THANK YOU ALL FOR BEING HERE, WHETHER YOU'VE TRAVELED FROM AFAR OR RIGHT UPSTAIRS OR ON CAMPUS, WE'RE DELIGHTED TO HAVE YOU HERE. AND WE'RE ALL HERE TO SHARE IMPORTANT RESEARCH RESULTS AND LESSONS LEARNED AND TO PROMOTE HOPEFULLY A VERY LIVELY DISCUSSION ON THE IMPORTANCE OF CONSIDERING SEX AS A BASIC BIOLOGICAL VARIABLE AND HEARING ABOUT ALL OF YOUR WONDERFUL WORK. I WANT TO BEGIN BY THANKING ALL OF MY WONDERFUL STAFF FOR YOU PUTTING IN COUNTLESS HOURS ORGANIZING THIS MEETING. IT TAKES AN INCREDIBLE AMOUNT OF WORK TO PUT THIS ON AND WE'RE DELIGHTED WHEN WE ANNOUNCED NIH'S INTENT TO EXPLORE, WE'VE BEEN IN VERY HIGH GEAR AND WE'RE A SMALL OFFICE SO THAT'S A BIG DEAL FOR US, SO THANK YOU VERY MUCH, ESPECIALLY DR. SHIRLEY AND DR. MILLER AND MY STAFF. I'M NOW THRILLED TO INTRODUCE NIH DIRECTOR DR. FRANCIS COLLINS, WHO WILL MAKE OPENING REMARKS TO GET US STARTED ON THE RIGHT FOOT. DR. COLLINS CONTINUES TO BE A STEADFAST SUPPORTER OF OUR EFFORTS TO LOOK AT SEX AND GENDER INFLUENCES ON HEALTH AND DISEASE WITH THE ULTIMATE GOAL OF INFORMING THE HEALTH OF WOMEN AND MEN. DR. COLLINS HARDLY NEEDS A FORMAL INTRODUCTION AS HE SERVED AS THE LAST FIVE YEARS AS YOU KNOW TO LEAD NIH. HE'S LED SEVERAL IMPORTANT INITIATIVES, NOT LIMITED -- INCLUDING BUT NOT LIMITED TO THE BRAIN, ACCELERATING MEDICAL PARTNERSHIPS, EMPHASIS ON THE WORKFORCE AND SCIENTIFIC WORKFORCE DIVERSITY, BD2K AND EFFORTS RELATED TO TRANSPARENCY, REPRODUCIBILITY AND RIGOR. AS I'M SURE YOU KNOW, DR. COLLINS IS A PHYSICIAN GENETICIST NOTED FOR HIS LANDMARK DISCAN COVER REOF DISEASE GENES AND HIS LEADERSHIP OF THE INTERNATIONAL HUMAN GENOME PROJECT, AND SERVED AS DIRECTOR OF THE INTERNATIONAL HUMAN GENOME RESEARCH INSTITUTE FOR MANY YEARS. BEFORE COMING TO NIH, DR. COLLINS WAS A HOWARD HUGHES INVESTIGATOR AT THE UNIVERSITY OF MICHIGAN AND IS AN ELECTED MEMBER OF THE INSTITUTE OF MEDICINE AND THE NATIONAL ACADEMY OF SCIENCES, AND HE'S ALSO AWARDED THE PRECEDENTIAL MEDAL OF FREEDOM IN NOVEMBER 2007 AND RECEIVED A NATIONAL MEDAL OF SCIENCE IN 2009. BEYOND THIS MORE FORMAL INTRODUCTION, I CAN EL IT YOU CONFIDENTLY THAT DR. COLLINS IS OUR ALLY AS WE CONTINUE TO WORK TOGETHER TO ADVANCE THE STUDY OF BOTH SEXES TO INFORM THE ADVANCEMENT IN HUMAN HEALTH. PLEASE JOIN ME IN A WARM WELCOME FOR DR. COLLINS. >> THANK YOU, JANINE. GOOD MORNING TO ALL OF YOU WHO ARE HERE IN MASUR AND THOSE WATCHING ON THE VIDEOCAST. I'M HONORED TO HAVE A CHANCE TO SAY A FEW WORDS AT THE BEGINNING OF THIS INTERDISCIPLINARY WOMEN'S HEALTH RESEARCH SYMPOSIUM. SPONSORED BY ORWH. THIS IS THE 11TH OF ITS KIND AND IT'S AN OPPORTUNITY TO SHOWCASE THE VALUE OF WORKING ACROSS DISCIPLINES TO IMPROVE WOMEN'S HEALTH. WE HAVE BROUGHT TOGETHER HERE PRINCIPAL INVESTIGATORS AND SCHOLARS FROM TWO DIFFERENT PROGRAMS, THE SPECIALIZED CENTERS OF RESEARCH, SCOR, ON SEX DIFFERENCES, AND THE BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH, BIRCWH, PRONOUNCED BIRCH. I GUESS THERE'S A SILENT W, BUT THERE'S NOTHING SILENT ABOUT THE "W" IN THIS PROGRAM OR IN ORWH, AND CERTAINLY IN MY PERSPECTIVE, THIS IS A VERY SIGNIFICANT PART OF WHAT WE AT NIH ARE TRYING TO DO HERE. SCOR AS YOU KNOW, I GUESS YOU ALL WILL BE MEETING TOMORROW AS A GROUP, USES A CENTER MECHANISM TO FOSTER INTERDISCIPLINARY RESEARCH ON WOMEN'S HEALTH, AND THE BIRCH PROGRAM, WHO MET YESTERDAY, ARE DESIGNED TO INCREASE THE NUMBER OF WOMEN'S HEALTH RESEARCHERS THROUGH STRONG MENTORING, INTERDISCIPLINARY RESEARCH AND CAREER DEVELOPMENT. THIS SYMPOSIUM HAS A SPECIAL FOCUS AND ONE THAT'S VERY TIMELY, GIVEN THE DISCUSSIONS THAT WE ARE HAVING BROADLY ACROSS MANY DIFFERENT AREAS OF BIOMEDICAL RESEARCH, NAMELY SEX DIFFERENCES METHODOLOGY AND REPORTING. AS ESSENTIAL FOR HIGH IMPACT HEALTH RESEARCH. STUDYING BOTH SEXES IS ABSOLUTELY CRITICAL FOR BUILDING A FOUNDATION OF KNOWLEDGE THAT INFORMS THE HEALTH OF ALL HUMANS. SEX IS A BIOLOGICAL VARIABLE OF SUBSTANTIAL IMPACT, AND JANINE AND I HAVE GOTTEN OURSELVES OUT THERE RATHER VISIBLY OF LATE IN MAKING THAT CASE, I THINK WITH A GOOD RESPONSE FROM THE COMMUNITY, RECOGNIZING THAT WE MAY NOT IN THE PAST HAVE NECESSARILY DONE THIS PART OF OUR RESEARCH AGENDA IN AN IDEAL WAY, AND IT'S TIME TO TIGHTEN THAT UP. IT'S ALL PART OF AN EFFORT ON SORT OF A BROADER PERSPECTIVE THAT LARRY TABAK, PRINCIPAL DEPUTY DIRECTOR, AND I HAVE BEEN FOCUSED ON, AND THAT IS TO TRY AND ENHANCE THE REPRODUCIBILITY OF NIH FUNDED RESEARCH. THIS IS A CENTRAL CONCERN, GIVEN THAT WE ARE FINDING THAT PARTICULARLY WHEN YOU LOOK AT ANIMAL MODELS OF DISEASE, AND STUDIES PUBLISHED IN HIGHLY RESPECTED JOURNALS, OFTENTIMES TESTING THERAPEUTIC INTERVENTION, THAT WHEN OTHERS TRY TO REPRODUCE THAT RESEARCH, IT DOESN'T ALWAYS SEEM POSSIBLE TO DO SO. THERE ARE A NUMBER OF REASONS FOR THAT, BUT ONE OF THOSE IS AN INATTENTION TO SEX DIFFERENCES, WHICH CAN BE QUITE PROFOUND BIOLOGICALLY AND CAN CERTAINLY EXPLAIN THE INABILITY OF ONE GROUP TO REPRODUCE RESULTS FROM ANOTHER IF THEY HAPPEN TO USE A DIFFERENT BALANCE OF MALES AND FEMALES. OR SOMETIMES SIMPLY STICK TO ONE SEX, WHICH IS SOMETHING THAT I THINK HAS TRADITIONALLY OFTEN BEEN THE CASE AND WHICH WE ARE NOW QUESTIONING QUITE SERIOUSLY ABOUT WHETHER THAT'S THE RIGHT WAY TO DO THIS SORT OF RESEARCH. MOST OF THE TIME, WE WOULD ARGUE, TESTING MALES AND FEMALES IS PART OF ANY RIGOROUS STUDY OF AN ANIMAL MODEL IN ORDER TO UNDERSTAND WHAT THOSE SEX DIFFERENCES TURN OUT TO BE BECAUSE THEY COULD TURN OUT TO BE HIGHLY RELEVANT, BOTH IN UNDERSTANDING DISEASE AND ULTIMATELY FOR HUMAN INTERVENTIONS THAT ONE MIGHT PROPOSE TO UNDERTAKE. SO AS PART OF THAT REPRODUCIBILITY EFFORT, LARRY AND I HAVE BEEN ENGAGED IN A WIDE VARIETY OF DISCUSSIONS WITH VARIOUS STAKEHOLDERS. ONE OF THOSE WAS IN JUNE, WHERE WE MET WITH THE EDITORS OF OVER 30 MAJOR JOURNALS IN A MEETING THAT WAS CO-SPONSORED BY NIH, "NATURE" AND "SCIENCE." THIS ALSO INVOLVED FUNDING AGENCY REPRESENTATIVES IN ADDITION TO NIH, INCLUDING NSF, TO DISCUSS WHETHER, IN FACT, PART OF THE PROBLEM MIGHT BE THE WAY IN WHICH PAPERS ARE REVIEWED AND ULTIMATELY PUBLISHED, IS THERE ATTENTION TO THESE ISSUES THAT MIGHT POTENTIALLY BE CONTRIBUTING TO THIS LACK OF REPRODUCIBILITY, INCLUDING IS THERE ATTENTION TO SEX AS A BIOLOGICAL VARIABLE. THAT MEETING, I THINK, WAS QUITE A LANDMARK AT THE END OF THAT MEETING, LARRY LED THE GROUP THROUGH A DISCUSSION ABOUT WHAT MIGHT BE DONE IN TERMS OF COMING UP WITH APPROACHES TO THIS, SOME OF THEM AS SIMPLE AS CHECKLISTS FOR EDITORS WHO ARE LOOKING AT SUCH PAPERS AND SENDING THEM OUT FOR REVIEW TO MAKE SURE THAT THE INFORMATION IS THERE THAT YOU WOULD WANT TO SEE TO BE ABLE TO ASSESS WHETHER SOME OF THESE IMPORTANT PRINCIPLES HAVE BEEN UNDERLINED. THAT INCLUDES ATTENTION TO THE SEX OF THE ANIMALS BEING STUDIED, BUT ALSO SUCH THINGS AS STSTUDY DESIGN, WAS THERE RANDOMIZATION, BLINDING, ALL OF THESE THINGS WHICH I THINK ARE TAKEN FOR GRANTED ALMOST IN HUMAN CLINICAL TRIALS BUT OFTEN ARE NOT SO CAREFULLY ATTEN ATTENDED TO IN ANIMAL STUDIES. I AM DELIGHTED TO NOTE THAT YESTERDAY, "SCIENCE" AND "NATURE" IN A RATHER UNPRECEDENTED JOINT EDITORIAL ANNOUNCED A COMMON SET OF PRINCIPLES AND GUIDELINES IN REPORTING PRECLINICAL RESEARCH THAT THEY INTEND TO ADHERE TO AND OVER 100 JOURNALS SIGNED ON TO THAT SAME SET OF PRINCIPLES AT THE SAME TIME. SO THIS IS A BIG DEAL. THANK YOU. [APPLAUSE] WE ALSO HAVE WORK TO DO IN TERMS OF TRAINING, AND WE'RE CREATING TRAINING MODULES AND ACTUALLY TESTING THEM OUT HERE IN THE INTRAMURAL PROGRAM TO SEE WHETHER THEY ARE, IN FACT, EFFECTIVE FOR GRADUATE STUDENTS AND POSTDOCS BASICALLY UNDERLINING THE IMPORTANCE OF PAYING ATTENTION TO THESE ISSUES. A BIG PART OF THIS REALLY HAS BEEN, AND JANINE AND I HAVE GOTTEN ENGAGED IN THIS AND JANINE HAS BEEN A WONDERFUL LEADER IN THIS CONVERSATION, TO MAKE SURE THAT ONE OF THE THINGS WE PAY ATTENTION TO IS TO REQUIRE OUR OWN GRANT APPLICANTS, IF THEY'RE COMING TO US WITH A PROPOSAL THAT'S GOING TO USE ANIMAL MODELS, TO CONSIDER SEX AS A BIOLOGICAL VARIABLE, AND WE WOULD EXPECT, THEREFORE, THAT ANY ANIMAL STUDIES THAT NIH IS GOING TO SUPPORT SHOULD STUDY MALES AND FEMALES UNLESS THERE CAN BE A STRONG ARGUMENT MADE ABOUT WHY THAT'S INAPPROPRIATE. AS YOU CAN IMAGINE MIGHT BE THE CASE IN CERTAIN SEX LIMITED CONDITIONS SUCH AS PROSTATE CANCER. THAT HAS CREATED, FRANKLY, A LITTLE BIT OF A STIR. SOME INVESTIGATORS ARE ANXIOUS THAT THIS MEANS THEY MIGHT HAVE TO DOUBLE THE SIZE OF THEIR STUDIES IF THEY'VE PREVIOUSLY BEEN LIMITING THEIR EFFORTS TO MALES ALONE, WHICH BY THE WAY IS SCIENTIFICALLY NOT VERY JUSTIFIABLE. WE DON'T QUITE SEE THAT ARGUMENT AS BEING ALL THAT COMPELLING. WHAT YOU WANT TO BE SURE IS THAT YOU HAVE POWER IN YOUR STUDY TO BE ABLE TO GET RELIABLE RESULTS AND IF THERE IS A SIGNIFICANT DIFFERENCE BETWEEN MALES AND FEMALES, TO BE ABLE TO ASCERTAIN THAT. OF COURSE A LOT DEPENDS ON HOW SMALL A DIFFERENCE ARE YOU WILLING TO BE ABLE TO MISS, WHICH IS, OF COURSE, A GENERAL QUESTION WHEN YOU'RE DOING EXPERIMENTAL DESIGN. WE OF COURSE ARE VERY INTERESTED IN THE COMMUNITY'S VIEWS ON HOW TO MOVE FORWARD WITH WHAT I THINK IS AN AGREED UPON SET OF PRINCIPLES, BUT IMPLEMENTATION IS NOW THE ISSUE, AND SO WE HAVE RELEASED AN RFI ON CONSIDERATION OF SEX AS A BIOLOGICAL VARIABLE AND BIOMEDICAL RESEARCH AND WILL BE VERY INTERESTED IN COMMUNITY VIEWS ABOUT HOW BEST TO IMPLEMENT THOSE PRINCIPLES. WELL TODAY'S SYMPOSIUM IS GOING TO BUILD ON A STRONG FOUNDATION THAT'S ALREADY IN PLACE IN TERMS OF THE VALUES OF USING A VIEW OF SEX AS A BIOLOGICAL VARIABLE. WE'RE GOING TO HEAR KEYNOTE ADDRESSES BY DAVID PAIGE OF MIT, SOMEBODY I'VE KNOWN FOR CLOSE TO 30 YEARS, A REMARKABLE INTERNATIONAL RECOGNIZED LEADER IN TERMS OF SEXUAL DIFFERENTIATION AND THE ROLE OF THE Y CHROMOSOME. WE WRER GOING TO HEAR FROM NORA VOLKOW BUT I HEAR SHE IS IN BED WITH THE FLU AND WE ARE FORTUNATE TO HAVE WILSON HERE, WHO'S GOING TO PRESENT WHAT SHE WOULD HAVE SAID, AND I'M SURE YOU WILL LEARN A LOT FROM IT JUST THE SAME, AND WE HOPE NORA GETS BETTER QUICKLY. I JUST WANT TO SAY, FOR THOSE OF YOU IN THE SCO R & B IRCWH PROGRAM, YOU'VE ALREADY PROVIDED A MODEL SYSTEM FOR BOTH SEXES, YOU SHOULD FEEL LIKE YOU'RE KIND OF OUT THERE IN THE VANGUARD OF WHAT THE REST OF THE COMMUNITY IS NOW BEING ASKED TO DO, SO THEY WILL PROBABLY BE LOOKING AT YOU FOR GOOD EXAMPLES OF HOW THIS KIND OF STUDY DESIGN CAN REALLY MAKE A DIFFERENCE IN OUR UNDERSTANDING OF BIOLOGY. SO I HOPE YOU WILL ALSO HEAR SOME EXCITING FINDINGS HERE TODAY. I HOPE YOU ALSO TREAT THIS AS AN ACTIVE EXPERIENCE, NOT JUST TO COME HERE AND SOAK UP INFORMATION BUT ALSO TO CONNECT, RECONNECT WITH YOUR COLLEAGUES, MEET NEW COLLEAGUES IF YOU HAVEN'T PREVIOUSLY COUNTERED, EXPLORE NEW IDEAS IN THE HALLWAYS AT THE BREAKS, AND IF YOU HAVE SPECIFIC IDEAS ABOUT HOW NIH SHOULD MOVE FORWARD ON ISSUES RELATED TO SEX AS A BIOLOGICAL VARIABLE, I'M SURE JANINE AND HER COLLEAGUES WOULD VERY MUCH LIKE TO HEAR THEM. THIS IS A GOOD OPPORTUNITY FOR US TO GET INPUT FROM YOU. SO FINALLY I'D JUST LIKE TO THANK OUR KEYNOTE SPEAKERS FOR TAKING PART IN TODAY'S SYMPOSIUM. THANK ALL OF YOU FOR BEING HERE. THANK THE STAFF OF ORWH WHO'VE DONE A GREAT DEAL OF WORK TO PREPARE FOR THIS SYMPOSIUM, AND PARTICULARLY THANK JANINE CLAYTON FOR HER REMARKABLE LEADERSHIP AND HER COMMITMENT TO WOMEN'S HEALTH. THANK YOU ALL VERY MUCH. [APPLAUSE] >> THANK YOU, DR. COLLINS. I REALLY APPRECIATE YOUR SUPPORT AND GLAD YOU WERE ABLE TO SHARE SOME TIME WITH US THIS MORNING. WE'RE GOING TO SWITCH THE SLIDES UP HERE TO WHAT'S ON COMPUTER HERE. I SEE MY SLIDES HERE BUT I DON'T SEE THEM UP HERE. HERE WE GO. AWESOME. OKAY. SO WHY ARE WE HERE TODAY? WE'RE HERE BECAUSE WE KNOW HOW MUCH WE CAN ALL LEARN FROM APPLYING A SEX AND GENDER PERSPECTIVE TO SCIENCE AND SCIENTIFIC INVESTIGATION. AGAIN I FEEL LIKE I'M PREACHING TO THE CHOIR WITH THIS REALLY FANTASTIC GROUP OF SCIENTIST INVESTIGATORS, SCHOLARS, MENTORS AND TEACHERS WHO HAVE BEEN DOING THIS FOR OVER 10 YEARS, SO I ECHO DR. COLLINS' REMARKS THAT YOU SHOULD ALL FEEL THAT YOU'RE AT THE VANGUARD AND FEEL VERY PROUD OF YOUR WORK, AND I APPRECIATE ALL THAT YOU'VE DONE, AS DONE NIH. SO WE'RE HERE TO SHINE A LIGHT ON THAT AND TO HEAR ABOUT SOME OF THE IMPORTANT FINDINGS COMING FROM YOUR RESEARCH AND FINDINGS GATHERED BY USING THIS NEW PERSPECTIVE AS A TOOL. SO EARLIER THIS WEEK, EXCITING PRELIMINARY DATA WAS PRESENTED AT THE HIV RESEARCH FOR PREVENTION CONFERENCE IN CAPE TOWN, SOUTH AFRICA. THIS WAS AN ORAL PRESENTATION WHERE IT EXAMINED MEN AND WOMEN, AND THE MODEL SHOWED, AND THIS WAS A COMPUTATIONAL MODEL, THAT SHOWED THAT DAILY TREVADA PREVENTS HIV INFECTION IN WOMEN VIA VAGINAL SEX, AND FOR MEN THE MODEL PREDICTED THAT TRUVADA AT A DOSE OF TWICE PER WEEK WOULD PREVENT HIV INFECTION IN MEN IN ANAL SEX. WE HAVE A COMPUTATIONAL MODEL THAT EXPLORES SEX DIFFERENCES AND HELPS US TO PERHAPS UNDERSTAND HOW THESE RESULTS FROM SOME OF THE PREVIOUS STUDIES MAY HAVE COME ABOUT WHERE WE DID NOT SEE THIS. SO THIS IS PRELIMINARY INFORMATION, AND WE'RE INTERESTED TO HEAR ABOUT THIS GOING FORWARD. PERHAPS IT WILL HELP US EXPLAIN SOME OF THE RESULTS THAT WE OBTAINED TO DATE. AS WE LOOK AT ORWH'S MISSION IN 2014, I WANT TO SHARE WITH YOU THE WAY WE'RE THINKING ABOUT IT, AND FIRST IT IS TO EXAMINE SEX AND GENDER INFLUENCES IN HEALTH AND DISEASE TO INFORM WOMEN'S HEALTH AND TO INFORM WOMEN'S HEALTH RESEARCH ACROSS NIH. WE ARE WORKING VERY HARD TO SPREAD THE WORD ABOUT STUDYING BOTH SEXES AS YOU'VE HEARD. WE'RE TALKING INTERNALLY, HEARING FROM OUR STAKEHOLDERS, HEARING FROM SCIENTISTS, AND I'M LOOKING FORWARD TO EXAMINING ALL OF THE INFORMATION WE'VE RECEIVED THROUGH THE RFI, FOR WHICH WE RECEIVED A REALLY EXUBERANT RESPONSE. SO THANK YOU VERY MUCH FOR YOUR INPUT. WE'RE WORKING WITH THE CENTER FOR SCIENTIFIC REVIEW, THE OFFICE OF EXTRAMURAL RESEARCH AND ALL THE NIH INSTITUTES AND CENTERS ON DEVELOPING A MEASURED POLICY THAT WILL BE EFFECTIVE IN ENCOURAGING -- EXAMINING BOTH SEXES IN PRECLINICAL RESEARCH. WHAT WE'RE AFTER IS CHANGING A MINDSET. SHIFTING THE PARADIGM TOWARD ROUTINE CONSIDERATION OF SEX AS A BIOLOGICAL VARIABLE, AND THAT'S NOT GOING TO HAPPEN OVERNIGHT. THE WAY WE'RE THINKING ABOUT THIS IN 2014 IS CERTAINLY BEYOND INCLUSION, AND THE SECOND ASPECT OF OUR MISSION IS TO ENSURE THAT WOMEN IN DIVERSE POPULATIONS ARE INCLUDED IN ALL NIH FUNDED CLINICAL RESEARCH STUDIES. SO IN 2014, THIS IS REALLY BEYOND INCLUSION, AND REALLY RESULTS -- WE NEED TO CHARACTERIZE THIS FROM PRECLINICAL WORK ALL THE WAY TO THE CLINICAL WORK, AS WELL AS INTO THE SEX-SPECIFIC DATA ANALYSES AND SEX-SPECIFIC REPORTING. SO FROM INCLUSION ALL THE WAY THROUGH REPORTING IS WHAT WE'RE LOOKING AT TO REALLY ACTUALLY BE ABLE TO REPORT ON AND TAKE ADVANTAGE OF UNDERSTANDING SEX AND GENDER INFLUENCES ON HEALTH AND DISEASE. THE SPECIALIZED CENTERS OF RESEARCH ON SEX DIFFERENCES SCORES ARE REALLY LEADING THE WAY. I'M PARTICULARLY PROUD TO BE HERE WITH MY FDA COLLEAGUES THAT I WILL INTRODUCE NEXT BECAUSE THIS HAS BEEN A LONG TERM COLLABORATION BETWEEN ORWH AND THE FDA, CERTAINLY AN INTERDISCIPLINARY APPROACH HAS BEEN CRITICAL TO THE SCORES AND WE'VE INVESTED A SIGNIFICANT AMOUNT OF ORWH FUNDS IN THIS EFFORT THROUGH THE YEARS. AND YOU CAN SEE THERE THE TOPICS AND I'M REALLY LOOKING FORWARD TO HEARING FROM YOU. THE SCIENCE OF SEX AND GENDER IN HUMAN HEALTH IS AN ONLINE COURSE AND WE ARE PROUD TO ANNOUNCE MODULE THREE WAS RELEASED FAIRLY RECENTLY. THE TOPIC OF MODULE THREE IS THE INFLUENCE OF SEX AND GENDER ON DISEASE EXPRESSION AND TREATMENT, AND EACH OF THE FIRST TWO MODULES HAVE SLIGHTLY DIFFERENT AREAS OF FOCUS, SO I ENCOURAGE YOU TO TAKE A LOOK AT THOSE AS WELL. THE TOPICS INCLUDE SEXUAL DIMORPHISM AND -- HEART FAILURE, PULMONARY DISEASE AND DIFFERENCE IN SUBSTANCE ABUSE AND TREATMENT. THE THIRD ASPECT OF OUR MISSION AND CERTAINLY IS SOMETHING THAT NEEDS TO BE MENTIONED IS PROMOTING RECRUITMENT RETENTION RE-ENTRY AND SUSTAINED ADVANCEMENT OF WOMEN IN BIOMEDICAL CAREERS, AND THE BIRCWH IS CERTAINLY A LANDMARK EXAMPLE OF HOW TO DO THAT. I ALSO WANT TO HIGHLIGHT THE FACT THAT THE HIV DATA I REFERENCED IN MY FIRST SLIDE, THE FIRST AUTHOR OF THAT PRESENTATION WAS DR. ANGELA KASHUBA, WHO IS A FORMER SCHOLAR AND NOW A MEMBER OF OUR ADVISORY COUNCIL. SO WE'D LOVE TO SEE THE FULL BENEFIT OF INITIAL BIRCH SCHOLARS AND THEN GROWING INTO THEIR FULL FRUITION. THE LAST STEP OF THIS CONTINUUM IS AGAIN THINKING BEYOND INCLUSION AND MOST OF YOU HAVE BEEN ON BOARD WITH THIS CONCEPT FOR A VERY LONG TIME AND FOR THAT WE'RE GRATEFUL, IS THAT YOU HAVE TO GO FROM THE INCLUSION IN THE RESEARCH TO THE REPORTING. TO CONNECT THE DOTS. IT DOES NO GOOD TO INCLUDE WOMEN OR FEMALES WITH THE DATA THAT'S NOT REFLECTED IN THE PUBLICATION, IF THE ANALYSES ARE THE NOT PERFORMED AND IF THAT INFORMATION IS NOT AVAILABLE TO OUR COLLEAGUES. SO WE'RE REALLY EXCITED TO HEAR ABOUT THE EDITORIAL THAT SCIENCE AND NATURE PUT OUT VERY RECENTLY THAT WILL BE ENCOURAGING THAT AS WELL. SO I WANT TO THANK ALL OF YOU PORE BEING HERE, AND I WANT TO HIGHLIGHT THE FACT THAT WE REALLY MUST BE DOING ALL OF THIS WORK TOGETHER, AND I'M GOING TO INTRODUCE MY COLLEAGUE, DR. PAMELA SCOTT. FOR SOME REASON I DON'T HAVE HER INTRODUCTION HERE SO ONE SECOND, I NEED TO GRAB THAT BINDER. MY APOLOGIES. I'M THRILLED TO INTRODUCE MY IF FDA COLLEAGUE, DR. PAM SCOTT. IN DOING SO, I ALSO WANT TO ADD MY EXPRESSION OF SINCERE GRATITUDE BOTH TO THE DIRECTOR OF THE OFFICE OF WOMEN'S HEALTH AT THE FDA, MS. MARSHA HENDERSON, FOR THE COLLABORATION AND SUPPORT FROM OUR SISTER AGENCY. AS YOU KNOW, FDA HAS BEEN A KEY SUPPORTER OF ORWH AND THE SCOR PROGRAM FROM THE BEGINNING AND IS OUR PARTNER IN THE ONLINE SEX AND GENDER COURSE. DR. SCOTT IS THE DIRECTOR OF RESEARCH AND DEVELOPMENT AT THE FDA'S OFFICE OF WOMEN'S HEALTH. SHE'S AN EPIDEMIOLOGIST AND STATISTICIAN AND HAS OVER 20 YEARS OF EXPERIENCE IN DEVELOPING AND LEADING RESEARCH PROGRAMS RELATED TO WOMEN'S HEALTH. HER RESEARCH, SHE'S WORKED ON SEVERAL AREAS INCLUDING THE INCLUSION OF WOMEN IN CLINICAL TRIALS, THE IMPACT OF SEX AND GENDER DIFFERENCES AND THE SAFETY AND EFFICACY OF FDA REGULATED PRODUCTS AND THE RISK OF DRUG EXPOSURES IN PREGNANCY. AS ONE KEY ACTIVITY, DR. SCOTT IS LEADING THE DEVELOPMENT OF A AN OFFICE OF WOMEN'S HEALTH RESEARCH ROAD MAP AT THE FDA TO INTEGRATE WOMEN'S HEALTH ACROSS THE FDA. BEFORE JOINING THE OFFICE OF WOMEN'S HEALTH, DR. SCOTT DEVELOPED AND MANAGED SEVERAL RESEARCH PROGRAMS AT THE FDA INCLUDING MEDICATION EXPOSURE IN PREGNANCY RISK EVALUATION PROGRAMS. DR. SCOTT RECEIVED HER PH.D. IN EPIDEMIOLOGY WITH A CONCENTRATION IN CLINICAL TRIALS METHODOLOGY FROM THE BLOOMBERG SCHOOL OF PUBLIC HEALTH AT JOHNS HOPKINS UNIVERSITY, MY ALMA MATER AS WELL. SHE ALSO HOLDS AN M.A. IN STATISTICS FROM AMERICAN UNIVERSITY. PLEASE JOIN ME IN WELCOMING DR. PAM SCOTT. [APPLAUSE] >> GOOD MORNING. IT'S MY PLEASURE TO BE HERE TO SHOW MY SUPPORT FOR NIH'S OFFICE OF RESEARCH AND WOMEN'S HEALTH AND THE SCOR PROGRAM AND ALSO TO LEARN FROM THE INNOVATIVE PROJECTS THAT WILL BE PRESENTED LATER TODAY. THE FDA RECOGNIZES THE IMPORTANCE THAT WE PLAY IN ENCOURAGING INCLUSION AND A ANALYSIS OF DEMOGRAPHIC DATA IN BIOMEDICAL RESEARCH. THE AGENCY HAS BEEN WORKING HARD OVER THE LAST 30 YEARS TO INCLUDE DATA COLLECTION, ANALYSIS AND COMMUNICATIONS ABOUT DEMOGRAPHIC SUBGROUPS IN CLINICAL TRIALS SUPPORTING APPLICATIONS SUBMITTED TO FDA. THE OFFICE OF WOMEN'S HEALTH AT FDA IN PARTICULAR HAS MADE IT ONE OF OUR PRIORITIES TO HELP ADVANCE KNOWLEDGE ABOUT SEX DIFFERENCES BY SUPPORTING RESEARCH AND POLICY INITIATIVES AT THE FDA. WE HAVE ALSO LENT OUR SUPPORT TO THE SCOR PROGRAM AND WORKED IN COLLABORATION WITH NIH AND OTHER PARTNERS TO ELEVATE THE IMPORTANCE OF SEX DIFFERENCE RESEARCH. I WANT TO TAKE A FEW MINUTES TO GIVE YOU OUR VIEW ON THIS SUBJECT AND HIGHLIGHT SOME OF THE WAYS IN WHICH WE TRY TO SUPPORT SEX DIFFERENCES RESEARCH. WHILE SEX IS NOT THE ONLY VARIABLE WE MUST CONSIDER, IT'S AN IMPORTANT FACTOR THAT MUST BE EXAMINED DURING ME CAL PRODUCT DEVELOPMENT IN REGULATORY DECISION-MAKING PROCESSES. FDA IS INTERESTED IN PATIENT OR POPULATION CHARACTERISTICS THAT MIGHT IMPACT THE SAFETY OR EFFECTIVENESS OF A MEDICAL PRODUCT. IT'S IMPORTANT TO UNDERSTAND THE LENGTH TO WHICH FDA EXAMINES SEX DIFFERENCES. OUR JOB IS THE NOT ONLY JUST TO IDENTIFY THAT A SEX DIFFERENCE EXISTS. WE MUST DETERMINE WHEN THE SEX DIFFERENCES HAVE A CLINICALLY MEANINGFUL IMPACT ON THE SAFETY AND EFFICACY OF FDA REGULATED PRODUCT. FOR EXAMPLE, WE'RE LOOKING FOR SEX DIFFERENCES IN DRUG EXPOSURE OR RESPONSE, OR DIFFERENCES IN DRUG DEVICE SAFETY THAT ARE CLINICALLY SIGNIFICANT. SO HOW DO WE GET THIS INFORMATION? SO WE USE A VARIETY OF METHODS TO GET THIS INFORMATION. ONE IS GUIDANCE TO INDUSTRY. AND IN TERMS OF GUIDANCE TO INDUSTRY, JUST THIS PAST AUGUST, WE RELEASED A FINAL GUIDANCE DOCUMENT ON THE EVALUATION OF SEX-SPECIFIC DATA AND MEDICAL DEVICE STUDIES. OUR GUIDANCE FOR INDUSTRY SERVES AS A SCHOOL IN WHICH WE LET INDUSTRY KNOW WHAT OUR CURRENT THINKING IS ABOUT THE INCLUSION OF VARIOUS DEMOGRAPHIC SUBGROUPS AND THE ANALYSIS OF THAT DATA IN THE APPLICATIONS THEY SUBMIT TO US FOR US TO CONSIDER PRODUCT APPROVAL. IN TERMS OF INTRAMURAL RESEARCH PROGRAMS, WE ALSO LEARN ABOUT SEX DIFFERENCES THROUGH OUR IN-HOUSE RESEARCH. THE OFFICE OF WOMEN'S HEALTH AT IT FDA HAVE SUPPORTED OVER 300 PROJECTS SINCE 1994, FOR A LARGE PART OF OUR PORTFOLIO FOCUSING IN ON THE EXAMINATION OF SEX DIFFERENCES AS IT RELATES TO FDA REGULATED PRODUCTS. WE HAVE ALSO SERVED AS A CATALYST FOR OTHER WOMEN'S HEALTH RESEARCH INITIATIVES AT FDA SUCH AS THE HEALTH OF WOMEN'S PROGRAM FOCUS IN ON SOME OF THEIR MEDICAL DEVICES RELATED TO WOMEN'S HEALTH. EXTRAMURAL RESEARCH COLLABORATION IS ALSO A VITAL COMPONENT. THERE ARE SOME REGULATORY QUESTIONS THAT FDA CANNOT SIMPLY ADDRESS ALONE AND WE MUST RELY ON OUR STAKEHOLDERS TO HELP US GET ANSWERS TO THOSE QUESTIONS. CURRENTLY WE ARE WORKING WITH NIH TO COLLABORATE ON A STUDY TO ACTUALLY EXAMINE OR TO FULLY UNDERSTAND THE MECHANISM FOR THE PK AND SUCH DIFFERENCES FOR -- PK OF AMBIEN -- THE ROLE OF THE SEX HORMONES HAS NOT BEEN FULLY ELUCIDATED, SO WE'RE WORKING WITH NIH TO TRY TO DEVELOP A STUDY TO EXAMINE THAT ISSUE. WE ALSO HAVE SCIENTIFIC DIALOGUE AND TRAINING, THE OFFICE OF WOMEN'S HEALTH ATED FDA WORKS TO ELEVATE AND ADVANCE THE UNDERSTANDING OF SEX DIFFERENCES BY PROMOTING DIALOGUE BETWEEN THE AGENCY AND THE RESEARCH COMMUNITY. AND THEN WE HAVE RECENTLY RELEASED IN AUGUST OF THIS YEAR AN ACTION PLAN IN RESPONSE TO SECTION 907. THIS PLAN OUTLINES THE AGENCY'S CURRENT POLICIES AND PRACTICES TO PRESENTS 27 ACTION ITEMS FOCUSED IN ON THREE RESEARCH PRIORITIES RELATED TO QUALITY -- AND TRANSPARENCY AS IT RELATES TO SUBGROUP ANALYSES AND THE RELEASE OF THAT DATA TO THE PUBLIC. IN TERMS OF QUALITY, WE STRIVE TO IMPROVE THE COMPLETENESS AND QUALITY OF DEMOGRAPHIC SUBGROUP DATA. IN TERMS OF PARTICIPATION, WE STRIVE TO IDENTIFY BARRIERS TO SUBGROUP ENROLLMENT IN CLINICAL TRIALS AND EMPLOY STRATEGIES TO ENCOURAGE GREATER PARTICIPATION. IN TERMS OF TRANSPARENCY, WE STRIVE TO IMPROVE THE PUBLIC AVAILABILITY OF I DEMOGRAPHIC DATA. AND AS PART OF THE ACTION PLAN, FDA WILL SOON LAUNCH A WEBPAGE WHERE THE PUBLIC CAN VIEW SEX-SPECIFIC INFORMATION WE RECEIVE IN SUPPORT OF NEW DRUG APPLICATION. THIS WEBPAGE IS A PILOT PROGRAM, AND WE'RE GOING TO BE RELEASING A PUBLIC DOCKET TO SOLICIT COMMENTS ON THE INFORMATION THAT'S ON THE WEBPAGE THE WAY IT'S PRESENTED, AND WE ENCOURAGE EVERYONE TO VIEW THE WEBPAGE AND SUBMIT COMMENTS SO THAT WE CAN MAKE SURE THAT WE IMPROVE THE TRANSPARENCY OF INFORMATION AS IT RELATES TO THE SEX ANALYSIS, DEMOGRAPHIC ANALYSIS THAT WAS DONE IN SUPPORT OF FDA'S DECISION TO APPROVE A PARTICULAR PRODUCT. THE WAY THE RESEARCH CAN HELP THE FDA INFORM FDA'S REGULATORY DECISION-MAKING, I ENCOURAGE YOU TO GO TO OUR WEBSITE TO LEARN MORE ABOUT THE ORWH FUNDED RESEARCH. I THANK YOU FOR YOUR TYP TIME AND LOOKING FORWARD TO THE PRESENTATIONS TODAY. [APPLAUSE] >> OUR FIRST KEYNOTE SPEAKER, DR. WILSON COMPTON, DEPUTY DIRECTOR OF THE NIH'S NATIONAL THE INSTITUTE ON DRUG ABUSE. AS ALL OF YOU KNOW, NIDA HAS BEEN A LON LONG TERM CHAMPION OF THE NEED TO STUDY SEXES IN BIOMEDICAL RESEARCH. IT HAS AN INSTITUTE WIDE WOMEN AND SEX GENDER DIFFERENCES RESEARCH GROUP WITH A LONG TERM PROGRAM ANNOUNCEMENT AS WELL TO PROMOTE RESEARCH IN THIS AREA. NIDA HAS BEEN A TERRIFIC PARTNER TO OUR OFFICE FOR MANY YEARS, IN ADDITION TO CURRENTLY COFUNDING THREE SCORES. COLLECTIVELY, NIDA SPONSORED RESEARCH FINDINGS HAVE BENEFITED WOMEN AND MEN FACING SUBSTANCE ABUSE. DR. COMPTON SUSTAINED DISTINGUISHED LEADERSHIP ALONG WITH NIDA DIRECTOR DR. NORA VOL VOLKOW -- ADDRESSING EPIDEMIOLOGY PREVENTION AND TREATMENT OF DRUG ABUSE. HE ALSO LED THE DEVELOPMENT OF A LARGE SCALE LONGITUDINAL POPULATION STUDY CO-SPONSORED BY THE FDA TO ASSESS THE IMPACT OF NEW TOBACCO REGULATIONS IN THE UNITED STATES. BEFORE JOINING NIDA, DR. COMPTON WAS ASSOCIATE PROFESSOR OF PSYCHIATRY AND THE DIRECTOR OF THE MASTER IN PSYCHIATRIC EPIDEMIOLOGY PROGRAM AT WASHINGTON UNIVERSITY IN ST. LOUIS. AS WELL AS MEDICAL DIRECTOR OF ADDICTION SERVICES AT THE BARNES JEWISH HOSPITAL IN ST. LOUIS. HE RECEIVED HIS UNDERGRADUATE EDUCATION FROM AMHURST COLLEGE, ATTENDED MEDICAL SCHOOL AND COMPLETED RESIDENCY TRAINING IN PSYCHIATRY AT WASHINGTON UNIVERSITY. PLEASE JOIN ME IN WELCOMING DR. WILSON COMPTON. [APPLAUSE] >> WELL, GOOD MORNING. GOOD MORNING, EVERYBODY. IT'S A PLEASURE TO BE HERE, A BIT UNEXPECTED ON MY PART. AS DR. COLLINS MENTIONED, THERE WAS A ORIGINAL SPEAKER ORIGINALLY SCHEDULED FOR THIS TALK. I'M SORRY FOR THAT ON MULTIPLE REASONS PARTLY BECAUSE NORA HAS BEEN LEADING OUR EFFORT IN UNDERSTANDING AND IMOF PROVING WOMEN'S HLT RELATEWOMEN'S HEALTH RELATED T O DRUG ABUSE AND DRUG ADDICTION FOR SO MANY YEARS NOW THAT I KNOW SHE WAS LOOKING FORWARD TO BEING ABLE TO SHARE WITH YOU HER ENTHUSIASM INTEREST AND SOME OF THE SCIENCE IN THIS AREA. I KNOW I'M ALSO SORRY BECAUSE SHE'S HOME IN BED WITH THE FLU. AND THAT'S A MISERABLE EXPERIENCE FOR ANYONE WHO HAS BEEN THROUGH THAT. I'VE HAD 24 HOURS TO TAKE DR.KO HER SLIDE AND FIGURE OUT WHAT I WANT TO SHARE WITH YOU. THAT BEING SAID, I'M ACTUALLY QUITE EXCITED ABOUT IT, AND WHEN I LOOKED AT NORA'S SLIDES YESTERDAY MORNING WHEN I GOT THE EMAIL, I REALIZED IT'S A REALLY IMPORTANT STORY I HAVE TO SHARE WITH YOU, SO I'M QUITE EXCITED TO BE ABLE TO PRESENT TO YOU A VERSION OF DR. VOLKOW'S PRESENTATION. SO DON'T THINK THIS IS A SUBSTITUTE FOR THE REAL THING. SO WHEN SHE HAS THE CHANCE TO PRESENT THE SAME MATERIAL, I ENCOURAGE YOU TO ENJOY THAT EXPERIENCE. I WANT TO THANK DR. CLAYTON FOR INVITING NORA AND SUBSEQUENTLY INVITING ME TO JOIN YOU THIS MORNING, AND IT'S CERTAINLY OUR PLEASURE TO JOIN THE OFFICE OF RESEARCH ON WOMEN'S HEALTH FOR THIS REALLY IMPORTANT OCCASION ON EXAMINING AND CELEBRATING INTERDISCIPLINARY RESEARCH. I WANT TO HIGHLIGHT, ALSO THANK YOU TO SHARELY AND SUSAN MEIER WHO MADE IT A PLATE GRATE PLEASURGREAT PLEA SURE TO PLEASURE TO JOIN YOU THIS MORNING. ALSO WANT TO HIGHLIGHT FOR YOU, WHEN YOU LOOK AT THE LIST OF THE SCOR CENTERS, THREE OF THEM ARE AT THE NATIONAL INSTITUTE OF DRUG ABUSE. SO I THINK THAT SPEAKS TO OUR SUPPORT AND OUR ENCOURAGEMENT FOR THIS REALLY IMPORTANT EFFORT TO EAX TO EXAMINE SEX AND GENDER RELATED TO WOMEN'S HEALTH ALL ACROSS THE SPECTRUM FROM THE EPIDEMIOLOGY AND HEALTH RESEARCH THAT I PERSONALLY BRING TO THE TABLE AS WELL AS THE CLINICAL NEUROSCIENCE THAT DR. VOLKOW PERSONALLY REPRESENTS AS WELL AS THE BASIC SCIENCE THAT SO MUCH OF OUR PROGRAM IS SUPPORTING. NOW, WHY DO WE HAVE THREE CENTERS? I THINK I CAN ATTRIBUTE IT TO ONE PERSON IN PARTICULAR. DR. WEATHERERRINGTON WHO I KNOW IS HERE HAS BEEN SPEARHEADING THIS EFFORT FOR NIDA. SHE DOES IT WITH CHARM, DIPLOMACY AND INCREDIBLE PERSISTENCE. SO I HOPE YOU ALL KNOW DR. WEATHERER INGETON, AND IF YOU DON'T, PLEASE SEEK HER OUT, ALONG WITH DR. NORSEY IN THAT PROGRAM, SHE'S DONE AN EXTRAORDINARY JOB IN ENCOURAGING AND HELPING TO DEVELOP THIS RESEARCH ON WOMEN'S HEALTH ISSUES. NOW WITH THAT, LET ME GET INTO THE HEART OF WHAT I WANT TO SHARE WITH YOU TODAY. IT WILL BE WHIRLWIND TOUR. IT'S MEANT TO ILLUSTRATE SOME OF THE PRINCIPLES RELATED TO WOMEN'S HEALTH AS IT RELATES TO SUBSTANCE ABUSE AND SUBSTANCE ADDICTION. I'VE BEEN IN THE FIELD LONG ENOUGH TO SORT OF BE PART OF A SHIFT IN UNDERSTANDING OF WOMEN IN THEIR RELATIONSHIP TO SUBSTANCE ABUSE. YOU DON'T HAVE TO GO BACK VERY MANY YEARS BEFORE THERE WERE ALL THESE MYTHS AND ASSUMPTIONS THAT WOMEN DIDN'T REALLY HAVE MUCH ADDICTION, IT WASN'T THAT MUCH OF AN ISSUE FOR WOMEN, AND DRUG AND ALCOHOL TREATMENT PROGRAMS WERE DESIGNED TO TAKE CARE OF MALES IN OUR COMMUNITY, SO THEY WERE IGNORING SOME OF THE REALITY, AND THAT AFTER ALL IS WHAT SCIENCE IS ALL ABOUT, IT A PUNCTURE MYTH AND PUNCTURE MISTAKE AND PARADIGM. SO SOME OF THE FIRST AREAS, OF COURSE, WE WANT TO START WITH ARE THE PUBLIC HEALTH RESEARCH DATA TO REMIND US OF THE SPREAD AND EXTENT OF THESE ISSUES FOR WOMEN IN OUR POPULATION. SO JUST A COUPLE SLIDES FOR YOU ON THIS. FIRST TO REMIND US ABOUT TOBACCO AS THE LEADING PREVENTABLE CAUSE OF DEATH IN THE U.S. AND INTERNATIONALLY. IT'S BEEN ESTIMATED IN THE PREVIOUS CENTURY, THERE WERE APPROXIMATELY 100 MILLION EARLY DEATHS DUE TO TOBACCO USE, A HUGE SCOURGE IN TERMS OF THE PUBLIC HEALTH IMPACT, BUT WHEN YOU LOOK AT THE EXPECTED NUMBER OF EARLY MORTALITY AND PREVENTABLE CAUS CAUSES OF DEATH IN THIS CENTURY, IT'S ESTIMATED THAT IT WILL REACH ABOUT 1 BILLION. THAT TELLS US ABOUT HOW MUCH FURTHER TOBACCO HAS SPREAD AROUND THE GLOBE. NOW, WE'VE MADE SOME GREAT STRIDES IN THIS COUNTRY BUT THEY HAVE NOT BEEN SIMILARLY MADE IN MANY OTHER PARTS OF THE WORLD, AND THE TOBACCO INDUSTRY CONTINUES TO PERVADE THEIR DEADLY PRODUCT IN MANY POPULATIONS ACROSS THE GLOBE. THIS LEADS TO OVER 200,000 PREMATURE DEATHS AMONG WOMEN IN THIS COUNTRY IN THE MOST RECENT DATA. SO WE SEE THAT EVEN THOUGH THE RATES ARE SLIGHTLY HIGHER FOR MEN THAN WOMEN IN CURRENT SMOKING, THE RATES ARE EXTRAORDINARILY AND SADLY EXTREMELY HIGH FOR WOMEN. WHEN WE LACK AT ALCOHOL, IT'S A SIMILAR STORY. WE SEE A SLIGHTLY HIGHER RATE FOR MEN THAN WOMEN, ALTHOUGH I WITH SAY THAT GAP BETWEEN THEM HAS BEEN NARROWING IN RECENT YEARS. IT TELLS ME WE'RE SEEING SOME IMPROVEMENT IN THE RATES OF ALCOHOL CONSUMPTION FOR MEN BUT WE HAVEN'T SEEN THESE SAME IMOF PROVEMENTS FOR WOMEN. WHEN WE LOOK AT -- A SLIGHTLY HIGHER RATE FOR MEN THAN WOMEN, WHETHER IT'S ANY DRUG USE OVER THE LIFETIME PARTICULARLY MOST IMPORTANT FOR SORT OF PUBLIC HEALTH PLANNING AND TREATMENT PLANNING WOULD BE THE CURRENT RATE, WHERE WE DO SEE A HIGHER RATE FOR MEN THAN WOMEN, BUT STILL A FRIGHTENINGLY HIGH RATE FOR WOMEN IN OUR COMMUNITY IN THE UNITED STATES. NOW THAT'S SORT OF THE OVERALL RATE OF DRUG USE. THERE ARE MANY REASONS WHY PEOPLE USE DRUGS. WE'LL COME TO THE BIOLOGY IN JUST A FEW MOMENTS, BUT SOME OF IT IS EXPLAINED BY YOUR SOCIAL CIRCUMSTANCES, WHO DO YOU ASSOCIATE WITH, WHO ARE THE TEENAGERS HANGING OUT WITH, ARE YOU HANGING OUT WITH OTHER KIDS AND YOUNG ADULTS WHO WILL OFFER YOU SUBSTANCES. THERE'S A WONDERFUL STUDY BY JIM ANTHONY AND COLLEAGUES THAT REMINDED US THAT PART OF THE EXPLANATION FOR DIFFERENCES IN THE DRUG USE RATE, WHICH IS KIND OF WHAT THAT PUBLIC HEALTH DATA SHOWS US, IS THAT THE SOCIAL NETWORK AND THE OFFERING OF DRUGS VARIES BETWEEN THE SEXES. SO THAT TYPICALLY BOYS, BECAUSE THIS IS TYPICALLY TEENAGERS, ARE OFFERED DRUGS MORE OFTEN THAN GIRLS AT THAT AGE AND STAGE OF DEVELOPMENT. HOWEVER, GIVEN EQUAL PROPENSITY TO BE OFFERED DRUGS, THERE'S NOT MUCH DIFFERENCE IN TERMS OF THE ACCEPTANCE. SO SOME OF IT RELATES TO THE SOCIAL NETWORKS, THAT'S WHAT DR. ANTHONY HAS REMINDED US. BUT ONCE PEOPLE START DOWN THAT DRUG USING PATHWAY, THE PROGRESSION INTO ABUSE, DEPENDENCE OR ADDICTION MAY EVEN MOVE FASTER FOR WOMEN THAN FOR MEN. SO IT TELLS US THERE'S SOME COMPLICATED ISSUES GOING ON HERE, SO I WOULD SUGGEST AND PART OF WHAT KEEPS ME EXCITED ABOUT THE DRUG ABUSE DEAL IS IT'S INHERENTLY A COMBINATION OF BIOLOGICAL AND ENVIRONMENTAL, OFTEN SOCIAL FACTORS. SO THIS IS ONE EXAMPLE WHERE IN TERMS OF THE SOCIAL DYNAMICS, THAT CAN PLAY A ROLE IN HELPING US UNDERSTAND THE GENDER AND SEX DIFFERENCES IN DRUG USE AND DRUG TRAJECTORY. HERE'S A KEY EXAMPLE THAT WE ARE SEEING LATELY THAT'S BEEN PARTICULARLY FRIGHTENING FOR THOSE OF US ON THE FRONT LINES WITH INFECTIOUS DISEASE AND THE MOST SERIOUS HEALTH CONSEQUENCE OF DRUGS. WE'VE SEEN A REAL SHIFT IN TREATMENT ADMISSIONS TO OPIOID TREATMENT PROGRAM OVER THE LAST DECADE. IF WE WENT BACK TO THE 60s, IT WAS RARE THAT WOMEN WERE ADMITTED TO A HEROIN TREATMENT PROGRAM. SO WHETHER IT'S METHADONE OR PSYCHOSOCIAL TREATMENT, MOST OF IT WAS -- MOST OF THE TREATMENT -- WERE BY MEN. BUT WE'VE SEEN THIS SHIFTING OVER THE YEARS TO WHERE IN RECENT YEARS, THE TREATMENT ADMISSIONS ARE AT LEAST EQUAL IF NOT SLIGHTLY HIGHER AMONG WOMEN THAN MEN. THAT'S QUITE A SHIFT FOR OUR TREATMENT PROGRAMS, AND SPEAK TO THE SHIFTING DYNAMICS OF DRUG USE IN THE COMMUNITY. I'M GOING TO SUGGEST TO YOU AND IF YOU'RE INTERESTED WE CAN TALK MORE ABOUT IT THE SHIFTING PATTERNS OF THE OPIOID USE EPIDEMIC, WHERE PART OF THE SHIFTS IN HEROIN ARE BASED ON EARLIER EX-PLOA SURE TO PRESCRIPTION OPIOIDS, AND THAT IS NOT SO SEX-SPECIFIC. SO THIS MIGHT HELP US UNDERSTAND WHY THAT PROGRESSION FROM OPIOID USE THROUGH PRESCRIPTION EXPOSURE, WHETHER THROUGH -- IT DOESN'T MEAN IT DIRECTLY CAME FROM YOUR OWN PRESCRIPTION, IT MIGHT BE SOMEBODY ELSE'S PRESCRIPTION, THAT THEY ARE WILLING OR ACCIDENTALLY SHARE WITH SOMEONE ELSE. SO WE DO SEE THE SHIFT AND WE THINK IT'S DRIVEN BY CHANGES IN THE UNDERLYING PRESCRIPTION OPIOID EPIDEMIC. SO IN THIS CASE, WE NO LONGER SEE A DIFFERENCE BASED ON SEX OR GENDER. WE SEE THE RATES FOR PRESCRIPTION DRUG ABUSE ARE QUITE SIMILAR FOR MEN AND WOMEN IN THIS COUNTRY. LET'S TALK ABOUT THIS A LITTLE BIT MORE. THIS HAS BEEN IN THE NEWS LATLY AND ILATELYAND HAS BEEN A MAJOR HEALTH CONCERN, PARTICULARLY BECAUSE OF THE EXCESS AND INCREASING MORTALITY ASSOCIATED WITH PRESCRIPTION OPIOIDS. PSYCHOTHERAPEUTICS, AS THE BROAD CLASS OF PRESCRIPTION DRUGS INCLUDES THREE MAIN CLUSTERS. OF COURSE WE HAVE THE OPIOID PAIN RELIEVERS AS THE MOST PROMINENT OF THOSE. WE ALSO HAVE THE SEDATIVE HYPNOTICS AND STIMULANTS AS THE OTHER TWO MAJOR CLASS. WHAT WE SEE IS THAT THERE ARE -- ALTHOUGH IN TERMS OF MISUSE, THAT'S ABUSE OF THE SUBSTANCES, IT'S SLIGHTLY HIGHER FOR MEN THAN WOMEN IN TERMS OF THE OPIOIDS, WE DON'T SEE ANY DIFFERENCE IN TERMS OF THE STIMULANTS OR THE SEDATIVE HYPNOTIC -- SO THIS TELLS US THERE HAS BEEN A SHIFT AND THAT THIS IS A VERY IMPORTANT AREA FOR WOMEN'S HEALTH. NOW WHAT SORT OF GALVANIZED OUR PUBLIC HEALTH ATTENTION TO THESE ISSUES? WHAT'S REALLY ALARMED PUBLIC HEALTH OFFICIALS IS THE INCREASE IN OPIOID-RELATED MORTALITY. SO THESE ARE OVERDOSES RELATED TO OPIOIDS IN PARTICULAR. LOOKING BROADLY AT DRUG OVERDOSES, THESE HAVE ABOUT TRIPLED OVER THE LAST 20 YEARS. THE MOST RECENT DATA SHOW ABOUT 40,000 PERSONS IN THE YEAR 2011 DIED FROM AN OVERDOSE OF ONE SUBSTANCE OR ANOTHER. THIS IS ABOUT A TRIPLING OF THE RATE 20 YEARS AGO, AND MOST OF HA INCREASE HAS BEEN DRIVEN BY THE INCREASES IN DEATHS DUE TO PRESCRIPTION OPIOIDS. WHEN A DEATH CERTIFICATE SPECIFIES THE DRUG, AND IT DOESN'T ALWAYS, WE GET ABOUT 16,000 DEATHS IN THE MOST RECENT DATA, SO THAT IS A LARGE NUMBER. CERTAINLY THE OVERALL DRUG OVERDOSE DEATHS EXCEEDS DEATHS FROM MOTOR VEHICLE ACCIDENTS OR EVEN FOR FIREARMS. SO THOSE ARE WELL-KNOWN PUBLIC HEALTH CONCERNS AND GALVANIZED TREMENDOUS POLICY IMPACT RESPONSE, AND YET WE'RE NOW SEEING MORSEESEEING MORE DEATHS FROM DRUG OVERDOSE. SO WE'RE SEEING MORE ATTENTION TO THIS ISSUE AND IT'S GALVANIZED THE RESEARCH AND PUBLIC HEALTH COMMUNITY. NOW WHILE THE RATES OVERALL HAVE INCREASED BY ABOUT THREEFOLD, THE INCREASES FOR WOMEN HAVE BEEN EVEN GREATER. THEY'VE INCREASED ABOUT FIVE FOLD. NOW THIS IS -- YOU'VE GOT TO GET YOUR HEAD WRAPPED AROUND THIS, BECAUSE THE RATES REMAIN HIGHER FOR MEN THAN WOMEN, BUT THE RATES HAVE INCREASED MUCH MORE RAPIDLY FOR WOMEN. SO FOR INSTANCE WE SEE ABOUT 6500 OVERDOSE DEATHS RELATED TO THE PRESCRIPTION OPIOIDS IN THE MOANT MOST RECENT DATA FOR WOMEN, IT'S ABOUT 9,000 FOR MEN IN THAT SAME YEAR. SO IT'S HIGHER FOR MEN BUT THAT INCREASE FOR WOMEN HAS BEEN REMARKABLE. I WANT TO POINT OUT THE OTHER SUBSTANCE THAT DOESN'T GET AS MUCH ATTENTION AS THE OPIOID. -- THEY'RE NOT AT COMMONLY RELATED TO OVERDOSE WHEN TAKEN BY THEMSELVES, SO TYPICALLY THE SEDATIVES ARE LETHAL IN COMBINATION WITH THE OPIOIDS OR IN COMBINATION WITH ALCOHOL, BUT THAT'S AN IMPORTANT MESSAGE FOR CLINICIANS WHO OFTEN THINK THAT MEDICATIONS LIKE DIAZEPAM OR AL PAZ LAMB, RARELY ARE FATAL. THIS SUGGESTED THAT'S NOT TRUE BECAUSE THEY'RE RARELY TAKEN BY THEMSELVES, AND BECAUSE OF COMBINATIONS OF WHAT PEOPLE END UP TAKING, THE RISK OF FATALITY IS QUITE SIGNIFICANT. WHAT'S DRIVING THIS? THE UNDERLYING FACTOR IS SOMETHING THAT WE HAVE TALKED ABOUT AS ENVIRONMENTAL AVAILABILITY OF THE OPIOIDS. NOW YOU HAVE TO THINK IN TERMS OF ENVIRONMENTAL AVAILABILITY, NOT SIMPLY PRESCRIBING A PRESCRIPTION AND THAT PATIENT WHO GETS THE PRIPS IS AT RISK FOR OVERDOSE. IT'S MORE A SENSE OF AVAILABILITY IN THAT THEY'RE IN THE MEDICINE CABINET, IN BAGS OR GYM BAGS OR IN PURSES THAT PEOPLE CARRY AROUND. THEY WILL THEN SHARE THEM WITH OTHER FAMILY OR FRIENDS, EITHER DIRECTLY AND INTENTIONALLY OR UNINTENTIONALLY WHEN THEY GET STOLEN OR PURR LOINED FROM THOSE PLACES. SO THAT'S WHEN I SAY IT'S A COMPLICATED SITUATION. I WISH IT WERE AS SIMPLE AS WE WRITE THE PRESCRIPTIONS AND THE PATIENTS TO WHOM THEY ARE WRITTEN ARE THE ONES THAT GET INTO TROUBLE. BUT IT TURNS OUT THAT IT'S NOT THE DIRECT PATIENT, BUT IT'S MORE THE COMMUNITY AT LARGE THAT'S PUT AT RISK FROM THIS INCREASING AVAILABILITY OF PRESCRIPTIONS. SO THAT'S WHY WHEN WE SEE THESE DATA SHOWING A HIGHER RAIB OF PRESCRIBING FOR WOMEN THAN MEN OVERALL AND A MARKED INCREASE OVER BOTH EXECUTORS IN TERMS OF PRESCRIPTION RATE, THE