WELCOME BACK TO THE WORKSHOP ON
THE SEX GENDERS SPECIFIC
COVID-19 OUTCOMES AND MANAGEMENT
RELEVANT FOR HEART, LUNG, BLOOD
AND SLEEP DISORDERS FROM BENCH
TO BEDSIDE.
SO BEFORE WE START WITH TODAY'S
AGENDA, I WOULD LIKE TO REMIND
BUT SEVERAL HOUSEKEEPING RULES.
SO, PLEASE STAY OFF CAMERA AND
MIKE IF YOU DO NOT SPEAK.
FOR SPEAKERS, PLEASE TURN ON
YOUR CAMERA AT THE END OF THE
TALK BEFORE YOURS AND BE READSY
TO IMMEDIATELY SHARE YOUR SLIDES
WHEN THE PREVIOUS TALK ENDS.
FOR EVERYONE, PLEASE POST YOUR
QUESTION INTO THE Q&A POD AND
USE CHAT FUNCTION FOR MESSAGING,
SO, PLEASE USE THE OPTION TO
SEND YOUR MESSAGES TO EVERYONE
OR TO THE HOST AND PANELISTS
EXCEPT IF YOU WOULD LIKE TO SEND
A PRIVATE MESSAGE AND I WOULD
ALSO LIKE TO ANNOUNCE A SLIGHT
CHANGE IN THE AGENDA.
AFTER SESSION 6, WE WILL GO
FIRST TO THE SUMMARY OF DAY 2
GIVEN BY DR. KANTHI AND THEN WE
WILL GO TO BREAK OUT SESSIONS,
SO THE BREAK OUTS WILL START
AROUND 3:15 THIS AFTERNOON.
THE ZOOM LINK FOR THE BREAK OUT
ROOMS WILL BE FREQUENTLY POSTED
IN THE CHAT.
YOU SHOULD ALSO RECEIVED BY
E-MAIL SENT YESTERDAY.
PANELISTS HAVE THEIR ASSIGNMENTS
ALREADY AND AFTER THESE WE CAN
CHOOSE WHICH ROOM TO JOIN.
AT THIS TIME, I WOULD LIKE TO
TURNOVER THIS MEETING TO
DR. SANDBERG TO GIVE A SUMMARY
OF DAY 1.
TAKE IT AWAY.
>> THANK YOU JASMINA AND ALL OF
US OWE A GREAT THINKS IT TO HER
FOR PUTTING TOGETHER THIS
INCREDIBLE WORKSHOP THAT WE
ALREADY HAD A WONDERFUL DAY
YESTERDAY EXPERIENCING AND IT IS
MY JOB TO TRY TO SUMMARIZE THE
RICHNESS OF ALL THE
CONVERSATIONS AND PRESENTATIONS
YESTERDAY.
SO WITH THAT I WILL START WITH
THE FIRST SLIDE.
AND WE KICKED OFF THE WORKSHOP
WITH DAVID GOFF WHO IS THE
DIRECTOR OF CARDIOVASCULAR
SCIENCES AT NHLBI AND HE WANTED
TO EMPHASIZE THE COMMITMENT
NHLBI HAS TO UNDERSTANDING THE
IMPACT OF SEX AND GENDER IN
CARDIOVASCULAR DISEASE, HEART,
LUNG, AND BLOOD AND SLEEP
DISORDERS.
AND THEN WE HAD A PRESENTATION
BY DR. JANINE AUSTIN CLAYTON WHO
IS DIRECTOR OF THE OFFICE OF
RESEARCH ON WOMEN'S HEALTH AND
SHE EXPLAINED HOW NIH THINKS
ABOUT DEFINED SEX AND GENDER AND
THE IMPORTANCE IN BIOLOGICAL
STUDIES AND CLINICAL TRIALS AND
CLINICAL RESEARCH.
NEXT SLIDE.
SO THEN WE HAD--WE WERE REALLY,
REALLY AND THIS WAS JUST A
WONDERFUL ADDITION TO THIS
WORKSHOP.
WE HAD INDIVIDUALS WHO ARE
HIGHLY DEDICATED TO THE
UNDERSTANDING COVID AND THEY
SHARED WITH US THEIR PERSONAL
EXPERIENCE WITH COVID.
AND IT WAS VERY BRAVE OF THEM
AND EXTREMELY VALUABLE FOR THE
BASIC SCIENTISTS AND THE
CLINICAL INVESTIGATORS TO HEAR
HOW THEY EXPERIENCE COVID AND
LONG COVID AND IT REALLY PUT IN
PERSPECTIVE WHAT ALL THE
SYMPTOMS WERE AND ALL THEIR
CHALLENGES AND CAN I HAVE THE
NEXT SLIDE.
SO WHAT I TOOK FROM THESE
INDIVIDUALS GENEROUS SHARING OF
THEIR EXPERIENCES IS THAT WE ALL
SHOULD REALLY LISTEN TO THE
PATIENT, WE SHOULD ALWAYS LISTEN
TO THE PATIENT, THE SCIENTISTS,
THE CLINICIAN, WE ALL NEED TO
LISTEN TO THE PATIENT AND OUR
JOB AS SCIENTISTS IS TRY TO MOVE
FORWARD, TO FRONTIERS OF
HEALTHCARE AND IF WE DON'T
LISTEN TO THE PATIENT, THEN
MAYBE WE'RE NOT STUDYING THE
RIGHT MODEL.
AND ANOTHER POINT THEY MADE IS
THAT WE HAVE TO FOCUS ON THE
CONSTELLATION OF SYMPTOMS AND
NOT JUST TREAT 1 SYMPTOM
INDIVIDUALLY BUT ABOUT IT AS THE
WHOLE CONSTELLATION.
AND THEN A THIRD POINT THAT WAS
RAISED BY ALL OF THEM IS THAT
THE AMOUNT OF STRESS THAT THEY
ENDURED REALLY HAD AN IMPACT, A
NEGATIVE IMPACT ON THE DISEASE
AND THERE WAS THE STRESS FROM
BEING 1'S OWN ADVOCATE, FROM THE
HURDLES, INITIALLY THERE WERE NO
ICD CODES SO THEY HAD A LOT OF
TROUBLE GETTING THEIR TREATMENT
COVERED AND IT WAS ALSO THE
STRESS OF BEING A MEMBER FROM A
MARGINALIZED COMMUNITY.
AND THE MAJOR TAKE HOME THAT I
THINK A LOT OF US GOT FROM
LISTENING TO THESE INDIVIDUAL
SYSTEM THAT WE REALLY, ALM OF
US, THE CLINICIANS, THE BASIC
SCIENTISTS, THE CLINICAL
INVESTIGATORS, WE REALLY BENEFIT
FROM ENGAGING THESE DEDICATED
STAKEHOLDERS, STAKEHOLDER IN THE
WHOLE SCIENTIFIC PROCESS FROM
START TO FINISH.
NEXT SLIDE.
SO THEN WE BEGAN, WE KICKED OFF
THE WORKSHOP WITH THE KEY NOTE
SPEAKER BY DR. OERTELT-PRIGIONE,
AND SHE GAVE SEVERAL EXAMPLES OF
HOW SEX CAN REALLY IMPACT
COVID-19 SUSCEPTIBILITY,
PROGRESSION AND THE RESPONSE TO
TREATMENT.
BUT ALSO HOW GENDER RELATED
FACTORS CAN IMPACT THESE VERY
SAME ASPECTS OF COVID-19.
AND THAT WE--THEY ARE SEPARATE
BUT THEY'RE ALSO--THEY ALSO
INTERSECT AND SO THAT WE NEED
NEED TO BE AWARE OF THIS
INTERSECTIONALITY BETWEEN SEX
AND GENDER AND TO GIVER YOU AN
EXAMPLE, OKAY, SO, SEX MIGHT
AFFECT THE VIRUS REPRODUCTION OR
THE DISTRIBUTION OF THE RECEPTOR
FOR THE VIRUS OR THE ANTIBODY
RESPONSE TO THE VIRUS BUT--AND
GENDER COULD AFFECT THE EXPOSURE
TO THE VIRUS, THE ACCESS TO
POTENTIAL THERAPEUTICS AND
PROTECTIVE EQUIPMENT AND ALSO IN
COMPLIANCE, THERE'S
SEX--DIFFERENCES BETWEEN MEN AND
WOMEN IN TERMS OF COMPLIANCE,
AND THEN THERE'S THE
INTERSECTION, YOU KNOW, WHO
MANAGES THE--WHO'S THE FIRST
RESPONDER SO THEY HAVE AN
INCREASED RISK BECAUSE OF THAT
AND THEN THE DECISION MAKERS,
THE DECISION MAKERS WHO ARE
ACTUALLY IMPACTING WHAT RESEARCH
GETS DONE AND WHAT GETS, YOU
KNOW WHAT KIND OF FOCUS THERE
SHOULD BE SO THE TAKE HOME IS WE
SHOULD DO A BETTER JOB BY
DISAGGREGATING OUR DATA BY SEX
AND GENDER AND BY RACE AND
ETHNICITY AND MARGINALIZED
COMMUNITIES.
WE HAVE ALL THIS DATA.
WE REALLY NEED TO DISAGGREGATE
IT SO THAT WE CAN ANALYZE IT TO
SEE WHAT THESE--HOW THESE
FACTORS IMPACT THE OUTCOMES.
THE NEXT SLIDE SHOWS OUR SESSION
1 SPEAKERS AND THIS SESSION WAS
MODERATED BY MARK CHAPPELL, AND
WE HAD STANLEY PERLMAN, DAN
BAROUCH, EILEEN SCULLY, AND JOHN
TSANG AND WHAT WE TOOK HOME FROM
THIS SESSION WAS SEVERAL POINTS,
FIRST OFLL THAT THE RENIN
ANGIO TENSIN SYSTEM IS A
CRITICAL COMPONENT OF COVID-19
PATHOLOGY AND IT'S NOT JUST
CONVERTS ENZYME 2, OTHERWISE
KNOWN AS ACE 2 AND A MAJOR
COMPONENT OF THE RENIN ANGIO
TENSINSYSTEM, IT'S NOT JUST THAT
IT'S THE VIRUS WHICH IS I
CRITICAL COMPONENT FOR THE VIRUS
TO GET INTO THE CELL AND INTO
THE BODY BUT ALSO THAT THIS
SYSTEM IS THEN REGULATED BY THE
COVID-19 AND IT PLAYS A CRITICAL
ROLE IN OUTCOMES AND RESPONSE TO
TREATMENT THEY'RE NOT GOING TO
HELP US WITH ALL THE QUESTIONS
THAT ARE IMPORTANT FOR
UNDERSTANDING HUMAN DISEASE BUT
THEY'RE REALLY HELPFUL TO
UNDERSTAND SOME OF THE
MECHANISMS THAT SAID WE REALLY
NEED TO KNOW MORE ABOUT HOW SEX
HORMONES AND SEX CHROMOSOMES CAN
IMPACT DISEASE AND USING THESE
ANIMAL MODELS COULD HELP US GET
SOME CLUES THAT COULD THEN
INFORM CLINICAL STUDIES.
BUT THESE ANIMAL MODELS NEED TO
BE FURTHER REFINED.
WE DON'T--MOST BASIC SCIENTISTS
HAVE BEEN STUDYING MICE AND RATS
AND YET THEY DON'T--UNLESS
THEY'RE MODIFIED THEY DON'T GET
COVID AND SO THERE ARE OTHER
MODELS OUT THERE LIKE HASMSTERS
AND FERRETS AND WE HAVE VERY
LITTLE DATA ON THESE ANIMALS,
ANIMALS THAT DO GET COVID.
SO WE NEED TO SPEND MORE TIME ON
OUR ANIMAL MODEL SO WE CAN ASK
THESE QUESTIONS THAT WILL THEN
INFORM CLINICAL STUDIES.
AND THEN THERE ARE NO LONG COVID
ANIMAL MODELS AND THESE NEED TO
BE DEVELOPED BECAUSE LONG COVID
IS TURNING OUT TO BE A REAL
CONCERN AND IT'S A MAJOR CONCERN
AND WE REALLY NEED WAYS TO STUDY
IT.
AND THEN ANOTHER KEY POINT FROM
THIS SESSION IS THAT THERE ARE
SOME DIFFERENCES IN IMMUNE
RESPONSE BUT WE REALLY BUT WE
SEE IN THE ANIMAL STUDIES BUT WE
DON'T KNOW THE CLINICAL
RELEVANCE AGAIN.
AGAIN, THE ANIMAL STUDIES ARE
HELPFUL AND INFORMING CLINICAL
RESEARCH AND THEN THE CLINICAL
RESEARCH ALSO IS VERY HELPFUL IN
INFORMING HOW WE DESIGN OUR
CLINICAL BASIC SCIENCE STUDIES.
THIS WAS WAY PRIOR TO THE
VARIANTS EMERGED SO IT'S ALMOST
AS IF WE HAVE TO START OVER AND
SEE HOW VACCINE EFFECTS EFFICACY
WHEN WE'RE NOT AT PEEK IMMUNITY
AND ALSO WHAT ABOUT THE DURATION
OF THE ILLNESS AND HOW DO THESE
VACCINES PROTECT US FROM EBE
MERGING VARIANTS AND HOW THEY
NEED TO BE DONE.
NEXT SLIDE.
SO SESSION 2 FOCUSED ON SECIAL
DETERMINANTS OF HEALTH IMPACTS
ON GENDER RELATED COVID-19 HEART
LUNG AND BLOOD SLEEP DISORDER
OUTCOMES AND WE--THIS SESSION
WAS MODERATED BY
DR. SHATTUCK-HEIDORN AND 1 OF
THE KEY QUESTIONS IN THIS
SESSION WAS HOW DO KEY
DETERMINANTS IMPACT OUTCOMES.
NEXT SLIDE.
AND SO WHEN WE TALK ABOUT SOCIAL
DETERMINANTS WE TALK ABOUT MANY,
MANY FACTORS SO RESEARCHERS NEED
TO CONSIDER HOW SEX AND GENDER
IS GOING WAY BEYOND HORMONES,
BUT LOOK AT GENDERED EFFECTS,
FOR EXAMPLE, THE PSYCHOSOCIAL
STRESS AND WE HEARD ABOUT THIS
PSYCHOSOCIAL STRESS IN OUR
INDIVIDUALS WHO CAME AND TALKED
TO US ABOUT THEIR EXPERIENCE
WITH COVID, WE HEARD ABOUT IT
FROM EACH 1 OF THEM.
TREMENDOUS, TREMENDOUS
PSYCHOSOCIAL STRESS WITH
DIFFERENT REASONS AND WE NEED TO
CONSIDER THAT AS SCIENTISTS.
BECAUSE SOCIAL DETERMINANTS OF
HEALTH, A LOST IT IS ABOUT THE
STRESS OF THESE SOCIAL
DETERMINANTS, THE FINANCIAL
STRESSORS AND OTHER STRESSORS.
WE ALSO NEED TO IMPROVE OUR--THE
WAY WE DEFINE AND OPERATIONALIZE
THE TERMS OF GENDER, AND WE NEED
TO INCLUDE SEXUAL ORIENTATION
AND GENDER IDENTITY VARIABLES.
IT'S NOT JUST MEN AND WOMEN.
THERE'S SO MUCH MORE THERE.
THERE'S TRANS--THE
TRANSCOMMUNITY AND THE
TRANSCOMMUNITY AND HAVE YOU THE
INTERSEX COMMUNITY AND YOU HAVE
INDIVIDUALS WHO HAVE DIFFERENT
GENDER HORMONE AFFIRMING
TREATMENTS AND YOU HAVE
DIFFERENCES IN TIMING OF WHEN
THESE TREATMENTS BEGAN AND
THERE'S JUST MANY ASPECTS THAT
WE REALLY--WE REALLY NEED TO
CONSIDER WHEN WE'RE THINKING
ABOUT SOCIAL DETERMINANTS OF
HEALTH AND HOW--HOW WE THINK
ABOUT GENDER AND BIOLOGICAL SEX
AND THESE GENDER IDENTITY
VARIABLES.
WE ALSO NEED TO DO A BETTER JOB
AT ENGAGING THE COMMUNITY IN OUR
RESEARCH.
WE NEED REPRESENTATIONOT STUDY
TEAM AND DECISION MAKING.
IT REALLY WELL HELP US, FIRST OF
ALL INFORM THE DESIGN OF OUR
RESEARCH TO UNDERSTAND THE
IMPORTANT ASPECTS THAT WE REALLY
NEED TO FOCUS ON AND WE NEED TO
TRUST OF THESE INDIVIDUALS.
AND SO THE ONLY WAY YOU CAN
REALLY BUILD TRUST IS TO ENGAGE
AT THE BEGINNING OF YOUR
STUDIES, YOU NEED TO GAUGE THE
COMMUNITY WITH YOUR RESEARCH AND
THEN WE ABSOLUTELY HAVE TO HAVE
LONGITUDINAL DATA, A SNAPSHOT IS
JUST NOT SUFFICIENT TO REALLY
UNDERSTAND THESE OUTCOMES.
AND WHEN WE'RE TALKING ABOUT
CARDIOVASCULAR AND LUNG AND
BLOOD AND SLEEP DISORDERS, WE
REALLY NEED TO THINK LONG-TERM
AND SOCIAL DETERMINANTS OF
HEALTH, PLACE, CONTEXTURAL
FACTORS AND THE
INTERSECTIONALITY REALLY HAVE A
PROFOUND INFLUENCES ON OUTCOMES
AND THEY MUST BE CONSIDERED.
NEXT SLIDE.
SO THAT LAST SESSION OF THE DAY,
FOCUSED ON PREGNANCY AND OTHER
CONDITIONS THAT AFFECT THE
SUSCEPTIBILITY TO SARS COV 2,
AND DR. GAROVIC WAS THE
MODERATOR OF THIS OUTSTANDING
SECTION.
CAN I HAVE THE NEXT SLIDE AND
SEVERAL, SEVERAL POINTS WERE
MADE DURING THIS SESSION.
ONE IS THAT THE EPIDEMIOLOGY
THAT WE HAVE SO FAR AND WE DON'T
HAVE A LOT YET IT SUGGESTS THAT
ESTROGEN, ESTRADISCIPLINARY
OLDER PEOPLE AND PROGESTERONE
THERAPY COULD ACTUALLY HAVE A
PROTECT EVALUATION PROCESS
EFFECT IN COVID-19 WHICH HAS
IMPLICATIONS FOR TO TENTIAL
THERAPEUTIC STRATEGIES.
POLYCYSTIC OVARY SYNDROME, THIS
IS A CONDITION THAT AFFLICTS
WOMEN AND IT'S A POTENTIAL RISK
FACTOR FOR COVID-19 SEVERITY AND
WE REALLY NEED TO UNDERSTAND WHY
AND AND BY UNDERSTANDING WHY, WE
MAY FIND CLUES FOR NEW
THERAPEUTIC STRATEGIES FOR
COVID.
AND THIRD THAT COVID-19, IT
INCREASES THE RISK OF MATERNAL
MORBIDITY AND MORTALITY, THE
RESK OF PREELAMPSIA AND OTHER
HYPER TENSIVE DISORDERS OF
PREGNANCY AND INCREASES THE RISK
OF ADVERSE NEONATAL OUTCOMES.
SO FINALLY THE TAKE HOME FROM
SESSION 3 IS THAT WE REALLY
DON'T KNOW MUCH.
WE DON'T KNOW ENOUGH ABOUT THE
IMPACT OF SEX HORMONES AND
PREGNANCY IN COVID-19, THERE'S
JUST NOT ENOUGH DATA ON YOU KNOW
WHAT'S HAPPENING, HOW THESE SEX
HORMONES, ESTROGEN,
PROGESTERONE, HOW THE STATE OF
PREGNANCY IMENT PACTS THE
STABILITY OF THE DISEASE,
PROGRESSION OF THE DEC, RESPONSE
TO TREATMENT, THE LONG-TERM
EFFECTS ON THE HEART LUNG BLOOD
AND SLEEP SEQUELA AND THERE'S
INSUFFICIENT DATA IN THIS REGARD
WITH LONG COVID.
AND WE REALLY DON'T KNOW MUCH
ABOUT THE MATERNAL COVID-19 AND
IT'S IMPACT ON OFFSPRING.
GONADAL HORMONE THERAPY HAS SOME
THERAPEUTIC POTENTIAL, IT'S
HINTED AT BY STUDIES THAT ARE
ONGOING AND WE NEED TO EXPLORE
THAT FURTHER AND GENDER
AFFIRMING HORMONAL THERAPY COULD
ACTUALLY OFFER US A NATURAL
EXPERIMENT TO GIVE US SOME
INFORMATION ABOUT THE OUTCOMES
AND ALSO AGAIN AS A POTENTIAL
FOR THERAPEUTICS FOR COVID-19
FOR THE GENERAL POPULATION.
AND WITH THAT I WILL TURN IT
OVER TO DR. KANTHI WHO WILL TAKE
US TO THE NEXT SESSION, SECTION
4.
>> WONDERFUL, THANK YOU VERY
MUCH DR. SANBBERG.
I THINK THAT WAS REALLY AN
EXCITING DAY YESTERDAY AND THANK
YOU FOR THE GREAT SUMMARY OF DAY
1 SESSIONS AND DISCUSSION.
SO TODAY AS YOU HEARD EARLIER
FROM OUR ORGANIZERS, WE ARE
BREAKING THE DAY UP INTO 3
SEPARATE SESSIONS, AND THAT WILL
BE FOLLOWED BY A SUMMARY OF THE
DAY AND THEN SOME BREAK OUT
ROOMS, SO OUR FIRST SESSION FOR
THE DAY HERE WHICH IS SESSION
NUMBER 4 OF THE WORKSHOP IS
CARDIOVASCULAR AND METABOLIC
ASPECTS OF COVID-19 AND HOW SEX
AND GENDER CONSIDERATIONS MAY
PLAY A ROLE IN THIS.
SO I WOULD LIKE TO INTRODUCE OUR
MODERATOR FOR THE SESSION,
DR. DELISSA FAIRWEATHER, SHE'S A
DIRECTOR OF MEDICINE AND
TRANSLATIONAL RESEARCH IN THE
DEPARTMENT OF CARDIOVASCULAR
MEDICINE AT THE MAYO CLINIC IN
SUNNY JACKSONVILLE, FLORIDA.
DR. FAIRWEATHER IS A BASIC AND
TRANSLATIONAL RESEARCH FOCUSES
ON SEX AND GENDER DIFFERENCES AS
A TOOL TO DISCOVER NEW THERAPIES
FOR BOTH CARDIOVASCULAR AND
AUTOIMMUNE DISEASES LIKE MY O
CARDITEIS.
HER RESEARCH HAS BEEN FUNDED BY
A VARIETY OF ORGANIZATIONS, NIH,
AMERICAN HEART ASSOCIATION,
BARTA AND OTHERS, SHE HAS A LONG
HISTORY OF CHAIRING SECTIONS FOR
THE NIH, EPA AND DEPARTMENT OF
DEFENSE AND WAS WITH THE BOARD
OF MY O CARDITIS AND MOST
RECENTLY SHE SERVED ON A
COMMITTEE FOR SCIENCE AND
MEDICINE WHO WAS REVIEWING THE
DISEASE PORTFOLIO OF THE NIH AND
THIS WAS COMMISSIONED BY
CONGRESS AND ALSO A LEADER OF
THE USFDA MAYO EXPANDED ACCESS
PROGRAM FOR THE USE OF
CONVALESCENT PLASMA FOR PATIENTS
WITH COVID-19 WHICH WE WILL
HADDER MORE ABOUT LATER TODAY.
SHE'S ALSO AN ACTIVE MEMBER OF
THE STUDY OF SEX DIFFERENCES AND
CHAIRED THEIR IMPORTANTANNUAL
MEETING IN THE PAST REAR SO I
WILL STOP HERE AND HAND THE MIC
OVER TO DR. FAIRWEATHER TO
INTRODUCE THE SESSION.
>> THANK YOU DR. KANTHI.
AND TODAY WELCOME EVERYBODY TO
SESSION 4 WHERE WE'RE TALKING
ABOUT CARDIOVASCULAR AND
METABOLIC ASPECTS OF COVID-19,
SEX AND GENDER CONSIDERATIONS.
WE'RE GOING TO FOCUS NOW ON
OUTCOMES FROM COVID-19 SO WE'RE
GOING TO GET AN OVERVIEW FROM
DR. NOEL BAIREY-MER0, I WILL
TALK ABOUT MY O CARDITEIS AND WE
WILL HEAR ABOUT LONG COVID,
ORGTOSTATTIC INTOLERANCE AND
POTS AND WE HEARD FROM MICHAEL
SIEVERTS WHO SUFFERS FROM POTS
AND THE SIMPLIFYS DESCRIPTION OF
THAT IS WHEN YOU STAND UP YOU
FEEL DIZZY, FAINT AND BLACK OUT
AND IT CAUSES A LOT OF SYMPTOMS
AND DIFFICULTY SAYS SO WE WILL
HEAR THAT DESCRIPTION AND ALSO
IMAGING BIOMARKERS WITH CARDIAC
MRI.
SO OUR MAIN DESCRIPTION OF THE
OVERVIEW IS GOING TO HAPPEN WITH
DR. BAIREY-MERZ SHE A LEADING
DOCTOR ON CARDIOVASCULAR DISEASE
AND SEX DIFFERENCES AND SHE'S
BEEN DOING THAT FOR DECADES AND
WE WILL HEAR THE BEST IN SCIENCE
FROM HER, SHE HOLDS THE IRON AND
SHEILA ALLEN CHAIR IN WOMEN'S
HEART RESEARCH AT CEDAR SINAI AS
WELL AS BEING A DIRECTOR OF MANY
WOMEN'S HEART PROGRAMS.
SHE HAS A LARGE RESEARCH
PORTFOLIO WITH OVER 425
SCIENTIFIC PAPERS PUBLISHED ON
THIS TOPIC SO WE'RE VERY EXCITED
TO HEAR HER OVERVIEW, I WILL
TALK ABOUT SEX DIFFERENCES IN MY
O CARDITEIS AND SEX DIFFERENCES
IN THE VACCINE AS WELL AS SOME
NEW AND UNPUBLISHED WORK ON
MITOCHONDRIA AND SEX
DIFFERENCES.
WE WILL HEAR FROM DR. RAJ, HE IS
THE SECTION CHIEF OF ADULT
CARDIAC ARRHYTHMIC GROUP AT
CALGARY WHERE HE'S LOOKED AT
AUTONOMIC MEDICINE AND HE'S ALSO
THE DIRECTOR OF EDUCATION AND AT
THE LIBIN CARDIO VASCULARY
INSTITUTE AND DIRECTOR OF
KNOWLEDGE TRANSLATION AT WOMEN'S
CARDIOVASCULAR INIT WHYATIVE SO
WE WILL HEAR FROM THE WORLD
AUTHORITY BOTH ON SEX
DIFFERENCES AND WHAT IS KNOWN
ABOUT POTS AND COVID.
AND THEN FINALLY WE WILL HEAR
FROM DR. MOON ON CARDIO MRI
IMAGING BIOMARKERS FOR COVID SO
HE'S A PROFESSOR OF CARDIOLOGY
AND LEADS CARDIAC MRI AND HEART
CENTER IN LONDON AND HE HAS A
DISTINGUISHED RECORD OF OVER 450
MANUSCRIPTS, HE'S VERY
INNOVATIVE AND HE CAME UP IN
MARCH, 2020 WITH SETTING UP THIS
COVID-SORTIUM WHICH IS LOOKING
AT IMMUNOLOGY OF MILD DISEASE IN
COVID WHERE HE'S HAD MANY HIGH
IMPACT IMPORTANT PAPERS COME OUT
OF THAT STUDY AND HE'S ALSO
LEADING ANALYSIS OF COVID HEART
WHICH IS A 23 CENTER STUDY OF
TROPONIN POSITIVE DISEASE.
SO WE WILL HEAR FROM EXCITING
SPEAKERS TODAY ON CARDIAC
OUTCOMES.
SO I WILL LIKE TO PASS THIS OVER
TO DR. BAIREY-MERZ TO GIVE US
OUR OVERVIEW.
THANK YOU SO MUCH
DR. FAIRWEATHER AND KANTHI.
LET ME SCREEN SHARE.
I'VE BEEN CHARGED WITH OVERVIEW
AND SO, IN MY ALLOTTED TIME WHAT
DO YOU SEE?
DO YOU SEE MY SCREEN?
>> YES.
>> OKAY, GREAT.
SO THIS WILL BE A BROAD BRUSH
OVERVIEW OF CARDIOVASCULAR
DOMINATED INFORMATION RELATED TO
COVID RESEARCH.
WE KNOW FOR A LONG TIME THAT
COVID IS CARDIOVASCULAR DISEASE
IS THE LEADING KILLER IN WOMEN
AND MEN, BUT WE WILL BREAK THESE
DOWN AND LOOK AT THEM
SPECIFICALLY TO SET YOU UP FOR
THE MORE SPECIFIC TALKS WE ALSO
KNOW THAT CARDIOVASCULAR
MORTALITY TRANSFER WOMEN AND MEN
IN 1984 WOMEN BECAME THE
MAJORITY OF VICTIMS.
NHLBI, AMERICAN HEART, AMERICAN
CARDIOLOGY ALL LAUNCHED
INITIATIVES RESEARCH AS WELL AS
PUBLIC AWARENESS AND IT RESULTED
IN A PRETTY DARN GOOD DECLINE
BUT AS WE SEE FROM THIS FINAL
ARROW, THE MORTALITY FOR WOMEN
AND MEN WAS GOING UP EVEN
PREPANDEMIC.
WHAT I WILL DO THEN IS DIVIDE
THIS UP INTO 3 WAVES OF COVID
PANDEMIC.
I BROAD PRUSH THE FIRST WAVE,
THE SECOND WAVE IS SOME SCIENCE
AND THE THIRD WAVE, WE NEED
SCIENCE, THIS IS GOING TO BE OUR
INCREASED PANDEMIC WAVE OF
INCREASED CBD AND I WILL SHOW
YOU HOW COVID IS CONTRIBUTING TO
THAT AND WILL NEED A LOT OF
WORK.
SO WHAT YOU SEE IS MEN LIKE
COVID OVERALL ARE SUFFERING
DISPROPORTIONATELY FOR
COMPLICATIONS INCLUDING ICU'D
MISSIONS AND DEATHS.
CAN YOU SEE ON THE RIGHT HAND
PANEL THAT IT'S NOT ALL ABOUT
EXPOSURE.
WE HEARD YESTERDAY ABOUT GENDER
AND WOMEN ARE MORE LIKELY TO BE
EXPOSED MEN WERE MORE AS
ESSENTIAL WORKERRINGS OUT IN THE
COMMUNITY MORE EXPOSED, MEN
DON'T WASH THEIR HANDS AS
RESEARCH BUT IF YOU LOOK AT
FRANCE AND PRETTY GOOD DATA AM
CANNING OUT OF FRANCE, EVEN
THOUGH WOMEN WERE MORE EXPOSED
AND HAD NOR CONFIRMED CASES, MEN
STILL DIED MORE OF
CARDIOVASCULAR DISEASE.
SO WE STRATIFY ACUTE
CARDIOVASCULAR DISEASE
INVOLVEMENT IN COVID-19 INTO 4
BROAD KACCT THE GORYS,
ARRHYTHMIAS AND HEART BLOCK,
THROMBOSIS, DVT AND PE, ARTERIAL
AND STENT THROMBOSIS, WE HARDLY
SEE ANY OF THIS IN CARDIOLOGY,
WE SAW A LOT IN COVID.
BIG BAD HEART ATTACKS CALL STEMI
IN PEOPLE UNDER 30.
THIS IS UNHEARD OF SO CLEARLY A
COMPLICATION AND THEN WE SAW A
LOT OF LATE PRESENTATIONS AND I
WILL SHOW YOU SOME PREPRENTDATA
ABOUT THAT FROM OUR GROUP.
MY O CARDITEIS WHICH YOU WILL
HEAR MORE ABOUT.
TAKOTSUBO SYNDROME, SOMETIMES
CALLED BROKEN HEART AND THEN
CARDIOVASCULAR COLLAPSE,
TRAGICALLY IN THE PEDIATRIC
POPULATION.
SO WE DIVIDE THOSE INTO 4
CATEGORIES.
OF COURSE, NOW THAT WOMEN AND
WOMEN ARE AT PARITY MORE OR LESS
IN THE UNITED STATES IN TERMS OF
EXISTING UNDERLYING CVD, CAN YOU
IMAGINE THEN THAT THOSE THAT
HAVE THAT WOULD BE MORE AT RISK
AND IN FACT, THAT'S WHAT THIS
PUBLICATION DEMONSTRATES AND
BECAUSE OF THE SEX, AGE
DIFFERENCE, WOMEN ON AVERAGE GET
THEIR CVD LATER THAN WOMEN ON
MEN THIS IT IS ON AVERAGE THEN
MORE MEN WERE DYING OF
CARDIOVASCULAR DISEASE BECAUSE
OF UNDERLYING CVD.
THERE WAS ALSO A HIGHER BURDEN
OF SMOKING AND OBESITY IN MEN.
AND THEN WE'LL DIVE INTO SOME OF
THE CARDIAC INFLAMMATION.
NOW NOTABLY LOAMACY WERE NO SEX
DIFFERENCES OBSERVED IN THE
ARRHYTHMIAS AND THE THROMBOSIS
AND THAT'S NOTE WORTHY BECAUSE
WOMEN SUFFERED
DISPROPORTIONATELY FROM
THROMBOSIS DOMINANTLY RELATED TO
EXOGENOUS AND ENDOGENOUS AS THAT
MIGHT BE A CLUE AS WE WERE
TALKING ABOUT IN THE SUMMARY.
HIGHER MORTALITY OF CVD 19 IN
MALES.
THIS IS A BROAD BRUSH, I'M NOT
AN IMMUNOLOGIST BUT WE DO
RECOGNIZE THE ROLE OF THE IMMUNE
SYSTEM AND THE CARDIOVASCULAR
DISEASE AND VASCULAR
INFLAMMATION SO OF COURSE A
HIGHER ANTIVIRAL RESPONSE HAS
BEEN NOTED IN FEMALES GREATER
VIRAL CLEARANCE SO MEN DO WORSE
IN THAT REGARD AND THEN A
CYTOKINE RELEASE SYNDROME, MUCH
HIGHER IN MALES AND THIS THEN
LEADS TO THE 2 PATHS OF DEATH,
ARDS AND CARDIOVASCULAR
COMPLICATIONS.
SO THIS IS AN IMPORTANT SEX
DIFFERENCE THAT'S PROBABLY
BIOLOGIC.
SO THEN, HERE'S THE SIMPLE
ANSWER TO THIS COMPLICATED
QUESTION, SO LET'S JUST TARGET
SEX DIFFERENCES IN IMMUNE
FUNCTION, RIGHT?
WELL, IF YOU GO TO OUR GOOD
FRIEND AND COLLEAGUE DR. SABRE
CLIEN'S LAB, YOU CAN SEE FROM
THIS PUBLICATION THAT CHANGES IN
IMMUNE RESPONSES, SEX
DIFFERENCES BETWEEN WOMEN AND
MEN, BOYS AND GIRLS, BABIES,
VARY OVER TIME AND IMPORTANTLY
WORSE FEMALE OUTCOMES HAVE BEEN
OBSERVED IN OTHER VIRAL
CONDITIONS, [INDISCERNIBLE],
HSV2, AND THE MEASLES VIRUS, AND
IAV, SO IT'S NOTTICISM THEY'LL
WE WOULD TARGET SEX DIFFERENCES
IN THE IMMUNE SYSTEM.
WHAT ABOUT THE SECOND WAVE AND
WHAT SCIENCE DO WE HAVE ABOUT
THE IMPACT OF DELAY AND DEFERRED
CARE RELATED TO THE PANDEMIC AND
OBVIOUSLY A LOT OF PEOPLE WERE
AFRAID TO COME IN.
HERE'S A PREPRINT FROM OUR
GROUP, THIS IS IMPRESS SECOND
WAVE IMPACT OF DELAY SO WE TOOK
SORT OF 1 OF THE MOST LETHAL
FORMS OF CARDIOVASCULAR DISEASE
THAT ST SEGMENT ELEVATION, MI,
THAT'S WHAT WE TALKED ABOUT
EARLIER AND IT WAS PRESENTING IN
PATIENTS UNDER30 AS WELL AS
DEFERRED AND DELAYED CARE
MEANING PEOPLE DIDN'T COME IN,
SO THIS IS A GOOD 1 TO LOOK AT
BECAUSE CORONARY HEART DISEASE
AND IS A LARGER CONTRIBUTOR AS
WE SAW IN THAT PANEL 1 AND SO
WHAT WE SEE IN THE SEX
DIFFERENCES IN THIS REGISTRY
STUDY, IS RELATIVELY MORE MEN,
THEY HAVE THESE STEMI TYPE OF
HEART ATTACKS,ET WOMEN ARE
USUALLY OLDER, THEY'RE LIKELY TO
BE DIABETIC OR HAVE A PRIOR
HISTORY OF STROKE AND IMPORTANT
SEX DIFFERENCES, THE EQUAL MORE
OR LESS PRESENTING WITH CHEST
PAIN THANKFULLY BUT MEN ARE MORE
LIKELY TO HAVE WHAT'S CALLED A
CORPORATE VESSEL WHICH THEN WE
CAN OPEN UP WITH 1 OF THOSE
STINTS AND THOSE ARE LIFE SAVING
IN THAT REGARD APPROXIMATE SO
WHAT YOU SEE IS AT THE END OF
ALL THESE SEX DIFFERENCES,
MORTALITY WAS ABOUT THE SAME.
WHEN WE THEN ADJUST ALL OF THESE
DATA, YOU CAN SEE THAT THE
RELATIVE RISK IS ABOUT THE SAME
BETWEEN WOMEN AND MEN.
SO WOO CAN ANTICIPATE IN THE
SECOND WAVE THAT WE'RE GOING TO
SEE A LOT OF PATIENTS WITH
DEFERRED AND DELAYED CARE AND WE
HAVE A LOT OF CATCH UP TO DO.
I SPENT A FULL DAY IN CLINIC
THIS WEEK OVERBOOKING BECAUSE OF
THIS DEFERRED AND DELAYED CARE.
LET'S TALK BRIEFLY THEN ABOUT
THE THIRD WAVE BECAUSE--OOPS
THIS NEEDS--NEEDS SCIENCE, THERE
IT IS.
SO HERE'S AN UPTO DATE NATURE
MEDICINE SUMMARY OF DATA
REGARDING WHAT WE WOULD CALL
MAYBE LONG HALL OR POST ACUTE
COVID-19 COMPOSITE
CARDIOVASCULAR OUTCOMES COMPARED
TO A CONTEMPORARY CONTROL COHORT
MEANING THEY DID NOT GET
INFECTED WITH COVID-19.
AND IT'S DIVIDED AGAIN INTO
THESE CATEGORIES, CEREBRAL
VASCULAR DISRYTH MIAS, INFLAMMA
TOREVALUATION PROCESS HEART
DISEASE, OUR MY O CARDITEIS,
ESCHEMIC HEART DISEASE, THE BIG
KILLER, OTHER CARDIAC DISORDERS,
THE BLOOD CLOTS AND THEN THIS IS
A SUMMARY OF ANY CARDIAC OUTCOME
AND WHAT YOU CAN SEE IS THAT MEN
AND WOMEN ARE PRETTY MUCH
EQUALLY LIKELY AND IIS A 2
FOLD INCREASE IN CARDIOVASCULAR
DISEASE BECAUSE OF THE INFECTION
OF COVID-19.
THIS IS CRITICALLY IMPORTANT
THIS IS DIFFERENT FROM OH MY
GOODNESS I GAINED 10-POUNDS OR
OH MY GOODNESS I SMOKED MORE
BECAUSE I WAS STRESSED.
THIS IS CRITICALLY IMPORTANT.
NEW PUTATIVE MECHANISMS, THESE
INVESTIGATORS WENT FORD WITH
THEIR MECHANISMS, HOW ABOUT
ENDOTHELLITEIS, THAT'S
ENDOTHELIAL DYSFUNCTION, HOW
ABOUT COAGULATION AND CO AG
LOPATHY, WE HAVE DRUGS FOR THIS,
WHAT ABOUT ANTIINFLAMMATORY
INTERVENTIONS, WE HAVE DRUGS
THAT HAVE BEEN TESTED FOR
CARDIOVASCULAR DISEASE, WE COULD
TRY THESE FOR COVID-19.
WHAT ABOUT ANTICO AGULATE
INTERVENTIONS?
SO THAT WILL BE IMPORTANT AS WE
GO FORWARD.
OF COURSE, A LOT OF PEOPLE DID
GAIN WEIGHT AND IN FACT, THE
AVERAGE AMERICAN GAINED
10-POUNDS.
I DIDN'T GAIN ANYONE, SO
SOMEBODY GAINED 20 FOR ME, THIS
WILL BE A HUGE BURDEN, WE ALSO
KNOW THIS PROPORTIONATELY
IMPACTED WOMEN.
WOMEN WERE MORE LIKELY TO DEFER
CARE, SO I WILL LEAVE YOU WITH
THESE 3 QUESTIONS: WHAT IMMUNE
SPECIFIC THERAPIES CAN ADDRESS
ACUTE COVID RELATED CVD, WE
SHOULD LOOK AT CROSS-TALK
BETWEEN IMMUNE MEDIATED AND
VASCULAR INFLAMMATION AND WE
HAVE DRUGS, WE HAVE DRUGS FOR
THAT ALREADY STOABED IN
CARDIOVASCULAR DEC.
WHAT EXISTING CARDIOVASCULAR,
METABOLIC AND IMMUNOLOGIC
THERAPIES ARE EFFECTIVE, WE HAVE
A LOT OF CROSS TALK WITH LUPUS
AND RA DRUGS AND EFFECTIVE
STRATEGIES ARE CVD AND THEN WHAT
SCORES CAN IDENTIFY THESE COVID
RELATED INCREASED CVD, IT'S A 2
FOLD INCREASE, WE FLEED TO FIND
THOSE PEOPLE, NOT EVERYBODY IS
AT RISK AND TREAT THEM
APPROPRIATELY WITH PREVENTIVE
STRATEGIES THAT WE KNOW WORK.
