>> GOOD MORNING,
AFTERNOON, WHEREVER YOU ARE, I
AM THRILLED TO SEE YOU ALL
HERE TODAY.
I WANT TO THANK YOU ALL FOR
YOUR TREMENDOUS HEALTH AND TO
MAKE THIS WORKSHOP HAPPEN.
PLEASE JOIN ME TO WELCOME
Dr. PATUTE-BELLO.
PLEASE JOIN ME TO GIVE OPENING
REMARKS.
GUS?
>>THANKS, GOOD MORNING OR
AFTERNOON, ON BEHALF OF THE
DIVISION OF LUNG DISEASE AT
NHLBI, IT IS REALLY A GREAT
PLEASURE TO WELCOME YOU ALL
TODAY TO THIS SYMPOSIUM ON
BRAIN AND MUSCLE DYSFUNCTION
IN ARDS SURVIVORS.
I DON'T THINK I NEED TO
EMPHASIZE TO THIS AUDIENCE
THAT ACUTE RESPIRATORY
SYNDROME OR ARDS REMAINS A
DEVASTATING CLINICAL SYNDROME
THAT LEADS TO ACUTE
RESPIRATORY FAILURE AND DEATH
MORE OFTEN THAN WE WOULD LIKE.
FORTUNATELY IN THE LAST FIVE
DECADES, A CONCERTED
EVIDENCE-BASED EFFORT IN
IMPROVING GENERAL CLINICAL
CARE AND VENTILATOR MANAGEMENT
HAS LED TO SIGNIFICANT
REDUCTIONS IN MORTALITY FROM
ABOUT 60 TO 80 PERCENT.
WHEN I STARTED AS A FELLOW, TO
THE CURRENT RATE OF 25 TO
40 PERCENT.
HOWEVER, THERE IS ALSO A
GROWING NUMBER OF ARDS
SURVIVORS AND VERY
UNFORTUNATE, WE ARE SEEING
THESE PATIENTS SUFFER FROM
LASTING SEQUELAE AND THIS
INCLUDES INCREASED MORTALITY,
PHYSICAL, COGNITIVE AND
PERMANENT AND REDUCED QUALITY
OF LIFE.
THESE END WHEN THE PATIENT IS
INTUBATED.
IN FACT, MUSCLE SYSTEMS ARE
SOME OF THE MAIN TARGETS OF
SURVIVORS.
IT HAS A VERY HIGH LEVEL
PREVALENCE OF COGNITIVE
IMPROVEMENT.
70 TO 80 PERCENT OF HOT
DISCHARGED IN ONE YEAR AND
REMAINS UP TO 40 PERCENT FIVE
YEARS AND CLINICAL
EFFECTIVENESS, SKELETAL MUSCLE
WEAKNESS OCCURS IN UP TO
10 PERCENT -- 670 PERCENT OF
ALL CLINICAL PATIENTS AND
THERE ARE SUBSTANTIAL
LONG-TERM IMPAIRMENTS IN
MUSCLE STRENGTH, WALKING
CAPACITY, FISCAL ACTIVITY
BETWEEN SIX MONDAYS ASK EVEN
TWO YEARS AFTER BEING
DISCHARGED FROM THE ICU.
MORE IMPORTANTLY PATIENTS WITH
COVID-19 PNEUMONIA HAVE HIGH
INCIDENCE OF ARDS, UP TO
42 PERCENT OF THESE PATIENTS
AND THE SURVIVORS FROM
COVID-19 ARDS ALSO DEVELOP
MUSCLE WEAKNESS, 35.7 PERCENT,
COGNITIVE IMPAIRMENT UP
17.1 PERCENT SO IT IS VERY
CLEAR THERE IS AN ON GOING
NEED IN THE CLINICAL
MANAGEMENT OF ARDS SURVIVORS
AND URGENCY FOR INTERVENTION
STRATEGIES FOR THESE PATIENTS.
THERE IS EMERGING DATA THAT
SHOWS WEIGHT AND MUSCLE
WEAKNESS CONTRIBUTE TO BRAIN
AND MUSCLE DISFUNCTIONS WE SEE
IN ARDS SURVIVORS ALTHOUGH THE
MECHANISMS THAT UNDER LIE
THESE ARE NOT KNOWN SO THERE
IS A CRITICAL GAP IN PART OF
THE PHYSIOLOGY OF THIS AREA
AND HERE IS WHERE THIS
WORKSHOP COMES IN.
SO NHLBI HAS CONVENED THIS
WORKSHOP WITH PANEL EXPERTS,
ALL OF YOU, TO SPEAK FROM THE
RESEARCH COMMUNITY AND KEY
STAKEHOLDERS.
THIS IS QUIETNESS AND TIMELY.
AND WE HOPE THAT THIS WORKSHOP
WILL CAPTURE THE STATE OF
SCIENCE AS IT RELATES TO BRAIN
AND MUSCLE DYSFUNCTION
FOLLOWING ARDS AND CRITICAL
ILLNESS.
WE ALSO HOPE THAT YOU WILL
HELP US EVALUATE CRITICAL
KNOWLEDGE GAPS AND KEY
BARRIERS IN THIS FIELD AND
IDENTIFY RESEARCH
OPPORTUNITIES IN UNDERSTANDING
THE PATH OF ETIOLOGY OF BRAIN
AND MUSCLE DYSFUNCTION IN
SURVIVORS OF ARDS.
WE CHALLENGE YOU AND HOPE THAT
YOU WILL SEND HIGH RISK HIGH
REWARD IDEAS ON HOW TO MOVE
FORWARD SCIENCE IN THIS FIELD
SO THAT ULTIMATELY WE CAN
ACHIEVE A LONG-TERM OBJECTIVE
OF IDENTIFYING ACTIONABLE
TARGET INTERVENTION AND
STRATEGIES THAT WILL REALLY
HELP IMPROVE THE OPTIONS FOR
PATIENTS.
SO THOSE ARE YOUR REQUESTS
FROM NHLBI TODAY.
THOSE ARE ALSO OUR CHALLENGES.
IT IS AN AMAZING PANEL.
I HAVE TO APOLOGIZE AHEAD OF
TIME BECAUSE I WILL HAVE TO BE
IN AND OUT THROUGHOUT THE NEXT
TWO DAYS BUT I WILL ATTEMPT TO
ATTEND AS MANY SESSIONS AS I
CAN AND HAVING SAID THAT, I
WILL THANK YOU ALL AND RETURN
THE MIC TO THE MODERATOR.
>>THANK YOU VERY MUCH, BUS,
SO I WOULD LIKE TO THANK THE
NHLBI FOR THE WORKSHOP, IF YOU
HAVE ANY QUESTIONS IN THE NEXT
TWO DAYS, PLEASE REACH OUT TO
THEM.
I WOULD ALSO LIKE TO ALSO
THANK MY COLLEAGUE, Dr.
CHRISTIAN GOMEZ WHO HAS BEEN
WORKING TAKING FOR THE LAST
YEAR WHEN WE PLANNED TO HAVE
THIS WORKSHOP.
NOW I TURN THE MICROPHONE OVER
TO Dr. CHRISTIAN.
>>GOOD MORNING, EVERYONE,
THANK YOU FOR THIS WORKSHOP.
MY NAME IS CHRISTIAN GOMEZ --
[INDISCERNIBLE]
THE FOCUS OF THIS IS THE.
[INDISCERNIBLE]
SO COMORBIDITIES IMPAIR
QUALITY OF LIFE IN PHYSICAL
AND MENTAL HEALTH.
THE HIGH COST OF SURVIVING
ARDS CAN BE VERY RELATED TO
DEVELOPING PNEUMONIA OF
SURVIVORS OF THIS CONDITION.
IT IS MY DISTINCT PLEASURE TO
INVITE Dr. KIRSTEN HARRELL
WHO HAS BEEN WORKING WITH
PATIENTS WITH HIGH RESULTS.
ADDITIONALLY, MS. HARRELL IS A
WRITER, SPEAKER AND WAS
ACCEPTED TO --
[INDISCERNIBLE]
WELCOME KIRSTEN.
PLEASE TAKE IT AWAY.
>>THANK YOU, Dr. GOMEZ.
FIRST I WOULD LIKE TO EXPRESS
MY GRATITUDE TO NIH AND TO ALL
OF YOU FOR YOUR RESEARCH AND
DEDICATION IN UNDERSTANDING
ARDS AND HELPING SURVIVORS
LIKE ME.
I AM HONORED TO BE HERE TO
SHARE MY STORY WITH ALL OF
YOU.
IT IS A LITTLE DIFFICULT FOR
ME TO SPEAK ABOUT SO I AM
GOING TO BE READING MY TALK
BECAUSE SOME OF THE IMPACTS
THAT I STILL EXPERIENCE MAKE
IT A LITTLE DIFFICULT FOR ME
TO KEEP TRACK AND KEEP ON
TARGET HERE.
SOME OF THE MAJOR HARDSHIPS
THAT I EXPERIENCED WITHIN THE
ICU INCLUDE FEELING COMPLETELY
AND UTTERLY HELPLESS WHEN I
WAS NOT ABLE TO COMMUNICATE.
THERE WERE A FEW TIMES
INITIALLY WHEN I WAS AWAKE
THAT I COULD WRITE BUT THEN
THAT ABILITY SHARPLY DECLINED
THROUGHOUT MY TWO WEEKS ON A
VENTILATOR AND AT OTHER TIMES
WHEN I WAS AWAKE, AND I CAN
REMEMBER PUTTING JUST AN
ENORMOUS EFFORT INTO TRYING TO
WRITE SOMETHING TO THE STAFF
OR FAMILY AND THEN I WOULD
SHOW IT TO THEM AND THEY
COULDN'T READ IT AND I WOULD
JUST BE SO FRUSTRATED AND
THINKING I JUST SPENT EVERY
LITTLE OUNCE OF ENERGY I HAD
TO WRITE THAT AND WHY AREN'T
THEY ABLE TO READ IT.
OF COURSE I DIDN'T REALIZE
THAT IT WAS BASICALLY CHICKE N
SCRATCH AND THEY COULDN'T READ
IT.
I EXPERIENCED DELEAR YUM AND
INDOZENS TERRIFYING
HALLUCINATIONS.
FOR EXAMPLE, I THOUGHT THAT I
HAD BEEN KIDNAPPED AND HELD
HOSTAGE FOR WEEKS IN A
RESEARCH FACILITY WHERE THEY
WERE EXPERIMENTING ON ME AND
KEPT ME FROM MY FAMILY, THAT I
WAS ALONE AND TRAPPED AND
TRYING TO GET OUT.
I HAD OTHER VIVID
HALLUCINATIONS THAT CONTINUED
UNTIL I WAS DISCHARGED.
WHEN I FIRST GOT OFF THE
VENTILATOR, I HAD TO LEARN HOW
TO WALK AGAIN AND I CAN
REMEMBER IN THE HOSPITAL THE
FIRST FEW STEPS THAT I TOOK
WERE SO DIFFICULT.
I HAD TROUBLE TRYING TO GET MY
BRAIN AND MY BODY TO WORK
TOGETHER.
THEY WOULD TELL ME TO LIFT A
FOOT, I WOULD THINK THAT, IT
WOULD TAKE QUITE A LONG TIME
BEFORE MY BODY WOULD RESPOND
AND I COULD LIFT THE FOOT AND
THEN TRYING TO FIGURE OUT HOW
TO LIFT ANOTHER FOOT, STAY
BALANCED, HOLD THE WALKER AND
BREATHE ALL AT THE SAME TIME
SEEMED LIKE AN ABSOLUTELY
IMPOSSIBLE TASK AT THAT POINT.
I COULD ONLY DO A FEW STEPS AT
A TIME BEFORE I WOULD FATIGUE
AND HAVE TO SIT BACK DOWN.
WHEN I FIRST GOT HOME,
EVERYBODY WAS SO HAPPY AND
GRATEFUL THAT I HAD SURVIVED.
FOR ME THE LONG AND DIFFICULT
ROAD TO RECOVERY WAS JUST
BEGINNING.
I WAS STILL VERY WEAK.
I REMEMBER THAT IT TOOK ME A
MONTH OF VERY HARD WORK WITH
PHYSICAL THERAPY BEFORE I WAS
EVEN RELEASED TO WALK BY
MYSELF WITH A WALKER TO THE
BATHROOM.
BEFORE THAT, I ALWAYS HAD TO
HAVE SOMEONE BEHIND ME BECAUSE
I HAD A TENDENCY TO FALL
BACKWARDS.
I HAD DIFFICULTY SWALLOWING
DUE TO VOCAL CORD DAMAGE AND I
HAD TO EAT ONLY SOFT FOODS FOR
QUITE A LONG TIME.
ALL THE PILLS I HAD TO TAKE
HAD TO BE CRUSHED AND MIXED
WITH APPLE SAUCE.
I HAD GREAT CARE FROM THE
PHYSICAL THERAPY AND IT WAS
REALLY HELPFUL TO HAVE THE
GUIDANCE AND GOALS AND
SPECIFIC TASKS.
SO THAT FIRST YEAR WAS SPENT
REGAINING MY ABILITY TO WALK,
INCREASE MY STRENGTH, MY
BALANCE, ENDURANCE.
UNFORTUNATELY THE SAME TYPE OF
CARE AND STRUCTURE WASN'T
THERE FOR THE COGNITIVE AND
PSYCHOLOGICAL RECOVERY AND SO
THAT PART FOR ME HAS BEEN THE
HARDEST AND MOST CHALLENGING
ASPECT OF RECOVERY FROM THE
ARDS FROM THE ICU.
WHEN I WAS IN THE ICU, MY
FAMILY WAS TOLD I MAY HAVE
SOME COGNITIVE IMPAIRMENTS BUT
WEREN'T GIVEN ANY OTHER
INFORMATION OR REFERRALS OR
ASSISTANCE FOR HOW TO HELP ME.
I HAD A LOT OF CONFUSION AT
FIRST AND VERY SIGNIFICANT
COGNITIVE DIFFICULTIES EARLY
ON.
THOSE JUST SLOWLY IMPROVED
OVER TIME.
I SOUGHT SOME HELP FROM MY PCP
AND NEUROLOGIST.
UNFORTUNATELY THEY DID NOT
KNOW ANYTHING ABOUT IT AND DID
NOT OFFER ANY HELP.
I DECIDED TO TRY THINGS ON MY
OWN LIKE PUZZLES AND GAMES.
I HAD GREAT DIFFICULTY READING
AND READING HAS ALWAYS BEEN A
HUGE LOVE OF MINE SO I WAS
DETERMINED TO TRY TO INCREASE
MY FOCUS AND ATTENTION SO I
COULD ENJOY READING AGAIN.
IT DID IMPROVE OVER TIME,
HOWEVER I STILL HAVE TROUBLE
AT TIMES AND CANNOT FOCUS
ENOUGH TO READ AND IT IS VERY
FRUSTRATING AND AT TIMES
DEPRESSING.
I CONTINUE TO HAVE EXPERIENCED
SOME MILD DEFICIT DISFUNCTIONS
THAT INTERFERE WITH MY DAILY
LIFE.
IN SOME OF THE DISFUNCTIONS I
CAN SUSTAIN FAIRLY WELL BUT
NOT FOR LONG.
IF I AM FATIGUED I STRUGGLE
WITH COGNITIVE TASKS.
I HAVE TROUBLE WITH ORGANIZING
AND PLANNING AND COMPLETING
TASKS WITH MULTIPLE STEPS.
SWITCHING GEARS IS CHALLENGING
AND I FIND THAT I NEED A LOT
OF STRUCTURE IN ROUTINES THAT
I DIDN'T NEED BEFORE BECAUSE
CHANGE CAN REALLY DERAIL ME.
AS A PSYCHOLOGIST, IT TOOK ME
SOME TIME TO REALIZE I WAS
EXPERIENCING PTSD FROM THE
ICU.
I HAD TO LEARN ABOUT PIS.
I TRIED TO READ ABOUT THAT BUT
THE THERAPISTS LACK OF
UNDERSTANDING ABOUT IT MADE
THE TREATMENT INEFFECTIVE.
AS AN ARDS SURVIVOR WITH
IMMUNE DEFICIENCY, THE
PANDEMIC FOR ME WAS MY WORST
NIGHTMARE COME TRUE AND
GREATLY SASS EXACERBATED MY
PTSD AND SENT ME INTO CRISIS.
IT WAS LIKE LIVING IN A
CONSTANT STATE OF TRIGGERING
AND AT TIMES I WONDERED IF I
WAS STILL IN THE ICU
EXPERIENCINGDELERIUM BECAUSE
IT SEEMED TO UNBELIEVABLE TO
ME.
THE DELERIUM AND
HALLUCINATIONS STILL HAUNT ME.
AND WITH LIVED TRAUMATIC
EXPERIENCES, EVEN THOUGH I
KNOW THEY ARE NOT REAL, MY
MIND STILL EXPERIENCES THOSE
EXPERIENCES AS IF I LIVED
THROUGH THEM.
I SUFFER SEVERE PTSD, ANXIETY,
EMOTIONAL LABILITY AND
DEPRESSION.
MY QUALITY OF LIFE IS REDUCED.
I SUFFER DESPAIR, FLASHBACKS,
IT TAKES TIME TO RECOVER AND
IS PHYSICALLY EXHAUSTING.
MEDICAL APPOINTMENTS AND
PROCEDURES ARE DIFFICULT FOR
ME NOW AND CAUSE A LOT OF
ANXIETY.
GOING TO THE EMERGENCY
DEPARTMENT CAN BE VERY
TRIGGERING AND AT TIMES TRAWL
MATIZING BECAUSE OF THE LACK
OF TRAUMA-INFORMED CARE.
IT WASN'T TILL FOUR YEARS
AFTER THE ICU THAT I FINALLY
FOUND A SUPPORT GROUP AT THE
VENDORRABILITY CENTER AND THE
SUPPORT WITH THOSE WITH PIS I
HAVE FOUND HELPFUL.
I HAVE A THERAPIST WHO IS
TRAUMA-INFORMED AND WILLING TO
LEARN ABOUT THIS AND I AM
MAKING PROGRESS AND JUST NOW
STARTING TO FOCUS ON CREATING
AWARENESS ABOUT ALD S&P IS AND
HELP SOME OTHER SURVIVORS.
SOME OF THE THINGS THAT CAN
HELP ARE HAVING
TRAUMA-INFORMED PROVIDERS IN
THE ICU.
THAT PERSON COULD HELP WITH
MAJOR EVENTS, PROCEDURES,
TRANSITIONS, HELP IDENTIFY
DEALMOST ERIUM AND REDUCE THE
TERROR.
PROVIDE SOME CONTINUITY OF
CARE IN THE STEPDOWN UNITS
BECAUSE IT CAN BE REALLY SCARY
TO GO FROM THE INTENSE AND
CONSTANT CARE OF THE ICU TO A
REGULAR FLOOR WITH LESS CARE,
LESS PEOPLE, LESS ATTENTION.
I THINK ACCEPTABLE
COMMUNICATION TOOLS ARE
ESSENTIAL TO REDUCE SOME OF
THE HELPLESSNESS AND ANXIETY.
THAT COULD ALSO HELP WITH THE
DELERIUM BECAUSE I WAS
TERRIFIED AND I COULDN'T TELL
ANYONE WHY.
AND FINALLY I THINK BETTER
CONTINUITY OF CARE POST-ICU
AND THAT INCLUDES EDUCATION
FOR FAMILY ABOUT WHAT TO
EXPECT AND HOW TO HELP THE
SURVIVOR AS WELL AS THEY MIGHT
EXPERIENCE THEIR OWN PTSD.
REFERRAL TO PROVIDERS WHO ARE
FAMILIAR WITH ARDS AND PIS
WOULD BE VERY HELPFUL AND IF
THERE COULD BE SOME STRUCTURE
AND ASSISTANCE IN PLACE TO
HELP WITH COGNITIVE AND
PSYCHOLOGICAL RECOVERY EARLY
ON, I AM CONVINCED I WOULDN'T
HAVE SUFFERED AS GREATLY AND
WOULD HAVE A BETTER QUALITY OF
LIFE NOW IF I HAD RECEIVED
THAT HELP EARLY ON.
I KNOW I WOULD NOT HAVE
SURVIVED ARDS WITHOUT THE ICU
STAFF.
MORE IMPORTANTLY, I WOULD NOT
HAVE SURVIVED THE FOLLOWING
FIVE YEARS WITHOUT THE AMAZING
LOVE AND SUPPORT FROM MY
FAMILY, FRIENDS, THE
VANDERBILT PIS GROUP AND MY
THERAPIST AS I FIGHT TO
RECOVER FROM PIS.
FINALLY I WANT TO THANK ALL OF
YOU AGAIN FOR ALLOWING ME TO
SHARE MY STORY WITH AND YOU
FOR WORKING HARD TO DEVELOP A
BETTER UNDERSTANDING AND
TREATMENT FOR ARDS.
THANK YOU SO MUCH.
>>THANK YOU FOR YOUR
INSPIRING TESTIMONY.
IT IS SAID THE DARKEST HOUR OF
THE NIGHT COMES JUST BEFORE
THE DAWN.
WITHOUT FURTHER ADIEU, LET ME
INTRODUCE OUR COCHAIRS NOW,
Dr. TERRI HOUGH AND Dr.
GIRARD.
Dr. HOUGH --
[INDISCERNIBLE]
USING CLINICAL TRIALS AT
CONVENTIONAL METHODS.
Dr. GIRARD IS ASSISTANT
PROFESSOR AT THE UNIVERSITY
SCHOOL OF MEDICINE AND
DIRECTOR OF THE UNIVERSITY'S
CLINICAL RESEARCH,
INVESTIGATOR OF SYSTEM
MODELING OF ACUTE ILLNESS.
HIS RESEARCH IS TO APPROACH
LONG STANDING ILLNESS WITH
SPECIFIC --
[INDISCERNIBLE]
BEFORE I DELIVER THE MIC TO
BOTH OF YOU, LET ME THANK YOU
FROM NHLBI FOR YOUR LEADERSHIP
AND COMMUNICATION FOR THIS
WORKSHOP.
IT HAS BEEN A PLEASURE WORKING
WITH YOU.
Dr. HOUGH, THE FLOOR IS
YOURS.
>>THANK YOU SO MUCH AND
THANKS TO THE WHOLE TEAM OF
NHLBI FOR FOCUSING ON THIS
WORK AND I LOOK FORWARD TO THE
NEXT TWO DAYS TOGETHER BUT
FIRST OF ALL THANK YOU TO
Dr. HARRELL FOR SHARING YOUR
STORY AND PUTTING A FACE AND
FOCUS ON THE WORK WE HAVE ALL
BEEN FOCUSSED ON FOR OUR
CAREERS AND HELPING US
UNDERSTAND THIS WORK IS
CRUCIAL AND WE STILL HAVE
SIGNIFICANT GROUND TO COVER IN
ORDER TO BE ABLE TO MOVE THE
NEEDLE AND OUTCOMES THE WAY WE
HOPE TO.
WE HAVE A COUPLE OF SLIDES TO
START AND I DON'T KNOW WHO IS
GOING TO PUT THOSE ON?
AH, OKAY, EXCELLENT.
SO Dr. GIRARD AND I WILL
JUST TAKE A FEW MOMENTS TO SET
THE STAGE FOR THE NEXT FEW
DAYS AND I THINK WE WILL COVER
A LOT OF WHAT WE HAVE ALREADY
HEARD FROM Dr. MATUTE-BELLO
AND Dr. GOMEZ AND Dr.
HARRELL.
NEXT SLIDE, PLEASE.
SO WE KNOW ACUTE RESPIRATORY
DEPRESS SIT SYNDROME IS
COMMON.
I FIRST LEARNED ABOUT THIS
THROUGH WORK AT THE UNIVERSITY
OF WASHINGTON AND IT SHOWED
RATHER THAN BEING THE WEIRD
OUTCOME THAT WAS CONSIDERED AT
THE TIME, IT WAS FAIRLY
COMMON.
WHAT WAS DERIVED FROM THIS
WORK WAS ALMOST 90 CASES OUT
OF 100 AND AN ESTIMATED
200,000 A CASES ACROSS THE
UNITED STATES.
NEXT SLIDE, PLEASE.
OBVIOUSLY IN THE AGE OF
COVID-19, ARDS IS CLEARLY NOT
A RARE DISEASE AND THE
DRAMATIC INCREASE IN NUMBERS
AND RECOGNITION OF ARDS HAS
REALLY COME TO THE FRONT OVER
THE LAST FEW YEARS.
I THINK WE CAN SAFELY ASSUME
THAT THE VAST MAJORITY OF
HOSPITALIZATIONS FOR COVID-19
INCLUDED ARDS OR SOMETHING
VERY SIMILAR AND THE NUMBERS
ARE TRULY STAGGERING.
JUST IN THE THIRD YEAR OF THE
PANDEMIC, ONLY 3.5 MILLION
CASES ALONE.
NEXT SLIDE, PLEASE.
AND FORTUNATELY WE'RE ALSO
SEEING A TREND OF INCREASING
SURVIVAL AFTER ARDS
HOSPITALIZATION.
THERE IS SOME WORK LOOKING
KIND OF OVER THE FIRST 30
YEARS OF ARDS AND SHOWING A
PRETTY DRAMATIC DECREASE IN
HOSPITAL MORTALITY FROM
50 PERCENT TO LESS THAN
30 PERCENT OVER THAT PERIOD OF
TIME.
NEXT SLIDE.
SO EVEN IF IT IS A LITTLE
EARLY IN YOUR TIME ZONE AS IT
IS FOR MINE TO DO MATH, IT IS
EASY TO CALCULATE THIS.
EVERY YEAR THERE ARE HUNDREDS
OF THOUSANDS OF ARDS SURVIVORS
JUST IN THIS COUNTRY --
[INDISCERNIBLE]
NEXT SLIDE, PLEASE.
SO THE ISSUES THAT Dr.
HARRELL DESCRIBED IN HER
RECOVERY FROM ARDS ARE JUST AS
STARTLING AND STAGGERING NOW
AS THEY HAVE BEEN FOR YEARS
BUT THEY ARE CERTAINLY NOT
NEW.
THIS IS NOT NEW INFORMATION.
WE HAVE STUDIED BACK TO THE
1990S DESCRIBING FUNCTIONAL
IMPAIRMENT, THE COGNITIVE
IMPAIRMENT THAT OUR PATIENTS
STRUGGLE WITH AFTER ARDS.
IT HAS NOW BEEN 20 YEARS SINCE
THE LANDMARK STUDY FOLLOWING
ARDS PATIENTS FOR A YEAR AND
THEN FIVE YEARS AFTER THEIR
CRITICAL ILLNESS AND AGAIN
THIS IS DEMONSTRATING THE
MARKED IMPAIRMENT AND HEALTH
STATUS OF PATIENTS.
NEXT SLIDE, PLEASE.
AND TRYING TO FIGURE THIS OUT
WE HAVE KIND OF LOOKED ACROSS
THE TRAJECTORY AND ARC OF
RECOVERY OF OUR PATIENTS AFTER
ARDS AND A LOT OF OUR WORK IS
FOCUSED ON THE EARLY CASES.
AGAIN, IT HAS NOW BEEN 20
YEARS SINCE WE FIRST READ
ABOUT THE PARESIS IN A
LANDMARK STUDY DONE BY OUR
COLLEAGUES IN FRANCE AND
SIMILARLY, THE DELIRIUM IN
MECHANICALLY VENTILATED
PATIENTS AND THEIR RECOVERY.
SO PERHAPS TRYING TO
UNDERSTAND SOME OF THE
PRECOURSE SORES OF COGNITIVE
ABILITY WE SEE AFTER THE
ILLNESS, NEXT SLIDE, PLEASE,
AND MANY OF US ON THIS CALL
TODAY SPENT A LOT OF TIME
TRYING TO IDENTIFY THE RISK
FACTORS ASSOCIATED WITH THESE.
AND THERE ARE MANY PAPERS OUT
THERE COMPILING ALL THE
DIFFERENT KINDS OF FEATURES
ASSOCIATED WITH THE ILLNESS
ITSELF AND THEN TRYING TO
IDENTIFY ASPECTS OF CARE AND
RISKS OF ACUTE MUSCLE AND
BRAIN DYSFUNCTION AS WELL.
NEXT SLIDE.
BUT DESPITE THE NOW DECADES OF
WORK WE HAVE BEEN DOING, THE
MANY ATTEMPTS AT USING
INTERVENTION TO TRY TO IMPROVE
THESE OUTCOMES HAVE REALLY NOT
RESULTED IN THE CHANGE WE HAD
HOPED AND MY GOODNESS THERE
HAVE BEEN A LOT OF STUDIES AND
CLINICAL IDEAS RANGING FROM
REHABILITATION MANUALS AND
EDUCATION, EXERCISE PROGRAMS,
COGNITIVE THERAPY, PHYSICAL
THERAPY, NUTRITION, MAKING
SURE PEOPLE HAVE INFORMATION
AND THEN TREATMENT TRYING TO
HELP THE PSYCHOLOGICAL
IMPAIRMENTS AS WELL, THE
COPING SKILLS, MINDFULNESS,
DIARIES AND MANY CLINICAL
APPROACHES AND FOLLOW UP
PROGRAMS.
NEXT SLIDE.
BUT I THINK LARGELY
UNFORTUNATELY DESPITE THESE
VERY GOOD IDEAS AND A LOT OF
WORK, WE REALLY STILL LACK
EVIDENCE-BASED APPROACHES TO
IMPROVE PHYSICAL AND COGNITIVE
OUTCOMES AFTER ARDS.
SO I WILL HAND IT OVER TO
Dr. GIRARD.
>>THANK YOU SO MUCH, DOCTOR
HOUGH.
NEXT SLIDE, PLEASE.
I DON'T HAVE A WHOLE LOT MORE
TO ADD BUT I WANT TO TIE
TOGETHER WHAT YOU SEE ON THE
AGENDA FOR THE NEXT TWO DAYS'
PROGRAMS FROM WHAT YOU HAVE
HEARD FROM DOCTOR HOUGH SO FAR
AND A GOOD PLACE TO START IS
TO LOOK AT THE RESEARCH
SPECTRUM.
ALL OF US ARE FAMILIAR WITH
THE CLINICAL PROCEDURES AT THE
BEDSIDE AND NHLBI HAS THEIR
OWN LINKS FOR THIS THAT YOU
CAN SEE AT THE BOTTOM OF THE
SLIDE.
WHAT WE WANT TO ACCOMPLISH FOR
THIS CONFERENCE OR WORKSHOP IS
NOT ONLY TO HIGHLIGHT NEW
ADVANCES AND KNOWLEDGE GAPS AS
THE BENCH AND ALSO AT THE
BEDSIDE BUT ALSO BRING THEM
TOGETHER AND WE HAVE TRIED IN
A STRATEGIC WAY TO GATHER SO
MANY MODERATORS, PRESENTERS
AND PARTICIPANTS THAT SPAN
THIS RESEARCH SPECTRUM.
AND WE WANT TO DO SO IN A WAY
THAT WILL EMPHASIZE THE FACT
THAT WE HAVE TO WORK TOGETHER.
THE CONVERSATION CAN'T JUST BE
WITHIN THE REALM OF BASIC
SCIENCE OR WITHIN THE REALM OF
CLINICAL AND WILL
TRANSLATIONAL SCIENCE, BUT IT
HAS TO BE ALL OF US TALKING
TOGETHER.
SO YOU WILL SEE TOMORROW, FOR
EXAMPLE, WHEN WE GET TO THE
POINT AT THE END OF THE
WORKSHOP WHERE WE HAVE THE
BREAKOUT ROOMS, THAT WE
VERYING TENSIONALLY CREATED
BREAKOUT ROOMS THAT WILL
FACILITATE A MIXTURE OF THE
FULL SPECTRUM FROM BASIC TO
TRANSLATIONAL TO CLINICAL
SCIENCE AND OTHER STAKEHOLDERS
SO THAT WE CAN WORK ON THIS
TOGETHER.
AND WE KNOW THIS CAN BE
ACCOMPLISHED.
WE KNOW THIS CAN BE DONE IN
MANY OTHER AREAS OF MEDICINE
BUT ALSO ARDS.
IF YOU WILL GO TO THE NEXT
SLIDE, JUST AN EXAMPLE, WE
HAVE TALKED A LOT HOW WE
HAVEN'T MADE MUCH PROGRESS IN
TERMS OF TRANSLATING
DISCOVERIES TO DIFFERENCES IN
OUTCOMES IN TERMS OF BRAIN AND
MUSCLE DYSFUNCTION AFTER ARDS
BUT WE DON'T HAVE TO LOOK VERY
FAR TO SEE AN EXAMPLE OF BENCH
TO BEDSIDESTEPS IN ARDS.
SO YOU GO BACK TO THE 80s,
FOR EXAMPLE, IN THIS PAPER,
WHERE THE STUDY IS DONE IN
RATS AND SUGGESTED INCREASED
INFLATION PRESSURES WERE
HARMFUL TO THOSE IN THE ANIMAL
MODELS AND CONVERSELY THAT WAS
TRANSLATED THEN TO WORK DONE
IN LARGER ANIMAL MODELS AND
THEN ADVANCED AGAIN.
EVENTUALLY THAT WAS BROUGHT TO
THE BEDSIDE IN A LARGE
POSITIVE CLINICAL TRIAL THAT
ULTIMATELY MADE THE DIFFERENCE
IN HOW PATIENTS WERE CARED FOR
AND THEIR OUTCOMES.
ADVANCE AGAIN, PLEASE.
AT THE SAME TIME AS DOCTOR
HOUGH MENTIONED, A NUMBER
OF -- ACTUALLY MANY DIFFERENT
INTERVENTIONS HAVE BEEN
STUDIED IN EFFORTS TO IMPROVE
LONG-TERM OUTCOMES FOR
PATIENTS WHO SUFFER ARDS OR
SOME OTHER CRITICAL SYNDROME.
AND I WANT TO MENTION THAT
ARDS IS SPONSORING THIS
WORKSHOP AS WELL BECAUSE THEY
RECOGNIZE HOW IMPORTANT THE
KNOWLEDGE GAGED FROM THE STUDY
OF ARDS IS TO SEPSIS AND THERE
IS A LOT OF CRITICAL OVERLAP
FOR THE SYNDROMES.
SO WHAT WE WILL BE FOCUSING ON
THE NEXT FEW DAYS IS NOT ONLY
RELIED TO ARDS BUT SEPSIS AND
OTHER CLINICAL SYNDROMES.
BUT WHAT WE HAVE SEEN IS THE
STUDIES AND ADVANCES, TRIALS
IN THESE AREAS THAT DETERMINED
LONG-TERM OUTCOMES HAVEN'T
ALWAYS NECESSARILY BEEN
INFORMED BY MECHANISMS AND
UNDERSTANDING OF MECHANISMS.
SO ADVANCE, PLEASE.
WE MAY SEE SOME POSITIVE
STUDIES LIKE THIS ONE BUT
STILL NOT EXACTLY SURE WHY.
WHAT IS THE MECHANISM OR
MECHANISMS THAT UNDERLIE THE
DIFFERENCE IN THE OUTCOME THAT
A FEW POSITIVE TRIALS HAVE
HAD?
THOSE ARE REALLY IMPORTANT
QUESTIONS BECAUSE IN ORDER FOR
US TO TRANSLATE THIS TO OTHER
EFFECTIVE INTERVENTIONS AND TO
REALLY IMPROVE OUTCOMES FOR
PATIENTS LONG-TERM AS THEY
RECOVER FROM ARDS, SEPSIS AND
OTHER CRITICAL ILLNESS
SYNDROME, WE HAVE TO
UNDERSTAND THE FULL SPECTRUM
FROM BENCH TO BEDSIDE.
SO THAT IS MY LAST SLIDE AND I
THINK I WILL TURN IT BACK OVER
TO Dr. HOUGH TO INTRODUCE
THE MODERATORS FOR THE SESSION
AND THANK YOU ALL FOR
PARTICIPATING.
>>Dr. GIRARD, THANK YOU AND
THANK YOU FOR NICELY
PROGRAMSING US FOR THE
DISCUSSIONS WE WILL BE HAVING
OVER THE NEXT TWO DAYS.
SO LET'S LAUNCH RIGHT INTO
SESSION 1.
SESSION 1 WILL BE RIGHT SMACK
IN THE MIDDLE OF THAT DIAGRAM,
FROM BENCH TO BEDSIDE AND
INTERVENTION AND BACK THAT
Dr. GIRARD JUST SHOWED US,
FOCUSING ON THE CLINICAL
PRESENTATION, RIGOROUS
MEASUREMENT AND SOCIAL
DETERMINANTS OF BRAIN AND
MUSCLE DYSFUNCTION IN ARDS
SURVIVORS.
SO TO LEAD US INTO THE NEXT
SESSION, I WOULD INTRODUCE
FRIENDS AND COLLEAGUES OF
MINE, FIRST Dr. LAUREN
FERRANTE WHO IS A PHYSICIANS
IN PULMONARY CARE AT YALE
UNIVERSITY.
Dr. FE RRANTE HAS BEEN SPE
INTERSECTION OF PUMMOLOGY AND
CRITICAL CARE AND THAT
KNOWLEDGE OF THE OUTCOMES, AND
HAS TAUGHT US A LOT HOW THE
BASELINE PLAYS INTO THE KEY
ILLNESS AS WELL.
THEN I WOULD LIKE TO INTRODUCE
Dr. IWASHYNA FROM HOPKINS
UNIVERSITY, AN EXPERT IN
CLINICAL EPIDEMIOLOGY AND
HEALTH SERVICES RESEARCH AND
ONE OF THE FEW CLINICAL CARE
DOCS I KNOW WHO HAS ADVANCED
TRAINING IN SOCIOLOGY AND I
THINK THIS SHOWS THE WAY THAT
DOCTOR IWASHYNA TACKLES THE
RECOVERY AND UNDERSTANDING THE
PATIENTS AND THEIR FAMILIES
AFTER CRITICAL ILLNESS SO
DOCTORS FE RRANTE AND
IWASHYNA, TAKE IT AWAY.
>>THANK YOU SO MUCH, TERRI,
WE'RE PLEASED TO MODERATE THIS
SESSION AND DELIGHTED TO
INTRODUCE OUR FIRST SPEAKER,
Dr. CARLA SEVIN FROM
NATIONALVILLE, TENNESSEE.
IN ADDITION TO CARING FOR
CRITICALLY ILL PATIENTS
INCLUDING THOSE WITH COVID.
AND IN 2017 STARTS A THRIVE
CAB -- COLLABORATIVE.
HE NOW LEADS A CLINICAL GROUP
AND WELCOME Dr. SEVIN,
THANKS FOR BEING WITH US
TODAY.
>>THANK YOU FOR THAT
FANTASTIC INTRODUCTION AND
PLEASED TO SEE SO MANY NAMES
AND FACES AND LOOKING FORWARD
TO THE SESSION.