DEATHS ARE MORE AMONG MEN AND THAT WOMEN. THERE'S SOMETHING THAT EXPLAINS THAT DIFFERENCE IN TERMS OF THAT DISTRIBUTION AND DIVERSION OF THESE PRESCRIPTIONS. FUNDAMENTALLY SOME OF THESE PRESCRIPTIONS ARE BASED ON OUR ATTEMPT TO TREAT PAIN IN OUR COUNTRY. IT'S BEEN A TREMENDOUS EMPHASIS ON SERIOUS AND -- UNDER RECOGNITION AND UNDERTREATMENT OF PAIN IN PUBLIC. WOMEN'S REPORTS OF PAIN ARE OFTEN -- ARE MORE LIKELY TO BE DISMISSED THAN MEN, AS A PSYCHIATRIST, THAT'S FAIRLY TYPICAL IN THAT WE THINK IT'S SOMETHING PSYCHOLOGICAL, SO THE PHYSICAL PAIN MAY BE IGNORED OR ATTRIBUTED TO NONSPECIFIC FACTORS AND NOT TAKEN SO SERIOUSLY. THAT'S A MEDICAL MISTAKE, AND SOMETHING THAT MANY HAVE BEEN WORKING TO ADDRESS. WOMEN APPEAR TO SUFFER MORE PAIN IN MULTIPLE CATEGORIES SO THEY MAY BE AT RISK IN MULTIPLE AREAS, AND THIS IS A CLUE THAT THERE ARE DIFFERENTS IN BOTH THE PHYSICAL ASPECT OF CAUSING -- THE CAUSES OF PAIN ACROSS THE SEXES AS WELL AS THE EXPERIENCE OF PAIN. SO UNFORTUNATELY, WE'VE HAD SORT OF A ONE TRACK APPROACH TO ADDRESSING PAIN IN THIS COUNTRY. IF YOU HAVE PAIN, YOU GET A PRESCRIPTION. TURNS OUT THAT'S A MUCH OVERLY SIMPLIFIED APPROACH, AND HAS BEEN PARTLY RESPONSIBLE FOR THE PROBLEMS WE SEE IN TERMS OF THE MORBIDITY AND MORTALITY ASSOCIATED WITH THE HIGH RATES OF PRESCRIBING. SO WHAT WE'RE WORKING ON NOW IS INVENT AGO NEW SYSTEM THAT'S MORE SOPHISTICATED THAT INCLUDES INTERDISCIPLINARY APPROACHES AND APPLIES OTHER MEANS TO ADDRESS PAIN. AT THE NIH, WE ARE CERTAINLY APPROACHING THIS BY TRYING TO UNDERSTAND THE BASIC BIOLOGY OF PAIN AND TO DEVELOP PAIN TREATMENTS TA DON' THAT DON'T INCLUDE A COMPLETE RELIANCE ON THE OPIOID AS A WAY OF ADDRESSING THIS EXCESS MORBIDITY AND MORTALITY. SO THAT WAS MY INTRODUCTION. PUBLIC HEALTH DATA SUGGESTS RATES ARE SLIGHTLY HIGHER AMONG MEN AND THAT WOMEN BUT THE RATES ARE EXTRAORDINARY HIGH FOR WOMEN. THAT WHEN IT COMES TO SOCIAL FACTORS, THERE'S SOME VERY INTERESTING SOCIAL DYNAMICS INVOLVED IN WHO'S EXPOSED TO DRUGS AND THEN WE SEE THE PROGRESSION OF DRUG ABUSE DIFFERENTLY IN THOSE ONCE THEY'RE EXPOSED FOR MEN THAN WOMEN. WHEN IT COMES TO THE PARTICULAR CURRENT ISSUES OF PRESCRIPTION DRUG USE, AN INTERESTING PHENOMENON, WOMEN GETTING MORE PRESCRIPTIONS BUT HAVING SLIGHTLY LESS OVERDOSE RATES, SPEAKING TO THE BROAD DYNAMICS OF THE DIVERSION AND MISUSE PATTERNS OF THESE DRUGS BUT YET -- TO DEAL WITH FOR BOTH MEN AND WOMEN. LET'S NOW TURN TO AN UNDERSTANDING OF WHY PEOPLE USE DRUGS AND LOOK AT WHAT'S DIFFERENT IN THE RESPONSE TO DRUGS AND WHAT'S DIFFERENT IN THE BRAIN. IT MIGHT HELP US UNDERSTAND SEX AS A SIGNIFICANT AND IMPORTANT BIOLOGICAL FACTOR IN THIS DRUG ABUSE TRAJECTORY. ALL DRUGS OF ABUSE RAISE DOPAMINE LEVELS. NOW THIS IS A CORE FEATURE THAT'S BEEN ESTABLISHED OVER THE LAST 20 YEARS OF BASIC SCIENCE, CLINICAL NEUROSCIENCE RESEARCH. WE THINK THESE DOPAMINE PATHWAYS ARE ESSENTIAL TO UNDERSTANDING WHY WHEN PEOPLE ARE EXPOSED, THEY DO IT AGAIN. THAT'S WHAT'S GOING ON IN DRUG ABUSE. IT'S A LEARNED I NO, MA'AM NON-. LEARNED P HENOMENON. THERE IS INCREASING EXPOSURE, THERE IS A REINFORCEMENT FOR THAT BEHAVIOR, THERE'S A STIMULATION OF THE FORMATION OF MEMORY. THERE'S PATHWAYS THAT LEADS TO OUR FRONTAL LOBE, WHERE JUDGMENT, DECISION-MAKING ARE LOCATED. SO THOSE A SYNERGY ACROSS THESE PATHWAYS THAT LEAD TO A LEARNED BEHAVIOR AFFECTING MEMORY, COGNITION, AND REINFORCING THOSE PATHWAYS OVER AND OVER, UNTIL IT BECOMES AN ESTABLISHED PATTERN WHERE WE BEGIN TO SEE WHAT LOOKS LIKE ADDICTION. BUT THE INITIAL PATHWAYS RELATE TO DOPAMINE NEUROTRANSMISSION AND ALL DRUGS OF ABUSE CAUSE AN INCREASE IN DOPAMINE. THEY DO IT BY DIFFERENT MECHANISMS, BUT THIS SEEMS TO AB COMMON PATHWAY ACROSS SUBSTANCES AND REINFORCED BEHAVIOR. I WILL SAY THESE ARE THE SAME PATHWAYS THAT ARE IMPORTANT FOR REINFORCING SEXUAL BEHAVIOR, FOR FEEDING BEHAVIOR, FOR FLUID INTAKE, AND ACTUALLY FOR SOCIAL INTERACTIONS A AS WELL. SO ALL THE THINGS THAT ARE ESSENTIAL FOR OUR SURVIVAL THAT ARE REALLY IMPORTANT FOR OUR BRAINS TO HAVE REINFORCED AND REMEMBERED AND LEARNED ABOUT ARE MEDIATED BY THIS COMMON PATHWAY. OF COURSE DRUGS DO THE SAME THING. DESPITE HA SORT OF COMMONALITY AMONG MEN AND WOMEN, THERE ARE SOME UNIQUE DIFFERENCES IN THE DOPAMINE SYSTEM FOR MEN VERSUS WOMEN. THIS IS A FASCINATING STUDY THAT SHOWS US THAT USING AN UNPREDICTABLE REWARD, SO THIS WAS MONEY AS A REWARD. THIS DIDN'T HAVE A PHARMICOLOGICAL FACTOR, SO WE CAN'T SAY IT IS A DIRECT RESULT OF THE DRUG IT SELF. THIS IS A PRETTY ABSTRACT PHENOMENON. YOU LET PEOPLE EARN MONEY IN UNEXPECTED WAYS. WHAT YOU SEE WHEN YOU GET A RYE A REWARD, YOU GET A LOTTERY TICKET, SOMETIMES YOU WIN, SOMETIMES YOU DON'T WIN, SOMETIMES YOU DO WIN, THAT'S AN EXAMPLE OF AN UNPREDICTABLE AWARD. IN THIS CASE, THE BRAIN RESPONDS DIFFERENTLY FOR MEN AND WOMEN SO THE DOPAMINE IS INCREASED IN WOMEN BUT NOT IN MEN IN THE VENTRAL STRIATUM AND DORSAL CONTAINMENT. SO THIS TELLS US THERE MAY BE SOMETHING DIFFERENT EVEN IN THIS CORE COMMON REWARD PATHWAY IN HOW THE BRAINS RESPOND FOR MEN AND WOMEN. NOW THIS BRINGS US TO SOME SORT OF WHAT EXPLAINS THIS? YOU KNOW, THE OLD-FASHIONED WAY THAT WE THINK, OH, IT'S ALL EXPLAINED BY HORMONAL DIFFERENCES AND PHASE IS SO IMPORTANT IN EXPLAINING THIS. THAT'S OBVIOUSLY AN OVERSIM POLICOVERSIMPLISTIC APPROACH, THAT'S AN IMPORTANT FACTOR BUT DOESN'T EXPLAIN MUCH OF THE DIFFERENCES. HORMONES MAY INCREASE THE DRUG'S REINFORCING EFFECT SO THIS CAN PLAY A ROLE ON THE DIFFERENCE IN SEX HORMONES AND OTHERS BETWEEN MEN AND WOMEN CAN PLAY SOME ROLE IN THESE FACTORS, BUT MORE IMPORTANT WILL BE BRAIN DYMORPHISM. WE'LL WALK THROUGH JUST SOME ANALYZING EXAMPLES OF WHERE WE HOPE THE SCIENCE WILL CONTINUE TO MOVE TO HELP US UNDERSTAND THE FUNDAMENTAL BIOLOGICAL DIFFERENCES THAT EXPLAIN WHY THERE ARE THE SOCIAL DIFFERENCES AND ULTIMATELY TO IMPROVE, PREVENT AND TREATMENT. SO WHAT DO WE SEE IN W? WE SEE SOME FASCINATING WORK OVER THE LAST DECADE LOOKING AT JUST DIFFERENCES IN TERMS OF SIZE OF VARIOUS BRAIN REGIONS. SO WE SEE THE PARIETAL AND TEMPORAL LOBE TEND TO BE LARGER TO OVERALL BRAIN SIZE SO YOU HAVE TO ADJUST FOR OVERALL BRAIN SIZE, BUT WE SEE THOSE REGIONS BEING GENERALLY LARGER IN A HEALTHY FEMALE BRAIN. WE SEE THE CORPUS CALLOSUM, FRONTAL CORTEX AND A COUPLE OTHER REGIONS BEING SLIGHTLY LARGER IN THE MALE BRAIN. SO THIS SPEAKS TO SOME TANTALIZING EVIDENCE FOR STRUCTURAL DIFFERENCE IN THE BRAINS OF MEN AND WOMEN. THE TECHNOLOGY IS IMPROVING TO DETECT THESE DIFFERENCES. NOW, WE KNOW THAT BOYS AND GIRLS DEVELOP DIFFERENTLY. THAT'S BEEN OBSERVED FOR MANY, MANY YEARS. BOTH IN TERMS OF THEIR SOCIAL DEVELOPMENT, IN TERMS OF THEIR SOCIAL INTERACTIONS, THAT'S GOING TO BE MEDIATED BY BRAIN DIFFERENCES. SO IT'S FASCINATING TO ME AS A SPECTATOR AND A MODEST PARTICIPANT IN THIS AREA OF SCIENCE TO SEE THAT WHAT WE'RE SEEING IS THAT THE RATE OF CHANGE VARIES BETWEEN BOYS AND GIRLS ACROSS CHILDHOOD AND EVEN THROUGH ADOLESCENCE. SO THAT WE SEE QUITE REMARKABLE DIFFERENCES IN THE MATURATION AND THE DEVELOPMENT OF BRAINS BETWEEN MEN AND WOMEN AND BOYS AND GIRLS. BUT THERE REALLY ARE BIOLOGICAL UNDERPINNINGS FOR SOME OF THE CAN DIFFERENCES THAT ARE OBSERVED. I'M FASCINATED BY THIS VERY RECENT STUDY THAT COMES OUT THAT BEGINS TO LOOK AT BRAIN CONNECTIVITY, SO I FIRST WAS SHOWING YOU STRUCTURAL IT DIFFERENCES IN TERMS OF SIZE, THAT'S KIND OF YOUR BASIC NEUROANATOMY DIFFERENCES. NOW WE'RE LOOKING AT PATHWAY AND CONNECTION DIFFERENCES. THIS IS BEGINNING TO LOOK AT HOW THE BRAIN ACTUALLY WORKS IN TERMS OF THE FUNCTIONAL CONNECTIONS ACROSS DIFFERENT BRAIN REGIONS. WHAT WE SEE IS THAT THE DIFFERENCES VARY BY SEX, SO WE SEE GREATER INTRA -- WITHIN EACH HEMISPHERE CONNECTIONS IN MEN COMPARED TO WOMEN. WE SEE GREATER CONNECTIONS ACROSS THE HEMISPHERES FOR WOMEN COMPARED TO MEN, THAT'S THE ORANGE LINE, BUT WHAT'S IMPORTANT TO ME IS THIS SPEAKS TO THE -- HOW DEVELOPMENT PLAYS A ROLE, IS IT THESE CONNECTIONS VERY SYSTEMATICALLY DEPENDING ON THE AGE AND DEVELOPMENTAL STAGE OF THE SUBJECTS. SO AS A SCIENTIST, I'M GOING, WE JUST ADDED ABOUT THREE MORE LEVELS OF COMPLEXITY THAT WE HAVE TO TAKE INTO ACCOUNT. THIS IS WHY I'M SO THRILLED WITH YOUR THEME OF THIS MEETING TODAY. IT'S NOT GOING TO BE ONE SCIENTIST THAT FIGURED THIS OUT. WE CAN ONLY BEGIN TO ADDRESS GENE, ENVIRONMENT, DEVELOPMENT, INTERACTIONS WHEN WE HAVE INTERDISCIPLINARY TEAMS TO BEGIN TO LOOK AT THESE FACTORS. I'VE HIGHLIGHTED FOR YOU JUST A GLIMPSE OF SOME WORK AROUND SEXUAL DYMORPHISM IN THE IMPORTANCE OF BRAIN STRUCTURE AND FUNCTION IN HELPING US UNDERSTAND PERHAPS THE RESPONSE TO DRUGS. ANOTHER KEY AREA FOR WOMEN'S HEALTH OF COURSE HAS TO DO WITH PREGNANCY. IT'S BEEN WELL-KNOWN THAT EXPOSURE TO SUBSTANCES DURING PREGNANCY IS A TREMENDOUS RISK FACTOR FOR POOR FETAL OUTCOMES, WHETHER THAT IS THE QUITE CLEAR FETAL ALCOHOL SYNDROME OUTCOMES OR THE MORE SUBTLE NEURAL DEVELOPMENTAL ABNORMALITIES RELATED WITH PRENATAL ALCOHOL EXPOSURE. WE'VE BEEN FOCUSING QUITE A BIT AT NIDA ON TOBACCO EXPOSURE. THAT CERTAINLY WOULD BE ONE OF THE MOST COMMON TERATOGENS THAT'S IN USE. I PERSONALLY AM A SMOKE BABY, SO I GET TO EXPLAIN SOME OF MY BEHAVIORS BASED ON PRENATAL EXPOSURE TO NICOTINE AND TOBACCO PRODUCTS. AS MANY OF US WERE WHO WERE BORN IN THE 1950s OR EARLY 60s. SMOKING WAS ENCOURAGED BY WOMEN IN THOSE DAYS. THIS IS AN AMAZING STUDY COMING FROM A PRIMATE LABORATORY IN BENAVITE'S LABORATORY USING PET SCANNING TO LOOK AT THE ANYTHING TEEN AND ITS METABOLITES IN THE BRAIN OF THE MOTHER AS WELL AS THE FETUS, AND IT'S FASCINATING TO SEE THIS IS A REMARKABLE AND CLEAR EVIDENCE OF THE CROSS PLACENTAL TRANSMISSION OF NICOTINE. WE DO SEE THE NICOTINE BEING DETECTED FOR MANY -- FOR AN EXTENDED PERIOD OF TIME AFTER TOBACCO OR NICOTINE EXPOSURE IN BOTH THE MATERNAL AS WELL AS THE FETAL BRAIN. I DON'T THINK THAT'S SHOCKING SINCE WE SAW FETAL ABNORMALITIES, AND BEHAVIORAL ABNORMALITIES, THOSE HAVE BEEN DETECTED FOR A WHILE, BUT NOW WE'RE GETTING THE TOOLS AND TECHNIQUES TO ACTUALLY BEGIN TO UNDERSTAND THEM. SO THIS IS WHAT WE'RE TALKING ABOUT, IS HOW THE REVOLUTION IN TECHNOLOGY FOR BRAIN SCIENCES WILL LEAD TO A REVOLUTION IN UNDERSTANDING OF THE EFFECTS OF SUBSTANCES. I TALKED TO YOU A BIT ABOUT DOPAMINE AND NICOTINE CERTAINLY CAUSES A MARKED RELEASE IN DOPAMINE AND THE REWARD CIRCUITRY, BUT THERE ARE OTHER FACTORS THAT NICOTINE AND CERTAINLY THAT OTHER PARTS OF THE TOBACCO PRODUCT MAY PLAY A ROLE IN. ONE THAT MAY B BE MORE THAN IN TERMS OF HELPING US UNDERSTANDING -- THIS IS A KEY ENZYME THAT ALLOWS THE PRODUCTION OF ESTRABIAL, DURING DEVELOPMENT, AND SINCE ACUTE NICOTINE INHIBITS AROMA TASTE IN THE BRAIN, THIS MAY HELP US UNDERSTAND SOME OF THE CAN DIFFERENTS IN RESPONSE TO NICOTINE FOR MALE VERSUS FEMALE OFFSPRING. HERE'S AN EXAMPLE. WHEN WE LOOK AT THE EFFECTS OF PRENATAL NICOTINE EXPOSURE ON BOYS AND GIRLS, THIS IS FROM A STUDY LINDA CHANG LED AND FUNDED UNDER ARA SUPPORT, MULTI-SEX CONSORTIUM LOOKING AT BRAIN DEVELOPMENT USING NEUROIMAGING, SO IT'S THE ABSOLUTE LATEST IN TERMS OF TECHNOLOGY. WHAT YOU SEE IS A BRAIN DEVELOPMENT AT DIFFERENT AGES, AND WHAT WE SEE ARE DIFFERENCES IN THE LEFT AND RIGHT PALLIDUM FOR BOYS, GIRLS, YOUNG MEN AND YOUNG WOMEN AT DIFFERENT AGES. THE TWO LINES AT THE TOP OF EACH OF THESE ARE THE LINES FOR MALES AND THE TWO LINES DIFFERENTIATED ARE FOR FEMALES. SO THAT'S WHERE YOU CAN SCENIC TEEN EXPOSURE HAS A MARKED DIFFERENCE IN BRAIN DEVELOPMENT FOR GIRLS COMPARED TO BOYS. SO THIS MAY -- PERHAPS THIS IS RELATED TO THE AROMATASE STORY, WHERE THERE'S A DIFFERENCE IN SEX HORMONE PRODUCTION AND THIS MIGHT HELP EXPLAIN WHY THE BRAINS DIFFER OVER TIME BETWEEN BOYS AND GIRLS. WHEN EXPOSED TO NICOTINE. SO OVERALL, WHAT IS THE IMPACT OF TOBACCO ON WOMEN'S HEALTH? I'VE ALREADY MENTIONED TO YOU THE VERY HIGH RATES OF MORTALITY ASSOCIATED WITH TOBACCO. I WANT TO MENTION TO YOU IN PARTICULAR MONOAMINE OXIDASE, THIS MAY HELP EXPLAIN SOME OF THE TOXICITY ASSOCIATED WITH NICOTINE AND TOBACCO PRODUCTS. CERTAINLY WHETHER IT'S FROM THE NICOTINE, MAO, OR FROM MANY, MANY OF THE TOXIC CHEMICALS IN TOBACCO PRODUCTS, WE SEE MUCH HIGHER RATES OF LUNG CAN SE, HEART ATTACK, AND BREAST CANCER IN WOMEN. IT'S INTERESTING THAT THE RISK FOR LUNG CANCER IS GREATER IN WOMEN THAN MEN, AND IT SEEMS TO DEVELOP LUNG CANCER WITH -- GIVING US CLUES THAT IT'S NOT JUST A BEHAVIORAL ASPECT THAT I'M TALKING TO YOU ABOUT TODAY BUT THE DIRECT BIOLOGICAL IMPACT IN MULTIPLE SPHERES WHEN IT COMES TO WOMEN'S HEALTH THAT SUBSTANCES PLAY A ROLE. SECONDHAND EXPOSURE IS THE OTHER WAY THAT PEOPLE GET EXPOSED. IT'S NOT JUST THROUGH DIRECT SOMEWHAT VOLUNTARY USE OF TOBACCO PRODUCTS. BUT THEY CAN BE INVOLUNTARY USE OF EXPOSURE TO TOBACCO AND THE TOXIC CHEMICALS. THIS MAY BE A PARTICULAR ISSUE IN DEVELOPING COUNTRIES, AND CERTAINLY THE CHILDREN EXPOSED TO SECONDHAND SMOKE HAVE MULTIPLE ISSUES, WHETHER THAT'S DUE TO PRENATAL EXPOSURE OR EARLY CHILDHOOD EXPOSURE. SO KEEP IN MIND SECONDHAND EXPOSURE AS A PARTICULAR ISSUE FOR WOMEN IN SOME CIRCUMSTANCES. AND CERTAINLY IN TERMS OF OCCUPATIONAL EXPOSURE, THIS IS WELL-KNOWN. MANY OF THE IMPORTANT STUDIES WERE DONE WITH AIRLINE STEWARDESSES FROM MANY YEARS AGO WHERE THAT WAS A TREMENDOUS OCCUPATIONAL EXPOSURE IN AN ENCLOSED SPACE, VERY FRIGHTENING HISTORY THERE. SO ONCE PEOPLE ARE ADDICTED, WHAT HAPPENS? WELL, HERE'S AN EXAMPLE FROM TOBACCO. WOMEN HAVE A HARDER TIME QUITTING. PERHAPS IT'S THAT WOMEN ARE SOMEWHAT LESS SENSITIVE TO NICOTINE AS THE PHARMACOLOGICAL AGENT BUT MAY BE MORE SENSITIVE TO NON-NICOTINE FACTORS. SO IT MAY BE MORE THAN JUST THE NICOTINE THAT PLAYS A ROLE IN THESE GENDER DIFFERENCES IN DIFFICULTY QUITTING. CERTAINLY THESE RELATE TO THE RELATIONSHIP TO DEPRESSION, STRESS, NEGATIVE AFFECT, AND EVEN CONCERNS OF WEIGHT GAIN AS A A MAJOR SOCIAL FACTOR INHIBITING PEOPLE FROM QUITTING SMOKING. I'M CURIOUS THAT SOME OF THE DIFFICULTIES IN QUITTING SMOKING MAY BE REFLECTED IN SOME OF THESE MEDICATION TRIALS. LOOKING ON THE LEFT-HAND SIDE, WE SEE A STUDY THAT COMPARED PLA SATISFY BOW VERSUS TOPIRAMATE, OVERALL YOU SEE NO EFFECT OF THE MEDICATION VERSUS PLACEBO, BUT YET WHEN WE LOOK AT MALES VERSUS FEMALES, WE SEE A REMARKABLE DIFFERENCE WHERE FOR MEE MALES, IT WAS ACTUALLY COUNTERPRODUCTIVE AND LED TO LESS QUITTING RATES, WHERE FOR MALES, IT WAS A HIGHER QUITTING RATE. NOW THIS IS PRELIMINARY WORK, IT'S ONE STUDY AND WE ARE NOT GOING TO BE PRESCRIBING THIS MEDICATION FOR MALES AND AVOIDING IT FOR FEMALES BASE ON THIS ONE STUDY, BUT IT'S AN IMPORTANT CLUE THAT WHEN WE DO OUR WORK AND LOOK AT JUST ONE GROUP OVERALL THIS, IS A CLEAR EXAMPLE HOW IF WE HADN'T LOOKED AT THE SEX DIFFERENCES, WE MIGHT HAVE MISSED AN IMPORTANT USEFUL MEDICATION AND AN IMPORTANT PERHAPS DANGEROUS MEDICATION DEPENDING ON THE SEX OF THE PERSON INVOLVED. SIMILARLY WHEN WE LOOK AT VARENICLINE AND ABOUT BUPROPION, WE SEE A RESPONSE FOR MEN BUT NOT WOMEN. NOW I CAN'T REALLY EXPLAIN THAT, BUT THAT'S WHAT SCIENCE IS ALL ABOUT, WE FIND THINGS THAT I DON'T REALLY UNDERSTAND THAT. WE NEED YOU ALL TO HELP YOURS EXPLAIN THOSE DIFFERENCES AND ALSO TAKE ADVANTAGE OF THESE DIFFERENCES FOR CLINICAL DECISION-MAKING. WE'VE TALKED ABOUT EPIDEMIOLOGY, THE PUBLIC HEALTH DIFFERENCES. I'VE MENTIONED THE POTENTIAL FOR HORMONE DIFFERENCES BUT MORE IMPORTANTLY FOR BRAIN DYMORPHISM TO EXPLAIN SOME OF THE DIFFERENCES BETWEEN MEN AND WOMEN, BETWEEN MALES AND FEMALES. USE TOBACCO AS AN EXAMPLE TO ILLUSTRATE SOME OF THE TREATMENT DIFFERENCES, BOTH IN TERMS OF QUITTING RATES OVERALL, AS WELL AS THE RESPONSE TO CESSATION AIDS. LET'S TURN JUST FOR A MOMENT TO THE DRUG ABUSE WORLD IN TERMS OF BALANCING SEX IN CELL AND ANIMAL STUDIES. WE'RE SO EXCITED THAT DRS. CLAYTON AND COLLINS ARE LEADING THE EFFORT OH HELP US RECONSIDER HOW WE CAN IMPROVE OUR BASIC AND CLINICAL SCIENCE STUDIES TO UNDERSTAND AN TAKE ADVANTAGE OF SEX AS AN IMPORTANT BIOLOGICAL VARIABLE TO GIVE US CLUES THAT EVENTUALLY WILL LEAD TO IMPROVED PREVEX AND TREATMENT PAIR DIMES. I KNOW YOU ALL WILL BE WRESTLING WITH HELPING US FIGURE OUT WHAT THESE POLICIES OUGHT TO BE AND I'M VERY EXCITED TO LEARN FROM YOU WHAT YOUR RECOMMENDATIONS WILL BE. SO WHY DO WE PARTICULARLY CARE ABOUT IT? HERE'S AN EXAMPLE FROM THE CANNABINOID WORLD. CANNABINOID SCIENCE IS OF COURSE MAJOR PART OF WHAT WE DO AT THE NATIONAL INSTITUTE ON DRUG USE, AND WE SEE THAT SEXUAL DID DYMORPHISM PLAYS A ROLE IN THE CB1, THAT'S THE CANNABINOID 1 SUBTYPE RECEPTOR DENSITY IN MULTIPLE PARTS OF THE BRAIN. SO WE SEE THAT THERE'S DIFFERENTIAL STRUCTURE AND FUNCTIONAL ABNORMALITIES AND DIFFERENCES IN THE PREFRONTAL CORTEX, IN THE BASAL BEGAN DLEE BEGAN GLEE A WE ALSO SEE THEM IN THE MIG DA LA, HIPPOCAMPUS, WE SEE THEM IN THE MID BRAIN REGION PART OF THE DOPAMINE THALAMUS, IN THE THALAMUS AND HYPOTHALAMUS, GENERAL BRAIN ORGANIZATION AND STRUCTURE. SO JUST IN TERMS OF THIS ONE RECEPTOR SYSTEM, THE CANNABINOID RECEPTOR, WE SEE ESSENTIAL DIFFERENCES BETWEEN MALES AND FEMALES THAT WE NEED YOUR HELP IN UNDERSTANDING. IF WE DON'T STUDY MALE AND FEMALE ANIMALS, INCLUDING HUMANS, WE'RE NOT GOING TO GET AT THIS IMPORTANT DIFFERENCE AND WE WILL MISS IMPORTANT TREATMENT -- PREVENTION AND TREATMENT OPPORTUNITIES. NOW WHAT'S HAPPENED IN TERMS OF OUR RESEARCH IN SOME OF THESE AREAS? WE'VE SEEN AN INCREASE OVERALL THE IN THE STUDIES OF CANNABINOID EFFECTS. THAT'S NOT TOO SHOCKING SINCE THE RECEPTORS WERE BASICALLY DISCOVERED ABOUT 22 YEARS AGO, AT LEAST SPECIFIED AT THAT TIME, SO WE'VE SEEN AN INCREASE IN BOTH HUMAN AND BASIC RESEARCH IN CANNABINOID RECEPTORS. WE HAVE SEEN A LARGE NUMBER OF STUDIES THAT LOOK AT MALES AND A LARGE NUMBER OF STUDIES THAT LOOK AT FEMALES, THERE'S NOT EQUAL REPRESENTATION BUT IT'S NOT TERRIBLE IN TERMS OF HAVING SOME STUDIES OF FEMALE ANIMALS AND FEMALE HUMANS, BUT WHAT ABOUT STUDIES THAT LOOK AT THE SEX DIFFERENCES? THAT HAS LAGGED TREMENDOUSLY, SO I THINK ONE OF THE GOALS AND CHALLENGES OF THE POLICIES THAT YOU ALL WILL BE WRESTLING WITH THIS AFTERNOON IS HOW DO WE MAKE SURE THAT THEY PLAY AN IMPACT IN IMPROVING OUR ATTENTION TO THE POTENTIAL SEX DIFFERENCES? SO THAT WE DON'T JUST HAVE ANIMAL STUDIES THAT HAVE QUITE A FEW MALES AND QUITE A FEW FEMALE, BUT REALLY TAKE ADVANTAGE OF THAT BURGEONING DATA TO TEACH US SOMETHING ABOUT WHY THERE ARE DIFFERENCES, SO THAT WE CAN THEN IMPROVE THE TREATMENT AND PREVENTION. WELL I HOPE I'VE SUCCEEDED IN PROVIDING FOR YOU A SENSE OF NIDA'S INTEREST IN THIS TOPIC OF WOMEN'S HEALTH. WE SEE SEX AS AN ABSOLUTELY ESSENTIAL BIOLOGICAL AND FROM MY PERSPECTIVE A SOCIAL FACTOR AS WELL, AND OUR PORTFOLIO WILL REFLECT OUR INTEREST IN THIS AREA AND THROUGH ESTEEMED COLLEAGUES LIKE CORA LEE AND OTHERS, WE WILL CONTINUE TO SUPPORT THIS AREA OF SCIENCE SO WITH THAT, I THANK YOU VERY MUCH. [APPLAUSE] I DID LEAVE A MOMENT OR TWO FOR A COUPLE OF QUESTIONS. I -- WE WEREN'T CLEAR ON WHETHER I WAS SUPPOSED TO TAKE QUESTIONS OR NOT, BUT IF THERE ARE SOME, I'D BE -- I LOVE ANSWERING QUESTIONS SO IF YOU HAVE ANY, I'D BE HAPPY TO TAKE SOME NOW. I SEE I HOPE SOMEBODY GOING TO THE MICROPHONE. >> THANK YOU VERY MUCH. I WAS GLAD THAT YOU ENDED P YOUR PRESENTATION WITH SOME WORK ABOUT THE CANNABINOIDS, BECAUSE AS A TAXPAYER, AS A WOMAN AND AS A MOTHER, I AM VERY CONCERNED THAT NIH ISN'T PUTTING FORTH A BIGGER PUBLIC HEALTH INITIATIVE TO IT DISCOURAGE THE SORT OF FREE USE OF MARIJUANA SMOKING AND NOT REALLY LOOKING AT SOME OF THE LONG TERM HEALTH DETERMINANTS. THE ONE FIGURE THAT YOU SHOWED THAT WAS VERY DRAMATIC IN REGARD TO THE NICOTINE EFFECTS CROSSING THE PLACENTA, I WOULD LIKE TO SEE SOMETHING SIMILAR IN REGARD TO SOME OF THESE OTHER SMOKING PRODUCTS THAT ARE BEING USED AND AS THAT THEY ARE HEALTHY OR BENEFICIAL OR PROGRESSIVE, INCLUDING THE COMPOUNDS THAT ARE IN E-CIGARETTES AND SO ON. SO COULD YOU COMMENT ON SOME OF THE EFFORTS TO SORT OF COUNTER THE PUBLIC MOVEMENT THAT THESE KINDS OF PRODUCTS AND USE ARE OKAY? I CAN REMEMBER GROWING UP SEEING THAT PICTURE ON TV, THIS IS YOUR BRAIN ON DRUGS AND THE FRIED EGG. WE DON'T SEE THAT ANYMORE. JUST PLEASE COMMENT. THANK YOU. >> WELL YOU'RE CERTAINLY RAISING A VERY IMPORTANT QUESTION ABOUT WHERE SCIENCE AND POLICY AND IN THIS CASE EVEN LEGISLATION INTERSECTS. OUR RESPONSIBILITY AT THE NIH IS TO MAKE SURE WE BRING THE POWER OF SCIENCE TO BEAR ON THESE QUESTIONS, WHICH WILL THEN BE REFLECTED, WE HOPE, IN POLICIES, PRACTICES, AND PROGRAMS ALL ACROSS THE COUNTRY. SO FOR INSTANCE, WE'VE BEEN DRAWING ATTENTION TO THE NEED FOR ADDITIONAL RESEARCH ON THE IMPACT OF THESE CHANGING POLICIES AND LAWS WHEN IT COMES TO MARIJUANA LEGALIZATION, FOR EXAMPLE, IN COLORADO AND WASHINGTON STATE AND JUST 48 HOURS AGO IN OREGON, ALASKA AND IN THE DISTRICT OF COLUMBIA. SO WE ARE SEEING MAJOR SHIFTS IN THE PUBLIC'S INTEREST AND WILLINGNESS TO ALLOW MARIJUANA PRODUCTS TO BE USED BY ADULTS. ALL OF THESE PROGRAMS IN THEORY LIMIT IT TO ADULTS, BUT WE'RE WELL AWARE THAT OTHER PRODUCTS THAT IN THEORY ARE LIMITED TO ADULTS AREN'T ADOLESCENTS. IF I HAD TO PICK AN AREA FOR MY GREATEST CONCERN, IT WOULD BE ADOLESCENT EXPOSURE TO THESE SUBSTANCES. ADOLESCENT BRAIN IS UNDERGOING EXTRAORDINARILY ACTIVE PERIOD OF CHANGE, SO THAT'S WHERE WE ARE PUTTING A GREAT DEAL OF EFFORT. BUT I WILL SAY WE NEED STUDIES JUST LIKE YOU JUST DESCRIBED, TO LOOK AT HOW CANNABINOIDS CROSS INTO THE FETUS FOR FETAL DEVELOPMENT TO UNDERSTAND SOME OF THOSE FACTORS. WE'VE CERTAINLY BEEN SUPPORTING STUDIES THAT LOOK AT THE OUTCOMES OF MARIJUANA EXPOSURE AND NICOTINE EXPOSURE. NO PUBLIC HEALTH OFFICIAL WOULD RECOMMEND ELECTRONIC NICOTINE DELIVERY SYSTEMS, SO-CALLED E-CIGARETTES, FOR PREGNANT WOMEN AS AN ALTERNATIVE, THAT IN THAT CASE, ABSTINENCE AND SESSIZATION IS THE ONLCESSATIONIS THE ONLY RECOMMENDED APPROACH. SO WE HAVE TO FIGURE OUT HOW WE GET THESE PUBLIC HEALTH -- FOR POLICY AND LEGISLATION. DR. VOLKOW AND I AND A FEW OTHERS RECENTLY WROTE AN ARTICLE SUMMARIZED FOR PHYSICIANS THE HEALTH CONSEQUENCES OF MARIJUANA. I ENKUCIALG YOU TO TAKE A LOOK AT THAT, IT'S A BRIEF SUMMARY BUT IT HIGHLIGHTS THE MAJOR HEALTH CONSEQUENCES OF MARIJUANA. AND I'LL TAKE ONE MORE QUESTION BEFORE YOU WRAP UP. >> THANK YOU FOR YOUR WONDERFUL PRESENTATION. JEAN FROM MEDICAID OF SOUTH CAROLINA. I'M A BIRCWH SCHOLAR. LAST WEEK, I ASKED DR. SAMIENT AND -- MY QUESTION TO YOU IS, WE ARE PERFORMING INTERDISCIPLINARY RESEARCH, IT'S A TEAM SCIENCE, SO WHAT'S YOUR VIEW OF THE CENTRAL ROLE OF EPIDEMIOLOGY IN TRANSLATIONAL RESEARCH? SO EPIDEMIOLOGY HERE, I MEAN, NOT A PERSON WITH A FORMAL DEGREE BUT IN TEAM SCIENCE, ANY INVESTIGATORS CARRY ALL THE METHODOLOGY, THE APPROACH WE LEARNED FROM EPIDEMIOLOGY IN TRANSLATIONAL RESEARCH? >> THANK YOU FOR THAT QUESTION. I'M A CARD CARRYING EPIDEMIOLOGIST SO THIS IS APPROPRIATE FOR ME. [LAUGHTER] I THINK THERE ARE TWO PLACES THAT EPIDEMIOLOGY PLAYS -- I'LL SAY THREE PLACES WHERE EPIDEMIOLOGY PLAYS A ROLE. ONE IS WE ARE TYPICALLY THE GROUP THAT PROVIDES SORT OF OUR INITIAL IMPETUS FOR A MASSIVE UNDERTAKE IN TERMS OF SCIENTIFIC RESEARCH. SO THE DATA DOCUMENTING THAT WOMEN HAVE HIGH RATES IN OUR GENERAL POPULATION OF SUBSTANCE USE AND SUBSTANCE DISORDERS DESPITE LOWER RATES IN TREATMENT SEEING WAS AN IMPORTANT CLUE THAT WE SHOULDN'T IGNORE THE ISSUES OF ADDICTION RELATED TO SUBSTANCE. THAT'S JUST ONE EXAMPLE. THIS IS THE DIFFERENCE IN TERMS OF WHILE THERE MAY BE DIFFERENCES IN EXPOSURE, ONCE OFFERED DRUGS, THE RATES OF USE, THEN DEPENDENCE SEEMS TO BE EQUAL OR EVEN MORE RAPID PROGRESSION INTO ADDICTION FOR FEMALES THAN MALES. SO THESE ARE CLUES THAT COME FROM EPIDEMIOLOGY THAT I'M NOT GOING TO BE ABLE TO EAP ANSWER WITH PUBLIC HEALTH RESEARCH, SO I NEED TO TAKE THAT INTO THE LABORATORY TO IT LOOK AT IT ONE FACTOR AT A TIME. SO THAT'S THE THEORETICAL WAY THAT EPIDEMIOLOGY HELPS DRIVE OUR INTEREST IN SOME OF THESE PROGRAMS. THE SECOND AREA IS SOME OF THE METHODS WE USE IN TERMS OF STATISTICS AND MAKING SURE THAT WE HAVE ADEQUATE POWER APPLIED TO THE ISSUES AROUND REPRODUCIBILITY AND WE MAY BE ABLE TO HELP SOME OF THE BASIC SCIENCE LABS THAT ARE SUFFERING FROM LACK OF REPRODUCIBILITY OF FINDINGS. ALTHOUGH I WILL SAY EPIDEMIOLOGY IS NOTORIOUS FOR SPURIOUS INCORRECT FINDINGS WHEN IT COMES TO LABORATORY STUDIES, SO EPIDEMIOLOGY IS IS SORT OF YOUR FIRST CLUE, BUT WE WILL RARELY MAKE A CONCLUSIVE DETERMINISTIC ANSWER FROM ANY KIND OF EPIDEMIOLOGY. I THINK THOSE ARE SOME OF THE -- THE TWO WAYS I WOULD THINK ABOUT IT, BOTH IN TERMS OF METHODOLOGY AND DRIVING SOME OF THE ORIGINAL QUESTIONS FOR WHAT WE ADDRESS. THANK YOU OF VERY MUC VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> THAT WAS FANTASTIC. WE'RE GETTING A GREAT START HERE. I'M GOING TO BRING TO THE PODIUM DR. SHIRLEY, ASSOCIATE DIRECTOR, SHE OVERSEES THE SCOR PROGRAMS, I'M SURE THAT MANY OF YOU KNOW HER. DR. SHIRLEY? >> THANK YOU, WELCOME, EVERYONE. I HOPE YOU'VE BEEN HAVING A WONDERFUL MORNING THUS FAR WITH SOME GREAT STIMULATION FROM OUR PRESENTERS. IT IS WITH GREAT PLEASURE THAT I INTRODUCE DR. DAVID PAGE AS OUR NEXT KEYNOTE SPEAKER. DR. PAGE IS DIRECTOR OF THE WHITEHEAD INSTITUTE, PROFESSOR OF BIOLOGY AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY, AND AN INVESTIGATOR AT THE HOWARD HUGHES MEDICAL INSTITUTE. PLAWSH THOSE LABORATORY STUDIES THE FOUNDATIONS OF MAMMALIAN REPRODUCTION WITH PARTICULAR ATTENTION TO THE X AND Y CHROMOSOMES AND FERTILITY, AND THE FETAL ORIGINS OF SEX CELLS. HE HAS RECONSTRUCTED THE EVOLUTION OF TODAY'S X AND Y CHROMOSOMES FROM AN ANCESTRAL PAIR THAT EXISTED 300 MILLION YEARS AGO, AS WELL AS DISCOVERED MOLECULAR EVOLUTIONARY MECHANISMS BY WHICH THE WHY CHROMOSOME BECAME FUNCTIONALLY -- HE DISCOVERED AND CHARACTERIZED THE MOST COMMON GENETIC CAUSE OF -- FAILURE IN HUMANS. HE ALSO FOUND THAT APPARENT CROSSING OVER WITHIN THE X CHROMOSOME TALL ENDROME UNDERLIES A WIDE RANGE OF DISORDERS OF SEXUAL DIFFERENTIATION INCLUDING TURNER SYNDROME. MORE RECENTLY, HIS EXPANDED GENOMIC STUDIES OF Y CHROMOSOMES IN EIGHT MAMMALS VEALED THAT MALE-SPECIFIC Y CHROMOSOME GENES ARE ENRICHED FOR GLOBAL REGULATORS OF CELLULAR PROCESSES, WHICH HAS IMPORTANT IMPLICATIONS FOR UNDERSTANDING FUNDAMENTAL DIFFERENCES BETWEEN MALES AND FEMALES. DR. PAGE HAS A NUMBER OF HONORS THAT INCLUDE A McARTHUR PRIZE FELLOWSHIP, SCIENCE MAGAZINE'S TOP 10 SCIENTIFIC ADVANCES OF THE AWARD, AS WELL AS THE 2011 MARCH OF DIMES PRIZE IN DEVELOPMENTAL BIOLOGY. HE IS A MEMBER OF THE NATIONAL ACADEMY OF SCIENCES. THE INSTITUTE OF MEDICINE, AND THE NATIONAL ACADEMIES -- OF THE NATIONAL ACADEMIES AND THE AMERICAN ACADEMY OF ARTS AND SIGH INS. AND SCIENCES. PLEASE HELP US WELCOME DR. DAVID PAGE. [APPLAUSE] >> WELL, THANK YOU FOR THAT VERY KIND INTRODUCTION AND ALSO FOR THE INVITATION. THANK YOU VERY, VERY MUCH OF. BEFORE I BEGIN, I WOULD LIKE TO SAY WHAT A GREAT HONOR IT IS FOR ME TO ADDRESS YOU. I ACTUALLY HAVE BEEN THINKING A LOT ABOUT THIS TALK, INCLUDING DURING MUCH OF LAST NIGHT. SO I CAN'T EXPRESS MY ENTHUSIASM FOR THE WORK THAT EVERYONE HERE IN THE OFFICE OF RESEARCH ON WOMEN'S HEALTH IS DOING, I CAN'T ADEQUATELY EXPRESS MY ENTHUSIASM FOR THAT AND I CAN'T ADEQUATELY EXPRESS MY ENTHUSIASM FOR THE WORK BEING DONE BY EVERYONE IN THIS AUDITORIUM, SO AGAIN THANK YOU, I'M VERY HONORED TO HAVE THE CHANCE TO SPEAK WITH YOU THIS MORNING. WHY AM I SO ENTHUSIASTIC ABOUT THIS? I WOULD LIKE TO SAY -- I WOULD LIKE TO SUGGEST THAT THE OPPORTUNITIES BEFORE US TO UNDERSTAND WHO WE ARE AND WHERE WE CAME FROM AND HOW WE MIGHT IMPROVE HUMAN HEALTH, I THINK THOSE OPPORTUNITIES GO FAR BEYOND OUR GREATEST IMAGINATION. AND THAT'S WHY I FIND THIS TOPIC SO EXCITING. SO THEN LET ME TURN TO THIS QUESTION OF SEX DIFFERENCES IN HEALTH AND DISEASE, AND I'D LIKE TO POSE TO YOU THE QUESTION OF DO MALES AND FEMALES READ THEIR GENOMES DIFFERENTLY. AS MARY ELLA INDICATED, MUCH OF MY OWN WORK HAS BEEN IN THE CONTEXT OF UNDERSTANDING NOT ONLY THE GENETIC BASIS OF SEX DIFFERENCES BUT ACTUALLY HOW THOSE GENETIC DIFFERENCES UNDERLYING -- THOSE GENETIC DIFFERENCES UNDERLYING SEX DIFFERENCES, HOW THOSE EVOLVED. SO LET ME OPEN THEN WITH SOMETHING THAT'S QUOTED QUITE OFTEN, THAT IS THAT NOTHING IN BIOLOGY, AS WAS SAID ABOUT 40 YEARS AGO, NOTHING IN BIOLOGY MAKES SENSE EXCEPT IN THE LIGHT OF EVOLUTION. AND SO WITH THAT IN MIND, LET ME TOSS UP HERE TWO IMAGES TO WILLY RETURN. WHICH I WILL RETURN. WE ACTUALLY NEED TO EMBRACE A WIDELY COMPARATIVE VIEW IF WE ARE TO UNDERSTAND WHO WE ARE AND WHERE WE CAME FROM. SO I OFFER ON THE LEFT MY FAVORITE PAIR OF CHROMOSOMES, THE X AND THE Y, AND AS I'LL EXPLAIN IN JUST A FEW MINUTES, I PUT UP HERE TO THE RIGHT THE TURTLE, BUT HAS NEVER HEARD OF THE X AND THE Y CHROMOSOMES. SO IF WE'RE GOING TO THINK ABOUT THIS FROM AN EVOLUTIONARY POINT OF VIEW, THE LIGHTS ARE BRIGHT BUT I THINK I CAN SEE YOU, SO IF WE'RE GOING TO THINK ABOUT SEX AND DISEASE FROM AN EVOLUTIONARY POINT OF VIEW, THEN I'M GOING INTO THE CLASSROOM MODE NOW, WHICH CAME FIRST, SEX OR DISEASE? WELL, HOW OLD IS SEX? HOW OLD IS SEX? WELL, LET'S SEE. I DON'T SEE ANYBODY JUMPING TO THE MICROPHONES QUITE YET. OKAY, LET'S START WITH SOME EASIER QUESTION, THEN. HOW OLD IS THE UNIVERSE? DO I HEAR ANY GUESSES? I'M SORT OF HOPING THE FIRST ANSWER ISN'T SIX TO 7,000 YEARS. [LAUGHTER] I'LL RESPECT THAT ANSWER, BUT ANY THOUGHTS AS TO THE AGE OF THE UNIVERSE? JUST SHOUT IT OUT. 13 BILLION -- GREAT, BRAVE PERSON SHOUTS OUT. SO 13, 14 BILLION YEARS IS THE AGE OF THE UNIVERSE. OKAY. QUESTIONS GET EASIER NOW. HOW OLD IS OUR PLANET? 5 BILLION, GREAT. OKAY. 4 1/2, 5 BILLION IS THE AGE OF THE PLANET. SO P IF THAT'S HOW OLD OUR PLANET IS, THEN HOW OLD IS SEX? I'M GOING TO SUGGEST THAT IN THE EVOLUTION OF SEXUAL REPRODUCTION, THE EVOLUTION OF SEX, THERE WERE FOUR GREAT INNOVATIONS. THE FIRST OF THESE WAS THE ABILITY TO EXCHANGE HEREDITARY INFORMATION. THAT'S ACTUALLY WHAT SEX IS ALL ABOUT AT A MOST FUNDAMENTAL BIOLOGICAL LEVEL. AND I'M GOING TO CREDIT WITH TAKING SEX TO THIS LEVEL, I'M GOING TO CREDIT PROCARIOTES. DEVISED MEANS FOR EXCHANGING SOME GENETIC HEREDITARY INFORMATION. WELL, BUT IT TURNS OUT THAT IN PRO CARIOTES, THIS EXCHANGE OF GENETIC INFORMATION IS A FAIRLY FREEFORM UNINHIBITED ACTIVITY. ALL OF THAT CHANGED WITH THE APPEARANCE OF NUCLEATED CELLS AND NUCARIOTES, WHO PUT GENES IN PAIRS. NOW, WHY DO WE AND ALL OF OUR EUCARIOTIC BROTHERS AND SISTERS HAVE GENES IN PAIRS? WELL, OF COURSE, SO WE CAN TEACH MENDELIAN GENETICS. [LAUGHTER] VIRTUALLY ALL OTHER GENETICISTS WOULD BE OUT OF BUSINESS IF GENES DID NOT COME IN PAIRS. SERIOUSLY, GENES ARE IN PAIRS, SO THOSE PAIRS CAN BE TAKEN APART AT MEIOSIS IN THE MAKING OF EGGS AND SPERM AND PUT BACK TOGETHER AGAIN AT FERTILIZATION. THIS IS A VERY FANCY INSTITUTIONALIZED WAY OF EXCHANGING AND MIXING GENETIC INFORMATION. SO THIS BRINGS WITH IT ANALITY NATION OF DIPLOIT AND HAPPENLOID PHASES, I OFFER UP HERE AS A POSTER -- PERHAPS ONE THAT PROBABLY DOESN'T RECEIVE A LOT OF ATTENTION FROM THE OFFICE OF RESEARCH ON WOMEN'S HEALTH OR ACTUALLY MAYBE IT DOES BUT IN A DIFFERENT CONTEXT, THIS IS YEAST YEAST. OKAY, A LITTLE SUBTLETY THERE BUT -- OKAY, SO YEAST ACTUALLY THEY ARE A SINGLE CELLED EU CARE YOAT, THE GENE COMES IN PAIRS. IN FACT A LOT OF THEM -- THE ORGANISM IN WHICH MEIOSIS AND THE SEPARATION OF THE GENES INTO PAIRS IS MOST INTENSELY STUDIED IS, IN FACT, YEAST, AND IT ACTUALLY LOOKS LIKE MEIOSIS, THIS ELABORATE MECHANISM OF HAVING OUR CHROMOSOME NUMBERED, IT LOOKS LIKE THAT EVOLVED ONCE ACTUALLY IN THE BASAL EU CARE YOATS ON THE ORDER OF -- ON THE ORDER OF 1 TO 2 BILLION YEARS AGO. SO, IN FACT, AS WE PRACTICE SEXUAL REPRODUCTION THROUGH MEIOS SI. AND FERTILIZATION, THAT MECHANISM HAS BEEN IN PLACE FOR 1 1/2 TO 2 BILLION YEARS. BUT IT TURNS OUT THAT IN YEAST, THEY MAKE TWO KINDS OF GA MATES, IF YOU WILL, THEY'RE CALLED SPORES, THEY'RE CALLED A & ALPHA, AND THEY ARE STRUCTURALLY INDISTINGUISHABLE, SO A, AN ALPHA SPORES WHICH CONFUSE TO MAKE A LLOYD YEAST, YOU CAN'T TELL THEM APART, SO THE NEXT CONVENTION THAT GETS PILED ON TOP OF MEIOSIS IN THE EVOLUTION OF SEX EU REPRODUCTION, THE NEXT IS DIMORPHIC -- AND BY CONVENTION, WE CALL THE BIG GAMETE. THE EGG, AND WHOEVER MAKES THE BIG GAMETE IN THE SPECIES, WE CALL A FEMALE, WHOEVER MAKES THE LITTLE TB. AMETE, WHICH WE CALL SPERM, WE CALL THOSE MALES. THOSE ARE THE MOST GENERALLY -- DO YOU MAKE THE BIG ONE OR THE LITTLE ONE, IT LOOKS LIKE THIS HAS EVOLVED SEVERAL TIMES. SO MEIOSIS EVOLVED ONCE BUT DIMORPHIC EVOLVED SEVERAL TIMES. NOW, HERE I WOULD LIKE TO OFFER UP AS THE POSTER SPECIES FOR TAKING SEX TO THIS LEVEL, I WOULD LIKE TO OFFER UP THE TURTLE. NOW AGAIN, I HAVE THE DIAGRAM OF -- PHOTOUP TOP OF SOME BOX TURTLES. AND DOWN BELOW, IN THE MIDDLE OF THE STREEN AR SCREEN ARE ACTUALLY LINE DRAWINGS OF THE INERDS OF A MALE TURTLE, ON THE RIGHT, A FEMALE TURTLE. WE DON'T HAVE TO GO THROUGH THE DETAILS EXCEPT ALL -- THE POINT I'M MAKING IS THAT THE INTERNAL REPRODUCTIVE ANATOMIES OF A MALE AND A FEMALE TURTLE ARE EVERY BIT AS DIFFERENT AS ARE THE INTERNAL REPRODUCTIVE ANATOMIES OF A HUMAN MALE AND A HUMAN FEMALE. HOWEVER, THERE'S A BIG DIFFERENCE WHICH I REALLY WANT TO UNDERSCOR IN THIS TALK, THAT IS THESE TURTLES HAVE NO SEX CHROMOSOMES. THERE ARE NO GENETIC DIFFERENCES BETWEEN MALES AND FEMALES IN TURTLES. WHICH IS TO SAY THAT THE EXISTENCE OF TWO SEXES IN TURTLES IS PURELY EPIGENETIC. THERE ARE NO DNA SEQUENCED DIFFERENCES BETWEEN MALE AND FEMALE TURTLES. WHAT IT MEANS IS THAT TURTLES HAVE FIGURED OUT HOW TO READ THE SAME GENOME IN TWO DIFFERENT WAYS. I WANT TO YOU HAVE THIS SINK IN. IT IS A SPECTACULARLY IMPORTANT REALIZATION. OKAY. SO NOW LET'S GO BACK TO THE EVOLUTION OF SEX. SO TURTLES HAVE AUTOSOME, THEY DON'T HAVE SEX CHROMOSOMES. THEY IN FACT -- CAN DO YOU KNOW HOW SEX IS DETERMINED IN TURTLES? IT'S DETERMINED BY THE TEMPERATURE AT WHICH THE EGG INK BAITS. SO THIS IS COMMONLY CALLED ENVIRONMENTAL SEX DETERMINATION. OR TEMPERATURE-DEPENDENT SEX DETERMINATION. BUT WHAT I WANT TO DO FOR YOU, TO HELP YOU FLIP YOUR MINDS AROUND ABOUT THIS A LITTLE BIT, IS TO NOT DRAW ATTENTION TO THE TEMPERATURE DEPENDENCE, BUT TO DRAW ATTENTION TO WHAT IT'S NOT CAN DEPENDENT ON. THE DNA SEQUENCE. NOT GENETICALLY DETERMINED, IT'S NOT CHROMOSOMALLY DETERMINED, IT'S EP GENETICALLY DETERMINED. THERE ARE MALE AND FEMALE READ READINGS WILDLY DIFFERENT OF EXACTLY THE SAME GENOME. SO NOW LET'S RETURN TO -- SO THE TURTLE HAS TAKEN US TO THE POINT OF DIMORFHIC GAMETES, THEY MAKE EGG AND SPERM BOTH THROUGH THE PROCESS OF FERTILIZATION BUT THEY HAVEN'T GONE ON TO THE FOURTH INVENTION, WHICH IS SEX CHROMOSOMES. AND THESE, OF COURSE, CAN TAME THE FORM OF XXXY, WHEN THE MALE HAS TWO DIFFERENT SEX CHROME SOAPS. THAT'S TRUE IN US, IN MAMMALS, IN DROSOPHILA, WHERE IT CAN BE A ZZZZW SYSTEM. WE US -- AS IS TRUE IN BUTTERFLIES AND BIRDS, FOR INSTANCE. IT TURNS OUT THAT SEX CHROMOSOMES HAVCHROMOSOMEHAVE EVOLVED FROM TAU AUTOSOMES MANY, MANY TIMES ACROSS THE ANIMAL KINGDOM. IT TURNS OUT THAT OUR SEX CHROMOSOMES ARE THE OLDEST DOCUMENTED, ON THE ORDER OF 200 TO 300 MILLION YEARS OF AGE. BUT THE POINT I REALLY WANT TO MAKE HERE IS THAT THE SEX CHROMOSOMES IN THIS SORT OF EVOLUTIONARY CASCADE OF EVENTS, THE SEX CHROMOSOMES ARE A JOHNNY COME LATELY. THEY WERE ADDED ON TO AN ALREADY PERFECTLY FUNCTIONING SYSTEM OF MAKING MALES AND FEMALES, MAKING EGGS AND SPERM, DOING MEIOSIS. AND I ALSO WANT TO EMPHASIZE THAT THIS EVOLUTIONARY PERSPECTIVE WHICH PUTS THE SEX CHROMOSOMES ON THE BOTTOM AS A COMPLETE INVERSION OF THE WAY WE TEACH ALL STUDENTS HOW SEX WORKS, HOW SEX DETERMINATION WORKS IN MAMMALS. HOW DOES THE STORY ALWAYS BEGIN? IT ALWAYS BEGINS WITH CHROMOSOMAL SEX, WE WORK DOWN THROUGH -- AND ON TO PHENOTYPIC SEX AND SO ON. AND THE POINT I'M MAKING IS THAT THAT'S NOT THE WAY IT EVOLVES AT ALL. SO I THINK WE ACTUALLY -- AS MUCH AS I ADMIRE AND HAVE STUDIED AND DEVOTE MIGHT LIFE TO STUDYING THE SEX CHROMOSOMES, THEY ARE ACTUALLY A LATE EDITION TO A MUCH MORE FUNDAMENTAL SET OF INNOVATIONS. BUT TO MAKE IT MORE CLEAR TO YOU, LET'S THINK ABOUT WHERE DID THOSE SEX CHROMOSOMES ACTUALLY COME FROM? I'M GOING TO TAKE YOU BACK TO THE COMMON ANCESTOR -- OUR LAST COMMON ANCESTOR WITH BIRDS, LIVED ABOUT 310 MILLION YEARS AGO. SO LET'S SEE THE PROBLEM HERE. SO THIS ANCESTOR GAVE RISE TO MAMMALS AND BIRDS, AND IN MAMMAL, WE HAVE AN XY SEX CHROMOSOME SYSTEM, BUT IN BIRDS, WE HAVE A ZW SYSTEM. THIS CAUSES A REAL PROBLEM. HOW DID THIS COME FROM A COMMON ANCESTOR? WELL, WHAT WE'VE COME TO UNDERSTAND OVER THE LAST 15, 20 YEARS, IS THAT -- I SHOULD SAY IN SUBSTANCE, THE FEMALE SPECIFIC W IN BIRDS IS IN AN ABSTRACT SENSORY SIP CAL OF A MALE-SPECIFIC Y IN MAMMALS AND THE Z SHARED BETWEEN THE SEXES IN BIRDS IS IN SOME SENSE A RECIPROCAL OF THE X SHARED BETWEEN THE SEXES IN MAMMALS. BUT IT TURNS OUT THAT HOW THIS ALL CAME TO BE, SOMETHING THAT WE'VE BEEN ABLE TO RECONSTRUCTION OVER THE LAST 15, 20 YEARS, IS THAT THE X & Y, AND HERE I COULD FRAME IT AS THE HUMAN X AND Y, THEY EVOLVED FROM ORDINARY AUTOSOMES THAT EXISTED IN OUR AMNIODE ANS I ANCESTOR, AND ONE OF THE STRONGEST EVIDENCE IS THAT WE CAN STILL FIND THOSE SAME AUTOSOMES AS AUTOSOMES TODAY IN BIRDS. SO IN JUST A COUPLE OF YEARS, YOU WILL BE CARRYING AROUND WITH YOU IN YOUR POCKET THAT AUTOMATED DNA SEQUENCER, SO THAT WHEN YOU GO TO VISIT A CHICKEN FARM AND YOU'RE DOING SOME ON THE SPOT DNA SEQUENCING OF THAT CHICKEN AND YOU'LL DO THE SEQUENCE ALIGNMENT WITH YOUR OWN GENOME, WHAT YOU'RE GOING TO FIND IS THAT YOUR X CHROMOSOME ALIGNS PERFECTLY, IT ALIGNS REALLY, REALLY WELL WITH CHICKEN CHROMOSOMES 1 AND 4. DEAD RINGER. NO MISTAKING THIS. SO OKAY, WHERE DID THE CHICKEN ZMW? IT TURNS OUT IT CAME FROM OTHER CHROMOSOMES OF OUR COMMON ANCESTOR, AND THOSE REMAIN AUTO SOMES IN US. SO IN PARTICULAR, YOU'RE GOING TO FIND THAT YOUR CHROMOSOME 9 ALIGNS VERY NICELY WHEN YOU DO THE SEQUENCE ALIGNMENT WITH THE CHICKEN Z CHROMOSOME. SO WHAT WE HAVE ARE THESE BEAUTIFULLY RECIPROCAL EXPERIMENTS OF NATURE. LIKE THE RECIPROCITY OF THESE EXPERIMENTS SO WELL THAT I'M GOING TO FLIP BACK AND FORTH BETWEEN THEM, I LIKE TO LOOK AT THIS, SO IT'S -- THIS LITTLE RECIPROCITY I REALLY LIKE. THE BEAUTIFULLY