ON BEHALF OF THE DIVISION OF
BLOOD DISEASES I WELCOME YOU TO
THIS WORKSHOP, UNRAVELING
SEPSIS, HEALTH INEQUITIES,
THROMBO INFLAMMATION MECHANIC
NICHES AND AI/ML FRONTIERS.
IT'S A PLEASURE TO HAVE YOU TO
IMPROVE HEALTH OUTCOMES.
I WANT TO TAKE A MOMENT THANK
THE NHLBI, ORGANIZERS, AND THE
CHAIRS, WHO HAVE ALL GRACIOUSLY
SHARED THEIR TIME TO HELP PUT
THIS WORKSHOP TOGETHER.
SEPSIS REMAINS A CRITICAL
CHALLENGE AND CONTRIBUTES TO A
BURDEN OF MORBIDITY AND
MORTALITY.
THE WORKSHOP TODAY AIMS TO
ADDRESS THE COMPLEX CONDITION BY
FOCUSING ON THESE THREE KEY
RESEARCH AREAS, HEALTH
INEQUITIES, MECHANISMS OF
THROMBO INFLAMMATION, AND THE
ROLE OF ARTIFICIAL INTELLIGENCE
AND MACHINE LEARNING IN SEPSIS
RESEARCH.
THREE SESSIONS WILL ADDRESS EACH
AREA, AND THROUGHOUT THE DAY
THERE WILL BE PANEL DISCUSSIONS
TO ALLOW FOR EXCHANGE OF IDEAS.
I'LL NOW TURN IT BACK TO DR.
AGRI WAL.
>> I'M THE PROGRAM DIRECTOR, AND
ON BEHALF OF THE ORGANIZING
COMMITTEE IT'S MY GREAT PLEASURE
TO WELCOME YOU TO THIS NHLBI
SEPSIS WORKSHOP.
THE PURPOSE IS TO BRING TOGETHER
EXPERTS AND STAKEHOLDERS TO
DISCUSS DEVELOPMENTS AND GAPS IN
UNDERSTANDING AND MANAGING
SEPSIS.
WE HAVE ABOUT 200 PARTICIPANTS
WHO HAVE REGISTERED FOR THIS
WORKSHOP, FROM 155
ORGANIZATIONS, WHICH REFLECTS
THE BROAD INTEREST IN THE GLOBAL
HEALTH CHALLENGE.
NEXT SLIDE.
FIRST I WOULD LIKE TO EXTEND
THANKS TO CO-CHAIRS AND
MODERATORS FOR DEDICATION AND
CONTRIBUTIONS OVER SEVERAL
MONTHS, WHICH HAS MADE THIS
EVENT POSSIBLE.
THANK YOU.
NEXT SLIDE.
I WOULD ALSO LIKE TO THANK MY
NHLBI CO-CHAIR FOR HIS INTEGRAL
ROLE IN THE ORGANIZATION OF THIS
WORKSHOP AND OUR NHLBI COLLEAGUE
WHO CO-CHAIRED THE PLANNING OF
THIS WORKSHOP, NOW AT NCI.
FINALLY A SPECIAL THANKS TO THE
ENTIRE WORKSHOP COORDINATING
TEAM THAT WORKED BEHIND THE
SCENES IN ENSURING LOGISTICS.
NEXT.
WHILE THE FIELD OF SEPSIS IS
QUITE BROAD, THIS WORKSHOP HAS
BEEN DIVIDED INTO THREE
SESSIONS, AS DR. PANEPINTO
MENTIONED, EACH EXPLORATION A
CRITICAL AND EMERGING AREA OF
SEPSIS RESEARCH.
THE FIRST WILL EXPLORE
DISPARITIES IN SEPSIS, AN ISSUE
THAT DISPROPORTIONATELY AFFECTS
VULNERABLE POPULATIONS,
UNDERSTANDING THE ROOT CAUSES
AND INFLAWNS -- INFLUENCES.
WE'LL DISCUSS NOVEL MECHANISMS,
EXAMINING HOW IMMUNE SYSTEM
CONTRIBUTES TO SEPSIS
PROGRESSION, IDENTIFYING THERAPY
TARGETS IS A KEY, THIS SESSION
WILL BE BY DR. SUND.
TECHNOLOGIES ARE FOR A PROMISING
FUTURE FOR PERSONALIZED CARE.
THERE BE PANEL DISCUSSION.
I'M CONFIDENT THAT THE
DISCUSSIONS TODAY WILL INSPIRE
NEW IDEAS.
>> WE'RE EXCITED TO HOST THIS
SESSION.
WE'LL COVERED ARRAY OF
DISPARITIES AND IMPACT ON
OUTCOMES AND TOUCH ON MECHANISMS
AS A SEPSIS DISPARITIES AND END
WITH WAYS TO ADDRESS THESE
DISPARITIES.
SO WITH THAT I'D LIKE TO
INTRODUCE OUR FIRST SPEAKER, DR.
CHRISTINA RUDD FROM UNIVERSITY
OF PITTSBURGH, WHO WILL SPEAK
ABOUT THE INFLUENCE OF
COMORBIDITIES ON SEPSIS
INCIDENCE AND OUTCOMES.
>> GOOD MORNING.
THANK YOU FOR HAVING ME.
I'M GOING TO LEAD OFF BY TALKING
ABOUT SEPSIS EPIDEMIOLOGY,
WORLDWIDE, PARTICULARLY IN THE
UNITED STATES, AND THIS REALLY
IMPORTANT ROLE OF COMORBIDITIES,
PARTICULARLY CLUSTERING OF
MULTIPLE COMORBIDITIES IN ONE
INDIVIDUAL, WHICH IS CALLED
MULTI-MORBIDITY.
AND WHAT IMPACT THAT MIGHT HAVE
WHEN WE THINK ABOUT SEPSIS
DISPARITIES IN INCIDENCE AND
OUTCOMES.
NEXT SLIDE PLEASE.
SO, WE KNOW THAT WORK THAT I
HAD -- FROM WORK I DID WITH
COLLEAGUES AROUND THE WORLD
SEVERAL YEARS AGO, WE KNOW
SEPSIS IS A MASSIVE PROBLEM ON A
GLOBAL SCHOOL WITH 50 MILLION
INCIDENT CASES EACH YEAR, 11
MILLION SEPSIS-RELATED DEATHS.
WE KNOW IT'S A BIG PROBLEM, WHAT
ARE WE GOING TO DO ABOUT IT?
WHAT WE FIRST DID IS DRILLED
DOWN ON WHAT'S CAUSING THESE
SEPSIS CASES AND SEPSIS-RELATED
DEATHS, WHAT WE MIGHT BE ABLE TO
DO ONES WE CAN LEARN FROM THAT.
NEXT SLIDE PLEASE.
WHAT WE FIRST DID IS WE
CATEGORIZED THESE DEATHS
ACCORDING TO THE DEATH
CERTIFICATE WHEN THEY DIED, WHAT
THEY PUT AS THE IMMEDIATE CAUSE
OF DEATH ON THE DEATH
CERTIFICATE WAS ALWAYS SEPSIS OR
SEPTIC SHOCK, BUT IN MANY, MANY
OF THESE CASES THE TREATING
CLINICIANS PUT ALL THEIR THINGS
ON THERE THAT IMMEDIATELY LED TO
THIS SEPSIS-RELATED DEATH.
WE FIRST BINNED THOSE ACCORDING
TO WHETHER IT WAS PURELY AN
ACUTE INFECTION THAT'S IN RED
HERE, OR WHETHER THERE WAS
SOMETHING ELSE THAT LED TO THAT
ACUTE INFECTION LIKE AN INJURY
IN YELLOW OR IN BLUE A
NON-COMMUNICABLE CHRONIC DISEASE
LIKE CIRRHOSIS THAT LED TO
SPONTANEOUS PER PERITONITIS OR
STROKE THAT LED TO PNEUMONIA.
AS HE MOVE FROM LOW
SOCIODEMOGRAPHIC ON THE LEFT, ON
THE X-AXIS, TO HIGH SDI ON THE
RIGHT HAND WHERE THE UNITED
STATES SITS YOU CAN SEE AT LEAST
HALF OF SEPSIS-RELATED DEATHS
WORLDWIDE HAVE SOMETHING OTHER
THAN JUST AN ACUTE INFECTION
THAT LED TO THAT SEPSIS DEATH.
AND IN THE U.S. IT'S WELL OVER
50% OF THOSE DEATHS HAD A
NON-COMMUNICABLE CONDITION.
WE CAN ALREADY SEE AT HIGH LEVEL
THERE'S SOMETHING GOING ON HERE.
NEXT SLIDE PLEASE.
WE DUG DOWN FURTHER AND
CATEGORIZED CAUSES AMONG 282
CAUSES, AND LOOKED TO SEE WHAT
ROSE TO THE TOP.
SO WHAT'S LISTED HERE IS THE TOP
20 UNDERLYING CAUSES OF
SEPSIS-RELATED DEATHS AT THREE
TIME POINTS.
ON THE LEFT 1990, MIDDLE IS
2007, RIGHT IS 2017.
MOSTLY I WANT TO DRAW YOUR EYES
TO THE COLOR HERE.
SO, AMONG THE TOP 20 UNDERLYING
CAUSES OF DEATH, PINK IS WHERE
IT WAS INFECTION LISTED AS
UNDERLYING CAUSE, BUT PURPLE IS
A NON-INFECTIOUS CONDITION THAT
LED TO THAT ACUTE INFECTION.
AGAIN, HERE YOU CAN SEE IN THE
TOP 20 YEAR ON YEAR ARE THINGS
LIKE STROKE, CIRRHOSIS, COPD,
DIABETES, CHRONIC KIDNEY
DISEASE, THAT YOU'LL HEAR MORE
ABOUT LATER THIS MORNING.
NEXT SLIDE PLEASE.
WELL, WHAT ABOUT IN THE UNITED
STATES?
I'VE ALREADY TOLD YOU WHEN WE
LOOKED GLOBALLY AND DRILLED DOWN
IN THE U.S., AT LEAST HALF OF
SEPSIS-RELATED DEATHS LOOKED
LIKE THEY WERE RELATED TO A
CHRONIC CONDITION, AND INDEED
AMONG THE 190,000 DEATHS THAT
ARE ESTIMATED TO BE DUE TO
SEPSIS IN THE UNITED STATES EACH
YEAR, AS OF 2017, THE NEXT SLIDE
PLEASE SHOWS THAT 58% OF THESE
DEATHS ARE ASSOCIATED WITH AN
UNDERLYING NON-COMMUNICABLE
DISEASE.
AGAIN, THESE ARE NOT JUST PEOPLE
THAT HAVE A CHRONIC DISEASE,
THESE ARE CASES WHERE THAT
TREATING CLINICIAN WHO WITNESSED
THE STAFF FELT THIS
NON-COMMUNICABLE CONDITION, THE
CHRONIC DISEASE DIRECTLY LED TO
THIS INCIDENCE OF SEPSIS
ULTIMATELY TOOK SOMEBODY'S LIFE.
NEXT SLIDE PLEASE.
SO, WE SEE THIS PATTERN
REPLICATED IN THE LITERATURE FAR
BEYOND WHAT WE DID WITH THE
GLOBAL BURDEN OF DISEASE
PROJECT.
SO THIS PAPER PUBLISHED LAST
YEAR WAS A SCOPING REVIEW OF
OVER 100 ARTICLES, ALL FOCUSED
ON THE UNITED STATES, AND THEY
SET OUT TO EXAMINE THE
RELATIONSHIP BETWEEN SEPSIS
INCIDENCE AND MORTALITY, AND
SOCIOECONOMIC DISADVANTAGE.
WHAT THEY ENDED UP FINDING IS
THAT THERE WAS THIS REALLY
IMPORTANT COMPONENT OF CHRONIC
DISEASE THAT FIT INTO THIS
RELATIONSHIP BETWEEN SEPSIS AND
DISPARITIES.
WHAT THEY FOUND IS THAT
CONSISTENTLY IN PAPER AFTER
PAPER, IN THE SCOPING REVIEW,
THAT AUTHORS WERE FINDING A
RELATIONSHIP WITH THIS
CLUSTERING OF SEPSIS INCIDENCE
AND MORTALITY OR ASSOCIATED
COMPLICATIONS OF SEPSIS IN
NEIGHBORHOODS WITH HIGH
SOCIOECONOMIC DISADVANTAGE,
SIGNIFICANT POVERTY, AT THE SAME
TIME PAPERS WERE REPORTING
CLUSTERING OF CHRONIC
HYPERTENSION AND DIABETES, IN
THE EXACT SAME GEOGRAPHIC
DISTRIBUTION, SUGGESTING MAYBE
THIS POTENTIAL SHARED
PATHOPHYSIOLOGY LINK.
WHAT THE AUTHORS ARE DEPICTING
IN THIS FIGURE HERE IS
HYPOTHESIS BASED ON THEIR
FINDINGS OF THE SCOPING REVIEW
THAT PERHAPS THERE'S SOME
PHYSIOLOGIC LEAN BETWEEN THE RED
STAR ON TOP HERE AND SEPSIS DOWN
IN THE BOTTOM RIGHT CORNER, AND
HYPOTHESIZED THAT VIA
ENVIRONMENTAL TRIGGERS AND I
WOULD SAY I CONCEIVE OF
ENVIRONMENT BROADLY WE'RE NOT
JUST THINKING ABOUT AIR
POLLUTION, I'M SEEING NOT
AUDIBLE.
LET ME PAUSE AND MAKE SURE
EVERYONE CAN HEAR ME.
>> WE ALL CAN HEAR YOU.
>> GREAT.
THANK YOU.
OKAY.
SO, THEY PROPOSED THAT THESE
ENVIRONMENTAL TRIGGERS WERE
LEADING TO ENDOTHELIAL
DYSFUNCTION, WHICH WE'LL HEAR
ABOUT LATER TODAY, AND THIS
DYSFUNCTION IS A SHARED FEATURE
OF THESE CHRONIC DISEASES THAT
WE SEE SHOWING UP CLUSTERING IN
THESE NEIGHBORHOODS WITH STRONG
SOCIOECONOMIC DISADVANTAGE, AND
WE SEE IT AS I'VE JUST SHOWN
CLUSTERING AMONG ACCEPT
'TIS-RELATED DEATHS AND MAYBE
THERE'S A LINK THROUGH THE
ENDOTHELIUM.
IT'S NOT JUST THESE SINGLE
COMORBIDITIES IN ISOLATION BUT
IT'S ACCUMULATION OF
COMORBIDITIES IN IN A SINGLE
INDIVIDUAL THAT PUTS THEM AT
RISK TO DEVELOP AND DIE FROM
SEPSIS.
THIS IS A REALLY NEAT PAPER THAT
WAS PUBLISHED SEVERAL YEARS AGO,
I THINK STILL RELEVANT, DR. BECK
AND COLLEAGUES TOOK ELECTRONIC
HEALTH RECORD DATA IN DENMARK
COVERING ALL HOSPITAL ENCOUNTERS
OVER 18-YEAR TIME PERIOD ACROSS
THE COUNTRY, OVER 6 MILLION
PATIENTS.
AND THEY FOUND THAT IN THE 30
DAYS BEFORE SOMEBODY WROTE CODE
A-41, ICD CODE ON THE FAR RIGHT
OF THE SLIDE HERE, OTHER
SEPTICEMIA, INDICATING SOMEBODY
DIED FROM SEPSIS, CODE A41, BACK
30 DAYS TO SEE WHAT OTHER ICD
CODES HAD SOMEBODY WRITTEN IN
THIS PERSON'S CHART IN THE
PRECEDING 30 DAYS.
AND WHAT THEY FOUND WAS THESE
RECURRENT TRAJECTORIES OF TIME
ORDERED ACCUMULATION OF CERTAIN
COMORBIDITIES ASSOCIATED WITH
SIGNIFICANTLY INCREASED SEPSIS
MORTALITY COMPARED TO PEOPLE WHO
DIDN'T FOLLOW THOSE TIME-ORDERED
TRAJECTORIES.
AND I WANT TO DRAW YOUR EYES TO
SOME OF THESE BIGGER NODES,
PARTICULARLY THE STARTING NODES
ON THE LEFT-HAND SIDE OF THE
SLIDE, DIABETES, ACUTE CORONARY
SYNDROME, HYPERTENSION AGAIN,
ALCOHOL USE DISORDER SHOWING UP
HERE AS REALLY SIGNIFICANT
STARTING POINTS IN THOSE 30 DAYS
PRECEDING SEPSIS-RELATED DEATH.
NEXT SLIDE PLEASE.
OTHERS LOOKED IN THE UNITED
STATES AND REPLICATED SIMILAR
FINDINGS.
THIS STUDY USED THE MIMIC
DATASET WHICH DRAWS FROM 40,000
PATIENTS IN THE UNITED STATES,
PEOPLE ADMITTED TO CRITICAL
CARE, INTENSIVE CARE UNITS.
AND THEY WANTED TO SEE IF THERE
WERE CERTAIN IDENTIFIABLE
SUBGROUPS OF PATIENTS THAT MIGHT
BE ASSOCIATED WITH INCREASED
RISK FOR SEPSIS, IS WHAT THEY
SET OUT TO DO.
SO FIRST THEY USED LATENT CLASS
ANALYSIS TO IDENTIFY DISTINCT
SIX PATIENT SUBGROUPS.
AND WHAT THEY FOUND IS THAT
THESE SIX SUBGROUPS ON THIS LEFT
FIGURE LISTED ACROSS THE BOTTOM
REALLY VARIED IN THE NUMBER OF
COMORBIDITIES THAT INDIVIDUALS
IN THAT GROUP HAD, AND THEY
FOUND THESE GROUPS PARTICULARLY
GROUPS 1, 3, AND 4, THAT HAD
REALLY HIGH MULTI-MORBIDITY
COUNTS.
THESE ARE PEOPLE IN THESE GROUPS
THAT HAVE FIVE, SIX, SEVEN,
SOMETIMES OVER EIGHT
COMORBIDITIES, AND THEY COULD
SEE THAT CLUSTERING BY
COMORBIDITY.
FOR THE GROUPS WITH HIGH
MULTI-MORBIDITY COUNTS, GROUPS
1, 3, AND 4, I WANTED TO SHOW
SOME COMORBIDITIES THAT ARE
SHOWING UP THERE.
AGAIN, YOU CAN SEE IN THE TOP
SUBGROUP 1 HYPERTENSION,
CONGESTIVE HEART FAILURE, IN THE
BOTTOM RIGHT SUBGROUP 4
HYPERTENSION AGAIN, THERE IT IS
WITH DIABETES, AND THE LEFT YOU
CAN SEE ALCOHOL USE, OTHER
SUBSTANCE USE, CLUSTERING WITH
LIVER DISEASE.
SO THEN WHAT THEY DID ON THE
NEXT SLIDE PLEASE IS ONCE THEY
IDENTIFIED SIX SUBGROUPS THEY
TESTED WHETHER MEMBERSHIP IN ONE
OF THESE LATENT SUBGROUPS MIGHT
BE ASSOCIATED WITH RISK FOR
BEING ADMITTED TO ICU WITH ORGAN
DYSFUNCTION OR SEPSIS, THAT'S
THIS PREVALENT GRAPH ON THE
LEFT, OR ULTIMATELY DYING, THE
GRAPH ON THE RIGHT.
SUBGROUPS 1, 3, AND 4 WITH HIGH
LEVELS OF MULTI-MORBIDITY ARE
ALSO THE SUBGROUPS THAT HAVE THE
HIGHEST PERCENT PREVALENCE OF
ORGAN DYSFUNCTION IN SEPSIS,
OTHER THAN SUBGROUP 6, WHICH IS
PATIENTS WITH ADVANCED
CONGESTIVE HEART FAILURE, ON THE
RIGHT THOSE PATIENTS HAD HIGH
MORTALITY.
BUT MY TAKEAWAY HERE IS THAT
MULTI-MORBIDITY IS STRONGLY
ASSOCIATED WITH SEPSIS AND ORGAN
DYSFUNCTION AND PEOPLE IN THE
UNITED STATES ARE DYING FROM
THIS KIND OF CLUSTERING.
NEXT SLIDE PLEASE.
SO, TO SUMMARIZE THIS FIRST KIND
OF MAIN POINTS OF MY TALK I HOPE
YOU CAN SEE THAT COMORBIDITIES,
PARTICULARLY CLUSTERING IS A
STRONG RISK FACTOR.
SOME CONDITIONS AT HIGHEST RISK
ARE ALCOHOL AND OTHER SUBSTANCE
USE, CIRRHOSIS, DIABETES,
HYPERTENSION, CUMULATIVE BURDEN,
PARTICULARLY ACCUMULATED IN
TEMPORAL DISTRIBUTION IS
IMPORTANT AND RISK OF
MULTI-MORBIDITY HAS BEEN
DEMONSTRATED ACROSS POPULATIONS,
AGES, SETTINGS, RESEARCH
THOUGHTS.
LESS WELL KNOWN WITH BETTER
APPROACHES AND MITIGATE.
I'M GOING TO USE LITERATURE TO
PROPOSE A COUPLE IDEAS TO GET US
STARTED IN OUR CONVERSATIONS.
SO IDEA ONE IS WHAT IF WE COULD
USE INNOVATEIVE RESEARCH METHODS
TO BETTER UNDERSTAND WHAT
MULTI-MORBIDITY, IS THIS
BIOLOGIC RISK THROUGH
ENDOTHELIAL DYSFUNCTION OR
DYSREGULATION OF THE IMMUNE
SYSTEM?
OR ARE THERE OTHER INDIVIDUAL
LEVEL RISKS LIKE SOCIAL
DETERMINANTS OF HEALTH,
COMMUNITY LEVEL EXPOSURES, EVEN
SYSTEMIC EXPOSURES THAT MIGHT
HAVE SYNDEMIC RELATIONSHIP OR
CLUSTERING WITH MULTI-MORBIDITY
AND SEPSIS TOGETHER.
THIS IS AN APPROACH I'M TAKING
CURRENTLY USING A GRANT FROM THE
NIH USING HIERARCHICAL MODELING
APPROACHES AND INTEGRATION OF
HEALTH RECORDS AND POPULATION
LEVEL DATA TO FURTHER UNPACK AND
TEASE APART THIS POTENTIAL
SYNDEMIC RELATIONSHIP BETWEEN
MULTI-MORBIDITY AND SEPSIS.
NEXT SLIDE.
IN ADDITION TO DESCRIBING
CLUSTERING OF RISK FACTORS WE
NEED TO UNDERSTAND MORE ABOUT
THE WHY AND HOW.
I THINK EPIGENETIC RESEARCH
WHICH I DO NOT DO BUT AM A BIG
FAN OF IN TERMS OF CONSUMER
LITERATURE, I THINK THIS IS ONE
REALLY INTERESTING AND IMPORTANT
WAY TO FURTHER UNPACK THESE
RELATIONSHIPS.
THIS IS ONE ARTICLE PUBLISHED
EARLIER THIS SUMMER FROM AN
INNOVATIVE SET OF STUDIES
PUBLISHED TOGETHER IN JULY IN
JAMA NETWORK OPEN FROM THE NIMHD
SOCIAL EPIGENOMICS PROGRAM.
AND I WANTED TO SHOW THIS AS AN
EXAMPLE OF THE INCREDIBLE WORK
THAT'S BEING FUNDED BY THE NIH,
PERFORMED ACROSS THE UNITED
STATES, TRYING TO UNDERSTAND THE
ROLE OF EPIGENETICS IN HEALTH,
AND PARTICULARLY IN HEALTH
DISPARITIES.
THIS PAPER'S SPECIFIC OBJECTIVE
TO EVALUATE WHETHER ACCELERATED
EPIGENETIC AGING IS RELATED
AMONG U.S.-BORN INDIVIDUALS IN
SEVERAL STATES.
NEXT SLIDE PLEASE.
>> TWO MINUTES REMAINING.
THANK YOU.
>> PERFECT, THANK YOU.
ANOTHER IDEA IN TERMS OF WHAT WE
MIGHT DO TO FURTHER UNDERSTAND
THIS RELATIONSHIP BETWEEN
MULTI-MORBIDITY AND SEPSIS IS
THINK ABOUT USING THESE TOOLS TO
IDENTIFY THOSE PEOPLE AT HIGHEST
RISK, THESE PEOPLE WITH MULTIPLE
COMORBIDITIES, THAT ARE
CLUSTERING AND ACCUMULATING OVER
TIME.
WE KNOW CERTAIN HIGH-RISK
CONDITIONS, ONCE WE CAN IDENTIFY
THOSE INDIVIDUALS WHAT WE DO TO
PROTECT THEM?
ONE OF THE STRONGEST TOOLS WE
HAVE TO PROTECT THEM IS
VACCINES.
WE KNOW FROM THIS TRIAL
PUBLISHED SEVERAL YEARS AGO THAT
TESTED POLYSACCHARIDE VACCINE
AGAINST PNEUMOCOCCAL VACCINE IN
ADULTS THAT VACCINES WORK TO
PREVENT SEPSIS.
YOU SEE THIS IN THE RIGHT PANEL
THAT THE VACCINE PREVENTS
INVASIVE PNEUMOCOCCAL DISEASE.
ON THE NEXT SLIDE, IS AN EXAMPLE
OF A TRIAL THAT TAKES THAT
EVIDENCE OF KNOWING VACCINES
WORK AND HELPS US PUSH FORWARD
HOW CAN WE BETTER PROTECT PEOPLE
WHO ARE AT RISK OF SEPSIS AND
WHO ARE UNDERVACCINATED, WHETHER
THEY ARE AT RISK DUE TO SOCIAL
RISK FACTORS, OR MEDICAL RISK
FACTORS, OR BOTH.
IN THIS A SLIDE TO THINK ABOUT
INNOVATIVE TRIAL DESIGN AND
THINKING HOW TO PROMOTE VACCINE
UPTAKE.
NEXT SLIDE.
THIS IS YET ANOTHER IDEA OF WHAT
WE MIGHT DO ABOUT THIS.
WHAT IF WE IDENTIFIED THOSE
PATIENTS WITH MULTI-MORBIDITY WE
THINK ARE AT RISK AND GIVE THEM
EDUCATION, MAYBE WEARABLE
DEVICES, IN-HOME ASSAYS, 24-HOUR
NURSE LINES TO REDUCE SEPSIS
EARLY, THERE'S MAJOR CHALLENGES
IN INEQUITY I HOPE WE'LL TALK
ABOUT TODAY BUT THIS IS
PROMISING PARTICULARLY IN THE
SESSION ON A.I. LATER ON TODAY.
NEXT SLIDE.
SO THIS SUMMARIZES FUTURE
DIRECTIONS.
I THINK THAT WE REALLY NEED MORE
EFFECTIVENESS AS WELL AS
IMPLEMENTATION RESEARCH FOCUSING
ON REDUCES SEPSIS INCIDENCE AND
MORTALITY AMONG PEOPLE WITH
COMORBIDITIES, ESPECIALLY
MULTI-MORBIDITIES AND PROPOSED
SOME IDEAS ON INTERVENTIONS THAT
COULD RANGE FROM THOSE THAT
REDUCED IMPACT OF COMORBIDITIES
TO IMPROVING CONTROL OF
COMORBIDITIES, PREVENTING
INFECTION, OR EVEN IDENTIFYING
EARLIER TREATING SEPSIS TO
REDUCE DELAYS.
AND FINALLY I THINK THAT
ACCOUNTING FOR THAT
INTERSECTIONALITY BETWEEN
MEDICAL AND SOCIAL RISK IS
CRITICAL AND LOOK FORWARD TO
CONVERSATION ABOUT THAT.
NEXT SLIDE IS JUST I THANK YOU
FOR INVITING ME TO SPEAK.
>> THANK YOU, DR. RUDD.
THAT WAS FANTASTIC.
I'LL OPEN UP TO QUESTIONS FROM
THE AUDIENCE, ASK A QUESTION OR
PLACE THE QUESTION IN THE CHAT
IF THERE'S QUESTIONS FOR DR.
RUDD.
WE WILL HAVE A DISCUSSION ABOUT
ALL OF THE TALKS IN THIS SESSION
AT THE END, SO WE'LL RESERVE
DISCUSSION FOR THE END.
BUT IF THERE'S A PARTICULAR
QUESTION FOR DR. RUDD PLEASE
FEEL FREE TO ASK THE QUESTIONS.
>> GO AHEAD, YOU HAVE A QUESTIO.
>> DR. ASHANA HAS A QUESTION?
>> WE CAN'T HEAR YOU.
>> SHE DIDN'T HAVE A QUESTION.
OKAY.
SO, WE'LL GO AHEAD AND MOVE ON
THEN AND --
>> CAN I ASK A QUESTION BEFORE
WE MOVE ON?
>> YES, OF COURSE.
>> DR. RUDD, SINCE YOU MENTIONED
ENDOTHELIAL DYSFUNCTION, I WAS
WONDERING IF NEUTROPHIL INVASION
INTO THE SITES OF INFECTION IS
ONE OF THE CAUSES FOR INCREASED
INFECTION BECAUSE OF ENDOTHELIAL
DYSFUNCTION.
I KNOW THIS QUESTION WILL COME
UP LATER ON IN OTHER TALKS ALSO
BUT SINCE YOU MENTIONED IT --
>> GREAT QUESTION.
I WILL ADMIT THAT IT'S OUTSIDE
MY PRIMARY AREA OF EXPERTISE BUT
WILL SAY THERE ARE A LOT OF
INTERESTING HYPOTHESES AROUND
THIS RELATIONSHIP BETWEEN WHICH
COMORBIDITIES ARE REALLY RISING
TO THE TOP IN TERMS OF STRONG
ASSOCIATION WITH SEPSIS AND
MORTALITY, AND I'M INTERESTED IN
KNOWING WHAT IS HAPPENING
CHRONICALLY IN THE IMMUNE SYSTEM
OF FOLKS THAT ARE ACCUMULATING
COMORBIDITIES, PARTICULARLY
THINGS LIKE DIABETES, CHRONIC
KIDNEY DISEASE, HYPERTENSION
THAT SHARE VASCULAR
PATHOPHYSIOLOGY AND HOW THAT
MIGHT PUT PEOPLE AT RISK ONCE
THEY DEVELOP INFECTION, SO I
THINK IT'S A GREAT QUESTION.
>> THANK YOU.
>> ANY OTHER QUESTIONS FOR DR.
RUDD?
>> I HAVE A QUESTION.
WHAT CAN YOU DO ABOUT ALCOHOL
USE DISORDERS, IS THERE ANYTHING
PREVENTIVE CAN YOU DO?
>> YEAH, THAT'S A REALLY
IMPORTANT QUESTION.
I THINK AS -- WHEN I THINK ABOUT
MULTI-MORBIDITY OR THESE
COMORBIDITIES THAT SEEM TO BE
STRONGLY ASSOCIATED WITH SEPSIS,
I THINK ABOUT PREVENTION OR
REDUCING RISK ALONG THE
SPECTRUM.
WE'LL TALK ABOUT IT LATER ON
WITH DR. ES PER AND DR. ASHANA
AS WELL BUT PREVENTING
COMORBIDITIES OR TREATING THEM
WELL ONCE THEY DEVELOP IS
ABSOLUTELY ESSENTIAL BECAUSE IF
WE WAIT TO THE END AND JUST
REDUCE, YOU KNOW, DELAY GETTING
TO THE HOSPITAL ONCE YOU HAVE
SEPSIS WE'RE WAY TOO LATE AND WE
DON'T HAVE A LOT TO CHANGE
OUTCOME AT THAT POINT OTHER THAN
ANTIBIOTICS.
SO, ABSOLUTELY THERE ARE
EFFECTIVE TREATMENTS, I'D SAY
MULTI-MODAL TREATMENTS VALUE FOR
ALCOHOL USE AND OTHER SUBSTANCE
USE DISORDERS, THAT ONCE
SOMEBODY HAS DEVELOPED THOSE,
PLUGGING PEOPLE INTO APPROPRIATE
CARE HOLISTIC WHOLE-PERSON CARE,
I THINK CAN ABSOLUTELY REDUCE
THEIR RISK.
THAT I WILL ADMIT IS MY
HYPOTHESIS.
I THINK WE DON'T HAVE THE DATA
YET, AND WE NEED THE DATA TO
TELL US WHAT DOES HAPPEN IF WE
TREAT THESE COMORBIDITIES WELL
IN TERMS OF PREVENTING SEPSIS
DOWN THE ROAD.
>> CAN YOU HEAR ME NOW?
>> DO YOU HAVE A QUESTION?
>> THANKS FOR A FANTASTIC TALK.
ONE QUESTION FOR YOU IS CURRENT
SEPSIS TREATMENT IS ONE SIZE
FITS ALL, I WONDER OF SOME OF
WHAT YOU'RE PROPOSING THERE MAY
BE DIFFERENT PHENOTYPES WHICH
PEOPLE HAVE ALREADY STARTED TO
PARSE OUT A BIT, AND IS THERE
POTENTIALLY DOWN THE LINE A
DIFFERENT SORT OF TREATMENT THAT
MIGHT BE NEEDED FOR FOLKS WHO
ARE SHOWING UP WITH
MULTI-MORBIDITY AND A LOT OF
SOCIAL RISK FACTORS AS WELL?
>> YEAH, I THINK THAT'S A GREAT
POINT.
ABSOLUTELY, I DO THINK THAT
THERE ARE MULTIPLE PHENOTYPES OF
SEPSIS.
DR. SEYMOUR AND OTHERS HAVE DONE
NIGHT WORK IN THAT SPACE.
AND THEY HAVE -- MOST OF THE
WORK I'M AWARE OF HAS PRIMARILY
FOCUSED ON THE ORGAN DYSFUNCTION
THAT'S PRESENT AT THE TIME THAT
PATIENT IS IDENTIFIED AND
ADMITTED WITH SEPSIS.
RATHER THAN LOOKING AT THE ORGAN
DYSFUNCTION THAT'S PRESENT IN
THE DAYS, WEEKS, MONTHS, YEARS
PRIOR TO THAT.
AND SO I GUESS WHEN I THINK
ABOUT SEPSIS TREATMENT, AGAIN, I
TEND TO THINK IN A MORE HOLISTIC
PUBLIC HEALTH PERSPECTIVE WHICH
IS, YES, FOR SURE, THERE
PROBABLY ARE DIFFERENCES IN
TREATMENT OF THAT ACUTE EPISODE
OF SEPSIS BUT THERE ARE PROBABLY
REALLY IMPORTANT DIFFERENCES IN
HOW WE'RE GOING TO PREVENT
SEPSIS, DEPENDING ON DIFFERENT
PEOPLE'S RISK FACTORS, AND THEN
ALSO HOW WE'RE GOING TO PREVENT
READMISSION WITH SEPSIS, WHICH
WE KNOW IS COMMON AFTER PEOPLE
HAVE BEEN HOSPITALIZED WITH
SEPSIS, AND I'M EXCITED TO HEAR
PEOPLE'S THOUGHTS IN THE
WORKSHOP TODAY ABOUT HOW WE
MIGHT USE INNOVATIVE RESEARCH
APPROACHES, TECHNOLOGIES, TO
PERSONALIZE THAT ACCORDING TO
THE PRESENCE OF MEDICAL AS WELL
AS SOCIAL RISK FACTORS.
>> THANK YOU, DR. RUDD.
>> THANK YOU.
>> WE'RE GOING TO MOVE ON TO OUR
NEXT TALK, I'D LIKE TO INTRODUCE
DR. GREG MARTIN FROM EMORY
UNIVERSITY, DISCUSSING MORE
SPECIFICS ABOUT COMORBIDITIES
AND IMPACT ON HEALTH
DISPARITIES.
>> THANK YOU, DR. ESPER.
I APPRECIATE THE OPPORTUNITY, A
TERRIFIC WORKSHOP, APPRECIATIVE
OF THE CHANCE TO PARTICIPATE AND
LEARN FROM EVERYONE HERE.
SO I'M GOING TO SHARE MORE ABOUT
COMORBIDITIES AND
MULTI-MORBIDITY AND WHAT I'LL
SHARE REALLY WILL COMPLEMENT
WHAT KRISTINA RUDD JUST
DESCRIBED, THINKING PARTICULARLY
WHERE THESE FIT TOGETHER WITH
THE DIFFERENT COMORBIDITIES AND
DISPARITIES THAT WE SEE IN
HEALTH INEQUITIES AND HOW THOSE
PLAY TOGETHER.
NEXT SLIDE.
I DON'T HAVE ANY CONFLICTS OF
INTEREST.
I'VE WORKED IN SEVERAL AREAS
RELATED TO SPACES.
GO AHEAD TO THE NEXT SLIDE.
I WILL JUST TOUCH ON THE FACT
THAT SEPSIS IS VERY, VERY
IMPORTANT, AS CHRISTINA
MENTIONED IT'S ONE OF THE MOST
COMMON DISEASES IN THE WORLD,
ALSO THE NUMBER THREE LEADING
CAUSE OF DEATH IN THE UNITED
STATES.
IT ACCOUNTS FOR SUBSTANTIAL
NUMBER OF HOSPITAL DEATHS.
OFTEN IS UNDERESTIMATED
PARTICULARLY IN RELATION TO
OTHER COMMON DISEASES WHERE WE
SEE A LOT OF RESOURCES AND A LOT
OF ATTENTION.
NEXT SLIDE.
I WANT TO FOCUS ON RISK FACTORS,
THINKING ABOUT RISK FACTORS
PARTICULARLY AS THEY RELATE TO
COMORBIDITIES, HEALTH EQUITY,
AND DISPARITIES.
NEXT SLIDE.
SO LET'S START HERE IN THE TOP
RIGHT-HAND CORNER, YOU SEE AGE
AS A RISK FACTOR FOR SEPSIS.
WE'LL TOUCH ON THAT.
ON THE LEFT HAND WHAT YOU SEE IS
THINGS LIKE RACE OR ETHNICITY,
AND GENDER AS RISK FACTORS FOR
SEPSIS, LOWER RIGHT-HAND CORNER
WHAT YOU SEE IS ONE WAY TO THINK
ABOUT THE VARIETY OF
COMORBIDITIES THAT MIGHT COME
TOGETHER.
WHAT I REALLY WANT TO FOCUS ON
IS WHAT UNDERLIES THESE RISK
FACTORS AND HOW DO THEY PLAY OUT
NOT ONLY IN INDIVIDUALS BUT IN
COMMUNITIES.
NEXT SLIDE.
LET'S START WITH GENDER
INFLUENCE IN SEPSIS, THIS IS
DATA WE GENERATED ABOUT 20 YEARS
AGO NOW LOOKING AT SEPSIS
INCIDENCE AND OUTCOME OVER MANY
YEARS IN THE UNITED STATES.
FROM A GENDER PERSPECTIVE WE SAW
MEN WERE 30% MORE LIKELY TO
DEVELOP SEPSIS, REALLY EVERY
YEAR COMPARED TO WOMEN.
NEXT SLIDE.
BUT THERE'S SEVERAL OTHER
ELEMENTS THAT COME TOGETHER
HERE, PARTICULARLY IF YOU'RE
TRYING TO UNDERSTAND THE GENDER
DISPARITIES THAT EXIST IN SEPSIS
INCIDENCE, ONE WAY TO THINK
ABOUT THAT WOULD BE ALSO THEN TO
THINK ABOUT COMORBIDITIES.
IN THIS SLIDE WHAT YOU SEE, THIS
IS DATA GENERATED BY ANNETTE
ESPER, COMORBIDITIES TRACK WITH
GENDER.
THE FIRST TWO ON LEFT, DIABETES,
MEN IN BLUE, WOMEN IN PINK, MEN
ARE MUCH MORE LIKELY TO HAVE
DIABETES.
WE KNOW DIABETES IS A STRONG
RISK FACTOR FOR INFECTION.
WE ALSO HAVE DATA ABOUT DIABETES
AND SEVERAL COMORBIDITIES YOU
ALSO SEE DISPROPORTIONATELY
REPRESENTED IN MEN COMPARED TO
WOMEN, HIV, COPD, CHRONIC KIDNEY
DISEASE, CANCER, ALCOHOLISM, ALL
THOSE PLAY A ROLE AND ARE
DISPROPORTIONATELY REPRESENTED
IN MEN COMPARED TO WOMEN.
THEY MAY WELL UNDERLIE SOME
DIFFERENCES IN SUBSTANCE
INCIDENCE THAT WE SEE.
NEXT SLIDE.
THERE'S OTHER THINGS WE SEE AS
WELL.
FOR INSTANCE, MEN ARE MORE LIKE
THROW HAVE GRAM POSITIVE
INFECTIONS.
YOU MIGHT INTUIT THAT'S RELATED
TO THE COMORBIDITIES, BUT ALSO
MAY BE RELATED TO TYPES OF
INFECTIONS THEY GET.
FOR INSTANCE, IN MEN, MEN ARE
MUCH MORE LIKELY TO DEVELOP
RESPIRATORY INFECTIONS, WOMEN
GENITOURINARY INFECTION, BUT I
WANT TO COME BACK TO THIS.
IT'S NOT AS SIMPLE AS WE'D LIKE
TO THINK IN TERMS OF GENDER
DISPARITIES, TYPES OF
INFECTIONS, EVEN BACTERIA
CAUSING THEM.
NEXT SLIDE.
SO LET'S JUMP FORWARD AND TALK
ABOUT RACIAL DISPARITIES USING
THE SAME DATA WE GENERATED
SEVERAL YEARS AGO.
THIS IS LOOKING AT RACE AND
ETHNICITY.
AFRICAN AMERICANS TWICE AS
LIKELY TO DEVELOP SEPSIS THAN
CAUCASIANS, BUT LOOK AT
COMORBIDITIES DISTRIBUTED BY
RACE, A RATE RATIO OR RISK
RATIO, SO ONE IS REFERENCE
VALUE, ANYTHING ABOVE ONE WOULD
IMPLY DISPROPORTIONATE
REPRESENTATION, HIV IS HIGHER
RISK OR REPRESENTATION IN
PATIENTS WHO ARE SELF-IDENTIFY
OR IDENTIFIED BY HEALTH SYSTEM
AS BLACK, ALSO TRUE FOR OTHER
RACES, BUT THERE'S OTHER
DISEASES INCLUDES DIABETES,
ALCOHOLISM, CHRONIC KIDNEY
DISEASE THAT ARE
DISPROPORTIONATELY REPRESENTED
AND DO TRACK WITH RACE AND
ETHNICITY.
NEXT SLIDE.
I WANTED TO TOUCH ON THE FACT
THERE ARE DIFFERENCES IN
ORGANISMS BUT ALSO DIFFERENCES
IN ORGANISMS WE MIGHT THINK ARE
RELATED TO THE SOURCE OF
INFECTION BUT WHAT YOU SEE HERE
USING THE SAME DATA, YOU SEE
HERE RACE PLOTTED ON THE FAR
AXIS, THE SOURCE OF INFECTION
PLOTTED ON THE X-AXIS IN FRONT,
PROPORTION OF GRAM-POSITIVE
INFECTIONS.
IN THE BACK LEFT-HAND CORNER
BLACKS WHO HAVE RESPIRATORY
INFECTION ARE MORE LIKELY TO
HAVE GRAM POSITIVE INFECTIONS,
WHICH MAY WELL CONNECT THIS MORE
TO THE SOCIAL DETERMINANTS AND
CO-MORBIDITIES THAN SOURCE OF
INFECTION BECAUSE WITHIN THE
SOURCE OF INFECTION THERE'S
STILL A DIFFERENCE IN ORGANISMS
THAT HAS TO BE EXPLAINED BY
OTHER FACTORS.
SO LET'S KEEP JUMPING FORWARD
NOW.
NEXT SLIDE.
WHAT UNDERLIES RACIAL
DISPARITIES SEPSIS INCIDENCE?
SEVERAL PEOPLE TACKLED THIS.
WE'LL HEAR MORE IN THE NEXT
TALKS AND REST OF THE DAY.
BUT SOME SUGGESTED THERE IS
INCREASE IN RISK OF INFECTION,
UNDERLYING INCITING EVENT, THERE
MAY ALSO BE RISK FOR INCREASED
ORGAN DYSFUNCTION, SEPSIS
PHENOTYPE MEANING WHAT HAPPENS
TO PATIENT AS THEY REPRESENT
SEPSIS, IMMUNE DYSFUNCTION THAT
LEADS TO ORGAN DYSFUNCTION
CAUSING SEPSIS.
SO THIS IS DATA AGAIN LOOKING BY
AGE, SHOWING PEOPLE WHO ARE
IDENTIFIED AS BLACK HAVE HIGHER
RISK OF INFECTION, ALSO HIGHER
RISK OF ORGAN DYSFUNCTION, THAT
SEEMS TO BE TRUE EVEN AT THE
EARLIEST STAGES WHICH IMPLIES
MAYBE THERE'S MORE IT TO, MAYBE
SOCIAL DETERMINANTS, MAYBE OTHER
FACTORS AS WELL.
NEXT SLIDE.
JUSTIN MOORE LOOKED AT THIS
WITHIN DIVERSE RESEARCH COHORT,
ACROSS AREAS OF PARTICULARLY
DIVERSE COHORT FOR
CARDIOVASCULAR REASONS,
REPRESENTED ACROSS THE UNITED
STATES.
I PUT HERE IN THE LAST COUPLE
LINES MAYBE WHAT'S MOST
IMPORTANT FROM THIS THAT MAYBE
THE RISK OF SEPSIS WAS NOT THAT
DIFFERENT BASED ON RACE, MEANING
GIVEN INFECTION WAS THE RISK OF
SEPSIS, THIS IS THE OLDER
DEFINITION OF SEPSIS MEANING
PATIENTS WHO HAD CRITERIA AND
MANIFESTATION THAT MIGHT HAVE
RESULTED IN HOSPITALIZATION BUT
GIVEN SEPSIS MEANING THAT
INCIDENT INFECTION WITH
INFLAMMATORY RESPONSE, ORGAN
DYSFUNCTION WAS MORE FREQUENT IN
BLACKS, SOMETHING WE'VE SEEN,
KRISTINA RUDD TALKED ABOUT THAT.
NOW WE'RE TALKING MORE ABOUT
COMORBIDITIES AND LINK TO ACUTE
ORGAN DYSFUNCTION.
ONE WAY TO THINK ABOUT THIS IS
RISK FACTORS FOR SEPSIS, GRAPH
SHOWING LONGITUDINAL INCREASE IN
RISK OF SEPSIS AT AGE BEYOND 50,
INCREASES OVER TIME.
USED DICHOTOMOUSLY, THE
GOVERNMENT DEFINITION OF AGE OF
65, YOU GET A RELATIVE RISK OF
13 TIMES, PEOPLE OVER AGE 65, 13
TIMES MORE LIKELY TO DEVELOP
SEPSIS THAN PEOPLE WHO ARE
YOUNGER.
NEXT SLIDE.
WHAT UNDERLIES THIS?
THIS IS THE CONNECTION BACK TO
HOW WE UNDERSTAND NOT JUST
SOCIAL DETERMINANTS BUT
PARTICULARLY COMORBIDITIES,
SPECIFICALLY.
WE KNOW BLACKS, PEOPLE
IDENTIFIED AS BLACK, DO DEVELOP
SEPSIS AT THE YOUNGEST AGE ON
AVERAGE, SEPSIS OCCURS IN PEOPLE
BETWEEN 60 AND 65 YEARS OF AGE.
IN BLACK INDIVIDUALS, SEPSIS
OCCURS MUCH YOUNGER, USUALLY
BETWEEN 45 AND 50 YEARS OF AGE,
BUT WE ALSO KNOW FROM OTHER DATA
THAT BLACKS, ADULT BLACKS, USING
THE HER STUDY, DEVELOP
MULTI-MORBIDITY AT EARLIEST
STAGE, LOOKING AT OTHER
ETHNICITIES THEY DEVELOP CHRONIC
DISEASE AT FASTER RATE.
WE'RE TALKING ABOUT DIFFERENT
ELEMENTS, HOW THESE MIGHT PLAY
OUT.
WE KNOW FROM WHAT I SHOWED
EARLIER COMORBIDITIES CONTRIBUTE
TO RISK FOR SEPSIS, WE'VE SEEN
THAT, MAY WELL INTO THE RACE AND
GENDER DISPARITIES WE SEE BUT
NOW WE'RE SEEING INFLUENCE ON
AGE, HOW AGE IS A STRONG POTENT
RISK FACTOR FOR SEPSIS AS WELL.
NEXT SLIDE.
I'LL TALK ABOUT CANCER
SIMILARLY, IF YOU USE CANCER AS
A PROTOTYPE DISEASE, SO CANCER
PATIENTS ARE TEN TIMES MORE
LIKELY TO DEVELOP SEPSIS
COMPARED TO PATIENTS WHO DON'T
HAVE CANCER.
NEXT SLIDE.
AND IF YOU USE CANCER AS ONE
PHENOTYPE, IT'S ACTUALLY VERY
COMMON AND CANCER TURNS OUT TO
BE MAYBE THE MOST FREQUENT.
HIV INCREASED OVER TIME.
THESE ARE DATA FROM SEVERAL
YEARS AGO NOW.
IT LOOKS LIKE NOW IF YOU LOOK AT
THESE DATA MORE RECENTLY CANCER
AND HIV ARE PROBABLY SIMILAR IN
INCIDENCE RATES FOR SEPSIS BUT
AVERAGE RATE IS YELLOW LINE
ACROSS THE BOTTOM THAT YOU SEE,
300 CASES PER 100,000.
BUT CANCER, HIV, COPD AND EVEN
HEART DISEASE ARE RISK FACTORS
FOR DEVELOPING SEPSIS.
KRISTINA SHOWED YOU THAT NIGHT
FIGURE THAT DISPLAYED SOME OF
THOSE INCITING EVENTS, HOW THEY
PLAY OUT IN THE PLOT BUT WE KNOW
THESE ARE CONTRIBUTIONS NOT JUST
IN THE RISK FOR INFECTION BUT IN
RISK OF ORGAN DYSFUNCTION AS
WELL.
NEXT SLIDE.
WE'VE STUDIED THIS IN OUR OWN
HOSPITAL SYSTEM, A COUPLE TIMES
NOW.
ONE OF THE THINGS APPARENT, IF
YOU'RE TRYING TO UNDERSTAND
WHETHER IT CONTRIBUTES TO ORGAN
DYSFUNCTION IT'S LESS CLEAR.
WE SEE THAT SIGNALS SUCH AS
ORGAN DYSFUNCTION ARE STRONG
PREDICTORS.
WE FOUND THEY WERE HOSPITALIZED
WITH LOW CD4 COUNT, NOT ON
ANTIRETROVIRAL THERAPY, STRONG
RISK FACTORS FOR INFECTION,
STRONG RISK FACTOR FOR MORTALITY
AS WELL.
NEXT SLIDE.
IF YOU USE ADJUSTED ANALYSIS,
LOOK AT OTHER VARIABLES THAT
MIGHT PREDICT THIS WHAT YOU SEE
IS HIV HAS AN ODDS RATIO OF 2
FOR MORTALITY, INCLUDING
SEVERITY OF ILLNESS, THIS IS
TRACKS WITH INCREASED RISK OF
INFECTION, TRACKS TO INCREASED
RISK OF HOSPITAL MORTALITY,
WHAT'S LESS CLEAR IS OBVIOUSLY
THE SOCIAL DETERMINANTS THAT GO
ALONG WITH HIV WHICH WE DO
UNDERSTAND BUT WHETHER IT
CONTRIBUTES TO ORGAN
DYSFUNCTION, WE'VE SEEN IN OTHER
PHENOTYPES FOR INSTANCE CANCER,
WHERE RISK OF INFECTION IS TIED
TO SOURCE OF CANCER, RESPIRATORY
INFECTION AND CANCERS TEND TO GO
TOGETHER BUT ORGAN DYSFUNCTION
AS WELL.
THE QUESTION REMAINS, IT'S
REALLY BEEN POSED IMPORTANTLY
HERE TODAY, IS MULTI-MORBIDITY
IS A MAJOR COMPONENT OF SEPSIS
AND WHY SEPSIS OCCURS AT ALL, SO
THIS IS A CASE PROPORTION
REPRESENTING COMORBIDITIES THAT
WE SEE AMONG SEPSIS PATIENTS,
AND CLEARLY SOME OF THESE ARE
THINGS RISK FACTORS FOR
INFECTION, THINGS LIKE CANCER,
COPD, CHRONIC KIDNEY DISEASE,
BUT SOME LESS SO.
YOU SEE HIV IS LOWER PROPORTION
BUT THE REASON I SHOWED HIV AS A
SPECIFIC COMORBIDITY IS IN
CERTAIN SUBSETS OF PATIENTS WITH
HIV THE RISK IS MUCH HIGHER, WE
DO KNOW THERE'S A STRONG
COMPONENT OF SOCIAL DETERMINANTS
AND HEALTH EQUITY THAT PLAYS OUT
IN HIV AS WELL.
I WANT TO SUMMARIZE TALKING
ABOUT CHRONIC CO-MORBIDITIES,
CLEARLY THE PRESENCE OF
COMORBIDITIES MAY BE SIMILAR
BETWEEN RACES BUT OCCURS WITH
GREATER SEVERITY IN BLACKS AND
MALES, THAT PLAYS A ROLE IN SOME
DISPARITIES THAT WE SEE IN
INCIDENCE OF SEPSIS.
THE RISK OF ORGAN DYSFUNCTION
INCREASES WITH NUMBER AND
SEVERITY OF CHRONIC CONDITIONS,
WHEN WE'RE TALKING ABOUT
INDIVIDUAL CONDITIONS SOME ARE
MORE SEVERE, SOME REPRESENT --
HIV FOR INSTANCE LOW CD4 COUNT,
NOT ON ANTIRETROVIRAL, HAS
HIGHER RISK OF DEVELOPING SEPSIS
AND SEPSIS-RELATED MORTALITY BUT
ALSO THE NUMBER OF COMORBIDITIES
AS WELL WHICH KRISTINA SHOWED,
THE CUMULATIVE EFFECT RESULTS OR
REPRESENTING MULTI-MORBIDITY,
WHAT I SHOWED IS THAT A LOT OF
COMORBIDITIES ARE MORE RAPIDLY
DEVELOPED, CUMULATIVELY AND OVER
TIME, IN NON-CAUCASIAN OR
NON-WHITE RACES.
HOW WE UNDERSTAND SOCIAL
DISPARITIES, DISPARITIES THAT
RESULTS, HOW WE MIGHT APPLY IN
SEPSIS.
IF WE UNDERSTAND WHAT LOOKS LIKE
SEPSIS MORTALITY, SO ONE WAY TO
THINK ABOUT IT, DARKER STATES OR
PLACES WITH HIGHER NUMBERS OF
DEATHS, YOU WITH BREAK THIS IN
CLUSTERS.
ACROSS THE UNITED STATES THERE'S
HOT SPOTS OF WHAT I CALL HOT
SPOTS FOR SEPSIS MORTALITY.
YOU'RE SEEK THE STROKE BELT AND
CARDIOVASCULAR DISEASE BELT.
IN THESE AREAS ACROSS THE
SOUTHEAST UNITED STATES AND
PARTICULARLY FOR US IN GEORGIA
THAT AREA ACROSS MIDDLE GEORGIA
IN THE MIDDLE THAT REPRESENTS
SOUTH OF ATLANTA IS AN AREA WITH
RELATIVE HEALTH CARE DESERTS,
HIGH RATE OF MOMENTS, THEY ARE
TIGHTLY TIED TO COMORBIDITIES IN
THOSE AREAS AS WELL.
NEXT SLIDE.
IN CONCLUSION I KNOW YOU REALIZE
HOW IMPORTANT SEPSIS IS.
IT IS ONE OF THE MOST COMMON AND
LETHAL DISEASES WE DEAL WITH.
WE CLEARLY SEE IT ALL OVER THE
WORLD, THE MORTALITY IS TIED TO
ATTENTIVENESS AND EFFORTS TO
IDENTIFYING SEPSIS PARTICULARLY
IN A TIMELY MANNER, HAVING
THINGS IN PLACE TO PREVENT AND
TREAT THE DISEASE.
COMORBIDITIES AS I'VE SHOWN ARE
NOT JUST COMMON IN SEPSIS, THEY
ARE THE RULE.
THEY ARE THE THING WE SEE VERY
COMMONLY AND BOTH -- THEY ATTACH
OR ASSOCIATE TO THE RISK OF
SEPSIS, RISK OF ORGAN
DYSFUNCTION AND MORTALITY THAT
GOES WITH IT.
AND THE RACIAL AND GENDER
DISPARITIES, EVEN OTHER THINGS
WE SEE IN DISPARITIES IN UP
SEPSIS ARE TIED TO PRESENCE OF
COMORBIDITIES, NUMBER OF
COMORBIDITIES, SPECIFIC TYPE OF
COMORBIDITY AND SEVERITY AS
WELL.
THANK YOU VERY MUCH.
YOU CAN GO TO THE NEXT SLIDE.
>> WE HAVE TIME FOR ONE
QUESTION.
STATE YOUR NAME AND INSTITUTION.
A QUESTION IN THE CHAT, GREG,
THE PRESENTATION SUGGESTS
INCREASED RISK OF DEVELOPING
SEPSIS BASED ON RACE OR
ETHNICITY.