IF THE PERSON IN CHARGE OF THE
SLIDES WILL NOTE I HAVE SOME
SLIDES AT THE END OF MY TALK
AND WILL TALK IN A STREAM OF
CONSCIOUSNESS AS I TEND TO DO
BUT HERE ARE MY DISCLOSURES.
MY MAJOR DISCLOSURE IS I AM
VERY PASSIONATE ABOUT THIS
WORK THAT COMES FROM WORKING
WITH PATIENTS AND FAMILIES AT
THE BEDSIDE SO IF I EDGE INTO
POSSIBLETIZING WITH POLICIES,
NEXT SLIDE, PLEASE.
I BECAME INTERESTED IN THIS
AREA OF MEDICINE WHEN I WAS A
RESIDENT AND FELLOW HERE AT
VANDERBILT.
TIM GIRARD WAS ONE OF MY
FELLOWS WHEN I WAS A LOCALLY
INTERN AND I WAS FORCED TO SAY
I DON'T KNOW MANY TIMES IN A
ROW IN THAT ROTATION WHICH WAS
A VERY FRUSTRATING EXPERIENCE
FOR ME.
AND WHEN I CAME ON TO FACULTY,
WE STARTED A POST BEDSIDE
CLINIC AND I NOW HAVE TO SAY I
DON'T KNOW MANY TIMES STILL
BUT IT DOESN'T BOTHER ME AS
MUCH BECAUSE EVERY TIME WE SAY
I DON'T KNOW, IT IS A PLACE TO
TARGET TO LEARN ABOUT FOR
INTERVENTION.
SO A COUPLE OF SLIDES TO BRING
TO TOP OF MIND WHY WE'RE HERE
AND WHAT WE WANT TO BUILD ON
TODAY AND THEN TALK ABOUT THE
CLINICAL PRESENTATION OF BRAIN
AND MUSCLE PROBLEMS WE SEE
WHEN PATIENTS COME INTO THE
CLINIC.
SO BY NOW YOU HAVE HEARD ABOUT
THE POST-INTENSIVE CARE
SYNDROME, I HOPE, AND Dr.
HARRELL TALKED ABOUT IT IN HER
TALK, IF YOU COULD CLICK
THROUGH THE NEXT FEW BUBBLES,
HERE, WHOEVER IS ADVANCING THE
SLIDES.
KEEP GOING.
SO THE POST-INTENSIVE CARE
SYNDROME WAS A TERM REALLY
DEVELOPED IN 2012 AND WILL BE
SHARED WITH US TODAY TO SORT
OF PUT A NAME TO THIS
CONSTELLATION OF PROBLEMS WE
WERE SEEING IN PATIENTS WHO
SURVIVED CRITICAL ILLNESS AND
IT IS MARKED BY MENTAL
IMPAIRMENT, FAMILY HEALTH
PROBLEMS AND HIGH BURDEN OF
CHRONIC HEALTH CONDITIONS.
NEXT SLIDE, PLEASE.
WE WILL HEAR IN MORE SPECIFIC
DETAIL ABOUT THE PHYSICAL
SEQUELAE WHICH ARE
LONG-LASTING.
NEXT SLIDE.
THE COGNITIVE IMPAIRMENTS THAT
ARE REALLY IMPACTFUL FOR
PATIENTS AND ARE NOT WELL
ADDRESSED IN OUR HEALTH
SYSTEM.
THIS SHOWS THE GLOBAL
COGNITION DECREASED IN
SURVIVORS WHO SURVIVED
CRITICAL AIRNESS, THE COLUMN
ON THE LEFT ARE PATIENTS UNDER
49 YEARS OLD SO EVEN YOUNGER
PATIENTS RAILROAD NOT
PROTECTED FROM COGNITIVE
ILLNESS.
AND POSTTRAUMATIC STRESS AS
Dr. HARRELL MENTIONED HAS A
HUGE IMPACT AFTER CRITICAL
ILLNESS.
Dr. HARRELL AND I DID NOT
COORDINATE OUR TALKS BEFORE
THIS SESSION BUT YOU WILL BE
SURPRISED TO HEAR BECAUSE HER
DESCRIPTION IS SO ACCURATE AND
A COMMON OUTCOME WE SEE, VERY
CRITICAL ILLNESS AND PATIENTS
ARE DEALING WITH SIMILAR
PROBLEMS.
POSTTRAUMATIC STRESS IS
ANOTHER SYMPTOM WE DON'T
SCREEN FOR AFTER CRITICAL
ILLNESS.
THIS IS A GRAPH OF PATIENTS
WHO SUFFERED CARDIAC ARREST
SPECIFICALLY AND THOSE WHO HAD
POSTTRAUMATIC STRESS SYMPTOMS
IN THE RED LINES COMPARED TO
THOSE WHO DID NOT IN THE BLUE
WERE MORE THAN LIKELY TO DIE A
YEAR AFTER WARDS SO IT IS
SOMETHING WE NEED TO LOOK FOR.
AND THEN AS CONSIDER HARRELL
MENTIONED, SUICIDE AND SELF
HARM UNDER ADULT SURVIVORS OF
CRITICAL ILLNESS, SOMETHING WE
SEE IN MANY CRITICALLY-ILL
PATIENTS.
NEXT SLIDE.
SO CRITICAL ILLNESS IS REALLY
THE ONSET OF A CHRONIC
ILLNESS.
I THINK MANY OF OUR PATIENTS
AND ARE US THINK OF SURVIVING
THE ICU AS THE END OF
SOMETHING BUT IN FACT IT IS
THE BEGINNING OF ANOTHER THING
AND THIS IS A REALLY PROLONGED
CHRONIC ILLNESS.
THIS IS ONE OF OUR PATIENTS
WHO CAME TO THE CLINIC WITH
HIS PARTNER AFTER A 4-MONTH
ICU STAY AND I THINK YOU CAN
APPRECIATE THIS IS A YOUNG
PERSON WHO IS STILL VERY
IMPAIRED DESPITE BEING WELL
ENOUGH TO LEAVE THE HOSPITAL.
NEXT SLIDE, PLEASE.
AND IN FACT WE HAVE SOME DATA
THAT SHOWS EVEN THE THINGS WE
TRADITIONALLY THINK OF AS
CHRONIC ILLNESSES, COPD,
DIABETES, HYPER LIPIDEMIA ARE
MORE PREVALENT THAN THOSE
HOSPITALIZED FOR OTHER
REASONS.
NEXT SLIDE.
THIS IS A VERY TYPICAL
PRESENTATION THAT WE SEE IN
OUR CLINIC.
IF YOU COULD CLICK THROUGH THE
TEXT AREA.
A 37-YEAR-OLD WOMAN WITH
CRITICAL ILLNESS DUE TO H1N1,
TRANSFERRED TO LTAC, A VENT,
TRACH, PARALYSIS, DELIRIUM,
DVT, AND UNFORTUNATELY THE
PATIENT WAS UNINSURED SO WE
HAD TO DO SOME WORK TO GET HER
TO THE RIGHT PLACE.
I WANTED TO GET HER
TRANSFERRED WHERE SHE COULD DO
THREE HOURS OF PHYSICAL
THERAPY PER DAY.
SHE WAS SUFFERING PARALYSIS
AND I MADE A DEAL WITH THE
DEVIL TO LET HER GO TO LTAC A
FEW DAYS UNTIL SHE COULD THEN
TRANSITION FOR REHAB.
I GOT A MESSAGE A FEW DAYS
LATER THAT SHE COULD WALK NOW
AND DIDN'T NEED TO GO TO
IN-PATIENT REHAB AND SAW HER
IN CLINIC FIVE WEEKS POST
HOSPITAL DISCHARGE.
BUT SHE COULD NOT WALK, NEEDED
A THREE-PERSON ASSIST TO GET
UP OFF THE EXAM TABLE, HAD
FOOD DROP AND NO BRACES TO
HELP WITH ANYTHING WITH THAT,
MALNOURISHED WITH A 26-POUND
WEIGHT LOSS WHICH IS TYPICAL
AND HAIR LOSS WHICH IS
SOMETHING WE CAN TREAT WITH
EDUCATION.
SHE WAS BACK ON LOVANOX, SHE
WAS HAVING HYPERTENSIVE
EPISODES ON A BETA BLOCKER
WITH SYNCOPE, DIARRHEA WAS
PROBABLY A SIDE EFFECT.
WANTED TO RETURN TO WORK,
COULD NOT DRIVE AND HER TRACH
WAS CANULATES SO THAT WAS THE
ONE THING WE DIDN'T HAVE TO
WORK ON.
NEXT SLIDE.
SO THE NECK SPEAKER, I AM VERY
LUCKY TO WORK WITH HIM EVERY
WEEK AND HE DID A TYPICAL
COGNITIVE EVALUATION FOR THIS
PATIENT INCLUDING A M O CA
WHICH WAS SIGNIFICANTLY
IMPAIRED, MULTIPLE ERRORS ON A
SERIAL 7'S TASK AND SIMILAR
TESTIFIES AND HIS CONCLUSION
WAS ALTHOUGH HER JOB WAS NOT
TYPICALLY COGNITIVELY
DEMANDING, HER COGNITIVE
PROBLEMS WERE SO GREAT THAT
THEY WOULD LIKELY INTERFERE
WITH PER PERFORMANCE AND IN
FACT WERE NOT ABLE TO
RECOMMEND A RETURN TO WORK
TILL NINE MONTHS LATER WHEN
SHE HAD A TRIAL RETURN TO
WORK.
NEXT SLIDE.
SO THIS IS A TABLE FROM OUR
DESCRIPTION OF THE FIRST
6 PATIENTS WE SAW IN CLINIC
AND IF YOU CLICK THROUGH THE
RED BOXES, I WANT TO HIGHLIGHT
WE HAD MEANINGFUL COGNITIVE
IMPAIRMENT IN 64 PERCENT OF
THE PATIENTS WE SAW THERE.
WE DO A SIX-MINUTE WALK TO
LOOK FOR A CRITICAL AWARENESS,
NEUROPATHY, WHAT THEIR SPECIAL
NEEDS ARE AND MORE THAN A
QUALITY OF OUR PATIENTS WERE
NOT ABLE TO DO THE SIX-MINUTE
WALK.
THOSE ARE ALL PATIENTS WELL
ENOUGH TO GO HOME AND WELL
ENOUGH TO GET TO IN PERSON
CLINIC AND WERE NOT WELL
ENOUGH TO WALK.
MANY OF OUR PATIENTS, NOT
UNSURPRISINGLY, WERE NOT
DRIVING AND 65 PERCENT WHO HAD
BEEN PREVIOUSLY WORKING WERE
NOT ABLE TO RETURN TO WORK.
AND THE SECOND CITATION THERE
AT THE POT IS A METAANALYSIS
BY JOE McPEAKE SHOWING THIS
IS NOT UNIQUE AND 46 PERCENT
OF PATIENTS UNABLE TO RETURN
TO WORK SIX MONTHS AFTER THEIR
HOSPITAL STAY.
SO WE GET TO MEASURE WHAT ARE
YOU DOING, HOW DO YOU RESPOND
AND WE DON'T KNOW THE RESPONSE
OF WHAT ARE THE MOST
EFFICACIOUS THINGS TO DO FOR
THESE PATIENTS BUT ONE TOPIC
THAT HAS COME UP QUITE A BIT
IS HOW TO MEASURE.
CAN WE TYING NOSED PICS, WE
DONALD HAVE A SCREEN FOR IT
BUT WE HAVE CLINICALLY
AVAILABLE TOOLS AND RESEARCH
TOOLS IN THE VARIOUS DOMAINS
AND THIS IS FROM A CONSENSUS
CONFERENCE UNDER THE SOCIETY
OF CRITICAL CARE MEDICINE THAT
WAS PUBLISHED IN 2020 LOOKING
AT WHAT SOURCE OF TOOLS ARE
BEING USED AND PEOPLE THINK
ARE A GOOD IDEA, EXPERTS DOING
THE WORK IN THE FIELD AND
THERE IS STRONG CONSENSUS
AROUND THE USE FORTH O C A FOR
COGNITION, THE HOSPITAL
SANCTION SITE AND DEPRESSION
SCALE FOR ANXIETY AND
DEPRESSION BUT WHEN IT COMES
TO SCREENING FOR POSTTRAUMATIC
DISTRESS OR ANXIETY, THERE IS
REALLY NO GOLD STANDARD.
NEXT SLIDE.
UNFORTUNATELY IF YOU DON'T
MEASURE, YOU WON'T FIND AND
MANY OF US CAME TO THIS FIELD
THROUGH CRITICAL MEDICAL
TRAINING WHICH IS VERY LIGHT
ON COGNITIVE AND MENTAL HEALTH
DOMAINS BUT WE HAVE HAD SOME
REALLY SHOCKING CASES WHERE
PEOPLE COME INTO CLINICS, LOOK
TOTALLY FINE.
MAYBE THEY HAVEN'T BEEN BACK
TO WORK AND IF YOU LOOK AT
THEM FROM THE OUTSIDE, THEY
LOOK OKAY AND THIS IS A
BARRIER TO THEM BEST OF THING
THE HELP THEY NEED.
HOWEVER IF YOU ASK SPECIFIC
QUESTIONS, YOU FIND A LOT OF
NEED.
FOR EXAMPLE, OUR LADY IN THIS
CASE WANTED TO RETURN TO WORK
BUT COULDN'T GET UP FROM AN
EXAM TABLE WITHOUT ASSISTANCE
AND WAS ONE OF THOSE WHO COULD
NOT DO THE SIX-MINUTE WALK.
I SAW A IT SPECIALIST IN HIS
40s, FOUR MONTHS OUT OF
HOSPITALIZATION AND TWO MONTHS
ON E CMO, HIS PFTS ARE ALMOST
NORMAL, HE CAN WALK AND EVEN
QUALITY A LITTLE BUT CAN'T GO
BACK WOULD WORK BECAUSE HIS
COGNITIVE DEFICITS ARE SO
SEVERE.
AND THEN A COLLEAGUE IN HIS
60s, WENT BACK TO WORK
PART-TIME, I HAD A LOVELY
CONVERSATION WITH HIM AND HIS
WIFE AND THOUGHT HE WAS DOING
QUITE WELL AND WILL THEN JIM
WENT IN TO DO THE MENTAL
STATUS EXAM AND HE WAS UNABLE
NO NAME THE YEAR OR THE
PRESIDENT.
NEXT SLIDE, PLEASE.
SO OUR CURRENT STATUS THAT WE
ARE VERY FOCUSED ON IN IC
WHICH WE NEED TO BE.
IF YOU DON'T SURVIVE YOUR
CHRIS CALL ILLNESS, YOU ARE
CAN'T GO TO ANY SURVIVOR
PROGRAM BUT WHEN A PATIENT
LEAVES ICU FROM A RESEARCH AND
CLINICAL STANDPOINT, THINGS
START TO GET FUZZY AND FALL
APART AND ANYONE WHO HAS READ
A DISCHARGE SUMMARY OF SOMEONE
THEY TOOK CARE OF IN IC HAD
YOU IS A LITTLE LIKE THE
TELEPHONES, A LOT OF DATA GETS
LOST AND THEY ARE TOLD YOUR
CARE ENDS THE DAY YOU ARE
DISCHARGED AND PATIENTS SEE IN
AS A BIG BLACK HOLE AND LEFT
WITH NO IDEA HOW TO ADDRESS
THE PROBLEMS.
THIS IS FROM AN ARTIST WHO IS
A FANTASTIC ARTIST WHO DID A
SERIES OF DRAWINGS ABOUT HER
OWN EXPERIENCE IN ICU AND WE
ALSO HAVE A HOLE IN DATA
BECAUSE IT IS VERY HARD TO
TRACK PATIENTS DOWN ONCE THEY
LEAVE THE HOSPITAL.
NEXT SLIDE, PLEASE.
OUR PATIENTS TOLD US THEY
DIDN'T EVEN KNOW WHAT TO
GOOGLE.
Dr. HARRELL LISTED THESE AND
SAID THIS BETTER.
THERE WAS NO SUPPORT GIVEN OR
OFFERED TO US, NO INFORMATION,
AND KNOWING YOUR CRITICAL CARE
Dr. AND TALKING ABOUT WHAT
IS NEXT IN THE PROCESS SHOULD
BE A MANDATORY PROCESS.
NOT EVERY PATIENT HAS THE SAME
CHANCE TO RECOVER.
THIS IS A VERY SIMILAR PATIENT
TO Dr. HARRELL WHO DID NOT
THINK SHE WOULD BE ABLE TO
WALK AGAIN BUT HAD GREAT
INSURANCE, A FAMILY, GREAT
COMMUNITY, A CHURCH, WENT FROM
LPAC IN-PATIENT REHAB TO
OUT-PATIENT REHAB AND WHEN SHE
GOT OUT OF OUT-PATIENT REHAB,
HIRED A TRAINER AND WENT TO
THE GYM FOR 180-STRAIGHT DAYS
AND THAT IS HOW SHE HAD AN
ADEQUATE RECOVERY.
SHE DID HER OWN COGNITIVE
REHAB BY MAKING COMPLEX REESE
PIECE AND FELT SHE WAS
PROVIDING SOMETHING TO THE
COMMUNITY WHEN THE RECIPES
WORKED OUT AND WAS ABLE TO
HAVE SUCH A GREAT RECOVERY SHE
WAS ONE OF OUR PATIENT
SPEAKERS SEVERAL YEARS AGO AND
HER NAME IS MILLIE AND IS HERE
WITH HER HUSBAND WOODY.
NEXT SLIDE.
IN CONTRAST, I HAD A PATIENT
IN HER 30s WHEN A
CATASTROPHIC PERIPARTUM
CRITICAL ILLNESS.
SHE HAD GOOD INSURANCE BUT NO
PCP TO SIGN PT PAPERWORK.
SHE HAD A SUPPORTIVE HUSBAND
WHO HAD TO BE DEPLOYED AGAIN
AND HAD A 6-YEAR-OLD AND
NEWBORN AT HOME AND WHEN HER
HUSBAND DEPLOYED AGAIN, I
ASKED HER HOW SHE WOULD TAKE
CARE OF THE NEWBORN AND SHE
TOLD ME SHE WOULD LIE DOWN AND
TAKE CARE OF THE BABY LYING
DOWN.
ANOTHER PATIENT IN HIS 40s,
NO INSURANCE, CAN'T WORK DUE
TO HIS ILLNESS AND HE WENT
HOME WITH A TRACH WHICH HE
BASICALLY IS HAVING THE
SUPPLIES AND OXYGEN DONATED.
HE IS DUE IN COURT FOR CHILD
SUPPORT AND NEEDING HELP WITH
HOW TO NAVIGATE THE LEGAL
SYSTEM AFRAID OF EXPOSURES SO
THESE PATIENTS IN CONTRAST ARE
NOT DOING SO WELL DESPITE THE
SAME CARE IN THE ICU.
SO I PUT TOGETHER THIS SLIDE
WITH THE INTERVENTIONS AT THE
BOTTOM OF THE SLIDE BUT WE
KNOW VERY LITTLE, KEEP
CLICKING, PLEASE, ABOUT EACH
OF THESE.
AND WE SEE THERE IS A TRAM
JECT TREE -- TRAJECTORY OF
RECOVERY.
NEXT SLIDE.
THE MAJOR GAPS WITH NO
UNIFYING DIAGNOSIS CODES, NO
CONSENSUS ON MEASUREMENT, NO
CARE PATHWAYS, NO INSURANCE
COVERAGE, DIFFICULT TO REACH
RESEARCH POPULATION, NO
FUNDING HOME SPECIFIC TO THIS
AREA AND LITTLE INTEGRATION
INTO TRAINING.
I AM SURPRISED THERE ARE A
VERY FEW CLINICAL PROGRAMS
FOLLOWING PATIENTS AFTER
DISCHARGE AND IN RURAL AREAS,
EVEN FEWER.
THERE IS LITTLE AWARENESS OF
WHAT IS KNOWN OR NEEDED AND
RESEARCH IN THIS AREA IS UNDER
DEVELOPED IN THESE AREAS.
NEXT SLIDE, PLEASE.
WE NEED THIS INFRASTRUCTURE,
HOWEVER, NOT ONLY TO PROVIDE
FOR CRITICAL AND CLINICAL CARE
BUT TO LEARN ABOUT THE
OUTCOMES OF THESE ILLNESSES TO
IMPROVE OUR IN-I CU CARE AND
THERE HAVE BEEN IN THE PLACES
THAT HAD HISTORY TO LEARN
ABOUT THE DISEASE.
SO I WAS ASKED TO COME UP WITH
A HIGH RISK-HIGH REWARD
CONCEPT FOR HOW TO PUSH THIS
FORWARD.
I DON'T HAVE ANY HIGH-RISK BUT
WE DO HAVE THE REWARD FOR
SUPPORT FOR SHARED DATA
INFRASTRUCTURE AND IMPROVE
SURVIVORSHIP FOR PATIENTS.
THERE IS A WEALTH OF DATA.
CAIRO, FOR EXAMPLE, WE MEET
EVERY MONTH AND SHARE
KNOWLEDGE AND PEER SUPPORT FOR
EACH OTHER.
WE CAN USE THOSE CLINICAL
SITES AS A LIVING LABORATORY
TO BOTH TEST INTERVENTION AND
ASK THE RIGHT QUESTIONS AND
THEN ALSO WHEN WE HAVE NEW
DATA TO DEPLOY THE NEW
KNOWLEDGE INTO CLINICAL CARE
AND Dr. SEMLER WILL TALK IN
SECTION FOUR ABOUT THIS WHICH
IS UNIQUELILY STUDYING THIS
POPULATION.
IT IS A COMPLEX PROBLEM BUT
SEEING THE PATIENTS IN A
CLINICAL SETTING IS THE FOCUS
IN VERY FEW CENTERS AND I WILL
END THERE.
THANK YOU FOR YOUR ATTENTION
AND LOOK FORWARD TO THE REST
OF THE SECTION.
>>THANKS SO MUCH CARLA FOR A
FANTASTIC TALK.
WE WANTED TO USE THIS TALK TO
SET THE STAGE FOR WORKING WITH
THE CLINICAL SYNDROME AND YOU
DID THAT NICELY FOR US.
I WILL REACH OUT TO MY
COMODERATOR AND DO WE HAVE ANY
QUESTIONS IN THE CHART?
>>WE'RE STARTING TO GET A
LITTLE BIT.
I WANT TO ENCOURAGE PEOPLE TO
USE THE CHAT FOR AN ADDITIONAL
CHANNEL IN THINKING ABOUT THE
ITEMS AVAILABLE TO THE REPORT.
I WILL START WITH THIS ONE,
WHY IS THIS YOUR PROBLEM?
SHOULDN'T PRIMARY CARE RESOLVE
THIS?
CAN YOU TALK ABOUT PRIMARY
CARE?
>>YES, THANK YOU FOR ASKING.
THIS HAS ACTUALLY BEEN LOOKED
AT, FOR EXAMPLE, IN EUROPE,
THAT HAS A MORE ROBUST MIAMI
MAYOR CARE INFRASTRUCTURE TO
WORK ON SURVIVORSHIP
PARTICULARLY AFTER SENSE SIS
BY COORDINATING PRIMARY CARE
PHYSICIANS AND HAS SOME
PRIMARY CARE PHYSICIANS TO
HELP WITH THE OUTCOMES OF
QUALITY OF LIFE.
IN THE U.S., AND THROUGHOUT
OTHER COUNTRIES, WE DO NOT
HAVE A VERY ROBUST PRIMARY
FIGURES INFRASTRUCTURE.
TYPICALLY IN THE U.S. MANY
PEOPLE DON'T HAVE A PRIMARY
PHYSICIAN AND IF THEY DO WE DO
NOT GIVE THEM ANY MONEY,
RESEARCH, TIME.
AND I AM OFTEN ASKED ABOUT
WHAT IS NECESSARY FOR A
POST-ICU CLINIC AND IT IS TO
HAVE ONE PERSON WHO CARES
ABOUT THIS PROBLEM.
ICU IS A CLINICAL
SUBSPECIALTY, WE WALK INTO A
ROOM AND GO WE NEED TO TIE
THAT UP AND THOSE THINGS ARE
INVISIBLE TO SOMEONE WHO IS
NOT ROUTINELY IN THE ICU.
AND EVEN IN A PRIMARY CARE
CLINIC, THEY MAY ONLY SEE A
HANDFUL OF SURVIVORS OVER THE
YEAR SO BUILDING UP THAT
CLINICAL RECOGNITION AND
EXPERTISE AND KNOWLEDGE, I
REALLY SPEND MOST OF TIME TIME
RESEARCHING ABOUT POST-ICU
PROBLEMS SO I FEEL WELL
QUALIFIED TO ADVICE PATIENTS
AND FAMILIES ABOUT POST-ICU
TREATMENT, ET CETERA.
BUT EVEN IF MY OWN POST-ICU
CARE SPECIALTY, I HAD A
PROBLEM WITH ONE OF MY
COLLEAGUES IN PULMONARY
MEDICINE, WE SAW HER AFTER HER
CRITICAL ILLNESS AND SHE SAID
I DON'T KNOW WHO TO ASK ABOUT
THIS BUT LIKE MY HAIR IS
FALLING OUT SINCE I WAS IN THE
ICU AND I WAS LIKE YES AND MY
COLLEAGUE WAS LIKE I DON'T
KNOW AND I AM LIKE YES, THIS
IS ONE OF THE THINGS WE KNOW,
LET'S TELL HER ABOUT IT AND
ADVICE VIES HER.
AND I WAS ABLE TO UNIQUELY DO
THAT.
I WAS ABLE TO GET HER THE
GERMAN STUDY FROM THE GROUP
YEARS AGO AND THESE ARE ALL
PRIMARY CARE FOLKS AND I ASKED
THE RESEARCHER DID YOU CONTROL
FOR HOW MUCH PRESSOR SOMEBODY
IS ON AND WE ALL KNOW A
TRICKLE IS DIFFERENT FOR TWO
DIFFERENT PATIENTS AND THEY
ALL JUST LOOKED AT ME AND LIKE
WHY DOES MA MATTER SO THAT IS
WHY WE ALL NEED TO BE IN THE
ROOM AND ASKING THE RIGHT
QUESTIONS AND BE AVAILABLE TO
PATIENTS TO ANSWER THOSE
QUESTIONS.
>>AWESOME, CARLA.
WE'RE STARTING TO GET SOME
QUESTIONS THAT WILL LIKELY
START A FULL DISCUSSION.
FOR THOSE WHO DON'T KNOW ME, I
AM A HUGE FAN OF PRIMARY CARE
AND WHAT WAS FANTASTIC IN AN
OPEN FORUM WILL NOT APPEAR ON
THE RECORD WHILE LAUREN WAS
SPEAKING SO IT IS LOVELY TO
WELCOME CARLA SEVIN AND
INTRODUES JAMES JACKSON.
JIM IS TOO NOISE TO MENTION
THIS SO I WILL MENTION HE HAS
A PATIENT ORIENTED BOOK ON
RECOVERY FROM LONG COVID OUT
NOW OR WITHIN A MONTH OR TWO,
ABOUT A WEEK OR TWO.
I AM STILL WAITING FOR MY
COPY, I HAVE ALREADY
PREORDERED AND THIS IS NOT
OFFICIAL OF COURSE BUT JIM
JACKSON, THE FLOOR IS YOURS.
>>YEAH, THANK YOU, JACK.
GOOD TO BE HERE WITH ALL OF
YOU.
NEXT SLIDE, PLEASE.
I AM GLAD TO TALK ABOUT THE
MOVIE.
FIRST REALLY WANTED TO THANK
KIRSTEN AND I NOTICE THAT
QUITE A FEW PEOPLE FROM OUR
ICU GROUP ARE HERE TODAY,
LOVELY TO SEE YOU AS WELL AND
REALLY GREAT TO BE HERE.
I DON'T USUALLY WEAR A TIE.
I WORE A TIE TODAY AND THERE
IS A LITTLE BIT OF A BACK
STORY.
I WAS AT GOOD WILL WHERE I
LOVE TO SHOP AND THERE WAS A
THANKSGIVING TIE WITH TURKEYS.
PROBABLY HARD TO SEE BUT THESE
ARE THANKSGIVING TURKEYS AND I
GOT THE TIE OUT THIS MORNING
AND I THOUGHT GOSH, I CAN'T
WEAR A THANKSGIVING TURKEY TIE
ALTHOUGH IT IS RED, CONTRASTS
WITH BLUE AND ALL THAT KIND OF
THING AND THEN I THOUGHT I AM
GOING TO WEAR THIS
THANKSGIVING TIE BECAUSE IT
REMINDS ME OF GRATITUDE AND AT
THE RISK OF SOUNDING A LITTLE
CHEESEY, IF YOU WILL, I HAVE A
LOT OF GRATITUDE FOR BEING
HERE AND THE WORK WE ARE ALL
DOING TOGETHER, THE WORK TO
PARTICIPATE IN IT AND DO
MEANINGFUL WORK, IT IS REALLY
A GREAT BLESSING AND TO BE
ABLE TO WORK WITH YOU ALL ON
THE CALL PATIENTS REALLY
ANIMATES ME.
AND ONE OF THE THINGS WE NEED
TO ENGAGE HAS TO DO WITH
MEASURING BRAIN DYSFUNCTION IN
SURVIVORS OF CARDS AND THAT IS
WHAT WE WILL TALK ABOUT.
I AM A VERY BIG-PICTURE
THINKER.
WHEN TIM GIRARD AND I WERE
TEAMMATES, IF YOU WILL, WHEN
HE WAS AT VANDERBILT, WE WOULD
OFTEN HAVE CONVERSATIONS AND
HE WAS ALWAYS IN THE DETAILS
AND I WAS ALWAYS NOT IN THE
DETAILS.
SO YOU WILL HEAR A LOT OF
BROAD BRUSH THEMES HERE TODAY
BUT I THINK THEY ARE REALLY
IMPORTANT SO BUCKLE YOUR SEAT
BELT.
WE WILL GO PRETTY FAST.
GOT A LOT OF SLIDES TO COVER.
NEXT SLIDE, PLEASE.
I HAVE NO DISCLOSURES.
NEXT SLIDE, PLEASE.
SO THAT COGNITIVE IMPAIRMENT
IS A PROBLEM AFTER CRITICAL
ILLNESS HAS BEEN WELL
ESTABLISHED.
I HAD A FOOTBALL COACH NAMED
BOB KNIGHT AND IN HIGH SCHOOL,
WE WOULD HAVE THESE TWO A DAYS
AND IT WOULD BE REALLY HOT AND
I WOULD SAY COACH IT IS REALLY
HOT AND HE WOULD SCREAM AT ME
IN A WAY YOU COULD IN THE
80s BUT NOT TODAY, HE WOULD
SAY JACKSON DON'T STATE THE
OBVIOUS AND WOULD GET SO SANG
AGREE WITH ME AND I AM STATING
THE OBVIOUS HERE WHEN I SAY
LONG-TERM COGNITIVE IMPAIRMENT
IS COMMON AFTER CRITICAL
ILLNESS.
WE'RE LESS GOOD AT FIGURING
OUT WHAT THAT MEANS FROM A
FUNCTIONAL STANDPOINT, IF YOU
WILL, AND THAT IS WHAT WE WILL
SPEND A LOT OF OUR TIME ON
TODAY.
NEXT SLIDE, PLEASE.
SO HOW DOES ONE DEFINE
COGNITIVE DYSFUNCTION OR
COGNITIVE IMPAIRMENT?
WHAT TERM DO WE EVEN USE?
IT IS A GREAT QUESTION AND ONE
OF THE PROBLEMS WE SHOULD JUST
ACKNOWLEDGE, NO DEFENSIVENESS
HERE, I MEAN THERE ARE AREAS
IN THE NEUROPSYCHOLOGY ARENA
WHERE WE NEED TO DO BETTER,
GET BETTER.
SO ONE CHALLENGE WE SHOULD
ACKNOWLEDGE HAS TO DO WITH THE
PROBLEM OF COGNITIVE DISPUCKS
AND -- DYSFUNCTION AND THAT IS
DIFFERENT PEOPLE USE DIFFERENT
TESTS AND STRATEGIES.
WHAT ONE PERSON MAY CALL IT
MAY NOT BE IDENTIFIED AS
COGNITIVE IMPAIRMENT BY
SOMEONE ELSE.
BUT IN GENERAL THE WAY WE HAVE
USUALLY DEFINED IT IN THE
CONTEXT OF MOST RESEARCH IS WE
USE A BATTERY OF TESTS -- I
HAVE GOT MANY OF THEM IN MY
OFFICE BEHIND ME -- AND YOU
KNOW IF SOMEONE HAS AN
ABNORMAL PERFORMANCE ON THAT
BATTERY OF OBJECTIVES TESTS,
THEY ARE IMPAIRED, THE WAY WE
THINK ABOUT IT.
AND WE TEND TO THINK OF
IMPAIRMENT IN A VERY BINARY
FASHION, HE EITHER ARE OR
AREN'T AND THAT I THINK IS
PROBLEMATIC.
THERE ARE CLEAR STRENGTHS AND
MEANINGFUL LIMITATIONS IN THIS
APPROACH AND WE'LL TALK ABOUT
THOSE.
YEARS AGO IN MY EARLY DAYS OF
MY CAREER, WE DID A STUDY OF
ADC TRIALS, TIM GIRARD LED IT,
I HAD A LITTLE MAZDA HATCHBACK
AND DROVE IT ALL OVER ALABAMA
AND TENNESSEE AND OCCASIONALLY
MISSISSIPPI, SOMETIMES
INDIANA, ALL OVER THE PLACE,
REALLY, GEORGIA, TO EVALUATE
PATIENTS.
AND ONE DAY THERE WAS AN OLDER
GENTLEMAN IN THE STUDY, I
DROVE UP TO HIS HOUSE, HE
LIVED OUTSIDE CLARKSVILLE AND
HE HAD DONE, I THINK FAIRLY
WELL FOR HIS AGE ON THE
COGNITIVE TEST THAT HE HAD
TAKEN AND AS I PULLED IN TO
HIS DRIVEWAY, KIND OF A
RECIVIL -- RESILIENT WORLD WAR
II VET, NOT MANY OF THOSE LEFT
BUT HE WAS ALIVE, 87, HAD A
SLEDGEHAMMER, WAS STANDING
BEHIND AN OLD SEDAN AND I SAID
MR. JOHNSON, WHAT ARE YOU
DOING AND HE SAID I AM TRYING
TO POUND THE DENTS OUT OF THE
BUMPER IN MY CAR AND I SAID
YOU KNOW PROBABLY NOT A GOOD
IDEA, I CAN HELP YOU OR
WHATEVER AND I SAID WHAT IS
GOING ON AND HE SAID YOU KNOW
I HAD A CAR ACCIDENT, BACKED
INTO A CAR AND STARTED HAVING
A LOT OF CAR ACCIDENTS AND
THAT REALLY STRUCK ME AND
STAYED WITH ME, HIS STORY,
BECAUSE THIS WAS A GENTLEMAN
WHO MAY NOT HAVE BEEN IMPAIRED
ON COGNITIVE TESTING BUT WITH
REGARD TO DAY-TO-DAY
FUNCTIONING, HE WAS AND THIS
IS A PROBLEM WE WILL TALK
ABOUT AND THE PARADOX SHIFT
WE WILL GET INTO, HOW TO LOOK
AT COGNITIVE TESTING.
SO WHAT DO CURRENT APPROACHES
TO COGNITIVE TESTING DO WELL?
THERE ARE SOME THINGS THEY DO
WELL.
THEY ARE REALLY GOOD AT
DESCRIBING HOW DIFFERENT AN
INDIVIDUAL'S PERFORMANCE IS
THAN IT IS EXPECTED TO BE.
SO THERE IS THE JOHN Q.PUBLIC
PATIENT BASED ON THEIR
DEMOGRAPHICS, THIS IS HOW THEY
ARE SUPPOSED TO DO WITHIN
THESE NORMS AND IF THEY FALL
WITHIN THAT RANGE, WE WILL
CALL THEM NORMAL AND IF THEY
FALL OUTSIDE, WE WILL CALL HIM
THIS DISPARATE.
THIS APPROACH WORKS VERY WELL
DETERMINING HOW SOMEONE IS
WITHIN EXPECTED NORMS.
THE OTHER THING IT DOES IS
IDENTIFY THINGS THAT THE
INDIVIDUAL DOES WELL.
THE OTHER THING THE APPROACH
IS GOING TO DO IS DO WELL
HIGHLIGHTING RELATIVE
STRENGTHS AND WEAKNESSES.
IT WILL SHOW JOHN AND JAME
DOUGH ARE GREAT AT PROCESSING
SPEEDS, LESS GOOD AT EXECUTIVE
FUNCTIONS, MAJOR PROBLEMS WITH
WORKING MEMORY, IT WILL SHOW
THE STRENGTHS AND WEAKNESSES
AND CHARACTERIZE CHANGE OVER
TIME.
OFTEN WE DO STUDIES AT THREE
MONTHS, SIX MONTHS, 12 MONTHS,
TWO, THREE YEARS AND OFTEN
TIME CHARACTERIZE THEM BY
THESE APPROACHES.
NEXT SLIDE.
BUT THERE IS A DOWN SIDE.
THIS KIP CALL BATTERY BASED
APPROACH DOES SOME THINGS
SOMEWHAT LESS WELL AND THOSE
ARE THAT COMMON COGNITIVE
TESTS OFTEN FAIL TO RESPOND TO
REAL WORLD CHALLENGES AND
SITUATIONS IN THE WAY WE MIGHT
HOPE THEY DID.
I AM HOLDING IN MY HANDS, HAD
NOT THOUGHT OF USING THIS TOP,
THIS IS A FANCY APPARATUS AND
BASICALLY WHAT YOU DO IS MOVE
THESE DISKS -- I AM VIOLATING
SOME RULES HERE.
YOU MOVE THESE DISKS IN A
PARTICULAR WAY, IN A
PARTICULAR SEQUENCE AND THAT
IS GOING TO TELL ME HOW GOOD
YOU ARE AT PLANNING, THAT IS
THE THEORY.
AND THE POWER TEST AS FAR AS
COGNITIVE TESTS GO IS PRETTY
GOOD AT BEING PREDICTIVE BUT
STILL A STEP AWAY FROM THE
REAL WORLD.
SO THIS BATTERY BASED
APPROACH, WHILE SOMETIMES
LOVELY, IS PERHAPS NOT AS
PREDICTIVE OF PERFORMANCE THAT
IS WE MIGHT LIKE IT TO BE OF
FUNCTION.
AND YOU KNOW WE HAVE HAD A
REVOLUTION THAT IS ONGOING AND
IS LOVELY OF INTEGRATING
PATIENTS INTO THE WORK THAT WE
DO, IT IS LONG OVERDUE, NEED
TO DO BETTER BUT WE'RE HEADING
IN THE RIGHT DIRECTION AND
WHEN YOU TALK TO PATIENTS
ABOUT IMPAIRMENT, THEY ARE NOT
CONCERNED ABOUT COGNITIVE
IMPAIRMENT, THEY ARE CONCERNED
ABOUT COGNITIVE IMPAIRMENT IN
THE TERMS OF FUNCTION,
FUNCTION IS ALL THEY CARE
ABOUT.
