I'D LIKE TO WELCOME EVERYONE TO FIFTH HUMAN PLACENTA PROJECT MEETING. I SEE OLD AND NEW FRIENDS. WE'RE EXCITED TO HAVE YOU HERE. I HOPE YOU DIDN'T HAVE TOO MANY DIFFICULTIES WITH THE RAIN LAST NIGHT. THE FOCUS OF THIS MEETING, EACH TIME WE HAVE A MEETING WE TRY TO HAVE AN ONGOING THEME. WE HAVE TWO AREAS OF FOCUS FOR THIS MEETING. ONE IS THE TRANSLATION TO CLINICAL CARE, AND THE OTHER IS CONSIDERATION OF IMPLEMENTATION OF THE TECHNOLOGIES ON A GLOBAL SCALE. SO, THINKING ABOUT LOW COST ALTERNATIVES TO SOME OF THE TECHNOLOGIES. SO I'M NOT GOING TO TAKE UP A LOT OF TIME TO GET THINGS STARTED BUT I WANT TO THANK THE VERY IMPORTANT PEOPLE WHO HAVE MADE THIS MEETING POSSIBLE, AND THEY INCLUDE DAVID WEINBERG, AFROUZ ANDERSON WHO IS ONE OF OUR INTRAMURAL RESEARCHERS, AND SHE WILL BE DOING ONE OF THE DEMONSTRATIONS TODAY. CHRISTY ROGERS, WHO IS REALLY THE GLUE WHO PUTS EVERYTHING TOGETHER, AND OUR CONTRACTORS, ALEX SIMPSON AND VALENTINE MARA AND A THIRD PERSON WHOSE NAME I DON'T KNOW. WE THANK HER TOO. WE'LL HAND IT OVER TO AFROUZ AND DAVID. OH, DAVID. >> THANK YOU, DR. BIANCHI. I APPRECIATE THAT. I WANT TO START THIS MEETING BY SINCERELY THANKING EACH AND EVERY ONE OF YOU, BECAUSE THIS MEETING IS AN OPPORTUNITY. IT'S A CHANCE TO HEAR WHAT HAS COME OUT OF HPP RESEARCH AND IMPORTANTLY IT'S AN OPPORTUNITY TO ENGAGE EACH OF YOU, OUR STAKEHOLDERS, IN A CONVERSATION. WHAT HAVE WE DONE WELL? WHAT IS MISSING? WHERE ARE THE GAPS? THAT'S THE REASON FOR BRINGING TOGETHER ALL THIS INTELLECTUAL HORSEPOWER IN THE ROOM. TO HAVE YOU BE PART OF CRAFTING THE HPP. SO, I SHOULD ALSO SAY HOW MUCH I APPRECIATE THE SUPPORT THAT NICHD LEADERSHIP HAS GIVEN TO THE HUMAN PLACENTA PROJECT FROM THE BEGINNING OF THIS PROJECT, AND WITHOUT IT WE WOULDN'T BE HERE. NOW DR. BIANCHI HAS ALREADY SAID SOME THANK YOUS. I WANT TO ADD MY OWN. THERE'S A LOT OF LOGISTICS THAT WENT ON BEHIND THE SCENES AND IT WOULD HAVE BEEN IMPOSSIBLE WITHOUT MY COLLEAGUE IN CRIME OVER THE LAST SEVERAL YEARS, CHRISTY ROGERS. ASSISTED THIS YEAR BY RIHAN HOLLOWAY, SO THE TWO OF THEM HELP KEEP US ON TRACK. PALLADIUM PARTNERS HAS BEEN FANTASTIC. I THINK THEY HAVE DONE ALL OF OUR HPP MEETINGS, AND THEY ARE SUPER TO WORK WITH AND THEY MAKE EVERYTHING GO SMOOTHLY. AND I HAVE SOMETHING ELSE TO SAY IN A MINUTE. I'LL DO THE HOUSE KEEPING. RESTROOMS ARE OUTSIDE, YOU CAN FIND SOME ON THE RIGHT. PUT YOUR PHONES ON SILENT OR VIBRATE. THE MEETING IS BEING WEBCAST, IT'S LIVE AND IT'S BEING RECORDED, SO I HAVE A FEW ASSOCIATED REQUESTS. ASK QUESTIONS FROM THE MICROPHONES AND DON'T YELL FROM YOUR SEAT BECAUSE EVEN THOUGH I MAY HEAR YOU, THE PEOPLE WATCHING ON THE RECORDING WON'T CATCH IT. STATE YOUR NAME. GET CREDIT FOR GIVING THE QUESTION. THAT YOU CAN BE HEARD BY THOSE LISTENING REMOTELY. AND I'LL ASK YOU TO PLEASE BE MINDFUL THAT WE'RE ON A TIGHT AGENDA SO PLEASE LEAVE TIME FOR OTHERS TO ASK QUESTIONS AS WELL. YOU CAN ALWAYS FIND THE SPEAKERS AT THE BREAK, THE LUNCH, THE DEMO POSTER SESSION. NOW, I'VE BEEN FORTUNATE THIS YEAR TO HAVE AN NICHD INTRAMURAL RESEARCHER ASSIST ME IN THINKING ABOUT THE MEETING. AND THAT IS DR. AFROUZ ANDERSON, WHO IS GOING TO HELP RUN THE MEETING AND IN ADDITION WE TOLD HER SHE HAS TO DO A DEMO AND GIVE A TALK. SO WE DECIDED TO PILE IN ON HER AND SEE HOW SHE DOES. WITH THAT I'M GOING TO TURN IT OVER TO AFROUZ. >> ALL RIGHT. HELLO, EVERYONE. SO I'M GOING TO CONTINUE WITH HOUSEKEEPING A LITTLE BIT MORE. IF YOU'RE A SPEAKER AND YOU'RE SCHEDULED FOR DAY 1, PLEASE FIND US IN THE BREAK, IF YOU HAVE NOT GIVEN US YOUR SLIDES YET. BECAUSE WE NEED TO HAVE THEM LOADED. THERE'S A LUNCH BOX REQUEST FORM IN THE REGISTRATION DESK, THERE'S A RESTAURANT ON SITE BUT IT'S SMALL, MIGHT NOT BE ABLE TO FILL ALL OF US SO THERE'S A FORM YOU CAN GET FROM THE REGISTRATION DESK, FILL IT OUT FOR LUNCH BOXES. WE WILL HAVE A GREAT DEMO AND POSTER SESSION. PLEASE MAKE SURE YOU'RE THERE. IT'S A GREAT OPPORTUNITY FOR NETWORKING AND ASKING THE QUESTIONS THAT YOU MIGHT HAVE DURING THE TALKS. THERE'S ALSO A SHUTTLE SERVICE BETWEEN THE HOTEL AND THE MEDICAL CENTER SO YOU CAN GO THERE, IT RUNS UNTIL 11:00 P.M. AND FITS ABOUT 11 PEOPLE SO CAN YOU GO IF THE METRO AND ACCESS TO D.C. IF YOU NEED TO. AND OKAY. THE OTHER PART IS THAT TODAY DAVID AND I ARE GOING TO ASK -- ACT AS TRAFFIC LIGHT AND OFFICER. THERE'S NO GREEN LIGHT BUT YOU'LL SEE THE YELLOW LIGHT, YOU'RE THREE MINUTES TO END OF TALK, AND HE WILL SHOW THE RED LIGHT WHICH MEANS YOU'RE ABOUT TO END IT. AND IF THIS DOESN'T HAPPEN UNFORTUNATELY I HAVE TO ENTER YOUR PERSONAL SPACE, WE DON'T WANT THAT TO HAPPEN. SO, THEN I WANT TO MAKE SURE. GROUP PICTURES, PLEASE BE HERE. WE WOULD LIKE TO HAVE ALL OF YOU WONDERFUL PEOPLE IN THERE. IT'S GOING TO HAPPEN RIGHT AT THE END OF THE LUNCH BREAK. AT THE BEGINNING. JUST BEFORE THE LUNCH BREAK. THAT'S EASIER. SO, I THINK I COVERED EVERYTHING. AND WITH THAT WOULD LIKE TO HAVE DR. BIANCHI COME UP AND INTRODUCE OUR SPECIAL GUEST. >> THANK YOU, AFROUZ AND DAVID. YOU HEARD DAVID SAY WE HAVE A LOT OF INTELLECTUAL POWER IN THIS ROOM. SO MUCH OF THE REST OF THE DAY IS GOING TO BE ABOUT SCIENCE AND ABOUT INTELLECTUAL ASPECTS OF THE HUMAN PLACENTA PROJECT. BUT WE NEED TO PUT SOME HEART INTO THE PROJECT AS WELL. THAT'S WHY WE LIKE TO INCLUDE A PERSONAL STORY BECAUSE