RECIPROCAL EXPERIMENTS OF NATURE. SO THIS UNDERSCORS THE FACT THAT WE DIDN'T -- OUR ANCESTORS DIDN'T START OUT WITH THESE SEX CHROMOSOMES. WE ADDED THEM RELATIVELY RECENTLY. WELL, SO IT TURNS OUT THAT THE -- THEN THERE'S THE SAGA OF THE Y CHROMOSOME IN PARTICULAR. WHAT HAPPENED ALONG THE WAY, THE EVOLUTION OF THE X AND Y CHROMOSOMES. IN VERY RECENT YEARS, WE'VE BEEN ABLE TO RECONSTRUCT THIS EVOLUTION OF THE X AND Y FROM ORDINARY AUTO SOMES TO BE ABLE TO RECONSTRUCT THIS IN GREAT DETAIL. THROUGH COMPARATIVE GENOMICS. COMPARING OUR X AND Y CHROMOSOMES WITH THOSE OF OTHER ANIMALS. THE OTHER MAMMALS AND ACTUALLY THE CHICKEN. AND WHAT BECOMES CLEAR IS THAT THE ANCESTRAL AUTO SOMES THAT GAVE RISE TO OUR X AND Y CARRIED, PLUS OR MINUS, ABOUT 649 GENES. AND PERHAPS THE WOMEN IN THE AUDIENCE WILL NOT BE SURPRISED TO HEAR THAT THE X CHROMOSOME MANAGED TO NURTURE AND MAINTAIN AND HANG ON TO 638 OF THOSE 649 GENES. I DON'T WANT THE WOMEN TO START SNICKERING, BUT BY COMPARISON, THE Y CHROMOSOME LOST ALL BUT 17 OF THOSE GENES. [LAUGHTER] WHY DO YOU FIND THIS FUNNY? I DON'T KNOW. OKAY. SO OF THE 649 GENES THAT WERE ONCE SHARED BETWEEN AND IDENTICAL ON THE X AND Y CHROMOSOMES, ONLY 17 OF THEM SURVIVE TO THIS DAY ON THE HUMAN Y CHROMOSOME. AND ACTUALLY ALL 17 OF THOSE ALSO SURVIVE ON THE X. SO NOW WE HAVE THIS VERY INTERESTING SITUATION WHERE THERE'S 17 X, Y AND GENE PAIRS. FOR THE OFFICIONADOS IN THE AUDIENCE, I WANT TO SAY THOSE ARE NOT PSEUDOAUTOSOMAL. I'LL COME BACK TO THAT IF TIME PERMITS. SO LET ME TELL YOU A LITTLE MORE ABOUT WHAT DO I MEAN BY THESE X-Y PAIRS? I WILL CALL THESE SURVIVORS ON THE HUMAN SEX CHROMOSOMES. THESE 17 PAIRS. THEY SURVIVE NOT ONLY ON AS A GENE ON THE Y BUT AS A GENE ON THE X. AND THESE ARE NOT PSEUDOAUTOSOMAL, THEY'RE NOT RECOMBINING BETWEEN THE IM. AND THX ANDTHE Y, THEY'RE NOT ACTUALLY IDENTICAL BUT THEY'RE SIMILAR. SO I'M PICKING OUT ONE EXAMPLE OF THIS GENE PAIR CALLED KDM5C ON THE X, KDM5G ON THE Y, THEY DISPLAY 85% NUCLEOTIDE IDENTITY. AND THESE AGAIN ARE SURVIVORS FROM THAT SHARED AUTOSOMAL ANCESTRY ON THE X AND THE Y. THEY ENCODE PROTEINS 87% IDENTICAL AT THE AMINO ACID LEVEL. SO WOULD FACE A VERY INTERESTING SITUATION HERE WHERE THE X AND THE Y GENES, IT TURNS OUT THAT BOTH THE X GENE AND THE Y GENE IN THIS CASE ARE EXPRESSED QUITE WIDELY THROUGHOUT THE BODY. SO THE X AND Y GENES ARE BOTH EXPRESSED IN HUMAN TISSUES. WHAT THIS MEANS IS THAT THE X-X TISSUES, FEMALE TISSUES, EXPRESS THE X ISOFORM, THE X VERSION OF THIS PROTEIN EXCLUSIVELY, WHEREAS X-Y TISSUES EXPRESS BOTH THE X AND THE Y ISOFORMS. AND I WILL POINT OUT THAT FOR MOST OF THESE XY -- SURVIVING XY GENE PAIRS, THEY HAVE NO CHARACTERIZED NO KNOWN ROLE IN SEX DIFFERENTIATION AS CLASSICALLY DEFINED. SO HOW DID THIS ALL COME TO BE? LET'S COME BACK TO THINK ABOUT THIS IN MORE DETAIL. HERE'S THE STORY OF THE X AND Y CHROMOSOMES, WHICH AS I'M SAYING OUR X AND Y STARTED OUT 300 MILLION YEARS AGO, WHEN WE WERE REPTILES. WE EXISTED AS MALES AND FEMALES, WE HAD NO SEX CHROMOSOMES, WE HAD ONLY ORDINARY PAIRS OF CHROMOSOMES, BUT THEN THERE AROSE ON A PERFECTLY ORDINARY UNSUSPECTED PAIR OF AUTO SOMES A MEU TAKE THAT WOULD GIVMUTATION TO WHAT LI VES AS THE SEX DETERMINING GENE ON THE Y CHROMOSOME, AND WHAT THEN HAPPENED WAS FIRST IN THE IMMEDIATE VICINITY OF SRY, THEN OVER IN AN ENLARGING AREA, IT TURNED OUT THAT THE -- THAT CROSSING OVER, THE EXCHANGE OF GENETIC INFORMATION BETWEEN THE X AND THE Y BECAME RESTRICTED, SO THIS SHUTTING DOWN OF EXCHANGE WITH THE X CHROMOSOME EVENTUALLY LED TO THE ACCUMULATION OF DELETERIOUS MUTATIONS AND SOMETIMES OUT RIGHT DELETION AND SO WITHIN THE REGION OF XY CROSSING OVER, Y BEGAN TO SHRINK, THE X RETAINED ITS ORIGINAL SIZE, AND SO THE Y LOST A LOT OF GENES ALONG THE WAY, THIS IS OUR UNDERSTANDING OF HOW THE Y CAME TO HAVE SO FEW SURVIVORS, AND OF COURSE IF TRUTH BE KNOWN, I'VE SPENT THE BETTER PART OF MY CAREER DEFENDING THE HONOR OF THE Y CHROMOSOME IN THE FACE OF SOME INSULTS TO ITS CHARACTER AND ITS FUTURE PROSPECTS. OF COURSE SOME HAVE EXTRAPOLATED SOME -- SOME OF MY COLLEAGUES HAVE EXTRAPOLATED THIS OUT TO 10 MILLION YEARS IN THE FUTURE PREDICTED THE DISAPPEARANCE OF THE Y CHROMOSOME ALL TOGETHER, BUT I'D LIKE TO PRESENT YOU WITH A DIFFERENT VISION OF THIS VOYAGE OF THE Y CHROMOSOME. WHEN I THINK ABOUT THIS VOYAGE OF THE Y CHROMOSOME ACROSS TIME, I'M REMINDED OF THE OFT RETOLD TRIP FIRST AND ONLY TRIP OF THE TITANIC. NOW, WHEN YOU LOOK AT THIS IMAGE, YOUR EYE IS FIRST DRAWN TO THE SINKING SHIP. BUT AS A STUDENT OF THE Y CHROMOSOME, AND THOSE 17 SURVIVORS, MY EYE IS DRAWN TO THESE LIFE BOATS IN THE FOREGROUND. AND SO I DON'T KNOW WHY YOU'RE LAUGHING. AND SO WE HAVE SET OUT SOME YEARS BACK ACTUALLY WITH SUPPORT FROM NIH TO RECONSTRUCT THE -- RECONSTRUCT THE VOYAGE OF THE X AND Y CHROMOSOMES FROM ANCESTRAL AUTO SOMES IN SOME DETAIL. SO WE HAVE IN RECENT YEARS BEEN WORKING AND WE'VE HAD SOME BIG PROGRESS IN THE LAST FEW YEARS, WE'VE BEEN RECONSTRUCTING THE EVOLUTION OF THE SEX CHROMOSOMES BY STUDYING NINE SPECIES. I TALKED WITH FRANCIS EARLIER THIS MORNING, I THOUGHT THIS WOULD BE AN APPROPRIATE SETTING IN WHICH TO ACKNOWLEDGE THE IDENTITY OF THE INDIVIDUAL WHOSE Y CHROMOSOME WE SEQUENCED SOME YEARS BACK UNTIL THIS MORNING WE HAVE NOT PROPERLY DEALT WITH THE ISSUES OF INFORMED CONSENT, BUT THAT'S NOW BEEN RESOLVED, I'M HAPPY TO SAY. SO IN ALL SERIOUSNESS, WE'VE COMPARED -- WHAT I WANT TO TELL YOU ABOUT -- VERY QUICKLY TELL YOU ABOUT WHAT'S ARISEN FROM COMPARING FRANCIS' Y WITH THAT OF THE CHIMPANZEE, THE RESEES MONKEY, AND FOR GOOD MEASURE WE ADD THE MOUSE, THE RAT, AND THE BULL, SOME OF OUR COLLABORATORS ARE FROM TEXT TAS. TEXAS. [LAUGHTER] AS A BIT OF AN OUTGROWTH TO THE PLACENTAL MAMMALS, I OFFER UP HERE THE SOUTH AMERICAN OWE POSSUM, THIS IS A MAR SUPERVISORIAL. THEN AS THE BIG OUTLIER, WE REALLY NEED A BIRD. SO I ADD THE CHICKEN. AND SO JUST TO REMINE YOU, ALL OF THESE HAVE XXXY SEX DETERMINING CHROMOSOMES. AND THE CHICKEN DOWN HERE, OF COURSE, IS A ZW, BUT THERE'S ACTUALLY A PROBLEM WITH THIS IMAGE. WHAT IS IT? DOWN THERE, THAT CHICKEN REALLY OUGHT TO -- THE ZW, IT ACTUALLY OUGHT TO BE NOT A ROOSTER, BUT A HEN. SO LET'S CORRECT THAT. OKAY. THERE WE GO. WE'RE ALWAYS TEACHING, YOU SEE. SO WHAT I WANT TO TELL YOU ABOUT IS JUST TO GIVE YOU A VERY QUICK UPDATE AS OF 2014, THE SEQUENCING OF THE XY PAIRED GENES FROM THESE EIGHT MAMMALIAN SPECIES IN A COMPARISON OUT TO THE CHICKENS. THAT SEQUENCING HAS NOW REVEALED ACROSS THESE EIGHT MAMMALIAN SPECIES A TOTAL, WE FIND IT OF ALL THE GENES THAT WERE ON THE ANCESTRAL AUTO SOAMS, THERE ARE A TOTAL OF 36 GENES THAT SURVIVE TODAY ON THE Y CHROMOSOME OF ONE OR MORE OF THESE EIGHT THE SPECIES. SO THESE INCLUDE 18 XY PAIR GENES THAT WE HAD PREVIOUSLY IDENTIFIED IN HUMAN CHIMP AND RHESUS, IT ADDS 18 NEWLY IDENTIFIED XY PAIRS FOR A TOTAL OF 36, AND THIS ENABLES A DEEP RECONSTRUCTION OF THIS VOYAGE OF THE TITANIC, IF YOU WILL. SO I'VE GOT THE SPECIES UP TOP HERE, THESE ARE ACTUALLY A LIST OF ALL THE SURVIVORRING ANCESTRAL GENES FOUND IN THOSE SPECIES. IF YOU HAVE A CHANCE TO STARE AT THIS, I WILL POSE THE QUESTION OF WHICH SPECIES HAS THE FEWEST SURVIVING X-Y PAIR GENES. THAT ACTUALLY IS OF SOME RELEVANCE TO OUR CONSIDERATION OF MODEL SYSTEMS. IT TURNS OUT IT IS THE MOUSE, WITH NINE SUCH SURVIVING GENES. WE HAVE 17. AND I WON'T GO INTO THE DETAILS OF IT, BUT THIS ACTUALLY RAISES SOME INTERESTING CHALLENGES AND OPPORTUNITIES WITH RESPECT TO OUR USE OF RODENTS AS MODELS IN THIS CONTEXT. SO BUT NOW LET ME LEAP TO SOME OTHER ASPECTS OF HOW THIS ALL PLAYED OUT. SO WERE THE GENES THAT SURVIVED IN THE Y, THOSE THAT MADE IT ON TO THE LIFE REST, WERE THEY LUCKY? OR DID THEY HAVE SPECIAL QUALITIES THAT FAVORED THEIR SURVIVAL, AND WHAT ARE THE IMPLICATIONS FOR SEX DIFFERENCES BEYOND THE REPRODUCTIVE TRACT? I WON'T GO INTO ALL THE DETAILS BUT LET ME SAY THAT ONE OF THE THINGS THAT'S REALLY STRUCK US IS THAT MOST OF THESE SURVIVING GENES, NOT JUST ON THE HUMAN WIDE BUT ON THESE OTHER SPECIES WHOSE SEX CHROMOSOMES WE'VE STUDIED, MOST OF THESE SURVIVING PAIRED GENES ENCODE GENOME WIDE REGULATORS OF GENE EXPRESSION. THESE ARE POWERFUL MODULATORS OF THE GENOME. OR IF I'D FLIM FLIP IT AROUND INTO THE LANGUAGE IEMED IEM USING FOR THIS LECTURE, I WOULD SAY THAT MOST OF THESE X-Y PAIR GENES, AND I'LL JUST CHANGE THE TITLE UP HERE, MOST OF THESE X-Y PAIR GENES ENCODE GENOME READERS. SO I TOLD YOU ALREADY THAT WE EVOLVED FROM SPECIES THAT KNEW HOW TO READ THE GENOME DIFFERENTLY IN MALES AND FEMALES, AND WHAT DID WE DO? OUR ANCESTORS PILED ON TOP OF THAT GENETIC DIFFERENCES THAT ARE FOCUSED ON GENOME READERS. SO GUESS WHAT, WE REALLY KNOW HOW TO READ OUR GENOMES DIFFERENTLY IN MALES AND FEMALES. SO LET ME SORT OF TIE THIS TOGETHER BY SAYING THAT WE HAVE OLD AND NEW UNDERSTANDINGS OF THE HUMAN X AND Y. WHY IS IT THAT UNTIL RECENTLY, WE COULD ESSENTIALLY IGNORE THE X AND Y CHROMOSOMES? I WANT TO SORT OF FRAME THIS IN ANSWERING THE QUESTION, WHY UNTIL RECENTLY COULD WE IGNORE THE X AND Y CHROMOSOMES IN THINKING ABOUT SEX DIFFERENCES BEYOND THE REPRODUCTIVE TRACT? WELL, IT WASN'T THAT MANY DECADES AGO THAT WE THOUGHT THAT THE Y CARRIED ONE GENE, ONE SEX DETERMINING GENE. WHAT WE NOW KNOW IS THAT THE HUMAN Y CARRIES ABOUT 76 PROTEIN CODING GENES THAT ENCODE 27 DISTINCT PROTEINS OR FAMILIES OF PROTEINS. OUR UNDERSTANDING IS A WHY FUNCTION WAS EXPRESSED, GENES WERE ACTIVE AND IT WAS FUNCTIONING ONLY IN THE GONAD. IT TURNS OUT OF THE 17 SURVIVING GENES ON THE Y CHROMOSOME, 12 OF THEM ARE EXPRESSED WIDELY IN MOST TISSUES OF THE BODY. BUT YET PLAYED NO IDENTIFIED OR CHARACTERIZED ROLE IN SEX DIFFERENTIATION. AND THESE WIDELY EXPRESSED Y GENES ENCODE GENOME READERS. THEN IN THE CASE OF THE X, IT WAS UNTIL THE LAST FEW DECADES OUR UNDERSTANDING THAT THE SECOND X CHROMOSOME IS TRANSCRIPTIONALLY SILENT, IS INACTIVATED. DOING NOTHING. BUT WHAT WE NOW KNOW IS THAT HUNDREDS OF GENES ARE ACTUALLY TRATRANSCRIBED FROM THAT SECOND, THAT INACTIVE X IS VERY ACTIVEMENT AND IT TURNS OUT THAT AMONG THESE GENES, THAT ESCAPE X INACTIVATION, AMONG THESE GENES ARE THE COUNTERPARTS OF THE Y ENCODED GENOME READERS. SO THESE GENOME READERS ARE EXPRESSED IN TWO ACTIVE COPIES IN X-X CELLS AND TWO ACTIVE COPIES IN X-Y CELLS. AND FINALLY, IT WAS OUR UNDERSTANDING AS A RESULT OF ALL THE PREVIOUS UNDERSTANDINGS THAT IT WAS OUR PRIOR UNDERSTANDING THAT OUTSIDE THE GONADS, X-X AND X-Y CELLS ARE FUNCTIONALLY OR MORALLY EQUIVALENT. BUT WE NOW UNDERSTAND THAT THROUGHOUT THTHROUGHOUT BODY, X-X AND X-WH Y ARE NOT THE SAME. SO JUST TO DEPICT THIS GRAPHICALLY, I WOULD LIKE TO SAY THAT UNTIL VERY RECENTLY, WE OPERATED UNDER THE MODEL THAT WHETHER YOU WERE CHROMOSOMALLY X-Y OR X-X MATTERED ONLY IN THE NETHER REGIONS. BUT I BELIEVE THAT WE ARE IN THE PROCESS NOW OF REPLACING THIS UNDERSTANDING WITH THIS ONE. NOURISH THAT ACTUALLY THROUGHOUT OUR BODIES, OUR CELLS AND TISSUES AT SOME LEVEL KNOW AND UNDERSTAND WHETHER THEY ARE X-X OR X-Y, AND THAT THERE MAY WELL, IN FACT, BE FUNDAMENTAL MOLECULAR AND BIOCHEMICAL DIFFERENCES BETWEEN X-X AND X-Y CELLS IN TISSUES BEFORE THOSE CELLS AND TISSUES ARE EVER EXPOSED TO CIRCULATING SEX HORMONES. HOW ARE WE DOING TIME WISE HERE? SO LET ME SAY THOUGH I'VE PRESENTED TO YOU AN EMERGING UNDERSTANDING FROM -- THE UNDERSTANDING THAT'S EMERGING FROM THE STUDY OF THE SEX CHROMOSOMES, BUT LET ME TELL YOU THAT WE ACTUALLY HAVE A VERY SERIOUS PROBLEM IN THE VERY EXCITINGLY EXPLOSIVE FIELD OF HUMAN MOLECULAR GENETICS. AND SO LET ME SORT OF BRING THIS BACK HOME BY SAYING THAT TO QUOTE I KNOW WE'RE IN THE IMMEDIATE WAKE OF AN ELECTION AND SO I'LL TRY TO BE A NON-PARTISAN HERE, I'LL JUST QUOTE FROM BILL CLINTON'S 2000 STATE OF THE UNION ADDRESS WHICH VERY NEAR THE END CLOSED WITH THIS STATEMENT. THIS FALL AT THE WHITE HOUSE WE HAVE THIS VERY DISTINGUISHED SCIENTIST, AND HE SAID THAT WE'RE ALL REGARDLESS OF RACE GENETICALLY 99.9% THE SAME. WELL, THE PROBLEM WITH THIS STATEMENT, WELL, IT TURNS OUT THIS STATEMENT IS TRUE, AS LONG AS THE TWO INDIVIDUALS YOU'RE COMPARING ARE BOTH MALE. IT'S ALSO TRUE IF THE TWO INDIVIDUALS YOU COMPARE ARE BOTH FEMALES. HOWEVER, IF YOU'RE COMPARING A MALE AND A FEMALE BECAUSE OF THE X-X, X-Y DIFFERENCE, IT'S ACTUALLY ONLY 98.5%, WHICH IS TO SAY THAT THE GENETIC DIFFERENCE BETWEEN A MALE AND A FEMALE IS 15 TIMES THAT BETWEEN TWO RANDOMLY SELECTED MALES OND TWO RANDOMLY SELECTED FEMALES. SO I LIKE TO MAKE THIS -- LET'S CONSIDER THE CASE THEN OF BILL AND HILLARY. WHO ARE, IN FACT, 98.5% IDENTICAL IN THEIR DNA SEQUENCES, BUT WHAT THIS MEANS IS BILL IS AS SIMILAR IN HIS DNA SEQUENCE IN HILLLY AS H HILLARY AS HE IS T O A MALE CHIMP. I DON'T KNOW WHY YOU'RE LAUGHING. I'M JUST POINTING OUT SOME BASIC UNDERLYING REALITIES. BUT DID -- AND WHAT IS THE DIFFERENCE? OF COURSE THE DIFFERENCE IS THE X AND THE Y CHROMOSOMES. BUT IT'S NOT JUST IN THE STATE OF THE UNION, BUT IN FACT IN TODAY'S PRACTICE OF HUMAN MOLECULAR GENETICS, WE HAVE A SERIOUS PROBLEM. IT TURNS OUT THAT NOT ONLY HAVE THERE BEEN -- IT'S BEEN A LOT OF DISCUSSION THE POSSIBILITY THE Y CHROMOSOME IS GOING TO DISAPPEAR, I WOULD LIKE TO SUGGEST, AND I'VE RAISED THIS WITH FRANCIS A FEW TIMES, THAT IT TURNS OUT THAT IN THE CURRENT -- IN THE RECENT ERA OF GENOME-WIDE ASSOCIATION STUDIES, IT HAS TAKEN ONLY SIX OR SEVEN YEARS OF GENOME WIDE ASSOCIATION STUDIES TO MAKE THE X CHROMOSOME DISAPPEAR. YOU MAY NOT BE AWARE OF THIS, SO LET ME SHOW YOU. TURNS OUT THAT A COMPENDIUM OF INHERITED TRAIX, THE X CHROMOSOME REALLY MATTER, SO HERE WE HAVE -- IT TURNS OUT THAT TRAITS -- WHOSE MOLECULAR BASIS IS KNOWN CONSTITUTES 6.7% OF ALL TRAITS, SUCH TRAITS CROSS THE BODY, WHERE WE DON'T KNOW THE MOLECULAR BASIS, THEY CONSTITUTE ABOUT 8%. BUT IT TURNS OUT THAT IF WE NOW GO, OH, SO I SHOULD SAY BUT IN THE WORLD OF GENOME WIDE ASSOCIATION STUDIES AS THEY'VE UNFOLDED OVER THE LAST SIX OR EIGHT YEARS, IT TURNS OUT IT'S QUITE A DIFFERENT PICTURE. THIS IS ACTUALLY A GRAPHIC PREPARED BY NHGRI PROVIDING EACH DOT IS A STATISTICALLY SIGNIFICANT GWAS HIT FOR ANY ONE OF 744 TRAITS THAT HAVE BEEN STUDIED THIS WAY. IT TURNS OUT THAT IF WE LOOK OVER HERE, FIRST AS YOU CAN SEE, THE Y CHROMOSOME HAS NO HITS. NOW IS THIS BECAUSE THE Y DOESN'T MATTER? IT'S ACTUALLY BECAUSE THE Y CHROMOSOME HAS GENERALLY THE NOT BEEN INCLUDED IN GENOME-WIDE ASSOCIATION STUDIES. BUT ALSO IT TURNS OUT THE X CHROMOSOME, WHICH I SAID IN OMAM, HAS ABOUT 7% OF -- IS RESPONSIBLE FOR ABOUT 7% OF THE CARGO. IN SIGNIFICANTLY SAYS STA TIS TICK -- THE -- PUBLISHED ASSOCIATIONS. IS THIS BECAUSE THE X CHROMOSOME IS BIOLOGICALLY INSIGNIFICANT? NO. IT TURNS OUT THE X CHROMOSOME HAS BEEN SYSTEMATICALLY EXCLUDED BY THE FIELD FROM GWAS STUDIES. IT IS BECAUSE IT IS CONSIDERED A TECHNICAL INCONVENIENCE. AND I'M NOT MAKING THIS UP. IT IS CONSIDERED CAN -- I'VE HAD VARIOUS PEOPLE SAY THE PROBLEM IS, THE X CHROMOSOME DOESN'T HAVE A NUMBER. SO COULD YOU CALL IT CHROMOSOME 23? WE TRIED THAT. THEN WE CALLED THE Y24. IT'S A COMPUTER CODING PROBLEM. SO IN THIS DAY OF HIGH THROUGHPUT STUDY STUDIES -- -- I'M NOT MAKING THIS UP. I KNOW IT SOUNDS UNBELIEVABLE BUT I AM NOT MAKING THIS UP. IN THIS DAY OF HIGH THROUGHPUT KEEP THE COST AS LOW AS POSSIBLE STUDY, THE X AND THE Y CHROMOSOMES ARE CONSIDERED TECHNICAL INCONVENIENCES. AND THAT'S WHAT'S RESPONSIBLE FOR THIS. SO IN FACT, I THINK INSTEAD OF CALLING THESE GENOME WIDE ASSOCIATION STUDY, I WOULD LIKE TO PROPOSE THAT WE CALL THESE NEUTEROME WIDE ASSOCIATION STUDIES. SO IN CLOSING, LET ME TAKE YOU BACK TO THIS IDEA THAT MALES AND FEMALES READ THEIR GENOMES DIFFERENTLY. FOR TWO REASONS. FIRST, WE HAVE EVOLVED FROM SPECIES, TURTLE BEING AN EXAMPLE, WE HAVE EVOLVED FROM SPECIES THAT OVER HUNDREDS AND HUNDREDS OF MILLIONS OF YEARS FIGURED OUT HOW TO HAVE TWO DIFFERENT READINGS OF THE SAME GENOME. YOU HAVE TO LET THAT SINK IN. IT'S A BIG, BIG IDEA. AND THENL WE ADDED TO THAT SOME DIFFERENCES IN OUR GENOME THAT ARE PARTICULARLY SPECIALIZED IN THE BUSINESS OF GENOME READINGS. SO I WOULD LIKE TO SAY THAT WE HAVE -- UNLESS AND UNTIL WE ARRIVE AT AN APPRECIATION AND UNDERSTANDING OF HOW MALE AND FEMALE GENOMES DIFFER, AND OF HOW MALES AND FEMALES READ THEIR GENOMES DIFFERENTLY, WE WILL BE CONSTANTLY SURPRISED AGAIN AND AGAIN AND AGAIN EVERY TIME WE ENCOUNTER A DIFFERENCE BETWEEN MALES AND FEMALES IN THEIR RESPONSE TO A SPECIFIC THERAPY. AND I WOULD SUGGEST THAT THERE IS BEFORE US AN ENORMOUS OPPORTUNITY TO UNDERSTAND WHO WE ARE, WHERE WE COME FROM, AND HOW WE CAN THEREBY CONTRIBUTE TO THE COMMON GOOD. THANK YOU. [APPLAUSE] I'D BE HAPPY TO TAKE ONE OR TWO QUESTIONS. QUESTIONS. BE BRAVE. >> GREAT TALK. THANK YOU VERY MUCH. SO IN THE FIELD OF MICROBIOLOGY, IS THERE A REASON TO BE STUDYING SEX IN THE ORGANISMS OR ONLY AS IT RELATES TO HOST ORGANISM IMMUNE RESPONSE? >> GREAT QUESTION. SO IN MICROBIOLOGY, TO THINK ABOUT, WELL, IN MICROBIOLOGY, OF COURSE, WE'VE GOT -- WE'RE STUDYING A WHOLE RANGE OF ORGANISMS FROM VIRUSES TO PRO CARE YOATS TO EU CARE YOATS, AND CLEARLY -- I THINK ONE OF THE THINGS THAT WE HAVE TO THINK ABOUT A LOT OF COURSE IN MICROBIOLOGY IS -- WE DO THINK IN TERMS OF EXCHANGE OF HEREDITARY INFORMATION INCREDIBLY, LET'S THINK ABOUT DRUG RESISTANCE, AS A RESULT OF HORIZONTAL GENE TRANSFER AND SO ON, BUT I THINK YOU'RE ABSOLUTELY RIGHT THAT WE -- AS WE NOW THINK ABOUT THE MICROBIOME, CLEARLY THE INTERACTION OF MICRO BUY OWN, THE INTERACTION OF PATHOGEN WITH HOST, HAS GOT TO BE SEEN THROUGH A LENS OF SEXUAL DYMORPHISM IN HUMANS, IN MODEL ORGANISMS AND SO ON, SO ABSOLUTELY. THANK YOU. ANOTHER QUESTION. >> MILLER MA MAYO CLINIC. I WILL BE BRAVE AND WOULD LIKE A BOLD RESPONSE FROM YOU, THAT IS THE OVERRELIANCE OF THE RESEARCH COMMUNITY CURRENTLY ON MICE AS THE ONLY EXPERIMENTAL MODEL TO LOOK AT MODELS OF DISEASE MAY NOT BE APPROPRIATE. AS SOMEONE WHO SPENT PART OF MY CAREER LOOKING AT PIGS AND DOGS AND RABBITS AND ALLIGATORS AND A VARIETY OF ANIMALS BASED ON THE QUESTION I WAS ASKING, I WOULD LIKE FOR YOU TO COMMENT ON HOW THAT RELIANCE ON ONE SINGLE ANIMAL SPECIES FOR ACALL RIGHT OFOR A LOT OF OURPRECLINICAL WORK MAY ACTU ALLY BE SLOWING PROGRESS. >> THAT'S A GREAT QUESTION. I THINK I INVITED THAT QUESTION BY -- WITH ONE LINE ON ONE SLIDE. >> YOU IT DID. >> THANK YOU. RIGHT. SO -- AND I SHOULD SAY TO COME CLEAN HERE, A BIG PART OF MY LABORATORY STUDIES MICE. THE I MEAN, MICE HAVE ENORMOUS ADVANTAGES AS GENETICALLY MANIPULATABLE ORGANISM, BUT I HAVE BEEN, TO BE HONEST, FOR DECADES HAVE A GROWING UNDERSTANDING OF HOW WITH REGARD TO THE SEX CHROMOSOMES, AND I'LL JUST KEEP IT IN THAT NARROW FOCUS, AS I POINT OUT, WITH REGARD TO THE SEX CHROMOSOMES, THE BIOLOGY OF THE SEX CHROMOSOMES IN MICE AND HUMANS IS VERY DIFFERENT. POINT OUT JUST ONE EXAMPLE. WE MENTIONED, MARY ELLEN IN THE INTRODUCTION MENTIONED TURNER SYNDROME. SO X-O -- SO IT IN HUMAN, THE X-O CONDITION IS ACTUALLY LETHAL. WE TALK ABOUT TURNER SYNDROME, 90% OF EX-OWE FETUSES IN HUMANS ABORT SPONTANEOUSLY. IN MICE, THE X-O CONDITION IS FULLY VIABLE, IS IN FACT COMPATIBLE WITH FEMALE FERTILITY. TREMENDOUS DIFFERENCES IN THE DEGREE OF ESCAPE FROM X -- ACTIVATION BETWEEN MICE AND HUMAN. SO THERE ARE TREMENDOUS DIFFERENCES IN THE SEX CHROMOSOMES BETWEEN HUMANS AND MICE, AS MUCH AS I WOULD NOT LIKE THAT TO BE THE CASE, SO WE HAVE TO THINK ABOUT OTHER MODEL ORGANISMS. I WILL ACTUALLY POINT OUT THAT WHEN WE SEQUENCED THE RHESUS Y CHROMOSOME AND REPORTED THAT A COUPLE OF YEARS AGO, WE WERE STRUCK BY THE FACT THAT ACTUALLY THE RHESUS Y CARRIES ALMOST EXACTLY THE SAME IS TH SET OF GENES AS IS PRESENT ON THE HUMAN Y CHROMOSOME. SO WHETHER WE WILL FOLLOW THE LEADS SUGGESTED BY THIS SORT OF WORK, I DO NOT KNOW, BUT I DO BELIEVE WE HAVE TO BE FULLY AWARE OF THE LIMITATIONS OF THE MODEL ORGANISMS AND IN FACT EVOLUTION IS SHOUTING OUT AT US THE DIFFERENCES. I THINK ACTUALLY THE SEX DIFFERENCES ARE GOING TO BE SUSCEPTIBLE TO INCREDIBLE -- WILL HAVE BEEN SUSCEPTIBLE TO INCREDIBLY STRONG EVOLUTIONARY PRESSURES OVER TIME. SO I BELIEVE THAT IN SOME SENSE, WHAT WE SHOULD LOOK FOR IN THE MODEL ORGANISMS ARE BROAD LESSONS. NOT NECESSARILY SPECIFIC 1 TO 2 CORRESPONDENCE WITH MOLECULES OR CORRESPONDING PHENOTYPES IN HUMANS. I THINK WE'LL SEE BROAD PARALLELS BUT I BELIEVE THAT WE WILL OFTEN FIND THINGS BREAKING DOWN IN DETAIL, WHICH MEANS WE'RE GOING TO HAVE TO DO A LOT OF HUMAN BIOLOGY AND A LOT OF PRIMATE BIOLOGY BUT A LOT OF HUMAN BIOLOGY IN ADDITION. >> PAULINE MACKEY, USC. THANK YOU FOR AN EXCELLENT PRESENTATION. CAN YOU EDUCATE US ON THE HE EXTENT TO WHICH THESE GENOME READERS ON THE SEX CHROMOSOMES ARE SPECIAL CASES OF WHAT ONE FINDS IN AUTOSOMES AND WHETHER OR NOT THERE'S CROSSTALK BETWEEN THEM? >> OKAY, GREAT QUESTION. SO YES, THE GENOME READERS THAT WE SEE ON THE X AND Y CHROMOSOMES THAT EXIST AS ISOFORMS ENCODED BY THE X AND THE Y, THESE ARE MEMBERS OF FAMILIES AND COMPLEXES, MOST OF WHOSE MEMBERS ARE ENCODED ON AUTOSOMES. OKAY? SO WHAT I'M SAYING, WE'RE JUST GOING TO HAVE A LITTLE BIT OF X AND Y FLAVORING OF MACHINERY, OF GENOME READING MACHINERY THAT IS LARGELY ENCODED BY THE AUTOSOMES. BUT WHAT I'M ESSENTIALLY RAISING IS THE POSSIBILITY THAT THIS X AND Y FLAVORING MIGHT, WHEN AGGREGATED ACROSS THE EXPANSE OF A LIFETIME, HAVE SERIOUS CONSEQUENCE WITH REGARD TO THE INCIDENCE AND SEVERITY OF A WHOLE RANGE OF DISEASES, MANY OF WHICH YOU AND THIS AUDIENCE ARE STUDYING. AND SO WE ACTUALLY HAVE TO EXPLORE THE POSSIBILITY THAT THE -- IT MAY BE THAT THE X AND Y ISOFORMS ARE AS PROTEINS SLIGHTLY FUNCTIONALLY DISTINCT OR IT MIGHT BE THAT THE X AND THE Y GENES HAVE DIFFERENT PATTERNS OF EXPRESSION. OKAY? SO WE'VE GOT TO THINK ABOUT THIS IS A VERY NEW PROPOSITION TO THINK ABOUT THESE X AND Y ISOFORMS, AND ACTUALLY TRUTH BE KNOWN, SOME OF THESE X-Y PAIRS WE HAD DISCOVERED SOME YEARS AGO. WE DIDN'T UNDERSTAND VERY MUCH ABOUT THEM. BUT IN THE ENSUING -- IN THE LAST DECADE, BIOCHEMISTS AND CELL BIOLOGISTS HAVE DONE INCREDIBLE AMOUNTS OF FUNDAMENTAL RESEARCH, IN MOST CASES ON THE X ISOFORMS AND SHOWN THEM TO BE, FOR INSTANCE, IF ANY OF YOU ARE STUDENTS OF THE HISTONE CODE AND CHROMATIN MODIFIERS, IT TURNS OUT THAT THE HISTONE H3K4 DEMETH LASE IS ENCODED AS X AND Y ISOFORMS. THE H3K27 DEMETHLACE IS ENCODED AS X AND Y ISOFORMS. TRANSLATION INITIATION FACTORS THAT ARE REQUIRED FOR THE PRODUCTION OF ALL PROTEINS, ALL PROTEINS AND ALL CELL TYPES ARE ENCODED AS X AND Y ISOFORMS. SO WHEN I SAY THESE ARE POWERFUL GENOME READERS, I MEAN POWERFUL GENOME-WIDE READERS. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, DR. PAGE, FOR HA WONDERFUL TALK. WE ARE NOW GOING TO TAKE A 10-MINUTE BREAK, 10 MINUTES ONLY, PLEASE. AND WHAT I'D LIKE TO ASK IS THE NEXT SET OF PRESENTERS FOR THE BIRCWH SCHOLAR SCOR ORAL PRESENTATION, IF YOU WILL PLEASE COME FORWARD TO THE FRONT OF THE AUDITORIUM SO THAT YOU'RE READY TO GO WHEN WE COME BACK FROM THE BREAK. THANK YOU. I WOULD LIKE TO INVITE DR. CORA LEE WETHERINGTON UP TO THE PODIUM FROM THE NATIONAL INSTITUTE ON DRUG ABUSE. CORA LEE. >> SO WELCOME, EVERYBODY, TO THIS ORAL PRESENTATION SESSION THAT WILL CONSIST OF EIGHT SPEAKERS. THEY WILL EITHER BE BIRCWH SCHOLARS OR INVESTIGATORS FROM THE SCORs. EACH PERSON WILL HAVE 10 MINUTES TO SPEAK AND THERE WILL BE FIVE MINUTES FOR QUESTION AND ANSWER. SO THE BIOGRAPHIES OR THE SHORT BIOS FOR EACH OF THE SPEAKERS ARE IN YOUR PACKET SO WE WILL NOT BE TAKING UP TIME GIVING EXTENSIVE BIOGRAPHICAL INTRODUCTIONS TO THESE INDIVIDUALS. SO LET'S GET STARTED AND BEGIN WITH CARMELA REICHEL, WHO IS A BIRCWH SCHOLAR AT THE MEDICAL UNIVERSITY OF SOUTH CAROLINA. SHE WAS PREVIOUSLY A BIRCWH SCHOLAR AND SHE IS NOW A SCOR INVESTIGATOR, AND SHE WILL BE SPEAKING ON SEX DIFFERENCES IN ATTENUATION OF COCAINE-CONDITIONED COURY INSTATEMENT BY CENTRAL OXYTOCIN. >> OKAY. SO EARLIER TODAY, WE HEARD A LOT OF INTRODUCTION ALREADY ABOUT SEX DIFFERENCES IN ADDICTION. SO JUST TO RECAP, THERE ARE DEFINITELY DIFFERENCES IN THE WAY MEN AND WOMEN APPROACH ADDICTION AND THEIR USE PATTERNS AND BEHAVIORAL DIFFERENCES THAT ARE OF PRIMARY INTEREST AND STUDY TO OUR SCOR COMPONENTS. SO I'M GOING TO BE TAKING THE TALK IN A LITTLE DIFFERENT DIRECTION RIGHT NOW. WE'RE GOING TO GET INTO SOME BASIC PRECLINICAL RESEARCH USING AN OPERANT SELF ADMINISTRATION MODEL WHERE WE GIVE THE ANIMALS I.V. CATHETER IMPLANTATION SURGERY, THEN THEY'RE TRAINED TO PRESS A LEVER FOR DRUG DELIVERY SO THE DRUG IS DELIVERED DIRECTLY INTO THEIR JUGULAR VEIN. AND WITH THIS, WE CAN SET UP CONTINGENT MODELS OF DRUG TAKING THAT ARE REMINISCENT OF THE WAYS HUMANS TAKE DRUGS. DURING THESE -- USING THIS MODEL, WE CAN ACTUALLY TEST FOR DIFFERENT PHARMACOLOGICAL COMPOUNDS THAT MAY BE EFFECTIVE DURING VARIOUS STAGES OF A SELF ADMINISTRATION PROCEDURE. IT'S NOT ADVANCING. SO IN HUMAN, WE KNOW THERE ARE VARIOUS RELAPSE TRIGGERS THAT HUMAN ADDICTS COME ACROSS WHEN THEY'RE TRYING TO REMAIN ABSTINENT FROM DI DRUGS, AND THOSE ARE COMING IN CONTACT WITH DRUG-ASSOCIATEASSOCIATE CUES ORIGINALLY PAIRED WITH DRUG TAKING CONTENT, THEY CAN GO BACK INTO A DRUG ASSOCIATED ENVIRONMENT WHERE THEY ARE USED TO TAKING THE DRUGS, OR THEY CAN COME IN CONTACT WITH PRE-EXPOSURE TO THE DRUG ITSELF OR DAILY LIFE STRESSORS CAN RESIP TATE RELAPSE EPISODE. BY RE-EXPOSING THE ANIMALS TO THEIR DRUG PAIRED CONTEXT, GIVING THEM A LITTLE BIT OF THE DRUG THAT THEY WERE EXPOSED TO PREVIOUSLY, OR BY INITIATING STRESSORS TO THEM. SO WHAT THIS LOOKS LIKE IN A BASIC SELF-ADMINISTRATION, EXTINCTION MODEL, YOU HAVE YOUR ANIMAL, A NICE ACQUISITION PATTERN WHERE IT EVENTUALLY STABILIZES. ONCE THE RESPONDING STABILIZES, ANIMALS ARE PLACED INTO EXTINCTION, WHERE NOW YOU HAVE THE REMOVAL OF THE DRUG, YET THE ANIMAL WILL CONTINUE TO PRESS ON THE LEVER UNTIL HE LEARNS THAT DRUG IS NO LONGER AVAILABLE. ONCE RESPONDING SUBSIDES, YOU CAN REINITIATE THE DRUG ASSOCIATED CUES AND YOU'LL SEE AN INCREASE IN BEHAVIOR, WHICH WE TAKE -- AN INCREASE IN LEVER PRESSING, WHICH WE TAKE TO INDICATE AS A MEASURE OF DRUG SEEKING. SO THE AT ANY ONE OF THESE PHASES, WE CAN ADMINISTER A PHARMACOLOGICAL COMPOUND TO TEST WHAT'S GOING ON AT THESE DIFFERENT PHASES. AND SO WHAT WE'VE BEEN STUDYING LATELY IS OXYTOCIN. OXYPITOCIN IS PRODUCED AND RELEASED THROUGH THE SUPER OPTIC KNEW US AND THE PARAVENTRICULAR NUCLEUS -- FOR SOCIAL BEHAVIORS, THAT WOULD INCLUDE PARENTAL, SOCIAL BONDING, SEXUAL BEHAVIOR, AND FOR NON-SOCIAL BEHAVIORS, THAT WOULD INCLUDE STRESS, ANXIETY AND AGGRESSION. AND SO OXYTOCIN ALSO INTERACTS WITH THE DOPAMINE SYSTEM IN THAT STIMULATION OF BOTH THE OXYTOCIN AND THE DOPAMINE PATHWAY HAVE SIMILAR EFFECTS ON SOCIAL BEHAVIOR, THEY HAVE RECEPTOR BINDING SITES AND NEURONAL FIBERS IN THE SAME CENTRAL NERVOUS SYSTEM REGION, AND HYPOTHALAMIC OXYTOCIN CELLS ACTUALLY EXPRESS DOPAMINE RECEPTORS. SO IF YOU DISRUPT EITHER ONE OF THESE SYSTEMS OR INTERACTIONS, BETWEEN THE SYSTEMS, YOU GET -- THEY RESULT IN DISORDER SUCH AS AUTISM, DEPRESSION, ADDICTION AND EATING DISORDERS. SO THE IDEA OF USING OXYTOCIN AS A TREATMENT COMPOUND IS NOT NECESSARILY NEW AND HAS BEEN AROUND FOR ABOUT 20 YEARS, THE FIRST REVIEW ARTICLE WAS PUBLISHED IN 1994, AND BEEN FOLLOWEFOLLOW UP ON 20 YEARS LATER WITH AN ARTICLE SUGGESTING OXYTOCIN AS A TREATMENT FOR ADDICTION. WHAT IS NEW ARE SOME PRECLINICAL -- I'M SORRY -- SOME CLINICAL STUDIES COMING OUT ADMINISTERING OXYTOCIN TO HUMAN SAMPLES FOR BOTH COCAINE AND MARIJUANA ADDICTION, AND EVEN MORE RECENTLY, THERE'S BEEN SEVERAL STUDIES IN THE PRECLINICAL MODELS OF SELF ADMINISTRATION THAT I JUST DESCRIBED USING OXYTOCIN AS A TREATMENT FOR COCAINE SEEKING IN RATS AND A STUDY FROM MY GROUP USING OXYTOCIN AS A TREATMENT FOR METH SEEKING IN BOTH MALE AND FEMALES. BUT TO DATE, THAT'S THE ONLY -- THE PAPER FROM OUR GROUP IS THE ONLY ONE THAT'S ACTUALLY LOOKED AT FEMALES IN THEIR SAMPLE, AND NONE OF THE PRECLINICAL LITERATURE AT ALL HAS INCLUDED FEMALES IN THAT THEIR OXYTOCIN WORK. THIS IS AS FAR AS THE ADDICTION SELF ADMINISTRATION MODEL THAT I'M TALKING ABOUT. SO THERE'S DEFINITELY REASON TO LOOK AT SEX DIFFERENCES WITHIN THE OXYTOCIN SYSTEM IF YOU ARE GOING TO BE USING THIS AS A TREATMENT COMPOUND BECAUSE GONADAL HORMONES REGULATE OXYTOCIN'S BINDING AFFINITY AND RECEPTOR -- IN VARIOUS BRAIN REGIONS. THERE ARE POLYMORPHISMS IN THE OXYTOCIN GENE THAT INFLUENCE DOPE MINNER JIK FUNCTION DIFFERENTLY IN MALES AND FEMALES, AND CLOSE TO OUR RESEARCH, FEMALES HAD FEWER OXYTOCIN RECEPTOR BINDING SITES THAN MALES IN MANY OF THE FOREBRAIN AREAS. MANY OF THESE FOREBRAIN AREAS ARE THOSE INVOLVED IN ADDICTION. SO WHAT THIS GRAPH IS SHOWING IS THAT YOU GET A DIFFERENT DISTRIBUTION OF OXYTOCIN RECEPTORS IN OTHER AREAS THAT ARE RELATED TO IT ADDICTION. SO USING OXYTOCIN DURING COCAINE SELF ADMINISTRATION WHERE THE ANIMAL IS PRESSING FOR AN IV DELIVERY OF COCAINE, USING IT DURING THAT, WE ACTUALLY SEE VERY LITTLE SEX DIFFERENCES IN THE BEHAVIORAL OUTPUT OF THE ANIMALS. SO IF I CAN JUST ORIENT YOU UP HERE TO THE GRAPHS, WE HAVE THE MALES ON THE TOP, FEMALES ON THE BOTTOM, LEVER PRESSING ON THE LEFT AND COCAINE INTAKE ON THE RIGHT. YOU SEE THAT OXYTOCIN AT MULTIPLE DOSE DOASES IS INCREASING COCAINE INTAKE HAD IN BOTH MALES AND FEMALES. THE ONLY MARGINAL DIFFERENCE IS OXYTOCIN IS DECREASING COCAINE INTAKE AT A LOWER DOSE IN FEMALES THAN IN THE MALES BUT OVERALL THE PATTERN OF DOSING IS THE SAME. THIS IS ALSO THE CASE FOR CONDITIONED CUE REINSTATEMENT WHEN WE PUT THE ANIMALS BACK IN THE BOX AFTER EXTINCTION TRAINING, THEY PRESSED THE LEVER FOR THE DRUG ASSOCIATED CUES, THERE WAS NO DRUG DELIVERY, BUT AS A MEASURE OF REINSTATEMENT, YOU CAN SEE THAT OXYTOCIN IS DECREASING, CUE INDUCED REINSTATEMENT IN BOTH MALES AND FEMALES. SO WHEN YOU SEE THE SUPPRESSION OF RESPONDING DURING SELF ADMINISTRATION, DURING A RELAPSE OR REINSTATEMENT EPISODE, ONE OF THE MAJOR QUESTIONS ABOUT THE SUPPRESSION OF READ SPONDIN OF RESPONDING IS WHETHER OR NOT IT COULD YOU DUE TO AN OVERALL EFFECT OF MOTOR ACTIVITY OF YOUR TEST COMPOUND, JUST LIKE SUPPRESSING MOTOR ACTIVITY DURING THE CHAMBER. SO WE DID DO SOME LOCAL MOTOR ACTIVITY TESTS ON THESE, AND IF YOU LOOK AT THE MALES, THE ANSWER TO THE QUESTION OF IS OXYTOCIN IMPACTING LOCAL MOTOR ACTIVITY, THE ANSWER IS NO. SO THE MALES ARE DEPICTED ON THIS GRAPH UP HERE, AND WHAT WE'RE FINDING IS THAT OXYTOCIN ONLY DECREASES COCAINE INDUCED LOCAL MOTOR ACTIVITY IN FEMALES. SO WHAT'S HAPPENED HERE IS ALL THE ANIMALS WERE GIVEN AN INJECTION OF EITHER VEHICLE OR ONE OF THE DOSES OF OXYTOCIN, AND THEN FOLLOWED UP 30 MINUTES LATER WITH A DOSE OF COCAINE AND LOCAL MOTOR ACTIVITY WAS ASSESSED. SO YOU CAN SEE THERE IS A SEX DIFFERENCE BETWEEN MALES AND FEMALES IN COCAINE INDUCED LOCAL MOTOR ACTIVITY, WHICH IS VERY COMMON AND OFTEN REPORTED IN THE LITERATURE. BUT WHEN YOU GIVE OXYTOCIN, IT HAS NO IMPACT ON MOTOR ACTIVITY IN MALES AND DECREASES COCAINE INDUCED LOCAL MOTOR ACTIVITY IN FEMALES. SO THE RESULTS OF OUR COCAINE TAKING-COCAINE SEEKING DATA FOR MALES, THERE IS NOT A LOCAL MOTOR SUPPRESSION EFFECT INVOLVED. HOWEVER, FOR FEMALES, THERE IS. WE ALSO FOLLOWED UP WITH JUST A TEST OF BASAL LOCAL MOTOR ACTIVITY, NO COCAINE ON BOARD, JUST OXYTOCIN ON LOCAL MOTOR ACTIVITY, AND WE'RE FINDING SAIMENT PATTERN OF FINDINGS WHERE IT TAKES THE HIGH DOSE OF OXYTOCIN TO IMPACT MALE LOCAL MOTOR ACTIVITY WHEREAS FEMALES ARE HAVING LOCAL MOTOR ACTIVITY SUPPRESSED AT LOCAL DOSES. SO AGAIN, WE HAVE THE LOCAL MOTOR ACTIVITY TESTS INDICATING THAT THERE IS SOME MOTOR SUPPRESSION IN FEMALES THAT COULD LEAD TO DIFFICULTY INTERPRETING OUR COCAINE SEEKING AND COCAINE REINSTATEMENT EFFECTS IN FEMALES ONLY. SO JUST AS A SUMMARY OF WHAT HE I SHOWED YOU RIGHT THERE, WE HAVE OXYTOCIN LEVER RESPONDING -- IN SELF ADMINISTRATION IN MALES AND FEMALES, WE HAVE OXYTOCIN REDUCED CUE REINSTATEMENT SIMILARLY IN MALES AND FEMALES, AND WE HAVE LOWER OXYTOCIN DOSES DECREASED MOTOR ACTIVITY AND COCAINE INDUCED MOTOR ACTIVITY GREATER IN FEMALES THAN MALES. SO GIVEN THAT MALES AND PEE MAILS HAVE A DIFFERENT DISTRIBUTION OF OXYTOCIN RECEPTORS IN THE BRAIN, THERE'S ALSO A DIFFERENT DISTRIBUTION OF OXYTOCIN RECEPTORS PERIPHERALLY, AND UNTIL NOW, ALL THE STUDIES THAT I HAVE SHOWN YOU HAVE DEALT WITH PERIPHERALLY ADMINISTERED OXYTOCIN VIA I.P. INJECTIONS. SO WE COULD BE GETTING THAT LOCAL MOTOR SUPPRESSION EFFECT DUE TO THE RAL ADMINISTRATION OF OXYTOCIN IN FEMALES. SO WE WENT DIRECTLY INTO THE BRAIN AND ADMINISTERED OXYTOCIN AND AN OX ZITO SIN AN TAGNESS DISTRICTLY INTO THE BRAIN IN ORDER TO BYPASS ANY PERIPHERAL EFFECTS THAT WE MAY BE HAVING. WE USED THE F ESM COMPOUND WHICH WAS A GIFT FROM FEHRING PHARMACEUTICALS BECAUSE THIS DRUG IS SUPPOSED TO HAVE A GREATER AFFINITY FOR OXYTOCIN REACCEPT INVENTORIES IN AND OF ITSELF RATHER THAN OXYTOCIN BINDING TO BOTH OXYTOCIN ANDPRESS ENT -- WITHOUT THE INFLUENCE OF THEPRESENT. SO WE USED MALES AND FEMALES, AND THEY WENT THROUGH THE SAME SELF ADMINISTRATION REGIMENT, EXTINCTION, AND THEN REINSTATEMENT. AND WHAT WE'RE FINDING IS THE DIFFERENT PATTERN OF RESPONDING. SO THIS IS THE RESULTS OF THE CUED REINSTATEMENT IT TEST, AND HERE WE HAVE THE MALE DATA, WHERE WE SHOW NICE ROBUST REINSTATEMENT BEHAVIOR IN ANIMALS THAT RECEIVED A VEHICLE INFUSION. WHEN YOU LOOK AT THE OXYTOCIN INFUSION, WHICH IS THE MIDDLE GRAY BAR, YOU SEE A DECREASE IN COCAINE SEEKING IN MALES TO THE CONDITIONED CUES. THE FE COMPOUND, ALTHOUGH IT IS DECREASED FROM THE VEHICLE, IT'S NOT NECESSARILY DECREASING TO THE SAME EXTENT AS THE OXYTOCIN ITSELF, SUGGESTING THAT OXYTOCIN'S EFFECTS MAY ACTUALLY HAVE SOME SORT OF VASOPRECENT INPUT AS WELL. YOU LOOK AT THE FEMALES, THERE'S NO EFFECT OF THE OXYTOCIN OR THE FE COMPOUND ON INDUCING -- SO WE DID ANOTHER REINSTATEMENT TEST AS WELL THAT IS A COCAINE PRIME WHERE YOU GIVE THE ANIMAL A LITTLE BIT OF THE DRUG, PUT HIM BACK IN A SELF ADMINISTRATION CHAMBER, THE PHYSIOLOGICAL EFFECTS OF THE DRUG IT SELF WOULD REINITIATE RESPONDING ON THAT COCAINE PAIRED LEVER, SO NOW WITH THE ICV ADMINISTRATION OF FE AND OXYTOCIN, YOU SEE IN BOTH MALES AND FEMALES, WE'RE GETTING A REDUCTION OF COCAINE SEEKING WHEN THE COCAINE IS ACTUALLY ON BOARD. SO HERE WE HAVE SOME DEFINITE DIFFERENCES BETWEEN MALES AND FEMALES ON THIS CUED REINSTATEMENT TEST. AND SO BASICALLY WHAT WE'RE SEEING, WHAT I'VE PRESENTED TO YOU SO FAR IS THAT FEMALES ARE MORE SENSITIVE TO PERIPHERAL OXYTOCIN IN GENERAL VIA MEASURES OF COCAINE SEEKING SUCROSE SEEKING AND LOCAL MOTOR ACTIVITY. ICV OXYTOE 16 AND THE FE COMPOUND BOTH INDUCED CUED REINSTATEMENT IN MALES AND BOTH SEXES HAD REDUCED COCAINE PRIMED REINSTATEMENT TO BOTH OF THESE COMPOUNDS. BUT WHAT THIS DATASET IS REALLY BRINGING UP IS REALLY HIGHLIGHTING THAT THERE ARE S.E.C. SIMILARITIES AND BEHAVIOR MAY ACTUALLY BE MEDIATED BY THE DIFFERENT NEUROLOGICAL MECHANISMS, SO HERE WE HAVE THIS BEHAVIOR DURING COCAINE SELF ADMINISTRATION WHERE OXYTOCIN IS DECREASING BOTH FOR MALES AND FEMALES. WE HAVE THE REDUCTION OF SUE CROW SEEKING THE SAME FOR BOTH MALES AND FEMALES, AND IF WE STOPPED RIGHT THERE, YOU WOULD CONCLUDE THAT OXYTOCIN IS HAVING A SIMILAR IMPACT IN BOTH MALES AND FEMALES ONCOCANE SEEKING. BUT GOING THE ONE STEP FURTHER, LOOKING AT THE LOCAL MOTOR EFFECTS, THERE WE HAVE A DIFFERENT MECHANISM BY WHICH COCAINE SEEKING AND TAKING MAY BE REDUCED IN FEMALES, AND THEN GETTING INTO THE ACTUAL NEUROBIOLOGY OF INFUSING THE DRUGS INTO THE BRAIN, THERE'S MORE SEX DIFFERENTS BEING CLARIFIED. SO EVEN THOUGH YOU MAY HAVE THE SAME BEHAVIORAL OUTPUT DOESN'T NECESSARILY MEAN IT'S BEING DRIVEN BY THE SAME UNDERLYING NEUROBIOLOGY. SO WITH THAT, I WILL THANK MY LAB AND THE PERSON THAT IT DID MOST OF THIS RESEARCH, DR. LOUIS VAO, WHO'S GONE ON TO OTHER THINGS. I DON'T KNOW IF WE HAVE TIME FOR QUESTIONS? >> THANK YOU VERY MUCH. [APPLAUSE] >> SO ARE THERE ANY QUESTIONS? SO I'LL ASK A QUESTION ABOUT YOU TALKED ABOUT THE DIFFERENT TRIGGERS FOR RELAPSE. THE CUES AND THE COCAINE PRIME AND IN YOUR INTRODUCTION, YOU ALSO MENTIONED STRESS AND YOU ALSO TALKED ABOUT -- EARLIER YOU TALKED ABOUT OXYTOCIN HAVING A POSITIVE EFFECT ON STRESS, SO WHAT ABOUT RESEARCH, ANY ANIMAL RESEARCH LOOKING AT THAT, LOOKING AT -- USING A VER USE A STRESSOR A S A TRIGGER FOR RELAPSE? >> YES, WE ACTUALLY DO HAVE SEVERAL LINES OF TRESS RESEARCH GOING ON IN MY LAB AND IN THE DEPARTMENT RIGHT NOW. ONE OF THE MOST TRADITIONAL WAYS TO INDUCE STRESS INDUCED RELAPSE IN THE ANIMAL MODELS IS WITH A PHARMACOLOGICAL STRESSOR YOHIMBINE. WHAT WE'VE BEEN TRYING TO DO LIGHTLY IS GET A MORE NATURAL STRESSOR TO THE ANIMALS LIKE USING PREDATOR ODOR REINSTATEMENT, THAT'S IN BEGINNING STAGES. THERE IS PRELIMINARY DATA COMING OUT FROM OUR LAB SHOWING THAT YOU CAN USE THESE NATURAL PREDATOR ODORS AND IF YOU DO GIVE OXYTOCIN, IT WILL DECREASE RESPONDING TO THE PREDATOR ODOR AS WELL. AND THAT'S SOME OF THE RESEARCH THAT'S COMING OUT OF ONE OF OUR OTHER PIs AT MUSD, DR. JAKE MCGINTY'S LAB, AND SHE'S USING THAT IN A METH-SEEKING MODEL. >> ANY OTHER QUESTIONS? SO I WOULD JUST LIKE IT TO END BY ADDING THAT HER LAST POINT ABOUT NOT FINDING A DIFFERENCE BETWEEN MALES AND FEMALES, WE OFTEN COMMONLY USE THE TERM SEX DIFFERENCES, BUT WHEN WE FIND SEX SIMILARITIES, THAT DOESN'T MEAN THAT THEY GOT TO THAT SAME END POINT BY THE SAME MECHANISMS AND PURSUING WHAT THOSE MECHANISMS MIGHT BE CAN GIVE US CLUES ABOUT THE NATURE OF THE PHENOMENA, AND EVENTUALLY HAVE IMPLICATIONS FOR PREVENTION OR TREATMENT. SO I THINK THAT'S JUST A REALLY IMPORTANT TAKE HOME MESSAGE. IF YOU FIND SEX SIMILARITIES, YOU MAY INTRODUCE ANOTHER VARIABLE INTO THAT PROCEDURE, AND THEN THAT BRINGS OUT THE SEX DIFFERENCES. SO WE NEVER KNOW WHEN IT'S SAFE TO STOP COMPARING OR LOOKING AT BOTH MALES AND FEMALES. SO THANK YOU VERY MUCH. [APPLAUSE] SO OUR NEXT SPEAKER WILL BE STEPHEN WILSON, WHO IS A BIRCWH SCHOLAR AT PENN STATE UNIVERSITY, AND HE WILL BE SPEAKING ON SEX DIFFERENCES AND THE BRAIN RESPONSE TO SMOKING CUES IN ADULT CIGARETTE SMOKERS. >> GOOD MORNING, EVERYBODY. SO AS MENTIONED, I'M FROM PENN STATE UNIVERSITY WHERE I'M IN THE DEPARTMENT OF PSYCHOLOGY AS AN ASSISTANT PROFESSOR, ALSO A BIRCWH SCHOLAR, AND