer, R., and
Kovelowski, C. Elucidating molecular mechanisms of Alzheimer’s disease
in microglial cultures. Ernst Schering Res. Found. Workshop. 39:25-44,
2002.
89. Stern, D., Yan, S-D., Yan, S-F., and Schmidt, A-M. RAGE and the
complications of diabetes. Aging Res. Rev. 1:1-15, 2002.
90. Stern, D., Yan, S-D, Yan, S-F., and Schmidt, A-M. Receptor for advanced
glycation endproducts: a multiligand receptor magnifying cell stress in
diverse pathologic settings. Adv. Drug Deliv Rev. 54(12):1615-25, 2002.
91. Hudson, B., Hofmann, M., Bucciarelli, L., Wendt, T., Moser, B., Lu, Y., Qu,
W., Stern, D., Agati, VD., Yan, SD., Yan, SF., Grant, PJ., Schmidt, AM.
Glycation and Diabetes: The RAGE connection. Current Science 83(12):
1515-1521, 2002.
92. Marrero, M. and Stern, D. Structure and Function of the Vessel Wall, in
Diabetes Mellitus and Cardiovascular Disease, Lippincott Williams &
Wilkins, Editors: Marso, S. and Stern, D., pp. 3-17, 2004.
93. Schmidt, A-M, Yan, S-F, and Stern, D. Receptor-mediated vascular stress
in diabetes, in Diabetes Mellitus and Cardiovascular Disease, Lippincott
Williams & Wilkins, Editors: Marso, S., and Stern, D., pp. 93-110, 2004.
94. Stern, D., “MCG School of Medicine works to fill its niche,” Augusta
Chronicle, page 5A, January 22, 2003.
95. Yan, S-F., Yan, S-D., Pinksy, D., Schmidt, A., and Stern, D. Vascular
dysfunction in ischemia and diabetes in cellular dysfunction in
atherosclerosis and diabetes – reports from bench to bedside. Romanian
Academy Publishing House, Editors: M. Simionescu, A. Sima and D.
Popov.
96. Hudson, B., Bucciarelli, L., Wendt, T., Sakaguchi, T., Lalla, E., Qu, W., Lu,
Y., Lee, L., Stern, DM., Naka, Y., Ramasamy, R., Yan, SD., Yan, SF.,
D’Agati, V. Blockade of receptor for advanced glycation endproducts: a
new target for therapeutic intervention in diabetic complications and
inflammatory disorders. Arch Biochem Biophys, 419(1): 80-88, 2003.
97. Chen, X., Lue, L-F., Schmidt, A.M., Walker, D., Stern, D., and Yan, S-D.
RAGE mediates A-induced cellular perturbations, in Alzheimer’s disease
and related disorders: In Research Advances, Janssen-Cilag, Bucharest,
Romania, Editors: K. Iqbal and B. Winblad, pp. 367-377, 2003.
98. Yan, S-F., Ramasamy, R., Bucciarelli, L.G., Wendt, T., Lee, L.K., Hudson,
B.I., Stern, D.M., Lalla, E., Yan, S.D., Rong, L.L., Naka, Y., Schmidt, A.M.
46
Stern, David M., MD
Curriculum Vitae
RAGE and its ligands: a lasting memory in diabetic complications?