SO I WILL CLOSE WITH THAT AND
THANK YOU FOR THIS IMPORTANT
SYMPOSIUM.
>> THANK YOU.
THAT WAS A WONDERFUL OVERVIEW
AND I WILL NOW GET MY SLIDES UP.
>> SO WE HAVE A LONG HISTORY OF
STUDYING SEX DIFFERENCES, IN THE
1980S IT STARTED WITH SALLY
HUBER AND I'VE BEEN STUDYING
THEM FOR THE LAST 20 YEARS AND
THIS STUDY BY DENNIS
Mc NAMARRA THIS 2011 DIDN'T
INTEND TO LOOK AT SEX
DIFFERENCES BUT ACTUALLY FOUND
THAT MEN PROGRESSED FROM MY O
CARDITEIS TO DILATED
CARDIOMYOPATHY WHILE WOMEN
TYPICALLY RECOVER.
AND THIS HIGHLIGHTS A REALLY
IMPORTANT ISSUE ABOUT MY O
CARDITEIS AND THAT IS
CLINICALLY, WE USUALLY DO NOT
CATCH ACUTE MY O CARDITEIS AND
IT--ACUTE MY O CARDITEIS LASTS
FOR ONLY A FEW DAYS AND MY O
CARDITEIS IS A DIAGNOSIS OF
EXCLUSION, IT'S USUALLY THE LAST
THING THAT'S CONSIDERED IN
EVERYTHING ELSE IS CONSIDERED
FIRST, SO IT'S OFTEN CALLED
ACUTE CARDIO MIRROR IMAGE
OPERATING GLOBALLYATHY THAT
WE'RE LOOKING AT AND WE'VE GONE
PAST THE WAXER CUTE PHASE GOING
INTO A CHRONIC PHASE WHERE WE
REALLY PICK UP--START TO PICK UP
NECROSIS AND FIBROSIS AS IT
PROGRESSES TO THAT PHASE WHICH
IS MORE EASILY PICKED UP ON
IMAGES AND CARDIAC MRI AND WE
SEE THIS REALLY IN OUR ANIMAL
MODEL THAT I DEVELOPED AS A POST
DOC BACK IN 2000 AND WITH THIS
ANIMAL MODEL WE USE HUMAN
[INDISCERNIBLE] VIRUS, WHAT I
DIDN'T REALIZE AT THE TIME WHEN
I DEVELOPED IT, I DEVELOPED IT
AS AN AUTOIMMUNE MODEL AND IT
ACTUALLY REALLY REQUIRES VIRUS
AND MITOCHONDRIA TO INDUCE THE
DISEASE.
WE GET ACUTE INFLAMMATION THAT'S
MUCH HIGHER IN MALES DURING
ACUTE MY O CARDITE EXPIS ALSO IN
THE DILATED CARDIOMYOPATHY PHASE
AND EVERYTHING WE EXAMINED IN
THIS MODEL AND LOOKED AT IN
PATIENTS FOLLOWS THE SAME TIME
COURSE AND THE SAME SEX
DIFFERENCES IN THE IMMUNE
RESPONSE.
WE ALSO SEE THIS PROGRESSION TO
DCM MAINLY IN MAILS AND MUCH
LESS IN FEMALES, AND WE ALSO SEE
THAT THERE IS NO NECROSIS OR
FIBROSIS DURING THE ACUTE PHASE
AND ACTUALLY THE TYPE OF IMMUNE
RESPONSE IS WHAT DRIVES
FIBROSEIS WHICH HAPPENS LATER
AND SO TO SUMMARIZE LOTS OF DATA
CLINICALLY IS WHAT'S CALLED
LYMPHOCYTIC CARDITEIS AND THE
MICE AND HUMANS HAVE A
DIFFICULTY SURVIVING THAT, BUT
DON'T IT'S A WHITE DISEASE IN
PATIENTS AND MAINLY MALES AND
PROGRESSES TO CARDIO MYOP APGHT
EXPE THAT'S DRIVEN BY
TESTOSTERONE AND ACUTE PHASES
THAT ARE TOLL-LIKE RECEPTOR 4
AND DRIVE THIS MACROFAJ TYPE
RESPONSE THAT IS PRO
INFLAMMATORY AND THIS IS IN
CONTRAST TO E-MAILS WHERE
ESTROGEN IS PROTECT EVALUATION
PROCESS AND THEY PRODUCE EVERY
IMMUNE FACTOR THAT CAN BE
PROTECTIVE INCLUDING IL10,
TREGULATORY CELLS AND REALLY
ANTIINFLAMMATORY MACROPHAGES.
SO WE LOOKED AT SOLIEWNL ST2,
THIS IS PART OF THE TLR 4 IL1
RECEPTOR COMPLEX AND WHEN IT'S
CLEAVED TO SOLUBLE ST2 HAS BEEN
FOUND TO BE A GOOD BIOMARKER OF
HEART FAILURE IN NO MATTER WHO
TYPE OF HEART DISEASE YOU LOOK
AT.
WE LOOKEDDA THE MY O CARDITEIS
PATIENTS AND SEE THAT IT IS
INCREASED IN MALES AND NOT
FEMALES BUT ONLY IN MALES UNDER
THE AGE OF 50 AND THIS
HIGHLIGHTS THE IMPORTANCE OF
LOOKING AT BIOMARKERS, AND OTHER
FACTORS IN MY O CARDITEIS BY SEX
AND AGE BECAUSE IT REALLY IS A
DISEASE OF THE YOUNG AND
PRIMARILY IN MEN AND SO WHAT
ABOUT COVID MY O CARDITEIS AND
VACCINES?
WELL, THERE'S MANY PUBLICATIONS
THAT HAVE SHOWN THAT SARS-COV-2
THE IMMUNE RESPONSE THAT IT
LEADS TO IS ELEVATED WITH THESE
TYPES OF IMMUNE RESPONSES AND
THAT THESE ARE ALL INCREASED IN
MALES, CRP WHICH IS NOT IN MICE,
TNF IL1, IL18 AND IL6 AND THE
TH17 MONOCYTES AND MACROPHAGES
AND THAT FEMALES HAVE MORE OF A
T-CELL RESPONSE AND B-CELLS AND
ANTIBODIES OR AUTOANTIBODIES
WITH A LOT OF AUTOIMMUNE
RESPONSES OR NUMBER OF
AUTOIMMUNE DISEASES COMING OUT
OF COVID.
AND THIS IS EXACTLY THE RESPONSE
THAT WE HAVE BEEN PUBLISHING
MYSELF AND OTHER INVESTIGATORS
WITH MY O CARDITEIS BOTH IN OUR
ANIMAL MODELS AND IN PATIENTS
FOR MANYIERS NOW SO IT'S
REMARKABLE HOW SIMILAR IT IS AND
I ACTUALLY HAVE A REASON I THINK
IT'S SO SIMILAR THAT DOESN'T
HAVE DO SO MUCH WITH THE
VIRUS ITSELF.
SO 1 THING I WILL LIKE TO POINT
OUT IS WHEN WE LOOK AT ALL OF
THESE OUTCOMES, CARDIOVASCULAR
OUTCOMES FROM COVID AND WE THINK
OF MY O CARDITEIS, WELL THE
CYTOKINE STORM IS ACTUALLY THE
CLASSIC CYTOKINE PROFILE THAT'S
ALWAYS BEEN ASSOCIATE WIDE MY O
CARDITEIS AND IT JUST DEPENDS ON
HOW SEVERE IT IS, AND SO IT'S
EXACTLY THE SAME, ALSO
THROMBOSIS IS SOMETHING THAT
THIS KIND OF PROFILE IS KNOWN
WITH MY O CARDITEIS AND WE DO
SEE ON SOME SECTIONS THROMBI AND
WE ALSO SEE IT IN MURAL THROMBI.
SO IT'S QUITE SIMILAR TO COVID.
SO LOOKING AT VACCINES WE SEE
RNA VACCINES ARE CAUSING MY O
CARDITEIS, IT'S UNDER 30 YEARS
OF AGE, TYPICALLY NOT LASTING
LONG AFTER THE SECOND
VACCINATION BUT OF COURSE
COMPARED TO WHAT WAS HAPPENING
WITH COVID DURING THE PEAK OF
THE FIRST 2 YEARS WITH THOASES
STRAINS, THIS TYPE OF
VACCINATION, MWHY, OCARDITIS, IS
VERY DIFFERENT COMPARED TO WHAT
YOU SEE WITH COVID.
SOPHISTICATEDY WE KNOW THAT
MYOCARDITIS, WHICH IS MAINLY
LYMPHOCYTIC IN THE U.S., WE
SURVIVE AND MOST PEOPLE DON'T
DIE AND IT REALLY IS QUITE
SURVIVABLE BUT WITH COVID-19 WE
WERE SEEING MORE DEATHS AND
PROBABLY FOR MULTIPLE REASONS
BECAUSE THERE WAS A LOT OF OTHER
THINGS GOING ON AS WELL.
AND THAT THIS ARTICLE HAD REALLY
LOOKED AT POTENTIAL INCIDENTS OF
DISEASE WHICH IS NOT VERY HIGH
BUT WAS MUCH HIGHER WITH
COVID-19 AND THE VACCINATION
GROUP IS MUCH LOWER THAN THE
NORMAL INCIDENTS BUT THERE IS A
STUDY IN ISRAEL THAT LOOKED AT 2
AND HAEVERL MILLION
VACCINATED--HALF MILLION
VACCINATED PATIENTS AND GAVE AN
INCIDENCE AND ACTUALLY LOOKED AT
SEX DIFFERENCES SO THEY
ESTIMATED 2 OUT OF A HUNDRED
THOUSAND CASES BUT IN MALES IT
WAS 4 OUT OF A HUNDRED THOUSAND
WITH ONLY .23 IN FEMALES IN SEX
DIFFERENCES AND IF THEY LOOK AT
THOSE UNDER 30, IT WAS QUITE A
BIT HIGHER, SO THIS IS ACTUALLY
GETTING TO THE NUMBER THAT YOU
SEE WITH REGULAR MYOCARDITIS,
AND IT MIGHT BE CAUSING IT IN
MALES WITH MYOCARDITIS IN WHAT
WE SEE, SO SEX DIFFERENCES IN
METABOLISM, SO THIS IS A NEW
AREA THAT MY LAB IS STARTING TO
RESEARCH AND THIS IS UNPUBLISHED
WORK BUT WE ARE GETTING CLOSED
TO PUBLISHING, SO THIS IS AN
RNASEQ WHERE WE LOOK AT
MYOCARDITIS VERSUS CONTROL, MALE
AND FEMALE.
AND THE TAKE HOME MESSAGE FROM
THIS STUDY IS THAT WE SEE THAT
FEMALES REALLY HAVE
MITOCHONDRIAL HOMEOSTASIS DURING
ACUTE MYOCARDITIS AND MALES
UPREGULATE VIRAL INFECTION GENES
AND INFLAMMATORY GENES.
THAT SEEMS LIKE A GOOD THING TO
DO EXCEPT WHAT WE HAVE SHOWN AND
FOUND WITH THIS IS THEY
UPREGULATE COMPLEMENTSES AND
THEY UPREGULATE STORMS AND
CYTOKINES AND EVERYTHING THAT
LEADS TO REMODELING, A BAD
OUTCOME FOR MALES.
AND SO, WE WERE ABLE TO LOOK
THEN AND SEE, JUST WHAT COULD BE
HELPING FEMALES, AND WE FOUND 2
GENES THAT ARE KNOWN TO BE
REGULATORS OF MITOCHONDRIAL
HOMEOSTASIS THAT ARE HIGHER IN
FEMALES AND 1 IS ESTROGEN
RELATED RECEPTOR AND THE OTHER
IS PGC-1 ALPHA SO THAT CAN
EXPLAIN THIS GLOBAL CHANGE
THAT'S GOING ON IN MALES VERSUS
FEMALES WITH THE MITOCHONDRIA.
SO WHY DO ALL OF THESE VIRUSES
WHICH REALLY HAVE NO VIRAL
TROAPISM FOR THE HEART ARE ABLE
TO CAUSE MY O CARDITEIS, AND SO,
1 THING THAT ALL THESE VIRUSES
SHARE IS THE ABILITY THAT THEY
GO IN AND THEY TARGET
MITOCHONDRIA.
AND SO I'LL JUST HIGHLIGHT THE
SPIKE PROTEIN HAS BEEN FOUND
TO--SARS-COV-2 TO INTERACT WITH
MITOCHONDRIA, THERE'S A COUPLE
PAPERS HERE SHOWING THAT.
THE HEART IS THE HIGHEST LEVEL
OF MITOCHONDRIA OUTSIDE OF THE
BRAIN AND OF COURSE VIRUSES
TYPICALLY CAN'T GET TO THE BRAIN
AND SO CVD3 HAS BEEN SHOWN TO
ACQUIRE MITOCHONDRIA AND TO REP
LAYICATE.
AND WE FOUND DURING MYOCARDITIS
THAT EVs THAT CONTAIN THE
MITOCHONDRIA IN AND OUT OF THE
BRAIN ARE RELEASED DURING ACUTE
MYOCARDITIS AND THESE EVs
CONTAIN INFECTIOUS VIRUS AND THE
VIRUS COMING FROM THE HEART ARE
IN THESE EVs AND THERE'S THIS
SEX DIFFERENCES IN DRP 1 WHICH
IS THE FISSION, SO WE SEE MORE
MALE VS DRP1 AND THIS ALLOWS THE
VIRUS TO ESCAPE AND MORE
AUTOPHAGY SEEN THROUGH PARKIN
WHICH CAUSES THESE EVs TO
RELEASE AND IT TURNS OUT THAT
THIS IS REALLY WHAT WE WERE
USING TO INFECT IN OUR ANIMAL
MODEL TO INDUCE THIS DISEASE.
SO IN SUMMARY, WE SEE THAT MALES
HAVE MORE MYOCARDITIS, IT'S MORE
SEVERE, THAT AGE IS REALLY
IMPORTANT BOTH CLINICALLY AND WE
SEE IT IN THE ANIMAL MODEL AS
WELL UNDER 50 YEARS OF AGE AND
IT'S WORSE, THE YOUNGER YOU ARE.
THERE'S AN INCREASED RISK OF
DEATH IF YOU EXERCISE, SPECIALLY
IF YOU ARE YOUNGER.
SEX DIFFERENCES IN THE RA
VACCINE ARE SAME AS MYOCARDITIS,
THE CVB3 IN HUMAN AND MOUSE
MODELS IS REMARKABLY THE SAME AS
WHAT WE SEE IN SARS-COV-2 AND
WHAT I THINK COULD BE HAPPENING
IS IF WE HAVE VIRUS AND THE
MIGHT O MORE IMPORTANT THAN
VIRUS PER SE AND I ALSO
DEVELOPED A MODEL OF CYTOMEGALOW
VIRUS WHICH IS COMPLETELY
DIFFERENT AND IT PRODUCES THE
SAME TIME COURSE AS
[INDISCERNIBLE] ILLUSTRATING THE
STAIMA THIS POINT AND EVs
CONTAINING VIRUS AND HAD MIGHT O
CAN BE A POSSIBLE EXPLANATION
FOR MYOCARDITIS AND HOW VACCINES
COULD CAUSE MILD MYOCARDITIS.
THEY DON'T HAVE ANY INFECTIOUS
VIRUS.
SO WHAT ABOUT GAPS AND FUTURE
DIRECTIONS?
WELL, WE NEED BIOPSY SAMPLES OF
MYOCARDITIS.
IN THE U.S. WE ARE NOT PROVIDING
THOSE AND WE NEED TO REVISE THE
DALLAS CRITERIA THAT REQUIRES
THAT NECROSIS IS PRESENT AND
ACTUALLY NECROSIS IS NOT THERE
DURING ACUTE MYOCARDITIS AND
WE'RE MISSING THOSE SAMPLES AND
IT REALLY IS WHAT WE SEE WITH
CHRONIC MYOCARDITIS.
WE NEED FUNDING, TO LOOK AT
TISSUE, BLOOD, AND DATA IN
SUFFICIENT NUMBERS FROM MULTIPLE
SITES SO WE CAN ANALYZE BY SEX
AND AGE TO DEVELOP HIGH THROUGH
PUT MULTIPARAMETER METHODS TO
DETECT VIRUSES IN PLASMA AND
EVs ACCORDING TO SEX AND AGE.
WE WERE INVOLVED IN A PAPER IN
NEW ENGLAND JOURNAL OF MEDICINE
LOOKING AT A MIRROR THAT COULD
DETECT MY O CARDITEIS FROM MI
AND THOSE KINDS OF THINGS WILL
BE IMPORTANT GOING FORWARD AND
UNDERSTAND HOW THE VIRUS AND
MITO INTERACT TO
PROAUTOANTIBODIES AND
INFLAMMATION AND AND HEART
FAILURE ACCORDING TO SEX, AND
ENSURE PARTNERSHIP OF
INVESTIGATORS NEW TO SEX
DIFFERENCES SO WE CANY PROPEL
THIS RESEARCH IN THIS AREA.
SO THANK YOU AND I WILL STOP
SHARING SO THAT WE CAN GO TO
DR. RAJ'S PRESENTATION.
>> HELLO.
THANK YOU VERY HAVING ME.
SO MY BRIEF TALK WILL DEAL WITH
THE SUBTYPE OR SUBGROUP OF LONG
COVID PEASHTS THAT HAVE
ORTHOSTATIC INTOLERANCE AND
THESE WAS INITIALLY LONG COVID
POTS AND I BRANCHED OUT AND
HOPEFULLY YOU WILL SEE WHY, BOTH
OVERALL AND WILL LOOK AT SEX AND
I'LL DISCUSS GENDER IF YOU WISH.
SO VARIOUS DISCLOSURES ARE HERE,
NONE OF THIS HAS ANYTHING TO DO
WITH DATA OR STUFF I'M
PRESENTING WITH THE EXCEPTION
FOR PRELIMINARY RESEARCH DATA I
WILL SHARE WITH THE COMMUNITY
HEALTH RESEARCH.
SO POTS HAS BECOME MORE VENUS IN
THE LAST COUPLE YEARS WITH LONG
COVID UNFORTUNATELY PRODUCING
MORE PATIENTS BUT BY WAY OF
BACKGROUND THESE ARE THE
TRADITIONAL COMMON CRITERIA FOR
POTS.
THEY'VE BEEN MODIFIED A LITTLE
BUT BASICALLY THEY'VE BEEN
STATIC FOR 30 YEARS NOW.
IT REQUIRES 2 THINGS, PHYSIOLOGY
THAT'S ABNORMAL, ECSETIONZIVE
HEART IT'S WORTH REMEMBERING
THAT INCREASE IN HEART RATE IS
NORMAL, IT'S NORMAL PHYSIOLOGY,
BUT THESE PATIENTS ARE ORE
ACHIEVERS AND THAT DEFINED AS AT
LEAST 30 BEATS PER MINUTE.
THE INCREASE IN HEART RATE IS
PHYSIOLOGIC AND GOES DOWN AS WE
GET OLDER, SO IN KIDS, A 30 BEAT
INCREASE IS QUITE NORMAL AND
INVESTIGATORS LOOK INTO THIS AND
REDEDPIENED THE CRITERIA YEARS
AGO UPPING IT TO 40 BEATS PER
MINUTE.
SO THAT'S JUST THE PHYSIOLOGY,
THE S-IN POTS SYNDROME BASICALLY
MEANS THAT THESE PATIENTS HAVE
TO QUITE SYMPTOMATIC AND THE KEY
TO THE SYMPTOMS ALTHOUGH THEY
CAN VARY IN SPECIFICS ARE THAT
THEY'RE WORSE WITH UPRIGHT
POSTURE AND BETTER RESILIENCE
CUMBENCE AND THERE'S THOUGHTS
HERE AS TO THINGS THAT COULD
CAUSE IT BUT NOT AS RELEVANT AS
THAT DRINICAL FEATURE.
EVERYTHING I DESCRIBE NOW WILL
PROBABLY HAPPEN TO ANY 1 OF US
IF WE GOT ACUTELY ILL WITH A
VIRUS, COVID OR NOT COVID IN THE
ACUTE PHASE.
THAT SYMPTOM SPECIFIC DETAILS ON
NOT GO AWAY.
IT'S A CHRONIC DISORDER,
DIFFERENT CRITERIA HAVE USED
THESE 6 MONTHS AND 3 MONTHS IN
THE CANADIAN CARDIOVASCULAR SEAT
STATEMENT, WE SETTLED ON 3
MONTHS BECAUSE AFTER 3 MONTHS WE
HAVEN'T NOTICED A LOT OF
IMPROVEMENT OR CHANGE AND
IMPORTANT THIS IS IN THE ABSENCE
OF ANOTHER CAUSE IDEALLY
REVERSIBLE BUT ANOTHER CAUSE FOR
THE TACHYCARDIA.
IT'S BEEN HARD TO DETERMINE
EXACTLY HOW MUCH, WHAT THE
PREVALENCE IS, WHAT'S ESTIMATED
BEE HALF A MILLION AND 3 MILLION
PATIENTS IN THE U.S. IS THE
REASON IS BECAUSE THERE HASN'T
BEEN ADMEN ADMINISTRATIVE CODING
FOR IT, ALTHOUGH JUST TODAY,
I'VE HEARD THAT THE CDC HAS
APPROVED AN ICD10 CODE FOR POTS
THAT WILL KICK IN IN THE PAUL
AND THAT WILL HELP US GOING
FORWARD AND THERE IS AN ICD11
CODE WHEN THAT KICKS IN.
SO THESE ARE BASED ON BACK OF
THE MAP AND THERE'S A HUGE
FEMALE PREDOMINANCE AND I PUT
THIS HERE IN A LOT OF STUDIES
OVER 90% AND THE PATIENTS ARE
TYPICALLY WOMEN OF CHILD BEARING
AGE, THE MOST COMMON AGES
BETWEEN SAY 13 AND 50, IT CAN
OCCUR IN OLDER PEOPLE, IT
DOESN'T STOP AT 50 BUT LESS
COMMON, AND IMPORTANTLY
ASSOCIATE WIDE A LOT OF
FUNCTIONAL DISABILITY.
SO THESE ARE NOT MY DATA, THESE
ARE PUBLISHED DATA USING SF-36 A
UBIQUITOUS HEALTH RELATED
QUALITY OF LIFE SCALE FOR 2
DISORDERS RECOGNIZED AS HAVING A
PRETTY CRAPY QUALITY OF LIFE,
PATIENTS WITH BACK PAIN OR
PATIENTS ON DIALYSIS DUE TO END
STAGE RENAL DISEASE.
AND WE ADDED DATA FOR POTS
PATIENTS THIS WAS COLLECTED BY
VANDERBILT.
SO THIS DOESN'T SPEAK TO WHY THE
QUALITY OF LIFE IS HORRIBLE, BUT
IT IS, RIGHT?
SO WORTH RECOGNIZING THAT BUT
THERE'S THIS DISORDER, WHATEVER
IT IS AND WE'RE STILL HAVING
TROUBLE GETTING OUR ARMS AROUND
IT HAS A HUGE IMPACT ON THE
LIVES OF OUR PATIENTS.
WE CONDUCTED IN COLLABORATION
WITH [INDISCERNIBLE] ADVOCACY
GROUP, A LARGE PATIENT BASED
SURVEY SEVERAL THOUSANDS OF
PATIENTS AND JUST A COUPLE OF
SLIDES FROM THAT, JUST
DESCRIBING AGAIN, 93% THAT
COMPLETED THIS ONLINE SURVEY,
WERE FEMALE AND ALMOST ALL
WHITE.
AND WE HAD A LAUNDRY LIST OF
SYMPTOMS THAT THEY COULD
INDICATE THEY HAD OR DIDN'T AND
THE COMMON 1S ARE SHOWN HERE,
YOU KNOW THE TOP FEW, LIGHT
HEADEDNESS, TACHYCARDIA, ARE 1S
YOU WOULD EXPECT WITH
TACHYCARDIA IN THE NAME BUT THE
NEXT FEW SEEN IN 90% GIVE OR
TAKE OF PARTICIPANTS WERE
HEADACHE, DIFFICULTY
CONCENTRATING, NAUSEA AND MEMORY
PROBLEMS, SO WHAT THIS SPEAKS TO
IS THAT THE POTS IS NOT JUST A
CARDIAC OR CARDIO VASCULARY
DISORDER, IT'S ACTUALLY A
SYSTEMIC ILLNESS WITH OBVIOUS
AN IMPORTANT CARDIOVASCULAR
PHENOTYPE AND THAT'S PART OF THE
CHALLENGE IN UNDERSTANDING
WHAT'S DRIVING IT AND HOW TO
TREAT THESE DIFFERENT TENTACLES
OF DISABILITY.
O JUST A COUPLE WORDS ON OTHER
DISORDERS, SO INAPPROPRIATE
SINUS TACKY DISORDER, A COULD
YOU SAYIN OF POTS ISN'T THAT THE
ISSUE IS A HEART RATE THAT GOES
UP ON STANDING BUT THE HEART
RATE CAN BE UP ALL THE TIME AND
OFTEN A RESTING HEART RATE OF A
HUNDRED PETES PERMINUTE IF THEY
WERE LYING DOWN ON YOUR CLINIC
TABLE.
OR AT 24 HOUR ULTRA HEART RATE
OF GREATER THAN 90 BEATS OF THE
CRITERIA, AGAIN, THIS IS IN THE
ABSENCE OF ANOTHER CAUSE OF
TACHYCARDIA YOU CAN FIND AND
THIS IS ALSO VERY SYMPTOMATIC.
THERE ARE ORTHOSTATIC HYPE OR
TENSION DISORDERS AND SOME ARE
LISTED HERE AND THERE'S
CLASSICAL HYPOTENSION OR
ORTHOSTATIC HYPOTENSION, I WILL
TOUCH ON THE FIRST AND THE
THIRD.
SO CLASSICAL ORTHOSTATIC
HYPOTENSION TYPICALLY AFFECTS
OLDER PATES, TYPICALLY IS DUE
SOME FORM OF AUTONOMIC
NEUROPATHY OR NEUROLOGIC
DISORDER AND ASSOCIATED WITH A
SUSTAINED DROP IN BLOOD PRESSURE
OF MERCURY AND DIASTOLIC
PRESSURE WITHIN 3 MINUTES.
RIGHT?
THE BLOOD PRESSURE GOES DOWN AND
IT STAYS DOWN AND HAS LOTS OF
SYMPTOMS UNDERSTANDABLY.
INITIAL ORTHOSTATIC HYPOTENSION
IS AT THE BOTTOM.
THIS IS ASSOCIATE WIDE A
TRANSIENT BUT LARGER DROP IN
BLOOD PRESSURE THAT RECOVERS
WITHIN THE FIRST MINUTE.
THAT INITIAL DROP OCCURS IN
UNDER 152ndS AND THIS CAN
OCCUR IN ALL AGES, YOUNG PEOPLE
AS WELL, THIS IS ACTUALLY THE
CAUSE OF THE LIGHT HEADEDNESS
BUT EVERYONE FELT AT LEAST ONCE
OR TWICE IN THEIR WHEN THEY GET
UP QUICKLY AND HAVE TO HOLD ON
FOR A FEW SECONDS BUT IN SOME
PEOPLE THIS CAN BE DAILY AND
MULTIPLE TIMES DEBILITATING, SO
JUST SHIFTING GEARS WE'VE BEEN
CONDUCTING A STUDY USING
AUTONOMIC TESTING TO UNDERSTAND
THE FREQUENCY AND PREVALENCE OF
AUTONOMIC DISORDERS IN IN LONG
COVID OR PAST POPULATION, IN OUR
STUDY THE PATIENTS HAVE TO BE
BETWEEN 18-80 YEARS OF AGE, HAD
SYMPTOMS FOR AT LEAST 3 MONTHS
HAVE A PC R MOVEN TEST AND AN
ONLINE QUESTIONNAIRE, AUTONOMIC
TESTING BATTERY SO WE STUDIED,
IT'S AN ONGOING STUDY, WE
STUDIED 78 PATIENTS SO FAR
ADDRESSIVELY ENROLLING SINCE
JANUARY AND FUNDAMENTALLY DNCH
THAN WHAT A LOT OF OTHER
AUTONOMIC PAPERS THAT HAVE COME
UP SO FAR IS INSTEAD OF USING A
TILT TEST, WE USE AN ACTIVE
STAND TEST, WE HAD PEOPLE LYING
DOWN FOR 10 MINUTES WHILE
INSTRUMENTED WITH CONTINUOUS
HEART RATE AND TILTS THEM
UP,--NO STOOD THEM UP AND
WATCHED THEM FOR 10 MINUTES AND
WITH THIS WE COULD DETERMINE THE
CRITERIA FOR 4 DIFFERENT
DISORDERS AT LEAST THE
HEMODYNAMIC CRITERIA AND
NONAPOPTOTIC THE ALL THE SYMPTOM
CRITERIA ALONE, HEART RATE
INCREASE OF 30 BPM, A IST WITH
GREAT THEY'RE AN 100, A DROP OF
20 IN SIS TOLL-LIKE RECEPTORIC
BLOOD PRESSURE AND IOH WAS THE
RAPID DROP WITH RECOVERY IN
BLOOD PRESSURE JUST A BIT OF
DATA SHOWING SYMPTOMS WE
REPORTED IN PATIENTS WITH LONG
COVID, IN SOME CASES WITH OTHER
AUTONOMIC DISORDERS AND YOU WILL
SEE THAT LOSS OF TASTE PERSISTED
IN A THIRD OF POPULATION,
FATIGUE WAS ALMOST UBIQUITOUS,
SLEEP PROBLEMS IN 3-QUARTERS,
LIGHT HEADEDNESS, PALPITATION,
AGAIN WHAT YOU WOULD EXPECT, I
THINK, BUT WHEN WE BROKE IT DOWN
BY SEX, SOME SYMPTOMS WERE
PRETTY COMMON AND EVEN IN BOTH
GROUPS, SHORTNESS OF BREATH,
LIGHT HEADEDNESS, SLEEP
PROBLEMS, SEEN IN BOTH GROUPS
EQUALLY BUT OTHERS WEREN'T.
HEADACHES, MUCH MORE COMMON IN
FEMALES, TASTE ISSUES, MUCH MORE
COMMON IN FEMALES, HARDLY
PRESENT IN MALES, CONSIPATION
ALMOST PRESENT IN MALES,
PALPITATIONS MORE COMMON IN
FEMALES THAN MALES.
SO AGAIN, IT'S 1 OF THOSE THINGS
THAT IF YOU DIDN'T LOOK FOR
THIS, WE WOULDN'T HAVE REALIZED
IT.
WE'RE HAPPY SAYING WE HAVE A
SENSE OF A SYMPTOM BURDEN IN THE
POPULATION BUT THE SYMPTOM
POPULATION IS DIFFERENT BASED ON
SEX.
IN TERMS OF AUTONOMIC DISORDERS
WE LOOKED AT OVERALL, 72% MET
CRITERIA FOR 1 OR MORE THOSE
DISORDERS, THE AGE IS SHOWNOT
BOTTOM RIGHT BROKEN DOWN BY SEX,
PRETTY COMPARABLE, IF YOU LOOK
VERSUS THE TACHYCARDIA
DISORDERS, THE HEART RATE
CRITERIA FOR PLOTS ONLY 1
PATIENT, SO VERY FEW MET
CRITERIA FOR THE SINUS
TACHYCARDIA.
WE LOOK AT THE HYPOTENSION
DISORDERS, AGAIN COUPLE MET
CRITERIA FOR HYPERTENSION, NOT
AT ALL, BUT LOOK AT ORTHOSTATIC
HYPOTENSION, 2/3RDS MET CRITERIA
FOR THIS AND THIS IS RELEVANT
BECAUSE THIS IS ALMOST
UNDIAGNOSABLE WITH A TILT TEST.
YOU HAVE TO STAND PEOPLE UP
BECAUSE THE PHYSIOLOGY INVOLVES
THAT ACTIVE MUSCLE CONTRACTION
ON STANDING.
SO THIS IS SOMETHING THAT HAS
BEEN MISS INDEED ALMOST EVERY
STUDY THAT'S BEEN PUBLISHED TO
DATE IN THIS LONG COVID
POPULATION.
AGAIN, BROKEN DOWN BY SEX.
WHAT I WOULD SAY IS IF YOU FOCUS
ON THE INITIAL ORTHOSTATIC
HYPOTENSION ON THE BOTTOM, NOT
MUCH DIFFERENCE, RIGHT?
BOTH MALES AND FEMALES GET THIS.
RATES HIGHER IN FEMALES BUT
PRETTY CLOSE BUT IF YOU LOOK AT
THE POTS GROUP IN THE TOP
MIDDLE, IT'S ALL FEMALES.
NONE OF THE MALES ACTUALLY MET
CRITERIA FOR POTS.
IF YOU LOOK AT THE OVERALL
GROUP, THERE'S MORE FEMALES THAN
MALES, NOT QUITE STATISTICALLY
SIGNIFICANT AS I MENTIONED THE
STUDIES NOT DONE, WE'RE STILL
ENROLLING, BUT THE POINT IS
THERE'S ACTUALLY A MARKED
DIFFERENCE NOT ONLY JUST SAYING
THAT FEMALES GET MORE ISSUES
WITH AUTONOMIC DISORDERS BUT IT
VARIES DEPENDING ON THE TYPE OF
DISORDER AND AGAIN SOMETHING WE
WOULDN'T HAVE PICKED UP WITHOUT
SPECIFICALLY LOOKING FOR IT.
>> YOUR TIME IS UP.
>> OKAY.
DO YOU WANT ME TO STOP OR--
>> YOU CAN JUST WRAP IT UP,
THANK YOU.
YOU CAN FINISH THE SLIDE.
>> OKAY, SO THE POINT IS
AUTONOMIC DISORDERS ARE COMMON,
POTS GETS ALL THE ATTENTION BUT
OTHER STUFF IS COMMON TOO IS THE
REALITY IS YOU FIND WHAT YOU
LOOK FOR SO IOH WASN'T DIAGNOSED
BECAUSE NO 1 IS LOOKING FOR IT,
SEX DIFFERENCES EXIST IN THE
SYMPTOMSAs WELL AS FREQUENCY
OF THESEOT NATIONAL LIBRARY OF
MEDICINIC DISORDERS AND I WILL
STOP, THANK YOU FOR LETTING ME
KICK THIS OFF.
>> THANK YOU DR. RAJ, WE WILL
GET THE NEXT SPEAKER WHICH IS
DR. MOON.
>> THANK YOU VERY MUCH, CAN YOU
HEAR ME AND SEE MY SLIDES IN
PRESENTATION MODE?
>> YES.
>> I WILL TALK ABOUT
CARDIOVASCULAR IMAGES AND
COVID-19 ESPECIALLY THE USE OF
BIOMARKERS TO ATTRACT DISEASE.
--TRACK DISEASE.
SO I'M A UK PROFESSOR OF
CARDIOLOGY AND I DID CARDIAC MRI
IT WASN'T USEFUL IN THE HEAT OF
THE HOT WAVES SO I SET UP A
STUDY OF MILD DISEASE USING A
HEALTHCARE WORKERS WHICH WAS
SUCCESSFUL, YOU MAY HAVE SEEN A
PAPER THIS WEEK ON WHAT OMICRON
SYSTEM, BUT I HAD TO WORK AS AN
ITU NURSE AS WE TRIED NOT TO BE
SWAMPED DURING 2 OF THE WAVES.
SO IMAGE SUGGEST ALL ABOUT
PRETEST PROBABILITY AND WHAT
YOU'RE LOOKING FOR AND WHAT YOU
WILL DO WITH THAT IMAGES BECAUSE
NO 1 GETS BETTER FROM IMAGING IT
HAS TO BE LINKED TO THERAPY.
AND THE EXPOSE OHM IF YOU LIKE
IS THESE MULTIPLE WEIGHS OF
SARS-COV-2 AS THEY GO THROUGH,
THOSE VARIANTS ARE CURRENTLY
LESS PATHOGENIC AND OF COURSE
HAVE YOU MANY PEOPLE WITH 3
VACCINES BY NOW.
YOU HAVE TO THINK IF YOU COMPARE
IMAGING RESULTS ABOUT WHO THE
PEOPLE ARE AND ESPECIALLY WHAT
PREDISPOSING RISK FACTORS THEY
HAVE AND OF COURSE IT'S NOT JUT
COVID AS CORONA VIRUS DISEASE,
IT'S WHETHER YOU'RE A
SYMPTOMATIC MILD OR ACUTE
INFECTION AND IF YOU WERE
HOSPITALIZED AND HOW LONG WERE
YOU HOSPITALIZED FOR.
AND ALL THAT GOES INTO THE
RESULTS.
AND WHAT WE FIND IN THE FIRST
WAVE MAY BE DIFFERENT THAN ANY
SUBSEQUENT WAVES BECAUSE THERAPY
HAS CHANGED AND THEN YOU HAVE TO
THINK OF MORE THAN JUST THE
HEART ALTHOUGH I VERY OFTEN JUST
THINK OF THE HEART IN IMAGING,
THERE IS THAT INTERACKING ACROSS
SCALES AND OF COURSE SOCIETAL
AND SCALABLE WORK.
IT IS REALLY UNLIKELY I THINK
NOW THAT FUTURE WAVES WILL HAVE
WILL HAVE SEVERE CARDIOVASCULAR
IMPACT.
SO IMAGING IS REALLY ESSENTIAL
SO IN CARDIOVASCULAR DISEASE, WE
DEFINE OUR DISEASES ESPECIALLY
HEARTS BY THE IMAGING
APPEARANCE, STRUCTURE AND
FUNCTION.
SO OUR DISEASES MIGHT BE CALLED
DILATED CARDIOMYOPATHY AND
HYPOTROPIC CARDIOMYOPATHY SO
WE'RE NOT VERY MOLECULAR, WE
LOOK AT APPEARANCE OF THE HEART,
SO WE ONLY HAVE 2 BLOOD
BIOMARKERS WE USE SO THOSE
APPEARANCES ARE VERY IMPORTANT.
NOW WE'VE OVERLAID THOSE WITH
SOME CHARACTERISTICS OF
PROCESSES USING TISSUE
CHARACTERIZATION SO WE CAN NOW
SEE ESCHEMIA AND FIBROSIS AND
SOME INFLAMMATION, ALTHOUGH OF
COURSE WE CAN'T TELL IF THE
INFLAMMATION IS CLEARS UP
DISEASE OR ACTUALLY THE
PATHOLOGICAL PROCESS.
SO WHEN WE THINK ABOUT IMAGING,
YOU NEED TO THINK ABOUT THE
DISEASE CHARACTERISTICS AND THEN
ALSO THE TEST CHARACTERISTICS,
SPECIFICITY, PRETEST
PROBABILITY, WE NEED TO KNOW
WHAT'S NORMAL AND YOU WILL SEE
MISTAKES ABOUT WHAT IS
INTERPRETING MISTAKES ABOUT WHAT
IS NORMAL FOR SOME PEOPLE DURING
THIS AND THEN OF COURSE YOU HAVE
TO HAVE IT AVAILABLE AND
EFFECTIVELY DELIVERED.
SO THE PROBLEM IS THAT WE HAVE
ASSOCIATION AND CAUSATION, SO
CARDIOVASCULAR DISEASE AS WAS
PREVIOUSLY SAID IS A RISK FACTOR
FOR SEVERE COVID, BUT COVID
CAUSES CARDIOVASCULAR DISEASE.
SO CAN YOU SEE THIS TWITTER
IMAGE MAKING LITTLE PAN ON CAUSE
THE VISITOR CENTER NEXT TO THE
ASTEROID SITE, HOW LUCK THAT'S
IS, BUT THERE'S MORE TO IT THAN
THAT BECAUSE IT SEEMS THAT COVID
IS ALSO A STRESS TEST FOR THE
CARDIOVASCULAR SYSTEM.
SO IF YOU FIND ABNORMALITIES BY
IMAGES FOR EXAMPLE, SOME OF IT
WAS PREEXISTING DISEASE THAT IS
REVEALED BY THE SEVERE--HAVING
SEVERE COVID.
SO YOU HAVE TO BE MORE COARSE
ABOUT DESCRIBING THINGS TO THE
SAR-COV-2 INFECTION AND HOW WE
CREATE CONTROLS FOR THIS IS HARD
BECAUSE WE KNOW HOW TO CONTROL
ALL THIS FOR CVD, BUT IT IS A
MORE COMPLEX PHENOTYPE AND IT
ALSO MEANS THAT WHILE THAT'S
MEASURED RISK FACTORS YOU HAVE
THE UNMEASURED RISK FACTORS AS
WELL AND WE KNOW THAT THOSE ARE
SIGNIFICANT IN HEART DISEASE.
SO EARLY IN THE PANDEMIC, THINGS
WERE OPEN ENDED.
PEOPLE SAW THAT THERE WAS
CARDIOVASCULAR DISEASE AND
MYOCARDIAL DISEASE AND THEY
CALLED IT SIMILAR TO MY O
CARDITEIS AND THERE WAS A LOT
TRIP OWNIN ELEVATION ESPECIALLY
IN SEVERE DISEASE AND ITU.
AND PEOPLE KEPT A BIG MIND AND
LATER A GERMAN PAPER CAME OUT
USING THE TECHNIQUE I'M SEEING
MOI AND SUGGESTED THAT MILD
DISEASE PEOPLE HAD ENORM USE
RATES OF WHAT THEY WERE THINKING
WAS MY O CARDITEIS WITH 78% OF
PEOPLE HAVING ONGOING
INFLAMMATION.
THIS CAUSED CONSIDERABLE CONCERN
AND AFFECTED LIVES IN MANY WAYS.