SO THE COGNITIVE TESTS
PREDICTOR FAIL AT FUNCTION AND
THE GREATEST CONCERN FOR
PATIENTS S-R NOT IMPAIRMENT
BUT IT IS FUNCTION.
CURRENT APPROACHES, THE OTHER
COMMENT I WOULD MAKE, TREAT
IMPAIRMENT AS ALL OR NOTHING
AND I WOULD MAKE KIND OF A
GENERATIONAL BROAD BRUSH
COMMENT HERE ABOUT THE
EVOLUTION OF THE WORK IN
COGNITIVE IMPAIRMENT OF ICU
SURVIVORS, IT USED TO BE IN
2001, 2, 3, 4, 2010 EVEN, MONA
HOPKINS WOULD GO TO A MEETING
AND SAY 30 PERCENT OF THE
PEOPLE WEREN'T THERE OR 20 OR
40 AND PEOPLE WOULD SAY WOW,
THAT IS AMAZING, THERE WOULD
BE ALL THESE OOS AND AHS AND
PEOPLE WOULD BE IMPRESSED BY
THAT.
IN 2023 WE NEED TO MOVE BEYOND
SIMPLY REPORTING FOR THE 47TH
TIME, WOW, COGNITIVE
APPROACHES NEED TO MEASURE
PEOPLE WHO ARE IMPAIRED.
WE NEED TO UNDERSTAND
IMPAIRMENT IMPACTS PEOPLE
DIFFERENTIALLY AND THINK HARD
OF THIS.
OH MY GOSH, SPEAKER HAS FOUR
MINUTES REMAINING.
SO IT COULD BE HOW WELL YOU
NOVEMBER BAIT THE TIME YOU
HAVE.
SO MILD COGNITIVE IMPAIRMENT
PLUS A FEW RESOURCES IN THE
CONTEXT OF HIGH RESILIENCE
EQUALS SIGNIFICANT FUNCTIONAL
IMPAIRMENT.
SIGNIFICANT COGNITIVE
IMPAIRMENT AND SUBSTANTIAL
RESOURCES EQUALS RELATIVELY
MILD COGNITIVE IMPAIRMENT.
NEXT SLIDE, PLEASE.
AND THE IMPAIRMENT VARIOUS
DRAMATICALLY.
IMPAIRMENT DURING A
DEVELOPMENTAL TRAJECTORY IN A
YOUNG ADULT IS SOMEWHAT MORE
IMPACTFUL THAN IN SOMEONE WHO
IS 92, PERSONS WORKING IN
COGNITIVELY DEMANDING JOBS
VERSUS JOBS THAT ARE SIMPLE
AND REPETITIVE.
IMPAIRMENT IN PEOPLE IN
INDIVIDUALIST AND COLLECTIST
JOBS, VERY DIFFERENT.
NEXT SLIDE, PLEASE.
IS COGNITIVE IMPAIRMENT DENINE
OR CONCERNING?
WE NEED TO FIGURE THIS OUT.
NEXT, SLIDE PLEASE.
I SAW A PATIENT, VERY
ACOMMUNITY, SAID I DON'T NEED
COGNITIVELY HABILITATION, MY
PLAN IS JUST TO HIRE A
FULL-TIME 14/7 PERSONAL
ASSISTANCE.
SO THERE IS SOMETHING CALLED
THE BEST KEPT SECRET FESTIVAL,
I GUESS IT WOULD HELD IN
JUNE 2013, I DIDN'T GO BUT
NOURISH KICK COL GEE'S --
NEUROPSYCHOLOGY'S SECRET, NEXT
SLIDE PLEASE, IS IN THE
CONTEXT OF NEUROPSYCHOLOGICAL
HITTING THE WALL.
NEXT SLIDE PLEASE.
OFFENSIVE LINEMEN NEVER RUN
40 YARDS YET IT IS THE
CORNERSTONE OF THE NFL
COMBINE.
WHY IS THAT?
DOESN'T SEEM LIKE WE NEED TO
KNOW HOW FAST AN OFFENSIVE
LINEMAN RUNS 40 YARDS WHEN HE
ONLY RUNS 5 YARDS.
NEXT SLIDE.
THE POINT IS WE NEED TO FOCUS
LESS ON THIS BINARY ALL OR
NOTHING CLASSIC APPROACH
TESTING USING THINGS LIKE THE
POWER TEST AND FOCUS MORE ON
MEASURES WHERE THEY GENERALIZE
TO THE REAL WORLD.
NEXT SLIDE, PLEASE.
I AM SKIPPING A FEW THINGS
HERE.
TIME FOR A PARADIGM SHIFT.
THIS IS TOMMY KOOMBS, WROTE WE
NEED A PARADIGM SHIFT.
NEXT SLIDE, PLEASE.
WE NEED TO FIGURE OUT CAN YOU
OPERATE A BACKHOE?
NEXT SLIDE, PLEASE.
ARE YOU FIT TO DRIVE?
NEXT SLIDE, CAN YOU CALCULATE
YOUR TAXES?
CAN YOU FIGURE OUT COMPLEX
FINANCIAL DATA?
NEXT SLIDE.
CAN YOU WORK ON AN ASSEMBLY
LINE?
THIS IS LUCY AND ETHYL HERE IF
YOU REMEMBER.
CRITICALLY CAN YOU REPORT
SURGERY.
CARLA REFERENCED A DOCTOR,
DIDN'T KNOW THE TIME OR THE
PRESIDENT.
DO WE WANT HIM TO DO SURGERY?
I DON'T THINK SO.
DOES THAT MEAN HE CAN'T DO
ANYTHING?
I DON'T THINK SO.
NEXT SLIDE, PLEASE.
CAN YOU MANAGE A COMPLEX
MEDICATION REGIMEN?
I AM JUST ABOUT OUT OF TIME SO
WHAT IS THE POINT I WOULD MAKE
HERE?
THE POINT I WOULD MAKE HERE IS
WE NEED TO SHIFT OUR FOCUS
FROM THE TRADITIONAL COGNITIVE
TESTS TO REAL WORLD OVERTURES
WHERE WE FIGURE OUT WHEN YOU
GO TO THE GROCERY STORE, HOW
DO YOU NAVIGATE.
WHEN YOU ARE IN YOUR CAR
DRIVING, HOW DO YOU MANAGE
THAT, WHEN YOU ARE IN SOCIAL
SITUATIONS, HOW DO YOU DO WITH
THAT AND THIS IS WHERE WE WILL
MEASURE A MEANINGFUL PARADIGM.
IF I FOLLOW A PATIENT IMPAIRED
IN A GROCERY STORE WITH A
LEGAL PAD AND GIVE HIM
INSTRUCTIONS AND I AM CAREFUL
TO NOTE WHAT HE DID AND DIDN'T
DO IN FOLLOWING THOSE
INSTRUCTIONS, HOW DO YOU
TRANSLATE THAT INTO A SCORE?
SO THE GAPS HERE ARE WE ARE
GREAT AT MEASURING COGNITIVE
IMPAIRMENT USING NEUROPSYCH
TECHNOLOGY.
WE ARE LESS GOOD THOUGH AT
MEASURING FUNCTION BECAUSE
TESTS DON'T NECESSARILY DO
THAT.
THE HIGH RISK HIGH REWARD
OPPORTUNITIES IS TO SHIFT
THEIR PAID DIME ENTIRELY AND
BEGIN TO FOCUS ON FUNCTION
USING NOVEL TOOLS AND
TECHNIQUES GETTING AT WHAT IS
HAPPENING IN THE REAL WORLD --
PARADIGM.
THANK YOU FOR YOUR ATTENTION.
>>THANK YOU, TERRORIST JACKS
SOP.
AMAZING AND A TRULY IMPRESSIVE
AMOUNT OF WORK COVERED IN THE
LAST FOUR MINUTES THERE.
IN THE ONE MINUTE WE HAVE
REMAINING, I HAVE A QUESTION
FROM THE CHAT.
PERHAPS FUNCTIONAL EVALUATIONS
BETTER RELATE TO TREATMENT
STRATEGIES.
SO THIS WILL BE SPECIFIC TO
BIOLOGY SO I CAN PAIR FRAYS.
DO WE KNOW WHETHER THE
COGNITIVE TEST OR FUNCTIONAL
TESTS ARE REFLECTIVE OF
BIOLOGY?
>>THAT IS A GREAT QUESTION.
I DON'T KNOW IF WE KNOW THAT.
I THINK WOULD HE DO NEED TO
FIGURE THAT OUT.
I THINK WE KNOW THE FUNCTIONAL
TESTS ARE WHAT THE PATIENTS
THEMSELVES GRAVITATE TO, BUT
WHETHER THEY REFLECT BIOLOGY
BETTER, I DON'T THINK WE
NECESSARILY KNOW.
>> AND OF COURSE THE
FASCINATION WITH ALZHEIMER'S,
COULDN'T HELP BUT SEE SOME
COMPARISONS HERE.
SO DOCTOR JACKSON, THANK YOU.
NEXT WE HAVE Dr. CONNOLLY,
SURVIVORSHIP OF CRITICAL ILL
PATIENTS AND CLINICAL
METHODOLOGY AROUND
REHABILITATION AND
INTERVENTION AND AS WELL AS
THAT STUFF, FINDING OUTCOMES
AND RETRO DUESABLE OUTCOMES
AND FINDING PATIENTS TO
REVERSE THESE OUTCOMES.
THANK YOU VERY MUCH.
>>THANK YOU FOR BEING A PART
OF THIS MEETING FOR THE NIH IN
WHAT I WOULD CALL A WORKSHOP.
SO YES, I AM DELIGHTED TO TALK
ABOUT MEASURING MUSCLES AND
FUNCTIONS.
IF YOU CAN SEE MY SLIDES?
>>WE CANNOT.
WHAT WE CURRENTLY SEE IS
WINDOWS DISPLAY MANAGER.
>>OKAY, THAT IS MORE LIKE IT.
THANK YOU VERY MUCH.
NEXT SLIDE, PLEASE.
I HAVE A COUPLE OF DISCLOSURES
BUT NONE OF THEM ARE RELEVANT
TO TODAY'S PRESENTATION.
NEXT SLIDE, PLEASE.
NEXT SLIDE.
THANK YOU.
LET'S START WITH WHAT DO WE
KNOW AROUND MEASURING MUSCLE
FUNCTION.
NEXT SLIDE PLEASE.
THESE WILL NOT BE UNFAMILIAR
TO ANYONE ON THE CALL AND
THESE ARE SELECT EXAMPLES OF
SURVIVORS WHO EXPERIENCED
PRONOUNCED AND PROTRACTED
PHYSICAL IMPAIRMENT AND SOME
OF THE WORK DONE AROUND FIVE
YEARS WHERE YOU HAVE THREE
QUARTERS OF THE COGNITIVE
FACTORS AND HERE LOOKING AT
THE SAME TWO MEASURES, AT THE
TOP I STRESS THE MUSCLE
STRENGTH IN THE SCORE.
JUST TO KEEP IN MIND THE
BARRIERS TO RECOVERY AS YOU
SEE ACROSS THESE THREE
DIFFERENT SECTIONS, THE MUSCLE
STRENGTH KIND OF PALES IN
RECOVERY.
AND THEN IN THE MOST RECENT
GROUP WHERE IT HAS BEEN
CHARACTERIZED WITH THE
PHENOTYPES, WHETHER THAT HAS A
PHYSICAL IMPAIRMENT AND WHAT
THEY SAW IS PHYSICAL
IMPAIRMENT WAS NOT EVIDENT IN
ALL CASES BUT IN CERTAIN
SUBTYPES AND I GUESS ONE OF
THE THINGS I HAVE LEARNED IN
THIS STUDY BETWEEN THE MUSCLE
STRENGTHS AND THE FISCAL
FUNCTIONS OUTCOMES THERE.
NEXT SLIDE, PLEASE.
SO IF WE KNOW THIS PHYSICAL
IMPAIRMENT EXISTS, WHAT ARE WE
PRETTY SURE OF.
NEXT SLIDE, PLEASE.
AND WE CAN BE PRETTY CERTAIN
MUSCLE FUNCTION HAS SOMETHING
TO DO WITH THIS AND THIS GRAPH
IS VERY ELEGANT IN SUMMARIZING
ALL THE PROBLEMS WE SEE IN A
TYPICAL MECHANIC CANNISTIC
LEVEL THAT EXPLAINS
NEUROMUSCULAR IMPAIRMENT WE
SEE IN PATIENTS AFTER CRITICAL
ILLNESS.
NEXT SLIDE, PLEASE.
SO IF WE THINK MUSCLE HAS
SOMETHING TO DO WITH IT AND IT
PROBABLY DOES, HOW GOOD ARE WE
AT MEASURING MUSCLE FUNCTION
IN CRITICALLY-ILL PATIENTS?
NEXT SLIDE, PLEASE.
AND THEN COMMON TECHNIQUES AND
MANY ON THE CALL WILL BE
FAMILIAR WITH THE WAYS WE
MEASURE MUSCLE FUNCTION SO
STARTING IN THE RIGHTHAND
CORNER OF THE SCREEN, YOU SEE
THE SEE THE ULTRASOUND VIEW --
[INDISCERNIBLE]
AND ON THE RIGHTHAND SIDE
THERE, THE MUSCLE BIOPSY DATA,
SOME PERIPHERAL MUSCLE BUT THE
MUSCLE DATA EXISTS AND WE ARE
ABLE TO LOOK AT BIOLOGY TO SEE
EXACTLY WHAT IS HAPPENING TO
THE MUSCULAR STRENGTH.
ON THE RIGHTHAND SIDE IS THE
GRAPH OF MUSCLE TESTING AND
THIS IS OFTEN MISDIAGNOSED AND
CLEARLY ONE OF THE MAIN AREAS
HEEDING TO BETTER-- LEADING TO
BETTER OUTCOMES FOR
PATIENTS --
[INDISCERNIBLE]
AND FINALLY IN THE BOTTOM
CORNER THERE YOU CAN SEE SOME
OF THE TABULATION DATA LOOKING
AT MUSCLE SOURCE AND CAPACITY
AND ABLE TO TAKE FROM IC
PATIENTS AND MEASURE WHAT WAS
THE DENSITY OF MUSCLES.
SO WE HAVE SEEN FOUR DIFFERENT
APPROACHES, THEY HAVE THEIR
PROS AND CONS, SOME OF THEM
HAVE.
[INDISCERNIBLE]
, CAVEAT OF BEING ABLE TO USE
ALL OF THEM, NEXT SLIDE,
PLEASE.
AND WHAT WE ARE PRETTY SURE IS
NONE IS COMPLETELY FIT FOR
PURPOSE TO TELL US THE
RELATIONSHIP BETWEEN MUSCLE
FUNCTION AND PHYSICAL
FUNCTIONING IN OUR PATIENTS
AND WE HAVE HEARD ALREADY THE
PHYSICAL FUNCTIONING IS THE
ABILITY TO DO SOMETHING WHICH
REALLY HEARTS TO PATIENTS THAN
ANY ISOLATED MEASUREMENT OF
FUNCTION.
AND SO THE CHALLENGES OF
CURRENT APPROACHES, THEY ALL
PROVIDE SOME DATA ON ISOLATED
ASPECT OF MUSCLE FUNCTION BUT
THEY DON'T NECESSARILY
INTERRELATE OR WHAT WE ARE
MEASURING, DO WE KNOW WHAT
THAT MEASUREMENT MEANS.
AND--
[INDISCERNIBLE]
AND IN ORDER TO BE ABLE TO
TEST THE PATIENTS ACCURATELY.
DO EACH OF THE MEASURES
CORRELATE WITH THE OTHERS.
THE GIRLIZE-ABILITY, WHAT IS
THAT ACROSS PATIENTS AND WE
WILL PICK THAT UP IN ONE OF
THE NEXT SLIDES.
YOU CAN APPRECIATE THE
DIFFERENCE BETWEEN MUSCLE
TESTING, NO EQUIPMENT REQUIRED
TO DO SOME OF THOSE QUICK
STUDIES AND WHETHER THAT IS
USEFUL FOR RELIABLE AND SOME
OF THE DATA WE GET FROM THE
STUDIES, DO WE HAVE A
TREATMENT PLAN, WHICH MUSCLE
SHOULD WE BE TESTING.
IT IS GREAT WE CAN TAKE LOVELY
PICTURES LOOKING AT RIGHT OR
LEFT SIDE, UPPER OR LOWER
LIMB, ANTIGRAPHY MUSCLES, LEFT
OR RIGHT, HO DO WE KNOW ONE
MUSCLE REPRESENTS THE OVERALL
MUSCLE STRENGTH FOR EVERY
PARTICULAR TASK WE WANT TO USE
THAT MUSCLE FOR?
HOW DO WE ATTACH THE RESULTS
AND BY THAT I MEAN WHAT IS
MEANINGFUL FOR THE PATIENT.
MEASURING WHAT WE THINK WE'RE
MEASURING AND DO WE EVEN KNOW
WHAT THAT MEASUREMENT MEANS?
DO WE REALLY UNDERSTAND WHAT
THAT MEASURE TELLS US AND WHAT
THAT MEANS AND WHAT TO DO WITH
IT.
HOW MUCH ARE WE MEASURING
DEFICITS ACQUIRED IN THE ICU?
WE DON'T OFTEN HAVE A BASELINE
SO HOW DO WE KNOW WHAT NEW
DEFICITS ARE ACQUIRED IN THE
ICU?
AND DO EACH OF THE
MEASUREMENTS CORRELATE WITH
THE OTHERS?
IF WE SAY THEY HAVE LOST
20 PERCENT AS A FINDING, DO WE
KNOW HOW THAT TRANSLATES TO
MUSCLE LOSS AND IS IT
GENERALIZABLE ACROSS PATIENTS.
NEXT SLIDE, PLEASE.
SO THE ANSWER IS TO MEASURE
MUSCLE BETTER, NEXT SLIDE,
PLEASE.
AND CURRENTLY THE ANSWER IS
NO.
IT IS NICE TO HAVE MUSH
FUNCTIONING BUT NOT ALWAYS
HELPFUL AND WHY IS THAT?
BECAUSE PATIENTS DON'T
PRIORITIZE MUSCLE STRENGTH.
THIS COMES FROM A CONSENSUS
PROCESS ASKING PATIENTS TO
RATE OUTCOMES OF IMPORTANT IN
RELATION TO PHYSICAL REHAB AND
74 PERCENT OF THEM RATED
MUSCLE FUNCTION VERSUS
100 PERCENT RATED PHYSICAL
FUNCTIONS AS IMPORTANT AND
WHY?
BECAUSE MUSCLE FUNCTION ON ITS
OWN IS NOT MEANINGFUL AND
DOESN'T TRANSLATE INTO A
PATIENT ABLE TO DO SOMETHING
ON HIS OWN.
AND MUSCLE FUNCTION DOES NOT
EQUAL PHYSICAL FUNCTION
BECAUSE THERE ARE MANY OTHER
THINGS THAT ARE REQUIRED
BESIDES MUSCLE FUNCTION,
BALANCE, MOTIVATION,
COORDINATION, SOME OF THE
THINGS WE SOMETIMES CAPTURE
BUT NOT ALWAYS AND ALSO IT
MODIFIES THEIR ADAPTATION TO
THE PATIENT STATUS.
THE PATIENT IS NATURALLY
CLIMATIZING AND SO WE NEED
SUPPORT PATIENTS WITH
ASSISTIVE DEVICES SO THEY CAN
FUNCTION.
AND INCREASING EQUITY IN
ACCESSIBILITY OF THE
ENVIRONMENT.
AND ALSO REPRIORITIZATION OF
PATIENT VALUES IN TERMS OF
WHAT IS IMPORTANT TO THEM.
NEXT SLIDE, PLEASE.
SO.
SO WHAT WE DON'T KNOW, ONE
MEASURE TO TRACK RECOVERY ON
THE CONTINUUM AND IF WE THINK
IT IS IMPORTANT TO HAVE SOME
MUSCLE FUNCTION BUT IF WE
RECOGNIZE IT ISN'T THE ONLY
CONSTRUCT TO PHYSICAL PUCKS,
WE NEED A PHYSICAL FUNCTION
MEASURE TO CAPTURE THAT.
NEXT SLIDE, PLEASE.
SO LET'S CHECK IN TO SEE ARE
WE MEASURING PHYSICAL FUNCTION
RIGHT?
BECAUSE WE HAVE OBJECTIVE AND
SUBJECTIVE MEASURES, THINGS WE
HEAR FROM THE PATIENTS
THEMSELVES AS IMPORTANT BUT DO
WE REALLY FOCUS ON INDIVIDUAL
PATIENT LEVELS?
THEIR PHYSICAL ENVIRONMENT,
THEIR SOCIAL ROLES, INTRINSIC
MOTIVATORS, PERSONAL
CIRCUMSTANCES, WHAT RESOURCES
DO THEY HAVE AND WHAT DOES
GOOD LOOK LIKE IN THE OUTCOME
OF THESE PATIENTS.
WE FOE WHAT IS GOOD BUT IS
THAT THE SAME FOR THE PATIENT?
NEXT SLIDE, PLEASE.
SO WHAT TO DO NEXT?
I THINK THERE IS A MAJOR GAP
IN UNDERSTANDING OR THINKING
AROUND HOW TO DESIGN THE RIGHT
MEASURE AND WHAT DEGREE IN ANY
ONE OF THOSE MEASURES OF
MUSCLE FUNCTION CORRESPONDS TO
A CHANGE AND HOW MUCH IF
PHYSICAL FUNCTION.
WHAT DEGREE OF CHANGE IN
PHYSICAL FUNCTION IS
CLINICALLY AND PERSONALLY
MEANINGFUL FOR AN INDIVIDUAL
PATIENT?
AND THAT COULD BE DIFFERENT
FROM PATIENT TO PATIENT.
AND WHAT PHYSICAL FUNCTION
TASK TO MEASURE, CAN THIS BE
DIFFERENT FOR DIFFERENT
PATIENTS WITHIN ONE MEASURE.
ABILITY TO CAPTURE OTHER
DOMAINS.
NEXT SLIDE, PLEASE.
AND THEN FINALLY A STUDY FOR
THE FUTURE WHICH WE'RE VERY
GRATEFUL FOR AND WHAT I WOULD
SUGGEST WE LOOK AT.
THIS HAS COME IN THE LAST
FIVE, TEN YEARS OR SO, WHERE
WE CAN VIEDIZE THE THRESHOLDS
FOR EACH PATIENT IN TERMS OF
CONTROL, INTERVENTION AND
OUTCOMES.
I AM NOT SURE WE HAVE MUCH FOR
A TRIAL ON THE PATIENT TO
ASSESS BUT LET'S USE THAT AS
WHETHER THEY HAVE A POSITIVE
CHANGE IN CONTRIBUTION.
SO THAT CHANGE IS DETERMINED
BY THEIR PERSONAL VALUES,
SOCIAL ROLES AND PHYSICAL
ENVIRONMENT.
SO WE MOVE THAT TO MEASURES
WHERE THEY HAVE AN ADJUSTED
DIFFERENCE SO THANK YOU VERY
MUCH FOR YOUR TIME.
>>THANK YOU DO CONNOLLY, THAT
WAS A FANTASTIC TALK AND ALSO
RESULTED IN A LOT OF
DISCUSSION AND QUESTIONS IN
THE CHAT SO THANK YOU SO MUCH
FOR GETTING US STARTED ON THE
MEASUREMENT FOCUS OF EACH
SESSION AND I WOULD LIKE TO
START WITH ONE QUESTION --
ACTUALLY THERE ARE SEVERAL BUT
I WILL START WITH ONE QUESTION
FROM THE CHAT WHICH ACTUALLY
CAME FROM MY COMODERATOR,
Dr. IWASHYNA.
AT THE PRESENT TIME
SHOW'MUSCLE LOSS AND THE
MODERATION ACROSS GROUPS.
>> GREAT QUESTION.
I THINK WE HAVE FOCUSED ON
MUSCLES THAT ARE EASY TO GET
TO AND EASY TO MEASURE AND
THEY ARE NORMALLY LARGE
DEFINED MUSCLES TO BEGIN WITH
SO WHEN WE WERE STARTING TO
GET EXCITED TO TAKE PICTURES
OF MUSCLES, THEY WERE EASY TO
GET TO AND EASY TO TAKE
PICTURES OF.
I DON'T THINK WE SEE ALL OF
THE SAME MUSCLE TYPES IN THE
SAME PATIENTS AS WELL AND
THERE WILL BE HUGE VARIABILITY
IN ONE PATIENT AND ACROSS
MULTIPLES OF PATIENTS SO WE
REALLY NEED A CONTROL WHERE WE
CONTROL THE MEASURES AND THAT
CAN BE GREAT AT COMPARING.
COMPARING PATIENTS IN THE BET
NEXT TO EACH OTHER IS REALLY
DIFFICULT BECAUSE THEY DON'T
KNOW WHAT THAT MEANS IN TERMS
OF WHAT THEY CAN DO
AFTERWARDS.
WE SEE PATIENTS WHO SIT UP ON
THE SIDE OF THE BED AND OTHERS
HAVE THE LOOKED AND LOADED
MUSCLES WHO SURPRISE US IN
ENGAGING IN THERAPY AND OTHER
UTILIZATION.
SO IT IS ONE OF THE CAVEATS TO
THE MEASURES, IT IS HELPFUL IN
THAT IT ALLOWS US TO EXAMINE
MUSCLES A LITTLE MORE BUT
DOESN'T NECESSARILY MEAN ONE
MUSCLE REFLECTS ALL THE
OTHERS.
>>THANKS, AND THEN THAT ALSO
RAISES AN IMPORTANT POINT
WHICH TE RRI BROUGHT UP IN THE
CHAT, THOSE ARE THE MOST
MUSCLE MASS MAY LOSE THE MOST
BUT ALSO HAVE THE GREATEST
POTENTIAL FOR RETURN TO
BASELINE AND RECOVERY.
>>AND SO IT SORT OF DEPENDS
ON WHAT PATIENTS COME IN WITH.
BUT ALSO PATIENTS WHO HAVE
CHRONIC DISEASE HAVE ALSO
ADAPTED TO NOT HAVING
COMPLETELY FUNCTIONAL MUSCLES
FOR LACK OF A BETTER TERM SO
THEY CAN REPORT DIFFERENTLY
BECAUSE THEY HAVE CLIMATIZED
AND ADAPTED.
>> AND THEN I ACTUALLY --
THAT IS A GREAT SEGUE INTO A
QUESTION I HAD FOR YOU WHICH I
THINK WE WILL END UP TALKING
AGAIN DURING THE PANEL
DISCUSSION BUT IN IN OUR WORK
WITH OLDER ICU SURVIVORS, WE
FOCUS ON ACTIVITY BECAUSE
GERIATRIC STUDIES HAVE SHOWN
FOR MANY YEARS THAT OLDER
PATIENTS VALUE FUNCTION AS A
PRIORITY AND SEEMS LIKE THAT
IS BEING SEEN IN PATIENTS ALL
AGES.
SO ARE YOU SUGGESTING WE
SHOULD BE SUGGESTING SERIAL
MEASURES AND FUNCTIONAL
ACTIVITIES ALONG WITH MEASURES
IN MUSCLE STRENGTH?
I DON'T WANT TO HAVE YOU JUMP
AHEAD BUT KIND OF WHAT I WAS
GATHERING FROM YOUR SLIDES.
>>NO, I THINK YOU ARE RIGHT
AND I THINK WHAT THAT MEASURE
IS WILL BE DIFFERENT FOR
DIFFERENT PATIENTS ACCORDING
TO AGE, WHAT THEIR PERSONAL
INTERESTS OR PERSONAL STATUS
IS SO ABSOLUTELY AND I THINK
THOSE ARE THE KIND OF THINGS
THAT MATCH TO PATIENTS AND
REGARDLESS OF YOUR AGE, YOU
STILL WANT TO BE INDEPENDENT.
WHAT YOUR PAST WAS WITH OTHER
PATIENTS, YOU MAY DIFFER BUT
YOU WANT TO GET BACK TO WORK
OR SIMPLY THE GARDEN OR JUST
TO GET AROUND AND BE
INDEPENDENT, THAT MAY VARY BUT
BEING ABLE TO MATCH THAT TO
THE PATIENTS AND INTERVENTION
FOR THAT IS IMPORTANT
ABSOLUTELY.
>>ABSOLUTELY AND WE WANT TO
MAKE SURE WE COME BACK TO THE
POINT ABOUT ADAPTATION DURING
THE PANEL DISCUSSION BECAUSE
ULTIMATELY PATIENTS ADAPT TO
OUTCOMES AND THAT DIFFERS WITH
EQUIPMENT VERSUS AT HOME.
SO THANK YOU SO MUCH, THAT WAS
FANTASTIC.
I AM NOW GOING TO INTRODUCE
OUR LAST SPEAKER IN SECTION 1,
Dr. JASON FA LVEY, ASSISTANT
PROFESSOR IN THE DEPARTMENT OF
PHYSICAL THERAPY AND
REHABILITATION STKAOEUPBZ AND
DEPARTMENT OF 'EM DEEM I DON'T
GO AND PUBLIC HEALTH TESTIFY
UNIVERSITY OF MARYLAND SCHOOL
OF MEDICINE.
HE HAS DEVOTED HIS YEAR TO
INCLUDE HIGH QUALITY AGING IN
PLACE FOR OLDER ADULTS
RECOVERING FROM ILLNESS AND
INJURIES.
HE IS THE SECOND EVER PHYSICAL
THERAPIST TO BE FUNDED BY
EMERGING LEADERS CAREER
DEVELOPMENT FROM THE NIA AND
ALSO SUPPORTED BY RESEARCH
GRANTS FROM NHLBI AND I AM
PROUD TO SAY HE IS A FORMER
MENTEE OF MINE AND DELIGHTED
HE IS SPEAKING IN THIS SESSION
SO THANK YOU FOR BEING HERE,
CAPTAIN WAIT TO HEAR FROM YOU.
>>HUMBLED BY THE INTRODUCTION
AND THANK Dr. JACKSON FOR
STARTING US OFF WITH THAT
WONDERFUL TIE.
REALLY EXCITED TO TALK ABOUT
THE SO MANY DETERMINANTS OF
HEALTH AND HOW THAT INFLUENCES
RORY FROM ACUTE RESPIRATORY
DISTRESS SYNDROME.
I THINK IT TIES IN WITH SO
MANY OF THE THINGS YOU HAVE
HEARD FROM THE SPEAKERS AND I
HOPE I HAVE DO JUSTICE IN
PULLING THESE THINGS TOGETHER.
NEXT SLIDE.
DISCLOSURES IN FUNDING, NONE
PARTICULARLY RELEVANT IN THIS
TALK.
MY HAIR LOS IS NOT CAUSED BY
CRITICAL ILLNESS BUT IS
INTENTIONAL.
NEXT SLIDE, PLEASE.
LET'S TALK ABOUT SOCIAL
DETERMINANTS OF HEALTH AND
WHAT WE REALLY MEAN IS WE ARE
ALL TALKING ABOUT THE SAME
LANGUAGE.
THIS GRAPHIC FROM THE 2030
INITIATIVE, I WANT TO POINT
OUT EDUCATIONAL ACCESS AND
QUALITY TRANSLATES DIFFERENTLY
FOR PATIENTS AND WHERE DO WE
FIND RESOURCES?
HEALTHCARE ACCESS AND QUALITY
IS HUGELY IMPORTANT AND Dr.
SEVIN POINTED THIS OUT EARLIER
IN TERMS OF HOW DO WE GET
PATIENTS INTO THESE CLINICS.
YOUR NEIGHBORHOOD BUILT
ENVIRONMENT WHICH WE HAVEN'T
HEARD A LOT ABOUT AND I WILL
SHARE MORE INFORMATION IN THAT
CONTEXT ON HOW THAT WILL
INFLUENCE YOUR RECOVERY AND
MAYBE INTERSECT MAKING THEM
LESS EFFECTIVE IF WE DON'T
ADDRESS SOME OF THE
CHALLENGES.
AND SOCIAL COMMUNITY CONTEXT,
WE RECOGNIZE THE IMPORTANCE OF
SOCIAL SUPPORT AND WE HAVE
MANY PATIENTS WHO WORK WITH
SURVIVORS IN COMMUNITIES THAT
REALLY BOOST THEM UP AND HELP
THEM FIND RESOURCES AND HELP
SHARE IN THEIR RECOVERY BUT I
WORK WITH SEVERAL PATIENTS ON
THE OTHER HAND WHO LIVE IN
FEAR OF THEIR COMMUNITY AND
SOCIAL NEIGHBORS, MAYBE FEAR
OF VIOLENT CRIME FROM PEOPLE
WHO LIVE IN THEIR
NEIGHBORHOODS SO THAT IS
ANOTHER SIDE OF THE COMMUNITY
CONTEXT TO BE AWARE OF AND HOW
DO WE HELP PEOPLE NAVIGATE
THROUGH THE COMMUNITY WITH
HIGH CRIME AREAS AND THE
ANSWER IS MORE EXERCISE.
ECONOMYING STABILITY IS
SOMETHING WE TALK A LOT IF
WITH CRITICAL ILLNESS.
SO I WILL BRING UP THE
NEIGHBORHOOD LEVEL RISK
FACTORS INFLUENCING DISABILITY
DEVELOPMENT AND RECOVERY.
WE KNOW IT NEEDS SOCIAL
SUPPORT BUT ALSO NEEDS
INTERVENTIONS TO BE HELPFUL.
NEXT SLIDE, PLEASE.
SO LET'S TELL A TALE OF TWO
RECOVERIES.
JIM, HOSPITALIZED FOR 17 DAYS,
MECHANICALLY VENTILATED, HAS
DELIRIUM, SIGNIFICANT
ICU-ACQUIRED WEAKNESS, MAY
HAVE MORE THAN 20 PERCENT
WHICH Dr. CONNOLLY WAS
MENTIONING AND MAYBE WAS FRAIL
WHICH IS A CERTAIN RISK
FACTOR.
BUT THEN THERE WAS MARVIN WITH
THE SAME LEVEL OF
HOSPITALIZATION, TWO PATIENTS
IDENTICAL IN TERMS OF THEIR
MEDICAL INFORMATION.
NEXT SLIDE.
SAY JIM LIVES IN CENTRAL PARK,
A SUPPORTIVE SPOUSE AND
SEVERAL PAID CAREGIVERS AND
FINANCIALLY WEALTHY TO PAY FOR
WHATEVER SUPPORTS HE NEEDS,
TAXIS, FINANCIAL SUPPORT.
AND GOES TO ONE OF THE
HOSPITALS IN NEW YORK.
CONTRAST THAT WITH MARVIN WHO
LIVES IN RURAL NORTHERN MAINE,
SOCIALLY ISOLATED AND MEDICAID
ELIGIBLE, LIVES NEAR A PAPER
MILL AND WITH THE POLLUTION
HAS DIFFICULTY BREATHING WHEN
HE IS OUTSIDE, NEXT SLIDE.
SO THE IMPLICATIONS OF POOR
SOCIAL CONNECTEDNESS, THERE IS
A 29 PERCENT INCREASE IN RISK
FOR CORONARY HEART DISEASE AND
INCREASE IN DEVELOPING
DEMENTIA IN PEOPLE WITH POOR
SOCIAL NETWORKS AND THESE
PATIENTS HAVE HIGHER RISK OF
DEVELOPING ADL DISABILITY OVER
SIX YEARS SO SOCIAL ISOLATION
AND LONELINESS IN OLDER
ADULTS.
SO HOW DO WE USE MEASURING
SOCIAL CONNECTIONEDNESS AS A
DRIVER, NEXT SLIDE, PLEASE.
WE ARE PRETTY GOOD AT
CONNECTING WITH FRIENDS AND
FAMILY.
WE OFTEN ASK IF PEOPLE HAVE A
PARTNER, ASK ABOUT FRIENDS OF
SOCIAL SUPPORT BUT DON'T OFTEN
ASK ABOUT CONNECTIONS WITH THE
COMMUNITY AND IF WE DO IT IS
MORE CONVERSATIONAL AND NOT
WITH EXECUTION.
NEXT SLIDE, PLEASE.
AND THAT MIGHT BE A MISSED
OPPORTUNITY -- SORRY, NEXT
SLIDE -- BECAUSE THIS SCORE OF
0 TO 6, 6 BEING THE MOST EYES
HATED SO WHEN WE DO THAT, WE
RECOGNIZE PEOPLE HOSPITALIZED
IN THE ICU ARE MUCH MORE
LIKELY TO DIE FOLLOWING THEIR
ADMISSION, IF WE CAN GO BACK
TO THAT GRAPH, PLEASE, THANK
YOU.
THEY ARE MUCH MORE LIKELY TO
DIE IF THEY ARE SOCIALLY
ISOLATED.
YOU CAN SEE THERE IS ALMOST A
PRO-FOLD INCREASE IN MORTALITY
BETWEEN THE MOST SOCIALLY
INGRADUATED, PEOPLE WITH THE
MOST SOCIAL SUPPORT, AND
PEOPLE WHO ARE MOST EYES LAID
AND -- ISOLATED AND THAT
DOESN'T JUST RELATE TO
MORTALITY.
AS SOCIAL EYESIZATION
INCREASES, THERE IS A INCREASE
IN CRITICAL ILLNESS.
THAT CAN BE THE DIFFERENCE
BETWEEN SOMEBODY GETTING IN
AND OUT OF THE SHOWER WHICH IS
A MAJOR SOURCE OF INDEPENDENCE
FOR ADULTS AND PROCESS NOT
TICK OF FUTURE
INSTITUTIONALIZATION, OTHER
OUTCOMES FOR OLDER ADULTS.
NEXT SLIDE, PLEASE.
BUT THIS IS MODIFIABLE.
WE KNOW WE CAN AFFECT THOSE BY
INTERVENING IN COMMUNITY
STAKEHOLDERS TO ADOPT
INTERVENTIONS, PEER SUPPORTS,
HELPING CONNECT PATIENTS WITH
SOCIAL SERVICES ACROSS THE
COUNTRY, LIKE TRANSPORTATION,
SENIOR COMPANION SERVICES LIKE
ARE OFFERED IN PREDATOR TO
HELP BRIDGE THESE SOCIAL MEETS
AND NOT JUST FOR QUALITY OF
LIFE, TO ALSO HELP THEM
PARTICIPATE IN RESTORATIVE
CARE TO IMPROVE PHYSICAL AND
COGNITIVE FUNCTION.
NEXT SLIDE, PLEASE.
BUT ALSO ECONOMIC STABILITY
GETS IN THE WAY OF SOME OF
THESE WELL MEANING
INTERVENTIONS.
WE DEVELOPED CLINICAL TRIALS
AND OFTEN FORGET PEOPLE HAVE
TO WORK TO RETURN THEIR
INCOME.