I'M GOING TO PRESENT SOME RESULTS FROM A PROJECT THAT I CONDUCTED WITH SHANNON HENRY, WHO'S A GRADUATE STUDENT IN MY LABORATORY. SO WE'RE GOING TO BE MOVING BACK TO SOME HUMAN DATA HERE. ONE OF THE NICE THINGS ABOUT COMING AT THIS POINT DURING THE DAY IS THAT SOME OF THE KEY POINTS WITH RESPECT TO THE MOTIVATION FOR THIS RESEARCH HAVE ALREADY BEEN MENTIONED, AND SO I'LL JUST KIND OF HIGHLIGHT A COUPLE OF THINGS. THE RESEARCH THAT I'LL BE TALKING ABOUT FOCUSES ON CIGARETTE SMOKING BEHAVIOR IN HUMANS AND IN PARTICULAR SEX DIFFERENCES AND SOME OF THE MECHANISMS THAT MIGHT UNDERLIE CLINICALLY RELEVANT OUTCOMES IN SMOKERS. IN GENERAL, AS I'M SURE MOST OF YOU KNOW, QUITTING SMOKING TENDS TO BE VERY DIFFICULT FOR INDIVIDUALS, AND WHILE THAT SEEMS TO BE TRUE FOR MOST SMOKERS, THERE'S COMPELLING EVIDENCE THAT QUITTING SMOKING MAY BE UNIQUELY CHALLENGING IN MANY WAYS FOR WOMEN. I WON'T GO INTO A LOT OF DETAIL IN THE INTEREST OF TIME. SOME OF THIS WE HEARD ABOUT EARLIER DURING DR. COMPTON'S EXCELLENT ADDRESS, WHEN YOU LOOK AT THINGS LIKE SELF-REPORTED CONFIDENCE IN THE ABILITY TO QUIT SMOKING, WOMEN TEND TO HAVE LESS CONFIDENCE WHEN MEN WHEN YOU ASK THEM, AND I THINK THE REALLY IMPORTANT PIECE IS THAT WOMEN TEND TO BE LESS SUCCESSFUL IN QUITTING SMOKING IN TERMS OF HOW LONG THEY SUSTAIN ABSTINENCE, WHICH IS REALLY THE KEY OUTCOME. AND THERE ARE CERTAIN FRONT LINE THERAPIES THAT WOMEN SEEM TO BENEFIT LESS FROM RELATIVE TO MEN, INCLUDING THE NICOTINE PATCH AND PERHAPS OTHER FORMS OF NICOTINE REPLACEMENT THERAPY. AND SO OVERALL, WOMEN SEEM TO HAVE A HARDER TIME AT QUITTING SMOKING THAN MEN, AND IT'S BEEN SPECULATED THAT THESE CLINICALLY RELEVANT SEX DIFFERENCES MAY BE LINKED TO UNDERLYING SEX DIFFERENCES IN THE MECHANISMS THAT DRIVE SMOKING BEHAVIOR. AND WE HEARD ABOUT THIS A LITTLE BIT AS WELL EARLIER TODAY. SO ONE BROAD DISTINCTION THAT YOU COULD MAKE WITH RESPECT TO THE FACTORS THAT MOTIVATE OR REINFORCE SMOKING BEHAVIOR IS BETWEEN THE NICOTINE ITSELF, THE ACUTE PHARMICOLOGICAL EFFECTS OF THE NICOTINE, THE PRIMARY PSYCHOACTIVE INGREDIENT IN CIGARETTES, VERSUS ALL OF THE NON-PHARMICOLOGICAL FACTORS THAT GO ALONG WITH SMOKING, SO THAT WOULD INCLUDE A WHOLE HOST OF THINGS. ONE THING THAT RECEIVED A LOT OF ATTENTION IN THIS KIND OF RESEARCH ARE THE SMOKING CUES, THE CONDITION CUES THAT GO ALONG WITH THE ACT OF SMOKING. SO THOSE THINGS THAT ARE PAIRED WITH NICOTINE INTAKE BUT THAT ARE NOT THE NICOTINE INTAKE ITSELF, THAT WOULD INCLUDE THINGS LIKE THE FEEL OF THE CIGARETTE, THE SENSATION OF THE SMOKE IN THE THROAT AND SO ON. SO THOSE SMOKING CUES SEEM TO BE MORE IMPORTANT AT REINFORCING THE SMOKING BEHAVIOR OF WOMEN THAN MEN, AND IN CONTRAST, SMOKING BEHAVIOR IN WOMEN SEEMS TO BE REINFORCED LESS STRONGLY BY THE NICOTINE ITSELF, AND THERE'S LOTS OF COMPELLING EVIDENCE SUPPORTING THOSE CONCLUSIONS, BUT AS OF NOW, THE MECHANISMS THAT UNDERLIE THOSE CLINICAL SIGNIFICANT SEX DIFFERENCES REMAIN UNCLEAR. I THINK REALLY GETTING TO THE BOTTOM OF THAT QUESTION AND TRULY SORT OF COMPREHENSIVELY UNDERSTANDING THE NATURE OF THOSE SEX DIFFERENCES IS GOING TO REQUIRE RESEARCH FROM MULTIPLE DIFFERENT DISCIPLINES AT MULTIPLE LEVELS OF ANALYSIS, SO IT'S REALLY GOING TO BE A TEAM SCIENCE APROA. ONE TOOL THAT I THINK WILL BE AN IMPORTANT CONTRIBUTOR IN THAT BROADER EFFORT IS FUNCTIONAL BRAIN IMAGING. AND THAT'S A METHODOLOGY THAT I USE A LOT IN MY RESEARCH, FUNCTIONAL BRAIN IMAGING, FM RSM I; A PARTICULARLY USEFUL TOOL WHEN IT COMES TO GETTING AT THE MECHANISMS THAT UNDERLIE OVERT BEHAVIOR, AND PARTICULARLY IN TERMS OF COGNITIVE AND AFFECTIVE MECHANISMS THAT MIGHT CONTRIBUTE TO THE MAY HAVE YOUR THAT YOU'RE MEASURING OVERTLY. IT'S CERTAINLY PROVEN TO AB VERY USEFUL TOOL FOR HELPING US TO UNDERSTAND THE WAYS IN WHICH SMOKERS PROCESS CONDITIONED SMOKING CUES. THERE'S BEEN A LOT OF RESEARCH IN THAT AREA OVER THE LAST 15 OR 20 YEARS. AND PEOPLE ARE ACTUALLY STARTING TO APPLY FUNCTIONAL BRAIN IMAGING AND IN PARTICULAR FMRI TO TRY TO UNDERSTAND SOME OF THE NEUROBIOLOGICAL MECHANISMS THAT UNDERLIE SEX DIFFERENCES IN THE RESPONSE OH SMOKING CUES. SO WHILE I THINK THAT FMRI AND OTHER BRAIN IMAGING METHODOLOGIES ARE GOING TO BE QUITE PROMISING, I THINK IT'S ALSO IMPORTANT TO KEEP IN MIND THERE ARE SOME VERY IMPORTANT CHALLENGES ASSOCIATED WITH USING BRAIN IMAGING TOOLS. SOME OF THEM ARE UNIQUE TO FMRI, SOME OF THEM ARE MORE GENERAL. I WON'T GO THROUGH ALL OF THESE IN THE INTEREST OF TIME BUT A COUPLE KEY POINTS, FOR ANY OF YOU WHO HAVE BEEN INSIDE AN MRI SCANNER, YOU PROBABLY REALIZE OR CAN RECALL THAT IT'S A NOISY, CRAMPED, UNCOMFORTABLE SPACE. FMRI IS A METHODOLOGY, AT LEAST THE WAY THAT MOST PEOPLE DO IT USING THE BLOOD OXYGEN LEVEL AS THE DEPENDENT MEASURE OF INTEREST HAS A VERY LOW SIGNAL TO NOISE RATIO AND SO THAT IMPOSES SOME CONSTRAINTS ON THE TYPES OF DESIGNS THAT ONE CAN TYPICALLY USES, AND ALL THOSE THINGS TOGETHER REALLY KIND OF MAKE IT VERY CHALLENGING TO INDUCE A POTENT RESPONSE TO SOMETHING LIKE A SMOKING CUE IN THE SCANNING ENVIRONMENT. SO I THINK THAT'S A VERY IMPORTANT CHALLENGE TO OVERCOME, BECAUSE IF OUR GOAL IS TO REALLY UNDERSTAND SEX DIFFERENCES IN NEUROBIOLOGICAL RESPONSES THAT HAVE RELEVANCE FOR BEHAVIOR OUTSIDE THE LABORATORY, THINK WE'RE PROBABLY GOING TO BE MISSING SOMETHING IMPORTANT IF WE CAN'T PROVOKE A POWERFUL RESPONSE. SO COMING TO THE CURRENT STUDY, THE BROAD GOAL WAS TO USE FMRI TO BEGIN TO TRY TO UNDERSTAND SOME OF THE SEX DIFFERENCES AND THE RESPONSE TO CONDITIONED SMOKING CUES, AND MORE SPECIFICALLY TO DEMONSTRATE THAT WE COULD, THROUGH A COMBINATION OF MANIPULATIONS, PRODUCE A POTENT RESPONSE TO THESE CUES THROUGH THE FMRI SCANNER NOT WITHSTANDING SOME OF THE CONSTRAINTS THAT I MENTIONED, SO WE WANTED TO PRODUCE A POWERFUL STATE IN ALL THE SMOKERS WE WERE MEASURING WITH THE HYPOTHESIS THAT WE WOULD SEE PARTICULARLY ROBUST RESPONSE IN WI. WE WANTED TO USE THIS POTENT MANIPULATION TO AGAIN SORT OF TEASE APART SOME OF THE SEX DIFFERENCES IN -- RESPONSE, AND IMPORTANTLY FOR U WE WANTED TO LOOK AT THE RELATIONSHIP BETWEEN THE SEX DIFFERENCES THAT WE EXPECTED TO SEE IN TERMS OF THE SUBJECTIVE RESPONSE AND SEX DIFFERENCES THAT WE EXPECTED TO SEE IN THE NEUROBIOLOGICAL RESPONSE, ESPECIALLY IN AREAS OF THE BRAIN LINKED TO REWARD AND MOTIVATION. AND WE WANTED TO IT SEE SOME COHERENCE BETWEEN THOSE RESPONSE SYSTEMS IN WAYS THAT MADE SENSE. SO JUST QUICKLY IN TERMS OF THE ME THOLLOLOGY, FOR THIS PARTICULAR PROJECT, WE CONDUCTED SECONDARY ANALYSIS ON A LARGER DATASET, OR A SUBSAMPLE FROM A LARGER DATASET, A LARGE PROJECT USING FMRI TO ASSESS THE EFFECTS OF SMOKING DRK AND TREATMENT -- THE ORIGINAL STUDY WASN'T DESIGNED TO LOOK AT SEX DIFFERENCES. THAT HAS SOME LIMITATIONS ASSOCIATED WITH IT THAT I'LL MENTION AT THE END IF I HAVE TIME. WE SELECTED A SUBSET OF MALES AND FEMALES FROM THIS LARGER STUDY. 47 ALL TOGETHER, 26 MALES AND 21 FEMALES. THEY WERE ALL MODERATE TO HEAVY SMOKERS SO TO BE INCLUDED IN THE STUDY, THEY HAD TO REPORT SMOKING AT LEAST 15 CIGARETTES PER DAY FOR AT LEAST WITH IT YEARS, SO THESE AGAIN ARE MODERATE HEAVY SMOKERS, THEY SMOKED AN AVERAGE ABOUT A PACK A DAY AND THEY WERE ALL INDIVIDUALS BETWEEN THE AGES OF 18 AND 45 AVERAGING ALMOST 30 IN AGE. THESE WERE ALL INDIVIDUALS WHO HAD NO EXPLICIT INTENTIONS TO QUIT SMOKING IN THE NEAR FUTURE, SO THESE WERE ALL WHAT I WOULD CALL ACTIVE SMOKERS. THEY CAME IN A COUPLE OF TIMES. THE KEY DATA, THEY CAME IN FOR AN FMRI EXPERIMENT AFTER HAVING ABSTAINED FROM SMOKING FOR 12 HOURS. SO THAT WAS ONE PIECE OF OUR MANIPULATION. WE DEPRIVED THEM FOR 12 HOURS, OVERNIGHT ABSTINENCE, TO INCREASE THEIR SENSITIVITY TO THESE QUEUES. SO WE WANTED THEM TO ALREADY BE PRIMED TO EXPERIENCE STRONG CRAVINGS. SO WE VERIFIED THAT BIOCHEMICALLY. THEY CAME IN FOR THE EXPERIMENT, THEY DID A VARIETY OF TESTS INCLUDING COMPLETING AN FMRI BASED -- WE PROVIDED THEM WITH SOME NEUTRAL CUES AND A CIGARETTE CUE. IN ADDITION TO SIMPLY PRESENTING THEM WITH A CIGARETTE CUE, WE ALSO PRESENT THE PARTICIPANTS AN OPPORTUNITY TO SMOKE. I'LL SAY MORE ABOUT THAT, THAT WAS ANOTHER PART OF OUR EFFORT OH IT REALLY RAMP UP THE POTENCY OF THE MANIPULATION. SO HERE'S OUR BASIC TASK, VERY SIMPLE PARADIGM THAT WE MODELED AFTER PROCEDURES THAT HAVE PROVEN VERY EFFECTIVE IN BEHAVIORAL RESEARCH FOR PROVOKING STRONG CRAVINGS. SO THIS TASK CONSISTS OF THREE PERIODS OF FMRI DATA COLLECTION OR WHAT ARE TYPICALLY CALLED RUNS. EACH RUN HAS A VERY SIMPLE STRUCTURE. IT BEGINS WITH A PERIOD WHERE PARTICIPANTS ARE SIMPLY LYING AND RELAXING, NOT DOING ANYTHING IN THE SCANNER, HOLDING REAL STILL, THEY DO THAT FOR CLOSE TO A MINUTE. AND THEN AT ABOUT A MINUTE INTO THE RUN, AN EXPERIMENTER STANDING NEXT TO THE SCANNER PLACES SOMETHING IN THE PARTICIPANT'S LEFT HAND, AND THAT OBJECT VARIED ACCORDING TO THE RUN. PARTICIPANTS WERE ABLE TO SEE WHAT THEY WERE HOLDING. WE SET UP A LIVE CAMERA FEED THAT WAS POSITIONED ON THEIR LEFT HAND, IT WAS FED BACK TO THEM IN REALTIME SO THEY COULD SEE WHAT THEY WERE HOLDING AS IT WAS BEING PLACED IN THEIR HANDS. WHEN THE OBJECT WAS PLACED IN THEIR HANDS, THEY HEARD INSTRUCTIONS THROUGH AN INTERCOM SYSTEM TELDIN TELLING THEM WHAT THEY WILL BE HOLDING. NOW YOU'LL BE HOLDING A NOTE PAD, A ROLL OF TAPE, A CIGARETTE. THOSE WERE THE THREE OBJECTS THEY HELD IN THE THREE RUNS. IN THAT FIXED ORDER. THE FIRST RUN WHERE THEY HELD THE SMALL NOTE PAD WAS JUST TO GET THEM USED TO THE TASK IN THE SCANNER, TO GET THEM USED TO HANDLING AN OBJECT AND TRYING TO WATCH IT WHILE BEING IN THE SCANNER WHICH WAS KIND OF A FOREIGN EXPERIENCE FOR THEM. THEN THE SECOND AND THIRD RUNS WERE THE RUNS WE FOCUSED ON IN TERMS OF ANALYSES. THE ROLE OF ELECTRICAL TAPE -- YOU MIGHT BE WONDERING WHY THESE CUES. THE ELECTRICAL TAPE WAS SELECTED AFTER A LOT OF TRIAL AND ERROR. WE WANTED SOMETHING THAT WAS GENERALLY SPEAKING COMPARABLE IN SIZE AND WEIGHT TO A CIGARETTE, BUT THAT HAD A VERY LOW CHANCE OF PROVOKING ANY SMOKING RELATED THOUGHTS. WE HAD SOME OTHER CUES IN OTHER WORK, WE USED OBJECTS THAT WERE WHITE BUT WERE NOTHING CIGARETTE-LIKE, BUT JUST THE FACT THAT THEY WERE WHITE PROVOKED CRAVINGS. SO YOU HAD TO BE VERY CAREFUL ABOUT WHAT KIND OF CUES YOU USE. SO THE ELECTRICAL TAPE DOESN'T SEEM TO REMIND TOO MANY SMOKERS OF SMOKING. THEN THE CIGARETTE CUE IS THE KEY CUE OF INTEREST. IT WAS A CIGARETTE OF THEIR PREFERRED BRAND. SO PARTICIPANTS RATED THEIR URGE TO SMOKE ON A ZERO TO 100 SCALE AT THE END OF THE SECOND AND THIRD RUN, AND THAT WAS ONE OF OUR KEY MEASURES OF INTEREST. AND SO YOU'LL RECALL THAT I MENTIONED WE ALSO GAVE PEOPLE AN OPPORTUNITY TO SMOKE. IN ADDITION TO TELLING PEOPLE THEY WOULD BE HOLDING A CIGARETTE WHEN IT WAS PLACED IN THEIR HANDS, WE ALSO INFORMED THEM THAT THEY WOULD BE REMOVED FROM THE SCANNER IMMEDIATELY AFTER THAT RUN AND THAT THEY WOULD HAVE A CHANCE TO SMOKE IF THEY WANTED TO. EVERYONE ANTICIPATED THE EXPERIMENTAL SESSION LASTING FOR SEVERAL HOURS, SO OTHER THAN THIS KIND OF BRIEF SMOKING BREAK AFT SCAN SESSION, THEY WOULD HAVE TO WAIT FOR A LONG TIME BEFORE HAVING TO SMOKE. SO WE WANTED THIS TO BE A POWERFUL SALIENT EXPERIENCE FOR THEM, BEING ABLE TO SMOKE IN A MATTER OF A MINUTE OR SO. SO HERE ARE THE RESULTS BEARING UPON AIM ONE. SO WE ANALYZE THE SELF-REPORTED URGE DATA, COLLECTED WHILE THEY WERE HOLDING THE CONTROL CUE AND THE CIGARETTE, USING VERY STRAIGHTFORWARD APPROACH, WE DID FIND A SIGNIFICANT EFFECT OF CUE, SO PARTICIPANTS REPORTED A MUCH STRONGER URGE -- A SIGNIFICANTLY STRONGER URGE WHEN THEY WERE HOLDING THE CIGARETTE RELATIVE TO WHEN THEY WERE HOLDING THE CONTROL CUE. WE ALSO FOUND A SIGNIFICANT SEX BY CUE INTERACTION. SO THE DATA ARE APPLAUDED OVER HERE ON THE -- THE LINE FIGURE ON THE LEFT WITH THE DATA FOR MEN PLOTTED IN BLUE AND FOR WOMEN PLOTTED IN RED, THIS IS SELF-REPORTED URGE FROM ZERO TO 100 FOR THE NEUTRAL CUE AND THE CIGARETTE. SO OVERALL OUR URGE RATINGS WERE ABOUT 76 OUT OF 100 ACROSS SEX, SO WE'RE PROVOKING POTENT URGES FOR BOTH GROUPS. BUT THE CHANGE IN URGE, THE INCREASE WAS GREATER FOR WOMEN RELATIVE TO MEN. AS A FUNCTION OF HOLDING THE CIGARETTE CUE. WE USED THE SAME BASIC ANALYTIC STRATEGY HERE, TALKING ABOUT THE BRAIN DATA BEING THE DEPENDENT MEASURE OF INTEREST. SO WE'RE LOOKING FOR AREAS THAT SHOW SIGNIFICANT EFFECT OF SEX AND SEX BY CUE INTERACTION. LOOKING THROUGHOUT THE WHOLE BRAIN, I'M GOING TO TALK ABOUT ONE AREA THAT WAS OF INTEREST THAT SHOWED A SIGNIFICANT SEX BY CUE FACT AND THAT WAS THE ORBITOFRONTAL CORTEX. SO THE REGION HERE IS DEPICTED IN THE BRAIN SLICES AT THE TOP. THIS IS NOT DATA FROM ANY GIVEN SUBJECT BUT THIS REPRESENTS THE AREA THAT SHOWED A SIGNIFICANT INTERACTION EFFECT AT THE LEVEL OF THE GROUP PLOTTED ON A REPRESENTATIVE BRAIN. SO YOU CAN KIND OF GET A SENSE FOR THE LOCATION OF THE AREA SHOWING THE INTERACTION EFFECT. AND HERE ARE THE DATA FROM THAT REGION. EXPRESSED AS PERCENT SIGNAL CHANGE. YOU CAN THINK OF THIS AS THE AMOUNT OF THE INCREASE IN THE SIGNAL THAT WE'RE MEASURING, WHEN YOU MOVE FROM THE PERIOD WHERE THE PERSON IS JUST RESTING TO WHEN THEY'RE HOLDING THAT OBJECT. SO WE IT DID SEE A SIGNIFICANT EFFECT, THAT WAS COMPLETELY DRIVEN BY WOMEN. SO WHEN YOU LOOK AT THINGS SPLIT BY SEX, IT WAS REALLY THE WOMEN WHO SHOW A VERY ROBUST INCREASE IN ACTIVATION WHEN A CIGARETTE CUE IS PLACED IN THEIR HAND RELATIVE TO THE NEUTRAL CUE, WHERE THERE WAS NOT MUCH CHANGE FOR THE MEN, SO THIS WOULD BE A CASE WHERE IF WE HADN'T LOOKED AT THINGS SPLIT BY SEX, WE WOULD CONCLUDE THAT THERE WAS A SIGNIFICANT EFFECT IN THIS AREA OF THE BRAIN TO THE SMOKING CUES, BUT REALLY IT'S THE WOMEN IN OUR SAMPLE THAT'S DRIVING THIS EFFECT. SO MOST IMPORTANTLY FOR US, WE WANTED TO SEE SOME -- AGAIN SOME COHERENCE BETWEEN WHAT WE'RE SEEING IN A SUBJECTIVE RESPONSE AND THE -- IN OUR BIOLOGICAL RESPONSE. WE TOOK A SIMPLE RESPONSE TO GET AT THAT ISSUE. SO WE LOOKED AT THE ASSOCIATION BETWEEN THE MAGNITUDE OF CHANGE IN SELF-REPORTED URGE WHEN YOU GO FROM NEUTRAL CUE TO A CIGARETTE CUE, AND THE MAGNITUDE OF THE CHANGE IN THE BRAIN RESPONSE WHEN YOU GO FROM THE NEUTRAL CUE TO THE CIGARETTE CUE. SEPARATELY FOR MEN AND WHIP. WOMEN. SO WE WERE LOOKING FOR MODULATION OF THAT ASSOCIATION BY SEX. SO HERE, THESE ARE THE DATA PLOTTED FOR MEN IN BLUE CIRCLES, THERE WAS A NON-SIGNIFICANT NEGATIVE ASSOCIATION TWIN BETWEEN THOSE TWO INDICES OF CHANGE. FOR THE WOMEN, A VERY DIFFERENT STORY. THERE WAS A SIGNIFICANT POSITIVE CORRELATION THERE, SO THE MORROW BUST THE CHANGE IN SELF-REPORTED URGE, THE MORROW BUST OF AN INCREASE OVER THE FRONTAL CORTEX ACTIVATION FOR WOMEN. THE CORRELATION VALUES FOR MEN AND WOMEN WERE SIGNIFICANTLY DIFFERENT AS INDICATED BY TEST. SO THIS WAS ENCOURAGING KIND OF INITIAL EVIDENCE FOR A LINK BETWEEN THE MOTIVATIONAL RESPONSE AS REPORTED BY THE PARTICIPANTS AND THEIR UNDERLYING OR BIOLOGICAL RESPONSE AND SEX DIFFERENCES IN THOSE TWO IN TERMS OF HOW THEY WERE CONNECTED. SO JUST TO KIND OF SUM UP, THESE ARE FIRST STEPS TOWARDS ADDRESSING THIS QUESTION AND A BIG GOAL FOR US WAS TO SHOW THAT WE COULD PRODUCE A POTENT RESPONSE THAT DIFFERENTIATED ACROSS MEN AND WOMEN. I THINK WE WERE SUCCESSFUL IN DOING THAT. THE RESULTS POINT TOWARDS THE FRONTAL CORTEX AS AN AREA THAT MIGHT BE -- THAT MIGHT PLAY A ROLE POTENTIALLY IN THE GREATER DIFFICULTY THAT WOMEN EXPERIENCE WHEN THEY'RE QUITTING SMOKING. AND I THINK THE EFFECTS THAT WE'RE SEEING IN THE OSH TOE FRONTAL CORTEX ARE INTRIGUING IN LIGHT OF A LOT OF INTEREST THAT THAT AREA HAS RECEIVED IN TERMS OF REWARD PROCESSING AND MOTIVATIONAL FUNCTIONING IN GENERAL, AND IN CODING THE SIGNIFICANCE OR SALIENCE OF CONDITIONED DRUGS USED IN THE CONTEXT OF ADDICTION SPECIFICALLY. SO JUST TO KIND OF MENTION A COUPLE KEY OBJECTIVES OF OH UR FUTURE WORK, WE WANT TO ADDRESS A NUMBER OF LIMITATIONS ASSOCIATED WITH THIS PROJECT. IT WASN'T DESIGNED INITIALLY TO LOOK AT SEX DIFFERENCES SO WE DIDN'T CONTROL FOR THINGS LIKE HORMONAL STATUS, WE WANT TO DEFINITELY TAKE THAT INTO ACCOUNT. WE WANT TO MOVE BEYOND LOOKING AT BRAIN REGIONS IN ISOLATION AND START TO LOOK AT PATTERNS OF CONNECTIVITY, SO HOW AREAS OF THE BRAIN ARE INTERACTING WITH ONE ANOTHER, WHICH IS SOMETHING THAT DR. COMPTON MENTIONED AS A REAL KEY TO UNDERSTANDING THE NEURAL SUBSTRAITS OF COGNITION AND AFFECT, AND THEN WE ALSO WANT TO GO BEYOND SIMPLY LINKING OUR BRAIN MEASURES TO SELF-REPORTED DATA AND LINK THEM TO CLINICALLY RELEVANT SMOKING BEHAVIOR, SO ACTUAL CHOICES TO SMOKE, AND IDEALLY OUTSIDE OF THE LABORATORY. SO I'LL JUST END BY ACKNOWLEDGING MY CLA COLLABORATORS, MY BIRCWH MENTORS FROM PENN STATE UNIVERSITY AND THE GENEROUS SUPPORT OF THE BIRCWH PROGRAM. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> HI. HOW MUCH DO YOU THINK YOUR RESULTS BASED ON MEN AND WOMEN WOULD BE DIFFERENT, ESPECIALLY FOR THE BRAIN FUNCTIONING, HOW MUCH DO YOU THINK THAT WOULD DIFFER IF YOU ISOLATED THE TYPE OF CUE THAT WAS USED? BECAUSE IN YOUR MODEL, OR IN YOUR PARADIGM, IT WAS AN AUDITORY, YOU'RE HOLDING A CIGARETTE OR YOU'RE HOLDING A PEN OR YOU'RE HOLDING THIS, AND THE TACTILE, AND THE VISUAL BECAUSE THEY COULD SEE IT. DO YOU THINK THAT -- AND YOU POINTED OUT THE ORBITO FRONTAL CORTEX INTERACTION, SEX BY CUE, BUT DO YOU THINK YOUR RESULTS WOULD BE DIFFERENT IF YOU HAD ISOLATED THE TYPE OF EXPERIENCE, THE SENSORY EXPERIENCE? >> THAT'S A GOOD QUESTION. I DON'T KNOW FOR CERTAIN. I KNOW THERE IS RESEARCH SHOWING YOU CAN BLOCK THE VISUAL MODALITY AND THE OLFACTORY MODALITY, WHICH IS SOMETHING WE WERE MISSING ENTIRELY, AND WOMEN SEEMED TO BE MORE SENSITIVE TO MOST OF THOSE SENSORY DOMAINS THAN MEN. BUT IT IS AN INTRIGUING QUESTION. I THINK IT WOULD BE INTERESTING TO START TO DISENTANGLE WHAT IS IT ABOUT THE CUES, ARE THERE PARTICULAR MODALITIES THAT ARE MORE IMPORTANT THAN OTHERS. >> WELL, AND SO TWO REASONS, ONE IS THAT YOU TALKED ABOUT THE CONNECTIVITY, FUNCTIONAL CONNECTIVITY, AND THAT MIGHT GIVE YOU SOME CLUES INTO THAT MODALITY ISSUE, IF YOU LOOK AT THE CONNECTIVITY AMONG BRAIN RENAL, BUT ALSREGION, BUT ALSO SOCIAL CONT EXT, SO WHEN WOMEN WERE EXPOSED TO CUES, YOU SAID THEY WERE MORE SENSITIVE TO DIFFERENT TYPES OF CUE, BUT I'M WONDERING GETTING INTO THE LABORATORY NOT CONTROLLING FOR THE MULTIMODAL CUES THAT YOU HAVE. >> THAT'S A GREAT POINT. >> SO IF I READ YOUR DEMOGRAPHICS PAGE CORRECTLY, WOMEN ON AVERAGE HAD 29 CIGARETTES PER DAY AND MEN 20 FOR A DIFFERENCE OF ABOUT 30%? >> NO, SORRY, THAT WAS MEAN AGE. >> OH, THAT WAS THE AGE. OKAY. >> FOR THE ENTIRE SAMPLE. >> WERE THEY MATCHED ON THE A CIGARETTES THAT THEY SMOKED? >> YES, THEY WERE MATCHED PRETTY CLOSELY. THEY WEREN'T MATCHED IN THE SENSE THAT I SELECTED THEM FOR -- TO BE MATCHED, BUT THEY WERE COMPARABLE. SO THERE'S ALWAYS ISSUES OF POWER WHEN YOU'RE LOOKING AT SAMPLE THIS IS SMALL, BUT THERE WERE NO SIGNIFICANT DIFFERENCES IN ANY RELEVANT SMOKING CHARACTERISTICS. >> DOES ONE USE AN ROI TO LOOK AT VTA DIRECTLY OR DO YOU DO A WHOLE BRAIN -- ANALYSIS? >> VTA WOULD BE CHALLENGING TO GET AT THE RESOLUTION OF FMRI. PEOPLE DO IT, I THINK YOU MIGHT NEED TO DO SOME SPECIFICS WITH RESPECT TO KIND OF HOW YOU SET UP YOUR SAMPLE -- BUT THIS WAS WHOLE BRAIN, YES. >> THANKS. >> SO I HAVE ONE FINAL QUESTION AND THAT IS WHAT THOUGHTS DO YOU HAVE ABOUT WHAT WAS A TREND TOWARD A NEGATIVE CORRELATION BETWEEN THE URGE AND THE OFC RESPONSE IN MALES? >> THAT IS -- I THINK I KILLED THE MICROPHONE. THAT'S A REALLY INTERESTING THING. WE'VE BEEN PUZZLING OVER THAT ONE. ONE WOULD THINK -- AND I'VE SORT OF PAINTED A PRETTY SIMPLISTIC STORY IN TERMS OF WHAT WE WERE LOOKING AT. TO THE EXTENT OF AREAS LIKE OVER THE FRONTAL CORTEX FOR MOTIVATION MORE GENERALLY, YOU MIGHT SEE A SIGNIFICANT EFFECT THERE AND GET THROUGH DIFFERENT MEANS, SO FOR WOMEN, THE PATHWAY THROUGH CONDITION CUES MIGHT BE MORE IMPORTANT, FOR MEN THE EXPECTATION OF NICOTINE ITSELF MIGHT BE MORE IMPORTANT, BUT YOU MIGHT SEE SIMILAR PATTERNS SHOWING UP. THE NEGATIVE EFFECT THERE, IT'S HARD TO SAY. ONE THING THAT CAN HAPPEN FOR SMOKERS VERY QUICKLY, AND I DON'T KNOW HOW MUCH THIS DIFFERS AS A FUNCTION OF SEX IS THEY CAN BECOME VERY FRUSTRATED WHEN THEY WANT TO SMOKE AND THEY ANTICIPATE EVEN VERY BRIEF DELAYS, SO A MATTER OF SECONDS CAN BE TOO MUCH FOR SMOKERS. TO THE EXTENT THAT WE WERE TRIGGERING FRUSTRATION MORE SO FOR MEN FOR WOMEN THAT MIGHT BE PART OF THE STORY, BUT IT'S SORT OF -- THE ANSWER TO THE QUESTION. >> INTERESTING EXPLANATION. THANK YOU SO MUCH. [APPLAUSE] >> OUR NEXT SPEAKER IS JOSHUA ALLEN, A BIRCWH SCHOLAR FROM THE UNIVERSITY OF ROCHESTER. HE'LL BE SPEAKING ON SEX DEPENDENT NEURODEVELOPMENTAL AND BAIF YORL CONSEQUENCES OF EXPOSURE TO CONCENTRATED AMBIENT ULTRA FINE PARTICLES. >> SO THANK YOU. SO WHAT I'M TALKING ABOUT TODAY IS ACTUALLY AIR POLLUTION AND SPECIFICALLY ULTRA FINE PARTICLES THAT ARE FOUND IN AIR POLLUTION. WE DIDN'T START OUT LOOKING FOR SEX DEPENDENT EFFECTS BUT THAT'S CERTAINLY WHAT WE ENDED UP FINDING. SO THE WHO ACTUALLY AS OF 2014 IS MAKING A PRETTY STRONG STATEMENT THAT AIR POLLUTION IS THE NUMBER ONE GLOBAL HEALTH CONCERN ACROSS THE WORLD. THEY'VE ACTUALLY PRODUCED THIS MAP IN 2012 LOOKING AT FINE PARTICLE EXPOSURE IN PLACES LIKE CHINA AND NORTHERN INDIA AND NORTHERN AFRICA, VERY HIGH LEVELS OF EXPOSURE INDICATED IN RED, BUT EVEN WHERE WE ARE IN THE UNITED STATES WAY OVER ON THE LEFT SIDE OF THE GRAPH THERE, WE STILL HAVE EXPOSURES THAT EXCEED THE REFERENCED DOSES THAT ARE -- BY WHO, E P PA AND THE LIKE. SO WHAT I'M TALKING ABOUT TODAY ARE ULTRA FINE PARTICLES, SO THESE ARE THE SMALLEST PARTICULATE SIZE FRACTION IN THE AM BENT AIR. THEY HAVE A LOT OF SPECIAL CHARACTERISTICS THAT MAKE THEM -- THEY'RE TYPICALLY -- AT THEIR CORE BUT THEY HAVE A LOT OF SURFACE AREA AND THEY HAVE THE ABILITY TO BIND OTHER AIR TOXICANTS SO THERE'S OTHER THINGS IN OUR AIR BESIDES PARTICLES, THERE'S OTHER GAS, METALS SUCH AS MANGANESE OR CADMIUM AS WELL AS POLYAROMATIC HYDROCARBONS. SO THESE NAKED PARTICLE, SO TO SPEAK, CAN ACTUALLY BIND THE OTHER TOXICANTS IN THE AIR TO CAUSE SORT AFTE OF A TROJAN HORSE EFFECT, HAVE A ADVERSE EFFECTS THAT WAY. THESE PARDON MES AR PARDON PART KELS ARE V ERY SMALL, ALLOW THEM TO DEPOSIT INTO THE UPPER AIRWAYS, THE NASAL SPACES AND AS WELL AS THE DEEP ALVEOLAR SPACES IN THE DEEP LUNG. THAT HAS FUNCTIONAL CONSEQUENCES FOR THE BRAIN BECAUSE THE PARTICLES THAT DEPOSIT IN THE NASAL AIRWAYS ACTUALLY CAN GET INTO THE BRAIN VIA THE OLFACTORY BULBS THAT COME THROUGH THE -- THE OLFACTORY NEURONS THAT COME THROUGH THE CRYPTOFORM PLATE. WHEN THE PARTICLES REACH THE DEEP LUNG, THEY CAN CAUSE AN INFLAMMATORY RESPONSE TO LEAVE THE GAS EXCHANGING AREA OF THE LUNG, GET INTO THE CIRCULATION AS WELL AND THOSE SOLUBLE MEDIATORS OF INFLAMMATION CAN CAUSE ADVERSE EFFECTS OP THE BRAIN. SO THERE'S BEEN A NUMBER OF STUDIES RECENTLY IN RECENT YEARS LOOKING AT AMBIENT AIR POLLUTION EXPOSURES AND BEHAVIORAL TBUNGS OR BEHAVIORAL DISEASES. THOSE INCLUDE EPIDEMIOLOGY STUDIES INCLUDING ADHD, AS WELL AS AUTISM AND SCHIZOPHRENIA WITH AIR PLUGS. THERE'SPOLLUTION. SOME COMING OUT OF SOUTHERN CALIFORNIA, AND AS WELL AS OTHER STUDY LOOKING AT AMBIENT CARBON BLACK AND REDUCED NEUROCOGNITIVE FUNCTION IN CHILDREN, MEN AND WOMEN. SO WE'RIN ORDER TO DO SO, WHAT WE DID WAS WE EXPOSED BLACK MICE TO SOMETHING CALLED CONCENTRATED AMBIENT ULTRA FINE PARTICLES. SO WE USED THIS SO CALLED SYSTEM THAT ACTUALLY IS SORT OF LIKE A VERY LARGE VACUUM CLEARER THAT DRAWS AIR IN AND CONCENTRATES THE ULTRA FINE PARTICLES ABOUT 10 TO 20 FOLD. SO AVERAGE OUTSIDE LEVELS NEAR OUR UNIVERSITY ARE ABOUT 20,000 PARTICLES PER CUBIC COUNCILMEMBER. AND SO THE SYSTEM CONCENTRATES THEM 10 TO 20 TIMES AND SO THE ANIMALS ARE ACTUALLY EXPOSED TO APPROXIMATELY 200,000 PARTICLES PER CUBIC COUNCILMEMBER. TO PUT THAT INTO SOME SORT OF PERSPECTIVE, YOU WOULD EXPECT TO FIND IN A -- AT PEAK EP SO TICK COUNTS OF ULTRA FINE PARTICLES IN SOME PLACES LIKE LOS ANGELES CAN ACHIEVE 2 MILLION PARTICLES PER CC, SO 200,000 PARTICLES PER CC AS WE'RE EXPOSING OUR ANIMALS IS SIMILAR TO WHAT YOU'D FIND IN AN ARTERIAL ROADWAY OR POTENTIALLY A BUSY HIGHWAY. SO WE EXPOSED ANIMALS AT TWO TIME POINTS IN THEIR LIFE, THE EARLY POSTNATAL PERIOD WHICH OCCURRED OVER THE FIRST TWO WEEKS OF LIFE AND THEY WERE EXPOSED AT A VERY CRITICAL TIME FOR POS POSTNATAL BRAIN DEVELOPMENT IN MICE. IT'S ROUGHLY EQUIVALENT TO THIRD TRIMESTER BRAIN DEVELOPMENT IN HUMANS. SOME ANIMALS WENT ON FOR REEXPOSURE AS ADULTS, YOUNG ADULTS FROM POSE NATAL DAY 56 THROUGH 50 NIEP. IT GIVES US FOUR TREATMENT GROUPS AND WE HAD ANIMALS EXPOSED IN THE EARLY POSTNATAL PERIOD ALONE WITH ADULT AIR -- EXCUSE ME -- EXPOSED TO AIR IN THE POSTNATAL PERIOD AND AIR IN THE ADULT PERIOD, AND THEN CAPS IN THE ADULT PERIOD ONLY, CAPS IN THE POSTNATAL PERIOD ONLY AND THE COMBINED -- WITH BOTH SEXES. SO OUR PRELIMINARY STUDIES ACTUALLY SHOWED THAT THERE WAS A GLIAL RESPONSE IN THE BRAIN ALONG THE ME SEW CORTICAL DOPAMINE TRACTS IN THE BRAIN SO WE ACTUALLY PUT THESE ANIMALS THROUGH A BATTERY OF BEHAVIORAL TESTS THROUGHOUT THEIR LIFESPAN OR EXCUSE ME AS THEY'RE YOUNG ADULTS, AND WE LOOKED AT COGNITIVE DOMAINS SUCH AS LEARNING AND MEMORY AND IMPULSIVITY, AND WHAT WE FOUND WAS THAT THERE WAS WIDESPREAD BEHAVIORAL TOXICITY OF THESE ULTRA FINE PARTICLES WHEN THE ANIMALS WERE EXPOSED. I'M JUST GOING TO USE ONE DOMAIN, THE TEMPORAL DISCRIMINATION, THE FIXED INTERVAL SCHEDULE OF REINFORCEMENT AS AN EXAMPLE OF THIS DATA. SO THE SCIJ HAS TEUMLY BEEN -- IT'S FRANC TRANSLATIONAL, WHERE AN ANIMAL HAS BEEN TRAINED TO PRESS A LEVER IN AN -- CHAMBER, AFTER THE ANIMAL HAS BEEN ADEQUATELY TRAINED, WE IMPOSED THE FIXED INTERVALINTERVAL SCHEDULE -- THE ONLY ONE THAT'S EVER REINFORCED SO IT CREATES THAT CUMULATIVE RECORD OF RESPONDING THAT YOU SEE ON THE RIGHT THERE, WHERE VERY EARLY THE IN THE INTERVAL, THE ANIMAL DOESN'T MAKE ANY RESPONSES, BUT US A GET LATER IN THE INTERVAL, THE ANIMAL MAKES PORMORE AND MORE RESPONSES UNTIL IT'S DELIVERED FOR THAT ONE LEVER CREST. SO THAT CUMULATIVE RECORD OF RESPONDING IS ACTUALLY VERY PRO TOE TYPICAL AND IT LOOKS LIKE FROM LIKE I SAID HOUSE FLIES ALL THE WAY UP TO HUMANS. SO WHAT WE CAN DO WITH THIS IS GET THE QUANTITATIVE DATA OF OVERALL RATE WHICH IS SIMPLY TOTAL RESPONSES PER SESSION TIME, AND THERE'S OTHER METRICS BUT THIS ONE SHOWS THE DATA THE BEST. WE SEE VERY SEX-DEPENDENT CHANGES -- THAT COULDN'T BECOME MORE OPPOSITE. SO ON LEFT I HAVE THE DATA FOR THE MALES IN BLUE, AND DATE TA FOR THE FEMALES IN PINK ON THE RIGHT. WHAT YOU SEE IS THAT THERE'S ACTUALLY A DECREASE IN RATE OF RESPONDING FOR THE MALES WHEN THEY'VE BEEN EXPOSED TO POSTNATAL CAPS IN THE BLUE. IN THE FEMALES, IT'S THE ADULT -- THAT INCREASES THEIR RESPONSE RATES. THE BEHAVIOR IS SORT OF BROKEN IN BOTH CASES. THEY'RE DIFFERENT FROM CONTROL BUT NEITHER AN INCREASE NOR DECREASE IN THIS RATE OF RESPONDING ACTUALLY CAUSES ANY SORT OF CHANGE IN THEIR REINFORCEMENT FREQUENCY. SO LIKE I WAS TELLING YOU BEFORE, WE LOOKED AT SEVERAL BEHAVIORAL DOMAINS AND ALL OF THE BEHAVIORAL DOMAINS THAT WE LOOKED AT INCLUDED SEX DEPENDENT DIFFERENCES. WE SEE CHANGES IN LEARNING AND IN MEMORY AND IN CAN -- WE ONLY LOOKED AT IMPULSIVITY IN MALES BUT IT DEFINITELY MAKES THE MALES IMPULSIVE. WHEN WE TAKE THE BRAINS OF THESE ANIMALS AND MEASURE THE NEUROTRANSMITTERS, THE MONO AMINES USED TO NEUROCOMMUNICATION IN THOSE REGIONS, WE SEE VERY DIFFERENT PROFILE CHANGES TWHEEL THE MALES AND FEMALES. THERE'S TOO MUCH QUANTITATIVE DATA TO SHOW, THERE'S PROBABLY 80 OR SO LINE GRAPH BUT I'VE TRIED TO SUMMARIZE IT, ANYWHERE YOU SEE A COLORED BOX IS WHERE I'VE NOTED A CHANGE INDUCED BY CAPS IN ONE OF THOSE NEUROTRANSMITTERS. SO YOU SEE THERE'S A LOT OF OVERLAP BETWEEN THE MALES AND FEMALES IN TERMS OF THIS NEUROTRANSMITTER DISTONGUES, FOR INSTANCE, STRIATUM, THERE SEEMS TO BE A LOT OF CHANGES FOR BOTH MALES AND FEMALES, BUT THE EXACT NATURE OF THE CHANGE IS DIFFERENT, DOESN'T INDICATE THE DIRECTIONALITY OF THE CHANGES BUT CERTAINLY SHOWS THAT THERE'S A WIDESPREAD MULTISYSTEM OF NEUROTRANSMITTER DISTONGUES THAT'S INDUCED BY CAPS HERE. SO THE OTHER INTERESTING COMPONENT IS WHEN WE LOOK AT THE EXCITE TRI AND INHIBITORY IMBALANCE IN MALES AND FEMALES, WE SEE THERE'S INCREASED GLUTAMATE SO THE ANIMALS WERE EXPOSED IN THE EARLY POSTNATAL PERIOD OR YOUNG ADULTS AROUND POSE NATAL DAY 60. WHEN WE LOOK AT THE BRAINS OF 270 DAYS OF AGE, WE ACTUALLY SEE SIGNIFICANTLY ELEVATED GLUTAMATE AND GABA IN BOTH THE MALES AND THE FEMALES. SO WE SEE THIS IN BOTH THE MALES AND FEMALES AT THE END OF THEIR LIFESPAN, BUT AT THE BEGINNING OF THEIR LIFESPAN, THERE'S ACTUALLY A VERY STRIKING IMBALANCE BETWEEN THIS GLUTAMATE IN THE GA GABA IN ONLY THE MALES, NOT IN THE FEMALES. SO THE MOST STRIKING AND SURPRISING PIECE OF DATA THAT WE GOT FROM THIS STUDY WAS THIS MALE-SPECIFIC CAPS INDUCED VEN TRICK LOWMEGALY. SO WE LOOKED AT THE -- THE HIS TOLL GIST SENT ME THIS PICTURE AND FIRST I THOUGHT IT WAS AN ARTIFACT BUT IT TURNS OUT TO BE A REAL TRUE CAPS-INDUCED EFFECT. WHAT YOU SEE ON THE FAR -- A VERY SMALL CHANNEL IN THE BRAIN THAT'S USED FOR CIRCULATION OF CEREBROSPINAL FLUID AND REMOVAL OF METABOLIC WASTE. YOU DON'T SEE IT IN THE MORE ROSTRAL PIECES OF THE BRAIN THAT ARE DEPICTED HERE. BUT IF YOU LOOK AT THE MALES THAT HAVE BEEN EXPOSED TO CAPS, AGAIN THESE ARE RELATIVELY -- NOT MODERATE LEVELS OF CAPS, YOU SEE THE LATERAL VENTRICLE IS SHOWING UP SOONER THAN THIS ROSTRAL EXPANSION. IT'S ACTUALLY VERY ENLARGED AND THAT'S WHAT YOU WOULD FIND HERE, AND THE OTHER INTERESTING IMPACT -- OR THE INTERESTING FINDINGS HERE IS THESE CAPS INDUCED COARCTATIONS. SO IT'S TYPICALLY ONE SPACE BUT WE'VE GOT BRIDGES OF TISSUE CONNECTING THE TWO SIDE ON EITHER SIDE OF THE VENTRICLE. WE'RE NOT SURE OF THE FUNCTIONAL SIGNIFICANCE OF THESE YET BUT THIS IS ONE OF THE PART OF THE PROFILE OF CHANGES. THE OTHER IMPACT IS THE CORPUS CALLOSUM, SO THAT'S IMPORTANT FOR -- WE'VE TALKED A LOT ABOUT FUNCTIONAL CONNECTIVITY TODAY ACTUALLY, INTERHEMISPHERIC COMMUNICATION ACROSS THE TWO BRAIN HEMISPHERES AND WE SEE THAT THERE'S SIGNIFICANT -- LOOKING LIKE THERE'S SIGNIFICANT DAMAGE AND I'LL HIGHLIGHT SOME OF THAT DATA NEXT. SO IN INTEREST OF FULL DISCLOSURE, THIS IS ACTUALLY THE MOST SEERL SEVERELY AFFECTED ANIMAL. THIS IS AIR TREATED CONTROL, CAPS TREATED MALE CONTROL. WHEN WE GO THROUGH AND QUANTIFY THE SIZE OF THE LATERAL VENTRICLES, IMMEDIATELY AFTER THEIR TWO WEEKS OF EXPOSURE ASSIGNEE OWE NATES, THERE'S ABOUT A 300% INCREASE IN THE LATERAL VENT TRICKLE SIZE IN THE CAPS TREATED MALE AND WE NEVER SEE THIS EFFECT IN FEMALES. THIS INCREASE IN LATERAL VENTRICLE SIZE PERSISTS ACROSS THE ANIMAL'S LIFESPAN. SO THIS TYPE OF PATHOLOGY ACTUALLY OCCURS IN HUMANS AND IT IS NOT VERY WELL CHARACTERIZED BUT IT'S BEEN ASSOCIATED WITH A LOT OF NEURODEVELOPMENTAL DISORDERS AND INDIVIDUALS BORN WITH THIS TYPE OF PATHOLOGY GO ON TO HAVE ADVERSE DEVELOPMENTAL OUTCOMES. SO I ALLUDED TO THE FACT THAT THE CORPUS CALLOSUM WAS DAMAGED IN THE MALES AND THE LITERATURE SUGGESTS THAT WHITE MATTER DAMAGE AND VEN VENEZUELA VENTRICULOMEGALY -- WHAT I'VE DONE HERE IS STAINED BRAINS IN THE CORPUS CALLOSUM FOR MYELIN BASIC PROTEIN THEN LOOKED AT THE HOMO JE NATE OF THE EXPRESSION AND INTENSITY OF THE EXPRESS IN THE CORPUS CALLOSUM US A SEE IN THE MOST MEDIAL PORGES, THERE'S ACTUALLY A REDUCTION IN THE MYELINATION EXPRESSION AS WELL AS A DIFFERENCE IN THE PATTERNING OF THE EXPRESSION. SO WHAT WOOR DOING RIGH WE'RE DOING RIGHT NOW IS TRY TO DETERMINE WHAT ACCOUNTS FOR THE FEMALE PROTECTION, THE MALE VULNERABILITY. WE'VE NARROWED IT DOWN BASED ON OUR UNDERSTANDING OF BRAIN DEVELOPMENT, IT IS DIFFERENT BETWEEN MALES AND FEMALES IN MICE AND IN HUMANS. AND WE THINK IT MIGHT BE A MICRO GLIAL MEDIATED MERCK NISM, SO MICRO GLIA ARE BRAIN MACROPHAGES, SORT OF THE BRAIN'S IMMUNE SYSTEM, AND THEY RESPOND TO XENOBIOTIC INSULTS, POTENTIALLY AIR POLLUTION EXPOSURES, AND THEY'RE ALSO STRIKINGLY IMPORTANT FOR NEURODEVELOPMENT -- SNAP TOE GENESIS AND SYNAPTIC PRUNING. WHAT'S INTERESTING IS THEY'VE PUT OUT VERY INTERESTING WORK SHOWING THAT MALES COLONIZE THEIR BRAIN EARLIER THAN FEMALES DURING EARLY POSTNATAL BRAIN DEVELOPMENT, SO WHAT ES HAPPENING OR WHAT WE BELIEVE IS HAPPENING IS THAT THIS WAVE OF CROW GLIA COLONIZATION -- IS CONFERRING THIS SORT OF MALE VULNERABILITY HERE, AND WE'RE GOING BACK TO SEE IF FEMALES ARE MORE SENSITIVE TO EXPOSURES THAT OCCUR LATER IN LIFE OR POTENTIALLY EARLIER BUT THE LATER TIME POINT SEEMS LIKE IT'S THE MORE PERTINENT EXPOSURE WINDOW. THE OTHER FACTOR HERE, HIGHLY TESTOSTERONE DEPENDENT SO WHEN MALE RODENTS ARE BORN, THERE'S A VERY LARGE SURGE IN TESTOSTERONE AT THEIR BIRTH AND IF YOU EE LIMB MATE THAT SURGE, YOU GET A MORE SEMI NIEZED MICRO GLIAL -- THERE'S FEWER MICRO GLIA. WHAT'S HAPPENING IN OUR CAPS ANIMALS IS VERY PRELIMINARY, THIS IS JUST AN NF4 AT THIS POINT, WE SEE CAPS IS CAUSING A REDUCTION IN TESTOSTERONE, BUT THIS IS OCCURRING ON PND14, WHICH IS AT THE END OF EXPOSURE, THEY'VE ALREADY GONE THROUGH EIGHT DAYS OF EXPOSURE AT THAT POINT, SO WE WANT TO GO BACK AND SEE IF THERE'S OTHER TESTOSTERONE CHANGES OCCURRING EARLIER. THIN SORTHEN IN SUPPORT OF THIS HYPOTHESIS, MECHANISM DUE TO THE MALE'S EARLIER COLONIZATION, WE ACTUALLY ONLY SEE MICROGLIAL ACTIVATION IN MALES IN THE CORPUS CALLOSUM, WE DON'T SEE THIS EFFECT IN FEMALES, WE ACTUALLY SEE A TREND TOWARDS DECREASED MICRO GLIAL IDA1 EXPRESSION BUT WITH THE MALES, WE SEE AN ACTIVATION PHENOTYPE. SO THIS IS THE MODEL THAT WE'RE WORKING OFF NOW. WE'RE TRYING TO -- WE'VE ALREADY SHOWN THE SEX BE DEPENDENT BEHAVIORAL IMPAIRMENT AND THE VENTRICULOMEGALY -- NEUROCHEMICAL DISRUPTION AND EXCITE TRI/INHIBITORY IMBALANCE, AND WHAT WE'D LIKE TO DO IS GO BACK AND LOOK AT THE FUNCTIONAL CONNECTIVITY IN THE BRAIN LATERALIZATION, THERE'S A LOT OF DATA TO SUGGEST THAT THE WAY IN WHICH THE BRAIN IS COMMUNICATING WITH ITSELF BASED ON THE WHITE MATTER DAMAGE WE'RE SEE AND WIDESPREAD CHANGES IN NEUROTRANSMITTER LEVELS MIGHT BE IMPAIRING FUNCTIONAL CONNECTIVITY AND WE THINK IT'S ALL MEDIATED BY THIS SORT OF STEROID MEDIATED INFLAMMATION SENSITIVE NEONATAL BRAIN DEVELOPMENT THAT INVOLVES THOSE MICRO GLIA THAT ARE ACTIVATED IN THE MALES. SO JUST TO MAKE SOME CONCLUSION WE EXPOSED ANIMALS TO REALTIME REAL WORLD RELEVANT EXPOSURES AND WE THINK THAT THIS MALE VULNERABILITY IS DUE TO MICRO GLIAL -- THE DI RUPTION OF THE WHITE MATTER AND THE CORPUS CALLOSUM AS WELL AS THE VEN TRICK ROWMEGALY ARE ASSOCIATED WITH SEVERAL NEURODEVELOPMENTAL DISORDERS LIKE THE AUTISM SPECTRUM DISORDERS AND WE'RE HOPING THAT OUR STUDIES CAN PROVIDE SOME OF THE BIOLOGICAL PLAUSIBILITY OR SOME MECHANISTIC UNDERSTANDING OF THESE EP DEEM EPIDEMIOLOGICAL STUDIES THAT ARE COMING OUT NOW. THAT'S ALL I HAVE SO I CAN TAKE ANY QUESTIONS. [APPLAUSE] >> HI. I'M REBECCA SCHMIDT FROM UC DAVIS. I JUST HAD A QUICK QUESTION AND YOU MIGHT HAVE MENTIONED IT BUT I CAN'T REMEMBER IF SHE LOOKED AND WHETHER OTHERS OF THESE AIR POLLUTION AUTISM STUDIES HAVE LOOKED AT SEX DIFFERENCES IN THEIR ASSOCIATIONS. >> I DON'T THINK SO. NOT THAT I -- NOTHING STRIKING. NOTHING STRIKES ME. AUTISM IS A VERY MALE BIASED DISORDER, 84% MALE, SO -- >> WE WOULD HAVE ENOUGH IN OUR STUDY WHICH IS WHERE HER DATA COMES FROM TO DO THAT. SO IF NOT, I'LL FOLLOW UP FOR HER ON THAT BUT THAT'S REALLY INTERESTING. >> I THINK MOST OF THOSE AUTISM STUDIES HAVE ALSO LOOKED AT GESTATIONAL AND EARLY POSTNATAL. I'M CURIOUS TO SEE IF THEY LOOK AT FEMALES THAT HAVE BEEN EXPOSED LATER IN LIFE, AFTER THE FIRST YEAR OF LIFE, PERHAPS, MIGHT BE SOMETHING THERE. >> I KNOW IN HER STUDY, SHE LOOKED AT TIMING AS MUCH AS SHE COULD, ALTHOUGH IT'S CORRELATED BECAUSE MOST WOMEN DON'T MOVE IN THE TIME THAT THEY'RE PREGNANT BUT THEY LOOKED AT BY TRIMESTER AND POST NATELY IN THE FIRST YEAR OF LIFE THAN THE SECOND YEAR, I THINK, TOO, BUT THEY SAW THE LARGEST EFFECTS FOR THE THIRD TRIMESTER AND THE FIRST YEAR OF LIFE SO I THOUGHT YOUR TIMING WAS ACTUALLY RIGHT ON. ALTHOUGH I AM STILL CURIOUS WHO EFFECTS YOU WOULD SEE IF YOU HAD EXPOSED EVEN EARLIER LIKE DURING PREGNANCY. >> WE HAD NO KNOWLEDGE OF THOSE STUDIES COMING OUT, THIS IS JUST WHERE IT'S LEADING US NOW. >> REALLY INTERESTING. THANKS. >> I HAVE A QUESTION ABOUT ANY EPIDEMIOLOGY RESEARCH CROSS COUNTRIES CORRELATING AUTISM SPECTRUM DISORDER AND EXPOSURE TO POLLUTION? >> SO CROSS COUNTRIES, THE ONLY STUDY I CAN RECALL THAT'S OCCURRED OUTSIDE OF THE UNITED STATES WAS AN ADHD STUDY IN INDIA. EVERYTHING ELSE HAS BEEN HERE, U.S. DAVIS, MOST RECENT STUDY CAME OUT OF PITTSBURGH. NOW I DON'T KNOW IF ANY STUDY IS COMING OUT OF -- THE MORE HEAVILY EXPOSED POPULATIONS. >> THANK YOU VERY MUCH. SO OUR NEXT SPEAKER IS A BIRCWH SCHOLAR FROM THE UNIVERSITY OF KENTUCKY. MICHELLE MARTEL. AND SHE WILL BE TALKING ABOUT PUBERTAL HORMONE ASSOCIATIONS WITH PSYCHOPATHOLOGY. WE JUST HEARD ABOUT FROM ENVIRONMENTAL INPUT AND SHE'S GOING TO BE TALKING ABOUT DYNAMIC CYCLIC AND MODERATED EFFECTS. >> THANK YOU SO MUCH. I WILL BE PRESENTING -- AS DR. MILLER SO NICELY PRESENTED YESTERDAY, IT CAN EXERT BOTH ORGANIZATIONAL AND -- EFFECTS ON PHYSICAL DEVELOPMENT AND BEHAVIOR. TODAY IN MY TALK I'LL BE FOCUSING ON ACTIVATIONAL EFFECTS. ACTIVATIONAL EFFECTS OF HORMONES REFERRED TO LATER OCCURRING EFFECTS OF HORMONES THAT SERVE TO ACTIVATE NEURAL STRUCTURES AND SOMATIC REGIONS THAT WERE PREVIOUSLY ORGANIZED BY GONADAL HORMONES. PUBERTY IS PERHAPS THE MOST WELL-KNOWN AND MOST WIDELY STUDIED ACTIVATIONAL PERIOD BEING ASSOCIATED WITH RAPIDLY RISING AND SURGING LEVELS OF GONADAL HORMONES. PUBERTY IS ALSO THE TIME WHEN GONADAL HORMONES BEGIN TO CYCLE AND FLUCTUATE CYCLICALLY IN WOMEN VIE AT MENSTRUAL CYCLE. MOST IMPORTANT FOR MY TALK TODAY I'LL BE FOCUSING ON ESTRO DOLL, STARTS AT A RELATIVELY LOW LEVEL, RISES TOWARDS THE END OF THE FOLLICULAR PHASE UNTIL IT PEAKS RIGHT BEFORE OFF LAITION, THEN DECLINES DURING THE LUTE YAL PHASE. I'LL ALSO BEING TAWING ABOUT PROGESTERONE, STAYS AT A RELATIVELY LOW LEVEL, PEAKING AT THE MID -- AND THEN DECLINING TOWARDS THE END OF THE CYCLE. IN FEMALES, TESTOSTERONE, ANOTHER HORMONE I'LL BE FOCUSING STAY AT RELATIVELY LOW LEVELS