AND YOU WOULD NOT BE SURPRISED
TO FIND OUT THERE WERE LOTS OF
PROBLEMS WITH THIS PAPER, IT GOT
COMPLETELY REVISED A GROUP OF
SCIENTISTS INCLUDE MYSELF HAD
CONCERNS ABOUT METHODS AND
TECHNOLOGY AND THEY WERE NOT
REPLIED AND LITTLERS HAD TO COME
IN AND SUGGEST THAT THIS WAS A
PROBLEM, THIS PAPER AND IT
CAUSED UNNECESSARY HYSTERIA AND
CEMENTED THE WARD MYOCARDITIS
INTO THE COVID SORT OF MIND SET.
THIS WAS PRETTY MUCH AS GOOD AS
CAN YOU GET FOR CONTROLS BECAUSE
WE RECRUITED PEOPLE BEFORE THEY
HAD COVID AND WE PRODUCED THIS
IN A MATCH LIKE THIS AND WE
MEASURED 10 PARAMETERS USING
MAINLY MRI AND THESE WERE
CONTROLLED AS WELL AS WE COULD
BLIEPPEDDING AI ANALYSTICS ET
CETERA INDEPENDENT DATA
ANALYSIS, BLINDED BY
[INDISCERNIBLE].
WE FOUND THAT NORMAL PEOPLE
QUITE OFTEN HAVE ABNORMALITIES,
70% FEMALE HEALTHCARE WORKERS
AND ABOUT 5% WERE ABNORMAL BUT
THE DEC THERE WAS NO SIGNAL OF
DIFFERENCE BETWEEN THOSE WHO HAD
COVID AND THOSE WHO HADN'T. AND
THAT CONSTRAINED THE MAXIMUM
INCREMENTAL WEIGHT IN MILD
DISEASE TO 4% AND IT'S VERY HARD
TO PROVE THE NEGATIVE.
AND THAT THAT SORT OF CHIMED
WITH SUBSEQUENT DATA ON ATHLETES
WHERE INFLAMMATORY DISEASE WAS
LOOKING VERY LOW IN THE
COMMUNITY.
.6.7% BUT SEVERE DISEASE IN HERE
WE'RE USING IMAGING AGAIN WAS A
DIFFERENT MATTER, IF YOU TAKE
PEOPLE WHO GET A TRIP OWNIN
ELEVATION IN THE HOSPITAL AND
MANY OF THOSE ARE IN ITU, YOU
FIND THAT WHILST THE HEALTHY
IMPAIRMENT IS MUCH MORE,
FUNCTION ISN'T MUCH WORSE IF
THEY SURVIVE AND YOU SCAN THEM
AS OUTPATIENTS.
THEY HAVE A LOT OF SCAR.
AND IT'S NOT JUSTA A PATTERN
THAT MIGHT BE MYOCARDITIS BUT IT
ALSO APPEARS TO BE AN INFARCT
PATTERN SO IT LOOKED LIKE IT
THERE FTIONA COMPLEX PICTURE
GOING ON.
PATHOTBOJICALLY AGAIN IN SEVERE
DISEASE, FOUND THAT INI RECALLLY
SUGGESTED LOTS OF REPORTS OF
MYOCARDITIS, BUT SUBSEQUENTLY
MORE LIKE 1.4% OF THOSE WHO DIED
FOR MOST AT RISK FOR COVID.
THE LATEST DATA PUBLISHED IN
ABSTRACT FORM IS THAT WE TOOK 23
SEN ILLEGALSENUS OF PATIENTS AND
LOOKED AT THOSE WITH TROPONIN
POSITIVITY AND THEN WE TOOK
CO-MORBIDITY POSITIVE PATIENTS,
THESE PEOPLE WITH LOTS OF
DIABETES AND HYPERTENSION LIKE
OUR SEVERE DISEASE POPULATIONS
AND THEN COVID POSITIVE TROPONIN
NEGATIVE SUBJECT WHO IS HAD BEEN
HOSPITALIZED AND WHAT WE FOUND
WAS FIRSTLY THAT THE TROPONIN
POSITIVE PEOPLE WERE MUCH MORE
MALE.
THERE WASN'T MUCH OF THE
IMPAIRMENT BUT THERE WERE
OUTLINES.
THERE WASN'T MUCH INFLAMMATION
AT 28 DAYS LATER BUT THERE WAS
AT LEAST TWICE AS MUCH SCAR IN
THOSE WHO HAD TROPONIN ELEVATION
AND HOSPITAL.
BUT THE EXCESS SCAR WAS
INFARCTION AND MICROINFARCTION,
WHAT WE FOUND WAS THAT THE
CONTROLS HAD LOTS OF MYOCARDITIS
LIKE SCAR.
SO THERE WAS A 13% AND 14%
RATING IN COMORBID CONTROLS AND
IF YOU DIDN'T HAVE ALL THOSE
CONTROLS YOU WOULD CALL ALL OF
THESE COVID RELATED MARKERS SO I
THINK WE ARE REALLY MOVING
TOWARDS THROMBOTIC AS THE
PRIMARY CAUSE OF MYOCARDIAL
JUDGE IN THE FIRST AND SECOND
WAVE OF INFECTION.
>> ONE MINUTE LEFT.
>> TO SUMMARIZE, WE'RE IN A
COMPLEX LANDSCAPE IF YOU WANT TO
DO IMAGING, YOU NEED TO
UNDERSTAND THE DISEASE BUT NOT
GET TOO HUNG UP ON WHAT SOME OF
THE EARLY LITERATURES TOLD YOU.
THE FUTURES ARE MUCH MORE LIKE
TO HAVE THIS.
WE HAVE THIS CAUSE TO THE ISSUE
ISSUES AND ASHING STZ IS A
STRESS TEST FOR THE HEART SO YOU
HAVE TO BE CAREFUL SELECTING
CONTROLS AND THINKING ABOUT
WHETHER THERE ARE UNMEASURED
RISK FACTORS.
>> THE SCENARIO MATTERS WITH
YOUR IMAGING AND YOU MAY THINK
OF THESE SCENARIOS, AND MILD
DISEASE REALLY--I WOULDN'T THINK
OF IT FOR STRUCTURAL OR
FUNCTIONAL PHENOTYPE AND
OBVIOUSLY IMAGES DOESN'T MEASURE
THE AUTONOMIC SIZE, SEVERE
DISEASE HOWEVER CAUSES THESE
WHICH MAY WELL HAVE DOWN STREAM
CONSEQUENCES AND THERE ARE
BETTER STUDIES NEED TO BE DONE.
SO TO SUMMARIZE, WE TRY TO
UNDERSTAND THE DISEASE AND I
FOCUSED ON CARDIAC MRI AS THE
BEST BIOLOGICAL IMAGING
DISCOVERY TECHNIQUE HERE.
THANK YOU VERY MUCH.
>> THANK YOU DR. MOON, SO WE'RE
GOING IT GO NOW TO OUR
DISCUSSION TIME SO IF YOU WANT
TO PUT ANY QUESTIONS INTO THE
QUESTION AND SW, WE WILL GET TO
THAT AND AND I AM GOING TO PULL
UP THE SUMMARY AND WHAT SOME OF
THE DIFFERENT END SLIDES THAT
WERE PRESENTED THAT WE CAN LOOK
AT TO JOG OUR THINKING.
BUT I HAVE A QUESTION FOR
DR. MOON RIGHT AWAY AND ACTUALLY
EVERYONE FROM OUR PANEL, YOU CAN
TURN YOUR CAMERA ON, DID YOU
LOOK AT DATA SETS AND FOR THE
ANALYSIS YOU WERE DOING WERE
THEY ANALYZING BY SEX?
AND REGARDING THE TYPE OF
RESULTS THAT YOU FOUND WHAT DO
YOU THINK SORT OF THE SEX
DIFFERENCES WOULD BE OR THE
IMPLICATIONS OF THAT FOR YOUR
METHOD?
>> SO FIRSTLY THANK YOU FOR
SETTING UP THIS SYMPOSIUM
BECAUSE I'VE BEEN CALLING BACK
AND POOLING MY TEAM TO DO
SUBGROUP ANALYSIS AND LOOK AT
THIS AND WE'VE BEEN LOOKINGA THE
TRANSCRIPT OHM AND PROTEOME OF
MILD DISEASE CASES WHERE WE HAD
BEFORE, DURING AND AFTER
SAMPLES.
FOR THE PROTEOME THERE WERE NO
SEX DIFFERENCES.
THERE WERE RESPONSE AND SYMPTOMS
BUT NOT WITH SEX.
FOR MANY OF THE STUDIES IN THE
LITERATURE THAT THE--THE BREAK
DOWNS ARE ARE BY SEX BUT YOU
DON'T GET THE IMPRESSION THAT
IT'S SEX IMPACT ON THE INFECTION
RATHER THAN THE UNDERLYING
CARDIOVASCULAR RISK FACTORS FOR
EXAMPLE.
SO I THINK THERE IS AS YOU SAY
MUCH MORE WORK TO DO, WITH
REGARDS TO LITERATURE, I TRY AND
KEEP UP BUT THERE HAVE BEEN
QUARTER OF A MILLION PAPERS SO
FAR SO I NEED TO READ SLIGHTLY
MORE THAN 1 PAPER PER SECOND TO
HAVE A CAP OFF I WANT TO IN THE
NEXT [INDISCERNIBLE].
THE COVID LITERATURE IS DAUNTING
FOR SURE.
I WILL THEN MOVE TO A QUESTION
THAT CAME UP IN THE--FOR DR. RAJ
AND IT'S WHY DO YOUNG CHILDREN
LESS THAN 10 YEARS OF AGE
DEVELOP POTS?
>> THE BROADER QUESTION IS WHY
DOES ANYONE DEVELOP POTS, I'M
NOT SURE WE FULLY UNDERSTAND
THAT?
YEAH, THIS IS BASED ON THE HEART
RATE THING THEY WAS MENTIONING.
WHAT I WOULD SAY IS THAT IT'S
NOT SO MUCH POTS BUT ACTUALLY
YOUNG KIDS HAVE AN ORTHOSTATIC
TACHYCARDIA THAT'S PHYSIOLOGIC
AND NORMAL THAT'S JUST HIGHER
THAN WE DO IN ADULTS AND THAT
GOES DOWN AS WE GET OLDER.
WE DICHOTOMIZE AND COME UP WITH
A CUT POINT FOR ADULTS FOR
SIMPLICITY BUT THE REALITY IS AN
INCREASE OF 30 FOR A 20 YEAR-OLD
AND AN INCREASE OF 30 FOR A 50
YEAR-OLD, PROBABLY HAVE
DIFFERENT MEANINGS AND LET'S SAY
AT 12 OR 13, IT'S WELL WITHIN
THE NORMAL RANGE.
THAT'S WHAT I WAS TRYING TO GET
ACROSS.
ONE OF THE CHALLENGES WITH KIDS
IS THAT MOST KRIST TERIS WITH A
POSSIBLE EXCEPTION OF GUIDELINES
FROM CHINA DON'T ACTUALLY DEFINE
WHAT THE RIGHT HEART RATE CUT
POINT SHOULD BE FOR KIDS UNDER
THE AGE OF 12 SO THE WHOLE
DIAGNOSIS OF POTS BECOMES MORE
PROBLEMATIC IN THAT AGE GROUP.
>> SO I HAVE A QUESTION RELATED
ALSO TO THIS, SO WE SEE THAT A
LOT OF THE RESPONSE,
INFLAMMATORY RESPONSE TO COVID,
A LOT OF THE OUTCOMES RELATED TO
INFLAMMATION AND I WONDER IF YOU
SEE ANY CONNECTION TO
INFLAMMATION IN OUR POTS
PATIENTS WHETHER THEY HAVE MORE
MASS CELL ACTIVATION OR OTHER
THINGS THAT WOULD INDICATE AN
INFLAMMA ATORY MECHANISM.
>> YEAH, SO PRECOVID IN THAT BIG
POT SURVEY I ALLUDED TO 1 OF THE
QUESTIONS WAS ABOUT POSSIBLE
TRIGGERS THAT PATIENTS NOTICED
IN THE 3 MONTHS PRIOR TO ILLNESS
AND THE MAJORITY DIDN'T BUT THE
1S THAT DID, THE MOST COMMON WAS
POST VIRAL, RIGHT?
THERE'S A VIRAL ILLNESS,
PRECOVID MOST OF THE VIRUSES
DIDN'T HAVE A NAME BECAUSE WE
WEREN'T AGGRESSIVELY TESTING AND
THERE WASN'T WOB DOMINANT VIRUS
SO THERE'S BEEN A LOT OF
INTEREST IN SORT OF
AUTOIMMUNITY, AS A TRIGGER FOR
POTS FAIRLY BROADLY AND
AUTOANTIBODIES IN PARTICULAR,
THERE'S A LOT OF SMOKE AROUND
THAT BUT I'M NOT SURE A KACCT
UNITED STATESSAATIVE
AUTOANTIBODY HAS BEEN FOUND
THERE. IS SOME INTEREST IN THE
POTS WORLD NOW AND NOW IN LONG
COVID ABOUT TRYING IMMUNE
SUPPRESSIVE THERAPIES.
AS YOU ALOUDED TO THERE IS A
SIGNIFICANT SET OF POTS PATIENTS
THAT SEEM TO HAVE A STRONG
ALLERGIC IMMUNE PRESENTATION SO
THE MASS CELL ACTIVATION
SUBGROUP THAT YOU'RE ALOUDING TO
SEE I DON'T THINK IT ACCOUNTS
FOR ALL OF POTS BUT IT ACCOUNTS
FOR A GOOD PORTION AND A HIGHER
PROPORTION OF LONG COVID POTS
POPULATION THAT WE SEE.
>> OKAY, AND THEN I WANTED TO
ASK A QUESTION TO DR. BARRY MERZ
AND WE SEE THERE'S SEX
DIFFERENCES IN INFLAMMATION AND
IN CO-MORBIDITIES WITH
CARDIOVASCULAR DISEASE HAVE BEEN
PRETTY WELL DEFINED AND I'M
WONDERING, YOU KNOW OVER THE
YEARS WHETHER WITH COVID, IF YOU
THINK THAT WHAT WE SEE IS REALLY
SIMILAR TO WHAT WE'VE SEEN IN
THE PAST WITH COVID OR ARE WE
SEEING NEW THINGS EMERGE AS
CO-MORBIDITIES OR THINGS THAT
REALLY STAND OUT DISTINCTLY
BECAUSE OF COVID IN THIS EITHER
JUST CAUSING DISEASE OR IN A
SEX-SPECIFIC MANNER?
>> I THINK THAT'S A REALLY GOOD
QUESTION.
MY REVIEW, I WOULD SAY OVERALL
DEMONSTRATED THAT IT'S JUST AN
EXACERBATER OF SEX DIFFERENCES
AND AGAIN, UNDERSCORED BY REALLY
EXPANDING OUR KNOWLEDGE ABOUT
SEX DIFFERENCES IN THE IMMUNE
SYSTEM.
WE'VE KNOWN FOR A LONG TIME FOR
EXAMPLE THAT WOMEN WHO
DISPROPORTIONATELY SUFFER FROM
LUPUS AND LUPUS HAS A TREMENDOUS
AMOUNT OF VASCULAR INFLAMMATION
WHICH CAUSES THE HEART AND
KIDNEY AND BRAIN PROBLEMS
IMPORTANT SEX DIFFERENCE AND
MOST LIKELY RELATED TO THAT
XX THAT THEY HAVE 2 COPIES OF
EVERYTHING AND NOT ALL OF THE
Xs ARE SILENCED.
SO WOMEN SUFFER
DISPROPORTIONATELY FROM
AUTOIMMUNE DISEASE.
WOMEN SUFFER DISPROPORTIONATELY
FROM AUTOIMMUNE DISEASE-RELATE C
VD.
THE INFORMATION I SHARED IN THE
PAPER SUGGEST THAT THEY HAVE A
INCREASE AND THEY WERE NOT
DISPROPORTIONATE AT THAT TIME
BUT I THINK WE WILL SEE SLIGHT
SEX DIFFERENCES, RIGHT?
WOMEN WILL HAVE MORE OF THE
VASCULAR ISSUES, MEN WILL HAVE
MORE OF THE STEMI OBLIGATIONS
VECT IT STRUCTURALLYIVE CORONARY
DISEASE ISSUES, I DON'T KNOW IF
I ANSWERED THE QUESTION, BUT I
THINK HOPEFULLY I DID.
>> YEAH.
>> YEAH, GO AHEAD.
>> I THINK SO I THINK THAT'S
GREAT.
I SEE 1 QUESTION AIMED AT ME,
ARE THERE INCREASES IN IMMUNE
CELLS, NUTRIFILLS AND
MACROPHAGES IN HEARTS OF COVID,
SO MY ANIMAL MODEL IS NOT A
DIRECT MODEL OF COVID BUT WE
KNOW WHAT'S BEEN PUBLISHED IN
THE LITERATURE FOR COVID THAT
THERE ARE INCREASE IN NUTRIFILLS
AND MACROPHAGES IN MALES AND
THAT'S THE DOMINANT EFFECT IN MY
[INDISCERNIBLE] MODEL NUTRIFILLS
COME BEFORE THE PEAK AND ARE
ELEVATED IN MALES AND THEN WE
SEE PEAK MACROPHAGES.
SO IN THAT WAY, THAT IS SIMILAR.
SOPHISTICATEDY WE HAVE ANOTHER
QUESTION FOR DR. MOON.
DO YOU NOTE DIFFERENCES IN THE
SEVERITY OF MY O CARDITEIS
DEPENDENT ON THE TYPE OF
SARS-COV-2 VARIANT.
>> YEAH, IT'S A REALLY DIFFICULT
QUESTION TO ASK BECAUSE FIRSTLY
WE DIDN'T SEE MUCH MY O
CARDITEIS.
>> WE SEE MY O CARDITE LIKE LATE
ENHANCEMENT BUT WE KNOW THAT
THAT ACTUALLY AND HISTOLOGICALLY
CAN BE MICROTHROMBI RATHER THAN
A PRIMARY [INDISCERNIBLE] OF
MYOCARDITIS, AND SECONDLY THE 80
TO DO SCANS DURING THE WUHAN
WAVE IS WAS VERY POOR AND OUR
EFFORT WAS NOT VERY GOOD EITHER,
SO ONLY BY DELTA COULD WE SEE IT
SO I DON'T THINK I CAN COMPARE
BUT THE PRIMARY THING IS THAT WE
DON'T SEE MUCH MYOCARDITIS
COMPARED WITH THROMBOTIC AND
MICROINFARCT EVENTS.
>> AND I GUESS TO FOLLOW UP ON
THAT, I HAD ANOTHER QUESTION,
THEY WERE ASKING ABOUT THE
MICRO--IF I SEE MICROTHROMBY IN
MY HEART--IN THE HEARTS AND THIS
DEPENDING ON SEX DIFFERENCES,
SO, I SHOWED A PICTURE OF
THROMBI, MURAL THROMBI IN OUR
ANIMAL MODEL BUT WHERE WE REALLY
SEE THAT IS WHETHER WE AMPLIFY,
WE'VE SHOWN THAT IF YOU GIVE
RECOMBIN ANT IL33 TO MICE WITH
THIS MODEL, THAT YOU CAN GET USE
AN AFFILLIC MY O CARDITEIS WHICH
IS A MORE RARE TEEP OF MY O
CARDITEIS THAT HAS I THINK A LOT
OF NUTRIFILLS AND A LOT OF
EOCENOFILLS AND WHEN THEY
RELEASE THEIR GRANULES THAT IS
PRO THROMBOTIC AND THAT'S WHERE
WE SEE A LOT OF LARGE MURAL
THROMBI AND IT LOOKS LIKE
MICROTHROMBI AS WELL, SO WE SEE
THIS RESPONSE IN THE MODEL BUT
IT'S REALLY AMPLIFIED.
IF YOU INCREASE THAT IL33
RESPONSE WHICH IS 1 OF THE TLR 4
ST-2 RESPONSES THAT WE SEE
UPREGULATED IN MALES.
TELL BE INTERESTING TO SEE.
I DON'T THINK THAT I'VE SEEN
ANYTHING REPORTED ON ST2 OR IL3
RELATED WITH COVID.
BUT THAT IS A TYPE OF RESPONSE.
WE HAVE A QUESTION HERE THAT IS
ANOTHER POTS 1 WHEN ASTRONAUTS
RETURN PRACTICES MICROGRAPHITY,
FEMALES EXPERIENCE TACKY CARDIO
MORE THAN MALE ASTRONAUTS, THEY
DO EXPERIENCE [INDISCERNIBLE],
SO NOT QUITE POTS CAN COULD YOU
WANTER MEASURES BEING MANAGED
FOR THIS WITH LIEWNOR
EXPLORATION, PERHAPS WORKING
WITH THE SPACE EXPLORATION MAY
ACCELERATE THERAPIES HERE ON
EARTH.
NOT REALLY A QUESTION BUT
INTERESTING HAVE YOU HEARD OF
THAT BEFORE?
>> YEAH THE NASA MICROGRAPHITY
EXPERIMENTS ARE VERY MUCH A
MODEL OF POTS AND THEY HAVE
CAUSED IT.
IT'S 1 OF THE REASONS WE TALK
ABOUT REVERSIBLE CAUSES, PEOPLE
ON PROLONGED BED REST, I DON'T
MEAN PEOPLE THAT ARE TIRED BUT
SOME PATIENTS THAT ARE IN BED 20
HOURS A DAY BECAUSE THEY FEEL
BETTER AND ACTUALLY DOES PROMOTE
ORTHOSTATIC TOLERANCE AND
PROMOTES A DROP IN BLOOD VOLUME
AND THESE COME OUT OF EXCELLENT
NASES NASA PREPARING FOR SPACE
STATION STUFF, THEY HAVE SOME
WORK THAT CERTAIN THAT ONGOING
TRAINING HELPS SO IN THE
MICROGRAPHITY ENVIRONMENT,
THAT'S AN IMPLEMENT ON THE SPACE
STATION FOR EXAMPLE TO HELP BACK
ON EARTH.
SO THEY'VE IDENTIFIED THIS TO
TRY TO ENGAGE IN PROGRAM THAT'S
NOT TOO AGGRESSIVE SO SOMETHING
THAT'S DOABLE, SUSTAINABLE AND
COMPRESSION TO STROKE VOLUME AND
THIS IN SOME FORM COMES OUT OF
OF NASA WORK,.
>> SO INTERESTING I'M ON AN EDS
CLINIC HERE AND THOSE PATIENTS
DEVELOP POTS AND IT IS 95% WHITE
WOMEN UNDER 50 EXACTLY LIKE
YOU'RE SEEING BUT IT ALSO
HEARING THE PATIENT STORYINGS,
ALL OF THEM EVEN IF THEY DIDN'T
HAVE POTS SOUND LIKE THE MORE
SEVERE CASES OF HYPER MOBILE
EEDS WITH THIS OVERLAP OF
CHRONIC FATIGUE SYNDROME SO
THERE'S OVERLAPS IN THINGS WE
DIDN'T UPON UNDERSTAND THAT
VIRUSES MIGHT ACTUALLY HAVE A
ROLE IN SOME OF THESE DISEASES
MORE THAN WE UNDERSTOOD BEFORE
AND TO TRY TO UNDERSTAND WELL I
WANT TO THANK EVERYONE FOR THE
TIME WE'VE HAD BUT HOW ARE WE
DOING ON TIME?
DO WE HAVE MORE TIME?
ANY OTHER QUESTIONS?
>> DR. FAIRWEATHER THERE WAS A
QUESTION IS THERE CONVINCING
EVIDENCE FOR ENDOTHELIUM
INFECTION BY THE VIRUS, I THINK
THAT'S PRETTY CLEAR, YES AND I
JUST GOOGLED PULLED UP A
FRONTIER IN MEDICINE 2021
ARTICLE MULTICENTER PATHOLOGY
REPORT AND YEAH, IT'S IN THE
ENDOTHELIUM AND YOU PROBABLY CAN
ANSWER THAT AS WELL.
>> GREAT.
THANK YOU SO MUCH SO DO WE HAVE
MORE TIME FOR QUESTIONS ARE WE
ALMOST OUT DR. KANTHI.
>> DR. FAIRWEATHER WE DO NEED TO
MOVE ON TO THE NEXT SESSION, BUT
THANK YOU VERY MUCH.
THIS WAS AN INTERESTING
DISCUSSION.
>> SO I'M DELIGHTED TO INTRODUCE
THE NEXT SESSION, GIVE ME JUST A
MOMENT HERE AND THIS IS ON SEX
AND GENDER RELATED MECHANISMS
THAT UNDERLIE BLOOD, DISEASES
AND COVID.
I WILL FIRST JUST PRESENT TO YOU
MY DISCLOSURES FOR FULL
TRANSPARENCY AND THEN AND THEN
INTRODUCE OUR SPEAKERS.
SO THE FIRST SPEAKER IS--SO WE
HAVE A VERY EXCITING SLATE OF
SPEAKERS HERE, OUR FIRST SPEAKER
IS DR. DALE ABEL, HE IS THE
WILLIAM S. ADAMS DISTINGUISHED
PRACTICES FESSOR OF MEDICINE,
CHAIR AND DEPARTMENT OF MEDICINE
AT THE DAVE I GEF, EN SCHOOL OF
MEDICINE AND HEALTH.
HE FORMERLY THE CHAIR OF
DEPARTMENT OF MEDICINE AND
DREBTOR THE DIABETES RESEARCH
CENTER AT THE UNIVERSITY OF IOWA
WHICH GREW CONSIDERABLY WITH HIS
LEADERSHIP.
HE'S A QUINTESSENTIAL SCIENTIST,
LONG DISTINGUISHED CAREER IN
ENDOCRINE AND METABOLISM
RESEARCH.
I LEARNED ABOUT HOW HIS RESEARCH
ON GLUCOSE TRANSPORT AND HOW
MITOCHONDRIAL METABOLISM HAS LED
TO A RELATED FIELD TO STUDY
MOLECULAR MECHANISMS THAT ARE
RESPONSIBLE FOR CARDIOVASCULAR
COMPLICATIONS, SO THIS INCLUDES
THINGS LIKE HEART FAILURE AND
WORK, HE WILL SHARE MORE DETAIL
TODAY EXPLORES MITOCHONDRIAL
ECANISMS THAT CROSS TALK AND
LINK METABOLISM WITH THROMBOSIS,
I WILL INTRODUCE OUR SPEAKERS AS
WE GET TO TIME.
DR. ABEL?
>> LET ME UNMUTE AND PUT MY
CAMERA ON, THANK YOU VERY MUCH
AND LET ME ALSO SHARE MY SCREEN
SO LET'S SEA.
I START TO SHARE, OKAY.
LET ME GO TO MY SLIDE SHOW.
OOPS.
OKAY, SO FIRST SLIDE.
THANK YOU VERY MUCH.
CAN YOU SEE MY SLIDE SHOW OKAY?
>> YES, IT'S VERY CLEAR.
SPHRKS PERFECT OKAY, SO TALKING
ABOUT RECENT WORK LOOKING AT THE
RELATIONSHIP BETWEEN ESTROGEN
AND MITOCHONDRIAL AND MY MAJOR
DISCLOSURE IS THAT THIS IS A
STUDY THAT WAS FUNDED IN
RESPONSE TO AN NHLBI RFA 18003
ON SEX HORMONE INDUCED THROMBOW
EMBOLISM IN PREMENOPAUSAL WOMEN
AND OUR FUNDING WORK IS ON OP A
1 AND ESTROGEN TYPE OF
ACTIVATION.
SO HERE'S BACKGROUND SO
MITOCHONDRIAL IS A PROCESS OF
REPEATED FISSION THAT ARE
REGULATED BY PROTEINS, DRP1 AND
FIS1 FOR FISSION, AND OP A 1 AND
MITOFUSEIN IN FUSION, ALSO
MAINTAINS MORPHOLOGY.
THE PROJECT BEGAN WITH AN
OBSERVATION WAS MADE BY JANE
FREED MAN WHERE HE DID
TRANSCRIPTOMIC ANALYSIS FROM THE
FRAMINGHAM COHORT AND THESE ARE
CT VALUES IN THE COHORT AND YOU
CAN SEE THAT THE CT VALUES ARE
LOWER MEAN THAT THE LEVELS ARE
HIGHER IN FEMALES AND MENTIONING
THE ANALYSIS OF MULTIPLE
TRANSCRIPTS, IT TURNED UP THAT
OPA 1 [INDISCERNIBLE] WAS HIGHLY
PREDICTIVE OF FEMALE SEX WITH
THE P-VALUE OF 10 TO THE MINUS
12 SO THAT GOT US CURIOUS ABOUT
THEN REGULAT OF OPA 1 BY
ESTROGEN AND SO, THIS IS JUST
ESTROGEN LEVELS IN PREGNANCY AND
YOU CAN SEE THAT FROM
PREPREGNANCY TO TRIMESTER IS A
SIGNIFICANT INCREASE IN
ESTROGENS NOW IF WE LOOK IN THIS
COHORT AND LOOK AT THE
REGULATION OF OPA 1 IN
PREGNANCY, YOU CAN SEE HERE ON
THE LEFT THAT IF YOU GO FROM
PREPREGNANCY AND TO THOROUGH
TRIMESTER IS AN INDUCTION OF OPA
1, EXPRESSION IN PREGNANCY AND
THIS GOES DOWN IN THE POSTPARTUM
PERIOD, THE ADDITION THE
PROTEASE 1 E1 THAT REGULATES
CLEAVAGE IS ALSO REGULATED IN
PREGNANCY PEEKS IN THE THIRD
TRIMESTER AND FALLING BACK IN
THE POSTPARTUM PERIOD.
SO A BIT OF HANDLE ON THE
BIOLOGY OF OPA 1 AND PLATELETS
WE GENETICALLY MANIPULATED
LEVELS IN MALE AND FEMALE MICE
SPECIFICALLY IN THEIR PLATELETS
AND WE WERE VERY INTRIGUED TO
SEE SEX DIFFERENCES SUMMARIZED
IN THE NEXT FEW SLIDES SO FIRST
OF ALL THESE ARE DATA FROM MALE
MICE, AND IF YOU LOOK HERE, CAN
YOU SEE MITOCHONDRIA IN THE
WILD-TYPE MICE, IT'S A VERY NICE
CLEAR SEQ IN THE MALE MICE WITH
THE PLATELETS, YOU CAN SEE THAT
THEY ARE ALL CANNED WHAT INSTEAD
OF GRANULAR WHICH IS WHAT WE
EXPECT WITH THE DEFICIENCY AND
THERE'S A [INDISCERNIBLE] DNA IN
CONTRAST IN THE FEMALES, YOU
CAN--WE OBSERVED INFREQUENTLY
THAT THE MIGHT O CHOND AREA WAS
UNAFFECTED IN THE OP A 1
DEFICIENT FEMALES AND THERE'S NO
EVIDENCE OF MITOCHONDRIAL DNA
DEPLETION IN THE FEMALES, WE
THEN DID ARCHITECT ON THE MALES
ON THE FEMALES AND JUST TO
QUICKLY SUMMARIZE IS THAT WHAT
WE LEARNED FROM THAT EXPERIMENT
IS THAT WHEN WE LOOKED AT MALES,
AFTER WE TOOK THEIR GONADs OUT
YOU CAN SEE THAT THE PLOIT THAT
YOU CAN AND SHOW THE MORPHOLOGY
IN THE MALES THAT WERE
[INDISCERNIBLE].
IN CONTRAST IN THE FEMALES WHO
HAD DEFICIENCIES WHERE THINGS
WERE NORMAL WHERE WE TOOK OUT
THEIR OVARIES WE SAW THAT THE
MORPHOLOGY WAS DISTURBED SO THIS
IS SHOWING THE CIRCULATING SEX
STEROIDS.
SO THEN ACTIVATION INVITRO AND
IN VIVO SO PATTERN A AND B IN
BLUE ARE SHOWING THE MALE KNOCK
OUT ANIMALS, HYPER ACTIVATION OF
PLATELETS, IN FEMALES THERE WAS
NO DIFFERENCE IN INVITRO
ACTIVATION.
WE DID A DVT EXPERIMENT AND YOU
CAN SEE THAT THE MALES HAD
BIGGER AND MORE THROMBI BUT THE
FEMALES HAD NO DIFFERENCE
COMPARED TO KNOCK OUTS AND
CONTROLS.
WE THEN LOOK AT ANOTHER MEASURE
OF THE FUNCTION WHICH IS
ARE--ADMINISTRATIVE TERIOLE
INCLUSION IN THE CAROTID ARTERY
AND WE OBSERVE THERE WAS A
REDUCTION IN THIS TABLE IN MALES
BUT IF FEMALES AS AN INCREASE IN
THE TIME TO [INDISCERNIBLE] SO
AGAIN 180-DEGREE DIFFERENCE IN
THE PHENOTYPE IN THESE ANIMALS.
SO WE WANT TO UNDERSTAND IF IN
IS SUBJECT TO THE HORMONE SO WE
DID A TRANSFER EXPERIMENT.
WHERE WE DEPLETED EITHER MALE OR
FEMALE MICE AND THEN TRANSFUSED
BACK INTO THEM, DONOR PLATELETS,
SO LET ME WALK YOU THROUGH THIS.
IN THIS EXPERIMENT WE'RE TAKING
MALE DONEAR PLATELETS AND
PUTTING THEM INTO A MALE HOST
AND CAN YOU SEE THAT WHEN YOU
PUT KNOCK OUT PLATELETS IN, WE
SAW THE REDUCTION TO STABLE
OCCLUSION, HOWEVER, WHEN WE
ACTUALLY DID THIS TRANSFUSION
INTO A FEMALE HOST WE SAW THAT
THE OP A 1 DEFICIENT PLATELETS
WHEN TRANSDUCED IS
[INDISCERNIBLE] INCREASED SO THE
OPPOSITE TO WHAT WE SAW IN THIS
EXPERIMENT.
SIMILARLY, WE DID A
FEMALE-FEMALE TRANSFER OF
PLATELETS, AGAIN WE SAW THAT
KNOCK OUT DONOR PLATE THAT'S IN
A FEMALE HOST SHOWED OCCLUSION
WHEREAS KNOCK OUT PLATELETS IN A
MALE HOST, THIS INFACT WENT AWAY
AND THEN WE FINALLY LOOKED AT
THE EFFECT OF CASTRATION ON BOTH
INVITRO AND IN VIVO MEASURES OF
PLATELET ACTIVITY.
SO IN PANEL E.
YOU CAN SEE THAT IN THE INTACT
ANIMALS THERE'S AN INCREASE IN
INVITRO ACTIVATION THAT WAS
ATTENUATE WHEN ANIMALS WERE
CASTRATED, WHEREAS IN THE
FEMALES YOU CAN SEE THAT THE
ABSENCE OF INCREASE IN
ACTIVATION INVITRO, WE NOW SEE
AN INCREASE IN THE ACTIVATION
INVITRO AFTER THE OVARIES WERE
REMOVED.
SIMILARLY WHEN WE TOOK MALES WHO
WERE INTACT AND I SHOWED YOU
THIS BEFORE, THEY HAVE A REDUCED
TIME TO OCCLUSION OF THEIR KNOCK
OUTS THAT REMOVAL OF THE GONADS
THERE IS NO OTHER INCREASE AND
IN FEMALES THAT WERE INTACT,
THAT WERE OP A 1 DEFICIENT IN
THE PLATELETS, THERE'S AN
INCREASE IN TERMS OF INCLUSION
WHICH IS IN FACT PREVENTED WHEN
WE TOOK THEIR OVARIES OUT AND
THEN WE TOOK MALE ANIMALS AND WE
IMPLANTED THEM WITH ESTRA-DIAL
PELLETS AND YOU CAN SEE THAT THE
TIME DEFICIENT WAS DECREASED
THIS WAS AGAIN REVERSED IN
ANIMALS THAT WERE TREATED
[INDISCERNIBLE].
SO THE REQUESTY IS COULD
ESTROGEN DIRECTLY MODULATE
MITOCHONDRIAL OP A 1 DEFICIENT?
SO THIS ON THE TOP ARE PLATELETS
ISOLATED FROM ACTUAL BONE
ADIPOSE TISSUE, FOR PLATELETS
AND THESE ARE MITOCHONDRIAL FROM
OPA 1 DEFICIENT MICE AND YOU CAN
SEE AGAIN THE DISMORPHIC
APPEARANCE OF THE MITOCHONDRIAL
AND THIS IS NOT CHANGED BY
COLLECTERAL BUT WITH INCUBATION
TISSUE AND MACROPHAGES OX FEN
AND HISTOLOGIC OR FORMAICOLOGGIC
ESTRA-DIAL, YOU SEE THE
RESTORATION OF THE MITOCHONDRIAL
MORPHOLOGY AND THIS IS
QUANTIFIED ON HERE.
ON THE BOTTOM YOU CAN SEE THAT'S
A LOSS IN THE KNOCK OUTS AND IN
FACT THERE WAS A RESTORATION OF
LAMELLAR- CRISTACE, WHEN WE
PLRVE OBSERVED THAT IN THE
TUBES.
AND WE SAW THERE'S UPTAKE IN
MALES AND FEMALES WHEN WE
ACTUALLY MEASURED THIS BY MASS
SPECTROSCOPY.
SO TO SUMMARIZE THEN WHAT WE SEE
IS WHEN WE DELETE OPA 1 IN
PLATELETS WE SEE THAT THERE IS A
STRIKING RESPIRATORY PHENOTYPE
IN MALES AND ACTIVATION IN
INCREASE IN THROMBOSIS IN MALES
WHICH IS REVERSED BY ADOPTIVE
TRANSFER WHEREAS IN FEMALES WE
SEE THAT IN FACT THIS IS VERY
WELL TOLERATED AND IN FACT,
THERE'S A DECREASE IN OUR
THROMBOSIS, SO THE QUESTION S&P
THERE TRUE IN THIS HUMAN
PLATELETS SO TO ADDRESS THIS WE
DEVELOPED A CRISPR METHOD TO
DEVELOP HUMAN HEMATOPOIETIC STEM
CELLS AND UCARIO SIGHTS TBR
HUMANS AND THEN WE USE CRISPR TO
KNOCK DOWN OPA 1 AND WE DID THAT
HERE AND THIS WAS CHARACTERIZED
BY A LOSS OF MITOCHONDRIAL
MEMBRANE PROTENTIAL.
WE THEN EXPOSE THESE HUMAN
DERIVED SACKS THROUGH INVITRO
AND YOU CAN SEE MITOCHONDRIAL
SHOWN HERE IN ANIMALS THAT
WERE--SORRY, IN MEGACARIO SIGHTS
AND THEN WHEN WE SAW INVITRO WE
SAW RESTORATION OF THE
MITOCHONDRIAL PRISTINE
MORPHOLOGY.
SO FINALLY, IF THIS IS TRUE IN
HUMANS?
SO TO ADDRESS THIS JENNIFER
STREETER, CARDIOLOGIST IN OUR
LAB LOOKED AT A LARGE DATABASE
THAT IS PULLED FROM MILLIONS OF
ELECTRONIC MEDICAL RECORDS
ACROSS THE WORLD AND
SPECIFICALLY THE QUERIES LOOKED
AT WAS PATIENT WHO IS WERE
ADULTS WHO HAD AUTOSOMAL
DOMINANT ATROPHY AND CONFIRMED
BY SEQUENCING OR A GENE TEST AND
THEN LOOK FOR THE PRESENCE OR
ABSENCE OF VENUS THROMBI
EMBOLISM AND LET ME SHOW YOU 1
TABLE FROM THIS ANALYSIS, IT'S A
BUSY TABLE SO I WILL WALK YOU
THROUGH IT.
WE'RE MAKING COMPARISONS HERE,
WE ARE COMPARING PATIENTS WITH
ALL CONTROLS, GOOD NUMBERS OR
BAD NUMBERS AND MALES IN CONTROL
MALES OR FEMALES AND CONTROL IF
FEMALES ARE OPA 1, AND WE LOOK
AT THEM IN THE SYSTEM, I'M
SHOWING YOU THIS DATA FOR THE
NERVOUS SYSTEM, IS TRUE FOR WHEN
WE CONTROL FOR THE SARS UPDATE
IN THE SYSTEM.
SO CAN YOU SEE THAT IF YOU LOOK
AT THE RISK RATIO FOR VENUS THOM
BI EMBOLISM IN PATIENTS WITH
CONTROLS IT IS SIGNIFICANTLY
INCREASED IN THE ENTIRE
POPULATION, THAT'S ALSO TRUE IN
MALES, DISP ALSO TRUE IN FEMALES
IN THOSE WITH NO DISEASES OFF
THE NERVOUS SYSTEM AND APREACHES
STATISTICAL SIGNIFICANCE WHEN
YOU COMPARE OPA 1 EFFECTED MALES
AND FEMALES.
HOWEVER WHEN WE LOOK AT PATIENT
WHO IS HAD THESE ORDERS OF
UPDATE NERVOUS SYSTEM OR THE
MUSCULAR SYSTEM, THE FIRST
RELATIONSHIPS CONTINUE TO HOLD
TRUE BUT IMPORTANTLY AT THE
BOTTOM HERE, THE RELATIONSHIP
BETWEEN OPA 1 AND FEMALES IS
ACTUALLY AN INCREASED RISK OF
VENUS THROMBOLLISM IN OPA 1
MALES RELATIVE TO OPA 1 FEMALES.
SO JUST TO SUMMARIZE THEN, THIS
PART OF THE STUDY, MALES OR
FEMALES WITH OPA 1 MUTATIONS
HAVE INCREASED VENOUS
THROMBOW-'EM BOL ITCH RELATIVE
TO SUBJECTS WITHOUT OP A 1
MUTATIONS AND MALES WITH OPA 1
MUTATIONS HAVE INCREASED VENOUS
THROMBO-EMBOLISM RELATIVE TO
FEMALES WITH OPA 1 DISORDERS
THAT ARE PRESENT.
SO WHAT THIS SHOWS IS THAT THIS
IS INTERESTING INTERACTION
BETWEEN MIGHT O CHOPPEDRIAL
DYNAMICS AND WHAT THIS TELLS US
IS THAT PERHAPS IN PREGNANCY FOR
EXAMPLE, WHAT THE
ESTRA- DIOLs, THERE, I THINK
THAT'S HOLDING TRUE FOR GAPS IF
FUTURE DIRECTION IS COULD OPA 1
EXPRESSION IN PLATELETS BE USED
AS A BIOMARKER TO PREDICT RISK
OF DISEASE IN WOMEN PRIOR TO
ESTROGEN ADMINISTRATION.
