>> GOOD MORNING, EVERYBODY.
THIS IS DAY 3 OF OUR ANNUAL
SICKLE CELL DEC MEETING AND
WELCOME.
WE HAVE A FULL DAY AND MOST OF
THE TOPICS TODAY WILL BE RELATED
TO SICKLE CELL PAIN, A VERY
IMPORTANT COMPONENT OF SICKLE
CELL DISEASE.
SO BEFORE WE GET STARTED I WILL
LET ALEXANDRA GIVE YOU A LITTLE
LOGISTICS COMPONENTS OF
HOUSEKEEPING SLIDE AND THEN WE
WILL GET STARTED.
ALEX?
>> GOOD MORPING AND WELCOME TO
DAY 3 I WANT TO LET YOU ALL KNOW
WE ARE RECORDING THE MEETING.
DAYS WOB AND 2 HAVE BEEN
RECORDED AS WELL.
WE DO HOPE THAT ATTENDEES WILL
INTERACT WITH THE SPEAKERS.
WE ASK STEANDEES TO INPUT YOUR
QUESTIONS INTO THE Q&A CHAT
WHICH IS LOCATED AT THE BOTTOM
OF YOUR SCREEN AND IF YOU HAVE
ANY SIDE CONVERSATIONS, LET'S
PUT THOSE IN THE CHAT BOX.
ONCE AGAIN, WE ARE RECORDING
THIS.
IF YOU DO NEED LIVE CAPTIONS, IT
IS AVAILABLE AT THE BOTTOM,
PLEASE CLICK LIVE CAPTIONS AND
THEN SHOW SUBSCRIPT.
ONCE AGAIN WE ARE NEEDING ALL
ATTENDEES, TURNING OFF CAMERAS
AND FOR ANY REASON, IT CHANGES
PLEASE TURN OFF YOUR CAMERAS IN
THE MAIN MEETING THROUGHOUT THE
MEETING.
ONCE AGAIN, WE HOPE YOU ALL
ENJOY DAY 3 AND THANK YOU FOR
JOINING US FOR THE LAST 2 DAYS.
WITH THAT, I WILL PASS IT BACK.
>> THANK YOU, ALEX.
OKAY SO WE HAVE IS DR. DAYSAI,
ARE YOU ON?
>> I AM THANK YOU.
>> I WAS TOLD YOU ARE
INTRODUCING THE CHAIRS SO I WILL
LET YOU DO THE HONORS AND LET'S
GET STARTED WITH FIRST COMPONENT
OF SYMPOSIUM 5 WHICH IS
MULTIDISCIPLINARY AND
ALTERNATIVE CHRONIC PAIN
MANAGEMENT.
>> GOOD, MORNING EVERYONE AND
THANK YOU SO MUCH.
I WANTED TO INTRODUCE OUR
DISTINGUISHED PANELISTS,
DR. JJ STROUSE, AND DR. JULIE
KANTER, WHO WILL LEAD THIS
DISCUSSION FOR US TODAY.
I WANT TO THANK THEM FOR COMING
ITTH WITH THIS FANTASTIC
PRESENTATION AND THAT IS VERY
TIMLY ON MULTIDISCIPLINARY
APPROACHES TO PAIN AND I ALSO
WANTED TO MENTION THAT I'M
INTRODUCING THEM AS PRESIDENT OF
SICKLE CELL ADULT PROVIDER
NETWORK, DR. KANTER IS THE HEAD
OF NATIONAL ALLIANCE OF SICKLE
CELL CENTERS AND THIS IS THE
FIRST I HOPE OF VERY MANY
PARTNERSHIPS OF US COMING
TOGETHER AS I GROUP WORKING ON
SICKLE CELL TLGT BOTH ON THE
EDUCATION PIECE AS WELL AS
QUALITY AND ALLIANCE IN TERMS OF
DELIVERING CARE SO THANK YOU
VERY MUCH.
AND I WILL HAND IT OVER TO THEM.
SO WE'RE EXCITED TO BE HERE TO
PRESENT SYMPOSIUM 5,
MULTIDISCIPLINARY AND
ALTERNATIVE CHRONIC PAIN
MANAGEMENT FOR ADULTS WITH
SICKLE CELL DISEASE.
AND YOU CAN SEE OUR SIMLE FOR
THE NATIONAL ALLIANCE AND THE
PROVIDER NETWORK, AND I
ENCOURAGE TO YOU REACH OUT TO
ANY OF US, PARTICULARLY KYLE AND
JULIE IF YOU'RE INTERESTED IN
LEARNING MORE.
SO THE NETWORK WAS ESTABLISHED
TO SUPPORT HEALTHCARE PROVIDERS
AND INVESTIGATORS TO SERVE
ADULTS WITH SICKLE CELL DISEASE
AND IT'S REALLY FOR PEDEIAT
PROVIDERS AND WE ALSO WELCOME
FAMILY MEMBERS LIVING WITHIC
ISLELE DISEASE.
THE NATIONAL ASSOCIATION OF
SICKLE CELL CENTERS IS TO
SUPPORT THEM IN DELIVERING HIGH
QUALITY CARE BY THE FOLLOWING,
SETTING AND PROMOTING THE
ADOPTION OF STANDARDS AND WE
RADIO RECENTLY HAD OUR FIRST
CONFERENCE TO DEVELOP STANDARDS
OF CARE, FOR SICKLE CELL
CENTERS, IDENTIFYING
OPPORTUNITIES AND RESOURCES TO
STRENGTHEN SICKLE CELL CENTERS
AND ADVOCATING FOR ACCESS TO
COMPREHENSIVE SICKLE CELL CARE
TO IMPROVE HEALTH OUTCOMES,
QUALITY OF LIFE AND SURVIVAL FOR
ALL PEOPLE WITH SICKLE CELL
DISEASE.
SO WHAT'S THE CHAL ENK OF TODAY.
TODAY WE'RE TALKING ABOUT SICKLE
CELL AND CHRONIC PAIN, I WILL
FOCUS ON MANY OF CHALLENGES.
WE KNOW THAT NEARLY 30% OF
PEOPLE REPORT PAIN ON GREATER
THAN 95% OF DAYS SO THAT MORE
THAN MEETS THE DEFINITION OF
CHRONIC PAIN, WHICH IS PAINOT
MAJORITY OF DAYS OVER A 6 MONTH
PERIOD FOR PEOPLE WITH SICKLE
CELL DISEASE AND THE ASH SICKLE
CELL PAIN GUIDELINES WHICH I WAS
1 OF THE PEOPLE THAT
PARTICIPATED NONAPOPTOTIC THIS
GUIDELINE PANEL SUGGESTED
AGAINST THE INITIATION OF
CHRONIC THERAPY FOR CHRONIC PAIN
UNLESS THE PAIN IS REFRACTORY TO
OTHER MULTIPLE TREATMENT
MODALITIES.
THERE WAS MOW CERTAINTY FOR THAT
SUGGESTION BUT THAT SUGGESTION
WAS MADE AND ALSO TO SUGGEST THE
SHARED DECISION MAKING ABOUT THE
CONTINUATION OF CHRONIC OPIATE
THERAPY FOR THOSE FUNCTIONING
WELL WITH TREATMENT AND
SUGGESTING DISCONTINUATION AND
THOSE FUNCTIONING POORLY OR AT
HIGH RISK FOR OPIATE USE FOR
TOXICITY AND WE SEE THIS IN OUR
PRACTICE, YOU KNOW WHAT TO DO
FOR PATIENTS THAT OPIATES MIGHT
NOT BE A GREAT CHOICE FOR THEIR
CHRONIC PAIN.
WE WILL TALK ABOUT THAT TODAY
ALONG WITH AN EXCELLENT GROUP OF
SPEAKERS AND ALSO A PANEL
DISCUSSION.
SO THESE ARE OUR SPEAKERS, WE
HAVE 4 SPEAKERS ON TOPICS ON
CHRONIC PAIN AND THEN DR. KANTER
AND I WILL SERVE AS MODERATORS
ON A SPEAKER PANEL AND THEN
DR. WILL PROVIDE CLOSING
REMARKS.
AND THEN FOR THE OTHER HALF WE
HAVE SPEAKERS AREYALATED TO
TOPICS IN SICKLE CELL DISEASE
MOSTLY FOCUSED ON PAIN AND THOSE
WILL BE INTRODUCED BY THE
LEADERSHIP OF OUR SYMPOSIUM.
SO WITH THAT, I WANT TO
INTRODUCE OUR FIRST SPEAKER WHO
IS DR. CHARLES JONASSAINT, WHO
IS A ENTHUSIASTIC ADVOCATE FOR
NONPREKRIPGZ PSYCHOLOGY AND
OTHER MIND-BASED APPROACHES FOR
PAIN.
HE WILL ALSO FOCUS ON OTHER
COGNITIVE BEHAVIORIAL THERAPY
AND.
>> THANK YOU VERY MUCH.
I APPRECIATE THE OPPORTUNITY TO
TALK ABOUT THIS, DOING
NONPHARMACOLOGICAL APPROACHES TO
PAIN MANAGEMENT AND SICKLE SEAL
DISEASE.
FIRST I WOULD LIKE TO TALK A BIT
ABOUT BEHAVIORIAL THERAPY IN
SICKLE CELL, I WILL TELL YOU
RIGHT AWAY I DON'T HAVE GREAT
NEWS ABOUT THE EVIDENCE THAT'S
CURRENTLY AVAILABLE BUT
HOPEFULLY, I CREATE EXPECTATIONS
FOR WHAT'S COMING DOWN THE PIPE.
ONE OF THE BIGGEST THINGS IS THE
ENGAGEMENT WITH OUR DIGITAL
INTERVENTIONS, WE THINK THAT
UPON DIGITAL MIGHT BE THE WAY TO
EXPAND OR SCALE BEHAVIORIAL
INTERVENTIONS FOR PAIN IN SICKLE
CELL DISEASE AND OTHER
UNDERSERVED POPULATIONS AND
THERE ARE PAIRIERS TO GETTING
DIGITAL INTERVENTIONS OUT.
AND THE LAST PIECE I'M GOING TO
PRESENT IS A LITTLE BIT OF WORK
FROM OUR COMMUNITY ENGAGED TRIAL
AND THE LESSONS THAT WE'VE
LEARNED AND HOPEFULLY THINGS WE
CAN CARRY FORWARD TO FUTURE
TRIALS TO SEE IF WE CAN BUILD
ECHEDZ FOR BEHAVIORIAL
INTERVENTIONS IN SICKLE CELL
DISEASE.
NOW, THERE ARE A FEW EXISTING
BEHAVIORIAL THERAPIES IN SICKLE
CELL DISEASE AND UNFORTUNATELY,
THOSE, THEY'VE BEEN HAMPERED BY
SMALL SAMPLE SIZES, POOR
TREATMENT ENGAGEMENT, FOR
OVERALL QUALITY OF EVIDENCE IN
THESE TRIES SO THE EVIDENCE IS
NOT GREAT, THERE'S STUDIES ON
ACUE PURVEGHTURE, MINDFULNESS
AND RECEIPTLY THERE'S STUDIES ON
PROBLEM SOLVING SKILLS,
TRAINING, OUR COLLEAGUES, SAM
ROGERS RECENTLY PUBLISHED ON
MUSIC THERAPY AND SICKLE CELL
DISEASE AND ALL OF THESE HAVE
PROMISE BUT AS HAS BEEN STATED
IN THIS COCHRAN REVIEW THIS, IS
AN OALTDER REVIEW BUT THE STATE
OF THE LITERATURE IS STILL
RELATIVELY THE SAME IS THAT THE
SAMPLE SIZES FOR THESE STUDIES
HAVE BEEN PRETTY SMALL.
AS MANY OF YOU HAVE EXPERIENCED
WITH SICKLE CELL STUDIES IS
ENGAGEMENT IS CHALLENGING.
NOW THERE ARE A FEW CBT STUDIES
AND I WANT TO HILIGHT 2, S SIL
HAS RECENTLY PUBLISHED FOR YOUTH
WITH SICKLE CELL DISEASE WHO
HAVE BEEN REFERRED TO
FACE-TO-FACE COGNITIVE
BEHAVIORIAL THERAPY AND THEY
SHOW THAT THERE IS REDUCTIONS IN
MAIN, LENGTH OF STAY, PAIN
INTENSITY AND DISABILITY, SO
OVERALL THE PATIENTS THAT HAVE
BEEN REFERRED AND HAVE GOTTEN TO
FACE-TO-FACE COGNITIVE
DEHAIEVERRIAL THERAPY DID NO AN
IMPROVEMENT IN PATIENT OUTCOMES.
TONYA PAL EMBRYONIC STEM O
CONDUCTED A LARGE TRIAL OF
COGNITIVE VERSUS DIGITAL VERSUS
EDUCATION IN 1 SEIVET
ADOLESCENTS THEY DID SEE
POSITIVE EFFECTS, OF COURSE
THERE WERE ISSUES WITH
ENGAGEMENT BUT THAT DATA IS
FORTH COMING SO I NOLL PRESENT
TO ANY OF HER DATA HERE.
NOW THIS IDEA OF USING COMPUTER
OR USING A MOBILE DEVICE TO
TREAT PATIENTS WITH THERAPY HAS
BEEN AROUND FOR OVER A COUPLE
DECADES.
AND THIS IS PROMISING JUST
BECAUSE THERE'S A LACK OF
AVAILABLE PROVIDERS, THERE'S
LIMITED ACCESS FOR OUR PATIENTS
AND OVERALL, IT IS JUST
DIFFICULT TO GET PATIENTS INTO
THE CLINIC TO DO BEHAVIORIAL
THERAPY, SO EVEN WITH THESE
EVIDENCE-BASED TREATMENTS, HOW
ARE WE ACTUALLY GOING TO GET IT
TO OUR PATIENTS AND DOING
THERAPY WITHOUT AN ACTUAL
THERAPIST IS 1 OF THAT'S
POTENTIAL AVENUES.
YOU MAY HAVE SEEN MANY OF THE
NEW THERAPY APPS THAT ARE OUT
THERE, WE HAVE HAPPIFY NOOM,
MOOD, TOOLS, MOOD FIT, THERE'S
SEVERAL TYPINGS OF MINDFULNESS
AND BEHAVIORIAL INTERVENTIONS
THAT ARE AVAILABLE AND YOU CAN
DOWNLOAD THEM ON THE APP STORE
AND YOU CAN SIGN UP TO HAVE
LAWEDDER DALE WOULD PROBABLY BE
DEFINED AS STANDARD CBT
TECHNIQUES BUT MOST OF THESE ARE
BEHAVIORIAL RATHER THAN
COGNITIVE SO THAT THEY'RE NOT
TRYING TO WORK ON COGNITIVELY
STRUCTURING BUT MORE LIKELY
BEHAVIORIAL CHANGE OR
BEHAVIORIAL ACTIVATION.
ONE OF THE MOST IMPORTANT
COMPONENTS OF THESE DIGITAL
INTERVENTION SYSTEM THAT YOU
STILL NEED TO HAVE A HUMAN
COMPONENT.
YOU NEED TO HAVE A HEALTH
EXPOACH THERE'S DATA THAT
SUGGESTS WITHOUT A HEALTH COACH
THESE TREATMENTS, THESE DIGITAL
TREATMENTS ARE NOT EFFECTIVE.
NOW THIS IS NOT A SICKLE CELL
THIS, IS JUST A GENERAL
POPULATION, BUT 1 THING I WANT
TO HIGHLIGHT HERE IS THAT THERE
IS A BEHAVIORIAL EFFECT FOR
COGNITIVE BEHAVIOR HAL THERAPY
ON OUTCOMES, THESE ARE MENTAL
HEALTH OUTCOMES, SUPPRESSION,
BUT THE SAME IS TRUE FOR SAME
MENTAL OUTCOMES FOR OTHER
POPULATIONS.
BUT THERE'S OHM 2 OF THESE
STUDIES IN THE U.S., SO MOST OF
THESE DIGITAL THERAPY STUDIES
HAVE BEEN DONE IN THE UK OR
AUSTRALIA AND IN ADDITION TO
THAT, NONE OF THESE STUDIES HAVE
INCLUDED ENOUGH AFRICAN
AMERICANS OR MINORITIES TO
ACTUALLY SEE IF THERE ARE
DIFFERENCES BETWEEN HOW WHITES
RESPOND TO DICK'RE DIGITAL
THERAPY AND HOW AIF I CAN AN
AMERICANS RESPOND TO ADDITIONAL
THERAPY.
SO THERE'S VERY LITTLE ALTHOUGH
WE SEE THERE IS PROMISE FOR A
POTENTIAL FOR DIGITAL CBT, EVEN
IN OUR SICKLE CELL POPULATION,
THERE'S SUCH LIMITED DATA JUST
TO ACTUALLY FIND OUT, DOES
DIGITAL THERAPY EVEN WORK INAC
AFRICAN AMERICANS.
THIS STUDY PUBLISHES PRIMARY
CARE POPULATION AND JUST SHOWING
THAT 1 OF THE FIRST STUDIES TO
SHOW THAT FOR AFRICAN AMERICANS
WE SEE A DECREASE IN DEPRESSION
AND IMPROVEMENT IN PAIN OUTCOMES
FOR AFRICAN AMERICAN SIMILAR TO
THAT FOR WHITES.
SO INDEED, WE'RE FINDING THAT
YOU KNOW AT LEAST IN THE PRIMARY
CARE POPULATION, WE DO SEE THAT
AFRICAN AMERICANS CAN BENEFIT
FROM DIGITAL THERAPY, AT THE
SAME LEVEL OR MORE SO THAN WHITE
PARTICIPANTS.
ONE OF THE ISSUES THOUGH IS
OBVIOUSLY IN ENGAGEMENT.
WE KNOW THAT THERE ARE
CHALLENGES TO GETTING AFRICAN
AMERICANS AND MINORITY
POPULATIONS INTO FACE-TO-FACE
THERAPY AND A LOT OF THOSE
CHALLENGES, USUALLY COME INTO
THE COST OF IT, AND
TRANSPORTATION, JUST BEING ABLE
TO GET TO A THERAPIST OR BEING
ABLE TO ACCESS A CULTURALLY
COMPETENT THERAPIST.
BUT EVEN IN THIS DIGITAL
DELIVERY WHERE A LOT OF THOSE
BARRIERS SHOULD BE OVERCOME,
THERE ARE STILL SOME BARRIERS TO
GETTING ENGAGEMENT WITH DIGITAL
CBT, AS CAN YOU SEE, FOR THE
WHITE POPULATION, 10% DID NOT
EACH START THE DIGITAL CBT
PROGRAM, WHEREAS FOR OUR
MINORITIES 25% DID NOT START THE
DIGITAL CBT PROGRAM, AND WE SEE
THIS PRETTY CONSISTORRENTLY THAT
ENGAGEMENT WITH THE DIGITAL CBT
PROGRAMS IS MUCH LESS FOR
AFRICAN AMERICANS THAN IT IS FOR
WHITES SO IN THIS STUDY WE
SHOWED FOR AFRICAN AMERICANS
THEY COMPLETED 2 AND HALF FEWER
DIGITAL SESSIONS THAN THEIR
WHITE COUNTERPARTS, AND EVEN IN
THE DIFFERENT STUDY WE LOOKEDDA
THE SAME THING AND AGAIN THIS IS
YESTERDAY A GENERAL POPULATION
BUT HOPEFULLY THE APPLICATION IS
RELEVANT BUT CAN YOU SEE THAT
FOR THOSE WHITE PARTICIPANTS IN
THE STUDY, THEY COMPLETED 8 AND
HALF SESSIONS VERSUS 4 SESSIONS
FOR PLAQUE, SO THAT'S HALF THE
NUMBER OF SESSIONS COMPLETED,
TECHNIQUES COMPLOATED AND THOSE
ARE DEEP BREATHING EXERCISES OR
TAKING A NICE WALK IN THE WOODS,
THOSE TECHNIQUES ARE ABOUT 12,
BUT HALF OF THOSE COMPLETED BY
THE BLACK PARTICIPANTS, USAGE
AND MESSAGES ARE A HEALTH COACH
ARE HALF.
SO WE SEE THERE'S A HUGE ISSUE
WITH ENGAGEMENT WITH THE DIGITAL
THERAPY AMONG AFRICAN AMERICANS
AND WE ALSO IN OUR PRELIMINARY
STUDY WE SEE THE SAME CHALLENGES
WITH ENGAGEMENT FOR OUR SICKLE
CELL PATIENTS.
BUT THIS IS 1 OF THE EXAMPLES
THAT I WANT TO PULL OUT JUST
QUICKLY, I'LL SPEED THROUGH THIS
BECAUSE IT'S NOT MUCH TIME BUT
MIKE IS A 55 YEAR-OLD AFFRIC ARN
AMERICAN WITH ANXIOUS, COACH
SAID THIS IS A DIGITAL COACH
THAT IS TEXT MESSAGES TO THIS
INDIVIDUAL, HI, CHECKING IN, HOW
ARE YOU DOING, HE SAYS I'M
DEALING WITH LIFE, CAR BROKE
DOWN, SERIOUS MONEY ISSUES NOT
SURE I WANT TO KEEP DOING THIS
APP.
BEING HONEST, BEING TRUTHFUL
BECAUSE THIS APP REQUIRES WORK,
WORK I'M SOMETIMES I'M NOT
WILLING TO DO BUT I WON'T
BECAUSE I CAN'T.
I'M FRUSTRATED WITH THE COUNTRY
AND THE BELIEF THAT THINGS WILL
NEVER GET BETTER FOR MY SON OR
HIS CHILDREN, IT'S IMPOSSIBLE TO
PLAIN TO A PERSON OF NO COLOR.
JUST NOW JUST THINKING ABOUT
THAT RESPONSE FROM MIKE AND A
PATIENT AND WHAT DOES THE HEALTH
COACH TEXT BACK, I'M SORRY TO
HEAR YOU'RE DEALING WITH SO MANY
DIFFERENT STRESSORS ARE
SOPHISTICATED SO MANY FRONTS, I
HEAR THE FRUSTRATION, I HOPE YOU
WON'T GIVE UP ON THIS APP,
DURING TIMES OF EXTREME STRESS,
THE SECTION ON THE HOME PAGE
LABELED IN THE MOMENT RELIEVE,
CAN BE HELPFUL WAY TOK SESES 2-3
MINUTE AUDIO RECORDING TO HELP
YOU FEEL BETTER.
IF WE'RE NOT DOING THIS IN A WAY
THAT ENGAGE THIS IS SPECIFIC
PATIENT POPULATION, WE WILL HAVE
CHALLENGES.
WE'VE TRIED TO USE A VERY
SIMILAR APPLICATIONS WITH OUR
SICKLE CELL PATIENTS, AND 1 OF
THE THINGS AND FEEDBACK WE GOT
WAS IT WAS COOL BUT IT WASN'T
RELEVANT TO ME.
PATIENTS DID ISN'T SEE SOMEBODY
THAT LOOKED LOAMACYIC THEM AND
SOMETHING WE HEARD FREQUENTLY
FROM THE COMMUNITY IS NOTHING
FOR US WITHOUT US.
AND WE RECOGNIZE IMMEDIATELY 1
OF THE BARRIERS TO US BEING ABLE
TO DELIVER BEHAVIORIAL
INTERVENTIONS FOR PAIN AND
MENTAL HEALTH AND MAKING SURE
THAT THIS--THIS TREATMENT WILL
BE RELEVANT AND REPRESENTATIVE
OF THE POPULATION THAT WE'RE
TRYING TO SERVE.
WHAT WE DID TO ADDRESS THESE
HUGE BARRIERS WAS TOOK 2
EXISTING PROGRAMS, I CAN COPE
SICKLE CELL, THIS IS THE PROGRAM
THAT TONYA PAL EMERGING O TESTED
IN PEDIATRICS AND WE TRIED TO
ADAPT AND TAKE PIECES AND USE IT
FOR ADULTS AND THEN ALSO WORKING
WITH THE COMMUNITY, SICKLE CELL
101 IS A COMMUNITY-BASED
ORGANIZATION THAT HAS BEEN
EDUCATING PASHTS AND THEIR
FAMILY MEMBERS OVER SOCIAL
MEDIA, SOCIAL MEDIA PLATFORMS
LIKE INSTAGRAM, TWITTER,
FACEBOOK, ET CETERA AND CLEARLY,
YOU CAN SEE THAT THE COMMUNITY
BASED ORGANIZATIONS ARE DOING A
MUCH BETTER JOB OF GETTING
EDUCATION TO OUR PATIENT
POPULATION EVEN THAN WE ARE HERE
AT THE IVORY TOWER, SO WHY TRY
TO RECREATE THE WHEEL WHEN WE
LEVERAGE WHAT'S EXISTING.
THE HIGHLIGHT OF THIS IS THAT
WE'RE ABLE TO GET PATIENTS
LIVING WITH SICKLE CELL DISEASE,
ADULTS WITH SICKLE CELL DISEASE
TO ACTUALLY DELIVER THE
INTERVENTION.
SO ALL THE RECORDINGS, ALL THE
MESSAGING, THAT IS DONE BY
ADULTS WITH SICKLE CELL DISEASE,
IT'S NOT COMING FROM DR. CHARLES
WHO THINKS HE KNOWS IT ALL BUT
IT'S COMING FROM PEOPLE WHO HAVE
REAL LIVED EXPERIENCE AND IN
ADDITION TO THE TRAINING AND
TEACHING ON COGNITIVE
BEHAVIORIAL THERAPY AND
EDUCATION, YOU ALSO HAVE WARRIOR
STORIES SO YOU HAVE PATIENT WHO
IS ARE TALKING ABOUT THEIR
EXPERIENCE WITH STRESS AND PAIN
AND WITH EDUCATION AND THE
UPTICK.
WE WERE FUNDED BY PATIENT
CENTERED OUTCOMES RESEARCH
INSTITUTE TO HAVE 6 DIFFERENT
CLINICAL SITES AND NOW WE ADDED
A SEVENTH SITE, VANDERBILT BUT
THE REAL PUSH OR DRIVER OF THE
STUDIES HAVING THESE
COMMUNITY-BASED ORGANIZATIONS
PARTICIPATING WITH US, SICKLE
CELL 101, SICKLE SOLE COMMUNITY
AND CONSORTIUM THEY'VE DONE A
FANTASTIC JOB OF RECRUELTIMENT
AND I WILL SHOW THAT YOU DAT A.
BUT JUST IN BRIEF, THE STUDY IS
RANDOMIZING TO DIGITAL CBT OR
DIGITAL EDUCATION.
OUR GOAL IS TO GET 350 PATIENTS
ALL PATIENTS IN THE STUDY
REGARDLESS OF WHAT ARM THEY'VE
BEEN ANDROGEN ORDER OF
MICRONSIZED TOO WILL GET HELT
COACH SUPPORT, THEY GET HEALTH
COACH SUPPORT FOR 3 MONTHS AND I
WILL TALK ABOUT THE HEALTH
COACHES IN A SECOND.
AND THE PRIMARY OUTCOMES FOR
THIS ARE PAIN INTENSITY, DAILY
PAIN INTENSITY AND PAIN
INTERFERENCE BUT THE OUTCOMES
COME AT 3, 6 AND 12 MONTHS.
NOW JUST A QUICK STORY BOARD OF
HOW PATIENTS GET INTO THE STUDY
BECAUSE WE THINK THIS IS NEW AND
INNOVATIVE AND MIGHT HELP
OVERCOME THE ISSUES WE'VE SEEN
WITH OTHER TRIALS IN TERMS OF
BEING ABLE TO RECRUIT AND
ENGAGE.
IT'S PATIENTS THAT COME INTO THE
CLINIC, THEY ARE GOING TO GET
ACCESS TO AN iPAD KIOSK, IT
WILL HAVE A LITTLE VIDEO ON IT
OR HAS A VIDEO ON IT THAT
EXPLAINS THE STUDY, SO WE'RE NOT
JUST GIVING PEOPLE A CONSENT
FORM, WE HAVE A VIDEO AND IT'S
ENGAGING, WE HAVE A VIDEO THAT
EXPLAINS, THE STUDY TO THE
PATIENTS AND WHAT THEY'RE
GETTING INTO.
WE KNOW YOU HAVE PAIN, WE KNOW
YOU HAVE STRESS, THIS IS THE
STUDY THAT WANTS TO ADDRESS THAT
IN AN NONFARM COLLAGE CALAWAY.
RIGHT THERE ON THE iPAD THEY
CAN SIGN UP FOR THE STUDY AND
COMPLETE THOSE BASE LINE
QUESTIONNAIRES AND THEN ONCE
THEY SIGN UP, EVERYBODY IMETS AN
ALERT ON THEIR PHONE, THE
COORDINATOR CAN GO AND PRESENT
THE STUDY OR HELP THE PATIENT OR
THE PARTICIPANT GET ON TO THE
APP AND GET ON TO THE SYSTEM AND
EXPLAIN ANY DETAILS OF THE STUDY
THAT THEY DIDN'T UNDERSTAND FROM
THE KIOSK AND THEN OF COURSE,
RIGHT AFTER THAT, AS SOON AS
THEY LEAVE THE CLINIC,
EVERYTHING IS REMOTE IS A
COMPLETELY REMOTELY DELIVERED
INTERVENTION.
WITHIN 24 HOURS WE HAVE THE
HEALTH COACH CONTACTED
INDIVIDUAL AND MAKE SURE THEY'RE
CONNECT WIDE THE STUDY AND WITH
THE ISHT VENTION WHICH IS THE
IPAD, WHICH IS THE APP THAT THEY
ACCESS ON THEIR PHONE EMPLOY ALL
THE ASSESSMENTS ARE DONE ON THE
PHONE, THEY DON'T HAVE TO COME
BACK TO CLINIC ABOUT YOU WE
ENCOURAGE THE PARENT TO CONTINUE
USING THE CHARISMA APP OVER THE
COURSE OF THOSE 3 MONTHS, EVERY
DAY AND OF COURSE THEY CAN
INTERACT WITH THESE LESSONS IT'S
AN AUTOMATED CHAT BOX AND IT HAS
THE HIGHLIGHT OF IT OF COURSE
ARE THOSE VIDEO LESSONS THEY
WILL GET AND LEARN ON COGNITIVE
BEHAVIORIAL THERAPY OR ON SICKLE
CELL AND PAIN EDUCATION AND ALL
IT IS DELIVERED BY PATIENTS WITH
LIVING SICKLE CELL DISEASE, I
TRIED TO DO 1 OF THE LESSONS
MYSELF AND WE TOO BEING IT OUT
OF THE PROGRAM BECAUSE PATIENTS
DID NOT LIKE IT, THEY MUCH MORE
PREFER LIVING OTHER PEOPLE
LIVING WITH SICKLE DISEASE.
WITH THE LAST FEW MINUTES
OVERALL, THE STUDY AS OF
JULY 2022, SCREEN OVER 440
INDIVIDUALS WE 277 CONSENTED AND
256 RANDOMIZED AND TO BE
RANDOMIZED PATIENTS NEED TO
COMPLETE THE BASE LINE
QUESTIONNAIRES AND THEN THEY GET
RANDOMIZED TO GET A HEALTH COACH
AND WE'RE TRYING TO GET THAT
NUMBER UP TO 350.
WITH A FEW THINGS AS WITH
EVERYBODY, WE HAD ISSUES WITH
COVID, IT WAS HARD TO GET THE
STUDY STARTED UP AND EVEN ONCE
WE GOT IT STARTED UP, THERE WAS
A 7-MONTH DELAY INET GOING ALL
OF OUR SITES ENROLLING BUT
STILL, WE'RE PUSHING ALONG, BUT
REALLY WE WANTED TO END WITH THE
HIGHLIGHT HERE, IS THE HEALTH
COACHING.
WE STARTED OUT, WE THOUGHT WE
WOULD BE ABLE TO HAVE JUST 2
HEALTH COACHES, BE ABLE TO SERVE
OVER 350 PATIENTS, AND THE
REALITY WAS IS THAT THE HEALTH
COACHING COMPONENT TO THIS WAS
SO POPULAR THAT WE HAD TO GO OUT
AND REKROWT MORE HEALTH COACHES.
IN FACT WE HAD TO STOP THE STUDY
AT 1 POINT BECAUSE WE DID NOT
HAVE ENOUGH HEALTH COACHES TO
SERVE THE NEED.
SO REALLY, I THINK THIS IS A
COMBINATION OF THINGS.
CLEARLY COVID HAS HAD AN IMPACT
ON EVERYBODY AND BEING SHUT-IN
BUT ALSO JUST THE STATE OF
SOCIETY RIGHT NOW AND WHAT IT'S
LIKE TO BEING PLACENTA IN
AMERICA HAS BEEN PARTICULARLY
STRESSFUL FOR OUR PATIENTS BUT
WITH OUR HEALTH COACHES WE HAD A
LOT OF SUCCESS, THEY MADE OVER
ALMOST 15 CONTACTS PER PATIENT
SO THAT'S JUST TEXT MESSAGES AND
PHONE CALLS TRYING TO REACH OUT
WHICH HAS MANY OF YOU KNOW,
HAVING--EVEN THE PATIENTS DON'T
ANSWER THE PHONE, KNOWING THAT
SOMEBODY CARES AND IS REACHING
OUT, CAN BE AN INTERVENTION IN
AND OF ITSELF, WE HAD AT LEAST 1
PHONE SESSION WITH 205 PATIENTS
SO THAT'S 80% OF OUR PATIENTS SO
OUR REACH HAS BEEN REALLY GOOD
AND JUST TO EMPHASIZE THE POINT
OF THE DIGITAL INTERVENTION IS
IMPORTANT AND IT'S CRITICAL
BECAUSE THAT'S WHERE THE ACTIVE
INGREDIENT IS BUT HAVING THAT
HEALTH COACH, THAT REAL LIFE
PERSON IS GOING TO BE CRITICAL
MOVING FORWARD AND THAT'S WHAT
REALLY THE PATIENTS WHO HAVE
PARTICIPATED IN THE TRIAL,
THAT'S BEEN THE PART THAT HAS
BEEN REALLY THE MOST ATTRACTIVE
TO THEM.
AND THEN OF COURSE, OUR HEALTH
COACHES HAVE DONE ABOUT 5
SESSIONS ON AVERAGE WITH THESE
PARTIC PLAN TO ANALYZE BY AGES
AND THOSE CAN BE PHONE OR TEXT,
BUT WE FEEL LIKE THE FIRST PHONE
CALL IS REALLY, REALLY CLITICAL.
ENDING WITH THIS, WE LEARNED SO
FAR, THERE'S SIGNIFICANT MENTAL
HEALTH NEED FOR THE POPULATIONS,
SO, ALL THE PATIENTS HAVE BEEN
ENROLLED IN THIS TRIAL HAVE TO
HAVE CHRONIC PAIN.
THEY'RE NOT GETTING TO THE
THRIEL, BECAUSE OF MENTAL HEALTH
NEEDS BUT WE FOUND OUT THAT VERY
QUICKLY WE HAD THE SUICIDALLITY,
MANAGEMENT SYSTEM, AND IT WOULD
SEND US AN ALERT ANYTIME
SOMEBODY INDICATED THEY FELT
SUICIDAL ON THE PH Q 9 IT WOULD
LEAD THEM THROUGH A SUICIDAL
SEVERITY INDEX, 10%, OVER 10%
NOW OF OUR PATIENT WHO IS HAVE
ENROLLED IN THIS STUDY HAVE
TRIGGERED THE SUICIDALLITY
INDEX.
NOW NO WOAN INDICATED INTENT BUT
JUST THE FACT THAT OUR PATIENTS
MORE THAN PREVIOUSLY HAVE BEEN
THINKING ABOUT DEATH AND DYING
IS REALLY CONCERNING AND I THINK
IT SPEAKS TO THE STATE OF OUR
SOCIETY RIGHT NOW AND OUR
PATIENT POPULATION THAT WE'RE
TRYING TO SERVE.
ONE THING IS WE'VE BEEN TRYING
TO TARGET JUST MENTAL HEALTH AND
ENROLLMENT IS NOT SUCCESSFUL SO
I THINK PATIENTS ARE MORE LIKELY
TO DO BEHAVIORIAL INTERVENTION
FOR PAIN THAN THEY ARE FOR HAD
MENTAL HEALTH AND THEN OF COURSE
THE HEALTH COACHES ARE THE
HIGHLIGHT FOR THIS, AGAIN, I
WANT THINGS TO GO DIGITAL
BECAUSE I THINK THAT'S THE WAY
TO CREATE SCALE BUT THE REMOTE
HEALTH COACHING INTERVENTION IS
SOMETHING THAT COULD BE REALLY
SUCCESSFUL MOVING FORWARD FOR
BEHAVIORIAL INTERVENTIONS TRYING
TO TREAT PAIN.
THEN THE FINAL THING IS, I THINK
THAT WITH ALL OF OUR STUDIES AND
ALL OF OUR BEHAVIORIAL
TREATMENTS, IS SIMPLIFY AND THEN
SIMPLIFY AGAIN.
WE LEARN QUICKLY YOU CAN'T MAKE
THINGS TOO COMPLICATED, KEEPING
IT STRAIGHT FORWARD BUT IF YOU
CAN SIMPLIFY IT, MAKE IT VERY
EASY FOR OUR POPULATION TO
ENGAGE WITH, AND MAKING SURE
THAT IT'S RELEVANT AND RELATABLE
FOR OUR PATIENTS, I THINK WE
WILL FIEBD THESE BEHAVIORIAL
TREATMENTS ARE EFFECTIVE FOR
PAIN.
WE DON'T HAVE THE DATA YET TO BE
ABLE TO RECOMMEND ANY SPECIFIC
BEHAVIORIAL TREATMENTS FOR PAIN
IN SICKLE CELL DISEASE BUT THE
DATA IS COMING AND I LOOK
FORWARD TO MAYBE NEXT YEAR
SHARING MORE OF WHAT'S--WHAT
WE'VE LEARNED.
>> SO THANK YOU VERY MUCH,
CHARLES.
THAT WAS PHENOMENAL, I WANT TO
NOTICE THAT THERE ARE A LOST
DISCUSSIONS IN THE CHAT SO
THAT'S GOING TO BE IMPORTANT FOR
YOU TO LOOK AT.
WE'RE GOING TO SAVE OUR Q&As
TO THE END SO I DON'T WANT
ANYBODY TO THINK WE'RE IGNORING
YOU, WE HAVE A PANEL AT THE END
FOR ALL OF OUR SPEAKERS ISSUES
DON'T WORRY THAT'S COMING UP
SOON.
I'M JULIE KANTER, THANK TO YOU
DR. SAYAI, AND DR. STROUSE, FOR
INTRODUCING OUR PANEL TODAY, WE
COULD TALK ABOUT ALL OF THIS FOR
DAYS, SO WE WILL GOET THROUGH AS
MUCH OF THIS HAS MUCH AS
POSSIBLE AND AS I SAID GET TO
ALL OF YOUR QUESTIONS LATER ON,
I AM REALLY EXCITED TO BE ABLE
TO INTRODUCE OUR NEXT SPEAKER.
DR. SCHLAEGER IS A PABLIST WITH
THE UNIVERSITY OF
ILLINOIS-CHICAGO, SHE HAS AN
EXTENSIVE BACKGROUND AS A
LICENSED ACCUPUNCTURIST WHERE
SHE DEVELOPED RESEARCH IN PAIN,
CERTIFIED MIDWIFE AND SHE IS
JUST REALLY AN AMAZING SPEAKER
AND I'M VERY EXCITED TO SEE WHAT
SHE HAS TO TELL US TODAY SO WITH
THAT I SHOULD ALSO MENTION SHE'S
AMAZINGLY WELL FUNDED AND IF I
WENT TO ALL HER GRANTS WE
WOULDN'T HAVE TIME TO GET
THROUGH HER PRESENTATION, SO
TAKE IT AWAY.
>> THANK YOU FOR THE WONDERFUL
DISTRIBUTION, DOCTOR.
TODAY I WOULD LIKE TO SPEAK WITH
YOU ABOUT NONPHARMACOLOGIC
MODALITIES FOR TREATING SICKLE
CELL PAIN SO WE WILL RUN THROUGH
SOME OF THOSE AND I WILL SHARE
WITH YOU OUR HUGE BABY WHICH IS
OUR GRACE TRIAL WHICH IS LOOKING
AT RELAXATION AS WELL AS
ACCUPUNCTURE FOR THE TREATMENT
OF SICKLE CELL PAIN.
AND WITH NO FURTHER ADO, LET'S
GET GOING HERE.
NEXT, PLEASE.
THE USE OF ACCUPUNCTURE AND
OTHER NONPHARMAICOLOGGIC
MODALITIES TO REDUCE PAIN,
OPIOID USE AND ENABLE THEMSELVES
TO BETTER COPE WITH THEIR PAIN
AND WELL KNOWN.
OUT OF 227 ADULT RESPONDENTS,
92% EXPERIENCE CHRONIC PAIN AND
92% OF THOSE RESPONDED TO USE
SOME FORM OF NONPHARMAICOLOGGIC
THERAPY TO MANAGE CHRONIC PAIN.
A FEW STUDY VS ADEQUATELY
EVALUATED THE EFFECTIVENESS OF
THESE THERAPIES, NEXT, PLEASE.
THERE ARE 2 METAANOLL SIS THAT
WE AS ACCUPUNCTURE
METHODOLOGISTS AND SCIENTISTS
USE TO SUBSTANTIATE USING
ACCUPUNCTURE FOR THE TREATMENT
OF CHRONIC PAIN, BOTH BY VICARS
ET AL, 1 WAS THE META-ANALYSIS
OF ALMOST 21 PATIENTS THAT
SHOWED A STATISTICALLY
SIGNIFICANT DIFFERENCE BETWEEN
THE ACCUPUNCTURE GROUP VERSUS
THE SHAM ACCUPUNCTURE GROUP, FOR
TREATING MUSK LO SKELETAL PAIN,
OFTIO RGTERATEIS EXPOO SHOULDER
AND NECK AND PAIN.
THEY LOOKED AT DURATION OF THE
ACCUPUNCTURE EFFECT ALMOST 6400
PATIENTS.
UP TO 90% OF THE ACCUPUNCTURE
EFFECT WAS PRESENT 1 YEAR AFTER
TREATMENT.
NEXT PLEASE.
IN TERMS OF PHYSIOLOGICAL
EFFECTS OF ACCUPUNCTURE, IT
RELIEVES PAIN BY THE EMILY
CIBOL, NEOCORTICALE SYSTEM, ACT
ACTIVATES RECEPTORS, INCREASES
SERUM, BETA ENDORPHINS, DOWN
REGULATES M1 MACROFAJS, IL1 B,
IL6 AND IL18 AND TNF,
ACCUPUNCTURE REGULATES CENTRAL
AND PERIPHERAL BLOOD FLOW AND
REGULATED THE HBA ACCESS BY
REDUCING ACTHRELEASE FROM THE
ANTERIOR PITUITARYY WITH THE
SUBSEQUENT REDUCTION IN ADRENAL
CORTEX.
NEXT, PLEASE.
IN TERMS OF PEDIATRIC
ACCUPUNCTURE, THERE ARE 4, 1 IS
FOCUSED ON CHRONIC PAIN, 2 ARE
FOCUS ONED ACUTE VOCs AND 1 ON
ACUTE AND CHRONIC PAIN.
THE FIRST WAS A RETROSPECTIVE
CHART REVIEW OF THE 16 YEAR-OLD
GIRL WHO RECEIVED 58 ACUE
PURNGHTURE IN-PATIENT AND
OUT-PATIENT TREATMENT OVER 3
YEARS.
NO PAIN SCORES WERE REPORTED BUT
THERE WAS AN 80% REDUCTION IN ED
VISITS.
FIRST UNCONTROLLED STUDY HAD
ONLY 2 PATIENTS.
THEY BOTH THOUGHT ACCUPUNCTURE
WAS BENEFICIAL FOR THEIR PAIN,
THE SECOND UNCONTROLLED STUDY
WAS FOR ACUTE AND CHRONIC PAIN
IN 12 CHILDREN WHO HAD
ACCUPUNCTURE A TOTAL OF 33
TIMES.
WITHIN GROUP SCORES FOR
ACCUPUNCTURE SHOWED A REDUCTION
IN PAIN, THE ONLY CONTROLLED
STUDY WAS AN RCT WHICH WAS DONE
FOR ACCEPTABILITY, THAT LOOKED
AT ACCUPUNCTURE VERSUS IN
CHILDREN VERSUS CHILDREN
UNINTERESTED IN RECEIVING ACUE
PUVENGHTURE FOR ACUTE VOCs,
ACCUPUNCTURE WAS FOUND TO BE
ACCEPTABLE AND THERE WAS A
REDUCTION WITHIN GROUP PAIN
SCORES IN THE ACCUPUNCTURE
GROUP.
NEXT PLEASE.
FOR ADULT--NEXT SLIDE, PLEASE.
THANK YOU.
FOR ADULT ACCUPUNCTURE, THERE
ARE 3 STUDIES, 2 FOR ACUTE
VOCs, 1 FOR CHRONIC PAIN, ALL
WERE UNCONTROLLED.
THE FIRST STUDY OF 9 IN-PATIENTS
HAD A MEDIAN OF 3 ACCUPUNCTURE
TREATMENTS EACH AND AVERAGE PAIN
REDUCTION OF 2 OUT OF 10.
SECOND EVALUATED 16 ACUTE
PAINFUL CRISIS, EXPERIENCED BY
10 PATIENTS, PATIENTS IN THE
STUDY ACHIEVED PAIN RELIEVE IN
15 OF 16 ACUTE PAIN EPISODES,
AFTER RECEIVING EITHER
ACCUPUNCTURE OR SHAM
ACCUPUNCTURE, THE THIRD WAS A 1
ARM FEASIBILITY AND
ACCEPTABILITY STUDY OF 5 ADULTS
WHO RECEIVED A STANDARD PROTOCOL
FOR 10 SESSIONS, 2 TIMES A WEEK
FOR 5 WEEKS, PAIN INTENSITY AND
PAIN INTERFERENCE WAS REDUCED AS
WELL AS ANXIOUS, DEPRESSION,
ANGER AND SLEEP DISTURBANCE.
NEXT, PLEASE.
THERE WAS 1 RCT AND 2
UNCONTROLLED STUDIES LOOKING AT
MASSAGE IN CHILDREN AND
ADOLESCENCE ALL FOR CHRONIC
PAIN.
THIRTY-FOUR CHILDREN IN
ADOLESCENCE AND THEIR APPARENTS
WERE ASSIGNED TO A MASSAGE
THERAPY OR AN ATTENTION CONTROL
GROUP.
PARENTS PROVIDED NIGHTLY
MASSAGES, THE PARENTS GIVING
MASSAGE HAD INCREASED ANXIETY
AND DEPRESSION, THE CHILDREN
RECEIVING MASSAGE HAD DECREASED
PAIN, ANXIETY AND DEPRESSION,
THE SECOND STUDY EXAMINED
MASSAGE IN 4 CHILDREN AND 1
ADULT, THE NUMBER OF SESSIONS OF
NOT SPEC PIED BUT GROUP PAIN
SCORES WERE REDUCED.
THE THIRD UNCONTROLLED STUDY WAS
A MASSAGE VERSUS A GUIDED
IMAGERY RELAXATION INTERVENTION
FOR THE MASSAGE GROUP WITHIN
GROUP PAIN SCORES WERE ALSO
REDUCED.
NEXT PLEASE.
NEXT, SLIDE, PLEASE.
THERE WERE 2 STUDIES OF YOGA IN
CHILDREN AND ADOLESCENCE, 1 WAS
A FEASIBILITY STUDY, THE OTHER
WAS AN RCT FEASIBILITY AND
ACCEPTABILITY STUDY, THE FIRST
STUDY FIRST PART WAS A SURVEY OF
15 ADOLESCENTS AND THEIR
PATIENTS TO DESCRIBE PAIN
CHARACTERISTICS, ATTITUDES AND
PRACTICES RELATED TO YOGA, AND
POTENTIAL ACCEPTABILITY OF A
YOGA PROGRAM FOR CHRONIC SICKLE
CELL PAIN.
PATIENTS WITH SICKLE CELL AND
CHRONIC PAIN OVERALL HAD A
POSITIVE OPINION OF YOGA, BUT
THERE WERE CHALLENGES WITH
RECRUITMENT AND RETENTION OF
PARTICIPANTS, AND BARRIERS TO
FEASIBILITY OF AN IN-PERSON
GROUP YOGA INTERVENTION.
THE SECOND STUDY WAS AN RCT OF
73 CHILDREN OF YOGA, VERSUS
ATTENTION CONTROL PERFORMED IN
PATIENT FOR UNCOMPLICATED
VOCs.
CHILDREN RANDOMIZED TOIOLA HAD A
SIGNIFICANTLY GREATER REDUCTION
IN MEAN PAIN SCORE AFTER 1 YOGA
SESSION COMPARED TO THE CONTROLS
THIS STUDY SUGGESTS THAT YOGA IS
ACCEPTABLE AND FEASIBILITY AND
MAY REDUCE PAIN IN HOSPITALIZED
CHILDREN WITH ACUTE VOCs.
NEXT PLEASE.
THERE WAS 1 UNCONTROLLED STUDY
OF 8 CHILDREN RECEIVING 12
SESSIONS EACH OF BIOFEEDBACK FOR
CHRONIC PAIN.
A REPEATED MEASURES OF NOVA
COMPARED THE FIRST AND LAST
WEEKS OF TRAINING AND REVEALED A
SIGNIFICANT REDUCTION IN
REPORTED PAIN INTENSITY AND THE
FREQUENCY OF SELF-TREATED VOCs
FROM THE FIRST 1-4 WEEKS
COMPARED TO THE LAST 9-12 WEEKS.
NEXT PLEASE.
--EXCUSE ME, PARDON ME, 1 MORE,
THERE WAS A CASE STUDY OF 1
ADULT LOOKING AT A REHAB THAT
INCLUDED EXERCISE, STRETCHING,
AEROBIC AND RELAXATION PROGRAMS
TWICE PER WEEK FOR 5 WEEKS WITH
SCORES FOR AVERAGE PAIN AND FOR
THE SENSORY PAIN INDEX FOR THE
MIGUEL PAIN QUESTIONNAIRE WERE
BOTH REDUCED.
NEXT, PLEASE.
FOR GUIDED RELAXATION, THERE
WERE 2 RCTs ARE FEASIBILITY
AND ACCEPTABILITY OF GUIDED
RELAXATION, VERSUS ATTENTION
CONTROL.
THE FIRST WAS 15 RESULTS WHO
USED A GUIDE EDUCATIONAL VIDEO
ONCE PERDAY FOR 2 WEEKS.
GUIDED RELAXATION WAS FOUND TO
BE FEASIBILITYIBLE AND
ACCEPTABLE AND THERE WAS A LARGE
REDUCTION IN THE COMPOSITE INDEX
IN THE GUIDED RELAXATION GROUP.
ONE LOOKED AT A 12 MINNITE VIDEO
OF RELUXURIATION ON A MOBILE
DEVICE VERSUS CONTROL.
FINDINGS SHOW IT WAS IT FEASIBLE
AND ACCEPTABLE TO DELIVER GUIDED
RELAXATION ON A COMPUTER TABLET.
NEXT, PLEASE.
IN TERMS OF OUR LIMITATIONS AND
CONCLUSIONS, AS DR. CHARLES HAD
MENTIONED, THERE'S A PAUCITY OF
STUDIES OVERALL IN ACCUPUNCTURE
AND OTHER NONPHARMAICOLOGGIC
INTERVENTIONS, PRELIMINARY
STUDIES HAD METHOD LOGIC ISSUES
HAMPERING GBLIZED ABILITIES,
WEAKNESSES INCLUDE RELIANCE ON
RETROSPECTIVE CHART REVIEWS AND
CASE STUDIES, LACK OF CONTROL
QUOM PAIR SONS AND SMALL SAMPLE
SYSTEMS, RESEARCH ON
ACCUPUNCTURE AND
UNNONFORMICOLOGGIC MODALITIES
FOR SICKLE CELL PAIN IS IN ITS
INFANCY AND ADDITIONAL RESOURCES
ARE NEED TO REDUCE CHRONIC PAIN
AND OPIOID USE FOR INDIVIDUALS
WITH SICKLE CELL.
NEXT, PLEASE.
NOW I WOULD LIKE TO SHARE WITH
YOU OUR CURRENT STUDY FUNDED
THROUGH NCCIH AND THE NIH
PRAGMATIC TRIALS COLLABRATORY AS
WELL AS NIH HEAL INITIATIVE,
HYBRID EFFECTIVENESS
IMPLEMENTATION TRIAL OF GUIDED
RELAXATION AND ACCUPUNCTURE FOR
CHRONIC SICKLE CELL DISEASE PAIN
OR THE GRACE TRIAL.
NEXT, PLEASE.
THE GRACE TRIAL IS PART OF THE
NIH PRAGMATIC TRIALS
COLLABRATORY.
THE NIH PRAGMATIC TRIALS
COLLABRATORY WAS INITIATED IN
THE NIH COMMON FUND IN 20 WITH
12.
SELECTED AS THE PRAGMATIC AND
IMPLEMENTATION STUDY FOR THE
MANAGEMENT OF PAIN TO REDUCE
OPIOID PRESCRIBING OR THE PRISM
FUND RESOURCE COORDINATING
CENTER IN 2019.
THE GOAL IS TO STRENGTHEN THE
NATIONAL CAPACITY TO IMPLEMENT
COST EFFECTIVE LARGE SCALE
RESEARCH STUDIES THAT ENGAGE
HEALTHCARE DELIVERY ORGANIZE
EGGs AS RESEARCH PARTNERS.
THE VISION, IS TO SUPPORT THE
DESIGN AND EXECUTION OF
INNOVATIVE PRAGMATIC CLINICAL
TRIAL DEMONSTRATION PROJECTS TO
ESTABLISH BEST PRACTICES AND
PROOF OF CONCEPT.
NEXT, PLEASE.
THE GRACE TRIAL IS 1 OF 22
DEMONSTRATION PROJECTS IN THE
NIH PRAGMATIC TRIALS, AND IF YOU
NOTICE THE POINTER RIGHT DOWN
HERE IN THE BOTTOM RIGHT CORNER,
PRAGMATIC TRIALS EMBEDDED IN
HEALTHCARE SYSTEMS TO ADDRESS
QUESTIONS OF MAJOR PUBLIC HEALTH
IMPORTANCE INCLUDE DEMONSTRATION
PROJECTS.
THE PROJECTS SPAN MULTIPLE NIH
INSTITUTES, CENTERS AND OFFICES.
THERE'S A 1 YEAR PLANNING PHASE
FOLLOWED BY IMPLEMENTATION PHASE
AND ALL OF THESE DEMONSTRATION
PROGECS.
NEXT PLEASE.
PRAGMATIC TRIALS PRODUCING
RESULTS IN THE REAL WORLD, THEY
MAY TEST THE SAME INTERVENTION
AS AN EXPLANATORY TRIAL.
WE USE TYPICAL PATIENTS, THEY
USE CLINICIANS WHO MAY NOT BE
RESEARCHERS, AND THEY MEASURE
EFFECTIVENESS, HOW WELL THE
INTERVENTION PERFORMS IN THE
REAL WORLD.
NEXT PLEASE.
EMBEDDED PRAGMATIC CLINICAL
TRIALS BRIDGE RESEARCH INTO
CLINICAL CARE.
EMBEDDED PRAGMATIC CLINICAL
TRIALS ARE STUDIES WITH INPUT
FROM STAKEHOLDERS SUCH AS
PATIENTS AND CLINICIANS AND
SOMETIMES HOSPITALS
ADMINISTRATION, DATA IS
COLLECTED THROUGH EHRs IN THE
HEALTHCARE SETTINGS.
AND THE OUTCOMES ARE IMPORTANT
TO DECISION MAKERS SUCH AS
POLITICIANS, MEDICARE AND
MEDICAID AND INTERVENTIONS ARE
INCORPORATED INTO ROUTINE
CLINICAL WORK FLOWS, OFTEN THESE
TRIALS USE DIVERSE
REPRESENTATIVES, TODAY
POPULATIONS, NEXT, PRAGMATIC AND
IMPLEMENTATION STUDIES FOR THE
PAIN FOR OPIOID PRESCRIBING OR
AS WE KNOW IT THE PRISON
PROGRAM.
NEXT.
THE PRISM PROGRAM IS FUNDED
THROUGH THE NIH HEAL INITIATIVE,
PRISM TRIALS FOCUS ON NONOPIOID
INTERVENTIONS TO MANAGE PAIN AND
REDUCE RELIANCE ON OPIOIDS,
PRISM PRAGMATIC TRIALS SEEK TO
IDIDN'TIFY EFFECTIVE STRATEGIES
TO IMPLEMENT EVIDENCE-BASED
INTERVENTIONS.
NEXT, PLEASE.
THE SIGNIFICANCE OF THE GRACE
TRIAL IS FOUND IN THAT
INDIVIDUALS WITH SICKLE CELL
HAVE A HIGH LEVEL OF PAIN, PAIN
IS THE LEADING CAUSE OF ED
VISITS AND HOSPITAL ADMISSIONS.
TREATMENTS FOCUS IS USUALLY ON
MEDICATION THERAPIES SUCH AS
OPIOIDS, FEW COMPLIMENTARY
INTEGRATIVE HEALTH THERAPIES ARE
TESTED TO REDUCE PAIN AND OPIOID
USE.
NEXT, PLEASE.
IN TERMS OF OUR UG3 UH 3, WHICH
IS OUR PRAGMATIC TRIAL OR GRACE
TRIAL, WE ARE A TYPE 1 HIBRIDE
EFFECTIVENESS IMPLEMENTATION
TRIAL, SO WE ARE LOOKING MORE AT
EFFECTIVENESS THAN I.
ELEMENTATION.
OUR FIRST NAME IS TO ASSESS THE
EFFECTIVENESS OF ACCUPUNCTURE
AND GUIDED RELAXATION IN TREATS
CHRONIC SICKLE CELL PAIN.
OUR FOURTH AIM IS TO IDENTIFY
FACILITATORS, CHALLENGES, AND
SOLUTIONS FOR SEAMLESS
INTEGRATION OF THESE CIH
THERAPIES IN 3 HEALTH SYSTEMS.
NEXT.
THE 3 HEALTH SYSTEMS ARE
UNIVERSITY OF ILLINOIS CHICAGO,
DUKE UNIVERSITY, AND UNIVERSITY
OF FLORIDA AT GAINSVILLE, ALL 3
SITES HAVE LARGE SICKLE CELL
DISEASE CLINICS.
NEXT, OUR SAMPLE WILL BE 330
ADULT PATIENTS WITH SICKLE CELL.
THEY MUST HAVE TO ENTER THE
STUDY OF PAIN INTERFERENCE SCORE
OF AT LEAST 3 OUT OF 10 IN THE
LAST WEEK.
THEY MUST HAVE CHRONIC PAIN
WHICH IS DEFINED AS A POSITIVE
RESPONSE TO SOME DAYS, MOST
DAYS, OR EVERY DAY WHEN ASKED AT
SCREENING IN THE PAST 3 MONTHS
HOW OFTEN HAVE YOU HAD PAIN.
NEXT, PLEASE.
>> OUR DESIGN IS A SEQUENTIAL
MULTIPLE ASSIGNMENT RANDOMIZED
TRIAL DESIGN OR A SMART DESIGN.
THE 3 GROUPS ARE RANDOMIZED 1 TO
1 TO 1, THAT IS GUIDED
RELAXATION, ACCUPUNCTURE AND
USUAL CARE.
IN TERMS OF IMPLEMENTATION, WE
ARE USING THE CONSOLIDATED FOR
IMPLEMENTATION, GUIDED BY CFIR,
WHICH IS GUIDED BY PATIENTS AND
SCD CLINICAL PROFESSIONALS.
HERE'S OUR SMART DESIGN.
ALL PARTICIPANTS ARE DOING STUDY
RECEIVED BASE LINE ASSESSMENT.
AND THEN THEIR RANDOMIZED GUIDED
RELUXURIATION, THE CONTROL GROUP
OR ACCUPUNCTURE, THEY RECEIVE
5-6 WEEKS OF THE INTERVENTION
ANDEN THIS THEA 6 WEEKS A GET A
MIDPOINT ASSESSMENT WHERE THEY
REPEAT THE SURVEYS IF THE
PARTICIPANTS RESPONDED TO THE
INTERVENTION, THEY WILL GO ON TO
CONTINUE DATA COLLECTION AT 12
AND 24 WEEKS, IF THEY DO NOT
RESPOND TO THE INTERVENTION,
THEY ARE RERANDOMMIZED TO EITHER
IN THIS CASE, GUIDED RELAXATION
TO CONTINUE EMBEDDED RELAXATION
OR SECOND WORLD WAR ITCH TO THE
ACCUPUNCTURE INTERVENTION AND
THEN MEASURES ARE COLLECTED AT
12 AND 24 WEEKS FOR THE
ACCUPUNCTURE WEEK, THE SAME
THING, IF THEY GET A RESPONSE WE
WILL CONTINUE DATA COLLECTION
AND COLLECT MEASURES AT 12 AND
24 WEEKS.
IF THERE'S NO RESPONSE, THEN,
THEY'LL EITHER CONTINUE IN THE
ACCUPUNCTURE GRUP OR SWITCH TO
GUIDED RELAXATION FOR ANOTHER
5-6 WEEKS WHERE THEY'LL THEN GO
ON A 12 AND 24 WEEKS TO COLLECT
MEASURES.
NEXT, PLEASE.
OUR INTERVENTIONS ARE GUIDED
RELAXATION IT IS A MIND-BASED
RELAKSZATION WITH COGNITIVE
BENEFITS.
IT'S DELIVERED THROUGH DAILY
VIDEOS VIA THE WEB, THERE'S A 12
MINUTE BASE LINE VIDEO, THEN
PARTICIPANTS CAN CHOOSE FROM 6
ADDITIONAL VIDEO CLIPS, RANGING
FROM 2-20 MINUTES.
WITH BENEFITS.
WE'RE USING A STANDARDIZED
ACCUPUNCTURE PROTOCOL OF 12--2
TREATMENTS PER WEEK FOR WEEK
WEEKS FOR A TOTEERAL OF 10
TREATMENTS.
NEXT, PLEASE.
OUR OUTCOMES IN TERMS OF
EFFECTIVENESS, THE PRIMARY
OUTCOME IS PAIN MEASURED BY THE
PAIN IMPACT SCORE WHICH IS A
COMPOSITE OF MEASURE OF PAIN
INTENSITY, PAIN INTERFERENCE AND
FUNCTION.
NEXT, PLEASE.
IN TERMS OF IMPLEMENTATION
CHALLENGES, THERE IS UNEQUAL
ACCESS TO ACCUPUNCTURE AT OUR 3
SIGHTS.
OUR 3 HEALTHCARE SYSTEMS SERVE
URBAN, SUBURBAN ASK RURAL
COMMUNITIES.
ACCUPUNCTURE 1 OF OUR CHALLENGE
SYSTEM THAT SOME OF THE PATIENTS
ARE NEEDLE AVERS, IN EMERGING
ITS OF GUIDED RELAXATION, CELL
PHONE DATA PLANS ARE DRAINED
BEFORE THE INTERVENTION PHASE IS
COMPLETED.
NEXT, PLEASE.
IN TERMS OF SOLUTIONS, WE'RE
PROVIDING CARE, AT DUKE WE OFFER
ACCUPUNCTURE THROUGH DUKE
INTEGRATIVE MEDICINE AND
COMMUNITY ACCUPUNCTURE OFFICES
AT UNIVERSITY OF FLORIDA, WE
OFFER ACCUPUNCTURE THROUGH THE
UNIVERSITY OF FLORIDA INTEGRATED
MEDICINE CLINIC AND AT UIC, WE
REIMBURSE FOR PARKING WHICH IS
THE BIGGEST ISSUE IN TERMS OF
AVERSION TO NEEDLES, RECRUITERS
SHOW THE ACUE PUNCTURE NEEDLES
TAPED TO A CARD EXPW THE
PATIENTS GET IT SEE THAT THE
NEEDLES ARE SOLID AND THEY'RE
MUCH THINNER, ABOUT THE SIZE OF
A HUMAN HAIR AS COMPARED TO A
HOLOCORE NEEDLE THAT'S USED TO
DRAW BLOOD OR START AN IV.
THE PATIENTS ARE GIVEN
REASSURANCE THAT THE NEEDLES
WON'T BE INSERTED INTO LEG
ULCERS OR SCARS AND WE ASSURE
THEM THAT THE DE QI SENSATION
THAT THE SENSATION FELT WHEN
NEEDLES ARE INSERTED IS NORMAL.
WE ALSO PROVIDE DATA PLANS FOR
CELL PHONE AND TABLET USE, IT
ALLOWS THE PARTIC PLAN TO
ANALYZE BY AGES TO KEEP FROM
RUNNING OUT OF DATA AND ENABLING
COMPLOOGZ OF OUR INTERVENTION.
NEXT PLEASE.
HERE'S OUR TEAM AND NEXT PLEASE.
AND WE WOULD LIKE TO THANK THE
SICKLE CELL DISEASE PATIENTS AND
COMMUNITIES FOR THEIR SUPPORT.
THANK YOU.
>> THANK YOU VERY MUCH FOR THE
EXCELLENT TALK.
VERY ENLIGHTENING FOR ME ABOUT
PHYSICAL MODALITIES AND THE
TREATMENTS FOR SICKLE CELL
DISEASE AND I LOOK FORWARD TO
ADDRESSING QUESTIONS THAT CAME
UP FOR OUR PANEL.
I WANTED TO INTRODUCE OUR NEXT
SPEAKER DR. LIZ PRINCE IS AN
ADIOF THE ANT PROFESSOR OF
PSYCHIATRIST TREE AT JOHNS
HOPKINS UNIVERSITY OF SCHOOL OF
MEDICINE AND I WANT TO SAY SHE'S
A UNICORN BUT I AT LEAST KNOW OF
2 PEOPLE LIKE HER BEING A
PSYCHIATRIST THAT FOCUSES ON THE
MANAGEMENT OF PAIN AND
PSYCHIATRIC ILLNESS IN PEOPLE
WITH SICKLE CELL DISEASE.