THROUGHOUT THE ENTIRETY OF THE CYCLE AND NOTABLY ALL HORMONES AT RELATIVELY LOW LEVELS OR DECLINING LEVELS. THESE REGULARLY OCCURRING CYCLICAL CHANGES IN HORMONES ACROSS THE MENSTRUAL CYCLE ALLOW FOR A NICE EXPERIMENTAL -- NATURAL EXPERIMENT BY WHICH WE CONTEST GONADAL ASSOCIATIONS WITH PSYCHOPATHOLOGY. GONADAL HORMONES MAY INFLUENCE PSYCHOPATHOLOGY BECAUSE MANY DISORDERS MOST NOTABLY BEING -- AND DEPRESSION HAVE PEAK RATES OF ONSET AND BEGIN TO EXHIBIT -- PREVALENCE RATE THAT BEGIN AROUND PEW BERTIE AND ARE PUBERTY AND SUST AINED FOR THE REST OF THE LIF LIFESPAN. CHILDHOOD DISORDERS, ADHD, CONDUCT DISORDER, EVEN MORE COMMON IN MALES, FEMALES WITH THE IT DISORDERS OFTEN BEGIN TO EXHIBIT MUCH MORE STRIKING LEVELS OF IMPAIRMENT INCLUDING HIGHER LEVELS OF CO-MORBIDITY OWE COOCCURRENCE AT PUBERTY AND AGAIN EXTENDING THROUGHOUT A LOT OF ADULTHOOD. DESPITE THESE WELL-KNOWN AND PRETTY COMMON -- DIFFERENCES ASSOCIATIONS BETWEEN CIRCULATING LEVELS OF GONADA HORMONES AND PSYCHOPATHOLOGY REMAIN RELATIVELY UNDERSTUDIED DURING AND AFTER PUBERTY. THIS IS THE GOAL OF THE PRESENT INVESTIGATION THAT I'LL BE DESCRIBING TODAY. WE EXAMINED IMPACT OF -- ON WITH YOU FEMALE BIASED DISORDER THAT OFTEN BEGINS DURING PUBERTY, BORDERLINE PERSONALITY DISORDER, A DISORDER CHARACTERIZED BY EXTREME -- DISREGULATION AS WELL AS MARKED IMPULSIVITY AND -- BEHAVIORS. THIS DISORDER IS APPROXIMATELY THREE TIMES AS COMMON IN FEMALES COMPARED TO MALES. IN ORDER TO EXAMINE THIS QUESTION, WE CONDUCTED A SHORT-TERM LONGITUDINAL STUDY IN WHICH WE FOLLOWED 40 NORMALLY CYCLING UNDERGRADUATE WOMEN BETWEEN THE AGES OF 8 AND 23. WE FOLLOWED THESE INDIVIDUALS OVER THE COURSE OF A MONTH AND OVERRECRUITED THE SA SAMPLE FOR BORDERLINE PERSONALITY DISORDER SYMPTOMS. BECAUSE WE WERE INTERESTING IN EXAMINING ENVIRONMENTAL AND TRAIT MODERATORS OF -- WE INVITED PARTICIPANTS TO COME IN FOR AN INITIAL LABORATORY VISIT AT WHICH TIME WE HAD PARTICIPANTS SIT DOWN AND CAN COMPLETE CHILDHOOD TRAUMA QUESTIONNAIRE FOCUSING ON SEXUAL ABUSE SUBSCALE AS WELL AS FIVE FACTOR MODEL RATING SCALE WITH A FOCUS ON NEUROTICISM. WE SUBSEQUENTLY HAD PARTICIPANTS COME BACK IN EACH WEEK AT THE SAME TIME AND DAY FOR THE NEXT MONTH TO PROVIDE -- SAMPLES FROM WHICH WE WERE ABLE TO ASCERTAIN CIRCULATING LEVELS OF ES TRA DOLL AND PROGESTERONE. WE HAD THEM MULTILEVEL MODELING INDICATED THAT WITH IN PERSON CYCLICAL DECREASES IN ESTRADIOL WERE ASSOCIATED WITH PERSONALITY DISORDER SYMPTOMS BUT ONLY FOR THOSE INDIVIDUALS WITH HIGH OR VERY HIGH TRAIT NEUROTICISM SHOWN ON THE LEFT, OR THOSE WHO ARE EXPOSED TO HIGH LEVELS OF CHILDHOOD SEXUAL TRAUMA SHOWED ON THE RIGHT. OVERALL THESE RESULTS ARE CONSISTENT WITH THE IDEA THAT AS ESTRADIOL DECREASES ACROSS THE MENSTRUAL CYCLE AND TOWARDS THE END OF THE MENSTRUAL CYCLE, PORE DER LINE PERSONALITY DISORDER SYMPTOMS INCREASE BUT ONLY IN THE CONTEXT OF HIGH TRAIT NEUROTICISM OR HIGH CHILDHOOD SEXUAL TRAUMA. WE ALSO EXAMINED THE RELATIONSHIP BETWEEN CIRCULATING ESTRADIOL, TESS TO THE TROAN AND A COMMON BEHAVIORAL DISORDER OF CHILDHOOD THAT OFTEN EXHIBITS WORSENING SYMPTOMS DURING ADOLESCENCE IN FEMALES ADHD, DEFINED BY CLINICALLY SIGNIFICANT HYPERACTIVITY AND IMPULSIVITY. WE CONDUCTED A CROSS-SECTIONAL STUDY OF 312 ADOLESCENTS AGES 8 TO 17, 134 OF WHOM WERE FEMALE, AND ALL OF WHOM WERE OVERRECRUITED FOR CLINICALLY SIGNIFICANT ATTENTION PROBLEMS. ALL PARTICIPANTS COMPLETED A MULTISTAGE MULTI-INFORMANT ASSESSMENT PROCEDURE DURING WHICH TIME PARENTS AND TEACHERS COMPLETED THE ADHD RATING SCALE AND WE OBTAINED CIRCULATING LEVELS OF -- VIA VENAPUNCTURE. MAIN STUDY RESULTS INDICATED THAT THE ASSOCIATION BETWEEN TESTOSTERONE SHOAP SHONE ON THE LEFT AND RATIOS SHOWN ON THE RIGHT WAS STRONGER IN FEMALES COMPARED TO MALES, SUCH THAT HIGHER LEVELS OF TESTOSTERONE WERE ASSOCIATED WITH DECREASED ADHD SYMPTOMS. IN FEMALES BUT NOT IN MALES. WITH THE SAME PATTERN EMERGING FOR TES TESTOSTERONE ESTRADIOL RATIOS THIS IS CONSISTENT WITH THE IDEA THAT INCREASED TESS TON TROAN IS ACTUALLY PROTECTIVE AGAINST ADHD SYMPTOMS IN FEMALES FEMALES. OVERALL, THESE RESULTS ARE CONSISTENT WITH THE IDEA THAT GO IINGOA NADAL HORMONES -- MAY ACHIEVE THESE EFFECTS BY -- IMPORTANT ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH PSYCHOPATHOLOGY SUCH AS SEXUAL ABUSE BY LITERALLY GETTING UNDER THE SKIN AND AFFECTING PHYSIOLOGY. IN ADDITION, GONADAL HORMONES MAY WORK TO ENFLEUNS INDIVIDUAL DIFFERENCES IN TRAITS THAT ARGUABLY CONFER RISK FOR PSYCHOPATHOLOGY SUCH AS NEUROTICISM. THESE RESULTS ARE ALSO CONSISTENT WITH EVOLUTIONARY THEORY, SPECIFICALLY THAT OF SEXUAL SELECTION THAT SUGGESTS THAT CERTAIN ACTIVITIES SUCH AS MATE SELECTION AND REARING OF OFFSPRING ARE MORE IMPORTANT FOR FEMALE, PARTICULARLY IN THE MORE TRADITIONAL HUNTER GATHERER SOCIETIES, WHICH MAY FACILITATE TRAITS SUCH AS ATTENTION AND NEUROTICISM, AND MAY MAKE THOSE TRAITS MORE INFLUENCED BY HORMONAL MECHANISMS LIKE ESTRADIOL, PROGESTERONE AND TESTOSTERONE. IN ADDITION, FEMALES MAY BE MORE SENSITIVE TO ENVIRONMENTAL FACTORS THAT EMPLOY IMPORTANT CLUES ABOUT THE HEALTHINESS OF THE CAREGIVING ENVIRONMENT SUCH AS SEXUAL ABUSE. FINALLY, BE AS TESSS T TESTOSTERONE IS THOUGHT TO BE ASSOCIATED WITH SOCIAL DOMINANCE, SOCIAL DOMINANCE MAY PROVIDE -- MAKE FOR GREATER IMPORTANCE OF TRAITS LATED TO INHIBITORY CONTROL TO ALLOW FEMALES TO MORE EFFECTIVELY MANIPULATE THE INTERPERSONAL CONTEXT INCLUDING ROMAN TAKE RELATIONSHIPS AND SOCIAL SUPPORT NETWORKS IMPORTANT FOR REARING YOUNG. IN ADDITION, THESE TYPES OF EFFECTS MIGHT BE EXPECTED TO CHANGE ACROSS THE LIFE SPAIN IN RESPONSE TO THE VERY PROMINENT BUT VARYING SOCIAL CHALLENGES EXPERIENCED AT DIFFERENT DEVELOPMENTAL PERIODS. SO FOR EXAMPLE, SOCIAL DOMINANCE MAY BECOME PARTICULARLY IMPORTANT AT PUBERTY AND, THEREFORE, IT MIGHT BE UNDERPINNED BY CERTAIN LEVELS OF HORMONES INCLUDING TESTOSTERONE AT THAT TIME. IN LINE WITH THIS IDEA, GONADAL HORMONES ASSOCIATED WITH BEHAVIOR MAY BE EXPECT TODAY CHANGE ACROSS THE MENSTRUAL NATURE DUE TO CHANGING -- SO FOR EXAMPLE, TOWARDS THE END OF THE MENSTRUAL CYCLE, WHEN PROGESTERONE AND ES TRO GENERAL ARE DECLINING, BORDERLINE PERSONALITY DISORDER AND DEPRESSION, WHICH WE ALSO HAVE DATA ON BUT I DIDN'T HAVE TIME TO PRESENT TODAY, MAY INCREASE, PERHAPS PARTICULARLY DURING CYCLES IN WHICH PREGNANCY HAS NOT OCCURRED DUE TO THEIR RELATIVELY LOW IMPACT ON CHANCE OF CONCEPTION AT THIS LOAFER TILT POINT IN THLOWFERTILITY POINT IN THE CYCLE. IN CONTRAST DURING THE MID LUTE YAL PHASE, BULIMIA SYMPTOMS, PERHAPS SYMPTOMS RELATED TO OVEREATING, MAY INCREASE IN ORDER TO FACILITATE PREGNANCIES AT THIS POINT IN THE CYCLE. WE HAVE DATA ON THIS THAT I DIDN'T HAVE TIME TO PRESENT TODAY EITHER, BUT KELLY'S LAB HAS DONE A LOT OF WORK ON THIS AS WELL. AND FINALLY, TOWARDS THE END OF THE FOLIC LAR PHASE, AS ESTROGEN AND ESTRADIOL ARE INREESING, ONE MIGHT SEE AIN CREASE IN RISK TAKING BEHAVIORS, SUCH AS ADHD IMPULSIVITY, PRO MISCU PRO MISCUE -- SEEIN G THESE TYPES OF DIFFERENTIAL EFFECTS ACROSS THE MENSTRUAL CYCLE SUGGEST THE IMPORTANCE OF EXAMINATION OF HORMONAL EFFECTS ON PSYCHOPATHOLOGY ACROSS DIFFERENT IMPORTANT DEVELOPMENTAL PERIODS SUCH AS AT PUBERTY. IN ADDITION, IT WILL BE IMPORTANT FOR FUTURE WORK TO CONTINUE TO EXAMINE TRAIT MARKERS AND ENVIRONMENTAL MODERATORS OF ASSOCIATIONS BETWEEN HORMONES AND PSYCHOPATHOLOGY, USING SOME TYPE OF A THEORY DRIVEN APPROACH, AND LAST BUT NOT LEAST, THIS KIND OF WORK HAS IMPORTANT IMPLICATIONS FOR INTERVENTION AND PREVENTION THAT COULD BE TARGETED TO DIFFERENT DEVELOPMENTAL PERIODS SUCH AS PUBERTY, TO IMPORTANT ENVIRONMENTAL FACTORS LIKE SEXUAL ABUSE, AS WELL AS POTENTIALLY MODIFIABLE TRAITS SUCH AS NEUROTICISM THAT ARGUABLY INCREASE RISK FOR PSYCHOTHAT POLG. PSYCHOPATHOLOGY. BIG THANKS TO MY BIRCWH FUNDING, MY EXTENSIVE TEAM AS WELL AS STUDY PARTICIPANTS, AND THANK YOU 230 FOR YOUR ATTENTION. [APPLAUSE] >> HI, FROM NORTHWESTERN. THIS TYPE OF RESEARCH IS VERY INTERESTING, BUT THE CONCLUSIONS ARE BASED ON CORRELATIONS. WHAT ABOUT INTERVENTIONS? I MEAN, I'M AN ENDOCRINOLOGIST, WE GIVE ESTRADIOL, TESTOSTERONE AND PROGESTERONE ALL THE TIME IN DIFFERENT MANIPULATIONS SO YOU COULD REALLY SPECIFICALLY ADDRESS YOUR HYPOTHESES. >> YES, THANK YOU. THAT'S AN EXCELLENT POINT. I'VE BEEN VERY INTERESTED IN PURSUING THAT, NOT IN IN LINE OF WORK BUT A LOT OF MY OTHER WORK LOOKS AT ETIOLOGY OF BEHAVIOR DISORDERS USING MORE EXPERIMENTAL QUOTE-UNQUOTE DESIGNS, SO BEHAVIORAL TREATMENT OUT COME FOR STUDYING PATHWAYS, BUT FOR THIS PARTICULAR PROJECT, I THINK WHAT YOU MENTION IS PARTICULARLY IMPORTANT. I'M VERY FORTUNATE TO BE PART OF THE BIRCWH, SO I HAVE ACCESS TO DATA IN WHICH HORMONES ARE EXPERIMENTING -- EXPERIMENTALLY MANIPULATED. FOR EXAMPLE, WOMEN UNDERGOING FERTILITY TREATMENTS, SO ONE THING I'D LINING TO DO IN THE FUTURE IS TO LOOK AT THAT, BUT I ALSO THINK THAT CLINICAL POPULATIONS LIKE FOR EXAMPLE THOSE WITH PCOS OR THOSE WHO HAD SILICATE PRENATAL IMFLEUNSES CAH, MAY ALSO BE USEFUL, BUT OF COURSE MEDICATIONS COULD BE YET ANOTHER ROUTE. I'D BE VERY INTERESTED IN HEARING YOUR THOUGHTS ABOUT IT OR TALKING ABOUT IT. >> I WOULD STRONGLY A ADVISE YOU TO DO VERY STRONGLY CONTROLLED HORMONAL ADMINISTRATION RATHER THAN STUDIES AND EXPERIMENTS IN NATURE. >> I THINK THAT IS AN IMPORTANT APPROACH. TYPICALLY THE WAY I KIND OF DESIGN MY WORK IS TO LOOK, YOU KNOW, KIND OF LEAST INVASIVE TO MOST INVASIVE, BUT DEPENDING ON WHAT -- CERTAINLY US A MOVE ALONG, IT WILL BE VERY IMPORTANT TO DO MORE RIGOROUS EXPERIMENTAL DESIGNS AND ALSO ANIMAL WORK CAN BE HELPFUL IN THAT WAY AS WELL. THANK YOU. OTHER QUESTIONS? >> THANK YOU VERY MUCH. [APPLAUSE] I WILL NOW TURN OVER TO WILLIAM MILLER, WHO WILL BE THE MODERATOR FOR THE REMAINING FOUR PRESENTATIONS IN THIS SESSION. I NOW HAVE THE PRIVILEGE TO INTRODUCE OUR NEXT SPEAKER, DR. REBECCA SCHMIDT, WHO IS A BART SCHOLAR AT THE UNIVERSITY OF CALIFORNIA DAVIS. SHE WILL BE TALKING ABOUT THE PERICONCEPTIONAL FOLIC ACID CONTAINING SUPPLEMENTS AND LINE-1 DNA METHYLATION IN THE MARBLES PERSPECTIVE STUDY OF AUTISM SPECTRUM DISORDER. >> HI. THANK YOU FOR THE CHANCE TO TALK ABOUT MY RESEARCH. AUTISM SPECTRUM DISORDERS IS A NEURODEVELOPMENTAL DISORDER CHARACTERIZED BY EXPERIMENTS IN SOCIAL RECIPROCITY, LANGUAGE AND COMMUNICATION DEFICITS, REPETITIVE BEHAVIORS AND RESTRICTED INTERESTS. AND ALL THESE SYMPTOMS ARE USUALLY PRESENT BY THE TIME THE CHILD IS AGE 36 MONTHS WHEN A RELIABLE DIAGNOSIS CAN BE MADE. THE PREVALENCE OF AUTISM HAS BEEN INCREASING AND IT IS NOW ESTIMATED BY THE CDC TO AFFECT 1 IN EVERY 68 CHILDREN IN THE UNITED STATES. AND THIS IS DOUBLED IN JUST THE TIME I'VE STARTED THIS RESEARCH. AND THE SEX RATIO IS HIGHLY SKEWED SUCH THAT IT AFFECTS 4 OR 5 MALES FOR EVERY ONE FEMALE. WE KNOW IT HAS A NEUROBUBIOLOGIC BASIS FROM AUTOPSY STUDIES THAT SHOW SIGNS OF ABERRANT BRAIN DEVELOPMENT, YET THE CAUSES OF AUTISM REMAIN UNKNOWN, AND MY WORK HAS BEEN -- THE GOAL OF MY WORK HAS BEEN TO LOOK FOR WAYS TO PREVENT AUTISM. AND SO I'VE STARTED WITH AN INTEREST IN FOLIC ACID, WHICH IS A SI SYNTHETIC FORM OF FOLATE BEING AN ESSENTIAL B VITAMIN THAT'S VERY IMPORTANT FOR THE DEVELOPMENT OF THE BRAIN AND VUS SYSTEM. WE KNOW FOLIC ACID CAN DECREASE THE RISK FOR NEURAL TUBE DEFECTS, WHICH ARISE FROM ABNORMAL DEVELOPMENT OF THE BRAIN, AND IT CAN PREVENT THAT BY UP TO 70%. WE ALSO HAVE HAD RECENT STU IT DIS, COHORT STUDIES THAT HAVE SHOWN DECREASED RISK FOR LANGUAGE DELAYS, BEHAVIOR, SOCIAL AND PEER PROBLEMS ASSOCIATED WITH FOLIC ACID INTAKE IN VERY EARLY PREGNANCY, AND ALSO WITH IMPROVED ATTENTION IN VERBAL FUNCTION AND SOCIAL COMPETENCE. SO MY PREVIOUS WORK HAS SHOWN IN A LARGE CASE CONTROL STUDY THAT TAKING PRENATAL VITAMINS AND FOLIC ACID AROUND CONCEPTION WAS ASSOCIATED WITH A 40% REDUCTION IN RISK FOR AUTISM SPECTRUM CAN DISORDERS IN THE CHILD. AND THAT WORK HAS NOW BEEN REPLICATED BY A VERY LARGE BIRTH COHORT STUDY IN NORWAY WITH OVER 85,000 CHILDREN. AND OUR WORK IN PARTICULAR SHOWED THAT THIS WAS TRUE FOR INDIVIDUALS WHEN EITHER THE MOTHER OR THE CHILD HAD GENETIC SUSCEPTIBILITY TO INEFFICIENT ONE CARBON METABOLISM. WA WE WANT TO KNOW NOW IS ARE THE POTENTIAL MECHANISMS BEHIND THIS -- THAT MIGHT BE ASSOCIATED WITH FOLIC ACID INTAKE NEAR CONCEPTION. WE SO FAR HYPOTHESIZE IT MIGHT HAVE SOMETHING TO DO WITH FOLATE'S ROLE AS A METHYL DONOR, WHICH IS THE ADDITION OF THIS METHYL GROUP TO DNA, USUALLY A CPD SITE WHICH CHANGES GENE EXPRESSION AND CONFIGURATION AND WHICH COULD BE REALLY IMPORTANT DURING TIMES OF EARLY DEVELOPMENT. SO IN MY STUDIES, THERE ARE THESE TWO PERIODS OF DYNAMIC DNA METHYLATION WHERE THE METH LOAN IS BASICALLY WIPED OUT AND RE-ESTABLISHED, AND NOW THIS HAS BEEN SHOWN JUST THIS YEAR THAT IT ALSO OCCURS IN HUMAN, SO RIGHT ABOUT THE TIME OF CONCEPTION, YOU CAN SEE THAT ON THE Y AXIS IS THE LEVELS OF DNA METHYLATION, WHICH ARE TYPICALLY VERY HIGH ACROSS THE GENOME, AND THEN RIGHT AROUND CONCEPTION, THE METHYLATION LEVEL IS GLOBALLY DEMETHYLATED AND THEN RIGHT AFTER IMPLANTATION, IT'S REMETHYLATED AND SO IT'S RE-ESTABLISHED AND YOU CAN IMAGINE THAT DURING THIS PERIOD AFTER IMPLANTATION, WHEN THE METHYLOME IS BEING RE-ESTABLISHED IN THE OFFSPRING, COULD BE A REALLY IMPORTANT TIME TO HAVE AN ADEQUATE SUPPLY OF METHYL DONORS FROM A SOURCE LIKE FOLATE. SO WE DO SEE THIS IN BOTH HUMAN AND ANIMAL STUDIES THAT THE LEVELS OF DIETARY METHYL DONORS CAN AFFECT THE OFFSPRING'S LEVEL OF DNA METHYLATION AND GENE EXPRESSION, AND THEN IN ANIMAL STUDIES, WITH THESE -- MICE HERE, IT'S ALSO BEEN SHOWN THAT THIS CAN IMPACT THE HEALTH OUTCOMES OF THE OFFSPRING, SO THESE ARE GENETICALLY IDENTICAL MICE, BUT YOU CAN SEE THE BROWN MOUSE ON THE RIGHT WHO'S SLEEKER TENDS TO BE HEALTHIER. THE ONLY DIFFERENCE IS THAT HIS MOTHER HAD A HIGH METHYL DIET DURING EARLY PREGNANCY, AS OPPOSED TO THE OBESE YELLOW MOUSE. WHOSE MOM HAD NORMAL DIET. SO WHAT WE WANTED TO SEE WAS WHETHER THESE EFFECTS WERE OCCURRING IN HUMAN STUDIES WITH EFFECTS LIKE AUTISM. SO WE DID THIS LOOKING IN THE MARBLES COHORT STUDY, WHICH IS PLANNING TO ENROLL 300 MOTHERS WHO HAVE A CHILD WITH AUTISM ALREADY AND THEN ARE PLANNING OR ARE PREGNANT WITH ANOTHER CHILD. AND WE FOLLOW THESE MOMS THROUGHOUT THEIR PREGNANCY, WE GET DIETARY INFORMATION AND LOTS OF SAMPLES, AND THEN WE FOLLOW THE CHILD ALL THE WAY THROUGH UNTIL THEY'RE AGE 36 MONTHS, WHEN A RELIABLE DIAGNOSIS OF AUTISM CAN BE MADE. AND WE BRING THEM IN TO SEE WHERE WE MAKE THAT DIAGNOSIS. WE STARTED BY LOOKING AT WHETHER WE COULD REPLICATE THE FINDINGS WE SAW WITH OUR CASE CONTROLLED STUDY WHICH WAS THE GENERAL POPULATION, AND THIS HIGH RISK POPULATION WHERE THERE'S A GENETIC SUSCEPTIBILITY ALREADY FOR AUTISM, THE SIBLINGS OF CHILDREN WITH AUTISM ARE USUALLY AFFECTED IN ABOUT ONE OF FIVE, ABOUT 20%, SO THEY HAVE A MUCH HIGHER GENETIC LOAD. WE DIDN'T KNOW IF ENVIRONMENTAL EXPOSURES WOULD HAVE AS MUCH OF A ROLE. BUT IT TURNS OUT, IN OUR DATA SO FAR, WE SEE THAT IF THE MOM DID NOT TAKE A PRENATAL VITAMIN IN THE FIRST MONTH OF PREGNANCY OR BEFORE, THE CHILD IS INDEED ASSOCIATED WITH A FOUR TIMES THE RISK FOR DEVELOPING AUTISM. THEN WHEN WE QUANTIFY FOLIC ACID INTAKE FROM ALL SOURCES, SUPPLEMENTS AND CEREALS, WE SEE THAT, AGAIN, SPECIFICALLY DURING THE VERY FIRST MONTH OF PREGNANCY, THAT MOTHERS WHOSE CHILDREN WENT ON TO DEVELOP AUTISM HAVE REPORTED TAKING LESS FOLIC ACID AND YOU CAN ALSO NOTE THAT ON AVERAGE, THEIR LEVELS WERE BELOW THE RECOMMENDED INTAKE, WHICH IS AROUND 600 MICRO GRAMS DURING PREGNANCY. WHEREAS THE PARENTS WHOSE CHILDREN WENT ON TO DEVELOP TYPICALLY WERE ON AVERAGE ABOVE THAT LEVEL. SO WE ALSO LOOKED A LITTLE BIT BY DOSE AS MUCH AS WE COULD WITH A FAIRLY SMALL SAMPLE SIZE WE HAVE SO FAR, AND WHAT WE FOUND WAS THAT THERE'S SOME EVIDENCE FOR DOSE -- IF THEY TOOK NO FOLIC ACID, THEIR RISK WAS CLOSER TO IT FOUR TIMES, BUT IF THEY TOOK SOME FOLIC ACID BUT STILL BELOW THE RECOMMENDATION, THEIR LEVEL IS ABOUT TWICE THE RISK. SO THEN WE WENT ON TO LOOK AT POSSIBLE MECHANISMS FOR THIS ASSOCIATION, AND WE DID THIS USING LINE-1 DNA METHYLATION SO THAT ALONG INTERSPERNSING NUCLEAR ELEMENTS THAT ARE REPEAT DNAs THROUGHOUT THE GENOME, AND THIS IS USED AS A MARKER OF GLOBAL LEVELS OF DNA METHYLATION. WE DID THIS IN BOTH MATERNAL SAMPLES THAT WERE COLLECTED THROUGHOUT PREGNANCY AND ALSO IN THE CHILD'S PERIPHERAL BLOOD USING WHOLE BLOOD. WE DID THIS USING A KIT AND WE DID DUPLICATE RUNS AVERAGES ACROSS STORE SITES. WHAT WE FOUND WAS THAT THERE WAS AN ASSOCIATION SUCH THAT MATERNAL FOLIC ACID INTAKE ON THE BOTTOM, AS IT INCREASED, THE LINE-1 DNA METH LITION ALSO IN THE CHILD, ALSO INCREASED. AND THIS IS LOOKING AT FOLIC ACID AGAIN IN THAT FIRST MONTH OF PREGNANCY. WE ALSO LOOKED AND LINE-1 DNA METHYLATION BY THE CHILD'S OUT COME. WE SEE JUST A TREND THAT THE CHILD'S DNA METHYLATION TENDS TO BE LOWER IN THE CHILDREN WHO WENT ON TO DEVELOP AUTISM. YOU CAN SEE OUR NUMBERS ARE SMALL BUT WE'RE CONTINUING TO DO MORE MEASUREMENTS AS THESE CHILDREN AGE. YOU CAN ALSO SEE THERE'S NO DIFFERENCE BETWEEN THE MOTHER'S DNA METHYLATION. SO IN SUMMARY, MATERNAL FOLIC ACID INTAKE IN THE FIRST MONTH OF PREGNANCY WAS ASSOCIATED WITH REDUCED RISK FOR AUTISM EVEN IN HIGH RISK OF CHILDREN WITH AUTISM SO THIS IS A WAY TO DO SECONDARY PREVENTION OF AUTISM WITHIN FAMILIES. WE ALSO SAW THAT HIGHER MATERNAL FOLIC ACID WAS ASSOCIATED WITH HIGHER GLOBAL DNA METHYLATION IN THE CHILD AND WE SAW THAT LOWER DNA METHYLATION SHOWED A TREND TOWARDS BEING ASSOCIATED WITH THE CHILD'S OUT COME OF ASD. SO OUR NEXT STEPS ARE TO FOLLOW UP THIS WORK AND DO DEEPER SEQUENCING OF THE METHYLOME SO WE GET SITE-SPECIFIC DNA DATA. WE STARTED TO DO THIS ON A SUBSET OF SAMPLES USING PLACENTA TISSUE, AND SO FAR WHAT WE'VE FOUND IS THAT THERE WERE DIFFERENTIAL METHYLATION BASED ON PRENATAL VITAMIN INTAKE EARLY ON IN GENES THAT WERE RELEVANT TO NEURAL DEVELOPMENT REGULATION. WE ALSO LOOK CLOSER AT THE FOLATE STATUS AND OTHER DNA VITAMINS USING DIET TRI DATA WE HAVE AND OTHER MEASURED METABOLITES. AND FINALLY WE WANT TO ADD PHENOTYPE DATA, WE HAVE SHOWN -- HAD BENEFITED MORE FROM FOLIC ACID SUPPLEMENTS, SO NOW WE WANT TO REPLICATE THIS IN THIS PRO PECK SPIFF STUDY OR AT LEAST TAKE THIS INTO ACCOUNT WHILE ALSO LOOKING AT DNA METHYLATION. SO ALL THESE THINGS HAVE NOW -- THIS WAS USED FOR PRELIMINARY DATA AND WE'VE SUBMITTED AN RO1 IN AUGUST TO DO SOME OF THESE NEXT STEPS. I'VE -- JOINT COLLABORATION TO START FOLLOWING UP EXISTING FOE KICFOLIC ACID INTERVENTION TRIALS WHERE THEY RANDOMIZED FOLIC ACID DURING PREGNANCY AND POLLED THOSE OUTCOMES UP FOR AUTISM. I'D LIKE TO ACKNOWLEDGE ALL THE PEOPLE THAT HAVE HELPED WITH THIS WORK INCLUDING COLLABORATORS AND ALSO THE MENTORS SHOWN IN THE PICTURES AND BOLDED NAMES, ALSO THE FUNDERS OF THIS WORK WHICH INCLUDE BIRCWH AND OTHERS AT THE NIH. ALSO THE BIRCWH DIRECTORS AND SCHOLARS FOR ALL OF THEIR VALUABLE INPUT. WITH THAT, I'LL TAKE ANY QUESTIONS. [APPLAUSE] >> EXCELLENT. EXCELLENT PRESENTATION. I DO HAVE ONE QUESTION. IN REGARD TO YOUR FUTURE EXPERIMENTS WITH THE DIETARY DATA, YOU MENTIONED THE HIGH METHYL DIET, SO WOULD IT BE BEN PICIAL DEPENDING ON THAT DAY TO REALLY EDUCATE THOSE WHO ARE AT HIGH RISK IN REGARDS TO WHAT CONSTITUTES A HIGH METHYL DIET AND ALSO PROCEDURES AS TO HOW PHYSICIANS SHOULD MOVE FORWARD IN TREATING THOSE PATIENTS? >> SO THAT'S A GREAT QUESTION. WE HAVE ALREADY THE RECOMMENDATION IS TO TAKE FOLIC ACID EARLY IN PREGNANCY. I WAS SURPRISE TODAY SEE EVEN IN THIS COHORT WHERE THEY'RE ALL PLANNING A PREGNANCY THAT SO MANY WERE NOT TAKING A PRENATAL VITAMIN AND NOT TAKING EXTRA FOLIC ACID, SO I DO THINK THERE'S EDUCATION THAT SHOULD BE DONE. AS FAR AS WHAT CONSTITUTE A METHYL -- HIGH METHYL DIET, I THINK IT'S IMPORTANT FOR US TO LOOK AT WHAT OTHER FACTORS MIGHT BE BENEFICIAL AND I THINK ONCE WE KNOW THAT, WE CAN ADD THAT TO LITERATURE, BUT I THINK WE ALREADY KNOW SOME THINGS LIKE B12 SHOULD ALSO BE GIVEN WITH FOLATE, AND B6, SO THAT IS SOMETHING ELSE THAT WE CAN START EDUCATING MOMS ON. >> AT THIS TIME, I WOULD LIKE TO CALL UP VALERIE O'BRIEN. SHE IS ACTUALLY A DOCTORAL CANDIDATE THAT IS PRESENTING ON BEHALF OF DR. THOMAS J. HANNAN, WHO IS A BIRCWH SCHOLAR, FROM WASHINGTON UNIVERSITY SCHOOL OF MEDICINE. AND WE'LL BE TALKING ABOUT INHIBITION OF CYCLOO X-Y GENASE-2 PREVENTS CHRONIC AND RECURRENT CYST STIETS. CYSTITIS. >> THANK YOU, EVERYBODY, GROWR ATTENTION, THANK YOU TO THE ORWH FOR THE INVITATION TO SPEAK, THE RESEARCH BEING DONE AT WASHINGTON UNIVERSITY IN ST. LOUIS, BEING SPEARHEADED BY TOM HANNAN WITHIN THE GROUP. SO WE STUDY URINARY TRACT INFECTIONS OR UTI, WHICH ARE A VERY COMMON AND HIGHLY RECURRENT BACTERIAL INFECTION. NOW NEUROPATHOGENIC E. COLI CAUSE ABOUT 85% OF COMMUNITY ACQUIRED UTI, THEY'RE THE DOMINANT PATHOGEN, AND IT'S IMPORTANT TO NOTE THAT MULTIDRUG RESISTANCE AMONG ISOLATES IS ON THE RISE AND WE ARE IN DANGER OF HITTING A TIPPING POINT WHERE WE MAY RUN OUT OF ANTIBIOTICS TO BE ABLE TO TREAT WHAT SHOULD BE A SIMPLE CLINICAL INFECTION. NOW THE RISK FACTORS OF UTI INCLUDE EXPOSURE PRIMARILY BUT NOT ALWAYS THROUGH SEXUAL ACTIVITY. HISTORY, WITH KNO WE KNOW HAVING UTI DURING CHILDHOOD SETS UP WOMEN FOR LIFETIME, TEND TO HAVE DAUGHTERS THAT HAVE RECURRENT UTI -- INCREASED RISK. SO IF WE'RE GOING TO STU IT DI THIS CLINICAL PROBLEM OF RECURRENT UTI IN MICE, WE NEED TO INCORPORATE THESE RISK FACTORS INTO A MOUSE MODEL. WHAT WE HAVE FOUND IS THAT BY USING DIFFERENT MOUSE STRAINS, WE CAN MODEL DIFFERENT OUTCOMES OF UTI. SO WHAT I'M SHOWING YOU ON THIS GRAPH HERE IS THE OUTCOME OF A FOUR WEEK EXPERIMENTAL INFECTION WITH A CLINICAL UPEC ISOLATE. I'M SHOWING BACTERIA BACK BACTERIAL TITERS , C57 BLACK SIX MICE, COMMONLY USED MOUSE STRAIN, IN FACT, YOU'VE ALREADY HEARD ABOUT THEM TODAY IN OTHER TALKS, AND YOU CAN SEE THAT BY FOUR WEEK, THESE MICE HAVE RESOLVED THE INFECTION. THEY HAVE LOW BLADDER BACTERIAL BURDEN. THESE MICE ARE ABLE TO GET ACUTE UTI BUT THEN THEY RESOLVE IT WITHIN A WEEK OR SO. HOWEVER ON THE RIGHT SIDE IS A DIFFERENT STRAIN, YOU CAN SEE THAT MANY OF THEM HAVE HIGH BLADDER BACTERIAL BURDEN AT TIME OF SACRIFICE, AS WELL AS HISTOLOGICAL EVIDENCE OF BLADDER INFLAMMATION SHOWN HERE BY LYMPHOID FOLLICLES AND DRAMATIC EXFOLIATION OF THE UROTHEEL YUM OR BLADDER EPITHELIUM. SO WE SAY THAT THESE MICE HAVE DEVELOPED CHRONIC CYSTITIS OR CHRONIC BLADDER INFECTION. WE WONDERED WHETHER THESE MICE HAD CHRONIC CYSTITIS BECAUSE THEY WERE IMMUNODEFICIENT IN SOME WAY AND UNABLE TO CLEAR OUT THE INFECTION, BUT THAT SEEMS NOT TO BE THE CASE. FIRST OF ALL W WE KNOW THE MICE HAD A VERY SEVERE ACUTE PYURIA OR KNEW FO NEUTROPHILS COMING OUT IN THE URINE, FURTHERMORE THEY ARE ACTUALLY RESISTANT TO DEVELOPING CHRONIC CYSTITIS. NIVE, WHAT WE FOUND IS A SERIES OF SERUM BIOMARKERS DURING THE ACUTE INFECTION THAT CORRELATE WITH CHRONIC CYSTITIS. WHEN WE LOOK AT THESE BIOMARKERS, THE MICE WITH THE HIGHEST LEVELS ALSO HAVE THE GREATEST ACUTE INFLAMMATION IN THE BLADDER, SUGGESTING THAT ACUTE INFLAMMATION MIGHT ACTUALLY BE CAUSING CHRONIC CYSTITIS. TO TEST THIS HYPOTHESIS, WE IMMUNOSUPPRESSED MICE USING DEX TA MESS ZONE, BROADLY ACTIVE, WE GAVE MICE PRIOR TO INFECTION AND THESE MICE THAT WERE DE CAN X TREATED HAD SIGNIFICANTLY REDUCED ACUTE BLADDER INFLAMMATION, AS WELL AS SIGNIFICANTLY DECREASED INCIDENCE OF CHRONIC CYSTITIS. SO BY PREVENTING THAT SEVERE ACUTE INFLAMMATION, WE COULD PREVENT CHRONIC CYSTITIS IN OUR MICE. THIS LED US TO A MODEL OF AN ACUTE HOST PATHOGEN CHECKPOINT THAT DETERMINES THE OUTCOME OF UTI. SO WHEN UROPATHOGENIC E. COLI ENTERS THE BLADDER AND BEGINS TO ESTABLISH INFECTION, IF THE HOST HAS A WEAK TO MODERATE IMMUNE RESPONSE THIS, IS AN APPROPRIATE RESPONSE THAT ALLOWS THE HOST TO RESOLVE THE INFECTION. HOWEVER, IF THE HOST HAS A VERY SEVERE INFLAMMATORY RESPONSE, THIS RESULTS IN THE DEVELOPMENT OF CHRONIC CYSTITIS. IN DATA THAT I DON'T HAVE TIME TO SHOW YOU RIGHT NOW, IT IF THE HOST IS ALLOWED TO HAVE THIS CHRONIC INFECTION FOR AT LEAST TWO TO FOUR WEEKS, THIS RESULTS IN BLADDER MUCOSAL REMODE ELING THAT SENSITIZES THE MOUSE OR THE HOST TO DEVELOP CHRONIC RECURRENT CYSTITIS. NOW THIS MODEL IS NICE BUT OF COURSE WE'VE GENERATED IT IF MICE AND WE WANTED TO SEE IF IT WAS RELEVANT TO WOMEN. SO WE USED CLINICAL SAMPLES FROM THE HOST STUDY OF RECURRENT UTI, WHICH IS A SCOR STUDY. 86 COLLEGE WOMEN WITH A UTI WERE ENROLLED, AND AT THE TIME OF ENROLLMENT, WE BANKED A SERUM SAMPLE FOR EACH OF THESE WOMEN. THEY WERE FOLLOWED FOR FOUR MONTHS, AND AT THE END OF THE STUDY, WE COULD SEGREGATE THEM INTO THE WOMEN WHO HAD A RECURRENCE DURING THE STUDY AND THE WOMEN WHO DID NOT HAVE A RECURRENCE. WE THEN WENT BACK TO THE BANKED SERUM AND ASSAYED IT FOR 48 DIFFERENT CYTOKINES AND GROWTH FACTORS AND ASKED WHETHER WE COULD USE ANY SORT OF SERUM CYTOKINE SIGNATURE TO PREDICT WHICH WOMEN WOULD HAVE RECURRENCE DURING THE STUDY PERIOD. WE DID FIND SEVERAL DIFFERENT HITS THAT INDICATED MYELOID CELL RESPONSES IN THE DEVELOPMENT OF RECURRENT UTI. I JUST WANT TO DRAW YOUR ATTENTION TO THE MARKERS SHOWN IN GREEN HERE, WERE ALSO STRONGLY PREDICTIVE SERUM BIOMARKERS IN OUR MOUSE MODEL. THESE ARE KNE NEUTROPHIL -- PURPLE MY LOYAL SELL DIFFERENTIATION AND THESE WERE ALSO PREDICTIVE IN OUR MOUSE MODEL. THEN WE HAVE A NICE EXAMPLE OF BASIC SCIENCE RESEARCH BEING DONE IN MICE AND LEADING TO TRANSLATIONAL FINDINGS IN WOMEN. SO BECAUSE OF THESE IMPLICATED MYELOID RESPONSES IN WOMEN WHO DEVELOPED RECURRENT U TCHT I, WE DEVELOPED THE HYPOTHESIS THAT THE ADVANCED ACTIVATION AND RECRUITMENT OF MYELOID IMMUNE CELLS TO THE BLADDER WILL CONTRIBUTE TO BLADDER IMMUNOPATHOLOGY THAT FACILITATES THE DEVELOPMENT OF SEVERE, ACUTE AND CHRONIC CYSTITIS. SO WE WENT BACK TO OUR MOUSE MODEL TO TEST THIS, THE FIRST THING WE DID WAS SOME FLOW CYTOMETRY TO INVESTIGATE WHAT ARE THE MYELOID CELLS THAT ARE RECRUITED TO THE BLADDER IN RESPONSE TO ACUTE INFECTION. THERE ARE RESIDENT MACROPHAGES IN THE BLADDER AND THEY DO NOT INCREASE IN RESPONSE TO UPEC INFECTION. INFLAMMATORY MONO SITES INCREASED DATELY BUT WE HAVE NOT FOUND THEM TO PLAY A STRONG ROLE IN CHRONIC CYS CYSTITIS. BUT BLADDER NEUTROPHILS ALSO STRONGLY INCREASE THE IN RESPONSE TO ACUTE UPEC INFECTION. NOW I ALREADY TOLD YOU THAT HAVING A LOT OF NEUTROPHILS IN THE URINE IS PREDICTIVE OF DEVELOPING CHRONIC CYSTITIS, SO IN THAT REGARD, IT SEEMED TOO MANY NEUTROPHILS WOULD BE BAD. WE HAVE FOUND IF YOU COMPLETELY ELIMINATE ALL KNEW TO NEUTROPHILS FROM MICE, THEY BECOME OVERWHELMED BY INFECTION. WE ASKED COULD WE PERHAPS TEMPER THE NEUTROPHIL RESPONSE? WE USED A NEUTROPHIL DEPLETION ANTIBODY, ANTITIE-LY6G BUT USED ONE-20TH OF THE DOSE IN ORDER TO TRANSIENTLY PARTIALLY DEPLETE NEUTROPHILS IN OUR MICE. THIS HAD NO AFFECT ON BLADDER RESIDENT MACS OR MONOCYTES BUT IT DID RESULT IN A 75% REDUCTION OF NEUTROPHILS INFILTRATING TO THE BLADDER IN RESPONSE TO ACUTE INFECTION. WE ASKED IF THIS HAD THERAPEUTIC CONSEQUENCES. AS EXPECTED, WE SAW A REDUCTION IN URINE NEUTROPHILS IN THE ANTIBODY TREATED MICE SHOWN HERE IN A SEMI QUANTITATIVE SCOR OF URINE SEDIMENTS. AND IMPORTANTLY, WE SAW A SIGNIFICANT REDUCTION IN CHRONIC CYSTITIS IN THE NEUTROPHIL DEPLETED MICE. SO TEMPERING THAT KNEW THROW NEUTROPHIL RESPONSE PROTECTED AGAINST CHRONIC CYSTITIS. I TOLD YOU EARLIER DEX PROTECTED AGAINST CHRONIC CYSTITIS BUT IT'S BASICALLY A SLEDGE HAMMER, IT AFFECTS MANY DIFFERENT PATHWAYS. SHOWN HERE ON THIS VERY COMPLICATED FIGURE. WE FOCUSED IN ON JUST ONE PART OF THE POTENTIAL PATHWAY, WHICH IS THE PROSTINOID PATHWAY. SO IT'S CONVERTED INTO LIPID MEDIATORS OF INFLAMMATION. NOW, CYCLOOXYGENASE ONE OR TOX-1 IS EXPRESSED BY MANY DIFFERENT CELLS BUT COX-2 IS TYPICALLY INDUCED BY INFLAMMATION. THESE ARE AT AN EXCITING TARGET BECAUSE THERE ARE SPECIFIC INHIBITORS OF COX-1 AND COX-2 AVAILABLE. AS WELL AS NSAIDS INHIBIT BOTH COX-1 AND 2. WE THOUGHT WE COULD EXPLORE COX INHIBITORS AND NSAIDS AS A MORE TARGETED APPROACH. SO WE WERE PLEASED TO FIND A PREVIOUSLY PUBLISHED STUDY IN WOMEN, WOMEN WITH AN ACUTE UTI WERE ENROLLED AND RECEIVED EITHER IBUPROFEN, AN NSAID, OR SIP PRO FLOXACIN, ANTIBIOTIC, FOR FIVE DAYS. ACTUALLY AT DAY FOUR AND SEVEN, THERE WAS NO DIFFERENCE IN CLINICAL OUTCOME IN THE WOMEN, WHETHER THEY RECEIVED THE IBUPROFEN OR THE ANTIBIOTICS. SUGGESTING THAT NSAIDS WERE NOT NEARLY MASKING SYMPTOMS BUT PERHAPS ACTUALLY ALTERING THE COURSE OF INFECTION. SO WE THEREFORE RETURNED TO OUR MOUSE MODEL TO TEST NSAIDs. WE FOUND IF MICE RECEIVED TREATMENT PRIOR TO INFEK SHOULD BE, MICE THAT RECEIVED IFDOMETHACIN AS WELL AS MICE THAT RECEIVED A COX-2 INHIBITOR HAD SIGNIFICANTLY REDUCED NEUTROPHILS AND WERE SIGNIFICANTLY PROTECTED FROM CHRONIC CYSTITIS. IT SEEMED TO BE SPECIFIC TO COX-2, BECAUSE IF WE USE THE COX-1 INMIB TORE, THERE IS NO REDUCTION IN URINE NUTRAFILLS AND NO REDUCTION IN CHRONIC CYSTITIS. SO WE ASKED WHY THIS WOULD BE. WE FOUND THAT COX-2 WAS ECK PRESSED BY THE UROTHEEL YUM, NOT BY IMMUNE CELLS IN THE BLADDER, AND ONLY IN THE BLADDERS OF THE MOST SEVERELY INFECTED MICE SHOWN HERE. WE ALSO FOUND THAT COX-2 INHIBITION DID NOT AFFECT NEUTROPHIL RECRUITMENT TO THE BLADDER. BUT I TOLD YOU THAT IT REDUCED THE AMOUNT OF NEUTROPHILS IN THE URINE. SO THIS SUGGESTS THAT CARBON COX-2 SIGNALING BY EPITHELIAL CELLS PROMOTES NEUTROPHIL TRANSMIGRATION THROUGH THE BLADDER OUT INTO THE URINE. IN FACT WHEN WE LOOKED AT HISTOLOGICAL SAMPLES OF THESE MOUSE BLADDER, WE FOUND THAT MOCK TREATED MICE HAD NECROSIS BUT COX-2 INHIBITOR TREATED NICE MEIST WERE PROTECTED FROM THAT AND THE BLADDERS LOOKED MUCH NICER. SO I MENTIONED EARLIER THAT WE HAVE A MO KEL DID FOR RECURRENT UTI, WHICH IS, OF COURSE, THE CLIN ISSUE THAT WE'RE REALLY TRYING TO SOLVE. SO IN THIS MODEL, MICE GET AN INITIAL CHRONIC BLADDER INFECTION LASTING FOR FOUR WEEKS, AND WE THEN TREAT THEM WITH ANTIBIOTICS TO CLEAR OUT THAT INFECTION. AT THAT POINT, WE KNOW IF WE CHALLENGE THE MICE, THEY'RE PREDISPOSED TO DEVELOPING RECURRENT UTI. SO WE ASKED WHETHER WE COULD USE A COX-2 INHIBITOR TO PREVENT THAT, TO PREVENT RECURRENT UC UTI IN THESE MICE. INDEED WHAT WE FOUND IS THAT TOX-2 INHIBITOR TREATED MICE BUT NOT COX-1 INHIBITOR TREATED MICE WERE PROTECTED AGAINST RECURRENT UTI. THE COX-2 INHIBITOR MICE HAD SIGNIFICANTLY LOWER ACUTE BACTERIAL BURDEN IN THE URINE, 24 HOURS AFTER CHALLENGE, AS WELL AS SIGNIFICANTLY REDUCED INCIDENCE OF CHRONIC CYSTITIS. THIS LEADS US TO OUR MODEL, WHERE UPEC ENTERS THE BLADDER AND BEGINS TO ESTABLISH AN INFECTION, A SEVERE INFLAMMATORY RESPONSE RESULTS IN THE RECRUITMENT OF INNATE MYELOID CELLS, ESPECIALLY NEUTROPHILS TO THE BLADDER, AND COX-2 SIGNALING BY THE BLADDER EPITHELIUM ALLOWS THESE NEUTROPHILS TO TRANSMIGRATE BY THE BLADDER THROUGH THE URINE CAUSING MUCOSAL WOUNDING THAT CAN ALLOW FOR THE DEVELOPMENT OF CHRONIC CYSTITIS. HOWEVER, BY TEMPERING THE NEUTROPHIL RESPONSE BY USING THE TRANSIENT PARTIAL DEPLETION, OR BY INHIBITING COX-2 SIGNALING USING NSAIDs OR COX-2 INHIBITORS, WE WERE ABLE TO PREVENT CHRONIC CYSTITIS IN OUR MICE. VERY EXCITED ABOUT THIS NOT ONLY BECAUSE NSAIDs ARE CURRENTLY WIDELY USED IN THE CLINIC, BUT ALSO BECAUSE I M IMMUNOMODULATION AS A THERAPEUTIC STRATEGY IS INTRIGUING BECAUSE IT ALLOWS US TO KEEP THE POTENTIALLY PROTECTED IMMUNE RESPONSES WHILE ABROGATING THE DAMAGING IMMUNE RESPONSES. SO MORE STUDIES ARE NEEDED TO DETERMINE WHETHER THIS IS GOING TO BE EFFECTIVE IN WOMEN OR NOT, BUT WE'RE VERY EXCITED TO START THAT WORK NOW. SO THANK YOU TO THE LAB AT WASHINGTON UNIVERSITY AS WELL AS TO OUR COLLABORATORS AND FUNDING SOURCES. I WOULD BE HAPPY TO TAKE QUESTIONS. [APPLAUSE] LEUSH >> HI, VANDERBILT UNIVERSITY. I HAVE A QUESTION REGARDING THE EPITHELIAL CELL DUCKS OF IL-8 AND IS THAT REDUCED WITH THE ADMINISTRATION OF THE COX-2 INHIBITORS. >> THAT IS A GREAT QUESTION. YOU KNOW, I'M NOT SURE, TO BE HONEST, ABOUT THE CYTOKINE DATA AFTER A COX-2 INHIBITOR TREATMENT. SO CERTAINLY WE'LL WANT TO LOOK AT THAT AS WE FLESH OUT THE USE OF COX-2 INHIBITORS IN OUR MOUSE MODEL. >> GREAT, THANK YOU. >> I HAVE ONE QUESTION. WHAT DO YOU HYPOTHESIZE AS YOU MOVE FORWARD IN UTILIZATION OF NSAIDS AND TREATING UT. UTIs OVER CURRENT UTI IN WOMEN? >> WELL, IDEALLY WHAT WE NEED IN TERMS OF RECURRENT UTI AS A CLINICAL PROBLEM -- SPREAD OF ANTIBIOTIC RESISTANCE AMONG -- SO I THINK WE'RE MOST EXCITED ABOUT NSAIDs AS PROPHYLAXIS TO PREVENT AGAINST RECURRENT UTI IN WOMEN WHO ARE ALREADY SUSCEPTIBLE. WE'RE ALSO WORKING ON OTHER THEITHERAPEUTICS LIKE ANTIVIRULENCE COMPOUNDS AS WELL AS VACCINES, SO WE'RE TRYING TO APPROACH THIS PROBLEM OF ANTIBIOTIC RESISTANCE FROM MULTIPLE ANGLES. >> THANK YOU. [APPLAUSE] AT THIS IT TIME, I WOULD LIKE TO INTRODUCE DR. COD FROM THE UNIVERSITY -- FROM HARVARD MEDICAL SCHOOL AND BRIGHAM AND WOMEN'S HOSPITAL. SHE WILL BE DISCUSSING PLACENTAL ABRUPTION IN TYPE 2 DIABETES RISK IN WOMEN. >> THANK YOU FOR THIS OPPORTUNITY. I AM AN EPIDEMIOLOGIST AT HARVARD MEDICAL CENTER FOR WOMEN'S HEALTH IN THE DIVISION OF WOMEN'S HEALTH AND THIS QUESTION ABOUT PLACENTAL ABRUPTION IS REALLY ROOTED IN OUR STUDY OF USING PREGNANCY COMPLICATIONS THAT WOMEN EXPERIENCE TO PREDID DICTIONARY A WOMAN'S FUTURE RISK OF DEVELOPING CHRONIC DISEASES. AND SO THERE'S A GROWING APPRECIATION NOW FOR PREGNANCY AAT A STRESS TEST. IN THE Y AXIS, WE ARE REPRESENTING VASCULAR DYSFUNCTION SO INCREASING VASCULAR CAN DYSFUNCTION AS SOME SORT OF INDICATOR OF THE FUTURE DEVELOPMENT OF TYPE 2 DIABETES OR CARDIOVASCULAR DISEASE. AND THE BLUE LINE HERE ACROSS THE MIDDLE IS REALLY REPRESENTING A CLINICAL THRESHOLD AT WHICH POINT IF A WOMAN CROSSES THAT THRESHOLD, SHE'S AT INCREASED RISK OR RATHER SHE IS CLINICALLY GOING TO BE DIAGNOSED WITH TYPE 2 DIABETES IN OUR EXAMPLE. SO THAT WOMEN THAT ARE ON THIS KIND OF BOTTOM BLUE LINE, THEY ARE GOING ON, THIS PARTICULAR HEALTHY POPULATION EXPERIENCES TWO PREGNANCIES. DURING PREGNANCY, THERE'S A BIT OF VASCULAR REORGANIZATION OR DYSFUNCTION THAT OCCURS THAT IS ELEVATED BUT A WOMAN WHO HAS A HEALTHY PROFILE IS ABLE TO ADAPT NATURALLY TO THIS AND SHE REALLY DOESN'T CROSS THAT CLINICAL THRESHOLD. BUT THEN YOU CAN THINK OF ANOTHER POPULATION OF WOMEN THAT HAS AN UNDERLYING ENDOTHELIAL OR VASCULAR DYSFUNCTION, AND THESE WOMEN, WHEN THEY EXPERIENCE PREGNANCY, THEY, IN FACT, CROSS THIS CLINICALLY RELEVANT THRESHOLD. AND ARE DIAGNOSED WITH A VARIETY OF DIFFERENT CONDITIONS, PREECLAMPSIA, PERHAPS PLACENTAL ABRUPTION THAT REALLY MAY SIGNAL DOWN THE LINE WOMEN DEVELOPING TYPE 2 DIABETES EARLIER IN LIFE AS WELL AS MAYBE PERHAPS A MORE SEVERE FORM OF THE CONDITION. SO WHAT WE MIGHT WANT TO CONSIDER IS ONCE WE SEE THAT A WOMAN HAS ACTUALLY DEVELOPED SOME SORT OF PREGNANCY COMPLICATION, WE MAY WANT TO DEVELOP A TARGETED INTERVENTION, YOU CAN THINK ABOUT A CONDITION LIKE GESTATIONAL DIABETES WHERE WE CURRENTLY KNOW THAT AMONG WOMEN WHO DEVELOP GESTATIONAL DIABETES, ABOUT 50% OF THOSE WOMEN ARE GOING TO GO ON TO DEVELOP TYPE~2 DIABETES. WE ALSO KNOW THAT WE CAN MODIFY THAT RISK THROUGH TARGETED INTERVENTION, SO OFTENTIMES THE GUIDELINES ARE REQUIRING THAT WOMEN COME BACK IN, THEY GET SCREENED AND THAT THROUGH Y CELL MODIFICATION THAT THEY CAN ACTUALLY REDUCE THE RISK BY ABOUT HALF. SO WHAT IF WE COULD DO THAT WITH OTHER COMMON PREGNANCY COMPLICATIONS? SO WE DIDN'T REALLY KNOW WHETHER OR NOT THERE WERE OTHER COMPLICATIONS THAT MIGHT BE ASSOCIATED WITH TYPE 2 DIABETES. OTHER THAN GESTATIONAL DIABETES, AND THERE'S A GROWING APPRECIATION THAT PERHAPS ECLAMPSIA WAS ASSOCIATED WITH AN INCREASED RISK OF TYPE 2 DIABETES. ONE OF THE REALLY COMMON PREGNANCY COMPLICATIONS IS PRETERM BIRTH. SO WHICH DECIDED TO LOOK AT THAT IN THE STUDY. SO I'LL GET INTO THE FACT BEHIND THAT, BUT WE FOLLOW THAT UP BY LOOKING AT THAT IN ANOTHER COHORT, THE BLACK WOMEN'S HEALTH STUDY. PRIMARILY BECAUSE WE KNEW THAT PRETERM BIRTH WAS MUCH MORE PREVALENT AMONG BLACK WOMEN AS WELL AS TYPE~2 DIABETES BEING MORE PREVALENT. WE PUBLISHED THIS DATA OVER THE LAST COUPLE OF YEARS, THIS IS LOOKING AT BOTH OF THOSE STUDIES SO IN THE STUDY WE HAD ABOUT 50,000 WOMEN THAT WE WER ABLE TO LACK AT, PRETERM BIRTHDAY TA AS WELL AS DATA ON TYPE 2 DIABETES. WE SAW THERE WAS ROUGHLY A 30 TO 40% INCREASED RISK AMONG THOSE WHO HAD A JES GESTATIONAL -- VERY EARLY PRETERM BIRTH FOR CONFERRING RISK OF TYPE 2 DIABETES. SO HERE WE'RE LOOKING AT FIRST PREGNANCIES AND ON AVERAGE, WE ARE ABLE TO LOOK AT A MEDIAN FOLLOW-UP TIME OF ABOUT 24 YEARS, BUT OF INTEREST IS THAT AS WE ANTICIPATED, WOMEN WHO EXPERIENCED A VERY EARLY PRETERM BIRTH, THAT THEIR INCREASE THE D RISK, THE TYPE 2 DIABETES OCCURRED MUCH EARLIER ON, SO THE RISK WAS ACTUALLY MUCH HIGHER DURING THE FIRST FIVE TO 10 YEARS FOLLOWING THAT FIRST PREGNANCY THAT WAS COMPLICATED BY A PRETERM BERTH. IN LOOKING AT THE BLACK WOMEN'S HEALTH STUDY AMONG 31,000 WOMEN, WE ALSO SAW INCREASED RISK OF VERY EARLY PRETERM BIRTH CONFERRING AT A HIG HIGHER RISK FOR DEVELOPING TYPE 2 DIABETES. YOU HAVE ROUGHLY A SIMILAR FOLLOW-UP TIME. IT'S ABOUT A 25% INCREASED RISK, AND IT WAS ACTUALLY A LINEAR ASSOCIATION WHEN WE LOOKED AT VERY EARLY PRETERM BIRTH AS WELL AS KIND OF A MORE MODERATE PRETERM BIRTH. YOU DIDN'T ASK THE QUESTION WHAT WAS THE CAUSE OF THE PRETERM BIRTH, WAS THIS A MEDICALLY INDICATED PRETERM BIRTH, SPONTANEOUS PRETERM BIRTH, WHAT WAS TH CONDITION? IN THE BLACK WOMEN'S HEALTH STUDY, THEY DID. TAKE A LOOK AT THE REASON FOR THE PRETERM BIRTH AND WHETHER OR NOT THERE WERE SPECIFIC CONDITIONS ASSOCIATED WITH PRETERM DIABETES, WE FOUND AN ALMOST TWOFOLD INCREASED RISK OF TYPE 2 DIABETES THAN THOSE WHO EXPERIENCED PLACENTAL ABRUPTION. WE REALLY DIDN'T HAVE THE POWER TO LOOK AT THIS WITHIN THIS POPULATION. SO LET ME BACK UP FOR A SECOND AND TELL YOU A BIT ABOUT WHAT IS PLACENTAL ABRUPTION. SO THIS ON THE FAR -- RIGHT HERE ON THE RIGHT-HAND SIDE, WE CAN SEE THE DEVELOPING FETUS. WHERE YOU SEE THE SQUARE, IT INDICATES WHERE THE PLACENTA OR THE BABY'S LIFE LINE IS CONNECT TODAY THE MOTHER, SO WHAT'S HAPPENING HERE IS THAT NUTRIENTS, OXYGEN, HORMONES ARE GOING TO THE FETUS AND ALL THE WASTE CARBON DIOXIDE AND SUCH IS BEING CARRIED AWAY. THE DEFINITION OF PLACENTAL ABRUPTION