IN U.S. THESE GROUPS TEND TO BE
SOCIOECONOMIC GROUPS THAT
STRUGGLE.
IS THERE STRATIFICATION, DOES
THE RATE OF SEPSIS AND MORBIDITY
REMAIN THE SAME RACIALLY?
>> YEAH, IT'S A REALLY GOOD
QUESTION.
HOW MUCH MUCH DISPARITIES IN
SEPSIS INCIDENCE, PARTICULARLY
WHEN YOU ADJUST FOR
SOCIOECONOMICS, NOT DONE AS
OFTEN, MORE DIFFICULT TO DO, IT
MITIGATES EFFECT BUT DOESN'T GO
AWAY.
SO WHEN I THINK ABOUT IT, IT'S
ONE OF THE COMPONENTS, AND I
THINK IT'S STILL DIFFICULT TO
ADJUST FOR THAT COMPLETELY,
RIGHT?
BUT AT THE SAME TIME IT DOESN'T
SEEM LIKE IT MAKES THE ENTIRE
DISPARITY GO AWAY OR BECOME
DIFFERENT, BECOME THE SAME FOR
ALL THE STRATA, FOR INSTANCE.
>> I HAVE A QUESTION.
>> GO AHEAD.
>> I SAW YOUR MAP, THE BELT YOU
SHOWED US ALSO HOT AND HUMID
REGIONS OF THE -- ESPECIALLY IN
THE U.S.
DO YOU THINK THAT PLAYS?
>> SORRY, THE REGIONS --
>> THE REGIONS, ATLANTA AND
THOSE AREAS, SOUTHERN AREAS,
ALSO THE AREAS MORE HUMID AND
HOT.
>> OH, I SEE.
>> DOES THAT PLAY OR DO YOU SEE
ALL THE OVER THE GLOBE THE BELT
PLAYS A ROLE?
>> IT'S A GOOD QUESTION, IT MAY
BE ONE KRISTINA WANTS TO THINK
ABOUT FROM GLOBAL PERSPECTIVE
BUT I DON'T THINK THAT IS THE
ANSWER COMPLETELY LARGELY
BECAUSE WE'VE SEEN SIMILAR DATA
OVER MANY YEARS, I WOULD NOT AT
ALL DISPUTE CLIMATE CHANGE
CERTAINLY IS CHANGING BOTH THE
ORGANISMS AND SUSCEPTIBILITY,
BUT I DON'T THINK IT EXPLAINS
WHAT WE'RE SEEING ON THAT
GEOGRAPHIC COUNTY-BY-COUNTY
LEVELS, IT'S MORE RELATED TO
COMORBIDITIES, ACCESS TO HEALTH
CARE, EDUCATION, SOCIAL
DETERMINANTS THAT WE THINK OF AS
INVARIABLY IN PLACE AND
CONTRIBUTING MORE STRONGLY.
>> ONE MORE QUESTION, ADAM
LEVINE AT BROWN.
SO, FROM KRISTINA, SORRY,
INTERESTING WORK ON RELATIONSHIP
BETWEEN ENVIRONMENT AND SEPSIS.
THANK YOU.
>> WHICH DEFINITELY EXISTS BUT I
DON'T THINK AT LEAST THE HEAT
MAPS, WHAT I'M THINKING OF HOT
SPOT MAPS, I DON'T THINK IT
EXPLAINS ALL OF THAT.
>> THANK YOU.
WE'LL MOVE TO THE NEXT SPEAKER,
DR. CHRISTOPHER CHESLEY,
UNIVERSITY OF PENNSYLVANIA,
DISCUSSING MECHANISMS OF RACIAL
DISPARITIES IN SEPSIS.
>> CAN EVERYONE HEAR ME?
>> YES.
>> THANKS FOR THE INTRODUCTION.
THANKS FOR EXTENDING THE
OPPORTUNITY TO GIVE THIS
PRESENTATION, TO BE PART OF
DIALOGUE WITH PROMINENT
RESEARCHERS IN THE FIELD.
I'M CHRISTOPHER CHESLEY,
ASSISTANT PROFESSOR OF MEDICINE,
ADULT PULMONARY CARE MEDICINE,
UNIVERSITY OF PENNSYLVANIA.
I'VE BEEN TASKED TO TALK ABOUT
MECHANISMS OF RACIAL
DISPARITIES, A TALK THAT'S GOING
TO DOVETAIL WITH THE TWO
PREVIOUS AND ADD TO THE
CONVERSATION DIFFERENT THAN WHAT
WE'VE BEEN DISCUSSING SO FAR.
NEXT SLIDE.
I'M FUNDED BY A DEVELOPMENT
AWARD FROM NHLBI.
NEXT SLIDE.
OBJECTIVE OF THE TALK, DISCUSS
SEPSIS RELEVANT DEFINITION OF
RACISM, IDENTIFY KNOWN
DISPARITIES RELATED TO SEPSIS,
DISCUSS SOME MOST RESEARCH
THEORIES FOR MECHANISMS,
EVALUATE STRENGTH OF THEORIES
THAT KIND OF ENCOMPASS
MECHANISMS AND DESCRIBE FUTURE
DIRECTIONS.
NEXT SLIDE.
WHY IS IT IMPORTANT TO BEGIN THE
CONVERSATION WITH DEFINITION OF
RACISM?
HOW IT'S RELEVANT TO THE DISEASE
OF SEPSIS IN PARTICULAR.
IT'S IMPORTANT TO ACKNOWLEDGE
ADVERSE OUTCOMES WHICH WE
DISCUSS IN CONTEXT OF RACIAL
DISPARITIES ARE ALSO -- CAN BE
THOUGHT OF MANIFESTATIONS EVER
STRUCTURAL RACISM.
WE ARE FAMILIAR WITH OUTCOMES,
DIFFERENT OUTCOMES BY NATURE OF
OUR PROFESSIONALS ROLES.
IT'S MORE THAN TO FRAME THIS
DISCUSSION NOT JUST ABOUT RACIAL
DISPARITIES BUT ALSO HOW
MULTIPLE FORCES THAT DECLINES
STRUCTURAL DISADVANTAGE
CULMINATE IN MEDICAL RACISM.
DEFINING TERMS FIRST, DEFINITION
OF -- CONCEPT OF RACE, A SOCIAL
CLASSIFICATION OF PEOPLE BASED
ON PHYSICAL OR OBSERVED
CHARACTERISTICS.
RACISM BECOMES THE STRUCTURING
OF OPPORTUNITY FROM SYSTEMIC
PERSPECTIVE THAT RELIES ON
ASSIGNING VALUE BASED ON SOCIAL
DEFINABLE PHENOTYPES.
THREE THINGS IT DOES,
DISADVANTAGES SOME INDIVIDUALS
AND COMMUNITIES, UNFAIRLY
ADVANTAGES OTHER INDIVIDUALS AND
OTHER COMMUNITIES, AND THROUGH
THAT KINDS OF SYNERGISTIC
RELATIONSHIP UNDERMINES
REALIZATION OF FULL POTENTIAL OF
AN ENTIRE SOCIETY THROUGH WASTED
HUMAN RESOURCES.
NEXT SLIDE.
SO RACISM CAN BE MEDIATED IN AT
LEAST TWO WAYS, I THINK TWO
PARTICULARLY USEFUL FOR
DISCUSSION TODAY, PERSONALLY
MEDIATED AND INSTITUTIONAL.
DISCRIMINATION REFERS TO
DIFFERENTIAL ACTION TOWARD
OTHERS BY RACE, CULMINATES INTO
DIFFERENT OUTCOMES AND ACCESS
AND POTENTIAL.
IT'S IMPORTANT TO ACKNOWLEDGE
THAT PERSONALLY MEDIATED CAN BE
INTENTIONAL OR NOT INTENTIONAL.
IN ADDITION, THIS CONCEPT OF
INSTITUTIONALIZED RACISM WHICH
REFERS TO STRUCTURES, POLICIES,
PRACTICES AND NORMS THAT RESULT
AND DIFFERENTIAL ACCESS TO
GOODS, SERVICES, OPPORTUNITIES,
WITHIN SOCIETIES BASED ON RACE,
MANIFESTED AS DIFFERENTIAL
ACCESS TO MATERIAL CONDITIONS,
THINGS LIKE QUALITY EDUCATION,
HOUSING, EVEN ACCESS TO
APPROPRIATE MEDICAL FACILITIES,
POWER WHICH CAN REFER TO THE
ABILITY TO INTAKE AND TO
LEVERAGE AND BE PART OF
INFORMATION GATHERING AND
FINANCIAL RESOURCES, AND EVEN
VOICE, ABILITY TO TELL ONE'S OWN
HISTORY AND TO BE REPRESENTED IN
THINGS SUCH AS MEDIA, EVEN IN
WORKING GROUPS.
IN TERMS OF TOUCHSTONES TO MOVE
TOWARDS DEFINITIONS OF RACISM
PROXIMAL TO OUR DISCUSSION
TODAY, MEDICAL RACISM IS
STRUCTURES, POLICIES, PRACTICES,
NORMS THAT CULMINATE IN
DIFFERENTIAL ACCESS IN DELIVERY,
EXPERIENCE OF HIGH QUALITY
MEDICAL CARE, THAT RESULT IN
INEQUITABLE CLINICAL PROCESSES
AND OUTCOMES.
FROM THAT DEFINITION OF MEDICAL
RACISM WE CAN THINK ABOUT
SEPSIS-RELEVANT RACISM RESULTS
IN DISPROPORTIONATELY RISK OF
MORBIDITY AND MORTALITY.
CONCEIVES OF SEPSIS RELEVANT,
TWO LOCATIONS, FIRST IN HEALTH
SYSTEMS, SECOND OUTSIDE OF THEM.
NEXT SLIDE. WHAT IS THE
EVIDENCE FOR DISPARITIES IN
SEPSIS?
NEXT SLIDE.
SOME OF THESE DATA WILL BE AN
ECHO OF PREVIOUS SPEAKER, BUT AS
WAS MENTIONED CERTAIN
MINORITIZED RACES HAVE INCREASED
INCIDENCE OF SEPSIS COMPARED TO
OTHERS.
SO IN THE SPECIFIC CASE OF
BLACK, IDENTIFIED AS BLACK BY
HEALTH SYSTEM, THESE PATIENTS
HAVE TWICE THE RELATIVE
INCIDENCE OF DEVELOPMENT OF
SEPSIS, NEARLY TWICE THE
MORTALITY RISK.
NEXT SLIDE.
A COUPLE THINGS TO NOTE, NOT ALL
RACIALIZED GROUPS SHARE THE SAME
RISK OF SEPSIS ADVERSE OUTCOMES.
SO THIS CHART OVER TIME
DEMONSTRATES THAT CERTAIN GROUPS
SPECIFICALLY BLACK AND NATIVE
AMERICAN REGARDLESS OF GENDER
HAD WORSE OUTCOMES COMPARED TO
OTHER GROUPS, THE THING TO NOTE
ABOUT THIS TREND THERE SEEMS TO
HAVE BEEN OVER TIME SOME
DIFFERENCE FOR BLACK PATIENTS
DECREASED INCIDENCE OF MORTALITY
RELATIVE TO WHITE PATIENTS BUT
DESPITE IMPROVEMENTS IN
MORTALITY OVER TIME THESE
DISPARITIES HAVE CONTINUED.
NEXT SLIDE.
EVEN SURVIVORSHIP HAS RACIAL
DISPARITIES, SO BLACK PATIENTS
ARE AT 50% INCREASED RISK OF
READMISSION COMPARED TO WHITE
PATIENTS.
WHAT ARE THE THEORIES FOR THE
MECHANISM UNDERLYING THESE
DISPARITIES?
IN GENERAL MECHANISMS CAN BE
GROUPED INTO THREE MAIN BUCKETS,
THAT EXPLAIN RISK FACTORS TO BE
ASSOCIATED WITH THESE
DISPARITIES.
CHARACTERISTICS WHICH DOVETAIL
WELL WITH THE CONCEPT OF
MULTI-MORBIDITY BUT ALSO THINGS
SUCH AS DISEASE SEVERITY,
PRESENTATION, PATIENT AGE,
THINGS LIKE THAT, CARE DELIVERY
SO THE ACTUAL HEALTHCARE
PROCESSES THAT RESULT IN
IMPROVEMENT IN UP -- SEPSIS CAE
AND LEAD TO ERRORS THAT MIGHT
CULMINATE IN ADVERSE OUTCOMES,
AND HOSPITAL CHARACTERISTICS,
SIZE, PAYER GROUP, GEOGRAPHIC
LOCATION, OTHER IMMUTABLE
CHARACTERISTICS OF HOSPITAL
ASSOCIATED WITH DISPARITIES.
NEXT SLIDE.
THIS LOOKS AT 28 HOSPITALS THAT
WERE TREATING PATIENTS WITH
SEPSIS, I'M SORRY, WITH
PNEUMONIA, SOME WENT ON TO
DEVELOP SEPSIS.
AND YOU CAN SEE EACH OF THESE
SQUARES THERE'S DIFFERENTIAL
ADJUSTMENT FOR EACH OF THESE
KIND OF CATEGORIES, AND SO FOR
THE OUTCOME, YOU SEE PATIENTS
WHO IDENTIFY AS BLACK STILL LESS
LIKELY TO GET ANTIBIOTICS IN A
RELEVANT TIME FRAME, EVEN
ADJUSTING FOR COVARIATES.
CERTAIN OTHER MEASURES SHOWN TO
BE MORE ASSOCIATED WITH RISK
FACTORS THAN INDEPENDENTLY WITH
PATIENT RACE.
NEXT SLIDE.
SO, AS I ILLUSTRATED IN THE LAST
SLIDE SOME OF THESE
RELATIONSHIPS SEEM TO BE A
LITTLE BIT VARIABLE IN TERMS OF
WHETHER ADJUSTMENT IS ASSOCIATED
WITH RACE OR SOME ASSOCIATED
RISK FACTORS.
ONE STUDY I WAS INTERESTED IN
LEADING LOOKED AT THIS QUESTION
OF HOW WELL THESE DIFFERENT
PROPOSED MECHANISMS -- PROPOSED
RISK FACTORS ACTUALLY REPRESENT
MECHANISMS FOR DISPARITIES IN
SEPSIS.
NEXT SLIDE.
SO MY APPROACH TO ADJUST THIS
QUESTION WAS TO GROUP SEVERAL
DIFFERENT VARIABLES WITHIN THE
SIX DIFFERENT CATEGORIES IN
ORDER TO DEVELOP A METHOD TO
MEASURE RELATIVE IMPORTANCE OF
EACH OF THESE DIFFERENT
CATEGORIES OF RISK FACTORS.
AND SO YOU CAN SEE THESE RISK
FACTORS HERE.
I WON'T BELABOR THE DETAILS IN
PARTICULAR, BUT THE OVERALL
METHOD FOR SPECIMEN OF
CATEGORIES IS TO USE EXTERIOR
MATCHING SCHEME TO DEVELOP A
RELATIVE ESTIMATE OF IMPORTANCE
OF EACH CATEGORIES.
WE PERFORMED THIS MATCHING STUDY
ACROSS 27 HOSPITALS BETWEEN
UNIVERSITY OF PENNSYLVANIA AND
KAISER PERMANENTE HEALTH SYSTEM,
BETWEEN 2013 AND 2018, THIS IS
WHAT WE FOUND.
X-AXIS YOU SEE DIFFERENCE IN
HOSPITAL LENGTH OF STAY EXPIRED
TO WHITE PATIENTS, FOR EACH OF
THE DIFFERENT RACIAL GROUPS WE
LIST ON THE LEGEND ON THE RIGHT.
EACH COLOR OF THESE DOTS
REPRESENTS A DIFFERENT RACIAL
GROUP.
EACH ONE OF THE LINES REPRESENTS
A SUCCESSIVE MATCHING SEQUENCE
THAT THROUGH ITS DEVELOPMENT,
ALLOWS US TO LOOK AT LENGTH OF
STAY DIFFERENCES, BASED ON
DIFFERENT MATCHING FACTORS.
AND SO TWO MAIN THINGS TO TAKE
AWAY FROM THIS FIGURE, FIRST OF
WHICH IS BLACK PATIENTS ON
AVERAGE HAVE LONGER HOSPITAL
LENGTH OF STAY, ALMOST 1 1/2
DAYS, COMPARED TO WHITE
PATIENTS, LONGER THAN ANY OTHER
GROUP WHILE HISPANIC GROUPS HAD
SHORTEST HOSPITAL LENGTH OF
STAY.
WHAT'S MORE IMPORTANT FOR THE
PURPOSES OF THIS DISCUSSION,
SUCCESSIVE ADDITION OF MATCHING
VARIABLES DID VERY LITTLE TO
CHANGE THE ESTIMATED LENGTHS OF
STAY DIFFERENCE BETWEEN
DIFFERENT GROUPS, EACH OF THE
IDENTIFIED VARIABLE GROUPS DOES
RELATIVELY LITTLE IN EXPLAIN THE
DISPARITIES BETWEEN PATIENT
GROUPS.
NEXT SLIDE.
AND SO WHAT ARE FUTURE
DIRECTIONS FOR ELIMINATING
SEPSIS AND SEPSIS-RELEVANT
RACISM?
AS MENTIONED BY THE PREVIOUS
SPEAKER, IT'S IMPORTANT TO
RECOGNIZE NATURAL TRENDS IN
SEPSIS DISPARITIES OVERLOOKING
REGIONAL DIFFERENCES IN SEPSIS
OUTCOMES, THIS LOOKS DIFFERENT
DIFFERENTLY
FROM PREVIOUS TALK BUT SIMILAR
IDEA, HEAT MAP LOOKS AT CHANGE
IN SEPSIS-RELATED MORTALITY IN
EACH STATE OVER THE STUDY
PERIOD.
AND SHOWS THAT IN SOME
LOCATIONS, SOME LOCATIONS ARE
DOING BETTER IMPROVING SEPSIS
MORTALITY, OTHER LOCATIONS HAVE
ON WORSENING IN SEPSIS-RELATED
OUTCOMES, ALSO THIS DIFFERS BY
PATIENT RACE.
AND SO IN ADDITION TO THINKING
OF JUST THE FACT THAT REGIONAL
DIFFERENCES EXIST IT'S IMPORTANT
TO UNDERSTAND LOCAL CONTEXT OF
WHAT DETERMINES HEALTH OUTCOMES
AND HOW ONE NUANCED
UNDERSTANDING HOW MEDICAL
OUTCOMES CAN BE RELATED TO MORE
LOCAL STRUCTURAL DETERMINANTS,
LIKE DE FACTO SEGREGATION, WHAT
THAT MEANS FOR ACCESS TO
HIGH-QUALITY FACILITIES COULD BE
IMPORTANT IN UNDERSTANDING THESE
DIFFERENCES, YET HAS BEEN
UNMEASURED AND UNSTUDIED.
NEXT SLIDE.
ANOTHER IMPORTANT SIGNAL THAT
EXISTS ALREADY IN LITERATURE IS
ROLE OF POVERTY ON OUTCOMES SUCH
AS INFECTIOUS RISK AND SEPSIS
OUTCOMES.
AND SO STARTING TO THINK MORE IN
DEPTH ABOUT HOW -- WHAT THE
MECHANISMS FOR POVERTY ARE FROM
NEIGHBORHOOD AND INDIVIDUALIZED
LEVEL, COULD BE TREMENDOUS IN
STARTING TO MOVE TOWARDS
INTERVENTIONS THAT COULD IMPROVE
DISPARITIES.
>> TWO MINUTES REMAINING.
>> GREAT.
AND BEYOND JUST THE IDEA OF
POVERTY, THIS STUDY LOOKED AT
SEVERAL DIFFERENT STRUCTURAL
DETERMINANTS, HOW ASSOCIATION
WITH NEIGHBORHOOD LEVELS OF THE
POPULATION THAT IDENTIFIED AS
BLACK ALSO IDENTIFIED -- ALSO
ASSOCIATED WITH SEPSIS
MORTALITY.
AND SO MORE NUANCED THOUGHTS
ABOUT HOW OTHER STRUCTURAL
DETERMINANTS CAN IMPACT SEPSIS
OUTCOMES I THINK ARE WARRANTED.
NEXT QUESTION.
I MEAN NEXT SLIDE.
AND SO I THINK LAST STUDY, GET
TO THE IDEA OF RACIAL
DISPARITIES, IT'S IMPORTANT TO
THINK ABOUT HOW STRUCTURAL
FACTORS ON EPIC HEALTH SYSTEM
LEVEL CAN INFLUENCE POPULATION
LEVEL PRE-SEPSIS CRITICAL CARE
ACCESS AND TREATMENT, HOW THAT
MIGHT INFLUENCE SEPSIS OUTCOMES.
NEXT SLIDE.
TO SUMMARIZE, NEXT SLIDE,
MINORITIZED PATIENTS EXPERIENCE
HIGHEST INCIDENCE IN MORTALITY
FROM SEPSIS BUT NOT ALL
MINORITIZED GROUPS EXPERIENCE TO
SUCH AN EXTENT.
CLINICAL PRESENTATION
CHARACTERISTICS AND
BETWEEN-HOSPITAL CARE DELIVERY,
MOST STUDIES POTENTIAL
DETERMINANTS HAVE YET TO
DEMONSTRATE A MECHANISTIC TOOL.
THE FIELD SHOULD MOVE TOWARDS
MORE IN-DEPTH CHARACTERIZING
STRUCTURAL RACISM HOW LIVED
CONTEXT LEADS TO AMERICAN HEALTH
DISPARITIES.
I WELCOME QUESTIONS.
>> IN THE INTEREST OF TIME WE'LL
MOVE TO THE LAST TALK, IF THERE
ARE QUESTIONS YOU CAN PUT THEM
IN THE CHAT OR WE'LL HAVE THE
PANEL DISCUSSION AFTER THE LAST
TALK AND YOU CAN ASK YOUR
QUESTIONS AT THAT TIME.
SO FINAL TALK IS DR. JOHN
DONNELLLY, UNIVERSITY OF
MICHIGAN, SEPSIS DISPARITIES,
ADDRESSING USING IMPLEMENTATION
SCIENCE.
>> THANK YOU FOR HAVING ME
TODAY.
I APPRECIATE BEING HERE WITH
THIS EXCELLENT PANEL OF EXPERTS.
SO, I'LL DISCUSS OUR APPROACH TO
ADDRESSING SOME INSURER WITHIN
SEPSIS CARE USING IMPLEMENTATION
SCIENCE AND LINK TO HEALTH
EQUITY AND SEPSIS DISPARITIES.
FUNDING DISCLOSURES, YOU CAN SEE
THOSE HERE.
VIEWS EXPRESSED HERE ARE MINE
ALONE, DO NOT REPRESENT
DEPARTMENT OF VETERANS AFFAIRS
OR THE FEDERAL GOVERNMENT.
NEXT SLIDE PLEASE.
IN THE V.A. WE DO BOTTOM LINE UP
FRONT A LOT.
NIECE ARE SOME OF THE IDEAS I'D
LIKE TO TALK -- THESE ARE IDEAS
I'D LIKE TO TALK ABOUT.
PERHAPS WE CAN THINK ABOUT
SEPSIS DISPARITIES IN TERMS OF
UNWANTED VARIATION IN OUTCOMES,
CLINICAL PRACTICE, OR ACCESS TO
INTERVENTIONS AND/OR QUALITY
IMPROVEMENT PROGRAMS.
THIS IS IMPORTANT BECAUSE
IMPLEMENTATION SCIENCE OFFERS A
SET OF RIGOROUS THEORY DEFINED
STRATEGIES TO REDUCE UNWANTED
VARIATION AND THIS IS
ACCOMPLISHED BY ENHANCING UPTAKE
OF EVIDENCE-BASED PRACTICES OR
INNOVATION.
AND IMPORTANTLY THOUGH CARE MUST
BE TAKEN TO INCORPORATE HEALTH
EQUITY INTO THIS PROCESS, AND
I'LL TRY TO MAKE THE ARGUMENT
IT'S IMPORTANT TO DO THIS
THROUGHOUT THE ENTIRE PROCESS.
NEXT SLIDE PLEASE.
I WANTED TO START QUICKLY WITH A
FEW EXAMPLES OF POTENTIALLY
UNWANTED VARIATION OR SIMPLY
VARIATION IN OUTCOMES AND
CLINICAL PRACTICE.
NEXT SLIDE PLEASE.
YOU MAY HAVE SEEN THIS FIGURE A
MOMENT AGO, DR. MARTIN, DR.
MOORE'S EXCELLENT WORK.
I WANT TO ADD ONE MORE SMALL
PIECE HERE WHICH WAS WHEN WE PUT
TOGETHER THIS MAP WHICH IS
COUNTY LEVEL SEPSIS MORTALITY,
AGE ADJUSTED, WE USED
STATISTICAL METHODS FOR
CLUSTERING.
SO WHAT YOU SEE WITHIN THESE
DISCRETE AREAS IS STRONGLY
CLUSTERED AREAS OF SEPSIS
MORTALITY.
THIS IS IMPORTANT BECAUSE LIKE
DR. CHESLEY MENTIONED AS WELL,
WE CAN THINK ABOUT THIS IN
ADDITION TO REPRESENTING
COMORBIDITIES, ACCESS TO CARE,
ALSO PERSISTENT POVERTY.
IF YOU OVERLAY THIS MAP WITH
PERSISTENT POVERTY IT OVERLAPS
QUITE EXTENSIVELY.
NEXT SLIDE PLEASE.
ONE STEP FURTHER WE DID A LOT OF
WORK WITHIN A LARGE LONGITUDINAL
COHORT OF COMMUNITY DWELLING
ADULTS.
HERE WE LOOKED AT TEN-YEAR RISK
OF SERIOUS INFECTION AND SEPSIS.
WE OFTEN LOOK AT COMORBIDITIES,
BASELINE CHARACTERISTICS, BUT
FOR THIS SPECIFIC PAPER WE
LOOKED AT NEIGHBORHOOD
SOCIOSTATUS, BLOCK GROUP LEVEL.
SIMILAR TO WHAT DR. CHESLEY JUST
MENTIONED WE FOUND GENERALLY
LOWER RATES OF SERIOUS INFECTION
AND SEPSIS IN THE COMMUNITIES IN
THE HIGHEST -- ABOVE THE HIGHEST
QUARTILE AS COMPARED WITH THOSE
IN THE LOWEST QUARTILE.
AND TO TAKE THAT ONE STEP
FURTHER RELEVANT TO OUR
CONVERSATION SO WHEN WE LOOK AT
MEDIATION, SO MEDIATION OF THE
ASSOCIATION, THINGS LIKE
PHYSICAL WEAKNESS, INDIVIDUAL
INCOME, DIABETES, ALL SEEM TO BE
RELEVANT POTENTIAL MEDIATORS.
THIS SUGGESTS THESE MIGHT
POTENTIALLY EXPLAIN THE
ASSOCIATION.
NEXT SLIDE PLEASE.
SO, THE LAST TWO EXAMPLES WERE
CLINICAL OUTCOMES BUT THIS IS
WHERE I'LL SPEND MOST OF MY TIME
TODAY, WHICH IS ON VARIATION IN
CLINICAL PRACTICE.
ONE AREA WE'VE BEEN VERY
INTERESTED IN IS LOOKING AT WAYS
THAT IMPLEMENTATION SCIENCE
COULD HELP IMPROVE ANTIMICROBIAL
USE IN SEPSIS.
THIS IS VARIATION IN TIME TO
DELIVERY FOR VETERANS
HOSPITALIZED ACROSS THE V.A.
HEALTH SYSTEM.
THERE'S FAIRLY PRONOUNCED
VARIABILITY BUT ALSO THE MEDIAN
TIME TO ANTIBIOTICS INCREASED
OVER TIME.
BETWEEN 2013 AND 2018.
THIS IS A SPACE WE THINK
INFILTRATION SCIENCE COULD MAKE
AN IMPACT.
NEXT SLIDE PLEASE.
SO A FEW QUICK DEFINITIONS IN
TERMS OF IMPLEMENTATION SCIENCE
AND IMPLEMENTATION RESEARCH, THE
STUDY OF METHODS AND STRATEGIES
TO IMPROVE UPTAKE OF
EVIDENCE-BASED PRACTICES, INTO
REGULAR USE.
AND WE THINK OF IMPLEMENTATION
STRATEGIES WHICH ARE KEY
COMPONENT OF IMPLEMENTATION WORK
AS THE METHODS OR TECHNIQUES
USED TO ENHANCE ADOPTION,
IMPLEMENTATION, SUSTAINABILITY
OF A CLINICAL PROGRAM OR
PRACTICE.
PUT IT ANOTHER WAY HOW-TWO
COMPONENT HOW WE GET FROM A
PROBLEM OR GAP TO A POTENTIAL
SOLUTION.
NEXT SLIDE PLEASE.
SO ONE IMPORTANT COMPONENT OF
IMPLEMENTATION RESEARCH IS
THEORETICAL FRAMEWORKS.
SO WE USE A LOT OF FRAMEWORKS
BUT THIS ONE IN PARTICULAR HAS
BEEN ESPECIALLY -- WHAT YOU SEE
HERE IS A GRAPHIC REPRESENTING
THE V.A. QUALITY ENHANCEMENT
RESEARCH INITIATIVE
IMPLEMENTATION ROAD MAP, THAT
WALKS THROUGH DIFFERENT
ACTIVITIES AND IMPORTANT
QUESTIONS WE NEED TO BE ASKING
ACROSS THREE PHASES OF
IMPLEMENTATION WHICH ARE
PRE-IMPLEMENTATION,
IMPLEMENTATION, AND
SUSTAINABILITY.
I WON'T GO INTO DETAIL HERE BUT
REALLY THE GENERAL IDEA IS JUST
THAT WITHIN EACH OF THESE BINS
WE HAVE DIFFERENT QUESTIONS WE
ASK AND DIFFERENT ACTIVITIES.
I'LL SPEND MOST OF MY TIME ON
THIS PRE-IMPLEMENTATION AND
IMPLEMENTATION PHASE, SIMPLY
BECAUSE THIS IS AN AREA WHERE
THERE'S BEEN QUITE A BIT OF
RECENT INTEREST AND RESEARCH IN
TERMS OF HOW WE INTERPRET HEALTH
EQUITY, WHICH COULD BE RELEVANT
IN ADDRESSING SEPSIS
DISPARITIES.
I'LL SPEND SOME TIME HERE.
THIS IS AN IMPORTANT COMPONENT
OF THE QUERI IMPLEMENTATION ROAD
MAP.
WE'RE HERE PLANNING FOR
IMPLEMENTATION.
AND SO YOU SEE A STEPPED
APPROACH TO GETTING FROM A
CLINICAL PROBLEM OR OBSERVED GAP
TO POTENTIAL SOLUTION, THE
IMPLEMENTATION STRATEGY.
STARTING ON THE FAR LEFT, OUR
FIRST STEP IS TO ASSESS PRACTICE
GAPS, TO UNDERSTAND WHERE
CURRENTS PRACTICE IS.
THE GRAPH I SHOWED WITH
VARIATION IN ANTIBIOTIC TIMES
WOULD BE AN EXAMPLE OF THIS.
THIS IS WHERE THERE MAY BE A GAP
WE CAN START TO ADDRESS.
KIND OF TWO BOXES TO THE RIGHT,
SO THIS IS WHERE WE'LL START
THINKING THROUGH WHAT POTENTIAL
INTERVENTIONS, SOLUTIONS, AND
INNOVATIONS MIGHT HELP ADDRESS
THIS IMPORTANT GAP.
STEP 4 IS A KEY ONE AS WELL.
THIS IS WHERE WE USE THEORETICAL
FRAMEWORKS TO IDENTIFY BARRIERS
AND FACILITATORS TO
IMPLEMENTATION OF INTERVENTION
OR PRACTICE THAT WE JUST
IDENTIFIED.
SO THIS IS REALLY KIND OF THE
BULK OF THE PRE-IMPLEMENTATION
PROCESS, AND THIS IS WHERE WE
REALLY TRY TO UNDERSTAND
CONTEXT.
SO WE'RE TRYING TO IMPLEMENT
SOMETHING, WHAT IS THE CONTEXT
THAT WE'RE WORKING IN.
SO IT'S JUMPING DOWN TO STEP 6,
HERE IS WHERE WE USE THEORY
AGAIN TO DESIGN IMPLEMENTATION
STRATEGY SO WE WANT OUR
STRATEGIES IN GENERAL TO BE
LINKED TO BARRIERS WE WANT TO
OVERCOME, HELPING TO IMPROVE OR
FACILITATE IMPLEMENTATION WITHIN
THE CONTEXT THAT WE'RE WORKING.
AND SO REALLY TO SUMMARIZE, THIS
IS A HELPFUL KIND OF STEPPED
APPROACH TO GETTING TO
IMPLEMENTATION STRATEGY.
NEXT SLIDE PLEASE.
AND JUST TO DRIVE THIS HOME I
WANTED TO TALK THROUGH THE
ANTIBIOTIC EXAMPLE, IN MORE
DETAIL.
SO HOW WE'VE THOUGHT ABOUT THIS
IN TERMS OF ANTIBIOTICS FOR
SEPSIS IS THAT WE WANT TO START
FROM A RECOMMENDATION WITH
FAIRLY STRONG EVIDENCE.
SO HERE ON THE LEFT WE SEE THE
REVISED RECOMMENDATION IN THE
SURVIVING SEPSIS TWAIN 2021
GUIDELINES, THE RECOMMENDATION
IS NOW STRATIFIED BASED ON
PATIENT SEVERITY, KIND OF WHAT
THE PRESENTATION LOOKS LIKE.
HERE THE GOAL FOR PATIENTS WHERE
SEPSIS IS DEFINITE OR PROBABLE
OR SHOCK IS PRESENT
RECOMMENDATION IS ANTIBIOTICS
WITHIN ONE HOUR.
OTHERWISE, RECOMMENDATION WOULD
BE WITHIN THREE HOURS IF THERE'S
SOME KIND OF LINGERING
CONCERNING FOR AN INFECTION.
BUT THIS DOESN'T NECESSARILY GET
US TO THE POINT OF PRACTICES.
SO BASICALLY WE THOUGHT THROUGH
WHAT ARE POTENTIAL PRACTICES
THAT MIGHT BE IMPLEMENTABLE TO
HELP ADDRESS THIS.
SO WE WON'T GO INTO DETAIL BUT
IN TERMS OF SCREENING WE NEED A
WAY TO IDENTIFY PATIENTS WHO
HAVE INFECTION AND SEPSIS, THERE
NEEDS TO BE REPEAT ASSESSMENT OF
CLINICAL CRITERIA, KIND OF ONCE
THE PATIENT HAS PRESENTED,
POTENTIALLY MOST IMPORTANTLY FOR
PURPOSES HERE PRESCRIBE
ANTIBIOTICS RAPIDLY FOR PATIENTS
WITH SHOCK OR OVERT ORGAN
FAILURE, A TRACTABLE PRACTICE WE
CAN LOOK AT.
AND THEN IF INDICATED WE WANT
ANTIBIOTICS WITH APPROPRIATE
COVERAGE, AND THEN IT COULD BE
POSSIBLE TO DEFER ANTIBIOTICS
FOR PATIENTS WITH UNCLEAR
DIAGNOSES WHILE WE COMPLETE THE
ASSESSMENT.
NEXT SLIDE PLEASE.
THE WAY WE'VE THOUGHT THROUGH
THIS, LEFT-HAND SIDE PRACTICE
ASSESSMENT, QUANTITATIVE EXAMPLE
I DESCRIBE AT THE BEGINNING,
LOOKING AT VARIATION, AN
EXAMPLE, BUT WE DO NEED TO
EXPAND UPON QUALITATIVE WORK AS
WELL.
SO WE WANT TO DO INTERVIEWS,
SURVEYS TO BETTER UNDERSTAND
BARRIERS AND FACILITATORS.
AND SPECIFICALLY RELEVANT TO
TAILORING ANTIBIOTICS, SO
TAILORING ANTIBIOTICS BASED ON
PATIENT SEVERITY.
AND SO JUST A FEW OF THE
POSSIBLE BARRIERS AND
FACILITATORS WE CAME UP WITH, IN
EARLY PILOT WORK, IS POTENTIAL
LACK OF FEEDBACK, SOME EMERGENCY
DEPARTMENT SPECIFIC ISSUES LIKE
OVERCROWDING, AS WELL AS
WORKFORCE-RELATED ISSUES, MAYBE
MORE ACCURATELY WORK FLOW
RELATED ISSUES, WAYS TO LEVERAGE
NURSING RESOURCES TO IMPROVE
ANTIBIOTIC USE.
THIS IS WHERE WE MATCH THESE
IDEAS WITH SOME POSSIBLE
STRATEGIES, POTENTIALLY MOST
IMPORTANT ON TOP, THINKING
THROUGH CREATIVE WAYS TO DELIVER
FEEDBACK IN A WAY THAT'S
MEANINGFUL TO CLINICIANS.
THE LAST MINUTE OR TWO HERE, ON
THIS ISSUE OF HEALTH EQUITY.
SO THE TWO PAPERS ON THE BOTTOM
LEFT, BOTH OF THESE REALLY MADE
A VERY STRONG CASE FOR
INCORPORATING HEALTH EQUITY INTO
THE IMPLEMENTATION PROCESS.
JUST THE KEY TAKEHOME MESSAGE
HERE WE NEED TO INCORPORATE
HEALTH EQUITY FROM OUTSET AND
WITHIN ALL IMPLEMENTATION
ACTIVITIES AND PHASES.
I THINK ONE OF THE MOST
IMPORTANT IS LIKELY THE ONE AT
THE TOP OF THE TABLE ON THE
RIGHT, ENGAGING INTERESTED
PARTIES AND/OR STAKEHOLDERS IN
THIS PROCESS FROM THE BEGINNING
AND MAKING SURE WE'RE TRYING TO
ENGAGE THEM THROUGHOUT THE
PROCESS AS WELL.
IT'S IMPORTANT TO LAY GROUND
WORK EARLY THAT HEALTH EQUITY IS
IMPORTANT AND WE WANT TO
ACTIVELY INCORPORATE THIS
THROUGHOUT IMPLEMENTATION AS
WELL.
NEXT SLIDE PLEASE.
SO LASTLY THAT IDEA OF
INCORPORATING HEALTH EQUITY INTO
IMPLEMENTATION IS FAIRLY BIG
PICTURE SO ONE EXAMPLE TRYING TO
MAKE THIS WAY MORE
UNDERSTANDABLE AND ACTIONABLE IS
THAT THE HEALTH EQUITY
IMPLEMENTATION FRAMEWORK, SO
WOODWARD ET AL. PRESENTED THIS A
FEW YEARS AGO, TO TAKE AN
EXISTING FRAMEWORK WHICH HELPS
US UNDERSTAND BARRIERS AROUND
FACILITATORS AND ADD DOMAINS
THAT ARE RELEVANT TO HEALTH
EQUITY.
THIS IS DEFINITELY PROBLEM OR
CONDITION SPECIFIC OR PROJECT
SPECIFIC.
BUT THIS IS A PROCESS WE CAN DO
THAT REALLY HELPS TO ACTIVELY
INCORPORATE HEALTH EQUITY.
AND SO JUST THE LAST FINAL
POINT, SO REALLY THE MAIN IDEA
HERE WITH THIS FRAMEWORK TO DO
TWO THINGS SIMULTANEOUSLY, SO TO
ACHIEVE SUCCESSFUL
IMPLEMENTATION BUT ALSO TO
ACTIVELY WORK TO IMPROVE HEALTH
EQUITY.
TO PUT THAT PART SLIGHTLY
DIFFERENTLY, ACTIVELY WORK TO
IMPROVE SEPSIS OR HEALTH
DISPARITIES.
NEXT SLIDE PLEASE.
SO JUST VERY QUICK FINAL
CONCLUSIONS, SO LIKE I MENTIONED
WE CAN REFRAME THE SEPSIS
DISPARITY QUESTION POTENTIALLY,
IN TERMS OF UNWANTED VARIATION
IN SEPSIS RISK AND OUTCOMES AS
WELL AS CLINICAL PRACTICE, AND
WE HAVE POTENTIALLY EFFECTIVE
TOOLS TO HELP REDUCE UNWANTED
VARIATION, IMPROVE CARE FOR ALL
SIMULTANEOUSLY.
BUT IT'S IMPORTANT TO USE THEORY
TO DERIVE THESE IMPLICATION
STRATEGIES, AND LASTLY LIKE I
MENTIONED, SO WE WANT TO FOCUS
ON TWO GOALS AT THE SAME TIME
WHICH IS ACHIEVING SUCCESSFUL
IMPLEMENTATION OF EVIDENCE-BASED
PRACTICES THAT WILL HELP IMPROVE
SEPSIS CARE, AND ALSO ENSURING
THAT DISPARITIES ARE
SUCCESSFULLY ADDRESSED AS WELL.
THANK YOU SO MUCH, AND I GUESS
NEXT SLIDE PLEASE.
THANK YOU SO MUCH FOR YOUR TIME
AND HAPPY TO TAKE ANY QUESTIONS
IF THERE'S TIME AVAILABLE.
>> ARE THERE QUESTIONS FOR DR.
DONNELLLY?
THIS IS A PERFECT SEGUE INTO THE
PANEL DISCUSSION, DR. ASHANNA
WILL MODERATE THAT SESSION.
>> THANKS.
WE INVITE ALL FOUR SPEAKERS TO
COME ON VIDEO.
THANK YOU FOR YOUR TALKS.
YOU MAY DROP ADDITION EQUAL
QUESTIONS IN THE CHAT.
FIRST FOR DOCTORS RUDD AND
MARTIN.
THANK YOU FOR YOUR TALKS.
A LITTLE BIT OF BACKGROUND, THIS
CLIFF ANALOGY WAS PROPOSED,
LEVELS OF HEALTH PREVENTION, SHE
DESCRIBED PEOPLE WALKING TOWARDS
THE EDGE OF A CLIFF AND FALLING
OFF THE BOTTOM WHERE AN
AMBULANCE IS WAITING TO RESCUE
THEM.
THE AMBULANCE IS REPRESENTING
TERTIARY PREVENTION, SECONDARY
PREVENTION WOULD ININVOLVE
INSTALLING SAFETY NETS BEFORE
THEY FALL TO THE GROUND.
PRIMARY PREVENTION WOULD INVOLVE
ENACTING A BARRIER SO THEY DON'T
FALL.
THIS IS PROVOCATIVE QUESTION BUT
WHAT WE DO IS A ANALOGOUS TO TE
AMBULANCE, PERHAPS THEY ARE
UNABLE TO MANAGE BECAUSE THEY
DON'T HAVE GOOD OUTPATIENT
HEALTH CARE ACCESS IN THEIR
COMMUNITIES.
WHEN THEY BECOME CRITICALLY ILL
WE MEET THEM.
WHAT ARE THE ADVANTAGES TO THIS
APPROACH FOCUSING ON SEPSIS IN
THE ICU AND WHAT MAY BE
DISADVANTAGES AND HOW MIGHT WE
ADDRESS THOSE?
DO YOU WANT TO START, KRISTINA?
>> SURE.
I CAN THINK OF ALL SORTS OF
DISADVANTAGES.
I'LL START THERE.
I CAN THINK ABOUT THE ADVANTAGES
AS WELL.
FOR ME, IT'S THE COMBINATION OF
THE SHEER NUMBERS OF INCIDENT
CASES OF SEPSIS EACH YEAR.
GLOBALLY IF WE CONTINUE TO ALLOW
50 MILLION CASES OF SEPSIS, LIKE
SOME OF THOSE PEOPLE AREN'T
GOING TO BE PICKED UP BY A GOOD
AMBULANCE, RIGHT?
THEY ARE NOT GOING TO -- WE CAN
STUDY TILL THE COWS COME HOME
BUT WHAT TO DO ONCE PEOPLE HAVE
SEPSIS, BUT WE'RE NOT GOING TO
BE ABLE TO GIVE EVERY ONE OF THE
50 MILLION PEOPLE THE BEST
EVIDENCE-BASED CARE.
SO I THINK WE DO NEED TO
CONTINUE TO IMPROVE THAT
TERTIARY LEVEL OF LIKE BUILD OUR
EVIDENCE BASE, KNOW WHAT WE CAN
DO TO IMPROVE CARE FOR PEOPLE
ONCE THEY HAVE SEPSIS, WE'VE GOT
TO SLOW THE VOLUME OF PEOPLE
SHOWING UP TO THE HOSPITAL WITH
SEPSIS.
I THINK THAT'S ONE.
AND THEN TWO IS I THINK IT'S THE
RIGHT THING TO DO AS HEALTHCARE
PROVIDERS TO WANT PEOPLE TO BE
HEALTHY AND NOT WAIT UNTIL THEY
ARE SICK.
AND SO I THINK THERE'S ALL SORTS
OF THINGS WE COULD BE DOING FOR
PRIMARY AND SECONDARY
PREVENTION, I'LL PAUSE AND LET
OTHERS MAYBE START THAT PIECE OF
THE CONVERSATION BUT I THINK
TRULY LOOKING AT THE NUMBERS AND
JUST LOOKING AT THE ETHICS OF IT
THERE'S A STRONG ARGUMENT FOR
PREVENTING SEPSIS, THROUGH ALL
SORTS OF METHODS I AND OTHERS
HAVE ALREADY STARTED TO BRING UP
TODAY.
>> I THINK KRISTINA SET IT
RIGHT, IT'S ETHICAL, MORAL,
HEALTHCARE CORRECT, AN
IMPERATIVE.
WE RECOGNIZE THE THE COMPLEXITF
SEPSIS.
WE SHOULD BE PREVENTING.
KRISTINA PROPOSED WHERE YOU MILD
BE ABLE TO USE TECHNOLOGY AND
TOOLS TO IDENTIFY HIGHER RISK
PATIENTS AND DO SURVEILLANCE AND
OTHER MONITORING WOULD HELP THEM
TO KNOW WHEN THEY SHOULD BE
CONCERNED OR SEEK HEALTH CARE.
AND THERE ARE OTHER ASPECTS TOO,
WE THINK OF SEPSIS AS INFECTION
THAT CREATES DYSREGULATED IMMUNE
RESPONSE, LEADS TO ORGAN
DYSFUNCTION, PREVENTION OF ORGAN
DYSFUNCTION MIGHT BE ANOTHER
ONE.
IT MAY TRACK WITH COMORBIDITIES,
HOW THOSE ARE RELATED, HOW WE
MIGHT BE ABLE TO HELP BETTER
UNDERSTAND THAT BUT THAT'S A
PATHOPHYSIOLOGIC COMPONENTS AND
MORE CLINICAL COMPONENT, ALMOST
EPIDEMIOLOGIC.
THE LATTER PART, WE FIND IT
EASIEST TO IMPLEMENT STRATEGIES
IN THE HOSPITAL.
PATIENTS HAVE ENGAGED THE
HEALTHCARE SYSTEM BUT WE'VE
MISSED A LOT OF EARLIER
OPPORTUNITIES, THAT'S NOT
CORRECT, IT'S NOT THE BEST WAY
TO DO IT.
I'M NOT ARGUING THAT HEALTHCARE
IS THE SAME BECAUSE CLEARLY IT'S
NOT.
HOSPITALS ARE DIFFERENT,
PROVIDERS ARE DIFFERENT.
YOU CAN'T ARGUE SOMEONE
PRESENTING TO THE HEALTHCARE
SYSTEM IS THE SOLUTION.
SO THERE IS STILL THINGS --
THERE ARE THINGS TO BE DONE IN
THAT REALM AS WELL, RIGHT, TO
BETTER DELIVER CARE FOR PEOPLE
WHO ARE CRITICALLY ILL OR HAVE
SEPSIS BUT I THINK SOMETIMES
WE'RE SIMPLISTIC THINKING THAT'S
THE PLACE TO START BECAUSE IT IS
PROBABLY EASIER BUT IT'S REALLY
MISSING PROBABLY THE BIGGER
PICTURE, WHERE WE HAVE THE
BETTER OPPORTUNITY TO PREVENT
SEPSIS.
>> I'M REMINDED OF HALLE
PRESCOTT'S WORK, PRE-HOSPITAL
TRAJECTORIES, HOW WE COULD
COMBINE THAT WITH
COMMUNITY-BASED PARTICIPATORY
RESEARCH, THINK ABOUT MODELS
COMMUNITIES THEMSELVES NEED TO
MOVE THAT CARE UPSTREAM.
>> YEAH.
>> ONE THING -- SORRY, GO AHEAD,
GREG.
>> QUICKLY, REMINDS ME OF WHAT
JOHN DONNELLY PUT IN, THERE'S
THE ACCESS TO CARE ELEMENT SO
THERE IS -- JOHN, YOU KNOW THIS
TOO, MANY OF YOU DO, THAT IN
MORE RURAL AREAS THERE ARE
CHALLENGES, RIGHT?
PARTICULARLY IN THE TIMELY
CONDITION LIKE THIS, PEOPLE
UNDERSTAND STROKE, CARDIAC
ARREST, MAYBE M.I.
THEY DON'T NECESSARILY
UNDERSTAND SEPSIS OR URGENCY OF
SEEKING CARE FOR PEOPLE THAT ARE
FURTHER AWAY FROM HEALTHCARE
SYSTEM THAT BECOMES A PROBLEM
FOR DELIVERING TIMELY CARE AS
WELL.
THERE'S AN EDUCATIONAL COMPONENT
THAT NEEDS TO HAPPEN AS WELL.
>> THE MESSAGING TO THE
COMMUNITY, THERE'S A LOT OF
POTENTIAL THERE, AND KRISTINA
MENTIONED WE TALK ABOUT THE LINK
BETWEEN COMORBIDITIES AND ORGAN
DYSFUNCTION AND OUTCOMES IN
SEPSIS BUT THERE'S ALSO THE
COMPONENTS OF HOW WE TREAT
MORBIDITY AND CONTROL OF THE
COMORBIDITY.
SO IF THERE'S AN OPPORTUNITY FOR
US TO HAVE MORE DATA REGARDING
THAT AND MESSAGING THE COMMUNITY
AND PATIENTS AND PROVIDERS,
THERE IS A BETTER OPPORTUNITIES
TO IMPACT PREVENTION.
>> YEAH, I AGREE.
I THINK I WOULD TAKE THAT ONE
STEP FORWARD.
EVEN THOUGH I FOCUS PRIMARILY IN
THINKING ABOUT INDIVIDUAL LEVEL
MEDICAL RISK FACTORS FOR SEPSIS,
PARTICULARLY CERTAIN
COMORBIDITIES, ESPECIALLY
MULTI-MORBIDITY AND GREG TOOK US
THROUGH RISKS, BIOLOGIC AND
SOCIAL, I THINK, YOU KNOW, WE
REALLY NEED TO BE THINKING MORE
ABOUT NOT ONLY INDIVIDUAL LEVEL
MEDICAL RISK BUT SOCIAL
DETERMINANTS OF HEALTH,
PARTICULARLY DETERMINANTS OF THE
COMMUNITY LEVEL AND SOCIETY
LEVEL, AND KIND OF THE DATA THAT
CHRIS IS PRESENTING, THINKING
ABOUT HOW CAN WE PREVENT SEPSIS,
NOT ONLY BY FINDING INDIVIDUAL
PATIENTS AT RISK AND TINKERING
WITH THEIR MEDICATIONS AND
MEDICAL MANAGEMENT TO REDUCE
THEIR RISK, THERE'S A LOT OF
THINGS WE CAN BE DOING AT THE
COMMUNITY LEVELS OR EVEN
SOCIETAL LEVELS TO BE THINKING
ABOUT HOW CAN WE PREVENT SEPSIS
AMONG WHOLE COMMUNITIES OF
PATIENTS WHO MIGHT BE AT RISK.
I'D LOVE TO HEAR DR. CHESLEY OR
DR. DONNELLY, THEY MAY HAVE
OTHER THOUGHTS, WHERE SHOULD WE
FOCUS BEYOND JUST THE
INDIVIDUAL?
>> I CAN JUMP IN.
YOU KNOW, I THINK ABOUT THIS IN
A FEW WAYS.
CERTAINLY THERE NEEDS TO BE MORE
UNDERSTANDING OF WHICH
STRUCTURAL DISADVANTAGE CONTEXTS
INFLUENCE SEPSIS RISK FACTORS,
PROBABLY ALSO THINGS THAT WERE
SORT OF MENTIONED BY DOCTORS
MARTIN AND RUDD, CAPTURING
PATIENTS THAT DON'T HAVE THAT
INTERSECTION WITH THE HEALTH
SYSTEM APPROPRIATELY, AND THAT
LEADS TO ADVERSE OUTCOMES.
SO IT'S CERTAINLY THAT NEEDS TO
BE AN AREA WHERE WE UNDERSTAND
MORE AS BOTH HEALTH CARE SYSTEM,
RESEARCHERS, HEALTH CARE
PROVIDERS.
THAT'S ONE.
BUT I HAVE THOUGHT ABOUT WHAT'S
ANALOGOUS IN OTHER FIELDS, AND
SO I REALLY THINK THE DEFINITION
OF SEPSIS ESPECIALLY AS EXISTS
NOW IS DIFFICULT TO WORK WITH AS
SOMEONE TRYING TO THINK ABOUT
DISEASE PREVENTION BECAUSE WHEN
YOU MAKE A A DEFINITION PREDICD
ON ORGAN FUNCTION, DIFFICULT TO
THINK ABOUT POPULATION AT
HIGHEST RISK, THERE'S
OPPORTUNITY THINKING ABOUT
STRUCTURAL DISADVANTAGE, HOW
THOSE RISK FACTORS COME TOGETHER
BECAUSE THAT INTERSECTION, I
I
ALLUDED IN THE CHAT, RISK
FACTORS CAN GET TO IDEAS OF
BIOLOGICAL PROFILES THAT PORTEND
THESE ADVERSE OUTCOMES THAT LEAD
TO DISPARITIES IN A WAY WE'RE
NOT THINKING ABOUT CURRENTLY AND
I'LL STOP WITH MY KIND OF LIKE
SOAP BOX HERE SAYING A TARGET
ED
BIOMARKER WOULD BE HELPFUL AS A
FIRST STEP.
I DON'T THINK WE'RE THERE YET,
AS A FIELD.
>> DEFINITELY.
THE COMMUNICATION WITH THE FIELD
AND WITH THE COMMUNITY HAS FELT
LIKE A REALLY BIG CHALLENGE, AND
KIND OF UNDERSTANDING, YOU KNOW,
HOW SOMETHING LIKE A FAIRLY
STRAIGHTFORWARD INFECTION COULD
END UP GOING TOWARDS SEPSIS.
SO IT FEELS LIKE THE SEPSIS
AWARENESS ORGANIZATIONS AND
LEVERAGING OTHER ASPECTS TO HELP
WITH THE COMMUNICATION PIECE IS
AN AREA THAT I DON'T PERSONALLY
HAVE EXPERIENCE OR EXPERTISE IN
BUT IT WOULD BE GREAT TO LEARN A
LITTLE BIT MORE ABOUT WHAT'S
BEEN EFFECTIVE THERE.
>> WE HAVE A QUESTION FROM THE
AUDIENCE.
>> YEAH, MAY I HAVE A QUESTION?
SO, YEAH --
>> PLEASE STATE YOUR NAME.
>> YEAH, DANIEL LEE FROM TEXAS
A & M UNIVERSITY.
SO, GREAT SESSION.
AND GREAT TALKS.
MY QUESTION IS IN ADDITION TO
THE LIVING CONDITION, SUCH AS
POVERTY, GENETIC BACKGROUND SUCH
AS GENE EXPRESSION LEVELS,
DIFFERENCE IN IMMUNE CELL
FUNCTION, RACIAL DISPARITIES.
>> I'M HAPPY TO TAKE A FIRST
PASS ON THAT QUESTION.
SO, IT'S A GOOD QUESTION, IT'S
TALKING ABOUT BIOLOGICAL
DETERMINANTS FOR SEPSIS AND
DISPARITIES.
I THINK IT'S THE FIRST PLACE TO
START, RECOGNITION THERE ARE NO
GENETIC EPITOPES THAT SEPARATE
RACIAL GROUPS FROM EACH OTHER IN
A WAY THAT HAS BEEN VALIDATED
CONSISTENT AND POPULATION
ATTRIBUTABLE.
ESPECIALLY GIVEN THE AMOUNT OF
GENETIC ADMIXTURE BETWEEN RACES,
IT BECOMES DIFFICULT TO THINK
ABOUT HOW GENETIC DIFFERENCES
COULD REPRESENT TARGETABLE OR
RELIABLE MARKER FOR ADVERSE
SEPSIS OUTCOME IN CONTEXT OF
RACE.
THE COMMENT ABOUT BIOLOGICAL
IMPACT ON RACIAL DISPARITIES, I
THINK ONE THING THAT WE HAVE NOT
DONE AS GOOD A JOB MUCH AT
UNDERSTANDING BEYOND JUST
GENETICS, BIOLOGICAL PROFILES
THAT COULD BE ASSOCIATED WITH
RACIAL DIFFERENCES, AND THEN HOW
MUTABILITY OF PROFILES OVER TIME
CONTRIBUTES TO DIFFERENT
POPULATION RISK, BUT IN TERMS OF
DISTINCT, YOU KNOW, IDENTIFIED
GENETIC EPITOPES THAT SEPARATE,
YOU KNOW, DISEASE OUTCOME
DIFFERENCES BETWEEN RACES HAVE
YET TO BE STUDIED BECAUSE IT'S A
SIMPLE MATTER BEING VARIABLE
GROUPS ARE ABLE TO BE HAVE
GENETIC ADMIXTURE, AND THAT'S
WERE GENETICS BECOME HELPFUL.