AND SHE IS GOING TO TELL US
TODAY ABOUT THE USE OF
ANTIDEPRESSANTS AND
ANTIEPILEPTIC DRUGS FOR PAIN AND
PEOPLE WITH SICKLE CELL DISEASE.
DR. PRINCE.
>> THANKS SO MUCH FOR HAVING ME,
IT WON'T LET ME START MY VIDEO,
I THINK I GOT DEACTIVATED.
EXCELLENT.
THANK YOU FOR HAVING ME AND FOR
THE KIND INTRODUCTION.
I'M EXCITED TO TALK TODAY ABOUT
ANTIDEPRESSANTS AND
ANTIEPILEPTIC OR ANTICONVULSANT
MEDICATION FOR PAIN.
SO CAN YOU GO TO THE NEXT SLIDE.
I DON'T HAVE ANY DISCLOSURES SO
WE WILL GO ON TO THE NEXT SLIDE
AS WELL.
FIRST I JUST WANT TO DESCRIBE
SOME CONNECTIONS BETWEEN
DEPRESSION AND CHRONIC PAIN,
DEPRESSION AND SICKLE CELL
DISEASE, THESE ARE SOME THINGS
THAT HAVE COME UP TODAY, GOING
TO GO OVER THE ASH GUIDELINES
FOR CHRONIC PAIN AND THE EVIDENT
BASE THAT WAS USED FOR THE
RECOMMENDATIONS AROUND THOSE
MEDICINES, IDENTIFY LIKELY
MECHIMISMS FOR HOW THESE
PARTICULAR MEDICATIONS EFFECT
PAIN AND GO OVER PRACTICAL TIPS
FOR HOW TO USE THESE MEDICATIONS
IN PATIENTS.
SO WE CAN GO TO THE NEXT SLIDE.
STARTING OUT, WE KNOW THAT
DEPRESSION AND CHRONIC PAIN ARE
CONNECTED SO JUST A FEW THINGS
TO HIGHLIGHT FIRST, WHEN YOU
LOOK AT PEOPLE WHO HAVE CHRONIC
PAIN COMPARED TO PEOPLE WHO
DON'T HAVE CHRONIC PAIN, THOSE
WITH CHRONIC PAIN ARE GOING TO
SCORE HIGHER ON DEPRESSION
SCREENING INSTRUMENTS LIKE THE
PH Q, THEY'RE MORE LIKE TOW TO
SCREEN POSITIVE FOR DEPRESSION,
THIS WILL BE A HIGHER PROPORTION
AND THEN ALSO ARE MORE LIKELY IN
CLINICAL POPULATIONS TO BE
DIAGNOSED WITH MAJOR DEPRESSIVE
DISORDER AND THEN PEOPLE WHO
HAVE CHRONIC PAIN AND A
PSYCHIATRIC ILLNESS, COMPARE TO
THOSE WITH ONLY PAIN WILL HAVE
HIGHER SCORES, MORE DISABILITY
FROM THE PAIN THAT HAVE BEEN
FOUND TO HAVE REDUCED QUALITY OF
LIFE.
GO ON TO THE NEXT SLIDE.
WHAT WE KNOW ABOUT THE
CONNECTIONS BETWEEN DEPRESSION
AND SCD, AGAIN CONTINUING A
THEME THAT WE HEARD ABOUT WHICH
IS THAT REALLY DON'T HAVE ENOUGH
EVIDENCE AND DATA BUT WHAT WE
KNOW IS THAT AT LEAST THERE'S 1
STUDY OR GREATER THAN 35% OF
ADULTS WITH SICKLE CELL DISEASE
HAD DEPRESSION IN THIS STUDY AND
THAT'S A MUCH HIGHER RATE, THAN
YOU WOULD SEE IN A GBL ADULT
POPULATION.
WHAT WE SUDDEN THAT IN CHILDREN,
WITH SICKLE CELL DISEASE, HAVING
CHRONIC OR RECURRENT PAIN
INCREASES THE LIKELIHOOD THAT
THEY WILL HAVE DEPRESSION.
AND REALLY ALL OF THIS
INFORMATION THAT I'M SHARING
WITH THE LAST 2 SLIDES IS TO
AFFIRM THIS IDEA THAT MENTAL
ILLNESS AND PAIN ARE CONNECTED
AND THERE'S MUTUALLY
REINFORCEMENT FACTORS.
ON TO THE NEXT SLIDE.
THIS IS AN IMAGE THAT I REALLY
LOVE THEY BORROW FRIDAY SOME
SLIDES THAT WERE MADE AS PART OF
THE ASH CLINICAL PRACTICE
GUIDELINES.
WHAT I LIKE ABOUT IS IT SHOWS
THESE DIFFERENT FACTORS THAT ARE
ALL INTERCONNECTED AND HOW THEY
RELATE TO ACUTE AND CHRONIC PAIN
IN PATIENTS WITH CIRCLE CELL
DISEASE AND I HIGHLIGHTED THIS
NERVOUS SYSTEM SENSITIZATION AND
THEN, PSYCHOLOGICAL FACTORS OF
DEPRESSION AND ANXIETY HERE
BECAUSE I THINK THAT THE
MEDICINE THAT I'M GOING TO BE
TALKING ABOUT ARE REALLY ACTING
ON THOSE ASPECTS OF FACTORS THAT
CONTRIBUTE TO PAIN, SO THE NEXT
SLIDE, PLEASE.
SO--I KNOW THERE'S LOT OF WORDS
HERE BUT WE WILL SPIN THROUGH
THIS QUICK, SO THE
RECOMMENDATIONS RELATED TO
AVASCULAR NECROSIS, IS THERE'S
NOT A LOT OF HUGE STUDIES WE CAN
MAKE SOLID RECOMMENDATIONS FROM,
SO A LOT OF THIS IS BORROWED
FROM THE MANAGEMENT OF PAIN AND
OFTIO ARTHRITIS SO THERE'S A
CONDITIONAL RECOMMENDATIONS FOR
NSNRIs, LIKE UPTAKE INHIBITORS
AND THERE'S ALSO 1 FOR NSAIDS
AND NONTERROIDAL INFLAMMATTORY
MEDICATIONS, THERE WAS NONE FOR
CHILDREN AND THEN WITH PAIN WITH
OTHER SORT OF RELATED TO ABM,
THIS IS THE DATA THAT THE
EVIDENCE BASED FOR THIS IS SORT
OF AMANAGEMENT OF FIBROMYALGIA
PAIN SO AGAIN, WE SEE SNRIs
BEING A CONDITIONAL
RECOMMENDATION, WE SEE TRICYC
LIKE ANTIDEPRESSANTS AND THEN WE
ALSO SEE CONDITIONAL
RECOMMENDATION FOR GABBA PENTINE
REGIMENINNOIDS WHICH ARE AN
ANTIEPILEPTIC MEDICATION.
SO THERE'S REALLY NOT ENOUGH
EVIDENCE TO MAKE RECOMMENDATIONS
ABOUT PAIN RELATED TO SO LET'S
GO TO THE NEXT SLIDE.
THERE'S A PICTURE THERE'S LAYOT
OF--WE HAVE THE RED AND BLUE
LINE WHICH ARE THE ASEBDING AND
DESCENDING PATHWAYS OF MESSAGES
THAT LEAD DOWN TO THE LOWER LEFT
HAND CORNER, A CROSS SECTION OF
THE SPINAL CORD WHICH YOU CAN
SEE, BLOWN UP IN THE UPPER RIGHT
HAND CORNER SHOWING THE NERVE
CONNECTION AND SYNAPSES AND THEN
IN THE LOWER RIGHT HAND CORNER
WE HAVE THE HER PERIPHERAL NERVE
ENDINGS AND WHAT THIS IS SHOWING
US IS ALL OF THE DIFFERENT
PLACES WHERE PINE MESSAGING IS
HAPPENING.
AND HIGHLIGHTED HERE, THE REASON
I LIKE THIS PICTURE IS THAT THEY
LIST SOME OF THE DIFFERENT KINDS
OF TREATMENTS, SOME ARE
MEDICATIONS BUT SOME ARE
INTERVENTIONS SOME OF WHICH WE
ALREADY HEARD ABOUT TODAY AND
WHERE THEY ACT, FOR EXAMPLE WITH
THE BIG LUMPY BRAIN, WE SEE CBT
BUT ALSO ANTIDEPRESSANTS AND
ANTICONSULS ANT OR ANTIEPILEPTIC
MEDICATIONS HAVING ACTION THERE
ASK WHAT I REALLY WANTED TO
HIGHLIGHT IS THAT THERE IS
SEVERAL PLACES IN WHICH THINGS
ARE REPEATED SO FOR
ANTIDEPRESSANTS WE SEE THEY'RE
MENTIONED AT THE LEVEL OF BRAIN
WHEN WE LOOK AT THIS CROSS
SECTION OF THE SPINAL CORD, WE
CAN LOOK AT TRICYC LICK
ANTIDEPRESSANTS AND SNRIs ARE
MENTIONED HERE AND THEN ALSO
DOWN AT THE PERIPHERAL LEVEL, WE
SEE ANTIDEPRESSANTS AND SEVERAL
OTHER MEDICINES THAT ARE ALL
ANTIEPT LEAPTIC MEDICATION, SO
THESE MEDICINES ARE ACTING AT
SEVERAL DIFFERENT PLACES ALONG
THE LINE OF WHERE PAIN MESSAGING
IS HAPPENING.
SO WE MOVE ON TO THE NEXT SLIDE.
THIS IS A ZOOMED IN SYNAPSE SO
WE CAN SEE THEAXON AND THE
DENDRITE AND ALL THESE DOTS
WHICH ARE THE NEUROTRANSMITTERS
THAT ARE GOING BETWEEN THEM.
THIS 1 HIGHLIGHTS SPECIFICALLY A
MEDICINE CALLED AMITRANSCRIPTY
LINE WHICH IS A ANTIDEPRESSANT
AND WE VIA THAT AMITRANSCRIPT
LINE IS ACTING AT THE SEROTONIN
AND THE NEUROEPIDRENNALLIST,
REUPTAKE TRANSPORTERS SO BY
VERMEN INFECTED PREVENTING THE
REUPTAKE OF THESE THINGS THERE'S
MORE OF THOSE CHEMICALS
AVAILABLE IN THE SYNAPSE AND
THAT'S 1 PLACE WHERE THESE
MEDICINES ARE HAVING ACTION, SO
WE WILL KEEP MOVING.
NEXT SLIDE.
GREAT.
SO, SNRIs, SEROTONIN
NOREPINEPHRINE, REUPTAKE INHIB
THORS IDENTITY ARES LIKE
VENLAFAXINE, AND THIS IS THE
PRESINAT INCREASE IN BODY
INHIBITION OF THE REUPTAKE OF
SEROTONIN AND NOREEPINEPHRINE IN
PAIN AND INHIBITORY PATHWAYS,
AND THEY DON'T HAVE A LOT OF
EFFECT ON THE RECEPTORS, SOME
GOOD THINGS ABOUT THESE
MEDICINE, GENERALLY PRETTY SAFE,
GENERALLY PRETTY WELL TOLERATED
SOME DOWN SIDES THEY HAVE A
PRETTY UNPLEASANT
DISCONTINUATION SYNDROME SO I DO
TALK TO PATIENTS THAT EVEN
MISSING A DAY OF THESE MEDICINES
CAN MAKE YOU FEEL PRETTY CRAPY
SO THAT'S SOMETHING TO CONSIDER
YOU KNOW, OUR GOAL WHEN WE GIVE
SOMEONE A MEDICATION IS THAT IT
HELPS THEM TO BE BETTER BUT IF
THEY CAN'T TAKE IT CONSISTENTLY,
IT WILL MAKE THEM FEEL WORSE
THEN MAYBE THAT'S NOT THE BEST
GAME PLAN.
NEXT SLIDE.
SO THIS IS DATED DATA FROM A
STUDY LOOKING AT PAIN FROM
DIABETIC PERIPHERAL NEUROPATHY
AND WHAT WE SEE ON THE Y-AXIS IS
A CHANGE IN PAIN AND ON THE
AX-AXIS IS TIME AND WEEKS, AND
THIS IS A STUDY OF DID YOU
LOCKSA TEEN SO THEY HAD A
PLACEBO AND 2 DIFFERENT DOSES OF
DULXOTEEN GIVEN TO PATIENTS AND
THE BIG THING TO LIE LIGHT HERE
IS YOU CAN SEE THAT THE PLACEBO
SEPARATES OUT FROM THE PEOPLE
WHO GOT THE DULOXETINE, BUT IT
DOES BECOME THE MOST REMAXABLE
SO IT LET'S MOVE ON TO THE NEXT
SLIDE.
WHICH IS GOING TO BE MORE
PATIENTS IN THE CLINIC UPPERS A
REALLY SIMILAR TYPE OF THING
WHERE ON THE Y-AXIS WE HAVE A
CHANGE IN PAIN AND THEN WEEKS OF
TREATMENTOT X-AXIS, THIS IS A
STUDY IN AFTIO ARTHRITIS AND
AGAIN OF DULOXEIT, INE, AND WE
SEE AGAIN THAT THE PLACEBO ON
THE TOP AND THE DULOXETINE
SEPARATE OUT, BUT THIS IS TAKING
AN INSTANTANEOUS EFFECT.
GOING ON TO THE NEXT SLIDE.
ONE MORE FOR YOU HERE, SO THIS
HAS BEEN THE VENLAFAXINE, AND
WITH SPINAL CORD INJURY AND ON
DEPRESSION, WE'RE LOOKING AT
TIME AND SEEING THAT THE PATIENT
WHO IS WERE GIVEN THE
VENLAFAXINE, DO SEPARATE OUT
FROM THE PLACEBO BUT TELL TAKE
SEVERAL WEEKS.
NEXT, SLIDE, PLEASE, GREAT, SO
NOW WE WILL SPIN THROUGH
TRICYCKIC ANTIDEPRESSANTS THESE
ARE THINGS LIKE NORA TRANSCRIPT
LINE OR AMITRIPTYLINE, THEY WILL
HAVE A SIMILAR MECHANISM WHICH
IS THE REUPTAKE, THEY DO ALSO
HAVE ACTION ON SOME OTHER KINDS
OF RECEPTORS SO THEY'RE ACTING
ON COLONERGIC, EFTHIMIOSA
MINERGIC RECEPTORS AS WELL, SO
THEY DO HAVE ADDITIONAL ACTIVITY
AT PERIPHERAL NERVES WHICH IS
GREAT, THE OTHER THING THAT'S
HELPFUL ABOUT THE PREFERENCES IS
YOU CAN DO A BLOOD LEVEL TESTING
SO YOU CAN DO A 12 HOUR BLOOD
LEVEL OF THESE MEDICATIONS AND
IT IS MEANINGFUL INFORMATION
THAT YOU CAN TITRATE INTO A
THERAPEUTIC RANGE TO HAVE
EFFECT.
WHEREAS MEDICINES LIKE AFEXER
AND SIM BALTA HAVE A
STANDARDIZED DOSE BUT WE'RE NOT
MEASURING THE LEVELS OF THOSE IN
OUR PATIENTS AND ADJUSTING THE
DOSE BASED ON THAT.
DOWNED ISS, AGAIN, I MENTION
WILL ALL THESE OTHER RECEPTORS
THAT THEY'RE ACTING ON, SO
THERE'S PROBLEM WITH
TOLERABILITY WITH THOSE AND
ANTICOLLINERGIC, CONSTIPATION
AND STUFF.
THERE'S CARDIAC CONDUCTION
POTENTIAL EFFECTS SO CAN YOU
MONITOR EKGs AND THEY HAVE
LOTS OF ACTION IN MANY WAYS BUT
IT ALSO MEANS THEY CAN CAUSE
SIDE EFFECTS IN MANY WAYINGS
WHICH NOT THE AGAIN WHEN WE'RE
STARTING MEDICINES.
NEXT SLIDE, PLEASE.
SO THIS IS A STUDY FROM POST
HERPETIC NEURALGIA, AND THEY
COMPARED NORTRIPTYLINE, VERSUS
MORIN AND PLACENTA SEEBY,
THERE'S MORE DROP OUT WITH THE
STUDY WITH THE PATIENTS ON
MORPHINE THAN OTHER PATIENTS BUT
FOR THOSE WHO STUCK WITH IT,
THERE WAS PAIN SCORE REDUCTION
FROM BOTH OPIOIDS AND TRICYCLE
ANTIDEPRESS ABTS, WE TALKED
ABOUT THE SIDE EFFECT PROFILES
OF THESE, AND THAIZ CAN BE
UNPLEASANT UNFORTUNATELY.
IT WAS AN OLDER POPULATION SO
MAYBE MORE VULNERABLE BRAINS
GOING ON AS WELL.
NEXT SLIDE.
SOY NOW WE WILL TALK ABOUT
ANTICONVULSANTS OR, AND ALSO
THINGS--THE OVERALL MEDICATIONS
ARE THE 1S THAT HAVE THE KNOWN
SAFETY AND EFFICACY, THEY HAVE A
CROSS SECTION OF SPINAL CORD BUT
ALSO IN OTHER PLACES.
NEXT SLIDE, PLEASE.
AS PROMISED PRACTICAL TIPS ABOUT
HOW TO USE THESE PATIENTS.
USE THESE MEDICATIONS FOR OUR
PATIENTS.
SO THE FIRST THING IS YOU WANT
TO GET TO A REAL DOSE, OF THE
MEDICATION, SO, THAT'S EITHER
FOR MEDICINES THAT HAVE A BLOOD
LEVEL, YOU KNOW GET INTO A
THERAPEUTIC BLOOD LEVEL BUT
OTHERWISE JUSTA TO A DOSE THAT
WAS SORT OF IN THE LITERATURE IS
SORT OF THE BOOK MAXIMUM IF YOU
WILL.
AND YOU WANT TO DO THAT FOR
SEVERAL WEEKS IF YOU RECALL ALL
THOSE PICTURES SHORT OF SHOWED
THAT SEPARATION IDENTITY FROM
PLACEBO WAS NOT AN INSTANTANEOUS
THING, THAT'S SOMETHING THAT
WILL TAKE WEEKS OF CONSISTENCY,
BECAUSE THESE ARE MEDICINE THAT
ARE SORT OF NOT SUPER FAST.
WHAT YOU WANT TO DO IS ENCOURAGE
YOUR PATIENT TO KEEP A PAIN LOG
WHEN YOU'RE TRIALS THESE
MEDICINE BECAUSE OTHERWISE IT'S
LIKE TRYING TO KEEP TRACK OF
YOUR OWN HAIR GROWING FROM 1 DAY
TO THE NEXT, YOU'RE NOT
NECESSARILY GOING TO NOTICE
THAT.
BUT, OVER TIME YOU DID GET A
BETTER SENSE OF THAT.
AND IF AT FIRST YOU DON'T
SUCCEED, SO YOU TRIED SIM BALTA
FIRST FOR EXAMPLE, AND IT'S NOT
EFFECTIVE, TRY ANOTHER, THESE
MEDICINES ARE ALL SLIGHTLY
DIFFERENT AND I WOULD SAY THE
TRICYC LICKS ARE WORTH THE TRY
BECAUSE THEY CAN BE VERY HELPFUL
SO THAT'S SORT OF--THOSE ARE MY
PRACTICAL EPIGENETIC ITS--TIPS I
THINK, IS 1 OTHER THING TO
HIGHLIGHT IS I TALKED ABOUT THE
CONNECTION BETWEEN PAIN AND
DEPRESSION AND THE MANY
DIFFERENT PLACES THAT THESE
MEDICATIONS ACT AND SO, I DON'T
THINK THAT THE WAY THAT WE TREAT
DEPRESSION WITH THESE
MEDICATIONS IS IT NOT
NECESSARILY GOING TO BE THE SAME
THAT WE TREAT PAIN WITH THESE
MEDICATIONS.
SO ON TO THE NEXT SLIDE, COME IS
MY LAST SLIDE, I FOUND THIS
SUPER EXCITING PICTURE OF A SIN
APTION ONLINE SO I HOPE YOU
ENJOY IT AS MUCH AS I DO, AND
THANK YOU SO MUCH FOR HAVING ME
AND THE CONFERENCE FOLKS FOR
KEEPING THE SLIDES GOING.
>> THANK YOU VERY MUCH, THAT WAS
FANTASTIC DR. PRINCE AND WE HOPE
TO FIND MORE UNICORNS LIKE YOU
TO WORK WITH OUR PATIENT
POPULATION.
WE KNOW THAT THERE IS SO MUCH
ABOUT SICKLE CELL DISEASE THAT
AFFECTS MENTAL HEALTH AND VICE
VERSA AND YOU KNOW THE MORE WE
CAN DESTIGMATIZE MENTAL HEALTH
IN TERMS OF IMPROVING OUTCOMES
AND SICKLE CELL SEIZE, THE
BETTER, I THINK THERE ARE SO
MANY ANECDOTES WE CAN COULD
SHARE THAT WOULD REALLY SPEAK TO
THAT AND JUST TO MOVE THINGS
ALONG, I AM REALLY PSYCHESSED TO
INTRODUCE OUR NEXT SPEAKER AS
WELL AND AGAIN THE KEEP THE
QUESTIONS COMING, PLEASE PUT
THEM IN THE Q&A, WE WILL GO
THROUGH THEM AT THE PANEL, OUR
OTHER UNICORN WE WOULD LIKE TOO
INTRODUCE T IS DR. CARROLL, HE
APPRECIATES I'M CALLING HIM A
UNICORN AS WELL.
HE'S AN INTERNATIONALLY
RECOGNIZED EXPERT IN PULTY
DISCIPLINARY MANAGEMENT OF
COMPLEX PAIN, HIGH UTILIZATION
IN INDIVIDUALS WITH SICKLE CELL
DISEASE, HE IS A PIONEER OF THE
INTEGRATION OF CHRONIC PAIN
MANAGEMENT AND PSYCHEIATIC CARE,
HE IS OUR GO-TO FOR INDIVIDUALS
WITH WHOM WE'VE RUN OUT OF OTHER
OPTIONS, HE IS JUST AN AMAZING
INDIVIDUAL, HE'S PROBABLY GOING
TO BE ANNOYED BY THIS
INTRODUCTION AND A MEMBER OF THE
JOHNS HOPKINS CENTER FOR ADULTS,
REALLY HELPING TO DIRECT THE
INTEGRATIVE CARE OF PATIENTS
THROUGH PARTICIPATION AND
MULTIDISPLNARY ROUNDS DIRECT
PATIENT SUPER VISION, WORKING ON
INTEGRATING BEHAVIORIAL AND
PSYCHIATRIC CARE FOR A LONG TIME
AND SICKLE CELL DISEASE AND
REALRE EXCITED TO HAVE HIM HERE
TODAY TO PRESENT ON BUPRENORPH
INE FOR CHRONIC PAIN AND WHERE
WE GO FROM THERE.
>> ALL YOU DR. CARROLL.
HEALTH OUTCOMES, EVERYBODY, I'M
NOT ANNOYED BUT, YEAH THAT WAS A
LITTLE MUCH, BUT THANKS
DR. KANTER, SO LET'S TALK ABOUT
A VERY STRANGE DRUG CALLED
BUPRENORPH INE, I HEAR A LOT OF
INTEREST IN IT RECENTLY AND IT'S
USEFUL PROPERTIES AND I THINK IT
CAN PROBABLY HELP A FAIR NUMBER
OF PEOPLE WHEN RPGHT THINGS
HAVEN'T WORKED BUT I'M ALSO
GOING TO POOR A LITTLE COLD
WATER, I THINK ON THE END.
BECAUSE I THINK WHENEVER
SOMETHING'S NEW, WE THINK IT'S
GOING TO BE A MIRACLE, AND THEN
AFTER 5 YEARS WE FIND OUT IT'S
BEING ABUSED AND ME BEING A
SKEPTIC, I HAVE TO THROW THAT
IN.
SO ON TO THE NEXT SLIDE ISSUE
PLEASE.
SO I THINK, LIKE 80ISH% OF
LAWEDDER DALE YOU NEED TO KNOW
ABOUT BUPRENOHPH INE, AND IT'S A
OPID IDENTITY, IT'S A PASHT
AGONIST ON THE RECEPTOR AND THE
NEWER THINGS ARE THE BRAIN,
SPINAL CORD AND COLON, THAT
REALLY MEDIATE WHAT WE USUALLY
THINK OF AS OPIOID EFFECTS LIKE
ANNAL GEEZIA, TOLERANCE,
WITHDRAWAL, POSITIVE
REINFORCEMENT OR REWARD WHICH IS
WHAT LEADS TO ADDICTION.
CONSTIPATION TO SOME EXTENT.
SO SOME OF THE STUFF YOU THINK
OF AS AN OPIOID EFFECT IS FROM
THE NEW OPIOID RECEPTOR AND SO
WHAT PARTIAL AGONIST DO UNLIKE
MORPHINE AND METHADONE AND ALL
THE OTHER STUFF YOU THINK OF,
WHERE THE FULL AG MIST, THE
HIGHER THE DOSE, THE HIGHER THE
RECEPTORS ARE ACTIVATED, WITH
OTHER PARTIAL AGONISTS, IT'S
ACTIVATED SORT OF STEADILY WITH
INCREASING DOSE UP TO A POINT
AND THEN IT FLATTENED OUT AND
YOU GET THIS CEILING EFFECT
WHERE AT A CERTAIN LEVEL OF
TOLERANCE OR STAY DAILY DOSE AND
TAKE MORE BIEWP NOEVERRINE IS
SAFER THAN OTHERS BECAUSE IT'S
HARD TO OVERDOSE ON IT.
SO THAT'S 1 THING THAT'S
DIFFERENT ABOUT BUPRENORPHINE,
IS THAT IT STICKS TO RECEPTORS
LIKE FLU, O THE RECEPTOR
AFFINITY WHICH A MEASURE OF WHAT
I JUST SAID IS SIGNIFICANTLY
HIGHER THAN FOR MULTIPLE OTHER
OPIOIDS MAINLY BECAUSE WHEN
BUPRENORPHINE GETS ON A RECEPTOR
IS LOCKS INTO IT AND TAKES A
LONG TIME TO COME BACK OFF.
SOA THIS BOILS DOWN TO IS IF YOU
ARE TAKING ANOTHER OPIOID, AND,
STANDARD OPIOID AND YOU TAKE
BUPRENORPHINE WITH IT, THEY WILL
KICK THE OTHERS OFF THE
RESUPPORTORS, GOING THE OTHER
WAY IF YOU ARE SORT OF STEADILY
TAKING BUPRENORPHINE AND YOU
TAKE ANOTHER OPIOID ON TOP OF
IT, THEN THOSE RECEPTORS WILL BE
MOSTLY OCCUPIED BY THE
BUPRENORPHINE AND SOME OF THE
EFFECT WILL BE BLOCKED.
SO THERE ARE OTHER THINGS ABOUT
BUPRENORPHINE THAT ARE FUNNY BUT
I THINK IF YOU KNOW THOSE 2
THINGS, YOU KNOW MOST OF WHAT
YOU NEED TO KNOW TO UNDERSTAND
WHERE IT'S USEFUL, WHY IT MIGHT
BE USEFUL BUT ALSO SOME OF THE
TRICKS THAT YOU HAVE TO DEAL
WITH TO MANAGE IT.
NEXT SLIDE.
I THINK I ALREADY SAID MOST OF
THIS, BUT THE MAIN THING IS
SAFETY, YOU GET HIGHER DOSES AND
1 OF THE REASONS IT'S USED TO
TREAT ADDICTIONS, AND SO THERE'S
A LOT OF BREAK THROUGH, AND
PARTICULARLY THE SUBLINGUAL
PREPARATIONS OR THE PREPARATIONS
THAT ARE USED FOR PAIN
BUPRENORPHINE LASTS A LONG TIME
SO YOU DON'T GET A LOT OF BREAK
THROUGH WITH WITHDRAWAL, THERE'S
LESS CRAVING, CAN YOU BACK UP,
PLEASE?
SO ALSO, IN WE TALK ABOUT
SUBSTANCE USE DISORDERS, IT
BLUNTS THE REINFORCEMENT AND SO
SOMEONE HAS A PROBLEM WITH
OPIOIDS, THEY TAKE THEIR
BUPRENORPHINE BUT THEY SLIP UP 1
DAY AND THEY TAKE SOMETHING
ELSE, THEN, THEY DON'T GET THE
SAME REWARD OUT OF THAT OTHER
THING AND IT HAS A WAY OF
HELPING THEM NOT GO INTO FULL
RELAPSE.
I MISSED A REFERENCE TO THIS
SLIDE, BY THE WAY, IT'S KNOWN
THAT BUPRENORPHINE HAS A MORE
MODEST WITHDRAWAL SYNDROME THAN
RPGHT OPIOIDS, THE FOLKS THAT
DID THAT WERE AT HOPKINS AND THE
FIRST AUTHOR WAS MY OLD
COLLEAGUE DR. ANDREW TOMPKINs,
IF YOU WANT TO KNOW MORE ABOUT
THAT, YOU CAN LOOK IT UP.
SO NEXT SLIDE.
IT'S LONG BEEN KNOWN THAT
BUPRENORPHINE WORKS WELL ON
PAIN, IN FACT THE FIRST 1 WAS
APPROVED FOR PAIN, IT WAS CALLED
BUPRINEX, IT'S AN IV OR IM
PREPARATION THAT WAS APPROVED
FOR ACUTE PAIN PROBABLY MID90S,
EARLY 2000S AT THE LATEST.
I REMEMBER USING AN OFFLABEL FOR
THE TREATMENT OF WITHDRAWAL AND
PAIN BACK IN THE EARLY 2000S.
BUT WITH RESPECT TO CHRONIC
PAIN, IT'S ALSO KNOWN THAT IT
CAN WORK FOR THAT, AND THERE ARE
PREPARATIONS OUT OF IT OR ARE
APPROVED FOR THAT USE, I THINK
WE SKIPPED A SLIDE, CAN YOU BACK
UP 1.
SO THIS IS A META-ANALYSIS OF
PEOPLE WHO ARE TREATED FOR
OPIOID USE DISORDER ALSO HAVE
CHRONIC PAIN AND BUPRENORPHINE
HAD A BIG EFFECT ON CHRONIC
PAIN.
ON NOW ON TO THE NEXT SLIDE.
AND THIS IS SYNTHESIS OF STUDIES
THAT WERE DONE WITH PEOPLE WHO
DID NOT HAVE AN OPIOID USE
DISORDER THAT WERE TREATED WITH
BUPRENORPHINE AND IT DID HAVE A
FAVORABLE EFFECT WHICH IS NOT
SURPRISING.
NEXT.
SO WHY SHOULD WE USE THIS THING?
WELL, I THINK THERE ARE 3 BASIC
REASONS.
ONE IS, IT'S SAFER, APPROXIMATE
I'VE ALREADY TALKED ABOUT THAT
AND I THINK, YOU KNOW, RELATIVE
TO LIKE HIGH DOSE CHRONIC OPIOID
THERAPY AND THERAPY IN
PARTICULAR, IT'S ALMOST
QUALITATIVELY SAFER THAN OTHER
OPIOIDS.
THE OTHER THING IS THAT IT'S
DIFFERENT, SO IF YOU HAVE
SOMEONE WHO HAS BEEN ON CHRONIC
THERAPY AT SOME REASONABLE DOSE
OR MORE THAN A REASONABLE DOSE
AND IT'S NOT WORKING, THEN, YOU
CAN USE BUPRENORPHINE TO ROTATE
TO AND STAY WITH A STRAIGHT
FACE, FIRST OF ALL, YOU KNOW
IT'S SAFER AND SECOND IT JUST
MIGHT ACTUALLY WORK IN A
DIFFERENT WAY THAT COULD HELP
THE PAIN.
AND WE'VE CERTAINLY SEEN THAT.
AND THE OTHER PART OF IT IS THAT
IT HAS A FAVORABLE PROFILE
BEHAVIORIAL EFFECT.
SO REDUCED POSITIVE
REINFORCEMENT, MODEST
WITHDRAWAL, LONG ACTING, YOU SEE
LESS BREAK THROUGH AND SO FORTH.
I'VE HAD SOME PEOPLE ALSO
SIGNIFY THAT IT JUST--THEY DON'T
HAVE TO THINK ABOUT IT AS MUCH,
YOU KNOW YOU DON'T HAVE TO SORT
OF LIKE STAY ON TOP OF TAKING A
MEDICINE 3 OR 4 TIMES A DAY.
SO MY SLIDES KEEP SKIPPING ON
THEIR OWN, NEXT SLIDE, SO HOW DO
YOU USE THE THING, I WILL TALK
ABOUT HOW YOU SWITCH PEOPLE FROM
ANOTHER OPIOID AGONIST ON TO
BUPRENORPHINE AND THAT REQUIRES
TECHNIQUE BECAUSE OF THE CEILING
EFFECT AND THE WAY IT WORKS ON
RECEPTORS AND I AM NOW GOING TO
USE HIGHLY ADVANCED WE WILL USE
THE GRAPHICS TO SHOW THIS WHOSE
TAKING A RELATIVELY HIGH AND THE
OPIOID GOES UNSUPPORTED,
METABOLIZED DOWN AND GOES UP AND
BACK DOWN.
IT'S ABOVE THEIR LEVEL OF
TOLERANCE, THEY'RE NOT GOING
INTO WITHDRAWAL OR SUCH THINGS
LIKE THAT BUT IF YOU GIVE
BUPRENORPH ALONG WITH THIS
RELATIVELY HIGH DOSE THAT
SOMEONE'S TOLERANT, TOO, THE
BUPRENORPH CAN OUTCOME PETE FOR
THE RECEPTORS, DISPLACE IT AND
IF THEY'RE TOLERANCE IS ABOVE
THAT BUPRENORPH CEILING EFFECT,
CAN YOU THINK I WILL RECIPITATE
WITHDRAWAL.
PEOPLE CAN GO INTO OPIOID
WITHDRAWAL WHICH IS MISERABLE,
NOW IT'S NOT AS BAD AS IF YOU
GAVE A FULL OPIOID AGANIST AND
THEN ALLOWED THEM TO GET DOWN TO
0, BUT UNLESANT AND THERE'S NOT
A LOT TO DO ABOUT IT BECAUSE YOU
HAVE TO WADE FOR THE
BUPRENORPHINE TO BE METABOLIZED
OUT AND GO AWAY.
SO THIS SHOULD BE BE,A VOIDED.
BUT ALTHOUGH BUPRENORPHINE CAN
PRECIPITATE WITHDRAWAL, IT CAN
ALSO TREAT PROJECTION NEURONS OR
PIONS SPAINIOUS WITHDRAWAL.
SO IF YOU HAVE SOMEONE WHO'S
TAKING AN OPIOID, THEIR
TOLERANCE ISN'T PARTICULARLY
HIGH, THEY COMPLETELY STOP AND
THEY GO INTO SOME LEVEL OF
WITHDRAWAL AND YOU GIVE THEM
BUPRENORPHINE AND THE CEILING
EFFECT IS ABOVE THAT LEVEL OF
TOLERANCE IT WILL ARREST THAT
SPONTANEOUS WITHDRAWAL.
SOY DEPENDING ON THE PERSON'S
LEVEL OF TOLERANCE AND WHAT'S
CIRCULULATING IN THE SYSTEM, YOU
CAN HAVE THE WITHDRAWAL OR
SPONTANEOUS WITHDRAWAL TREATED
NEXT SLIDE.
OR WEIRDLY ENOUGH, THE SAME
PERSON WHO HAS A RELATIVELY HIGH
TOLERANCE, IF THEY COMPLETELY
STOP THE OPIOID THEY'RE TAKING
AND WAIT LONG ENOUGH, YOU CAN GO
INTO REALLY SEVERE WITHDRAWAL,
BUT THEN, BUPRENORPH, IF THERE'S
NO OTHER AGONIST TO IN THIS
PLACE CAN MODERATE THAT, BECAUSE
AT LEAST IT HAS SOME OPIOID
EFFECT, PROBABLY UP TO 90 OR
MORE CLINICAL TODAY, SO IT CAN
ACTUALLY MODERATE SPONTANEOUS
WITHDRAWAL FOR ALMOST THE SAME
PERSON THAT WOULD HAVE
PRECIPITATED WITHDRAWAL IF THEY
HAD CIRCULATING AGONIST, SO THIS
GETS WEIRD TO THINK THROUGH.
SEE, NEXT SLIDE.
BI BUT THERE'S A WAY TO THINK
ABOUT IT THAT SIMPLIFYS IT AND
IT COMES DOWN TO IS THE LOWER
SPRN'S TOLERANCE IS BEFORE THEY
HAVE TO TRANSITION OVER TO
BUPRENORPHINE, THE LESS LIKELY
YOU'RE GOING TO GET ABOUT BAD
THING HAPPEN.
SO THE LESS LIKELY YOU WILL HAVE
SPONTANEOUS WITHDRAWAL OR SEVERE
SPONTANEOUS WITHDRAWAL AND IF
YOU DO THE BUPRENORPHINE WILL
PROBABLY HELP IT.
AT THE SAME TIME IF SOMEONE'S
TOLERANCE IS LOW, THE
BUPRENORPHINE IS UNLIKELY TO
PRECIPITATE MUCH WITH THE
WITHDRAWAL.
SO REALLY THE MAIN THING THAT
CAN HELP TO GET PEOPLE FROM
ANOTHER AGONIST ON TO
BUPRENORPHINE IS TO HAVE THEM
TAPERED DOWN TO A LEVEL OF
TOLERANCE THAT THE BUPRENORPH
ARE LIKELY TO CAUSE TROUBLE SO
FOR US WHEN WE TRANSITION
PEOPLE, WE TYPICALLY TARGET
AROUND 90 TO A HUNDRED QUOTES
PER DAY, WE TAPER PEOPLE OFF
WITH THE LONG ACTING MEDICINES
FIRST THEY SEEM TO HAVE AN
EASIER TIME WITH THAT.
THEN WE DO THE TRANSITION IN A
FAIRLY CLASS CALAWAY, WE STOP
THE AGONIST, WAIT UNTIL IT'S
CLEARED OUT UNTIL PEOPLE HAVE
SOME MILD WITHDRAWAL, THEN KNOW
THAT IT'S PRETTY MUCH NOT
BOTHERING THEM AND DISPLACE, AND
THEN START THE BUPRENORPHINE AND
AS THE BUPRENORPH'SINE IS ADDED,
YOU SEE AUTOGONE AWAY AND THEN
THERE'S A DONE.
SO THEN YOU START WITH THE
AGONIST BUT YOU HAVE TO DO IT
SLOWLY TO, VOID PRECIPITATE
WITHDRAWAL AND THEN YOU'RE LEFT
AT THE END WITH THE PERSONS ON 2
DRUGS INSTEAD OF 1 YOU HAVE TO
TAPER OFF THE OLD AGONIST BUT
THERE ARE WAYS OF DOING THAT BUT
I WILL NOT GO INTO THAT TOO
MUCH.
NEXT SLIDE, PLEASE.
SO HERE'S SOME OF OUR EXPERIENCE
WITH SWITCHING PEOPLE OVER.
FOLKS WHO WE TARGET GET
HAPPENING PEOPLE DOWN TO 90 TO A
HUNDRED MORPHIN A DAY BEFORE WE
SWITCH OVER AND THAT'S THE BLUE
LINE ON THIS PICTURE HERE, YOU
CAN SEE WE HAVE TRIED SOME
PEOPLE WHO ARE HIGHER DOSES,
SOMETIMES WE'VE DONE THAT IN THE
HOSPITAL, BUT WHAT REALLY
HAPPENS IS PEOPLE WIND UP TAKING
BETWEEN 8 AND 16-MILLIGRAMS OF
EQUIVALENTS AND I HAVEN'T SPOKE
ON SUBOXONE YET, I WILL IN A
MINUTE BUT THESE ARE FAIRLY MISS
OF THE ROAD DOSES SO PEOPLE CAN
COME ON TO RELATIVELY MODEST
DOSES.
NEXT SLIDE.
SO THIS IS USED FOR TREATMENT
DISORDERS, THIS IS THE EASY TO
DOSE AND CAN YOU HAVE RELATIVELY
FINE CONTROL OF THE DOSING, 1
THING TO POINT OUT IS THAT THEY
CONTAIN A MEDICINE CALLED
NALOXONE, WHICH IS A MEDICINAN
TAGANIST, SOMETIMES IT'S
MISUNDERSTOOD WHAT IT'S DOING IN
THERE,.
NALOXONE WOULD BE THERE TO
PREVENT AN EFFECT OR CAUSE
WITHDRAWAL AS A DETERRENT.
IT'S NOT ABSORBED SUBLINGUAL AND
NOT A PART OF THE THERAPY AND
IT'S JUST USED FOR PREPARATION,
AND SOMETIMES PEOPLE WONDER WHAT
THAT'S DOING IN THERE AND THAT'S
WHAT IT'S THERE FOR.
AS I SAID YOU CAN TAKE IT
SUBLINGUALLY, OFTEN 2-3 TIMES A
DAY WORKS JUST FINE AND YOU DO
HAVE TO GET A PRESCRIPTION FOR
IT.
--DEA WAIVER TO PRESCRIBE IT.
NEXT SLIDE.
AS I MENTIONED BEFORE, THE FIRST
THING THAT WAS BUPRENORPHINE WAS
APROWFED FOR WAS FOR ACUTE PAIN,
BUPRENEX IS STILL AVAILABLE AND
IT WORKS FINE IF YOU HAVE PAIN
AND LOW TOLERANCE, IT HAS A
REMARKABLY SHORTER DURATION OF
SO YOU HAVE TO GIVE IT Q6 OR 4
HOURS AND IT'S APPROVED FOR USE
IN CHILDREN.
IT'S A BELBUCA IS LIKE A BUCCAL
FILM BUT IT'S HARD TO GET
INSURANCE TO PAY FOR AND
BUTRANSIS A PATCH THAT CAN LAST
FOR SEVERAL DAYS AT AIM TIME.
NEXT SLIDE.
SUBLOCADE IS AN EXTREMELY LONG
ACTING DURATION FOR THE USE OF
SUBSTANCE DISORDERS, 1 INJECTION
IT LASTS FOR A MONTH.
THERE'S ANOTHER THING CALLED
PROBUPH INE, AND IMPLANTABLE
RODS AND IT'S BEEN MADE
OBLIGATIONS SOLEAT SO IT'S NOT
WORTH TALKING ABOUT.
WHAT WE'VE - LOOKED AT IN FOLKS
THAT WE TRANSITION OVER TO
BUPRENORPHINE HAS MAINLY BEEN
ABOUT ACUTE CARE USE, AND THESE
ARE THE FIRST 40 SOME-ODD FOLKS
THAT WERE TRANSITIONED OVER TO
BUPRENORPHINE, WE'RE UP TO
70-SOMETHING, I THINK WHO
SWITCHED OVER AT OUR CENTER.
THESE ARE 6 MONTHS PREAND POST
ACUTE CARE VISITS.
SO YOU KNOW YOU COULD SEE THAT
OVERALL ACUTE CARE USE REALLY
DROPS OFF A GOOD BIT ON AVERAGE
WHEN PEOPLE TRANSITION BEFORE
AND AFTER.
AND YOU CAN ALSO SEE, I DON'T
KNOW IF YOU CAN SEE MY POINTER
BUT YOU GET THE OCCASIONAL
MIRACLE, YOU KNOW WE HAVE A FEW
PATIENTS WHO WERE IN AS MUCH AS
WEEKLY OR MULTIPLE TIMES A MONTH
WHOSE ACUTE CARE REALLY, REALLY
DROPPED OFF.
WE ALSO HAD SOME PEOPLE WHO HAVE
SIGNIFICANT CHRONIC PAIN WHO
FELT WAY BETTER ON BUPRENORPHINE
THAN THEY DID ON OTHER OPIOIDS
EVEN IN HIGH DOSES BUT HERE'S
WHERE I START POURING COLD WATER
ON, IN CONTRAST,OT POST SIDE,
THAT IS A LOT LESS BUT IF YOU
LOOK AT ABSOLUTE NUMBERS, THAT
IS NOT A LOW FREQUENCY OF ACUTE
CARE VISITS FOR PEOPLE WITH
SICKLE CELL DISEASE.
THAT'S ACTUALLY A PRETTY HIGH
FREQUENCY OF ACUTE CARE.
SO, THIS CAN HELP PEOPLE TO STAY
OUT OF THE INFUSION CENTER, FOR
ED AND SO FORTH BUT IT DOES NOT
CONVERT A VERY ILL AND COMPLEX
POPULATION EVER FOLKS WITH
CHRONIC PAIN AND FREQUENT ACUTE
PAIN TO TO FOLKS WHO ARE CURED.
THERE AREN'T NECESSARILY ALL
THAT MANY MIRACLES TO BE HAD AND
EVEN THOUGH THIS CAN BE USEFUL,
IT DOESN'T MAKE ALL THE PROBLEMS
GO AWAY.
ON THE SAME NOTE, WHEN PEOPLE
TRANSITION TO BUPRENORPHINE AT
OUR CENTER, IT'S PART OF A
LONG-TERM PRETTY HIGH INTENSITY
INTEGRATED THOUGHT PROCESS
AROUND HOW TO MANAGE CHRONIC
PAIN SO THESE ARE FOLK WHO IS
ARE OFTEN SEEN WEEKLY BY PRETTY
MUCH THE SAME PROVIDER, THEY'RE
OFTEN VERY AGGRESSIVE DISEASE
MODIFYING, PARTICULARLY AS
OPIOID DOSES TAPER, THEY'VE BEEN
TALKING ABOUT ARE THE OPIOIDS
WORKING OR NOT, WHAT'S THE RISK.
DO YOU WANT TO STAY ON THESE
THINGS, WE HAVE THIS THING
CALLED BUPRENORPHINE DO YOU WANT
TO TRY IT FOR MONTHS AND YEARS
PROBABLY BEFORE THIS HAPPENS,
AND I DON'T THINK IT'S SIMPLE
AS, YOU KNOW YOU CAN FIND OF
LEAP ON SOMEONE WITH A VERY
COMPLEX PROBLEM, PUT THEM ON
BUPRENORPH AND YOU KNOW
CELLESTIAL LIGHT SHINES DOWN.
THE THERE'S A LOT THAT GOES INTO
THIS THAT'S NOT JUST THE PILL.
NEXT SLIDE.
AND I THINK I JUST SAID ALL OF
THAT, WILL POINT OUT THAT IF YOU
HAVE SOMEONE ON BUPRENORPHINE
FOR THE RECEPTOR PHARMACOLOGY
THAT YOU HAVE TO HAVE A PLAN FOR
WHAT THEY DO WHEN THEY HAVE
ACUTE PAIN.
VERY OFTEN WE WILL HAVE PEOPLE
WHO TREAT OVER WITH FULL
AGONISTS, ALSO THERE ARE A FEW
PEOPLE WE HAD TO STOP THE
BUPRENORPHINE, START FULL
AGONIST AND AS THEIR CRISIS
RESOLVED SWITCH TO REINDUCTION
OVER.
SO YOU HAVE TO HAVE A THOUGHT
ABOUT HOW YOU WILL DO NAAND YOU
HAVE TO TALK ABOUT IT WITH THE
PATIENTS BEFORE YOU START.
AND THE OTHER THING IS, I THINK
I KIND OF TOUCHED ON THIS, BUT
YOU KNOW BUPRENORPHINE DOESN'T
CHANGE OUR BEHAVIOR.
SO, IF YOU DON'T HAVE AN
INTEGRATED SYSTEM FOR MANAGING
ACUTE CHRONIC PAIN, IF YOU DON'T
HAVE A WAY TO TALK TO PEOPLE
ABOUT THIS CSR IF YOUR ED PEOPLE
AND YOUR HOSPITAL PEOPLE AND
YOUR PAIN PEOPLE AND YOUR SICKLE
CELL PEOPLE ALL HAVE DIFFERENT
APPROACHES TO PAIN AND DON'T
KNOW WHAT TO DO WITH BUPRENORPH,
IT'S PROBABLY NOT GOING TO WORK
SO THIS HAS TO BE PART, I THINK,
OF A COMPREHENSIVE TOOL OF THAT
CONTEXT AND I WOULDN'T WANT TO
SELL IT AS SOME MIRACLE PILL YOU
COULD THROW AT EVERYONE.
I THINK THAT'S ALL I HAD TO SAY.
NEXT SLIDE, LET ME BE SURE.
OH YEAH, THAT WAS IT.
>> THANK YOU VERY MUCH
DR. CARROLL, I KNOW THERE A LOT
OF QUESTIONS, I CAN SEE THEM
BOTH POPPING UP IN THE CHAT AND
THE Q&A, WE WILL INVITE ALL 4 OF
OUR SPEAKERS UP SO WE CAN HAVE A
PANEL DISCUSSION AND DR. ST
ROUSE AND I WILL BE MODERATING
THAT.
I THINK THERE IS SO MUCH TO
LEARN ABOUT WHAT YOU SAID AND WE
NEED TO COORDINATE AND STUDY, I
CAN'T ECHO ENOUGH WITH WHAT
DR. CARROLL ENDED WITH, THE
IMPORTANCE OF TREATING SICKLELE
DISEASE AND REMINDING EVERYONE
THAT ALL THESE METHODS WORK BUT
THEY DON'T LEAD TO SICKLE CELL
DISEASE SO WE HAVE TO MAKE SURE
WE'RE TREATING SICKLE CELL IN
ADDITION TO TREATING PAIN AND
SOMETIMES THEY'RE NOT THE SAME
THING.
SO, I THINK THE COORDINATED
EFFORTS THAT HE SPOKE ABOUT ARE
SUPER IMIMPORTANT.
I'M GOING AHEAD IF IT'S OKAY
WITH YOU, DR. STROUSE, AND ASK
THE FIRST QUESTION, I SEE SO
MANY OF THEM, IT'S SORT OF HARD
TO KNOW WHERE THEY START AND
LET'S START WITH THE BEGINNING
ON THIS 1, PEOPLE LIVING WITH
SICKLE CELL TEASE HAVE LONG
KNOWN THAT ALTERPATIVE
THERAPIES, AND BENEFICIAL FOR
PAIN TREATMENT BUT MEDICAID AND
MEDICAID MANAGE TD CARE OF
COURSE DO NOT PAY FOR THESE
ALTERNATIVE THERAPIES.
AND THAT HAS MADE ACCUPUNCTURE
VERY COST PROHIBITIVE.
THIS CAME FROM GINGER DAVIS AND
I HAD THE SAME QUESTION FOR I
THINK DR. SCHLAGER, HOW DO WE
WELCOMER WOSTATE HEALTH
INSURANCES TO GET ALTERNATIVE
MEDICINE AND PLANS TREATMENT
PAID FOR?
>> WELL, FIRST OF ALL, THANK YOU
FOR THE QUESTION, IT'S OF GREAT
IMPORTANCE FOR OUR WORK WITH
SICKLE CELL AND FOR OUR WORK
WITH ALL CHRONIC PAIN PATIENT
WHO IS NEED ACCUPUNCTURE.
RIGHT NOW TO TELL YOU WHERE THE
STATE OF THE SCIENCE IS AT,
MEDICARE DOES COVER ACCUPUNCTURE
BUT ONLY FOR LOWER BACK PAIN AND
MEDICAID COVERS ACUE PINKTURE IN
13 STATES.
I AM A CONSULTANT FOR ILLINOIS,
WE'RE ABOUT TO GET MEDICAID
COVERAGE IN IMPEDIMENTS
ELIMINATED; WE WILL BE THE
14th STATE AND WE'RE HARBING
OUT ALL THE PAIN CONDITIONS IT
WILL TREAT.
ONE THING IN TERMS OF HEALTH
EQUITY THIS, IS A VERY STRONG,
VERY IMPORTANT HEALTH EQUITY
ISSUE THAT ACCUPUNCTURE IS ONLY
AFFORDABLE MANY TIMES OUT OF
POCKET, PAYMENT WHO ARE UPPER
MIDDLE CLASS, AND ACCUPUNCTURE
CLINICS ARE OFTEN IN UPPER
MIDDLE CLASS, UPPER CLASS AREAS,
AND NOT ACCEPTABLE TO SICKLE
CELL PATIENTS WHO OFTEN LIVE IN
URBAN OR RURAL POPULATIONS.
NIH AND PARTICULARLY THE NIH
PRISM--THE PRISM PROGRAM AS WELL
AS THE NIH PRAGMATIC TRIALS
COLLABRATORY UNDER THE DRUKS OF
WENDY WEBER WHO'S THE BRANCH
MANAGER FOR NCCIH IS ACUTELY
AWARE OF THIS HEALTH INEQUITY
AND 1 THING ABOUT PRAGMATIC
TRIALS, PRAGMATIC TRIALS PRODUCE
RESULTS THAT CAN BE GENERALIZED
AND APPLIED IN ROUTINE CLINICAL
SETTINGS AND THE NIH PRAGMATIC
TRIALS COLLABRATORY, BECAUSE
THEY FUND EMBEDDED PRAGMATIC
TRIALS THAT ARE EMBEDDED INTO
THE HEALTHCARE SETTING, THEY ARE
SERIOUS AND COMMITTED TO
SHIFTING THE POLITICAL CLIMATE
AND THE FUNDING CLIMATE IN THE
UNITED STATES AND SO, WENDY
WEBER HAS ALREADY BEEN TO
CAPITOL HILL TO THINK OF THE
HEAD OF CMS ABOUT EXPANDING
ACCUPUNCTURE TO THE TREATMENT OF
SICKLE CELL DISEASE PAIN AND
IT'S THIS KIND OF COLLABORATION
BETWEEN NIH AND THE NIH HEAL
INITIATIVE AND THE PRAGMATIC
TRIALS COLLABRATORY, AND
MEDICARE THAT IS GOLDEN.
IF MEDICARE STARTS FUNDING
ACCUPUNCTURE FOR CHRONIC SICKLE
CELL DISEASE PAIN, MEDICAID WILL
CONTINUE TO HAVE THE DOMINO FALL
AND COVER IT IN MORE STATES.
AND SO, THERE'S BASICALLY 2
THINGS GOING ON, ALL THE
WONDERFUL WORK THAT NIH AND THE
HEAL INITIATIVE AND THE
PRAGMATIC TRIALS COLLAB RATOORY
IS DOING TO HELP PEOPLE WITH
CHRONIC PAIN, PARTICULARLY
SICKLE CELL DISEASE, THEN WE'RE
ALSO APPROACHING IT ON THE STATE
LEVEL, SO HOW DO YOU DO IT ON
THE STATE LEVEL, IT IS--YOU NEED
A CHAMPION AND TO APPROACH A
STATE LEGISLATURE, A
REPRESENTATIVE WHO IS VERY
PROACUE PUNCTURE AND IN THIS
CASE, WE HAVE REPRESENTATIVE
TERRIES MAH WHO IS OF CHINESE
AMERICAN HERITAGE WHO HAS
CHAMPIONED THE WHOLE CAUSE OF
GETTING ACCUPUNCTURE COVERED BY
MEDICAID.
HER CONSTITUENTS IN HER DISTRICT
ARE CHINESE AND THEY WANT TO
MEDICAID TO COVER ACCUPUNCTURE
SO THIS IS THE WAY YOU START SO
I WOULD SAY, PARTNER WITH NOT
ONLY A REPRESENTATIVE WHO HAS A
VESTED INTEREST IN MEDICAID
COVERING ACCUPUNCTURE FOR THEIR
DISTRICT, BUT ALSO CONTACT THE
ACCUPUNCTURE ORGANIZATION SO
THOSE 2 IN TANDEM WORK AND THEN
RESEARCH, RESEARCH, RESEARCH,
THE MEDICAID AS WELL AS MEDICARE
PEOPLE, THESE STAKEHOLDERS WANT
TO SEE RESEARCH, THE VICARS
META-ANALYSIS THAT I SHARED WITH
YOU, HAS BEEN CRUCIAL, AS BEEN
INTEGRAL IN TERMS OF HAVING
SCIENTIFIC, BEING SCIENTIFIC
JUSTIFICATION FOR DOCUMENTING
THE EFFECTIVENESS OF
ACCUPUNCTURE SO THEY'RE COMING
FORTH, I HAVE OTHER RESEARCH AND
CHRONIC PAIN THAT I'M FUNDED ON
AND I WILL MOVE THOSE FORWARD
INTO KNOCKING AT THE DOOR OF MED
XAIR AND MEDICAID, ANY
QUESTIONS, YOU'RE MORE THAN
HAPPY TO CONNECT WITH ME, BUT
NA'S BASICALLY THE PROCESS, AND
IN--BECAUSE HEALTH EQUITY IS
SUCH A HOT ISSUE RIGHT NOW, AND
THE IMPORTANCE OF HAVING HEALTH
EQUITY AND COVER MANY DISEASE
CONDITIONS FOR PEOPLE ON
MEDICARE AND MEDICAID, BUT
PARTICULARLY CHRONIC PAIN AND
CERTAINLY SICKLE CELL, THIS IS
AN ISSUE THAT THE LEGISLATURES,
AS WELL AS THE STAKEHOLDERS AT
MEDICARE AND MEDICAID ARE VERY
OPEN TO.
>> THANK YOU.
I WILL ASK THE NEXT QUESTION
WHICH ALSO ADDRESSES QUESTIONS
ABOUT ISSUES TO ACCESS, IF THE
FIRST WAS PEER TO PEER, WHAT CAN
WE DO INCREASE ACCESS TO THESE
AND SPREAD THEM TO DIFFERENT
AREAS AND THE SECOND IS THAT FOR
PEOPLE THAT TELEMEDICINE DOESN'T
SEEM TO WORK THAT WELL, WHAT
SORT OF INTERVENTIONS ARE THERE
TO IMPROVE TELEMEDICINE FOR
BEHAVIORIAL HEALTH SERVICES FOR
PEOPLE WITH SICKLE CELL DISEASE
WITH A FOCUS ON PAIN MANAGEMENT?
>> YEAH, WELL, I WILL GO FIRST,
JUST QUICK ON THE PEER TO PEER
INTERVENTIONS, I THINK THAT
THOSE--THE PEER TO PEER MODELS
CAN BE EXTREMELY SUCCESSFUL, I
THINK THERE'S 2 THINGS THAT ARE
MAJOR BARRIERS, I THINK 1 IS THE
SYSTEM, WE WOULD LOVE TO SEE
CBOs RUNNING THESE PEER TO
PEER INTERVENTIONS BUT VEHICLE A
SYSTEM THAT CAN HAVE INTAKE AND
THEN DISTRIBUTE THE DIFFERENT
PEERS TO INDIVIDUALS FOR THEIR
THERAPY OR COACHING, WHATEVER IT
IS, I THINK HAVING A SYSTEM
THAT'S ROBUST AND IS FUNCTIONAL,
I THINK THAT'S CRITICAL TO HAVE
THAT.
THE OTHER PART IS THE TRAINING,
AND WE GOT A QUESTION ABOUT THIS
IN THE CHAT WHICH IS VERY GOOD,
LIKE WHAT LEVEL OF TRAINING DO
THE HEALTH COACHES GO THROUGH.
WE ACTUALLY STARTED OUT FOR THE
CHARISMA STUDY, WE STARTED OUT
WITH AN INTENSIVE TRAINING
PROGRAM.
I KNOW THAT EV'S GROUP WHO HAS
ALSO A PC ORI, THEY'RE DOING
TRAINING AS WELL AND THEY HAVE A
REALLY INTENSE TRAINING PROGRAM
FOR THEIR PEERS BUT THERE'S MUCH
ATTRITION AND IT'S REALLY HARD
TO GET THESE--EVEN THOSE WHO ARE
EXCITED ABOUT BEING A HEALTH
COACH OR BEING A PEER MENTOR TO
GET THEM THROUGH THE AMOUNT OF
TRAINING THAT WE REQUIRE FOR
THEM TO BE EFFECTIVE, SO WE
TRIED SCALING BACK THE TRAINING
QUITE A BIT AND HAVING A BIT OF
ON THE JOB TRAIN ASKING THAT'S
BEEN A LOT MORE--A LOT MORE
PROMISING OR EFFECT FOR US IN
TERMS OF RETAINING PEOPLE SO I
THINK THE TRAINING PIECE WE HAD
TO KIND OF GET THE SWEET SPOT OF
GIVING THEM ENOUGH THEY'RE NOT
DANGEROUS BUT NOT TOO MUCH BUT
IT'S NOT TOO ARDUOUS TO GET
THROUGH.
>> AND THE SECOND PART WAS THE
TELEMEDICINE PER BEHAVIORIAL
THELGT FROM THE A STANDPOINT OF
LICENSED SOCIAL WORKERS,
PSYCHOLOGISTS AND PSYCHIATRISTS
MOW DO WE APPROVE THE UPTAKE OF
THOSE?
>> I'M SURE LIZ HAS OPINIONS ON
THIS CONSIDERING SHE'S TRYING TO
WORK ON THINGS IN AIR RURAL AREA
NEAR US.
>> YEAH, YOU KNOW I DON'T
THINK--UNFORTUNATELY I DON'T
THINK THERE'S SORT OF A MAREACLE
SOLUTION HERE EITHER, I THINK
ENGAGEMENT IN CARE IS SOMETHING
THAT IS CLEARLY A CHALLENGE WITH
HER TODAY ABOUT YOU KNOW WE HAVE
THESE INTERVENTIONS THAT HAVE
DATA TO SUPPORT THEM TO BE
HELPFUL BUT GETTING THOSE
DELIVERED IS A CHALLENGE AND I
THINK WE EVEN HEARD TODAY ABOUT
SOME OF THESE BARRIERS WHERE
THERE'S TRANSPORTATION OR DATA
PLANS ON CELL PHONES OR YOU KNOW
JUST THE ACCEPTABILITY OF
PATIENTS FEELING THAT THIS IS
SOMETHING THEY THINK IS WORTH
WHILE.
AND I THINK THAT THE
JUSTICE--THERE'S A REALLY GREAT
QUESTION IN THE CHAT ABOUT YOU
KNOW HOW DO WE--WHICH OF THESE
INTERVENTIONS DO WE PICK FOR OUR
PATIENTS?
WE HAVE SO MANY OPTIONS, HOW DO
WE DECIDE?
AND ULTIMATELY I THINK 1 OF THE
BIGGEST DECIDERS IN THE THING
THAT HELPS WITH THE ADDRESS OF
THIS ISSUE OF ENGAGEMENT IS WHAT
DOES THE PATIENT WANT.
IT SOUNDS SO BASIC, BUT WHAT ARE
THEY INTERESTED IN, WHAT DID
THEY BELIEVE WILL BE EFFECTIVE
FOR THEM.
AND THAT'S HOW YOU KNOW YOU ARE
OFTEN--THAT IS 1 OF THE MOST
HELPFUL THINGS I THINK IN
ADDRESSING THESE ISSUES OF
ENGAGEMENT AND HAVING THIS BE
SOMETHING THAT'S MEANINGFUL FOR
THE PATIENT AND SO SORT OF
SAYING EVERYONE GETS
ACCUPUNCTURE, EVERYONE GETS
SYMBALTA, EVERYONE GETS
BUPRENORPHINE, NONE OF THESE
THINGS ARE THE 1 ANSWER AND IT'S
REALLY SORT OF WORKING WITH OUR
PATIENTS AND FINDING OUT WHAT
THE ISSUES OF ENGAGEMENT ARE FOR
THEM AND THESE PEER
INTERVENTIONS COMMUNITY AND
HEALTH WORKER INTERVENTIONS,
THESE ALSO HELP US DRILL DOWN TO
WHAT ARE THE BARRIERS FOR
ENGAGEMENT OF OUR PATIENTS.
>> I'M--SORRY.
>> NO, NO, THAT WAS MY THING.
>> 1 THING I WANT TO SAY AND SAY
DIRECTLY IS Y'ALL NEED TO KNOW
SOME PSYCHIATRY.
ONE OF THE MOST DIFFICULT THINGS
THAT I HAD TO DEAL WITH WHEN I
FIRST STARTED WAS HAVING THE
PATIENT COME IN, SIT IN THE
CHAIR AND I SAY, WELL WHAT
BRINGS YOU BY AND THE PATIENTS
SAY, I DON'T KNOW THEY JUST SAID
I NEEDED TO COME TALK TO
SOMEBODY.
THIS IS NOT A SET UP FOR
SUCCESS, Y'ALL.
WE NEED SOME SOPHISTICATION.
WE'RE DEALING WITH PEOPLE WHO
ALMOST ALL HAVE CHRONIC PAIN OR
WILL HAVE CHRONIC PAIN, WE NEED
SOME SOPHISTICATION ABOUT HOW
THIS INTERACTS WITH PSYCHIATRIC
ILLNESS, YOU NEED TO BE ABLE TO
TALK INTELLIGENTLY ABOUT HOW
DEPRESSION INTERACTING WITH
CHRONIC PAIN AND THE CAUSATION
IS NOT JUST 1 DIRECTION, AND IT
IS AN ILLNESS AND YOUR PAIN CAN
GET BETTER IF YOU GET YOUR
DEPRESSION TREATED.
VERY FREQUENTLY WHEN I HEAR
SOMEONE SAYS, WELL YOU HAVE BAD
PAIN AND YOU SEEM TO FEEL BAD,
MAYBE YOU SHOULD TALK TO
SOMEONE, THE ANSWER IS I CAN
TALK TO MY PASTOR, MY WIFE, WHY
DO I NEED TO SEE SOME GRAY
HAIRED WHITE GUY IN A TIE FOR
AND YOU NEED TO ANSWER THIS
QUESTION?
>> I THINK ALONG THOSE SAME
LINES BECAUSE I THINK IT'S SO
IMPORTANT AND HIGHLIGHTS HOW
MUCH WE NEED MULTIDISCIPLINARY
CARE, WE NEED MORE PSYCHIATRIST
LIKE DR. CARROLL AND DR. PRINCE
TO BE PART OF OUR TEAM TO HELP
US HAVE THESE CONVERSATIONS AND
ENGAGE US AND INDIVIDUALS AND AS
MANY PEOPLE KNOW, THERE'S
CERTAINLY STIGMA AGAINST
PSYCHIATRY IN ADDITION TO SIGMA
THAT'S ASSOCIATE WIDE PAIN SO
HAVING ALL PEOPLE IN 1 PLACE,
THEY WILL CAN TOM OUR SICKLE
CELL CENTER AND SO WE WANT TO
MAKE SURE THAT WE'RE ABLE TO
ENGAGE THEM IN PSYCHIATRIC
ASSISTANCE WHEN THEY'RE ALREADY
THERE FOR OTHER PURPOSES.