THEY MAY NOT HAVE INSURANCE
COVERAGE TO FULLY PARTICIPATE
AND IT COSTS A LOT TO GO TO
MEDICAL APPOINTMENTS, SOME
LIMPING IN RURAL ENVIRONMENTS
HAVE TO TRAVEL SEVERAL HOURS
TO GET TO YOUR MEDICAL CARE.
AND EQUIPMENT THAT IS ADAPTIVE
TO DISABILITY IS OFTEN NOT
COVERED SO THERE IS A LOT OF
FINANCIAL COSTS THAT
CONTRIBUTE TO THIS ECONOMIC
STABILITY BEYOND DIRECT
EMPLOYMENT.
NEXT SLIDE, PLEASE.
AND THESE FINANCIAL BURDENS
DEFINITELY IMPACT FROM THE
PERSPECTIVE OF PATIENTS AND
LIMIT MUSCLE AND BRAIN
RECOVERY.
ONE PATIENT POINTED OUT THEY
DIDN'T HAVE RECOVERY SERVICE
BECAUSE THEY DIDN'T HAVE
INSURANCE.
I HAVE BEEN MY OWN RECOVERY
SERVICE AND NOT SURE HOW TO
PROMOTE BRAIN AND MUSCLE
OUTCOMES AND EVEN IF THEY HAVE
INSURANCE, IT MAY BE FAIRLY
BRIEF.
NEXT SLIDE, PLEASE.
AND POVERTY ISN'T A NEGATIVE
INCOME BY ITSELF, IT IS ALSO
LIKELY TO INCREASE AFTER A
DISABILITY WITH ICU
HOSPITALIZATION.
A STUDY BY JAIN SHOWING
INCREASE IN ELIGIBILITY FOR
MEDICAID.
PEOPLE WHO ADD MEDICAID AT
EVERY LEVEL OF ICU DISABILITY
ELEVATED AT POST-ICU
DISABILITY AND WHAT I DON'T
PRESENT IN THIS PRESENTATION
IS ALSO HIGHER ODDS OF
DEVELOPING COGNITIVE
IMPAIRMENT LATER ON DOWN THE
ROAD SO VERY TROUBLING
POVERTY.
AND WE'RE NOT GOING TO GIVE
PEOPLE MONEY AS PART OF OUR
INTERVENTION BUT WE DEFINITELY
HAVE TO TAKE THIS INTO ACCOUNT
AND HELP BRIDGE SOME OF THESE
UNMET NEEDS.
NEXT SLIDE, PLEASE.
WE ALSO KNOW OUR PATIENTS
DON'T LIVE IN THE SAME AREAS
OR HAVE THE SAME LEVEL OF
NEIGHBORHOOD AND SOCIAL
RESOURCES.
SO THE NEIGHBORHOOD BUILT
ENVIRONMENT IS A HUGE
CONTRIBUTOR TO DISABILITY
AFTER CRITICAL ILLNESS.
NEXT SLIDE, PLEASE.
THIS PHOTOGRAPH WHICH WAS
TAKEN ACTUALLY IN BALTIMORE IS
ONE OF THE REASONS WHY WE
MIGHT KNOW THAT DISABILITY
DEVELOPED DURING ICU STAYS IS
LESS LIKELY TO RESOLVE IN
LOW-INCOME NEIGHBORHOODS.
OUR SIX MINUTE WALK TEST IS
NOT TRANSLATEIVE TO THIS TYPE
OF ENVIRONMENT BUT WE HAVE
PATIENTS WHO NEED TO WALK TO
GET TO LIKE THE GROCERY STORE
OR OTHER PLACES.
NEXT SLIDE, PLEASE.
THAT MIGHT EXPLAIN WHY THERE
IS A 10 TO 15 PERCENT INCREASE
IN DISABILITY BURDEN OVER A
YEAR AFTER THE ICU STAY.
EVEN AFTER MECHANICAL CALL
DISABILITY, A LOT OF OTHER
FACTORS, CAN BE SEEN UNDER
NEIGHBORHOOD BUILT SITUATIONS.
AND IF YOU LIFE IN A LOW
INCOME NEIGHBORHOOD, YOU ARE
MORE LIKELY TO DEVELOP
COGNITIVE IMPAIRMENT.
NEXT SLIDE, PLEASE.
NEIGHBORHOOD LEVEL FACTORS ARE
ASSOCIATED WITH GREATER
COGNITIVE DECLINE AND ME
CLINICAL NEUROLOGICAL
DEGENERATION IN ADULTS BIKE
ALD HYPER'S DISEASE.
AND MOMENT ENVIRONMENTS ARE
ALSO A MAJOR CONTRIBUTOR TO
DISABILITIES.
SO HOME ENVIRONMENTS LIKE
CAPABLE WHICH INTERVENE LIKE
PAYING A HANDYMAN TO DO
MODIFICATIONS AND PERSONALIZED
COACHING ON WAYS TO GET AROUND
FISCAL INTERVENTIONS AND HAVE
DIFFERENT APPROACHES IN ACTIVE
LIVING ARE A MODEL FOR HELPING
ADL SURVIVORS.
AND THIS WORK EXPLORES THE
UNMET NEEDS SPECIFIC TO OLDER
CRITICAL ILLNESS SURVIVORS,
UNDERSTANDING TAILORING TO THE
POPULATIONS AND HOW TO MOVE
TOWARDS THAT.
SO YOU MAY BE FAR FROM BEEN
ABOR, MAINE WHICH IS --
BANGOR MAINE WHICH, NEXT
SLIDE, THE HOSPITAL MAY BE IN
PORTLAND, MAINE.
SO IF YOU HAVE TO TRAVEL MORE
THAN A HUNDRED MILES FOR POST
ICU CARE, YOU ARE LESS LIKELY
TO HAVE FOLLOW UP CARE AND
THEN PEOPLE WHO LIVE FARTHER
OUT ARE LESS LIKELY TO HAVE
INTERNET ACCESS.
SO WHEN BEE THINK ABOUT WHAT
PEOPLE NEED TO GET TO PLACES
WHERE THEY NEED
TRANSPORTATION, NEARLY 700,000
OLDER ADULTS IN URBAN AREAS
RELINE ON PUBLIC
TRANSPORTATION AND HAVE
BARRIERS TO ATTENDING MEDICAL
APPOINTMENTS.
IF YOU LIVE IN AN AREA WITH
BROKEN SIDEWALKS, FOR EXAMPLE,
THEY ARE 65 PERCENT LESS
LIKELY TO REPORT TO MEDICAL
APPOINTMENTS.
NEXT SLIDE, PLEASE.
SO WHEN WE TALK ABOUT HOW TO
ADDRESS SOCIAL DETERMINANTS OF
HEALTH AND ARDS WITH
INTERVENTION FOR DELIVERING
HELP TO ARDS SURVIVORS, WE
HAVE TO HAVE A BETTER WAY OF
DETECTING AND ASKING THE
QUESTIONS ABOUT HEALTH
DISPARITIES, VULNERABLE
POPULATION FACTORS AND
UNDERSTAND THE NEIGHBORHOODS
WHERE THEY LIVE.
WE HAVE TO UNDERSTAND THE
DISPARITY AT SEVERAL LEVELS,
NOT JUST THE INDIVIDUAL LEVEL
BUT THE LEVEL OF THE
HEALTHCARE SYSTEM, HOW WELL IS
THE HEALTHCARE SYSTEM EQUIPPED
TO DEAL WITH THESE NEEDS AND
THEN WE HAVE TO HAVE
INTERVENTIONS TO REDUCE THE
DISPARITIES.
NEXT SLIDE, PLEASE.
SO THE SUGGESTION WOULD BE TO
QUEEN FOR THESE FACTORS IN THE
E MR.
IT CAN'T BE SOMETHING WE CHART
FOR AND WE HAVE TO IDENTIFY
THE SUBGROUPS EITHER THROUGH
CLINICAL INTERVENTION OR USING
STATISTICAL METHODS AND
UNDERSTANDING HOW THEY
INTERACT WITH SYSTEMS, OFFER
SUPPORTS NOT ONLY INDIVIDUALLY
BUT ADVOCATE FOR POLICY CHANGE
DOWNSTREAM.
SO WHAT DO WE NEED TO KNOW?
WE NEED TO KNOW IF ARDS
INTERVENTIONS THAT ADDRESS
SOCIAL DETERMINANTS OF HEALTH
ARE MORE EFFECTIVE.
IF WE GIVE THE SAME
INTERVENTIONS TO JIM AND
MARVIN IN A CLINICAL TRIAL AND
EXPECT THE SAME OUTCOMES
BECAUSE THEY ARE MEDICALLY THE
SAME, WE ARE REALLY BEING
SHORTSIGHTED IN TERMS OF WHAT
IS INFLUENCING PEOPLE FOR
RECOVERY.
SO WE NEED TO KNOW IF WE CAN
ADD SOME OF THESE PIECES IN
AND IN A WAY THAT PRODUCE
SOCIAL ENHANCED OUTCOMES.
SO HIGH RISK HIGH REWARD
INNOVATION, WE NEED TO DEVELOP
AND EVALUATE MULTICOMPONENT
INTERVENTIONS.
TO MAKE SHE IS SUCCESSFUL, YOU
HAVE TO HAVE PERSON-CENTERED
OUTCOMES RESEARCH MODELS WITH
STAKEHOLDER ENGAGEMENT AND
PRACTICE-BASED RESEARCH MODELS
TO FIGURE OUT HOW TO TRAPS
LATE INTO CLINICAL MODELS AND
THAT ARE ADAPTABLE AND
FLEXIBLE LIKE DO CONNOLLY
MENTIONED TO MAKE SURE WE'RE
GETTING OUT TO PATIENTS AND
GETTING AT TRUE BARRIERS OF
THE INDIVIDUALS AND NOT JUST
THE PHYSICAL IMPAIRMENTS WE
NEED TO ADDRESS.
SO WITH THAT I WILL END IT
THERE TO LEAVE PLENTY OF TIME
FOR DISCUSSION, I AM GRATEFUL
FOR THE INVITATION AND LOOK
FORWARD TO HEARING YOUR
QUESTIONS.
>>THANK YOU, SQUARES SON,
THAT WAS A FANTASTIC TALK.
THANKS SO MUCH.
SO WE ACTUALLY DO HAVE SEVERAL
QUESTIONS IN THIS CHAT AND I
AM GOING TO -- WE'RE GOING TO
ACTUALLY KICK OFF THE PANEL
DISCUSSION BUT I WILL ASK ONE
OF THE OTHER QUESTIONS.
Dr. CONNOLLY WHO SPOKE
EARLIER IN THE SESSION WANTED
TO HIGHLIGHT DOING THE
6-MINUTE WALK AND EVEN IN THE
BUILT CORRIDOR LIKE WE TALKED
ABOUT IS NOTHING LIKE THE REAL
WORLD.
SO THINKING ABOUT PRAGMATIC
REAL WORLD FOLLOW UP, PIVOTING
ON THIS IDEA, HOW DO YOU SEE
THAT HAPPENING, JASON?
SO WE'RE GOING TO PROBABLY
STILL DO THAT SIX-MINUTE WALK
BUT SHOULD WE BE ADDING
SOMETHING ELSE TO THAT
MEASURE?
WHAT DO YOU SEE PRAGMATIC REAL
WORLD FOLLOW-UPS LOOKING LIKE
AND I HAVE ANOTHER RELATED
MEASUREMENT QUESTION BUT WE'LL
START WITH THAT FIRST.
>>THAT IS A GREAT QUESTION
AND CLINICALLY WHAT I DO IS I
OFTEN MEASURE PARTICIPATION,
LIFE-SAVING MOBILITY, HOW
OFTEN ARE PEOPLE GOING OUT IN
THE COMMUNITY, HOW MUCH HELP
DO THEY NEED SO THAT PROMPTS
KNEE AND A DIFFERENT QUESTION
VERSUS THE PERSON WHO HAS MORE
STRENGTH AND NOT GOING OUT,
THAT TELLS ME THAT THE
INTERVENTIONS WOULD BE
DIFFERENT.
SO MAYBE EXPLORE THE
MISMATCHES OF CAPACITY VERSUS
WHAT THEY ARE ACTUALLY DOING
IS I THINK A REALLY VALUABLE
TOOL.
SO NOT REPLACING THE
SIX-MINUTE WALK WHICH IS
INCREDIBLE VALUABLE AND GIVES
YOU GREAT INSIGHT BUT ADDING A
MEASURE IN, TRANSLATING TO
GETTING OUT OF THE HOUSE AND
DOING STUFF.
>>OKAY, THANK YOU.
SO SPECIFIC TO YOUR TALK, FROM
Dr. MOSS, ARE THERE SOCIAL
DETERMINANT FACTORS THAT ARE
SPECIFIC INTO ICU OR ARDS
SURVIVORS WITH SOCIAL
DETERMINANT FACTORS WITH ARDS
DISEASE.
>>THAT IS A GREAT QUESTION
AND I MIGHT DEFER TO THOSE WHO
ARE IN THE GROUP WHO ARE
PHYSICIANS AND HAVE THOSE
EXPERIENCES BUT I WOULD SAY
THE DETERMINANTS OF PERSONS
WITH SIMILAR LOSS OF FUNCTIONS
TEND TO BE SIMILAR.
HIP FACT SURE, HEART FAILURE,
CRITICAL ILLNESS, HAVING
POVERTY, YOU KNOW, ON TOP OF
HAVING A DIVERT YACHT TICK
ABILITY -- GERIATRIC ABILITY
AND HAVING POVERTY MAKES IT
WORSE.
SO THE MEDICAL FACTORS WILL
DRIVE IT AND THEN THERE WILL
BE A INTERSECTION BETWEEN
MEDICAL FACTORS AND SOCIAL
VULNERABILITY THAT MAGNIFIES
THE EFFECTS.
SO IT IS NOT AS CLEAN CUT A
THING.
THERE IS A SPECIFIC ONE FOR
EACH CONDITION.
I DON'T SEE IT AS
CONDITION-SPECIFIC.
I TEND TO BE MORE DYING
FEDERAL GOVERNMENT TICK IN
THINKING ABOUT CATASTROPHIC
LOSS OF FUNCTION AND HOW
POVERTY OVERPLAYS THAT.
>>THANKS JASON AND KIND OF TO
THAT END, THIS PIVOTS BACK TO
THE MEASUREMENT QUESTION I
HAD.
WE TALKED ABOUT CAPTURING
MUSCLE STRENGTH AND DISABILITY
AND TALKED ABOUT COGNITIVE
MEASURES BUT YOU JUST
HIGHLIGHTED THE IMPORTANCE OF
SOCIAL DETERMINANTS OF HEALTH
AND SPECIFIC NEIGHBORHOOD
DISADVANTAGE SO SHOULD WE BE
CAPTURING CODE DATA OR ADI IN
OUR STUDIES FOR CRITICAL
ILLNESS?
>>THAT TOOL IS AVAILABLE AND
EASY TO MATCH TO ADDRESSES SO
BEING LOW BURDEN, ABSOLUTELY I
THINK WE SHOULD USE IT.
I THINK THE QUESTION IS DO
CLINICIANS KNOW WHAT TO DO
WITH THE NUMBER?
BUT I THINK OUR SOCIAL WORK
ALL RIGHT INTEGRATES THAT KIND
OF INFORMATION IN
DECISION-MAKING BUT DOESN'T
FACTOR INTO RESEARCH AND I
THINK THAT IS THE BIG BARRIER.
LIKE PEOPLE WHO USE PUBLIC
TRANSPORTATION AND I KNOW THE
SIDEWALK IS ALL BROKEN AND SO
I HAVE THAT DEEPER LEVEL OF
UNDERSTANDING ACROSS SEVERAL
STUDIES TO AT LEAST CATCH
PEOPLE IN EXTREME POVERTY,
20 PERCENT OF NEIGHBORHOODS,
WE'RE ALL URBAN REGARDLESS OF
NEIGHBORHOODS, YOU ARE GOING
TO HAVE MORE DIFFICULTY
ACCESSING HIGH QUALITY THERE.
>>THANKS, JASON, AND A GREAT
QUESTION AND FOLLOW UP TO THE
CONVERSATION WHICH WE WILL
SAFE FOR THE PANEL DISCUSSION
SINCE WE'RE NOW TO THE BLOCK
OF TIME FOR THE PANEL.
SO FOR THE NEXT FEW MINUTES, I
GUESS NOW FOUR, I WILL
SYNTHESIZE WHAT WE HAVE
LEARNED IN SECTION 1 AND THEN
WE'RE GOING TO MOVE TO A PANEL
DISCUSSION THAT JACK AND CAN I
WILL MOT RATE.
WE HAVE ALREADY MAPPED OUT
SOME REALLY IMPORTANT
QUESTIONS AND THANKS TO ALL OF
YOU FOR SENDING THOSE TO US
FOR SPARKING DISCUSSION AND
THOUGHT.
SO FIRST, MANY THANKS TO Dr.
SEVIN, CONNOLLY AND JACKSON
FOR A FANTASTIC STEP TO THE
FIRST SESSION IN THIS
CONFERENCE.
TO THINK ABOUT SOME DEEP
POINTS RAISED IN THE FIRST
SESSION, I WILL RUN THROUGH
SOME OF THEM.
I THINK STARTING OUT THAT WE
WANT TO ANCHOR OUR DISCUSSION
AND PATH FORWARD IN PATIENT
STORIES AND THANK YOU AGAIN
CARLA FOR REALLY HAVING US
UNDERSTAND THAT.
ONE SENTENCE THAT CARLA SAID
THAT STOOD OUT TO ME, ONLY THE
IC AND REHAB PEOPLE
UNDERSTAND.
AND I THINK CARLA'S CALL FOR A
PATH FORWARD, THAT WAS ONE OF
THE POINTS THAT SHE MADE WHICH
WAS IN THINKING ABOUT THE
NEEDS FOR THE FUTURE OF THIS
WORK, THERE ARE A FEW
DIFFERENT ASPECTS OF THIS.
SO FIRST THINKING ABOUT BETTER
INFRASTRUCTURE FOR CONDUCTING
THESE STUDIES AND ALTHOUGH
RIGHT NOW THAT HAS FOCUSSED A
LOT TO DATE ON THE ICU AND
REHAB PEOPLE WHICH ARE A LOT
OF PEOPLE IN THIS ROOM, WE MAY
ALSO WANT TO THINK ABOUT
EXPANDING INFRASTRUCTURE,
INFORMATION AND PRIMARY CARE
RESOURCES TO THE COMMUNITY.
AND TALKING ABOUT RECENT
ACCESS, ANOTHER KEY POINT THAT
CAME OUT IN THE SESSION AND
CHAT TO THE DISCUSSION WAS
EXPANDING REACH IN UNDERSERVED
COMMUNITIES AND ALTHOUGH THAT
WAS THE POINT, AS I READ THAT
AND THOUGHT ABOUT THAT MORE, I
REALIZED THERE ARE ACTUALLY A
COUPLE OF SPECIFIC POPULATIONS
WE MAY WANT TO THINK ABOUT
MORE PROPERLY AS WE MOVE
FORWARD AND THAT INCLUDES
UNDERSERVED COMMUNITIES BUT
ALSO RURAL COMMUNITIES THAT
ARE FARTHER AWAY FROM MAJOR
MEDICAL CENTERS AND ALSO
SPECIFIC POPULATIONS AND I DO
HAVE TO PUT IN A PLUG HERE FOR
OLDER ADULTS BECAUSE THEY MAY
HAVE MORE DISABILITIES AND
MOBILITY LIMITATIONS AFTER
CRITICAL ILLNESS THAT MAY
PREVENT THEM FROM COMING TO A
RECOVERY PROGRAM SUCH AS THE
FANTASTIC ONE AT VANDERBILT.
SO THINKING ABOUT THOSE
SPECIFIC POPULATIONS.
IN TERMS OF MEASUREMENT, I
THINK WE HAVE BEEN CHALLENGED
WITH THINKING ABOUT HOW THE
TESTS WE'RE USING SOMETIMES
FAIL TO CORRESPOND TO REAL
LIFE SITUATIONS AND
CHALLENGES.
AND JIM DID A WONDERFUL JOB IN
HIGHLIGHTING THIS.
AND A POINT THAT ALSO CAME UP
IN BRONWEN'S TALK.
HOW DO WE KNOW THAT IT
TRANSLATES TO MUSCLE STRENGTH
AND ABILITY TO DO A DESIRED
TASK, VERY IMPORTANT.
SO WE FOCUS ON THE VALUE AND
HOW TO THINK ABOUT THE DESIGN
OF FUTURE STUDIES TO CONSIDER
THAT AND ALSO WHICH WE WILL
TALK ABOUT IN THE PANEL, HOW
PATIENTS CAN ADAPT AND MAY
ADAPT TO WHAT THEIR OUTCOME
GOAL IS.
AND THEN I THINK ADDING IN THE
ELEMENT OF SOCIAL DETERMINANTS
OF HEALTH, BOTH IN TERMS OF --
AND ACTUALLY I DON'T WANT TO
CALL THESE -- I THINK THEY ARE
VERY DIFFERENT FACTORS IN THIS
VERY BROAD CATEGORY SO
THINKING ON THE ONE END OF
CRITICAL FACTORS SUCH AS
SOCIAL SUPPORT AND SOCIAL
ISOLATION, WOULD HE KNOW THIS
IS IMPORTANT.
WE ARE NOT CURRENTLY
SYSTEMATICALLY CAP COOPERING
THIS IN OUR STUDIES AND
SOMETHING WE NEED TO THINK
ABOUT MOVING FORWARD BECAUSE
IT MAY BE RIGHT FOR
INTERVENTION.
I HAVE A PATIENT WHO IS A ARDS
COVID SURVIVOR, HAS SEVERE
IMPAIRMENTS AND ACTUALLY COMES
FROM AN UNDERSERVED COMMUNITY
BUT HAS SUCH STRONG SOCIAL
SUPPORT FROM HIS FAMILY THAT A
YEAR OUT HE HAS RECEIVED
FUNCTIONAL HEALTH RECOVERY,
MENTAL HEALTH RECOVERY, BACK
AT WORK PART-TIME, 67 AND
STILL WORKS, AND HAS A BIT OF
A MILD COGNITIVE IMPAIRMENT.
SO THESE IMPAIRMENTS CAN
OVERCOME, PEOPLE CAN RECOVER
WITH THINKING ABOUT HOW
IMPORTANT SOCIAL SUPPORT IS
AND THEN OF COURSE THE
COGNITIVE BARRIERS THAT WAS
HIGHLIGHTED IN THIS TALK.
SO I HAVE NOW SPOKEN MY FIVE
MINUTES AND DON'T WANT TO GO
OVER TIME SO THIS WILL BE A
GOOD TIME TO SEGUE INTO THE
PANEL DISCUSSION AND TURN IT
OVER TO JACK.
>>THIS COULD BE AWESOME BUT
WE HAVE SEVEN HOURS WORTH OF
THINGS THAT WE NEED TO TALK
ABOUT COMPRESSED IN 23 MINUTES
SO THAT MEANS AT SOME LEVEL,
THERE ARE FIVE BROAD STATIC
AREAS WE NEED TO COVER AND
THINK ABOUT AS A FOUR MINUTE
TALK CYCLE.
EVERY TIME ONE OF THOSE FIVE
MINUTE NUMBERS COMES UP, WE
SHOULD BE MOVING ON.
SO LET'S START WITH -- THERE
ARE A WHOLE BUNCH OF QUESTIONS
ASKING WHAT THE NEXT
GENERATION MEASUREMENT LOOKS
LIKE, WAYS SORT OF BRINGING
TECHNOLOGY TO DO IN VIVO, IN
PEOPLE'S HOMES, MEASUREMENTS
OF HOW THEY ARE DOING AND I
THINK THERE COULD BE A LOT OF
ENTHUSIASM STARTING WITH JIM
AND THEN WHAT YOU THINK YOUR
NEAR HORIZON LOOKS LIKE FOR
NEXT GENERATION MEASUREMENTS.
>>YEAH, I AM SURE.
I WILL BE QUICK.
I THINK THAT'S EXACTLY THE
RIGHT AVENUE THAT WE NEED TO
BE WALKING DOWN, THAT IS
EITHER IN VIVO OR SOME KIND OF
VIRTUAL REALITY WHICH DOES
EXIST.
IT IS CUMBERSOME STILL AND
SORT OF IN DEVELOPMENT BUT
EVEN VIRTUAL REALITY LIKELY
CAPTURES REAL WORD FUNCTIONS
BETTER THAN WHAT WE USED.
THERE ARE SOME COGNITIVE TESTS
DEVELOPED IN THE UNITED
KINGDOM WHICH HAVE A SLIGHTLY
DIFFERENT APPROACH.
THEY HAVE YOU EXPLICITLY WORK
ON REAL WORLD COGNITIVE PATHS
THAT MIMIC REAL WORLD
COGNITIVE PATHS SO I THINK
THAT IS HELPFUL.
I THINK OTHER THINGS WE NEED
TO THINK ABOUT WOULD BE
LOOKING IT THE WAY WE ENGAUGE
SOCIAL MEDIA, FOR INSTANCE,
ARE THERE CHANGES OVER TIME IN
MISSPELLINGS.
ON TWITTER, ARE THERE CHANGES
IN CONTENT, ON FACEBOOK
POSTINGS, ARE THERE ERRORS IN
TEXTING THAT PEOPLE ARE
STARTING TO ENGAGE IN, THINGS
OF THAT SORT THAT ARE REAL
WORLD.
THIS IS GOING TO REQUIRE
LETTING GO OF AN APPROACH THAT
IS PRETTY COMFORTABLE WHICH IS
THIS AND I AM READY TO DO THAT
AND HOPEFULLY OTHERS WILL
JOIN.
>>ANYBODY WANT TO GO NEXT AND
THEN WE WILL GO TO JASON?
>>THANK YOU, I AGREE.
IT IS A WAY FORWARD TO MEASURE
PHYSICAL FUNCTION, THERE MAY
BE A FEW PRACTICAL ASPECTS TO
CONSIDER IN TERMS OF HOW DO WE
HAVE UP WITH DEVICE THAT
ALLOWS US TO FOLLOW A PATIENT
AROUND IN THEIR ENVIRONMENT,
AND I THINK A SETUP IS
REQUIRED TO MEASURE PHYSICAL
FUNCTION IN THE HOME
DEVELOPMENT WHICH WOULD BE
FANTASTIC AND REAL WORLD
BECAUSE THEN YOU CAN SEE THE
PHYSICAL AREAS THAT IS
IMPACTING THEM AND WE CAN
ADAPT THAT.
I THINK THERE'S SOME PRACTICAL
LOGISTICAL ISSUES AROUND
GETTING TECHNOLOGY IN THERE TO
ALLOW US TO SEE THE WHOLE
ENVIRONMENT EASILY VERSUS SOME
TESTS THAT THEY CAN DO IN ONE
PHYSICAL TEST LIKE SITTING ON
A TABLE OR AROUND THE HOUSE
AND LOGISTICS AROUND IT.
I GUESS USING DIGITAL
COGNITIVE AND HOME HEALTH AND
THINKING ABOUT THE AGE OF THE
POPULATION, THERE ARE STUDIES
FOR PEOPLE WHO ARE OLDER AND
BEING TECH SAVVY AND SO FORTH
BUT YES, I WOULD LIKE TO THINK
OF THAT IN TERMS OF THE MOMENT
ENVIRONMENT.
>>THANK YOU AND WHILE YOU ARE
GETTING READY, I WILL REMIND
PEOPLE THE CHAT IS HIGHLY
VISIBLE AND IS A GREAT PLACE
TO MAKE ADDITIONAL POINTS
SINCE WE ARE NOT GOING TO GET
THROUGH ALL OF THEM IN 25
MINUTES.
GO AHEAD.
>>YES, THANK YOU AND I AGREE
THE DIGITAL TECHNOLOGY HAS SO
MUCH PROMISE AND ARE THE
COMPONENTS MATCHING UP TO WHAT
WE ARE SEEING.
EXTENDING THAT OUT TO THE
COMMUNITY, I HAVE GIVEN A LOT
OF THOUGHT TO USING PS AND
OTHER THINGS AND THEN HOW FAR
ARE FAR ARE PEOPLE GETTING
AWAY FROM THEIR HOME?
ARE THEY MOVING BACK TO PLACES
THEY WANT TO GO BECAUSE I
THINK TOO OFTEN WE ESPECIALLY
TEND TO STOP BEFORE BECOMING
INDEPENDENT OR AMBULATORY,
ONCE YOU CAN WALK 150 FEET AND
OUT THE DOOR, YOU ARE SAID TO
BE ABLE TO MEET ALL OF THEIR
SCORES BUT I DON'T THINK THAT
TRANSLATES WELL TO A PATIENT
WHO HAS TO WALK TWAOUPB
SIDEWALKS I SHOWED -- WALK
DOWN THE SIDEWALKS I SHOWED
YOU AND THEN TO THE BUS STOP.
I THINK TECHNOLOGIES BUT
POLICIES FOR RURAL COMMUNITIES
OR MAKING SURE THERE IS
DIGITAL EQUITY IN LOWER INCOME
NEIGHBORHOODS IN URBAN
DEVELOPMENTS AND SOMETHING WE
CAN DO TO SET PEOPLE UP WITH
DIGITAL DEVICES, I KNOW THE VA
DOES THIS AND DON'T KNOW WHY
WE CAN'T HAVE THAT FOR
EVERYONE.
>>AND --
[INDISCERNIBLE]
CARLA, YOU WANT TO TALK TO GO
NEXT?
>> YES, I WILL SAY WE HAD
MANY IDEAS WHAT WE WERE GOING
TO LEARN FROM THESE CASES AND
WE FOUND SO MUCH LOW-HANGING
FRUIT, LIKE ALL THE CONCRETE
THINGS WE THINK ARE ALREADY
HAPPENING THAT ARE NOT
HAPPENING ARE -- THERE'S JUST
AN ENDLESS AMOUNT OF DATA THAT
WE NEED TO GET IN THIS AREA.
SO I ALSO, WHILE ASPIRING TO
FUTURE TECH, I HAVE TO REMIND
OURSELVES TO LIKE BRING US
DOWN AND WE CAN USE THE TOOLS
WE ALREADY HAVE AND WE CAN USE
THEM IN A DIFFERENT WAY.
SO FOR EXAMPLE EVEN THE
SIX-MINUTE WALK WHICH IS
WIDELY USED, EVEN AT THE
HALLWAY WE ARE' USING TO
WALK-IN CLINIC IS NOT THE SAME
AS THE STREETS THE PATIENT
WILL BE ON BUT WE CAN STARTIZE
AND GET A LOT OF DATA FROM.
WE CAN ALSO AND THIS HAS BEEN
DIFFERENT FOR US IN THE
CLINICAL SETTING, WE CAN USE
IT AS AN INTERVENTIONAL TOOL.
A PATIENT WILL SAY I AM FINE,
GOING BACK TO WORK AND WE WILL
SAY YOUR SIX-MINUTE WALK IS
ONLY 47 PERCENT PREDICTIVE AND
THEY ARE LIKE OH MY GOSH, HOW
CAN I MAKE THAT NUMBER BETTER,
THAT DATA IS VERY MOTIVATING
TO ME AND NOW WE'RE USING THAT
AS AN INTERVENTION TO INCREASE
PHYSICAL THERAPY.
I WILL SAY NOT BEING AN EARLY
ADOPTER OF TECH, THE
TELEMEDICINE VERSION OF
OUTREACH FOR THESE PATIENTS
HAS ALLOWED US TO OVERCOME A
LOT OF BARRIERS AND, YOU KNOW,
RURAL TENNESSEE NO EXCEPTION
IN TERMS OF UNDER RESOURCING
AND WE HAD FEARS WHEN WE
STARTED OUR TELEMEDICINE
PROGRAM AND ADDRESSED IN CHAT,
WE WOULD NOT BE ABLE TO MEET
THE NEEDS OF RURAL
POPULATIONS, WOULD NOT BE ABLE
TO SEE OLDER POPULATIONS
BECAUSE OF THEIR DIFFICULTY
ACCESSING TECH.
BUT GOOD NEWS! THEY SEEM TO
ALL HAVE GRANDCHILDREN AND
FOUND A WAY TO GET ON THE
VISIT AND IF ANYTHING GOOD CAN
BE ASCRIBED TO COVID, THE
FACILITY WITH TELEMEDICINE IS
ONE OF THOSE THINGS.
LIKE WE MOVED FOR YEARS TO GET
A TELEMEDICINE PROGRAM GOING
AND STARTED IT IN
DECEMBER 2019 AND THEN IN
MARCH 2020, WE HAD
TELEMEDICINE OVERNIGHT AND ALL
THE BARRIERS FELL AWAY AND
SOMEHOW WE WERE DOING
TELEMEDICINE.
SO THAT WAS BOTH FRUSTRATING
AND REFRESHING.
SO WE KNOW WE CAN DO HARD
THINGS AND OVERCOME BARRIERS
IF THERE IS WILL AND, YOU
KNOW, FUNDING AND MOTIVATION
TO DO SO.
SO WHILE WE ARE THINKING ABOUT
THESE NEXT-GEN MEASUREMENTS, I
WOULD SAY DON'T THROW AWAY THE
SIMPLE MEASURES WE CAN USE AND
GET A LOT OF INFORMATION FROM
THAT ARE ALREADY AVAILABLE AND
YOU KNOW INCREMENTALLY USE THE
TECH THAT IS AVAILABLE TO
SQUEAK WHAT WE CAN -- TWEAK
WHAT WE CAN DO LIKE TODAY.
>>AWESOME, LOVE YOU GUYS,
SPENT FOUR MINUTES WHICH MIGHT
BE THE SHORTEST SO --
[INDISCERNIBLE]
>>JACK, WE COVERED
TELEMEDICINE SO CAN WE PLEASE
CROSS THAT OFF OUR PLAN?
>> YES.
NEXT ONE ACCIDENT WE TALKED A
LOT ABOUT FIXING MUSCLES IN
BRAINS BUT FOR MANY OF US, OUR
EYES DON'T WORK TERRIBLY WELL
AND IT TURNS OUT INSTEAD OF
RESHAPING OUR EYES, WE HAVE A
UBIQUITOUS FUNCTION THAT
ALLOWS US TO SEE BETTER IN
LIGHT.
WITH THE NIH AND THEIR
DIVERSITY PROGRAM AND MANDATE
TO SUPPORT DISABILITY, HE
CANNABILITY AND WILL INCLUSION
AS OPPOSED TO CORRECTION, HOW
DOES THAT CHALLENGE US TO
THINK ABOUT OUR RESEARCH
AGENDA IN TERMS OF SUPPORTING
DISABILITY WITH REGARD TO
CORRECTIONS?
>>THAT IS A GREAT QUESTION
AND IT STARTS WITH WHO ARE WE
INCLUDING IN RESEARCH AND HOW
ARE WE ADDRESSING SOME OF THE
SUPPORTS LIKE VISUAL
IMPAIRMENTS, DETERIORATING
COGNITIVE AND VISUAL IMPAPERS
AND WITH HEARING IM--
IMPAIRMENTS, AND WITH HEARING
IMPAIRMENTS, ARE WE EXCLUDING
THEM BECAUSE WE KNOW THEY
CAN'T PROVIDE INFORMED CONSENT
OR ARE WE REALLY NOT TRYING
HARD ENOUGH TO GET IT.
SO I THINK IT STARTED FROM OUR
CRITERIA AND THEN MOVED INTO
OUR APPROACH.
IF WE SCREEN FOR THESE THINGS
AND, YOU KNOW, WE CAN EASILY
PUT PATHWAYS IN TO ADDRESS
THEM, MORE PEOPLE WILL FEEL
LIKE THE RESEARCH IS
ADDRESSING THEIR CLEAR
CLINICAL NEEDS AND I THINK
THAT IS WHERE IT STARTS.
I DON'T WANT TO BE LABOR IT
AND I THINK A LOT OF OTHER
PEOPLE HAVE SOME OPINIONS HERE
BUT CERTAINLY THINK FROM A
RESEARCH STANDPOINT, THAT IS
WHERE IT STARTS, AT THE
BEGINNING. TO BRONWEN.
>>YES, THANK YOU, IT IS GREAT
THAT WE HAVE A ENVIRONMENT BUT
THE BEST THING TO DO IS MAKE
SURE THE PATIENT FEELS
CONFIDENT SO IF THEY END UP
NEEDING SOME DEVICE
ASSISTANCE, THAT THE SOCIETY
TO SCALE WILL FACILITATE THAT
FOR THEM AND ESPECIALLY WHEN
THEY START OUT DIFFERENT FROM
WHAT THEIR PRE-ICU STAY WAS.
SO COMING UP WITH A DEVICE
THAT YOU ARE INDEPENDENT ON
IMPACTS FROM A PSYCHOLOGICAL
STANDPOINT HOW YOU FEEL ABOUT
RECOVERY.
SO IT IS GREAT WE HAVE THE
ASSISTANCE BUT NEED TO
REMEMBER THAT AFFECTS THEIR
RECOVERY AS WELL AND THEN WITH
THE INCLUSIVE ENVIRONMENT, WE
CAN PUSH PEOPLE AS MUCH AS WE
CAN TO GET BACK TO THE LEVEL
THEY WOULD LIKE TO GET BACK TO
ESPECIALLY LEAVE IF THE
DISABILITY LOOKS DIFFERENT
THAN WHAT IT LOOKED LIKE
BEFORE SO PUTTING PATIENT
VALUES AND EXPECTATIONS IN
THERE INVOLVED WITH WHAT THEY
WOULD NORMALLY BE DOING AND
HOW WE TRACK THAT AND BOTH USE
THE ABILITY TO, SAY A PATIENT
TALKS WELL BUT TO USE A
DEVICE, DOESN'T MEAN YOU ARE
OFF THE SCALE FOR THAT.
BECAUSE SOMETIMES WE SEE A
WALKING STICK AND SAY WELL
THAT IS GREAT BUT IN SCORING
THESE THINGS, SOMEHOW IT MUST
BE APART FROM INDEPENDENT.
>>BR ONWEN, I WAS GOING TO
COMMENT LATER BUT I WANT TO
FOLLOW UP ON THIS VERY
IMPORTANT POINT OF YOURS.
EVEN WHEN WE'RE MEASURING
DISABILITY STUDIES, YOU ARE
STILL DEPENDENT ON ANOTHER
PERSON TO COMPLETE IT AND AN
ADAPTIVE DEVICES IS EXACTLY
THAT, THAT ALLOWS A PERSON TO
COMPLETE THE TASK AND NOT BE
DISABLED IN IT.
SOMETIMES THEY NEED TO USE IT
TEMPORARY OR SOMETIMES THEY
USE IT LONG-TERM BUT THE THING
IS IT ALLOWS THEM TO COMPLETE
THE TASK WHICH IS SO
IMPORTANT.