>> ONE THING I'LL ADD, I TOTALLY
AGREE, DR. CHESLEY PUTTING
TOGETHER PIECES FROM DR. MARTIN
AND DR. RUDD'S TALKS, DR. MARTIN
SHOWED HOW AGE IS SUCH A HUGE
RISK FACTOR FOR SEPSIS INCIDENCE
AND MORTALITY, DR. RUDD, YOU
WERE TALKING ABOUT DIFFERENCE
BETWEEN BIOLOGICAL AND
CHRONOLOGICAL AGE WITH
EPIGENETIC STUDY YOU SHARED,
THAT THERE'S RACISM GETS UNDER
YOUR SKIN, POVERTY GETS UNDER
YOUR SKIN, LITERALLY, THE
CONCEPT OF EMBODIEDNESS THAT
HUMAN BEINGS EMBODY THEIR
EXPERIENCES, MEANING THAT THE
SOCIAL CONDITIONS THAT WE FACE
CAN GET PROGRAMMED
EPIGENETICALLY AND THEN CHANGED,
THE WAY WE AGE, SO THAT MAY BE
ONE POTENTIAL MECHANISM THAT MAY
ALSO EXPLAIN WHY BLACK PATIENTS
ARE SO MUCH YOUNGER ON AVERAGE
WHEN THEY BECOME CLINICALLY ILL
AND THERE BY CHRONOLOGICAL AGE
IS YOUNG BUT BIOLOGICAL AGE MAY
BE GREATER BECAUSE OF THE SOCIAL
DISADVANTAGES BEING FACED.
>> I THINK THAT'S ONE MORE
ELEMENT LIKE CHRIS WAS SAYING
THERE'S THE ELEMENT OF
BIOLOGICAL AND STRUCTURAL
ELEMENTS, BUT THAT'S ANOTHER
ONE, GOOD TO BETTER UNDERSTAND
CHRONOLOGIC AGE.
I WOULD ADD, CHRIS SAID NICELY,
MUCH OF THE DISPARITY WORK IN
SEPSIS IS BASED IN THE U.S.
WHAT CHRIS SAID IS ABSOLUTELY
RIGHT, LIKE RACE AND GENETICS DO
NOT TRACK IN THE U.S., RACE AND
POLYMORPHISMS.
THERE ARE GENDER DIFFERENCES
ELSE IN THE WORLD, OTHER
DISPARITIES, BUT IF THERE IS A
GENETIC FACTOR, FOR INSTANCE
DISPARITIES BASED ON RACE OR
GENDER IN NEONATES, WHERE MAYBE
OTHER THINGS, RIGHT, YOU'RE IN
THE HOSPITAL, YOU'RE NEWBORN,
STILL THAT DOESN'T MITIGATE SOME
SOCIAL DETERMINANTS SO WE
REALIZE THERE'S OTHER FACTORS.
SOMETIMES PEOPLE POINTED TO THAT
AS ONE WAY OF SAYING WELL, MAYBE
THERE'S SOMETHING MORE
BIOLOGICAL.
CHRIS IS ABSOLUTELY RIGHT.
THERE'S NO GENETIC FACTOR THAT'S
GOING TO TRACK AND CERTAINLY
IT'S OUTWEIGHED BY OTHER THINGS
WE SEE, VASTLY LARGER COMPONENTS
OF DISPARITIES.
>> DR. AGRIWAL, YOU HAVE A
QUESTION?
>> I WANT TO CIRCLE BACK ON THE
DEFINITION OF SEPSIS THAT TOOK
US -- ORGAN FAILURE OR THE
INFECTION OR IS IT BIOMARKER, I
WAS WONDERING WHAT'S THE
STANDARD OF CARE OR DIAGNOSTIC
PROCEDURE TO IDENTIFY THAT THE
PATIENT IS GOING INTO SEPSIS AND
IS IT THE BIOMARKER DISCOVERY OR
IS IT IMMUNE RESPONSE OF
NEUTROPHILS, HOW IS IT DONE AND
HOW SOON IS IT DONE AFTER WHICH
THE ANTIMICROBIAL REGIMEN CAN BE
ADMINISTERED?
AND HOW EFFECTIVE IT IS, IN THE
CURRENT STATE OF THE ART?
>> I'LL MAYBE TACKLE THAT FIRST.
I MIGHT EVEN THINK ABOUT WHAT
JOHN WAS DESCRIBING FOR
IMPLEMENTATION SCIENCE, HOW YOU
THINK ABOUT THAT FROM A PROCESS
PERSPECTIVE.
I THINK WE ALL HAVE EXPERIENCE
WIT.
WE ALL REALIZE THERE'S
INITIATIVES IN PLACE.
I DON'T THINK WE'RE CONSISTENT
ABOUT IT IN MANY WAYS, I THINK
SURVEY LINK FOR INFECTION MAY BE
ONE OF THE KEYS, WHY KRISTINA
WAS USING TECHNOLOGIES TO
IDENTIFY HIGH RISK POPULATIONS
WHICH ARE PROBABLY LOOKING FOR
INFECTION AMONG PEOPLE WHO ARE
AT HIGHER RISK OF DEVELOPING
SEPSIS, IDENTIFYING PEOPLE WITH
ORGAN DYSFUNCTION IS TOO FAR
DOWN THE ROAD TO HAVE THE
OPPORTUNITIES FOR PREVENTION.
IN MY MIND, AND THIS GETS BACK
TO UP IS SIS -- SEPSIS
DEFINITION WHICH I'LL TACKLE, I
WAS A CO-AUTHOR, WE STEPPED AWAY
FROM A COUPLE THINGS.
WE DO REALIZE SIRS WAS A
SURVEILLANCE TOOL, LARGELY USED
TO TRY AND IDENTIFY PEOPLE
HAVING THAT ABERRANT RESPONSE.
IT'S STILL DOWNSTREAM OF THE
INFECTION AND POTENTIALLY
DOWNSTREAM OF WHAT WE MIGHT BE
ABLE TO IDENTIFY PEOPLE AT RISK
OF SEPSIS AND ORGAN DYSFUNCTION.
AND THE OTHER PART IS THAT ORGAN
DYSFUNCTION COMPONENT IS
IMPERFECT.
I WAS ONE OF THE DISSENTERS IN
THAT GROUP THAT FELT LIKE
MAINTAINING AN ELEMENT OF MOVING
FROM UPSTREAM TO FURTHER
DOWNSTREAM WAS IMPORTANT, FOR
EPIDEMIOLOGIC AND CLINICAL
PURPOSES, BUT CONCEPTUALLY THE
CONCEPT STILL WORKS.
THE PURPOSE HERE IS TO SAY, YOU
KNOW, IF SEPSIS IS DEFINED BY
ORGAN DYSFUNCTION WE NEED TO BE
UPSTREAM OF THAT, WHETHER YOU
CALL THAT INFECTION, WITH
SEPSIS, EVERYTHING UPSTREAM IS
INFECTION, THAT SURVEILLANCE
ELEMENT STILL NEEDS TO BE IN
PLACE WHETHER YOU'RE SURVEILLING
USING BIOMARKERS FOR ABERRANT
RESPONSE TO THE INFECTION OR
SURVEILLING FOR THE INFECTION OR
USING CLINICAL RISK FACTORS,
WHAT THE IMPLEMENTATION SCIENCE
PIECE COMES IN.
I'D LOVE TO HEAR OTHERS, BECAUSE
EVERYONE ELSE WORKS ON THIS TOO.
>> SUPER QUICKLY, I FULLY AGREE
AND I THINK ONE CHALLENGE KIND
OF WITH THAT, THE UPSTREAM
PIECE, HAS BEEN WORKING IN
SYSTEMS THAT AREN'T NECESSARILY
FULLY INTEGRATED SO I THINK
FULLY INTEGRATED WE'LL CALL IT
PRAGMATIC QUALITY IMPROVEMENT
WORK COULD BENEFIT FROM THINKING
THROUGH HOW WE CONSIDER SEPSIS
RISK, AND WHETHER THERE'S A WAY
TO INCORPORATE SOME MORE
ADVANCED STATISTICAL TECHNIQUES
OR AT LEAST EVEN LIKE A MORE
SIMPLISTIC RISK SCORE, I THINK
THAT PIECE HAS NOT BEEN FULLY
DEVELOPED FOR TOTALLY
UNDERSTANDABLE REASONS THAT
WOULD BE VERY DIFFICULT TO
IMPLEMENT.
>> I HAVE A QUESTION.
REGARDING WHAT CHRIS WAS
MENTIONING, SO WHAT I UNDERSTAND
IS THAT THERE'S NOT MUCH STRONG
EVIDENCE TO SUPPORT GENETIC
FACTORS ASSOCIATED WITH
SUSCEPTIBILITY ESPECIALLY IN
AFRICAN AMERICANS.
IS IT -- DO YOU THINK IT HAS
MORE TO DO WITH THERE ARE NOT
STRONG GENOMIC DATABASES FOR
THIS POPULATION GROUP BECAUSE
MOST DATABASES ARE PRIMARILY
CAUCASIANS?
BECAUSE THERE ARE SOME STUDIES,
MAYBE VETERANS AFFAIRS, I
HAVEN'T SEEN MUCH STRONG GENOMIC
STUDIES DONE IN THESE PATIENTS,
SO DO YOU THINK THAT COULD BE A
FACTOR?
BECAUSE WE DON'T SEE ANYTHING
BECAUSE DATABASE DOESN'T EXIST?
>> YEAH, I THINK MULTIPLE
FACTORS.
I THINK ONE OF THEM HAS TO DO
WITH REPRESENTATION AND GENETIC
STUDIES CERTAINLY.
ALSO IT BECOMES CHALLENGING
MOVING FROM LIKE A STUDY IN
POPULATION, LIKE A NATIONAL
SCALE, EVEN MORE REGIONAL SCALE,
ENSURING THERE'S ENOUGH
DIVERSITY IN RECRUITING
POPULATIONS IS ONE THING.
BUT FOR ME, AGAIN I'M NOT A
GENETICS RESEARCH, I'M A HEALTH
THE QUESTION RESEARCHER, THE
IDEA THAT GENETICS AS A
BIOLOGICAL DIFFERENCE BETWEEN
RACES FALLS FLAT ON ITS HEAD
WHEN YOU ACKNOWLEDGE THAT RACIAL
GROUPS ARE ABLE TO HAVE -- TO
PROCREATE AND HAVE GENETICS AS
ANY KINDS OF, YOU KNOW,
COMBINATION SO IT'S REALLY A
SNAPSHOT.
LIKE EVERY GENETIC STUDY FROM
THAT PERSPECTIVE BECOMES A
SNAPSHOT IN TIME AND GIVEN TIME,
YOU KNOW, THESE POPULATION
DIFFERENCES THERE'S NOTHING
THAT, YOU KNOW, WOULD PREVENT
SOMEONE TO IDENTIFY AS ONE OR
OTHER RACE, SO SOME OF THIS --
THIS IS THE STUFF OF THE SOCIAL
CONTEXT, SOCIAL DEFINITION OF
RACE AS A SOCIAL CONSTRUCT,
RATHER THAN BIOLOGICAL
CONSTRUCT.
AND SO I THINK IF WE THINK ABOUT
WHAT IS MOST USEFUL BANG FOR
BUCK WITH LIKE EITHER
INTERVENTION OR FOR LIKE THE
CONTEXT OF DESIGNING A STUDY,
FOCUSING PURELY ON THE GENETIC
PIECE OF SEPSIS RISK FACTOR AND
RACIAL DISPARITY SEEMS -- VERY
ALSO PROBABILITY THAT WOULD BE
EFFICIENT USE OF STUDY TIME, AS
A RESEARCHER THAT'S HOW I THINK
ABOUT IT.
ON SMALLER TIME SCALES, IT
SHOULD BE STUDIED, WHAT IT MEANS
TO BE GENERALIZABLE BUT IF I
DON'TS DON'T HAVE IT, MY
GRANDPARENTS DON'T HAVE THAT,
THEY ARE STILL AT RISK, FROM A
PRACTICAL PERSPECTIVE AND
RESEARCH AND KNOWN BIOLOGIC
CONSTRUCT, THAT'S KINDS OF
MATCHED TOGETHER.
>> I TOTALLY AGREE WITH WHAT DR.
CHESLEY SAID.
IT'S BEEN SHOWN INDIVIDUALS WITH
AFRICAN BACKGROUND HAVE MORE
GENETIC DIVERSITY.
A PERSON OF EUROPEAN ANCESTRY,
MORE SIMILAR THAN TWO SPECIES OF
AFRICAN ANCESTRY.
THERE'S BEEN MORE TIME ON THE
AFRICAN CONTINENT FOR GENETIC
DIVERSITY TO DEVELOP BECAUSE
THAT WAS SORT OF THE
ORIGINATION, AND THE SPECIES --
THERE'S MORE GENETIC DIVERSITY
AMONG PEOPLE WHO WE IDENTIFY AS
BLACK IN THE UNITED STATES AND
SO IT WOULD NOT BE POSSIBLE FOR
THERE TO BE A SINGLE AGAINST
ROOT CAUSE OF THIS HIGHER
INCIDENCE OF SEPSIS IN THAT
GROUP.
DR. LEE WAS NEXT.
>> THANK YOU SO MUCH.
REALLY SOME WONDERFUL TALKS.
WHAT STRUCK ME FROM WHAT YOU ALL
DESCRIBED TOGETHER WAS THE
CHALLENGE OF WHO IS SPEAKING ON
THIS TOPIC.
LIKE EVERYONE HERE, LARGELY
PULMONARY AND CRITICAL CARE,
RESEARCH IN THE DOMAIN OF
HOSPITAL BASED OR SEVERE
INFECTION, BUT MANY OF THE
POINTS RAISED REALLY HAVE TO DO
WITH THE PRECURSORS, SYNDEMIC,
MULTI-MORBIDITY, GEOGRAPHIC OR
SEGREGATION, ALL THOSE OTHER
FACTORS.
I WONDER IF YOU HAVE THOUGHTS
WHO WE NEED TO BRING INTO THIS
CONVERSATION, HOW DO WE DO SO,
SO THAT WE CAN MAKE SURE WE
HAVE, YOU KNOW, REALLY SMART AND
TALENTED AND INNOVATIVE PEOPLE
WHO ACTUALLY HAVE THE LEVER AND
CAPE
CAPABILITY TO DO THAT WORK AND
IMPLEMENTATION OR INTERVENTION
ULTIMATELY.
>> TERRIFIC POINT.
THANK YOU FOR MAKING IT.
CLEARLY I'LL SAY SOMETHING THAT
EVERYONE WILL CONSIDER TO BE
OBVIOUS BUT IT NEEDS TO INVOLVE
DIVERSE GROUP OF PROFESSIONALS,
BUT I HAS TO ENGAGE HEALTH
SYSTEMS AND COMMUNITIES BECAUSE
IT'S ALL OF THOSE PIECES
TOGETHER AND IF I SAID HOW MIGHT
YOU DO THIS I WOULD THINK YOU
MIGHT START INTEGRATED HEALTH
SYSTEMS LIKE THE V.A. OR KAISER
WHERE SYSTEMS ARE INTEGRATED,
PATIENT ENCOUNTERS ARE CAPTURED,
PARTICULARLY IF ENGAGED IN A
COMMUNITY WITH A BETTER WAY TO
ROLL OUT AND TEST INTERVENTIONS
BUT THAT WOULD BE ONE WAY TO
BETTER UNDERSTAND A LOT OF
FACTORS WE'RE TALKING ABOUT, HOW
TO PULL THEM TOGETHER, WHAT
INTERVENTIONS ARE MOST
EFFECTIVE, BUT IN MY MIND IT'S A
HUGE OPPORTUNITY.
YOU CAN START IN DIFFERENT
PLACES BUT I THINK MAYBE THAT'S
THE EASIEST PRAISE -- PLACE TO
START BUT IT HAS TO PULL
TOGETHER STAKEHOLDERS TO MAKE IT
WORK.
>> I WILL PLUG SOCIOLOGISTS HERE
BECAUSE THEY HAVE A MORE ROBUST
UNDERSTANDING HOW TO
OPERATIONALIZE DISCRETE
STRUCTURAL DISADVANTAGE AND
DETERMINANTS THAT I THINK HAS
NOT BEEN EASILY OR MORE WIDELY
ADAPTED IN MANY HEALTHCARE
SITUATIONS SO A LOT OF WORK I
DO, IT IS TRYING TO LEARN ABOUT
HOW DIFFERENT STRUCTURAL
DETERMINANTS HAVE BEEN
OPERATIONALIZED IN THE FIELDS
SUCH AS EDUCATION, ECONOMICS
MORE GENERALLY, TRYING TO THINK
ABOUT WHAT WE KNOW ABOUT OTHER
FIELDS AND WHAT THAT MEANS FOR
LIKE BUILDING THAT SOCIAL
CONTEXT, WHAT THAT MEANS FOR
HEALTHCARE EXPERIENCE.
BUT IT'S LIKE ON TOP OF THAT
PROBABLY THE FIRST STEP IS LIKE
ENGAGING COMMUNITY AND SO LIKE
ESPECIALLY WHEN YOU THINK ABOUT
INTERVENTION DEVELOPMENT, I
THINK THE SUCCESSFUL STUDIES
HAVE BEEN ABLE TO MAKE A
DIFFERENCE, MORE LOCAL LEVEL,
LIKE CARDIOVASCULAR HEALTH HAVE
PARTNERED WITH CAPTIVE AUDIENCE
OR CAPTIVE STAKEHOLDERS THAT
HAVE A DIRECT CONNECTION TO
PEOPLE THAT EXPERIENCE THESE
DISPARITIES AND SO IT'S KIND
OF -- IT WOULD MAKE SENSE TO GO
BACK TO DISCUSSIONS ABOUT
AWARENESS, VACCINATION CAMPAIGNS
AND THINGS LIKE THAT, MAKE THE
CONNECTION TO SEPSIS AS RELATED
TO THINGS LIKE YOUR FLU VACCINE,
STREP, PNEUMONIA VACCINES,
THINGS WE DO FOR CHILDREN SHOULD
BE IMPORTANT FOR ADULTS, LIKE
THAT KIND OF DISCUSSION.
SO THERE ARE MANY OPPORTUNITIES.
THE PROBLEM IS COMPLICATED, MANY
OPPORTUNITIES TO GET STARTED
LITERALLY ANYWHERE, IT WAS A
GREAT QUESTION.
>> I THINK TOM BELLI AT MICHIGAN
WORKS WITH MARIE HUFF, SOCIAL
EPIDEMIOLOGIST, DR. RUDD SHARED
WORK BY NANCY KRIEGER, SOCIAL
EPIDEMIOLOGIST, IN A DIFFERENT
FIELD FOCUSING ON ONCOLOGY BUT
THAT MIGHT BE A GOOD MODEL.
THERE ARE DIVISIONS, FOR EXAMPLE
HOPKINS DIVISION OF PULMONARY
AND CRITICAL CARE HIRED KATIE, A
SOCIOLOGIST, INTO THEIR
DIVISION, MODELS OF WAYS THAT
COULD BE SUCCESSFUL.
>> I THINK WE'RE NEARING OUR
BREAK.
WE HAVE TIME FOR ONE MORE
COMMENT OR QUESTION.
>> THANK YOU SO MUCH FOR THE
WONDERFUL TALKS.
I HAVE A COMMENT AND QUESTION.
WE ALL SHARE THE STRUGGLE WITH
SEPSIS DEFINITIONS.
THEY ARE DIFFICULT IF YOU DON'T
HAVE, YOU KNOW, AN AMAZING
DEFINITION, THAT'S WHAT YOU
NEED.
I CAN TELL YOU FOR PEDIATRIC
SEPSIS WORLD WHICH IS RELEVANT
TO MY WORK, WE HAVE THE PHOENIX
CRITERIA BUT WE'RE WORKING NOW
AS A GROUP WORKING ON DEFINITION
FOR EMERGENCY SETTINGS WHICH
MEANS WE'LL TRY TO USE EARLIER
DATA TO HELP, YOU KNOW, WITH
DEFINING AND STUDYING SEPSIS.
ONE QUESTION I HAVE, IT WAS THE
FIRST TALK, ABOUT SUBTYPES AND
THE COMORBIDITIES IN DIFFERENT
PATIENT GROUPS, ARE THERE ANY
STUDIES ABOUT POTENTIALLY SOME
OF THOSE COMORBIDITIES SHARING
SPECIFIC PATHWAYS OR TARGETS?
BECAUSE IF WE'RE TRYING TO
TACKLE RACIAL DISPARITIES MAYBE
WE SHOULD LOOK INTO
COMORBIDITIES THEMSELVES AND SEE
IF THERE ARE ANY COMMONALITIES
THERE THAT WE COULD TARGET WITH
TREATMENTS.
>> GREAT QUESTION.
I THINK THAT WAS ONE OF THE
STUDIES I SHARED THAT HAD USED
THE MIMIC DATA, LATENT CLASS
ANALYSIS TO IDENTIFY DIFFERENT
CLASSES OF PATIENTS ADMITTED TO
ICUs IN THE U.S. AND THEN
LOOKED TO SEE ASSOCIATION OF
THOSE CLASSES WITH RISK FOR
ORGAN FAILURE AND SEPSIS AND
RELATED MORTALITY.
I AM NOT AWARE OF STUDIES THAT
HAVE LIKE WATCHED THAT FULL
CHAIN OF LIKE FROM ASSOCIATION
TO CAUSATION OF FIRST
IDENTIFYING PEOPLE THAT CLUSTER
BASED ON BASELINE RISK FACTORS,
PARTICULARLY I THINK YOU'RE
ASKING ABOUT MEDICAL BASELINE
RISK FACTORS.
AND THEN LOOKED TO SEE WHETHER
THERE'S ASSOCIATION IN THE
PHYSIOLOGY OF THOSE RISK FACTORS
AND THEN SEE IF THAT MAPS ON TO
SOME PHENOTYPES OF SEPSIS, MAYBE
IT'S NOT IMPORTANT THEY DO MAP
ON.
MAYBE IT'S JUST ENOUGH TO KNOW
THERE'S THAT SHARED PHYSIOLOGY
WE MIGHT BE ABLE TO INTERVENE
UPON.
I WOULD DEFER TO SOME OF MY
COLLEAGUES THAT HAVE MORE
TRANSLATIONAL EXPERTISE THAT
REALLY UNDERSTAND MORE OF THE
INFLAMMATORY PATHWAYS OR LOOKING
AT MICROVASCULAR CHANGES FOR
EXAMPLE, I THINK SOME THINGS
HAVE BEEN PROPOSED BUT I'M NOT
AWARE OF CLEAR CONCRETE EVIDENCE
THAT IS SHOWING US SHARED
PATHOPHYSIOLOGY BETWEEN THESE
REALLY IMPORTANT COMORBID
CONDITIONS PUTTING PEOPLE AT
RISK.
>> THANK YOU.
>> ANYONE ELSE WANTS TO TACKLE
THAT?
I'LL AGREE COMPLETELY WITH WHAT
KRISTINA SAID.
I DON'T KNOW PATHOPHYSIOLOGY
LINKS FOR ORGAN DYSFUNCTION.
CHRONIC LUNG DISEASE LEADS TO
RESPIRATORY FAILURE BUT WHETHER
PATHWAYS INVOLVED ARE THE SAME
BIOLOGICALLY FOR INSTANCE I
DON'T KNOW THAT WE KNOW.
>> THINK YOU ALL FOR A GREAT
DISCUSSION.
DEEP AND I WOULD LIKE TO THANK
THE SPEAKERS IN THE FIRST
SESSION.
THIS PUTS AN END TO SESSION 1.
I WANT TO TURN IT OVER TO NITIN
AND THANK ALL THE SPEAKERS FOR A
FANTASTIC TALK.
>> THANK YOU.
IT WAS A GREAT DISCUSSION.
I HOPE THAT EVERYBODY HAD A
CHANCE TO TAKE AWAY SOME
CRITICAL MESSAGES FROM THIS
PANEL.
LET'S TAKE A QUICK BREAK.
WE WERE SUPPOSED HAVE THE BREAK
FROM 11:15 BUT IT SHOULD BE
ENOUGH TO GRAB COFFEE OR LUNCH
QUICKLY.
WE'LL RECONVENE A COUPLE MINUTES
BEFORE 12:15 SO WE CAN GET STARTED.
I WOULD LIKE TO WELCOME US.
THIS IS GOING TO BE AN EQUALLY
EXCITING SESSION, AS SESSION 1.
>> THANKS, NITIN, FOR INVITING
US.
CAN EVERYONE HEAR US?
WE HAVE A NICE SESSION LINED UP,
FOUR SPEAKERS, FOCUSING ON BASIC
TRANSLATIONAL ASPECT OF
IMMUNOTHROMBOSIS, RANGING
FROM -- A SESSION ON WHERE WE
STAND ABOUT THE THERAPY AND
CLINICAL TRIALS IN SEPSIS, WHY
THINGS HAVE FAILED, WHAT HAS
FAILED, THAT WOULD BE THE LAST
TALK OF THE SESSION.
SO, WITH MY GREAT PLEASURE I
WOULD LIKE TO INTRODUCE THE
DISTINGUISHED PROFESSOR OF
MEDICINE FROM UNC CHAPEL, AND HE
HAS DECADES OF EXPERIENCE IN
STUDYING SPECIFICALLY HOW EXTRA
VASCULARS CONTRIBUTE IN SEPSIS
AND OUTSIDE OF SEPSIS, HERE TO
SHARE THE WEALTH OF KNOWLEDGE.
PLEASE, THANK YOU VERY MUCH.
>> I'D LIKE TO THANK THE
ORGANIZERS FOR INVITING ME.
I'M GOING TO TALK ABOUT
COAGULATION, IMMUNOTHROMBOSIS,
EXTRACELLULAR VESICLES AND
SEPSIS.
NEXT SLIDE PLEASE.
SO THIS IS THE OUTLINE OF MY
PRESENTATION.
I'M GOING TO GIVE YOU AN
INTRODUCTION TO COAGULATION.
AND THEN THE DEFINITION OF
IMMUNOTHROMBOSIS, INTRODUCE
EXTRACELLULAR VESICLES, EVS, AND
GO THROUGH HISTORY ON THE
LESSONS WE'VE LEARNED FROM E.
COLI SEPSIS, EFFECT OF
ANTICOAGULANTS, MODELS OF SEPTIC
PATIENTS, AND TALK ABOUT MY
FAVORITE MOLECULE, THE ROLE OF
TISSUE MONOCYTES, AND MOUSE
MODELS AND ENDOTOXEMIA AND
CONCLUSIONS.
THIS IS A SIMPLIFIED VERSION OF
THE CASCADE, ESSENTIAL FOR
HEMOSTASIS BUT CAUSES
THROMBOSIS.
TWO PATHWAYS, ONE IS EXTRINSIC.
I WORK ON TISSUE FACTOR,
CLOTTING CASCADE.
THERE ARE THREE MAJOR PATHWAYS,
IN ORANGE INHIBITS PROTEIN
SYSTEM THAT CLEAVES, FACTORINGS
8 AND 9, AND THAT'S ALSO
THROMBOMODULIN, AND
ANTI-THROMBIN.
THAT WILL COME UP IN MY TALK
LATER.
NEXT PLEASE.
SO, I THOUGHT IT WAS IMPORTANT
TO DEFINE WHAT I DEFINE
IMTHROMBOSIS VERSUS
THROMBOINFLAMMATION.
IMMUNE CELLS CONTRIBUTE TO
THROMBOSIS WITHIN A BLOOD
VESSEL.
THIS WAS FIRST COINED IN 2013 BY
ENGELMANN AND MASS BEGGAR.
THE RIGHT-HAND SIDE IS
NEUTROPHIL EXTRACELLULAR
TRAPPING RELEASED FROM A
NEUTROPHIL.
NEXT PLEASE.
THERE IS THROMBOINFLAMMATION,
THAT DESCRIBED PROCESS WHERE
INFLAMMATION OF THROMBUS LEADS
TO INFLAMMATION AND RECRUITMENT
OF IMMUNE CELLS.
EXAMPLE IS ISCHEMIC STROKE.
THROMBUS COMES FIRST, BLOCKS THE
BLOOD VESSEL, SECONDARILY LEADS
TO INFLAMMATION.
NEXT SLIDE PLEASE.
EXTRACELLULAR VESICLES ARE
MICROPARTICLES, MICROVESICLES
RELEASED FROM CELLS, A VARIETY
OF SIZES BUT THE GLOBAL TERM IS
EXTRACELLULAR VESICLES, EVS.
SO, IMPORTANT COMPONENTS OF THE
EXTRACELLULAR VESSELS ARE PRO
COAGULANT ACTIVITY, THERE ARE
HIGH LEVELS OF PS-POSITIVE
EXTRACELLULAR VESICLES IN THE
BLOOD, MODEST LEVEL OF PRO
COAGULANT EVS.
A PHOSPHOLIPID BINDS, MORE
PROCOAGULANT.
THE EXTRACELLULAR VESICLES WE'RE
INTERESTED IN ARE IT POSITIVE
EXTRACELLULAR VESICLES, ALSO
HAVE PS, THEY ARE NOT DETECTED
IN HEALTHY INDIVIDUALS BUT
INCREASES IN DIFFERENT DISEASE
STATES SUCH AS SEPSIS AND ARE
RELEASED FROM ACTIVATED
MONOCYTES, ALSO FROM TUMOR
CELLS.
NEXT PLEASE.
SO THIS IS SUMMARY FROM FLETCHER
TAYLOR'S WORK, MODELS OF SEPSIS.
AND WHAT THEY DIVIDED THESE
SEPSIS PHASES INTO, TWO PHASES,
FIRST BETWEEN ZERO AND EIGHT
HOURS, YOU CAN SEE INCREASE IN
TISSUE FACTOR EXPRESSION,
DYSREGULATION OF THE
ANTICOAGULANT SYSTEM,
ENDOTHELIAL CELL DYSFUNCTION,
THAT LEADS TO ACTIVATION OF
COAGULATION THAT ULTIMATELY
LEADS TO SHOCK AND DISSEMINATED
INTRAVASCULAR COAGULATION.
NEXT PLEASE.
BETWEEN NINE AND 24 HOURS, THERE
IS THE SECOND PHASE WHICH IS
ASSOCIATED WITH RELEASE OF
HISTONES, REPERFUSION INJURY,
OXIDATIVE STRESS TO ULTIMATELY
LEADS TO ORGAN FAILURE.
NEXT PLEASE.
SO, WHAT IS EFFECT OF
ANTICOAGULANTS IN SEPTIC
PATIENTS?
WITH ANIMAL MODELS EVERYTHING IS
SUCCESSFUL BECAUSE YOU CAN
INTERVENE BEFORE THE DISEASE
HAPPENS, SO IF YOU SEE
PROTECTIVE OF BABOONS FROM
DEATH, TISSUE FACTOR PATHWAY
INHIBITOR PROTECTIVE, REDUCE THE
IL-6 LEVELS, ANTI-THROMBIN WAS
PROTECTED IN BABOON MODEL.
IF YOU MOVE TO, NEXT PLEASE, THE
HUMANS, YOU'RE FAMILIAR WITH APC
TRIAL THAT REDUCED ALL-CAUSE
MORTALITY BY 6.1% IN SEVERE
SEPSIS.
TFPI WAS NOT SUCCESSFUL AND WAS
ASSOCIATED WITH INCREASED
BLEEDING.
ANTI-THROMBIN DID NOT AFFECT
ALL-CAUSE MORTALITY.
IN FACT COMBINING ANTI-THROMBIN
WITH HEPARIN INCREASED BLEEDING.
NEXT PLEASE.
SO, AN INTERESTING MOLECULE IN A
TRIAL, IT DID NOT REDUCE
ALL-CAUSE MORTALITY IN SEPSIS,
AND WHAT WAS CALLED SCHOLAR
TRIAL, NEXT PLEASE.
IF WE LOOK AT EFFECT OF SOLUBLE
THROMBO MODULIN, COMPARED WITH
HEPARIN, ANOTHER STUDY IN 2016
REDUCED THE IN-HOSPITAL
MORTALITY, SMALL STUDY WAS NOT
POSITIVE, BUT THEN IN A POST HOC
ANALYSIS OF THE TRIAL BENEFITS
WITH HIGHER PATIENTS WITH HIGHER
LEVELS OF THROMBIN,
ANTI-THROMBIN COMPLEXES, OTHERS
WITH LOWER LEVELS, AND IN FACT A
META-ANALYSIS OF THREE
RANDOMIZED TRIALS SHOWED THE
SOLUBLE REDUCED 28-DAY MORTALITY
WITH SEPSIS COAGULOPATHY BUT NOT
WITHOUT.
NEXT SLIDE PLEASE.
SO I THINK DATA IS INTERESTING
BECAUSE WHAT IT SHOWS HERE IS AS
YOU INCREASE THE COAGULOPATHY
FROM LEFT TO RIGHT, THERE'S
INCREASE IN MORTALITY, AND THEN
WHEN THE TWO GROUPS ARE TREATED
WITH EITHER THE SOLUBLE THROMBO
M
ODULIN OR PLACEBO, GREAT
IN THOSE WITH HIGHEST LEVEL OF
THE COMPLEX.
IN CONTRAST A COMMON MARKER
FOREACTIVATION COAGULATION
THERE'S NO RELATIONSHIP AT ALL,
AND THAT'S PROBABLY BECAUSE
DURING SEPSIS THERE'S INCREASE
IN INHIBITOR 1 BUT WOULD PREVENT
RELEASE OF THE D-DIMER FROM
CROSS-LINKED FIBRIN.
NEXT PLEASE.
WHAT ABOUT THE USE OF
ANTICOAGULANTS TO TREAT SEPSIS
PATIENTS AND PATIENTS WITH VIC?
NEXT.
APC WAS APPROVED IN 2001, FOR
TREATMENT OF PATIENTS WITH
SEVERE SEPSIS BUT WITHDRAWN FROM
THE MARKET IN 2011 DUE TO LACK
OF EFFICACY.
NEXT.
SO SOLUBLE THROMBOMODULIN HAS
BEEN USED IN JAPAN FOR 2008 FOR
TREATMENT INCLUDING
SEPSIS-INDUCED DIC.
NEXT.
SO, A QUESTION IS WHY IS
CLOTTING SYSTEM ACTIVATED DURING
MICROBIAL INFECTION?
NEXT.
AND CLOTTING IS PART OF THE
INNATE IMMUNE SYSTEM.
NEXT.
SO, THE HORSESHOE CRAB HAS A
HEMOCYTE RELEASING CLOTTING
FACTORINGS THAT ENDS UP CAUSING
A CLOT.
THAT'S THE BASIS OF THE ASSAY.
HUMANS HAVE A MONOCYTE, LPS
ACTIVATES MONOCYTE TO EXPRESS
TISSUE FACTOR, THAT DOES THE
SAME AS HEMOCYTE, ACTIVATION OF
CLOTTING SYSTEM, TO WALL OFF THE
INFECTION SO IT DOESN'T BECOME
SYSTEMIC.
NEXT PLEASE.
SO THIS IS THE LPS INDUCTION IN
HUMAN MONOCYTES.
IT IS ONLY EXPRESSED BY
MONOCYTES, NOT BY NEUTROPHILS OR
B CELLS, AND THIS IS A
HOST/DEFENSE RESPONSE IN
IMMUNOTHROMBOSIS.
NEXT.
WHEN WE ADD LPS TO HUMAN
MONOCYTES WE GET A TRANSIENT
INDUCTION ACTIVITY ON THE CELLS
THAT WOULD LEAD TO ACTIVATION
CLOTTING IN THE CIRCULATION.
NEXT PLEASE.
HERE IS A SUMMARY OF HUMAN AND
MOUSE MODELS OF ENDOTOXEMIA.
YES, PEOPLE DO GIVE VERY LOW
DOSE 4 NANOGRAMS PER KG, TISSUE
FACTOR INDUCED IN A TIME
DEPENDENT MANNER SIMILAR TO IN
VITRO STUDIES I SHOWED
PREVIOUSLY.
THERE'S ALSO AN INCREASE IN
EXTRACELLULAR TISSUE FACTOR
ACTIVITY THAT IS PEAKING A
LITTLE LATER THAN INDUCTION AND
MONOCYTE CONSISTENT WITH RELEASE
OF TF-POSITIVE EVS FROM
ACTIVATED NANOSITE.
FINALLY ACTIVATION OF CLOTTING
SYSTEM.
WE USE A MOUSE MODEL OF
ENDOTOXEMIA.
WE SEE TIME DEPENDENT INCREASE
IN ACTIVITY PEAKING AROUND THREE
TO FOUR HOURS, AROUND WE SEE
ACTIVATION OF CLOTTING SYSTEM AS
MEASURED BY INCREASED
THROMBIN/ANTI-THROMBIN
COMPLEXES.
NEXT PLEASE.
SO WHAT IS THE ROLE OF TISSUE
FACTOR IN ACTIVATION OF
COAGULATION AND ENDOTOXEMIA?
WE KNOW ADMINISTRATION OF
ANTI-TISSUE FACTOR PROTECTED
BABOONS IN A MODEL PUBLISHED IN
1991.
NEXT.
AND WE USED GENETIC APPROACH IN
WHICH WE DELETED TISSUE FACTOR
GENE IN MYELOID CELLS, REDUCING
ACTIVATION OF COAGULATION IN A
MOUSE MODEL OF ENDOTOXEMIA.
HOW DO MONOCYTES DETECT LPS IN
THE BLOOD?
LPS BINDS TO BINDING PROTEIN,
DELIVERED TO CD14, THAT THEN
LEADS TO ACTIVATION OF THE
COMPLEX INDUCTION OF TISSUE
FACTOR GENE EXPRESSION,
EXPRESSION OF TISSUE FACTOR ON
CELL SURFACE.
NEXT PLEASE.
SO WE'VE BEEN LOOKING AT THE
ROLE OF 4 IN INDUCTION OF TISSUE
FACTOR AND EV RELEASE AND
COAGULATION IN A MOUSE MODEL OF
ENDOTOXEMIA, LATE TIME POINTS OF
8 HOURS.
WILD TYPES IN GRAY, KNOCKOUTS IN
ORANGE.
YOU CAN SEE IF WE DON'T HAVE TLR
4 THERE'S SEVERE BLUNTING OF
ACTIVITY.
NEXT.
WE ALSO SEE A BLUNTING OF THE
ACTIVATION OF COAGULATION
SHOWING THE DETECTION OF THAT
LPS IS BY THE TLR 4.
NEXT PLEASE.
SO, THE NEXT QUESTION WAS DO
INFLAMMASOMES PLAY A ROLE IN
ACTIVATION DURING INFECTION?
NEXT.
SO, THERE ARE TWO STUDIES.
NEXT.
FIRST STUDY YOU'LL HEAR MORE
ABOUT FROM DR. LEE IN THE NEXT
PRESENTATION BUT TO INTRODUCE
IT, WE FOUND THERE WAS AN
INDUCTION OF TISSUE FACTOR
EXPRESSION DURING INFLAMMASOME
ACTIVATION.
THAT WAS ASSOCIATED WITH RELEASE
OF EXTRACELLULAR VESICLES THAT
LED TO DISSEMINATION
INTRAVASCULAR COAGULATION AND
LETHALITY.
THEY SAID THERE WAS INCREASE IN
EXPOSURE OF THAT MOLECULE I WAS
TALKING ABOUT EARLIER.
THAT WAS INCREASING THE TISSUE
FACTOR ACTIVITY IN A WAY I
DESCRIBED EARLIER.
THESE ARE TWO PATHWAYS.
NEXT PLEASE.
>> TWO MINUTES REMAINING.
>> THANK YOU.
WE LOOKED AT INFLAMMASOMES AND
EXPRESSION ACTIVATION OF
COAGULATION.
WE IS SUMMARIZE IN SAYING LPS IS
LEADING TO TRL4 ACTIVATION, AND
THEN THROUGH THE INFLAMMASOMES
CASPASE-11 GOING TO TISSUE
FACTOR EXPRESSION, THERE'S
INCREASED RELEASED OF EVS FROM
ACTIVATED MONOCYTES LEADING TO
ACTIVATION OF COAGULATION.
IN PARALLEL TO THAT PATHWAY IS
THE RELEASE, LEADING TO NANOPORE
FORMATION, CALCIUM INFLUX,
SERINE EXPOSURE.
NEXT PLEASE.
WE FOUND RECENTLY THAT
CASPASE-11 DOES NOT CONTRIBUTE
TO EARLIER ACTIVATION AT THREE
HOURS, BUT PLAYS A ROLE IN LATE
ACTIVATION OF COAGULATION EIGHT
HOURS IN THE MOUSE MODEL WITH
ENDOTOXEMIA.
NEXT PLEASE.
CONCLUSIONS, FIRST SEPSIS
ASSOCIATED COAGULOPATHY IS
ASSOCIATED REDUCED SURVIVAL IN
PATIENTS WITH SEPSIS,
ADMINISTRATION OF SOLUBLE
THROMBO MOD LYNN REDUCES
MORTALITY IN SEPSIS PATIENTS,
ASSOCIATED WITH COAGULOPATHY.
NEXT.
AND FROM A BASIC SCIENCE POINTS
OF VIEW, TISSUE FACTOR TRIGGERS
ACTIVATION COAGULATION
CONTRIBUTES TO DEATH IN BABOON
MODEL OF SEPSIS, PLAYS A MAJOR
ROLE IN ACTIVATION OF
COAGULATION IN MOUSE MODEL OF
ENDOTOXEMIA AND BLOCKING ON
MONOCYTE EXPRESSION MAY REDUCE
ACTIVATION OF COAGULATION OF
PATIENTS WITH SEPSIS WITHOUT
INCREASING
SO I'D LIKE TO ACKNOWLEDGE
PEOPLE THAT HAVE DONE THE WORK.
ANNA SAKITO HAS REALLY PIONEERED
ALL THE WORK THAT I PRESENTED
HERE TODAY, COLLABORATORS AT UNC
AND DIFFERENT COLLABORATORS THAT
I'VE PRESENTED SOME OF THAT
WORK.
PARTICULARLY THANKFUL FOR NIH
FUNDING TO SUPPORT THIS WORK.
THANK YOU FOR YOUR ATTENTION.
>> THANKS A LOT.
I THINK WE CAN MOVE TO THE NEXT
TALK.
WE CAN HAVE THE DISCUSSION AND
QUESTIONS AT THE END.
SO DO YOU WANT TO INTRODUCE?
>> YES, HELLO, EVERYONE.
I WILL INTRODUCE OUR NEXT
SPEAKER, PROFESSOR OF
PHARMACEUTICAL SCIENCES AT TEXT
AT A & M UNIVERSITY.
TALKS ABOUT DRIVERS OF
COAGULATION IN SEPSIS.
PLEASE WELCOME.
>> THANKS I'D LIKE TO THANK THE
ORGANIZERS FOR THIS OPPORTUNITY
AND ALSO THANK MY COLLABORATOR
DR. MACKMAN TO INTRODUCE OUR
FINDINGS.
THE TITLE OF MY TALK IS PYRO
PTOSIS DRIVES COAGULATION IN
SEPSIS.
SO I WILL USE THIS SLIDE AS
BACKGROUND.
ABOUT 10 YEARS AGO NOW, TWO IND
PEBT GTWOINDEPENDENT GROUPS PUBA
PAPER IN SCIENCE, THE MORTAL
MORTALITY -- WHAT THEY DID IS
THEY FIRST PRIMED THE MICE WITH
LOW DOSE LPS FOLLOWED BY -- AND
WHAT THEY FOUND IS IF THEY PRIME
THE MICE WITH LOW DOSE FIRST,
DEFICIENCY OF -- PROTECTED
AGAINST THE MORTALITY.
BUT IF THEY PRIME THE MICE
WITH -- IC -- AGONIST --
DEFICIENCY OF 11 PROTECT AGAINST
THE MORTALITY BUT THE
DEFICIENCIES OF -- HAVE NO
EFFECT.
SO BASED ON THIS THEY CONCLUDED
THAT -- 11 DEPENDED ON --
PATHWAY, HOWEVER IN THEIR
STUDIES, THEY DID NOT REPORT --
BY WHICH THE -- 11 ACTIVATION
LEADED TO MORTALITY.
THAT'S WHAT WE WANT TO EVALUATE.
BRIEFLY INTRODUCE, FIRST
DISCOVERED 20 YEARS AGO NOW, THE
MAIN FUNCTION OF INFLAMMASOMES
IS INNATE IMMUNITY,
MULTI-PROTEIN OLIGOMERS
CONSISTING OF AT LEAST THREE
COMPONENTS, NLR PROTEINS, ASC
ADAPTER PROTEIN AND CASPASE 1.
ACTIVATION OF CASPASE 1 LEADING
TO THE PRODUCTION OF CYTOKINE
INTERLEUKIN 1 BETA 18 AS WELL AS
PYRO PTOSIS.
SO WE FOCUS ON GRAMS -- BACTERIA
THAT CAN ACTIVATE -- COMBINES
DIRECTLY TO CASPASE 11, LEADING
TO THE NON-CLINICAL ACTIVATION
AND BACTERIA CAN ALSO ACTIVATE
NLRC4 -- PROTEINS.
FOUND ON THE SURFACE OF
GRAM-NEGATIVE BACTERIA.
THE STRUCTURE OF -- IS LIKE A
SYRINGE, HAVE A LONG NEEDLE
PROTEIN FOLLOWED BY A LOT OF
PROTEIN AND A BASE.
WHEN BACTERIA ENCOUNTERS HOST
CELLS, THE NEEDLE PROTEIN CAN BE
INJECTED INTO THE MEMBRANE OF
THE HOST CELLS, AND THE PROTEIN
FACTORS CAN BE DELIVERED FROM
THIS SYSTEM FROM BACTERIA INTO
THE HOST CELLS, SO BACTERIA
USES -- TO CONTROL AND EFFECT
THE SIGNALING OF THE HOST CELLS.
IN THE LATEST, PEOPLE FOUND THAT
THE NEEDLE PROTEIN, STRUCTURAL
PROTEIN, THE NEEDLE PROTEIN
ESPECIALLY THE ROD PROTEIN
ARE -- SO WE USED EPRJ FROM THE
E. COLI AS A TOOL FOR
INVESTIGATING HOW -- ACTIVATION
CAN CAUSE MORTALITY IN THE HOST.
SO WE FIRST INJECT -- VERIFIED
THE -- CAN LEAD TO THE MORTALITY
IN THE MICE, AND -- INJECTING --
POTENTLY KILLED THE MICE AND
THELY TTHELETHAL DOSE IS ABOU
3-MICROGRAM.
WE KNOW THAT CYTOKINE STORM IS
ONE OF THE MAJOR COMPLICATIONS
LEADING TO THE DEATH OF THE
SEPTIC PATIENTS.
SO THE FIRST -- WE FOUND A VERY
INTERESTING FINDINGS FOR THE
FIRST EXPERIMENT.
WE FOUND THAT SIX OUT OF EIGHT
MICE INJECTED WITH EPRJ, THAT --
SO WE WERE REALLY EXCITED ABOUT
THIS FINDING BECAUSE WE KNOW
THAT HEMOLYSIS IS ONE OF THE
COMMON COMPLICATIONS OF SEPTIC
PATIENTS.
WE THOUGHT WE MIGHT DISCOVER
THE -- OF -- SEPSIS.
INITIAL HYPOTHESIS, THE PYRO
PTOSIS OCCURRED IN THE RED
CELLS, CONTRIBUTED TO THE --
LEADING TO THE HOMO LYSIS, SO
THE NEXT DAY WE DID AN
INDIVIDUAL EXPERIMENT, WE
ISOLATED -- MICE, INCUBATED WITH
EPRJ, BUT WE DID NOT HIT TARGET,
THE PYRO PTOSIS IN THE RED
CELLS, BUT SIX OUT OF EIGHT MICE
HAD SUCH PHENOMENON, SO -- AFTER
WE LOOK AT THE LITERATURE, WE
REALIZE THAT COAGULATION WITH
THE -- IS ONE OF THE -- LEADING
TO HOME LY HEMOLYSIS IN SEPSIS.
SO THEN WE START TO ESTABLISH
ASSAYS FOR DIAGNOSIS OF
COAGULATION.
COAGULATION -- DIAGNOSED IN
CLINICAL -- BY A SCORING SYSTEM
BASED ON ASSAYS LISTED HERE.
PROTHROMBIN TIME IS PROLONGED
BECAUSE OF THE CONSUMPTION OF
COAGULATION FACTORS.
-- INCREASED DUE TO THE
ACTIVATION OF COAGULATION SYSTEM
AND -- WHERE PEOPLE CAN -- FOO
FIBRIN.
SO FIBRIN CONCENTRATIONS WERE
REDUCED, SEPTIC PATIENTS MOSTLY
HAVE THROMBOCYTOPENIA, THE COUNT
IS REDUCED, TISSUE FACTOR IS A
TRIGGER OF COAGULATION IN SEPSIS
AND ALSO D-DIMER IS INCREASED.
WE INVESTIGATED WHERE
COAGULATION IS ACTIVATED BY EPRJ
AND INDEED WE FOUND THAT
INJECTION OF EPRJ SIGNIFICANTLY
INCREASED THE PROTHROMBIN TIME
ALSO DECREASED THE FIBRIN
CONCENTRATION BY MORE THAN 50%.
THOSE MICE HAVE INCREASED
THROMBIN CONCENTRATION AND THEY
HAVE SEVERE THROMBOCYTOPENIA AND
TISSUE -- INCREASED.
THIS ASSAY WAS DONE BY DR. NIGEL
MACKMAN IN A DOUBLE BLIND
MANNER.
YES, PLEASE.
AND WE FURTHER INVESTIGATED
WHETHER THE ICs HAPPENED IN
THOSE MICE BY IMMUNOSTAINING AND
MULTIPHOTON MICROSCOPE.
IN THIS SLIDE WE SHOW THAT
FIBRIN -- IN THE MICE -- AND
INJECTION OF EPRJ INCREASED
FIBRIN -- AND THROMBOSIS.
WHICH WAS ABOLISHED IN THE
CASPASE 1 AND 11 KNOCKOUT MICE.
AT THAT TIME, WE ONLY HAVE THESE
DOUBLE KNOCKOUT MICE AVAILABLE
FOR INJECTION AND LATER WE USED
THE CASPASE 1 SINGLE KNOCKOUT
MICE AND VERIFIED THAT EPRJ
INDUCED THE IC OF FIBRIN
DEFINITION IS CASPASE
1 DEPENDENT.
THE COAGULATION ASSAYS, WE FOUND
THAT' LON GAITION OF PT TIME WAS
ABOLISHED IN THE CASPASE 1 AND
11 DOUBLE KNOCKOUT MICE AND THE
REDUCTION IN FIBRIN
CONCENTRATION IS ABOUT -- EPRJ
WAS ALSO ABOLISHED IN THE
CASPASE 1-11 KNOCKOUT MICE, TAT
ALSO DID NOT INCREASE IN THE
DOUBLE KNOCKOUT MICE.
BUT IN THE CASPASE 1 KNOCKOUT
MICE IS JUST LIKE -- MICE.
SO FROM THIS DATA, WE CAN
CONCLUDE THAT EPRJ INDUCED
COAGULATION MAY -- CASPASE
1 DEPENDENT -- SO WE USE CASP
CASPASE -- INDEED THE EPRJ
INDUCED COAGULATION WAS
ABOLISHED IN THE -- KNOCKOUT
MICE.
AND WE KNOW FROM DR. MACKMAN'S
EXHIBIT DDR. MACKMAN'S -- INTRO,
WE KNOW TISSUE FACTOR -- IN
SEPSIS, SO WHEN YOU INVESTIGATED
WITH EPRJ INDUCED COAGULATION,
REQUIRES TISSUE FACTOR, WE USE
THE TISSUE EFFECT TO NEUTRALIZE
THE ANTIBODY -- THE MICE AND
INJECT EPRJ INDUCED MICE AND WE
FOUND THAT PROLONGATION OF PT
TIME WAS LARGELY PREVENTED BY
1H1 TREATMENT AND THE --
CONCENTRATION WAS ALSO REDUCED.
IMPORTANTLY, WE FOUND FOR
TREATMENT OF THE MICE WITH
1H1 INCREASED SURVIVAL RATE.
SO THIS DATA SUGGESTS THAT AT
LEAST THE IC IS ONE OF THE
MECHANISMS CONTRIBUTED TO THE
MORTALITY FOR -- BE ACTIVATION.
OTHER DATA SHOW ACTIVATION OF --
PATHWAY LEAD TO -- IC.
SO WE USED THE LPS MODEL AND
FOUND INJECTION OF -- IN MICE
INDUCED -- MARKETLY INCREASED
IN -- MICE ALSO PT TIME IS
PROLONGED AND FIBRIN
CONCENTRATION IS REDUCED.
DEFICIENCY OF CASPASE 11 PROTECT
THE IC INDUCED -- BUT IN THE --
MAINLY IT'S SAME AS WILD TYPE
MICE.
SO THE CONCLUSION IS LPS INDUCED
COAGULATION -- THROUGH THE
CASPASE-11 DEPENDENT MECHANISM,
NOT THE -- WHICH IS CONSISTENT
WITH THE FINDINGS OF TWO SCIENCE
PAPERS.
HOW ABOUT BACTERIA?
WE USE -- CONTRIBUTE TO
COAGULATION IN THE -- BACTERIA
AND A SALMONELLA IS GRAM --
BACTERIA, AND FIRST WE USE THE
IN VITRO EXPERIMENT TO VERIFY
THAT SALMONELLA INDUCED THE PIE
RPYROPTOSIS -- MACROPHAGES AND E
FOUND SALMONELLA INDUCED CELL
DEATH MAY -- CASPASE 11 --
AND -- NOT BY CASPASE 11.
INJECTION OF SALMONELLA INTO THE
MICE CAUSED COAGULATION,
INCREASED THE PROTHROMBIN TIME
AND INCREASED THROMBIN AND --
CONCENTRATIONS.
AND COAGULATION INDUCED BY
SALMONELLA IS LARGELY PREVENTED
BY CASPASE 1 DEFICIENCY SHOWN IN
GREEN AND THE -- SHOWN IN BLUE.
AND TO A LESSER EXTENT,
DEFICIENCY OF PA CASPASE 11 OR E
NAIP WHICH IS A RECEPTOR OF
THE -- FOR THE -- AND --
PROTEINS ALSO INHIBITED THE
COAGULATION.
SO THE CONCLUSION OF FINDINGS OF
ACTIVATION OF BOTH -- AND
NON- -- COMB S CHROMOSOME LEADI-
OF THE MACROPHAGES AND RELEASED
MICRO PARTICLES FROM THIS PYRO
PTOTIC CELLS -- LEADING TO DEATH
OF THE HOST.
I'D LIKE TO THANK MY
COLLABORATORS AND ALSO
DR. MACKMAN AND THIS WORK WAS
MAINLY DONE BY MY POSTDOC,
DR. WU, WHO GOT THE K-9 # 9 --
GRANTED BY THE FACULTY POSITION
AT THE UNIVERSITY AND ALSO THANK
YOU FOR THE FUNDING FROM NIH FOR
SUPPORT.
THANK YOU FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH, DR. LI,
FOR A GREAT PRESENTATION.
WE WILL HAVE A Q & A SESSION AT
THE END OF THE LAST SPEAKER'S
PRESENTATION.
SO PLEASE FEEL FREE TO LEAVE
YOUR QUESTIONS IN THE CHAT BOX.
SO I THINK NOW WE MAY MOVE ON TO
OUR NEXT SPEAKER, DR. KANDACE
GOLLOMP, ASSISTANT PROFESSOR OF
PEDIATRIC HEMATOLOGY AT
CHILDREN'S HOSPITAL OF
PHILADELPHIA.
DR. GOLLOMP WILL TALK ABOUT
NEUTROPHIL EXTRACELLULAR TRAPS,
PLATELET FACTOR 4 AND BACK TIER
YOUR INFORECAST: A CHARGED
SUBJECT.
THANK YOU.
>> THANK YOU SO MUCH FOR THAT
WARM INTRODUCTION AND I WANT TO
THANK THE ORGANIZERS AND
PARTICULARLY DR. SUND FOR THE
OPPORTUNITY TO PRESENT SOME OF
THIS WORK.
SO I'LL BEGIN THE PRESENTATION
BY TALKING ABOUT NEUTROPHILS.
THEY'RE THE PREDOMINANT
CIRCULATING WHITE BLOOD CELLS IN
HUMANS AND WE THINK ABOUT THEM
AS THE FIRST CELLS TO ARRIVE AT
SITES OF INFECTION, INFLAMMATION
OR VASCULAR DAMAGE.
WHEN THEY GET THERE, THEY CAN
MEET BACTERIA.