DOES THE RELATIONSHIP BETWEEN
OPA 1 AND THROMBOSIS RISK HOLD
TRUE IN POST MENOPAUSAL WOMEN
AND WHAT ADDITIONAL BIOMARKERS
OF PLATELET ACTIVATION MIGHT BE
RELATED TO VARIATIONS FOR
OPARE--ADMINISTRATIVE 1 RISK
MODULATION?
THANK YOU FUR YOURCANDIDATES
ATTENTION.
>> RIGHT ON TIME.
THANK YOU.
AND SO I CERTAINLY HAVE A LOT OF
QUESTIONS, WE NEED TO MOVE TO
THE NEXT SPEAKER HERE, SO I
WOULD LIKE TO INTRODUCE
DR. ZUBAID RAFIQUE, ASSOCIATE
PROFESSOR AND ASSOCIATE RESEARCH
DIRECTOR OF EMERGENCY MEDICINE
AT BAYLOR AND FACULTY OF THE
AMERICAN COLLEGE OF EMERGENCY
PHYSICIANS, HIS RESEARCH
INTERESTS ARE IN HYPER COLEMMIA,
KIDNEY BIOMARKERS AND TBI.
DURING THE PANDEMIC HE ACCEPTED
UP TO DO WORK ON MULTIPLE COVID
RELATED STUDIES INCLUDING C3 PO
WHICH IS A CONVALESCENT PLASMA
TRIAL WHICH HE WILL SHARE TODAY.
HE'S BEEN AN EMERGENCY
DEPARTMENT BASE STUDIES AND HIS
EXPERIENCE RANGES FROM CUTTING
EDGE BIOMARKER TESTING AND
EVALUATING DRUGS FOR USE IN THE
SETTING, SO I WILL STOP HERE AND
DR. RAFIQUE, EXCITED TO SEE WHAT
YOU HAVE FOR US.
>> THANK YOU.
I WILL SHARE MY SCREEN FIRST.
>> THANK YOU TO THE ORGANIZERS
FOR INVITING ME.
CAN YOU SEE MY SCREEN?
DISMRKS --
>> YES WE CAN.
>> I AM ZUBAID, RAFIQUY, BAYLOR
COLLEGE OF MEDICINE AND I WILL
TAKEN--THEYUC ABOUT CONVALESCENT
PLASMA STUDY, AND I AM GIVING
THIS TALK ON BEHALF OF THE
CPOPTRKS NO RELEVANT DISCLOSURES
SO THIS IS AGENDA FOR BACKGROUND
I WILL BRIEFLY DISCUSS GENDER
SPECIFIC OUTCOMES AND TALK ABOUT
THE C3 PO STUDY AND THIS WAS A
STUDY WITH DATA FROM HERE TO DO
THE GENDER SPECIFIC OUTCOME
STUDY.
HYPOTHESIS RESULT AND THEN OUR
CONTROL.
SO AS FAR BACKGROUND, THE
LAST--TODAY AND YESTERDAY WE
HAVE PLENTY OF STUDIES AND I
DON'T THINK I NEED TO CONVINCE
ANYMORE THAT MEN ARE ADVERSELY
OR MORE ADVERSEEE EFFECTED THAN
FEMALES IN OOSKT 19.
SO THERE ARE MULTIPLE STUDIES
OUT THERE.
NOW THERE ARE SOME STUDIES, SO
THIS IS NOT, UNIQUE TO COVID-19.
THERE IS A WHOLE BUNCH OF VIRAL
DID THEA AS WELL THAT MALES ARE
ADVERSELY AFFECTED IN NOSE IN
HEPATITISA AND TB AND HEP-C AS
WELL AS HIV VIRAL LOADS ARE
HIGHER IN MALES AND FEMALES MORE
ROBUST IMMUNE RESPONSE TO
VACCINES.
SO THESE STUDIES ALL SUGGEST
THAT A MORE ROBUST ABILITY AMONG
WOMEN TO CONTROL INFECTIOUS
AGENTS.
NOW THE TRENDS ARE REVERSED IN
LONG COVID WHERE FEMALE SEX AND
ASSOCIATED WITH LOWER LIKELIHOOD
TO RECOVER AT 1 YEAR.
THIS IS A STUDY OF 2000 PATIENTS
FOLLOWED FOR A YEAR AND ODDS
RATIO OF FEMALES.
SO WE HAVE THESE DISCREPANCIES
BETWEEN MALES AND FEMALES, THE
QUESTION IS DO WE FULLY
UNDERSTAND THE MECH INFORMS,
RIGHT?
AND THE EARLY STAGE WE ARE STILL
KIND OF UNDERSTAND.
NOW, NOW THERE ARE LOTS OF
HYPOTHESIS OUT THERE AND THERE
ARE LOTS OF SOCIAL DETERMINANTS
AND WE CHOSE TO WORK ON 1 OF THE
BIOLOGICAL DETERMINANTS.
SO CONVALESCENT PLASMA STUDY, SO
I WILL GO OVER TO THE PLASMA
STUDY, SO WE UNDERSTAND WHAT
KIND OF DATA, WHAT KIND WE CAN
LOOK AT SO THIS STUDY DOES CP
PREVENT PROGRESSION OF EARLY
MILD COVID ILLNESS FROM BECOMING
THIS WAS SPONSORED BY NHLBI,
PROGRAM OFFICER IS D
R. NAHED EL KASSAR, THIS WAS
COORDINATED BY SIREN BUT WE HAVE
MULTILE PIs AND FRED AND
VALERIE WORKED TOGETHER FOR THE
GENDER DISEASE RESEARCH AND THE
RESULTS WERE PUBLISHED LAST YEAR
IN THE NEW ENGLAND JOURNAL.
SO HERE'S THE PRIMARY OUTCOME OF
THE STUDY WHICH IS DEATH,
HOSPITAL ADMISSION OR EMERGENCY
OR RETURN VISITS.
AND SO HOW THIS HAPPENED IS,
PATIENTS WITH MILD DISEASE CAME
INTO THE EMERGENCY DEPARTMENT
AND THEY GOT RANDOMIZED TO
CONVALESCENT PLASMA OR SAILEN
AND THEY WERE FOLLOWED FOR PANE
DAYS AND PRIMARY OUTCOME FOR 30
DAYS, AND OVERHERE SAMPLE 1, 2,
3, AND 4, THESE ARE THE PLACES
WE COLLECTED BLOOD FROM THE
PATIENT, AND THOSE ARE THE BLOOD
SAMPLES WE USED FOR OUR STUDY.
SO ONCE AGAIN THE STUDY
PUPPULATION IS ADULTS WITH MILD
SYMPTOMS OF COVID-19 WHO ARE AT
RISK FOR PROGRESSIVELY SEVERE
ILLNESS AND AT THE TIME THEY
PRESENTED THEY
WERE--[INDISCERNIBLE] INCLUSION
CRITERIA WAS 1 OR MORE SYMPTOMS
OF COVID AND LAB CONFIRMED
DIAGNOSIS OF COVID, AND 1 OF THE
RISK FACTORS AGE, HYPERTENSION,
DIABETES, CDC RISK FACTORS FOR
SEVERE DISEASE.
PATIENTS FOR MANAGEMENT AND CP
AVAILABLE AND DURATION OF SIM
TOMS GREATER THAN 7 DAYS, AND
SIGNED INFORMED CONSENT.
EXCLUSION CRITERIA, YOUNGER THAN
18, IF YOU HAD REACTION TO BLOOD
TRODUCTS THEN YOU WERE EXCLUDED
OR YOU COULDN'T FOLLOW UP.
SO HERE'S THE PRIMARY COMPOSITE
OUTCOME WHICH IS YOU HAD 511
PATIENTS, 1 VALLEYSENT PLASMA
OVER HERE, PLACEBO GROUP OVER
HERE AND PATIENTS WITH DISEASE
PROGRESSION, SO IN THE
CONVALESCENT PLASMA GROUP, 30%
SEVERE ILLNESS OR PRIMARY
OUTCOME AND IN THE PLACEBO GROUP
IT WAS 95%, AND IT WAS NOT
SIGNIFICANT BETWEEN THE 2.
THERE WERE SUBGROUP ANALYSIS
DONE AND THERE WAS NO DIFFERENCE
BETWEEN THE SUBGROUPS FOR
TREATMENT EFFECT.
ALL RIGHT, I WILL TAKE A LOOK AT
THE MALE-FEMALE HOW THIS IS
PRESENTED TO THE NEXT SLIDE.
AND HERE WE GO, MALES HAD A
LITTLE WORSE OUTCOME THAN
FEMALES BUT THIS WAS NOT
SIGNIFICANTLY SIGNIFICANT.
THAT'S WHERE WE LEFT THAT.
WHAT WE DID FIND IS WE LOOKEDDA
THE JUST MALES OR JUST FEMALES,
THE WHOLE GROUP MALES HAD
PROGRESSED TO SEVERE ILL PS,
VERSUS 27%.
RIGHT?
SO THERE'S A 10% DIFFERENCE
BETWEEN MALES AND FEMALES IN 511
PATIENTS THAT WERE INVOLVED.
WHICH WE HAVE SEEN IN MULTIPLE
OTHER IS IT THES THAT THERE ARE
DIFFERENCES BETWEEN MALES AND
FEMALES IN THE LAST COUPLE DAYS
AND ALSO META-ANALYSIS OUT
THERE, LOOKING AT THIS
DIFFERENCE.
NOW THE QUESTION IS WHY THAT IS.
AND THE FIRST THING WE REACHED
OUT TO WAS THE ANTIBODIES RIGHT?
SO ANTIBODY LEVEL, VACCINES AND
ANTIBODY LEVELS HAVE BEEN AT THE
FOREFRONT OF THIS PANDEMIC FIGHT
SO WE THOUGHT MAYBE FEMALES WILL
HAVE HIGHER ANTIBODY LEVELS AND
THAT'S WHY THEY'RE PROTECTED.
SO THAT'S WHAT WE LOOKED AT.
SO BEFORE WE GET TO THE ANSWERS
THERE YOU WANTED TO MAKE SURE
THE GROUPS, MALES AND FEMALES
HAD SEVERE ILLNESS SEVERITY,
SIMILAR ILLNESS SEVERITY AND HOW
WE CONTROL THOSE WERE SYMPTOM
ONSET SO MEDIAN DAYS FROM ONSET
OF SYMPTOMS FOR MEN 4 DAYS,
WOMEN THEY WERE 3 DAYS AND THEY
WERE NOT SIGNIFICANTLY
DIFFERENCE IN THE 2 GROUPS.
HOWEVER, SYMPTOM ONSET IS
CORRELATED WITH OUTCOMES SO
THAT'S SOMETHING TO CONSIDER.
WE ALSO LOOKED AT A NUMBER OF
SYMPTOMS, SO, MEDIAN NUMBER OF
SYMPTOMS FROM MEN WERE 5 AND FOR
WOMEN WERE 6, AND THERE WAS NO
DIFFERENCE BETWEEN THE GROUPS
AND THEN NO RELATIONSHIP
OUTCOME.
WHAT WE DID FIND IN DIFFERENCES
IN THE GROUPS WERE AGE, TOBACCO
USE AND CORONARY ARTERY DISEASE,
CORONARY ARTERY DISEASE WE
DIDN'T HAVE AS MANY PATIENTS,
LESS THAN 10% AND MOW OUTCOME
EFFECT.
WITH CORONARY ARTERY DISEASE BUT
AGE AND TOBACCO WE ENTER THESE
IN THE REGRESSION MODEL AND SEX
WAS STILL A DRIVER FOR THE
OUTCOME DIFFERENCE.
WE ALSO LOOKEDDA THE COMORBID
CONDITIONS, OBESITY,
HYPERTENSION, DIABETES, THERE'S
1 ANOTHER THAT WE WILL SEE HERE,
COPD AND THERE WERE NO
DIFFERENCES BETWEEN THE
DIFFERENT GROUPS, OR, SORRY, 2
GROUPS OF THE HYPERTENSION WAS
THE ONLY 1 THAT WAS MORE LIKELY
TO HAVE AN OUTCOME IF YOU HAD
HYPERTENSION.
ALL RIGHT, SO THESE ARE ANTIBODY
TITERS SO AT BASE LINE MALES IF
FEMALES WERE SIMILAR.
SO THEY STARTED OFF SIMILAR,
WHICH IS GOOD AND THEN AT 15
DAYS, THE RISE IN ANTIBODY
LEVELS IN MALES WAS HIGHER THAN
IN FEMALE.
THIS IS THE MODEL OVER HERE, SO
MALES WERE A LITTLE HIGHER THAN
FEMALES, AND WHAT WE WERE
EXPECTING WITH THE FEMALES
HIGHER THAN MALES BECAUSE THEY
HAD A PROTECTED EFFECT, RIGHT?
SO WE--WE DIVIDED THIS UP
FURTHER CATEGORIZED IT BY
OUTCOME, OUTCOME 1 IS ACTUALLY
POOR OUTCOME, AND OUTCOME 2 IS
PATIENT WHO IS ARE NOT HAVING
SEVERE DISEASE.
O OUTCOME 1 SEVERE DISEASE,
OUTCOME 2 NOT SEVERE DISEASE AND
SAME TREND EXISTS, MALE HAVING
HIGHER ANTIBODY LEVELS
REGARDLESS OF OUTCOME.
SO IF THEY'RE SICK, OR NOT SICK,
MALE ALL HIGHER ANTIBODY LEVEL
ALTHOUGH THESE NUMBERS WERE NOT
SIGNIFICANT [INDISCERNIBLE].
SO OUR CONCLUSIONS WERE MEN HAD
10% HIGHER RATE OF PROGRESSION
FROM MILD TO MODERATE DISEASE,
BASE LINE ANTIBODY LEVELS SAME
IN MEN AND WOMEN REGARDLESS
OUTCOME, RISE IN ANTIBODY LEVELS
IS LARGER IN MEN, REGARDLESS OF
OUTCOME AND THEN THE HIGHER
ANTIBODY LEVEL IN MEN REGARDLESS
OF OUTCOME.
THERE WERE LIMITATIONS INNED
STUDY FOR SYMPTOM SEVERITY, WE
WITH DAYS AND MOW MANY SYMPTOMS
THAT I CAME IN WITH AND THERE
ARE MUTATIONS THERE, THERE ARE
SOME MISSING DATA OVER HERE,
HOSPITAL INTERVENTIONS, PATIENTS
WHO ENDED UP IN HOSPITALS, AND
WHAT KIND OF INTERVENTIONS THEY
HAD, WE DON'T HAVE THAT DATA
OVER HERE IN THIS MODEL, AND
COULD THAT HAVE EFFECTED THE
ANTIBODY LEVEL AT 15 DAYS, IF
POSSIBLE SO WE DON'T HAVE THAT
AND AND WHOLE HOST OF OTHER
THINGS AND I AND INVOLVED IN
THIS, .
>> WONDERFUL THANK YOU VERY MUCH
VERY MUCH, THAT WAS REALLY
INTERESTING EXPW I HAVE A NUMBER
OF QUESTIONS I KNOW OTHERS DO AS
WELL, I'M GETTING MESSAGES ABOUT
THAT, SO, LET'S MOVE TO OUR NEXT
TALK.
THIS IS DR. MATTHEW NEAL WHO IS
ROBERTA SIMONS ASSOCIATE
PROFESSOR OF SURGERY, ASSOCIATE
PROFESSOR OF CRITICAL MEDICINE
AND CLINICAL TRANSLATIONAL
SCIENCE AT THE UNIVERSITY OF PIT
PITS, DR. NEAL IS A PRACTICING
TRAUMA SURGEON AND INTENSE
SURGEON SCIENTIST AT UPMC,
SERVES AS THE DOCTOR OF
PITTSBURGH TRAUMA AND
TRANSFUSION MEDICINE CENTER
WHICH COLLABORATION THROUGH
TRAUMA RESOURCE CONFUSION, AND
CLINICAL TRIALS AND AND
PERSONALLY ON MORE THAN 1
OCCASION, ACTIVE FOR A TRIAL,
AND 1 OF THE DIRECTORS OF THE
ACTIVE 4 CLINICAL AND DATA
COORDINATING CENTER WHICH ARE
NHLBI SPONSOR.
DR. NEAL WAS AN ORGANIZING AND
FOUNDING MEMBERS OF THE
MULTIPLATFORM RANDOMIZED
CLINICAL TRIAL, AND DR. NEAL
WILL SHARE WITH US HOW COVID
THROMBOTIC COMPLICATIONS MAY BE
PRESENT AND INFLUENCE--
>> ISSUES RELATED TO SEX AND
GENDER.
--MENTIONED AS THE CO CHAIR OF
THE ACTIVE 4A TRIAL.
AND SO, I THINK NICELY SUMMARIZE
OVER THE COURSE OF MULTIPLE
TALKS THE LAST DAY AND A HALF IS
THE ROLE OF IMMUNO THOMBOSIS AND
THROMBOTIC COMPLICATIONS IN
COVID-19 AND I WANT TO EMPHASIZE
JUST BY BRIEF INTRODUCTION THAT
WE SOUGHT OUT WITH GREAT
INTEREST IN UNDERSTANDING BOTH
THE ROLE OF MICROVASCULAR AND
MACROVASCULAR THROMBOSIS IN
PATIENTS WITH COVID-19 AND THIS
REALLY SERVED AS THE RATIONAL
FOR THE INITIATION OF THE ACTIVE
4A TRIAL AND OTHER PLATFORMS
THAT STUDIED VARIOUS MECHANISMS
OF THROMBOW PROPHYLAXIS AND
ANTITHROMBOTTIC STRATEGIES IN
THE VASCULAR BIOLOGY OF
COVID-19.
DR. KANTHI MENTIONED THE
RANDOMIZED PLATFORM TRIAL AND I
WANT TO SUMMARIZE THAT BRIEFLY
HERE BEFORE THE RESULT SO THAT
YOU--SO THAT YOU UNDERSTAND THE
OUTCOMES AND HOW WE GOT THERE.
THIS INITIATIVE IS BY FAR THE
MOST COLLABORATIVE 1 THAT I HAVE
EVER BEEN A PART OF IN SCIENCE
AND ESSENTIALLY WHAT THE MPRCT
WAS A PROSPECTIVE ALIGNMENT OF
PLATFORMS, THE CANADIAN CHR
FUNDED ATTACK TRIAL.
THE INTERNATIONAL CAP REMAP
CONSORTIUM AND THE NHLBI ACTIVE
FUNDED 4 PROGRAM TO ALIGN
PLATFORMS TO DESIGN A HARMONIZED
TRIAL TO STUDY IN THE FIRST 2
ARMS THERAPEUTIC VERSUS USUAL
CARE OR PROLACTIC DOSE HEP A RIN
HAD HOSPITALIZED PATIENTS WITH
COVID-19.
NOW THERE HAVE BEEN NUMEROUS
OTHER STUDIES IN ANTICOAGULATION
AND THROMBOTICS I WILL TALK ONLY
ABOUT THE MPRCT AND ACTIV-4 NOW.
BUT I WILL HIGHLIGHT THAT IT WAS
ORGSUPPORT FREE DAY ANDS IT WAS
DAYS FREE OF ORGAN SUPPORT AND
IT ALIGNED WITH THE HYPOTHESIS
THAT REQUIREMENT FOR ORGAN
SUPPORT WAS SECONDARY TO
MICROVASCULAR THROMBOSIS AND
INJURY WITH THE HOPES THAT
INITIATION OF ANTICO AGZULATION
COULD REDUCE OR PREVENT THAT.
AS I MENTION THE FIRST 2 ARMS OF
THE MPRCT WERE STUDYING
THERAPEUTIC VERSUS USUAL CARE OF
HEP A RINs, THIS WAS A
MAGMATIC INTERNATIONAL TRIAL
CONTUCTED IN 10 COUNTRIESA THE
393 SITES.
SUBSEQUENT TO THE MPRCT, THE
ACTIV-4 PLATFORM AS CONTINUED
AND THE ACTIV-4 A HAS STUDIED
OTHER ARMS IN ADDITION TO
HEPARINS.
WE REPOTENT STATED ON THE ROLE
OF P2 Y12 IN JAMA OR IN MODERATE
STATE OR IN AWARD LEVEL CARE AND
IN SEVERELY PATIENTS IN THE
INTENSIVE CARE UNIT WITH
COVID-19 WE ARE ACTIVELY
ENROLLING IN THE P2 Y 12 DOMAIN
WITH 947 PATIENTS ENROLLED AS OF
EARLIER THIS WEEK.
WE ALSO HAVE ADDITIONAL ARMS
STUDYING SGLT2 INHIBITION AND
CRIZANLIZUMAB AS OTHER STRATEGY
FOR THE INTERSECTION OF
INFLAMMATION AND VASCULAR
BIOLOGY INJURY IN COVID-19.
SO I WANT TO SHOW YOU THE
RESULTS OF THESE STUDIES AND
WHAT I'VE HIGHLIGHTED ON EACH OF
THE SLIDES FOR THE RESULTS THAT
HAVE BEEN PUBLISHED TO DATE IS
THE ENROLLMENT BY SEX.
THE FIRST RESULT OF THE MPRCT
WAS IN THE SEVERE OR ICU STATES
STUDYING THERAPEUTIC VERSUS
PROPHYLACTIC DOSE HEPARINS, THIS
WAS STOPPED BY THE DSMB IN TBEPT
20 FOR A FINDING OF FUTILITY AND
WHAT YOU CAN SEE IF YOU'RE NOT
FAMILIAR WITH THE STACKS BAR
GRAPHS, I CALL YOUR ATTENTION TO
WHAT IS LABELED AS PANEL B, AND
FOR SIMPLICITY, RED IS BAD AND
BLUE IS GOOD.
THIS COMPOSITE OUTCOME ORGAN
SUPPORT FOR 3 DAYS INCLUDES
DEATH WHICH RECEIVES THE WORST
SCORE OF NEGATIVE 1.
SO FURTHER TO THE LEFT IS
NEGATIVE DEATH ON OUT TO THE
BLUEST BAR WHICH IS 21 DAYS FREE
OF REQUIREMENT FOR ORGAN SUPPORT
AND WHAT YOU CAN SEE IS THAT IN
THE BASIAN STAOF THETICICAL
MODEL UTILIZED IN THESE TRIAL,
THERE WAS A 99.9% POSTERIOR
PROBABILITY OF FUTILITY AND
ACTUALLY A TREND TOWARDS HARM
WITH HIGHER RISK OF PLEADING
COMPLICATIONS IN PATIENTS
RECEIVING THERAPEUTIC DOSE
ANTICOAGULATION.
SO YOU'LL SEE THAT A MAJORITY OF
THE PATIENTS ENROLLED IN THAT
STUDY WERE MALE SEX REFLECT
BEING LIKELY SOME OF THE DATA
THAT'S BEEN SUGGESTED EARLIER
ABOUT--ESPECIALLY EARLY IN THE
PANDEMIC, IN EARLY PHASES.
THE WORSENING DISEASE SEVERITY
IN MEN AND THE HIGHER LIKELIHOOD
FOR A REQUIREMENT OF ICU CARE.
SHORTLY THEREAFTER AND REALLY 1
OF THE MARVELS OF THE MPRCT IS
HOW QUICKLY WE WERE ABLE TO
ACCUMULATE DATA WAS A REPORTING
OF THE MODERATE STATE OR AWARD
LEVEL CARE AND HERE WE WERE
DELIGHTED TO BE ABLE TO REALLY
REPORT A POSITIVE OUTCOME AND IN
ICE--IN NONICU LEVEL OR HOSPITAL
BASED PATIENTS WITH COVID-19.
ED STUDY WAS ACTUALLY STOPPED
BUYER FOR A FINDING HITTING A
TRIGGER OF SUPERIORITY WITH A
98.6% POSTERIOR PROBABILITY FOR
BENEFIT OF THERAPEUTIC
ANTICOAGULATION WITH HEPARIN
OVER USUAL CARE.
IN THESE PATIENTS ENROLLED OVER
THE SAME TIME PERIOD, A SLIGHTLY
MORE BALANCED ENROLLMENT OF MEN
VERSUS WOMEN WITH RATES
APPROACHING THESE TODAYS?
THE MALES AGAIN BENEFITING
ANTICOAGULATION IN THE MODERATE
STATE.
AS I MENTIONED 4A CONTINUED ON
POST FINDINGS OF THE 2 ARMS IN
THE MPRCT TO STUDY THE
ANTIPLATELET STRATEGIES AND THE
USE OF P2 Z 12 INHIBITION, WE'VE
REPORTED AS RECENTLY AS THE
BEGINNING OF THIS YEAR ON THE
NONICU MODERATE STATE WITH A
FINDING OF NO BENEFIT, NEEDING A
TRIGGER FOR FUTILITY OF THE
ADDITION OF P2 Y 12 ININCREASE
IN BODY HIB THORSITION TO
ANTICOAGULATION AGAIN WITH A
MORE BALANCED ENROLLMENT OF MEN
AND WOMEN IN THIS PUBLICATION.
YOU CAN SEE THE CITATION LISTED
BELOW.
SO I WANT TO COVER THE SEX AND
GENDER SPECIFIC OUTCOMES AND YOU
KNOW I WOULD SAY THAT WE SORT OF
HAD A PRETEST PROBABILITY TO SAY
THAT THERE REALLY WOULD BE A
SIGNIFICANT DIFFERENCE AND A LOT
OF THAT IS DRIIVE BY WORK IN THE
LITERATURE THAT IS SUMMARIZED BY
THIS NICE PUBLICATION IN THE
AMERICAN JOURNAL OF CARDIOLOGY
FROM THE NYU GROUP PUBLISHED
JUST LAST MONTH WHICH SHOWS THE
DISPROPORTIONATE BURDEN OF
MACROTHROMBOTTIC COMPLICATIONS
IN MEN AS COMPARED TO WOMEN, BUT
WA'S REALLY INTERESTING IN THIS
STUDY WHEN YOU LOOK AT THE BAR
GRAPHS FURTHEST TO THE RIGHT IN
EACH COLUMN OR IN THE FOREST
PLOTS TO THE RIGHT, THAT THESE
FINDINGS OF A DISPROPORTIONATE
BURDEN OF DEATH OR
PROMULGATEBOSIS HOALTD UP WORSE
IN MEN AT YOUNGER AGE GROUPS BUT
ONCE WE REACH AN AGE OF GREATER
THAN 75, AS WE ALL HAVE LEARNED,
WHERE THERE IS A
DISPROPORTIONATE BURDEN OF
DISEASE IN COVID-19 THE
DIFFERENCE IN SEX FALLS OUT HERE
AND SO, A REALLY IMPORTANT
OBSERVATION OF THIS BURDEN OF
PERHAPS IN YOUNGER INDIVIDUALS
BUT MAYBE OUTCOME PETEED OUTCOE
WAYS.
SO WE'VE GONE BACK TO THE DATA
AS I CONCLUDE FOR THE MPRCT AND
THE ACTIV 4A TRIAL AND THERE'S A
LOT MORE WORK TO BE DONE BUT I
WILL SHARE WITH YOU WHAT WE
WHICH IS REALLY ALL UNPUBLISHED
DATA IN THIS SUMMARY SLIDE.
I WILL TUMOR SPECTRUM IN
PRESPECIFIED SUBGROUP ANALYSIS,
THERE WAS NO TREATMENT EFFECT
WHEN STRATIFIED BY SEX AND A
NUMBER OF OTHER VARIABLES BUT
IMPORTANTLY THIS IS FOR THE
PRIMARY OUTCOME OF ORGAN SUPPORT
DAYS AND YOU WILL REMEMBER THAT
WE BELIEVE THAT THIS REFLECTS
THE BURDEN OF MICROVASCULAR
THROMBOSIS, BUT AS HIGHLIGHTED
BY THE SECOND BULLET POINT,
WE'VE NOT DONE A DETAILED
ANALYSIS OF THE IMPACT OF
TREATMENT UPON PLOOK THROMBOW
BOLLIC EVENTS.
IMPORTANTLY WE HAVE A STRONG
INTEREST IN 90 DAY OUTCOMES
WHICH WE HAVE FROM THESE STUDIES
AS A PROXY AND AS EXTENSION INTO
THE STUDY OF LONG COVID.
IN INITIAL STUDIES WE HAVE NOT
SEEN SEX/GENDER AS AUNE VALID
AND RELIABLEIATE VARIABLE.
BUT A STUDY ONGOING NOW LOOKING
AT HETEROGENERATED AITY
TREATMENT EFFECT, WE FOUND
THERAPEUTIC BENEFITS BUT WE NEED
TO STUDY IT.
AS CAN YOU SEE IN THIS BULLET
POINT WHAT I'VE HIGHLIGHTED IS
THAT WE THINK IN OUR ONGOING
STUDIES THAT THE THERAPEUTIC
ANTICOAGULATION APPEARS TO BE
MOST BENEFICIAL IN PATIENTS WITH
ELEVATED D-DIMERS AND HIGH BASE
LINE OXYGEN REQUIREMENT THAT
SHOULD NOT BE SURPRISING TO
ANYBODY.
THESE ARE PERHAPS THE SICKER
PATIENT WHO IS ARE GOING TO BEN
FRIT FROM AN INTERVENTION BUT
SUGGESTLY THERE DOES SEEM TO BE
AN ASSOCIATION OF BENEFIT OF
THERAPEUTIC ANTICOAGULATION, 2
FEMALES BUT ONLY WHEN THEY DO
NOT MEET CRITERIA FOR OBESITY.
AND O I'M GOING TO CLEES HERE
AND SAY THAT YOU KNOW WE KNOW
FROM A LOT OF OBSERVATIONAL DATA
THAT THERE'S A CLEAR INCREASE IN
MACROTHROMBOTTIC RISK IN MEN.
WE KNOW FROM OUR STUDIES NOW
THAT THERE'S NO OBVIOUS
TREATMENT BENEFIT DIFFERENTIAL
AND ANTICOAGULATION IN MALE
VERSUS FEMALE SEX OR OUR PRIMARY
OUTCOME BUT WE REALLY NEED AN
INDEPTH ANALYSIS OF SEX AND
GENDER ON THERAPY FOR
MACROTHROMBOTTIC EEIVETS.
BUT WHAT I WOULD PROPOSE TO THIS
AUDIENCE IS THE CONSIDERATION OF
NOT JUST SEX OR GENDER ASUNE
VALID AND RELIABLEIATE VARIABLES
BUT BASED ON THESE OBSERVATIONS
OF COMPETING RISK WITH AGE AND
BMI THAT WE'VE SEEN, IS TO
REALLY LOOK AT THE INTERACTION
VARIABLE OF SEX AND GENDER WITH
OTHER CRITICAL PARTS OF THE
PATHOPHYSIOLOGY AND PREDICTERS
OF DISEASE SEVERITY WITH
COVID-19 AND I THINK THAT'S GOT
TO BE REALLY CRITICAL FOR US IN
MOVING FORWARD AND IN THAT VAIN
AND AS I CLOSE, I JUST PUT UP A
CONTACT INFORMATION THERE
BECAUSE WE ARE VERY MUCH OPEN
FOR OPPORTUNITIES FOR
COLLABORATION AND FOR FUTURE
ANALYSIS AS WE BETTER UNDERSTAND
THE IMPORTANT IMPLICATIONS OF
SEX AND JEBDER ON OUR
ANTITHROMBOTTIC THERAPIES FOR
COVID-19.
THANK YOU VERY MUCH.
SNRK EXCELLENT.
THANK YOU VERY MUCH DR. NEAL, WE
WILL FIELD QUESTIONS IN THE
DISCUSSION SECTION THAT WILL
FOLLOW OUR NEXT PRESENTER.
SO THIS IS DR. ALEX TSOI.
DR. TSOI IS A RESEARCHER
INVESTIGATOR AT THE UNIVERSITY
OF MICHIGAN.
HIS RESEARCH FOCUSED ON
IDENTIFYING GENETIC AND
DENATIONAL LIBRARY OF MEDICINIC
COMOPPOSITE BEHAVIORIAL
PHENOTYPENTS FOR AUTOIMMUNE
DISEASES AND HOW THEY MAY
TRIBUTE TO DISEASE
HETEROGENERATED AITY, DR. TTOI
IS THE DIRECTOR OF THE CENTER
FOR CUE TAINIOUS BIO-INFORMATICS
AT THE UNIVERSITY OF MICHIGAN
AND DIRECTOR OF FUNCTIONAL
ANALYTIC CORE OF THE P30 FUNDED
UNIVERSITY OF MICHIGAN SKIN
BIOLOGY DISEASE AND RESOURCE
CENTER.
DR. TSOI HAS BEEN CONDUCTING
STUDIES TO HAPPENED THE POGHT O
PHYSIOLOGY FOR DISORD EROZANS
SUCH AS SORTING SIGNALS ICEIS,
SORTING SIGNALSIATIC ARTHRITIS
AND LUPUS, BY USING APPROACHES
HIS GROUP REVEALED DISEASE
SIGNALS IN CANDIDATES FOR DOWN
TREME ASSAYS OF PSORIASIS AND
GENETIC CIGNA NATURE FOR SORTING
SIGNALSIATIC ARTHRITIS RISK AND
HIS RESEARCH FOCUS ON THE
DEVELOPMENT AND IMPLEMENTATION
OF PIPELINES FOR GENOMIC DATA TO
HELP IDENTIFY NOVEL DISEASE
ASSOCIATED TRANSCRIPTS AS WELL
AS CONTACTS SPECIFIC RESPONSES
AND DISORDERS.
THEY WILL SPEAK TO US TODAY
ABOUT ELECTRONIC HEALTH RECORDS
AND SKIN AND BLOOD STUDIES AND
HOW THEY MIGHT INTERSECT IN
COVID-19 INFECTION.
DR. TSOI.
>> THANK YOU.
[INDISCERNIBLE].
GOOD AFTERNOON EVERYONE, THANK
YOU FOR LETTING ME SHARE OUR
WORK WITH YOU ALL.
SO MY RESEARCH FOCUSED ON
IDENTIFYING AND UNDERSTAND
GENETIC COMPONENT FOR DIFFERENT
INFLAMMATTORY CONDITIONS.
IN MY PRESENTATION TODAY, I WILL
SHARE WITH YOU SOME RECENT WORK
HOW THE SKIN DISEASES COULD BE
RELATED TO COVID INFECTION.
AND WE ALSO TRY TO LINK SOME OF
THESE OBSERVATIONS TO POETIC
KENTIAL CONTEXT SPECIFIC
INFLAMMATORY RESPONSE IN SKIN
AND HOW WOULD THEY PLAY A ROLE
IN POTENTIAL SEX BIAS OF
PHENOTYPES.
I HAVE NO CONFLICTS TO DISCLOSE.
BUT TO GIVE YOU BACKGROUND
INFORMATION, STUDIES SHOW THAT
20% OF COVID PATIENTS PRESENT
WITH A SKIN RASH AS A SYMPTOM
AND IN PATIENTS WITH SKIN
DISEASE SUCH AS PSORIASIS CAN BE
A GREATER RISK OF COVID
INFECTION AND COVID COULD ALSO
EXACERBATE EXISTING SKIN
CONDITIONS.
SO THERE WILL BE 3 MAJOR TALK
PARTS OF MY PRESENTATION, I WILL
SHARE WITH YOU RECENT FINDINGS
ABOUT HOW WE IDENTIFY SOME
SHARED COMPONENT WITH COVID AND
SKIN DISEASES, FOCUSING ON THE
SKIN CONDITIONS AND THE WORK
WITH YOU AND HOW WE IDENTIFY
CONTACTS DEPENDENT ON THE
INTERFERON RESPONSES IN SKIN AND
AT THE END I WILL SHARE WITH YOU
RECENT FINDINGS ABOUT THE SEX
DIFFERENCES IN MONOCYTE AND
DENDRITIC CELLS AMONG COVID
PATIENTS.
SO 1 OF OUR EARLY WORK WAS TO
PROVIDE BETTER BEDDING OF--HOW
WE CONDUCT THIS 2 YORES AGO AND
WE TRY TO ACTUALLY LOOK INTO THE
EPIDEMIOLOGICAL STUDY OF 400,000
PATIENTS AND AT LEAST 1 HEALTH
SYSTEM ENCOUNTER THAT INCLUDED
OVER 1000 COVID PATIENTS.
SO STUDIES AND THOSE AS WITH
OTHER SPEAKERS, NOW OLDER AGE
GROUP, OBESITY, AFRICAN AMERICAN
HAVE A HIGHER RISK OF COVID
INFECTION AND FOR THE OTHER
DIFFERENT CLINICAL FEATURES SUCH
AS--WE WILL ALSO BE ABLE TO
REPLICATE THAT INCLUDES
DIABETES, HEART DISEASES, ALSO
HAVE HIGH RATE OF COVID
INFECTION.
SO INTERESTINGLY EVEN SOMEONE
CAN INDIVIDUALLY BUT WE FIND
THAT MULTIPLE DIFFERENT SKIN
CONDITIONS, HAVE A HIGHER RISK
OF COVID INFECTION SO THEN WE
TRY TO GROUP THOSE TOGETHER,
THAT INCLUDE ACME ALOPECIA,
DERMA TITIS, LUPUS, PSORIASIS,
ROSE ASIA, AND WHEN WE GROAP
THIS SIGNATURE AND SEE THE
OBSERVATION, ASSOCIATIONS WITH
COVID INFECTION, WE FIND THESE
RESULTS.
AND INDICATING THOSE INDIVIDUALS
AT LEAST SOME KIN CONDITION TEND
TO HAVE A HIGHER INFECTION RATE.
SO SIMILARLY WE CONDUCT THE
ANALYSIS TO ASK WHAT DEMOGRAPHIC
OR CLINICAL VARIABLES WOULD BE
ASSOCIATED WITH MORE SEVERE FORM
OF COVID.
USING THE REQUIREMENT OF
MECHANICAL VENTILATION AS A
SURROGATE, SO I THINK AMERICAN
OLDER AGE GROUP, NOW OBESITY
TEND TO HAVE MORE SEVERE FIRM,
RESULT IS A BIT SURPRISING FOR
US, HIGHLIGHTING THAT
INDIVIDUALS WITH SKIN CONDITIONS
ACTUALLY TEBD TO HAVE LOWER RISK
OF HAVING MORE SEVERE FORM OF
INFECTION.
SO, OUR HR ANALYSIS TRY TO
EXAMINE IF OUR OBSERVATIONS
COULD BE BIAS OR SKEWED TOWARDS
THE IMMUNOSUPPRESSIVE TREATMENT
BECAUSE OF THOSE--MANY OF THOSE
SUPPRESSIVE TREATMENT HAVE BEEN
USED TO DESCRIBE TO TREAT
DIFFERENT SKIN CONDITIONS.
BUT EVEN OTHER CONTROLLING FOR
THE IMMUNO [INDISCERNIBLE]
TREATMENT, THE OBSERVATIONS THAT
I JUST SHARED WITH YOU STILL
HOLD.
SO NEXT WE WANT TO ASK WHAT KIND
OF--HOW WOULD THE SKIN DISEASES
WE POTENTIALLY SHARE INTRINSIC
FACTORS WITH COVID INFECTION,
SOPHISTICATEDY WE USE SORTING
SIGNALS ICA SIS AS A MODEL,
GENETIC FOR, YOU KNOW, FOR A
WHILE AND THEN WE COLLECTED OVER
10,000 GENO TYPES, OR I TAKE
INDIVIDUALS SO WE TRY TO SEE,
COMPARE THESE GENETIC SIGNALS
WITH ANOTHER INDEPENDENT STUDY,
THE STUDY, THE GENDER SPECIFIC
SUSCEPTIBLE FOR COVID INFECTION,
THAT CONSISTS OF 1600
INDIVIDUALS AT THAT TIME.
SO THIS IS--AMONG THE MANY
VARIANTS WE EXAMINED WE REVEALED
1 LOCUS FOR EACH ASSOCIATION, SO
EACH IS THE GENETIC VALID AND
RELIABLE YAGZ AND THE LONG TIME
P-VALUE FOR THE ASSOCIATION,
THIS IS LOCUS AND THEN THE 1S WE
HIGHLIGHT IN COLOR HERE ARE THE
1S SHOWING WHEN WE CONDUCTED
TIMES, DISEASE, ANALYSIS AND
SHOWED MOST OF THE CELLS.
SO WHAT POTENTIALLY EFFECT THESE
LOCUS WOULD HAVE.
SO THIS IS A LOCUS THAT
[INDISCERNIBLE] GENETIC SIGNAL
SOCKED WITH EXPRESSION OF
LCE-GENES, SO THESE LCE-GENES
FROM THE [INDISCERNIBLE] COMPLEX
IN CHROMOSOME 1 HAS BEEN SHOWN
TO PLAY ROLE IN SKIN INJURY,
INFLAMMATION OR HAVE
ANTI[INDISCERNIBLE] ACTIVITY.
SO INTERESTINGLY THIS GENES ALSO
UPREGULATED IN AN
RNARE--ADMINISTRATIVE-SEQ
INVESTIGATOR, AND HOW THESE
CELLS WOULD RESPOND TO THE COVID
INFECTION, SO WHEN WE
INVESTIGATE THIS GENES
EXPRESSIONS, A PROFILE ACROSS
MULTIPLE DIFFERENT
[INDISCERNIBLE] THESE SHOW THE
HIGHEST EXPRESSIONS IN SKIN AND
THE ESOPHAGUS, SO THE RISK CAN
HIGHLIGHT THAT FOR INDIVIDUALS
THAT CARRYING THE GENETIC BURDEN
OF THESE LOCUS TEND TO HAVE A
HIGHER TENDENCY TO RESPOND TO
INFLAMMATION OR INFECTION,
FUTURE STUDY, WOULD LEAD TOO
INVESTIGATOR IF THIS INDIVIDUAL
WERE TO BE LESS LIKELY TO BE
[INDISCERNIBLE] WHEN INFECT WIDE
COVID.