SO THERE IS A POSITIVE WAY TO
FRAME THOSE DEVICES AND
PATIENTS MAY HAVE TO
EMOTIONALLY ADAPT TO USING ONE
BUT SOMETIMES IT IS NOT JUST
FOR A MINUTE AND GET THE
PATIENTS TO VALUE.
SO JASON SAYS EXACTLY,
EMPHASIZING IN THE CHAT.
THANK YOU FOR THAT POINT
>>WHEN WE TALK ABOUT
ACCOMMODATION AND
ADAPTATION -- JACK, I AM
SORRY, I CUT YOU OFF.
I WILL BE REALLY QUICK.
THOSE ARE TASKS THAT OFTEN
EXIST IN THE REHABILITATION
ARENA AND I THINK AS A
REMINDER AS WE THINK ABOUT
PARADIGMS, WE NEED TO BE
THOUGHTFUL ABOUT INTRODUCING
EXPLICITLY REHABILITATIVE
APPARENTLY DIMES, PHYSICIANS,
OCCUPATIONAL THERAPISTS,
PEOPLE WHO AREN'T AT THE TABLE
AS MUCH AS WE WOULD LIKE THEM
TO BE IN REHAB.
YES, THE OTHER THING TO KEEP
IN MIND IS REBUILDING BRAINS
AND BODIES BUT THE OTHER THING
WE NEED TO GET BETTER AT IS
COMING ALONGSIDE PEOPLE SAYING
WE WANT THIS OUTCOME FOR YOU
BUT HOW CAN WE HELP YOU HAVE A
MEANINGFUL LIFE EVEN IF YOU
NEVER GET ANY BETTER?
EVEN IF YOUR COGNITIVE
IMPROVEMENT DOESN'T IMPROVE AS
ALL, HOW CAN WE HELP YOU LEAN
INTO YOUR VALUES AND PURSUE A
MEANINGFUL LIFE AND THAT IS AN
IMPORTANT OUTCOME.
IT IS NOT NECESSARILY A WIN,
REPACK BILLATION OR GO HOME,
IT IS HOW CAN WE HELP YOU HAVE
A MEANINGFUL WORK.
>>AND I THINK THERE IS A LOT
OF RESEARCH TO BE DONE CLEARLY
WITH A PSYCHOLOGICAL IMPACT ON
IT BUT WITHIN THE SOCIAL SIGNS
OF NIH, HOW WE DO THAT WELL
AND DEVELOP THOSE TECHNIQUES
RATHER THAN JUST ASSUME THAT
IS HOW THE WORLD DOES IT, IT
IS PROBABLY GOOD.
CARLA?
I KNOW ADAPTATION AND GETTING
INTO DEVICES IS A BREAD AND
BUTTER PART OF YOUR LOW
HANGING FRUIT.
THOUGHTS?
>>YEAH, I MEAN I WOULD ECHO
WHAT BRONWEN SAID.
ANY MARKER OF PHYSICAL
DISABILITY IS SOMETHING THEY
ARE AND YOU RESISTANT TO.
OXYGEN IS ONE WE HAVE A LOT
AND WE ALSO TRY TO FORM LATE
IT TO HOW CAN WE HELP YOU DO
MORE.
I WOULD PROBABLY USE LANCE
ARMSTRONG AS MY SPORTS ANALOGY
BUT THIS IS SOMETHING TO
AUGMENT YOUR PERFORMANCE AND
GET TO DO THE THINGS YOU WANT
TO DO IN A LEGAL WAY.
AND YOU KNOW SUPPORTING THAT
SENSIBILITY AND ADAPTABILITY
BUT ALSO GIVING THEM HOPE,
RIGHT, THAT THIS WILL CONTINUE
TO RECOVER WHERE SUCH HOPE IS
APPROPRIATE.
THAT IS WHERE I THINK SEEING A
LOT OF THESE PATIENTS IS VERY
BENEFICIAL IN TERMS OF
PROGNOSTICATING AND PREDICTING
A TRAJECTORY FOR THEM.
YOU KNOW OFTEN FOLKS WILL COME
IN ON OXYGEN, CAN'T WALK,
STILL USING A WALKER, LIKE
FOUR WEEKS OUT AND COMPLETELY
DERESPONDENT AND WE'RE LIKE
YOU ARE RIGHT AT THE BEGINNING
OF THIS RECOVERY TRAJECTORY
AND GIVING SOME TIME FRAME OF
WE ARE IN THE EVEN GOING TO
TALK ABOUT THIS FOR A YEAR OR
NOT EVEN SAY RETURN TO WORK
TILL XYZ HAPPENS.
SO FRAMING THAT ACCESSIBILITY,
THERE IS A COMMENT IN THE CHAT
ABOUT, YOU KNOW, PATIENTS WHO
ARE OFFERED FOLLOW UP AND
DON'T WANT TO TAKE IT, WE SEE
THAT ALL THE TIME.
THEY ARE LIKE I AM DONE,
CRITICAL ILLNESS IS DONE,
HOSPITAL WAS TERRIBLE, LET ME
LEAVE THAT IN THE REAR VIEW
AND THEY DECLINE TO
SCHEDULE -- OR WE HAD ONE
PATIENT DECLINE TO SCHEDULE
BECAUSE WE TOLD HIM PART OF
THE IT WAS A SIX MINUTE WALK
AND HIS WIFE IS LIKE HE HAVE
CAN'T WALK SIX MINUTES AND I
AM LIKE IT IS PART OF THE
TREATMENT AND YOU HAVE 46
GRANDCHILDREN SO PART OF THE
RECOVERY IS WALKING.
BUT WE HAVE PATIENTS WHO SAY
NO, WE DON'T WANT TO COME BACK
TO CLINIC, LIKE IF COGNITIVE
IMPAIRMENT IS ON THE TABLE,
GIVING THEIR FAMILIES THAT
INFORMATION TO CALL.
HAVING THE ACCESSIBILITY AND
HAVING CONVERSATIONS WITH
PATIENTS, WE'RE LEARNING MORE
AND MORE ABOUT WHAT THEY NEED
AND BEING ABLE TO COLLECT THAT
DATA IN A WAY THAT IS
DIGESTIBLE AND
DISSEMINATE-ABLE -- SORRY, NEW
WORD, THAT IS BEING
DISSEMINATED TO PEOPLE WHO
NEED TO SEE THESE PATIENTS WHO
WILL BE N MR, PRIMARY CARE,
ICU FOLKS, GETTING THAT
KNOWLEDGE OUT IN THE PUBLIC
DOMAIN.
>>ALL RIGHT, WE WILL THROW
THE REST OF MY PLAN OUT AND
END WITH LIGHTNING ROUND, JUST
LIKE IN FRIENDS WHICH WE USED
TO BE ABLE TO WATCH, RIGHT, IS
SHORT ANSWERS.
SO I WILL PROPOSE THERE ARE AT
LEAST 30 BIOLOGISTS ON THIS
CALL SAYING GEE BEING A POST
ICU CLINICIAN IS REALLY HARD,
GLAD YOU ARE DOING IT, HOW DO
I HELP.
SO THE QUESTION IN THE ORDER
YOU CAME, WHAT IS A QUESTION
YOU REALLY WISH SOMEONE
FUNCTIONING MORE AT THE BASIC
BIOLOGY LEVEL COULD ANSWER OR
THE QUESTION YOU WISH YOU KNEW
THE ANSWER TO.
SO THIS IS TO PROMOTE
CONVERSATION AND WE WILL CALL
ON LAUREN AT THE END TO CLOSE
US OUT.
SO CARLA, GO.
>>SO HARD.
BUT SINCE WE'RE TALKING ABOUT
MUSCLE, I WILL SAY IF WE HAD
SOME KIND OF MARKER, BIOMARKER
OBJECTIVE CLINICALLY
AVAILABLE, MUSCLE STRENGTH
TOOL THAT PERHAPS COULD
PREDICT RECOVERY THAT WE COULD
TRACK FOR PATIENTS AND SHOW
THEM TO OUTLINE THEIR DEFICITS
AND THOUGH THEM TO GET BETTER,
THAT WOULD BE FANTASTIC.
SIDE NOTE, IT IS A JOY TO SEE
THESE PATIENTS IN CLINICS.
IF MY PATIENT SURVIVES THE
ICU, I LIKE FOR GO IN BETTER
TO SEE THEM IN CLINIC.
>>JIM?
>>I AM NOT A BIOLOGIST, NOT,
NOT, NOT, BUT I AM INTERESTED
IN THIS QUESTION.
THERE ARE A LOT OF PEOPLE,
MOST PEOPLE WHO ARE NOT
COGNITIVELY IMPAIRED WHEN THEY
LEAVE THE ICU AND THERE ARE
SOME PEOPLE WHO THRIVE AFTER
LONG STAYS ON THE VENTILATOR,
DELERIUM, ET CETERA.
I AM INTERESTED IN WHAT IS
HAPPENING IN THE BRAINS OF
PEOPLE WHO ARE DOING BETTER
THAN WE THINK THEY SHOULD BE
DOING.
>>SO HOW DO WE DESCRIBE SUPER
SURVIVORS, LOVE IT.
BRONWEN?
>>THE ONE THING WE SHOULD BE
DOING THAT TELLS US EVERYTHING
NOBLY FOR PATIENTS.
SO WHAT MUSCLE CAN I TEST THAT
WILL ALLOW THAT TO OPEN FOR
ME.
>>IT SEEMS LIKE YOU HAVE THE
GAUGE FOR --
>>NO, BUT THAT IS A CLUE FOR
ME, LIKE WHAT MUSCLE THAT HAS
PARTICULAR MUSCLE FIBERS AND
THAT GIVES ME THE GLOBAL
ANSWER IN TERMS OF OTHER
MEASURES TO MEASURE OR OTHER
MUSCLE GROUPS AS WELL.
SO THAT IS WHAT I WOULD ASK
ABOUT.
>>AWESOME, Dr. FALVEY?
>>I WOULD ASK ABOUT
RESILIENCE AND HOW DOES
SOCIALABILITY ALTER THAT FROM
A BIOLOGICAL STANDPOINT.
>>Dr. FERRANTE, YOU WANT TO
ANSWER THE QUESTION AND TAKE
US OUT?
>>YES, AS OTHER SPEAKERS WERE
CHIMING IN, I WAS THINKING
ABOUT RESILIENCE AND
PARTICULARLY PATIENTS WHO HAVE
ESCAPED FUNCTIONAL RECOVERY
AND CONTINUE TO HAVE
IMPAIRMENT SO MY SPECIFIC ASK
WOULD BE A BIOMILE -PER-HOURER
OF COGNITIVE RESILIENCE OR
SOME SORT OF BIOMARKER
FOCUSING MORE ON THE COGNITIVE
ASPECTS MEASURED ACROSS THE
CRITICAL ELEMENTS.
>>I STARTED THE CONVERSATION
ABOUT RESILIENCE WHICH WE HAVE
NOT DEALT WITH IN THESE TALKS,
A MORE COGNITIVE SPACE, WHO
ARE THE PEOPLE WHO SHOULD BE
CONSULTING WITH AS STAFF ARE
THE QUESTION AND WITH THAT HE
WILL TURN OVER TO TERRI AND
TIM BECAUSE I THINK WE ARE AT
OUR LUNCH BREAK.
>>WHINING WE HAVE 30 SECONDS
IN OUR LIGHTNING ROUND FOR
Dr. IWASHYNA TO ANSWER HIS
OWN QUESTION.
[LAUGHTER]
>>OH, I FEEL LIKE WE ACTUALLY
KNOW THAT FROM ANIMAL MODEL OF
SOCIALABILITY ARE INCREDIBLY
IMPORTANT AND THAT
FOUNDATIONALLY, IF YOU LEAVE A
RAT ALONE, IT WILL NOT DO WELL
AND WILL YOU KEEP IT IN A
COLONY, IT DOES IT BETTER AND
HOW THE PRESENCE OF OTHER
ANIMALS HELP OR DOESN'T HELP
RECOVERY FUNCTION ARREST
WARDS.
I THINK IT IS IMPORTANT TO
HAVE YOUR SPOUSE AT THE
BEDSIDE.
>> TERRIFIC, I DON'T THINK
ANYONE IS GOING TO ARGUE WITH
THAT POINT.
WHAT AN INCREDIBLE KICKOFF FOR
A DAY.
THAT SESSION WAS ABSOLUTELY
INCREDIBLE.
THANK YOU IS A MUCH FOR THE
FANTASTIC QUESTIONS IN THE
CHAT AND REALLY RICH
DISCUSSION.
I THINK WE GET A 15-MINUTE
BREAK SO PLEASE SAY HELLO TO
YOUR SPOUSE IF YOU ARE HOME
AND BENT A CUP OF TEA AND WE
WILL SEE YOU ALL BACK AT A
QUARTER TO THE HOUR.
THANK YOU SO MUCH.
WE ARE JUMP BACK IN WITH SESSION
2, HOPEFULLY EVERYBODY MADE GOOD
USE OF THAT LONG LUNCH BREAK
THAT WE BUILT INTO THE DAY.
SESSION 2 FOCUSES ON
PATHOGENESIS AND RECOVERY OF
NEUROCOGNITIVE DYSFUNCTION IN
ARDS SURVIVORS. I WILL
INTRODUCE THE MODERATOR WHOSE
WILL INTRODUCE THE SESSION
SPEAKERS. JOE IS A PHYSICIAN AND
PROFESSOR MEDICINE UNIVERSITY OF
COLORADO HE STUDIES THE
COGNITIVE CONSEQUENCES OF SEPSIS
AND CRITICAL ILLNESS. AND
SPECIFICALLY FOCUSES ON USING
BASIC TRANSLATIONAL RESEARCH TO
IDENTIFY THE RELEVANCE OF BRAIN
PENETRATING HEPARIN SULFATE AND
CHONDROITIN SULFATE. BEN SINGER
IS A PHYSICIAN AND PROFESSOR
UNIVERSITY OF MICHIGAN WHERE HE
IS A NEUROSCIENTIST AND FOCUSES
ON BOTH INPATIENT AND OUTPATIENT
CARE FOR PATIENTS WITH CHRONIC
RESPIRATORY FAILURE REQUIRING
INVASIVE -- NON-INVASIVE
VENTILATORY SUPPORT. HIS LAB
FOCUSES ON COVERING MECHANISMS
OF CHRONIC BRAIN DYSFUNCTION AND
INJURY AND SURVIVORS OF CRITICAL
ILLNESS USING MOUSE MODELS
SEPSIS AND PNEUMONIA. THANKS SO
MUCH FOR MODERATING JOE AND BEN,
TAKE IT AWAY.
>> THANKS SO MUCH FOR THAT
INTRODUCTION. REALLY EXCITED FOR
THIS PART OF THE SYMPOSIUM. I
WANT TO SAY FIRST THANK YOU FOR
ALL THOSE WHO ARE ATTENDING AND
BE SO ENGAGED I HOPE YOU
CONTINUE TO DO SO. PLEASE FEEL
FREE TO THROW A QUESTION INTO
CHAT AS YOU HAVE BEEN DOING WITH
GREAT SUCCESS. WE WILL ASK THOSE
QUESTIONS TO THE BEST OF OURANT
THROUGHOUT THE TALKS. WE HAVE A
TALL ORDER TO FOLLOW THE FIRST
SESSION I HAVE TO SAY. WHY ARE
THERE SUPER SURVIVORS OF ARDS
AND HOPEFULLY WE CAN PROVIDE
REALLY NICE INSIGHT INTO THIS
QUESTION. WE HAVE A DIVERSE SET
OF SPEAKERS THAT COME FROM THE
NEUROSCIENCE SIDE OF THINGS, THE
LUNG BIOLOGY SIDE OF THING AND
ALL PLACES IN BETWEEN SO REALLY
EXCITED TO BE ABLE TO SHARE
THEIR IDEAS WITH YOU TODAY.
AGAIN, REMINDER JUST FEEL FREE
TO THROW QUESTIONS INTO THE
CHAT. ALSO REMIND EVERYBODY IN
CASE YOU COME AFTER THE FIRST
SESSION THAT THE CHAT WILL BE
CAPTURED AT THE END AND WILL BE
PUBLICLY AVAILABLE SO AS JACK
MENTIONED, BE AS COURTEOUS AS
YOU CAN BE, SURE EVERYBODY WILL
BE AND EXTRAORDINARILY
PROFESSIONAL. WITH THAT I WANT
TO INTRODUCE OUR FIRST SPEAKER
AND IT IS AN ABSOLUTE PLEASURE
TO BE INTRODUCING HER TODAY. HER
NAME IS MICHELLE MONJE, SHE IS
AN M.D. Ph.D. AT STANFORD
UNIVERSITY. SHE IS PROFESSOR
NEUROLOGY AND NEUROLOGICAL
SCIENCES AND HOWARD HUGHES
MEDICAL INSTITUTE INVESTIGATOR,
SO A TRUE PLEASURE. SHE IS A
NEUROSCIENTIST I THINK BY
BACKGROUND, SHE WILL TALK MORE
TO THAT IN HER TALK TODAY. AND
SHE'S HAD A LOT OF RECOGNITION
HAVING RECEIVED NUMEROUS AWARDS
INCLUDING NIH DIRECTORS PIONEER
AWARD, MCARTHUR FELLOWSHIP AND
ELECTED TO THE NATIONAL ACADEMY
OF MEDICINE. THIS YEAR RECEIVED
A RICHARD LUNGSBURY AWARD
NATIONAL ACADEMY OF SCIENCES.
WITH THAT PASS TO MY SHE WOULD
TO CONTINUE THIS DISCUSSION.
>> WONDERFUL. THANK YOU SO MUCH
FOR THAT WONDERFUL INTRODUCTION.
THANK YOU SO MUCH FOR HAVING A
NEURAL ONCOLOGIST JOIN THIS
INCREDIBLY INTERESTING AND
ENGAGING DISCUSSION TODAY. I
WANTED TO TAKE EVERYONE A LITTLE
BIT THROUGH MY HONE SCIENTIFIC
JOURNEY AS A NEURAL ONCOLOGIST
AND CANCER THERAPY RELATED
COGNITIVE IMPAIRMENT AND HOW
THAT LED ME TO STUDY COGNITIVE
IMPAIRMENT AFTER LUNG INFECTION
THESE ARE MY DISCLOSURES. BY
TRAINING AND PACK IT IS I'M A
NEUROSCIENTIST AND AS MANY
PEOPLE IN THIS AUDIENCE
APPRECIATE HEALTHY COGNITIVE
FUNCTION DEPENDS UPON INTACT
MECHANISMS OF NEURAL HOMEOSTASIS
AND PLASTICITY. THAT INCLUDES IN
ORDER FOR THESE NICE ORANGE
NEURONS TO COMMUNICATE WITH EACH
OTHER ESTABLISHING SYNAPSES,
HAVING THAT CONNECTIVITY OF
APPROPRIATELY PRUNED AND
CONNECTED. AND BOTH OF THOSE
FUNCTIONS ARE REALLY ENABLED
LIKE GLIAL CELLS, ASTROCYTES
ENABLE FORMATION AND FUNCTION OF
SYNAPSES MICROGLIA AND
ASTROCYTES PRUNED SO THE
CONNECTIONS ARE WELL TRIMMED AND
APPROPRIATE FOR THAT CIRCUIT.
THEN TESTIMONY SPEED NEURAL
IMPULSE CONDUCTION IS REALLY
IMPORTANTLY MODULATED BY THE
FUNCTION OF OLIGODENDROCYTES
WHICH ARE GENERATED BY
OLIGODENDROCYTE PRECURSOR CELLS.
MYELINATION IS IMPORTANT NOT
JUST FOR SPEED OF INFLAMMATION
INFORMATION PROCESSING AND
SIGNALS DERIVED IN A SYNCHRONOUS
AND COORDINATED WAY. IT IS VERY
IMPORTANT FOR COGNITION
HOMEOSTASIS OF MYELIN AND PALACE
AT THIS THE PLASTICITY ADAPTIVE
CHANGES. ANOTHER IMPORTANT
CONTRIBUTION OF NEURAL
PLASTICITY THROUGHOUT THE LIFE
SPAN IS SOME DEGREE OF NEW
NEURON PRODUCTION IN MEMORY
CENTERED CALLED THE HIPPOCAMPUS
SO THIS PROCESS OF NEW NEURON
PRODUCTION OR NEUROGENESIS IS AN
ONGOING MECHANISM OF PLASTICITY
THAT CONTRIBUTES TO SOME FORMS
OF MEMORY FUNCTION. WHAT WE FIND
IS THAT EACH OF THESE MECHANISMS
OF PLASTICITY AND HOMEOSTASIS
CAN BE PROFOUNDLY AFFECTED AFTER
CANCER THERAPIES AND AS I HOPE I
CAN CONVINCE YOU IN MY 15
MINUTES AFTER A RANGE OF IMMUNE
CHALLENGES. I WOULD LIKE TO
FOCUS TO SOME DEGREE ON
UNDERSTAND UNDERSTANDING
ESPECIALLY THE WAY THAT CANCER
THERAPIES AND OTHER IMMUNE
CHALLENGES DISREGULATE THIS
PROCESS BY WHICH MYELIN
HOMEOSTASIS AND PLASTICITY
COORDINATE CIRCUIT FUNCTIONS
RELATIVE TO COGNITION. SO CANCER
THERAPY RELATED COGNITIVE
IMPAIRMENT ALSO SOMETIMES
COLLOQUIALLY CALLED CHEMO FOG,
IS A SYNDROME THAT SOUNDS
FAMILIAR TO MANY BECAUSE IT IS
VERY SIMILAR AS WELL POST
INTENSIVE CARE SYNDROME. IT IS
CHARACTERIZED BY IMPAIRED
ATTENTION, SCONATION, MEMORY,
COHEN CENTRATION MEMORY SPEED OF
INFORMATION PROCESSING
MULTI-TASKING AND COGNITIVE
FATIGUE. IN MANY CASES STANDARD
NEUROIMAGE IMAGING IS
UNREMARKABLE BUT MORE ADVANCE
IMAGING REVEALS SUBTLE WHITE
MATTER AND DECREASED HIPPOCAMPAL
VOLUMES. -AFFECTS CANCER
SURVIVORS TO EXTEND AND OVER 20
YEARS TRYING TO UNDERSTAND THE
NEUROLOGICAL UNDERPINNINGSES OF
THERAPY COGNITIVE IMPAIRMENT I
AND OTHERS DISCOVER BRAIN IMMON
IS REACTIVE TO IT. MICROGLIAL
CELLS HAVE IMPORTANT HOMEO
STATIC AND PLASTICITY FUNCTIONS
DISREGULATE ALL THOSE PROCESSES
I JUST TOLD YOU ABOUT AND
DISREGULATE HIPPOCAMPAL
NEUROGENESIS AND NEUROTOXICS
STATE OF ASTROCYTES AND IMPAIR
OLIGODENDROCYTE FUNCTION AND
INCLUDING HOMEOSTASIS AN
PLASTICITY. AFTER
CHEMOTHERAPEUTIC METHYL TREK
SATE PARTICULARLY ASSOCIATED
WITH SYNDROME OF COGNITIVE
IMPAIRMENT METHYL TREK SATE
INDUCES DIRECT ACTIVATION OF
MICROGLIA IN THE WHITE MATTER,
IN AXON TRACKS. THOSE REACTIVE
MICROGLIA THEN ACTIVATE
ASTROCYTES LUCY CREASE OF
SPECIFIC IMMUNE SIGNALING
MOLECULES AN TOGETHER REACTIVE
MICROGLIA AND ASTROCYTES
DISREGULATE THE OLIGODEN DR.
GLIAL LINEAGE DISRUPTING MYELIN
HOMEOSTASIS AND PLASTICITY, THIS
EXPERIENCE DEPENDENT TUNING SO
OF MYELIN SO IMPORTANT FOR
MEMORY AND LEARNING. MICROGLIAL
ARE ESSENTIAL TO THIS, WE CAN RE
RE RETHAT CAPITULATE IN BY
SYSTEMIC POLYSACCHARIDE AND
DEPLETE MICROGLIA USING
EXPERIMENTAL APPROACH USING CSF
1R INHIBITORS THAT DEPLETE
MYELOID CELLS BROADLY. THAT
RESCUES MYELINATION AND RESCUES
COGNITION AND PRE-CLINICAL
MODELS WE NODE THE MICROGLIA ARE
REALLY IMPORTANT. I WANT TO
SPEND A COUPLE OF MINUTES
TELLING YOU HOW CANCER THERAPIES
THAT ARE CHIEFLY IMMUNOLOGICAL
IN NATURE AND THEN ACTUALLY
MIMIC BROAD IMMUNE CHALLENGES
AND INDUCE THINGS LIKE CYTOKINE
RELEASE SYNDROME INDUCE THIS
PATHOPHYSIOLOGY IN THE BRAIN AS
WELL. I WAS WORRIED THAT
SYSTEMIC INFLAMMATION CAUSED BY
CANCER IMMUNOTHERAPIES LIKE CAR
T-CELL THERAPY CAUSE SIMILAR
NEUROINFLAMMATORY PHENOTYPE THAT
DISREGULATES GLIA AND THEREFORE
NEURAL CIRCUIT FUNCTION AND
COGNITION. AS A LOT OF PEOPLE IN
THIS CALL KNOW PROMISING FDA
APPROVED IMMUNOTHERAPY IS
CHIMERIC ANTIGEN RECEPTOR T-CELL
THERAPY, A PATIENT'S OWN T-CELLS
ARE TAKEN AND THEN ENGINEERED TO
TARGET SPECIFICALLY TARGET
ANTIGEN ON THEIR CANCER IN THE
CASE OF ACUTE LYMPHOBLASTIC
LEUKEMIA OR ALL THAT ANTIGEN
OFTEN CALLED CD 19 AND THEN
T-CELLS SEEK AND DESTROY THE
CANCER CELLS. THIS IS ASSOCIATED
WITH A VERY HIGH RATE OF
CYTOKINE RELEASE SYNDROME AS
WELL AS HIGH RATE OF I A CUTE
TRANSIENT NEUROLOGICAL SYMPTOMS
INCLUDING DELIRIUM AND
HALLUCINATIONS. THE LONG TERM
EFFECTS ON COGNITION ARE
UNDERSTUDIED BUT EARLY CLINICAL
REPORTS ARE FAIRLY CONCERNING
THAT A SIMILAR SYNDROME SIMILAR
TO CHEMOTHERAPY RELATED
COGNITIVE IMPAIRMENT IS
EMERGING. SO WE WONDERED WHETHER
CAR T-CELL THERAPY CAUSE SIMILAR
NEUROINFLAMMATORY CHANGES,
DISREGULATE NUMEROUS GLIAL
INTERACTIONS AND IMPAIR
COGNITION. THESE ARE PEOPLE IN
THE LAB WHO LED THIS PROJECT ANN
GARETY. WE LOOKED AT THREE
PRE-CLINICAL MODELS OF CAR
T-CELL THERAPY ONE THERAPY WE
ARE INTERESTED BECAUSE WE ARE
CURRENTLY LEADING CLINICAL WORK
IN THIS REALM TARGETING A
TERRIBLE MIDLINE GLIOMA CALLED
ACUTE TRANSITIVE GLIOMA AND CAR
T-CELL MODELS OUTSIDE THE
THERAPY SYSTEM, ONE FDA APPROVED
ANTI-CD 19 CAR T-CELL THERAPY
FOR LEUKEMIA AND THEN AS CANCER
THAT NEVER ENTERS THE NERVOUS
SYSTEM OSTEO SARCOMA. AND WE
LOOKED AT BOTH ON TARGET K FOR
CELLS THAT TARGET TUMOR AS WELL
AS OFF TARGET CAR T-CELLS THAT
TARGET ANTIGEN NOT EXPRESSED ON
TUMOR IN THAT MODEL TO CONTROL
FOR ON TARGET OFF TUMOR EFFECTS
AND FINALLY, A THIRD CONTROL
GROUP MOCK T-CELLS. WHAT WE FIND
IS THAT WE SEE COGNITIVE
DEFICITS AFTER CAR T-CELL
THERAPY IN MICE. WE SEE IN CNS
CAR T-CELL THERAPY AS WELL AS
T-CELL THERAPY FOR LEUKEMIA AND
OSTEO SARCOMA. ONLY SEEN WHEN
THERE IS EFFECTIVE IMMUNE
RESPONSE. IF WE LOOK AT OFF
TARGET CD 19 TARGETING CASH
T-CELL IN BRAIN CANCER MODEL
WHERE NO CD 19 ON CANCER WE
DON'T SEE COGNITIVE IMPAIRMENT
IN THAT PARTICULAR CASE. BUT IF
THE CAR T -- IF THE CD 19
TARGETING CAR T-CELLS NIGHT
LEUKEMIA AND THERE IS A TUMOR
CLEARING IMMUNE RESPONSE WE SEE
CD 19 CAR T-CELLS CAUSING
COGNITIVE IMPAIRMENT. TOGETHER
WITH THE COGNITIVE IMPAIRMENT
THERE IS PERSISTENT ELEVATION IN
CSF KITE INTOS AND CHEMOKINES
AFTER EACH -- KITEKINES AND
CHEMOKINES AFTER EACH T-CELL
STRATEGY AS WELL PASS SIMILAR --
CYTOKINES AND CHEMOKINES. THIS
IS A POPULATION OF BRAIN
RESIDENT IMMUNE CELLS THAT ARE
VERY, VERY RESPONSIVE TO
SYSTEMIC IMMUNOTOXIC CHALLENGES.
WITH THE WHITE MATTER SPECIFIC
ELEVATION AND MICROGLIAL
ACTIVITY AFTER THERAPY WE SEE
DECREASE IN EACH MODEL AND
MYELINATING OLIGODENDROCYTES AND
DROP OUT OF MYELINATED AXONS.
TOGETHER WITH THAT, AS WE
PREDICT, BASED ON WHAT WE SEE
AFTER MORE TRADITIONAL CANCER
THERAPIES LIKE CHEMOTHERAPY AND
RADIATION WE SEE A DECREASE IN
HIPPOCAMPAL NEUROGENESIS THAT
CORRELATES WITH INCREASE IN HIP
CAM PAL WHITE MATTER MICROGLIAL
REACTIVITY. IF WE TARGET
MICROGLIA, DEPLETE
EXPERIMENTALLY USING CSFNR
INHIBITOR THAT RESCUES THE
OLIGODENDROCYTE PHENOTYPE
PARTIALLY AND RESCUES COGNITION
AT LEAST IN THIS TEST OF
ATTENTION AND MEMORY CALLED THE
NOVEL OBJECT RECOGNITION TEST.
SO WE THINK IMMUNOTHERAPY
RELATED COGNITIVE IMPAIRMENT
RECAPITULATES A SIMILAR
PRINCIPLE WE SEE AFTER CANCER
TRADITIONAL CHEMOTHERAPIES LIKE
METHYL TRACK SATE, A KNOWN --
TREK SATE, ANONYM
IMMUNOCHALLENGE IN THE NERVOUS
SYSTEM WHICH TENDS TO BE
PERSISTENT AND LOCALIZED TO AXON
TRACKS THAT INDUCES NEURONAL AND
GLIAL DISREGULATION THAT THEN
RESULTS IN LASTING BRAIN FOG
SYNDROMES. WE KNOW THAT
ANTITUMOR CAR T-CELL THERAPIES
REQUIRED FOR THIS IS REALLY THE
IMMUNE RESPONSE WE BELIEVE IS
RESPONSIBLE FOR THE CNS
DISREGULATION. AND THE
DISREGULATING OLIGODENDROGLIAL
HOMEOSTASIS AND HIPPOCAMPAL
NEUROYENSIS IS IMPORTANT TO
PERSISTENT IMPAIRMENT IN
ATTENTION AND MEMORY. MICROGLIA
EMERGE AS AN INTERESTING
THERAPEUTIC TARGET, CSF 1R
INHIBITORS ARE NOT THE BEST WAY
TO DO IT CLINICALLY BUT IT
PRESENTS SOMETHING THAT WE CAN
WORK TOWARDS TARGETING. SO WHEN
THE PANDEMIC BEGAN IN -- WHEN I
BECAME AWARE OF IT IN 2020, I
WAS REALLY WORRIED SEEING HOW
VERY PROFOUNDLY IMMUNOGENIC CAR
COV-2 SEEMED TO BE. I WORRIED WE
WOULD BEGIN TO SEE COGNITIVE
IMPAIRMENT AS AFTER CHEMOTHERAPY
AND AFTER CAR T-CELL THERAPY.
AND VERY QUICKLY BECAME EVIDENT
EVEN PEOPLE WHO HAD EXPERIENCE
RELATIVELY MILD RESPIRATORY
COVID, WERE COMING TO THE
NEUROLOGIST OFFICE IN DROVES
WITH VERY SIMILAR SYNDROME OF
IMPAIRED ATTENTION,
CONCENTRATION, MEMORY, SPEED OF
INFORMATION, PROCESSING
MULTI-TASKING AND COGNITIVE
FATIGUE. AND JUST LIKE AFTER
CANCER THERAPIES, STANDARDS
NEURAL IMAGING IS TYPICALLY
UNREMARKABLE BUT ADVANCE
NEUROIMAGING REVEALS CELL WHITE
MATTER ABERRATIONS AND DECREASED
VOLUME IN THIS CASE LIMB BIC AS
WELL AS OLFACTORY STRUCTURES.
THIS AFFECTS A LARGE PORTION OF
COVID SURVIVORS THE NUMBERS VARY
DEPENDING ON THE MEASURE THAT
ONE IS USING BUT ONE META
ANALYSIS OF 10,000 SUBJECTS
FOUND THAT AS MANY AS ONE IN
FOUR PEOPLE EXPERIENCE SOME
DEGREE OF PERSISTENT COGNITIVE
DYSFUNCTION. SO WE WONDERED
WHETHER SIMILAR GLIAL
DISREGULATION MAY CONTRIBUTE TO
COGNITIVE SYMPTOMS AFTER COVID.
AND TO ANSWER THOSE QUESTIONS, I
REACHED OUT TO IN THE MIDST OF
LOCK DOWN COLLABORATED WITH
THESE TWO WONDERFUL PEOPLE,
AKIKO AT YALE AND AVINDA AT
NINDS TOGETHER WITH MANY PEOPLE
FROM OUR LABS. WE USED A MODEL
SYSTEM DEVELOPED IN AKIKO'S LAB
OF MILD RESPIRATORY RESTRICTED
SARS COV-2, SO IN THIS MOUSE
MODEL WE CAN RESTRICT INFECTION
TO RESPIRATORY TRACT. IN THIS
MODEL A MILD DISEASE MICE CLEAR
THE VIRUS WITHIN ABOUT SEVIN
DAYS IN THE RESPIRATORY SYSTEM,
THEY DON'T LOSE WEIGHT, THEY
CONTINUE TO GROOM WELL, THERE'S
NO EVIDENCE OF INFECTION IN THE
BRAIN. AND YET WHEN WE LOOK
EITHER 7 DAYS OR WEEKS T A SERA
OR CSF WE CAESARSIS TENT
PROFOUND ELEVATION IN BOTH SERUM
AND CSF KITE SIGNS AND
CHEMOKINES. -- CYTOKINES AND
CHEMOKINES. THIS RESPIRATORY
CHALLENGE IS BEING SUBMITTED
BECOMING NEUROINFLAMMATION. AS
WE SAW WITH CHEMOTHERAPY AND CAR
T-CELL CHEMOTHERAPY THERE IS A
REACTIVITY OF MICROGLIA AND
GENETIC STRAINS OF MICE AND
HUMANS WHO DIED EARLY IN THE
PANDEMIC WITH SARS COV-2
INFECTION BUT WHO DID NOT HAVE
SEVERE LUNG DISEASE. THERE WAS
NO EVIDENCE OF INFECTION IN THE
BRAINS OF THESE PEOPLE AND YET
THERE WAS WHITE MATTER SELECTIVE
ELEVATION IN MICROGLIAL
REACTIVITY. AS WE PREDICT, WE
SEE AGAIN THIS LOSS OF
OLIGODENDROCYTES, THIS HAPPENS
QUICKLY AFTER MILD RESPIRATORY
SARS COV-2 IN MICE BY 7 DAYS
THROUGH 7 WEEKS. WE SEE A DROP
OUT IN MYELINATED AXONS IN THE
SUB CORTICAL WHITE MATTER
EVIDENT AT 7 DAYS AND 7 WEEKS
AND THIS IS MEASURE OF THE KIND
OF LOSS OF MYELINATED AXONS WE
SEE AFTER METHYL TREXATE
CHEMOTHER THIS PI COMPARING THE
DECREASE IN EACH CASE. --
THERAPY. WHAT WE KNOW FROM
CANCER THERAPY RELATED
NEUROBIOLOGY WE FIND THAT THERE
IS A DECREASE IN HIPPOCAMPAL
NEUROGENESIS THAT IS PERSISTENT
AND WE NOTICED RELEVANT TO THAT,
THAT THERE WAS PERSISTENT
ELEVATION OF CHEMOKINE CALLED
CCL 11 AND CSF OF MICE FOLLOWING
MILD RESPIRATORY SARS COV-2.
THAT WAS REALLY INTERESTED
BECAUSE CCL 11 IS ASSOCIATED
WITH DECREASED HIPPOCAMPAL
MYELINATION WITH AGING. SO WE
COLLABORATED WITH DAVID A REHAB
MEDICINE SPECIALIST WHO
SPECIALIZES NOW IN LONG COVID
AND IN HIS COHORT OF PATIENTS WE
FOUND THAT THOSE WITH LONG COVID
WHO HAD COMPLAINED WITH
SELF-REPORTS REPORTED COGNITIVE
SYMPTOMS COMPARED TO THOSE WITH
WITH NOT THERE WAS INCREASE IN
SERUM CCL 11 LEVELS. THERE IS A
LARGE SPREAD HERE IN THE DATA
AND SO WE DID A MULTI-VARIANT
ANALYSIS AND FOUND THAT IN THOSE
THAT HAD A HISTORY OF BRAIN FOG
SELF-REPORTED BRAIN FOG WITH
ELEVATED CCL 11 LEVELS, THAT
THAT CORRELATED WITH A HISTORY
OF AUTOIMMUNE DISEASE SUGGESTING
SOMETHING ABOUT THE PATIENT'S
IMMUNE SYSTEM MAY DISREGULATE
THIS RESPONSE AND INCREASE THE
RISK OF ELEVATED CCL 11 WHICH
CORRELATES WITH COGNITIVE
IMPAIRMENT. SO WE WONDERED
WHETHER CCL 11 WAS CAUSATIVE OR
CORRELATIVE. SO WE TOOK HEALTHY
MICE AND JUST ADMINISTERED CCL
11 SYSTEMICALLY. WHAT WE FOUND
IS THAT THAT ADMINISTRATION
PARADIGM RESULTED IN NO INCREASE
IN MICROGLIAL REACTIVITY IN THE
CORTEX OR SUB CORTICAL WHITE
MATTER BUT WE DID SEE THAT THAT
SYSTEMIC CCL 11 INCREASED
HIPPOCAMPAL WHITE MATTER
MICROGLIAL REACTIVITY AND THAT
WAS SUFFICIENT TO DECREASE
HIPPOCAMPAL NEUROGENESIS. CCL 1
# 1 IS ONE MECHANISTIC COMPONENT
BUT NOT THE ONLY WAY LUNG IMMUNE
CHALLENGE IS TRANSMITTED TO CNS
IMMUNE CHALLENGE. I HAVE TWO
SLIDES LEFT. GOING TO FINISH ONE
MINUTE LATE. I APOLOGIZE. SO WE
WONDERED WHETHER THIS WAS
SPECIFIC TO COVID OR WHETHER
THIS WAS A MORE BROAD REFLECTION
OF RESPIRATORY IMMUNE CHALLENGE.