ULTIMATELY OUR RESEARCH HELPS PEOPLE. AND NO ONE CAN SAY IT BETTER THAN SOMEONE WHO HAS ACTUALLY BEEN THROUGH THE EXPERIENCE. SO IT'S MY GREAT PLEASURE TO INTRODUCE MS. ANGELICA HANLEY WHO PARTICIPATED IN THE TRIAL PRAVASTATIN FOR THE PREVENTION OF PREECLAMPSIA, PHASE 1 THROUGH THE NICHD OBSTETRIC FETAL PHARMACOLOGY RESEARCH CENTER. TREATMENT ISN'T SPECIFICALLY HUMAN PLACENTA PROJECT, THE TRIAL REPRESENTS OUR ULTIMATE DREAM THAT EARLY DETECTION LEADS TO INTERVENTIONS THAT CAN THEN PREVENT A CONDITION. SO, WE HAVE INVITED A SPEAKER LIKE MS. HANLEY TO SHARE HER PERSONAL STORY, TO KEEP IT FIRMLY IN OUR MINDS WHY WE DO WHAT WE DO. AND WITH THAT I'D LIKE TO INVITE MS. HANLEY TO COME UP AND SHARE HER STORY. SHE'S COME ALL THE WAY FROM TEXAS, SO LET'S GIVE HER A BIG HAND. [APPLAUSE] 1*. >> THANK YOU VERY MUCH FOR HAVING ME. YES, I TRAVELED FROM TEXAS. I'M FROM GALVESTON, I'M NERVOUS. I DO SPEAK IN FRONT OF CROWDS FREQUENTLY WITH MY JOB BUT NOT REALLY ON A PERSONAL LEVEL. SO I'M SHARING MY PERSONAL STORY, WHICH PUTS A LITTLE NERVES IN MY BODY. SO PLEASE BEAR WITH ME ON THAT. FROM-- YES, UTMB, UNIVERSITY OF TEXAS MEDICAL BRANCH WHERE I HAD MY FIRST CHILD. MY HUSBAND AND I LONGED FOR CHILDREN THROUGH OUR MARRIAGE, AND IT WAS VERY DIFFICULT FOR ME TO BECOME PREGNANT. SO, WITH THE HELP OF UTMB I WAS ABLE TO BECOME PREGNANT, AND I HAD OUR SON AT 32 WEEKS. SO, MY FIRSTBORN WAS -- I DID SUFFER FROM SEVERE PREECLAMPSIA WITH THAT SON. I WASN'T ABLE TO HOLD HIM FOR THREE DAYS WITH THE NICU AND LOGISTICS. AS A NEW MOTHER THAT'S TRAUMATIZING TO NOT BE ABLE TO HOLD YOUR CHILD. HE WAS IN THE NICU FOR 36 DAYS, HE'S NOW HAPPY, HEALTHY, A BEAUTIFUL CHILD. WE WERE NOT PLANNING ON HAVING ANOTHER CHILD AFTER WHAT I CONSIDER A TRAUMA OF THE BIRTH OF OUR FIRST CHILD. SO-- BUT BY THE GRACE OF GOD WE WERE ABLE TO HAVE ANOTHER CHILD. I BECAME PREGNANT AND MY FIRST VISIT TO THE CLINIC, DR. CONSTANTINE CAME IN AND VISITED WITH ME AND TOLD ME ABOUT THE STUDY THAT HE WAS DOING, AND MY FIRST REACTION WAS, YES, ABSOLUTELY. I ABSOLUTELY WANT TO DO THIS. AND MY HUSBAND WAS A LITTLE HESITANT, AND HE SAID, WELL, LET'S TALK ABOUT IT. SO WE WENT HOME AND WE TALKED ABOUT IT. I SAID TO HIM, WE HAVE AN OPPORTUNITY HERE TO HELP OTHERS. AND HELP OTHERS WHO HAVE -- WHO MAY HAVE TO GO THROUGH WHAT WE WENT THROUGH, AND I DON'T -- I WANT TO PLAY A ROLE IN THAT. AND MY HUSBAND'S SELLING POINT, AS YOU COULD SAY, HE'S IN SALES, SO HE HAS TO LOOK FOR THE SELLING POINT, WAS THAT DR. CONSTANTINE WAS GOING TO BE WITH US THROUGHOUT THE PREGNANCY, SO I HAD MY PRIMARY DOCTOR AND DR. CONSTANTINE ALONG WITH HIS STAFF. DR. CONSTANTINE CAME IN TO THE CLINIC FREQUENTLY TO VISIT WITH ME. HE WATCHED ME THROUGHOUT MY WHOLE PREGNANCY. AND FOR THAT, I WILL FOREVER BE GRATEFUL TO HIM. HE STILL REACHES OUT TO ME, AND I SEND HIM PICTURES FREQUENTLY OF MY BOYS. I REALLY WANT HIM TO KNOW -- JUST SO YOU KNOW I DID FIND OUT LATER I WAS IN FACT ON THE DRUG, SO I BELIEVE THAT IT PLAYED A LITTLE ROLE, IF IT WASN'T THE FACT THAT THE DRUG PLAYED A ROLE, THEN THE FACT THAT DR. CON WAS WITH ME. HE HE WAS BORN AT 36 WEEKS, I WAS ABLE TO HOLD HIM WHEN HE WAS BORN, SOMETHING I WILL CHERISH FOREVER. WITH THAT, I DID MAKE A LITTLE HAVE VIDEO TO SHARE OF MY FAMILY. LET ME SEE IF I CAN GET IT UP HERE. OH, THAT'S NOT ME. I'M SORRY. [ MUSIC ] >> THANK YOU FOR LETTING ME SHARE THAT. I WAS ASKED TO LET YOU KNOW THE BIRTH WEIGHT OF BOTH OF MY SONS, THE FIRST WAS RIGHT AT 4 POUNDS, OF COURSE HE LOST A LITTLE WEIGHT. AND THE SECOND WAS, AS YOU CAN SEE, HE WAS 6 POUNDS, I THINK 9 OUNCES OR SO. BUT I JUST WANT TO LEAVE YOU ALL WITH THANK YOU. THANK YOU, ALL OF YOU, FOR ALL OF THE WORK THAT YOU'RE DOING. IT TRULY HELPS FAMILIES LIKE MINE ACROSS THE COUNTRY. I JUST WANT TO SAY THANK YOU. IT MEANS SO MUCH TO ME. I KNOW THAT THE FUTURE IS BRIGHT BECAUSE OF ALL OF YOU. THANK YOU VERY MUCH. [APPLAUSE] >> I'D LIKE TO SAY THANKS FOR TELLING US YOUR STORY, AND JUST SAY YOU'RE NOT ALONE. BOTH MY KIDS WERE NICU AS WELL. >> THANK YOU. >> VERY MUCH MOTIVATED BY THAT IN THE WORK THAT I DO. >> THANK YOU. >> I'M GEORGE SADI, CHIEF OF OBSTETRICS AT UTMB. THANK YOU FOR MENTIONING US AND DR. CONSTANTINE. HE'S ONE OF OUR STARS. >> YES. >> I CAN TELL YOU NOTHING WOULD HAVE BEEN POSSIBLE WITHOUT THE SUPPORT OF NICHD, BECAUSE THAT NETWORK THAT YOU MENTIONED WHERE YOU'RE PARTICIPATING IN, IT'S SUPPORTED BY NICHD. AND BECAUSE OF YOU AND MANY OTHERS WHO CONTRIBUTED SO MUCH TO THE STUDY, THE STUDY IS MOVING FORWARD INTO WHAT WE CALL A PHASE 3 TRIAL, WHICH IS A MUCH LARGER STUDY. THE RESULTS OF THAT FIRST PILOT STUDY WERE SO POSITIVE THAT I'M GLAD YOU WERE ON THE TREATMENT. >> YES. >> HOPEFULLY MANY MORE WOMEN WILL BE ON THE TREATMENT AND WE CAN PREVENT WHAT HAPPENED TO YOU IN THE FIRST PREGNANCY. THANK YOU SO MUCH FOR SHARING YOUR STORY. >> THANK YOU. THANK YOU TO UTMB. FROM THE BOTTOM OF MY HEART, ALL OF THE STAFF AT UTMB IS SO WONDERFUL. >> THANK YOU. FREE ADVERTISING. [LAUGHTER] >> THANK YOU. THANK YOU. [APPLAUSE] >> NOW I HAVE TO GET OUT OF THE VIDEO. IT'S ALWAYS THE CASE THAT YOU HAVE TO TRAVEL TO WASHINGTON TO MEET SOMEONE FROM YOUR HOMETOWN, RIGHT? EXCELLENT. I SHOULD HAVE WORN MY HIGH HEELS TODAY. GOOD MORNING. IT'S MY GREAT PLEASURE TO GIVE YOU AS IS TRADITION AN