WE ORGANIZE THIS MEETING TO BRING TOGETHER GROUPS TO UNDERSTAND CHALLENGES WOMEN FACE WITH TBI AND TO UNDERSTAND CHALLENGES AND SOLUTIONS RESEARCHERS FACE WE HAVE THE DIRECTOR OF NINDS THE PRIMARY INSTITUTE FOR TBI AT NIH. [APPLAUSE] . >> THANK YOU VERY MUCH. THANKS FOLKS FOR COMING FOR WHAT I THINK IS GOING TO BE A REALLY INTERESTING WORKSHOP TODAY AND. . WE HAVE GREAT SPEAKERS. WE HAD A POWER OUTAGE IN ATLANTA AND A COUPLE PEOPLE COULDN'T GET OUT OTHERWISE I THINK WE DID PRETTY WELL. I WANT TO START OFF BY JUST THANKING PAT AND DIANA CUMMINGS FOR ALL THE WORK DONE IN GETTING THIS TOGETHER AND TO START OFF I WANT TO TALK TO YOU A LITTLE BIT ABOUT, FROM MY POINT OF VIEW, THE MAIN ISSUES TO BE DISCUSSED DURING THE NEXT TWO DAYS. OUR INSTITUTE IS TO SEEK FUNDAMENTAL KNOWLEDGE WITH THE BRAIN AND NERVOUS SYSTEM AND REDUCE THAT KNOWLEDGE TO REDUCE THE NEUROLOGICAL DISEASES. AND SO THAT MEANS MEN AND WOMEN, CHILDREN AND THE ELDERLY. OUR STRATEGIES IN DOING THIS IS TO INVEST ACROSS A SPECTRUM OF RESEARCH AND HEAVY ON THE BASIC SIDE OF RESEARCH. LESS HEAVY ON THE TRANSLATIONAL AND CLINICAL SIDE AND THAT PYRAMID OF RESEARCH IS CRITICAL TO THE INDUSTRY BECAUSE THERE'S A DOVETAIL WITH THE INDUSTRY TO GET TREATMENTS OUT. WE TRY TO IDENTIFY GAPS IN RESEARCH IN PUBLIC HEALTH NEEDS. YOU'LL BE HEARING A LOT ABOUT GAPS IN THE NEXT TWO DAYS. WE HAVE THE EFFECTS OF TBI IN WOMAN AND WE'RE ALSO INTERESTED IN LOOKING TO THE FUTURE AND SEEING THAT THE FUTURE IS REALLY DEPENDENT UPON TRAINING AND DIVERSE WORKFORCE. ANOTHER REASON WHY I THINK THIS IS GOING TO BE IMPACTFUL BECAUSE I THINK IT WILL INFLUENCE EIGHT OF PARTICULARLY YOUNGER FOLKS TO LOOK AT THE PROBLEM AND GIVE US NEW INSIGHTS. YEAR ALSO LOOKING TO LOOK TO NEW TOOLS TO ENABLE DISCOVERIES AND YOU'LL BE HEARING ABOUT SOME OF THOSE ADVANCED TECHNOLOGIES THAT CAN BE BROUGHT TO BEAR ON THE ISSUES COMING UP. THE NIH IS CLEARLY A GOVERNMENT AGENCY SO THE NIH IS YOU OR IN THE ROOM, IT'S A COMMUNITY OF SCIENTISTS AND THE NIH IS THE FUNDING SIDE OF THIS. BUT THAT MEANS FOR US TO MAKE DOES DECISIONS, WE NEED TO UNDERSTAND WHAT THE SCIENTIFIC NEEDS ARE FOR THE COMMUNITY AND CONTINUALLY LOOK TO IMPROVE THE PROGRAM. SEX IS A BIOLOGICAL VARIABLE AND HAS TREMENDOUS IMPACT, WE KNOW, ON MOST OF OUR NEURAL -- NEUROLOGICAL DISORDERS AND SOME THINGS ARE MORE COMMON IN FEMALE THAN MALES AND VICE VERSA. SOME OF THE BIOLOGY AND THE DIFFERENCES MAY COME TO PLAY IN UNDERSTANDING THE DIFFERENCE IN OUTCOMES AND EXPERIENCES THAT WOMEN HAVE WHO ARE EXPOSED TO TRAUMATIC BRAIN INJURY AS COMPARED TO MEN. THERE'S ALSO LOTS OF THINGS THAT WE HAVE TO DEAL WITH THAT ARE IN COMMON. AND ON THE BIOLOGY SIDE, THERE IS A GROWING AND IMPRESSIVE SCIENCE AS DEMONSTRATED WITHOUT ANY DOUBT ON THE BIOLOGICAL SIDE THERE'S REAL DIFFERENCES THAT NEED TO BE TAKEN INTO CONSIDERATION IF YOU LOOK AT THE LONG TERM PRODUCT WHICH IS DEVELOP A THERAPY, THERE ARE CERTAIN PATHWAYS THAT ARE DIFFERENT IN MEN AND WOMEN AND A PATHWAY THAT'S MANIPULATED FOR HEALTH IN A MALE, MAY NOT WORK IN A FEMALE OR VICE VERSA. IT MAY MAKE THINGS WORSE IN A FEMALE AND VICE VERSA, CERTAINLY THE PROGESTERONE STUDY IN TRAUMATIC BRAIN INJURY IN TRYING TO LEARN FROM THE PROTECTIVE FACTORS FOR FEMALES APPLY TO ALL TRAUMATIC BRAIN INJURIES SO THERE'S LESSONS TO BE LEARNED IN THE DIFFERENCES. LOOKING AT THE FIELD, THERE'S BEEN MORE WORK IN THE STROKE AREA THAT ARE SOME WHAT REGULATED TO THE TRAUMATIC BRAIN INJURY. THERE'S TYPES OF BRAIN INJURIES AND THE EFFECTS OF HORMONES ON OUTCOME FROM STROKE IN ANIMALS AS WELL AS HUMANS, THINGS THAT ARE IMPORTANT SUCH AS EVEN THE REPRODUCTIVE EXPERIENCE OF PEOPLE AND ANIMALS IN TERMS OF THEIR VULNERABILITY TO THREATS SUCH AS ISCHEMIA. AS YOU RECALL IF THE FIRST SLIDE, THE DISORDERS THAT ARE MORE PROMINENT IN WOMEN ARE THOSE MEDIATED BY IMMUNE SYSTEM ABNORMALITIES AND THE IMMUNE SYSTEM HAS A ROLE TO PLAY IN THE RESPONSE TO TRAUMATIC BRAIN INJURY NOT ONLY POTENTIALLY ON THE SIDE OF MAKING INJURY AND DAMAGE WORSE, BUT ON THE SIDE OF RECOVERY. THE IMMUNE SYSTEM IS INTEGRALLY RELATED TO AND INTEGRATED INTO THE RECOVERY PROCESS. CERTAINLY PAIN, A COMMON PROBLEM IN POST CONCUSSION SYMPTOMS IS GOING TO BE HEADACHE AND MIGRAINE IS INCREDIBLY COMMON AND THERE'S DIFFERENCES IN WHAT MEDIATES PAIN SYMPTOMS IN MEN VERSUS WOMEN AND IN BRAIN ITSELF, WORK HAS BEEN DONE SHOWING THE SYNAPTIC ORGANIZATION AND CONTROL OCCURS DIFFERENTLY IN MEN AND WOMEN IN SOME CIRCUITS. THE CEREBELLUM AND HIPPOCAMPUS AND IF WE LOOK AT ANIMAL MOD DEVELOPS OF BEHAVIOR COMPARED TO POST-CONCUSSIVE TYPE OF BEHAVIORS, THOSE WILL HAVE DIFFERENT NORMS IN MALE AND FEMALE ANIMALS AND WE SEE DIFFERENCES IN MEN AND WOMEN COMPARED TO DIFFERENT INJURIES SUCH AS TRAUMATIC BRAIN INJURY. THEY'RE BIOLOGICALLY AND SOCIALLY ATTUNED BEHAVIORAL RESPONSE. THE POINT IS IT'S REALLY HARD TO TREAT THE ANIMALS, MALE AND FEMALE, THE SAME. SO NIH, AS I MENTIONED, THE PROBLEM OF SEX AS A BIOLOGICAL VARIABLE IN THE GAPS IN EXPLORING THAT HAVE COME TO THE ATTENTION OF NIH OVER A NUMBER OF YEARS AND WOMEN'S HEALTH RESEARCH HAS BEEN IN THE FOREFRONT LEADING TO THIS CHANGE IN THE NIH POLICY PUT OUT HERE SAYING THAT NIH NOW EXPECTS THAT IN THE SEX AS A VARIABLE HAS BEEN FACTORED IN ANIMAL AND HUMAN STUDIES. SO STRONG JUSTIFICATION FROM THE SCIENTIFIC LITERATURE MUST BE PROVIDED FOR APPLICATIONS PROPOSING TO STUDY ONLY ONE SEX. THIS HAS HAD A MAJOR IMPACT ON THE RESEARCH COMMUNITY IN GETTING PEOPLE TO TAKE A LOOK AT THE BIOLOGICAL DIFFERENCES AND NOT IGNORING THEM AS THEY HAD IN THE PAST. SO THE POINTS TO CONSIDER ARE TO DESIGN THE STUDIES TO TAKE SEX INTO ACCOUNT, TO COLLECT DATA, TABULATING IT ON SEX-BASED DATA AND SURPRISINGLY HOW MANY REPORTS IN THE LITERATURE HAVE BEEN LOOKED AT AND YOU CAN'T TELL WHAT SEX THE ANIMALS WERE IN THAT REPORT AND THEN TO CHARACTERIZE THE DATA IN A WAY TO SEE THE DIFFERENCES AS THEY COME OUT OF THE EXPERIMENTS. THEN COMMUNICATE THE DATA BASED ON THE ALLOCATION IN THE SEX-BASED STUDIES. SO WHEN THIS CAME OUT THERE WAS A FLURRY OF COMMENTARY BY DIFFERENT FOLKS AROUND THE COUNTRY BECAUSE IT WAS A SIGNIFICANT CHANGE. PEOPLE COMPLAINED IT WAS GOING TO TAKE MORE ANIMALS TO DO THE EXPERIMENTS. AND I WANTED TO POINT YOU TO THIS PAPER BY CHANSKI AND WILLIE LOOKING AT THEIR SCIENCE RESEARCH. THE FIRST POINT WHICH WAS IN THE FIRST FEW SLIDES, THE SEX BIAS IN BRAIN DISORDERS IS EVIDENT AT ALL LIFE STAGES AND THERE IS A PROBLEM IN THE STUDIES THAT WERE LOOKED AT OF NEUROSCIENCE STUDIES, FIVE STUDIES EXCLUSIVELY MALES TO EVERY ONE USING FEMALES. FIGURING OUT THE IDEA WAS YOU COULD FIGURE OUT THE FUNDAMENTALS FIRST IN MALES AND WORRY ABOUT THE SEX DIFFERENCES LATER AND THAT'S A FLAWED RATIONALE BECAUSE YOU'RE NOT GETTING AT THE BIOLOGY AT 50% OF THE PEOPLE THAT WOULD APPLY TO 50% OF THE PEOPLE AND THERE'S NO DIFFERENCE BETWEEN TRUTH IN THE BIOLOGY IN MALE VERSUS FEMALE AND THEY HAVE TO BE EQUIVALENT. THE QUESTIONS THAT WILL COME UP HAVE THE EFFECT OF SEX CHROMOSOMES, INFLUENCE OF GONADAL HORMONES AND THE INFLUENCES OF THE MENSTRUAL CYCLE IN THE LIFE SPAN AND WAYS IN WHICH THAT CAN BE EXPLORED. AS I MENTIONED, ANOTHER FINAL POINT WAS THE RESPONSES IN OF BEHAVIORAL ASSAYS IN ANIMAL EXPERIMENTS AND HUMAN STUDIES WERE ALSO DIFFERENT BASED ON SEX OF THE ANIMAL. SO WE'RE HERE TO TALK ABOUT TRAUMATIC BRAIN INJURY AND THIS IS RECENT DATA FROM THE C.D.C. IT INDICATE THE RATE OF TBI FOR 100,000, SO A RATE-BASED GRAPH, IS INCREASING IN BOTH MALES AND FEMALES. AND TBI-HOSPITAL RELATED HOSPITALIZATIONS IS INCREASING. SO THE HEALTH ISSUE IN TBI IN WOMEN IS AS MAJOR OF AN ISSUE AS IN MEN. AND THE DIFFERENCES TWO I'M SURE WILL BE TALKING ABOUT IS THE HIGHER CONCUSSION RISK IN ATHLETE WHO'S ARE WOMEN COMPARED TO MEN. THIS IS AS YOU KNOW, I THINK 43% OF NCAA ATHLETES ARE WOMEN NOW. IN TERMS OF NUMBERS THEY'RE ONLY GROWING. AND IT SHOWS CONCUSSION SYMPTOMS IN THE STUDY OF SAY ATHLETES WERE WORSE IN WOMEN COMPARED TO MEN. SO THE REASONS FOR UNDERSTANDING THIS IS IMPORTANT AS IS RECOVERY FROM THE SAME STUDY AS FROM BAKER AND ALL SHOWING WOMEN TAKE LONGER TO RETURN TO PLAY. THERE'S BEEN A NUMBER OF STUDIES THAT HAVE LOOKED AT THE ISSUES. THE TOP ONE IS A STUDY LOOKING AT I THINK IT WAS ICE HOCKEY PLAYERS PRESEASON TO POSTSEASON. AND LOOKING AT DIFFERENCES. AS YOU KNOW, ONE OF THE MAIN PROBLEMS IN HEAD INJURIES CLEARLY IN THE MODERN SEVERE HEAD INJURY IS SHEARING OF THE WHITE MATTER TRACKS AND THIS CAN LOOK AT THE FUSION OF WATER IN THE TISSUE AND WE CAN LOOK AT THAT IN DIFFERENT WAYS. IN THE MEASUREMENTS YOU FIND THE WORSENING IN THE POSTSEASON BUT ONLY IN THE WOMEN. THESE ARE PEOPLE WHO DID NOT SUFFER CLINICAL CONCUSSION. THE PROBLEM IS THEY PROBABLY HAD NON-CONCUSSIVE HITS DURING THE SEASON AND THEY SEEM TO SHOW UP IN THIS AND IT SHOWS HOW TECHNOLOGY CAN BE USED TO EXPLORE THE DIFFERENCES. THE LOWER ONE IS THE ONE I WASN'T NOT AWARE OF SHOWING THE EXOMAL DIAMETER IN WHITE BRAIN METATRACKS AND THE EXXONONS HAVE SMALLER DIAMETER IN FEMALES THAN MADE AND BECAUSE THE AXONS ARE LIKE WIRES AND HAVE STRUCTURAL COMPONENTS TO THE MICROTUBULES IT MAKES OUT MORE VULNERABLE TO THE SHEAR STRESSES I MENTIONED EARLIER. THIS IS AN EXAMPLE AND IT'S NOT A PATHOLOGICAL STUDY BUT THEY TOOK IPS CELLS -- THEY LOOKED AT RODENTS AS WELL AS HUMAN, YOU CAN SEE AT THE TOP THE FEMALE AXONS COMPARED TO THE MALE AXONS ARE DEFINITELY SMALLER. HERE'S THE DATA SHOWING THE SAME THING AND YOU SEE THE CALCIUM INFLUX AND IT BREAKS DOWN MICRO TUBULES AND IT'S GREATER IN THE FEMALES THAN MALES. THEY'RE ALL TINY FINDINGS AND ONE THAT IS ATTRACTED TO EXTRAPOLATE TO THE CLINICAL SPACE BUT THERE'S A LOT OF GAPS WITH A FINDING SUCH AS THIS AND WHAT'S GOING ON CLINICALLY. THESE THE BUILDING CLOCKS WE CAN WORK ON TO BETTER UNDERSTAND THE BIOLOGICAL DIFFERENCES IN MALES AND FEMALES. WE FUNDED OVER 190 GRANTS GOING OUTSIDE. WE HAVE AN INTRAMURAL PROGRAM THAT'S THERE IS LOOKING AT -- IS ON THE COMMUNITY PRACTICE GIVING IT'S NOT GOING TO BE RANDOMIZED CONTROL DATA BUT SOME DATA IS REALLY QUITE CAREFULLY COLLECTED. HERE'S OUR TBI PORTFOLIO OVER THE YEARS. IT'S BROKEN DOWN IN DIFFERENT YARS AND WE HAVE BEEN LUCKILY TO WORK WITH THE DEPARTMENT OF DEFENSE AND IT'S A COMBINED PROGRAM BETWEEN INTRAMURAL H NIH AND THE PROGRAM ACROSS THE STREET. AND WE'VE HAD A LOT OF INTERNATIONAL INTEREST IN TRYING TO UNDERSTAND TRAUMATIC BRAIN INJURY IN THE LAST FEW YEARS AND THE DIFFERENT NEURO MECHANISMS AS WELL AS THE PSYCHO, SOCIAL FACTORS THAT WILL BE AFFECTING THE OUTCOME OF WOMEN WHO SUFFERED A CONCUSSION OR MORE SEVERE TBI. PEOPLE HAVE BEEN CAREFUL ABOUT LUMPING TBI. PEOPLE HAVE SEEN THE SPECTRUM AND THERE'S DIFFERENT OUTCOMES. LUMPING AND CALLING TBI THE SAME IS FRAUGHT WITH DANGER. THE BIG PROBLEM WE'RE FACING IS HOW TO NORMALIZE THE DOSE OF TRAUMATIC BRAIN INJURY. GIVE AN ADULT OR ANIMAL A TOXIN YOU CAN GIVE A PARTICULAR DOSE AND YOU GIVE IT TO THE FEMALE AND MALE ANIMALS AND YOU LOOK AT THE AFFECTS ONE HAS TO WANT TO GET TO THE POINT IN THE HUMAN STUDIES SO WE KNOW WE'RE STUDYING THE SAME DOSE IN BRIN INJURIES FOR MALES AND FEMALES. WE HAVE TO BE CAREFUL IN ASSUMPTIONS IN THE CLINIC AND LOOK AT THE ASSUMPTIONS FROM THE ANIMALS TO THE PATIENT AND THIS IS REALLY IMPORTANT IN TRYING TO IMPROVE THE CLINIC DESIGN SEX AS AN OUTCOME AND ONE PROBLEM HAS BEEN THE INADEQUATE CHARACTERIZATION IN FEMALE VERSUS MALE. AT THE END WE HOPE TO PUT THINGS TO PAPER SO THERE'S SOMETHING WE CAN CHEW ON IN THE COMMUNITY AND THE COMMUNITY CAN SEE IN THINKING ABOUT AND USING THAT TO EXPLORE THE SCIENCE. WE WANT GRANTEES TO UNDERSTAND THE CHALLENGES OF DOING THIS RESEARCH. NOT TO BE NAIVE ABOUT THE AND THE AREAS OF RESEARCH MORE NEEDED AND CLINICALLY FEASIBLE AND INSIGHT ON THE CHALLENGES OF DOING THE RESEARCH IN TBI. WITH THAT I'D LIKE TO THANK AGAIN EVERYONE FOR COMING AND ASK PAT TO COME UP AND INTRODUCE OUR KEYNOTE SPEAKER AND I THINK IT WILL BE A GREAT CONFERENCE OVER THE NEXT COUPLE DAYS. >> THANK YOU, WALTER FOR CLEARLY OUTLINING OUR MISSION HERE OVER THE NEXT COUPLE OF DAYS. SO IT'S MY PLEASURE TO INTRODUCE OUR KEYNOTE SPEAKER DR. McCARTHY AT THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE AND LEADING NEUROSCIENTIST WHO MADE SIGNIFICANT RESEARCHES IN DIFFERENCES IN THE BRAIN AND FOCUSSING ON THE INFLUENCE OF STEROID HORMONES WITH AN EMPHASIS IN SEX DIFFERENCE. SHE STUDIED THE FIRST DIFFERENCES IN STEROID HORMONES AND HOW THEY CAN BE USED TO ORGANIZE DIFFERENCES IN MALES AND FEMALES AND BEHAVIOR AND HERE TO GIVE US PERSPECTIVE ON THE STUDY OF SEX DIFFERENCES SO PLEASE WELCOME DR. McCARTHY. . >> THANK YOU VERY MUCH FOR THAT INT INTRODUCTION. IT'S AN HONOR TO KICK OFF THIS CONFERENCE. INSTEAD OF DIVING INTO MY OWN RESEARCH MY GOAL WAS TO GIVE A BROAD OVERVIEW AS MENTIONED AND HOPEFULLY GIVE HINTS AND TOOLS HOW TO STUDY SEX DIFFERENCE. THE BRAIN'S COMPLICATED BUT SOMETIMES WE LOSE SIGHT OF HOW DIFFICULT IT IS AND WE DON'T HAVE LIVER PHYSIOLOGISTS PLAY A ROLE IN THE BODY AND HOW THEY'RE IMPACTED THROUGHOUT LIFE. FOR ONE THING, THE BRAIN IS THE FIRST ORGAN TO FORM AND LAST TO MATURE. YOU'RE BORN WITH A FULLY FUNCTIONING HEART, LIVER, LUNGS, ETCETERA BUT THE BRAIN IS IN NASCENT STAGES AND DESIGNED THAT WAY BY NATURE TO IMPRINT EVERYTHING HAPPENING TO IT. IT BEGINS IMPRINTING THE ENVIRONMENT IN UTERO AND AS WE KNOW EVERYONE CHILD THE BRAIN IS JUST SO MALLEABLE AND AFFECTED BY WHEN GOES ON. THIS IS WHERE THE DIFFERENCE WHERE GENDER AND SEX CAN BE VERY IMPORTANT. I STUDY SEX DIFFERENCES BECAUSE ANIMALS DON'T HAVE GENDER. GENDER IS A PURELY HUMAN CONSTRUCT COMPOSED OF ONE'S SELF AND GENDER IS THE FIRST VARIABLE YOU KNOW IN THE OTHER INDIVIDUAL. WE NAME THEM IN GENDER SPECIFIC WAYS AND DRESS THEM IN GENDER SPECIFIC WAYS AND COMPLETE THEIR NURSERIES. IT DOESN'T AFFECT THE WAY YOUR HEART DEVELOPS SO WE HAVE A UNIQUE CHALLENGE TO INCORPORATE THAT VARIABLE AS WELL. IT ALSO HAS DIFFERENT REGIONS AND MOST SPEND OUR WORLD DWELLING ON ONE PARTICULAR REGION AND WE MAY THINK ABOUT HOW IT'S CONNECTED TO OTHERS BUT WE TEND TO FOCUS VERY MUCH ON ONE PARTICULAR AREA AND CHANGES IN ONE AREA OF THE NETWORK WILL INFLUENCE OTHER AREAS AND OFTEN THEY CAN BE IN RECIPROCAL, RECURSIVE LOOPS. YOU CAN HAVE A SEX DIFFERENCE IN A DIFFERENT BRAIN SITE AFFECTING THE BRAIN REGION YOUR STUDYING BECAUSE OF THE WAY THEY'RE CONNECTED. THEN THE CELL TYPE ISSUE. WE HAVE MANY CELL TYPES AND THE NUMBER SEEMS TO KEEP GROWING. YET AS NEUROSCIENTISTS WE TEND TO BE NEUROCENTRIC. IN THE AREA OF TBI YOU THINK OF WHITE MATTER. WE'VE STARTED TO THINK ABOUT THE OTHER SYSTEMS AND WITHIN NEURONS THERE'S CELL TYPES. ANYTHING IN THE BRAIN DID, THE COMMON CRITICISM IS I WILL TEND TO DISSECT OUT A SMALL AND SPECIFIC BRAIN REGION AND I'LL MUSH IT UP AND MEASURE SOMETHING. I CAN'T TELL THE GABA NEURONS OR pWE'RE ALL FACING AND WE'RE E SEEING AN ONGOING CHALLENGE. WHEN I STARTED STUDYING SEX DIFFERENCES IT WAS ALL ABOUT REPRODUCTION. WE THOUGHT THE ONLY CELLS IN THE BRAINS WERE THOSE ASSOCIATED WITH REPRODUCTIVE BEHAVIOR OR PHYSIOLOGY. BUT IN THE 20, 30 YEARS WE'VE FIGURED OUT DIFFERENCES ARE EXTREMELY WIDESPREAD AND FOUND EVERYWHERE AND AFFECT EVERY END POINT. YOU CAN START WITH THE FORMATION OF THE NEURAL TUBE AND IF YOU'RE AN XX PERSON IN AN XY FETUS IT WILL EFFECT. AP APOP TSOSIS AND EACH ONE HAS BEEN FOUND TO BE MODIFIED BY SEX AT SOME POINT IN THE BRAIN. IT DOESN'T MEAN THE ENTIRE BRAIN IS DIFFERENT BETWEEN MALES AND FEMALES. IN FACT THERE ARE LARGE SWATHS OF THE BRAIN VIRTUALLY IDENTICAL AND INDISTINGUISHABLE AND OUR CHALLENGE IS TO FIND OUT WHAT SEX DIFFERENCES THEY ARE, WHERE THEY ARE AND WHEN THEY ARE PRESENT AND LASTLY WHAT KIND OF FUNCTIONAL IMPACT DO THEY HAVE. SO AS I MENTIONED I JUMPED AHEAD OF MYSELF. GENDER IS A PURELY HUMAN CONSTRUCT AND I HAVE A LOT OF COLLEAGUES WHO LIKE TO ARGUE WITH ME WHEN ANIMALS HAVE GENDER AND THEY'RE OFTEN FROM CALIFORNIA, GO FIGURE. TO THIS POINT WE'RE PRETTY MUCH IN AGREEMENT THAT ANIMALS, IF THEY HAVE A GENDER, THEY CAN'T TELL US SO WE'RE SAYING IT'S PURELY HUMAN. ONE OF THE THINGS IN OUR QUEST SO I AM SEX AS A BIOLOGICAL USEFUL IS TO REMIND RESEARCHERS YOU'RE STUDYING SEX AND IT EMBODIED CHROMOSOME COMPLIMENT AND PHENOTYPE. BECAUSE OF GENDER AND BECAUSE GENDER IMPACTS EVERYBODY'S EXPERIENCE UNIQUELY AND WE CAN'T GET IN IT BIOLOGICALLY THE WE WE'D LIKE WE HAVE TO USE ANIMAL MODELS TO GOT AT THE BIOLOGICAL QUESTIONS. HERE WE CAN CONTROL THE ENVIRONMENT AND EXPERIENCE AS BEST WE CAN TO ANSWER THE QUESTION. SO THESE ARE SOME OF THE MORE COMMON MODELS USED. THE QUESTION IS WHY IS IT SO IMPORTANT TO INCORPORATE SEX AS A BIOLOGICAL VARIABLE AND IT GOES TO FAILED TRIALS AND THERE'S RESEARCH RIFE WITH INACCURACIES BECAUSE THEY'RE BASED SOLELY ON THE MALE WHICH IS STATED IN ABSOLUTE. I GET PUSHBACK ON STUDYING SEX DIFFERENCES. WHY DO I WANT TO PROVE A MALE AND FEMALE'S BRAINS ARE DIFFERENT OR SAYING A WOMEN SHOULD NEVER BE PRESIDENT, NO, THAT'S NOT THE REASON. THE REASON FOR STUDYING SEX DIFFERENCES IS BECAUSE MUCH THIS ENORMOUS GENDER BIAS. WE SAW AN IMPRESSIVE LIST OF DISORDERS OF THE NERVOUS SYSTEM. THE SIZE OF THE WEDGE IN THE PIE IS THE MAGNITUDE AND ADHD AND AUTISM IS ONE OF THE MOST GENDER-BIASED DISORDERS AND ALL THE LANGUAGE DISORDERS ARE MORE PROMINENT IN MALES AND THEY TEND TO BE DIAGNOSED AROUND PUBERTY WHERE FEMALES HAVE LATE ONSET SCHIZOPHRENIA IN THE 30s, BULIMIA, PTSD AND OTHERS HAVE A POST-PUBITAL ONSET. IF MALES MAKE IT PAST PUBERTY THEY'LL DO WELL AND WOMEN START OUT PROTECTED AND ONCE THEY GO TO PUBERTY EVERYTHING GOES TO HELL IN THE RISK OF DISORDERS. ALL THAT WILL BE INTEGRATED WITH GENDER BUT THERE'S A BIOLOGICAL COMPONENT IT'S NOT EXPLAINED WITH JUST PINK OR BLUE. THE EFFECT OF TRAUMATIC BRAIN INJURY IS VERY EXCITING. MY OWN RESEARCH IS VERY BLUE SKY. I DON'T DO MUCH DISEASE MODEL. I HAVE ONE PROJECT ON PERI-NATAL HE IS SCHEME -- ISCHEMIA AND I SEE LITTLE WORK ON THE WORK AND I SEE PEOPLE TODAY AND STROKES ARE WAY UNDER INVESTIGATE. AND NEUROSCIENCE HAS AN ARTICLES IN WHICH THERE WAS A DETAILED ANALYSIS OF JOURNALS AND LOOKED AT THE PERCENTAGE OF ARTICLES BY DISCIPLINE AND WHETHER THEY SPECIFIED THE SEX AND THIS IS BASIC PRE-CLINICAL RESEARCH AND YOU SEE OVER 50% ARE MALE, 10% HAVE FEMALES AND 20% TO 30% HAVE BOTH AND THEN THERE'S UNSPECIFIED AS A GOOD HEALTHY 30% TO 40%. THAT MEANS FEMALES ARE ONLY PRESENT IN THESE TWO RIGHT HERE AND MOST OF THESE FEMALES ONLIES ARE RELATED TO REPRODUCTION. AND IN PHARMACOLOGY THEY'RE NEUROSCIENCE JOURNALS SO IT'S WORSE THAN IT APPEARS AND IF WE LOOK AT IF THEY HAD DONE BOTH SEXES BUT DID THEY ANALYZE AND ALMOST 80% OF THE STUDIES DID NOT BOTHER TO LOOK IF FEMALES AND MALES WERE DIFFERENT FROM EACH OTHER. IT HAS NOT MARKEDLY IMPROVED. IT'S GETTING BETTER BUT THERE'S STILL A HUGE NUMBER OF STUDIES THAT FOCUS ONLY ON MALES. CAN ASK WHY IS THAT AND OVER HERE IN THE IMMUNOLOGY WHERE IT LOOKS LIKE IT'S TERRIBLE BECAUSE THE ENTIRE DISCIPLINE OF IMMUNOLOGY STUDIES IS ONLY FEMALES. WHY DO THEY STUDY ONLY FEMALES BECAUSE THEY'RE DEVOTED. AND WE LOOK AT GENES XX VERSUS XY ARE DETERMINED BY YOUR ENVIRONMENT AND YOUR HORMONES. SO YOU START OUT LIFE AS A GONAD AND IT'S CAPABLE OF BEING AN OVARY OR TESTES. BY DEFAULT IT WILL BE AN OAF OVER OVARY AND IT WILL IT NEED THE ENERGY. THE TESTES MAKES TESTOSTERONE. YOU CAN'T GET TO THAT WITHOUT TESTOSTERONE AND BOTH MEN AND WOMEN MAKE IT. AND IT WILL BE EQUALLY FEMALE OR MALE. THERE'S NOTHING DIRECTLY DRIVING IT EITHER WAY. BY DEFAULT IT WILL BE A FEMINIZED BRAIN. THERE'S NO PINK BRAINS OR BLUE BRAINS BUT IT WILL TAKE ON A FEMINIZED PHENOTYPE IF IT'S EXPOSED TO TESTOSTERONE IT WILL BE MALE AND MOTHER NATURE WANTS TO MAKE SURE YOU'RE GOING TO REPRODUCE SO THIS WAY YOU CAN MAKE SURE BEHAVIOR AND BEHAVIOR AND ACTUALLY IT OCCURS IN HUMANS ENTIRELY IN UTERO. TESTOSTERONE PRODUCES IN FETUS IN THE UTERUS AND IT WILL GO HIGH AND GO DOWN TO UNDETECTIBLE AND COMES BACK AT PUBERTY. THERE'S ALREADY DONE AN ENORMOUS AMOUNT OF PROGRAMMING AND IN ANIMALS THE OPEN WINDOW OF THAT ACTIVATIONAL PROCESS HAPPENS POST NATALLY. IF WE'RE GOING TO COMPARE MALES AND FEMALES AT BIRTH, RIGHT OR IN UTERO. MALE IS A DIFFERENT ANIMALS IN TERMS OF TESTOSTERONE AND IT HAS EFFECTED AT BIRTH. AT PUBERTY WOMEN GO THROUGH IT TWO TO THREE YEARS EARLIER THAN BOYS SO WHEN YOU COMPARE THEM THEY'RE AT DIFFERENT PLACES REPRODUCTIVELY AND HORMONALLY. WOMEN GET PREGNANT AND LACTATE AND VARY WITH HORMONES. MALES ARE STEADY AND TESTOSTERONE WILL DECREASE SLIGHTLY IN OLDER YEARS BUT ONLY SLIGHTLY. ANYTIME THE ORANGE LINE OR YOU BISECT ACROSS EXCEPT DURING CHILDHOOD WHEN FEMALES AND MALES HAVE NO HORMONES ON BOARD. YOU ARE COMPARING APPLES AND ORANGES. BUT I DON'T WANT TO ACTUALLY GIVE THE IMPRESSION THOUGH THAT WOMEN ARE JUST A BAG OF HORMONES. THEY'RE JUST A PRODUCT OF THEIR HORMONES. THERE'S BEEN EMPHASIS AS THE ONLY DIFFERENCE AND I WOULD ARGUE THAT'S WHAT LED TO THE DECLINE OF FEMALES BEING USED IN NEUROSIGN RESEARCH. A LAB SHOWED THERE WAS A VARIANCE OF 30% ACROSS THE CYCLE KNOWLEDGE THE LESS, STEROIDS ARE VERY POWERFUL. AS PEOPLE HAVE STUDIED THEM THEY'VE TREATED THEM LIKE A DRUG BUT STEROIDS ARE NOT LIKE OTHER NEUROCHEMICALS IN YOUR BODY. THEY MOSTLY BIND TO NUCLEAR TRANSCRIPTION FACTORS AND GO TO THE NUCLEUS AND INTERACT DIRECTLY WITH THE GENETIC MACHINERY AS WELL AS THEY ARE TRANSCRIPTION FACTORS SO BIND DIRECTLY TO THE DNA AND KICK OFF SINGLE PATHWAYS AND INTERACT WITH RECEPTORS. BASICALLY THEY'VE SHOCKED US IN THEY CAN DO EVERYTHING YOU CAN THINK OF. THERE'S A CROSS TALK WITH WHAT'S GOING ON IN THE MEMBRANE AND NUCLEUS. THEY'RE POWERFUL AND ACUTELY ACTING MOLECUES ACTING IN THIS DAYS AS RECEPTOS AND WE HAVE TESTOSTERONE RECEPTORS WE'LL HEAR ABOUT TODAY. AND THEY DIVERGE DURING DEVELOPMENTAL CRITICAL STAGE AND DIVERSE FOR LIFE. STEROIDS AND GENETICS CAN CONVERGE. THE X CHROMOSOME IS ENRICHED IN GENES ASSOCIATED WITH COGNITION AND ENRICHED IN IMMUNE RELATED GENES AND ENRICHED IN MICRO RNAs. YOU MAY SAY IT'S NOT DOESN'T MATTER AND IT'S BEEN EMERGING IN THE LAST COUPLE YEARS IS UP TO 30% OF X GENES IN HUMANS MAY ESCAPE INACTIVATION SO ONLY 15% IN OUR ANIMAL MODELS AND THERE'S A HUGE NUMBER IN HUMANS FOR A VERY LARGE IF YOU SEE THE MAP OF THE CHROMOSOMES THEY GET SMALLER UNTIL THEY GET TO THE X AND Y. IT'S ALMOST AS BIG AS CHROMOSOME ONE AND TWO. THERE'S THOUSAND OF GENES. AND BOTH DESTROYED AND GENES EXPERT EPIGENETIC EFFECTS SO THE GENES CAN ENDURE. THIS IS AN OUT OF FOCUS IMAGE TO SHOW YOU ON THE Y CHROMOSOME WE HAVE EPI GENETIC GENES ASSOCIATED WITH THE HISTOMS AND THERE'S MECP2 A CLASSIC BINDING PROTEIN AND WE HAVE STEROID CAN CHANGE THE DNA. ONE CHALLENGE IS TO FIND OUT WHERE THIS IS HAPPENING SPECIFICALLY IN THE BRAIN AND WHAT GENES ARE BEING MODULATED. AND IN TALKING ABOUT SEX DIFFERENCES IT'S INTUITIVELY OFFENSE IT'S DIFFERENT BETWEEN MALES AND FEMALES BUT MORE NUANCED. NOT ALL SEX DIFFERENCES ARE CREATED EQUAL. WHAT YOU HEAR PEOPLE REFER TO ALL THE I'M IS SEX DIMORPHISM AND IT'S TWO FORMS IN MALES AND FEMALES. THIS IS MORE THE EXCEPTION THAN THE RULES. AND SOMETIMES SEX DIFFERENCES ARE LATENT OR HIDDEN. AND LASTLY WE HAVE SOME THAT ARE POPULATION FREQUENCY MEANING THE MANIFESTATION OF A DISORDER IS MORE COMMON IN ONE VERSUS THE OTHER. I HAVE EXAMPLES. SEX DIMORPHISM IS ASSOCIATED WITH REPRODUCTION AND MALES WILL RELEASE LH FROM THE PITUITARY AND FEMALES HAVE A SURGE. AND THAT'S ORGANIZED DEVELOPMENTALLY. THE SEX DIFFERENCES ARE THINGS MOST ARE STUDYING THE FACIAL REASONING AND ET SET ARE AND VOLUME OF GRAY MATTER. MALES AND FEMALES, OUR BRAINS DO THE SAME THING BUT ON AVERAGE THEY'LL DO ONE THING OVER AN OTHER AND YOU CAN TELL THE SEX OF AN ANIMAL BY IT'S LH SURGE YOU CANNOT TELL THE SEX OF A MALE OR FEMALE BECAUSE THESE CAN OVERLAP. AND THE COMPLICATED ONE IN CONVERGENT, DIVERGE ENT, LATENT AND COMPENSATORY IS WHERE THE SEX DIFFERENCE IS NOT READILY APPARENT. THERE'S CLASSIC WORK ON STRESS. FEMALES PERFORM WORSE ON LEARNING UNDER STRESS CONDITIONS AND THERE'S SYNAPTIC DIFFERENCES AND THE POPULATION FREQUENCY, ALZHEIMER'S. WE DON'T HAVE EVIDENCE ALZHEIMER'S IS A DIFFERENT DISEASE FOR MALES THAN FEMALES BUT SEEKS TO BE MORE FREQUENCY IN FEMALES BUT AUTISM IS MORE PREVALENT IN MALES AND THERE'S DIFFERENCES IN MALES AND FEMALES IN SOME REGIONS AT SOME TIME AND EVERYTHING I HAVE HERE IS PRETTY MUCH FOCUSSED ON NEURONS BUT WE DO NEED TO THINK OF OTHER TYPES OF CELLS. LONG MY SRRESEARCH I STARTED LOOKING AT NEURONS AND STARTED LOOKING AT OTHER RITES AND THERE'S MORE AND THAT'S MICRO GLIA AND HAVE NOTHING TO DO WITH ASTROCYTES AND THEY'RE AN ENDOGENOUS PART OF THE CREAM AND THEY'RE TRAPPED IF THE BRAIN FOR THE REST OF THEIR LIFE. THEY TILE THROUGHOUT THE BRAIN AND THEY'RE THERE -- WE USED TO THINK OF THEM AS SEN CENT NALS AND THEY OFTEN AMPLIFY SIGNALS AND MAKE THINGS ENDURE AND CARRY ON LONGER THAN THEY OTHERWISE WOULD. ONE THING ABOUT MICROGLIA IS THEY POSITION THEMSELVES TO MODULATE EVERYTHING ELSE. THIS SAY RODENT AND THEY START ON EMBRYONIC DAY 9½ AND DONE BY BIRTH AND ARE THERE FOR EVERYTHING THAT MATTERS IN THE BRAIN. SO WE USED TO THINK OF THEM AS CENTINAL. THEY'RE THE BUSIEST BEES IN THE BRAIN. HERE'S A LOOPED IMAGE AND IT SHOWS THE MICROGLIA ARE CONSTANTLY SURVEYING AND THIS IS AN IMAGE FROM OUR LAB AND IT HAS ITS ARMS AROUND 10, 11 CELLS. SO EACH MICROGLIA HAS A STABLE IT'S CONSTANTLY CHECKING, EVERYBODY SOUND OFF AND ALWAYS SURVEYING THE BRAIN. THEY SAY IT TAKES ABOUT TWO HOURS FOR YOUR ENTIRE BRAIN TO BE SURVEYED BY YOUR MICROGLIA AND THEN THEY START OVER AGAIN. THAT CONSTANTLY CHECK ON THE HEALTH OF THEIR STABLE. THEY'RE BUILD AND DESTROY SYNAPSES. SOME SHOWS THEY CAN PRUNE SYNAPSES. MY OWN WORK SHOWS THEY'RE ESSENTIAL TO THE BUILDING OF SYNAPSES AND IT WAS MENTIONED THE IMMUNE SYSTEM AND MICROGLIA INTERACT. HERE'S A NON-NEUROMAL GRAPH. THIS IS WORK FROM MY OWN LAB THAT SHOWS HOW PROFOUNDLY THE MICROGLIA CAN BE IN SOME BRAIN REGIONS. HERE'S A MALE. ALL HIS MICROGLIA ARE WHAT WE CALL ACTIVATED. THEY'RE PRODUCING HIGH LEVELS OF INFLAMMATORY MOLECULES OPPOSED TO HERE IN THE FEMALE WHERE THEY'RE LACY AND LADY LIKE AND SITTING THERE QUIETLY. THESE ARE SURVEYING MICROGLIA. THESE ARE PERFECTLY HEALTHY BORN FEMALES AND MALES AND HAVE HAD NO INSULT AND IN A DIFFERENT STATE. THESE MICROGLIA IN ADDITION TO THE SURVEYING, THEY'RE NOT JUST PRUNING, THEY CAN CONTROL CELL NUMBERS THROUGH PHAGOCYTIC CUPS. THIS IS DIFFERENT MICROGLIA. SO AS YOU CAN SEE THEY HAVE ENORMOUSPHAGOCYTIC EVENT. IN A NEWBORN FEMALE AND ALMOST 30% OF HIS MICROGLIA IS PHAGOCYTIC. THIS IS AN ACTIVE PROCESS. THIS IS ONE WITH THREE CUPS. AND THE BIG QUESTION IS WHAT ARE THEY EATING? IT'S HARD TO GET TO THE CONTENT. WE YOU'D NEWBORN CELLS AND THE PCNA INSIDE THE PHAGOCYTIC CUP AND THESE ARE CELLS WITHIN THE NEWBORN AND THIS IS A NEWBORN MICROGLIA EAT NEWBORN CELL. HERE'S ANOTHER PHAGOCYTIC CUP. THEY WRAP THEMSELVES AROUND THE CELL BODY AND THIS SAY 3-D RENDERING. HERE'S A PHAGOCYTIC CUP AND THE NUCLEUS SHOWING IT WAS JUST BORN WITHIN THE LAST 48 HOURS AND WOKE UP HUNGRY AND GOING AROUND GORGING ON OTHER NEWBORN CELLS AND IT'S PHAGOPTOSIS. AND IT'S THE ENGULFING AND KILLING OF NEWBORN CELLS. AND WE LOOK AT MAST CELLS. THIS WAS A SHOCK TO US THAT WE SAW THEY WERE ACTIVELY PARTICIPATING IN SEX DIFFERENCE. THEY ALSO HAVE A BRAIN RESIDENT POPULATION BUT THEY'RE THROUGHOUT YOUR BODY IN YOUR SKIN, EYES AND ANNOY YOU THROUGH ANAPHYLACTIC SHOCK. THIS IS HOW YOU COUNT MAST CELLS, ONE, TWO, THREE, FOUR, FIVE, SIX. YOU CAN SEE MALES HAVE MORE THAN THE FEMALES AND WE HAVE SHOWN AND THEY'RE ESSENTIAL PARTICIPANTS IN THE BRAIN REGION WITH THE MAST CELLS TALK TO THE MICROG MICROGLIA AND WE GET THE FORMATION OF A PARTICULAR SYNAPTIC PATTERNS AND WE HAVE FOUR SEX CELL TYPES. AND THE LIST OF MECHANISMS KEEPS GROWING. IF WE LOOK AT CELL DEATH WE KNOW IT'S CASPASE THREE AND THERE'S RGULATIONS IN NUCLEAR GENESIS AND WE LOOK AT THE SEX DIFFERENCES IN IN THE SYNAPSE FORMATION AND IT'S DEPENDENT ON GABA AND ASTROCYTES. THERE'S NO SUCH THING AS A MALE OR FEMALE BRAIN. . IT'S NOT POSSIBLE TO HAVE 50 MECHANISMS ACTING IN CONCERT. HAVE YOU GENETIC VARIATION AND EXPERIENCE AND ENVIRONMENT AND DIFFERENCES IN HORMONES AT ABSOLUTE LEVELS. A MOSAIC -- WHAT YOU CAN HAVE IS FEMALES THAT WILL HAVE EFFECT WILL REGIONS AND SWATHS OF THE BRAINS THAT ARE NOT DIFFERENT IN MALES AND FEMALES. A MOW -- MOSAIC IS NOT A BLEND. BASED ON 25 YEARS OF STUDYING SEX DIFFERENCES I SEE THE SAME PATTERN OVER AND OVER AGAIN WHICH IS MALES OR FEMALES THE OTHER WAY AROUND HAVE TWICE AS MUCH AS THE OTHER SEX ALL THE TIME. IF I GIVE A FEMALE HORMONE TO MASCULINIZE HER I NEVER MAKE A SUPER MALE AND IF I GAVE HER MORE I CAN'T MAKE HER MORE MASCULINE AND THE VARIANCE IS ALWAYS SMALL AND HIGHLY CONSISTENT. IF I SAY SOMETHING IS SQUASHING DOWN THE DIFFERENCE BETWEEN MALES AND FEMALES BUT SOMETHING ELSE IS PUSHING THEM A PART. IT BRINGS ME TO THE WADDINGTON'S EPI GENETIC LAND SCAPE. ONE YOU GO DOWN ONE CANAL YOU'LL BE A HEPATOCYTE AND THE FEMALE AND MALE CAN VARY WITHIN THEIR CANAL BUT CAN'T EVER CROSS OVER TO THE OTHER CANAL AND SOMETHING PUSHES THE CANALS CLOSE TO EACH OTHER BECAUSE MOTHER NATURE HAS TO MAKE SURE WE STAY WITHIN RANGE AND DON'T FLY APART. I ANALYZED 35 PAPERS IN MY LAB AND I LOOKED AT THE DIFFERENT END POINTS, STRUCTURE AND BIOCHEMISTRY AND THE DIFFERENCE IS LOOKING AT MALES VERSUS MALES AND MALES VERSUS MASCULINIZED -- FEMALES VERSUS MAG -- MASCULINIZ MASCULINIZED AND NON MASCULINIZED. AND SO ANATOMY IS NOT DESTINY. BEHAVIOR CANNOT BE PREDICT SEX DIFFERENCES IN STRUCTURE OF PHYSIOLOGY. BEHAVIOR IS SUBJECT TO CONTEXT, PAST EXPERIENCE AND CURRENT PHYSIOLOGY AND GENDER. WE SHOULD NEVER SAY WE CAN PREDICT BEHAVIORS FROM WHAT WE HAVE SEEN IN THE BRAIN BECAUSE IT'S FAR MORE COMPLICATED. I'LL THANK YOU THERE AND THANK YOU FOR YOUR ATTENTION. I'M REALLY LOOKING FORWARD TO TODAY. >> WE'LL HAVE THREE SPEAKERS ONE OF TWO COMING TO US FROM ATLANTA BECAUSE HE COULD NOT GET OUT OF ATLANTA LAST NIGHT AND I'LL INTRODUCE EACH SPEAKER AND WE'LL HAVE 20 MINUTES EACH AND COME TOGETHER FOR A 20 MINUTE DISCUSSION SO IF YOU CAN HOLD YOURS UNTIL THEN. -- YOUR QUESTIONS UNTIL THEN. OUR FIRST SPEAKER IS FROM THE CENTERS FOR DISEASE CONTROL. BRIEFLY HE'S THE TEAM LEAD FOR THE TRAUMATIC BRAIN INJURY TEAM IN THE DIVISION OF UNINTENTIONAL INJURY PREVENTION AT C.D.C. HE RECEIVED HIS DOCTORATE IN COUNSELING PSYCHOLOGY OF NOTRE DAME AND CONCENTRATE ON VIOLENCE AND ABUSE. I APPRECIATE THE OPPORTUNITY TO TALK TO YOU TODAY. I'M DISAPPOINTED I WAS VERY MUCH LOOKING FORWARD TO THIS MEETING. TODAY I'M GOING TO KIND OF FOCUS AND TALK ABOUT THE EPIDEMIOLOGY OF SEX DIFFERENCES IN TBI. AND TODAY WHAT I'D LIKE TO FOCUS ON IN PARTICULAR ARE TBI, ED VISIT AND HOSPITALIZATIONS AND DEATHS FOR THE MOST RECENT YEAR WE HAVE AVAILABLE, 2014, DATED BUT THE MOST CURRENT DATA WE HAVE. THE FOCUS LARGELY ON SEX DIFFERENCES AND IN DOING SO TALKING ABOUT MECHANISM BY AGE AND TYPE. I'LL ALSO DESCRIBE TRENDS IN THE DATA FROM 2006 TO 2014 AND TALK ABOUT IPV-RELATED TBI WHICH IS A CONCERN WITH WOMEN. WE DON'T KNOW MUCH SO THAT WILL BE RELATIVELY BRIEF BUT I'LL TOUCH ON WHAT WE DO KNOW. SO THE DATA I'LL TALK ABOUT TODAY COMES FROM THE AGENCY FOR HEALTH CARE AND EQUALITY. HCUP DATA AND IT PROVIDES ESTIMATES OF NUMBER OF ED VISITS AND HOSPITALIZATIONS AND THE BIOSTATISTICS PROVIDES ESTIMATES OF THE NUMBER OF DEATHS THESE ARE BASED ON CODES IN THE MORTALITY RECORD AND IN ALL THESE ESTIMATES, DEATHS WERE TAKEN TO MARK THE CASE. THOSE WHO PASSED IN THE EMERGENCY DEPARTMENT OR HOSPITAL WERE NOT COUNTED OR THOSE TRANSFERRED FROM THE E.D. TO THE HOSPITAL WERE ALSO NOT COUNTED. THEN THE DATA ARE A 20% SAMPLE AND WEIGHTED TO THE UNITED STATES POPULATION. SO THEY'RE BASED ON SURVEILLANCE DEFINITION FOR TBI AND E.D. VISITS AND BASED ON ICD9 CODES AND NEXT YEAR THEY'LL BE BASED ON THE ICD10 CODES INCLUDING SKULL FRACTURES, CONCUSSIONS, CEREBRAL LACERATIONS AND UNSPECIFIED HEAD INJURIES WHICH WILL BECOME A LARGER CONTRIBUTOR AND SHAKEN INFANT SYNDROME. TBI RELATED DEATHS ARE BASED ON THE FOLLOWING ICD-10 CODES WHICH I WON'T LIST HERE. REAL QUICKLY, IN 2014 THERE WERE NEARLY 2.9 MILLION E.D. VISITS, HOSPITALIZATIONS AND DEATHS. THIS IS 88% MORE E.D. VISIT AND 10% MORE HOSPITALIZATIONS AND 2% MORE DEATHS. SO AS WE LOOKED AT THE COMPOSITION IN TERMS OF SEX, ABOUT 49% OF E.D. VISITS WERE FROM FEMALES AND 41% WERE FEMALES AND ABOUT 27% OF TBI-RELATED DEATHS OR 15,000 WERE AMONG FEMALES. SO AS YOU GROUP THE LADDER OF SEVERITY AND YOU SEE MORE COMPOSITION OF MALES RELATIVE TO FEMALES. ADDS WE LOOKED AT THE LEADING CAUSES, THE MAJOR CONTRIBUTORS ARE BEING STRUCK BY OR AGAINST AN OBJECT COMPRISED ABOUT 15% AND MOTORCYCLE VEHICLE CRASHES ARE 14%. THE STRUCK BY AN OBJECT CATEGORY IS COMPRISED OF MANY DIFFERENT MECHANISMS. UNFORTUNATELY IT'S NOT A WHOLE LOT OF DETAIL THERE. THERE'S LIMITATIONS OF THE DATA IS TO UNDERSTANDING WHAT EXACTLY IS GOING ON WITH THAT PARTICULAR MECHANISM OF INJURY. SHIFTING TO HOSPITALIZATIONS FOR FEMALES IN 2014, FALLS, AGAIN, COMPRISED THE MAJORITY WITH MOTOR VEHICLE CRASHES AND OTHER SMALLER CATEGORIES COMPRISING THE REST. AND THEN LOOKING AT TBI RELATED DEATHS FOR FEMALES IN 2014 AS THE LEADING CAUSE AND MOTOR VEHICLE CRASHES AND YOU SEE LARGER CONTRIBUTORS THAT WEREN'T THERE FOR E.D. VISITS SO INTENTIONAL SELF-HARM OR SUICIDE AND HOMICIDE COMPRISED OF 9% OF TBI RELATED DEATHS. IF WE THEN LOOK AT SEX DIFFERENCES BY MECHANISM SHOWING MALES IN BEFORE YOU AND FEMALES IN GREEN, FEMALES ARE SLIGHTLY HIGHER IN MOTOR VEHICLES AND FALLS AND MALES ARE HIGHER IN THE STRUCK BY OR AGAINST CATEGORY AS WELL AS ASSAULT. AND MOVING ON TO HOSPITALIZATION, MALES ARE QUITE A BIT HIGHER IN ALL THE MAJOR MECHANISM MECHANISMED -- MECHANISMS AND MALES HAVE A SIGNIFICANTLY HIGHER NUMBER OF DEATHS FOR EACH OF THE MECHANISMS. SO IF WE WANT TO LOOK AT THE LEADING CAUSES OF E.D. VISITS AND HOSPITALIZATIONS AND DEATHS AMONG FEMALES, BY AGE GROUP WE NOTICE IT CHANGES OVER THE LIFE SPAN. IF WE LOOK AT E.D. VISITS HIGHLIGHTED IN RED, FOR THE GROUP AT THE TOP COMPRISED OF CHILDREN, FALLS AND BEING STRUCK BY OR AGAINST ARE THE FIRST AND SECOND LEADING CATEGORIES. IF YOU WORK YOUR WAY DOWN THE VARIOUS AGE GROUPS, FALLS IS A LEADING CONTRIBUTOR THROUGHOUT MOTOR VEHICLES IS ALSO A SIGNIFICANT CONTRIBUTOR WITH STRUCK BY AGAINST FOR THE YOUNGEST AND OLDEST. AND HOSPITALIZATION FOR CHILDREN FALLS IS THE LEADING CAUSE AND CRASHES BEING THE SECOND FOR CHILDREN AND FALLS AND MOTOR VEHICLE CRASHES ARE THE FIRST OR SECOND LEADING CAUSE OF TBI RELATED HOSPITALIZATIONS FOR ALL AGE GROUPS. THEN WHEN YOU MOVE ON TO DEATHS YOU SEE OTHER CONTRIBUTORS. OVERALL, HOMICIDES. THESE ARE HEAD TRAUMA IS THE SECOND LEADING CAUSE AND THAT'S LARGELY DUE TO THE 0-4 AGE GROUP. THIS COMPRISES LARGE NUMBERS IN CHILDREN ABOUT 250 A YEAR BUT STILL THEY ARE THE LEADING CAUSE FOR 0-4-YEAR-OLDS. AS YOU'D EXPECT AS CHILDREN LEARN TO DRIVE VEHICLE CRASHES BECOME MORE PROMINENT AND IN PARTICULAR IN MEN AND WE'RE ALSO SEEING INCREASES IN WOMEN AND FALL-RELATE DEATHS WE'RE SEEING SIGNIFICANT RISES IN THOSE OVER TIME. I'LL TALK ABOUT TRENDS IN TBI-RELATED VISITS FROM 2006 TO 2014. THE REASON WE DON'T GO BACK FURTHER IS THE DATA IS INCOMPARABLE SO WE GO BACK TO THAT PARTICULAR DATE. WHAT WE FOUND AS WALTER TALKED ABOUT EARLIER AND IT'S A CONTINUATION OF THAT FOR 2013 AND A SIGNIFICANT INCREASE OVER THE LAST DECADE AND A HALF IN TBI RELATED E.D. VISITS SO THE NUMBERS HAVE SHOT UP ABOUT 980,000 MORE IN 2014 THAN IN 2006. THEN IF WE LOOK AT THE PARTICULAR MECHANISMS THAT CONTRIBUTE TO THE INCREASES WHAT WE FIND IS THAT THEY'RE LARGELY DUE TO FALLS AND I DON'T TALK ABOUT THIS IN PARTICULAR TALK BUT IN A PUBLICATION REALEASED RELEASED EARLIER THERE'S AN INCREASE WITH NO SIGN OF THAT DISCONTINUING. IT'S NOT ONLY AN INCREASE IN THE NUMBER BUT RATE. SO THERE'S AN INCREASE IN THOSE BEING STRUCK BY OR AGAINST. IT'S NOT QUITE