Diabetes Vasc Dis Res, 1:10-20, 2004.
99. Stern, D.M., and Yan, S-D. Comment on, “Promoter bashing-mitochondrial
genes damaged in AD brain.” Alzheimer Research Forum, August 11,
2004. On-line publication.
100. Stern, D., Hess, D., and Borlongan, C. Healing a broken heart with stem
cells. Cell Transplant. 13(7-8): 725-7, 2004.
101. Yan, S., and Stern, D. Mitochondrial dysfunction and Alzheimer’s disease:
role of amyloid-beta peptide alcohol dehydrogenase (ABAD). Int J Exp
Pathol. 86: 161-71, 2005.
102. Marrero, M.B., Fulton, D., Stepp, D., and Stern, D.M. Angiotensin II-
induced insulin resistance and protein tyrosine phosphatase. Arterioscler
Thromb Vasc Biol, 24:2009-13, 2004.
103. Bierhaus, A., Humpert, P.M., Stern, D.M., Arnold, B., and Nawroth, P.P.
AGE-receptor mediated cellular dysfunction. Annals of the NY Acad.
Science 1043:676-680, 2004.
104. Nawroth, P., Bierhaus, A., Yamamoto, H., Marrero, M., and Stern, D.
Atherosclerosis and restenosis: is there a role for RAGE? Current Diabetes
Reports, 5:11-16, 2005.
105. Takuma, K., Yan, S.S., Stern, D., and Yamada, K. Mitochondrial
dysfunction, Endoplasmic Reticulum Stress and Apoptosis in Alzheimer’s
Disease. Journal of Pharmacological Sciences 97:312-316, 2005.
106. Bierhaus, A., Humpert, P., Morcos, M., Wendt, T., Chavakis, T., Arnold, B.,
Stern, D., and Nawroth, P. Understanding RAGE, the Receptor for
Advanced Glycation Endproducts. J. Molecular Medicine 83:876-886,
2005.
107. Lue, LF., Yan, SD., Stern, DM., and Walker, DG. Current Drug Targets:
CNS and Neurological Disorders. 4:249-266, 2005.
108. Yan, SD., and Stern, DM. Comment on Schriner, SE., et al, “Extenstion of
Murine Lifespan by Overexpression of Catalase Targeted to Mitochondria”.
Posted on Alzheimer Research Forum website, 2005.
109. Marrero, M., Banes, A., Stern, D., and Eaton, D. Role of the JAK/STAT
signaling pathway in diabetic nephropathy. Am. J. Physiology. 290: F762-8,
2005.
47
Stern, David M., MD
Curriculum Vitae
110. Xiong, W., and Stern, D. The marriage of glucose and blood vessels: it
isn’t all that sweet. Cell Metab. 2:212-215, 2005.
111. Feuerstein, G., and Stern, D. The coagulation factor lottery – is 9 the
winning number? Drug Disc. Today: Therapeutic Strategies 2:279-283,
2005.
112. Marrero, M., Fulton, D., Stepp, D., and Stern, D. M. Angiotensin II-induced
signaling pathways in diabetes. Current Diabetes Rev. 1(2):197-202, 2005.
113. Yan, S.D., Xiong, W-C., and Stern, D. M. Mitochondrial Amyloid-Beta

Peptide: pathogenesis or late-phase development? J. Alz. Dis. 9:127-137,
2006.
114. Bierhaus, A., Stern, D. M., and Nawroth, P. RAGE in inflammation: a new
therapeutic target? Curr. Opin Investig. Drugs 7:985-991, 2006.
115. Chen, X., Stern, D. M., and Yan, S-D. Cellular targets of amyloid-beta
peptide: potential roles in neuronal cell stress and toxicity. Neurobiology of
Alzheimer’s Disease (Molecular and Cellular Neurobiology). Third Edition.
Eds. Dawbarn, D. and Allen, S. Chapter 11, pp 227-243, 2007.
116. Nawroth, P. and Stern, D. M. Soluble forms of RAGE: an index of vascular

stress? Free Rad. Biol. Med. 43:506-510, 2007.
117. Yan, S-D., Bierhaus, A., Nawroth, P., and Stern, D.M. RAGE and
Alzheimer’s disease: a progression factor for amyloid beta-peptide-induced
cellular perturbation? J. Alz. Disease. 16:833-43, 2009.
118. Yan, S-D., Bierhaus, A., Nawroth, P., and Stern, D.M. Endothelial
precursor cells and CRP on the RAGE: activation or cell death? J.
Cardiovasc. Phamacol. 53:349-51, 2009.
119. Kumar, V., Nawroth, P., and Stern, D.M. RAGE: A new member of the
nuclear receptor family is essential for DNA repair. In The Receptor RAGe
in Vascular and Cerebral Dysfunction. Editor, J-L Wautier. Cambridge
Scholars Publishing. pp. 121-146, 2019.
III. Books Edited
1. Marso, S.P. and Stern, D.M. Diabetes and Cardiovascular Disease –