ON THAT SAME NOTE, I WANTED TO
THROW OUT A QUESTION THEY FIND
PROBABLY THE MOST DIFFICULT IS
THAT OR A THOUGHT, I GUESS FOR
1, FOR A LONG TIME, TD IDEA OF
WHY SEE, WE BELIEVE YOUR PAIN
HAS BEEN ASSOCIATED WITH
THEREFORE WE USE OPIOIDS MPLET
AS OPPOSE TO SEE SEE AND WE
BELIEVE PAIN, WE KNOW DEEPLY HOW
MUCH PAIN IS A PART OF SICKLE
CELL DISEASE, BUT HOW DO WE
DISASSOCIATE THOSE 2 THINGS?
HOW DO WE HELP PEOPLE UNDERSTAND
THAT BY SEEING AND BELIEVING
YOUR PAIN IT DOESN'T JUST MEAN I
HAVE TO ESCALATE RAIN SHOWER
OPIOIDS TO SEE AND BELIEVE YOUR
PAIN AS OPPOSED TO ALSO USING
THESE OTHER OPTIONS.
I'LL THROW THAT OUT, MAYBE
CHARGZ, START WITH YOU AND GET
EVERYBODY ELSE'S THOUGHTS?
>> YEAH, YOU KNOW BECAUSE I
THINK THAT WHAT PAT WAS TALKING
ABOUT, I THINK LENDS TO IT, JUST
IN TERMS OF THE EDUCATION AT THE
OUTSET, YOU KNOW I HAD THE
EXPERIENCE, I WAS SMILING
BECAUSE I HAD THE EXPERIENCE
WHERE A PROVIDER SAID, HEY, YOU
KNOWY WOO WILL CUT YOUR OPIOIDS
IN HALF AND THEN THE PATIENT WAS
LIKE, OH WHAT AM I GOING TO DO,
AND THEY'RE LIKE OH, HERE'S
DR. CHARLES HE'S GOING TO WORK
WITH YOU ON DEEP BREATHING OR
SOMETHING LIKE THAT, RIGHT?
SO, YOU KNOW--
>> HOW'S THAT SESSION GO.
>> YEAH THAT WAS FANTASTIC AND
THE THING I'M A BLACK
PSYCHOLOGIST, RIGHT I'M NOT EVEN
A GRAY HAIRED WHITE GUY BAH
STILL THAT THAT INTRODUCTION AND
THE EDUCATION ON WHAT WE'RE
GOING TO DO IN TERMS OF OUR
BEHAVIORIAL APPROACH IS NOT
THERE FROM THE VERY, VERY
BEGINNING AND OBVIOUSLY IT HAS
TO START AT PEDIATRICS
BECAUSE--AND WHETHER THAT
EDUCATION IS APPROPRIATE OR NOT
BECAUSE I KNOW A LOT OF PATIENTS
TRANSITION AND THEY'RE LIKE OH
THEY'VE BEEN SHOVING THAT
PSYCHOLOGY STUFF DOWN MY THROAT
AND THE DEEP BREATHING AND I I'M
TIRED I DON'T WANT TO HEAR IT
AND THE MINDFULNESS SO THEY'RE
SICK OF IT BY THEN, BUT THEY
NEED TO CHANGE IT IN A DIFFERENT
WAY BUT THE EDUCATION NEEDS TO
BE THERE AND THE EXPECTATION AND
PART OF THE CULTURE AND I THINK
THAT THE PEER MODEL IS PIECE OF
THAT, AND PATIENTS HAVE SAID TO
ME SPECIFICALLY LIKE HEY,
DR. CHARLES WE LOVE AND YOU
EVERYTHING, BUT IF WE'RE GOING
TO LEARN ABOUT HOW TO MANAGE MY
SICKLE SEAL PAIN, I DON'T WANT
TO HEAR IT FROM YOU.
I WOULD MUCH RATHER HEAR IT FROM
SOME BE WHO'S BEEN THROUGH THIS
BEFORE.
SO I DO THINK IT'S A COMBINATION
OF THINGS.
>> I HAVE THOUGHTS ON THIS
ISSUE.
SO I THINK 1 PART OF IT IS I
THINK BELIEVING SOMEONE HAS PAIN
IS MORE THAN 1 WAY TO MANAGE IT.
SO THERE'S A DIAGNOSIS
ASSESSMENT PROBLEM AND THERE'S A
MANAGEMENT PROBLEM AND YOU KNOW
1 OF THE THINGS I THINK WE KIND
OF GOT TO ACKNOWLEDGE IS OPIOIDS
CAN FAIL.
YOU KNOW IF YOU LOOK AT CLINICAL
TRIALS EVEN AT 6 WEEKS, YOU GET
LIKE 10-20% DROP OUT AND WITH
THE NUMBER NEEDED TO TREAT THE
BENEFITS IS LIKE 3 SO IT FAILS
2/3RDS OF TIME AND WE OFTEN ACT
LIKE THAT AIN'T TRUE, LIKE YOU
HAVE TO DO IS FIND THE RIGHT
OPIOID AND DOSE, AND THERE ARE
SOME PEOPLE GET WAY UP THE TREE
AND HAVING THAT ITERATE OVER
MANY YEARS AND SO THERE'S 1 PART
IS, YOU KNOW WE HAVE TO
ACKNOWLEDGE THAT CHRONIC PAIN IS
HARD TO TREAT, NOTHING'S
UNIVERSALLY EFFECTIVE INCLUDING
OPIOIDS, WHICH MEANS YOU HAVE TO
HAVE A PLAN FOR WHEN THEY DON'T
WORK AND A DEFINITION OF WHEN
THEY DON'T WORK WHICH WE NEED
AND THAT'S ANOTHER PROBLEM AND
ANOTHER IS, YOU KNOW CHRONIC
PAIN DOESN'T HAPPEN TO 14
YEAR-OLDS OR 10 YEAR-OLDS.
AND IF FOLKS NEVER KNOW WHAT'S
COMING TO THEM UNTIL IT'S
ALREADY THERE AND THEY'RE AT 22,
25 AND THE PANE DOESN'T GO AWAY,
AND FOR THE LAST 2 DECADES
THEY'VE BEEN TOLD THIS IS THE
WAY YOU MANAGE SICKLE PAIN, YOU
KNOW, THAT'S HARD TO UNDO.
SO I THINK PEOPLE NEED TO KNOW
WHAT'S COMING THEIR WAY BEFORE
IT HITS THEM AND THAT WOULD HELP
US TO HAVE A MORE REALISTIC
CONVERSATION.
>> I THINK THAT THAT'S SO SMART
DR. CAROL AND 1 THE THINGS THAT
THE ALLIANCE HAS UNDERTAKEN
LENIENT THAT I HOPE YOU ALL WILL
HEAR MORE ABOUT IN THE COMING
MONTHS AND THE IMPORTANCE EVER A
LIFE SPAN APPROACH TO PAIN AND
THAT WE HAVE STOCK EXCHANGE STOP
THINKING IN EMERGING ITS WHAT
HAVE WE DO IN PEDIATRICS AND HAD
WHAT WE DO IN ADULT CARE AS
SEPARATE ENTITIES AND SO THE
MORE WE START TO WORK ON THIS
LIFE SPAN APROETCH TO PAIN WE
CAN DO WHAT YOU SUGGEST, BOTH
BEGINNING EARLY IN PEDIATRICS,
WITH OTHER INTERVENTIONS BESIDES
OPIOIDS BUT ALSO WITH THE
RECOGNITION OF COURSE THAT
CHRONIC PAIN WILL HAPPEN TO
QUITE A LOT OF PEOPLE AND SO,
MAYBE IF WE TAKE THAT APPROACH
AND TAKE A REAL LIFE APPROACH WE
WILL BE ABLE TO HOPEFULLY
IMPROVE ON SOME OF THIS GOING
FORWARD.
DR. STROUSE, DO YOU WANT TO ASK
THE NEXT QUESTION?
YOU HAVE TO GET OFF MUTE FIRST.
>> I WANTED TO ASK A QUESTION
ABOUT WHAT'S THE RIGHT TIME TO
INITIATE BUPRENORPHINE, WE
RECEIVED A REQUESTY ABOUT
WHETHER EARLY ON AS PEOPLE ARE
DEVELOPING CHRONIC PAIN ARE
THERE POTENTIAL ROLES VERSUS
DESENSITIZATION AND YOU KNOW
WHO'S THE RIGHT PERSON TO START
BUPRENORPHINE AND IT SHOULD IT
BE PEOPLE THAT WE FEEL LIKE ARE
NOT RESPONDING WELL TO OPIATES
OR OR CHALLENGES WITH OPIATES OR
SHOULD IT BE A BROADER
POPULATION?
>> I GUESS I WILL TAKE THAT 1,
WE DON'T KNOW IS THE ACTUAL
ANSWER TO THE QUESTION, NOW I
WILL WAVE MY HANDS IF AREA I
MACHINEUTE OR 2.
YOU KNOW WHAT WE'VE USED IT FOR
IS WHEN WE FUNDAMENTALLY THINK
THAT OPIOIDS EITHER BECAUSE THE
RISK IS UNACCEPTABLE OR THE
PATIENT'S JUST IN BAD PAIN OR
YOU GOTTA TRY SOMETHING ELSE,
AND SO WHAT WE'VE USED IT FOR
HAS BEEN ESSENTIA WILY OPIOID
FAILURE AT LEAST A SAFER AND
MAYBE DIFFERENT ALTERNATIVE.
AND I ALWAYS THINK THIS SORT OF
SELECTION CRITERIA IS TRICKY
BECAUSE YOU'RE TRYING TO FIGURE
OUT WHO'S THE LEAST LEAST BAD
OFF PERSON THAT MIGHT BENEFIT
WHICH IS A TRICKY THING TO
FIGURE OUT AND WE TOOK THE OTHER
WAY WE TOOK THE FOLKS IN THE
WORST SHAPE AND REALLY UP THE
TREE AND TRY TO HELP THIS WAY,
SO I DON'T KNOW HOW FAR DOWN THE
LADDER IT REALLY GOES I DO, I AM
A CORROSIVE SKEPTIC AND THERE
ARE STUDIES ON THAT TO THE MDNA
AND THE ANTAGONIST AND THE OTHER
THING, YOU BE SHOW ME.
SHOW ME THIS THING IS REALLY A
DIFFERENT OPIOID BECAUSE HISTORY
IS NOT KIND TO PEOPLE WHO COME
UP WITH A NEW OPIOID AND SAY
HEY, THIS 1'S REALLY DIFFERENT.
SO THAT BEING SAID AS FAR AS
LIKE USING IT EARLY I THINK
LOWISH DOSES IS JUST ANOTHER
OPIOID, AT HIGHER DOSES IT'S
SAFER BUT THEN HAVE YOU THE
PROBLEM OF WHERE DO YOU GO WITH
A HIGH DOSE IF SOMEONE HAS ACUTE
PAIN, SO THE SHORT ANSWER IS I
DON'T KNOW BUT LIKE I SAID
HISTORY IS NOT KIND TO PEOPLE
WHO THROW SOME NEW SHINY OPIOID
AND SAY THIS IS REALLY, REALLY
DIFFERENT SO I'M INCLINED TO BE
CAREFUL I TEND TO THINK WE
SHOULD RESERVE IT FOR WHEN THING
VS GONE GONE BADLY AND AND THEN
WE CAN USE BUPRENORPH.
I THINK WHAT YOU'RE SAYING TOO
IS REARRANGE OUR THOUGHTS ON
CHRONIC PAIN TO GET PEOPLE UP
THE TREE YOU'RE TALKING ABOUT
AND THAT'S WHAT YOU'RE SAYING
AND THE LIFE SPAN APPROACH,
SUPER, SUPER IMPORTANT WE ARE
FORTUNATE TO BE IN A AGE WHERE
WE ARE FINALLY MOVING FORWARD IN
OUTCOMES ON SICKLE CELL DISEASE
SO WE HAVE PLAN FOR NOT ONLY A 2
WEEK COURSE OF PAIN BUT HOW DO
WE APPROACH THAT.
THERE IS A QUESTION IN THE Q&A
FROM LORI VIC ABOUT TIME
INVESTMENT SHE FOUND THAT IN HER
STUDY BUILDING A RELATIONSHIP
TOOK A LOT OF TIME WHICH ALL OF
US WOULD ABSOLUTELY AGREE ON AND
SHE SPENT YEARS TRYING WITH
PARTICIPANTS TO BUILD
RELATIONSHIPS AND I THINK
DOCTOR, THIS IS A QUESTION MORE
FOR YOU, HOW DID YOU FIND TIME
INVESTMENT IN GETTING PATIENTS
ERNE GAUGED IN THE CHARISMA
STUDY?
>> YEAH, SO I DON'T THINK THAT
WE AS PROVIDERS DO A VERY GOOD
JOB BECAUSE THERE IS SUCH A TIME
RESTRICTION ON EVERYTHING WE'RE
DOING SO EVEN AS A PSYCHOLOGIST
I DON'T HAVE THAT MUCH TIME AND
TO SPEND ENOUGH TIME WHERE OR
THE TIME THAT'S NECESSARY TO
STAY IN CONTACT WITH SOMEBODY
AND DEVELOP THAT LEVEL OF TRUST
THAT THEY KNOW THAT YOU'RE GOING
TO BE THERE AND YOU KNOW THEY'RE
GOING TO EXPLIVEN THAT YOU'RE
GOING TO ACTUALLY ACTOT THINGS
THEY FIND TO BE IMPORTANT
AUTODIFFICULT SO TD 1 THING WE
REALLY DID IS LEVERAGE THE
COMMUNITY, OFTEN TIMES THE
COMMUNITY IS ESTABLISHED A MUCH
BETTER RELATIONSHIP WITH THE
PATIENTS THAN WE HAVE SO IF WE
CAN USE THESE COMMUNITIES AS THE
BRIDGE FOR THAT RELATIONSHIP, I
THINK THAT WORKS REALLY WELL, IT
HAS FOR US.
NOW IT'S NOT A PANACEA, IT'S NOT
GOING TO FIX EVERYTHING, OFTEN
TIMES SOME OF OUR PATIENTS HAVE
HAD NEGATIVE EXPERIENCES WITH
COMMUNITY-BASED FOLKS AS WELL
BUT IT IS REALLY A LOT BETTER
THAN US JUST TRYING TO DO IT ON
OUR OWN.
>> FANTASTIC, THANK YOU VERY
MUCH.
I SAW DR. CARROLL VIGOROUSLY
NODDING AS WELL AND THAT'S JUST
IMPORTANT.
THE TIME COMMITMENT IS REAL IN
WHAT WE ALL DO.
THIS IS A DISEASE THAT'S NOT
GETTING THE ATTENTION IT NEEDED
AND REALLY HAS SO MUCH STIGMA
ASSOCIATED THAT IT ALL TAKES ME
A LOT OF TIME, I WALK INTO A
ROOM JUST TO TALK ABOUT BLOOD
TRANSFUSIONS OR HYDROXY URAIA
AND SOMETIME ITS TAKES MONTHS
FOR SOMEONE TO LISTEN AND 1
THING I HEARD PAT SAY AND OTHERS
SAY, RIGHT IS MEETING THAT
INDIVIDUAL WHERE THEY ARE, IS
SUPER IMPORTANT WHEN YOU FIRST
MEET THAT INDIVIDUAL PATIENT
WHETHER THEY'RE 3 OR 30
UNDERSTAND WHAG THEIR BIGGEST
CONCERN IS RIGHT NOW TO GET BUY
IN BEFORE YOU GET TO SOME OF THE
HARDER PARTS, I THINK IS KEY,
DR. CARROLL DID YOU WANT TO ADD
ANYTHING ELSE TO THE TIME
INVESTMENT DISCUSSION.
>> NO, I DO THINK 1 THING I SAID
ABOUT THE TIME INVESTMENT IS
BEFORE YOU SEE THE PATIENT, 1 OF
THE--NOTHING FEEDS STIGMA LIKE
LACK OF KNOWLEDGE, YOU KNOW?
SO IF YOU KNOW SOMETHING ABOUT
WHAT DEPRESSION IS AND HOW IT
INTERACTING WITH CHRONIC PAIN
AND WHAT TREATMENT ACTUALLY
MEANS, AND YOU CAN SPEAK IN GOOD
FAITH WITH BOTH CARE AND
KNOWLEDGE, THAT HELPS A LOT.
YOU KNOW?
THAT BEATS THE HECK OUT OF WELL
I THINK YOU NEED TO TALK TO
SOMEBODY BUT I DON'T KNOW WHAT
TO TELL YOU ABOUT IT.
>> RIGHT.
>> SO, THE MORE YOU KNOW, THE
MORE YOU CAN PREPARE PEOPLE WITH
THAT UPON.
>> I AND I FOUND IT HELPFUL TO
TALK ABOUT MULTIDISCIPLINARY
PAIN MANAGEMENT AS THE STANDARD
OF WHAT PEOPLE THAT HAVE
RESOURCES GET AND OUR JOB IS TO
TRY TO CREATE THAT SYSTEM FOR
PEOPLE THAT DON'T HAVE A LOT OF
MONEY.
SO YOU KNOW A WE HAVE NOT ENOUGH
PSYCHOLOGISTS BUT WE HAVE 2
PSYCHOLOGISTS FOR A HALF DAY A
WEEK, THAT DON'T BILL BECAUSE
WHEN THEY HAVE TO BILL THEY
CAN'T SEE PEOPLE WITHOUT
SURPRISE BILLING, RIGHT?
AND YOU KNOW YOU HAVE SOMEONE
WHO GETS THE $500 BILL FOR THEIR
PSYCHOLOGY VISIT THEY TELL THEM
IS AN ESSENTIAL PART OF THEIR
CARE BECAUSE THEY HAVE PRIVATE
INSURANCE THAT CARVES OUT DUKE
PSYCHOLOGY, THEY DON'T COME
BACK.
RIGHT?
SO WE BOTH FRAME IT AS PART OF
THEIRENTIOUS SENTIAL PAIN
MANAGEMENT THAT BEHAVIORIAL
INTERVENTIONS ARE AN ESSENTIAL
COMPONENT OF PAIN MANAGEMENT AND
THEN WE TRY TO OVERCOME SOME OF
THE BARRIERS, WE CAN'T DO THE
TREATMENT INTENSITY WE WOULD
LIKE FOR PEOPLE THAT ARE BEING
SUPPORTED BY OUR STATE GRANT
BECAUSE WE DON'T HAVE THAT MUCH
PSYCHOLOGY SUPPORT AND NOW WE
HAVE 2 PSYCHOLOGISTS THAT
RECOGNIZE THAT OUR VERY
INTELLECTUAL WHITE GUY WASN'T A
GOOD FIT FOR EVERYONE, SO WE TRY
TO HAVE SOME CHOICES ABOUT WHO
PEOPLE CAN SEE, WE CAN'T--YOU
KNOW WE CAN'T MEET ALL THE
DIFFERENT IDENTITIES THAT
SOMETIMES PEOPLE NEED BUT WE TRY
TO AT LEAST ACKNOWLEDGE THAT AND
HAVE CHOICES FOR THEM.
>> YEAH.
>> I WANTED TO MAKE SURE THAT
WE--
>> SORRY, 2 QUICK COMMENTS, JUST
WANTED TO COMMENT ON WHAT JULIE
WAS SAYING IN TERMS OF OFTEN
TIMES ROLLING WITH RESISTANCE,
IT'S A MOTIVATIONAL
INTERVIEWINGEC ITNIQUE BUT THERE
ARE A LOT OF TIMES PATIENTS ARE
WILLING WHETHER IT'S RATIONAL OR
NOT TO DO WHAT WE THINK IS BEST
FOR THEIR CARE AND OFTEN TIMES
THAT MIGHTIC MONTHS BEFORE THEY
SAY YES BUT IF WE FORCE
SOMETHING ON THEM, THAT
RELATIONSHIP IS BROKEN ALMOST
FOREVER AND IT'S HARD TO COME
BACK FROM THAT.
THE OTHER THING I WAS GOING TO
SAY IS THAT IN DOING QUALITATIVE
INTERVIEWS OUR PATIENTS HAVE
SAID THAT THAT KNOWLEDGE IS
ALMOST BETTER THAN THE IDENTITY
OF THE PERSON DOING THE THERAPY
OR THE COACHING, SO, THEY WANT
SOMEBODY WHO KNOWS ABOUT SICKLE
CELL AND KNOWS ABOUT MENTAL
HEALTH MORE SO THAN SOMEBODY WHO
ACTUALLY LOOKS LIKE THEM.
SO, YOU KNOW JUST TO POINT THAT
OUT.
>> THANK YOU.
I WANT TO MAKE SURE THAT WE ASK
NANCY'S QUESTION, HAS ACUE
PRESSURE BEEN CONSIDERED STUDIED
INSTEAD OF ACCUPUNCTURE FOR
PEOPLE WITH SICKLE CELL DISEASE?
>> SO, NO.
AS FAR AS I KNOW IT HAS NOT, BUT
AS YOU KNOW PEOPLE WHO HAVE
SICKLE CELL DISEASE HAVE SUCH A
HIGH BURDEN OF PAIN THAT IN MY
OPINION AND MY Ph.D. IS IN
ACCUPUNCTURE SCIENCE AND DM MY
OPINION, I DON'T THINK IT'S
STRONG ENOUGH.
I I'M NOT SAYING THAT ACUE
PRESSURE CAN'T BE USED IF
PATIENTS HAVE MUSK LO SKELETAL
PAIN AND WE COULD TEACH THEM HOW
TO DO IT, THAT WOULD BE
BENEFICIAL FOR SUPERFICIAL PAIN
BUT FOR DEEPER PANE WE HAVE TO
ACCESS WHAT ARE CALLED THE
CHANNELS IN THE MERIDIANS WHICH
ARE ACCESSED ON THE SURFACE OF
THE SKIN BUT ARE DEEPER ON THE
BODY AND THAT'S DONE WITH
ACCUPUNCTURE NEEDLES.
>> 2-MINUTE WARNING.
>> SO THANK YOU ALL VERY MUCH.
WE HAVE A COUPLE CLOSING
COMMENTS I WANT TO MAKE, AGAIN,
I THINK WE COULD ALL TALK ABOUT
THIS, RIGHT, ALL DAY LONG ABOUT
HOW IMPORTANT IT IS TO ENHANCE
THE WAY WE MANAGE AND TREAT PAIN
IN SICKLE CELL DISEASE HOW WE
PREVENT AND MANAGE CHRONIC PAIN
AND SORT OF WHERE DO WE GO FROM
LEER?
AND SO, WITH THAT I WANT TO
SHARE SOME SLIDES AND MOVE US
FORWARD A LITTLE BIT.
AGAIN, THANK YOU TO ALL OF OUR
AMAZING SPEAKERS.
SO,IME GOING TO TALK OVER THE
PERSPECTIVE OF THE NATIONAL
ALLIANCE OF SICKLE CELL CENTERS
ONCE I GET TO THE RIGHT
PRESENTATION MODE.
WHICH WE ALL KNOW TAKES A
SECONDS MORE IMPORTANTLY I WANT
TO RECOGNIZE A GENTLEMAN WHO HAS
BEEN A FOUNDER IN BRINGING TO
LIGHT THE AMOUNT OF PAIN THAT
HAS REAL REALLY AFFECTED
INDIVIDUALS LIVING WITH SICKLE
CELL DISEASE AND DR. BALLAS IS
SUCH AN AMAZING FIXTURE IN OUR
WORLD, HE'S BOARD CERTIFIED IN
INTERNAL MEDICINE, BLOOD
BANKING, PAIN MEDICINE AND PAIN
MANAGEMENT, I DON'T THINK YOU
WILL FIND ANYBODY ELSE LIKE
THAT, HOO IS EMERITUS PROFESSOR
OF POODIATRICS AT THOMAS
JEFFERSON, FORMER DIRECTOR OF
THE COMPREHENSIVE SICKLE CELL
DISEASE CENTER THERE, HE IS AT
END STAGE CANCERS AND THEY ASKED
US TO NOTIFY THE SICKLE CELL
COMMUNITY AND REQUEST PRAYERS
FOR A PEACEFUL END OF LIFE
TRANSITION FOR DR. BALLAS, EVEN
AT THE END OF HIS LIFE, HE
EXPRESSED HIS DEEP LOVE AND
ENDURING COMMITMENT TO
INDIVIDUALS LIVING WITH SICKLE
CELL DISEASE AND THEIR FAMILIES
AND THOSE HE WORKED WITH DURING
THE TIME OF HIS PRACTICE AND I
JUST WANT TO TAKE, YOU KNOW A
COUPLE OF SECONDS TO JOIN IN
REFLECTION THAT RELATE TO
SUPPORT DR. BALLAS AND HIS
FAMILY DURING THE SAN FRANCISCO
KRET TIME ANDA A TRUE TIME OF
FOR A DOCTOR WHO WAS COMMITTED
AND CARED FOR THE ENTIRE SICKLE
CELL COMMUNITY.
THANK YOU.
I KNOW HIS FAMILY APPRECIATES
THE LOVE AND THOUGHTS THAT WE
WILL SEND BACK TO THEM TO LET
THEM KNOW HOW MUCH HE WAS LOVED
WITHIN OUR COMMUNITY.
SORRY THESE ARE MY DISCLOSURES.
SO WHEN WE'RE TALKING ABOUT THE
NATIONAL ALLIANCE, WE ALL KNOW
AS WE'VE DISCUSSED THAT SICKLE
CELL IS A RARE DISEASE, IT
LIMITS LIFE EXPECTANCY DUE TO
CHRONIC COMPLICATIONS AND MANY
INDIVIDUALS AS WE SPENT THE LAST
COUPLE HOURS, THESE ONLY GET
MORE COMPLICATED AS PEOPLE GROW
OLDER AND LIFE GETS MORE
COMPLICATED.
SO WE NEED MORE HEALTHCARE
PROVIDERS WITH DISEASE SPECIFIC
KNOWLEDGE, AND AS REALLY JUST
DISCUSSED NOT JUST
PSYCHOLOGISTS, PSYCHIATRIST,
PEOPLE WHO CAN BE INVOLVED AND
TREATING COMPLICATIONS
THROUGHOUT THE LIFE SPAN.
WE ALSO KNOW IT'S ABOUT WHERE
YOU LIVE ON AN INDIVIDUAL LEVEL
AND HEALTHCARE ISN'T ALWAYS
STATE BASED BUT SOMETIMES COUNTY
BASED, YOU CAN HAVE INSURANCE
BUT NOT BE DIRECTED TO A
KNOWLEDGEABLE SICKLE CELL CENTER
OR PROVIDER AND WE @ ALLIANCE
ARE WORKING TO SHIFT THAT
PROGRAMMATIC CAMPUS ON WOULD
ABOUTING A SYSTEM OF CARE TO
ENHANCE ACCESS AND COORDINATION
THROUGHOUT THE LIFE SPAN.
AND TRULY INSURING THAT ALL WHO
LIVE WITH SICKLE CELL DISEASE,
AND HAVE ACCESS TO A SPECIALIST
AND APPROPRIATE COMPREHENSIVE
CARE AND THIS MEANS WOO VERMEN
INFECTED TO CHANGE THE SYSTEM OF
CARE FOR MORE PEOPLE IN MORE
AREAS USING HUB AND SPOKE, USING
TELEMEDICINE.
SO THE ALLIANCE WAS FOUNDED IN
2020 TO REALLY COME TOGETHER AS
A COORDINATED NETWORK TO
STANDARDIZE PRACTICE TO SAY THAT
EVERY INDIVIDUAL SHOULD EXPECT
TO RECEIVE THE SAME EQUITABLE
TREATMENT RELESS OF WHERE THEY
LIVE, WE ARE USING GRNDAD FOR
GLOBIN RESEARCH NETWORK FOR DATA
AND DISCOVERY AND WE'RE USING
ASH TO PROVIDE NECESSARY EXPERT
CARE TO ALL AGES LIVING WITH
SICKLE CELL DISEASE.
WE ARE RECOGNIZING SICK CELL
CELL THAT OFFER
MULTIDISCIPLINEAR COMPETENT CARE
ANDEE SIGNIFICANTLY INCREASED
THE NUMBER OF THOSE CENTERS AND
WE NOW HAVE DEFINITIONS OF BOTH
PEDIATRIC AND ADULT SICKLE CELL
CENTER BECAUSE BEFORE 2020 WE
DIDN'T KNOW WHAT THE SICKLE CELL
WAS, WE SAID THIS IS WHAT WE
THINK IT IS SO NOW WE HAVE
DEFINITIONS, AND NOW WE'RE
WORKING ON REICHING CONSENSUS ON
RECOMMEND MENDATIONS FOR WHICH
THERE ISN'T TRUE DATA SO WE CAN
MAKE THAT TRUE DATA AND DO
QUALITY IMPROVEMENT.
THIS IS A MAP OF OUR CURRENTLY
RECOGNIZED SICKLE CELL CENTERS
AND THIS IS REALLY AMAZING TO
ME, JUST HOW MUCH WE'VE GROWN,
WE OBVIOUSLY STILL HAVE A LOT OF
WORK TO DO, AND THERE ARE
SEVERAL CENTERS WHO ARE STILL
BUILDING AND ENGAGING AND I
FOLLOW YOU SINCE THIS SLIDE WAS
MADE A WEEK AND HALF AGO, THERE
ARE MORE SHOULD HAVE IT HAVE
BEEN RECOGNIZED THEY'RE NOT ON
THE MAP YET THESE ARE ALSO
CENTERS THAT ARE DEVELOPING SOON
TO BECOME FULL CENTERS AND
THERE'S A LOT MORE INFORMATION
TO COME ABOUT THAT, THIS IS AN
OLD ARTICLE NOW THATTA BEEN
REFERENCED MANY TIMES ABOUT WHAT
IS AN ADULT SICKLE CELL HAVE RHA
IS REQUIRED AND WHAT IS OPTICAL
IMAGES ARE MALAND WHAT IS
ADJUNCT.
AND THE REASON WE HAVE THIS AND
THAT IT'S SO SPRNT THAT IF WE
DON'T START SAYING THE SAME
THING ABOUT WHAT WE HAVE TO
HAVE, WE WILL NEVER GET IT AND
WE NEED TO MAKE SURE THAT THE
PAYORS THAT WE LIVE IN
UNDERSTAND ALL OF OUR
INDIVIDUALS LIVING WITHIC ISLE
CELL DISEASE DESERVE THIS AS AN
ADULT.
I ALWAYS SAY THAT YOU KNOW IF
YOU HAVE A BREAST CANCER PATIENT
LIVING IN RURAL ALABAMA YOU
DON'T ASK THEIR PRIMARY CARE
DOCTOR TO DREET THEIR BREAST
CANCER WE SHOULDN'T ASK THEIR
PRIMARY CARE DOCTOR TO TREAT
THEIR SICKLE CELL AS WELL, WE
SHOULD WORK WITH THE PRIMARY
CARE DOCTOR TO MAKE SURE THEY
GET EVERYTHING THEY NEED IN A
COMPREHENSIVE SETTING AND IT HAS
TO BE A THOUGHTFUL TEAM BASED
APPROACH, IT HAS TO BE CONSIST
AND THEN THE COORDINATED
THROUGHOUT THE MEDICAL
ENVIRONMENT AND IT HAS TO HAVE
POSITIVE OUTCOMES FOR PEOPLE
WITH SICKLE CELL DISEASE.
WE NOW HAVE ELMETROPOLITANS THAT
DEFINE A PEDIATRIC SICKLE CELL
CENTER AS WELL THORS FIND THE
SAME THINGS THAT WE'VE DONE IN
THE ADULTS SICKLE CELL CENTER,
WE'VE DONE AN IDENTIFY PROCESS
WITH THE COLLEAGUES ACROSS THE
COUNTRY AND ELSEWHERE, I DON'T
HAVE TIME TO TELL YOU ALL ABOUT
THAT DE PH I PROIEDURE TODAY BUT
THESE WERE THE ELEMENTS THAT
WERE REQUIRED TO BE A CENTER FOR
CHILDREN LIVING WITHIC ISLE CELL
DISEASE, THIS PAPER WILL BE
PUBLISHED VERY SOON AND HAS ALL
THE ADDITIONAL INFORMATION, IT'S
BEEN SUBMITTED AND IS IN PRESS
FOR PUBLICATION BUT AGAIN
RECOGNIZING WE'VE KNOWN ABOUT
THE TREATMENT OF SICKLE CELL AND
PEDIATRICS FOR A LONGER TIME SO
THERE'S MORE ELEMENTS THAT ARE
REQUIRED TO BE A PEDIATRIC
SICKLE CELL CENTER, OVERALL
WHETHER YOU'RE A CHILD OR ADULT,
YOU HAVE TO HAVE ACCESS TO
DISEASE MODIFYING THERAPY.
YOU HAVE TO HAVE DISEASE FOR
SICKLE CELL PRACTICE RESEARCH
NIEHS YOUR CENTER, THAT ENCLOUDS
IRON OVERLOAD TREATMENT AS WELL
AS APPROPRIATE BLOOD TRANSFUSION
MANAGEMENT, PAIN MANAGEMENT,
PLANNING AND NOT NEGLECTING THE
MENTAL HEALTH PLANNING AS WE
TALKED ABOUT TODAY, THE
IMPORTANCE OF MENTAL EXPHELGT
SICKLE CELL DISEASE CANNOT BE
SAID ENOUGH AND WE NEED TO KNOW
SAYING THAT OUTLOUD AND SHOUTING
IT FROM THE ROOF TOPPINGS,
INDIVIDUALS NEED BOTH
METROPOLITANNAL HEALTH AND
PHYSICAL HEALTH AND MENTAL
HEALTH IS PHYSICAL HEALTH.
SEE WHAT ABOUT CENTERS THAT
DON'T MEDE THESE DEFINITIONS,
WELL THERE'S ASSOCIATE CENTERS
WHICH I MENTIONED HAVE
COMPONENTS OF A SICKLE CELL
CENTER, THEY'RE IN DEVELOPMENT.
DATA COLLECTION CAN BE ONGOING,
AND THEY THEY HA GROW AS GROWTH
AS LOWS.
THESE ARE HUB AND SPOKE MODELS,
SO THEY CAN PROVIDE CARE AS AN
AFFILIATE CENTER, THEY CAN
RELYOT CENTER FOR SOME OF THE
COMPONENTS FOR EXAMPLE, A LOT OF
PLACES IN RURAL ALABAMA DON'T
HAVE THE CAPACITY TO DO AN MRI
OF THE LIVER TO ASSESS FOR IRON
OVERLOAD BUT THEY CAN CERTAINLY
GET A LOT OF THEIR TREATMENT IN
THEIR AFFILIATE CENTER AND THEN
COME ANNUALLY OR COME EVERY YEAR
AS NEEDED AND CAN WE WORK WITH
OUR COMMUNITY ON ONCOLOGY
PROGRAMS AT CENTERS AND HOW DO
WE GET BUY-IN FROM THEM BECAUSE
THAT WOULD INCREASE ACCESS TO
IRB, TOO, SO THE BOTTOM LINE IS
WE AT SICKLE CELL DISEASE
CENTERS MUST PROVIDE
COMPASSIONATE COMPREHENSIVE
CARE, TO BE COORDINATED HAVE TO
INSURE CONTINUOUS AND
PERSONALIZED CARE TO THAT
ATTENDS TO BOTH THE PHYSICAL AND
EMOTIONAL WELL BEING OF THE
INDIVIDUAL.
IT HAS TO BE EQUITABLE, THE TIME
FOR SAYING THAT INDIVIDUALS LIVE
IN THE SICKLE CELL DISEASE DO
NOT DESERVE A SICKLE CELL
SPECIALIST IS GONE, WE HAVE TO
ALL WORK TOGETHER TO SAY, WE
HAVE TO CREATE MORE SICKLE CELL
SPECIALISTS AND IT DOESN'T JUST
HAVE TO BE MDs, IT CAN BE OUR
APPs WHO ARE AMAZING TEAM
MEMBERS AS WELL AS PSYCHOLOGISTS
AND PSYCHIATRIST TRYSTS AND
COMMUNITY HEALTH WORKERS,
THERE'S A LOT OF WAYS TO
INCREASE ACCESS TO CARE, THIS
HAS TO BE A MORE COST EFFECTIVE
WAY TO CARE FOR THIS VULNERABLE
PATIENT POPULATION.
SO, I DIDN'T HAVE ANYTHING ELSE
TO SAY, I JUST WANT TO THANK THE
SPEAKERS AGAIN FOR SHARING ALL
OF THIS,A MAZING DATA TODAY, FOR
THOSE WHO ARE INTERESTED IN
LEARNING MORE ABOUT THE
ALLIANCE, GO TO SICKLE CELL
CENTERS, WWW .SICKLE CELL
CENTERS.ORGAND WE ARE GOING TO
MAKE THIS A REALITY FOR PEOPLE
LIVING WITH SICKLE CELL DISEASE
IN THE UNITED STATES EVERYWHERE.
SO WITH THAT, AGAIN, ON BEHALF
OF MYSELF, FROM THE NATIONAL
ALLIANCE OF SICKLE CELL CENTERS
AND SCAFIN OUR OUR SICKLE CELL
PROVIDER NETWORK, ALL OF OUR
SPEAKERS TODAY, THANK YOU SO
MUCH FOR YOUR ATTENDANCE AND WE
WILL TURN IT BACK OVER TO THE
NHLBI.
>> THANK YOU SO MUCH, WOW.
WHAT A SESSION.
EXCELLENT.
THANKS JULIE AND JJ AND
EVERYBODY ELSE ON THE PANEL.
SO I THINK I UNDERSTAND
DR. STROUSE, IS THAT HE WILL
INTRODUCE THE NEXT 4 PEEKERS,
ALSO, SO, IF HE'S STILL UP FOR
IT, PLEASE LET ME KNOW.
>> I AM, I AM NOT ALLOWED TO
PULL UP MY SLIDES?
I CAN DO IT IF--OH, I GUESS HAVE
YOU IT THERE.
GREAT.
>> IT IMIFS ME GREAT PLEASURE TO
INTRODUCE OUR NEXT SPEAKER,
DR. MODUPE IDOWU, DISCUSSING
MODIFYING SICKLE CELL THERAPIES
BASED ON SYMPTOMATOLOGY.
WITH THAT, LET'S HAVE YOU START
SO WE STAY ON TIME.
>> THANK YOU VERY MUCH FOR THE
INTRODUCTION, I WOULD LIKE TO
SHARE MY SLIDE.
IS SOMEONE GOING TO HELP SHARE
MY SLIDE.
>> I REALLY THANK THE ORGANIZER
OF THIS CONFERENCE FOR THE
INVITATION TO PRESENT TODAY.
YOU CAN GO ON TO THE NEXT SLIDE.
THESE ARE MY DISCLOSURES.
HEMOGLOBIN S IS IN THE SIXTH
QUADRANT OF THE BETA DPLOABIN
GENE REPLACES [INDISCERNIBLE]
RESIDUE BY UNVEILING RESIDUE,
FOR DEOX GENERATEDDATION,
[INDISCERNIBLE] FORM CAUSING
CELL PSYCHE LINING AND DAMAGE TO
THE MEMBRANE.
SOME CELLS [INDISCERNIBLE]
LEADING TO OCLOWGZ, THE
PATHOPHYSIOLOGY OF SICKLE CELL
DISEASE ASK COMPLEX AND IT
INVOLVES EREGHTROCYTE PSYCHE
LINE, [INDISCERNIBLE] EVENTS
EVENTS
HEMOLSIS, AND YOU CAN GO TO THE
NEXT SLIDE.
IT'S MANY COMPLIKAIGHTZS OF
SICKLE CELL DISEASE CAN BE
DIVIDE INTO 2 OVERLAPPING
SUBTYPES, EACH DRIVEN BY
DISTINCT MECHANISMS, LEG
ULCERATION, SUDDEN DEATH, STROKE
ARE ASSOCIATED WITH LOW STEADY
STATE HEMOGLOBIN LEVELS AND AN
INCREASED RATE OF INTRA RASCULAR
HEMOLYSIS, THAT'S SHOWN ON THE
LEFT HERE.
THIS VASE O-O'CLUESIVE RESULT
FROM [INDISCERNIBLE].
THIS IS MEDICATED BY NITRIC
OXIDE AS CAN YOU SEE IN THE
FIGURE THERE, BY FREE PLASMA
HEMOGLOBIN AND REACTIVE SPECIES
AS WELL LOS ANGELES METABOLISM
BY PLASMA AGENICS, THIS PROCESS
OF HEME OLSIS, THE,A CUTE
SYNDROME, IF VASCULAR NECKROSIS
OF BONES AND VASCULAR RETINAL
LOCATION TIN OPEN MEETINGATHY,
AND STEADY STATE LEUKOCYTE AND
HIGH HEMOGLOB LYNN RESULTS.
THIS IS POST CAPILLARY VENUES BY
EREGHT
EREEGHT ROUGH ATOM VIETS AS
SHOWN HERE AND YOU CAN GO ON TO
THE NEXT SLIDE.
YOU CAN SEE ON THIS SLIDE, THE
ACUTE AND CHRONIC COMPLICATIONS
OF SICKLE CELL.
THE ACUTE COMPLICATIONS ARE
THOSE THAT WOULD BRING AN
INDIVIDUAL TO IMMEDIATE MEDICAL
ATTENTION AND I WILL TALK ABOUT
UP TO HOW WE CAN USE THE NEW
THERAPEUTICS WITH THE OLDER 1S
TO MANAGE SOME OF THIS
COMPLICATIONS AS OUTLINES HERE.
YOU CAN GO ON TO THE NEXT.
ON THIS PICTURE HERE, YOU CAN
SEE THE AGE DISTRIBUTION OF
CHRONIC SICKLE CELL DISEASES
COMPLICATIONS, THOSE THAT ARE
YOUNGER THAN AGE 6, YOU CAN SEE
THAT THEY'RE MOSTLY AFFECTED BY
ACUTE SYNDROME AND THE OLDER
THEY GET, SUCH COMPLICATIONS AS
KIDNEY DISEASE, AVASCULAR
NECROSIS, INCREASE.
GO ON TO THE NEXT, PLEASE.
THESE ARE THE MULTIPLE BIOLOGIC
TARGETS IN SICKLE CELL DISEASE
AND YOU CAN SEE THAT THE 1S THAT
ARE AIMED AT THE FETAL STEM
CELLS AND GENE THERAPY.
AND AS YOU GO ON, YOU CAN SEE
THOSE THAT I HIGHLIGHTED IN
BLUE, THOSE ARE THE 1S THAT HAVE
BEEN APPROVED, OWEVER, THERE ARE
SEVERAL THERAPEUTICS THAT ARE
QUITE PROMISING THAT ARE IN
CLINICAL TRIALS AND I WILL
MENTION A COUPLE OF THEM.
YOU CAN GO ON TO THE NEXT SLIDE.
STEM CELL TRANSPLANT AND CHRONIC
TRANSFUSION HAVE BEEN USED FOR
YEARS.
IN PEDIATRIC POPULATION FOR
EXAMPLE, STEM CELL TRANSPLANTS
HAS BEEN USED AND NOW, IN ADULT
POPULATION, WE THAN WE'RE USING
IT MORE.
I WILL NOT DISCUSS THIS MUCH
FURTHER.
FOR CHRONIC RED CELL
TRANSFUSION, WE DO USE THIS IN
MOST OF THE MOST SEVERE
COMPLICATIONS OF SICKLE CELL
SUCH AS THOSE AFFECTED WITH
ACUTE CHEST SYNDROME, MULTIORGAN
FAILURE, PULMONARY HYPERTENSION,
CHRONIC HYPOXIA, THOSE AFFECTED
WITH STROKE AND OTHER SEVERE
COMPLICATIONS OF SICKLE.
>> NEXT, PLEASE.
AND WITH HYDROXY URIA, THAT WAS
APPROVED IN 1988 AND IT'S STILL
THE STANDARD THERAPY FOR SICKLE
CELL ANEMIA, FOR THOSE THAT ARE
9 MONTHS OR AS DR. WARE
MENTIONED EARLIER FOR EVEN AS
YOUNG AS 6 MONTHS OLD CHILDREN.
AND ARE DIFFERENT WAYS THAT IT
HAS EFFECT, YOU KNOW IT DOES
INCREASE NITRIC OXIDE, DECREASE
MARKERS OF ADHESION, EBD O
THELLIAL ACTIVATION AND WE KNOW
IT DEFINITELY IMPROVED MOTILITY
AND MODEL CITIZEN BIDDITY IN THE
PATIENTS.
AND IT IS SAFE.
WE DO NOT HAVE CLINICAL EVIDENT
FOR CANCER OR MULTIDEN GIS WITH
THE USE OF HYDROXY UREA.
GO ON TO THE NEXT 1 PLEASE.
AND THIS DIAGRAM JUST BASICALLY
MENTIONED, YOU KNOW THE
MECHANISMS OF ACTION OF HYDROXY
UREA, THE NEXT SLIDE, PLEASE.
SO I WILL GO THROUGH JUST FEW
CASES TO TALK ABOUT THE USE OF
OTHER THERAPEUTICS.
CASE 1 THIS IS A PATIENT WITH
SICKLE SEAL DISEASE WITH 2-3
HOSPITALIZED FOR VOC PER YEAR,
AND ACUTE CHEST SYNDROME WHO IS
INTO NATURAL PRODUCTS, NOT
WANTING TO DRY HYDROXY UREA AND
RPGHT DISEASE MODIFYING
THERAPIES JUST BY THE FACT OF
TELLING THEM PATIENT ABOUT THE
EFFECTIVENESS OF THESE
THERAPEUTICS, WELL, I WOULD
NORMALLY, PATIENTS LIKE THIS, I
WILL LET THEM KNOW, STILL ABOUT
ALL THESE THERAPEUTICS BUT IN
ADDITION TO THAT, I WILL TELL
THEM ABOUT THE NEXT SLIDE.
L-GLUTEA MINE WHICH IS MORE OF
AN NATURAL PRODUCT.
IT IS AN ORAL PREDUSKERROR FOR
NADH THAT REDUCED FORNL OF NICK
O TINA MID ADENINE DINUCLEOTIDE
AND IT RESULTS IN
DECREASEDOXIDATIVE STRESS WITHIN
THE SICKLE REBLOOD CELLS
APPROVED IN 2017 AND YOU CAN
SEE, ON THIS SLIDE, YOU KNOW
JUST THE DIAGRAM OF HOW IT
WORKS.
YOU CAN GO TO THE NEXT SLIDE.
SO L-GLUTEA MINE SHOWED 25%
REDUCTION IN THE PAIN CRISIS,
30% LOWER HOSPITAL EYATION RATE
AND REDUCED NUMBER OF EPISODES
OF ACUTE CHEST SYNDROME.
SO FOR A PATIENT LIKE THAT, WITH
HISTORY OF ACUTE CHEST SYNDROME,
INCREASED VOCs, VERY RESERVED
IN TERMS OF THERAPEUTICS BUT
MORE INTO NATURAL PROD UBTS THIS
IS A VERY GOOD THERAPY THAT 1
CAN INTRODUCE TO SUCH PATIENTS.
NEXT, PLEASE.
CASE 2, MR. S IS A 25 YEAR-OLD
HBSS WITH MAJOR DEPRESSIVE
DISORDER WHO HAS BEEN ON MTB FOR
HYDROXY UREA FOR 7 YEARS;
HOWEVER IT IS BETTER CONTROL OF
SICK CELL CELL IS IMMUNE GLOBINS
IS A CLEAR RANGE OF 7-8,
INDIRECT BILI, TYPICALLY QUITE
HIGH AT 5 AND LDH OF 450 WITH A
NORMAL LEVEL OF 195.
KRE TINS ATINE IS .5, HE MENTION
THAD HE IS EMBARRASSED ABOUT THE
YELLOWISH DISCOLORATION OF HIS
EYES AND IS EVEN MORE DEPRESSED
BECAUSE HE'S TRYING TO FIT IN,
INTO HIS PEER GROUP BECAUSE, YOU
KNOW OF HIS YELLOWISH EYES,
DISCOLORATION, THAT'S
CONTRIBUTING TO HIS EMOTIONAL
STATE.
NEXT SLIDE, PLEASE.
SO FOR THIS PATIENT, YOU KNOW, I
WOULD TYPICALLY TALK ABOUT, YOU
KNOW HOW HEME HEMOLYSS CAN HELP, BUT
PATIENT IS TILL PRONE TO
MULTIORGAN DISEASE AND
DYSFUNCTION AND FAILURE BECAUSE
IT'S STILL CONSIDERED A HIGH
HEMOALIZER AT STEADY STATE SO AN
VOXELOTOR WOULD BE A GOOD DRUG
FOR THIS PATIENT, IT BINDS TO
THE GLOBIN CHANGE OF HEMOGLOBIN
RESULT NOTHING AN ALOESTERRIC
MODIFICATION OF WHICH INCREASES
THE HEMOGLOBIN, AND DECREASES
POLYMERIZATION OF TEND ENSEL OF
THE DEOXY-HBS, AND IMPROVING
SICKLE CELL RED CELL SURVIVAL,
INCREASE WITH HB AND DECREASE
RETICULOCYTE, AND TYPICALLY
THERE'S A DECREASE IN BILIRUBIN.
YOU CAN GO TO THE NEXT.
AND THEN HOPE, WHICH MANY OF YOU
ARE FAMILIAR WITH, YOU CAN SEE
274 PARTICIPANTS RANDOMIZED TO
900-MILLIGRAM AND 1500-MILLIGRAM
OF VOXELOTOR DOSE, AND
APPROXIMATELY 2/3RDS OF
RECEIVING HYDROXY UREA AND
VOXELOTOR SIGNIFICANTLY
INCREASED HEMODPLOABIN LEVELS
AND REDUCED HEMOLOGY SIS.
NEXT, THIS IS A REAL PERSON'S
SMEAR ON DAY 1 AND DAY 20.
YOU CAN APPRECIATE THAT THIS DAY
1 SLIDE BEFORE THE FIRST DOSE OF
VOXOLETOR, HAD MANY SICKLE RED
CELLS, HOWEVER, DAY 21, REALLY
YOU COULD SEE VERY FEW RED CELLS
AND THE PATIENT WAS LESS ANEMIC
ON DAY 21.
NEXT.
AND SAME PERSON'S LABS, ON DAY
1, HEMODPLOABIN FINE .4, DAY
2112.1.
ARE YOU COULD SEE THE TOTAL
BILIRUBIN GOING FROM 4.7 TO
NORMAL RANGE, 0.9, LDH FROM 300
TO 132.
AND THIS PATIENT FELT MUCH
BETTER, DOING BETTER IN TERMS OF
JUST HIMSELF OVERALL, EMOTIONAL
AND EVERYTHING ELSE.
AND THIS JUST SHOWED US THAT
MANY OF THESE PATIENTS STILL
SUSTAINED THEIR HEMOGLOBIN
RESPONSE EVEN FOR 72 WEEKS.
1 GRAM INCREASE WAS SUSTAINED BY
88.9% OF THE PATIENT COMPARED TO
25% OF THE PLACEBO GROUP.
AND 58.9% OF THE PATIENTS
SUSTAINED DECREASE OF THE GRAM,
COMPARED TO 3.3% OF THE PLACEBO
GROUP AND 20% OF THOSE PATIENT
ON BOTH VOXOLOTOR OBTAINED A
HEMOGLOBIN OF 3-GRAM HIGHER
COMPARED TO NONE OF THOSE ON
PLACEBO.
NEXT, PLEASE.
AND INCIDENTS OF VOIRKS Cs WAS
ALSO NOTED TO THE LOWEST IN
PATIENTS WITH HIGHEST HEMOGLOBIN
LEVELS FOR THOSE ON VOXOLOTER,
NEXT, PLEASE, BACK TO CASE 2,
MR. S, THE 25 YEAR-OLD THAT HAD
MAJOR DEPRESSIVE DISORDER WHO
WAS ON MTD FOR 7 YEARS, AND HE
IMPRIEWED TO 10, HEME OLDER
PEOPLE SIS PANEL IMPROVED
SIGNIFICANTLY AND EMOTIONAL
STATUS ALSO IMPROVED AND HE ALSO
NOTED IMPROVEMENT IN THE NATURE
AND DURATION OF HIS PAIN
EPISODES.
WE PUBLISHED IN THE NEW ENGLAND
JOURNAL LARN LAND JOURNAL OF
MEDICINE, PATIENTS OF VOXELOTOR
BENEFIT, FEWER PATIENTS REPORTED
THAT THEINATE IRB AND DURATION
OF THEIR PAIN IMPROVED WITH THE
VOXELOTOR THERAPY.
NEXT, PLEASE.
GBT601 IS A NEXT GENERATION HBS
POLYMERIZATION INHIBITOR THAT IS
IN CLINICAL TRIALS CURRENTLY.
NEXT.
PLEASE.
CASE 3, MS. K, PLS K, THAT'S A
TYPEY, IS A 24 YEAR-OLD MAN WITH
HBSS, WHO HAS 3-4
HOSPITALIZATIONS ARE VOC, HE HAS
CHRONIC BONE PRAIN, FREQUENT
PRIMATESSA PIMP, AND THAT IS
UNRESPONSIVE TO UROLOGY AND
OTHER INTERVENTIONS HE IS ON THE
HYDROXYEUREA AT MDD AND HE IS
INTERESTED IN ANY OTHER SICKLE
CELL THERAPY THAT WILL HELP HIM
AND ALSO BYE-BYE VO C, INDIRECT
BILLY OF 2, KID NEUROECTODERMAL
FUNCTION NORMAL.
NEXT.
SO FOR THIS PATIENT, I WOULD
CONSIDER THE ANING IT NASTI THE
UPREGULATION EVER P-SELECTIN AND
EBD O THELLIAL CELLS AND PLATE
THES CONTRIBUTES TO THE
CELL-CELL ISHT ACTIONS THAT ARE
INVOLVED IN THE PATHOGENESIS OF
THIS OCCLUSION AND THIS PAIN
CRISIS AND THE INTERFERANCE WITH
SELECTIN SEEMED TO BE A POWERFUL
OPTION FOR THE DISEASE, THE
SELECTIVITY HAVE BEEN ELEVATE
INDEED PATIENTS WITH SICKLE CELL
DISEASE, NEXT, PLEASE--AND IN
THE LOW DOSE 44%.
COMPARED TO PLACEBO.
NEXT.
PLEASE?
SO BACK TO CASE 3, MR. K GOT
STARTED ON PRES MEAS LAB, AFTER
2 MONTHS ON THERAPY HE NOTICED
IN HIS PRIAPISM, AND HE ALSO
IMPROVED TO 1-2 TIMES PER YEAR,
FOR HOSPITALIZATION, THIS
HIGHLIGHTED THAT IF THEY'RE
READY ON ON HYDROXY UREA, THERE
ARE OTHER THERAPIES, THERE'S
MORE THERAPIES THAT WILL HELP
AND WITH VOC BECAUSE OF THE
SELECTING INHIBITION, THERE,
NEXT.
INCLACUMAB, IS A AN INHIBITOR IN
THE PHASE 3 CLINICAL TRIAL TO
EVALUATE AND IS ADMINISTERED
EVERY 12 WEEKS.
AND ALSO THERE'S ANTIE-SELECTIN
THAT IS ALSO IN CLINICAL TRIAL
AND THIS IS GIVEN AS SUBCUE
INJECTION AND IT DEMONSTRATES
LONGER HALF LIFE, THAN
PREZULAMAB AND MAYBE EVEN REDUCE
NUTRIFILL ADDITION AND, THERE
ARE ALSO AND ACTIVATORS, THIS
WAS PRESENTED IN LAST--DURING
LAST KD--SALLY WAAND WITH VERY
GOOD EFFECT AND IMPROVEMENT IN
HEMEAT O LOGIC AND HEMOLYTIC
PARAMETERS AS YOU CAN SEE ON
THIS SLIGHT, AND YOU THE SITES
DECREASED AND LDH AND BILIRUBIN
ARE DECREASED IN MAJORITY OF THE
PATIENTS.
NEXT, PLEASE.
AND THEY ALSO HAD SIMILAR
EFFECTS ON HEME OLDER PEOPLE SIS
AND PARAMETER AS SEEN ON THIS
SLIDE.
NEXT SLIDE.
PLEASE.
SO, I WILL--I TREAT PATIENTS
WITH DIFFERENT SYMPTOMS, ALL
CONDITION I WOULD OFFER
HYDROXYEUREA AS STANDARD THERAPY
AND IN ADDITION TO THAT, THESE
PATIENTS IF THEY HAVE CHRONIC
SYMPTOMS HERE, LEG ULCER,
EXTENSIVE RBC IMMUNIZATION OR
THEY HAVE A STEADY STATE IN THE
BILL BILIRUBIN OR THEY HAVE HIGH
HEME OLYSIS AND I WILL
ACCELERATE PER FELPS AS APPROVED
THERAPY IN ADDITION TO THEIR
HYDROXY UREA, AND ALSO IF THEY
HAVE HIGH HEME OLSYS, AT THE
ESTATE STATE, IF THEY HAVE
FATIGUE OR SEVERE ANEMIA AND AT
A WILL ALSO CONSIDER OTHER
AFFINITY MEDICATIONS, IF THEY'RE
NOT IMPROVED, [INDISCERNIBLE] OR
ANOTHER OR THEY'RE
[INDISCERNIBLE] INTOLERANT, I
WILL ACTUALLY CONSIDER OFFERING
THEM AND TELLING THEM ABOUT
CLINICAL TRIAL DRUGS BECAUSE IN
MY OWN EXPERIENCE WITH PATIENTS
ARE HAVE BEEN TOLD OR INSTRUCTED
ABOUT THIS CLINICAL TRIAL
MEDICATIONS AND THEY'RE ABLE TO
TRY THIS EARLY, SOMETIMES THEY
GAIN BENEFIT EARLIER AND THEY'RE
ABLE TO EVEN REQUEST THAT AS
SOON AS THIS THERAPY GETS
APPROVED, THEY WANT TO BE ON
THESE THERAPIES.
SO I WILL HELP OUT SUCH
PATIENTS, PK ACTIVATORS SUCH AS
[INDISCERNIBLE],
META[INDISCERNIBLE].
AND EVEN, YOU KNOW THE SECOND
GENERATION, YOU KNOW DRUGs
SUCH AS GBT 601.
SO CHRONIC SYNDROME PATIENTS OR
ANY PATIENT THAT IS NOT
RESPONSIVE TO UROLOGIC
INTERVENTIONS, I WILL RECOMMEND
TO THAT PATIENT TO CONSIDER
CRIZANLIZUMAB AND IF THEY ALSO
HAVE, IF A PATIENT HAS PROTEIN
UREA MAY ALSO CONSIDER CRISWR,
ANLIZUMAB, FOR PATIENTS WITH THE
SYNDROME, L-GLUTEA MINE IS ALSO
AN OPTION FOR THE PATIENT SO I
WILL TELL THEM ABOUT THIS
OPTION, FREQUENT VOC INTOLERANT
TO OR NOT INTERESTED IN
CRIZANLIZUMAB WILL CONSIDER
OTHER CLINICAL TRIAL THERAPY,
P-SELECTIN AND E-SELECTIN
IBT--INTEGRATE HIB THORS
IDENTITY ARES, AND OTHER YOU
KNOW E-SELECTIN DRUGS I JUST
TALKED ABOUT.
SO IN CONCLUSION, SICKLE CELL
DISEASE AND A DISABLES CONDITION
THAT AFFECTS MULTIPLE ORGAN
SYSTEMS.
SCD IS A SINGLE GENE DISORDER
WITH A COMPLEX PHENOTYPIC
EXPRESSION.
TREATMENT FOR SCD PATIENTS
SHOULD BE INDIVIDUALIZED.
NOVEL SCD MODIFYING THERAPIES
ARE NOW APPROVED FOR USE IN SCD
POPULATION AND SOME ARE
CURRENTLY IN CLINICAL TRIALS
WITH ENCOURAGING RESULTS.
EACH OF THE FDA APPROVED
PHARMACEUTICAL THERAPIES FOR
SICKLE SEAL DISEASE CAN BE
DESCRIBED AS COMBINATION THERAPY
WITH HYDROXY UREA AND OTHER
THERAPIES WHILE A SINGLE AGENT
IF THE PATIENT IS NOT TOLERANT
TO HYDROXEUREA.
THANK YOU VERY MUCH FOR YOUR
ATTENTION.
>> THANK YOU FOR YOUR EXCELLENT
PRESENTATION.
I THINK THE NEXT TALK IS
DR. COSTA.
>> HELLO.
>> I WILL SHARE MY SCREEN.
>> YES, IN THE MEAN TIME, YES,
THERE ARE SOME COMMENTS IN THE
CHAT FOR THE PREVIOUS TALK SO
PLEASE TRY TO RESPOND TO THOSE.
SORRY DR. COSTA PLEASE GO AHEAD.
SPEAKING ABOUT HEMATOPOIETIC
STEM CELL TRANSPLANTATION
REVERSES WHITE MATTER INJURY IN
SICKLE DISEASE DISEASE PATIENTS.
>> HELLO, I WOULD LIKE TO THANK
THE ORGANIZING COMMITTEE FOR
CUED COORDINATING THE EERVET AND
THE INVITATION, I AM A IN THE
BONE MARROW TRANSPLANT UNIT AT
THE RIBEIRAO PRETO MEDICAL
SCHOOL UNIVERSITY OF SAO P A
ULO, BRAZIL.
I HAVE NO CONFLICTS OF INTEREST.
OUR SERVICE HAS 53 LEE IDENTIFY
SIBLINGS IN THE STEM CELL
TRANSPLANT FOR DISEASE TRUSTEES
2000LY-2021, SURVIVAL WAS AROUND
5%, IT CONSISTED OF REGIMEN IN
ALL PATIENTS ACCEPT THOSE THAT
REDUCED IT IN CONDITIONING
REGIMEN IS FR USE OF HGT WAS THE
MOST USED REGIMEN IN DOSE AND
CHILDREN.
DURING MY PRESENTATION, I WILL
SHOW A DECISION IMAGING TO
[INDISCERNIBLE] INVOLVING 28
PATIENTS AND A CASE REPORT.
BRAIN INJURY SICKLE CELL DISEASE
COMPRICES OF A WIDE SPECTRUM OF
NEUROLOGICAL DAMAGE.
ALLO HSCT IS THE ONLY BROADLY
AVAILABLE CURATIVE TREATMENT FOR
SCD, WITH A 5 YEAR SURVIVAL FOR
TRANSPLANTATION.
TRANSPLANT CAN REDUCE
VELOCITIES, STOP PROGRESSION OF
VASCUE LOPATHY AND HELP WITH
STROKES.
DTI IS A MAGNETIC IMAGING
RESMANS NECKNIQUE OF WATER
MOLECULES IN THE CELL VALID AND
RELIABLE ENVIRONMENT, THIS
MOTION IS A RANDOM MOTION OF
PARTICLES CESS PEND IN A FLOAT
RESULTING FROM THEIR COLLISION.
WE CAN SEE IN THE FIGURE ON THE
LEFT, A FREE WATER WITH
ISOTROPIC, OUR OWN RESTRICTED
AFFUSION AND ON THE RIGHT, A
BUNDLE WITH THE TROPIC
RESTRICTED DIFFUSION.
DEPISHT IMAGING IS USED IN
DIFFERENT SITUATIONS SUCH AS TO
THE FACT ACUTE CEREBRAL
ISCHEMIA, AND VASE O GENIC AND
WHITE MATTER CONNECTIVITY.
IT IS A RAPID NONINVASIVE AND
NONCONTRAST METHOD THAT ENABLING
DETECTION OF WHITE MATTER
LESIONS NOT DETECT BIDE
CONVENTIONAL MAGNETIC RESONANCE
IMAGING.
MRI.
PREVIOUS STUDIES USING DTI
METHOD HAVE DETECTED WHITE
MATTER DAMAGE IN SCD PATIENTS
WITHOUT NEUROLOGICAL
MANIFESTATIONS OR ABNORMAL
IMAGING WHEN COMPARED TO
CONTROLS.
>> WE EVALUATED 28 PATIENT WHO
IS RECEIVED AN ALLO
TRANSPLANTATION, HL-IDENTICAL
TRANSPLANT, OVERT STROKE IN 11
PATIENTS, ABNORMAL TCD, VELOCITY
IN 7 PATIENTS AND OTHERS IN 10
PATIENTS.
DTI ACQUISITION WAS PERFORMED
BEFORE AND AFTER TRANSPLANT.
AND COMPARED TO THE DATA WITH 26
HEALTHY CONTROLS, MATCHED BY AGE
AND GENDER.
FRACTIONAL ANISOTROPY FA IS MOST
WIDELY USED DTI METRIC AND
REFLECTS HOW DIRECTIONAL
RESTRICTION OF WATER DIFFUSION
OCCURS ALONG AXONS.
WE CAN OBSERVE IN THE FIGURE,
THE EVALUATION OF DIFFUSION
SCALES ON TD LEFT IS THE
FRACTION ON THE MAP, IN THE
MIDDLE WAS IN THE MIDDLE BRAIN
MASSES WERE GENERATED AND EACH
COLOR REP AREY SENTS A CORTICALE
AREA.
AND ON THE WHITE ISSUES THE
WHITE MATTER MASK WAS ADAPT
OFFICE OF DIVERSITY THE
[INDISCERNIBLE] MAP.
THERE ARE OTHER DTI METRICS LIKE
MEAN DIFFUSIVITY THAT CAPTURES
THE AVERAGE DIFFUSION RATE IN
ALL DIRECTIONS.
ACKIAL DIFFUSIVITY WHICH
ENCOMPALSZS INFORMATION ON THE
PARALLEL MOVEMENT OF ACONNAL
FIBERS AND IS ASSOCIATED WITH
AXONAL INJURY.