IS WHEN YOU SEE HA THERE'S BLEEDING THAT OCCURS BETWEEN THAT INTERFACE BETWEEN THE MOTHER AND THE FETAL CONNECTION, SO IT'S THAT BLEEDING THAT CAN EITHER CAUSE PARTIAL OR COMPLETE DETACHMENT OF THE PLACENTA RESULTING IN THOSE SEVERE CASES IN FETAL DEATH. IT IS A VERY SEVERE CAUSE, ABOUT 10 TO 20% OF FETAL DEATH ARE CAUSED BY -- ABOUT 70 TO 80% OF THOSE OCCUR IN UTERO. THE OLDER MATERNAL AGE OR HAVING THREE OR MORE CHILDREN, SMOKING OR DRUG USE, HAVING TWINS OR TRIP LETS, MULL PEL -- THAT I'VE MENTIONED AS WELL AS NUTRITIONAL DEFICIENCIES AND INTERESTINGLY ENOUGH HAVING MALE FETUS. PLACENTAL ABRUPTION ALMOST ALWAYS OCCURS DURING THAT VERY EARLY PRETERM BIRTH AND JUST FOR SAKE OF DEFINITION, PLACENTAL ABRUPTION REALLY IS DEFINED AS HAVING THAT PULLING AWAY OF THE PLACENTA AT 20 WEEKS OR AFTER. SO AS I MENTIONED TO YOU -- WE REALLY COULDN'T LOOBLG A LOOK THE AT THIS QUESTION BECAUSE THE PREVALENCE -- OVERALL GEOGRAPHICALLY IT RANGES IN THE ORDER OF .4 TO 1%, IT HAS BEEN GROWING, MUCH MORE IN CERTAIN POPULATIONS THAN OTHERS, BUT IT'S RARE AND SO WHEN YOU WANT TO LOOK AT THE RO RELATIONSHIP BETWEEN A RARE EXPOSURE AND WHAT COULD POTENTIALLY BE SOMEWHAT OF A RARE OUTCOME DEPENDING ON WHAT TIME PERIOD YOU'RE LOOKING AT, YOU REALLY NEED A LARGE DATASET, SO COLLABORATORS OF OURS WITH THE NATIONAL BIRTH REGISTRY HAD PREVIOUSLY ALSO DOCUMENTED THAT PRETERM BIRTH CONFERRED AN INCREASED RISK OF DEVELOPING TIME 2 DIABETES BUT THEY HAD NOT LOOKED AT PLACENTAL ABRUPTION. DELIVERED BETWEEN 1980 AND 2010. BECAUSE OF VAST MAJORITY OF WOMEN WITHIN THE DATASET HAD AT LEAST TWO PREGNANCIES, WE -- TWO PREGNANCIES OR MORE, WE EXCLUDED THOSE WERE PRE-EXISTING DIABETES, THOSE WERE GREATER THAN ONE FETUS AND THEN ANYONE WHO WAS MISSING INFORMATION ON PLACENTAL ABRUPTION AS A PREGNANCY HISTORY, AS WELL AS TYPE 2 DIABETES STATUS OR COVAIR THE YACHTS OF INTEREST, THIS RESULTS IN A POPULATION -- A SAMPLE SIZE OF 600,000 OR SO WOMEN. WE CONSIDERED WERE MATERNAL AGE, EDUCATION, MARITAL STATUS, HOUSEHOLD INCOME AND IMMIGRANT STATUS. UNFORTUNATELY THIS IS A REGISTRY SO A LOT OF THE LIFESTYLE FACTORS THAT WE MIGHT BE INTERESTED IN WHICH LOOKED AT WOMEN WHO DID NOT HAVE A HISTORY OF GESTATIONAL DIABETES OR PREECLAMPSIA TO REALLY GET AT THE INDEPENDENT EFFECT OF PLACENTAL ABRUPTION ON TYPE 2 DIABETES RISK. SO THIS IS JUST A GENERAL OVERVIEW OF THE STUDY POPULATION, AND JUST WOULD LIKE TO BRING YOUR ATTENTION TO PLACENTAL ABRUPTION. AS I MENTIONED, IT IS RARE, .5% OF THE POPULATION HAD A PLACENTAL ABRUPTION AND THE FIRST PREGNANCY LIKEWISE THE SAME IN THE SECOND PREGNANCY, WE ALSO JUST TO TAKE A LOOK AT CERTAIN PREGNANCIES APPROACHING THAT 1% THAT I MENTIONED TO YOU BEFORE, YOU MIGHT BE SURPRISED BY THE PREVALENCE OF TYPE 2 DIABETES IN THIS POPULATION. THE DELIVERIES OCCURRED BETWEEN 1980 AND 2010, SO THESE WOMEN ARE QUITE YOUNG BUT ALSO LIFESTYLE FACTORS WITHIN THE DANISH PO POPULATION ARE VERY DIFFERENT THAN HERE IN THE U.S. SO WHEN WE LOOK AT PLACENTAL ABRUPTION OCCURRING WITHIN THE FIRST PREGNANCY, WE SAW THAT THIS COFFIN FER THE A ROUGHLY 47% INCREASED RISK OF DEVELOPING TYPE 2 DIABETES, THE MEDIAN FOLLOW-UP TIME IS 13 YEARS. OUR HYPOTHESIS IS THAT THERE'S UNDERLYING VASCULAR DYSFUNCTION THAT IS GOING ON SO THAT THESE SIGNALS ARE POPPING UP AS WOMEN GO THROUGH PREGNANCY. SO WHEN WE LOOK AT HAVING PLACENTAL ABRUPTION EITHER OF THE PREGNANCIES WE SEE ROUGHLY THE SAME AFTER CONTROLLING FOR THOSE POTENTIAL CONFOUNDERS, THE POINT ESTIMATE IS ACTUALLY STILL FAIRLY HIGH, WE SEE ABOUT A 45% INCREASED RISK OF DEVELOPING TYPE 2 DIABETES IN THESE WOMEN RELATIVE TO WOMEN WHO DO NOT HAVE PLACENTAL ABRUPTION. SO JUST TO KIND OF SAY THAT THERE'S SOME STRENGTHS TO LOOKING AT THIS DATASET. IT'S QUITE LARGE, WE'RE ABLE TO LOOK AT MULTIPLE OCCURRENCES OF A VERY RARE PREGNANCY COMPLICATION. AND WE ARE USING CONFIRMED MEDICAL DIAGNOSES FROM THE ICD-9 CODES. BUT SOME OF THE LIMITATIONS ARE THAT WE ARE ONLY ABLE TO LOOK AT FIRST AND SECOND PREGNANCIES. I MENTIONED THAT MULTIPARITY HAVING THREE OR MOTHER PREGNANCIES IS A RISK FACTOR FOR PLACENTAL ABRUPTION. WE'RE ALSO UNDERPOWERED TO LOOK AT PREGNANCY COMPLICATION, SO PREECLAMPSIA WAS ONE OF THE POTENTIAL CONFOUNDERS AND -- ONE OF THE -- THE CONDITIONS THAT TRAVELED ALONG WITH PLACENTAL ABRUPTION SO WE HAVE TO THINK ABOUT WHAT ARE WE REALLY GETTING AT HERE AND THAT WE CAN'T -- AT THE SAME TIME. IT'S ALSO THE DANISH POPULATION AND OF INTEREST IS WE DID TAKE A LOOK AT STRATIFIED BY IMMIGRANT STATUS, AND IN DENMARK, THE VAST MAJORITY OF IMMIGRANTS ARE FROM THE MIDDLE EAST AND FROM EAST AFRICA, AND WE DID SEE ABOUT A 70% INCREASED RISK OF HAVING TYPE 2 DIABETES IF A WOMAN EXPERIENCED PLACENTAL ABRUPTION, IT'S PRIMARILY BECAUSE IT'S A PRETTY TI HOMOGENEOUS POPULATION. WE ALSO HAVE LIMITED DATA ON THOSE LIFESTYLE RISK FACTORS THAT I MENTIONED TO YOU TAKE A LOOK AT THAT WITHIN THIS REGISTRY, BUT MIGHT BE SOMETHING THAT WE WOULD LIKE TO LOOK AT IN FUTURE STUDIES. SO JUST TO SUMMARIZE, WE SAW THAT PLACENTAL ABRUPTION CONFERRED ROUGHLY A 50% INCREASED RISK OF TYPE 2 DIABETES. HERE IN THE UNITED STATES, ONE OF THE BIGGEST ISSUES IS THAT A WOMAN GOES INTO PREGNANCY, SHE SEES HER OBVIOUS TA TRISH,,, "LOST IN TRANSLATION," IT NEVER GETS TRANSFERRED IN WHICH THEIR PRIMARY JOB IS TO PREVENT CHRONIC DISEASE DEVELOPMENT. AND WHAT IF WE COULD REALLY UTILIZE THE INFORMATION THAT WE LEARN IN A WOMAN'S PREGNANCY TO INTERVENE. AND ACTUALLY REDUCE THEIR FUTURE RISK OF GOING ON TO DEVELOP CONDITIONS LIKE TYPE 2 DIABETES. SO ONE OF THE THINGS WE ARE PRENTDLY DOING WITHIN OUR GROUP IS WE HAVE A NUMBER OF STUDIES WHERE WE ARE UTILIZING THAT INFORMATION AND WE'VE MADE VARIOUS WEB BASED TECHNOLOGIES TO ASSIST IN EDUCATING WOMEN THROUGH NUTRITIONAL PHYSICAL ACTIVITY INTERVENTIONS TO TRY TO REDUCE THEIR RISK OF DEVELOPING TYPE 2 DIABETES AFTER HAVING A PREGNANCY COMPLICATED BY A VARIETY OF THESE DIFFERENT CONDITIONS. I WOULD LIKE TO THANK MY CO-AUTHORS AS WELL AS OUR FUNDING SOURCE, THE BIRCWH, AS WELL AS THE HEALTH INSURANCE FOUNDATION AND OUR BIRCWH PROGRAM DIRECTOR. THANK YOU. [APPLAUSE] >> HI. UC DAVIS. I SHOULD KNOW THIS ANSWER BUT I DON'T OFF THE TYPE OF MY HEAD. I WAS WONDERING IF YOU KNEW HOW YOUR INCREASED RISK OF 40 OR SO PERCENT COMPARED TO GESTATIONAL DIABETES. >> SO CERTAINLY GESTATIONAL DIABETES IS A MUCH MORE -- IT HAS A MUCH HIGHER RISK THAN PLACENTAL ABRUPTION OR PRETERM BIRTH. THE PROBLEM IS THAT GESTATIONAL DIABETES AFFECTS ROUGHLY 3 TO 5% OF THE POPULATION IN GENERAL. CERTAINLY THERE'S POPULATIONS THAT HAVE A MUCH HIGHER PREVALENCE OF GESTATIONAL DIABETES, BUT WHEN YOU'RE STARTING TO TALK ABOUT CONDITIONS LIKE PRETERM BIRTH, WHICH AFFECTS ABOUT 10% OF THE POPULATION, WE REALLY MIGHT WANT TO CONSIDER THAT AS A POSSIBLE -- ONE OF THE THINGS WE DID, WE RECENTLY PUBLISHED ON THE EXCESS RISK FO OR THE ABSOLUTE RISK WE SEE AMONG THOS THOSE WOMEN WHO EXPERIENCE A PREDETERMINE RISK GO ON TO DEVELOP DIABETES, SO THAT'S ONE OF THE MAJOR ISSUES THAT YOU CAN'T JUST FOCUS ON GESTATIONAL DIABETES BUT IT MIGHT BE IMPORTANT FOR US TO DEVELOP INTERVENTIONS THAT REALLY LOOK AT WOMEN WHO HAVE A VARIETY OF THESE PREGNANCY COMPLICATIONS WHICH, BY THE WAY, HAPPEN TO TRAVEL TOGETHER. >> IS GESTATIONAL DIABETES THE RISK LIKE 80% COMPARED TO THE 40 YOU SAW? >> IT'S MUCH HIGHER. >> HI. SHAN TALE FRASIER. THANK YOU, THAT WAS A GREAT PRESENTATION. I WAS JUST INTERESTED IN THE INCOME OF YOUR SAMPLE. COULD YOU TALK A LITTLE ABOUT THE RANGE FOR THE WOMEN YOU LOOKED AT, AND ALSO WHETHER OR NOT YOU FOUND OUT ANY OUT COME DATA, IF IT VARIES BY INCOME LEVEL. >> SO WE DID NOT TAKE A LOOK AT OUTCOMES DATA BY INCOME. AND I DON'T KNOW A WHOLE LOT ABOUT THE INCOME, WHAT WE DID HERE IS WE JUST -- WITH THAT QUINTILES OF INCOME, AND KNOW THAT IT DIFFERS AND EDUCATION WAS A MUCH BETTER INDICATOR OF SOCIOECONOMIC STATUS IN THIS POPULATION THAN -- SAMPLE. >> SO WHAT DID YOU FIND AS FAR AS VARIATION BY EDUCATION LEVEL? >> SO THERE WEREN'T MUCH -- MANY DIFFERENCES. IMMIGRANT STATUS HAD THE BIGGEST DIFFERENCE BUT AGAIN OUR P COMPETENCE INTERVALS ARE QUITE WIDE, WHICH IS WHY I DIDN'T TAKE A LOOK AT THAT MORE EXTENSIVELY. >> OKAY. >> THANK YOU. >> HI. THAT WAS GREAT. MICHIGAN STATE UNIVERSITY. AS YOU MENTIONED, THERE'S MANY PATHWAYS TO ABRUPTION AND I'M WONDERING IF YOU WOULD HAVE ANY DATA ON THE HISTORY OF BLEEDING IN THE FIRST OR SECOND TRIMESTER OF THESE WOMEN AND WHETHER SUBSETTING THAT ON THAT HISTORY WOULD BE OF INTEREST TO SORT OF TEASING OUT DIFFERENT PATHWAYS. >> SO WE DO HAVE THAT, AND THAT IS SOMETHING THAT I'M VERY INTERESTED IN TAKING A LOOK AT DEFINITELY. >> GREAT. >> THANK YOU. >> HI. UIC. INTERESTING PRESENTATION. SO YOU MENTIONED PLACENTAL ABRUPTION IS HIGHLY RELATED TO PREECLAMPSIA AND OTHER HYPERTENSIVE DISORDERS AND IT'S HARD TO TEASE OFF WHAT THE CAUSES ARE OF PLACENTAL ABRUPTION BUT PREECLAMPSIA AND -- ARE ALSO A RISK FACTOR FOR INSULIN RESISTANCE AND DIABETES, SO HOW CAN YOU FIGURING OUT SO THE PRETERM RISK -- PATIENTS HAVING TO BE INDUCED EARLY, HYPERTENSIVE DISORDER WORSE THAN PARISI CLAMS YA, SO HOW CAN YOU TEASE OUT THE CORRELATION BETWEEN TYPE 2 DIABETES AND PLACENTAL ABRUPTION WITH OR WITHOUT THE HYPERTENSIVE DISORDERS. >> WHAT WE'RE INTERESTED IN -- SO THAT CAN MANIFEST -- BUT ONE OF THE WAYS THAT IT COULD ALSO BE MANIFESTING ITSELF IS IN PLACENTAL ABRUPTION, SO WE'VE TAKEN A LOOK AT PRETERM BIRTH, WE KNOW GESTATIONAL DIABETES, WE HAVE SOME INDICATION OF PREECLAMPSIA, SO WHAT WE'VE DONE IS WE'VE RESTRICTED OUR POPULATION WHICH I DIDN'T PRESENT THE DATA ON BUT WE DO SEE THAT IT MAINTAINS THAT 40% TO 50% INCREASED RISK EVEN WITHIN THE RESTRICTED POPULATION. OF WOMEN WHO DO NOT HAVE PREECLAMPSIA OR GESTATIONAL DIABETES. AND WE DO, IN FACT, THINK THAT THAT'S EXACTLY WHAT'S HAPPENING, THAT THESE WOMEN PROBABLY HAVE SOME SORT OF VASCULAR DYSFUNCTION, INCREASE IN INSULIN RESISTANCE THAT JUST DOESN'T CROSS THAT CLINICALLY RELEVANT THRESHOLD EXCEPT DURING PREGNANCY, BUT THEN THEY'RE RETURNING BACK TO THE PRIMARY CARE SETTING WHERE THE PRIMARY CARE DOCTOR NEVER KNEW THAT THAT WAS SOMETHING THAT COULD HAVE BEEN PICKED UP ON AND INTERVENED UPON TO PREVENT THEIR RISK OF DEVELOPING TYPE~2 DIABETES. >> THE SAME THING WITH THOSE WHO DON'T HAVE PREECLAMPSIA OR ANY UNDERLYING DISORDER. >> RIGHT. >> THANK YOU. [APPLAUSE] AT THIS TIME I HAVE THE PRIVILEGE OF INTRODUCING DR. KIRSTIE DANIELSON OF THE UNIVERSITY OF ILLINOIS AT CHICAGO, SHE'S A BART SCHOLAR, AND SHE WILL BE DISCUSSING SEX DIFFERENCES IN HUMAN PANCREATIC ISLETS, SURVIVAL, FUNCTION AND GENETIC EXPRESSION. >> I GUESS IT'S GOOD AFTERNOON NOW, THANK YOU ALL FOR STICKING IT OUT AS I'M YOUR LAST PRESENTER BETWEEN YOU AND LUNCH. PROVIDE IMPORTANT INSIGHTS FOR TREATING AND CURING DISEASES, IN OUR CASE, TYPE I DIABETES. SO FIRST MANY OF YOU MAY BE WONDERING WHAT IN THE WORLD IS AN ISLET AND HOW IS IT RELATED TO DIABETES. ACTUALLY BEING THIS CLOSE TO LUNCH, IT'S HIGHLY RELEVANT. ACTUALLY ISLETS ARE VERY ACTIVE IN YOU RIGHT NOW. SO WHAT AN ISLET IS -- OH, SORRY. FIRST I WILL BE DESCRIBING AN ISLET, AND THEN DISCUSS WHY STUDYING SEX DIFFERENCES IN ISLETS IS IMPORTANT FOR MOVING DIABETES RESEARCH FORWARD. I WILL THEN HIGHLIGHT EXAMPLES FROM OUR DATA DEMONSTRATING SEX DIFFERENCES IN HUMAN ISLETS WHICH SHOW A CONSISTENT PATTERN FROM CELL-BASED MODELS TO ANIMAL MODELS TO OUTCOMES OF CLINICAL TRIALS. WHEN DIABETES IN OUR FUTURE RESEARCH. ISLETS ARE LOCATED WITHIN THE PANCREAS. AND IT'S ESTIMATED THAT THERE ARE 1 MILLION ISLETS WITHIN AN ADULT HEALTHY PANCREAS. ISLETS ARE CLUSTERS OF HORMONE SECRETE CELLS, THE MAJORITY BEING BETA CELLS, WHICH ARE SHOWN HERE IN GREEN, AND THESE SECRETE THE INSULIN. SO INSULIN HELPS YOU TO USE AND STORE THE GLUCOSE, PERHAPS THE SUGAR IN YOUR COFFEE THAT YOU'RE DRINKING RIGHT NOW OR THE FOOD YOU WILL EAT. SO ISLETS ALSO CONTAIN ALPHA CELLS AND DELTA CELLS. ALPHA CELLS SEE CRETE GLUE KA GONE WHICH HELPS RELEASE GLUCOSE BACK INTO THE CIRCULATION TO PREVENT YOU FROM BECOMING HYPOGLYCEMIC, AND DELTA CELLS REGULATE BOTH BETA AND ALPHA CELLS, BUT I WILL BE FOCUSING ON OUR BETA CELL DATA TODAY. SO TYPE I DIABETES IS CAUSED BY AN AUTOIMMUNE DESTRUCTION OF THESE INSULIN SEE CREATING BETA CELLS. SO WITHOUT A CURE, THESE INDIVIDUALS WILL NEED INSULIN THERAPY THE REST OF THEIR LIVES IN ORDER TO SURVIVE. TYPE 1 DIABETES AFFECTS 3 MILLION INDIVIDUALS IN THE U.S. ALONE, AND THE INCIDENCE IS RISING GLOBALLY. SO OUR TEAM IS CURRENTLY CONDUCTING CLINICAL TRIALS ON A FUNCTIONAL CURE FOR TYPE 1 DIABETES CALLED ISLET TRANSPLANTATION. WHICH RESTORES THE INSULIN SECRETION TO THOSE WITH TYPE 1 DIABETES. SO FIRST THE ISLETS ARE ISOLATED FROM A DECEASED DONOR'S PANCREAS THROUGH -- WITH A GOAL OF -- THESE ISLETS ARE CULTURED IN MEDIA TO HELP THE ISLETS SURVIVE WHILE THE PATIENT IS BEING PREPARED FOR TRANSPLANT. THE ISLETS ARE THEN GIVEN TO THE PATIENT WITH TYPE 1 DIABETES, THEY'RE INFUSED THROUGH THE PORTAL VEIN WHERE THE ISLETS GRAFT THROUGH THE LIVER AND SECRETE INSULIN. SO IN ORDER FOR THIS PROCESS TO BE SUCCESSFUL, WE HAVE TO MEET SOME PRIMARY GOALS. THE FIRST BEING WE WANT TO ISOLATE A LARGE NUMBER OF ISLETS FROM THE PANCREAS. WE ALSO WANTED TO SUPPORT THEIR SURVIVAL IN CULTURE WHILE THE PATIENT IS BEING PREPARED. WE ALSO WANT TO KEEP THOSE BETA CELLS INSIDE THE ISLETS FROM DYING, AND ALSO TO OPTIMIZE THE FUNCTION OF THOSE ISLETS. AND I WILL BE PRESENTING OUR DATA ON SEX DIFFERENCES ON THESE LATTER THREE. SO WHY DO WE NEED TO INVESTIGATE SEX DIFFERENCES IN HUMAN ISLETS? SO LOOKING AT THE EPIDEMIOLOGICAL EVIDENCE, WE SEE THAT TYPE 1 DIABETES IS ONE OF THE FEW AUTOIMMUNE DISEASES THAT IS NOT MORE PREVALENT IN WOMEN. LOOKING AT THE INCIDENCE, WE SEE THAT BEFORE PEW BERTIE PUBERTY -- ACTUALLY PUBERTY MALES HAVE A SLIGHTLY HIGHER INCIDENCE. SO WE HAVE TO ASK OURSELVES, IS THIS UNEXPECTED EQUAL RATE A LOWER RATE OF TYPE 1 IN FEMALES RELATED TO SOME SORT OF FEMALE ADVANTAGE IN ISLET SURVIVAL, THEIR COMPOSITION OR FUNCTION. AND P IF SO, COULD THESE PROTECTIVE MECHANISMS THEN BE TARGETED INTO FUTURE SPHRAT GEES TO ENHANCE EFFICACY OF ISLET TRANSPLANT TO CURE TYPE 1 IN BOTH MEN AND WOMEN. SO NOW TURNING BRIEFLY TO A FEW EXAMPLES FROM THE TRANSPLANT IN CELL THERAPY LITERATURE, WE SEE AN EMERGING THEME WHERE THE SEX OF THE DONOR AND THE SEX OF THE RECIPIENTS ARE IMPORTANT IN THE CLINICAL OUT COME SUCCESS, AND IT EVEN FURTHER DIFFERS BIT ORGAN TYPE AND THE CELL TYPE THAT'S USED IN THE TRANSPLANT. SO FOR EXAMPLE, IN THE WHOLE ORGAN TRANSPLANT, INCLUDING KIDNEY AND A HEART TRANSPLANT, FEMALE ORGANS ARE ACTUALLY REJECTED AT A HIGHER RATE, AND SPECIFICALLY WITHIN MALE RECIPIENTS. CONVERSELY, IN OUR EXAMPLE HERE FROM THE CELL THERAPY LITERATURE, WE SEE THAT IT'S ONLY FEMALE CELLS THAT ARE GIVEN TO MALE RECIPIENTS THAT REVERSE@LOW SCLEROSIS. THE OTHER DONOR -- DID NOT REVERSE ATHEROSCLEROSIS. SO OTHER IMPORTANT SEX DIFFERENCES TO HIGHLIGHT BEFORE WE PRESENT OUR DATA HAS TO DO WITH THE ISLET TRANSPLANT PROCESS ITSELF. FIRST MORE MALE DONORS ARE USED TO ISOLATE ISLETS. THIS IS BASED ON SOME EVIDENCE THAT MALES MAY HAVE MORE ISLETS THAN FEMALES, THOUGH THE LITERATURE IS CONFLICTED IN THIS AREA. AND SECOND, MORE FEMALES RECEIVE AN ISLET TRANSPLANT AS THEY MORE OFTEN MEET THE WEIGHT CRITERIA BECAUSE OUR REQUIRED DOSE IS AT LEAST 5,000 ISLETS PER KILOGRAM WEIGHT OF THE RECIPIENT. SO NOW TURNING TO OUR SURVIVAL DATA, THIS STUDY I WILL SHOW YOU LOOKED AT ISLETS ISOLATED FROM THE DECEASED DONOR'S PANCREAS AND THEY ARE PUT INTO CULTURE PRIOR TO TRANSPLANT. WHEWE LOOKED AT HOW MANY OF THOSE ISLETS DIED WHILE IN CULTURE. SO WE SEE THAT PRIOR TO CULTURE, MALE DONORS HAD SLIGHTLY MORE ISLETS ISOLATED FROM THE PANCREAS, BUT AFTER CULTURE, FEMALE DONORS HAD MORE ISLETS REMAINING IN CULTURE. THIS IS A SIGNIFICANT SEX DIFFERENCE WHERE FEMALES ONLY LOST 18% OF THE ISLETS IN CULTURE VERSUS 34% OF THE MALE ISLETS WERE LOST IN CULTURE. IN OUR SECOND STUDY ON SURVIVAL, WE EXAMINED A DIFFERENT SET OF ISLETS FROM A DIFFERENT SET OF DONORS, AND THIS TIME WE LOOKED INSIDE THE ISLETS AT THE BETA CELLS. TO DETERMINE HOW MANY OF THE BETA CELLS WERE DYING OR UNDERGOING WHAT'S CALLED APOPTOSIS. HERE WE SEE THAT THERE WAS A SIGNIFICANTLY LOWER PE PERCENT OF BETA CELLS UNDERGOING APOPTOSIS IN THE FEMALE ISLETS THAN OTHERS NND MALE ISLETS. SO IF THERE IS A FEMALE ADVANTAGE, IT APPEARS IT MAY BE CUMULATIVE, WHERE FEMALE ISLETS ARE SURVIVING LONGER IN CULTURE AND THEN THE BETA CELLS WITHIN THOSE ISLETS ARE ALSO SURVIVING AT A BETTER RATE. AND HOW THIS WOULD TRANSLATE INTO ACTUAL TRANSPLANT OUTCOMES IS CURRENTLY UNKNOWN BUT WE WOULD HIG HYPOTHESIZE THAT BETTER SURVIVAL WOULD CORRELATE WITH BETTER OUTCOMES IN THE RYE RECIPIENTS. TO CONDUCT THIS STUDY, WE DID A SLIGHTLY DIFFERENT APPROACH. WE TOOK A BIOPSY OF THE PANCREAS PRIOR TO THE ISLETS PRIOR TO TRANSPLANT. SO THE ISLETS IN THIS STUDY WERE IN THEIR ORIGINAL ENVIRONMENT WITHIN THE PANCREATIC TISSUE. WB THAT BIOPSY, WE COUNTED THE VARIOUS CELL SUBTYPES, BAIT TA, ALPHA AND DELTA CELL SUBTYPES. HERE AGAIN, WE SEE SIGNIFICANT SEX DIFFERENTS WHERE THERE'S A HIGHER PROPORTION OF THE INSULIN PRODUCING BETA CELLS WITHIN THE FEMALE ISLETS, AND WITHIN THE MALE ISLETS, THERE'S A HIGHER PROPORTION OF THE ALPHA CELLS AND OTHETHAN OTHER CELL TYPES. WE CLIRNT HAVE A MANUSCRIPT UNDER REVIEW THAT SHOW -- ACTUALLY CORRELATED WITH BETTER OUTCOMES IN THE RECIPIENT, SO WE WOULD ARGUE THE SEX DIFFERENCE WE SEE HERE COULD HAVE CLINICALLY RELATIVE OUTCOMES IN ISLET TRANSPLANT. NOW TURNING IT OUR FUNCTIONAL STUDIES, THE CURRENT GOLD STANDARD METHOD TO ASSESS EYE ISLET FUNCTION IS TO TRANSPLANT THEM INTO MICE. SO WE TRANSPLANTED 2,000 ISLET FROM HUMAN DONORS INTO MICE, AND THE DATA I'M GOING TO SHOW YOU HERE CAME FROM 48 HUMAN DONORS INTO 230 MICE WHO HAD TYPE 1 DIABETES. THEN WE DETERMINED HOW MANY OF THOSE MICE WERE CURED OF THEIR DIABETES OVER ONE MONTH OF FOLLOW-UP. LET ME POINT OUT HERE THAT THE MICE IN THIS STUDY WERE ALL MALE, SO WE DO NEED TO REPEAT THE STUDY WITH FEMALE MICE. SO CONSISTENT WITH THE DATA I PRESENTED ON ISLET SURVIVAL AND COMPOSITION, FEMALE ISLETS CURED DIABETES IN MICE AT A HIGHER RATE THAN MALE ISLETS. 43% OF THE MICE WERE CURED WITH THE FEMALE ISLET VERSUS 26% OF THE MICE WERE CURED WITH THE MALE ISLETS. FINALLY OUR DATA ARE FROM OUR CLINICAL TRIALS ON 23 PATIENTS WITH TYPE 1 DIABETES AT THE UNIVERSITY OF ILLINOIS CHICAGO, AND THEY INCLUDE 18 FEMALE RECIPIENTS AND FIVE MALE RECIPIENTS FOLLOWED FOR ONE YEAR AFTER TRANSPLANT. WE FOUND HERE AGAIN THE ISLETS FROM THE FEMALES FUNCTIONED BETTER. WE MEASURE C PEPTIDE BECAUSE THIS ALLOWS US TO MEASURE HOW WELL THEY'RE SEE CREATING THE INFLUENCE. WE SEE IT SECRETED C PEP TIGHT AT A HIGHER RATE, OVER ONE, A CLINICALLY RELEVANT LEVEL WHEN YOU'RE ASSESSING ISLET FUNCTION. CORRESPONDINGLY, RECIPIENTS OF FEMALE ISLETS HAVE LOWER GLUCOSE LEVELS, HERE AGAIN, THE FASTING GLUCOSE FROM THE FEMALE ISLET ON AVERAGE WAS LESS THAN 100 AND THIS IS ANOTHER CLINICALLY RELEVANT LEVEL IN ASSESSING DIABETES. SO ALTHOUGH WE SEE SEX DIFFERENCES BY DONOR SEX, THESE TWO OUTCOMES ARE NOT DIFFERENT BY THE RECIPIENT SEX, AND IT COULD BE A FUNCTION OF THE SMALL SAMPLE SIZE, WE ONLY HAVE FIVE MALES HERE. I JUST SUBMITTED MY FIRST RO1 THIS FALL TO LOOK AT THESE OUTCOMES IN HUMAN ISLET TRANSPLANT RESI RECIPIENTS, THE INTERACTION BETWEEN THE RECIPIENT SEX AND DONOR SEX IN THE LARGER COHORT. SO TO SUMMARIZE, FEMALE EYELETS DEMONSTRATED IMPROVED SURVIVAL AND THE BETA CELLS WITHIN THOSE ISLETS. THEY ALSO DEMONSTRATED A GREATER PROPORTION AND THEN ENHANCED FUNCTION IN THEIR ABILITY TO CURE TYPE 1 DIABETES IN MICE AND TO SEE CRETE C PEPTIDE WITHIN THE HUMAN ISLET TRANSPLANT RECIPIENTS. ZOO IN CONCLUSION, WE WOULD PROPOSE THERE IS SIGNIFICANT PRO TENSION FOR THESE CLINICALLY RELEVANT SEX DIFFERENCES -- ISLET TRANSPLANT AS A CURE FOR TYPE 1 DIABETES. FIRST WE SH EXPANDING THE DONOR POOL TO INCLUDE MORE FEMALE DONORS. ONLY 40% OF THE DONORS CURRENTLY ARE FEMALE. EVEN AS FEMALES HAVE SLIGHTLY FEWER ISLETS IN THEIR PANCREAS TO BEGIN WITH, IN THE END, ULTIMATELY MORE FEMALE ISLETS SURVIVED AND WERE ABLE TO BE TRAN PLANTED INTO THE RECIPIENT. THIS INTERACTION BETWEEN DONOR AND RECIPIENT SEX ARE IMPORTANT IN ISLET TRANSPLANT OUTCOMES. FURTHER WE NEED TO DETERMINE WHETHER THE MENOPAUSAL STATUS OF THE RECIPIENT, THEIR HORMONE USE MAY ALSO IMPACT THEIR TRANSPLANT OUTCOMES. SO HERE IS WHERE I WILL NEED THE EXPERTISE OF MY COLLEAGUES WHERE WE NEED TO DO RESEARCH TO DETERMINE THESE MECHANISMS UNDERLYING WHAT SEEMS TO AB FEMALE ADVANTAGE IN ISLET, SUCH AS WHETHER IT'S A GREATER EXPOSURE TO ES TRADIOL, DIFFERENT EXPRESSION OF ISLET EEN GENES O GENES OR COMBINATION OF ALL OF THE ABOVE. ONCE THESE MECHANISMS ARE UNDERSTOOD, WE CAN NOW DESIGN STRATEGIES TARGETING THESE MECHANISMS TO ENHANCE ISLET TRANSPLANT EFFICACY FOR BOTH MEN AND WOMEN WITH TYPE 1 DIABETES. SO LET ME END BY ACKNOWLEDGING MY CO-AUTHORS AND MY RESEARCH TEAM AND FUNDING SOURCES AND MY BIRCWH MENTORS AND PEER SCHOLARS AT THE UNIVERSITY OF ILLINOIS. [APPLAUSE] >> TOM, NIDDK. GREAT TALK. THANK YOU FOR PRESENTING. I HAD A COUPLE QUESTIONS. ONE IS YOU LOOKED AT GENDER BUT I DIDN'T SEE NORMALIZATION FOR THE ISLET COUNT OR AGE OF THE DONOR, AND DID ANY OF THOSE FACTORS AFFECT YOUR ANALYSIS? >> YES. WE DID DO MULTIVARIABLE ADJUSTMENT, SO I UNFORTUNATELY -- DUE TO LIMITED TIME, I COULDN'T GO INTO ALL OUR METHODS, BUT I DID TEST FOR CONFOUNDING AND WE DID ADJUST WHERE IT DID DID AFFECT OUR DIFFERENCES, SO THAT INCLUDED IN SOME INSTANCES DONOR AGE, RECIPIENT AGE, AND THEN IN THE CLINICAL OUTCOMES, WE ALWAYS ADJUSTED FOR ISLET EQUIVALENCE TRANSPLANT, YES, SO WE DID EXPLORE FOR CONFOUNDING AND THESE ARE THE INDEPENDENT AFFECTS AFTER WE RE-ADJUSTED FOR CONFOUNDERS. >> I TALKED ABOUT -- I' THE UNIVERSITY OF ALABAMA GROUP SUGGESTED THAT ESTROGEN TREATMENT FOR INSTANCE PRIOR TO ISLET ISOLATION HAD GREAT BENEFITS IN OUTCOME TOO, SO THAT CERTAINLY MAY HELP YOUR HYPOTHESIS ABOUT THE ESTROGEN EFFECTS. >> EXACTLY. AND OUR TEAM AT THE UNIVERSITY OF ILLINOIS ACTUALLY DID AN IN VIVO TREATMENT OF ESTRADIOL IN MICE, AND THAT DID SHOW A PROTECTIVE EFFECT TOO AT BEING ABLE TO REVERSE DIABETES QUICKER IN THE MOUSE MODELS WITH TYPE 1. SO ESTROGEN DOES HAVE A ROLE. I'M SURE IT'S MULTIFACTORIAL AND THERE'S OTHER FACTORS INVOLVED AS WELL. THEN I WASN'T ABLE TO PRESENT HERE TOO THAT ACTUALLY WHEN WE'RE LOOKING AT THE RECIPIENTS OF ISLET TRANSPLANT, AND THE FEMALE RECIPIENT, IF WE LOOK AT THEIR MENOPAUSAL STATUS, PREMENOPAUSAL WOMEN ACTUALLY DO BETTER AFTER ISLET TRANSPLANT THAN THE POST-MENOPAUSAL WOMEN AND THEN WITHIN THE POST-MENOPAUSAL WOMEN, THOSE USING THE COMBINED ESTROGEN PROGESTERONE HORMONE THERAPY DID BETTER THAN THOSE WHO DID NOT TAKE HORMONE REPLACEMENT THERAPY. SO THERE'S I DEFINITELY A HORMONAL EFFECT. >> REALLY VERY INTERESTING TALK. IN YOUR MOUSE MODEL, HAVE YOU EXPERIMENTED WITH GIVING THE MICE JUST MORE ISLETS FROM THE MALE DONORS TO TRY TO COMPENSATE FOR THE FACT THAT THOSE ARE GOING TO DIE MORE? YOU KNOW, MORE THAN YOU WOULD GIVE FROM THE FEMALE DONORS? >> WHY WOULD WE WANT TO -- YOU MEAN JUST TO SEE IF WE WOULD NEED LIKE IN A HUMAN TO TRANSPLANT MORE MALE? >> ESPECIALLY SINCE THERE ARE MORE MALE DONORS, YOU MENTIONED AT THE END TRYING TO INCREASE THE NUMBER OF FEMALE DONORS BUT IF MALES ARE WHAT WE'VE GOT, COULD WE POSSIBLY JUST SEE IMPROVED CLINICAL OUTCOME BY GIVING MORE CELLS TO TRY TO -- >> SO WE TRANSPLANT WHAT WE CAN GET. UNFORTUNATELY WE CAN'T -- I MEAN, WE TRY AND GET UP TO 500,000, IT'S OFTEN LESS, AND WE JUST DO ONE DONOR PER RECIPIENT. SO IT'S HARD TO LOOK AT THAT QUESTION BECAUSE WE COULD NEVER ADD MORE TO THE RECIPIENT. IN THE MOUSE MODELS, IT'S SLIGHTLY DIFFERENT BECAUSE THE ONLY TRANSPLANT WAS CALLED A MINIMUM MASS, SO IT'S THAT AMOUNT THAT WILL CURE IT IN 50%. OF THE MICE. SO YEAH, UNFORTUNATELY IN THE RECIPIENT WE CAN'T JUST GIVE MORE BECAUSE WE OFTEN DON'T HAVE MORE, AND THEN THE MAIL BIAS IN THE DONORS SEEMS TO BE MORE OF A SELECTION BIAS BY ORGAN PROCUREMENT MORE SO THAN THE AVAILABILITY OF THE ORGAN. >> THANK YOU. >> ORGAN HEALTH AND SCIENCES UNIVERSITY. SO IN HUMAN STUDY, WHEN THESE ISLETS ARE TRANSPLANTED, ARE THEY ALSO GIVEN SOME IMMUNOSUPPRESSIVE AGENTS, IS THERE ANY GENDER DIFFERENCES IN HOW MEN AND WOMEN RESPOND TO THOSE TRIALS AND REJECTION? >> THAT THE FEMALEWELL, IN THIS CASE THE FEMALES MAY NOT BE REJECTING AS OFTEN AS THE MALES, SO AS FAR AS LOOKING AT IMMUNOSUPPRESSANT THERAPY, I LOOK AT IT AS A COVARIANT, WE ADJUST FOR THE TYPE OF THERAPY THAT THEY'RE ON, BUT IT'S TRUE, IN A LARGER COHORT, THIS IT MIGHT BE SOMETHING WE COULD LOOK AT IN THE REGISTRY OF ISLET TRANSPLANT TO SEE WITHIN GENDER IS THERE A DIFFERENT EFFECT OF THE IMMUNOSUPPRESSANT DRUGS. GOOD IDEA. OKAY. THANKS. [APPLAUSE] >> EXCELLENT TALK. WE WOULD LIKE TO THANK ALL OF OUR PRESENTERS, EXCELLENT PRESENTATIONS. AT THIS TIME WE WILL BE BREAKING FOR LUNCH. WE'RE GOING TO EXTEND THAT PERIOD TO 2:00 TO GIVE YOU ALL -- TO CHECK OUT THE POSTER PRESENTATIONS WHICH ARE LOCATED IN THE SAES TERRACE, AND WE INVITE YOU VIEWING ONLINE, OF COURSE, THOSE WITHIN -- TO COME BACK AT 2:00 AND OUR PANEL TO COME BACK AT ABOUT 1:50. WE WILL HAVE AN EXCITING SPECIAL PANEL DISCUSSION THIS AFTERNOON. SO PLEASE COME BACK. I WOULD LIKE TO WELCOME OUR SPECIAL PANEL TO COME UP TO THE PODIUM. WE'LL BEGIN WITH OUR MODERATOR DR. MARGARET MCCARTHY FROM THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE. THANK YOU. >> THANK YOU VERY MUCH, DR. MILLER. IT'S A PLEASURE TO BE HERE TODAY AND TRY TO MODERATE THIS DISCUSSION ON HOW WE MOVE FORWARD AND IMPLEMENT THIS VERY EXCITING NEW POLICY CHANGE. IT'S BEEN SO INTERESTING TO HAVE A POLICY ANNOUNCEMENT BUT NOT KNOW EXACTLY HOW IT WILL BE IMPLEMENTED AND MAKING THE COMMUNITY PART OF THAT PROCESS IS REALLY A WONDERFUL THING THAT WE ALL HAVE HERE THE OPPORTUNITY TO IMPACT HOW NIH FUNDS RESEARCH GOING FORWARD IN TERMS OF HOW IT'S EVALUATED. THIS IS A VERY COMPLICATED TOPIC. THERE ARE MULTIPLE LAYERS THAT HAVE TO BE ADDRESSED BUT WE'RE GOING TO BE FAIRLY SPECIFIC HERE TODAY TO TALK ABOUT HOW DOES ONE DO RESEARCH ON SEX DIFFERENCES AND HOW SHOULD IT BE IMPLEMENTED IN YOUR STUDY. SO I'M GOING TO GIVE A VERY, VERY BRIEF BACKGROUND, ONE OF OUR PANEL MEMBERS WILL GIVE A SHORT TALK THEN OPEN UP TO QUESTIONS FROM THE AUDIENCE BECAUSE THAT'S WHAT THIS IS ABOUT IS A DIALOGUE SO THIS IS THE TIME TO BE PART OF THE CONVERSATION. HOW DO I ADVANCE? >> IT LIKES THE SLIDE. WHAT AM I SUPPOSED TO -- VERY SHORT INTRODUCTION. OKAY. SO I WANT TO START WITH BASICS TO MAKE SURE I KNOW YOU HAD A GREAT TALK THIS MORNING FROM DAVID PAGE SO IT'S REDONE DAN BUT JUST TALK ABOUT MULTIPLE PROCESSES THAT GO ON THAT LEAD TO SEX DIFFERENCES. WE START WITH SEX DETERMINATION, XXXY THE SRY GENE I DON'T NEED TO REPEAT THAT. THAT LEADS TO SEX DIFFERENTIATION AND THAT'S A DIFFERENTIATION OF THE GONADS AND THE SECONDARY SEX CHARACTERISTICS THE REPRODUCTIVE TRACT. THERE IT IS. BUT THEN THERE'S THIRD PROCESS CALLED SEXUAL DIFFERENCE DIFFERENTIATION OF THE THE BRAIN, THAT IS A SECONDARY PROCESS TO SEX DIFFERENTIATION OF THE GONADS, THAT'S HORMONALLY DRIVEN EARLY IN LIFE AND THEN LAST THERE IS GENDER WHICH IS UNIQUELY HUMAN, WOE DON'T ABOUT THE GENDER OF MICE AN RATS SO MANY INVESTIGATORS THINK THEY'RE BEING POLITICALLY CORRECT WHEN THEY PUBLISH THE GENDER IN THEIR MOUSE STUDIES BUT THEY'RE BEING BIOLOGICALLY INCORRECT, THE AMOUNT IS NOT AWARE OF WHETHER OR NOT IT'S A MALE OR A FEMALE AND DOESN'T HAVE ANY INTEREST IN KNOWING SO WHILE WE EMPHASIZE THESE HORMONAL EFFECTS THE GENETIC EFFECTS THE SEX DIFFERENCES ARE DETERMINED MULTI-FACTORALLY AS A COMBINATION OF YOUR GENES ENVIRONMENT AND HORMONES. THE IMPACT OF EACH OF THESE WILL CHANGE ACROSS YOUR LIFE SPAN. THEY'RE GOING TO INTERACT IN UNIQUE AND NOVEL WAYS IN EVERY SINGLE INDIVIDUAL PARTICULARLY IN HUMANS. SO WHEN WE TALK ABOUT SEX DIFFERENCES, EVERYBODY SORT OF THROWS IT OUT THERE, IT'S A UNITARY TERM BUT A FEW YEARS AGO WHEN COLLEAGUES OF MINE AND I WERE WRITING A TOOLBOX ARTICLE JOURNAL OF NEUROSCIENCE TO HELP INVESTIGATORS WHO WANT TO STUDY SECTION DIFFERENCES WE REALIZE -- SEX DIFFERENCES THE FIRST THING WAS TO DEFINE WHAT IS IT WE'RE TALKING ABOUT AND WE DIVIDE INTO THREE OPERATIONALLY DEFINED CATEGORIES. BIOLOGICAL CATEGORIES SO MUCH AS THEY ARE OPERATIONALRY DEFINED. TO GIVE SOME STRUCTURE WHAT IS IT YOU'RE REALLY STUDYING. THE FIRST THING IS A SEX DIE MORPHISM, THAT IS WHEN AN END POINT HAS TWO UNIQUE END POINTS IN MALES AND FEMALES WITH DIVING TO MORPHINE FORM. THESE ARE RELATIVELY RARE SEX DIFFERENCES YET EVERYBODY CALLS EVERY TINY SEX DIFFERENCE A SEX DIMORPHISM, THE REFRACTIVE TRACT, GONADS IN ANIMAL MODELS, THERE'S SOME TYPES OF BEHAVIORS LIKE SEX BEHAVIOR,OTHER CONTROL GONAD TROPIC REGION, THEY'RE RESTRICTED TO THE REPRODUCTIVE BIOLOGY OF ANIMALS. MOST SEX DIFFERENCES ARE THIS TYPE, THEY ARE A SEX DIFFERENCE, THEY ARE AN END POINT THAT LIES ALONG A CONTINUUM AND THE MEAN MIGHT VARY IN MEALS AND FEMALES BUT THERE COULD BE -- MALES AND FEMALES BUT TREMENDOUS OVERLAP. SO HEIGHT MALE AND FEMALE HEIGHT, WOMEN ARE TALLER THAN MEN AND THINGS OF THAT SORT CAN BE STRESS RESPONDING, DIFFERENT KINDS OF COGNITIVE PROCESSES, IT CAN BE EMOTIONALITY, FOOD PREFERENCES, BODY LANGUAGE, EVERYTHING, LIVER FUNCTION ENZYME, WHATEVER WE WANT TO NAME, THIS IS THE MAJORITY. THE THIRD ONE IS A LITTLE BIT MORE UNUSUAL AND IT HAS TO DO WITH SOMETIMES THE SEX DIFFERENCES ARE HIDING IN PLACE SIGHT. SO SOMETIMES MALES AND FEMALES WILL BE THE SAME AT REST, UNDER UNCHALLENGED CONDITIONS BUT THEN IN RESPONSE TO A CHALLENGE THEY MIGHT FLY APART. WE HAVE SEEN IN N EMPIRICALLY IN RESPONSE TO THINGS LIKE STRESS, INJURY, MECHANISMS OF SELF-DOUBT FOLLOWING INJURY, IMPACT OF STRESS ON LEARNING STRATEGIES, WHICH MALES AND FEMALES IMPROVE OR GET WORSE IN OPPOSITE DIRECTIONS DEPENDING ON BIOLOGICAL SEX. CONVERSELY THERE'S A PROCESS SOMETIMES MALES AND FEMALES TRY TO GET THE SAME PLACE, REPRODUCTIVE PHYSIOLOGY HAS A COST. SO THAT THE MALE HAVING CONTINUOUSLY HIGH TESTOSTERONE THROUGHOUT ADULTHOOD HAS IMPACTS ON PHYSIOLOGY AND BEHAVIOR, AND SOMETIMES IS NOT BENEFICIAL TO THE MALE AND HE'S TRYING TO MOVE BACK TOWARDS CENTER AND FEMALES ARE ALSO TRYING TO CONVERGE FROM THE DEMANDS OF THE REPRODUCTIVE PHYSIOLOGY OF THEIR OWN PARTICULAR SYSTEM SO HAVING THOSE IN MIND GIVES A FRAMEWORK FOR DISCUSSING DIFFERENCES. I WANT TO BRING UP THIS POINT ALREADY BECAUSE I KNOW A POINT OF DISCUSSION, WHICH IS HOW IMPORTANT ARE HORMONES, ALL OF US IN THE FIELD OF SEX DIFFERENCES RESEARCH HAVE HEARD FROM OUR COLLEAGUES MANY, MANY YEARS, IT'S NOT THAT I DON'T WANT TO STUDY FEMALES, I JUST DON'T WANT TO HAVE TO DEAL WITH THESTER CYCLE, I WAS AT A MEETING RECENTLY WHICH A COLLEAGUE OF MINE PRESENTED WORK ON CONCUSSION AND TRAUMATIC BRAIN INJURY EFFECTS AND I ASKED HIM WHAT WAS THE SEX OF THE ANIMAL HE WAS STUDYING. HE SAID ALL MALES OF COURSE. I SAID OF COURSE WHY AREN'T YOU COOING FEMALE? HE SAID WE DID DO FEMALES THEN WE RAN INTO THIS ESTER CYCLE AND THEY ALL DIED. SO WE DON'T STUDY HA ANY MORE. I THOUGHT I WAS LISTENING TO STEVEN COBERRT WE WON'T BOTHER TO STUDY THAT ANY MORE, THIS IS KIND OF EXAMPLE OF THINGS THAT SOMETIMES SOME OF THE PEOPLE IN MY DISCIPLINE WHICH IS SEX DIFFERENCES RESEARCH. SO THIS IS A VERY IMPORTANT PAPER THAT WAS PUBLISHED BY BRIAN PANDERERGRASS IN HIS FORMER MEN TEAR THEY LOOKED AT HUNDREDS OF BIOLOGICAL END POINTS IN A META ANALYSIS FROM HUNDREDS OF DIFFERENT STUDIES AND THEY FOUND THAT ON AVERAGE THE VARIABILITY IN THE FEMALES WAS NO GREATER THAN THE VARIABILITY IN MALES WHEN THEY DID NOT CONTROL FOR ESTER CYCLE, THIS DOESN'T MEAN IT'S NOT IMPORTANT, IT DOESN'T MEAN HORMONAL STATUS IN WOMEN IS NOT IMPORTANT BUT IT ALSO MEANS IT'S IN THE A STRAIGHT JACKET AND IT DOES NOT HAVE TO BE INCORPORATED TO EVERY STUDY THAT COMPARES THE SEX. SO TAKE HOME MESSAGE, NOT ALL DIFFERENCES ARE EQUAL, SOME ARE INTRINSIC AND SOME CON TIN GENERAL, WITHIN SEX DIFFERENCES ALSO GREATER BETWEEN SEX DIFFERENCES DUE TO VARIABILITY IN EXPERIENCE HORMONE HORMONES AND ENVIRONMENT. WE NEED TO CHEEP THOSE IN MIND, IT ISN'T THE ONE BE ALL AND IN ALL VARIABLE. THAT'S THE KIND OF DISCUSSIONS THAT WE WANT TO HAVE, HOW DO WE KEEL WITH SOMETHING AS COMPLEX AS THAT. SO I'LL STOP THERE AND WE'LL CALL UP OUR NEXT SPEAKER, ONE OUR PANEL MEMBERS, DO YOU HAVE HER SLIDES? >> HI. I GUESS I HAVE -- CAN YOU HEAR ME ALL RIGHT? OKAY, IT TAKES A WHILE TO WORK. SO I DON'T REALLY HAVE A TALK BUT I THOUGHT THAT I -- IF WE WERE ALL SITTING AT THE TABLE I WOULD INTERRUPT WITH SOME SLIDES SO I GUESS IT'S TALK BUT IT'S PRETTY INFORMAL, THE WHILE IDEA IS COMING FROM A DIFFERENT PLACE FROM ALL OF Y'ALL, THE WORD META ANALYSIS WAS JUST MENTIONED SO THAT WAS A GOOD SEGUE. MY NAME IS KAY DICKERSON, I STUDY CLINICAL TRIALS AND SYSTEMATIC REVIEWS OF CLINICAL TRIALS. THAT IS TREATMENT EFFECTS PREVENTION, DIFFERENT INTERVENTIONS AND I WANT TO EXPLAIN FIRST WHAT A SYSTEMATIC REVIEW IS. MAYBE ALL OF YOU KNOW, BUT AS A REFRESHER, WHAT'S WHERE I'M COMING FROM, I'M GOING TO COVER THAT TOPIC. IF WE HAVE ALL LITERATURE REVIEWS, THERE IS A SUBSET THAT WE CALL SYSTEMATIC REVIEWS. THE IDEA OF SYSTEMATIC REVIEWS AND META ANALYSES IS THAT WE HOLD SYSTEMATIC REVIEWS TO THE SAME STANDARDS WE HOLD PRIMARY STUDIES LIKE CLINICAL TRIALS TO -- THERE'S A METHODS SECTION A RESULTS SECTION A DISCUSSION SECTION SO THAT SYSTEMATIC REVIEWS ARE SCIENTIFIC APPROACH TO SAY AHEAD OF TIME WHAT STUDIES ARE YOU GOING TO INCLUDE AND WHAT DID ALL THOSE STUDIES SHOW TOGETHER. THERE'S SUBSET OF ALL REVIEWS. SOMETIMES YOU HAVE QUANTITATIVE DATA THAT CAN BE COMBINED FROM THOSE SYSTEMATIC REVIEWS. THAT'S A META ANALYSIS. SO SYSTEMATIC REVIEWERS ARE DEPENDENT ON WHAT'S INCLUDED IN THE SYSTEMATIC REVIEW. SO IF FOR EXAMPLE YOU'RE LOOKING AT CLINICAL TRIALS FOR EXAMPLE THE EFFECTIVENESS OF ARTHROSCOPY ON OSTEOARTHRITIS OF THE KNEE, YOU HAVE TO BE LOOKING AT TRIALS THAT AND YOU WANT TO LOOK AT SEX DIFFERENCES BUT ALSO LOOK AT SEX DIFFERENCES. IF THOSE TRIALS DON'T HAVE ANY INFORMATION ABOUT SEX DIFFERENCES THEN THERE'S NO WAY THAT YOU CAN LOOK AT THEM IN YOUR SYSTEMATIC REVIEW. SO THERE ARE PEOPLE WHO ARE INTERESTED IN LOOKING AT ALL KINDS OF DIFFERENCES IN SYSTEMATIC REVIEWS AND THE QUESTION IS WHETHER THIS INFORMATION IS INCLUDED IN THE ORIGINAL TRIAL. I SHOULD SAY CLINICAL TRIALS WHICH AGAIN IS MOSTLY WHAT I DEAL WITH, THERE ARE LOTS OF THINGS THAT ABOUT INCLUDE THERE INCLUDING ITEMS WE SAY ARE ASSOCIATED WITH QUALITY. SO I'M NOT -- THERE'S MUCH MORE THERE THAN JUST SEX AND GENDER DIFFERENCES. THIS IS DIRECTOR OF THE UNITED STATES COCHRAN CENTER, WE HAVE A DIRECTOR ASSOCIATE DIRECTOR OF THE WEST COAST COCHRAN CENTER BRANCH. SO THE REVIEWS I'M TALKING ABOUT ARE RELATED TO THE COCHRAN COLLABORATION. IT'S A GROUP THAT'S BEEN GOING ABOUT 20 YEARS, IT'S MOSTLY VOLUNTEER, THEY'RE NOW 31,000 PEOPLE AROUND THE WORLD CONTRIBUTING TO THESE SYSTEMATIC REVIEWS AND ABOUT 6,000 SYSTEMATIC REVIEWS ON I'M SURE TOPIC THAT YOU'RE INTERESTED IN. PEOPLE WHO ARE INTERESTED IN ANIMAL STUDIES ARE JUST GETTING INVOLVED NOW BOTH TOXICOLOGY AND PRE-CLINICAL STUDIES. SO THERE IS A GROUP WITHIN THE COCHRAN COLLABORATION CALLED THE EQUITY GROUP WHO IS INTERESTED IN SEEING THAT SYSTEMATIC REVIEWS ALSO CONSIDER ISSUES THAT ARE RELATED TO THE EQUITY OF HEALTHCARE SO THEY'RE LOOKING FOR GENDER AND SEX DIFFERENCES, LOOKING FOR RACIAL DIFFERENCES, FOR PEOPLE WHO ARE FROM RESOURCE POOR ENVIRONMENT VERSUS A RESOURCE RICH ENVIRONMENT, SO FORTH. AND MANY OF THEM HAVE BEEN INVOLVED IN REPORTING STANDARD BECAUSE I KNOW SOMETHING THAT I HEARD PEOPLE TALKING ABOUT IS REPORTING IS THE LEAST -- AT LEAST HALF THE PROBLEM, NOT JUST WHETHER SOMETHING WAS STUDIED, IT'S WHETHER IT WAS REPORTED. IT CERTAINLY IS A PROBLEM IN CLINICAL TRIALS. SO NOW WE'RE TRYING TO CHANGE THE REPORTING STANDARD SO THAT IT INCLUDES INFORMATION ABOUT SEX AND GENDER BUT ALSO OTHER EQUITY VARIABLES. SO THIS IS THE SEX AND GENDER METHODS GROUP WHICH IS SPECIFICALLY CONCERNED WITH ISSUES PEOPLE HERE ARE CONCERNED WITH, IT'S JOINTLY BETWEEN COCHRAN COLLABORATION AND THE CAMEL COLLABORATION WHICH DEALS WITH SOCIAL SCIENCES, EDUCATION, CRIMINAL JUSTICE QUESTIONS. AS I SAID, THERE'S AN ANIMAL STUDIES GROUP, THEY'RE VERY INTEREST IN SEX DIFFERENCES AS WELL. SO THEY ARE TELL YOU ABOUT WHEN YOU'RE PLANNING YOUR SYSTEMATIC REVIEW, WHO SHOULD YOU DO THIS, THEY HAVE MADE A TOOL KIT SO THAT YOU TAKE INTO ACCOUNT THESE DIFFERENCES, IT DOESN'T MEAN YOU'RE GOING TO FIND THE DIFFERENCES IN THE TRIALS AS THEY'RE REPORTED BUT YOU SHOULD AT LEAST LOOK, THIS IS PART OF THE TOOL KIT FOR YOUR SYSTEMATIC REVIEW. SOME OF THE GROUPS, THESE ARE ONLY THREE OUT OF 53 GROUPS THAT DO THE SYSTEMATIC REVIEWS, THANK YOU ACTUALLY ARE PAYING ATTENTION TO THIS. SO I AM ASSOCIATED WITH THE EYES AND VISION GROUP AND SHOULD WE PAY ATTENTION TO SEX AND GENDER DIFFERENCES. WE WERE JUST TALKING ABOUT IT, YOU WILL HEAR LATER SO MANY EFFECTS ON EYES RELATE TO AGING. MAYBE THERE ARE SEX AND GENDER DIFFERENCES, WE HAVEN'T LOOKED FOR BUT AS YOU CAN SEE ONLY THREE OF THE 53 GROUPS HAVE REALLY TAKEN THIS INTO ACCOUNT WHAT THEY DO. THEN THERE'S SOME ARTICLES THAT HAVE BEEN PUBLISHED BY THE SEX AND GENDER GROUP, THIS IS ONE WHICH IS A QUALITATIVE STUDY ASKING SYSTEMATIC REVIEWERS WHO ARE INTERESTED IN SEX AND GENDER WHAT'S THE PROBLEM WITH DOING A REVIEW AND TRYING TO TAKE INTO ACCOUNT SEX AND GENDER DIFFERENCES. WHAT THEY SAID IS, THERE ARE CONCEPTUAL PROBLEMS, THAT IS, PEOPLE DON'T DIFFERENTIATE BETWEEN SEX AND GENDER AND THEN DO WE CONSIDER THIS KNOWLEDGE IF THEY HAVEN'T TAKEN INTO CONSIDERATION SEX AND GENDER OF THE PEOPLE WHO PARTICIPATE IN THE STUDY. ALL SORTS OF METHOD LOGIC PROBLEMS WITH THE REPORTING AS WE MENTIONED, AND THE EMPHASIS ON LOOKING AT DIFFERENCES BETWEEN SAY MEN AND WOMEN IS USUALLY A SUBGROUP ANALYSIS. SOME OF THE PEOPLE INTERESTED IN THIS SAY WHY SHOULD THAT BE A SUBGROUP ANALYSIS AND NOT THE PRIMARY ANALYSIS OF THESE STUDIES. FINALLY THEY MENTIONED