AS LARGE AN INCREASE IN TERMS OF FALLS AND IN TERMS OF THE NUMBERS BUT THE RATES HAVE SHOT UP QUITE A BIT AS WELL. AN INCREASE OF 83% AMONG MALES AND 45% AMONG MALES. WE SEE AN INCREASE IN MOTORCYCLE VEHICLE INCREASES. MOVING ON TO TBI-RELATED HOSPITALIZATIONS. THERE'S A SLIGHT DECREASE OVERALL INCLUDING MALES AND FEMALES. THAT MATCHED DIFFERENCES UNDER THE SURFACE. WE LOOKED AT THE PARTICULAR MECHANISMS. WE FIND A 31% INCREASE IN THE RATE AMONG FEMALES AND 24% AMONG MALES AS IT RELATE TO HOSPITALIZATIONS DUE TO FALLS. THE HEADING'S MISSING THERE. THERE'S ALSO A DECREASE IN TERMS OF MOTORCYCLE VEHICLE CRASHES. AND THE TWO RESULT IN A SLIGHT DECREASE. THERE'S ALSO A SOMEWHAT DECREASE IN ASSAULT RELATED TBIs FOR MALES AND THE NUMBERS REMAIN FLAT. MOVING ON TO TRENDS IN TBI-RELATED DEATHS. WE SEE A SLIGHT DECREASE OVER TIME OF ABOUT 6%. AGAIN THAT MASKS A COUPLE CHANGES. THERE'S AN INCREASE DURING THAT TIME PERIOD OF ABOUT 30% IN TBI RELATED DEATHS AND SLIGHTLY LARGER FOR FEMALES THAN MALES THOUGH THERE'S HIGHER RATES FOR FEMALES THAN FOR MALES. AND THERE'S SIMILAR DECREASES FOR FEMALES AND MALES OVER THAT TIME PERIOD. AND THERE'S A DECREASE IN TBI DEATHS RELATED TO HOMICIDE THAT'S OCCURRING. I'LL TALK ABOUT AN ISSUE IN TERMS OF TBI THAT TOUCHES ON AND AFFECTS WOMEN. IN THE EPIDEMIOLOGY OF TBI. THERE'S BEEN PREVIOUS ESTIMATES. HOWEVER, THESE ARE NOT NATIONAL LEVELS. THE PREVIOUS ESTIMATES HAVE TYPICALLY TAKEN PLACE IN EMERGENCY DEPARTMENTS OR DOMESTIC VIOLENCE SHELTERS AND 30% TO 74% HAVE FOUND WOMEN TO HAVE A HISTORY OF TBI AND OTHER STUDIES HAVE LOOKED AT PHYSICAL VIOLENCE BY AN INTIMATE PARTNER AND 90% HAVE INJURY TO A HEAD OR NECK. HOWEVER, THE BEST ESTIMATES I CAN FIND IS THE C.D.C. SURVEILLANCE SYSTEM WHICH IS I CAME IT WORK ON FOUR YEARS AGO AND THIS IS A RANDOM TELEPHONE SURVEY OF U.S. ADULTS AND IT FOUND OVERALL ABOUT 33% OF WOMEN AND 28% OF MEN HAVE EXPERIENCED SOME FORM OF PHYSICAL VIOLENCE IN THEIR LIFE TIME. ABOUT .5% OF MEN OR NEARLY 600,000 REPORTED THE SAME GIVEN A MINORITY OF TBIs INCLUDE LOSS OF CONSCIOUSNESS WE EXPECT THAT TO BE HIGHER SO IN CLOSING TALKING ABOUT THE LIMITATIONS IN THE DATA THERE'S AN INCREASING USE OVER THE TIME PERIOD OF THE DIAGNOSIS CODE THERE'S SPECULATION THAT'S PEOPLE SEEKING CARE FOR MINOR INJURIES THEY MAY NOT HAVE SOUGHT CARE FOR BEFORE AND MAYBE NOT CLEARLY TBIs. AND SOME DATA SHOWS A SIGNIFICANT PROPORTION AREN'T TRULY TBI. THERE'S REASON TO THINK THE DATA IS AN UNDER ESTIMATE AND THE DATA DOESN'T CAPTURE EMERGENCY CARE SETTINGS OR THOSE ON THE FEEFLD PLAY. -- FIELD OF PLAY OR THOSE WHO DO NOT KEEP HEALTH CARE AT ALL. AND THE STRUCK BY OR AGAINST MECHANISM IS WHERE WE THINK IS THE SPORTS-RELATED INJURIES ARE REPORTED AND SOME IN FALLS BUT WE CAN'T SEPARATE THAT OUT IN THIS SUMMARY. MALES HAVE THE MORE SEVERE FORMS OF TBI REPRESENTED BY HOSPITALIZATIONS AND DEATHS. AND WE'VE SEEN AN INCREASE FROM 2006 TO 2014 IN E.D. VISIT AND SMALL DECREASES IN HOSPITALIZATIONS AND DEATHS. THE PATTERN SUGGESTS THE INCREASES IN THE PARTICULAR MECHANISMS ARE HIGHER FOR WOMEN OVER THAT TIME PERIOD. WHEN WE LOOK AT THE LEADING CONTRIBUTORS OF THE INCREASE IN E.D. VISITS, STRUCK BY AND AGAINST ARE LIKELY SPORTS INJURIES WAS A CONTRIBUTOR AND FALLS IN ADULTS IS THE LARGEST INCREASE IN E.D. VISITS AND WE SEE INCREASES IN HOSPITALIZATIONS AND DEATHS AND THEY'RE WORKING ON A MORE COMPREHENSIVE SURVEILLANCE SYSTEM AND WE NEED BETTER ESTIMATES OF ICD RELATED TBI. WE'RE ASKING QUESTIONS ON INTIMATE PARTNER VIOLENCE THAT CONCLUDES MY PRESENTATION. THANK YOU. >> THANK YOU, DR. BREIDING. WE'RE GOING TO TAKE BACK CONTROL OF THE SLIDES NOW AND THANK YOU FOR WORKING WITH US TO BE ABLE TO PRESENT THIS IMPORTANT TALK. HOPEFULLY YOU'LL BE ABLE TO STAY LATE BY PHONE AND THEN JOIN US FOR THE PANEL. >> YES, I'D BE HAPPY TO. >> THANK YOU. OUR SECOND SPEAKER IS HERE IN PERSON, WE'RE PLEASED ABOUT THAT. DR. COURTNEY ROBERTSON IS THE CO-DIRECTOR OF THE PEDIATRIC NEUROCRITICAL CARE PROGRAM ATTONS HOP KINGS. HER RESEARCH IS ON PEDIATRIC TRAUMATIC BRAIN INJURY AND CONDO AND -- AND LOOKS AT ACUTE PEDIATRIC TBI AND HER TALK TODAY WILL BE SEX DIFFERENCES IN PEDIACASES OF TBI. >> THANK YOU. THERE'S DIFFERENCES IN REMEMBER EVERYTHING WE STUDY AND FOR PEOPLE FOR A WHILE FELT LIKE THE DEVELOPING BRAIN DIDN'T HAVE SUCH A DIFFERENCE. IN OTHER WORDS, THERE'S NOT CIRCULATING SEX HORMONES DEVELOPING IN THE EARLY BRAIN AS DR. McCARTHY SHOWED YOU GUYS. THE BRAIN MIGHT BE FREE OF THOSE INFLUENCES, HOWEVER MOST THINGS WE'VE LOOKED AT NOW HAVE SHOWN TO BE SIGNIFICANT DIFFERENCES. I'M GOING TO SUMMARIZE A FEW UNIQUE FEATURES OF THE YOUNG BRAIN AND DISCUSS IMPORTANT DIFFERENCES BETWEEN BOYS AND GIRLS IN RECOVERY FROM TBI AND DIFFERENCES IN ANIMALS FROM PDI AND I JUST PICKED A FEW I FOUND REALLY IMPORTANT AND INTERESTING AND TALK ABOUT A FEW OF THE POTENTIALLY CELLULAR PATH LOGIC DIFFERENCES THAT MAY GO ON AFTER HEAD INJURY. AS MAX STATED BEFORE, I'LL SHOW YOU A FEW OF THE NUMBERS HE HIGHLIGHTED SOME IN THE EPIDEMIOLOGIC TALK. AND IT'S THE LEADING CAUSE OF CHILDREN 1-18 AND HALF A MILLION KIDS AGES 1-14 VISIT THE E.D. EACH YEAR AND AS A PEDIATRICIAN I FIND THIS SHOCKING EVERY TIME, IT'S THE LEADING CAUSE OF LONG-TERM DISABILITY IN CHILDREN IN THE UNITED STATES. IF YOU THINK OF ALL THE ILLNESSES WE SEE IT'S A PROFOUND STATEMENT. WHAT'S UNIQUE ABOUT THE YOUNG BRAIN VERSUS THE FULLY MATURE BRAIN. AS MATT MENTIONED BRIEFLY, MECHANISMS ARE AGE DEPENDENT. IN THE INFANT WE WORRY ABOUT SHAKEN INFANT SYNDROME. TODDLERS ARE PARTICULARLY PRONE TO FALLS AND THERE'S A BLIP IN TODDLER AGES AND CHILDREN ARE THEY'RE MORE ACTIVE RIDING BICYCLES AND PEDESTRIANS THEY BECOME INVOLVED IN TRANSPORTATION-RELATED INJURIES AND THEN ADOLESCENTS AND SPORTS DIFFERENCES. THERE'S ANATOMIC DIFFERENCES. THE HEAD CIRCUMFERENCE INCREASES ABOUT A CENTIMETER A MONTH IN THE FIRST YEAR OF LIFE AND THE BRAIN TRIPLES WITHIN THE ONE YEAR AND MOST THE BRAIN GROWTH IS DONE IN THE FIRST FEW YEARS. AND THE FIGURES SHOW YOU THE ANATOMIC DIFFERENCES IN THE UPPER RIGHT. AND YOU SEE IT ACROSS THE LIFE SPAN. THE RELATIVELY THIN SKULL OF THE YOUNG SKULL VERSUS A MATURE SKULL. THE FACE TO CRANIA RATIO 1-8. THE YOUNG SKULL MAKING IT MORE LIKELY TO HIT THE CRANIUM THAN THE FACE WHERE IT'S 1-5 IN THE MATURE SKULL AND THE PROMINENT FOREHEAD. IN ADDITION TO THE BASIC ANATOMICAL FEATURES THERE'S OTHER INTRINSIC BRAIN DEVELOPMENT THEMES GOING ON AND HIGH BRAIN WATER CONTENT IN NEWBORNS, PROGRESSIVE MIELINATION AND WE CONTINUE TO MYELINATE DURING LIFE AND THESE ARE IMAGES OF MRIs OF CHILDREN IN DIFFERENT AGES. THE FIGURE A IS A 25-WEEK PREMATURE INFANT AND THE OTHER IS A HEALTHY TERM INFANT AND YOU SEE THE IMPRESSIVE DEVELOPMENT I CAN TALK ABOUT THE IMPORTANT DIFFERENCES IN TERMS OF THE PATHOBIOLOGY AND ITS RESPONSE TO IMAGERY BUT I'LL SUMMARIZE ONE IMPORTANT CONSIDERATION. THINGS AS BASIC AS CEREBRAL BLOOD FLOW ARE REGULATED WITH PEAKS IN EARLY CHILDHOOD THIS IS AGE IN YEARS ON THE X AXIS AND THE PEAK IS BETWEEN 5 AND 10 YEARS IN TERMS OF CEREBRAL BLOOD FLOW AND THE GLUCOSE AND THERE'S BLOOD FLOW REGULATION ACROSS EACH. SO ARE THERE SEX DIFFERENCES IN CLINICAL STUDIES OF PEDIATRIC TBI. I'LL HIGHLIGHT THOSE FOR YOU IN THE NEXT COUPLE SLIDES. AS MENTIONED EARLIER, PERHAPS TBI AS A FIELD IS A LITTLE BIT BEHIND. AND IN LOOKING AT SEX DIFFERENCES, I THINK PEDIATRIC TBI IS FURTHER BEHIND. THEED THE PEED >> THE PEDIATRIC REGISTRY LOOKS AT 37% FEMALE AND THEY LOOKED AT SUB AGE GROUPS AND 0-7 AS PREPUBITAL. AND USE INJURY SCORES AS A MARKER OF SEVERITY. THEY FOUND NO DIFFERENCE BETWEEN BOYS AND GIRLS IN THE STUDY. HOWEVER, IN OTHER MARKERS SUCH AS ICU AND LENGTH OF STAY GIRLS HAD TRENDS TOWARDS WORSE OUTCOMES IN THESE MAKERS. THEY HYPOTHESIZED THE PUBERTY FEATURES IN THE MALE MAY BE MORE PROTECTIVE IS TO THE 13 TO 19-YEAR-OLDS THE GIRLS MIGHT LOOK BETTER BUT IN FACT THEY FOUND THE OPPOSITE AND SHOWED 13 TO 19-YEAR-OLD GIRLS HAS LONGER HOSPITAL STAYS AND A TREND TOWARDS LENGTHIER STAY AND IF YOU LOOK AT MORE SEVERE PUBITAL GIRLS AND THE FEMALES HAD A SIGNIFICANTLY GREATER LIKELIHOOD. ANOTHER LARGE DATABASE STUDY WAS OUT OF THE CEDAR SINAI GROUP IN LOS ANGELES WHERE THEY LOOKED AT ABOUT 20,000 PATIENTS. THIS WAS PRIMARILY FOCUSSED ON COMPARING TEENS TO PRETEENS AND THEY SHOWED A LOWER MORTALITY IN PUBESCENT FEMALES. IF YOU LOOK AT THE GRAPH AT THE BOTTOM THERE'S DIFFERENT SUB CATEGORIES BASED ON SEVERITY AND GCS BUT YOU SEE THE PRE-PUBESCENT FEMALES DIDN'T HAVE A DIFFERENT IN MORTALITY BUT THE PUBESCENT FEMALES HAD A LOWER OVERALL MORTALITY RATE THAN THE MALES. ONCE AGAIN WITH THE LIMITATION OF LARGE DATABASE STUDIES. THERE'S BEEN A FEW STUDIES LOOKING AT SEX DIFFERENCES IN FUNCTIONAL OUTCOMES COMPARING BOYS TO GIRLS. AN EARLIER STUDY IN 1993 SHOWED THE VIOLENT ADAPTIVE BEHAVIOR SCORE GIRLS SCORED HIGHER AND FOLLOW-UP STUDIES IN THE EARLY 2000s BY A GROUP IN MICHIGAN SHOWED BOYS HAD LOWER LEARNING AND MEMORY SCORES USING THE CALIFORNIA VERBAL LEARNING TEST. AND THIS GRAPH AT THE BOTTOM SHOWS THIS. OVERALL MOST THE SCORES BY BOYS WERE LOWER THAN GIRLS BY AVERAGE AND THE STATISTICAL DIFFERENCE WAS IN THE LONG DELAY RECALL SIGNIFICANTLY WORSE FOR BOYS. THIS GROUP USED 30 BOYS AND 30 GIRLS AND THE LAST WAS A LARGER COHORT OF 70 BOYS AND 70 GIRLS WITH AGE-MATCHED GIRLS AND THE BOYS' FINDINGS WERE WORSE COMPARED TO THE CONTROL GIRLS OR INJURED GIRLS. IT'S MOSTLY RELATED TO DIFFERENCES IN PROCESSING SPEED IS WHAT THEY CONCLUDED. I HAVE TWO SLIDES ON CONCUSSION AND THINK IT WILL BE COVERED LATER BUT SINCE A PREDOMINANT AMOUNT OF ATHLETE-BASED CONCUSSION HAPPEN IN THE PEDIATRIC AGE RANKS THIS STUDY WAS PUBLISHED THIS YEAR BY A GROUP OUT OF NORTHWESTERN. THEY LOOKED AT HIGH SCHOOL ATHLETES FR ATHLETES FROM 2005 TO 2015 AND ALL THESE DIFFERENCE COLORS AND TYPES OF LINES ARE DIFFERENT SPORTS, FOOTBALL, SOCCER, WRESTLING, BASKETBALL, VOLLEYBALL AND BROKEN DOWN BOYS VERSUS GIRLS. THE IMPORTANT PART IS THIS SECTION UP HERE AND THIS IS THE GIRLS SOCCER SECTION AND THEY CONCLUDED THE INJURY PROPORTION RATIO OF CONCUSSIONS WERE MOST COMMON IN GIRLS SOCCER THAN ANY OTHER SPORT IN THE LAST TWO YEARS STUDIED. ANOTHER GROUP LOOKED AT SEX DIFFERENCES IN CONCUSSION RECOVERY IN TEENAGERS. THIS WAS PUBLISHED IN 2015 AND YOU CAN SEE THIS IS ONE CONCUSSION, TWO CONCUSSIONS OR THREE CONCUSSIONS, FEMALES IN RED, MALES IN BLUE AT BASELINE AND EARLY AFTER INJURY THE FEMALES HAD MORE SYMPTOMS REPORTED COMPARED TO THE MALES BUT THE TRAJECTORY WAS NO DIFFERENT BETWEEN THE TWO GROUPS. THEY CONCLUDED THE TRAJECTORIES WERE SIMILAR. THIS IS A NICE REVIEW PUBLISHED ONCE AGAIN THIS YEAR FOR THE PMR GROUP WHERE THEY LOOKED AT STUDENT-ATHLETES AND LOOKED AT 101 ARTICLES. THEY'RE CONCLUSIONS I HIGHLIGHTED THE LITERATURE ON SEX AND RECOVERY TIME AND PERSISTENT SYMPTOMS ARE SOMEWHAT MIXED. YOU CAN SEE IMPROVEMENTS IN MALES AND IN AND IMPROVEMENTS ON FEMALES AND SOMETIMES NET EQUAL. FEMALES TAKE A LONGER RECOVERY TIME WITH SYMPTOMS PERSISTING MORE THAN A MONTH AND IT MAY RELATE TO THE BIOMECHANICS IN ATHLETICS IN FEMALES AS WELL AS INJURY RATE DIFFERENCES MAY BE A BIG INFLUENCER OF THE SEX-BASED DIFFERENCES. THIS LOOKS AT OUTCOMES IN ADULT TESTING SO THESE ARE MILD AND MODERATE HEAD INJURIES AND LOOKED AT BONEY FRACTURES AND KIDS WHO HAVE UNDERGONE CONTROLS AND THEY ASSESSED 18 TO 31 YEARS OF AGE OR FIVE YEARS SINCE THE HEAD INJURY AND WHAT THEY FOUND WAS FEMALES, IN OTHER WORDS, PATIENTS INJURED AS GIRLS HAD HIGHER RATES OF INTERNALIZING PROBLEMS SUCH AS DEPRESSION AND ANXIETY AND MALES HAD HIGHER EXTERNALIZING SUCH AS ANTI-SOCIAL BEHAVIOR AND CRIME AND IT COULD EFFECT THE NEUROPSYCHOLOGICAL PROFILE INTO ADULTHOOD. I WANTED TO HIGHLIGHT A FEW THINGS WHAT WE FOUND OUT USING THE ANIMAL STUDIES. SO BRIGITTE SIMPLE DID A STUDY ON BEHAVIORAL BRAIN RESEARCH AND THEY NOTED CHILDHOOD VICTIMS OF HEAD INJURY SUFFERED LONG-TERM SOCIAL DEFICITS AND FOUND INTERESTING FINDINGS THAT THE ANIMALS INJURED AS PE21 MICE WITH THE CONTROLLED CORTICOMODEL HAD NORMAL AND WHEN THEY LOOKED INTO ADULTHOOD THEY HAD SIGNIFICANT DEFICITS IN SOCIOSEXUAL FUNCTION AND THEY PUBLISHED THE STUDY LOOKING AT THE DIFFERENCE BETWEEN MALES AND FEMALES. IN THIS STUDY THEY TOOK THE SAME CCI MODEL IN MICE AND LOOKED AT HISTO LOGIC OUTCOMES AND LOOK AT BEHAVIORIAL TESTING AND THEY FOUND THE FEATURES AND SHOWED THE DIFFERENCE IN THE RECOVERY. THE GRAPHS ARE FROM THE LAYER THREE OF THE PREFRONTAL CORTEX AND THEY SAW SIMILAR CELLS IN THE HIPPOCAMPUS. AND THEY SAW BOTH SEXES HAD REDUC REDUC REDUCED SOCIABILITY AND THERE WAS SPECIFIC PSYCHO, SOCIAL DEFICITS OVER TIME. AND THERE WAS STUDIES AT PENN AND SEATTLE AND A PEDIATRIC ANESTHESIOLOGIST AND AND WHEN THEY LOOKED AT BOYS THEY SEEMED TO HAVE DIFFERENCES COMPARED TO THE GIRLS. THE NUMBERS WERE SMALL IN THE CLINIC SO THEY THOUGHT THEY'D TAKE IT BACK AND THEY SAW THAT THE BLOOD FLOW REGULATION WAS MORE INFORMED AFTER TBI AND THEY LOOKED AT THE FACT IT WAS RELATED TO THE CONASE DIFFERENCES AND YOU CAN PAY ATTENTION TO THE -- SO THIS IS MALE ON THE LEFT, FEMALE ON THE RIGHT. THE SHAM ARE OPEN BARS AND YOU SEE THE LIGHT GRAY AND IT TARGETS BLOOD FLOW AND PRESSURE AND FLUID PERCUSSION PLUS NOREPINEPHRINE PLUS AN INHIBITOR IN BLACK. SO AFTER FLUID PERCUSSION THERE WAS A SIGNIFICANT REDUCTION IN CEREBRAL BLOOD FLOW AND REGULATION WHEN NOREPINEPHRINE WAS ADDED YOU WERE ABLE TO REVERSE THIS BUT AT MALES FOUR HOURS AFTER INJURY NOREPINEPHRINE DID NOT IMPROVE BLOOD FLOW TO THE BRAIN BUT WHEN THEY ADDED THE INHIBITOR THEY WERE ABLE TO IMPROVE THAT. IN THE PREVIOUS STUDY WAS NEWBORN PIGLETS THE FINDING WAS AGE DEPENDENT AND IT PROTECTS THEM IN THE JUVENILE AGES. IT'S A SIMILAR GRAPH FOR THE INJURED MALES AND THERE'S A STATISTICALLY IMPROVEMENT HERE AND IT CAN BE IMPROVED FURTHER. THEY DID A SERIES OF STUDIES PUBLISHED LOOKING AT THE VASO PRESSER CHOICE BEING PARTICULARLY IMPORTANT. PHEN PHEN PHENYLEF RIN PROTECTED IT AND IT FEMALES PROTECTED AND THE MOST RECENT STUDY SHOWED EPINEPHRINE PRESERVED THE NEURONS IN NEWBORN MALES, FEMALES AND JUVENILE FEMALES BUT NOT JUVENILE MALES. I BECAME INTERESTED IN PROGESTERONE AND I WANTED TO LOOK AT IT IN THE DEVELOPING BRAIN BECAUSE I FELT THAT WAS A UNIQUE ENVIRONMENT FROM THE OTHER STUDIES DONE. WE RECENTLY PUBLISHED THE LOOK AT MIGHT -- MITOCHONDRIAL AND THIS WAS NOT STATISTICALLY SIGNIFICANT THOUGH THE NUMBER WAS HIGHER IN THE FEMALES AND THERE WAS MORE VARIABILITY IN THE MITOCHONDRIAL CONTENT IN THE MALE RATS. AFTER INJURY THERE WAS A SIGNIFICANT REDUCTION IN MALES AND FEMALES AND PROGESTERONE WAS ABLE TO PROTECT THE MALES BUT NOT THE FEMALES. THERE WAS A CORRELATIVE TISSUE LOSS SO THE MIGHT COND AND 20 20-HETE IS PRODUCED BY THE P450 SYSTEM AND THEY PLAY MANY ROLES IN THE BODY. AND INHIBITERS OF 20-HETE ARE NEUROPROTECTIVE AND WERE IN BRAIN STUDIES AND WE LOOKED AT TREATMENT AND WE LOOKED AT THE CORTICOIMPACT AND WE SAW REDUCTIONS IN LESION VOLUME AT 3 AND 30 DAYS AND IMPROVEMENT IN FUNCTION FOR RECOGNITION BUT DID NOT SEE ANY DIFFERENCE IN THE FEMALES. AND MANY OTHER FOLKS HAVE LOOKED AT SEX DIFFERENCES IN OTHER BRAIN INJURY MODELS. I WON'T GO THROUGH ALL THESE BUT NOT ONLY IS THERE A PROFOUND DIFFERENCE BUT THEY'RE RESPONSE TO TREATMENT SUCH AS THE RECENTER AND PROGESTERONE WORK AND IT SHOWS DIFFERENCES IN RESPONSE TO TREATMENT. SO IN CONCLUSION, THERE ARE SIGNIFICANT SEX DIFFERENCES IN FUNCTIONAL OUTCOMES AND IN MORTALITY AND OTHER MAKERS OF HOSPITAL LENGTH OF STAY. THERE'S DIFFERENCES IN CONCUSSION RECOVERY AND IN SOME OF THE SEX DIFFERENCES PERSIST INTO ADULTHOOD. FINDINGS IN ADOLESCENCE MAY BE INFLUENCED BY SYSTEMIC DIFFERENCES AND THE PEDIATRIC ANIMAL MODELS TO THE DIFFERENT RESPONSES AND IN THE RESPONSE IN NEUROPROTECTIVE TREATMENTS AFTER TBI SUPPORTED BY THE HHI WORK AND SEX DIFFERENCES ARE SEEN IN THE STUDIES PRIOR TO PUBERTY IN THE ANIMALS. SO IN CONCLUSION, IT'S VERY IMPORTANT TO EVALUATE MALE AND FEMALE ANIMALS SEPARATELY AND GET ANSWERS ON MECHANISMS. THANKS TO MY SCIENCE, NEUROSCIENCE COLLABORATORS AT JOHNS HOPKINS AND THE FOLKS I WORK WITH AT MARYLAND AND MY PEDCRITICAL CARE PROGRAM. THANK YOU. OUR THIRD SPEAKER IS DR. COLANTONIO AT THE UNIVERSITY OF TORONTO. AND HAS STUDIED THE DISABILITY OF OLDER PEOPLE WITH DEMENTIA AND STROKES AND FOCUSES ON TBI AMONG VULNERABLE POPULATION AND THE TITLE OF HER BOOK IS THE SEX DIFFERENCES FOR OLDER ADULTS WITH TBI. PLEASE WELCOME DR. COLANTONIO. >> SO I WANT TO SAY IT'S TERRIFIC TO BE HERE AT THE NATIONAL INSTITUTE OF HEALTH AND WANT TO THANK THE INVITATION. I'M PROFESSOR AND DIRECTOR AT THE REHABILITATION INSTITUTE AT TORONTO AND ONE OF THE REASONS I BECAME DIRECTOR OR AGREED TO BE DIRECTOR IS I WAS INTERESTED IN TRAINING THE NEXT GENERATION OF SCIENTISTS IN THEIR WORK AIS NECESSARY FOR GOOD SCIENCE. I ALSO THE FIRST SPEAKER DID A FANTASTIC JOB EXPLAINING THE DIFFERENCES BETWEEN SEX AND GENDER AND THESE RELATIONSHIPS ARE INTERRELATED AND THE RELATIONSHIPS ARE VERY COMPLEX. SO I HAVE BEEN ASKED TO TALK ABOUT OLDER ADULTS AND TRAUMATIC BRAIN INJURY. I WANT TO THANK DR. BREIDING FOR DOING A GREAT JOB IN TERMS OF SHOWING THE LANDSCAPE IN TERMS OF TRAUMATIC BRAIN INJURY EPIDEMIOLOGY AND WHAT HE'S OUTLINED IS ONE OF THE MOST DRAMAT DRAMATIC INCREASES ARE IN THE OLDER AGE GROUP FOR WOMEN. AND SOME OF THE GREATEST INCREASES SHOWN IN CANADA TOO AS WELL HAVE BEEN IN THE OVER 85 CATEGORY FOR BOTH MALE AND FEMALE. RESEARCHERS IN THE U.S. HAVE PUBLISHED OLDER ADULTS UNTIL EPIDEMIOLOGY OF OLDER ADULTS AND THEY FOUND THAT THE 85 CATEGORY WAS MOSTLY WOMEN WITH CRITICAL RATES OF 75 AND 85. ALSO, PERFECT -- DR. BREIDING SPOKE ABOUT HOW FEMALES WERE MORE PRESENTED IN THE TRAUMATIC BRAIN INJURY AND YOU NEED TO LOOK AT THE SEVERITY LEVEL BECAUSE FEMALES PRESENT MORE AND THE STUDY SHOWS AND STUDIES SHOW DATA FROM HOME CARE RECIPIENTS FOUND TO BE 53% WOMEN. WOE KNOW FALLS ARE A SIGNIFICANT CAUSE OF INJURY AND THAT TENDS TO BE SIGNIFICANTLY MORE WOMEN. I WENT OVER SEVERAL REVIEWS AND JUST TO SUMMARIZE THE KEY ISSUES AND GAPS, FOR OLD ADULTS IS POOR FUNCTIONAL OUTCOMES AND HIGHER MORTALITY. AND THEY'RE OFTEN TREATED MORE CONSERVATIVELY. I DON'T KNOW IF IT'S BECAUSE THEY'RE OLDER ADULTS AND ALSO MOSTLY WOMEN, HIGHER INSTITUTIONALIZATION AND IT'S FOUND MODELS DO NOT FORM AS OPT OPTIMALLY IN THIS OLDER ADULT POPULATION. THERE'S ALSO A NEED TO KNOW WHAT THE PRE-INJURY FUNCTIONAL STATUS IS OF THE OLDER ADULTS. WHEN THEY COME IN FOR A TRAUMATIC BRAIN INJURY THESE REVIEWS HAVE HIGHLIGHTED THE NEED FOR EVIDENCE-BASED GUIDELINES, COMMON DATA ELEMENTS AND PROGNOSTIC MODELS SPECIFIC TO THE GERIATRIC POPULATION. THOUGH LARGE NUMBERS OF WOMEN ARE AFFECTED WITH TRAUMATIC BRAIN INJURY IN OLDER ADULTHOOD, THERE'S A LACK OF INFORMATION ON SEX DIFFERENCES AND SEX SPECIFIC. AND AGING WITH BRAIN INJURY IS IDENTIFI IDENTIFIES FIDE AS A GAP AND -- IDENTIFIED AS A GAP AND WE'LL HEAR MORE ABOUT MENSTRUAL CYCLES AFFECTING THIS AND THE WAY WOMEN EXPERIENCE MENOPAUSE AND HOW THAT MIGHT AFFECT OUTCOMES AND AFFECT THE RELATIONSHIP WITH NEURODEGENERATIVE DIVISIONS IS A HUGE GAP. HOW WE EXPERIENCE MENOPAUSE. SO I JUST WANTED TO SAY A WORD ABOUT THAT. I ALSO THOUGHT I'D TALK A LITTLE BIT ABOUT WHAT WE HAVE DONE ON LONG-TERM OUTCOME AFTER A TRAUMATIC BRAIN INJURY. THIS IS WORK NNDS HAS FUNDED AND LOOKED AT GENDER DIFFERENCES OR SEX DIFFERENCES. IT'S HARD TO DISENTANGLE THE WORK WE'RE DOING AND WE COLLECTED DATA ON 306 INDIVIDUALS. AND THE KEY DIFFERENCES WERE WOMEN RECORDED MORE HEADACHES AND DIZZINESS AND LOSS OF CONFIDENCE COMPARED TO MEN. SOME SYMPTOMS THEY IDENTIFIED AS MORE LIKELY TO EFFECT DAILY FUNCTIONING OF WOMEN WERE THEIR ABILITY TO INITIATE DAILY ACTIVITIES, A NEED FOR SUPERVISION AND ASSISTANCE AND THESE ARE THINGS YOU WOULD THINK SPEAK TO SOME OF THEIR ROLES THEY HAVE. ALSO WHAT AFFECTED THEM WERE HIGH SEX DRIVE. THOUGH MALES WERE TWICE AS LIKELY TO REPORT THIS, WOMEN IDENTIFIED THIS AS AN ISSUE. IN OUR FOCUS GROUPS WITH MATURE WOMEN THEY'VE IDENTIFIED THIS AS SOMETHING THAT HAS LED OR THEY FEAR WILL LEAD TO PHYSICAL AND SEXUAL ABUSE. AND WE HAVE DATA SETS BASED LARGELY IN ONTARIO, CANADA. THIS IS BASED ON OUR PUBLICLY FUNDED HEALTH CARE SYSTEM WHERE RESIDENTS RESIDENTS HAVE ACCESS TO PHYSICIAN VISIT AND HOSPITALIZATIONS. WE ALSO HAVE DATA ON EVERY REHAB DEBT WE LOOKED AT IT AND FEMALES WERE MORE LIKELY TO BE INSTITUTIONALIZED FOR LENGTH OF STAY, COMORBIDITIES AND WE DIDN'T LOOK AT THEIR LIVING SITUATIONS WHICH MAY EXPLAIN FOR SOME OF THE OUTCOMES. WHEN WE DID DO THIS, LOOKING AT REHAB DATA, ONCE WE LOOKED AT WHETHER THEY LIVED ALONE. ONCE WE LOOKED AT PREINJURY LIVING SITUATION AND THEIR SOCIAL SUPPORT, THAT AFFECT WAS NO LONGER SIGNIFICANT. THERE WERE PERSONS WITH TRAUMATIC BRAIN INJURY AND WE CAPTURED COMORBICOMORBIDITIES AND WE'VE BEEN ABLE TO LOOK BACKWARDS TO SEE HOW MUCH COMORBIDITY WE CAN LOOK BACK TO PRIOR TO HOSPITALIZATION. THIS GIVES YOU AN IDEA OF THE DISTRIBUTION OF COMORBIDITIES BY AGE GROUP AND THE NUMBER OF COMORBIDITIES RISES DRAMATICALLY WITH AGE. BOTH FEMALES AND MALES ARE SIMILAR IN TERMS OF THEIR LEVELS OF COMORBIDITIES IN GROUPINGS AND THE CHALLENGE IS LOOKING AT THEM IN A MEANINGFUL WAY AND WHAT COMBINATION CAN INFLUENCE OUTCOMES. YOU CAN SEE IT'S VERY COMPLEX. WE'VE LOOKED AT HOSPITALIZATIONS AFTER TRAUMATIC BRAIN INJURY AS YOU CAN SEE FOR MALES AND FEMALES AFTER BY THREE YEARS THERE WAS OVER 50% REHOSPITALIZATION RATE AND THAT RISES DRAMATICALLY WITH OLDER ADULTHOOD AND WE STRATIFIED BY SEX. THE MOST COMMON REASON FOR HOSPITALIZATION WERE DUE TO DISEASES WITHIN THE ICD CHAPTER AND HEADINGS OF CIRCULATORY SYSTEM AND WITH URINARY TRACT INFECTIONS AND WE LOOKED AT THE COMORBIDITY TRAUMATIC INJURIES AND WE RECENTLY PUBLISHED A PAPER LOOKING AT THE CLINICAL PROFILE AND COMORBIDITY AMONG OLDER AND YOUNGER MEN AND WOMEN. AND SO CIRCULATORY SYSTEM WAS THE MOST COMMON FOLLOWED ENDO ENDOCRINE SYSTEMS AND I WANT TO HIGHLIGHT ONE OF THE MOST STATISTICALLY SIGNIFICANT DIFFERENCES BETWEEN MALES AND FEMALES IN TERMS OF CO COMORBIDITIES WAS IN OSTEOPOROSIS AND ARTHRITIS AND THERE WERE COMORBIDITIES ASSOCIATED WITH MENTAL HEALTH. THOSE CONDITIONS WERE THINGS LIKE DEPRESSION, ANXIETY AND I KNOW THAT OTHER AUTHORS IN THE U.S. FOUND IT MORE COMMON IN OLDER WOMEN USING LARGE DATA SETS AS WELL. WE LOOK AT OLDER ADULTS AND WE LOOKED AT HOW MUCH CHANGE THERE UNDER 65 IN TERMS OF ADMISSION - AND DISCHARGE SCORE. WHAT WE FOUND IS THAT EVEN THOUGH OLDER ADULTS STARTED AT A LOWER SCORE THEY MADE SIMILAR GAINS IN PATIENT REHABILITATION. WE SAW NO SIGNIFICANT DIFFERENCE IN FEMALES AND MALES IN THIS CHANGE AND DR. GRAEME HAS ALSO PUBLISHED SIMILAR FINDINGS. THE BOTTOM LINE IS IN TERMS OF WORSE OUTCOMES A KEY MESSAGE IS THAT OLDER ADULTS CAN MAKE SIGNIFICANT GAINS IN REHABILITATION AND SHOULD BE OFFERED THESE SERVICES. JUST SWITCHING GEARS, A BIT, I HAVE DONE WORK ON INJURED WORKERS AND THE DEFINITION OF AN OLDER WORKER IS AGE 45. IT'S A MORE MATURE POPULATION WE'VE BEEN LOOKING AT AND ESPECIALLY WOMEN ARE SIGNIFICANTLY OLDER IN THIS INJURED POPULATION THEN MEN. THIS IS A FACT SHEET ON TRAUMATIC BRAIN INJURY WE PREPARED FOR THE CANADIAN CENTER OF OCCUPATIONAL SAFETY THAT IS SHARED CLOSE TO 1 MILLION TIMES AND WE HAVE A CONCUSSION VIDEO ON OUR WEBSITE THAT ADDRESSES WITH A FEMALE PROTAGONIST. I GUESS SOW WITH HAVE NUMEROUS PAPERS WITH RESPECT TO INJURED WORKERS WITH MILD TO MODERATE PERSISTENT SYSTEMS AFTER BRAIN INJURY. WE HEARD EXCELLENT DATA ON PAIN-SPECIFIC MECHANISMS FOR MALES AND FEMALES. WHAT WAS INTERESTING IS WHEN WE MODELS MALES AND FEMALES SEPARATELY, MORE OF THE VARIANCE WAS EXPLAINED THEN WHEN WE HAD BOTH MALES AND FEMALES. LIKE 36% WITH BOTH MALES AND FEMALES AND FOR MALES IT WENT UP TO 60% AND 46% FOR WOMEN. JUST AND YOU YOU RARELY SEE SEX-SPECIFIC MODELS SO WE LIKE TO SEE THAT IN OUR LAB. I WANT TO SAY BEING INVOLVED IN THE GUIDELINE FOR CONCUSSION AND MILD TRAUMATIC BRAIN INJURY IT'S BEEN REALLY DIFFICULT TO TRY TO INTEGRATE MORE SEX AND GENDER SPECIFIC INFORMATION WITH THE GUIDELINES BECAUSE THERE'S NOT A LOT OF DATA OUT THERE TO DO THAT. I GUESS THIS IS WHAT WE'RE ALL HERE WITHIN THE NEXT COUPLE DAYS TO ADDRESS. NOW, I'VE DONE WORK ON MENSTRUAL CYCLES IN TERMS OF MORE PRE-MENOPAUSAL WOMEN. WE MUST EXTEND OUR RESEARCH TO KNOWLEDGE AND TRANSFER AND HAVE THIS BROCHURE TO ADDRESS SPECIFIC ISSUES AROUND WOMEN AND BRAIN INJURY BASED ON OUR RESEARCH. I LEAD AN INTERNATIONAL TASK FORCE ON GIRLS AND WOMEN WITH BRAIN INJURY WHICH EVOLVED FROM OUR INITIAL MEETING IN MONTREAL WHICH WAS DONE IN COLLABORATION WITH THE AMERICAN FOUNDATION OF MEDICINE AND IT WAS AT THE MEETING I WANT TO RECOGNIZE DR. MARILYN S MARILYN SPEVAK WHO SAID WE MUST HAVE A TASK FORCE ON THIS. ONE OF THE PRODUCTS OF OUR TASK FORCE IS THIS SPECIAL ISSUE IN THE ARCHIVES OF PHYSICAL MEDICINE AND IT'S FREELY AVAILABLE AND IS A RESOURCE. AND I HAVE THE GLOBAL ACTION PLAN WITH A GOAL TO STRENGTHEN DISABILITY DATA AND RESEARCH AND IS DATA STRATIFIED BY AGE AND SEX. THE EFFECTS MAY NOT BE LINEAR OVER TIME. SO I ALSO WANT TO RECOGNIZE THE CANADIAN HEALTH RESEARCH AND SHARE THERE'S NUMEROUS RESOURCES ON THEIR WEBSITE AND THE OFFICE OF RESEARCH AND WOMEN'S HEALTH IN TERMS OF SEX AND GENDER, ANALYSIS RESOURCES AND FINALLY I WANT TO THANK THE ORGANIZERS AND FOR THE AMAZING ADVOCACY ON THE TOPIC. THIS IS NOT THE WORK OF ONE PERSON BUT OF MANY MANY DEDICATED TRAINEES AND COLLABORATE AND WOMEN WITH EXPERIENCE WHO HAVE MENTORED US AND I WANT TO SAY THE INTERNATIONAL BRAIN INJURY ASSOCIATION CONFERENCE IS IN TORONTO IN 2019 SO PLEASE COME VISIT US. >> HI, KATHERINE ZENEKER HERE. THANK YOU FOR THE PRESENTATIONS. IT'S AWESOME. THE ONE SLIDE ON THE CEREBRAL BLOOD FLOW IN THE PEDIATRIC SLIDES WAS THAT FEMALE OR MALE CHILDREN OR BOTH COMBINED? >> I THINK YOU WERE TALKING ABOUT THE BLOOD FLOW DIFFERENCES ACROSS AGES. THAT WAS BOTH. THE ACTUAL FIGURE WAS ONE OF THE OTHER GRAPHS WAS THE VELOCITY AND ARTERY BLOOD FLOW AND SHE COMBINED BOTH FOR THE GRAPH. >> DO YOU KNOW IF THERE'S DIFFERENCES BETWEEN MALE AND FEMALE AT THAT AGE? >> I DON'T BELIEVE THERE WERE DRAMATIC DIFFERENCES THERE BUT LIKE I STATED, HER WORK SHE HAS ONE PUBLICATION ON THIS BUT ONLY HAD A HANDFUL OF FEMALES AND LOOKED AT BLOOD FLOW REGULATION AND IT WAS PREDOMINANTLY MALE AND FEELS THERE WERE SOME DIFFERENCES BUT I DON'T KNOW IF SHE'S BEEN ABLE TO QUANTIFY THAT. >> NTHANK YOU. >> SURE. >> HELLO. I HAD A COUPLE QUESTIONS AND ONE DOES TRANSPORT PLAY A ROLE IN THE OUTCOME OF YOUR RESULTS. WHETHER THE PATIENT HAD MORE PRESSURE ON THEIR BRAIN VERSUS BEING AMBULANCE. DID YOU LOOK AT THAT WITH ANY OF YOUR CONCUSSED BRAIN DAMAGED PATIENTS? >> MINE WAS PEDIATRIC FOCUSSED. SOME WORK WAS BEING DONE LOOKING AT THE HYPOBARIC EXPOSURE WITH SHOCK AND THERE'S CONFLUENCE OF THAT BUT I CAN'TCYTE CITE CITE THE NUMBERS BUT THE EARLY EVACUATION MODELLED IN THE LAB HAS INFLUENCE ON OUTCOMES. >> OKAY. AND THE SECOND QUESTION I HAD WAS WITH EVERY STUDY YOU GUYS DID, THE THREE DIFFERENT ONES EVERY ONE BROUGHT UP THE FACT OF WOMEN HAVING DEPRESSION AFTERWARDS. I KNOW FROM SELF-EXPERIENCE BECAUSE I HAD A TBI THEY WERE PUSHING ANTI-DEPRESSANTS AND LATER ON GOING THROUGH THE V.A., GOING THROUGH THE REHAB PROGRAM OF SPEECH AND NEUROPSYCHOLOGY, MEETING WITH THE TBI DOCTORS CHANGED THINGS FOR ME VERSUS THE DEPRESSION. SO ARE THE STUDIES THAT YOU'VE DONE DO YOU TAKE IN ACCOUNT THESE ARE GIRLS WHO HAVE NOT HAD FOLLOW UP AFTER TBI OR WOULD IT BE AFFECTED BY WOMEN AND GIRLS AND MOSTLY ADOLESCENT ONES GOING THROUGH THE TBI GOING THROUGH LIKE I WENT THROUGH AN 11-MONTH POST TBI POLY-TRAUMA PROGRAM. >> YOU'RE RIGHT, DEPRESSION IS VERY COMMON BUT I REALLY CAN'T COMMENT ON THE TREATMENT EFFECTS. I KNOW WHAT COMES UP OVER AND OVER AGAIN IS A LOT OF WOMEN FEEL DISMISSED SOMETIMES WHEN THEY'RE REPORTING THEIR SYMPTOMS. BUT SOME LITERATURE SHOWS THE SYMPTOMS ARE PROTRACTED FOR WOMEN AND GIRLS. >> SO NOT REALLY KNOWING HAD THEY GONE THROUGH POST CONCUSSION TREATMENT -- >> IF I CAN JUST COMMENT, MOST OF THE DATA WILL BE ON POPULATION BASE. THAT'S SOMETHING THAT SHOULD BE BROUGHT UP IN TERMS OF FUTURE DIRECTION. IF YOU DON'T MIND, WE ONLY HAVE A FEW MORE MINUTES. >> IT WAS JUST THE TWO. SORRY >> THANK YOU. YES. >> GOOD MORNING. FOR THE THREE PRESENTERS FROM THIS FIRST PANEL, ONE OF THE THINGS THAT CAME UP PRETTY CONSISTENTLY WAS FOCUSSED ON SEX DIFFERENCES AND HOW MEN AND WOMEN EXPERIENCE THESE THINGS AND THE HEAD INJURIES DIFFERENTLY. ONE OF THE THINGS I WAS WONDERING IS WITHIN YOUR WORK AND YOUR RESEARCH AND JUST SOME OF THE REVIEWS OF LITERATURE YOU'VE DONE, WHEN WE TALK ABOUT THE DIFFERENCES AND WE ACKNOWLEDGE THEM FOR WHAT THEY ARE, HAVE EITHER OF YOU ALSO CONSIDERED THE MEDICAL BIAS THAT IS IN SOME CASES PRETTY CLEAR WHEN PEOPLE ARE REPORTING THE DIFFERENCES IN MEN AND WOMEN AND THE WAY THEY EXPERIENCE HEAD INJURY. >> CAN YOU DEFINE MEDICAL BIAS. >> ONE OF THE EXAMPLES I TEND TO GIVE MY STUDENTS A LOT IS THE WAY THAT FOR EXAMPLE MEN REPORT CONCUSSION AND WOMEN COMPLAIN ABOUT IT. ONE THING I OFTEN THINK ABOUT WHEN WE CONSIDER THE ANATOMICAL DIFFERENCES AND OTHERWISE EXPERIENCED BETWEEN THE TWO POPULATIONS, ONE OF THE THINGS I LIKE TO STEP BACK AND THINK ABOUT IS HOW IS THIS INFORMATION BEING PRESENTED. AND WHILE THERE ARE ANATOMICAL DIFFERENCES BETWEEN MEN AND WOMEN, I THINK OFTEN WE CONJURE UP IMAGES OF MALE ATHLETES BEING BIG, STRONG FOOTBALL PLAYER TYPES AND FEMALE ATHLETES AS SLENDER AND DELICATE AND PARTICIPATE IN SPORTS THEY'RE SOCIALLY PUSHED INTO AND LESS AGGRESSIVE ETCETERA. . AS WE THINK ABOUT THE DIFFERENCES EXPERIENCED IN HEAD INJURY, I'M WONDERING IF SORT OF ANY OF YOU THAT PRESENTED ARE READING BETWEEN THE LINES IN TERMS OF THE WAY SOME OF THESE DIFFERENCES ARE TALKED ABOUT IN THE LITERATURE. I KNOW THERE'S A SCALE LOOKING AT GENDER IN TERMS OF GENDER NORMS AND GIRLS RELATE MORE TO MALE GENDER NORMS MAY BE MORE WILLING OR PLAY THROUGH SYMPTOMS MORE. I DON'T KNOW IF IT'S MALES OR FEMALES ALONG GENDER LINES. THERE'S STUDIES LOOKING AT THAT AND IT'S MORE SOCIALLY ACCEPTABLE FOR WOMEN TO REPORT THEIR SYMPTOMS. >> THAT'S WHAT I WAS THINKING WHEN WE WERE TALKING ABOUT THE DIFFERENCES. I THINK THE WAY WE CAN START TO POSITION SOME OF THERE INFORMATION I THINK ALSO MATTERS. JUST IN TERMS OF THE WAY MASCULINITY AND FEMININITY ARE EMBODIED THROUGH A MALE OR FEMALE PARTICIPANTS. >> IT'S BEEN ADVOCATED WE LOOK AT BIOLOGICAL SEX AND SOME RESEARCH HAS SHOWN WITH RESPECT TO CARDIOVASCULAR DISEASE THE DIFFERENCE. >> THANK YOU. >> WE HAVE TIME FOR ONE LAST QUESTION. >> THIS IS FOR DR. ROBERTSON INITIALLY. DR. McCARTHY TALKED WITH THE DIFFERENCES AT THE BIOLOGICAL LEVEL YET YOU CAN'T TAKE PROBABLY ANY ONE OF THEM AND DIFFERENTIATE A MALE FROM FEMALE AND YOUR RESEARCH SHOWS THESE BEAUTIFUL DIFFERENCES IN TERMS OF POTENTIAL INTERVENTIONS, I WAS WONDERING FROM A CLINICIAN'S POINT OF VIEW, IF YOU HAD THOUGHTS HOW YOU'D EVEN BEGIN TO GET AT WHO WE SHOULD GIVE WHAT MEDICATION TO UNDER THESE CIRCUMSTANCES. >> I THINK IT'S PROBABLY EARLY TO MAKE ANY OF THOSE KINDS OF INFERENCES. I'M CERTAINLY BIASSED TOWARDS FURTHER INVESTIGATION IN THE PRECLINICAL ENVIRONMENT AND TRYING TO PARSE THAT OUT. I THINK DR. McCARTHY'S SPEECH ON MULTIPLE CELLS AND THERE'S AN AGE DEPENDENCE EVEN AMONG PEDIATRICS. COMPLEXITIES ARE WE NEED FURTHER STUDY AND I WOULD ADVOCATE TO START TO DO THAT IN THE LAB. WOULD YOU TREAT A TODDLER BOY THAN A TODDLER GIRL WITH TRAUMATIC BRAIN INJURY OR AND WE NEED MORE INVESTIGATION IN THE LABS AND THE SUBTLE TYPE AND WE SEE MICROGLIAL AFFECTS IN MODELS TOO. >> THIS CLOSES OUT THE FIRST PANEL. IF WE CAN THANK OUR THREE SPEAKERS. [APPLAUSE] >> I'M GOING TO TURN IT OVER TO THE CHAIR. >> THANK YOU, PATRICK. THE VOLUME HAS BEEN A LITTLE LOW SO WE'LL TRY TO TALK MORE. IF WE TALK TOO LOUD WE'LL LET PEOPLE KNOW. I'D LIKE TO INTRODUCE JACQUELINE CAMPBELL AND PROFESSOR AT JOHNS HOPKINS SCHOOL OF NURSING AND WILL PRESENT AN EVERY VIEW OF TBI IN ABUSED WOMEN AND TALK ABOUT REGULATION. >> GOOD MORNING. MY TOPIC IS GOING TO BE FAR MORE TRANSLATIONAL I REPRESENT A RESEARCH TEAM. WE HAVE A RECENT PUBLICATION OUT IN THE JOURNAL OF WOMEN'S HEALTH. DR. BREIDING COVERED THIS DATA. THIS IS FROM THE STUDY HE EXPLAINED IN TERMS OF INTIMATE PARTNER VIOLENCE. 27% OF WOMEN REPORT SEVERE PARTNER VIOLENCE WITH IMPACT OR PTSD COMPARED TO 12% OF MEN. USING THIS BROAD DEFINITION OF TBI, THIS IS WHERE I COME TO THE PLACE THAT WHEN YOU'RE DEALING WITH ABUSED WOMEN OR SEE AN ABUSED WOMEN IN FRONT OF YOU AND RESIDENT IN A DOMESTIC VIOLENCE SHELTER SHE'S LIKELY TO HAVE EXPERIENCED BOTH HEAD INJURIES AND STRANGULATION. WHEN WE LOOK BACK AT DR. BREIDING'S DATA IN TERMS OF THE MERSAGE OF -- PERCENTAGE OF WOMEN WHO EXPERIENCED THIS WE HAVE SIGNIFICANT PROPORTIONS. WHAT IS NOT REPRESENTED IS HOW MANY WOMEN EXPERIENCE BOTH. SO WHEN WE THINK ABOUT A TBI -- AND THIS IS A VERY BASIC KIND OF A SLIDE, BUT WHAT'S IMPORTANT HERE, OFTEN YOU SEE A WOMAN WITH A BLACK EYE OR FRACTURED ORBITAL AND AS TREATED AS JUST HAVING A BLACK EYE AND OFTEN NOT LOOKED UP FOR TBI -- WORKED UP FOR TBI ESPECIALLY FOR THESE REPEATED HEAD INJURIES SHE'S OFTEN INCURRED. WE OFTEN SEE WOMEN CLINICALLY AND IN PRIMARY CARE AND OTHER ASPECTS. WE KNOW WOMEN ARE VULNERABLE TO TBI BECAUSE OF THE INFLAMMATORY CYTOKINES. AND INCREASED VULNERABILITIES THROUGH DISRUPTION OF THE BLOOD BRAIN BARRIER. WE FIND THERE'S LOWER LEVELS OF NEUROPEPTIDES IN ABUSED WOMEN WITH PTSD THOUGH IT'S ALL ONE BRAIN AND WE TREAT PTSD VERY DIFFERENTLY MANY SYMPTOMS OVERLAP WITH TBI. THE OTHER THING THAT'S VERY IMPORTANT TO KEEP IN MIND IS THE REPETITIVE NATURE OF INTIMATE PARTNER VIOLENCE. MANY ABUSED WOMEN HAVE HAD MULTIPLE VIOLATE ATTACKS EVERY YEAR OVER MANY YEARS. REPETITIVE TBI IS PART OF THE ISSUE. WE FIND THESE LONG-TERM COGNITIVE SYMPTOMS IN ABUSED WOMEN. WE FIND THEY HAVE SIGNIFICANTLY MORE WOMEN CONCENTRATING AND FAINTING, DIZZY SPELLS THAN NON-ABUSED WOMEN. WE ALSO FIND STRANGULATION AND MEMORY PROBLEMS, DEPRESSION, HEADACHES, DIZZINESS AND LOSS OF SENSATION. WE FIND THIS WHEN THERE'S BEEN MULTIP MULTIPLE STRANGULATIONS. WE ALSO FIND WITH TBI FROM BLUNT-FORCE TRAUMA THE SAME SORTS OF SYMPTOMS MORE OFTEN IN ABUSED WOMEN BUT YET AGAIN THEY'RE OFTEN TIMES NOT WORKED UP FOR EITHER TBI OR POST CONCUSSION. SO STRANGULATION IS EXTERNAL PRESSURE TO THE NEXT AND IT DEPRESSES A PERSON OF OXYGEN. THIS MEN ARE MORE LIKELY TO STRANGLE THEIR PARTNERS IN FACT WOMEN HARDLY EVER STRANGLE THEIR PARTNERS AND DEATH CAN COME IN MINUTES. IT'S BEEN NOTED IT TAKES LESS PRESSURE THAN OPENING A CAN OF SODA TO OCCLUDE OXYGEN AND IT'S OFTEN A FOREARM AGAINST THE THROAT AGAINST THE WALL UNTIL THEY SLUMP TO THE GROUND UNCONSCIOUS AND WE SEE MORE AND MORE THE CHOKE HOLD BEING TAUGHT IN EVERY MART MARTIAL ARTS CLASS. AND WE HAVE 56% OF ABUSED WOMEN WE DID THE ONES ALMOST KILLED OR KILLED BY THEIR PARTNERS WERE MORE LIKELY TO EXPERIENCED PRIOR STRANGULATION. E STRANGULATION INSTITUTE IS DOCUMENTING THE ISSUE IN TERMS OF HELPING OUR LAW ENFORCEMENT PROSECUTE FOR STRANGULATION AND DOCUMENTING THE LONG-TERM HEALTH EFFECTS BUT THE INCREASED REPORTS OF PHYSICAL LONG TERM IS YET UNDER STUDIED. OUR STUDY WAS DONE IN THE U.S. VIRGIN ISLANDS IN THE UNITED STATES AND RECRUITED WOMEN 18-25 AND HAD CASES FOR WOMEN WHO WERE ABUSED AND/OR SEXUAL AND ABOVE A PSYCHOLOGICAL THRESHOLD AND CONTROLS FOR NEVER ABUSED BY ANYONE. WE RECRUITED UP PRIMARY CARE CLINIC AND OUR PRESSURE OF TBI WAS RELATIVELY CRUDE. WE ASKED IN THE PAST YEAR HOW MANY TIMES HAD YOU HAD A BROKEN DISLOCATED JAW, HIGH OR HEAD INJURY WITH DAMAGE TO THE, FACIAL INJURIES, BLACK EYES, BLOODY NOSES AND DENTAL INJURIES. WE ALSO ASKED IN THE PAST 12 MONTHS HAS YOUR PARTNER EVER CHOKED YOU BECAUSE WOMEN DO NOT RESPOND TO STRANGULATION BUT WILL SAY THEY WERE CHOKED AND WE LOOKED AT SYMPTOM, DIZZY SPELLS, MEMORY LOSS, DIFFICULTY CONCENTRATING, HEADACHES, SEIZURES, RINGING OR VISION PROBLEMS. WE FOUND SIGNIFICANTLY MORE OF THE HEAD INJURIES WITH ABUSED WOMEN THAN WITH CONTROLS. WE FOUND MORE IN THE SYMPTOMS THAN WITH CONTROLLED AND WE LOOKED AT THOSE WITH HEAD INJURY THAN CONSCIOUS SYMPTOMS AND WE SAW MORE FREQUENCY OF THE SYMPTOMS. WHEN WE COMBINED THOSE WITH HEAD INJURY AND OR STRANGULATION WE SAW THE SIGNIFICANT DIFFERENCE WITH THOSE WITH HISTORY OF TBI OR NO TBI AMONGST THE ABUSED WOMEN. AND WHEN WE LOOKED AT WOMEN WHO WERE CHOKED BY A PARTNER AT LEAST ONCE 8% SAID THEY HAD SOME SORT OF A HEAD INJURY AND 6% HEAD INJURY PLUS LOSS OF CONSCIOUSNESS. WHEN WE LOOKED AT THE PAST YEAR CENTRAL NERVOUS SYSTEM SYMPTOMS WE FOUND A SIGNIFICANT DIFFERENCE BETWEEN THOSE WHO REPORTED A TBI AMONG THE ABUSED WOMEN AND THOSE WHO HAD NOT. ALSO WE FOUND MORE CASES THAN CONTROLS. WHEN WE LOOKED AT IT IN CONJUNCTION WITH PTSD AND TBI IT WAS STILL A SIGNIFICANT PREDICTOR OF THE CENTRAL NERVOUS SYSTEM SYMPTOM FREQUENCY SI SCORE. WE MEASURED IN TERMS OF HOW MANY WOMEN REPORTED BEING BLACKE OUT BY BEING HIT ON THE HEAD. THESE ARE WHEN POLICE HAD BEEN CALLED TO THE HOME BECAUSE OF DOMESTIC VIOLENCE. 