SO IN ADDITION TO GERONTOLOGYSTS
GENETIC WE LOOK AT GENOMEEC SO
WE'RE TRYING STUDY HOW THESE
GENES DIFFERENT IN SKIN
CONDITIONS COULD BE SHARING SOME
GENES THAT ALSO HAVE THE SAME
DIRECTION OF DISREGULATION IN
EPITHELIAL STYLES WHEN INFEBLGHT
WIDE COVID, SO THIS IS A LIST OF
GENES AND WHEN WE LOOK INTO THE
SHARED PATHWAY, WE IDENTIFY
MULTIPLE PATHWAY THAT ARE TO BE
SHARED THAT INCLUDE SIGNALING,
TNP SIGNALING AND ALSO IRPT
FERON SIGNALING.
SO I'M GOING TO SWITCH GEARS A
BIT AND SHARE WITH YOU HOW WE
SCHEME FROM DIFFERENT
INDIVIDUALS CAN RESPOND
DIFFERENTLY TO SIGNALING.
SO INTERFERON SIGNAL WAS IN
DIFFERENT SKIN CONDITIONS
INCLUDING LUPUS, PSORIASIS, AND
WE TRIED TO EXAMINE HOW THE
KERATINOCYTES FROM THE PATIENTS
WOULD RESPOND POTENTIALLY
DIFFERENTLY.
SO WE GOT LUPUS IN PATIENTS AND
THEN WE TRIED TO STIMULATE WITH
TYPE 1, TYPE 2 INTERFERONS, SO
WHAT WE'RE SHOWING HERE IS
ACTUALLY THE EFFECTS SIZE OF THE
STIMULATIONS, AND THEN, EACH DOT
HERE REPRESENTING A GENE AND THE
Y-REPRESENTING THE EFFECT IN THE
INTERFERON STIMULATION FOR
KERATINOCYTES COMING FROM THE
INBE FEKSS AND WE SEE
CONSISTENTLY BIASED TOWARDS A
HIGHER ASKED WHAT IN INDUCTION
AMONG THE LUPUS PATIENTS WHEN
THE CAR O 10 O SIGHTS ARE
INDUCED BY INTERFERON SO NOT
ONLY THE CONNOTATIVE BIAS, THAT
WHO WAS THE LUPUS PATIENT BUT AT
THE SAME TIME WE WERE ABLE GIIVE
THE SAME NUMBER OF PATIENTS
GIVEN THE SAME NUMBER OF
KERATINOCYTES THAT WERE USED
THERE ARE MORE NUMBERS OF GENES
THAT ARE DISREGULATED FOR
KERATINOCYTES COMES FROM LUPUS
AND THE HISTOGRAM IS LIKE THE
[INDISCERNIBLE] JUST TO SHOW YOU
THE DIFFERENCES IN THE EFFECTS
SIZE UPON STIMULATION BETWEEN
THE LUPUS AND THE CONTROL AND
LOOKING AT ALL THE GENES AND
WHEN WE LOOK AT GENES THAT TEND
TO BE INDUCED BY INTERFERON,
AGAIN, THEY ARE THE EFFECTS SIZE
TEND TO BE HIGHER AMONG THOSE
PATIENTS.
SO SINCE MANY CONDITIONS LIKE
WILL YOU PLEASEUS HAVE STRONG
SEX BIAS WE IDENTIFY POTENTIAL
MECHANISMS FOR THAT OBSERVATION
BI COMPARING SKIN FROM MALE AND
FEMALE, SO WE WE BUILD LIKE OVER
600 EXPRESSED GENES AND THEN
THAT INCLUDES TRANSCRIPTION
FACTOR FOR IGGIL3 AND THIS IS
REGULATING MULTIPLE GENES
ASSOCIATE WIDE AUTOIMMUNE
CONDITIONS.
SO THE SEX DIFFERENCES CAN BE
CONTEXT SPECIFIC AS WELL, SO A
RECENT WORK WITH US, TRYING TO
STUDY THE IMENT PACT OF SEX UPON
STIMULATION IN CAR O 10 O SIGHTS
SO THIS IS ANALOGOUS TO WHAT I
JUST SHARE WITH YOU, SO THIS IS
HERE IN THE LUPUS, WE ARE
LOOKING AT THE EFFECTS SO IF
THERE ARE STIMULATION IN FEMALE
AND THEN, THIS IS ACTUALLY IN
THE STIMULATION IN MALE AND YOU
CAN SEE HOW THE [INDISCERNIBLE]
FEMALE EXHIBIT HIGHER EFFECT
SIZES IN ENDOCRINE RESPONSE.
SO ARE WE ABLE TO SEE SIMILAR
EFFECT DIFFERENCES IN OTHER CELL
TYPES?
SO THIS A RECENT STUDY--SO THE
SEX DIFFERENCES IN THE STUDIES
AMONG PATIENTS USING SINGLE CELL
RNASEQ, FOR WHOLE BLOOD, SO HERE
ARE THE DIFFERENT CELL TYPES
THAT WE IDENTIFY BUT WHEN WE
LOOK AT DIFFERENT SEX
DIFFERENCES FOR EACH CELL TYPES
BETWEEN MALE AND FEMALE SO WE
WERE ABLE TO SHOW DIFFERENCES IN
MONOCYTES AND DENDRITIC CELLS.
AND WE LOOK INTO THE MONOCYTES
AND THIS PATIENT WITH COVID,
THEY ACTUALLY SHOW ENHANCED
CYTOKINE RESPONSES AND CYTOKINES
THAT HAVE BEEN EMERGED AS THE
ACTIVATED IN MAU THAT, WILL
INCLUDE INTERFERON IL6 AND IL1
BETA.
SO I WILL RESULTS, WE HIGHLIGHT
THERE ARE CELL TYPES TO SEE IF
THEY'RE SEX BIAS GENETIC AND WE
TRY TO UNDERSTAND INFECTION AND
PROGNOSIS OF COVID AND THEN, THE
FINDINGS LEAVE US WITH MORE
QUESTIONS TO UNDERSTAND THE
MECHANISM.
SO THAT CLIEWNDS WHY WOULD COVID
INFECTION ASSOCIATED WITH SKIN
CONDITIONS AND GIVEN THE STRONG
IMMUNE RESPONSE FOR MALE OR
FEMALE IS THERE ANY ASSOCIATION
BETWEEN SEX BIAS IN COVID
INFECTION OR SEX BIAS IN
INFLAMED RESPONSE AND HOW SEX
BIAS RESPONDS WITHIN DIFFERENT
CELL TYPES, THAT WOULD BE SEX
BIAS AS WELL AND HOW WOULD THAT
AFFECT PATIENTS.
SO WITH THEY WOULD LIKE TO THANK
ALL MY COLLEAGUES AND WE WILL BE
HAPPY TO DISCUSS A FEW MORE IN
THE PANEL DISCUSSION.
SNRKSZ FAB TAFTIC THANK YOU VERY
MUCH DR. TSOI.
IF I COULD ASK THE PANELISTS TO
TURN YOUR CAMERAS AND
MICROPHONES ON.
WONDERFUL WE HAVE--SO WE HAVE A
NUMBER OF QUESTIONS THAT HAVE
COME THROUGH.
THIS WAS REALLY TERRIFIC.
IF I MAY JUST START, WITH
DR. TSOI, ON YOUR LAST SLIDE,
YOU STARTED TO ASK A QUESTION,
AN IMPORTANT 1 IS THERE AN
INTERACTION BETWEEN SEX BASED
DIFFERENCES IN COVID INFECTION
AND SEX BASED DIFFERENCES IN
INFLAMMATORY DISEASE AS IT MIGHT
RELATE TO SKIN AS BEING A
SOURCE?
SO SKIN OF COURSE IS A LARGE
IMMUNE ORGAN AND RESERVOIR AS
WELL, SO WOULD YOU COMEBT A BIT
MORE ON THAT AND MAYBE WE ADD
SOME INSIGHT?
>> YEAH, I WOULD PROBABLY NEXT
TIME COMMENT BUT I MAY ADD MORE
CONFUSION.
YOU KNOW THAT'S ACTUALLY, YOU
KNOW [INDISCERNIBLE] LIKE LUPUS,
THERE WOULD BE FEMALE BIAS, WE
ALSO ENCOUNTER CONDITIONS LIKE
SORTING SIGNALS ICA SIS DOES NOT
HAVE THAT SEX BIAS AS WELL.
BUT IF WE'RE USING THE
INTERFERON STIMULATION AS AN
EXAMPLE, WE DO SEE INFUSED
RESPONSES ONLY FER CAR O 10 O
SIGHTS, WE DIDN'T SEE THIS ON
OTHER CELL SITES SEE WE DON'T
KNOW THE EFFECTS.
AND 1 OF THE THINGS I WANT TO
BRING UP AND I DIDN'T PUT IT IN
THE SLIDE IS THAT THERE ARE
DIFFERENT SKIN CONDITIONS THAT
ACTUALLY SHOW ELEVATED
EXPRESSION FOR [INDISCERNIBLE].
SO FOR LIKE FOR EXAMPLE IN
PSORIASIS THEY HAVE ELEVATED
EXPRESSION OF [INDISCERNIBLE],
SO I'M NOT SAYING THAT THOSE
PISHTS WITH SKIN DISEASE MAKE
THAT IN FACT WITHED WHAT.
BECAUSE THAT WOULD BE A SYSTEMIC
INFLAMMATION GOING ON SO THIS
COULD BE ELEVATED IN BLOOD FOR
THOSE PATIENTS.
SO I THINK THAT COULD BE A GOOD
INTERACTION WHEN WE TRY TO LINK
THE ELEVATED COVID INFECTION,
WEIGHT FOR SKIN OF THESE
PATIENTS AND THEN WITH WE LOOK
INTO THE SPECS, DIFFERENCES, WE
SEE THE SKIN, WE DO NOT FIND ANY
DIFFERENCE BUT WE HAVE NOT
REALLY TRIED TO LOOK INTO THE
AC2 EXPRESSION IN BLOOD FOR
BETWEEN SEX.
SO THAT COULD BE--THERE'S A LOT
OF THINGS TO LOOK AT.
>> SO, YOU KNOW BUILDING A
LITTLE BIT ON SOME OF OUR OTHER
PRESENTATIONS ESPECIALLY
DR. NEAL'S, HESERVED SERVED--OBD
AND SHARED THAT THE DIFFERENCES
IN THROMBOSIS BY SEX WERE MOST
PROMINENT IN YOUNGER MALES AND
SO I WONDERED, YOU KNOW IN YOUR
SINGLE CELL RNA SEQUENCING
STUDY, YOU NOTE THAD THERE WAS
MORE INFLAMMATORY SIGNATURES AND
CYTOKINES AND MONOCYTES AND
DENDRITIC CELLS IN MALES DO YOU
THINK THAT MIGHT SEPARATE OUT BY
AGE AS WELL, IS THERE A
TEMPERRAL ASPECT TO THIS?
>> YEAH, I THINK THIS IS
SOMETHING THAT WE WOULD BE WANT
TO LOOK INTO ESPECIALLY SOME OF
THE SPEAKERS BROUGHT UP ANY
INTERACTION BETWEEN AGE AND THE
SEX.
I THINK THIS WOULD BE A REALLY
GOOD DIRECTION FOR US TO REALLY
LOOK INTO.
YEAH.
>> THANKS.
AND THEN SO PERHAPS A GOOD TIME
TO ACTUALLY JUST ASK DR. NEAL, A
VERY SIMILAR QUESTION, YOU KNOW
WHAT DO YOU THINK MIGHT DRIVE
THESE DIFFERENCES IN THROMBOSIS
THAT THROMBOTIC RISK THAT MAY
HAPPEN WITH AGE?
AND USING SEX AS AN INTERACTION
VARIABLE AS YOU MENTION.
>> YEAH, GREAT QUESTION.
DR. KANTHI, AND THE SHORT ANSWER
IS I DON'T KNOW.
I LED WITH THIS AS I THINK AN
EXAMPLE OF YOU KNOW IMMUNO
THROMBOSIS AT AN INTERSECTION
WITH INFLAMMATORY SIGNALING AND
THROMBOTIC DEVELOPMENT AND SO, I
THINK THAT THERE ARE MULTIPLE
PATHWAYS THAT CHANGE
SIGNIFICANTLY WITH AGE THAT
REGULATE RESPONSE TO
INFLAMMATION AND SO WHETHER
THERE ARE UNIQUE THROMBOTIC
COMPONENTS YOU KNOW WHETHER
THAT'S PLATELET BASED BIOLOGY AS
WE HEARD FROM DR. ABEL'S TALK OR
OTHER ELEMENTS OF COAGULATION
THAT ARE ORDERED OR IS IT A
REACTION TO THE WAY THAT
INFLAMMATION IS INITIATED IN AND
THEN THE SAME IS TRUE FOR THE
SEX BASED DIFFERENCES.
I THINK A LOT OF THIS GOES BACK
TO THE BASIC BIOLOGY OF
INFLAMMATION AS IT CHANGES
BETWEEN MALES AND FEMALES AND
SO, IT'S NOT TO MINIMIZE
THROMBOSIS AS A UNIQUE RISK AND
THE SPECIFIC MECHANISMS OF IT,
BUT I THINK WE--THOSE OF US THAT
THOUGHT A LOT ABOUT IMMUNO
THROMBOSIS AND STUDIED IT AND
HAD TO INTRODUCE IT PRECOVID
DON'T HAVE TO DO THAT ANYMORE.
>> THAT'S WONDERFUL THANK YOU.
DR. ABEL, BUILDING ON
THROMBOSIS AND AGE, YOU KNOW I'M
INTERESTED TO HEAR, YOU'RE AN
ENDOCRINOLOGIST BY TRAINING AND
YOU'VE MANAGED TO CROSS
BOUNDARIES AND DO A LOT OF
CARDIOVASCULAR AND HEMEATOLOGY
WORK AS WELL, SO HOW MIGHT WE
START TO THINK ABOUT DECISIONS
ABOUT HORMONE THERAPY AND I
DON'T WANT TO SAY HORMONE
REPLACEMENT THERAPY I LEARNED
YESTERDAY THAT'S NOT THE RIGHT
TERMINOLOGY BECAUSE THERE'S NO
REPLACEMENT BUT HOW DO YOU
APPROACHY DECISIONS ABOUT
HORMONE THERAPY IN POST
MENOPAUSAL WOMEN WITH REGARD TO
THE CARDIOVASCULAR RISK AND
THROMBOTIC RISK.
>> YEAH, THAT'S AN INTERESTING
QUESTION BECAUSE FOR ME THERE'S
VERY CLEAR EPIDEMIOLOGY THAT
HORMONE THERAPY CERTAINLY DOES
INCREASE THE RISK OF THROMBOSIS
IN POST MENOPAUSAL WOMEN.
SO THE QUESTION THEN IS HOW CAN
WE ACTUALLY MITIGATE THAT,
SEEING THERE ARE CLEARLY
BENEFITS POTENTIALLY OF HORMONE
REPLACEMENT THERAPY.
AND SO I THINK THAT, YOU KNOW
WHAT HER APPLIEDS NEEDS TO BE
DONE IS TO UNDERSTAND WHAT ARE
THE OTHER DRIVERS OF THE
INCREASE TD RISK FOR THROMBOSIS
FOR AGING AND HOW MIGHT THIS BE
EXACKER BITED BY H. I.T. SO IN
WORK THAT IS PUBLISHED BUT
PREPARED FOR SUBMISSION, WE AND
OTHER COLLABORATORS HAVE SHOWN
THAT FOR EXAMPLE, AS YOU AGE AND
STUDIES FROM HUMAN SAMPLES,
THERE'S ACTUALLY MORE OXIDATIVE
STRESS IN THE PLATELETS.
AND AGAIN WE THINK THIS IS
COMING IN PARPT FROM
MITOCHONDRIA, SO 1 KIND OF
THOUGHT MIGHT BE IF THERE ARE
WAYS WE CAN ACTUALLY MITIGATE
SOME OF THAT, THEN POTENTIALLY,
THE LIKELIHOOD OF ESTROGENS
INCREASING RISK OF THROMBOSIS
COULD BE SOMEWHAT MITIGATED SO
THAT IS REALLY 1 APPROACH THAT 1
COULD TAKE TO KIND EVER DO THAT
YING-YANG IN TERMS OF DERIVING
BENEFIT AT THE SAME TIME NOT
EXACERBATING THOSE PATHWAYS
EVERY TIME YOU GET THE
THROMBOSIS?
SO A QUESTION THAT HAS BEEN
POSED TO ME SEVERAL TIMES NOW
INCLUDING JUST 2 WEEKS AGO AND
WHAT DO--WHAT SHOULD PEOPLE WHO
ARE TAKING HORMONE THERAPY DO
WITH THAT HORMONE THERAPY IF
THEY GET ACUTE COVID FOR
EXAMPLE.
>> WOW THAT'S A GREAT QUESTION.
I DON'T THINK WE HAVE EVIDENCE
TO ACTUALLY REALLY MAKE A
RECOMMENDATION AS TO WHAT THEY
DO.
AND SO, I THINK IT'S GOING TO BE
1 OF THESE KIND OF CONVERSATIONS
WITH YOUR PHYSICIAN IN TERMS OF
SHARED DECISION MAKING IN TERMS
OF WHAT MIGHT BE THE BEST
APPROACH THAT THERE'S MUTUAL
COMFORT IN TERMS OF MOVING
FORWARD.
BECAUSE I CAN IMAGINE THERE
WOULD BE SOME WOMEN WHO MAY
REALLY HAVE SIGNIFICANT BENEFITS
FROM HRT, AND YOU KNOW SOME OF
THE SYMPTOMS FOR EXAMPLE OF
MENOPAUSE MAY OVERLAP WITH SOME
OF THE SYMPTOMS OF LONG COVID SO
HOW DO YOU THEN BEGIN TO MANAGE
THAT?
AND I THINK THERE REALLY HAS TO
BE A REALLY OPEN CONVERSATION
ABOUT YOU KNOW THE RISK AND
BENEFITS AND ESSENTIALLY, YOU
KNOW A PLAN TO DEROOT SYMPTOMS
IF THEY DECIDE TO STOP THERAPY
AND WITH THE SYMPTOMS
CONCURRENTLY WITH THE RISK THAT
SYMPTOMS MIGHT BE ATTRIBUTABLE
TO A POST VIRAL SYNDROME.
>> AND CERTAINLY EMPHASIZES,
THANK YOU FOR THOSE COMMENTS IT
EMPHASIZES PART OF THE
CONVERSATION WE HAD YESTERDAY
ABOUT HORMONE THERAPY IN
TRANSGENDER POPULATIONS AS WELL.
SO, THIS CERTAINLY DOES
UNDERLINE IT, THERE'S A QUESTION
DR. ABEL FROM THE VIDEOCAST AND
I WILL STATE THE QUESTION HERE
IN BRIEF FORM, ESTROGEN MAY BE A
CARCINOGEN OF MANY CANCERS BUT
IN YOUR STUDIES YOU SUGGEST THAT
THAT IT MAY BE PROTECTIVE.
COULD YOU SHED LIGHT ON THE
POSITIVES AND NEGATIVES ON
ESTROGEN?
CANCER AND COVID?
>> YEAH, AGAIN, SO A VERY
COMPLEX QUESTION, RIGHT?
AGAIN IN THE SENSE THAT YES,
THERE ARE ESTROGEN DEPENDENT
TUMORS.
I THINK 1 TAKES A STEP BACK AND
AGAIN LOOKING AT THE
EPIDEMIOLOGICAL STUDIES
PARTICULARLY FOR THOSE
INDIVIDUAL WHO IS ARE STARTING
EARLY ON HRT, I THINK PART OF
THE ISSUE WITH ERT IS THAT OTHER
STUDIES PUT ALL COMERS IN HRT
EVEN A DECADE AFTER MENOPAUSE SO
IF YOU LOOK CLOSELY, ARE THOSE
INDIVIDUAL WHO IS ARE PUT ON I
WILL SAY LOW DOSE REPLACEMENT TO
MANAGE SYMPTOMS EARLY IN THE
POST MANY O PAUSAL PERIOD, THE
EVIDENCE, THE RISK OF CANCER IS
NOT AS COMPELLING.
THERE WAS ANOTHER QUESTION IN
THE CHAT AND I'M ADVISED I
SHOULD SPEAK TO IT BECAUSE NOT
EVERYBODY ON THE WEBCAST IS
KNOWLEDGEABLE AND IT'S THE
QUESTION WAS THE MOLECULAR
MECHANISMS FOR THE LACK OF
CHANGES IN MEDICAL
[INDISCERNIBLE] IN FEMALES, AND
THEN ALSO SECONDLY WHAT WAS THE
[INDISCERNIBLE] CONTENT IN THESE
MICE?
SO THEREYA NO DIFFERENCE IN THE
KOWBTS, ARE THERE PROTEINS THAT
DRIVE MITOCHONDRIAL INTEGRITY
CALLED MCOS COMPLEX, AND THOSE
ARE THERE, AND I THINK WHAT'S
HAPPENING IS THE ESTROGEN IS
PROBABLY IMPACTING MITOCHONDRIAL
IN THE MEMBRANE FLU ID SO THAT
THE REMAINING PROTEINS ARE ABLE
TO KIND OF RESTORE, MAINTAIN THE
[INDISCERNIBLE] IN THE ABSENCE
OF OPARE--ADMINISTRATIVE 1 IN
MALES THAT DOESN'T HAPPEN
BECAUSE THEY HAVE LESS ESTROGEN,
IN THEIR MITOCHONDRIAL.
>> WONDERFUL AND ARE THERE--IS
OPA 1 REGULATED BY ACUTE
STRESSORS LIKE INFECTIONS OF
COVID OR WOULD YOU SPECULATE
WHAT MIGHT HAPPEN IN THE POST
ACUTE--
>> GREAT QUESTION.
SO WE ACTUALLY DON'T KNOW BUT I
THINK THAT THERE MUST BE PEOPLE
ON THIS CALL OR ANSWER WHO HAVE
SAMPLES OF PATIENTS THAT WE
COULD LOOK AT THE TRANSCRIPT
LEVELS OF OP A 1 IN PLATELETS IN
INDIVIDUALS WITH COVID AND
NONCOVID IN THE RECOVERY PERIOD
SO I THINK THAT WILL BE A REALLY
INTERESTING QUESTIONS, I DON'T
KNOW THE ANSWER TO THAT BUT I
THINK THERE'S SAMPLES WHERE DO I
HAVE THIS IN FACT COULD BE
EVALUATED THERE.
>> THAT'S A PERPECT SEGUE TO ASK
ANOTHER QUESTION, DR. NEAL, AND
DR. RAFIQUE, YOU BOTH HELPED
LEAD VERY, VERY LARGE CLINICAL
TRIALS THAT HAVE CROSSED, THAT
HAVE CROSSED BOUNDARIES AND YOU
KNOW WOULD YOU SHARE WITH US
WHETHER THERE ARE
BIOREPOSITORIES THAT WERE BUILT
IN THIS AND IF SO, HOW DO
INVESTIGATORS ACCESS THOSE
EITHER CLINICAL OR RESEARCH
SAMPLE BIOREPOSITORYS.
>> --THANK YOU FOR THAT.
THE PROGRAM HAS BUILD A ROBUST
BIOREPOSITORY THAT'S RUN BY RUSS
TRACE NEUROECTODERMAL THE
UNIVERSITY OF VERMONT WHO
OVERSAW ALL THE BIOREPOSITORY
CONNECTION FOR THE NHLBI
CONNECTS SPONSORED TRIALS AND
SO, THE PROCESS FOR OBTAINING
SAMPLES EXTERNAL TO THE TRIALS
IS ACTIVELY BEING DEVELOPED AND
I THINK WE HOPE WILL BE FORTH
COMING VERY SOON.
I THINK ANYONE WHO HAS SPECIFIC
QUESTIONS CERTAINLY WELCOME TO
REACH OUT TO ME OR ANY OF THE
INVESTIGATORS AND WE CAN CONNECT
AND THE SAME IS TRUE FOR
CLINICAL DATA.
ALL THE CLINICAL DATA OF COURSE
WILL BECOME PUBLICLY AVAILABLE
AND AT LEAST THE FIRST VERSION
OF THE DATA FROM THE FIRST 2
MANUCRYPTS THAT I SHOWED YOU NEW
ENGLAND JOURNAL ARE NOT ONLY
AVAILABLE THERE BUT HAVE BEEN
PLACED INTO A PUBLIC DATA
REPOSITORY AND AGAIN THAT
INFORMATION IS BROADLY AVAILABLE
EITHER THERE OR BI REQUEST.
>> WONDERFUL, DR. RAFIQUE, WHAT
ABOUT FROM THE C3 PO TRIAL.
>> THERE IS A BIOREPOS
IDENTITIORY AND THERE ARE
SECONDARY ANALYSIS BEING ROWN
NOW AND IT DEPENDS ON WHAT KIND
OF SAMPLES YOU NEED AND HOW MUCH
AND THAT ARE COMPATIBLE WITH HOW
IT WAS COLLECTED SO THAT'S
SOMETHING TO LOOK INTO BUT IF
YOU HAVE A--THIS IS WHAT YOU
NEED AND THE COLLECTION AND HOW
MUCH, THEN THAT'S SOMETHING WE
CAN ALWAYS LOOK INTO AND SEE IF
THAT'S AVAILABLE.
>> WONDERFUL.
THANK YOU DR. RAFIQUE, IN THE C3
PO TRIAL, YOU SHOWED US THAT
THERE WAS NO DIFFERENCE BETWEEN
PLACEBO AND CONVALESCENT PLASMA
TRANSFUSION PATIENTS TO PATIENT
WHO IS REPORTED TOAGE EMERGENCY
DEPARTMENT WITH SYMPTOMS.
THERE HAVE BEEN VARIED DATA
ACROSS DIFFERENT STUDIES AND I
HOPE YOU MIGHT BE ABLE TO SPEAK
TO THE HETEROGENERATED AITY OF
THAT AND OTHER FACTORS THAT WE
NEED TO BE CONSIDERED WHETHER
IT'S WHAT'S IN THE PLASMA OR
WHETHER THERE IS SOME
SPECIFICITY TO THE PATIENT'S
SEVERITY LOCATION, SEX, GENDER
AND OTHER POTENTIAL VARIABLES.
>> ABSOLUTELY, THERE WERE MIXED
DATA SO INITIALLY, CONVALESCENT
PLASMA WAS SUPPOSED TO HELP AND
THEN IT WAS THOUGHT THAT MAYBE
IT WAS GIVEN PRETTY LATE SO
MAYBE WE SHOULD MOVE IT EARLIER
BECAUSE GIVING CONVALESCENT
PLASMA WHICH IS PASSIVE IMMUNITY
IF YOU GIVE IT TOO LATE HOW DOES
THAT HELP, RIGHT?
SO GIVING TO PATIENT WHO IS ARE
HOSPITALIZED OR IN THE ICU ALL
RIGHT MAY NOT BE HELPFUL.
SO THERE WAS MIXED DATA SO WE
TRY TO MOVE IT UP EARLIER AND
EARLIER AND SAY HEY, IF MACS ARE
LESS SEVERELY ILL MAYBE THAT
WOULD HELP IN THAT REGARD.
I THINK AT THIS POINT IT
[INDISCERNIBLE] HELP I HAVE TO
SAY, WE ARE DOING REANALYSIS OF
END POINT WE LOOKEDDA THIS THE
IS ALL COMER, ALL COMPOSITE
GOING, EVERYONE GOING TO THE
HOSPITAL OR HAVING DEATH OR VIS
WILLING EMERGENCY DEPARTMENT OR
URGENT CARE WHICH INITIALLY WE
DID NOT BREAK IT DOWN WAS THE
REASON WAS FOR COVID OR NOT AND
THAT'S SOMETHING ELSE TO LOOK
INTO, BECAUSE THEY'RE ALL COMERS
IF YOU END UP IN THE ENGINEER
DEPARTMENT, WE COUNT YOU AS 1
BUT AT THIS TIME, I DON'T--I
DON'T THINK CONVALESCENT PLASMA
IS HELPING, SO THAT'S THE
QUESTION THAT WE LOOKED AT
RIGGOUSLY AND THAT'S WHAT WE
HAVE AT THIS POINT.
>> AND CERTAINLY INTRIGUING TO
THINK ABOUT WHETHER THERE'S
POTENTIAL FOR DIFFERENT FACTORS
IN PLASMA TO HAVE DIFFERENT
EFFECTS AND YOU SHOWED THE
LEVELS OF ANTIBODIES WERE HIGHER
IN MALES BUT IT DOESN'T
TRANSLATE TO ANY DIFFERENCE IN
OUTCOMES AND I WONDER IF THERE
ARE OTHER NONSARS COV-2
NEUTRALIZING ANTIBODIES AND
OTHER FACTORS THAT MIGHT BE IN
CIRCULATION THAT MIGHT AFFECT
SOME OF THESE CHANGES SO WE WILL
HAVE TO WAIT TO SEE WHAT SOME OF
THE SECONDARY ANALYSIS HAVE FROM
THE BIOREPOSITTORIES AND I THANK
YOU FOR THAT INFORMATION AS
WELL.
SO 1 LAST QUESTION HERE AND I
THINK THIS IS--IT'S NOT MEANT TO
BE A LEADING QUESTION BUT 1 THAT
WE CAN START TALKING ABOUT LEER
AND WE MAY NEED TO DISCUSS LATER
IN THE BREAK OUT SESSION.
SO THIS IS FOR ALL 4 PANELISTS,
WHAT IS THE RIGHT WAY AS WE
THINK ABOUT MOVING FORWARD TO BE
ABLE TO INCORPORATE SEX AND
GENDER INTO CLINICAL TRIALS.
THIS IS NOT JUST IN THE ANALYSIS
OF THE RESULTS BUT HISTORICALLY
DR. BAIRY-MERZ DID NOT
NECESSARILY ENROLL RATES AS MEN
AND THAT HAS IMPROVED OVER TIME
BUT HOW DO WE DO THIS IN THE
FUTURE?
SHOULD WE BE PRESPECIFYING
RANDOMIZATION CRITERIA SO THAT
WE HAVE STRATA WHERE WE TARGET
EQUAL NUMBERS OF MEN AND WOMEN
AND ALSO--LET ME REPHRASE THAT
TSHOULD BE MEN, WOMEN AND
TRANSGENDER.
>> SO THAT'S A--I'M NOT SURE I
HAVE A BRIEF ANSWER TO A REALLY
COMPLEX QUESTION DR. KANTHI, I
WILL OPINE ON 1 PART, THE
CONTRUCT OF THE MPRCT WAS A
BASIAN ADAPTIVE TRIAL DESIGN AND
1 OF THE BENEFITS OF AN ADAPTIVE
PLATFORM DESIGN ALLOWS FOR
PRESPECIFIED STOPPING RULES
WITHIN STRATA AND LOOKING AT
SUBGROUPS TO FIND AS PRIORITY AS
A DOMAIN WITHIN THAT SO THE
CHALLENGE IS WHEN YOU DON'T KNOW
WHETHER THERE'S GOING TO BE A
DIFFERENTIAL EFFECT AND ARE
CHALLENGED IN CREATING SORT OF A
PRETEST PROBABILITY, BUT I THINK
FOR A SPECIFIC AREA WHERE THAT
QUESTION IS THOUGHT TO BE HIGHLY
RELEVANT, UTILIZING ANALYSIS
PLAN THAT ACCOUNTS FOR SEX AND
GENDER BASED DIFFERENCES IN
ADVANCE WITH, YOU KNOW UNIQUE
STOPPING RULES AS PART OF AN
ADAPTIVE DESIGN IS 12 TENTIAL
STRATEGY WHERE YOU COULD LOOK TO
ENHANCE ENROLLMENT IN A SPECIFIC
STRATA IF YOU SUE A PLAN.
>> WOULD YOU LIKE TO COMMENT?
YEAH, DR. KANTHI, THERE IS
PRECEDENT FOR NHLBI FOR THIS
ENROLLMENT TO BE PROPORTIONATE
TO THE PRETENSE OF MEN AND WOMEN
IMPACTED BY IT IN THE NHLBI
DYNAMIC REGISTRY WHICH IS AN
EARLY STINT REGISTRIES, IT WAS
DETERMINE THAD IT WOULD BE
50/50, WOMEN AND MEN AND ASOON
AS THEY HIT THE 50% MEN, SOMEHOW
THEY FOUND THOSE WOMEN.
SO I THINK WE COULD CONSIDER
THOSE KINDS OF STRATEGIES GOING
FORWARD AND REMEMBER THAT IN THE
PAST IT ACTUALLY WORKED AND
ENROLLMENT ENDED ON TIME.
WE'VE HAD NO TROUBLE ENROLLING
OUR WOMEN ONLY STUDIES AND
PEOPLE HAVE THIS IDEA THAT WOMEN
WON'T PARTICIPATE IN RESEARCH
AND IT'S JUST NOT TRUE.
>> THANK YOU FOR THAT COMMENT IT
CERTAINLY GIVES US A CALL TO
ACTION.
THERE ARE SEVERAL OTHER COMMENTS
AND QUESTIONS THAT HAVE POPPED
UP IN THE CHAT BOX, I WILL ASK
OUR PANELISTS TO KINDLY ADDRESS
THOSE.
WE DO NEED TO TAKE A BREAK FOR
LUNCH AND IF OKAY WITH THE GROUP
WE WILL RESUME IN ABOUT 22
MINUTES AT 1:55 P.M. EASTERN FOR
OUR NEXT SESSION WHICH WILL
FOCUS ON SLEEP AND LUNG RELATED
DISEASES.
WONDERFUL, THANK YOU TO ALL OF
OUR SPEAKERS, OUR PANELISTS AND
THOSE WHO AD HOCS ADDED
COMMENTS.
>>WELCOME BACK, EXCITED THAT
THE MORNING SESSIONS HAVE
BEEN FUN, INTERESTING,
DYNAMIC AND
ENGAGING AND LOOKING FORWARD
TO THE REST OF THE AFTERNOON.
IF YOU HAVE QUESTIONS OR
COMMENTS PLEASE PLACE US IN
THE Q&A BOX.
YOUR ENGAGEMENT IS VITAL TO
THE SUCCESS OF THIS WORKSHOP.
I THINK THE PANELISTS ARE
REALLY EXCITED AND INTERESTED
AS YOU CAN SEE FROM THE
MORNING SESSION IN
ENGAGING WITH YOU AND HELP TO
CREATE NEW SYNERGIES FOR
COLLABORATION AS WE ADVANCE
OUR SCIENCE SO
OUR NEXT SESSION IS GOING TO
BE ON SESSION 6: SEX/GENDER
DIFFERENCES IN COVID RELATED
TO SLEEP AND
LUNG DISEASE,
I'D LIKE TO INTRODUCE OUR
MODERATOR, DR. PATRICIA
SILVEIRA ASSOCIATE PROFESSOR
AT THE INDIANA
UNIVERSITY SCHOOL OF PUBLIC
HEALTH AND HER RESEARCH IS
FOCUSED ON SECTOR DIFFERENCES
IN THE ROLE
OF STEROID HORMONE RECEPTORS
IN LUNG FORMATION, AND
NACELLE FACULTY POSITIONS AT
PENN STATE,
DIVERSITY OF NORTH CAROLINA
WHERE SHE LED THE
BIOBEHAVIORAL LAB BEFORE SHE
WAS RECRUITED TO
INDIANA UNIVERSITY WORK WHERE
SHE DEVELOPED AN NIH FUNDED
PROGRAM TO STUDY DIFFERENCES
OF -- IN
AIRWAY DISEASE AND RECEIVED
NUMEROUS AWARDS IN HER
EFFORTS TO PROMOTE DIVERSITY
IN STEM 'S TERMS
IN VARIOUS NATIONAL
ORGANIZATIONS AND COMMITTEES
INCLUDING THE SOCIETY FOR THE
ADVANCEMENT OF
CHICANOS, HISPANICS, NATIVE
AMERICANS IN SCIENCE, AND IS
A MEMBER OF THE BOARD OF
HIGHER EDUCATION
AND WORKFORCE AND COCHAIR OF
THE NEW VOICES IN SCIENCE
ENGINEERING MEDICINES. I LOOK
FORWARD TO
THIS EXCITING SESSION.
>> DR. SILVEIRA:
THANK YOU FOR THE ORGANIZERS
AND INVITING ME TO MODERATE
THE SESSION, SESSION 6:
SEX/GENDER
DIFFERENCES IN COVID RELATED
TO SLEEP AND LUNG DISEASE.
WE ARE GOING TO BE HEARING
FROM FOUR EXPERTS IN THESE
TOPICS. WE ARE GOING TO BE
DISCUSSING SEX
DIFFERENCES IN MECHANISMS IN
LUNG INFECTION AND IMMUNE
MEDIATORS IN CVOID-19 AND
HEARE ABOUT
DIFFERENCES IN CLINICAL
FEATURES OF POSTACUTE
SEQUELAE OF SARS COV-2
(PASC)
INTRODUCE NOVEL SIX SPECIFIC
MECHANISMS AND TALK ABOUT
DIFFERENCES.
YOU HAVE THE BIOS FROM THE
SPEAKERS THAT WILL BE
SPEAKING TODAY.
I HAVE SUMMARIZED THEM IN THE
INTEREST OF TIME.
I AM GOING TO START WITH OUR
FIRST SPEAKER, DR. CHARLES
DELA CRUZ, . ASSOCIATE
PROFESSOR AT YALE
UNIVERSITY SCHOOL OF MEDICINE
>> LUNG INFECTION IN
MEDIATORS, BY DR. DELA CRUZ.
COVID-RELATED LUNG
MICROVASCULAR AND PARENCHYMAL
SEQUELAE.
>> THANK YOU DR. SYLVEIRA FOR
THE INTRODUCTION OF THE
SESSION INTO THE ORGANIZERS
ON THIS
IMPORTANT TOPIC.
I WAS ASKED TO TALK ABOUT IS
CURRENTLY KNOWN ABOUT
CVOID-19 LUNG INFECTION AND
SIX/GENDER
DIFFERENCES.
I DO NOT HAVE ANYTHING TO
DISCLOSE.
>> DR. DELA CRUZ:
BY NOW WE KNOW THAT AFTER TWO
YEARS AND MORE OF THIS
PANDEMIC THAT THERE ARE SECTS
AND GENDER
DIFFERENCES IN CVOID-19.
YOU HAVE HEARD ELOQUENTLY
FROM OTHER SPEAKERS DURING
THIS WORKSHOP THAT THERE ARE
SOME
DISPARITIES IN TERMS OF THE
OUTCOME OF CVOID-19.
MALES HAVE A HIGHER
MORTALITY,
AND DIFFERENCES WITH
COMPLIANCE FOR PREVENTIVE
MEASURES HIGHER RISK
BEHAVIORS AND RISKS AND JOBS
AND THERE ARE OTHER HORMONAL
FACTORS.
SPECIFICALLY WE KNOW THAT
ESTROGEN IS ASSOCIATED WITH
DECREASED ACE2 RECEPTORS,
TESTOSTERONE IS
HAVING SUPPRESSIVE EFFECT ON
IMMUNE FUNCTIONS.
---
AND I WILL SUMMARIZE WHAT IS
KNOWN IN REGARDS TO SOME OF
THESE DIFFERENCES IN
NEUROLOGICAL AND
INFLAMMATORY RESPONSES.
---
FOR MANY YEARS WE KNOW THAT
THERE ARE SIX DIFFERENCES IN
IMMUNITY ESPECIALLY AGAINST
RESPIRATORY
INFECTION INCLUDING VIRUSES.
THERE ARE X-LINKED GENES
ENCODING IN IMMUNE RELATED
PROTEINS,
CONTRIBUTING TO MECHANISMS
AND PATHOGENESIS OF INFECTION
INCLUDING CVOID-19
SPECIFICALLY TLR 7 HAS
BEEN HIGHLIGHTED IN THIS
PANDEMIC AND ALL OF THIS
LEADS TO SECTOR DIFFERENCES
IN BOTH INNATE AND
ADAPTIVE RESPONSES LEADING TO
THESE DIFFERENTIAL RESPONSES,
DURING ACUTE INFECTION WITH
MALES.
---
WE ALSO KNOW THAT THERE ARE
MECHANISMS-- FOR EXAMPLE
IMMUNEMODULATORY EFFECTS,
MORE SEEN IN THE
FEMALE POPULATION WHICH IS
IMPORTANT AS POSSIBLY
IDEOLOGY FOR SOME OF THE
DISCREPANCIES IN TERMS
OF PREFERENTIAL SEXTON
DIFFERENCES IN PATIENTS WITH
PAC AND LUNG COVID.
---
SOME OF THE WORK DONE IN YALE
LED BY DR. TAKAHASHI AND
OTHER, HAVE TRIED TO
UNDERSTAND
INFLAMMATORY RESPONSES TO
CVOID-19.
MOST OF THE INNATE
INFLAMMATORY RESPONSES HAVE
BEEN SIMILAR BETWEEN MALES
AND FEMALES.
SOME OF THE INITIAL
DESCRIPTION HAS SHOWN FOR
EXAMPLE THAT IN INFECTED
MALES COMPARED TO CONTROLS
THAT ARE HIRED LEVELS OF IL18
AND IL-8 AND CONTRIBUTE TO
THESE CONSEQUENCES AND IN
ADDITION
CHEMOLINES LEVELS OF CCL5
HAVE BEEN INCREASING MALE
POPULATIONS.
---
INTERFERE IN RESPONSE IN
EARLY STAGES IS IMPORTANT FOR
ANTIVIRAL EFFECTS IN BC AND
INCREASE THE
CORRELATES WITH SEVERITY
DISEASE AND THE INITIAL EARLY
RESPONSES OF THE INFECTIONS
HAVE BEEN SHOWN
IN OTHER DISEASES TO BE MORE
ENHANCED IN FEMALES RATHER
THAN MALES AND LIKELY
CONTRIBUTED
POTENTIALLY THE PROTECTION
THAT WE WILL HAVE SEEN FOR
ACUTE PNEUMONIA FOR CVOID-19.