INTRODUCTORY OVERVIEW TO NOT ONLY WHERE WE ARE IN TERMS OF THE HUMAN PLACENTA PROJECT BUT ALSO SOME THINGS HAPPENING AT NICHD. MANY OF YOU HAVE BEEN PARTICIPATING IN OUR STRATEGIC PLANNING. THE PLACENTA IS NOT JUST NICHD'S ORGAN BUT APPEARS IN POP PART, THIS IS FROM THE BRITISH MEDICAL JOURNAL. I WOULD LOVE TO GET A COPY AND HAVE IT IN OUR NICHD OFFICES. I'M GOING OVER THE GOALS FOR THE MEETING,I RELATED TO BUDGET, PEOPLE ARE ALWAYS INTERESTED IN MONEY. THE STRATEGIC PLANNING PROCESS AND OTHER RESEARCH INITIATIVES THAT MAY BE OF FROM BECAUSE BY DEFINITION YOU'RE INTERESTED IN PLACENTAL AND PREGNANCY RESEARCH. AGAIN, THE NATIONAL EYE INSTITUTE HAS THE EYES. NATIONAL INSTITUTE OF DIABETES, DIGESTIVE DISORDERS AND KIDNEY HAVE THE GUT AND KIDNEY, AND WE HAVE THE PLACENTA. MOST OF YOU KNOW BECAUSE YOU'RE FUNDED RESEARCHERS THE HUMAN PLACENTA PROJECT WAS LAUNCHED IN 2014 TO DEVELOP NOVEL NON-INVASIVE REALTIME TECHNOLOGIES FOR ASSESSMENT OF PLACENTAL DEVELOPMENT AND FUNCTION. WE HAVE CURRENTLY INVESTED MORE THAN $80 MILLION IN PLACENTA-RELATED RESEARCH, THAT'S NOT JUST THE HPP, THAT INCLUDES R O 1s AND INTRAMURAL RESEARCH SUCH AS DR. ANDERSON'S. SO CONSIDER THAT WHEN YOU PAY YOUR TAXES IN APRIL. ARE WE HAVE A FOCUS ON IMAGING AND OMICS, SOME OF THE WORK YOU'LL BE HEARING ABOUT TODAY. OUR GOALS ARE THE FOLLOWING, FOR THE MEETING. WE'VE SUCCEEDED IN BRINGING TOGETHER EXPERTS AND THINKERS INCLUDING COMPUTER SCIENTISTS, ENGINEERS, PLACENTAL BIOLOGISTS, CLINICIANS AND PATIENTS TO DISCUSS HOW TO ACHIEVE THE GOALS OF THE HPP. AND MUCH OF WHAT YOU'LL HEAR ABOUT IN THE NEXT TWO DAYS IS THE PROGRESS TO DATE OF THE HPP-FUNDED PROJECTS THROUGH PRESENTATIONS, POSTERS ACROSS THE HALL AND DEMONSTRATIONS. AND WE HOPE TO PROVIDE THOUGHT-PROVOKING PRESENTATIONS TO INSPIRES CURRENT AND POTENTIAL GRANTEES TO THINK ABOUT THE HPP'S FUTURE DIRECTIONS WITH EMPHASIS ON TRANSLATION, AS I SAID EARLIER, OF HPP RESEARCH INTO THE CLINIC AND INTO LOW-RESOURCE SETTINGS GLOBALLY. SO, OUR CONTINUED COLLABORATION WILL MAKE HPP A CONTINUED SUCCESS. WE ASK YOU TO NETWORK DURING THE POSTER AND DEMONSTRATION SESSION. WE HAVE OVER 30 POSTERS TODAY. AND WE HAVE FIVE DEMONSTRATIONS. THIS WILL BE AN OPPORTUNITY TO LEARN ABOUT THE VARIOUS TYPES OF PLACENTAL RESEARCH BEING DONE AND HOW IT MIGHT INFORM THE HPP. SO PLEASE USE THE OPPORTUNITY TO NETWORK WITH YOUR OLD AND NEW COLLEAGUES, MAKE NEW CONTACTS, AND CREATE POSSIBLE NEW PARTNERSHIPS. MONEY. WELL, I HAVE GOOD NEWS. WE JUST COMPLETED FISCAL YEAR 2018, NIH RECEIVED A $3 BILLION INCREASE WHICH BROUGHT TOTAL BUDGET TO A LITTLE OVER $37 BILLION. OUR APPROPRIATED BUDGET WAS 1.43, REPRESENTING AN INCREASE OF $75 MILLION. HOW MANY PEOPLE KNEW THAT WE ACTUALLY HAVE A REAL BUDGET AS OF OCTOBER 1 THIS YEAR? SO DID YOU KNOW THAT? THIS IS THE FIRST TIME IN 22 YEARS WE ACTUALLY HAVE A BUDGET AS OF OCTOBER 1, WHICH MEANS WE CAN PLAN AND ACTUALLY GIVE GRANTS OUT INSTEAD OF BEING IN A HOLDING PATTERN. SO FOR FISCAL YEAR 2019 CONGRESS WAS ONCE AGAIN VERY GOOD TO US. WE RECEIVED A $2 BILLION INCREASE WHICH BROUGHT THE TOTAL BUDGET TO AROUND $39 BILLION WHICH WAS 5.4% INCREASE OVER THE PREVIOUS FISCAL YEAR. AND OUR APPROPRIATED BUDGET IS $1.506 BILLION WHICH REPRESENTS AN INCREASE OVER LAST YEAR OF APPROXIMATELY 4%. WELL, WHEN I SPEAK WITH GROUPS OR WHEN I GO TO CAPITOL HILL, VERY FREQUENTLY WE'RE ASKED HOW DID WE USE THE INCREASED FUNDS IN THE PRIOR FISCAL YEAR. SO YOU'LL BE HAPPY TO KNOW THAT WE HAD AS A BIGGEST PRIORITY HELPING EARLY-STAGE INVESTIGATORS, SO THESE ARE PEOPLE TRANSITIONING FROM TRAINING GRANTS OR CAREER DEVELOPMENT GRANTS TO THEIR FIRST INDEPENDENT RESEARCH GRANT SUCH AS AN R01. WE WERE ABLE TO DOUBLE THE NUMBER OF PEOPLE WHO GOT THEIR FIRST RPGs FROM 29 TO 60. THAT IS HUGE. THAT MEANS THERE ARE 31 RESEARCHERS WHO HAVE MADE THAT TRANSITION AND WE'RE NOT LOSING THEM FROM THE PIPELINE. WE ALSO USED OVER 800,000 IN RESEARCH MANAGEMENT SUPPORT, TO FACILITATE THE TASK FORCE ON MEDICATIONS IN PREGNANCY AND LACTATION WHICH I'LL GET TO IN A MINUTE. WE ALSO ALLOCATED $30 MILLION TO LAUNCH CLINICAL TRIALS TO IDENTIFY, TREAT AND CARE FOR BABIES EXPOSED TO OPIOIDS IN UTERO. AND WE DEDICATED MORE THAN $39 MILLION TO SUSTAIN EXISTING RESEARCH PROGRAMS IN PREECLAMPSIA, MATERNITY MORTALITY AND FERTILITY. PEOPLE WORKING IN THOSE AREAS DID NOT GET A BUDGET CUT. SO, WHAT WE'RE WORKING ON THIS YEAR WHICH IS TAKING REALLY A LOT OF TIME IN CALENDAR YEAR 2018 IS OUR STRATEGIC PLANNING PROCESS. NICHD HAS NOT HAD FORMAL STRATEGIC PLANNING PROCESS SINCE THE YEAR 2000. MANY OF YOU PARTICIPATED IN THE SCIENTIFIC VISIONING PROCESS THAT OCCURRED IN 2012 BUT THAT WAS NOT SPECIFIED TO NICHD. THAT WAS DESIGNED TO IDENTIFY GAPS IN THE FIELD, AND YOU COULD ARGUE THAT THE HUMAN PLACENTA PROJECT CAME OUT OF THAT PROCESS, A DIRECT CONNECTION TO TODAY. WITH A BUDGET OF $1.5 BILLION WE NEED TO SPEND IT RESPONSIBLY. THE PURPOSE OF STRATEGIC PLANNING IS ENABLE STAKEHOLDERS TO LOOK AT NICHD'S PORTFOLIO WITH A FRESH PERSPECTIVE. WE'RE REVIEWING AND REFOCUSING NICHD'S SCIENCE, WILL ALIGN RESOURCES WITH SCIENTIFIC PRIORITIES THAT COME OUT OF THAT PROCESS. AND THE GOAL ULTIMATELY IS TO IMPROVE THE HEALTH OF THE POPULATIONS WE SERVE. SO, ALL OF THIS IS AVAILABLE PUBLICLY. WE HAVE INFORMATION ON OUR WEBSITE