20% HAD BEEN BLACKED OUT FROM BEING HIT IN THE HEAD IN THEIR LIFE TIME AND 4.4% IN SEVEN MONTHS IN THE FOLLOW-UP PERIOD THEY LOST CONSCIOUSNESS DUE TO STRANGULATION AND 23.8% SAID THEY LOST CONSCIOUSNESS. 2.6% IN A SEVEN-MONTH FOLLOW-UP PERIOD. THE NEXT ONE LOST CONSCIOUSNESS DUE TO INJURIES. MANY PEOPLE DON'T KNOW EXACTLY WHAT YOU'RE TALKING ABOUT AND THINK YOU LOST CONSCIOUSNESS OR TOTALLY WIDE AWAKE AND THERE'S A SPECTRUM IN BETWEEN. WHEN WE LOOKED LONG-TERM THERE WAS A HIGHER RISK OF BEING NEARLY KILLED OR SEVERELY INJUR INJURED AFTERWAD OR HIGHER RISK OF MISCARRIAGE. WE ALSO FOUND WOMEN STRANGLED WERE MORE LIKELY TO SEEK MEDICAL CARE THEN THOSE ABUSED BUT NOT STRANGLED AND SO IN TERMS OF FUTURE RESEARCH NEEDS, EVEN WITH THESE CRUDE MEASURES AND WE LUMPED TOGETHER JUST AS WE WERE TOLD IN THE ONSET WAS A TERRIBLE THING TO DO BUT WE DID, THERE ARE STILL IMPORTANT CLINICAL FINDINGS. WE LUMPED IT TOGETHER BECAUSE IT'S ALL ONE WOMAN. ABUSED WOMEN ARE NOT EVEN USUALLY WORKED UP FOR CONCUSSIONS LET ALONE TBIs WHEN THEY PRESENT TO THE EMERGENCY DEPARTMENT BECAUSE OFTEN FACIAL INJURIES NO ONE EVEN FINDS OUT THEY WERE HIT AGAINST THE WALL WHEN THE ORBITAL WAS FRACTURED AND RECEIVED A TBI FROM THE BACK OF THEIR HEAD. OFTEN THEY SAY I FELL. I WAS NOTICING THE DATA, WHEN JUDY FOLLOWED UP ON WOMEN WITH A COMPLAINT OF FALLING THAT'S WHAT THEY SAID THEY GOT THE INJURY FROM AND A SIGNIFICANT PROPORTION OF WOMEN HAD BEEN HIT BY A PARTNER. THAT'S WHAT THEY SAID BECAUSE THEY THOUGHT THAT WAS LESS STIGMATIZING. ABUSED WOMEN FREQUENTLY ARE DESCRIBED AS HAVING DIFFICULT PRIORITIZING. OFTEN THE ATTRIBUTIONS TO THE ABUSED WOMEN AND DIFFICULTIES PROBLEM SOLVING ARE ASCRIBED TO MENTAL HEALTH PROBLEMS OR INTELLIGENCE DEFICITS RATHER THAN ANYBODY FINDING OUT WHAT'S REALLY BEHIND THAT. AND THE WOMEN THEMSELVES ARE CONFUSED WITH THEIR SYMPTOMS. SOME SAY GO TO A THERAPIST AND OTHERS SAY IT'S ALL IN YOUR HEAD AND OTHERS SAY DON'T GET ABUSED ANY MORE. THOUGH THERE'S DIFFERENT MECHANISMS WE NEED TO LOOK AT BOTH AND SORT OUT THE EFFECTS. THE INTERPLAY OF PHYSIOLOGICAL AND PSYCHOLOGICAL MECHANISMS IS IMPORTANT TO UNDERSTAND AND HELP WOMEN UNDERSTAND SO THEY KNOW WHAT THEY CAN DO ABOUT IT. WE HAVE TO DO A STUDY AND DO THAT CLINICAL TRANSLATIONAL RESEARCH NOW. THERE'S TOO MANY WOMEN WHO NEED OUR HELP AND NEED RESULTS IN EASY TO UNDERSTAND NOT JUST WHITE PAPERS FOR OUR RESEARCH COMMUNITY BUT EASY TO UNDERSTAND FACT SHEETS FOR DOMESTIC VIOLENCE SERVICE ORGANIZATIONS AND IT'S IMPORTANT ACROSS OUR DISCIPLINES. THANK YOU. >> THANK YOU, JACQUELINE. I'D NOW LIKE TO INTRODUCE EVE VALERA. [AUDIO DIFFICULTIES] >> THANKS SO MUCH FOR BEING HERE TODAY AND WHAT I'M GOING TO TALK ABOUT IS NEUROPSYCHOLOGICAL ITB RELATED TBI. FIRST I'D LIKE TO GIVE YOU AN IDEA OF WHAT HAPPENS IN PARTNER VIOLENCE BECAUSE SOMETIMES PEOPLE DON'T GET IT UNTIL THEY SEE THIS. WOMEN IN PARTNER VIOLENCE SITUATIONS ARE PUNCHED IN THE HEADS WITH FIST AND HIT IN THE HEADS WITH BATS. THEY HAVE THEIR HEADS SLAMMED AGAINST WALLS AND DOORS AND FLOORS AND THEY HAVE THEIR HEADS STOMPED ON LITERALLY WITH THINGS LIKE WORK BOOTS OR HIT IN THE HEAD WITH HAMMERS. THEY'RE THROWN DOWN STAIRS AND OFF PORCHES. THEY'RE VIOLENTLY SHAKEN AND STRANGLED OFTEN TIMES INTO UNCONSCIOUSNESS. THIS IS NOT LIKE IT HAPPENS ONCE AND IT'S OVER AND DONE. FOR WOMEN THIS IS A PATTERN OF BEHAVIOR THEY'VE BEENIEN BEEN ENDURING FOR A LONG TIME AND THE RESULT FROM TBIs IS MORE THAN THEY CAN COUNT AND 80% OF INJURIES ARE FROM THE NECK AND HIGHER. THAT SAID MOST OF THE WOMEN TALK ABOUT HAVE NOT BEEN SEEN IN A HOSPITAL FOR THE TRAUMATIC BRAIN INJURY THEY'VE SUSTAINED. THESE WOMEN HAVE THESE HORRIBE THINGS HAPPEN TO THEIR HEAD AND WOMEN WHO ARE IN PHYSICALLY ABUSIVE SITUATION HAVE PHYSICAL PROBLEMS SUCH AS MIGRAINES, PSYCHOLOGICAL PROBLEMS SUCH AS DEPRESSION, ANXIETY AND COGNITIVE PROBLEMS DIFFICULTY CONCENTRATING AND ANYBODY WITH TBI WOULD SAY IT COULD BE TBI RELATED THOUGH BEFORE I STARTED DOING THE RESEARCH OF COURSE THERE'S DIFFICULTIY WITH DEPRESSION AND REMEMBERING BECAUSE THEY'RE IN A PARTNER ABUSIVE SITUATION THAT'S STRESSFUL. AT THE TIME THERE WAS NO INTER INTERVIEWS FOR WOMEN AND I HAD QUESTION TO DETERMINE WHETHER ABLE ALTERATION IN CONSCIOUSNESS HAD OCCURRED SO AFTER ANYTHING YOUR PARTNER EVER DID DO YOU DID YOU EVER BLACK OUT. DID YOU EVER FEEL STUNNED OR DAZED OR CONFUSED SO I ASKED IN A SYSTEMATIC WAY AND ACCORDING TO TBI DEFINITION. AND I ASKED FOLLOW-UP QUESTIONS TO GET TO THE NUMBER AND SEVERITY AND THE RECENCY BECAUSE ALL THESE THINGS FACTOR INTO HOW YOU MAY BE DOING AND CREATED A BRAIN INJURY SCORE. I INTERVIEWED 99 WOMEN AND THIS IS SHELTER AND NON-SHELTERED WOMEN. IT'S NOT A NATIONWIDE PREVALENCE STUDY BUT I FOUND THREE-QUARTERS OF THE WOMEN REPORTED AT LEAST ONE TRAUMATIC BRAIN INJURY. WHAT'S FRIGHTENING AND OVER HALF REPORTED REPETITIVE TRAUMATIC BRAIN INJURY. SOME WERE TOO MANY TO COUNT. WHILE HE WOULD HIT MY HEAD WHEN HE WALKED BY ME INTO THE WALL BECAUSE HE WAS HAVING A BAD DAY, A COUPLE TIMES A DAY FOR YEARS. AND YOU ASK WHY DON'T THEY LEAVE? WOMEN ARE THREATENED TO BE CUT INTO LITTLE PIECES AT TIME IF THEY LEAVE THESE RELATIONSHIP. AND THE MOST LIKELY TIME FOR A WOMEN TO BE KILLED IS WHEN SHE LEAVES OR AFTER SHE'S LEFT SO IT'S A THREAT TO HER STAYING IN THIS WORLD IN TERMS OF JUST LEAVING. THEN I WANT TO SEE IF IT WAS ASSOCIATED WITH COGNITIVE MEASURES. I SEE THAT THEY ARE. I SHOW A RELATIONSHIP BETWEEN THE BRAIN INJURY SCORE IN TERMS OF MEMORY AND LEARNING AND COGNITIVE FLEXIBILITY AND IT'S NOT JUST BEING ACCOUNTED FOR BEING IN A PHYSICALLY ABUSIVE RELATIONSHIP. IT'S NOT BEING ACCOUNTED FOR BY BEING ANXIOUS OR HAVING PTSD. THIS IS RELATED TO HAVING TRAUMATIC BRAIN INJURIES. IF YOU LOOK AT IT THE OTHER WAY AROUND, PARTNER USE SEVERITY IS ASSOCIATED WITH THESE BUT NOT AS MUCH AS AS THE TRAUMATIC BRAIN INJURY AND WE LOOKED AT PATHOLOGY. IT WAS ASSOCIATED ACROSS THE BOARD WITH DEPRESSION, PTSD SYMPTOMS VARY AND WHEN YOU TAKE OUT THE VARIANCE ASSOCIATE WITH BEING IN A PARTNER ABUSIVE SITUATION WE STILL SEE THOSE AS EFFECTS REMAINING STRONG. IN CONTRAST, IF YOU LOOK AT PARTNER USE SEVERITY IT SHOWED VARIABLES BUT WHEN YOU TAKE OUT THE ASSOCIATION OF A TRAUMATIC ABUSE INJURY THE EFFECTS GO AWAY I'LL SHOW YOU THE ONLY ONE OF THESE STUDIES I KNOW OUT THERE AND WE PUBLISHED IT A COUPLE YEARS AGO BUT BASICALLY IN THE INTEREST OF TIME WE DECIDED TO INVESTIGATE USING IMAGES AND RESTING STATE DATA. SO WOMEN DON'T HAVE TO DO ANYTHING NICE BUT IT'S WHAT IT'S DOING AT RISK. WE LOOKED AT TWO NETWORKS IN THE BRAIN THE DEFAULT AND SALIENCE NETWORK WE KNOW HAVE TO HAVE A GOOD REASONABLE INTERACTION FOR YOU TO HAVE COGNITIVE FLUENCY AND THIS IS IMPORTANT AND THAT DRIVES THAT INTERACTION. SO WE SAID, WELL, LET'S SEE IF IT'S ASSOCIATED WITH THE DEGREE TO WHICH THING COMMUNITIES. THIS IS BASED ON LITERATURE FROM OTHER STAM PALS. WHAT WE FOUND WAS THE MORE THEY HAD THE MORE POSITIVELY THEY COMMUNICATED WITH ONE ANOTHER. INITIALLY, THE LESS THE TWO BRAIN REGIONS COMMUNITY, THE WORSE WOMEN WERE ABLE TO LEARN A LIST OF WORDS AND REMEMBER THE WORDS 20 MINUTES LATER. SO NOT ONLY WILL YOU HAVE A FINDING HERE IN TERMS OF FUNCTIONAL IMAGING BUT IT HAS A REAL LIFE IMPLICATION AND THAT IF YOU REALLY HAVE THIS YOU'RE NOT AS ABLE AS QUOTE, UNQUOTE, NORMAL PEOPLE TO DO AND REMEMBER ON A DAILY BASIS. WHAT'S VERY IMPORTANT -- I CAN'T EMPHASIZE THIS ENOUGH IN TERMS OF THIS DATA, PEOPLE THINK IT'S HARD TO DO THE BECAUSE THERE'S NO WAY YOU'LL GET EVERYTHING DONE AND THIS CAN ACCOUNT FOR WHAT WE SEE AND THERE'S CHILD ABUSE AND STRESS AND POST TRAUMATIC STRESS DISORDERS AND WE CONTROLLED FOR AGE, HEAD MOTION, PARTNER ABUSE SEVERITY AND CHILD ABUSE, DEPRESSION AND ANXIETY WITH THE SYMPTOM QUESTIONNAIRE AND PTSD SYMPTOMATOLOGY AND THAT WAS STILL SHOWING A NEGATIVE RELATIONSHIP BETWEEN THE NUMBER OF BRAIN INJURIES AND THE AMOUNT OF INTERACTION THEY WERE HAVING. AND WE EXCLUDED THOSE TAKING PSYCHO TROPEIC MEDICATIONS. THOUGH THEY'RE POTENTIAL CONFOUNDS WE ADDRESSED AS MANY THINGS WE COULD THINK OF AND THE EFFECTS REMAIN SO THIS IS A ROBUST FINDING. IN THE OTHER STUDY WE'RE ABOUT TO PUT OUT, WE LOOKED AT STRUCTURAL CONNECTIVITY. WE LOOKED AT A MEASURE OF THE FIBER TRACKS AND SELECTED REGIONS THAT HAVE LONG FIBERS GOING THROUGH THEM. THE SUPERIOR AND POSTERIOR LOCATIONS AND IN LOOKING AT REPETITIVE INJURIES IN FOOTBALL PLAYERS WE SPECIFICALLY SELECTED THESE REGIONS TO LOOK AT WOMEN AS WELL. SO AS IN PREVIOUS STUDIES WE LOOKED AT WHETHER THE WHITE MATTER DIFFUSION IN THE RADIATA WE SAW THE MEASURE OF LEARNING AND THIS IS THE MEASURE OF MEMORY AND WE SEE THEY'RE POSITIVELY ASSOCIATED WITH THE RAID IAT RADIATA BUT THE CORRELATION VALUES ARE ABOVE THREE .35, .36. I THINK IT'S PROBABLY SOMETHING THERE BUT WE HAVE A SMALL SAMPLE. WE NEED TO DO MORE RESEARCH IN THE DATA. THESE ARE THE ONLY STUDIES LOOKING AT IT RELATED TBI. IN SUMMARY, A LARGE PERCENTAGE OF WOMEN SUSTAINING TBI ARE SUSTAINING REPETITIVE HEAD INJURIES AND HAVING A HIGHER NUMBER OF PARTNER-RELATED INJURIES IS RELATE TO POORER COG COGNIZANCE AND REDUCED CAPACITY TO REDUCE IN CROSS-NETWORK INTERACTIONS, THE LESS CONNECTIVITY FOR EFFICIENT COGNITIVE PERFORMANCE AND THE DEGREE OF NETWORK CONNECTIVITY AND WHITE MATTER DIFFUSION IS WHERE WE HAD THE NOT SIGNIFICANT CORRELATION IS RELATED TO LEARNING ABILITIES. WHAT DO WE KNOW? THERE'S THE ACUTE MANAGEMENT OF TBI. FEW OF THE WOMEN EVER GO TO AN EMERGENCY ROOM OR SEEK TREATMENT FOR TBIs. IN FACT, I CAN'T REMEMBER A SINGLE WOMEN WHO TOLD ME SHE WENT TO THE E.R. BECAUSE SHE SUSTAINED A MILD BRAIN INJURY AND WANTED TO GET IT CHECKED OUT. THERE'S NO MANAGEMENT OF THESE. THAT WILL BE A NEGATIVE IN THE MANAGEMENT CATEGORY. PREVIOUS CONCUSSION, AT LEAST HALF THE WOMEN SUSTAINED REPETITIVE BRAIN INJURIES AND OF THE OFTEN LENGTHY RECOVERY TIME. THEY OFTEN HAVE BROKEN ARMS, PUNCTURED LUNGS, FRACTURED ORBITALS AND EARS SMASHED IN. THEY HAVE OTHER BODILY INJURIES THAT WOULD AGAIN REDUCE THE RECOVERY -- LENGTHEN THE RECOVERY TIME. PSYCHOLOGICAL FACTORS SUCH AS DISTRESS INCREASES RECOVERY TIME AND THESE WOMEN ARE ENDURING INTENSE PSYCHOLOGICAL DISTRESS ON AN ABSOLUTELY BASIS. GENERAL LIFE STRESS. YOU HAVE A WOMAN NOT ONLY TRYING TO DEAL WITH THIS HORRIBLE SITUATION WHERE SHE FEELS SHE'S QUOTE, UNQUOTE IN A WAR ZONE EVERY DAY AND GETTING HER KIDS TO SCHOOL AND GET TO WORK AND EVERYTHING SHE HAS TO DO AND IS BEING IMPEDED LIKELY BY HER ABILITY TO DO THINGS AS WELL AS SHE WOULD WITHOUT THE TRAUMATIC BRAIN INJURY AND SEX. AS LITERATURE HAS SHOWN WOMEN TENT TO HAVE EXTENDED RECOVERY TIMES. BASICALLY IF YOU LOOK AT THIS, IT TELLS ME THAT MOST OF THE DATA WE HAVE RIGHT NOW THAT ARE STUDYING TRAUMATIC BRAIN INJURIES ARE ON MEN. WE KNOW VERY LITTLE ON WOMEN IN THIS POPULATION. THE TAKE-HOME POINT MORE DATA IS DESPERATE DESPERATELY NEEDED. IT HIGHLIGHT THE CRITICAL NATURAL AND IT SHOWS WE CAN DO THE WORK. PARTNER-ABUSED WOMEN ARE A UNIQUE GROUP OF TBI SUFFERERS. WE CANNOT JUST TAKE WHAT WE KNOW ABOUT ATHLETE WHO'S ARE GENERALLY HEALTHIER OR MILITARY AND APPLY IT TO THESE WOMEN. YET, AT THE SAME TIME WE NEED TO APPLY THE SAME BEST APPROACHES AND OUTCOMES MEASURES THAT HAVE SHOWN FRUITFUL IN OTHER POPULATION. SINCE WE DON'T HAVE MUCH TO START WITH, WE CAN DRAW FROM THAT LITERATURE, USE THE VARIABLES AND MEASURES AS BEST WE CAN, MODIFY THEM APPROPRIATELY AND TRY TO INTEGRATE THIS CRITICAL PIECE OF THE PUZZLE THAT'S MISSING INTO THE OTHER HUGE LITERATURE. START WITH HYPOTHESES AND EXPLORE THESE IS WHAT JACKIE DID WHAT THE STUDY WHERE THEY WEREN'T EXPECTING TO FIND THIS IN THE BEGINNING AND THEY WENT BACK AND SAID WHAT CAN WE FIND THAT LOOKS LIKE TBI OR SYMPTOMS RELATED TO IT. WOMEN ARE KILLED EVERY DAY BY THEIR PARTNERS. THIS WORK IS NEEDED AND IT'S NEEDED NOW. THANK YOU. THAT'S AN INCREDIBLE PRESENTATION, THANK YOU. OUR NEXT SPEAKER IS JESSICA GILL. SHE'S A REASONABLE SCHOLAR AND HER RESEARCH FOCUSES ON BIOMARKERS. >> THANK YOU SO MUCH. IT'S GREAT TO BE HERE TODAY TO HAVE AN OPPORTUNITY TO TALK A LITTLE BIT ABOUT SOME OF THE BIOMARKER WORK WE DO IN OUR LAB. I'LL TALK ABOUT OUR STUDIES ON CIVILIANS AND ATHLETE AND THOSE WITH MULTIPLE CONCUSSIONS AND HEAD INJURIES AND LAY THE PLATFORM HOW TO DO THE WORK MOVING FORWARD UP INDIVIDUALS WITH INTIMATE PARTNER VIOLENCE AND OFTEN SUSTAIN INJURIES. WE LOOK AT BIOMARKERS AT ANYTHING FROM GENETIC PREDISPOSITION AND LOOK AT THE PROTEINS FOLLOWING A BRAIN INJURY. WE DO THIS BECAUSE WE RECOGNIZE THAT INDIVIDUAL HAVE CUMULATIVE LIFE STRESSORS AND IMPACT AND IT'S ONLY THROUGH LOOKING THE THE COMPLEX MECHANISMS WE CAN UNDERSTAND WHY SOME INDIVIDUALS WILL GO ON TO HAVE LASTING NEUROLOGICAL SYMPTOMS AND OTHER INDIVIDUALS WHO OFTEN HAVE SIMILAR INJURIES WILL RECOVER JUST FINE. SO THE FOCUS OF OUR WORK IS TO LOOK AT THE MECHANISMS TO IDENTIFY PATHWAY MAY BE DISRELATED AND THEN IDENTIFY AND FURTHER CHARACTERIZE AND MODULATE THE ACTIVE AND IMPROVE RECOVERY ACUTELY AND CHRONICALLY. ONE OF THE PROTEINS WE LOOK AT IS THAT OF TAU. BUT WE KNOW NOW IS THAT MANY ATHLETES WHO SUSTAIN MULTIPLE BRAIN INJURIES AS WELL AS CONCUSSIONS IN CONCUSSIVE HITS GO ON TO DEVELOP CTE. THIS IS NOT UNIVERSALLY XPERIENCED. MANY WILL HAVE HEAD HITS AND GO ON TO RECOVER AND NOT HAVE THE SYMPTOMS IN DEFICITS. THIS LEADS US TO QUESTION AND HOW TO MODIFY THOSE RISKS SO WE'RE NOT SEEING INDIVIDUALS IN THEIR 40s AND 50s DEVELOPING DEMENTIA LIKE MEDICATIONS AND WE'RE FINDING AGGREGATION IN TAU SIMILAR TO ALZHEIMER'S DISEASE. IT LEADS US TO QUESTION WHEN WE SEE WOMEN WITH MULL PAL BRAIN INJURIES OVER A LIFE TIME, IS THIG SOMETHING THAT MAY BE PRESENT IN THEM ALSO. THIS IS EXTENDING WHAT WE PURSUE IN ATHLETES TO UNDERSTAND ACCUMULATIVE HEAD INJURIES AND WE CAN LOOK TO MAKE THEM ASYMPTOMATIC AND WE SEE WOMEN COME CLINIC AND THE SYMPTOMS AND DEFICITS THEY DESCRIBE ARE ZEV DEVASTATING. THEY HAVE A MAJOR IMPACT ON THEIR QUALITY OF LIFE. MANY ARE NOW OUTSIDE OF AN ABUSIVE RELATIONSHIP BUT EVERY DAY THEY SUFFER FROM LASTING COGNITION AND MEMORY AND MOOD PROBLEMS AND SO WE NEED TO BE ABLE TO UNDERSTAND THIS AT EARLY AGES. WE FOCUS A LOT ON TAU. IT'S A PROTEIN THAT'S LONG BEEN A PROTEIN WE KNOW CAN BE DAMAGED AND GOES INTO CEREBRAL SPINAL FLUID INTO BLOOD AND WHERE WE CAN DETECT IT IT MAY MAKE SOME INDIVIDUALS MORE AT RISK TO HAVE LASTING SYMPTOMS AND DEFICITS. WE DO THIS USE TECHNOLOGY THAT ALLOWS US MEASURE TAU IT'S LIKE GRAINS OF SAND IN AN OLYMPIC SIZE SWIMMING POOL BUT HAVING FIVE GRAINS IS DIFFERENT THAN 50 GRAINS AND WE NEED TO LOOK AT SUBTLE CHANGES IN BLOOD TO SEE HOW SOME INDIVIDUALS ARE RECOVERING AND MAKE AN INDIVIDUALIZED RECOVERY PLAN FOR INDIVIDUALS. IN ONE OF OUR FIRST STUDIES WE LOOKED AT INDIVIDUALS WHO DEPLOYED TO AFGHANISTAN AND HAD AT LEAST ONE DEPLOYMENT. MANY WERE YEARS FROM THEIR INJURY BUT WE FOUND TAU REMAIN ELEVATED AND ALSO INDIVIDUAL WHO'S HAD MORE THAN THREE TBIs HAD SIGNIFICANT ELEVATIONS OF TOU COMPARED TO THOSE WITH ONLY ONE TBI. WE'RE SEEING A CUMULATIVE IMPACT OF THE HEAD INJURIES. WE ALSO REPLICATED THIS RECENTLY IN A COHORT OF MILITARY COHORT. THESE WERE IN THEIR 20s AND 30s. SO THESE LEVELS OF TAU WERE ELEVATED FOR WHAT WE WOULD EXPECT IN THESE INDIVIDUALS. WE'RE NOT SEEING -- MOST ARE STILL ACTIVE DUTY AND WALKING AROUND AND HAVE ELEVATED LEVELS OF TAU WHICH MAY BE SIGNALLING SOMETHING BUT NOT SHOWING THEY HAVE MAJOR DEFICITS YET AND NOT MAJOR ELEVATED TAU ORGANIZATIONS AND THE INDIVIDUALS IF THEY HAD A BLAST EXPOSURE AND THIS COULD BE A TRAINING-RELATED TAU THEY ALSO HAD ELEVATIONS OF TAU IN THEIR PERIPHERAL BLOOD. RECENTLY, WE PARTNERS WITH WALTER REED TO LOOK AT BLAST EXPOSURE AND THAT HAT PARALLELS WHEN WE TALKED ABOUT STRANGULATION AND BLAST EXPOSURE RESULTED IN OVERALL DAMAGE TO THE BRAIN THAT'S NOT LOCALLY SPECIFIC. SO INDIVIDUALS HAD A CHANGE IN ACTIVITY ACROSS THE BRAIN WHICH IS SIMILAR TO WHAT WE SEE WHEN A BRAIN IS DEPRIVED OF OXYGEN IN A SITUATION OF STRANGULATION. IF WE CAN APPROXIMATE THE BLAST EXPOSURE SO WE'RE ABLE TO GET BLOOD AT BASELINE PRIOR TO EXPOSURE AND LOOK AT CHANGES EACH DAY AND RELATE THEM BACK TO THE EXPOSURE THE INDIVIDUAL HAD. WE LOOKED AT BIOMARKERS I'LL SHOW TODAY BUT WHAT WE DID IS PAIRED -- BECAUSE ONE SIDE THERE WAS A BLAST EXPOSURE OVER FIVE PSI TO GIVE YOU AN IDEA WHAT THAT IS, ANYTHING OVER 7PSI A PERSON CAN HAVE BURST EAR DRUMS SO THIS IS A MODERATE TO HIGH EXPOSURE LEVEL. THESE ARE THE CHANGES IN PROTEINS. THESE ARE THE EXACT WRONG DIRECTION OF WHAT WE SEE IN CIVILIAN COHORTS. WE SEE REDUCTION IN TAU AND ON THE DAY OF THE BLAST AS WELL AS THE NEXT DAY. WE LOOK AT IMPAIRED CLEARANCE AND IF WE GET THEM ABROGATING THEY CAN RESULT THE FORMATION OF THE PLAQUES AND THE TAU GOES UP SUGGESTING EVEN ONE BLAST EXPOSURE IS SUBJECTING THERE MAY BE SOME NEURODEGENERATIVE PATHOLOGY WITH THE ONE BLAST EXPOSURE. WE CAN LOOK AT THESE PROTEINS AND IT ALLOWS US TO THINGS SHAPING RECOVERY. CONCUSSIONS ALSO MIRROR SYMPTOMS IN WE SEE IN WOMEN. WE FOCUS ON RETURN TO PLAY AND THE STUDIES I'LL PRESENT TODAY. WHAT WE KNOW IS IF YOU HAVE A BRAIN INJURY OR CONCUSSION AND YOU GO BACK TO PLAY AND HAVE ANOTHER ONE YOU'RE AT THE HIGHEST RISK TO HAVE A LONG-LASTING RECOVERY AND HAVE LONG-LASTING SYMPTOMS. THIS PARALLEL IS IPV BECAUSE WE SEE THE VIOLENCE IN WHICH WOMEN HAVE REPEATED INJURIES AND NOT NECESSARILY HAVE THE RECOVERY TIME NECESSARY FOR THE INDIVIDUAL TO HAVE FULL NEURONNAL RESOLUTION. SO IN THIS WE REPORTED OUR FINDINGS BUT WE ALSO HAVE GENDER-RELATED FINDINGS WE HELD BACK A LITTLE BIT. WE COMPARED THEM TO NORMAL ATHLETES WITH RETURN TO PLAY DEPENDING ON THE NCAA GUIDELINES. WHAT WE FOUND WAS INTERESTING WAS WOMEN OVERLY MADE UP THE LONGER TERM TO PLAY 61% AND THE OTHER GROUP WAS SMALLER. WHEN WE LOOKED AT OBJECTIVE MEASURES OF COGNITION AND BALANCE THE WOMEN WERE FINE. THEY DIDN'T HAVE DIFFERENCES COMPARED TO MALES WITHIN THE PROLONGED RETURN TO PLAY AND LONGER RETURN TO PLAY AND WOMEN WERE MORE LIKELY TO REPORT SYMPTOMS LEADING TO US QUESTION WE SAW IF THERE'S AN ELEVATION OF TAU IN PERIPHERAL BLOOD THAT PERSON IS MORE LIKELY TO HAVE A PROLONGED RETURN TO PLAY. AND THIS GROUP IS WOMEN. AND WE DID A RECENT CIVILIANS COMING INTO A LEVEL 2 TRAUMA CENTER. I THESE COME INTO LEVEL 2 TRAUMA CENTERS AND HAVE SCALES OF 13 TO 15. THESE ARE MORE MILD PATIENTS THAT WON'T GO TO TRAUMA SERVICE. AS YOU CAN SEE WE HAVE A GROUP OF INDIVIDUALS WHO HAVE AN MRI OR CT FINDING AND A CT NEGATIVE GROUP. WHAT'S INTERESTING WITHIN THIS, IT'S NOT TECHNICALLY SIGNIFICANT BUT WE DO SEE THERE TENDS TO BE MORE EVIDENCE OF WOMEN WHO HAVE THIS AND WHEN WE LOOKED AT RECOVERY SAW A DIFFERENCE IN GENDER AND THIS IS SOMETHING WE'RE SEEING IN OUR LAB AND I WANT TO TALK ABOUT THE DIRECTION WE'RE TAKING THIS. WE SEE A DIFFERENCE IN RECOVERY RATES FOR MEN AND WOMEN. WE SEE WOMEN MORE LIKELY TO REPORT SYMPTOMS ON THE NEURAL SYSTEM INVENTORY AND COMPARED TO MEN WITH SIMILAR DEMOGRAPHICS AND TYPES OF INJURIES AND SEVERITY OF INJURIES. THE MOST COMMON INJURIES ARE SLEEP DISORDERS, ANXIETY AND HE HEADACHES. AND WE FOUND THERE WERE NO DIFFERENT AT BASELINE IN THE FOUR BIOMARKERS INCLUDING TAU, AND WE DID FIND IS WHEN WE LOOKED AT RECOVERY, WE FOUND BIOMARKERS DID PREDICT RECOVERY AND THERE WERE DIFFERENCES IN THE GFAP AND HE HAD MATE THE FINDING NO LONGER SIGNIFICANT WHEN WE CONTROLLED FOR GENDER. THIS IS WHAT WE'RE LOOKING AT TO SEE OU THE BIOMARKERS MAY BE INFLUENCING THE GENDER-RELATED CHANGES. PUTTING TOGETHER THE FINDINGS WE FIND EVIDENCE TO MOVE FORWARD WITH MEMBERS ON THE PANEL AS WELL AS OTHERS TO ADDRESS THIS ISSUE AND LOOK AT BIOMARKERS IN THE ACUTE PERIOD AND CHRONIC. WE AND GFAP RELATE TO IMAGING AND IN THE INDIVIDUALS WITH MULTIPLE INJURIES EITHER DURING SPORTS OR OTHER INJURIES, THEY CAN HAVE HIGHER LEVELS OF TAU EVEN YEARS FOLLOWING THE INJURIES. SUGGESTING IN SOME INDIVIDUALS THERE MAY BE A NEURODEGENERATIVE PROCESS AND WE CAN USE THE BLOOD-BASED BIOMARKERS TO UNDERSTAND THIS AND IDENTIFY THE INDIVIDUALS AT RISK THAT CAN PREVENT THAT AND IDENTIFY THERAPEUTIC TARGETS TO MODULATE AND IMPROVE RECOVERIES AND TAU ELEVATION RELATE TO RECOVERY SYMPTOMS AND HIGHER TAU IS PREDICTIVE IN RECOVERY IN SPORTS, CIVILIANS AND ATHLETE. SO WHEN WE PUT THIS TOGETHER, IT GIVES US AN IDEA IN DESIGNING THE STUDIES HOW CAN WE LOOK AT THESE IN THE MOST THOUGHTFUL WAY TO DO THE SCIENCE WHO HAVE HELPED WOMEN SUSTAINING MULTIPLE INJURIES DURING ABUSE. LOOKING AT BIOMARKERS AND HOW THEY'RE IMPACTED IN GENDER IS IMPORTANT. ARE WE LOOKING AT THE RIGHT BIOMARKERS. WE'VE BEEN FOCUSSED IN ON A SET AND THERE MAY BE AN IMPACTIVE GENDER AND FINDINGS ARE OUR LAB ARE LEADING US DOWN THAT DIRECTION. ALSO, WE TALKED ABOUT HOW WE LOOK AT THE CUMULATIVE IMPACT. MANY HAD INJURIES STARTING IN CHI CHILDHOOD. HOW CAN WE UNDERSTAND THE IMPACT AND PUT IT TOGETHER TO UNDERSTAND THE TIME FROM THE LAST INJURY AND MOST SEVERE INJURIES AND THINGS WOMEN MAY NOT UNDERSTAND ARE INJURIES, BEING KNOCKED INTO A DOOR OR SOMETHING TO THAT EFFECT. WE NEED TO UNDERSTAND THE MORE SUBTLE INJURIES WE SEE IN SPORTS AND MILITARY HAVING BIOLOGICAL UNDER PINNING SO MAKE THEM MORE AT RISK. HOW CAN WE PAIR THEM IN THE MILITARY TO SAY THIS IS THE OVERALL IMPACT AND THIS IS HER RISK FOR SYMPTOMS AND HOW CAN WE INTERVENE TO MODIFY THOSE RISK. CURRENTLY WE HAVE NO MEDICATIONS TO IMPROVE OR TREAT THE SYMPTOMS EVEN WHEN WE KNOW A WOMAN HAS BEEN ABUSED AND HAS A TBI AND WE NEED TO IDENTIFY THERAPEUTIC TARGETS TO MODULATE THEIR OUTCOMES AND LOOK AT MECHANISM TO PAIR THEM WITH THE WORK EVE IS DOING AND LOOKING AT NEUROIMAGING AND APPROXIMATE BLOOD-BAS BLOOD-BASED BIOMARKERS AND INTERVENE TO HELP WOMEN IMPROVE THEIR WELL BEING. THANK YOU. >> OUR FINAL PANELIST IS KATHERINE IVERSON AN ASSOCIATE PROFESSOR OF PSYCHOLOGY AT BOSTON UNIVERSITY. >> THANK YOU. IT'S SUCH AN HONOR AND PRIVILEGE TO SPEAK TO YOU AND THIS AMAZING GROUP OF WOMEN I LOOK UP TO SO MUCH. I APPRECIATE KATHERINE'S WORK. I'M TALKING ON A SPECIAL POPULATION TODAY, WOMEN VETERANS. WOMEN VET RAND ARE THE LARGEST GROUP OF POPULATIONS USING V.A. CARE AND MEETING THEIR NEEDS IS A HIGH PRIORITY. WE KNOW 10% OF WOMEN SCREEN POSITIVE FOR DEPLOYMENT RELATED TBI. WE'LL HEAR MORE ABOUT THAT TOMORROW ON OUR SPECIAL SESSION ON MILITARY POPULATION. THIS TALK'S GOING TO FOCUS ON IPV. WHAT'S IMPORTANT TO KNOW IS WOMEN EXPERIENCE MORE COMORBIDITIES IN THAT THEIR MALE COUNTERPARTS AND CIVILIAN WOMEN. WE'VE LOOKED AT THE ISSUE OF IPV YOUNG WOMEN VETERANS AND IT'S HAD A ROLE IN IMPACTING POLICY AND PRACTICE WITHIN THE VA. SOME WORK BY MELISSA DICHTER LOOK AT THEM OVER THEIR PEERS AND THE REF -- PREVALENCE OF WOMEN EXPERIENCING INTIMATE ABUSE HAS GONE UP. IT MEANS UPWARDS OF 90,000 OF THEM MAY HAVE EXPERIENCED PASS YEAR IPV. TODAY I'LL PRESENT ON A COUPLE STUDIES SPECIFICALLY ON WOMEN VETERANS. THE FIRST IS MALE SURVEY CONDUCTED WITHIN THE NEW ENGLAND REGION USING THE V.A. IN THE PAST YEAR AND WE WANTED TO IDENTIFY THE OCCURRENCE AND LOOK AT THE OHS BETWEEN IPV RELATED TBI AND PAST YEAR V.A. HEALTH CARE USE. SO WE LOOKED AT IPV RELATED TBI, SELF-REPORTEDLY. WE MODIFIED THE SCREENING TOOL WOMEN WERE TO HAVE EXPERIENCED A HEAD EVENT IF THEY ENDURED BEING STRANGLED OR HAVING THEIR HEAD BASHED AGAINST THE WALL OR PUNCHED IN THE FACE. NEXT, THEY WERE CONSIDERED TO MEET CRITERIA IF THEY ALSO REPORTED THE HEAD EVENT WAS ASSOCIATED WITH A LOSS OF CONSCIOUSNESS, ALTERNATIVE CONSCIOUSNESS AND WE LOOKED AT THE CHECKLIST AND FROM THE CENTER OF EPIDEMIOLOGICAL STUDIES AND WE ASSESSED MEDICAL AND MENTAL HEALTH CARE WITHIN THE V.A. YOU CAN SEE THE CHARACTERISTICS. A QUARTER HAD BEEN DEPLOYED AT LEAST ONCE IN THE WARS IN IRAQ AND AFGHANISTAN. WHAT WE FOUND IN THE GENERAL SAMPLE IS 90% MET SCREENING CRITERIA FOR TBI RELATED HISTORY. AN ADDITIONAL 14% EXPERIENCED AN IPV RELATED HEAD HAVEN'T BUT DIDN'T HAVE THE ALTERATIONS OR LOSS OF CONSCIOUSNESS, ETCETERA. THIS IS A PRETTY NUMBER CONSIDERING IT'S A PATIENT SAMPLE. IT'S NOT A SAMPLE OF WOMEN SEEKING HELP FOR IPV. HERE YOU SEE A FIGURE IN THE IPV RELATED TBI GROUP COMPARED TO WOMEN WHO SUSTAINED A HEAD HAVEN'T BUT DID NOT MEET CRITERIA FOR TBI TO GIVE YOU A SENSE OF THE ITEMS THEY'RE ENDORSING. WHAT STRUCK OUT TO ME WAS THE PROPORTION OF WOMEN WHO HAD REPORTED THEY HAD BEEN STRANGLED BY AN INTIMATE PARTNER AS WE KNOW FROM JACKIE CAMPBELL'S WORKS, IT'S ONE THING WE KNOW CAN PREDICT INTIMATE PARTNER HOMICIDE SO IT'S SERIOUS BUT MOST WOMEN EXPERIENCED MULTIPLE HEAD EVENTS AS WE HEARD FROM MANY SPEAKERS TODAY. AS YOU SEE ON THE LEFT FOR PTSD SYMPTOMS THE TBI HISTORY GROUP IS IN THE DARK BLUE BAR. WE FOUND THESE WOMEN HAD SIG SIGNIFICANTLY SEVERE SYMPTOMS AND WHAT THIS TELLS US IS THAT TBI MAY HAVE AN EFFECT AND BEYOND BEYOND EXPERIENCING ITB TO THE HEAD WHICH IS A SEVERE FORM WHICH IS PROBABLY IN THE CONTEXT OF CONTROLLING BEHAVIORS. WE ALSO FOUND IPV RELATED TBI HISTORY WAS ASSOCIATED WITH A GREATER OVERALL VOLUME OF PAST V.A. USE AND EMERGENCY ROOM AND MENTAL HEALTH CARE RECEIPT AND THEY REPORTED MORE PAST YEAR PHYSICAL AND SEXUAL ABUSE. IT TELLS ME THE E.R. AND MENTAL HEALTH IN PARTICULAR MAY BE IMPORTANT PLACES TO BE IDENTIFYING IPV AND PERHAPS DO FURTHER SCREEN FOR IPR-RELATED TBI SO APPROPRIATE RECOMMEND S S -- RECOMMEND S CAN -- RECOMMENDATIONS CAN BE MADE AND THE NEXT IS A REPRESENTATIVE SAMPLE. WE LOOKED AT WOMEN WITH CURRENT TBI SYMPTOMS AND WANTED TO LOOK AT ASSOCIATIONS WITH PROBABLE PTSD AND THE SYSTEM CLUSTERS FOR PTSD AND IPV-TBI RELATED STATUS. THERE COULD BE OVERLAP BUT IT COULD BE TBI IS DIFFERENTIALLY ASSOCIATED WITH DIFFERENT SYMPTOM CLUSTERS. AND WE PERSISTED TO THE LAST WEEK IF SO THE WOMEN WERE EXPERIENCED TO HAVE EXPERIENCED IPV-RELATED TBI WITH CURRENT SYMPTOMS. WE USE THE WELL VALIDATED PTSD CHECK HIS AS ARE THE SYSTEM CLUST. -- CLUSTER. SAMPLE CHARACTERISTICS ON THE LEFT. IN THE SAMPLE OF WOMEN VETERAN IPV SURVIVORS WE FOUND 28% MET SCREENING CRITERIA FOR IPV-RELATED TBI. 12.5% MET CRITERIA FOR IPV-RELATED TBI WITH CURRENT SYMPTOMS SUCH AS DIZZINESS OR DIFFICULTIES WITH BALANCE AND A QUARTER OF THE SAMPLE OVERALL HAD A PROBABLE DIAGNOSIS OF PTSD STEM FROM THE ABUSIVE RELATIONSHIP. WE FOUND SOME WOMEN WERE SIX TIMES MORE LIKELY TO HAVE PROBABLE PTSD THAN WOMEN WITH NO IPV-RELATED TBI HISTORY. AND DESPITE OVERLAP WITH PTSD AND IPV TBI WERE LIKELY TO MEET SYMPTO SYMPTOMS. AND IF THIS WAS AN OVERLAP YOU MAY HAVE EXPECT TO SEE DIFFERENCES AND THE INTRUSION AND THE AROUSAL SYMPTOMS. I FEEL FORTUNATE TO WORK IN THE V.A. WHERE WE HAVE ALSO OF PROGRAMS AND SERVICES TO LEVERAGE AND ADDRESS IN THE MAT MAT -- INTIMATE PARTNER VIOLENCE AND WE HAVE ELECTRONIC RECORDS THAT ARE ACCESSIBLE. IN FACT WE ARE USING THE EMRs TO ROLL OUT ROUTINE SCREENING TO ROLL OUT THOSE WHO HAVE EXPERIENCED INTERMAT PARTNER VIOLENCE. AND MANY NOW HAVE IPV COORDINATORS AND WE HAVE ONE IN THE AUDIENCE TODAY JULIA KAPLAN FROM LITTLE AND THEY PLAY A CRITICAL ROLE IN GETTING LOCAL PROGRAMMING ON THE GROUND, DOING TRAINING, DEVELOPING PROTOCOLS, RAISING AWARENESS OF THESE ISSUES AND MEETING WITH WOMEN TO UNDERSTAND WHEN THEY SCREEN POSITIVE WHAT THEIR HEALTH NEEDS ARE AND WHAT OTHER REFERRALS THEY WANT AND CONNECT WITH THE GREAT RESOURCES IN THE COMMUNITY. AND WE NEED TO BE STUDYING IN TERMS OF HOW IT CAN BENEFIT WOMEN WHO EXPERIENCED IPV-RELATED TBI AND WE HAVE MANY SERVICES AS WELL AS HOMELESSNESS SERVICES. THERE'S A NUMBER OF OUTREACH EFFORTS GOING ON IN THE V.A. TO EDUCATE CLINICIANS AND PROVIDERS ABOUT NOT JUST IPV BUT IT CAN RESULT IN TRAUMATIC BRAIN INJURY AND THERE MAY BE IMPLICATION FOR ADDRESSING THIS IN OTHER HEALTH CARE SYMPTOMS AS WELL. MANY ARE PROBABLY FAMILIAR WITH THE CONCUSSION COACH AND PTSD COACH. THESE ARE GREAT RESOURCES AND WE SHOULD EVALUATE THEY'RE CLEARLY LOOKING 59 THE TRAUMA. IN CLEARLY LOOKING AT THE SEXUAL TRAUMA AND IN THE MILITARY IT'S ANOTHER HIDDEN CONSEQUENCE AND MILITARY SEXUAL TRAUMA CAN ALSO CAUSE TRAUMATIC BRAIN INJURY. I HEARD OF WOMEN WAKING UP IN CONSCIOUS AND MISSING TEETH AFTER BEING BRUTALLY RAPED. THIS IS SOMETHING WE NEED TO PAY ATTENTION TO AND OWE IT TO OUR WOMEN VETERANS TO ASK ABOUT THIS. WE NEED BETTER TOOLS FOR IDENTIFYING IPV-RELATED TBI IF WE'RE GOING MORE IN THIS DIRECTION. THERE'S A TOOL THAT MAY HAVE UTILITY. IT NEEDS TON TESTED AGAINST OLD STANDARDS SUCH AS A COMPREHENSIVE TBI INTERVENTION AND WE NEED TO WOMEN AS WE TRY TO IMPLEMENT NEW PROCESS TO ENSURE WE'RE DOING IT IN A WAY THAT'S SAFE AND PATIENT CENTERED. >> IN CONCLUSION, WOMEN VETERANS ARE AT HIGH RISK AND IT'S OFTEN A HIDDEN CONSEQUENCE OF INTIMATE PARTNER VIOLENCE. AND WE SAW THE COMORBIDITY IS THE NORM AND CLINICIANS AND RESEARCHERS USE CAUTION WHEN ATTRIBUTING IT JUST TO PTSD. WE SAW THAT WOMEN AT LEAST IN THIS SAMPLE WERE USING MORE EMERGENCY ROOM AND MENTAL HEALTH CARE SO LET'S LOOK AT CLINICIAN AND TAKE ON ANOTHER SET OF SCREENING AND ASSESSMENT AND HOW CAN WE MAKE THE REFERRAL PROCESS POSSIBLE. WITHIN V.A. WE CAN FOLLOW WOMEN THROUGH THEIR COURSE OF IDENTIFICATION, REFERRALS, CONNECTION WITH THE COMMUNITY AND TRACKING THEM OVER TIME. I'D LOVE TO SEE THAT HAPPEN. AS HAS BEEN ALLUDED TO ALREADY, THERE'S BEEN SO MANY FOCUS ON CONCUSSIONS RESULTING FROM SPORT AND ON THE BATTLEFIELD AND WE HAVE TO REMEMBER THAT FOR WOMEN LIVING IN ABUSIVE ENVIRONMENTS, THERE'S NO PROTECTIVE FACTORS IN PLACE FOR THEM SO IT'S UP TO DO TO DO MORE RESEARCH AND CLINICAL WORK TO ADDRESS THIS UNDER SERVED ISSUE. THANK YOU. [APPLAUSE] >> I WANT TO THANK EVERYBODY FOR AMAZING TALKS AND OPEN IT UP TO THE AUDIENCE FOR QUESTIONS. YES ON THE FIRST MICROPHONE HERE. >> A REALLY INFORMATIVE SERIES OF TALKS AND FROM BIOMARKERS TO THE EPIDEMIOLOGY OF THIS SITUATION HAVE SPENT TIME FOCUSSING ON THE COMPONENT OF THIS IPV RELATE TO TBI, I WONDERED HOW DIFFERENT OR SIMILAR IS THIS IN THE COMPLEX SITUATION TO BIOMARKERS. I SEE HAVE THERE BEEN PATH YO PHYSIOLOGICAL COMPARISONS IN BIOMARKERS IN THOSE AREAS THAT SAY IS THIS SIMILAR OR UNIQUELY DIFFERENT FROM REPETITIVE TBI? >> WITH IMAGING THERE'S NO OTHER IMAGING STUDIES LOOKING AT THE RELATIONSHIP BETWEEN PARTNER-RELATED TBI AND ANY IMAGING FINDINGS OR ANYTHING LIKE THAT. EVEN THE COGNITIVE STUDIES THERE'S A HANDFUL DOING THAT IN A SYSTEMATIC WAY. WHAT JACKIE DID WAS SOMETHING WAS GREAT BECAUSE WE TOOK DATA WITHOUT THIS IN MIND AND SHE CAME UP WITH SUPPORT FOR THE IDEA THAT WOMEN ARE SUSTAINING TBIs AND SHOWING HIGHER RATES OF OTHER THINGS. PEOPLE IN TERM OF STUDYING WOMEN OTHER THAN SCREENING THEM IN A DB SHELTER OR SOMETHING LIKE THAT THERE'S VERY LITTLE DATA AT ALL TRYING TO MAKE A CONNECTION BETWEEN PARTNER-RELATED TBI AND IMAGING, COGNITIVE OR PSYCHOLOGICAL FUNCTIONING. THAT'S WHY WE NEED TO DO THE WORK. I DON'T KNOW IF YOU WANT TO SAY ANYTHING -- >> ABSOLUTELY. WE'VE DONE STUDIES IN BIOMARKERS AND WE HAVE DONE STUDIES IN TBI BUT NOT LOOKED AT THE CUMULATIVE IMPACT. THAT'S WHAT WE'RE TRYING TO DO IS CHALLENGE EVERYBODY'S BELIEFS ON THIS AND TACKLE THE COMPLEX PROBLEM AND IT TAKES BIGGER SAMPLE SIZES AND MIRRORS OTHER METHODS TO UNDERSTAND CUMULATIVE IMPACT OF BIOMARKERS AND THE DEFICITS INCLUDING NEUROIMAGING TO ADDRESS THIS AND IT WILL TAKE TIME TO DO THE RESEARCH BUT WE HOPE IN FIVE YEARS TO SAY YES, WE HAVE AN ANSWER FOR THAT QUESTION. >> IF YOU LOOK AT THE IMPACT ASSESSMENT YOU DON'T NECESSARILY SEE DIFFERENCES. THE OPEN ENDED QUESTION IS WHAT DO YOU THINK ABOUT THE DIFFERENCE BETWEEN MEN AND WOMEN IN THIS REGARD AND DO WE NEED TO DESIGN BETTER OBJECTIVE MEASURES THAN TO GET AT THIS IF THERE'S SOMETHING GOING ON THERE? >> THERE'S A GENDER EFFECT IN ALL INSTRUMENTS AND WE'RE NOW STARTING TO LOOK AT IT WITH TBI AND IPV IN GENERAL WOMEN TEND TO OVER REPORT AND WE SEE IT ACROSS DIFFERENT STUDIES AND LOOKING AT PTSD AND DEPRESSION AND THOSE STUDIES. IT'S SOMETHING WE NEED TO MAKE SURE WE'RE LOOKING AT WHEN WE LOOK AT THE STUDIES AND DESIGN FUTURE INVENTIONS. >> GREAT TALK ALL OF YOU. I'M FROM THE OFFICE OF RESEARCH AND DEVELOPMENT AT THE DEPARTMENT OF VETERANS AFFAIRS. UNFORTUNATELY THERE'S REPEAT ABUSE HAVE YOU SEEN AND JESSICA AND OTHERS CAN ANSWER, HAVE YOU SEEN IN BIOMARKERS ANYTHING WITH THE NEUROINFLAMMATORY MARKERS YOU SPOKE ABOUT TAU AND OTHER NEUROINFLAMMATION AND FROM YOUR GENERAL KNOWLEDGE, ARE WOMEN MORE LIKELY TO HAVE AUTOIMMUNE INJURY. >> YES, WOMEN HAVE A HIGHER RATES OF AUTOIMMUNE. MY DISSERTATION STUDY JACKIE WAS THE CHAIR AND MY ADVISER ON WE LOOKED AT ABUSE AND WOMEN WITH PTSD IN BALTIMORE AND WHEN WE STIMULATED THE BLOOD THE ELEVATIONS WERE HIGHER AND THERE WAS AN EFFECT OF DEPRESSION AND I'VE GONE ON TO LOOK AT TBI AND LOOK AT SIMILAR RELATIONSHIPS AND IT'S GOING ON TO BE SYSTEMATIC THAT RELATE TO THE HIGHER LEVEL OF IN FLAM -- INFLAMMATION. >> THAT WAS GOING TO BE MY FOLLOW-UP QUESTION. WE TEND TO SEE A HIGHER LEVEL OF INFLAMMATION AND WE SEE THAT WITH CARDIOVASCULAR OBESITY AND IT'S IMPORTANT TO SEE THAT AND INTERVENE. >> ONE OF THE THINGS I OFTEN THINK ABOUT IN THE REALM AND WE KNOW, UNFORTUNATELY, WOMEN WHO ARE ABUSED AS CHILDREN EITHER SEXUAL ASSAULT OR BY PARENTS ARE MORE LIKELY TO BE ABUSED BY ADULTS. IT'S A COMPLEX AND IT'S NOT JUST THEY CHOOSE ABUSIVE MEN BUT PART IS THINKING, IF YOU HAVE SHAKEN BABY AND HAVE LIVED THROUGH IT, IF YOU HAVE CHILD ABUSE WHAT'S THAT DO TO THE CHILDHOOD BRAIN IN MAKING AN EFFECT ON IMMUNE SYSTEM ON OTHER PARTS OF THE BODY. SO IT IS COMPLEX THAT'S THAT'S WHAT WE'RE HOPING TO SORT OUT BETTER. >> NEXT QUESTION, PLEASE. >> YOUR LAST COMMENT DOVETAILS TO THE QUESTION I WAS GOING TO ASK. AS A PEDIATRIC ICU PHYSICIAN I SEE INFLICTED HEAD INJURY IN CHILDREN IN TERMS OF LATE PRESENTATIONATIN PRESENTATIONATION -- PRESENTATION TO CARE AND FOR WOMEN WHO GET DELAYED LIKE WITH CHILDREN WITH HEAD INJURY HAVE HIGHER PREVALENCE OF SEIZURES AND IN THE EMERGENCY ROOM, FOR EXAMPLE, WE SEE CHILDREN WIN VOMITING AND SYMPTOMS THAT ARE MISSED PERHAPS WOMEN WITH FIRST-TIME SEIZURES CAN HAVE A HIDDEN TBI. >> ABOUT WHAT I FIRST STARTED OUT AT WAS LACKING AT THE 99 WOMEN AND THEN IN LOOKING AT THE COGNITIVE FUNCTIONING I PARED IT DOWN BECAUSE I WANTED TO MAKE A & MORE CLEAN STAM -- SAMPLE. SOME WOMEN EXCLUDED WERE THOSE WITH SEIZURES AND THERE WERE MORE THAN I WOUL HAVE -- WOULD HAVE EXPECTED IN A SAMPLE OF 99. I'D BE SURPRISED OF THE EFFECTS OF WHAT'S GOING ON. >> WE SAW A LOW PREVALENCE WHETHER IT START WITH IPV, NOT CLEAR, BUT ENOUGH TO SAY WE HAVE TO LOOK AT THAT. WE HAVE TO THINK ABOUT THAT. . . >> IN REGARDS TO YOUR DATA I WAS WONDERING IF THERE'S FINDINGS OR ORAL -- CORRELATIONS WITH THEENING NIS TI OF THE ETHNICITY OF THE WOMEN OR BACKGROUND AND NEUROLOGICAL FINDINGS AND SO ON. >> THAT'S A GREAT QUESTION. THERE ARE VERY FEW STUDIES AND GETTING THAT NUMBER OF SUBJECTS WAS QUITE A FEET. THERES WITH A FAIR PERCENTAGE OF AFRICAN AMERICAN WOMEN AND WHITE WOMEN AND THEN SMALLER NUMBERS