SO WE TREATED MICE, THE INFECTED
MICE WITH A MOUSE MODEL MILD
RESPIRATORY INFLUENZA. AND THEN
WE EXAMINED THE BRAIN 7 DAYS OR
7 WEEKS LATER AND FOUND THAT
AFTER MILD RESPIRATORY INFLUENZA
THERE WAS A TRANSIENT SUB
CORTICAL WHITE MATTER MICROGLIAL
REACTIVITY AFTER COVID AT 7 DAYS
WE SAW MICROGLIAL REACTIVITY
BOTH IN THE HIPPOCAMPAL WHITE
MATTER AND SUB CORTICAL WHITE
MATTER. AFTER 7 WEEKS THOUGH,
THAT SUB CORTICAL WHITE MATTER
MICROGLIAL REACTIVITY RESOLVED
INFLUENZA WHILE THE OTHER
PERSISTED. WE SAW A RESOLUTION
OF POST INFLUENZA
OLIGODENDROCYTE LOSS BY 7 WEEKS
AND SYSTEMIC OF HIPPOCAMPAL. IN
THE CYTOKINE AND CHEMOKINE AFTER
COVID AND INFLEW INFLUENZA THERE
IS PERSISTENT ELEVATION OF CCL
11 WHICH SPECIFICALLY AFFECTED
HIPPOCAMPUS. THERE IS ALSO
REALLY INTERESTED DIFFERENCES
THOUGH. AFTER COVID THERE IS
ACUTE ELEVATION IN THE CSF
INTERLEUKIN 7 AND INTERLEUKIN
ALPHA THAT RESOLVES AFTER
INFLUENZA, YOU DON'T SEE IL 6
ELEVATION UNTIL LATER IN DISEASE
COURSE, CURRENTLY TRYING TO
UNDERSTAND HOW THE DIFFERENCES
IN SIGHT COIN AND CHEMOKINE
PROFILES IMMUNE CHALLENGES BY
THE SAME ORGAN MIGHT BE
DIDN'TIALLY AFFECTING DIFFERENT
NEURAL CIRCUITS LONG TERM. SO I
WOULD LIKE TO CONCLUDE WITH THE
IDEA THAT SYSTEMIC IMMUNE
CHALLENGES CAUSE
NEUROINFLAMMATORY CHANGES AND
CONSEQUENT GLIAL DISREGULATION
THAT INDUCES NEURAL CIRCUMSTANCE
DYSFUNCTION AND CAUSES COGNITIVE
IMPAIRMENT. THIS SEEMS TO BE A
SORT OF COHESIVE PRINCIPLE OF
WAYS WHICH PREFERRIAL IMMUNE
CHALLENGES INFLUENCE THE BRAIN
IN LONG TERM WAY. THINKING COVID
IN PARTICULAR THIS RESPIRATORY
IMMUNE CHALLENGE INDUCE
NEUROINFLAMMATION AND GLIAL
DISREGULATION IS LIKELY COMMON
MECHANISM OF BRAIN FOG AND
NEUROBIOLOGICAL DYSFUNCTION BUT
THERE IS CERTAINLY MANY OTHER
THINGS THAT CAN HAPPEN
ESPECIALLY CRITICAL ILLNESS LIKE
COVID AND MANY OTHERS. WE HAVE
TO ALSO CONSIDER THINGS THAT
HAPPEN ALSO IN VARIOUS
COMBINATIONS INCLUDING
AUTO-IMMUNITY, NEUROINVASIVE
INFECTION, REACTIVATION OF OTHER
INFECTIONS IN THE CASE OF COVID,
REACTIVATION OF EBB SEEMS COMMON
THROMBOTIC AND MICROVASCULAR
DISEASE AND MENTAL ILLNESS
MULTI-ORGAN FAILURE CONTRIBUTES
TO NUMEROUS METABOLIC
DISTURBANCES THAT INFLUENCE THE
BRAIN IN PERMANENT DETRIMENTAL
WAYS. OUR GAPS IN KNOWLEDGE
INCLUDE UNDERSTANDING IN
COMPREHENSIVE WAY HOW
INFLAMMATORY SIGNALS ARE
TRANSMITTED FROM LUNG TO BRAIN.
I WOULD LIKE TO UNDERSTAND WHY
WHITE MATTER MICROGLIA SEEM SO
SENSITIVE TO IMMUNE CHALLENGES
AND REMAIN ACTIVE IN SUCH
PERSISTENT WAY. AFTER MANY
CHALLENGES. THE ROLE THAT
NEUROTOXIC ASTROCYTES PLAY IN
COGNITIVE IMPAIRMENT IN NON-CNS
IMMUNE CHALLENGE REMAINS FULLY
UNDERSTOOD AND QUITE IMPORTANT.
AND OF COURSE HOW CAN WE TAKE
THESE NEW UNDERSTANDINGS AND
LEVERAGE FOR THERAPY. HOW WE USE
TO DEVELOP NEW TREATMENTS, HOW
CAN WE RESTORE HEALTHY
NEUROCIRCUIT HOMEOSTASIS AND
PLASTICITY TO RESCUE COGNITION.
SO I WILL CONCLUDE AT THE HIGH
RISK HIGH REWARD IDEA THAT A
COMMON PRINCIPLE OF BRAIN FOG
SYNDROMES ARE EMERGING. AND
MICROGLIAL REACTIVITY IS
ESSENTIAL. SO CAN WE DISCOVER
WAYS TO COACH MICROGLIA FROM
REACTIVE STATE TO A MORE
HOMEOSTATIC STATE. AND
UNDERSTANDING THAT IS GOING TO
BE RELEVANT TO A NUMBER OF
DIFFERENT NEUROLOGICAL
DISORDERS. MANY PEOPLE TO THANK
SORRY FOR GOING OVER MY TIME.
THANK YOU VERY MUCH FOR YOUR
ATTENTION. LOOK FORWARD TO
DISCUSSION.
>> MICHELLE, THANK YOU FOR
SETTING US UP ON A GOOD
TRAJECTORY TO START, PHENOMENAL
WORK. COUPLE O QUESTIONS FROM
THE AUDIENCE BASED UPON YOUR
TALK. THE FIRST COMES FROM
TAREK, A SPEAKER IN ABOUT 45
MINUTES. HE'S WONDERING HE
MENTIONS THAT MICROGLIA CAN HAVE
NEUROTOXIC AND NEUROPROTECTIVE
PROFILES. DO YOU HAVE A SENSE OF
WAYS TO MONITOR FOR USING
BIOMARKERS PERIPHERALLY OR
OTHERS TO ASSESS WHETHER
MICROGLIA ARE DOING GOOD OR BAD?
>> IT IS SUCH AN IMPORTANT
QUESTION. SO MICROGLIA ASSUME
MANY REACTIVE STATES, SOME
HELPFUL SOME HARMFUL, THEY DO
IMPORTANT PROCESSES SO CAN'T GET
RID OF THEM. QUESTION IS WHAT
DISEASE ASSOCIATED STATE ARE IN,
THERE ARE NUMEROUS DISEASE
ASSOCIATED STATES IN MICROGLIAL
DESCRIBED. WE HAVE DONE SINGLE
CELL SEQUENCING OF MICROGLIA
AFTER SARS COV-2 INNEXT IN MICE
AND THE STATE MICROGLIA ARE IN
SHARES A LOT OF FEATURES WITH
VARIOUS OTHER DISEASE ASSOCIATED
MICROGLIA, WE THINK IT IS NOT
HELPFUL, IT IS NEUROTOXIC BUT
THERE IS UNIQUE FEATURES OF
MICROGLIA AFTER SARS COV-2
INFECTION CHEMOKINE EXPRESSION.
AS WE UNDERSTAND MORE AND
IDENTIFY EXACTLY WHICH
CHEMOKINES ARE CONSISTENTLY
EXPRESSED BY MICROGLIA IN THIS
NEUROTOXIC STATE WE MAY THEN BE
ABLE TO DEVELOP A CSF OR
POTENTIALLY PROBABLY CSF BIOMOCK
ER TO MONITOR STATE BUT
THE FIELD TRYING TO MONITOR
ENTIRE STATES.
>> MICHELLE WILL HAVE MORE
QUESTIONS DURING POST SESSION.
THANK YOU MORE THE TIME. NEXT
SPEAKER TROY STEVENS, Ph.D.
FROM UNIVERSITY OF SOUTH
ALABAMA. HE IS THE WILL NOR LOCK
PROFESSOR AND CHAIR DEPARTMENT
OF PHYSIOLOGY AND CELL BIOLOGY
AT SOUTH ALABAMA, DOES REALLY
INCREDIBLE WORK AS DIRECTOR FOR
THE CENTER FOR LUNG BIOLOGY.
HE'S GOING TO BE TALKING ABOUT
INTERACTION BETWEEN LUNG AND
BRAIN WHICH IS BROUGHT UP IN THE
CHAT ALREADY SPECIFICALLY
INTERESTED IN HOST PATHOGEN
INTERACTION AND HOW THAT MIGHT
AFFECT THE BRAIN. SO EXCITED
TROY TO HAVE YOU TODAY. LET YOU
GET GOING.
>> GREAT. THANK YOU SO MUCH FOR
THE OPPORTUNITY TO BE HERE.
REALLY EXCITED TO TALK ABOUT
WORK OUR LARGER GROUP HAS BEEN
PERFORMING TO TRY TO ADDRESS
THIS IMPORTANT PROBLEM. TITLE IS
INFECTIOUS PROTEINOPATHY OF THE
LUNG. WHAT WE WE ARE GOING TO
TRY TO EXPRESS IS THE IDEA THAT
LUNG INFECTION CAN ELICIT
PRODUCTION OF CYTOTOXIC AMYLOID
IN THE PARENCHYMA OF THE LUNG
AND THESE CONTRIBUTE TO END
ORGAN DYSFUNCTION. WE WILL
MARROW THIS A BIT FOR PURPOSES
TODAY FOCUS ON PRODUCTION OF
CYTOTOXIC VARIANCE OFFER TAU AND
TALK HOW THOSE VARIANTS OF TAU
CONTRIBUTE TO NEUROTOXIC
DYSFUNCTION.
THIS IS THE INFECTIOUS
PROTEINOPATHY OF THE LUNG IDEA.
LET ME START WITH WHAT WE
LEARNED THE LAST 10, 15 YEARS
THAT INFORM OUR POSITION OF HOW
WE THINK ABOUT THIS PROBLEM. THE
FIRST THING THAT IS REALLY
IMPORTANT TO UNDERSTAND IS THAT
LUNG ENDOTHELIAL CELLS EXPRESS
MICROTUBULE ASSOCIATED PROTEIN
TAU. SO FOR ABOUT 15 YEARS WE AN
OTHERS HAVE DISCOVERED THE
EXPRESSION OF TAU IN CELLS
ENDOTHELIAL CELLS IN CULTURE AND
PROVIDE A SIGNIFICANT EVIDENCE
TOWARD THIS IDEA BASED ON RT PCR
CLONING WESTERN BLOTTING
PROTEOMIC ANALYSIS AN FUNCTIONAL
STUDIES OF MICROTUBULE
STABILITY. FOR THE MOST PART
THESE STUDIES OR THESE EARLY
STUDIES REALLY FOCUSED ON CELL
CULTURE MODELS AND ONLY RECENTLY
SORT OF TRANSLATED THIS INTO
PRE-TRANSLATIONAL MODELS AND
CLINICAL SETTING. SO THIS IS A
MOUSE, SIGNIFICANT FOR TAU KNOCK
OUT WITH INSERTION OF REPORTER
EGFP AND EXON 1 OF THE MAPT
GENE. SO IN PRINCIPLE CELL
EXPRESSING TAU SHOULD BE GREEN.
SO WITH THIS IN MIND WE PERFORM
STUDIES TO FULLY RECRUIT THE
MICROCIRCULATION AND THEN
SECTIONED LARGE SECTIONS OF THE
LUNG IMAGED BY MULTI-PHOTON
IMAGING THROUGH THAT WHOLE
SECTION AND SO THE FIRST THING
THAT YOU NOTICE IS THAT IN THIS
MOUSE, THERE IS EXTENSIVE
EXPRESSION OF TAU OR EGFP IN THE
LUNG PARENCHYMA. WHEN YOU LOOK
MORE CLOSELY AT WHERE IN
MICROCIRCULATION THAT TAU IS
EXPRESSED WHAT YOU CAN BEGIN TO
APPRECIATE IS IN THESE CAPILLARY
LOOPS. SO IF YOU LOOK ACROSS
THIS SECTION, WHAT YOU CAN SEE
VERY CLEARLY HERE IN THESE TWO
CAPILLARIES THAT ARE HIGHLIGHTED
ON THIS RIGHT SIDE, THE ADJACENT
EPITHELIUM SEEMS NEGATIVE FOR
TAU BUT CAPILLARY ENDOTHELIUM
SEEMS TO BE QUITE POSITIVE FOR
TAU EXPRESSING. THIS IDEA WAS
FURTHER SUPPORTED BY THE MESNER
GROUPS IN THIS PAPER THEY
IDENTIFY DIFFERENT ENDOTHELIAL
ARCHETYPES IN THE CAPILLARY
PLEXUS OF THE LUNG. THE PRIMARY
FOCUS ON RESOLVING AEROCYTE AS
PHENOTYPE OF THE CELL IN THE
MICROCIRCULATION AS BEING PART
OF THE ENDOTHELIUM THAT THERE
WAS ADJACENT TO TYPE 1
EPITHELIAL CELLS IN THIN PORTION
OF THE BLOOD GAS BARRIER AN
GENERAL CAPILLARY MORE ASSOCIATE
WITH THE THE THICK REGION OF
BLOOD GAS BARRIER AND
COMMUNICATING WITH OTHER CELLS
IN THAT THICK REGION. WHAT THEY
FOUND OR WHAT THEY SUGGEST WAS
THE AEROCYTE WAS A LARGER CELL,
A LARGER CELL IN THE G CAP WAS A
SMALLER NUMEROUS CELL MOST
RESPONSIVE TO INJURY AND REPAIR.
BOTH THESE CELLS WERE ORIGINATED
FROM A COMMON BIPOTENT
PROGENITOR CELL AS EARLY AS
PSEUDOGLANDULAR STAGE OF LUNG
DEVELOPMENT. WHAT WAS
INTERESTING TO US IS THEY FOUND
ONLY A SMALL NUMBER OF GENES
THAT WERE EXPRESSED IN ALL OF
THE CAPILLARY ENDOTHELIAL CELLS
THEY STUDIED. ONE OF THOSE GENES
EXPRESSED EARLY AND MAYBE
EARLIER THAN THE PSEUDOGLANDULAR
STAGE OF LUNG DEVELOPMENT WAS IN
FACT TAU. FURTHER SUPPORT FOR
THIS GENERAL IDEA COMES FROM
THIS SINGLE CELL ATLAS OF THE
ENDOTHELIUM FROM THE YALE GROUP
WHERE YOU CAN ARCHETYPE CELL
PHENOTYPES BASED ON SINGLE CELL
RNA ANALYSIS. IF YOU
SPECIFICALLY LOOK AT THE
ENDOTHELIAL POPULATIONS WITHIN
THOSE ARCHETYPES YOU SEE HERE
THE AEROCYTE POPULATION AND
GENERAL CAPILLARY POPULATION,
YOU CAN QUANTIFY THAT AND YOU
CAN SEE IN FACT THE TAU IS
HIGHLY EXPRESSED IN THE LUNG
MICROCIRCULATION MORE SO THAN IN
OTHER KINDS OF ENDOTHELIAL CELLS
INCLUDING ARTERIAL VENOUS
BRONCHIAL AND LYMPHATIC
ENDOTHELIAL CELLS SO LOOKS CLEAR
THAT TAU IS EXPRESSED IN THE
LUNG MICROCIRCULATION. AND THEN
MOST RECENTLY CHOW AND LYNN HAVE
CLONED THE LUNG ENDOTHELIAL TAU
BOTH FROM LUNG ITSELF AND THEN
FROM ENDOTHELIUM. THEY CLONED AT
LEAST FOUR ISOFORMS AT THE
ENDOTHELIAL TAU INCLUDING SO
CALLED ZERO IN O ALREADY 1N 4R
2N 4R TAU, THESE ARE TAUS
PREVIOUSLY KNOWN TO BE IN THE
CENTRAL NERVOUS SYSTEM AND THEY
IDENTIFIED A BIG TAU WHICH IS A
TAU ISOFORM THAT IS PROMINENT IN
PERIPHERAL NERVES. WHAT IS
NOTABLE IS ALL FOUR OF THESE
ISOFORMS POSSESS A CONSERVED
REGION IN THE MICROTUBULE
BINDING DOMAINS OF THIS TAU.
THESE TWO CONSERVE SEQUENCES ARE
SO CALLED AGGREGATION DOMAINS
AND THOSE ARE KNOWN TO BE
MECHANISTICALLY INVOLVED IN
PRODUCTION OF CYTOTOXIC VARIANTS
OF TAU CHRONIC NEURODEGENERATIVE
DISEASE. SO THE TEACHING POINTS
FROM THIS FIRST SECTION HERE IS
THAT LUNG CAPILLARY ENDOTHELIAL
CELLS INCLUDING AEROCYTE AND
GENERAL CAPILLARY CELLS, IN THE
LUNG EXPRESS TAU AND AT LEAST
ONE OF THE FUNCTION OF THESE TAU
OF THESE TAU ISOFORMS IS TO
STABILIZE MICROTUBULES. SO FIRST
THING WE KNOW IS ENDOTHELIAL
CELLS IN THE LUNG PARENCHYMA
HAVE A TAU. WHAT WE HAVE ALSO
LEARNED IS THAT LOWER
RESPIRATORY TRACK INFECTION
DRIVES THE PRODUCTION OF TAU
VARIANTS THAT ARE CYTOTOXIC. SO
WHEN YOU HAVE A LOWER
RESPIRATORY TRACK INFECTION WE
OBSERVE THE PHOSPHORYLATION OF
THESE TAU VARIANTS. AND WHEN
THESE TAU VARIANTS BECOME
PHOSPHORYLATED THEY ACQUIRE
UNUSUAL PHYSICAL CHEMICAL
PROPERTIES THAT AS THEY ARE EACH
STABLE, THEY ARE RHESUS TENT TO
PROTEASES, -- RESISTANT TO
PROTEASES TRANSMISSIBLE FROM ONE
CELL TO ANOTHER ONE ORGAN TO
ANOTHER TO FROM ONE ANIMAL TO
ANOTHER AND ACROSS SPECIES AND
SELF-REPLY REPLICATE -- REPLY
SATING. MISVARIANT FORM OF TAU
CAN DRIVE THE NEW CYTOTOXIC
VARIANTS IN OTHERWISE UNINFECTED
NAIVE CELLS. THESE BECOME SIGH
TOY TOXIC. YOU WILL RECOGNIZE
THIS AS BEING A FREION LIKE
PHENOMENON, KEEP STABLE PROTEASE
RESISTANT TRANSMISSIBLE
SELF-REPLICATING AND CYTOTOXIC.
SO PNEUMONIA LOWER RESPIRATORY
TRACT INFECTION IS INITIATING A
FREION LIKE PHENOMENON. STUDIES
FOCUS ON PSEUDOMONAS AEROGINOSA.
ONE THING THAT IS EXTREMELY
IMPORTANT, NOT ALL VARIANTS OR
STRAINS OF PSEUDOMONAS DO THIS.
THE CHRONICALLY COLONIZING
AIRWAYS IN CYSTIC FIBROSIS
PATIENTS DON'T HAVE TYPE 3
SECRETION SYSTEM AND DON'T DRIVE
THIS PHENOMENON. IN STARK
CONTRAST DISSEMINATED VARIANTS
OF PSEUDOMOW IN THIS THAT
UPREGULATE THE TYPE 3 SECRETION
SYSTEM DRIVE THIS PHENOMENON. WE
HAVE LEARNED ABOUT THE
MECHANISMS BY WHICH THIS WORKS.
THE PSEUDOMONAS TYPE 3 SECRETION
SYSTEM INTRODUCES EXO ENZYMES TO
THE HOST CELL AND SOME OF THESE
ENZYMES DRIVE THE HOST CELL
KINASE ACTIVITY THAT CAN CAUSE
TAU PHOSPHORYLATION AND
CONCURRENTLY DIS DISASSEMBLE OR
REORGANIZE MICROTUBULES
CONTRIBUTING TO
HYPERPERMEABILITY. WHEN THE TYPE
3 SECRETION SYSTEM EFFECTORS
TARGET THE LUNG MICROGENERATION,
THEY GENERATE VARIANTS OF TAU
RELEASED TO THE PERIPHERY AND
THEY BREAK DOWN MICROTUBULES
THAT BREAK DOWN THE ALVEOLAR
CAPILLARY BARRIER. NOTABLY, THE
CYTOTOXIC OR TAU VARIANTS
RELEASED FROM THE ENDOTHELIUM
ARE IN FACT CYTOTOXIC TO
OTHERWISE NAIVE CELLS. SO ONE OF
THE EXOENZYMES TO HIGHLIGHT FOR
REFERENCE TO COME BACK TO THIS
IS THIS EXOENZYME CALLED Y. THIS
IS A PROMISE PROMISE PROMISE
PRO-- PROMISE PROMISCUOUS
CYCLASE IN ABSENCE OF THAT CUREA
TO DRIVE TAU PHOSPHORYLATION.
THIS CYTOTOXIC VARIANTS OF TAU
ARE POWERFUL IF WE IMMUNOISOLATE
AFTER INFECTION AND PUT ON NAIVE
CELLS WHAT YOU CAN SEE IN 24
HOUR MOVIE COMPRESS IS WITHIN
SIX TO EIGHT HOURS THE CELLS
WILL UNDERGO CYTOTOXIC RESPONSE.
SO THIS IS A VERY PROFOUND
EFFECT, NOT SUBTLE AT ALL. THE
CYTOTOXIC VARIANTS ARE PRODUCED
BY PSEUDOMONAS EARGENOSA LIKE XO
Y BUT NOT LIKE IT BUT INCLUDING
XOY. WE HAVE SEEN THIS ACROSS
MULTITUDE OF ORGANISMS
PHENOMENON OF CYTOTOXIC
ENDOTHELIUM LIKE MRSA CLUB SEAL
CLUB SEE YELL -- IN OTHER CASES
ABOUT THE VIRULENCE ARSENAL
THESE ORGANISMS ARE USING TO
DRIVE THE CYTOTOXIC TAU
PRODUCTION. SO THE SECONDS THING
WE HAVE LEARNED IS THAT BOTH
GRAM POSITIVE AND NEGATIVE
MICROORGANISMS ELICIT CYTOTOXIC
TAU PRODUCTION AND WE HAVE SEEN
IT IN VIRAL INFECTION AND WE CAN
TALK ABOUT THIS MORE LATER.
IMPORTANTLY THE VIRULENCE
ARSENAL THAT IS USED BY THESE
MICROORGANISMS IS ESSENTIAL FOR
DRIVING THE INTERKINGDOM OF
COMMUNICATION THAT CULMINATES IN
THE PRODUCTION OF THIS CYTOTOXIC
TAU VARIANTS. SO WE KNOW THE
LUNG ENDOTHELIUM HAS TAU. WE
KNOW INFECTION CAN DRIVE
CYTOTOXIC TAU VARIANTS THAT CAN
BE DELETERIOUS. WHERE DOES IT
GO? WHAT WE KNOW FROM STUDIES IS
WHEN CYTOTOXIC TAU IS GENERATED
IN THE NATURAL COURSE OF
INFECTION, IT CAN BE RECOVERED
FROM THE LAVAGE FLUID, BLOOD,
HEART, CEREBRAL SPINAL FLUID AND
BRAIN PARENCHYMA. SO A LITTLE
BIT ON THIS, IF WE LOOK AT
ALVEOLAR LAVAGE FLUID FIRST,
LET'S HIGHLIGHT THIS EXPERIMENT,
THIS STUDY THAT WAS DONE WITH
OUR COLLEAGUES AT UAB AND RON
HERE ALSO AT UNIVERSITY. WHICH
WE STUDIED EIGHT PATIENTS FOUR
WHOM HAD ONGOING LOWER
RESPIRATORY TRACK INFECTION AND
FOUR WHOM DIDN'T. ALL EIGHT
PATIENTS HAD SIMILAR SOFA SCORES
AND THEY WERE MEDICALLY
CLINICALLY INTERESTING BECAUSE
THEY HAD WRONG CLEO LAR LAVAGE
FLUID AND CSF FROM THE SAME
PATIENT. WHEN RON DID THE
WESTERN BLOTTING OF THE BRONC
OWE LAR LAVAGE FLUID HE
IMMUNOPRE PRECIPITATED WITH
AMYLOID ANTIBODY CALLED A 11 AND
IMMUNOBLOTTED WITH TNT 1
ANTI-TAU ANTIBODY. AND WHAT YOU
SEE IS THAT IN THE BALF OF THE
FOUR PATIENTS ALL HAD PROMINENT
TAU IMMUNOREACTIVE BANNING,
WHEREAS THE PATIENTS THAT DID
NOT HAVE ONGOING INFECTION HAD
ONLY MINOR OR NO TAU
IMMUNOREACTIVITY. WE CAN FOLLOW
THIS PATTERN SYSTEMATICALLY IN
PNEUMONIA MODEL. REINFECT
RODENTS WITH PSEUDO PSEUDOMONAS.
WE STUDY RESPONSE TO INFECTION
AND COLLECT ARTERIAL PLASMA FOR
ANALYSIS. THIS IS AN EXAMPLE OF
THE KIND OF TAU IMMUNOREACTIVE
BANDING WE SEE IN THE PLASMA,
THE HEART AND THE BRAIN IN THESE
ANIMALS AFTER INFECTION. SO WE
KNOW THAT WHEN WE HAVE INFECTION
CYTOTOXIC TAU VARIANTS ARE
GENERATED AND THEY ARE PRESENT
IN THE BALF, THE PLASMA, THE
HEART AND THE BRAIN OF BOTH
ANIMAL AND HUMAN SUBJECTS WITH
ONGOING PNEUMONIA, AND TAU DISIS
ASSOCIATED WITH END ORGAN
DYSFUNCTION. THE BALF
CONCENTRATIONS OF T 22
IMMUNOACTIVE TAU ARE HIGHLY
ASSOCIATED WITH THE FOUR POINT
LUNG INJURY SCORE AMONG OTHER
INDICES OF END ORGAN
DYSFUNCTION. SO WE GENERATE
CYTOTOXIC VARIANTS OF TAU, THIS
TAU CAN DISSEMINATE INTO VARIOUS
BIOCOMPARTMENTS AND IT CAN BE
INJURIOUS. WHAT HAPPENS WHEN IT
GETS TO THE BRAIN? SO WHAT WE
HAVE LEARNED OVER THE YEARS IS
THAT THE INFECTION ELICITED
CYTOTOXIC TAU VARIANTS ARE
DELETERIOUS TO THE HIPPOCAMPUS.
THEY CAN INHIBIT LONG TERM
POTENTIATION, CAUSE
HYPEREXCITABILITY AND OVER TIME
CAN REDUCE SPINE DENSITY MANY
THE CA 1 NEURONS. -- IN THE CA 1
NEURONS. BACK TO THE STUDY WE
PERFORMED WITH THESE EIGHT
PATIENTS, AND NOW LET'S EXAMINE
WORK THAT WAS DONE BY
NEUROSCIENTIST MIKE LYNN WITH
THE CSF OBTAINED FROM THESE
PATIENTS. SO I JUST WANT TO
POINT OUT WHEN THE CSF WAS
OBTAINED IT WAS BOILED OR NOT
BOILED BEFORE IT WAS STUDIED.
AND THIS ALLOWED US TO
INACTIVATE HEAT SENSITIVE HEAT
LAY BILE MOLECULES AND STUDY
ONLY HEAT STABLE MOLECULES AND
COMPARE THEM. WHAT MIKE DID IS
TOOK THE CSF AND INCUBATED ON
HIPPOCAMPAL SLICES FROM RODENTS
AND EXAMINED LONG TERM
POTENTIATION. SO ON THE Y AXIS
HERE WHAT WE HAVE IS THE FIELD
POTENTIAL, FIELD EXCITATORY POST
SYNAPTIC POTENTIALIAL PLOTTED
AGAINST TIME AND THE RESPONSE IN
THIS CASE WAS TO HIGH FREQUENCY
STIMULATION. AND THE WHITE
CIRCLES AT THE TOP REPRESENT THE
LTP LONG TERM POTENTIAL THAT WAS
OBSERVED IN THE HIPPOCAMPUS
AFTER THE RODENT HIPPOCAMPUS WAS
INQUEUE INCUBATED WITH CSF FROM
THE NON-INFECTED PATIENT.
REMEMBER THIS PATIENT HAD THE
SAME APACHE SCORES AN SOFA
SCORES WITH THE INFECTION.
HOWEVER, WHEN THE CSF OBTAINED
FROM THE PATIENT WITH PNEUMONIA
PATIENTS WITH PNEUMONIA
INCUBATED ON HIPPOCAMPUS, LTP
WAS ALTOGETHER ABOLISHED. WE
THEN NEUTRALIZED THAT CSF WITH
AN ANTI-TAU ANTIBODY, T 22
ANTIBODY AND REPEATED
EXPERIMENT. WHAT YOU SEE IS THAT
WHEN THE PNEUMONIA PATIENTS CSF
WAS NEUTRALIZED WITH ANTI-TAU
ANTIBODY, THE LONG TERM
POTENTIATION WAS ENTIRELY
RECOVERED. SO WE CAN FOLLOW THIS
PROCESS IN PRE-CLINICAL MODELS
OF PNEUMONIA, WE CAN ADDRESS
TIME LINE AND SENSITIVITY WITH E
SEE IN THE BRAIN FOLLOWING
PNEUMONIA INFECTION. SO FIRST
QUESTION DOES PNEUMONIA SUPPRESS
LONG TERM POTENTIATION? TO
ADDRESS THE ISSUE WE USED
INTRATRAINIAL INOCULATION OF
PSEUDOMONAS AND STUDIED 24 AND
48 HOURS LATER. YOU CAN SEE OVER
24 AND 48 HOURS THERE IS
PROGRESSIVE DECLINE IN LONG TERM
POTENTIATION. THIS IS NOTABLE
FOR US BECAUSE IT MAKES US THINK
WE MIGHT HAVE A THERAPEUTIC
WINDOW IN THE EARLY ADVANCE UPON
INFECTION. IN ADDITION OVER THE
SAME TIME COURSE WHAT WE SEE IS
THAT THE CA 1 VIRUS IS
HYPEREXCITABLE AS ILLUSTRATED BY
THE RED LINE HERE IN THE POST
PSEUDOMONAS INFECTION PERIOD.
WHEN MIKE STUDIED ORGANIZATION
OF THE ARCHITECTURE OF THE SPINE
DENSITY, 1, 2, 3, 4 WEEKS AFTER
PNEUMONIA, WHAT HE FOUND SUDS
SIGNIFICANT REDUCTION IN NOT
ONLY WAS SIGNIFICANT REDUCTION
IN KINDS OF SPINES PRESENT IN CA
1 FIBERS. SO OVER TIME A
SIGNIFICANT REMODELING OF SPINE
DENSITY WE SEE IN THE
HIPPOCAMPUS. SO THAT IS
INTERESTING HOW IMPORTANT
PSEUDOMONAS -- OR PNEUMONIA IS
TO DRIVING COGNITIVE
DISFUNCTION. WHAT ROLE DOES TAU
LAW? WE REPEAT EXPERIMENTS IN
WILD TYPE AND TAU KNOCKOUT MICE
IF WE JUST TAKE A LOOK AT THE
BLACK CIRCLES HERE THIS IS THE
WHY WOULD TYPE LTP WE SEE BEFORE
PNEUMONIA, THEN THE OPEN CIRCLES
DOWN HERE AFTER PNEUMONIA, WILD
TYPE MICE ARE SENSITIVE TO
PNEUMONIA INDUCED REDUCTION IN
LTP. YOU SEE THE BLACK SQUARES
REPRESENT TAU KNOCKOUT MICE,
THEIR LTP IS NORMAL AND STILL
NORMAL AFTER INFECTION SO THERE
IS A TAU REQUIREMENT HERE THE
SUMMARY DATA ARE HIGHLIGHTED
HERE. UP B NEXT LOCK TERM
POTENTIATION INDUCES
HYPEREXCITABILITY AND REDUCES
SPINE DENSITY IN THE HIPPOCAMPUS
AND THERE IS TAU RELIANCE IN
THIS PHENOMENON. WE WERE ASKED
TO ADDRESS THE QUESTIONS IN
TERMS OF HOW THE STUDIES WE HAVE
DONE INFORM OUR POSITION FOR OUR
OPINION AND IDEAS ABOUT BRAIN
INJURY AND ARDS, ONE OF THE
QUESTIONS, DO YOU BELIEVE THERE
IS A COMMON FINAL PATHWAY FOR
BRAIN INJURY IN ARDS. SO BASED
ON WHAT WE DISCUSS CYTOTOXIC TAU
VARIANTS ARE LISTED BY
MICROORGANISMS THE VIR LANCE
ARSENAL IS IMPORTANT TO INITIATE
THE TAUOPATHY AND WHAT WE HAVE
SEEN TO THIS POINT STERILE
INFLAMMATION HAS NOT BEEN ABLE
OR SUFFICIENT TO ELICIT THE
PRODUCTION OF CYTOTOXIC TAU
VARIANTS. SO WHEN WE THINK ABOUT
QUESTION LIKE THIS, WE WOULD SAY
NO, THAT THERE IS AN INFECTION
ENDOTYPE AND EVEN WITHIN THE
INFECTION IN IN IN-- -- INDOE
TYPE WE HAVE TO THINK ABOUT THE
ARSENAL USED. WILL INTERVENTIONS
TARGETING ACUTE OUTCOMES IMPROVE
COG I THINKTIVE OUTCOMES IN
SURVIVORS. SO BASED UPON WHAT
WE DISCUSS CYTOTOXIC TAU
VARIANTS CONTRIBUTE TO END ORGAN
INJURY DURING CRITICAL ILLNESS
THEY INDUCE LONG TERM INJURY.
THEY ARE SELF-REPLICATING AND
TRANSMISSIBLE AND WE THINK THERE
IS WINDOW TO TARGET THE
CYTOTOXIC TAU VARIANTS BY
MEDICAL THERAPY DURING AND
PERHAPS THE AFTER MATH OF
INFECTION. SO WE THINK THE
ANSWER HERE IS YES. SO WE USE
THIS THIS REALLY COMMONLY COMMON
PHOTO TO ILLUSTRATE WE LEARNED A
LOT BUT THERE IS A LOT HIDDEN
BELOW WHAT WE ARE UNDERSTANDING.
SO THINGS GOING FORWARD WE NEED
TO UNDERSTAND WHICH AND HOW ARE
THEY DOING IT AND WHEN IS IT
TRUE AN MORE SPECIFICALLY WHEN
IT IS NOT TRUE. SOME ONGOING
EFFORTS OUR GROUP AND THE WAGNER
GROUP ARE TRYING TO UNDERSTAND
THIS. WE CHOSE CELLS IN ADDITION
TO THE ENDOTHELIUM ARE
CONTRIBUTING TO THIS PHENOMENON,
AND IMPORTANTLY WHAT IS THE
STRUCTURAL BASIS OF TAU
VARIANTS, COULD THIS BE
SOMETHING WE NEED TO KNOW WHAT
THE BASIS IS AND WHETHER OR NOT
THERE'S TROPISM TO VARIANTS
BRAIN REGIONS DRIVEN BY
STRUCTURAL BASIS OF THE TAU
VARIANTS. TO AN EARLIER POINT IN
THIS SYMPOSIUM, I THINK THIS
MIGHT BE A SENSITIVE BIOMARKER
OF INFECTION END ORGAN
DYSFUNCTION. WE NEED TO
UNDERSTAND THE BIODISTRIBUTION
AND HALF LIFE. THIS IS
ESPECIALLY IMPORTANT DO WE
DEVELOP IMMUNE RESPONSE AND
ANTIBODY MEDIATED RESPONSE
AGAINST CYTOTOXIC VARIANTS OR
CAN WE USE IMMUNOTHERAPY TO
LIMIT DISTRIBUTION OF THESE
CYTOTOXIC VARIANTS.
>> YOU HIT YOUR TIME. THE OTHER
ISSUE HOW TO GET INTO CSF. WE
DON'T KNOW AND NEED TO AND ONCE
IN THIS CSF HOW TO DISRUPT
HIPPOCAMPAL INFORMATION
TRANSFER. THEN FINALLY CAN WE
DEVELOP MEDICAL THERAPY TO
REDUCE THIS. SO AS A PATHWAY
FORE, I WANT TO MAKE A POINT
THAT I THINK IT IS REALLY
IMPORTANT WE IDENTIFY THE
VIRULENCE ARSENAL OF ORGANISMS,
THAT MAY PRODUCE CYTOTOXIC TAU
AND ELICIT END ORGAN DYSFUNCTION
AND EVALUATE EFFICACY FOR
ANTI-TAU THERAPY. WITH THAT
I'LL END AND TAKE QUESTIONS.
THANK YOU.
>> THANK YOU. FOR YOUR TIME
TROY. WE ARE GOING TO SAVE THE
QUESTIONS FOR THE DISCUSSION
AFTERWARDS. I'M GOING TO HAND
THE REIGNS TO BEN. TO INTRODUCE
THE NEXT SPEAKER. PLENTY OF
TIMES TA END TO CONTINUE TO
DISCUSS. THANK YOU AGAIN.
>> THANK YOU, TROY. IT IS MY
PLEASURE TO INTRODUCE DR. SHOURI
LAHIRI FOR THE NEXT TALK. DR.
LAHIRI IS PHYSICIAN SCIENTIST
AND ASSOCIATE PROFESSOR CEDAR
SINAI MEDICAL CENTER, DIRECTOR
OF THE NEUROSCIENCE CRITICAL
CARE UNIT AS WELL AS CRITICAL
CARE RESEARCH. HIS LABORATORY TO
US CONSIST ON MECHANISTIC
UNDERPINNINGS OF ACUTE BRAIN
DYSFUNCTION OR DE DELIRIUM
INCLUDING DISCOVERY OF
BIOMARKERS OR OTHER MARKERS FOR
CLEARING AN ACUTE BRAIN
DYSFUNCTION AND ALSO MECHANISMS
THAT LEAD TO BRAIN DYSFUNCTION.
DR. LAHIRI, THANK YOU FOR JOIN
US.
>> PLEASURE TO BE HERE. SHOUT
OUT TO DR. HAROLD FROM THE FIRST
SESSION AND THANK HER FOR THAT
NARRATIVE AND ALSO MOTIVATION
HEART WRENCHING BUT MOTIVATING
STORY OF HER STRUGGLES.
ROLE OF EL 6 IN INDUCED
DELIRIUM, DISCLOSURES. AS HAS
BEEN IT RATED, DELIRIUM IS ACUTE
CONFUSIONAL STATE CHARACTERIZED
BY INTENTIONAL PROBLEMS
EXECUTIVE DISFUNCTION, SHORT
TERM MEMORY IMPAIRMENT. IT MAYBE
INVARIABLE FEATURE OF ARDS
OCCURRING IN BETWEEN 70 TO 100%
PATIENTS. IT IS NOT JUST A
MARKER OF BAD BRAIN SUBSTRATE,
UNMASKING OF BAD BRAIN SUBSTRATE
BUT SOMETHING THAT ACT SET RATED
DEMENTIA AND LONG TERM
NEURODEGENERATION. THAT IS
CLEARING NOW INSUSCEPTIBLE
PATIENT POPULATION THE RISK OF
DEMENTIA DOUBLES WITH EXPOSURE
TO DELIRIUM VERSUS NOT. SO MAYBE
ONE FEW MUCH NEEDED
OPPORTUNITIES TO MODIFY LONG
TERM COGNITIVE IMPAIRMENT AND
ADDRESS NEW PANDEMIC WE ARE
GETTING INTO OF DEMENTIA
ALZHEIMER'S DISEASE AND RELATED
DEMENTIAS. CLEARLY THERE IS A
SIGNIFICANT NEED TO UNDERSTAND
UNDERLYING BIOLOGICAL MECHANISMS
IT IS HETEROGENOUS DISEASE BUT
SPECIFIC SPECIFICALLY PHENOTYPE
POPULATIONS IT GREATLY HELP OUR
CAUSE TO ADDRESS BIOLOGICAL
MECHANISMS THAT REMAIN UNKNOWN.
ONE OF THE REASONS IT IS
REMAINED UNKNOWN IS BECAUSE WE
HAVE LACKED OF COURSE CLINICAL
LITERATURE IS IT RATED MULTIPLE
TIMES IN THE PRIOR SESSION BUT
WHAT WE DON'T HAVE IS MECHANISMS
FROM PRE-CLINICAL MODEL OR
ANIMAL MODELS. BECAUSE DELIRIUM
IS NOT STUDIED THROUGH BASIC
LEVEL OF ANALYSIS SO IN ORDER TO
GET TO SOME OF THAT WHAT WE
FOCUS ON AND SHARE THAT DATA
WITH YOU OR THAT APPROACH WITH
YOU. INTERLEUKIN 6 POPS UP
EVERYWHERE, THERE IS A REASON
STUDY ON POST-OPERATIVE DELIRIUM
AND ROAM OF IL 6. THIS IS
UNPUBLISHED HUMAN DATA FROM
VANDERBILT COHORT PROVIDED TO ME
BY DR. WEST HEELEY. THESE ARE
LUNG RELATED REASONS. INCLUDE
PATIENTS WITH ARDS AND PATIENTS
WITH COPD OR INTUBATED FOR
AIRWAY SUPPRESSION. ET CETERA.
THIS IS UNADJUSTED FOR AGE SEX
AND OTHER FACTORS BUT IT IS
STRIKING THAT IN SUCH A
HETEROGENOUS PATIENT POPULATION
IN ICU, THAT IL 6 EXPLAINED 6%
VARIATION OF DELIRIUM DURATION.
SO THAT IS STARTING POINT.
CORRELATION DOESN'T PROVE
CAUSATION SO WE NEEDED TO
ADDRESS THIS WITH IN ISOLATED
MANNER ISOLATING VARIABLES, SO
WE DEVELOPED A MODEL FOR
VENTILATOR INDUCED INJURY TO
SIMULATE ARDS. SO TO DO THAT,
THE FIRST ASPECT OF THAT IS TO
DEVELOP BEHAVIOR I DON'T RECALL
PHENOTYPES THAT REPLICATE
DELIRIUM. SO WE LOOK AT MULTIPLE
DIFFERENT ASSAYS ONE OF THEM IS
THE OPEN FIELD ASSAY,
QUANTIFYING AMOUNT OF TIME THE
ANIMAL SPENDS IN THE PERIPHERY
OF THE MAZE COMPARED TO CENTER.
AS MARKER OF ANXIETY EXECUTIVE
DYSFUNCTION, WE ALSO LOOK AT
ELEVATED PLUS MAZE WHICH IS A
CROSS SHAPE MAZE WITH AN OPEN
ARM AND CLOSED ARM AND ANXIOUS
ANIMALS AVOID THE OPEN ARM AND
PREFER STAY IN THE CLOSED ARM.
ALSO ABLE TO CAPTURE THE
FLUCTUATING ACTIVITY OF THE
ANIMAL'S COURSE OF ACTIVITY VIA
CALCULATION OF COEFFICIENT OF
VARIATION. THAT'S ALL PART OF
THE OPEN FIELD ASSESSMENT. WE
EVALUATE ATTENTION AND SHORT
TERM MEMORY FOR RECOGNITION,
PRESENCING A NOVEL OBJECT AND
FAMILIAR OBJECT TO ANIMAL, AND
THEN ASSAY TIME SPENT WITH EACH
OBJECT AND IF THEY SPEND MORE
TIME WITH NOVEL OBJECT THAT'S
NORMAL, THEY GO BACK TO THE
FAMILIAR OBJECT AND THAT'S
ABNORMAL RESPONSE AND INDICATING
LACK OF SHORT TERM MEMORY OR
ATTENTION. THE Y MAZE
SPONTANEOUS ALTERATION IS
ANOTHER ASSAY WHICH LEVERAGES
THE IDEA NORMAL ANIMAL
ALTERNATES BETWEEN ARM ARMS OF
YMA AND THE THE INJURED ANIMAL
BACK TO SAME ARM YMA INDICATION
OF ATTENTION AND SHORT TERM
MEMORY. SO WE USE A WIDE RANGE
OF BEHAVIORAL ASSAYS AND TEST
PRE-INJURY AND POST INJURY READ
OUTS. IN THE VENTILATOR INDUCED
LUNG INJURE SRI MODEL, WE USE
DIFFERENT APPROACHES TO INDUCE
LUNG INJURY. ONE WE USED MOST IS
THE 35CC KILOGRAM HYDRIDER
VOLUME, THIS IS ALSO USED IN ONE
OF THE EARLIER STUDIES DR.
GERARD MENTIONED THAT LED TO THE
RECOMMENDATIONS OF LARGE
CLINICAL TRIAL ON USING LOW
TITER VOLUME VENTILATION THAT
RESULTED IN CHANGE OF OUTCOMES.
WE QUANTITY QUANTIFIED PRESENCE
OF VENTILATOR INJURY BY LOOKING
AT LUNG INFLAMMATION, ALBUMIN,
STAINING THINNING OF ALVEOLAR
WALLS ET CETERA. OUR BRAIN READ
OUT IS THAT OF CASPASE 3,
SOMETHING WE FOUND TO BE
PREDICTIVE OF BEHAVIORAL
IMPAIRMENT SO THIS CLEAVE
CASPASE 3 EXPRESS IN FRONTAL
CORTEX HIPPOCAMPUS WHICH ARE THE
AREAS OF THE BRAIN THAT SYMPTOMS
OF DELIRIUM LOCALIZE TO APPEAR
TO PREDICT BEHAVIORAL
PERFORMANCE OF INDIVIDUAL ANIMAL
LEVEL BUT INCLUDE 10 CC
MECHANICAL VENTILATION GROUP TO
DISENTANGLE VENTILATOR EFFECTS.
SO WHAT WE SEE IN GREEN IS
EXPRESS OF CC 3 FRONTAL CORTEX
HIPPOCAMPUS, SIGNIFICANTLY MORE
SO IN THE LUNG INJURY GROUP THE
VILLE -- COMPARED TO THE
BREATHING GROUP. AT INDIVIDUAL
ANIMAL LEVEL AMOUNT OF CC 3
EXPRESSION APPEARS TO PREDICT
PERFORMANCE OF BEHAVIORAL
TESTING MORE THEY SPENDS HIGHER
RIFF PRIA, THE HIGHER THE CC 3
LESS TIME OPEN ARM OF ELEVATED
PLUS MAZE AND HIGHER THE CC 3
LESS SPONTANEOUS ALTERNATIONS
THEY PERFORM. SO IT IS A
STRUCTURAL MARKER OF DELIRIUM.
SO IN ORDER TO EVALUATE EFFECT
OF PERIPHERAL I L 6 ANING THE
NICHE WE DID AN EXPERIMENT
ADMINISTERING TWO TYPES OF IL 6
INHIBITORS IN THE PERIPHERY THAT
WAS IL 6 ANTIBODY AND RECEPTOR
AND WE ADMINISTERED THIS AS A
PREVENTIVE TREATMENT PRIOR TO
THE ONSET OF VENTILATION AND
LUNG INJURY. WE FOUND CC 3 FULLY
REVERSED ABOUT IL 6 TREATED
GROUP FRONTAL CORTEX HIPPOCAMPUS
WITH NO EFFECT OF LUNG
INFLAMMATION ITSELF THIS
CORRESPONDED TO IMPROVEMENTS IN
DELIRIUM LIKE BEHAVIOR ACROSS
MULTIPLE ASSAYS IN OPEN FIELD, Y
MAZE. WE HAD TO OPTIMIZE TIME,
THIS IS A TRICKY MODEL BECAUSE
YOU HAVE TO DISENTANGLE AFFECT
OF LIMITED MOBILITY FROM LUNG
INJURY LUNG INFLAMMATION AND THE
FACT IF YOU LET THEM RECOVER
LONGER PERIODS OF TIME THEIR
BRAIN FUNCTION RECOVER BUT THIS
IS ACUTE BILI MODEL. SO THE
MOUSE DATA INDICATES PERIPHERAL
PLASMA IL 6 PREDICTS THE
STRUCTURAL DELIRIUM LIKE
PHENOTYPE CC 3 AND CLINICAL DATA
SHOWED EARLIER SEEMS TO SUGGEST
THAT IL 6 IN THE PERIPHERY
PREDICTS DELIRIUM SEVERITY. SO
WHICH HYPOTHESIZE IL 6
TRANSITIONNALLING PATHWAY
UNDERLYING THE DELIRIUM LIKE
PHENOTYPE WE SEE IN THIS PATHWAY
YOU HAVE RELEASE OF I IL 6
INDUCED FROM LUNG INFLAMMATION
BUT ALSO INFECTIOUS MODELS OF
INTRATRACHEAL LPS AND URINARY
TRACT INFECTION MODEL. AND FOUND
THAT WHEN YOU RELEASE IL 6 IT
BINDS TO SOOLABLE IL 6 RECEPTOR
IN THE BLOOM PERIPHERY AND THEN
IT -- BLOOD PERIPHERY AND GAIN
ENTRY TO NEURONS GP 130
TRANSMEMBRANE PROTEIN WITHOUT
NEEDING TO BIND CLASSICAL
MEMBRANE RECEPTORS WHICH NEURONS
WOULD LACK ANYWAY. SO THIS
PATHWAY IS IN SOME WAYS
INDEPENDENT OF THE MICROGLIA
STORY BUT CERTAINLY I ALSO AGREE
WITH PRIOR SPEAKERS THAT THERE
IS SIGNIFICANT RELEVANCE OF THE
MICROGLIA PATHWAY AS INFECTION
PARTICULARLY AS INFECTION
EVOLVES OVER TIME. TO TEST THIS
THEORY IN PATIENT, I AGAIN
DISCUSSED THE FINDINGS WITH MY
FRIEND MENTOR AND COLLEAGUE WE S
ELI VANDERBILT. WE DECIDED TO
LOOK AT THE DATA IN HIS CLINICAL
PATIENT COHORT. THIS IS PRE-AND
POST ADVENT OF TOZILIZMAB
INHIBITOR FOR COVID TREATMENT.
THE THEORY WAS AFTER THE ONSET
OR AFTER THE ADVENT OF TOCI
THERE IS SIGNIFICANTLY LESS
DELIRIUM IN MATCHED PATIENTS. SO
INCLUDED PATIENTS WITH AGE
ADULTS DIAGNOSE WITH COVID
INFECTION ADMITTED TO THE NICU
IN VANDERBILT OR COVID ICU. THE
CONTROL GROUP RECEIVED STEROIDS,
TOCI GROUP RECEIVED STEROIDS AND
TOCI AND EXCLUDED PREGNANT WOMEN
AND PRISES NEARS IN THE STUDY.
THE LIKELY OUTCOME IS 21 DAY,
PRETTY STANDARD WELL ESTABLISHED
PRIMARY OUTCOME LOOKED MULTIPLE
STUDIES VANDERBILT GROUP AND
SECOND ONES WE KNOW ARE AFFECTED
POSITIVELY BY TOCI TREATMENT, 90
DAY MORTALITY, HOSPITAL LENGTH
OF THE STAY NUMBER OF DAYS
MECHANICAL VENTILATION. THIS IS
UNPUBLISHED DATA IN GOING
THROUGH THE PROCESS OF
SUBMITTING NOW BUT SO THERE IS
SOME DIFFERENCES, SOME
DIFFERENCES IN AGE, SEX,
CHARLESTON INDEX SEVERITY INDEX
AND NONE IN USE OF OPIATES OR
MEDAZLAM, KNOWN CONFOUNDERS IN
DELIRIUM. AND THOSE ARE THE
OUTCOME DAYS IN THIS UNIVARIANT
ANALYSIS. THERE'S THREE DAYS OF
DELIRIUM FREEDOM IN CONTROL
GROUP, SEVIN IN THE THE,OCI
GROUP, THAT WAS SIGNIFICANTLY
DIFFERENT IN UNIVARIANT
ANALYSIS. NO DIFFERENT IN IN
MORTALITY ICU LENGTH OF STAY
HOSPITAL LENGTH OF STAY. THAT IS
INTERESTING BECAUSE THOSE ARE WE
KNOW THAT TOCI POSITIVELY
AFFECTS OUTCOMES BUT HERE STILL
EFFECT ON DELIRIUM AND
MULTI-DURATIONAL ANALYSIS THIS
HELD TRUE WITH THE TOCI GROUP
PREDICTING THE TOCI GROUP HAVING
INCREASE ODDS OF DELIRIUM
FREEDOM OR IN THE FIRST # 1 DAYS
WITH P VALUE .007. SO IN
SUMMARY, THERE WAS NO DIFFERENCE
IN VENTILATOR LENGTH, VENTILATOR
DOES RATION, HOSPITAL LENGTH OF
STAY, ICU LENGTH OF STAY OR
MORTALITY 90 DAYS BUT
SIGNIFICANT DIFFERENCE IN
DELIRIUM COMA FREE DAYS IN THE
TOCI TREATED GROUP. THE ANTI-IL
6 TREATED GROUP SO I MANY TAKE
OF THIS IS, DESPITE BEING
UNDERPOWERED TO DETECT THE KNOWN
DESPITE UNDERPOWERED TO DETECT
THE KNOWN EFFECTS OF TOCI ON
VENTILATOR DURATION HOSPITAL
LENGTH OF STAY, ISO LENGTH OF
STAY MORTALITY, THERE WAS EFFECT
ON DELIRIUM AND COMA. WHICH
SUGGESTS THAT PERHAPS THE
ANTI-IL 6 TREATMENT IS ACTUALLY
HAS A GREATER TREATMENT EFFECT
ORNATE LEER YUM THAN OTHER YOU
OUT COMES KNOWN TO AFFECT BY
TOCI. SO IN SUMMARY, THE CURRENT
KNOWLEDGE GAPS IN FUTURE
RESEARCH IN MY MIND WE HAVE TO
DO A PROSPECTIVE CLINICAL TRIAL
INHIBITS IL 6 TRANSITIONNALLING
BASED ON DATA, WE NEED TO
DISAGGREGATE DELIRIUM TO
DISTINCT PATIENT SUB SETS BASED
ON MOLECULAR CLASSIFIERS IN THIS
INCLUDES LOOKING AT HYPO ACTIVE
AND HYPERACTIVE PHENOTYPES, COMA
IS CERTAINLY FORM OF HYPO ACTIVE
DELIRIUM, THESE DISTINCT DISEASE
OR REFLECT CONTINUUM OF
SEVERITIES. WE HAVE DATA TO
SUGGEST THAT THE LATTER IS TRUE
WE NEED TO LOOK AT PERIPHERAL
HORMONAL AND IMMUNOLOGICAL
INTERACTIONS IN DELIRIUM. WHAT
IS THE ROLE OF ESTROGEN IN
SUPPRESSING PERIPHERAL
INFLAMMATIONMATION AND
MITIGATING DELIRIUM. WE HAVE
OTHER DATA THAT I HAVEN'T SHOW
THAT SHOWS POST MENOPAUSAL MICE
REPLEASE OF 17 BETA AS STRAY
DIAL AMELIORATES DELIRIUM AND
THAT OCCURS THROUGH PERIPHERAL I
ALREADY -- IL 6 SUPPRESSION. AS
MENTIONED BY PRIOR SPEAKERS
EVALUATE BRAIN IMMUNOLOGICAL SO
FAR FOCUSED ON SYSTEMIC
IMMUNOLOGICAL RESPONSE MICROGLIA
IN PARTICULAR AND MICROGLIAL
REACTIVITY IN DELIRIUM.
PARTICULARLY AS THE INFECTION
TAKES OR INJURY TAKES HOLD IT
OFTEN CLINICALLY SEE THIS
DISCONNECT WHERE SYSTEMIC
PROCESSES RESOLVE BUT PATIENT
REMAINS PERSISTENTLY DELIRIOUS.
THAT MIGHT REFLECT THIS ONGOING
FEET FORWARD MECHANISM WITHIN
THE BRAIN MEDIATED BY REACTIVE
MICROGLIA. RELATED TO THAT WE
NEED TO LOOK AT DIFFERENCE
BETWEEN INFECTION AND HOST
IMMUNE RESPONSES IN DELIRIUM
VERY FOCUSED ON TREATING
INFECTION WHEN AS AN APPROACH
TREATING DELIRIUM BUT OBVIOUSLY
THAT MIGHT NOT BE THE FULL
STORY, THE HOST IMMUNE RESPONSE
WE NEED TO BE MODULATED AND
PERHAPS EVEN TREATMENT FOR
INFECTION SOMETIMES MAYBE WORSE
FOR DELIRIUM AND SO THAT RISK
BALANCE NEEDS TO BE ASSESSED.
AS MENTIONED BY PRIOR SPEAKERS
EVALUATE BLOOD AND PHYSIOLOGICAL
MARKERS IN DELIRIUM ONES THAT
AUTOMATE THE PROCESS AND REMOVE
THE BURDEN OF DIAGNOSIS AND
DETECTION IN THE ICU SO
TREATMENTS CAN BE IMPLEMENTED ON
A MORE TIMELY BASIS. SO IF THERE
IS ONE HIGH RISK HIGH REWARD
STUDY, A PROSPECTIVE CLINICAL
TRIAL OF IL 6 TRANSITIONNALLING
INHIBITION AND HUE FOR YOUR
ATTENTION -- THANK YOU FOR YOUR
ATTENTION. T HAPPY TO TAKE
QUESTIONS. DELIRIUM IS A RISK
FACTOR FOR POOR OUTCOMES AFTER
ARDS. BUT IS THERE A MECHANISTIC
LINK THERE? ?
>> I DO. THE CONNECTION BETWEEN
THE TWO MAY BE ACTUALLY
INACTIVATED MICROGLIA AN
NEUROTOXIC PHENOTYPES THAT ARE
OF MICROGLIA THAT BASICALLY SET
THE STAGE FOR LONG TERM
NEURODEGENERATION. SO CERTAINLY
NEED DO THAT AND LOOK AT THESE
PATIENT COHORT. ONE ASPECT OF IT
OR ADVANTAGE OF DOING A CLINICAL
TRIAL WITH IL 6 INHIBITOR IS
LOOK AT LONGER TERM OUTCOMES.
>> IT IS MY PLEASURE TO
INTRODUCE THE FOURTH SPEAKER IN
OUR SESSION. DR. TAREK SHARSHAR.
DR. SHARSHAR IS JOINING US FROM
PARIS, HEAD OF NEUROINTENSIVE
CARE UNIT AT THE POLE OF GHU
PSYCHIATRY AND NEUROSCIENCE
INSTITUTE. HE HAS BACKGROUND
BOTH IN NEUROLOGY AND INTENSIVE
CARE MEDICINE AND SUPERVISES A
MULTI-DISCIPLINARY EFFORT TO
UNDERSTAND PHENOTYPES OF BRAIN
INJURY IN THE SETTING OF SEPSIS
ARDS AND OTHER FORMS OF CRITICAL
ILLNESS. DR. SHARSHAR, THANK YOU
FOR JOINING US.
>> THANK YOU, VERY MUCH. I'M
VERY GRATEFUL TO THE NIH FOR THE
KIND INVITATION TO THIS VERY
STIMULATE LATING WORKSHOP. THERE
IS A GREAT HONOR FOR ME. I DON'T
SEE MY SLIDES SO I DON'T KNOW IF
I HAVE TO PULL UP THEM.
SO WE SIGH BRAIN DISFUNCTION IN
CRITICAL I WILL PATIENTS. WE
HAVE INDIVIDUALIZED FREE
PHENOTYPES INCLUDING SICKNESS
BEHAVIOR, CAPABILITY IN TERMS OF
COMA, AND PARTICULAR CONDITION
OF (INAUDIBLE) PATIENT, TRY
PHENOTYPES AN RELATIONSHIPS WITH
THE PSYCHOCONNECTIVE AND
(INAUDIBLE) OUTCOMES. I WILL
FOCUS ON THE FIRST AND THIRD
PHENOTYPES. BY MY COLLEAGUES.
THIS IS FROM SICKNESS BEHAVIOR
WHICH (INAUDIBLE) NEUROENDOCRINE
AUTONOMIC SYSTEMS.
PSYCHOLOGICAL DISORDERS
INCLUDING ANXIETY (INAUDIBLE).
SICKNESS BEHAVIOR IS A MAYOR
HIGHLY PRESERVED ADAPTIVE
RESPONSE TO PERIPHERAL
INFORMATION, RELATED TO
INFECTION. IT IS CHARACTERIZED
BY STEREOTYPE CALLED CHANGES IN
BEHAVIOR WHICH WE HAVE
EXPERIENCE IN OUR LIFE. THESE
CHANGES ARE SPECIFIC ACT
INVESTIGATION OF NEUROENDOCRINE
SYSTEM WHICH ARE (INAUDIBLE)
AXIS THAT ALLOWS NERVOUS SYSTEM
THE LIMB MIC BIC AND AUTONOMIC
NERVOUS SYSTEM ARE DIVIDED BY
TWO PATHWAYS. THE HUMORAL
PATHWAY, WHICH ARE LOCATING THE
VICINITY OF THE NEUROENDOCRINE
METABOLOMIC (INAUDIBLE)
RESPECTIVELY. LY PH INFLAMMATORY
MEDIATION OF THE BLOOD TO
NEUROENDOCRINE (INAUDIBLE). THE
NEURAL PATHWAY INVOLVED NERVE
WHICH DETECTS LOCAL INFLAMMATION
THAT CONTROL IT. IT PLAY AS SHE
SURABLE ROLE IN (INAUDIBLE).
THIS IS A MATURE MOUSE AUTONOMIC
LIMB BIC SYSTEM, AS YOU CAN SEE
THERE ARE HIGHLY INTERCONNECTED.
WE HAVE PARTICULARLY INTERESTED
IN THE AMYGDALA WHICH IS A
COMPONENT OF THE LIMBIC SYSTEM.
THE COMPLEX OF THE (INAUDIBLE)
NUCLEUS STRUCTURE WHICH CONTROLS
BLOOD PRESSURE IN THE AMYGDALA.
THIS IS A REALLY SCHEMATIC VIEW
OF NEURAL SIGNALING DYSFUNCTION
AT ANY LABEL, ANY DYSFUNCTION
RESULT IN MAL ADAPTIVE BEHAVIOR,
THESE CAN BE THE CASE OF ANXIETY
. WE HAVE ASSESSED
RELATIONSHIP BETWEEN ANXIETY AT
ICU ADMISSION AND OCCURRENCE OF
ORGAN -- FIRST SEVIN DAYS AND
ANXIETY WAS CONSIDERED MODERATE
WHEN THE CITRATE SCALE WAS ABOVE
40 OUT OF 80. WE FOUND ANXIETY
WAS ASSOCIATED WITH ORGANS THAT
ARE PARTICULAR SEVERITY OF
TESTIFY SCORE. IN ANCILLARY
STUDY WE ASSESS MANY FIERCE OF
THESE PATIENTS ADMITTED IN ICU.
WE FOUND ABSENCE OF FEAR OF
DYING WAS ASSOCIATED WITH ORGAN
FAILURE ALONG WITH INTENSITY OF
ANXIETY SITE AND SCALE. SO THE
QUESTION, WHAT IS THE MECHANISMS
UNDERLYING (INAUDIBLE). NEXT
SLIDE. IMPAIRMENT OF
INTERCEPTION OR -- WHICH PLAY A
MAJOR ROLE IN BEHAVIORAL DANGER
AND TO STRESS. IS THERE ANY
HUMAN FOR ACUTE DYSFUNCTION,
YES, BRIEFLY WE HAVE SEPSIS
INDUCES INACTIVATION OF --
FEATURES IN PATH LOGICAL
RECORDING, MOREOVER WE FELT THAT
PHARMACO PHARMACO GENOMICS OF
PHARMACOLOGICAL (INAUDIBLE)
SPECIFIC INHIBITION PREVENTS
OCCURRENCE OF PTSD BEHAVIOR IN A
MOUSE (INAUDIBLE) IN CONCLUSION
THERE'S EVIDENCE FOR ACUTE
AMYGDALA DYSFUNCTION IMPAIRED
PERCEPTION OF DANGER THAT MIGHT
CONTRIBUTE TO SOMATIC
DETERIORATION BY IMPAIRMENT OF
FEAR. WHICH ALSO RESULTSES IN
PTSD BY INACTIVATION OF FEAR
CIRCUIT. WE ARE CURRENTLY
INVESTIGATING WHETHER EARLY
AMYGDALA OF GAY VALUE NERVE.
PHARMACOLOGICAL AND
NON-PHARMACOLOGICAL APPROACH
PREVENTS INAPPROPRIATE EARLY
AMYGDALA ACTIVATION. IN THE.
ING MONTHS WE WILL CARRY OUT A
RANDOMIZED CLINICAL TRIAL IN
SEPTIC SHOCK PATIENT IN ORDER TO
INCREASE OUTCOME BY THREE DAYS
BUT ALSO MODULATE MICROGLIAL
ACTIVATION. AND DIRECTION OF
PTSD. -- REDUCTION OF PTSD. THEN
BEGIN IN 7 DAYS. NEXT SLIDE. SO
WE NOW BETWEEN DEEP SEDATION AND
THAT INVOLVE THE BRAIN STEM
DYSFUNCTION. THERE ARE MANY
MAJOR CHALLENGES IN DEEP SEDATED
PATIENTS. HOW DO -- WHAT CAN WE
DETAIL BRAIN DYSFUNCTION, IN
PATIENT, POSITIVE SEDATION ON
WHY DEEP SEDATION IS ASSOCIATED
WITH INCREASED MORTALITY. WE
WERE INTERESTED IN ASSESSING
WHETHER NEUROINFLAMMATION IS
INFORMATIVE (INAUDIBLE) HAS
SHOWN NOT AFFECT BRAIN STEM --
NEXT SLIDE COHORT SOME BRAIN
STEM REFLECTS LESS THAN OTHERS
INCLUDING THE LIGHT REFLECT
CORNEAL REFLECT NEXT SLIDE. WE
FOUND THE B A SENSES OF
(INAUDIBLE) REFLECTS
INDEPENDENTLY ASSOCIATED WITH
MORTALITY AND (INAUDIBLE)
RESPECTIVELY. NEXT SLIDE. OUR
FIRST FINDING SHOWED THAT
NEUROLOGICAL EXAMINATION IN DEEP
SEDATED PATIENTS WAS FEASIBLE
REPRODUCIBLE AND INTERPRETABLE
PHARMACOLOGICAL SIDE. BUT ALSO
ENABLES TO DETECT NECESSITY IN
TERMS OF PATIENT WAYS TO DEVELOP
DISCONTINUATION OF SEDATION.
THEN WE INVESTIGATED WHETHER
THERE WAS BRAIN STEM SYNDROME IN
REASON DEEPLY SEDATE CRITICALLY
ILL PATIENTS. NEUROLOGICAL
QUESTION BUT BECOMING
INTERESTING TO I DRESS. NEXT
SLIDE WE NAME OURSELVES THE --
WE HAVE ASSESS IN 140 THE 2
PROFILES OF HALF PATIENT AGE,
THE RED ONE (INAUDIBLE)
HOMOGENOUS SEPARATION OF THE
BRAIN STEM REFLEXIA, MEANING
THEY ARE UNIFORMLY PRESENT OR
ABSENT TOGETHER. THE SECOND
PROFILE, BLUE ONE IS
CHARACTERIZED BY HETERO
ACTIVATION. THE BLUE PROFILE WAS
ASSOCIATED WITH INCREASE
MORTALITY WITH ISSUE ABOUT SIX.
NEXT SLIDE. THE RIGHT PROFILE,
MAINLY EFFECT OF OBSERVATION,
WHILE BLUE ONE REFLECTS BRAIN
STEM INSULT LIKELY
NEUROINFLAMMATORY FROM THE AREA
WHICH BEFORE MENTIONED
MEASURABLE ROLES AS REALLY --
PATHWAYS. WE DEVELOPED BRAIN
STEM ASSESSMENT SCALE SCORING
THE DYSFUNCTION IN DEEPLY
SEDATEDDISH PAS. WE ARE
VALIDATING THE SCORE.
INTERESTINGLY WE FOUND THAT
INCREASE SCORE IN COVID ARDS
PATIENTS. AS YOU KNOW THE BRAIN
STEM IS AWAKENING THE OTHER
SYSTEM AND VITAL FUNCTION AND
IMMUNE RESIDENCY OF THE
AUTONOMIC NERVOUS S. THERE'S
BRODY OF -- BODY OF EVIDENCE,
ACTIVITY REFLECTING IN CELLULAR
DYSFUNCTION OF ACTIVITY SYSTEM
WHICH MAY CONTRIBUTE TO THE
AWAKENING OF THE (INAUDIBLE).
IMPAIRED HEART RATE VARIABILITY
CONTROLLED BY AMYGDALA IS
ASSOCIATED WITH MORTALITY AND
ORGAN FAILURE. IT HAS BEEN SHOWN
THAT VARIABILITY OF (INAUDIBLE)
IS ASSOCIATED WITH (INAUDIBLE).
IT HAS BEEN SHOWN THAT THERE IS
SHORT CONNECTION OF THE ESS AND
PATHOLOGICAL STUDIES EVIDENCE
NEUROINFLAMMATION AN NEURONAL
APOP STOWSIS BUT ALSO MICROGLIAL
A APOPTOSIS SYSTEM AND THE THE
AUTONOMIC (INAUDIBLE). NEXT
SLIDE. WE HAVE JUST ACHIEVED A
MULTI-CENTER OBSERVATIONAL
STUDY. TO DETERMINE WHETHER
POTENCY VALUE OF P 1478
RESISTANCE OF THE SA -- SSEP, IT
IS GENERATED BY AMYGDALA. AND WE
FOUND INCREASE LATENCY OF P 14
WAS ASSOCIATED WITH INCREASE
MORTALITY AND CRITICAL SEVERITY
PRESERVATION AND PRIMARY BRAIN
INJURY SO WE THINK THIS IS IN
SOME WAY PROOF THAT THERE IS A
BRAIN SCAN DYSFUNCTION OF THE
THE AMYGDALA. AND IN CONCLUSION,
THERE IS EVIDENCE FOR BRAIN STEM
DYSFUNCTION IN DECREASING ATP IN
PATIENT INCLUDING PATTERNS OF
BRAIN STEM REFLEXES ABOLITION,
IMPAIRED NEUROPHYSIOLOGICAL
RESPONSE, IMPAIRED BRAIN STEM
OUTPUT HEART RATE VARIABILITY
AND MAYBE SOME WE KNOW IMPORTANT
OF THE NEUROPATHOLOGICAL
FINDINGS. EVIDENCE FOR PROCESS
ORIGINATING FROM THE BRAIN STEM
DYSFUNCTION AND EVIDENCE FOR
NEUROINFLAMMATORY PROCESS
ORIGINATING FROM THE AREA
POSTREMA. SO WHAT I WILL GAPS I
THINK THE MAIN GAPS WE HAVE
REALLY UNDERSTANDING OF BETTER
GENETIC MECHANISMS OF BRAIN
DYSFUNCTION AND ITS COURSE
TOWARD LONG TERM PSYCHOCOGNITIVE
DYSFUNCTION. BUT ALSO MAYBE WE
SHOULD PROMOTE A CHANCE BETWEEN
PRIMARY (INAUDIBLE) WE HAVE MANY
OPPORTUNITIES AND I THINK THAT
WE CAN SHOULD PROBABLY REACH A
MODEL APPROACH. WE HAVE INCLUDE
REFINE PHENOTYPING OF ACUTE
BRAIN DYSFUNCTION BASED ON
NEUROANATOMICAL APPROACH AND
CLINICAL RESEARCH NEUROLOGICAL
MODELS. TRANSLATIONAL RESEARCH
AND WE HAVE AT OUR DISPOSAL
VALIDATED EXPERIMENTAL MODELS
AND SOPHISTICATED EXPERIMENTAL
TECHNIQUES. AND I THINK THAT WE
SHOULD CARRY OUT PHARMACOLOGICAL
CLINICAL TRIALS BASED ON ROBUST
PRE-CLINICAL EVIDENCE. NEXT
SLIDE. SO HIGH RISK HIGH REWARD
ING IDEAS IS DEVELOPING A
DETECTION TOOL OF BRAIN STEM
DYSFUNCTION APPLICABLE AT
BEDSIDE. DELINEATING ADAPTIVE
FROM MAL ADAPTIVE RESPONSE TO
STRESS. INCLUDING MALADAPTIVE
PSYCHOLOGICAL RESPONSE. AND
RESTORING THE LUNG GUT BRAIN
AXIS. THIS IS JUST AN
ADVERTISEMENTED, VERY HAPPY TO
WELCOME YOU TO SYMPOSIUM IN ICU.
NEXT SLIDE. FINALLY I WOULD
LIKE TO THANK ALL MY FRIENDS AND
COLLEAGUE FROM INSTITUTE PASTEUR
AND ASSISTANCE HOSPITAL PUBLIC
DEPARIS. THANK YOU FOR YOUR
ATTENTION. READY TO TAKE ANY
QUESTIONS.
>> THANK YOU VERY MUCH. I WILL
START WITH A QUESTION, RELATED
TO WORK YOU ARE DOING ON BRAIN
STEM DYSFUNCTION. I UNDERSTAND
WHY THAT IS VERY IMPORTANT FOR
PHENOTYPING ESPECIALLY DEEPLY
SEDATED PATIENTS. BUT AS WE
THINK ABOUT THE BROAD SPECTRUM
OF BRAIN BASED DYSFUNCTION OR
DISABILITY THAT PATIENTS
EXPERIENCE DO YOU THINK THAT
PHENOTYPE IS ALSO RELATED TO
SOME INJURY IN OTHER AREAS OF
THE BRAIN? IS THERE ANY EVIDENCE
OR -- FOR THAT?
>> YOU ASKING WHETHER THE
MECHANISMS THAT INVOLVE THE
BRAIN STEM ALSO PLAY A ROLE --
YES, I THINK WHEN
NEUROINFLAMMATORY PROCESS IS NOT
ONLY RELATED TO THE BRAIN STEM,
IT HAS BEEN HOE IT CAN GO OVER
ALL PARTS OF BRAIN. MICROBIAL
ACTIVATION IS EVIDENCE IN
VARIOUS MODEL, SEPSIS MODELS BUT
ALSO SHOWN ON NEUROPATHOLOGICAL
STUDIES, LONG TIME AGO WE HAVE
NEUROPATHOLOGICAL STUDY OF
PATIENT DIE FROM SEPTIC SHOCK
AND FOUND THAT INACTIVATION OF
MICROGLIAL CELLS, INTERESTINGLY
IT WAS RATHER PARTICULAR AREAS
OF THE BRAIN, BRAIN STEM BUT
ALSO THE LIMBIC SYSTEM ALSO
FRONTAL LOBE. SO SEEMS THAT
THERE IS A NUMBER OF REACTIVITY,
MORE IN SOME PARTICULAR AREAS
WHICH COULD ACCOUNT FOR THE
PHENOTYPE, CLINICAL PHENOTYPES
AN LONG TERM PSYCHOLOGICAL
DISORDERS. WE -- REGARDING BRAIN
STEM DYSFUNCTION WE ILLUSTRATED
EVIDENCE IT IN THE DEEPLY
SEDATED PATIENTS BUT MAYBE CAN
PLAY A ROLE LONG-TERM
DISABILITY. WE KNOW WHEN THE
BRAIN STEM IS INVOLVED IN
PARKINSON DISEASE FOR INSTANCE,
IT CAN COME FROM MANY, MANY
SYMPTOMS LIKE FOG, LOCOMOTIVE
DISABILITY. SO MAYBE THERE IS A
SUB CLINICAL BRAIN STEM
DYSFUNCTION THAT CAN LAST FOR
SOME LONG TERM DISORDER. I DON'T
HAVE PROOF OF THAT.