RADIAL DIFFUSIVITY REFLECTING
PERP END DICKULAR DIFFUSION AND
IS ASSOCIATED WITH
DEMILENNATION, AND WHEN WE HAVE
WHITED MATTER LESIONS LIKE
EDEMA, DISCIPLINARY MILEINATION,
GLUE MARIOUSOSEIS AND THERE IS A
REDUCTION IN THIS AND INCREASED
[INDISCERNIBLE].
DTI ALSO DEMONSTRATES BRAIN
CONNECTION THROUGH GRAPH
THEORIES, GLOBALENTIOUS
FICIENCYS CLUSTERING CO
EFFICIENTS AND PATH LENGTH
MEASURE THE NETWORK'S ABILITY TO
EXCHANGE PARALLEL INFORMATION
WITH ALL BRAIN AREAS, CONNECT
IVITY INTEGRATION AROUND
INDIVIDUAL NODES.
HIGHER VALUES OF GE REFLECT
BETTER INFORMATION TRANSITS AND
BRAIN FUNCTION.
WE USE IT FOR RESULTS.
BONE MARROW WAS USED AS A SOURCE
OF HSC, IN 27 PATIENTS AND
PERIPHERAL BLOOD IN 1 PATIENT,
ALL FACIENTS WE CEIVED MILE
ABRAITIVE CONDITIONING REGIMEN
AND ALL PATIENTS FULLY GRAFTED
AFTER TRANSPLANT.
THIRTEEN PATIENTS HAD HEMOGLOBIN
S LEVELS LOWER THAN 30% BEFORE
STARTING THE CONDITIONING
REGIMEN.
ALL PATIENTS LOWER THAN 50% AT
TIME OF POST TRANSPLANTED DTI
EVALUATION, ACCEPT FOR 1 PATIENT
THAT DEVELOPED SECONDARY GRAPHED
FAILURE.
THREE PATIENTS HAD NEUROLOGICAL
TOXICITY ASSOCIATED WITH
CYCLOSPORIN WHICH WAS COMPLETELY
REVERSED AFTER THIS
CONCONTINUATION OF THE
TRANSPLANTATION, AT THE MOMENT
OF FOLLOW UP, 15 PATIENTS WERE
UNDERIMMUNOSUPPRESSION AND MEAN
LEVELS OF HB WERE HIGHER THAN
BEFORE TRANSPLANT.
ROBBER DTI EVALUATION WAS
PERFORMED BEFORE AND AT THE
MEETING OF 17 MONTHS AFTER
TRANSPLANT, MOST TRANSPLANTED
DTI OCCURRED AT LEAST 6 MONTHS
AFTER THE LESS BLOOD TRANSFUSION
IN ALL PATIENTS AND NONE OF THE
PATIENT PRESENT THE NEW STROKES
AFTER TRANSPLANT BUT ARE SILENT
ARE OVER.
FRACTIONAL AND THE RESULT OF
INCREASE, THE MEAN RATIO IS
MAXIMUM REDUCE IT AND GLOBAL
EFFICIENCY IMPROVED.
THE REVERSIBLE OF CHANGE AFTER
TRANSPLANT SUGGESTS AN
INCOMPLETE TISSUE IPT GREATER
PAIRMENT.
IMPROVED MEASUREMENTS REFLECT
SOME DEGREE OF MILEIN REPAIR,
[INDISCERNIBLE].
SICKLE CELL PATIENT HAD A LOWER
[INDISCERNIBLE] BEFORE
TRANSPLANT COMPARED TO HEALTH
CONTROLS, AFTER TRANSPLANT IT
WAS INCREASE AND WAS NOT
DIFFERENT FROM HEALTH CONTROLS.
GLOBAL EFFICIENCY INCREASED
AFTER THE PROCEDURE,
DEMONSTRATING A POTENTIAL
IMPROVEMENT OF BRAIN
STRUBLGHTURE CONNECTIVITY, WHICH
CAN BE ASSOCIATED WITH BETTER
NEUROLOGICAL
OUTCOMES--NEUROPSYCHOLOGICAL
OUTCOMES.
WE WILL INCORPORATE THIS IN
FUTURE STUDIES.
WE CONCLUDE THAD WE CAN REVERSE
STRUCTURAL BRAIN TISSUE DAMAGE
IN SCD PATIENTS BUT SPECIFIC
MECHANISMS OF IMPROVEMENT AND
CONTRIBUTING FACTORS SHOULD BE
BETTER INVESTIGATED BY FUTURE
STUDIES.
LIKE INCREASE HBS, AND REDUCED
HBS LEVELS AND ATTENUATE
ENDOTHELIAL DAMAGE.
NOW, I'M GOING TO PRESENT THE
CLINICAL CASE OF A PATIENT WHO
WAS NOT INCLUDED IN THE PREVIOUS
STUDY DUE TO EXTENSIVE
INVOLVEMENT OF CENTRAL NERVOUS
SYSTEM BEFORE TRANSPLANT.
IT IS AN 11 YEAR-OLD BOY, WITH
SICKLE CELL ANEMIA, HE HAD 3
ESCHEMIC STROKES WITH LEVEL
HEMIPARISSIES BEFORE THE
TRANSPLANT.
HE RECEIVED AN HLI IDENTICAL
SIBLING TRANSPLANT, THE DONOR
WAS A 12 YEAR-OLD BY WITH SICKLE
CELL TRAIT.
THE CO CONDITIONING RENAL CANCER
MEN CONSISTED OF FLUBU, AND ATG,
THE SOURCE OF THE STEM CELL WAS
BONE MARROW.
THE GVHD CONSISTED OF
METHOTREKSATE, CYCLOSPORIN AND
SEBS QUENT SIROLIMUS, AND AFTER
TRANSPLANT HE HAD MIXED CHIMERA
AND SICKLE CELL TRAIT.
HERE IS THE PRETRANSPLANT, MRI
WITH EXTENSE IEVER LESIONS
MAINLY IN THE RIGHT HEMEIS FEAR.
HE HAD MARKED STENOSIS OF THE
ARTERY WITH COLLATERAL
CIRCULATION WITH [INDISCERNIBLE]
PATTERN.
ONE YEAR AFTER TRANSPLANTATION,
HE HAD A MARKED REDUCTION OF
STENOSIS AND COLLATERAL THROUGH
COLLECTION.
WE PERFORMED DTI ASSESSMENT AND
IDENTIFY AN INCREASE IN
FRACTIONAL [INDISCERNIBLE] IN
THE LEFT HEMEIS FEAR AND NO
DIFFERENCE IN THE RIGHT HEMEIS
SPHERE, PROBABLY BECAUSE THERE
WAS NO VIABLE BRAIN TISSUE IN
THAT, IN THE RIGHT HEMISPHERE.
EIGHTEEN MONTHS AFTER
TRANSPLANT, THE PATIENT WAS NOT
USING IMMUNOSUPPRESSION AND HAD
NO GVHD.
TWO YEARS AFTER THE PROCEDURE,
THERE WAS NO EVIDENCE OF SICKLE
CELL ANEMIA, THE PATIENT HAD
IMPROVEMENT OF STRENGTH AND
MOTOR COORDINATION AND WAS
ATTENDING REGULAR SCHOOL.
IN CONCLUSION, IMPROVEMENTS IN
DTI MEASURES OF BRAIN TISSUE AND
IN VASCUE LOPATHY PATIENTS
DEMONSTRATE THAT ENTERTAIN
INJURY MAY BE REVERSIBLE AFTER
TRANSPLANTATION, IN THIS WAY,
EFFORTS ARE WARRANTED TO REFER
PATIENTS TO HSCT EARLY IN
DISEASE COURSE.
I WOULD--
>> THANK YOU SO MUCH, THERE ARE
A COUPLE OF QUESTIONS FOR THE
CHAT, I WOULD LOOK AT THOSE AND
RESPOND.
STEPHANIE WHAT'S THE EXPERIENCE
OF DTI IN OTHER HOGGER ANS SUCH
AS BONE MARROW?
>> WE DIDN'T PERFORM THIS UNTIL
NOW BUT IT'S POSSIBLE TO DISCUSS
IT FOR THE FUTURE.
ROOK, I DON'T SEE ANY OTHER
QUESTIONS AT THE MOMENT SO THANK
YOU AGAIN FOR YOUR PRESENTATION
AND IF THERE ARE ANY COMMENTS IN
THE CHAT, PLEASE RESPOND TO
THEM.
THANK YOU.
>> OKAY, SO WE MOVE NEXT TO CURE
SICKLE SET
METADALLASCOWBOYS.COMA CATALOG
AND DR. JERREN STRATFORD, WILL
BE PRESENTING INSTEADY OF
DR. HELEN PAN.
DR. STRATFORD?
>> HELLO, CAN YOU SEE MY SLIDES?
>> YES WE CAN,.
>> YES, UNFORTALATELY DR. PAN IS
UNDER THE WEATHER AND WAS NOT
ABLE TO PRESENT SO I AM GOING TO
TAKE HER PLACE AND TALK ABOUT
SOME OF THE WORK THAT WE'VE
ABOUT KNOW DOING WITH THE CURE
SICKLE CELL METADATA CATALOG.
SO THE CATALOG IS A TOOL TO MAKE
DETAILSA FAIR, SO IT'S IT STANDS
FOR ACCESSIBLE, INTEROPERABLE
AND MAKING IT MORE, AND WE'RE
FOCUSING ON MAKING THE DATA MORE
FINDABLE.
SO SICKLE CELL RESEARCH HAS BEEN
ONGOING FOR SOMETIME AND SOME OF
THESE STUDIES HAVE IMMENSE
RESOURCES THAT WERE INVESTED
INTO THEM AND CONTINUE TO ADD
VALUE TO RESEARCH COMMUNITY AND
SO BEING ABLE TO IDENTIFY THE
STUDIES THAT ARE THAT CONTAIN
INFORMATION THAT MAY BE
APPLICABLE TO YOUR SCIENTIFIC
QUESTION, IS A GREAT WAY FOR US
TO REUSE SOME OF THE INVESTMENT
THAT HAS GONE INTO THESE STUDIES
IN THE PAST AS WELL AS COMBINE
THEM WITH SOME OF THE OTHER
STUDIES TO ASK ADDITIONAL
SCIENTIFIC QUESTIONS.
AND SO TO DO THIS, WE CREATEDDA
I PUBLIC TOOL WHICH IS A PEB
PORTAL WHERE USERS CAN COME, AND
IDENTIFY DATA SETS THAT MAY BE
APPLICABLE TO THEIR SCIENTIFIC
QUESTIONS.
SO TO DATE, WE'VE ALREADY
INCLUDED 20 STUDIES INTO THE
METADATA CATALOG, A NUMBER OF
THESE HAVE COME FROM EITHER
BIOLINK OR BIODATA CATALYST, WE
HAVE STUDIES FROM TOP MED AS
WELL AS 8 OTHER STUDIES, WHICH
WE WILL TALK ABOUT IN A MINUTE.
AND THE METHOD THAT WE HAVE GONE
THROUGH, TO MAKE THESE DATA MORE
FINDABLE IS BY CURATING THE
STUDIES INTO A SET OF DATA
ELEMENTS, SO WE HAVE LOOKED AT
THE VARIABLES THAT WERE
COLLECTED, AND ORGANIZED THEM IN
A WAY THAT THERE IS AN OVERLYING
CONCEPT, SUBCONCEPT AND THE DATA
ELEMENT THEMSELVES, AND HAVE
CURATED THE VARIABLES ACROSS
THESE STUDIES INTO THERE
HIERARCHY.
IN ADDITION WE'VE IDENTIFIED
STUDIES THAT USED PATIENT
REPORTED OUTCOMES, AND
IDENTIFIED WHICH 1S DID THIS AS
THAT IS A STANDARDIZED METRIC
AND EACH OF THESE STUDIES VALID
USED THE SAME RUBRIC AS THEY
COLLECTED THIS INFORMATION.
AND SO, BY HAVING THIS, YOU KNOW
KIND OF FRAMEWORK, WE'RE ABLE TO
BROWSE THESE STUDIES WITHOUT
ACTUALLY NEEDING TO KNOW MUCH
ABOUT WHAT THE ORIGINAL STUDY
INTENT WAS IN ORDER TO DETERMINE
WHETHER THAT DATA IS VALUABLE
FOR YOUR PARTICULAR QUESTION.
SO THE METADATA CATALOG IS
INDEXED SO THE WAY WE CAN GO
ABOUT THIS IS BY BROWSING THIS
CURATION AT BOTH THE STUDY LEVEL
AND AT THE VARIABLE LEVEL, AND
WE CAN THEN START TO COMBINE
INFORMATION ACROSS THE VARIOUS
ELEMENTS IN ORDER TO IDENTIFY
THE STUDIES AND THE VARIABLES
THAT ARE APPLICABLE TO OUR
QUESTIONS.
WE CAN BROWSE THEM IN A
HIERARCHY, WE CAN ALSO DO KEY
WORD SEARCHES OR IN COMBINATION
SEARCHES WHICH I WILL SHOW
NUCLEOTIDES THE NEXT FEW SLIDES.
SO THIS IS A SCREEN SHOT OF THE
WEB PORTAL.
AND THIS IS KIND OF THE LANDING
PAGE.
SO THERE'S A NUMBER OF DIFFERENT
RESOURCES AND DIRECTIONS CAN YOU
GO.
ONE OF THE FIRST THINGS THAT
PEEP -
-PEOPLE MAY WANT TO
UNDERSTAND IS THAT THE STUDIES
THAT HAVE BEEN INGESTED SO IF
YOU CLICK ON OUR BROWSE STUDIES
IT WILL TAKE YOU TO A PAGE THAT
LOOKS LIKE THIS.
FROM THISPARAGE, YOU CAN--FROM
THIS PAGE, YOU CAN IDENTIFY THE
STUDIES.
AS WELL AS VICTORIES THAT ARE
INVOLVE WIDE CREATING IT AND MAY
HAVE INFORMATION FOR YOU AS WELL
AS THE DATA LOCATIONS.
SO THERE ARE A NUMBER OF STUDIES
WHICH ARE AVAILABLE IN PUBLIC
LOCATIONS.
AND REPOSITORIES THAT YOU CAN
PULL, HOWEVER THERE ARE SOME
STUDIES THAT ARE ONGOING AND MAY
RESIDE WITH THE INVESTIGATORS OR
THEIR INTUITY.
SO BEING ABLE TO IDENTIFY WHERE
THOSE STUDIES ARE AND HOW YOU
CAN GET ACCESS TO THAT DATA IS
ALSO HIGHLY VALUABLE.
IN ADDITION, WE ALSO CURATE THE
NUMBER OF PARTICIPANTS WHICH
WERE IN THE STUDIES SO CAN YOU
UNDERSTAND THE SCOPE AND THE
SIZE OF THE STUDY, NOW FOR
INSTANCE WITH THIS PLACE HERE,
THIS DISPLACE WAS INFORMATION WE
PULLED FROM CLINICAL TRIALS .GOV
VERY EARLY IN THE PROCESS AND WE
KNOW THERE ARE MORE THAN 16
SUBJECTS SO WE'RE CONSTANTLY
LOOKING TO GET ADDITIONAL
RESOURCES TO BE ABLE TO UPDATE
THIS INFORMATION AND MAKE IT THE
MOST UP TO DATE INFORMATION SO
THAT PEOPLE CAN UNDERSTAND THE
SIZE OF THE STUDY AND HOW MANY
PARTICIPANTS, POTENTIALLY HAVE
THAT INFORMATION AND SO WE'RE
ALWAYS LOOKING FOR COLLABORATORS
WHO MAY BE ABLE TO PROVIDE US
WITH ADDITIONAL INFORMATION
WHICH WAS BEYOND THE KIND OF
PUBLIC DATA THAT WE ORIGINALLY
WERE ABLE TO GATHER.
SO WHEN WE LOOK AT THE STUDIES
WE CAN CLICK ON AN INDIVIDUAL
STUDY AND WE CAN GAIN MORE
INFORMATION ABOUT IT SO THIS IS
INFORMATION AT THE STUDY LEVEL.
THE METADATA FROM THE STUDY
LEVEL THAT WE HAVE CURATED INTO
A STANDARDIZED FORMAT SO WE CAN
GET INFORMATION ABOUT THE STUDY,
WHEN IT WAS CONDUCTED, WHAT TYPE
OF STUDY IT WAS, LINKS TO ANY
SORT OF OTHER DATABASES OR
WEBSITES THAT CONTAIN
INFORMATION ABOUT IT, AS WELL AS
BEING ABLE TO SEE THE RESEARCH
THAT HAS COME FROM IT AND
PUBLICATIONS, INFORMATION ABOUT
THE STUDY POPULATION, ALL
SUBJECT, OR SORRY, STUDY LEVEL
METADATA THAT WE WERE ABLE TO
GATHER ABOUT THE STUDY.
BUT IN ADDITION, THERE'S ALSO
VARIABLE LEVEL METADAT AND
THAT'S CONTAINED HERE IN THE
LAST 2 TABS HERE IN YELLOW AND
THE DAILY BASIS AT ELEMENTS AND
THE PRO MEASURES.
SO FOR INSTANCE IF YOU CLICK ON
THE DATA ELEMENTS TAB, CAN YOU
SEE A NUMBER OF THE CONCEPTS
WHICH ARE KIND OF THE HIGH LEVEL
OF OUR HIERARCHY AND THE NUMBER
OF VARIABLES THAT WERE COLLECTED
WITHIN THAT CONCEPT AND IF YOU
WERE TO CLIEK ON THIS BAR, IT
WOULD EXPAND AND YOU WOULD BE
ABLE TO SEE ALL OF THE
SUBCONCEPTS AND YOU CAN CLICK ON
THOSE FURTHER TO GET THE
ELEMENTS THAT RESIDE IF THERE SO
CAN YOU REALLY DIG DOWN INTO A
PARTICULAR STUDY AND SEE WHAT
TYPE OF DATA WAS COLLECTED.
NOW SIMILAR, CAN YOU ALSO DO
THAT FOR SOME OF THE PATIENT
REPORTED OUTCOMES SO THAT OUR
PRO MEASURES, SO IN THIS CASE,
THERE WAS A NUMBER OF PRO
MEASURE VARIABLES THAT DEALT
WITH MENTAL HEALTH AND
NEURODEVELOPMENT AND SO IF THIS
IS SOMETHING THAT IS INTEREST TO
YOUR STUDY, THAT MIGHT BE 1 WAY
CAN YOU GO ABOUT IT IS TO COME
TO THE STUDY PAGE AND LOOK AT
THE PARTICULAR PRO MEASURES.
NOW, HOWEVER, THERE ARE 20
STUDIES AND BEING ABLE TO LOOK
IN EACH 1 INDIVIDUALLY, HAS
VALUE BUT IF YOU WANTED TO LOOK
AT ALL OF THEM, THAT MIGHT TAKE
A LITTLE BIT OF TIME AND SO
THERE ARE OTHER BROWSING
FEATURES IN THE CATALOG THAT
MAKE IT EASY TO LOOK ACROSS ALL
OF THE STUDIES.
SO FOR INSTANCE, WHEN WE LOOK
HERE AT THE BROWSE BY DATA
ELEMENT, WE CAN SEE THAT THE
HIGH LEVEL CONCEPTS WITHIN OUR
HIERARCHY OVER HERE ON THE
LEFT-HAND SIDE OF THE SCREEN AND
WE CAN CLICK ON THOSE AND EXPAND
THOSE MENUS AND WE CAN APPLY
FILTERS, SO WITHOUT APPLYING ANY
FULTERS TO THE DATA WE HAVE 20
STUDIES AND WE CAN SEE ALL OF
THOSE 20 STUDIES, BUT LET'S SAY
THAT WE'RE PARTICULARLY
INTERESTED IN SKELETAL AND JOINT
PAIN, SO IF WE WERE TO COME TO
OUR HIERARCHY ON EVERY HERE WE
CAN LOOK AT THE CLINICAL STATUS
CONCEPT, WE CAN COME DOWN TO THE
PAIN SUBCONCEPT AND WE COULD SEE
SKELETAL AND JOINT PAIN RIGHT
HERE AND WHEN WE APPLY THAT
FILTER WE NOW HAVE ONLY 8
STUDIES THAT WERE ABLE TO
COLLECT INFORMATION ON THE
SKELETAL AND JOINT PAIN.
AND SO WE NOW KNOW THE STUDIES
BUT WE ALSO MAY WANT TO DIG IN A
BIT DEEPER SO OVER HERE ON THE
RIGHT HAND SIDE OF THE SCREEN,
WE HAVE THE SHOW VARIABLES, SO
WHEN WE COMPLIK ON SHOW
VARIABLES, WE CAN HAVE A POP UP
THAT SHOWS US THE STUDY THAT
COLLECTED THE INFORMATION.
THE VARIABLE NAME FROM THE
STUDY, AND A DISKRIPGZ OF THE
VARIABLE THAT THEY CAPTURED.
SO HAVING THIS CURATED STRUCTURE
IS VERY VALUABLE, BECAUSE, IF I
WERE TO COME IN HERE AND JUST DO
A SEARCH FOR PAIN, I WOULD
PROBABLY GET PAIN ACROSS ALL
DIFFERENT TYPES OF DOMAINS SO I
CAN HAVE ABDOMINAL PAIN,
HEADACHES BUT I'M INTERESTED
PARTICULARLY IN SKELETAL PAIN.
ALSO FIELD FUNCTIONS WERE TO
SEARCH FOR JUST FOR SKELETAL
PAIN I WOULD MISS A LOT OF THESE
VARIABLES BECAUSE I DON'T HAVE
THESE KEY WORDS AND SOMETIMES WE
HAVE INFORMATION ABOUT PAIN AND
SO BY HAVING THESE CLUSTERED
TOGETHER WE CAN CURATE THESE
ACROSS MULTILE STUDIES WHICH
COLLECTED SIMILAR DATA AND THIS
HELPS US TO REALLY DIG DOWN AND
FIGURE OUT WHICH DATA IS
AVAILABLE FOR US IN ORDER TO
ANSWER SOME OF OUR SCIENCE
QUESTIONS.
SO THIS TABLE RIGHT HERE KIND OF
GRIEBS, WE HAVE THE STUDIES OVER
HERE ON THE LEFT-HAND SIDE, AND
WE HAVE THE--YOU KNOW OUR HIGH
LEVEL CONCEPTS IN OUR HIERARCHY
KRSES THE COLUMNS SO WHAT YOU
CAN SEE IS THAT WE DO HAVE VERY
GOOD COVERAGE ACROSS THE
CLENICAL STATUS OF PATIENTS AND
PARTICIPANTS IN THE STUDIES,
MOST OF THE STUDIES COLLECTED
IT, WE HAVE A LOT OF VARIABLES
ACROSS A LOT OF THESE DIFFERENT
DOMAINS HOWEVER WE DO NOTICE
THAT WE'RE KIND OF HAVE LOW
COVERAGE ON INFORMATION ABOUT
STUDIES THAT COLLECTED
INFORMATION ON ENVIRONMENTAL
EXPOSURES.
SO WE'RE CONSTANTLY LOOKING FOR
NEW STUDIES WHICH CAN COME IN
AND BE CURATED INTO THE METADATA
CATALOG THAT CAN HELP US BOLSTER
SOME OF THESE STUDIES AND MAKE
MORE DATA AVAILABLE ACROSS SOME
OF THESE CONCEPTS WHICH WE MAY
NOT HAVE HAD AS MUCH INFORMATION
ON FOR THE STUDIES THAT HAVE
ALREADY BEEN ADJUSTED TO THE
CATALOG.
SO THIS IS ALSO A VISUAL VIEW OF
THAT SO IF WE LOOK AT ALL OF THE
VARIABLES WE HAVE ACROSS ALL 20
OF OUR STUDIES WE CAN SEE THAT
THE VAST MAJORITY OF THEM ARE
COVERING INFORMATION ABOUT THE
CLINICAL IS IT THEUS AND
LABORATORY TESTS.
BUT WE ALSO DO HAVE A NUMBER OF
STUDIES WHICH ARE HELPING US
UNDERSTAND EXPOSURE, UTILIZATION
AND QUALITY OF HEALTHCARE
INFORMATION ABOUT THE OTHER
PEOPLE THAT ARE CARING AND
FAMILY MEMBERS THAT ARE
SUPPORTING AND BUILDING THIS OUT
AND BEING ABLE TO IDENTIFY NEW
AREAS OF RESEARCH WHICH MAY BE
VERY RELEVANT, THIS IS THE BREAK
DOWN OF HOW THE CURATION HAS
GONE FOR DATA ELEMENTS TO GIVE
YOU A BETTER IDEA ABOUT WHAT
TYPE OF VARIABLES ARE IN THE
STUDY SO FAR: SO IN ADDITION TO
VARIABLES ABOUT THE STANDARDIZED
METRICS AND RUBRICS FOR PATIENT
REPORTED OUTCOMES SO SIMILAR TO
THE WAY THE DATA ELEMENTS WERE,
WE HAVE 16 STUDIES THAT
COLLECTED INFORMATION ON PATIENT
REPORTED OUTCOMES.
HERE IS A LIST OF ALL 16 OF
THOSE STUDIES AND THE NUMBER OF
SUBJECTS THAT WERE INVOLVED IN
THOSE.
SIMILAR TO THE DATA ELEMENTS WE
HAVE OUR HIERARCHY OVER HERE ON
THE LEFT-HAND SIDE OF THE SCREEN
THAT LISTS, THE PATIENT REPORTED
OUTCOMES.
SO YOU'LL NOTICE THAT A LOT OF
THESE PATIENT REPORTED OUTCOMES
WERE ONLY USED BY 1 OF THE
STUDIES AND THAT IS--A LOT OF
STUDIES WE SRO BEEN GOING ON AND
HAVE A HISTORY AND SO BEING ABLE
TO HAVE THESE PATIENT REPORTED
OUTCOMES BECOME MORE PREVALENT
IS AS WE INJECT NEW STUDIES INTO
THE METADATA CATALOG, WE GET
ADDITIONAL STUDY SAYS WE'RE
USING SIMILAR INSTRUMENTS.
SO OUR PROMEASURES ARE A BIT
MORE IMMATURE, BUT AS WE INGEST
MORE AND MORE STUDIES WE'RE
FINDING THERE ARE MORE AND MORE
STUDIES THAT USE THEM AND WILL
HAVE DIRECTLY COMPARABLE DATA
ACROSS THE 2 DIFFERENT STUDY
TYPES.
SO SIMILAR TO WE DID WITH
DATA--[SO SIMILAR TO THE DATA
ELEMENTS, YOU KNOW THIS IS THE
LIST OF THE 16 STUDIES THAT WE
HAVE AS WELL AS THE HIGH
LEVEL,IRE ARCHY FOR FOR THE
PROMEASURES, SO THE PRO MEASURES
THAT WERE COLLECTED ACROSS THE
DIFFERENT IS IT THES ACROSS
VARIOUS DIFFERENT TYPES AND IF
WE CAN BUILD THIS OUT WITH
ADDITIONAL STUDIES THIS WILL BE
A USEFUL RESOURCE FOR THE
COMMUNITY IN THE FUTURE.
ONE OF THE THINGS WE HAVE AS
WELL IS A SEARCH FEATURE, AND
THE TOP OF MY SLIDE MIGHTING
MISSING OKAY, HERE IT IS.
SO WHAT WE HAVE HERE IS THE
ABILITY TO BY KEY WORD ACROSS
BOTH THE SUBJECTS LEVEL METADATA
AS WELL AS STUDY LEVEL METADAILY
BASIS THEA SO IN THIS CASE IF WE
WANT TO COLLECT STUDIES WITH
PATIENTS TAKING HYDROXY UREA, WE
IESHES DENTIFIED 20 OF THE
STUDIES THAT COLLECTED THAT
INFORMATION.
BUT LET'S SAY WE'RE INTERESTED
IN AND THAT ALSO HAVE BRAIN, MRI
OR MRA IMAGING SO WE CAN COMBINE
INFORMATION AND STUDIES THAT
STUDY HYDROXY UREA FOR
INFORMATION THAT WE CAN BROWSE
DOWN AND SELECT THIS BOX HERE
FOR COLLECTING OF BRAIN MRIs
AND WE CAN SEE NOW THAT WE HAVE
7 STUDIES THAT ARE, THAT
COLLECTED BOTH AND HAD
INFORMATION ABOUT THESE BRAIN
IMAGING AS WELL AS INFORMATION
ABOUT PATIENTS TAKING HYDROXY
UREA, AND THERE'S A NUMBER OF
DIFFERENT DATA ELEMENTS THAT WE
CAN USE TO KIND OF DO THIS
FILTERING STRATEGY BOTH ACROSS
THE DATA ELEMENT DOMAINS AS WELL
AS PATIENT REPORTED OUTCOMES.
AND SO, WE CAN BUILD OUT THESE
KIND OF QUERIES BY ADDING NEW
LAYERS TO OUR SEARCH FEATURE.
SO IN THIS CASE, WE ADDED THE
DATA ELEMENT HERE FOR IMAGING,
WE CAN FURTHER EXPAND THAT OUT
TO SAY WELL, WE ALSO WANT TO
KNOW WHETHER THE STUDIES
COLLECTED BIOSPECIMENS FOR URINE
AND HAVE ACCESS TO THOSE STUDIES
TO QUERY FOR ADDITIONAL OR THOSE
SAMPLES TO QUERY FOR ADDITIONAL
MARKERS OR THINGS, AND IN THAT
CASE, NOW, WE'VE IDENTIFIED 2
STUDIES WHICH HAVE MET ALL THE
CRITERIA FOR HAVING HYDROXY UREA
FOR BRAIN IMAGING FOR MRI OR MRI
AS WELL AS DIRECTION OF
BIOSPECIMENS, SO IN THIS WAY, WE
CAN FILTER DOWN AND IDENTIFY THE
STUDIES WHICH MAY BE MOST
APPLICABLE SO WE CAN REUSE SOME
OF THE STUDIES WE HAVE ALREADY
COLLECTED AND INVESTED IN IN THE
PAST.
ONE OF THE NEW FEATURES THAT
WE'RE WORKING ON IN THE METADATA
CATALOG IS OUR SUBJECT FREQUENCY
TOOL.
SO FOR INSTANCE IF WE'RE LOOKING
TO BUILD A COHORT, AND
UNDERSTAND A NEW SCIENTIFIC
QUESTION, WE MAY BE INTERESTED
IN ONLY RECRUITING A SPECIFIC
NUMBER OF PATIENTS OR
AGGREGATING OR PATIENTS WITH A
SPECIFIC SET OF CRITERIA.
SO IN THIS CASE, YOU KNOW THIS
IS A NEW FEATURE THAT WE'VE
ADDED.
WE ONLY HAVE 2 STUDIES IN WHICH
ARE BROUGHT INTO THIS TOOL BOTH
SC DATA AND SCDIC, WE HAVE 6000
PATIENTS ACROSS THESE 2 STUDIES
AND IF WE'RE INTERESTED IN
FINDING INFORMATION ABOUT ONLY
PATIENTS WHICH HAVE AN SS-GENO
TYPE, WE CAN AND ONLY PATIENTS
THAT ARE AT LEAST 18 YEARS OF
AGE, WE CAN CLICK ON THESE
BOXES, AND WE CAN IDENTIFY THAT
THERE ARE 808 SUBJECTS IN THE
C-DATA AND 1500--ABOUT 1500 IN
THE SCDID DATA SET WHICH MEET
THAT CRITERIA, SO THESE MIGHT BE
AN OPPORTUNITY WHERE WE CAN PULL
THE INFORMATION FROM THESE
PATIENTS ACROSS THE 2 STUDIES
TOGETHER TO BUILD OUT OUR
COHORT.
SAME WAY WE WERE ABLE TO HAVE
ADDITIONAL LAYERS IN OUR SEARCH
FUNCTION, WE BUILT THAT IN HERE,
SO IN THIS CASE, IF WE WANTED TO
ONLY HAVE FEMALES WHICH HAVE A
HISTORY OF TAKING HYDROXY UREA,
WE CAN ADD THOSE BOXES AS WELL,
TO OUR FILTERS AND THAT NOROS
OUR COHORT DOWN TO ABOUT 462
SUBJECTS, ABOUT HALF OF THEM
COMING FROM C-DATA AND A LITTLE
MORE FROM SCIDID, SO THIS IS A
WAY WE CAN BUILD OUT THOSE
COHORTS HOE THAT WE CAN
INTERROGATE SOME OF THOSE
QUESTIONS THAT ARE APPLICABLE TO
OUR QUESTIONS.
ONE OF THE FEATURES WE'RE
LOOKING TO BUILD OUT FURTHER IS
BEING ABLE TO IDENTIFY THE
NUMBER OF SUBJECTS THAT MAY HAVE
ANY OF THE CURATED DATA
ELEMENTS, SO IN THIS PARTICULAR
CASE WE'RE NOTED ACTUALLY
LOOKING AT SOME OF THE RESPONSE
OPTIONS LIKE WE MAY NOT HAVE
INFORMATION ABOUT THE PARTICULAR
RESULTS OF A BRAIN SCAN, WE WILL
KNOW IT IS NUMBER OF
PARTICIPANTS THAT HAD THAT DATA
COLLECTED SO WE MAY NOT KNOW
WHAT THE RESULTS WERE AND THE
COHORT MAY NOT BE AS CLOSED,
HOWEVER, WE DO KNOW THAT THERE
WERE A CERTAIN NUMBER OF
PATIENTS THAT HAD THIS
INFORMATION COLLECTED AND SO WE
CAN BUILD OUT ADDITIONAL
INFORMATION CONSTRAINTS ON OUR
COHORTS, BY SAYING YOU HAVE TO
HAVE THIS INFORMATION COLLECTED,
SO THIS IS A NEW FEATURE, THAT
WE'RE IN THE PROCESS OF
DEVELOPING AND HOPEFULLY WILL BE
AVAILABLE, SOON IN ORDER TO HELP
PEOPLE TO BUILD OUT THESE
COHORTS AND INVESTIGATE NEW
QUESTIONS.
SO WITH THE METADATA CATALOG, WE
ARE LOOKING FOR OPPORTUNITIES TO
COLLABORATE WITH THE SICKLE CELL
COMMUNITY AND WE WOULD ENCOURAGE
YOU ALL TO GO TO THE METADATA
CATALOG AND TAKE A LOOK.
OUR CONTACT INFORMATION CAN BE
FOUND ON THE CATALOG, AND IF YOU
HAVE A STUDY THAT YOU WOULD LIKE
TO HAVE BROUGHT INTO THE
METADATA CATALOG AND IF YOU HAVE
ADDITIONAL INFORMATION THAT IS
AVAILABLE ABOUT SOME OF THE
STUDIES THAT WE'VE ALREADY
INGESTED THAT MAY NOT BE
PUBLICLY AVAILABLE, WE ARE VERY
INTERESTED IN COLLABORATING WITH
YOU.
TYPICALLY WE'VE BEEN DOING A
DATA CURATION TO DO OUR LIBRARY
SO IF YOU HAVE ANNOTATIONS OR
ADDITIONS TO THE DICTIONARYS
THAT WOULD BE HELPFUL AND WE'RE
WILLING TO KIND OF WORK WITH
INVESTIGATORS TO HELP BRING THE
MOST VALUABLE FROM THIS TOOL TO
THE INVESTIGATORS.
IN ADDITION, THE SUBJECT
FREQUENCY TOOL, WE'VE COLLECTED
INFORMATION AND RESPONSES FOR 10
OF THE KEY VARIABLES.
SO THESE ARE THINGS LIKE THE
GENO TYPES AND THE DEMOGRAPHICS
THAT WE WOULD USE TO BUILD
COHORTINGS BUT WE'RE ALWAYS
INTERESTED IN UNDERSTANDING THE
NEEDS OF THE COMMUNITY, SO IF
THERE ARE SPECIFIC THINGS THAT
YOU WOULD USE IN ORDER TO BUILD
YOUR COHORTS, WE WOULD LOVE TO
UNDERSTAND WHAT THOSE ARE AND
POTENTIALLY WE COULD THEN BUILD
THAT INTO THE SUBJECT FREQUENCY
TOOL AND MAKE THAT PUBLICLY
AVAILABLE TO OTHER RESEARCHERS
AS WELL.
SO IF YOU'RE INTERESTED IN
COLLABORATING WITH US, YEAH,
EVERYONE PLEASE GO CHECK OUT THE
METADATA CATALOG, ANY FEEDBACK
YOU HAVE OR IDEAS ABOUT HOW TO
BUILD IT OUT AND ADD ADDITIONAL
VALUE WOULD BE WONDERFUL.
AND WITH THAT, WE WOULD LIKE TO
ACKNOWLEDGE A NUMBER OF OUR
COLLABORATORS AND CONSULTANTS
WHO HAVE HELPED US TO BUILD OUT
THIS METADATA CATALOG, SO OUR
TEAM HERE AT RTI HAS BEEN
EXTENSIVE AND CONTRIBUTING FOR
ALL THE CURATION EFFORTS, AS
WELL AS MARTIA TREAD WELL WHO
HELPED CAN CONSULLING, THE
SICKLE CELL CONSORTIUM AND ALL
THE RESEARCHERS WHO HAVE OFFERED
UP ADVICE AND DATA DICTIONARIES
AND DATA SETS TO MAKE THIS
POSSIBLE AS WELL AS FUNDING.
AND THAT IS WHAT WE I'VE GOT TO
SHARE TODAY AND I GUESS, I CAN
TAKE A LOOK TO SEE IF THERE'S
ANY QUESTIONS IN THE CHAT.
>> THANK YOU DR. STRATFORD, VERY
NICE PRESENTATION, I THINK THERE
ARE A FEW COMMENTS IN THE CHAT,
I DON'T SEE ANY PARTICULAR
QUESTIONS.
>> YEAH.
NO, THANK YOU LUIS FOR POINTING
OUT THE OVERLAP BETWEEN SOME OF
THE ENROLLMENT, WE WILL HAVE TO
LOOK INTO THIS A BIT MORE ABOUT
HOW TO IDENTIFY IF THERE ARE ANY
PARTICULAR PATIENTS WHICH ARE
FOUND IN BOTH DATA SETS BECAUSE
THAT WOULD ALSO BE INKRED
BELIEVELY USEFUL ESPECIALLY IF
THERE IS A TIME DIFFERENCE
BETWEEN THE ENROLLMENT FROM 1
STUDY TO THE NEXT.
SO THANK YOU FOR POINTING THAT
OUT.
>> ANY OTHER QUESTIONS FOR
DR. STRATFORD AT THIS POINT.
SEEING NONE AT THE MEMORY CLONE
ENTD OUR NEXT SPEAKER IS
DR. CLAUDIA MORRIS ON?
DRRN DR. MORRIS?
I DON'T SEE DR. MORRIS ON AT THE
MOMENT.
SHE'S SUPPOSED TO GIVE THE NEXT
TALK, WHAT'S NEW WITH
ARGININE THERAPY IN SICKLE CELL
DISEASE?
>> SHE'S NOT ON THE CALL.
>> SHE'S NOT ON THE CALL, WELL,
IN THAT CASE, GIVEN THAT THIS
WAS GOING TO BE THE FINAL TALK
BEFORE WE BREAK FOR LUNCH, I
THINK IT MIGHT BE BETTER IF WE
BREAK FOR LUNCH NOW, INSTEADY
BECAUSE WE DON'T HAVE THE
SPEAKER AVAILABLE AT THE MOMENT.
UNFORTUNATELY SO WE WILL HAVE TO
SKIP THIS PART OF THE TALK IN
THE AGENDA AT THE MOMENT AND WE
WILL GET AN EXTRA 30 MINUTES.
WHY DON'T WE TRY TO COME BACK A
LITTLE EARLY INSTEADY OF COMING
BACK AT 1:15, WHY DON'T WE COME
BACK AT 1:00 O'CLOCK IF THAT IS
OKAY WITH THE NEXT SESSION
CHAIRS?
>> THIS IS NANCY, I KNOW SHE WAS
PLANNING TO SPEAK AND IT'S A
LITTLE BIT AHEAD OF SCHEDULE SO
MAYBE SHE WILL BE ABLE TO JOIN
WHILE WE'RE AT LUNCH?
>> OKAY.
WELL, I MEAN--
>> ARE YOU LOOKING FOR ME.
>> YEAH, HERE'S CLAUDIA NOW.
>> HEY, SORRY.
>> SHE'S HERE, OH, OKAY, GREAT.
>> ARE WE STARTING EARLY?
>> WE WERE PREEMPTING YOU OUT
BUT I GUESS NOT.
SO THANK YOU FOR JOINING,
DR. CLAUDIA MORRIS IS GOING TO
TALK ABOUT THE ARGININE THERAPY
IN SICKLE CELL DISEASE AND
RESULTS OF PHASE 2 RANDOMIZED
CONTROLLED TRIALS IN THE U.S.
AND NIGERIA.
>> THANK YOU SO MUCH.
CAN YOU HEAR ME OKAY.
>> WE WE CAN HEAR YOU FINE?
, CAN YOU SEE MY SLIDES.
>> YES, WE CAN.
>> PERFECT.
>> THANK YOU.
WELL I APPRECIATE THE
INTRODUCTION AND THE INVITATION
TO TALK TODAY ON
ARE--ADMINISTRATIVE
GENERATEDDINE THERAPY.
SO I HAVE NO RELEVANT
DISCLOSURES BUT I WILL BE
SPEAKING ABOUT OFFLABEL USE
ABOUT L-ARGININE, UNDER AN
ACTIVE IND, THERE ARE PEOPLE IN
THE AUDIENCE WONDERING OH MY
GOSH IS SHE STILL TALKING ABOUT
THE ARGINE THERAPY, AND THATY
TRUE, WE STARTED TALKING ABOUT
ARGININE, THERAPY WITH MY K23
AWARD THAT WAS GRANTED FROM
NHLBI AND THIS IS JUST TO GIVE
THE YOUNG INVESTIGATORS IN THE
ODD EN--STRATEGIES AN IDEA OF
HOW IMPORTANT THE PERSISTENCE IS
ALONG THE JOURNEY BECAUSE IT HAS
BEEN AN INCREDIBLE JOURNEY TO
GET US TO 2020 WHEN WE WERE
FUNDED AGAIN BY NHLBI TO DO OUR
DEFINITIVE PHASE 3 TRIAL.
BUT I WANTED TO POINT OUT THAT
ALONG THE WAY, THERE WERE
MULTIPLE SCORES THAT DID NOT GET
FUNDED AND REVISIONS AND
ULTIMATE AWARDS THAT IF YOU'RE
NOT SUCCESSFUL INITIALLY, TRY,
TRY, AGAIN.
SO FOR THOSE UNFAMILIAR WITH
ARGININE, IT'S AN AMINO OOH SID
IN DIETARY PROTEIN AND
SINGICIZED TO THE INTESTINAL
ACCESS AND IT BECOMES ESSENTIAL
UNDER CONDIPGZS OF STRESS,
CATAGOLLIC STATE AND
PARTICULARLY FROM HOMOLYSIS,
IT'S NATURALLY FOUND IN THE DIET
AND INMEAT, DAIRY, SEAFOOD, NUTS
AND WATERMELON, AND NORMAL
BETWEEN 7-GRAMS A DAY AND IT IS
A NUTRITIONAL SUPPLEMENT WITH
THE LOW TOXICITY, AND ULTIMATELY
IT'S THE SUBSTRATE FOR POTENT
VASE O DILATORS, AND AND IT'S
BEEN RECENTLY MARKETED IN A
NATURAL ALTERNATIVE TO VIAGRA,
YOU WILL NEVER LOOK AT THE SAME
WAY AGAIN.
--THERE--THIS SLIDE SHOWS THE
SOURCE OF ARGININE, AND I WON'T
GO OVER THIS IN TOO MUCH DETAIL
BUT WE ALSO TALK ABOUT ARGININE
AS THE PRECURSOR TO NITRIC OXIDE
BUT YOU CAN SEE THAT THERE ARE A
NUMBER OF ENZYMES THAT ARE
INVOLVED, AND A NUMBER OF
BIOLOGICAL PATHWAYS THAT
ARGININE IS PLAYING A ROLE,
AGAIN HIGHLIGHTING FOR THOSE IN
THE AUDIENCE WHO ARE WONDERING
HOW THEY CAN COME UP WITH THE
NOVEL IDEA, ARGININE IS ALSO THE
PRECURSOR TO CREA TIN WHICH IS
REALLY IMPORTANT IN THE
METHYLATION PATHWAY AND
DETOXIFICATION AND THERE IS VERY
LITTLE INFORMATION ON ARGININE
THE PATHWAY ON SICKLE CELL
DISEASE, SO AGAIN, A GAP IN OUR
KNOWLEDGE.
IN THE PRESENCE OF NITRIC OXIDE,
IT GETS CONVERTED TO NITRIC
OXIDE AND WE HAVE THIS
PARADOXICAL DECREASE IN NITRIC
OXIDE PRODUCTION DESPITE NITRIC
OXIDE APPEARS TO BE ELEVATED IN
OTHER SICKLE CELL DISEASE AND
OTHER INFLAMMAR TOY CONDITIONS
BUT WORK HAS SHOWN THAT IN THE
SICKLE CELL MOUSE MODEL, THE
NITRIC OXIDE SYNTHASE IS
FUNCTIONAL AND IT WILL REOXIDIZE
WITH HEMOGLOBIN AND IT'S PRESENT
IN THE RED BLOOD CELLS AND IT'S
INCREASED FROM LIVER AND LIVER
DAMAGE AND DECREASED TRAUMA AND
THEREY A NUMBER OF ETIOLOGIES,
BUT THE BODY DOESN'T CARE WHERE
IT'S COMING FROM, ONCE IT'S IN
CIRCULATION, IT CONVERTS IT TO
ARGININE, AND THEN YOU HAVE
PROLIF RATESTIFY PATHWAYS THAT
LEAD TO THINGS LIKE VASCULAR
SMOOTH MUSCLE PROLIFERATION,
REMODELING, COLLAGEN
COMPOSITION, LUNG FIBROSIS WHEN
YOU THINK ABOUT THE LUNG BUT
THIS IS PROBABLY IMPORTANT IN
EVERY ORGAN WHERE IT'S IN
EXCESS, SO IT'S ARGININE IS JUST
IMPORTANT IT SHOULD NEVER BE
DEFICIENT PARTICULARLY SINCE WE
HAVE THE ABILITY TO SYNTHESIZE
IT, AND SO TAKEN UP IN THE FORM
OF DPLIEWTA MINE, CONVERTED IN
FROM THE DIET, TO SIT ROW LEAN
IN THE SMALL INTESTINE AND SIT
ROUGH ATOM LINE GETS CONVERT
INDEED THE KIDNEY.
ALTHOUGH THE MECHANISM IS LIKELY
MULTIFACTORIAL, WE RECENTLY
PUBLISHED OUR PHARMACOKINETIC
DATA TO SHOW THAT OUR DPLIEWTA
MINE LOAD DOES INFACT INCREASE
VIAABILITY AND THIS IS LIKELY
THAT THIS PATHWAY IS PLAYING A
ROLE AS WELL.
BUT IF HAVE YOU KIDNEY
DYSFUNCTION, WERE YOU AWARE NOT
ABLE TO CONVERT FROM SIT ROUGH
ATOM LEAN TO ARE--ADMINISTRATIVE
GENERATEDDINE AND APPROXIMATE
WITH THE WORK WE DID WITH MARK
AND COLLEAGUES WE FOUND IN OUR
DATABASE RISING LEVELS STRONGLY
CORRELATED TO KRE TINSA TIEN
LEVELS IN OUR PATIENTS WITH SICK
CELL CELL DISEASE AND THEY HAD
LOW ARGININE LEVELS SO THERE WAS
A--VERY VULNERABLE TOOXIDATIVE
STRESS AND CAN GET KNOCKED OUT
PRETTY QUICKLY.
SO AGAIN ANOTHER GAP IN OUR
KNOWLEDGE AND OUR AREA WHERE WE
NEED MORE STUDY.
BUT BECAUSE OF THIS, WE COINED
THE TERM GLOBAL ARCHINGLY
BIOAVAILABILITY RATIO BECAUSE IT
IS MORE THAN JUST THE ARGININE
IN YOUR PLASMA MAKES A
DIFFERENCE, IN THE PLACE OF
ARE--ADMINISTRATIVE GENERATED
ACE, IT GETS CONVERTED SO THIS
RATIO IS PLUS SIT ROUGH ATOM
LEAN, SO AS YOU'RE
ORNITHINCEREBELLUMSY, USE THE
SAME TRANSPORTER SO THE ARGININE
NEEDS TO GET FROM THE PLASMA
INTO THE CELLS SO NOW HAVE YOU
TRANSPORT DIFFICULTIES AND THEN
IF YOU THROW IN KIDNEY
DYSFUNCTION YOU, YOU WILL
NOTABLA TO SUPPORT THIS FROM SIT
ROUGH ATOM LEAN, AND I WANT YOU
TO KEEP IT IN MIND AS WEAUK
ABOUT OUR CLINICAL TRIALS.
SO A LOT OF DITS CUSHION ABOUT
AMINO ACIDS BUT A DROP IN ANY
SPECIFIC AMINO ACID DOES NOT
TRANSLATE TO--DOES NOT ALWAYS
TRANALATE TO A CLINICAL
SIGNIFICANT DEFICIENCY, SO
INERED ONER TO FOR A
NUCLEOTIDESITRATIONAL DEFICIENCY
HAS TO BE PRESENT, YOU HAVE TO
HAVE THESE 3 PRIMATES SESESS, A
BIOLOGICAL PROCESS DEPENDENTOT
NUTRIENT, THAT COMPROMISE LEADS
TO AN ABNORMAL PHYSIOLOGIC
RESPONSE THAT'S POSITIVE FOR
OUTCOMES AND THOSE POUR
OUTOUTCOMES ARE REPLACED FOR
AMINO ACIDS FOR REPLACEMENT SO
KEEP IN THIS MIND AS WE TALK
ABOUT CLINICAL TRIALS BUZZ I
WILL MAKE THE ARGUMENT THE END
THAT WE'RE REALLY TREATING A
NUTRITIONAL DEFICIENCY.
>> CLAUDIA,.
>> CLAUDIA, SORRY TO INTERRUPT
YOU BUT I THINK YOUR--ARE YOU
SEEING YOUR SLIDES, ARE SLIDES
THE RIGHT SLIDE BEING PROJECTED?
>> IT SAYS AMINE'S ACID
DEFICIENCIES ARE YOU NOT SEEING
MY SLIDES?
WE ARE SEEING SLIDES NHLBI IS
FORWARDING THEM SO MAKE YOU SAY
NEXT SLIDE.
NO, NO, I WAS MOVING THEM
MYSELF.
>> WE'RE LOOKING AT THE SLIDE
FOR DPLIEWTA MINE--DPLIEWTA MINE
AND CITRULLINE.
>> DO YOU WANT TO CONTINUE?
>> YES.
>> SO, HERE LET ME SEE.
SORRY ABOUT THAT.
YEAH, I REALIZED YOU WERE BEHIND
THE SLIDES.
SORRY, I THOUGHT--OKAY, HERE WE
GO, CAN YOU SEE THAT?
>> YES.
>> SO THIS WAS THE SLIDE THAT WE
HAD SPOKEEB SO TELL ME SOME I
START FROM HERE.
SO NANCY I HEARD YOU ASK
SOMETHING ABOUT THE PATHWAY,
WHAT WAS YOUR QUESTION.
, NO THIS WAS THE SLIDE WE'RE
LOOKING AT AND CLAUDIA YOU'RE
NOT IN FULL SCREEN VIEW RIGHT
NOW, I'M NOT SURE IF YOU CAN
CHANGE THAT, WE'RE LOOKING AT 2
SLIDES.
>> OH GEEZ.
OKAY.
SORRY ABOUT THAT.
>> THE IT PEOPLE KNOW HOW TO DO
THIS STUFF.
>> YOU CAN GO TO PRESENTER MODE.
>> IS--
>> I THINK THE PROBLEM IS, I
STOPPED SHARING.
>> YOU DID.
>> OKAY.
CAN YOU SEE MY SLIDES NOW?
>> NO.
>> I AM SO SORRY.
>> YES.
>> YES, OKAY.
>> SORRY FOR INTERRUPTING.
>> NO WORRIES, THANK YOU FOR
TELLING ME.
SO WE JUST WENT THROUGH THE KIND
OF THE BIOLOGY SLIDE ANDIME
HAPPY TO SHARE THESE SLIDES WITH
ANYONE WHO WANTS TO SEE THEM IN
MORE DETAIL.
BUT AS WE TALKED ABOUT, IN ORDER
TO HAVE AMINO DEFICIENCY, YOU
HAVE TO HAVE THESE 3, ESTATES
PRESENT, THE BIOLOGICAL PROCESS
DEPENDENTOT NUTRIENT
COMPROMISED, THE COMPROMISE
LEADING TO POSITIVE AND POOR
OUTCOMES AND THOSE POOR OUTCOMES
NEED TO BE REVERSED BY AMINO
ACID PLACEMENT.
SO ULTIMATELY SICKLE CELL
DISEASE IS A MODEL FOR OTHER
DISEASE BUT HAS IMPLICATION FOR
SO MANY OTHER DISEASES SO WHEN
WE THINK ABOUT MECHANISMS OF
VASCUE LOPATHY, YOU ARE SIGHING
MY SLIDE, NO IN THE CENTER, YOU
CAN SEE MY POINTER.
>> PERFECT, OKAY, SO WHEN YOU
HAVE ENDONEALIAL DYSFUNCTION NO
DOES TAKE CENTRAL STAGE AND WE
TALKED BEFORE ABOUT THE
CONTRIBUTION OF HEME OLDER
PEOPLE SIS, SO YOU NORMALLY HAVE
SAFELY INCAPSULATED IN THE RED
BLOOD CELL ALL THE CONTENTS
WHICH INCLUDES SELF-HEMOGLOBIN
WHICH WILL CONSUME NITRIC OXIDE,
AND WE HAVE ARITHROCYTE THAT'S
RELEASED DURING HOMOLYSIS, AND
THEN RAPIDLY, AND CONSUMES THE
SUBSTRATE FOR NITRIC OXIDE
UPTAKE.
SO NOW YOU HIT THIS LEVEL, THE
ENZYME THAT CONEXPOSURE CONVERTS ARGININE ,
IS PRODUCING SUPEROXIDE AND
WHICH FURTHER CONFIRMS AND ADDS
TO THE MILIEU OFOXIDATIVE STRESS
AND THIS IS AN IMPORTANT
PARADIGM NOT JUST FOR SICKLE
CELL DISEASE BUT FOR THALSEMIA,
MALARIA, RED BLEED CELL STORAGE
LESION, ANY TIME HAVE YOU HEME
OLDER PEOPLE SIS, YOU HAVE
IMPACT ON THIS IMPORTANT
PATHWAY, AND THERE ARE CLINICAL
CONSEQUENCES OF THIS, HEME
OLYMPIC SIS AND THIS HAS BEEN
KNOWN AS THE HEMOLYTIC
SUBPHENOTYPE, SICKLE CELL
DISEASE BY COLLEAGUES, THAT
INVOLVES EMPLOY LUG ULCERS,
PRIAPISM, AND WE'VE SEWN THAT
THERE'S ARGININE INSUFFICIENCY
AND ELEVATED ARGININE ACE IN
SICKLE CELL DISEASE, SO IF YOU
ARE HEGHTY YOU SHOULD NOT HAVE
ARGININE FLOATING AROUND IN OUR
PLASMA, IT'S AN INTRACELLULAR
ENZYME THAT'S RELEASED UPON CELL
DAMAGE OR CELL DEATH AND HAD IS
A REALLY IMPORTANT OBSERVATION
AS FAR AS UNDERSTANDING THE
MECHANISM OF THIS ACUTE ARGININE
DEFICIENCY.
WE ALSO LEARNED THAT ARGININE
LEVELS GET DROPPED TO LOWEST
LEVELS DURING ACUTE EPISODES OF
PAIN AND DIN DROAMS AND SO FROM
THE LAST BIOLOGY SLIDE THOUGH WE
TALKED ABOUT ARGININE AND
CONVERTS IT TO ORNITHINE, AND
IT'S LOW IN SICKLE CELL DISEASE
COMPARED TO NORMAL CONTROLS BUT
PROBABLY 1 OF MY MOST IMPORTANT
EARLY OBSERVATIONS WAS THAT THE
LOWEST LEVELS WERE FOUND IN
PATIENTS THAT ARE DIAGNOSED
CLINICALLY WITH PULMONARY
HYPERTENSION AND THIS IS BUYER
WE WERE DOING PULMONARY
HYPERTENSION SCREENING, AND
THESE WERE PATIENTS IN KNOWN TO
HAVE PULMONARY HYPERTENSION.
SO IF IT'S LOW GIVE IT BACK
THINKING THIS ISENT POSITIONAL
CLONING TENTIALLY A NUTRITIONAL
DEFICIENCY, THIS IS A FIRST
INTERVENTION STUDY, I DID THIS
WORK WHILE I WAS STILL AT K23,
AWARDEE AND WE GAVE A HUNDRED
MILLIGRAMS PER KILOORAL ARGININE
TO PATIENTS WHO HAD PULMONARY OR
SYSTOLIC DOPPLER ECEE AND WE
FOUND A SIGNIFICANT IMPROVEMENT
IN OVER 15% OF THE PULMONARY
PRESSURES BY 5 DAYS IN THESE
PATIENTS WITH PULMONARY
HYPERTENSION RISK AND THIS IS
SIMILAR TO THE CHANGES YOU SEE
WITH OTHER PULMONARY
HYPERTENSION DRUGS SUCH AS
SULDENAPH IL, AND THERE WERE
PATIENTS IN IN GROUP WHO HAD
SIGNIFICANT CHRONIC LEG ULCERS
AND THEIR LEG ULCERS RESOLVED
WHILE THEY WERE ON ARGININE
THERAPY.
SO ALSO IMPORTANT TO NOTE THAT
LOW VIABILITY HAS BEEN ASSOCIATE
WIDE INCREASED RISK OF DEATH BY
ARGININE-TO ORN, AND AS I
MENTIONED BEFORE THE RATIO SO WE
OBLIGATIONS STAINED A BLOOD TEST
ON AT A 0 AND FOLLOWED THESE
PATIENTS OUT OVER 4 + YEARS AND
NO DEATHS IN THE PATIENT WHO IS
HAD THE HIGHEST ARGININE VIA
BILITY AND WITH A RISK RATIO OF
3.6.
THIS HAS BEEN LOOKEDDA THE IN
PATIENTS WITHOUT SICKLE CELL
DISEASE, AT RISK FOR
CARDIOVASCULAR DISEASE AND IT IS
A MORE SENSITIVE PREDICTER OF
ADVERSE OUTCOMES THAN
CHOLESTEROL.
SO SUGGESTS THAT ARGININE PLAYS
A REALLY IMPORTANT ROLE IN
ENDOTHELIAL DYSFUNCTION THAT
GOES BEYOND SICKLE CELL DISEASE.
SO GOING BACK TO THE RESULTS OF
MY K23 STUDY, THIS WAS OUR
BLINDED RANDOMIZED PLACEBO PHASE
2 TRIAL, WHERE WE GIVE THE
ARGININE A HUNDRED MILLIGRAMS
FOR KILOFOR 53 TIMES A DAY FOR 5
DAYS, WE STARTED OUT RAPID
LOAMACYY, AND SWITCHED TO IV
BECAUSE WE HAD A HECK OF A TIME
GETTING PATIENTS TO COMPLY AND
ACTUALLY DRINK THE COCKTAIL WHEN
THEY'RE NOT FEELING WELL BUT NO
ISSUES WITH COMPLIANCE WITH
DELIVERING BY IV, SO 56 PATES
OVER AGE 3 ADMITTED FOR PAIN,
SIGNIFICANT DECREASE IN THE
OPIOID USE IN IV MORPHIN
EQUIVALENTS MILLIGRAM PERKILOIN
THE ARGININE ARM COMPARED TO
PLACEBO AND THIS REMAINED DEEP
EVEN WHEN WE EXCLUDED THESE 2
OUTLIERS, ALSO FOUND DECREASE IN
PAIN SCORES AND WE FOUND A
NONSTATTISTICALLY SIGNIFICANT
BUT CLINICALLY RELEVANT DEE
CREASE OF LENGTH IN HOSPITAL
STAY BY 17 HOURS.
THIS YOUNG INVESTIGATOR STUDY
WAS NOT A DECREASED LECT IN
HOSPITAL STAY BUT THE GOAL WAS
TO GENERATE DATA FOR OUR HOPE
FOR A PHASE THRIE TRIAL BUT WE
DID FIND A STRONG CORRELATION
BETWEEN TOTAL OPIOID USE AND THE
LINK TO HOSPITAL STAY AND OPIOID
USE IS A NICE SURROGATE FOR THIS
OTHER OUTCOME THAT WOULD
ACTUALLY REQUIRE HUNDREDS OF
PATIENTS TO ENROLL.
UNBEIMOWNST TO ME DURING THIS
TIME, DR. RICHARD ONALO WAS
FOLLOWING OUR WO, AND SCHEMING
ON HOW THIS COULD BE HELPFUL FOR
HIS PATIENTS IN NIGERIA WITH
SICKLE CELL DISEASE.
SOPHISTICATEDY HE REACHED OUT TO
ME AND HE VERY QUICKLY BECAME 1
OF MY STAR K24 MENTEES AND HE
WAS RECENTLY AWARDED HIS Ph.D.
FOR THE WORK HE DID IN ARGININE.
SO HIS GOAL WAS TO DETERMINE THE
ROLE OF OVERALL ARGININE IN
CHILDREN ADMITTED FOR PAIN IN
NIGERIA, WE PERFORMED A BLINDED
PHASE 2 RANDOMIZED CONTROL TRIAL
IN 2 HOSPITALS HE USED ORAL
ARGININE, AND MIXED IT WITH
GRAPE JUICE AND USED THE DOSE WE
HAD OUT OF THE OAKLAND STUDY,
THE 1 MG, DOSE EVERY 8 HOURS FOR
5 DAYS.
EVERYBODY WANTED THE GRAPE JUICE
AND WAS ASKING FOR IT WHEN IT
WASN'T TIME FOR THEIR STUDY
DRUG, SO A VERY DIFFERENT
POPULATION AND THINGS TO
CONSIDER WHEN WE'RE DOING
CLINICAL TRIAL DESIGN IN THE
UNITED STATES COMPARED TO LOW
RESOURCE ENVIRONMENT IN NIGERIA.
HE OBTAINED DRUG SAMPLES AT DAY
5 AND DISCHARGE AND HIS PRIMARY
OUTCOME MEASURE WAS THE MEASURE
QUANTIFICATION SCALE, MQS TOOL
THAT WAS VALIDATED IN 2007 AND
THIS PAISKLY ASSESSED ALL ANNAL
GEEZIA USE AND AGAIN WE HAD TO
THINK HARD ON WHAT WAS THE BEST
OUTCOME MEASURE FOR NIGERIA
BECAUSE I WAS USED TO USING IV
OPIOIDS AS OUR OUTCOME BUT THEY
JUST DON'T USE PARENT OPIOIDS
LIKE WE DO IN THE UNITED STATES.
PATIENTS MAY GET 1 DOSE OF AN IV
OPIOID WHEN THEY HIT THE
ENGINEER DEPARTMENT BUT THEN
THEY QUICKLY CHAIMPLE THEM OVER
TO ORALS SO THERE'S NOTHING WE
DO IN AN INTERVENTION STUDY THAT
WOULD AN IMPACT ON IV OPIOIDS.
INCLUSION KRIST TIER REVIEWIA
WAS AGE 5-17 YEARS WITH SICKLE
CELL DISEASE WITH A PAIN SCORE
OF 7 OR HIGHER AND THIS WAS A
NUMBER OF CLINICAL OUTCOMES HE
LOOKED AT BESIDES THE MQS SCORES
HE LOOKEDDA THE PAIN SCORES,
CARDIO PULMONARY OUTCOMES, DID
ECHOCARDIOGRAPHY ON DAY 0 AND
THEN AT DAY 5 FOR THE PATIENTS
WERE STILL ADMITTED AND TIME TO
CRISIS RESLIEWGZ AND TOTAL
LENGTH OF HOSPITAL STAY.
SO 68 PATIENTS WERE RECRUITED
AND THERE WERE NO RANDOMIZED
STUDIES, 50% OF THEM WERE MAIP,
PRETTY LOW HU USE ABOUT THAT'S
REFLECTIVE WHAT HAVE'S GOING ON
IN NIGERIA AND THEN WE FOUND
ARGININE AND GLOBAL ARGININE VIA
BILITY COMPARED TO CLA SEEB O IS
NOT UNEXPECTED BUT YOU CAN SEE
THAT EVEN IF YOU DO NOTHING,
YOUR LOW ARGININE DOES INCREASE
OVER TIME AT THE TIME OF
DISCHARGE BUT ARGININE
SUPPLEMENTATION INCREASED THAT
AMOUNT AND MYOCARDITIS SEEB O
THERE'S NO GLOBAL DIFFERENCE IN
VIABILITY, WHERE WE NOTED AN
IMPROVEMENT IN THE ARGININE ARM.
SO WE ALSO SAW A SIGNIFICANT
DISCIPLINARY CREASE IN THE MQS
SCORE IN THE ARM COMPARED TO
PLACEBO, THIS IS THE PRIMARY
OUTCOME MEASURE, SO HERE YOU
HAVE ARGININE VERSUS PLACEBO AND
IF YOU LOOK AT THE MEAN
CUMULATIVE MQS SCORE BEGAN TO
DIVERSE AFTER 24 HOIRS OF
THERAPY.
ALSO FOUND THAT THE MEAN DAILY
RATE OF DECLINE IN PAIN SCORES
WAS FASTER THAN IN PLACEBO AND
LOOKEDDA THE LOWEST PAIN SCORE
REPORTED FOR EACH DAY AND THE
HIGHEST PAIN SCORE REPORTED FOR
EACH DAY AND SO THE RED LINE IS
PLACEBO AND THE BLUE LINE IS
ARGININE SO DIFFERENT IN PAIN
SCORES DAILY, AGAIN STARTED TO
DIVERGE BY DAY 2.