OF EVERYTHING ELSE. IT WOULD BE VERY DIFFICULT TO LOOK AT THAT. THE THING IS THIS IS WHAT WE'RE ALL DOING UP HERE IS TRYING TO SAY WE NEED TO DO MORE RESEARCH TO ANSWER SOME OF THE QUESTION. WE'VE DONE SOME OF THE ONLY STUDIES LOOKING AT IPV RELATED TBI OUT THERE. THERE'S LITERALLY A HANDFUL AND I STARTED DOING THIS OVER 20 YEARS AGO AND HAD TO DO OTHER WORK BECAUSE THAT'S WHAT I WAS GRANT FUNDING TO DO. IT'S NOT EASY TO DO THE GRANT FUNDING FOR THIS AND I DID THE STUDY BY THE SEAT OF MY PANTS AFTER AN IMAGING STUDY FROM HARVARD AND WE NEED IT MIRACULOUS BUT WE NEED FUNDING TO DO THE WORK AND ANSWER THOSE QUESTIONS. WHAT'S SHOCKING IS THE NUMBER OF WOMEN SUSTAINING THE INJURIES FAR EXCEED THE NUMBER OF MEN IN THE MILITARY OR NFL WHO ARE SUSTAINING BRAIN INJURIES YET THERE'S MILLIONS GOING TO THAT AND TONS OF RESEARCHING EXAMINING ALL THOSE QUESTIONS AND WE'RE ARE SOME OF THE ONLY PEOPLE THERE ARE A FEW OTHERS BUT THE WORK IS DESPERATELY NEEDED. >> WE DO THE LAST SAMPLE I REPORTED ON IS ALL AMERICAN AMERICAN BUT WE FOUND SIMILAR DIFFERENCES WITH WHITE SAMPLES AND PRIOR RESEARCH IN TERMS OF THE CHRONIC NEUROLOGICAL SYMPTOMS. WE DIDN'T DO THE KIND OF TBI RELATED PIECE OF IT. THERE'S AN INDICATION THERE'S A PROBLEM CROSS GROUPS BUT NOT ENOUGH WORK TO FIGURE THAT OUT. THE OTHER THING I WANT TO POINT OUT IS IN OUR COUNTRY, WE'RE CONSIDERING A RELATIVELY SAFE COUNTRY FOR WOMEN SO THE PREVALENCE IS 18% TO 66% AND WE'RE CLOSE TO 20%. SO THERE'S SOME AREAS OF THIS WORLD AND A LOT OF PLACE WHERE'S PARTNER VIOLENCE ISN'T EVEN CONSIDERED A CRIME. THIS IS AN INTERNATIONAL EP EPIDEM EPIDEMIC AND MANY POPULATIONS ARE SUFFERING MORE THAN WHITE WOMEN OR AFRICAN AMERICAN WOMEN. I DON'T KNOW -- I DON'T -- I CAN'T GIVE PROOF BUT I WOULD BET MY LIFE ON IT, LET'S JUST PUT IT THAT WAY. >> I'M EDISON WONG FROM THE MILITARY RESEARCH CENTER AND YOUR PRESENTATIONS LEADS TO ONE ADDITIONAL QUESTION I WANT YOUR THOUGHTS ON. AND I'D LIKE TO HEAR YOUR THOUGHTS ON CTE FOR WOMEN. >> WE ARE IN TOUCH WITH WOMEN IN EARLY PHASE AND INCREDIBLY DEMENTED WITH WELL DOCUMENTED HISTORY OF ABUSE WITH HEAD INJURIES. THAT'S WHAT WE LOOK TO TO HEAD THAT OFF AND THAT'S WHAT WE'RE MOST CONCERNED WITH. >> IN AGING, WOMEN TEND TO OUTNUMBER MEN AND IT MAY BE A SEQUELA AND AND MY GUESS IS THAT THERE IS SOMETHING AKIN TO CTE THAT OCCURS AS A RESULT OF THIS AND WE NEED TO HAVE THE FUNDING TO DO THE STUDIES THAT WILL ALLOW US TO GET BRAIN BANKS IN THE ANALYSES BEING DONE WITH THE FOOTBALL PLAYERS. >> IT'S IN THE JUST DOCUMENTING AND SAYING THIS IS WHAT IS SIMILAR TO WHAT FOOTBALL PLAYERS ARE SUFFERING FROM BUT WE CAN MODIFY THE RISK TO APPROVE THINGS. I GET E-MAILS TWICE A DAY FROM WOMEN WHO SAY I'VE GOT CTE, I'VE BEEN ABUSED MY WHOLE LIFE, THIS IS MY STORY. WE DON'T WANT TO JUST DOCUMENT THAT BUT WANT TO DO RESEARCH THAT HELPS AND MOVES THINGS FORWARD. THAT'S WHY WE'RE ALL HERE TODAY TO DISCUSS HOW TO DO THAT BEST. >> THANK YOU. CAN WE HAVE THE SLIDE THAT WE HAVE ON THE PODIUM UP ON THE SCREEN? CATHERINE AND I ARE INCREDIBLY EXCITE TO THE ANNOUNCE A NEW PARTNERSHIP BETWEEN THE U.S. DEPARTMENT OF VETERANS AFFAIRS NATIONAL CENTER FOR POSTTRAUMATIC STRESS DISORDER AND PAIN CONCUSSION >> I'M HONORED TO REPRESENT DR. MATTHEW FREEDMAN WHO ESTABLISHED AND DIRECTED THE U.S. DEPARTMENT OF VETERANS AFFAIRS NATIONAL UNDER THE FOR POST-TRAUMATIC STRESS DISORDERS AN ESTABLISHED AND STILL DISTRICTS THE NATIONAL PTSD BRAIN BANK. OUR COLLEAGUE DR. CAROLYN CLANCY IN CHARGE FOR THE VETERANS HEALTH INFORMATION, HAS STATED QUOTE, IN THE PAST, THE FOCUS OF TBI AND PTSD BRAIN RESEARCH HAS BEEN PRIMARILY BASED ON MALE BRAINS WITHOUT ACTIVE RECRUITMENT FOR WOMEN TO PLEDGE THEIR BRAINS AFTER LIFE. >> THAT'S BEEN A SHORTAGE OF POST-MORTEM BRAIN TISSUE. TODAY NEUROPATHOLOGICAL STUDIES HAVE BEEN ON MEN BUT NOT WOMEN AND THERE'S A LACK OF RESEARCH ON TE IN WOMEN. THOUGH THE ISSUE DONATION MAY OCCUR MANY YEARS OR DECADES FROM NOW, IT IS ESSENTIAL FOR WOMEN TO TAKE THE PLEDGE NOW AND BEGIN TO PARTICIPATE IN THIS BRAIN BANK STUDY. THIS WILL ALLOW RESEARCHERS TO LEARN AS MUCH AS POSSIBLE ABOUT THE HEALTH AND EACH ENROLLED FEMALE PARTICIPANT AND HOW HER HEALTH CAN CHANGE OVER THE YEARS AS HE STUDY CONTINUES. WE'D LIKE TO POST INFORMATION UP THERE AND WE POST EVERYBODY FOR PARTICIPATING TODAY. JOIN US FOR THE OPTIONAL LUNCH AND LEARN ACROSS THE HALLWAY WHICH PROVIDES A NICE LUNCH BOX, BEVERAGE AND LOVELY CUPCAKE AND WE HAVE SIX AMAZING WOMEN THAT WOULD LIKE TO SHARE BITS OF THEIR STORY WITH YOU SO THANK YOU FOR YOUR ATTENTION THIS MORNING AND THANK YOU FOR YOUR THE ORGANIZERS AND NIH AND WE'RE ALL HAPPY YOU'RE HERE. THANK YOU. [APPLAUSE] WE'RE GOING TO GET STARTED WITH SESSION 3, WHICH IS ABOUT THE TRANSLATIONAL CHALLENGES IN TBI AND IT'S GOING TO BE MODERATED BY DR. JEREMY BROWN FROM NINDS -- NIGMS. I NEVER KNOW WHICH ONE. >> GOOD AFTERNOON, EVERYONE. WELCOME BACK AFTER LUNCH. AS MANY OF YOU KNOW, THERE WAS A LITTLE BIT OF A ELECTRONIC CATASTROPHE IN ATLANTA AND TWO OUR PRESENTERS WERE NOT ABLE TO MAKE IT IN PERSON BUT THROUGH THE WONDERS OF TECHNOLOGY WE HOPE THEY WILL BE ABLE TO TAKE PART TO PRESENT AND ALSO TO ADDRESS YOUR QUESTIONS. SO WE'LL START THE SESSION WITH DR. DAVID WRIGHT, PROFESSOR OF MEDICINE EMORY AND DIRECTOR OF THE EMERGENCY NEUROSCIENCES SECTION, HE WAS ALSO THE PI OF THE NIH SPONSORED PROTECT TRIAL WHICH LOOKED AT PROGESTERONE FOR ACUTE TBI. DR. WRIGHT, WE ARE SEEING YOUR SCREEN. GO AHEAD. >> CAN YOU HEAR ME, JEREMY? >> YES, WE CAN. >> COULD YOU JUST STAND UP AT THE PODIUM AND SMILE AND LOOK GOOD BECAUSE I'M SURE IT'S BORING FOR PEOPLE HERE WITHOUT SOMEBODY STANDING THERE. SO FIRST OF ALL I WANT TO APOLOGIZE THAT WE'RE NOT THERE, DON AND I, WE'RE REALLY TRYING. IT WAS A STUNNING EVENT TO WITNESS BUSIEST AIRPORT IN THE NATION COMPLETELY, COMPLETELY SHUT DOWN. THERE WAS NO LIGHTS, THERE WERE HORDES, HUNDREDS OF THOUSANDS OF PEOPLE TRYING TO FIND DIRECTION. PROBABLY APPROPRIATELY SO, THE DELTA FOLKS WERE GONE, THEY WERE HIDING, I'M SURE SOMEWHERE. BECAUSE YOU COULD NOT FIND ANYBODY ANYWHERE. ANYWAY, WE ARE THERE IN SPIRIT AND HOPEFULLY WE'LL HAVE SOME GOOD INFORMATION TO CONTRIBUTE. I THINK I WAS ASKED TO PRESENT BECAUSE OF THE PROGESTERONE TBI TRIAL OBVIOUSLY AND FORGIVE ME, DON, I'M GOING TO STEAL SOME OF YOUR THUNDER, IS BASED ON SEX DIFFERENCES THAT WERE NOTED IN ANIMALS. SO THIS IS AN INCREDIBLY RELEVANT TRANSLATION OF SOME OF THE PRE-CLINICAL FINDINGS. SO FIRST THIS SLIDE THAT I'M SHOWING HERE, I THINK PROBABLY A NUMBER OF YOU HAVE SEEN IT BEFORE WHEN I PRESENTED, I REALLY LIKE IT BECAUSE IT'S JUST A LITTLE BIT OF A PLAY ON WHAT THE POSSIBILITIES ARE AND WHAT THE HIDDEN MESSAGES IS AND SOME OF THE WORK WE OTHER DOING. AND I THINK HOPEFULLY I USUALLY ASK FOLKS TO RAISE THEIR HAND AND SAY HOW MANY PEOPLE SEE THE MOTHER AND HER CHILD. I'LL PAUSE FOR EFFECT SINCE I CAN'T SEE YOU RAISING YOUR HANDS. THEN EVERYBODY TURN YOUR HEAD SLIGHTLY THOSE OF YOU WHO CAN'T SEE MOTHER AND CHILD SIDEWAYINGS. -- SIDEWAYS AND MAYBE IT WILL COME IN TO WHERE YOU CAN SEE IT WITH THE REFLECTION. SO ANYWAY THIS IS JUST WHAT A POINT BEHIND US IS THAT I THINK THERE'S A LOT OF ANSWERS THERE, WE HAVE TO BE LOOK AT THEM A LITTLE BIT DIFFERENTLY TO REALIZE WHAT'S THERE. A LOT OF THAT HAS TO DO WITH THE DIFFERENCES IN SEX AND THE HORMONAL TREATMENT WHICH DON AND I SPENT YEARS STUDYING. SO JUST THE MAKE SURE THE CONFLICTS OF INTEREST ARE PRESENTED, NONE OF THESE POTENTIAL CONFLICTS ARE RELATED TO THE TOPIC THAT I'M SPEAKING ABOUT TODAY. MANY OF YOU HAVE SEEN THIS SLIDE WHICH I PRESENT IN JUST ABOUT EVERYTHING WHERE I GIVE A TALK. AND THAT'S JUST REALLY THE STATE OF TRAUMATIC BRAIN INJURY, TRANSLATIONAL RESEARCH, WE HAVE NOTHING TO OFFER PATIENTS FROM STANDPOINT IN TERMS OF INTERVENTION OR DRUG INTERVENTION. DESPITE QUITE A BIT OF EFFORT AND MANY YEARS OF RESEARCH, ALMOST ALL PREVIOUS CLINICAL TRIALS HAVE FAILED TO DATE. WHILE ALL OF THEM HAVE AT PHASE 3 LEVEL. SO IT REALLY LEAVE US US IN TERRIBLE POSITION WHICH IS WE DON'T HAVE ANY EFFECTIVE DRUG TREATMENT FOR OUR PATIENTS. AND THOSE OF YOU WHO WORK IN THE CLINICAL FIELD, YOU HEARD HARVEY LEVIN AND OTHERS KNOW HOW BIG AN ISSUE THIS IS. IT'S TRAGIC. BECAUSE OFTENTIMES THERE'S LITTLE TO OFFER. THE STORY REVOLVES AROUND A DISCOVERY THAT DON STEIN AND HIS TEAM, I HAVE NO IDEA YOU CAN JUMP IN AND TELL ME WHAT YEARS WERE WHEN YOU FIRST NOTICE THAT HIS FEMALE RATS WERE DOING BETTER THAN MALE RATS. AND THIS WAS AFTER A TRAUMATIC BRAIN INJURY, EXPERIMENTAL TRAUMATIC BRAIN INJURY. INSTEAD OF IGNORING THIS HE EXPLORED IT WHICH AGAIN AT THE TIME PEOPLE WERE TRYING TO REDUCE VARIATION IN THEIR RESEARCH EXPERIMENTS WHILE HE CONTINUED TO EXPLORE IT AND WHAT LED TO REALLY FANTASTIC DISCOVERIES. THROUGH A NUMBER OF ELOQUENT EXPERIMENTS HE SHOWED THAT IT WAS ENDOGENOUS PROGESTERONE AND LATER EXOGENOUS PROGESTERONE REDUCED THROUGH CEREBRAL EDEMA SIGNIFICANTLY IN THE INJURED ANIMAL. SO IF YOU ARE A FEMALE ANIMAL AND YOU HAD THE SAME INJURY YOU HAD LESS EDEMA, IF YOU WERE PSEUDOPREGNANT AND PROGESTERONE WAS HIGH, THIS IS THE ELOQUENT EXPERIMENTS HE USED TO DIFFERENTIATE THIS, THEN YOU CAN SEE ALMOST KNOW DEE MA. YOU CAN SEE START HOFFMAN IN THAT PICTURE, I HEARD YOU VOICE IN THE CROWD. SO THE COOL THING ABOUT PROGESTERONE AND THE HOPE FOR PROGESTERONE IS IT HAD MANY, MANY, MANY EFFECTS. IT REDUCED INFLAMMATORY CYTOKINES, REDUCED CEREBRAL EDEMA, APOPTOSIS, BLOCK STEPS CYTOTOXICITY, YOU NAME IT, IT'S A LOT. SO WE WERE HOPING THAT THIS WAS NOT A SINGLE TARGET TYPE OF DRUG BUT COCKTAIL ALL IN ONE. THERE WERE MULTIPLE LABS BEGINNING TO POUR IN THE EFFECTS OF PROGESTERONE IN A VARIETY OF TYPES OF DISEASES AN BRAIN INJURIES. YOU CAN SEE HERE THE SIZE OF THE CIRCLE IS HE WILL ARE EVENTUAL TO NUMBER OF SIGNIFICANCE OF THE DATA. THE PROGESTERONE STUDY BEFORE WE WENT TO PHASE 3 HAS REALLY MET ALMOST ALL OF THE STAIR RECOMMENDATIONS WHICH WERE DESIGNED REALLY FOR STROKE BUT NONETHELESS ARE APPLICABLE TO TRAUMATIC BRAIN INJURY SEARCH. WITH MAYBE THE EXCEPTION THAT WE HAD NOT DONE ANY NON-HUMAN PRIMATE RESEARCH. THEN OF COURSE AT THE TIME WE TOOK THIS INITIATIVE, THERE WERE OVER 200 PUBLICATIONS SHOWING A POSITIVE RESULT. IN A VARIETY OF LABS AND ANIMAL SPECIES. SO WE TOOK THIS INFORMATION AND STARTED TO PROTECT CLINICAL TRIAL FIRST IN HUMAN STUDY WITH A PILOT, 100 PATIENTS SINGLE CENTER AT GRADY MEMORIAL HOSPITAL IN ATLANTA. WHAT WE FOUND WAS ALSO EQUALLY NOT SURPRISING BUT WE WERE VERY ENTHUSIASTIC ABOUT THE RESULTS BECAUSE IT WAS ABOUT A 50% REDUCTION IN DEATH. SO WE -- IN ADDITION TO THAT, THERE WAS ANOTHER STUDY IN CHINA -- REPLICATED THE FINDINGS. NONETHELESS A POSITIVE RESULT SO THIS IS WHAT WE USED WHETHER HEN WE MADE APPLICATION TO NIH FOR PHASE 3 TRIAL. WHICH WAS PROTECT. SO THE PROTECT 3 PHASE 3 CLINICAL TRIAL WAS REALLY DESIGNED TO IDENTIFY THE EFFICACY OF PROGESTERONE IN STUDYING BLUNT TRAUMATIC INJURY. WE DID OF NOTE JUST TO SAY WE DID BLOCK RANDOMIZE BY GENDER BECAUSE WE THOUGHT IT WAS IMPORTANT TO DO THAT AS WELL AS OF COURSE THE VERY -- SEVERITY. UNFORTUNATELY I THINK EVERYONE BY NOW KNOWS THE STORY THE STUDY WAS STOPPED IN 2013 AT AN INTERIM ANALYSIS WHICH SHOWED THE -- THAT IT WAS UNLIKELY PROGESTERONE WAS GOING TO SHOW A SIGNIFICANT RESULT. YOU CAN SEE HERE I KNOW IT'S PROBABLY SMALL ON YOUR SCREEN, BUT YOU CAN SEE THAT THERE WAS 48 VERSUS 52 OR 5 PROGESTERONE VERSUS PLACEBO IN FAVORABLE GROUP SIGNIFYING THE DIFFERENCE. SAME FOR MORTALITY. THAT WAS THE GLASGOW SCALE FOR MORTALITY, REALLY NO SIGNIFICANT DIFFERENCE ABOUT 19 VERSUS 16 IN THE PROGESTERONE PLACEBO GROUP. I WILL SAY IF YOU LOOK AT THIS DATA HERE, IN MODERATE SEVERES AND SEVERE, IF YOU LOOK AT THE MORTALITY IN THESE GROUPS, IT IS AN EXCEEDINGLY LOW MORTALITY FOR THIS GROUP OF PATIENTS. SO I THINK WE DID MAYBE ALMOST TOO GOOD OF JOB WITH CONTROLLING STANDARDIZING OUR CARE. SHOWING REALLY THAT WHEN YOU FOLLOW A GUIDELINE BASED INTERVENTION YOU CAN REALLY IMPROVE OUTCOME. REGARDLESS OF TREATMENT. THERE WAS AN INTERESTING FINDING IN THIS COHORT OR IN THESE PATIENTS. AND A GENDER-BASED DIFFERENCE. WE DON'T KNOW WHAT TO MAKE OF THIS WHETHER THIS IS A LITTLE BIT OF WHETHER IT WAS JUST A POSITIVE RESULT TO STATISTICAL ERROR, BUT IF YOU LOOK THE ONLY THING THAT CAME OUT SIGNIFICANTLY WAS FEMALES DID WORSE WITH PROGESTERONE TREATMENT AND THAT WAS MARGINALLY STATISTICALLY NOT QUITE ADS SIGNIFICANT BUT PEAK 107. THAT WAS ONLY THING THAT CAME OUT EVEN CLOSE TO DIFFERENCE. BUT IT DOES BODE TO SOME BIOLOGICAL EFFECT THAT MIGHT BE OCCURRING HERE THAT WE MIGHT AGAIN WANT TO EXPLORE AT SOME POINT. WHERE DOES THAT LEAVE US? I THINK YOU HEARD THIS MORNING, THERE WERE CLEAR EVIDENCE THAT THERE ARE SEX DIFFERENCES IN THE BRAIN. AND THAT WOMEN AND MEN RECOVER DIFFERENTLY, THEY HAVE DIFFERENT RESILIENCE PATTERNS. THEY HAVE DIFFERENT RECOVERY PATTERNS, FOR DIFFERENT AREAS OF THE BRAIN EFFECTED. SO IT WOULD BEHOOVE US TO EXPLORE THOSE LEVERAGE THOSE AND TAKE ADVANTAGE OF THOSE DIFFERENCES IF WE CAN. THE FAILURE -- WON'T SAY FAILURE BUT THE NEGATIVE TRIAL SORT OF STOPPED US IN OUR TRACKS. BECAUSE IT JUST REALLY LOOKED SO GOOD. AND HAD SUCH A GREAT BIOLOGICAL BASIS. SO THE NEXT PART OF WHAT I WILL TALK ABOUT IS WHERE DO I THINK WE WENT WRONG JUST SPEAKING AS NOW AN INDIVIDUAL GONE THROUGH THE VALLEY OF DEATH FREQUENTLY. RELATED TO THE TRIAL. SO AGAIN, WHEN IT COMES TO TRANSLATING TREATMENT AND NEUROPROTECTION WHETHER IT BE STROKE OR TBI OR ANY OTHER DISEASE, WE HAVE REALLY YET TO FIND A DRUG THAT HAS DONE THAT. SO THERE'S STILL HUGE GAPS THAT EXIST. THE QUESTION IS, ARE ALL OF OUR DRUGS BAD? IS EVERYTHING THAT WE HAVE DONE IN THE PRE-CLINICAL TRIAL BAD? I WOULD ARGUE WITH YOU OF COURSE I THINK EVERYONE, MOST PEOPLE WOULD AGREE THAT NO, WE PROBABLY DO HAVE SOME DRUGS THAT HAVE -- THAT ARE WORKING BUT WE JUST HAVEN'T FIGURED OUT THE RIGHT WAY TO TEST THEM. I THINK THAT'S A LITTLE BIT OF A THEME FOR THE REST OF THE FEW SLIDES. FIRST QUESTION, ARE WE ASKING TOO MUCH OF ANIMAL MODELS. WE ARE, WE ARE ASKING A SINGLE TREATMENT OVER AMAZING HETEROGENEOUS PERIOD OF TIME TO GIVE US A HOME RUN. AND TO BE ABLE TO CHANGE A PERSON'S GLOBAL OUTCOME WHICH I THINK IS VERY NAIVE FRANKLY BUT THAT'S WHAT WE CONTINUED TO DO OVER THE YEARS. THERE IS A LOT OF PROBLEMS WITH BASIC SCIENCE, I DON'T THINK THAT'S THE ISSUE HERE. THERE'S ISSUES OF REPRODUCIBILITY. AS YOU HAVE SEEN THERE ARE HUNDREDS OF PAPERS PROGESTERONE WORKING IN A VARIETY OF ANIMAL MODELS. SO AS OUR MODELS ARE THEY INFORM TV OF HUMAN MODELS AND THAT OBVIOUSLY IS ANOTHER BIG ISSUE. WE SHOULD BE DOING MORE CEPHALIC ANIMALS OR EVEN HUMANS IN THE LAB. SO ONE OF THE OTHER THINGS THAT'S THAT HAS GAINED SOME MOMENTUM IS MULTI-CENTER ANIMAL LABS OR TRIALS RATHER. AND HAS THE TIME COME. AND I THINK IT HAS. I THINK WE HAVE GOT TO LEARN FROM THE RIGOR WE'RE REQUIRED TO DO IN A HUMAN CLINICAL TRIAL, IF WE'RE GOING TO SPEND HUNDREDS OF MILLIONS OF DOLLARS ON TRIALS, NEEDS TO BE REPRODUCED IN ANIMAL WORLD SAME INTENTION TO TREAT BLINDING THAT WE WILL BE USING THOUGH I WILL ARGUE THAT WE NEED TO CHANGE OUR CLINICAL TRIALS AND SIGNS AS WELL. SO TIMING WINDOW AND DOSE, WE NEED TO KNOW WHAT WE'RE GOING FOR BECAUSE EACH TIME EACH WINDOW IS DIFFERENT AND I WON'T SAY MORE ABOUT THAT. I WILL ARGUE THERE WAS PRESENTATION ON BIOMARKERS FILED SPECIFICALLY THIS MORNING, OTHER IMPORTANT I THINK IS DEVELOPMENT OF MARKERS AT THE PRE-CLINICAL STAGE THAT ARE GOING TO HELP US BETTER UNDERSTAND THE PHARMACODYNAMICS OF THE DRUG, MAKING SURE THERE'S STILL ACTIVITY OF THAT DRUG AS IT CROSSES DIFFERENT SPECIES AND ALSO HELPS US BETTER DEFINE INJURY AND TARGET THAT INJURY SPECIFICALLY WITH OUR DRUGS. I MENTIONED EARLIER SINGLE DRUG MECHANISMS NOT LIKELY TO WORK IN A COMPLEX HETEROGENEOUS DISEASE. YOU HAVE HEARD HEARD MULTIPLE TALKS I'M SURE ABOUT HETEROGENEITY AND MECHANISM, THE RESILIENCE IN GENETICS, AGE AND PHENOTYPE WITH INDIVIDUALS, COMORBIDITIES OF INDIVIDUALS, UNDERLYING PATHOLOGY, TREATMENT VARIABILITY WHICH IS ABSOLUTELY HUGE. AND THEN THE BLACK BOX OF REHABILITATION, WHICH WHEN THEY LEAVE ACUTE DRUG THERAPIES, I DON'T KNOW, MAYBE SOMEONE IN THE AUDIENCE CAN, -- HARVEY MAYBE YOU CAN MENTION OR CORRECT ME HERE BUT I DON'T THINK THERE'S BEEN A ACUTE INTERVENTION TRIAL THAT'S CONTROLLED REHABILITATION AS WELL. IT SEEMS WE DISCHARGE THEM AND IN SIX MONTHS LATER WE COME BACK TO TEST THEM. SOME HAVE REHAB, SOME HAVE NOT. WE HOPE THAT THE GROUPS ARE EQUALLY DISTRIBUTED. THEN THERE'S OTHER ISSUES SUCH AS THE SOCIAL DETERMINANTS OF PEOPLE THAT ARE GOING HOME. SO UNDERSTANDING ANDING A BETTER TAXONOMY OF WHAT THE UNDERLYING INJURY IS, TRAUMATIC BRAIN INJURY ISN'T ONE INJURY WHETHER FEMALES OR MALES, IT'S MULTIPLE DIFFERENT TYPES OF INJURIES. BEING ABLE TO UNDERSTAND WHAT WE ARE TARGETING WITH OUR THERAPY. CURRENTLY, AND YOU HAVE SEEN JEFF MANLY AND OTHERS PRESENT ON THIS TOPIC HOW IT'S A BIT CRAZY. AND HOW IMMATURE THE FIELD IS WHEN IT COMES TO DEFINING THE PATHOLOGY THAT WE'RE TREATING WE ARE USING THE GLASS COW SCALE WHICH IS A MEASURE HOW YOU ARE INTERACTING WITH THE ENVIRONMENT. WHEN YOU LOOK AT PATIENTS WITH THE SAME GLASGOW, COMA SCALE THEY HAVE DIFFERENT PATHOLOGIES WITH DIFFERENT OUTCOMES BASED ON THESE PATHOLOGIES. ALSO THE HETEROGENEITY AND TREATMENT ACROSS PRE-HOSPITAL SYSTEMS, EMERGENCY DEPARTMENT, SURGEONS NEUROSURGEONS AND REALLY HOW TO CONTROL FOR THAT WHEN WE'RE DOING HUMAN TRIALS SO THAT THE OUTCOME IS BASED ON THE INTERVENTION AND NOT ALL THESE TREATMENTS. FOR THE PURPOSE OF THIS TALK, ANOTHER THING THAT'S NOT PAID ATTENTION TO FRANKLY IN MOST OF THESE CLINICAL TRIALS, ARE GENDER DIFFERENCES. WE CERTAINLY WERE AWARE OF IT IN THIS TRIAL BECAUSE IT'S VERY CLEAR THERE ARE DIFFERENCES AND EVEN OUR DATA ADS I HAVE SHOWED YOU THAT ONE OUTCOME SLIDE THAT ALLUDED TO MAYBE SOME DIFFERENCES, IN HOW THE MEN AND WOMEN ARE EVEN RECOVERY BASED ON PROGESTERONE TREATMENT ITSELF. THEN THE BLACKS BOX OF NEUROREHABILITATION. OUTCOME MEASURES, DON WILL TALK ABOUT OUTCOME MEASURES BUT WE CAN'T DO THE MORRIS WATER MAZE IN HUMANS AT LEAST NOT AT MY SHOP. HOW DO WE MAKE SURE THE OUTCOME MEASURES WE ARE GETTING POSITIVE RESULTS FOR IN THE HUMANS ARE REALLY TRANSLATABLE INTO -- IN THE ANIMALS TRANSLATABLE TO HUMAN MODELS AND WE ASKING TOO MUCH OF THESE OUTCOME MEASURE? SHOULD WE NOT LOOK AT MORE INTERMEDIATE MEASURES? AND WITH THE CUMULATION OVER TIME OF MULTIPLE DIFFERENT TREATMENTS THAT DO AFFECT INTERMEDIATE MEASURES MAYBE WE'LL BEGIN TO SEE A GLOBAL OUTCOME MEASURE THAT IMPROVES. I THINK LASTLY, I'M GOING TO MENTION THE WAY WE HAVE BEEN DESIGNED CLINICAL TRIALS THE STRICT METHODOLOGY, MAYBE MAY NOT WORK FOR US. AS I CALLED IT BEFORE RIDING THE PYRAMID, SHOULD WE BE LOOKING AT LARGER PHASE 2 TRIALS AND SMALLER PHASE 3 TRIALS. USING IT, ADAPTIVE DESIGNS, AND TO BETTER DELINEATE WHAT'S THE GROUP, THE RESPONDER GROUP THAT WILL WIN PHASE 3. SO TWO SUMMARY SLIDES, NOT PRETTY PICTURES ANY MORE, JUST WORDS BUT FROM THE ANIMAL MODEL SIDE, EXPLORE DIFFERENCES, SEX DIFFERENCES IN ANIMAL MODELS MAKING SURE THAT'S ACCOUNTED FOR AND THEN DEVELOPING A BIOMARKER ALONGSIDE WITH THE DRUG TREATMENT YOU'RE DOING MAKING SURE THERE'S SCIENTIFIC RIGOR SIMILAR HOWEVER THAT DESIGN THE HUMAN TRANSLATION IS GOING TO BE. CONSIDER SOME MULTI-CENTER DESIGNS SUCH AS OPERATION BRIGHT THERAPY THAT DEB SHEER AND FRANK FORTELLA HAD BEEN DOING SO ELOQUENTLY IN THEIR PROGRAMS. SO AGAIN LOOKING AT TARGETING AND DEVELOPING A BIOMARKER THAT CAN HELP US TRANSLATE ACROSS FROM ANIMAL MODELS INTO HUMANS, KNOWING WHETHER THE DRUG IS GETTING THERE, WHETHER THE MECHANISMS IS CONSERVED BEFORE WE MOVE FORWARD. LOOKING FOR, YOU CAN SEE THE LAST THING THERE, RESPONDERS, WHO ARE THE RESPONDERS? ARE FEMALES RESPONDING THE SAME AS MALES? IS THERE A GROUP THAT'S GOING TO RESPOND BETTER TO THIS TREATMENT? BECAUSE EACH INDIVIDUAL THAT'S DIFFERENT PHENOTYPE AND DIFFERENT RESILIENCE. SO ON THE CLINICAL SIDE, PRINCIPLE LOOKING FOR TARGET, LOOKING FOR PHARMACODYNAMICS, ADAPTIVE DESIGNS FOR PHASE 2 TRIALS, LARGER PHASE 2, SMALLER PHASE 3, DEVELOPING BIOMARKERS THAT IDENTIFY RESPONDERS, AGAIN MAKING SURE THAT GENDER IS A CRITICAL PIECE AND MAKING SURE IT'S A CENTERPIECE TO THIS STUDY. AND THEN UNDERSTANDING TIMING AND THERAPY MANAGEMENT VARIABILITY AND OUTCOME MEASURES. THOSE IN GENERAL, THIS IS JUST SORT OF MY VERSION OF WHAT I THINK REALLY NEEDS TO BE DONE FOR US TO SUCCESSFULLY TRANSLATE SOMETHING FROM THE PRE-CLINICAL TO THE CLINICAL WORLD. AND THAT'S MY LAST SLIDE. >> THANK YOU VERY MUCH, DR. WRIGHT. IT WAS A FLAWLESS PRESENTATION. WE HOPE THE AV WILL CONTINUE TO OPERATE. NEXT, THIS AFTERNOON IS DR. HARVEY LEVIN, PROFESSOR OF PHYSICAL MEDICINE REHABILITATION AT THE BAILOR COLLEGE OF MEDICINE. HIS WORK IS INCLUDES MRI IMAGING IN VETERANS WITH TRAUMATIC BRAIN INJURY AND BIOMARKERS AND BRAIN INJURY IMAGING IN SPORTS-RELATED CONCUSSIONS. FROM BAYLOR. SO PLEASE GIVE YOUR ATTENTION TO DR. LEVIN. [APPLAUSE] >> GOOD AFTERNOON. DR. MANNELLY REGRETS HE'S NOT ABLE TO BE HERE TODAY BUT I'M GOING TO PRESENT A PRELIMINARY ANALYSIS OF THE TRACK TBI PILOT DATA. DR. JOHN YU (PHONETIC) ANALYZED THESE DATA VERY RECENTLY. AND SENT ME THE OUTPUTS. IT WAS GOOD TIMING THIS MEETING. SO THE GOALS OF THIS ARE TO PRESENT THE GENERAL DEMOGRAPHIC FEATURES AND PSYCHIATRIC HISTORY OF THE PATIENTS WHO CONTRIBUTED TO THIS SUBSET OF THE TRACK TBI PILOT DATA AND PRESENT TO YOU SOME OF THE PRELIMINARY FINDINGS SEX DISHESES AND OUTCOMES. AND CONSIDER IMPLICATIONS FOR FURTHER ANALYSIS. THIS WAS A PROSPECTIVE MULTI-CENTER STUDY OF MILD TBI, ALL THE PATIENTS WERE SEEN IN THE EMERGENCY DEPARTMENT WITHIN 24 HOURS AND TRIAGED FOR CT. THEY HAD FOLLOW-UP AT THREE MONTHS AND SIX MONTHS. IN THIS PARTICULAR PAPER THE PATIENTS WERE SELECTED WHO BASED ON AGE, STRATIFICATION, AND ALSO HAVING COMPLETE SIX MONTH OUTCOME DATA. THE PATIENTSES WERE DIVIDEDDED TO TWO AGE GROUPS, 18-29 YEARS OLD AND 30-39 YEARS OLD. SO THERE WERE 70 PATIENTS IN THE 18 TO 29-YEAR-OLD SUBGROUP AND 30 PATIENTS WHO WERE 30 TO 39. THERE WAS 71 MALE AND 29 FEMALE MILD TBI PATIENTS THAT DISPROPORTIONALTY IS FAIRLY TYPICAL AS YOU KNOW IN EMERGENCY DEPARTMENT ADMISSIONS. IN THIS PARTICULAR PAPER, THE INTERACTION OF AGE GROUP AND SEX WAS ANALYZED IN A MULTI-VARIANT MODEL FOR OUTCOME. AND IF IT WAS NOT STATISTICALLY SIGNIFICANT IT WAS REMOVED FROM THE REGRESSION. -- HOAR WE SEE THE DEEM -- HERE WE SEE THE DEMOGRAPHIC CHARACTERISTICS. THE WOMEN IN THIS STUDY HAD ABOUT A YEAR ADDITIONAL EDUCATION AS COMPARED TO THE MEN. OTHERWISE THE -- THERE WERE NO DIFFERENCES. IN TERMS OF INJURY MECHANISM AND SEVERITY OF TBI, WHEN WE COMPARE ASSAULTED VERSUS THOSE INJURED BY UNINTENTIONAL INJURIES WE CAN SEE A DIRECTIONAL TREND FOR HIGHER PERCENT ASSAULT IN THE MALE PATIENTS AS COMPARED TO THE FEMALES. BUT THIS DIFFERENCE WAS NOT SIGNIFICANT NOR WAS DIFFERENCE IN CONSCIOUSNESS IN THE GLASGOW COMA SCALE SCORE. IN THE CT SCAN THERE WAS A TREND OF HIGHER PERCENT OF MEN HAVING NORMAL CT SCANS YOU CAN SEE 28.2% COMPARED TO 10.3% IN THE WOMEN. FOR POLYTRAWL MA DIRECTIONALLY IT WAS SLIGHTLY HIGHER IN MEN BUT AGAIN NOT SIGNIFICANT. I THINK THIS PATTERN OF FINDINGS IN TERMS OF THE INJURY SEVERITY AND MECHANISM IS ESPECIALLY INTERESTING WHEN YOU CONSIDER WHAT THE RESULTS ARE. YOU WILL SEE IN A MINUTE. LET'S FIRST CONSIDER THE PSYCHIATRIC SYMPTOMS AS MEASURED BY SELF-REPORT MEASURES. HERE WE SEE RESULTS FOR THE PTSD CHECKLIST AND THIS WAS -- THIS DATA WERE COLLECTED AT SIX MONTHS ON THE X AXIS, YOU CAN SEE THE TWO AGE GROUPS. WHAT WE CAN SEE IS THAT THE 30 TO 39-YEAR-OLDS, WOMEN, HAD A HIGHER PTSD SYMPTOM SCORE THAN MEN. THE INTERACTION OF SEX BY AGE WAS SIGNIFICANT. IN COMPARISON THE SCORES ARE ABOUTCAL IN THE YOUNGER AGE -- ABOUT IDENTICAL IN THE YOUNGER AGE GROUPS. BOTH AGE AND SEX REMANDED INDEPENDENT PREDICTORS. HERE WE SEE A SIMILAR GRAPH FOR THE POST CONCUSSION SCORE. THERE WAS INTERACTION OF AGE BY SEX SUCH THAT IN THE 30-39 GROUP WOMEN HAD HIGHER POST CONCUSSION SYMPTOM SCORES THAN MEN. THIS WAS LOCK AGENT THE TOTAL SCORE. 13 OF THE RIVERMEED ITEMS. AGE GROUPS AND SEX WERE INDEPENDENT PREDICTORS OF THE POST CONCUSSION SYMPTOM SCORES SIX MONTHS. IN CONTRAST TO THE RIVER MEED AND PTSD CHECKLIST, THE PREYFUL SYMPTOM INVENTORY, 18 DOES NOT SHOW SEX DIFFERENCES BUT THERE WAS AN AGE EFFECT AS YOU CAN SEE. NOW WE WILL TURN TO THE GLOBAL OUT COME AND QUALITY OF LIFE -- OUTCOME AND QUALITY OF LIFE. ON SATISFACTION WITH LIFE SCALE, THERE WAS A MARGINAL DIFFERENCE IN THE AGE GROUPS BUT THE DIFFERENCE BETWEEN MEN AND WOMEN WAS NOT SIGNIFICANT EVEN THOUGH THERE WAS A TREND. ON THE GLASGOW OUTCOME EXTENDED, IT IS CLEAR THAT WOMEN HAD MORE SEVERE DISABILITY AT SIX MONTHS AND THIS FINDING I THINK IS PARTICULARLY INTERESTING IN VIEW OF THE COMPARABILITY OF THE ACUTE INJURY SEVERITY INDICES. FOR COGNITIVE OUTCOMES, THE RESULTS ARE LESS CONSISTENT IN TERMS OF SEX DIFFERENCES AND THERE WAS CONSIDERABLE VARIABILITY WHICH I THINK TENDED TO MITIGATE SIGNIFICANT DIFFERENCES. ON THE WAIST PROCESSING SPEED INDEX AT SIX MONTHS,, COGNITIVE PROCESSING SPEED WAS LOWER IN THE 18-29-YEAR-OLDS COMPARED TO THE 30-39-YEAR-OLDS BUT EFFECT OF SEX WAS NOT SIGNIFICANT. THIS INDEX OF EXECUTIVE FUNCTIONING WHICH IS SUBTRACTING ONE CONDITION OF TRAIL MAKING TEST FROM A MORE COMPLEX CONDITION, BOTH TIMED MEASURES AND THE DIFFERENCE BETWEEN THEM IS THOUGHT TO REPRESENT EXECUTIVE FUNCTION. THE -- IT WOULD APPEAR THAT THERE WAS A SEX DIFFERENCE BUT IT WAS NOT SIGNIFICANT. ON THE CALIFORNIA VERBAL LEARNING TEST, AGAIN, THERE WERE NO SIGNIFICANT DIFFERENCES BY SEX OR AGE. ALTHOUGH DIRECTIONALLY, IT WOULD APPEAR THAT THE OLDER PATIENTS PERFORMED AT A LOWER LEVEL. SO WHAT ARE THE MOST SALIENT FINDINGS FROM THIS PRELIMINARY ANALYSIS OF THE TRACK TBI PILOT STUDY? PERHAPS THE MOST SALIENT FINDING WAS OF MORE SEVERE DISABILITY IN WOMEN AT SIX MONTHS. AS COMPARED TO MEN. DESPITE COMPARABILITY IN ACUTE INJURY AND THE FIND THAT MEN HAD HIGHER RATE OF HAVING BEEN ASSAULTED THAN WOMEN. SO IT'S NOT READILY ASCRIBED TO A MORE STRESSFUL CAUSE OF INJURY, AT LEAST IN TERMS OF ASSAULT. WE ALSO SAW THERE WAS A SIGNIFICANT AGE BY SEX INTERACTION IN BOTH PTSD SYMPTOMS AND POST CONCUSSION SYMPTOMS WERE MORE SEVERE IN WOMEN, CONDITIONED BY BEING IN THE 30-39-YEAR-OLD AGE GROUP. THIS WAS NOT PRESENT IN THE 18-29-YEAR-OLDS. WE COULD SPECULATE THE BASIS FOR THIS INTERACTION. WE DIDN'T FIND ANY SEX DIFFERENCES IN TERMS OF PROCESSING SPEED MEMORY OR EXECUTIVE FUNCTION. I THINK MANY OF YOU ARE AWARE THAT SEX HORMONE LEVELS AT THE TIME OF TRAUMATIC BRAIN INJURY VERY IMPLICATED AS A RISK FACTOR FOR OUTCOMES WORK BY JEFF BAZARIAN (PHONETIC) AND HIS COLLEAGUE, DR. WONDERLY. BUT THIS EVIDENCE IS ADMITTEDLY PRELIMINARY. AND HORMONE LEVELS WERE NOT MEASUREDDED IN THE TRACK TBI PILOT. BIOMECHANICS OF TBI HAVE BEEN POSTULATED TO EXPLAIN SEX DIFFERENCES FOR EXAMPLE DIFFERENCE IN GIRTH OF THE NECK. WE SAW THE SEVERITY OF ACUTE IMPAIRMENT OF CONSCIOUSNESS WAS COMPARABLE IN THE TWO GROUPS. SO THAT WOULD NOT APPEAR AT LEAST TO BE THE MOST LIKELY EXPLANATION FOR THESE FINDINGS. OTHER POSSIBILITIES INCLUDES DIFFERENCE IN RECALL BIAS, WAVES MENTIONED EARLIER -- WHICH WAS MENTIONED EARLIER IN THIS WORKSHOP. ANOTHER POSSIBILITY MAY BE THE MOTIONAL MEMORY OF INJURIES, EVEN THOUGH WE SAW THE MEMORIES WERE COMPARABLE IN ACUTE SEVERITY, THE PROCESSING OF THE EMOTIONAL ASPECTS OF THIS EXPERIENCE LIKELY INVOLVING ORBITAL FRONTAL AMYGDALA INTERACTION MAYBE DIFFERENT IN WOMEN THAN MEN. THIS INTERPRETATION WOULD BE INFORMED BY HAVING AN EXTRA CRANIAL CONTROL GROUP TO STUDY WHETHER THIS INTERACTION IS SPECIFIC TO TBI AN IT CAN ALSO BE EXPLORED IN PRE-CLINICAL RESEARCH. WE WILL ALSO USE ONGOING AN MUCH LARGER TRACK TBI PROJECT TO REPLICATE THESE FININGS AN SEE IF THEY HOLD UP. LIMITATIONS OF THIS TRACK TBI PILOT STUDY INCLUDE SAMPLE SIZE, LACK OF HORMONE DATA, LACK OF A VANCEED IMAGING AN -- ADVANCED IMAGING AN RELATIVELY -- AND RELATIVELY MAYBE SUPERFICIAL IS TOO STRONG A OR WORD BUT SELF-REPORT MEASURES OF PSYCHIATRIC EFFECTS OF THESE JURYRIES. INJURIES. PERHAPS DOING A STRUCTURED INTERVIEW LONGITUDINAL STUDY BEGINNING AT THE EARLY PHASE OF RECOVERY, MAY ALSO DISCLOSE SOURCES OF PTSD SYMPTOMS AND CONCUSSION SYMPTOMS. REGARDING TAKE HOME MESSAGES, IT APPEARS THOUGH PRELIMINARY, WOMEN IN THE 30-39 YEAR AGE RANGE HAVE MORE SEVERE DISABILITY, PTSD AND POST CONCUSSION SYMPTOMS AT SIX MONTHS AFTER MILD TBI THAN MEN. BUT WE KIN SEE SEX DIFFERENCES IN COGNITIVE OUTCOME. PENDING CONFIRMATION OF THESE FINDINGS IN THE TRACK TBI PROJECT, CURRENT FINDINGS WOULD SUGGEST THAT FOLLOW-UPS PSYCHOSOCIAL AND PSYCHIATRIC SERVICES MAY MITIGATE PERSISTENT SYMPTOMS IN DISABILITY IN THE WOMEN WHO ARE -- WERE AT RISK IN THE PRESENT STUDY. PRE-CLINICAL TBI STUDIES COULD MANIPULATE THE LEVEL OF ACUTE STRESS AND ANXIETY LEVELS IN MALE AND FEMALE ANIMALS AND MEASURE HORMONES. THIS MAYBE AN ENTRE TO IDENTIFY THE RELEVANT MECHANISMS. THANK YOU. [APPLAUSE] >> NEXT IS DR. MICHAEL BELL WHO COMES TO US FROM ACROSS TOWN, DIRECTOR OF DIVISION OF CRITICAL CARE MEDICINE AT THE CHILDREN'S NATIONAL MEDICAL CENTER HERE IN D.C. AND HE LEADS THE ADAPT TRIAL. >> THANK YOU VERY MUCH, APPRECIATE THE INVITATION TO COME. I DO WANT TO DISPEL A RUMOR THAT DR. WRIGHT SOMEHOW CAUSED THE OUTAGE IN GEORGIA AIRPORT, JUST SIMPLY A RUMOR, I HAD -- FIRST ONE I HIDER ANYWAY. IT'S A PLEASURE TO BE HERE, I WOULD LIKE TO TALK TO YOU ABOUT THE ADAPT TRIAL WHICH IS A PEDIATRIC TBI TRIAL AND I DO WANT TO POINT OUT OUR LOGO IS ON OUR SLIDE AND IF YOU THINK THIS IS A BRAIN EXPLODING YOU'RE '-- IF U YOU ERR BRAIN YOU'RE A NEUROLOGIST THAT'S FOR THAT. SO I HAVE NO DISCLOSURES TO MAKE BESIDES GENEROUS FUNDING FROM THE NINDS, I APPRECIATE ALL THE SUPPORT. THE GOAL OF MY TALK IS TO SUM RYE RATIONALE PRELIMINARY FINDINGS OF ADAPT TRIAL WHICH IS A OBSERVATIONAL COHORT STUDY, NOT A TRIAL ITSELF. AND I WANT TO SUMMARIZE THE PRELIMINARY DATA REGARDING SEX AND SEVERE TBI IN CHILDREN WHICH I THINK IS INTEREST OF THIS GROUP IN THE MAIN. MANY PEOPLE DISCUSSED WITH YOU, TBI IS IMPORTANT CAUSE OF DEATH AND DISABILITY IN CHILDREN. THIS IS DATA FROM 2004 CDC, I CAN TAKE A SLIDE FROM ANY PAST 25 YEARS THE BLUE BOXES ARE UNINTENTIONAL INJURY, MAJORITY TBI RELATE. FROM AGE 1 THROUGH 44, MOST LIKELY CAUSE OF DEATH FROM UNINTENTIONAL INJURY OF SOME SORT HOMICIDES AND SUICIDES WITH THE RED AN GREEN BOXES HAVE A LARGE COMPONENT OF TBI DISCUSSED BY CDC COLLEAGUES. SO POINT OUT THE IMPORTANCE OF THIS TOPIC TO THIS GROUP BUT I DID WANT TO MENTION IT. IN ADDITION MANY GROUPS OF PEOPLE TALKING ABOUT THE GLASGOW COMA SCALE SCORE AN LACK OF HOMOGENEITY. THE GLASGOW SCORE IS 41 YEARS OLE, THE GOLD STANDARD HOW TO ENROLL CHILDREN AN ADULTS INTO CLINICAL TRIALS AND OBSERVATIONAL STUDIES. BASICALLY BASED ON THESE GCS IN THE FIRST PLACE, 8, MORATS 9 TO 12 AND MILDS ARE 13-15. THIS STRATIFICATION SYSTEM IS A FOCAL POINT OF TRACK TBI GROUP DR. LEVIN IS WORKING WITH, THEIR GOAL TO REDEFINE TBI NOT JUST ON GCS SCORES ALONE AND I SUPPORT THEIR ENDEAVORS. I WANT TO GIVE THE GROUP AN IDEA OF WHAT THE PROBLEM THAT I'M TALKING ABOUT, THIS IS A 4-YEAR-OLD CHILD, A GIRL WALKING BY HER DAD'S PICK UP IN PITTSBURGH WHEN I WAS THERE AND DAD BACKED IT UP OVER HER WHICH CAUSED DAD PTSD AND THE CHILD A SEVERE TRAUMATIC BRAIN INJURY. SHE SPENT ABOUT A MONTH WITH US AND DID WELL AT THE END OF THE DAY FROM IC DOCTOR POINT OF VIEW, HAD TO GO HOME TO REHABILITATION AND GO ON WITH HER LIFE BUT I WANT TO GIVE YOU AN IDEA THE COMPLEXITY OF THIS DIAL'S CARE. SINCE I DON'T THINK IT'S APPRECIATED BY FOLKS NOT USED TO TAKING CARE OF KIDS IN ECUs. SO YOU CAN SEE IN THE CIRCLE IS AN CATHETER TO MEASURE THE PRESSURE OF THE CHILD MEASURING INTRACRANIAL PRESSURE IS A FOUNDATION OF NERVE CARE SINCE THE '60s, THIS DEVICE MEASURED ON A CONTINUOUS BASIS. WE HAVE ANOTHER DEVICE HERE, BRAIN TO BRAIN FLUID OUT OF THE BRAIN TO LOWER PRESSURE AND MEASURE ICP AT THE SAME TIME. WE HAVE A DEVICE IN PLACE, OXYGEN IN THE PARENCHYMA OF THE BRAIN AND USE THIS TO MANIPULATE OUR VENTILATION SCHEMES OXYGEN DELIVERED TO HOW MUCH WE BLOW OFF. LITTLE GREEN CATHETER, ENDOTRACKIAL TUBE CARBON DIOXIDE OUT OF THE BODY, TO TITRATE HYPERVENTILATION AS WELL, ANOTHER THERAPY FOR ICP. WE HAVE A CATHETER IN PLACE IN THE CHILD'S WRIST TO MEASURE EXACTLY HOW MUCH TO 2 IS IN THE BLOOD, MEASURE OF HYPERVENTILATION. WE HAVE A VENUS CATHETER IN HER LEG TO PROVIDE MEDICATIONS, FLUIDS AS WELL AS SUPPORT. WE HAVE A FEEDING TUBE IN HER GI TRACK TO TRY TO GIVE NUTRITIONAL SUPPORT. WE HAVE AN EEG AT TOP OF THIS TO SEE IF SHE'S HAVING SEIZURES SO SO ALL THIS IS GOING ON IN CONSTANT BASIS IN ICU AN THESE WILL GO ASTRAY AT ANY NUMBER OF TIME OVER COURSE OF DAY AND HOW THE TAKE CARE OF A CHILD WITH SEVERE TBI IS MANAGE THESE THINGS AN MORE THAT I'M NOT SHOWING YOU INCLUDING VENTILATOR AN CARDIOVASCULAR SUPPORT AND BEST OUTCOMES POSSIBLE. ONE THERAPY, THERE'S MANY FACTORS INVOLVED IN TRYING TO COORDINATE THAT HAS BEEN A CHALLENGE. SO THERE HAVE BEEN EVIDENCE BASED GUIDELINES FOR MANAGEMENT OF SEVERE TRAUMATIC BRAIN INJURY IN CHILDREN AND ADOLESCENTS THIS IS THE SECOND VERSION, THE FIRST IN 2003, FIRST IN 2012. I WAS PRIVILEGED TO BE PART OF THE PANEL OF EXPERTS TO LOOK AT THESE GUIDELINES AN DEVELOP THEM. THERE WERE THREE STATISTICIANS FROM OREGON HEALTH UNIVERSITY AS WELL AS FORENSIC LIBRARIANS, WE IDENTIFIED 15 TOPICS HIGHLY ASSOCIATED WITH OUTCOME OF TBI AND OUR FINDINGS WERE PEER REVIEWED BY MORE THAN A DOZEN EXPERTS, ENDORSED BY MORE THAN TEN SOCIETIES. TO BE INCLUDED NO THE GUIDELINES SEVERE TBI WHICH LESS THAN NINE OR LESS OR EQUAL THAN 8 IS A SEMANTIC DIFFERENCE. POPULATION OF CHILDREN UNDER 18 YEARS OF AGE, AND MEASURABLE RELEVANT HEALTH OUTCOME WHICH IS ICP BUT SOMETIMES WAS USUALLY WAS A LONG TERM OUTCOME SUCH AS MORTALITY OR GOS OUTCOMES BUT COULD BE ISP IF TARGETED TO THAT. VARIOUS LEVELS OF CONTRIBUTIONS WERE MADE, CLASS 1 THERAPIES MUST BE DONE BECAUSE THE EVIDENCE IS SO COMPELLING FROM THE LITERATURE. CLASS 2 CONSIDERED AND CLASS 3 THINGS MAYBE CONSIDERED. THIS IS WHEN I GET DEPRESSING, I APOLOGIZE. REVIEWED 5,000 AND 600 MANUSCRIPTS GETTING 37 TO THE GUIDELINES, THESE WERE BEING UPDATED CONTINUOUSLY SO WE HAVE A NEW VERSION COMING OUT THE NEXT FEW MONTHS. THERE WERE NO, MA'AM LEVEL 1 RECOMMENDATIONS SO YOU COULDN'T TELL ANYONE SOMETHING MUST BE ACCOMPLISHED SO YOU COULDN'T TELL EVERYONE YOU MUST DO THERAPY, MUST PROVIDE IMMUNOTHERAPIES. THERE ARE TWO RECOMMENDATIONS WHICH WOULD BE AVOIDED, SO STEROIDS SHOULD BE AVOIDED BASED ON RCTs THAT FAILED. HYPERTHERM AREA ALSO FAIL AND DYE DONE IN 40 KIDS IN GREECE SHOULD BE AVOIDBECAUSE IT DIP DO ANYTHING. PLUS OR MINUS. (INDISCERNIBLE) THIS WAS DONE FROM STUDY OF 18 CHILDREN IN SEATTLE IN 1992. THE ENTIRETY OF THE RECOMMENDATIONS ARE BASED ON VERY SMALL EVIDENCE AND SMALL PATIENT POPULATIONS. I WROTE THE LEVEL 3 RECOMMENDATIONS OUT SO YOU CAN SEE HOW PROMISE SKEW WOWS, MONITORING MAYBE CONSIDERED, MAYBE CONSIDERED CONSIDERED AND DECIDED NOT TO. SOMEONE WHO BELIEVES IN THESE THERAPIES HELPFUL, OBVIOUSLY I BELIEVE IN IT BUT THERE'S NOT ENOUGH EVIDENCE IN THE LITERATURE TO COMPEL PEOPLE TO DO IT. TREATMENT OF A THRESHOLD OF 20-MILLIMETERS OF MERCURY FOR ICP STANDARD ACROSS THE FIELD BUT NO COME TELLING EVIDENCE TO COMPEL PEOPLE TO TREAT THAT BESIDES SOME MAY CONSIDER. YOU CAN SEE THE LIST OF THINGS DOWN HERE THAT HAVE LED TO IN MY OPINION PRACTICES ACROSS THE COUNTRY AN ACROSS THE WORLD THAT ARE UNSTANDARDIZED. MY THEORY IS THESE UNDERSTANDARDIZED PRACTICE AFFECT RCT AND LEVEL OF GUIDELINES IN CIRCULAR REASONING PROBLEM. SO DR. MANLY AND THE TRACK TBI FOLKS BELIEVE STRONGLY THAT THE CATEGORIZE PATIENTS BETTER, HOMOGENOUS PATIENT POPULATION, TO GET BETTER OUTCOMESS FROM THE RCT, I DON'T DISAGREE AS FIRST PART OF THE STEP BUT MY POINT OF VIEW WAS A DIFFERENT PROBLEM. THIS IS A PARADIGM WE HAVE LEARNED FROM MEDICAL SCHOOL ON WORD, YOU SEE A PROBLEM AND IF YOU DO A THOUGHT EXPERIMENT TO THINK OF MANNITOL TO LOWER ICP IMAGINE SOME POINT 1900 WHEN FIRST GOT INTO CLINICAL PRACTICE SOME NOVEL OBSERVATION OR NOVEL IN A LAB WE HAVE A SMALL FURRY ANIMAL WITH HEAD INJURY, YOU GIVE MANNITOL AN SEE BRAIN SHRINK WHICH IS WHAT YOU WANT TO SEE HAPPEN IN CLINICAL SETTING. A NEW A HA MOMENT OBSERVATION. IF BUT REQUEST SEE ONE OF THOSE OBSERVATIONS IN PRE-CLINICAL WORK YOU DESIGN A PHASE 1 PHASE 2 TRIAL AS DR. WRIGHT WAS SAYING AND YOU TRY TO DO IT IN YOUR OWN CENTER, YOU DO A FEW PATIENTS CENTER OR AS MANY AS YOU CAN TO GET PHASE # DATA MAKE SURE YOU'RE NOT DOING ANY HARM THEN TRYING TO SEE IF IT'S SAFE AND EFFICACY THEN START DOING PHASE 2 TRIAL. AFTER THAT PROCESS HAPPENS WHETHER SMALL NUMBER OF CENTER OR YOUR OWN YOU GO TO A PHASE 3 TRIAL. THE PHASE 3 TRIAL YOU REACH OUT TO EVERYONE ACROSS THE COUNTRY, ACROSS THE WORLD TO GET THESE STUDIES DONE, SO YOU CAN ACTUALLY MAKE IT APPLICABLE ACROSS THE FIELD. THIS IS WHERE -- THIS IS A STEP WHERE ALMOST ALL THE NEUROPRACTICE STUDIES NOT JUST TBI BUT OTHER STUDIES ALL TEN TO FAIL -- TEND TO FAIL. ONCE YOU GET A PHASE 3 STUDY THAT SUCCEEDS, FOR ISCHEMIC STROKE IN ADULTLESS YOU IMPLEMENT ACROSS THE -- ADULTS YOU TRY TO POLICE DEPARTMENT EXCEPT FOR THE INTERVENTION AS WE HAVE HEARD ALREADY WITH THIS GROUP THE SEX DIFFERENCES HAPPEN ACROSS GROUPS ALL CARE IDENTICAL AND NEED ARE THE PATIENTS SO TRY TO UNDERSTAND THIS PART AS WHAT ADAPT IS TRYING TO DO AT A FUNDAMENTAL WAY. SO WE DURING ADAPT WE -- THE PLANNING STAGES WE LOOK AT MEDICAL THERAPIES PEEP USE, WE -- PEOPLE USE, WE REACHED OUT TO THE CLINICAL CENTERS, ASKED BASIC QUESTIONS, DO YOU DO CSF, A THIRD OF THE CENTERS NEVER DIVERT CSF AND THEY ARE LYING BECAUSE THEY DO. AND A THIRD OF CENTERS SAID THEY USE CONTINUOUSLY ONLY AND (INAUDIBLE) BECAUSE THEY DONE, VARIOUS PEOPLE DO SOMETHING BETWEEN THAT. WE ASK PEOPLE TO USE MANNITOL OR SALINE, THREE CENTERS SAID THEY DON'T USE IT AND THEY LIED BECAUSE THEY DO. ONE OTHER CENTER LIE BECAUSE THEY DO ALSO. WE ASKED WHAT (INAUDIBLE) THIS IS ALL OVER THE PLACE, ONE CENTER THAT CLAIM TO USE SEVEN CONCENTRATIONS, BASED ON PERSON WHO IS IN CHARGE THAT DAY. SO THE VARIATIONS OF CARE IS QUITE SUBSTANTIAL ACROSS THE BOARD. WE ASKED WHEN DO YOU START FEEDING PATIENTS, SOME EARLY, SOME FEED LATE. YOU CAN SO E HERE THE RANGE BETWEEN 0 TO 96 HOURS, IF WE THINK FEEDING SOMEONE MAKES A DIFFERENCE IN OUTCOME, FEED PEOPLE AT THE SAME TIME SO WE DON'T MESS UP DR. WRIGHT'S PROGESTERONE STUDY OR HYPERTHERMIA STUDIES. THIS IS A CONFOUNDER THAT WE CONTROL -- DON'T CONTROL FOR IN CLINICAL STUDIES. WE ASKED WHEN START GLUCOSE, 0 TO 72 HOURS. AND THESE RANGES WERE LARGER. THIS IS THE REPORTED RANGES AND ACTUAL DATA IS LARGER THAN THIS. SO THE GOAL FOR THAT IS TRYING TO STANDARDIZE THESE APPROACHES. SO RATHER THAN DOING A DESIGN RCT, THE HOPE THE CLINICAL SITES PERFORM BASIC CARE AND EXCLUDE PATIENTS WHO MIGHT SCREW UP OUR STUDY. COMPARING THE EFFECT TVNESS OF REAL WORLD IN OUR CASE COHORT DESIGN. WE ALLOW SITES TO TAKE CARE OF PATIENTS IN OWN WAY, MEASURE IT VIGOROUSLY AND STATISTICALLY TO SAMPLE SIZE TO ALLOW FOR COMPARISONS. SO ADAPT WAS NAMED MULTI-MEDICAL THERAPIES TRIAL, WE WROTE THOUSAND CHILDREN OVER 51 CLINICAL CENTERS, 34 U.S. SITES AND 17 ENTERNARCNAL SITES ACROSS EIGHT -- INTERNATIONAL SITES ACROSS 8 COUNTRIES. WE HAVE THREE NAME AN SUBNAMES. AND GSOP WAS PRIMARY OUTCOME. WE INCLUDED KIDS UNDER 18 YEARS OF AGE AT THE STUDY HOSPITAL, SEVERE T TBI BASED ON CURRENT DEFINITION AND ONLY EXCLUDED CHILDREN PREGNANT. THE IRB ALLOWED US TO COLLECT -- THERE WAS NO SELECTION BIAS, EVERY PATIENT THAT CAME TO THE HOSPITAL WAS ENROLLED. CONFIRM OUTCOMES TESTING AT APPROPRIATE TIME WHEN PATIENT RECOVERED. HERE ARE OUR STRAW MEN, WE HAVE 12 STRAW MEN LISTED HERE, I'LL LEAVE IT UP TO READ. BASICALLY TRYING TO PROVE WHICH WHICH THERAPIES IS BENEFICIAL IN OBSERVE -- OBSERVATIONAL WAY. CONTINUE TO SEE A WORSE VERSION IN -- IT DOES NOT AFFECT WHATSOEVER. SO WE CAN MAKE RECOMMENDATIONS TO THE FIELD, IT'S ALSO FINE WITH ME IF SOME OF THESE DO NOT ARE NOT EFFECTIVE FOR OUTCOME BECAUSE WE CAN QUIT WORRYING IN MULTI-CENTER RCTs, STANDARDIZE THINGS THAT DON'T NEED TO BE. THE GOAL IS TO GET THESE 12 QUESTIONS ANSWERED, HAVE 12 NEW LEVEL GUIDELINE RECOMMENDATIONS WHICH WE CAN PULL OUT TO A FIELD AND DEVELOP CLINICAL PROTOCOLS FOR PATIENT CARE ADS WELL AS CLINICAL PROTOCOLS FOR RCTs. A LITTLE FLAVOR WHAT WE SAW SO FAR. CHILD ABUSE AN MORTALITY WHICH WHICH ABUSE IS PROBABLY MENTIONED THIS MORNING. Z FIRST # HUNDRED PATIENTS WE CATEGORIZED DEFINITIVE OR PROBABLY ABUSE. IN THE YES CATEGORY AND NO I ABUSE IN NO CATEGORIES. 