>> ALL RIGHT. THANK YOU. I DON'T
THINK WE HAVE I HAVE BEEN COMING
QUESTIONS -- INCOMING QUESTIONS
FROM THE CHAT SO MAYBE 60
SECONDS EARLY WILL TURN TO THE
PANEL DISCUSSION AND TRY AND
SUMMARIZE THESE VERY INTERESTING
DIVERSE TALKS WE HEARD DURING
THE SESSION AND TURN BACK TO OUR
PANELISTS. SO SOME COMMON THEMES
EMERGING FROM THESE
PRESENTATIONS ARE ATTENTION
BETWEEN COMMON MECHANISMS AND
COMMON FINAL PATHWAYS THE
COMMONALITY BETWEEN BIOMARKERS
OF DELIRIUM IN URINARY TRACT
INFECTION AND VENTILATE TORR
INDUCED -- VENTILATOR INDUCED
THERAPY, CHEMOTHERAPY, CAR T
THERAPY AS WELL AS IN COVID,
VERSUS SOME OTHERS THAT MAYBE
MORE DISTINCTLY RELATED TO
INFECTION LIKE TAU AND OTHER
PRION LIKE PROTEINS INTRODUCED
INTO THE CIRCULATION. I WOULD
ALSO LIKE TO TOUCH ON ANOTHER
THEME EARLIER MAYBE START WITH
QUESTIONS FOR PANELISTS THERE,
ANOTHER COMMON THEME TO ALL WORK
PRESENTED IS WE AS
NEUROSCIENTISTS
NEUROIMMUNOLOGIST IMMUNOLOGISTS,
WORK WITH ANIMALS A DISTINCT
TOOL KIT DESIGNED TO TRY AND
LOCALIZE BRAIN DYSFUNCTION TO
UNDERSTAND NEUROAN TOM INC.
BASIS OF BEHAVIOR. WE HEARD A
LOT THIS MORNING ABOUT
QUESTIONING WHETHER TOOL KITS WE
USE ARE REFLECTING THE
EXPERIENCE OF PATIENTS AND TRULY
FUNCTIONAL OUTCOMES IMPORTANT
FOR SURVIVORS OF ARDS. TURN THAT
QUESTION ASKED ABOUT CLINICAL
OUTCOMES AND MEASUREMENTS TOOLS
BACK TO THE PANEL AND ASK DO WE
THINK THERE IS SPACE WITHIN THE
MODELS WE ARE USING AND THE WAY
WE ASK OUR QUESTIONS TO PERHAPS
BE MORE FOCUSED ON FUNCTIONAL
OUTCOMES, THAT MAYBE RELEVANT TO
ARDS SURVIVORS RATHER THAN THE
CLASSICAL TOOLS WE HAVE USED,
THAT FOCUS ON REALLY STRONG
CORRELATIONS BETWEEN BEHAVIOR
AND NEUROANATOMY. ONE EXAMPLE
WE MIGHT THINK OF IS -- SORRY,
MICHELLE YOU ARE UNMUTING.
>> I WOULD LOVE TO HEAR YOUR
EXAMPLE BUT TO ACKNOWLEDGE THIS
EMERGING THEME, SEEMS THERE ARE
COMMONALITIES ACROSS IMMUNE
CHALLENGES AFFECTING THE NERVOUS
SYSTEM, THAT MIGHT BE SIMILAR
SYMPTOMS THAT PEOPLE EXPERIENCE
AFTER CANCER THERAPY, AFTER UTI
AFTER LUNG INFECTION; WE SEE
COMMON SYNDROME THAT IS VARYING
SEVERITY BUT SEDUCING TO BE
PATHOGENS SPECIFIC
NEUROBIOLOGICAL CHANGES AND
SPECIFIC MECHANISMS ONE MIGHT
SEE IN ARDS THAT YOU DON'T SEE
IN MILD KNEW MOANIA, YOU SEE ON
TOP OF WHAT YOU SEE WITH
PNEUMONIA WHEN MORE SEVERE,
THERE IS IN ADDITION TO THAT
EFFECTS OF HYPOXIA AND OTHER
MECHANISMS.
>> LIKE TO GIVE OTHER SPEAKERS A
CHANCE TO RESPOND AS WELL. THIS
IS WHAT I TRY TO SAY DURING MY
TALK. WE CAN SEE UNDER MANY
CONDITION, INFECTION BUT ALSO
(INAUDIBLE) FROM DELIRIUM, I
THINK WE KNOW THAT SICKNESS
BEHAVIOR CAN BE ASSOCIATED WITH
LONG TERM PSYCHOLOGICAL
DISORDERS. WILL IS A LOT OF
LITERATURE LINKING SICKNESS
BEHAVIOR WITH ANXIETY,
DEPRESSION, AND PTSD I THINK
THIS SHOULD BE SEPARATED FROM --
FOR ME AND CHEMOTHERAPY SO WE
DISORDERS. THERE ARE CERTAINLY
THE OTHER MECHANISMS LIKE
DISRUPTION, ET CETERA, I THINK
WE SHOULD BE ABLE TO
DISCRIMINATE SICKNESS BEHAVIOR
FROM DELIRIUM. SOMETIMES WE COME
FROM (INAUDIBLE). I'M NOT SURE
THE MODEL WE ARE TESTING IN OUR
LAB IS A MODEL OF DELIRIUM OR
MODEL OF SICKNESS BEHAVIOR.
>> (INAUDIBLE) DELIRIUM, SHE
DIED.
>> SO I THINK THAT IN THE HUMANS
IT MAKES SENSE TO DISTINGUISH
BETWEEN THE TWO, IN MICE IT IS A
LOTTERY CAN YOUER BECAUSE
SICKNESS BEHAVIOR STARTS TO LOOK
LIKE THEY ARE NOT DOING
ANYTHING. IT IS HYPO ACTIVE
STATE WHICH IS ALSO PERHAPS
MANIFESTATION OF HYPO ACTIVE SO
WE NEED TO LOOK AT DIFFERENT
PHENOTYPES AND CLASSIFY, USE
MOLECULAR CLASSIFIERS. ONE
THING WE HAVE SEEN AS CCL 3 GOES
UP ANIMALS ARE MORE LIKELY TO
GET HYPO ACTIVE. SO SOME POINT,
EIGHT MIGHT BE A -- SICKNESS
BEHAVIOR MAYBE A SUB ET SIT OF
DELIRIUM, WE HAVE TO
INTENTIONALLY MODEL HYPO ACTIVE
DELIRIUM LIKE STATE BECAUSE IT
IS HARD TO CONVINCE REVIEWERS
ABSENCE OF SOMETHING IS
SOMETHING. WHAT YOU JUST SAID
SICKNESS BEHAVIOR BUT I THINK
THE NEXT STAGE OF THIS WILL
INVOLVE CONSIDERING HYPO AND
HYPERACTIVE CONTINUUM OF INJURY
AIDED BY MOLECULAR CLASSIFIERS
OR EVEN BRAIN STRUCTURAL
SUBSTRATES LIKE CC 3. I THINK
SICKNESS BEHAVIOR IS A FORM OF
DELIRIUM IN ANIMALS. OR CAN BE
I SHOULD SAY. BUT IT IS ON THE
EXTREME END WHEN WE TAKE THOSE
ANIMALS AND GIVE ANTI-IL OF THEY
BECOME APPEAR MORE HYPERACTIVE.
HYPERACTIVE PHENOTYPES. SO IT
APPEARS THAT THIS IS ON A
CONTINUUM AT LEAST IN THE WORK
BUT IT IS HARD TO DEVELOP A
MODEL AND NEW FIELD AND SAY THE
LACK OF SOMETHING IS SOMETHING,
LACK OF BEHAVIOR SOMETHING BUT
THAT IS SOMETHING THAT WE ARE
SEEING.
>> LOOKS LIKE JACK IS ASK YOU TO
ANSWER THE SAME QUESTION.
>> WILL IS A ROLE FOR THE WORD
ECOLOGICAL WAS USED IN TALKS
THIS MORNING, FOR TASKS THAT
REFLECT SOMETHING IMPORTANT TO
NATURAL BEHAVIOR AND WHETHER
MENTION A FEW SPECIFICALLY LIKE
NEST BUILDING TASKS, THAT YOU
USE OR JULIE USES. OR OTHER MORE
COMPLEX TASKS LIKE PUZZLE BOX
AND EXECUTIVE FUNCTION ORIENTED
TASKS ARE REALLY IMPORTANT. IT
IS FRUSTRATING BECAUSE WE NEVER
LOOK AT HISTOLOGY AND SAY YES,
THERE IS NEURONAL DEATH OR
MICROGLIAL ACTIVATION IN ONE
SPECIFIC REASON THAT WENT TO
THAT BUT MODELING HETEROGENEITY
AND MODELING CLOTS TORE PATIENT
CENTERED OUTCOMES, THOSE ARE
CLOSER TO PATIENT CENTERED
OUTCOMES ARE NICE OUTCOMES.
>> QUESTION, RESEARCHER AT THE
UNIVERSITY OF VIRGINIA WHO HAS
DONE THIS REALLY WELL WHO IS
INTEGRATED A LOT OF FACTORS INTO
A MODEL, A MOUSE MODEL, THAT ONE
OF THE BENEFITS OF BEING BASIC
TRANSLATIONAL SCIENTIST IS WE
CAN DO A LOT OF CONTROLLING. BUT
THE QUESTION THAT BEGS THE
QUESTION HOW DO WE MANAGE
CONTROLLING FOR FACTORS OR HOW
DO WE INVESTIGATE INTRINSIC
HETEROGENEITY OF A MOUSE MODEL
TO UNDERSTAND THE PATHWAYS THAT
ARE RESPONSIBLE FOR LONG TERM
CONSEQUENCES OF THESE DISEASES.
HOW MUCH THOUGHT PUT INTO
MECHANICALLY VENTILATING ANIMAL
VERSUS JUST GIVING LPS VERSUS
SOME CONTINUUM ADDING NOISE TO
EQUATION AS (INAUDIBLE) HAS DONE
KEEPING ANIMALS AWAKE AND
CHANGING CIRCADIAN RHYTHMS AND
MANAGING THESE COMPLEXITIES IN A
MODEL WHERE WE DO HAVE CONTROL.
>> TO REALLY LEARN SOMETHING WE
HAVE TO CHANGE ONE VARIABLE AT A
TIME. BUT THAT DOESN'T MEAN WE
CAN'T STUDY HETEROGENEITY, WE
HAVE TO UNDERSTAND WHAT FACTORS
CONTRIBUTE TO DIFFERENT
OUTCOMES. ONE POINT DISCUSSED
THAT I WANTED TO CLARIFY, THE
ACUTE NEUROLOGICAL SYNDROME IS
DISTINCT FROM CHRONIC
NEUROLOGICAL SYNDROME, THEY
MAYBE RELATED IN IMPORTANT WAYS
ONE MAY PREDICT THE OTHER BUT
MIGHT NOT SO IT IS IMPORTANT TO
THINK ABOUT ACUTE NEUROLOGICAL
DYSFUNCTION VERSUS CHRONIC. KIND
OF LIKE I CAN LONG HE WERE
DEVELOPMENT VERSUS T-CELL
THERAPY, MAYBE RELATED BUT ALSO
DISTINCT. THE TIME COURSE AFTER
THE INSULT LOOKING HOW A
PARTICULAR RESPIRATORY INFECTION
MAY INFLUENCE THE LONG TERM
OUTCOME IN MICE THAT HAD
DIFFERENT EARLY LIFE EXPERIENCE
UNDERSTAND OR DIFFERENT
CONCOMITANT EXPERIENCE BUT
VARYING ONLY ONE THING. THIS IS
THE SECOND TIME YOU GET
PNEUMONIA CHANGE THE WAY YOUR
BRAIN RESPONDS TO VARIOUS WAYS
TO THIS CHALLENGE. DOES SLEEP
DEPRIVATION INFLUENCE THAT,
CONCOMITANT MEDICATION INFLUENCE
IT BUT ONLY TEST ONE THING AT A
TIME SO YOU HAVE TO BE COG
COGNIZANT OF JUST THAT
PRINCIPLE. THIS IS ARE
IMPORTANT VARIABLES TO
UNDERSTAND.
>>
>> A FIZZ YOU LOGICALLY MORE
INTEGRATED PRE-TRANSLATIONAL
MODELS ARE REALLY IMPORTANT FOR
PROVIDING INSIGHT. I THINK WE
NEED MORE COMPREHENSIVELY
INTEGRATED PHYSIOLOGICAL
MEASUREMENTS TO GO WITH WHAT WE
NORMALLY HAVE AS OUTCOMES IN
THESE PRE-CLINICAL MODELS. THAT
WILL HELP A LOT AND MATCH
CLINICAL SCENARIO BETTER.
>> I WAS GOING TO SAY, I THINK
WE HAVE TO MEASURE ONE VARIABLE
AT A TIME BUT TO OVERCOME THE
HETEROGENEITY OF A CLINICAL
POPULATION TO AID TRANSLATION WE
HAVE TO LOOK FOR BIG TREATMENT
EFFECTS. NOT SMALL TREATMENT
EFFECTS ON ISOLATED VARIABLES
AND THAT MAYBE WITH STANDS
HETEROGENEITY OF THE CLINICAL
POPULATION. I AGREE WITH
MICHELLE THAT THE ACUTE AND
CHRONIC ARE VERY DIFFERENT IN
OUR MODELS WHEN WE LOOK AT A
DIFFERENT TIME LINE, IF WE
ADMINISTER INFLAMMATORY
MODULATION AT DELAYED TIME POINT
THE TREATMENT EFFECT IS LOWER.
THAT'S PROBABLY BECAUSE THERE IS
ALREADY BRAIN IS ON FIRE SO TO
SPEAK, THERE IS MICROGLIAL
ACTIVATION, ALL THE OTHER THING
WE TALKED ABOUT.
>> THERE IS AN OPPORTUNITY HERE
TO MATCH PRE-CLINICAL STUDIES
TOGETHER WITH COHORT OF PATIENTS
SIDE BY SIDE. AND CONTROL
VARIABLES IN A WAY IN BOTH
POPULATIONS TO SEE HOW CLOSELY
THEY RELATE. I THINK THERE'S
REAL OPPORTUNITY THERE.
>> I THINK THAT ANYTHING WE FIND
IN MICE WE HAVE TO SEEK THE
GROUND TRUTH IN OUR PATIENTS AND
SEE THAT IT IS REALLY HAPPENING
AND WE HAVE TO TAKE VARIABLES IN
OUR PATIENTS THAT CORRELATE WITH
THE OUTCOME AND TEST THEIR
MECHANISM IN MICE. THE MICE ARE
ONLY A MEANS TO THE END. TO HELP
OUR PATIENTS SO P IT IS NOT
HAPPENING WITH PATIENT, WHAT
HAPPENS IN OUR MICE DOESN'T
MATTER.
>> YOU HAVE A PROBLEM WITH
HETEROGENEITY IF YOU WANT TO
ADDRESS THE HETEROGENEITY YOU
NEED A LOT OF MICE. I DON'T KNOW
HOW IT IS IN THE UNITED STATES
BUT IN FRANCE YOU HAVE TO HAVE
(INAUDIBLE) EVERYWHERE AND YOU
CANNOT -- NO. IN ORDER TO
EVALUATE HETEROGENEITY.
SPEAKER5: (OVERLAPPING
SPEAKERS).
>> IT IS MORE DIFFICULT FOR
SURE. CERTAINLY COMMITTEES BUT
EASIER TO DO SMALL ANIMAL
EXPERIMENTS IN THE US. ONE
THING I THINK POWERFUL MODEL I
HAVE SEEN INCREASINGLY IN
NEUROSCIENCE BEING USED
ROCKEFELLAR IS DOING THIS REALLY
BRILLIANT NEUROSCIENTIST THERE,
TO USE I FORGET HOW SHE --
BASICALLY THEY ARE GETTING MICE
AND RATS FROM THE SUBWAY,
GETTING NATURAL ENVIRONMENT RATS
THAT ARE HETEROGENOUS. OUR LAB
MICE AND RATS ARE GENETICALLY
IDENTICAL WITHIN A STRAIN. AND
SO THEY BECOME VERY, VERY, VERY
SIMILAR AN IT IS HARD TO SEE
HETEROGENEITY BUT IF YOU JUST
GET HETEROGENOUS POPULATION OF
NATURALISTIC MICE YOU
AUTOMATICALLY HAVE MORE GENETIC
VARIABILITY DIFFERENCES IN LIFE
EXPERIENCE, EXPOSURES. AND THE
RESULTS ARE NOT NEARLY AS CLEAN
BUT YOU CAN LEARN INTERESTING
THINGS ABOUT SUBPOPULATIONS THAT
HAVE DIFFERENT RESPONSES SO
ANOTHER WAY TO STAY WITHIN SMALL
ANIMAL BUS BETTER MODEL THE
HETEROGENEITY AND LIFE
EXPERIENCE THAT PEOPLE HAVE.
>> THERE HAVE BEEN GREAT POINTS
BROUGHT UP IN CHAT AS AS WELL,
TIM BROUGHT UP LARGE PANEL
STUDIES VALUE EXPANDING WHICH
MAYBE DIFFICULT TO IMAGINE IN
EUROPE BUT U.S. IT IS CERTAINLY
FEASIBLE AND JULIE FROM
VANDERBILT BROUGHT UP THE NEED
FOR CLINICAL TRIALS THAT INCLUDE
BIOSPECIMENS THAT WE CAN
LEVERAGE TO APPLY TO OUR
PRE-CLINICAL AND TRANSLATIONAL
MODELS.
>> ALONG THOSE LINES I WANT TO
TURN TO THE PANEL AND AS WELL AS
THE CHAT THE QUESTION THAT JACK
ASKED EARLIER TURN ON ITS HEAD.
IF WE HAVE TOOLS TO STUDY
MECHANISM OF INJURY, MANY OR ALL
OF YOU INCORPORATE SOME CLINICAL
SPECIMENS OR BIOMARKERS INTO
ANIMAL STUDIES THAT YOU
DESCRIBED BUT IF THERE IS
SOMETHING FROM THE CLINICAL
TRANSLATIONAL WORLD WE CAN USE
TO HELP WITH REVERSE TRANSLATION
OR INCREASING RELEVANCE OF THE
ANIMAL STUDIES WE DO WHAT WOULD
THAT BE?
>> TIGHTLY CONTROLLED TIME LINES
REALLY VALUABLE THROUGH CLINICAL
COURSE AND GETTING UNDERSTANDING
OF NATURAL HISTORY OF INFECTION
RECOVERY IS REALLY IMPORTANT.
FEASIBLE TO DO ONE TIME POINT
BUT HAVING TEMPORAL SENSITIVITY
IS VALUABLE AND SOMETHING MATCH
PRE-CLINICAL MODELS.
>> I THINK ONE QUESTION IS WHAT
DO WE WANT TO STUDY, THE INSULT
PROCESS? WHAT IS HAPPEN IN THE
ACTIVE PHASE THAT CAN EXPANDS
WHAT WE HAVE AFTER? DO WE WANTS
TO ADDRESS THE RECOVERY PROCESS?
THIS IS IMPORTANT. IF WE WANT TO
ADDRESS MECHANISMS THAT
(INAUDIBLE) LONG TERM
PSYCHOLOGICAL OR CONNECTIVE
DISORDER WE HAVE LONG TERM
RECOVERY PROCESS AND SO
PLASTICITY, ET CETERA SO MAYBE
SOME TIME LINE. SO I THINK THAT
IS TWO QUESTIONS WHAT ARE
MECHANISMS OF ACUTE INJURY OF
BRAIN CELLS AND HOW CAN EXPLAIN
LONG TERM SEQUELAE BUT ALSO THE
OTHER QUESTION IS HOW WE CAN
ASSESS AND ADDRESS MECHANISMS OF
RECOVERY PROCESS. I DON'T THINK
THERE ARE MANY STUDIED. SO IT IS
NOT THE SAME TIME, WE ARE NOT ON
THE SAME TIME LINE. BUT I DON'T
KNOW IF I'M CLEAR WHAT I'M
SAYING. AS MICHELLE SAID, WE
CANNOT MIX ACTIONS AND MAYBE THE
CHRONIC PHASE. IF WE WANT TO
LOOK AT CHRONIC PHASE MAYBE WE
HAVE TO LOOK AT MECHANISMS OF
RECOVERY AND HOW CAN -- WE CAN
STIMULATE RECOVERY PLASTICITY.
>> I THINK THERE IS A PARADIGM
IN NEUROSCIENCE THAT THERE IS --
YOU CAN EITHER AFFECT ACUTE
INSULTS AND IMPROVE OUTCOMES BY
AFFECTING WITHIN THE FIRST 30
MINUTES OR 60 MINUTES OF STROKE
VERSUS TRYING TO FIND WAYS TO RE
RECOVER. NEURORESTORETIVE
THERAPIES. IN THIS FIELD IN
PARTICULAR OFTEN I FEEL AS BASIC
SCIENTIST OFTEN DAMAGE IS DONE
PATIENT COMES TO HOSPITAL AND
CERTAINLY THAT CAN BE LEVERAGED
BY CHANGING DELIRIUM OR
AFFECTING ACUTE INFLAMMATION THE
FIRST SEVERAL DAYS OF
HOSPITALIZATION WITH POTENTIAL
NEGATIVE EFFECTIVE WORSENING
OUTCOMES WHICH I THINK IS OUR
BIGGEST FEAR. BUT MICHELLE, I
THINK YOU HAVE SOMETHING TO ADD
>> YEAH. I WOULD JUST POINT OUT
THAT A LOT OF WHAT MAYBE GOING
ON NEURO BIOLOGICALLY IS
DISCRIMINATION RATHER THAN
DESTRUCTION. WE DON'T SEE CELL
DEATH OF IRREPLACEABLE CELLS WE
SEE DISREGULATION OF PLASTICITY,
WE SEE DISREGULATION OF
COMMUNICATION. AND THAT CAN AT
LEAST IN PRE-CLINICAL MODELS
WITH MILD DISEASE, AGAIN THERE
ARE THINGS LIKE STROKE THAT
CAN'T BE REGENERATED BUT JUST
INFLAMMATION INDUCE
DISREGULATION CAN BE RESTORED
EXPERIMENTALLY SO THAT GIVES ME
HOPE THAT WE CAN FIND WAYS TO
MOLECULARLY COACH THESE CELLS
BACK TO HOMEOSTATIC AND PLASTIC
STATE IN A WAY TO IMPROVE
COGNITION AND IMPROVE COGNITIVE
ENERGY THROUGHOUT THE DAY. AND
REALLY HELP QUALITY OF LIFE. I'M
ENCOURAGED BY SYMPTOMATIC
TREATMENTS IN CANCER RELATED
COGNITIVE SPACE, ONE OF MY
CLINICAL SPECIALTIES WHERE
PEOPLE YEARS AFTER VERY
NEUROTOXIC THERAPIES LIKE
CRANIAL RADIATION CAN DO BETTER
WITH SIMILAR SYMPTOMATIC
MANAGEMENT WITH METHYLPHENIDATE
AND OTHER THINGS TO HELP GET
THEM THROUGH THEIR DAY. IN A WAY
THAT MAKES MY REALLY BELIEVE
THAT IF WE COULD REGENERATE OR
RESTORE HOMEOSTASIS, CELLULARLY,
PERHAPS ADDRESS NEURAL
INFLAMMATION, ENCOURAGE
MECHANISMS OF PLASTICITY,
REPLACE MECHANISMS OF
PLASTICITY, WE CAN MAKE PEOPLE
BETTER. SO SOME OF THE
CHALLENGES WE THINK ABOUT
REGENERATION AFTER STROKE THAT
IS A HUGE CHALLENGE, TO REGROW
THE HOLE IN THE BRAIN, THAT IS
NOT THE SITUATION WE HAVE HERE.
WE HAVE A MUCH EASIER SITUATION
BUT WE HAVE TO UNDERSTAND THE
MECHANISMS IN ENOUGH DETAIL TO
TARGET THEM.
>> I FULLY AGREE. WE THE SAME
TYPE AS BRAIN CHRONICITY
MATTERS. IN OUR MODEL THE CC 3
EXPRESSION EARLY APOPTOTIC
MARKER ACTUALLY IT REVERSES IF
THE INSULT IS TAKEN AWAY. SO
WHEN WE LOOK AT MARKERS OF
INREVERSIBLE CELL DEATH WE ARE
NOT SEEING THAT IN ACUTE PHASE,
ONLY WHEN YOU LET THAT INJURY
PERSIST FOR A WHILE. SO WHETHER
THAT REFLECTS LIKE SENESCENCE OR
SOMETHING ELSE WHICH IS
REVERSIBLE AND IS STILL AN OPEN
QUESTION. BUT I THIS I THAT THAT
IS VERY ENCOURAGING. AS MICHELLE
SAID.
>> I WOULD LIKE TO MAKE ANALOGY.
FEW YEARS AGO WE HAVE SHOWN
(INAUDIBLE) MODEL MICE KNOW THAT
THERE IS A (INAUDIBLE) SATELLITE
CELLS, SATELLITE CELLS ARE
IMPORTANT FOR REGENERATION OF
MUSCLE. SO WE FOUND THAT DURING
THE SEPSIS, THERE IS A
(INAUDIBLE) OF THE SATELLITE
CELLS AND SO THE (INAUDIBLE) SO
MAYBE COULD BE A MECHANISM OF
CRITICAL -- TWO QUESTIONS, IS
THIS OCCURRENCE WHERE THE ACTIVE
PHRASE OF SEPSIS, THERE ARE TWO
QUESTIONS, IS THERE A WAY TO
PROTECT SATELLITE CELLS THEN
MUSCLE COULD REGENERATE OR IS
THERE A WAY AFTER THE INSULT TO
MAKE THE SATELLITE CELLS WORK
AGAIN. I THINK THAT THESE ARE
TWO DIFFERENCE APPROACH TRYING
TO PROTECT THE BRAIN FROM THE
ACTIVE INSULT, AFTER ACUTE
TRYING TO MAKE IT WORKING AGAIN
AS YOU SAID MICHELLE TRYING TO
RESTORE BRAIN FUNCTION. I THINK
THAT NOT THE SAME.
>> THERE COULD BE POTENTIAL
CUMULATIVE EFFECT, THE INITIAL
INJURY LEADS TO MORE SECONDARY
HITS AND PROGRESSIVE WORSENING
OVER TIME. THAT SOME OF THESE
FACTORS WE DON'T KNOW WHAT THEIR
HALF LIFE IS. IT MAY NOT GO
AWAY, MAY SET YOU UP FOR
WORSENING OF CONDITIONS AND
PROGRESSIVE WORSENING OF
COGNITIVE DYSFUNCTION AND THOSE
ARE ALL REALLY IMPORTANT
QUESTIONS TO ANSWER,
RELATIONSHIP BETWEEN INITIAL
DISREGULATION, VERSUS
PROGRESSIVE WORSENING. AND THEN
ALONG THOSE LINES, WE HAVEN'T
TALKED ABOUT A SECONDARY
GENOTYPE BACKGROUND APOE 4 GENE
NEUROCOGNITIVE INFECTION IN
SETTING OF INFECTION. ALL NEEDS
TO BE CONSIDERED AND ADDRESS.
THE MULTIPLICITY OF FACTORS THAT
INFLUENCE HETEROGENEITY HAVE TO
BE BROKEN DOWN AND I THINK AS
MICHELLE SAID YOU CAN ONLY STUDY
ONE THING AT A TIME. BUT THERE
NEEDS TO BE PROGRESSIVE
CONSIDERATION OF THE
MULTIPLICATIVE EFFECTS WE SEE.
>> I WANT TO BRING IN P
FASCINATING QUESTIONS TO THE
CHAT TO RECOVERY AND RESILIENCE
RELATING TO DYSFUNCTION VERSUS
DESTRUCTION. WE KNOW THAT
MICHELLE PRESENTED DATA ABOUT
ADULT NEUROGENESIS. WE KNOW
THINGS THAT ARE EXTRINSIC TO
INDIVIDUAL ANIMAL LIKE EXERCISE
PHYSICAL ACTIVITY CAN HAVE
IMPORTANT EFFECTS FOR BRAIN
HEALTH. AND FOR RESILIENCE --
RECOVERY OR SOCIOECONOMIC
DEPRIVATION. DO WE THINK THOSE
FLAYPLAY A ROLE IN THE TYPES OF
PROCESSING THAT YOU HAVE BEEN
DECEMBER KISSING HERE? THE --
DISCUSSING HERE IN THE ANIMAL
MODELS?
>> ABSOLUTELY. SO MANY WAYS. I
CAN GIVE ONE QUICK EXAMPLE, I
DON'T WANT TO TALK TOO MUCH BUT
ONE ONE OF THE KEY
NEUROBIOLOGICAL MECHANISMS
INFLUENCED BY INFLAMMATION AND
IS IMPORTANT FOR THE KIND OF
COGNITIVE DYSFUNCTION THAT
PEOPLE HAVE CHRONICALLY, IS
DISRUPTION OF MYELIN PLASTICITY
ONE MECHANISM THAT EBB ABLES
MYLOPLASTICITY IS SIGNALING
BRAIN DERIVED NEUROTROPIC
FACTOR, NEURONS AND OLIGO
OLIGODENDROCYTE PRECURSOR CELLS,
WE DON'T KNOW WHY BUT THAT IS A
CRITICAL PART OF WHY
CHEMOTHERAPY AT LEAST IN MICE
CAUSES WE THINK THIS KIND OF
IMPAIRMENT TO ATTENTION AND
MEMORY FUNCTION. SO BDNF IS AN
ACTIVITY REGULATED MOLECULE
IMPORTANT FOR NUMEROUS FORMS OF
NEURAL PLASTICITY DEVELOPMENTAL
HOMEOSAYSIS. EXERCISE INCREASES
IT, AS ONE EXAMPLE, SOCIAL
INTERACTIONS INCREASE BDNF
LEVELS IN THE BRAIN. THERE'S
LOTS OF WAYS TO START TO THINK
ABOUT HOW ENRICHED OR NOT OR
PAUCITY OF EXPERIENCE MIGHT BE
PLAYING A VERY IMPORTANT WAYS
INTO THE EXTENT TO WHICH CERTAIN
MECHANISMS OF PLASTICITY ARE
MAINTAINED OR NOT.
>> GOODS FOR THE BRAIN AND GOOD
FOR THE MUSCLE. WE HAVE FEW
YEARS AGO WE DID THE PILOT STUDY
ON MICE (INAUDIBLE)
CHARACTERIZED BY (INAUDIBLE)
WHETHER EXERCISE GOOD FOR
REDUCING MICE LIMITATIONS. WE
FOUND IT WAS GOOD AND WELL
TOLERATED AND GOOD FOR THE
MUSCLE, AND EVEN HOW WE PUT
(INAUDIBLE) POTENTIAL IMPACT AND
THERE ARE STUDIES SHOWING THAT
EXERCISE REDUCE INFLAMMATION OF
SYSTEMIC INFLAMMATION. , I I
THINK EXERCISE CAN BE GOOD. I
REMEMBER THE STUDY OF TOO MUCH
GWAS SHOWING THAT EXERCISE OR
OCCUPATIONAL THERAPY REDUCE
(INAUDIBLE) IT WAS EVEN BETTER
FOR THE BRAIN, REDUCING DELIRIUM
THEN IMPROVING THE MUSCLE
STRENGTH.
>> IN PRE-CLINICAL MODELS OF
METHYL TREXATE INDUCED COGNITIVE
IMPAIRMENT WHERE MICROGLIAL
REACTIVITY TARGETING THAT FIXING
THE PROBLEM SO TOO EVEN IN THE
CONTEXT OF INFLAMMATION ARE BDNF
AGONISTS SO WE HAVE A 2019 PAPER
PUBLISHED IN NEURON THAT SHOWS
THAT BDNF PARTIAL AGONIST SMALL
MOLECULE COMPOUND RESCUES
COGNITIVE FUNCTION AND RESTORE
MYELIN REGULATION AFTER ACUTE
THERAPY. SO WE CAN -- AS WE
UNDERSTAND SOME OF THESE
FACTORS, THERE ARE POTENTIAL
THERAPEUTIC AVENUES WHEN DRUGS
BECOME CLINICALLY AVAILABLE OF
COURSE A PRE-CLINICAL TOOL.
>> YOU SHOULD COMMENT ON THE
HEPARIN SULFATE AND LINK OF BDNF
TOO.
>> SO MY WORK TRAY GRACIOUS HI
FOCUSED ON ENDOTHELIAL INJURY
AND HOW IT IMPACTS BRAIN AS WELL
FROM INTERESTING -- HELIX WITH
HEAP RIP SULFATE CROSS IT IS
BLOOD BRAIN BARRIER TO THE
HIPPOCAMPUS AND ACTUALLY
INTERFERES WITH BDNF SIGNALING.
IT IS INTERESTING FOR YOU
MICHELLE, HEPARIN SULFATE PRO
OWE GLYCANS PRESENT IN THE BRAIN
MAYBE A FACTOR IN THIS BDNF
INTERACTION BETWEEN GLIA AND
NEURONS IS SOMETHING TO THINK
ABOUT. AND LOTS OF TOOLS TO PLAY
WITH IN GLYCO BIOLOGY OF THE
BRAIN. PROBABLY YEAH. THANK YOU
TRAY.
>> INTERESTING.
>> I WOULD LIKE TO ASK ALL OF
YOU A QUESTION THAT JIM JACK SOB
BROUGHT UP, IT -- JACKSON
BROUGHT UP, ALLUDED TO ALREADY.
BUT IN YOUR MIND ARE THERE
THERAPIES THAT ARE GOING ON BORN
FROM THE TRANSLATIONAL WORK WE
ARE DOING THAT'S BEEN ALLUDED TO
IN MOST OF YOUR TALKS. CAN YOU
PUT YOUR MONEY DOWN WHAT YOU
THINK IS THE MOST EFFECTIVE
TREATMENT FOR SURVIVORS. TAKE
HETEROGENOUS PATIENTS. TREAT
WITH ALL THE SAME PATIENTS
PHENOTYPING USING BIOMARKERS FOR
INFORMED TREATMENTS OR WITH THIS
ANTI-IL 6 THERAPY OR OTHERWISE?
>> I'M STRUCK BY HOW IL 6, NO
SKIN IN THE GAME, I DON'T HAVE
SHARES WITH IL 6 OR STOCK WITH
BIG IL 6 MORE TYPE SIMILAR
ASSOCIATIONS AND I THINK THIS --
THE DATA I PRESENTED FROM
PATIENTS THAT IN COVID
POPULATION THAT IS EVEN MORE
HETEROGENOUS THAN AVERAGE ICU
PATIENT IS REALLY I THINK THAT
THAT IS WHERE IT IS AT, AT LEAST
WE NEED TO DO SOMETHING IN THAT
AREA. ANTI-IL 6 TREATMENT.
>> TO ADD TO THAT THE INFECTIOUS
HISTOPOPULATION IN PARTICULAR
WHICH FOOD ED TO TEST WHETHER
THERE'S EFFICACY IN MEDICAL OR
THERAPY AGAINST CYTOTOXIC TAU
VARIANTS. THAT HAS -- NEEDS TO
BE TESTED WE NEED TO SEE IF THAT
CAN BE EFFECTIVE. THERE ARE I
THINK LAST I LOOKED 13 CLINICAL
TRIALS WITH ANTI-TAU
IMMUNOTHERAPY CHRONIC
NEURODEGENERATIVE DISEASE, SOME
OF THE SAFETY TRIALS HAVE BEEN
SUCCESSFUL I THINK THERE IS GOOD
SPACE AND GOOD OPPORTUNITY TO
DEVELOP THAT AS CLINICAL TEST.
>>
>> MICHELLE?
>> I MEAN, I HAVE TO SAY I THINK
THERE ARE POTENTIAL CANDIDATE
THERAPIES BUT I REALLY STILL
THINK THERE NEEDS TO BE QUITE A
BIT OF PRE-CLINICAL WORK TO TEST
THOSE THERAPIES BEFORE YOU BRING
THEM FORWARD. SO THE MOLECULAR
COACHING OF MICROGLIA AND
TARGETING THE MECHANISMS OF
PLASTICITY AND HOMEOSTASIS THAT
THAT INFLAMMATION DISREGULATES
WILL PERHAPS BOTH IN IMPORTANT
STRATEGIES BUT I DON'T FEEL THAT
THERE IS A CLEAR WINNER IN MY
MIND TO WHAT WE NEED TO TARGET.
>> I THINK TARGETING THE
NEUROINFLAMMATORY PROCESS IS ONE
WAY. IN MY PRESENTATION WE
CARRY OUT CLINICAL TRIAL RELATED
TO (INAUDIBLE) WE FOUND EARLY
ACTIVATION OF AMYGDALA AND
PROTEASE ACTIVITY CAN OCCUR FROM
OCCURRENCE OF PTSD. IT WAS A
MOUSE MODEL AND WE FOUND THAT WE
HAVE TO REDUCE EARLY AMYGDALA
ACTIVATION OF PTSD, WHY WE
DECIDED TO DO THE CLINICAL
TRIAL. SO THERE ARE DIFFERENT
MECHANISMS AND THAT NOT THE SAME
EACH TIME BUT WE THOUGHT THIS
EARLY ACTIVATION COULD ACCOUNT
FOR SOME DISORDERS. IT WAS
CLINICAL PRE-CLINICAL FINDING
TRYING TO TRANSLATE TO PATIENTS.
FOR THE COMING YEARS IT IS
POSSIBLE AND THE (INAUDIBLE)
COULD BE NEGATIVE.
>> ALL RIGHT. LOOKS LIKE WE ARE
AT THE END OF THE SCHEDULED TIME
FOR THIS SESSION. THANK YOU SO
MUCH TO THE SPEAKERS AS WELL AS
ALL THE PARTICIPANTS FOR REALLY
THOUGHT-PROVOKING QUESTIONS IN
THE CHAT. I KNOW IT IS REALLY
LED ME TO THINK ABOUT SOME OF MY
OWN WORK IN A DIFFERENT WAY.
>> THANK YOU.
>> THANK YOU SO MUCH TO ALL THE
SUBSTITUTE SPEAKERS AND TO JOE
AND BEN FOR LEADING THE SESSION.
I HAVE TO TELL YOU ALL I WAS A
LITTLE BIT WORRIED WHEN I LOOKED
AT THE AGENDA AND I THOUGHT WOW
WE ARE GOING TO BE SITTING AT
COMPUTERS FOR A REALLY LONG
TIME. AND IT IS GOING TO BE
EXHAUSTING BUT AT LEAST FOR ME
IT WAS REALLY EXCITING AND I WAS
GLUED TO MY CHAIR THE WHOLE TIME
AND I'M LOOKING FORWARD TO
TOMORROW. I DO WANT TO POINT OUT
TO ALL OF YOU, IT LOOKS LIKE
THERE MAY BE A MISTAKE ON THE
AGENDA TOMORROW SO WE START AT
10 A.M. AND THE FIRST SPEAKER IS
AT 10:15 A.M., EASTERN STANDARD
TIME IN THE U.S. BUT THERE IS
ONE PART OF THE AGENDA SAYING
SESSION 3 AT 10:35. I DON'T
BELIEVE THAT'S CORRECT. MAYBE
SOMEBODY FROM NHLBI CAN CHIME
IN. SO THE PLAN TO START AT 10,
YOU SHOULD HAVE THE LINKS
TOMORROW, WE WILL HAVE ANOTHER
GREAT DAY WITH TWO SESSIONS AND
THEN BREAK OUT ROOMS AT THE END
OF THE DAY. PLEASE TUNE IN
AGAIN TOMORROW AND THANKS
EVERYONE FOR YOUR PARTICIPATION
TODAY.