, BACTERIAL TOXINS, THEY CAN
MEET INFLAMMATORY CYTOKINES AND
ALSO MEET DAMAGE ASSOCIATED
MOLECULAR PROTEINS, ONE THAT I
THINK ABOUT A LOT IS HEME, AND
ALL OF THESE CAN THROUGH
DIFFERENT PATHWAYS INTRODUCE
NEUTROPHILS TO RELEASE
NEUTROPHIL EVER BEEN EXT
EXTRACELLULAR TRAPS.
THIS IS HOW YOU SEE THEM ON THE
PERIPHERAL SMEAR.
SO NET ARE COMB TIN THAT'S BEEN
EXTRUDED INTO THE EXTRACELLULAR
SPACE.
THEY'RE COMPOSED OF CELL-FREE
DNA MIXED WITH HISTONES AS WELL
AS NEUTROPHIL ANTIMICROBIAL
PROTEINS.
ON ONE HAND THAT'S REALLY GOOD
AT HELPING TO CAPTURE AND
POTENTIALLY KILL CERTAIN
BACTERIA, BUT YOU CAN IMAGINE
ALL OF THOSE THINGS IN THE NETS
SUCH AS THE CELL-FREE DNA, THE
HISTONES, THE ANTIMICROBIAL
PROTEINS WHEN RELEASED IN A
DYSREGULATED MANNER CAN CAUSE
HARM TO THE HOST AND JUST AS DRS
CAN CONTRIBUTE TO THROMBOSIS.
I DO WANT TO HIGHLIGHT A PROTEIN
THAT IS VERY IMPORTANT TO NET
RELEASE IS SOMETHING CALLED --
4, IT TRANS LOCATES TO THE
NUCLEUS WHERE IT MODIFIES
HISTONES TO DECREASE THEIR
OVERALL POSITIVE CHARGE, THEREBY
DECREASING THEIR AFFINITY FOR
NEGATIVELY CHARGED DNA AND THIS
POTENTIATES CHROMATIN D
CONDENSATION.
SO BECAUSE NETS CAN CAUSE
COLLATERAL HOST TISSUE INJURY
THAT RESULTS IN ORGAN
DYSFUNCTION AND MORTALITY IN
SEPSIS, THERE'S REAL INTEREST IN
DEVELOPING THERAPEUTICS THAT CAN
TARGET NETS.
THESE ARE FOUR CATEGORIES OF
THERAPEUTICS.
THIS IS PRIMARILY DONE WITH
NUCLEASES.
CAN YOU NEUTRALIZE THE TOXICITY
OF NET COMPONENTS, FOR EXAMPLE
LIKE DR. MACKMAN MENTIONED, CAN
YOU USE SOLUBLE -- TO NEWT LICE
HISTONES.
THERE'S ALSO THE DEVELOPMENT OF
CELL-FREE DNA SCAVENGERS THAT
CAN REDUCE THE INFLAMMATORY
POTENTIAL OF NETS.
BUT I'M GOING TO FOCUS THE REST
OF THE TALK ON THE LAST TWO.
ONE IS CAN YOU MODIFY A NET TO
MAKE IT LESS TOXIC BUT DO ITS
JOB BETTER, AND THEN WHAT
HAPPENS TO THE INFLAMMATORY
MILIEU WHEN YOU INHIBIT THE
RELEASE OF NETS.
SO WE'LL START BY TALKING ABOUT
NET MODIFICATION.
THE NET IS IN GREEN.
WE CAN PLAY THE VIDEO.
THIS IS BEING INFUSED WITH
PLATELET RICH PLASMA.
WHAT I WANT TO HIGHLIGHT IS JUST
HOW GREAT THESE NETS ARE AT
COMPANY TOURIN --AT CAPTURING T.
IT BECOMES A LITTLE CONDENSED AS
THOSE PLATELETS ARE INFUSED IN.
ONE OF THE REASONS I THINK THAT
HAPPENS IS THAT THESE PLATELETS
ARE CAPTURED, THEY REDUCE THE
CONTENTS OF THEIR GRANULES.
ONE OF THE MAJOR COMPONENTS OF
PLAY LET ALPHA GRANULES IS A
PLATELET SPECIFIC HEMOKINE
CALLED PLATELET FACTOR 4 THAT
FORMS AT THE T TETROMERS.
YOU CAN SEE THIS ILLUSTRATED IN
ORANGE AND RED.
BECAUSE OF THIS POSITIVE CHARGE,
IT LOVES TO BIND TO POLYANIONS,
SO IT CAN COMBINE TO HEPARAN, WE
CAN THINK OF THAT AS -- IT CAN
ALSO CORRESPOND TO NEGATIVELY
CHARGED DNA, A N A MAJOR CONSTIT
OF NETS AND IT CAN ALSO COMBINE
ON THE SURFACE OF BACTERIA.
IF YOU'RE A GRAM POSITIVE
BACTERIA, THAT'S VERY NEGATIVELY
CHARGED.
IF YOU'RE A GRAM GRAM-NEGATIVE
ORGANISM, IT GOING TO BE -- WILL
FORM COMPLEXES WITH PLATELET
FACTOR 4.
SO TO INVESTIGATE INTERACTIONS
BETWEEN PLATELET FACTOR 4 AND
NETS, I DEVELOPED A MICRO FLEW
DICK ASSAY.
IN THIS ASSAY, YOU TAKE
NEUTROPHILS FROM A HEALTHY HUMAN
DONOR AND IMMOBILIZE THEM ON
FIBRIN ENACTED CHANNELS AFTER
WHICH YOU CAN ACTIVATE THEM TO
RELEASE NETS.
HERE YOU CAN SEE ON THE TOP
THERE ARE NETS THAT WERE JUST
INCUBATED WITH BUFFER ALONE AND
BEFORE THEY GOT DIGESTED, THEY
HAVE A FLUFFY CLOUD-LIKE
APPEARANCE.
BUT THE NETS ON THE BOTTOM
CHANNEL WHICH WERE INCUBATED
WITH PF4 TAKE ON THIS SORT OF
FILAMENTOUS APPEARANCE BECAUSE
PF4 WILL TETHER TOGETHER THE
DIFFERENT STRANDS OF DNA AND
MAKE THE NETS BECOME COMPACT.
BUT THAT CHANGE IN MORPHOLOGY,
THAT COMPACTION, ALSO GOES ALONG
WITH AN ACQUISITION OF
RESISTANCE TO NUCLEASE
DIGESTION.
THIS HOLDS THROUGH TO
NNASE1 THAT IS PRESENT IN THE
CIRCULATION AND CONSTANTLY
SLOWLY DIGESTING NETS AND THIS
IS ALSO TRUE FOR BACTERIAL
DERIVED NUCLEASES THAT CAN BREAK
DOWN NETS.
WHAT DOES THIS MEAN IN TERMS OF
ENDOTHELIAL TOXICITY?
SO IF YOU INCUBATE UNMODIFIED
NETS WITH ENDOTHELIUM AS
INDICATED IN THE IMAGE ON TOP
IT'S QUITE TOXIC TO THE END TEAL
YUM AND WILL CAUSE EC CELL DEATH
AND DETACHMENT FROM THE
CHANNELS.
HOWEVER, IF YOU ADD IN PLATELET
FACTOR 4 TO THOSE NETS AND YOU
COMPACT THEM, IT CAUSES
PROTECTION TO THE ENDOTHELIAL
CELLS AND THESE ENDOTHELIAL
CELLS REMAIN INTACT AND MAINTAIN
THEIR CONFLUENCE.
FOR THE SAKE OF TIME WE'LL JUST
SWITCH TO THE NEXT SLIDE.
NOW WHAT DOES THIS CHANGE IN NET
MORPHOLOGY HAVE TO DO WITH
BACTERIAL KILLING?
DOES IT INFLUENCE THE ABILITY OF
NETS TO DO THEIR JOB?
TO ANSWER THAT, WE WENT BACK TO
THESE MICRO FLUIDIC CHANNELS.
WE HAVE BACTERIA NOW LABELED IN
GREEN.
WHAT YOU'LL NOTICE IS THAT WHEN
WE INFUSE IN THAT BACTERIA TO
THE TOP CHANNEL THAT'S JUST BEEN
INCUBATED WITH BUFFER ALONE, THE
NETS THEMSELVES DO QUITE A POOR
JOB OF CAPTURING BACTERIA, AND I
THINK THIS IS A CHARGE-MEDIATED
PHENOMENON WHERE THE DNA OF THE
NET IS REPELLING THE
PREDOMINANTLY NEGATIVELY CHARGED
BACTERIA.
HOWEVER, WHEN YOU'VE COMPACTED
YOUR NETS WITH PF4, YOU HAVE
THIS CAT IONIC GLUE BETWEEN THAT
DNA BACKBONE AND THE NEGATIVELY
CHARGED BUG AND IT ACTUALLY
HELPS TO TETHER THE BUGS TO THE
NETS.
NOW THIS IS ALSO RELEVANT
BECAUSE OUR PF4 COMPACTED NETS
ARE RESIST TABT TO NUCLEASE
DIGESTION, SO WHILE NAKED NETS
ARE RAPIDLY INGESTED WHEN WE --
RELEASING A LARGE BOLUS OF
BACTERIA, THESE DO A MUCH BETTER
JOB OF RETAINING THE BACTERIA.
THIS CAN BE BOTH HELPFUL IF YOUR
NETS ARE EXPOSED TO NUCLEASES
THAT ARE ENDOGENOUSLY PRODUCED
OR IF THE BACTERIA IS MAKING
NUCLEASE TO EVADE NET, THIS
STRATEGY COULD HELP TO OVERCOME
THAT.
WHAT DOES THIS MEAN IN VIVO?
WE MODIFIED THE SURREY MODEL OF
SEPSIS.
WHEN YOU HARVEST THE CECAL
CONTENTS AND I JECT IT INTO A
MANUAL TO INDUCE POLYMICROBIAL
SEPSIS.
WE MODIFIED IT A LITTLE BIT
BECAUSE WE TOOK OUR DONOR CS
INKNOCK LUM AND MIXED IT WITH
JUST DEXTROSE ALONE OR IN BLUE
WE COMBINED IT WITH PF4 AND THEN
SUBSEQUENTLY INJECTED INTO
ANIMALS TO IB DUES BA BACTEREMI.
WHEN WE COLLECTED BLOOD, SPLEEN
AND LIVER AT 24 HOURS WHAT WE
TOABED IS THAT IS THAT PLATELET
FACTOR 4 TREATMENT LED TO
REDUCTION IN BACTEREMIA AS WELL
AS A REDUCTION IN THE BACTERIAL
LOAD THAT WE WERE ABLE TO
APPRECIATE IN THE LIVER AND THE
SPLEEN.
THEN WHEN WE WENT TO LOOK AT
SURVIVAL WHAT WE FOUND USING
THIS MODEL IS THAT THERE WAS A
RAPID DEMISE OF THE WILD TYPE
ANIMALS THAT WERE TREATED WITH
CECAL SLURRY ALONE, HOWEVER,
WHEN THAT CECAL SLURRY WAS
COMBINED WITH PLATELET FACTOR 4,
WE HAD 100% SURVIVAL IN THIS
SMALL UNPUBLISHED COHORT AND
WHEN WE LOOKED AT PF4 DEFICIENT
ANIMALS THERE WAS A SLIGHTLY
MORE RAPID DEMISE BUT WHEN WE
TREATED THOSE ANIMALS WITH
EXOGENOUS PLATELET FACTOR 4 WE
WERE ABLE TO RESCUE SURVIVAL,
NOT QUITE TO THE SAME LEVEL AS
PF4 EXPRESSING ANIMALS BUT WE
WERE ABLE TO GET CLOSER.
SO MOVING ON A LITTLE BIT FROM
NET MODIFICATION TO NET
INHIBITION.
SO I'M INTERESTED IN WHAT
LOCKING MU PTOSIS MIGHT MEAN --
THERE'S A BIT OF A CONTROVERSY
ABOUT THIS BECAUSE ON ONE
HANDSOME PEOPLE ARGUE NET DO
MORE HARM THAN GOOD, GET RID OF
THEM, BLOCK THEM, BUT IT'S A
RELATIVELY CONSERVED FUNCTION
AND IT POSSIBLE THAT BLOCKING
MIGHT INCREASE SUSCEPTIBILITY TO
BACTERIAL INFECTION.
STOSO OTHER PEOPLE HAVE GOTTEN N
WELL WILL HAVE ME, THEY
DEVELOPED A PAD 4 DEFICIENT
MOUSE, AN ESSENTIAL MEDIATOR OF
NET RELEASE.
SINCE THAT TIME, IT BEEN
DISCOVERED THAT THERE ARE PAD
4 INDEPENDENT WAYS THAT YOU CAN
GO ABOUT JEB RATI GENERATING A T
HOWEVER PAD DEFICIENCY DOES LEAD
TO A MARKED DEFECT.
THESE MICE HAVE BEEN USED IN A
HOST OF STUDIES IN THE SETTING
OF DIFFERENT INFECTIOUS
DISEASES.
IN THIS STUDY LED BY DR. BARONE
ET AL. AT BROWN UNIVERSITY BACK
IN 2018, INTERESTINGLY THEY USED
THE CLP MODEL OF SEPSIS IN WHICH
THE CECUM IS PERFORATED AND THEN
GI MICROBIOTA GO ON TO INDUCE
POLYMICROBIAL SEPSIS TO
ILLUSTRATE THAT THERE WAS A
PROTECTION IN PAD4 NET DEFICIENT
ANIMALS FROM MORTALITY AND THEIR
POLYMICROBIAL SEPSIS MODEL.
THAT'S JUST ILLUSTRATED WITH
THIS SURVIVAL CURVE.
I WANTED TO SEE IF WE COULD
RECAPITULATE THESE FIND NGS OUR
CECAL SLURRY MODEL OF SEPSIS.
AND SO TO TRY TO BE AS CLOSE TO
THE CLP MODEL IN WHICH ALL
ANIMALS BECOME SEPTIC WITH THEIR
OWN ENDOGENOUS G.I. MICROBES,
WHAT WE DID IS WE HARVESTED
CECAL CONTENTS FROM PAD4 OR WILD
TYPE DONOR MICE AND THEN WE WERE
ABLE TO USE THE SAME INNOCULUM
TO INFECT MULTIPLE ANIMALS.
FOR THE FIRST ROUND OF STUDIES,
WE MADE SURE OUR CS AND REA SIP
YENT MICE WERE ALL JEA KNOW
TYPE-MATCHED.
AND I WAS ACTUALLY QUITE
SURPRISED, I DIDN'T THINK THE
DIFFERENCES WERE GOING TO BE
THIS STRIKING.
WE FOUND THAT OUR WILD TYPE
ANIMALS GOT MUCH SICKER, SO WHEN
WE LOOKED AT THEIR MEAN SEPSIS
SCORE, WHICH IS A MARKER OF
CLINICAL SEPSIS SEVERITY, THE
WILD TYPE MICE WERE MUCH MORE
ILL COMPARED TO THE
PAD4 DEFICIENT ANIMALS.
THEY HAD MUCH MORE SEVERE
THROMBOCYTOPENIA AND THEY HAD
MUCH MORE SEVERE HYPOTHERMIA,
WHICH I ACTUALLY REALLY LOVE AS
A MA MARKER OF SEPSIS SEVERITY.
THEN WHEN WE LOOKED AT THE
EXTENT OF BACTERIA
DISSEMINATION, WE FOUND HIGHER
LEVELS OF BACTERIA IN THE BLOOD
OF OUR WILD TYPE ANIMALS
COMPARED TO OUR PAD4 DEFICIENT
ANIMALS AND FOUND HIGHER LEVELS
OF BACTERIA IN THE LIVER.
SO OF COURSE ALL OF THIS GOES
CONTRARY TO MY CONFIDENCE THAT
PAD 4 AND NETS ARE AN IMPORTANT
EVOLUTIONARY CONSERVED PART OF
THE INNATE IMMUNE RESPONSE.
AND I WAS EVEN MORE SURPRISED
WHEN WE WENT AND DID SURVIVAL
STUDIES AND FOUND THE KNOCKOUT
MICE INJECTED WITH KNOCKOUT CS
HAD 100% SURVIVAL, WHEREAS OUR
WILD TYPE MICE WITH WILD TYPE CS
HAD A VERY HIGH RATE OF
MORTALITY.
SO WE WERE SCRUNCHING OUR HEADS
LOOKING AT THIS DATA THINKING IS
THIS THE PERIPHERAL IMMUNE
RESPONSE, A PRODUCT OF IMPAIRED
NET RELEASE THAT'S BEING
PROTECTIVE OR IS THERE SOMETHING
GOING ON WITH THE CECAL SLURRY
BACTERIAL INNOCULUM.
SO WE LOOKED AT OUR INITIAL
BASELINE CBC, SO THIS IS LOOKING
AT THE ANIMALS WHEN THEY WERE
WELL.
WE FOUND THERE WAS A LITTLE BIT
OF A HIGHER WHITE BLOOD CELL
COUNT IN THE PAD 4 DEFICIENT
MICE.
OUR PAD4 DEFICIENT ANIMALS WERE
NOR NEUTROPHILIC COMPARED TO OUR
WILD TYPE MICE.
WE DID SOME PLASMA CYTOKINE
ANALYSIS AND WE FOUND THAT OUR
PAD4 DEFICIENT MICE HAD HIGHER
LEVELS OF INFLAMMATORY
CYTOKINES, INCLUDING IL-6, IL-1
BETA, TNF AND IL-17.
THEY ALSO HAD A REDUCTION IN
IL23R, THE RECEPTOR FOR IL23,
WHICH CAN BE DECREASED BY
INCREASED LEVELS OF IL-17 AND
IL23.
AND SINCE THIS PATHWAY IS
INVOLVED -- WELL-KNOWN TO BE
INVOLVED IN INFLAMMATORY BOWEL
DISEASE AND RECRUITMENT OF
NEUTROPHILS TO THE GUT IN THAT
CONTEXT, WE DID WANT TO LOOK AT
THE PATHOLOGY OR SEE IF THERE'S
ANY PATHOLOGY MOUNTAIN
INTESTINES OF OUR ANIMALS.
AND WHILE WE DIDN'T SEE EVIDENCE
OF EROSIONS OR ABSCESSES OR
THINGS, WHAT WE DID APPRECIATE
WHEN WE STAINED THESE SECTIONS
IS THAT THERE WAS INCREASED
NEUTROPHIL INFILTRATION AS SHOWN
IN GREEN HERE, IN THE LAMINA
PROPRIA OF THE GI TRACT, SO
INCREASED -- IN OUR PAD
4 DEFICIENT ANIMALS.
THEN WE DID SOME MICROBIAL
SEQUENCING OF THE CECAL CONTENT
OF OUR WILD TYPE VERSUS OUR PAD.
IN LOOKING AT THE RELATIVE
ABUNDANCE OF DIFFERENT BACTERIA,
WE FOUND THAT THERE WERE
STRIKING DIFFERENCES BETWEEN
THESE ANIMALS AND WHEN WE DID A
PCA ANALYSIS, YOU CAN SEE THEY
CLUSTER INDEPENDENTLY WITH THE
PAD 4 ANIMALS IN RED, NOOKOUT
WILD TYPEANIMALS IN BLUE.
SO DETERMINE IF THESE
DIFFERENCES THAT WE WERE SEEING
WERE PHYSIOLOGICALLY RELEVANT OR
RELEVANT TO THE OBSERVED
DIFFERENCES IN OUTCOME, WE ENDED
UP TREATING OUR WILD TYPE
ANIMALS WITH CS FROM BAD PAD
4 DEFICIENT MICE.
AND WHAT WE DID FIND IS THAT,
AGAIN, WHEN ANIMALS RECEIVED
GENOTYPE MATCH CS WILD TYPE
ANIMALS THAT GOT WILD TYPE CS
WERE SICKER THAN PAD 4 KNOCKOUT
ANIMALS THAT GOT.
CS FROM PAD 4 KNOCKOUT MICE.
WHEN EVERYBODY RECEIVED WILD
TYPE CECAL SLURRY THEY BECAME
EQUALLY ILL AND WHEN EVERY MOUSE
RECEIVED PAD 4 KNOCKOUT CECAL
SLURRY, THEY HAD AN EQUAL SORT
OF DECREASE IN THE SEVERITY OF
SEPSIS.
AND THIS ALSO HELD TRUE WITH
EVIDENCE OF BACTEREMIA WITH,
AGAIN, EQUAL LEVELS OF
BACTEREMIA OF ANIMALS THAT
RECEIVED WILD TYPE CS AND
REDUCTION OF BA BACTEREMIA IN BH
WILD TYPES THAT RECEIVED
KNOCKOUT CS.
THEN WHEN WE WENT BACK TO LOOK
AT SURVIVAL, THIS IS JUST A
LITTLE REMINDER OF THE BASELINE
SURVIVAL WITH THAT REAL
PROTECTION IN THE KNOCKOUT MICE
THAT GOT KNOCKOUT CS.
BUT WHEN WE SWITCHED THE -- WHEN
WE DO THESE GENOTYPE SWAPS, WHAT
WE FOUND IS THAT OUR KNOCKOUT
MICE HAD EQUAL TO MORE SEVERE
MORTALITY TO OUR WILD TYPE MICE
WHEN THEY BOTH RECEIVED WILD
TYPE CS, AND THE WILD TYPE MICE
THAT RECEIVED KNOCKOUT CS HAD
PROTECTION FROM MORTALITY.
SO NOT COMPLETELY RESTORED TO
THE LEVELS OF THE PAD
4 DEFICIENT MICE, BUT MUCH
BETTER THAN THEIR COHORT THAT
RECEIVED WILD TYPE CS.
SO JUST TO SUMMARIZE, THERE'S
ACTIVE RESEARCH INTO MULTIPLE
DIRECTED THERAPEUTIC STRATEGIES.
ALL OF WHICH HAVE SOME UNIQUE
ADVANTAGES AND DISADVANTAGES,
AND I SUSPECT THAT WE'LL GET
INTO THIS IN THE NEXT TALK.
NET MODIFICATION WITH PLATELET
FACTOR 4 CAUSES NETS TO BECOME
COMPACT AND RESISTANT TO
NUCLEASE DIGESTION WHICH IN TURN
LIMITS THEIR THROMBOTIC
POTENTIAL, AND PAD 4 DEFICIENT
MICE HAVE INTERESTING CHANGES IN
THEIR BASELINE INFLAMMATION,
CHANGES IN TISSUE INFILTRATION
AND ALSO INTERESTING CHANGES IN
THE COMPOSITION OF THEIR GI
MICRO BUY YOAM THAT IN TURN
INFLUENCE -- I THINK THESE
CHANGES INFLUENCE SURVIVAL TO
SOME EXTENT IN THE CECAL
LIGATION PUNCTURE MODEL OF
SEPSIS, AND ALTHOUGH THESE
FINDINGS WERE PREVIOUSLY
ATTRIBUTED EXCLUSIVELY TO
PROTECTION FROM SOME OF THE
IMMUNOTHROMBOTIC EFFECTS OF NET
RELEASE, I'D SUSPECT THAT SOME
OF THIS WAS RELATED TO CHANGES
IN THE COMPOSITION OF THE
INFECTIOUS INNOCULUM IN THAT
MODEL.
IN OUR HANDS WE OBSERVED
OUTCOMES IN THE CECAL SLURRY
MODEL ARE INFLUENCED BY BOTH PAD
4 EXPRESSION IN THE C SDOH NOR
AS WELL AS TO SOME EXTENT PAD
4 EXPRESSION IN THE RECIPIENT
ANIMALS.
SO I THINK THAT THIS DATA WILL
SORT OF MAYBE HELP US UNDERSTAND
WHAT SOME OF THE EFFECTS OF
PROLONGED NET INHIBITION MIGHT
BE, BUT ALSO WILL INFORM OUR
UNDERSTANDING OF THE RESULTS
THAT WE SEE IN DIFFERENT MODELS
OF POLYMICROBIAL SEPSIS.
I JUST WANT TO THANK THE LARGER
GROUP AND FUNDING SOURCES THAT
HAVE CONTRIBUTED TO THIS WORK
AND LOOKING FORWARD TO THE
CONTRIBUTION AT THE END OF THE
SESSION.
>> THANK YOU VERY MUCH, THIS IS
A FANTASTIC AND WONDERFUL
PRESENTATION.
I THINK --
>> I THINK I CAN --
>> INTRODUCE OUR LAST SPEAKER.
THANK YOU.
>> SO OUR LAST SPEAKER OF THIS
SESSION IS DR. PATRICIA LIAW,
PROFESSOR OF DEPARTMENT OF
MEDICINE AT MCMASTER UNIVERSITY.
SHE'LL BE TALKING ABOUT
THERAPEUTIC STRATEGIES TO TARGET
IMMUNOTHROMBOSIS IN SEPSIS.
EVERYONE PLEASE POST YOUR
QUESTIONS IN THE CHAT BOX AND WE
WILL HAVE THEM ADDRESSED DURING
THE DISCUSSION SECTION.
THANK YOU VERY MUCH, PLEASE.
>> GOOD AFTERNOON.
HI, EVERYONE.
VERY PLEASED TO BE INVITED TO
GIVE A TALK IN THIS FASCINATED,
VERY INFORMATIVE AND UP TO DATE
SESSION ON IMMUNOTHROMBOSIS.
SO MY PRESENTATION FOCUSES ON
THERAPEUTIC -- TO TARGET --
IMMUNOTHROMBOSIS AND SEPSIS.
IS MY AUDIO OKAY?
>> I THINK WE CAN HEAR YOU.
I THINK SOMEONE'S SPEAKER IS ON.
>> WONDERFUL.
NEXT SLIDE, PLEASE?
SO THE PRESENTATION LEARNING
OBJECTIVES ARE TO UNDERSTAND
SOME OF THE BARRIERS TO SUCCESS
OF CLINICAL TRIALS IN SEPSIS, TO
IDENTIFY THERAPEUTIC STRATEGIES
THAT TARGET MULTIPLE PATHWAYS
AND TO UNDERSTAND THE BENEFITS
OF ENRICHMENT STRATEGIES IN
CLINICAL TRIALS IN SEPSIS.
SO AS WE HEARD IN THE FIRST
SESSION, SEPSIS IS DEFINED AS A
LIFE-THREATENING ORGAN
DYSFUNCTION DUE TO A
DYSREGULATED HOST RESPONSE TO
INFECTION.
THERE ARE MANY DIFFERENT SITES
OF INFECTION AS WELL AS TYPES OF
MICROORGANISMS.
IT'S A LEADING CAUSE OF DEATH IN
THE ICU WITH MORTALITY RATES OF
UP TO 50% FOR PATIENTS WITH
SEPTIC SHOCK, OVER 11 MILLION
DEATHS WORLDWIDE.
IMMUNOTHROMBOSIS IS CONSIDERED A
BIN FICIAL MECHANISM OF INNATE
IMMUNITY.
IT INVOLVES THE ACTIVE
PARTICIPATION OF IMMUNE CELLS
WHICH FACILITATES THE
RECOGNITION, CONTAINMENT AND
DESTRUCTION OF PATHOGENS BUT
HAVE LEFT DYSREGULATED, IT CAN
ALSO BE A DRIVER OF
INTRAVASCULAR THROMBOSIS.
THIS DIAGRAM DESCRIBES SOME OF
THE COMMON MECHANISMS BY WHICH
MICROBES COULD INDUCE
IMMUNOTHROMBOSIS.
SO REGARDLESS OF THE SOURCE OF
INFECTION, WHETHER IT'S
BACTERIAL OR VIRAL, THE
PATHOGENS WILL UPREGULATE TISSUE
FACTOR EXPRESSION ON MONOCYTES
IN THE CASE OF BACTERIA, OR
THEY -- THAT LEADS TO THE
ACTIVATION OF COAGULATION AND
ALSO THE PRODUCTION OF
CYTOKINES, WHICH WILL CAUSE
SYSTEMIC ENDOTHELIAL INJURY.
THE ACTIVATED ENDOTHELIAL
SURFACE WILL RELEASE ULTRA --
VON WILLEBRAND FACTOR, LEADING
TO PLATELET ACTIVATION AND ALSO
THE RELEASE OF NEUTROPHIL
EXTRACELLULAR TRAPS, WHICH WAS
NICELY SUMMARIZED IN THE
PREVIOUS PRESENTATION.
THE NET RESULT IS
IMMUNOTHROMBOSIS IN WHICH THE
CLOT CONSISTS NOT ONLY OF
PLATELETS AND FIBRIN, BUT ALSO
IMMUNE CELLS, NOTE PLI
> NOTABLY
NEUTROPHILS MONOCYTES AND THEIR
COMPONENTS, AND HISTONES.
SO THERE HAD BEEN OVER 60
RANDOMIZED CONTROL CLINICAL
TRIALS IN SEPSIS OVER THE PAST
THREE DECADES INVOLVING OVER
22,000 PATIENTS.
HOWEVER, NONE HAVE RESULTED IN
NEW TREATMENT STRATEGIES.
THE INTERVENTIONS INCLUDE
STRATEGIES TO REDUCE
INFLAMMATION OR TO NEUTRALIZE
BACTERIAL EN ENDO TOXINS, AS WEL
AS ANTICOAGULANTS, WHICH I'LL
DESCRIBE A LITTLE MORE LATER ON
IN THE PRESENTATION.
SO WHY HAVE CLINICAL TRIALS
FAILED IN SEPSIS?
THERE ARE POTENTIAL REASONS
INCLUDING THE CHOICE OF TIMING
AND THE DOSE.
SO THE ONSET OF SEPSIS AND DIC
ARE ILL DEFINED AND THE TARGET
OF THERAPY MAY CHANGE OVER TIME
DUE TO DISEASE EVOLUTION.
THE SECOND REASON IS THE CHOICE
OF INTERVENTION.
WHAT IS THE BEST ANIMAL MODEL TO
USE, WHAT IS THE CORRECT TARGET,
AND WILL SINGLE THERAPIES BE
EFFECTIVE GIVEN THE COMPLEX
NATURE OF THE IMMUNE RESPONSE IN
SEPSIS?
AND THEN FINALLY, THE CHOICE OF
POPULATION.
SO THERE'S HETEROGENEITY IN
PATIENTS AS WELL AS PROCESS OF
CARE AND STRATIFICATION SYSTEMS
MAY BE NEEDED TO GUIDE TREATMENT
DECISIONS.
IN TERMS OF THE TIMING, BECAUSE
SEPSIS IS A CONTINUUM, THE
TIMING OF THEIR PEES MAY AFFECT
THEIR EFFICACY.
SO THE INITIAL INFECTION MAY BE
LOCALIZED, BUT WHEN THE
INFECTION IS DYSREGULATED AND
SYSTEMIC, THAT COULD LEAD TO
SEPSIS, SEPTIC SHOCK, MULTIPLE
ORGAN FAILURE, AND FINALLY,
DEATH.
IN RECENT YEARS, THERE HAVE BEEN
RENEWED INTEREST IN REVISITING
HEPARIN AS A POTENTIAL THERAPY
FOR SEPSIS.
HEPARIN IS A NEGATIVELY CHARGED
GLYCOSAMINOGLYCAN.
IT ALSO HAS ANTI-INFLAMMATORY,
ANTIMICROBIAL PROPERTIES.
IF WE LOOK AT THIS DIAGRAM, YOU
CAN SEE THAT HEPARIN CAN TARGET
MULTIPLE PATHWAYS, SO IN
ADDITION TO INHIBITING CLOTTING,
IT HAS THE ABILITY TO NEUTRALIZE
THE TOXIC EFFECTS OF
EXTRACELLULAR HISTONES, AND
THROUGH THIS, IT CAN REDUCE
TISSUE FACTOR EXPRESSION ON
MONOCYTES, PREVENT ENDOTHELIAL
CELL DEATH AND ALSO PREVENT
PLATELET ACTIVATION.
THERE HAVE BEEN MAJOR RANDOMIZED
CONTROL TRIALS EXAMINING THE
PROTECTIVE EFFECTS OF
THERAPEUTIC DOSE
ANTI-COAGULATION IN PATIENTS
WITH COVID-19-RELATED SEPSIS.
WHAT HAS EMERGED FROM THESE
TRIALS IS THAT THERAPEUTIC DOSE
HEPARIN APPEARS TO BE BENEFICIAL
IN MODERATELY ILL BUT NOT IN
CRITICALLY ILL PATIENTS WITH
COVID-19-RELATED SEPSIS.
THERE'VE ALSO BEEN CLINICAL
TRIALS LOOKING AT IL-6 RECEPTOR
ANTAGONISTS.
IL-6 IS AN INFLAMMATORY CYTOKINE
RELEASED IN RESPONSE TO
INFECTION.
IT'S PART OF THE ACUTE PHASE
RESPONSE.
THERE ARE MONOCLONAL ANTIBODIES
THAT CAN INHIBIT BOTH THE
MEMBRANE BOUND AS WELL AS THE
SOLUBLE FORM OF INTERLEUKIN 6.
THE RESULTS OF CLINICAL TRIALS
RESULTS THAT IL-6 RECEPTOR
ANTAGONIST IS BENEFICIAL IN
CRITICALLY ILL PATIENTS WITH
COVID-19-RELATED SEPSIS.
SO WE GO BACK TO THIS CONTINUUM.
IT SUGGESTS THAT THERE ARE
THERAPIES SUCH AS HEPARIN THAT
MAY BE BENEFICIAL IN THE EARLY
PHASE OF SEPSIS, AS THERAPIES
SUCH AS ALL SIX RECEPTOR
ANTAGONISTS MAY BE BENEFICIAL IN
THE LATER STAGES.
SO WHAT ABOUT THE CHOICE OF
INTERVENTION?
WHAT IS THE BEST ANIMAL MODEL TO
USE?
ARE THERE DIFFERENT TARGETS THAT
MAY BE CONSIDERED NOVEL
THERAPIES?
THERE ARE METHODOLOGICAL
CHALLENGES OF PRE-CLINICAL
ANIMAL RESEARCH.
IN PRE-CLINICAL RESEARCH, THE
STUDIES ARE USUALLY SINGLE
CENTER, THEY'RE NOT RANDOMIZED
OR BLINDED.
SOMETIMES SAMPLE SIZE
CALCULATIONS ARE NOT PROVIDED.
THERE'S VARIATIONS IN PROTOCOL,
AND INCOMPLETE REPORTING, WHICH
MAKES THE STUDIES DIFFICULT TO
REPRODUCE BETWEEN CENTERS.
IN CONTRAST, CLINICAL RESEARCH
IS OFTEN MULTICENTER RANDOMIZED
ADEQUATELY POWERED WITH SHARED
PROTOCOLS AND STANDARDIZED
REPORTING.
SO TO ADDRESS SOME OF THE
LIMITATIONS IN PRE-CLINICAL
ANIMAL STUDIES OF SEPSIS, IN
2019, WE ESTABLISHED THE
NATIONAL PRE-CLINICAL SEPSIS
PLATFORM, WHICH IS A
COLLABORATIVE NETWORK OF
CANADIAN SEPSIS RESEARCHERS AND
VETERINARIANS TO CREATE A
MULTICENTER INFRASTRUCTURE TO
RIGOROUSLY STUDY THE
PATHOPHYSIOLOGY OF SEPSIS AND TO
ACCELERATE THE MOVEMENT OF
PROMISING THERAPIES INTO EARLY
PHASE CLINICAL TRIALS.
SO THE SCIENTIFIC GOALS OF THE
NATIONAL PLATFORM ARE TO CREATE
A MULTI-LABORATORY
INFRASTRUCTURE TO EVALUATE THE
PATHOPHYSIOLOGY OF THEIR HOST
RESPONSE AS WELL AS THE
BIOLOGICAL HETEROGENEITY OF
SEPSIS IN A CONTROLLED
PRE-CLINICAL ENVIRONMENT.
ALSO TO IDENTIFY RESEARCH GOALS
THAT ARE CLINICALLY RELEVANT AND
PATIENT-CENTERED, ULTIMATELY TO
ACCELERATE THE MOVEMENT OF NOVEL
THERAPEUTICS INTO EARLY CLINICAL
TESTING.
THIS JUST SHOWS SOME OF THE
CENTERS THAT ARE PARTICIPATING
IN THE NATIONAL PRE-CLINICAL
SEPSIS PLATFORM.
SO ONE OF THE MODELS THAT WE'VE
RECENTLY DEVELOPED AND
CHARACTERIZED IS THE
FECAL-INDUCED PERITONITIS MODEL,
WHICH IS A POLYMICROBIAL MODEL
OF ABDOMINAL SEPSIS.
SO THERE ARE SEVERAL ADVANTAGES
OF THIS MODEL.
THE FIRST IS THAT THE INOCULUM
CAN BE STANDARDIZED, SO WE
HARVEST CECAL CONTENT FROM
MULTIPLE RATS.
THE REASON WE CHOOSE RATS IS
THAT THEY'RE MUCH LARGER, SO
THEY JUST HAVE MORE FECAL
CONTENT THAT WE CAN HARVEST, AND
WE FREEZE THEM IN BATCHES UP TO
2,000 -- AT A TIME THAT CAN BE
SHARED AMONGST DIFFERENT SITES.
THE TECHNIQUE IS VERY SIMPLE.
IT INVOLVES IP INJECTION, AND AS
KANDACE MENTIONED IN HE HURDLE,,
YOU CAN EASILY ALTER DISEASE
SEVERITY BY CHANGINGS THE DOSE
OF THE SLURRY YOU INJECT.
WE INCLUDE CLINICALLY RELEVANT
TREATMENTS CLINKING ANTIBIOTICS
AS WELL AS FLUID RESUSCITATION.
WE ALSO STANDARDIZE SCORING
SYSTEM, BECAUSE IN CANADA, AT
LEAST, WE AREN'T ALLOWED TO HAVE
DEATH AS AN END POINT, SO WE
NEED TO HAVE SURROGATE MARKERS
FOR HUMANE END POINTS, AND THIS
IS RELATED TO COMPONENTS OF THE
SEPSIS SCORE SUCH AS POSTURED
ACTIVITY, RESPIRATION QUALITY,
RUFFLED FUR AND RESPONSIVENESS.
FOR ANYONE WHO IS INTERESTED, WE
DO HAVE VIDEO RESOURCES RELATED
TO THIS MODEL, AND ALSO HOW
DIFFERENT ORGANS I AND BLOOD ARE
COLLECTED.
SO USING THIS MODEL, WE HAD THE
OPPORTUNITY TO LOOK AT THE DATA
THAT HAS EMERGED FROM THE
CLINICAL RESEARCHERS TO BRING IT
BACK INTO THE LAB TO BETTER
UNDERSTAND, FOR EXAMPLE, IF
THERE IS AN OPTIMAL DOSE AND
TIME TO ADMINISTER HEPARIN.
SO IN THIS MODEL, WE KNOW WHEN
SEPSIS IS INITIATED, BY THE TIME
AT WHICH THE FECAL SLURRY IS
INJECTED.
WE CAN THEN INJECT THE THERAPY
OF CHOICE N THIS CASE, I'M USING
HEPARIN AS AN EXAMPLE, AT
DIFFERENT TIMES AND AT DIFFERENT
DOSES.
THE END POINT WOULD BE 72 HOUR
SURVIVAL, AT WHICH TIME WE CAN
HARVEST THE O ORGANS, WE CAN
ANALYZE BIOMARKERS IN THE PLASMA
AND WE CAN LOOK AT BACTERIAL
BUILDS.
SO MOVING ON TO NOVEL THERAPIES,
A DECADE AGO, WE WERE LOOKING AT
BLOOD SAMPLES FROM ICU PATIENTS
WITH SEPSIS, AND WE MADE THE
OBSERVATION THAT THE SAMPLES
CONTAIN VERY HIGH LEVELS OF
EXTRACELLULAR DNA, AND WE'VE
IDENTIFIED THAT NEUTROPHILS ARE
THE MAJOR SOURCE OF THE
EXTRACELLULAR DNA.
THEY ARE RELEASED IN THE PROCESS
OF -- FACTOR 12 AND 11 DEPENDENT
MECHANISMS.
IT ALSO CHANGES THE MORPHOLOGY
OF THE BLOOD CLOT AND IT
PREVENTS CLOT BREAK DOWN BY
INHIBITING PLASMA -- SO WE
HYPOTHESIZED THAT PERHAPS WE'RES
RECOMBINANT DNASE1 -- PART OF
THE RATIONALE IS THAT IN ANIMAL
MODELS, ADMINISTRATION OF THIS
ENZYME REDUCES ORGAN DAMAGE AND
IMPROVES OUTCOME IN SEPTIC MICE.
IN PATIENTS, HIGH LEVELS OF DNA
PREDICTS POOR OUTCOME.
AND THERE'S ALSO ACQUIRED
DEFICIENCY OF ENDOGENOUS
DNASE1 IN ICU PATIENTS.
SO WE HAVE INITIATED A PHASE ONE
SAFETY AND FEASIBILITY STUDY TO
LOOK AT INTRAVENOUS D NAIS ONE
FOR THE TREATMENT OF PATIENTS
WITH SEPSIS.
IT'S A PHASE ONE LABELED DOSE
ESCALATION SAFETY AND
FEASIBILITY STUDY.
THE INTERVENTION IS INTRAVENOUS
DNASE 1 FOR 2 DOSES FOR EITHER
THREE DAYS OR SEVEN DAYS.
I JUST ALSO WANT TO MENTION THAT
THERE IS ANOTHER PHASE
1 CLINICAL STUDY LOOKING AT A
VARIANT OF DNASE 1 --
COVID-19-RELATED SEPSIS.
SO FINALLY, CHOICE OF
POPULATION.
SO WILL ONE SIZE FIT ALL IN THE
TREATMENT OF SEPSIS?
THIS IS A NICE REVIEW BY STANSKI
AND WONG WHICH SUGGEST THAT
PROGNOSTIC ENRICHMENT AS WELL AS
PREDICTIVE ENRICHMENT MAY HELP
TO -- THE PATIENTS ARE
STRATIFIED BASED ON MORTALITY
RISK.
IN PREDICTIVE ENRICHMENT,
THEY'RE STRATIFIED BASED ON
BIOLOGICAL PATHWAYS THAT MAY BE
TARGETED THROUGH SPECIFIC
INTERVENTIONS.
SO WE CONDUCTED A LARGE
MULTICENTER STUDY TO LACK LOOKT
VARIATIONS BETWEEN INDIVIDUAL
PATIENTS WITH SEPSIS.
WE USED A COMBINATION OF ROUTINE
LABORATORY PARAMETERS SUCH AS
LACTATE PLATELET COUNT,
CREATINE, AS WELL AS CELL-FREE
DNA AND PROTEIN C.
WHAT WE FOUND IS THAT THERE ARE
MORTALITY RISK PROFILES THAT ARE
UNIQUE TO EACH PATIENT, AND THIS
JUST HIGHLIGHTS THAT, FOR
EXAMPLE, IN PATIENTS WITH HIGH
LEVELS OF CIRCULATING DNA,
PERHAPS DNASE ONE THERAPY IS
APPROPRIATE.
IN PATIENTS WITH REDUCED LEVELS
OF ANTICOAGULANTS, PERHAPS
HEPARIN THERAPY MAY BE
BENEFICIAL.
SO THIS IS JUST AN EXAMPLE OF
HOW A TARGETED APPROACH MIGHT
LOOK LIKE IN FUTURE CLINICAL
TRIALS.
SO THERE WOULD BE A POINT OF
CARE RISK ASSESSMENT TOOL, IN
THIS CASE, I'M USING THE EXAMPLE
OF THE ROUTINE LABORATORY
INVESTIGATIONAL PARAMETERS THAT
COULD IDENTIFY WHICH INDICATOR
CONTRIBUTE THE MOST TO MORTALITY
RISK.
THE APPLICATIONS MAY THEN BE
TARGETED THERAPY AS WELL AS
MONITORING RESPONSE TO
TREATMENT.
SO JUST WANT TO SUMMARIZE THAT
THERE ARE STRATEGIES TO OVERCOME
BARRIERS IN CLINICAL TRIALS IN
SEPSIS.
THIS IS RELATED TO THE TIMING OR
DOSE OF THERAPY, THE TYPE OF
INTERVENTION, AND HETEROGENEITY
IN THE POPULATION.
THE ULTIMATE GOAL IS TO SELECT
THE RIGHT TREATMENT AT THE RIGHT
TIME AND AT THE OPTIMAL DOSE FOR
THE RIGHT PATIENT.
I'D JUST LIKE TO THANK MY LAB
MEMBERS, AS WELL AS MANY
COLLABORATORS WITHIN THE
CRITICAL CARE FIELD, AS WELL AS
OUR COLLEAGUES AT UNIVERSITY OF
MONTREAL.
THANK YOU.
>> VERY NICE, VERY NICE TALK.
THANK YOU VERY MUCH.
I THINK WE SHOULD START THE
DISCUSSION PANEL.
WE HAVE LIKE -- HOW MUCH TIME DO
WE HAVE?
SAY -- 1:45?
>> ABOUT 21 MINUTES.
>> OKAY.
>> YEAH, UNTIL 1:45.
>> I THINK WE CAN BRING
EVERYBODY ON THE SPEAKERS ON THE
PANEL.
I CAN START WITH THE DISCUSSION
ACTUALLY.
OKAY, I THINK THERE IS A
QUESTION.
PLEASE GO AHEAD.
>> YES, THANK YOU.
THESE WERE GREAT PRESENTATIONS.
I HAD ACTUALLY TWO QUESTIONS.
REGARDING THE PAD 4 EXPERIMENTS,
WITH THE CECAL SLURRY THAT WERE
DONE AT CHOP.
SO DID YOU LOOK AT CLINICAL
SCORES LIKE JUST NOW WE HEARD
ABOUT THE SCORING SYSTEM THAT
THEY'RE USING IN CANADA, THERE'S
THE SHROOM ET AL. CLINICAL
SCORES FOR MICE SINCE 2014.
HAVE YOU LOOKED INTO HOW THEY
DID CLINICALLY?
AND ALSO FROM THE LAST TALK, I
WAS WONDERING, SINCE WE TALKED
ABOUT THE I MAWN RESPONSE AND ID
HOW -- WE KNOW THERE'S AN
IMBALANCE OF HYPERIMMUNE AND
IMMUNE PARALYSIS IN SEPSIS.
HAVE WE LOOKED AT OTHER THAN THE
IMMUNE RESPONSE LIKE METABOLIC
CHANGES, FOR EXAMPLE, THAT CAN
DRIVE OR CHANGE THE IMMUNE
RESPONSE IN SEPSIS, ARE YOU
AWARE OR HAVE YOU DONE ANY
RELEVANT STUDIES WITH
IMMUNOTHROMBOSIS?
>> WELL, I CAN ANSWER QUICKLY TO
START AND THEN PASS THE BATON TO
DR. LIAW, BUT WE DID DO A
CLINICAL SEPSIS SCORE.
WE USED THE MEAN SEPSIS SCORE
WHICH TAKES INTO ACCOUNT REGS
PIER TRI RATE, EYE OPENING, SKIN
TURGOR AND MOVEMENT, AND IT PUTS
ALL THOSE TOGETHER AND YOU KIND
OF GET A FINAL CLINICAL SCORE,
SO WE USE THAT TO ASSESS OUR
ANIMALS CLINICALLY.
I WILL SAY FOR OUR -- PROTOCOL,
IT'S WRITTEN IN THERE THAT WHEN
ANIMALS EXCEED AN MSS OF 14,
THEY HAVE TO BE EUTHANIZED.
SO WE'RE ALSO IN THE BOAT OF
HAVING TO UTE NIEZ OUR ANIMALS
BEFORE THEY EXCEED THAT LEVEL,
SO THAT IS A COMOANT OF THOSE
STUDIES.
A COMPONENT OF THOSE STUDIES.
>> COULD YOU REPEAT THE SECOND
HALF OF YOUR QUESTION?
SORRY, I JUST WANT TO --
>> YES, IF THERE WERE -- IF WE
LOOK AT OTHER PARAMETERS OTHER
THAN THE IMMUNE RESPONSE, AND I
KNOW YOU TALKED ABOUT THE USE OF
HEPARIN, BUT WERE THERE OTHER
COMPONENTS LIKE THE ROLE OF
METABOLISM, FOR EXAMPLE, IN
THOSE EXPERIMENTS AND HOW THAT
CHANGES THE IMMUNE RESPONSE, AND
IF THERE IS ANY CORRELATION WITH
CHANGING IMMUNOTHROMBOSIS AND
WHETHER HEPARIN HAS ANY -- IS
THERE ANY INDICATION THAT
HEPARIN CHANGES ANY OF THAT AS
WELL?
>> THERE ARE IN VITRO STUDIES
WHICH SHOULD SUGGEST THAT
HEPARIN CAN ACTUALLY CHANGE THE
GENE EXPRESSION PROFILE OF
MACROPHAGE.
WE HAVE STARTED TO LOOK AT THE
EPIGENETICS OF SEPSIS TO SEE IF
THERAPY SUCH AS HEPARIN THAT
HAVE THE POTENTIAL TO CHANGE
GENE EXPRESSION, IF THAT
MODIFIES THE EPIGENETIC
LANDSCAPE OF THE MICE DURING THE
PROGRESSION OF SEPSIS.
IN TERMS OF THE EFFECTS OF
ALTERATIONS IN METABOLISM, WE
HAVEN'T SPECIFICALLY LOOKED AT
THAT, AND I THINK THAT'S AN AREA
THAT IS DEFINITELY WORTH
EXPLORING.
THE OTHER LIMITATION OF USING
ANIMAL MODELS IS THAT WE OFTEN
USE HEALTHY YOUNG MICE, AND OF
COURSE IN SEPSIS, THE PATIENTS
ARE OLDER AND WE HEARD IN THE
FIRST SESSION THAT THERE ARE
CO-MORBID ITS.
SO THERE ARE OPPORTUNITIES TO
LOOK AT THE IMPACT OF AGING IN
THESE MODELS, AS WELL AS OTHER
COMORBIDITIES.
WE PUBLISHED A SMALL STUDY WHERE
WE LOOKED AT 12 MONTH OLD MICE,
WHICH I GUESS WOULD BE
CONSIDERED ELDERLY.
THEY'RE AROUND 65 HUMAN YEARS,
AND THERE IS A SIGNIFICANT
DIFFERENCE IN THE IMMUNE
RESPONSE WHICH REFLECTS THEIR
POOR SURVIVAL COMPARED TO YOUNG
HEALTHY MICE.
WE'RE ALSO LOOKING AT DIABETES
MODELS TO SEE HOW DIABETES
IMPACTS OUTCOME IN THE CONTEXT
OF SEPSIS AS WELL.
>> THANK YOU.
>> COULD I ASK A QUESTION FOR
PATRICIA.
IN TERMS OF THE SORT OF THERAPY
DISMANTLING THE NETS, NUMBER ONE
IS, WHEN IS THE TIMING OF THE
DNASE ADMINISTRATION, AND NUMBER
TWO, ARE YOU CONCERNED THAT
DISMANTLING THE NETS MAY
ACTUALLY RELEASE A LOT OF NET
FACTORS THAT COULD ACTUALLY
THEMSELVES EXACERBATE THE
DISEASE?
WHAT ARE YOUR VIEWS ON THAT?
>> WE'VE DONE A TIME COURSE
STUDY WHICH SHOWED THAT IF YOU
ADMINISTER DNASE VERY EARLY ON,
IT ACTUALLY WORSENS OUTCOME,
AND -- BECAUSE CONCEPTUALLY THAT
DOES MAKE SENSE BECAUSE YOU
COULD THINK OF THE NETS BEING
DISMANTLED WHICH CONTRIBUTES TO
BACTERIAL DISSEMINATION.
SO IN OUR MOUSE MODELS, IT'S
PROTECTIVE IN THE LATER STAGES
OF SEPSIS, MEANING WE ADMINISTER
IT, I THINK BEYOND EIGHT HOURS.
IN TERMS OF DISMANTLING NET
COMPONENTS, THE OBVIOUS ONE
WOULD BE EXTRACELLULAR HISTONES,
WHICH WERE CYTOTOXIC AND THEY
CAN ACTIVATE PLATELETS, WE'VE
DONE A COMBINATION THERAPY WITH
DNASE ENZYME AS WELL AS HEPARIN,
SO THE STRATEGY WAS THAT
HEPARIN, WHICH HAS THE ABILITY
TO NEUTRALIZE HISTONES, MAY BE
THAT COMBINATION WOULD ACTUALLY
BE SYNERGISTIC AND HAVE AN
ADDITIVE BENEFIT.
BUT IN THE MICE, WE ACTUALLY
DIDN'T SEE THAT.
IN THE ANIMAL -- IN THE HUMAN
CLINICAL TRIALS, THAT'S
DEFINITELY SOMETHING THAT WE DO
NEED TO CONSIDER.
SO THAT'S WHY WE'RE STARTING
WITH THE SAFETY STUDY, AND AT
EACH DOSE OF THE DNASE 1,
THERE'S A DATA SAFETY MONITORING
COMMITTEE THAT WILL ASSESS
WHETHER OR NOT IT IS SAFE TO
PROGRESS TO THE NEXT HIGHER DOSE
AND ALSO FOR LONGER LENGTH OF
TIME.
BUT NIGEL, THAT'S AN EXCELLENT
POINT BECAUSE THERE ARE SO MANY
PRO THROMBOTIC AMINO --
PRO-INFLAMMATORY COMPONENTS IN
NETS AS WELL THAT COULD EASILY
BE RELEASE.
>> AND YOU'VE CHOSEN HEPARIN,
YOUR FAVORITE MOLECULE IS APC.
IS THAT OFF THE TABLE NOW, ARE
PEOPLE NOT INTERESTED IN APC?
BECAUSE IT OBVIOUSLY WAS A VERY
GOOD MOLECULE AS AN
ANTICOAGULANT.
IT'S ALSO CLEAVES AND
INACTIVATES THE HISTONES, SO WHY
THE CHOICE OF HEPARIN VERSUS
OTHER SORT OF ANTICOAGULANTS?
>> I STILL HAVE A BOTTLE OF
CLINICAL GRADE APC IN MY FRIDGE
AT HOME.
IT NEXT TO THE KETCHUP BOTTLE.
I'M NOT SURE IF I KNOW
ACTUALLY -- I THINK THE REASON
WE STARTED WITH HEPARIN, IT'S A
CLINICAL GRADE COMPOUND.
I DON'T KNOW IF CLINICAL GRADE
APC IS AVAILABLE.
THERE'S RESEARCH GRADE, BUT WE
HAVEN'T LOOKED AT THAT
CURRENTLY.
WE DO MEASURE PROTEIN C LEVELS
IN THESE MICE, AND AS YOU WOULD
EXPECT, THERE IS ACQUIRED
DEFICIENCY, SO CONSUMPTION OF
PROTEIN C WITHIN THE FIRST EIGHT
HOURS.
BUT DEFINITELY THAT'S SOMETHING
WE COULD INVESTIGATE AS WELL.
>> AND JUST A LAST QUESTION IS,
IS THE SOLUBLE THROMBOMOD LIPMON
WAS VERY FASCINATING TO ME WHEN
I STARTED LOOKING INTO THIS
BECAUSE I WANT WASN'T REALLY
SORT OF AWARE OF THAT BEING
USED.
THAT CLEARLY IS AN ACTIVATOR OF
THE PROTEIN C PATHWAY, AND
THAT'S HOW IT'S ACTING TO
BENEFIT AND REDUCE THE DIC.
WHAT ARE YOUR THOUGHT ON SOLUBLE
THROMBOMODULIN?
>> IN MICE WE HAVEN'T BEEN ABLE
TO CONSISTENTLY DEMONSTRATE THAT
THEY ACTUALLY WOULD GET DIC, AT
LEAST BASED ON THE ISTH DH
SCORES THAT MEASURES FIBRINOGEN
LEVELS, INR.
THE FIBRINOGEN LEVELS IN MICE,
UNLIKE IN HUMAN DIC, IN MICE THE
LEVELS DECREASE.
WE ALSO DON'T SEE THE SAME
REDUCTION IN PLATELETS AS YOU
WOULD SEE IN HUMAN DIC.
SO I JUST DON'T KNOW IF IT'S A
SPECIES THING OR MAYBE THERE
NEEDS TO BE A MODIFICATION OF
THE SCORE THAT WOULD BE
APPROPRIATE FOR MICE, BECAUSE
WHEN WE TRY TO USE THE HUMAN
SCOAR, WE SCORE, EVEN THOUGH THK
SEPTIC, THEY HAVE ALL THE
PHYSIOLOGICAL SIGNS AND THERE IS
MORTALITY, AT LEAST BASED ON THE
SCORE, THEY DON'T HAVE DIC, IF
THAT MAKES SENSE.
>> WHAT ABOUT D-DIMERSER?
WE ACTUALLY DON'T SEE D-DIMER.
I KNOW OTHERS HAVE SEEN D-DIMER
GO UP IN THEIR MODEL.
WE DON'T SEE IT.
HAVE YOU SEEN D-DIMERSER GO UP
IN YOUR MODEL?
>> NO, WE DON'T SEE IT ELEVATED
AN THAT'S THE OTHER DIFFERENCE
AS WELL.
TAT LEVELS ARE INCREASED BUT NOT
D-D IMER.
>> OKAY, I'LL GO.