---
AND THIS IS THE CASE FOR
CVOID-19 AND SOME OF THE
EARLY STUDIES HAVE SHOWN THAT
THERE ARE EARLY
INTERFERON ALPHA 2 RESPONSES
INTIMATES COMPARED TO MALES
AND WE DON'T SEE THESE OTHER
KINDS OF
DIFFERENCES IN OTHER
INTERFERENCE IN THIS COULD BE
DUE TO THE TLR7 ENCODED IN
THE X-LINKED
CHROMOSOME.
---
AND AUTOANTIBODIES HAVE BEEN
ISOLATED AND DETECTED WHEN
PEOPLE WITH CVOID-19 AND
TYPICALLY WITH
THE STUDIES LISTED HERE THEY
HAVE SHOWN THAT IN MALES
THERE ARE MORE OF THESE
AUTOANTIBODIES IN
TYPE I IFNS COMPARED TO WOMEN
OF THESE ARE IMPORTANT FOR
THE EARLY CONTROL OF VIRUS IS
NOT LIKELY
ABLE TO NEUTRALIZE LEVELS OF
THIS IN THE PATIENTS. SOME OF
THEM HAVE LOW AND UNDETECTED
LEVEL.
HOWEVER THERE ARE DIFFERENCES
IN THE AUUTOANTIBODIES
BETWEEN MALE AND FEMALE
POPULATIONS AND IN
TERMS OF ANTIBODY RESPONSES
THERE HAVE BEEN MANY STUDIES
LOOKING AT PACIFIC ANTIBODY
RESPONSES
INSPECTING PROTEINS IGG AND
IGM, NO DIFFERENCES BETWEEN
MALES AND THE MOTION WAS
STUDY HAS SHOWN
AND INCREASE IN ANTIBODY
STEWARDS SPIKING PROTEINS
INCLUDING NEUTRALIZING
ANTIBODY SHOWN HERE AND
THE EFFECT IS RELATIVELY
MODEST MOST OF THIS LIKELY
RELATED TO THE FACT THAT MEN
TEND TO HAVE MORE
SEVERE DISEASE.
---
T CELL RESPONSE IS IMPORTANT
AGAINST CVOID-19.
MOST OF THE STUDIES HAVE
SHOWN THAT TOTAL CIRCULATING
T CELLS ARE VERY SIMILAR WITH
REGARDS TO
ITS FREQUENCY.
ONE STUDY SHOWS THAT IN
FEMALE CVOID-19 PATIENTS
THERE IS A HIGHER FREQUENCY
OF ACTIVATED T CELLS.
STUDIES USING BALF CELLS
SHOW THE TORRENTIAL RESULTS
BETWEEN MALES AND FEMALES.
ONE SHOWS THAT
MALES HAVE POOR T-CELL
ACTIVATION, INEFFECTIVE VIRAL
CLEARANCE AND THE STUDY THAT
WAS DONE AT
JAILS HAS SHOWN THAT IN MALES
THERE ARE ASSOCIATIONS WITH
POOR CD8 T CELL ACTIVATION
AND
PRODUCTION OF IFNG AND IT IS
CORRELATED WITH THE PATIENT'S
AGE IS SEEN IN THE GRAPH
ALTHOUGH NOT
SEEN IN FEMALE PATIENTS.
SO IT SUGGESTS THAT THIS IS
POTENTIALLY A PROTECTIVE
(INDISCERNIBLE).
---
OTHERS HAVE SHOWN THAT USING
THE IMMUNO METABOLOME STUDIES
THAT THERE ARE OTHER MARKERS
AND HERE
YOU CAN SEE KYNURENIC ACID
CORRELATED, AND PATIENTS WITH
WORSE OUTCOMES AS YOU SEE IN
THIS BOX
HERE, ESPECIALLY IN THE MALE
POPULATION, THIS TENDS TO BE
A GOOD MARKER FOR THIS
INFECTION.
THERE ARE ALSO DIFFERENTIAL
MONOCYTE DIFFERENCES COMPARED
TO INFECTED AND UNINFECTED
PATIENTS.
IN GENERAL WHAT HAS BEEN SEEN
IS THAT THERE ARE SOME
INCREASED NONCLASSICAL
MONOCYTES IN MALES.
AND THIS IS SUGGESTIVE THAT
POSSIBLY PROGRESSION FROM THE
CLASSICAL MONOCYTES SOMEHOW
INSTEAD OF
BEING ARRESTED IN THE
INTERMEDIATE PHASE IN THE
FEMALE PATIENTS.
---
A LITTLE BIT ABOUT COVID.
WE KNOW THAT CVOID-19 AS BEEN
SHOWN TO SHOW THE FEMALE
SECTOR BE MORE AT RISK FOR
LUNG COVID
SYNDROME AND THERE ARE MANY
PHENOTYPES AND FLAVORS, MORE
NEUROLOGICAL SYMPTOMS, MORE
CARDIAC
SYMPTOMS AND THERE ARE MANY
MECHANISMS THAT HAVE BEEN
PROPOSED TO SUGGEST WHETHER
OR NOT THE
REASONS FOR LONG COVID,
WHETHER VIRAL PERSISTENCE OR
AUTOIMMUNITY AND OTHERS IN
THIS STUDY SHOWS
THAT THERE IS IN GENERAL-- IN
THIS POPULATION-- THE
MAJORITY OF THE POPULATION
ARE FEMALES AND
IL-6 HAS MORE ELEVATION AS A
BIOMARKER IN THE FEMALE
POPULATION COMPARED TO MALES.
AND WORK FROM THE NIH HAS
STARTED TO REPORT SOME OF
THIS POST-COVID STUDIES IN
SOME OF THE EARLY
EXPLORATORY STUDIES HAVE NOT
SHOWN CLEAR EVIDENCE OF
PERSISTENT VIRAL INFECTION,
AUTOIMMUNITY OR
ABNORMAL IMMUNE ACTIVATION IN
PARTICIPANTS WITH PASC,
DESPITE THE FACT THAT THERE
IS AN INCREASE
IN RISKS FOR WOMEN AND WE ARE
DISSECTING THIS FROM THE
SINGLE CELL APPROACH AND
IDENTIFIED WITH
SENSUAL RISK FACTORS SUCH AS
PRE-EXISTING CONDITIONS LIKE
DIABETES, AUTOANTIBODIES AND
VIREMIA AND
LIKELY WITH SEVERAL POTENTIAL
CLUSTERS OF PASCS SYMPTOMS.
---
THE LAST STUDY SHOWS THAT
DESPITE THE FACT THAT AUDIT
IMMUNITY COULD BE A HALLMARK
FOR LONG COVID,
THE ANTIBODIES FOR LAMBDA
WERE MORE ASSOCIATED WITH
ORATORY SYMPTOMS.
---
WE KNOW THAT THERE ARE
DIFFERENCES WITH MALES AND
FEMALES HAVE GREATER
ANTIVIRAL, HUMORAL AND
ADAPTIVE RESPONSES LIKELY TO
HORMONAL EFFECTS BUT THESE
EFFECTS COULD POTENTIALLY
EXPLAIN SOME OF
THE INCREASED HETEROGENEITY
IN THE PREDISPOSITION WOMEN
WITH PASC AND LONG COVID
SYMPTOMS SO SOME
OF THESE FUTURE STUDIES NEED
TO CONSIDER THAT MANY OF THE
STUDIES DID NOT HAVE CAREFUL
CONSIDERATION UPSET AND
GENDER, AND THE ROLE OF
SECTION GENDER NEEDS TO BE
EVALUATED APPROPRIATELY
AND THERE ARE OPPORTUNITIES
TO EVALUATE EARLY
NEUROLOGICAL DYSFUNCTION
BASED ON THE DIFFERENCES
FOR TARGETED APPROACHES AND I
HAVE NOT DISCUSSED THE ROLE
OF PERIPARTUM AND INTRAPARTUM
IMPACT ON
IMMUNITY AND WITH REGARDS TO
THE VARIOUS PHENOTYPES WE
NEED TO CONSIDER VARIOUS
FACTORS SUCH AS
STRESS LEVELS, TREATMENT
EFFECTS AND IMPACT ON
IMMUNITY.
THANK YOU VERY MUCH.
>> THANK YOU DR. DELA CRUZ.
DR. OELSNER?
>> DR. OELSNER:
LET ME SHARE MY SCREEN.
THANK YOU SO MUCH FOR BELLAMY
TO SPEAK WITH YOU TODAY ABOUT
COVID-RELATED LUNG
MICROVASCULAR AND
SEQUELAE.
TO START IS A GENERAL
INTERNIST LET'S STEAK A STEP
BACK AND DISCUSS WHAT WE HAVE
DISCUSSED OVER
THE PAST FEW DAYS BUT
CVOID-19 IMPACTS THE LUNGS
AND CAUSE ACUTE GENERATE WITH
RESPIRATORY FAILURE
BEING THE LEADING CAUSE OF
COVID-RELATED DEATH AND
COVERT MORTALITY IS HIGHER IN
MALES AND FEMALES
AND OFTEN ACUTE ILLNESS MAY
BE WORSE IN MALES VERSUS
FEMALES.
--- AN INCREASINGLY WE ARE
SEEING THAT COVID CAN BE
ASSOCIATED WITH POST-COVID
LUNG SEQUELAE.
UP TO ONE IN FIVE PERSONS
INFECTED WITH SARS COV-2 MAY
HAVE AT LEAST ONE
COVID-ATTRIBUTABLE
CONDITION DEVELOP SUBSEQUENT
TO INFECTION AND LOOK LIKELY
POLYMERIC CONDITIONS ARE THE
MOST
PROBLEMATIC SO THERE'S A
TWO-TIME HIGH-RISK A
PULMONARY EMBOLISM'S AFTER
INFECTION ACCORDING TO
RECENT CDC ESTIMATES AND
AFTER SIX MONTHS POSTCOVID
THE BURDEN OF COUGH AND
SHORTNESS OF BREATH
SINCE HIGHER IN FEMALES AND
MALES.
---
THIS IS ALL OCCURRING IN A
BROADER CONTEXT OF TAKING UP
A FURTHER STEP BACK ACUTE
LUNG INJURY DUE
TO COVID AND POST-COVID LUNG
SEQUELAE MAY BE IN PERSONS
WITH CHRONIC LUNG DISEASE,
FOURTH LEADING
CAUSE OF DEATH AND COPD WAS
HIGHER IN MALES THAN FEMALES
AND WHAT I WANT TO TALK ABOUT
TODAY IS
HOW WE CAN LEVERAGE SOME OF
THE TOOLS TO BETTER
UNDERSTAND THE MECHANISMS OF
LUNG DISEASE, LUNG
SEQUELAE AND SIX DIFFERENCES
AND FOR MANY YEARS WE HAVE
BEEN WORKING TO UNDERSTAND
CHRONIC
DISEASES SUCH AS COPD,
ASTHMA, BY SAMPLING DIVERSE
POPULATIONS AND APPLYING
QUANTITATIVE LUNG
IMAGING THAT CAN GENERATE
IMAGING BIOMARKERS OF
SPECIFIC ASPECTS OF LUNG
STRUCTURE AND FUNCTION
INCLUDING MICROVASCULAR
PROFUSION, INFLAMMATION AND
OTHERS AND HOW WE APPLY THESE
TOOLS TO
UNDERSTAND COVID-RELATED LUNG
DAMAGE.
---
IN THE SPRING OF 2022, A
32-YEAR-OLD WHITE MALE
MARATHON RUNNER AND ROLL IS A
HEALTHY, NEVER
SMOKING CONTROL SUBJECT IN
THE LUNGS (CORRECTION)
LONGITUDINAL STUDY AND RAN 5
MILES BEFORE COMING
IN FOR THE BASELINE STUDY.
THE RADIOLOGIST FOR THE STUDY
PROMPTLY REACHED OUT TO THE
PARTICIPANT AND NOTIFIED
THEM ABOUT THE
ABNORMALITY AND ENCOURAGED
COVID TESTING AND
PARTICIPATING BEING
COMPLETELY WELL TESTED
POSITIVE
FOR SARS COV-2 LATER THAT
DAY AND THE PERSON KINDLY
AGREED TO UNDERGO ADDITIONAL
IMAGING AT 30,
60, 90 DAYS AFTER DIAGNOSIS
REMAINING ASYSTEMATIC
THROUGHOUT AND SOME OF THE
THINGS WE SAW ON THE
QUANTITATIVE IMAGING.
---
THE STANDARD RESULTS ARE
SHOWN AT THE TOP AT BASELINE
30 DAYS AND 90 DAYS FOLLOW-UP
AND AFTER 30
DAYS LUCKILY HIS LUNGS LOOK
COMPLETELY NORMAL AND THE
LUNG CAPACITY GGO DISAPPEARED
AND WHEN YOU
LOOK AT THE QUANTITATIVE
MEASURES FOR RESEARCH WE FIND
SOME ABNORMALITIES THAT
PERSISTED OR
INCREASED OVER TIME. SO THE
SECOND ROW SHOWS SOME
PARENCHYMAL MEASURES IMPROVED
WITH 30 DAYS BUT
SUBTLE CHANGES AT 60-90 DAYS.
BY 90 DAYS OF THE GREEN SPOT
OCCURRED IN NEW AREAS AS WELL
AS SOME OF THE EMERGING
HETEROGENEITY
OF EXPANSION OF THE LONG BUT
AS MENTIONED THE PATIENT
REMAINED COMPLETELY
ASYMPTOMATIC.
IN THE BOTTOM ROW YOU LOOK AT
BASILAR MEASURES AND IN THESE
MEASURES WHAT IS OUR INTEREST
IS WHERE
THE BLOOD IS GOING AND YOU
SEE THAT ON THE LEFT BASELINE
THERE WERE A LOT OF PLACES
WITH ORANGE
WHERE THE BLOOD WAS GOING.
THERE WERE A LOT OF PLACES
WHERE THE BLOOD WAS NOT GOING
THAT WERE
STILL GETTING VENTILATED AND
THE V/Q MISMATCH WERE
ELEVATED AT BASELINE AND
LUCKILY FOR THIS
PARTICIPANT OF DAYS 30 AND 90
THE V/Q HAS RESOLVED AND
APPEARS NORMAL SO NOTHING
DEFINITELY TO BE
EXTRAPOLATED BECAUSE IT IS
ONE INDIVIDUAL BUT THIS CAN
PROVIDE INFORMATION THAT IS
NONCLINICAL CT
SCAN TO THE NAKED EYE.
---
SO IMAGING HAS BEEN APPLIED
OVER THE PAST TWO YEARS TO
BETTER UNDERSTAND SPECIFIC
MECHANISMS OF
COVID SEQUELAE AND I WILL
SHOW YOU A FEW EXAMPLES.
THIS IS A SMALL STUDY OF 23
POST-COVID CASES OF MEDICALLY
AND EXPAND DYSPNEA,
INDIVIDUALS WITH
SYMPTOMS AFTER COVID BOTH
HOSPITALIZED AND NOT
HOSPITALIZED PARTICIPANTS AND
CONTROL SUBJECTS AND
CONTINUE WITH THE DIFFERENCE
OF THE UNDERLINING EPD
ANALOGY (CORRECTION)
EPIDEMEOLOGY, ALL HAD
NORMAL/NEAR-NORMAL CT AFTER
MRI POST INHALATION OF HYPER
POLARIZED XENON GAS,
WHICH CAN BE USED AS A
CONTEXT OF THE DIFFUSION
CAPACITY OF THE LOGAN THESE
ARE PARTICIPANTS WHO
HAD CVOID-19 AND RESIDUAL
PULMONARY SYMPTOMS AND AT THE
TOP YOU HAVE THE BEST RESULTS
IN TERMS OF
THE DIVISION YOU SEE A LOT OF
THE GAS IN THE IMAGE BELOW
HERE YOU SEE VERY LITTLE
DIFFUSION.
INDEED ACROSS THE ROOT
IMPAIRMENT OF GAS TRANSFER
WAS OBSERVED IN POST COVID
CASES IN BOTH
HOSPITALIZED AND
NON-HOSPITALIZED ROUTING
CORRELATED WITH THE MORE
TRADITIONAL MEASURE OF DLCO,
POSSIBLY SHOWING
MICROVASCULAR DAMAGE BECAUSE
OF THE THICKENING OF THE
ALVEOLAR MEMBRANE, AND
CERTAINLY SOMETHING THAT
OTHER STUDIES ARE LOOKING
INTO.
---
IN THIS SEPARATE STUDY IT
LOOKED MORE AND AIRWAYS, 100
PATIENTS WITH POST SYMPTOMS
OR COMPARED
WITH 106 CONTROLS AND THERE
WERE CTS PERFORMS AT FULL
EXPLORATION AND INSPIRATION.
THIS FIGURE PRETTY MUCH
SPEAKS FOR ITSELF THE IMAGE
OF THE LUNGS SHOWS IN PINK
AREAS OF THE LUNG
THAT SEEMS TO HAVE AIR
TRAPPING IN A REPRESENTATIVE
POST COVID PATIENT AND
COMPARED ACROSS THE
GROUPS IT SEEMS THAT IT WAS
MUCH HIGHER IN THE POST COVID
CASES THAT IN ANY OF THE
CONTROL CENTER
THE SAME TIME THE MORE
TRADITIONAL MEASURE OF
AIRFLOW STRUCTURE, FEV1/FVC,
NOT SIGNIFICANTLY
DIFFERENT ACROSS GROUPS,
THERE MAY BE SMALLER CHANGES
IN AIRWAY STRUCTURE THAN THE
TRADITIONAL
SPIROMETRY MEASURES.
---
TAKING ANOTHER STEP BACK. HOW
ABOUT COULD TEACH IT WILL
CHANGE YOUR LIABILITY TO HAVE
A MORE
SEVERE COVID INFECTION?
THIS WORD IMAGES DONE BY --
COMPARING FULL LUNG VOLUME
AND UNLESS YOU SEE SOMEONE
WITH A SMALL AIR
ENTRY COMPARED TO THE SIZE OF
THEIR LUNGS, AIRWAY TREE
CALIBER AND IN THE MIDDLE YOU
SEE SOMEONE
WITH AN AVERAGE AIRWAY TREE
COMPARED TO THE LUNG SIZE
ANOTHER BOTTOM RIGHT YOU SEE
SOMEONE WITH A
RELATIVELY LARGE AIRWAY TREE
CALIBER AND THE SMALLER
CALIBER MAY INCREASE
PARTICULATE DEFINITION
FOR BOTH TOBACCO SMOKE AND
PROVIDE PROTOCOLS SUCH AS
CVOID-19.
---
AND WOMEN HAVE A SMALL AIRWAY
TREE CALIBER THAN MEN ON
AVERAGE AND THIS IS NOT
INSTANT AND IN
ADULT STUDIES THE AIRWAY TREE
CALIBER HAS PREDICTED RISK OF
LUNG MORTALITY, LUNG CANCER
AND COPD.
WHETHER IT IS A RISK FACTOR
FOR CVOID-19 ILLNESS OR
SEQUELAE IS WORKING PROGRESS
IT REQUIRES WE
HAVE THESE MEASURES AVAILABLE
IN LARGE NUMBERS OF PEOPLE
BUT ALSO HAVE INFORMATION
UNDER COVID
OUTCOMES WE ARE WPPORTING
THIS KINK BY TRYING
TO HARMONIZE CT DATA ACROSS
COHORTS THAT
HAD PRE-EXISTING LUNG CT
BEFORE THE PANDEMIC AND A
COLLABORATIVE COHORT OF
COHORTS FOR CVOID-19
RESEARCH BRINGS TOGETHER 14
NIH COHORTS TO PERFORM
STANDARDIZED COVID
ASSESSMENTS IN 50,000
DIVERSE PARTICIPANTS AND
HARMONIZING LUNG STRUCTURE
AND THERE WERE MEASURES. ONE
IMPORTANT
ISSUE IS THAT MANY OF THESE
ARE THE VASCULAR COHORT THAT
OBTAINED CARDIAC CT SO THEY
NEED TO BE
CARDIAC CTS TO HARMONIZE
STANDARDIZED MEASURES AND THE
GOAL IS TO TEST ASSOCIATIONS
BETWEEN PRE-
AND POST COVID LONG HEALTH
AND DISTINGUISH RISK FACTORS.
IN CONCLUSION CVOID-19 IS
ANTICIPATED TO SAP
SUBSTANTIAL CLINICAL ANSWER
CLINICAL SEQUELAE FOR
LUNG HEALTH.
SECTOR DIFFERENCES ARE
OBSERVED WITH RESPECT TO
PRE-COVID.
I WANT TO THANK MY KEY
COLLABORATORS INCLUDING
DOCTORS BARR, HOFFMA, SMITH,
WILD AND LAINE AND THE
ENTIRE C4R LUNG STUDY GROUP.
>> THANK YOU VERY MUCH FOR
YOUR INTERESTING DATA, PUT
QUESTIONS IN THE Q&A, SO WE
CAN DISCUSS
LATER.
AND THE NEXT SPEAKER WILL BE
DR. OKUDA.
>> DR. OKUDA>
THANK YOU FOR INVITING ME FOR
THIS IMPORTANT WORKSHOP AND
I'M GLAD TO PRESENT OUR DATA
HERE.
POSTACUTE SEQUELAE OF COVID,
PASC.
PERSISTENT SYMPTOMS AND/OR
OBLIGATIONS OF SARS MORE THAN
FOUR WEEKS AFTER THE INITIAL
ONSET.
PREVALENCE, 52.5% AT 30 DAYS,
35.0% AT 60 DAYS POST ONSENT
IN MILD CVOID-19.
WE FOCUS ON THE PASC-RELATED
LUNG DISEASE AND CT STUDIES
SHOW THAT 72% OF SEVERE TO
MODERATE HAD
FIBROSIS LIKE CHANGES, AND
ANOTHER STUDY SHOWING AN
INCREASE IN SPECIAL
PREVAILING THESE STUDIES
ESPECIALLY POST MORTEM
CVOID-19 LUNGS ARE VERY
VALUABLE RESOURCE TO STUDY
MECHANISMS OF CVOID-19.
HOWEVER, THESE LINES
REPRESENT SEVERE END OF STAGE
PHENOTYPE.
WE NEED A MODEL SO WE CAN
STUDY ACUTE AND CHRONIC
DISEASE IN THE
(INDISCERNIBLE).
---
WE UTILIZED A SARS COV-2
VIRUS CALLED >> MAN:
-- >> MAN:
(CORRECTION)
CALLED >> MAN:
CALLED MA 10.
>> THIS FIBROSIS SCORE DATA
SHOWS PERSISTENT FIBROSIS
THROUGH 120 DAYS
POST-INFECTION.
AND THIS REPRESENTS AN IMAGE
OF MICE AT 120 DAYS
POST-INFECTIONS.
IT SHOWS THE --
(INDISCERNIBLE) --.
AND ALSO WHEN WE LOOK AT THE
IMMUNE CELLS, THERE IS AN
ABNORMALLY EXTENDED,
PROLONGED INFILTRATION
OF IMMUNE CELLS THAT INCUR
SOME (INDISCERNIBLE) AND
MACROPHAGES.
AND IN THE INFECTED, 30 DAYS
POST INFECTION IT SHOWS A
MACRO PHASE SUBSET INCREASE
IN INFECTED
MICE.
---
TO BETTER UNDERSTAND
(INDISCERNIBLE) WE UTILIZE
THE GEOMX DSP ANALYSIS AT 2,
15, AND 30 DAYS
POST-INFECTION.
OUR PREVIOUS STUDY IDENTIFIED
THE CELLS IN THE AIRWAYS AND
THE (INDISCERNIBLE) AND ALSO
WE
SELECTED ROIS, IN THE
MORPHOLOGICALLY INTACT
REASONS AND MORPHOLOGICALLY
DISORGANIZED SUB
(INDISCERNIBLE) REGION
BECAUSE OF THE HETEROGENEITY
OF LUNG DISEASE AT THE
CHRONIC TIME POINT.
---
FIRST WE LOOKED AT THE VIRAL
GENES IN THE (INDISCERNIBLE)
AND DISTAL AND ALVEOLI
REGIONS.
THE VARIOUS GENES ARE NOT
IDENTIFIED AFTER 15 DAYS POST
INFECTION, AND THESE VIRAL
EXPRESSIONS
AFFECTED THE GLOBAL
TRANSCRIPTIONAL PROFILE IN
ROIS.
SO THESE PURPLE SQUARES, THE
ROI IS IN THE DISEASED MICE 2
DAYS POST-INFECTION.
AND THESE ARE MOCK AND INTACT
ROIS 15, 30 DPI.
THE ALVEOLAR ROIS, MOCK AND
INTACT ROIS 15, 30 DPI.
THIS MORPHOLOGICAL
DISORGANIZED ROIS ARE
SEPARATED FROM MOCK AND
INTACT REGION. SO THE DATA
FOR
THE TRANSCRIPTIONAL NETWORK,
IN THE MORPHOLOGICALLY
DISEASED REAGIONS.
AND THIS PINK BAR IS A MOCK
ROI AND THE SECOND ROW IN RED
ARE DAY 2, GREY IS INTACT AND
THIS IS
DAY 30 INTACT DISEASE.
15 CAN SEE A DRAMATIC
DECREASE AND A DRAMATIC
INCREASE IN ISGS.
THIS UP-AND-DOWN RECOVERS
AFTER 15 DAYS POST INFECTION.
YOU CAN SEE FIBROSIS RELATED
GENES UPREGULATED.
INCLUDING (INDISCERNIBLE).
CONSISTENT WITH THIS, SFTPC,
IS A DRAMATICALLY DECREASED
UPDATE POSTINFECTION.
AND THEN NORMAL AND MIDDLE
HYPERACTIVE AFTER 15 DAYS
POST INFECTION.
ALSO THIS DATA SHOWS SPP1,
MACROPHAGE MARKER AND THIS IS
A FIBROSIS MARKER, HIGHLY
AGGREGRATED AND
(INDISCERNIBLE).
---
ANOTHER THING WE FOUND IN OUR
MICE IS A TRANSITIONAL
ALVEOLAR EPITHELIAL CELLS
INVOLVED IN
FIBROTIC ALVEOLAR REMODELING
FOLLOWING SARS COV-2 MA10
INFECTION.
THESE MARKERS UPDATE TOO AND
ALSO AT DAYS 15, 30.
HOWEVER THIS TIMING OF
UPREGULATION OF THESE GENES
DEPENDS ON EACH GENE AND THAT
SUGGESTED
ALTHOUGH THE GENES ARE
REPORTED IN TERMS OF
(INDISCERNIBLE) EACH GENE
PLAYS A DIFFERENT ROLE AT A
DIFFERENT STAGE.
THESE ARE IMAGES SHOWING THE
DRAMATIC INCREASE OF THE
(INDISCERNIBLE) CELLS 2 DAYS
POST INFECTION.
AND THIS NUMBER OVER THE
CELLS IS GETTIN GLESS BUT AT
15 DPI THESE CELLS STILL
REMAIN ACCUMULATED
IN THIS REGION.
ALSO POSITIVE.
THIS DATA MIGHT SUGGEST AN
INTERACTION OF
(INDISCERNIBLE).
---
AND FINALLY WE TEST IF THE
REDUCTION OF ANTIVIRAL IN THE
EIDD-2801 REDUCES FIBROSIS.
IN THIS ANTIVIRAL DRUG
IMPROVED SURVIVAL AND LUNG
DAMAGE AND FIBROSIS ALSO
IMPROVED.
THIS DATA SUGGESTS A
REDUCTION OF THE
(INDISCERNIBLE) OF THE VIRUS
THAT MIGHT PREVENT SUBSEQUENT
FIBROTIC REMODELING.
---
IN CONCLUSION OUR MOUSE MODEL
STUDY SHOWS SARS INFECTION IN
MICE PRODUCES CHRONIC
PULMONARY
DISEASES.
PERSISTENT IMMUNE CELL
INVITATION.
FIBROTIC AVAILABLE REMODELING.
ACCUMULATION OF POPULAR
INTERMEDIATE CELLS.
QUESTIONS.
ANY SEXIST DIFFERENCES IN
MAJOR COMPONENTS OF PASC
PATHOGENESIS?
WHAT IS A MECHANISM THAT
PRODUCES THE SPECIFIC
DIFFERENCES IN THESE
COMPONENTS?
MAGNITUDE OF SARS COV-2 VIRAL
INFECTION: RECEPTOR BINDING
DOMAINS,
SIX DIFFERENCES IN THE
RECEPTOR BINDING DOMAIN
EXPRESSION OR ANY DIFFERENCE
IN THE TISSUE AND
CELLULAR TROPISM.
ACUTE LUNG INJURY> IMMUNE
RESPONSE, HOUSED IN A DEFENSE
RESPONSE, ISGS.
AND FIBROTIC ALVEOLAR
REMODELING.
THOSE ARE POSSIBLE QUESTIONS
BUT I WOULD BE HAPPY TO
DISCUSS MORE IN THE BREAKOUT
SESSIONS LATER.
THANK YOU SO MUCH.
>> DR. SILVEYRA:
THANK YOU SO MUCH DR.
OKAYURA.
I LOST CONNECTION SO DR.
MULLINGTON IS A PROFESSOR OF
-- (READING BIO)
DR. MULLINGTON?
>> DR. MULLINGTON:
THANK YOU FOR THE INVITATION
AND THE INTRODUCTION.
I'M GOING TO TALK ABOUT
ISSUES RELATED TO SLEEP IN
CIRCADIAN RHYTHMS.
I HAVE NO CONFLICTS IN THIS
PRESENTATION AND I WANT TO
COLLEGE MY TEAMING
PARTICULARLY MONICA
HAACK INVOLVED IN MUCH OF THE
RESEARCH THAT I WILL SHOW BY
WAY OF BACKGROUND.
SO AS WE HAVE HEARD, THERE'S
AN OVERREPRESENTATION OF
WOMEN IN AUTOIMMUNE DISEASE,
CHRONIC PAIN
CONDITIONS, PSYCHIATRIC
DISORDERS AND INSOMNIA.
CHRONIC INSOMNIA IS 1.5 TIMES
MORE COMMON IN WOMEN THAN IN
MEN.
DISTURBED SLEEP IMPACTS MANY
PHYSIOLOGICAL SYMPTOMS. SLEEP
IS REALLY A BIOLOGICAL
IMPERATIVE.
AND SLEEP PROTECTS THE HOST
IF THERE'S MICROBIAL OR VIRAL
CHALLENGES. IT AFFECTS SLEEP.
AND AT THE RIGHT LEVEL OF
CHALLENGE, HOST DEFENSES ARE
SUPPORTED AND SLOW AIRWAY IS
ENHANCED AND
IF IT IS INSUFFICIENT AND
DISTURBED IT MAY LEAD TO
DISEASE.
AND SLEEP DISTURBANCE IMPACTS
HYPOTHALAMIC PITUITARY-
ADRENAL AXIS.
IT IS VERY IMPORTANT FOR
ANCHORING THE CIRCADIAN
RHYTHMS.
IT HELPS IN RELATING THE
GLYMPHATICS IN A CENTRAL
NERVOUS SYSTEM AND IT IS
INVOLVED IN PAIN
SENSITIVITY REGULATION,
AUTONOMIC MODULATION,
HYPERTENSION IS ASSOCIATED
WITH INSUFFICIENT SLEEP
OR SLEEP THAT IS LESS THAN
THE RECOMMENDED 7-8 HOURS.
AND SLEEP INSUFFICIENCY HAS A
TIGHTER CORRELATION IN WOMEN
THAN IN MEN ACROSS THE ADULT
LIFESPAN.
---
SLEEP HAS A REGULATORY
INFLUENCE IN ALL MAJOR
PSYCHOLOGICAL SYSTEM.
MELATONIN IS REGULATED, THE
MASTER CLOCK.
CORTISOL, PEAKING AFTER
RISING.
>>
SEX/GENDER-SPECIFIC CVOID-19
OUTCOMES RELEVANT FOR HLBS
DISORDERS: FROM BENCH TO
BEDSIDE>>
>> DR. MULLINGTON:
THERE ARE LARGE COHORTS WE
NEED TO LOOK AT BIOLOGICAL,
SEX AND GENDER VARIABLES.
AND WITH REGARDS TO SLEEP WE
REALLY NEED TO BE ABLE TO
TRACK THE TIME COURSE. THERE
ARE REPORTS OF
INSOMNIA LEADING TO
HYPERSOMNIA. THERE'S BEEN
REPORTS OF CONDITIONS THAT
MAY BE RELATED TO
NEURODEGENERATIVE DISEASE,
REM BEHAVIOR DISORDER HAS
BEEN DOCUMENTED.
ALSO BE PREVALENT IN PASC.
AND THIS LEADS TO PARKINSON'S
DISEASE.
I THINK THE CONCOURSE NEEDS
TO BE ADDRESSED.
AND I THINK WE NEED TO TAKE
ADVANTAGE OF THE OPPORTUNITY
TO DEVELOP SOME BIOMARKERS SO
WE CAN
BETTER TRACK AND INVEST IN
PIPELINE DEVELOPMENT AND
COMMUNITY ENGAGEMENT.
WE NEED A DIVERSE WORKFORCE
AS WE DISCUSSED YESTERDAY OF
INVESTIGATORS ABLE TO REACH
OUT TO THE
COMMUNITY, AND LEAD TO A
BETTER SCIENTIFIC
UNDERSTANDING FOR ALL.
SO I WILL STOP THE SHARE
>>
>> DR. DELA CRUZ:
THERE'S BEEN SOME DIFFERENCES
BETWEEN THE BIOLOGICAL
FACTORS, AND FOR THE HUMAN
STUDIES WE DON'T
REALLY HAVE A CLEAR APPROACH
ESPECIALLY WITH COVID,
BECAUSE THERE'S MANY
DIFFERENT THINGS THAT
IMPACT.
FOR EXAMPLE -- ACTIVITY, ACE
PRECEPTORS, THE HORMONAL
IMPACT ITSELF ON IMMUNITY. IT
IS A REALLY
COMPLICATED SYSTEM TO DISSECT.
BUT GIVEN THE NUMBERS OF
PATIENTS THAT WE HAVE
EXPERIENCED,
THAT QUESTION CAN BE ANSWERED.
WE HAVE TONS OF BIOLOGICAL
SAMPLES FROM MULTIPLE STUDIES
AND CLINICAL TRIALS TO SOME
OF THE
EFFORTS WITH NIH, THE ACTIVE
TRIALS AND THINGS LIKE THAT.
IT WILL BE REALLY IMPORTANT
TO ADDRESS.
THAT AND EMERGING ARE SOME OF
THE IMMUNOMODULATORS AGAINST
CVOID-19.
I HEARD THROUGH THE GRAPEVINE
THAT SOME THE
IMMUNOMODULATORS STUDIES
POTENTIALLY HAVE SEXY
RESPONSE DIFFERENCES IN TERMS
OF THE TREATMENT,
AND AT THIS STAGE WE DON'T
KNOW THE ANSWER TO WHAT
YOU'RE ASKING.
>> DR. SILVEYRA:
I HAVE A QUESTION FOR DR.
OELSNER.
CAN YOU TALK ABOUT THE
QUALITATIVE IMAGING MARKERS
CORRELATE WITH CLINICAL
PRESENTATION AT
DIFFERENT TIME POINTS IN YOUR
STUDY AT 30 OR 90 DAYS AND
WHETHER YOU FIND ANY
DIFFERENCES IN
GENDER DIFFERENCES?
>> DR. OELSNER:
IT IS AN IMPORTANT QUESTION.
THE DATA I PRESENTED WAS VERY
SMALL, ONE PERSON WHO
REMAINED A SYMPTOMATIC,
THROUGHOUT SO WE
HIGHLIGHTED THE IMAGING THAT
HE CAN BE -- WITH SYMPTOMS
AND THERE COULD BE A LONG
ANSWER TO THIS
QUESTION.
INSTEAD I WANTED TO-- BECAUSE
I CANNOT GET THERE IN A
COUPLE OF MINUTES -- I WANTED
TO HIGHLIGHT
THAT THERE'S A LOT OF STUDIES
AND GOING, AND A LOT OF WORK
IT IS TO BE DONE ON THIS IN
SOME
IMPORTANT AREAS WHERE WE CAN
DO THAT WORK WHICH IS WITH
THE RECOVER INITIATIVE WHICH
OTHERS
MENTIONED, DOING REPEAT
IMAGING AFTER ACUTE ILLNESS.
WE ARE REALLY GOING TO NEED
TO SEPARATE MORE SEVERE LESS
SEVERE AND ACUTE ILLNESS
UNDERSTAND THE
DIFFERENCE WITH WHAT HAS BEEN
SEEN WITH MANY ACUTE LUNG
CASES POST ALI FIBROSIS
BECAUSE MANY THAT
IS MEDICAL WITH SPECIFIC
PROCESS VERSUS THINGS THAT
ARE SUCH AS SARS COV-2.
AND WE CAN MAKE A LOT OF
HYPOTHESES IN OUR UPCOMING
BRAINSTORMING SESSIONS AND IN
ADDITION TO THE
RECOVERY, C4R PARTICIPATES IN
THE RECOVERY AND HAS IMAGING
BIO BANK.
AND IN SOME OF THESE SUBTLE
CASES WHERE PEOPLE ARE NOT SO
ASYMPTOMATIC, WE NEED TO KNOW
WHETHER
SOME ABNORMALITY OF FIBROSIS
OR AIRWAY DISEASE OR AIRWAY
DISEASE WAS PRESENT BEFORE
COVID
INFECTION THEREFORE BETTER
LOOK THAT BEFORE THE ILLNESS
VERSUS SEQUELAE OF THE
ILLNESS AND ALL
THIS NEEDS TO BE ASSESSED
INTENTIONALLY.
>> DR. SILVEYRA:
I HAVE TWO QUESTIONS FOR DR.
ODUKA.
IF YOU'RE ABLE TO OBSERVE
MICRO THROMBOSIS IN THE MODEL
AND THE SECOND QUESTION COMES
AFTER
LISTENING TO THE LAST TALK.
HAVE YOU MEASURED ANY STRESS
MARKERS IN THE BLOOD OF THE
ANIMALS WERE IDENTIFIED ANY
BEHAVIORAL
SLEEP PATTERNS?
>> DR. OKUDA:
WE LOOKED AT THE HISTORY OF
THE LONG AND DID NOT FIND
DIRECT MICRO THROMBOSIS IN
THE LUNG BUT WE
DID NOT STUDY ANY OTHER
ORGANS. IT IS POSSIBLE THAT
THERE COULD BE MICRO
THROMBOSIS IN SOME OTHER
ORGAN.
>> DR. SILVEYRA:
REGARDING BLOOD BIOMARKERS
FOR STRESS OR ANYTHING?
>> DR. OKUDA:
WE HAVE NOT CHECKED THE
(INDISCERNIBLE) IN THE BLOOD
SERUM, AND IN THE REGULAR
(INDISCERNIBLE),
ARE UPREGULATED AS EXPECTED.
THERE ARE DIFFERENCES IN THE
AGE BUT WE HAVE NOT FOUND SEX
DIFFERENCES.
BUT IT IS A GREAT IDEA.
>> DR. SILVEYRA:
THANK YOU. THEY'RE INTERESTED
IN YOUR TALK ABOUT POSSIBLE
BIOLOGICAL EFFECTS ASSOCIATED
WITH SLEEP
DEPRIVATION DR. MULLINGTON.
FOR CAREGIVERS, SOCIAL
WORKERS, ETC.
>> DR. MULLINGTON:
ACTUALLY, THAT IS AN
IMPORTANT AREA TO UNDERSTAND
PARTICULARLY WHEN WE ARE
TALKING ABOUT SEX AND
GENDER.
AND IT IS KNOWN THAT SHIFT
WORK INCREASES YOUR
VULNERABILITY TO A NUMBER OF
DISEASES, METABOLIC
AND CANCER RELATED DISEASES.
AND THIS MAY BE DUE TO
SHIFTING AND DISREGULATION OF
THE CIRCADIAN
SYSTEM, BUT ALSO THE
IRREGULARITY OF THE SLEEP
PERIOD CAUSES DYSREGULATION
OF THE CIRCADIAN
RHYTHMS; IT MAKES IT
DIFFICULT FOR THOSE RHYTHMS
TO ALIGN AND OPTIMALLY
SUPPORT HEALTH.
AND THIS IS FREQUENTLY SEEN
IN SHIFTWORK BUT ALSO IN
CONDITIONS WHERE PEOPLE HAVE
TO WORK LONG
HOURS OR DON'T HAVE ADEQUATE
OPPORTUNITY FOR SAFE SLEEP.
AND AS IN SOME COMMUNITIES
WHERE THERE ARE FRONT LINES,
THIS IS A VERY IMPORTANT AREA
FOR FURTHER
INVESTIGATION.
---
ALSO, FOR NEW PARENTS, THIS
IS A COMMON STRUGGLE.
>> DR. SILVEYRA:
THANK YOU.
THERE IS A SIMILAR QUESTION
ABOUT WHETHER THESE SLEEP
DISTURBANCES ARE SIMILAR OR
DIFFERENT TO
(INDISCERNIBLE).
>> DR. MULLINGTON:
WHAT WAS THE LAST PART OF THE
QUESTION?
>> DR. SILVEYRA:
HOW SIMILAR THEY ARE WITH
PATIENTS THAT SUFFER FROM
POST SEPSIS SYNDROME
(PHONETIC)?
>> DR. MULLINGTON:
SO WHAT WE ARE SEEING WITH
THE COMPLAINTS OF-- SLEEP
CONCERNS-- IS A LOT OF
INSOMNIA AND
DISRUPTION OF SLEEP
FRAGMENTATION.
THIS PREVENTS CONSOLIDATED
SLEEP NEEDED TO DO THE
LYMPHATIC CLEARANCE, THE
CONSOLIDATION OF
LEARNING AND MEMORY.
WE NEED A CERTAIN AMOUNT OF
CONSOLIDATED SLEEP.
FRAGMENTATION OF SLEEP CAUSES
AN INABILITY TO
REGULATE HOMEOSTATIC
FUNCTIONS.