HE ALSO LOOKED AT BLOOD
PRESSURE, SO WE KNOW AS
CLINICIANS KIDS WILL COME IN
WITH HIGH BLOOD PRESSURE WHEN
THEY'RE IN ACUTE PAIN AND HE
FOUND THAT THE DAILY PERCENT OF
DECLINE IN SYSTOLIC AND
DIASTOLIC WAS STEEPER IN THE
ARGININE ARM COMPARED TO PLACEBO
AND THIS WAS ALSO RECENTLY
PUBLISHED AND THEN LOOKINGA THE
CARDIO PULMONARY EFFECTS AND I
ENCOURAGE EVERYONE TO TAKE A
LOOK AT THIS PAPER BECAUSE IT'S
REALLYKS SIGHTING RESULTS BUT
IESM FOCUSING JUST NOW, BECAUSE
WE DON'T HAVE ENOUGH TIME TO GO
THROUGH IT ALL ON THE TR JET,
HERE YOU HAVE THE ARGININE
VERSUS PLACEBO, BLUE IS THE
PRESUPPLEMENT, TRJET, PINK IS
THE POST SUPPLEMENT TRJET, AND
QUH WE LOOK AT IT ALTASD
TOGETHER, THERE WAS A 22%
DECREASE IN THE JETS COMPARED TO
3.8% IN THE PLACEBO ARM.
NOW SOME OF THESE PATIENTS HAD A
NORMAL TRJET, BUT ON 60% OF
THESE PATIENTS HAD AN ELEVATED
TRJET AS AND THIS HAS BEEN
REPORTED BY DR. MATCHAD O AND
COLLEAGUES, SO WHEN WE BEING LAT
PATIENT BHOS HAD HAD AN
ABNORMALITIES NORNLAL TRJET, AND
THEY THERE WERE AN 82% REDUCTION
IN THE TRJET, SO WHAT'S
INTERESTING ABOUT IN IS THAT
THIS IS ACTUALLY POSSIBLY, A YET
UNRECOGNIZED BENEFIT OF ARGININE
THERAPY BECAUSE WE KNOW THESE
PATIENTS HAVE THE TRANSIENT
ELEVATIONS IN TRJET BUT IF
THERE'S ANY OXYGEN COMPROMISE
FRIDAY THAT, THAT WILL ACTUALLY
LEAD TO HIPOXEMIA AND INCREASED
SICKLING SO IT APPEARS THAT
ARGININE IN THE ACUTE PHASE LIKE
OUR PROPHYLACTIC STUDY HAS AN
INL PACT ON TRI KUS PUD AND
DOPPLER ECHO.
DR. ONOLAO'S GROUP ARE AND
SPECIFICALLY AND TRIP OWNINS,
NOW THESE ARE THE SORT OF
BIOMARKERS I GET IF A 60
YEAR-OLD PRESENTS TO MY
EMERGENCY DEPARTMENT WITH CHEST
PAIN YOU DON'T WANT TO GO INTO
MY PEDIATRIC EMERGENCY
DEPARTMENT BECAUSE THEN I'M
GETTING A TRIP OWNIN AND THEN
I'M CALLING 911, THEY BUT WITH
KIDS THEY COME IN WITH OOH CUTE
CHEOF THE PAIN AND TRIP OWNIN
AND THIS GIVES ME PAUSE AS TO
WHAT'S GOING ON.
SO HERE YOU HAVE THE TROPONIN
LEVELS AND THE BNP, IF WE LOOK
AT ALL PATIENTS THEY'RE ELEVATED
BUT REALLY THE DIFFERENCE IS IN
PATIENTS WITH AND WITHOUT ACUTE
CHEST SYNDROME SO VERY HIGH
LEVELS AND PATIENTS WITH ACUTE
CHEST SYNDROME AND HIGH TROPONIN
LEVELS AND YOU KNOW BARELY--THEY
WERE NORMAL IN PATIENTS WITH
SICKLE CELL PAIN WITHOUT CHEST
PAIN.
SO THEN, THERE WAS NO--THERE WAS
NO CORRELATION BETWEEN THESE
BIOMARKERS AND [INDISCERNIBLE]
VELOCITY, WHEN WE LOOK AT PREAND
POST SUPPLEMENTATION, ALTHOUGH
THE BMP AND TROPONINs TREND
INDEED THE RIGHT DIRECTION AT
THE TIME OF DISCHARGE SO SHOWING
THE PARENTS WERE IMPROVING THERE
WAS A STATISTICALLY SIGNIFICANT
PRIMARY REVIEWER UFMENT IN BNP
THAT WAS SIGNIFICANT IN THE
ARGININE ARM AND THEN FINALLY
THE MOST IMPORTANT CLINICAL
OUTCOMES, WERE THE TIME TO
CRISIS RESOLUTION AND LENGTH OF
HOSPITAL STAY, NOW, TIME TO
CRISIS RESOLUTION WAS DEFINED IN
THIS STUDY AS A PAIN SCORER OF
LESS THAN 4.
AND WE KNOW THAT THAT'S
PROBLEMATIC BECAUSE WE ALL KNOW
MANY PATIENT WHO IS NEVER LEAVE
THE HOSPITAL WITH A PAIN SCORE
THAT'S LESS THAN 4.
SO THERE WERE A NUMBER OF
PATIENT WHO IS HAD TO BE
SENSORRED FROM THIS BUT EVEN
STILL LOOKING AT THESE PATIENTS
THERE WAS A SIGNIFICANT DECREASE
IN TIME TO CRISIS RESLIEWGZ IN
THE ARGININE ARM COMPARED TO
PLACEBO AND THEN LOOKING AT BY
DAY 5, 54% OF THE CHILDREN ON
ARGININE HAD ALREADY BEEN
DISCHARGED COMPARED TO ONLY 24%
IN THE LA SEEB O ARM SO AGAIN
STATISTICALLY SIGNATURES 95
SCANT AND CLINICALLY RELEVANT
OBSERVATION AND HERE WE HAVE
LENGTH OF HOSPITAL STAY, WE HAD
THAT OUTCOME ON EVERY SINGLE
PATIENT AND THERE WAS A
SIGNIFICANT DECREASE IN LECT OF
HOSPITAL STAY BY NEARLY 2 DAYS
COMPARE TO PLACEBO.
SO MANY PATIENTS WERE SICK, THE
AVERAGE HOSPITAL STAY WAS 10
DAYS WHICH WAS VERY DIFFERENT
THAN THE MEAN HOSPITAL STAY IN
THE UNITED STATES WHEN WE TALK
ABOUT A LITTLE BIT MORE WHEN WE
LOOK AT SOME OF OUR OTHER STTDS
SO AS FAR AS SERIOUS ADVERSE
EVENTS THERE WERE NO AEs IN
THE ARM, THEY WERE MILD, SIMILAR
IN BOTH GROUPS, THERE WAS A
TREND TOWARDS INCREASED VOMITING
AND IT WASN'T SIGNIFICANT BUT I
THINK THIS IS CLINICALLY REVANT.
TWENTY% OF THESE PATIENTS HAD
NAUSEA AND VOMITING WE KNOW THAT
ORAL ARGININE WILL CAUSE STOMACH
UPSET SO WE MAY WANT TO BE MORE
LIBERAL WITH USING ZOFRAN IN
THESE PATIENTS TO TREAT THIS
SIDE EFFECT.
SO NOW SWITCHING GEARS TO THE
RESULTS OF OUR ATLANTA STUDY SO
WE ARE FOR THE FIRST TIME
REPORTING PHASE 2 RCT OF IV
ARGININE IN CHILDREN WITH SICKLE
CELL DISEASE AND PAIN SUPPORTED
BY THE FDA ORPHANED PRODUCTS
GRANT PROGRAM WHEN I GOT TO
EMORY.
SO OUR GOAL WAS TO DETERMINE
EFFICACY AND SAFETY OF CHILDREN
WITH SCD.
AND THE STUDY WAS DONE AT EMORY
CHILDREN'S HEALTHCARE ATLANTA.
ANOTHER BLINDED RANDOMIZED MA
SEEB O CONTROL PHASE, UTELIZING
2 OF OUR CHILDREN'S HOSPITALS,
WE USED IV ARGININE COMPARED TO
PLACENTA SEEBY, IV, 8 HOURS
DISCHARGE FOR A MAXIMUM OF 7
DAYS SUBJECTS WERE RANDOMIZED TO
1 OF 3 ARMS, THEY WERE
STRAIGHTIFIED FOR HYDROXUREEA
USE BECAUSE WE HAD PUBLISHED IN
BACK IN 20,032 THERE WAS A
SINNER GESTIC IMPACT ON NITRIC
OXIDE ROUGH ATOM DUKS WHEN
ARGININE AND HYDROXY UREA WERE
GIVEN TOGETHER SO WE USED OUR
STABBED ARD DOSE THAT WAS
SIMILAR TO THE DOSE WE USED IN
OAK LAND, A HUNDRED MILLIGRAMS
PER KILOGRAM FOR DOSE, 3 TOO
MANYS A DAY, AND THERE WAS A AN
ARM THAT RELIEVED A LOADING
DOSE, FOLLOW BIDE STANDARD DOATS
AND PLACEBO.
BLOOD SAMPLES WERE ABNORMALITIES
TAINED PRIOR TO ADMINISTRATION
AND DISCHARGED AGAIN PUTTING
TOGETHER A SCD PAIN REPOSITORY
AND O GROWING THIS A RESOURCE
AND OPEN TO COLLABORATORS.
ANY GENO TYPE REQUIRING OV
OPIOIDS HOSPITALIZED FOR PAIN.
AND PRIMARY OUTCOME AND TOTAL
OPIOID USE, TIME TO CRISIS
RESOLUTION, PATIENT REPORTED OUT
COMES, WE WOULD NEED OVER 300
PATIENTS BUT THAT WAS A
SECONDARY OUTCOME MEASURE,
LOOKING AT THE TIME OF STUDY
DRUG DELIVERY TO LAST IV OPIOID
SORT OF BORROWING THIS
DEFINITION FROM SOME OF THE
BIOFACAS REMEMBERRA STUDIES,
LOOKED AT PAIN SCORES AND
PATIENT REPORTED OUTCOMES, WE
OBTAINED BIOMARKERS OFOXIDATIVE
STRESS AND MITOCHONDRIAL
FUNCTION AND THAT UTILIZED A
FACT OF IND AND REGISTERED WITH
CLINICAL TRIALS .GOV.
SO IF OUR ENROLLMENT, WE KREENED
OVER 1500 PATIENTS AT OUR SINGLE
SITE TO HOSPITAL AREA.
AND WE ENDED UP RANDOMIZING A
HUNDRED OF THEM, AND CONSENTED
TO 114, AND THE PATIENTS WHO
WERE SCREEN FAILS WERE BASICALLY
PATIENTS WHO WE RANDOMIZED TRIAL
OHMIZED BEFORE THE PHARMACY,
ENROLLED BEFORE THE PHARMACY
WOULD LEAD BUT THEN GOT
DISCHARGED FROM THE HOSPITAL AND
MET A EXCLUES CRITERIA
CONSIDERED AN EXCLUSION CRITERIA
FAILURE SO THIS STRATEGY IS
REALLY PART OF THE SECRET TO OUR
SUCCESS BECAUSE WE ACTIVELY
RECRUIT PATIENTS IN THE
EMERGENCY ROOM DEPARTMENT, 74%
OF OUR PATIENTS WERE CONSENTED
IN THE ED, WE WERE APPROACHING
PATIENTS ON THE FLOOR AS WELL IF
THEY WERE ADMITTED OVER NIGHT
BUT MOST OF THE TIME THE PARENTS
WERE NOT THERE TO CONSENT SO WE
NOT ABLE TO ENROLL THOSE
PATIENTS OR THE PATIENTS AND
PARENTINGS WERE SO TIRED THEY
COULDN'T BE PROPERLY CONSENTED.
SO HERE'S OUR 108 PATIENTS.
WE HAVE 36 PATIENTS IN EACH ARM.
THIS IS THE STANDARD DOSE, THIS
IS THE ARGININE LOADING DOSE AND
THIS IS PLACEBO, NO DIFFERENCES
ACROSS OUR ARMS, THE AGE OF
PATIENTS WERE ABOUT 12, THERE
WAS A LITTLE BIT OF A TREND OF
OLDER KIDDINGS IN THE ARGININE
GROUPS COMPARED TO PLACEBO BUT
IT WASN'T STRATEGIC
PLANNISTICALLY SIGNIFICANT, 50%
MAIL, OVER 67% WERE ON HYDROXY
UREA WHICH IS PRETTY GOD AND
THEN ABOUT 70% OF THE PATIENTS
WERE SINGLE SS OR SINGLE S-0.
SO WE HERE WE HAVE CLINICAL OUTS
SO AS IRB MENTIONED WE LOOK THE
AT TOTEDDAL EQUIVALENTS AND
LOOKED AT TIME TO CRISIS
RESOLUTION.
WE ALSO DID A SUBANALYSIS TO
LOOK AT YUNGER KIDS
BECAUSE--YOUNGER KIDS BECAUSE WE
DID ADENTIFY A LOT OF KID
NEGLIGENCE THE OLDER GROUP, AND
SOME OF THE CHRONIC PATIENTS
WHICH WERE HOPE HOPING TO A
DEEPER DIVE WITH OUR ANALYSIS,
WE WILL GET YOU A BOX SHEET, SO
OUR TYPE WE HAD, WE WERE
PRESENTING THE UNADJUSTED VALUES
AND THE ADJUSTED VALUES, AND THE
AGGRESSION WAS JUSTIFIED FOR
HYDROXY UREA USE, AND WHICH
WE'RE ALL ITEMS THAT POTENTIALLY
IMPACT OUR OUTCOME MEASURES SO
IF YOU LOOK AT OUR P-VALUES,
NOTHING WAS STATISTICALLY
SIGNIFICANT BUT THERE WAS A
RELEVANT TREND ACROSS THE BOARD,
SO, LOOK BEING AT TOTAL IV
OPIOID USE, AND AND REQUIRED 45%
MORE IV OPIOIDS, IN THE ARMS,
AND OBSERVATION FRIDAY, IF WE
LOOKED JUST AT THE KIDS UNDER
17, THAT WAS MORE THAN 80%
INCREASED TOTAL OPIOID USE IN
THE PLACEBO ARM COMPARED TO
ARGININE, AND THEN LOOKING AT
OUR TIME TO CRISIS RESOLUTION,
SO IT WAS OVER 15 HOUR,
DIFFERENCE, LONGER TIME TO
CRISIS RESOLUTION IN THE
ARGININE COMPARED TO PLACEBO,
BUT, AND IF YOU LOOK AT THIS,
THOUGH, MOST OF OUR TIME TO
CRISIS RESOLUTION WAS LESS THAN
72 HOURS, SO I JUST WANTED TO
POINT OUT THAT THIS MAY NOT
ACTUALLY BE AN IDEAL OUTCOME
MEASURE, AND WE THINK ABOUT THE
STUDY WHERE PATIENTS WERE
HOSPITALIZED FOR DEN A DAYS WHEN
I LOOKEDDA THE MEAN OVER ALL
HOSPITAL STAY FOR THESE PATIENTS
IS ABOUT 2 AND HALF DAYS, SO
WE'VE REALLY DECREASED FROM 2000
WHEN I STARTED MY K23 PHASE 2
TRIAL, THE LENGTH OF HOSPITAL
STAY WAS 6 DAYS, THE BY THE TIME
I ENDED IT WAS DOWN TO 4 DAYS,
NOW WE'RE PUSHING IT BETWEEN 2
AND HALF AND 3 DAYS SO I THINK
AS A COMMUNITY OF CLINICAL
TRIALISTS, PAINS WE REALLY NEED
TO THINK ABOUT WHERE OR NOT
WE'LL BE ABLE TO PUSH THAT
NEEDLE ANY FURTHER BEYOND 24
HOURS WHEN THESE PATIENTS ARE
ONLY ADMITTED FOR 2 AND HALF FOR
3 DAYS, SO THE CHANGE HERE WAS
ABOUT 16 HOURS AND THE ADJUSTED
ANALYSIS, WHEN WE LOOKEDDALET
JUST THE YOUNGER KIDS JUST A BIT
BETTER CLOSE TO 21 HOURS AND
AGAIN, WE WOULD NEED A LARGER
SAMPLE SIZE FOR STATISTICAL
SIGNIFICANCE, FORTUNATELY WE
HAVE INTERESTING BIOLOGICAL
OBSERVATIONS, MORE INTERESTING
EVEN AFTER ANGELLA RIVERS
PRESENTATION YESTERDAY ABOUT THE
RED BLOOD CELLS, NOW WE HAVE
PUBLISHED IN BLOOD, THE LAST
YEAR, THAT THERE WAS A DOSE
DEPENDENT IMPROVE NMENT
MITOCHONDRIAL FUNCTION AND
OXIDATIVE STRESS, AND CONTROL
STUDY, AND DATA, FROM
PHARMACOKINETICS DATA THAT WAS
UTILIZE FRIDAY OUR R34 CLINICAL
TRIALS PLANNING GRANT TO PLAN
OUR PHASE 3 TRIAL SO WHAT WE
FOUND FROM THE PHASE 2 TRIAL
SUPPORTED THOSE ORIGINAL
OBSERVATIONS BUT NOW WE HAVE
PLACEBO GROUP, SO WHAT WE HAVE
IS SIGNIFICANT INCREASE, DOSE
DEPENDENT INCREASE AND COMPLEX 5
ACTIVITY AND COMPLEX 4 ACTIVITY
AFTER ARGININE SO THE FILLED
CIRCLES ARE ED PRESENTATION, AND
THE OPEN CIRCLES ARE ED
DISCHARGE, THE RED CIRCLES ARE
NOT ON HYDROXY UREA, AND
VISUALLY YOU CAN SEE THE
DIFFERENCE IN MITOCHONDRIAL
FUNCTION ANDOXIDATIVE STRESS ON
PATIENT WHO IS ARE NOT ON
HYDROXY UREA AND THIS IS
SIGNIFICANT SO PATIENTS WHO DO
NOT USE HYDROXY UREA HAVE WORSE
MIGHT O CHOBD RIA FUNCTION AND
HIGHER STRESS THAN THOSE
PATIENTS WHO ARE ON HYDROXY UREA
AND THAT'S NEVER BEEN REPORTED
BEFORE.
SO AGAIN, NO DIFFERENCE IN
CHANGES IN MITOCHONDRIAL
ACTIVITY AND PATIENTS IN THE
PROSEEB O ARMS AND THIS IS
CARBONYL ACTIVITY, THIS IS
PATIENTS IN RECEIVED ANY FORM OF
ARGININE, WHAT'S INTERESTING IS
THERE WAS ARN INCREASE IN THE
PLACEBO ARM SO ALTHOUGH THEY'RE
GETTING BETTER CLINICALLY
THERE'S STILL A LOT GOING ON
THAT'S MEN FASTING AN
INCREASEDOXIDATIVE STRESS AT THE
TIME OF DISCHARGE FROM THE
HOSPITAL.
SO AS FAR AS SAFETY, SAEs AND
AEs WERE SIMILAR ACROSS THE
STUDY ARMS AND THE SAFETY DATA
HAS BEEN ACTUALLY REPORTED BY
LORA RAY ESTIMATE THAD, WE ARE
TRYING TO BRING HER IN BECAUSE
WE NEED TORE NEPHROLOGISTS
THINKING ABOUT THESE PATIENTS.
SO WE HAD NO UNEXPECTED AEs
ARE SAEs BUT THERE WERE A LOT
OF--A LOT OF AEs SO ANYONE
DOING AN ACUTE PAIN STUDY NEEDS
TO BE PREPARED TO FILL OUT A LOT
OF FORMS, 360 AEs THEY WERE
ALL RELATIVELY MILD AND THE MOST
COMMON WERE GI COMPLAINT ASKS
THERE WERE NO DRVESS WITH ACROSS
THE STUDY ARMS AND I THINK THAT
THE TAKE AWAY MESSAGE FROM THIS
IS THAT A LOT OF OUR PATIENTS
ARE VOMITING IN THE EMERGENCY
DEPARTMENT AND WE'RE NOT ALWAYS
TREATING THEM WITH ZOFRAN,
INDEPENDENT OF THAT, SOMETHING
WE TBHEED TO PAY ATTENTION TO
BECAUSE THESE ARE ALSO SIDE
EFFECTS OF OPIOIDS.
AS FAR AS OUR SAEs, THERE WERE
27 IN THIS 18 PATIENTS ALL
INVOLVED HOSPITAL EYATION WITHIN
30 DAYS OF PROLONGED ADMISSION
BUT LOOKING AT THE 72 HOUR
REHOSPITALIZATION RATE WAS 6%
WHICH WAS MUCH LESS WHICH HAS
BEEN PREPORTED IN LITERATURE AT
20%.
SO 1 OF THE QUESTIONS THAT OFTEN
COMES UP, IS IMPACT ON LIVER AND
RENAL FUNCTION SO WE DID HAVE
SAFETY LA LABS IN THE STUDY AND
1 THING THAT WAS INTERESTING TO
OBSERVE IS THAT THERE WAS A
SUBGROUP OF PATIENT WHO IS
PRESENTED WITH ELEVATED LFTs
AND ABNORMAL LIVER FUNCTION THAT
WE WOULD NEVER KNOW BECAUSE I
USUALLY DON'T GET CMPs IN
THESE PATES, IT WAS INCREASED AT
THE TIME OF RANDOMIZATION BUT
OVER THE COURSE OF THEIR
ADMISSION, THE BILIRUBIN AND AST
EITHER REMAIN STABLE OR
DECREASED AT THE TIME OF
DISCHARGE, WHAT'S INTERESTING IS
THAT ALT CONTINUED TO INCREASE
ACROSS ALL STUDY ARMS SO THERE
WAS NO DIFFERENCE IN THOSE WHO
RECEIVED ARGININE VERSUS PLACEBO
BUT I YOU DID SEE THIS ONGOING
INCREASE, THIS MAY REPRESENT THE
COURSE OF LIVER DYSFUNCTION
DURING ACUTE PAIN WHICH IS
SOMETHING I HAD PREVIOUS THOUGHT
ABOUT EITHER, BUT IT DOES GIVE
ME PAUSE CONSIDERING ALL THE
TYLENOL WE TEND TO GIVE THESE
PATIENT WHEN IS THEY'RE ADMITTED
TO THE HOSPITAL.
KRE TINSA TIENINE WAS STABLE
ACROSS STUDY ARMS.
THERE WAS A MILD TO INCREASE IN
THE UN BETWEEN ANDROGEN ORDER OF
MICRONSIZATION AND TIME OF
DISCHARGE IN ARGININE GROUPS
ONLY WHICH MAKES SENSE BECAUSE
IT IS A NITROGEN LOAD BUT THIS
WAS NOT CLINICALLY RELEVANT AND
YOU CAN SEE IT WAS A INCREASE IN
BUN WITHIN THE RANGE OF NORMAL.
SERUM BI CARB REDECKED SLIGHTLY
IN THE ARGININE LOAD ARM BUT
AGAIN, IT WAS WITHIN THE RANGE
OF NORMAL AND NOT CLINICALLY
RELEVANT, AND THEN FINALLY,
POTASSIUM, INCREASED SLIGHTLY
FROM THE TIME OF RANDOMIZATION
IN THE STANDARD DOSE OF ARGININE
BUT AGAIN NO 1 BECAME HYPER
K-LEEMIC AND IT WAS WITHIN THE
RANGE OF NORMAL AND NONE OF THIS
WAS CLINICALLY RELEVANT.
SO THE REASON WE LOOK AT THESE
SPECIFICALLY IS BECAUSE ARGININE
IS DELIVERED AS L-ARGININE HYDRO
CHLORIDE WHICH IS ACIDIC BUT THE
SALINE, SO MAYBE WE WOULD HAVE A
DIFFERENT POINT THAT WOULD BE
NONACIDIC.
SO IT'S BEEN VERY SAFE, THERE'S
BEEN EXTENSIVE ANIMAL AND MUSEUM
MAN STUDIES, THE 921972 IT WAS
APPROVED USING HIGHER DOSES THAN
WE USE IN OUR STUDY AND IN FACT
THERE'S BEEN CONSIDER THAT I
HEARD FROM HEMEATOLOGY
COLLEAGUES ABOUT ITS POTENTIAL
FOR IMPACT ON THE LIVER, BUT
MORE AND MORE DATA IS USE COMING
OUT THAT IT'S USED FOR LIVER AND
IT'S USED FOR ACUTE HYPER
PNEUMONIA.
HYPER KALEMIA, RISKS IN PATIENTS
WITH ADVANCED RENAL HEPATICIN
SUFFICIENCY, SIDE EFFECTS ARE
NAUSEA AND VOMITING AND IF YOU
SLOW THE INFUSIONS IT MAY HELP,
BUT PFIZER HAS REPORTED THESE
SYMPTOMS IN ABOUT 3% OF PATIENTS
AND WE NOW HAVE GROWING
EXPERIENCE WITH SICKLE CELL DEC
WITH OUR STUDIES OVER THE 20
YEAR JOURNEY OF OVER 270
PATIENTS BEING RANDOMIZED INTO 1
STUDY OR ANOTHER OF IV ARGININE
OR PLACEBO.
AND ULTIMATELY ACROSS ALL THOO
TIME THERE'S BEEN NO UNEXPECTED
AEsOR SAEs RELATED TO STUDY
TO DATE.
SO IN CONCLUSION WE KNOW THAT
THE DEFICIENCY DOES PLAY A ROLE
IN SICKLE CELL DISEASE AND PAIN
AND ORAL ARGININE IS HELPFUL IN
ENVIRONMENTS, ORAL ARGININE HAS
BEEN PEN FICIAL, GENERALLY SAFE,
INIMPROVES CARDIO PULMONARY
INJECTION AND KUDOS TO DR. ONALO
FOR BEING MY STAR MENTEE IN THE
WORK HE WAS ABLE TO DO WITH VERY
LITTLE RESOURCES.
AND THEN AS FAR AS IV ARGININE,
SAFE, NUTRITIONAL SUPPLEMENT,
IMPROVES MITOCHONDRIAL FUNCTION.
>> ONE MINUTE WARNING.
>> OKAY, DECREASED OXIDATIVE
STRESS, BUT THERE'S A TREND IN
OPIOID USE AND A TREND TOWARDS
SHORTER TIME TO CRISIS
RESOLUTION, OUR LIMITATION IS
THAT THIS IS SINGLE CENTER,
SMALL SAMPLE SIZE AND WHAT WE
REALLY NEED IS THE PHASE 3
MULTICENTER TRIAL, IT'S
WARRANTIED AND I WANT TO THANK
NHLBI FOR SPONSORING START WHICH
IS A SICKLE CELL DISEASE
TREATMENT WITH ARGININE THERAPY
WHICH IS A 10 SITE STUDY RUN
OVER 6 YEARS THAT WILL HOPEFULLY
BE THE DEFINITIVE STUDY TO
ANSWER THIS QUESTION, SOMETIME
BEFORE I RETIRE, IT IS ENDORSED
BY PC ARN, WHICH IS THE APPLIED
RESEARCH NETWORK, SOME OF YOU
MAY REMEMBER THIS, WORK BY DAVID
AND COLLEAGUES, THE MAGIC STUDY,
FOR MING NEEZIUM STUDY CRISIS,
HE MADE HISTORY WHENEE ENROLLED
OVER 200 PATIENTS IN LESS THAN 3
YEARS KNOWING THE CHALLENGES
EVER ENROLLING IN SICKLE SEAL
CLINICAL TRIALS, VOV REMAINS BUT
KIDS WITH SICKLE CELL DISEASE
APPEAR, WELL THE MAGIC IS REALLY
PKARN AND USING THE NETWORK FOR
SUCCESSFUL TRIALS.
SO FOR OUR START TRIAL IS 360
WITH A LOFTY GOAL WITH JUST 10
CENTERS, I HAD TO CHANGE THE
NUMBER BECAUSE WE HAD ANOTHER
PATIENT RANDOMIZED WE ARE WELL
ABOVE OUR MILESTONES AND AGAIN
THAT'S THE POWER AND MAGIC OF PC
ARN AND ALL THE EMERGENCY
DEPARTMENT LEADERS WORKING WITH
TOGETHER WITH THE
HEMEATOLOGYISTS TO ACTUALLY
SUCCESSFULLY ENROLL IN STUDIES.
SO, KEY POINTS ARGININE IS
CONDITIONALLY EMINNOW ACID,
BECOMES ESSENTIAL UNDER
CONDITIONS OF STAT AND CATABOLIC
STATE AND CAPACITY OF THE
AMINE'S ACID SENTH SIS IS
EXCEEDED.
SICKLELE DISEASE REPRESENTS
ARGININE SYNDROME, DISTINCT
NUTRITIONAL REQUIREMENT, IT MAY
BENEFIT FROM ARGININE
REPLACEMENT THERAPY OR ART, IF
YOU REMEMBER WHAT I TOLD YOU IN
THE BEGINNING ABOUT WHEN A
NUTRITIONAL DEFICIENCY TO BE
PRESENT, YOU HAVE TO HAVE THE
BIOLOGICAL PROCESS, AND IT'S
COMPROMISED AND THINK ABOUT
PULMONARY RETENTION AND PAIN,
THAT LEADS TO PHYSIOLOGIC
RESPONSES AND POOR OUTCOMES THAT
ARE REVERSED BY AMINEEE ACID
REPOLICEMENT AND THE MECHANISM
OF ACTION IS MULTIFACTORRIA AND
MITOCHONDRIAL FUNCTION MAY
REPRESENT A NOVEL BIOLOGICAL
OUTCOME WE CAN USE IN THESE
TRIALS, MANY THANKS TO EVERYBODY
ALONG THE WAY AND MY METRICS OF
FOR K23, FOR HER EXCELLENT
MITOCHONDRIAL WORK, THE TEEM I
TEAM I HAVE THAT'S ENROLLING
EVENT TODAY IN THE START TRIAL,
IS THEN OF COURSE MY FAMILY BHO
PUT UP WITH ALL MY WORK ON THIS
FOR THE LAST 20 YEARS, THANK
YOU.
>> THANK YOU VERY MUCH
CONGRATULATIONS AND GREAT DATA
AND GREAT PRESENTATION.
MY APOLARIZEDS I ALMOST BOTCHED
YOUR PRESENTATION.
WE WERE RUNNING A LITTLE AHEAD
OF TIME WHICH USUALLY DOESN'T
HAPPEN BUT THANK YOU SO MUCH
AGAIN.
YOU HAVE QUITE A FEW COMMENTS
AND QUESTIONS IN THE Q&A, SO
WHICH YOU CAN RESPOND TO.
LET ME JUST READ 1 COMMENT, OR
QUESTION FROM A COLLEAGUE: CAN
YOU ELABORATE MORE ON
RELATIONSHIP BETWEEN ARGININE
DEFICIENCY OR CONVERSION AND CKD
IN SICKLE CELL?
>> SO I THINK THAT THAT'S AGAIN
A GAP IN OUR KNOWLEDGE AND WITH
LORETTA REYES IS 1 OUR MENTEES,
I AM ENCOURAGING HER TO WORK IN
THIS SPACE FYOU HAVE CKD, CAN
DEPENDS ON OW BAD YOUR KIDNEY
DYSFUNCTION IS, BUT TO THAT
ENZYME, IT CAN GET KNOCKED OUT
AND THEN YOU WOULD LOSE YOUR
ABILITY TO CONVERT SIT ROUGH
ATOM LEAN TO ARGININE AND THEN
YOU WILL HAVE A CONTRIBUTION TO
ARGININE DISREGULATION JUST BY
WAY OF KIDNEY DYSFUNCTION, AND
WE'VE SEEN IN THIS IN OUR ADULT
PATIENTS THAT THE PATIENT WHO IS
HAD PULT PULMONARY HYPERTENSION
WERE THERE'S A STRONG
CORRELATION BETWEEN TRJET AND
YOUR GLOBAL ARGININE
BIOAVAILABILITY RATIO AND THOSE
PATIENTS TENDED TO BE THE
PATIENT WHO IS HAD RENAL
DYSFUNCTION SO I THINK THERE'S A
COMBINATION OF EFFECTS THAT COME
TOGETHER THAT LIMIT YOUR
ARGININE VIA BILITY AND THE
KIDNEY IS IMPORTANT BECAUSE IT
SHOULD BE ABLE TO SYNTHESIZE
ARGININE WHEN IT COMES LOW AND
IT'S A PROBLEM WITH OUR PATIENTS
WITH SICKLE CELL AND CKD.
>> THANK YOU.
APPROXIMATE WITH THAT I THINK WE
WILL--THIS WAS THE LAST TALK
BEFORE WE BREAK FOR LUNCH.
WE HAVE ANOTHER EXCELLENT
SYMPOSIUM AGAIN TALKING ABOUT
PAIN AND SICKLE CELL THAT WILL
START EXACTLY AT 1:15 SO, PLEASE
MUTE YOUR MICROPHONES AND YOUR
CAMERAS AND WE WILL TUNE BACK AT
1:15.
SEE YOU THEN.
WE ARE GOING TO GET START WITH
LAST COMPONENT OF THIS THREE DAY
TALK. REALLY EXCITING TALKS AND
WE HAVE SAVED THE BEST FOR THE
LAST. SYMPOSIUM 6. THIS IS GOING
TO BE TALKING ABOUT REFINING THE
RESEARCH AGENDA FOR PAIN AND
SICKLE CELL DISEASE AND DR.
SMITH WALLY CHERYL STUDY AND
KALPNA GUPTA ARE THE CHAIRS FOR
THIS SESSION. TAKE IT AWAY.
>> THANK YOU. I WILL SHARE MY
SCREEN.
LET ME KNOW IF YOU CAN SEE IT.
>> YOU MAY WANT TO PUT IT IN
PRESENTATION MODE.
>> GOOD.
>> OKAY. SO AS STATED, WE ARE
GOING TO BE TALKING ABOUT
MECHANISTIC AND BASIC
TRANSLATIONAL APPROACHES TO
SICKLE CELL DISEASE AND PAIN. IT
MIGHT HAVE BEEN BETTER IF WE DID
THIS THIS MORNING AND THEN THIS
MORNING SESSION THEN THIS
AFTERNOON BECAUSE THOSE WERE
MORE APPLIED TREATMENT BASED
RECOMMENDATIONS BASED OFF WHAT
SOME OF THE THINGS WE ARE ARE
GOING TO TALK ABOUT THIS
AFTERNOON THOUGH KALPNA WILL
BRING YOU INTO THE TREATMENT
REALM. WHAT I WOULD LIKE TO DO
IS START BY TELLING YOU WHO IS
GOING TO SPEAK. AND THEN NOT
INTERRUPTING YOU ANY FURTHER. SO
WE WILL HAVE CHERYL STUDY, AND
AMANDA BRANDOW TALKING ABOUT
BRIDGING FROM BASIC TO
TRANSLATIONAL RESEARCH AND PAIN.
WE'LL HAVE NITYA BAKSHI TALK
ABOUT PHENOTYPIC EXPRESSIONS AND
OTHER WAYS OF EXPRESSING PAIN.
WE WILL HAVE PAT -- I THINK PAT
MIGHT GET THE PRIZE FOR SPEAKING
THE MOST AT THIS SERIES OF
MEETINGS. PAT CARROLL TALKING
ABOUT GUIDELINES AND TALKING
ABOUT APPROACHES TO CLINICAL
MANAGEMENT. THEY WILL GO WITHOUT
INTERRUPTION. WHAT I'M GOING TO
DO IS JUST SHOW YOU THAT IT DOES
TAKE A WHOLE DAY TO TALK ABOUT
PAIN. AND THAT THE NUMBER OF
ARTICLES PUBLISHED ON THIS TOPIC
IN SICKLE CELL DISEASE HAS
SKYROCKETED SINCE THE 1960s,
IT IS THE MOST COMMON SYMPTOM.
AND YET THE LEAST AMOUNT OF
CLEAR GUIDANCE ABOUT WHAT TO DO
FOR PAIN AND A LOT LESS
UNDERSTANDING ABOUT PAIN AND
SICKLE CELL DISEASE THAN WE
WOULD HAVE LIKED. THAT STEMS IN
PART FROM OUR LACK OF
UNDERSTANDING ABOUT PAIN IN
GENERAL. IT WAS ORIGINALLY KNOWN
PATIENTS WITH SICKLE CELL
DISEASE HAD PAIN BY TRIBAL
ELDERS IN AFRICA WHO USED
ONOMOTOPEA, THINGS LIKE CHEW WII
CHEW WII TO DESCRIBE SYMPTOMS OF
PATIENTS WITH SICKLE CELL
DISEASE AND THE NOTED TRIBAL
PREVALENCE AND NOTED FACT THAT
PATIENTS DIED SOON RATHER THAN
LATER. IN BIOLOGY OF SICKLE CELL
WAS CLEARLY WHAT HAPPENED IN THE
CENTURY OF THE 1900s AND WE
HAVE THE DISCOVERY OF THE
ABNORMAL CELLS IN 1910 IN
CHICAGO AT RUSH AND THEN THE
RELATIONSHIP OF PAIN RATE TO
MORTALITY BY PLATT AND OTHERS IN
THE COOPERATIVE STUDY, IN 1991
WITH A RELATIONSHIP OF
HEMOGLOBIN AS ONE BIOMARKER TO
MORTALITY. THEN WE BEGAN TO
EXPAND OUR UNDERSTANDING OF PAIN
AND SICKLE CELL DISEASE AS WE
DID PAIN IN OTHER DISEASES TO
SAY THAT IT IS A BIOPSYCHOSOCIAL
PHENOMENON, FIRST THAT PAIN
COMES WITH DAILY PREVAILING
WINDS, CHRONIC PAIN INTERCEPTED
BY HURRICANES AND TORNADOES OF
BASAL OKAY COLLUSIVE CRISES WE
CANNOT PREDICT. MANY WHICH ARE
MANAGED AT HOME. BUT THE
ACCOMPANYING PROBLEMS WITH THE
DAILY PREVAILING WINDS AND THESE
TORNADOES AND HURRICANES
ACCOMPANYING PROBLEMS ARE LEE
GENERAL AND NOT BIOLOGICAL BUT
BIOPSYCHOSOCIAL DEPRESSION
ANXIETY AND EVEN A BONE MARROW
TRANSPLANT DOESN'T GET RID OF
PAIN IN SICKLE CELL DISEASE, SO
THE PAIN MUST NOT BE BASAL OKAY
COLLUSIVE. OUR UNDERSTANDING OF
PAIN WAS VERY CAUSE EFFECT
RELATIONSHIP EARLY ON, WE
THOUGHT THE PAIN STIMULUS WAS
THE ONLY THING THAT COULD CAUSE
THE PAIN. WE NOW KNOW THAT IS
NOT TRUE. IT IS A
BIOPSYCHOSOCIAL PHENOMENON. THE
AMOUNT OF PAIN INPUT FOR EXAMPLE
VASVASOVASOOKAY COLLUSIVE BIOLOGY DOES
NOT DICTATE PAIN EXPRESSION.
THERE IS A COMMON NEUROMETRICS
WE ADAPTED IN OUR REVIEW
MULTI-MODAL ANALGESIC REGIMENS
THIS MORNING, WE REVIEWED THAT
RECENTLY AND IN THAT REVIEW
TRIED TO PUT THIS UNDERLYING
MODEL TO EXPLAIN WHY THOSE
ANALGESIC REGIMENS MIGHT BE
APPROPRIATE. SO ON THE LEFT-HAND
SIDE YOU HAVE COGNITIVE THAT IS
KNOWLEDGE OF PAIN, EITHER MEMORY
OF PAIN WHICH CAUSE
CATASTROPHIZING OR YOU MIGHT
THINK OF BIOLOGICAL MEMORY IN
THE FORM OF NEURAL PLASTICITY,
NEURAL PLASTICITY. YOU HAVE
SENSORY CHANGES VISCERAL CHANGES
MUSCULOSKELETAL CHANGES. THIS
TERM HAS COME INTO PLAY AND
DEFINITELY AFFECTS SICKLE CELL
DISEASE. THEN PEOPLE REACT TO
THEIR PAIN, DEPRESSION, ANXIETY,
THE WAY THEY FEEL ABOUT THEIR
PAIN MAY CHANGE BIOLOGY,
VASOCONSTRICTION ASSOCIATED WITH
NEURAL CHEMICAL RELEASE RELATED
TO ANXIETY. VERY COMPLEX SET OF
INPUTS. THE OUTPUTS ARE NOT
JUST PAIN BUT ALSO KENESIA
PHOBIA, INVOLUNTARY LACK OF
MOTION AND BEING STILL AND NOT
PARTICIPATING IN DAILY
ACTIVITIES. THEN THE STRESS
ASSOCIATED WITH IT. AGAIN IN THE
FORM OF CORTISOL WHICH IS A VASO
VASOACTIVE SUBSTANCE. THERE'S
MORE THAN WHAT IS ON THIS PAGE.
THIS IS A START TO TRY TO
EXPLAIN WHAT THE PAIN EXPERIENCE
IS AND IT IS BASIS FOR SOME OF
THE TARGETED THERAPIES THAT YOU
HEARD ABOUT THIS MORNING. SO NOT
ONLY ANALGESICS, NOT ONLY
DISEASE MODIFIERS, BUT ALSO
ACCEPTANCE COMMITMENT THERAPY,
COGNITIVE BEHAVIORAL THERAPY,
MIND BODY THERAPIES TO EXPOSE
THE PATIENT TO A DIFFERENT WAY
OF COPING WITH YOUR PAIN IN A
DIFFERENT WAY OF REACTING TO
THEIR PAIN HYPNOSIS, ET CETERA.
ACUTE PAIN HAS BEEN DEFINED FOR
SICKLE CELL DISEASE THAT'S HOW
FAR BEHIND WE ARE, TOOK UNTIL
018 TO SAY WHAT ACUTE PAIN IN
SICKLE CELL DISEASE WAS OTHER
THAN HOSPITAL UTILIZATION. THIS
IS A AGREED UPON DEFINITION
PUBLISHED ON THE ACCOUNT OF THE
AAAPT GROUP. SIMILARLY CHRONIC
PAIN IS DEFINED WE SAY PERSISTS
PAST NORMAL TIME OF HEALING, AND
CHRONIC NON-CANCER PAIN, IT IS
EITHER EVERY SIX MONTHS, EVERY
THREE MONTHS DEPENDING WHO YOU
READ AND SICKLE CELL DISEASE WE
PICKED SIX MONTHS AND SAID PAIN
ON MOST DAYS ARE MAJORITY OF
DAYS. OVER THE PAST SIX MONTHS.
WITH DIAGNOSTIC MODIFICATIO MODIFICATIONS
THAT TRY TO GIVE YOU AN IDEA
WHETHER NOSEY PLASTIC PAIN IS
ALSO PRESENT OR MOST COMMONLY A
MIXED PAIN PHENOTYPE. WITHIN
THAT PATIENTS CAN HAVE
EXACERBATION OF THEIR CHRONIC
PAIN THAT ARE NOT CALLED
VASOOCCLUSIVE CRISES. HERE YOU
CAN SEE THE NUMBER OF EPISODES
OF PATIENTS WHO HAD
EXACERBATIONS THAT DID NOT CALL
THEM VASOOCCLUSIVE CRISIS WAS
NOT ZERO. SO YOU HAVE A
WANDERING DAILY WINDS,
PREVAILING WINDS WANDERING UP
AND DOWN IN TERM OF INTENSITY,
AND THEN YOU HAVE PUNCTUATED HER
CANES AND TORNADOES. SOMEWHERE
ALONG THE WAY PAIN IN SICKLE
CELL DISEASE TRANSFORMS IN SOME
PATIENTS, IT TRANSFORMS FOR FROM
ACUTE CHRONIC VASOOCCLUSIVE
PHENOMENON, INFLAMMATORY
PHENOMENON TOP THE BEGINNING OF
CENTRAL AND PERIPHERAL
NEUROPATHIC PAIN OR NOCI PLASTIC
PAIN AND THAT TRANSFORMATION IS
STILL BEING STUDIED. WHY DOES IT
OCCUR IN SOME AND NOT IN OTHERS?
IS THAT GENES, HOW MUCH DOES IT
TAKE FOR IT TO OCCUR, IS THERE A
THRESHOLD AFFECT, IS IT GRADUAL
IN EVERY ONE? IT SEEMS TO HAPPEN
IN THE TEEN YEARS, MAYBE SICKLE
CELL DISEASE SHARES THIS WITH
OTHER SYNDROMES SO THE SAME
THERAPIES THAT YOU HEARD ABOUT
THIS MORNING THAT COULD BE USED
FOR SICKLE CELL DISEASE ARE
USEFUL IN OTHER SYNDROMES,
WORKING IN THE SAME MECHANISM.
WE JUST DON'T YET KNOW HOW ALL
OF IT WORKS. SOME OF WHAT YOU
ARE GOING TO HEAR TODAY IS
EXPLORING THAT. YOU HAVE ALREADY
HEARD ABOUT ALL THOSE DIFFERENT
COMPLIMENTARY INTEGRATIVE
APPROACHES TO CARE THIS MORNING
BUT GUESS WHAT, MOST PATIENTS
CAN'T GET THEIR HANDS ON THEM.
INSURANCE WILL NOT PAY FOR THEM.
CMS ACKNOWLEDGED THIS IN A VERY
DETAILED DIAGRAM PUBLISHED ABOUT
A MONTH AGO SHOWING THE
FINANCIAL BURDENS, THE MENTAL
HEALTH BURDENS, THE STIGMA FROM
FAMILY FRIENDS AND PHYSICIANS,
AND THE DYSFUNCTION ASSOCIATED
WITH CHRONIC PAIN. OF ALL KINDS.
INCLUDING SICKLE CELL DISEASE.
THE LACK OF INSURANCE COVERAGE
AND THE PROBLEMS THAT PEOPLE GO
THROUGH TRYING TO GET TREATMENTS
LIKE YOU HEARD THIS MORNING AND
WE WILL HEAR SOME THIS
AFTERNOON. AMANDA ALLOWED ME TO
USE THIS SLIDE, THIS IS WHAT YOU
SHOULD DO WHEN SOMEBODY COMES IN
WITH SICKLE CELL PAIN. DON'T
JUST ASSUME IT IS ALL A SIMPLE
STIMULUS RESPONSE PHENOMENON.
TRY AND ASSOCIATE SOME OF THOSE
PHENOTYPE DESCRIPTORS I TALKED
ABOUT WITH THERE SYMPTOMS AND
WITH THEIR DESCRIPTIONS AND TRY
TO COME UP WITH A PERSONALIZED
TARGETED TREATMENT STRATEGY,
INDIVIDUALIZED FOR THAT PERSON.
LIKELY MULTI-MODAL AND GET AS
MUCH PAID FOR AS YOU CAN. SO
RATHER THAN GO THROUGH ALL THESE
INDIVIDUALIZED DETAILS, I'M
GOING TO KEEP GOING AND HAND OFF
TO DR. STUFFCKY STUCKY. CLAUDIA CAMPBELL
WON'T BE PRESENTING. SO DR.
STUCKY, BRANDOW AND BAKSHI WILL
PRESENT. CHERYL.
>> THANK YOU VERY MUCH. AMANDA,
WE -- AMANDA AND I APPRECIATE
THIS OPPORTUNITY TO SPEAK TO
YOU. WE DECIDED THAT AMANDA
WOULD LEAD US OFF WITH HER
DESCRIPTION OF HER CLINICAL
STUDIES WITH PATIENTS WITH
SICKLE CELL DISEASE. SO I WILL
TURN THIS OVER TO AMANDA FIRST.
>>THANK YOU, DR.
SMITH AND EVERYONE AT THE NHLBI
FOR THE OPPORTUNITY TO TALK
TODAYTODAY. DR. STUCKY AND I WILL
GIVE COMBINED ENTITLED
INVESTIGATING SICKLE CELL
DISEASE PAIN FROM HUMAN TO MOUSE
AND IN BETWEEN. AND I WILL START
US OFF AS CHERYL SAID. SO
OVERVIEW TODAY I WILL IDENTIFY
GAPS IN PAIN RESEARCH THAT OUR
WORK IS ATTEMPTING TO FILL I
WILL DISCUSS CLINICAL
TRANSLATIONAL RESEARCH. DR.
STUCKY WILL DISCUSS BASIC PAIN
RESEARCH THEN CONCLUDE. SO THIS
SLIDE CAME FROM THE 2021
WORKSHOP THAT NIH SPONSORED
LOOKING AT SICKLE CELL DISEASE
PAIN LAST SUMMER. THIS SLIDE
DESCRIBES SOME OF THE GAPS THAT
NEED TO BE FILLED AND THE ONES
HIGHLIGHTED IN YELLOW ARE THE
ONES THAT OUR TOP WILL ADDRESS
TODAY INCLUDING OUR ACUTE PAIN
MECHANISM SIMILAR OR DIFFERENT
ACROSS PATIENTS, WHAT MECHANISMS
UNDERLIE THE ACUTE ON TOP OF
CHRONIC PAIN AND EITHER
INDIVIDUAL DIFFERENCES IN
BIOLOGY THAT UNDERLINE PAIN
SEVERITY. SO I WILL START
PRESENTING SOME OF THE WORK WE
ARE DOING IN MY LAB ON BEHALF OF
THE CO-AUTHORS ON THE SLIDE.
THIS IS ENTITLED IDENTIFICATION
OF BIOLOGICAL PROCESSES
ASSOCIATED WITH PAIN IN
INDIVIDUALS WITH SICKLE CELL
DISEASE. SO AS MOST KNOW DESPITE
THE SAME MUTATION THAT CAUSES
SICKLE CELL DISEASE THERE IS
SIGNIFICANT VARIABILITY IN PAIN
EXPRESSION BETWEEN INDIVIDUALS
AS DR. SMITH OPENED UP AND
TALKED ABOUT. MANY PATIENTS
EXPERIENCE FREQUENT AND
RECURRENT PAIN AND CHRONIC PAIN
WHILE OTHERS EXPERIENCE
FORTUNATELY ONLY OCCASIONAL
PAIN. HOWEVER THE KNOWLEDGE OF
THE BIOLOGY THAT DISTINGUISHES
THIS ENTERINDIVIDUAL PAIN
VARIABILITY IS NOT WELL
UNDERSTOOD. WORK IN OTHER PAIN
MODELS SHOWS THAT A VARIETY OF
NEURAL AND IMMUNE INTERACTIONS
DRIVE ACUTE AND CHRONIC PAIN.
THIS IS RELEVANT IN SICKLE CELL
DISEASE BECAUSE IT IS A KNOWN
CHRONIC INFLAMMATORY DISORDER.
WHICH CHRONIC IMMUNE ACTIVATION.
SO IF WE CAN IDENTIFY SOME OF
THESE BIOLOGICAL PATHWAYS
THROUGH GENE EXPRESSION ANALYSES
THAT CONTRIBUTE TO THIS
HETEROGENEITY, WE MIGHT BE ABLE
TO OVERCOME BARRIERS IN SICKLE
CELL SPACE HOW TO PROGNOSTIC
PAIN OUTCOMES FOR OUR PATIENTS.
THAT IS SOMETHING WE GET ASKED
AS PEDIATRIC PROVIDERS. WE ALSO
COULD HELP US IDENTIFY NOVEL
TARGETS THAT COULD BE LEVERAGED
FOR PAIN THERAPEUTICS. SO OUR
STUDY ADDRESSED TWO WAYS FIRST
TO IDENTIFY GROUPS OF GENES OR
MODULES THAT SIGNIFICANTLY
CORRELATE WITH HEALTHCARE
UTILIZATION FOR PAIN. AND
IDENTIFY GROUPS OF GENES THAT
SIGNIFICANTLY CORRELATE WITH
PAIN -- PATIENT RELATED -- PAIN
RELATED PATIENT REPORTED
OUTCOMES. WE HYPOTHESIZED THAT
GENE MODULES RELATED TO THE
IMMUNE SYSTEM WILL CORRELATE
WITH INCREASE CLINICAL
EXPRESSION OF PAIN IN
INDIVIDUALS WITH SICKLE CELL
DISEASE. WE STUDIED 27
INDIVIDUALS LESS THAN EQUAL TO
18 YEARS OF AGE, WE OBTAINED
PAIR SAMPLE DURING BASELINE
STATE OF HEALTH AND DURING ACUTE
PAIN EPISODE. WE COMPARED THESE
TO 45 HEALTHY BLACK CONTROLS.
WE CONDUCT PLASMA INDUCED
TRANSDUCTION ANALYSES AND FOR
THESE ANALYSES WE OBTAINED A
PERIPHERAL BLOOD NON-NUCLEAR
CELL FROM WELL CHARACTERIZED
DONOR. WE INCUBATED THE PBMCs
WITH PLASMA MA FROM INDIVIDUALS
WITH SICKLE CELL DISEASE DURING
BASELINE STATE AND ACUTE PAIN
AND HEALTHY BLACK CONTROLS. THIS
PBMC ACTED AS A SENSOR FOR
FACTORS THAT EXISTED IN THE
PATIENT AND CONTROL PLASMA. WE
PURIFIED THE RNA FROM THESE
PBMCs, LABELED AND HYBRIDIZED
IT TO AFFYMETRICS ARRAY TO LOOK
AT TRANSCRIPTION CHANGES. THEY
ALSO HAD CLINICAL PAIN
ASSESSMENTS THROUGH PAIN RELATED
PATIENT REPORTED OUTCOMES WHERE
WE USE THE PEDSQL SICKLE CELL
DISEASE MODULE SUB SCALES PAIN
AND HURT AND IMPACT. THESE ARE
SCORED ON DEVELOPER GUIDELINES
RANGING FROM 0 TO 100, HIGHER
SCORES REFLECT BETTER
FUNCTIONING. AND WE ALSO LOOK AT
THE NUMBER OF ACUTE CARE
ENCOUNTERS FOR PAIN THE PRIOR
THREE YEARS. DATA ANALYSIS
INCLUDED WEIGHTED GENE
CO-EXPRESSION NETWORK ANALYSIS,
OR WGCNA. WHICH IS A DATA
REDUCTION TECHNIQUE FOR VARIETY
OF GENETIC DECEMBER WHICH GROUPS
GENES WITH SIMILAR EXPRESSION
PATTERN VARIATION INTO SOMETHING
CALLED A MODULE. THESE MODULES
THEN REPRESENT CLUSTERS OF
HIGHLY INTERCONNECTED GENES.
EACH MODULE HAS A MODULE
EIGENGENE, REPRESENTATIVE OF THE
GENE EXPRESSION PROFILES IN THAT
MODULE. THIS MODULE GENE IS
CORRELATED WITH PHENOTYPIC
TRAITS AND IN OUR STUDY WE LOOK
AT PAIN RELATED PROS AND PAIN
HISTORY OF INDIVIDUAL. THE
MODULE EIGEN GENE OF 0.3 OR
HIGHER BETWEEN ONE PHENOTYPIC
SICKLE CELL DISEASE TRAIT WAS
RETAINED. THIS IS CALLED THE
EEGEN GENE SIGNIFICANCE. WE THEN
LOOKED AT THE BIOLOGICAL
PATHWAYS ASSOCIATED WITH THOSE
MODULES THROUGH ON TO LOGICAL
ANALYSES USING DATA. THIS IS
DEMOGRAPHICS OF OUR POPULATION.
OUR MEAN AGE OF OUR PATIENTS WAS
10.9 YEARS AND CONTROLS WAS
13.3. SIMILAR SEX IN BOTH GROUPS
OUR PATIENTS HAD APPROXIMATELY
FOUR PAIN EVENTS IN THEIR PAIN
HISTORY THAN THE PRIOR THREE
YEARS AND DIFFERENCES IN PATIENT
REPORTED OUTCOMES BETWEEN
BASELINE HEALTH AND ACUTE PAIN
ARE ON THE SLIDE. THESE
REPRESENT OUR HEAT MAPS FOR OUR
GENE EXPRESSION DATA AND I WILL
WALK YOU THROUGH THIS. AS
REMINDER RED REPRESENTS
UPREGULATION OF GENE OR
INCREASED EXPRESSION. THE PANEL
ON THE LEFT REPRESENTS THE MEAN
GENE EXPRESSION OF GROUPS AS A
WHOLE. THE PANEL HERE REPRESENTS
INDIVIDUAL EXPRESSIONS OF OUR
CONTROLS AND AS REMINDER A
COLUMN REPRESENTS AN INDIVIDUAL
AND A ROW REPRESENTS A DIFFERENT
GENE THAT CAN BE MAINTAINED
THROUGHOUT ALL THREE OF THESE
PANELS. THE TWO PANELS ON THE
RIGHT REPRESENT PATIENTS WITH
INDIVIDUAL SICKLE CELL DISEASE
DURING BASELINE STATE OF HEALTH
AND ACUTE PAIN AND AS A REMINDER
THESE ARE PAIRED SAMPLES FROM
THE SAME INDIVIDUALS AT
DIFFERENT STATES OF DISEASE.
GOING BACK TO THIS MEAN
EXPRESSION DATA, CONTROL IS ON
THE LEFT COLUMN AND THE PAIRED
SAMPLES ARE ON THE RIGHT. WE
ALSO ANALYZE AN UNPAIRED SAMPLE
DURING BASELINE STATE OF HEALTH
AND I WON'T TALK ABOUT THAT
DETAIL BUT REASON I RETAIN THIS
ON THE SLIDE IS TO JUST POINT
OUT THE IMPORTANCE OF ANALYZING
PAIRED SAMPLES. AS YOU CAN SEE
IF YOU FIRST LOOK AT THE
UNPAIRED DATA, THAT BASELINE
HEALTH AND COMPARE TO THE ACUTE
PAIN WHICH IS THE COLUMN ON THE
RIGHT YOU SEE THERE APPEARS TO
BE DIFFERENCES. HOWEVER, WHAT
YOU CAN SEE IS WHEN YOU LOOK AT
THE SAME PATIENT THOSE
DIFFERENCES AREN'T AS PRONOUNCED
BETWEEN THE TWO STATES OF
HEALTH. SO IT ALSO SUGGESTS THAT
INTERPATIENT INTERPATIENT
VARIABILITY THAT WE ARE SEEING
AND THAT WERE FURTHER TRYING TO
UNDERSTAND. SO OVERALL YOU CAN
SEE THAT PATIENTS WITH SICKLE
CELL DISEASE DO APPEAR DIFFERENT
FROM HEALTHY CONTROLS AND THEIR
GENE EXPRESSION. ALSO WHAT WE
WERE SURPRISE IS HOW SIMILAR IN
GENERAL THE PATIENTS LOOKED
BETWEEN THE TWO STATES OF
HEALTH, HOWEVER, IF YOU REALLY
LOOK AT AN INDIVIDUAL AND FOLLOW
WHAT COLUMN COMPARED TO ANOTHER
COLUMN ON THE DIFFERENT PAIN
STATES OR DIFFERENT DISEASE
STATES YOU CAN SEE THERE ARE
DIFFERENCES IN INTERINDIVIDUAL
VARIABILITY WHICH WE ARE TRYING
TO FULLY UNDERSTAND IF THAT IS
BIOLOGICALLY MEANINGFUL. THIS
SLIDE SHOWS OUR WGCNA ANALYSIS.
I WILL WALK YOU THROUGH THE
SLIDE NOW. WHAT YOU ARE SEEING
HERE IS THIS COLUMN HERE, OF THE
INDIVIDUAL COLORS REPRESENTS THE
MODULES THAT THESE GENES ARE
CLUSTERED INTO. THE NUMBER
REPRESENTS THE NUMBER OF GENES
WITHIN EACH MODULE. THE ROWS OR
COLUMNS REPRESENT DIFFERENT
PHENOTYPIC TRAITS WE WERE
INTERESTED IN BOTH PROS AND PAIN
HISTORY. TO THE LEFT OF THE
BLACK LINE ARE THOSE REPRESENTED
DURING ACUTE PAIN TO THE RIGHT
ARE THOSE REPRESENTED DURING
BASELINE STATE OF HEALTH. THE
NUMBERS CONTAINED WITHIN THESE
BOXES IS THE MODULE EEGENE GENE
CORRELATION TO PHENOTYPIC TRAIT
OF INTEREST ON THE BOTTOM BOTTOM
AND THE P VALUE IS IN
PARENTHESES. ON THE LEFT YOU SEE
THE GENE ONTOLOGY TERMS THAT ARE
RESULT OF OUR DATA ANALYSIS TO
HELP UNDERSTAND WHAT THESE
MODULES POTENTIALLY REPRESENT
FROM BIOLOGICAL PERSPECTIVE OR
CLUSTERS OF GENES. FOR THE SAKE
OF THIS TALK I WOULD LIKE TO
DRILL DOWN ON TWO OF THESE
MODULES THAT WE ARE SIGNIFICANT
AND RETAIN IN OUR ANALYSIS BOTH
THE GREEN MODULE AND THE BLUE
MODULE. THE REASON FOR THIS IS
THEIR BIOLOGICAL PATHWAYS
REPRESENT A LOT OF IMMUNE OR
INFLAMMATORY PATHWAYS. THESE
BOTH MODULES HAS MODULE
EEGENGENES ASSOCIATED WITH THE
PHENOTYPIC PAIN RELATED THAT WE
ARE INTERESTED IN. WHEN WE
FURTHER DRILL DOWN ON WHAT THESE
PATHWAYS REPRESENT, AS YOU CAN
SEE IN THE GREEN AND BLUE BOXES
ON THE LEFT THERE IS A VARIETY
OF IMMUNE MEDIATED PATHWAYS THAT
APPEAR TO BE CLOSELY ASSOCIATED
WITH PAIN PHENOTYPIC TRAITS THAT
DESERVES FURTHER EXPLORATION AND
WHETHER PATHWAYS MODULATE
BIOLOGICALLY AS NOVEL PAIN
THERAPEUTICS. FINALLY WE DRILL
DOWN FURTHER ON SOME OF THE
INDIVIDUAL CANDIDATE GENES
WITHIN THE MODULES AND THIS
REPRESENT -- THIS TABLE
REPRESENTS CANDIDATE GENES FROM
THE GREEN MODULE. AND WHAT WE
DID IS WE LOOK AT ASSOCIATION OF
THESE INDIVIDUAL GENES WITH SOME
OF O OUR PHENOTYPIC TRAITS AND
NUMBERS IN THE TABLE REPRESENT P
VALUES FOR THESE ASSOCIATIONS.
WE SELECTED SOME OF THESE GENES
TO ILLUSTRATE DISEASE GENES HAVE
BEEN SHOWN IN THE LITERATURE TO
BE ASSOCIATED WITH PAIN. OR PLAY
A ROLE IN PAIN. SO OF COURSE
WITH ANY SCIENTIFIC RESEARCH WE
ARE LEFT WITH MORE QUESTIONS
THAN ANSWERS AND ONE OF THE KEY
QUESTIONS, ARE THESE PATHWAYS
POTENTIAL TARGETS FOR
BIOLOGICALLY BASED NOVEL PAIN
TREATMENT. WE NEED TO REALLY
DEFINE THE PAIN BIOLOGY, AND
UNDERSTAND WHAT IS GOING ON
WITHIN THESE PATHWAYS AND NEED
TO TEST THESE TARGETS FOR PAIN
EFFICACY AND CLINICAL STUDIES.
WHAT I SHOWED YOU AS WE STARTED
WITHOUT WITH CLINICAL RESEARCH
FINDINGS WITH REALLY COLLECTING
PAIN DATA USING PATIENT REPORTED
OUTCOMES AND HEALTHCARE
UTILIZATION. WE LEVERAGED
TRANSLATIONAL RESEARCH AS A
BRIDGE IN USING PLASMA BASED
TRANSCRIPTION AND WGCNA ANALYSES
TO BRIDGE US TO OUR BASIC PAIN
RESEARCH WHERE WE CAN DRILL DOWN
FURTHER LEVERAGING THE ANIMAL
AND OTHER BASIC PAIN MODELS TO
GET AT PAIN MECHANISM TO TRY TO
DELIVER NOVEL THERAPIES SO NOW
TURN IT TO DR. STUCKY TO TALK
BASIC RESEARCH SHE IS DOING IN
HER LAB.
>> THANK YOU, AMANDA. SO NEXT WE
WANTED TO IDENTIFY NOVEL
CANDIDATE FACTORS IN SICKLE CELL
PATIENT PLASMA THAT IS ELEVATED
DURING ACUTE PAIN THAT MAY
SENSITIZE SENSORY NEURONS AND
NOCICEPTORS, THESE PAIN SENSING
NEURONS. SO OUR HYPOTHESIS IS
THAT FACTORS THAT ARE
CIRCULATING IN PATIENT PLASMA
MAY SENSITIZE THESE SENSORY
NEURONS AND PAIN SENSING
NOCICEPTORS IN ORDER TO DRIVE
EXCITABILITY AND THEN THE
SENSITIZATION OF THESE ASCENDING
PAIN PATHWAYS IN SICKLE CELL
DISEASE THAT G GO TO THE BRAIN.