SO I WAS QUITE FASCINATED BY THE
SIX PROGNOSTIC PARAMETERS THAT
PATRICIA YOU PRESENTED AND ALSO
THE SCORING SYSTEM, AND THAT
REMINDED ME OF A COUPLE OF
STUDIES FROM HARVARD AND TEMPLE
UNIVERSITIES WHERE THEY ARE
LOOKING AT NEUTROPHIL MIGRATION
PROFILES AS A PROGNOSTIC FACTOR,
AND IT HAS BEEN SHOWN THAT THE
NEUTROPHIL MIGRATION IMPAIRMENT
OCCURS AND IT CORRELATES WITH
THE SEVERITY OF SEPSIS.
SO WHAT ARE YOUR THOUGHTS ABOUT
IT AND DO YOU THINK THAT IT
COULD SERVE AS A PROGNOSTIC
FACTOR ONE DAY, AS A FUNCTION OF
RESPONSE OF IMMUNE CELLS?
>> YES, DEFINITELY, I THINK THE
REASON WE PICK THE SIX
INDICATORS IS THAT THESE WERE
INDICATORS THAT THE SITES COULD
EASILY MEASURE BECAUSE NOT ALL
OF THE SITES HAD RESEARCH LABS
ATTACHED TO THEM, SO I GUESS IF
YOU WANTED TO LOOK AT NEUTROPHIL
MIGRATION, I'M NOT SURE THE TIME
FRAME OF THAT, BUT IF IT
REQUIRES THE NEUTROPHILS TO BE
ISOLATED, MY SENSE IS THAT THAT
PROBABLY WOULD BE AN ASSAY THAT
WOULD REQUIRE SEVERAL HOURS
VERSUS THE POINT OF CARE DEVICE
WHERE THESE ROUTINE CLINICAL
PARAMETERS OR INDICATORS COULD
BE VERY EASILY MEASURED AT THE
BEDSIDE.
>> YEAH, I THINK I CAN ELABORATE
ON THAT A LITTLE BITMENT THEY
ARE USING THESE MICRO FLEW TICKC
CHIPS -- FINGERPRINT SO IT COULD
BE A POINT OF CARE ASSAY.
>> RIGHT.
AND I GUESS WOULD YOU NEED TO
JUST HAVE WHOLE BLOOD, THEN,
RIGHT?
YOU DON'T EVEN NEED TO PROCESS
IT.
>> YEAH.
>> THAT'S INTERESTING.
>> EVERYONE, THANKS.
I HAVE A FEW QUESTIONS FOR
EVERYONE ACTUALLY.
SO WHEN I TALK TO THIS
SPECIFICALLY, PATRICIA, WHEN I
TALK TO THESE CRITICAL CARE
SPECIALIST, THEY OFTEN -- THEY
TELL YOU THAT THE BIGGEST
TREATMENT -- SEPSIS PATIENT IS
IN ICU TO MAINTAIN GLUCOSE
LEVELS.
SO REGARDING THE QUESTION, IT
STRUCK ME THAT METABOLISM PLAYS
A ROLE THAT MAYBE HASN'T BEEN
INVESTIGATED.
SO IT A VERY TIGHTROPE YOU HAVE
TO MAINTAIN THE GLUCOSE LEVEL?
>> THE CHALLENGE WITH MICE IS
THAT UNLIKE IN HUMANS WHO
DEVELOP HYPERGLYCEMIA, IN MICE
IT ACTUALLY THE OPPOSITE.
SO WE SEE A RAPID DROP IN BLOOD
GLUCOSE WITHIN FOUR HOURS OF
INDUCING SEPSIS.
SO TRYING TO MAINTAIN BLOOD
GLUCOSE IN THE MICE, WE'VE GIVEN
IP INJECTIONS OF DEXTROSE, FOR
EXAMPLE, TO SEE IF THAT HELPS TO
IMPROVE SURVIVAL, BUT BECAUSE
IT'S THE OPPOSITE OF HUMANS, I'M
NOT REALLY SURE HOW WE WOULD
STUDY THAT, AND IN HUMANS, MAYBE
SOME OF THE CLINICIANS COULD
COMMENT, BUT I'M NOT AWARE OF
MAINTAINING TIGHT BLOOD GLUCOSE
IS SOMETHING THAT IS STANDARD OF
CARE.
>> I'M A PEDIATRICIAN SO THINGS
ARE DIFFERENT FOR US BECAUSE OUR
PATIENTS TEND TO BE HEALTHIER AT
BASELINE, BUT A LOT OF TIMES
THESE KIDS WILL END UP IN
STEROIDS, AND IN THAT CONTEXT
OFTEN, WE HAVE GLUCOSE CONTROL
BECOMING AN ISSUE, BUT AT LEAST
IN THE CONTEXT OF PEDIATRIC
SEPSIS OUTSIDE OF STEROID
TREATMENT, GLUCOSE CONTROL IS A
HUGE COMPONENT OF WHAT WE USE.
GRANTED I'M A HEMATOLOGIST, NOT
AN INTENSIVIST, BUT THAT'S BEEN
MY EXPERIENCE.
>> THANK YOU.
>> I HAVE ANOTHER QUESTION
REGARDING NETS.
SO DNASE HAS BEEN AROUND FOR A
WHILE, AND I KNOW -- IT ALSO
FDA-APPROVED FOR CYSTIC
FIBROSIS.
SO WHY NOT SOMETHING LIKE
NEUTROPHIL ELASTASE, WHICH HAS
SO MANY INHIBITORS AND
PREPARATION.
WHY HAS THAT NOT BEEN -- IS
THERE AN ISSUE WITH IT, OR
SOMETHING MORE THEIR
POUTICALLY -- ANTITRYPSIN.
IS THERE SOME INTEREST IN THAT
OR IT'S BEEN THERE ARE ISSUES
WITH TESTING SOMETHING LIKE THAT
IN PATIENTS?
OR AT LEAST IN MICE MODELS.
>> I THINK DANARIXIN AND -- ARE
USED IN THE TREAT M OF COPD.
I HAVEN'T SEEN THEM OUST USED
TYPICALLY IN THE TREATMENT OF
SEPSIS, BUT THAT CLASS OF
MOLECULES CERTAINLY DOES EXIST.
>> I HAVE ONE QUESTION FOR YOU,
KANDACE.
SO WHERE THIS PFO COMES, IS IT
PLATELET DERIVED, PLATELETS
RELEASE THAT OR IT'S IN THE
CIRCULATION OR IT COMES FROM THE
ENDOTHELIUM?
WHERE DO YOU THINK THIS
PF4 COMES FROM?
>> PLATELET FACTOR 4 IS MAINLY
MADE BY -- CARRIER SITES AND
LOADED INTO THE PLATELET ALPHA
GRANULES.
SO PLATELETS ARE GOING TO DO THE
BULK OF THE WORK OF SORT OF
MOVING PF4 AROUND THE
CIRCULATION.
ONE OF THE QUESTIONS IN THE CHAT
IS HEY, DOESN'T IT GET ELEVATED
IN THE PLASMA OF PATIENTS?
AND ABSOLUTELY, YOU GET PLATELET
ACTIVATION, YOU GET
DEGRANULATION.
I THINK THERE'S BEEN A FEW
STUDIES WHERE WE SEE THERE'S
ELEVATED PLATELET FACTOR 4 IN
BOTH MURINE AS WELL AS HUMAN
SEPSIS.
BUT PF4 IS A VERY PEER MISCUE US
MOLECULE IN THAT IT LOVES TO
BIND TO NEGATIVELY CHARGED
COMPOUNDS, SO IT DOESN'T STAY IN
THE CIRCULATION FOR ALL THAT
LONG BECAUSE IT WILL BIND TO
GLYCO -- GL ON TOP OF THE
ENDOTHELIUM OR ON TOP OF
CIRCULATING CELLS.
SO IF YOU WANT TO GET YOUR
HIGHEST LOCAL CONCENTRATIONS OF
PF4, I THINK THE BEST WAY TO DO
IT IS THROUGH KIND OF A
PLATELET, AND SO MY HYPOTHESIS
IS THAT NETS, SINCE THEY DO SUCH
A GREAT JOB OF BINDING
PLATELETS, THAT YOU PROBABLY --
WHEN YOU'RE NOT SEVERELY
THROMBOCYTOPENIC, YOU GET A
DECENT DELIVERY OF PLATELET
FACTOR 4.
>> THERE'S A QUESTION IN THE
CHAT THAT I'LL TAKE.
IT'S SORT OF DIRECTED AT
PATRICIA BUT IT HAS TISSUE
FACTOR IN IT.
SO IT'S ASKING ABOUT WHETHER
DOES TISSUE FACTOR THAT'S
ALREADY ARRIVED FROM A VIRAL
RILY INFECTED CELL WILL BE
ACTIVE.
THERE'S A DIRECT ACTIVATION OF
THE MONOCYTE IN THOSE CASES.
BUT DELIVERY AND PACKAGING OF
THE TISSUE FACTOR FROM THE VIRAL
INFECT CELLS IS MORE DEBATABLE
EXACTLY HOW THAT'S CONTRIBUTING
TO DIC, BUT THERE IS DIRECT --
WITH THE EMERGING HEMORRHAGIC
VIRUSES.
>> ONE QUICK FOLLOW-UP COMMENT
TO NIGEL'S QUESTION IN REGARDS
TO ALL THE TOXIC MOLECULES THAT
ARE RELEASED WHEN YOU DISMANTLE
THE SCAFFOLD THAT IS DNA.
THERE ARE HOST ACUTE PHASE
PROTEINS SUCH AS C REACTIVE PRO
TPROTEIN THAT CAN NEUTRALIZE
HISTONES, SO MAYBE THERE ARE
SAFETY MECHANISMS IN PLACE TO
NEUTRALIZE THOSE MEDIATORS.
>> IF I REMEMBER MINUTE FILL --
THERE ARE STUDIES DONE LIKE THE
BACTEREMIA STUDIES AND OTHERS
HAVE SHOWN THAT IF THEY GIVE
DNASE, THE LIVER INJURY WAS NOT
PREVENTED.
THEY GIVE NEUTRALIZING STONES IT
WAS NOT PREVENTED AND FINALLY IT
WAS FOUND THAT IT WAS ALL THE
NEUTROPHIL ELASTASE THAT WAS
STILL THERE AND THEY TAGGED --
SORRY, GO AHEAD.
>> THE NEUTROPHIL EE LAS TAINS
AND HISTONES.
>> FOR EVERYONE'S KNOWLEDGE, SO
WHY DO YOU THINK DFPI FAILED IN
SEPSIS?
DO YOU HAVE ANY -- I'VE HEARD A
LOT ABOUT THIS, YOU KNOW, WHEN
YOU GO TO SEPSIS TALKS, THEY
TALK ABOUT THIS TFPI CLINICAL
TRIALS BUT SOME PEOPLE STILL
BELIEVE THAT IT WAS NOT THE
PROPER TRIAL.
IS THERE ANY REASON YOU THINK
THAT WHY TFPI DIDN'T WORK?
>> I THINK IT'S POTENCY AND ALSO
TIMING.
YOU HAVE TO GET THAT DRIG IN AT
THE EARLY PHASE.
IF YOU GET IT IN TOO LATE, IT
NOT GOING TO DO ANYTHING.
6.1% -- IS NOT PARTICULARLY
IMPRESSIVE, SO DEPENDING ON HOW
YOU DESIGN THE TRIAL, AND THE --
THEY ADDED HELP TRIN ON TOP, SO
THAT THEN COMPROMISED LACKING AT
THE -- HALF THE POPULATION GOT
HEPARIN AS WELL.
SO I THINK THE EARLY EXCITEMENT
OF USING THESE ANTICOAGULANTS
WAS SOMEWHAT -- THE TRIALS
WEREN'T AS DESIGNED, AND I THINK
WE CAN DO A MUCH BETTER JOB IF
WE STARTED TOMORROW DESIEB DESIA
NEW TRIAL.
AND CERTAINLY WHAT'S FASCINATING
TO ME IS IT ONLY EFFECTIVE IN
PATIENTS WITH A DIC.
IT'S COMPLETELY INEFFECTIVE IN
PATIENTS WITHOUT DIC.
SO THERE'S A GOOD SORT OF
INDICATION THAT YOU'VE GOT TO
HAVE DIC BEFORE -- IF YOU GAVE
TO THE WHOLE POPULATION, IT
FAILS.
AND IN A SEPTIC BASIC
POPULATION, IT FAILED.
>> OKAY.
SO DO THEY HAVE ANY CHARACTERS
WAY OF IDENTIFYING PATIENTS WHO
ARE DEVELOPING DIC VERSUS NOT
DIC OR ARE THEY JUST SAYING
THAT'S SEPSIS?
>> THEY DO ROUTINELY COLLECT THE
INR DEDIMER IN FIBRINOGEN SO IT
CAN BE -- ICU PATIENTS WITH
SEPSIS, ROUGHLY ONE-THIRD OF
THEM DID HAVE DI THIC, AND THE
CHALLENGE IS TO IDENTIFY
BIOMARKERS THAT PREDICT DIC.
SO WE FOUND THAT ANTITHROMBIN
COCONSUMPTION AND ALSO PROTEIN C
CONSUMPTION WERE USEFUL TO
PREDICT THE PRE-DIC STATE.
BUT I DON'T KNOW IF CLINICALLY
DIC STATUS CHANGES TREATMENT
STRATEGIES.
>> THANK YOU VERY MUCH.
AND I THINK I WILL HAVE ONE MORE
QUESTION TO BOTH NIGEL AND -- SO
WHAT ABOUT THE ROLE FOR
ENDOTHELIAL TISSUE FACTOR?
IS IT IMPORTANT OR HOW THAT
PLAYS IN CONTEXT?
>> WELL, I CAN TELL YOU IF YOU
PUT AN ANTIBODY AGAINST TISSUE
FACTOR IN ILS MODEL, YOU BLOCK
ABOUT 80 TO 85% OF THE
ACTIVATION OF COAGULATION.
IF YOU SELECTIVELY TARGET THE
HEMATOPOIETIC CELL POPULATION,
YOU BLOCK ABOUT 50%.
SO WE CAN CONCLUDE THAT THE
MONOCYTES -- COMING FROM ANOTHER
SOURCE, WHICH WE BELIEVE IS
INCREASED VASCULAR PERMEABILITY,
NOT THE ENDOTHELIAL CELLS, SO
WHEN WE DID THE TI TISSUE FACTON
MICE, WE ACTUALLY DIDN'T SEW
ANOTHER -- PEOPLE ARE A LITTLE
UPSET US BECAUSE THEY SPENT
YEARS WORKING ON -- WELL, THE
DATA IS DATA.
IT'S NOT DOING ANYTHING THAT WE
CAN DETECT.
IF YOU INCREASE VASCULAR
PERMEABILITY, WHAT ARE YOU GOING
TO DO?
YOU'RE GOING TO EXPOSE THAT
TISSUE FACTOR AND THAT'S GOING
TO LEAD TO AN ACTIVATION.
SO I THINK IF YOU WANT TO
COMPLETELY BLOCK THE TISSUE
FACTOR ACTIVATION OF
COAGULATION, YOU'D HAVE TO BLOCK
THE MONOCYTE AND PROTECT THE
VASCULAR -- SUCH AS APC, THIS
SITE OF PROTECTIVE APC --
>> AND I THINK THERE IS ONE
QUESTION FOR -- CHAT BOX, YOU
CAN READ THAT, BUT I HAVE ONE
MORE QUESTION.
FOR MY GEL.
SO EXTRACELLULAR VESICLES, WOULD
THAT EXPRESS TISSUE FACTOR, THEY
HAVE TO BE EXCLUSIVELY DERIVED
FROM MONOCYTES, BECAUSE
PLATELETS -- CORRECT ME,
PLATELETS DON'T EXPRESS TISSUE
FACTOR, RIGHT?
>> IN OUR VIEW.
IT A LITTLE CONTROVERSIAL, BUT
IN OUR VIEW, THEY DON'T EXPRESS
TISSUE FACTOR.
BUT A STUDY SHOWED IF HE DAMAGED
THE VASCULATURE, HE GOT EXTRA
VASCULAR TISSUE POSITIVE TISSUES
COMING OUT.
SO ALL CELLS CAN RELEASE TISSUE
FACTOR IF THEY CAN EXPRESS IT ON
THE SURFACE.
SO WHEN WE LOOK AT THAT EV
TISSUE FACTOR, WE CAN'T TELL YOU
WHERE IT'S FROM, WE JUST KNOW IT
ELEVATED IN THE CIRCULATION.
A LOT OF IT IS PROBABLY COMING
FROM THE MONOCYTES BUT WE CAN'T
EXCLUSIVELY SAY -- ON THE
MONOCYTE AND MACROPHAGES.
I THINK IN THE ENDOTHELIAL
CELLS, WHY THEY NEED THE
INDUCTION, IN REAL SEPSIS, THE
TISSUE FACTOR FROM END THEEL
YELL CELLS CAN ALSO CONTRIBUTE
TO THE COAGULATION.
>> GREAT STUDY MANY YEARS AGO
AND HE -- AND REALLY COULDN'T
FIND IT APART FROM A COUPLE
SOURCES, AND THEN THE
DIFFICULTIES, IF YOU SEE A
POSITIVE ENDOTHELIAL CELL, THEY
DON'T KNOW WHETHER THE
ENDOTHELIAL CELL MADE IT OR
WHETHER THE VESICLE FROM A
MONOCYTE GOT BOUND TO THAT AND
THAT CAUSED THE SIGNAL BEING
ELEVATED IN THE ENTHEEL YELL
CELL.
>> GO AHEAD.
THERE IS A QUESTION FOR YOU --
>> -- OF ANTI-COAGULATION IN
SEPSIS, I THINK TIME SOMETHING A
CRITICAL ISSUE.
OUR DIAGNOSIS OF DIC IS BASED ON
THE SCORE -- I THINK MOST FASTER
TIMING FOR INTERVENTION FOR
COAGULATION I THINK IS AT THE
EARLY STAGE.
AFTER THAT TIME, THOSE PATIENTS
MAY NOT REACH THE DIC CRITERIA.
>> FROM ALL OF YOUR TALKS, ONE
THING I UNDERSTOOD, YOU CAN ALL
CORRECT ME, THAT THE LATE
STAGES, THE MORE INFLAMMATORY
STAGE THE POPULATION IS DRIVEN
BY PRIMARILY INFLAMMATION.
>> NO, I DON'T AGREE WITH THAT
STATEMENT.
I THINK THE EARLY PHASE IS
INFLAMMATION AND COAGULATION.
AND THE LATER STAGE IS MORE OF A
COMPLEMENT -- SO THAT IS CLEARLY
COMING OUT OF THE -- STUDIES,
THERE WERE TWO PHASES.
BUT INFLAMMATION GOES UP VERY,
VERY RAPIDLY, IN THE MOUSE
MODEL, TNF IS UP BY ONE HOUR.
THE OTHER INFLAMMATORY MEDIA IS
THREE TO FOUR HOURS AND THEN
THEY'RE ELEVATED.
SO THE FIRST TP PHASE IS COY AGO
LAITION AND INFLAMMATION, AND I
DON'T THINK THEY'RE AS CLOSELY
CONNECTED AN AS EVERYBODY WOULD
LIKE THEM CONNECTED.
CROSSTALK GOES UP INDEPENDENTLY
AS WELL.
>> YEAH, BECAUSE LIKE I REMEMBER
DURING COVID, THERE WOULD BE
FIVE, SIX RECEPTOR TRIALS AND
THEY ALSO FOUND THE SAME THING,
THEY WERE MORE EFFECTIVE AT THE
LATER STAGE, AM I RIGHT?
CORRECT?
>> YES.
AND I WONDER IF THAT'S
BECAUSE -- I REALLY DON'T KNOW
THE MECHANISM.
INTUITIVELY, IT DOESN'T REALLY
MAKE SENSE.
BUT MAYBE HAVING IL-6
NEUTRALIZED TOO EARLY IS
HARMFUL, BECAUSE YOU DO NEED AN
INFLAMMATORY RESPONSE TO FIGHT
THE INFECTION IN THE FIRST
PLACE.
>> I HAVE A LAST QUESTION FOR
THIS FOR ZHENYU.
SO -- WHERE THAT FIT IN THE
INFLAM ZONE DRIVEN COAGULOPATHY?
>> WHAT'S THE QUESTION?
>> SO I'M SAYING THAT JUST
WONDERING, WHEN THE INFLAMMASOME
ACTIVATION IS CLASSICALLY
ASSOCIATED WITH -- WHICH CAN
BIND TO RECEPTOR AND PROMOTE
THROMBOINFLAMMATION.
SO IN THE PIE ROP PTOSIS DRIVEN
COAGULATION PATHWAY, HOW WOULD
THIS IL -- I DIDN'T SEE THAT
INTERLEUKIN ONE BETA.
>> YEAH, WE TESTED THIS
INFORMATION -- THE CYTOKINES IN
THE COAGULATION FOR -- AND FOUND
INTERLEUKIN ONE BETA AND
INTERLEUKIN 18 ACTUALLY DO NOT
CONTRIBUTE TO COAGULATION.
SO MAINLY OUR CONCLUSION IS THAT
TISSUE FACTOR RELEASED FROM
THE -- CELLS.
>> SO BEN CONFIRMS THAT BECAUSE
HE TOOK THE IL-1 RECEPTOR IN
KNOCKOUT MICE AND LOOKED AT THE
EFFECT ON THE COAGULOPATHY AND
THERE WAS NO EFFECT AS ALL.
>> THERE IS A QUESTION FOR WOT H
OF YOU.
I DON'T KNOW IF WE HAVE TIME OR
NOT, BUT -- TO RELEASE TISSUE
FACTOR IS THE QUESTION.
>> IN OUR VIEW, NO.
THE ONLY THING WE FOUND TO
INDUCE TISSUE FACTOR MON SUIT MS
ARE LPC.
THERE ARE SOME SPORADIC VERY
HIGH DOSE STUDIES WITH
MONOCYTES, WHICH YOU ALWAYS ARE
CONCERNED ABOUT LPS
CONTAMINATION OF THE CYTOKINE,
BUT I HAVEN'T SEEN NATISH EU
FACTOR IN MONOCYTES.
>> I THINK I'M USING THE BREAKS,
SO SHALL WE GO ON THE BREAK?
>> YES, LET TAKE A BREAK AND I
THINK ACCORDING TO THE AGENDA,
WE WILL BE BACK AT 2:15, I
GUESS?
>> THANKS TO EVERYONE.
REALLY WONDERFUL TALKS.
I'M SURE EVERYBODY LEARNED A
LOT. THANK YOU.
SO WHO ISN'T FAMILIAR WITH
ARTIFICIAL INTELLIGENCE THESE
DAYS, THANKS TO THE MEDIA, AND
WE ARE EXCITED TO SEE HOW A.I.
CAN BE USED FOR SEPSIS RESEARCH.
SO I WOULD LIKE TO INVITE
DR. VINCENT LIU FROM KAISER
PERMANENTE AND DR. IOANNIS
KOUTROULIS FROM GEORGE
WASHINGTON UNIVERSITY AND
CHILDREN'S NATIONAL HOSPITAL TO
LEAD THIS UPCOMING SESSION.
PLEASE GO AHEAD.
>> THANK YOU SO MUCH.
I AGREE WITH YOU, IF YOU HAVEN'T
HEARD OF A.I., YOUR HEAD IS
TRULY BURIED IN THE SAND, OR YOU
LIVE IN ONE OF THESE POPULATIONS
THAT'S NEVER BEEN TOUCHED
BEFORE.
IT MY PLEASURE REALLY TO BE
JOINED BY DR. IOANNIS KOUTROULIS
AS WE HOPE TO, YOU KNOW, OVERSEE
SOME OF THE MOST INNOVATIVE AND
IMPORTANT WORK THAT'S HAPPENING
IN A.I. AND SEPSIS.
I THINK IT'S GOING TO BE A
FANTASTIC TOUR THROUGH THE
DIFFERENT OPPORTUNITIES, AS WELL
AS CHALLENGES.
SO WITH THAT, I'M GOING TO TURN
IT OVER TO OUR FIRST PRESENTER,
DR. ANDRE HOLDER, WHO'S JOINING
US FROM EMORY UNIVERSITY TO
SPEAK ON TOWARDS EARLIER
RECOGNITION: A.I. IN SEPSIS
PREDICTION AND PROGNOSTICATION.
DR. HOLDER?
>> YES.
GOOD AFTERNOON.
CAN EVERYONE HEAR ME OKAY?
>> YES.
>> PERFECT.
SO THANK YOU FOR THE
INTRODUCTION.
SO AGAIN, MY TALK IS GOING TO BE
ON A.I. SEPSIS PREDICTION AND
PROGRPROGNOSTICATION.
SO THE OBJECTIVES HERE ARE TO
DISCUSS EXISTING AND EMERGING
APPROACHES TO SEPSIS PREDICTION
MODELING USING A.I. AND THEIR
EFFECTS ON PATIENT OUTCOMES, AND
I'M GOING TO USE A COUPLE OF
EXAMPLES FROM WORK FROM MYSELF
AND MY COLLABORATORS, BUT
THERE'S TONS OF OTHER WORK OUT
THERE THAT TOUCHES ON THE SAME
THING.
THE SECOND OBJECTIVE IS TO
HIGHLIGHT EXAMPLES OF BOTH
SUCCESSES AND CHALLENGES ACROSS
THE FIELD THAT ENLIGHTEN -- THAT
CAN ENLIGHTEN THE AUDIENCE ABOUT
WHERE THE FIELD NEEDS TO BE
MOVING.
SO MY FINANCIAL DISCLOSURES.
SO FIRST, LET'S TALK ABOUT WHAT
A.I. IS.
SO ARTIFICIAL INTELLIGENCE IS
SIMPLY THE USE OF MACHINES TO
SIMULATE THE ABILITY OF HUMANS
TO ACQUIRE KNOWLEDGE AND SKILLS.
AND HOW THOSE MACHINES DO THAT
IS THROUGH A PROCESS CALLED
MACHINE LEARNING.
AND IN THIS CASE, THE KNOWLEDGE
THAT WE'RE TRYING TO ACQUIRE IS
HOW TO PREDICT VARIOUS ASPECTS
OF SEPSIS, WHETHER IT'S SEPSIS
ITSELF OR ITS SEQUELAE.
NOW ONE THING THAT WE CAN DO IS
USE LABORATORY DATA, EMR DATA,
VITAL SIGNS, IMAGING, PERHAPS
OMICS AND GENETICS DATA, PUT
THAT INTO A MACHINE AND THEN
THAT MACHINE GENERATES SOME
OUTPUT WE FIND INFORMATIVE AND
HELPFUL WITH PATIENT CARE.
I TEND NOT TO LIKE TO USE THE
TERM ARTIFICIAL INTELLIGENCE
BECAUSE PEOPLE THINK OF
SOMETHING THAT'S AUTOMATED TO
TAKE THE PLACE OF HUMANS AND
REALLY THE WORK I WANT TO FOCUS
ON TODAY IS REALLY BEST
DESCRIBED AS AUGMENTED
INTELLIGENCE.
SO HOW CAN WE HELP PHYSICIANS
AND HEALTHCARE PROVIDERS ENHANCE
THEIR ABILITIES TO MAKE BETTER
PROGNOSTICATION AND PREDICTIONS
AS IT RELATES TO SEPSIS TO HELP
IMPROVE PATIENT CARE.
SO THE APPROACHES TO PREDICTION
AS IT PERTAINS TO SEPSIS AND THE
USE OF A.I. REALLY FOR ME FALL
INTO TWO CATEGORIES.
ONE WOULD BE TO PREDICT SEPSIS,
SO THAT IS IN PATIENTS WHO MAY
NOT HAVE CLINICAL SIGNS OF
SEVERE INFECTION, IDENTIFYING
WHO WILL BE AT RISK FOR
DEVELOPING IT, AND THEN ALSO
AMONG THOSE WHO ALREADY HAVE
SEPSIS, WHAT UNTOWARD OUTCOMES
CAN HAPPEN IN THE FUTURE, SUCH
AS DEATH OR, WORSE, AN ORGAN
FAILURE OR PERHAPS ONSET OF
SEPTIC SHOCK OR ACUTE FAILURE
REQUIRING MECHANICAL
VENTILATION.
SO AGAIN I'M GOING TO HIGHLIGHT
SOME WORK THAT WAS DONE BY MY
COLLABORATORS AND MYSELF, BUT
AGAIN, THERE ARE TONS OF OTHER
EXAMPLES IN THE LITERATURE.
SO TO HIGHLIGHT THE IDEA OF THE
USE OF A.I. FOR SEPSIS
PREDICTION, I'M GOING TO TOUCH
ON THIS WORK WE DID A FEW YEARS
BACK.
SO THE GOAL HERE WAS TO IDENTIFY
THOSE WHO WERE AT HIGHER RISK
FOR NEW ICU SEPSIS BEFORE IT
BECOMES CLINICALLY APPARENT.
WE USED A WEIBULL COX
PROPORTIONAL HAZARDS MODEL, WE
USED A LITTLE UNDER 80,000
PATIENTS TO TRAIN AND TEST THE
MODEL AT TWO DIFFERENT SITES,
AND USED VARIOUS CLINICAL
VARIABLES FROM THE EMR INCLUDING
VITAL SIGNS, DEMOGRAPHIC DATA,
LABORATORY DATA, ET CETERA.
AS YOU CAN SEE HERE, THE MODEL
THAT WE CREATED DETECTS SEPSIS
EARLIER, WITH AN AUC THAT'S
ABOUT .79 OR ABOVE.
NOW, WE HAVE A RANGE BECAUSE
WHAT WE DID WAS LOOK AT -- WE
USED DISCRETE TIME INTERVAL
ANALYSIS TO MAKE OUR
PREDICTIONS.
THAT IS, WHAT IS THE LIKELIHOOD
THE PATIENT MAY DEVELOP SEPSIS
FOUR HOURS FROM NOW, SIX HOURS
FROM NOW, EIGHT HOURS AND 12
HOURS.
THIS IS AKIN TO WHAT YOU MIGHT
SEE ON THE WEATHER CHANNEL
WHENEVER WE'RE TRYING TO MAKE
WEATHER PREDICTIONS.
SO -- AND THE KEY POINT I WANT
TO MAKE HERE, IF YOU LOOK -- IF
YOU FOCUS ON THAT GREEN SOLID
LINE ON THE BOTTOM, AS WE
INCREASE THAT TIME OVER WHICH
WE'RE TRYING TO PREDICT SEPSIS,
THE PERFORMANCE OF THE MODEL
DECREASE AND AGAIN, THIS IS AKIN
TO HOW WEATHER IS PREDICTED.
IT'S EASIER AND MORE ACCURATE TO
PREDICT WEATHER FROM -- SAY FROM
TODAY TO TOMORROW, VERSUS TRYING
TO PREDICT THE WEATHER SEVEN
DAYS FROM NOW.
SO THE SAME IS TRUE HERE.
BUT WE OVERALL HAD REASONABLE
PERFORMANCE UP TO 12 HOURS OF
PREDICTION IN THE FUTURE.
NOW OUR MODEL DIDN'T ALWAYS GET
IT RIGHT AND WE HAD SOME FALSE
POSITIVES BUT ONE INTERESTING
THING WE NOTED IS THAT AMONG
THOSE PATIENTS IN WHOM OUR
MODEL -- THE HIGHER THE
PROBABLE -- THE PROBABILITY OF
SEPSIS AS DESCRIBED BY THE
MODEL, THE HIGHER THE MORTALITY.
EVEN AMONG THOSE PATIENTS WHO
DID NOT HAVE SEPSIS.
AND THAT'S HIGHLIGHTED IN THAT
MIDDLE BAR THERE IF YOU SEE THE
FALSE POSITIVES, AS THE
PROBABILITY OF SEPSIS ACCORDING
TO THE MODEL INCREASED AS YOU GO
FROM THE MIDDLE NUMBER 8.3% TO
20.1%, 56.3%, THE PROBABILITY OF
DEATH ALSO INCREASED.
SO NOW SWITCHING GEARS HERE AND
TALKING ABOUT HOW TO PREDICT
SEQUELAE OF THOSE WHO ALREADY
HAVE SEPSIS, THIS IS ANOTHER
STUDY THAT HE WITH WE DID LOOKT
PATIENTS WHO ALREADY HAD SEPSIS
AND WE'RE TRYING TO PREDICT
THOSE WHO REQUIRE VASOPRESSORS
IN THE FUTURE AND CALLING THAT
SEPTIC SHOCK.
SO WE USE AGAIN A WEIBULL-COX
SURVIVAL MODEL BUT ADDED A
NEURAL NETWORK ON TOP OF THAT,
AND AGAIN USED ALL EMR DATA
USING 40 VARIABILITIES THIS TIME
THROUGHOUT THE ICU STAY.
AND AS YOU SEE THE SAME PATTERN
HERE, IF YOU LOOK AT THE TWO
LEFT PANELS, LOOKING AT THE
PREDICTION WINDOW AS THAT
PREDICTION WINDOW INCREASED,
BOTH THE AUC AND THE SPECIFICITY
DECREASED, BUT THE AUC AGAIN WAS
STILL PERFORMING AROUND .79.
NOW, LOOKING AT THE PREDICTION
WINDOW ON THE RIGHT, LOOKING AT
POSITIVE PREDICTIVE VALUE, THAT
ACTUALLY INCREASED AND THE
REASON FOR THAT IS SIMPLE,
BECAUSE WE USE DISCRETE TIME
INTERVAL PREDICTION.
ANYONE WHO DEVELOPED SEPTIC
SHOCK OR THE NEED FOR
VASOPRESSORS AFTER OUR WINDOW
WAS CONSIDERED A NEGATIVE.
SO AS WE INCREASE THAT LENGTH,
IF THE MODEL PREDICTED SEPSIS --
PREDICTED SEPTIC SHOCK IN THOSE
PATIENTS IT WAS GOING TO IMPROVE
ITS ACCURACY BECAUSE THEY
DEVELOPED SEPTIC SHOCK WITHIN
THE WINDOW OF PREDICTION.
SO I ALSO WANT TO HIGHLIGHT THE
WORK OF OTHERS HERE, AND THIS
WORK IS PRETTY INTERESTING
BECAUSE THIS IS FROM THE INSIGHT
GROUP OUT OF THE WEST COAST.
THEY CREATED A MODEL TO PREDICT
SEPSIS USING WHAT THEY CALLED
EXTENDED VITALS.
IT'S BASICALLY JUST VITAL SIGNS
PLUS THE USE OF PULSE OXIMETRY
AS WELL AS GCS.
AND AS YOU CAN SEE, IT MIGHT BE
A LITTLE HARD TO READ, BUT ON
THE TOP LEFT PANEL, YOU CAN SEE
THE AUC ON THE Y AXIS AND THE
HOURS PREDICTING SEPSIS ONSET ON
THE X AXIS.
YOU SEE THAT SIMILAR TO OUR
MODEL, THEIR MODEL PERFORMED
REASONABLY WELL AND COMPARED TO
OTHER METRICS, PERFORMED BETTER
THAN THOSE METRICS AT PREDICTING
SEPSIS.
NOW, WHAT I WANT TO HIGHLIGHT AS
WELL, THOUGH, IS THEY TOOK THIS
NOT JUST USING RETROSPECTIVE
DATA, BUT THEN THEY APPLIED THIS
PROSPECTIVELY IN WHAT I BELIEVE
TO BE THE FIRST RCT USING A.I.
FOR SEPSIS CARE.
AND FOUND THAT THERE WAS A
DECREASE IN MORTALITY AS WELL AS
ICU LENGTH OF STAY, THE
MORTALITY WENT DOWN FROM 21% TO
9%, AND THE LENGTH OF STAY WENT
DOWN BY ABOUT ONE DAY.
AND ALSO IMPROVEMENTS IN
ANTIBANTIBIOTIC PRESCRIPTION,
ANTIBIOTICS WERE PRESCRIBED
EARLIER.
I SHOULD MENTION THE CONTROL
GROUP IN THIS STUDY WAS AN
EXISTING SEPSIS DETECTION TOOL
THAT THEY USED IN THEIR
PRACTICE.
SO THIS MODEL OUTPERFORMED THAT
SEPSIS DETECTION TOOLI TOOL.
SO IN OTHER WORDS, IT SEEMS THAT
PREDICTION OF SEPSIS CAN
ACTUALLY HAVE IMPROVEMENTS IN
OUTCOME.
NOW I WANT TO HIGHLIGHT A COUPLE
THINGS HERE.
SO FAR BESIDES THE EXAMPLE I
JUST MENTIONED EARLIER, SO FAR
I'VE BEEN TALKING ABOUT THINGS
WE SHOULD HIGHLIGHT WHEN WE'RE
DEVELOPING A SEPSIS PREDICTION
MODEL.
SO QUESTIONS THAT YOU WANT TO
ASK ARE WHAT DATA DO YOU WANT TO
USE?
SO ARE WE USING EMR DATA, ARE WE
USING JUST VITAL SIGNS, ARE WE
INCLUDING WA WAVEFORM DATA?
WHAT ENVIRONMENTS?
ARE WE PREDICTING SEPSIS OR
SEQUELAE IN THE EMERGENCY
DEPARTMENT, IN THE ICU, IN THE
WARDS?
ALL OF THOSE AREAS HAVE
DIFFERENT INCIDENCES OF SEPSIS
AND PERHAPS DIFFERENT DATA
AVAILABILITY.
WHAT SEPSIS DEFINITION ARE WE
USING?
THERE ARE TONS OF WAYS TO DEFINE
SEPSIS AND DEPENDING HOW YOU
DEFINE IT, THAT CAN AFFECT THE
PERFORMANCE OF YOUR MODEL, AND
ALSO OF COURSE WHAT MODEL DO YOU
WANT TO USE.
AS WE MOVE FROM CREATING THESE
MODELS, THE QUESTIONS THAT WE
ASK AND WERE TRYING TO DEPLOY
WERE VERY DIFFERENT.
SO A FEW QUESTIONS THAT YOU'D
WANT TO ASK THAT ARE RELEVANT
ARE, WHAT KIND OF ALERT ARE WE
USING?
SO IS IT JUST TO PREDICT A --
ARE YOU JUST PREDICTING -- ARE
YOU CLASSIFYING WHETHER OR NOT
THEY'RE AT RISK OR NOT?
ARE YOU PROVIDING A PROBABILITY?
ARE YOU PROVIDING OTHER
ANCILLARY DATA THAT INFORMED HOW
THAT MODEL CAME UP WITH THAT
PREDICTION?
SO CALLED EXPLAINABLE A.I.?
AND THEN WHAT DEPLOYMENT
STRATEGY?
SO THE IMPLEMENTATION PIPELINE
IS IMPORTANT.
THIS IS THINGS ON THE BACK END.
SO HOW ARE WE ENSURING PATIENT
PRIVACY, FOR INSTANCE?
HOW ARE WE ENSURING THAT THE
MODEL IS BEING USED IN AN
EFFICIENT WAY ON THE BACK END?
AND ALSO WHAT DOES THAT END USER
EXPERIENCE?
WHAT ARE HE TH THEY ACTUALLY SEG
AND HOW IS THAT DATA BEING
PRESENTED TO THEM?
WHAT OUTCOME ARE WE LOOKING AT?
ARE WE LOOKING AT IMPROVEMENTS
IN STEP ONE BUNDLE COMPLIANCE
OR -- THEN WHAT ACTION SPHWH
J?WE HAVE TO MAKE SURE THAT'S TE
CASE.
SO I'M GOING TO TALK ABOUT A
COUPLE OF CASE STUDIES HERE AND
IMPLEMENTATION.
THIS WAS THE EWS MODEL OUT OF U
PENICILLIN.
SU -- U-PENN.
PERFORMANCE WAS GOOD, REALLY
WHAT THEY ONLY FOUND WAS THAT
3.7% INCREASE IN SERUM
LACTATE -- PRESCRIPTION.
WHEN THEY USE THIS MODEL TO
ACTUALLY DETECT SEPSIS, THEY
FOUND A MUCH MORE ROBUST
RESPONSE BY PATIENTS.
OR BY CLINICIANS.
SO THEY WERE IMPROVING LACTATE
ORDERS, ANTIBIOTIC PRESCRIPTION
WAS EARLIER.
SO WHAT THIS SAYS IS, JUST
BECAUSE WE PREDICT SOMETHING
DOESN'T MEAN THAT CLINICIANS ARE
GOING TO ACT ON IT BECAUSE IT
MAY NOT BE SOMETHING THAT'S
IMMEDIATELY OBVIOUS TO THEM,
THEY MAY NOT ACTUALLY DO
ANYTHING ABOUT IT.
SO THESE ARE VERY IMPORTANT
CONSIDERATIONS WE HAVE TO MAKE
AS WE'RE TRYING TO MOVE FROM
CREATION TO DEPLOYMENT.
SO ANOTHER EXAMPLE, VERY
DIFFERENT EXAMPLE WAS THE TREWS
SCORE, OUT OF HOPKINS.
SO MODEL PERFORMANCE WAS PRETTY
SIMILAR, SENSITIVITY WAS PERHAPS
BETTER.
THEY PROSPECTIVELY STUDIED THIS
IN SEVEN HOSPITALS AND FOUND A
MUCH MORE ROBUST RESPONSE.
SO IN OTHER WORDS, THE UPTAKE
WAS MUCH HIGHER.
WHY MIGHT THAT BE?
WELL, A LOT OF THIS HAD TO DO
WITH HOW THE DATA WAS PRESENTED.
SO IT WAS -- THE TREWS SCORE
MODEL THEY CREATED WAS
INTEGRATED WITHIN THEIR
WORKFLOW, SO AS YOU CAN SEE HERE
AS AN EXAMPLE HERE, THIS WAS AN
EXAMPLE OF ONE OF THE POP-UPS.
IF YOU NOTICE IT LOOKS VERY
SIMILAR TO SOME OF THE
CHECKLISTS THAT ARE FAMILIAR TO
A LOT OF CLINICIANS AND ALSO IT
WAS EXPLAINABLE.
ON THE BOTTOM IT SHOWS WHAT ARE
THE THINGS DRIVING THE PREDEXES?
THE CREATININE WAS HIGHER, THE
LACTATE WAS GOING UP.
AND IT SERVED A SPECIFIC NEED,
MEANING IT HAD TO HAVE
SEP-1 BUNDLE COMPLIANCE.
SO WE HAVE TO MAKE IT SOMETHING
USEFUL FOR THE END USERS.
AND THEN -- SO I WANT TO TALK A
LIT ABOUT BARRIERS TO WIDESPREAD
ADAPTATION OF THESE MODELS.
I'M GOING TO HIGHLIGHT THREE.
SO ONE IS DISTRUST.
SO JUST BECAUSE WE HAVE
SOMETHING THAT'S PRESENTED TO US
DOESN'T MEAN THAT WE BELIEVE IT
AS CLINICIANS.
SO I WANT TO -- IF YOU CAN HIT
NEXT, PLEASE.
NOW WHAT I WANT TO HIGHLIGHT IS
IT ONE ASPECT OF THE ACE MODEL
THAT WE CREATED IS
EXPLAINABILITY.
SO YOU CAN SEE THE AREA THAT'S
CIRCLED ON THE BOTTOM SHOWS ALL
OF THE VARIABLES THAT ARE
DRIVING THE PREDICTIONS SO THAT
CLINICIANS CAN KNOW WHETHER OR
NOT THEY CAN TRUST THE
PREDICTIONS THAT ARE BEING MADE
OR IF THEY THINK THEY MAY BE
SPEUR JUST.
THE NEXT ISSUE IS
GENERALIZABILITY.
SO JUST BECAUSE IT WORKS AT SITE
A DOESN'T NECESSARILY MEAN IT
WILL WORK IN SIGHT D.
SO PART OF THE SECOND STUDY THAT
I MENTIONED WITH PREDICTING
SEPTIC SHOCK WAS THIS USE OF
TRANSFER LEARNING.
THAT IS WE TRAIN A MODEL AT ONE
SITE, USE THAT SAME MODEL AT A
DIFFERENT SITE, AND SIMPLY TWEAK
IT USING A SUBSET OF PATIENT
DATA, AND, THEREFORE, THE MODEL
PREDICTION WAS MORE ACCURATE.
AND THAT'S WHAT WE FOUND IN OUR
STUDY.
SO THIS IS BEING USED MORE, THIS
IS ACTUALLY BEING USED A BIT IN
THE SECOND VERSION OF THE EPIC
SEPSIS PREDICTION MODEL.
SO THIS CONCEPT CAN HELP WITH
GENERALIZABILITY.
SO THE OTHER ISSUE IS ALARM
FATIGUE.
I'M GOING TO HIGHLIGHT SOME WORK
THAT WAS DONE AGAIN BY MY
COLLEAGUE NEMATI IN HIS
CONFORMER ALGORITHM.
WHAT THIS MODEL BASICALLY DOES
IS SAY "I DON'T KNOW."
SO IF -- IN OTHER WORDS, IT'S
NOT BEING FORCED TO MAKE A
DECISION ONE WAY OR THE OTHER
BASED ON THE OUTPUT IT HAS, IT'S
ALLOWING THAT ROOM TO SHOW, YOU
KNOW WHAT, I'D RATHER NOT MAKE A
PREDICTION BECAUSE IT MIGHT NOT
BE ACCURATE AND USE YOUR BEST
JUDGMENT OR PERHAPS ORDER MORE
TESTS TO IMPROVE MY ACCURACY AND
MY PERFORMANCE.
SO ANOTHER ISSUE THAT I'LL
HIGHLIGHT IS BIAS.
AND THE FACT THAT SIMILAR TO THE
GENERALIZABILITY ISSUE, IF THERE
ARE PATIENTS IN WHOM YOUR MODEL
MAY NOT HAVE BEEN EXPOSED TO AND
YOU TRY TO MAKE PREDICTIONS ON
THEM, THOSE MODELS MAY BE WRONG.
SO THERE ARE A LOT OF DIFFERENT
WAYS THAT WE CAN TRY TO
POTENTIALLY SOLVE THAT PROBLEM
AND SOME OF THEM ARE LISTED
THERE.
>> ONE MINUTE REMAINING.
THANK YOU.
>> THANK YOU.
SO ON THE HORIZON I THINK IS THE
USE OF GEN A.I.
I'M NOT GOING TO TOUCH TOO MUCH
ON THIS BUT WANT TO HIGHLIGHT
ONE STUDY THAT CAME OUT VERY
RECENTLY LOOKING AT PREDICTION
OF FUTURE -- PREDICTION OF
FUTURE PANDEMICS.
SO THIS MODEL ACTUALLY SEEMED TO
DO PRETTY WELL AT PREDICTING
FUTURE PANDEMICS BASED ON
DIFFERENCES IN THE DATA
DISTRIBUTIONS WITHIN THE
PATIENTS IN WHOM IT WAS EXPOSED.
SO IN SUMMARY, SEPSIS PREDICTION
AND PROGNOSIS IS POSSIBLE USING
A.I. TOOLS AND CAN HAVE
CLINICALLY MEANINGFUL OUTCOMES.
THERE ARE CHALLENGES,
SPECIFICALLY DISTRUST,
GENERALIZABILITY, ALARM FATIGUE
AND BIAS, BUT THERE ARE
POTENTIALLY WAYS AROUND THAT
THAT HOPEFULLY WILL BE
INTEGRATED AND WORK IN THE
FUTURE.
AND FUTURE DIRECTIONS, BESIDES
THAT DEALING WITH THOSE
CHALLENGES, COULD POTENTIALLY
INVOLVE DEPLOYMENT STRATEGIES
THAT IMPROVE GENERALIZABILITY
AND ACCEPTANCE AND INTEGRATION
INTO WORKFLOWS THAT WILL
HOPEFULLY MAKE THESE MODELS MORE
ACTIONABLE AND IMPROVE PATIENT
OUTCOMES.
AND WITH THAT, I THANK YOU VERY
MUCH FOR YOUR TIME.
>> THANK YOU, DR. HOLDER.
WE HAVE TIME MAYBE FOR ONE
QUESTION.
FOLKS CAN GO AHEAD AND RAISE
THEIR HANDS IF THEY HAVE A
QUESTION.
DR. KOUTROULIS.
>> THANK YOU FOR THIS GREAT
PRESENTATION.
YOU MENTIONED BRIEFLY ABOUT THIS
SEPSIS DEFINITION THAT CAN BE
USED IN THOSE MODEL, AND THAT
CAN VARY.
AGAIN, WE TALKED BEFORE IN THE
PREVIOUS TALKS ABOUT HOW THE
DEFINITION HAS CHANGED.
WHAT ARE YOUR THOUGHTS ABOUT
WHAT TO USE, ACCEP SEPSIS 2, SE,
OR EVEN CLINICAL JUDGMENT HERE
AND THE ICD10 CODE, WHICH WE
KNOW IS NOT A PERFECT WAY TO DO
IT.
WHAT ARE YOUR THOUGHTS ON THAT?
>> THAT'S A GREAT QUESTION AND I
THINK IT'S A VERY LOADED ONE AND
VERY HOTLY DEBATED.
I THINK A LOT OF IT DPSH I WILL
TELL YOU A LOT OF THE STUDIES
THAT HAVE DONE WORK IN SEPSIS
PREDICTION INCLUDING OURS USE
SEPSIS 3.
NOW, OF COURSE SEPSIS 3 IS
PROBABLY A -- THERE'S A LOT OF
DEBATE ABOUT WHICH ONE IS
BETTER.
I THINK IT DEPENDS ON WHAT
YOU'RE TRYING TO DO.
SO AS AN EXAMPLE, IF YOU'RE
FOCUSED ON SEP-1 COMPLIANCE,
SEP-1 DOES NOT REALLY TAKE -- IT
DOESN'T USE SEPSIS 3.
THERE ARE OTHER DEFINITIONS AS
WELL.
THERE'S THE CDC DEFINITION, ET
CETERA.
A LOT OF IT REALLY DEPENDS ON
THE DATA THAT YOU'RE USING AND
WHAT YOU'RE TRYING TO DO WITH
IT.
FOR US, WE WANTED TO MAKE THIS
AS CLINICALLY MEANINGFUL AS
POSSIBLE, SO WE DIDN'T
NECESSARILY WANT TO USE ICD-10
CODES.
AND OF COURSE WE KNOW THE ISSUES
WITH OVERDIAGNOSIS OF SEPSIS
SINCE THE PURPOSE OF THAT IS FOR
BILLING.
I THINK THAT ANY WAY THAT YOU
CAN BEST OPERATIONALIZE IT BASED
OON YOUR DATA, WHAT YOU HAVE
AVAILABLE TO YOU AND WHAT YOU
WANT TO DO WITH IT IS HELPFUL.
MY PERSONAL BIAS WAS TO MAKE
THIS AS ACTUAL AS POSSIBLE AND
ALSO TO USE WAYS OF IDENTIFYING
SEPSIS THAT HAVE ALREADY BEEN
VALIDATED.
SO FOR INSTANCE, IN OUR STUDY,
IN OUR STUDIES, WE USED SEPSIS
3, USING THE WAY THAT CHRIS SEE
SEYMOUR'S GROUP USED IT FOR
THEIR VALIDATION PAPER A FEW
YEARS BACK.
SO AS WELL AS MAKING IT SEEM A
LITTLE MORE ACTIONABLE FOR
CLINICIANS.
>> FANTASTIC.
THANK YOU, DR. HOLDER, FOR AN
EXCELLENT KICKO KICKOFF AND OVEW
OF WHAT THE OPPORTUNITIES ARE.
BECAUSE YOU TOUCHED ON KIND OF
CHALLENGES IN IMPLEMENTATION AND
WHAT IS ACTIONABLE, WE'RE GOING
TO BE NEXT JOINED BY DR. CARA
O'BRIEN, WHO IS FROM DUKE
UNIVERSITY, AND HAS A LOT OF
EXPERIENCE IN THIS DOMAIN, AND
SHE'S GOING TO SPEAK ON TOWARDS
AUGMENTED INTELLIGENCE:
EFFECTIVE INTEGRATION OF SEPSIS
A.I. AT THE BEDSIDE.
DR. O'BRIEN?
>> THANK YOU VERY MUCH, DR. LIU.
I THINK THERE'S SIGNIFICANT
OVERLAP BETWEEN WHAT I'M GOING
TO TALK ABOUT AND WHAT
DR. HOLDER JUST COVERED, BUT I
LOVE THE FACT THAT HE
HIGHLIGHTED AT THE END SEAMLESS
INTEGRATION.
WE'RE GOING TO SPEND SOME TIME
AT THE END TALKING ABOUT WHY I
THINK THAT'S PROBABLY ONE OF THE
MOST IMPORTANT ASPECTS OF
AUGMENTED INTELLIGENCE
IMPLEMENTATION FOR SEPSIS.
YOU CAN HAVE THE PERFECT A.I.
MODEL BUT IF IT'S NOT
IMPLEMENTED IN A WAY THAT HAS
IMPACT FOR PATIENTS THEN IT'S A
USELESS MODEL.
JUST TO BACK UP A MINUTE, I KNOW
THIS HAS BEEN COVERED IN SEVERAL
PRESENTATIONS ALREADY BUT I
REALLY THINK THE PREVALENCE AND
SEVERITY OF SEPSIS ARE WHAT
MAKES IT MOST CONDUCIVE FOR A.I.
IMPLEMENTATION.
SO BECAUSE IT'S EXCEEDINGLY
COMMON IMPACTING PATIENTS ACROSS
THE U.S. ALONE, HAS A HIGH RATE
OF MORTALITY, BUT HAS TREATMENTS
THAT HAVE BEEN SHOWN TO IMPACT
PATIENT OUTCOMES, IT'S AN IDEAL
DISEASE TO PREDICT.
HOWEVER IT'S EXTREMELY
CHALLENGING TO DIAGNOSE.
THE SIGNS AND SYMPTOMS ARE VAGUE
AND OVERLAP WITH MANY OTHER
DISEASES.
SO THERE'S A HIGH LEVEL OF
CLINICAL SUSPICION AND JUDGMENT
REQUIRED IN ORDER TO MAKE THE
DIAGNOSIS.
I THINK LASTLY, SEPSIS LIKELY
INCORPORATES MANY SUBTYPES OF
ILLNESS IN DIFFERENT POPULATIONS
OF PATIENTS LIKELY HAVE
DIFFERENT DISEASE -- AND MAY BE
IMPACTED DIFFERENTLY BY
TREATMENT.
SO WHAT'S THE SPECIFIC
OPPORTUNITY FOR A.I. IN SEPSIS?
I THINK NOW THAT WE HAVE ALMOST
UNIVERSAL DEPLOYMENT OF
ELECTRONIC HEALTH RECORD SYSTEMS
AS WELL AS BEDSIDE MONITORS THAT
ARE RECORDING CONTINUOUS VITAL
SIGNS, WE'RE CAPTURING JUST AN
ENORMOUS AMOUNT OF DATA, OFTEN
IN A CONTINUOUS FASHION.
I'M A BUSY HOSPITALIST.
I MAY LOOK AT A PATIENT'S VITAL
SIGNS IN THE COMPUTER, MAYBE TWO
TO THREE TIMES A DAY BUT
CERTAINLY NOT CONTINUOUSLY.
THESE A.I. TOOLS ARE CAPABLE OF
ANALYZING LARGE SETS OF DATA IN
NEAR REALTIME.
RECOGNIZING RELATIONSHIPS OF
DISEASE PRESENTATION THAT WE
WOULDN'T BE ABLE TO RECOGNIZE AS
HUMANS.
THESE SUBTLE PATTERNS CAN BE
INDICATIVE OF EARLY SEPSIS OR
HIGH RISK PATIENTS
POTENTIALLY -- ADDITIONALLY,
FEATURE ENGINEERING WHICH IS A
KEY COMPONENT OF MANY MACHINE
LEARNING MODELS CAN ENHANCE
A.I.'S ABILITY TO DETECT SEPSIS
BY FOCUSING ON IDENTIFYING THE
MOST RELEVANT AND PREDICTED
FEATURES.
SO SIMILAR TO DR. HOLDER, I
THINK THERE ARE SEVERAL
DIFFERENT APPLICATIONS OF
AUGMENTED INTELLIGENCE IN
SEPSIS.
PROBABLY THE MOST COMMON IS IN
DIAGNOSIS OR PREDICTION AS HE
WAS JUST COVERING, BUT I ALSO
THINK THERE ARE ASPECTS OF
APPLICATIONS IN TREATMENT
DECISION CHOICES AS WELL AS IN
PROGNOSIS.
SO AGAIN BECAUSE SEPSIS OFTEN
PRESENTS WITH VERY VAGUE SIGNS
AND SYMPTOMS AND THERE'S
SIGNIFICANT MORBIDITY ASSOCIATED
WITH EVEN HOURS OF DELAYED
DIAGNOSIS, MUCH OF THE RESEARCH
FOR A.I. IN SEPSIS HAS FOCUSED
ON IMPROVING PREDICTION AND
EARLY DIAGNOSIS.
THERE WERE 130 DIFFERENT SEPSIS
PREDICTED MODELS EXTRACTED AND
FOR THE PREDICTION OF SEPSIS
DIAGNOSTIC TEST ACCURACY
ASSESSED BY THE AUC RANGED FROM
ANYWHERE FROM .7 TO NEARLY 1.