BUT BASICALLY SINCE THE BEGINNING OF THIS CALENDAR YEAR WE HAVE BEEN INVOLVED IN A VERY EXTENSIVE COLLECTION OF DATA REGARDING OUR FUNDING PORTFOLIO AND ANALYZING THAT PORTFOLIO FOR IMPACT. SINCE SEPTEMBER WE'VE BEEN PRESENTING THAT INFORMATION TO OUR ADVISORY COUNCIL, TO THE PUBLIC, TO THE WORKING GROUP. SOME OF YOU WERE MEMBERS OF THE WORKING GROUP AND WE REALLY APPRECIATE YOUR TIME. AND YOU WILL NOW ALL HAVE AN OPPORTUNITY TO PARTICIPATE IN THIS. THE CORE PRINCIPLES FOR THE STRATEGIC PLANNING PROCESS INCLUDE TRANSPARENCY, EVERYTHING IS BEING PUT ON THE WEBSITE. STAKEHOLDER PARTICIPATION, DON'T THINK THAT YOU DON'T HAVE INFLUENCE. IF YOU THINK WE SHOULD BE SPENDING MORE MONEY ON A, B OR C, THIS WILL BE YOUR CHANCE TO WEIGH IN. WE DIDN'T WANT PEOPLE SHOOTING FROM THE HIP. WE WANTED THE DECISIONS TO BE INFORMED BY EVIDENCE. SO WE HAD AN EXTENSIVE ANALYSIS OF HOW WE ACTUALLY SPEND OUR MONEY. SO WHEN WE WERE DOING THIS IT WAS AT THE BEGINNING OF CALENDAR YEAR 18, WHICH WAS AT THE START OF FISCAL YEAR 18 SO WE JUST HAD THE NUMBERS FROM FISCAL YEAR 2017, WE HAD A BUDGET OF $1.37 BILLION. AND 55% OF OUR BUDGET GOES TO PEDIATRICS AND CHILD DEVELOPMENT. WE ARE NOT THE ONLY INSTITUTE AT NIH THAT DOES RESEARCH IN CHILD HEALTH, EVEN THOUGH IT'S OUR NAME. WE ONLY FUND 18% OF THE RESEARCH IN CHILD HEALTH ACROSS NIH. 15% OF OUR BUDGET IS ASSOCIATED WITH GYNECOLOGIC AND REPRODUCTIVE HEALTH. THAT IS EVERYTHING PRIOR TO PREGNANCY THAT INVOLVES REPRODUCTIVE ORGANS AND INCLUDES MALE INFERTILITY AS WELL AS FEMALE INFERTILITY. PREGNANCY AND MATERNAL, THAT'S THE PIECE OF THE PIE THAT THIS GROUP IS PROBABLY THE MOST INTERESTED IN. THAT REPRESENTS 14% OF THE BUDGET. 18% HAS TO DO WITH INTELLECTUAL, DEVELOPMENTAL, LEARNING AND PHYSICAL DISABILITIES, AND THERE'S A MISCELLANEOUS CATEGORY. BUT IF YOU ZOOM DOWN INTO THE PREGNANCY AND MATERNAL HEALTH RESEARCH PORTFOLIO, YOU CAN SEE THAT WE'RE SPENDING THE MOST MONEY ON PREECLAMPSIA BUT ALSO OTHER SIGNIFICANT AMOUNTS ON OBESITY, GESTATIONAL DIABETES, DEPRESSION, MOSTLY POSTPARTUM DEPRESSION. YOU MIGHT WONDER WHY IS PRE-TERM BIRTH NOT IN THE SLIDE. THAT WAS CATEGORIZED WITH CHILD HEALTH. THE WORK THAT WE ARE DOING HAS TREMENDOUS IMPACT, AND I'LL SHOW YOU, GEORGE MENTIONED SOME OF OUR NETWORKS. HERE WE ARE LOOKING AT IMPACT ON PRACTICE GUIDELINES, AS ONE OF OUR METRICS TO SEE, DOES THE RESEARCH THAT WE'RE DOING ULTIMATELY IMPACT UPON HEALTH. AND SO EACH OF THESE NETWORKS WAS EXAMINED, AND THE NUMBER OF PUBLICATIONS FROM THE START OF THAT NETWORK TO THE PRESENT TIME WAS EXAMINED, AND THE METRIC WAS HOW MANY OF THOSE PUBLICATIONS WERE CITED IN CLINICAL PRACTICE OR PROFESSIONAL SOCIETY GUIDELINES. AND SO I'VE CIRCLED MATERNAL-FETAL MEDICINE NETWORK BECAUSE THEY HAD 90 PUBLICATIONS, ONE OF OUR MORE MATURE NETWORKS BUT 90 PUBLICATIONS CITED IN PROFESSIONAL PRACTICE GUIDELINES, SO 25% OF THEIR TOTAL PUBLICATIONS HAVE BEEN CITED IN PROFESSIONAL GUIDELINES, SO THAT PARTICULAR NETWORK IS HIGHLY IMPACTFUL WHEN IT COMES TO THE PRACTICE OF MATERNAL-FETAL MEDICINE. YOU CAN SEE THAT THE PELVIC FLOOR DISORDERS NETWORK IS SIMILAR. THE PUBLICATIONS ARE ALSO CITED IN MORE THAN ONE GUIDELINE SO THIS TELLS US THIS TYPE OF WORK IS HAVING A CLINICAL IMPACT. AND JUST SOME PICTURES TO SHOW YOU HOW ENGAGED PEOPLE WERE DURING THESE WORKING GROUPS, THERE ARE PEOPLE WHO PARTICIPATED IN THESE MEETINGS, THEY CAN SHARE THAT INFORMATION. WE'RE STILL LOOKING FOR SOME BIG IDEAS. I CHARGED THE GROUP TO GIVE US SOME IDEAS, DON'T TELL US WHAT'S HAPPENING NOW BUT TELL US WHERE WE'RE GOING TO BE IN FIVE YEARS. WE WANT TO SKATE AS WAYNE GRETZKY SAYS TO WHERE THE HOCKEY PUCK IS GOING AND WE REALLY WANT INNOVATION. SO HERE ON THE RIGHT IS PAUL WISE AND WANDA BARFIELD TALKING ABOUT THEIR VISION FOR THEIR GREAT GREAT GRANT CHILDREN'S HEALTH AT THEIR 103rd BIRTHDAYS. ON THE LEFT WE HAD GRAPHIC RECORDERS RECORDING THE PROGRESS OF THE MEETING. FOR THOSE WHO HAVEN'T HAD A CHANCE TO PARTICIPATE IN THE STRATEGIC PLAN AT ANY TIME YOU CAN GO TO OUR WEBSITE, YOU DON'T NEED THIS WEBSITE ADDRESS, JUST GO NICHD STRATEGIC PLAN ON GOOGLE. YOU WILL SEE THE OVARY PAGE WITH AN INTRODUCTORY VIDEO. THERE'S A WEBINAR FOR THE PUBLIC. THERE'S A SITE, NICHDSTRATEGICPLAN.NIH.GOV, YOU CAN SAY I WANT TO FOCUS ON SUCH AND SUCH. WE'RE IN THE PROCESS OF WORKING WITH INTERNAL AND EXTERNAL STAFF MEMBERS WEIGHING IN ON WHAT THEIR THOUGHTS ARE. WE ARE EQUALLY WEIGHING THE WORKING GROUP, OUR INTERNAL STAFF MEMBERS AND THE PUBLIC'S COMMENTS TO COME UP WITH OVERALL THEMES. THEN THERE WILL BE A REQUEST FOR INFORMATION WHERE WE WILL ASK ANYONE WHO WANTS TO WEIGH IN ARE WE HEADED IN THE RIGHT DIRECTION, WHAT'S MISSING, WHAT ARE THE GAPS. THE REMAINING TIME I'D LIKE TO GO OVER RESEARCH INITIATIVES RELEVANT TO PREGNANCY AND PLACENTAL RESEARCH. THE HPP IS NOT OUR ONLY FUNDED OPPORTUNITY TO HAVE RESEARCH ON THE PLACENTA. WE HAVE 2018 FUNDING OPPORTUNITY ANNOUNCEMENTS, FOAs. AND THEY INCLUDE NOVEL APPROACHES TO SAFE NON-INVASIVE REALTIME ASSESSMENT OF DIRECTION ACROSS PREGNANCY, NOT A CLINICAL TRIAL. THESE ARE R01 OPPORTUNITIES, EXPLORATORY AND DEVELOPMENTAL RESEARCH GRANTS, AND THEN MOVING BEYOND STANDARD ASSESSMENTS. SO THESE ARE NEW OPPORTUNITIES FOR YOU. THE STREET LIVE RECENTLY, LAST FEW WEEKS, OUR PLACENTAL