Integrating Science and Clinical Medicine. Philadelphia, PA: Lippincott
Williams & Wilkins, 2004.
48
Stern, David M., MD
Curriculum Vitae
IV. INVENTIONS
U.S. Patent No. 4,885,277 "Anticoagulant therapy"
U.S. Patent No. 5,227,368 “Endotoxin-induced thrombosis factor which induces

procoagulant activity in endothelial cells”
U.S. Patent No. 5,370,989 “Solution for prolonged organ preservation”
U.S. Patent No. 5,552,267 “Solution for prolonged organ preservation”
U.S. Patent No. 5,641, 867 “Antibody which specifically binds to Endothelial-
Monocyte Activating Polypeptide II”
U.S. Patent No. 6,391,300 “A method for inhibiting thrombosis in a patient whose
blood is subjected to extracorporeal circulation”
U.S. Patent No. 5,839,443 “A method for inhibiting thrombosis in a patient whose
blood is subjected to extracorporeal circulation”
U.S. Patent No. 5,728,705 “Method of inducing vasorelaxation to treat pulmonary

hypertension”
U.S. Patent No. 5,968,911 “Method of inducing vasorelaxation to treat pulmonary

hypertension”
U.S. Patent No. 5,426,097 “Calreticulin: a novel antithrombotic agent”
U.S. Patent No. 6,228,837 “Endothelial Monocyte Activating Polypeptide II: a

mediator which activates host responses”
U.S. Patent No. 6,316,403 “Methods for treating an ischemic disorder and
improving stroke outcome”
U.S. Patent No. 6,315,995 “Methods for treating an ischemic disorder and
improving stroke outcome”
U.S. Patent No. 6,268,479 “Intracellular amyloid-beta peptide binding (ERAB)

polypeptide”
49
Attachment B

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IN THE CIRCUIT COURT FOR SULLIVAN COUNTY

BARRY STAUBUS, in his official capacity as the District )

EXPERT REPORT OF DAVID M. STERN, M.D.

3. As a leader of academic health centers, I am known for my emphasis on

Expert Report of David M. Stern, M.D.

5. My focus on addiction medicine started with a personal tragedy with my younger

Expert Report of David M. Stern, M.D.

8. Because of the scarcity of addiction medicine specialists, Integrated Addiction

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

III. Opioid Epidemic in Northeast Tennessee

A. Hancock County Case Study

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

B. Opioid Addiction, Abuse, Diversion, Overdose, and Death

American Journal of Public Health, 99(2), 2009, pp. 221-227.

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

27. As Volkow observed, although overprescription of opioid medications triggered

(https://www.johnsoncitypress.com/Government/2018/05/20/Controlling-the-cost-of-autopsies); 2017 Annual

Expert Report of David M. Stern, M.D.

C. The Opioid Epidemic’s Impact on Infants, Children, Families, and the

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

IV. Opioid Use Disorder

A. Addiction, Opioids and the Underlying Neurobiology

35. The American Society of Addiction Medicine defines addiction as follows:

Addiction is a primary, chronic disease of brain reward, motivation, memory and

Expert Report of David M. Stern, M.D.

• Naturally occurring substances from opium poppy

• Synthetic or partly synthetic compounds mimicking structure of opiates

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

B. A Chronic, Relapsing Condition

48. Addiction is a chronic, relapsing disorder characterized by compulsive drug

Expert Report of David M. Stern, M.D.

50. In patients in treatment with either buprenorphine or methadone medication-

multi-site trial,” Addiction, 111(4), 2016, pp. 695–705.

Expert Report of David M. Stern, M.D.

A. A Chronic Care Model

Addictions have historically been misunderstood by the public as a bad habit,

52. Based on the scientific conceptualization of addiction, the Institute of Medicine

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

B. Medication Assisted Treatment and Abstinence

a. Methadone. According to this approach, the patient takes the drug

Expert Report of David M. Stern, M.D.

b. Buprenorphine. According to this treatment, the patient takes the drug

c. Naltrexone. According to this treatment, the patient takes the drug

Expert Report of David M. Stern, M.D.

60. In general, it is difficult to determine which treatment will be optimal for a

 Decreased opioid use,

 Decreased opioid-related overdose deaths,

 Decreased infectious disease transmission (HIV, hepatitis C, bacterial

 Increased social functioning,

 Retention in treatment, and

Expert Report of David M. Stern, M.D.

Expert Report of David M. Stern, M.D.

64. The National Academies of Sciences, Engineering & Medicine (NASEM),

[M]ultiple studies with longer-term follow-up indicate that extending treatment

65. The National Institute on Drug Abuse (NIDA) states: