>>WE INVITE YOU TO
THE TACKLING BRAIN AND MUSCLE
DISFUNCTION IN AXE RDS WORKSHOP.
THIS SESSION IS BEING RECORDED
AND PLEASE MAINTAIN RESEARCH
INTEGRITY AND CONFIDENTIALITY
AND WOULD LIKE FOR YOU TO USE
THE CHAT FOR DISCUSSION AND
ENCOURAGE YOU TO PUT QUESTIONS
IN THE CHAT. MODERATORS WILL
MODERATE THE CHAT BOX. KEEP
YOUR CAMERAS OFF UNLESS YOU ARE
SPEAKING. PLEASE ENJOY THE
WORKSHOP. THANKS FOR JOINING US
TODAY.
>> GOOD MORNING, EVERYONE. I'M
CHRISTIAN GOMEZ AND PROGRAM
OFFICER IN DIVISION OF LAND
DISEASES AND CHARGE TODAY TO
KICK OFF ACTIVITIES FOR THE
SECOND DAY OF EXCITING WORKSHOP
TACKLING BRAIN AND MUSCLE
DYSFUNCTIONS IN ARDS SURVIVORS
AND RECAP OF YESTERDAY'S
ACTIVITIES. SESSION 1 WE DID
MUSCLE DYSFUNCTIONS AND CAN
MEASURE AND HOW MANY MEASURE
TRANSLATES TO BE VALUABLE FOR
PATIENTS IS A CHALLENGE WE NEED
TO MEET.
NEXT ISSIN VIVO AT HOME AND
SOCIAL MEDIA AND TEXT ANALYSIS
CAN INCORPORATE REAL-WORLD TASKS
INTO STANDARD MISSIONS AND
[INDISCERNIBLE] WHEN CONSIDERING
NEXT INNOVATION MEASUREMENTS
INCLUDING INCORPORATING H AND
[INDISCERNIBLE] ARND AND DIGITAL
POVERTY AMONG OTHERS. WITH SUCH
TOOLS, WE COULD BE ABLE TO
ASSESS HOW PATIENTS ADAPT TO
THEIR ENVIRONMENT FOLLOWING
ACUTE DISEASES AND FOR
IDENTIFICATION WE NEED TO
DISCUSS IT AND WILL CONSIDER
ADAPTATIONS AS THOSE RELATED TO
STATUS AND ASSISTIVE DEVICES AND
EQUITY AND EPRIORITIZATION OF
PATIENT VALUES AND SUCH EFFORT
MAY HELP TO OVERCOME BARRIERS
FOR PATIENTS AND INFORM POLICY
DEVELOPMENTS AND MEDICINE DURING
COVID AND OVERCOMING CAREERS AND
SOMETHING WE CAN MAKE AND
ANOTHER CHALLENGE.
PERTAINS TO PRIMARY CARE
COMMUNITY AND RESOURCES TO REACH
OUT TO UNDERSERVED COMMUNITIES
TO THOSE AWAY FROM MAJOR URBAN
AREAS AND TO SPECIAL POPULATIONS
IS INTENSIVE SUPPORT AND
RELATIONSHIP BETWEEN STAFF AND
PATIENT MIGHT HELP TO OVERCOME
CRITICALLY RELEVANT SOCIAL
DETERMINANTS OF HEALTH SUCH AS
CONNECTIVENESS.
LET'S COME BACK TO TOPIC OF
ADAPTATION AND IN CONTEXT OF
DIVERSITY, EQUITY, INCLUSION,
AND ACCESSIBILITY.
HOW IS THAT'LL EFRNGS RESEARCH
AGENDA AND INVESTIGATORS MIGHT
START BY ADDRESSING POINTS IN
CLARIFICATIONS AND SPECIFICALLY
IN RESEARCH STRATEGY SECTIONS,
SOMETHING WE ARE NOT
APPRECIATIVE OF PROG IT GRAM
SITE HERE. WE MIGHT ADDRESS
SOME FORMAL ASPECT. HERE IS
MAIN QUESTION. IF THIS IS A
CASE FOR THE PATIENT, WOULD THEY
BE COMFORTABLE WITH ADDED
REFINEMENT OR MODIFY OR EFFECT
BASIS ROAD TO RECOVERY AND
IMPORTANTLY HAVING A MEANINGFUL
LIFE IS SOMETHING FOR US TO
THINK.
IN SOME, WE PROBABLY MEASURE AND
NEED TO GET BETTER AT
INDIVIDUALIZED PATIENT LEVEL FOR
THAT PURPOSE AND APPROACH TO
DEVELOP ADAPTIVE OUTCOME
MEASURES INCLUDING PATIENTS
INDIVIDUALIZED THRESHOLD ON
OUTCOME THAT BENEFIT COULD BE
PROPOSED AND PARADIGM SHIFTS
THEM AND PROPOSES ADAPTATION AND
ACCOMMODATION. TOGETHER,
PATIENTS ROAD TO HAVING A
MEANINGFUL LIFE SHOULD BE
CONSIDERED.
SESSION 2, COMMONALITIES IN
PATHOGENESIS AND NEUROCOGNITIVE
DISFUNCTION AND SCENARIOS LIKE
-- AND CLINICAL MANIFESTATIONS
AND COVID FOLK SEEM TO BE
EXPLAINED BY BIOLOGICAL
MECHANISM IN CENTRAL SERVOUS
SYSTEM AND REGULATION AND
NEGATIVE IMPAIRMENT AND BASED ON
COMMONALITIES BIOMARKERS OF
MANIFESTATIONS OF IMPAIRMENT MAY
BE REVEALED AND NOTED THAT
PATHOLOGY.
PROTEINO PATH ESIS OF THE LUNG
LEAD TO INFERIOR PRODUCTION OF
[INDISCERNIBLE] FOR EXAMPLE THAT
CONTRIBUTES TO [INDISCERNIBLE]
SUCH AS INFECTION AND DISCUSSED
IN SESSION 1 WE NEED TO DEVELOP
A TOOLKIT OF PRECLINICAL
DISCOVERY SCIENCE THAT CAN
REFLECT UNIQUE EXPERIENCES OF
PATIENTS AND RELATIVE VALUE OF
EXPERIMENTAL MODELS AND TOOLS
INTRODUCING OUTCOMES RELATED TO
SURVIVORS AND THOSE RELATED
CORRELATIONS AND BEHAVIORS AND
ANATOMY WAS DISCUSSED AND
PARADIGM SHIFT TO DISCUSS WE
SHOULD INCLUDE [INDISCERNIBLE]
TO PATHOGEN AND SPECIFIC
MECHANISMS TO DISCRIMINATE
SICKNESS BEHAVIOR AND TO STUDY
LEARNED AND DISEASED
[INDISCERNIBLE] SUCH AS PSTD.
OUR ASPIRATIONAL STATE IS STRONG
FACE AND GOING TO BE USEFUL FOR
HUMAN-BASED RESEARCH AND MODERN
REAL-WORLD SCENARIOS AND FOR
FORMER BASED ON SPECIFIC DATA
LEADING TO MOLECULAR CLASSIFIER
IS NEEDED AND LATTER EXPOSED
ANIMALS ADDRESSING CHALLENGE OF
HETEROGENOUS POPULATIONS TOWARDS
ROUTE OF RECOVERY AND RESILIENCE
WE HAVE TO DISTINGUISH BETWEEN
THIS REGULATION SUCH WE THINK OR
SEE NEUROPLASTICITY INFLAMMATION
VERSUS DISTRACTION AND WE DON'T
SEE AS MUCH IN PATIENTS AS WE
SEE THIS REGULATION AND
REVERSING PATHOLOGY BY
MOLECULARLY COACHING CELLS SO
THEY COME BACK TO HOMEOSTASIS
WOULD BE A REASONABLE STRATEGY
ANDALITY TERN TIFLY PROTECTING
BRAIN DURING ACUTE FACE AND
TACKLE COMPLICATIONS THAT HAVE
[INDISCERNIBLE] WE MAY HAVE
PATIENTS OF SEVERE COGNITIVE
DISFUNCTION AND MAYBE WE WANT TO
TEST THIS INTERESTING HYPOTHESIS
WITH RELEVANCE TO RECOVERY AND
RESILIENCE, ANIMAL MODELS TO BE
SUITED FOR THE PURPOSE AND
DISCUSSING PRECLINICAL DATA IS
STILL NEEDED AND FOLLOWING THIS
RECAP OF DAY 1, I WOULD LIKE TO
TICK OFF DAY 2 AND CONTINUE WITH
THE EXCITING PROGRAM.
SESSION 3, PATHOGENESIS AND
RECOVERY OF BASAL DISFUNCTION IN
ARDS SURVIVORS IS BY
[INDISCERNIBLE] AND IS AN
ASSOCIATE PROFESSOR AND
ASSISTANT CHIEF AT DEPARTMENT OF
MEDICINE -- IMMUNOLOGICAL
DISEA
DISEASES.
-- PARTICULARLY THOSE WITH ARDS
AND [INDISCERNIBLE] SCIENTISTS
AND HOSPITAL DURING HEALTH
[INDISCERNIBLE] AND ASSOCIATE
PROFESSOR OF MEDICINE AT
UNIVERSITY OF TORONTO AND HAS
PROGRAM OF BASIC AND
TRANSLATIONAL RESEARCH FOCUSED
ON PREVENTION AND CONTRACTED
DISFUNCTION AND THE FLOOR IS
YOU
YOURS.
>> THANK YOU, DR. GOMEZ AND
SESSION CHAIRS.
THANKS TO ALL OF YOU AND WELCOME
TO SESSION 3 ON LBI WORKSHOP.
WE ARE HONORED TO CHAIR THIS
SESSION WITH THREE OUTSTANDING
SPEAKERS RANGING FROM MECHANISMS
UNDERLYING MUSCLE ATROPHY TO
COMPLEX PRECLINICAL AND
TRANSLATIONAL HUMAN STUDIES
MODELING THE ICU ENVIRONMENT TO
MUSCLE REGENERATION.
SOME DISCUSSION WITH PROGRAM
CO-CHAIRS IN THE LAST MONTHS
ABOUT THIS SESSION FOCUSED ON
TRYING TO COME UP WITH PRIORITY
CONSENSUS WHERE TO FOCUS
MECHANISTIC INVESTIGATION IN
THIS FIELD.
FOR INSTANCE, SHOULD WE FOCUS
INVESTIGATION AND INTERVENTIONS
ON MINIMIZING MUSCLE WASTING OR
FOCUS ACCELERATING MUSCLE
RECOVERY AND SPEAKERS WILL FOCUS
ON KEY MECHANISMS UNDERLYING
SKELETAL MUSCLE INJURY AND
RECOVERY PLAYING A MAJOR ROLE IN
SYNDROME OF PICS WE HEARD SO
MUCH ABOUT YESTERDAY AND WILL
OFFER INSIGHT INTO THESE
QUESTIONS.
WHILE WE MAY COME TO SOME
CONSENSUS ABOUT WHICH AREA IS
THE MOST IMPORTANT TO FOCUS ON
OVER THE NEXT YEARS, IT IS MY
HUMBLE OPINION THAT THE
PROCESSES OF MUSCLE INJURY AND
RECOVERY ARE SO INTERTWINED THAT
IT IS HARD TO SAY WE SHOULD
PRIORITIZE ONE OVER THE OTHER.
FOR INSTANCE, MANY INTERVENTIONS
TARGETING -- MIGHT HAVE EFFECT
ON MUSCLE INJURY AND WE MIGHT
NEED TO STUDY IT BETTER.
LASTLY, IT IS IMPORTANT TO
REMEMBER WHILE SKELETAL MUSCLE
IS CLASSICALLY RECOGNIZED AS
LARGEST ORGAN IN THE BODY
COORDINATING LOCOMOTION AND
PHYSICAL FUNCTION, IT IS ALSO
INCREASINGLY RECOGNIZED AS
ENDOCRINE IMMUNE ORGAN THAT IS
INVOLVED IN CRITICAL
ORGAN-TO-ORGAN CROSS-TALK, A
PROCESS SO FUNDAMENTAL TO
PATHOLOGY OF ARDS THAT WE ALL
KNOW.
AS WE CONSIDER TARGETING
INVESTIGATION AND INTERVENTIONS
ON SKELETAL MUSCLE SYSTEM IN
ARDS WE MUST CONSIDER CONCEPTUAL
INTERVENTIONS IN LIGHT OF
NONCLASSICAL SKELETAL MUSCLE
FUNCTIONS AND WITH THAT, WE WILL
KICK OFF OUR SESSION ENTITLED
PATHOGENESIS AND MUSCLE RECOVERY
IN DISFUNCTION IN ARDS SURVIVORS
AND I'M REALLY PLEASED TO
INTRODUCE OUR FIRST SPEAKER.
SUE BODINE IS FULL MEMBER IN
AGING AND METABOLISM RESEARCH
PROGRAM AND RESEARCH IS ON STUDY
OF NEUROMUSCULAR SYSTEM AND
VARIOUS STRESSORS EXERCISE MICRO
GRAVITY DE-JENNERVATION AND
AGING AND FOCUS OF LAB IS
UNDERSTANDING MECHANISMS
REGULATING SKELETAL MUSCLE SIZE
AND FUNCTION UNDER ATROPHY AND
MAJOR CONDITIONS AND FOCUS OF IT
IS IDENTIFICATION OF IN VIVO
SKELETAL MUSCLE SUBSTRATES AND
LYINGACE IS [INDISCERNIBLE] AND
LAB IS INVESTIGATING EFFECT OF
AGING ON SKELETAL MUSCLE MASS
AND FUNCTION AND IDENTIFICATION
OF MECHANISMS UNDERLYING CORE
RECOVERY OF MASS AND FUNCTION
FOLLOWING ATROPHY IN AGE IN
LABS.
HER LAB IS A PRECLINICAL ANIMAL
STUDY SITE INVOLVED IN MOLECULAR
TRANSDUCERS OF PHYSICAL ACTIVITY
CONSORTIUM OR MOTOR PACK.
WITHOUT FURTHER ADO, DR. BODINE.
>> THANK YOU CLARK AND JAIN FOR
THE INVITATION TO PARTICIPATE IN
THIS WONDERFUL WORKSHOP.
NEXT SLIDE I WILL TALK ABOUT
REGULATION OF MUSCLE MASS AND
FUNCTIONS AND MECHANISMS
UNDERLYING MUSCLE AT TROPHY.
I WANT TO HIGHLIGHT MUSCLE IS A
HIGHLY PLASTIC TISSUE AND
MULTICELLULAR TISSUE AND AS SEEN
IN THIS ILLUSTRATION, MUSCLE
RELIES ON AN IN TACT MOTOR
INNERVATION TO MAINTAIN MASS AND
FUNCTION AND BESIDES MOTOR
FUNCTION IT IS A SIGNIFICANT
SENSORY ORGAN WITH MANY SENSORY
RECEPTORS PROJECTING BACK TO THE
BRAIN STEM AND OTHER ORGANS AND
MUSCLE RELIES HEAVILY ON
MECHANICAL LOADING AND MAINTAIN
FUNCTION AND ELEMENTS ARE
IMPORTANT FOR PRODUCING FORCE
AND MUSCLE ALSO HAS A VERY
HIGHLY STRUCTURED MICRO VASCULAR
SYSTEM CRITICAL FOR DELIVERY OF
OXYGEN AND NUTRIENTS AND WASTE
REMOVAL AND MUSCLES HIGHLY
METROBOLIC ORGAN DEPENDENT ON
MITOCHONDRIA FOREIGN ERNL JI
PRODUCTION AND IS A MAJOR
REPOSITORY FOR GLUCOSE AND
STORAGE OF GLUCOSE AS GLYCOGEN
AND CLARK MENTIONED THAT MUSCLE
IS HIGHLY RESPONSIVE TO HORMONES
AND GROWTH FACTORS. AS A
MULTINUCLEATED TISSUE HAS A STEM
CELL POPULATION SATELLITE CELLS
THAT ARE CAPABLE IN PRODUCING
REGENERATION OF MUSCLE FIBERS
AND THAT ARE CRITICAL FOR
GROWTH. NEXT SLIDE.
SO, MUSCLE WASTING CAN BE
INDUCED BY A NUMBER OF
STRESSORS.
NEXT SLIDE. TWO OF THE MOST
CRITICAL STRESSORS ARE EXTERNAL
LOADING AND NEURAL ACTIVATION
AND DECREASES IN EXTERNAL
LOADING AND RECRUITMENT AND
ACTIVATION OF MUSCLE INDUCE
MUSCLE WASTING AND MITOCHONDRIAL
DISFUNCTION CAN ALSO PLAY A ROLE
IN REGULATION OF MUSCLE MASS.
NEXT, OTHER FACTORS SUCH AS NEXT
SLIDE.
NEXT, INFLAMMATION AND TREATMENT
INFLAMMATION WITH
GLUCOCORTICOIDS AND VASCULAR
INT
INTERFUNCTION AND ORGAN FAILURES
SUCH AS LIVER, RENAL AND HEART
FAILURE CAN CONTRIBUTE TO MUSCLE
WASTING AND LAST BUT NOT LEAST,
AGING INDUCES PROLONGED OR A --
PROLONGED DECREASE IN MUSCLE
MASS.
NEXT.
NEXT SLIDE.
GENERALLY WHEN WE THINK OF
REGULATION OF SKELETAL MUSCLE
MASS, WE THINK OF THE BALANCE
BETWEEN PROTEIN SYNTHESIS AND
PROTEIN DEGRADATION AND WITH
MUSCLE LOSS, THINKING THAT THE
BALANCE GOES TOWARDS AN INCREASE
IN PROTEIN DEGRADATION AND MOST
PEOPLE THINK OF THIS AS DECREASE
IN PROTEIN SYNTHESIS AND
INCREASE IN PROTEIN DEGRADATION
AND HOWEVER MORE RECENT DATA
SHOWS PROTEIN SYNTHESIS CAN GO
UP IN SOME CASES AND WE NEED TO
KNOW AND NEED A BETTER
UNDERSTANDING OF WHICH PROTEINS
ARE IN FACT ARE BEING SUPPRESSED
SYNTHESISWISE AND WHICH ARE
INCREASED IN SYNTHESIS AND
TRANSLATIONS DURING@TROPHY
PROCESSES AND SHOWN HERE ARE
MULTIPLE DEGRADATION PATHWAYS
CRITICAL FOR DEGRADATION OF
PROTEINS AND PROETEE OHM SYSTEM
AND THEY ALL PLAY A ROLE IN THE
DEGRADATION OF SPECIFIC PROTEINS
AND OVER THE LAST 20 YEARS WE
HAVE BEGUN TO UNDERSTAND SOME
MOLECULAR PATHWAYS THAT ARE
ACTIVATED OR SUPPRESSED
UNDER@TROPHY CONDITIONS.
NEXT SLIDE.
YOU CAN SEE HERE NEXT THAT UNDER
MECHANICAL LOADING OR CHANGES IN
MECHANICAL LOADING AND
ACTIVATION OF THE MUSCLE THROUGH
THE NEUROMUSCULAR JUNCTION CAN
HAVE EFFECTS ON PROTEIN
SYNTHESIS PATHWAYS SPECIFICALLY
MTOR PATHWAY AND OTHER NON-MTOR
PATHWAYS COULD BE EFFECTED WITH
DECREASES IN MECHANICAL LOADING
AND SUPPRESSION OF AKT CAN
EFFECT TRANSCRIPTION FACTORS
SUCH AS FOXOS THAT CAN BECOME
ACTIVATED TURNING ON VARIOUS
TRANSCRIPTIONAL PROGRAMS THAT
INCREASE PROTEIN DEGRADATION AND
NEXT IS OTHER PAMPHLETS ALSO
HERE INFLAMMATORY PATHWAYS COULD
ACTIVATE.
INFLAMMATION COULD ACTIVATE
ADDITIONAL PATHWAYS THAT COULD
CONTRIBUTE TO THE ACTIVATION
EITHER SUPPRESSION OF PROTEIN
SYNTHESIS AND/OR ACTIVATION OF
PROTEIN DEGRADATION.
YOU CAN SEE HERE GLUCOCORTICOIDS
COULD INDUCE MUSCLE AT TROPHY.
IN CRITICALLY ILL PATIENT, IT IS
LIKELY MANY PATHWAYS ARE
ACTIVATED WITH UNLOADING
DECREASED NEURAL ACTIVATION AND
INFLAMMATION THAT IS ALL
CONTRIBUTING TO THIS ENHANCED
BREAKDOWN OF SARCOMERES.
NEXT SLIDE.
TWO PROTEINS THAT HAVE BEEN
SHOWN TO BE UPREGULATED UNDER A
VARIETY OF ATROPHY AND
CONDITIONS ARE E23 LYINGASES AND
IMAGINE BOX [INDISCERNIBLE] AND
THESE ARE E3 LYINGASES THAT
IDENTIFY SPECIFIC SUBSTRATES AND
ADDING UBIC WINATION TO THESE
TARGETS.
IT IS GENERALLY THOUGHT THAT
ADDITION TO U- BIK WIT AN CHAINS
LEADS TO PROTEIN DEGRADATION
THROUGH THE PROETEOSOME AND CAN
HAVE OTHER FUNCTIONS SUCH AS
ALTERING ACTIVITY OF SPECIFIC
PROTEIN OR LOCALIZATION WITHIN
THE CELL.
AND MURF AND MAFBX WERE
IDENTIFIED THROUGH
IMMOBILIZATION.
NEXT.
YOU CAN SEE HERE THEY ARE
RELATIVELY LOW EXPRESSION IN
NORMAL MUSCLE BUT BECOME HIGHLY
UPREGULATED IN RESPONSE TO
DISUSE.
THEY HAVE BEEN SHOWN TO BE
ACTIVATED UNDER A NUMBER OF
CONDITIONS.
NEXT, AS SEEN HERE.
NEXT.
DENERVATION AND FASTING AND
GLUCOCORTICOID AND SEPSIS AND
ACUTE LUNG INJURY AND MURF AND
MAFBX ARE IN ANIMAL AND IN HUMAN
HUMANS.
HOW THEY ARE WORKING TO INDUCE
AT TROPHY IS SOMETHING MY LAB
HAS WORKED ON NEXT AND IT IS
SUGGESTED THAT MURF BY ITSELF
CONDITIONED INDUCE@TROPHY AND
THEY CAN IN FACT INDUCE MUSCLE
WASTING. NEXT.
YOU CAN HIT IT AGAIN. NEXT.
WE HAVE USED DIGLIDE PROTEOMICS
TO IDENTIFY SPECIFIC TARGETS OF
MURF1 AND IDENTIFYING PROTEINS
THAT ARE IN FACT UB IQUITED AND
THAT HAVE RESPONSE TO
UPREGULATION OF MURF1. THEY ARE
SHOWN HERE.
NEXT, THIS TABLE SHOWS ALL 45
PROTEINS THAT HAD UPREGULATED U-
BIK WINATION IN RESPONSE TO MURF
AND GENERALLY SUGGESTED THAT
PRIMARY TARGETS IN MURF ARE
HEAVY CHAINS AND DATA SUGGESTS
NUMBER OF TARGETS FOR MURF AND
TIGHTEN AND DEZ BIN ARE HIGHLY
U- BIK WITTED PROTEINS WITH MURF
DEREGULATING ASSEMBLY OF
SARCOMERE AND PATHWAYS THAT
MIGHT BE ACTIVATED IN RESPONSE
TO MURF UPREGULATION AND NEXT I
WANT TO SWITCH TO WORK WE HAVE
DONE IN A MODEL OF UNLOADING AND
RELOADING.
TAIL SUSPENSION OR HIEM YEM
LOADING MODEL AND USE THIS MODEL
TO STUDY UNLOADING PROCESS AND
LOOK AT WHAT HAPPENS DURING
RELOADING AND RECOVERY OF MUSCLE
AND LOOKING AT COMPARING EFFECT
OF AGE BY LOOKING AT ADULT AND
OLD FISHER BROWN NORWAY RATS.
THESE SHOW LOSS OF MUSCLE MASS
OVER 14 DAYS OF UNLOADING AND
INCREASE OF MUSCLE MASS DURING
14 DAYS OF RELOADING AND MUSCLES
SHOWN HERE, THE SOLEOUS A
PREDOMINANTLY SLOW MUSCLE IN THE
RAT.
PLAN TARRIS IS A MIXED EXTENSOR
MUSCLE AND TIBIALIS INTERIOR IS
A MIXED FLEXOR MUSCLE. YOU CAN
SEE HERE IN THE ADULT IS THE
MUSCLE SHOWING THE GREATEST LOSS
IS THE SOLEOUS PREDOMINANTLY
SLOW MUSCLE AND MUSCLE WITH
LEAST LOSS OF MUSCLE MASS IS
FLEXOR OR TIBIALIS INTERIOR AND
FULL RECOVERY OF MASS WITHIN 14
DAYS OF RELOADING.
IN OLDER ANIMAL, NEXT.
YOU CAN SEE THAT THE@TROPHY
RESPONSE TO YOUNG AND OLD
ANIMALS HOWEVER, UPON RELOADING
YOU SEE ATTENUATED RECOVERY IN
MUSCLE MASS WITH ALL OF THE
MUSCLES WITH SOLEOUS BEING THE
BEST AT RECOVERY AND TIBIALIS
INTERIOR BEING ONE OF THE WORST.
IT SHOWS MUSCLES MIGHT HAVE A
SMALL AMOUNT OF AT TROPHY AND
MIGHT NOT RECOVER WELL AND WE
SEE MUSCLES WITH GREATEST
PERCENTAGES AND LARGE TYPE 2B
FIBERS HAVING WORST RECOVERY
UPON RELOADING.
NEXT.
IN ADDITION TO MUSCLE MASS, WE
LOOKED AT MUSCLE STRENGTH. IN
ADULT ANIMALS YOU CAN SEE THAT
RED DOTS SHOW RESPONSE TO 14
DAYS UNLOADING AND IS A DECREASE
IN STRENGTH. THIS IS ISOMETRIC
TORQUE ABOVE THE ANKLE JOINT
MEASURED USING AUR ORROUS SYSTEM
AND ELOADING YOU SEE FULL
RECOVERY OF STRENGTH AND IN OLD
ANIMALS DROPPING FORCE IS
GREATER THAN IN ADULT ANIMALS
EVEN THOUGH AMOUNT OF@TROPHY IS
SIMILAR AND NO RECOVERY OF
MUSCLE STRENGTH OVER 14 DAYS OF
RELOADING AND WOULD BE
INTERESTING TO SEE WHAT IS
RESPONSIBLE FOR THIS SIGNIFICANT
DROP IN STRENGTH IN OLDER
ANIMALS AND WHAT IS RESPONSIBLE
FOR LACK OF RECOVERY.
NEXT.
ONE THING, WE LOOKEDALITY
BASELINE DIFFERENCES BETWEEN OLD
AND ADULT ANIMALS AND
UNFORTUNATELY, THE DATA IS NOT
SHOWING UP.
WHAT WE SEE IS A SIGNIFICANT
DIFFERENCE BETWEEN OLD AND YOUNG
AT BASELINE WITH DIFFERENTIALLY
EXPRESSED GENES HERE THAT IS 393
IN THE UPREGULATED GENES THAT
ARE DIFFERENTIALLY UPREGULATED
AND 281 DIFFERENTIALLY
DOWNREGULATED AND GENONTOLOGY
PATHWAYS UPREGULATED IN OLD
ANIMALS ARE INFLAMMATION T
MEDIATED CYTOTOXICITY AND
INSTABILITY AND DOWNREGULATED
GENES HAVE CORRESPONDED TO
VASCULAR OR ANGIOGENESIS AND
EXCELLENT GUIDANCE AND DECREASES
IN EXTRA CELLULAR MATRIX. WE
LOOKED AT VARIOUS PROPERTIES AND
MEASURED VARIOUS PROPERTIES OF
THE MUSCLE.
WE SEE ACTUALLY IN OLD ANIMALS
INCREASE IN PROTEIN SYNTHESIS
AND NOT A DECREASE.
THIS HAS BEEN SEEN IN A NUMBER
OF AGING MODELS WITH INCREASE IN
MTOR ACTIVATION AND DON'T SEE
ELEVATIONS IN PROETEOSOME
ACTIVITY AT THIS AGE AND SEE
SUPPRESSION OF PROETEOSOME
ACTIVITY AND INCREASE IN
AUTOPHAGY THAT IS IN RESPONSE TO
INHIBITED PROETE OHM ACTIVITY
AND AGGREGATES AND SIGNIFICANT
ER STRESS INFLAMMATION AND
INCREASED GENES SUGGESTING
NEUROMUSCULAR JUNCTION,
INSTABILITY AND/OR DENERVATION.
NEXT.
WHAT IS RESPONSIBLE FOR THIS
LARGE DROP IN STRENGTH?
ONE OF THE FIRST THINGS WE
THOUGHT OF WAS NEUROMUSCULAR
JUNCTION.
NEXT.
WE LOOKED AT GENES THAT HAVE
BEEN ASSOCIATED WITH INACTIVITY
OR DENERVATION AND THERE IS
GENES HERE AND YOU CAN SEE HERE
AT BASELINE THAT THERE IS RED
BEING OLD ANIMALS AND INCREASE
IN BASELINE EXPRESSION IN GENES
UPON UNLOADING THESE GENES ALL
GO UP AND IN SOME CASES LIKE
NCAM AND ACETYL CHOLINE
RECEPTORS INCREASE MORE IN THE
OLD THAN IN THE ADULT AND
INTERESTINGLY UPON RELOADING
WHERE GENES ARE OFTEN SUPPRESSED
IN ADULT ANIMALS UPON RELOADING,
GENES STAY UP IN THE OLD AND
SUGGESTING THAT THERE IS
MAINTAINED OR THAT THERE IS
POTENTIALLY EVEN -- THAT
UNLOADING ITSELF IS INDUCING
INCREASED NEUROMUSCULAR JUNCTION
AND INSTABILITY AND POSSIBLY
DENERVATION THAT IS ENHANCED OR
EXACERBATED IN THE -- UPON
RELOADING.
NEXT.
WE HAVE LOOKED AT DURING
UNLOADING PERIOD WHAT IS
DIFFERENT IN UNLOADING PERIOD
BETWEEN YOUNG AND OLD ANIMALS --
YOUNG AND OLD DURING UNLOADING
PROCESS AND LOOKING AT OVERLAP.
AND WE SEE SIGNIFICANT OVERLAP
BETWEEN YOUNG AND OLD AND ARE
GENES DIFFERENTIALLY UPREGULATED
IN OLD AND DOWNREGULATED IN OLD
DURING UNLOADING RESPONSE
AND@TROPHY RESPONSE LOOKS
SIMILAR AND IS SOMETHING
DIFFERENT WITH THE RESPONSE.
NEXT, LOOKING AT GENES THIS IS
MURF AND GAD45A IS SHOWN TO BE
ACTIVATED WITH MUSCLE ATROPHY
AND MIOGENERALIN AND SEE GENES
ARE UPREGULATED DURING BASELINE
DURING UNLOADING RESPONSE, THEY
GO UP TO A GREATER DEGREE SUCH
AS GAD 45A AND AGENERALINE AND
REMAIN LOADING AND INCREASE
EXPRESSION BEYOND WHAT WAS SEEN
DURING UNLOADING AND IN THE CASE
OF MURF1, WHAT IS INTERESTING IS
IN ADULT ANIMALS, THIS GENE GETS
SUPPRESSED AND USUALLY BELOW
BASELINE AND IN OLDER ANIMALS,
MURF1 IS STAYING ELEVATED AND
INTERFERING WITH REMODELING
PROCESS AND ASSEMBLY OF NEW
SARCOMERES AND WE LOOKED AT
DURING RELOADING PERIOD WHAT IS
DIFFERENT.
HERE I WANT TO SHOW WITH ADULT
AND UNLOADING 83% OF GENES
DIFFERENTIALLY UNREGULATED WITH
LOADING AND RETURN BACK TO
BASELINE WITHIN 3 DAYS AND IN
OLD ANIMALS LESS THAN 64% OR
LESS THAN THE GENES THAT ARE
RETURNED TO BASELINE.
THERE IS A DELAY IN PROCESS THAT
RETURN TO BASELINE IN OLD
ANIMALS.
NEXT.
SOME PROCESSES THAT SEEM DELAYED
IN OLD ANIMALS ARE MITOCHONDRIAL
FUNCTION AND ENERGY GENERATION
AND MIGHT BE A DEFICIENCY IN
BIOENERGETICS THAT COULD INHIBIT
RECOVERY AND DECREASE IN MUSCLE
CONTRACTION AND DEVELOPMENT AND
DECREASE IN PROETEOSOME
CATABOLISM AND THERE IS A
PROTEIN WITH PROTEIN TURNOVER
AND PROTEINSTASIS IN MUSCLES AND
GLUTO THYMINE TRANSFER IN THESE.
>> SORRY TO INTERRUPT. YOU ARE
A FEW MINUTES OVER HERE.
>> OKAY. I'M JUST FINISHING
UP. WE ARE SEEING A DIFFERENCE
AND CHANGE IN PROTEE OESTASIS IN
ANIMALS AND I CAN FINISH UP
HERE, NEXT.
CURRENT KNOWLEDGE GAPS PRIMARY
MECHANISMS UNDERLYING LOSS OF
MUSCLE MASS AND LACK OF RECOVERY
AND ARDS SURVIVORS ARE UNKNOWN
AND AGE AND COMORBIDITIES ARE
LIKELY HAVING MAJOR IMPACT ON
EXTENT OF MUSCLE WASTING AND THE
LACK OF RECOVERY OF MASS AND
STRENGTH HOWEVER THE EFFECTS
HAVE NOT DIRECTLY -- THANK YOU
VERY MUCH.
>> THANK YOU VERY MUCH, SUE,
THAT WAS OUTSTANDING.
WE HAVE SEVERAL QUESTIONS THAT
ARE IN THE CHAT. WE HAVE A
COUPLE OF MINUTES TO ANSWER
THEM.
SO, THIS IS A QUESTION THAT IS
REGARDING SUPPLEMENTATION. ONE
ISSUE THAT CAME UP IS THE
INABILITY TO RECOVER AND YOU
SHOWED US A LOT OF
TRANSCRIPTOMIC CHANGES IN
RECOVERY IN OLD VERSUS IN THE
YOUNG. ONE QUESTION WAS IS THIS
A DIFFERENCE POTENTIALLY IN
PROTEIN INTAKE OR
SUPPLEMENTATION DIETARY
REQUIREMENTS OPPOSED TO
SOMETHING INTRINSIC OR STRESS
RELATED WITHIN THE OLDER MUSCLE
VERSUS YOUNGER MUSCLE?
COULD YOU COMMENT ON THAT A
LITTLE MORE?
>> YEAH. I MEAN, I SUSPECT
THIS IS SOMETHING INTRINSIC TO
THE MUSCLE AND I DON'T -- THESE
ANIMALS ARE NOT ENERGY DEPRIVED
AT ALL. THEIR EATING BEHAVIOR
IS SIMILAR FOOD INTAKE AND THINK
THIS IS SOMETHING INTRINSIC TO
THE OLDER MUSCLE THAT IS
PREVENTING RECOVERY OR
ATTENUATING RECOVERY.
>> THANK YOU VERY MUCH.
ANOTHER QUESTION HERE AT THE
BEGINNING THAT IS QUITE
INTERESTING AND IS FROM JACK AND
YOU DIDN'T SPEAK TO THIS
DIRECTLY. I'M NOT SURE HOW MUCH
OF IT WE CAN DISCUSS HERE. WE
WANT TO KNOW TALKING ABOUT
MUSCLE AS AN IMMUNOLOGICAL
ORGAN. DO WE KNOW TO WHAT
EXTENT MOBILITY PARALYSIS WOULD
ALTER MUSCLES IMMUNOLOGICAL
FUNCTION?
THIS IS SOMETHING YOU SPOKE
ABOUT HERE AND NOT SURE IF YOU
ARE ABLE TO COMMENT ON THAT OR
IF YOU LOOKED AT IT WITHIN YOUR
CELLS.
>> WE DID LOOK AT ACTIVITY
LEVELS IN THE ANIMALS UPON
RECOVERY OR RELOADING AND
THINKING THAT THEY WERE MORE
INACTIVE IN THEIR CAGE.
ACTUALLY, THE FIRST COUPLE OF
DAYS THEY WERE LESS ACTIVE.
OVER THE COURSE OF A WEEK, THEIR
ACTIVELY LEVELS AND OLD ANIMALS
WERE AS ACTIVE IN THEIR KANL AS
YOUNG ANIMALS AND WE ALSO PUT
THEM ON A TREADMILL TO TRY TO
INCREASE A SMALL AMOUNT OF
ACTIVITY.
THEY ARE NOT PARALYZED AND THEY
CAN WALK.
SO, I DON'T THINK THAT THEIR
OVERALL BASELINE ACTIVITY IS THE
PROBLEM.
IT MAY TAKE MORE, YOU KNOW,
LOADING OR ACTIVITY TO ENHANCE
THE RECOVERY IN THESE OLDER
ANIMALS.
THEY ARE NOT PARALYZED IN THAT
REGARD, YEAH.
>> THERE IS A LOT OF QUESTIONS
COMING UP, SUE, IN THE CHAT.
THEY ARE REALLY INTERESTING FOR
LATER AND UNFORTUNATELY WE HAVE
TO MOVE ON TO THE NEXT SPEAKER
AND WILL KEEP TRACK OF THIS AND
BRING IT UP IN THE DISCUSSION.
THANK YOU VERY MUCH.
>> WELCOME.
>> I WOULD LIKE TO INTRODUCE
THE NEXT SPEAKER DR. LARS
LARSON.
-- TO STUDY MUSCLE CONTRACTION
RANGING IN SINGLE UNIT MUSCLE
CELL DOWN TO THE MOTOR PROTEINS
THEMSELVES AND RESEARCH IS
FOCUSED ON DELINEATING
MECHANISMS IMPROVING DIAGNOSTICS
EVALUATING INTERVENTIONS
COMBINING NOVEL EXPERIMENTAL
MODELS WITH CLINICAL STUDIES AND
COLLABORATORS AROUND THE WORLD
AND HE IS CURRENTLY A PROFESSOR
AT INSTITUTE IN SWEDEN AND
DIRECTOR OF MUSCLE BIOLOGY
PROGRAM AT MMI IN BOSTON AND DR.
LARS TALK IS VENTILATOR INDUCED
LUNG INJURY AND ACQUIRED
MIOPATHY IN MODERN CRITICAL
CARE.
>> THANK YOU FOR THE KIND
INTRODUCTION AND INCLUDING IN
THIS INTERESTING WORKSHOP THAT
IS REALLY EXCITING.
CAN WE GO BACK TO THE FIRST
SLIDE?
THIS IS THE ORIGINAL TITLE OF
THE PRESENTATION IN PREMEETING
WE THOUGHT TO TAKE ANOTHER
APPROACH THAT IS PUBLISHED AND
THAT IS INTERESTING AND CAN FIND
IT AND LONGITUDINAL STUDY IN
PATIENTS EXPOSED TO CONTROLLED
MECHANIC INTERVENTION FOR 12
DAYS AND 6 TIMES AND PAIRED
BIOCONTRACTOR MEASUREMENTS AND
THOSE IN-BETWEEN WERE GENE
PROTEIN EXPRESSION AND ALL
PATIENTS DEVELOPED WHAT WE CALL
HALLMARK.
FOR CRITICAL ILLNESS MODEL
PREFERENTIAL LOSS OF MYOSIN.
SEEING PATIENTS THAT DON'T HAVE
THIS CENTRAL RESPIRATORY DRIVE
HAS TO BE VENTILATED IN
CONTROLLED MODE AND SOMETHING TO
AVOID IN GENERAL ICU IT INDUCES
MUCH MORE SEVERE LUNG INJURY AND
THEY PUT THIS NOT SO COMMON
MAYBE 1/3 OF PATIENTS EXPOSED TO
LONG-TERM MECHANICAL
INTERVENTION WITH MYOSIN LOSS
AND THIS HAS A MUCH LESS LUNG
INJURY.
THAT IS IF YOU GO TO THE NEXT
SLIDE, THEN WE SORT OF SWITCHED
TO THE SCOPE OF THIS
PRESENTATION BY FOCUSING ON
WHICH I THINK IS A MAJOR
PATHOPHYSIOLOGICAL FACTOR IN
THIS ACQUIRED MI OP THINK AND
CRITICAL CARE THAT WE CALL
CRITICAL ILLNESS MIOPATHY AND
LOOK AT THIS DISFUNCTION AND
RESEARCH ON THREE DIFFERENT LEGS
IMPROVED DIAGNOSTIC MONITORING
AND MAJOR FOCUS IS ON DIFFERENT
INTERVENTIONS AND SKIPPING OVER
THE MONITORING DIAGNOSIS QUICKLY
AND FOCUS ON MECHANISM
INTERVENTIONS.
NEXT SLIDE.
AS FAR AS I KNOW, THIS IS THE
FIRST PUBLICATION ON THIS
CRITICAL ILLNESS MI MYOPATHY.
CAME TO THE EMERGENCY ROOM AND
HAD TO BE TRANSFER TODAY ICU.
GIVEN MASSIVE DOSES OF STEROIDS
AND HOOKED TO VENTILATOR TO
ENSURE OXYGENATION TO CENTRAL
NERVOUS SYSTEM AND AT THAT TIME
[INDISCERNIBLE] PATIENT WOULD
NOT WORK AGAINST THE VENTILATOR.
WHEN INFECTION WAS CURED AND WE
KNEW PATIENT FROM VENTILATOR WAS
QUADROPLEGIC AND CRANIO FACIAL
MUSCLES WERE IN TACT
COMMUNICATING WITH SPATIAL
FUNCTION AND [INDISCERNIBLE] WAS
IN TACT AND SHE GRADUALLY
RECOVERED AND CONSIDERED TO BE
RARE CONDITION OF CLINICAL
SIGNIFICANCE AND WE KNOW IT IS A
VERY COMMON COURSE OF MUSCLE
PARALYSIS IN THE ICU.
FOR DECADES AND STILL FREQUENTLY
BEING MISDIAGNOSED AS NEUROPATHY
MISINTERPRETATION AND
[INDISCERNIBLE] SIGNALS AND
HEARD THIS IS THE FIRST TIME AND
PROFESSOR AROUND NEUROLOGICAL
CENTER AND HOSPITAL AND IT WAS
AT THIS WAS ABOUT 30 YEARS AGO I
WAS SETTING UP THIS SINGLE CELL
CONTRACTOR MUSCLES IN PATIENTS
WITH DIFFERENT NEUROMUSCULAR
DISORDERS AND SMALL MUSCLE
BIOPSIES AND CAME INTO THE LAB
UNANNOUNCED THIS WOULD BE
PERFECT TECHNIQUE TO STUDY OF
PATIENT AND HE DID SOMETHING
THAT NO ONE ELSE HAD DONE BEFORE
AND TOOK A MUSCLE BIOPSY FROM A
QUADROPLEGIC NEW ICU PATIENT AND
TLIFRED MICROSCOPY AND THERE IS
NO -- THE MOLECULAR MODEL IN THE
SKELETAL MUSCLE.
NEXT SLIDE. 1995 IN CHRISTMAS I
WAS ON CALL AND GOING TO ANOTHER
HOSPITAL TO LOOK AT PATIENT THAT
WAS QUADROPLEGIC AND DIAGNOSIS
AND ATYPICAL [INDISCERNIBLE] OF
ACQUIRED NEUROPATHY AND WENT
THERE AND THESE INDICATOR MOTOR
AXONO PANELY AND REMEMBER WHAT
THEY TOLD ME BEFORE. I TOOK A
MUSCLE BIOPSY FROM THIS PATIENT
AND TO THE LEFT HERE, YOU CAN
SEE MUSCLE CELL FROM A NORMAL OR
CONTROLLED PERSON THAT IS
RELAXING AND THIS IS ACTIVATING
THESE AND THESE CELLS DEVELOP
SAME FORCE AS IN VIVO
PREPARATION THAT IS FROM PATIENT
THAT YOU CAN SEE PATTERNS
LAUNCHED AND THESE DEVELOP
[INDISCERNIBLE] ACTIVATION AND
CELLS THAT LOOK AT EXPRESSION OF
MYOSIN ISOFORMS AND SLOW AND TOO
FAST AND THIS IS IN SLOW MYOSIN
HERE AND WE SEE IT EVERY IT ENTO
20 MUSCLE CELLS AND DIFFERENT
JAIL SYSTEM AND 1, 2, 3 IS FROM
A PATIENT WITH HEMIPLEGIA DUE TO
[INDISCERNIBLE] AND NONPAR ETIC
SIDE WE HAVE FULL EXPRESSION OF
MYOSIN AND MYOSIN ASSOCIATED
PROTEINS AND THERE IS ACTIN AND
REGULATORY PROTEINS THAT ARE
FULLY EXPRESSED. NEXT SLIDE,
PLEASE.
THIS IS AN EM PICTURE FROM
NORMAL MUSCLE SEA LION AND IT
HAD IS FROM PATIENT. SEA LION
SEA LION WITH NO MOTOR PROTEINS
AND NOT SURPRISING THAT PATIENTS
ARE [INDISCERNIBLE].
NEXT SLIDE.
THIS TIME WE DIDN'T HAVE
SOPHISTICATED METHODS WE HAVE
AVAILABLE NOW AND DEVELOPED IN
THIS SESSION WE CAN LOOK AT
ACTIN AND THREEMYCIN HEAVY
ISOFORMS AND NOT FOR MYOSIN AND
DISEASE THAT DOESN'T SHOW ANY
NEITHER SLOW OR FAST MYOSIN IN
MUSCLES AND WE HAVE PROTEIN
SYNTHESIS IN PATIENTS.
NEXT SLIDE.
THIS IS JUST SHOWING A PATIENT
FROM WHOM WE HAVE A BIOPSY ONE
MONTH BEFORE WE WENT INTO THE
ICU AND THEY BECOME QUADROPLEGIC
WE HAVE MYOSIN AND NORMAL
RECOVERY AND SURVIVED MYOCORDIAL
FUNCTION DURING THIS TIME
PERIOD.
THIS IS -- WE HAVE ACTUALLY SEEN
ONE PATIENT FROM WHOM BIOPSY WAS
TAKEN PRIOR TO GOING INTO ICU.
THEY BOTH HAVE SOME SORT OF
IMMUNOLOGICAL DISORDER THAT IS
UNCHARACTERIZED AND WE PROBABLY
NEED SOMETHING AND DON'T KNOW
WHAT. ANYWAY, IF YOU SURVIVE A
PRIMARY STEEZ, NEXT SLIDE,
PLEASE.
THIS IS SHOWING REEXPIRATION OF
4TH GENERATION CAPACITY AND
UPREGULATION AND EXPRESSION OF
MY FAVORITE PROTEINS.
NEXT SLIDE.
SO, FACTORS THAT HAVE BEEN TO BE
SEPSIS BROKERS AND STEROIDS AND
SEE THIS MYOPATHY IN PATIENTS
WITHOUT ANY OF THESE FACTORS AND
ARE LIKE YESTERDAY IN FIRE MAKES
THINGS WORSE AND ONLY THING THAT
PATIENTS HAVE IN COMMON WITH
THIS CRITICAL ILLNESS MYOPANELY
WITH MYOSIN IS LONG-TERM
MECHANICAL VENTILATION AND
COMPLETE IMMOBILIZATION THAT WE
CALL MECHANICAL SILENCING
MEANING NO WEIGHT BEARING AND NO
INTERNAL STRAIN RELATING
ACTIVATION CONTRACTING TO
PROTEINS THAT IS UNIQUE FOR ICU
PATIENTS BEING PARALYZED
[INDISCERNIBLE] OR
[INDISCERNIBLE].
NEXT SLIDE. NEXT SLIDE
UNDERSTANDING MECHANISMS
IMPORTANT TO GO INTO
EXPERIMENTAL ANIMAL MODEL. NEXT
SLIDE. SO MANY CONFOUNDING
FACTORS IN ICU PATIENTS STARTING
WITH THIS PORESINE MODEL AND
THEY WERE IMPORTANT FACTORS AND
WE EXPOSED THESE PIGS DURING 5
DAYS TO [INDISCERNIBLE] OF
COURSE AND MECHANICAL
VENTILATED.
WITH NEUROMUSCULAR BROKERS AND
IN 5 DAYS DON'T SEE MUSS MUSCLE
ATROPHY.
WE DON'T SEE A SIGNIFICANT DROP
HERE IN THE GROUPS AND WHEN WE
START TO ADD COURTI CO STEROIDS
AND SEPSIS COMBINED WE SEE
SIGNIFICANT DROP IN THESE AND
SHOW [INDISCERNIBLE] ACTS DUE TO
DEEP MUSCLE MEMBRANE
EXCITABILITY AND OFTEN MOTOR
AXON LOSS AND [INDISCERNIBLE] AT
THAT TIME TO DO THIS LOOKING AT
GENES EXPRESSING ROUTES AND PIGS
AND THESE ARE ROUTES SEEING NO
CHANGE IN MUSCLE FIBER SIZE OR
FOR GENERATING CAPACITY AND SOME
OF THE GENES WEPT UP AND DOWN
SIGNIFICANTLY THAT TO ME WAS A
LITTLE OVERSURPRISED AND THERE
WAS ALSO PROTECTIVE MECHANISMS
AND REASON WE DON'T WAIT UP
AFTER LONG NICE SLEEP WITH
MUSCLE WASTING AND WHY
HIBERNATING IN SPRING COMES UP
WITH WELL FUNCTIONING MUSCLES
AND HAVING COMPROMISED FUNCTION
YOU COULD SEE THERE WERE
DIFFERENCES AND FUNCTION WAS
COMPROMISED.
>> YOU HAVE FIVE MINUTES
REMAINING.
>> WOW. I BETTER SPEED UP
THEN. WE CAN SKIP OVER THIS
ONE.
LOOKING AT ANOTHER MUSCLE THAT
IS VENTLATORY MUSCLE AND
DIAPHRAGM THAT IS MUSCLE AND
VERY INTERESTED IN.
IT TERMS HOW QUICKLY WE CAN WEEN
PATIENT OFF VENTILATOR AND HERE
THE SITUATION IS COMPLETELY
DIFFERENT.
THOSE ARE CONTROLS AND OTHERS
WITH DIFFERENT INTERVENTION AND
ONLY COMMON DENOMINATOR HERE IS
MECHANICAL VENTILATION.
NEXT SLIDE.
WE WENT INTO DIFFERENT MODELS
THAT IS RODENT MODEL KEEPING
MECHANICAL VENTILATED AND
DENSELY MONITORED AND THIS IS BY
PROFESSOR ROCKEFELLER. NEXT
SLIDE.
THESE ARE TO BE MONITORED FROM
C02 AND [INDISCERNIBLE] GAS AND
EEG AND PRESSURE IN VENTLATORY
SYSTEM AND ECG MATERIAL AND
THESE ARE INVENOUS PRESSURE AND
MEASURE SATURATION AND
OXYGENATION IN LENS AND IN URINE
PRODUCTION.
NEXT SLIDE.
THESE WHEN EXPOSED TO LONG-TERM
MECHANICAL VENTILATION AND UP TO
THREE WEEKS LOOSE MYOSIN@TROPHY
AND 4TH GENERATION CAPACITY.
NEXT SLIDE.
MYOSIN IS FASTER MUSCLE AND
TRANSCRIPTION DOWNREGULATION
CONTRACTING PROTEINS AND LOOKING
ON EXPRESSION OF DIFFERENT
PROTEIN AGGRAVATION PATHWAYS
OVER TIME.
NEXT SLIDE. AGAIN, CRANIO
FACIAL MUSCLES IN LIMB MUSCLES
SEEING IN PATIENTS AND NEXT
SLIDE.
DIAPHRAGM WE SEE A DIFFERENT
PATTERN AND AS I SAID BEFORE,
DIAPHRAGM FUVENLGS DETERMINES
HOW QUICKLY WE CAN WEEN PATIENTS
OFF THE VENTILATOR AND 40% OF
TIME ON VENTILATOR IS WEENING
FROM THE VENTILATOR.
PATIENTS COST $64 PL IN US PRIOR
TO PANDEMIC. YOU CAN PROBE
SIGNIFICANT FACTORS DURING THE
PANDEMIC.
NEXT SLIDE.
IN THE DIAPHRAGM MUSCLE CELLS WE
SEE SAME THING, ATROPHIED AND
LOSS IN SPECIFIC [INDISCERNIBLE]
AND NO TRANSCRIPTION AND
DOWNREGULATION.
NEXT SLIDE.
THERE IS A DIFFERENT MECHANISM
HERE. IT IS MODIFICATIONS OF
MYOSIN THAT ARE VERY DIFFERENT
TECHNIQUES THEN.
NEXT SLIDE. I THINK THIS GETS
DIAGNOSTIC AND INTERVENTIONS AND
NEXT SLIDE.
WE LOOK AT DIFFERENT TYPES OF
INTERVENTION TARGETING MUSCLE
SILENCING AND LUNG INJURY. NEXT
SLIDE STARTED WITH SMALL
MOLECULE AND PROTEIN UPREGULATOR
AND MULTIPLE OTHER FUNCTIONS.
NEXT SLIDE.
WHAT WE CAN SEE THEN IS IF I
SIZE THEM DOWN SHOWN BEFORE AND
10 DAYS REPEATED WITH BP FIFTEEN
THAT IS IN DIAPHRAGM AND FORCE
THE GENERATION CAPACITY WAS
ALMOST DOUBLED. NEXT SLIDE.
PULLING OUT MYOSIN FROM SINGLE
CELLS AND ACTUALLY 4TH GENERATED
BY MYOSIN AND SAME THING AS
MOTOR PROTEIN LEVEL AND CELLULAR
LEVEL. NEXT SLIDE.
THESE ARE RELATION AND ALSO MANY
OTHER MONTHED FICTIONS.
NEXT SLIDE.
WE HAD A SIDE EFFECTS THAT WAS
IMPROVED SURVIVAL AND WE ARE NOT
QUICK ENOUGH TO REMOVE A MUCUS
PLUG AND HAVE ZERO MORTALITY AND
WITHOUT INTERVENTION, MORE THAN
60% OF [INDISCERNIBLE]. WE
DON'T KNOW WHY. THIS IS A SIDE
EFFECT WE CAN ACCEPT.
NEXT SLIDE.
WE TESTED BONE MARROW DERIVED
MESEN CHIMIAL STROMAL CELLS.
IT ALSO INCREASES DIAPHRAGM
MUSCLE CELL AND [INDISCERNIBLE]
LUNG INJURY AND HAS POSITIVE
EFFECT ON METABOLIZED
GENEGRESSION AND PROTEOMIC CELL.
NEXT SLIDE. TARGETING MUSCLE
CELL AND MECHANICAL SILENCING IS
ANECDOTAL OBSERVATION THAT IS 6
YEAR OLD BOY AND POST MORTAL
BIOPSY AND MUSCLE CELLS THAT
EXPRESS MYOSIN THAT ARE
INTERFUSED MUSCLE CELLS IN
MUSCLE SKIN AND SENSES AND
LENGTH CHANGES IN MUSCLE AND
CELLS ARE EXTRA FUELS OF FIBERS
SEVERELY TROPHIC MYOSIN WITH
THIS SIZE AND WHAT IS
DIFFERENCE? MECHANICAL LOADING
CELLS ON CONSTANT TENSION --
IMPORTANT ROLE AND MUSCLE CELLS
ARE EXTREME IN CANCER SENSITIVE.
NEXT SLIDE. DOING SIMPLE
EXPERIMENTS MECHANICAL LOADING
AND SEEING RESTORATION ON MUSCLE
SIZE AND 4TH GENERATING CAPACITY
AND SAME THING WITH RESTORED
MUSCLE SIZE.
NEXT SLIDE. ELECTRICAL
STIMULATION AND SIMILAR EFFECT
THAT IS NOT AS DRAMATIC AS WE
HAD EXPECTED. NEXT SLIDE.
REMARKABLE OBSERVATION THOUGH.
WE COULD SEE THAT GLUTE4
SIGNALING IS EFFECTIVE IN ROUTES
CONTROL 8 DAYS IN COMPLETELY
IMMOBILE ROUTE AND DEPLETED
GLYCOGEN AND -- GLYCOGEN LEVELS
INCREASED IN CONTRALA THORRAL
SIDE THAT WAS NOT STIMULATED.
NEXT SLIDE.
EXPERIMENTS WE DID LONG TYPE AGO
LOOKING AT SPATIAL
[INDISCERNIBLE] AND EFFECTIVE BY
AGING AND SLOW MUSCLE BEING ABLE
TO DO THIS IDENTIFYING
[INDISCERNIBLE] VENTRAL ROOT AND
YOU ONLY HAVE ONE MOTOR NEURON
GOING TO MUSCLE AND STIMULATE IT
100 HERTZ 20 MILLISECOND UNTIL 4
STOPS -- THAT DOESN'T HAPPEN IN
THE CELL AND YOU HAVE TO MAKE
ITIS CHEEMIC AND THAT HAPPENED
AND IDENTIFY THESE CELLS AND IF
THIS CASE COMPLETELY DIFFERENT
STORY.
NO ACTIVATION AT ALL. NEXT
SLIDE.
>> [INDISCERNIBLE].
>> YUP. ALMOST DONE.
WE SEE GLUTE FORCING SIGNAL
EFFECTIVE. NEXT SLIDE.
ALSO, WITH MECHANICAL LOADING WE
SEE SAME THING, CROSSOVER
EFFECTS. NEXT SLIDE.
NEUROMUSCULAR JUNCTION ADDITION
AND PRODUCING ACTUAL OUTGROWTH
IN THE STIMULATED UNSTIMULATED
SIDE THAT IS AT GENE LEVEL.
NEXT SLIDE.
WE CAN SEE THIS IS RELATED ALSO
TO -- I MEAN MORE THAN 6 FICHLT
-- WE TRIED TO LOOK AT
EXPRESSION OF MYOKINDS THAT ARE
DOWNREGULATED AND LOW BUT
INCREASED RESPONSE TO MECHANICAL
ELECTRICAL STIMULATION THAT IS
AS WELL AS IN [INDISCERNIBLE].
NEXT SLIDE. I WILL SKIP OVER IT
AND COME TO THE CONCLUGS.
NEXT.
THERE IS NO MUSCLE THAT IS
EFFECTED.
NEXT SLIDE.
ALSO BONE. BONE LOSS AND
REDUCING STRENGTH TO BONE.
NEXT SLIDE.
I LOOK AT LEVEL AND THERE IS
GLYCOGEN LIVER OVER TIME AND
AFTER 8 DAYS ELECTRICAL
STIMULATION AND ONE MUSCLE AND
ONE LIMB ACTUALLY INCREASES
GLYCOGEN LEVEL IN THE LIVER. WE
THINK WE HAVE LUNG INJURY
INDUCED BY -- PERIPHERAL ORGANS
INTERACTS WITH OTHER ORGANS AND
NEXT SLIDE. DOING RIGHT NOW
TRYING TO -- NEXT SLIDE.
LOOKING AT SINGLE CELL RNA SEEK
IN MUSCLE BIOPSY AND MUSCLE
CELLS AND OTHER CELLS THAT
INTERACT ALSO.
NEXT SLIDE. TRYING TO
UNDERSTAND CROSSOVER EFFECT
BETTER. NEXT SLIDE.
WE TRY TO DO THIS BY USING ORGAN
CROSS-TOOL IN MICRO FLUID
[INDISCERNIBLE]. NEXT SLIDE.
THESE ARE PEOPLE TO THANK. THEY
HAVE BEEN WORKING IN LAB. NEXT
SLIDE.
OUR COLLABORATORS AND THANK YOU
FOR YOUR ATTENTION.
>> THANKS SO MUCH, DR. LARSON.
AMAZING BODY OF WORK IN
PRECLINICAL AND HUMAN STUDIES
HERE.
SO MUCH TO DISCUSS AND LOTS OF
GREAT QUESTIONS IN THE CHAT. I
THINK WE ARE AT OUR 20 MINUTES
HERE.
SO, MAYBE WHAT WE CAN DO IS
ADDRESS SOME OF THE QUESTIONS IF
IN OUR PANEL DISCUSSION THAT
STARTS AT 11:15.
KEEPING US ON TRACK HERE, I WILL
MOVE TOWARDS THE NEXT SPEAKER.
I WOULD LIKE TO INTRODUCE DR.
JASON DOLES. DR. DOLES IS AN
ASSOCIATE PROFESSOR AND VICE
CHAIR FOR DIVERSITY, EBBING
WITHIT AND INCLUSION IN
DEPARTMENT OF ANATOMY CELL
BIOLOGY AND PHYSIOLOGY AT
INDIANA SCHOOL OF MEDICINE AND
-- AND PHD IF IN BIOLOGY FROM
MIT. HIS RESEARCH PROGRAM
CENTERS AROUND THREE MAIN THEMES
CANCER COCK EXIA LAB USED
VARIETY OF CELL BASED MODELS AND
MODEL -- SPANNING BASIC
DISCOVERY TO PRECLINICAL
TRANSLATIONAL STUDIES.
DR. DOLES TALK IS ENTITLED A
ROLE FOR MUSCLE STEM CELLS IN
LONG-TERM TISSUE REPOLICING AND
RECOVERY FOLLOWING SURGICAL
SEPSIS.
DR. DOLES.
>> THANK YOU. CAN YOU HEAR ME,
CLARK.
>> YES.
>> WE GOOD?
>> YES.
>> THANK YOU TO ORGANIZERS AND
CLARK AND JAIN AND VERY MUCH TO
SUE AND LARS FOR SETTING UP
GETTING THE SESSION GOING ON A
VERY POSITIVE NOTE.
TODAY I WANT TO PIVOT YOU KNOW
FROM FOCUSING ON ACUTE INJURY OR
EVEN JUST OUTLINING LACK OF
RECOVERY IN CRITICALLY ILL
PATIENTS TO THINKING ABOUT WHAT
PROCESSES ARE ACTUALLY
CONTRIBUTING TO THE POOR
RECOVERY WHETHER MUSCLE MASS.
FAILURE TO RECOVER MASS OR
FAILURE TO RECOVER FUNCTION AND
ARGUE A ROLE FOR MUSCLE STEM
CELLS AND REGENERATIVE PROCESS
IN LIKELY ADDITION TO MYOFIBER
AND INTRINSIC BALANCES OF
ANANABOLIC AND CATABOLIC
PROCESSES AND WE WILL SEE AND
HOPEFULLY HAVE A DISCUSSION
LATER ON OR BREAKOUT SESSIONS
ABOUT WHETHER THIS IS AN
INTERESTING APPROACH OR WHETHER
IT IS POSSIBLY NOT FEASIBLE IN A
CLINICAL SETTING.
NEXT SLIDE, PLEASE A LITTLE
BACKGROUND TO SEPSIS IT OFTEN
OCCURS AND IS LIFE-THREATENING
AND NOT SURE IF MOST POPULAR BUT
SOME MODELS OF ACUTE RESIDENT
CHTORY DISTRESS SYNDROME INVOLVE
-- PRESENTING SIMILAR IN TERMS
OF ACUTE SEPSIS AND RECOVERY
DYNAMICS AND MUSCLE MASS AT
LEAST TO MODEL WE USE AND
WITHOUT TIMELY TREATMENT ALL
THESE ACUTE CRITICALLY ILL
INJURY MODELS LEAD TO TISSUE
DAMAGE AND MULTIORGAN FAILURE
AND SEPSIS AND ARDS IS IMPROVING
AND IS A RATHER OLD DIAGRAM AND
IMPROVEMENT OF CLINICAL
MANAGEMENT AND SEPSIS AND ARDS
SURVIVAL THERE IS INCREASED
NUMBER OF SURVIVORS AND LARGE
NUMBER OF SURVIVORS WHETHER YOU
WANT TO LOOK AT THOSE WHO ARE
JUST SEPTIC OR THOSE THAT SUFFER
FROM ARDS.
AT LEAST, YOU KNOW, DEPENDING ON
METRICS USED TO MEASURE IT, 1/3
TO A HALF OF PATIENTS SUFFER
FROM LONG-TERM CHRONIC ISSUES
WHETHER MUSCULOSKELETAL IN
NATURE OR RISK FOR INFECTION OR
COGNITIVE ISSUES AND IS SIMILAR
AND LOTS OF OVERLAP HEARING
ABOUT PICKS.
MODEL I WILL TALK ABOUT TODAY
HAS SIGNIFICANT CLINICAL AND
MOLECULAR OVERLAP WITH LONG-TERM
SUSTAINED MUSCLE DIS FUFRFUNCTI
SO, I LIKE AND PUT IT IN. I
DIDN'T HAVE TO.
I THINK LOTS OF PEOPLE THINK
ABOUT MUSCLES SOMETIMES SIMPLY
AS SOMETHING THAT IS AN ORGAN OR
TISSUE INVOLVED IN LOCOMOTION
AND IS LOTS OF OTHER
CONSEQUENCES ENDOCRINE OR
HORMONAL, ET CETERA AND THESE
ARE VERY SEVERE AND SOMETHING TO
BE TAKEN VERY SERIOUSLY IN THE
CLINICAL -- FROM A CLINICAL
PERSPECTIVE INCLUDING FUNCTIONAL
CHANGES IN STRENGTH AND MOBILITY
AND THIS GROUP DOESN'T HAVE TO
FORGET THAT SKELETAL MUSCLE AND
DIAPHRAGM IS SKELETAL MUSCLE AND
RESPIRATORY ISSUES ARE
ASSOCIATED WITH EFFECTS IN
DIAPHRAGM ASSOCIATION AND THAT
ARE ASSOCIATED WITH --
RESISTANCE IN SOME CASES AND
PROTEIN TURNOVER, ET CETERA.
NEXT SLIDE.
SIMILAR TO ARDS AND IN MOUSE
MODELS WHERE YOU SEE RECOVERY
AND WOULD BE PROBABLY YOUNGER
MIDDLE AGED THAT GETS WORST IN
MICE AND RATS SHOWN BY SUE AND
OTHERS THERE IS EARLY PHASE
DRIVEN BY HIGHLY INFLAMMATORY
AND HIGHLY CAT BOLIC ENVIRONMENT
THAT IS ASSOCIATED USUALLY WITH
SEPSIS OR WHATEVER THE CRITICAL
INJURY IS. YOU ENHANCED
[INDISCERNIBLE] AND
GLUCOCORTICOID ATROPHY THAT IS
PART OF THE CLINICAL MANAGEMENT
OF SEPSIS. YOU SEE ISSUES WITH
MUSCLE STRUCTURE AND MEMBRANE
HYPOEXCITABILITY AND
NEUROMUSCULAR JUNCTION ISSUES
AND NERVES AND PHYSIOLOGICAL
IMPACTS ON CNS AND LATE PHASE
YOU SEE SIMILARITIES AND --
ALTERED PROTEIN DISFUNCTION AND
I WILL FOCUS ON FAILURE TO
REPLETE TISSUE LO S AND
REGENERATIVE PROCESS AND HOW IT
CONTRIBUTES TO THAT. NEXT. BIG
QUESTIONS I HAD AT LEAST WHEN I
FIRST START TODAY THINK ABOUT
THIS IS FIRST OF ALL IS THE
RECOVERY OF MUSCLE MASS AND DOES
IT EVEN INVOLVE REGENERATION AND
LOOKING AT LITERATURE I WASN'T
SURE MUSCLE STEM CELLS PER-SE
AND REGENERATIVE PROCESS
INVOLVED AS ALL AND HOW DO THEY
CONTRIBUTE TO THE RECOVERY AND
LARS MENTIONED TOWARDS END OF
HIS TALK -- MUSCLE MICRO
ENVIRONMENT IS COMPLEX AND OTHER
CELLS IN MICRO ENVIRONMENT HOW
THEY CONTRIBUTE TO THE PROCESS
AND SIGNALING IN DEFICITS IN
STEM CELLS AND ENVIRONMENT TO
IMPROVE TISSUE RECOVERY. NEXT.
YOU CAN DO ANOTHER NEXT.
SOME OBSTACLES HAVE BEEN REALLY
AT LEAST FROM A RESEARCH
STANDPOINT HISTORIC FOCUS ON
ACCUSE PHASE ON SEPSIS THAT IS
PROBABLY TRUE IN ARDS FIELD AS
WELL AND HYPERCATABOLIC PHASE
AND IN MOUSE MODELS AND IN
HUMANS AND IS CHANGING IN RECENT
YEARS AND MODELING SEPSIS IN
ARDS AND MICE IS COMPLEX AND NOT
HUGE FAN USING MOUSE MODELS
STUDYING ACUTE SEPSIS AND
PRIORITIES AND MUSCLE RECOVERY
ASPECTS ARE MICE ARE APPROPRIATE
AND RATS ARE APPROPRIATE FOR
LOOKING AT SOME RECOVERY
DYNAMICS IN THOSE MODELS.
AND I THINK THAT IMPORTANTLY WE
ARE KIND OF AT A JUNCTURE IN
SCIENCE RIGHT NOW. THERE IS A
LOT OF OPPORTUNITIES THAT ALLOW
US TO UNDERSTAND MOLECULAR
MECHANISMS AND IN GREATER AND
FAR MORE DETAIL THAN WE WERE
ABLE TO 10 YEARS AGO INCLUDING
CELL SEQUENCING AND MENTIONING
ADVANCED IMAGING TECHNIQUES AND
OTHER WAYS OF MODELING AND
STUDYING THESE COMPLEX
PHENOMENON.
FROM AT LEAST MY PERSPECTIVE,
I'M A RELATIVE NEWCOMER TO
CRITICAL ILLNESS MYOPATHY FIELD
TAKING LESSONS FROM OTHER MUSCLE
WASTING DISORDERS WITH
OVERLAPPING AND SOMEWHAT
DISTINCT MECHANISMS CANCER CAR
CHASM YA AND SARCOPENIA USING IT
TO BETTER UNDERSTAND MUSCLE
DISFUNCTION AS CONSEQUENCE OF
ACUTE TRAUMA.
NEXT.
YOU CAN JUST GO FORWARD ANOTHER
ONE AND ONE MORE.
YEAH. SORRY HEAVY ON ANIMATION
THAT IS A LITTLE TRICKY.
FIRST THING IS WHETHER OR NO THE
TO MODEL LATE EFFECTS THAT ARE
LONG-TERM -- THIS LONG-TERM
DISFUNCTION IN MICE.
MODEL IN SURGICAL SEPSIS AND
PUNCTURE CECUM AND LIGATE IT
USING THIS VERSION FROM FOLKS AT
UNIVERSITY OF FLORIDA AND
COUPLED IT WITH DAILY CHRONIC
STRESS MODEL THAT IN CASES COULD
BE USED AS A -- MIMICKING
NEUROLOGICAL STRESS PHENOMENON
OCCURRING IN PATIENTS IN ICU
THAT ARE LIMITED IN MOBILITY AND
INDEED ADDITION OF DAILY CHRONIC
STRESS TO THIS MODEL AND CLP
MODEL DOES HAVE PROFOUND
ADDITIVE EFFECT NOT SIN ERNLY
EFFECT AND ADDING IN MICE THAT
EXHIBIT IN RED LINE AND GRAPH ON
RIGHT AND SHOWING THEY LOSE
WEIGHT ACUTELY AND RECOVER
SLOWLY OVER TIME AND THEY
RECOVER POORLY GOOD MODEL TO
STUDY THAT AND BOTTOM GRAPHS
SHOWING MUSCLE MASS RECOVER OF
INDIVIDUAL MODELS AND WE SEE
LESS RECOVERY OF MUSCLES THAT
ARE MORE HIGHLY ENRICHED WITH
LARGER TYPE 2B FIBERS PRA EVER
GOOD THING IS MICE -- I DON'T
HAVE TIME TO SHOW IT EXHIBITING
LONG-TERM ISSUES ASSOCIATED WITH
FUNCTION OR SUBSTANCE
ASSOCIATED.
POST SEPSIS SYNDROME THEY HAVE
VASCULAR ISSUES AND EVIDENCE OF
IMPAIRED MUSCLE REGENERATION.
NEXT SLIDE. BEFORE I DO THAT GO
ONE MORE TRACKING AND STUDYING
MUSCLE REGENERATION IN VIVO IS
USING USEFUL MODEL AND WE CAN
TRACK LOOKING ATTACKTIVATION AND
EXPANSION OF MUSCLE PROGENITORS
IN MICE.
NEXT SLIDE, PLEASE.
IN THIS CASE INDUCING INJURY AND
SEEING IN MICE 96 HOURS YOU SEE
RAPID EXPANSION OF
BIOLUMINESCENCE SIGNAL AND WE
HAVE POSITIVE CELLS INTO MUSCLE
BASELINE CONDITION LABELING THEM
THEY ARE TOO RARE AND SPARSE TO
SEE SIGNAL.
>> [INDISCERNIBLE].
>> OKAY. IN MICE THAT ARE
PREVIOUSLY SEPTIC THERE IS
FAILURE TO ACTIVATE THESE CELLS.
INTERESTING THING HERE MUSCLE
CELLS ARE EFFECTED BY MICIS.
THERE IS INTRINSIC DEFEBLGS
ABILITIES TO DIFFERENTIATE AND
MOLECULAR DEFECTS IN CELLULAR
METABOLISM, ET CETERA DOES IT
MATTER? ARE THEY REQUIRED FOR
RECOVERY AND EXHIBIT MOLECULAR
CHANGES APPEARING TO BE
DYSFUNCTIONAL WITH TRACER ASSAYS
GOING FORWARD A COUPLE. NOT A
GIVEN THEY ARE IMPORTANT DURING
MUSCLE RECOVERY PHASE.
YOU KNOW, WHEN YOU HAVE
TRAUMATIC INJURIES YOU SEE A
FAILURE TO RECOVER IF IN THESE
EXPERIMENTAL INJURY MODELS OF
TRAUMATIC INJURY AND DOESN'T
APPEAR AS IF IMPORTANT FOR
LIFELONG MAINTENANCE AND
SEDENTARY MICE AND ARE THEY
INVOLVED IN SEPSIS AND POST
RECOVERY AT ALL AND TOOK
ADVANTAGE OF THIS -- REPORTER
AND WE HAVE WE TOOK OBLATION
STRATEGY AND GOT RID OF MUSCLE
STEM CELLS SUBJECTING INTO SAME
SEPSIS PROTOCOL AND GETTING RID
OF THEM ENTIRELY OBLATE MUSCLE
RECOVERY AND NEXT IS SPECIFIC TO
THE MUSCLE AND IS SPECIFIC IN
ALL OF THE OTHER TISSUES RECOVER
IN THIS MODEL AND NO IMPACT ON
RECOVERY AS WELL AND COULD
ARGUABLY LOSE WEIGHT IN MICE AND
STILL NOT UNCLEAR TO US AND THEY
DON'T RECOVER AS WELL.
NEXT. YEAH. THERE IS MORE TO
THE MUSCLE MICRO ENVIRONMENT IN
STEM CELLS AND GOING TO THE NEXT
SLIDE.
SINLE CELL SEQUENCING WE DID TO
BETTER UNDERSTAND WHAT IS
HAPPENING HERE AND TAKE-HOME
MESSAGE NOT ONLY DECREASE IN
STEM PROGENITOR CELLS INCREASED
ABUNDANCE AND IMPORTANCE ON
MACROPHAGES AND PRESENCE AND
PERSISTENCE OF MYELOSUPPRESSOR
CELLS SHOULDN'T BE THERE AND
T-CELL FUNCTION PROPORTIONS OF
THEM WE SHOULD ARGUE IS
CONSEQUENCE OF PERSISTENT MDC
AND ENDOTHELIAL CELLS THAT WE
ALSO SEE LOSS OF CELLS FOLLOWED
BY PHENOTYPE SWITCH. NEXT.
YOU CAN GO FORWARD ONE OR TWO
AND INTEGRATED ANALYSIS TO
UNDERSTAND IF WE COULD PREDICT
INTERVENTIONS THAT IS INFORMATIC
-- THIS IS BASICALLY, YOU KNOW,
CONCURRENT REGULATOR ANALYSIS OF
SINGLE CELL DATA FROM INDIVIDUAL
IMMUNE CELL POPULATIONS
TARGETING COMPOUNDS REVERSING
TRANSCRIPTIONAL SIGNATURES.
NEXT.
THIS IS MY FINAL SLIDE, I
BELIEVE. YUP. WE ARE
EVALUATING COMPOUNDS NOW TO SEE
HOW EFFECTIVE THEY ARE IN POST
SEPSIS TISSUE RECOVERY AND NEXT
IS A SUMMARY SLIDE HERE YOU CAN
GO FORWARD ON ALL OF THEM. I
COVERED THIS AND DON'T HAVE TO
GO OVER IT BUT WOULD LIKE TO
TALK ABOUT IMPLICATIONS ON NEXT
SLIDE AND OPPORTUNITIES MOVING
FORWARD, WE SEE EVIDENCE OF
FUNCTIONAL STEM CELL IMPAIRMENT
AND THINKING ABOUT WHETHER OR
NOT THERAPIES TARGETING STEM
CELL DEFICIENCIES IS TARGETING
COMPLICATIONS WITH
IMMUNOTHERAPIES AND THOSE
DYSREGULATED IN ACUTE PHASE AND
WE DON'T WANT TO IMPAIR ABILITY
TO ACUTELY MANAGE SEPSIS AND
WOULD LIKE TO FOCUS ON RECOVERY
AND A LOT OF THE PATHWAYS
APPEARING TO BE INVOLVED IN
ACUTE MUSCLE DISFUNCTION MIGHT
BE SOMETHING THAT WOULD, YOU
KNOW, INTERFERE WITH ABILITY TO
MANAGE SEPSIS CLINICALLY. ALSO,
IT IS POSSIBLE WE MIGHT NEED
CATABOLISM TO PROVIDE NUTRIENTS
TO OTHER ORGANS TO ASSIST IN
RECOVERY FROM SEPSIS AND MY
ARGUMENT WOULD BE TO -- MY
THOUGHTS ARE TO INTERVENE LATER
AND HELP WITH MUSCLE RECOVERY
RATHER THAN MESS WITH HIGHLY
COMPLICATED AND COMPLEX SCENARIO
OF ACUTE MUSCLE LOSS THAT WILL
REQUIRE MORE NUANCE AND
UNDERSTANDING OF MUSCLE MASS
VERSUS FUNCTION IN RECOVERY IN
ICU SURVIVORS DOING METABOLIC
STUDIES AND ARE OPPORTUNITIES TO
BOOST METABOLIC RECOVERY AND
INTERESTING IMPLICATIONS
PROGENITOR MICRO -- OR ALSO
DISRUPTED IN PATIENTS TAKING
APPROACH TO STUDY LONG TERM
SEPSIS DISNUFRNGS HEART AND LUNG
AND BONE MARROW OF SEPSIS MICE
AS WELL.
THAT IS THE END, I BELIEVE.
YEAH. JUST THANKING EVERYONE IN
THE LAB FOR HELPING OUT
COLLABORATORS BOTH AND WE HAVE A
FEW AT UP SOUTHWESTERN AND UW AS
WELL AS UNIVERSITY OF FLORIDA
GANG THAT IS LED BY PHIL EH RON
AND THANKS FOR LISTENING.
>> THANK YOU VERY MUCH, JASON.
THAT WAS REALLY INTERESTING. IT
IS A MASSIVE AMOUNT OF WORK THAT
IS PRESENTED IN A VERY SHORT AND
CONCISE AND EASY TO UNDERSTAND
TIMELINE.
THANKS VERY MUCH.
WE HAVE TIME FOR A COUPLE
QUESTIONS SPECIFICALLY. ONE IN
THE CHAT BASICALLY SAYS IT IS
SHOWN THAT STEM CELLS COULD
PROVIDE MITOCHONDRIAL MATERIAL
TO THE SATELLITE CELL AT ACUTE
PHASE OF SEPSIS IN THE MOUSE AND
ARE NECESSARY FOR MUSCLE
REGENERATION.
QUESTION IS, SHOULD STEM CELLS
BE GIVEN AT ACUTE PHASE OR
EFFECTIVENESS BE BETTER AT
RECOVERY PHASE?
>> I THINK YOU ARE TALKING
ABOUT THE BAPER FROM THE FRENCH
GROUP IN 2015.
THEY NOT ONLY SAW DIFFERENCES IF
INTRINSICALLY IN MITOCHONDRIA OF
STEM CELLS AND ARGUED BOOSTING
MITOCHONDRIA FUNCTION IN
SATELLITE CELLS COULD BE
IMPORTANT THERAPEUTIC STRATEGY
AND COULDN'T SEE FOLLOW UP FROM
THAT PARTICULAR GROUP. WHETHER
OR NOT SATELLITE CELLS COULD BE
SOURCE OF MITOCHONDRIA FOR
MYOFIBERS IS REALLY INTERESTING.
IT COULD BE USED PERHAPS
THERAPEUTICALLY IF THINKING OF
EXOGENOUS SATELLITE CELLS OR
EXOGENOUS TREATMENTS. I WOULD
PROBABLY DO THAT LATER. I DON'T
KNOW. I GUESS IT IS PURE
SPECULATION, I GUESS. I DON'T
KNOW.
>> THANK YOU. WHAT WE CAN DO,
I THINK, IS BRING SOME OF THIS
UP IN THE DISCUSSION THAT WE
HAVE HERE.
I THINK WHAT I WILL DO AT THIS
TIME IS JUST TRY TO SUMMARIZE
THE OUTSTANDING DATA AND
FANTASTIC IDEAS THAT SPEAKERS
HAVE BROUGHT TO THE TABLE.
THEN WE WILL MOVE FORWARD FOR
MORE IN-DEPTH DISCUSSION.
CLARK, PLEASE HOP IN HERE IF I
MISSED SOMETHING AND GENERAL
THEMES BRINGING FORWARD FROM
WORK WE HAVE SEEN TODAY IS AGE
IS HUGELY IMPORTANT AND IS
IMPACTING REALLY A BASELINE
MUSCLE STATUS AND BIOLOGICAL
FUNCTION.
THIS IS CRITICAL. THERE --
ALTHOUGH THERE SEEMS TO BE A
SIMILAR LOSS, RATE OF LOSS OF
MUSCLE THAT IS SIMILAR IN OLD
AND YOUNG, CERTAINLY SIGNALING
THAT MEDIATES THAT LOSS IS
DIFFERENT.
THAT MEANS WE CAN'T APPROACH OLD
AND YOUNG NECESSARILY THE SAME
AND MOREOVER, THERE IS ACTUALLY
IMPEDIMENT OF RECOVERY OF THE
MUSCLE IN THE AGE COMPARED TO
THE YOUNG.
NOT ONLY ARE WE SEEING
DIFFERENCES IN CELLULAR
SIGNALING IN THE RACE THIS IS
BOTH AT LOSS AND RECOVERY. AGE
IS A HUGE CONSIDERATION AND
GIVEN AGE RANGE OF THE PATIENTS
IN THE ICU, WHAT WE DO FOR THE
YOUNG MAY KRERMLY NOT WORK FOR
THE OLD AND WORK ON PERSONALIZED
MEDICINE APPROACHES HERE. THAT
IS A BIG THEME, AGE IS CRITICAL.
THE OTHER REALLY INTERESTING
FACTOR THAT CAME OUT IS AS WE
TALKED BEFORE, DIFFERENT MUSCLES
SEEM TO RESPOND IN DIFFERENT
WAYS.
THIS CAN NOW ACTUALLY BE SHOWN
WITH SOME WORK THAT LARSON HAS
DONE FOR EXAMPLE AT A MOLECULAR
LEVEL AND SEE THAT WE ACTUALLY
LOSE MYOSIN IN PERIPHERAL
MUSCLES BUT ISSUE IN DIAPHRAGM
IS POSTTRANSLATIONAL
MODIFICATION.
WE HAVE, AGAIN, IMPAIRMENT OF
THE MECHANICAL MOTOR.
IF YOU WANT TO PUT THAT WAY.
THE REASON THAT WE ARE HAVING
THAT IMPAIRMENT IS LOSS VERSUS
IMPAIRED FUNCTION.
IT SEEMS TO BE DIFFERENT MUSCLE
TO MUSCLE.
THIS WILL BE HUGELY IMPORTANT AS
WELL WHEN WE LOOK AT THE
INDIVIDUAL AS A WHOLE.
LOADING IS CRITICAL AS
ELECTRICAL AND CAME OUT THAT WE
-- MUSCLES NEED TO BE ACTIVE TO
BE HEALTHY.
SO, THESE ARE THE THREE THEMES.
MOVING FORWARD TO THE OTHER END
OF THE SPECTRUM WHICH IS, YOU
KNOW, RECOVERY. THE QUESTION
COMES UP, SHOULD WE EVEN BE
TARGETING LOSS OF MUSCLE?
BECAUSE PERHAPS IF WE TRY TO
INHIBIT RELEASE OF AMINO ASS
SITS, ET CETERA, THIS WILL BE
HARMFUL TO THE ORGANISM THAT IS
TRYING TO SURVIVE CRITICAL
ILLNESS AND WE ARE LUCKY IN
MUSCLE IN THAT WE HAVE ANOTHER
END THAT IS RECOVERY AS JASON
WENT INTO. RECOVERY IS
IMPORTANT IN MUSCLE AGAIN.
WE ARE ADVANCING -- ADVANTAGE WE
CAN STICK ALL PROTEIN BACK IN
AND TRY TO MAKE IT BIGGER AND
FUNCTION BETTER AND WE CAN
REGENERATE IT AND MAKE NEW
MUSCLE.
STEM CELL IS ANOTHER POPULATION
WE CAN SPECIFICALLY TARGET IF IN
THE MUSCLE AND TRY TO MAINTAIN
HEALTH AND BRING BACK. WE HAVE
KEY THEMES, I THINK, THAT CAME
OUT IN THIS.
AGE AND -- AND IT IS HUGELY
IMPORTANT.
THE TYPE OF MUSCLE THAT YOU ARE
LOOKING AT IS GOING TO BE
MANIFESTING DIFFERENT THE
INSIDES DIFFERENTLY.
WE ARE LOOKING AT NOT JUST LOSS
BUT RECOVERY AND TRYING TO
TARGET 1 OR THE OTHER OR BOTH.
MAY BE DIFFERENT DEPENDING ON
AGE OF THE PATIENT AND MIGHT BE
EASIER TO RESCUE 1 VERSUS THE
OTHER. THAT IS MY SYNOPSIS.
CLARK, WANT TO ADD ANYTHING
ELSE?
>> REALLY GOOD AND CAN LINK
MAJOR POINTS TO A FEW QUESTIONS
IN THE CHAT.
ONE I WOULD LIKE TO ADD FOR OUR
DISCUSSION NOW LINKS BACK WITH
THE DISCUSSION IN SESSION 2
YESTERDAY.
IT IS ABOUT USING COMPLEX ANIMAL
MODELS THAT REPLICATE ICU
ENVIRONMENT AND THINK THAT DR.
LARSON HAS EXTENSIVE AMOUNT OF
EXPERIENCE IN THIS AREA AND
THINK WE SHOULD BRING FORWARD
THE DISCUSSION ABOUT, YOU KNOW,
HOW DO WE THINK ABOUT THESE
COMPLEX MODELS?
AND, YOU KNOW, THEY ARE
CHALLENGING TO SET UP.
THEY INFORM THE COMPLEXITY AND
HETEROGENEITY OF THE ICU
ENVIRONMENT AND HOW WE SHOULD BE
THINKING OF THOSE MODELS IN OUR
FIELD.
THE OTHER QUESTION OR SORT OF
ADD-ON, I THINK, IS TO THINK A
BIT MORE ABOUTISH AUTO YOU WITH
IMPAIRED REGENERATION.
SO, THERE IS REALLY KEY POINTS
THAT I THINK ARE BROUGHT UP
HERE.
ONE, I PUT IN THE CHAT RELATED
TO JASON'S WORK IN POST SEPSIS
MOUSE MODEL AND APPEARS TO BE
FAILURE OF STEM CELL ACTIVATION.
OF COURSE, YOUR WORK, JAIN, IN
THIS AREA IN HUMANS SHOWS IN
WEAK PATIENTS THAT HAVE SURVIVED
CRITICAL ILLNESS AND THOSE THAT
REMAIN WEAK APPEAR TO HAVE
IMPAIRED STEM CELL REGENERATION
AND THINK THAT ACTIVATION,
QUESTION HERE IS, WHAT IS
DRIVING THAT?
WHAT IS OCCURRING?
DR. LANGLY PUT A REALLY GOOD
QUESTION IN THE CHAT AS TO WHAT
IS HAPPENING HERE AND WHAT IS
THE MECHANISM?
ARE THERE -- IS THIS ROSS
INDUCED DAMAGE THAT IS EFFECTING
SKELETAL MUSCLE LONG TERM?
WHAT DO WE THINK THE MECHANISM
IS THAT WE MIGHT BE DRIVING AT?
GREAT.
MAYBE WE COULD START WITH THAT,
THAT QUESTION RIGHT THERE. SO,
MAYBE I WILL POSE THAT BACK TO
DR. DOLES.
WHAT DO YOU THINK MIGHT BE
DRIVING THAT IMPAIRED ACTIVATION
OF SATELLITE CELLS IN YOUR
MODEL?
>> YEAH. NO. I MEAN, I THINK
THAT IS A BIG -- I MEAN, IT IS A
BIG ONE. ONE THING WE NOTICED
AT LEAST FROM A WHOLE MUSCLE
STANDPOINT AND HAVEN'T LOOKED AT
SATELLITE CELLS SPECIFICALLY, WE
DON'T SEE PERSISTENT LOSS IF IN
MODEL AND LOOKING AT THAT IS
CONCURRENT WITH SATELLITE CELL
DISFUNCTION AND DON'T THINK
REQUIRED DRIVER OF SUSTAINED
SATELLITE CELL DISFUNCTION AND
WE DO SEE INCREASES IN DNA
DAMAGE MIGHT NOT BE ROSS DRIVEN
BUT DRIVEN BY SOMETHING ELSE, I
DON'T KNOW.
I THINK THAT THE IMPORTANT THING
IS WE DO SEE BOTH, YOU KNOW,
CELL INTRINSIC AND PERSISTENT
DEFECTS IN SATELLITE CELLS AND
NOT ONLY ARE DAMAGED AND
FUNCTIONING IN VIVO AND PULLING
OUT CULTURING THEM FOR WEEKS
THESE PERSIST AND CAN'T DO
NORMAL THING SUPPOSED TO DO IN
CULTURE AND [INDISCERNIBLE] ET
CETERA. SOMETHING IS HAPPENING
ALTERING NOW SOMEWHAT
PERMANENTLY HAVEN'T LOOKED SUPER
LONG TERM AT INTRINSIC FUNCTION
OF SATELLITE CELLS THAT WE HAVE
NOT QUITE TEASED OUT.
I'M NOT SURE ABOUT ROSS AS A --
AS A CRITICAL DRIVER.
CERTAINLY, WE HAVE TO ADDRESS
ISSUES THAT ARE CELL AND
EXTRINSIC TO THE SATELLITE CELL.
>> ONE THING TO THINK ABOUT
ENVIRONMENT IN THE MUSCLES.
IN THE AGING ANIMALS, WE DON'T
SEE ANY IMPAIRMENT IN THE
ABILITY FOR PROTEIN SYNTHESIS
AND MYOFIBULAR PROTEINS ARE
BEING MADE AND NOT ASSEMBLED AND
NOT BEING FOLDED OR ASSEMBLED
PROPERLY INTO SARCOMERES AND YOU
MIGHT BE ABLE TO PRODUCE
PROTEINS AND MIGHT NOT BE ABLE
TO ASSEMBLE THEM CORRECTLY AND
WITH AGING THERE IS CHANGES IN
PROETEOSTASIS AEFFECTING
PROTEINS AND ADDING STEM CELLS
TO A BAD ENVIRONMENT MIGHT NOT
ENHANCE RECOVERY.
THERE IS A LOT WE STILL NEED TO
UNDERSTAND ABOUT WHAT IS
HAPPENING IN THESE PATIENTS POST
RECOVERY AND LARS MIGHT BE ABLE
TO ADDRESS THAT MORE.
>> ONE THING I WOULD LIKE TO
ADD IS LIFE-SAVING INTERVENTIONS
IN ICU HAVE ALSO NEGATIVE
CONSEQUENCES UNRELATE TODAY
SEPSIS AND OTHER INTERVENTIONS.
MAYBE ONE WAY TO REDUCE NEGATIVE
IN THE ELDERLY ESPECIALLY IS
REDUCING LUNG INDUCED INJURY BY
VENTILATOR THAT IS A LARGE
SAVING INTERVENTION.
AND THERE MAY BE OTHER WAYS.
AND LONG TIME AGO DURING POLIO
PANDEMIC, IRON LUNG WAS USED
WITH NEGATIVE PRESSURE
VENTILATION AND ONE COULD
MONITOR 50 PATIENTS AND ANOTHER
USING -- ONE IS MONITORING TWO
PATIENTS AND AT SAME TIME GET
LUNG INJURY AND FACTORS WITH
PERIPHERAL ORGANS AND NOT GOING
BACK TO IRON LUNG AND SOMETHING
THAT WE COULD THINK OF USING
DIFFERENT MODES OF VENTILATION
THAT INDUCES LESS LUNG INJURY.
I WAS ALSO VERY INTRIGUED ALSO
BY THE PRESENTATIONS YESTERDAY
ABOUT THE LUNG INDUCED LUNG
INJURY INFECTION CENTRAL NERVOUS
SYSTEM AS WELL AND THIS HAS SITO
TOXIC EFFECTS ON CELL TYPES AND
PERIPHERY AND CENTRAL NERVOUS
SYSTEM AND INTERVENTIONS TRY TO
TALK AND REDUCE NEGATIVE EFFECTS
OF MECHANICAL VENTILATION OF THE
LUNG REDUCING NEGATIVE EFFECTS
OF PERIPHERAL ORGANS AND
ACTUALLY MYOSIN AND
[INDISCERNIBLE] MUSCLES MODIFIED
THAT IMPAIRS FUNCTION BUT THEN
OF COURSE WHEN YOU HAVE
PREFERENTIAL MYOSIN LOSS, THIS
BECOMES NOT SO IMPORTANT.
AT THE SAME TIME, THE DIAPHRAGM
IS CONSTANTLY BEING MECHANICALLY
LOADED BY VENTILATOR AND WHEN WE
DID, THIS IS JUST A SIMPLE
EXPERIMENT NEEDING TO BE
REPEATED. WHEN WE DOUBLE NUMBER
OF MECHANICAL LOADINGS IN
MUSCLES WE HAVE NO MYOSIN LOSS
THERE IS STILL COMPROMISED
FUNCTION AND THINK IT MAY BE --
THE LIMB MUSCLES BECOME LIKE A
DIAPHRAGM WHEN YOU ARE
CONSTANTLY LOADED. OF COURSE,
IT HAS A CROSS-EFFECTS ON
FUNCTION DOESN'T REDUCE LIMIT ON
FUNCTION THOUGH.
>> THOSE ARE REALLY, REALLY
INTERESTING POINTS.
AS YOU WERE TALKING ABOUT
MECHANICAL INTERVATION ON MUSCLE
WASTING AND THINKING OF PAST
THREE YEARS THINKING ABOUT
THROUGH COVID PANDEMIC AND WE --
WORLDWIDE I THINK WE ARE USING A
MUCH HIGHER LEVEL OF HEATED HIGH
FLOW NASAL OXYGEN RATHER THAN
INVAESSIVE MECHANICAL
VENTILATION IN PATIENTS WITH
SEVERE ACUTE RESPIRATORY FAILURE
AND ARDS NOW.
I DON'T KNOW OF ANY STUDIES
DURING THE PANDEMIC THAT
COMPARED RATE OF MUSCLE WASTING
IN COVID PATIENTS WHO WERE
INVASIVELY MECHANICALLY
VENTILATED VERSUS THOSE ON HIGH
HEATED FLOW AND ANYONE IN THE
PANEL IF YOU KNOW OF THAT
INFORMATION AND COULD THINK OF
THAT, IT MIGHT BE INTERESTING
WAY TO GET AT THAT REALLY
IMPORTANT QUESTION.
ALTHOUGH, THERE IS CLEARLY GO TO
BE CONFOUNDING BY INDICATION
BECAUSE SICKER PATIENTS TEND TO
BE ON MECHANICAL VENTILATOR MORE
OFTEN.
>> I SKIP OVER THIS AND MAYBE
IT DOESN'T FULLY ADDRESS YOUR
QUESTION. IN BEGINNING OF
PANDEMIC 15 OUT OF 16 PATIENTS
AND COVID MODEL AND OTHER ONE
WAS BORDER LINE AND THERE WAS A
PAPER IN THE AGE RELATED
DIFFERENCES IN THE INCREASED
MORTALITY AND ELDERLY COVID
PATIENTS AND, OF COURSE,
ESPECIALLY IN THE BEGINNING,
THESE PATIENTS WERE VENTILATED
IN THE PRO ENPOSITION AND USE
CONTROLLED MECHANICAL
INTERVENTION AND USING -- WE HAD
THESE RATS YOUNG AND OLD
MECHANICALLY VENTILATED AND
CYTOKINES CONSIDERED TO BE VIRAL
EFFECT IN THE ELDERLY AND WENT
BACK AND CHECKED IN DIAPHRAGM OF
YOUNG AND OLD RAT AND YOUNG RATS
WE SAW AT GENE LEVEL
TRANSCRIPTION BIOREGULATOR
METABOLIC PATHWAY.
IN OLD ANIMALS IMMUNE RESPONSES
WERE SKYROCKETING.
ACTUALLY, YOU SEE A CYTOKINE
STORM AS RESPONSE TO MECHANICAL
VENTILATION AND PROBABLY HAVE A
LUNG MUCH MORE VULNERABLE TO
VENTILATOR INDUCED LUNG INJURY
AND FACTORS AND WE HAVE
INTERESTING AGE EFFECT AS WELL
--
>> MAYBE THIS IS A QUESTION
REALLY THAT IS TO MAYBE TO THE
NIH LCHLTD BI STAFF TO WHAT
EXTENT THESE INFORMATIONAL
SESSIONS ARE GREAT GETTING
PEOPLE INTERESTED IN THIS HLBI
SUPPORTING -- P. PGS THAT WILL
ALLOW US TO -- IT SEEMS LIKE A
ONE PERSON OR LAB EFFORT TO DO
THIS. IS THIS SOMETHING ON
RADAR THAT WILL BE PRIORITY TO
ASSEMBLE TEAMS TO HAVE COMPLEX
MODELS AND ADJUST MULTIPLE
TISSUES AND RESEARCH TOGETHER?
JUST WONDERING.
>> I DON'T WANT TO SPEAK FOR
NHLBI THERE IS A LARGE FUNDED
OBSERVATIONAL STUDY THAT WILL BE
MULTICENTERED THAT IS NIGMS AND
NHLBI FUNDED LOOKING AT
COLLECTING BIOSAMPLES AND
PATIENTS WITH PNEUMONIA SEPSIS
AND ARDS THAT SHOULD BE GETTING
STARTED SOON AND MAY HELP.
WE WILL LET SESSION CHAIRS TALK
MORE ABOUT THIS AT THE END OF
THE SESSION AND WANT TO MOVE TO
A POINT THAT CAME UP IN THE
DISCUSSION A COUPLE TIMES HERE
THAT IS FROM TERRI HUH AND
LAUREN F.
ADDRESSING THIS ISSUE THAT TENDS
TO COME UP IN DISCUSSIONS WHEN
GETTING HEALTH OUTCOMES
RESEARCHERS AND CLINICAL
TRIALISTS AND MUSCLE BIOLOGISTS
TOGETHER.
THAT IS WHAT IS RELATIONSHIP
BETWEEN MUSCLE ATROPHY AND
FUNCTIONAL OUTCOMES IS TARGETING
ATROPHY IMPORTANT AT ALL OR SIZE
IMPORTANT? HOW DOES IT RELATE
TO PHYSICAL FUNCTION AND
RECOVERY?
WE HAVE REALLY EXPERT SKELETAL
MUSCLE BIOLOGISTS HERE ON THE
PANEL THAT MIGHT BE ABLE TO HELP
US THINK THROUGH THESE ISSUES
AND I MAYBE WILL TURN TO SUE TO
ANSWER THAT QUESTION.
>> YEAH. I THINK LARS CAN
ANSWER THIS TOO.
I THINK SIZE IS IMPORTANT AND WE
KNOW IN NORMAL MUSS THAT'LL
CROSS-SECTIONAL CORRELATES WITH
FORCE PRODUCTION AND MUSCLE HAS
TO BE ABLE TO BE ACTIVATED AND
IF THERE IS PROBLEMS WITH
NEUROMUSCULAR JUVENGS OR
ACTIVATION OF MUSCLE DOESN'T
MATTER HOW MUCH MUSCLE IS THERE
IF CAN'T BE ACTIVATED DON'T GET
FORCE PRODUCTION AND EFFECTING
FORCE TRANSDUCTION.
SO, IN THESE DISEASE CONDITIONS
OR ACUTE CONDITIONS, THEY DON'T
ALWAYS CORRELATE.
SO, YEAH. I MEAN IT IS COMPLEX
AND WE HAVE TO CONSIDER SIZE AND
INTERVATION AND HOW THESE
CROSS-BRIDGES ARE
INTERFUNCTIONING.
>> ALL RIGHT.
>> CAN I ASK -- I WANT TO ALSO
MAKE THE POINT HOW WE MEASURE
SIZE IN MUSCLE MASS IS ALSO
IMPORTANT.
I THINK IN HUMANS THAT HAS BEEN
A PROBLEM OF GETTING ACCURATE
MEASUREMENTS OF LEAN MUSCLE
MASS.
JUST SOMETIMES IN ANIMAL MODELS
JUST WEIGHING MUSCLE DOESN'T
REALLY REFLECT WHAT IS GOING ON
INSIDE AND HAVING BETTER WAYS OF
MEASURING MUSCLE MASS GETTING
BETTER INDICATION OF LEAN MASS
AND FUNCTIONAL MASS.
>> SO, I THINK I TRIED TO PUT
AN ANSWER IN THE CHAT RELATED TO
WHAT DR. BODEN JUST MENTIONED
AND THINK THAT THIS ISSUE OF
OUTCOMES AND FUNCTIONAL RECOVERY
AND DEFINING FUNCTIONAL RECOVERY
IS CRITICALLY IMPORTANT HERE.
SO, IF WE HAVE A -- IF WE DESIGN
A CLINICAL TRIAL FOCUSED ON
PHYSICAL FUFRJS RECOVERY
OUTCOMES SAY A 6 MINUTE WALK OR
SOMETHING SUCH, YOU MIGHT HAVE A
DRUG OR INTERVENTION IMPROVING
MUSCLE MASS OR MITIGATING MUSCLE
MASS MAKING MUSCLE MASS STRONGER
NOT DOG ANYTHING TO 6 MINUTE
WALK TEST AND CARDIOVASCULAR
COMPONENT TO 6 MINUTE WALK AND
PHYSICAL -- SO, I DO THINK WE
NEED TO BE VERY CAREFUL ABOUT
WHAT INTERVENTION IS AND WHAT WE
THINK WE ARE TARGETING IN THE
EXCEL TAR MUSCLE.
AND HOW WE MEASURE THAT IN A
CLINICAL OUTCOME.
>> DON'T FORGET THAT PHYSICAL
FUNCTION ALSO EMOTIONAL HOW
PATIENTS ARE FEELING COGNITIVELY
IMPACTED AND BECOMES REALLY
CHALLENGING TO MEASURE POST ICU.
WE DO A 6 MINUTE WALK TEST ONE
DAY AND THEY WILL DO EXCELLENT
AND DOING IT A FEW DAYS LATER
ANXIETY AND TRAUMATIC EVENT YOU
WILL GET HETERO JENAETY EVEN
WHEN FOLLOWING STANDARDIZED
PROTOCOL.
I WOULD LIKE TO MAYBE ASK DR.
LARSON A QUESTION AND TRY TO
LINK BACK TO THE SESSION
YESTERDAY THAT WAS FOCUSED ON
MECHANISMS OF NEUROCOGNITIVE
INJURY.
THE ROLE FOR COMPLEX ANIMAL
MODELS.
LARS, I'M INTERESTED TO KNOW
WHAT YOUR TAKE IS ON THE VALUE
OF THE MODELS THAT YOU HAVE
CREATED OF A PRECLINICAL ICU
ENVIRONMENT, NO. 1.
NO. 2, HAVE YOU LOOKED AT BRAIN
INJURY IN ANY OF YOUR MODELS?
>> I WILL START WITH A SECOND
QUESTION AND EXPERIMENTS ARE
DEMANDING AND WE HAVE TO BE
THERE 24 HOURS A DAY THOUGH.
IN 40 YEARS I DON'T THINK THEY
HAVE BEEN OPERATING AND WOKEN UP
FROM ANESTHESIA, SO TO SAY.
WE HAVE A SPECIAL ETHICAL XITEE.
ANYWAY, SO, WE ARE THERE 24
HOURS A DAY.
AT THE END, I THINK THAT WE ARE
INTERESTED IN MUSCLE AND I
COLLECT MORE THAN 92 AND AT END
OF THE EXPERIMENTS INCLUDING
BRAIN ONE WE FREEZE AND OTHER WE
FIXATE AND ARE THERE RAISING
HAND AND COLLECT A LOT OF TISSUE
AND LARGE BIOBANK FROM THIS.
WE HAVE TISSUE AND HAVEN'T
ANALYZED IT AND DON'T HAVE
EXPERTISE AND IF SOMEONE HAS
EXPERTISE WE ARE MORE THAN HAPPY
TO COLLABORATE AND USE OF MODELS
THOUGH AND THINK THAT PROBLEM
WITH CLINICAL STUDIES IS SO MANY
CONFOUNDING FACTORS AND FOCUSING
ON ICU CONDITION ITSELF. IT HAS
IMPACTS ON MUSCLE AND RAT MODEL
AND MODIFY IT AND MAKE IT LESS
INVASIVE.
WE SEE JEANO TYPE AND PHENOTYPE
IS SAME AS WE SEE IN ICU
PATIENTS AND STRONG SIMILARITIES
OF THESE COMMON DENOMINATOR IS
ICU CONDITION ITSELF AND MODEL
IS COMPLEX.
I THINK THAT ONLY ONE TRYING TO
REPLICATE MODEL AND KNOWING HOW
MUCH WORK IT WAS FROM BEGINNING
I WOULDN'T HAVE DONE IT EITHER
GIVING INFORMATION BITS AND
PIECE ABDZ WE THERE AND ANYONE
CAN DO IT.
IT IS A LOT OF WORK. THING FOR
ME IT HAS BEEN REWARDING.
WE HAVE LOTS OF TISSUE AND ARE
LOOKING AT -- SORRY.
>> I WAS GOING TO ASK, LARS
COULD YOU -- WOULD YOUR MODEL BE
ABLE TO BE ADAPTED TO ALLOW
ANIMALS TO RECOVER LOOKING AT
POST RECOVERY.
>> IN PRINCIPLE YES ABOUT YOU
IN PRACTICE EXPERIMENT I DON'T
WANT IT DO AND OTHER HAND OTHER
PATIENT IS VERY, VERY USEFUL AND
DID LONG TIME AGO AND FOLLOWED
PATIENTS LONGITUDINALLY AFTER
RECOVERY AND PATIENT HAS OWN
CONTROL AS WELL.
IT IS EASIER TO DO IN PATIENT
THAN RAT MODEL AND OUR MODEL IS
TERMINAL EXPERIMENT AND LOWEST
GRADE OR ANIMAL SUFFERING AS
WELL AND WOULD LIKE TO KEEP THAT
WAY AS WELL.
I WAS GOING TO BRING IT UP AND
ANIMAL MODELS ARE FABULOUS AND
LOOKING AT RECOVERY COMPONENT OF
THIS IN HUMANS ARE NOT PLEASANT
AND SERIAL BIOPSIES ARE POSSIBLE
AND YOUR INDIVIDUAL THAT YOU CAN
EXERCISE OR ELECTRICALLY
STIMULATE OR CHAFRJ DIET AND
INDIVIDUAL WHO IS NOT
PERSISTENTLY WEAK AND HEALTH AND
AGE AND -- YOU CAN DO
EXPERIMENTS IN HUMAN BEING
THEMSELVES POST ICU.
WE CAN PROBABLY DO CAUSE AND
EFFECT AND MECHANISTIC STUDIES
IN COMPLEX CREATURE ROLE IN THE
HUMAN AND THANKS FOR BRINGING IT
UP THAT WE OFTEN FORGET ABOUT
GOING BACK TO HUMANS TRYING TO
DO INTERVENTIONAL STUDIES WITHIN
HUMANS THAT ARE NOT JUST FARM
COLONL CAL BUT DOING LOADING AND
EXERCISE AND SEEING WHAT HAPPENS
TO SATELLITE AND SATELLITE CELL
IN INDIVIDUAL POST ICU RESPOND
THE SAME WAY TO HEAVY ISOMETRIC
IS EXERCISE THAT INDIVIDUAL WHO
DOESN'T HAVE PERSISTENT WEAKNESS
DOES. THERE ARE STUDIES WE CAN
DO IN PATIENT POPULATION.
>> WONDERFUL DISCUSSION.
WE HAVE FIVE MINUTES LEFT AND
THOUGHT THAT MAYBE WE COULD
SPEND THE LAST FEW MINUTES
TALKING ABOUT A QUESTION THAT
CAME INTO THE CHAT BY DR. SHAR
SHAR EARLY THAT IS A -- ALSO
ANOTHER GREAT TOPIC OF DEBATE
THAT CRITICAL CARE DOCTORS AND
MUSCLE PHYSIOLOGISTS DISCUSS AT
CONFERENCES.
I THINK THIS IS TRYING TO
PREVENT MUSCLE AT TROPHY OR
MUSCLE CATABOLISM IMPORTANT?
SHOULD WE JUST ACCEPT THAT THE
SKELETAL MUSCLE IS THERE?
THIS IS A TEEL LOGIC MECHANISM
IN PLACE TO PRESERVE AN ORGANISM
WHEN THERE IS A MAJOR CAT BOLIC
EVENT?
WHAT WOULD HAPPEN IF WE TRIED TO
PREVENT THIS CAT BOLIC EVENT?
MIGHT WE GET OURSELVES INTO MORE
TROUBLE THAN BENEFIT?
>> MAYBE I WILL ASK DR. BODINE
THAT.
>> [LAUGHING]. YOU ARE
PICKING.
>> I KNOW.
>> YEAH. I DON'T KNOW.
IS THERE A WAY TO SUPPLEMENT THE
PATIENT NUTRITIONALLY SO THEY
ARE NOT RELYING AS MUCH ON
MUSCLE BREAKDOWN?
OTHER CORING AN AND WHAT IS
HAPPENING IN LIVER AND TISSUES
AND PROTEIN BREAKDOWN IS GOOD
ALSO.
I DON'T KNOW YOU WANT COMPLETE
SUPPRESSION OF METABOLISM AND
WILL BE DIFFICULT TO DO.
JASON HAS HIS HAND UP.
>> I HAVE TO REMEMBER TO
UNMUTE. SUE, USING YOUR MICE
AND MICE THAT ARE DEFICIENT IN
MURF1 EXHIBIT LESS SKELETAL
MUSCLE WASTING FOR CONDITIONS
FOR OTHERS ON THE CALL. THEY
DIE ACTUALLY MORE READILY
ACUTELY TRYING SEPSIS THAT IS
UNPUBLISHED STUFF.
WE WERE INTERESTED IN STUDYING
RECOVERY AND OPPOSED TO -- IN A
CONDITION WHERE WE HAVE MILD
SEPSIS SO LESS THAN 20% ACUTE
MORTALITY ASSOCIATED WITH INSULT
OR LESS THAN 10% HALF OF MURF
MICE DIDN'T MAKE IT AND ARGUES
TO ME ACTIVE WASTING IS
IMPORTANT IN THE ACUTE PHASE.
AND IMPORTANT FOR THE RECOVERY
AS A NUTRIENT SOURCE FOR
SOMETHING AND NOT ACUTELY WITHIN
FIRST 20 BUT 24 TO 48 HOUR
WINDOW WHERE MICE WERE NOT --
CLEARLY NOT RECOVERY AND REACHED
EXPERIMENTAL ENDPOINTS AND DON'T
KNOW WHAT YOU THINK ABOUT THAT,
SUE.
>> ONE THING I WOULD LIKE TO
ADD IS MAYBE IT IS IMPORTANT
SOURCE IN THE FIGHTING INFECTION
BUT I THINK THAT FIGHTING THE
CAUSE RELATED TO MODERN CRITICAL
CARE MECHANICAL VENTILATION
ITSELF AND LUNG INJURY COULDN'T
BE SOMETHING TO TRY TO AVOID, I
THINK.
THAT IS I THINK ACTUALLY A MAJOR
SOURCE AND MAYBE CHANGES THAT WE
SEE AS WELL.
I SEE NO REASON WHY ONE SHOULD
TRY TO AVOID THAT.
SOMETHING WE ARE TRYING TO DO
EXPONENTIALLY. SO FAR, IT LOOKS
PROMISING WITH SPECIFIC
INTERVENTIONS AND THESE BONE
MARROW DERIVED IN CHEMOSTROMAL
CELLS TARGETING INJURED LUNG
CELLS INDUCED BY MECHANICAL
VENTILA
VENTILATION.
>> GREAT DISCUSSION. I WILL
TRY TO HIT ONE MORE QUESTION IN
THE CHAT HERE.
THIS IS A QUESTION BROUGHT UP BY
MARK MOSS AND LAUREN.
IT IS THAT IF WE MEASURE MUSCLE
MASS OR STRENGTH OR FUNCTION AT
BEDSIDE OF CRITICALLY OLD
PATIENT, WHICH MUSCLE SHOULD WE
MEASURE? DIAPHRAGM BY
ULTRASOUND OR QUADRICEPS OR
ANKLE FLEXOR EXTENSOR?
WHAT SHOULD WE MEASURE?
WHAT IS IMPORTANT?
ANYONE ON THE PANEL WITH A
THOUGHT ABOUT THAT?
>> THANK YOU FOR ASKING.
DIAPHRAGM THAT I THINK IS HOW
QUICKLY THEY CAN TAKE PATIENT
OUT WITH AN ICU.
WHEN IT COMES TO LIMB MUSCLES,
PRIME OVER IS [INDISCERNIBLE]
MUSCLE CELL FOR WALKING, ET
CETERA.
SAME TIME MRC SCORES ARE USED TO
FOR DIAGNOSTIC PURPOSES I DON'T
UNDERSTAND HOW TO DO THIS
UNKROUSHS MECHANICAL EVENT
PATIENT THOUGH.
>> EXCELLENT. WE ARE ALMOST AT
TIME AND ONE MORE POINT TO MAKE
HERE THAT IS HAVING SOME
TRAINING IN GERIATRICS AS A
BYSTANDARD.
I HAVE LEARNED A BIT ABOUT
GERIATRICS FIELD. I THINK IT IS
IMPORTANT TO RECOGNIZE THAT KEY
EXPERIMENTS DR. BODINE SHOWED OF
DIFFERENT RESPONSE IN AGING MICE
IS DIFFERENT THAN YOUNGER
ANIMALS AND DOESN'T MEAN THAT
OLDER MICE WON'T RESPOND TO
INTERVENTIONS.
THERE IS A NUMBER OF STUDIES IN
OLDER HUMANS AND OLDER GERIATRIC
POPULATIONS WITH AGED MUSCLE
THAT ARE SHOWING OLDER HUMANS
CAN RESPOND TO INTERVENTIONS.
WE SHOULDN'T FEEL IT IS A LOST
CAUSE AND MIGHT BE A DIFFERENT
INTERVENTION BUT CRITICALLY
IMPORTANT POINT THAT I THOUGHT
WE COULD MAYBE FINISH WITH HERE.
SO -- ALL RIGHT. I THINK THAT
WE ARE AT TIME HERE.
>> THANK YOU, CLARK. TAKING A
15 MINUTE BREAK AND RECONVENING
AT 12 O'CLOCK EASTERN TIME.
THANK YOU, ALL. TAKE TIME TO
STRETCH OR GET A SIP OF WATER OR
ANYTHING AND SEE YOU SOON.
>> DR. MOSS IS HEAD OF THE
DIVISION OF PULMONARY SCIENCE
AND CRITICAL CARE MEDICINE AT
UNIVERSITY COLORADO SCHOOL OF
MEDICINE AND DR. STEPHANIE
TAILOR IS CHIEF DIVISION OF
MEDICINE AND STARTED POSITION
THIS MONTH AND CONGRATULATIONS
TO STEPHANIE AND WITHOUT FURTHER
ADO WEL COCOME MARK MOS AND
STEPHANIE TAILOR.
>> THANK YOU. SESSION 4 WE PUT
TOGETHER A CALL TO ACTION
SYNTHESIZING GREAT INFORMATION
YOU HEARD SO FAR THAT IS
RECOGNIZING WE HAVE COME SO FAR.
WE HAVE COME A LONG WAY
UNDERLYING MECHANISMS -- SUPPORT
ING INTERVENTIONS IN THE SETTING
WE ARE DEALING WITH SYNDROMES
AND DISEASES AND HARD TO KNOW
WHO SHOULD BE ENL ROLLED IN
TRIALS AND MULTICOMPLEX AND
THERE IS ISSUES WITH
IMPLEMENTATION AND QUESTIONS
COMING UP ALREADY WHAT TO
CONTROL AND BE HETEROENEOUS
OUTCOMES WE CARE ABOUT ARE HARD
TO MEASURE AVEND SOMETIMES DON'T
KNOW IF WE SHOULD CARE ABOUT
THEM OR NOT ASKING YOU TO
DECLARE LACK OF EVIDENCE
INTOLERABLE THINKING HOW TO
DESIGN TRIALS FOR INTERVENTIONS
FOR BRAIN DISFUNCTION IN NRDS
AND WE LIKE TO DO IT NOW AND
BROUGHT TOGETHER A LOT OF WORK
THAT WE HEARD ABOUT AS WELL AND
DISCUSSION WILL BE GREAT PLACE
TO DO THAT INTRODUCING OUR FIRST
SPEAKER WHO IS ASZANT PROFESSOR
OF MEDICINE AND BIOINFORMATICS
AND RESEARCH PROGRAM HAS NON
PATIENT TO UNDERSTAND WHAT
TREATMENTS HAVE BEST RESULTS FOR
PATIENTS AND TURNING IT TO DR.
SEMLER FOR HIS TALK.
>> THANK YOU FOR HAVING ME. I
WAS ABLE TO SIT IN THE LAST HOUR
AND LEARN MORE THAN IN PAST YEAR
COMBINED AND TRIALS AND HOW THEY
MIGHT INFORM BRAIN DISFUNCTION
AND APPRECIATIVE FOR FUNDING
FROM NIH AND DISCLOSURE IS I'M
AN INTENSIVE CLINICAL TRIALIST
BUT NOT EXPERT IN BRAIN
DISFUNCTION AND FORGIVE ME FOR
ERRORS I MIGHT HAVE.
NEXT SLIDE.
>> STARTING POINT CONCEPTUAL
FRAMEWORK WHAT WE ARE TALKING
ABOUT HERE BEGINS WITH A GOAL
AND ROUGH VERSION IS IDENTIFYING
PREVENTIONS TO TREAT SPEED
RECOVERY FROM.
WE HAVE TWO PATHWAYS TO THE GOAL
AND FIRST IS ONE WE THINK AND
TALK ABOUT A LOT DISCOVERIES AT
CELLULAR LEVEL IMPLEMENTING
CRITICAL PRACTICE TO IMPROVE
OUTCOMES AND TODAY'S TALK
FOCUSES ON OTHER PATHWAY THAT
PATHWAY IS REVERSE TRANSLATION
STARTING WITH PATIENT THAT IS
CRITICALLY ILL AND WHAT PATIENTS
MIGHT RECEIVE MIGHT EFFECT BRAIN
DISFUNCTION AND CLINICAL TRIALS
TO UNDERSTAND TREATMENT AND
OUTCOMES AND WALKING THAT BACK
TO BIOSPECIMENS AND TECHNIQUE
FRAMING ASPECTS OF RESEARCH
PORTFOLIO IS A POINT TO NOTE AND
CRITICAL ILLNESS TO DATE WE HAVE
TRIED TO WALK THINGS THROUGH
THAT TRANSLATION PATHWAY AND HAD
TROUBLE GETTING TO NEW DRUGS AND
DEVICES PROVING OUTCOMES FOR
ADULTS THAT IS ENGENDERING SENSE
OF ANILISM THAT I DON'T THINK IS
NECESSARY AND WE SHOULD KEEP
FOCUS ON FACT THAT WHEN WE
EXAMINE TREATMENTS THAT PATIENTS
RECEIVE IN IDENTIFYING
TREATMENTS PRODUCING DIFFERENT
OUTCOMES AND PLACE TO WORK
HARDER IS WALKING BACKWARDS TO
NSHS MECHANISMS FOR CRITICALLY
ILL PATIENTS USING THAT PATHWAY
MORE HEAVILY AND PORTFOLIO NOT
JUST BENCH TO BEDSIDE BUT
EXAMINING THINGS HAPPENING AT
BEDSIDE USING THAT LEVERAGE TO
GO BACKWARDS AND THAT IS
CRITICAL.
THIS FRAMING EFFECTS HOW WE
DESIGN CLINICAL TRIALS AND OUR
HISTORICAL REGULATORY FRAMEWORK
AND FRAMEWORKS FOR CLINICAL
TRIALS WAS DEVELOPED FOR
DEVELOPMENT OF NEW DRUGS AND
DEVICES LIVING IN THIS FORWARD
TRANSLATION MINDSET HEAVILY AND
IS NOT WELL SUITED.
NEXT SLIDE. THIS IS THE
FRAMEWORK AND BASIC FRAMEWORK
FOR CLINICAL TRIALS AND CLINICAL
CARE AND BUSY WORLD OF HOSPITAL
AND DIVERSITY OF PATIENTS AND
CLINICIANS USE TREATMENT A AND
SOME CLINICIANS USE TREATMENT B
NOW HERE TOTALLY SEPARATELY IS
THAT OF CLINICAL TRIALS
PRIORITIZING DRUGS AND DEVICES
IGNORING EXISTING THERAPIES
PATIENTS ARE GETTING AND SUBSET
OF PATIENT CARE AND PRACTICE AND
HIGHLY TRAINED RESEARCHER PERSON
ELDOESN'T MIMIC HOW
INTERVENTIONS WOULD BE USED TO
PRACTICE.
AS A RESULT TRIALS ARE NARROW
AND LONG AND EXPENSIVE AND
DESIGNED TO UNDERESTIMATE
BENEFIT AND UNDERESTIMATE HARM
AND ENRICHMENT AND INCREASINGLY
FOCUSED ON THIS AND THE SILOED
WORLD IS DEVELOPED FOR AND
STARTING WITH PATIENT AND
TREATMENT THEY ARE RECEIVING AND
DOING PARADIGM FOR CLINICAL
TRIALS AND WE ENVISION THAT.
NEXT SLIDE. BEING THIS KIND OF
SINGLE WORLD INSTEAD OF THESE
WORLDS SINGLE LEARNING HEALTH
SYSTEM PATIENTS CLINICIANS
RESEARCHERS DIET STATISTICIANS
IN ONE TEAM AND WORKPLACE COMMON
TREATMENTS AND CONDITIONS
PATIENTS ARE EXPOSE TODAY ALL
DAY EVERY DAY AT PRACTICE AND
USING RANDOMIZED TRIALS IMBEDDED
IN CLINICAL CARE TO UNDERSTAND
EFFECTS OF THOSE TREATMENTS ON
OUTCOMES FOR THE ENTIRE
DIVERSITY OF PATIENTS RECEIVING
TREATMENTS AND PRACTICE AND
SELECTED 5% ENROLLED IN REGULAR
CLINICAL TRIAL STUDYING
TREATMENTS TO BE ADMINISTERED
COULD GENERATE RESULTS
ADMINISTERED AND APPLY TO
PRACTICE AND NOT JUST GENERATING
KNOWLEDGE BUT IMPROVING CARE AND
STUDIES TO WHERE THIS IS
HAPPENING.
NEXT SLIDE.
WE NEED TO DO THIS WORK WORKING
TOWARDS VISION OF IMBEDDING
PRAGMATIC TRIALS INTO PRACTICE
TO UNDERSTAND EFFECT OF COMMON
TREATMENTS AND PATIENT OUTCOMES
THERE IS FIVE KEY THINGS AND
FIRST IS WE HAVE TO FIND WAYS TO
TREAT CLINICIANS TO DELIVER
INTERVENTIONS PART OF THE TRIAL
RATHER THAN IN A WAY THEY WOULD
IN CLINICAL PRACTICE RATHER THAN
HAVING INVENTIONS DELIVERED
EXCLUSIVELY BY RESEARCH PER SSO
EL.
TWO FINDING WAYS TO EFFICIENTLY
COLLECT LONG TERM OUTCOMES THAT
HAVE BRAIN AND MUSCLE
DISFUNCTION EXTENSIVE AND
INTEGRATED IN CLINICAL CARE AND
3 MOVING FROM ESTIMATING AVERAGE
TREATMENT EFFECTS TO ESTIMATING
INDIVIDUAL TREATMENT EFFECTS AS
STEP TOWARDS PERSONALIZED
MEDICINE AND 4 HAVING BETTER
WAYS INTEGRATING BIOMARKERS INTO
PRAGMATIC TRIALS TO WORK BACK TO
UNDERSTAND WHY TREATMENTS HAVE
EFFECTS THEY DID FIFTH IS
SOMETHING I WON'T TALK ABOUT
TODAY. WE NEED ETHICAL AND
REGULATORY FRAIM WORKS THAT ARE
DIFFERENT AND COMPARING
TREATMENTS OF PATIENTS THAT LE
WILL RECEIVE.
AT SCALE IN WAY THAT GENERALIZES
PRACTICE FINDING WAYS TO TREAT
CLINICIANS TO DELIVER TRIAL
INTERVENTIONS THAT IS EXAMPLE
HOW WE DID THIS.
I PICKED THIS BECAUSE IT IS AN
EMERGENCY PROCEDURE AND THERE IS
NO POSSIBLE WAY TO HAVE A
RESEARCH PERSON THERE TO DELIVER
TRIAL INTERVENTIONS.
THIS TRIAL RAN AT CENTERS ACROSS
UNITED STATES AND ENROLLED POOR
PATIENTS AND INTERVENTIONS WERE
ABLE TO BE SUCCESSFULLY
DELIVERED IN TREATING CLINICIANS
IN ABSENCE OF RESEARCH PERSON
ELAND DATA COLLECTED TRAINED
OBSERVERS IN CLINICAL
ENVIRONMENT AND TRIAL OCCURRED
AND IDEA OF RESEARCH AND
CLINICAL CARE INTEGRATED DON'T
HAVE TO BE SEPARATE TREATING
CLINICIANS ARE KEY ROLES IN
DELIVERING TRIAL INTERVENTIONS.
SUMMARY POINT ADMINISTERING
EVERY DAY CARE AND CLINICIANS
CAN DELIVER TRIAL INTERVENTIONS
WITHOUT RESEARCH PERSONNEL.
NEXT SLIDE.
THIS IS A EXAMPLE WE HAVE BEEN
ABLE TO DO FOR 10 TRIALS AND
MRNL PROCEDURE.
NEXT SLIDE INTEGRATING LONG TERM
PATIENT OUTCOMES COMPARATIVE
EFFECTIVENESS TRIALS IS EXAMPLE
OF THAT AND EACH OF WHOM IS
ENROLLED AS TRASH LAR
INTERBASING AND DURING EMERGENCY
PROCEDURE APPROACHING PATIENTS
AND FAMILIES.
PRAG MMATIC TRIAL.
BEING ABLE TO MARRY THOSE IN A
PRAGMATIC TRIAL DURING EMERGENCY
PROCEDURE LONG TERM OUTCOMES
IMPORTANT TO RESEARCH QUESTION
FINDING WAYS TO INTEGRATE THOSE.
NEXT SLIDE.
DOING THAT REPRODUCIBLY WE WILL
NEED EFFICIENCIES WE DON'T HAVE
TODAY OUTCOMES RELATIVE TO BRAIN
AND MUSCLE DISFUNCTION AND YOU
ARE TALKING ABOUT NOT SURE WHICH
ARE RELEVANT IN HEALTH
ELECTRONIC RECORD IN A WAY AND
APPROACHING THIS INCREASINGLY
MOBILE TOOLS CELL PHONES AND
PATIENTS CAN REPORT OUTCOMES AND
WEARABLES I THINK INCREASINGLY
FOCUS SHOULD BE ON MAKING SURE
OUTCOMES IMPORTANT TO PATIENTS
ARE [INDISCERNIBLE].
>> [INDISCERNIBLE].
>> THANK YOU EFFORT AT
VANDERBILT AND REPORTED OUTCOMES
IN ELECTRONIC HEALTH RECORD FOR
650,000 PATIENTS CLINICAL CARE
ARE REPORTING MEASURES WE WANT
FOR RESEARCH. NEXT SLIDE.
I WON'T DWELL ON THIS.
THIS IS A SEPARATE HOUR PRACH
TRYING TO ANALYZE TRIALS AND
OUTCOMES STATISTICAL METHODS CAN
DO THAT AND PRODUCE AN ANSWER
AND WE DON'T HAVE THOSE AND
SOMETHING TO FOCUS ON IN THE
FUTURE AND NEXT SLIDE.
SPEAKING OF STATISTICAL METHODS
WE KNOW WE NEED TO MOVE FROM
AVERAGE TREATMENT EFFECTS TO
INDIVIDUALIZED TREATMENT EFFECTS
AND WE HAVE WAYS OF DOING THAT
INSTEAD OF ENROLLING IN DIVERSE
POPULATION IN TRIAL AND A IS
BETTER THAN B ANSWER AND APRYING
THAT GOING FORWARD NEW WAYS
ENCOUNTERING PATIENTS USING
THOSE WHO ARE SIMILAR IN TRIALS
CAN WE KNOW WHAT IS BEFLT FROM
THIS PATIENT THAT DIFFERS FROM
OTHER PATIENTS WE TOOK
RANDOMIZED TRIALS USING THIS TO
DEVELOP ESTIMATES SECOND ACT
VALIDATED THOSE AND FOUND IN
NULL TRIAL PATIENTS BENEFITED
FROM XAIRTIVE EFFECTIVENESS
INTERVENTION AND MOVING TOWARDS
THIS BEING STANDARD APPROACH.
THESE ARE MEANT TO TELL WHAT YOU
TO DO FOR VISUAL PATIENT.
NEXT SLIDE.
I WILL MOVE QUICKLY THROUGH THIS
BIOMARKERS HAVE TO BE PIECE OF
THIS AND WHAT BIOMARKERS AND HOW
TO DO EFFICIENTLY IS EXAMPLE OF
INCLUDING URINARY AND BLOOD
BIOMARKERS PRAGMATIC TRIAL MORE
EFFORT AND EXPENSE AT BIOMARKERS
THAN PRAGMATIC TRIAL AND
EFFICIENCIES HAVE TO BE THERE TO
WHOLLY LEARN FROM TRIALS AND
FINAL TWO SLIDES TALKED ABOUT
BALANCE OF FORWARD AND REVERSE
TRANSLATION AND MEANS MORE
TRIALS COMPARING CURRENT
TREATMENTS AND GENE DIFFERENCES
IN TREATMENTS TO UNDERSTAND
BRAIN AND MUSCLE FUNCTION.
PROBLEMS WITH EXPLANATORY TRIALS
PRAGMATIC TRIALS CAN OVERCOME
AND LAST SLIDE PITCHING HIGH
RISK AND REWARD IDEA ON THIS IT
WOULD BE A PLATFORM AND GOAL IS
TO IMBED PRAGMATIC TRIALS IN
CLINICAL CARE COMPARING COMMON
INTERVENTIONS THAT MIGHT ALREADY
EFFECT BRAIN AND MUSCLE
DISFUNCTION.
EXAMPLES OF THAT 7 TAENVERSUS
[INDISCERNIBLE] TWO COMMON
ANTIBIOTICS ADMINISTERED IN
SEPSIS AND ONE PROBABLY CAUSES
BRAIN DISNUFRNGS WAYS WE DON'T
FULLY UNDERSTAND AND COMPARING
AND USING THOSE AS AN
OPPORTUNITY AND DIAPHRAGM
PROTECTIVE INTERVATION SLOW
TITLE VOLUME DIFFERENT
APPROACHES TO ANALGEEZIA
SEDATION IN THE ICU AND WHOLE
LAUNDRY LIST OF EVERYTHING YOU
HAVE AS A CLINICIAN MAKING A
CHOICE YOU HAVE WITHOUT EVIDENCE
USING POTENTIAL DIFFERENCES TO
WORK BACKWARDS UNDERSTANDING HOW
THESE EFFECT BRAIN AND MUSCLE
INFECTION AND EVERY TIME WE FIND
SOMETHING EFFECTING BRAIN AND
MUSCLE FUNCTION, STANDARDIZE
CARE AND MAKE SURE WE DELIVER
BEST CARE TO IMPROVE PATIENT
OUTCOMES.
NEXT SLIDE. THAT IS ALL. I
WANT TO THANK YOU. A LITTLE
RUSHED AND APPRECIATING YOUR
TIME AND ENJOYING OPPORTUNITY TO
TALK ABOUT ALL THIS WITH YOU.
>> THAT WAS GREAT, MATT. THANK
YOU SO MUCH.
MARK, DID YOU GET A CHANCE TO
LOOK THROUGH THE CHAT?
>> I DID, STEPHANIE.
>> OKAY.
>> MATT, A LOT OF GREAT
QUESTIONS AND ONE THING THAT
CAME UP THAT YOU MIGHT BE ABLE
TO ADDRESS IS A QUESTION
>> THANK YOU SO MUCH FOR THE
KIND INTRODUCTION. CAN YOU HEAR
ME ALL RIGHT?
>> THAT IS GREAT.
>> GREAT. LET'S GO TO THE NEXT
SLIDE.
I DON'T HAVE ANY CONFLICT OF
INTEREST TO DISCLOSE AND I DO
INVESTIGATIONS INVOLVING
IMPLEMENTATION SCIENCE
APPROACHES AND HAVE THE
RELATIONSHIP SEEN. NEXT SLIDE.
I HAVE A FEW OBJECTIVES FOR
SHORT TIME THAT WE HAVE
TOGETHER. YOU CAN TAB THROUGH
THESE 3 AND HOPEFULLY BY END OF
THE TIME YOU CAN UNDERSTAND
DIFFERENCE BETWEEN
IMPLEMENTATION OUTCOMES AND
EFFECTIVENESS OUTCOMES AND
COULDN'T ASK FOR A BETTER SETUP
AND HOPEFULLY YOU WILL BE PRIMED
TO HEAR ABOUT IMPLEMENTATION
SCIENCE AND EXPLAIN ROLE OF
QUASI EXPERIMENTAL DESIGNS IN
IMPLEMENTATION RESEARCH IN ARDS
LISTING CHALLENGES TO RESEARCH
IN ARDS.
NEXT SLIDE.
I DO QUALITATIVE MIXED METHODS
AND WE DO REFLEXIVITY STATEMENTS
TO HELP YOU UNDERSTAND WHO IS
TALKING TO YOU AND WHAT
PERSPECTIVES THERE ARE NEXT
SLIDE.
I WEAR HATS AS AN ANTHESE YOLS I
TRY TO GET PEOPLE TO NOT KILL
PATIENTS AND SPEND TIME DOING
HEALTH SERVICES RESEARCH. NEXT
SLIDE. I RUN A LAB FOCUSED ON
IMPLEMENTATION SCIENCE THAT WE
USE TO IMPROVE PERIOPERATIVE
CARE AND OTHER TYPES OF PATIENT
CARE AND NEXT SLIDE I RUN THE
PEN IMPLEMENTATION SCIENCE
CENTER WE MAKE SURE TO DO
RIGOROUS IMPLEMENTATION RESEARCH
TO SEE ACTUAL EXECUTION OF
INTERVENTIONS THAT ARE
EFFICACIOUS AND [INDISCERNIBLE].
NEXT SLIDE.
YOU HEARD TERM IMPLEMENTATION
SCIENCE LEVEL SETTING BECAUSE
YOU DON'T KNOW WHAT THAT IS AND
TELLING WHAT YOU IT IS AND
HELPING GET CLINICIANS AND
ORGANIZATIONS TO CHANGE.
FAVORITE DEFINITION OF
IMPLEMENTATION SCIENCE COMES
FROM SCIENCE OF JERNL AND GOD
PARENT OF THE FIELD AND PROCESS
OF PLANNED HUMAN BEHAVIOR CHANGE
UNDER ORGANIZATIONAL CONSTRAINTS
WHAT IS IMPORTANT HERE SIGN
POSTING HERE WE ARE TRYING TO
CHANGE BEHAVIOR AND DOING IN
CONTEXT OF ORGANIZATION AND ALL
SCIENCES AND SOCIAL SCIENCES WE
THINK ABOUT WITH RESPECTIVE
BEHAVIOR CHANGE PSYCHOLOGY AND
SOCIOLOGY AND ANTHROPOLOGY, ALL
COME TO BARE AND ORGANIZATIONAL
SCIENCE AND ALL THAT IS CHANGE
MANAGEMENT AND IMPLEMENTATION
SCIENCE IS ALL OF THOSE PUT
TOGETHER AND IMPLEMENTATION
SCIENCE AND HEALTH APPLIES
SCIENCE OF IMPLEMENTATION AND
RELATED PROCESSES CHANGING
PATIENT BEHAVIOR THAT IS
DIFFERENT TO HEALTH CARE
SERVICES POSSIBLY SECONDARILY TO
HEALTH BEHAVIOR AND SHE IS NOT
INTO HERE THIS IDEA THAT I
CLASSICALLY CONCEIVED
IMPLEMENTATION SCIENCE IS ABOUT
CHANGING BEHAVIOR OF PEOPLE THAT
ARE DELIVERING SERVICES
IMPLEMENTATION SCIENCE IS
APPLIED TO PHYSICIANS AND HEALTH
CARE PROVIDER AND WHAT WE ARE
DOING HERE.
IF NOT AS NATURAL OF A FIT AND
SERIES MODELS AND FRAMEWORKS WE
HAVE NEED TO BE RESPONSIVE TO
THAT.
THAT IS AN EMERGING AREA IN THE
FIELD.
NEXT SLIDE. IMPLEMENTATION
SCIENCE IS ON TRANSLATIONAL
RESEARCH SPECTRUM PUTTING IN
LATE STAGE TRANSLATION AND LIKE
WHAT DR. SEMLER SAID ABOUT GOING
TO BEFRNL TO BEDSIDE AND BACK
AGAIN AND NEUROCONDITION OF
RESEARCH SPECTRUM GOING FROM
BENCH TO BEDSIDE AND
IMPLEMENTATION SCIENCE
PRESUPPOSES AN INTERVENTION THAT
WORKS AND CLASSICALLY TALK ABOUT
EVIDENCE COMING FROM RANDOMIZE
CHONDRTROLL TRIALS AND
PROBLEMIZE RTC AS PEOPLE HAVE AS
WELL AND IT ASSUMES THERE IS A
THING THAT OUGHT TO BE DONE. IT
TRIES TO FIGURE OUT HOW TO GET
PEOPLE AND SYSTEMS TO DO IT.
COLLEAGUES CONCEPTUALIZE
IMPLEMENTATION SEGUE TO HELP
PEOPLE UNDERSTAND WHETHER THING
THEY ARE INTERESTED IN
IMPLEMENTATION SCIENCE WAYS IT
WORKS IDENTIFY PRACTICE OF
INTEREST AND EARLY MOBILIZATION
DURING ICU STATE TO TRY TO
PREVENT WEAKNESS LATER AND ASK
QUESTION HOW IS IT SHOWING
EFFICACY IN RCT OR IDEAL WORLD
DOES IT WORK MEKNISTICALLY CAN
IT WORK?
WE HEARD GREAT SCIENCE EARLIER
IN THE CONFERENCE ABOUT
UNDERSTANDING PATHOPHYSIOLOGY
WEAKNESS AND CLINICAL ILLNESS AT
THIS LEVEL AND DOES INTERVENTION
WORK AT THAT LEVEL?
NOT SURE IF WE KNOW FOR SURE AND
IF WE DON'T KNOW WE WANT TO DO
THAT EFFICACY RESEARCH AND AT A
MECHANISTIC LEVEL MAKES SENSE TO
LOOK AT INTERVENTION AT ALL. IF
IT HAS SHOWN EFFICACY AT ALL WE
MOVE ON AND ASK OURSELVES IF IT
SHOWS EFFECTIVENESS IN REAL
WORLD DOES IT WORK AND
HETEROGENOUS DELIVERY SYSTEM HAS
IT BEEN SHOWN TO WORK?
IF NOT WE WOULD DO THAT
EFFECTIVENESS RESEARCH TO FIGURE
OUT THAT QUESTION AND IF WE KNOW
IT WORKS AND IS A MATTER OF
GETTING PEOPLE TO DO IT YOU FIND
YOURSELF IN LOWER RIGHT CORNER
THAT IS IMPLEMENTATION SCIENCE
INCREASINGLY WE ARE IN MIDDLE WE
ARE NOT SURE AND THINK IT MIGHT
WORK AND PEOPLE WANT US TO
REALLY DO IT.
WE GET INTO HYBRID EFFECTIVENESS
IMPLEMENTATION TRIALS I WILL
TELL YOU ABOUT. NEXT SLIDE.
LET'S TALK ABOUT STUDY DESIGN
CONSIDERATIONS FOR INTERVENTIONS
FOCUSED ON ARDS SURVIVORS AND
BRINGING [INDISCERNIBLE]. NEXT
SLIDE.
SO, PIECING IMPLEMENTATION
SCIENCE I WANT TO MAKE SURE
STUDENTS UNDERSTAND A DIFFERENCE
BETWEEN STUDY DESIGN AND
METHODS.
NEXT SLIDE. I WILL FOCUS ON
STUDY DESIGN AND I WILL MAKE A
NOD TO QUALITATIVE AND MIXED AND
OTHER TYPES OF METHODS AND
FOCUSED ON RESEARCH DESIGN HERE
OVERALL APPROACH TO RESEARCH
QUESTION AND UNDERSTANDING
RELATIONSHIP BETWEEN EXPOSURES
AND OUTCOME. NEXT SLIDE.
RCTS RANDOMIZED CONTROL TRIALS
WE LOVE. THEY ARE LOVELY ON SO
MANY LEVELS AND IS SIMPLE
CONCEPTUALLY.
NEXT SLIDE. THERE ARE PROBLEMS.
PEOPLE HAVE ALREADY IN THE
CONFERENCE NODDED TO PROBLEMS
WITH RCTS AND TAKING A DEEPER
DIVE THERE IS POTENTIAL FOR
CONTAMINATION DOG TRADITIONAL
PATIENT LEVEL RANDOMIZED CONTROL
TRIAL AND WHEN YOU GET INTO MORE
COMPLEX BEHAVIORAL INTERVENTIONS
AND QUESTIONS IN CHAT FROM PRIOR
TALK GREAT SIMPLE INTERVENTION
AND COMPLEX INTERVENTION GOING
BACK TO IDEA AND TRIAL FOCUSED
ON EARLY MOBILIZATION AND I
REMEMBER BEING A PARTICIPANT IN
STUDY AND TELLING US WE WANT YOU
TO MOBILIZE PATIENTS I DON'T
WANT TO TO EARLY MOBILIZATION OR
NOT IMMOBILIZING THEM SEEMS
UNETHICAL TO NOT MOBILIZE MR.
SMIDGE BUT TO MR. JONES AND
PROBLEMS ARE WITH TRYING TO KEEP
ARTIFICIAL SDIVENLGS AND YOU MAY
FIND PARTICIPANTS SABOTAGING
INADVERTENTLY OR MAYBE NOT
INTERVENTION AND ISSUES ARE WITH
CONTAMINATION THAT RCTS ARE NOT
WELL EQUIPPED TO DEAL WITH AND
OFTEN IN IMPLEMENTATION SCIENCE
YOU SEE CLUSTER DESIGNS AND MAY
SEE A UNIT AWARD RANDOMIZED TO
SOMETHING THAT YOU MAY SEE
HOSPITAL OR RANDOMIZED STUDENT
INTERVENTION THAT IS EASIER TO
PRESERVE AND YOU CAN RANDOMIZE
AT LEVEL OF CLINICIAN THAT IS
ANOTHER WAY TO TRY TO AVOID
CONTAMINATION AND SECONDARILY
STAKEHOLDERS HAVE FEELINGS ABOUT
RANDOMIZATION AND IF YOU ARE
TELLING YOUR STAKEHOLDERS THAT
YOU WANT TO TRIAL SOMETHING YOU
THINK IS EFFICACIOUS YOU HAVE
REASON TO BELIEVE IT WORKS.
YOU ARE TELLING THEM YOU KNOW
THERE IS A 50% CHANCE YOU WILL
GET THIS GREAT THING AND 50%
CHANCE YOU WON'T. PLEASE GIVE
US OUTCOMES ANYWAY. THAT
DOESN'T ALWAYS WORK.
SO, IT IS IMPORTANT WHEN YOU ARE
DOING ESPECIALLY COMPLEX
BEHAVIORAL INTERVENTION TO WORK
WITH STAKEHOLDERS IN CRAFTING
RESEARCH QUESTION AND CHOOSING A
STUDY DESIGN THAT THEY FEEL THEY
CAN ENDORSE AND PARTICIPATE IN.
THIRDLY, IT IS DIFFICULT TO
COMPLEX AND TO RULE OUT COMPLEX
INTERVENTIONS ALL AT ONCE AND
RCT WOULD SUGGEST TO GO FROM OFF
TO ON AND IF YOU HAVE SOMETHING
WITH MORE MOVING PIECES TO IT IT
CAN BE DIFFICULT TO DO THAT YOU
END UP WANTING TO LOOK AT
STAGGERED APPROACHES SO WHEN YOU
EXECUTE YOUR INTERVENTION YOU
ARE DOING IT WELL AND PAYING A
LOT OF ATTENTION TO FIDELITY AND
EASIER TO DO THAT IN COMPLEX
INTERVENTION STAGGERING
EXCLUSION AND 4TH, APPROACH TO
IMPLEMENTATION MAY NEED TO
DIFFER ACROSS SITES THAT IS NOD
TO QUESTION IN THE CHAT EARLIER
TOO.
IF YOU IMPLEMENT AT A COMMUNITY
HOSPITAL VERSUS ACADEMIC
HOSPITAL AND IMPLEMENTING AT
NURSING HOME VERSUS LONG-TERM
ACUTE CARE FACILITY APPROACH TO
IMPLEMENTATION MIGHT NEED TO
DIFFER PRESENTING PROBLEMS FOR
TRADITIONAL RCT.
NEXT SLIDE.
QUASI EXPERIMENTAL DESIGNS AND
PLACE FOR DESIGNS IN WORK
FOCUSED ON ARDS AND ARE DESIGNS
THAT DON'T EMPLOY TRADITIONAL
PATIENT LEVEL RANDOMIZATION AND
GOOD THINGS ABOUT QUASI
EXPERIMENTAL DESIGNS EASIER TO
EXECUTE AND EXPLAIN EVERYONE
GETS THE SAME AND NOT EVERYONE
GETS IT AT ONCE AND DIFFICULT TO
DO THAT PRACTICE MANAGERS AND
THOSE WORKING IN REAL WORLD
UNDERSTAND THAT RESEARCH TEAM
CAN'T EXECUTE AT 10 SITES AT
ONCE.
IT IS STRAIGHTFORWARD TO EXPLAIN
TO FOLKS AND TEND TO BE RELEVANT
TO PRACTICE.
YOU CHOOSE SITES LOOKS AT PLACES
WE PROVIDE.
WE COULD BE REALLY COMPLEX FROM
AN ANALYTIC PERSPECTIVE AND YOU
MAY BE EXPLANATORY ACT WITH
CONFOUNDING FACTORS TO ADDRESS
AND THEY HAVE [INDISCERNIBLE] ON
INTERNAL VALIDITY.
>> FIVE MINUTES REMAINING.
>> THANK YOU.
NEXT SLIDE.
ALL RIGHT. REAL BRIEF DETOUR
INTO HYBRID TRIALS AND
EFFECTIVENESS TRIALS MENTIONING
WHETHER INTERVENTION WORKS IN
REAL WORLD AND IMPLEMENTATION
TRIALS FOCUSED ON HOW TO GET
PEOPLE TO DO THE THING YOU WANT
THEM TO DO. IN THE MIDDLE THERE
ARE P HYBRID TRIALS.
NEXT SLIDE.
SO, THERE ARE REASONS TO DO
HYBRID TRIALS AND JEFF WHO IS A
FRIEND AND COLLABORATOR AT
UNIVERSITY OF ARKANSAS MEDICAL
SCIENCES ORIGINATED CONCEPT AND
IDEA OF HYBRID TRIAL TWO TRIALS
IN 1 IS SPEEDING PROGRESS ALONG
TRANSLATIONAL SPECTRUM.
ACKNOWLEDGING ULTIMATE GOAL OF
IMPLEMENTATION SCIENCE.
NEXT SLIDE.
HYBRID TRIALS ARE POPULAR AND
INCREASINGLY CITED AND
INCREASING APPROACH TO TRY TO
MAKE SURE THAT THOSE
EFFECTIVENESS THAT WE ARE DOING
IS INTO THE REAL WORLD.
NEXT SLIDE.
BRIEFLY THERE IS THREE TYPES OF
HYBRID TRIALS WITH DIFFERENTIAL
FOCUS ON EFFECTIVENESS VERSUS
IMPLEMENTATION AND EARLIER STAGE
THAT EVIDENCE IS, LESS CERTAIN
WE ARE IN EVIDENCE AND WHETHER
INTERVENTION AND INTEREST WORKS
AND WE ARE LIKELY TO DO TYPE 1
GATHERING A LITTLE INFORMATION
ABOUT IMPLEMENTATION AND MORE
CONFIDENT WE ARE IN EVIDENCE
BASE MORE QUESTION SHIFTS TO HOW
TO GET PEOPLE TO DO THE THING
AND YOU MOVE TO A TYPE 3. NEXT
SLIDE.
HYBRID TRIALS COMBINE TWO TRIAL
TYPES THAT ARE COMPLEX AND DO
YOU TWO TRIALS IN TANDEM USING
DIFFERENT METHODS AND WILL USE
DIFFERENT OUTCOMES AND INSTEAD
OF CLINICAL OUTCOMES LOOKING FOR
IN EFFECTIVENESS TRIAL YOU LOOK
FOR IMPLEMENTATION OUTCOMES
ACCEPTABILITY APPROPRIATENESS
AND FEASIBILITY.
NEXT SLIDE. GETTING BACK
QUICKLY TO QUASI EXPERIMENTAL
DESIGNS.
NEXT SLIDE. I LOVE THIS
DECISION TREE THAT APPLIES TO
IMPLEMENTATION RESEARCH AND
APPLIES TO RESEARCH FOCUSED ARDS
AND ONE WAY TO THINK ABOUT
CHOOSING QUASI EXPERIMENTAL
DESIGNS AND COLLEAGUES AT UCSF
AND THINKING ABOUT WHAT TYPES OF
OUTCOMES MAKE SENSE FOR YOUR
QUESTION OF INTEREST AND TIME
POINTS AND SITES AND THINKING
THROUGH WHAT GOOD QUASI
EXPERIMENTAL DESIGN MIGHT BE.
NEXT SLIDE. HIGHLIGHTING THREE
WE USE IN IMPLEMENTATION SCIENCE
AND WENLED TRIAL EACH SITE GETS
INTERVENTION STAGGERED OVER TIME
AND EACH SITE SERVES AS OWN
CONTROL AND STATISTICALLY IT IS
ELEGANT AND REALISTICALLY HARD
TO EXECUTE AND I'M IN THE MIDDLE
OF A TRIAL NOW NOT FOR FAINT AT
HEART BUT POWERFUL WAY TO LOOK
AT COMPLEX INTERVENTION ROLLING
OUT ACROSS SITES OVER TIME.
NEXT SLIDE.
INTERRUPTED TIME SERIES APPROACH
IS LOVELY WITH A SINGLE SITE TO
LOOK AT WHAT OUT COME THIS IS
QUANTITATIVE OUTCOME HERE AND
ASSESSING OVER TIME INSTITUTE
CHANGE AND LOOK FOR CHANGE IN
SLOPE OF INTERVENTION OVER TIME
AND YOU CAN DO IT AT ONE OR
MULTIPLE SITES AND NICE WHERE
YOU HAVE A CONTROL YOU HAVEN'T
INSTITUTED INTERVENTION AND YOU
CAN DO A DIFFERENCE IN
DIFFERENCES APPROACH.
NEXT SLIDE.
THIRD ONE DR. JORGE WILL COVER
AS WELL IS ADAPTIVE DESIGN AND
DESIGN AND PRE-SPECIFIED RULES
TO CHANGE EXPOSURE THAT YOU
ASSESS OUTCOMES CYCLICALLY BASED
ON HOW RESPONSIVE PARTICIPANTS
ARE TO THE INTERVENTION.
NEXT SLIDE.
THIS IS A EXAMPLE OF ADAPTIVE
TRIAL AND IMPLEMENTATION SCIENCE
AND AUTHORS CHOSE TO HAVE A
SPECIFIC INTERVENTION THAT IS
MEANT TO PREVENT SUICIDE IN VA
POPULATION AND LOOKED AT
IMPLEMENTATION IN SITE IS
IMPLEMENTED ADEQUATELY LEFT
ALONE IF DIDN'T CHOSE SPECIFIC
INTERVENTION FOR IMPLEMENTATION
AND IF THAT WORKS LEFT ALONE AND
IF DIDN'T CHOSE A DIFFERENT
APPROACH AND WHAT ADAPTIVE TRIAL
MIGHT LOOK LIKE WITH 6 DIFFERENT
ANALYTIC GROUPS AT THE END.
NEXT SLIDE, CHALLENGES AND WILL
WRAP UP AFTER THIS. NEXT SLIDE.
THIS IS NOT FOR FAINT OF HEART.
TAP FORWARD IF YOU COULD. WE
DON'T KNOW WHAT EVIDENCE IS
READY FOR TRANSLATION AND BASHED
RCT AND THEY HAVE UTILITY AND
HELP US TO UNDERSTAND WHETHER
INTERVENTIONS WORK AND IN
ABSENCE OF THAT HOW DO WE KNOW
WHEN SOMETHING IS READY TO
TRANSLATE. THERE IS A QUESTION
IN THE FIELD WHEN SOMETHING IS
READY FOR IMPLEMENTATION AND
SECONDARILY WE NEED TO DO
QUALITATIVE AND QUANTITATIVE
WORK DOING IMPLEMENTATION WORK
RESEARCH AND WE DON'T ALWAYS
THINK ABOUT THAT PIECE BUT
HAVING TEAMS TO DO THAT.
CERTAINLY WE HAVE TO FIGURE OUT
HOW TO BALANCE INTERNAL VALIDITY
SO WE CAN CREATE GENERALIZABLE
OR TRANSFERABLE KNOWLEDGE THAT
APPLIES ACROSS SETTINGS AND
FINALLY AND CERTAINLY NOT LEAST
IMPORTANT IS HAVING SITE OF
EQUITY AND IMPLEMENTATION TRYING
NO THE TO RECREATE GAPS AND
PRACTICE LEAVING BEHIND
IMPORTANT SETTINGS WHEN WE DO
THIS WORK.
NEXT SLIDE.
THAT IS ALL I HAVE. THANKS SO
MUCH.
>> THAT WAS AWESOME. MEGAN,
THANKS SO MUCH.
QUESTIONS COMING THROUGH THE
CHAT AND I HAVE A COUPLE
QUESTIONS FOR YOU.
ONE, RELATED TO -- SO, I THINK
IN RANDOM MUSCLE DISFUNCTION
AFTER ARDS WE ARE STUCK AT THAT
TOP NODE NOT HAVING A LOT OF
EVIDENCE; RIGHT?
MY PERSONAL THOUGHT WE DON'T
HAVE LOTS OF EVIDENCE WE ARE
MAYBE NOT IMPLEMENTING
INTERVENTIONS CORRECTLY AND WE
CAN TALK ABOUT THISSOID YAF
DESIGNING WITH IMPLEMENTATION IN
MIND AS A FIRST START TO TRY TO
SPEED TRANSLATION WITH SOME OF
THIS DISCOVERY.
>> I'M SO GLAD YOU ASKED THAT
QUESTION. THERE IS SOME
INTERVENTIONS THAT ARE PROBABLY
READY FOR IMPLEMENTATION MAYBE
AND POST IC CLINICS IN THERE.
THERE IS A LOT AND PREPONDERANCE
OF THE THINGS WE ARE INTERESTED
IN AT THAT EARLIER STAGE. IT IS
REALLY IMPORTANT TO WORK WITH
EITHER I WOULD SAY ENGINEERS OR
IMPLEMENTATION SCIENTISTS AND
FOLKS WITH WORKFLOW IN MIND TO
HELP YOU CRAFT INTERVENTION THAT
IS IMPLEMENTABLE AND ONE
APPROACH IS -- WHICH IS DESIGNED
BY -- I FORGOT HER FIRST NAME
BUT THE IDEA IS YOU ARE
DESIGNING INTERVENTION IN
PARTNERSHIP WITH STAKEHOLDERS
RAPIDLY ITERATING ON
INTERVENTION ITSELF AND YOU
DESIGN SOMETHING OPTIMALLY
IMPLEMENTABLE AND YOU ARE
TESTING A MEDICATION THAT NEEDS
TO BE DELIVERED 6 TIMES A DAY.
GUESS WHAT, THAT WON'T HAPPEN
AND WORKING WITH STAKEHOLDERS TO
COME UP WITH AN INTERVENTION
THAT COULD ACTUALLY BE
DOVE-TAILED INTO THE WORKFLOW OF
WHOEVER IT IS THAT WILL DELIVER
IT OR THAT WILL BE A RECIPIENT
OF IT. OUTCOMES ARE NOT
IMPLEMENTATION OUTCOMES BUT YOU
ARE AT LEAST CONSIDERING WHAT
WILL BE DONE TO GET THERE.
>> AWESOME. THANK YOU. I HAVE
ONE MORE QUESTION IF YOU DON'T
MIND.
>> OF COURSE.
>> IT IS TAKING THIS IDEA OF
FORWARD TRANSLATION AND REVERSE
TRANSLATION.
YOU KNOW, GIVEN LIMITED SOURCES
TO DO THIS WORK, HOW MUCH DO YOU
ACTUALLY CARE IF SOMETHING WORKS
AS AN IMPLEMENTATION SCIENTIST
AND PRACTICING BEDSIDE
CLINICIAN? IF SOMETHING WORKS
HOW MUCH DO YOU CARE ABOUT
WORKING BACKWOODS TO FIGURE OUT
WHY IT WORKS AND IF IT IS
POSSIBLE TO UNDERSTAND AT
BIOLOGICAL MECHANISM LEVEL THAT
SOMETHING WORKS AND WORKING ON
IMPLEMENTATION FROM THERE.
>> GOOD QUESTION. I LOVE THAT
QUESTION. IT REALLY DEPENDS WHO
YOUR STAKEHOLDERS ARE AND ONE
THING WE DO AT IMPLEMENTATION
SCIENCE IS ENGAGE DEEPLY AT
EVERY LEVEL WITH STAKEHOLDERS
NOT JUST TO DO WORK BUT DEFINE
INTERVENTION AND DEPENDING ON
RISK PROFILES OF INTERVENTION
YOU MIGHT GO INTO IMPLEMENTATION
AND SOMETHING LIKE EARLY
MOBILIZATION AND CRITICAL
ILLNESS WE KNOW IS GOOD FOR SO
MANY REASONS AND MAYBE NOT GOOD
FOR BRAIN DISNUFRNGS ARDS BUT
GOOD FOR OTHER REASONS THAT
THERE IS VERY LITTLE DOWNSIDE
AND THAT TYPE OF INTERVENTION
YOU MIGHT MOVE QUICKLY TOWARDS
LOOKING AT IMPLEMENTATION AND
WHAT ISSUES ARE INFLUENCING
PEOPLE AND SYSTEMS THAT WILL DO
INTERVENTION AND NEW DEVICE FOR
NEW DRUG AND SIGNIFICANT RISK
PROFILE I WOULD SAY FILL YOUR
ROLE A LITTLE BIT. WE PROBABLY
WANT TO KNOW MORE ABOUT EFFICACY
BEFORE WE DIVE INTO
IMPLEMENTATION.
>> OKAY.
>> DON'T WANT TO LOSE SIGHT OF
MECHANISM. YOU HAVE A GUIDELINE
AND BODY TELLING YOU TO GO DO
THE THING.
I DON'T THINK WE WANT TO LOSE
SIGHT WHERE WE CAN TRYING TO
UNDERSTAND HOW IT WORKS.
>> ABSOLUTELY. I AGREE. DR.
JER REGARD PUT IN THE CHAT AS
WELL UNDERSTANDING MECHANISM
THAT CAN CERTAINLY HELP TO
GENERALIZE ABILITY TO OTHER
CONDITIONS.
SO, I THINK FINDING THE RIGHT
BALANCE AND DR. HUH MENTIONS
REVERSE TRANSLATION
OPPORTUNITIES FOR TARGETING
POPULATIONS BENEFITING THE MOST
AND PRECISION MEDICINE THAT IS
ABSOLUTELY TRUE.
THANKS SO MUCH, DR. LANE FALL.
WE WILL INTRODUCE OUR NEXT
SPEAKER, DR. DALE WHO IS A
PROFESSOR OF PULMONARY CARE
MEDICINE AND REHABILITATIONS AT
JOHNS HOPKINS UNIVERSITY IN
BALTIMORE AND -- HE IS AN
ATTENDING PHYSICIAN IN MEDICAL
INTENSIVE CARE UNIT AT JOHNS
HOPKINS AND DIRECTOR AT CRITICAL
CARE PHYSICIAN MEDICINE
REHABILITATION PROGRAM AND THANK
YOU FOR BEING HERE DR. NEED HAM.
>> GREAT. YOU CAN HEAR ME AND
SEE MY SLIDES? CAN YOU HEAR ME?
>> YES, WE CAN, DALE.
>> GREAT. THANKS.
>> >> I WILL FOCUS ON IC-BASED
PHYSICAL REHABILITATION THAT IS
A KIND OF NICE CASE EXAMPLE FOR
-- THAT REALLY BUILDS ON LAST
COUPLE PRESENTATIONS AND IN
TERMS OF DISCLOSURES I'M
PRINCIPLE INVESTIGATOR ON
NIH-FUNDED RANDOMIZED TRIAL
NEARLY EARLY REHABILITATION AND
PROTEIN SUPPLEMENTATION APP AT
ICU AND WE HAVE SUPPORT FROM REC
MEDICAL DEVICES IN BAXTER THAT
WON'T INFLUENCE THE GIST OF
TODAY'S PRESENTATION AND KNOW IN
TERMS OF SPECIFIC INTERVENTION
THERE IS A REALLY GROWING BODY
OF DATA ON ICU-BASED REHAB
INTERVENTIONS AND IS MORE THAN
150 STUDIES INCLUDING MORE THAN
50 RANDOMIZED TRIALS WITH
PATIENTS WITH ACUTE RESPIRATORY
FAILURE REQUIRING MECHANICAL
INTERVENTION IN ICU AND SIGNALS
OF BENEFIT IN TERMS OF MUSCLE
AND PHYSICAL FUNCTION AND DELL
EARIUM AND COGNITION AND
CONDITIONAL RECOMMENDATIONS SUCH
AS SCCM PADDIS GUIDELINES THAT
SUPPORT THIS AND MORE AND MORE
STUDIES PUBLISHED WE ARE SEEING
CONFLICTING RESULTS.
THERE IS HETEROGENEITY AMONG
RESULTS AND RISK OF BIAS. IT IS
USEFUL TO DIG IN A LITTLE BIT
THINKING ABOUT THIS AS CANDIDATE
INTERVENTION AND WHAT ARE
CHALLENGES, GAPS AND
OPPORTUNITIES WE NEED TO THINK
ABOUT.
I WANT TO PRESENT TWO OR THREE
SYSTEMATIC REVIEWS BEFORE I DIVE
INTO GAPS AND OPPORTUNITIES AND
WHAT IS IMPORTANT IS THIS
SYSTEMATIC REVIEW OVER 20 YEARS
SUMMARIZED 43 RANDOMIZE TRIALEDS
AND 20 OF THEM LOOKED AT
PROTOCOLIZED APPROACHES TO PT
INTERVENTIONS AND 14 LOOKED AT
NEUROMUSCULAR ELECTRICAL
STIMULATION TALKED ABOUT IN
EARLIER TALKS IN THE CHAT AND 9
IN CYCLAR GOM ETTRY AND ALMOST
ALL STUDIES ARE RELATIVELY SMALL
AND 86% OF THEM DID NOT REPORT
THE DOSE THAT IS DELIVERED THAT
BROADHAM CONELLY PUT IN THE
CHAT.
WE SEE DECREASED UTILIZATION AND
COMING TO FUNCTIONAL OUTCOMES
COULDN'T EVALUATE STRENGTH AND
FUNCTION IN SYSTEMATIC REVIEW
AND LOTS OF HETEROGENEITY FOR
POST DISCHARGE OUTCOMES AND
LIMITATIONS LOOKING AT SUBGROUP
ANALYSIS THERE ARE DIFFERENCES
AMONG TYPES OF REHAB
INTERVENTIONS DELIVERED WITH
GREATER BENEFIT IN THOSE
PROTOCOLIZED PHYSIOTHERAPIST
BASED INTERVENTIONS AND
HETEROGENEITY AMONG PATIENT
CHARACTERISTICS AS WELL THAT
WILL ADDRESS HOW WE INTERPRET
AND THINK ABOUT THESE TRIALS AND
A SECOND SYSTEMATIC REVIEW WITH
60 TRIALS MORE THAN 5 THOUSAND
INUM NUMB PATIENTS THAT I WOULD
LIKE THIS ONE AND THEY DID A
SUBGROUP ANALYSIS BASED ON
CONTROL GROUPS.
HERE THEY LOOKED AT -- THEY DID
A METAANALYSIS WHERE CONTROL
GROUPS HAD LOWER DOSES OF IC
REHAB INTERVENTIONS THEY DEFINE
AS LESS THAN 5 TIMES A WEEK FOR
ASSESSMENTS AND MY EXPERIENCE IN
THE US IS THAT IS A VERY HIGH
DOSE INTERVENTION. THAT IS TO
FIND LOW DOSE FOR THIS.
TAKE THAT INTO CAN THE WHEN YOU
SEE FINDINGS.
MORE THAN 50% OF TRIALS HAVE
HIGH RISK OF BIAS COMPARED TO
LOW DOSE CONTROL GROUP AND
CONSISTENT SIGNALS OF BENEFIT OF
DECREASE IN RESOURCE UTILIZATION
MEASURES AND SMALL EFFECT AND NO
EFFECT FOR MUSCLE STRENGTH
ACROSS THIS AND HETEROGENEITY
DEPENDING ON RESULTS WITH TYPES
OF INTERVENTION AND
HETEROGENEITY AND OUTCOMES
REPORTING LED TO IMITATIONS IN
METAANALYSIS AND WHY WE ARE
HAVING SO-CALLED CONFLICTING
RESULTS -- FOR PREVENTING OR
TREATING DELL EARIUM AND PRIMARY
OUTCOME IS -- SYSTEMATIC REVIEW
FOR ICU REHAB INTERVENTIONS TO
PREVENT DELL EARIUM AND 300
STUDIES AND PATIENTS FOR
TREATMENT AND EVIDENCE THAT
EARLY MOBILIZATION REDUCED ODDS
OF INCIDENT DLEERIUM BY 50%
REDUCING DURATION OF DELL EARIUM
OF TREATMENT INTERVENTION BY TWO
DAYS AND WAS DIFFICULTIES
BECAUSE STUDIES DID NOT -- THERE
ARE MANY MORE STUDIES THAT
DIDN'T REPORT DATE NAH A
STANDARDIZED WAY TO BE
SYNTHESIZED IN METAANALYSIS AND
WERE ISSUES WITH RISK OF BIAS
AND HETEROGENEITY AND IS SIGNAL
THAT INTERVENTIONS THAT ARE
FOCUSED ON BODIES ALSO DO
IMPROVE COGNITION AS I ALWAYS
SAY HEAD BONE IS CONNECTED TO
BODY BONE AND RESEARCH DOES
REALLY NEED TO LOOK AT BOTH OF
THESE TOGETHER AND OT AND PT
COLLEAGUES IN ADDITION TO NURSES
NEED TO DO STANDARDIZED DLEERIUM
WITH INTERVENTIONS AND ROUTINE
CARE IN ICU AND FOCUSING ON
CHALLENGES AND GAPS AND
OPPORTUNITIES AND USING THIS
HERE AND PATIENT CHALLENGES
MOVING FIELD FORWARD AND DEFINE
WHOG TARGET POPULATION IS SICK
ENOUGH FOR MUSCLE BRAIN
IMPAIRMENTS AND LONG ENOUGH STAY
IN ICU IF ICU-BASED INTERVENTION
AND HEALTHY ENOUGH TO SURVIVE
HOSPITAL STAY TO SAFELY
PARTICIPATE IN INTERVENTIONS
THAT OFTEN REQUIRE ACTIVE
PATIENT PARTICIPATION AND THEY
HAVE PHYSIOLOGIC EFFECTS ON
PATIENTS WANTING THEM TO IDEALLY
BE ACTIVELY PARTICIPATING RATHER
THAN A PASSIVE INTERVENTION THAT
CALLS OUT TO NEUROINJURY AND USE
OF SEDATION AND HAVE MANY, MANY
SMALL STUDIES BUT WILL NEED
LARGER STUDIES AND I TALKED
ABOUT WE NEED TO MINIMIZE LOSS
TO FOLLOW UP AND THINK ABOUT
DEATH AND TRADITIONAL LOSS TO
FOLLOW UP AND RECOGNIZING THAT
PATIENTS MOVING TO A LONG-TERM
ACUTE CARE HOSPITAL MAY NO THE
BE ABLE TO HAVE PERFORMANCE
BASED ASSESSMENTS PERFORMED AND
NEED PEOPLE WHO SURVIVE AND
RECOVER AND WHAT ABOUT
INTERVENTION?
THIS IS VERY COMPLEX.
WHEN DO WE START REHAPPEN
INTERVENTION?
THERE IS ENOUGH DATA TELLING US
EARLIER IS BETTER AND DOSE
COMING TO REHAB IS COMPLICATED
AND WE HAVE TO THINK ABOUT
DURATION AND FREQUENCY AND
INTENSITY.
IN FACT, STEPHANIE AT JOHNS
HOPKINS JUST COMPLETED HER PHD
SPECIFICALLY FOCUSED ON QUESTION
OF INTENSITY ALONE FOR ICU REHAB
AND NEED TO THINK ABOUT
COORDINATION OF COMPLEX
INTERVENTION WITHIN ENTIRE
SYSTEM WHAT IS HAPPENING FOR
PATIENT CARE THAT IS VERY
COMPLICATED AND NEED TO THINK
ABOUT HOW LONG IT SHOULD
CONTINUE IN ICU ON HOSPITAL
FLOOR AFTER HOSPITAL DISCHARGE
AND NEED TO THINK ABOUT TYPES OF
INTERVENTION AND WHO WILL BE
PERFORMING IT. THERE IS MANY
DIFFERENT PEOPLE AND WE HAVE TO
REMIND OURSELVES THAT WORD
PHYSIOTHERAPY OR PHYSICAL
THERAPY IS THE NAME OF A
PROFESSION.
IT IS NOT THE NAME OF AN
INTERVENTION AND WE SHOULD
PLEASE STOP SAYING THAT PATIENT
NEEDS TO GET PHYSICAL THERAPY OR
PATIENT NEEDS TO GE MEDICINE OND
DOKTORRING DONE TO THEM AND ICU
REHAB INTERVENTIONS COMPLETELY
DIFFERENT AND TILT TABLE ALLOWS
GRADUATED WEIGHT BEARING AND
NEUROMUSCULAR ELECTRICAL
STIMULATION TALKED ABOUT A LOT
IN THE CHAT FOR THE EARLIER
SESSION AND IN-BED PSYCH LAR GOM
ETTRY THAT COULD BE PASSIVE OR
ACTIVE AND COMBINATION OF
ELECTRICAL STIMULATION WITH
INBED PSYCH LAR GOM ETTRY
FUNCTIONAL ELECTROSTIMULATION
AND WHAT MANY THINK ABOUT SAYING
P. T THAT IS FUNCTIONAL
MOBILITY WHERE PT IS BEHIND A
RESPIRATORY THERAPIST OUT FRONT
AND INTERACTIVE VIDEO GAMES
COINED AS WE HAVE. HYDROTHERAPY
AND MY HOSPITAL DOESN'T HAVE A
SWIMMING POOL. THIS IS IN THE
NENLERLANDS PATIENT ON
VENTILATOR ENDO TRACHIAL TUBE IN
POOL WITH PT AND THIS IS AN
OCCUPATIONAL THERAPIST WITH
COGNITIVE REHAB AND COLLEAGUE IN
JAPAN SHARING THIS PHOTOGRAPH
AND WE NEED TO REMIND OURSELVES
IT THIS IS A REALLY IMPORTANT
SLIDE AND FOR MOST
PHARMACEUTICALS WE KNOW EVERY
ROW IN THIS TABLE AND WHEN IT
COMES TO ICU REHAB ACTIVE
INGREEDIENT AND MECHANISM OF
ACTION AND PATHWAY OF ACTIVE
INGREEDIENT AND HALF LIFE HOW IT
INTERACTS WITH CO-INTERVENTIONS
AND MOST OF THOSE ARE NOT KNOWN
CONTINUING TO DO RANDOMIZED
TRIALS IN THE AREA.
WHAT ABOUT THE C AND COMPARISON
GROUP?
MANY TRIALS HAVE USED USUAL CARE
CONTROL GROUPS AND WE NEED TO
RECOGNIZE ARE THESE CONTROL
GROUPS TRULY REPRESENTATIVE?
MOST OF THE INTERVENTIONS ARE
COMPLEX TO DELIVER AND STUDY
SITES THAT PARTICIPATE HAVE AS
PART OF USUAL CARE RELATIVELY
ADVANCED ICU OR REHAB AND
REPRESENTATION OF THE CONTROL
GROUPS IN THOSE HOSPITALS MAY
NOT BE POSSIBLE. IF WE GO TO
OTHER HOSPITALS WHERE PTS HARDLY
EVEN ENTER ICU MIGHT NOT BE
POSSIBLE TO DELIVER INTERVENTION
AND NEED TO RECOGNIZE THAT USUAL
CARE CHANGES OVER TIME FROM
PLANNING OF RCT UNTIL ITS
COMPLETION AND BIG HETEROGENEITY
ACROSS STUDY SITES AND
CO-INTERVENTIONS ARE IMPORTANT
AND HEAD BONE IS CONNECTED TO
BODY BONE AND PROVIDING SEDATION
TO PATIENTS DELL EARYING STATUS
AND INTERVENTIONAL -- THESE ARE
IMPORTANT AND MAY EFFECT
EFFICACY OF INTERVENTION AND
FEASIBILITY YOU CAN'T DO ACTIVE
FUNCTIONAL MOBILITY INTERVENTION
IN SOMEONE WHO IS DEEPLY SEDATED
THAT WILL EFFECT FIDELITY TO THE
RESEARCH PROTOCOL AND IN TERMS
OF CORE OUTCOMES AND OUTCOME
CHALLENGES CORE OUTCOME SETS ARE
REALLY IMPORTANT TO REDUCE
HETEROGENEITY AND SPEAKER WILL
FINISH OFF CORE OUTCOME SET
SPECIFIC FOR ICU OR REHAB AND
TEXTED IN CHAT MANY TIMES ABOUT
NHLBI FUNDED EXISTING CORE
OUTCOME SET FOR ACCUSE
RESPIRATORY FAILURE AND RDS AND
PUBLISHED CORE OUTCOME SET AND
MEASUREMENT SET FOR DELL OOERIUM
IN THE ICU. THESE ARE AVAILABLE
AND WE NEED TO USE THEM.
>> FIVE MINUTES REMAINING.
>> FOCUS ON STRENGTH AND
FUNCTION AND INFORMATION ON
SYSTEMATIC REVIEWS AND LENGTH OF
STAY IN MORTALITY ARE NOT SAME
THINGS AND NEED TO RECOGNIZE
THAT PERFORMANCE-BASED MEASURES
6-MINUTE WALK TEST HAVE VERY
DIFFERENT OUTCOME MEASUREMENT
THAT PATIENT REPORTED OUTCOME OF
PHYSICAL FUNCTION ARE NOT
MEASURING SAME THINGS THAT ARE
COMPLEMENTARY NOT REDUNDANT AND
HOW DO WE BUILD BOTH IN?
WE NEED TO RECOGNIZE REQUIRED
EXPERTISE IN THE FEASIBILITY AND
COST.
MOST RESEARCH TEAMS AND ICS
DON'T KNOW HOW TO PERFORM MUSCLE
STRENGTH TESTING IN MECHANICALLY
VENTILATED PATIENT AND REQUIRE
EXPERTISE FOR PERFORMANCE-BASED
ASSESSMENTS AND RECOGNIZE ABOUT
TIMING AND LOCATION OF
ASSESSMENTS ESPECIALLY IF PEOPLE
ARE DISCHARGED TO LONG TERM
ACUTE CARE HOSPITALS AND NEED TO
RECOGNIZE THAT OUTCOMES NEED TO
BE PATIENT CENTERED AND NEED TO
HAVE PSYCHOMETRICS AND KNOW
MINIMUM IMPORTANT DIFFERENCES
AND LOTS OF GAPS SYSTEMATIC
REVIEWS TOLD US AND COUPLE
SLIDES LEFT TO TELL US WHAT GAPS
ARE AND TALKED A LOT ABOUT
EARLIER SESSIONS IN MECHANISMS
AND NEED LOTS OF MECHANISTIC
DATA HERE REQUIRING TEAM
COLLABORATION AND WE NEED SERIAL
MEASUREMENTS AND THOSE OF
PROTEIN METABOLISM AND
INFLAMMATION AND BODY
COMPOSITION AND ELECTRO
PHYSIOLOGY WE HAVEN'T TALKED
ABOUT VERY MUCH THAT IS HARD TO
DO ALL THOSE IN THE SAME STUDY
IN TERMS OF FEASIBILITY AND
RESOURCES AND EXPERTISE AND NEED
CONSENSUS AROUND WHAT CONTROL
GROUPS IN FUTURE TRIALS SHOULD
BE AND I HAVE A HALF DAY FREE OF
CHARGE MEETING THIS SATURDAY
WHERE THIS AIS ONE MENL LOGIC
ISSUES WE WILL ADDRESS AND CAROL
AND MICHELLE TWO FANTASTIC PT
COLLABORATORS AND THINK ABOUT
ISSUES OF REHAB DESIGN
DELIVERING OUTCOME MEASUREMENTS.
HAS TO BE MULTI-DISCIPLINARY AND
NEED EVERYBODY TO GET ENGAGED
AND REHAB PEOPLE TO UNDERSTAND
ICU AND ICU PEOPLE TO UNDERSTAND
REHAB. THAT IS WHY WE HAVE HAD
FOR 12 YEARS JOHNS HOPKINS
CRITICAL CARE REHAB CONFERENCE
AND OTS AND PTS TO BE MEASURING
DLEERIUM PART OF STANDARD CARE
AND RESEARCH AND COGNITIVE
SCREENING IN ALL FUTURE TRIALS
AND PATIENTS MAYBE STOP
EXCLUDING PATIENTS WITH IMPAIRED
BASELINE FUNCTION THAT IS REALLY
MOST PATIENTS COMING TO ICU AND
WE MIGHT NEED TO BE STRATIFYING
AND COMING TO INTERVENTIONS I
HAVE EXPLAINED HOW THERE IS SO
MANY TYPES OF INTERVENTIONS AND
SO MANY DIFFERENT PEOPLE WHO CAN
PROVIDE IT AND ISSUES AROUND
FREQUENCY AND INTENSITY AND
DURATION ALL NEED TO BE
CONSIDERED AND WE NEED TO
COMPARE THESE THINGS HEAD TO
HEAD AND NO WAY WE WILL FIGURE
THIS OUT WITHOUT HAVING DIRECT
COMPARISONS AS WELL AS
CO-INTERVENTIONS THAT WE TRIED
TO TACKLE THROUGH NHLBI FUNDED
NEXUS TRIAL OF PROTEIN
SUPPLEMENTATION WITH EXTRA
EXERCISE AND THINKING ABOUT
BUNDLED INTERVENTIONS AND CAN'T
DO ACTIVE INTERVENTIONS IF
PATIENTS ARE SEDATED THAT
REQUIRES BIG, BIG CULTURE CHANGE
THAT MAY REQUIRE CLUSTER
RANDOMIZED TRIALS AND STEP WEDGE
THAT WAS JUST TALKED ABOUT AND
NEED RESOURCES FOR COHORT
RETENTION AND CORE OUTCOME SETS
THAT WE ARE ALREADY ELUDING TO
IN MATT'S TALK. MY HIGH RISK
AND HIGH REWARD TIES IN NICELY
TO THE LAST COUPLE OF TALKS AND
COULD WE HAVE A BAYESIAN
ADAPTIVE PLATFORM TRIAL TO ALLOW
US TO THINK ABOUT ALL THESE
DIFFERENT TYPES OF INTERVENTIONS
AND THINK ABOUT THE DITCH WAYS
THAT WE DO DOSE.
I THINK THAT WE NEED TO PROCEED
IT WITH A STEP-LENLED RANDOMIZED
TRIAL TO GET ICUS UP TO SPEED
CHANGING CULTURE TO REDEUCE
SAIDDATION-REDUCED DELL EARIUM
AND PATIENT AS WAKE PERFORMING
REHAB INTERVENTIONS AND USING
MOST APPROACH TO LOOK AT
DIFFERENT WAYS OF LOOKING AT
MANY DIFFERENT INTERVENTIONS AND
I DON'T HAVE EXPERTISE AROUND
MOST OR PLATFORM TRIALS AND
[INDISCERNIBLE] IN THE ICU
TOGETHER WHEN WE DREAMT THIS UP
TOGETHER AND THERE ARE PEOPLE ON
THE ZOOM WHO HAVE EXACT
EXPERTISE IN TERMS OF CONTROL
GROUP THIS IS THE MEETING I WAS
TALKING ABOUT COMING TO ATS AND
INTERESTED IN CONTROL GROUPS AND
ICU REHAB AND COGNITION FREE OF
CHARGE A DAY AND UNDERSTANDING
REHAB AND REHAB PEOPLE TO
UNDERSTAND CRITICAL CARE IS 2 OR
3 OR 4 DAYS VIRTUAL CONFERENCE
WAND THAT I HAVE FINISHED ON
TIME. I'M HAPPY TO TAKE
QUESTIONS AND PARTICIPATE.
SORRY I TALKED QUICK AND WANTED
TO GET THROUGH ALL THIS AS QUICK
AS I COULD.
>> THAT WAS AMAZING AND IT DOES
NOT SURPRISE ME YOU ENDED ON
TIME. I'M SURE THAT YOU -- YOU
PACK AD I LOT IN THIS AND IT WAS
AN AMAZING TALK.
WHILE THE QUESTIONS ARE COMING
IN, I WANT TO ASK YOU 2
QUESTIONS.
FIRST IS THERE ARE A LOT OF
ISSUES YOU RAISED IN A VERY
IMPORTANT WAY.
IF YOU HAD TO PRIORITIZE ONE OR
TWO OF THEM, OF THE GAPS.
YEAH.
WHAT DO YOU THINK THEY ARE?
CONTROL GROUP ISSUE I THINK IS
IMPORTANT?
YOU SAID YOU WILL DEVOTE ETS
SYMPOSIUM AND FOCUSING ON ONE
ORE 2 WHAT COMES TO TOP OF LIST
OF WHAT PROBLEMS NEED TO BE
ADDRESSED FIRST?
>> I THINK IT WOULD HELP IF WE
COULD GET EXPERTISE TOGETHER TO
LOOK AT MECHANISMS OF HOW THESE
INTERVENTIONS MAY BE EFFECTING
PATIENTS SO THAT WE CAN DESIGN
INTERVENTIONS THAT WE THINK WILL
HAVE THE MOST BENEFIT AND FIELD
MATURING THIRD LAST BULLET POINT
HAVE TO COMPARE TRIALS LOTS AND
LOTS OF TRIALS AND THESE ARE NOT
DIFFERENT AND TEAM TRIAL
PUBLISHED IN NEW ENGLAND JOURNAL
THAT DR. MOS WROTE EDITORIAL ON
IS A FANTASTIC TRIAL TESTING
QUESTION OF INTENSITY AND
INTERVENTION GROUP IS VERY
SPECIFICALLY DESIGNED AND IS
VERY DIFFERENT THAN USUAL CARE.
BOTH INTERVENTION AND CONTROL
GROUP RECEIVE EARLY ONSET AND
HIGH FREQUENCY INTERVENTION.
DIFFERENCE BETWEEN TWO GROUPS IS
INTENSITY AND HOW INTERVENTION
IS DELIVERED AND WE WILL NEED A
LOT OF THE KINDS OF TRIALS THAT
IS WHY I WAS SUGGESTING A
PLATFORM WHERE WE COULD BEGIN TO
TEST MANY DIFFERENT THINGS.
IN A HEAD TO HEAD SORT OF BASIS
THAT ARE MY PROBABLY TOP 2.
>> SOUNDS GREAT.
ANOTHER THING I WILL ASK YOU IS
A DIFFICULT QUESTION, DALE. I
KNOW YOU HAVE THOUGHT ABOUT THIS
A LOT.
THERE IS A BALANCE BETWEEN DOING
SOME OF THE OBSERVATIONAL COHORT
TYPE OF STUDIES TO IDENTIFY
WHICH PATIENTS TRULY RESPOND OR
WHO, YOU KNOW, TREATMENT
ENRICHMENT STRATEGIES AND VERSUS
DOING RANDOMIZED CLINICAL TRIALS
AND WE ARE NOT REALLY SURE WHO
WE SHOULD BE ENROLLING.
HOW WOULD YOU BALANCE THOSE?
I MEAN, SHOULD WE DO MORE
OBSERVATIONAL THINGS AND NOT AS
MANY OF THE CLINICAL TRIALS NOW
TO TRY TO FIGURE OUT WHO TO
STUDY.
OR WOULD YOU SAY KEEP DOING THE
PRAGMATIC CLINICAL TRIALS AND
PLATFORM DESIGN WHERE WE CAN
FIGURE IT OUT ALONG THE WAY AND
REALIZE IT IS A TOUGH QUESTION.
>> I DON'T KNOW THE RIGHT
ANSWER. I WOULD LEAN TOWARDS I
THINK THAT WE HAVE LOTS OF
OBSERVATIONAL RESEARCH AND I
WOULD LEAN TOWARDS DOING MORE
RIGOROUS CLINICAL TRIALS AND
PLEASE STOP DOING UNBLINDED
TRIALS AND IS OKAY. WE MAY NEED
TO DO SINGLE CENTERED TRIALS FOR
EARLY STAGE INTERVENTIONS AND
THEY HAVE TO BE RIGOROUS THAN
TRIALS OF BEING TO DATE AND DO
MECHANISTIC PART OF THAT
TOGETHER.
I WOULD RATHER SEE 10 TRIALS
THAT BEGIN TO LOOK AT A NUMBER
OF DIFFERENT ASPECTS OF DOSE OR
TYPES OF INTERVENTIONS THAT FWIN
TO LOOK FOR SIGNALS FOR WHAT
COULD THEN BE PROGRESSED TOWARDS
LARGER TRIALS WOULD BE MY BIAS
WITH SOME MECHANISM BUILT IN.
IT WILL REQUIRE PARTNERSHIP TO
HAVE ALL NECESSARY SKILLS.
>> IN INTEREST, DALE, THAT IS
AWESOME. IN INTEREST, THERE IS
OTHER THINGS IN THE CHATS. WE
ARE KEEPING VERY CLOSE AND
WATCHING TO ADDRESS THOSE ISSUES
IN THE PANEL DISCUSSIONS.
I WANT TO TURN IT OVER TO
STEPHANIE TO INTRODUCE THE FINAL
SPEAKER OF THE SESSION.
>> THANK YOU.
FINAL SPEAKER IS [INDISCERNIBLE]
AND ASSISTANT PROFESSOR OF
EPIDEMIOLOGY AND MEDICINE IN
PULMONARY CRITICAL CARE. SORRY
HE IS THE DIRECTOR OF NIH PECK
CORI CLINICAL TRIALS OUTCOMES
LAB -- AT UNIVERSITY OF COLLEGE
LONDON AND PRIMARY FOCUS OF
RESEARCH AND IMPROVING PRAG.
YOU CAN SEE WHY WE THOUGHT HE
WAS A TREMENDOUS PERSON TO CLOSE
OUT THIS SESSION.
DR. JORGE, TAKE IT OVER.
>> THANK SO YOU MUCH,
STEPHANIE.
>> I HAVE LOTS OF OVERLAPPING
THEMES AND ADAPTING TO RESPOND
TO SOME QUESTIONS AND BARE WITH
ME.
NEXT SLIDE, PLEASE.
ACKNOWLEDGING FUNDING FROM PEK
ORRI AND NHLBI AND WHAT HAS BEEN
SAID IS GENERATING IN SUPPORT
AND I WILL THINK ABOUT IT AND I
HAVE PERSONAL FEES AND DON'T
THINK THEY ARE RELEVANT TO WHAT
I WILL SAY TODAY BUT TALK ABOUT
TRIALS TO LOTS OF PEOPLE.
I WILL TRY TO TALK ABOUT FOUR
BRIEFLY DISTINCT THINGS TODAY
AND IMBEDDING ARTICLES TO GIVE
PEOPLE WHO WANT TO EDUCATE
THEMSELVES GUIDANCE WHERE TO
LOOK AND MENTIONING AND STARTING
SAYING THINGS ABOUT OUTCOME
MEASURES LOTS HAS BEEN SAID
ALREADY AND PIVOTING AND TALKING
ABOUT HOW TO USE MORE WHAT I
THINK OF AS KIND OF REALINO
VATTIVE STATE OF THE ART
OBSERVATIONAL DATA METHODS AND
LAST COUPLE YEARS EMULATED
TRIALS AND WALKING THROUGH
EXAMPLE AND SHOULD USE TO INFORM
TRIAL DESIGN AS WELL AND GIVING
EXAMPLE IN A FEW YEARS AND
SPOILER ALERT MY HIGH RISK AWARD
OR IDEA IS ADAPTIVE PLATFORM
TRIAL THAT I WILL TALK ABOUT
WHAT I THINK THAT IS AND WILL
TRY TO ADD NUANCE THERE AND TALK
A LITTLE ABOUT WHY I THINK WE
HAVE TO PIVOT AWAY FROM P VALUE
BASED WORLD FULL-FLEJ BAYESIAN
AND WILL CONVINCE YOU TO GIVE
YOU A CHANCE IF YOU ARE NOT
ALREADY IN THAT DIRECTION.
NEXT SLIDE, PLEASE.
OKAY. VERY MUCH I THINK THAT
EVERYBODY KNOWS THE WHITE WHALE
OF THE CRITICAL CARE COMMUNITY
IS OUTCOME MEASURE AND 30 YEARS
FOCUSED ON DEATH AS PRIMARY
ENDPOINT WE WERE STRUGGLING AND
MOVED TO REALM OF FOCUSING ON
NONMORTALITY THAT IS CHALLENGING
IN ACUTE PHASE AND 90 DAYS AND
CHALLENGE RING IN LONG TERM AND
IT IS CHALLENGING WE KNOW WHAT
MATTERS LOTS OF CREDIT TO PEOPLE
ON THIS CALL AND COLLEAGUES AND
WHAT WE HAVE SEEN IS THIS
CONCEPT WE UNDERSTAND THERE IS
KINETICS AND ACUTE PHASE OF
CRITICAL ILLNESS AND LONG TERM
MULTIFACTORIAL TIME VARYING AND
HARD TO MEASURE THINGS THAT
MATTER TO PEOPLE AND HARD TO
MEASURE THEY HAVE TO COME FROM
INSTRUMENTS AND HAVE SUBJECTIVE
IMBEDDED IN THEM AND HAVE TO
MAKE A DECISION AT TRIAL STAGE
AND DECISION ABOUT WHAT ONE OR
TWO OUTCOME MEASURES TO HEDGE
EFFICACY DECISIONS ON AND MAKING
IT ABOUT A TIME HORIZON THAT IS
TRICKY AND YOU HAVE WHAT I CALL
COMPLIANCE ISSUES AND PEOPLE
LOSS FOLLOW UP AND SOME
PERMANENTLY HAVE LOSS TO FOLLOW
UP WHEN THEY DIE THAT IS REALLY
CHALLENGING.
NEXT SLIDE, PLEASE.
WHAT CAN WE DO?
RESEARCH OUT THERE AND THINK
ABOUT IN THREE BUCKETS CALL TO
INFERENCE METHODS AND PAPER THAT
WAS MENTIONED YOU CAN ANALYZE
GROUP THAT PEOPLE CALL ALWAYS
SURVIVORS.
I DO RESEARCH IN HERE. I LIKE
IT CONCEPTUALLY APPEALING AND
REQUIRES LOTS OF LONG-TERM DATA
AND STATISTICAL ASSUMPTIONS AND
DISCARDS LOTS OF PEOPLE. YOU
DON'T WANT TO DO THAT AND WANT
TO LEARN SOMETHING ABOUT
EVERYONE AND LOSE STATISTICAL
POWER THAT IS PERSISTENT
CHALLENGE FOR US STATISTICAL
APPROACHES JOINT MODELING AND
CHALLENGE IS THEY SOLVE DATA
ISSUE AND CREATE STATISTICAL
ISSUE AND EFFECT ESTIMATE WITH
NO REAL INTERPRETABILITY AND
CLINICAL TRANSLATION AND WE HAVE
FALLEN BY NECESSITY TOWARDS
COMPOSITE OUTCOMES AND NEXT
SLIDE, PLEASE.
SO, I WILL TALK ABOUT VENTILATOR
FREE DAYS AND WITH THIS WE HAVE
A MOVEMENT FROM MORTALITY BEING
TREATED 0 FREE DAYS TO NEGATIVE
1 AND NUMERICAL MOVE MAKING IT
HIERARCHICAL I LIKE IT AND
CHALLENGE WITH COMPOSITE
OUTCOMES NOT INTERPRETABLE
ACROSS TRIALS OR COMPARABLE AND
FIGURING HERE WE HAVE A Y AXIS
MEDIAN DAYS OF MECHANICAL
VENTILATION THAT RANGES FROM
TRIALS A THROUGH E AND 7 DAYS TO
18 AND ACROSS X AXIS WE HAVE
MORTALITY RATES FROM 0 TO 40 AND
ALL FIVE TRIALS HAVE SAME MEDIAN
VENTILATOR FREE DAYS OF MEDIAN
OF 10 NOT LEARNING WHAT IS
HAPPENING BUT GETTING A NET
SUMMARY AND CURRENT ENDPOINTS
FUNCTIONALLY ARE SOLVING
STATISTICAL PROBLEM WITH
TRADEOFF OF CONCEPTUAL PROBLEM
AND NEXT SLIDE SEEING AT
SUSTAINING LEVEL AND TRIAL LEVEL
AND MULTIPLE PEOPLE WITH SAME
VALUE OF OUTCOME MEASURE IN
TRIAL AND TWO HYPOTHETICAL
EXAMPLES VENTILATOR FREE DAYS
ASDOET AND AT 14 AND WE TROOID
TO MAP OUT RANDOM TRAJECTORIES
COULD BE DIFFERENT AND
STATISTICAL DISTRIBUTION YOU
WILL SEE SAME VALUES.
NEXT SLIDE, PLEASE.
SO, WE SPENT TIME OVER THE LAST
COUPLE YEARS THINKING ABOUT WHAT
WOULD BE WE STARTED DE NOVO
IDEAL LONG-TERM CRITICAL CARE
ENDPOINT THAT IS SUBJECTIVELY
RANKED ORDER AND MY
INTERPRETATION I THINK THAT MOST
IMPORTANT THING WE FIND A
NATURAL PLACE FOR DEATH AND
THINK OF HIERARCHICAL ENDPOINT
AND DECIDE THAT IS WHAT WE VALUE
MONTHEST TO ACCEPT IT AND THINGS
TO WORK THROUGH AS STAKEHOLDERS
IN THE COMMUNITY AND NEXT TWO
THINGS ARE TO ME INTERVIEW
RELATED WITH BEAUTIFUL DIAGRAM
AND TRAJECTORIES PEOPLE HAVE
WITH CRITICAL ILLNESS AND BLUE
JOURNAL AND FORGET TITLE JACK IF
YOU ARE LISTENING COMPELLING
FIGURE AND PEOPLE COMING INTO
RECOVERY AT DIFFERENT STARTING
POINTS DIFFERENT POST RECOVERY
AND KINETICS OR CONTINUUM
RECOVERY AND THINK THAT IDEAL
ENDPOINT ALLOWS US TO PICK THAT
UP AND IDEALLY IS SOMETHING OF A
MORE CONTINUOUS LEVEL AND FOCUS
ON ORDINAL OUTCOMES GOING FROM 0
TO 7 AND 0 TO 9 AND CEILING
EFFECTS TOUGH TO FIND MOVEMENT
IN IT AND NICE TO FIND SOMETHING
STATISTICALLY SIMPLE AND ROBUST
AND ADAPTABLE WHAT MATTERS TO
PEOPLE AND ALIGNING WITH
SOMETHING FAMILIAR TO REGULATORS
AND NEXT SLIDE, PLEASE.
WE HAVE PLAYED WITH GETTING
TOWARDS SOME OF THESE AND
PERHAPS NOT PERFECTLY AND
DEFINITELY NOT PERFECTLY DAYS
ALIVE OUT OF THE HOSPITAL AND
HOSPITAL FREE DAYS CONCEPT OF
STATISTICS [INDISCERNIBLE]
DEMANDS IDEAL QUANTITY TO TARGET
THAT GETS THERE AND IS ABOUT
WHAT PEOPLE WANT AND YOU CAN
START TO MANIPULATE IT FOUR
DIFFERENT PEOPLE AND STAKEHOLDER
POPULATIONS FOCUSING BEING OUT
INSTITUTION AND FREE DAYS
GETTING OUT OF REHABILITATION OR
GETTING OUT OF MEDICATION THAT
IS FLEXIBLE AND IS NICE
MEASURING IN TRIALS THAT 180
DAYS IS A BEAUTIFUL CONTINUOUS
OUTCOME AND STARTING TO THINK
ABOUT ME AND MEDIAN DIFFERENCE
AND RELATIVE SCALES AND RATIO TO
WIN ODDS AND SOMETHING WE ARE
TINKERING WITH AND PATIENT
CENTERED MEANINGFUL TO
REGULATORS AND PATIENT CAREGIVER
RS.
COLLEAGUE FIRST AUTHOR PAPER K
AWARD HLVI TRYING TO RANK ORDER
OR QUALITY RANK DAYS. I'M
EXCITED ABOUT WHERE THAT WORK
GOES AND IT WILL SOLVE PROBLEMS
AND IS BASED ON ONE INSTRUMENT
THAT MAY NOT CAPTURE EVERY
DOMAIN.
NEXT SLIDE, PLEASE.
HARD PIVOT. I WANT TO TALK
ABOUT MOVING FROM OBSERVATION TO
EXPERIMENTATION BETTER. I'M
IMPRESSED WITH HOW WELL TARGET
TRIALS ARE DOG AND IDEA IS THREE
FOLD AND HEARING MORTAL TIME
BIAS AND GOAL OF RANDOMIZED
TRIAL IS CONCEPT OF -- GROUPS
ARE MORE OR LESS IDENTICAL AT
BASELINE AND OBSERVATIONAL
RESEARCH IS WORKING WITH A
COHORT AND BEING CAREFUL ON
SOMEONE'S STARTING POINT AND YOU
ARE ASSUMING PEOPLE ARE MORE OR
LESS RANDOMIZED AT BASELINE.
NEXT SLIDE.
TALKING ABOUT ODD ELEMENTS OF IT
PAPER WRITTEN BY PEOPLE ON THE
CALL AND INCREDIBLY ELEGANT
WISHING TO DO IT FOR EVERY
TRIAL. NEXT SLIDE, PLEASE.
NEXT ELEMENT OF EMULATED TRIAL
IS TAKING TABLE MAPPING OUT
PERFECT TRIAL TO RUN IN THIS
EXAMPLE IS PREVENT AND MAKING
OBSERVATIONAL ANALYSIS IDENTICAL
TO IT OR MIRROR IT AS MUCH AS
POSSIBLE ELIGIBILITY CRITERIA
AND OMIZING TREATMENT STRATEGIES
AND MAPPING TO EXPOSURES AND
CONTROL GROUPS WE SEE IN
OBSERVATIONAL COHORT. NEXT
SLIDE, PLEASE.
CONTINUE AND GET TO THE LAST
THIRD ELEMENT YOU CAN'T DO
UNADJUSTED ANALYSIS YOU WOULD
CONVENTIONALLY DO IN RCT AND
THERE IS BALANCING WAY TO
APPROACH THIS PROPENSITY SCORES
AND THEY ARE GOOD AT THIS IF YOU
DO FIRST AND SECOND STEP
ELEMENTS CORRECTLY. NEXT SLIDE,
PLEASE.
I WILL SHOW YOU HOW CLOSE YOU
CAN GET. THIS IS A NICE PANEL
THAT I THINK SHOWS THAT YOU HAVE
IN THE MIDDLE COLUMNS TREATMENT
EFFECTS FROM OBSERVATIONAL STUDY
AND RANDOMIZED TRIAL AND LAST
COLUMN TO THE RIGHT YOU HAVE A
DIFFERENCE AND DIFFERENCE AND
THEY ARE QUITE CLOSE ACROSS
ELEMENTS AND LEARNING FROM
OBSERVATION AT DATA WHAT IS
BASELINE MORTALITY RATE WHAT IS
CLINICAL DELTA IN POWER
REGULATIONS SUPPLEMENTING
AUGMENTING WHAT WE DO IN PILOT
TRIALS AND WOULD LOVE TO SEE
MORE OF IT IN EXPECTATION DONE
FOR FUTURE TRIALS.
NEXT SLIDE, PLEASE PIVOTING
AGAIN. LONG TIME FOCUSED ON
FIXED TRIAL AGAIN AND YOU HEARD
IN LAST COUPLE TALKS A MOVEMENT
TOWARDS THIS WHERE WE HAVE TO GO
REMAP CAP AND PLATFORMS BROUGHT
UP DURING PANDEMIC HAVE SHOWN
HOW MUCH WE CAN LEARN AND REMAP
CAP IS PUBLISHED 25TH ARTICLE
AND RCT MORE RECENTLY THAT IS
AMAZING AND IDEA BEHIND ADAPTIVE
TRIAL IS KEEPING ON LEARNING AND
LOOKING AT DATA AND COUPLE
HUNDRED PATIENTS OR 1 PATIENTS
ADAPTING INPUTS AND PERPETUAL
PERSISTENT LEARNING NEXT SLIDE.
TAPPING THROUGH THESE BOXES
MOVING AND IDEA IS THAT YOU
START TO RANDOMIZE PEOPLE AND
CONTROL ARM AND INTERVENTION 1,
2, 3, OR 4 WHATEVER YOUR
POPULATION ALLOWS AND TAKE A
LOOK AT 100 AND TREATMENT EFFECT
DISTRIBUTION WE ARE STARTING TO
SEE IF DOESN'T BE COMPELLING AND
YOU CAN ADJUST RANDOMIZATION
PROBABILITIES AND KEEP ON GOING
SUCH THAT YOU START TO MIX
SUBGROUPS AND ADD PLATFORMS INTO
IT. YOU CAN ADD MULTIPLE
DOMAINS AND PLATFORM TRIALS HAVE
ANTIBIOTIC AND VENTILATION
DOMAIN AND ORGAN FAILURE AND AI
DOMAIN. YOU CAN TEST MULTIPLE
INDIVIDUALS IN A FACTORIAL WAY
THAT COULD GET VERY COMPLEX.
NEXT SLIDE, PLEASE.
THIS IS A DIAGRAM THAT I WON'T
WALK THROUGH TOO MUCH. NUMBERS
AND STATISTICS.
>> FIVE MINUTE ROOEZ MAINING.
>> GOT IT.
WHAT YOU CAN SEE IN FIRST COLUMN
IS EQUAL SHADING OR EQUAL SIZED
BOXES THAT START TO CHANGE THAT
IS PROBABILITY OF BEING
RANDOMIZED IN DIFFERENT ARMS
CHANGING HAPPENING STATISTICIAN
AND INFORMATICS SYSTEM PEOPLE
CONSTANTLY WATCHING AND LEARNING
AND NEXT SLIDE, PLEASE.
POINTS I WANT TO MAKE CLOSING
THIS OUT DESIGNING TRIAL THAT
CAN LEARN AND ADAPT AND RUN LIKE
THAT INVESTING MORE TRIAL
INFRASTRUCTURE NOT TRIALS THAT
ARE IN STADIUMS THAT GUITAR
BUILT LAST YEAR FOR WORLD CUP
AND CAN'T HELP THAT THIS IS WHAT
WE WERE DOING FOR A LONG TIME
AND TRIALS BUILDING STATIUM FOR
SINGLE GAIN AND HAVE TO MOVE
AWAY FROM PULLING TALENT AND
INFORMATICS INFRASTRUCTURE HOW
TO LEARN AND BE ADAPTIVE
BRINGING ME TO NEXT POINT NEXT
SLIDE, PLEASE.
WON'T TRY TO TEACH YOU WHAT
BAYESIAN IS BUT CONVINCING YOU
WHY YOU SHOULD GIVE IT A CHANCE
LAND TEACH YOU WHAT BAYESIAN IS
IF YOU WANT TO TALK ABOUT IT.
FIGURED IT WASN'T BEST ENDING OR
TALK. WHAT WE HAVE TO DO AT A
PHILOSOPHICAL LEVEL IS THINKING
ABOUT WHAT LEVEL OF EVIDENCE DO
WE NEED TO MAKE MOVE ON TESTING
NEW THERAPY AND WE ARE MOVING
INTO PHASE 2 OR 3 AND LONG
RELIED ON CONCEPT OF .5 OR NOT
AND NOTHING FUNDMENTMENT ALLEY
DIFFERENT BAYESIAN OR FREQUENCY
TRIAL AND CALCULATING TREATMENT
EFFECTS AND WHAT IS DIFFERENT IS
PROCESSING THINKING ABOUT MOVING
ON EVIDENCE AND BAYESIAN IS IF
YOU REMEMBER Z SCORES NORMAL
DISTRIBUTION AND LINE AND
PERCENT TO THE RIGHT AND PERCENT
TO THE LEFT AND THINKING ABOUT
THAT PERCENT TO LEFT OR RIGHT IS
AROUND NULL AND ODDS RATIO OF 1
AND HOW MUCH DISTRIBUTION IS
SUGGESTIVE BENEFIT OR EQUIPOISE
OR HARM AND DESIGNING TO MOVE
AND ADAPTIVE BAYESIAN TRIALS ARE
DOING THAT OBSERVING PROBABILITY
DISTRIBUTIONS COMING IN AND
DECIDING IF IT IS ENOUGH TO
MOVE.
NEXT SLIDE, PLEASE.
I LIKE THAT WAY OF THINKING
BECAUSE I'M KIND OF DRIVEN BY
THIS EXAMPLE.
IF YOU HAVE NEVER READ THIS
PAPER IT IS ONE OF MY FAVORITES
USING IT A LOT WHEN I TEACH AND
WHAT DO WE WANT WHEN WALKING
INTO NEW TREATMENT WE WANT TO
KNOW FIRST IS IT BETTER THAN
WHAT WE USE NOW? IF NOT IS IT
INFERIOR? IDEAL TRIAL ANSWERS
QUESTIONS AND IS THERE A
COMMENT?
WAY WE ARE DOING THINGS P
VALUE-BASED TRIALS ALLOWING TO
ANSWER QUESTIONS SIMULTANEOUSLY.
NEXT SLIDE, PLEASE.
I THINK IT IS BECAUSE WE ARE
MOVING AWAY FROM SCIENTIFIC
QUESTION AND QUESTIONS ARE
ASKING IS TRIAL IN PREVIOUS
SLIDE FORCING INTO STATISTICAL
FRAMEWORK DOESN'T ANSWER THAT
START TO THINK ABOUT NULL
HYPOTHESES THAT ARE RIGID AND GO
SO FAR TO SAY NONSENSICAL AND
THIS IS A NICE QUOTE THAT SAYS
ONCE TO ME AND PHILOSOPHICAL
PERSPECTIVES THEY CAN'T BE --
THAT IS NOT WHAT P VALUES DO FOR
US THEY TELL US HOW COMPATIBLE
ALTERNATIVE AND NULL HYPOTHESIS
ARE. THAT IS NOT SCIENTIFIC
QUESTION. NEXT SLIDE, PLEASE.
SCIENTIFIC QUESTION IS WHETHER
OR NOT THERE IS A TREATMENT
EFFECT WE CAN OBSERVE THAT IS
ACTIONABLE OR MEANINGFUL AND ARE
THREE DISTRIBUTION AND LOOK LIKE
THEY DIDN'T COME UP FULLY.
BUT THERE IS SOME THAT IS FROM
REMAP CAP AND HOW THEY MAKE
EFFICACY DECISIONS UP TOP. 99%
OF CLINICAL TRIAL DISTRIBUTIONS
TO THE RIGHT SUGGESTING BENEFIT
THEY SAY IS SUPERIOR AND IF
LEVEL OF INFERIORITY THEY WILL
HAVE FUTILITY THAT IS IN THE
MIDDLE AND JUMPING OVER THIS
WITH FULL WALK THROUGH OVER
TIME.
SORRY ABOUT THAT.
BOTTOM IS EQUIVALENT TREATMENT
EFFECT DISTRIBUTION SAME AS 95%
CONFIDENCE INTERVAL LOOKING AT
IT VISUALLY INSTEAD OF TWO
NUMBERS IS HOW WE MAKE DECISIONS
AND WANT FROM A TRIAL THAT
ALLOWS ALL QUESTIONS REGARDLESS
WHAT TRIAL PANS OUT AND WHAT I
THINK WE HAVE NOT DONE FOR THE
LAST 30 OR 40 YEARS.
NEXT SLIDE, PLEASE.
AND IF I HAVE NOT CONVINCED YOU
GIVING A CHANCE I WILL CLOSE WE
HAVE TO FOR NO OTHER REASON THAT
WHAT WE ARE DOING IS NOT WORKING
AND OLDER PAPER ALMOST A DECADE
NOW AND ONLY DIFFERENCE IS
DENOMINATOR PROBABLY TOWARDS 200
NOW AND LOOKING AT ATS AND
MULTIPLE SOCIETY CLINICAL
GUIDELINES AND PROMOTES WITH
EVIDENCE BASED IS PRONE
POSITIONING AND LONG TIME WITH
SUCCESS AND CAN'T DO IN ACUTE
PHASE WILL BE HARDER IN
LONG-TERM PHASE KNOWLEDGE GAPS
TWO THINGS TO FOCUS ON IS
FINDING P MULTICOMPONENT OUTCOME
MEASURE AND PATIENTS MOVING INTO
OUTCOME WE CAN ACTUALLY MAKE
SENSE OF GETTING TREATMENT
EFFECT AND FIGURING OUT WHAT
COMPONENTS OF THAT IS AND WILL
BE COMPLEX AND KNOWING
COMPONENTS THAT ARE RELEVANT AND
KNOWLEDGE GAP IS THRESHOLD
MOVING ON FROM EVIDENCE WE HAVE
TO CHOOSE SOMETHING TO RESPOND
TO AND THINK THAT CURRENT
APPROACH OF 99% EVIDENCE IS HIGH
AND UNDERSTAND WHY REMAP CAP DID
IT FIRST IN THE FIELD AND DON'T
KNOW IF 75% IS TOO LOW ALL DAY
LONG MAKE PROBABILISTIC
DECISIONS AND KNOW YOU DO
CLINICALLY DAUGHTER TELLS ME
WANTS TO WEAR NEW SHOES 75%
CHANCE OF RAIN DECISION WILL BE
NO MOVING FROM PHASE 2 OR 3
TRIAL DON'T HAVE THAT ANSWER BUT
AS A COMMUNITY WE CAN MOVE
TOWARD AND DECIDE AND NEXT
SLIDE, PLEASE.
HIGH RISK AND REWARD BEING
REPETITIVE NOW AND OTHER
SPEAKERS PLEASED TO SEE WHEN WE
TOOK A STAB AT IT WE ARRIVED AND
I DON'T THINK IT HAS TO BE
FOCUSED JUST NECESSARILY ON LONG
TERM BUT IDEAL TRIAL IS
SOMETHING THAT INTEGRATES WITH
NEW CONSORTIUM THAT IS COMING
TESTING SHORT-TERM THERAPIES OR
LONG-TERM THERAPIES AND
REPOSTORY AND INTEGRATION AND
THINK THIS IS SOMETHING THAT
NHLBI COULD LEAD THE FIELD IN
AND IF LISTENING I WOULD SAY
CANADA AND SCOTLAND AND DENMARK
ARE ALL FUNDING AT NATIONAL
LEVEL AND THERE IS NO REASON WE
HAVE SHOWN IT EITHER.
I AM SORRY THAT I SPOKE FAST. I
INHERENTLY DO BUT WANTED TO SAY
A LOT AND THANKS SO MUCH.
APPRECIATE BEING HERE. IT HAS
BEEN REALLY INTERESTING.
>> AWESOME, MICHAEL. THANKS SO
MUCH. WE ALL LEARNED A LOT IN
ADDITION TO THE FACT THAT YOU
ARE VERY, VERY MEAN DAD ABOUT
YOUR DAUGHTER'S SHOES AND LOTS
OF QUESTIONS TO GET INTO. A FEW
EARLY QUESTIONS FOCUSED ON DAYS
ALIVE OUTSIDE OF THE HOSPITAL
AND HOSPITAL-FREE DAYS MEASURE
THAT I THINK PROBABLY ASKING
ABOUT GETTING GRANULAR ABOUT
DEFINING THAT. DR. CONNOLLY
ASKED ABOUT CAPTURING BURDEN OF
DISABILITY AND SUPPORT NEEDS AND
FURTHER IN REFINING DAYS AT HOME
WHETHER GOOD OR BAD DAYS AT HOME
AND MAYBE I DON'T KNOW IF YOU
CAN SPEAK TO OUTCOMES RESEARCHER
KNOWING KATIE'S WORK?
>> GREAT QUESTION.
WE -- I THINK ATTRACTION TO THAT
INHERENTLY HAS BEEN THAT IT IS
WHEN YOU THINK OF GUIDELINES FOR
PRAGMATIC TRIALS IT IS PERHAPS
ONE OF MOST PRAGMATIC ENDPOINTS
YOU CAN GET AND DON'T NEED A LOT
OF INFORMATION AND SELF-REPORT
IS TRICKY. YOU CAN CALL SOMEONE
UP. HAVE YOU BEEN IN HOSPITAL
FOR LAST 90 DAYS? BECOMES LESS
PRAGMATIC LOSING ATTRACTION WHEN
YOU WANT TO INTEGRATE ALL
DIFFERENT ELEMENTS OF CAREGIVER
BURDEN AND HOW PATIENTS HAVING
GOOD OR BAD DAYS AND SPECIFIC
DOMAINS AND I DON'T REALLY KNOW
A PERFECT WAY TO DO IT.
KATIE HAS BEEN DOING A CONCEPT
WE HEARD FOR THE LAST COUPLE
DAYS SEQUENTIAL SERIAL FOLLOW
UPS CONTACTING PEOPLE REGULAR
INTERVALS AND HAVING
[INDISCERNIBLE] AND WE HAVE
TALKED ABOUT WAYS THAT SHE
PROPOSED WAYS DON'T WANT TO TAKE
IDEAS IT IS HER TALKING ABOUT
WAYS TEXTING PEOPLE AND HAS BEEN
CLEVER GETTING PEOPLE TO RESPOND
ELECTRONICALLY AND ONE THING
MATT SAID FIGURING OUT
REASONABLE SET OF INSTRUMENTS IN
WAY TO BEHAVIORALLY NUNL PEOPLE
TO RESPOND WE CAN START TO GET
THERE AND ADDS LAYER OF
COMPLEXITY THAT IS REAL.
>> YEAH. THAT IS GREAT AND
KIND OF FOLLOWING A FOLLOW UP TO
THE NEXT QUESTION SOMEONE ASKED
ABOUT LOSS TO FOLLOW UP AND
HANDLING THAT STATISTICALLY AND
WONDERING IF YOU HAVE BRILLIANT
IDEAS ABOUT BEST WAY TO HANDLE
LOSS OF FOLLOW UP AND
POPULATIONS THAT ARE PRONE TO
NOT HAVING FULL FOLLOW UP.
>> I AM SAD TO SAY THAT GRANTS
LATER MY WHOLE PHD I DON'T --
MORE I TRY TO STUDY IT I FEEL IT
IS SUBOPTIMAL AND COMING TO
TERMS STARTING TO NOT LIKE
COMPOSITE ENDPOINTS THEY ARE
RIGHT ANSWER AND WE HAVE TO
FIGURE OUT HOW TO PUT THEM
TOGETHER.
I'M NOT A FAN AS MUCH AS I USED
TO BE OF LOTS OF STATISTICAL
APPROACHES AND THEY TRANSFORM
DATA INTO AN EFFECT ESTIMATE
WITH STATISTICAL ASSUMPTIONS
THAT ARE HARD TO UNDERSTAND AND
THESE ARE ALWAYS INHERENT THINGS
TO THEM.
OTHER ONES LIKE ADVERSE
PROBABILITY WAITING AND JOINT
MODELING MAKE ASSUMPTION AND
ESTIMATE REPRESENTS
COUNTERFACTUAL POPULATION IF NO
ONE DIED OF THIS REASON THAT IS
AN ODD CONCEPT WHEN YOU THINK
ABOUT IT.
SO, I FEEL THEY GET TOO FAR AWAY
FROM WHAT WE ACTUALLY WANT TO
KNOW.
SO, THAT IS NOT A GREAT ANSWER.
I WILL ACKNOWLEDGE IT IS A HARD
-- I DON'T THINK THERE IS A GOOD
ANSWER BUT SUBOPTIMAL SOLUTION.
>> FAIR.
>> WE SHOULD PROBABLY.
>> DO PANEL DISCUSSION, YEAH.
PERFECT.
>> LET'S DO THAT.
SO, WHAT I THOUGHT WE WOULD DO
IS THIS IS -- THIS HAS BEEN
REALLY GREAT AND WANT TO COMMEND
4 SPEAKERS ON GIVING SUCCINCT
AND PROVOCATIVE TALKS NOT ALWAYS
EASIEST THING TO DO. STEPHANIE
AND I TALKED ABOUT GIVING A
BRIEF SUMMARY OF MAJOR ISSUES
THAT ARE RAISED AND ACTUALLY I
THINK FLOWS VERY NICELY.
IT SPEAKS TO STRENGTH OF TALKS
AND SO THE THING OR ISSUES
GETTING RAISED FIRST IS CONCEPT
OF REVERSE TRANSLATION AND WHAT
PEOPLE THAT STUDY AT BEDSIDE DO
TO HELP FUEL BASIC SCIENCE
RESEARCH AND WHY IT MATTERS AND
GENERALIZABILITY AND TARGETING
CERTAIN POPULATIONS THAT GOT
RAISED AND WE GOT INTO THE WHOLE
STUDY DESIGN CONCEPTS OF WHAT DO
WE STUDY?
WHAT ARE INTERVENTIONS THAT NEED
TO BE INVESTIGATED?
MATT TALKED ABOUT PICKING SOME
AND THINGS USED IN PRACTICE THAT
CAN EFFECT BRAIN AND MUSCLE
OUTCOMES AND WE TALKED ABOUT
ALSO HOW TO MOVE FORWARD WITH
THE TREATMENT AND SOMETHING THAT
MICHAEL TALKED ABOUT AND HOW DO
WE TALK ABOUT WHAT WE SHOULD BE
STUDYING?
DALE RAISED EXTREMELY IMPORTANT
ISSUES FOCUSED ON REHAB THAT I
THINK CAN BE EXPANDED.
INTENSITY DURATION AND WHO
PERFORMS IT AND HOW LONG IS
PERFORMED AND WHERE IT IS
PERFORMED AND WHO, ET CETERA.
ALL THESE QUESTIONS THAT ARE
IMPORTANT NOT ONLY TO REHAB BUT
OTHER INTERVENTIONS THAT WE DO.
THEN HOW DO WE IMPLEMENT
INTERVENTIONS AT EARLY STAGES?
MEGAN RAISED ISSUES ABOUT
LOOKING AT WORKFLOWS IN MIND AND
COMBINING IMPLEMENTATION SCIENCE
TYPES OF INTERVENTIONS.
WHAT DO WE STUDY?
LOTS OF QUESTIONS ARE OUT THERE
AND IN A VERY POSITIVE GOOD WAY
AND WHO TO STUDY AS DALE SAID
WOULD BE SECOND OP AND ABLE TO
PARTICIPATE AND ONE THING TO
TALK ABOUT IS MEASURING BASELINE
NUFRNGS REHAPPEN TRIALS AND WHAT
RIGHT CONTROL GROUP IS AND AS
DALE SAID I THINK IS A VERY
IMPORTANT QUESTION.
WHAT IS THE RIGHT STUDY DESIGN?
MICHAEL AND OTHER PEOPLE WERE
TALK BEING T I THINK IT IS
INTERESTING THAT WE DIDN'T HAVE
PEOPLE THAT ALL TALKED TOGETHER.
PEOPLE THAT ARE LEADERS IN THE
FIELD CAME UP WITH SIMILAR
SOLUTIONS FOR THE END.
BUT, YOU KNOW, DIFFERENT TYPES
OF STUDY DESIGNS.
HOW DO WE CONTROL FOR
CO-INTERVENTIONS?
ONCE WE FIGURED OUT WHAT
INTERVENTIONS DO HOW DO WE
DELIVER IN PROPER WAY ACROSS ICU
AND ON THE FLOOR AND GOING HOME
IN LONG-TERM CARE FACILITIES AND
THERE IS A TREATMENT FIDELITY
WITH COMPLEX INTERVENTIONS AND
IN PRAGMATIC TRIALS WE HAVE TO
BE VERY CAREFUL AND WATCH VERY
CLOSELY TREATMENT FIDELITY. IF
YOU DON'T GET SEPARATION BETWEEN
GROUPS IT WILL BE HARDER TO FIND
EFFECT SIZE.
LAST PART THAT IS I THINK ALSO
EXTREMELY IMPORTANT IS RIGHT
OUTCOME VARIABLES AND HOW TO
MEASURE THESE THINGS WHETHER
THEY ARE APPS OR WEARABLES AND
CHANGES IN THE EMR AND COMPOSITE
OUTCOMES AND HOW DO WE ADJUST
FOR A LOSS TO FOLLOW UP?
THEN I THINK THAT THE LAST PART
OF THIS IS WHO PERFORMS
INTERVENTIONS AND JOE RAISED
THIS. IT IS SOMETHING THAT IS A
BIT NEAR AND DEAR TO MY HEART
THAT WE JUST WENT THROUGH A
PANDEMIC AND PEOPLE ARE LEAVING
HEALTH CARE AND HAVING YOU KNOW
WHO IS GOING TO BE ABLE -- WHO
WILL STILL BE AROUND TO DO THESE
INTERVENTIONS IS I THINK
SOMETHING THAT IS IMPORTANT AND
TO JUST SUMMARIZE KIND OF
REVERSE TRANSLATION AND WHAT DO
WE STUDY?
WHO DO WE STUDY?
WHAT ARE RIGHT STUDY DESIGNS AND
HOW DO WE MAKE SURE TREATMENT
INTERVENTION IS DONE IN A
FIDELITY WAY?
WHAT ARE RIGHT OUTCOMES AND
THESE ARE I THINK BASIC
SUMMARIES.
FIRST QUESTION I WOULD LIKE TO
A
ASK.
PLEASE CHIME IN WITH QUESTIONS
IF IN THE CHAT AND I WAS TALKING
ABOUT HOW WE MEASURE BASELINE
FUNCTION IN REHAB TRIALS.
LY ASK DALE THAT DIRECTLY. MATT
HAD TO GO.
DALE, THAT IS SOMETHING YOU HAVE
THOUGHT ABOUT A LOT. HOW DO WE
MEASURE BASELINE FUNCTION?
>> LOWEST HANGING FRUIT IS NOW
STUDIES USE EXISTING INSTRUMENT
AND ENROLL PEOPLE PATIENTS HAVE
HIGH INDEX SCORES THAT CAN BE
EVALUATED IN APPROXIMATELY BY
FAMILY MEMBER AND TIME OF
CONSENT THAT IS BASIC WAY IN
FUNDED RANDOMIZED TRIAL GOING ON
NOW WE HAVE A WALKING DISTANCE
PRIOR TO ICU AND ONE BLOCHL
BASED ON EXISTING INSTRUMENT.
THEY ARE PERFECT WAYS AND
ENROLLING PEOPLE WITH PERFECT
BASELINE FUNCTION AT LEAST USING
EXISTING INSTRUMENTS MOVING
FURTHER DOWN SCALE AND
STRATIFYING AND THINK THAT IS A
FEASIBLE WAY AND PEOPLE HAVE
BETTER IDEAS.
>> DO YOU HAVE A QUESTION?
WANT TO CHIME IN.
>> HIGHLIGHTING JACKS QUESTION
MATTER IF WE MEASURE BASELINE
FUNCTION AND RANDOMIZE ACROSS
BOTH GROUPS EVENLY IS IT SUPER
IMPORTANT TO MEASURE BASELINE
FUNCTION?
>> I THINK IT IS.
INTERVENTION MIGHT HAVE A BIG
IMPACT OUTCOME AND THINK
UNDERSTANDING OUTCOMES WE WANT
TO KNOW SOMETHING ABOUT BOOIS
LINE STATUS FOR INTERP
RECEIPTING IT.
YOU KNOW, TWO RANDOMIZED TRIALS
PUBLISHED IN LANCIT IN MEDICAL
PATIENTS IN US AND CANADA
ENROLLED PATIENTS -- 13 OF
PEOPLIN DEPENDENT LY -- I WOULD
UNDERSTAND DIFFERENTLY BASED ON
KNOWING THAT BASED ON FUNCTION.
I APPRECIATE WHAT JACK IS SAYING
THAT IS IMPORTANT AND NOT DOING
SUPER LARGE TRIAL SUCH IT WILL
MAKE ITS WAY OUT IN THE WASH.
THAT IS MY FEELING.
>> GREAT. THANKS.
ANOTHER QUESTION FROM ME TO YOU
AND MICHAEL AND MARK.
EVERYONE PROPOSED PLATFORM
ADAPTIVE TRIAL WITH
IMPLEMENTATION FOCUS THINK THAT
IS FEASIBLE IN NEAR TERM WITH
REGULATORY CONDITIONS AND TRIALS
AND STRUCTURES AND FUNDING MOON
SHOT PIE IN SKY LOTS OF THINGS
HAVE TO CHANGE BEFORE WE GET
THE
THERE.
>> I DON'T MIND FIRST WE HAVE
BENEFIT OF MULTIPLE OTHER
COUNTRIES REMARKABLE TEAM AT
TORONTO GO LIVE AND LEARNED LAST
THREE YEARS GOING TOGETHER WE
CAN JOIN THEM BIG PROPONENT OF
MULTINATIONAL PLATFORM TRIAL AND
REMAP CAP I DON'T KNOW HOW THEY
ARE FUNDED HE NO REASON THAT
FUNDING AGENCY CAN'T GET
TOGETHER WORKING INTERNATIONALLY
AND I THINK WE COULD -- THERE IS
A REASON TO RELEARN AND WE CAN
ADAPT AND PARTNER UP AND THERE
IS HUGE POTENTIAL THERE IN
SAMPLE SIZE ALONE BEYOND
ANYTHING ELSE.
>> I WILL GIVE TWO CENTS
STEPHANIE. I AGREE WITH MICHAEL
AND THINK IT IS A WAY TO GO. I
THINK THAT PEOPLE SOMETIMES WHEN
THERE IS A NEW IDEA COMING UP
PEOPLE ARE LIKE THIS IS GREAT
AND LET'S DO THIS. WILL ANSWER
ALL PROBLEMS AND CENTRAL IRB IS
GOOD EXAMPLE IF WE HAVE THIS
WON'T HAVE ISSUES AT ALL AND
ISSUES CHANGED A LITTLE BIT AND
THINK IT IS A WAY TO GO AND
DESIGNING THESE AND GETTING THEM
TO BE ALIGNED EFFECTIVELY AND
HOW YOU IMPLEMENT IT AMICHAEL
NOT SURE IF YOU SAID
SPECIFICALLY BUT TAKES A LONG
TIME TO DO THAT MAYBE THREE
YEARS OR SO. WE CAN LEARN FROM
OTHER PEOPLE.
THIS WILL BE A HEAVY LIFT BUT
THINK IT WOULD BE WORTH THE
EFFORT.
THERE IS A QUESTION I HAD AND
WILL ASK MEGAN YOU MIGHT BE
INTUBATING OR TAKING CARE OF
PATIENTS AND NOT SURE IF SHE IS
STILL ON THE CALL BUT QUESTION
IS IT GOT RAISED ABOUT
OBSERVATIONAL STUDIES LOOKING AT
PEOPLE THAT ARE EXCEPTIONALLY
RESILIENT AND WHAT WE CAN LEARN
FROM PEOPLE THAT DON'T DEVELOP
ISSUES AND WHAT IS DIFFERENT
ABOUT THEM. MEGAN, HOW WOULD WE
DESIGN THAT OR IDENTIFY PEOPLE
EARLY ENOUGH THAT MIGHT BE A
STUDY IN ITS OWN WAY WHO PEOPLE
ARE THAT DON'T RUN INTO THE
PROBLEMS MEGAN MIGHT NOT BE ON
THE CALL. DALE, WANT TO ADDRESS
THAT?
IMPORTANT AREA TO LOOK AT?
IF SO, HOW WOULD WE DO THAT?
>> SURE. BORROWING ON EARLIER
EXAMPLES ABOUT TEACHING AND I
THINK ABOUT A PATIENT OF MINE IN
RESEARCH STUDY LONGITUDINAL
RELATIVELY COMPREHENSIVE
COGNITIVE TESTING THIS PERSON
SAID FAMILY SAID THEY WOULDN'T
WANT TO LIVE PRACTICING NURSE
AND COGNITIVE IMPAIRMENT
INDEPENDENT PERSON AND THEY HAD
CARDIAC ARREST IN ICU AND
LONGEST DURATION OF DLEERIUM I
HAD SEEN MONTHS AND DIFFERENT
SERVICES LOOKED LIKE DLEERIUM
AND LOOKED LIKE SOMETHING ELSE
WASN'T CATATONIA OR SOMETHING.
SHE WAS IN STUDY AND ENDED UP
STILL TESTING MONTHS LATER AT
SCORES WELL ABOVE NORMAL VALUES
BACK TO WORK AND SHE FELT SHE IS
PERFORMING RELATIVELY NORMAL AND
WONDERED WHAT IS DIFFERENT ABOUT
THIS PERSON? HOW MANY TIMES
HAVE I MAYBE MADE
RECOMMENDATIONS TO FAMILY
MEMBERS IN PERHAPS IN YOUNGER
YEARS WITH GREATER CONFIDENCE
THAN MAYBE I HAVE.
I THIS I IT IS IMPORTANT TO
LEARN FROM THIS AND THINK AS
JASON WAS SAYING WE WILL NEED TO
EXPAND MEASUREMENT TOOLS TO BE
MANY THINGS OTHER THAN WHAT WE
TYPICALLY MEASURE. WE NEED
OTHER DETERMINANTS OF HEALTH
RATHER THAN FIZZ LOGIC AND
MEDICAL THINGS SOCIAL
DETERMINANTS OF HEALTH THINKING
OF FEASIBLE WAYS TO MEASURE
THOSE THINGS AND MEASURING THEM
ROUTINELY AND THINK THAT SMALL
SAMPLES AND PATIENTS MAY HELP US
BEGINNING TO STIMULATE AROUND
THAT GOING TO DATA AND
RETROSPECTIVELY COLLECTING DATA
ELEMENTS AND TREATMENT EFFECTS
AND DON'T HAVE DETAILED ANSWER
BUT VALUABLE AND INSIGHTFUL WILL
EFFECT CLINICAL CARE AND
DESIGNING INTERVENTIONS AND
UNDERSTANDING DATA AND THINK IT
IS A GREAT IDEA.
>> STEPHANIE, HAVE A QUESTION
THAT YOU WANT TO RAISE?
I HAVE ONE BUT WHY DON'T YOU.
>> I WILL JUMP IN WITH ONE
QUICKLY. WE TALK ABOUT TRIALS
AND MICHAEL BROUGHT UP
OBSERVATIONAL DATA AND WAYS TO
USE OBSERVATIONAL DATA WITH
TARGET TRIAL EMULATION AND
REANALYZING TRIALS WITH BAYESIAN
ANALYSIS FRAMEWORKS AND DO YOU
THINK THAT, THAT -- WE SHOULD
ALSO BROADEN OUR MINDS IN TERMS
HOW WE LOOK AT OBSERVATIONAL
DATA AND LOOKING AT WHAT
INTERVENTIONS MIGHT BE
EFFECTIVE?
IS THERE A BIG OPPORTUNITY FOR
THAT OR THINKING IT IS STILL
TRIALS ALL THE WAY?
>> NOT SURE IF ANYBODY -- I CAN
PUT IN CHAT ARTICLE IN JAMA THIS
WE'RE THERE IS 32 TRIALS AND
THEY DID EMULATED TRIALS AND
RESULTS ARE NOT DISSIMILAR TO
WHAT I SHOWED IN ANDREW'S PAPER.
SO, I MEAN, THINGS YOU NEVER
KNOW TRUTH EVEN IN A TRIAL AND
THINK THERE IS STILL VALUE IN
TRIALS IN LEARNING FROM THEM.
SCIENCE IS GETTING REALLY G I
MEAN, THERE IS ALWAYS AEND USER
AND UP TO THE PERSON EXECUTING
IT BUT ARE REALLY GOOD PEOPLE
THROUGHOUT. MIGUEL AND
[INDISCERNIBLE] AND HAVE BEEN
SEVERAL PAPERS IN THE PANDEMIC
THAT PERFECTLY REPLICATE RESULTS
OF RANDOMIZED TRIALS I USED TO
BE A CHEMIST BUT I'M QUITE
IMPRESSED RECENTLY AND WILL PUT
IT IN THE CHAT.
>> THANKS, MICHAEL.
>> GLAD YOU COULD POINT THAT
OUT.
>> QUESTION FOR MICHAEL ALSO.
I WILL LET YOU TYPE. ONE I WANT
TO SAY IS I THINK YOUR ANALOGY
OF THE FOOTBALL OR SOCCER
STADIUMS IN QATAR IS A REALLY
GOOD ONE. HAVING BEEN TO FOUR
OF THEM I WENT TO ACTUALLY THE
WORLD CUP. IT IS INTERESTING
BECAUSE OUTSIDES ARE VERY
DIFFERENT AND THERE IS ONE BUILT
FROM SHIPPING CONTAINERS AND
INSIDE OF THE STADIUMS WERE VERY
MUCH THE SAME AND WASN'T THAT
EVERYTHING WAS TOTALLY
DIFFERENT.
THERE WAS STANDARDIZATION TO IT
BUT WITH ADAPTATION ON OUTSIDE.
>> YEAH.
>> YOU CAN BETTER HAVE AN
ANALOGY THAT MAYBE YOU REALIZED
AND QUESTION I SHOULD HAVE.
>> [INDISCERNIBLE].
>> OH, OKAY.
>> SORRY NOT TO TAKE YOUR
QUESTION SCOMBL I WILL TALK TO
DEREK ABOUT IT AND LET HIM KNOW.
QUESTION IS ABOUT OUTCOME
VARIABLES AND COMPOSITE OUTCOMES
AND RAISING ISSUE ABOUT WHAT DO
WE DO WITH SHORT-TERM ENDPOINTS
AND [INDISCERNIBLE] WE TRIED TO
IDENTIFY SURROGATE OUTCOMES IN
ICU FOREVER. THEY DON'T WORK
VERY WELL. WHAT IS YOUR THOUGHT
ABOUT DEVELOPMENT OF OR TRYING
TO DEVELOP BETTER SURROGATE
OUTCOMES SO WE DON'T -- SO THAT
NOT EVERY STUDY HAS TO FOLLOW
PEOPLE FOR FIVE YEARS, ET
CETERA?
>> YEAH. I KNOW IT IS ANOTHER
ONE OF THOSE PURSUITS THAT HAVE
BEEN KIND OF FRUITLESS. WE ARE
THINKING ABOUT SUR GASSY AND --
AND USING THIS GROWING KIND OF
USING WHAT I CALL MULTICOMPONENT
RISK SCORES AND MULTIVARIABLE
RISK SCORES DON'T PROVE TO BE
GOOD SEROGATES BUT LIKE CONCEPT
THEY WANT TO FIGURE OUT MONTH 2
OR 3 THAT IS A DIFFERENT TIME
HORIZON WHAT IS SOMEBODY'S RISK
PROFILE AND IS THAT SOMETHING WE
ARE SEEING TWO YEARS LATER? I
DON'T KNOW HOW TO TIE TOGETHER
SUR GASSY MEASURES AND
STATISTICS IS QUITE GOOD AND
CAUSAL DEVELOPMENT IN THE LAST
COUPLE YEARS AND THINK IT IS
WORTH REVISITING SOME HISTORICAL
-- IF WE HAVE DATA WE CAN
REVISIT SOME CONTESTANTS BETTER
AND DON'T RECALL SEEING
SURROGATES ANALYSIS IN CLINICAL
CARE AND STATS THAT ARE FIRST
THOUGHT THAT STATS ARE TIMED AND
SO I THINK IT IS WORTH
REVISITING AND MAYBE THAT IS
ALSO A RESEARCH PRIORITY THAT
COMES FROM THE TALK AND HAPPY TO
HELP IF YOU HAVE THOUGHTS ABOUT
DATA.
NOT A PERFECT ANSWER BUT COULD
BE PROMISING.
>> I THINK IT IS -- I THINK IT
IS AN AREA THAT NEEDS TO BE
DEVELOPED.
>> YEAH.
>> TALKING ABOUT WHAT WE
MEASURE IN OUTCOMES THAT IS VERY
IMPORTANT THAT DIFFERENT THINGS
MEASURE DIFFERENT DOMAINS.
>> YEAH.
>> THEY ARE NOT RIGHT OR WRONG
BUT MEASURING DIFFERENT THINGS
AND WE HAVE TO DESIGN STUDIES
THAT ARE ANSWERING QUESTIONS
THAT WE CAN AND WANT TO ANSWER
AND THEREFORE ALIGN RIGHT
OUTCOME VARIABLE WHAT RIGHT
STUDY IS.
QUESTION IS: ARE THERE -- IS
THERE NEED FOR DEVELOPMENT OF
OTHER OUTCOMES THAT COULD BE
USED FOR SURROGATE OUTCOMES, ET
CETERA?
I THINK ANSWER IS YES,
PERSONALLY.
>> YEAH.
>> BUT, I -- JUST BECAUSE
SOMETHING IS DIFFICULT DOESN'T
MEAN WE SHOULDN'T TRY TO DO IT.
>> I WANT TO TIE BACK THAT I
THINK JIM AND KARLA YESTERDAY
HAD REALLY GREAT INFORMATION AND
IDEAS ABOUT DIFFERENCES AND JIM
ESPECIALLY WITH STANDARDIZED
COGNITIVE FUNCTIONING VERSUS
WHAT IT TAKES TO PERFORM AND IS
VALUABLE TO PEOPLE AND JASON
TALKING ABOUT SOCIAL
DETERMINANTS THAT WE HAVE TO
BUILD INTO RESEARCH MUCH MORE
AND PEOPLE LIKE JASON CAN GUIDE
US INTO WHAT TO DO AND JOHNS
HOPKINS AND EPIDEMIOLOGIST THAT
WILL GET NIH FUNDED R01 THAT
WILL BUILD ON PRIOR RESEARCH TO
LOOK AT ROLE OF HEALTH
EXPECTATIONS AND VERY, VERY
DIFFERENT. WHAT YOU ARE
EXPECTING EARLY ON MIGHT HAVE
BIG IMPACT HOW YOU PERCEIVE LIFE
AFTERWARDS INCLUDING DIIAD
ANALYSIS LOOKING AT PATIENTS
CAREGIVER SPOUSE AND WHAT
EXPECTATIONS ARE AND WHAT
ALLISON IS ALSO TRYING TO MODIFY
THIS IS THIS SOMETHING WE CAN
MODIFY AS CLINICIANS HELPING
PEOPLE EXPECT WHAT TO GET FROM
ICU CLINIC WHEN GETTING TO
FOLLOW UP CLINIC AND LEADING
EDGE IF WE DON'T KNOW ANSWERS
AND IN TURN SHOULD HELP INFORM
THAT AND ONE VARIABLE TO
UNDERSTAND TO LOOK AT PATIENT
REPORTED OUTCOMES LONGER.
>> AWESOME. I THINK WE MIGHT
HAVE TIME FOR ONE MORE QUESTION.
DALE, YOU BROUGHT IT UP A LITTLE
BIT IN YOUR TALK AND DR. SHAR
SHAR ASKED A QUESTION ABOUT
TIMING OF INTERVENTION DELIVERY
AND WHETHER TO BE FOCUSED ON --
OUR INTERVENTIONS IMPROVING
BRAIN AND MUSCLE DISFUNCTION AND
SHOULD THEY BE IN ACUTE OR
WEENING PHASE OR RECOVERY PHASE?
I THOUGHT I THINK IT WAS JASON
WHOSE BIOLOGICAL MODELS ARGUMENT
IS FOCUSING ON RECOVERY AND
INJURY BREAKDOWN FOR MUSCLES
MIGHT BE ADAPTIVE AND FOCUSING
ON RECOVERY PHASE AND INTERESTED
IN WHAT YOU THINK ABOUT TRIAL
DESIGN AND INTERVENTION DELIVERY
TIMING.
>> FOR ME, I THINK THERE IS
ENOUGH DATA THAT EARLIER IS
BETTER.
I THINK THAT IS NOT AN IMPORTANT
QUESTION FOR THE FIELD.
I RECOGNIZE THAT PEOPLE MAY
DISAGREE WITH ME.
I THINK THAT WE SEE CONSISTENTLY
THAT INTERVENTIONS STARTING IN
DAY 1, 2, OR 3 HAVE BETTER
OUTCOMES THAN SAME INTERVENTION
STARTING AROUND DAY 7 LOOKING
FOR EXAMPLE UNIVERSITY OF
CHICAGO'S RANDOMIZED CONTROL
TRIAL 2009 PUBLISHED IN LANCIT
AND RESPIRATORY -- LOOKING AT
SAME INTERVENTION THAT WAS
DELIVERED EARLIER RATHER THAN
LATER AND PRIMARY OUTCOME IN
LAST RANDOMIZED TRIAL PUBLISHED
WEEKS AGO IS IMPROVED COGNITION
ONE YEAR LATER FROM EARLY ONSET
OF OT AND PT INTERVENTIONS
MECHANICALLY VENTILATED PATIENTS
WALKED IN DAY 2 IN THEIR STUDY
WITH LIKE SEDATION SO OTS AND
PTS COULD ACCESS PEOPLES
COGNITION FOR MOBILITY IN DAILY
LIVING AND BEFORE WE HAD MANY
PROBLEMS THAT IS GOOD AND NEEDS
TO BE PAIRED WITH WAKEFULNESS SO
THERE IS A BENEFIT ON THE BRAIN
AND BODY.
>> DO YOU THINK THAT DEPENDS ON
WHAT TYPE OF INTERVENTION IS
BEING DELIVERED OR IS -- DO YOU
THINK CONCEPTUALLY?
>> I THINK CONCEPTUALLY FOR
FUNCTIONAL INTERVENTIONS.
I WOULD PROBABLY EVEN ARGUE FOR
PASSIVE INTERVENTIONS LIKE
NEUROMUSCULAR ELECTRICAL
STIMULATION IN DED PSYCHOGOMTRY
AND WE COULD DO A LARGER
RANDOMIZED TRIAL BUT HAVE ENOUGH
SMALLER TRIALS SHOWING THAT
EARLY COMPARED TO LATE WERE LATE
PATIENTS GETTING BED REST FOR
DAYS CONSISTENTLY IMPROVES
PATIENT OUTCOMES AND THAT IS NOT
SUCH AN IMPORTANT QUESTION AND
SATURDAY BEFORE START OF ATS WE
WILL HAVE A BUNCH OF EXPERTS
COMING TOGETHER TO SPECIFICALLY
BE EXPRESSING THEIR THOUGHTS ON
THAT SORT OF IN A DELPI LIKE
MANNER WHAT EXPERTS THINK RATHER
THAN MY BIASED OPINION. GO
AHEAD.
>> I WILL TRY TO GET ONE MORE
QUESTION IN. WE ACTUALLY HAVE
FIVE YOU KNOW A MINUTE.
MEGAN, ARE YOU STILL BACK ON THE
CALL?
>> AWESOME. QUESTION I HAVE
THAT BUILDS ON WHAT DALE SAID IS
I AGREE, DALE. IT ALWAYS MAKES
SENSE TO START SOMETHING EAR
EARLIER.
QUESTION FOR MEGAN IS PEOPLE
DON'T SPEND THAT MUCH TIME IN
THE ICU. I THINK THAT SOME OF
THESE INTERVENTIONS NEED TO BE
IMPLEMENTED FOR LONGER PERIODS
OF TIME.
WHETHER IT IS ON THE FLOOR OF
THE HOSPITAL OR THEN THEY GO TO
A LONG-TERM CARE FACILITY THAT
YOU LOSE CONTROL OVER THE
INTERVENTION AND PEOPLE
DISAPPEARING LEAVE THE NEXT DAY
IMBEDDED IN LONG TERM CARE
FACILITY AND NOT A LOT OF TIME
OR PLANNING TO COORDINATE THAT
FROM IMPLEMENTATION SCIENCE
STANDPOINT, HOW DO WE WORK IT TO
PROLONG DURATION OF
INTERVENTIONS OR MAKE SURE THAT
THE INTERVENTIONS ARE CONTINUED
ONCE THEY LEAVE THE HOSPITAL?
>> SO, I THINK THERE IS A
COUPLE WAYS TO THINK ABOUT THAT.
ONE, INCREASING TREND THAT WE
ARE SEEING IS CERT CAL
INTEGRATION ACROSS PAYERS AND
SETTINGS AND STRIKES ME VERTICAL
INTEGRATION -- PAYER PAYING FOR
HOSPITAL STAY OWNING LTAC AND
SNIFF AND HAVE EMR THAT
POTENTIALLY IS CAPTURING DATA
ACROSS ALL SETTINGS AT VERY
LEAST YOU MIGHT HAVE DATA KANT
TOO YOU ARE THAT IS USEFUL FROM
STUDY DESIGN PERSPECTIVE WOULD
BE USEFUL TO ENGAGE STAKEHOLDERS
UP FRONT AND FIGURE OUT HOW TO
CREATE SOMETHING THAT IS
WORKABLE AND THINKING BACK TO
SIMILAR POINTS TO MAKE SURE YOU
HAVE CONTROLS IN PLACE TO PICK
UP IF YOU HAVE DROPOFF IN
EARLIER INTERVENTION AND IS
THERE AN ANSWER TO THAT OTHER
THAN BIG TEAM FROM OUTSET THAT
HAS ALL THOSE TRANSITION POINTS
TO LOOK FOR WAYS TO SMOOTH
TRANSITION AND COLLECTION OF
DATA ACROSS SETTINGS.
WE HAVE TO DO IT. PATIENTS ARE
GOING THROUGH THAT.
>> YEAH.
>> STEPHANIE, TURNING IT TO YOU
TO TURN IT OVER TO.
>> YEAH.
>> LOOKS LIKE WE ARE OUT OF
TIME AND THANKS TO THE PANEL AND
AMAZING SET OF SPEAKERS AND TO
THE REST OF THE SESSION. YOU
ASKED GREAT QUESTIONS.
I WILL EXCEPTED IT BACK OVER TO
TERRI AND TIM.
>> THANK YOU, SESSION 4.
WHAT A WAY TO FINISH UP. MY
GOODNESS. DON'T KNOW IF ANYONE
ELSE IS FEELING PRESSURE IN YOUR
HEAD AND FROM ALL OF THE GREAT
IDEAS AND THOUGHTS.
SO, A DEEP BREATH. WE WILL
TRANSITION INTO THE NEXT AND
FINAL PHASE OF OUR WORKSHOP.
AND I RECOGNIZE PEOPLE MIGHT
HAVE TO TAKE A COUPLE MINUTES
AWAY BIO BREAK OR GETTING A
LITTLE BLOOD FLOW TO YOUR LEGS
BUT MOVING INTO BREAKOUT ROOM
>> WELCOME BACK.
THAT TIME WENT REALLY QUICKLY
AND WE WILL MOVE TO THE REPORT
OUT PHASE NOW. EACH ROOM WILL
HAVE FIVE MINUTES TO PRESENT
THEIR THOUGHTS AND KIND OF
HIGH-LEVEL POINTS.
THEN WE WILL HAVE FIVE MINUTES
FOR QUESTIONS FROM THE CHAT AND
ANYONE FROM THE PANEL. WE ARE A
TIGHT KNIT GROUP NOW OF 52.
TURNING IT TO LAUREN