ATLAS TOOL, A WEB-BASED RESOURCE FREELY ACCESSIBLE TO ALL INTERESTED RESEARCHERS. THERE WILL BE A DEMONSTRATION OF IT TODAY. I'VE PLAYED WITH IT ONLINE. IT'S ACTUALLY REALLY, REALLY COOL. I THINK IT WILL BE ENORMOUSLY HELPFUL FOR YOUR TRAINEES AS WELL AS GETTING PEOPLE INTERESTED IN THE PLACENTA. IT RETRIEVED PLACENTAL MOLECULAR DATASETS INTO AN INTEGRATED RESOURCE AND PROVIDES ANALYTICAL TOOLS FOR SECONDARY ANALYSIS TO ENCOURAGE SYSTEMS BIOLOGY APPROACH TO PLACENTAL RESEARCH, AND FACILITATES HYPOTHESIS GENERATION, IDENTIFICATION OF POTENTIAL BIOMARKERS AND IDENTIFICATION OF POTENTIAL THERAPEUTIC TARGETS. SOME PEOPLE ON THE ADVISORY GROUP ARE IN THE GROUP, I'D LIKE TO THANK THEM FOR THEIR INPUT AND YOU WILL SEE THE FRUITS OF YOUR LABOR LATER ON TODAY AS ONE OF THE FIVE DEMONSTRATIONS. THERE ARE DIFFERENT FUNCTIONALITIES. THERE'S A DATASET EXPLORER THAT RETRIEVES PLACENTAL GENE EXPRESSION SETS BASED ON SEARCH TERM, THERE ARE ROBUST ANALYTIC TO MANIPULATE AND ANALYZE, RETRIEVE DATASETS, THE ANALYTICAL FEATURES INCLUDE GENERATION OF HEAT MAPS, PATHWAY ANALYSIS AND NETWORK RELATIONSHIPS, THERE'S AN IMAGE EXPLORER TO BROWSE AND SEARCH PLACENTAL IMAGES OF VARIOUS MODALITIES, EXACTED FROM NATIONAL LIBRARY OF MEDICINE OPEN EYE AND PATHOLOGY PROPRIETARY IMAGES. THERE'S A TAXONOMY BROWSER FROM MOLECULAR PATHOLOGY AND METADATA AND IMAGES RELATED TO PLACENTAL CONCEPTS AND THERE'S A WORKSPACE AREA THAT PROVIDES RESEARCHERS WITH A SECURE ENVIRONMENT TO SAVE, MANAGE AND ANALYZE DATA AVAILABLE THROUGH THE P.A.T. FOR SECONDARY ANALYSIS AND HYPOTHESIS GENERATION. DON'T TAKE MY WORD. PLAY WITH IT THIS AFTERNOON. I WILL BE TOO. WE HAVE PREGSOURCE, USING CROWD SOURCING TO DEFINE TYPICAL PREGNANCY. YOU MAY HAVE HEARD ABOUT THIS IN OTHER CONTEXTS BUT THIS IS AN OPPORTUNITY FOR PREGNANT WOMEN TO PROVIDE INFORMATION ABOUT THEIR REALTIME PREGNANCY EXPERIENCES, INCLUDING HOW MUCH SLEEP THEY ARE GETTING, WHETHER THEY ARE NAUSEOUS, HOW LONG THEY ARE NAUSEOUS, WHETHER THEY EXERCISE IN PREGNANCY, WEIGHT AND MEDICATIONS THEY ARE TAKING. ANSWERS TO THESE TOPICS WILL HELP RESEARCHERS BUILD A MORE COMPLETE PICTURE OF TYPICAL PREGNANCY AND DEVELOP STRATEGIES FOR IMPROVING MATERNAL CARE. SO THIS IS WHAT THE SITE LOOKS LIKE. YOU FILL IN SOME INITIAL INFORMATION AND YOU HAVE A DUE DATE, AND THEN YOU'RE ASKED HOW YOUR DUE DATE WAS DETERMINED. THERE ARE GESTATIONAL AGE APPROPRIATE QUESTIONNAIRES, AS WELL AS DEMOGRAPHICS AND OTHER HEALTH HISTORY. NOW, YOU IN THE AUDIENCE MAY BE INTERESTED IN SPECIFIC CONDITIONS THAT AFFECT DEVELOPMENT OF THE PLACENTA SO WE PICKED OUT PREECLAMPSIA, FOR EXAMPLE. SO IF WOMEN HAVE PREECLAMPSIA, THEY WILL CHECK OFF SOME OF THESE PARTICULAR BOXES HERE AND THAT WILL TRIGGER SUBSEQUENT PULLDOWN MENUS. SO FOR RESEARCHERS, RESEARCHERS CAN GO TO THE RESOURCE LIBRARY AND TYPE IN THE KEY WORD, PREECLAMPSIA, FOR EXAMPLE, AND GET REALTIME INFORMATION ON THE NUMBER OF WOMEN IN THE DATABASE WHO HAVE PREECLAMPSIA AND PERHAPS WHAT SOME MEDICATIONS ARE THAT THEY ARE TAKING. SO SPEAKING OF MEDICATIONS, WE HAVE THE TASK FORCE ON RESEARCH SPECIFIC TO PREGNANT WOMEN AND LACTATING WOMEN, WHICH WAS A TASK THAT WAS ASSIGNED TO NICHD THAT WAS INCLUDED IN THE 21ST CENTURY CURES ACT LEGISLATION IN DECEMBER OF 2017. THIS SAID NOT LATER THAN 90 DAYS AFTER THE ENACTMENT OF THE ACT THE SECRETARY OF HEALTH AND HUMAN SERVICES SHOULD CREATE THIS TASK FORCE AND THE TASK FORCE WOULD PROVIDE ADVICE AND GUIDANCE TO THE SECRETARY, SECRETARY AZAR, THAT IS, REGARDING FEDERAL ACTIVITIES, RELATED TO IDENTIFYING AND ADDRESSING GAPS IN KNOWLEDGE AND RESEARCH REGARDING SAFE AND EFFECTIVE THERAPIES FOR PREGNANT WOMEN AND LACTATING WOMEN. SO I'M PLEASED TO SAY THAT WE MADE THE TIMELINE. WE HELD FOUR MEETINGS WHICH I'LL DESCRIBE IN A MOMENT. AND IT TURNS OUT THAT THERE'S VERY LITTLE RESEARCH ON MEDICATIONS TAKEN DURING PREGNANCY AND LACTATION. AN INITIAL SEARCH OF THE LITERATURE SHOWS VERY LIMITED INFORMATION IN PREGNANCY ABOUT WHAT MEDICATIONS WERE TAKEN WERE IT WAS WORSE FOR LACTATING WOMEN, WHICH I'LL SHOW YOU IN A MINUTE. THERE'S COMPLEXITIES, AS YOU ALL KNOW, ASSOCIATED WITH PREGNANCY RESEARCH. SO THE FETUS AND THE PLACENTA ARE CHANGING OVER GESTATION. I KNOW THAT IN OUR LAB WE NEED TO -- WHEN WE LOOK AT CASES AND CONTROLS NEED TO MATCH THEM IN THE SAME GESTATIONAL WEEK BECAUSE THERE ARE SO MANY CHANGES IN GENE EXPRESSION ON ANY GIVEN DAY. THERE ARE PHYSIOLOGIC CHANGES IN THE WOMAN IN TERMS OF HER OWN DRUG METABOLISM. AND THEN THERE'S AN IMPACT OF EXTERNAL FACTORS SUCH AS MATERNAL OBESITY, OR THE ENVIRONMENT. WE ALSO NEED TO CONSIDER COEXISTING CHRONIC OR ACUTE CONDITIONS. AND LACTATION, WE NEED TO CONSIDER THE BENEFITS OF BREASTFEEDING FOR THE WOMAN AND THE BABY, VERSUS -- AND WHETHER OR NOT THE WOMAN WILL DO THAT WITHOUT TAKING HER OWN MEDICATIONS, OR SHOULD SHE TAKE THE MEDICATIONS AND THEN BE ADVISED NOT TO BREASTFEED? SO THERE'S A RISK VERSUS BENEFIT CONSIDERATION, AND THE DEFAULT HAS ALWAYS BEEN DON'T TAKE ANY MEDICATIONS BUT IF THE MOTHER DOESN'T TAKE MEDICATIONS THAT SHE NEEDS FOR HER OWN HEALTH THAT'S HARMFUL FOR HER AND MAY BE HARMFUL FOR THE BABY, PARTICULARLY IF SHE'S STILL PREGNANT. THERE ARE ALSO LIMITED ASSAYS FOR ASSESSMENT OF MEDICATIONS IN BREAST MILK AND A LIMITED PIPELINE. AND THE TASK