189 PATIENTS OF 200 WE CAN ANALYZE. INTERESTINGLY IN THIS GROUP THE FEMALES HA HIGHER ABUSE PERCENTAGE THAN THE MALES. BUT ULTIMATELY WE LOOKED AT DID THEY HAVE MORE DEATH AS A RESULT OF THOSE STUDIES. CHILD ABUSE REALLY IS CONSIDERED BY NEUROSURGEONS IT CAN A LETHAL DISEASE, WE FOUND INCIDENCE OF DEATH BUT NOT STATISTICALLY SIGNIFICANT SO FROM OUR POINT OF VIEW STUDYING CHILD ABUSE AN ANALYZING IT IS AN IMPORTANT PART OF OUR JOB. WE HOOK AT GCS SCORES AS WELL. THIS IS BREAKDOWN. I CAN SHOW MORE COMPREHENSIVELY IN THIS SLIDE SO FIRST 200 PATIENTS THERE WAS 3, WE LUMPED FOUR AND FIVE TOGETHER AND HAVE 6 AND 8 TOGETHER. YOU CAN SEE HERE THE ODDS RATIO OF DEATH IS 22 FOLD HIGHER FOR 3s COMPARED TO THE 6 TO 8. CORRECT FOR VARIABLES WE CORRECT FOR 13 FOLD HIGHER. IF YOU'RE DOING DR. WRIGHT RANDOMIZED CONTROL TRIAL FOR 3, 4, 5, KIDS, YOU CAN HAVE MORE MORTALITY IT IS THAN THE ONE GROUP BECAUSE OF THE SCORES ALONE. LOOKING AT SEX DIFFERENCES WE DID ANALYSIS OF FIRST 500 PATIENTS IN THE STUDY, WE HAVEN'T COMPLETED THE ENTIRE THOUSAND, THIS IS NOT PUBLISHED FOR NOW. YOU CAN SEE HERE THAT AS DR. ROBERT SAID, TWO THIRD ONE-THIRD THING WE ENDED UP EXACTLY TWO THIRD ONE-THIRD WHICH IS NOVEL OBVIOUSLY. THE GIRLS IN OUR GROUP TENDED TO BE YOUNGER WITH 49% OF THE FEMALES IN THE 0 TO 4 CATEGORY. S IN RACIAL AND ETHNIC DIFFERENCES WE CAN IDENTIFY IN THESE 500 PATIENTS. WE LOOK AT VARIOUS OTHER POSSIBILITIES HOW THEY WERE TRANSFERRED TO THE HOSPITAL, THE LIKELIHOOD OF INTENTIONAL INJURY, LIKELIHOOD OF INJURY DUE TO ABUSE. YOU CAN SEE HERE IN THE ABUSE CATEGORY GIRLS WERE SLIGHTLY -- THE PROBLEM DEFINITIVE GROUP IS 17% HERE VERSUS 12% HERE SO PREDOCUMENT INNOCENCE OF FEMALES IN ABUSE CATEGORY, 500 PATIENT SAMPLE. SELF-INFICTED INJURY WAS DIFFERENT BECAUSE MORE MALES WERE DOING IT. MORE MALES HAD DEFINITIVE INJURIES. LIKELIHOOD BEING UNDER INFLUENCE OF ALCOHOL, WAS NOT DIFFERENT AND CAUSE OF INJURIES LIST HERE. MY TIME IS ALMOST OUT, JUST GIVE AN IDEA OF THE FLAVOR OF THE RICHNESS OF THE DATA WE HAVE. WE CAN SEE HERE EXACTLY ALL THE DIFFERENT TYPES OF INJURIES MECHANISM OF THOSE INJURIES GCS SCORES AS MONITOR PLACE IN THE INJURIES SCORE FOR EACH OF THE DIFFERENT CATEGORIES WHICH WAS COLLECTED BY THESE 51 CLINICAL CENTER. WE ARE NOW -- ANALYZING THE FULL THOUSAND PATIENTS FOR THIS. AND WE ARE PLANNING RENEWAL FOR THE ADAPT TRIAL WHICH QUESTION SUBMITTED ONCE. THE PURPOSE IS TO LOOK AT SUBTYPES BECAUSE WE THINK BOYS VERSUS GIRLS IS A RELEVANT QUESTION. DO SOME THERAPY WORK BETTER FOR BOYS THAN GIRLS. SOME WORK BETTER FOR 6 TO 8, BASED ON IMAGE AND OTHER THINGS SO WE HAVE A SECOND COHORT OF ADAPT PATIENTS TO COMBINE WITH FIRST GROUP TO LOOK AT THESE SUBSTIPES IN A MORE RIGOROUS WAY, THAT'S THE GOAL OF THE STUDY AT THE CURRENT MOMENT. THANK YOU VERYTHANK YOU VERY MUCH, APPRECI ATE YOUR ATTENTION. [APPLAUSE] >> THANK YOU,. I WOULD LIKE TO INTRODUCE DR. DONALD STEIN, PROFESSOR EMERGENCY MEDICINE AT EMORY UNIVERSITY, EMORY HOSPITAL. AND DIRECT THEIR BRAIN RESEARCH LAB FOCUSING ON RECOVERY AFTER TBI. DR. STEIN, ARE YOU THERE? >> DONALD? >> CAN YOU SEE EVERYTHING NOW? >> YES, SIR, WE CAN. YOU CAN GO AHEAD AND START YOUR PRESENTATION. >> THANK YOU. I'M REALLY SORRY AS WITH DAVID I CAN'T BE THERE IN PERSON THANKS TO THE TREMENDOUS TRAUMAS EVERYBODY HAD GETTING IN AND OUT OF ATLANTA. THE ONLY GOOD THINGS THAT COMES OF IT IS ANYBODY THAT MIGHT BE INTERESTING IN STUDYING ACUTE STRESS E WOULD HAVE 35 ADDITIONAL SUBJECTS THAT YOU CAN LOOK TO FOR YOUR RESEARCH. I HAVE BEEN ANDED TO TALK A LITTLE BIT ABOUT CHALLENGES FACING PRE-CLINICAL TO CLINICAL PRANCELATION AN RESEARCH. I HAVE TO SAY THAT THIS IS GOING TO BE A BRIEF REVIEW BECAUSE THANKS TO ALL THE COLLEAGUES OF MINE THAT YOU HAVE HEARD SPEAK THIS MORNING ESPECIALLY DAVE, HE'S DONE A REALLY GOOD IMPRESSION OF WHAT MOM SOME OF THE PROBLEMS ARE. SO I'M GOING TO BE BRIEF, I SHORTENED MY TALK A LITTLE BIT. BECAUSE IT REALLY IS ALMOST A REITERATION OF MOST OF WHAT YOU'VE HEARD EARLIER TODAY. WHY SHOULD PRE-CLINICAL RESEARCHERS BE CONCERN ABOUT SEX DIFFERENCES? THE REALITY IS WHEN YOU LOOK IN THE NEUROSCIENCE LITERATURE, THE VAST MAJORITY OF STUDIES ARE STILL OVERWHELMINGLY DONE IN MALES AND FEMALES JUST SOMETIMES AS A SINGLE SEX STUDY. THIS IS A BIG PROBLEM FOR US HOW WE GO FORWARD. ONE OF THE THINGS YOU HEARD IS FEMALE ESTRA CYCLE CAN INFLUENCE EFFECTS OF DRUGS OR EXPERIMENTAL MANIPULATIONS BECAUSE YOUR BODY METABOLISM CHANGES. THIS IS RARELY IF EVER STUDIED IN ANIMAL STUDIES AND NOT THAT MUCH FROM WHAT I GATHER FROM TODAY'S SESSIONS IN HUMAN CLINICAL TRIALS AS WELL, REGARDLESS WHETHER IT'S TBI STROKE, CANCER OR ANY OTHER DISEASE. ONE OF THE BIG PROBLEMS FOR ANIMAL INVESTIGATORS IS IT'S EASY TO SAY THAT ONE SHOULD STUDY MALES AND FEMALES BUT THIS CAN REALLY DOUBLE THE COST OF MOST LABORATORY STUDIES. AND WHEN GRANTS FUNDING ARE LIMITED SO FIXED AMOUNT, USUALLY IN THE HUNDREDS OF THOUSANDS OF DOLLARS, IT'S VERY DIFFICULT TO BUDGET ACCORDINGLY AND CONDUCT VARIOUS PARAMETERS THAT NEED TO BE STUDIED. FINALLY, NOT FINALLY BUT AS ANOTHER POINT, SUBTLE DIFFERENCES IN BEHAVIORS CAN BE MISSED AND THUS CONFOUND EXPERIMENTAL RESULTS. IN THE LITERATURE LOOK IN THE NEUROSCIENCE JOURNALS THAT YOU SEE, THE STUDIES ARE MOSTLY FOCUSED ON MOLECULAR SIGNALING, GENOMIC PROTEOMIC PATHWAY AND THE BEHAVIORAL NATURES ARE RUDIMENTARY. SO IF YOU ARE LOOKING FOR VERY GROSS HIGHLY SIGNIFICANT CHANGES THAT DRAMATIC LIKE WHETHER YOU CAN WALK OR BREATHE OR NOT THAT'S ONE THING. BUT OFTEN RECOVERY REQUIRES TIME AND DIFFERENCES SUSSING AND OFTEN MISSED IF GROSS ANALYSIS OF BEHAVIOR AND FUNCTIONAL OUTCOMES ARE USED. THERE ARE A LOT OF OTHER FACTORS YOU HEARD ABOUT TODAY SO REITERATING HERE, ONE, THIS IS TRUE FOR ESPECIALLY TRUE FOR SEX DIFFERENCES, AGE AT TIME OF TESTING, IS A CRITICAL VARIABLE BECAUSE OF MATCH RAYING AT BOTH END OF THE SPECTRUM. 40 YEARS AGO PEOPLE WERE SHOWING THAT MALE AND FEMALE DIFFERENCES IN THE RESPONSE TO BRAIN INJURY IN NON-HUMAN PRIMATES VARIED TREMENDOUSLY. MALES START OUT SHOWING MORE PROFOUND DIFFERENCES IN MONKEY RESEARCH, AND THEN GROW OUT OF THE DEFICIT, WHERE FEMALES ON CERTAIN TASK MACE GO EXACTLY IN THE OPPOSITE DIRECTION HAVING DIFFERENCES LATER IN LIFE AND NO DIFFERENCE EARLY IN LIFE, THESE FACTORS ARE RARELY STUDIED.& ONE THING THAT NEEDS TO BE INCLUDED IN TRANSLATIONAL RESEARCH, SEX DIFFERENCES IN ONE PARTICULAR AGE, YOU HEARD THIS EARLIER TODAY, MAY NOT BE APPARENT IN ANOTHER. AGAIN, I THINK IT'S IMPORTANT TO HIGHLIGHT AND EMPHASIZE IF YOU INCLUDE FEMALE ANIMALS OR HUMANS THAT THEY DIFFER FROM MALES ON SOME DAY OF THE ESTRA CYCLE AND OTHERS. THIS MAYBE PARTICULARLY TRUE FOR METABOLIC MEASURES, IMAGING STUDIES, AND WHAT HAVE YOU. SO WHEN YOU DO AN IMAGING STUDY IN AN INDIVIDUAL WITH AND WITHOUT BRAIN DAMAGE IT MAYBE VERY IMPORTANT TO CONSIDER HORMONE FLUCTUATIONS AT THE TIME THOSE SPECIFIC MEASURES ARE TAKEN. LIKEWISE I THINK IT'S IMPORTANT TO POINT OUT DOSING CAN VARY ACROSS ESTRA CYCLE SO A DOSE THAT MAYBE HIGHLY EFFECTIVE AT ONE STAGE, TALKING ANIMAL STUDIES WHEN THE FEMALE IS LOW IN PROGESTERONE, MIGHT HAVE A VERY DIFFERENT AFFECT THAN SAME DOSE WHEN ANIMAL IS HIGH. BECAUSE THAT IS BASICALLY RECEPTOR SATURATION AND BLOCK THE EFFECTS. THESE VARIABLES HAVE RARELY IF EVER STUDIED IN AT LEAST ANIMAL STUDIES AND I'M NOT SURE THIS IS LOOK AT WIDELY ACROSS THE WORLD IN HUMAN STUDY BUS VERY RARELY SEE THESE FACTORS BEING CONSIDERED. FINALLY WHEN IT COMES TO HUMAN, THIS IS NEVER IN ANIMALS TO THE BEST KNOWLEDGE, WOMEN CONTRACEPTIVES CAN HAVE DIFFERENT OUTCOMES THAN THOSE NOT. BOTH DIFFERENT FROM MEN. IN PARTICULAR, IF WOMEN ARE ON SYNTHETIC ESTROGEN AND PROGESTERONE, THAT CAN HAVE DRAMATIC EFFECTS ON THE OUTCOME OF ANY MEASURES THAT ONE MIGHT BE TAKING ESPECIALLY IF ONE IS LOOKING FOR TREATMENTS FOR WHATEVER DISEASE YOU MIGHT HAVE IN MIND. ONE THING I HAVE COME UP WITH OVER MANY YEARS LOOKING AT SEX DIFFERENCE, DAVE MENTIONED HE DIDN'T HAVE THE EXACT DATE, WE STARTED THIS WORK BACK IN THE MID '80s WHEN WE FIRST NOTED THAT FEMALES RATS SUBSUBSANTIA FRONTAL INJURIES ARE MORE SUBSTANTIAL. I WON'T REPEAT THEM HERE. ONE THING WHEN E TALK THE COLLEAGUES SEX DIFFERENCES ARE SMALL UNRELIABLE AN THEREFORE ANIMAL STUDIES NOT WORTH CONSIDERING, NOT THAT IMPORTANT. SEX DIFFERENCES IN BRAIN FUNCTION ARE RARE AND DUE TO A FEW EXTREME CASES. PEOPLE ALLUDED TO THIS EARLIER TODAY, THE ARGUMENT IS DIFFERENCES WITHIN SEX MORE IMPORTANT THAN BETWEEN SEXES. THE OTHER THING WE CAME ACROSS BECAUSE AS YOU KNOW WE FOCUS HEAVILY ON PROGESTERONE AS WELL AS ESTROGEN BUT MOST PEOPLE, NEVER REALLY PAID MUCH ATTENTION TO PROGESTERONE BECAUSE DIFFERENCES ARE ONLY DUE TO ESTROGEN DURING DEVELOPMENT, THAT WAS THE THOUGHT AMONG MANY PEOPLE WORKING IN ANIMAL RESEARCH. AND THAT ONE SENSITIVE ISSUE IS WHETHER OR NOT HIGHLY DEBATABLE ISSUE IS WHETHER OR NOT NEURAL MECHANISMS UNDERLYING BEHAVIOR ARE IDENTICAL FOR MALES OR FEMALES. THIS RISK OF COURSE DEPENDS ON TYPE OF INJURIES YOU MIGHT WANT TO STUDY, WHEN YOU APPLY THE INJURY AND A WHOLE HOST OF OTHER PARAMETRIC FACTORS THAT HAVEN'T BEEN CONSIDERED VERY MUCH. PHYSIOLOGICAL DIFFERENCES AFFECT ANIMAL STUDIES AS WELL AS I'M SURE PEOPLE, AND I DON'T KNOW AGAIN IF I CAN SAY FOR SURE AT LEAST IN ANIMAL STUDIES THESE VARIABLES HAVEN'T BEEN CONSIDERED IN GREAT DETAIL OR STUDIED STRATIFICATION IN ANY WAY IN ANIMAL STUDIES BUT THERE ARE DIFFERENCESES IN TERMS OF PERCENTAGE BODY FAT, WOMEN HAVE OVERALL BODY WEIGH, LESS BLOOD VOLUME, LOWER PLASMA PROTEIN BINDING WHICH IS VERY IMPORTANT FOR DRUG STUDIES, LOWER HEPATIC BIOTRANSFORMATION OF DRUG. SLOWER RENAL CLEARANCE, AND SLOWER GASTRIC EMPTYING TIMES. THESE ARE ISSUE US THAT IF YOU'RE GOING TO BE DOING DESIGNS OF STUDIES THAT TRY TO MODEL WHAT MIGHT BE MOST EFFECTIVE, IN GOING FORWARD TRANSLATION RESEARCH ARE VERY RARELY ADDRESSED. YET WE PLAY A VERY IMPORTANT ROLE IN MODIFYING THE OUTCOMES OF BRAIN INJURY WHICH FROM EVERYTHING I HAVE BEEN ABLE THE SEE OVER ALL THE YEARS I HAVE BEEN DOING IT, BRAIN INJURIES ARE NOT JUST LIMITED TO THE BRAIN, THEY AFFECT EVERY OR ORGAN OF THE BODY AND RARELY IN ANIMAL STUDIES DUE LOCK WHAT HAPPENS WITH TRAUMATIC BRAIN INJURY TO THE SPLEEN, THE GUT, THYMUS, WHERE THERE'S MARKED INFLAMMATORY RESPONSES IN ALL STRUCTURES AFTER TRAUMATIC BRAIN INJURY AND STROKE. AND RARELY ARE THESE STUDIES SYSTEMATICALLY IN ANIMALS AND IF YOU GO FORWARD, NOT COMPLETELY CONVINCED WELL STUDIED WITH RESPECT THE BRAIN INJURY IN STROKE IN PEOPLE EITHER. I WON'T GOEN INTO A LOT OF DIFFERENCES BECAUSE THIS IS JUST -- AND AFTER LAUNCH REVIEW IN CASE YOU HAVE FORGOTTEN THE WONDERFUL PRESENTATION PEGGY MCCARTHY AND OTHERS, FEWER CEREBRAL ASYMMETRIES IN IMAGING WHEN NORMAL HEALTHY WOMEN WERE HIGH IN PROGESTERONE THAN ESTROGEN. WHEN DO YOU IMAGE, WHEN IS PROPER TIME TO IMAGE AFTER BRAIN DAMAGE OR CONTROLS? FEMALES IT'S BEEN REPORTED HAVE MORE NEUROPHIL THAN MALES BUT MALES HAVE HIGHER SYNAPTIC DENSITY. IF U YOU'RE COUNTING HOW DOES THAT PLAY INTO THE ROLE WHAT HAPPEN EFFECTS DUE TO TREATMENT VERSUS NORMAL CHANGES. NERVE CELLS ARE LARGER IN FEMALES ESPECIALLY THE LEFT HEMISPHERE BUT MALES HAVE MORE CELLS. HOW DOES THIS AFFECT OR CONFOUND INTERPRETATION AFTER TRAUMATIC BRAIN INJURY STROKE OR ANY OTHER CNS DEGENERATIVE DISORDERS? I WOULD -- FEMALES ARE MORE FREQUENTLY RIGHT HAND AND BETTER LANGUAGE SKILLS. THEY'RE MUCH MORE LIKELY TO REPORT SYMPTOMS THEY SEEM TO BE MUCH MORE SENSITIVE THE THEIR BODILY CHANGES THAN MALES TEND TO BE. DON'T THINK THERE'S NOT VARIABLE OBVIOUSLY IN ANIMALS. THE LITERATURE IS VERY CONTROVERSIAL BUT IN ANIMAL STUDIES, THIS IS PROBLEM WITH TRANSLATION, FEMALES TEND TO SURVIVE BETTER THAN MALES. THIS COULD BE A CONFOUNDING FACTOR. SO ALL -- I'M GOING TO SKIP OVER THESE SLIDES BECAUSE YOU HEARD THIS BEFORE AND I DON'T WANT TO BE TOO REPETITIVE. SEX DIFFERENCES IN BRAIN INJURY, YOU HEARD THAT IN FEMALES TIMING OF BRAIN INJURY RELATIVE TO STAGE OF ESTRA CYCLE PLAY A KEY ROLE. YOU CAN SEE SOME OF THAT HERE ON THIS SLIDE. WHEN YOU TIME SURGERY, IT WILL BE CRITICAL IN DOING ANY OUTCOME STUDIES WHETHER SHORT OR LONG TERM. AND MEASURING ESTROUS OR MENSTRUAL CYCLE MEASURING HORMONES AT THE TIME STUDIES ARE DONE AS WELL AS INJURY DONE AND OUTCOME MEASURES TAKEN IF YOU'RE COMPARING MALES AND FEMALES THESE ARE IMPORTANT FACT TO THINK ABOUT WHEN YOU LOOK AT POST TREATMENT EFFECTS ON BOTH. STUDIES SHOWING FEMALE RATS AND MICE INBRED STRAINS AN OUTBRED STRAINS SUSTAIN SMALLER TISSUE DAMAGE AND ENJOY BETTER IMPROVED FUNCTIONAL OUTCOME COMPARED TO MALES BUT DOING ANIMAL STUDIES YOU HAVE TO REALLY BE CONCERNED ABOUT WHAT STRAIN OF RAT OR MOUSE YOU USE. THIS MAY BE ONE REASON TO GO TO AS THEY SUGGESTED A STEP AWAY A LITTLE BIT FOR ANIMALS WITH SMOOTH BRAIN TO MORE COMPLICATED ANIMALS LIKE PIGS OR PRIMATES BUT AGAIN DOING HUGE COURSE AND HOST OF OTHER FACTORS. YOU CAN EVEN LOOK AT SEX DIFFERENCES IN CELL CULTURES, AND THIS IS STUDIED AND REPORTED IN A PAPER BY PATTY HER NONAND COLLEAGUES, MORE SUSCEPTIBLE THAN FEMALES TO CHALLENGES FROM PHARMACOLOGIC CELLS LIKE GLUTAMATE OR PERINITRATE OR OTHER NEUROTOXIC AGENTS. SO THOSE ARE FACTORS TO BE CONSIDERED AS WELL. AGAIN, OVERLOOKING THE INTERACTIONS, ESTROGEN PROGESTERONE AND ANY BRAIN INJURY OUTCOME MEASURE MAYBE A RISK TO TRY TO TRANSLATE TO THE HUMAN CONDITION. SO THE OTHER FACTOR THAT I WANT TO MENTION LATER, I'LL START HERE, IT'S OFTEN REALLY IMPORTANT TO LOOK AT COMORBIDITIES, PERHAPS SUCH AS DIABETES, THINGS LIKE VITAMIN D DEFICIENCY, ALL THESE THINGS CAN PLAY A ROLE IN INCREASING SIZE OF AN INJURY AND ARE RARELY STUDIED IN ANIMAL MODELS AND WE ALSO LOOK AT IN IN CLINICAL MODELS AS WELL, REPRESENT WORK ON ANESTHETIC PRE-CONDITIONING THAT CONTINUES NOW THAT SHOWS THAT ANESTHETICS IN FEMALES DON'T WORK THE SAME WAY AS THEY DO IN MALES. SO THIS IS AN IMPORTANT FACTOR PATIENTS FOR EXAMPLE GOING INTO A CLINICAL TRIAL ARE BEING GIVEN INTUBATIONS OR GIVEN OTHER TYPES OF HOSPITAL INTERVENTIONS OR IN HOSPITAL WHERE THEY MAY REQUIRE VARIOUS TYPES OF ANESTHETICS AND THEN THIS IS GOING TO INTERACT SUCH AS IN ANIMALS'S A BIG PROBLEM IS GIVING KETAMINE AS A TREATMENT, IT WILL DRAMATICALLY AFFECT HOW THE OUTCOME OF PROGESTERONE TREATMENT MIGHT OR MIGHT NOT WORK. THERE'S LOTS OF THINGS, AGAIN YOU HEARD THIS EARLIER, PEOPLE ARE NOW BEGINNING TO TAKE SERIOUSLY DIFFERENCES IN MITOCHONDRIAL RESPIRATION AS PRIMARY CAUSE IN EARLY STAGES OF SIGNALING PATHWAY CHANGES. AT THIS LEVEL, I CAN'T TALK ABOUT ALL THESE STUDIES BUT I WANT TO SHOW YOU A NUMBER OF THEM JUST TO SHOW YOU THAT THERE'S A LOT OUT THERE, LOOKING AT SEX DIFFERENCES IN MITOCHONDRIAL FUNCTION AN RESPIRATION, SO THIS PARTICULAR VERY EARLY STAGE CHANGE IN THE WHOLE CYCLE OF INJURY CAN'T BE OVERLOOKED IF THEY'RE IMPORTANT SEX DIFFERENCES AND SHOULD YOU BE STUDYING THESE KINDS OF CHANGES IN ANIMAL MODELS AS WELL AS IN PEOPLE. THERE ARE LOTS OF SEXUALLY DIMORPHIC OUTCOMES YOU HEARD ABOUT IN ANIMAL STUDIES, IN HYPOXIC INJURY, MALE ANIMAL BASICALLY SHOW MORE MICROGLIAL ACTIVATION, MUCH MORE INFLAMMATORY RESPONSE COMPARED TO DAY 3 AND DIFFERENCE DISAPPEAR AS LITTLE LATER IN LIFE. SO WHETHER YOU'RE REALLY DOING THESE RECORDINGS, THEY ALSO HAVE LESS, MAYBE LESS BRAIN TISSUE LOSS AND LESS BEHAVIORAL DEFICITS COMPARED TO THE MALES AN DEPENDS ON WHEN YOU MEASURE THIS. BASICALLY THERE ARE IMPORTANT CHALLENGES IN TRANSLATION FROM THE ANIMAL STUDIES OVER TO HUMANS. AND THEY ARE NOT SYSTEMATICALLY ADDRESSED AS MUCH AS THEY SHOULD BE, PROBABLY BECAUSE OF THE PRESSURES FROM TIME, THESE LIMIT UP YOU CAN DO IN A SINGLE STUDY AND HOW YOU'RE GOING TO THEN BE REVIEWED WHEN IT COMES TO STUDY SECTION EVALUATION OF ONE'S PROGRESS. THE OTHER THING CLEARLY TREATMENT FOR -- HAVE TO BE DONE. ONE OF THE THINGS THAT PEOPLE RARELY NEED TO RECOGNIZE IS THAT ANIMALS ESPECIALLY RODENT VERSUS HIGHER METABOLISM RATES THAN HUMANS SO HUMANS OFTEN REQUIRE LOWER DOSES OF RODENTS. -- IN RODENTS IF YOU'RE EXTRAM LATING DIRECTLY FROM ANIMAL DOSING TO HUMAN DOSING WITHOUT CONSIDERING PROPER ALLO METRIC SCALING AND EVEN WITHIN ANIMAL SCALING BECAUSE I MENTIONED EARLIER, FEMALES METABOLIZE DRUGS DIFFERENTLY AND THE ROOT OF ADMINISTRATION AND DURATION CAN PLAY AN IMPORTANT ROLE. AND HOW YOU MODEL THIS EFFECTIVELY TO COINCIDE WHAT'S BEING DONE IN HUMANS OR WHETHER HUMANS YOU CAN ASK SHOULD BE IF A STUDY SHOULD BE MORE OR LESS MODELING HOW THESE DOSING AND IN ANIMAL STUDIES MAYBE AN DONE- IMPORTANT STEP. YOU HAVE HEARD FROM CLINICAL COLLEAGUES CLEARLY IT'S IMPORTANT TO BEGIN THINKING ABOUT NOT JUST THE FAILURES BUT WHAT YOU CAN DO TO CHANGE THE PARADIGMS OF STUDY THAT ARE USED IN THE CONDUCT OF CLINICAL AS WELL AS IN ANIMAL TRIALS. HERE IS ONE REPORT WE FOUND EXAMPLE IN THE -- TRIAL MAY VERY WELL HAVE BEEN INADVERTENTLY THE ANIMAL DOSES WERE NOT PROPERLY SCALED UP. OR DOWN IN THE -- IN THIS CASE TO HUMAN TREATMENT. WHERE IT MIGHT HAVE BEEN MAYBE MORE EFFECTIVE, SLIGHTLY LOWER DOSES THAN IN HUMANS THAN IN MALES BECAUSE RATS HAVE A FOUR FOLD HIGHER METABOLISM RATE THAN HUMANS DO SO DRUG IS EXTREATED MORE QUICKLY SO DOSING IS A VERY DIFFERENT ISSUE AS THEY ALSO MENTIONED -- DAVE MENTIONED IN HIS TALK. SO BASICALLY, FOR BOTH ANIMAL STUDIES AN HUMAN, WE HAVE TO LOOK MUCH MORE CAREFULLY AT SELECTION PROCEDURES. WHAT TYPE OS INJURIES ARE WE DOING? IT WAS REPORTED JUST EARLIER THAT IT'S IMPORTANT TO STRATIFY PEOPLE SO YOU'RE NOT DEALING WITH ALL THESE MULTIPLE TYPES OF INJURIES AN COMORBIDITIES. WE HAVE TO DO THE SAME THING FOR ANIMAL STUDIES. THE BIG QUESTIONS ALL RELATE TO HOW FUNDING THIS VERY DIFFICULT TIME WILL BE MADE SHOULD ANIMAL MODELS ALSO MULTIPLE TYPES OF INJURY, MOST TIME IN ALMOST EVERY ANIMAL STUDY ONE ENTRY, MAYBE SLIGHTLY LARGER OR SLIGHTLY SMALLER BUT NOBODY IS REALLY DONE STUDIESES WITH MULTIPLE TYPE OF INJURY, FRONTAL CORTEX, AND HIPPOCAMPUS AND MOTOR CORTEX AN VISUAL CORTEX. AND ON TOP OF THAT, IF YOU'RE GOING TO DO THESE MULTIPLE INJURIES DO YOU INCLUDE MALES AND FEMALES AND HOW WILL THAT A TO THE TIME PRECIOUS TO GET THE WORK DONE AS WELL AS THE FUNDING HOUSING OF THE ANIMALS, ALL OTHER CHARACTERISTICS THAT HAVE TO GO INTO DECIDING HOW MUCH WORK YOU CAN GET DONE AND PROPOSE TO STUDY SECTION WITHOUT BEING ACCUSED OF BEING OVERLY AMBITIOUS OR UNDERAMBITIOUS ONE WAY OR THE OTHER, YOU'RE CAUGHT IN A TRAP. BASICALLY OTHER FACTORS THAT WE DO AND MOST LABORATORY STUDIES IS WE USUALLY ENSURE THAT ALL ANIMALS ARE THE SAME AGE. COMING FROM A HANDFUL OF DIFFERENT LEADERS. BUT CLINICAL STUDIES AS YOU HAVE SEEN OVER AN OVER HERE TODAY INCLUDE A RANGE OF AGES, FROM 18 TO 95 OR 18 TO 40 OR 40 TO 60. THAT'S NOT TYPICALLY THE CASE, HOW SHOULD THEY BE REFLECTING A WIDE RANGE OF AN MA'AMS WHERE YOU TAKE THE MEAN AT DIFFERENT AGES AND THROW TO NEW GROUP AN ON TOP OF THAT BE REQUIRED TO INCLUDE DUPLICATE 100% THAT SAME STUDY IN FEMALES ALL WITHIN ONE STUDY. IF YOU ARE DOING THE FEMALES IN THIS NOW LARGER STUDY, ARE YOU SUPPOSED TO BE DOING IT REGARDLESS WHETHER THEY ARE IN ESTRA CYCLE OR AT LEAST TAKING SMEARS OF THE -- THAT YOU KNOW EXACTLY WHEN A TREATMENT OR MANIPULATION THE INJURY OR THE TREATMENT, IS GIVEN, TIME WEES STRAY CYCLE TO EXAMINE LATER ON. IN HUMANS WITH TBI THEY OFTEN HAPPEN AS SEEN TODAY NUMBER OF CONDITIONS LIKE DIABETES OR OBESITY OR OTHER FACTORS THAT HYPERTENSION THAT CAN ALSO VARY BY SEX. AND I DON'T KNOW OF ANY STUDIES THAT WE CAN ACTUALLY JUST STARTED DOING, WE'RE LOOKING AT THESE COMORBIDITIES AS POTENTIAL (INAUDIBLE) SO IT'S NOT ALL ABOUT JUST ANIMAL STUDIES. WE ALSO AS DAVE CORRECTLY POINTED OUT AND OTHERS, YOU HAVE TO LOOK HOW CLINICAL STUDIES ARE DONE. SHOULD THE CLINICAL TRIALS BE LESS HETEROGENEOUS? SHOULD WE FOCUS MORE ON VERY SPECIFIC TYPE OF INJURY, SPECIFIC SEVERITY. MAYBE NOT INCLUDE PATIENTS. WHO ALSO HAVE HYPERTENSION. WHAT ABOUT SELECTING PATIENTS WITH SIMILAR INJURIES, THAT'S THE WHOLE POINT. WE DO THIS IN THE LAB ALL THE TIME. WE TRY TO ACHIEVE EVERY SINGLE ANIMAL AS EXACTLY THE SAME TYPE OF INJURE TO THE INTEREST OF OUR ABILITY, YOU CAN'T DO THAT IN THE HUMAN CONDITION SO SHOULD WE CHANGE OUR MODEL OR THOUGH MIGHT TAKE LONGER AT CLINICAL TRIALS, SHOULD YOU FOCUS MORE ON SPECIFIC TYPE OF INJURY? FINALLY, I THINK WHEN WE LOOK AT OUTCOME AFTER STROKE OR TBI, WE DO GAIN ANALYSES THAT MEASURE # 52 PARAMETERS HOW ANIMAL WALKS ACROSS PLATFORM. THESE QUANTITATIVE MEASURES. ALL TODAY I HEARD ABOUT IS GOS SELF-REPORTED STUDIES, THESE KINDS OF QUALITY OF LIFE OUTCOME MEASURES THAT ARE VERY, VERY DIFFERENT THAN QUANTITATIVE MEASURES YOU'RE DOING IN THE LAB. EVERYBODY IS WILLING TO DO EXTREME QUANTIFICATION OF BIOMARKERS AND OTHER MEASURES BUT YET PULL BACK ON WHAT ARE RELATIVELY IF I CAN SAY THIS, INSENSITIVE MEASURES THAT DON'T REPEAT OR REPLICATE THE KINDS OF MEASURES WHETHER GAIN ANALYSIS, GRIP STRENGTH, ALL THESE OTHER VARIABLES THAT ARE VERY CAREFULLY QUANTITATIVE MEASURES IN BOTH MALES AN FEMALESES IN THE LAB IRTO. SO WHERE ARE WE? PRE-CLINICAL REPORTS ON BENEFITS O NEUROPROTECTIVE AGE AND TREATMENT IN CNS INJURY CONTINUE TO REPEAT OVER AN OVER. AS DAVID MENTIONED, PROGESTERONE HAS A STRONG BIOLOGICAL SIGNAL, CLOSE TO 500 PUBLICATIONS SHOWING EFFICACY IN OVER 22, MAYBE EVEN MORE INJURY MODELS NOW. IT'S CLEARLY GETTING MORE DIFFICULT TO GET SUPPORT FOR CLINICAL TRIALS IN TBI AND IN STROKE BECAUSE OF THE CONTINUOUS FAILURE RATE. PHARMACEUTICAL COMPANIES DON'T WANT TO CONTINUE TO INVEST IN IT. NIH IS OBVIOUSLY RELUCTANT TO DO IT FOR THE OBVIOUS REASONS BUT YET HERE WE ARE. AS DAVID POINTED OUT, STILL IN GREAT NEED OF APPROPRIATE THERAPEUTIC TOOLS WE CAN USE. SO EVERYBODY ALL TRIALS CLEARLY THERE'S GOT TO BE A DIFFERENT REMEDIATIONS WHEN YOU STOP AND THINK IT'S HARD TO BELIEVE ALL ANIMAL STUDY IF ALL CLINICAL TRIALS FAIL MAYBE IT'S TIME TO ALSO LOOK AS DAVID POINTED OUT HOW TO IMPROVE CLINICAL TRIALS. THEN TELL US INVESTIGATORS WHAT SPECIFICALLY TO SEE US DO TO WORK HAND IN HAND TO MAKE THINGS BETTER FOR YOU. SO I THINK WE NEED TO PAY MORE ATTENTION TO SEX DIFFERENCES CLEARLY AS WELL AS COMORBIDITIES, IN ANIMAL MODELS. THAT'S SOMETHING THAT IS DONE. WE LOOK AT OTHERS VITAMIN D AND THE INSUFFICIENCY WHICH IS A RELATIVELY EASY THING TO TREAT, IS A FACTOR IN OUTCOME IN OUR STROKE STUDIES AND TBI STUDIES, IF YOU HAVE A DEFICIENCY OR INSUFFICIENCY IN VITAMIN D LEVELS, SIMILAR LIKE A COUSIN OF PROGESTERONE, IT WILL HAVE IMPORTANT OUTCOME -- IT WILL AFFECT OUTCOMES, GOING TO INCREASE THE SIZE OF THE STROKE, IT WILL DECREASE BEHAVIORAL RECOVERY AND HERE THERE'S STUDIES SHOWING THAT IT AFFECTS OUTCOME SCORES, THREE MONTH GOSS SCORES IN PATIENT VITELLIN D DEFICIENCY DO WORSE, JUST APPEARED IN 2017, IN TRAUMA. I WANT TO BRING OUT THIS SLIDE, THERE'S RECENTLY A PUBLICATION PUT OUT IMPROVING TESTIMONY -- NERVOUS SYSTEM DISORDERS. THIS WORKSHOP IS AN IMPORTANT STEP FORWARD BECAUSE WHEN I WEPT THROUGH THIS, I DID A WORD SEARCH ON SEX OR SEX DIFFERENCES IN THIS NATIONAL ACADEMY OF SCIENCES AN INSTITUTE OF MEDICINE REPORT. I FOUND ONLY FOUR MENTIONS IN THE ENTIRE STATEMENT. THOSE IN PARENTHESES AS IN THIS STATEMENT ON HE ROW GENEITY, CAREFUL MATCHING OF CONTROL EXPERIMENTAL GROUPS, EG SEX, AGE, STRAIN, THAT WAS THE EXTENT. THE DOCUMENT WHICH CONSTANTLY NATIONAL ACADEMY INSTITUTE OF MEDICINE, MAKES NO SPECIFIC RECOMMENDATIONS ON HOW TO IMPROVE STUDY ON WHAT SPECIFICALLY NEEDS TO BE DONE TO EVALUATE TBI OR OTHER CNS DISEASE OUTCOMES AND HOW THEY DIFFER FROM MALES AN FEMALES. SO PEOPLE AT AD MAXIMUM STRAYTIVE POLICY MAKING LEVEL THEY REALLY HAVE TO PUT THEIR MONEY WHERE THEIR MOUTHS ARE, IF WE'RE GOING TO MAKE THESE CHANGES AT BOTH PRE-CLINICAL AN CLINICAL LEVELS. SO I WAS ASKED TO WHAT THE NIH CAN DO TO IMPROVE THE SITUATION. WITH THE PRE-CONFERENCE TELEPHONE CALL. IMPORTANT TO STUDY MALES AN FEMALES IN BASIC RESEARCH CLINICAL STUDIES HAS TO BE DONE AND RECOGNIZE THAT IT WILL TAKE LONGER AND THAT IT WILL TAKE MORE EXPENSE. AND THAT RESEARCHERS ARE GOING TO HAVE TO BE CONVINCING, THAT THEY WILL BE PUNISHED IF THEY TAKE THE TIME TO DO THESE THINGS. I BELIEVE THIS IS A PERSONALITY STATEMENT. ALL THE BIOMARKERS ARE FINE, IT'S IMPORTANT TO STUDY, THAT'S WHAT WE DO IN OUR LAB ADS WELL BUT I THINK THAT LONG TERM STUDIES OF MAPPINGS BILL FUNCTIONAL OUTCOMES IN CONTEXT OF SEX DIFFERENCES MAYBE MORE RELEVANT TO PATIENTS AND THEIR CAREGIVERS. THEY MAY NOT BE INTERESTED IN DOPAMINE LEVELS OR P-53 GENE BUT THEY WILL BE INTERESTED IN WHETHER THEY CAN WRITE A CHECK, DRIVE, GET BACK TO WORK. AND OUTCOMES THAT MEASURE THESE KINDS OF THINGS AND THERE ARE OUTCOMES LIKE THIS IN ANIMAL STUDIES, THAT CAN BE DONE IN SIMILAR PARALLELS, THESE TWO NEED TO BE GIVEN MORE CONSIDERATION. I SEE IN GREAT APPLICATIONS THAT I SUBMIT WHEN READING THEM, THE OVERWHELMING EMPHASIS IS FIRST DETERMINING MECHANISMS BEFORE SAFETY AND EFFICACY OF ANY NEUROTHERAPEUTIC TOOL AND IS SUPPORTED. AND THIS -- THE FIRST COMMENT YOU GET BACK, WHAT IS THE SPECIFIC MECHANISM? WE KNOW FROM HEARING OTHER TALKS, MANY DRUGS FOR EXAMPLE LIKE PROGESTERONE ARE PLEIOTROPIC, AS SOON AS YOU MENTION THAT, IF YOU DEAL WITH DRUGS WITH MULTIPLE SIGNALING PATHWAYS, RIGHT AWAY THE STUDY, IT IS NOT MECHANISTIC ENOUGH TO SPECIFY SIGNAL PATHWAY. THAT APPROACH IS A FLAWED APPROACH. AND THESE MAGIC FLAWED APPROACHES TO TREATMENT DEVELOPMENT IN LIGHT OF ALL THE FAILURES, THEY HAVEN'T WORKED AND WHY SHOULDN'T WE CONSIDER NOW MAYBE MULTIPLE COMBINATION THERAPIES OR HORMONAL DRUGS THAT AFFECT COMPLICATED SYSTEMS LIKE STEROIDS OR LIKE AFFECT MULTIPLE SYSTEMS MAKE WE KNEE THE LOOK AT THE FACT THAT YOU'RE NOT GOING TO SOLVE PROBLEM BY TARGETING A SPECIFIC DRUG. IT'S VERY INTERESTING ONE PERSONAL ANECDOTE THEN I'M THROUGH. WHEN WE SUBMITTED A SMALL GRANT BECAUSE OF ALL EMPHASIS ON MECHANISM WE TRY TO PUT IN A MECHANISM WHEN WE GO TO ANY OF THE STUFF ON TBI OR STROKE. WE'RE LOOKING AT EFFECTS OF PROGESTERONE ON MITOCHONDRIAL DYSFUNCTION AND OTHER BIOMARKERS IN TUMOR MODEL BECAUSE CNS TUMORS ARE DEVASTATING. WHATEVER THEY ARE, THEY CERTAINLY BRING INJURIES. ONE OF THE FIRST COMMENTS BACK IS WHY ARE YOU SAYING MECHANISM IRST SHOWN THAT IT WORKS AND IT HAS SAFETY AND EFFICACY IN KINDS OF OUTCOME MEASURES WE'RE INTERESTED IN. THERE ARE DIFFERENT APPROACHES, IT DOESN'T NECESSARILY BE -- IT ISN'T NECESSARILY AN ABSOLUTELY WRITTEN IN STONE, TRYING TO UNDERSTAND A MECHANISM OF SOMETHING BEFORE IT'S EVER TESTED FOR ITS POTENTIAL SAFETY EFFICACY IN ANIMAL OR PATIENT MODELS. SO MY CONCLUSIONS ARE, FROM EVERYTHING WE WERE HER TODAY FOLLOWING THE LITERATURE ADS LOG AS I HAVE, THE MAGIC APPROACH SEEKING SPECIFIC DRUGS TARGET ONE MECHANISM, IT HASN'T WORK. THAT'S WHY PART AND PART 100% FAILURE RATE. TARGETS ARE NOT THE SAME FOR MALES AND FEMALES, WE HEARD THAT TODAY, THAT THANKS TO OTHERS NEED TO BE GIVEN MORE CONSIDERATION. I THINK CLEARLY MAYBE TIME TO BE A LITTLE LESS INCLUSIVE AND MORE FOCUS ON SELECTION LASES PHICATION OF PATIENTS RATHER THAN BROADEST RANGE POSSIBLE. I BELIEVE FROM MY PERSPECTIVE WORKING IN THE FIELD FOR DECADES, IS THAT PRE-CLINICAL STUDIES NEED TO INCORPORATE CAREFUL ATTENTION TO DOSING, THAT REFLECTS WHAT HAPPENS WITH PEOPLE. THIS IS OFTEN OVERLOOKED IN ANIMAL STUDIES WHERE YOU GO FROM ONE DOSE PRODUCING A SPECIFIC TARGETED EFFECT T ON MARKET THAT YOU WANT TO SEE. RECOVERY OF SURROGATE MARKERS, REPAIR, STILL REALLY REMAIN TO BE DEFINED LIKE THE HOLY GRAIL OF THE FIELD. AND I BELIEVE FROM THAT PERSPECTIVE FROM THE WORK WE HAVE DONE, THAT WHILE FOCUSING ON BIOLOGICAL MARKERS, IS ALSO IMPORTANT, YOU HAVE TO REMEMBER BEHAVIOR IS A BIOLOGICAL MARKER NOT FROM OUT OF SPACE SO WE NEED TO HAVE BETTER FUNCTIONAL BEHAVIOR END POINTS FOR HUMAN AND ANIMAL STUDIES TO BETTER INFORM ONE ANOTHER. AND I THINK AT THIS STAGE, CLEARLY WE MAY NEED TO BEGIN TO INVOLVE MORE RETENTION TO GYNOING DIFFERENCE TYPES OF THERAPIES, DAVE TALKED ABOUT REHABILITATION. REHABILITATION IS A FORM OF THERAPY. EARLY EXPOSURE TO STIMULI, CHRONIC STRESS, ALL THESE FACTORS, MAY ALSO PLAY AN IMPORTANT ROLE AND YOU MAY HAVE TO HAVE COMBINATION TREATMENTS LIKE SIMPLEST ONE I CAN THINK OF VITAMIN D, SUPPLEMENTATION, AND PROGESTERONE OR ANY OTHER IF YOU WANT TO IMPORTANT METABOLIC CONTINUE POINT, MORE LIKELY DIMINISH EFFECTS OF THERAPEUTIC TREATMENT. IMPORTANT TO EVALUATE SEX DIFFERENCES IN CLINICALLY RELEVANT COMORBIDITIES SO I FEEL JUST AS BAD AS DAVE, I DON'T THINK FAIR Y'ALL IS FAILURE IS FATAL. THANK YOU FOR YOUR ATTENTION. SORRY I COULDN'T BE HERE WITH YOU. [APPLAUSE] >> THANK YOU, DR. STEIN. OUR NEXT SPEAKER IS DR. CANDACEFULLY FROM UNIVERSITY OF UTAH. SHE IS ASSOCIATE PROFESSOR VICE CHAIR OF RESEARCH IN THE PHYSICAL MEDICINE AN REHABILITATION DEPARTMENT AT THE UNIVERSITY OF UTAH. AND RESEARCH FOCUS CONSIST ON MODELS OF TBI AN SPINAL CORD INJURY. >> THANK YOU ALL FOR HANGING IN THERE AT THE ALMOST THREE O'CLOCK HOUR AFTER THOSE DELICIOUS CUP CAKES. 