POLICIES ARE AN ISSUE, WHAT ARE WE WORKING FOR HERE, THE POLICIES DON'T CHANGE, ET CETERA. IT'S AN INTERESTING QUALITATIVE PIECE OF RESEARCH HOW SYSTEMATIC REVIEWERS FEEL WITH THE DATA THEY'RE FACED WITH. THEN I WAS GOING TO MENTION AN EXAMPLE, I WENT AROUND THE HALLS OF SCHOOL YESTERDAY ASKING FEMALE FRIEND, I GAVE TWO EXAMPLE, ARTHROSCOPY OF THE KNEE FOR OSTEOARTHRITIS AND TAKING ASPIRIN TO PREVENT CARDIOVASCULAR OUTCOMES. ONE, THE CARDIOVASCULAR OUTCOMES IN ASPIRIN, THERE'S BEEN A DIFFERENT WHERE THE MEN SHOULD BE TAKING ASPIRIN, IN THE WOMEN THERE'S NO EVIDENCE ASPIRIN IS BENEFICIAL. WITH ARTHROSCOPY OF THE KNEE, THE BIG IMPORTANT TRIAL IS JUST DONE IN MEN. BUT I THINK PEOPLE FEEL THERE'S ENOUGH EVIDENCE AS A WOMAN THEY DON'T WANT THIS SURGERY SO IT'S VERY INTERESTING, COMPLETELY DIFFERENT SITUATION SO OSTEOARTHRITIS OF THE KNEE, THIS IS THE SYSTEMATIC REVIEW. JUST FOR THE PAIN OUTCOME SHOWING THAT LINE, THAT VERTICAL LINE THERE DIFFERENCE BETWEEN THE TREATED AND UNTREATED GROUP IN THIS PARTICULAR STUDY HAD A SHAM TREATMENT. NO DIFFERENCE AND IT WAS ONLY DONE IN MEN. WHAT DO YOU DO IF YOU'RE A WOMAN, DO YOU BELIEVE IT OR NOT? MY COLLEAGUE WHO STRONGLY BELIEVES IN LOOKING FOR SEX DIFFERENCES IN ANIMAL STUDIES SAID I'M HAVING ARTHROSCOPY SO THEY'RE ALL DIFFERENT. HOWEVER INTERESTING THE GUIDELINE FOR CLINICIAN SAYS DON'T HAVE ARTHROSCOPY WHETHER MAN OR -- ARTHROSCOPY WHETHER YOU'RE A MAN OR WOMAN. HARDLY EVER FOUND ON EVIDENCE BUT THIS WAS. SO I THOUGHT I WOULD THROW THOSE THINGS OUT THERE, PROVOCATIVE AND GET US TALKING. OKAY. (OFF MIC) BEFORE I OPEN TO THE AUDIENCE I WANT TO ASK THE FIRST WE WHICH IS I THINK ALL OUR PANEL MEMBERS ARE CLINICAL RESEARCHERS BY AN LARGE WHICH IS REALLY EXCITING BECAUSE IT BRINGS IN A REALLY IMPORTANT PERSPECTIVE. FOR ONE THING CLINICIANS ARE WAY AHEAD OF THE BASIC SCIENCES ON HAVING BEEN USED INCLUDING GENDER AS VARIABLE AS A REQUIREMENT, WE UNDERSTAND IT FOR SOME 25 YEARS NOW. SO I WANT TO ASK EACH OF THE PANELISTS IF YOU CAN JUST SPEAK TO WHAT IS IT -- WHAT ARE THE LESSONS LEARNED AND A LITTLE ALARMING TO HEAR DR. DICKERSON MAYBE NOT INCLUDED AS MUCH AS WE THINK IT IS, WHAT ARE LESSONS LEARNED FROM INCLUSION OF GENDER AS VARIABLE IN CLINICAL TRIALS FOR BETTER OR WORSE AND HOW CAN THEY INFORM US TO IMPLEMENT THIS GOING FORWARD FOR BASIC SCIENCE. START AT THE END WITH YOU. >> I'M SANDY (INAUDIBLE) I'M NOT A RESEARCHER MYSELF. >> I FORGOT. PLEASE INTRODUCE YOURSELF AND YOUR BACKGROUND. >> OKAY I AM A CLINICIAN, I'M INTERNIST, BUT I WORK AT THE FOOD AND DRUG ADMINISTRATION. AND IN THE CENTER FOR DRUG EVALUATION AND RESEARCH. WHERE WE ARE FACED WITH ASSESSING NEW THERAPIES, STUDY OF NEW THERAPIES BOTH PRE-CLINICALLY ANIMALS IN VITRO MODELS AND CLINICAL TRIALS FROM SOUP TO NUTS AS WELL AS MAKING DECISIONS ON THE MARKETING OF NEW DRUGS AND WHAT THE LABELING WILL SAY ABOUT THOSE, WHAT CONCLUSIONS CAN BE REACHED FROM THE DATA. I THINK ONE OF THE THINGS THAT'S VERY CLEAR TO ME FROM MY EXPERIENCE IS THAT IT'S IMPORTANT TO ASK THE RIGHT QUESTIONS. UNFORTUNATE LIT WHERE THERE'S -- WE'RE IN A PLACE WITH REGARD TO UNDERSTANDING SEX DIFFERENCES WHERE THERE ARE MANY MORE QUESTIONS THAN ANSWERS. QUESTIONS ABOUT HOW TO APPROACH THE ISSUES, QUESTIONS ABOUT METHODOLOGY, QUESTIONS ABOUT BASIC BIOLOGY OF SEX DIFFERENCES. IT'S GREAT TO HAVE A SYMPOSIUM LIKE THIS, PARTICULARLY THE POSTERS AND ABSTRACTS WHERE PEOPLE CAN SHARE WHAT THEIR FINDINGS ARE. I THINK WE WILL GET BETTER AT THIS OVER TIME AS WE LEARN TO ASK THE QUESTIONS BETTER. ONE THING WE OFTEN SEE FROM WHAT I SEE FROM WHERE I SIT, PEOPLE COMING IN AND SAYING I WANT SEX SUBGROUP ANALYSES ON EVERY CLINICAL TRIAL FOR EVERY DRUG. WELL IF YOU DO SUBGROUP ANALYSES YOU WILL SEE DIFFERENCES. AND MAYBE IT'S BY SEX, MAYBE BY AGE, MAYBE IT'S BY GEOGRAPHIC AREA, BY SOCIO ECONOMIC STATUS. YOU'RE GOING TO SEE MOVEMENT AROUND YOUR POINT ESTIMATES, WHAT'S DIFFERENT ACROSS THESE DIFFERENCE SUBGROUPS AND WHAT'S THE SAME. AND THEY'RE JUST VERY HARD TO INTERPRET UNLESS YOU HAVE SOME BASIC THINKING ABOUT BIOLOGY GOING IN TO KNOW WHAT YOU'RE LOOKING FOR, NOT TO SAY YOU SHOULDN'T LOOK, A BROAD BRUSH LOOK HELPS YOU ASK GOOD QUESTIONS BUT IT'S REALLY IMPORTANT AS WE GROW THIS FIELD TO DISTINGUISH BETWEEN WHAT'S A QUESTION THAT NEEDS A FURTHER LOOK AND WHAT'S A CONCLUSION. >> SO MY NAME IS RICK FERRIS. I HAVE BEEN DOING CLINICAL TRIALS FOR MORE THAN FOUR DECADES AND HERE AT NIH IN EYE DISEASE. HOWEVER, I HAVE BEEN INVOLVED IN DATA MONITORING COMMITTEES FOR THE PHYSICIAN HEALTH STUDY, WOMEN'S HEALTH STUDY AND OTHER HEALTH STUDIES AND ACTUALLY IN THINKING ABOUT THIS PARTICULAR CONFERENCE IT SEEMS TO ME IT MIGHT BE USEFUL TO TAKE A COUPLE OF MINUTES AND LOOK AT WHAT HAPPENED WITH THE PHYSICIAN HEALTH STUDY AND DIFFERENT PEOPLE WILL SAY MISTAKES WERE MADE OR WEREN'T MADE DEPENDING ON YOUR PERSPECTIVE. BUT IN TALKING TO CHARLIE HAHN CONDITION AND JULIE AS THEY WERE PUTTING TOGETHER THE APPLICATION TO LOOK AT ASPIRIN AND BETA CAROTENE FOR CARDIOVASCULAR DISEASE IN PARTICULAR, THAN OTHERS THE GRANT APPLICATION THEY PUT IN WAS TO ALL PHYSICIANS OVER AGE 50. SO THEY WERE NOT BEING EXCLUSIVE BUT WHEN THE GRANT APPLICATION WAS REVIEWED, WAIT A SECOND, TWO PROBLEMS. NUMBER ONE, HOW MANY WOMEN OVER AGE 50 ARE PHYSICIANS? YOU HAVE TO UNDERSTAND THIS IS BACK IN THE '70s. SO TO BE 50 YOU HAD TO BE BORN IN THE 20s THE REALITY WAS RELATIVELY FEW, I DON'T REMEMBER THE PERCENTAGE BUT 10, 20% INSTEAD OF 50%, WERE WOMEN. AND THE SECOND THING WAS WOMEN JUST DON'T HAVE THAT MUCH CARDIOVASCULAR DISEASE COMPARED WITH MEN. ONE CAN DEBATE WHETHER THOSE ESTIMATES WERE APPROPRIATE OR NOT APPROPRIATE BUT THE REALITY WAS BASICALLY THEY WERE TOLD IT'S POINTLESS TO INCLUDE WOMEN. NOW IN RETROSPECT THAT MIGHT HAVE TURNED OUT TO BE A LUCKY DECISION BECAUSE THINK OF WHAT MIGHT HAVE HAPPENED IF THEY INCLUDED WOMEN SO FIRST OFF, THEY'RE UNDERPOWERED FOR TWO REASONS I MENTIONED, THEY HAVE TOO FEW AND THEY'RE GOING TO HAVE LESS EVENT RATE IN THE WOMEN THAN THE MEN BUT IF YOU THEN WANT TO LOOK FOR INTERACTIONS ARE THE RATES DIFFERENT IN MEN OR THE TREATMENT EFFECTS DIFFERENT IN MEN OR WOMEN BECAUSE YOU'RE UNDERPOWERED YOU MIGHT COME TO THE CONCLUSION THAT NO, THERE'S NO DIFFERENCE. WHEN IN REALITY, BECAUSE THEY DIDN'T INCLUDE WOMEN IN THE FIRST PLACE, THEY WOUND UP DOING A STUDY THAT WAS APPROPRIATELY POWERED. AND WHAT DO YOU KNOW? THAT HE OAR NOT THE SAME. SO HERE IS THIS TALE, I'M JUST A POOR CLINICAL TRIALIST THAT CURT MINER IS FOND OF SAYING, WHAT'S A CLINICAL TRIALIST TO DO WHEN THEY'RE BESIEGED BY YOU NEED TO LOOK AT RACE DIFFERENCES, LOOK AT SEX DIFFERENCES AND NOW WE'RE TOLD THERE'S SEX AND THERE'S GENDER. OH, MY GOD. HOW WILL I KEEP THIS UP? THIS IS ALL THE MORE WAYS THAT I CAN BE SOCIALLY INAPPROPRIATE BY MAKING A MISTAKE AS TO WHAT I'M DOING. I THOUGHT IT WAS MEN AND WOMEN AND THAT'S HARD ENOUGH. SO OUR RESEARCH IN SOME WAYS I THINK WE HAVE BEEN FORTUNATE THAT THERE ARE NOT A LOT OF DIFFERENCES IN AT LEAST THE DISEASES THAT I STUDY A LOT LIKE DIABETIC RETINOPATHY AND AGE RELATED MACULAR DEGENERATION AND CATARACT. MEN OR WOMEN THEY GET AND SEEM TO GET THEM ABOUT THE SAME. IS THERE SOMETHING IN THAT LITTLE ASPIRIN TALE THAT SAYS MAYBE WHEN YOU OUGHT TO BE MORE INTERESTED THAN LESS INTERESTED WITH REGARD TO WHETHER THERE ARE GENDER DIFFERENCES. SANDRA JUST MENTIONED A SECOND AGO, THAT IS I THINK IS THERE BIOLOGIC PLAUSIBILITY THAT THESE DISEASES ARE DIFFERENT IN MEN AND WOMEN? SO FOR CAD OWE VASCULAR DISEASE THERE'S BIOLOGIC PLAUSIBILITY OF A DIFFERENCE. THE AGES ARE DIFFERENT, THE MANIFESTATIONS OF THE DISEASE ARE DIFFERENT. SO THERE ARE LOTS OF REASONS THAT SAY THROWING EVERYONE IN THE SAME BIN MAY NOT BE SUCH A GOOD IDEA. WHEREAS IN AGE RELATED MACULAR DEGENERATION WE DON'T SEE MUCH DIFFERENCE IN MEN AND WOMEN, EXCEPT -- THIS IS THE LAST -- I'M GOING TO SHUT UP IN A SECOND BUT ONE OF THE PROBLEMS WITH MEN AND WOMEN AND DIFFERENTIATION IS WHAT KAY MENTIONED EARLIER, THAT IS FOR SOMEBODY DEALING IN EYE DISEASE WHERE IT'S -- THESE DISEASES TEND TO BE DISEASES LATER IN LIFE AND MACULAR DEGENERATION, OUR AVERAGE AGE IS AROUND 8. SO AGE DIFFERENCES ARE IMPORTANT NOT ONLY THAT IT'S CALLED AGE RELATED MACULAR DEGENERATION. THAT'S -- IT IS HIGHLY AGE RELATED. SOME STUDIES HAVE SHOWN THAT WOMEN ARE MORE LIKELY TO HAVE AGE RELATED MACULAR DEGENERATION AND OTHER STUDIES HAVEN'T FOUND THAT. ONE OF THE THINGS THAT MAKES ME CONCERNED ABOUT THE DATA IS THAT THE STUDIES THAT HAVE SHOWN A DIFFERENCE, THE AGES TEND TO BE GROUPED. IN DECADES. IF YOU'RE GROUPED IN DECADES I WOULD ARGUE THAT THERE IS GOING TO BE AGE DIFFERENCES. THAT YOU CAN'T ADJUST FOR BECAUSE YOU ONLY HAVE # 0 TO 90. IN THAT 80 TO 90 GROUP PROBABLY MORE WOMEN THAN MEN AND HOD YOU ADJUST FOR AGE IS DIFFICULT BECAUSE THEY'RE IN THE GROUP. YOU CAN'T SEPARATE 890 FROM 81s. SO WHETHER THERE'S A DIFFERENCE IN MACULAR DEGENERATION OR NOT, I DON'T KNOW. WE ALWAYS LOOK BY SEX DIFFERENCE, MEALS AND FEMALES AT LEAST. AND WE HAVEN'T SEEN ANYTHING. THAT DOESN'T MEAN THAT THERE ISN'T SOMETHING SOME NEW TREATMENT WHERE THERE WILL BE A DIFFERENCE BUT LOTS OF EXAMPLES LIKE STUDIES OF ANTI-VEGF OR AGE RELATED MACULAR DEGENERATION WHERE YOU HAVE SIX OR SEVEN TRIALS. AND IF IN EVERY ONE OF THOSE TRIALS YOU LOOK BY MALE AND FEMALE, AND THERE'S NO DIFFERENCES IN TREATMENT EFFECT, MY GUESS IS THERE'S NO DIFFERENCES IN TREATMENT EFFECT AND WE DON'T HAVE TO SEPARATELY STUDY THEM. BUT I GRANT YOU THIS IS AN INCREDIBLY COMPLEX SITUATION AND WITH ALL THE MONEY AND PEOPLE IN THE WORLD YOU CAN DO TRIALS THAT WOULD FULLY ADJUST FOR ALL THESE VARIABLES BUT THAT'S NOT THE REALITY. >> HI. I'M KATHLEEN BRADY. I'M A PSYCHIATRIST AND PHARMACOLOGIST FROM THE MEDICAL UNIVERSITY OF SOUTH CAROLINA. I DO MOSTLY, I'M MOSTLY CLINICAL RESEARCH, MOSTLY CLINICAL TRIALS IN ADDICTIONS AND SOME CO-OCCURRING MOOD AND ANXIETY DISORDER MOSTLY PEOPLE WITH ADDICTION. SO JUST TO GET BACK TO YOUR POINT, THE INITIAL ONE, IS WE HAVE BEEN REQUIRED FOR 25 YEARS OR WHATEVER BUT THE BOTTOM LINE IS THAT SORT OF WHAT YOU PUT IN YOUR -- YOU PUT IN YOUR ANTICIPATE -- YOUR PROPOSED RECRUITMENT PLAN AND CERTAINLY IF YOU'RE GOING FOR REGULATORY APPROVAL, PEOPLE ARE GOING TO HOLD YOUR FEET TO THE FIRE ABOUT THAT, BE BUT IF IT'S NOT A REGULAR STUDY, I THINK OFTEN IF YOU ACTUALLY LOOK AT THE DATA RECRUITMENT OF WOMEN TO CLINICAL TRIALS ACROSS THE BOARD IS GENERALLY LOWER THAN MEN AND IT'S SOMEWHERE -- SO EVEN THOUGH WE HAVE BEEN SAYING FOR A WHILE WE WOULD DO 50/50 AND DO THESE GENDER SPECIFIC ANALYSES AT THE END OF THE DAY, YOU RECRUIT IN LESS -- IN MANY DISEASE STATES I THINK UNLESS THERE ARE REALLY SPECIFICALLY TARGETED RECRUITMENT EFFORTS WITH THE INTENTION OF KEEPING THE RECRUITING EQUAL NUMBERS OF MEN AND WOMEN SO YOU CAN DO A GENDER ANALYSIS BY GENDER OFTEN AT THE END OF THE DAY IN THE LAST 25 YEARS, CLINICAL TRIALS THAT ARE PUBLISHED AND REPORTED DO NOT REPORT BY GENDER AND OFTEN DON'T HAVE ADEQUATE SAMPLE SIZE TO DO AN ADEQUATELY POWERED GENDER ANALYSIS. MY THOUGHT ABOUT THIS, SO I COME AT THIS FROM A DIFFERENT THERAPEUTIC AREA, AN AREA WHERE THERE HAS BEEN EVERY TIME, EVERYWHERE YOU HAVE LOOKED THERE ARE REALLY PROFOUND GENDER DIFFERENCES. SO MY APPROACH TO THIS WOULD BE CONSIDERABLY DIFFERENT BECAUSE I WOULD SAY FROM THE DATA I SEE FROM WHAT WE SAW WILSON COME TON PRESENTED THIS MORNING, (INDISCERNIBLE) DATA IN SMOKING CESSATION, HUGE GENDER DIFFERENCE, EVEN WE WERE INVOLVED IN A NATURAL TREK SEWN TRIAL, INJECTABLE NALTREXONE, AND 0 EFFECT IN WOMEN AND THE TIRE EFFECT WAS DUE IN MEN SO IF YOU HAVE HADN'T DONE THAT GENDER ANALYSIS YOU MUST HAVE MISSED THE MAIN POINT. I WAS PIVOTAL IN THE TRIAL FOR PTSD WHERE THE EFFECT WAS SO MUCH GREATER IN WOMEN THAN MEN THAT THERE WAS DISCUSSION AT THE FDA ABOUT WOULD THEY ONLY APPROVE THE TREATMENT OF WOMEN WITH PDSC, THAT WAS A SERIOUS CONSIDERATION, AGAIN WITHOUT HAVING DONE THE GENDER ANALYSES IN THESE KINDS OF STUDIES WE WOULD HAVE COMPLETELY MISSED THE POINT. SO YEAH, AND I DO UNDERSTAND, TWO THINGS I WANT TO SAY, WHY IS IT THAT MAYBE HARDER TO -- I THINK THERE ARE MORE BARRIERS TO WOMEN PARTICIPATING IN CLINICAL TRIALS, AGAIN, PARTICULARLY MAYBE IN THIS THERAPEUTIC AREAS THAT I WORK IN IN ADDITIONS AND CO-OCCURRING DISORDERS, I THINK TRANSPORTATION BARRIERS, CHILD CARE BARRIERS AND IF WE THINK THIS IS EVEN EDUCATION LEVEL BARRIERS, IF WE THINK THIS IS A PROBLEM IN THE UNITED STATES, THINK HOW MUCH LARGER THAT PROBLEM IS IN OTHER COUNTRIES WHERE IT'S PROBABLY A LOT HARDER FOR WOMEN TO PARTICIPATE IN CLINICAL TRIALS. SO FOR US TO GET -- SO I CAN UNDERSTAND WHEN I LOOK AT STUDIES AND SEE THAT IN SPITE OF THE FACT THAT PROBABLY THEIR PROPOSE RED CUTEMENT WAS EQUAL NUMBERS OF MEN THAN WOMEN AT THE END OF THE DAY WHEN ANALYZING THE RESULTS THEY HAVE LOWER PERCENTAGES OF WOMEN IN THERE, IT TAKES TARGETED RECRUITMENT EFFORTS. I THINK WE NEED TO INSIST ON THAT. I DO THINK ESPECIALLY IN THERAPEUTIC AREAS WHERE WE KNOW TIME AND AGAIN WE HAVE SEEN PROFOUND GENDER DIFFERENCES IN RESPONSE. I THINK THERE'S JUST -- I DON'T THINK WE HAVE ANY CHOICE. AND I DO UNDERSTAND THAT THERE'S A LOT OF THINGS THAT PEOPLE NEED TO -- THERE'S A MILLION OTHER THINGS PEOPLE MAYBE NEED TO CONSIDER AND CONTROL FOR IN TRIALS BUT AGAIN, I THINK YOU DO NEED TO LOOK AT BIOLOGIC PLAUSIBILITY BUT WHEN YOU'RE IN AN AREA MENTAL HEALTH ADDITION IS THE ONE THAT I HAVE BEEN SPENT MY CAREER IN, I DON'T -- I THINK THAT THE EFFECTS OF SEX AND GENDER ARE SO PROFOUND THAT IT'S REALLY AGAIN OUTWEIGHS ANY OF THE OTHER VARIABLES THAT WE ARE TAKING INTO CONSIDERATION THAT MIGHT MAKE FEASIBILITY OF RECRUITMENT AND GETTING THE RIGHT SUBGROUPS IN THERE SOMETHING THAT CAN BE DONE. >> GREAT. I THINK MY QUESTION SORT OF FALLS TO PART 2 A LITTLE PREMATURELY BUT WHERE WE'RE GOING TO TALK MORE CLINICAL TRIALS BUT IT DID RUN THE GAMUT FROM PROFOUNDLY IMPORTANT AND SHOULD BE INCLUDED TO AN ALMOST APOLOGETIC SORRY I DIDN'T FIND ANY SEX DIFFERENCES APPROACH. THAT'S ONE OF THE THINGS WE WANT TO BE SURE TO TALK ABOUT IS IT'S OKAY SOMETIMES WHEN YOU DON'T FIND SEX DIFFERENCES THAT YOU ARE NOT CHARGED WITH FINDING SEX DIFFERENCES PROBABLY EQUALLY IMPORTANT. SO WHAT I WANT TO DO IS I KNOW THE AUDIENCE IS FULL OF SCIENTISTS SO I WANT TO GIVE YOU AN OPPORTUNITY TO ASK THE PANEL QUESTIONS FROM CLEARLY NOT WET BENCH ANIMAL MODEL POINT OF VIEW AS TO HOW THEY CAN HELP INFORM OUR DISCUSSION ABOUT PRE-CLINICAL RESEARCH AND HOW CAN WE BEST INCORPORATE SEX AS A VARIABLE TOWARDS HIGH IMPACT RESEARCH. I INVITE ANYBODY WHO HAS ANY QUESTIONS TO COME TO THE MICROPHONE OR ANY STATEMENTS, ANY POSITIONS YOU WANT TO TAKE, ANY ADVICE OR GUIDANCE. >> WE WERE TALKING PRE-CLINICAL, I WANT TO MAKE THE POINT FOR STUDIES OF DRUGS UNDER -- BEING INVESTIGATED FOR FIRST TIME USE IN HUMANS HISTORLY THE ANIMAL STUDIES HAVE ALWAYS BEEN IN BOTH GENDERS. THERE'S NEVER BEEN A REQUIREMENT THEY BE SINGLE OTHER THAN CERTAIN REPRODUCTIVE TOX STUDIES. SO TYPICALLY IN A MIX UNLESS THERE'S A REASON NOT TO HAVE A MIX. BECAUSE OF SOMETHING SOMEBODY KNOWS ABOUT THE DRUG BUT IN GENERAL THEY TEND TO BE A MIX. THE ANALYSES ARE -- WE'LL LOOK FORWARD DIFFERENCES BY SEX AND IT'S ALMOST ALWAYS IN MULTIPLE SPECIES. WHERE THERE ARE DIFFERENCES SEEN IN THOSE EARLY PRE-CLINICAL STUDIES BY SEX, THEY'RE TYPICALLY -- THEY ARE OFTENTIMES FOLLOWED UP ON BUT USED IN THE BROADER -- KEEPING IN MIND THE REASON THOSE ANIMAL STUDIES ARE DONE IN THE FIRST PLACE IS TO LOOK FOR AN ASSESSMENT OF A SAFE DOSE TO START WITH IN HUMANS, ARRANGE OF DOSES THAT ARE LIKELY SAFE OR EVEN IN SOME CASES HAVE OTHER TYPE OF CLINICAL POSITIVE EFFECT BEING SOUGHT. IF THERE -- THERE ARE SIGNALS THERE THAT ARE INFORMATIVE THAT WILL USUALLY BE PURSUED IN THE CLINICAL STUDIES RIGHT FROM THE GET GO IN THE DESIGN PHASE. >> I HAVE TO RESPONSE RESPOND TO THAT, THAT'S IN TOXICOLOGY. BUT THE BASIC SCIENCE RESEARCH IS OVERWHELMING. >> RIGHT. WE DON'T -- WE SEE THE -- THE ONES WE REQUIRE, IT'S A BIG MIX. >> COLLEEN MACKEY, UNIVERSITY OF ILLINOIS CHICAGO. I THINK THIS MORNING WE HAD A REALLY GOOD REMINDER TO BE CAUTIOUS WHEN LOOKING ONLY AT EPIDEMIOLOGICAL DATA TO SUGGEST THAT IF THAT'S NO SEX DIFFERENCE INCIDENCE OR PREVALENCE THAT THE WAY THE SEX GETS TO THAT END POINT IS THE SAME. EYE DISEASE IS A REALLY GOOD EXAMPLE OF THAT, FOR EXAMPLE, USING GLAUCOMA, FROM THE MAYO CLINIC O FREAKTOMY STUDIES WOMEN WHO HAVE OVARIES OUT BEFORE 43, HAVE DOUBLE THE RISK GLAUCOMA. WOMEN RANDOMIZED TO ESTRADIOL HAVE HAVE A LOWER IOP SO THERE'S SEX SPECIFIC RISK FACTORS THAT CAN BE MASKED WHEN WE LOOK PURELY AT EPIDEMIOLOGY TO INFORM UNDERSTANDING HOW THE SEX GET TO AN END POINT THAT'S AN IMPORTANT LESSON WE NEED TO REMEMBER. O OOPHORECTOMY -- >> MAKE A COMMENT THAT'S RELATED. I AGREE. IT'S VERY INTERESTING TO ME BECAUSE I HAVE HEARD US TALK ABOUT MECHANISM OF ACTION AND STUFF THAT THIS ACTUALLY THE MECHANISM OF ACTION STUFF HASN'T PANNED OUT. MUCH OF THE TIME. IT HISTORICALLY MY UNDERSTANDING IS IT STARTED WITH THE FLEXOR REPORT IN 1910 OF ALL MEDICAL SCHOOLS AND FLEXOR WHO WAS CORRECT TO COMMENT ON THE WAY MEDICAL TRAINING OCCURRED, IT WASN'T SCIENTIFIC SAID WE HAD TO GET BACK TO BIOLOGY. THINGS HAVE TO MAKE SENSE BIOLOGICALLY. SO WAYS WE TEACH NOW ESPECIALLY CLINICIANS, LOOK AT THE MECHANISM OF ACTION, IF IT MAKES SENSE THEN MAYBE IT'S TRUE. SO I THINK WE ARE VERY ORIENTED TO MECHANISMS OF ACTION AND JUST LIKE WITH THE WOMEN'S HEALTH INITIATIVE, IT DOESN'T PAN OUT. SO I THINK WE HAVE TO LET GO OF THAT A LITTLE BIT. IT MAYBE A PLACE TO BEGIN BUT WE HAVE TO LET GO OF IT IN TERMS OF WHAT'S THE EVIDENCE ACTUALLY. >> COULD YOU EXPAND? I'M SORRY, I DON'T UNDERSTAND WHAT YOU MEAN BY IT HASN'T PANNED OUT. FROM THE >> FOR EXAMPLE, THE WHOLE IDEA OF TALK ABOUT THIS MORNING OF MUST BE THE HORMONES. THAT'S WHY WOMEN HAVE LESS CARDIOVASCULAR DISEASE THAN MEN BEFORE MENOPAUSE. WHO KNOWS WHAT'S REALLY GOING ON. I DON'T ANYWAY. BUT I THINK WE HAVE TO LET GO A LITTLE BIT OF IT BEING ESTROGEN, I WONDERED WHY IT'S NOT TESTOSTERONE. AND SO WE'RE SPENDING A LOT OF EVIDENCE LOOKING AT WHAT WE THINK MUST BE TRUE BECAUSE WE'RE OBSERVED SOMETHING, THERE'S MORE BLOOD VESSELS GROWING. SO THAT MUST BE THE EXPLANATION FOR WHATEVER. LET GO OF IT A LITTLE AND OPEN OUR MINDS TO MAYBE IT'S SOMETHING WE DON'T UNDERSTAND. >> JUST TO RESPOND TO THAT, VIRGINIA MILLER WILL RESPOND AS WELL, BUT ACTUALLY IT WAS THE WOMEN'S HEALTH INITIATIVE WOMEN'S HEALTH INITIATIVE THAT SHOWED US THAT THERE IS CARDIO PROTECTION WITH ESTROGEN WHEN GIVEN TO YOUNG WOMEN AND HOWARD LOADSS LEAD TRIAL REPLICATED THAT. SO I THINK WE HAVE TO BE CAUTIOUS ABOUT EXTRAPOLATING FROM ALL ASPECTS OF THE WHI TO REALLY WHAT THE STUDIES INFORMED OUR UNDERSTANDING OF, IS THERE IS IN FACT A ROLE FOR HORMONES IN THE RIGHT PLACE, THE RIGHT TIME. >> SO I WOULD LIKE -- >> YEAH. >> I WOULD LIKE TO ADDRESS THE ISSUE OF MECHANISM. AS A CLINICAL TRIALIST WE DO CLINICAL TRIALS AND THE RESULT COMES OUT AND PEOPLE WILL TELL YOU WHAT THE MECHANISM IS. AND OF COURSE, YOU HAVE HAD SOME THOUGHT TO WHAT THE MECHANISM IS BEFORE YOU STARTED THE TRIAL. BUT AT THE END OF THE TRIAL YOU WILL NOT HAVE A PROBLEM FINDING PEOPLE, TELLING YOU WHAT THE MECHANISM IS. AND AS A TRIALIST I DON'T KNOW WHAT THE MECHANISM IS, I KNOW A IS BETTER THAN B, I KNOW HOW TO DO THAT, THAT'S THE WAY IT CAME OUT, SO IT WAS ROY COLLINS AND RICHARD PEDO IN A MEETING THAT WE WERE IN IN OXFORD, WE WERE TALKING ABOUT THIS MECHANISM AND HE SAID HE'S BEEN -- DEVELOPED A NEW MEASURE RELATED TO DETERMINING MECHANISM, CALLED THE INVERSION TIME, IT GOES LIKE THIS. YOU TELL SOMEONE THAT YOU DID THIS CLINICAL TRIAL OF A VERSUS B, AND A WAS BETTER THAN B AND YOU ASKED THEM BUT I'M TRYING TO FIGURE OUT WHY A IS BETTER THAN B. IT WILL TAKE THEM A LITTLE WHILE, THEY WILL COME UP WITH SOME MECHANISMS AS TO WHY A IS BETTER THAN B. THEN YOU TELL THEM, DID I SAY A WAS BEAR THAN B? B WAS BETTER THAN A. AND INVERSION TIME IS HOW LONG IT TAKES THEM TO COME UP WITH AN EQUALLY PLAUSIBLE MECHANISM AS TO WHY B SHOULD BE BETTER THAN A. THE REALITY IS, IF YOU TALK TO CLINICIANS, THEY ARE SUPERB AT COMING UP WITH MECHANISM, WHETHER THEY'RE RIGHT OR NOT IS A TOTALLY DIFFERENT QUESTION. SINCE I DEAL WITH SURGEONS I NOTICED THEY'RE FASTER. COMING UP WITH EQUIVALENT MECHANISMS. >> SO I WASN'T GOING TO TALK ABOUT THE WHI BUT I CAN'T HELP NOT TO COMMENT. I THINK THIS IS AN SITUATION WHERE THE EPIDEMIOLOGY DID NOT INFORM THE DESIGN OF THE TRIAL. THE DESIGN OF THE TRIAL HAD LOOKED AT THE POPULATION, THAT THEY WERE SEEING THE DIFFERENCE IN, THAT TRIAL WOULD HAVE BEEN DESIGNED DIFFERENTLY. SO IT'S ALSO A MIND SET AMONG CLINICIANS THAT THEY HAVE TO MEASURE HARD END POINTS AND NOT LOOK AT PHYSIOLOGICAL PROCESSES LIKE ACTUALLY ACCUMULATION OF PLAQUE WITH AN INDIVIDUAL WHICH TO ME IS A PROCESS, PHYSIOLOGICAL PROCESS, NOT A SURROGATE END POINT. YOU SLOW PROGRESSION OF DISEASE, YOU STOP IT, YOU DON'T HAVE TO WAIT FOR THE OUTCOME BECAUSE NOW WE HAVE THE TOOLS TO MEASURE THAT PROGRESS. THAT'S WHI. OVER, DONE WITH, LET'S MOVE ON, ANY QUESTION WAS FOR THE DR. COOLER, WHY IS THE FDA SO RELUCTANT TO APPROVE DRUGS OR DOSING BEFORE MEN AND WOMEN? AMBIEN TOOK A CRISIS TO HAPPEN. AND WHY CAN'T THAT -- WHY CAN'T THIS BE MORE GENERALLY APPLIED? WE HEARD A COUPLE OF WEEKS AGO ONE OF THE OTHER NIH CONFERENCES THAT THE WHOLE GROUP OF DRUGS CALLED LAZAROIDS COULDN'T GO TO MARKET BECAUSE THEY WERE ONLY FOUND EFFECTIVE IN ONE SEX AND THE DRUGS WITHDRAWN FROM THE MARKET THAT THE GOA IDENTIFIED HAS SIDE EFFECTS IN WOMEN DUE TO POTASSIUM CHANNEL DIFFERENCES IN THE HEART WHICH IS A MECHANISM BUT YOU'RE DENYING THOSE DRUGS TO MEN OR WOMEN OR SO WHAT'S THE RELUCTANCE TO SAY WE SHOULD HAVE THIS DOSAGE FOR MEN OR THIS DRUG ONLY WORKS IN WOMEN. WHY IS THERE RELUCTANCE TO DO THAT? >> FIRST I DON'T KNOW WHAT LAZEROIDS ARE SO I CAN'T COMMENT ON THAT EXAMPLE, IT'S NOT SOMETHING I'M PERSONALLY FAMILIAR WITH. BUT I CAN TELL YOU THERE IS ABSOLUTELY NO RELUCTANCE. ABSOLUTELY NONE, AND WHAT WE SEE IS THAT FOR THE VAST MAJORITY OF DRUGS THE DOSES AT WHICH THEY ARE TESTED, ARE ON A FLAT PART OF THE DOSE RESPONSE CURVE. VERY FLAT. COMPANIES SPECIFICALLY DEVELOP DRUGS AND STOP DEVELOPMENT OF DRUGS EARLY ON IF THEY THINK THERE IS GOING TO NEED TO BE DIFFERENTIAL DOSING IN ANY POPULATION OF PATIENTS, WHETHER IT'S BY AGE, BY YOU NAME THE VARIABLE UNLESS IT'S A DRUG THAT'S USED IN AND IN HOSPITAL SETTING WHERE YOU'RE DOSING ON A WEIGHT BASIS, MILLIGRAM PER KILOGRAM. COMPANIES SEEKING TO DEVELOP THESE PRODUCTS WE ENCOURAGE OTHERWISE THEY COME IN AND WANT TO STUDY ONE DOSE. THAT YOU GET FROM EXTRA MILLIGRAMS OR FREQUENCY OF DOSING, WHATEVER THAT MAYBE. BUT IN -- WHAT ULTIMATELY ENDS UP HAPPENING IS USUALLY YOU SEE -- I LOVE THIS TERM FROM INITIAL PRESENTATION WE SEE FAR MORE WITHIN SEX DIFFERENCES IN A DOSE EFFECT THAN ACROSS SEX DIFFERENCES IN A DOSE EFFECT. YOU GET A DIFFERENCE. AM BEE YEN, THAT WASN'T EVIDENT IN THE EARLY TRIALS, IT WAS ONLY IN THE ACTUAL PHARMACODYNAMIC STUDIES THAT THE METHODOLOGY DIDN'T EXIST WHEN THAT DRUG WAS APPROVED BACK IN THE '90s TO TEST IN THAT MANNER. WHERE WE GO BACK AND PIECE TOGETHER THE STORY IN A DIFFERENT WAY. TESTING FOR DRIVING TODAY IS A COMPLETELY DIFFERENT WORLD THAN IT WAS BACK THEN. WE HAVE NO RELUCTANCE, NONE AT ALL. COMPANIES OFTEN DROP DEVELOPMENT OF A PRODUCT IF THEY SEE THAT THAT'S GOING TO NEED TO BE THE CASE. >> SO LISTENING TO THIS END OF THE TABLE, I WOULD GET THE IMPRESSION THAT YOU WOULD ALL AGREE WITH THE STATEMENT THERE'S NOTHING WRONG WITH THE WAY WE'RE DOING BUSINESS RIGHT NOW. PRE-CLINICALLY. WOULD THAT BE A FAIR CHARACTERIZATION? >> I DON'T DO ANY PRE-CLINICAL WORK, SO IT'S EASY FOR ME TO SAY IF YOU'RE ASKING ME THAT QUESTION, I'M NOT GOING TO SAY YES. >> MY UNDERSTANDING TALKING TO PEOPLE WHO DO THE PRE-CLINICAL ANIMAL WORK IS THERE'S A LOT OF PROBLEMS. BUT PEOPLE HAVEN'T EXAMINED IT ENOUGH TO KNOW WHETHER IT MAKES A BIG DIFFERENCE, IS MY UNDERSTANDING. BUT AGAIN, IT'S NOT MY FIELD. >> ANYBODY IN THE AUDIENCE HAVE ANY OPINIONS ON THAT? SHOULD WE TELL JANINE CLAYTON SHE'S BEEN WASTING YOUR TIME AND WE SHOULD ALL GO BACK TO STATUS QUO? OKAY. LET'S GO HOME. WHY ARE WE DOING THIS? DOES ANYBODY KNOW -- WHAT IS ALL OF THIS ABOUT? HOW MANY PEOPLE IN THIS ROOM DO RESEARCH ON ANIMALS? HOW MANY PEOPLE IN THIS ROOM DO RESEARCH ON HUMAN? OKAY THANK YOU. THAT HELPS ME, HOW MANY PEOPLE BELIEVE THAT MISTAKES HAVE BEEN MADE IN THE CLINICAL REALM OR IN FAILURE TO REPLICATE BECAUSE OF FAILURE TO INCLUDE SEX AS A VARIABLE IN PRE-CLINICAL TRIAL? NOT VERY MANY. SO WHAT ARE -- HAS BEEN THE NUMBER ONE VARIABLE THAT IS LEADING TO FAILURE TO REPLICATE? SEX. A LOT OF US BELIEVE IT IS FAILURE TO CONTROL FOR SEX BUT WHAT ARE OTHER VARIABLE? THERE'S OTHER BIOLOGICAL VARIABLES. MR. DID YOU SAY FAILURE TO REPLICATE? >> REPLICATE. YES. YES. THE PHARMACEUTICAL INDUSTRY CLAIMS THAT THEY CAN -- THEY CAN'T REPLICATE 70% OF WHAT WE DO IN OUR LABORATORIES. ARE THEY RIGHT? DO WE BELIEVE THE PHARMACEUTICAL INDUSTRY? >> COVER ON SCIENCE LIKE IN THE LAST FEW WEEKS, OR MIGHT BE READING, SHOWED SOMETHING IN MICE BUT OPPOSITE IN RATS AND IT SHOWS SOMETHING DIFFERENT IN -- A BIG SPLASH OF A STUDY ON -- HAD TO DO WITH ANAPHYLACTIC SHOCK AFTER BURN INJURY. >> IT WAS MORE THAN THAT, IT WAS ALL DIFFERENT CONDITIONS SO I THINK WE CAN'T JUST THINK, WE HAVE KNOWN THIS A LONG TIME WHAT'S SHOWN IN AN ANIMAL MODEL, INFLAMMATION STUDY A FEW YEARS AGO SO IN ANIMAL MODEL ISN'T NECESSARILY GOING TO PREDICT WHAT'S IN HUMAN IT IS MAIN REASON WE CAN'T REPLICATE IS STUDIES ARE BAD AND NOT REPORTED TRUTHFULLY. >> OKAY. THAT'S A CLEAR STATEMENT. >> AND THERE'S PRESSURE TO COME WITH THE RIGHT RESULT. AND THE ONE THING WE PROBABLY CAN AGREE ON IS THAT MICE AREN'T PEOPLE. SO SOMETIMES WHAT WORKS IN MICE WORKS IN PEOPLE, SOMETIMES IT DOESN'T, THAT'S WHY WE DON'T JUST DO MOUSE STUDIES. >> THE FAILURE TO REPLICATE ISSUE ISN'T TRYING TO REPLICATE IN HUMAN, WHAT'S DONE IN A MOUSE, IT'S TRYING TO REPLICATE IN MOUSE WHAT WAS DONE IN A MOUSE. >> I CAN'T SPEAK SPECIFICALLY TO THE REPLICATION PIECE, WHEN THERE'S FAILURE TO REPLICATE IT'S IMPORTANT THE LOOK AT THE DATA AND TRY TO UNDERSTAND WHERE THE DIFFERENCES COME FROM. OFTENTIMES WHEN YOU'RE JUST LOOKING AT THE END RESULTS, OF TWO STUDIES THAT SEEM TO COME UP WITH VERY DIFFERENT RESULTS, TRYING TO UNDERSTAND WHY THEY'RE DIFFERENT IS A REAL CHALLENGE, ONE EXAMPLE IN CLINICAL TRIALS WHERE WE OFTEN HAVE WIDELY DIVIR GENT RESULTS IS ANTIDEPRESSANTS. MOST CLINICAL TRIALS IS ANTI-DEPRESSIVES -- AS ANTI-DEPRESSIVES FAIL. MOST DO. YET SOME ARE SUCCESSFUL AND YOU CAN LOOK AT ALL THE CHARACTERISTICS THE PATIENTS IN THOSE TRIALS THE DOSES IN THOSE TRIALS, YOU CAN LOOK AT EVERY WAY BUT FOR SOME REASON YOU CAN GET VERY DIFFERENT RESULTS THAT ARE VERY DIFFERENT TO EXPLAIN. A LOT OF PEOPLE SPEND TIME TRYING TO FIGURE THAT OUT. I THINK THE PRINCIPLE TRYING TO UNDERSTAND, THERE IS SOME WORK GOING ON THAT'S GETTING TO THAT, THERE'S PROBABLY THE SAME IN ANIMAL TRIALS AS WELL. IS SEX IN ANIMALS ONE FACTOR? IF YOU'RE USING FEMALE ANIMALS WHAT ABOUT THE AGE OR CYCLE WHERE THERE MAYBE SENSE ACTIVITY IN THAT ANIMAL MODEL THAT MAY OR MAY NOT BE THE SAME IN ANOTHER SPECIES. ONE THING WE ALSO LOOK AT AS I'M SURE IN OTHER -- COMPARING RESULTS I THINK SOMEBODY SAID THIS, IN A MOUSE AND A RAT MAY NOT BE A RELEVANT COMPARISON BECAUSE THEY'RE QUITE DIFFERENT. >> SO I'M GOING TO GO BACK TO YOUR ORIGINAL QUESTION, WHEN YOU SAY WHY SHOULD WE DO THIS? BECAUSE THERE ARE DIFFERENCES IN DISEASE PREVALENCE MORBIDITY AND MORTALITY BETWEEN MEN AND WOMEN. AND WE DON'T UNDERSTAND THOSE SO THAT'S CONSIDER AD HEALTH DISPARITY. IF WE'RE GOING TO REDUCE THE HEALTH DISPARITY, I'M GOING TO USE THE M WORD HERE, THE MECHANISMS OF THOSE DISEASES IN THOSE TWO SECTION SEXES SO WE HAVE TO STUDY THEM. >> I COME FROM THE PERSPECTIVE OF A GENETICIST, I DON'T WORK IN ANIMALS SO SOME OF THIS COULD BE MY IGNORANCE FROM THAT REGARD BUT MOST ANIMAL MODELS ARE VERY INBRED AND THEY REFLECT ESSENTIALLY THAT STRAIN OF AN ANIMAL. HUMANS ARE NOT. THAT COULD BE ONE REASON WHY MANY THINGS DON'T REPLICATE IS THAT IN ANIMALS WE'RE LOOKING AT ONE ANIMAL, YOU MIGHT LOOK AT MANY COPIES BUT YOU'RE NOT LOOKING AT THE VARIATION THAT YOU SEE IN POPULATIONS. >> I WANT TO MAKE A COMMENT WITH REGARD TO MECHANISM, NOT SAYING WE SHOULDN'T TRY TO UNDERSTAND MECHANISMS OF DISEASE TO THE CONTRARY WE SHOULD. I'M JUST SAYING OFTEN THE ATTRIBUTED MECHANISM FOR TREATMENT DIFFERENCE IS WRONG AND AS WAS POINTED OUT THERE'S LOTS OF EXAMPLE WHERE IS YOU THOUGHT THE MECHANISM WAS THIS, IT TURNED OUT TO BE SOMETHING TOTALLY DIFFERENT. AND JUST ONE FINAL POINT, WHICH I THINK IS NOT NECESSARILY APPRECIATED VERY WELL, JUST BECAUSE YOU DON'T UNDERSTAND THE MECHANISM, DOESN'T MEAN THAT THE TREATMENT DOESN'T WORK. >> (INAUDIBLE) TULANE UNIVERSITY. WE'RE TALKING SEX DIFFERENCES HERE. I THINK THAT TOTALLY CORRECT. BUT YES SHOULD BE AWARE OF OTHER DIFFERENCES TOO, RISK DIFFERENCES, AGE DIFFERENCES, EVEN GEOGRAPHIC DIFFERENCES. THERE'S SO MANY HETEROGENEITY IN TERMS OF ETIOLOGY OF DISEASE, PRESENTATION OF DISEASE AND SO FORTH. >> CAN WE CONTROL FOR THOSE? >> WHAT DO YOU MEAN BY CONTROL? >> I MEAN, WE CAN -- EVERY INDIVIDUAL CAN BE CLEARLY IDENTIFIED AS MALE OR FEMALE, PRE-CLINICAL STUDIES. WE CAN'T CONTROL FOR RATE OR GEOGRAPHY OR WHERE YOU ORDER YOUR RATS. WHICH ACTUALLY HAS AN IMPACT. SOMETIMES STUDIES CAN'T BE REPLICATED BECAUSE OF A ANIMAL FACILITY CLEANLYNESS. >> IN TERMS OF ANIMAL IT IS SAME STRAIN OF MICE, THEY ARE DIFFERENT IF THEY ARE FROM DIFFERENCE LABORATORIES. >> YOU MAKE AN INTERESTING POINT. IT'S THE BAIN OF THE CLINICAL TRIALIST LIFE. WE COLLECT DOZENS OF CONFOUNDING VARIABLES AND I HAVE SPENT MY LIFE LOOKING AT AGE, MALE, FEMALE, SOCIO ECONOMIC STATUS. RACE, ALL THESE FACTORS YOU WIND UP WITH A DOZEN, 15, 20 FACTORS, AND OF COURSE YOU GOT THAT MANY FACTORS YOU'RE LIKELY TO FIND ONE OF THEM THAT IS SHOWING .05 DIFFERENCE AND WE ALL RECOGNIZE MULTIPLE COMPARISON ISSUE, SO WHAT DO YOU DO WITH THAT? TO ME, YOU NEED TO PAY ATTENTION TO THOSE THINGS BUT YOU PAY ATTENTION TO THESE SUBGROUP ANALYSES FROM THE PERSPECTIVE OF HYPOTHESIS DEVELOPMENT, NOT HYPOTHESIS TESTING. SO IF YOU SEE A DIFFERENCE BY MALE FEMALE OR RACE OR SOCIO ECONOMIC STATUS, YOU CAN COME UP WITH MECHANISMS IF YOU WANT BUT THE MORE INTERESTING THING IS CAN YOU REPLICATE THAT IN ANOTHER STUDY. IF YOU FIND IT, MAYBE THAT'S AN INDICATION YOU DRILL MORE DEEPLY AND YOU HAVE TO DO ANOTHER STUDY. >> THE PRE-CLINICAL STUDIES, ONE OF THE THINGS THE TRIALISTS AND SYSTEMATIC REVIEWERS OF TRIALS TALKED ABOUT A LONG TIME AND I HAVEN'T SEEN TOO MUCH OF, LET'S LOOK AT ALL THE TREATMENTS THAT WE HAVE ESTABLISHED AS THEY WORK? AND LET'S SAY WORK IN BOTH SEXES BECAUSE I WILL ASSUME FOR A MOMENT THAT PEOPLE HAVEN'T LOOKED AT SEX AND GENDER ACROSS THE BOARD. IT'S REALLY RATHER SAD. LET'S LOOK AT TREATMENTS THAT WORK AND SEE WHAT THE ANIMAL STUDY SHOWED AND DIFFERENT KINDS OF ANIMALS. BECAUSE NO ONE HAS REALLY DONE THIS. IT'S ODD, WE DO THESE PRE-CLINICAL STUDIES MAYBE IT GOES TO THE FDA HERE ANIMAL STUDIES AND HERE ARE TRIALS BUT THERE REALLY ISN'T A LITERATURE SHOWING WHETHER WHAT WE DO IS BACKED UP. SO WE DON'T ACTUALLY KNOW EXCEPT ON A CASE-BY-CASE BASIS WHETHER WHAT WE DO IS BACKED UP BY ANIMAL STUDIES SO WE PROBABLY -- I'M A POPULATION PERSON YOU CAN TELL SHOULDN'T WE LOOK. LATION WISE TO SEE WHETHER THIS WORKS, THIS APPROACH. THIS IS AN APPROACH THAT MAKES SENSE BUT ARE WE DOING THE RIGHT THING. >> ARE YOU TALKING ABOUT IN CIRCUMSTANCES WHERE THERE'S AN ANIMAL MODEL, REASONABLE -- REASONABLY PARALLEL ANIMAL MODEL FOR THE CONDITION, A LOT OF DISEASES THERE ISN'T. THE ANIMAL MODELS ARE MOSTLY DONE, MAYBE FOR CELLULAR MECHANISTIC THING EARLY ON, THEN THE TOXICOLOGY BUT OFTEN THERE ISN'T A GOOD ANIMAL MODEL THAT WOULD BE PARTICULARLY TELLING. SO THERE ARE CERTAINLY, FOR EXAMPLE, IN CERTAIN VIRAL DISEASES THE ANIMAL MODELS ARE POORLY PREDICTIVE IN ANY WAY OF HUMAN RESPONSE. THERE'S A BIG GAP THERE. SO YOU MIGHT NOT FIND SOME OF THE SAME THINGS. >> ACTUALLY THINKING BEYOND DRUGS, IT SOUNDS LIKE YOU ARE TOO, THINKING ABOUT SURGERY, SAY SOME OF THESE SURGICAL APPROACHES DID THEY WORK IN AN ANIMAL BEFORE WE TRIED THEM. >> I WASN'T ABLE TO ATTEND ALL DAY SO SORRY IF YOU ADDRESSED THIS, AND I'M NOT QUITE SURE WHERE MY QUESTION FITS BUT I KNOW IT FITS SOMEWHERE. CURIOUS FOR THE HUMAN RESEARCH FOLKS WHERE TRANSGENDER FOLKS FIT IN THIS WHOLE SCENARIO OF SEX DIFFERENCES. THERE'S KIND OF A LOT OF INTERESTING THINGS GOING ON WITH KIDS COMING OUT OF TRANSGENDER AND TAKING HORMONES TO SUPPRESS PUBERTAL DEVELOPMENT OR FOLKS TAKING HORMONES IN LIFE AND HOW THOSE THINGS CAN BE OF AN ADVANTAGE IN A RESEARCH DESIGN. >> MOST CLINICAL TRIALS, YOU TALK PANT A POWER PROBLEM. WE HAVE GOT A POWER PROBLEM IN MEN VERSUS WOMEN IN MY STUDIES OF 80-YEAR-OLDS IF THERE'S TRANSGENDER PEOPLE IN THERE, I PROBABLY DON'T KNOW IT BECAUSE THEY'RE NOT TELLING ME SO THE KINDS OF STUDIES THAT I THINK YOU WOULD HAVE TO DO TO FOCUS ON QUESTIONS LIKE THAT WOULD BE MUCH MORE SPECIFICALLY RECRUITED TO LOOK AT THOSE SUBGROUPS BECAUSE IF YOU TAKE THE POPULATION AS THEY'RE COMING, THEY'RE PROBABLY WOEFULLY SHORT IN TERMS OF BEING ABLE TO ANSWER THE QUESTION. THAT DOESN'T CHANGE THE FACT THAT THE QUESTION ISN'T AN IMPORTANT OR INTERESTING ONE, IT SAYS YOU HAVE TO CHANGE YOUR STUDY DESIGN IF THAT'S THE QUESTION THAT YOU WANT TO ANSWER. JUST AS I PROBABLY WON'T BE ABLE TO TELL YOU WHETHER MY TREATMENT IS DIFFERENT, IT'S JUST THAT I DON'T HAVE ENOUGH, SO IF IT'S AN IMPORTANT QUESTION I NEED TO FIGURE OUT WAY OF GETTING ENOUGH PEOPLE IN MY STUDY TO BE ABLE TO ADDRESS THE QUESTION. >> SEEMS LIKE YOU BROUGHT UP A GREAT POINT, THAT THEY MIGHT ALREADY BE IN YOUR STUDY BUT IF THE -- ONLY TWO SEX OPTIONS ARE MALE AND FEMALE YOU MIGHT NOT BE ABLE TO TAP INTO REALLY GOOD DATA THAT YOU ALREADY HAVE. >> MOST OF US EVOLVED TO ALLOWING MORE THAN TWO CHOICES. BUT IN MY STUDIES I DON'T GIVE PEOPLE WHO CHOOSE THE THIRD CHOICE. THERE'S PROBABLY A LOT OF REASONS FOR THAT, NOT THE LEAST OF WHICH IS MOST OF MY STUDIES ARE IN MUCH OLDER PEOPLE WHO FOR WHATEVER REASON ARE GOING TO DEAL WITH THAT. >> YOU BRING UP A REALLY INTERESTING POINT THOUGH, I THINK -- I COULDN'T AGREE MORE, JUST IN TERMS OF NUMBERS YOU PROBABLY WOULD NEED A FOCUSED RECRUITMENT EFFORT AND FOCUS STUDY TO DO THAT. THIS IS CERTAINLY AN AREA WHERE THERE'S GROWING AWARENESS AND GROWING WILLINGNESS I THINK FOR PEOPLE TO TALK ABOUT AND IT PROVIDES AN AN INCREDIBLE WAY TO LOOK AT ISOLATE THE EFFECTS OF HORMONES. SO I THINK IT'S REALLY AN INTERESTING AREA THAT WE SHOULD REALLY DEVELOP SOME FOCUS STUDIES OVER THE NEXT FEW YEARS. >> SO MAYBE TO TURN THIS AROUND A LITTLE BIT, IF THERE IS A REASON TO BELIEVE THAT THAT DIFFERENCE OR OTHER DIFFERENCES MIGHT BE BIOLOGICALLY IMPORTANT, AND I THINK IT'S IMPORTANT IN YOUR STUDY DESIGN TO TRY TO FIGURE HOW YOU CAN GET ENOUGH OF THEM IN YOUR STUDY TO BE ABLE TO ADDRESS THE QUESTION. THAT WOULD GO FOR ANY OF THESE DIFFERENCES THAT YOU MIGHT BE ABLE TO COME UP WITH, RACE, GENDER OR EVEN SOCIO ECONOMIC STATUS. >> THANKS. >> PAUL MCCLEAN, COLORADO. THE BOTTOM LINE WITH THE POLICY IS HOW IS IT GOING TO BE IMPLEMENTED AND WHAT'S GOING TO HAPPEN. I THINK ON THE MINDS OF PRE-CLINICAL RESEARCHERS OR EVEN THOSE WHO STUDY IN VITRO, IT'S WHAT IS THIS -- WHAT'S THIS GOING TO LOOK LIKE. A LOT SEE IT'S GOING TO COST THEM A LOT MORE MONEY I THINK PEOPLE WHO ATTEND THIS MEETING MIGHT SEE THE VALUE AND DOING BOTH SECONDS, PEOPLE WHO ARE INVOLVED IN THE -- BUT THERE'S A HUGE SCIENTIFIC COMMUNITY THAT HAVE A DIFFERENT OPERATING APPROACH TO THEIR RESEARCH. SO I GUESS MY QUESTION FOR THE CLINICAL SIDE WHO HAS DONE THIS FOR 25 YEARS, HOW WOULD YOU SEE IT BEING BENEFICIALLY IMPLEMENTED. IS IT AT THE LEVEL OF THE STUDY SECTION OR THE LEVEL OF THE PROGRAM OFFICER, OR ARE WE GOING TO REQUIRE THEM TO THINK ABOUT IT OR ARE WE GOING TO REQUIRE EVEN TO DO BOTH SECONDS IN THEIR CELL CULTURE STUDIES OR ANIMAL MODELS. THAT'S I GUESS THAT'S THE BOTTOM LINE FROM THE PRE-CLINICAL SEARCH, WHAT IS YOUR GUY'S OPINION ON THAT? >> I ONLY KNOW WHAT'S REQUIRED FOR CLINICAL STUDIES. THERE'S A REQUIREMENT FOR CLINICAL STUDIES ABOUT TAKING ACCOUNT OF SEX AND GENDER AN RACE. >> I KNOW THERE IS RIGHT NOW FOR THE CLINICAL, THE BIG THING WITH THIS POLICY IS WHAT -- HOW IS THIS GOING TO CHANGE JUST BASIC SCIENCE. >> YOU NEED A POLICY, THAT'S WHAT CHANGES AND PEOPLE CAME KICKING AND SCREAMING AND THERE WERE EDITORIALS ABOUT IT. I THINK THERE'S ALSO A BIGGER QUESTION WHICH IS RIGHT NOW IN SCIENCE I THINK SOMETIMES THAT WE THINK IT'S OKAY TO CUT CORNERS AND NOT BE TOTALLY SCIENTIFIC. BECAUSE IT COSTS TODAY. I'M FRUSTRATED WITH THAT POINT OF VIEW, WE SHOULD HAVE A DEBATE BUT PEOPLE FEEL LIKE IT COSTS A LOT, IT TAKES TOO MANY PEOPLE OR I DON'T HAVE SO I'M NOT GOING TO DO THAT. ASH WE SCIENTISTS I UNDERSTAND THERE ARE CONSTRAINTS BUT WE CERTAINLY NEED TO AGREE THAT AS A COMMUNITY IT'S OKAY TO SAY SOMETHING LIKE THAT. I THINK IT'S OKAY YOU HAVE TO GET THE POLICY IN PLACE. >> I KNOW WHAT'S THE POLICY. >> I JUST HAVE -- I DON'T REALLY KNOW WHAT I THINK FOR ANY POLICY TO HAVE SOME TEETH ANYTIME TO HAVE SOMETHING THAT GETS IMPLEMENTED BROADLY, THAT IT PROBABLY NEEDS TO BE REGULATED AT THE LEVEL OF THE FUNDING AND REVIEW. BUT THAT BEING SAID, I UNDERSTAND -- I TOTALLY UNDERSTAND THAT THERE ARE SOME AREAS IN WHICH IT PROBABLY DOESN'T MAKE SENSE TO HAVE THIS HARD AND FAST YOU HAVE TO DO 50 -- YOU HAVE TO USE 50% FEMALES AND MALES IN THIS RESEARCH SO I THINK -- SO THE OTHER WAY TO DO THAT, MIGHT BE TO SAY TO MAKE PEOPLE MAKE IT CLEAR IN THEIR APPLICATION THAT THEY HAVE GIVEN CAREFUL THOUGHT TO WHETHER THEY'RE DOING IT -- YOU KNOW, WHETHER THEY'RE USING HALF MALE HALF FEMALE, HALF FEMALE CELLS AND HALF MALE CELLS, IF NOT JUSTIFY THAT CLEARLY AND THEN FOR GOODNESS SAKE I THINK ONE THING THAT'S VERY CLEAR IS REPORTING IT ACCURATELY WHEN YOU GO FOR PUBLICATION SO AT LEAST THE