SO WE HAVE MANY A VERY ACCURATE
MODEL.
JUST AS DR. HOLDER WAS
MENTIONING, A LOT OF THE EMR
DATA NOW IS NOT STRUCTURE DATA
ELEMENTS.
ONE STUDY FOUND 80% OF CLINICAL
DATA NOW IS -- THAT'S DATA
CAPTURED IN CLINICAL NOTES AND
IMAGES, FOR EXAMPLE.
THERE HAVE BEEN A COUPLE OF
STUDIES WITHIN THE LAST FEW
YEARS COMMENTING ON ADDITION OF
UNSTRUCTURED DATA IN PREDICTED
MODELS HAVING ADDED ACCURACY.
SO YOU CAN IMAGINE A FUTURE
HAVING MODELS THAT INCORPORATE
BOTH STRUCTURED DATA ELEMENTS AS
WELL AS UNSTRUCTURED DATA
ELEMENTS THAT HAVE A NEARLY 100%
ACCURACY IN PREDICTING SEPSIS.
SO THIS WAS A SCOPING REVIEW
INCLUDING 29 STUDIES OF MACHINE
LEARNING MODELS FOR SEPSIS
DETECTION ACROSS DIVERSE
CLINICAL SETTINGS, HAD OVER
1 MILLION PATIENT ENCOUNTERS AND
IT LOOKED AT THE DEDYNAMIC
VARIABLES INCLUDED IN THE MODEL.
AS YOU CAN SEE THE TOP FIVE WERE
ALL VITAL SIEB TRAM TERES.
THESE ARE THE VITAL SIGNS
COMMONLY MEASURED IN A
CONTINUOUS FASHION FOR MANY
PATIENTS IN THE HOSPITAL.
SO AGAIN AS I MENTIONED
PREVIOUSLY, WE HAVE THE
OPPORTUNITY TO CONTINUOUSLY
EVALUATE THESE DYNAMIC VAISH
VARIABLES.
I LOVE THE FACT THAT DR. HOLDER
ALSO CAPTURED THE IMPORTANCE OF
THE WINDOW OF PREDICTION.
SO THIS IS CRITICALLY IMPORTANT
PARTICULARLY FOR SEPSIS IN TERMS
OF CLINICAL INTERVENTION, WEE
SOURCE ALLOCATION, AS WELL AS
PLANNING FOR TREATMENT.
SO THIS FIGURE SHOWS THE IMPACT
OF DIFFERENT PREDICTIVE TIME
MODELS -- ON THE X AXIS YOU HAVE
TIME WINDOW TO SEPSIS AND THE
AUC ON THE Y AXIS.
YOU CAN SEE THAT ALL OF THEM
OVERALL PERFORMED VERY WELL
ACROSS THE ENTIRE SPECTRUM OF
PREDICTION, BUT FROM A CLINICIAN
PEPERSPECTIVE, WHAT WE'RE REALLY
HONING IN ON IS BETWEEN THE
1 AND 6 HOUR WINDOW.
AND MANY MODELS WITHIN THIS TIME
WINDOW WITH SIGNIFICANT ACCURACY
IN TERMS OF PREDICTING SEPSIS.
SO WITHIN THE POTENTIAL
APPLICATION OF A.I. FOR SEPSIS
DIAGNOSIS, I ALSO THINK IT'S
IMPORTANT TO THINK ABOUT THE
POTENTIAL FOR A.I. MODELS TO --
SUBTYPES OF SEPSIS, SO THIS
PHENOMENAL PAPER BY DR. SEYMOUR
PUBLISHED IN 2019, HE DID A
RETROSPECTIVE ANALYSIS OF
DATASETS FROM PATIENTS WITH
SEPSIS AND IDENTIFIED FOUR NOVEL
SEPSIS PHENOTYPES.
I THINK THIS WAS SHOWN IN ONE OF
THE FINAL TALKS EARLIER TODAY,
THE A ALPHA, BETA, GAMMA AND
DELTA.
THE FOUR PHENOTYPES WERE
STRONGLY CORRELATED WITH OUTCOME
AND SIMULATION OF THREE --
ESTIMATED TREAT FMENT WAS ALSO
SENSITIVE TO THE PHENOTYPE
DISTRIBUTION.
THIS SUGGESTS -- GROUPING
PATIENTS INTO DIFFERENT
PHENOTYPES.
IT MIGHT BE ABLE TO IDENTIFY
PATIENTS WHO WOULD BENEFIT FROM
SPECIFIC TREATMENT.
SO IN ADDITION TO GROUPING
PATIENTS INTO CERTAIN PHENOTYPES
WITH POTENTIALLY DIFFERENT
RESPONSES TO TREATMENT, A.I.'S
TOOLS HAVE ALSO BEEN USED TO
IDENTIFIED POSITIVE PATHOGENS
WHICH ALLOWED FOR TAILORED
TREATMENT FOR SEPSIS PATIENTS
WITH ANTIBIOTIC THERAPIES.
OR THE INFECTED ORGANISM.
SO GIVEN THE ABILITY TO ANALYZE
THESE HUGE DATASETS, A.I. HAS
THE CAPABILITY TO LOOK AT HOW
DIFFERENT PATIENT STRATEGIES MAY
IMPACT PATIENT OUTCOMES.
SO MODELS EVALUATING TREATMENT
STRATEGIES HAVE NOT YET BEEN
COMPREHENSIVELY VALIDATED BUT
THIS IS REALLY AN EXCITING AREA
OF OPPORTUNITY FOR A.I. AND
SEPSIS.
SO IN ADDITION TO ASSISTING
CLINICIANS WITH DIAGNOSIS AND
TREATMENT DECISIONS, TOOLS CAN
ALSO BE USED TO PREDICT PATIENT
OUTCOMES AND DR. HOLDER TOUCHED
ON THIS AS WELL.
THIS IS REALLY IMPORTANT WHEN
YOU THINK ABOUT SYSTEM-WIDE
RESOURCE ALLOCATION, SO BY
PREDICTING WHICH PATIENTS ARE
MORE LIKELY TO HAVE HIGHER
MORBIDITY OR MORTALITY,
HEALTHCARE SYSTEMS CAN USE THE
MODEL -- NURSE STAFFING RATIOS,
CLINICIAN WORKFLOWS, AND ALSO
FOCUS CLINICIAN ATTENTION WHERE
IT'S NEEDED MOST.
SO IF THESE A.I. MODELS WORK AND
THEY'RE ACCURATE IN TERMS OF
PREDICTION, WHY HAVE SO FEW BEEN
IMPLEMENTED IN CLINICAL
PRACTICE?
AND I APPRECIATE DR. HOLDER HIGH
LIEGHT THE SEVERAL THAT HAVE
BEEN IMPLEMENTED.
AND SOME OF THE CHALLENGES
ASSOCIATED WITH THAT.
A.I. MODELS RELY ON HIGH QUALITY
COMPREHENSIVE DATASETS TO
FUNCTION EFFECTIVELY.
HOWEVER, HEALTHCARE DATA IS
OFTEN FRAGMENTED ACROSS VARIOUS
SYSTEMS, THEY THERE ARE OFTEN
INCONSISTENCIES IN THE EHR,
THERE'S A LOT OF MISSING OR
INACCURATE DATA, WHICH ALL CAN
LEAD TO POOR MODEL PERFORMANCE.
ALSO MANY -- SINGLE INSTITUTION
OR A POPULATION OF PATIENTS AS
HE MENTIONED, WHICH MAKES IT
DIFFICULT TO GENERALIZE TO OTHER
SETTINGS.
A MODEL DEVELOPED USING DATA
FROM ONE HOSPITAL MAY NOT
PERFORM AS WELL DUE TO
VARIATIONS IN PATIENT
DEMOGRAPHICS, CLINICAL PRACTICE
AND DATA COLLECTION METHODS.
IN ADDITION, AS MENTIONED
PREVIOUSLY, SEPSIS HAS VAGUE
SYMPTOMS THAT OVERLAP WITH LESS
SEVERE FORMS OF INFECTION AND
WITH MANY NON-INFECTIOUS
DISEASES.
CLINICAL PRESENTATIONS CAN VARY
FROM PATIENT TO PATIENT SO THESE
FACTORS MAKE SEPSIS A DIFFICULT
DOAD, ADDITIONALLY YOU DON'T
HAVE THE BENEFIT OF TIME TO
OBTAIN -- BECAUSE EFFECTIVE
TREATMENT HAS TO BE INITIATED
WITHIN THE FIRST FEW HOURS OF
PRESENTATION.
SO THIS LEADS TO A PROBLEM
THAT'S INHERENT IN MANY -- FOR
THE MODEL TO BE ACCURATE,
OFTENTIMES IT INCORPORATES
DECISIONS THAT CLINICIANS HAVE
ALREADY MADE THAT INDICATE THAT
THEY SUSPECT IT'S SEPSIS, AND AT
THAT POINT, OBVIOUSLY THE OUTPUT
IS RELEVANT.
SO I THINK THIS IS THE
PARTICULAR ISSUE THAT WAS
HIGHLIGHTED IN THE STUDY ON THE
EPIC EHR MODEL DONE BY
UNIVERSITY OF MICHIGAN.
I THINK THIS REALLY HIGHLIGHTED
ONE OF THE MAIN ISSUES WITH
SEPSIS PREDICTIVE MODELS.
SO THIS STUDY LOOKED AT THE EPIC
EHR MODEL.
EPIC IS NOW SERVING OVER 50% OF
THE POPULATION IN THE U.S., 2.5%
OF PATIENTS INTERNATIONALLY, SO
IT'S A WIDELY USED EHR, AND IN
THIS STUDY, THEY LOOKED AT
77,000 ADULT PATIENTS
HOSPITALIZED IN -- OF THOSE
PATIENTS 5% WERE ULTIMATELY
DIAGNOSED AS HAVING SEPSIS AND
WHILE THE MODEL ACCURATELY
PREDICTED THE PATIENTS HAVING
SEPSIS 87% OF THE TIME, IT ONLY
DID SO 53% OF THE TIME BEFORE
PATIENTS HAD A BLOOD CULTURE
ORDER, SO ONLY ABOUT HALF THE
TIME DID IT PREDICT IT PRIOR TO
A CLINICIAN'S SUSPICION.
THE MODEL WHILE ACCURATE SEEMS
TO BE CUING IN ON DIAGNOSTIC
TESTS OR TREATMENTS THAT MADE
PREDICTIONS USELESS TO
CLINICIANS AT THIS POINT.
SO AGAIN THIS HIGHLIGHTS THE
MODEL IS INTEGRATED INTO THE
CLINICAL WORKFLOW AND IT
SOMETHING THAT SHOULD BE
EVALUATED WITH ANY NEW MODEL.
SO IN TERMS OF INCORPORATING IT,
IT'S CRITICALLY IMPORTANT THAT
THE IMPLEMENTATION BE SEAMLESS.
A.I. SYSTEMS HAVE TO BE EASY TO
USE, SEAMLESSLY INTEGRATED, AND
FOR SEPSIS, GIVEN THE PA RIDDITY
WITH WHICH IT MUST BE IDENTIFIED
AND TREATED, IT'S PARTICULARLY
CHALLENGING.
TRADITIONALLY, THERE IS THE
ISSUE OF ALARM FA TEAL.
AND THIS CAN CONTRIBUTE TO ALERT
FATIGUE, REDUCING YOUR
LIKELIHOOD OF THE SYSTEM BEING
TRUSTED AND USE.
IN ADDITION FALSE POSITIVES
ACTED UPON CAN HAVE IMPACT TO
THE PATIENT IN TERMS OF
UNNECESSARY ANTILIGHT IK
PRESCRIPTION, UNNECESSARILY DAIG
GNOSTIC TESTING.
SO AGAIN HIGHLIGHTED BY
DR. HOLDER ARE BARRIERS IN TERMS
OF TRUST.
SO THERE ARE SEVERAL FACTORS
THAT HELP WITH TRUST OF A.I.
MODELS.
FIRST OF ALL IS THE ACCURACY OF
THE MODEL ITSELF.
SO UNFORTUNATELY A.I. MODELS FOR
SEPSIS OFTEN LACK RIGOROUS LARGE
SCALE VALIDATION IN A DIVERSE
SETTING.
AND CLINICIANS WANT TO HAVE
EVIDENCE THAT THE A.I. TOOL
THAT'S IN USE IS HIGHLY ACCURATE
AND RELIABLE IN DIAGNOSING OR
PREDICTING CONDITIONS
PARTICULARLY FOR A CONDITION
SUCH AS SEPSIS WITH HIGH
MORBIDITY AND MORTALITY.
MANY A.I. MODELS PARTICULARLY
THOSE USING DEEP LEARNING ACT AS
BLACK BOXES, MAKING IT DIFFICULT
TO UNDERSTAND HOW PREDICTIONS
ARE MADE.
SO HAVING MODELS THAT ARE TRANTS
PARENT AND EXPLAINABLE ALSO
HELPS WITH TRUST.
AND THEN THERE ARE A NUMBER OF
HUMAN FACTORS THAT INFLUENCE
TRUST IN A.I. TOOLS.
SO CLINICIANS WHO HAVE MORE
EXPERIENCE ACTUALLY TEND TO BE
LESS TRUSTING OF A.I. SYSTEMS
DUE TO THE CONFIDENCE IN THEIR
OWN CLINICAL DECISION-MAKING,
WHEREAS JUNIOR CLINICIANS TEND
TO BE MORE OPEN TO TRUSTING A.I.
AS A SUPPORT TOOL.
STUDIES ALSO SHOW CLINICIANS ARE
LIKELY TO TRUST A.I. SYSTEMS
THAT ALIGN WITH THEIR OWN
EXPERTISE.
AND CLINICIANS WHO ARE JUST MORE
COMFORTABLE WITH DIGITAL TOOLS
AND A.I. IN GENERAL ARE LIKELY
TO HAVE HIGHER TRUST IN THESE
SYSTEMS.
AND CONTEXTUAL FACTORS FOR
TRUST, ALSO HAS TO DO WITH PEER
EB DORSMENT, SO CLINICIANS TEND
TO TRUST RECOMMENDATIONS FROM
THEIR COLLEAGUES, AND THIS CAN
HAVE A SIGNIFICANT IMPACT ON
PERCEIVED TRUSTWORTHINESS OF A
GIVEN A.I. TOOL.
LASTLY CLINICIANS AWARENESS OF
POTENTIAL BIASES IN THE A.I.
ALGORITHM CAN LEAD TO DISTRUST
IF THEY PERCEIVE THE A.I. TOOL
MIGHT BE UNFAIRLY TREATING
CERTAIN PATIENT GROUPS, SO
TRANSPARENCY IS CRITICALLY
IMPORTANT IN TERMS OF EFFORTS TO
MITIGATE BIAS AND FAIRNESS IN
MODEL DEVELOPMENT.
IF SHOULD INCLUDE A ROBUST
SYSTEM OF GOVERNANCE WITHIN THE
HEALTH SYSTEM.
GIVEN THE AFOREMENTIONED
CHALLENGES, HOW DO YOU
EFFECTIVELY INTEGRATE AN A.I.
TOOL INTO THE BEDSIDE?
STEP ONE IS TO FIND A MODEL THAT
WORKS.
SO THIS IS WHAT WE DID AT DUKE
BACK IN 2015, WHICH IS WHY THE
DEFINITION TO BE HONEST IS -- WE
CHOSE THE DEFINITION ON THE LEFT
AS OUR ELECTRONIC DEFINITION AND
THEN WE CONDUCTED A
RETROSPECTIVE DATA ANALYSIS
INCLUDING MORE THAN 42,000
INPATIENT ENCOUNTERS, AND WE
DEVELOPED A MACHINE LEARNING
MODEL.
SIMILAR TO SOME OF THE DATA
YOU'VE SEEN ALREADY, OUR MODEL
LISTED THERE IS MGP-RNN BECAUSE
IT'S A RECURRENT NEURAL NETWORK
MODEL OUTPERFORMED TWO OTHER
MACHINE LEARNING MODELS AND THEN
SOME OF THE POINT-BASED SCORING
SYSTEMS PRE-EXISTING.
FOR THE PURPOSE PS OF
TRANSPARENCY AND I WILL BE
HONEST AND SAY THIS IS ACTUALLY
A BLACK BOX MODEL SO IT DOESN'T
HAVE FULL TRANSPARENCY, BUT WE
DEVELOPED A SYSTEM TO EDUCATE
PHYSICIANS ABOUT CONTENT USE TO
BUILD MODEL AS WELL AS HOW
EFFECTIVE AND ACCURATE IT WAS IN
DETERMINING THE OUTCOME.
SO THEN AS I WAS GETTING TO, THE
IMPLEMENTATION IS CRITICALLY
IMPORTANT.
I JUST WANT TO HIGHLIGHT HOW WE
CHOSE TO IMPLEMENT IT.
SO WE ACTUALLY IDENTIFIED A
SINGLE END USER FOR OUR MODEL
OUTPUT AND BUILT AN A.I.
INTERFACE FOR THAT END USER
WHICH IS SHOWN ON THE RIGHT.
WHICH WAS BUILT IMPORTANTLY WITH
FRONT LINE STAFF FEEDBACK.
THIS WAS THEN INTEGRATED PRETTY
SEAMLESSLY INTO THE WORKFLOW AT
DUKE HOSPITAL IN THE EMERGENCY
DEPARTMENT.
THEN WE DEVELOPED A METHODOLOGY
FOR MODELING PATIENT OUTCOMES.
I'M GOING FAST TO TRY TO GET TO
THE HIGHLIGHT AND THAT IS THIS.
SO IN TERMS OF OUR PATIENT
OUTCOMES, THESE ARE OUR PROCESS
MEASURES.
IN ORDER TO VALIDATE THIS, THIS
IS AGAIN OUR PROSPECTIVE
IMPLEMENTATION, WE DID A
PRE/POST ANALYSIS.
THE POPULATIONS INCLUDED ARE
THOSE THAT MET THE CDC ADULT --
I FELT LIKE THIS WAS THE MOST
ROBUST ELECTRONIC DEFINITION OF
PATIENTS.
YOU CAN SEE THAT IN ALL ELEMENTS
OF THE BUNDLES OF CARE WE SHOWED
IMPROVE THE PRE AND POST
IMPLEMENTATION, AND NEXT SLIDE,
THIS IS THE BIG HIGHLIGHT.
THIS IS OUR MORTALITY RATIO,
EXPECTED MORTALITY SINCE
IMPLEMENTATION, WE'VE NOW BEEN
LIVE FOR THE LAST FIVE YEARS AND
WE'VE SEEN A SUBSTANTIAL
IMPROVEMENT IN PATIENT MORTALITY
IN THAT POPULATION OF PATIENTS.
SO THIS IS THE CONCLUSION.
I THINK THESE ARE THE CRITICAL
ELEMENTS FOR EFFECTIVE A.I.
INTEGRATION INTO SEPSIS BEDSIDE
CARE AND I NOT FOR THE INTERESTF
TIME I'LL CLOSE THERE AND SEE IF
WE HAVE TIME FOR QUESTIONS.
>> THANK YOU VERY MUCH,
DR. O'BRIEN.
WE HAVE TIME FOR QUESTIONS.
YOU IDENTIFIED TECHNOLOGY, HUMAN
AND CONTEXTUAL FACTORS AS THREE
MAIN BUCKETS OF AREAS WHERE
THERE'S POTENTIAL BARRIERS AND
GAPS THAT NEED TO BE OVERCOME.
IN THE WORK THAT YOU LED AROUND
SEPSIS WATCH INTEGRATION, WHAT
DID YOU FIND TO TAKE THE MOST
TIME, TO BE THE MOST DIFFICULT,
YOU KNOW, AGAIN, TECH, I THINK,
HUMAN AND CONTEXTUAL?
>> BY FAR AND AWAY HUMAN.
AND IT REMAINS -- DESPITE OUR
SUCCESS, IT CONTINUES TO BE KIND
OF THE ONGOING SOURCES OF
CHALLENGE FOR THIS MODEL.
WE DESIGNED OUR IMPLEMENTATION
WORKFLOW WITH FRONT LINE STAFF
FEEDBACK.
BUT I THINK OVERCOMING THOSE
TRUST BARRIERS, PARTICULARLY AT
THE PROVIDER LEVEL, AND HOWING
THIS WAS GOING TO IMPACT
PROVIDER LEVEL AUTONOMY, TRYING
TO SELL IT THAT THIS WASN'T A
TOOL TO REPLACE DECISION-MAKING
BUT TO AUGMENT DISSECTION MAKING
TO BE ANOTHER PIECE OF EVIDENCE
THAT THE CLINICIAN COULD
ULTIMATELY USE TO MAKE THEIR
DECISION ABOUT CARE FOR THE
PATIENT, BUT HOW THAT WAS
MESSAGED, THE WORKFLOW WE
ACTUALLY USED IS THROUGH AN I
KRMECULEVEL NERS.
A SINGLE NURSE MONITORS OUR
PREDICTIVE MODEL ON ANY GIVEN
DAY AND THAT NURSE IS
RESPONSIBLE FOR MONITORING THE
ENTIRE BHJ DEPARTMENT AND
COMMUNICATING VIA EPIC WITH THE
CARE TEAM FOR THE PATIENT.
SO A LOT OF THOUGHT AND FEEDBACK
WENT INTO HOW THAT COMMUNICATION
ACTUALLY IS WORDED, SO THAT THE
PROVIDER DOESN'T FEEL LIKE THEIR
TOES ARE BEING STEPPED OP IN
TERMS OF DECISION-MAKING BUT YET
THEY'RE ALERTED TO PATIENTS
BEING HIGH RISK, AND THEN OF
COURSE A KEY ASPECT OF THE MODEL
THAT WE BUILT IS NOT JUST
IDENTIFICATION, BUT
FOLLOW-THROUGH FOR THE PATIENT
IN TERMS OF THE BUNDLE OF CARE.
SO THERE HAD TO BE ONGOING
COMMUNICATION OR AVENUES OF
COMMUNICATION BETWEEN THE
EMERGENCY DEPARTMENT TEAM AND
THE NURSE WHO'S MONITORING OUR
PREDICTIVE MODEL, SO FIGURING
OUT HOW TO MAKE THAT SEAMLESS SO
IT WOULDN'T WORK ADDITIVE FOR
TEAM AND THE ED.
INCLUDING HAVING OUR NURSE GO
DOWN TO THE EMERGENCY DEPARTMENT
TO HELP WITH CARE DELIVERY IF
THAT WERE NECESSARY, BUT WE
CONTINUE TO ITERATE ON HOW TO
MAKE THAT WORK BENEFICIAL FOR
THE FRONTLINE TEAM TAKING CARE
OF THE PATIENT.
>> AND THAT GETS A LITTLE BIT
INTO THE QUESTION OF WHAT DOES
THAT STAFFING LOOK LIKE?
IS THAT LIKE A 24 HOURS 7 DAYS A
WEEK S IT A WEEKDAY, DAY TIME
HOURS?
HOW WOULD YOU CROSS THAT
BARRIER?
>> YEAH, SO WE ACTUALLY STAFF IT
24/7, AND INTERESTINGLY, IT'S
PAIRED WITH OTHER DUTIES.
SO THE NURSE WHO'S MONITORING
THIS PARTICULAR PREDICTIVE MODEL
ALSO HAS OTHER CLINICAL
RESPONSIBILITIES, AND SO AT THIS
POINT, NOW WE'RE LOOKING INTO
HAVING THAT PARTICULAR NURSE
ALSO REMOTELY MONITOR OUR TWO
COMMUNITY HOSPITALS THAT ARE NOW
ALSO LIVE WITH OUR PREDICTIVE
MODEL, AND SO WE'RE WORKING
THROUGH WHAT IS THE ADDED
WORKLOAD, BUT ACTUALLY WHEN WE
MEASURED IT, WE'VE HAD SEVERAL
SOCIAL SCIENTISTS FOLLOW OUR
NURSE AROUND, AND MEASURE A
TIMELINESS OF CARE AND TIME
REQUIRED FOR THE ACTUAL WORKFLOW
ASSOCIATED WITH SEPSIS WATCH,
AND ACTUALLY FOR EACH ADDITIONAL
PATIENT ENCOUNTER, IT ONLY TAKES
THE NURSE FIVE MINUTES TO REVIEW
THE PATIENT'S CHART, COMMUNICATE
WITH THE E.D., DOCUMENT IN THE
CHART.
FROM A WORKFLOW PERSPECTIVE
ACTUALLY, THEY'RE CAPABLE OF
DOING A LOT OF OTHER CLINICAL
TASKS AND AT THE SAME TIME,
MANAGING MULTIPLE PATIENTS WHO
ARE EITHER IDENTIFIED AS HIGH
RISK OR HAVING SEPSIS AND
FOLLOWING THROUGH THOSE THAT
HAVE BEEN IDENTIFIED AS HAVING
SEPSIS THROUGH THEIR BUNDLES OF
CARE.
SO ACTUALLY ADDING -- WE DID NOT
ADD ANY ADDITIONAL FTE WHEN WE
WERE ADDING IN THE COMMUNITY
HOSPITALS BECAUSE THE AMOUNT OF
INCREMENTAL TIME -- COMMUNITY
HOSPITALS ARE 300 BEDS AND 600
BEDS, AND IN TERMS OF THE
INCREMENTAL ADDITIONAL CASES, IT
WAS WITHIN THE WORKFLOW OF THE
EXISTING NURSE TO DO REMOTELY.
>> GREAT.
OKAY, IN THE INTEREST OF TIME
WE'LL KEEP MOVING.
WE'LL HAVE A CHANCE TO CIRCLE
BACK HERE.
THANKS, DR. O'BRIEN.
IT'S MY PLEASURE TO INTRODUCE
DR. PRATIK SINHA, WHO IS AT THE
WASHINGTON UNIVERSITY SCHOOL OF
MEDICINE TO SPEAK TO US ABOUT
TOWARDS PERSONALIZED CARE: A.I.
FOR UNPACKING SEPSIS
HETEROGENEITY.
GO FOR IT.
>> THANK YOU, VINNY AND THE
TEAM, FOR THE INVITATION.
THESE ARE MY DISCLOSURES.
NONE OF THEM ARE DIRECTLY
RELEVANT TO THIS TALK.
AN OVERVIEW OF MY TALK IS I'M
GOING TO FIRST START TALKING
ABOUT HETEROGENEITY IN SEPSIS
AND WHY IT'S A PROBLEM.
AND THEN VERY BRIEFLY TOUCH UPON
SOME OF THE APPROACHES TO
TACKLING HETEROGENEITY IN
SEPSIS, AND I HAVE TO SAY
BECAUSE OF THE CONSTRAINT OF
TIME, ANOTHER DISCLOSURE IS THAT
I'M MOSTLY FOCUSED ON SEPSIS
PHENOTYPING FROM OUR LAB, PARTLY
BECAUSE I THINK IT'S ONE OF THE
CLOSEST THAT'S COMING TO THE
POINT OF INTERFACING WITH
CLINICAL TRIALS AND CLINICAL
IMPLEMENTATION, AND TO SHOW HOW
WE HAVE USED CLINICAL
IMPLEMENTATION, WE'VE USED
MACHINE LEARNING APPROACHES TO
GET AT THE CLINICAL
IMPLEMENTATION OF THESE SEPSIS
PHENOTYPES.
ALSO TO REMEMBER THAT I MIGHT
NOT EMPHASIZE THIS BUT
THROUGHOUT MOST OF THE DATA I'M
GOING TO SHOW YOU FROM OUR LAB,
WE HAVE LEVERAGED DEEPLY MACHINE
LEARNING ALGORITHMS TO TRY AND
IDENTIFY PHENOTYPES AND THE
CLINICAL IMPLEMENTATION.
SO A GOOD PLACE TO START THIS
TALK WOULD BE TO ASK THE
QUESTION WHAT IS SEPSIS.
ACCORDING TO THE BIOLOGICAL
DEFINITION IN THE SEPSIS 3 KRAI
T3 CRITERIA, SEPSIS IS DESCRIBED
AS A LIFE-THREATENING ORGAN
DYSFUNCTION CAUSED BY A
DYSREGULATED HOST RESPONSE TO
INFECTION.
ALL THE TEXT YOU SEE IN COLORED
FONT ARE REALLY THE TRIUBERATE
THAT BIOLOGICALLY DESCRIBE
SEPSIS BUT EVEN A MOMENTARY
PAUSE WILL LEAD US TO ALL AGREE
THAT ALL OF THESE STATEMENTS ARE
INCREDIBLY NEBULOUS AND TO A
LARGE EXTENT SUBJECTIVE.
SO UNSURPRISINGLY, IT CAPTURES A
WHOLE HOST OF -- A MYRIAD OF
BIOLOGICAL PATHOPHYSIOLOGIES,
ETIOLOGIES INTO THIS DEFINITION.
NOW WHILE WE'VE SPENT A LOT OF
TIME TRYING TO UNDERSTAND THE
MOLECULAR BASIS OF THE HOST
RESPONSE, WE'VE NOT MANAGED TO
PIN IT.
WHAT WE DO KNOW IS THAT IT'S
HIGHLY COMPLEK, COMPLEX AND ALST
IT'S HIGHLY TIME VARIANT AND
DYNAMIC.
SO WE'VE TAKEN ALL THIS
INCREDIBLE 50 YEARS OF
BIOLOGICAL INFORMATION WE'VE
GATHERED ABOUT PATHOGENS, THE
HOST RESPONSE, AND THIS IS
CURRENTLY HOW WE DEFINE SEPSIS.
THIS LIFE-THREATENING ORGAN
DYSFUNCTION OF DYSREGULATED HOST
RESPONSE TO INFECTION.
IF YOU HAVE A SUSPECTED
INFECTION, YOU HAVE A SOFA SCORE
OF 2 OR MORE, ACCORDING TO THE
SEPSIS 3 KRAI TIER 3 CRITERIA, E
SEPSIS.
UNSURPRISINGLY, WHEN WE LOOK AT
HOW THIS SLO SHOWS UP IN THE
CLINICAL SPECTRUM IN THIS HIGHLY
UNDERRATED PAPER, THIS IS A CORE
DIAGRAM THAT LOOKS AT THE
DOMINANT TREATMENT TOPICS ON
HOUSE PATIENTS THAT MEET THE
SEPSIS DEFINITION SHOW UP IN
EHR.
I'M GOING TO GIVE YOU A PITHY
SUMMARY OF THIS, BUT AS YOU CAN
SEE SEPSIS IS A HOT MESS AS WE
DEFINE IT CLINICALLY.
SO WHY IS THIS A PROBLEM?
WELL, ROGER BONE ASKED WHY DO
SEPSIS TRIALS FAIL AND SEPSIS IS
REFERRED TO AS THE GRAVEYARD FOR
PHARMACOTHERAPIES.
OVER 200 TRIALS, WE'VE FAILED TO
IDENTIFY ANY BIOLOGICAL
INTERVENTION THAT IMPROVES
OUTCOMES.
SO IT'S A PROBLEM, PARTICULARLY
WHEN YOU'RE TRYING TO ATTRACT
PHARMA TO TRY AND SUPPORT SEPSIS
RESEARCH.
SO THE QUESTION IS CAN WE DO
SEPSIS TRIALS BETTER?
SO ONE APPROACH IS ABOUT
PHENOTYPING, THE IDEA BEING YOU
TAKE A HETEROGENEOUS POPULATION
AND YOU IDENTIFY UNIQUE
DISCRIMINATING FEATURES TO
SUBGROUP PATIENTS INTO AND THEN
TEST OUT THERAPIES ON THAT.
BROADLY SPEAKING, THERE ARE TWO
ARMS TO THIS ONE.
THIS ONE IS PROGNOSTIC
ENRICHMENT.
HERE YOU IDENTIFY SUBGROUPS OF
PATIENTS WHERE THE OUTCOME OF
INTEREST, SAY FOR EXAMPLE,
MORTALITY, OR VASOOPPRESSOR USE
IS HIGHER AND YOU TEST YOUR
INTERVENTION IN THAT GROUP, BUT
THE HOLY GRAIL, REALLY, IS
PREDICTIVE ENRICHMENT, AND THIS
MEANS THAT YOU IDENTIFY
SUBGROUPS WITH UNIFORM BIOLOGY
AND THEN YOU IDENTIFY THERAPIES
TO MATCH THAT PATHOPHYSIOLOGICAL
FEATURE AND THIS IS DONE QUITE
FREQUENTLY IN CANCER BIOLOGY.
AND THIS IS THE DOMAIN THAT OUR
LAB AND OUR COLLABORATORS ARE
MOST INTERESTED IN.
SO THERE ARE -- I'M GOING TO
SORT OF PASS AN ODOR NOW TO THEE
FACT THAT SEPSIS IS A COMPLEX
SYSTEM BIOLOGY PROBLEM.
IN MY BIASED OPINION, THE WAY WE
CAN IDENTIFY ROBUST SUBGROUPS IS
THROUGH USING MULTIVARIATE
MODELING, AND POTENTIALLY WHEN
WE EVENTUALLY GET THERE,
MULTIDIMENSIONAL MODELING.
SO IT IS HARDLY SURPRISING THAT
THE LARGEST GAINS BEING MADE IN
THIS FIELD OF SEPSIS PHENOTYPING
IS TO TAKE THIS NEBULOUS
SYNDROME, AND TRY AND FIND
UNDERLYING DISEASE STATES,
BECAUSE BIOLOGICAL THERAPIES ARE
ONLY -- PROBABLY ONLY LIKELY FOR
DISEASE STATES.
IN FACT, MACHINE LEARNING
MODELS, WHEN YOU TRAIN THEM TO
DISEASE STATES, ARE MUCH MORE
LIKELY TO WORK BETTER THAN THEY
ARE IF YOU TAKE A NEBULOUS SOME
SYNDROME OR COLLECTION OF
SYMPTOMS.
SO THESE ARE SOME OF THE
MEASUREMENT SYSTEMS USED TO
IDENTIFY THE PHENOTYPES.
IN TERMS OF DNA, WE'RE STILL IN
ITS INFANCY.
ARGUABLY SOME OF THE BIGGEST
GAINS THAT HAVE BEEN MADE HAS
BEEN THROUGH TRANSCRIPTOMICS.
HECTOR WONG, WHO WAS A PIONEER
IN THIS FIELD 15 YEARS AGO IN
PEDIATRICS DESCRIBED SUBCLASS A
AND B BASED ON -- AND MORE
RECENTLY THERE HAVE BEEN THE SRS
AND THE MARS PHENOTYPES.
CHRIS SEYMOUR AND HIS GROUP HAVE
USED EHR-BASED DATA.
THE SENECA GROUPS BUT ALSO
TEMPERATURE TRAJECTORIES.
METABOLOMICS, POTENTIALLY
EXCITING MODE OF INVESTIGATION,
GIVES YOU QUITE A LOT OF DATA
BUT IT'S STILL IN ITS INFANCY.
THE BULK OF THIS TALK IS GOING
TO BE FOCUSED ON THE WORK THAT
WE'VE BEEN DOING, WHICH IS THE
HYPO AND HYPERINFLAMMATORY
PHENOTYPES BASED ON PROTEIN
SIGNATURES BUT THERE'S ALSO
GREAT WORK DONE IN THIS FIELD IN
THOSE THAT HAVE LOOKED AT
BIOMARKERS IN CIRCULATION TO TRY
AND DEFINE SUBGROUPS AND
PHENOTYPES.
AS YOU CAN SEE THESE ARE ALL
COMPLEX DATA, AND BECAUSE THESE
ARE MULTIVARIATE DATA THAT ARE
ASSOCIATED, SOMETIMES LINEAR,
SOMETIMES NON-LINEAR
ASSOCIATIONS WITH EACH OTHER.
THE USE OF ARTIFICIAL
INTELLIGENCE AND MACHINE
LEARNING HAS BEEN CRITICAL TO
TRY AND BETTER UNDERSTAND THIS
DATA.
AND I AM GLAD THAT THIS IS ON
ZOOM BECAUSE NO STATISTICIANS
CAN BEAT ME UP, BUT I DO WONDER
WHETHER SOMETIMES OUR RELIANCE
ON STUDYING THIS COMPLEX SYSTEMS
BIOLOGY PROBLEM WITH STANDARD
STATISTICAL LINEAR AND
LOGISTICAL REGRESSION MAY HAVE
UNDERMINED OUR EFFORTS TO
UNDERSTAND THESE COMPLEX
BIOLOGICAL INTERACTIONS.
SO MOVING ON TO THE WORK THAT WE
HAVE BEEN DOING, THIS WORK HAS
BEEN PIONEERED BY PROFESSOR AT
UCSF, AND HERE WHAT SHE DID WAS
USE UNBIASED APPROACHES TO
IDENTIFY SUBGROUPS USING
MULTIVARIATE SOLUTIONS, USING AN
APPROACH CALLED LATENT CLASS
ANALYSIS, A COMPOSITE OF
CLINICAL AND BIOLOGICAL DATA.
REALLY THE PREMISE OF
IDENTIFYING PHENOTYPES WITHIN A
SYNDROME OR A DISEASE IS THAT IT
SHOULD BE USEFUL, ROBUST,
REPRODUCIBLE, GENERALIZABLE AND
CLINICALLY IMPLEMENTABLE.
I HOPE TO SHOW YOU THAT WE HAVE
AT LEAST ATTAINED SOME OF THESE
OVER THE COURSE OF TIME.
SO WE'VE IDENTIFIED TWO
PHENOTYPES, IN THE RED IS THE
HYPERINFLAMMATORY, IN THE BLUE
IS THE HYPOINFLAMMATORY
PHENOTYPE.
ON THE X AXIS ARE THE CONTINUOUS
CLASS DEFINING VARIABLES AND THE
Y AXIS IS THE MEAN STANDARDIZED
DEFINING VARIABLES.
THE HYPERINFLAMMATORY PHENOTYPE
IS CALLED OUT BECAUSE IT'S
ASSOCIATED WITH HIGHER
PRO-INFLAMMATORY CYTOKINES,
LOWER BICARBONATES, LOWER BLOOD
PRESSURE AND INCREASED ORGAN
FAILURE.
ABOUT 30% OF THE POPULATION
ACROSS MULTI-BEL MULTIPLE COHOR.
MORTALITY INCLUDING PEDIATRIC --
WHERE WE FOUND -- IN
CONSISTENTLY HIGHER IN THE
HYPERINFLAMMATORY PHENOTYPE
COMPARED TO THE
HYPERINFLAMMATORY PHENOTYPE.
WE'VE ALSO IN SECONDARY ANALYSIS
OF -- WE'VE HEARD DIFFERENTIAL
TREATMENT AND IN THE
SECONDARY -- OF HARP 2 WE SAW
SURVIVAL BENEFIT IN THE
HYPERINFLAMMATORY PHENOTYPE BUT
NOT IN THE HYPO.
IT'S IMPORTANT TO EMPHASIZE IN
ALL OF THESE THREE TRIALS BASED
ON CO CONVENTIONAL METRICS OF A,
SUGGESTING THESE PHENOTYPES
IDENTIFY FEATURES THAT MAY BE
AMENABLE TO DIFFERENTIAL
TREATMENT RESPONSES.
SO WHERE MY SORT OF RESEARCH
PROGRAM HAS BEEN LEADING IS TO
ASK THE QUESTION, CAN WE EXPAND
THESE PHENOTYPES INTO SEPSIS?
AGAIN USING LATENT CLASS
ANALYSIS IN EARLY WHICH IS AN
OBSERVATIONAL COHORT OF
CRITICALLY ILL PATIENTS IN --
WITH SEPTIC SHOCK, WE OBSERVED
THE SAME TWO PHENOTYPES WITH THE
SAME TWO FEATURES.
WE TOOK A PARSIMONIOUS MODEL, I
WILL SPEAK OF IT A LITTLE BIT
MORE, WHICH WE TRAINED, WE
REDUCED THESE LCA MODELS OF 30
TO 40 VARIABLES DOWN TO THREE OR
FOUR VARIABLES, TO PREDICT THESE
FINE PHOENIX TYPES, SO THESE
PHENOTYPES, WE POINTED TO
PREDICT THESE SEPSIS PHENOTYPES
AND THEN WE REPEATED THIS IN
ANOTHER 1100 PATIENTS SO IN TWO
INDEPENDENT COHORTS TOTALING
2,000 PATIENTS, THE SAME TWO
PHENOTYPES WERE IDENTIFIED IN
PATIENTS, CRITICALLY ILL
PATIENTS WITH SEPSIS.
ANOTHER INTERESTING FEATURE THAT
WE WERE ABLE TO DO THROUGH THE
SEPSIS ANALYSIS WAS THAT 30% OF
THE PATIENTS WITH THE
HYPERINFLAMMATORY PHENOTYPE HAVE
POSITIVE BLOOD CULTURES, AND NOT
ONLY THAT THERE WAS A
PREDOMINENCE OF GRAM-NEGATIVE
SEPTICEMIA IN THE
HYPERINFLAMMATORY PHENOTYPE BUT
NOT THE HYPOINFLAMMATORY
PHENOTYPE.
THIS WAS CONSISTENT ACROSS FOUR
DIFFERENT COHORT WHICH I DON'T
HAVE TIME TO SHOW YOU, BUT
YOU'LL HAVE TO BELIEVE ME,
AROUND 30% IS CONSISTENT.
WE THEN USED AGAIN SON MACHINE
LEARNING APPROACHES WITH META
GENOMICS SEQUENCING SO WE LOOKED
AT THE DNA OF PATHOGENS AND
CIRCULATION AND FOUND THAT
PATHOGEN DOMINANCE WAS SIG
RANTLY HIGHER IN THE
HYPERINFLAMMATORY COMPARED TO
THE HYPOINFLAMMATORY PHENOTYPE
AND THIS SLIDE IS NOT SHOWN
PROPERLY BUT I ASSURE YOU THAT
THERE WAS, AGAIN, A PREDOMINENCE
OF THE -- ACCORDING TO META
GENOMICS FROM BLOOD OF PATIENTS
WITH SEPSIS THAT THE
HYPERINFLAMMATORY PHENOTYPE
STRONGLY ASSOCIATED WITH IT.
FINALLY AND MOST RECENTLY IN THE
SECONDARY ANALYSIS OF THE
CLOVERS TRIAL WHICH IS A SEPTIC
SHOCK TRIAL OF FLUIDS, WE AGAIN
OBSERVED THE SAME TWO
PHENOTYPES, AND I WILL TAKE YOUR
ATTENTION TO THE FACT THAT ONLY
3% PATIENTS HAD ARDS, AND
BECAUSE THIS CLOVERS COHORT WAS
IN THE PLJ DEPART EMERGENCY DEPD
IT WAS EARLY, 50% OF THESE
PATIENTS HAD POSITIVE
BACTEREMIA, SUGGESTING THAT BACT
RBACTEREMIA IS AN IMPORTANT
FEATURE THAT EXPLAINS THE
VARIANCE OF THE
HYPERINFLAMMATORY PHENOTYPE.
SO A BIG ROADBLOCK IS THAT HOW
DO YOU TAKE THESE COMPLEX MODELS
AND IMPLEMENT THEM TO THE
BEDSIDE?
HOW DO WE TAKE THESE 30, 40
MULTIVARIATE SOLUTIONS AND BRING
THEM TO THE BEDSIDE SO THAT WE
CAN DO CLINICAL TRIALS AND TEST
THERAPIES?
WE'VE TAKEN TWO APPROACHES.
ONE IS TO TAKE THESE 30 OR 40
VARIABLES AND REDUCE THEM TO
THREE OR FOUR.
I SHOWED YOU THE PARSIMONIOUS
MODEL.
AND THE SECOND, AND AGAIN, THIS
IS THE SORT OF RESEARCH THAT MY
GROUP HAS BEEN DOING, IS TO TAKE
PROTEIN BIOMARKERS SUCH AS
IL-6 -- WHICH WE DON'T HAVE
POINT OF CARE MEASURES FOR, TAKE
THAT OUT OF THE EQUATION AND
JUST USE CLINICAL DATA.
IN TERMS OF THE PARSIMONIOUS
MODEL IN THIS SMALL PROOF OF CON
ACCEPT CONCEPT STUDY WE DID, BOH
INVESTIGATORS IN THE U.K., WE
USED THE PARSIMONIOUS MODEL OF
IL-6, SOLUBLE TNFR-1 AND SODIUM
BICARBONATE IN 40 PATIENTS WITH
COVID-19, AND CLASSIFIED THEM IN
REALTIME IN LESS THAN TWO HOURS,
TO THE HYPER SC AND
HYPOINFLAMMATORY PHENOTYPE.
THIS WAS USING A NOVEL POINT OF
CARE DEVICE TO QAWPT FIGHT THESE
PROTEINS, THERE'S A LARGER STUDY
THAT JUST STOPPED RECRUITING AND
WE'RE HOPING TO GET DATA FROM
THIS SOON.
THIS IS A FINE STUDY WHICH USED
THIS POINT OF CARE DEVICE TO
CLASSIFY THE PATIENT INTO THE
HIGH POPE AND HYPERINFLAMMATORY
PHENOTYPE IN 550 PATIENTS.
THIS IS IMPORTANT BECAUSE IT
TAKES THE NEXT STEP TOWARDS A
CLINICAL TRIAL.
HOWEVER WHAT WE FOUND WAS NOT
IMMEDIATELY POSSIBLE WAS TO
MEASURE THESE PROTEIN MARKERS
UBIQUITOUSLY AT THE BEDSIDE, SO
THESE ARE STANDARD DATA
COLLECTED ACROSS MULTIPLE --
ACROSS MOST I KRMECUs, THEY SAID
GOOD PERFORMANCE METRICS, AND WE
OBSERVED THAT THERE WAS
DIFFICULT RENGDIFFERENTIAL RESPH
BENEFIT IN THE -- AS YOU CAN
SEE, THIS MACHINE LEARNING MODEL
THAT ONLY USED CLINICAL DATA,
NOT ONLY HAVE HIGH PERFORMANCE
METRICS IN IDENTIFYING THE
COMPLEX LCA DERIVED PHENOTYPES,
BUT ALSO WAS ABLE TO CAPTURE THE
DIFFERENTIAL TREATMENT
RESPONSES.
SO WHAT WE DID WAS LOOKED AT
WHICH OF THESE FEATURES ARE MOST
PREDOMINANT AND THE MOST
IMPORTANT FEATURES WITHIN THE --
MODEL, BUT FROM THE RED AND THE
ORANGE OR YELLOW AS YOU PROBABLY
SEE IT HERE, YOU CAN SEE THAT
THE PREDOMINANT FEATURES WERE
LABORATORY VALUES AND VITAL
SIGNS.
SO WHAT WE DID WAS WE TOOK OUT
ALL OF THE DEMOGRAPHIC
VARIABLES, WE TOOK OUT ALL OF
THE HESS PRIOR TRI -- AND
DEVELOPED A VITAL SIGNS AND
LABORATORY ONLY XG BOOST MODEL
TO PREDICT THESE PHENOTYPES.
THEN WE POINTED TO SEPSIS RCT --
LARGE MULTICENTER TRIAL THAT
TESTED THE TREATMENT EFFICACY OF
ACTIVATED PROTEIN C VERSUS
PLACEBO AND THE ORIGINAL TRIAL
SHOWED NO BENEFIT, INCLUDING
WHEN THEY DID A ROBUST SUBGROUP
ANALYSIS WHICH INCLUDED APACHE
SCORES, SURFACE SCORES, PROTEIN
SEA LEVELS, BUT NONE OF THESE
WERE ABLE TO SHOW HETEROGENEITY
OF TREATMENT EFFECT.
SO WE TOOK THE CLINICAL
CLASSIFIED MODEL OF, I DON'T
HAVE TIME TO SHOW YOU THIS DATA,
BUT THE CLIL CAL FEATURES AND
OUTCOMES WERE CONSISTENT WITH
ALL OF OUR PREVIOUS DATA.
INTERESTINGLY, HOWEVER, WHAT WE
FOUND WAS THAT THERE WAS
SIGNIFICANT DIFFERENTIAL
TREATMENT RESPONSE IN THE HYPER
AND HYPOINFLAMMATORY PHENOTYPE.
ON THE X AXIS HERE IS A
PROBABILITY OF BELONGING TO THE
HYPERINFLAMMATORY PHENOTYPE,
WHILE ONE IS THAT YOU HAVE 100%
PROBABILITY OF HYPER AND ZERO IS
THAT YOU HAVE 100% PROBABILITY
OF THE HYPO.
THEN ON THE Y AXIS, IT'S THE
28-DAY MORTALITY.
AS YOU CAN SEE, AS YOUR
PROBABILITY OF BELONGING TO THE
HYPERAPPROACH IS ONE, IN GREEN
HERE IS ACTIVATED PROTEIN C.
THERE'S A SIGNIFICANT TREATMENT
BENEFIT WHEREAS IF YOU'RE THE
MORE HYPOYOU ARE, THE MORE
LIKELY YOU ARE TO BE HARMED BY
ACTIVATED PROTEIN SEE, SHOWING
AGAIN THAT OUR SIMPLISTIC
DEFINITIONS SUBSUMES SO MUCH
HETEROGENEITY IN PATIENT
POPULATION THAT THIS PHENOTYPING
SCHEMA MAY HAVE PERTINENT
TREATMENT IMPLICATIONS.
AGAIN I WILL EMPHASIZE WE'VE
DONE THIS JUST USING MACHINE
LEARNING MODELS THAT USE READILY
AVAILABLE CLINICAL DATA.
SO WE TOOK THE CLINICAL MODEL
AND POINTED THIS TIME TO THE
EUPHRATES TRIAL, A SLIGHTLY
SMALLER TRIAL OF ABOUT 4050
PATIENTS THAT TESTED POLYMYXIN
B, AGAIN I WILL EMPHASIZE THESE
WERE VERY SICK PATIENTS WITH
VERY HIGH ENDOTOXIN MODELS.
THERE WERE NO BENEFITS IN THE
ORIGINAL TRIAL.
HERE TOO, USING THIS CLINICAL
CLASSIFYING MODEL ON THE X AXIS
PROBABILITY BELONGING TO THE
HYPERINFLAMMATORY PHENOTYPE,
AGAIN DIFFERENTIAL TREATMENT
INTERACTION.
AGAIN, SIGNAL TO BENEFIT IN THE
HYPER AND THE MORE HYPERYOU GOT
SIGNAL TO HARM IN THE HYPO.
AND IT'S WORTH THINKING THAT IF
YOUR OVERALL MORTALITY IS
APPROACHING 10% AND YOU USE
THESE INTERVENTIONS THAT HAVE
RELATIVELY HIGH RISK IN TERMS OF
SIDE EFFECTS, IT IS HIGHLY
IMPROBABLE THAT YOU'RE GOING TO
IMPROVE OUTCOMES HERE.
TO MY MIND, AT LEAST, IT SEEMS
NOW ILLOGICAL, HAVING SEEN ALL
OF THIS DATA, TO INCLUDE BOTH OF
THESE POPULATIONS INTO THE SAME
BIOLOGICAL INTERVENTION TRIAL.
WHAT ARE THE NEXT STEPS FOR
PHENOTYPE-SPECIFIC TRIALS?
SO WE'RE WAITING ON THE PHIND
RESULT WHICH INCLUDES BIOLOGICAL
FEATURES IN ITS MODEL TO SEE
WHETHER OR NOT WE CAN DO SOME
REALTIME PHENOTYPING AT THE
BEDSIDE.
CONTINGENT ON THAT AND OTHER
POTENTIAL AVENUES, THE PANTHER
CONSORTIUM WHICH IS UP AND
RUNNING, THIS IS A MULTICENTER
INTERNATIONAL CONSORTIUM WHICH
IS TRYING TO DO PRECISION
MEDICINE, ADAPTIVE TRIALS IN
HYPOXEMIC ACUTE RESPIRATORY
FAILURE BUT WITH A VIEW TO
EXPANDING IT, THIS IS BASED ON
OUR PHENOTYPING SCHEMA,
EXPANDING IT TO POTENTIALLY --
THE FINE TECHNOLOGY TO DO A
RANDOMIZED TRIAL OF PATIENTS
WITH ACUTE HYPOXIC RESPIRATORY
FAILURE AND SEPSIS.
SO WHAT ABOUT THE CLINICAL
CLASSIFIER MODEL?
DOES IT HAVE VALIDITY FOR
CLINICAL DECISION-MAKING AND ALL
OF THE THINGS THAT DR. O'BRIEN
AND HOLDER TALKED ABOUT, THAT WE
ARE LOOKING TO IMPLEMENT THIS
INTO THE EHR AND STUDY THIS
PROSPECTIVELY AND WE WILL FACE
THE STANDARD SKEPTICISM, BUTLY
SAY THE MODEL PERFORMANCE
METRICS ARE AMAZING AUCs OF .9 I
THINK I'M GREAT AT TRAINING
MODELS OR THAT XG BOOST IS
TERRIFIC, BUT ACTUALLY I DO
GENUINELY BELIEVE THAT IF YOU
SEEK DISCRETE BIOLOGICAL DISEASE
STATES, YOUR MODELS WILL WORK
MUCH MORE BETTER.
AS LONG AS YOU HAVE THE RIGHT
FEATURES THAT PREDICT THOSE
SPECIFIC DISEASE STATES.
THEN THE OTHER QUESTION IS, OF
COURSE, WHAT INTERVENTIONS DO WE
TEST?
I THINK ACTIVATED PROTEIN C
WOULD BE A PRETTY GOOD TEST FOR
THE HYPERINFLAMMATORY PHENOTYPE.
HOWEVER, I THINK OUR OWN FIELD
UNFORTUNATELY HAS BEEN BURNED
WITH THAT PARTICULAR
INTERVENTION.
SO WE HAVE -- WE'RE CURRENTLY
DECIDING IF THE PANTHER TRIAL
GOES AHEAD WHICH WE USE.
FIRST WE NEED TO CHARACTERIZE
THE HOST RESPONSE USING
BIOLOGICAL MEASUREMENTS.
A QUICK PLUG TO CHECK OUT THE
APS CONSORTIUM FUNDED BY THE
NHLBI.
NEXT IS TO USE MACHINE LEARNING
TO TRY AND IDENTIFY MORE
BIOLOGICALLY HOMOGENEOUS
SUBGROUPS, AND THEN TRANSLATE TO
THE BEDSIDE.
FOR SUBGROUPS THAT ARE ROBUST, I
DO BRI BELIEVE WE NEED TO GO BAO
ANIMAL MODELS AND TRY YOU AND
STAND ITS PATHOPHYSIOLOGY,
BETTER UNDERSTAND THE ROLE OF
PATHOGEN AND HOST FOR
PRECISION-BASED CARE.
AND ALSO TO STUDY IMMUNOLOGICAL
CHANGES IN THE HEALTH AND
DISEASE WITH AGING AND THIS IS
SORT OF THE -- THIS FAR OUT KIND
OF STAR TREKY TYPE VISION THAT
I'M SORT OF ENGAGING WITH, IS
THAT IF WE CAN PREVENT PEOPLE
FROM GETTING SEPSIS AND OTHER
METHODS THAT WE CAN -- OTHER
APPROACHES THAT WE CAN USE TO
TRY AND UNDERSTAND THE
COMMUNITY-BASED EP GENETIC
INTERACTIONS THAT LEAD PEOPLE TO
HAVING THESE ABNORMAL RESPONSES
TO PATHOGENS, THAT WE MIGHT BE
ABLE TO CORRECT IN THE COMMUNITY
TO TRY AND PREVENT SEPSIS BEFORE
IT GETS TO THE ICU.
SO IN SUMMARY OF THE WORK THAT
I'VE SHOWN YOU, WE HAVE
DESCRIBED TWO PHENOTYPES OF
SEPSIS, THE HYPER AND
HYPOINFLAMMATORY IN ABOUT 15,000
PATIENTS.
30% OF THE HYPER.
THE HYPER HAS HIGHER --
INKREASED ORGAN FAILURE IN THE
HYPERINFLAMMATORY PHENOTYPE,
INCREASED BACTEREMIA WITH ENROW
BACTERIAEA.
SO WITH THAT, I WILL JUST LEAVE
A SLIGHT ACKNOWLEDGMENT OF
DIFFERENT COLLABORATORS.
THIS IS JUST THE TIP OF THE
ICEBERG.
PEOPLE HAVE BEEN GENEROUS
LENDING THEIR TRIAL DATA AND
OBSERVATIONAL COHORTS TO CARRY
OUT OUR INVESTIGATIONS AND
GRATEFUL TO THE NIH FOR ALL THE
FUNDING THEY PROVIDED FOR THIS
RESEARCH.
I'M HAPPY TO TAKE QUESTIONS.
>> THANK YOU SO MUCH, DR. SINHA.
DR. KOUTROULIS -- OH, WE HAVE A
QUESTION IN THE AUDIENCE.
DR. LIAW?
>> THANKS, GREAT PRESENTATION.
I SAW A QUESTION ON THE
CLASSIFICATION OF THE
PHENOTYPES.
IS THAT BASED ON A SINGLE TIME
POINT?
FOR EXAMPLE, AT ICU ADMISSION,
AND WHAT ABOUT THE TRAJECTORY OF
SUBSTANCES, WOULD THERE BE
CHANGE IN THE PHENOTYPE OR IT'S
A STATIC ASSESSMENT?
>> THAT IS SUCH A GREAT
QUESTION.