THE RATIONALE FOR THIS IS THAT
THE DORSAL ROOT GANGLIA WHICH
LIE OUTSIDE THE SPINAL CORD ON
BOTH SIDES OF THE SPINAL CORD
FROM THE NEXT ON DOWN TO THE
SACRUM IN YOUR BODY, CONTAIN ALL
THE CELL BODIES OF ALL
PERIPHERAL SENSORY NEURONS AND
PAIN SENSING NEURONS THAT INNER
INVESTIGATINNERVATE TARGET THE SKIN MUSCLE
BONE TENDONS, AND JOINTS. SO
THIS IMAGE, THIS IMAGE SHOWS THE
VERTICAL COLUMN AND THESE
NOCICEPTORS AND IF I CAN HAVE
THE NEXT SLIDE. THIS IMAGE SHOWS
ON THE LEFT HERE THE HUMAN
SPINAL COLUMN WITH THE SPINAL
CORD AND THEN DORSAL ROOT
GANGLIA IF YOU CAN SEE ON THIS
INSET THE DORSAL ROOT GANGLIA
LIE BETWEEN THE PED CAN BELIEVESICLES OF T HE
BONE AND THE DORSAL ROOT GANGLIA
LIE ON EITHER SIDE OF SPINAL
COLUMN AND CONTAIN CELL BODIES
OF SENSORY NEURONS. SO
INTERESTINGLY IT IS FLOWN SINCE
THE 1970s THAT THE DORSAL ROOT
GANGLIA AND NERVES THAT LIE
AROUND THE DORSAL ROOT GANGLIA
LACK A BLOOD NERVE BARRIER. THIS
IS A CONCEPT THAT MANY PEOPLE
DON'T REALIZE AND HAVE OFTEN NOT
REALIZED OR THEY DON'T THINK
ABOUT OFTEN BUT THE IDEAS THAT
SUBSTANCES THAT ARE DELIVERED OR
OCCUR ARE ELEVATED IN THE
BLOODSTREAM CAN PROFUSE FROM THE
BLOOD TO GANGLIA IN ORDER TO
CIRCULATE AROUND THE CELL BODIES
OF THE SENSORY NEURON. THIS
STUDY IS FROM THE MID 1970s
WHERE A DYE HORSERADISH
PEROXIDASE WAS INJECTED IV INTO
A PATIENT AND WITHIN MINUTES
THAT HRP DYE IS SHOWN INTER
COLLATING INTO THE DORSAL ROOT
GANGLIA AND SURROUNDING
OUTLINING THE SINGLE CELL BODIES
OF SENSORY NEURONS AND
NOCICEPTORS. SO IF I CAN HAVE
THE NEXT SLIDE. OUR HYPOTHESIS
IS THEN THAT THESE FACTORS THAT
ARE ELEVATED IN PATIENT PLASMA
IN SICKLE CELL DISEASE
INDIVIDUALS MAY ACTUALLY INTER
COLLATE INTO THE DORSAL ROOT
GANGLIA AND SENSORY NEURONS,
SENSITIZE THOSE NEURONS AND
THERE BY DRIVE THE EXCITABILITY
AND THE SENSITIZATION OF THESE
PAIN PATHWAYS IN SICKLE CELL
DISEASE THAT GO O THE BRAIN.
NEXT SLIDE. FOR THIS STUDY WE
IDENTIFY GENES THAT WERE
DIFFERENTIALLY EXPRESSED IN
PATIENTS WITH SICKLE CELL
DISEASE VERSUS HEALTHY CONTROLS.
THIS IS FROM AMANDA'S DATA SET.
WE ASK DO THESE GENES DIRECTLY
INTERACT WITH HUMIDOR SAL ROOT
GANGLIA. AND CAN WE THERE BY
DETECT INTERACTIONS BETWEEN
LIGANDS IN THE PLASMA OF SICKLE
CELL DISEASE PATIENTS, RECEPTORS
ON HUMAN DRG NEURONS. NEXT
SLIDE. WE DID THIS IN
COLLABORATION WITH DR. TED PRICE
WHO IS AT UNIVERSITY OF TEXAS
DALLAS AND TED IS A WORLD EXPERT
IN EXAMINING HUMIDOR SAL ROOT
GANGLIA, THE GENES THE
TRANSCRIPTS IN HUMAN DRGs BOTH
UNDER NORMAL CONDITIONS AND NOW
IN PATIENTS WITH A VARIETY OF
DIFFERENT TYPES OF PAIN. SO WE
COLLABORATED WITH TED, TO USE
WHAT HE HAS DESIGNED AS A HUMAN
SENSORY NEURON INTERACTOME. THIS
IS AN INTERACTOME IN WHICH ONE
CAN LOOK AT DIFFERENT LIGANDS
AND RECEPTORS ON HUMAN DRG
NEURONS. IN DOING THIS WE FOUND
IN SICKLE CELL PATIENT PLASMA,
THERE WERE 29 UNIQUE
INTERACTIONS BETWEEN 11 LIGANDS
IN THE PLASMA AND 21 RECEPTORS
ON THE HUMAN DRG NEURONS. MOST
OF THESE ARE CYTOKINES OR
CHEMOKINE RECEPTORS. NEXT SLIDE.
THESE ARE SOME OF OUR TOP
CANDIDATES. IF YOU LOOK AT THE
TOP THOSE IN YELLOW, WHAT THESE
CANDIDATES ARE DEFINED BY IS THE
NUMBER OF INTERACTIONS OF THE
LIGAND WITH SENSORY NEURONS IN
THESE HUMAN NEURONS. SO THE MORE
NUMBER OF INTERACTIONS THE
HIGHER LIKELIHOOD THAT THERE IS
INTERACTION IN SICKLE CELL
DISEASE PLASMA WITH HUMAN
SENSORY NEURONS. SO NEXT SLIDE.
I WANT TO HIGHLIGHT A COUPLE OF
THESE THAT WE ALREADY FIGURED
OUT ARE ELEVATED AND INVOLVED IN
SICKLE CELL DISEASE, THEY WOULD
BE IN THE RED BOX HERE,
ENDOTHELIN 1 AND CHEMOKINE
LIGAND 7. SO FIRST FOR CHEMOKINE
LIGAND 7 CCL 7 HAS BEEN SHOWN TO
BE INVOLVED IN CHRONIC AND
INFLAMMATORY AND NEUROPATHIC
PAIN AND OTHER TYPES OF PAIN
DISORDERS OTHER THAN SICKLE CELL
DISEASE. AND ONE OF THE
CANNINGNATE RECEPTORS FOR CCL 7
IS THE CCR 2, CCR RECEPTOR 2, A
COGNATE GCL COUPLE RECEPTOR FOR
CCL 7. SO WHAT WE DID IS TO
INVESTIGATE THE ROLL OF CCR 2
RECEPTOR IN SICKLE CELL DISEASE,
WE KNOW PATIENTS WITH SICKLE
CELL DISEASE HAD
HYPERSENSITIVITY TO TOUCH AND
PAIN FROM THE MECHANICAL
STIMULI. SO WE USE OUR MOUSE
MODELS OF SICKLE CELL DISEASE,
THE BERKELEY MODEL AND THE TOWNS
MODEL AND WE DETEST BEHAVIORAL
TESTS WHERE WE CAN TEST
MECHANICAL SENSITIVITY OF MICE
BY TOUCHING THE BOTTOM OF PAW
WITH A VON CALIBRATED FILAMENT
AND MEASURE THE THRESHOLD WHICH
THE ANIMAL PULLS THE PAW AWAY
FROM THE STIMULUS. FOR THIS
STUDY WE INJECTED INHIBITOR OF
LOCKER TO THE CCR 2 RECEPTOR TO
DELIVER IP INTERPERITONEALLY OR
INTERPLANT OR DIRECTLY INTO THE
PAW. WHAT WE SEE AS FIRST OF ALL
COMPARED TO THE CONTROLS WHICH
ARE IN WHITE, THE BERKELEY
SICKLE CELL ANIMALS ALL IN PINK
ARE VERY, VERY SENSITIVE TO
MECHANICAL STIMULI COMPARED TO
THE CONTROLS. AND WHEN WE INJECT
THE CRR 2 INHIBITOR INTO THE
PAW, THIS DOSE DEPENDENTLY
REVERSES THE MECHANICAL
HYPERSENSITIVITY. WE ALSO KNOW
PATIENTS WITH SICKLE CELL
DISEASE HAVE EXTREME HIGH
SENSITIVITY TO COLD AND THAT
COLD STIMULI CAN EXACERBATE
PAINFUL EPISODES. SO WE ASKED
WHETHER OUR SICKLE CELL MICE
WOULD EXHIBIT COLD
HYPERSENSITIVITY AND WHETHER THE
CCR 2 BLOCKER WOULD AFFECT THAT.
SO FOR THIS WE PLACED ANIMALS ON
THE GLASS TABLE TOP AND WE PUT A
STICK OF DRY ICE AT BOTTOM OF
THE PAW AND THEN MEASURED THE
SPEED WHICH THE ANIMAL PULLED
ITS PAW AWAY FROM THE ICE. WHAT
YOU CAN SEE IS THE ANIMALS CAN
SICKLE CELL DISEASE WHETHER THEY
BE TOWNS OR BERKELEY SHOWN IN
THE WHITE BARS, ARE VERY
SENSITIVE TO COLD STIMULI
COMPARED TO CONTROLS. BUT WHEN
WE INJECT THE CCR 2 INHIBITOR
INTO THE PAW, WE CAN BLOCK OR
REVERSE THAT COLD
HYPERSENSITIVITY. SO THAT IS
QUITE EXCITING. NEXT SLIDE
PLEASE. THEN THE OTHER MOLECULE
THAT IS UP IN OUR INTERACTOME
WITH HUMAN NEURONS WAS
ENDOTHELIN 1. ENDOTHELIN 1 IS A
MOLECULE SHOWN TO BE INVOLVED IN
CHRONIC INFLAMMATORY AND
NEUROPATHIC PAIN IN OTHER
DISORDERS BESIDES SICKLE CELL
DISEASE. WE FOUND THAT IN THE
DORSAL ROOT GANGLIA OF SICKLE
CELL ANIMALS, ENDOTHELIN 11
ELEVATED IN THE DORSAL ROOT
GANGLIA SHOWN BY THIS RED ARROW
HERE. ANOTHER GROUP BRIANNA LUTZ
AND TAU SHOWED WHEN THEY LOOK AT
MECHANICAL SENSITIVITY IN SICKLE
MICE, WHAT THEY DID HERE IS
LOOKING AT VON BRIAN THRESHOLD
THEY LOOK AT FREQUENCY OF
RESPONSES TO A GIVEN SUPER
THRESHOLD FORCE TO THE PAW. AND
WHEN THEY INJECTED THE
ENDOTHELIN RECEPTOR INHIBITOR
INTO THE PAW, UNDER NORMAL
BASELINE SICKLE CONDITIONS, THEY
FOUND THAT REVERSED THE PAW
HYPERSENSITIVITY THAT'S THE ABT
COMPOUND IS THE ENDOTHELIN
RECEPTOR BLOCKER AND THAT
COMPLETELY REVERSED THE
MECHANICAL HYPERSENSITIVITY AT
BASELINE CHRONIC SICKLE CELL
CONDITIONS BUT ALSO WHEN THEY
INDUCED RED CELLS SICKLING ON AN
ACUTE LEVEL WITH HYPOXIA
TREATMENT SO DURING ACUTE PAIN
EVENT, IT REVERSES THE
HYPERSENSITIVITY TO MECHANICAL
TOUCH. NEXT SLIDE PLEASE.MENT
THEN THEY TESTED COLD
SENSITIVITY USING A COLD PLATE,
THEY PUT THE MICE ON A COLD
PLATE AND MEASURE HOW QUICKLY
ANIMALS PICK UP THEIR PAW IN
RESPONSE TO COLD STIMULUS. WHAT
THEY FOUND IS WHEN THEY INJECT
ENDOTHELIN RECEPTOR BLOCKER INTO
THE PAW, THAT REVERSED IN THE
ABT COMPOUND REVERSE THAT COLD
HYPERSENSITIVITY OF BASELINE
CHRONIC HYPERSENSITIVITY
CONDITIONS AND ALSO WHEN THEY
INDUCE ACUTE RED CELL SICKLING
WITH HYPOXIA TREATMENT. BUT WAIT
THERE IS MORE. BECAUSE YOU MIGHT
HAVE NOTICED IN IN OUR SENSORY
NEURON INTERACTOME THERE'S
SEVERAL CANDIDATES THAT HAVE
MORE INTERACTIONS BETWEEN THE
PLASMA LIGANDS AND DORSAL ROOT
GANGLIA, THE HUMAN GANGLIA. SOME
HAVE UP TO FIVE DIFFERENT
INTERACTIONS THESE ARE NOVEL
CANDIDATES NOT INVESTIGATED YET,
IL 16, CHEMOKINE LIGAND 5 AND
THEN COLONY STIMULATING FACTOR.
AND WE THINK THAT MAKES GOOD
SENSE BECAUSE THERE IS ALREADY
EVIDENCE IN THE LITERATURE IN
OTHER WAYS WHERE THERE IS A
LITTLE BIT OF EVIDENCE IN THE
LITERATURE THESE CANDIDATES
MAYBE INVOLVED IN SICKLE PAIN.
FIRST IL 16, POLYMORPHISMS IN IL
16 ARE SHOWN TO BE INVOLVED IN
PAINFUL ENDOMETRIOSIS. ENDOMETRIOSIS.
POLYMORPHISMS IN THE IL 16 ARE
SHOWN TO INCREASE THE RISK FOR
ISCHEMIC STROKE. SECOND CCL 5 IS
SHOWN TO DEHYDRATE RED BLOOD
CELLS AND THERE BY AGGRAVATE
VASOOCCLUSIVE CRISES IN SICKLE
CELL DISEASE AND CCL 5 IS SHOWN
INVOLVED IN MULTIPLE TYPES OF
CHRONIC PAIN. AND FINALLY COLONY
STIMULATING FACTOR 2 HAS BEEN
SHOWN TO MEDIATE INFLAMMATORY
AND ARTHRITIC PAIN IN NON-SICKLE
PAIN MODELS. SO WE THINK THAT
POTENTIALLY THESE NEW CANDIDATES
FOR SICKLE CELL DISEASE MIGHT BE
INVOLVED IN DRIVING THE PAIN
FROM THE PERIPHERY TO THE
ASCENDING PATHWAYS, IN SICKLE
CELL DISEASE. SO FINALLY, WE
THINK THAT A STRONG
TRANSLATIONAL APPROACH IS TO
FIRST IDENTIFY FACTORS IN
PATIENT PLASMA IN PATIENT PLASMA
AND THEN TEST INTERACTION WITH
HUMAN SENSORY NEURONS USING THIS
INTERACTOME AND THEN TAKE THESE
BACK INTO THE ANIMAL MODELS TO
TEST FOR EFFICACY IN PAIN
INHIBITION IN THE ANIMAL MODELS
AND LOOK FOR THE UNDERLYING
MECHANISMS THAT DRIVE THE PAIN
IN THESE ANIMAL MODELS OF SICKLE
CELL DISEASE, AND THEN
POTENTIALLY TAKE THESE
CANDIDATES BACK INTO PATIENTS
AND DO HUMAN TRIALS, SENSORY
NEURONS, TEST IN HUMAN TISSUE
AND POTENTIALLY TEST IN HUMAN
TRIALS AND POTENTIALLY PATIENTS
WITH SICKLE CELL DISEASE. SO WE
ARE VERY EXCITED ABOUT THIS,
BACK AND FORTH TRANSLATIONAL
MODEL THAT AMANDA AND I ARE --
HAVE BEEN USING AND WE THINK
THAT IT IS HOPEFULLY A WAY TO
IDENTIFY VIABLE CANDIDATES FOR
NOVEL TREATMENT FOR SICKLE CELL
DISEASE IN PATIENTS. FINALLY
AMANDA AND I WOULD LIKE TO THANK
ALL OF OUR MANY COLLABORATORS AT
MEDICAL COLLEGE OF WISCONSIN, WE
ARE SO GRATEFUL FOR THESE
EXCELLENT COLLABORATORS AND
ESPECIALLY PATIENTS AND FAMILIES
THAT HAVE GIVEN THEIR TIME AND
WE HOPE TO HELP. THANK YOU FOR
OUR FUNDING. WITH THAT, THANK
YOU, VERY MUCH. ON BEHALF OF
AMANDA AND MYSELF.
>> NITYA.
>> GOOD AFTERNOON, THANK YOU FOR
INVITING ME TO PRESENT TODAY. I
JUST WANT TO BE SURE YOU CAN
HEAR ME CLEARLY. TODAY I'M GOING
TO TALK TO YOU ABOUT PAIN
PHENOTYPE AND SICKLE CELL
DISEASE, INSIGHTS FROM THE PAIN
AND SICKLE CELL DISEASE
EPIDEMIOLOGY STUDY OR PISCES.
I'LL PRESENTING ON BEHALF OF
(INAUDIBLE) FROM TABLE RECENTLY
PUBLISHED IN PAIN. NEXT SLIDE
PLEASE. AS WE KNOW
EPIDEMIOLOGICAL STUDY OF PAIN IN
SICKLE CELL DISEASE AND STUDY IN
ANALYZED 232 INDIVIDUAL WITH
SICKLE CELL DISEASE. AND IT
SHOWED US THAT ONLY MINORITY OF
DAYS PAIN WERE ASSOCIATED WITH
(INAUDIBLE) AND MOST PATIENTS
HAD PAIN ON MORE THAN HALF THE
DAYS AND SUBSTANTIAL ONE-THIRD
OF THEM NEARLY EVERY DAY OR
EVERY SINGLE DAY. NEXT SLIDE. T
IN PISCES AS IN MOST STUDIES,
PAIN EVENTS REPORTED OUTCOME OF
THE STUDY. WITHIN THE STUDY YOU
CAN SEE HERE THAT (INAUDIBLE)
INCREASED AS THE FREQUENCY OR
PROPORTION OF INSULIN INCREASED.
PAIN INTENSITY WAS INDEPENDENTLY
ASSOCIATED WITH HEALTH RELATED
QUALITY OF LIFE. AT A -- LEVEL
MAINTAIN INTENSITY PATIENT
OUTCOMES. HOWEVER, THERE ARE
SOME MANIPULATIONS PARTICULARLY
AT THE INDIVIDUAL LEVEL. MENTION
SLIDE PLEASE. AT THE INDIVIDUAL
LEVEL (INAUDIBLE) PAIN
PHENOTYPE. WE CAN SEE HERE THESE
DATA FROM ONE INITIAL STUDIES
WERE PAIN INTENSITY WAS STUDIED
USING ON BOTH INDIVIDUALS
INTENSITY IS IDENTICAL. HOWEVER
JUST LOOKING AT THESE GAPS YOU
KNOW PAIN PHENOTYPES ARE NOT
IDENTICAL AS ONE 50% AND AT
INDIVIDUAL LEVEL PAIN DELIVERY
IS NOT IDENTICAL. PROPOSED TO
INVESTIGATE INDIVIDUAL IN SICKLE
CELL DISEASE FOLLOWING FREQUENCY
(INAUDIBLE) DETERMINE
DEVELOPMENTS OF INTERINDIVIDUAL
TO PATIENT REPORTED OUTCOMES
OTHERS WITH SICKLE CELL DISEASE
WITH TWO SPECIFIC SUBTYPES IS IN
ASSOCIATED WITH PSYCHOLOGICAL
CHARACTERISTICS IN SICKLE CELL.
AND COULD BE USED TO IDENTIFY
SUB GROUPS OF PAIN PHENOTYPES ON
SICKLE CELL. NEXT SLIDE PLEASE.
SO IN ORDER TO STUDY VARIABILITY
MEASURABLE WE NEED WE DECIDED TO
STUDY THREE DIFFERENT ASPECTS OF
INTERINDIVIDUAL VARIABILITY ONE
IS THE (INAUDIBLE) STANDARD
DEVIATION. YOU CAN SEE IN THE
TWO GRAPHS THE INEQUITY THAT YOU
CAN SOMEWHAT MEASURE EXTENT
FLUCTUATION AT THE STANDARD
DEVIATION. THE OTHER ASPECT OF
INTERINDIVIDUAL IS TEMPORAL
INSTABILITY OF -- SO THE MEAN
SQUARE OF SUCCESS LOOKS AT THE
BOTH THE AMPLITUDE OF
FLUCTUATION AS WELL AS THE
TEMPORALTY FLUCTUATIONS SO IT
CAN MEASURE COME AT THE
BEGINNING OR END FOR EXAMPLE.
THE PROBABILITY OF ACUTE CHANGE
IS FREQUENCY OF THE
FLUCTUATIONS. YOU CAN SEE THESE
MEASURES CAN DISTINGUISH BETWEEN
PAIN INTENSITY COLLECTED OVER
TIME. THE LAST ONE IS TEMPORAL
DEPENDENCY OR FIRST QUARTER
AUTOCORRELATION WHICH
ESSENTIALLY TRIES TO MEASURE HOW
DOES PAIN FROM ONE DECOR LATE
WITH TO THE NEXT DAY. OR
YESTERDAY PAIN TODAY AND HERSIS
TENSE OF -- OR THAT ONCE PAIN
FLUCTUATES HOW LONG DOES IT STAY
ABOVE (INAUDIBLE) PAIN
INTENSITY. WE CALCULATED THESE
IN 139 INDIVIDUALS FROM THE 232
LESS THAN -- IN THE FIRST
(INAUDIBLE) SMALL NUMBER OF PAIN
SCORES, NO MORE THAN (INAUDIBLE)
AND REPRESENTS LESS THAN 2% OF
THE DATA. CALCULATED METHODS OF
PAIN INTENSITY VARIABILITY FOR
EACH INDIVIDUAL. NEXT SLIDE.
MEDIAN AGE WAS 33 YEARS WITH
MORE THAN HALF FEMALE. THE VAST
MAJORITY, 79% HAVE SICKLE CELL
(INAUDIBLE) PHENOTYPE. NEXT
SLIDE PLEASE. WHEN WE LOOKED AT
THESE ARE MEDIANS OF ONE OF THEM
AT A INDIVIDUAL LEVEL. YOU CAN
SEE THE MEAN -- 2.3 AND
PROPORTION OF IS ABOUT 70%.
WHICH THE OTHER MEASURES
(INAUDIBLE) PRESENTED HERE. NEXT
SLIDE PLEASE. WE THEN LOOK TO
SEE WHETHER THERE WAS A
CORRELATION BETWEEN
INTERINDIVIDUAL PAIN VARIABILITY
AND THE PAIN INTENSITY. SO FROM
THE SUBGROUP THAT'S THE FIRST
COLUMN TO THE NEXT THAT
REPRESENTS ALL PATIENTS YOU CAN
SEE THAT THERE ARE CORRELATIONS
BETWEEN METHODS OF PAIN
VARIABILITY SUCH AS STANDARD
DEVIATION, PROBABILITY OF KEY
CHANGE, AND SSD ON
AUTOCORRELATION WITH MEAN PAIN
INTENSITY. HOWEVER, THE PICTURE
IS A LITTLE MORE NUANCED WHEN
YOU EVALUATE THIS RELATIONSHIP
ON THE BASIS OF PAIN FREQUENCY.
SO AMONG THOSE WITH LESS THAN
50% -- WE FIND THE PAIN
INTENSITY VERY STRONGLY
CORRELATED. MORE THAN HALF BUT
LESS THAN 95%, CORRELATIONS ARE
STILL BUT THE CORRELATION, THOSE
WHO EXPERIENCE NEAR (INAUDIBLE)
CORRELATION BETWEEN PAIN
INTENSITY AND VARIABILITY
METHODS. THIS SUGGESTS THAT
THERE MAYBE -- PAIN VARIABILITY
PARTICULARLY IN EXPERIENCES ON
ALL THINGS ALMOST EVERY DAY.
NEXT SLIDE PLEASE. SO WHEN WE
LOOK AT THE RELATIONSHIP,
PSYCHOLOGICAL AND CLINICAL
CHARACTERISTICS, THIS COHORT WE
SEE PAIN VARIABILITY METHODS IN
GENERAL AS PAIN INTENSITY ARE
NEGATIVELY CORRELATED WITH
QUALITY OF LIFE. POSITIVELY
CORRELATED PSYCHOLOGICAL
DIAGNOSTICS WHICH ARE SUBMITTED
IN THE SYSTEM (INAUDIBLE)
OUTCOMES SUCH AS ANXIETY
DEPRESSION, COPING
CATASTROPHIZING AND STRESS. WE
ALSO SEE THAT PAIN (INAUDIBLE)
PROPORTION OF PAIN WITH
UTILIZATION. NEXT LIED PLEASE.
HOWEVER ONCE YOU START AGAIN
EVALUATING THIS IN THE CONTEXT
OF PAIN FREQUENCY, YOU SEE THE
RELATIONSHIPS ARE A LITTLE MORE
NUANCED IN THOSE WITH LESS THAN
50% PAIN DAYS YOU CAN SEE PAIN
VARIABILITY ACTUALLY CORRELATES
WITH PHYSICAL HEALTH. WHEREAS
ONCE YOU -- THOSE WITH THE ONLY
OUTCOME THAT ACTUALLY CORRELATES
IS (INAUDIBLE) AUTOCORRELATION.
SO THEREFORE WE NOW --
INDIVIDUAL VARIABILITY IS
ASSOCIATED WITH PATIENT OUTCOMES
AND PSYCHOLOGICAL -- IN SICKLE
CELL DISEASE AND WE LOOK TO
QUESTION WHETHER INTRAINDIVIDUAL
COMPARABILITY COULD BE USED TO
SUBGROUPS OF PHENOTYPES WITH
SICKLE CELL DISEASE. NEXT SLIDE
PLEASE. TO DO SO WE ACTUALLY
USED UNSUPERVISED LEARNING
METHODS WHICH HAVE THE ADVANTAGE
WE DON'T RELY ON THE (INAUDIBLE)
AND IDENTIFY PREVIOUSLY UNDECKED
PATTERNS OF GROUPINGS IN DATA,
FOR THIS PARTICULAR STUDY WE
USED A K MEANS CLUSTER ANALYSIS
APPROACH. THIS IS A PARTITIONING
ALGORITHM THAT PARTITIONS INTO A
SPECIFIED NUMBER OF
NON-OVERLAPPING CLUSTERS. BASED
ON STRUCTURAL RELATIONSHIPS
AMONG THE VARIABLES. AND THE
GOAL IS TO MINIMIZE WITHIN
CLUSTER VARIATION SO
OBSERVATIONS IN THE CLUSTER ARE
SIMILAR TO EACH OTHER AND
DISTINCT FROM OBSERVATIONS IN
OTHER CLUSTERS OR SUB GROUPS.
NEXT SLIDE PLEASE. WE CHOSE
SINCE WE SPECIFIED CLUSTERS WE
-- BASED ON MULTIPLE TESTS THAT
WE HAD DONE THAT INDICATED THAT
-- CLUSTERS. NEXT SLIDE PLEASE.
THIS IS A HIGH LEVEL RESULT OF
OUR CLUSTER ANALYSIS. YOU CAN
SEE THREE DISTINCT
NON-OVERLAPPING CLUSTERS,
CLUSTER 1 HAD A -- MEDIAN
(INAUDIBLE) WITH 20% OF PAIN
DAYS AND -- PHYSICAL FUNCTION
SCORE. IT WAS ALSO THE CLUSTER
WITHIN -- EACH PATIENT CLUSTER
TWO AND THREE HAD SIMILAR
(INAUDIBLE) BUT CLUSTER 2 HIGH
-- HAVE PATIENTS THE HIGHEST --
(INAUDIBLE) AND THE LOWEST
PHYSICAL FUNCTION SCORE. CLUSTER
3 HAD HIGH INSTABILITY SO HIGH
FLUCTUATIONS AND LOWER CLUSTER 2
BUT WITH CLOSE TO DAILY PAIN,
OPIOID USE PHYSICAL FUNCTION
SCORE ENDOCRINE CLUSTERS 1 AND
3. NEXT SLIDE. SO OUR --
INTERINDIVIDUAL VARIABILITY IS
ASSOCIATED WITH PATIENT OUTCOMES
AND CHARACTERISTICS IN SICKLE
CELL DISEASE AND PAIN INTENSITY
WITHIN INDIVIDUAL VARIABILITY
PHENOTYPES IN SICKLE CELL
DISEASE. WE THINK THE NEXT STEPS
HERE (INAUDIBLE) CO-OPS. THEN
FROM HERE ONCE WE HAVE A GOOD
WAIVER CLINICALLY PHENOTYPE TO
THEN USE EXPERIMENT WITH CORTICO
SENSORY TESTING SEE DEFENSES
EXPERIMENTAL AMONG THESE
CLINICAL RELATED SUB GROUPS. I
WANT TO THANK EVERYBODY FOR THIS
PAPER AS WELL AS THE -- THANK
YOU.
>> THANK YOU. WE WILL MOVE
STRAIGHT AHEAD TO PAT AND THEN
HAVE A GOOD AMOUNT OF TIME FOR
DISCUSSION.
>> I'M NOT SEEING ME OR MY
SLIDES I SEE START VIDEO. THERE
I AM. SO I THINK I HAD A SLIDE
THE LAST TIME SO HOPEFULLY WON'T
AUTOADVANCE ON ME AGAIN. WE CAN
ACTUALLY MOVE TO THE FIRST
SLIDE. AS IS OFTEN THE CASE I
THINK MY ROLE HERE IS TO BE THE
DUMB GUY IN THE ROOM. I -- MY
TALK IS GOING TO BE FAR MORE
DATA FREE THAN THOSE OF MY
COLLEAGUES HERE. AS PARTS OF MY
ROLE BEING THE DUMB GUY IN THE
ROOM I HAVE TO CONFESS VERY
OFTEN I DON'T KNOW WHAT I'M
DOING. I TEND TAKE CARE OF
PATIENTS WHO HAVE VERY COMPLEX
CHRONIC PAIN, PSYCHIATRIC
CO-MORBIDITIES WITH SEVERE
SICKLE CELL DISEASE. I DON'T
THINK WE KNOW ENOUGH ABOUT WHAT
TO DO ABOUT CHRONIC PAIN. I WILL
LOOK AT -- SHOCKING STATEMENT.
BUT WHAT I WOULD LIKE TO DO IS
SAY WHAT I THINK WE NEED OR WHAT
PEOPLE LIKE ME MIGHT NEED TO DO
BETTER NOW WHILE HOPEFULLY DR.
BRANDOW AND DR. STUCKY AND
BAKSHI FIGURE WHAT WE CAN DO
WITH THE FUTURE. SO I WILL START
OUT TALKING ABOUT THE ASH
GUIDELINES. YOU CAN SEE THIS IS
TALKED ABOUT A FEW TIMES
ALREADY, I DON'T WANT TO BORE
YOU BUT THE POINT AND DR.
BRANDOW IS LEADER OF OUR PIRATE
DAN SO YOU CAN LOOK UP TO
MANUSCRIPT FROM A COUPLE OF
YEARS AGO TO SEE MORE DETAILS
AND THIS IS MY TAKE ON THINGS SO
MANY THINGS LEFT OUT. I ALSO
WILL HAVE A FEW THOUGHTS ABOUT
WHERE THEY FALL SHORT. THOSE
CRITIQUES HAVE NOTHING TO DO
WHATSOEVER WITH THE PEOPLE WHO
DEVELOP THEM, WHO WERE SOME OF
THE FINEST PEOPLE HAD THE HONOR
OF SITTING IN THE ROOM. IN
ESSENCE, WE ARE THE GUIDELINES
STOOD WAS WITH YEWS THE AAPT
CRITERIA, DR. SMITH MENTIONED
AND LOOK AT THE SPECIFIC CAUSES
OF AVASCULAR NECROSIS AND LEG
ULCERS AS WELL AS UNSPECIFIED
SICKLE CELL DISEASE PAIN.
BECAUSE THERE WAS SO LITTLE
DIRECT EVIDENCE TO PULL ON FOR
ANY OF THESE THINGS WE HAD TO
LOOK FOR ANALOGOUS CONDITIONS
AND AVASCULAR NECROSIS WE LOOK
AT OSTEOARTHRITIS AND FOR SICKLE
CELL DISEASE ITSELF WITH NO
OTHER ASSOCIATED OR IDENTIFIABLE
ASSOCIATED CAUSE WE LOOK FROM
FIBROMYALGIA, MOST INCOMPLETE
ANALOGIES OBVIOUSLY. BASED ON
THOSE ANALOGIES WE SUGGESTED
THAT THE INTERVENTIONS THAT DR.
-- MENTIONED EARLIER, SNRE
TRICYCLIC ANTI-DEPRESS SENTS AND
GABBAPENTINOIDS WITH OTHER
GENERAL MEDICINES. WE PUT IN A
JUSTIFIED THOUGHT THAT N SAIDS
MIGHT RECUR PARTICULAR THOUGHT
IN FOLKS WITH SICKLE CELL
DISEASE AND CHRONIC USE BECAUSE
OF RISK OF RENAL INJURY, THE
RISK OF ANTI-COAGULATION,
BLEEDING CLOTTING AND SO ON. SO
WHILE I THINK THEY ARE
FREQUENTLY USED, WE ALSO DON'T
KNOW THEIR RISK VERY WELL AND
THAT IS A BIG GAP THAT WE HAVE
GOT. AS NON-PHARMACOLOGIC
INTERVENTIONS, THEY WERE MANY OF
THE THINGS ALSO COVERED MANY THE
MORNING SESSION. WE HAD THE BEST
EVIDENCE FOR COGNITIVE
BEHAVIORAL PAIN MANAGEMENT
STRATEGIES AND THOSE THINGS THAT
DR. JOHN DISCUSSED THIS MORNING.
WE DIVIDED OTHER
NON-PHARMACOLOGIC TREATMENTS,
AND THOSE THINGS SOMEONE HAS TO
DO FOR YOU, ACUPUNCTURE AND
MASSAGE THERAPY AND PEOPLE
SELF-MANAGE PHYSICAL ACTIVITY OR
EXERCISE OR THINGS LIKE YOGA OR
COMBINED MOVEMENT PROGRAMS. WE
HAVE EVIDENCE FOR MASSAGE
THERAPY AND ACUPUNCTURE WHICH
WAS COVERED THIS MORNING AND
THOSE WERE SUGGEST WITH U WE
DIDN'T HAVE EVIDENCE TO SAY
ANYTHING ABOUT THE OTHER
INTERVENTIONS. MENTION SLIDE
PLEASE. SORRY PRESSING BUTTONS
ON MY OWN. AS TO OPIOIDS, WHAT
WE SAID WAS RELATIVELY SIMILAR
TO WHAT OTHER GUIDELINES HAVE
SAID WHICH IS TO SAY THAT PEOPLE
ARE EARLY IN THE COURSE CHRONIC
PAIN JUST DEVELOPING IT WE
SUGGESTED AGAIN STARTING CHRONIC
OPIOID THERAPY AND LESS PAIN
REFRACTORY TO OTHER THINGS. AND
IF PEOPLE ARE ALREADY ON CHRONIC
OPIOID THERAPY FOR CHRONIC PAIN
THEY ARE DOING WELL AND
PERCEIVED BENEFIT IN ESSENCE
THERE IS ONGOING DISCUSSION
ABOUT WHETHER THE RISKS ARE
WORTH THE CONTINUED BENEFIT AND
WHAT CAN BE DONE TO MODERATE
THEM WHILE MAINTAINING THAT
BENEFIT. BUT IF PEOPLE ARE DOING
POORLY OR AT RISK OF DOING
POORLY, THEN SHOULD TALK ABOUT
STOPPING IT THAT BEING DONE
CAREFULLY. NEXT SLIDE PLEASE.
THESE ARE SMALL SAMPLE OF OTHER
GUIDANCE THAT WERE SUGGESTED.
FIRST THAT I THINK IS ALWAYS
IMPORTANT TO SAY IS YOU CAN'T
TREAT SICKLE CELL DISEASE JUST
BY TREATING CHRONIC PAIN, THINK
IT IS IMPORTANT. SO OPTIMIZING
SICKLE CELL DISEASE MODIFYING
SICKLE CELL DISEASE PRIORITY AND
SHOULD BE TREAT WITH A PAIN
STRATEGY MORE POINTS MADE IN THE
MORNING. WHEN POSSIBLE
COLLABORATE WITH A PAIN
SPECIALIST AND SCREEN FOR
DEPRESSION AND TREAT IT. WITH
RESPECT TO OPIOID, PROBABLY
WEANING PEOPLE OFF OPIOID OR
DOWN OPIOID WITH SICKLE CELL
DISEASE MAYBE HIGHER RISK
PROPOSITION THAN OTHER
POPULATIONS BECAUSE OF THE ROLE
OF STRESS. IN ACUTE PAIN OR
DISEASE EXACERBATIONS. ALSO IF
OPIOID HAVEN'T WORKED FOR
CHRONIC PAIN FOR SOMEONE THAT
DOESN'T WANT TO WORK WITH ACUTE
PAIN SO ONE DOESN'T OBVIATE THE
USE FOR THE OTHER. NEXT SLIDE
PLEASE. HERE IS WHERE I THINK
THE WARTS WERE. ALL THESE THINGS
WERE BASED ON LOW CERTAINTY
EVIDENCE MOSTLY INDIRECT
EVIDENCE THOUGH WE HAD A LITTLE
BIT OF DIRECT EVIDENCE FOR SOME
OF THE COGNITIVE INTERVENTIONS.
BECAUSE WE HAD INDIRECT EVIDENCE
AND HAD TO PICK A PARTICULAR
ANALOGOUS CONDITION THERE ARE
LIMITS TO WHAT YOU CAN SAY FROM
THIS. PRAGMATICALLY SPEAKING, I
THINK IT IS LESS A PROBLEM THAN
IT MIGHT OTHERWISE BE. BECAUSE
OVERALL THESE RECOMMENDATIONS
KIND OF HARMONIZE WHAT WE KNOW
WORKS FOR CHRONIC PAIN IN
GENERAL. THE MEDICINES WE
SUGGESTED AS WELL AS THE OTHER
INTERVENTIONS WE SUGGEST ARE
THINGS BROADLY SPEAKING HAD BEEN
KNOWN TO WORK FOR CHRONIC PAIN
FOR QUITE A LONG TIME TIME. BIGGER
PICTURE QUESTIONS WE COULDN'T
ADDRESS WITH GUIDELINES
PARTICULARLY THE ISSUE OF
PREVENTION, WHAT CAN WE DO TO
KEEP PEOPLE FROM DEVELOPING
CHRONIC PAIN. NEXT SLIDE PLEASE
I THINK WE HAVE A BIGGER PROBLEM
THAN SIMPLY GUIDELINES BECAUSE I
THINK ONE OF THE -- WHERE I FIND
MYSELF STUCK IS I THINK WE HAVE
A SET OF TOOLS THAT WE HAVE GOOD
REASON TO BELIEVE WORK WHICH IS
TO SAY THEY SEPARATE FROM
PLACEBO, OR FOR COMPARATORS FOR
MULTIPLE OTHER PAINFUL
CONDITIONS OR EVEN SOMETIMES
SOME DATA IN SICKLE CELL DISEASE
BUT WHAT I HAVE TO FIGURE OUT
WHEN SOMEONE SITS DOWN IN FRONT
OF ME IS WHAT DO WE TRY FIRST
FOR HOW LONG AT WHAT DOSE OR
INTENSITY HOW DO I KNOW IF IT IS
WORKING OR NOT OR IF THERE IS A
PARTIAL RESPONSE DEPENDING ON
THE CLINICAL OUTCOME, WHAT IS
THE NEXT STEP? THAT IS CLINICAL
STRATEGY. OUR GUIDELINES AND
EVIDENCE BASE IS HEAVY ON
TACTICS AND TOOLS AND RELATIVELY
SHORT ON CLINICAL STRATEGY. AND
THEN ON THE SAME NOTE FOR
OPIOID, WHAT WE DID SAY AS FAR
AS IT WENT EACH OF THOSE TERMS I
WILL SHOW MY COMPULSIVE SIDE, I
THINK IS REALLY QUITE VAGUE.
WHAT IS MULTIPLE OTHER TREATMENT
MODALITIES MEAN SPECIFICALLY?
WHICH AND FOR HOW LONG? DO WE
KNOW WHAT FAILURE MEANS? THIS IS
ANOTHER DIFFICULTY THAT WE HAVE
IN CHRONIC PAIN IN GENERAL MANY
OUTCOMES OF CLINICAL TRIAL ARE
THINGS LIKE CHANGE FROM BASELINE
AT SIX WEEKS. THIS CAN BE FINE
AT SIX WEEKS BUT IF YOU HAVE
BOTH CHRONICALLY PAINFUL
CONDITION JUST TO SAY LIFE LONG
PLUS A SOLID CHANCE THAT IT IS
PROGRESSIVE WHICH IS TO SAY
DISEASE COURSE ITSELF MIGHT
WORSEN, HOW DO YOU TRANSLATE
THAT INTO A DEFINITION OF
SUCCESS OR FAILURE FIVE YEARS
LATER? SO MAYBE SOMEONE GETS
BETTER BY SAYING ONE OR TWO
POINTS ON THE NUMERIC RATING
SCALE IN SIX WEEKS BUT IF PAIN
IS 6 OUT OF 10 OR 7 OUT OF 10 ON
AVERAGE THREE YEARS, IS IT STILL
WORKING OR IS IT NOT WORKING AND
WHAT SHOULD WE DO ABOUT IT? ALSO
I HAVE TO GO ON RECORD BEING A
BIT OF A SKEPTIC ON THE PROBLEM
OF USING FUNCTION AS A OUTCOME.
ON THE ONE HAND I THINK IT IS
HIGHLY CLINICALLY RELEVANT.
HOWEVER I THINK TRYING TO
MEASURE IT IN A WAY IS BOTH
GENERAL AND VALID IS RICKY
BECAUSE BECAUSE SO MUCH A
FUNCTION IS ROLE DEPENDENT, WHAT
FUNCTION MEANS FOR A PARENT IS
DIFFERENT THAN WHAT IT MEANS
FROM A NURSE OR A BRICKLAYER. SO
I THINK THAT ITSELF ADDS LEVEL
OF VARIABILITY VERY TRICKY TO
MANAGEMENT WITH RESPECT TO
BALANCING RISK AND BENEFIT ONE
DIFFICULTIES IS THE RISKS AND
THE BENEFITS ARE QUALITATIVELY
DIFFERENT TYPES. SO THE BENEFITS
ARE OFTEN RELATIVELY STRAIGHT
FORWARD WHICH IS DOES IT IMPROVE
PAIN. OR AT LEAST PAIN
INTENSITY. WHEREAS THE RISKS
CAN VARY FROM STUFF THAT IS
REASONABLY IMMEDIATE AND
RELATIVELY EASY TO MEASURE LIKE
CONSTIPATION ALL THE WAY TO
RELATIVELY -- VERY LOW
PROBABILITY OF CATASTROPHIC
OUTCOME HAPPENING WITHIN THE
NEXT FIVE YEARS, BUT THAT
OUTCOME BEING CATASTROPHIC. SO
HOW IT IS SORT OF LIKE TRYING TO
COMPARE APPLES TO ROCKS. SO I
THINK BALANCING THOSE ON THE
SAME SCALE IS ALSO QUITE
DIFFICULT. NEXT SLIDE PLEASE.
HERE IS WHERE I SEE CLINICAL
STRATEGY AT RIGHT NOW. AND
GRANTED THIS IS A BIT OF A
CARICATURE. THERE IS TRUTH TO
IT. WE HAVE A BUCKET OF THINGS
WE ARE PRETTY SURE WORK. AND
ANOTHER BUCKET OF THINGS REASON
TO BELIEVE WORK BUT NOT
SUPPORTED QUITE AS MUCH BY
EVIDENCE AS WE WOULD LIKE. WE
MAINLY MINE FROM THE THINGS WE
ARE PRETTY SURE WORK. HOWEVER,
WE DON'T HAVE GREAT GUIDANCE OF
WHICH ONE WE SHOULD TRY FIRST OR
IN WHAT COMBINATIONS THAT GIVE
US THE BEST SHOT. WE ARE LEFT TO
DEVELOP IDIOSYNCRATIC IDEAS
ABOUT WHAT TO DO, HOW MANY TIMES
TO GO THROUGH THE CYCLE WHEN TO
DECLARE FAILURE. AT WHICH POINT
WE OFTEN WIND UP GOING TO
OPIOID. WITH OPIOID ROTATION CAN
WORK, DOSE ACCELERATIONS CAN
WORK, DOSE ACCELERATIONS
INCREASE RISK AND WE THEN HAVE
THIS QUESTION OF HOW MANY TIMES
WE GO THROUGH THOSE CYCLES,
UNTIL WE CALL IT A DAY. WHEN
BEDO CALL IT DAY, WHAT DO WE DO?
WE OFTEN HAVE CHRONIC OPIOID
THERAPY SOMETIMES AT HIGH DOSES
AND WE DON'T KNOW WHETHER TO
DECLARE FAILURE OR LEAVE WELL
ENOUGH ALONE OR PUT SOMEONE
THROUGH THE TROUBLE OF COMING
OFF OPIOID WHICH IS A TASK. SO
THE STRATEGIC PROBLEMS THAT I
WOULD LIKE US TO TRY TO SOLVE IS
FIRST OF ALL WHO IS IT THAT WE
SHOULD DO SOMETHING FOR AT ALL?
I KNOW I HAVE MOSTLY TALKED
ABOUT MEDICINE SO FAR, BUT WHEN
SHOULD WE OFFER COGNITIVE
THERAPIES SO FORTH FORTH. THERE IS
ALWAYS A LEVEL OF PAIN INTENSITY
OR OTHER BAD THING THAT IS LOW
ENOUGH THAT EXPOSING SOMEONE TO
ANY RISK IS NOT PROBABLY WORTH
ANY CHANCE OF BENEFIT BECAUSE
THEY ARE NOT ENOUGH TROUBLE TO
POSE BENEFIT BUT WE NEED TO HAVE
SOME IDEA WHAT THAT THRESHOLD
IS. THEN WHAT IS THE FIRST THING
WE SHOULD TRY? PROBABLY THIS IS
NOT NECESSARILY ONE THING, IT
MIGHT BE A SET OF TWO OR LEE
THINGS POSSIBLY COMBINATION. BUT
IT WOULD BE NICE TO HAVE SOME
AGREEMENT ON THIS SO WE CAN TEST
IT AND PROVE OURSELVES WRONG AND
DECIDE MAYBE IT SHOULDN'T BE
THESE THREE THINGS, ONLY THESE
TWO OR MAYBE THIS ONE. THIS IS A
THING THAT I THINK IS VITALLY
IMPORTANT AND I IMPORT THIS FROM
MY EXPERIENCE IN PSYCHIATRY,
REALLY, HOW DO YOU TELL IF IT IS
WORKING? IN PSYCHIATRY TALKING
TREATMENT FOR DEPRESSION, I
THINK WE ARE PRETTY GOOD AT
THIS. WE HAVE LEVELS OF OUTCOMES
FOR DEPRESSION. THERE IS
REMISSION. WHICH IS SUCCESS.
THERE IS RESPONSE WHICH IS
BASICALLY PARTIAL SUCCESS BUT
PEOPLE ARE STILL HIGH RISK OF
RELAPSE IF YOU ONLY LEAVE IT
THERE SO YOU HAVE TO KEEP IT
GOING. AND THERE IS NEITHER OF
THOSE. THEN THE BASED ON THOSE
DIFFERENT LEVELS OF RESPONSE, WE
HAVE REASONABLE EVIDENCE BASE
BEHIND WHAT TO DO. SO FOR
EXAMPLE, IF SOMEONE HAS
RESPONDED NOT OFTEN AUGMENT THE
THERAPY, IF THE PERSON HAS NOT
RESPONDED AT ALL WITHIN SIX
WEEKS MAXIMALLY TOLERATED DOSE
YOU DECLARE FAILURE AN SWITCH.
SO NEXT SLIDE PLEASE. HERE IS
WHAT I WOULD DO LOVE FOR US TO
HAVE. DEARLY LOVE FOR US TO HAVE
AN IDEA OF FOR WHOM WE SHOULD
START OFFERING THERAPY. AND MENU
OF THE FIRST FEW THINGS TO TRY.
WITH AN IDEA OF WHAT CONSTITUTES
AN ADEQUATE TRIAL FOR EACH ONE
OF THOSE THINGS. SOME IDEA ABOUT
WHAT THE IMPORTANT RESPONSES AND
LEVELS OF RESPONSES THAT TRIGGER
CLINICAL DECISIONS. SO FOR
EXAMPLE, IF WE ARE DOING
DELOXATINE, TRY UP TO 90
MILLIGRAMS TO 120 MILLIGRAMS PER
DAY FOR FOUR TO SIX WEEKS. IF
THAT DOESN'T WORK MEANING THERE
IS NO CHANGE IN PAIN INTENSITY,
SWITCH TOKING WITH ELSE.SWITCH TO SOMETHIN G ELSE OR IF
THERE IS PARTIAL RESPONSE ADD TO
SOMETHING ELSE THAT MIGHT HAVE A
CHANCE OF WORKING. IF THERE ARE
SUCH TRIALS, DR. SWEGER
DISCUSSED ONE FOR HER
INTERVENTIONS EARLIER THIS
MORNING AND ALSO AGAIN DRAWING
FROM EXPERIENCE IN PSYCHIATRY,
THE STAR AND D TRIAL, SIMILARLY
DESIGNED. SO THIS IS DOABLE AND
WE HAVE PARADIGMS AND I WOULD
LIKE TO SEE US TAKE SOMETHING
LIKE THIS ON. SO I THINK THAT IS
WHAT I HAD TO SAY. ONE OTHER
THING. WITH RESPECT OPIOID ONCE
PEOPLE DO ARE ON CHRONIC OPIOID
THERAPY I THINK THIS QUESTION OF
HOW MANY TIMES DO YOU ROTATE AND
WHAT DOSES DO YOU USE, IS
ANSWERABLE SO NICE IF WE HAD
SOME IDEA OF THAT, PROBABLY
CLINICAL OUTCOME FUNDAMENTALLY
DIVIDES INTO THREE AGAIN, THIS
IS ME BEING THE DUMB GUY, THREE
BUCKETS. ONE SET OF PEOPLE FOR
WHOM OPIOIDS FUNDAMENTALLY DON'T
WORK TO JUSTIFY MUCH RISK IN
WHICH CASE WE SHOULD TRY
SOMETHING ELSE. OTHER PEOPLE
FROM WHOM OPIOIDS WORK AND
SIMPLY WHAT WE ARE TRYING TO DO
IS MANAGE RISK, REDUCE IT IF
POSSIBLE, A THIRD GROUP OF
PEOPLE WHOM THERE ARE OPIOIDS
THE RISK IS LOW AND JUST LEAVE
WELL ENOUGH ALONE. AGAIN, I
THINK THESE QUESTIONS ARE
FUNDAMENTALLY ANSWERABLE. REALLY
HOPE WE COULD MAKE ESTABLISH
THEM. NEXT SLIDE. SEE I IF I HAD
ANYTHING ELSE. THAT IS ALL I
HAVE TO SAY. THANKS.
>> WE HAVE UNTIL 2:50 TO
ENTERTAIN QUESTIONS, TALK TO ONE
ANOTHER, AND I WILL TAKE THE
PREROGATIVE OF ASKING THE FIRST
QUESTION. WHICH WILL GO TO MY
FRIEND PAT. PAT, WE ARE
CRITICIZED OFTEN FOR WHAT WE DO
IN MANAGING PAIN AS
PSEUDOSCIENTIFIC AND THEN
CRITICIZED FOR NOT LIVING UP TO
THAT PSEUDOSCIENCE. CAN YOU GIVE
US DEFENSES AND I'M SPEAKING
ABOUT THE DEA PHARMACEUTICAL
DISPENSARIES, THE DRUGSTORES
THAT GIVE THE DRUGS OUT,
INSURANCE COMPANIES,
FORMULARIES, I'M REFERRING BACK
TO THAT VIDEO, TO THAT GRAPHIC
THAT I SHOWED CMS PUBLISHED
WHERE IN A GREAT ENVIRONMENT
LIKE SWEDEN WE CAN DO ANYTHING
WE WANT TO GET PAID FOR BUT NOT
SO IN THE UNITED STATES.
EVERYTHING YOU JUST SAID IS
SUBJECT TO THOSE RESTRICTIONS
AND CAN YOU GIVE US -- GIVE THE
AUDIENCE A LITTLE BIT OF HOW YOU
DEFEND GETTING SOME OF THOSE
THINGS DONE THAT YOU WOULD LIKE
TO DO AND YOU ARE TRYING TO DO
FOR YOUR PATIENTS.
>> SO I GET HIRED TO BE THE DUMB
GUY AND ALSO TO GET IN TROUBLE
SO I GUESS I'M ABOUT TO GET
MYSELF IN TROUBLE. I MEAN, I
DON'T KNOW, WALLY. THE BEGINNING
OF THE ANSWER, AIN'T NOBODY
BETTER OFF, CHRONIC PAIN IS HARD
TO TREAT, EVERYTHING WE USE HAS
RELATIVELY SMALL EFFECTS THAT
ARE HARD TO DETECT. AND I THINK
EVERYTHING I SAID ABOUT LACK OF
CLINICAL STRATEGY CHRONIC PAIN
IN GENERAL, WE ARE ALL IN THE
SAME BOAT. SO I THINK THERE IS
THE FIRST THING, WE NEED TO BACK
IT UP WITH EVIDENCE. WHAT I
SUGGESTED ABOUT HOW WE START
DEFINING, WHAT IS THE FIRST
THING -- FIRST FEW THINGS TO
OFFER AND SEE WHAT ACTUALLY
HAPPENS IS THE BEGINNING. AS TO
REGULATORY BODIES SO FORTH, A
LOT OF TIMES THAT GOES TO
OPIOIDS. I THINK THERE IS TWO
PARTS TO THAT, ONE PART OF IT IS
EVERYBODY HAS GOT TO REALIZE
OPIOID ARE COMPLICATED, AND THEY
WORK. BUT THEY OFTEN ALSO FAIL.
WE HAVE TO KEEP THOSE TWO THINGS
IN OUR HEADS SIMULTANEOUSLY. AND
THEY HAVE SIGNIFICANT ADVERSE
EFFECTS AND RISKS. SO IT IS WAY
TOO EASY TO LOOK AT ONE, GRAB
ONE ELEPHANT AND THINK YOU GOT A
ROPE AND GRAB ONE OF THE
ELEPHANT AND THINK IT IS A SNAKE
AND BUT YOU KNOW IT IS AN
ELEPHANT. AS TO THAT PART WE DO
HAVE TO REALIZE THAT OPIOID
CANNOT WORK AND SAY OUTLOUD THAT
LOT OF TIMES WE DON'T WORK AND
WE HAVE TO DECLARE FAILURE. WE
CAN'T KEEP ACTING LIKE YOU GOT
TO RESPOND TO RIGHT DOSE RIGHT
DRUG. I DON'T THINK IT IS THAT
SIMPLE. BUT OTHERS MIGHT
DISAGREE. AT THE SAME TIME THEY
DO WORK FOR SOME PEOPLE AND HAVE
BENEFIT CAN WELL BE SUSTAINED.
SO WE HAVE TO I THINK
DEMONSTRATE THAT BENEFIT AND FOR
WHOM IT IS SUSTAINED, BUT AT THE
SAME TIME GOT TO BE HONEST WITH
EVERYBODY AND OUR PATIENTS AND
HAVE A DEFINITION OF WHEN IT
DOESN'T WORK TOO AND THAT WILL
IMPROVE CONFIDENCE ON ALL PARTS.
THE PATIENTS TALKING FROM PLACE
OF CONCERN AND KNOWLEDGE AND
REGULATORS BEING RESPONSIBLE.
>> IS IT THE PLACE OF RESEARCH
OF CLINICIANS OR OF BOTH? TO
DEFINE THAT TERM WORKS? FOR
INSURANCE THAT DEFINES IT FOR
US, THEY OFTEN WILL DEFINE IT
FOR US. HOW DO WE DEFEND
OURSELVES WHEN THEY DEFINE IT
FOR US AND WE GO I BEG TO
DISAGREE? I SPEND MY TIME ON THE
PHONE, IN FACT I HIRED SOMEBODY
JUST TO SPEND THEIR TIME ON THE
PHONE SAYING NO IT WORKS. PLEASE
DO THIS. PLEASE LET OUR PATIENT
HAVE THIS.
>> WE HAVE CERTAIN WILL I TALKED
ABOUT CASES WHERE THE INSURANCE
THOUGHT THEY WERE DOING
SOMETHING TO PROTECT THE
PATIENT, IN FACT DISRUPTING CARE
O THE POINT PATIENT CARE FLU
APART. I DON'T HAVE MIRACULOUS
ANSWER. I THINK ETHICALLY
SPEAKING. CLINICIANS WE HAVE TO
HAVE A DEFINITION OF WORK OR
NOT. THE PROBLEM IS WE ARE
OPERATING FROM INACT CAT
EVIDENCE BASE. IF YOU DON'T HAVE
ANY DEFINITION OF FAILURE YOU
ARE NOT GOING TO STOP ANYTHING
AND YOU ACT LIKE EVERYTHING
WORKS AND THAT CLEARLY IS NOT
TRUE SO YOU WILL BE WRONG A LOT.
YOU WON'T SEEK SUCCESS BECAUSE
YOU WILL KEEP DOING STUFF THAT
IS NOT WORKING INSTEAD OF STUFF
THAT DOES. YOU EXPOSE PEOPLE TO
RISK BECAUSE THEY DON'T NEED TO
BE EXPOSED TO BECAUSE IT AIN'T
WORKING. WE AS CLINICS HAVE TO
HAVE A DEFINITION OF SUCCESS AND
FAILURE. OUR FUNDAMENTAL PROBLEM
IS WE HAVE GOT SOME ROUGH GUIDE
POSTS BUT IT REQUIRES US BEING
ARBITRARY. WITHIN THOSE GUIDE
POSTS, THAT IS DEEPLY
UNCOMFORTABLE. I THINK WE HAVE
TO BE STRAIGHT WITH PEOPLE. WE
HAD SOME ROUGH GUIDE POSTS, I'M
TAKING A GUESS HERE, I DON'T
KNOW THE EXACT RIGHT THING. IF
WE GO UP ON THE DOSE YOUR RISK
INCREASES AND PROBABLY THE
BENEFIT DOESN'T MUCH PAST A
CERTAIN POINT AT SAME TIME I
CAN'T SQUARE TO YOU EITHER WAY
SO WE BOTH HAVE TO DO SOME
NAVIGATING HERE.
>> ONE QUESTION IN THE -- TWO
QUESTIONS ABOUT THIS POINT. ONE
PERSON WANTED TO KNOW, YOU SORT
OF SAID YOU DON'T KNOW, WHEN
PAIN IS REFRACT TRY TO OPIOID,
AND ANOTHER WANTED TO MOW IF THE
PERSON IS ON ELOQUIST FOR ATRIAL
FIBRILLATION DOES THAT MATTER,
DOES THAT CHANGE ANYTHING?
>> IF YOU TOLD ME N SAIDS THEN
YEAH. WHERE I -- THERE ARE
PEOPLE HERE WHO KNOW WAY MORE
ABOUT THIS THAN I DO. AND THEY
ARE LOOKING AT YOU BUT THE WAY I
READ THINGS OUR PATIENTS ARE AT
RISK FOR CLOTTING AND BLEEDING
AND IMPORTANT CLOTTING
COAGULATION. WE HAVE THIS
PROBLEM OF RENAL DISEASE AND
ALSO STROKE. ALL THESE THINGS
ARE THINGS THAT COULD BE RISK
FOR CHRONIC N SAID THERAPY AND I
WORRY A LOT ABOUT IT. IF YOU
LOOK AT THE SPACE TRIAL WHERE
PEOPLE SPENT THEIR TIME
RANDOMIZE TO ALL NON-OPIOIDS OR
OPIOIDS, WHERE PEOPLE SPEND
THEIR TIME NON-OPIOID ARM WAS ON
N SAIDS SO SEEMS TO BE AN
IMPORTANT TOOL YET WE OFTEN USE
IT BUT DO WE REALLY KNOW WHAT WE
ARE DOING TO PEOPLE FOR FIVE TEN
YEARS? DO WE KNOW WHAT THEY ARE
DOING AT HOME? A LOT OF PEOPLE
TAKE DOSES OF IBUPROFEN
SOMETIMES.
>> TOM ASKED THE QUESTION HAS
ANYBODY LOOKED AT PERCEPTION OF
THE CARING OF THE PROVIDER AND
WITH RESPECT TO PAIN TREATMENT
THERE HAVE BEEN A NUMEROUS
STUDIES OF ADDITIVES OF PAIN
PROVIDERS, PEOPLE ASSIGNED TO
RELIEF PAIN AND BASICALLY THEY
ARE NOT DOING THEIR JOB. I WOULD
PUT IT THAT WAY. THEY ARE
FEELING UNCOMFORTABLE LIKE PAT
SAID. THEY DON'T FEEL
COMFORTABLE. THAT IS THEY DON'T
KNOW WHAT THEY ARE DOING, THEY
KNOW THEY DON'T KNOW WHAT THEY
ARE DOING AND THAT MAKES THEM
UNCOMFORTABLE. AND THEY DON'T
LIKE HAVING TO DO IT. THAT IS
THE SUMMARY WOULD YOU ADD TO
THAT ANYBODY SUMMARY OF THE
LITERATURE ON THAT? I THINK THAT
IS THE SUMMARY.
>> I DO THINK SIGNIFICANT CHUNK
OF THIS IS ABOUT ADDICTION. THAT
IS ONE OF THE THINGS THAT
TERRIFIES PEOPLE. ONE OF THE
PROBLEMS WE GOT THERE IS THAT I
DON'T THINK YOU CAN GET
NECESSARILY DEFINE QUOTE UNQUOTE
ADDICTION IN THIS CONTEXT ALL
THAT WELL. JUST BECAUSE OF THE
WAY OPIOIDS WORK ON BEHAVIOR. SO
I THINK -- I HAVE A CERTAIN
AMOUNT OF SYMPATHY FOR THE
COGNITIVE DISSONANCE SOME HAVE.
THEY ARE HELD TO ACCOUNT TO
PREVENT SOMETHING THEY CAN'T
SEE, HIGH INDEX OF SUSPICION FOR
IT BUT THEY ARE GOING TO SUSPECT
PEOPLE WHO HAVE NO REASON OF
BEING SUSPECTED. SO I THINK WE
GET STUCK IN THIS SITUATION
WHERE ALL OUR PATIENTS GET
LOOKED AT WITH A STAKE EYE BUT
IT DOESN'T CHANGE THINGS. IT
DOESN'T PREVENT THE TROUBLE NOR
DOES IT DO ANYTHING TO GET PAIN
CARE BETTER, OFTEN MAKES IT
WORSE. SO I THINK IF WE CAN HELP
OUR COLLEAGUES WITH DIFFERENT
PARADIGM AROUND THAT, IT WOULD
PROBABLY HELP.
>> I DON'T SEE ANY OTHER
QUESTIONS IN THE CHAT SO I HAVE
NO PROBLEM ASKING OTHER SPEAKERS
QUESTIONS, I REALLY APPRECIATED
THE ANALOGY OF THE CYCLE OF
TRANSLATIONAL RESEARCH. I'M NOT
SURE I SAW THAT PICTURE BEFORE.
BACK AND FORTH BETWEEN MAN AND
MOUSE. AND I LIKE THAT CONCEPT
AND WONDERED IF, STARTING WITH
DR. STUCKY, WONDERED IF YOU FELT
LIKE I'M GOING TO USE THE HEEL
INITIATIVE BECAUSE I KNOW ABOUT
THE HEEL INITIATIVE. IF YOU FELT
LIKE THE HEEL INITIATIVE IS
AWARE OF THIS APPROACH, YOU GOT
A TARGET YOU HAVE POTENTIAL
PROBE INTO THAT TARGET THAT
COULD TURN INTO POTENTIAL DRUG
AND YOU TESTED AND YOU GO TO
ANIMAL STUDIES AND BACK TO
HUMAN.
>> THANKS, WALLY. I THINK THEY
ARE AWARE OF IT BUT I DON'T
THINK THEY ARE ENCOURAGING
ENOUGH STUDIES THAT COULD REALLY
DO THIS. PARALLEL BACK AND FORTH
WAY. I ALSO THINK THAT THERE IS
NOT ENOUGH ENCOURAGEMENT FOR
PIs WHO ARE WORKING ON SICKLE
CELL DISEASE WHETHER CLINICAL OR
BASIC RESEARCH TO SUBMIT FOR
THESE KINDS OF STUDIES. SO I
THINK THERE NEED TO BE MORE
CALLS FOR THIS TYPE OF WORK AND
I THINK THERE NEED TO BE MORE
ANSWERS IN SUB -- AND
SUBMISSIONS FOR THIS KIND OF --
THESE KINDS OF BACK AND FORTH
STUDIES. I THINK ALSO THERE IS
NOT ENOUGH STUDIES ON SICKLE
CELL DISEASE PAIN THAT ARE
GETTING FUNDED. AS WELL.
>> YEAH. I THINK THE HEEL
INITIATIVE IS SENSITIVE TO THAT.
THEY ARE ALSO SENSITIVE TO THE
DUAL PROBLEM OF SUBSTANCE USE
WITHIN THE CONTEXT OF SOMEBODY
WITH CHRONIC PAIN. THAT IS A NEW
SENSITIVITY ON THEIR PART. THEY
ARE FOR THE FIRST TIME PUTTING
OUT RFAs ABOUT THAT. SO THAT
MADE ME EXCITED ABOUT IT. THERE
ARE FUNDING SICKLE CELL SPECIFIC
STUDIES. I KNOW THAT. Y'ALL
PROBABLY EVERYBODY KNOWS ABOUT
THE RFAs ON THE STREET.
RELATED TO SICKLE CELL DISEASE.
>> ABSOLUTELY. I THINK WE NEED
MORE INDIVIDUALS ANSWERING THOSE
CALLSES AND SUBMITTING STRONG
APPLICATIONS AND WE NEED TO HAVE
THOSE APPLICATIONS SCORE WELL.
AND GET FUNDED.
>> QUESTION FOR AMANDA. IS THE
GUT BRAIN CONNECTION WELL
EMPHASIZED ENOUGH IN OTHER
CONDITIONS THAT WE CAN COPY THE
METHODS THEY ARE USING AND SHOW
THAT THEY ARE TRUE FOR SICKLE
CELL DISEASE? OR ARE YOU BLAZING
THE TRAIL BY YOURSELF?
>> THANKS, WALLY, IT IS STARTING
TO BE UNCOVERED AND INVESTIGATED
A LOT MORE IN DEPTH AND OTHER
PAN CONDITIONS. THERE IS
PROPOSED HYPOTHESIS HOW THE
CONNECTION EXISTS IN CONTEXT OF
PAIN. THERE IS BETTER MECHANISMS
WORKED OUT IN OTHER PAIN
DISORDERS I THINK THERE IS A
POST DOC WHO IS WORKING IN DR.