'S ALREADY BEEN A GREAT SESSION. THAT'S REALLY HIGHLIGHTED THIS ISSUE THAT'S CALLED THE VALLEY OF DEATH. THE TITLE OF THE SESSION ALSO HIGHLIGHTS THIS LACK OF TRANSLATION. SO WHAT I WANT TO TALK TO YOU ABOUT TODAY IS A SLIGHTLY DIFFERENT APPROACH, THE IDEA WE CAN POTENTIALLY USE LARGE ANIMAL MODELS AS A TRANSLATIONAL INTERMEDIARY. SO THE VIEW THAT YOU HAVE ALREADY BEEN PRESENTED IS THAT SOME OF THE FINDINGS FROM SMALL ANIMALS RODENTS RATS AND MICE WHICH ARE VERY IMPORTANT TO OUR RESEARCH HAVE NOT TRANSLATED. MANY HAVE NOT TRANSLATED. SO THERE ARE MANY MODELS LARGE ANIMAL MODELS, THE POINTER MAY WORK HERE ARE USED IN NEUROTREMOR RESEARCH. I'M GOING TO FOCUS ON PIG MODELS TODAY. SO PEOPLE HAVE USED MONKEY MODELS, SHEEP MODELS AND THEN NATURALLY OCCURRING MODELS IN TERMS OF SPINAL CORD INJURY ARE USED THE DOGS AS WELL. BUT FOR REASONS I'LL FOCUS ON THE PIG. ONE REASON FOR THINKING ABILITY LARGE ANIMAL MODELS AS A TRANSLATIONAL ENTERNEED WARE IS SIMPLY THE BIOLOGY -- INTERMEDIATE AREA IS THE BIOLOGY, THERE'S ANATOMICAL DIFFERENCES SOME ALLUDED TO TODAY, BETWEEN RODENTS AND HUMANS, MAYBE REDUCED IN LARGE ANIMAL MODELS SO THE IDEA IS THAT YOU MIGHT HAVE THAT BRIDGE TO GET US OVER THE VALLEY OF DEATH. SO SOME OF THE THINGS THAT HAVE BEEN MENTIONED I'LL HIGHLIGHT THIS IDEA OF GYRUS AND FAFFIC BRAINS WALTER BROUGHT UP EARLIER, HOW IMPORTANT THAT MAYBE IN TERMS OF TRAUMATIC BRAIN INJURY. OTHER THINGS I WON'T TALK ABOUT TODAY BUT ARE IMPORTANT WHEN THINKING BIOMECHANICAL LOADING OF INJURY INCLUDING BONY SKULL STRUCTURE, DURAL STRUCTURES IN THE PIG BRAIN NEARLY IDENTICAL TO HUMAN -- IN THE FOR SEEN BRAIN MIRROR THOSE OF THE HUMAN BRAIN. THERE'S SOME THINGS THAT ARE NOT ON THE LIST BROUGHT UP BY DON AND OTHER COLLEAGUES, SO THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PIGS NEARLY IDENTICAL TO THAT OF HUMANS. THEN I WILL TALK ABOUT SOME OF THESE IMPORTANT CHARACTERISTICS RELATED TO SEX. THIS IS A NICE FIGURE BY MY FRIEND AN COLLEAGUE BOB WHERE HE'S LOOKING AT THE BIOMECHANICAL COMPONENTS OF A GYRUS CEPHALIC BRAIN. HE MAKES POINT ANGULAR ACCELERATION, ONE ACCELERATION MODALITIES THAT'S CRITICAL IN TBI, ANGULAR ACCELERATION THE FOCUS THE MAXIMAL STRESS FIELDS OF THE BASE OF EACH OF THOSE SO IS IT'S ILLUSTRATED HERE, YOU CAN SEE IN THE CEPHALIC BRAIN AND ILLUSTRATED HERE IN RAT BRAIN, THERE'S UNIFORM STRESS FIELDS AROUND THAT LIST OF CEPHALIC BRAIN SO ANY POINT IN CORTEX YOU SEE BIOMECHANICAL LOADING THAT'S SIMILAR. MAY NOT BE A REGIONAL HETERO GENERAL NAYTY REFLECTIVE OF HUMAN BRAIN INJURY. IF YOU COMPARE THAT TO THE MAXIMAL STRESS FIELDS IN THE HUMAN BRAIN, WHAT YOU CAN SEE ARE THE DARKER AREAS INDICATED AS POINTS OF STRESS. SO YOU CAN SEE A DIFFERENT PATHOPHYSIOLOGY AT THE BASE OF THE SULKI. AS ILLUSTRATED HERE SO ADDITIONAL ASPECT OF THE BIOMECHANICS OF A GYRUS CEPHALIC BRAIN, THE PRESENCE OF GIRI AFFECTS THE BRAIN DEFORMATIONS. THAT'S SHOWN HERE IN A DIFFERENT WAY BY RECENT STUDY BY MCMAHAN IN THIS ET AL, THE QUESTION THEY ASK HERE IS HOW MUCH FORCE IT TAKES TO CAUSE A DEFORMATIONS OR DISPLACEMENT OF THE BRAIN COMPARING MOUSE IN BLUE, RATS IN RED, AND PIG IN GRAIN. -- GREEN. IT TAKE AS LARGER AMOUNT OF FORCE TO CAUSE THE SAME LEVEL OF DISPLACEMENT IN THE CORTEY SEIZE OF THESE BRAINS. SUGGESTING THAT ATMOSPHERE IS NOT PRODUCING THAT SAME LEVEL OF INJURY IN GYRUS CEPHALIC BRAIN AND MAKES US WONNER ABOUT THE HUMAN BRAIN. SO LET'S LOOK AT THIS IN A SLIGHTLY DIFFERENT WAY. SO LET'S TAKE A LITTLE BIT ABOUT WHAT GYRUS AND FALLIC BRAINS MIGHT BE GOOD MODELS SO'S A/NEUROANATOMY SAYING THE LARGER THE BRAIN THE MORE GIRI OR GREAT EGEE REIFICATION INDEX MAYBE. IN GENERAL THAT'S TRUE. BUT THIS IS A PLUG FOR PIGS. WHO DOESN'T LIKE BACON. ONE THING TO LOOK AT IN THIS, LOOK AT THE HUMAN BRAIN WEIGHT AND YOU CAN SEE THE INDEX IS 2.5 FOR HUMAN BRAIN. IN THE MONKEY PEOPLE SAY WE SHOULD HAVE DONE THIS TRANSLATIONAL WORK IN NON-HUMAN PRIMATE. THE PRIMATE MOST OFTEN USED, YOU CAN SEE THE BRAIN IS ABOUT 90 GRAMS, JEWRY PHICATION IS.91. COMPARED WITH THE DOMESTIC PIG BRAIN WEIGHT BUT MUCH HIGHER INDEX. SO INTERESTINGLY IF YOU HAVE USED THIS INDICES OF IMPORTANCE IN BRAIN THE PIG IS A GOOD MODEL FOR TRAUMATIC BRAIN INJURY. ARE THE TOOLS VAILIAL? NEXT THICK PEOPLE SAY, I HAVE TO START AT THING BEING AND REINVENT THE WHEEL TO STUDY TRAUMATIC BRAIN INJURY IN PIGS. ANSWER IS NO. THERE'S SEVERAL WELL ESTABLISHED MODELS IN PIGS, CONTROLLED CORTICAL IMPACT, ROTATIONAL INJURY TO NAME A FEW WELL CHARACTERIZED MODELS IN SEVERAL LABS. WHAT'S INTERESTING IS THAT MY ACUTE PIG ICU LOOKS LIKE THE PIG MICHAEL SHOWED YOU MINUS THE TEDDY BEAR. SO I USE EXACTLY THE SAME MONITORS AND THE SAME WAY THAT MICHAEL SHOWS IN THE ICU. THE SAME INSTRUMENTATION. SO IF YOU THINK ABOUT TRANSLATION, RESIDENCES LOVE TO WORK IN MY LAB BECAUSE THEY'RE LIKE OH THIS IS REALLY WHAT WE'RE DOING OVER ACROSS THE STREET. THERE'S INTERESTING EVIDENCE BASE INFORMATION THAT CAN COME FROM PORCINE STUDIES MIMIC THE HUMAN ICU IN CRITICAL CARE. HOW DO YOU MEASURE MEMORY IN PIG? IN VERY SOPHISTICATED WAYS AND MANY HAVE DONE THIS ALREADY. SO NEUROLOGICAL SEVERITY SCORES HAVE BEEN CHARACTERIZED IN PIGS. PIGS ARE SMART ANIMALS, THEY SEE COLOR. WE TRAIN THE PIGS TO TARGET COLORS SO THEY COME WHEN CALLED, THEY RESPOND TO SIMPLE COMMANDS, THEY SIT, ROLL OVER, COLOR, WHOLE BOARD DISCRIMINATION, TEAMMATE TASKS OPEN FEEL INVESTIGATOR APPROACH TASK USED FOR ANXIETY. WE HAVE STARTED, I DIDN'T BRING THE DATA TO THIS TIME TO LOOK AT BIOACOUSTICS SO PIGS VOCALIZE IN THE AUDIBLE RANGES. WE HAVE IDENTIFIED 37 UNIQUE VOCALIZATIONS THAT PIGS -- WE CAN SEPARATE USING BIOACOUSTIC TECHNIQUES DEVELOPED FOR BIRD SONG, STRESS AND ANXIETY CAUSED IN PIGS FROM THOSE IN JOY AN PLEASURE SITUATIONS WITH. WE CAN SPEAK PIG IN A WAY TO INTERPRET WHETHER THEY'RE IN PAIN OR ANXIETY. SO I DID A QUIT SEARCH TO LOOK AND SEE, WE DIDN'T START TIMER BUT YOU PROBABLY WANT TO GET ME GOING. RESEARCH TO SEE WHAT PERCENTAGE OF RECENT STUDIES IN 2017 IN PIG TBI, LOOK AT SEX DIFFERENCES. 'S NOT SURPRISING. THERE WAS OF THE 14 PAPERS PUBLISHED IN 2017 IN PIG MODELS OF TBI, ONLY ONE CONSIDERED SEX. THE REST DID NOT. OF THAT SAME 14 PAPERS DO THEY EVEN TELL US WHAT SEX WAS USED? A LITTLE BIT OF WHAT DOUG WAS SAYING. FEMALES ONLY NO REPORT OF INJURY, MOST DON'T REPORT IF FEMALES ARE CYCLING AND VARIES BY TYPE OF PIG WHEN THEY CYCLE AND HOUSING CONDITIONS MATTERS HAVE TO HAVE BOYS IN THE ROOM. THEY DON'T HAVE TO BE IN THE SAME CAGE BUT YOU NEED MALE PIGS IN THE ROOM FOR FEMALE PIGS TO GET TO CYCLE. SO MALE PIGS SOME DO MALE PIGS ONLY, ONE DIDN'T REPORT AND SOME USE BOTH SEXES. ONE THING THAT'S IMPORTANT TO NOTICE ABOUT PIGS, PIGS ARE TRADITIONALLY CASTRATED AT BIRTH SO THE PIGS THAT COME FROM FARM SOURCES WE USE QUITE A BIT OF FARM PIGS AS WELL YOU HAVE CALL AHEAD, MAYBE WAIT ON THAT PHONE CALL BUT YOU DO HAVE TO CALL AHEAD TO GET PIGS IN ADVANCE TO USE AS ADULTS IN THE STUDY. ONLY TWO TALKED CASTRATION STATUS. IT'S INTERESTING THAT SOME OF THE GAPS HERE IS NOT ONLY NEED MORE EVALUATION OF SEX AS BIOLOGICAL VARIABLE IN TBI RESEARCH, THERE'S GAP DOUG AND OTHERS ALLUDED TO, TO DEFINE THE SEX BASED VARIABLES IN THE STUDIES MUCH MORE CLEARLY. WE TALK ABOUT THIS ALREADY, ONE PAPER IN 2017 DID MENTION SEX DIFFERENCES COME FROM THAT COLLABORATIVE GROUP. THIS IS PIG, COURTNEY PRESENTED HUMAN DATA BUT FINDING IS SAME, THERE'S A SEX AN AGE DIFFERENCE, IN RESPONSE TO EPINEPHRINE AUTOREGULATION AND TRAUMATIC BRAIN INJURY. IN THEIR PIG DATA THEY SHOW THE MALES ARE MUCH LESS RESPONSIVE TO EPINEPHRINE THAN FEMALES SO THIS IS A NICE EXAMPLE OF TRANSLATIONAL BRIDGING THIS TRANSLATIONAL INTERFACE WHERE THE TEAM BILL AND MONICA USE THE PIGS AS TRANSLATIONAL MODEL AND DO SAME THINGS IN THE KIDS THEY DO IN THE JUVENILE PIG LETSES IN THEIR STUDY. THIS IS WORK FROM OUR GROUP FOCUSING OWN DOWN ON THE IDEA OF ESTROUS CYCLE DOUG AND OTHERS BROUGHT UP. THE INTERESTING THING IN RODENT, I HAVE DONE SOME WORK IN RODENT NOT TALKING TODAY, RODENT VERSUS A SHORT ESTROUS CYCLE, ABOUT THEE DAYS IS THE DURATION OF THE CYCLE. AS ILLUSTRATED HERE. MOST OF YOU KNOW, HUMAN ESTROUS CYCLE IS 28 DAYS. WHEN YOU LOOK AT HORMONES OF ESTROGEN AND PROGESTERONE, PARTICULARLY WEES STROW GENERAL YOU HAVE THIS BIMODAL AFFECT THAT YOU DON'T SEE IN RODENT. PROGENERAL ROANE AND PATHOLOGY IS DIFFERENT IN HUMAN VERSUS ROW KENT. WE ASK THE QUESTION WHAT IS THE PIG ESTROUS CYCLE LIKE AND WHAT ARE THE LEVELS AND INTERESTINGLY THERE WASN'T A LOT OF THIS IN THE BIOMEDICAL RESEARCH LITERATURE BUT WE FOUND IT IN THE FARM LITERATURE. MAYBE NOT SURPRISING. SO THESE ARE OUR DATA AND WHAT WE SHOW IS THE PIG ESTROUS CYCLE, THIS IS IN YUCATAN PIGS, WE REPLICATED IN FARM PIGS AS WELL IS ABOUT 23 DAYS SOME THE NICE THING ABOUT STUDYING THE EFFECTS OF ESTROUS CYCLE AND ALTERATIONS OF INJURY ON ESTROUS CYCLE IS THE PIG ESTROUS CYCLE MUCH MORE CLOSELY MIMICS THE HUMAN THAN THE RAT. SO YOU HAVE A LONGER MORE CLINICALLY RELEVANT PHYSIOLOGICALLY RELEVANT TIME WINDOW TO ADDRESS THOSE MANY QUESTIONS DON AND OTHERS HAVE BROUGHT UP. TELL ME TIME. I'LL GO FAST. SO WE DID A QUICK STUDY IN SPINAL CORD INJURY R. I'LL GO THROUGH THE DATA QUICKLY BECAUSE IT IS SPINAL CORD INJURY, NOT BRAIN INJURY BUT THE QUESTION IS, ONE OF THOSE BROUGHT UP AS A GAP IN THE LITERATURE, SO WHAT IS THE EFFECT OF INJURING PIGS AT DIFFERENT STAGES OF ESTROUS ON OUTCOME. THIS IS A SPINAL CORD INJURY MODEL. AGAIN OUR GROUPS WERE INTACT MALE PIGS, MEANING GONAD INTACT NON-COST STRAITED MALE -- CASTRATED MALE PIGS. PEOPLE INJURED IN LOW ESTROGEN AND HIGH ESTROGEN BUT NO OTHER MANIPULATIONS IN SEX HORMONES, NOT PIG MATCH BECAUSE THEY GROW AT DIFFERENT WEIGHT BUT WEIGHT MATCHED, I MENTION HAVING CO-ED HOUSING ROOMS IS CRITICALLY IMPORTANT TO MEASURING ESTROUS IN PIGS. SO WE LOOK AT ACUTE AND SIX WEEK TIME POINTS, WITH BASIC STEP OF HIND LIMB LOCO MOTION, SPINAL CORD INJURY MODEL ADS WELL AS TISSUE OUTCOME MEASURES. SO I'LL TALK TO YOU ABOUT THE DATA, I WANTED TO HAVE THIS CAVEAT HERE THIS IS AN ONGOING STUDY, SO PRELIMINARY DATA, THE ENDS ARE ALWAYS PUT HERE IN UNPUBLISHED DATA SO KEEP IT IN MIND WHEN THINKING ABOUT THE INTERPRETATION. I DON'T USUALLY PRESENT PRENARY DATA THIS WAY. BUT WHEN -- PLENARY DATA THIS WAY. THE PRO-INLAMMATORY CYTOKINE AT 48 HOURS POST INJURY, HERE ARE THE UNJURIED CONTROLS -- INJURED CONTROLS, FEMALES AND MALES HAVE LOW LEVELS, INJURY IN FEMALES AND LOW ESTROGEN CAUSES THIS SIGNIFICANT INCREASE IN IL 6 AT 48 HOURS AND MALES ARE A LITTLE LOWER. SO WHAT'S INTERESTING IS DEPENDING WHEN ANIMALS ARE INJURED IN ESTROUS CYCLE MIGHT AFFECT THE EARLY PATHOPHYSIOLOGY. WE'LL PROBABLY HEAR MORE ABOUT THAT IN A MINUTE. SO THEN WE'RE LOOKING AT GRAY MATTER DISTRIBUTION, WE FOUND SOME SEX DIFFERENCES HERE AS WELL. THIS IS GRAY MATTER SPARING AT THE EPICENTER. WHAT WE SAW IS THAT THE MALES, HERE ARE THE UNINJURED CONTROLS AND THIS IS LOOKING AT NEURONAL COUNTS IN THE VENTRAL HORN EPICENTER OF THE SPINAL CORD INJURY, WE SAW THERE WAS A SIGNIFICANT INJURY AFFECT IN ALL THIS INJURY GROUPS BUT INTERESTINGLY THE MALES AT THIS ACUTE TIME POINT, HAD MORE PRESERVATION OF NEURONS WHICH IS A LITTLE BIT DIFFERENT THAN WHAT WE HAD ANTICIPATED. WHEN WE LOOKED AT WHITE MATTER AT THE SAME EARLY TIME POINT WE SEE THE SAME THING. GREATER WHITE MATTER IN THE MALES THAN IN EITHER TWO FEMALE GROUPS. WE GO SIX WEEKS OUT AND EVALUATE MOTOR RECOVERY, QUICK WITH THIS SO SAY TEN IS NORMAL TALKING, -- WALKING. ANIMALS ON TOP UNINJURED, SURGICAL CONTROLS LAMBNECTOMY AS SURGICAL CONTROL. FEMALES OR MALES COVER WELL FROM THAT BACK SURGERY BUT WHAT YOU CAN SEE IS THAT ZERO IS COMPLETE PARALYSIS, 10 NORMAL WALKING. 4 IS WEIGHT BARING SUPPORTING OF THE HIND LIMB AND WHAT YOU CAN SEE IS THERE IS A SLIGHT BUT NOT SIGNIFICANT TREND TO HAVE SEX DIFFERENCES. SO IT SEEMS LIKE THOUGH THERE ARE DIFFERENCES IN THE ACUTE PATHOPHYSIOLOGY, WHEN YOU USE THIS AS A BIOLOGICAL MARKER OF HIND LIMB LO CO-MOTION IT'S NOT CLEAR HOW MUCH DIFFERENCES WEIGH SO BRINGS UP THE QUESTION WHAT SEX DIFFERENCES TURN INTO CLINICALLY BIOLOGICAL RELEVANT OUTCOMES. THAT'S REALLY SOMETHING THAT'S VERY DIFFICULT TO UNDERSTAND AND NEEDS FOR PROBING. GOING TO SKIP AHEAD. TOP SOME OF THIS. EXCEPT TO SAY THAT AT SIX WEEKS POST INJURY YOU CAN SEE AS GRAY AND WHITE MATTER DIFFERENCES ARE SUBTLE. SO LIKE WE EQUILIBRATED OVER SEX AT THAT LATER TIME POINT. THE MAIN FINDINGS FROM THIS PRELIMINARY STUDY USING SPINAL CORD INJURY IS EXAMPLE OF CNS NEUROTRAUMA, SEX DIFFERENCES OBSERVED IN EARLY PATHOPHYSIOLOGICAL MARKERS WERE NOT OBSERVED IN LATER MARKERS. THAT SUGGESTS TO US IT IS VERY SIMILAR TO SOME OF THE COMPLEXES YOU HAVE HEARD TODAY SO NOT JUST SEX AND NOT JUST INJURY BUT IT'S INJURY AND TIME AND PATHOPHYSIOLOGY AN SEX INTERPLAYING IN THIS COMPLEX SCENARIO SO NOT JUST ONE SNAP SHOT IN TIME, YOU NEED TO LOOK AT MANY TIMESES. DIFFERENCES MAYBE SUBTLE AND TIME COURSE DEPENDENT. DON AND OTHERS SUGGESTIONED MAYBE THAT DIFFERENT TIMES INJURY DIFFERENCE SEXES AN STAGES OF ESTROUS CYCLE OR DIFFERENT HORMONAL LEVELS IN THE MALE YOU MIGHT USE DIFFERENT THERAPEUTIC APPROACHES. THIS IS A VERY COMPLEX MOSAIC THAT NEEDS TO BE BETTER UNDERSTOOD AND PART OF THE IDEA IS PERHAPS THESE LARGE ANIMAL MODELS ARE GREAT TRANSLATIONAL IMMEDIATE AREA TO UNDERSTAND COMPLEXITY. THEY HAVE COMPLEXITY IN IN THEIR BRAIN ANATOMY AS WELL AS COMPLEXITY IN THE ESTROUS CYCLE WHICH MAKE THESE REALLY GOOD MODEL AND THERE ARE MANY TOOLS IN PLACE FOR STUDYING TRAUMATIC BRAIN INJURY IN PIGS. WE ARE COLLABORATIVE LAB, YOU HAVE SOMETHING IN RODENT OR SOMETHING IN HUMAN, YOU WANT TO TEST IN A MECHANISTIC WAY, CALL ME WE'LL DO IT SO IT'S A GREAT TOOL THAT CAN BE USED AND IS A SUPPLEMENTARY RESEARCH TO THAT DONE IN RODENTS SO SEX DIFFERENCES IN IN PATHOPHYSIOLOGY ARE COMPLEX AND CERTAINLY NEED MORE STUDY. THANK YOU SO MUCH FOR YOUR ATTENTION. [APPLAUSE] >> KEEPING NOTE. WE HAVE A HARD STOP TODAY AT FIVE O'CLOCK. ARE WE GOING TO NOT HAVE A QUESTION-AND-ANSWER SESSION FOR THIS SESSION, SESSION 3, WHICH IS A BIG SHAME BECAUSE I PERSONALLY HAVE DOZEN OF QUESTIONS ON WHAT WAS PRESENTED. I'M SORRY? THAT'S A GREAT IDEA. OUR FINAL SPEAKER IS DR. ANN RASMUSSON, ASSOCIATE PROFESSOR PSYCHIATRY AT BOSTON UNIVERSITY, BASIC RESEARCH FOCUSES ON THE HYPOTHALAMIC PITUITARY ADRENAL AXIS AND IS PI ON STUDIES BY BOTH THE NIH AND THE DOD. >> AN VA I MIGHT ADD. EVERYBODY DESERVES CREDIT. THANK YOU MUCH FOR THE INVITATION. AND THANK YOU, KATHERINE AND NIH FOR ORGANIZING THIS REALLY IMPORTANT SYMPOSIUM. WE OBVIOUSLY HAVE A LOT OF WORK TO DO BEFORE WE HAVE THIS THING FIGURED OUT. JUST ACKNOWLEDGING MY SUPPORT, COLLABORATORS, ALSO MY COMMERCIAL DISCLOSURES. I WORK AT THE VA AND I WORKED AT NATIONAL CENTER FOR PTSD SINCE THE EARLY '90s. THE FOCUS ON TBI AS YOU MAYBE AWARE IS MORE RECENT, I WORK UP AT VA BOSTON AT WOMEN HEALTH SCIENCE DIVISION NATIONAL CENTER FOR PTSD AT THE VA, THE VA ARE ADD PROGRAMS SPONSORED A LONGITUDINAL STUDY OF THE VETERANS OF THE OEF OIF CONFLICTS AND ARE CHARACTER RIDING THEM IN EXCRUCIATING DETAIL, ACROSS TIME WITH TWO TIME POINTS, I WANT THE POINT OUT ONE OF THE VERY -- ONE OF THE VERY -- ONE OF THE VERY IMPORTANT OBSERVATIONS IS THAT YOU VERY RARELY SEE TBI MILD TBI IN THE ABSENCE OF PTSD IN THIS COHORT THAT HAS BEEN HIGHLY EXPOSED TO TRAUMA. SO THAT'S LIFETIME MILD TBI AN PTSD COHORT OF 500 PLUS. 9% FEMALE, YOU CAN DEFINITELY DO BETTER. AND HERE IS MILITARY TBI AS WELL AS CURRENT PTSD. AGAIN, LARGE PROPORTION HAVE THE COMORBIDITY. THE COMORBIDITY BETWEEN MILE TBI AND PTSD MANY HAVE ALLUDED TODAY MAYBE DUE TO NUMBER OF FACTORS. FIRST THERE'S LIKELY SOME COMMON OVERLAPPING EXPOSURE TO MOTIONAL AND PHYSICAL TRAUMA AT THE SAME TIME. YOUR GET A BLAST INJURY AT THE SAME TIME THAT YOU'RE BEING EXPOSED TO HIGHLY EMOTIONAL AND AROUSING TRAUMATIC STIMULI. THERE'S SYNERGY OR MUTUAL EXACERBATION BETWEEN TWO AND AN AREA I'M GOING TO FOCUS ON THE REST OF THE TALK IS THERE'S LIKELY A SHARED BIOLOGICAL VULNERABILITY AND MOLECULAR PATHOPHYSIOLOGY THAT PLAYS INTO BOTH NEGATIVE OUTCOMES OF TRAUMATIC BRAIN INJURY AN SYMPTOMS OF BEHAVIORAL SYMPTOMS OF PTSD AS WELL AS CO-MORBID MEDICAL DISORDERS SO WE'RE TALKING ABOUT SYNDROMES. THIS HAS BEEN DISCUSSED A LOT TODAY, SAY THAT THE SEX DIFFERENCES IN MILE TBI OUTCOME IS STILL A BIT OUT FOR THE JURY. FEMALES MAY HAVE LONGER RECOVERY TIME AND IT'S AT LEAST SOME STUDIES SHOW INCREASE POST CONCUSSIVE SYMPTOMS IN FEMALES, SOME HAVE SHOWN THAT SOME OF THOSE SYMPTOMS HAVE BEEN HIGH BEFORE EXPOSURE TO TRAUMA. SOME OF THAT MIGHT MAKE SENSE IN LIGHT OF THE REST OF THE TALK. THIS IS A META ANALYSIS SHOWING INCREASE RISK FOR PTSD IN WOMEN. AND PARTICULARLY WHERE YOU LOOK AT NOB SEXUAL ASSAULT WHICH PROBABLY ENCOMPASSES DOMESTIC VIOLENCE WHICH IS DIFFERENCE THAN SAY GETTING INTO A BAR BRAWL. THE SECOND DIFFERENCES IN PTSD SUGGEST THIS IS JESSICA GILL'S WORK, FEMALES HA LONGER RECOVERY TIME. SHOWED INCREASE INCIDENT RISK IN FEMALES BUT NO INCREASE IN INCIDENT RISK FOR PTSD AMONG FEMALE MILITARY PERSONNEL ONCE TRAUMA EXPOSURE WAS CONTROLLED FOR IN ANALYSES INCLUDING MILITARY SEXUAL TRAUMA, SO MAYBE A HARDIER POPULATION BUT SUGGEST WE SHOULD CONTINUE TO LOOK AT THAT. PTSD ITSELF WAS DISORRER OF NON-RECOVERY, IE ALMOST EVERYBODY HAS DEVELOPS PTSD AFTER A SEVERELY TRAUMATIC EVENT LIKE RAPE SAME IN PEN AN FEMALE AND YOU CAN SEE OVER NATURAL COURSE OF 12 WEEKS, ABOUT 50% OF THE WOMEN IN THIS STUDY LOST THEIR DIAGNOSIS WITH LESSER DEGREES OF SEVERITY MANY TERMS OF ASSAULT, YOU CAN SEE THE SAME DOWN WAR CURVE SO BY 12 WEEKS ONLY A PROPORTION OF THE ORIGINAL SAMPLE WITH PTSD HAVE IT. WHAT'S IN THE WAYS OF RECOVERY? THERE MAYBE AVOIDANCE OF REPROCESSING AND EXTINCTION. PEEP DON'T WANT TO COME INTO TREATMENT, OR THINK ABOUT IT AND FIND ANY WAY POSSIBLE NOT TO GO THERE. THE COGNITIVE EXPOSURE BASED THERAPIES HELPED WITH THAT REASON TREMENDOUSLY. SECONDLY THERE'S ON GOING PSYCHOSOCIAL STRESS WHICH GETS IN THE WAY, THAT IS ALSO TO INTERFERE WITH RECOVERY FROM TRAUMATIC BRAIN INJURY, THERE MAYBE NEURAL BIOLOGICAL VULNERABILITIES SOME PEOPLE ARE MORE PRONE THAN OTHERS. WHEN YOU LOOK AT THE COGNITIVE PROCESSING THERAPY OUTCOMES APPRECIATE THERE'S GREAT INTERINDIVIDUAL VARIABILITY. THAT WILL BE A THEME THE REST OF THE TALK. THERE'S SEX DIFFERENCES BUT ALSO INTERINDIVIDUAL VARIABILITY THAT WE HAVE TO CAPITALIZE IF WE'RE GOING TO BE ABLE TO TARGET TREATMENTS APPROPRIATELY TO INDIVIDUALS S DR. MCCARTHY'S TALK CERTAINLY POINTED TO THAT. THESE ARE STUDIES OF THE CPT COGNITIVE PROCESSING THERAPY IN CIVILIANS, YOU CAN SEE THAT THERE WERE QUITE DRAMATIC CHANGES ANYWHERE BETWEEN 48 AND 86 PEGS DECREASE IN SYMPTOM OF PTSD ACROSS THE TREATMENT. BUT NOW, LOOK AT THE STUDIES IN VETERANS WHICH HAVE BEEN RECENTLY COMPLETED WITH LOTS OF FUNDING OVER EIGHT YEARS. THE CHANGES IN THE CAP SYMPTOMS ARE MUCH MORE MODEST AND ACTUALLY HOVER AROUND THE PLACEBO EFFECT ANYWHERE BETWEEN 15 TO 37% REDUCTION IN IN PTSD SYMPTOMS WITH OUR BEST TREATMENT SO FAR FOR PTSD. WHY? LOTS OF STRESS SHORT PERIOD OF TIME AN POSSIBLY THE AFFECTS OF EXPOSURE TO BLAST BLOUNT HEAD TRAUMA. THINGS THAT HAVEN'T BEEN FAIR ROTTED OUT IN THESE STUDIES THUS FAR. SO WE HAVE A WAYS TO GO IN TERMS OF TREATING PTST AS WELL AS TBI. NOW I WANT TO POINT OUT THE BRAIN STRUCTURES, I LIKE YOU TO THINK ABOUT IN TERMS OF RECOVERY FROM PTSD. THE HORMONES I'M TALKING ABOUT AND TBI. FOR PTSD THESE ARE AREAS THAT ARE FOCUSED ON A LOT YOU'RE EXPOSED TO STRESS OR PAIN TRAUMA , CONDITION ONE PAIRED UP WITH BASAL LATERAL NUCLEUS OF THE AMYGDALA, ACTIVATES ESSENTIAL NUCLEUS, OUTPUT TO BRAIN STEM, RELEASE A TONE OF MONOAMINES THAT IMPACT FRONTAL LOBE FUNCTION. IF THOSE ARE HIGH YOU WILL ACTIVATE LOW AFFINITY ALPHA ONE RECEPTOR, WHICH THEN CAUSES THE FRONTAL LOBE TO GO OFFLINE. NORMALLY THE PRE-FRONTAL CORTEX PROVIDES TONIC GLUTAMETERGIC INPUT TO THE AMYGDALA, THAT CAUSES A RELEASE OF GABBA AS WELL AS RELEASE OF METABOLITE OF PROGESTERONE CALLED ALLO PREGNANTNENALONE WHICH PUTS A BLOCK IN THE AMYGDALA OR TRANSMISSION. IF THE STRESS IS TOO HIGH, THE BREAK IS REMOVED. AND YOU FUNCTION AS AMYGDALA C CROWTURE WITH REFLEXIVE RESPONSES. MOVING TO THE SPECIFICS OF MY TALK I WILL TALK SEX AND MENSTRUAL CYCLE RELATED RISK FOR TBI AN PTSD OUTCOME IN WOMEN, POTENTIALLY AND ALSO MEN. METABOLITES PROGESTERONE UPON WHICH I'M GOING TO FOCUS ARE ALLO PREGNANTNAN LOAN. STEREO ISOMERS, APPROXIMATELY EQUIPOTENT. THEY POSITIVELY MODULATE GABBA EFFECTS AT THE GABBA RECEPTOR INCREASING CHLORIDE INFLUX 7 TO 10 TIMES SO VERY POTENT. TOGETHER I'M GOING TO BE CALLING THEM ALLO. ONE SHOULD NOTE IN RESPONSE -- REDUCTIONS IN THESE NEUROACTIVE STEROIDS ALLO PREGNALANE HAVE BEEN REPORTED IN IN TRAUMATIC BRAIN INJURY IN LARGE COHORT OF MOSTLY MALE VETERANS OF THE OEF CONFLICTS IN A CHAPTER IT HAZEN BEEN ANALYZED IN IN GREAT DETAIL, MORE TO COME FROM THAT STUDY. TO POINT OUT ALLO IS SYNTHESIZED IN THE BRAIN. IN ADRENAL GLAND AND OFRIES. -- OVARIES, IT HAS BROAD IMPACT. IF IT LOOKS LIKE THE MAGIC PILL. IT HAS POTENTLY ANGIOLYTIC, ANTIDEPRESSANT, ANTI-CONFLICT PARADIGMS, VERY POTENT ANTI-CONVULSANT, THE MOST POTENT ENDOGENOUS WE WE HAVE, NEUROPROTECTIVE AND REGENERATIVE , WHILE PROGESTERONE DECREASED ISCHEMIC BRAIN TRAUMA, NEGATIVE OUTCOMES, THE METABOLITE WAS FOUR TIMES MORE POTENT. IT'S CRITICAL FOR MYELINATION, IT PROVIDES LONG NEGATIVE FEEDBACK TO THE AXIS. WHEN YOU ARE STRESS, IT IS MADE DEVOW VOW, IN YOUR BRAIN, AN GLANDS, IT TAKES AN HOUR TO PEAK, VERY IMPORTANT WHEN YOU CONSIDER IMPORTANT ROLE IN MEMORY. IT BRINGS STRESS BACK DOWN, INVOLVED IN PAIN REDUCING PAIN AT THE SPINAL AND SUE PROWS SEEN LEVELS, HIGH DOSES ANESTHETIC. IT LIMITS CONFLICT MEDIATED NEURAL INFLAMMATION. IT UPREGULATINGS METALLO PROTONASE BLOOD BAYIER DISRUPTION DURING TRAUMA AN INVOLVED IN MEMORY SO IT'S LEVELS ARE ASSOCIATED IN MATURE EXCITATORY SYNAPSES ON DENDRITES IN THE HIPPOCAMPUS AND RECENT WORK AT WASU SHOWS WHEN YOU INDUCE LONG TERM DEPRESSION, YOU INDUCE PRODUCTION OF ALLO PREGNALONE IN NEURONS, SO STIMULATED BY ACTIVATION OF NMDA RECEPTOR. WHEN YOU ACTIVATE THE NMDA RECEPTOR YOU ACTIVATE VARIOUS INTRANEURONAL PATHWAYS, MEK, ET CETERA. YOU INCREASE BDNF, PRODUCTION OF ALLO PREGNALONE AT THE END THAT PROVIDES LTP INTERFERENCE THAT. SOUNDS LIKE A BAD THING. BUT IT'S ACTUALLY VERY IMPORTANT. INITIATION WHEN THE NMDA RECEPTOR IS ACTIVATED YOU STRENGTHEN THE SYNAPSE BY INSERTING AM PA RECEPTOR. THAT NEEDS TO BE CONSOLIDATED. AS ALLO PEEKS IT INCREASES GABBA TONE AND THAT REDUCES CAPACITY FOR EXCISATION, ALSO INTERESTINGLY, -- EXITATION. IT'S CONVERTED TO SULFATE WHICH IS NMDA RECEPTOR ANTAGONIST SO THAT WAS THOUGHT PREVENT NEWLY MODULATED SYNAPSE WHETHER UP STRENGTHENED OR WEAKENED FROM FURTHER EXCITATORY INPUT TO PERMIT CONSOLIDATION. WHICH MAKES SENSE THEN OF OBSERVATIONS THAT IT IS ESSENTIAL FOR EXTINCTION RETENTION. AND OBSERVATION THAT WE HAVE ALSO MADE IN WOMEN WITH PTSD DURING THE PHASE OF THE MENSTRUAL CYCLE. ALLO WAS INVOLVED IN SLEEP, SEDATING AND DECREASES LATENCY TO NON-RIM SLEEP AN ENHANCES SPINDLE SLEEP WHICH AGAIN, IS ASSOCIATED WITH MEMORY CONSOLIDATION. SO IT HAS FACTORS PROBABLY RELEVANT TO THE TBI EMPHASIS. THESE ARE THE PATHWAYS. NOTE IN THE ADRENAL GLAND THIS PATHWAYS KICKED OFF BY ECTH IN THE GONADS, OVARIES BY LH. AND IN THE BRAIN BY ACTIVATE OF THE NMDA RECEPTOR, PRODUCED FROM PROGESTERONE, WHICH IS MADE BY 5 ALPHA PROGESTERONE BY THREE ALPHA Hs D IN WOMEN, TWO ALLO PREGNILONE AND THE OTHER PATHWAY WHICH GETS TO PREGNALONE. THERE WERE OTHER GABAERGIC NEUROACTIVE STEROIDS WITH THESE TWO ENZYMES IN THE PATHWAY TO THEIR SYNTHESIS AT THE END OF THE CORTICOID, CORTISOL PATHWAY ACTUALLY, ALSO AN DROVESER ROAM ROANE AND TEST TOES ROANE, TESTOSTERONE MADE INTO REDUCTASE TO ALPHA DHD THE POTENT TESTOSTERONE, REDUCED THE ANDROSTANE DIOL WHICH IS A WEAK STEROID AND ALSO A GABAERGIC NEUROACTIVE STEROID. THIS ALL STARTS WITH CHOLESTEROL HITTING THE NEURON AND THAT VARIOUS MOLECULES IN THE PATHWAY PASS THROUGH THE MITOCHONDRIA AND THEN IT IS KICKED OUT BACK INTO THE CYTOSOL ANIMA INTO ALLO PREGNALONE SO THAT HAPPENS IN PACKAGE MANY THE VESICLES. AND THEN THIS IS THE SCHEMA FOR THE LTP. YOU CAN SEE DIFFERENT PATHWAYS LEAD TO ACTIVATION OF ALL THESE SECONDARY PATHWAYS THAT LEAD TO MEMORY STRENGTHENING AND STRENGTHENING SYNAPSE BUT MAKE ALLO WHICH FEEDS BACK TO PROVIE THAT LTP INTERFERENCE. SO ALLO ACTS BOTH SYNAPTIC AN EXTRA SYNAPTIC GABBA RECEPTORS. YOU WILL SEE WHOA I THAT'S IMPORTANT. EXTRA SYNAPSE TICK GABBA RECEPTORS ARE RHESUS ABOUT THE BENZODYADS PEENS WHICH DON'T WORK FOR TREATMENT OF PTSD. THEY'RE ALSO SENSITIVE THE LOW LEVELS OF ALLO AN TO ALCOHOL WHICH IS THE -- SAY THE AGE OLE TREATMENT FOR PTSD. THEY EXTRA SYNAPTIC GABBA RECEPTORS MADE OF DELTA ALPHA 4 AN 6, FIRING RATE OF STIMULATED NEURONS. SO THIS IS A CELLULAR MODEL WHERE IF YOU HAVE THIS TONIC INHIBITION PROVIDED BY ALLO YOU SEE IT WITHOUT IT YOU GET INCREASE IN THE FIRING RATES AT 0 TO 150-HERTZ BUT WITH INHIBITION 0 TO # HUNDRED. AND AGAIN SORT OF MATCHES WHAT WE SEE WITH PTSD. PEOPLE GO NOT WELL MODULATED LIKE SAY DOCTORS IN THE ER SPECIAL FORCES PEOPLE KEEP HEADS ON BOARD DURING STRESS. IN THE AMYGDALA YOU SEE DECREASE IN MULTIPLE GABBA SYSTEM CONSTITUENTS INCLUDING DOWN REGULARS LAYING OF SYNAPTIC RECEPTORS WHICH LEADS THE EXTRA SYNAPTIC GABBA REACCEPT TOES SO THOSE ARE REALLY IMPORTANT IN MODULATING ACTIVITY AFTER TRAUMA. AN THOSE ARE THE ONES RESISTANT TO BENZOSENSITIVE TO ALLO. NOW, WHAT IMPACTS ALLO? INTENSE STRESS HAS BEEN SHOWN TO DECREASE IT, ISOLATION IN MALE BUT NOT FEMALE RODENTS. STEROID CONTRACEPTION DECREASES ALLO LEVELSES IN THE BRAIN AN IN THE PERIPHERY AND ALSO BING DRINKING DECREES ALLO LEVELS SO IF YOU THINK ABOUT ATHLETES THINK ABOUT DOMESTIC ABUSE VICTIMS WHO MAY DRINK, THINK ABOUT PEOPLE WHO ISOLATE THAT WILL SET THEM UP FOR LOW ALLO LEVELS. JUSTIFY WHIP THREW A FEW STUDIES IN TERMS OF FINDINGS WE DID A LUMBAR PUNCTURE STUDY IN WOMEN WITH AN WITHOUT PTSD, WHEN PROGESTERONE IS LOW AN FLAT. AND WE FOUND THAT PROGESTERONE AND FIVE ALPHA DHP WEREN'T DIFFERENT BUT ALLO LEVELS WERE ONLY 40% OF NORMAL. QUITE LOW. THEN WE LOOKED WHERE THE BLOCK WAS AN FOUND IT WAS AT THREE ALPHA HSD BECAUSE RATIO OF ALLO TO PRE-CURSOR FIVE ALPHA DHP WAS LOW. THESE ARE WOMEN WITH PTSD, THEY HAD EVERY ANXIETY DISORDER DEPRESSION AND PTSD, WE HAVE TO SCHEDULE HER THREE TIMES FOR EVERY APPOINTMENT BECAUSE SHE COULDN'T GET OUT OF THE HOUSE. THIS PERSON RECOVERED OVER THE COURSE OF DOING STUDIES SHE NEVER PROCESSED TRAUMA WHATSOEVER PRIOR TO COMING IN. THEN NOW MY COLLEAGUE SUZANNE AND I FINISHED ANOTHER STUDY WHERE WE LOOKED IN PLASMA RATHER THAN CSF, AT ALLO, ACROSS MENSTRUAL CYCLE IN CONDITION AT REST AFTER PRE-PULSE INHIBITION, MILD STRESS AN DIFFERENTIAL FEAR CONDITIONING. THEN AFTER FEAR EXTINCTION. THIS IS THE PARADIGM. AND WE FOUND THREE MAIN FININGS. MENSTRUAL PHASE WAS ASSOCIATED WITH INCREASED CONVERSION OF PRE-CURSOR TO ALLO. SO THAT'S UPREGULATED DURING THE PHASE YOU'LL MAKE MORE. ESTROGEN UPREGULATES THE ENZYME THAT MAKES IT SO THAT'S THE PHASE WHEN HEALTHY WOMEN ACTUALLY DO FEAR EXTINCTION BETTER. WHEN PTSD DO WORSE THAN THE -- PHASE. WE ALSO FOUND A DIAGNOSTIC DIFFERENCE WITH PTSD, HAD LOWER ALLO THE RATIO WHICH IS A MEASURE OF THE ENZYME EFFICACY. THEN STRESS RESPONSE SO THAT THE NORMAL WOMEN INCREASE PRODUCTION OF THE ALLO FROM FROM THE PRECURSOR, MODERATELY STRESSED WITH PTSD, SUGGESTING THE VERY IMPORTANT NEUROPROTECTOR MAYBE PARTICULARLY LOW AN NON-RESPONSIVE IN INDIVIDUALS WITH TBI AND PTSD AND MAYBE ONE MECHANISM BY WHICH THEY HAVE LONG TERM NEGATIVE OUTCOMES. SO THE MODEL FOR PTSD IN WOMEN, A BLOCK AT THREE ALPHA HSD THEN MOVING I BRING UP AN INTERESTING FINDING OF YOUNG PEOPLE HAVING BETTER OUTCOMES THAN JUST OLDER PEOPLE HAVE THE NEGATIVE OUTCOMES. DHEA DROPS PRECIPITOUSLY BETWEEN 20 AND 40. THE RATIO OF ALLO TO THAT, WAS A STRONGER PREDICTOR OF NEGATIVE OUTCOME WITH DEPRESSION, THE HIGHER THE DHEA. SO DHEA IS NORMALLY THOUGHT PROTECTIVE, RELEASE FROM ADRENAL GOES TO YOUR BRAIN.& BY IN THE BRAIN IT'S MADE I DIOL LIKE ALLO, THAT'S ANTI-INPROGRAMTORY. SO IF YOU HAVE A HIGH LEVEL OF DHEA IN YOUR CSF, IT MAY MEAN YOU'RE NOT CONVERTING TO THE NEURAL PROTECTOR. FINALLY, THIS IS THE GENE, IT SHOULD BE UPREGULATED BY CORTISOL, UPREGULATED BY TEST TON TOAST ROANE. UPREGULAR HATES IN MENOPAUSAL WOMEN, IT'S AN IMPORTANT CO-FACTOR, ALCOHOL SHUT OFF NEDPHND YOU GET A PICTURE OF ALLO PRODUCTION DEFICIT IN BING DRINKING MICE LIKE IN WOMEN. SO ANOTHER FACTOR TO CONSIDER IN VETERANS, FOLKS IN SPORTS, ET CETERA. FINALLY IN MEN JUST TO SAY THERE IS SEX DIFFERENCE BUS THERE'S A COMMON PTSD PHENOTYPE. BUT DIFFERENCES IN THE ENZYME WHERE STUFF SMUTS DOWN. SO WE FINISHED THIS STUDY AND FOUND THAT THERE WAS A STRONG NEGATIVE CORRELATION BETWEEN ALLO LEVELS AN PTSD SYMPTOMS. WHEN WE LOCKED AT THE ALLO TO ACTH WE NORMALIZE FOR THE SIGNAL THAT TURNS ON, YOU CAN SEE THAT IT WAS STRONGLY BROUGHT OUT NEGATIVE CORRELATION BETWEEN THAT AN DYSPHORIA, FACTOR OF PTSD IN MEN. WHICH IS THE IRRITABILITY INSOMNIA, POOR CONCENTRATION, DECREASE INTEREST, THE DEPRESSIVE STUFF LIKE IN WOMEN. IF WE LOOK AT CORRELATION WITH DHEA YOU SAW THIS STRONG NEGATIVE CORRELATION WITH DYSPHORIA FACTOR IN MEN. WE FOUND THE BLOCK IN MEN NOT AT THREE ALPHA HSD BUT RATHER FIVE ALPHA REDUCTASE. ONE WORD ABOUT THAT, THAT DOESN'T MEAN NO WOMEN HAVE A BLOCK THERE. HOWEVER, IN MEN, THERE ARE MANY POLYMORPHISMS OF THIS GENE AND ALSO EPIGENETICALLY REGULATED. IT'S ALSO HUT DOWN BY FANASTRIDE (PHONETIC) SO TO THE EXTENT MEN ARE BEING GIVE THAT FOR ALOPECIA OR PROSTHETIC HYPERTROPHY COULD BE A RISK FACTOR. THERE'S NOW POST SYNDROME FOUNDATION FOR PEOPLE WHO DEVELOP SUICIDE DEPRESSION CHRONIC PAIN, POOR SEXUAL FUNCTION AFTER TAKING THAT, SO IT'S SOMETHING FOR US TO BE AWARE OF. SO THE CONCLUSIONS ARE PTSD RELATED DEFICITS IN THE ENZYMEIC CONVERSION OF PROGESTERONE TO DOWNSTREAM GABAERGIC METABOLITES IN EXISTING IN WOMEN AN MEN, THERE ARE APPARENT SEX AND ENVIRONMENTALLY CONFER DIFFERENCES IN POINT OFFAL FUNCTION IN IT WILL ALLO SYNTHETIC PATHWAY, SO THERE ARE IMPLICATIONS FOR DEVELOPMENT OF TARGETED TREATMENTS FOR PTSD AND TBI, DEFROM, PAIN, ET CETERA, ET CETERA. ADMINISTRATION OF ALLO PRECURSORS MAY NOT BE HELPFUL SO A POINT PERHAPS ABOUT THE PROTECT STUDY, THERE MAYBE INDIVIDUALS SUBGROUP FOR WHOM THESE COULDN'T BE CONVERTS ODD THE LOW ALLO. I'M JUST GOING TO MAKE ONE POINTS IN TERMS OF TREATMENT THERE'S NOW AN IV ALLO PROBABLY LIKELY TO BE APPROVED SHORTLY. AND ALSO A PO VERSION. BUT I THINK AGAIN, SOME CAUTION MAYBE IN ORDER IN OUR RODENT WORK WHERE WE DEVELOPED A MODEL OF PTSD DECREASING ALLO IN SOCIAL ISOLATION. THEY SHOWED PROFOUND EXTINCTION DEFICITS AS WELL AS PROBLEMS WITH EXTINCTION RETENTION. WE WERE ABLE TO FIX WITH ONE DOSE OF ALLO AFTER THE FIRST EXTINCTION TRIAL. SO WE TARGETED THE TREATMENT TO THE ACTUAL PATHOPHYSIOLOGICAL PROCESS OF REMODELING THE BRAIN OPPOSED TO GIVING 24/7. WE ALSO GIVEN A STUDY PTSD, THAT'S ALLO SYNTHETIC ALLO. COMPOUND. DIDN'T WORK. ZERO. IN OUR ANIMAL WORK THOUGH, THE ALLO DIDN'T WORK IN ANIMALS THAT DID NOT HAVE LOW ALLO. IN OUR RESEARCH ABOUT 25 TO 30% POPULATIONS THAT WE HAVE STUDIES HAVE DEFICIT IN ALLO FORMATION SO IT'S A SUBGROUP OF INDIVIDUALS WHO DEVELOP PTSD AND MAYBE A PARTICULAR SYNDROME ASSOCIATED WITH ALL THAT. SO AGAIN, TO INDIVIDUAL TARGETING AND PRECISION MEDICINE IS I GUESS THE POINT. THANK YOU. [APPLAUSE] SORRY FOR GOING OVER. THIS NEXT SESSION IS THE SPORTS CONCUSSION UNDERSTANDING TBI AN SPORTS CONCUSSION OUR FIRST SPEAKER IS DR. DAWN COMSTOCK, PROFESSOR EPIDEMIOLOGY COLORADO SCHOOL OF PUBLIC HEALTH SHE RECEIVED A MASTERS IN EPIDEMIOLOGY FROM UNIVERSITY OF IOWA AN UPDATED Ph.D. IN PUBLIC HEALTH EPIDEMIOLOGY UNIVERSITY OF CALIFORNIA SAN DIEGO. SHE FOCUS CONSIST ON EPIDEMIOLOGY OF INJURY AMONG PHYSICALLY ACTIVE AND SPECIFICALLY STUDY OF SPORTS RECREATION AN LEISURE RELATED INJURIES IN CHILDREN AND ADOLESCENTS AS WELL AS LIFE LONG BENEFITS ASSOCIATED WITH ACTIVE CHILDHOOD. PLEASE WELCOME DR. DAWN COMSTOCK. [APPLAUSE] >> APPRECIATE PEOPLE COMING BACK TO LUNCH AND BEING HERE THE END OF THE DAY SO AS A YOU CAN SEE I'M AN EPIDEMIOLOGIST AND I WOULD BE REMISIF I DIDN'T HOST THE NIH FOR HOSTING THIS AND IT'S COMPULSION I COUNT THINGS SO I WENT THROUGH THE AGENDA FOR THE WORKSHOP TODAY AN THIS IS AMAZING. 55% OF THE PEOPLE THAT WILL BE AT THE MICROPHONE DURING THIS WORKSHOP ARE WOMEN. I TOLD PAT USUALLY I'M AT SCIENTIFIC MEETINGS WHERE I HAVE THE WOMEN'S RESTROOM ALL TO MYSELF. THIS IS COOL. BUT IT ALSO SHOWS THE IMPLICIT BIASES WE STILL HOLE. I'M SPEAKING ON THE SPORTS RELATED CONCUSSION SESSION. IT IS 20% FEMALE. EARLIER WE HAD THE SESSION ON INTIMATE PARTNER VIOLENCE, 100% FEMALE. SO WE STILL HAVE THIS MISPERCEPTION INTIMATE PARTNER VIOLENCE ONLY HAPPENS TO WOMEN AN SPORTS ARE A MALE PRESERVE. HOPEFULLY WE CAN GET RID OF SOME OF THAT THIS WEEK. NO CONFLICT OF INTEREST, NOBODY LIKES TO PAY US BUT I DO GOAT DINGED BECAUSE EVERYBODY IN THIS THEY UNDERSTAND SPORTS AND WHEN THEY HEAR ME TALK SPORTS INJURIES THEY'RE AFRAID I'M TRYING TO WRAP THEM IN BUBBLE WRAP AND NOT LETTING THEM PLAY. I HAVE ALSO BEEN DOGGED A BIT AT TIMES FOR TALKING ABOUT GENDER DIFFERENCES IN SPORTS RELATED CONCUSSIONS, I HAVE BEEN ACCUSED OF BEING SEXIST WHICH I REPORT THE DATA. I I CAN ASSURE THAT NOTHING IS FART FROM THE TRUTH. I PLAYED RUG BY FOR 13 YEARS,, MUMP TO FATHER'S CHAGRIN MY SISTER AND I BOTH PLAYED SO I APPRECIATE AND UNDERSTAND ALL SPORTS EVEN CONTACT SPORTS OR COMBAT SPORTS, BUT WE MUST USE EPIDEMIOLOGICAL DATA THE DRIVE PREVENTION EFFORTS TO KEEP ATHLETES AS SAFE AS POSSIBLE WHILE BENEFIT OF PHYSICAL ACTIVITY WHILE PLAYING SPORTS. THIS IS MY OBLIGATORY SLIDE FOR THIS PRESENTATION. FOR THE LAST FIVE YEARS TO SHOW HOW FAR BEHIND WE ARE. AS EARLY AS 1928 RESEARCHERS DENOTED THE IMPORTANCE OF SPORTS RELATED CONCUSSIONS. WE'RE STILL TALKING ABOUT IT TODAY. QUICK PRIMER, WHAT EPIDEMIOLOGY IS, IT'S AN EVIDENCE BASED EFFORT, THE GOAL IS TO PROMOTE SCIENCE BASED INTERVENTIONS AND POLICIES TO IMPROVE POPULATION LEVEL HEALTH. SO WHERE ARE WE HERE IN TO 17 ALMOST 2018? IN THE AUDIENCE REMEMBER IN 20 IOM WAS PRODUCED IN SPORTS CONCUSSION AND YOUTH. THEY HIGHLIGHTED THREE SURVEILLANCE SYSTEMS THEY SAY PROVIDED MOST OF THE EPIDOOM LOGICAL DATA ON SPORTS RELATED INJURIES. THE CONSUMER PRODUCT SAFETY COMMISSION NATIONAL ELECTRONIC INJURY SURVEILLANCE SYSTEM, THE NCAA SURVEILLANCE PROGRAM, HIGH SCHOOL NATIONAL HIGH SCHOOL SPORTS RELATED INJURIES SURVEILLANCE STUDY. ONLY ONE IS FEDERALLY FUNDED. LUCKILY THERE ARE MANY MORE SOURCES OF GOOD QUALITY SPORTS RELATED CONCUSSION DATA NOW. WHETHER CLINICAL OR POPULATION BASED. AND MANY REALLY EXCITING NEW RESEARCH EFFORTS SOME WHICH ARE GOING TO BE TALKED ABOUT BY MY COLLEAGUES ON THIS PANEL. WE HAVE ONGOING GAPS OR WEAKNESSES IN THE AVAILABLE EPIDEMIOLOGICAL DATA BUT NO WAY TO EFFECT TESTIFILY LINK DATA SOURCES CONSISTENTLY AND INEXPENSIVELY. WE DON'T HAVE A WAY FOLLOW INDIVIDUAL ATHLETES ACROSS SPORTS, ACROSS SYSTEMS AS THEY AGE, BOTH IN THE SCHOOL BASED SETTING IN THE RECREATION BASED SETTING. THERE'S A LACK OF CONSISTENCY STILL FROM CLINICIAN TO CLINICIAN OR REGION TO REGION SOMETHING AS SIMPLE AS DIAGNOSE, MANAGING CONCUSSION. WE HAVE MISINTERPRETATION OR INTENTIONAL MISUSE OF HIPAA AND FERPA AND NOT EVERYBODY WANTS THE PLAY TOGETHER WHICH IS IRONIC SINCE WE ARE TALKING ABOUT SPORTS. WHAT DO WE KNOW? THIS IS WHERE THE MAC CONVERSION GETS PROBLEMATIC. WHAT WE KNOW ABOUT THE EPIDEMIOLOGY OF GENDER DIFFERENCES IN SPORTS RELATED CONCUSSION? WE'RE LUCKY BECAUSE THERE'S BEEN AN EXPLOSION OF THE LEASER 10, 15 YEARS IN PUBLISHED PAPERS REPORTING EPIDEMIOLOGICAL DATA. TWO EXAMPLES, ONE IN MIDDLE SCHOOL ATHLETES, ANOTHER IN COLLEGIATE ATHLETES. THEY HAVE VERY SIMILAR FINDINGS. ACROSS MOST OF THESE STUDIES. BUT ONE OF THE DRAW BACKS IS THE VAST MAJORITY OF PUBLISHED WORK IS BASED ON COMPETITIVE SPORTS WITHIN THE SCHOOL SETTING. WE ARE NOT LOOKING YOUNGER ASSETS OUTSIDE THE SCHOOL SETTING. A FEW STUDY BUT MOST AREN'T -- AND WE HAVE VERY LITTLE WORK ON ADULT RECOMMENDATION RATIONAL ATHLETES. AND BUYER BEWARE, MY SOAP BOX MOMENT. WE'RE SEEING MORE IS SYSTEMATIC REVIEWS, MED CAM HOE CLINICAL REVIEWS. IF YOU'RE A GOOD SCIENTIST READ THESE BUT LOOK AT THE SOURCE MATERIALS. AND PLEASE BE REALLY CAREFUL ABOUT READING THE METHODOLOGY SECTION BECAUSE I JUST TOLD YOU THAT THE IOM REPORT LISTED THREE SOURCES THAT THEY SAID PROVIDED THE BEST EPIDEMIOLOGICAL DATA AND YET HERE IS TWO EXAMPLES OF SYSTEMATIC REVIEWS THAT DIDN'T SITE ANY OF THE DATA ANY PUBLICATIONS THAT REPORTED DATA FROM THOSE SOURCES, YOU SEE THE SYSTEMATIC REVIEWS OFTEN REPORT ONLY SMALL FRACTION OF WHAT'S OUT THERE. IT'S OFTEN TERMINOLOGY BASED. WHAT'S ON THAT ONE LINE THAT SAYS STUDY DESIGN. IF I CALL MY STUDY DESCRIPTIVE EPIDEMIOLOGY STUDY IT'S NOT INCLUDED. IF I CALL IT A COHORT STUDY, IT DOES. THOUGH THE ONLY DIFFERENCE IS WHAT I CALL IT. SO BUYER BEWARE. PLEASE. SO WHAT DO WE KNOW ABOUT THE EPIDEMIOLOGY OF GENDER DIFFERENCES IN SPORTS RELATED CONCUSSIONS? ACROSS ALMOST EVERY STUDY THERE'S CONSISTENCIES. FIRST, THE COMBAT SPORTS, FOOTBALL, ICE HOCKEY, BOXING, FULL CONTACT SPORTS, THEY HAVE THE HIGHEST RATES OF CONCUSSION BY FAR. BECAUSE MALES PLAY IT MORE FREQUENTLY AND OVERALL WE HAVE MORE MALE ATHLETES THAN FEMALE ATHLETES, IT MEANS JUST IN TERMS OF RAW COUNTS, THERE ARE MORE MALE CONCUSSIONS THAN THERE ARE FEMALE CONCUSSIONS. IF WE ADJUST FOR THE NUMBER OF ATHLETES IN GENDER COMPARABLE SPORTS CONSISTENTLY ACROSS AGE GROUPS AND SPORTS, WE SEE FEMALES HAVE HIGHER RATES OF CONCUSSION THAN MEALS. WE AREN'T SURE WHY. BIOPHYSIOLOGY, SOCIO CULTURAL, MULTI-FACTORIAL, PROBABLY THE LATTER BUT WE NEED TO MORE RESEARCH TO FIND OUT OUR FEMALE -- ARE FEMALES MORE VULNERABLE TO INJURY, ARE THEY SUSTAINING MORE INJURIES OR, THIS IS WHERE I HAVE BEEN CALLED SEXIST, ARE THEY BETTER AT ACKNOWLEDGING WHEN THEY HAVE BEEN INJURED AN REPORTING THEIR SYMPTOMS OF INJURY TO HEALTHCARE PROVIDER? THAT'S IN THE A SEXIST COMMENT, WE KNOW ACROSS THE BOARD WOMEN IN GENERAL ARE BETTER ABOUT TALKING ABOUT THEIR HEALTH THAN MEN ARE. SO WE SHOULDN'T BE SURPRISED TALKING ABOUT CONCUSSIONS THAN MALE ATHLETES. WE SEE GENDER DIFFERENCES AMONG CON CUSSED