THIS IS A HUGE LIMITATION OF THE
WORK THAT WE'VE -- THAT I'VE
SHOWN YOU, IS THAT WE HAVE STU
STUDIED AT CROSS-SECTIONAL TIME
POINTS.
AND THESE PHENOTYPES ARE HIGHLY
DYNAMIC.
AND WE HAVE SOME EMERGING DATA.
INITIALLY WE HAD PUT A PAPER OUT
THAT SHOWED THAT THERE WERE
QUITE -- THEY WERE QUITE STABLE
OVER THE LAST 48 HOURS BUT I
THINK IT'S A MISINTERPRETATION
ABOUT DATA.
WE HAVE A PAPER THAT'S CURRENTLY
UNDER REVIEW, I'VE BEEN ACROSS
ABOUT 5,000 PATIENTS, WE'VE
SHOWN THAT THESE ARE HIGHLY
UNSTABLE AND HOW QUICKLY THE
HYPERINFLAMMATORY PHENOTYPE
RESOLVES IS HIGHLY PREDICTIVE.
ONE OF THE MOST IMPORTANT
PREDICTIVE FEATURES OF THESE
PHENOTYPES IS HOW QUICKLY YOU GO
FROM HYPERTO NOT BEING HYPER IN
TERMS OF YOUR PROGNOSIS.
SO IF YOU GO FROM HYPER TO
HYPOIN THE FIRST 48 HOURS YOUR
OUT COME IS ALMOST THE SAME AS
BEING HYPO AT THE START.
SO THE LONGER YOU SPEND IN THE
HYPERINFLAMMATORY STATE, THE
WORSE YOUR OUTCOME IS.
SO I THINK WE HAVE TO BE VERY
MINDFUL WHEN WE'RE INTERPRETING
THIS DATA AND DOING REALTIME
PHENOTYPING HOW DO WE CONSUME
THIS INFORMATION ABOUT THE
TEMPORAL DYNAMICS OF THE
PHENOTYPE.
>> THANK YOU.
>> FANTASTIC.
WE'RE GOING TO KEEP MOVING AND
CIRCLE BACK TO SOME OF THESE
QUESTIONS IN OUR TIME TOGETHER
LATER.
IT'S MY PLEASURE TO INTRODUCE
DR. BIHORAC, SENIOR ASSOCIATE
DEAN FOR RESEARCH AT THE
UNIVERSITY OF FLORIDA.
SHE'S GOING TO SPEAK ON A.I. FOR
THE FUTURE OF SEPSIS MANAGEMENT.
TAK IT AWAY.
>> THANK YOU SO MUCH, VINNY.
CAN YOU HEAR ME?
>> YES, WE CAN.
>> IT'S GREAT TO BE THE LAST
SPEAKER TALKING ABO ABOUT THE
FUTURE.
IT'S REALLY A GREAT DAY, I
LEARNED SO MUCH, EXCITED TO BE
TOGETHER, LIKE-MINDED RESEARCHER
SCIENTISTS.
I APOLOGIZE THAT I DID NOT PUT
MY DISCLOSURES.
I DO NOT HAVE ANY CONFLICT
EXCEPT MY FUNDING FROM NIH.
SO I WANT TO THINK BUS FRAMEWORK
ABOUT HOW WE THINK RIGHT NOW
THAT OUR PREDETION -- OUR MENTAL
MODEL AROUND SEPSIS GOES FROM
CAN WE ANTICIPATE OR PREDICT
RESOURCE SEPSIS AND HOW WE
DIAGNOSE IT AS SOON AS POSSIBLE
AND THEN MOVING TO THE
TREATMENT.
SO IN THAT KIND OF FRAMEWORK,
WHAT CAN A.I. BRING IN TERMS OF
ENRICHING OUR APPROACH TO SEPSIS
PATIENTS.
I FIRMLY BELIEVE IN PREVENTION.
IF WE FOCUS ON TWO MAJOR TYPES
OF SEPSIS, COMMUNITY ACQUIRED
AND IN MY OPINION IS A VERY
IMPORTANT SUBTYPE OF SEPSIS.
AND HOSPITAL ACQUIRED WE HAVE
FOCUSED MOSTLY FOR NOW BECAUSE
THEY HAVE MOSTLY DATA IN THE
HOSPITAL, WE NEED TO START
THINKING ABOUT HOW DATA CAN BE
GENERATED IN BOTH SETTINGS
TOWARDS TRUE PREDICTION TOWARDS
FULLY BLOWN SEPSIS.
AND MOVING TO DIAGNOSIS, HOW CAN
A.I. HELP US GET MORE PRECISE,
MORE BIOLOGICALLY ACCURATE
DIAGNOSIS AS OUR PRIOR SPEAKER
ELOQUENTLY BROUGHT FORWARD.
I THINK WE ARE DESPERATELY
NEEDING MORE TREATMENTS AND
RECOVERY ENHANCING STRATEGIES
THAT AT THIS TIME ARE REALLY
LIMITED AND EVENTUALLY
MONITORING, BUT MONITORING OF
THE PATIENTS CAN HELP US
LONGITUDINALLY PREDICT NOT ONLY
TO HAVE WHAT HAPPENS TODAY BUT
WHAT HAPPENS THREE MONTHS LATER
OR ONE YEAR AFTERWARDS AS WE ALL
KNOW THAT SEPSIS DOES NOT END AT
THE HOSPITAL DISCHARGE.
AND THEN THAT KIND OF
LONGITUDINALLITY APPROACH,
SCALING, WE NEED TO GO FROM ONE
INDIVIDUAL PATIENT AND SCALE
REALLY OUR APPROACH FROM
HEALTHCARE SITUATION TO LEARNING
HEALTH SYSTEMS, STATES, NATION
AND MAYBE GLOBAL ABILITY TO SEE
WHAT'S HAPPENING ON A GLOBAL
SCALE WITH SEPSIS.
SO I WAS JUST GOING TO REVIEW A
COUPLE THINGS MANY OF YOU HAVE
MENTIONED, WE HAVE THE FIRST
FDA-APPROVED MODEL FOR SEPSIS
PREDICTION IN HOSPITAL
IMMUNOSCORE.
AMONG MANY STUDIES HERE IS A.I.
MODEL IN HOSPITAL WAS DEPLOYED
FOR EXPERIMENTAL CLINICAL STUDY
AND SHOWED SOME REDUCTION IN
MORTALITY PRE AND POST
IMPLEMENTATION ANALYSIS USING
DEEP LEARNING MODEL AND REALLY
WITH SOME EXPLAINABILITY AND
PROJECTING ACTUALLY WHO MIGHT
DEVELOP SEPSIS.
BUT WHAT ABOUT COMMUNITY
ACQUIRED SEPSIS?
WELL, I WANT TO ARGUE THAT THE
FIRST STEP IN A PREDICTION
STAGE, WITH HE NEED TO FOCUS ON
GETTING MORE DEPS D DENSE DATA E
ARE SOME VIEWS OF THE WEARABLE
BIOSENSORS AT HOME EVEN BEFORE
YOU COME TO HOSPITAL, WHETHER
YOU WILL BE ABLE TO ACTUALLY
CAPTURE YOUR SYMPTOMS BEFORE YOU
EVEN DEVELOP FULL BLOWN EITHER
INFECTION OR SEPSIS.
THIS IS SOME DATA FROM THE USE
OF VARIABLES IN DEGENERATIVE
DISEASE OR PARKINSON'S DISEASE,
ANOTHER BIG DISEASE WOULD BE
CONGENITAL HEART DISEASE, AGAIN,
YOU HAVE AN ENTIRE SPECTRUM OF
DIFFERENT BIOSENSORS, RIGHT NOW
MAINLY FOCUSED ON PHYSIOLOGICAL
PARAMETERS BUT A LOT OF UNTAPPED
POTENTIAL FOR THAT, BOTH IN
HOSPITAL AND I THINK ESPECIALLY
OUTSIDE OF THE HOSPITAL.
AND WHAT IS MOST EXCITING FOR
ME, WE ARE APPROACHING THE ERA
OF COMPLETELY DIFFERENT NEXT
GENERATION SENSORS THAT CAN NOW
WATCH MANY MORE THINGS, FROM
GASTROINTESTINAL TRACT
METABOLITES TO SWEAT SENSING
PLATFORMS FOR CHEMICAL ANALYSIS
TO EVEN MOBILE BIOADHESIVE
ULTRASOUND THAT CAN GIVE US
ACTUAL IMAGING IN REALTIME.
SO I THINK THAT'S ANOTHER REALLY
EXCITING AREA THAT WE WILL SEE A
LOT OF MOVEMENT.
I THINK WHAT I CALL IT
MULTIDIMENSIONAL BIOHACKING.
SO I THINK IN OUR CURRENT
APPROACH, WE ARE LACKING
DIMENSIONS BOTH IN A SCALE AND
IN THE -- HOW WIDE THEY ARE.
HERE IS AN EXCITING STUDY
FROM -- A NASA TWIN STUDY FROM
TWO IDENTICAL BROTHERS, MANY OF
YOU HAVE READ THE STUDY IN 2019,
PRO FILING OF TWO BROTHERS, ONE
STAYING ON EARTH, ONE GOING INTO
SPACE AND NOT ONLY -- HIGHLY
DENSE DATA, SHOWED SOME REALLY
EXCITING CHANGES THAT ARE
HAPPENING ON VERY GRANULAR LEVEL
IN THE HUMANS ONCE THEY LAUNCH
TO SPACE.
SO THIS MULTIDIMENSIONAL
BIOHACKING NOW HAVE ANOTHER
DIMENSION AND IT'S ONE I THINK
THE ERA, THE NEXT 10 YEARS WILL
BE ALL ABOUT N EQUAL 1ISM, GOING
FROM THE CENTRAL PLACE OF A
HOSPITAL OR THE PLACE WHERE WE
GATHER MORE TO THE HOMES
INDIVIDUAL PATIENTS WHERE WE CAN
TRACK OURSELVES, THESE ARE ALL
MY SENSORS THAT I HAVE CHECKING
MYSELF, YOU ARE HAVING NOW, EVEN
MORE COMMERCIALLY AVAILABLE
ALGORITHMS THAT WILL JUST TELL
YOU WHEN YOU AREN'T FEELING
WELL.
I DON'T THINK WE'RE FAR AWAY
FROM THE HOAMENT THAT WE WOULD
BE ABLE TO ACTUALLY ?A SIGNAL TO
OUR PATIENT AT WHICH TIME THEY
NEED ANTIBIOTICS AND WHICH TIME
POINT THEY MAYBE NEED TO GO TO
THE HOSPITAL.
THIS VERY VAGUE TERM OF THE
DYSFUNCTIONALLY IMMUNE RESPONSE.
ADDING TO THE PHYSIOLOGICAL
MAINLY PHYSIOLOGICAL SIGNALS
MONITORING THEY'RE GOING TO HAVE
ENTIRE SPECTRUM OF CHEMICAL OR
EVEN IMAGING SENSORS.
WHETHER WE CAN DO SOMETHING LIKE
THAT EVEN IN HOSPITAL WHERE
WE'RE VERY MUCH LIMITED NOW ON A
STRUCTURED CLINICAL DATA, THIS
IS A STUDY USING A LITTLE BIT OF
NO STRUCTURE IN THE TEXT, BUT AN
ENTIRE SECTOR OF IMAGING IS NOTE
YET PLUGGED IN TO ANY OF THE
MODELS WE ARE USING AND EVEN
MORE IMPORTANTLY, MORE
BIOLOGICAL DATA.
SO THAT WOULD BE LIKE HOW DO YOU
IN COMPARISON MOVE TOWARDS
MULTI-MODALITY BUT THEN YOU NEED
TO VERTICALLY INTEGRATE ALL OF
THAT I THINK IN A COMMUNITY
SETTING, MULTIDIMENSIONAL
BIOHACKING TO VERTICAL
CONNECTION WITH THE PROVIDERS
EITHER TO THE TELEHEALTH OR TO
THE DIGITAL TWINS OF HOSPITAL OR
PRACTICES OR SOME SUBSCRIPTION
SYSTEM THAT LU ACTUALLY BE ABLE
TO ACT ON WHAT YOU ARE SENSING
OR DECIDING AS N EQUAL
1 INDIVIDUAL PATIENT AND I THINK
WE'RE GOING TO SEE THE
CENTRALIZATION PERHAPS EVEN ON
THOSE WHO TAKE CARE OF THESE
PATIENTS BEFORE THEY COME TO
HOSPITAL SO THEY NEVER COME TO
HOSPITAL.
I WOULD SAY TH THE COMPRESSIONAL
MORBIDITY, THE BEST APPROACH TO
GET HEALTHY IS TO NEVER GET
SICK.
AND WE WILL BE MORE MOVING
TOWARDS WHAT WE ARE WORKING --
WHAT WE CALL REALTIME AMBIENT
INTELLIGENCE, MORE TO THE
HOSPITAL SETTING.
BESIDES DATA GENERATED THROUGH
THE CLINICAL CARE, IT CAN BE
USED OTHER SENSORS AND COLLECT
DIFFERENT TYPE OF DATA THAT MAY
MORE AMBULATE HUMAN PERCEPTION.
AS AN EXAMPLE, NONE OF OUR
MODELS USE ANY VISUAL CUES.
AS A PHYSICIAN, WE ENTER
PATIENT'S -- VISION, SMELL, TO
REALLY MAKE DECISIONS ABOUT
WHAT'S HAPPENING TO OUR
PATIENTS.
SO WE HAVE USED SENSORS SUCH AS
RGB INTERNAL CAMERAS, SOME OF
THE DEPTH CAMERA AND SO ON TO
DEVELOP THESE SERIES OF DEEP
LEARNING ALGORITHMS TO DETECT
CERTAIN CHARACTERISTICS OF THE
PATIENT REALTIME.
HERE IS OUR END TO END PLAS FORM
TO TRACK MOBILITY IN THE ROOM
WITHOUT ANY HUMAN INPUT SO YOU
CAN ACTUALLY 24/7 MONITOR
PATIENT IN THE ROOMS, AND REALLY
USE THAT DATA TO PREDICT AS
EXAMPLE MORE BUILT PATTERN,
ACTIVITY PATTERN, AND I WILL
SHOW ON THE NEXT SLIDE THESE NOW
MOVING NOT ONLY FROM OUR
MOBILITY BUT ALSO THE FACIAL
EXPRESSION.
ONE OF OUR APPROACH IS TO USE
END TO END ACTION UNIT DETECTION
ON THE FACE WITH VISION
TRANSFORMER SO YOU CAN ACTUALLY
COMPOSE HUMAN FACE IN 48 ACTION
UNIT.
THESE ACTION UNITS ARE COMBINED
TO CREATE OUR EMOTIONS, SO A
COMBINATION OF SOME ACTION UNIT
EQUALS CERTAIN EMOTIONS.
SO IN OUR APPROACH, WE ARE NOW
ACTUALLY ABLE TO AUTONOMOUSLY
CAPTURE A PATIENT'S FACE IN A
ROOM FULL OF OTHER HUMANS, TRAP
THAT FACE IN REALTIME AND ASSESS
THE ACTIVITY OF CERTAIN ACTION
AND THEN CORRELATE THEM WITH
CLINICAL SEVERITY.
AND HERE'S A VERY SMALL -- HERE
IS A PLACE WHERE WE USE OUR
CLINICAL MODEL AND USE TRANSFER
LEARNING IN OUR SMALLER COHORT
AND VISUAL CUES, WE CALLED IT
VISUAL CUES, EACH ACTION UNIT
WAS INPUTTED IN THE CLINICAL
MODEL, AND THERE WAS SIGNIFICANT
IMPROVEMENT IN THE ABILITY TO
PREDICT THE SEVERITY OF ILLNESS
AND INCORPORATE THESE VISUAL
CUES IN THE REGULAR CLINICAL
MODEL THAT IS CLINICAL DATA.
JUST PUTTING THAT BACK TO THE
BEDSIDE, HOW MANY TIMES YOU
ENTER PATIENT ROOM, TAKE A LOOK
AT PATIENT AND SAY YOU DON'T
LOOK GOOD.
AND I THINK THAT IS SOMETHING
THAT WE ARE GOING TO BE ABLE TO
INCORPORATE IN OUR PRACTICE MORE
AND MORE NOT ONLY THROUGH THE
VISUAL BUT ALSO OUR ACOUSTIC
TOOLS, PATIENT VOICES, ALSO
ENVIRONMENTAL CUES,
ENVIRONMENTAL TREM T TELEMETRY L
BECOME PART OF THIS
DECISION-MAKING.
BACK TO DIGITAL TWIN, THE IDEA
THAT WE CAN ACTUALLY USE THIS
DENSELY MULTI-SCALE SAMPLE
LONGITUDAL DATA TO KR CREATE SOE
TWINNING OF THE EXISTING
PATIENT.
UNFORTUNATELY FOR THE TRUE
BIOLOGICAL TWIN, WE NEED TO HAVE
A DEEPER UNDERSTANDING OF FIRST
PRINCIPLE.
MANY COMPLEX PROCESSES IN A
SEPSIS -- THERE ARE SOME AGENT
BASED MODELING GROUPS THAT ARE
WORKING REALLY HARD ON THAT.
I THINK WE ARE FAR AWAY FROM
THIS, AND FOR ME, THIS IS ONE OF
THE BIGGEST -- REALLY THE
BIGGEST MISSING POINT WHERE WE
NEED TO COMBINE THESE BIOLOGICAL
MECHANISTIC MODEL WITH OUR
CLINICAL MODEL AND REALLY MOVE
TOWARDS THIS TRUE DIGITAL
TWINNING.
NEXT A.I. TREATMENT AND
RECOVERY, I THINK WE DESPERATELY
NEED NEW TREATMENTS, HOPEFULLY
MORE DIGITAL TWINS AND MORE
DEEPER MULTI-SCALE MODELING CAN
HELP US FIND NEW TARGETS AND
TEST THEM, AT THE SAME TIME THE
NEW THERAPIES NEED PERHAPS
BETTER PROCESSES, AND THESE
PROCESSES CAN BE SOMETIMES
FACILITATED BY USE OF
REINFORCEMENT LEARNING.
THIS IS A STUDY FROM MY
COLLEAGUE AT EMORY WHERE HE USED
DYNAMICALLY ENFORCING A.I.
FRAMEWORK TO INCORPORATE
REALTIME PHYSIOLOGIC DATA --
PROCESSES OF CARE BASED ON THESE
REALTIME INPUTS AND AGAIN THIS
IS SOMEWHERE IN THE FUTURE.
SIMILAR STUDY BY KOMOROWSKI TO
USE OPTIMIZATION OF FLUID --
WHERE THE COMBINATION OF
GRANULAR PHENOTYPING AND
DECIDING WHAT STATES OR
PHYSIOLOGICAL STATE OF DISEASE
YOU MAY BE BASED ON PARAMETERS
WE COLLECT, AND THEN TRYING TO
SIGN REALLY OUR FLUID THERAPY
AND VASOPRESSOR THERAPY BASED ON
THOSE STATES, AGAIN IT WOULD BE
IN THE FUTURE, MUCH MORE
COMPREHENSIVE OR MORE
BIOLOGICALLY DEEPER
UNDERSTANDING OF THESE STATES,
WHAT DO THEY MEAN NOT ONLY ON A
HOLISTIC LEVEL BUT DIFFERENT
ORGAN LEVEL AND HOPEFULLY WE
WILL HAVE MORE THAN JUST SALTY
WATER AND GOOD AIR TO DELIVER TO
OUR PATIENTS FOR TREATMENT OF
SEPSIS.
AGAIN SIMILAR ANOTHER STUDY THAT
LOOKED AT USE OF REINFORCEMENT
LEARNING TO UTILIZE
CORTICOSTEROID THERAPY, SOME OF
THESE ENDO TYPES WE'RE ABLE TO
CLASSIFY PATIENTS WHO MIGHT BE
STEROID RESPONSIVE, THIS IS NOW
USING COMPUTATIONAL APPROACHES
THAT CAN AUTOMATICALLY MAP
PATIENTS' PHENOTYPE PERHAPS
TAKING HUMAN FACTOR OUT.
SO THE FUTURE OF A.I. FOR SEPSIS
IN ONE SLIDE, I WOULD SAY IT'S A
FULL STACK OF APPROACH FROM
PREVENTION TO DIAGNOSIS
TREATMENT RECOVERY MONITORING
AND THEN BACK TO PREVENTION, I
THINK IT NEEDS TO HAPPEN NOT
ONLY IN THE HOSPITAL, WE NEED TO
GET OUT OF THE HOSPITAL AT HOME
IN ANY SETTING, USING MUCH MORE
THAN CURRENTLY COLLECTED
CLINICAL DATA, EXPANDED USE OF
PERVASIVE SENSING, AMBIENT
INTELLIGENCE AND DEVELOPING AND
MERGING A LOT OF INSIGHT WE HAVE
ON ANIMAL MODELS AND MORE
BIOLOGICAL WORK THAT WAS DONE IN
SEPSIS MERGING OUR CLINICAL
UNDERSTANDING OF DISEASE AND
PUTTING ALL THESE DOTS TOGETHER
TO CREATE LIKE FULLY EXPLAINABLE
MMODEL, DYNAMIC MECHANISTIC MODL
OF SEPSIS THAT IS TRANSLATABLE
TO CLINICAL PRACTICE.
I HOPE WE WILL SEE LESS SEPSIS
THAT EFFICIENTLY WE WILL BE OUT
OF THE BUSINESS BECAUSE ALL
SEPSIS WILL NEVER BE SEPSIS, IT
WILL JUST BE INFECTION THAT WE
TAKE CARE.
SO THAT'S MY VISION FOR THE
FUTURE, WE WILL BE OUT OF THE
BUSINESS HOPEFULLY.
THANK YOU.
>> WONDERFUL.
WHAT GREAT BLUE SKY FOR US IN
THE FUTURE THAT WE ARE GOING TO
BE OUT OF JOBS.
WHICH WOULD BE GREAT.
I THINK WE'RE GOING TO TAKE THIS
TIME TO BRING TOGETHER ALL THE
PRESENTERS SO WE CAN HAVE SOME
DISCUSSION AND ADDRESS SOME
QUESTIONS.
SO WHILE WE DO THAT, I SEE
THERE'S A COUPLE QUESTIONS IN
THE CHAT.
AND WE CAN GET TO THOSE.
MAYBE I'LL TURN IT OVER TO
DR. KOUTROULIS TO KICK US OFF.
>> YES, THANK YOU, VINNY.
SO THIS WAS VERY INTERESTING,
ALL THE SESSIONS WERE REALLY
AMAZING AND VERY INSIGHTFUL.
ONE QUESTION FROM THE LAST
SESSION IS ABOUT THE DIFFERENCES
AT BASELINE AND IN RESPONSE TO
TREATMENT AND HOW DIGITAL TWIN,
YOU KNOW, DIGITAL TWIN WOULD
TAKE THAT INTO ACCOUNT, LIKE
PEOPLE HAVE DIFFERENT BASELINE
CO-MORBID ITS OR PROBLEMS AND
THEY DON'T MOVE THE SAME WAY.
THEY'RE VERY DIFFERENT.
HOW IS THAT ACCOUNTED INTO THE
MODEL?
>> VINNY, YOU WANT ME TO TAKE
IT?
>> YEAH, SURE.
WHY DON'T YOU START.
I THINK HE HAVE BEEN HAS SOME
THOUGHTS.
>> I'LL GIVE YOU MY REASON, SO
LIKE I THINK THAT WE NEED TO GET
OUT OF OUR MENTALITY THAT ONLY
THINGS THAT WE KNOW WHAT TO DO
WITH, WE'RE GOING TO COLLECT,
BECAUSE THAT'S NOT GOING TO TAKE
US WHERE WE WANT TO GO.
THE DATA NEEDS TO BE SO DENSE.
SO I ENVISION DEEPLY THAT IF YOU
THINK ABOUT TRUE TWINNING, WHEN
YOU START GETTING BORN, YOU'RE
GOING TO BE COMPLETELY SAMPLED.
LIKE THIS IS -- I'M GOING TO
OMIC OR IMAGE MYSELF
CONTINUOUSLY.
UNTIL WE HIT ENOUGH DATA WITH
THAT TYPE OF DENSE AT THIS TIME
THAT YOU CAN START ASKING THESE
QUESTIONS AND CREATE A REPLICA,
BECAUSE I CAN MAKE A SKETCH OF
MYSELF WITH THREE LINES OF A
BLACK PENCIL BUT THEN I CAN DO
BEAUTIFUL COLORS, RIGHT?
SO WE WANT TO COME IN THE MOST
BEAUTIFUL PAINTING RATHER THAN
KIND OF ROUGH SKETCH.
SO WE DON'T HAVE THAT TYPE OF
DATA, WE HAVE NOT ENOUGH DATA ON
HEALTHY SUBJECTS.
WHAT IS WORRISOME FOR ME IS THAT
WE WILL SEE WITH THE TECHNOLOGY
DIGITAL DIVIDE MIGHT BE EVEN
BIGGER BECAUSE PEOPLE WILL HAVE
A CAPACITY OR ABILITY TO GAIN
THAT INTENSITY OF DATA.
MIGHT NOT BE EVERY PERSON EVEN
IN THIS COUNTRY.
SO THIS IS GOING TO BE EXPENSIVE
DIVERGENCE IN WHAT IS ACCESSIBLE
FOR EVERYONE OR MAYBE FOR --
ACCESSIBLE ONLY FOR FEW.
THAT'S JUST MY VIEW.
>> GREAT.
>> ANYONE ELSE WANT TO ADD SOME
THOUGHTS TO THAT?
I GUESS I'LL JUST ADD A COMMENT
WHICH IS WHAT STRUCK ME FROM
THIS CONVERSATION WAS THAT WE'RE
TALKING ON MANY DIFFERENT
RESOLUTIONS AND SCALES SOME OF
THIS STUFF THAT PRATIK HAS
GOTTEN INTO IS TRYING TO UNPACK
THE BIOLOGICAL PROCESSES AND
THEN CARA IS SPEAKING AT THE
HUMAN LAYER OF INTERVENTION THAT
IS REALLY LIKE SOCIOTECHNICAL,
NOT BIOLOGIC AND THEN I THINK
ANDRE YOU'VE ADDRESSED SOME OF
THAT TRANSLATION, WHAT ARE WE
CAPTURING AND HOW DO WE LEVERAGE
EHR DATA WHICH IS A PROXY OF
SOME TREATMENT, SOME BIOLOGIC
PROCESSES, WHATEVER, THEN AZRA,
WERE YOU TALKING, I MEAN, LIKE
INSTRUMENTING THE ENTIRE THING,
BOTH TEMPORALLY AND WITH
EXPANSIVE MULTIMODAL CAPTURE.
WE DON'T EVEN HAVE DEPTH IN ONE
VERTICAL TODAY, I WOULD SAY, YOU
KNOW, AND SO THAT VISION -- AND
PART OF THAT CHALLENGE IS HOW DO
WE TURN THE DIAL ON THE
RESOLUTION, BOTH WITH RESPECT TO
ANY ONE OF THOSE MULTIMODAL
ASPECTS BUT ALSO WITH RESPECT TO
THE TRAJECTORY OF ILLNESS BOTH
IN THE PRESEPSIS PHASE AND THEN
THROUGH KIND OF LIKE THAT
TRANSITION.
SO I WONDER IF ANYONE HAS
THOUGHTS ON WHAT DO WE TACKLE
STRATEGICALLY AS WE MOVE
FORWARD?
>> I'M GOING TO STEP IN BUT
MOSTLY RAMBLING THROUGH MY VERY
BIASED PERSPECTIVES.
I DON'T KNOW, I'VE BEEN A
PRACTICING INTENSIVIST NOW FOR
20 YEARS.
I DON'T KNOW WHAT SEPSIS MEANS.
AND I THINK THAT'S A FUND MENTAL
PROBLEM THAT WE NEED TO GET
AROUND.
IT'S NOT EVEN THAT COMPLICATED.
WE CAN BREAK IT DOWN THROUGH A
NUMBER OF TANGIBLE POTENTIALLY
CLINICALLY INTUITIVE WAYS BUT WE
JUST HAVE TO AT THE OUTSET HELP
BROADER POPULATIONS TO BE
CAPTURED IN SUBSEGMENTS.
AND YOU KNOW, I'VE BEEN
FORTUNATE ENOUGH TO WORK IN THE
ED AND IN THE ICU, AND THEY ARE
FUNDAMENTALLY VERY DIFFERENT
SPACES.
EVEN JUST BREAKING IT DOWN
THROUGH THOSE DOMAINS WILL
PROVIDE US A RI LITTLE BIT OF
VALIDITY AND HOMOGENEITY WHICH
WE CAN THEN STUDY.
I NOTICED THAT CORA IS A
HOSPITALIST AND HER TAKE OF
SEPSIS IS PROBABLY MUCH EARLIER
AND HAS VERY DIFFERENT OUTCOMES
AND INTERESTS THAN WHAT I'M JUST
AS AN INTENSIVIST SEES.
SO I THINK THAT IS A FUNDAMENTAL
PROBLEM THAT WE NEED TO TRY AND
GET OVER, AND AT THE SAME TIME,
I THINK THERE HAS NEVER BEEN A
BETTER TIME TO BE ALIVE TO BE A
SEPSIS RESEARCHER.
BECAUSE WE DO -- AND YOU KNOW, I
AGREE WITH WHAT AZRA SAID, THAT
WE HAVEN'T COLLECTED THE DATA
THAT WE NEED TO, BUT WE'RE
DEFINITELY FURTHER ALONG IN OUR
JOURNEY AND THERE ARE THESE
MULTIMODAL DATA THAT I HAVE
ACCESS TO WHICH LIKE 15 YEARS
AGO I COULDN'T EVEN DREAM.
AND I THINK THAT IS WHERE THE
OPPORTUNITY LIES, AND WHERE WE
CAN START BREAKING THEM DOWN FOO
PATHOGEN AND HOST RESPONSE
INTERACTIONS THAT ARE MEANINGFUL
AND POTENTIALLY
TREATMENT-RESPONSIVE AND TURNING
SEPSIS INTO DISEASE RATHER THAN
WHAT IT IS RIGHT NOW.
>> I THINK I'LL STEP IN ALSO.
BUT TO ADD TO THAT, I THINK ONE
OF THE REASONS WHY IT'S A GREAT
TIME TO BE A SEPSIS RESEARCHER
IS BECAUSE NOT ONLY DO WE HAVE
ACCESS TO THE COMPUTATIONAL
RESOURCES TO CAPTURE AND ANALYZE
A LOT OF THIS DATA, BUT THERE'S
ALSO -- WE ALSO HAVE THE EAR OF
A LOT OF INVESTMENT, BOTH
FINANCIAL AND TIME WISE, IN
CAPTURING A LOT OF THE KIND OF
DATA THAT WE WOULD NEED TO HELP
IDENTIFY EXACTLY WHAT SEPSIS IS
TO PRATIK'S POINT, AND ALSO HOW
WE CAN BETTER UNDERSTAND WHAT
MAY HAPPEN BEFORE IT'S
CLINICALLY RECOGNIZABLE, AND
ALSO BREAK DOWN THOSE DIFFERENT
TYPES OF SEPSIS ONCE IT'S
IDENTIFIED TO CAPTURE THE
HETEROGENEITY AND TREATMENT.
SO I THINK THAT'S ONE THING.
AND I THINK THERE'S ALSO SOME
EXAMPLES IN THE CURRENT -- IN
CURRENT PRACTICE AND ALSO IN
CERTAIN INSTITUTIONS THAT ARE
TRYING TO CAPTURE MORE OF THAT
DATA INDISCRIMINATELY, SO THAT
PERHAPS WE CAN THEN USE IT LATER
ON TO ANALYZE AND TO HELP ANSWER
SOME OF THESE QUESTIONS.
ONE EXAMPLE THAT I WOULD USE IS
THE UC SYSTEM, SO THEY CURRENTLY
HAVE, SPEAKING AS A PERSON WHO'S
NOT WORKED THERE, SWEEING TO
SOMEONE WHO BASICALLY KNOWS
SECONDHAND ABOUT THIS, BUT MY
UNDERSTANDING IS THEY HAVE THE
CAPABILITY TO CAPTURE A LOT OF
THAT DATA AND HAVE INVESTMENT
AND TRY TO STORE IT AND ANALYZE
IT FOR THE PURPOSES THAT WE'RE
DISCUSSING.
SO I THINK USING THAT AS AN
EXAMPLE, IF THERE ARE OTHER
INSTITUTIONS THAT IMPLEMENT
SIMILAR PROCESSES, AND
ESSENTIALLY ARE CAPTURING DATA
THAT WE DON'T REALLY KNOW WHAT
TO DO YET WITH, I THINK THAT'S
GOING TO HELP PUSH THE NEEDLE
AND MOVE THE RESEARCH ALONG TO
WHERE WE'RE ENVISIONING IT.
>> GREAT DISCUSSION.
I DON'T SEE ANYBODY WITH
QUESTIONS.
>> I'D LIKE TO MAKE A COMMENT IF
I MAY FROM THE FUTURE TO
CURRENT.
I THINK -- I FEEL OUR BIGGEST
RESPONSIBILITY AS PHYSICIAN
SCIENTISTS IS TO AVOID
SHORTCUTS, TO REALLY DON'T ALLOW
SHORTCUTS PAUSE THERE ARE NO
SHORTCUTS HERE.
DEPLOYING SOMETHING THAT IS
INADEQUATE, THAT IS LIMITED IS
NOT GOING TO HELP ANYONE.
I THINK I'M VERY WORRIED ABOUT
THAT WITH THE HYPE.
IF YOU WORKED IN ICU LONG ENOUGH
AND YOU WORKED WITH THE DATA
SCIENCE LONG ENOUGH, YOU
ABSOLUTELY KNOW THAT THE
SHORTCUTS ARE DANGEROUS.
AND FOR ME, THAT IS CRITICAL,
THAT ACTUALLY WE NEED TO STEP UP
AS A PHYSICIAN AND BECOME A
GUARDRAIL OF SAFETY OF THIS
TECHNOLOGY, THAT WILL PENETRATE
EVERYTHING, AND WE NEED TO
EDUCATE OUR PHYSICIAN BECAUSE
EVENTUALLY THERE IS ONLY ONE
PERSON WHO IS LIABLE, AND THAT'S
PHYSICIAN.
SO NO MATTER WHAT TECHNOLOGY
SAYS, YOU WILL BE SIGNING YOUR
LIABILITY.
SO I THINK THAT'S FOR ME A
REALLY IMPORTANT AND KIND OF
CAPTURES MY IMAGINATION ON A
DAILY BASIS.
>> YOU AGREE, SUCH A GOOD POINT.
I'M ALSO PUTTING IN A PLUG FOR
THE NEED FOR -- AND QEN I'M
TALKING MYSELF OUT OF A JOB HERE
BUT A NEED FOR DIVERSITY OF
VOICES.
I THINK FOR TOO LONG, SEPSIS HAS
FALLEN IN THE DOMAIN OF CRITICAL
CARE.
BY THE TIME THEY GET THERE, IT'S
PROBABLY -- IT'S KIND OF TOO
LATE, AND YOU GET INTO THIS
BOTTLENECK OF PATHOPHYSIOLOGICAL
PATHWAYS THAT ARE CLOSER TO
DEATH THAN THEY ARE TO THE HOST
TRYING TO MAKE THEMSELVES
BETTER.
AND THAT WE NEED TO DIVERSIFY
WHERE WE'RE DOING THESE STUDIES
AND I THINK AS WE'RE TOUCHED
UPON IT TOO, MY THING IS, YOU
KNOW, HOW MUCH OF THIS IS
ACTUALLY PREVENTABLE?
AND YOU KNOW, I REALLY WANT TO
FOCUS GOING FUTURE -- GOING INTO
THE FUTURE AND TO ANDRE'S POINT,
WE NEED TO COLLECT DATA THAT WE
DON'T KNOW WE NEED, AND WE NEED
TO COLLECT IT INDISCRIMINATELY,
AND THINK IT IS HAPPENING MORE
AND MORE.
SO ANOTHER PLUG FOR OUR APS
CONSORTIUM, WHICH IS SPONSORED
BY THE NHLBI AND N IGMS.
WE ARE ACTUALLY COLLECTING
MULTIDIMENSIONAL CLINICAL AND
BIOLOGICAL DATA AND THAT
RESOURCE IS AVAILABLE FOR
EVERYBODY.
SO PLEASE REACH OUT AND TAP INTO
THAT FOR YOUR RESEARCH PROGRAMS.
>> IT'S IMPORTANT ALSO, THAT'S A
VERY GOOD POINT ABOUT
DIVERSIFYING THE SETTINGS.
I'M A PEDIATRIC ER DOC, AND WE
NEED TO UTILIZE THE EMERGENCY
ROOM.
THAT'S WHERE THE PATIENT SHOWS
UP, YOU KNOW, BEFORE THEY GET TO
THE ICU OR TO THE FLOOR, SO
THERE'S A LOT TO BE DONE THERE.
UNFORTUNATELY ONE OF THE MAJOR
PROBLEMS AND I'M GOING BACK TO
THE DEFINITIONS IS THAT THE
DEFINITIONS ARE MOSTLY FOR THE
ICU BECAUSE EVEN SEPSIS 3, WE
DON'T HAVE ALL THAT DATA IN THE
FIRST HOUR OR TWO IN THE
EMERGENCY ROOM, SO THAT BECOMES
A HUGE PROBLEM.
>> EXCELLENT POINT.
PRATIK, I LIKE TO USE THE SLIDE
WHERE I SAY THE ICU IS AN EXIT
WOUND.
LIKE YOU CAN PATCH UP AN EXIT
WOUND BUT BY THE TIME YOU'RE
THERE, IT'S A BYPRODUCT OF A
BULLET THAT'S GONE THROUGH AND
CREATED ITS OWN KIND OF
WHATEVER, YOU KNOW, TRAJECTORY.
WE HAVE TO GET TO PROJECTILE
ITSELF AND TO THE GUN OR
WHATEVER.
AND SO WE DO NEED TO INCLUDE
THOSE VOICES.
ABSOLUTELY.
IT LOOKS LIKE NITIN, YOU HAVE A
QUESTION.
>> THIS IS A VERY INTRIGUING
DISCUSSION, ESPECIALLY WHAT
PRATIK SAID, HE STILL KIND OF
TRIES TO UNDERSTAND WHAT SEPSIS
IS.
YOU DID SHARE SOME PARTS ABOUT
WHY YOU THINK SO.
BUT MY QUESTION WAS THAT IF --
AND THIS QUESTION IS FOR
EVERYBODY HERE ON THE PANEL OR
IN THE WHOLE MEETING, THAT IF
YOU HAVE TO DEFINE CERTAIN
PARAMETERS THAT SHOULD BE THE
PATHWAY TO IDENTIFY SEPSIS, THEN
WHAT WOULD THEY BE?
BECAUSE RIGHT NOW WE HAVE
IDENTIFIED A CRITICAL GAP IN THE
KNOWLEDGE BASICALLY THAT IT'S
NOT WELL-DEFINED WHAT MEANS --
WHAT SEPSIS MEANS AT THAT END.
SO HOW SHOULD IT BE DEFINED IN
YOUR VIEW?
>> I HAVE TO LEAVE, I'M AFRAID.
I CAN'T ANSWER THAT QUESTION.
IT'S TOO HARD.
AGAIN I'M JUST GOING TO GIVE A
VERY SHORT ANSWER.
I THINK THERE ARE PRACTICAL
UTILITIES OF HOW WE'VE BEEN
DOING SEPSIS SO FAR.
I THINK IT HAS FOCUSED THE MIND
TOWARDS EARLY ANTIBIOTICS,
RESUSCITATION OF PATIENTS WHO
ARE DEMONSTRATING EARLY SIGNS OF
ORGAN FAILURE.
BUT BEYOND THAT, IT IS REALLY,
REALLY DIFFICULT TO FIND
FEATURES THAT WOULD EXIST IN
THIS IDEAL MODEL BECAUSE
INFECTIOUS RESPONSES ARE SO
VARIED, THEY ARE SO DYNAMIC,
THAT I THINK WE NEED TO START
FROM THE BEGINNING AND WE NEED
TO COLLECT DATA AND UNDERSTAND
EXACTLY WHAT IT IS AND WHAT ARE
THE FACTORS THAT DRIVE THE HOST
RESPONSE.
WE HAVE SOME VERY EARLY TA THAT
SUGGESTS EVEN IN BACTERIAL
INFECTIONS, THE PATHOGEN
SPECIFIC RESPONSE OF THE HOST IS
QUITE DIFFERENT.
THESE ARE SORT OF FOUNDATIONAL
PRINCIPLES THAT WE HAVE NOT GOT
AT.
SO I THINK EVEN BEFORE WE CAN
GET TO THESE FEATURES THAT COULD
UNIFY THIS SORT OF DISEASE
STATE, WE NEED TO BETTER DEFINE
WHAT IT IS, WHAT DRIVES IT.
>> I JUST -- WE'VE SPENT ENDLESS
AMOUNT OF TIME TRYING TO FIGURE
OUT WHAT OUR ELECTRONIC
DEFINITION WOULD BE, RECOGNIZING
THAT ALL OF THEM WOULD BE
IMPERFECT, AND I FEEL LIKE
THERE'S A RELIANCE ON OUR
IMMUNOLOGIC COLLEAGUES DOING
BASIC SCIENCE RESEARCH TO
ACTUALLY FIGURE OUT WHAT THE
PATHOPHYSIOLOGY IS TO TEST THAT
WE CAN THEN BUILD OUT CLINICALLY
AND INCORPORATE INTO OUR MODELS
BUT UNTIL IT EXISTS WE'RE USING
ALL OF THESE ROUGH PARAMETERS.
I LIKE TO USE THE ANALOGY, I
DON'T KNOW IF YOU'VE HEARD THAT
QUOTE FROM THE SUPREME COURT,
THAT THEY DIDN'T KNOW WHAT
PORNOGRAPHY WAS, THEY KNOW IT
WHEN THEY SEE IT, AND I FEEL THE
SAME WAY AS A CLINICIAN, IT
LIKE, I CAN'T DEFINE SEPSIS BUT
I KNOW IT WHEN I SEE IT.
BUT HOW DO YOU ACTUALLY, LIKE,
MAKE THAT A PREDICTABLE OUTCOME?
OBVIOUSLY THE CLINICIAN GESTALT
JUST IMPOSSIBLE TO CAPTURE IN
STRUCTURED DATA.
WHICH IS WHY I DO THINK THERE'S
A LOT OF OPPORTUNITY IN THIS
UNSTRUCTURED DATA, BUT IT'S
STILL NOT THE KEY
PATHOPHYSIOLOGY OF WHAT'S GOING
WRONG WITH THE IMMUNE RESPONSE
THAT WE NEED OUR BASIC SCIENCE
RESEARCHERS TO ANSWER FOR US.
>> AND MAYBE JUST TO EXPAND, IF
YOU DON'T MIND, CARA, IS LIKE,
YOU KNOW, THE WAY HOW I ALSO
THINK ABOUT IT AS A MENTAL MODEL
IS THAT FOR ME, SEPSIS IS JUST
ANOTHER MANIFESTATION OF, YOU
KNOW, AGING HUMAN BODY IN
CONTACT WITH THE ENVIRONMENT.
LIKE WE ARE CONSTANTLY BATTLING
THE WORLD.
AND YOU KNOW, THE INFECTION IS
JUST ONE THING THAT CAN KILL US.
THERE'S INJURY, THERE'S TRAUMA,
ALL KIND OF STUFF.
SURGERY, CANCER.
BUT IT IS A VERY HOLISTIC
PROCESS.
I WOULD SAY IT'S A CONTROL
SYSTEM PROBLEM, IT A PROBLEM
WITH THE CONTROL, SO IT IT AFFES
EVERY SINGLE ORGAN.
WE CALL IT HOMEOSTASIS.
WE STILL DON'T UNDERSTAND
COMPLETELY HOW IT HAPPENS, HOW
WE AGE, AND GETTING DEEPER
UNDERSTANDING OF HUMAN HEALTH
WOULD HELP US ALSO DEFINE ALL OF
THESE VERY COMPLEX PRACTICES
THAT HAPPENS WITH AGING.
THAT'S WHY YOU SEE
COMORBIDITIES, ELDERLY, WHEN YOU
ADD ADDITIONAL INSULTS, IT
BECOMES REALLY HARRER.
AND I THINK AS MUCH AS I WANT US
TO BE OUTSIDE OF THE WORK, I
WOULD SAY WE CAN PROBABLY LEARN
HOW TO TAKE CARE OF A LOT OF
THESE THINGS SO THEY DON'T LAP
BUT THERE WILL ALSO BE VERY
OLDER PEOPLE THAT WE WILL HAVE
TO DEAL WITH, AND AT THAT POINT
WE NEED TO UNDERSTAND WHAT DOES
IT NEED TO CONTROL IN THE BODY
LIKE WHAT AND HOW DO WE -- I
DON'T KNOW WHAT, BUT IT WILL
COME, NOT MAYBE IN MY LIFETIME,
BUT I HOPE IT IS MAYBE BECAUSE I
PLAN TO LIVE 150 YEARS SO WE
WILL SEE.
>> I THINK PART OF IT ALSO IS
NUMBER ONE, THERE'S THIS
DISCONNECT BETWEEN THE DATA
CLINICIANS HAVE ACCESS TO AND
WHAT WE POTENTIALLY COULD BE
TESTING.
SO A LOT OF THAT ISN'T AT THE
BEDSIDE.
I THINK IF WE GET TO THAT POINT
WHERE WE CAN HAVE A LOT OF THAT
DATA AVAILABLE TO US, MAYBE IT
MIGHT BE EASIER FOR US TO
IDENTIFY EXACTLY WHAT SEPSIS IS.
THE OTHER THING -- THE OTHER
DATA THAT WE'RE MISSING TO
AZRA'S POINT BEFORE IS THAT I
HAVE NO IDEA AT WHAT STAGE THIS
PATIENT IS COMING TO ME IN THEIR
SEPSIS.
SO PATIENTS THAT I SEE IN MY
HOSPITAL, FOR INSTANCE, TEND TO
COME PRETTY LATE.
WHEN THEY'VE ALREADY EXHIBITED
LOTS OF SIGNS OF ORGAN
DYSFUNCTION.
BUT THERE ARE PATIENTS IN OTHER
HOSPITALS WHO MAY COME VERY
EARLY IN THEIR CLINICAL CORKS CE
AND THOSE TWO DISEASE STATES AT
THAT PARTICULAR TIME MAY BE VERY
DIFFERENT IN TERMS OF THEIR HOST
RESPONSE.
SO I CAN'T REALLY QUANTIFY
EXACTLY WHAT THAT LOOKS LIKE
WITHOUT KNOWING WHAT THEIR
BASELINE DATA IS.
SO ACCESS TO THAT KIND OF DATA I
THINK WOULD ALSO INFORM HOW WE
DEFINE SEPSIS IN THE FUTURE.
>> I READ A BOOK ABOUT
HURRICANES AND THE TECHNOLOGY
THEY USED OVER TIME TO IMPROVE
OUR FORECASTING AND NOT
TREATMENT BUT WHATEVER THEY
COULD DO TO MINIMIZE THE
BYPRODUCTS OF THAT, AND I THINK
OUR -- ARE SOMEWHERE LIKE THE
WIND SPEED, BUT THEY'RE VERY
INCOMPLETE.
I THINK A LOT OF THAT HISTORY
STARTED WITH THE MODELING
APPROACHES, TRAJECTORIES THAT
CAN START FROM THE VERY INITIAL
STAGE, LIKE AZRA HAS DESCRIBED,
WE'RE CONSTANTLY BEING INSULTED,
FOR SOME REASON AT TIMES WE CAN
PUT THAT DOWN AND AT OTHER TIMES
IT BECOMES THIS RAGING
HURRICANE.
BUT THEN INSTRUMENTING THAT
PROCESS OVER TIME, THEY USED TO
FLY AIRPLANES REALLY CLOSE OR IN
AND NOW THEY HAVE ALL THESE
ACCEPT SORES WHICH THEY CAN
DEPLOY, ACTUALLY DIRECTLY INTO
THAT HURRICANE.
SO THINKING -- BUT THE TAXONOMY
OF IT ALL WAS VERY, VERY
IMPORTANT TO DRIVE KIND OF THE
UNDERSTANDING OF HOW TO MITIGATE
THE BYPRODUCTS.
IT LOOKS LIKE WE HAD SOME OTHER
HANDS.
LET'S START WITH DR. LIAW
BECAUSE THE OTHERS HAVE
RETRACTED THEIR HANDS FOR NOW.
>> HI.
I WAS JUST WONDERING, IN THE
U.S., IS THERE A NETWORK FOR
SEPSIS?
I'M JUST THINKING IN CANADA, WE
HAVE SEPSIS CANADA, WHICH IS A
RESEARCH NETWORK MADE UP OF
RESEARCHERS, HEALTHCARE
PROVIDERS AND PATIENT PARTNERS,
AND WE HAVE SEVERAL GOALS THAT
RANGE FROM BASIC RESEARCH TO
POPULATION STUDIES.
I'M JUST WONDERING, IS THAT
SOMETHING THAT'S ALSO PRESENT IN
THE U.S.?
>> THERE ARE MULTIPLE NETWORKS.
I CAN TALK ABOUT PEDIATRIC
NETWORKS.
STUDY FOR KRIN CAL CARE
MEDICINE, THE P CARD, ACTUALLY
AN ASSOCIATION OF EMERGENCY
DEPARTMENTS ACROSS THE U.S.
AND THERE IS CRITICAL CARE,
SEVERE ILLNESS AND TRAUMA
SUBGROUP THIS WORKS ON SEPSIS.
SO THERE ARE MULTIPLE DIFFERENT
ORGANIZATIONS AND CONSORTIA THAT
WILL WORK ON SEPSIS IN THE U.S.
AGAIN, I KNOW MORE ABOUT THE
PEDIATRIC WORLD, BUT MANY OF YOU
KNOW ABOUT THE ADULT WORLD AS
WELL.
>> OKAY, THANK YOU.
>> I SAW HANDS UP BEFORE, DID
YOU WANT TO COME BACK ON AND ASK
YOUR QUESTION?
>> GUOFEI I AM ASSUMING THAT
MOST HOSPITALS HAVE THE DATA FOR
PATIENTS WHO DIED OF SEPSIS,
WHICH WERE SEVERE SEPSIS.
IS IT POSSIBLE OR MAYBE YOU
ALREADY HAVE THE -- THAT THESE
A.I. ALGORITHMS, YOU CAN TRAIN
THEM, FOR ALL THOSE PATIENTS AND
BASED ON THEIR EMR DATA PO
PREDICT MORTALITY OR SEVERITY OF
SEPSIS RATHER THAN DIFFERENT
STAGES OR TREATMENT THAT SOME
PATIENT WHETHER IT'S A
TRAJECTORY TOWARDS MORTALITY OR
NOT.
>> GO AHEAD, ANDRE.
>> WELL, I WAS JUST GOING TO
SAY, SO THERE ARE -- AS A MATTER
OF FACT, IN THE EARLIER STAGES
OF THIS RESEARCH, THERE WERE A
LOT OF MODELS THAT PREDICTED
MORTALITY IN PATIENTS WITH
SEPSIS.
THE PROBLEM WITH PREDICTING
MORTALITY IS AS A CLINICIAN, I
HAVE NO IDEA WHAT TO DO WITH
THAT INFORMATION.
SO WHAT IS THE ACTIONABLE THING
THAT I CAN DO THAT I CAN PREVENT
THAT FROM HAPPENING?
AND SO THAT'S PARTLY WHY A LOT
OF IT, THE WORK THAT'S HAPPENED
SINCE THEN, IS STO HELP IDENTIFY
THINGS THAT WE CAN ACTUALLY FIND
SOMETHING THAT THAT OUTCOME IS
ASSOCIATED WITH, AND LINK IT
BACK TO SOMETHING THAT I CAN DO
TO CORRECT IT.
>> GREAT.
AND GUOFEI, FINAL QUESTION?
>> SURE, THANK YOU, VINNY.
SO REGARDING THE DIFFERENT
VOICES, SO YOU GUYS WANT THE
MULTIPLICITY OF DATA IN SAMPLING
OF BIOMARKERS.
I DID NOT HEAR YOU GUYS TOUCHING
UPON THE PATIENT ANGLE, HOW THE
PATIENT THINKS AND HOW DOES
PATIENT PERSPECTIVE CONTRIBUTE
TO THE A.I. MODELS YOU GUYS
BUILD UPON.
WE ARE DEALING WITH PATIENTS WHO
ARE CRITICALLY ILL, FOR EXAMPLE,
PATIENTS THAT PRATIK MENTIONED,
WE COLLECT A LOT OF DATA IN OUR
SAMPLES BUT THE PATIENTS ARE
UNDER A LOT OF DISTRESS, THE
RATE IS NOT REALLY GREAT.
SO I'M THINKING IF WE NEEDED TO
LISTEN TO PATIENT, WHAT IS A
MINIMAL DATA ELEMENTS OR THE
SAMPLE ELEMENTS YOU WOULD LIKE
TO HAVE?
THAT WAY, IT WILL HELP US AS A
RESEARCHERS TO BE ABLE TO ANSWER
THE SCIENTIFIC QUESTIONS.
MEANWHILE WE CAN MITIGATE THE
STRESS, OUR PROCESS CAN IMPOSE
ON THE PATIENT.
THANK YOU.
>> MAYBE IT IS A QUESTION FOR
AZRA.
BECAUSE YOU WANT EVERYBODY TO
INSTRUMENT THEMSELVES, RIGHT?
QUANTIFIED SELF, YOU KNOW,
COLLECTING THEIR SAMPLES AND
RINGS AND HELMETS WITH
NEUROLOGIC SIGNAL?
I THINK THE PATIENTS ARE
CRITICAL BECAUSE I THINK THERE'S
A BIG EDUCATION GAP IN TERMS OF
THE INCIPIENT SYMPTOMS,
CIRCUMSTANCES THAT LEAD TO
INFECTION AS A PRECURSOR TO
DYSREGULATED IMMUNE RESPONSE AND
RISK OF MORTALITY.
I THINK THE TOOL SETS DO EXIST
TO INSTRUMENT -- HAVE PATIENTS
INSTRUMENTING SO THAT WE COULD
UNDERSTAND THOSE FACTORS, AND
THEY'RE GOING TO BE CRITICAL
PARTNERS TO DO THAT, BECAUSE I
DON'T THINK IT'S FEASIBLE FOR US
TO -- IT WOULD BE VERY
CHALLENGING FOR US TO DO THAT AT
SCALE WITHOUT PATIENTS BUYING
INTO THAT PROCESS AND ACTIVELY
BEING -- YOU KNOW, UNDERSTANDING
THE RATIONALE FOR WANTING TO
LINK UP THESE DATA WITH WHAT WE
ONLY OBSERVE DOWNSTREAM OR ONLY
IN PARTIAL WAYS.
SO I THINK WE DO NEED TO DO A
BETTER JOB IN THAT DOMAIN.
I THINK IT'S A CHALLENGING AREA.
>> AND ALONG THOSE LINES FOR AT
THE DIGITAL TWIN, I LIKE THAT
IDEA.
MAYBE WE NEED TO FOCUS ON
PRECISION MEDICINE INSTEAD OF
TRYING TO TACKLE THIS AS HAVING
ONE DEFINITION, ONE APPROACH,
MAYBE THIS HETEROGENEITY IS SO
HARD TO OVERCOME THAT WE NEED TO
FOCUS MORE ON EACH PATIENT
INDIVIDUALLY.
>> YES, SO WE -- INSTEAD OF ONE
COLOR WE SEE THE ENTIRE
SPECTRUM.
AND THAT IS HARD FOR HUMAN
BECAUSE WE TEND TO THINK MORE
REDUCTIONIST.
BUT I THINK THAT'S WHERE I SEE
TECHNOLOGY CAN HELP US, RIGHT?
I ALWAYS THINK THAT WE CAN GET A
SAW PER POWER OF A.I. TECHNOLOGY
BECAUSE -- INTO HUMAN WAY OF
THINKING THIS, THAT IS AGAIN
WHAT WE WANT, SO I WOULD JUST
ADD ON WHAT ARE YOU WHAT VINNYK
PATIENTS NEED TO BE EMPOWERED TO
UNDERSTAND THAT THERE IS NO
BETTER DOCTOR THAN YOURSELF.
YOU ARE YOUR BEST HELPER.
DEEP UNDERSTANDING HOW MUCH
CONTROL WE HAVE AS HUMANS, AND
HOW MUCH SIMPLE THINGS LIKE WHAT
WE EAT, HOW WE FEEL AND HOW WE
CONNECT INFLUENCE OUR HEALTH,
THAT IS ABSOLUTELY CRITICAL.
SO I'M MORE THAN A NEPHROLOGIST
AND INTENSIVIST, MORE AND MORE I
THINK OF IT, GO BACK TO PRIMARY
CARE, REALLY PREVENTION IS THE
KEY AND EDUCATION ABOUT
IMPORTANCE OF PREVENTION.