FORCE ANALYZED THE RESULTS OF RANDOMIZED CLINICAL TRIALS AND THERE ARE VERY FEW RANDOMIZED CLINICAL TRIALS IN PREGNANCY, WHAT EXISTS, IS MAINLY RELATED TO GESTATIONAL DIABETES, TREATMENT OF HYPERTENSION, TREATMENT OF PRE-TERM LABOR, WHICH -- SORRY -- WHICH AS YOU CAN SEE HAS THE MOST BASIC SCIENCE, HAS THE MOST PHARMACOKINETICS, PHARMACO DYNAMICS, POPULATIONS AND STUDIES AND MOST RANDOMIZED CLINICAL TRIALS. IF YOU LOOK AT MENTAL HEALTH, FOR EXAMPLE, SO MANY WOMEN ARE TAKING MEDICATIONS FOR THEIR OWN MENTAL HEALTH, VIRTUALLY UNSTUDIED IN HUMAN PREGNANT WOMEN. AND VERY, VERY LITTLE IN TERMS OF PAIN AND SUBSTANCE ABUSE AS WELL. SO PART OF THIS IS CHALLENGED BY THE FACT THAT IT'S HARD TO GET DATA. WE WERE UNAWARE OF HOW MUCH MONEY WAS BEING EXPENDED ON PREGNANCY-RELATED RESEARCH BECAUSE THERE WAS NO CATEGORY. THE WAY THE GOVERNMENT REPORTS OUT TO THE PUBLIC HOW MUCH MONEY THEY ARE SPENDING ON DIFFERENT CATEGORIES IS USING SOMETHING CALLED THE RCDC CODES. THE RESEARCH CONDITION AND DISEASE CATEGORIZATION CODES. UNTIL 2017, WHEN WE WERE MANDATED BY CONGRESS TO GET THIS INFORMATION, THERE WAS NO CATEGORY FOR PREGNANCY. SO, 90% OF WOMEN HAVE AT LEAST ONE PREGNANCY IN THEIR LIFETIME. AND THESE RCDC CODES HAVE BEEN AROUND FOR A WHILE, YET THERE WAS NO CODE FOR PREGNANCY. SO, AS PART OF THIS TASK FORCE WE WERE ABLE TO ACCELERATE CREATION OF RCDC CODES ON PREGNANCY, MA TERRIBLE HEALTH, BREASTFEEDING, LACTATION AND BREAST MILK. WE CAN TRACK FROM 2017 GOING FORWARD BUT DON'T KNOW BEFORE THEN BECAUSE IT WASN'T CATEGORIZED AS SUCH. YOU CAN SEE THAT WE ARE CURRENTLY SPENDING CLOSE -- THIS IS NIH OVERALL, NOT JUST NICHD, CURRENTLY SPENDING CLOSE TO $320 MILLION IN RESEARCH ON PREGNANCY, A LITTLE BIT LESS ON MATERNAL HEALTH WHICH INCLUDES COMPLICATIONS OF PREGNANCY AND EVEN LESS ON BREASTFEEDING. AFTER FOUR TASK FORCE MEETINGS, AND ENORMOUS 400-PAGE REPORT WAS CREATED AND DELIVERED TO THE SECRETARY ON TIME AND THAT REPRESENTS THE WORK OF A LOT OF PEOPLE BUT PARTICULARLY OUR FORMER DEPUTY DIRECTOR, CATHY SPONG, WHO IS HERE IN THE ROOM, CHRISTY ROGERS AND LISA KAISER FROM NICHD AS WELL WE'RE GOING TO SPARE YOU THE 400 PAGES BUT HERE ARE THE HIGHLIGHTS. WE RECOMMENDED THERE SHOULD BE A CHANGE IN THE EXISTING CULTURE THAT HAS LIMITED SCIENTIFIC KNOWLEDGE OF THERAPEUTIC PRODUCT SAFETY, EFFECTIVENESS AND DOSING FOR PREGNANT AND LACTATING WOMEN. WE NEED TO CHANGE THE CULTURE TO PROTECTING PREGNANT WOMEN THROUGH RESEARCH INSTEAD OF FROM RESEARCH. WE ALSO RECOMMENDED WE REMOVE PREGNANT WOMEN AS A VULNERABLE POPULATION THROUGH THE COMMON RULE. THERE WAS AN EDITORIAL OR COMMENTARY IN JAMA RECENTLY THAT REALLY SPOKE TO THE FACT PREGNANT WOMEN CAN THINK FOR THEMSELVES AND DECIDE WHETHER OR NOT THEY WANT TO PARTICIPATE IN THIS RESEARCH AS WELL. YOU HEARD MS. HANLEY TALK ABOUT HER DECISION DURING HER PREGNANCY. WE NEED TO EXPAND THE WORKFORCE OF CLINICIANS AND RESEARCHERS WITH EXPERTISE IN OBSTETRIC AND LACTATION PHARMACOLOGY AND THERAPEUTICS, REMOVE REGULATORY BARRIERS, WE NEED TO MODIFY SUBPART B OF THE COMMON RULE WHICH CURRENTLY IS DIFFERENT FROM THE PEDIATRIC SITUATION WHERE ONLY THE MOTHER IS NEEDED TO GIVE CONSENT FOR HER CHILD TO PARTICIPATE IN RESEARCH. DURING PREGNANCY THE MOTHER AND FATHER ARE REQUIRED. THE FULL REPORT SHOULD YOU WANT MORE INFORMATION IS AT THIS PARTICULAR SITE BUT, AGAIN, YOU CAN GO TO NICHD AND PRGLAC, OUR ABBREVIATION. WE GOT IT TO THE SECRETARY ON TIME IN SEPTEMBER AND WE EXPECT THAT HE WILL RESPOND, EITHER ACCEPTING OUR RECOMMENDATIONS OR RECOMMENDATIONS, AND ONE OF THE RECOMMENDATIONS WAS TO DO ADDITIONAL STUDY AND PERHAPS INCLUDE NON-PHARMACOLOGIC MEDICATIONS SUCH AS HERBAL SUPPLEMENTS USED TO SUPPLEMENT MILK PRODUCTION. SO WE'RE WAITING TO HEAR FROM SECRETARY AZAR AND EXPECT TO HEAR FROM HIM AND HIS STAFF IN DECEMBER. SO THAT WOULD BE NEXT MONTH. IN SUMMARY I GAVE YOU GOOD NEWS ABOUT OUR BUDGET. WE REALLY WANT TO THANK OUR MEMBERS OF CONGRESS. WE HAVE BIPARTISAN SUPPORT FOR THE NIH IN CONGRESS. WE HAVE AN ONGOING STRATEGIC PLANNING PROCESS AND I ENCOURAGE ALL OF YOU TO WEIGH IN. WE'RE KEEPING TRACK OF ALL THE COMMENTS, AND THEY WILL BE SERIOUSLY CONSIDERED. AND I ALSO TOLD YOU ABOUT SOME OF OUR OTHER KNISH ACTIVITIES THAT -- INITIATIVES THAT ARE RELEVANT. WE LOOK FORWARD TO THE DEMONSTRATION FOR THE P.A.T. AND FOUR OTHER PROJECTS. I'M HAPPY TO TAKE QUESTIONS AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE] I WANT TO MENTION I WON'T BE HERE TOMORROW BECAUSE I HAVE TO REPRESENT NICHD IN THE COMBINED FEDERAL CHARITIES DIRECTOR'S CHALLENGE, SO EVERY YEAR THE INSTITUTES COMPETE AGAINST EACH OTHER, AND WE ARE STRONG-ARMED INTO PARTICIPATING. LAST YEAR I HAD TO TAKE LESSONS FROM MY SON ON BASKETBALL BUT I DID SCORE A BASKET. AND THIS YEAR I'M NOT GOING TO SPOIL THE SURPRISE BUT IT'S GOING TO BE SOMETHING THAT IS PROBABLY GOING TO BE EXTREMELY HUMILIATING BUT YOU'LL SEE IT TOMORROW. ALL RIGHT, SERIOUS QUESTIONS. NO QUESTIONS? YES? >> MICROPHONE. >> YES, WE NEED THE MICROPHONE. THERE ARE TWO MICROPHONES. >> DINESH SHAH, UNIVERSITY OF WISCONSIN. THE NEW R01 PLACENTA RESEARCH FUNDING ANNOUNCEMENTS WE'RE CURIOUS IF MONIES ARE SET ASIDE FOR FUNDING THOSE OR DOES IT COME OUT OF THE GENERAL POOL. >> THIS IS NOT SET ASIDE. IT COMES OUT OF THE GENERAL POOL. BUT