WHAT WE ARE NOTICING IS
INSOMNIA MAY LEAD TO
HYPERSOMNIA; WE KNOW THAT
FATIGUE IS INCREASED IN
PATIENTS THAT HAVE SLEEP
DISTURBANCES BUT ALSO
INSOMNIA.
---
ONE THING THAT HAS BEEN
REPORTED, OR HAS BEEN NOTED
CLINICALLY IS INCREASED
COMPLAINTS OF DAYTIME
SLEEPINESS AND ONSETS WHICH
MAY INDICATE CHANGES IN THE
CNS; REM ONSETS ARE NORMALLY
JUST SEEN IN
NARCOLEPSY. AND THE REM
BEHAVIOR DISORDER, THE
INCREASING NIGHTMARES ARE
ALSO SYMPTOMS THAT
WARRANT FURTHER
INVESTIGATION.
>> DR. SILVEYRA:
THANK YOU.
I HAVE ONE MORE QUESTION.
IT COULD BE FOR DR. DELA CRUZ
OR OTHERS.
THE PERSON WHO AFTER HIS
WONDERING WHY THERE IS SUCH A
FOCUS ON DLR7 AND NOT DLR8 AS
BOTH ARE IN
THE X CHROMOSOMES.
AND ALSO THE FACT THAT THE
PRIMARY INTERFERON RESPONSES
ALMOST NONEXISTENT IN HUMAN
LUNGS AND THE
DLR7 MAY NOT BE INACTIVATED
DUE TO DLR8.
CAN ANYBODY COMMENT ON THIS?
>> DR. DELA CRUZ:
THAT IS A GREAT QUESTION AND
I SUSPECT THAT THE TLR7 FOCUS
IS BEEN SHOWN IN INDIVIDUALS
WHO HAVE
HAD GENETIC MUTATION IN SOME
OF THESE PATHWAYS, INCLUDING
SOME OF THE OTHER TLR ANOTHER
INTERFERENCE AS WELL AND THE
ROLE OF TLR7 IS PROBABLY MORE
LOCAL FROM THE NASAL PASSAGES
IN THE
UPPER AIRWAY FOR SOME EARLY
PROTECTION I SUSPECT.
PART OF THE REASON WE HAVE
NOT LOOKED AT THE ROLE OF THE
OTHER TLRS INCLUDING TLR7 AS
POINTED OUT
BY YOUR PARTICIPANT IS THAT
WE DON'T HAVE A LOT OF
BRONCHOSCOPIES ON THESE
PATIENTS AND SO IN SOME
INSTITUTIONS THEY HAVE DONE
THAT MORE THAN OTHERS TO LOOK
FOR CONGENIC SUSCEPTIBILITY
OF SOME OF
THESE CASES.
WOULD WE HAVE AUTOPSY
SAMPLES, THE GENETIC
EXPRESSION IN TERMS OF MRNA,
PROTEIN EXPRESSIONS ARE
ALTERED BY OTHER THINGS SO IS
HARD TO TEASE THAT APART.
I THINK PRIMARILY A LOT OF IT
IS DRIVEN BY SOME OF THE
GENETIC ANALYSIS INITIALLY
FOR PATIENTS WHO
HAVE KNOWN MUTATIONS FROM
THIS ASSOCIATION.
>> DR. SILVEYRA:
THANK YOU SO MUCH.
UNFORTUNATELY WE HAVE TO WRAP
UP.
I WANT TO THANK ALL THE
SPEAKERS IN THE SESSION AND
THE AUDIENCE FOR THE
WONDERFUL QUESTIONS.
THIS WAS VERY INTERESTING,
AND WE LEARNED A LOT.
>> THANK YOU SO MUCH DR.
SYLVEIRA AND ALL OF THE
PANELISTS.
IT WAS A DYNAMITE DISCUSSION
AND THE CONVERSATION STARTED
TO ENCOMPASS BROADER CONCEPTS
THEN LUNG
AND SLEEP DISORDERS SO THIS
WILL BE QUITE AN INTERESTING
BREAKOUT SESSION THAT WE HAVE
AS WELL.
I WOULD LIKE TO REMIND
EVERYONE THAT WE HAVE HAD A
SLIGHT CHANGE IN SCHEDULE TO
SMOOTHEN THE FLOW
HERE.
NEXT I WILL GIVE A SUMMARY
OF-- OR WILL TRY TO
SUMMARIZE-- SOME ASPECTS OF
WHAT WE HAVE DISCUSSED
TO DAY ON DAY 2.
AND THEN WILL HAVE A 45
MINUTE DISCUSSION IN THE
BREAKOUT SESSIONS AND TAKE A
10-MIN. BREAK AND
THEN COME BACK TO HAVE
ANOTHER 45 MINUTE DISCUSSION
TO REPORT SOME OF THE
FINDINGS AND WE HAVE
BOTH GROUPS FROM THE BREAKOUT
SESSIONS CROSS POLLINATING
IDEAS AND FIGURE OUT WHAT
FUTURE
DIRECTIONS MIGHT BE.
X SO I WILL START BY SHARING
SOME SLIDES, SPECIFICALLY
ABOUT THE SESSIONS.
AND BEFORE WE SUMMARIZE, I
WANT TO FOREMOST THANK OUR
PATIENTS WILL SHARE THEIR
EXPENSES WITHOUT.
I THINK WE CAN ALL
ACKNOWLEDGE THE STRENGTH OF
WHICH THEY PROVIDED THEIR
INPUT.
IT IS AN HONOR THAT THEY'RE
SHARING THE VOICE AND INPUT.
THERE INSIGHT AND INPUT WILL
INFORM THE DIRECTION OF
RESEARCH AS WE SEEK TO TRY TO
UNDERSTAND THE
BIOLOGIC AND NONBIOLOGICAL
SEX AND GENDER RELATED
FACTORS THAT INFLUENCE THIS
DISEASE BOTH COVID
AND THE POSTACUTE SEQUELAE OF
COVID.
---
TODAY WE STARTED WITH SESSION
4 WHERE WE HAD A NUMBER OF
LUMINARY SPEAKERS WHO TALK
ABOUT
CARDIOVASCULAR AND METABOLIC
ASPECTS OF COVID AND
POST-ACUTE COVID. FIRST
DESCRIBING SEX DIFFERENCES IN
PRE-EXISTING CARDIOVASCULAR
DISEASE DO IMPACT COVID
OUTCOMES UNDER
OUR SEX DIFFERENCES IN THE
IMMUNO BIOLOGY OF
CARDIOVASCULAR AND LET THIS
IS A VERY BY CONTEXT AND
BY AGE.
WE SEE THAT THERE IS A COMMON
THEME THAT POPS UP ACROSS ALL
ORGAN SYSTEMS.
---
COVID CAN BE A STRESS TEST
LINCOLN SUB MASK SOME
CLINICAL DISEASE OR IT CAN
TRIGGER DE NOVO
DISEASE
Q LIKE ACUTE VENOUS AND
ARTERIAL THROMBOSIS.
--- IN THE FIRST WAY THERE
WAS A LOT OF GREAT WORK THAT
HAPPENED AND IN THE SECOND
WAVE THERE WAS
ALSO SOME WORK THAT HAPPENED
BUT IN THE THIRD WAVE WE ARE
GETTING PERHAPS A LITTLE BIT
OF COVID
FATIGUE IT STARTS TO SET IN
ON ALL SIDES OF DISCUSSION WE
NEED TO KEEP ATTENTION TO IT
BECAUSE
THERE ARE OTHER FACTORS THAT
COME INTO PLAY, NOT JUST WITH
A VARIANCE BUT ALSO
UNDERLINING
COMORBIDITIES OR DISEASES
THAT CAST ILLNESS THAT
MANIFEST IN DIFFERENT WAYS.
---
WE NEED TO HAVE ACCURATE
DIAGNOSIS OF CARDIOVASCULAR
DISEASE AND THAT REQUIRES
BOTH APPROPRIATE
TESTING MODALITIES, WHETHER
BIOLOGIC OR IMAGING BASED.
AND WE NEED APPROPRIATE
CONTROLS IN ORDER TO BE ABLE
TO DRAW CORRECT CONCLUSIONS.
---
WE HEARD A FEW DIFFERENT
SIDES OF MYOCARDITIS,
STRESS-RELATED
CARDIOMYOPATHY; ALSO DILATED
CARDIOMYOPATHY FROM OTHER
ETIOLOGY THAT CAN VARY BY
DIFFERENT SEVERITIES, AND
THERE IS CLINICAL
DIFFERENCES SUPPORT SEX
DIFFERENCES IN MYOCARDITIS
MORE COMMON IN SEVERE COVID.
AND WE HEARD ABOUT
TRAUMATIC INFARCT IN UP TO
1/4 OF THE PATIENTS WITH
SEVERE COVID THAT CAN LEAD TO
SCAR TISSUE AND
WE NEED TO HAVE A FIRST AND
SUPPORT NEEDED TO CONTRIBUTE
DATA TO UNMASK THIS DISEASE.
---
WE ALSO HEARD ABOUT POSTACUTE
COVID DISPROPORTIONATELY
AFFECTING FEMALES.
AND THESE COMPLICATIONS THAT
COME WITH IT ARE OFTEN
MANIFESTED WITH VASCULAR,
NEUROVASCULAR
DYSFUNCTION, PERSISTENT
IMMUNE ACTIVATION ALTHOUGH
THERE MAY BE NUANCES TO THIS.
THERE IS DISCUSSION ABOUT
COAGULOPATHY AND THE DATA IS
STILL MIXED IN THIS SPACE BUT
IT IS WORTH
INVESTIGATING.
---
WE HEARD FROM -- AND THE
INCIDENCE MAY BE EXACERBATED
IN COVID BUT THERE IS A
DISTINCT LACK OF
STUDIES ON THE MECHANISM,
TREATMENT AND TRAFFIC WE NEED
TO ADVANCE TO UNDERSTAND AND
MANAGE THE
DISEASE BETTER.
AND THEN WE HAD A
CONVERSATION ABOUT
MULTIDISCIPLINARY COORDINATED
CARE WITH ALL STAKEHOLDERS
THAT
IS IMPORTANT IN ALL OF THIS
DISEASE MANIFESTATIONS IN
ORDER TO MAKE BREAKERS AND WE
HEAR ABOUT
THIS IN CLINIC THAT EXPLORE
IMMUNO BIOLOGY, AUTONOMIC
DYSFUNCTION ACROSS
DISCIPLINES THAT ALLOW US
TO BRING TOGETHER DIFFERENT
PEOPLE AND DIFFERENT
EXPERTISE TO THE TABLE.
---
THERE HAS BEEN DISCUSSION
ABOUT POLICY STUDIES IN ACUTE
COVID AND ALSO IN LONG COVID
THAT MAY BE
GOOD VENUES TO REPURPOSE
EXISTING DRUGS THE WEEKEND
TARGET PLACES THAT MIGHT BE
LEADING SITES OF
INJURY LIKE THE ENDOTHELIUM,
INFORMATIONAL THROMBOSIS AND
DEVELOP RESCORING SYSTEMS TO
TAILOR OR
TREATMENT/PREVENTIVE
STRATEGIES IN ACUTE
TREATMENT.
---
THE NEXT SESSION NUMBER 5,
UNDERLINING BLOOD DISEASES IN
CVOID-19 WITH THE TERRIFIC
SLATE OF
SPEAKERS THAT SPAN THE
SPECTRUM FROM BIOINFORMATICS
TO ELECTRONIC HEALTH RECORDS,
MOLECULAR
CELLULAR BIOLOGY AND CLINICAL
TRIALS.
WILL LEARN THAT ELECTRONIC
HEALTH RECORDS IN DATABASES
CAN BE LEVERAGED AS IMPORTANT
TOOLS TO HELP
US SEE AND STUDY PATTERNS AND
OCCULT DISEASE RELATIONSHIPS
WE HAVE NOT THOUGHT ABOUT AND
DOCTOR --
TALK ABOUT IMPORTANCE OF
SKIN CONDITIONS AND COVID
SEVERITY AND PRE-EXISTING
LUNG DISEASE OF
RESOURCE SECTION 6 THAT IS
ALSO IMPORTANT IN THE IDEA
THAT SIX PACIFIC GENE
EXPRESSION CAN BE
IMPORTANT IN SKIN AND BLOOD
AND OTHER ORGAN SYSTEMS TO
INFORM INFORMATION ACROSS
TRADITIONAL ORGAN
BOUNDARIES AND
HEART/LUNG/BLOOD/SLEEP ACROSS
IMMUNE DISORDERS AND HOW SKIN
MANIFESTATIONS ARE
COMMON IN COVID.
---
WE ALSO HEARD ABOUT FROM
DOCTOR ABLE ABOUT THREE AND
POST CLINICAL EVIDENCE THAT
SUPPORTS
TREATMENT AND THROMBOSIS AND
THERE IS CLINICAL EVIDENCE
FROM THE ACTIVE >> [RECORDING
IN PROGRESS]
(CORRECTION)
ACTIVE 4A TRIAL, AND
DIFFERENCES THAT ARE WORTH
INVESTIGATING, AND BOTH -- --
EXPLORE REPOSITORIES
THAT CAME OUT IN SPONSORED
TRUST TO ADDRESS ACUTE COVID
AND THIS MIGHT BE USEFUL TO
OTHER
INVESTIGATORS AND HEARD ABOUT
TRANS ORGAN AND TRANSISTOR
INTERACTIONS NEED TO BE
CONSIDERED IN
MECHANISTIC AND CLINICAL
STUDIES OF BLOOD AND VASCULAR
DISORDERS AND I WOULD ARGUE
MOVING THIS
BEYOND TWO OTHER DISORDERS.
DOCTOR-- SHOWED US THAT
IMMUNE DISORDERS CAN START TO
CROSS OVER
MULTIPLE DIFFERENT ORGAN
SYSTEMS.
---
AND EXAMPLES PRESENTED WERE
HOW HORMONES CAN INTERACT
WITH PLATELETS AND
MITOCHONDRIA AND HAVE
INNATE IMMUNITY IN
COAGULATION START INTERSECT
INTO DIFFERENT NETWORKS.
I HEARD ABOUT HOW SKIN AND
AUTOIMMUNE DISEASES CAN START
INDIRECT CHAPTER AS WELL.
---
WE ALSO LEARNED THAT
THROMBOINFLAMMATION MAY BE A
DOMINANT CAUSE OF ORGAN
FAILURE AND DEATH.
AND HOW TREATMENTS TARGETING
TRHOMBOINFLAMMATION IMPROVE
MODERATE COVID OUTCOMES.
SEX GENDER DIFFERENCES IN
MICROVASCULAR
THROMBOSIS/DEATH
ARE MORE PRONOUNCED THE
GENDER AGE AND MORE STUDIES
ARE NEEDED IN
MACRO/MICROVASCULAR
THROMBOINFLAMMATION FOR
TREATMENT.
---
AND THERE IS DISCUSSION ABOUT
PATIENT SELECTION AND TIMING,
ANTIBODY PROFILES, RECIPIENT
POST
ISSUE RESPONSES IT CAN HELP
REFINE SOME OF THE RESULTS
AND IT IS WORTH DISCUSSING IN
OUR BREAKOUT
SESSION HOW WE GO ABOUT DOING
THIS WE ARE TRYING TO DESIGN
TRIALS PROACTIVELY.
---
-- SHARE THE PASSIVE IMMUNITY
TRANSFER TO TREAT ACUTE COVID
HAS VIABLE CLINICAL TRIALS
AND THERE
IS NO BENEFIT CONFERRED BY
PASSING IMMUNITY TRANSFER BUT
HE DID SHOW THAT MALES
RECEIVING
CONVALESCENT PLASMA HAD
HIGHER RATES OF DISEASE
PROGRESSION AND THE
IMPLICATIONS ARE NOT REALLY
CLEAR AND THE MECHANISMS
UNDERLINING INTERNET PEERS WE
DO NOT KNOW HOW TO ADVANCES
WE NEED TO HAVE
MORE STUDIES TO UNDERSTAND
THE POTENTIAL DIFFERENCES.
---
WITHIN MOVED ONTO SESSION 6,
WHERE WE ADDRESSED SLEEP AND
LUNG DISEASES WITH A TERRIFIC
GROUP OF
SPEAKERS THAT STARTED TO
BRING TOGETHER A LOT OF HOW
WE THINK ABOUT PRE-EXISTING
DISEASE, ACUTE
DISEASE AND POSTACUTE
SEQUELAE OF COVID.
AND CERTAINLY SEX AND GENDER
DIFFERENCES AND LUNG DISEASE
ESPECIALLY COPD PREDATE COVID
BUT IN
ACUTE COVID THESE DIFFERENCES
MAY BE AMPLIFIED.
AT LEAST IN PULMONARY AND
IMMUNE MANIFESTATIONS.
WE SAW THAT MALES HAVE MORE
INFORMATION, MORE TYPE I
OTHER ANTIBODIES, T CELL
DYSFUNCTIONS AND
FEMALES HAVE A MORE ANTIVIRAL
RESPONSE, BETTER HUMORAL
RESPONSE AND ADAPTIVE
RESPONSES AND
X-LINKED GENES MAY PROTECT,
SET HORMONES MAY MODULATE
IMMUNITY AND QUESTIONS WERE
RAISED ABOUT HOW
THIS MIGHT PLAY ROLES IN
PERIPARTUM/INTRAPARTUM AND IN
DEVELOPING POST PARTUM, AND
WE NEED TO
IDENTIFY EARLY IMMUNE
DYSFUNCTION BIOMARKERS
INTELLIGENT STUDIES AND USER
STUDIES TO COLLECT BLOOD
SAMPLES AND BIO REPOSITORIES
THAT WILL ALLOW US TO PROBE
HOW THIS WORKED OR NOT
WORKING WE HEARD
ABOUT MECHANISTIC AND
CLINICAL STUDIES THAT ARE
NECESSARY AND CALL FOR TRYING
TO UNDERSTAND WHY
THE MORE FREQUENT RESPIRATORY
SYMPTOMS THAT WE SEE IN
POSTACUTE COVID ARE MORE
FREQUENT IN FEMALES
AND WHY FEMALES HAVE MORE
FREQUENT POSTACUTE SEQUELAE
OF COVID ANYWAY. AND HOW THIS
MAY BE
DIFFERENT OVER THE SPECTRUM
OF MANIFESTATIONS OF THE
DISEASE BECAUSE SOME HAVE
QUITE MILD SYMPTOMS
AND WE ASKED THE PATIENT
WITNESSES, THERE ARE
MANIFESTATIONS THAT ARE
EXTREMELY SEVERE AND
LIFESTYLE LIMITING.
AND WE HEARD ABOUT
HYPOTHESIS, SOME CLINICAL
STUDIES THAT SUPPORT
HYPOTHESES FOR THIS FUNCTION
IN
SMALL AIRWAYS AND GAS
TRANSFER AND WHERE THERE ARE
OCCLUSIONS IN THE
MICROVASCULARTURE OR SCARRING
AND SUGGESTIONS THAT LARGE
COHORT STUDIES LIKE THE C4R
THAT WE HEARD ABOUT ARE
IMPORTANT
AND CAN BE LEVERAGED TO
IDENTIFY WHAT IMAGING
BIOMARKERS CAN BE USED TO
CORRELATE WITH CLINICAL
OUTCOMES TO REACH BIOLOGICAL
OUTCOMES.
---
WE HEARD IN THE SECOND TO
LAST SPEAKER THAT SEX
DIFFERENCES IN THE
BIOLOGICAL RESPONSES TO SLEEP
DISTURBANCE MAY CONTRIBUTE TO
SIX DISPARITIES IN IMMUNE
RESPONSES, CARDIOVASCULAR,
METABOLIC,
AUTONOMIC, AUTOIMMUNE
DISORDERS AND PASC.
---
WE HEARD FROM OUR SPEAKER
FROM NORTH CAROLINA THAT THE
ANIMAL MODELS OF LONG COVID
ARE NEEDED TO
STUDY DISEASE BIOLOGY AND
INTERVENTIONS IN ONE MODEL
PROPOSED BY THE MODIFICATION
OF THE SARS
COV-2 WHERE THE RBD DOMAIN
WAS ADAPTED TO BE ABLE TO
TEST IT IN MICE, SPECIFICALLY
DR. OKUDA
TESTED THIS IN FEMALE MICE.
AND THERE WAS LONG
DYSFUNCTION FIBROSIS MYLAR
CELLS PRESENT IN THE LUNGS.
AND BRINGING BACK CONCEPTS
FROM DOCTOR ACKERMAN'S PAPER
IN THE NEW ENGLAND JOURNAL
WITH A
DEMONSTRATED EMERGENT AND IN
NEO ANGI-GENESIS WITH
PATIENTS WITH ACUTE COVID.
AND USING ANIMAL MODELS COULD
REDUCE THE LONG TERMS
SCARRING.
AND WE SHOULD BE ABLE TO TEST
THIS IN ANIMAL MODELS FOR
THIS DISEASE.
---
I WILL STOP HERE.
AND HAND THIS BACK OVER TO
RASHAD TO HELP US FIGURE OUT
HOW WE NAVIGATE THE BREAKOUT
SESSIONS.
REALLY LOOKING FORWARD TO
THESE DISCUSSIONS.
I THINK THEY WILL BE DYNAMIC,
AND ENGAGING AND REALLY WILL
HELP US SET A ROADMAP FOR
WHERE WE
SHOULD GO FROM HERE. THANK
YOU RASHAD.
>> WERE GOING TO TRANSITION
TO THE BREAKOUT SESSIONS.
PLEASE SELF-SELECTED TWO
SESSIONS BELOW
EITHER BREAKOUT 1 OR 2.
YOU SHOULD HAVE RECEIVED AN
EMAIL WITH THE LINKS. WE HAVE
ALSO POSTED THEM IN THE CHAT
INVOLVING
THE BREAKOUT SESSIONS WE WILL
RETURN TO THIS ROOM USING THE
SAME LINK YOU USED TO ENTER
EARLIER
TODAY.
---
FOLLOWING THE BREAKOUT THERE
WILL BE ANY REPORT OUT
SESSION AT 4:15 P.M.
WE WILL SEE YOU THEN.
ENJOY YOUR SESSION.
WELCOME BACK EVERYBODY, WE
ARE ALMOST DONE AND I LOOK
FORWARD TO SEEING EVERYBODY
AT THE BAR.
WE WERE TASKED IN BREAKOUT
ROOM 1 ABOUT WHAT OTHER
GROUPS, AND KNOWLEDGE ABOUT
THE MECHANISMS OF
CVOID-19 IN TERMS OF THE ROLE
OF SEX AND GENDER.
WE SPENT HALF THE TIME
TALKING ABOUT ANIMAL MODELS,
AND THE REFINEMENT NEEDED
WHICH WAS MADE CLEAR
BY DOCTOR PERLMAN.
AND SO WE TALKED ABOUT WHAT
CAN ANIMALS WE REALLY NEED
AND WHETHER WE SHOULD INVEST
IN A MOUSE,
EVEN THOUGH THE MOUSE DOES
NOT DEVELOP AS A SEVERE
DISEASES OTHER MODELS.
THE CONSENSUS OF THE GROUP
WAS THAT LET'S NOT THROW OUT
THE MOUSE MODELS.
THEY ARE ACTUALLY REALLY
VALUABLE.
WE CAN USE THEM TO GET SOME
CLUES ABOUT THE MECHANISMS OF
COVID EVEN IF WE HAVE TO
MODIFY THE
VIRUS SOMEWHAT OR MODIFY THE
ACE THAT THE ANIMALS USES TO
RESPOND TO THE VIRUS.
BUT WE HAVE TO CONSIDER THAT
ONE MOUSE IS NOT ALL MICE. WE
NEED TO CONSIDER THAT THERE
ARE
DIFFERENT STRAINS OF MICE,
AND THAT WILL BE AN IMPORTANT
CONSIDERATION BECAUSE SOME
MICE STRAINS
ARE MUCH MORE SUSCEPTIBLE AND
IT COULD BE MORE VALUABLE
THAN OTHER MOUSE STRAINS.
AND THEN WE HAVE ALL THE
OTHER KNOCKOUT MODELS AND THE
RESEARCH COMMUNITY HAS PUT A
LOT OF
INVESTMENT IN THIS KNOCKOUT
MODELS AND WE SHOULD LOOK AT
WHAT GENES ARE PLAYING KEY
ROLES
PARTICULARLY SINCE THIS IS
SUCH A BIG ROLE, THE IMMUNE
SYSTEM, THERE ARE SO MANY
IMMUNE FACTOR
THAT WE COULD TAKE ADVANTAGE
OF. BUT THAT IS NOT TO SAY
THAT WE SHOULD FORGO OTHER
MODELS AND
OTHER ANIMAL MODELS AND THAT
INCLUDES THE HAMSTER, WHICH
DOES HAVE MORE SEVERE DISEASE
THAN MOST
OF THE MICE.
AND ALSO THE FERRET, ALTHOUGH
THAT IS MORE MILD THAN A
HAMSTER.
---
AND THEN THERE IS A NONHUMAN
PRIMATES. AND
EVEN THOUGH WE ARE LIMITED
WITH THEM BECAUSE OF THE MANY
REASONS,
THERE'S NOT THAT MANY CENTERS
THAT CAN STUDY THESE ANIMALS.
AND YOU HAVE ISSUES NOT
HAVING MANY FEMALES BECAUSE
THEY ARE USED FOR BREEDING
BUT STILL WE NEED
TO DO SOME WORK WITH THIS
NONHUMAN PRIMATES SINCE WE
ARE INTERESTED IN THE EFFECTS
ON THE BRAIN
AND COGNITION AND THEY ARE A
MUCH BETTER MODEL, MUCH
CLOSER TO US.
LOOKING AT BRAIN FUNCTION.
---
WE ALSO NEED TO CONSIDER THE
FACT THAT THE VARIANT THAT
WE'RE STANDING TODAY MAY NOT
BE THE VERY
END THAT IS INFECTING THE
POPULATION IN SEPTEMBER.
HOPEFULLY IT IS.
BUT IT MAY NOT BE.
WE GO BACK TO DOCTOR PERLMAN
WHO HAS BEEN STUDYING
CORONAVIRUSES FOREVER.
THEY'RE HERE TO STAY. WE HAVE
TAKE INTO ACCOUNT THE FACT
THAT THERE WILL BE MANY
VARIANTS AND WE
HAVE TO CONSIDER THAT ONE
VARIANT WILL GIVE US SOME
INFORMATION.
BUT WE CAN'T JUST IGNORE THE
FACT THAT THE VARIANCE OR
CHANGING.
--- AND WE ALSO NEED TO STUDY
THESE MODELS IN THE CONTEXT
OF WHAT ARE THE OTHER RISK
FACTORS, WE
NEED TO THINK ABOUT AGE,
OBESITY DIABETES AND
HYPERTENSION.
THESE ARE IMPORTANT VARIABLES.
IF THERE IS NOT THAT MUCH
DISEASE IN THE BASAL
CONDITION BUT ALL OF A SUDDEN
WHEN THE ANIMAL GETS
OLDER THEY ARE MUCH MORE
SUSCEPTIBLE LIKE IN HUMANS,
OR MORE SUSCEPTIBLE IF THEY
HAVE LIABILITIES
THEN WE NEED TO MODEL THAT IN
OUR ANIMALS.
--- AND THEN --
NEXT SLIDE --
WE NEED TO BE AWARE THE FACT
THAT IF WE ARE USING THESE
TRANSGENIC MOUSE MODELS,
WHERE WE GET THE
HUMAN GENE AND PUT IT INTO
THE MOUSE THE REGULATION OF
THIS GENE IS NOT UNDER THE
SAME HORMONAL
CONTROL THAN IF IT WERE THE
NORMAL MOUSE'S ACE 2, AND
THAT NEEDS TO BE IN THE BACK
OF OUR MINDS.
IT CAN BE A USEFUL MODEL BUT
WE NEED TO CONSIDER THE FACT
THAT IS NOT UNDER THE NORMAL
HORMONAL
REGULATIONS AND IF WE NEED TO
CONSIDER THE SEX, THAT IS
SOMETHING WE NEED TO CONSIDER.
---
ALSO THE ORGANOIDS CAN BE A
VALUABLE MODEL.
THERE'S A LOT OF ADVANCES IN
ORGANOIDS, WE CAN STUDY LONG
AND MULTIPLE ORGANOID MODEL
AND THE ART
MULTIPLE SEX DIFFERENCES THAT
WE CAN LAY ON TOP OF THE
HORMONES.
IT WOULD BE VERY VALUABLE FOR
LOOKING AT SPECIFIC
MECHANISMS LIKE LOOKING AT
DRUG EFFECTS,
PHARMACEUTICAL EFFECTS,
ADVERSE EFFECTS ON THAT
ORGAN.
SO LET'S NOT FORGET ABOUT THE
VALUE OF ORGANOIDS.
NEXT SLIDE.
SO WE SPENT MOST OF THE TIME
TALKING ABOUT MODELS, AND
THEN WE SAID ONCE WE HAVE OUR
MODEL OR
MODELS THAN WHAT DO WE REALLY
NEED TO FOCUS ON NEXT?
AND THE IMMUNE SYSTEM CAME UP.
---
I HAVE TO SAY THAT WE RAN OUT
OF TIME BECAUSE WE JUST RAN
OUT OF TIME.
DON'T FEEL THAT WE ARE
IGNORING THE OTHER GAPS AND
KNOWLEDGE SHARE.
THIS IS JUST BECAUSE WE DID
NOT HAVE ENOUGH TIME BUT WE
DID TALK ABOUT THE IMMUNE
SYSTEM.
IT IS INCREDIBLY IMPORTANT
ROLE AND WE NEED TO
UNDERSTAND THE SPECIFIC
MECHANISMS IN MANY
DIFFERENT CONDITIONS LIKE
VASCULAR DYSFUNCTION, BLOOD
DISORDERS AND WE NEED TO LOOK
AT DOCTOR --
MADE THE POINT THAT IF WE
WANT TO LOOK AT PARTICULAR
CYTOKINES AND INHIBIT CERTAIN
CYTOKINES WE
NEED TO REALIZE THAT MAYBE WE
ARE INTERFERING WITH THE
PATHOLOGY. AND SO THAT MAY
NOT BE A VALUE.
SO WE SHOULD LOOK AT OTHER
WAYS IN MODULATING THE IMMUNE
SYSTEM.
WE NEED TO LOOK AT HOW THE
DISEASE IS CLEARED OR
DISRUPTED.
WE NEED TO FOCUS ON INNATE
IMMUNITY, ABSOLUTE CRITICALLY
IMPORTANT AND THE GREAT THING
ABOUT
STUDYING ANIMAL MODELS IS
THAT WE CAN GET, WE CAN START
AT THE VERY BEGINNING WHEN
THE DISEASE
STARTS AND WE CAN LOOK AT
THE VERY BEGINNING OF THE
INFECTION AND LOOK AND WHAT
IS HAPPENING IN
THE IMMUNE SYSTEM.
THIS IS NOT AS EASY IN HUMANS
SO WE WILL GET CLUES FROM
STUDYING THESE ANIMAL MODELS.
JUST THE VERY BEGINNING START
OF THIS.
THE IMMUNE RESPONSE.
--- WE ALSO WANT TO FOCUS ON
THE TIMING.
SO THAT WE CAN LOOK OBVIOUSLY
IN THE UPPER AIRWAVES IN THIS
RESPONSE.
WE ALSO WANT TO LOOK AT THE
BASELINE FOR THE IMMUNE
STATUS BECAUSE THIS CAN BE
AFFECTED BY
DIFFERENT CONDITIONS.
DOCTOR FAIRWEATHER MADE THE
POINT THAT WE NEED TO
CONSIDER THE BONE MARROW, THE
INNATE CELLS' BONE
MARROW, THE SET POINT AND WE
HAVE THE RIGHT MODEL FOR THIS?
DO WE HAVE ANOTHER SLIDE?
---
WE HAVE ANOTHER DATA NOT A
WHOLE LOT. THERE ARE A LOT OF
STUDIES BUT NOT THAT MANY
HAVE SEX
DIFFERENCES. WE WANT TO
BRING ATTENTION TO THE FACT
THAT IT IS IMPORTANT TO
DISAGGREGATE YOUR
DATA BY SEX AS A BASIC
SCIENTIST. AND TO THINK ABOUT
WHEN LOOKING AT YOUR
MECHANISMS.
--- IT IS NOT TO SAY THAT
EVERYTHING IS GOING TO HAVE A
SEX DIFFERENCE.
THAT IS TOO SIMPLISTIC.
IT MAY BE THAT IT IS NOT A
MAJOR FACTOR ENOUGH ITSELF.
(CORRECTION) IN AND OF ITSELF
. AND IT IS ACTUALLY ON A
CONTINUUM.
AND DOCTOR REYNOLDS TALK
ABOUT HOW WE HAVE TO THINK
ABOUT SEX DIFFERENCES AND THE
IMPACT OF SEX
AND GENDER IS NOT JUST MEN
VERSUS WOMEN.
THERE ARE MANY DIFFERENCES.
THERE ARE TRANS INDIVIDUALS
AND INDIVIDUALS WHO HAVE
DIFFERENT HORMONAL STATES.
AND IT IS ALSO ON TOP OF THAT
WE HAVE TO THINK ABOUT
LAYERING THE SOCIAL
DETERMINANTS OF HEALTH IN
ANIMAL MODELS.
WE COULD LAYER PERHAPS STRESS.
WE HAVE NOT TALKED ABOUT THIS
IN OUR BREAKOUT SESSIONS BUT
I CAN IMAGINE THAT WE COULD
TALK ABOUT
SLEEP AND HOW SLEEP
DISTURBANCES CAN BE AFFECTED
BY SOCIAL DETERMINANTS OF
HEALTH.
THAT CAN IMPACT OUR
MECHANISMS AS WELL.
--- AND WE NEED TO LOOK AT
THE -- PRECEPTORS ANOTHER
INITIAL RECEPTORS IN IMMUNE
CELLS WHERE SEX
DIFFERENCES IN PHENOTYPES;
AND ANOTHER POINT THAT WAS
RAISED WAS THAT THE
MALE/FEMALE COMPARISONS COULD
BE MORE TRAUMATIC IN
THE ANIMAL MODELS THAN
INHUMAN CONDITIONS AND THAT
IS OKAY.
IN THAT IT BRINGS UP THESE
DIFFERENCES. BUT WE NEED TO
BE CAUTIOUS
IN OUR INTERPRETATION AND
AGAIN IT GOES BACK TO THE
FACT THAT THERE IS THIS
OVERLAP.
THERE IS NOT THIS
BLACK-AND-WHITE, AND WE HAVE
TO BE CAREFUL NOT TO SAY THAT
THE MALES ARE THIS
WAY AND THE FEMALES ARE THAT
WAY. BUT THERE ARE THESE
MECHANISMS THAT CAN BE
HAPPENING IN BOTH
SEXES.
IT MAY BE MORE THAT THIS
MECHANISM IS MORE PROMINENT
IN MALES WERE WHEREAS IT MAY
STILL BE THERE
IN THE FEMALES.
BUT IT IS NOT AS IMPORTANT.
THERE MAY BE A SECOND
MECHANISM THAT PLAYS A
GREATER ROLE IN THE OUTCOME
THAT WE ARE INTERESTED IN
STUDYING.
SO WE REALLY HAVE TO THINK
ABOUT BEING INCLUSIVE OF ALL
THE POPULATIONS.
TO MODEL SOCIAL DETERMINANTS
OF HEALTH AS A CHALLENGE FOR
BASIC SCIENTISTS.
BUT IT IS SOMETHING THAT WE
SHOULD CONSIDER.
WE CAN DO THAT BY LOOKING AT
DIFFERENT STRAINS.
WE CAN DO THAT BY LOOKING AT
DIFFERENT MODELS OF STRESS.
AND WE CAN DO THAT BY LOOKING
AT OTHER FACTORS THAT ARE
CAPTURED IN THE SOCIAL
DETERMINANTS OF
HEALTH.
--- HOW AM I DOING FOR TIME?
JASMINA?
>> JASMINA VARAGIC:
I THINK YOU ARE OKAY. IT
WOULD BE GOOD IF YOU COULD GO
THROUGH IT.
>> I WANT TO MAKE SURE.
SO THE ANIMAL MODELS CAN
POINT TO POTENTIAL SIGNALS,
REGULATED PATHWAYS IN FUTURE
STUDY AND THIS
IS WHAT WE REALLY HOPE, OUR
BASIC SCIENCE WILL DO, INFORM
HUMAN SUBJECT STUDIES.
--- AND WE ALSO THINK-- AND
THESE ARE BEING TIED IN
REAL-TIME-- IT'S NOT THE
CLEANEST ENGLISH
HERE. BUT WE DO WANT TO LOOK
AT THE RAPID VIRAL
REPLICATION MECHANISMS.
THE FACT THAT THE INTERFERON
RESPONSE IS LACKING AND THAT
WE HAVE IN SOME CASES AN
EXAGGERATED
CYTOKINE RESPONSE ASSOCIATED
IN SOME CASES WITH SEVERE
OUTCOMES.
WE WANT TO LOOK AT THAT.
THAT IS AN IMPORTANT
MECHANISM THAT WE REALLY
DON'T FULLY UNDERSTAND YET.
AND IT COULD VERY WELL BE
WHAT IS UNDERLINING SOME OF
THIS COVID PHENOMENA.
IT COULD ALSO UNDERLINED LONG
COVID AND IF I HAVE NOT SAY
IT BEFORE WE NEED A MODEL FOR
LONG
COVID.
WE DO NOT HAVE THAT.
WE NEED TO BE ABLE TO MODEL
WHAT IS HAPPENING WAY AFTER
THE VIRUS IS NO LONGER
PRESENT AND WE JUST
DON'T HAVE THAT MODEL YET.
WE NEED TO LOOK AT SPECIFIC
PROGNOSTIC MARKERS.
WE NEED TO IDENTIFY THEM SO
WE CAN THEN IN OUR ANIMAL
MODELS-- TAKE THEM AND SEE
IF THEY ARE ALSO
OCCURRING HUMANS.
THAT WOULD BE VERY USEFUL FOR
HUMAN SUBJECT STUDIES.
--- AND I EMPHASIZE THE
DIVERSITY IN THE
SUBPOPULATIONS.
WE HAVE TO CONSIDER OTHER
MODELS
AND WE ARE GOING TO CONCLUDE
THAT SOMETHING IS PLAYING A
BIG ROLE ON THE MECHANISM OF
DISEASE.
AND THEN LASTLY, I WOULD SAY
THAT IT IS IMPORTANT THAT WE
FIND WAYS TO STANDARDIZE OUR
DESCRIPTION
OF SEX AND GENDER.
I KNOW SOME JOURNALS ARE
REQUIRING YOU TO STATE THE
SIX OF YOUR ANIMAL BUT IT IS
NOT JUST THE SEX
OF THE ANIMAL. IT IS ALSO THE
AGE AND HORMONAL STATUS AND
THAT IS AN IMPORTANT
CONSIDERATION,
COMPARING OUR LAB WITH OTHER
LABORATORIES AND THAT IS AN
IMPORTANT COMPONENT.
IF WE ARE INTERESTED IN
GETTING TO THE BOTTOM OF WHY
SEX DIFFERENCES EXIST.
AND THE SUSCEPTIBILITY AND
THE PROGRESSION OF DISEASE
AND POSSIBLY RESPONSE TO
TREATMENT ALTHOUGH
WE DON'T HAVE A GOOD FEELING
FOR THAT YET AND THEN
OUTCOMES.
SO I THINK YOU CAN SEE THAT
THERE IS A TREMENDOUS AMOUNT
THAT WE STILL NEED TO LEARN
AND THIS IS
NO WAY I THE MOST IMPORTANT
NECESSARY.
DR. VARAGIC WILL ASK YOU FOR
INPUT TO MAKE SURE WE DO NOT
LEAVE ANYTHING OUT.
>> DO YOU WANT TO TAKE OVER?
>> THANK YOU VERY MUCH DOCTOR
SANDBERG.
IF YOU STOP SHARING.
>> DR. KANTHI:
WE MADE A FEW MODIFICATIONS.
>> WE HAD A BROAD DISCUSSION.
WOULD YOU LIKE TO START WITH
THIS ONE WHICH IS MORE ON THE
TECHNICAL SIDE?
I DIVIDED THEM A LITTLE BIT
INTO THE MEDICAL AND SOCIAL
ECONOMIC ASPECTS.
>> DR. KANTHI:
WONDERFUL KNOW WILL BE GLAD
TO START SO THE DISCUSSION
WAS WIDE-RANGING AS IT SEEMS
LIKE BREAKOUT
ROOM 1 WAS.
CLEARLY THERE IS A LOT OF
IMPORTANT INTEREST AND INPUT
AND WE TRY TO CAPTURE -- WE
KNOW WE MISSED
SOME, AND WE WILL LOOK AT THE
NOTES TO PULL THOSE OUT AND
IF AT ANY POINT YOU FEEL THAT
THE
SUMMARY DOES NOT CAPTURE SOME
OF THE THOUGHTS AND OPINIONS
THAT CAME OUT AS LEAD
INITIATIVE TO
CONSIDER, PLEASE SEND THOSE
TO THE CHAT BOX FOR THE
DISCUSSION THAT FOLLOWS HER
LATER ON BY EMAIL.
AND WE WILL DO OUR BEST TO
MAKE SURE THAT WE INCORPORATE
YOUR FEEDBACK.
--- SO THE CLINICAL TRIAL
DISCUSSION WAS QUITE
INTERESTING.
THERE WAS A THOUGHT THAT WE
NEED TO BE ABLE TO IMPROVE
CLINICAL TRIAL ENROLLMENT AND
ARE
DIFFERENT ASPECTS THAT WILL
COVER SHORTLY AS WELL BUT ONE
OF THE CHALLENGES THAT CAME
UP IN ACUTE
COVID WAS THE DIFFICULTY OF
BEING ABLE TO START TRIALS
AND ENROLL PATIENTS IN THOSE.