ATHLETES. DIFFERENCES IN REPORTED SYMPTOMOLOGY, SYSTEM SYMPTOM RESOLUTION TIME, I WILL SHOW YOU DATA THAT GENDER GAPS ARE NARROWING OVER TIME. WHICH IS REALLY FASCINATING. AND EPIDEMIOLOGY AGAIN WE WANT INTERVENTIONS AN POLICIES TO PREVENT INJURIES, THIS IS WHERE SPORTS IS MAYBE A LITTLE BIT AHEAD OF MOM SOME OF THE OTHER TOPICS ABOUT THIS WORKSHOP. BECAUSE SPORTS HAVE RULES, IT'S A PRIVILEGE, NOT RIGHT TO PLAY SPORTS. SO WE HAVE THESE REALLY UNIQUE OPPORTUNITIES TO IMPLEMENT INTERVENTIONS THAT CAN PREVENT CONCUSSIONS. NO OFFENSE TO ALL CLINICIANS AND AMAZING WORK PRESENTED ALREADY, I DON'T CARE WHAT'S HAPPENING AT THE CELLULAR LEVEL. AS A SPORTS INJURY EPIDEMIOLOGIST I KNOW IF I PREVENT THAT DIRECT BLOW, DIRECT TRANSFER OF COURSE TO THE HE OR BLOW TO THE BODY, THE STRUCK THAT CAUSES ASELL RATION DECELERATION OF ROTATIONAL A FORCES OF THE BRAIN WITHIN THE SKULL I I CAN PREVENT THE CONCUSSION. I DON'T HAVE TO KNOW WHAT'S HAPPENING CELLULAR LEVEL AN PRIMARY PREVENTION EFFORTS ARE LARGELY AS EFFECTIVE IN FEMALE AS WELL AS MALE ATHLETES WHETHER BANNING HEADING OR ELIMINATING ATHLETE TO ATHLETE CONTACT OR PUTTING A HE WILL H MET ON BOTH GIRLS AND BOYS LA CROSS PLAYERS. SO HERE IS DATA TO BACK UP EVERYTHING. LOOK AT CPSC NICE DATA ACROSS ALL AGES FOR THREE GENDER COMPARABLE SPORTS, BASKETBALL AN BASEBALL SOFTBALL THE, DEAR LINE IS MALES, LIGHTER LINE REPRESENTS FEMALES, YOU SEE ACROSS THE BOARD SOCCER CHANGED A BIT ACROSS THE BOARD THERE'S MORE NUMBERS OF CONCUSSION INJURIES PRESENTING TO EDs FROM MALE ATHLETES THAN FEMALE ATHLETES IN ALL THREE SPORTS. BUT THINKING ABOUT RATES, HERE IS HIGH SCHOOL REAL DATA TO GIVE AN EXAMPLE, AGAIN YOU SEE FOOTBALL BY FAR HAS HIGHER CONCUSSION RATES THAN ANY OTHER SPORT. DESPITE DREW BREEZE PERPETUATING THAT HIGH SCHOOL SOCCER PLAYERS HAVE MORE CONCUSSIONS THAN FOOTBALL. THAT'S OOH IN THE RIGHT. THEY HAVE MORE CONCUSSION IN COMPETITION AN PRACTICE THAN ANY OTHER SPORT BUT WHEN CAN YOU LOOK AT GENDER COMPARABLE SPORT, YES. IN EVERY SPORT FEMALES HAVE HIGHER CONCUSSION RATES THAN MALES. IF WE LOOK AT RATES OVER TIME, YOU SEE THE IMIS A. U YOU SEE THE SAME COLORS SAME FORMAT AT THE LAST CPSC FLIES SLIDE AN NOW IT'S FLIPPED. FOR EVERYONE OF THE SPORTS GIRLS HAVE HIGHER RATES THAN BOYS, THE LYTER LINE IS HIGHER THAN THE DARKER COLORED LINE. SO I TOLD YOU THE OUTCOMES, THERE'S GENDER DIFFERENCES IN OUTCOMES. THIS IS THE PROPORTION OF ALL HIGH SCHOOL STUDENTS ATHLETES IN MY SURROUND SYSTEM ALL 22 SPORTS, THAT REPORT DIFFERENT SYMPTOMS AT PRESENTATION. YOU CAN SEE THAT THE PROPORTION REPORTING SOME SYMPTOMS HAS GONE DOWN OVER TIME, THE PROPORTION REPORTING OTHER SYMPTOMS IS UP OVER TIME. BUT THIS IS LOOKING AT EVERYBODY. WE NEED THE MAKE SURE THAT WE'RE DOING GENDER COMPARISONS AND WE'RE LOOK AT GENDER COMPARISONS OVER TIME, NOT JUST IN BLOCKS. WHEN WE DO THAT, LOOK JUST AT SOCCER BASKETBALL BASEBALL SOFTBALL GIRLS REPORT A SLIGHTLY HIGHER NUMBER OF CONCUSSION SYMPTOMS THAN BOYS BUT NO DIFFERENCE OVER TIME AN EITHER GENDER. THERE ARE SIGNIFICANT CHANGES OVER TIME FOR BOTH GENDERS NUMBER OF REPORTED AMNESIA, INCREASE IN NUMBER THAT REPORTED LIGHT SENSITIVITY NOISE SENSITIVITY. SIGNIFICANT CHANGE LOWER NUMBER OF GIRLS REPORTED LOSS OF CONSCIOUSNESS BUT NO SIGNIFICANT CHANGE AMONG BOYS. ONE THING TO POINT OUT IS THIS GENDER GAP APPEARS TO BE SHRINKING. IT WAS 14.1% VERSUS 32% FOR AM KNEE SHAH BACK IN 2007, NOW 9.5% VERSUS 12.3% IN 2016, 17. THE GENDER GAP IS SHRINKING. LOOK AT SYMPTOM RESOLUTION TIME WE SEE THE SAME THING, OVERALL SIGNIFICANT DECREASES IN THOSE LESS THAN A DAY.PTOMS RESOLVE IN- INCREASE THOSE THAT DAY # 1 DAYS O MORE. WHEN WE LOOK SPECIFIC THROUGH WE SEE GENDER DIFFERENCES IN GENDER COMPARABLE SPORTS. SIGNIFICANT DECREASES IN BOTH GENDERS FOR THOSE THAT SAY SYMPTOMS RESOLVE IN LESS THAN A DAY BUT SIGNIFICANT INCREASE FOR GIRLS IN THOSE THAT SAID SYMPTOMS TOOK MORE THAN THREE WEEKS TO RESOLVE. LOOKING AT RETURN THE PLAY BOTH MALE AND FEMALE ATHLETES APPEAR TO BE MANAGED SIMILAR NOW. THEIR BOTH HELL OUT OF PLAY FOR THE APPROPRIATE RETURN TO PLAY GUIDELINE REQUIRED WEEK WHICH IS GOOD. WHERE ARE THE GAPS? I'M GOING FAST BECAUSE I WAS TOLD TO. I TALKED ABOUT MOST ALREADY. WE DON'T HAVE FEDERAL FUNDING NOR NATIONAL SPORTS RELATED INJURY SURVEILLANCE BESIDES CPSC NICE ED CASES, WE DON'T HAVE DATA ON ATHLETES YOUNGER THAN MIDDLE SCHOOL AGE. WE HAVE HAD VERY LITTLE DATA ON EXTRA CURRICULAR OUTSIDE SCHOOL SETTING SPORTS. WE DON'T HAVE ANSWERS WHY SOME OF THESE EPI DIFFERENCES IN GENDER DATA EXIST. WE DON'T HAVE ENOUGH DIVERSITY IN THE FUNDING FOR SPORTS RELATED RESEARCHERS. I KNOW THIS HASN'T BEEN TALKED ABOUT A LITTLE BIT BUT WE HAVE NO DATA, JUST LOOKING AT GENDER DIFFERENCES WE DON'T HAVE DATA ON OTHER SUBPOPULATIONS OF INTEREST. WE DON'T HAVE DATA ON RURAL KIDS WITH SAME ACCESS TO HEALTHCARE, YOU ARE OR HIGH SES KIDS SO WHERE THE BIOPHYSIOLOGY OF SEX INTERACTS WITH THE SOCIO CULTURE ASPECT OF SPORTS AND GENDER. WE LOOKING AT TRANSGENDER ATHLETES YET THOUGH THERE'S A RAPIDLY GROWING NUMBER OF TRANSGENDER KIDS PLAYING HIGH SCHOOL AND COLLEGE SPORTS. WE NEED TO LOOK AT THOSE AS WELL. SO I'M AT THE POINT IN MY CAREER FRANKLY I'M CONSIDERING RETIREMENT, I HAVE NO FEDERAL FUNDING, SO I DON'T CARE IF I DON'T EVER GET FUNDING AGAIN. SO IN LIGHT OF WHAT'S HAPPENED THE LAST FEW DAY I'M GOING TO GET ON MY SOAP BOX ONE MORE TIME TODAY AND SAY THAT ALL OF US SCIENTISTS MUST ENSURE THAT SCIENCE IS NOT CENSORED A. AND I DON'T CARE IF IT'S EXTERNAL CENSORING UPON US OR INTERNAL CENSORING BECAUSE OF OUR FEAR THAT THE UNEDUCATED OR THE UNINFORMED OR THE UNRECEPTIVE WILL NOT UNDERSTAND. WE'RE SCIENTISTS, WE HAVE TO SPEAK THE TRUTH USING THE MOST APPROPRIATE TERMINOLOGY. THANK YOU FOR YOUR TIME TODAY. [APPLAUSE] >> THANKS, DAWN. SO OUR NEXT SPEAKER WILL SPEAK TO AT THIS ABOUT PEDIATRIC SPORTS AND -- DR. CRIST GIZA, HE LEADS THE PROFESSOR OF PEDIATRIC NEUROSURGERY AT SCHOOL OF MEDICINE AND MATTEL CHILDREN'S HOSPITAL. HE SERVES ON THE CENTER OF DISEASE CONTROL PEDIATRIC MILD TBI COMMITTEE, THE NCAA CONCUSSION TASK FORCE, MAJOR LEAGUE SOCCER CONCUSSION PROGRAM COMMITTEE AND DR. GIZA ALSO DIRECTS THE NFL NEUROLOGICAL CARE PROGRAM AT,CLA, RESEARCH INTERESTS INCLUDE NEUROPLASTICITY, RECOVERY FROM INJURY, SPORTS TRAUMATIC CONCUSSION IN EPILEPSY AND BRAIN DEVELOPMENT. LOOKS LIKE YOU'RE DONE ALREADY. [APPLAUSE] >> OKAY. SO IT SHOULDN'T BE TOO HARD TO STAY WITHIN THE TIME LIMITS. IF YOU NONE YOU KNOW I LIKE TO TALK. THE TOPIC I HAVE BEEN GIVEN IF I WANT TO STAY EVIDENCE BASED IS SHORT BECAUSE THERE'S NOT A LOT OF DATA. WE HEARD THE EPIDEMIOLOGICAL SIDE OF THINGS HOW THERE'S LIMITED DATA MIDDLE SCHOOL AND YOUNGER EPIDEMIOLOGICALLY AND LOOKING AT OUTCOMES AND RECOVERY IS GOING TO BE LESS. BE WE'LL TALK SEX RELATED DIFFERENCES AS BEST WE CAN IN PEDIATRIC FROM RESEARCH. IT IS THE CREW BACK AT UCLA EXCEPT DR. CHAI WHO IS HERE. SO SITTING THERE. SO THESE ARE THE TEAM THAT ARE REALLY HELPING US AT UCLA MOVE THINGS FORWARD AND WE DO HAVE RESEARCH THAT'S STARTING TO ENTER AN AREA OF LOOKING AT SEX RELATED DIFFERENCES. I'M GOING TO TALK ABOUT A FEW BASICS THEN TALK ABOUT CLINICAL STUDIES THEN A SLADE OR TWO ABOUT RULES AN POLICIES BECAUSE WE NEED TO THINK ABOUT ALL THESE THINGS AND IF WE HAVE TIME FOR DISCUSSION OR AT THE BAR LATER, WE NEED TO TALK ABOUT ALL THESE THINGS AS THEY ARE RELEVANT FOR YOUNGER POPULATIONS BECAUSE THAT IS WHERE MOST SPORTS PARTICIPATION IS IN ORGANIZED SPORTS. IF YOU INCLUDE RECREATIONAL SPORTS AND PLAYGROUNDS AND BICYCLES AND EVERYTHING ELSE YOU REALIZE KIDS ARE THE ONES AT GREATEST RISK. WHY ARE THERE SEX DIFFERENCES A ALL? THESE ARE SOME REASONS, THESE AREN'T KID SPECIFIC BUT WE KNEE TO THINK ABOUT THESE IN A PEDIATRIC PREPPILY WAY. SO THERE ARE CLEARLY BIOMECHANICAL FACTORS, WE HAVE TALKED ABOUT HOW NEXT STRENGTH AND OTHER THINGS MAY IMPACT THE SEX DIFFERENCES IN CONCUSSION. AND WHEN WE BRING IT DOWN INTO THE PEDIATRIC AGE RANGE, WE NEED TO THINK ABOUT SOME OTHER THINGS TOO. THERE ARE SPORTS THAT CHILDREN PLAY THAT DO REQUIRE USE OF HELMETS AND YET GENERALLY BOYS DOING THAT BUT YOUNG BOYS WEARING HELMETS ARE WEARING HELMETS THAT ARE MEETING STANDARDS THAT ARE AIMED AT MUCH OLDER ATHLETES. SO IF WEAK NECK STRENGTH IS A RISK FACTOR FOR MALE FEMALE CONCUSSION RISK IT MAY BE A FACTOR FOR SMALL CHILDREN TO TEENAGER CONCUSSIVE FORCES. HORMONE FACTORS WE ALSO HER ABOUT, SUPERCOMPLEX, I THINK AN IMPORTANT ISSUE IS THAT SEX BASED DIFFERENCES ARE NOT SOLELY HORMONE BASED AND DR. MCCARTHY GAVE GREAT TOUR DEFORCE OVERVIEW TO START OFF HOW EVEN PRE-ADOLESCENCE, THERE ARE SIGNIFICANT MALE TO FEMALE DIFFERENCES IN ALMOST ALL DEVELOPMENTAL PROCESSES SO IT'S MORE THAN HORMONES. THE SYMPTOM REPORTING FACTORS WE TALKED A LITTLE BIT ABOUT AND DON WAS MENTIONING -- DAWN WAS MENTIONING HOW YOU CAN BE ON THE WRONG SIDE OF THE FENCE IF PEOPLE THINK YOU'RE TALKING SYMPTOMS AND TRYING TO MINIMIZE ONE SEX OR THE OTHER IN TERMS OF THEIR SYMPTOM REPORTING BUT THEY'RE CLEARLY ARE EVIDENCE OF DIFFERENCES IN SYMPTOM REPORTING AND YOU'LL SHOW ONE SLIDE ON BASELINE INFORMATION. COMORBIDITIES. WE KNOW THERE ARE COMORBIDITIES. COMMON ONE IS MIGRAINE WHICH SHOWS UP MORE OFTEN IN FEMALES, EXCEPT IF YOU'RE A PEDIATRIC DOCTOR PRE-ADOLESCENCE, THE INCIDENCE OF MIGRAINE IS EQUAL BETWEEN TWO GENDERS SO DOES THAT MAKE A DIFFERENCE IN SYMPTOM REPORTING AFTER CONCUSSION AN PRE-ADOLESCENT KIDS? WE DON'T KNOW. THEN THE ISSUE OF PROVIDER IMPLICIT BIAS AND DO WE TAKE CARE OF BOYS DIFFERENTLY FROM THE WAY WE TAKE CARE OF GIRLS? DO WE IMPART THAT BIAS INTO OUR RETURN TO PLAY. HERE IS THE TALK REALLY. THESE ARE THE DIRECT STUDIES I FOUND WITH SEX DIFFERENCES AND REPEAT MILD QUOTE UNQUOTE SPORTS TBI IN BASIC OR CLINICAL LITERATURE. WE DON'T HAVE TIME TO GET THE BAR NOW. I HAVE TO TAKE THE LIBERTY OF SOME OF THE STUDIES THAT ARE PROBABLY RELEVANT FOR OUR CONVERSATION THOUGH MAY NOT BE SPECIFICALLY TARGETING ALL THE BUZZ WORDS WE NEED. REPEAT MILD TBI QUOTE UNQUOTE LIKE SPORTS CONCUSSION, SEX AN GENDER, I DON'T KNOW WHY -- KEEPS WANTING TO GO ON ITS OWN. TRYING TO ET KEEP ME GOING FAST. THIS IS WORK FROM TIFFANY AND OUR GROUP. ONE YOUNG RESEARCHER WHO IS LOOKING AT SEX BASED DIFFERENCES IN THE ANIMAL MODEL, SHE FOUND NUMBER OF THINGS AFTER MILD TBI INCLUDING DIFFERENCES IN OPEN FIELD EXPLORATION, THERE WAS LESS IN FEMALES WITH SINGLE INJURY OR REPEAT MILD TBI, COMPARE TO MALES. THEY HAD LESS PLAY TIME, MORE AVOIDANT BEHAVIOR. IMPORTANT THINGS COME OUT OF THIS, INCLUDING IF YOU LOOK AT DIFFERENT SEXES, THE OUTCONTROL MEASURE MAYBE DIFFERENT AND THE BEHAVIORAL MEASURES THAT YOU SEE AFTER A MILD TBI REPEAT MILD TBI MAYBE SEX SPECIFIC. THIS IS WORK FROM SONYA LEAPOLD AND MARK BURNS FROM GEORGETOWN, THIS IS A BASIC SCIENCE ARTICLE CHARACTERIZING BROAD RANGE OF INJURY RESPONSES. IT'S NOT CONCUSSION, THIS IS A MORE SEVERE CONTOURSIVE INJURY, BUT CHARACTERIZE THESE CELLS WE PREVIOUSLY IGNORE. WE HEARD EARLY YOUR TALKING NEURONS BUT ALSO WANT TO TALK ABOUT MICROGLIA MACROPHAGES ASTROCYTES AND THE LONG AND SHORT IS THEY DID THE VERY LABORIOUS ANALYSIS OF MICROGLIAL AN ASTRO GLIAL ACTIVATION IN DIFFERENT GENDERS, DIFFERENT SEXES ACROSS TIME AND FOUND IN GENERAL FEMALES SHOWED LESS ROBUST EARLY INFLAMMATORY ACTIVATION FOR MICROGLIA AND FOR ASTRO GLIA. IT MAY HAVE HAD RELEVANCE FOR HISTOLOGICAL OUTCOMES. SO YOU CAN SEE HERE THE MALES HAD HIGHER PEAK OF CELLS THAT WERE DYING, YOU CAN SEE THAT CONTUSION VOLUMES IN THE VARIOUS BRAIN REGIONS HERE, AND THE MALES HAD GREATER LESION VOLUME DOCUMENT PAIRED TO FEMALES IN THE ACUTE PHASE COMPARED TO FEMALES BUT OVER TIME CAME OUT AS A WASH. WE DON'T KNOW WHETHER DAYED ONSET OF INFLAMMATORY RESPONSE IS NEUROPROTECTIVE OR NOT. DOES THAT GIVE THE FEMALE BRAIN MORE TIME TO REORGANIZE? BEHAVIORAL OUTCOME INTERESTING TO SEE HERE. MY POINT IS THAT, WE SHOULD MAKE SURE WE DON'T BIAS OURSELVES IN THINKING THAT THE YOU COMES THE SEX BASED OUTCOMES HAVE TO BE AGAINST FEMALES. HERE IS ONE WHERE THERE'S AN INFLAMMATORY RESPONSE SEEMS DIFFERENT. WE SAW IT FROM DR. KOROSHETZ EARLIER, THIS WAS PUBLISHED IN THE LAST MONTH. SHOWING THAT CYTOSKELETAL COMPONENTS IN RAT AN HUMAN MALE AN FEMALE AXONS WERE DIFFERENT. IN THE STUDY THEY REPORT THAT MALE AXONS WERE MORE CHECKS AN ROBUST, I PREFER TO THINK OF IT AS FEMALE AXONS WERE MORE FLEXIBLE AND ADAPTABLE. ALL IN THE ADJECTIVES BUT THIS WAS BASELINE. AND THEN YOU CAN SEW THERE WERE MORE UNDERLAYINGS IN THE FEMALE AXONS THAN THE MALE AXONS. UNDERLATIONS. THE MORE UNDERLAKES THERE ARE, THAT COLLEGIATES AXON PERMEABILITY THAT ALLOWS CALCIUM IN. UNDUELATIONS. SO IN THESE FLUORESCENT IMAGES YOU CAN SEE THE FEMALE AXONS HAD GREATER PHYSIOLOGIC RESPONSE IN TERMS OF CALCIUM INFLUX. THIS MIGHT BE AN ARGUMENT THAT AXONAL RESPONSE TO INJURY IN FEMALES MAYBE DISADVANTAGEOUS. THIS IS WORK FROM TIFFANY GRECCO, THIS IS DIFFERENT WAY OF LOOKING AT SEX DIFFERENCES. SO IN THESE STUDIES WE DID THEM -- THEY WERE ONLY DONE IN MALES BUT THE IDEA IS LOOK AT REPETITIVE MILD TBI ON PITUITARY AND HORMONE FUNCTION. AND LOOK AT SEX BASED BEHAVIORS. AND WHAT TIFFANY AND MIAMI FOUND WAS THAT SHAM IS IN WHITE, SINGLE TBI IS IN GRAY AND REPEAT TBI IS IN BLACK. WHAT THEY FOUND WAS THAT EMERGING OVER ONE MONTH AFTER REPETITIVE INJURY, MARKERS OF DIMINISHED PITUITARY FUNCTION IN CLOSED HEAD INJURY IN THE RODENT. WE TALKED ABOUT HEARD A LOT ABOUT THE IDEA THAT REPETITIVE CONCUSSION MIGHT CAUSE IMPAIRMENTS IN PITUITARY FUNCTION IN HUMANS BUT IT'S LIMITED TO CASE REPORTS RIGHT NOW. THIS IS AN EXAMPLE IN ANIMAL MODEL THAT CAN HAPPEN, AND THEN IN A DIFFERENT STUDY DIFFERENCES IN TESTOSTERONE AFTER REPETITIVE TBI IN MALE RATS AND FOUND THEREUPON CHANGES IN TESTOSTERONE AND THAT IN THE RED LIGHT PART OF THE STUDY WHICH I DON'T HAVE HERE, THEY ACTUALLY OBSERVED MALE SEXUAL BEHAVIOR UNDER RED LIGHT MS. THE LAB AND SHOWED THAT THE MALES WITH REPEAT TBI ACTUALLY HAD DYSFUNCTIONAL SEXUAL BEHAVIORS SUCH AS MOUNTING AND COPULATION SO THE IDEA THAT THE HORMONES WERE AFFECTED BY THE REPEAT TBI THROUGH PI TOUR TEAR DIFUNCTION AND LED TO SEX SPECIFIC BEHAVIORAL IMPAIRMENT. SO THAT'S WHAT I HAVE FOR BASIC SCIENCE OR HOPEFULLY TO ADD TO SOME OF THE BASIC SCIENCE THAT WE HAVE ALREADY DISCUSSED TODAY. NOW LET'S TALK ABOUT CLINICAL STUFF. SO ONE OF THE THINGS IMPORTANT IS THE QUESTION OF IS THERE A DIFFERENCE IN SYMPTOM REPORTING AND I'M USING THIS TO ILLUSTRATE THAT. DEPENDING STUDY AN AGE. YOU MIGHT FIND AGAIN UNEXPECTED THINGS. WE HAVE HEARD THINGS SAYING IN GENERAL EITHER FEMALES TAKE LONGER TO GET BETTER FROM CONCUSSION OR REPORT THEIR SYMPTOMS MORE HONESTLY OR WE PROTECT THEM OR WE DON'T LET THEM RETURN THE PLAY BECAUSE WE MANAGE THEM MORE CONSERVATIVELY. THERE'S ACTUALLY A LOT OF STUDIES INCLUDING STUDIES LIKE THIS OVER HERE BY GRANT IVERSON WITH 3 # THOUSAND TEENAGE -- 31,000 TEENAGE ATHLETE BASELINES SHOWING FEMALES TEND TO REPORT MORE SYMPTOMS BASELINE WHICH IS AN IMPORTANT THING TO FACTOR INTO POST INJURY ANALYSIS. IT ALSO SHOWS THOUGH THAT DEPENDING OTHER COMORBIDITIES BOYS AN GIRLS HAVE A LOT OF SYMPTOMS BEFORE ANY INJURY OKAY CUFF SO THEY LOOKED -- OCCUR SO THEY LOOK AT SYMPTOMS THAT MATCH DIAGNOSIS OF POST CONCUSSION SYNDROME AND SAW HOW MANY KIDS AT BASELINE WOULD HAVE MET ICD DIAGNOSIS FOR POST CONCUSSION SYNDROME. YOU CAN SEE HERE WITH SUBSTANCE BECAUSE HALF THE BOYS AN THREE QUARTERS OF THE GIRLS MET CRITERIA FOR PCS PRIOR TO INJURY AT BASELINE. BUT IN THIS ONE, GIRLS ALWAYS LOOKED WORSE IN TERMS OF THEY ALWAYS HAD MORE SYMPTOMS. MORE RECENT STUDY BY ALICE AND BROOKS LOOKING AT CHILD BASELINE SMALLER POPULATION A FEW HUNDRED KIDS, SHOWED A NUMBER OF THINGS MOSTLY BOYS DID WORSE, BUT EFFECT SIZE WAS SMALL. SO THEY WERE SLIGHT DIFFERENCES A FEW SYMPTOM POINTS, BUT AT LEAST IT'S CHALLENGING THE WAY WE THINK ABOUT THIS IS FEMALES REPORT MORE SYMPTOMS. NOT IN THE YOUNGER AGE RANGE. SEEMS BOYS REPORTED MORE SYMPTOMS BASELINE BUT NOT ROBUST DIFFERENCE. WORK FROM THE 5P GROUP, ROGER ZEMICK AND CANADIAN EMERGENCY DEPARTMENTS AND DOESN'T SPECIFICALLY FOCUS ON SPORTS CONDITION CUSHION BUT IT IS YOUTH MILD TBI THAT REPORTS TO THE EMERGENCY DEPARTMENT, A FEW THOUSANDS PATIENTS WITH VALIDATION -- DERIVATION AND VALIDATION COHORT SO IT'S A ROBUST STUDY, AND IN THIS STUDY CLINICAL RISK SCORE FOR INDIVIDUALS WITH SYMPTOMS AT ONE MONTH OR LONGER, ELECTRONIC FOLLOW-UP FOR PATIENTS AFTER THEY LEFT THE ED. AND I WANT TO POINT OUR, THIS IS A SOLID STUDY, ONE OF THE THINGS YOU CAN GET TWO POINTS FOR IS FOR BEING FEMALE. SO NOT SPORTS SETTING BUT THESE ARE KIDS. BETWEEN 5 AND 18 YEARS OF AGE, BEING FEMALE WAS ASSOCIATED IN THE PATIENT WHOSE GO TO THE EMERGENCY DEPARTMENT. WITH HAVING PROLONGED SYMPTOMS. THIS WAS ANOTHER STUDY LOOKING AT SMALLER NUMBER OF INDIVIDUALS, SPORTS RELATED CONCUSSIONS SO THIS IS MORE RELEVANT TO THE DISCUSSION AT HAND, IT POINTS OUT ONE OF THE CHALLENGES IN TRYING TO FIND PEDIATRIC SPECIFIC DATA AND I DON'T WANT TO WON'T OVERLAP WITH HARVEY'S TALK THE HIGH SCHOOL DATA THERE'S A LOT BUT YOUNGER THAN HIGH SCHOOL IS TOUGH. THIS STUDY COMPARED ADULTS TO THOSE UNDER AGE 17 AND ESSENTIALLY WHAT THEY FOUND HERE, THEY DIDN'T SEPARATE ONES UNDER 17 ANY FURTHER THAN THAT. BETWEEN HIGH SCHOOL AND MIDDLE SCHOOL OR GRADE SCHOOL. BUT DO KNOW THE DIFFERENCES IN POST CONCUSSIVE SYMPTOMS AT THREE MONTHS AFTER A SPORT RELATED INJURY, A SPORT RELATED CONCUSSION, WERE NOT SEEN IN THE YOUNGER POPULATION. IN THE YOUNG ADULT POPULATION 17 AND OLDER, THE FEMALES HAD MORE SYMPTOMS. NOW WE SHIFT AGAIN, THIS IS A STUDY, PEDIATRIC STUDY IN A PEDIATRIC CONCUSSION CLINIC. SO NOW WE'RE NOT IN THE ED, NOT DOING COMPARISON ACROSS AGES, OUTSIDE OF PEDIATRICS, THESE ARE ALL KIDS BETWEEN AGE 10 AND 17 AND THEY LOOKED ACROSS RECOVERY TIMES AND LOOKED TO SEE WAS THERE A DIFFERENCE IN MALE FEMALE, AND WHAT THEY FOUND IN GENERAL WAS THAT FEMALES HAD LONGER RECOVERY TIMES IN THIS STUDY UNDERSTANDING THAT THE PATIENT POPULATION THAT COMES TO CONCUSSION CLINICS ASKEWED IN FAVOR OF FEMALES. MORE COME FROM THOSE CLINICS IN GENERAL AND THAT'S OUR OWN EXPERIENCE IS MORE FEMALES. THE ODDS RATIO HAVING POST CONCUSSION SYMPTOMS GREATER THAN FOUR WEEKS FOR FEMALES AND THAT MALES IS # .1. SO FEMALES WORSE ON THIS ONE. ANOTHER CONCUSSION CLINIC SET, THIS IS FROM MIKE MCCRANE, HIS GROUP LOOKING AT RECOVERY TRAJECTORIES. YOU CAN SEE HERE. DO IT AGAIN HERE. MALE RECOVERY FASTER THAN FEMALE RECOVERY AND COMING TO SIMILAR CONCLUSION THAT FEMALES TOOK LONGER IN THEIR RECOVERY. FEMALES WORSE THANS MALES, AGE RANGE 10 TO 18 OVERLAPS BETWEEN GRADE SCHOOL MIDDLE SCHOOL AND HIGH SCHOOL AND CAN'T PARSE IT OUT. WE DIDN'T FIND A PRIMARY EFFECT OF AGE IN EITHER OF THE TWO STUDIES. POST TRAUMATIC HEADACHE IS A SPECIFIC SYMPTOM PARTICULARLY PROBLEMATIC. WE KNOW IN GENERAL IT SHARES FEATURES WITH MIGRAINE, PROBABLY DUE TO SHARED PATHOPHYSIOLOGY, WE ALSO KNOW THAT IN GENERAL AT LEAST AFTER ADOLESCENCE, MIGRAINE OCCURS ABOUT TWO TO ONE FAVOR IN FEMALES COMPARED TO MALES. BUT WHAT HAPPENS IN YOUNGER KIDS? WE DON'T KNOW HOW THAT MIGRAINE RISK TRANSLATES. LOOKING AT POST TRAUMATIC HEADACHE, HIGH DIBLOOM AND UNIVERSITY OF WASHINGTON SHOWED THAT AT THREE MONTH TIME POINT AFTER MILD TBI GIRLS REPORTED SIGNIFICANTLY MORE POST TRAUMATIC HEADACHES THAN BOYS. NOT NECESSARILY MIGRAINE BUT ANY POST TRAUMATIC HEADACHE, AND LATER TIME POINTS, AT YEAR LATER, IT WAS NOT STATISTICALLY SIGNIFICANT BUT THERE WAS STILL HIGHER PROPORTION OF GIRLS REPORTING PROBLEMATIC HEADACHES AT THE 12 MONTH POST INJURY TIME POINT COMPARED TO BOYS. THE LAST MINUTE YOU'LL SPEND HERE, WE NEED SOME DISCUSSION ABOUT RULES AND POLICY AS RELATES TO THE YOUNGER POPULATION. WE DIDN'T REALLY HEAR ANYTHING ABOUT THIS TODAY. I HAVE ONLY GOT THESE QUESTIONS, I DON'T HAVE ANSWERS FOR YOU. BUT SHOULD YOUNGER KIDS PARTICIPATE IN SAME SEX OR CO-ED SPORTS? YOUTH MMA ALLOWS BIAS AND GIRLS TO WRESTLE IN THE SAME CAGE. UP UNTIL I THINK AGE OF 10 OR SOMETHING LIKE THAT. SO WHATEVER YOU FEEL ABOUT MMA BUT IT'S INTERESTING TO THINK ABOUT THERE COULD BE CO-ED SPORTS, HERE IS CO-ED SOCCER ALSO. SO WHEN SHOULD BOYS AND GIRLS SEPARATE? WHEN THEY START TO HAVE PHYSICAL DIFFERENCES FROM ETCH OOH OTHER? SHOULD THERE BE SEX SPECIFIC PROTECTIVE EQUIPMENT? FOR FEMALE BOXERS VERSUS MALE BOXERS THERE'S FROM TECHTIVE EQUIPMENT. A SEPARATE POLICY POINT NOT RELATED TO HOW WE MANAGE KIDS WHO ARE PLAYING SPORTS, BUT IS MORE QUESTION FOR FUNDING AGENCIES AN THINGS LIKE A WHETHER OR NOT WE NEED TO HAVE AN AUTOMATIC REQUIREMENT THAT FEMALES ALL RESEARCH STUDIES TO GET GRANT FUNDING IS THAT IS THE BEST WAY TO GET MORE INTEREST IN RESEARCH INTO SEX DIFFERENCES? OR TO FAVOR STUDIES THAT HAVE A SEX BASED HYPOTHESIS? WE HER EARLIER FROM SEVERAL SPEAKERS THAT THE IDEA OF JUST SAYING OH, WE'RE GOING TO ADD A FEMALE GROUP TO THIS STUDY WHICH ISN'T DESIGNED TO ADDRESS A SPECIFIC SEX BASED HYPOTHESIS MAY OR MAY NOT BE AS SIMPLE AS DOUBLING THE N AND INCREASING THE NUMBER OF SUBJECTS. YOU HAVE TO TAKE INTO ACCOUNT THE AGE OF DEVELOPMENT, YOU HAVE TO MAYBE TAKE INTO ACCOUNT THE STAGE OF THE MENSTRUAL CYCLE. AND IT BECOMES A MORE COMPLICATED STUDY, IF YOU JUST ADD FEMALES ABOUT DON'T CONSIDER THOSE THINGS YOU'RE WASTING MONEY. THERE IS LESS ACUTE INFLAMMATION, GREATER DAMAGE, MORE -- BUT DEVELOPMENTAL SIX COMPARISONS ARE NOT DONE AFTER REPEAT MILD TBI. YOU SEE PITUITARY FUNCTION OCCURS IN ANIMAL MODELS OF REPEAT MILD TBI AND IT'S LOGICAL THAT HORMONAL DISCUSSION FUNCTIONS FROM PITUITARY IMPAIRMENT COULD HAVE SEX RELATED SEQUELAE AND DEVELOPMENTAL RECEIVE DEALLY. WE KNOW THERE'S A SMALL EFFECT OF SEX ON CHILDHOOD BASELINE SCORES, SEEMS THAT THE MALES MAYBE PRESENT MORE AND THEN IN THE ADOLESCENCE, THE FEMALES PRESENT WITH MORE. FEMALES SEX MAY ALSO BE PREDICTOR OF MORE PROLONG SYSTEMS IN ED COHORTS AND CONCUSSION CLINIC COHORTS. BUT IT WON'T BE IN ALL COHORTS AND WE WILL SEE LATER TODAY COHORT WHERE FEMALE SEX DIDN'T PREDICT LONGER SYMPTOMS. THEN RATHER THE THAN STATING I THINK THAT FEMALES ARE MORE OR LESS VULNERABLE OR RESILIENT AFTER SPORTS CONCUSSION OR TBI, I THINK WE NEED TO THINK ABOUT THIS A LITTLE DIFFERENTLY AND MAYBE THE WAY DR. MCCARTHY GAVE US AT THE VERY BEGINNING, NOT JUST TWO BOXES WITH BOYS AN GIRLS IN SEPARATE BOXES. THERE'S DIFFERENT WAYS SEX BASED DIFFERENCES AFFECT EACH OTHER AND WE RECOGNIZE THAT BOYS AN GIRLS, MALES AN FEMALES ARE DIFFERENT AND TRY TO CHARACTERIZE THOSE DIFFERENCES, RATHER THAN SORT OF PITTING ONE AGAINST THE OTHER THAT ONE HAS TO BE BETTER THAN THE OTHER. OF COURSE WE NEED SEX SPECIFIC DEVELOPMENTAL HYPOTHESES IN OUR FUTURE STUDIES. AS A FINAL THOUGHT, TAKE LOOK AND SEE IF YOU SEE ANY GENDER BIAS IN THE ROLES HERE. ATTENTIVE -- INATTENTIVE BOY. THE STUDIOUS GIRL. DIDN'T SEE THAT ONE COMING. THANKS FOR YOUR ATTENTION. [APPLAUSE] >> OUR NEXT SPEAKER IS INTRODUCE BEFORE BECAUSE HE WAS KIND ENOUGH TO STEP IN FOR DR. MANLY IN AN EARLIER SESSION, IT'S HARVEY LEVIN FROM BAYLOR COLLEGE OF MEDICINE. PLEASE WELCOME HARVEY. [APPLAUSE] >> THANK YOU. I'M GOING TO FOCUS ON HIGH SCHOOL ATHLETES. I'M GRATEFUL FOR SUPPORT APPROXIMATE THE OPPORTUNITY TO BE HERE TODAY. I WOULD LIKE TO BRIEFLY REVIEW METHODOLOGICAL ISSUES IN THIS AREA OF RESEARCH. SOME OF THESE WILL BE REDUNDANT WITH PREVIOUS SPEAKERS SO I'LL GO FAST. TALK ABOUT SYMPTOM RESOLUTION, COGNITIVE FUNCTION AFTER CONCUSSION, MECHANISMS AND GAPS IN RESEARCH AS WELL AS TAKE HOME MESSAGES. YOU JUST HEARD FROM CHRIS ABOUT DIFFERENCES IN SPORT AND PROTECTIVE EQUIPMENT AND ALSO WHETHER HELMETS ARE EVEN WORN. DAWN ALLUDED TO THAT AS WELL. METASTASIS SOME STUDIES HIGH SCHOOL AND COLLEGIATE SAMPLES ARE COMBINED. OTHERS COMBINE YOUTH AND HIGH SCHOOL. AND AS CHRIS MENTIONED IT'S DIFFICULT TO ISOLATE THE STUDIES FOCUSED ON HIGH SCHOOL AGE ATHLETES. SEX DIFFERENCES IN COGNITIONEN TYPICALLY DEVELOPING UNINJURED ADOLESCENTS IS IMPORTANT TO TAKE NOTE OF. DEVELOPMENTAL STUDIES OF VERBAL LEARNING AND MEMORY, HAVE OFTEN REPORTED A SUPERIORITY IN GIRLS COMPARED TO BOYS. SIMILARLY, IN VISUAL SPATIAL FUNCTION THERE'S LITERATURE INDICATING THAT BOYS PERFORM AT HIGHER LEVEL. THIS HAS TO BE TAKEN INTO ACCOUNT IN LOOKING AT COGNITIVE CHANGES AFTER CONCUSSION. WHEN THERE'S BASELINE TESTING AVAILABLE, HOOKK AT THE CHAIN FROM BASELINE CAN MITIGATE THIS ISSUE. I COME ACROSS STUDIES OR MEETING COLLEAGUES AT MEETINGS WHERE I HEAR ABOUT SOMETIMES STUDENT ATHLETES PURPOSEFULLY DON'T PERFORM AT THEIR HIGHEST LEVEL ON THE PRE-SEASON BASELINES. SODS THAT IS ANOTHER CONCERN -- SO THAT IS ANOTHER CONCERN. ESTIMATING PRE-COGNITIVE FUNCTION APART FROM WHAT'S INCLUDE IN THESE WIDELY USED COMPUTERIZED TASKS IS ALSO RELEVANT AND SELDOM DO YOU SEE THAT IN ANY OF THE LITERATURE. SCREENING FOR DEVELOPMENTAL PSYCHIATRIC NEUROLOGIC DISORDERS IS OBVIOUSLY IMPORTANT. OFTEN IN THIS LITERATURE ONE SEES PERHAPS CHECKLISTS OR FORMS FILLED OUT BY MAYBE BY A PARENT BUT THERE ARE MORE RIGOROUS WAYS TO EVALUATE PRE-CONCUSSION CONDITIONS. SPORTS EXPOSURE HISTORY AND CONCUSSION HISTORY ARE OBVIOUSLY IMPORTANT. AND AGAIN THIS CAN BE DONE IN A RIGOROUS WAY. AND SOME OF THE HISTORY MAYBE OUTSIDE OF ORGANIZED SPORTS. WE HEARD A NUMBER OF SPEAKERS TODAY, PARTICULARLY DR. MCCARTHY , ABOUT CHARACTERIZING BIOLOGICAL AS SPECIFICS OF SEX. ONE THING TO TAKE NOTE OF IS VARIABILITY IN MENSTRUAL PATTERN IN ADOLESCENTS EVEN WHO HAVE NOT BEEN CONCUSSED. ESPECIALLY YOUNG ADOLESCENTS. SO ONE OF THE INTERESTING STUDIES I CAME ACROSS WAS BY (INDISCERNIBLE) THIS WAS NOTED I THINK BY AT LEAST ONE OF THE PREVIOUS SPEAKERS, LIMITATION WAS THAT THE DATA POST INJURY WOULD ONE TO TWO DAYS, THERE WASN'T LOANINGER TERM FOLLOW-UP BUT INTERESTINGLY THE FEMALE ATHLETES HAD MORE SYMPTOMS AND MALES WHO NOT WEARING HELMETS HAD FEWER SYMPTOMS THAN THE ONES WHO WERE. IN THIS STUDY THE AUTHORS ALSO CALCULATED RELIABLE CHANGE IN COGNITIVE FUNCTION FROM PRE-INJURY. THEY USED A AS FAR AS I CAN TELL, ASSESSMENT THEY DEVELOPED, IT WASN'T ONE I RECOGNIZE BUT COMPLEX REACTION TIME WHICH IS ON THE LEFT, YOU CAN SEE A MAYOR CHANGE IN THE FEMALE ATHLETES AND THIS WAS SIMPLE REACTION TIME, THIS WAS PROCESSING SPEED. THERE WERE SIGNIFICANT SEX DIFFERENCES ON ALL THOSE MEASURES. MOST OF YOU ARE FAMILIAR WITH THIS POST CONCUSSION SYMPTOM SCALE. THIS IS THE MOST COMMONLY USED SCALE IN THE SPORTS CONCUSSION LITERATURE. THE LIKERT SCALE. THE STUDIES THAT I'M GOING TO DESCRIBE USE THAT SCALE, TRACY CORVASIN STUDIES LONGITUDINALLY STUDENT ATHLETES AT TWO DAYS 7 DAYS AND 14 DAYS AND INCLUDING A BASELINE. THE TOTAL SYMPTOMS WERE HIGHER IN THE FEMALE ATHLETES, THIS INCLUDED HIGH SCHOOL AND COLLEGE. SO NOT SPECIFIC TO HIGH SCHOOL. INTERESTINGLY THE VISUAL MEMORY COMPOSITE ON IMPACT SHOW AD DEFICIT IN THE FEMALE ATHLETES RELATIVE TO THE MALES. I'LL RETURN TO THAT POINT. NO SEX DIFFERENCES ON VERBAL MEMORY, MOTOR PROCESSING SPEED OR REACTION TIME COMPOSITES. HERE YOU SEE A PLOT OF THE TOTAL SYMPTOMS. AND THIS SEX DIFFERENCE PERSISTED OVER THE TWO WEEKS. THERE WAS NO INTERACTION BETWEEN THE OCCASION AND SEX. HERE WE SEE ON THE RIGHT, SORRY, WE SEE ON THE LEFT THE VISUAL MEMORY FOR THE GIRLS VERSUS THE BOYS. K SEE A CONSIDERABLE DIFFERENCE WHICH PERSISTED OVER THE TWO WEEKS. YET AT THE PRE-SEASON BASELINE THERE WAS RELATIVELY LITTLE DIFFERENCE BETWEEN THE MALE AND FEMALE ATHLETES. IT'S POSSIBLE PERHAPS THERE'S A GREATER VULNERABILITY IN VISUAL MEMORY. FEMALE ADOLESCENT ATHLETES. ON VERBAL MEMORY, THERE WAS NO SIGNIFICANT DIFFERENCE. THIS WAS AN INTERESTING FINDING IN MY VIEW, IT IT WASN'T THE PRIMARY PURPOSE OF THE STUDY. BUT IT CONFIRMED THE GREATER -- THE VULNERABILITY TO VISUAL MEMORY. IN THIS STUDY MAJEWSKI ET AL FOUND PERFORMANCE ON THE VISUAL MEMORY IN THE FEMALE ATHLETES WAS PREDICTIVE OF FROM LONGED TIME BEFORE RETURN TO PLAY. THERE ARE RELATIVELY FEW STUDIES THAT I FOUND ON REPEATED CONCUSSION COMPARING HIGH SCHOOL AGE MALE AND FEMALE ATHLETES. THE DIRECTION WAS SIMILAR AS THE SINGLE INJURY FOR TWO CONCUSSIONS FOR THREE OR MORE IT MAYBE LESS CONSISTENT BUT TWO OR MORE FEMALE ATHLETES PERFORM BETTER THAN MALE ATHLETES VERBAL MEMORY AND VISUAL MEMORY. THE INCONSISTENCY WAS ON REACTION TIME AND MOTOR PROCESSING SPEED. POSTURAL ABILITY AND VESTIBULAR OCULAR MOTOR FUNCTION. EVERY HERE IS FAMILIAR WITH THE BEST AND TRACY COVASIL ALSO REPORTED ON THIS. WITHOUT BASELINE AND SHE FOUND THAT INTERACTION OF AGE BY SEX WAS SIGNIFICANT. COLLEGIATE FEMALES PERFORM WORSE THAN MALES, WHEREAS HIGH SCHOOL FEMALES SENNED TO HAVE LOWER ERROR SCORES THAN MALES BUT THE DIFFERENCE WAS NOT SIGNIFICANT. YOU CAN SEE THAT HERE. THESE ARE THE COLLEGIATE ATHLETES. YOU CAN SEE THAT THERE IS A SEX DIFFERENCE WHERE IT'S RELATIVELY LITTLE DIFFERENT AT THE HIGH SCHOOL LEVEL. THIS WAS A LONGITUDINAL STUDY BY HENRY AND COLLEAGUES USING MEASURES OF OCULAR VESTIBULAR DYSFUNCTION AND MEASURING REPORT OF DIZZINESS. IN THIS STUDY IN THIS STUDY, TOTAL POST CONCUSSION SYMPTOMS THERE HAVE A CONFIRMATION OF THE INCREASED NUMBER OF SYMPTOMS REPORTED BY FEMALE ATHLETES. BUT THIS WAS ALSO CONFIRMED ON THE DIZZINESS HANDICAP INVENTORY YOU CAN SEE THIS AND THIS IS OVER A PERIOD OF FOUR WEEKS. LOOKING AT VESTIBULAR OCULAR MOTOR SYMPTOMS, THERE WAS AGAIN FEMALES HAD MORE VESTIBULAR OCULAR SYMPTOM OVER THE FOUR WEEKS. THAN MALE COUNTERPARTS. HERE I PUT TOGETHER A FEW STUDIES THAT LOOK AT BOTH SYMPTOMS AND COGNITIVE FUNCTION. AND ONE CONSISTENT PATTERN IS INCREASE SYMPTOM REPORTING IN THE FEMALE ATHLETES COMPARED TO MALES. THE DIFFERENCES IN COGNITIVE PERFORMANCE WERE NOT AS CONSISTENT. BUT I THINK THAT THE POSSIBILITY OF A RELATIVE VULNERABILITY OF VISUAL MEMORY IN THE FEMALE ATHLETES PERHAPS SHOULD BE FURTHER EXPLORED. WE HEARD ABOUT DIFFERENCESES IN THE PATTERN OF SYMPTOMS SO WE'LL SKIP OVER THAT. AND THIS WAS CASE CONTROL STUDY, IT WAS BASED ON CONSECUTIVE REFERRALS TO A SPORTS CONCUSSION CLINIC AND ALSO AN ED. THE REFERRALS HAD TO ARRIVE BEFORE 28 DAYS AND THEN THERE WAS FOLLOW-UP AFTER 28 DAYS. THE CASES WERE -- THE CASE GROUP WERE THOSE ATHLETES WHOSE SYMPTOM PERSISTED LONGER THAN 28 DAYS, THE CONTROLS HAD THEIR SYMPTOMS RESOLVED WITHIN 28 DAYS. AND YOU CAN SEE THE MEAN AGE WAS 13 YEARS IN BOTH GROUPS, WITH MULTIPLE REGRESSION, THE FEMALE ATHLETES AT HIGHER RATE OF DELAYED SYMPTOM RECOVERY. >> VERY SIMILAR TO STUDIES THAT WERE MENTIONED IN PREVIOUS TALKS. AS WE HAVE HEARD, IMPLICATE DIFFERENCES IN HORMONE LEVELS AS EXPLAN TOWER MECHANISM, IS NOT THAT STRAIGHT FORWARD. THIS STUDY WHICH WAS PUBLISHED IN A CURRENT YEAR COMPARED POST CONCUSSION MENSTRUAL PATTERNS. THE AGE RANGE WAS 12 TO 21, WASN'T EXCLUSIVELY HIGH SCHOOL. BUT AUTHORS INCLUDED A ORTHOPEDIC INJURY CONTROL GROUP THEY USED TEXT MESSAGING TO OBTAIN DATA ABOUT ABNORMAL BLEEDING IN THE BEGINNING THEY HAD A MENSTRUAL QUESTIONNAIRE AND ABLE TO CRYIATE MENSTRUAL DIARIES BASED ON HISTORY AND THE POST INJURY TEXT MESSAGING. THEY DEFINED ABNORMAL PATTERNS OF INTRAMENSTRUAL INTERVALS BY FINDINGS IN THE CONTROL GROUP. AFTER SPORTS CONCUSSION THE RISK OF HAVING A SHORT INTERMENSTRUAL INTERVIEW OR LONGER INTERVAL WAS 16.2% AFTER CONCUSSION VERSUS 3.3% IN THE ORTHOPEDIC CONTROLS. HORMONE LEVELS AND RECOVERY OF SYMPTOMS AND COGNITION WERE NOT REPORTED IN THIS STUDY. I DON'T KNOW WHETHER THEY EVALUATED ATHLETES, BUT I CONSIDER THIS TO BE VERY INFORMATIVE STUDY AND I THINK IT REMINDS US LIKELIHOOD OF MENSTRUAL IRREGULARITIES FOLLOWING CONCUSSION. WE HAVE ALREADY HEARD ABOUT THE HYPOTHESIZED MECHANISMS TO EX PLAIN SEX DIFFERENCES I'M NOT GOING TO SPEND TIME ON THIS. TAKE HOME MESSAGES. WE PROBABLY AGREE MOST STUDIES REPORT MORE SEVERE SYSTEMS IN FEMALE ATHLETES AFTER CONCUSSION. WE ALSO SEE THAT IN DIZZINESS AND OCULAR VESTIBULAR DYSFUNCTION. SEX DIFFERENCES COGNITIVE EFFECTS ARE LESS CONSISTENT VISUAL MEMORY WAS MORE EFFECTED IN FEMALE ATHLETES IN TWO STUDIES. MENSTRUAL PATTERNS ARE AFFECTED BY SPORTS CONCUSSION. THE RELATION TO COGNITIVE SYMPTOMATIC RECOVERY AND THE MECHANISMS ARE UNKNOWN. PRELIMINARY SUPPORT FOR INDIVIDUALIZATION, OF CLINICAL ASSESSMENT AND MANAGEMENT OF SPORTS CONCUSSION IN FEMALE ADOLESCENTS IS CERTAINLY SUGGESTED BY THE AVAILABLE LITERATURE. GAPS INCLUDE MECHANISM OF SEX DIFFERENCES IN RECOVERY, THE LACK OF FOLLOW-UP. PRE-CLINICAL RESEARCH MAY ELUCIDATE THE MECHANISMS. THANK YOU. [APPLAUSE] >> THANK YOU, HARVEY, LAT SPEAKER FOR PAMMABLE IS DR. MICHAEL MCCREA, INJURY DIRECTOR AT THE MEDICAL CLEM OF WISCONSIN. HE'S DONE LARGE STUDIES IN TRAUMATIC BRAIN INJURY AND SPORTS CONCUSSION, HE'S IN A CARE CONSORTIUM AND SEVERAL LARGE ACUTE AND CHRONIC EFFECTS OF T BI AND VARIOUS POPULATIONS AT RISK SO PLEASE WELCOME DR. MCCREA. >> THANK YOU, PAT. GRATEFUL TO YOU AND WALTER AND ALL THE EVENT ORGANIZERS HERE FOR THE INVITATION TO JOIN DON, CHRIS AN HARVEY ON THIS PANEL. I HAVE ENORMOUS RESPECT FOR THEIR WORK AND TO BE SHARING THE PODIUM WITH THEM THIS AFTERNOON IS TRUE HONOR. BY BUT DIPAT MUST HAVE THOUGHT THERE WAS SOME CRUEL IRONY IN ME BEIN THE ONLY THING OR PERSON BETWEEN YOU AND HAPPY HOUR. I KNOW YOU STAGED THAT, PAT, DON'T DENY IT. SO CONTINUING OUR PROGRESSION IN THIS LAST SESSION THIS AFTERNOON, FROM PEDIATRIC& PATIENTS TO HIGH SCHOOL AGED ATHLETES, I HAVE BEEN ASKED TO TALK LITTLE BIT ABOUT SOME EARLY FINDINGS, HOT OFF THE PRESS NOT YET PUBLISHED FROM THE CARE CONSORTIUM FOCUSED ON SPORT RELATED CONCUSSION AND MILITARY RELATED CONCUSSION IN NCAA STUDENT ATHLETES AND MILITARY SERVICE ACADEMY CADETS. I'LL SPEAK MORE ABOUT THE OVERALL STRUCTURE AND FUNCTION OF THE CARE CONSORTIUM HERE AT WE GO. FOR THOSE NOT FAMILIAR WITH THE DARE CONSORTIUM, THIS WAS STOOD UP THROUGH A PUBLIC PRIVATE PARTNERSHIP BETWEEN NATIONAL COLLEGIATE ATHLETIC ASSOCIATION NCAA AND U.S. DEPARTMENT OF DEFENSE WHO SHARE A LOFT THE SAME CHALLENGES IN WITH RESPECT TO THE RAPID DIAGNOSES ASSESSMENT AND MANAGEMENT OF ATHLETES OR MILITARY SERVICE MEMBERS AN CADETS WHO ARE AFFECTED BY CONCUSSION. THIS GIVES AN OVERALL ILLUSTRATION OF STRUCTURE OF THE CARE CONSORTIUM AND I HAVE THE HONOR OF CO-LEADING THIS EFFORT WITH STEVE AT THE UNIVERSITY OF MICHIGAN AND TOM MECHANICALSER AT IU SCHOOL OF MEDICINE, I HAVE SEEN SITE PIs OR OTHER MEMBERS OF TEAM THAT MAKE UP THE COURSE SOURCE YUM. THE EFFORT WAS LAUNCHED IN SUMMER OF 2014. IT CONSISTS OF THREE PILLARS. FIRST BEING ADMINISTRATIVE OPERATION CORE BY TOM AN TEAM AT I,. THE LONG STEWEDNAL CLINICAL STUDY CORE GREAT DEAL OF DATA THIS AFTERNOON DIRECTED BY STEVE BROLIO AN TEAM AT MICHIGAN. AND STEVE AND THE SITE PI AT THESE 30 SITES NATIONALLY GET CREDIT. I'M INVITED TO BE THE MESSENGER TODAY BUT AS YOU MIGHT GRASP IS MASSIVE HERCULEAN EFFORT AT THESE 30 SITES. HERE YOU SEE THESE 30 PARTICIPATING SITES THAT MAKE UP THE CARE CONSORTIUM STRATIFIED ACROSS ONE, TWO, THREE, INSTITUTIONS THAT ARE NCAA MEMBER INSTITUTIONS. WE HAVE FOUR MILITARY SERVICE ACADEMIES AT AIR FORCE WEST POINT NAVAL ACADEMY AND THE U.S. COAST BARD. IN ADDITION, I'LL SPEAK MORE TO THIS BUT I LEAD THE ADVANCED RESEARCH CORPS. AT 6 OF 30 SITES WE DIVE DEEPER AND IN ADDITION TO CLINICAL STUDY PROTOCOL, WE INTRODUCE ADVANCE MULTI-MODAL IMAGING EMPLOYMENT OF BLOOD BIOMARKERS GENETIC TESTING AN HEAD IMPACT MEASUREMENT TECHNOLOGY. SO I'LL WALK THROUGH A LITTLE BIT OF THE PROTOCOL. BUT THE OVERERR. ING AIM OF THE CARE CONSORTIUM WAS A STUDY LARGEST MOST COMPREHENSIVE STUDY OF THE NATURAL HISTORY OF CONCUSSION AND NCAA STUDENT ATHLETES AND MILITARY SERVICE ACADEMY CADETS. THERE ARE THREE AIMES HERE TO COLLEGIATE THE PLATFORM AND INFRASTRUCTURE IN WHICH TO CONDUCT THIS STUDY. THAT'S THE AOC, THAT TOM LEADS OUT OF MICHIGAN. I'M SORRY, OUT OF IU AT INDIANA. STEVE BROLIO LEADS THE CLINICAL STUDY CORPS WHICH IS AGAIN A PROSPECTIVE LONGITUDINAL MULTI-CENTER STUDY INTENDED TO STUDY THE NATURAL HISTORY OF CONCUSSION IN BOTH MALES AN FEMALES. MANY OF YOU IN THE ROOM WHO HAVE BEEN AT THIS A LISTENING TIME LIKE ME, I'M AS GUILTY AS ANYONE RECOGNIZE THAT UP UNTIL ABOUT THREE OR FOUR YEARS AGO THE LION'S SHARE OF ALL