AND IMPORTANCE OF THESE TOOLS
THAT MAYBE ONE DAY THERE ARE
GOING TO BE HOSPITALS WHO CAN ON
CELL PHONE TELL YOU, NOT FEELING
WELL G TO DOCTOR.
THAT IS GOING TO BE AT THE TIP
OF THE HAND, NOW OUR JOB IS TO
EDUCATE OUR PATIENTS AND THINK
ABOUT THAT.
>> GREAT, WONDERFUL.
WELL, THANK YOU ALL FOR JUST A
TOUR OF WHAT THE OPPORTUNITIES
ARE FOR A.I. IN SEPSIS, AND I
THINK IT'S REALLY, REALLY
INTRIGUING TO SEE WHAT THESE
NEXT FIVE OR 10 YEARS WILL BRING
IN TERMS OF PRECISION MEDICINE
AND IN TERMS OF OUR
UNDERSTANDING OF THE FULL KIND
OF SPECTRUM OF SEPSIS FROM
COMMUNITIES ALL THE WAY DOWN TO
PROTEINS.
SO THANK YOU AGAIN FOR THAT, AND
WITH THAT, I'LL TURN IT OVER
BACK TO NITIN.
>> ALL RIGHT.
THANK YOU, VINNY.
AND FIRST OF ALL I WOULD LIKE TO
CONGRATULATE ALL THE SPEAKERS
HERE AND ALL THE CHAIRS FOR
KEEPING THE CLOCK OF TIME SO
MUCH.
WE ARE ONLY FIVE MINUTES BEHIND
IN THE ENTIRE DAY MEETING, WHICH
IS AMAZING.
SO THANK YOU ALL AGAIN FOR
KEEPING THIS ON TRACK.
LET'S TAKE A QUICK 10-MINUTE
BREAK, AND WE CAN RECONVENE AT
4:15, AND AFTER THAT, WE WILL
HAVING THE CONCLUDING REMARKS
FROM THE CHAIRS AND MODERATORS
FROM EACH SESSION AND THAT WILL
BE THE END OF THE MEETING AFTER
THAT.
I'M GUESSING THAT WE CAN DO
IT BY INVITING ALL THE CHAIRS
TOGETHER AS A JOINT PANEL
BECAUSE THERE'S BEEN A LOT OF
OVERLAP ACROSS THE SESSIONS WE
HAVE SEEN TODAY DURING THE
DISCUSSION PANELS.
SO FOR EXAMPLE, HOW THE CLINICAL
PRACTICES CAN OVERLAP THE
ONGOING RESEARCH AS THE
TECHNOLOGY INTERVENTIONS.
SO IT WOULD MAKE A LOT OF SENSE
TO ESTABLISH LINKS BETWEEN THE
THREE AREAS THAT WE HAVE
DISCUSSED T TODAY, AND CONCLUDE
THE TAKEAWAY LESSONS FROM THE
DISCUSSION, WHICH EACH SESSION
CHAIR CAN DO ONE AT A TIME
STARTING WITH SESSION ONE.
BUT IT COULD BE -- [INAUDIBLE] E
AS WELL AS NEEDED.
>> THANK YOU, NITIN, AND
DR. ASHANA IS GOING TO GO AHEAD
AND GIVE THE REPORT OUT FOR
SESSION ONE.
WE CAN'T HEAR YOU.
>> AUDIO ISSUES AGAIN, I
BELIEVE.
SOUNDS GOOD.
THANK YOU.
>> ARE YOU ABLE TO HEAR ME NOW?
GREAT.
>> YES, PERFECT.
>> ALL RIGHT.
AWESOME.
THANK YOU SO MUCH.
FIRST THANKS TO THE FOUR
PRESENTERS AND REALLY ALL OF THE
PRESENTERS TODAY.
THIS IS A FANTASTIC DAY AND I'VE
LEARNED A LOT.
SO I'LL JUST BE SUMMARIZING AS
YOU MENTIONED THE TALKS AS WELL
AS THE DISCUSSION FROM THE FIRST
SESSION ON DISPARITIES IN
SEPSIS.
WE HEARD TODAY SEPSIS IS A
LEADING CAUSE OF MORTALITY IN
THE WORLD AND THE U.S.
THERE ARE 11 MILLION ANNUAL
SEPSIS-RELATED DEATHS GLOBALLY.
DR. RUDD SHARED IT IS THE MOST
COMMON CAUSE OF DEATH WORLDWIDE
RESPONSIBLE FOR 1 IN 5 DEATHS
GLOBALLY, ALSO THE THIRD MOST
COMMON CAUSE OF DEATH IN U.S.,
EQUIVALENT TO HEART ATTACKS AS
SHARED BY DR. MARTIN.
SURVIVAL IS NO DOUBT AN
IMPORTANT END POINT, HOWEVER,
THERE IS ALSO SUBSTANTIAL
MORBIDITY AMONG SURVIVORS OF
THIS GROUP.
THERE'S SUBSTANTIAL COGNITIVE,
PSYCHOLOGICAL AND FUNCTIONAL
IMPAIRMENTS AMONGST SURVIVORS OF
CRITICAL ILLNESS.
WE ALSO HEARD THOSE HARMS
DISPROPORTIONATELY ACCRUE TO
PATIENTS WHO EXPERIENCE SOCIAL
AND/OR ECONOMIC DISADVANTAGES.
SO DR. RUDD SHARED SOME OF HER
WORK IN LOW AND MIDDLE INCOME
COUNTRIES, AND WE ALSO HEARD IN
THE U.S. THAT PATIENTS WHO LIVE
IN RURAL AREAS, PATIENTS WHO
IDENTIFY AS BLACK, FO FOR EXAMP,
EXPERIENCE GREATER INCIDENCE AND
RISK OF MORTALITY FROM SEPSIS.
WE TALKED A LOT ABOUT POTENTIAL
ROOT CAUSES FOR THESE
DISPARITIES IN SEPSIS, AND
SPECIFICALLY THE INTERACTION OF
BIOLOGICAL AND SOCIAL RISK
FACTORS.
THERE WAS A LOT OF ATTENTION TO
NON-COMMUNICABLE DISEASES OR
CHRONIC ILLNESSES AND IN
PARTICULAR MULTI-MORBIDITY.
THE CONTRIBUTION OF
MULTI-MORBIDITY TO SEPSIS DEATH.
I WAS SURPRISED TO LEARN THAT
ABOUT 50% OF SEPSIS DEATHS CAN
BE ATTRIBUTED TO CHRONIC
ILLNESSES AND MULTI-MORBIDITY.
WE ALSO SPOKE A LOT ABOUT SOCIAL
RISK FACTORS THAT MAY CONTRIBUTE
TO SEPSIS RISK AND POOR OUTCO
OUTCOMES.
SO WE HEARD ABOUT TWO IMPORTANT
CONCEPTS WHICH MAY BE NEW TO
SOME OF THE AUDIENCE SO I'LL
JUST REDEFINE THEM.
WE HEARD ABOUT SYNDEMICS AND
ABOUT THIS CONCEPT OF
EMBODIMENT.
SYNDEMIC SIMPLY STANDS FOR
SYNERGISTIC EPIDEMIC, AND WHERE
THERE ARE SYNERGISTIC SOCIAL
RISKS AND BIOLOGICAL RISKS THAT
INTERACT WITH EACH OTHER TO
PRODUCE A HIGHER INCIDENCE OF
DISEASE IN A CERTAIN POPULATION.
SO DR. RUDD POSTULATED THAT THIS
MAY BE ONE POTENTIAL MECHANISM
BY WHICH WE ULTIMATELY SEE
DISPARITIES IN SEPSIS.
SO ONE EXAMPLE OF THAT IN
DR. MARTIN'S TALK IS WHEN HE
SHARED THAT IN THE STROKE BELT
OF THE UNITED STATES, THAT
THERE'S HIGHER SEPSIS-RELATED
MORTALITY IN THIS AREA THAN
RURAL SOUTHERN U.S. AND OF
COURSE THERE'S ALSO HUGE SOCIAL
BARRIERS TO HEALTHCARE IN THOSE
AREAS.
A LOT OF THOSE AREAS ACTUALLY
HAVE NO ACCESS TO ICUs IN
THEIR COMMUNITIES.
SO THAT WAS ONE IMPORTANT
CONCEPT THAT WE SHOULD TAKE AWAY
FROM THE TALKS THIS MORNING.
ANOTHER WAS THIS IDEA OF
EMBODIMENT THAT EXPOSURE TO
RACIALIZED AND ECONOMIC
INJUSTICE ACTUALLY RESULTS IN
BIOLOGICAL CHANGES.
WE HEARD ABOUT SOME WORK FROM
NANCY KRUEGER ABOUT EPIGENETIC
AGING, THE EXPOSURE TO SOCIAL
INJUSTICE, EVEN HISTORICAL
SOCIAL INJUSTICE SUCH AS LIVING
IN A STATE THAT PREVIOUSLY HAD
JIM CROW LAWS, EVEN TODAY FOR
FOLKS WHO WERE NOT ACTUALLY
EXPOSED TO THOSE LAWS, SIMPLY
LIVING IN A STATE THAT
HISTORICALLY HAD THOSE LAWS IS
ACTUALLY STRONGLY ASSOCIATED
WITH EPIGENETIC MARKERS OF
AGING.
SO THAT'S ONE IMPORTANT CONCEPT
THAT WE SHOULD TAKE AWAY, IS
THIS DISTINCTION BETWEEN
BIOLOGICAL AND CHRONOLOGICAL AGE
AND HOW THAT MAY INFLUENCE
SEPSIS RISK AND OUTCOMES.
THIS IS ESPECIALLY RELEVANT
BECAUSE DR. MARTIN SHIRRED
THERE'S AN EXPONENTIAL INCREASE
IN SUBSTANCE INCIDENCE.
WE ALSO HEARD ABOUT ENDOTHELIAL
DAMAGE AS A POTENTIAL COMMON
CAUSE OF CHRONIC ILLNESS IN
SEPSIS, BUT THIS WAS IDENTIFIED
AS A KNOWLEDGE GAP THAT REQUIRES
ADDITIONAL STUDY.
TO DR. AGARWAL'S POINT TO THE
INTERCONNECTION BETWEEN THE
THREE SESSIONS TODAY, I THINK
THIS IS AN IMPORTANT ONE THAT
CONNECTS TO THE SECOND SESSION
AND COULD BE AN IMPORTANT AREA
OF COLLABORATION BETWEEN
POTENTIALLY SOCIAL SCIENTISTS
AND TRANSLATIONAL SCIENTISTS.
THERE WAS A LOT OF DISCUSSION IN
THE PANEL DISCUSSION ABOUT
GENETIC RISK FOR SEPSIS AND
BECAUSE WE HAD TALKED ABOUT THE
LACK OF EVIDENCE FOR THE
ASSOCIATION BETWEEN GENETICS AND
RACE IN THE UNITED STATES.
I THOUGHT I WOULD JUST SHARE
SOME OF THE EVIDENCE THAT DOES
EXIST SO WE HAD REFERENCE TO
SARAH TISHKOFF'S WORK.
THESE ARE SOME KEY PHRASES FROM
HER ARTICLE SO I'LL JUST READ
THEM OUT.
SHE SAYS THAT BECAUSE MODERN
HUMANS ORIGINATED IN AFRICA AND
HAVE ADAPTED TO DIVERSE
ENVIRONMENTS, AFRICAN
POPULATIONS HAVE HIGH LEVELS OF
GENETIC AND PHENOTYPIC
DIVERSITY, AND IN FACT AFRICAN
POPULATIONS HAVE THE HIGHEST
LEVELS OF GENETIC VARIATION
AMONG ALL HUMANS, THAT CANNOT BE
THE CASE AMONG INDIVIDUALS WHO
WE CLASSIFY AS BLACK IN THE
UNITED STATES, THAT THERE WOULD
BE A COMMON GENETIC ROOT CAUSE
TO EXPLAIN THE HIGHER PREVALENCE
OF SEPSIS IN THAT POPULATION.
AND SHE ALSO NOTES IN HER WORK
THAT GENETIC DIVERSITY DECLINES
WITH DISTANCE FROM AFRICA
CONSISTENT WITH PROPOSED SERIAL
FOUNDER EFFECTS, WHICH MEANS
THAT IN INDIVIDUALS WITH
EUROPEAN ANCESTRY THERE'S MORE
HOMOGENEITY.
AS SOMEONE WHO STUDIES HEALTH
EQUITY, I AM A BIG FAN OF
FRAMEWORKS AND THEORIES AND I
WILL JUST SHARE ONE OF MY
FAVORITE ONES BECAUSE I THINK
THESE ARE REALLY USEFUL FRAME
WORKS FOR ORGANIZING OUR STUDY
OF CERTAINLY SOCIAL SCIENCE
TOPICS BUT POTENTIALLY OTHER
TOPICS AS WELL.
THIS IS A THEORY PROPOSED BY
NANCY KRUEGER MORE THAN 10 YEARS
AGO NOW.
IT'S CALLED THE ECOSOCIAL
THEORY.
IT'S A FRAMEWORK TO UNDERSTAND
SOCIAL INEQUITIES AND HEALTH
OUTCOMES.
NOT ALL OF THESE AREAS ARE
RELEVANT TO WHAT WE'RE TALKING
ABOUT TODAY, SO I'LL JUST HIDE
SOME OF THESE SO WE CAN FOCUS ON
WHAT IS RELEVANT.
SO THE CENTER OF THIS FIGURE IS
WHAT WE OBSERVE IN OUR CLINICAL
PRACTICE AND OUR DATA.
WE SEE POPULATION DISTRIBUTION
OF DISEASE AND HEALTH, AND THEY
SEEM TO DIFFER BY RACIAL -- BY
RACE, ETHNICITY, CLASS.
WE TALKED A LITTLE BIT ABOUT
GENDER TODAY, NOT SO MUCH ABOUT
SEXUALITY BECAUSE THIS IS WHAT
WE OBSERVE.
BUT WHAT UNDERLIES THIS, AND IF
WE ADVANCE AGAIN P THESE ARE THE
ROOT CAUSES SHE POSTULATES.
AGAIN WE TALKED ABOUT A LOT OF
THESE TODAY.
WE TALKED ABOUT THE CONCEPT OF
EMBODIMENT, WHAT ARE THE
PATHWAYS OF EMBODIMENT.
I THINK ONE KEY THING WE SHOULD
TAKE YOU A WAY TODAY IS WE
REALLY DON'T KNOW PRECISELY WHAT
THOSE PATHWAYS OF EMBODIMENT ON
EPIGENETIC AGING IS DEFINITELY
AN AREA WE SHOULD FOCUS ON IN
FUTURE RESEARCH.
WE ALSO TALKED ABOUT THE
CUMULATIVE INTERPLAY BETWEEN
EXPOSURE SUSCEPTIBILITY AND
RESISTANCE.
AND THAT ALL OF THIS IS SORT OF
FILTERED THROUGH THE LENS OF
POLITICAL ECONOMY AND POLITICAL
ECOLOGY, WHICH MEANS THAT
PATIENTS EXPERIENCE BIOLOGICAL
RISK BUT HOW THEY ACCESS THE
HEALTHCARE SYSTEM ALSO DEPENDS
ON THE COUNTRY IN WHICH THEY
LIVE, SO WE HAVE A DEFECTIVE
SYSTEM OF WEALTH-BASED INSURANCE
AND HEALTHCARE ACCESS IN THIS
COUNTRY, AND INSURANCE IS TIED
TO THE JOB THAT YOU HAVE FOR
VERY MANY PEOPLE, AND THE TYPES
OF HOSPITALS THAT YOU HAVE
ACCESS TO DEPENDS ON WHERE YOU
LIVE.
AND SO THAT'S WHY ALL OF THESE
MECHANISMS ARE SORT OF FILTERED
THROUGH THAT POLITICAL ECONOMY
AND ECOLOGY.
AND THEN THE LAST THING SHE
TALKS ABOUT IS ACCOUNTABILITY IN
AGENCY, WHICH ALSO MEANS THAT
WHEN WE'RE STUDYING HEALTH
EQUITY -- HEALTH INEQUITIES,
IT'S VERY IMPORTANT TO
UNDERSTAND HOW POWER IS
DISTRIBUTED IN THE HEALTHCARE
SYSTEM AND THAT SHOULD DICTA
DICTATE -- IT IS THE CASE THAT
THE HEALTHCARE SYSTEM HAS POWER
TO CHANGE THE WAY IT DELIVERS
CARE TO THOSE PATIENTS AND SO
BECAUSE WE HAVE MUCH MORE POWER
THAN PATIENTS, AND I WOULD
CONTEND THAT OUR FOCUS OF
SCHOLARSHIP REALLY SHOULD BE ON
THE HEALTHCARE SYSTEM AS WELL.
SO WE REALLY TALKED ABOUT WHAT
IS THE CONTRIBUTION OF
CLINICIANS AND HEALTHCARE
SYSTEMS FOR DISPARITIES IN
SEPSIS.
AND THIS ON THE LEFT IS ONE OF
MY FAVORITE FIGURES.
AGAIN, IT'S A THEORY TO
UNDERSTAND INEQUITIES IN
HEALTHCARE, IT WAS ORIGINALLY
PROPOSED IN 1971 AND UPDATED IN
2021.
IT'S THE DISPROPORTIONATE CARE
LAW, AND PACEICA BASICALLY WHATS
SHOWS IS AS ON THE X AXIS,
DISADVANTAGE ACCRUES TO
POPULATIONS.
THE Y AXIS WE SEE THAT THERE IS
RELATIVELY LESS RESOURCE INPUT
PER CAPITA.
LET ME JUST EXPLAIN WHAT THAT
MEANS.
ON THE LEFT-HAND SIDE OF THIS
GRAPH, WHAT WE SEE IS THAT VERY
ADVANTAGED, VERY WEALTHY
POPULATIONS HAVE A NEED FOR
HEALTHCARE, OF COURSE, BUT THEY
HAVE EXCESS AVAILABILITY OF
HEALTHCARE RESOURCES.
THESE ARE THE PATIENTS WHO HAVE
ACCESS TO LIKE FOR MYSELF FOR
EXAMPLE, I DON'T NEED A REFERRAL
TO SEE ANY SPECIALIST THAT I
WANT.
I HAVE EXCESS AVAILABILITY OF
HEALTHCARE RESOURCES AVAILABLE
TO ME.
ON THE OTHER HAND, ON THE
RIGHT-HAND SIDE OF THE GRAPH,
MORE DISADVANTAGED POPULATIONS
HAVE COMPARATIVELY GREATER NEED
BUT RELATIVELY LESS AVAILABILITY
OF HIGH QUALITY HEALTHCARE
RESOURCES SO THEY ULTIMATELY
HAVE A GREATER UNMET NEED.
WE SEE THIS IN SEPSIS CARE IN
THE U.S. AS WELL, AND IN THE
RURAL U.S., THERE'S ABSOLUTE
SCARCITY OF CRITICAL CARE
RESOURCES.
AS I MENTIONED MANY COMMUNITIES
WITH NO ICU BEDS AND THEN WILL
LARGER CITIES THERE'S RELATIVE
SCARCITY OF CRITICAL CARE
RESOURCES.
DR. DONELY SPOKE A LOT ABOUT
VARIABILITY -- WE KNOW WHAT WE
SHOULD BE DOING AND YET WE DON'T
DOUGH THOSE THINGS CONSISTENTLY
AND THAT REALLY VARIES BASED ON
THE DEMOGRAPHICS OF THE
HOSPITAL, SO THAT IS A GROWING
CAUSE OF DISPARITY.
AND ANOTHER WE DIDN'T GET INTO
TOO MUCH IS PAYING PENALTIES FOR
ADHERING TO SEPSIS BUNDLES HOW
THEY MAY ACTUALLY PARADOXLY WORK
INTO -- FOR ADHERING TO SEPSIS
BUNDLES -- EVEN WITHIN HOSPITALS
DURING TIMES OF STRAIN, THERE
CAN BE BREAKDOWNS IN THESE
EVIDENCE-BASED CARE PROCESSES.
WE'VE COVERED ALL LOI THE LOT S
ALREADY, BUT THE MAIN KNOWLEDGE
GAPS WE HIGHLIGHTED WERE
BIOLOGICAL MECHANISMS THAT LINK
SOCIAL RISKS, AND THE SECOND WAS
ABOUT INTERSECTION BETWEEN
PATIENT CHARACTERISTICS,
CERTAINLY THE POTENTIALLY PAYING
GREATER ATTENTION TO THE CARE
DELIVERY PROCESSES AND HOSPITAL
CHARACTERISTICS.
AND THEN FINALLY, WE'LL END WITH
POTENTIAL SOLUTIONS AND FIRST
I'LL JUST NOTE THAT THERE AREN'T
ENOUGH ON THIS SLIDE BECAUSE OUR
FIELD REALLY HAS NOT MOVED IN
THIS SPACE YET.
BUT MAYBE THAT WILL BE FOCUS OF
THE NEXT ITERATION OF THIS
WORKSHOP.
ONE POTENTIAL SOLUTION IS USING
IMPLEMENTATION SCIENCE TO
STANDARDIZE EVIDENCE-BASED CARE
DELIVERY AND REALLY CREATING
SEPSIS CARE BUNDLES THAT ARE
INDIVIDUALIZED TO CONTEXT, SO
EVEN TO LOW RESOURCE CARE
SETTINGS.
AND DR. CHESLEY SPOKE ABOUT
INCLUSION OF CRITICAL ACCESS IN
MINORITY SERVING HOSPITALS IN
RESEARCH TO DEVELOP THOSE
CONTEXTUALLY TAILORED SOLUTIONS.
THERE WAS A LOT OF DISCUSSION
ABOUT MOVING RESEARCH UPSTREAM,
HOW DO WE REALLY THINK ABOUT
PRIMARY AND SECONDARY
PREINVESTIGATION OF SEPSIS.
SOME IDEAS THAT WERE SHARED WERE
MORE PRECISE RISK STIDGES FOR
PREVENTIVE CARE DELIVERY.
HOW DO WE USE WEARABLES,
PATIENT-REPORTED OUTCOMES, THIS
IS POTENTIALLY A CONNECTION WITH
THE THIRD SET OF TALKS, FOCUSING
ON A.I.
HOW DO WE USE THE TECHNOLOGY
THAT'S AVAILABLE TO US TO REALLY
IDENTIFY THE INDIVIDUALS WHO ARE
AT HIGHER RISK OR HIGHEST RISK
FOR DEVELOPING SEPSIS AND THEN
HOW DO WE CREATE CULTURALLY
TAILORED EDUCATION AND OUTREACH
TO REDUCE THEIR RISK.
AND THE RESULTS OF DISCUSSION --
PRESEPSIS, HOW DO WE STANDARDIZE
THE MESH MEASUREMENT OF THAT FR
RESEARCH.
THEN A DISCUSSION ENGAGING ALL
RELEVANT PARTIES NOTING THAT
EVERYBODY WHO SPOKE TODAY IS A
PHYSICIAN -- OR NOT A PHYSICIAN,
I SHOULD SAY, A SCHOLAR AT A
VERY WELL RESOURCED HOSPITAL,
AND ARE THOSE THE ONLY PEOPLE
THAT NEED TO BE AT THE TABLE IF
WE WANT TO DO THIS WORK VERY
WELL.
AND THEN FINALLY, ARE THERE NIH
MECHANISMS THAT COULD ENCOURAGE
MULTIDISCIPLINARY RESEARCH WITH
THE SOCIAL SCIENCES, AND I WILL
END THERE.
THANK YOU.
>> I THINK DR. BAE WILL GIVE THE
REPORT.
SO GO AHEAD, PLEASE.
>> HELLO, EVERYONE.
THIS IS FOR THE REPORT OUT OF
SUMMARY FOR SESSION TWO.
SO THE SESSION WAS CHAIRED BY
DR. PRITHU SUNDD AND MYSELF FROM
THE NHLBI PRIDE SCHOLAR PROGRAM.
WE DISCUSSED ABOUT MECHANISM
UNDERLYING THROMBOINFLAMMATION
RESPONSE IN SEPSIS.
WE FIRST WANT TO THANK OUR
SPEAKERS, DR. ZHENYU LI WHO
DISCUSSED ABOUT HOW PYROPTOSIS
DRIVES COAGULATION IN SEPSIS.
AND DR. KANDACE GOLLO MP, HOW
PF4 AND NEUTROPHIL EXTRACELLULAR
TRAPS PROMOTE PATHOGENESIS OF
SEPSIS, THEN DR. NIGEL MACKMAN
CONTINUED TO EXPLAIN HOW
COAGULATION, IMMUNOTHROMBOSIS
AND EXTRACELLULAR VESICLES
PROMOTE THE PATHOGENESIS OF
SEPSIS.
AND LASTLY, DR. PATRICIA LIAW
DISCUSSED HOW IMMUNOTHROMBOSIS
CAN BE THERAPEUTICALLY TARGETED
IN SEPSIS.
SO THIS IS THE LESSONS FROM THE
WORKSHOP.
SO THE NEW FINDINGS, WE HAD
SEVERAL NEW FINDINGS OVER --
BACTERIAL ROD PROTEINS EPRG
TRIGGER INFLAMMASOME ACTIVATION
AND PYROPTOSIS WHICH PROMOTES
TISSUE FACTOR RELEASE THAT CAN
LEAD TO INTRAVASCULAR
COAGULATION IN SEPSIS.
DR. NIGEL MACKMAN'S FINDINGS AND
DR. LI'S FINDINGS WERE COMBINED
TOGETHER TO EXPLAIN THAT OTHER
INCREASE OF TISSUE FACTOR
EXPRESSION AND ACTIVITY IN THE
MICROPHAGES PLAY A SIGNIFICANT
ROLE IN THE ACTIVATION OF
COAGULATION IN SEPSIS AND ENDO
TOXEMIA.
AND WE DISCUSSED THAT IF YOU
HEARD THAT OF BLOCKING THE
INDUCTION OF MONOCYTE TISSUE
FACTOR EXPRESSION AND RELEASE OF
TISSUE FACTOR POSITIVE
EXTRACELLULAR VESICLES OR THE
ACTIVITY OF TESH EU FACTOR
EXTRACELLULAR VESICLES MAY
INTRODUCE INTRAVASCULAR
COAGULATION IN SEPSIS PATIENTS
WITHOUT INCREASING THE RISK OF
BLEEDING.
AND WE'VE HEARD THAT FROM
DR. KANDACE THAT NEUTROPHIL
EXTRACELLULAR THAT TRAPS
MODIFICATION BY PLATELET FACTOR
4 CAUSES NETs TO BECOME
COMPACT AND RESISTANT TO
NUCLEASE DIGESTION, THAT MAY
LIMIT THEIR DISSEMINATION AND
THROMBOTIC POTENTIALS WHEREAS
ENHANCING THEIR ABILITY TO
CAPTURE AND KILL BACTERIA.
WE'VE ALSO -- PAD 4 REGULATES
SEPSIS PATHOGENESIS BY IMPACTING
BASELINE INFLAMMATORY RESPONSE
AND NEUTROPHIL TISSUE,
INFILTRATION AND COMPOSITION OF
THE GI MICROBIOMES.
SO AGAIN WE HEARD THAT SEPSIS
OUTCOMES IN CECAL SLURRY MODEL
MAY INFLUENCE BOTH BY
PAD4 EXPRESSION IN THE CECAL
SLURRY MODEL DONOR AS WELL AS
PAD4 EXPRESSION IN RECIPIENT
SUBJECTS.
AND AFTER THAT, WE ALSO HAVE
HEARD FROM DR. LIEW ABOUT
POTENTIAL FACTORS THAT IMPACT
EFFICACY OF THERAPEUTIC AGENTS
IN SEPSIS TREATMENT.
WE DISCUSSED POTENTIAL FACTORS
SUCH AS THE TIME OF
ADMINISTRATION AND ENDORSED
AGENTS AND TYPES OF
INTERVENTIONS AND HETEROGENEITY
IN PATIENTS.
WE ALSO DISCUSSED ABOUT THE
ADMINISTRATION TIME FOR
THERAPEUTICS BY USING THE
EXAMPLES OF HEPARIN AND THE
INTERLEUKIN 6 RECEPTOR
ANTAGONISTS AND THEY MAY BENEFIT
IF WE ADMINISTER THEM AT THE
EARLY OR LATE STAGES OF SEPSIS
RESPECTIVELY.
SO AS SPEAKERS IN THE WORKSHOP
DISCUSSED, THE TIME OF THE OTHER
ADMINISTRATIVE TIME WILL BE
BENEFICIAL IF WE CAN FIGURE IT
OUT TO IMPROVE THE OUTCOMES OF
THERAPEUTICS.
WE ALSO DISCUSS ABOUT THE
POTENTIAL OF PRECISION MEDICINE
OPPORTUNITIES TO IMPROVE USING
THE GENETIC STRATIFICATION OF
UNDERLYING RISK.
FURTHER EXPLAINED ABOUT
FECAL-INDUCED PERITONITIS MODEL
OF MURINE SEPSIS AS A SIMPLE AND
STANDARDIZED EXPERIMENTAL MODEL.
SO WE ALSO DISCUSSED ABOUT THE
POTENTIAL THERAPEUTIC AGENTS,
RECOMBINANT DNASE 1 TO IMPROVE
OUTCOMES IN SEPSIS.
IF IT WILL HELP US TO OBTAIN
BETTER -- PATIENT.
LASTLY WE DISCUSS ABOUT
PROGNOSTIC AND PREDICTIVE
ENRICHMENT STRATEGIES AND THAT
IT WILL PROFILE A TARGETED
OPPORTUNITY IN SEPSIS TREATMENT.
THIS IS OVERALL A VIEW FROM
PRESENTATIONS FROM OUR SPEAKERS,
AND THERE WAS ALSO A FEW EXTRA
POINTS DEVELOPED FROM THE
QUESTIONS AFTER THE
PRESENTATION.
WE DISCUSSED ABOUT TIMING NEEDS
TO BE CAREFULLY DETERMINED.
THIS IS ALSO ALIGNED WITH OUR
SPEAKERS FROM OUR -- FROM THE
WORKSHOP.
SO WE ALSO DISCUSSED THAT
FINDING THE BIOMARKERS THAT CAN
PROTECT -- DISSEMINATE
INTERVASCULAR COAGULATION AND
SEPSIS IS CHALLENGING AT THE
MOMENT, BUT IT WILL BENEFIT US
TO DETECT OUR DISEASE AND WE MAY
BE ABLE TO COME UP WITH THE
PROPER AND EFFECTIVE STRATEGIES.
AND THERE WAS ALSO DISCUSSION
ABOUT EVALUATING THE PROGNOSTIC
PARAMETERS FOR IMMUNE RESPONSES
AND WE DISCUSSED THAT IT
IMPROVED POINT OF CARE FOR OUR
PATIENTS, AND BECAUSE IT
REQUIRES A SMALL VOLUME OF BLOOD
SAMPLES.
WE DISCUSSED THE ROLE OF
POTENTIAL FACTORS -- METABOLISM
THAT CAN POTENTIALLY --
INFLAMMATORY RESPONSES.
SO WE THOUGHT THAT INVESTIGATING
THESE FACTORS MAY HELP US TO
BETTER UNDERSTAND THE MECHANISMS
OF SOME INFLAMMATORY RESPONSES
FURTHER.
THIS IS A SUMMARY OF THE SESSION
TWO.
I HOPE IT WAS USEFUL FOR OUR
AUDIENCE TO BETTER UNDERSTAND
THE MECHANISM UNDERLYING
INFLAMMATORY RESPONSES IN
SEPSIS.
THANK YOU.
>> THANK YOU, MISUK.
ANY QUESTIONS FOR THE FIRST TWO
SESSIONS BEFORE WE MOVE ON TO
THE THIRD?
OKAY.
VINNY AND --
>> YEP.
THANK YOU.
I'M GOING TO TURN IT OVER TO DRN
SESSION THREE.
>> GREAT.
THANK YOU.
FIRST OF ALL I WANT TO
CONGRATULATE EVERYONE FOR THE
AMAZING TALKS AND THE
DISCUSSIONS THAT WE'VE HAD.
IT WAS A VERY INTERESTING DAY,
AND ALSO FOR OUR SESSION WE
REALLY ENJOYED HEARING TO ALL
THE DISCUSSIONS.
I WANT TO THANK DR. LIU ALSO FOR
WORKING TOGETHER ON THIS.
SO WE'RE GOING TO BE PRETTY
BRIEF.
ONE OF THE THINGS I WANTED TO
MENTION IS THAT WE ALL FELT VERY
OPTIMISTIC AND WE THINK AS
DR. LIEW JUST MENTIONED TO ME,
WE ARE VERY HAPPY AND EXCITED
THAT WE ARE SEPSIS RESEARCHERS
AT THIS TIME, BECAUSE THE FIELD
IS PROGRESSING AND THAT'S HOW WE
WANT TO CLOSE ANYWAY, WITH SOME
OPTIMISM THAT WE'RE GOING TO BE
ABLE TO MOVE THE FIELD FORWARD.
SO IN SUMMARY, WHAT CAN A.I.
PREDICTIVE ANALYTICS DO AND WHAT
ARE SOME BARRIERS IN THEIR
ADOPTION?
SO WE HEARD FROM OUR SCIENTISTS
THAT THE PREDICTIVE TOOLS WE
HAVE ARE PROMISING.
THEY'RE NOT PERFECT, THERE ARE
SOME DEFICIENCIES, WE KNOW THAT
THERE'S STRONG CONCERNS WITH THE
SEPSIS DEFINITIONS, WITH HOW WE
USE THE DATA, THE HETEROGENEITY
OF THE CONDITION ITSELF, WHICH
CREATES A LOT OF BARRIER, A LOT
OF PROBLEM, BUT SOME EXAMPLES
WERE GIVEN.
YOU CAN SEE HERE ON THE LEFT
UPPER THAT SOME TOOLS HAVE A
GOOD PROGNOSTIC ABILITY, GOOD
SPECIFICITY, GOOD SENSITIVITY,
AND CAN HELP IN DECREASING
MORTALITY, BUT ALSO LOOKING INTO
THE SEQUELAE.
WE'RE NOT LOOKING ONLY INTO
SEPSIS MORTALITY.
THAT ACTUALLY DURING ONE OF OUR
DISCUSSIONS, IT WAS BROUGHT UP
EVEN IF WE KNOW ABOUT THE
INCREASED MORTALITY, WHAT DO WE
DO ABOUT IT.
SO WE'RE ALSO LOOKING AT THE
MORBIDITY IN THE SEQUELAE, WHICH
IS IMPORTANT.
A LOT OF HIGH PERFORMANCE
PREDICTION MODELS FOR NEW ICU
SEPSIS CAN BE DERIVED FROM A
COMBINATION OF EHR DATA AND ALSO
IT WAS MENTIONED THAT THERE ARE
OTHER MARKERS THAT COULD BE USED
ALONG WITH EHR DATA LIKE
METABOLOMICS, LIKE RNA
SEQUENCING, TRANSCRIPTOMICS AND
SO FORTH.
ADDITIONALLY, THERE WERE
DISCUSSIONS ABOUT THE UTILITY OF
THE PHENOTYPES, THE SEPSIS
PHENOTYPES.
ARE THERE ANY SIMILAR
CHARACTERISTICS IN SEPTIC
PATIENTS THAT WE COULD USE TO
GROUP THEM AND ACTUALLY TAILOR
THE TREATMENTS OR USE THEM AS --
USE THEM FOR THE PROGNOSIS IN
THE RISK ASSESSMENT OF SEPSIS.
AND WE KNOW IN MOST CASES WE
HAVE AN INFLAMMATION-BASED
SUBTYPES LIKE THE
HYPERINFLAMMATORY AND
HYPOINFLAMMATORY SUBTYPES THAT
COULD BE USEFUL IN TREATMENT AS
WELL, YOU KNOW THAT
IMMUNOMODULATORS AND IMMUNE
TREATMENTS TREATMENTS GIVEN AT T
TIME MIGHT BE BENEFICIAL BUT WE
ALSO TALKED ABOUT THE CHALLENGES
OF THOSE SUBTYPES CHANGING AS
SEPSIS PROGRESSES AND VARY WITH
TIME.
WHAT ARE SOME OF THE BARRIERS
WITH THE USE OF A.I. AND
PREDICTIVE ANALYTICS IN SEPSIS.
THERE'S SOME DISTRUST FROM THE
PROVIDERS.
THEY WANT TO MAKE SURE THE
MODELS ARE EXPLAINABLE, THAT THE
TIME FRAME IS BELIEVABLE.
THEY NEED TO BE GENERALIZABLE
AND THAT CREATES A PROBLEM
BECAUSE OF THE HETEROGENEITY
THAT WE JUST DISCUSSED IN THE
DIFFERENCES IN THE POPULATIONS
THAT ARE STUDIED.
THE ALARM FATIGUE, WE'VE SEEN
THAT MULTIPLE TIMES.
WHEN PROVIDERS RECEIVE ALERTS
EVERY TIEF MINUTES ABOUT SEPTIC
PATIENTS AND IN MANY CASES THESE
ARE NOT CORRECT, THEN --
[INTERRUPTION]
>> SORRY I'M HEARING SOME
BACKGROUND NOISE.
SO WE'VE ALL FACED ALERT FATIGUE
AND IT'S A PROBLEM THAT REMAINS.
AND BIAS AS WELL, IS THE DATA
PROCESSED IN A WAY THAT DOES NOT
INCREASE BIAS AND ARE THERE
GROUPS -- SPECIFIC GROUPS,
AGAIN, DISCRIMINATED AGAINST IF
THE DATA IS NOT CORRECT AND THEY
DON'T HAVE ACCESS, THEY DON'T
HAVE THE RIGHT TREATMENT.
SO THESE ARE THINGS TO CONSIDER
WHEN THOSE TOOLS, THE A.I. TOOLS
ARE DEVELOPED.
I'M GOING TO CLOSE WITH WHAT WE
HEARD TODAY FROM DR. BIHORAC
ABOUT THE A.I. AT HOME A AND IN
THE HOSPITAL AND HOW MANY
DIFFERENT APPLICATIONS A.I. CAN
HAVE FOR PREDICTION, DIAGNOSIS,
TREATMENT AND RECOVERY, AND
MONITORING, WHICH IS IMPORTANT,
AND WHERE DO WE MONITOR THOSE
PATIENTS?
DO WE DO IT IN THE HOSPITAL, IN
THE EMERGENCY ROOM, IN THE ICU,
IN THE WARDS, OR DO WE EVEN
START AT HOME FOR SPECIFIC
PATIENTS.
AND DEVELOPING DIGITAL TWINS
LIKE THEY HAVE AT THE UNIVERSITY
OF FLORIDA, AND WHERE WE CAN
ACTUALLY TAYLOR SPECIFIC
TREATMENTS AND LOOK AT SPECIFIC
CHARACTERISTICS OF THOSE
PATIENTS IN TERMS OF PAIN OR
MOVEMENT AND SO FORTH, THIS CAN
BE REVOLUTIONARY AND HAVING
THOSE CLINICAL BIAS SENSORS CAN
MAKE A HUGE DIFFERENCE IN THE
PREDICTION BUT ALSO IN HAVING --
IN TAILORING THOSE TREATMENTS
FOR THE SPECIFIC PATIENTS.
THERE ARE MULTIPLE MOBILE APPS
THAT HAVE BEEN DEVELOPED WITH
TEXT MESSAGING, LIVE VIDEO
CALLS, SYNCHRONOUS VIDEO CALLS,
AND A.I. ASSISTIVE COMMUNICATION
THAT CAN ALL HELP WITH
TELEHEALTH AND AGAIN TRYING TO
DIAGNOSE THOSE PATIENTS AS SOON
AS -- AS EARLY AS WE CAN, AND
THEN TAYLOR THOSE TREATMENTS TO
BE ABLE TO MOVE TOWARDS
PRECISION MEDICINE.
THANK YOU.
>> GREAT.
THANK YOU, IOANNIS AND VINNY AND
ALL THE MODERATORS AND CHAIRS,
THANK YOU FOR PROVIDING A
SUMMARY OF THE SESSIONS.
I'M HOPEFUL THAT ALL THE
AUDIENCE HAD A LOT TO TAKE AWAY
FROM EACH SESSION AS THE
SUMMARIES.
I THINK WE HAVE A FEW MINUTES IF
ANYBODY HAD ANY LAST-MINUTE
QUESTIONS FROM EACH OTHER OR
FROM ANY OF THE PANELISTS OR
SPEAKERS.
>> I HAVE A QUESTION.
SO NOW WE HEARD ABOUT ALL THE
TALKS, DISCUSSIONS AND WE HAVE
HEARD OF THE REPORT OUT, SO
FANTASTIC.
NOW MY REQUEST TO ALL OF US NOW
HERE IS THAT IF WE CAN DO ONE
THING AND ONE THING ONLY, WHAT
WOULD YOU LIKE US TO DO IN THIS
CASE TO REALLY ADVANCE THE
SEPSIS FIELD?
THANK YOU.
>> I CAN GO FIRST IF THAT'S
OKAY.
I WOULD SAY, YOU KNOW, REGARDING
UNDERSTANDING MECHANISMS OF
DISPARITIES IN SEPSIS, ONE OF
THE MAIN CHALLENGES IS DATA.
SO WE HAVE ON THE ONE HAND VERY
LARGE ADMINISTRATIVE DATA THAT
LACKS GRANULAR VARIABLES RELATED
TO EQUITY SO WE CAN'T EVEN
MEASURE AN INDIVIDUAL'S INCOME
OR WEALTH, FOR EXAMPLE, IN THOSE
SORTS OF DATA.
ON THE OTHER HAND, WE HAVE THE
EHR DATA WHICH ARE VERY DETAILED
BEEN NOT GENERALIZABLE, SO IT
STRIKES ME THAT SOMETHING IN THE
MIDDLE IS NEEDED, LIKE SOME SORT
OF REGISTRY THAT INCLUDES
VARIABLES RE VA RELEVANT TO SOCL
DETERMINANTS OF HEALTH THAT'S
GRANULAR BUT ALSO HAS THE
NECESSARY BREADTH.
>> ONE THING I WOULD ALSO ADD TO
THAT, THE NIH CAN HELP WITH
HAVING MORE -- BRINGING ALL THE
SCIENTISTS TOGETHER, DATA FROM
SINGLE INSTITUTION OR FROM TWO
INSTITUTIONS, NOT THAT GREAT.
URGENCY IN SEPSIS IS THERE, IT'S
EVIDENT, AND WE NEED TO STUDY
MULTIPLE DIFFERENT POPULATIONS.
THERE ARE MANY DIFFERENT
UNDERLYING CONDITIONS AND
SOCIOECONOMIC CONDITIONS AS
WELL, SO WE NEED TO MAKE SURE
THAT ALL THE STUDIES INCLUDE
DIFFERENT POPULATIONS, DIVERSE
POPULATIONS FROM THROUGHOUT THE
COUNTRY, AND IT WOULD BE GREAT
TO BRING SCIENTISTS AND SCIENCE
TOGETHER FOR MULTISITE STUDIES
TO TACKLE THAT.
>> AZRA.
>> FIRST OF ALL I WANT TO THANK
YOU FOR PUTTING US ALL IN ONE
ROOM.
THAT WAS A FANTASTIC WORKSHOP.
I WANT TO SAY, I'M A PART OF THE
BRIDGE TO A.I. COMMON FUND.
ONE OF OUR DATA GENERATION
PROJECTS IS A CHORUS OF ICU
COHORTS OF 100,000 PATIENTS FROM
10 INSTITUTIONS, WITH NOT
PARTICULAR FOCUS ON SEPSIS, BUT
WILL INCLUDE SEPSIS.
BUT IT WILL CREATE A NETWORK I
THINK THAT CAN GO IN ENRICHMENT,
BECAUSE WE SPOKE WITH COMMON
FUND SAYING WE NEED TO ENRICH
FOR CERTAIN CONDITIONS AND WE
NEED TO GO DEEPER BIOLOGICAL
SAMPLING FOR THOSE COHORTS, AND
I THINK THAT COULD BE
INTERACTION BETWEEN THE
INSTITUTES.
I THINK OF TWO -- IF I WANT TO
GO MORE GRANULAR DEEPER, I WILL
GO IN KIDNEY, LUNG AND HEART.
LIKE IN THE SEPSIS, WE NEED TO
HAVE A DEEPER BIOLOGICAL
UNDERSTANDING OF THESE ORGANS'
ROLE IN THE SEPSIS.
I GET NIGMS, THEY NEVER WANT TO
HEAR ABOUT ORGANS.
I THINK THIS IS A GREAT IDEA TO
START BUILDING ON WHAT WE HAVE
ALREADY BUILT WITH COMMON FUND.
>> VINNY?
>> I AGREE WITH ALL OF THAT.
I ALSO THINK WE NEED TO EXPAND
THE STAKEHOLDERS AND THE SEPSIS
DISCUSSION.
IF WE'RE REALLY GOING TO MOVE
UPSTREAM, WE HAVE TO INCLUDE THE
DATA SOURCES, THE
INSTRUMENTATION, AND THE PEOPLE
WHO WORK IN THOSE ENVIRONMENTS,
INCLUDING THE PATIENTS.
SO I KNOW IT'S A LITTLE BIT OF A
DIVERGENCE, IT CAN BE ALSO VERY
MESSY AS YOU MOVE UPSTREAM
BECAUSE PEOPLE -- THERE'S SO
MANY TRAJECTORIES, BUT WE JUST
DON'T HAVE INSIGHT AT SCALE, I
DON'T THINK, TODAY ABOUT WHAT'S
HAPPENING IN THOSE CONTEXTS,
ESPECIALLY WHEN WE THINK ABOUT
DISPARITIES AND COMMUNITY LEVEL
INPUTS INTO ACUTE SEVERE
ILLNESS.
SO I DO THINK WE CAN EXPAND IN
THAT DOMAIN.
IT'S GOING TO BE CRITICALLY
IMPORTANT IF WE'RE GOING TO GET
TO THE INJURY ITSELF.
AS EARLY AS WE CAN, EVEN BEFORE
PATIENTS GET TO THE HOSPITAL.
>> FANTASTIC.
ANYTHING ELSE?
>> I HAVE ONE QUESTION OUT OF
CURIOSITY BECAUSE WE HAVE SO
MANY CLINICIANS HERE AS WELL, AS
WELL AS VINNY FROM KAISER.
SO HE COULD PROBABLY SPEAK FROM
THE HEALTH INSURANCE POLICIES
STANDPOINT.
MY MOM RECENTLY WAS HOSPITALIZED
A COUPLE OF YEARS BACK AND SHE
HAD CANCER, BUT THEN SHE HAD
INFECTION IN HER BLOOD AND WE
TOOK HER TO THE HOSPITAL JUST
BECAUSE OF THAT.
AND SHE WAS GIVEN A VERY HIGH
DOSE ANTIBIOTIC, OVERNIGHT SHE
WENT INTO DELIRIUM AND AFTER A
FEW WEEKS, SHE PASSED AWAY.
SO WHEN IT COMES TO
ACCOUNTABILITY -- AND WHEN SHE
HAD THE INTERNAL BLEEDING, SHE
WAS NOT BEING GIVEN BLOOD
TRANSFUSION UNTIL HER HEMOGLOBIN
LEVEL WAS FALLING BEYOND A
CERTAIN THRESHOLD.
SO IS THAT A STANDARD PRACTICE
IN SEPSIS ALSO OR IN GENERAL, OR
WHERE DOES THAT ACCOUNTABILITY
COME INTO PLACE LIKE THAT?
>> WELL, I THINK THAT IS, AS WE
HEARD EARLIER, SOME OF THE PUSH
THAT'S HAPPENED IN SEPSIS OVER I
WOULD SAY THE PAST ONE OR TWO
DECADES, IS TRY TO STANDARDIZE
PRACTICE, SO THAT WE ARE AT
LEAST ALIGNING MORE TO
STANDARDS.
I THINK WHAT WE'RE FINDING IS
THAT THE ONE SIZE FITS ALL, YOU
KNOW, THAT AT THIS THRESHOLD OR
THAT THRESHOLD, WE SHOULD DO
THIS OR THAT, FLUIDS, BLOOD
TRANSFUSION, ANTIBIOTICS, ET
CETERA.
SO I WOULD SAY, THERE'S BEEN A
LARGE PUSH TOWARDS STAND DAITION
IN ORDER TO DELIVER TIMELY AND
EFFECTIVE CARE, AND NOW WE'RE IN
THAT DOMAIN OF PRECISION, WHICH
IS THAT WE REALLY HAVE TO
INDIVIDUALIZE CARE, AND ONCE
WE'VE GOTTEN KIND OF THE RISING
TIDE TO LIFT ALL BOATS IN TERMS
OF OUR EARLY DETECTION AND
AGGRESSIVE INTERVENTIONS, NOW
LIKE WE'RE REALIZING THOSE ARE
INSUFFICIENT.
SO NOT KNOWING TOO MUCH ABOUT
THE PERSONAL OR INDIVIDUAL
DETAILS THERE, IT'S ALWAYS A
TENSION TO TRY TO STAY WITHIN
LARGER GUIDELINES, BUT
INDIVIDUALIZE THE CARE BASED ON
WHAT'S HAPPENING IN FRONT OF YOU
AT THE BEDSIDE.
>> DEEP, GO AHEAD.
>> I'M SO SORRY THAT THAT
HAPPENED WITH YOUR MOM FIRST OF
ALL.
SECONDLY, I WOULD SAY YES,
ACCOUNTABILITY IS HELPFUL.
IT REALLY MATTERS HOW WE HOLD
HOSPITALS ACCOUNTABLE TO THE
CURRENT SYSTEM, WE PENALIZE
HOSPITALS FOR NOT MEETING
CERTAIN QUALITY METRICS, AND
RELEVANT TO DISPARITY, ONE THAT
HAS BEEN SHOWN IS THAT LOWER
RESOURCE HOSPITALS ARE MUCH LESS
LAKELY TO CONSISTENTLY MEET
THOSE QUALITY METRICS BECAUSE
THEY HAVE FEWER RESOURCES TO
INVEST IN AIR-TIGHT CARE
PROCESSES, AND THEN THEY GET
PENALIZED AND THEN THEY HAVE
FEWER RESOURCES.
SO IT'S THIS VICIOUS CYCLE.
AND I WONDER IF THERE IS A WAY
INSTEAD TO REWARD HOSPITALS THAT
DO A GOOD JOB RATHER THAN
INSTITUTE PENALTIES.
THAT WOULD BE ONE IDEA.
THE OTHER IDEA IS THAT WE DIDN'T
GET TO TALK MUCH WHEN JOHN
DONELY WAS HERE BUT I WAS
CURIOUS TO ASK HIM ABOUT THE
MICHIGAN HOSPITAL MED SIB SAFETY
CONSORTIUM IN MICHIGAN BECAUSE I
THINK THEY HAVE -- BLUE CROSS IS
A RELATIVE MONOPOLY IN THE STATE
OF MICHIGAN AND THEY'RE ABLE TOO
INCENTIVIZE GROUPS OF HOSPITALS
TO MEET QUALITY METRICS, SO IT'S
NOT THAT THE VERY WELL RESOURCED
UNIVERSITY OF MICHIGAN ALWAYS
DOES A GOOD JOB, BUT THEY ALSO
HAVE TO BE RESPONSIBLE FOR OTHER
HOSPITALS IN THEIR COMMUNITY SO
THEY'RE REWARDED BASED ON
AGGREGATE OUTCOMES FOR AN ENTIRE
REGION.
AND I THINK THAT'S JUST A GREAT
MODEL BECAUSE THEN HOSPITALS
SHARE BEST PRACTICES BETWEEN
EACH OTHER AND I THINK THOSE ARE
REALLY TWO MODELS WE NEED TO
WORK TOWARDS, MAIBL POTENTIALLY
INSTEAD OF PENALIZING REWARDING
AND THEN ENCOURAGING HOSPITALS
TO WORK COLLABORATIVELY.
>> THAT'S GREAT MODEL.
THANKS FOR SHARING.
PATRICIA.
>> I JUST WANTED TO ADD FROM THE
BASIC SCIENCE PERSPECTIVE, I
THINK IT WOULD BE GREAT TO
ENCOURAGE A BIDIRECTIONAL LINK
BETWEEN THE BASIC RESEARCHERS
AND THE CLINICIANS, AND FOR
TRANSLATIONAL STUDIES IN THE
FIELD OF SEPSIS, THERE ARE, I
THINK, MISSED OPPORTUNITIES TO
COLLECT BIOLOGICAL SPECIMENS AND
OFTEN WHEN THEY'RE COLLECTED,
THEY'RE COLLECTED AT A SINGLE
TIME POINT.
SO AT ICU ADMISSION.
BUT BEING ABLE TO BETTER
UNDERSTAND THE TEMPORAL CHANGES
THAT HAPPENS IN THE IMMUNE
SYSTEM AS A PATIENT RECOVERS OR
DOES NOT, I THINK THERE'S A LOT
OF VALUE IN THAT, AND BEING ABLE
TO LINK THE CLINICAL DATA WITH
THE BIOLOGICAL DATA WOULD BE I
THINK, A HUGE IMPROVEMENT IN THE
WAY THAT WE UNDERSTAND SEPSIS
PATHOPHYSIOLOGY.
>> THANK YOU, PATRICIA.
SO I REMEMBER YOU MENTIONED
WHETHER U.S. HAS A SEPSIS CANADA
LIKE CONSORTIUM.
SO LAST YEAR'S STUDY, THE APS
CONSORTIUM PARTICULARLY
MENTIONED THE -- APS CONSORTIUM
COLLECTING MULTIPLE TIME POINTS,
THAT'S WHAT WE ARE TRYING TO DO,
BUT IT'S ALSO LIKE ALL OF US
DISCUSSED TODAY, IT'S VERY
CHALLENGING.
BUT -- SO WE ARE WORKING ON
THAT.
ALL RIGHT, IT'S ALMOST ON TOP OF
HOUR.
I WOULD LIKE TO TAKE THIS
OPPORTUNITY TO THANK YOU ALL.
IT HAS BEEN A WONDERFUL DAY.
IT IS LONG BUT IT'S A WONDER --
A LOT OF INFORMATION, A LOT OF
IDEAS, CONCEPTS, NEW IDEAS
COMING OUT.
I THINK THE DISCUSSION WAS
FANTASTIC.
I WANT TO SEND EACH OF YOU, OUR
SPEAKERS, MODERATORS, CHAIRS AND
ATTENDEES, AND I WANT TO ALSO
GIVE A BIG SHOUT OUT FOR OUR AV
TEAMS AND WORKSHOP -- NHLBI
WORKSHOP THAT HAVE BEEN WORKING
WITH US FROM THE VERY BEGINNING
FROM THE GRAPHIC DESIGN, THE AV
AND ALL THE LOGISTICS OF
PLANNING.
JOSHUA HAS BEEN LEADING THAT
EFFORT SO I WANT A BIG SHOUT OUT
FOR HIM AS WELL.
SO REGARDING FOR NEXT STEPS, OUR
WORKSHOP IS CLOSE TO END, BUT
OUR JOB IS NOT DONE YET.
SO FOR SPEAKER, MODERATORS AND
CHAIRS, WE WILL REACH OUT LATER
FOR A WHITE PAPER.
SO FOR THE FUTURE DEVELOPMENTS,
SO AS WE ALL DISCUSSED, SO
THE -- SEPSIS -- THE -- IS GOING
TO BE A LONG JOURNEY, A
CHALLENGING JOURNEY, ALTHOUGH
EVERYBODY EXPRESSED SOME
OPTIMISM, BUT I DON'T THINK
ANYBODY IS GOING TO LOSE THEIR
JOB ANYTIME SOON.
SO WE'RE STILL GOING TO BE
WORKING ON THAT, AND WE ARE HERE
TO HELP YOU IN ANY WAY WE CAN TO
HELP ADVANCE THE FIELD, TO HELP
OUR PATIENTS.
SO ANY TIME IF YOU HAVE ANY
THOUGHTS, IDEAS, REACH OUT TO
US, SO SEPSIS IS A BIG TOPIC.
IT'S NOT LIMITED TO BLOOD
DIVISION, IT'S ALSO A BIG
PORTFOLIO IN THE LUNG DIVISION,
IN THE HEART DIVISION, AS MANY
OF YOU MENTIONED ABOUT KIDNEY AS
WELL, SO ANYTHING YOU THINK THAT
WILL HELP US HELP THE PATIENT,
PLEASE REACH OUT TO US.
WE ARE HERE TO HELP YOU, TO HELP
OUR PATIENTS.
SO WITH THAT, I WANT TO GIVE THE
FINAL THANK YOU TO YOU ALL, AND
CLOSE OUT OF THE SESSION.
SO NOW THE WORKSHOP IS
ADJOURNED.
THANK YOU.
>> CAN I -- CAN I ALSO SAY
SOMETHING?
>> SURE.
>> ONE OF THE FOCUS AREAS OF
THIS WORKSHOP -- ONE OF THE
OBJECTIVES OF THIS WORKSHOP WAS
TO FOSTER COLLABORATIONS, SO IF
ANY OF YOU START A NEW
COLLABORATION OR IF YOU FEEL
THAT IT REALLY HELPED YOU IN
FINDING NEW PROJECTS TOGETHER
AFTER LEARNING NEW THINGS,
PLEASE LET US KNOW LATER.
THANK YOU ALL VERY MUCH.