STUCKY'S LAB NOW MOVING TO A
FACULTY POSITION DOING EXCITING
WORK IN THE MURINE MODEL. SHE
HAS A K99 ROO TO LOOK AT THIS TO
UNDERSTAND MECHANISMS OF THE GUT
BRAIN CONNECTION. MY RO1 IN
HUMANS IS LOOKING AT HUMAN
ASPECTS OF THE GUTS CONNECTION
TO POTENTIALLY PAIN THROUGH
IMMUNOLOGIC PATHWAYS. THERE IS
OTHER WAYS OTHER THAN THE IMMUNE
SYSTEM THE GUT BRAIN CONNECTION
ACTUALLY COULD IMPACT PAIN AND
CENTRAL PAIN MECHANISMS IN THE
BRAIN AND SPINAL CORD. WE ARE
DOING PARALLEL WORK BOTH MYSELF
AND DR. SADLER TO TRY TO
INVESTIGATE THIS AT THE
MECHANISTIC LEVEL. WHAT YOU
REFER TO ABOUT TRANSLATIONAL
APPROACH IS IMPORTANT BECAUSE AS
CLINICAL TRANSLATIONAL
RESEARCHER I CAN LOOK AT
ASSOCIATIONS AND A LOT OF
CLINICAL STUFF AND DERIVE
QUESTIONS. IF WE WANT TO DRILL
DOWN DEFINITIVE MECHANISM
COLLABORATING WITH BASIC
SCIENTISTS IS REALLY IMPORTANT.
TO BRING DOWN TO MECHANISM TO
LOOK AT PATHWAYS THAT CAN BE
TARGETED, BROUGHT BACK TO HUMAN.
GREAT COLLABORATIONS I HAVE WITH
BASIC SCIENTISTS HAS BEEN NOT
ONLY INCREDIBLY HELPFUL FOR ME
AS CLINICAL TRANSLATIONAL
RESEARCHER AS FAR AS LEARNING
BUT ALSO MOVES THE FIELD
FORWARD. SO ANYONE WITH THE
OPPORTUNITY TO WORK IN THAT
MODEL IS IMPORTANT. TO ANSWER
QUESTION ABOUT MICROBIOME, IT
NEEDS TO BE FURTHER STUDIED IN
SICKLE CELL DISEASE BECAUSE
THERE'S SOME THINGS EVEN IF
FOUND IN OTHER PAIN CONDITIONS,
SICKLE CELL DISEASE IS IN ITSELF
A DIFFERENT DISEASE IN MANY
ASPECTS. SO I THINK WILL IS A
UNIQUE THINGS RELATED TO SICKLE
CELL DISEASE WE MAY BE FINDING
IN OUR DATA THAT DESERVES
FURTHER EXPLORATION IN CONTEXT
OF THE DISEASE MODEL. NOT JUST
COPY PASTE FROM DIFFERENT
DISEASE. NITYA'S QUESTION. YOU
GOT THIS NEAT THING THAT CAN USE
TO PHENOTYPE PATIENTS. WHAT DO
YOU NIH FUND NEXT? HOW ABOUT
THAT FOR A SOFTBALL?
>> I THINK WITH RESPECT TO
IDENTIFYING PAIN PHENOTYPES, I
THINK WE SHOULD FOCUS ON
MULTI-MODAL PHENOTYPING OF PAIN.
NOT JUST USING HEALTHCARE
UTILIZATION USED LONGEST TIME
AND NOT JUST USING PAIN
INTENSITY BUT COLLABORATION OF
PATIENT REPORTED OUTCOMES, SOME
DEEP UNDERSTANDING OF CLINICAL
PAIN FEELS LIKE IN TERMS OF
DECRYPTERS AND -- DESCRIPTORS
AND NOT JUST AT THE CONCEPTUAL
LEVEL BUT ALSO LONGITUDINALLY,
WHETHER TO SEE WHETHER THE
PHENOTYPES ARE --
>> SO THE PATIENTS COMPLAIN
BECAUSE YOU TAKE 20 MINUTES TO
ASK ABOUT -- I SAID WHAT IS YOUR
PAIN LIKE? WHAT IS YOUR PAIN
LIKE? JUST ASK THEM UP DOWN AND
SIDEWAYS AND NAY ARE LIKE ENOUGH
ALREADY. YOU TOLD ME THIS
YOURSELF, IN YOUR HARD TO GET
THEM TO TELL YOU EVERY DAY OR
TELL YOU FOR 20 MINUTES. WHAT --
HOW DO WE BALANCE RESPONDENT
BURDEN WITH NEED TO KNOW TO HAVE
ADEQUATE --
>> I THINK THAT IS A GREAT
QUESTION. IF WE INVEST IN
RESEARCH THAT CAN IDENTIFY THE
MOST HIGH YIELD ITEMS THAT
PREDICT OUTCOMES, THAT WOULD BE
THE WAY TO GO BUT TO START OFF
WE WOULD HAVE TO GET A GOOD DEEP
UNDERSTANDING AT THE SAME TIME
TO BE ABLE TO MOVE FORWARD I
THINK NOT DOING THIS DOESN'T
ALLOW US TO INTERFACE WITH
TRANSLATIONAL RESEARCHERS,
BECAUSE AT THE END OF THE DAY
WHAT WE NEED MEASURING IS
HEALTHCARE UTILIZATION WHICH WE
KNOW HAS GONE DOWN OVER TIME OR
ON AVERAGE ESPECIALLY HYDROXY
UREA AND DEPENDING ON MULTIPLE
OTHER VARIABLES THAT MAY NOT BE
RELATED TO PAIN FREQUENCY. IT
IS HARD TO ASSESS PAIN FREQUENCY
BY RESPECT OF THIS. I KNOW AAPT
DEFINITION, HOW MANY OF YOU HAD
PAIN THE LAST SIX MONTHS BUT
OPERATIONALIZING IT IN CLINIC IS
--
>> TERRIBLE.
>> IT IS DIFFICULT. UNLESS PAIN
IS ON MOST DAYS THEN EASY,
OTHERWISE IT IS HARD TO TELL.
WHAT THEY WERE ACTUALLY GETTING
(INAUDIBLE)
>> WE ARE GOING TO DONATE OUR
THREE MINUTES TO THE NEXT
SESSION BUT I WOULD ENCOURAGE
OUR PANELISTS TO KEEP AN EYE OUT
ON THE CHAT. AND AS AT HAS BEEN
DOING PLEASE ANSWER QUESTIONS
THAT COME UP IN THE CHAT THAT
ARE SEEMINGLY DIRECTED TO YOU.
OR YOU HAVE KNOWLEDGE ABOUT. I
WANT TO THANK THESE PARTICULAR
PANELISTS, FOR DEEP EXPERTISE
CRISP PRESENTATIONS THAT
SUMMARIZED A WHOLE LOT OF DATA
AND LOT OF WORK IN SOME CASES
TEN MINUTES. AND I THANK YOU FOR
CONTRIBUTING TO THIS TALK.
THANKS FOR PAT FOR BEING THE
OWL, THE WISE OWL. I DIDN'T SAY
OLD. THE WISE OWL OF OUR
DISCUSSION.
>> OLD WOULD BE MORE ACCURATE.
>> SO I'M GOING TO HAND IT OVER
TO DR. GUPTA.
>> THANK YOU WALLY.
CAPNA, ALL YOURS.
>> CAN YOU HEAR ME ALREADY?
>> YES WE CAN WE CAN.
>> CAN I SHARE MY SLIDES PLEASE.
I STARTED MY VIDEO BUT I DON'T
KNOW WHY IT IS NOT SHOWING. I AM
SHOWING. THAT'S ALL RIGHT. OKAY.
SO AS YOU SAW EARLIER TODAY,
FROM JULIE'S PRESENTATION, SHE
HAS SPOKEN ABOUT DR. BELL'S --
VERY HARD TIME FOR US AND I'M
DEEPLY SADDENED TO INFORM YOU
THOSE WHO WERE NOT HERE IN THE
MORNING THAT OUR DEAR DR.
BALLAS, COMPASSIONATE PHYSICIAN
LEADING IN SICKLE CELL PAIN, HE
IS A GREAT SPIRIT, A HEELER AND
SO KNOWLEDGEABLE AND GREAT
FRIEND TO ALL OF US. HE -- I
CAN SAY PERSONALLY HE WAS MY
INSPIRATION AND ENCOURAGED ME
FROM THE START BEFORE I STARTED
STUDYING PAIN. THEREFORE I
COULDN'T START WITHOUT
REMEMBERING HIM AT THIS TIME,
BECAUSE HE WAS ALWAYS PRESENT AT
ALL OF OUR MEETINGS. NEVER
MISSED ASH OR SICKLE CELL
CLINICAL MEETING. THEREFORE, I
AM SHOWING HIS PICTURE AGAIN
TODAY AND HIS FAMILY WANTS US TO
PRAY FOR HIM. AND WISH HIM A
SMOOTHER TRANSITION AS HE IS
STRUGGLING IN HOSPICE CARE
FOLLOWING DIAGNOSIS OF END STAGE
CANCER TWO MONTHS AGO. THIS IS
ALL I LEARNED FROM MISDAUGHTER.
AND I'M CONVEYING IT TO YOU. I
HOPE YOU WILL JOIN ME IN PRAYING
FOR HIM AND HIS FAMILY TO BE IN
PEACE AND HAVE A SMOOTH
TRANSITION. THANK YOU, VERY
MUCH.
>> I WOULD LIKE TO START THIS
SESSION
>> CAN YOU SPEAK UP? ON
INTEGRATED TECHNOLOGY ENHANCED
APPROACH TO TARGET SICKLE CELL
PAIN. I'M SURE BY NOW ALL OF YOU
ARE EXPERTS IN SICKLE CELL PAIN.
AFTER THIS TOWER D E FORCE, IT
IS TIME FOR DESERT. I WILL NOT
SAY IT IS THE LAST SESSION BUT
IT IS A SWEET SESSION. AND I
HOPE YOU CAN BEAR WITH ALL OF US
SITTING HERE SINCE THE MORNING
AND I THANK YOU FOR THAT. THIS
SESSION IS AIMED AT DISCOVERY
SCIENCE, SO YOU WILL HEAR
NASCENT RESEARCH WHICH NEED SOME
TRANSLATION. THAT IS WHY IT IS
VERY IMPORTANT TO BRING IT
FORTH. WHAT IS OUR GOAL HERE?
OUR GOAL IS TO DEVELOP IN
MECHANISM BASED APPROACH TO FILL
THE GAPS THAT WE HAVE HEARD
DURING THE LAST THREE DAYS IN
UNDERSTANDING AND TREATMENT OF
PAIN, AND WHAT WE ARE TARGETING
IS USING NON-PHARMACOLOGIC
INTERVENTIONS USING A
MULTI-DISCIPLINARY EXPERTISE, WE
HEARD ABOUT PERIPHERAL
MECHANISMS VERY ENLIGHTENING
TALKS BY AMANDA BRANDOW AND
CHERYL STUCKY AND COLLEAGUES IN
BASIC SCIENCE BUT THERE IS A
LACK IN UNDERSTANDING THIS
COMPLEX LITTLE ORGAN, THE BRAIN,
AND HOW THE NERVOUS SYSTEM USING
TOP DOWN NEUROMODULATION AND
PERCEPTION WHICH ACTUALLY VERY
ELEGANTLY PAT CARROLL TALKED
ABOUT, PERCEPTION, WHAT HAVE WE
DONE WITH IT? HOW CAN WE USE IT
OR DO WE KNOW IT? IT IS VERY
CONFUSING AS YOU SAID. SO WHAT
HE ARE TRYING TO DO IS DISSECT
OUT THIS WHOLE TOP DOWN
NEUROMODULATION, THE ROLE OF
BRAIN AND HOW DO WE TAME THE
BRAIN? WHAT IS THE ROLE OF
ENVIRONMENT IN THIS
NEUROMODULATION INCLUDING
NUTRITION, COMPANIONSHIP AND
SLEEP? AND EGG GANTLY CLAUDIA
MORRIS HAS -- ELEGANTLY HAS
SHOWN NUTRITION FROM ARGININE
PLAYS A MAJOR ROLE IN PAIN. WE
HAVE BEEN TALKING ABOUT CHRONIC
PAIN QUITE A LOT. BUT WE
PROBABLY NEED TO KNOW CAN WE
PREDICT VOC? THIS IS THE BIGGEST
IRONY OF THIS DISEASE
SPECIFICALLY THAT IS
UNPREDICTABLE. THIS IS WHERE WE
BROUGHT EXPERTISE TOGETHER FROM
LEADING EXPERTS IN ENGINEERING
AND PHARMACOLOGIC INTERVENTIONS,
AND LITTLE ME TO BRING TO YOU
OUR THOUGHTS AND WORK OF MANY
YEARS. TOM COATS HAS BEEN
SHOWING FOR FEW YEARS NOW THAT
HOW THE CENTRAL NERVOUS SYSTEM
OR SYMPATHETIC NERVOUS SYSTEM
MODULATE PERIPHERAL ACTIVITY BY
WHEN HE JUST TOLD THE PATIENTS
THAT YOU WILL FEEL PAIN THEY
STARTED FEELING PAIN BEFORE THEY
INDUCED PAIN. SO THIS TELLS US
PERCEPTION IS A BIG MODULATOR OF
PAIN AND PERHAPS AS PAT SAID IN
HIS COMMENTS, FROM THE NERVOUS
SYSTEM FROM THE CENTRAL ACTIVITY
TO THE PERIPHERAL AND FROM THE
PERIPHERAL TO THE CENTRAL, THIS
IS WHAT WE ARE GOING TO SHOW
TODAY. SO WITH THIS I WOULD HAND
OVER THE FLOOR TO DR. KIMBERLEI
RICHARDSON, THE WHOLE CHAIR OF
THE SESSION, BUT BEFORE THAT, I
WOULD ALSO LIKE TO INTRODUCE DR.
HE WHO WILL GIVE THE FIRST TALK.
DR. HE ARE YOU READY?
>> YES.
>> OKAY. I WILL STOP SHARING MY
SLIDES. DR. HE IS PROFESSOR OF
BIOMEDICAL ENGINEERING AND
NEUROSCIENCE AT CARNEGIE MELLON
UNIVERSITY IN PITTSBURGH. PRIOR
TO JOINING CARNEGIE MELLON HE
WAS THE DIRECTOR OF FOUNDING
DIRECTOR OF THE INSTITUTE FOR
ENGINEERING MEDICINE UNIVERSITY
OF MINNESOTA AND ORGANIZATION ON
STEROIDS FOR RESEARCH. HE HAS
RESEARCH EXPERTISE IN NEURAL AND
-- INCLUDE -- ENGINEERING
INCLUDING NON-MODULATION
ULTRASOUND NEUROMODULATION. AND
EEG. HE DEVELOPS NON-TECHNIQUES
TO QUANTIFY SICKLE CELL PAIN AND
INDUCE OR SUPPRESS SICKLE CELL
PAIN USING FOCUSED ULTRASOUND
NEUROMODULATION. AS MULTIPLE PI
ON NHLBI EXCELLENCE RESEARCH
HUMAN -- HIS LABORATORY
ESTABLISHED THE POTENTIAL OF
QUANTITATIVE EEG FOR
QUANTITATION OF PAIN IN SICKLE
CELL DISEASE. WOULD BE GLAD TO
HEAR IT IS CLINICALLY, IT IS
UNDER CLINICAL TRANSLATION BY
SOME INDUSTRIES NOT BY HIM. HE
IS ALSO A FUNDED INVESTIGATOR OF
THE HEEL INITIATIVE ON WHAT HE'S
GOING TO PRESENT TODAY. DR. HE,
THANK YOU VERY MUCH FOR AGREEING
TO ACCEPT OUR INVITATION TO
SPEAK.
>> THANK YOU, DR. GUPTA. THANK
YOU FOR THE ORGANIZER. IT IS A
PLEASURE TO HAVE THIS
OPPORTUNITY TO PRESENT THE WORK
THAT AS YOU CAN SEE FROM THIS
SLIDE PAGE. THE WORK THAT IS A
CLOSE COLLABORATION BETWEEN MY
LAB AND CARNEGIE MELLON
UNIVERSITY TO DEVELOP FOCUS
ULTRASOUND NEUROMODULATION IN
DR. GUPTA'S LAB IN CALIFORNIA
WHERE HUMAN SICKLE MICE MODEL
WAS DEVELOPED AND PRODUCED HAS
SHIFTED TO PITTSBURGH AND WE
TESTED OUR DEVICE AND THAT -- SO
MY PRESENTATION WILL INCLUDE TWO
PART, ONE IS SOME OF THE GENERAL
INTRODUCTION UNIQUE
NEUROMODULATION TECHNOLOGY,
USING FOLKS ULTRA -- FOCUSED
ULTRASOUND, THEN I WILL PRESENT
OUR LATEST UNPUBLISHED RESULTS,
TO SHOW FOLKS ARE ULTRASOUND
NON-INVASIVELY SUPPRESS SICKLE
CELL PAIN IN P HUMAN MICE AND
MICE MODEL. AS GENERAL INTRO, I
WANT TO REITERATE MANY THINGS P
BEING SAID, CHRONIC PAIN WHICH
ARE RELEVANT TO SICKLE PAIN AND
AFFECTS A SIGNIFICANT PORTION OF
GENERAL POPULATION. AS YOU CAN
SEE THIS SLIDE HERE, THE CURRENT
PAIN TREATMENT METHOD INCLUDES
PHARMACOLOGY APPROACH OR NEURAL
MODULATION APPROACH,
NEUROMODULATION APPROACH
NEUROINVASIVE APPROACH SUCH AS
DEEP BRAIN STIMULATION, AND THE
MOTOR CORTEX STIMULATION SPINAL
CORD STIMULATION ALSO. THERE IS
A CLASS OF NON-INVASIVE
NEUROMODULATION TECHNOLOGY,
INCLUDING THE TRANSCRANIAL
DIRECT STIMULATION MAGNETIC
STIMULATION AND RECENTLY
TRANSCRANIAL FOCUSED ULTRASOUND
STIMULATION ARE BEING DEVELOPED
FOR THIS PURPOSE. THIS IS SCD
MEETING AND WE KNOW THIS IS A
CHALLENGE ONE COMMON HERE IS
THAT THE SICKLE PAIN, IT IS A
VERY WIDESPREAD SOMETIMES
UNPREDICTABLE PERIPHERAL PAIN.
YOU DO NOT KNOW WHICH PART OF
THE PERIPHERAL SYSTEM IS GOING
TO EXHIBIT IN PAIN. SO
MODULATING CENTRAL NERVOUS
SYSTEM AND TO SUPPRESS THE PAIN
MANAGE THE PAIN, REPRESENT A
IMPORTANT APPROACH. AS DR.
GUPTA MENTIONED IN PREVIOUSLY
FUNDED NIH PROGRAM GRANT, WE USE
EEG AND FUNCTIONAL MRI TO
CONDUCT NEUROIMAGING IN CONTROL,
HEALTHY HUMAN SUBJECT AND SSCD
PATIENT. AFTER WE FOUND THERE
IS BRAIN ACTIVATION GENERATED
THAT COULD BE OBSERVED IN THE
ALPHA REGION AND BETA REGION, WE
LOOK AT CONTRAST BETWEEN SICKLE
PATIENT AND HEALTHY PATIENT WE
CAN IDENTIFY CERTAIN BRAIN
TARGET INCLUDING ACC INSULA AND
THALAMUS. FROM THIS IMAGING
RESEARCH PROVIDE INFORMATION TO
HELP US TO DETERMINE WHERE FOCUS
ULTRASOUND STIMULATION CAN BE
DIRECTED. A LITTLE BIT INTRO
ABOUT NEUROMODULATION THOUGH WE
ALL I ASSUME MOST OF US KNOW
ALREADY, THE NEUROMODULATION
ESSENTIALLY INVOLVE DELIVERING
IF AS ICAL OR CHEMICAL ENERGY
INTO NERVOUS SYSTEM. IN
PARTICULAR IN THIS PRESENTATION
WHERE WE ARE FOCUSING ON BRAIN
SO IT WOULD BE FOR EXAMPLE
INVASIVE APPROACH INCLUDING DEEP
BRAIN STIMULATION OR CORTICO
STIMULATION AT MOTOR CORTEX OR
HERE NON-INVASIVE APPROACH
INCLUDING RAINS CRANIAL DIRECTED
STIMULATION TRANSCRANIAL
MAGNETIC SIMULATION AND
TRANSCRANIAL FOCUS ULTRASOUND
STIMULATION. HERE IS A PICTURE
TAKEN FROM A REVIEW ARTICLE
ILLUSTRATING VARIOUS APPROACH
INCLUDING DRUG DELIVERY AND
CERTAINLY INVASIVE LIKE
OPTOGENETICS KY CANNOT BE
APPLIED TO HUMAN TRANSLATION BY
NOW. HERE ARE GREEN COLOR
ILLUSTRATING VARIOUS
NON-INVASIVE NEUROMODULATION,
BRAIN NEUROMODULATION APPROACH,
HERE IS SPATIAL RESERVATION,
TEMPORAL RESOLUTION AN FOCUS
ULTRASOUND NEUROMODULATION HAS
PARTICULAR UNIQUE AND PROMISE
WHICH OFFER HIGH SPATIAL HIGH
TEMPORAL RESOLUTION FOR
NEUROMODULATION. WHAT EXACTLY
IS THE FOCUS ULTRASOUND
NEUROMODULATION? PARTICULARLY
TALKING TRANSCRANIAL. HERE THIS
IS ILLUSTRATION YOU CAN SEE
THERE COULD BE A MULTIPLE
ULTRASOUND TRANSDUCER, THAT CAN
DELIVER PHYSICAL ACOUSTIC ENERGY
WHICH GENERATE ESSENTIALLY
MECHANIC ALIBI OPERATION WAVE
THAT CAN GO TO ANY SPOT INSIDE
THE BRAIN, MEANING IT HAS DEEP
BRAIN PENETRATION, IT HAS HIGH
SPATIAL RESOLUTION, AND ALSO
HIGH TEMPORAL RESOLUTION, FOR
VARIOUS PURPOSE. THIS PICTURE IS
TAKEN FROM REVIEW PAPER WE
PUBLISH ABOUT FOCUS ULTRASOUND
NEUROMODULATION TO TREAT THE
PAIN. WHAT I MENTION FROM
NEUROIMAGING STUDY WHICH KNOW
CERTAIN TARGET NEUROSIXTY
CIRCUIT ARE INVOLVED IN PAIN
PROCESSING SO THAT IS ONE OTHER
-- A TARGETING AND SPOT THAT WE
STARTED OUR INVESTIGATION. ONE
QUESTION, WHAT WOULD BE THE
MECHANISM, WHY FOCUS ULTRASOUND
NEUROMODULATION WOULD WORK?
MULTIPLE HYPOTHESIS ABOUT WHAT
WOULD BE POSSIBLE MECHANISM
INCLUDING MEME BRAIN CAPACITY
AND MECHANOSENSITIVE ION
CHANNEL, EFFECTS MULTIPLE. OUR
GROUP AND THE (INAUDIBLE) WE
DIDN'T PROPOSE IT BUT WE
HYPOTHESIZE ACOUSTIC RADIATION
FORCE ACTING ON THE
MECHANOSENSITIVE ION CHANNEL
WOULD BE IMPORTANT MECHANISM WHY
FOCUS ULTRASOUND WOULD WORK. SO
I KNOW THE EQUATION IS TOO
DETAIL, I WANT TO POINT OUT
ACOUSTIC RADIATION FORCE CAN BE
DERIVED AS PROPORTIONAL TO A
IMPORTANT ULTRASOUND PARAMETER
CALLED PULSE REPETITION
FREQUENCY. ILLUSTRATE IN THIS
CARTOON HERE. SO NOW WE HAVE
BEEN LOOKING INTO THIS WHETHER
WE CAN WOULD USE THIS ACOUSTIC
RADIATION FORCE MODULATION TO
REIT PAIN. IN PARTICULAR SICKLE
PAIN SO THAT IS THE FOCUS WE ARE
LOOK INK TO. WE CONDUCT BASIC
RESEARCH HERE ILLUSTRATING IN
THE RODENT MODEL AND WITH
MULTI-ELECTRIC ARRAY O TO RECORD
YOU CAN SEE THE MULTI-UNIT
ACTIVITY ONCE THESE FOCUS
ULTRASOUND STIMULATION AT THE
SOMATOSENSORY CORTEX. WITH ALL
THE VARIOUS SHAM CONTROL, WE DID
NOT OBSERVE THIS. ALSO WE SOUGHT
OUT NEURON BASED ON WAVE FORM
ACTION POTENTIAL TO DIVIDE INTO
REGULAR SPIKING AND THE FASTEST
SPIKING OUT, THERE IS CLEAR
CORRESPONDENCE AND ONCE FOLKS
ULTRA -- FOCUS ULTRASOUND
STIMULATION THE NEURAL SPIKE
INCREASE WITH THIS PRF PARAMETER
INCREASE AND YOU CAN SEE
NEUROSPIKE IN FIRST INCREASE. IN
THE FASTEST SPIKING UNIT WE DID
NOT OBSERVE THIS PHENOMENON.
AFTER SPOTTING A GROUP OF RATS,
WE FOUND THERE IS A VERY
INTERESTING THAT NEUROTYPE
SPECIFIC RESPONSE TO FOCUS
ULTRASOUND NEUROMODULATION. THIS
IS IF YOU CHANGE THE PULSE
REPETITION FREAK CITY NEURAL
SPIKE FIRING RATE WILL CHANGE
BUT IN INHIBITORY NEURONS YOU DO
NOT OBSERVE THIS PHENOMENON. WE
FURTHER USE OPTOGENETICS AND TO
STUDY THIS EFFECT IN TRANSGENIC
MICE AND SIMILARLY FOUND IN A PV
NEURON, CAM K 2 ALPHA NEURON,
THERE IS A NEURON TYPE SPECIFIC
EFFECT OF FOCUS ULTRASOUND. SO
NOW COME TO SICKLE CELL PAIN
MANAGEMENT. WE USE THIS
HUMANIZED SICKLE CELL MICE MODEL
DR. GUPTA DEVELOP BUT THIS IS --
MICE MODELS IS VERY SMALL. IN
ORDER TO HAVE THE SPECIFICITY
AND THE RESOLUTION WE HAVE
DEVELOPED A NOVEL ULTRASOUND
DEVICE ILLUSTRATE HERE WHICH AS
SHOWN ON PANEL B YOU CAN SEE
FROM HERE TO HERE IS ONE
MILLIMETER. OUR DEVICE AS A SUB
MILLIMETER LATERAL SPATIAL
SPECIFICITY. WHICH TO OUR
KNOWLEDGE THIS BIT -- ALL THE
EXISTING NON-INVASIVE NEURAL
MODULATION TECHNOLOGY IN TERMS
OF SPATIAL SPECIFICITY. THAT'S
ONE OF THE MERIT OF THE FOCUS
ULTRASOUND. WE CONDUCTED
EXPERIMENTATION AND THERE IN A
NUMBER OF EXPERIMENTAL MICE, AND
WE DID TWO EXPERIMENT. BEHAVIOR
TEST, ONE IS HOT PLATE TEST, TO
SEE THAT WHAT PAIN SENSITIVITY,
IN THIS EXPERIMENTAL MICE,
ANOTHER IS ROUTE OF PASSAGE YOU
SEE INTO THE MOTOR COORDINATION
AND THEN BALANCE WOULD BE -- BY
FOCUS ULTRASOUND STIMULATION. SO
WE DID ACTIVE CONTROL WITH OTHER
FOLKS ULTRA SOWN, SHAM CONTROL,
THAT FOCUS ULTRASOUND
STIMULATING DIFFERENT SPOT AND
THE TFAS SIMULATION, ULTRASOUND
STIMULATION AT SOME OTHER --
>> TWO MINUTE WARNING.
>> THANK YOU. HERE IS THE
RESULT. FIRST WE TESTED THE Y --
WILD TYPE MICE, YOU CAN SEE HERE
COMPARE WITH BASELINE THE RED
COLOR ILLUSTRATING THIS DECREASE
PAIN SENSITIVITY AND AFTER THREE
MINUTE OR AGO MINUTE WILL IS
STATISTICALLY SIGNIFICANT
DECREASE IN PAIN SENSITIVITY IN
THIS EXPERIMENTAL MICE. NEXT WE
LOOK INTO SICKLE CELL MICE.
SIMILARLY, SIMILAR TO WILD TYPE
MICE, THREE MINUTE OR EIGHT
MINUTE AFTER STIMULATION BY
USING LOW PRF, IN A SENSE IS
WITH LOW PULSE REPETITION
FREQUENCY WE FOUND WE CAN
SUPPRESS PAIN SENSITIVITY IN
SICKLE MICE. VERY INTERESTINGLY
IF WE USE VERY HIGH PRF IN THE
SAME SICKLE CELL MICE, WE FOUND
THIS PAIN SENSITIVITY ACTUALLY
WAS INCREASE. WHICH SUGGEST A
BIDIRECTIONAL MODULATION OF PAIN
SENSITIVITY BY USING FOCUS
ULTRASOUND THROUGH MODULATING
PRF PARAMETER AND ALSO SUGGEST
WE NEED TO BE CAREFUL IN TERMS
OF ACTUALLY CONDUCT CLINIC
TRANSLATION IN PATIENT. WE LOOK
INTO INSULA STIMULATION, IN THIS
CASE WE NOT JUST STAY AT THREE
MINUTE 8 MINUTE BUT WE ALSO
EXTENDS TO 13 MINUTES AND 60
MINUTES POST STIMULATION. AND
WE FOUND THAT USING LOW PRF,
THERE IS SIGNIFICANT DECREASE OF
THE PAIN SENSITIVITY, UP TO 30
MINUTES, AFTER STIMULATION. I
KNOW MY TIME IS COMING UP SO TO
SUMMARIZE WHAT WE FOUND. A
SINGLE SESSION OF FOCUS
ULTRASOUND STIMULATION AT
SPECIFIC PAIN PROCESSING
CIRCUITS AND THE RESULT IN
SIGNIFICANT CHANGES IN PAIN
RELATED BEHAVIOR EVOKED BY --
>> WE LOST THE VOICE.
>> SORRY. AND IN SICKLE MICE.
SHORT TERM ATTENUATION OF
HYPERALGESIA IN FEMALE SICKLE
MICE AND CAN INDUCE THROUGH
FOCUS ULTRASOUND STIMULATION AND
FURTHERMORE IN THE SOMATOSENSORY
CORTEX BIDIRECTIONAL MODULATION
WAS OBSERVED WITH CERTAIN FOCUS
ULTRASOUND AND PARAMETER.
ROBUST LONG LASTING ATTENUATION
OF THERMAL HYPERALGESIA CAN
INDUCE IN SINGLE CELL TFAS
STIMULATION AT INSULA IN SICKLE
MICE. WHILE I DO NOT HAVE TIME
TO SHOW SLIDE, WE DID NOT
OBSERVE SIGNIFICANT CHANGE IN
MOTOR COORDINATION AND BALANCE
AFTER THE FOCUS ULTRASOUND AND
THE TREATMENT IN THIS
EXPERIMENTAL MICE. SO HIGH LEVEL
SUMMARY IS WE HAVE DEVELOPED A
NOVEL FOCUS ULTRASOUND
NEUROMODULATION TECHNOLOGY WITH
SUB MILLIMETER LATERAL SPATIAL
SPECIFICITY. WE DEMONSTRATE
FOCUS ULTRASOUND MODULATION AT
PRIMARY SOMATOSENSORY CORTEX
INSULA SUPPRESS PAIN SENSITIVITY
IN HUMANIZED MICE. I WOULD LIKE
TO ACKNOWLEDGE FUNDING SUPPORT
AND ALSO FOR COLLABORATORS WHO
CONTRIBUTED TO CERTAIN SLIDES AS
PRESENTED TODAY WHO ARE NOT
INCLUDED IN THE CO-AUTHORSHIP.
THANK YOU VERY MUCH.
>> THANK YOU, DR. HE. VERY
DELIGHTFUL PRESENTATION. WITH
THIS I WILL TURN THE FLOOR TO
DR. RICHARDSON TO CO-CHAIR. WE
WILL TAKE THE QUESTIONS AN
ANSWERS AT THE END OF THE
OVERALL SESSION.
>> THANK YOU, KALPNA. WE WILL GO
FURTHER INTO THE PRESENTATIONS
FOR TODAY. AND OUR NEXT
PRESENTER WILL BE ACTUALLY THE
CHAIR. DR. KALPNA GUPTA. GOING
TO INTRODUCE HER, DR. GUPTA IS
PROFESSOR OF MEDICINE DIVISION
OF HEMATOLOGY ONCOLOGY AND SUSAN
SAM WELLA INTEGRATIVE HEALTH
INSTITUTE AT THE UNIVERSITY OF
CALIFORNIA YO IRVINE. HER GOALS ARE
TO IDENTIFY MECHANISM BASED
TREATABLE TARGETS AT THE
INTERSECTION OF THE SICKLE CELL
DISEASE PROCESS AND PAIN. SHE
ALSO SERVES AS A MEMBER OF THE
DIVERSITY AND EQUITY INITIATIVE
OF THE AMERICAN SOCIETY OF
HEMATOLOGY. SCIENTIFIC WORKING
GROUP OF THE NATIONAL HEMOPHILIA
FOUNDATION. JUST TO ADD A
PERSONAL NOTE, I WILL SAY KALPNA
WAS VERY INSTRUMENTAL IN
FOSTERING MY RESEARCH INTERESTS
IN SICKLE CELL RESEARCH. SO
KALPNA. LOOKING FORWARD TO YOUR
TALK.
>> I AM DELIGHTED TO BE SPEAKING
ABOUT MY PASSION FOR PAIN IN
SICKLE CELL DISEASE. CAN I
SHARE MY SLIDES PLEASE. OUR
GOAL IS TO WORK ON APPROACHABLE
MECHANISM BASED INTEGRATIVE
STRATEGIES TO AMELIORATE PAIN.
WHEN I SAY APPROACHABLE, IT
MEANS WHETHER CAN BE DONE, WHAT
CAN WE DO NOW? MANY TIMES WHEN
SPEAKING IN COMMUNITY OR
DISCUSSING WITH PEOPLE SINCE I
DON'T TREAT PATIENTS PEOPLE ASK,
YOU HAVE DONE ALL THIS RESEARCH
BUT WHEN ARE YOU GOING TO
TRANSLATE IT MOST TRANSLATIONAL
GRANTS WE SUBMITTED GOT SHOT
DOWN. SO WE ARE STILL TRYING BUT
THERE ARE THINGS THAT CAN BE
DONE BASED ON WHAT WE HAVE FOUND
IN TERMS OF THE MECHANISM.
BEFORE I SPEAK ON ANYTHING THESE
ARE MY DISCLOSURES. NOT
TARGETING PAIN IN SICKLE CELL
DISEASE IS VERY COMPLEX AS WE
HAVE ALREADY HER. DR. STUCKY
AND BRANDOW NICELY LAID OUT THE
PERIPHERAL MECHANISMS WHICH ARE
MEDIATED THROUGH THE DORSAL ROOT
GANGLIA AND WE HAVE KNOWN FOR
MANY YEARS NOW NOT TOO MANY BUT
AT LEAST A DECADE WHAT ARE
PERIPHERAL MECHANISMS AND THE
MEETING FROM THE SICKLE CELL
DISEASE PROCESS, INCLUDING
CRISES, HYPOXIA ISCHEMIA
HEMOLYSIS, ORGAN DAMAGE ALL
WHICH CAN EVOKE PAIN. HYPOXIA
ISCHEMIA REPERFUSION INJURY, ALL
THESE CHEMICAL AND
NEUROMODULATORS IN THE PERIPHERY
RA WORKED OUT AS PRESENTED IN
THE PREVIOUS SESSION PART 1. --
>> SORRY TO INTERRUPTS. SORRY TO
INTERRUPT CAN YOU SPEAK UP A
LITTLE BIT OR COME CLOSER TO THE
MICROPHONE? HAVING HARD TIME
HEARING YOU.
>> SORRY ABOUT THAT. WHAT IS
HAPPENING IN THE CENTRAL NERVOUS
SYSTEM OR THE BRAIN. BRAIN IS
MASTER ORCHESTRA AN IT IS
INVOLVED IN PERCEPTION OF PAIN.
WE KNOW ONE WAY STREET THAT IS
FROM THE PERIPHERY TO THE BRAIN
WHERE THE PAIN IS PERCEIVED. HOW
BRAIN CAN CHANGE THIS, OR CAN
BRAIN BE INITIATOR OF PAIN,
WHICH BRINGS BACK TO PERCEPTION.
HOW DOES IT DO THAT?
UNDERSTANDING IS VERY CLEAR AND
EVEN POORER IN SICKLE CELL
DISEASE. DR. (INAUDIBLE) HAD
ELEGANTLY SHOWN HYPNOTIC NUCLEI
IN THE HIPPOCAMPAL REGION OF
SICKLE CELL MICE YEARS AGO BUT
THAT IS ALL WE KNEW FROM THE
MECHANISM POINT OF VIEW. SO WE
STARTED ASKING THESE QUESTIONS
HOW DOES IT DO THAT. WE KNOW
WHEN THE SIGNAL GO FROM
PERIPHERY TO BRAIN, FROM P THE
BRAIN THROUGH TO LIMB BIC OR
DESCENDING PATHWAY SHOWN IN THE
BLUE ARROW, THIS CAN GO BACK TO
THE SPINAL CORD WHERE THEY CAN
BE MODIFIED AND THEN THROUGH
ANATOMIC RELEASE THROUGH BLUE
ARROWS, GO BACK TO DRG AND GO TO
PERIPHERY. SO WHAT GOES UP COMES
BACK. THIS MEANS ONCE THE SYSTEM
IS ACTIVATE THROUGH SOME
PERIPHERAL INJURY, OR NOXIOUS
INSERT, ACTUALLY THE SYSTEM CAN
BE ON AUTOREGULATION. THESE
DIFFERENT SPECIES OF
NEUROMODULATORS ARE SICKLE CELL
INFLAMMATION INCREASE DUE TO
DISEASE CAN BE FURTHER AUGMENTED
BY THIS ANATOMIC ACTIVITY GUIDED
BY THE BRAIN. SO IN ORDER TO
EXAMINE THIS WE THOUGHT WHAT IS
IT THAT REALLY INDUCES THE
BRAIN. THE QUESTION WAS, IT IS
USUALLY THE ENVIRONMENT. WE HEAR
BAD NEWS PAIN CAN INCREASE. CAN
THEN ENVIRONMENT INFLUENCE PAIN?
THE FACTORS ARE IN THE
ENVIRONMENT ARE BOTH ENDOGENOUS
WHICH IS IN THE BODY AND WHICH
ARE OUTSIDE THE BODY LIKE
NUTRITION, COMPANIONSHIP, SOCIAL
ISOLATION, WE HEARD ABOUT ALL
THESE LONELINESS STIGMAS, SLEEP,
SOMETHING WHICH HAS NOT BEEN
ADDRESSED IN THIS THREE DAY
MEETING. PLEASURE TRAUMA,
DEPRESSION ANXIETY, FOOD
SUPPLEMENTS, CANDIES HAVE IMPACT
ON THE PAIN SINCE THESE CAN BE
AUTOREGULATED BY INDIVIDUALS
THEMSELVES. AND THE EVIDENCE
COMES FROM THESE THREE VERY NICE
STUDIES FROM THREE DIFFERENT
PARTS OF THE WORLD. ONE FROM
ATLANTA IN 2001 WHERE WE FOUND
THAT PAIN WAS SIGNIFICANTLY
REDUCED AS FREQUENCY OF PAIN
EVENTS WITH FISH OIL. THE NEXT
STUDY WAS WITH OMEGA 3 CAPSULES
DRG AND EPA SIGNIFICANTLY REDUCE
CLINICAL VASOOCCLUSIVE EVENTS
FROM SUDAN THEY FOUND CO-ENZYME
Q 10 REDUCE INFLAMMATION AND
LIPID PEROXIDATION. SO OXIDATIVE
STRESS AND INFLAMMATION, WE
SPOKE ABOUT INFLAMMATION IN THE
PRIOR SESSION. NOW, IT IS VERY
DIFFICULT, ALMOST IMPOSSIBLE TO
OPEN UP THE BRAIN AND SEE WHAT
WE ARE LOOKING FOR IN A HUMAN
BRAIN. THESE HUMANIZED BERKELEY
MICE IS WHAT WE USE, AND WE ARE
ALL FAMILIAR WITH THIS MODEL,
THEY EXPRESS MORE THAN 99% HUMAN
SICKLE HEMOGLOBIN, SHOW MANY
SALIENT FEATURES BOTH
PATHOLOGICAL AND PAIN WHICH WE
OBSERVE -- WHICH ARE OBSERVED IN
SICKLE CELL DISEASE.
SO WHAT WE DID THE FIRST THING
WAS DIETARY MANIPULATION. SO TO
GIVE THESE MICE TWO DIFFERENT
KINDS OF DIET, ONE WAS THE
RODENT REGULAR DIET BY LABS ALL
OVER. AND THE OTHER WAS
FORMULATED DIET WHICH WE CALL
SICKLE DIET OR ENRICHED DIET.
THE INCREASE MINERALS AMINO
ACIDS FATTY ACIDS OMEGA 3 FATTY
ACIDS TO ACTUALLY INCREASE THE
DIETARY REQUIREMENT FOR THE HIGH
METABOLIC NEED OF SICKLE CELL
DISEASE PATIENTS AS -- OF THESE
MICE. AND VERY TALENTED YOUNG
MAN CAME IN MY LAB FOR MANY
YEARS AND SAYS UNDERGRADUATION
ACTUALLY OBSERVE THAT SOME OF
THE MICE DID NOT SHOW THE
FEATURES OF PAIN THAT WE HAVE
BEEN OBSERVING. AND WHAT
HAPPENED WAS BY ACCIDENT THESE
MICE WERE GIVEN SICKLE DIET FOR
LONG TIME AND SO HE UNDERTOOK A
STUDY WITH SEVERAL GROUPS OF
MICE WHERE HE HAD MICE DEPRIVED
OF THE RICH DIET GIVEN REGULAR
DIET DENOTED AS RD HERE. AND
ISOLATED WITHOUT FEMALE IN A
CAGE OR MALE IN A CAGE SO THEY
LIVED -- MALE WAS PLACED IN A
CAGE AND WE CALLED IT THE
DEPRIVED GROUP. NETTED E HAD
GOOD DIET NOR ISOLATED. HAPPY
GROUP WHERE MALE WAS HOUSED WITH
FEMALE COMPANION AND GIVEN THE
RICH SD SICKLE DIET. THAT WAS
UNHAPPY GROUP TO SIMULATE TRAUMA
OR STRATEGY OR OTHER
PSYCHOSOCIAL EFFECTORS. WHERE
THE MICE -- THE MALE MOUSE WAS
LIVING HAPPILY AS WE DENOTED IN
THE RED SQUARE HERE, WITH FEMALE
AND GOOD DIET AND WE WITHDREW
BOTH AND LEFT THE MALE ALONE.
WHAT WE FOUND WAS IN THE
DEPRIVED GROUP THERE WAS HIGHER
THING, HIGHER NUMBER ON THE
DASHED LINE ACTUALLY SHOWS PAIN
AND THE SOLID BARS SHOW THE
LEVELS. WHAT HE SERVED WAS THE
LEVELS IN THE SPECIFIC REGIONS
OF THE BRAIN OF THESE MICE, WERE
VERY LOW. BUT IN THE GROUP MALE
MOUSE WAS HOUSED WITH FEMALE AND
RECEIVED AN ENRICHED SICKLE
DIET, PAIN WAS LESS AND THE
SEROTONIN LEVELS WERE HIGH.
WHEN THEY WITHDREW THE FEMALE
FROM THIS MOUSE AND ALSO GAVE
THE MOUSE A POOR DIET, THE PAIN
LEVELS WENT UP AND SEROTONIN
LEVELS IN THE BRAIN WENT DOWN.
HOW DOES THIS HAPPEN? HOW DO WE
EXPLAIN THIS? SO WHAT HAPPENS IS
I SPOKE ABOUT THE BRAIN TARGETED
MECHANISMS, OR TOP DOWN
MECHANISMS THESE ARE DIFFERENT
REGIONS OF THE BRAIN ON THE LEFT
SIDE. AND AT THE BOTTOM IS THE
SPINAL CORD SECTION. THESE
DIFFERENT REGIONS OF BRAIN
HOUSED WITH NON-EPINEPHRINE
EJECT NEURONS IN DIFFERENT PARTS
OF THE BRAIN IN THE GYRUS, IN
PAG AND IN THE RBM REGIONS. WHAT
WE ARE DOING IS UPON
STIMULATION, FROM THE PERCEPTION
OR THROUGH THE CHEMICAL
MEDIATORS THAT CAN ALSO HAPPEN
BUT IT IS IMPORTANT TO NOTE
HERE, THAT IT CAN HAPPEN WITH
PERCEPTION. LIKE WE SAW THAT
WITHDRAWING THE FEMALE WE FAST
FRAME, DECREASE SEROTONIN
LEVELS. THESE ARE STIMULATED AND
RELEASE THEIR CONTENTS INTO THE
DORSAL HORN OF THE SPINAL CORD.
THAT IS WHERE THE GATE WHICH
ACTUALLY PROCESSES THE PAIN
NOCICEPTIVE INPUTS. ON THE RIGHT
YOU WILL SEE THAT THERE ARE
SYNAPTOSOMES WHERE -- PRIMARY
AND SECONDARY NEURONS WHICH MEET
IN THIS REGION. WHEN THERE IS A
HIGHER CONCENTRATION OF
SEROTONIN THERE IS LESS PAIN OR
THERE WOULD BE ACTIVATION OF THE
SENERTINERGIC RECEPTORS. IN
ORDER TO INCREASE CERTAIN DRUGS
ARE DEVELOPED LIKE DULOXETINE
SNRI PRIMARILY DEVELOPED FOR
DEPRESSION ANDEAN SHYTY BUT ALSO
HAS PA PAIN -- AND ANXIETY BUT
ALSO HAS PAIN RELIEVING EFFECTS
AS WE HEARD ABOUT TODAY. WHAT
HAPPENS IS WE BELIEVE THAT THERE
WAS STIMULATION OF THESE HIGHER
BRAIN CENTERS WITH THE DIETARY
AND COMPANIONSHIP MANIPULATIONS
THAT WE DID WITH THESE MICE MICE. AND
SHOWING US WHAT HE FOUND WAS
THAT WITHDRAWING OF PLEASURE
DIMINISH HEARSAY SPINAL
NOCICEPTIVE MECHANISMS THAT I
JUST SPOKE ABOUT. IN MANY THE
RPM REGION OF THE BRAIN IN THE
HEAVY CIRCUMSTANCES MICE HAD A
SIGNIFICANTLY HIGHER LEVEL OF
SEROTONIN. IT WAS ALSO INCREASE
BECAUSE RELEASED FROM THE RDP TO
THE SPINAL CORD IN THE SPINAL
CORD. SIMILARLY DOPAMINE WHICH
IS ALSO CALLED A HAPPY MOLECULE
WAS ALSO INCREASE IN THE
SPECIFIC PAG BRAIN REGION OF
THESE MICE WHICH WERE HAPPY RED
BARSS. WHAT WAS VERY EXCITING TO
NOTE HERE, 7 WITHDRAWAL OF THE
PLEASURE MAKING THEM UNHAPPY
REALLY REDUCED THE CONTENT OF
BOTH SEROTONIN AND DOPAMINE IN
THESE MICE. THIS SUGGESTS THESE
TOP DOWN MECHANISMS PLAY A
CRITICAL ROLE IN THE PERCEPTION
OF PAIN. AND WHAT WE FOUND WAS
EVEN MORE INTERESTING THERE WERE
MANY DIFFERENT GROUPS AND I'M
NOT GOING TO GO INTO DETAILS,
THAT COMPANIONSHIP WAS VERY
IMPORTANT. IF YOU LOOK AT THE
RIGHT SIDE ON THE TWO BARS THE
BLACK AND GREEN, THE GREEN BAR
SHOWS THAT THE MICE WERE STILL
ON THE POOR DIET BUSHY HAD A
COMPANION. AND WHEN WE DID THIS,
THEY STILL HAD HIGHER SEROTONIN
LEVELS IN T BRAIN RVM REGION.
WHICH SHOWS BY JUST PERCEPTION,
THERE WAS NO CHEMICAL STIMULUS,
THERE WAS NOTHING GOING INTO THE
BODY BUT BY JUST HAVING THE --
ANOTHER COMPANION THEY HAD
INCREASE IN THE SEROTONIN LEVELS
HENCE THE LOWER PAIN. WE CAN
ALSO SEE BETWEEN RED AND MAGENTA
BARS ON THE RIGHT WITHDRAWING
THE COMPANION AND LIVING THE
POOR DIET LED TO A SHARP
DECREASE IN THE SEROTONIN
LEVELS. THIS WAS MATCHED WITH
INCREASE IN THE SPINAL CORD AND
SHOWS THE RESULTS. BUT WHAT CAME
AS A BIGGER SURPRISE TO US WAS
THESE MICE WERE ABOUT EIGHT
MONTHS OLD SO THEY HAD VERY
CHRONIC ORGAN DAMAGE AND
EVERYTHING IN THE PATHOBIOLOGY
WAS REALLY VERY HIGH. BUT IN
SPITE OF THAT WHEN WE WITHDREW
-- IF YOU LOOK AT THE FIRST
GRAPH AND THE BLUE BAR ON THE
RIGHT, THE RIGHT MOST BAR, WHICH
WAS THE WITHDRAWAL OF THE FEMALE
FROM THE MALE MOUSE THAT WAS
BEING FED SICKLE DIET AND WAS
COMPANION LED TO A INCREASE IN
THE WHITE BLOOD CELL COUNT WHICH
MEANS THERE WAS INCREASE IN
INFLAMMATION. AND WHAT WAS EVEN
MORE SURPRISING WAS THAT THERE
WAS AN INCREASE IN THE SPLEEN
SIZE. AGAIN AS PAT COMMENTED
WHATEVER HAPPENS IN THIS CENTRAL
NERVOUS SYSTEM INFLUENCE IT IS
PERIPHERY.
>> I HAVE ALREADY SHOWN YOU THIS
CARTOON AND SUGGEST -- THIS
MECHANISM SUGGESTS THAT
DULOXATENE CAN HAVE AN
ANTI-NOCICEPTIVE EFFECT. THOUGH
THESE STUDIES ARE NOT DONE IN
SICKLE PATIENTS OR MICE. WE
TREATED THESE MALE AND FEMALE
SICKLE MICE, NOW WE COULD NOT DO
DIETARY MANIPULATIONS AND
COMPANION MANIPULATIONS IN
FEMALE MICE BECAUSE WHEN WE
HOUSE THEM WITH MALES THEY
BECAME PREGNANT. SO WE GAVE THEM
DULOXATINE TO USE IT AS AN
INTERVENTION OF THE MECHANISM.
LOOK AT THE LOWER PANEL WHERE
LOWER VALUES ARE LESS PAIN AND
HIGHER VALUES ARE MORE PAIN,
THIS IS A TEST FOR HYPERALGESIA,
WHERE MICE ARE ON A POOR
PLATFORM AND NUMBER OF TIMES
THEY WITHDREW PAW TO AVOID COLD
WAS COUNTED EVERY TWO MINUTES.
WE FIND DULOXATINE AMELIORATES
HYPERALGESIA IN THESE MICE AT
BOTH DOSES 3-MILLIGRAM PER
KILOGRAM AND TEN MILLIGRAM PER
KILOGRAM IN MALE AND FEMALE
MICE, AND IT WAS TIME DEPENDENT.
SO THIS WAS FURTHER FOUND TOP
DOWN MECHANISMS PLAY A ROLE IN
PERCEPTION OF PAIN IN SICKLE
CELL DISEASE. SOMETIMES WE
REALIZE FROM THE CLINICAL
LITERATURE PEOPLE DEVELOP COPING
MECHANISMS AND CAN OVER RIDE
THESE EFFECTS SO STACY IN OUR
LAB NOW AT GEORGETOWN UNIVERSITY
REALLY WAS CURIOUS TO KNOW WHAT
HAPPENS IN THE OLDER MICE, SHE
TOOK THE MICE WHO SURVIVE --
>> TWO MINUTE WARNING. AND 18
MONTHS OF AGE FOUND THE MALE
MICE WHICH WERE WITH COMPANION
HAD LESS PAIN BUT WHAT WAS
SURPRISING WAS BODY WEIGHT ALSO
INCREASE THOUGH ALL THE MICE ARE
FED SIMILAR DIET. THEY WERE
HAPPIER AND EATING MORE THOUGH
THE DIET WAS REGULAR, NOT THE
ENRICHED DIET. WITH THIS I WOULD
LIKE TO CONCLUDE THAT WE HAVE TO
THINK ABOUT THE ENVIROSOME AS
REGULATOR OF PAIN PERCEPTION.
AND THIS INCLUDES ALL THAT WE
DISCUSSED IN THE MORNING
SESSION, PSYCHOSOCIAL FACTORS
ANXIETY, DEPRESSION, STIGMA,
ISOLATION, SLEEP, DIET
SURROUNDING. WE KNOW WE CANNOT
PREVENT WHAT HAS BEEN STARTED IF
YOU SEE IN THE BLUE AND THE PINK
BATCHES ON THE BOTTOM BY THE
SICKLE CELL DISEASE OR SICKLING
OF RED BLOOD CELLS. MY HOPE IS
THAT WITH THIS KNOWLEDGE WE MAY
TRY TO CONTROL OUR ENVIRONMENT
WHICH CAN PROBABLY IF NOT CREATE
THE PAIN, BRING DOWN THE PAIN OR
IMPROVE OPIOID REQUIREMENT AND
MANY STUDIES OUT OF HOPKINS AND
DR. CARO'S WORK HAS SHOWN
FLUCTUATION IN/DR. CARROLL'S
WORK HAS SHOWN RESPONSE TO
TREATMENT. IS THIS THE REASON
THE ENVIRONMENT IS CHANGING?
SUPPOSING STUDENT GOT A BAD
GRADE, MAYBE PAIN GOES UP EVEN
THOUGH THE AMOUNT OF MORPHINE IS
THE SAME. THERE IS SOME ILLNESS
IN THE FAMILY. THIS BRINGS TO
ATTENTION THAT WE NEED TO DO
SOME MODIFICATION IN IF HOUR
ENVIRONMENT WHICH CAN BE UNDER
OUR CONTROL. OFTEN I'M ASKED ARE
THESE MICE OR MEN? HERE THIS
FIGURE SHOWS WHAT MODIFICATIONS
HAVE BEEN DONE TO ACTUALLY AT
DIFFERENT LEVELS WHICH IN MICE
MICE AND HUMANS MICE LEFT SIDE
HUMANS RIGHT SIDE, WITH
CANNABINOID DONE IN BOTH IN
HUMANS MANY STUDIES PRESENTED
TODAY AND OTHERWISE HAVE USED
PSYCHOSOCIAL MODULATION TO
REDUCE PAIN WHICH IS CBT
HYPNOSIS VIRTUAL REALITY,
RELAXATION, GUIDED IMAGERY,
ANTI-DESAINTS. WITH THAT HOE
ANTIDEPRESSANTS. WITH THAT I
HEARD A LOT ABOUT SOCIAL
PSYCHOLOGICAL FACTORS, THEIR
CONTROL, BUT EXCEPT DR. MORRIS'S
ELEGANT TALK ABOUT THE
INTERVENTION OF DIETARY
SUPPLEMENT ARGININE WE NEED TO
FOCUS ON FOOD ALSO AND AS WELL
AS COMPANIONSHIP. SHARING THE
BURDEN WILL DEFINITELY REDUCE
THE BURDEN. AND IN A HEALTHY
BODY WILL KEEP A HEALTHY MIND
AND THE MIND IS THE MASTER
ORCHESTRA TO REALLY GUIDE THE
BODY TO FEEL OR NOT TO FEEL THE
PAIN. THIS ALSO TELLS US THAT
WHAT DR. HE SHOWED WITH HIS DFUS
CAN BE EVEN MORE EFFECTIVE. ANY
INTERVENTION CAN BE MORE
EFFECTIVE IF WE CAN TAKE CARE OF
THESE FACTORS WHICH CAN BE
CONTROLLED BY US. WITH THAT I
WOULD LIKE TO THANK MY TEAM. WHO
HAD BEEN WORKING DAY AND NIGHT
AND MY COLLABORATOR DR. BADGAYAN
WHO IS INSTRUMENTAL, BECAUSE I
AM NOT A BRAIN SCIENTIST. AND HE
IS AN EXPERT IN SEROTONIN ERGIC
MECHANISM, BECAUSE OF HIM IT WAS
POSSIBLE TO UNDERTAKE THE STUDY.
I WOULD LIKE TO THANK YOU AND
THE ORGANIZERS. THANK YOU, VERY
MUCH. I THINK OUR NEXT SPEAKER
IS DR. KI KIMBERLEI RICHARDSON,
ASSOCIATE PROFESSOR MANY THE
DEPARTMENT OF PHARMACOLOGY AT
HOWARD UNIVERSITY COLLEGE OF
MEDICINE. HER LABORATORY
UTILIZES NEUROCHEMICAL
PHARMACOLOGICAL AND BEHAVIORAL
STRATEGIES TO STUDY THE ROLE OF
NEUROPEPTIDE REGULATION ON
CONSUMMATORY BEHAVIORS INCLUDING
FEEDING FORAGING AND ADDICTION.
SHE IS EMBARKED UPON PAIN
PROCESSING. SHE WILL PRESENT
VERY NOVEL FINDINGS ON THE
INFLUENCE OF A NOVEL SYSTEM,
OREXIN SYSTEM IN MEDIATING
HYPERALGESIA IN SICKLE CELL
DISEASE. AND DISCUSS THIS SYSTEM
AS A TARGET FOR INTERVENTIONS.
THIS IS ALSO BRAIN FOCUSED.
PROET NOD TO THE PROMOTING
DIVERSITY EQUITY AND INCLUSION
INITIATIVES TO INCREASE NUMBER
OF UNDER-REPRESENTED MINORITIES
IN BIOMEDICAL RESEARCH. WELCOME
DR. RICHARDSON AND THANK YOU FOR
ACCEPTING THE INVITATION.
>> THANK YOU VERY MUCH. I WILL
START MY SLIDES NOW. HOPEFULLY
ABLE TO SEE THEM. ARE YOU ABLE
TO SEE THEM? I THINK I'M
SHARING.
>> NO. NO.
>> MAYBE TAKING A LITTLE WHILE.
>> WE CAN SHARE THE SLIDES IF
YOU LIKE.
>> I'M GOING TO TRY ONE MORE
TIME. TODAY I WILL TALK ABOUT
TARGETING THE OREXIN SYSTEM FOR
PAIN SENSITIVITY AND SLEEP
INTERVENTIONS IN MANY SICKLE
CELL DISEASE. I'M GOING TO BE
PRESENTING DATA FROM A PILOT
STUDY TO INTRODUCE NEUROPEPTIDE
SYSTEM TO THIS PARTICULAR
COMMUNITY. AS A POSSIBLE
PHARMACOLOGICAL TARGET TO
IMPROVE THE QUALITY OF LIFE FOR
THOSE LIVING WITH SICKLE CELL
DISEASE. SO JUST TO GIVE YOU A
FLOW IN TERMS OF HOW THE
PRESENTATION WILL BE SET UP. I'M
GOING TO GIVE A LITTLE
BACKGROUND ABOUT OREXINS AND
PAIN, THEN SHARE SOME OF THE
DATA IN TERMS OF ESTABLISHING
BASELINE MEASUREMENTS OF PAIN
RESPONSES AND FALSE EXPRESSION
IN OREXIN NEURONS IN BOTH
CONTROL AS WELL AS SICKLE MICE.
THEN GIVE SOME BACKGROUND ABOUT
OREXIN RECEPTORS AND PAIN AND
PRESENT SOME DATA ASSESSING THE
ROLE OF OREXIN RECEPTOR
ANTAGONISM THEN FOLLOW WITH A
BRIEF DISCUSSION ABOUT TESTIMONY
ROLE OF OREXIN SIGNALING IN
DISREGULATION OF SLEEP, PAIN
PROCESSING AND HOW THAT MAY BE
ACTUALLY IMPORTANT IN SICKLE
CELL DISEASE. I HAVE NO
FINANCIAL INTERESTS TO DISCLOSE.
SICKLE CELL DISEASE IS A
HEMOGLOBINOPATHY THAT CAUSES
SICKLING OF RED BLOOD CELLS
RESULTS IN VESSEL DAMAGE, STROKE
ANEMIA, INFLAMMATION AND EXTREME
PAIN. THE PAIN IN SICKLE CELL
DISEASE IS ASSOCIATED WITH
SIGNIFICANT MORBIDITY AND
INCREASE MORTALITY. BECAUSE
EFFECTIVE PAIN MANAGEMENT IS A
CHALLENGE IN THIS POPULATION,
THERE IS A GREAT NEED TO
IDENTIFY SOME ALTERNATIVE
ANALGESIC AGENTS. BECAUSE OF
THIS, MANY PEOPLE REPORTED THAT
THEIR PAIN IS NOT NECESSARILY
MANAGED EFFECTIVELY SO IT IS
NECESSARY TO TRY TO PURSUE NEW
OPTIONS FOR PAIN TREATMENT. I
BELIEVE THE OREXIN SYSTEM MAY
OFFER A NOVEL APPROACH TO
TREATING PAIN. SO THIS
PARTICULAR NEURAL PEPTIDE SYSTEM
ALSO KNOWN AS HYPERCREE TINS
THEY ARE SYNTHESIZE WITHIN THE
DORSAL MEDIAL HYPOTHALAMUS, THE
PERIFORNICAL AREA AND LATERAL
HYPOTHALAMUS. THERE ARE TWO PEP
SIDES OREXIN A AND B. THERE ARE
TWO RECEPTORS THAT ARE G
COUPLED. SO THE OREXIN RECEPTOR
1 IS SELECTED FOR THE OREXIN A
PEPTIDE WHILE THE OREXIN
RECEPTOR 2 IS NON-SELECTIVE FOR
BOTH PEPTIDES. THE OREXIN
NEURONS INNERVATE VARIOUSRY
GENERALS INCLUDING SOME IN THE
DORSAL HORN. THEY ARE INVOLVED
IN AROUSAL, FEEDING NARCOLEPSY,
ENERGY BALANCE AND REWARD
PROCESSING SO MY BACKGROUND IS
DEALING WITH THE INFLUENCE OF
THIS PARTICULAR SYSTEM AND
REWARD PROCESSING. BUT IT IS
ALSO BEEN SHOWN THAT IT IS
INVOLVED IN ANALGESIA. THESE
PROJECTIONS GO TO BRAIN REGIONS
THAT PLAY A ROLE IN DESCENDING
PAIN INHIBITION. GIVEN THAT
THERE WERE SEVERAL STUDIES THAT
HAVE FOCUSED ON THE OREXIN
SYSTEM AND REWARD PROCESSING SO
TODAY WE WILL MOVE BEYOND THAT
AND FOCUS MORE SO ON ITS
RELATIONSHIP WITH PAIN. SOME OF
THE STUDIES HAVE SHOWN THAT THE
OREXIN A PEPTIDE HAS ANALGESIC
EFFECT ON INFLAMMATORY PAIN. IT
MAY AFFECT MECHANISMS UNDERLYING
THE MAINTENANCE OF NEUROPATHIC
PAIN. IT HAD BEEN STATED IN
PRIOR STUDIES THAT THE
OCCURRENCE OF NEUROPATHIC PAIN
WITHIN THE SICKLE CELL
POPULATION, MAYBE IN FACT TWICE
AS MUCH AS WHAT IS FOUND IN
OTHER CHRONIC PAIN POPULATIONS.
AND THERE ARE DEFINING
CHARACTERISTICS OF NEUROPATHIC
PAIN, TODAY I'M GOING TO FOCUS
ON HYPERAJEEZIA WHICH IS THAT
INCREASE PAINFUL SENSATION TO
NOXIOUS STIMULUS. IT IS ONE OF
THE FACTORS THAT IS USED TO
CHARACTERIZE NEUROPATHIC PAIN.
BEFORE IT CAN BE DETERMINED HOW
THE OREXIN SYSTEM IS INVOLVED IN
MEDIATION OF PAIN, AND HOW THAT
IS APPLIED TO SICKLE CELL, WHAT
WE WANT TO DO IS FIRST DETERMINE
WHETHER THERE WERE CHANGES IN
VARIOUS SUB POPULATIONS OF
OREXIN NEURONS, NOTHING IN THE
LITERATURE AS FAR AS ASSOCIATION
BETWEEN THIS PARTICULAR PEPTIDE
SYSTEM AND SICKLE CELL. WE
WANTED TO DO THAT IN ORDER TO
REALLY START TO GET AT THE
ACTIVITY OF THE NEURONAL
CIRCUITRY AND ALL THAT BECAUSE
THAT ULTIMATELY WILL HELP TO
ALLOW US TO HAVE A BETTER
PERSPECTIVE IN TERMS OF
DIFFERENT PATTERNS OF ACTIVITY
OF THE SUBPOPULATIONS OF THESE
NEURONS. SO IN ORDER TO DO THIS
WE COLLABORATED MY LAB
COLLABORATED WITH DR. GUPTA'S
LAB AND WE UTILIZE TRANSGENIC
MOUSE MODEL THAT EXPRESSES THE
SICKLE HEMOGLOBIN, HUMAN
HEMOGLOBIN. THAT FIRST GOAL WAS
TO KIND OF ESTABLISH BASELINE
MEASUREMENTS OF PAIN RESPONSES,
IN ADDITION TO ASSESSING FALSE
EXPRESSION IN OREXIN NEURONS. WE
DID THIS IN FEMALE MICE.