RESULTS CAN BE ENTERPREAT A TIMED -- INTERPRETED IN THE RIGHT CONTEXT BECAUSE THERE'S AGAIN LOOK IN THE LITERATURE AND SEE SO MANY THINGS REPORTED WHERE YOU DON'T EVEN KNOW THE GENDER OF THE CELL OR EVEN GENDER SPLIT OF CLINICAL POPULATION SO I THINK THE ACCURATE REPORTING AND I THINK TO HAVE A POLICY ENFORCED IT HAS TO AFFECT PEOPLE'S FUNDING. >> I THINK WE HAVE TO MOVE. >> I WANT TO COMMENT ON THE PREVIOUS COMMENT AND ADD THE THOUGHTS I HAVE BEEN HAVING SITTING IN THE BACK TRYING NOT TO, I APOLOGIZE, FALL ASLEEP. IT'S BEEN A REALLY LONG FALL FOR THE OFFICE OF RESEARCH ON WOMEN'S HEALTH. WE HAVE HAD A LOT OF EXCITING THINGS GOING ON, WE ARE VERY INVESTED IN THIS PERSPECTIVE. BUT I WANT TO SAY I THINK WHETHER WE'RE TALKING ABOUT CLINICAL RESEARCH, CLINICAL TRIALS, WHETHER TALKING ANIMAL RESEARCH, IN VITRO STUDIES, THE BASIC PREMISE FOR EVERY SINGLE PERSON DOING THIS IS TO DO GOOD SCIENCE. TO IMPLEMENT THE PRINCIPLES OF THE SCIENTIFIC METHODS AND EXPERIMENTAL DESIGN. THAT'S BEEN BROUGHT UP BY THE PANEL ALREADY FOR CLINICAL WORK AND I REITERATE THAT AS A PRE-CLINICAL PERSON WHO USED TO DO RATS AND MICE AND FISH AND SHEEP AND I DON'T KNOW WHATEVER ELSE IS IN THE LAB. INCLUDING MY LAB MATES. BUT THE POINT IS THAT I WANT TO MAKE IS WE NEED TO DO GOOD SCIENCE. THAT IS IT. SO WHEN WE TALK ABOUT THE POLICY DEVELOPMENT WHEN WE TALK ABOUT HOW WE'RE GOING TO DO THIS, WHAT ARE THE NUTS AND BOLTS OF DOING TEN MALES AND FIVE FEMALES OR THIS MANY OF THAT, THE BASIC THING WE HAVE TO THINK ABOUT IS WHAT, WE HAVE TO THINK ABOUT WHERE IT'S SCIENTIFICALLY JUSTIFIED. IS IT SCIENTIFICALLY JUSTIFIED TO ONLY INCLUDE ONE SEX IN YOUR STUDY? IT MIGHT BE. BUT IT HAS TO BE SCIENTIFICALLY VALID AND JUSTIFIABLE. AND NOT THAT FEEDS INTO EMPERIMENTAL DESIGN AND DOING GOOD SCIENCE. THAT'S IT. >> I BET WE ALL AGREE GOOD SCIENCE IS A GOOD THING. AND MOST HAVING WORKED WITH FOR THE GOVERNMENT FOR MORE THAN 40 YEARS THE WORD POLICY GIVES ME THE COLLYWOBBLES BECAUSE ALL OF A SUDDEN A POLICY COMES DOWN THAT WE HAVE TO LIVE WITH. AND THE WORRY THAT A LOT OF US HAVE HAD NOBODY TALKS ABOUT MUCH WHEN THE POLICY CAME DOWN AND SAID YOU NEED TO TAKE INTO ACCOUNT SEX AND RACE WHEN DOING YOUR -- AN AGE DOING YOUR CLINICAL TRIALS. WE WERE SCARED TO DEATH THAT THE NEXT THING COMING, YOU HAVE TO POWER YOUR STUDY TO MAKE SURE THAT YOU CAN TEST THESE QUESTIONS SEPARATELY. IF THAT HAPPENED OR IF IT DOES HAPPEN IN THE FUTURE IT WILL HAVE A CHILLING EFFECT ON CLINICAL TRIALS BECAUSE IT'S GOING TO MEAN A LOT OF CLINICAL TRIALS BECAUSE WE'RE FORCING OURSELVES TO PUT EFFECT TRAY EFFORT WITHIN THE ONE CLINICAL TRIAL. GETTING BACK TO YOUR POINT ABOUT THE SCIENTIFIC METHOD A KEY PIECE OF THE SCIENTIFIC METHOD IS REPLICATING THE CLINICAL RESEARCH. OR THE RESEARCH. IN THIS CASE I THINK WITH REGARD TO SEX DIFFERENCES IN PARTICULAR, WE'RE IN A PRETTY GOOD PLACE WHERE AT LEAST IN OUR STUDIES WE HAVEN'T HAD THE PROBLEM OF NOT HAVING OR HAVING BIG DIFFERENCES BETWEEN MEN AND WOMEN IN OUR STUDIES, YOU HAVE GOT REASONABLE POWER TO LOOK AT A DIFFERENT, LET'S FORGET P VALUES BUT LOOKING AT A RELATIVE RISK DIFFERENCE. IF YOU SEE A RELATIVE RISK THAT'S INCREASED IN WOMEN COMPARED WITH MEN, THAT IS A LITTLE CHECKBOOK A CHECK MARK ON YOUR HYPOTHESIS DEVELOPMENT BECAUSE THE NEXT TRIAL YOU'RE GOING TO LOOK AND IF THE NEXT ONE SHOW IT IS SAME THING, THE SCIENCE WILL EVOLVE TO I THINK GET THE RIGHT ANSWER IN A MUCH BETTER AND PROBABLY MORE EFFECTIVE WAY THAN ONE TRIAL THAT COVERS TALL VARIOUS GENDER OF SEX, RACE, DIFFERENCES. >> I WOULD SAY SYSTEMATIC REVIEWS AN META ANALYSIS COME INTO PLAY, YOU HAVE YOUR FIVE TRIALS IF THEY REPORT BY SEX AND GENDER YOU CAN COMBINE -- YOU HAVE GREATER POWER EFFECTIVELY P THE PROBLEM THERE IS IN THE REPORTING. AND I SHOWED YOU THE GUIDELINES FOR TRIALS, THEY'RE ALSO META ANALYSIS SYSTEMATIC REVIEWS, CONTOUR GUIDELINES FOR TRIALS, STROKE, ANIMAL, THEY'RE ALL SORTS OF REPORTING GUIDELINES, DO PEOPLE FOLLOW THEM? NO. THERE'S TONS OF RESEARCH OUT THERE T JOURNALS ABOUT FOLLOWING AND WE AREN'T FOLLOWING. I SAT NEXT TO JOURNAL EDITORS AT LUNCH IN A PEER REVIEW CONGRESS EVERY FOUR YEARS. THEIR SPECIALTY JOURNALS THE BIG JOURNALS ARE BETTER, BUT THE SPECIALTY JOURNALS AREN'T. I SAID WHY DON'T YOU GUYS ENDORSE THE GUIDELINE? THEY SAID BECAUSE NO ONE WOULD SUBMIT TO US. THE SMALLER JOURNALS WANT TO GET ALL THE SUBMISSIONS THEY CAN SO THAT I BELIEVE THE MORE BARRIERS WHICH THEY SEE REPORTING STANDARDS THEY PUT UP, THE FEWER SUBMISSIONS THEY'RE GOING TO GET. SO WE HAVE ALL KINDS OF ACADEMIC REWARDS SYSTEMS THAT DON'T HELP WHAT WE'RE STRIVING FOR SO YOU CAN'T WORK ON ONE PROBLEM LIKE MORE RESEARCH THAT LOOKS AT SEX AND GENDER DIFFERENCES, YOU HAVE TO WORK ON PUBLISHING, EVERYTHING TO GET THIS WORKED OUT. >> FOLLOWING ON TO THAT, I HAVE OFTEN THOUGHT THE WAY WE LOOK AT THE ISSUE IS VARIED AS OFTEN IS, THE POINT OF VIEW OF DISCOVERY RESEARCH IS PEOPLE ARE CONCERNED IF A REPLICATED IN A DIFFERENT SEX OF ANIMAL THEY WILL FIND A DIFFERENT RESULT, THAT'S VERY EXCITING. AND TRYING TO CAPTURE FOR PEEP IT WILL EXCITEMENT OF THE FACT IF WE'RE FINDING COMPLETELY DIFFERENT RESPONSES IN DIFFERENT SEXES THAT THAT'S A NEW LINE OF INVESTIGATION AND I KNOW IT WILL BE DIFFICULT FOR THE COMMUNITY WITH CHANGE, THERE ALWAYS IS WHEN SOMEBODY SAYS WE'LL CHANGE THE RULE OF THE SUPPORT WE'RE PLAYING AND NO LONGER CAN YOU DO THIS OR THAT. THAT'S A PERIOD OF TIME PEOPLE UNDERSTANDING WHAT THAT MEANS. BUT I WONDER ABOUT PEOPLE'S COMMENTS ABOUT THE ISSUE OF DISCOVERY THAT'S INVOLVED IN RAISING THE CONSCIOUSNESS OF INVESTIGATORS TO SAY BE ALERT TO INSTANCES IN WHICH YOU CAN FIND SOMETHING BECAUSE THAT MAYBE YOUR NEXT PROPOSAL. THAT MAY NOT NECESSARILY RELATE TO THIS PROPOSAL BUT MAYBE RELATE TO THE NEXT THING PEOPLE FOLLOW-UP ON. INTERESTED IN YOUR COMMENTS. >> CERTAINLY IS THE GOAL OF SYSTEMATIC REVIEW AND META E ANALYSIS, PEOPLE SATE HETEROGENEITY OF YOUR FRIEND. LOOK AT THAT TIME OUTLINE STUDIES WHY ARE THEY DIFFERENT? AND MAYBE THEY'LL LEARN SOMETHING FROM IT. >> I THINK IT'S PROBABLY TRUE THAT THE ONLY THING THAT LIKES CHANGE IS A WET BABY, BUT CHANGE EVENTUALLY CHANGE IT IS WAY WE THINK ABOUT THINGS AND IF YOU THINK ABOUT HOW RESEARCH IS EVOLVED OVER THE LAST FOUR DECADES THAT I HAVE BEEN DOING IT, THE CHANGE HAS BEEN GOOD, IT'S PAINFUL AND WE HAVE TO ADJUST TO IT. BUT I CAN'T THINK OF ANYTHING THAT I SAY, THAT WAS REALLY A BAD THING THAT WE DID. I THINK YOUR POINT IS WELL TAKEN THAT WE NEED TO PAY ATTENTION TO THESE DIFFERENCES AND IT WILL IMPROVE OUR UNDERSTANDING, NOT MAKE IT MORE DIFFICULT. >> I ECHO THAT, IT'S EXCITING. AND THERE WILL BE, HELPING INVESTIGATORS RESEARCHERS DEAL WITH THIS, BECAUSE YOU CAN'T -- IF THIS GETS BACK TO THE MECHANISM OF ACTION, BECAUSE YOU CAN'T EXPLAIN IT DOESN'T MEAN IT'S NOT THERE AND DOESN'T MEAN YOU'RE NOT SMART ENOUGH BECAUSE SOMETIMES WE GO DECADES OBSERVING PHENOMENON THAT EXISTS BUT WE CAN'T EXPLAIN THEM AND THAT IS OKAY BUT TO A RESEARCHER IS OFTEN NOT SATISFACTORY, IT SEEMS TO THROW UP THE BARRIER TO SUCCESS. MANAGING THAT IS GOING TO BE PART OF THE UPHILL ON THIS. BUT WE'LL NEVER LEARN UNLESS WE LOOK. >> THAT COMMENT ON DISCOVERY SCIENCE IS SO IMPORTANT, IF YOU THINK OF THE WORK OF LAWRENCE TAYLOR, WE THOUGHT SEMICELLS DIDN'T WORK IN REGENERATIVE MEDICINE AND UNTIL SHE USED THE SEX CHROMOSOME TO TAKE STEM CELLS, REGENERATION IN THE HEART, BUT THOSE FOR DIDN'T. IT REVOLUTIONIZED HOW WE THINK ABOUT REGENERATIVE MEDICINE AND THAT'S THOUGHT OF ON THE BASIS OF CLINICAL TRIALS OR EPIDEMIOLOGICAL DATA. CHRISTY DANIELSON'S DATA TODAY TYPE ONE DIABETES AND AUTOIMMUNE DISEASE SHOWS NO SEX DIFFERENCE AND WAS THERE WORK SHOWING, THAT IS THE BETA CELLS FROM FEMALE MORE VIABLE CLINICAL OUTCOMES LOOK BETTER SO SOMETIMES WE DON'T KNOW WHERE THERE'S A SIGNAL TO SEX DIFFERENCE THAT REVOLUTIONIZE THE WAY WE THINK ABOUT MEDICINE. ANOTHER WORD OF CAUTION ABOUT USING CLINICAL EPIDEMIOLOGICAL FINDINGS AS THE WAY OF DEFINING THE DECISION SPACE FOR WHEN WE'RE GOING TO LOOK AT SEX DIFFERENCES. THEN FINALLY STEVE COLE, SUCH A GIFTED BUY STATISTICIAN HAS POINTED TO THIS PROBLEM OF CLINICAL TRIALS GENERALLY AND THEY DON'T GENERAL LIZLYZE TO THE OVERALL POPULATION, WE ARE CONCERNED ABOUT SAFETY, IN CLINICAL TRIALS, SO WE RESTRICT WHO PARTICIPATES IN THOSE CLINICAL TRIALS AND WOMEN AND MINORITIES AS DR. BRADY POINTED OUT DON'T PARTICIPATE IN THOSE SO THE EXTENT TO WHICH CLINICAL TRIALS DATA GENERALIZES THE OVERALL POPULATION AS A SECOND LEVEL OF COMPLEXITY HERE THAT HAZEN REALLY BEEN DISCUSSED. >> HI, JUST A SPECIFIC COMMENT MAYBE STEP BACK A MORE GENERAL COMMENT FIRST IS HAVING RECENTLY TRIED TO DO A META ANALYSIS WHERE WE CAN BOOST UP POWER ENOUGH TO TEST SEX DIFFERENCES AND KNOWING THAT AT LEAST IN MY AREA, I'M A CLINICAL PSYCHOLOGIST BUT MECHANISMS OF ACTION AND NEUROPHYSIOLOGY, YOU CAN'T GET PEOPLE TO SEND THEIR DATA. SO THAT'S ONE BARRIER THAT'S HUMONGOUS IN MY EXPERIENCE SO FAR SO MY FRUSTRATION ABOUT STUDIES ARE EMPOWERED, THEY'RE NOT LOOKING AT THAT ANYWAY. WHEN YOU TRY TO ASK THOSE QUESTIONS AN APPROACH PEOPLE AND SAY CAN YOU SEND ME ME YOUR DATA OR WHATEVER AND DO THIS COMPARISON THEN YOU DONE HEAR FROM THEM AT ALL, THEY JUST IGNORE YOU, I'M FRUSTRATED AS WELL AS MANY IN THE ROOM, IN GENERAL CONSIDERING SEX DIFFERENCES OR OTHER MODERATOR VARIABLES BASED ON DEMOGRAPHICS NEW SENSE OF VARIABLES THAT'S KIND OF THE APPROACH, SOUNDS LIKE THERE'S NUISANCES, THEY HAVE THIS MENSTRUAL CYCLE, IT'S A NUISANCE, THERE'S SEX DIFFERENCES THAT'S A KNEW SENSE, I WONDER UNTIL THAT MIND SET IS CHANGED, AND POLICIES WOULD BE NICE, I FEEL LIKE BEING A CLINICAL PSYCHOLOGIST I'M SENSITIVE TO THE REINFORCING SCHEDULES AND PUNISHMENTS AND THINGS LIKE THAT, I THINK POLICIES WOULD BE NICE ALSO AND I JUST WONDER HOW YOU'RE GOING TO CHANGE THE MIND SET BECAUSE PEOPLE ARE GOING TO FIND THE NEW POLICIES TO BE NUISANCES WOULD BE MY GUEST AS YOU ALLUDED TO WITH JOURNALS. >> WE HAVE POLICIES AND REINFORCEMENT SCHEDULES, I DO THINK ONE OF THE THINGS THAT -- AND I HAVE TO CONGRATULATE ORWH AND OTHERS FOR -- IF YOU FUND THAT, IF YOU FUND PEOPLE SPECIFICALLY TO LOOK AT THAT OR AS JOHN WAS SAYING, IF WE CAN LEARN TO TURN THIS AROUND, BOY, THE HETEROGENEITY AND LOOKING, IN MY RESULT ACTUALLY GIVES ME THE NEXT GREAT RESEARCH QUESTION AND IF WE CAN GET FUNDING AGENCIES TO APPRECIATE THAT AND ENCOURAGE PEOPLE TO LOOK AT THOSE GENDER DIFFERENCES, IT DOES TURN IT FROM AN AVERSIVE THING TO SOMETHING PEOPLE WILL GO AFTER. >> I CAN COMMENT, IF WE JUST TAKE A STEP WAY BACK. I THINK WHAT WE'RE -- WHAT'S THE NUISANCE IS THE CHANGE. THAT'S THE KNEW SENSE, WE ALL LIKE OUR COMFORT ZONE, WE ALL LIKE TO THINK WE HAVE GOT OUR METHODS FIGURED OUT, WHATEVER FOR WHATEVER AN EVER -- WHATEVER ENDEAVOR WE ARE INVOLVED AT A MARITIME, A SEE CHANGE COMES AND THAT'S THE KNEW SENSE. WHEN IT COMES TO CLINICAL TRIALS IF YOU THINK ABOUT THE WHOLE SCIENCE OF CLINICAL TRIALS, REALLY HAS NOT BEEN IN EXISTENCE FOR VERY LONG. BACK IN THE 'OF 0s TO THE EARLY '70s, THAT WAS THE INFANCY OF THE CONCEPT OF RANDOMIZATION. FIVE THAT WAS WHOLE NEW THING. WHAT WAS SOUGHT IN CLINICAL TRIALS IS A POPULATION THAT WAS QUITE HOMOGENOUS. BECAUSE THAT'S WHERE YOU -- WHERE IT WAS BELIEVED MOST LIKELY TO SEE A DIFFERENCE BETWEEN AN ACTIVE AND A CONTROL. AS WE LEARNED MORE AND BEGUN TO ACCEPT THINGS LIKE GENETIC VARIABILITY, AND MANY OTHER TYPES OF VARIABILITY, SOCIAL CONSTRUCTS THAT LEAD TO VARIABILITY. WE HAVE CHANGED THAT, THE TRIALS BECAME LARGER TO TRY AND ACCOUNT FOR THAT BUT IT'S BEEN A CHANGE. AND I THINK THAT THERE HAVE BEEN -- THERE HAVE BEEN RESEARCHERS WHO HAVE RESISTED THAT CHANGE SINCE THE BEGINNING. AND IT'S OKAY. BUT REWARDING THE SUCCESSES, REWARDING THE PEOPLE WHO DO IT WELL, AND WHO ULTIMATELY SHOW THERE IS SOMETHING THERE TO BE FOUND, I THINK THAT'S WHERE THE COMFORT WILL BEGIN. THE EXCITEMENT WILL BEGIN. >> I THINK WE SHOULD MIX THINGS UP A LITTLE BIT MORE, I DON'T ORDINARILY COME TO MEETINGS LIKE THIS BUT THE PRESENTATIONS THIS MORNING I FOUND REALLY I LEARNED A LOT, I WAS INSPIRED, I WAS IMPRESSED. SO WE HAVE TO GET ONE ANOTHER AT OUR MEETINGS AND NOT JUST HAVE THE SOCIETY FOR CLINICAL TRIALS BECAUSE I CHANGE MY OPINION BASED ON WHAT I HEAR AND I HOPE ALL OF US DO. AND WE LEARN FROM ONE ANOTHER. THE MORE WE SPLIT OFF INTO OUR OWN MEETINGS THE LESS POSSIBILITY OF LEARNING. THE TROUBLE IS WE HAVE SO MANY THINGS TO DO RIGHT NOW. WE CAN'T MIX IT UP BUT I'M IN A FIELD WHERE WE ARE HAVING TO WORK WITH PATIENTS MUCH MORE AS PART OF OUR RESEARCH TEAMS. I PUT IN A GRANT PROPOSAL WITH A COUPLE OF PATIENTS AND I CAN'T TELL YOU HOW MUCH I LEARNED IN THAT PROCESS. THAT'S A SECOND STUDY WHERE WE HAD PATIENTS, WE DON'T SEE EYE TO EYE WHICH IS THE POINT. THEY BRING UP SOMETHING, YEAH, YOU'RE RIGHT. WE HAVE TO SEE IT THAT WAY SO WE HAVE TO MIX IT UP MORE. >> I'M SHELLEY (INAUDIBLE) NATIONAL INSTITUTE ON DRUG ABUSE, WE'RE ALL IN AGREEMENT ELUCIDATING SEX DIFFERENCES OR AT LEAST IF THERE IS NO SEX DIFFERENCES IN A CERTAIN PHENOMENON IS IMPORTANT, I REPRESENT A LOT OF PRE-CLINICAL, PRE-CLINICAL BASIC SCIENCE, WE'RE TALKING ABOUT THE RODENTS AND THE PRIMATES. I THINK ONE OF THE THINGS THAT WE'RE GETTING PUSH BACK ON IS NOT ONLY ARE WE GOING TO HAVE TO DOUBLE THE NUMBER OF SUBJECTS, NOW WE CONTROL FOR ESTRA CYCLE, WHICH IS IMPORTANT. IF WE DOUBLE THE END THAT'S GOING TO HIDE POTENTIAL IMPORTANT CYCLE EFFECTS. THIS MAY NOT BE THE MOST APPROPRIATE PANEL TO ANSWER THIS TYPE OF QUESTION AND I WOULD ENCOURAGE ORWH TO HOLD A SEPARATE SEMINAR SERIESES ON THIS, BUT WE NEED TO BE ABLE TO PROPERLY PROVIDE OUR APPLICANTS THE METHODOLOGIES TO PROPERLY EXECUTE CYCLICAL AND ESTRA EFFECTS. WE HAVE TO TRAIN PROPERLY BECAUSE INCORRECTLY CAN INDUCE YOU PREGNANCY AND THAT CAN HAVE A SOURCE OF NEUROBIOLOGICAL CHANGES. THIS IS A CLINICAL PANELIST BUT THAT'S SOMETHING THAT I THINK HAS BEEN LACKING IN OUR DISCUSSION. >> I'LL ASK YOU A QUESTION. COULD BIT USEFUL MAYBE THIS EXISTS ALREADY, IF YOU HAD SOME GENERAL PRINCIPLES OF UNDER WHAT CIRCUMSTANCES IS IT IMPORTANT TO CONTROL FOR ESTER CYCLE. WOULD THAT BE SOMETHING -- AND WHEN IS THAT PROBABLY UNNECESSARY? IS THAT THE GUIDANCE YOU'RE LOOKING FOR? >> I THINK IT'S PARTIALLY ON THE PROGRAM SIDE AND ALSO CSR AND HOW WE ADVISE COMMITTEES TO SCORE THESE GRANTS. THE SAD TRUTH IS FOR DIFFERENT PROCESSES, ESPECIALLY IN ADDICTION, WE DON'T KNOW THE CYCLIC EFFECTS BETWEEN PROGESTERONE AND ESTROGEN ON THE MOST BASIC COGNITIVE EFFECTIVE PROCESSES. SO I GUESS THE THINGS MAYBE STUDIED BUT EVERY SCIENTIST HAS THEIR NICHE. SO IDENTIFYING POTENTIAL SEX DIFFERENCES IS INTERESTING BECAUSE IT MAY NOT BE THEIR NICHE. I THINK BIMODAL PROBLEM. I WOULD LIKE TO SPEAK TO THAT, I AM A BASIC SCIENTIST LIKE YOU. AND THERE ARE THERE'S A LOT -- I PRESENTED THE STUDY BY PENDERGAST THE FEMALE ROAD AND YOU DON'T HAVE TO ALWAYS CONTROL FOR ESTRA CYCLE BUT SOMETIMES IT IS A GOOD IDEA, THERE IS AN EFFORT NOW TO PUT TOGETHER DATABASES IN -- OF ANIMAL MODELS, NOT A META ANALYSIS BUT IT'S SORT OF A WAY TO HAVE A DATA SET THAT WILL GIVE THESE GUIDELINE PRINCIPLES OF WHEN TO AND ALSO THERE'S QUITE A FEW TOOLBOX ARTICLES THAT GIVE SPECIFIC HOW TO LAVAGE A MOUSE OR RAT, HOW TO DO IT PROPERLY. YOU BRING UP AN INTERESTING POINT IN OTHER PANELS WE HAVE BEEN DISCUSSING QUITE A BIT, HOW IS THIS GOING TO ROLL OUT IN STUDY SECTIONS. BECAUSE THE ONE THING WE CAN ALL HAVE GREAT IDEAS IN THE WORLD BUT ALL OF US INDIVIDUALLY HAVE TO GET FUNDED. WE CAN'T DESIGN OUR EXPERIMENT TO DEVELOP YOUR CLINICAL TRIALS BECAUSE WE HAVE TO CONVINCE OUR STUDY SECTION THEY DO NOT WANT US DOING DESCRIPTIVE, MECHANISM AND THINGS OF THAT SORT. THESE ARE REALLY CRITICAL ISSUES. ARE WE GOING TO HAVE TO HAVE SEX DIFFERENCES EXPERT EVERY STUDY SECTION? ALL FIVE ARE GOING TO BE BUSY. SO THAT'S NOT GOING TO WORK. THERE HAVE BEEN OTHER PANELS HAVING THESE DISCUSSIONS. >> I DON'T KNOW IF THIS IS RELEVANT TO THE DISCUSSION BUT AS I TALKED TO OUR BASIC SCIENTISTS, I DO STATISTICS FOR A LIVING. THEY SAY TO ME, IF I HAD TO USE STATISTICS TO ASSESS WHETHER THIS TREATMENT WORKED OR DIDN'T WORK, I'M ON TO THE NEXT STUDY. PART OF IT IS BECAUSE -- I SAID SUPPOSE YOU HAD TO LET YOUR MICE GO AND YOU CAN ONLY GET ONES THAT CAME BACK IN YOUR EXPERIMENT. IT WOULD BE MORE COMPLICATED BECAUSE THEY'RE EATING LORD KNOWS WHAT, YOU HAVE THE CERTAIN STRAIN OF MICE THAT ARE EATING THIS CERTAIN FOOD THAT ARE -- YOU HAVE CONTROLLED ALL THE VARIABLES THAT I DON'T HAVE ANY CONTROL OVER BUT A LOT OF THOSE VARIABLES MIGHT HAVE AN EFFECT ON OUTCOME SO MAYBE IT'S NOT SO SURPRISING THAT WHEN YOU TRY TO REPLICATE EXPERIMENTS USING A DIFFERENT ANIMAL OR DIFFERENT UNDERLYING DIET, AND OTHER THINGS THAT YOU WIND UP WITH DIFFERENT RESULTS. IT BRINGS TO MIND MAYBE SOME OF THAT NEEDS TO BE RELAXED. WE'RE TALKING RELAXING ONE BIT OF IT. WE'RE SAY INK STEAD OF JUST USING -- SAYING INSTEAD OF ALL MALE MICE USE A MIX. AND MAYBE MY FRIENDS WILL SAY THOSE STATISTICS MIGHT BE GOOD TO USE IN ANIMAL EXPERIMENTS BECAUSE WE CAN THEN LOOK BY SEX AND WE CAN SEE WHETHER THERE'S IMPORTANT INTERACTIONS AND DISCOVER SOME THINGS THAT ARE INTERESTING. SO LOOK AT THIS AS AN OPPORTUNITY NOT A BURDEN. >> SOME OF THE CONFUSION RESULTED FROM THE FACT THAT THE INITIAL ARTICLE IS SAYING THAT THE SEX WAS GOING TO BE BALANCED IN STUDIES AND OTHER PRESSES GOING ON REGARDING THIS RESEARCH FOR ALL ACT, WHICH SORT OF SAID EVERY EMPERIMENT HAS TO HAVE MALE AND FEMALE ANIMALS, THERE'S A DISCONNECT BETWEEN WHAT WAS WRITTEN IN THE EDITORIAL AND THE IDEA OF WHAT WAS GOING TO BE DONE AN THIS ACT THAT HASN'T BEEN I DON'T THINK PASSED YET. NOT SURE WHAT THE STATUS IS. THE IDEA EVERY ONE HAS TO HAVE EQUAL NUMBER IS NOT REALISTIC AND IS BAD POLICY SO THAT ENDS UP BEING WHAT IS THE THING, IT'S JUST BAD AND THE IDEA THAT YOU CAN STUDY -- IDENTIFY A SEX DIFFERENCE WITHOUT ASKING THE QUESTION WHY, ARE TWO THINGS. IF YOU DON'T UNDERSTAND WHAT PROGESTERONE DOES TO THE NEURONAL CIRCUIT SURELY DESIGN EXPERIMENTS ADDRESS THAT SPECIFIC QUESTION. THAT'S JUST DONE IN FEMALES, THAT'S PERFECTLY OKAY. THE SCIENCE QUESTION HAS TO DRIVE WHAT THE EXPERIMENTSAL DESIGN IS. SO I THINK THERE'S A DISCONNECT IN THE RESEARCH COMMUNITY OF JUMPING THE GUN ON SOMETHING NOT THOUGHT CAREFULLY AND ANNOUNCED TO COMMUNITY IN A MEANINGFUL WAY, THEY'RE GATHERING INFORMATION AND THE PRESS RELEASE STUFF GOING ON IN TERMS OF WHAT'S GOING ON IN CONGRESS, THE TWO AREN'T MATCHING RIGHT NOW. THAT IS WHAT STIRRED UP THE SCIENTIFIC COMMUNITY AND FOR LIKE FOR THE WRONG REASONS. SO THERE'S NOTHING THAT SAYS WE HAVE TO PUT EQUAL NUMBERS IN EVERY EXPERIMENT YET. HOPEFULLY IT WON'T HAPPEN. >> THAT CAN BE FRAMED AS A QUESTION WHEN ARE CIRCUMSTANCES THAT SEX SHOULD BE CONTROLLED FOR AND WHAT ARE THE CIRCUMSTANCES IT SHOULD BE STUDIED. ANYBODY LIKE TO SPEAK TO THAT? >> IN THAT QUALITATIVE PAPER THAT I SHOWED, THE STATEMENT THAT I FOUND SO PROVOCATIVE, I NEED THINK ABOUT LONGER, WAY CAN'T SEX AND GENDER DIFFERENCES BE PRIMARY OUTCOME INSTEAD OF SUBGROUP ANALYSIS. WHICH IS KIND OF WHAT YOU'RE SAYING. >> I HAVE TO THINK ABOUT THAT MORE. >> JUST A READER. THAT'S WHY I HAVE TO THINK ABOUT IT MORE. SO MAYBE SOME PEOPLE IN THE AUDIENCE BECAUSE YOU BROUGHT IT UP. WHAT WOULD BE CASE THE MAIN OUTCOME WOULD BE SOMETHING ABOUT DIFFERENCES? I'M THINKING OF A STUDY WE DID, IT'S NOT ABOUT SEX. IT IS SYSTEMATIC REVIEW AND LUND DIBROWN AT BROWN UNIVERSITY GETS THE CREDIT; I WAS JUST IS SYSTEMATIC REVIEWER ALONG FOR THE RIDE, SHE WAS LOOKING AT RACE DIFFERENCES IN LUNG FUNCTION THAT HAVE BEEN A LONG STANDING SUPPOSITION ABOUT LUNG FUNCTION THE SIR ROM TEAR HAS BUILT INTO IT CORRECTION FOR AGE RACE SEX SO WHEN YOU HAVE LUNG FUNCTION DONE YOU PUT IN AGE RACE SEX OF THE PERSON TESTED AND IT CORRECTS, THERE'S A CORRECTION FACTOR BASED ON DATA. WHEN WE DID SYSTEMATIC REVIEW ON WHAT DATA IS THEY'RE LOOKING AT RACE DIFFERENCES IN LUNG FUNCTION, DATA IS NOT THERE. IT'S SURPRISING AND PEOPLE DIDN'T DEFINE RACE, THE STUDIES DIDN'T HAVE CONCURRENT CONTROL GROUPS. AND THERE REALLY RELYING ON OLD STUDIES AND ALL REFERRING TO ONE ANOTHER. IT'S INTERESTING SO THAT'S A STUDY WHERE THE MAIN OUTCOME WAS IS THERE AN ASSOCIATION HERE, THEN GO FROM THERE TO SAY NOW WHAT ARE WE GOING TO DO ABOUT OUR SIR ROM TEARS. I WAS TELLING RICK BEFORE THE MEETING THAT ONE OF THE INTERESTING THINGS WAS THAT HER ARTICLE KEPT GETTING TURNED DOWN. PEOPLE WILL SAY WE SOLVED THE PROBLEM BECAUSE OF N HAYNES DATA WHICH I DON'T THINK SOLVE IT IS PROBLEM THE SIR ROM TEAR MAKES THE CORRECTIONS AND MAKES ASSUMPTIONS ABOUT PEOPLE JUST BASED ON REALLY THE COLOR OF THEIR SKIN AND DIDN'T TAKE INTO ACCOUNT THE ENVIRONMENT, DIDN'T TAKE INTO ACCOUNT THE DIFFERENT THINGS WE'RE EXPOSED TO, CERTAINLY SEX WASN'T TAKEN INTO ACCOUNT. SO THAT'S AN EXAMPLE OF WHERE THE MAIN THING BEING ADDRESSED WAS WHETHER LUNG FUNCTION HAS AN ASSOCIATION AND HOW STRONG IS IT. SHE PUBLISHED THE WORK IT'S FASCINATING. I TAKE THE CREDIT. >> IF YOU'RE IN AN AREA WHERE THE PRELIMINARY -- EITHER PATHOPHYSIOLOGY OF THE DISEASE STATE SUGGESTS GENDER WILL BE ONE OF THE MOST IMPORTANT VARIABLES AND/OR THERE'S PRELIMINARY DATA OR YOU HAVE PILOT DATA TO SUGGEST VERY IMPORTANT ASPECT OF PREDICTING OUTCOME I THINK CLEARLY NEXT STEP IS TO MAKE GENDER THE OBJECT OF THE STUDY RATHER THAN CO-VARIANT. >> SO WITH ALL DUE RESPECT TO THE FACT EPIDEMIOLOGY CAN MAKE MISTAKES, I THINK IT'S ALSO IMPORTANT TO LOOK AT EPIDEMIOLOGY TO GET CLUES, IF YOU DON'T SEE A DIFFERENCE IT MAYBE IN THE WASH AND THERE MAYBE BIG DIFFERENCES THAT YOU HAVEN'T BEEN ABLE TO PICK UP, I AGREE WITH THAT. ON THE OTHER HAND WHEN THERE ARE DIFFERENCES WE NEED TO PAY ATTENTION TO THAT AND SO THAT EXAMPLE THAT I GAVE ABOUT ASPIRIN AND CARDIOVASCULAR DISEASE, THERE ARE OBVIOUS DIFFERENCES IN CARDIOVASCULAR RISK, STROKE AND IN ADDITION TO THE MALE FEMALE DIFFERENCES, SO WHEN THERE ARE OBVIOUS DIFFERENCES, MAYBE THAT'S WHEN YOU SHOULD BE SPECIFICALLY WORRIED ABOUT MAKING SURE THAT YOU HAVE A REASONABLE NUMBER TO HAVE SENSITIVITY TO LOOK FOR THOSE DIFFERENCES. WHEN THERE ARE NO DIFFERENCES, YEAH YOU'RE GOING TO MAKE SOME TYPE 2 ERRORS, I DON'T HAVE A GREAT SOLUTION FOR THAT BUT I DO THINK WHEN THERE ARE REASONS FOR DIFFERENCES IN MECHANISMS, I HOPE PEOPLE DON'T LEAVE THINKING THAT I DON'T LIKE MECHANISMS, I LOVE THEM. I COME UP WITH NEW MECHANISMS EVERY DAY. BASED ON MECHANISM AND BIOLOGIC PLAUSIBILITY THERE'S A DIFFERENCE OR EPIDEMIOLOGIC DATA NOSHOWING A DIFFERENCE OR ANIMAL DATA SHOWING A DIFFERENCE YOU ARE RESPONSIBLE FOR MAKING SURE YOU'RE POWERED ENOUGH, MAYBE NOT STATISTICALLY SIGNIFICANT DIFFERENCE BUT TO BE ABLE TO HAVE A GOOD SENSE AS TO WHETHER THERE'S A TREND THAT THEN NEEDS TO BE FOLLOWED UP ON. >> MY NAME IS KAREN HAHN BOMB, INSTITUTE OF GENDER AN HEALTH APT THE CANADIAN HEALTH INSTITUTES. AS THE MEETING DRAWS TO A CLOSE I WANT TO ASSURE THE AUDIENCE WE IMPLEMENTED A POLICY THREE YEARS AGO ASKING RESEARCHERS APPLYING FOR FUNDING TWO QUESTIONS. DID YOU CONSIDER SEX AND WE MAKE IT MORE COMPLICATED, GENDER AND WE INSIST WE KNOW SEX IS A BIOLOGIC VARIABLE AND GENDER IS A SOCIAL VARIABLE THAT INFLUENCES HEALTH. DID YOU CONSIDER THAT IN THE DESIGN ANALYSIS OF YOUR STUDY, YES OR NO. IF YES WHY. IF NO WHY. WE MADE THEM REFLECT ON CAN THEY JUSTIFY TO US IT RALEIGH ISN'T REQUIRED -- REALLY ISN'T REQUIRED. CAN THEY GO BACK TO EPIDEMIOLOGY, SHOW US THERE'S NO REASON TO CONSIDER IT. I THINK THIS REFLECTION PROGRESSES WITH EVERY GRANT APPLICATION BECAUSE OF THE NEW DATA AND FINDINGS THEY NEED TO LOOK TO SEE IF IT'S STILL JUSTIFIED OR UNJUSTIFIED TO BE CONSIDERING. THIS MORNING I WAS IMPRESSED BY THE PRESENTATION BY DAVID PAGE SHOWING WE NEED A PARADIGM LEAP IN THE WAY WE CONSIDER EPIGENETICS AND DRUG GENE INFLUENCES AND WHETHER THE MOUSE MODEL IS THE RIGHT MODEL TO STUDY LOOKING AT THESE INTERACTIONS, I'M GOING TO BRING THAT HOME BACK TO CANADA. HOW LONG DID WE THINK THE WORLD WAS FLAT? HOW MANY YEARS DID WE BELIEVE WE LIVED ON A WORLD THAT WAS FLAT WHEN IT'S ROUND. RESEARCHERS SURVIVED. PEOPLE WHO ARE GOOD SCIENCE STILL GETTING FUNDED BUT IT'S PUSHING THE ENVELOPE SO TO SEE IF WE NEED TO MOVE IN OUR THINKING, MAYBE WE ARE TOO SILO ED. MAYBE HARVARD BUSINESS REVERRUCAES WE NEED A BUNCH OF DISCIPLINES TOGETHER TO MOVE FORWARD TO BE CREATIVE TO BE INNOVATIVE AND I DO WANT TO CONGRATULATE THE OFFICE OF WOMEN HEALTH RESEARCH AND THE NIH AND ALL OF YOU FOR DOING THIS, YOU DO FABULOUS RESEARCH, TEN TIMES MORE THAN US TEN TIME MORRIS, MORE PEOPLE, MORE EVERYTHING, I LOOK FORWARD NORTH AMERICA WIDE TO SEE HOW WE CAN ADVANCE RESEARCH BECAUSE OF THE CHANGE. HAVE HOPE, IT'S NOT THE END OF THE WORLD AND I THINK IT WILL HELP. >> THANK YOU VERY MUCH FOR THAT COMMENT. >> QUICK STORY. ANYBODY REMEMBERS ESTELL RHAMEY? SHE ALWAYS TOLD THIS STORY WHENEVER I WOULD HEAR HER TALK, IT STAYED BECAUSE IT'S WONDERFUL AND SHE TALKED ABOUT THE DIFFERENCES BETWEEN MEN, WOMEN AND CARDIOVASCULAR DISEASE. THESE WERE THE DAYS WHEN WE WERE STUDYING MEN MORE THAN WOMEN. IF YOU WANT TO START A NEW DRUGSTORE DON'T STUDY DRUGSTORES THAT FAIL, YOU STUDY THE DRUGSTORES THAT SUCCEED. SO WHY NOT STUDY MORE WOMEN? >> CHRISTY (INAUDIBLE) NHLBI. I WANT TO CAUTION COMMENT AND CAUTION AGAINST INSTANCES WHERE THERE ARE NO OBVIOUS SEX DIFFERENCES. I WILL GIVE YOU A SPECIFIC EXAMPLE. SO WE ALL PROBABLY WILL AGREE THAT YOUNGER WOMEN DON'T SUFFER AS MUCH FROM CARDIOVASCULAR DISEASE AS OLDER WOMEN AND YOUNGER WHEN DON'T GET AS MUCH CARDIOVASCULAR DISEASE AS MEN. SO IN A SETTING OF DIABETES, REGARDLESS OF YOUR BEIGE, A WOMAN -- AGE, A WOMAN IS NO LONGER PROTECTED AGAINST CARDIOVASCULAR DISEASE SO COMPARED TO MEN THEY ARE EQUAL. IS THAT A REASON TO STUDY THAT MECHANISM? BECAUSE WE SHOULD BE ASKING MYSELF WHY AREN'T THERE DIFFERENCES FOR EXAMPLE IN SETTING OF DIABETES, WHY IS THAT PROTECTION LOST? THERE IS A LOT TO LEARN FROM ACTUALLY STUDYING NO DIFFERENCE AT ALL RATHER THAN IGNORING IT. >> I DON'T THINK ANYONE IS SAYING DON'T STUDY MECHANISMS THEY WERE SAYING I KNOW WHY IT WORKS BECAUSE I HAVE MADE UP THIS MECHANISM SO WE CAN'T ASSUME THAT WE KNOW JUST BECAUSE -- I DON'T KNOW WAS SAYING DON'T STUDY MECHANISMS. >> LIGHT, MECHANISMS ARE AT THE BASIS. -- RIGHT. SO THE VERY FACT THAT YOU IN ONE CASE FIND NO DIFFERENCE IN ANOTHER CASE YOU DO FIND DIFFERENCE, WHAT HEIGHTENS AND MAKES IT INTERESTING IF YOU DIDN'T FIND DIFFERENCES I WOULDN'T BE INTERESTED IN PURSUING BUT WHERE THERE ARE DIFFERENCES UNDERSTANDING WHY OR UNDERSTANDING WHETHER THERE ARE THERE COULD BE TREATMENT OF DIFFERENCES THAT APPLY DIFFERENCELY TO THOSE POPULATIONS, MAYBE ASPIRIN IN OUR STUDIES ASPIRIN IS PRETTY EFFECTIVE FOR WOMEN BUT THEY'RE DIABETICS. THAT'S EXACTLY WHAT YOU'RE SAYING SO LOOK AT THOSE POPULATIONS. >> WE ARE STARTING TO DRAW TO A CLOSE HERE, AT THE END I WOULD LIKE TO ASK EACH PANELIST TO SAY A FINAL THING IN TERMS OF FROM YOUR PERSPECTIVE AS CLINICAL RESEARCHERS WHAT WOULD BE YOUR BEST ADVICE TO US PRE-CLINICAL SCIENTISTS AS TO HOW TO GO FORWARD TO MAXIMIZE THE IMPACT OF THE RESEARCH WITHOUT HARMING THE MACHINE AND DOING THE BEST JOB TO HAND OFF HIGH QUALITY RESEARCH TO THE CLINICAL FIELD. >> I LIKE OUR CANADIAN COLLEAGUES THAT THAT APPROACH IS SAYING EITHER IF YOU ARE INCLUDING IT TELL US WHY, IF NOT, TELL US WHY. JUST THE IDEA THAT THERE'S A LOT OF THOUGHT AND 'IT IS THE GOOD SCIENCE DRIVING THE FOCUS ON SEX OR GENDER, SEX I GUESS IN PRE-CLINICAL VERSUS NOT AND BEING ABLE TO ARTICULATE THAT AND THINK IT THROUGH I THINK IS IMPORTANT. >> I WOULD SAY KEEP GOING. AND OFFICE OF RESEARCH WOMEN'S HEALTH KEEP DOING THIS SO EXCITING, BY PUBLISHING IT KEEP ONGOING JUST THIS TRIAL. >> MAYBE YOU NEED TO CELEBRATE THE DIFFERENCES. MAYBE YOU CAN LOOK AT THIS A LITTLE DIFFERENTLY AND THINK THAT IF OUR EXPERIMENT WORKS WHEN WE DO HAVE A MIX IT'S MAYBE MORE ROBUST EXPEOPLE, MAYBE WE'LL HAVE FEWER TIMES WHERE THE EXPERIMENT COULDN'T BE REPRIA KATEED BECAUSE YOU HAVE A MORE DIVERSE GROUP YOU'RE STUDYING. THIS IS NOT ALL THAT DIVERSE. IF YOU THINK ABOUT WHAT'S DIVERSE IN THIS COUNTRY OR IN THE WORLD THAT'S THE ONE THING ACCEPT FOR THE FACT THAT WOMEN ARE SMARTER AND LIVE LONGER. THAT'S ONE THING THAT'S EQUAL. >> I WOULD SAY DON'T GET DECEMBER COURAGED. THIS IS A HUGE CHANGE FOR A GENERATION OF RESEARCHERS. WHO THOUGHT THEY HAD IT FIGURED OUT, AS YOU CELEBRATE SUCCESS AND HELP PEOPLE THINK ABOUT IT I LOVE THE CANADIAN EXAMPLE, TELL US WHAT YOU'RE THINKING. TELL US WHY YOU THINK THIS ISN'T IMPORTANT. WE MAY COME BACK AND TELL YOU YOU'RE WRONG AND THAT IF YOU REALLY WANT FUNDING YOU NEED TO DO THIS. BUT I THINK MAKING FACILITATING THE THINKING, ACROSS THE BOARD IS REALLY ONE OF THE KEYS. THERE WILL BE SUCCESS STORIES AND THOSE SHOULD BE REWARDED. AS THEY OCCUR, THIS WILL BE COMFORTABLE FOR PEOPLE. WHY WOULD WE EXPECT OTHERWISE? LIKE ANY OTHER CHANGE IN LIFE, WHETHER IT'S RELATED TO SOMETHING IN OUR SOCIAL LIFE OR WHETHER RELATED TO SCIENTIFIC RESEARCH, RESEARCHERS DON'T LIKE TO BE TOLD THEY HAVE TIE DRESS ANY PARTICULAR ISSUE. IT'S ALL UP TO THEM. THIS IS TOUGH, GOING TO BE TOUGH FOR PEOPLE. ACKNOWLEDGING THAT AND FACILITATING IT, BY ALSO, THIS IS WHERE THE OFFICE OF RESEARCH WOMEN'S HEALTH CAN MAKE A BIG DIFFERENCE BY FOSTERING THE SCIENTIFIC DISCOURSE DOING THINGS LIKE ISSUING THOUGHT PROVOKING, EXAMPLE, GUIDELINES ON HOW TO THINK ABOUT THESE QUESTIONS, SHARING THIS SUCCESSES IN THIS FIELD ACROSS INSTITUTES. WHAT TENDS TO HAPPEN IS SOMEBODY PARTICULAR AREA OF INQUERY NOBODY KNOWS ABOUT IT, NOBODY IS EXCITED IN DRUG ABUSE, THE CARDIO VAS ALREADY PEOPLE HAVE NO IDEA THIS IS GOING ON. IT'S NOT THE REAL WORLD. SO MAKING SURE THOSE KIND OF -- THOSE KINDS OF SUCCESSES AND WHERE LEARNINGS OF ANY TIME, ARE SHARED WIDELY IS GOING TO BE IMPORTANT. TO MAKE THIS CHANGE STICK. MAKE THOSE CHANGES STICK. >> THE COMMENT NOT A QUESTION, WE'RE WRAPPING UP, I THINK ONE THING WE HAVEN'T REALLY DISCUSSED IS WHY THESE POLICIES OR WHY THE STATUS QUO CAME INTO PLACE IN THE FIRST PLACE. I THINK ONE POTENTIAL ANSWER IS WOMEN REALLY HAVEN'T HAD A VOICE, THE HISTORY OF BIOMEDICAL RESEARCH HAS BEEN OVERREPRESENTED IN MEN, ALL STEM FIELDS SO YOU WANT TO ACKNOWLEDGE THE FACT THAT I DON'T THINK IT'S AN ACCIDENT WE'RE BEGINNING TO ASK THESE TODAY WITH HISTORY OF BERNADINE HEELEY AND JANINE CLAYTON AND VIVIAN PENN AT THE HELM SO THAT'S IMPORTANT TO CONSIDER, THIS IS WONDERFUL PROGRESS WE'RE MAKING WHICH IS ENCOURAGED HAVING WOMEN LEADERSHIP. >> EXCELLENT POINT. I WILL GIVE ANECDOTE AT THE PREVIOUS OFFICE OF RESEARCH WOMEN HEALTH PANEL THAT I WAS AT, WE WERE IN THE MIDST OF A VERY EXCITING DISCUSSION ABOUT VARIOUS APPROACHES, SENIOR DISTINGUISHED SCIENTIST SITTING NEXT TO ME I HAVE KNOWN HIM 30 YEARS, HE SAID THIS WOULD BE BE HAPPENING IF THERE WEREN'T SO MANY WOMEN SCIENTISTS NOW. YOU'RE ABSOLUTELY RIGHT. I WOULD LIKE TO THANK OUR PANEL MEMBERS, WE HAVE SOME CLOSING REMARKS FROM JANINE CLAYTON BUT I WOULD LIKE TO THANK THEM FOR AN INTERESTING NEW DISCUSSION, SO WONDERFUL TO HAVE Y'ALL. [APPLAUSE] IA KNOW, A FEW CLOSING REMARKS. >> NOT JANINE. BUT SHE WILL COME UP MOMENTARILY. SHE'LL COME UP MOMENTARILY. SO I WANTED TO TAKE THIS OPPORTUNITY TO THANK EVERYBODY FOR COMING OUT TODAY. s SPECIALLY FOR ALL OF OUR SPEAKERS AND OUR PANEL AND I HOPE THAT WE WILL ALL TAKE THIS HOME WITH US AND MAKE US CONSIDER WHY WE DO WHAT WE DO. THE KINDS OF CHOICES WE MAKE CONDUCTING RESEARCH AND WHERE WE CAN MOVE THE FIELD FORWARD. BUT I WANT TO SAY A SPECIAL THANK YOU TO ONE ORWH STAFFER WHO MANY OF YOU MIGHT KNOW I'M FROM PANAMA, CENTRAL AMERICA ORIGINALLY, IF YOU HAVE HAD THE OPPORTUNITY TO VISIT PANAMA AND TRANSIT THE PAN MALL CANAL, YOU KNOW THERE ARE A SET OF LOCKS AND YOU KNOW THOSE LOCKS ARE QUITE NARROW. AND YOU KNOW THAT IT TAKE AS VERY SPECIAL PILOT TO HELP NAVIGATE THE HUGE CRUISERS THROUGH THE LOCKS. I'M FORTUNATE TO HAVE A STAFFER WORKING FOR ME BY NAME OF DR. LIAM MILLER. PLEASE GIVE HER A ROUND OF APPLAUSE AND THANK YOU. [APPLAUSE] >> WHAT A FANTASTIC DAY. WE STARTED OFF THIS MORNING, EARLY THIS MORNING, I HAVE ANIMY NOTES UP HERE AND I'M GOING TO MAKE A COUPLE OF HIGHLIGHTS BECAUSE WE HAVE HAD A WONDERFUL DAY. WE STARTED OFF THIS MORNING WITH FRANCIS MENTIONING THERE'S BEEN AN INATTENTION TO THE ISSUE OF SEX AS A BIOLOGICAL VARIABLE AND WE NEED TO RETHINK HOW WE'RE DOING PRE-CLINICAL RESEARCH IN THIS CONTEXT. THAT THIS IS PART OF THE ISSUE OF IMPROVING TRANSPARENCY AND ENHANCING RIGOR IN SERVICE OF INCREASING REPRODUCIBILITY AND IN FACT IN THE CONDUCT OF HIGH QUALITY RIGOROUS SCIENCE. IN THESE PARTICULARLY FISCALLY CONSTRAINED TIMES, IT IS ABSOLUTELY IMPERATIVE THAT WE LEARN THE MOST FROM EVERY SINGLE INVESTIGATION. FROM EVERY SINGLE DOLLAR THAT WE SPEND WHICH IS YOUR TAX DOLLARS, ON RESEARCH WE NEED TO GET THE MAXIMUM RETURN ON INVESTMENT, WE NEED TO LEARN THE MOST WE CAN. THAT'S WHAT WE'RE ABOUT AS SCIENTISTS. WE HEARD ABOUT THE FACT THAT WE WILL BE DEVELOPING AND RELEASING TRAINING MATERIALS AROUND SCIENTIFIC METHODS ENHANCING TRANSPARENCY AND RIGOR. WILSON STEPPED IN AND GAVE A FANTASTIC PRESENTATION MADE US THINK ABOUT SOME OF THE DISTURBING TRENDS WE'RE SEEING IN SEX DIFFERENCES AND THE DRUG ABUSE FEEL. AND I PULLED ONE OF IN THIS SENTENCES OUT BECAUSE I THOUGHT IT WAS VERY PLAIN LANGUAGE AND I'M LOOKING FOR PLAIN LANGUAGE WAYS TO TALK ABOUT WHAT WE'RE CONCERNED ABOUT AS SCIENTISTS AS RESEARCHERS. I ALWAYS GO BACK TO THE WORD RESEARCH, WHAT DOES IT MEAN? THE WORD ITSELF MEANS TO LOOK AGAIN. THAT'S WHAT WE DO. WE LOOK, WE KEEP LOOKING WE LEARN A LITTLE MORE, WE LOOK AGAIN, WE PARSE IT APART. WE DISSECT ROOK AT IT AGAIN, THAT'S WHAT WE DO AND WE LEARN AND WE LEARN, WE LEARN SO MUCH MORE NOW THAN WE HAVE EVER KNOWN BEFORE SO WE CAN SEE MORE, WE HEARD ABOUT AMAZING IMAGING TECHNIQUES THE CONNECTOME THE OTHER STRATEGIES APPROACHES TECHNICAL ADVANCES, SCIENTIFIC ADVANCES THAT ALLOW US TO KNOW MORE. WE KNOW NOW THAT SEX CAN MATTER AT A VARIETY OF LEVELS ALL THE WAY DOWN TO THE MOLECULAR LEVEL. SO WHAT WILSON SAYS WE NEED TO EXPLAIN THE DIFFERENCES THAT WE SEE. EXPLAINING THEM, JOHN DYLAN SAY'S COMMENT ABOUT DISCOVERY SCIENCE, THAT'S WHAT WE DO. IF YOU SEE A DIFFERENCE WE NEED TO LEARN HOW TO EXPLAIN IT AND TAKE ADVANTAGE OF THE DIFFERENCE. THEN WE HEARD FROM DR. PAGE INCREDIBLE PRESENTATION THAT MADE US ALL THINK IN DIFFERENT WAYS AND KIND OF TURN THE WORLD UPSIDE DOWN IN TERMS OF SEX AND SEX DETERMINATION. I PULLED OUT TWO QUOTE FROM DAVID'S PRESENTATION, THE FIRST IS HE BELIEVES THE OPPORTUNITIES BEFORE US GO FAR BEYOND OUR GREATEST IMAGINATION. HE ALSO ENCOURAGED US TO EMBRACE A WIDELY COMPARATIVE VIEW TO UNDERSTAND WHO WE ARE. AND I WAS JUST THRILLED TO HEAR THE COMPARATIVE, IT'S A POWERFUL YET SIMPLE TOOL THAT WE USE, COMPARE AND CONTRAST. COMPARE AND CONTRAST. AND DAVID'S PRESENTATION, THERE WAS A COMPARATIVE APPROACH THROUGHOUT THE ENTIRE PRESENTATION THAT ALLOWED HIM TO COME THE A DIFFERENT UNDERSTANDING COMPARING MALES AND FEMALES, NOT TO EMPHASIZE THE DIFFERENCE BUT TO TAKE ADVANTAGE OF THE NATURAL BIOLOGICAL VARIABLE AND LEARN FROM IT. AND STUDY BOTH SEXES, STUDY FEMALE BIOLOGY, PATHOPHYSIOLOGY, STUDY WOMEN WHEN IT'S THE SAME, STUDY WHEN IT'S DIFFERENT. THE INFLUENCE OF SEX AS A BIOLOGICAL VARIABLE, THE INFLUENCE OF SEX AND GENDER ON DE HEALTH AND DISEASE IS WHAT WE'RE TRYING TO ENCOURAGE. THERE ARE MANY WAYS TO DO THAT, WE HEARD THROUGH THE SAGA OF Y CHROMOSOME PART OF THE STORY I LOOK FORWARD TO HEARING MORE ABOUT. WE HEARD THE PROVOCATIVE COMMENT THAT PERHAPS MOUSE MODELS ARE NOT THE BEST MODEL HUMAN DISEASE, THERE'S A LOT TO DEBATE THERE, HOW WE ARE DOING SCIENCE OUR WHOLE APPROACH HOW WE'RE DOING SCIENCE. WE HAVE TO THINK ABOUT THAT. WE HAVE NOT SOLVED MAJOR HEALTH PROBLEMS. AND THERE ARE MORE NEW MAJOR HEALTH PROBLEMS. WHAT WE HAVE BEEN DOING IS NOT GOTTEN THE ANSWERS WE NEED. FOR NIH I THINK WE CAN TRANSFORM WHAT WE DO BY JUST THESE THREE LETTER WORDS WHICH IS AND. INSTEAD OF LOOKING AT THINGS IN AN EITHER/OR WAY WE NEED TO LOOK AT THINGS IN A BOTH AND WAY. VERY STRAIGHT FORWARD. I KNOW IT'S NOT EASY BUT IT IS SIMPLE AND STRAIGHT FORWARD. NOT EITHER MALE OR FEMALE BOTH MALE AND FEMALE WE NEED TO UNDERSTAND THAT. THE MISSION OF NIH IS TO EXPAND UNDERSTANDING OF FUNDAMENTAL LIVING THINGS AND TO APPLY THAT INFORMATION TO IMPROVE HEALTH, REDUCE ILLNESS, REDUCE DISABILITY AND IMPROVE QUALITY OF LIFE. THERE IS AN AND IN THERE. WE HAVE LOTS OF WORK TO DO. WE HAVE TO BUILD A VERY FIRM FOUNDATION SO WE CAN CONTINUE TO GROW, WITH THIS AMAZING PROMISE OF SCIENCE, WE NEED TO DIG DEEPER IN OUR FOUNDATION, I THINK THAT'S WHAT WE KNOW NOW OUR PRE-CLINICAL WORK HAS DONE AMAZING THINGS BUT WE HAVE HOLES IN OUR FOUNDATION. IF YOU WANT TO BUILD A HIGHER SKYSCRAPER YOU NEED TO DIG A DEEPER FOUNDATION AND YOU CAN BLAME OWL OF THAT -- LAY ALL OF THAT ON TOP, WE NEED TO REGROUP IN SOME AREAS AND I THINK THE MOST IMPORTANT THING IS WE ABSOLUTELY HAVE TO WORK TOGETHER IN NEW AND DIFFERENT WAYS. INTERDISCIPLINARILY TRANSDISCIPLINARILY, MULTI-DISCIPLINARILY, HOWEVER YOU WANT TO PUT IT, WE NEED EACH OTHER'S DIFFERENCES IN HOW WE APPROACH PROBLEMS AND COMPLIMENTARY EXPERTISE AND WE DIDN'T EVEN TALK ABOUT GENDER BUT WE NEED ALL OF THAT EXPERTISE INCLUDING FROM OUR SOCIAL SCIENCE COLLEAGUES, TO IMPROVE HEALTH, SO I'M SO DELIGHTED THAT WE HAD SUCH A WONDERFUL, LINE UP OF SPEAKERS TODAY AND YOU HUNG IN UNTIL THE END. WE HAVE A FANTASTIC PANEL, I WILL SAY WE ARE LOOKING -- WE ARE DEVELOPING THIS POLICY, WE WANT TO HEAR FROM YOU, WHAT YOUR THOUGHTS ARE, WE WANT THIS TO HAVE THE FLEXIBILITY TO ALLOW US TO DO THE BEST SCIENCE WE RECOGNIZE THAT WE CAN'T PREDICT ALL THE THINGS THAT ARE GOING TO HAPPEN IN SCIENCE, THAT'S WHY WHAT WE WANT TO HEAR FROM YOU SO WE CAN THINK ABOUT AS MANY POSSIBILITIES, AND CIRCUMSTANCES AND NOT HAVE UNINTENDED CONSEQUENCES THAT THAT WART SCIENCE, THAT'S NOT WHAT WE'RE ABOUT. SO THANK YOU VERY VERY MUCH. I WANT TO THANK ORWH STAFF THE SCORE DIRECTORS, THE SCORE PIs, THE BURR. SCHOLARS AND ALL YOU ATTENDING. THANK YOU, VERY MUCH FOR BEING HERE AND WE'LL SEE YOU NEXT YEAR. [APPLAUSE]