THE RISING TIDE LIFTS ALL BOATS. SO THAT EXTRA 4% THAT WE'VE RECEIVED, YOU KNOW, THAT MEANS THAT IN THE EXTRAMURAL POOL WE'VE GOT 4% MORE MONEY. AND IT ALSO MEANS THAT IN THE TRAINING PART OF OUR BUDGET WE'VE GOT 4% MORE MONEY. >> THANK YOU. >> THAT'S IT? REALLY? COME ON. YOU CAN ASK ME ANYTHING. I ANSWERED QUESTIONS FOR 45 MINUTES ON THE INTERACTIVE WEBINAR ABOUT THE STRATEGIC PLAN. >> SO I UNDERSTAND WE'RE AT A HUMAN PLACENTA MEETING BUT HOW DO YOU VIEW THE RODENT PLACENTA AND BLENDING OF HUMAN AND RODENT WORK AND ITS FUNDING? >> GREAT QUESTION. I'M LOOKING AT APRIL ADAMS, IN MY LAB WORKING ON THE RODENT PLACENTA. SO THE RODENT PLACENTA WOULD BE PART OF OUR BASIC SCIENCE PORTFOLIO. SO IT'S NOT -- DOESN'T COME UNDER THE HUMAN PLACENTA PROJECT, EVERY MAMMAL HAS A DIFFERENT KIND OF PLACENTA. WE CAN LEARN SOME THINGS, IT'S NOT DIRECTLY -- SORRY, IT'S NOT, YOU KNOW, AN EXACT MODEL OF THE HUMAN PLACENTA BUT DOESN'T MEAN WE'RE LESS ENTHUSIASTIC ABOUT ANIMAL MODELS. SO THE -- WE WOULD ENCOURAGE ANYBODY WORKING ON ANIMAL MODELS OF THE PLACENTA TO BE APPLYING FOR INVESTIGATOR-INITIATED R01s. >> WHAT ABOUT BLENDING OF RODENT RESEARCH WITH HUMAN PLACENTA WORK IN THE SAME GRANT, IS THAT A POSITIVE OR -- >> SURE, SURE. BUT IT WOULDN'T COME UNDER THIS PARTICULAR MECHANISM, THE HUMAN PLACENTA PROJECT, BUT THAT WOULD BE A VERY NOVEL IDEA TO LOOK AT SIMILARITIES, DIFFERENCES, ET CETERA. SO WE WOULD CERTAINLY ENCOURAGE THAT. >> SO THE FOLLOW-UP TO THAT, I'VE HAD A DISCUSSION WITH DAVID IN THE PAST BUT IT'S WORTH SAYING IT HERE PUBLICLY. I'VE REVIEWED A LOT OF NICE PLACENTAL GRANTS, AND GENERALLY IN NICHD BUT ALSO IN NHLBI. THERE'S OBVIOUSLY A POSSIBILITY THERE FOR TALK WITH NHLBI ABOUT SHARING THE COST. I OBJECT TO AS A REVIEWER GENERALLY I SEE DISCONNECTED SCATTER SHOT, SHOT IN THE DARK TYPE PROJECTS WITH THE BUDGET EACH YEAR IS 3 -- $350,000, MICE COLONY. I RECOGNIZE VALUE OF MICE RESEARCH, NOT TRYING TO CONDEMN ANIMAL RESEARCH BUT IT'S TIME TO HAVE THE GROWNUP DISCUSSION ABOUT HOW CAN WE MAKE SURE THERE'S FUNDING OF A COLLECTIVE SERIES OF SUCH STUDIES THAT ARE WORKING TO A COMMON PURPOSE, RATHER THAN JUST SOMEONE SAYING HALF PERCENT LINKAGE IN THIS GENOME STUDY SO I'M GOING TO KNOCK IT OUT AND SEE WHAT HAPPENS. HALF PERCENT IS WEAK. >> THANK YOU FOR THE COMMENT. TWO THINGS. FIRST, I WANT TO MENTION OVERALL NIH IS LOOKING AT THE RIGOR AND REPRODUCIBILITY ISSUE, AND ONE OF THE THINGS THAT THEY ARE CONCERNED ABOUT IS THE REPRODUCIBILITY OF ANIMAL MODELS, PARTICULARLY RODENTS. SO THAT DOESN'T PREVENT YOU FROM SUBMITTING A PROPOSAL WITH ANIMAL MODELS BUT MAKE SURE THAT YOU HAVE APPROPRIATE NUMBERS AND MECHANISMS TO TEST REPRODUCIBILITY, AS AN OVERALL FOCUS THAT CAME OUT OF THE INSTITUTE DIRECTOR LEADERSHIP FORUM A FEW WEEKS AGO. I FORGET WHAT THE OTHER THING WAS. IT WILL COME TO ME, DEFINITELY INTEGRATION BUT I'LL REMEMBER. ANTONIO? >> I WANTED TO ASK TO GET SOME INSIGHT ON NICHD INTEREST IN SUPPORT THE BUILDING OF INFRASTRUCTURE FOR HOUSING SOME OF THE IMAGING DATA THAT WE'RE COLLECTING. IN A FORMAT THAT CAN BE UTILIZED. LIKE THE PLACENTAL OUTLETS, TOOLS, SO OTHER INVESTIGATORS CANNOT ONLY ASSESS OR RUN PROTOCOLS WITH THAT DATA BECAUSE IF THERE'S A FRAMEWORK FOR THAT, THEN WE CAN REALLY EXPAND WHAT CAN BE DONE. THIS IS REALLY AN ENGINEERING COMPUTER SCIENCE PROBLEM, IN THE WAY PLACES CAN HOST ANALYSIS PROTOCOLS AND THINGS THAT CAN BE COMPARED BETWEEN GROUPS. >> YEAH, ANOTHER GREAT QUESTION. YOU KNOW, AS YOU -- AS THE IMAGING GETS MORE DETAILED, OF COURSE THERE'S MORE REQUIREMENTS FOR STORAGE. SO, FIRST OF ALL, YOUR QUESTION BRINGS UP THE FIRST ISSUE WHICH IS AS A FIRST PRINCIPLE WE STRONGLY BELIEVE IN DATA SHARING, THAT, YOU KNOW, WE HAVE INVESTED EVERYONE'S TAX DOLLARS IN FUNDING YOUR RESEARCH. NOW EVERYONE SHOULD BE ABLE TO TAKE ADVANTAGE OF THAT. SO THAT'S ALWAYS ON OUR MIND. THAT'S WHY WE HAVE DASH, THE HUB, BUT DASH IS NOT DESIGNED TO INCLUDE IMAGING AT THIS POINT. IN PARALLEL, NIH OVERALL HAS PARTNERED RECENTLY WITH AMAZON AND WITH GOOGLE TO DEVELOP NEW WAYS OF DATA STORAGE SO WHAT I SUSPECT WILL HAPPEN IS WE WILL HAVE SOME PIECE OF THE CLOUD THAT WILL HOST THE IMAGING DATA AND WE'LL COME UP -- WE'RE NOT READY TO DO THIS YET BUT EVENTUALLY WE'LL COME UP WITH SOME SORT OF MECHANISM TO HOST DATA GENERATED, FOR EXAMPLE, FROM THE HPP IN A WAY THAT MAKES IT PUBLICLY ACCESSIBLE. I REMEMBER WHAT I WAS GOING TO SAY, WHICH IS YOU HAD MENTIONED NHLBI. I KNOW IN THE PEDIATRIC PART OF OUR PORTFOLIO WE'VE BEEN LOOKING AT HOW DO WE INTEGRATE THE WORK OF ALL OF THE INSTITUTES TO, YOU KNOW, LEVERAGE THE VOICE OF CHILDREN AND MAKE IT MORE OF A UNIFIED PERSPECTIVE THAN IT CURRENTLY IS. WE DON'T DO THAT YET FOR PREGNANCY AND MATERNAL HEALTH, AND I'M A LITTLE WARY OF TAKING ON TOO MUCH AT ONE TIME, BUT OUR TRANS-NIH PEDIATRIC RESEARCH CONSORTIUM IS ACTUALLY GOING VERY WELL, AND ONE OF THE PROJECTS THAT I THINK WILL MOVE FAIRLY QUICKLY IS CREATION OF PEDIATRIC DATA COMMONS, ADDRESSING IAN'S AND ANTONIO'S QUESTION THAT, YOU KNOW, THE SILOING OF THE INDIVIDUAL INSTITUTES SOMETIMES IS YOU COUNTER ACTIVE BECAUSE IT LISA TO DUPLICATION OF SILOING OF RESOURCES. SO IF WE CAN GET THE PEDIATRIC DATA COMMONS TO PLAY OUT WHICH WILL ALLOW, YOU KNOW, SEQUENCING DATA SETS THAT ARE PRESENTLY FUNDED