STUDIES IN SPORT RELATED CONCUSSION WERE RESTRICTED TO MALE ATHLETE AND 90% WERE RESTRICTED TO MALE AMERICAN FOOD BALL PLAYERS SUCH ADS NCAA CONCUSSION STUDY KEVIN AND I LED BACK IN THE 1990s. THE THIRD AIM RELATE TO ADVANCE RESEARCH CORPS AT MEDICAL COLLEGE OF WISCONSIN, AGAIN, CREATING THIS INTEGRATED APPROACH THAT BRINGS BIOMECHANICAL IMMA'AMING NEUROLIE BIOLOGICAL AND GENETIC STUDIES IN ADDITION TO AND OVER AND ABOVE CLINICAL STUDY CORE. JUST TO GIVE A BIRD'S EYE VIEW OF THE AHRQ AN CSC PROTOCOLS. THIS IS A HIGHLY AMBITIOUS EFFORT, FOR THOSE ANYONE WHO SITE PIs OR OTHERWISE IN THE ROOM REALLY DESERVE THE CREDIT FOR WHAT I'M ABOUT TO PRESENT HERE THIS AFTERNOON. ALL THESE INDIVIDUALS BOTH STUDENT@LEES AND CADETS, AND BY THE WAY AT THE SERVICE ACADEMIES ENROLLING ALL DEBTS ON CAMPUSES NOT -- CADETS ON CAMPUSES NOT JUST THOSE THAT PARTICIPATE IN NCAA ATHLETICS. BUT ALL THESE INDIVIDUALS ARE RICHLY CHARACTERIZED AT BASELINE, AT TIME OF ENROLLMENT PRIOR TO EXPOSURE IN SPORTS SEASON OR MILITARY TRAINING, WITH DETAIL HISTORY TAKING AND ARRAY OF COMMON DATA ELEMENT ASSESSMENT MEASURES. AND THEN ANY ATHLETE OR CADET WHO SUSTAINING A CONCUSSION IS REREVALUE WAITED WITHIN SIX HOURS OF INJURY 24 TO 48 HOURS AN FLOATING TIME POINTS THAT ARE ANCHORED TO THEIR OBSERVED CLINICAL RECOVERY WITHIN REMOTE FOLLOW-UP SIX MONTHS POST INJURY. OVER AN ABOVE CSC AS PART OF THE AHRQ PROTOCOL SUBSTUDY LAUNCHED AT WEST POINT AIR FORCE UCLA LED BY DR. GIZA, ONE ESTEEMED PANELIST TODAY, UNIVERSITY OF WISCONSIN LED BY HE WILY SON BROOKS WORK CITED A BIT AGO AT NORTH CAROLINA LED BY KEVIN AN VIRGINIA TECH LEFT -- LED BY STEPHAN DUMA MANY OF YOU KNOW IN THIS SPACE OF TBI AND CONCUSSION. AT BASELINE WE COLLECT DNA AND BLOOD BIOMARKERS ON ALL OF THE ATHLETES WHO PARTICIPATE IN ADVANCE RESEARCH CORE. WE COLLECT BLOOD BIOSPECIMENS AT SIX HOURS POST INJURY IN ADDITION TO CLINICAL ASSESSMENTS AND AT 24, 48 HOURS ADVANCE MULTI-MODAL 3T IMAGING AND THE ELEMENTS ARE REPEATED AT SEVERAL TIME POINTS AS PART OF THE OVERALL PROTOCOL. BECAUSE RESOURCE UTILIZATION AND THE AHRQ, THE ENROLLMENT AND POST INJURY APPROVAL AS PART OF THE ADVANCE RESEARCH CORE AT THE SIX INSTITUTIONS IS RESTRICTED TO MENS AND WOMEN'S SOCCER, MEN FOOTBALL, LA CROSS, ICE AND FEEL HOCKEY AN RUG BY. WE ONLY HAVE IMAGING AT THE NCAA SITES BECAUSE WEST POINT AND AIR FORCE DO NOT YET HAVE 3T IMAGING ON THEIR CAMPUS. SO IN ADDITION, AS PART OF THIS PROTOCOL AND THE OVERALL STUDY DESIGN, OUR SCIENTIFIC REVIEWERS AT THE TIME THIS PROPOSAL WAS REVIEWED,DED A VERY INSIGHTFUL RECOMMENDATION. HISTORICALLY OUR STUDY ENROLLED A LARGE NUMBER OF CONCUSSED STUDENTS ATHLETES. AND WE HAVE TYPICALLY HAD A CONTACT SPORT CONTROL. SOMEONE A DEMOGRAPHICALLY AND BASELINE MATCHED ATHLETE FROM THE SAME CONTACT SPORTS SAME INSTITUTION, WHO WAS YOLKED TO THE CON CUSSED@-- CONCUSSED ATHLETE. FROM THE CONSORTIUM ADVANCE RESEARCH CORE WE HAVE CONCUSSED COHORT, CONTACT CONTROL FROM THE SAME INSTITUTION MATCHED ON DEMOGRAPHIC BASELINE PERFORMANCE VARIABLES AN NON-CONTACT CONTROL FROM BASEBALL TRACK FEEL OTHER SPORTS, THE OOHED HERE AND URNING OUR SCIENTIFIC REVIEWERS IS FIRST CONTROL GROUP ALLOW US TO DIFFERENTIATE ACUTE CONCUSSION FROM EXPOSURE IN THE ABSENCE OF ACUTE DIAGNOSED CONCUSSION. THE SECOND CONTROL GROUP ALLOWS US TO DIFFERENTIATE THE AFFECTS OF REPETITIVE HEAD IMPACT EXPOSURE FROM ROUTINE HIGH INTENSITY EXERCISE. AS Y'ALL ARE PROBABLY AWARE, THE NARRATIVE AROUND CONCUSSION AN SPORTS HAS REALLY EVOLVED AND EXPANDED OVER TEN YEARS WHERE THERE ARE CONCERNS NOT ONLY ABOUT THE EFFECTS OF REPETITIVE CONCUSSION BUT EVEN REPETITIVE HIGH VOLUME HEAD IMPACT EXPOSURE IN ABSENCE OF CONCUSSIVE INJURY. SO THE DATE, THIS IS JUST A QUICK OVERVIEW OF WHERE WE ARE TO DATE AS PART OF THE OVERALL CONSORTIUM. AGAIN, WE HAVE THIS STUDY FULLY OPERATIONAL AT 30 SITES, ENROLLING NCAA ATHLETES AN MILITARY SERVICE ACADEMY CADETS, ALL CADETS ON THOSE CAMPUSES, DATA AS RECENT AS A FEW DAYS AGO, THEY'RE JUST SHY OF 40,000, 60% ARE NCAA ATHLETE, ABOUT 40% ARE FEMALE AT BOTH ACROSS THE ENTIRE ENROLLED SAMPLE OF 40,000. SO YOU CAN SEE WE HAVE A VERY RICHLY CHARACTERIZED SET OF DATA ON MALES AND FEMALES, SERVICE ACADEMY CADETS AND NCAA ATHLETES. WE HAVE OVER 2500 CONCUSSIONS IN OUR POST INJURY ASSESSMENT PROTOCOL. WHOPPING NUMBER OF DATA ELEMENTS AND WE ARE A MAJOR CONTRIBUTOR TO THE NINDS FOR TBI. I'M GOING TO RESPECTFULLY ASK, I KNOW MANY OF YOU ARE ACTIVE SOCIAL MEDIA FOLKS, DR. GIZA. A LOT OF DATA -- AS A MATTER OF FACT ALL DATA I'LL PRESENT TODAY HAS NOT YET BEEN PUBLISHED. SEW AS I MAKE MY WAY THROUGH THE SLIDES THAT ARE DATA RICH, DON'T PHOTOGRAPH OR DISTRIBUTE THEM BY SOCIAL MEDIA AND THOSE OF YOU HA THAT ARE WATCHING BY VIDEO CONFERENCE I WOULD RESPECTFULLY ASK YOU TO DO THE SAME. EVERYONE IN THE AUDIENCE IS WELL AWARE HOW WHAT STICKLERS JOURNALS ARE THESE DAYS FOR PUBLISHED OR UNPUBLISHED DATA. JUST TO LEVEL SET HERE, THE DATA I'M GOING TO BE SHOWING IN TERMS OF OVERALL SAMPLE NUMBER OF CONCUSSIONS DATA AVAILABLE ON RECOVERY ANDEN RETURNED TO ACTIVITY IS THROUGH JUNE OF 2017. THIS IS -- THESE ARE DATA SPECIFIC TO SPORT RELATED CONCUSSION. ANY DATA SPECIFIC TO MILITARY RELATED CONCUSSION OUT OF SPORTS IS NOT INCLUDED IN THIS. BUT AT THAT TIME IN JUNE OUR OVERALL ENROLLMENT WAS ABOUT 20,000, NCAA ATHLETES. ABOUT 40% FEMALE IN THE ORIGIN OF ABOUT 8500 FEMALES AND JUST OVER 11,000 MALES. YOU CAN SEE HERE THE DEMOGRAPHIC COMPARISON MALES AN FEMALES, STRIKING SIMILARITY, THE ONE EXCEPTION IS MALES HAVE ABOUT YEAR AND A HALF MORE PARTICIPATION IN PRIMARY SPORTS. ONE CAVEAT THAT IS PERHAPS NOTEWORTHY TO STUDY OF EXPOSURE. WE SEE THIS ACROSS STUDIES OVER SEVERAL YEARS, ON ENTRY INTO THE STUDY, OUR ATHLETES HAVE BEEN PLAYING THEIR PRIMARY SPORT MR. SOCCER LA CROSS FOOTBALL, THEY HAVE BEEN PLAYING IT ALMOST DECADE. SO THIS GIVES AN INCREDIBLE OPPORTUNITY TO BETTER UNDERSTAND WHAT ARE THE LONG RANGE NEUROLOGIC HEALTH EFFECTS OF EXPOSURE WITHOUT CONCUSSION, WE DON'T HAVE TO WAIT UNTIL THEY'RE 40 YEARS OLD BECAUSE THEY HAVE ALREADY BEEN PARTICIPATING FOR ROUGHLY NINE OR TEN YEARS. FURTHERMORE, WE -- I THOUGHT IT MIGHT BE INTERESTING FOR THOSE INTERESTED IN THIS TOPIC, TO LOOK AT THE COMPARISON OF REPORTED PRIOR CONCUSSION HISTORY IN THESE 20,000 ATHLETES COMPARING MALES AND FEMALES, AND THERE'S REALLY A STRIKING SIMILARITY HERE IN THE DISTRIBUTION OF 0, 1, 2, 3 OR MORE IN MALE AN FEMALES IF YOU GET OUT TO THE 3 OR MORE CATEGORY WHICH IS A MILE MARKER FOR CONCERNS LONG TERM, WE HAVE ROUGHLY 2% MALES AN FEMALES WHO REPORT AGAIN NOT A REVIEW OF MEDICAL RECORDS, THIS IS BASED ON SELF-REPORT. BOTH MALES AND FEMALES. SO VERY BRIEFLY HERE, AND I REALIZE I'M GOING TO RACE THROUGH THIS TO GET EVERYBODY OUT THE DOOR ON TIME. THROUGH JUNE WE HAVE DATA ON ROUGHLY 1800 CONCUSSED STUDENT ATHLETES. 1100 MALE, THIS IS NOT EPIDEMIOLOGIC DIVE TO THE SIZE DAWN COMSTOCK WOULD GIVE YOU. BUT OVERVIEW DATA THAT DAWN AND OTHERS ALLUDED TO HERE THIS MORNING AND THIS AFTERNOON, COMPARING MALE AND FEMALE SPORTS PARTICIPANTS IN CONTACT, LIMITED CONTACT AND KNOP CONTACT SPORTS DEFINED BASED ON EARLIER PUBLISHED CRITERIA, QUESTION SEE A HIGHER RATE -- WE SEE HIGHER RATE OF CONCUSSION IN FEMALES PARTICIPATING IN SOCCER, WATER POLO AND SWIMMING. YOU CAN SEE BOTH WATER POLO AND SWIMMING HAVE OVERALL VERY LOW NUMBER OF CONCUSSIONS AND PARTICIPANTS OVERALL. SOCCER BEING LARGEST NUMERATOR AND DENOMINATOR, WE SEE SIGNIFICANT DIFFERENCE, 13%, 13 1/2 PERCENT OF FEMALES SUSTAINING CONCUSSION, VERSUS LESS THAN 10% OF MALES. VERY CONSISTENT WITH WHAT DAWN SHOWED EARLIER. WE LOOK AT COMPLEX OF INJURIES THAT MALES AND FEMALES SUSTAIN. THESE ARE VERY CONSISTENT WITH DATA THAT I HAVE SEEN PRESENTED HERE AND THERE THROUGHOUT THE AFTERNOON. WE FIND HIGHER PRE-LENS OF CERTAIN -- PREVALENCE OF ACUTE INJURY CHARACTERISTICS LOSS OF CONSCIOUSNESS, POST TRAUMATIC AMNESIA, ALTERED MENTAL STATUS IN MALES THAN FEMALES HOWEVER NO SEX RELATED DIFFERENCES IN DURATION OF PTA OR LOC WHEN IT OCCURS IN SUBGROUPS. SIMILARLY, THOSE OF YOU THAT DO THIS RESEARCH ARE AWARE OF THE FACT THAT A HIGH PROPORTION ATHLETES DON'T REPORT THE INJURY IMMEDIATELY, NOT DURING PRACTICE OR GAMES THEY SHOW UP IN THE TRAINING ROOM THE NEXT DAY AND WE FIND THE DISTRIBUTION OF THAT DELAY, TO BE SIMILAR BETWEEN MALES AN FEMALES. I DON'T HAVE THE DATA AT MY FINGERTIPS BUT TO GIVE AN IDEA, THE LAST TIME WE LOOKED AT THIS MAYBE IN THE SUMMER OF 2017, WE DISCOVERED THAT ABOUT A THIRD OF ALL ATHLETES ARE NOT REPORTING THEIR CONCUSSION IMMEDIATELY. BECAUSE THEY DON'T RECOGNIZE THE SIGNS AN SYMPTOMS, A LOT OF THEM PLAY THE I'M GOING TO WATCH AN SEE GAME. I WILL SEE HOW I DO OVER THE NEXT FEW HOURS AND IF I'M NOT DOING WELL I'LL COME FORWARD THE NEXT MORNING. AT THE SAME TIME WE PUBLISHED PAPERS INDICATING THIS IS MAYBE THE MOTIVATION AND CURRENCY EXCHANGE ATHLETES NEED TO HEAR. IF THEY DELAY THEIR OWN REPORTING THEY'RE COSTING THEMSELVES TIME SO THOSE THAT PLAY WAIT AN SEE HAVE MUCH LONGER RETURN TO PLAY THAN THOSE WILLING TO COME FORWARD IMMEDIATELY REPORTING INJURY. OVERALL HERE, CONSISTENT WITH I THINK SOME DATA THAT HARVEY SHOWED, WE SEE A PATTERN OF HIGH PREVALENCE, MAYBE MORE SEVERE ACUTE CHARACTERISTICS IN MALES AND THIS FEMALES. I WILL NOW WALK THROUGH A COUPLE OF SETS OF RECOVERY CURVES, COMPARING CLINICAL RECOVERY TIME BASED ON COMBINATION OF CLINICAL EVALUATION SYMPTOM CHECKLISTS, AND OBJECT TV ASSESSMENTS THAT I WILL GET TO ON ANOTHER SLIDE. THIS IS COMPARING 1100 MALES AN 700 FEMALES WHERE THE OVERALL CLINICAL RECOVERY TIME MEDIAN RECOVERY TIME FOR FEMALES IS EIGHT DAYS, MALES IS 7 DAYS. THAT DOES NOT REACH STATISTICAL SIGNIFICANCE BUT I GUESS WE COULD SAY TRENDING BUT IN A SAMPLE SIDES OF THIS MAGNITUDE I'M GUESSING THAT AFFECT SIZE WOULD BE VERY SMALL. HERE YOU SEE THE ACTUAL DISTRIBUTION CATEGORIZED BY LESS THAN SEVEN DAYS 8 TO 14. SO FORTH. ROUGHLY SEE ABOUT 75% RECOVERING IN THE FIRST TWO WEEKS. ONE THING IF YOU HAVE BEEN DOING THIS LONG ENOUGH, THERE'S A LEGACY POSE OF INFORMATION HERE. THAT IS IN BOTH MALES AND FEMALES, LE COVERRY TIME IS TWO TIMES IF NOT THREE TIMES LONGER THAN 20 YEARS AGO. WE BELIEVE ATHLETES ARE MORE WILLING TO COME FORWARD MAYBE MORE ABLE TO HAVE GREATER AWARENESS OF THEIR SIGNS AN SYMPTOMS AN MORE FORTHRIGHT, WE DON'T ANY WAY TO DEMONSTRATE THAT BUT OTHERS HAVE SUGGESTED IT THROUGH EDUCATIONAL CAMPAIGNS. AND SO FORTH. BOLL LINE, WE SEE A VERY -- BOTTOM LINE, WITH SEE A SIMILAR TRAJECTORY OF RECOVERY TIME IN MALES AN FEMALES ACROSS ALL OF OUR STUDENT ATHLETES. SO THESE ASSESSMENT DATA SIMILAR TO WHAT YOU SAW FROM HARVEY, COLLECTION OF STUDY OVER SEVERAL YEARS COMPARING MALES AN FEMALES AND IN FACT SIMILAR WITH THE FINDINGS REPORTED BY SEVERAL INVESTIGATORS HERE TODAY, WE DO SEE A HIGHER TRAJECTORY OR SEVERITY OF SYMPTOMS REPORTED BY FEMALES AGAIN IN THAT FIRST SIX HOURS AN AT 24 HOURS POST INJURY, THEN THE DIFFERENCE BETWEEN MALES AND FEMALES LEVELS OFF OVER THE NEXT COUPLE OF DAYS AND THEN THEIR RECOVERY TRAJECTORY AFTER 24 HOURS IS MUCH THE SAME. BSI HARVEY PRESENTED SOME TRACK DATA EARLIER TODAY, BSI IS A MEASURE OF PSYCHOLOGICAL HEALTH, DEPRESSION, ANXIETY, SOMATIZATION. WE DO SEE A SIMILAR DIFFERENCE IN SELF-REPORTED SYMPTOMS ON BSI BY FEMALES, 24 HOURS AND OUT TO ASYMPTOMATIC TIME POINT. IN THE TRAJECTORIES BETWEEN MALES AN FEMALES ARE THE SAME. CONVERSELY, WE SEE ON A COGNITIVE SCREENING TOOL, CALLED THE STANDARDIZED ASSESSMENT OF CONCUSSION, THIS IS BRIEF COGNITIVE SCREENING THAT'S MEANT TO BE ADMINISTERED ON THE SIDELINE OR TRAINING ROOM. WE SEE A PATTERN OF MORE SEVERE COGNITIVE DECLINE, IN P MALES RELATIVE TO FEMALES, AT THAT 6 HOUR TIME POINT WHICH THEN THAT GAP CLOSES EVEN WITHIN 24 HOURS OF INJURY. WE SEE NO DIFFERENCE ON BALANCE TESTING HERE ON THE BEST. SIMILARLY WE SEE THESE ARE FOUR IMPACT SUBTESTS ON VERBAL MEMORY VISUAL MEMORY, VISUAL MOTOR SPEED AN REACTION TIME. WE DO IN FACT SEE SLOWER REACTION FILE IN MALES THAN FEMALES NOT ONLY WITHIN THAT SUPER ACUTE 24 HOUR WINDOW BUT EXTENDS OUT WARDS 7 TO 14 DAYS WHICH WE THINK IS SOMETHING WORTHY OF FOLLOW-UP. I SHOULD HAVE POINTED OUT TOO ON ALL THESE FIGURES, OUR MODEL CONTROLS FOR BASELINE AND LEVEL OF PERFORMANCE IN THESE SUBJECTS SO THESE ARE FINDINGS THAT ARE EVIDENT INDEPENDENT AFTER CONTROLLING FOR BASELINE PERFORMANCE. WHAT ABOUT RETURN TO ACTIVITIES? TO THIS POINT RECOVERY LOOKS VERY SIMILAR BETWEEN MALES AN FEMALES IN THIS LARGE SAMPLE FROM THE CARE CONSORTIUM. WE DO FIND THOUGH THAT FEMALES ARE WITH HELL FROM ACTIVITY FOR ABOUT DAY AND A HALF LONGER THAN MALES AND THAT DOES REACH SIGNIFICANT STATISTICALLY IN OUR LOG RANK TEST OF MEDIANS HERE. THAT TENDS TO FLATTEN OUT PAST THE 15 DAY POINT WHERE YOU WILL SEE SIMILAR PERCENTAGES OF MALE AN FEMALES THAT ARE WITH HELL MORE THAN 15 DAYS MORE THAN 21 DAYS AND IN FACT MORE THAN 228 DAYS. MY EDITORIAL COMMENT ABOUT RECOVERY TIME. WHAT IS DRASTICALLY DIFFERENT HERE. SOME OF YOU MAYBE AWARE THAT KEVIN AND I PUBLISHED PAPERS SEVERAL YEARS AGO A TANDEM SET OF PAPERS IN JAMA INDICATING RECOVERY TIME AND NCAA FOOTBALL PLAYERS WAS THREE DAYS. BASED ON THEIR SELF-REPORT. AND AVERAGE RETURN TO PLAY WAS FIVE DAYS. WE TOOK A DEEPER DIVE AND SHOWED A HIGH PERCENTAGE OF ATHLETES RETURNING ON THE SAME DAY, VERY HIGH WHILE SYMPTOMATIC WITHIN TWO OR THREE DAYS POST INJURY, WHAT IS EVIDENT HERE IN MALES AND FEMALES, AND I THINK DAWN POINTED THIS OUT, WE DO A MUCH BETTER JOB BASED ON INTERNATIONAL GUIDELINES OF TAKING CARE OF ATHLETES. WE HAVE A PAPER UNDER REVIEW RIGHT NOW INDICATING THAT RETURN TO PLAY THE SAME DAY IS ZERO. LESS THAN 25% OF ATHLETES RETURN TO PLAY IN THE FIRST FIVE DAYS. THAT'S HAVING A MAJOR IMPACT ON REDUCING THE INCIDENCE OF SAME WHICH GOES ALONG WAY INN. PROTECTING THE HEALTH AND SAFETY OF ATHLETES. CLEARLY WE ARE -- THE DATA HERE WOULD SUGGEST WE'RE MANAGING FEMALES SLIGHTLY DIFFERENT THAN MALES, GIVING THEM SOMEWHERE IN THE ORDER OF A DAY TO TWO DAYS LONGER FOR RETURN TO ACTIVITY DESPITE SIMILAR RECOVERRY TIME. RECOVERY TIME. RETURN TO LEARNER RETURN TO SCHOOL, THIS IS INTERESTING IN MALES AN FEMALES. ON AVERAGE -- WHEN WE LOOK AT MEDIANS MALES MISS ABOUT TWO DAYS OF SCHOOL AND FEMALES ABOUT THREE DAYS. THAT DIFFERENCE TRENDS BUT IS NOT SIGNIFICANT. YOU CAN SEE THAT A VERY SMALL PERCENTAGE OF STUDENT ATHLETES ARE WITHHELD FOR ANY PROLONGED PERIOD -- WITHHELD FROM SCHOOL, FOR ANY PROLONGED PERIOD OF TIME. SO OBVIOUSLY THAT'S ALL MALE AND ALL FEMALE ATHLETES ACROSS A MULTITODAY TUESDAY OF SPORTS AND WE WERE HAVING A DISCUSSION THAT YOU MIGHT CALL IT MEN'S AN WOMEN'S LA CROSS BUT THEY'RE NOT APPLES AND APPLES SO WE WANTED TO TAKE THE LARGEST COHORT OF MALES AND FEMALES, THAT BEING NCA PARKS SOCCER AND LOOK AT CLINICAL RECOVERY TIME RETURNING TO ACTIVITY AND RETURN TO LEARN. WE SEE A SIMILAR PATTERN IN THAT LOOKING AT ROUGHLY 150 FEMALES AND 80 MALES, WE DON'T SEE A DIFFERENCE IN MEDIAN RECOVERY TIME. THE DIFFERENCE IN RETURN TO ACTIVITY IS EXPANDED WHEN WE LOOK AT THE SUBSET OF SOCCER PLAYERS. FEMALES ARE NOW WITH HELL TWO AND A HALF DAYS LONGER. OPPOSED TO A DAY LONGER. THREE DAYS LONGER AN RETURN TO SCHOOL HAS A SIMILAR PROFILE BETWEEN MALES AND FEMALES. SO AGAIN SOME SUGGESTION OUR APPROACH TO MANAGING FEMALE ATHLETES TENDS TO BE PERHAPS MORE CONSERVATIVE. THAN IT IS IN MALES, WITH RESPECT TO RETURN TO PLAY AN RETURN TO ACTIVITY. WE TOOK EARLY FACTORS THAT PREDICT LARGER REGRESSION BASE MODEL THAT PREDICT RETURN TO ACTIVITY, RETURN TO PLAY IN FEMALES. AND IN MALES AND NOT SURPRISINGLY THOSE OF YOU WHO HAVE BEEN INVOLVED IN THIS WORK OR CIVILIAN NEUROTRAUMA WORK, IT TURNS OUT TO BE A COMBINATION OF NEURAL BIOPSYCHOSOCIAL FACTORS THAT PREDICT RECOVERY AND RETURN TO ACTIVITY. THE PRESENCE OF CERTAIN ACUTE INJURY CHARACTER TICKERS. OR POST EXPOSURE AMNESIA, LONGER OUT THAN NOT. SIMILARLY IF YOU HAD IMPAIR OR SIGNAL IF YOU WILL ON STONN DOOR DIESED ASSESSMENTS OF SYMPTOMS COGNITION AND BALANCE, DURING THAT ACUTE PERIOD, YOU WERE MORE LIKELY TO BE WITHHELD LONGER AND THEN IF YOU HAD SIGNIFICANT NUMBER OF PRIOR CONCUSSIONS OR HISTORY OF PRE-INJURY PSYCHOLOGICAL HEALTH ISSUES DEPRESSION, ANXIETY, ET CETERA, YOU CAN SEE THE PROFILE IN THIS REGRESSION MODEL PROFILE OF FACTORS THAT INFLUENCE RECOVERY AN RETURN TO ACTIVITY IS VERY SIMILAR BETWEEN MALES AND FEMALES. SO JUST TO SUMMARIZE, DATA AT THIS STAGE OF THE GAME FROM LARGE DATA SET OF MALE AND FEMALE STUDENT@LEES ACROSS ALL SPORTS WE SAW HIGHER CONCUSSION RATES IN FEMALES IN SELECT SPORTS. I WILL GIVE THE BIGGEST BILL HERE TO SOCCER GIVEN THE VERY SMALL NUMBERS AND WATER POLO AND SWIMMING. WE SEE MORE SEVERE ACUTE INJURY CHARACTERISTICS AND MORE SIGNIFICANT COGNITIVE IMPAIRMENT IN MALES. WE SEE MORE SEVERE SELF-REPORTED SYMPTOMS. IN FEMALES DURING ACUTE WINDOW AND TRAJECTORY OF SYMPTOM RECOVERY LEVELS OFF AND IS SIMILAR BETWEEN MALES AN FEMALES AFTER ABOUT 48 HOURS. NO SEX DIFFERENCES IN CLINICAL RECOVERY TIME, FEMALES HAVE A SLIGHTLY LONGER RETURN TO PLAY TIME, RETURN TO ACTIVITY TIME. IF WE LOOK OVERALL, IT'S ABOUT DAY AND A HALF, IF WE LOOK APPLES AND APPLES IN MEN'S AND WOMENS NCAA SOCCER IT'S SOMEWHERE ON THE ORDER OF TWO AND A HALF TO THREE DAYS DIFFERENCE. NO DIFFERENCES IN RETURN TO LEARN OR RETURN TO SCHOOL. SIMILAR SET OF FACTORS PREDICTED RECOVERY AND RETURN TO ACTIVITY IN MALES AND FEMALES, OVERALL SUGGESTING I THINK AT THIS STAGE OF THE GAME LOOKING SOLELY AT CLINICAL DATA, MORE LIKENSES THAN DIFFERENCES BETWEEN MALES AND FEMALES WITH RESPECT TO RECOVERY AND RETURN TO ACTIVITY. VERY BRIEFLY, I MENTION ADVANCE RESEARCH CORPS AN CAPABILITIES, AGAIN IN A SUBSET OF SIX INSTITUTIONS AND THE ATHLETES, PARTICIPATING IN NCAA SPORTS, AT THOSE SIX AS WELL AS CADETS AT AIR FORCE AND WEST POINT THAT ARE INJURED IN THE MIDST OF MILITARY TRAINING. SO AS PART OF THE ADVANCE RESEARCH CORE, WE BILL ON TOP OF THE CLINICAL INFRASTRUCTURE, THE INCLUSION OF 3T IMAGING, COLLECTION OF BLOOD BIOSPECIMENS, TO EXAMINE CERTAIN CANDIDATE BIOMARKERS, TO DATE ALL -- WE HAVE ABOUT 450 FOOTBALL PLAYERS STREW MEANTED WITH HEAD IMPACT -- STREW INSTRUMENTED WITH HEAD IMPACT TO UNDERSTAND BETTER EXPOSURE AND WE COLLECT DNA ON ALL INDIVIDUALS ENROLLED IN THE AHRQ. TO DATE WE HAVE ENROLLED 2500 IN THE AHRQ PROTOCOL, AGAIN VERY AMBITIOUS,ABLE IT'S ABOUT 5050 MILITARY SERVICE ACADEMY, NCAA. 22% ENROLLMENT AND 23% OF OUR INJURIES, ARE FEMALE. TO DATE WE HAVE ABOUT 80 FEMALES IN THE INJURED COHORT AND THEIR MATCHED CONTROLS IN THOSE TWO CONTROL GROUPS WHO MADE THEIR WAY THROUGH THAT EXTENSIVE POST INJURY PROTOCOL WITH IMAGING BIOMARKERS, DNA COLLECTION, ET CETERA. AGAIN, THE OVERARCHING AIM OF ADVANCE RESEARCH CORPS IS TO UNDERSTAND THE NATURAL HISTORY OF NEURAL BIOLOGICAL EFFECTS AND RECOVERY AFTER THESE INJURIES IN ADDITION TO CLINICAL RECOVERY. SOME OF YOU ARE FAMILIAR WITH EARLY WORK OUT OF THE AHLQ LOOKING AT ADVANCED IMAGING, CHANGES IN WHITE MATTER ON DIFFUSION IMAGING DTI OR DIFFUSION CRYPTOSIS IMAGING SHOWING CHANGES IN WHITE MATTER INTEGRITY DURING ACUTE WINDOW. RESTING STATE FUNCTIONAL CONNECTIVITY, CHANGES IN CEREBRAL BLOOD FLOW AND TRACKING SIGNALS OVER TIME. SO AGAIN, THE FIRST IMAGING POINT IS 24 HOURS, THEN THE IMAGED FOUR MORE TIME OVER A PERIOD, THEY'RE IMAGED THREE TIMES IN THE PERIOD OF TWO WEEKS. AND THEN THERE'S A REMOTE TIME POINT SIX MONTHS OUTS. ONE OF THE VERY INTERESTING AND INTRIGUING FINDINGS TO US SO FAR, IS THAT WE'RE NOT ONLY FINDING FAIRLY ROBUST SIGNAL ABNORMALITIES ON BIOMARKERS AND IMAGING WITHIN THAT SUPER ACUTE WINDOW, 24 TO 48 HOURS POST INJURY BUT ALSO FINDING THAT THE SIGNALS PERSIST BEYOND THE TIME POINT OF CLINICAL RECOVERY. SO WHEN WE STUDY ATHLETES WHO ARE -- HAD RESOLUTION OF SIMPLES, RETURN TO BASELINE OR BETTER ON OUR ASSESSMENT MEASURES WE CONTINUE THE FIND ALL BE IT IN MORE DIMINISHED MAGNITUDE, THE SIGNAL ABNORMALITIES ON THE MULTI-MODAL IMAGING BEYOND THE TIME POINT OF OBSERVED CLINICAL RECOVERY. SO ROAD MAPPING AHEAD. SEVERAL SPEAKERS TODAY REFERENCED THIS REALLY TERRIFIC PAPER FROM DOUG SMITH AND GROUP AT PENN SUGGESTING AXONAL STRUCTURE AND SKELETAL DIFFERENCES BETWEEN MALES AN FEMALES IN VITRO TBI MODEL. WE ARE NOW IN THE PROCESS OF ROADMAPPING THE NEXT PHASE OF ADVANCE RESEARCH CORPS SO FROM THE NEUROIMAGING CORE STANDPOINT WE'LL CONTINUE TO PUBLISH, ANALYZEN A PUBLISH ON ACUTE INJURY IN TIME COURSE OF NEUROBIOLOGICAL RECOVERY AND ALSO LOOKING AT THE EFFECTS OF EXPOSURE IN THE ABSENCE OF CONCUSSION ON BRAIN STRUCTURE AN FUNCTION. THE PROTEOMICS CORE WE HAVE A DR. JESSICA GILL HERE AT THE NIH, SHE WAS HERE THIS MORNING, I DON'T KNOW IF SHE IS STILL HERE WHERE WE'RE CURRENTLY ANALYZING ALL OF OUR POST INJURY -- BASELINE AND POST INJURY BIOMARKERS ACROSS A NUMBER OF TARGETED BIOMARKERS THAT WERE PART OF OUR SPECIFIC AIMS BOTH ACUTE AND PROGNOSTIC. WITH THE POTENTIAL OF ALSO RELATIONSHIP WITH ABBOTT LABORATORIES IN 2018 THAT GIVE THE ABILITY TO LOOK AT CERTAIN NEUROENDOCRINE MARKERS DIRECTLY RELEVANT TO THE DISCUSSION HERE TODAY AND TOMORROW AND WAS SO ELOQUENTLY DESCRIBED IN SEVERAL BASIC SCIENCE SPEAKERS HERE THIS AFTERNOON. ULTIMATELY WE WILL HAVE THE ABILITY WITH A LARGER COHORT, AS WE CONTINUE TO ENROLL NEXT PHASE OF CARE CONSORTIUM ROLE OF GENETICS NOT ONLY RISK OF INJURY BUT PROPENSITY OF RISK OF POOR OUTCOME AFTER INJURY. ONE OF THE THINGS THAT IS EVIDENT IN ALL MEETINGS LIKES THIS IS SOMEONE MADE THE REFERENCE EARLIER IT'S NOT AS SIMPLE AS BOY GIRL. THERE'S A NUMBER OF FACTORS THAT ARE GOING TO MAKE THEIR PLAY IN SOME BIG LARGE MATRIX MODEL OF UNDERSTANDING LONG TERM RECOVERY AND OUTCOME AFTER TRAUMATIC BRAIN INJURY NOT CONFINED TO DISCUSSION OF SPORT RELATED CONCUSSION BUT UNDERSTANDING HOW INDIVIDUAL FACTORS PREDICT RECOVERY OUTCOME AN LONG TERM RISK AFTER THIS INJURY. AND AS PARTS OF THE CARE CONSORTIUM WE HAVE A VERY RICHLY CHARACTERIZED COHORT PRE-INJURY BASELINE AND THEN A VERY AMBITIOUS POST INJURY PROTOCOL WITH A LARGE NUMBER OF FEMALES AND MALES IN THE STUDY TO DATE. I THINK YOU HEARD SOME COMPELLING NARRATIVES FROM THE BEST AT THE LUNCH TODAY, BRAIN INJURY IS PROBABLY NOT ABOUT A MOMENT TEAR EVENT WITH STATIC COURSE OVER LIFETIME, WE UNDERSTAND THE EFFECTS OF INJURY PARTICULARLY IN THE CONTEXT OF MULTIPLE INJURIES OR HIGH VOLUME EXPOSURE, MAY HAVE ABILITY TO PLAY OUT OVER COURSE OF LIFETIME. SO WE'RE NOW LOOKING AT THE PROSPECT IN COLLABORATION WITH A NUMBER OF INVESTIGATORS, WITH TRACK TBI AND OTHERS, THE ABILITY THROUGH THIS RICHLY CHARACTERIZED SAMPLE OF 40,000 ENROLLED AND NEARLY 3,000 INJURED, AS WELL AS CONTROLS TO FOLLOW THEM PROSPECTIVELY AN LONGITUDINALLY TO INVESTIGATE WHAT ARE THE INDIVIDUAL FACTORS THAT PRE-DISPOSE A PERSON TO LONG RANGE NEUROLOGIC HEALTH PROBLEMS. THERE'S A LOT MADE OF CONCUSSION AND EXPOSURE. IF THAT SIMPLE, DIFFICULT THE UNDERSTAND HOW THIS INDIVIDUAL WHO IS SHOWING SIGNS OF NEUROLOGIC DECLINE IN 40s AND 50s AND EVIDENCE OF NEURODEGENERATIVE DISEASE ON PATHOLOGY, HAS THE SAME EXPOSURE FROM FILE AS THE PERSON WHO IS GONE ON TO LIVE A COMPLETELY NORMAL AND PRODUCTIVE LIFE AS A CEO. IT'S PROBABLY -- WE KNOW THIS IN THE SPACE OF MEDICAL SCIENCE. IT'S NOT ANY SING OR INDIVIDUAL FACTOR, IT WILL BE A VERY COMPLEX MATRIX OF INDIVIDUAL FACTORS THAT PREDICT ONE'S RISK AND OUTCOME. SO I'M GOING TO AGAIN SAY THERE'S OVER 300 PEOPLE ON THE GROUND THAT COLLECT THESE DATA, CLEAN THESE DATA, OUR BDMT WHO WORK TO PUT THE WORK INTO ANALYZING THE DATA FOR TODAY'S MEETING BUG MOST OF ALL ALL 30 SITES AND THEIR PERSONNEL ON THE GROUND THAT WORKED THEIR BUTTS OFF LAST THEE YEARS TO GIVE US ANSWERS TO KEEP QUESTIONS -- KEY QUESTIONS LIKE WE HAVE TALKED ABOUT HERE TODAY AND WILL TOMORROW. THANK YOU, VERY MUCH. [APPLAUSE] >> SO EVEN THOUGH MIKE TRIED TO FILIBUSTER, DIANA PUSHED SOME THINGS BACK. SO WE DO HAVE ABOUT TEN MINUTES IF PANELIST CONSIST COME UP AND TAKE QUESTIONS. -- CAN COME UP AND TAKE QUESTIONS. THEN I HAVE AN ANNOUNCEMENT THAT JUST TO REMINDER THAT THE SESSIONS TOMORROW THAT ARE NOT CLOSED, CLOSED MEANT CLOSED TO THE VIDEOCAST. SO COME UP HERE. IT'S CLOSED TO VIDEOCASTING SO THERE'S NO VIDEOCASTING OF DISCUSSIONS IN BREAK OUT SESSIONS. THAT'S ALL THAT MEANS. WE DO WANT EVERYONE TO ATTEND BREAK OUT SESSIONS. PLEASE DON'T THINK CLOSED MEANS DON'T COME. IT MEANS PLEASE COME. IT WON'T BE VID -- WE WON'T BE VIDEOTAPED SAYING THINGS -- ARE THERE ANY QUESTIONS FOR SPORTS CONCUSSION PANELIST? OR I GUESS WE RAN -- >> THANK YOU, EVERYBODY, GREAT PANEL. I WANT TO ASK MIKE IF YOU HAD SEEN ATHLETES THAT DIP GET BETTER AND WENT INTO POST CONCUSSIVE SYNDROME. ANY DIFFERENCE WITH MALES AN FEMALES ON THE LONGER FOUR OR SIX MONTHS NOT BACK TO THEIR SPORTS? >> I DIDN'T SHOW THE DATA THIS AFTERNOON BECAUSE THINK OOHER IN PREPARATION. BUT SOME OF YOU MIGHT BE AWARE THAT WE HAD A PAPER A FEW YEARS AGO, IT WAS A TANDEM SET OF PAPERS THAT FIRST LOOKED AT THE TYPICAL RECOVERY GROUP. THEN WE HAD A PAPER THAT WAS SOLELY FOCUSED ON THOSE IN THAT CATEGORY THAT DID NOT FOLLOW THE TYPICAL COURSE OF RECOVERY. WE'RE PLANNING TO DO THAT NOW. WE HAVE A TANDEM SET OF PRIORITY PAPERS THAT ARE GOING TO LOOK AT THAT ACROSS ALL JR. -- INJURIES IN CARE. IT'S STRIKING THAT DATA ON RECOVERY AND RETURN TO ACTIVITY IN 2014 TO 17 COMPARED TO OUR PUBLISHED STUDIES FROM 1999 TO 2001. WHICH REALLY SHOWS ENORMOUS PROGRESS. I THINK WHAT WE ARE ALSO LIKELY TO FIND, IS A HIGHER PROPORTION OR FRACTION OF INDIVIDUAL SYMPTOMATIC BEYOND 28 DAY AND WE WANT TO UNDERSTAND PARTICULARLY GIVEN HOW RICHLY CHARACTERIZED WE HAVE THESE COHORTS AT BASELINE. WE WANT TO KNOW WHAT ARE THE FACTORS THAT PUT A PERSON AT RISK FOR PERSISTENT SYMPTOMS, FOR INSTANCE BEYOND A MONTH. >> (INDISCERNIBLE). SO FASCINATING DATA, IT'S PRELIMINARY SO THIS -- WHAT YOU SHOWED US IS COMPLETELY UNCONTROLLED. IT'S ALL COMMERCE, MALES VERSUS FEMALE. >> ALL COMERS IN THAT THESE STUDENT ATHLETES AND CADETS HAVE TO BE ENROLLED IN THE STUDY AT BASELINE. SO THE CADETS UNDERSTOOD GO A DETAILED BASELINE EVALUATION ON ENTRY INTO THE ACADEMY. AT AIR FORCE WEST POINT SO FORTH A. AND COLLEGE ATHLETES UNDERGO BASE LANE TO INJURY UNTIL THEIR FRESHMAN YEAR AT UNIVERSITY OF X Y Z. >> BUT YOU HAVEN'T CONTROLLED FOR DEMOGRAPHIC ISSUES OR TREATMENT ISSUESES OR ANY OTHER GEOGRAPHIC ISSUE? >> IN THAT ONE SLIDE I SHOWED COMPARING RECOVERY AND RETURN TO ACTIVITY FOR MALES AND FEMALES, WE LOADED A WHOLE HOST OF VARIABLES INTO THAT REGRESSION INCLUDING WE HAVE SES, HOLLINGS HEAD AND OTHER MEASURES. NUMBER OF YEARS THEY PLAYED THEIR PRIMARY SPORT, NUMBER OF PRIOR CONCUSSIONS, WHICH DID SURVIVE THE MODEL. THE PRIMARY DRIVERS REALLY WERE PRESENCE OF CERTAIN ACUTE INJURY CHARACTERISTICS, LOSS OF CONSCIOUSNESS, POST TRAUMATIC AMNESIA, IMPAIRMENT ON ACUTE EVALUATIONS AT 24 HOURS. THEN HISTORY. NUMBER OF PRIOR CONCUSSIONS IN ANY HISTORY OF DEPRESSION ANXIETY. I THINK IT IN MALES ALSO ADHD. >> I'M GOING TO JUMP IN BECAUSE I THINK THIS USE OF THE TERM ALL COMERS SHOWS ONE OF THE BIASES FOR CLINICAL STUDIES, AGAINST SURVEILLANCE STUDIES. THIS ISN'T A CONVENIENT SAMPLE, IT'S A WELL DESIGNED PROSPECTIVE LONGITUDINAL COHORT STUDIES. SO THIS PERCEPTION IT'S ALL COMERS. >> I DIDN'T MEAN TO IMPLY THAT AT ALL. IT'S ALL THE STUDENTS WHO ARE ENROLLED IN THE COHORT. >> MY NEXT QUESTION IS SOME SITES MUST DO BETTER THAN OTHERS IN TERMS OF RETURN TO PLAY RETURN TO SCHOOL. DO YOU SEE VARIATION IN THAT AND ARE THERE THINGS SOME SITES ARE DOING THAT ARE UNIQUE AND BETTER THAN OTHER? >> STEVE MARSHALL, COLLEAGUE EPIDEMIOLOGIST AT CAROLINA IS ACTUALLY WORKING ON DATA ANALYSIS NOW THAT TAKES IT EVEN ONE LAYER, I DON'T KNOW IF I THINK DAVID WRIGHT MIGHT HAVE MADE REFERENCE OR MIKE BAIL MIGHT HAVE MADE REFERENCE, WE LEARN A LOT IN STUDY VARIATION CIVILIAN NEUROTRAUMA WORK AS WELL. IF YOU GO INTO THE SAME SITE THERE'S VARIATION ACROSS CLINICIANS SO WHAT WE'RE LOOKING AT NOW IS WHAT KIND OF VARIATION IS THERE IN AND RETURN TO ACTIVITY ACROSS SITES, WHICH THERE WILL BE VARIABILITY. BUT THEN WE HAVE THE OPPORTUNITY TO ALSO LOOK AT WITHIN INTRAINSTITUTION WHAT IS DEGREE OF VARIABILITY? IN MOST SETTINGS, A CERTIFIED ATHLETIC TRAINER TEAM PHYSICIAN HAS ASSIGNMENT TO MEN'S FOOTBALL AND IT'S A DIFFERENT DYAD THAT TAKES CARE OF WOMEN'S ICE HOCKEY. IN FACT WE MIGHT FIND LIKE WE DO IN CIVILIAN NEUROTRAUMA STUDIES THERE'S VARIATION ACROSS SITE AND PROVIDERS AT THE SAME SITE. GREAT QUESTION. GREAT DISCUSSION AND PRESENTATION. QUESTION FOR MIKE. DAWN SHOUT OUT BECAUSE THE REASON I'M HERE IS BECAUSE TWO YEARS AGO YOU SHOVED ME TO MY DISSERTATION. JUST TOLD ME TO TAKE THE BULL BY THE HORNS AND NEAL ARMSTRONG MY AREA OF INTEREST IN CONCUSSIONS AN REPRODUCTION IN WOMEN. SO THANK YOU. MY QUESTION IS REALLY ABOUT HOW YOU SELECT YOUR CONTROL GROUPS. THE EPIDEMIOLOGICAL STUDIES THE DIFFICULTY IS IDENTIFYING THE UNINJURED. SO THE FACT THAT YOU ARE ABLE TO IDENTIFY AND MATCH YOUR INJURED TO THESE CONTROL GROUPS IS ABSOLUTELY FASCINATING TO ME AND I WANT TO KNOW HOW YOU'RE ABLE TO DO THAT. >> THE LUXURY WE HAVE IN SPORT CONCUSSION RESEARCH IS THAT ALL 40,000 HAVE A BASELINE. WE LOAD THE BASELINE DATA SOMETHING CALLED NEAREST NEIGHBOR STATISTICAL APPROACH. DAWN KNOWS THIS. SO ESSENTIALLY WE HAVE NINE MATCHING CRITERIA, SOME DEMOGRAPHIC AND BASELINE PERFORMANCE VARIABLES ON MAIN OUTCOME MEASURES AND WE LOAD THEM ALL IN TO THE ALGORITHM AND THEN THE ALGORITHM FIND THE NEAREST NEIGHBOR. SO IF MIKE MCCREA IS THE CONCUSSED FOOTBALL PLAYER THEN THE DATABASE WILL FIND OUR ALGORITHM WILL FIND THE NEAREST NEIGHBOR FOOTBALL PLAYER BECAUSE THEY'RE MATCHED ON SPORT BUT MATCHED MOST CLOSELY ON ALL THOSE OTHER MATCHING VARIABLES. THEN IT WILL SEARCH THE NON-CONTACT SPORT ATHLETES IN BASEBALL TRACK AN FIELD, SO FORTH AND FIND THE NEAREST NEIGHBOR. SO THEY'RE NOT YOLKED PER SE ONE TO ONE BUT THIS NEAREST NEIGHBOR, IT'S A LABORIOUS PROCEDURE AND I'LL CONFESS THAT I THOUGHT IT WAS OVERKILL. ON THE FRONT EN. BECAUSE WE HAVE BEEN ABLE TO DO THIS EFFECTIVELY FOR A LOT OF YEARS BUT NOT ON A SCALE THIS BIG. STATISTICIANS REALLY -- THEY GET ALL THE CREDIT. >> EXCELLENT. THANK YOU. >> MY NAME IS CANDACE FLOYD, UNIVERSITY OF UTAH. SO I HAVE A QUESTION FOR EVERYONE ON THE PANEL ABOUT TERMINOLOGY AND I'M JUST GOING TO TELL YOU THIS IS LIKE A SELF-SERVING QUESTION SINCE I GAVE A SHORT TALK. I FEEL LIKE I GET TWO MINUTES BACK SO I'M INTERESTED IN COMMON DATA ELEMENTS IN SOME OF THE TRIALS AND TRIBULATIONS YOU HAVE EACH HAD IN DEFINING THESE VARIABLES ACROSS THE STUDIES. AND MY FULL DISCLOSURE IN MY MY SELF-SERVING INTEREST, CHRIS MAY HELP THIS TOO, I'M INTERESTED IN BRIDGING SOME OF THE GAPS BETWEEN PRE-CLINICAL AND CLINICAL RESEARCH BY USING COMMON ELEMENTS IN THE PRE-CLINICAL SIDE TO TRY TO BETTER INFORM OUR VARIABLES IN PRE-CLINICAL TO HAVE BETTER PREDICTIVE TRANSLATIONAL ABILITY SO I WANTED TO HEAR SOME COMMENTARY ON HOW USEFUL THE CDEs HAVE BEEN, WERE THERE BIG AREAS THAT NEEDED REDEFINITION AND WHAT ARE TARGET AREAS TO HELP DEFINE PRE-CLINICAL RESEARCH? >> I THINK I HAVE PARTICIPATED ON THE SPORTS CONCUSSION COMMITTEE REVIEWING CANDIDATE MEASURES TO BE COMMON DATA ELEMENTS. IN CLINICAL RESEARCH, IT GREATLY FACILITATES COMMUNICATION ACROSS DIFFERENT CENTERS. THE POSSIBILITY OF REPLICATING STUDIES, AND OF COURSE WITH THE FITBER OTHER INVESTIGATORS CAN GO IN AND TAKE DATA FROM STUDY AND HAVE ASSURANCE THAT MEASURES ARE COMPARABLE. SO THOSE ARE I THINK ALL GREAT CONTRIBUTIONS OF THE COMMON DATA ELEMENTS. I'LL SHARE A PERSONAL CONCERN, WHICH RELATES TO MORE TRANSLATIONAL RESEARCH. IN REGARD TO WHEN YOU LOOK AT THE LITERATURE, WHETHER LET'S SAY MEMORY IN EXPERIMENTAL STUDIES OF AM NIECIC PATIENTS, AMNESIC PATIENTS. YOU CAN FIND STUDIES IN WHICH THE INVESTIGATOR HAS BEEN QUITE INNOVATIVE. IN DEVELOPING PROCEDURES TO ADDRESS VERY SPECIFIC HYPOTHESES THAT PERHAPS ARE RELATIVELY -- THAT HAVE NOT BEEN WIDELY STUDIES OR CAN'T BE TESTED WITH EXISTING CLINICAL MEASURES OF MEMORY LIKE CALIFORNIA VERBAL LEARNING OR WHATEVER. I THINK IT'S IMPORTANT TO RESERVE SOME LEEWAY FOR THESE INVESTIGATOR BECAUSE WHAT THEY DEVELOP THIS YEAR IN FIVE OR TEN YEARS PERHAPS MAY BECOME COMMON DATA ELEMENTS. SO IT'S IMPORTANT TO RECOGNIZE THAT TYPE OF INNOVATION. >> CANDACE, I HAVE TWO COMMENTS. ONE ON THE CLINICAL SIDE. I THINK THE PRE-CLINICAL PEOPLE NEED TO UNDERSTAND THAT WE HAVE KIND OF A ALMOST FALSE DEFINITION OF CONCUSSION, IT'S EITHER CONCUSSION OR NOT. AND OUR GROUPS LOOKING INTO WAYS TO TRY TO INCORPORATE THE CLINICAL UNCERTAINTY WHEN PATIENTS PRESENT WITH A CERTAIN CONSTELLATION OF SYMPTOMS THINGS WERE DEFINITELY CONCUSSION, POSSIBLY A CONCUSSION, THIS IS AN ALTERNATE OF EXPLANATION FOR THESE SYMPTOMS. THESE ARE DON CUSHION LIKE SYMPTOMS BUT NOT ACTUALLY CONCUSSION BECAUSE ON THE CLINICAL SIDE IF WE CAN'T CLEAR THAT UP, IT'S GOING TO BE REALLY HARD TO TRANSLATE INTO THE LAB IN A MEANINGFUL WAY. ON THE TRANSLATIONAL SIDE, MY EXPERIENCE WITH MIUMI (PHONETIC) ON THE CLOSED HEAD INJURY MODEL WE USE, WE ACTUALLY MADE SOME CHOICES RIGHT AWAY WHEN WE WERE GOING TO DO THAT AND WE DECIDED WE WERE NOT GOING TO TRY TO MODEL BIOMECHANICAL FORCE IN A RAT COMPARED TO HUMAN, IT'S IMPOSSIBLE. AND WE CHOSE INSTEAD TO MODEL EVIDENCE OF WHITE MATTER INJURY AN MEMORY DEFICITS THAT WERE MINIMAL BUT DETECTABLE AFTER A SINGLE INJURY. BUT GREATER AFTER REPETITIVE INJURY. SO I THINK THAT'S SOMETHING THAT TRANSLATIONAL SCIENTISTS CAN DO IS PICK PATHOPHYSIOLOGY THEY TRY TO MODEL AND DEMONSTRATE FEATURES LIKE REPETITIVE MILD HEAD INJURY. >> YOU'LL JUMP IN TOO. I THINK THAT -- I THINK COMMON DATA ELEMENTS WORK WELL IN CLINICAL STUDIES WHICH TEN TO BE EXPERIMENTAL STUDIES, RESEARCHERS HAVE CONTROL OVER VARIABLES, WORK LESS EFFECTIVELY IN POPULATION BASED AND WE HAVE MUCH LESS CONTROL OVER VARIABLES. >> ONE MORE QUESTION FROM DR. KOROSHETZ BUT TO REMIND PEOPLE THAT WE HAVE BREAK OUT GROUPS TOMORROW TO ASK QUESTIONS, PEOPLE WILL BE AROUND. PLEASE FEEL FREE TO ASK QUESTIONS, THIS IS I HAVE OVER RUN OUR TIME. DR. KOROSHETZ. >> IN TERMS OF DATA ON WHAT PROBABLY PEOPLE CARE MOST ABOUT IN KIDS IS THEIR ACADEMIC PERFORMANCE. THEY HAVE GRADE, IS SPORTS BETTER FOR PERFORMANCE OR WORSE, WHAT KIND OF DATA IS OUT THERE, PARTICULARLY WITH REGARD TO CONCUSSION, YOU HAD GPA PEOPLE COCOMING IN, WHICH IS NOT SURPRISING. BUT WHAT HAPPENS OVER TIME WITH THAT? AS PART OF FIRST FADES OF CARE WE HAVE INJURED CONTROL COHORTS THROUGH SIX MONTHS. WE ARE GOING TO EMBARK ON CARE 2.0. THREE COHORTS CONCUSSED, EXPOSED AND CONTROL COHORTS. THOSE CONCUSSED DURING THE PHASE OF STUDY, THOSE INVOLVED IN CONTACT SPORTS WITH REPETITIVE EXPOSURE BUT NOT CONCUSSED AND THOSE NON-CONTACT SPORT. THEY WILL UNDERGO EXIT ASSESSMENTS PRIOR TO GRADUATION WHICH TIME WE'LL HAVE A BETTER UNDERSTANDING OF WHAT WAS THERE MEANINGFUL CHANGE IN ACADEMIC PERFORMANCE OVER THE COURSE OF FOUR TO FIVE YEARS CAREER AT UNIVERSITY OF SERVICE ACADEMY, SO THAT'S PART OF THE NEXT PHASE. >> THERE IS ALMOST NO DATA AT ALL HIGH SCHOOL MIDDLE OR YOUNGER AGE KIDS ON ACADEMIC PERFORMANCE FOLLOWING SPORTS RELATED CONCUSSION BECAUSE SCHOOLS ARE WEIRD ABOUT HIPAA AND FRPA ISSUES. THEY DON'T WANT TO SHARE GRADES IN STUDIES OF SPORTS INJURIES. >> THAT IS AN EXCELLENT POINT. SO THERE'S A LOT OF CRITICISM ABOUT SELF-REPORTED ACADEMIC PERFORMANCE BUT TRY TO OBTAIN ACADEMIC INFORMATION FROM HIGH SCHOOLS OR ELEMENTARY SCHOOLS, LIKE FORT KNOX. WE CAN GET DNA EASIER THAN GRADES. THAT IS THE TRUTH. THE KITS ARE GETTING STANDARDIZED TESTING BUT WE ALSO LOOKED INTO THAT AND STANDARDIZED TESTING ISN'T GIVEN WITH A CONSISTENCY THAT ALLOWS YOU TO USE THAT AS A GOOD OUTCOME VARIABLE. THE TEST TEMPERATURES THEMSELVES CHANGE AND THEY'RE NOT GETTING REGULAR -- IT'S NOTS EVERY YEAR, SOMETIMES EVERY OTHER YEAR, SO THERE'S CHALLENGES WITH THERE'S OUTCOMES THOUGH THEY'RE SUPER IMPORTANT. >> THANK YOU FOR SUCH A GREAT PANEL. I WANT TO REMIND THE SPEAKERS THAT THERE'S A BUS IN THE FRONT TO PICK YOU UP. IT WILL BE THERE AT 5:30. THANK YOU ALL AGAIN. [APPLAUSE]