VARIOUS BEHAVIORAL TESTS WERE
PERFORMED TO CHARACTERIZE THE
HYPERALGESIA IN THE SICKLE MICE,
TRANSGENIC HOMOZYGOUS MICE THAT
EXPRESSED HUMAN SICKLE
HEMOGLOBIN. OF COURSE THE
CONTROL MICE, THESE ARE MICE
THAT HAVE THE SAME GENETIC
BACKGROUNDS BUT EXPRESS NORMAL
HEMOGLOBIN EXCLUSIVELY SO THE
BRAIN REGIONS WERE
IMMUNOHISTOCHEMICALLY PROCESSED
FOR CFOS USE AS MARKER FOR
NEURONAL ACTIVITY AND SECTIONS
WILL PROCESSED FOR THE OREXIN A
PEPTIDE. FOLLOWED BY THOSE
SALES ACTUALLY BEING QUANTIFIED
TO DETERMINE CHANGES IN DORSAL
MEDIAL HYPOTHALAMUS, THE LATERAL
HYPERTHALAMUS AFTER THE
BEHAVIORAL TEST. FOR THE SAKE
OF TIME I WILL PRESENT THE DATA
RELATIVE TO MECHANICAL AND
THERMAL OR HEAT HYPERALGESIA. SO
TO ASSESS SENSITIVITY TO THE
MECHANICAL STIMULUS, THE MICE
WERE PLACED ON A WIRE MESH UNDER
GLASS CONTAINER AND THE FILAMENT
WAS APPLIED TO THE SURFACE OF
THE HIND PAW, THE MICE. THE
FREQUENCY IN WHICH MICE MOVED
THEIR HAND FROM THE MESH WAS
RECORDED SO WHAT THIS IS SHOWING
IS SICKLE MICE INDICATED BY THE
BLACK BAR DISPLAY SIGNIFICANTLY
MORE PAW WITHDRAWAL FREQUENCY
VERSUS OUR CONTROL MICE. IN
ADDITION TO THAT, TO TEST FOR
HEAT SENSITIVITY, PAW WITHDRAWAL
LATENCY WAS RECORDED WHEN THE
PLANTAR SURFACE OF THE HYPPED
PAW WAS WITHDRAWN FROM THE HEAT
SUSURFACE. SHORTER INTERVALS
INDICATE HEAT SENSITIVITY AS BY
PAW WITHDRAW LATENCY IN THE
CONTROL. OUR CONTROL MICE WERE
ABLE TO ENDURE THE HEAT STIMULUS
MUCH LONGER THAN THE SICKLE MICE
WERE AND INCREASE SENSITIVITY TO
COLD AND TO HEAT, IS POSSIBLY
CUTANEOUS HYPERALGESIA,
CONSISTENT WITH OBSERVATIONS
THAT PAINFUL CRISIS IN PATIENTS
WITH SICKLE CELL MAYBE RELATED
TO WEATHER EXTREMES. FOLLOWING
ALL OF THE BEHAVIORAL TESTS,
AGAIN I'M PRESENTING THE MEEKAL
AND THERMAL HYPERALGESIA TODAY
BUT FOLLOWING THE TEST THE MICE
WERE PROFUSED AND SECTIONS WERE
PROCESSED FOR DOUBLE LABEL
IMMUNOHISTOCHEMISTRY. THE
PICTURE ABOVE SHOWS VARIOUS CELL
TYPES THAT WE SAW. SO THE RED
ARROWS ARE INDICATIVE OF SINGLE
SALE, CELLS ACTIVATED AS A
RESULT OF BEHAVIORAL TESTING BUT
THEY ARE NOT NECESSARILY OREXIN
POSITIVE. WE SAW SINGLE CELL
OREXIN CELLS, THESE ARE
INDICATED -- INDICATIVE OF GREEN
OWLS AND THESE STAINING FOR
OREXIN A PEPTIDE. THESE CELLS
WERE NOT ACTIVATED AS A RESULT
OF BEHAVE I DON'T RECALL TEST.
THE MOST RELEVANT FOR THIS ARE
DOUBLE LABEL CELLS WHICH ARE
FALSE POSITIVE OREXIN CELLS
INDIANA KAYTIVE OF THE BLUE
INDICATIVE OF BLUE ARROWS.
WHETHER THE LATERAL HYPOTHALAMUS
OR THE PERIFOREIGNCAL AREA. JUST
AS ASIDE THE LATERAL
HYPOTHALAMUS HAS BEEN A
ASSOCIATED WITH REWARD
PROCESSING. WHEREAS THE DORSAL
MEDIAL HYPOTHALAMUS HAVE BEEN
MORE ASSOCIATED SAY WITH AROUSAL
AND STRESS. SO THE RESULTS FROM
THE QUANTIFICATION IN FACT SHOW
THAT THE PERCENTAGE OF OREXIN
POSITIVE NEURONS THAT ARE FALSE
POSITIVE WITHIN THE PERIFORNICAL
AREA, THIS REPRESENTING OUR
CONTROL ANIMALS. WITHIN THE
PERIFORNICAL AREA THEY WERE
HIGHER THAN WHAT WAS SEEN WITHIN
THE LATERAL HYPOTHALAMUS. WHICH
MAKES SENSE BECAUSE AGAIN
LATERAL HYPOTHALAMUS IS MORE
ASSOCIATED AT LEAST WITH MORE
REWARD PROCESSING. IN IN TERMS
OF PERCENTAGE OF OREXIN FOS
CELLS RELATED TO THE CIRCLE
ANIMALS, WE SEE WITHIN THE
PERIFORNICAL AREA, YOU HAVE
SIGNIFICANTLY HIGHER PERCENTAGE
VERSUS WHAT YOU HAVE IN THE LH
BUT WE ALSO SAW SIGNIFICANT
DIFFERENCE WITHIN THE DORSAL
MEDIAL HYPOTHALAMUS. SO THE
TOPOGRAPHICAL DATA INDICATE THE
PERIFORNICAL AREAS MAYBE A
GENERAL TARGET REGION FOR
STUDYING PAIN, GIVEN THE
INCREASE ACTIVATION THAT WE SEE
IN BOLD GROUPS OF ANIMALS AFTER
THE PAIN -- THE DORSAL MEDIAL
HYPOTHALAMUS MAY PLAY A GREATER
ROLE IN MEDIATING THE MECHANISMS
ASSOCIATED WITH HYPERALGESIA IN
OUR SICKLE ANIMALS VERSUS THE
CONTROL ANIMALS. SO WE BELIEVE
MAYBE MORE DIVERSE DISTRIBUTION
OF OREXIN NEURONS ARE REQUIRED
TO PRODUCE THE ANALGESIA AFTER
PAIN TESTING IN SICKLE ANIMALS.
SO PERHAPS WHAT IS GOING ON IS
THE DORSAL MEDIAL OREXIN NEURONS
ARE PREFERENTIALLY RECRUITED
DURING THE PAIN TESTING, AND A
MORE GREATER DISTRIBUTION IN
TERMS OF DIVERSITY OF OREXIN
NEURONS MIGHT BE REQUIRED TO
PRODUCE ANALGESIA IN CIRCLE
ANIMALS. ONE THING FOR SURE,
IDENTIFYING SPECIFIC OREXIN
NEURONAL POPULATIONS IS INTEGRAL
IN TERMS OF UNDERSTANDING PAIN
PROCESSING. AND OF COURSE
HOPEFULLY THAT WILL ALLOW US TO
ELUCIDATE MECHANISMS THAT CAN
PROVIDE A MORE SELECTIVE
TARGETED APPROACH IN TERMS OF
TREATING PAIN IN SICKLE CELL
DISEASE.
>> TWO MINUTE WARNING.
>> SO IN ADDITION TO THE
FOCUSING ON THE NEUROPEPTIDE WE
WERE INTERESTED IN TERMS OF THE
RECEPTORS. THERE'S BEEN SEVERAL
REPORTS IN TERMS OF HOW THE
OREXIN RECEPTORS AND PAIN ARE
ASSOCIATED. OUR FIRST
EXPERIMENTS REALLY FOCUSED ON
THE PEPTIDE IN PARTICULAR. THESE
SPECIFIC REPORTS BASICALLY
SHOWING THAT IT IS THE OREXIN
RECEPTOR 1 MAY IN FACT BE MORE
IMPORTANT IN TERMS OF MEDIATING
THE PAIN. ONE OF THE QUESTIONS
CAN HYPERALGESIA BE POTENTIATED
WHEN OREXIN EFFECT IS
ADMINISTERED. WE HAD ANIMALS,
SICKLE AND CONTROL THAT
UNDERSTOOD WENT PAIN TESTING,
THEY WERE GIVEN RECEPTOR 1
ANTAGONIST 30 MINUTES PRIOR TO
TESTING AND ANIMALS ARE TESTED
ONE HOUR AND 24 HOURS AFTER
ADMINISTRATION OF THE OREXIN
RECEPTOR 1 ANTAGONIST. WE USE SB
338467. FOR SAKE OF TIME I'M
ONLY GOING TO PRESENT THE FEMALE
DATA. JUST TO KIND OF SUMMARIZE
BASICALLY WHAT IT IS SHOWING IS
THAT YOU HAVE A REDUCTION IN PAW
WITHDRAWAL LATENCY WITH PRIOR TO
GIVING THE OREXIN ANTAGONIST BUT
FURTHER POTENTIATION IN TERMS OF
-- FURTHER REDUCTION IN LATENCY
ONE HOUR AFTER THE SB IN FEMALE
ANIMALS. AND I WILL JUST LIKE TO
SAY THAT THIS IS SPECIFICALLY
FOR SICKLE ANIMALS SO WE DON'T
SEE THIS REDUCTION IN LATENCY
AFTER THE OREXIN ANTAGONIST IN
NORMAL ANIMALS, ONLY THE SICKLE
ANIMALS. SO BASICALLY WHAT WE
KNOW IS THE FACT THAT ONE, THE
DORSAL MEDIAL HYPOTHALAMUS, THAT
PARTICULAR SUBPOPULATION OF
NEURONS MAY IN FACT BE MORE
HEAVILY RECRUITED IN SICKLE CELL
AFTER PAINFUL STIMULUS AND ALSO
THAT IN FACT, FOR SICKLE CELL
FEMALE ANIMALS WE SEE THIS
FURTHER REDUCTION IN TERMS OF
LATENCY TO HEAT. SUGGESTING THAT
THERE MAYBE SOME DIFFERENTIAL
RESPONSIVENESS TO OREXIN
RECEPTOR ANTAGONIST. SO JUST TO
FINISH UP, IN TERMS OF OREXIN
SYSTEM IT PROJECTS SEVERAL BRAIN
REGIONS THAT MEDIATE SLEEP AS
WELL AS AROUSAL. SO STUDIES
REALLY HAVE SHOWN A GREAT DEGREE
OF CO-MORBIDITY BETWEEN PAIN AND
SLEEP IMPAIRMENT. BECAUSE OF
THIS THE THOUGHT IS SLEEP LOSS
MAY RESULT IN DEVELOPMENT OF
HYPERALGESIA, SO A CRITICAL ROLE
FOR THE OREXIN SYSTEM IN TERMS
OF REGULATION OF SLEEP AND PAIN
RELATIONSHIP REALLY SHOULD BE
INVESTIGATED. ALSO THE PAIN AND
SLEEP IMPAIRMENTS ARE TWO MAJOR
IMPORTANT OBSERVATIONS THAT ARE
FOUND WITHIN THE SICKLE
POPULATION. SO THIS IS JUST TO
SHOW SOME OF THE LITERATURE THAT
SO FAR HAS BEEN PUBLISHED AS FAR
AS RELATIONSHIP BETWEEN SLEEP
DISORDERS AND HOW OREXIN SYSTEM
CAN BE IMPACTED. WITH SLEEP
PATIENTS OFTEN TIME THERE IS IS
DECREASED DURATION, THEY HAVE
LATE ONSET OF SLEEP, I WILL
SPEND MORE TIME AWAKE -- OR
SPEND OR TIME AWAKE DURING THE
NIGHT OR INCREASED
FRAGMENTATION. THERE'S TWO
OREXIN SPECIFIC DUAL OREXIN
RECEPTOR ANTAGONIST, THEY
INHIBIT RECEPTOR SIGNALING AND
PROMOTE SLEEP BY REDUCING
WAKEFULNESS AND LATENCY TO
PERSISTENT SLEEP. THERE HAVE
BEEN CLINICAL TREATMENTS OF
SLEEP DISORDERS BUT IT MAINLY IS
FOCUSED ON THE OREXIN RECEPTOR
2. IT SEEMS AS IF THAT
PARTICULAR RECEPTOR IS MORE
IMPORTANT IN TERMS OF AROUSAL
AND SLEEP. HOWEVER THERE ARE TWO
DUAL OREXIN RECEPTOR ANTAGONISTS
NOW BEING USED AS SLEEP AIDS.
THEY HAVE BEEN FDA APPROVED.
>> SO IN CLOSING, THE POINT IS
THAT THE OREXIN SYSTEM MAYBE A
GOOD TARGET FOR PHARMACOLOGICAL
TREATMENT. REALLY TO ADDRESS
HYPERALGESIA EXPRESSED IN THIS
CASE IN FEMALES THAT HAVE SICKLE
CELL DISEASE.MENT DRUGS THAT
TARGET OREXIN A PEPTIDE
EXPRESSION AND TORR SAL MEDIAL
POPULATION MAY PROVE TO BE
EFFECTIVE IN REDUCING PAIN. AS
FAR AS SLEEP WHAT WE KNOW IS
THAT THESE DUAL OREXIN
ANTAGONISTS MAYBE USED TO TREAT
SLEEP DISORDERS WITHIN THE
SICKLE CELL POPULATION. THE GOOD
THING IS THEY DO POSE A LOWER
ABUSE POTENTIAL VERSUS OTHER
SLEEP AIDS. AND THAT IS THE
CONCLUSION OF THE TALK. JUST
WANTED TO HIGHLIGHT SOME OF THE
RECENT STUDIES THAT HAVE BEEN
DONE AND ACKNOWLEDGE THE FACT
THAT THE OREXIN SYSTEM HOPEFULLY
MAYBE A TARGET SYSTEM THAT OTHER
RESEARCHERS WHO ARE ON THIS
PARTICULAR MEETING MAY BE
INTERESTED IN STARTING TO
INVESTIGATE. I WANT TO
ACKNOWLEDGE IN IT NHLBI FOR THE
INVITATION, DR. GUPTA AND MY LAB
MEMBERS. THANK YOU.
>> THANK YOU, DR. RICHARDSON,
NOW I WILL INTRODUCE DR.
(INAUDIBLE) -- OUR NEXT SPEAKER
IS DR. MICHAEL KHOO, HE IS
CURRENTLY INTERIM CO-CHAIR OF
THE DEPARTMENT OF BIOMEDICAL
ENGINEERING AND DIRECTOR OF THE
USC CENTER FOR SLEEP HEALTH
USING BIOENGINEERING. HIS
PRIMARY RESEARCH FOCUS HAS BEEN
THE APPLICATION OF PHYSIOLOGICAL
CONTROL AND SIGNAL ANALYTICS TO
BETTER UNDERSTAND THE MECHANISMS
UNDERLYING SLEEP RELATED
BREATHING DISORDERS AND OTHER
CONNECTIONS WITH CARDIOMETABOLIC
DISEASE. HE IS CONTRIBUTING HIS
LEADING EXPERTISE IN SLEEP
HEALTH TO IMPROVE THE
UNDERSTANDING AND THE THERAPY OF
SICKLE CELL PAIN. .
DR. KHOO.
>> THANK YOU, DR. RICHARDSON.
LET ME SHARE MY SLIDES. SEE MY
SLIDE?
>> YES.
>> THANKS DR.S SMITH AND STUCKY
FOR ORGANIZING THIS SYMPOSIUM. I
WILL GIVE YOU -- THANK YOU DR.
RICHARDSON FOR STOPPING BEFORE
SOUTH CAROLINA SOUTHERN
CALIFORNIA. THANK YOU FOR THAT.
I WAS -- I WAS FIRST INVITED BY
KALPNA SHE GAVE A LONG BROAD
TITLE THAT ENCOMPASSED
EVERYTHING UNDER THE SUN SO I
DECIDED I WOULD TRY TO FOCUS ON
SUBJECT THAT IS MORE COMPLEX
WHAT WE ARE TALKING ABOUT TODAY.
PARTICULARLY ON -- I'M SPEAKING
AFTER YOU DR. RICHARDSON ON
SLEEP, DISORDERED BREATHING AND
SICKLE CELL PAIN. BEFORE I START
I WANT TO ALSO ACKNOWLEDGE MY
PARTNERS IN CRIME, DR. SANG
CHALACHEVA POST-DOC AT CARNEGIE
MELLON, DR. COATS MY LONG TIME
COLLABORATOR CHLA H. I WILL
START BY TALKING A LITTLE BIT
ABOUT THE PATHOPHYSIOLOGY SLEEP
DISORDERED BREATHING WHICH I
STUDIED FOR MANY YEARS. FIRST
THE MOST COMMON FORM OF SLEEP
DISORDERED BREATHING IS
OBSTRUCTIVE SLEEP APNEA, WHICH
MOST OF YOU KNOW ABOUT. THERE IS
WHAT HAPPENS IS THAT THERE IS
EPISODIC COLLAPSE SO IF YOU LOOK
AT THE PHYSIOLOGICAL --
(INAUDIBLE) SLEEP STUDY FOR
EXAMPLE, THE SECOND PANEL SHOWS
RESPIRATORY AIR FLOW SO THERE IS
NO AIR COMING OUT OF YOUR NOSE.
THAT IS WHAT IS HAPPENING WHEN
YOU HAVE UPPER AIRWAY COLLAPSE,
YOU HAVE OBSTRUCTIVE VENTILATION
BUT IF YOU RESCUE EFFORT PUT IN
ESOPHAGEAL CATHETER TO MEASURE
EFFORT YOU CAN SEE SUBJECT IS
TRYING TO BREATHE WHILE UPPER
AIRWAYS COLLAPSE. YOU CAN SEE
LARGER AND LARGER BECAUSE CO 2
IS LOADING UP HYPOXIA IS LOADING
UP YOU CAN SEE BLOOD CULTURE
SATURATION IS GOING DOWN LIKE
CRAZY,. SO YOU HAVE THIS HYPOXIA
GOING ON. SO HEART RATE ALSO
GOES UP DURING THIS APNEA UNTIL
YOU HAVE A UPPER AIRWAY BECOMES
OPEN WHICH IS WHEN YOU START
BREATHING AGAIN. THIS OPENING
REOPENING OF UPPER AIRWAY IS
MOST OF THE TIME DUE TO BRIEF
AROUSAL FROM SLEEP IF YOU LOOK
AT THE EEG A PERSON STILL ASLEEP
ALL IS WELL UNTIL THE EFFORTS
BREAK OUT THE UPPER AIRWAY AND
NOW SUBJECT TO BREATHE AGAIN SO
THIS BREATHE AROUSAL FROM SLEEP,
WHEN THIS HAPPENS MANY, MANY
TIMES A NIGHT LEAD TO SLEEP
FRAGMENTATION SO TWO MAJOR
EFFECTS OF SLEEP DISORDERED
BORROWING IS HYPOXIA AND AROUSAL
PRODUCE FRAGMENTATION. THE THING
THAT ALSO SLEEP DISORDERED
BORROWING IS COMMON IN SICKLE
CELL DISEASE ESPECIALLY UP TO
69% REPORTED IN CHILDREN. SICKLE
CELL DISEASE, CAN -- HYPOXIA
FROM SICKLE CELL DISEASE TRIGGER
LARGE SCALE VASOOCCLUSION IN
SICKLE CELL DISEASE SO SO TURNS
OUT THEN AFTER THIS FEW STUDIES
DONE AT LARGER STUDY DONE ON
SUBJECT, THERE WAS SOME YEARS
AGO, THIS WAS DONE ONCOSHORT OF
OVER 200 CHILDREN SICKLE CELL
DISEASE, THIS IS A SLEEP COHORT
OF CHILDREN AND STUDIED HE IS
SUBJECTS FOR OVER FIVE YEARS,
RECORDED SICKLE CELL SAD
ASSOCIATED PAIN EPISODES WHICH
REQUIRE HOSPITAL ADMISSION AND
TREATMENT WITH OPIOID. HE ALSO
LOOKED AT ASSOCIATION BETWEEN
SLEEP PARAMETERS AND VOC PAIN
FREQUENCY. SO THE LONG SHOT OF
IT WAS THAT THERE WAS LOW
NOCTURNAL SPO 2 HYPOXIA AND THE
APNEA HIGH POP KNEEIA INDEX
WHICH HOW MANY -- FOR HOUR,
THOSE INDICES DID NOT PREDICT
FREQUENCY, WHICH WAS SURPRISING
HYPOXEMIA DUE O -- CONTRIBUTE TO
MORE VOC. SO THEN NOW WE WANT TO
SHOW YOU ANOTHER THING THAT
RELATES TO THE SLEEP
FRAGMENTATION THAT ACTUALLY
PEOPLE HAVE FOUND VERY MUCH FOR
IN TERMS OF SICKLE CELL DISEASE
WHICH IS THE (INAUDIBLE) OF
SYSTEM. FOR EXAMPLE MEASURE
SYMPATHETIC NERVE ACTIVITY,
DURING WAKEFULNESS AND DURING
STAGE 4 SLEEP. STAGE 3 SLEEP YOU
CAN SEE THAT THE SYMPATHETIC
ACTIVITY DECREASE SLEEP AS WELL
SYMPATHETIC DECREASE SLEEP BUT
IN THIS SUBJECT FOR EXAMPLE THIS
IS STUDY FROM MORGAN AND SKATRUD
IN 1990s IF YOU AROUSE WITH
ACOUSTIC TONE YOU HAVE SURGE OF
SYMPATHETIC ACTIVITY, SURGE OF
ACTIVITY. WHICH THEN LEADS TO A
QUICKENING OF HEART RATE. SOME
MORE VENTILATION AND INCREASE IN
BLOOD PRESSURE THAT GOES UP.
LOOK AT WHAT HAPPENS, PERSON
WITH SLEEP DISORDERED BREATHING.
ON VOCATIVE SLEEP APNEA, WHAT
PES IS WITH THESE CYCLES OF THE
APNEAS, YOU CAN SEE THE
RESPIRATORY EFFORTS DURING THE
-- ARE VERY STRONG AND THAT THEN
IT GOES BACK TO SLEEP AGAIN, SO
ON. SO BLOOD PRESSURE FLUCTUATES
SICKICALLILY I CAUSES SLEEP
BECAUSE OF THE BUILD UP DRIVE SO
LOOK AT THE SYMPATHETIC ACTIVITY
WAXES AND WANES THROUGHOUT THE
WHOLE TIME. WITH THAT BACKDROP
WE ARE ASKING THE QUESTION THEN,
THESE CHANGES IN THE -- OF THE
SYSTEM DURING SLEEP CAN HAVE AN
EFFECT ON SICKLE CELL DISEASE,
CAN HAVE IMPLICATIONS IN TERMS
OF MAYBE PROMOTING MORE VOC SO
AGAIN MANY STUDIES HAVE SHOWN
SICKLE CELL DISEASE PATIENTS
HAVE ABNORMAL FUNCTION DR.
COLLINS AND COATS AND SO ON AND
FROM OUR GROUP TO PATIENT
STUDIES HAVE ALSO FOUND THAT
THERE IS VENTRAL STRESS EXPOSURE
AND PAIN CAN TRIGGER VOC FROM
PATIENT REPORTS AND OUR STUDIES
NOW HAVE SHOWN THAT FOR SEVERAL
REASONS SHOWN THAT PAIN
EXPERIMENTAL PAIN MENTAL STRESS,
COLD EXPOSURE, COLD FACE
EXPOSURE LEAD TO
VASOCONSTRICTION. ALSO SICKLE
CELL SUBJECTS ALSO TEND TO PRIOR
TO ONSET OF VOC, THAT IS SHOWN
STUDY BY CHLA. SO THAT THE
(INAUDIBLE) OVER ITS PLACE OVER
A TIME TO SELF-ADMINISTER --
FAST COMPARED TO CHRONIC STEADY
STATE GOING ON IN BLOOD -- BLOOD
FLOW, IN THE DISCUSSION THE PAST
COUPLE OF DAY DAYS SO THE ANALYSIS
IS THAT THIS MEDIATED
VASOCONSTRICTION WOULD LEAD TO
DROP IN PERFUSION WHICH INCREASE
TRANSIT TIME OF RED BLOOD CELLS
WHICH ARE SICKLING THROUGH
CAPILLARIES. LEAD TO LOWER
REPROFUSION LEAD TO MORE
VASOOCCLUSION. ADHESION
(INAUDIBLE) BEING STUCK IN THE
CAPILLARIES. SO TO QUANTIFY VASO
VASOCONSTRICTION IN HUMAN
SUBJECTS, WE CAN'T GO MEASURE IN
SMALL CAPILLARIES SO ON SO WHAT
WE DO EXTERNALLY TO MEASURE
NON-INVASIVELY, IS TO USE PULSE
OXIMETER. WHERE THERE IS
VASOCONSTRICTION YOU FIND THE
PPG DECREASE AMPLITUDE, INCREASE
IN AMPLITUDE. WHAT QUALIFY AS
AMPLITUDE OF PPG SIGNAL BEAT BY
BEAT, THIS GOES DOWN AND THEN
GOES BACK UP AGAIN. SO WHEN YOU
LOOK AT THE PPG SIGNAL AND
QUANTIFY BIT BY BIT YOU SEE
DURING VASOCONSTRICTION THIS
GOES DOWN AND SO THAT WHOLE AREA
WE IDENTIFY VASE SEW
CONSTRICTION IS QUANTIFIED IN
TERMS OF AVERAGE MAGNITUDE AND
IF THAT MAGNITUDE IS NOW
NORMALIZED BY MEAN LEVEL OF THE
PPG AMPLITUDE, WE ESTABLISH
PARAMETER WHICH CALL ELEVATES
THE VASOCONSTRICTION SO THAT IS
ALL WE USE TO QUANTIFY EXTENT OF
VASOCONSTRICTION, IN THIS CASE
ESTABLISH PRECIPITATED BY
AROUSAL FROM SLEEP WHICH CAUSES
THE VASOCONSTRICTION. SO WE
CALCULATED THIS BASED FROM THAT
WHETHER OR NOT HE WILL BUNCH OF
PATIENTS THAT WERE STUDIED BY
(INAUDIBLE) OVER 200 PATIENTS.
AND WE USE THIS PARAMETER ALLOW
SOME OTHERS TO TEST WHETHER OR
NOT THIS PARAMETER WOULD BEAT US
TO PREDICT THE VOC PAIN RATE
THEY MEASURED IN THAT BUNCH OF
PATIENTS AND IT DID. WITH QUITE
STRONG SIGNIFICANCE. ALLOWING
AGE AN HEMOGLOBIN LEVEL, WITH
THIS NEGATIVE REGRESSION MODEL
PREDICTED TO -- IF WE LOOK AT
THE SLEEP INDICES, AROUSAL INDEX
MOVEMENT INDEX AROUSAL, THOSE
WHICH SHOW SLEEP PRACTITIONERS
MEASURE, THEY DID NOT PREDICT
VOC RATE. THOUGH THEY DID
PREDICT (INAUDIBLE). SO THE
QUESTION WAS WHY WAS THAT THE
CASE? BEFORE I MOVE ON, JUST TO
SHOW IF YOU DIVIDE PATIENTS INTO
HIGH PAIN AND LOW AND NO PAIN
HIGH PAIN BEING MORE THAN
ONE-HALF EVENTS PER YEAR AND
THIS IS OVER PERIOD OF FIVE
YEARS, MANY OF THESE PATIENTS,
YOU FIND THAT TO ELEVATE HIGH
PAIN PATIENTS ARE SICK CLICKLY
HIGHER COMPARED TO LOWER LOW
PAIN PATIENTS. SO TO BETTER
UNDERSTAND THAT WE LOOK MORE
CLOSELY AS TO WHAT IS HAPPENING
DURING THE NIGHT MEDIAN OVER
NIGHT FOR EACH PATIENTS, SO THIS
WAS ONE NUMBER TO LOOK AT HOW
ACTUALLY SLEEP MODULATES H MORE
CLOSELY TO SEE FOR EXAMPLE WHEN
VASOCONSTRICTIONS ARE HAPPENING,
DOING WAKEFULNESS STAGE 1 SLEEP,
STAGE 2, DEEP SLEEP AND REM
SLEEP YOU CAN SEE SLEEP STATE,
IT DOES MODULATE THIS
(INAUDIBLE) AS YOU GO DEEPER,
THE EXTENT OF RESTRICTIONS ARE
REDUCED. AND IF YOU GO TO REM
SLEEP INCREASES (INAUDIBLE) IN
THIS CASE. THEN ALSO IF YOU LOOK
AT ALL THESE VASOCONSTRICTIONS
AND YOU TRY TO ASSOCIATE THEM
WITH EVENTS THAT ARE HAPPENING
DURING THOSE VASOCONSTRICTIONS
YOU LOOK AT ALL
VASOCONSTRICTIONS THESE
MAGNITUDE WE SAW, IF YOU LOOK AT
THOSE VASOCONSTRICTIONS WITHOUT
ANY ASSOCIATED SLEEP EVENTS
HERE, YOU CAN SEE THAT IS CLOSE
TO WHAT ALL THE OTHER --
ASSOCIATES WITH THOSE THAT HAVE
-- HAPPENING WITHIN 37 THAT KIND
OF GRANT YOU CAN SEE INCREASES
VASOCONSTRICTION MAGNITUDE. YOU
HAVE AROUSALS AS WELL AND THAT
INCREASE EVEN MORE. SO THE
AROUSALS OF SLEEP ALONG WITH THE
EVENTS INCREASES (INAUDIBLE).
BUT THEN SO NOW IF YOU LOOK AT
IT NOW MORE DETAIL HERE, FOR
EXAMPLE, THIS SHOWS AN EXAMPLE
OF THE PPG AMPLITUDE BEAT BY
BEAT DURING SLEEP AND PATIENT
WHO HAVE HIGH -- LOW PAIN RATE
SO ZERO PAIN RATE PER YEAR,
WHEREAS IN THE BOTTOM PANEL HERE
IT SHOWS THE SAME TRACING IN
ANOTHER SUBJECT WITH HIGH PAIN
RATE, 7.2 EVENTS PEREE. SO YOU
CAN SEE THE AVERAGE OFF THIS
PATIENT IS 13% AND THE AVERAGE
FOR THE HIGH PAYMENT WAS 27%
TWICE AS MUCH. YOU CAN SEE HERE
PPG SHOWS AROUSAL EXAMPLE, THERE
IS A VASOCONSTRICTION GOING ON
AT THIS POINT. THEN AT THE SAME
TIME THERE ARE OTHER WAYS OVA
CO-CONSTRICTIONS GOING O OTHER
VASOCONSTRICTIONS. WHICH ARE
HAPPENING WITHOUT SLEEP EVENTS
ASSOCIATED WITH THEM. FOR THE
PATIENT WITH HIGH PAIN RATE YOU
CAN SEE THE VASOCONSTRICTIONS
ARE LARGER, NOT JUST DURING THE
AROUSAL BUT OTHER
VASOCONSTRICTIONS HAPPENING
BOUGHT ANY AROUS AROUSALS. IF YOU LOOK
AT WHAT HAPPENS THE PATIENTS IS
WHEN YOU HAVE NO EVENTS NO SLEEP
EVENTS VASOIS SMALLER AND
AROUSAL SOMETHING GOING ON,
RESPIRATORY EVENTS GOING ON YOU
HAVE HIGHER WHICH CONSISTS OF
WHAT WE JUST SHOWED. BUT AT THE
SAME TIME IF YOU LOOK AT THE
NUMBER OF VASOCONSTRICTIONS
GOING ON WITH NO EVENTS YOU FIND
THAT ALMOST 80% OF THOSE ARE
HAPPENING WITHOUT ANY EVENTS,
WHEREAS THOSE THAT ARE HAVING
EVENTS GOING ON AROUSAL, ONLY
ACCOUNT FOR 15%. SO YOU CAN SEE
HERE THAT VASOCONSTRICTION GOING
ON, PRETTY MUCH ALL THE TIME
PEOPLE WITH HIGH PAIN RATE THE
VASOCONSTRICTIONS LEAD TO LARGER
VASOCONSTRICTIONS THAN PEOPLE
WITH LOWER PAIN RATE. NOW THIS
IS JUST ANOTHER FIGURE WHICH
SHOWS OVER LARGER SPAN OF TIME,
WHICH IS MORE THAN HOUR HERE,
AGAIN, SHOWING THE (INAUDIBLE)
>> TWO MINUTE WARNING.
>> TENDS TO SHOW DETAIL BUT LOOK
AT THE PPG AMPLITUDE HERE THE
RED LINES INDICATE ALL THE
VASOCONSTRICTIONS ARE HAPPENING
BUT THEN YOU CAN COMPARE WITH
THE AROUSAL EVENTS, THE -- EVANS
ARE MUCH LOWER IN FREQUENCY,
COMPARED TO THESE
VASOCONSTRICTION EVENTS. SO IF
YOU LOOK AT THE TABLE THEN ABOUT
36 SRI CO-CONSTRICTIONS
HAPPENING PER HOW IN LOW PAIN
AND HIGH PAIN GROUP THERE IS NO
DIFFERENCE BUT IN THE AROUSALS
AND RESPIRATORY EVENTS MUCH
LOWER FREQUENCY HERE. SO TO LOOK
AT IT BIT MORE DETAIL, WE LOOK
AT THE SPECTRUM, THE CONTENT OF
THIS RESPIRATORY EVENTS SO FAR
SO IN -- YOU HAVE LOW PAIN
PATIENT WITH LOW BRAIN LEVEL
SLEEP DISORDERED BRAT BREATHING.
LOW PAIN PATIENT WITH HIGH
READING AND HIGH PAIN PATIENT
WITH LOW READING. IN THE
RESPIRATORY FREQUENCY YOU SEE
HERE, 3 HERTZ BREATHING
FREQUENCY, THAT'S THE BREATHING
FREQUENCY BUT AT THE SAME TIME
YOU SEE THIS LUMP, BUMP HERE
WHICH SHOWS THE FREQUENCY
ASSOCIATED WITH THE SLEEP
DISORDERED BORROWING SO PERSON
WITH HIGH YOU CAN SEE MUCH
DENSER -- HERE. IF YOU LOOK AT
THE HEART RATE AND THE PPG
AMPLITUDES YOU HAVE THOSE WITH
THE RESPIRATORY FREQUENCIES BUT
DOWN HERE AT THE VERY LOW
FREQUENCIES HERE, THERE'S NO
RESPIRATION INVOLVED SO THESE
THINGS ARE NOT ASSOCIATED WITH
ANY OF THESE SLEEP DISORDERED
BREATHING EVENTS THESE ARE
THINGS HAPPENING AT THE
INTRINSIC LEVEL AND YOU CAN SEE
THAT WITH THE HIGH PAIN SUBJECT
EVEN WITH NO SLEEP DISORDERED
BORROWING, THESE OSCILLATIONS
ARE LARGE IN AMPLITUDE COMPARED
TO SOMEONE WITH LOW PAIN, MUCH
HIGHER AMPLITUDES IN THE PPG
AMPLITUDE AND ALSO IN TERMS OF
CHANGES IN HEART RATE. SO THAT
IS DELINEATES WHAT IS HAPPENING
WITH SLEEP DISORDERED BORROWING
FROM THE OSCILLATION SEEING IN
THE PATIENTS IN ALL THE SICKLE
CELL PATIENTS. IN SUMMARY, THE
MAGNITUDE OF SRI CO-CONSTRICTION
REFLECT IT IS COLLECTIVE EFFECT
OF ALL SYMPATHETIC INPUTS AND
REPRESENTS THE NET IMPACT ON
MICROVASCULAR BLOOD FLOW AND
CONSEQUENCE LIKELIHOOD FOR
TRIGGERING LARGE SCALE
VASO-OCCLUSION IN SCD. SO SLEEP
DEPTH AND SLEEP DISORDERED
BREATHING MODULATE -- AROUSAL
INDEX AND MOVEMENT INDEX ARE
FREQUENCY MEASURES, DO NOT
ADEQUATELY REFLECT THE TOTAL
SYMPATHETIC INPUT FROM SBD. SO
ALTHOUGH SLEEP AND SDB PLAY A
MODULATORY ROLE IN INFLUENCING,
THE EPISODIC VASOCONSTRICTIONS
THAT OCCUR AT BRAIN ALL
FREQUENCIES .01 HZ, ARE MOST
PREVALENT AND BEST PREDICT THE
VOC PAIN EVENTS. SO THESE
FINDINGS ARE CONSISTENT WITH
HYPOTHESIS THAT THESE NEURALLY
INDUCE SRI CO-CONSTRICTION DUE
TO STRESS EXPOSURE PAIN ITSELF
SYMPATHETIC SURGES IN SLEEP
COULD TRIGGER VOC. FINALLY JUST
TO MAKE THE POINT HERE, I THINK
WHAT PEOPLE HAVE SAID HERE, ANS
VASOCONSTRICTION AND PAIN IS A
CLOSED LOOP SYSTEMMEN SYSTEM SO WHEN YOU
HAVE SOME STIMULUS THAT TRIGGER
ANS DEEP BRAIN CONSTRICTION
WHICH LEADS TO VASOOCCLUSION AND
PAIN, AT THE SAME TIME THE PAIN
ITSELF CAN CAUSE SIMILAR --
ACTIVATE THE SYMPATHETIC NERVOUS
SYSTEM WHICH LEADS TO FURTHER
VASE SEW CONSTRICTION SO THERE'S
A FEEDBACK CYCLE THAT GOES ON IN
CASES OF VOC THAT'S WHAT I
BELIEVE HAS (INAUDIBLE) VERY
QUICKLY ONGOING STUFF GOING ON
TRY NOT TRYING TO DEVELOP A
WEARABLE DEVICE WITH CELL PHONE
CONNECTIVITY. THAT WE CAN
MEASURE THE (INAUDIBLE) IN
PEOPLE OUT OF THE LAB THE SLEEP
LAB BY LOOKING NIGHT BY NIGHT,
THIS EXAMPLE OF PILOT STUDY DONE
HERE, WE FIND IN THIS CASE
INCREASE -- NEXT DAY THE PATIENT
REPORTED PAIN. SO INCREASE IN
VOC HERE, MAYBE POST -- FOLLOWED
BY PAIN THE FOLLOWING DAYS.
THAT'S SOME EXCITING RESULTS
THAT WE HAVE HAD SO FAR BUT
STILL DOING LOT OF STUDIES TO
TRY TO VERIFY THIS. THANKS TO MY
COLLEAGUES HERE, WE HAVE A BIG
GROUP THANKS TO NHLBI FOR YOUR
FUNDING FOR THAT. ALSO OF COURSE
MICHAEL DEBAUN AND CARROLL ROSEN
AND OTHER STUDENTS, THESE
INDIVIDUALS HERE WHO ARE NOW
CARRYING AN TH ON NEW STUDIES. THANKS
TO OUR SOURCES OF FUNDING
PREVIOUSLY. THANKS VERY MUCH.
I'M DONE HERE.
>> THANK YOU VERY MUCH, DR.
KHOO. VERY ENLIGHTENING
PRESENTATION. COMPLEX BUT NICELY
PRESENTED. WITH THAT I WOULD
LIKE TO INTRODUCE NEXT SPEAKER.
DR. SARAH MARTIN Ph.D.
CLINICAL PSYCHOLOGIST AND
ASSISTANT PROFESSOR DEPARTMENT
OF ANESTHESIOLOGY AND OPERATIVE
-- PERIOPERATIVE CARE,
UNIVERSITY OF CALIFORNIA IRVINE
AND STAFF AT DEPARTMENT OF
EMERGENCY MEDICINE AT CHILDREN'S
HOSPITAL ORANGE COUNTY. SHE IS
ONE OF THE PRINCIPLE
INVESTIGATORS IN THE UNIVERSITY
OF CALIFORNIA IRVINE CENTER ON
STRESS AND HEALTH. HER RESEARCH
UTILIZES A BIOPSYCHOSOCIAL
APPROACH TO STUDY PEDIATRIC PAIN
AND CLINICAL OUTCOMES
SURROUNDING MEDICAL PROCEDURES
SICKLE CELL DISEASE AND CHRONIC
PAIN WITH A PARTICULAR INTEREST
IN ADDRESSING HEALTHCARE
DISPARITIES. WELCOME SARAH. LOOK
FORWARD TO HEARING YOUR
WONDERFUL PRESENTATION.
>> THAW. I WILL SHARE MY SCREEN.
CAN YOU SEE EVERYTHING OKAY?
>> IT IS IN PRESENTER MODE?
>> IT IS, DO YOU WANT ME TO NOT
SHARE IT THAT WAY?
>> CURRENTLY SEE YOUR NOTES AS
WELL AS THE NEXT SLIDE. THERE
YOU GO. GOOD TO GO.
>> ALL RIGHT. SO THANK YOU SO
MUCH FOR INVITING ME TO BE PART
OF THIS SESSION, HONORED TO BE
HERE AND THANK YOU TO THE
AUDIENCE FOR STICKING WITH US
UNTIL THE END. SO QUICK OVERVIEW
OF MY TALK OUTLINE, I WILL
DISCUSS PAIN STRESS AND VASCULAR
FUNCTION IN SICKLE CELL DISEASE
AND TALK ABOUT PSYCHOLOGICAL
NEUROMODULATORY INTERVENTIONS
SPECIFICALLY HYPNOSIS AND
PRESENT RESULT A PILOT HYPNOSIS
INTERVENTION FOR PAIN AND SICKLE
CELL AND DISCUSS SOCIAL
ECOLOGICAL DISADVANTAGE IN
SICKLE CELL DISEASE AND PRESENT
SOME NEW FINDINGS FROM
EXAMINATION ASSOCIATION AMONG
SOCIO ECOLOGICAL PAIN RESPONSES
AND END WITH NEXT STEPS. BEFORE
I GET TO THAT, I WOULD LIKE TO
ACKNOWLEDGE MY FUNDERS AND
MENTORS. WITHOUT WHOM NONE OF
THIS RESEARCH WOULD BE POSSIBLE.
DATA I PRESENT TODAY CAME OUT OF
MY F 32 FELLOWSHIP FUNDED BY
NHLBI AND CONDUCTED UNDER THE
MENTORSHIP OF DR. COATS, DR.
LAURA PAIN AND HAD SOME
EXTREMELY VALUABLE COMMUNITY
CONSULTATION FROM DR. CAROLYN
RALLY. ALSO I WOULD LIKE TO
THANK THE PARTICIPANTS AND
INDIVIDUAL C SICKLE CELL WHO HAD
THE PRIVILEGE TO LEARN FROM AND
COLLABORATORS WHO ALLOW ME TO
CONTINUE THIS WORK. AS WE KNOW,
YOU HAVE A GREAT OVERVIEW TODAY
SO FAR, DISEASE COMPLICATIONS
FROM SICKLE CELL DISEASE,
SPECIFICALLY, PAIN IN
PSYCHOSOCIAL IMPAIRMENT AND
HEALTHCARE UTILIZATION. DR. KHOO
HAD PROVIDED GREAT OVERVIEW ON
THIS PHI BURR AND MODEL AND
DISCUSSION ON HOW AUTONOMEICALLY
MODULATED VASOCONSTRICTION AND
SUBSEQUENT REDUCE PERIPHERAL
BLOOD FLOW MAY PLAY IMPORTANT
ROLE IN SICKLE CELL DISEASE PAIN
AND VASCULAR OCCLUSIVE EPISODES.
PAIN STRESS AND ANXIETY ALL
EFFECT AUTONOMIC FUNCTION AND
SYMPATHETIC ACTIVATION
POTENTIALLY CAUSING DOWNSTREAM
EFFECTS ON VASCULAR RESPONSES.
THINKING INTRODUCTION --
INTERVENTION FOR THIS POPULATION
WE WANT TO CONSIDER SOMETHING TO
MODULATE THESE EFFECTS. SO WE
GOT A GREAT OVERVIEW OF NON-CARL
COLLAGECAL APPROACHES THIS
MORNING. AND DR. ASSANT PROVIDED
A DETAILED REVIEW OF THE CURRENT
EVIDENCE FOR COGNITIVE
BEHAVIORAL TREATMENT FOR PAIN. I
WILL ECHO HIS MESSAGE AND WHAT
HE PRESENTED IN SAYING THERE IS
GROWING EVIDENCE FOR COGNITIVE
BEHAVIORAL NEUROMODULATORY
INTERVENTION FOR PAIN, LESS SO
FOR SICKLE CELL. WHEN I SAY
THAT, I REFER TO BROADLY
INTERVENTIONS THAT TARGET
MODULATION AT CORTICAL LEVEL AND
ONE SUCH INTERVENTION IS
HYPNOSIS. I WAS THRILLED TO SEE
HYPNOSIS DR. SMITH SLIDE EARLIER
TODAY. HYPNOSIS IS BRIEFLY A
STATE OF FOCUSED ATTENTION BUT
ENGAGES INDIVIDUAL IMAGINATION
AND MIND BODY CONNECTION TO HELP
INDIVIDUAL FA FACILITATE CHANGES
IN PERCEPTION AND EXPERIENCE.
BROADER PAIN LITERATURE HYPNOSIS
IS CONSIDERED EVIDENCE BASE
TREATMENT FOR PAIN AND SHOWN TO
ALTER CENTRAL PAIN PROCESSES,
EFFECT AUTONOMIC STRESS RESPONSE
AND REDUCE DISSTRESS IN
INDIVIDUALS WITH PAIN. WE WANTED
TO ASSESS THE EFFECTIVENESS
HYPNOSIS ON EXPERIMENTAL
RESPONSES IN YOUTH WITH SICKLE
CELL. AND THE SPECIFIC AIMS OF
THIS STUDY WERE TO EXAMINE
EFFECT OF A SINGLE SESSION OF
SIP KNOWSIS VERSUS ATTENTION
CONTROL. ON TWO OUTCOMES, PAIN
SENSE TVTY, AND BLOOD FLOW
RESPONSES DURING EXPERIMENTAL
PAIN TASKS. SO BRIEFLY I WILL
DESCRIBE MORE DETAILS OF THE
METHODS IN THE NEXT FEW SLIDES
BUT THIS IS A RANDOMIZE CONTROL
TRIAL THAT INCLUDED 25 ADDRESS
SENTS YOUNG ADULTS 12 TO 21 WITH
SICKLE CELL. WE HOPED TO INCLUDE
A LARGER SAMPLE, HOWEVER, COVID
INTERRUPTED THE RECRUITMENT
EFFORTS. TWO MAIN OUTCOMES WERE
EXPERIMENTAL PAIN RESPONSE, SO
PAIN THRESHOLD PAIN TOLERANCE
AND INTENSITY. AND THEN ALSO
LOOKING AT VASCULAR RESPONSE IN
CHANGE BLOOD FLOW AMPLITUDE
MEASURED BY PPG. THIS FIGURE
PROVIDES AN OVERVIEW OF OUR
STUDY PROCEDURES SO STARTING
HERE ON THE LEFT, PARTICIPANTS
WEPT THROUGH TWO BLOCKS OF PAIN
TESTS SO THE FIRST BLOCK WAS
BEFORE TREATMENT CONDITION,
SECOND BLOCK WAS AFTER
RANDOMIZED WITH HYPNOSIS OR
RANDOM CONTROL. WITHIN EACH PAIN
BLOCK EXPOSED TO THERMAL HEAT
STIMULI REPRESENTED BY THESE
BLUE LINES HERE. IS AND THEY
UNDERWENT TWO SETS OF PAIN
TASKS, THRESHOLD INTOLERANCE AND
SECOND ASSESS SELF-REPORTED PAIN
INTENSITY. WE ALSO, DR. KHOO
PROVIDED SOME INTRODUCTION TO
THIS IDEA AS WELL, WE WERE
INTERESTED IN EFFECT OF THE PAIN
WARNING. SO ABOUT A MINUTE
BEFORE WE STARTED THE PAIN
PULSE, WE WARNED THE
PARTICIPANTS AND ABOUT A MINUTE
YOU WILL START TO FEEL PAIN. AND
WHAT WHAT DR. COATS AND DR. KHOO
AND TEAM HAVE FOUND IN THE LOWER
CORNER, THIS CHANGE IN BLOOD
FLOW AFTER THAT PAIN WARNING,
EVEN BEFORE THEY GET THE PAIN
PULSES SO WE WERE LOOKING AT
EFFECT OF INTERVENTION ON THAT
SPECIFIC PERIOD FOR THIS STUDY.
A QUICK OVERVIEW FOR TREATMENT
CONDITIONS BOTH 20 MINUTE FOR
HYPNOSIS, WE INCLUDED STANDARD
PROCEDURES FOR HYPNOSIS OR SELF
HYPNOSIS. AND INCLUDED INDUCTION
PHASE, AND INTENSIFICATION WHICH
HELPED HIGHEN THE PARTICIPANTS
FOCUSED ATTENTION AND THEN
SUGGESTIONS TO INCREASE COMFORT
OR REDUCE DISCOMFORT AND
SPECIFICALLY SPENT TIME
INCORPORATING HYPNOTIC
ANALGESIA. THIS PROVIDES
SUGGESTIONS TO COACH
PARTICIPANTS THROUGH CREATING
WHAT WE CALLED THEIR OWN SPECIAL
COMFORT MEDICINE. AND PRACTICE
USING THAT TOOL TO CONTROL
PERCEPTION WITH SPECIFIC
ATTENTION TO ARM THAT WAS
RECEIVED THE PAIN PULLETSES FOR
ATTENTION CONTROL YOU LISTEN TO
A COLLECTION OF HISTORICAL
STORIES. FOR RESULTS WE LOOK AT
PAIN SENSITIVITY AND PERIPHERAL
VASCULAR RESPONSES -- VAS
CO-CONSTRICTION RESPONSES.
STARTING WITH PAGE SENSITIVITY.
THE DATA HERE REFLECT PERCENT
CHANGE FROM PRE-TREATMENT TASK
TO POST TREATMENT TASK. THE Y
AXIS INDICATES THAT PERCENT
CHANGE SO HIGHER NUMBERS
INDICATE LESS PAIN SENSITIVITY
FOLLOWING INTERVENTION. SO
IMPROVEMENT. FOR PAIN THRESHOLD
STARTING ON THE LEFT WE DID SEE
A SIGNIFICANT TREATMENT EFFECT.
SO SIGNIFICANT DIFFERENCES
ACROSS TREATMENT CONDITION. FROM
PRE- TO POST TREATMENT PERIOD
WERE THOSE IN THE HYPNOSIS GROUP
DEMONSTRATED INCREASE PAIN
THRESHOLD FOR PAIN TREATMENT. ON
THE RIGHT WE SAW A SIMILAR TREND
BUT NO SIGNIFICANT PAIN EFFECT
OR SIGNIFICANT EFFECTS. SAME
FOR PAIN INTENSITY. WHILE THERE
WAS A MODERATE EFFECT AS
INDICATED BY THIS PARTIAL
SQUARED HERE AND AVERAGE 25%
REDUCTION IN PAIN INTENSITY WE
DIDN'T SEE A SIGNIFICANT AFFECT
FOR TREATMENT. SO NOW MOVING TO
THE VASCULAR RESPONSES. JUST AS
A REMINDER, THIS FIGURE DEPICTS
OR PROCEDURES AND WE WERE
INTERESTED IN CHANGE IN BLOOD
FLOW FROM BASE LINE OR RECOVERY
TO AFTER THAT VERBAL WARNING. SO
THE DATA HERE REPRESENT CHANGE
IN BLOOD FLOW. WITH LOWER LEVELS
INDICATING DECREASE BLOOD FLOW
OR VASCULAR CONSTRICTION. SO
STARTING THE RIGHT WITH FIRST
PAIN TASK WE DIDN'T SEE
SIGNIFICANT EFFECT BUT FAIRLY
LARGE EFFECT IN EXPECTED
DIRECTIONS. SO THERE WAS A TREND
FROM PRE TO POST TREATMENT,
TENDED TO INCREASE FOLLOWING
VERBAL WARNENING THE HYPNOSIS
GROUP. FOR PAIN TASK TOO WE SAW
A SIMILAR PATTERN, THIS WAS IN
FACT SIGNIFICANT SO A POSITIVE
CHANGE IN THAT BLOOD FLOW
RESPONSE IN THE HYPNOSIS GROUP.
SO PULLING RESULTS TOGETHER THEY
SUGGEST THAT THIS SINGLE SESSION
OF HYPNOSIS, MAY INFLUENCE SOME
ASPECT OF PAIN SENSITIVITY,
THESE WERE NAIVE HYPNOSIS
PARTICIPANTS SO THRILLED TO SEE
THESE EFFECTS. THE EFFECT OF
HYPNOSIS ON THE BLOOD FLOW
RESPONSE SUGGESTS THAT MAY HELP
MODULATE OR ATTENUATE THE
VASOCONSTRICTION RELATED TO PAIN
ANTICIPATION. THIS IS A SMALL
SAMPLE SO DEFINITE LIMITATIONS
AN FUTURE WORK IS NEEDED TO
EXPAND THESE FINDINGS AND
EXAMINE LONG TERM EFFECTS. NOW
SHIFTING GEARS TO THINK ABOUT
SOCIAL ENVIRONMENTAL CONTEXT IN
SICKLE CELL DISEASE. I LOVE DR.
GUPTA'S ENVIROSOME TERM, THIS IS
FACTORING IN THAT ENVIROSOME.
FOR THIS WE WANTED TO LOOK AT
THE EFFECT OF SOCIO HE CAN
LOGICAL STRESSORS AND WE KNOW
FROM BROADER LITERATURE THAT
THESE TYPES OF STRESSORS HAVE
BEEN SHOWN TO BE ASSOCIATED WITH
A VARIETY OF HEALTH INDICATORS
INCLUDING IMPORTANT
CARDIOVASCULAR AND AUTONOMIC
HEALTH INDICATER TOES AND WE
WANT O LOOK A THE EFFECT OF
STRESS IN SICKLE CELL DISEASE.
SO USING THAT SAME SAMPLE
DESCRIBED BEFORE PULLING DATA
FROM THE PRE TREATMENT PERIOD,
ALSO INCLUDING A MEASURE OF
SOCIAL ECOLOGICAL DISADVANTAGE
AND WE USE THE AREA DEPRIVATION
INDEX WHICH INCLUDES A VARIETY
OF FACTORS REFLECTING EMPLOYMENT
HOUSING QUALITY NEIGHBORHOOD
INCOME EDUCATION. IT RANGES FROM
1 TO 10, HIGHER NUMBERS INDICATE
MORE DISADVANTAGE. FOR THIS
OUTCOME WE LOOK AT VASCULAR
REACTIVITY AND THIS METRIC AND
ANALYSES WERE DEVELOPED BY DR.
KHOO AND HIS LAB AND I WILL DO
MY BEST TO DESCRIBE WHAT IS
SHOWN HERE. SO THROUGH COST
RELATION THEY INVERTED THE PAIN
PULSES SO HERE THESE BLUE LINES
THAT WE SAW EARLIER, INVERTED
THOSE. PAIN PULSE STIMULI ON TO
RECORDINGS OF BLOOD FLOW. IN
THIS LOWER FIGURE THE BLOOD FLOW
IS BLUE LINES AND THE PAIN
TEMPERATURE STIMULI ARE THE RED.
THEY LINE THOSE UP AND CREATED A
CROSS CORRELATION. WHICH
INDICATED SLOPE OF THE THE
LINEAR REGRESSION OF BLOOD FLOW
SIGNAL ON THE PAIN SIGNAL. SO
THIS GAVE A SLOPE OF
VASOREACTIVITY. LOWER NUMBERS
INDICATE A STRONGER
VASORESTRICTION RESPONSE TO THAT
PAIN STIMULI. FOR THE RESULTS
HERE, ON THE LEFT WE FIRST LOOK
AT BASELINE BLOOD FLOW, WE SAW
SIGNIFICANT ASSOCIATION. SO
HIGHER STRESS WAS ASSOCIATED
WITH LOWER BASELINE BLOOD FLOW.
ON THE RIGHT YOU LOOK AT THAT
VASCULAR REACTIVITY TO THE PAIN
STIMULI AND SAW ANOTHER
SIGNIFICANT ASSOCIATION. SOCIAL
ECOLOGICAL STRESS WAS ASSOCIATED
WITH STRONGER VASCULAR
RESTRICTION RESPONSE TO PAIN. SO
THINKING OF PULLING THIS ALL
TOGETHER COLLECTIVELY THE
RESULTS SUGGEST COGNITIVE
BEHAVIORAL NEUROMODULATORY BASE
INTERVENTIONS SUCH AS HYPNOSIS,
MAY BE A PROMISING APPROACH TO
TARGET SOME IMPORTANT
PSYCHOPHYSIOLOGICAL RESPONSES IN
PAIN IN SICKLE CELL DISEASE. IT
IS IMPORTANT TO CONSIDER BROADER
SOCIAL STRESS AS THEY -- THESE
MAY BE FURTHER FACTORS THAT MAY
EXACERBATE THESE RESPONSES IN
PAIN SICKLE CELL. SO POTENTIAL
NEXT STEPS, DEFINITELY AS I
MENTION BEFORE FUTURE WORK
NEEDED TO CONFIRM THE RESULTS IN
LARGER SAMPLES, AND WE WOULD
LIKE TO BUILD ON THESE FINDINGS,
DEVELOP AND TEST COMMUNITY
INFORMED ACCESSIBLE
INTERVENTION, POTENTIALLY
CONSIDER DIGITAL REMOTE
TREATMENT DELIVERY AND WEARABLE
DEVICES TO MONITOR OUTCOMES. AND
IN CLOSING LEAVE YOU ARE WITH
THIS FRAMEWORK. SO THE -- IN
THINKING ABOUT NEXT STEPS, NIMHG
PUT TOGETHER A FRAMEWORK TO
GUIDE FUTURE RESEARCH THAT
ADDRESSES COMPLEX AND
MULTI-FACETED NATURE OF MINORITY
HEALTH AND HEALTH DISPARITIES
AND THEY PUT TOGETHER THIS
FRAMEWORK TO ENCOURAGE
RESEARCHERS TO CONSIDER
DIFFERENT DOMAINS, AND DIFFICULT
LEVELS OF INFLUENCE WHEN
DESIGNING RESEARCH AND
INTERPRETING RESULTS SO WE CAN'T
INCLUDE ALL THESE THINGS BUT
KNOWING THAT INDIVIDUALS WITH
SICKLE CELL DISEASE ARE AT RISK
FOR EXPERIENCING HEALTH
DISPARITIES AND DIFFICULTY
ACCESSING CARE WE WANT TO FACTOR
IN BROADER SOCIAL INFLUENCES OR
MECHANISMS. THANK YOU SO MUCH.
FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH, SARAH.
THAT WAS A VERY NICE
PRESENTATION. IT IS OPEN FOR
DISCUSSION AND I WOULD START
WITH THE QUESTIONS I HOPE ALL
THE SPEAKERS ARE THERE AND THEY
WILL BE ABLE TO ANSWER THEM. DR.
STUCKY HAS A QUESTION FOR DR.
HE. DR. HE, ARE YOU THERE TO
ANSWER? YES. THANKS FOR YOUR
TALK, IT IS VERY INTERESTING,
CAN YOU SPEAK TO WHICH
MEEKICALLY SENSITIVE ION
CHANNELS ACTIVATED BY ULTRASOUND
-- MECHANICKICLY ACTIVATED BY
ULTRASOUND AND WHAT REGION OF
THE NERVOUS SYSTEM OR BRAIN?
>> THANK YOU VERY MUCH, GREAT
QUESTION. FIRST OF ALL I HAVE TO
SAY VERY LITTLE KNOWLEDGE IS
AVAILABLE AT THIS TIME. THERE
WAS A RECENT CAL TECH STUDY IN
VITRO NEURON THAT -- WE FOUND
CALCIUM VOLTAGE GATED ION
CHANNELS INVOLVED THE ULTRASOUND
ACTIVATED IN NEURONAL
EXCITATION. THAT'S ALL WE KNOW.
SO THERE IS VERY LITTLE
KNOWLEDGE, IT IS STILL JUST ONE
HYPOTHESIS. GAINING SOME SUPPORT
INCLUDING OUR IN VIVO BOTH
ANIMAL MODEL AND NOT IN SICKLE
PAIN PATIENT BUT TO SUPPORT THIS
HYPOTHESIS.
>> THANK YOU VERY MUCH, DR. HE.
NEXT QUESTION IS FROM DR.
MORRIS, WAS THE FEMALE MOUSE
REALLY HAPPY AND COMMENT THAT
HEALTHY FOOD AND COMPANIONSHIP
IS EQUAL TO HAVE BEEN -- I CAN'T
ANSWER THIS QUESTION BECAUSE
FEMALE MICE OFTEN BECAME
PREGNANT SO IT IS CHALLENGING TO
ANALYZE PAIN IN THEM. DR.
(INAUDIBLE) HAS NICE SUGGESTION.
THE BIOPSYCHOSOCIAL MODEL OF
WORK SIMILARLY IF YOU GIVE
MOUSE OXYCODONE THEY WON'T EAT
SLEEP OR HAVE SEX, JUST MORE
OXYCO-DONE. GREAT IDEA. MAYBE I
WONDER IF OXYCODONE RELIEVE PAIN
OR NOT, THAT REMAINS TO BE SEEN
IN THIS MODEL. DR. (INAUDIBLE)
HAS A NICE COMMENT. THIS
DEMONSTRATES AND PROVIDES
EVIDENCE THAT IT IS NOT SIMPLY
ABOUT PERCEPTION. THIS WILL GO
LONG WAY ADDRESSING THE STIGMA
THAT INDIVIDUALS WITH SICKLE
CELL DISEASE FACE FROM
HEALTHCARE PROVIDERS AND
SCIENTISTS. I HOPE WE CAN
RECTIFY THIS AND DR. GREEN HAS
QUESTIONS FOR DR. MCFEARSON. CAN
YOU -- RICHARDSON, CAN YOU
INFORM THE NAMES OF THE OREXIN
PHARMACEUTICALS AND SHE ADMIRES
YOUR PRESENTATION.
>> YES, ACTUALLY PUT IN THE CHAT
THERE WERE -- THERE ARE ACTUALLY
TWO SO FAR THAT ARE FDA
APPROVED, SUBAREXIN AND
(INAUDIBLE) ARE APPROVED AS
SLEEP AIDS.
>> DR. STEPHANIE HAS A QUESTION.
HAVE YOU SEEN ANY CORRELATION
BETWEEN ACUTE CARE UTILIZATION,
THIS IS FOR DR. KHOO.
>> I WOULD REPLIED IN THE CHAT
THIS THAT THE DATA WE ANALYZE
FROM (INAUDIBLE) COHORT STUDY
WERE BASED ON VOC FREQUENCY
SPACE OF HOSPITALIZATION. AND
PATIENTS SO I GUESS IN THAT
SENSE, HAS TO DO WITH ACUTE CARE
UTILIZATION.
>> ANOTHER QUESTION FROM DR.
GREEN FOR YOU, DR. KHOO, HOW
DIFFICULT IS IT TO GET A READING
OF THE FINGER DEVICE? THIS SEEMS
TO BE IMPORTANT AND MAYBE
ADAPTABLE FOR CLINICIANS TO HELP
PATIENTS READILY.
>> ALSO ACTUALLY -- IT IS ON
EVERY PATIENT WHO IS UNDERGOING
SLEEP STUDY OR IN THE HOSPITAL.
SO BECAUSE PEOPLE ONLY LOOK AT
THE ULTRA SATURATION. THEY DON'T
LOOK AT THE PULSE SIGNAL. AND WE
ARE THE ONLY ONES WHO LOOK AT
THE MAGNITUDE OF THE PULSE
SIGNAL, PEOPLE LOOK AT PULSE
RATE OF THAT. SO THAT'S ONE OF
THE THINGS WE DID THAT IT IS
FROM A SICKLE THAT IS USED
ANYWHERE. BUT NOW WHAT WE ARE
TRYING TO DO IS MEASURE IN T
HOME SO THAT IS WHY WE TRY TO DO
IT ON A RISK LIKE THE APPLE
WATCH -- WRISTBAND LIKE THE
APPLE WATCH. MEASURE THAT.
>> THANK YOU. A QUESTION FOR DR.
HE FROM BOTH DR. STUCKY AND
COATES THEY WONDER IF THE
CHANNELS ARE INVOLVED.
>> I REPLY IN THE CHAT, I THINK
THESE ARE GREAT QUESTIONS,
PARTICULARLY INTERESTED IN THIS
RELEVANCE TO SSCD. VERY
INTERESTING TO LOOK INTO THEM
BUT TO NOT TO MY KNOWLEDGE NOT
AWARE OF A DIRECT ANSWER TO THE
QUESTION AS THEY SPAN FROM THE
LITERATURE.
>> THANK YOU VERY MUCH. FOR
STICKING IT OUT THIS LONG. I
HOPE EVERYBODY CAN RELAX, EAT
WELL, ENJOY GOOD COMPANY
TONIGHT.
>> THANK YOU SO MUCH, KALPNA FOR
A GREAT SESSION. THIS WAS A
GREAT 3 WONDERFUL DAYS OF FULL
SESSIONS. I WOULD LIKE TO THANK
ALL THE PRESENTERS AND ALL THE
FOLKS WHO HAVE ATTENDED THE
MEETING. THANK YOU SO MUCH. I
THINK WE HAVE LEARNED A LOT IN
THE THE LAST THREE DAYS ABOUT
SICKLE CELL AND LOT MORE. WE
REACHED FROM BASIC SCIENCE TO
CLINIC AND TO QUALITY OF LIFE
CURATIVE THERAPY GENE THERAPY,
WE DID OMICS AND DATA SCIENCE
AND SICKLE TRAIT AND OF COURSE
PAIN. SO SPECIAL THANKS TO TWO
IMPORTANT PEOPLE WORKING IN THE
BACKGROUND ALL THIS TIME MAKING
YOUR PICTURES AND SLIDE
MAGICALLY APPEAR AN DISAPPEAR
MANY THANKS TO AMIR AND TO ALEX
(INAUDIBLE) I HOPE I PRONOUNCED
THE LAST NAME CORRECTLY AND TO
NAOMI AND DELL,A AND MY
COLLEAGUES DBDR AND THANK YOU
ALL. STAY SAFE. AND GOODBYE
UNTIL WE MEET NEXT TIME. THANK
YOU.