ONCE PATIENTS WERE BEING
ENROLLED THERE WERE A LOT OF
DIFFERENT TRIALS AT THE SAME
AS ADDITIONAL
FUNDING WAY TO HARMONIZE
THAT-- AND IT'S ADDITION CAN
HAVE MULTIPLE TRIALS GOING
BUT IT IS
IMPORTANT THAT PATIENTS ARE
PRESENTED WITH THE
OPPORTUNITY TO PARTICIPATE IN
MULTIPLE TRIALS SO
GIVING PATIENTS THE OPTION
SEEMS IMPORTANT.
SO WE WILL COVER THIS LATER.
--- THE GROUP FELT THAT AS
THE SHIFTING LANDSCAPE OF
WHAT IS CONSIDERED STANDARD
THERAPIES FOR
COVID CHANGES, AND WE START
LOOKING TOWARDS WHAT IT MIGHT
LOOK LIKE IN LONG COVID,
TRYING TO
UNDERSTAND HOW TO SET THE
STAGE FOR MULTIPLE DIFFERENT
THERAPIES AND THINKING ABOUT
COMBINATION
THERAPIES.
IN TRYING TO UNDERSTAND HOW
THOSE MIGHT BE PUT TOGETHER
IN SOME SORT OF AN
ARCHITECTURE TO BE ABLE
TO PRESENT THE PATIENTS
EITHER AS COMBINATION
THERAPIES, OR THERAPIES THAT
ARE GUIDED MORE BY IN A
PERSONALIZED MANNER TO
PROVIDE PATIENTS THAT WOULD
BE MUCH MORE RELEVANT TO
THEIR BIOLOGY.
OR THEIR NONBIOLOGICAL
FACTORS. AND THIS
WOULD INCLUDE SEX AND GENDER
AS PART OF IT.
--- YOU HAVE SEEN THAT MANY
OF OUR CLINICAL TRIALS DON'T
SINCERELY INCORPORATE SEX AND
GENDER AS
CONSIDERATIONS.
AND SO FINDING WAYS TO BE
ABLE TO DO THIS AND OFFER
THIS IN AN EQUITABLE MANNER
AND OFFERED
TAILORED TRIALS IS IMPORTANT
AND THERE WAS A DISCUSSION
ABOUT HAVING AN INTENTIONAL
DESIGN THAT
INCORPORATES BAYSIAN ANALYSIS
THAT INCLUDES WOMEN WOULD BE
IMPORTANT TO BE ABLE TO HAVE
TRIALS
THAT CAN BE DESIGNED QUICKLY,
BEING POWERED UP EASILY AND
BE USEFUL, AND THEN TAKING
THESE TRIALS
AND INTERPRET AND APPLY TO
PATIENTS WHEREVER THEY ARE.
---
THE THOUGHT ABOUT USING SOME
OF THESE NEWER APPROACHES--
WHICH CAN SOMETIMES INCLUDE
THIS BAYSIAN
DESIGN BUT ALSO BEING ABLE TO
USE MULTIPLE AGENTS IN AN
ADAPTIVE PLATFORM APPROACH
WOULD ALLOW US
TO TRY AND REACH SOME OF
THESE GOALS.
--- AND ALSO THINKING ABOUT
HOW WE LOOK AT SUBGROUPS,
AND THINK ABOUT ANALYZING
THEM BEFORE WE START THE
TRIAL.
AND SO INCORPORATING THAT AS
A DESIGN FACTOR.
AND THE SUBGROUPS WOULD
INCLUDE SEX, GENDER,
SOCIOECONOMIC STATUS AS WELL.
SO THE IMPORTANCE OF BRINGING
THAT IN, IN A VERY
PURPOSEFUL, INTENTIONAL WAY
WOULD PROBABLY ALTER
THE CLINICAL TRIAL DESIGN.
AND ALSO ITS EXECUTION.
--- SO LOOKING BEYOND WHAT
ARE LARGE CLINICAL CENTER
SITES AND MOVING THIS OUT
INTO COMMUNITIES TO
ESSENTIALLY GO WHERE THE
PATIENTS ARE.
---
THERE WAS A DISCUSSION ABOUT
IDENTIFYING BIOMARKERS SINCE
THEY MIGHT BE IMPORTANT FOR
PROGNOSTICATION.
THE BIOMARKERS COULD BE
IMPORTANT FOR BEING ABLE TO
GET TO MORE PRECISE
TREATMENTS.
AND FOR A TAILORED APPROACH
TO BE ABLE TO TREAT PATIENTS
WITH.
AND PERHAPS TO THINK MORE
ABOUT PERSONALIZED MEDICINE
ON THE BACK END.
SO WE WILL BE ABLE TO REACH
THAT GOAL.
--- IN ORDER TO DO THAT, WE
DO NEED TO HAVE STUDIES THAT
INCORPORATE BIO REPOSITORIES
AND SO THAT
BECOMES A CENTRAL PORTION.
AND THIS BIO REPOSITORIES
WOULD NOT BE THE STEPCHILD
BUT AN IMPORTANT
PART OF THE INITIAL DESIGN.
BIOMARKERS NEED TO BE
ACCESSIBLE MUCH IN THE WAY
THAT WE HEARD THE ACTIVE 4A
TRIAL AND THE 3CPO
TRIAL AND BEING ABLE TO PAIR
THAT WITH CLINICAL DATA TO BE
ABLE TO REALLY TRY AND DRILL
DOWN TO
UNDERSTANDING WHY A
PARTICULAR INTERVENTION
WORKED.
OR WHY IT DID NOT WORKED.
AND HOW WE USE THAT
INFORMATION TO BE ABLE TO
DESIGN BETTER TRIALS IN THE
FUTURE.
---
THERE WAS DISCUSSION ABOUT
NIH POLICIES.
I THINK THE SPECIFICALLY
REFERRED TO THE CONVERSATION
ABOUT HOW WE WILL ENROLL
PATIENTS AND MAKING
SURE THAT ALL POPULATIONS ARE
REPRESENTATED APPROPRIATELY
IN CLINICAL TRIALS UNDER
RULES AND
REGULATION SURROUNDING THIS
AND THERE WAS DISCUSSION
ABOUT THERE NEEDING TO BE
SOME WAY TO BETTER
ENFORCE OR ASSESS IT.
ANDDOCTOR-- MENTIONED THAT
THIS IS PART OF CLINICAL
TRIALS AND THIS IS WHY WE SEE
MORE WOMEN
ENROLLED IN CLINICAL TRIALS
NOW THAN WE DID 20-25 YEARS
AGO.
>> I WILL TAKE OVER FROM HERE.
WE FOCUSED A LOT ON HOW TO
MAKE SURE THAT THE PUBLISHERS
IN THE TRAILER MUCH MORE
PRESENTATIVE.
THAT WE SHOULD FOCUS ON CROSS
DISCIPLINARY SETUPS.
THAT COMMUNITY ENGAGEMENT IS
ESSENTIAL IN ACTUALLY
ACHIEVING REPRESENTATION NOT
JUST IN TERMS OF
SEX AND GENDER BUT IN BROADER
TERMS OF DIVERSITY. AND THIS
NEEDS TO BE CONSIDERED
BROADLY IN THE
STUDIES.
---
IT WAS POINTED OUT THAT THERE
IS SOME CODIFICATION BETWEEN
SEX AND GENDER AND WE HAD
BINARY
DISCUSSIONS AND THIS WAS NOT
REPRESENTATIVE OF THE FULL
RANGE OF SEX AND GENDER.
SO WE NEED TO BE MORE PRECISE
IN THE METHODOLOGY WE ARE
APPLYING AND THAT ALSO MEANS
THAT WE MIGHT
NEED TO BETTER HARMONIZE
TERMS FOR THE FUTURE.
CREATE SOME SORT OF DATA
DICTIONARY.
AND MAKE SURE THAT WHEN
PEOPLE ARE ENROLLED THAT WE
HAVE THE WORDS TO ADDRESS
THIS.
AND MAKE SURE THAT THIS IS
DONE IN AN INCLUSIVE WAY
DEVELOPED WITH THE COMMUNITY
BECAUSE NOT ALL
TERMINOLOGY WORKS FOR OUR
COMMUNITIES AS YOU PROBABLY
ALL KNOW.
--- WE HAD SEVERAL POINTERS
TO THE FACT THAT THE
COMMUNITIES NEED TO BE
INVOLVED, THAT YOU SHOULD
BE INTENTIONAL FROM THE START
IF YOU WANT TO WORK WITH THE
COMMUNITY. AND THIS SHOULD
NOT BE AN
ADD-ON LATER BECAUSE YOU WILL
NOT BE ABLE TO RECRUIT THE
POPULATION THAT YOU WOULD
LIKE AND IT
WOULD FEEL SOMEWHAT
INADEQUATE AND NOT AUTHENTIC
AND IT PROBABLY ISN'T.
IT IS A RELEVANT POINT IN THE
BEGINNING.
--- AND AS DOCTOR CONTI
(PHONETIC) ALREADY POINTED
OUT WE SHOULD OFFER TRIALS
ACTIVELY TO
DIFFERENT POPULATIONS AS WAS
MENTIONED YESTERDAY AS WELL.
BY SOME OF THE PATIENT
PARTICIPANTS THAT SHARED
THEIR STORIES WITH US.
NOT EVERYBODY FELT THAT THEY
WERE BEING OFFERED TO
PARTICIPATE IN TRIALS IN WE
SHOULD BE MORE
INTENTIONAL TO INCLUDE
EVERYBODY.
--- THERE WAS ALSO DISCUSSION
ABOUT THE IMPACT OF
SOCIOECONOMIC FACTORS.
AND THAT THIS SHOULD BE
COLLECTED IN ADDITION TO
BIOLOGICAL FACTORS BECAUSE
THEY PLAY A CRITICAL
ROLE TO ACCESS OF HEALTHCARE
AND RISK MODIFIERS.
IT IS ESSENTIAL TO
COLLABORATE WITH GROUPS THAT
ARE THE ONE HAND SIGN HAVE
THIS EXPERTISE AND ALSO
COLLECTED DATA SO WE MAY
TRIANGULATE LIGHT SOME OF
THIS INFORMATION AND SET UP
AN INTERSECTIONAL
ANALYSIS.
--- WE ALSO TALK A LITTLE BIT
ABOUT THE FACT THAT IT MIGHT
BE NECESSARY TO LOOK AT
COMMUNITY LEVEL
FACTORS.
TO MAKE SURE THAT WE RECRUIT
OUR POPULATIONS FROM
DIFFERENT SETTINGS AND THAT
THIS MIGHT NOT JUST
BE IN ACADEMIC HOSPITALS BUT
TO MAKE SURE THAT WE INCLUDE
COMMUNITY LEVEL HEALTHCARE
PROVIDERS
AND CAST A BROADER NET IN
ORDER TO REALLY ACCESS
EVERYBODY.
--- THERE WAS A POINT THAT
DIVERSE POPULATION SHOULD BE
FOLLOWED LONGITUDINALLY SO IT
IS NOT JUST
A CROSS-SECTIONAL MOMENT. AND
AS I SAID AT MULTIPLE SITES.
--- AND IT SHOULD REALLY BE
POINTED OUT THAT
DECENTRALIZED DESIGNS
INCLUDING REMOTE AREAS ARE
MORE
DIFFICULT TO ACCESS SHOULD BE
SPECIFICALLY TARGETED AS WELL
IF WE ARE TRYING TO GET
REPRESENTATION
AND INCREASE DIVERSITY.
--- ANOTHER IMPORTANT POINT,
INCLUDING PREGNANT WOMEN IN
CLINICAL TRIALS AND
INDIVIDUALS WITH
SPECIFIC DISEASES.
AND OF COURSE WE CAN LEARN
FROM THE HIV STUDIES WHICH
HAVE DONE A GREAT JOB IN THE
PAST IN
RECRUITING A DIVERSE GROUP OF
INDIVIDUALS HIGHLY INVOLVED
IN THE DESIGN OF RESEARCH AND
THESE ARE
DEFINITELY COMMUNITIES AND
EXPERTISES.
---
DOCTOR CONTI MENTIONED SOME
OF THESE TRIALS AND WE MOVED
THROUGH SEVERAL EXAMPLES.
AND THE ECHO
TRIALS AS MENTIONED NOT TO
INCLUDE PATIENTS WITH FATIGUE.
THERE WAS AN ACTIVE CALL TO
POTENTIALLY SUPPORT AND
MAKING SURE THAT YOU HAVE A
DIVERSE
POPULATION, 70 SITES,
RECRUITING ACROSS THE UNITED
STATES AND IF YOU HAVE THE
OPPORTUNITY TO GET
POTENTIALLY WITH THE SITES IN
ORDER TO MAKE SURE THAT A
DIVERSE POPULATION WILL BE
PARTICIPATED.
IT IS A CROSS DISCIPLINARY
TRIALS AND IT WILL COLLECT
ENTER INFORMATION.
---
THEN WE HAD THE C4R TRIAL
ALREADY MENTIONED, THE PLUS
THIS CASE WAS THAT THERE WAS
GREAT DIVERSITY
AND INFORMATION IN THE
COMMITTEE BUT NO DETAILED
INFORMATION ABOUT GENDER SO
FOCUSING ON ANOTHER
ASPECT OF DIVERSITY IS NOT A
GIVEN THAT WE WILL HAVE
INFORMATION ABOUT GENDER.
AND AS SAID BEFORE THIS NEEDS
TO BE DONE DELIBERATELY IN
THE BEGINNING.
--- IT WAS ALSO POINTED OUT
THAT ESPECIALLY WHEN ASKING
INDIVIDUALS FROM MARGINALIZED
COMMUNITIES
THAT MAYBE DO NOT HAVE ACCESS
TO HEALTHCARE.
ASKING ABOUT POSITIVE TESTS
MIGHT BE A MECHANISM OF
EXCLUSION BECAUSE NOT
EVERYBODY HAS ACCESS TO
THESE COMMUNITIES.
AND ASKING ABOUT LONG COVID
IT MIGHT BE POTENTIALLY
CHALLENGING AND POTENTIALLY
EXCLUSIONARY FOR
CERTAIN COMMUNITIES BECAUSE
OF COURSE, IT MIGHT BE
STIGMATIZED AS WELL AND IT
COULD HAVE
CONSEQUENCES.
--- THE LAST EXAMPLE
MENTIONED BY DOCTOR BARRY
MERZ, WE WANTED TO KNOW WHAT
THEY DID WELL AT
CEDARS AND WHAT WE CAN LEARN
HERE.
AND SHE MADE A POINT THAT
THEY ARE DOING GREAT BUT THEY
ALSO HAVE A SOMEWHAT
ADVANTAGE GIVEN BY
THE COMMUNITY WHERE THEY ARE
LOCATED, BEING A DIVERSE AREA
IN A LARGE INSTITUTION THAT
TAKES CARE
OF EVERYONE AND ONE HAS TO BE
DELIBERATE IN RECRUITING THIS
MAKES IT SOMEWHAT EASIER THAN
IN OTHER
INSTITUTIONS THAT MIGHT LACK
SUCH AN INFRASTRUCTURE OR
CATCHMENT AREA.
--- THAT IS PRETTY MUCH WHAT
WE TALKED ABOUT.
IF ANY OF THE PARTICIPANTS IN
THE BREAKOUT ROOMS STILL HAVE
POINTS TO ADDRESS THAT WE
HAVE MISSED
HERE PLEASE FEEL FREE TO CHIP
IN.
OTHERWISE I THINK THAT IS IT
FORM OUR SIDE NOW.
>> DR. KANTHI:
WONDERFUL THANK YOU.
THE NEXT PHASE HERE IS FOR US
TO HAVE MORE OF AN OPEN
CONVERSATION AND THINK ABOUT
WHETHER YOU AS
THE AUDIENCE HAVE COMMENTS.
HOW MIGHT YOU INFORM
DIFFERENT ASPECT OF THE
REPORT? FOR THE ONES YOU WERE
IN OR PERHAPS YOU ARE
NOT IN, AND HOW YOU WOULD
MAKE MORE BROAD, MORE
INCLUSIVE, MORE THOROUGH
ALIGNMENT WITH THE
MISSION OF THIS WORKSHOP.
>> DR. SANDBERG:
EVERYBODY HAD SO MANY IDEAS
BUT WE DID NOT HAVE ENOUGH
TIME.
WE JUST TALKED ABOUT TWO
TOPICS AND THERE WERE ANOTHER
20, AND WE COULD SPEND THE
WHOLE TIME AT
THE BAR TALKING ON THIS.
>> DR. KANTHI:
I AGREE THAT WE CAN USE ALL
TIME BUT WE ONLY HAVE A FIXED
AMOUNT OF TIME SO WE HAVE TO
MOVE
SOMETHING FORWARD.
--- PERHAPS I CAN START WITH
ONE IDEA.
I WAS STRUCK WITH THE TALKS
BOTH YESTERDAY AND TODAY.
AND CAME AWAY WITH A BIT OF A
MESSAGE IS I THOUGHT ABOUT
THE COLLECTIVE EXPERIENCE OF
THIS GROUP.
AND THERE WERE COMMENTS FROM
SEVERAL OF THE SPEAKERS.
WE HAVE WHAT IS LIKELY A
ONCE-IN-A-LIFETIME
OPPORTUNITY TO BE ABLE TO
STUDY HOW OUR ORGAN SYSTEMS
INTERACT WITH ONE ANOTHER.
AND SO WE HOPE WE WOULD NOT
HAVE THIS OPPORTUNITY BUT IT
IS HERE.
IT IS IMPORTANT TO ENSURE
THAT WE ARE LEVERAGING IT AS
MUCH AS POSSIBLE TO BE ABLE
TO THINK ABOUT
NOT JUST ACUTE ILLNESSES BUT
CHRONIC ILLNESSES AS WELL.
THINGS LIKE AUTOIMMUNE
DISEASE.
SO TO THAT END, ONE EXAMPLE
THAT WAS PRESENTED BY THE
GROUP IN YALE THERE ARE AUTO
ANTIBODIES
FORMED.
IN THE GROUP DESCRIBE SOME OF
THE -- ONES.
IT IS A BROAD REPERTOIRE AND
WE DON'T KNOW WHAT THIS MEANS.
--- AS WE THINK FORWARD MAYBE
THERE IS A TERM THAT CAN BE
COINED HERE.
THAT BRINGS TOGETHER SOME OF
THESE OTHER DISCIPLINES.
MAYBE SOMETHING LIKE VASCULAR
IMMUNO BIOLOGY.
I MENTIONED THAT IN OUR LAST
DISCUSSION SESSION.
THAT IS SOMETHING TO THINK
ABOUT AND I AM INTERESTED TO
HEAR FROM THOSE WHO HAVE BEEN
DOING THIS
LONGER THAN I HAVE, .
>> WE HAVE KNOWN THAT THERE
IS A RELATIONSHIP BETWEEN
VIRAL INFECTIONS AND
AUTOIMMUNE DISEASES BUT
IT IS DIFFICULT TO PROVE
BECAUSE CLINICAL DISEASES
PRESENTS A MUCH LATER AND
VIRAL INFECTIONS SO
MUCH SOONER.
MANY OF THEM ARE COMMON
INFECTIONS THAT ARE DIFFICULT
TO DISTINGUISH.
I THINK COVID HAS SHOWN US
THAT VIRUSES CAN CAUSE
AUTOIMMUNE DISEASE REALLY
WITHOUT ANY DOUBT.
AND VIRUSES ARE VERY GOOD AT
INDUCING THIS BY CAUSING THE
TYPE OF DAMAGE THAT THEY DO.
BUT ALSO HAVE AN IN, AND
INTEGRATE WITH MITOCHONDRIA
AND THE CELLS.
AND PRODUCE DAMAGING PROFILE
TO PRODUCE STRONG AUTOIMMUNE
RESPONSES.
WE HAVE AN OPPORTUNITY TO
UNDERSTAND MANY THINGS.
AUTO VIRUSES CAN CAUSE POTS,
WE DID NOT THOUGHT THAT WAS
POSSIBLE BEFORE SEEING THIS.
THIS IS
BROUGHT VIRUSES TO THE
FOREFRONT WHERE THEY HAVE
BEEN IGNORED QUITE A WHILE
FOR WHAT THEY CAN DO
IN THEIR ROLE IN DISEASE AND
THERE ARE STRONG SEX
DIFFERENCES IN ALL OF THE
AUTO IMMUNE DISEASES
AND THE PATHOLOGY DIFFERENCES
IN MALES AND FEMALES IF YOU
ARE A SMALL NUMBER OF MALES
GETTING IT
AND HIGHER NUMBER FEMALES AND
VICE A VERSA.
WE HAVE ALL OF THESE FACTORS
PLAYING OUT SO WE DON'T HAVE
A MORE REMARKABLY STRONG SEX
DIFFERENCE
IN MALES.
THE IMMUNE RESPONSE SUGGEST
WE SHOULD HAVE AN
OVERWHELMING RESPONSE IN
MALES WITH TISSUE
PATHOLOGY BUT ALL THE
AUTOIMMUNE RESPONSES SHOWS
THAT WE HAVE FACTORS GOING UP
IN MALES THAT ARE
BAD, AND UP IN FEMALES THAT
ARE BAD. AND THEY ARE
COUNTERACTING IN SOME SENSES
OUR OLD SEX
DIFFERENCES SO WE HAVE A
WONDERFUL OPPORTUNITY TO
UNDERSTAND THESE THINGS
BETTER.
>> DR. KANTHI:
DR. DELA CRUZ FEEL FREE.
THIS IS AN OPEN CONVERSATION.
>> DR. DELA CRUZ:
I AGREE WITH WHAT HAS BEEN
COMMENTED BY DR. KHANTI IN
THE PREVIOUS SPEAKER.
THIS IS AN OPPORTUNITY TO
UNDERSTAND WHAT THIS ONE
VIRUS CAN CAUSE AND IT IS
OBVIOUSLY REALLY
COMPLICATED.
WE HAVE BEEN STUDYING THE
ROLE OF RESPIRATORY VIRUSES
AND LONG-TERM OUTCOMES IN
LUNG DISEASES BUT
THE PROBLEM IS THAT WE NEVER
HAD AN INITIATING EVENT IN
LARGE NUMBERS. WE WANTED TO
INFER FROM
HISTORY AND HISTORICAL
EFFECTS.
AND THIS IS THE TIME TO DO
THIS.
WE KNOW WHO ARE INFECTED.
WE KNOW WHO THEY ARE.
THERE'S TONS OF CLINICAL
TRIALS DONE CURRENTLY AND
SOME OF THE SEX AND GENDER
FACTOR DISCUSSED
OVER THE PAST TWO DAYS CAN BE
MOBILIZED AND USE THOSE DATA
IN BIO SPECIMENS TO ADDRESS
THESE
COMPLICATIONS.
---
AND I DON'T THINK THIS IS ONE
THING CAUSING ANOTHER GENE,
ANOTHER RECEPTOR.
I THINK IT IS A COMPETITION
ISSUE.
THE OTHER THING WE REALLY
NEED TO DISSECT ARE THE
DIFFERENT PHENOTYPES, PASSED
PHENOTYPES.
AND EVEN ERDS FROM FLU OR
FROM COVID.
WE KNOW THERE ARE DIFFERENT
PHENOTYPES, INFLAMMATORY
VERSUS NON-INFLAMMATORY. THIS
IS ALL REALLY
IMPORTANT DISCUSSIONS.
AND ACTUALLY HIGHLIGHTED THAT
WE NEED TO DO A LOT MORE FOR
THIS KIND OF WORK.
AND GENDER AND SEX THAT HAS
BEEN DISCUSSED IS ONE OF THE
ONLY FEW FACTORS THAT
CONTRIBUTE TO THIS
HETEROGENEITY.
IT IS AN IMPORTANT ONE.
WE DO NOT KNOW WHAT IS GOING
ON IN HUMANS TO BE HONEST.
IN SOME OF THE HUMAN STUDIES
I PRESENTED THE EFFECTS WERE
SMALL COMPARED TO THE
MILLIONS OF PEOPLE
COMPARED TO WE NEED TO THINK
ABOUT LARGE-SCALE APPROACHES
TO SEE THE EFFECTS AND BETTER
PHENOTYPING TO REALLY
UNDERSTAND THE MECHANISM THAT
TIES THIS TOGETHER.
THANK YOU FOR GIVING THIS
EVENT.
>> AND WOULD MAKE THE POINT A
LITTLE MORE SPECIFICALLY THAT
I MADE IN MY PRESENTATION.
THAT WE HAVE BEEN RECOGNIZING
THE ROLE OF INFLAMMATION,
TRIGGERED BY X, Y AND Z IN
CARDIOVASCULAR
DISEASE FOR THREE DECADES.
WE HAVE THREE RANDOMIZED
CONTROLLED TRIALS, AND TWO
OUT OF THE THREE WERE
POSITIVE TRIALS
ENDORSING THAT THIS IS A
CONCEPT THAT WE CAN ADDRESS
CARDIOVASCULAR DISEASE IN
WOMEN AND MEN, BY
ADDRESSING IMMUNE FUNCTION
AND VASCULAR INFORMATION.
(CORRECTION) INFLAMMATION.
---
I WOULD SAY THAT WE SHOULD BE
DOING PILOT PHARMACOLOGICAL
TRIALS AND USING BIOMARKERS,
AND MAYBE
CARDIAC MRI AS A BIOMARKER.
I DON'T THINK THAT IS
PREMATURE TO LOOK AT THIS
BECAUSE A) WE HAVE IT; B) WE
KNOW HOW IT WORKS,
KIND OF.
AND THERE'S PLENTY OF PEOPLE
AS DR. DELA CRUZ SAID, THAT
THERE ARE PLENTY OF FOLKS AT
RISK FOR CPT
BECAUSE OF THEIR COVID
STATUS.
>> I AGREE HUNDRED PERCENT.
HE SAID A LOT OF THE THINGS
AND WANTED TO REITERATE
FOLLOWING TODAY'S DISCUSSION
AND YESTERDAY'S
AS WELL.
AND I THINK THIS IS THE USE
OF ANIMAL MODELS IN STUDYING
THE DIFFERENCES IN THE
PATHOLOGY AND LONG
COVID SYNDROME WILL HELP US
DECIPHER WHICH MECHANISMS
MIGHT PLAY A ROLE BETWEEN THE
DIFFERENT
SEXES.
AND WHICH MAY BE MORE
PERTINENT AND ACUTE VERSUS
LONG COVID.
--- I THINK THIS IS A GOOD
OPPORTUNITY TO CONTINUE
STUDYING THE ROLE OF
INFLAMMATION IN CAUSING
CARDIOVASCULAR EVENTS AND
LONG COVID CARDIOVASCULAR
EVENTS AND NEUROVASCULAR
EVENTS.
SO THAT WE CAN LEARN MORE
ABOUT HOW PREVENTING SOME OF
THAT CHRONIC INFLAMMATION CAN
IMPROVE
LONG-TERM HEALTH OUTCOMES FOR
MEN AND WOMEN.
AND WOMEN POST PREGNANCY AS
WELL.
DO NOT FORGET ABOUT OUR
PREGNANT WOMEN.
DELTA HAD A DEVASTATING
EFFECT WORLDWIDE ON THESE
WOMEN AND -- AS WELL AS SO IT
OPEN OUR EYES WITH
DELTA.
AND SO WHEN YOU SEE WOMEN
THAT HAD COVID DURING THEIR
PREGNANCY IN YOUR CLINICS AND
THEY ARE
SUFFERING FROM SOME OF THESE
LONG COVID SYMPTOMS, KEEP
THAT IN MIND.
IF YOU WANT TO YOU CAN
ACTUALLY MAY BE COLLECT SOME
BLOOD AND SENT IT TO US AND
LET'S SEE IF THEY
ARE PRODUCING AND
AUTOANTIBODY OR SOMETHING
LIKE THAT AND WE CAN START
SOME CROSS-COUNTRY
COLLABORATIONS SO THAT WE CAN
ALL LEARN A LITTLE BIT MORE
ABOUT HOW LONG THESE PEOPLE
ARE GOING TO
SUFFER AND HOW DEVASTATING
THEIR LONG-TERM EFFECTS CAN
BE.
>>
-- --
>> DR. KANTHI:
THANK YOU.
ARE THERE OTHER THOUGHTS FROM
THE GROUP?
PLEASE FEEL FREE TO TURN YOUR
CAMERA ON IF YOU WISH.
BUT UNMUTE YOURSELF, AND
SHRE.
I KNOW IT'S BEEN A BIT OF A
LONG DAY, WITH A LARGE VOLUME
OF INFORMATION AND A LOT OF
ENERGY
EXPENDED.
I WAS SHARING THAT MY
CAFFEINE LEVELS HAVE DROPPED
PRETTY LOW.
I WILL NEED TO SPIKED THAT UP
AGAIN SOON.
--- SOMETHING THAT STOOD OUT
TO ME.
I WILL MAKE A COMMENT HERE.
THIS DISEASE SEEMS TO AFFECT
ALL ORGAN SYSTEMS AND ACROSS
TISSUES.
IT MIGHT BE IMPORTANT FOR US
TO THINK ABOUT ENSURING THAT
WE-- WE CREATE A FINAL REPORT
FROM
THIS-- THAT WE HAVE INCLUDED
REFERENCES TO VASCULAR,
IMMUNE, EPITHELIAL CONNECTING
TISSUE, MUSCLE
TISSUE, NEUROLOGICAL TISSUE,
THESE ARE ALL DIFFERENT WAYS
THAT PATIENTS ARE MANIFESTING
WITH
COMPLICATIONS BOTH ACUTE AND
CHRONIC.
AND THERE SEEMS TO BE SOME
DIFFERENCES THAT ARE BASED ON
SEX AND GENDER AND THE
HETEROGENEITY OF
THESE MANIFESTATIONS.
DR. -- YOU ARE WELCOME TO
UNMUTE YOURSELF IF YOU WISH.
>> DR. MULLINGTON:
THANK YOU.
I WANTED TO SAY THAT IT IS
ALSO A GREAT OPPORTUNITY TO
UNDERSTAND STRESS BETTER.
AND THE MIND/BODY CONNECTION.
WHAT CAN WE DO TO TURN THIS
AROUND?
WHAT KIND OF STRESS REDUCTION
APPROACHES MIGHT WE BE ABLE
TO DEVELOP?
HOW WILL OUR UNDERSTANDING OF
THE PATHOBIOLOGY HELP US
BETTER UNDERSTAND HOW
COGNITIVE STRATEGIES
AND BEHAVIORAL MANIPULATIONS
TO IMPROVE SLEEP AND
COGNITIVE BEHAVIORAL THERAPY
APPROACHES AND HOW
THEY CAN POTENTIALLY TURN
SOME OF THE BIOLOGY.
THIS IS A GREAT OPPORTUNITY
TO DO SOME OF THAT.
THANKS.
>> ABSOLUTELY.
DR. OERTELT-PRIGIONE:
IT IS I THINK A VERY RELEVANT
POINT.
WE HAVE HAD SOME INTERESTING
DATA COMING OUT OF THE UNITED
KINGDOM LAST WEEK, LOOKING AT
THE
PEOPLE MOSTLY AFFECTED BY
LONG COVID AT THIS TIME.
PREMENOPAUSAL WOMEN ARE MORE
AFFECTED WE DO NOT KNOW WHY.
AND DATA AROUND PROFESSIONS.
THEY FOUND THAT A RELATIVELY
HIGH INCIDENCE IN TEACHERS,
HEALTHCARE WORKERS; I WOULD
SAY A NUMBER
OF PROFESSIONS WHICH HAVE
BEEN UNDER A HIGH-LEVEL
STRESS THROUGHOUT THE
PANDEMIC AND STILL ARE
NOW. YOU KNOW THE MANAGEMENT
IN THE UK IS ALSO QUITE OPEN
AS IS IN THE NETHERLANDS,
ASSUMING THAT
COVID IS OVER.
EXPOSURE MEAN STRESS.
--- I WAS WONDERING LOOKING
AT THE DATA IS, IS BASELINE
STRESS DUE TO EXPOSURE TO
MULTIPLE DUTIES,
CONVERGENCE OF CARE AND WORK
AND SO FORTH.
IF THIS LEVEL OF STRESS IS
ALREADY HEIGHTENED BEFORE AND
THEN YOU HAVE A COVID
INFECTION ON TOP OF
THAT IF THAT DOES NOT SOMEHOW
INCREASE YOUR RISK POTENTIAL
OF DEVELOPING LONG COVID.
THERE IS AN INTERACTION AT
THAT LEVEL AND GOES IN THE
DIRECTION OF WHAT YOU WERE
MENTIONING,
STRESS AND PRIMING.
AND HOW FAR THIS COULD PLAY A
ROLE IN POTENTIAL PREVENTION
STRATEGIES GOING IN THAT
DIRECTION.
>> AND BECAUSE YOU MENTIONED
THAT, I WOULD MENTION ALSO
THAT IN RELATION TO THAT AND
PUT IT IN
CHAT BUT ENDOCRINE
DISRUPTORS, WE HAVE NOT
DESCRIBED THAT IN THE TARGET
ESTROGEN REFLECTORS ALPHA
AND BETA UBIQUITOUS IN OUR
ENVIRONMENT AND THEY SHOW AN
INCREASINGLY STRONG
RELATIONSHIP WITH
MANY DISEASES INCLUDING
CARDIOVASCULAR DISEASE AND IN
ANIMAL MODELS AFFECTING THE
ANIMALS AND THE
TISSUE CULTURE STUDIES.
AND THE INTERACT WITH A VIRAL
INFECTION.
AND PUBLISHED ON THAT
RECENTLY.
WE DID NOT SEE ANY EFFECT ON
THE IMMUNE SYSTEM WITHOUT THE
VIRAL INFECTION THERE.
BUT WHEN YOU CHANGE THE
ESTROGEN RECEPTOR EXPRESSION,
IT HAS A BIG EFFECT ON THE
IMMUNE RESPONSE
SO IT COULD BE ALTERING
PARTICULAR FEMALES BUT ALSO
ALTERING WHAT IS HAPPENING IN
MALES.
BECAUSE OF COURSE THEY ALSO
HAVE ESTROGEN RECEPTORS.
--- AND ONE OTHER THING WE
DID NOT DESCRIBE HERE WHICH I
BELIEVE HAS BEEN SHOWN TO BE
SOMETHING
IMPORTANT IN COVID IS ALSO
VITAMIN D AND THE ELEMENT D
RECEPTOR. VITAMIN D IS NOT A
VITAMIN BUT A
STEROID.
IT STRONGLY INFLUENCES THE
NATIVE IMMUNE RESPONSE IN A
SEX SPECIFIC MANNER.
IT IS IMPORTANT TO LOOK AT IN
THE FUTURE FOR COVID.
---
>> DR. KANTHI:
THANK YOU. I WAS ALSO VERY
EXCITED ABOUT-- WE'VE
DISCUSSED ABOUT HOW THIS IS
AN OPPORTUNITY FOR
US TO BE ABLE TO STUDY HUMAN
PHYSIOLOGY.
AND UNDERSTAND HOW WE MIGHT
BE ABLE TO BETTER MANAGE AND
TREAT DISEASE IN THE FUTURE.
BUT ANOTHER LARGE REVOLUTION
I THINK-- AND I THINK IT IS A
FAIR TERM TO USE-- THAT IS,
AS A
RESULT OF THE PANDEMIC IS
RAPIDLY ADVANCING HOW WE
THINK ABOUT CLINICAL TRIALS;
WE HAVE
TRADITIONALLY LOOKED AT A
SINGLE INTERVENTION,
RANDOMIZED
PLACEBO-CONTROLLED. AND IN
THIS CASE,
THE PANDEMIC AND FACILITATED,
PERHAPS FORCED THE COMMUNITY
TO BE ABLE TO COME TOGETHER.
AND DESIGN THIS LARGER
PLATFORM TRIALS THAT ALLOW US
TO GENERATE RESULTS MUCH MORE
QUICKLY EVEN IF
THEY ARE NOT AS CLEAN AS WE
WOULD LIKE.
THE SIGNALS DO REALLY STAND
OUT WHEN WE LOOK AT THIS
LARGE DATA SETS.
ARE THE COMMENTS FROM THE
GROUP ON THIS?
WHERE COULD WE GO FROM THIS?
IS THE NEW NORM FOR US?
>> AGAIN I WOULD TAKE LESSONS
FROM CANCER.
THEY DO A LOT OF
BAYSIAN-STAGE TRIALS.
THEY STARTED WITH 10 ARMS,
DIFFERENT DOSING AND
DIFFERENT MEDICATIONS AND
THEY CAN DO THIS BECAUSE
CANCER IS SO PREVALENT.
SO WE SHOULD BE ABLE TO DO
THIS. BAYSIAN DESIGN.
AND YOU LEARN WITH EACH PHASE.
IT BECOMES EFFICIENT.
YOU DROP ARMS THAT ARE NOT
PROMISING WITH THE BAYESIAN
ANALYSIS.
>> DR. KANTHI:
THANK YOU.
>> DR. KANTHI:
OTHER ADDITIONAL COMMENTS OR
THOUGHTS? THAT YOU ARE
ITCHING TO GET IN?
WONDERFUL.
ON BEHALF OF DR. SANDBERG,
SABINE OERTELT -PRIGIONE AND
DR. -- I WILL HANDED BACK TO
JASMINA.
>> JASMINA VARAGIC:
I AM HERE TAKING NOTES.
WE WILL BE IN TOUCH OF COURSE
TO ADVANCE THIS DISCUSSION.
WE ARE REALLY THINKING ABOUT,
FIRST WE WILL HAVE AN
EXECUTIVE SUMMARY AND THEN
THINKING ABOUT
APPLICATION SO WE WILL BE IN
TOUCH FOR SURE.
AND WOULD LIKE TO GIVE LIKE A
CLOSING COMMENT.
IF I CAN HAVE MY SLIDES ON.
THAT WOULD BE REALLY NICE. I
APPRECIATE IT.
--- AND OF COURSE TAKING THIS
OPPORTUNITY TO THANK AGAIN
OUR WONDERFUL COCHAIRS -- DR.
KHANTI,
DOCTOR SANDBERG.
I WOULD ALSO LIKE TO THANK
ALL PHENOMENAL PRESENTERS AND
MODERATORS AND EVERYONE WHO
JOINED US AND
CONTRIBUTED TO THE GREAT
DISCUSSION IN THE WORKSHOP.
THANKS FOR THE COMMUNITY
REPRESENTATIVES. MR.
SIEVS, MR. KUSIC, MS. --
AND FOR SHARING THE PERSONAL
JOURNEYS AND REMINDING US HOW
MUCH WE HAVE
TO DO AND MANY THANKS TO THE
NIH, MY COLLEAGUES FROM THE
NHLBI, NATIONAL HEART, LUNG
AND BLOOD
INSTITUTE.
AND THE EUNICE SHRIVER
INSTITUTE-- AND INSTITUTE FOR
MINORITY HEALTH DISPARITIES.
THEIR ENTHUSIASM
AND EXEMPLARY DEDICATION MADE
THE WORKSHOP A SUCCESS. AND
THE NIH FOR THE TECHNICAL
SUPPORT.
---
I WOULD LIKE TO CLOSE ON OUR
VIEW, OUR PLANS ON HOW TO
LEVERAGE THIS WORKSHOP AND
IDEAS WE HAVE
GATHERED THROUGH THE
STIMULATING DISCUSSIONS.
AND MENTIONED WE WILL PUBLISH
AN EXECUTIVE SUMMARY ON THE
NIH WEBSITE AND I HOPE THAT
THIS IS A
GOOD RESOURCE FOR ALL
ATTENDING AND FOR ANYONE WHO
DID NOT ATTEND. AND IN
ADDITION THE WORKSHOP IS
RECORDED AND THE RECORDING
WILL BE IN THE ARCHIVES AND
ACCESSIBLE THROUGH THE LINKS
ON THE SLIDE
AND IN THE BOOKLET AND WITH
PLAN LANDSCAPE ANALYSIS OF
NHLBI GRANTS WITH RESPECT TO
SECTION THE
RESEARCH, AND PUBLICATIONS IN
PEER-REVIEWED JOURNALS. AND
WE SEE THIS AS AN OPPORTUNITY
TO TO
SHARE MORE BROADLY DETAILS
IDENTIFY CRITICAL RESEARCH
GAPS AND OPPORTUNITIES TO
ADDRESS THIS.
---
WILL ALSO EXPLORE
OPPORTUNITIES TO DEVELOP OUR
YOUTH INITIATIVE AS MENTIONED
ON THE SEX AND GENDER
EMPHASIS ON COVID-RELATED
HEART, LUNG AND BLOOD
DISORDERS. AND WILL INDICATE
TO THE RESEARCH
COMMUNITIES THAT WE ARE
INTERESTED IN THIS TYPE OF
RESEARCH QUESTIONS AND THEY
STRATEGICALLY
ALIGNED WITH THE INSTITUTE
PRIORITIES.
---
FINALLY DURING THESE TWO DAYS
OF THE WORKSHOP WE FREQUENTLY
HEARD ABOUT LACK OF SEX AND
GENDER
SPECIFIC DATA IN CVOID-19
RESEARCH AND UNFORTUNATELY,
CVOID-19 IS NOT AN ISOLATED
EXAMPLE,
REPORTING SEGREGATED DATA
BISECTS AND GENDER IS NOT ,
AND OTHER RESEARCH AREAS BUT
WE HOPE THAT
THIS WORKSHOP REFLECTED WHAT
HAS BEEN ACCOMPLISHED IN
CVOID-19 RELATED HEART, LUNG
AND BLOOD
RESEARCH INCORPORATING SEX
AND GENDER.
--- AND MOST IMPORTANTLY WE
HOPE WE UNDERLINE AND WE CAN
DO BETTER IN UNDERSTANDING
THE IMPACT OF
BOTH SEX AND GENDER IN HEALTH
AND DISEASE IN ORDER TO
PROMOTE DISCOVERY, INNOVATION
AND EQUITY IN
CVOID-19 RESEARCH BECAUSE THE
ULTIMATE GOAL IS TO IMPROVE
HEALTH, AND REDUCE HEALTH
DISPARITIES IN
ALL AFFECTED.
WITHOUT THANK YOU VERY MUCH
AGAIN AND HAVE A GREAT
EVENING.