BY A WHOLE NUMBER OF DIFFERENT INSTITUTES, AND THAT BECOMES A UNIFIED RESOURCE, I THINK THAT WILL GIVE US THE OPPORTUNITY TO THEN TAKE ON PERHAPS IMAGING FOR PREGNANCY AND MATERNAL HEALTH BECAUSE THAT'S A VERY IMAGING-CENTRIC AREA, IN ADDITION WE WOULD BE DOING THAT FOR A BRAIN DEVELOPMENT AS WELL. >> THIS IS ANOTHER POINT TO INTERINSTITUTE COLLABORATIONS I GUESS. I'M FROM UCLA. I DON'T GET FUNDED BY NICHD. I'M AN NIEHS INVESTIGATOR. SO THE ENVIRONMENT THAT YOU MENTIONED IS REALLY WHAT I STUDY, AND I'VE BEEN STUDYING FOR 25 YEARS AIR POLLUTION, GAVE THE KEYNOTE AT THE W.H.O. ON THIS LAST WEEK IN GENEVA FOR MATERNAL HEALTH AND CHILDREN'S HEALTH. WHAT ALWAYS PUZZLES ME IS THAT AFTER ALL THIS WORK WE'VE DONE WORLDWIDE MATERNAL HEALTH AND PREGNANCY IS NOT PART OF THE GLOBAL BURDEN ASSESSMENT FOR AIR POLLUTION, EVEN THOUGH BILLIONS OF WOMEN IN CHINA, INDIA AND AFRICA ARE SUFFERING FROM THE WORST AIR POLLUTION WE CAN IMAGINE, AND IT'S REALLY A PUBLIC HEALTH ISSUE. AND EVERY TIME I TURN AROUND AND SAY, WELL, I'VE DONE ALL THESE EPISTUDIES, BUT WHAT IS IT THAT'S MISSING, IT'S THE BIOLOGY PIECE. FOR SOME REASON, WE'RE NOT GETTING ENOUGH INFORMATION ON THE BIOLOGY OF PREGNANCY AND CAN RELATE THAT TO THE ENVIRONMENT TO MAKE THAT STATEMENT THAT WE SHOULD TAKE OUR ENVIRONMENT MORE SERIOUS. SO, AGAIN, I USUALLY GO TO NIEHS FOR MONEY BUT, YOU KNOW, THEY HAVE LIMITED RESOURCES AND HAVE TO MAKE DECISIONS HOW MUCH IS NICHD ACTUALLY INTERESTED IN THOSE KIND OF COLLABORATIONS. >> THAT'S A GREAT QUESTION. THANK YOU. SO, SOMETHING THAT OFTEN COMES UP WHEN I SPEAK TO GROUPS IS I DON'T THINK INVESTIGATORS REALIZE HOW MUCH WE COLLABORATE WITH OUR OTHER 26 INSTITUTES AND CENTERS. SO THERE'S SOME VERY NATURAL AREAS FOR COLLABORATION. THERE'S OFTENTIMES SHARING OF COST FOR BIG PROJECTS, BUT THERE'S ALSO DISCUSSION BACK AND FORTH IF ONE INSTITUTE CAN'T FUND A PROJECT THAT WAS WELL SCORED THEY WILL DISCUSS IT WITH ANOTHER ONE. NIEHS, YOU'RE ABSOLUTELY RIGHT, THEY HAVE A VERY LARGE PORTFOLIO THAT OVERLAPS IN OUR INTERESTS, BOTH IN PREGNANCY AND CHILD HEALTH. AND LINDA BIRNBAUM, THE DIRECTOR OF NIEHS, HAS BEEN HAFT AFTER ME TO COME AND TALK TO THEM. I PLAN TO DO THAT. BUT PART OF THE OVERALL VISION IS ENHANCE PARTNERSHIPS WITH OTHER INSTITUTES BUT ENVIRONMENT, CLEARLY HAS A ROLE IN PREGNANCY. SO MAYBE WE NEED TO, YOU KNOW, VERBALIZE THAT A BIT MORE. >> THANK YOU SO MUCH FOR THIS PRESENTATION. I WANT TO BRING UP SOMETHING THAT'S BEEN ON MY MIND FOR SEVERAL YEARS NOW. AND THAT'S THAT WE TEND TO DO A LOT OF WORK PRE-CLINICAL IN THE LAB. NICHD HAS BEEN VERY GOOD AT SUPPORTING THAT AS WELL AS OTHER INSTITUTES. BUT THEN I SEE LIKE A BLOCK OR A LIMITED WAY FROM GOING FROM THE PRE-CLINICAL TO THE CLINICAL BECAUSE MANY REASONS THAT ARE NOT REASONS FOR OTHER SPECIALTIES, FOR EXAMPLE, YOU KNOW, IN ONCOLOGY OR MENTAL HEALTH OR CARDIOLOGY, FREQUENTLY NIH FUNDS THE RESEARCH PRE-CLINICAL AND THEN THERE'S INDUSTRY OR SOMEBODY WHO TAKES IT TO THE CLINICAL, DOES THE LARGE TRIAL. UNFORTUNATELY, OBSTETRICAL CARE IS THE LAST FRONTIER OF CLINICAL RESEARCH, I SEE IT. SO THERE'S THIS BLOCK, AND I SEE A LOT OF PROMISING THINGS IN THE LAB THAT DON'T MAKE IT CLINICALLY. FORTUNATELY SOME DO, LIKE WE HEARD TODAY, WHICH IS REALLY A GOOD ONE BUT WHAT ARE WE DOING TO IMPROVE THIS BRIDGE, THIS GAP THAT WE HAVE TO BRIDGE, MAYBE BE IT INTERACTION OR COLLABORATIONS, OTHER INSTITUTES, WITH INDUSTRY, LOOKING AT WHAT ARE WE FUNDING CLINICALLY, SO JUST -- I KNOW YOU'RE NOT GOING TO BE ABLE TO ANSWER IT IN ONE OR TWO SENTENCES BUT JUST YOUR THOUGHTS ABOUT THAT. >> YEAH, SO YOU'RE TALKING ABOUT TRANSLATION, WHICH IS ONE OF THE THEMES OF THIS MEETING. BUT I THINK YOU'RE RIGHT. WHAT'S DIFFERENT ABOUT PREGNANCY IS IT'S TIME LIMITED, SO IT'S NINE MONTHS. IT'S NOT LIKE -- YOU KNOW CANCER IN MANY WAYS HAS BECOME A CHRONIC DISEASE WHERE PEOPLE, YOU KNOW, ARE FIGHTING IT INITIALLY AND THEN MAYBE THEY GET RESISTANCE TO THE FIRST DRUG AND THEY HAVE TO TRY ANOTHER DRUG. SO, I THINK THERE'S A PERCEPTION THAT IT'S NINE MONTHS, WE DON'T HAVE TO INVEST THAT MUCH EFFORT INTO IT. WE CAN ALL HELP TO CHANGE THAT PERSPECTIVE IN THAT, YOU KNOW, PREGNANCY AND YOUR TIME IN THE WOMB INFLUENCES YOUR ENTIRE LIFETIME OF HEALTH. AND I KNOW THIS IS SOMETHING THAT YOEL ORGANIZED AN ENTIRE CONFERENCE ON. SO, I THINK WE NEED TO COMMUNICATE BETTER THAT PREGNANCY IS NOT TIME LIMITED. IT'S REALLY LAYING THE FOUNDATION FOR A LIFETIME OF HEALTH. WE CERTAINLY WILL EXPLORE PARTNERSHIPS TO THE EXTENT THAT WE CAN. AS YOU KNOW, THAT'S ONE OF THE AREAS OF THE STRATEGIC PLANNING PROCESS, JUST AS A CAUTION NIH HAS, YOU KNOW, HAD SOME DIFFICULTY RECENTLY WITH THE ALCOHOL-INDUSTRY FUNDED MOCK TRIAL. SO THERE'S A LOT OF CONCERN ABOUT HOW TO MOVE FORWARD ON THESE PRIVATE/PUBLIC PARTNERSHIPS, BUT WE WILL EXPLORE THEM TO THE EXTENT THAT WE CAN. YOU'RE RIGHT, TRANSLATION IS AN IMPORTANT AREA. LAST QUESTION. >> TEN SECONDS. DO YOU HAVE A COMMENT ON CONNECTING THE PEOPLE IN THIS ROOM AND WHAT THEY ARE CAPABLE OF DOING TO THE MSN NETWORK? >> SO WHAT DO YOU MEAN BY THAT? >> WELL, THE EXPERTISE FOR MRI IMAGING IN PARTICULAR FOR THE PLACENTAL PROJECT IS NOT NECESSARILY IN THE HANDS OF THE PEOPLE IN THE MSN NETWORK. HAVE YOU THOUGHT ABOUT CONNECTING THEM AND CONNECTING THEM. >> THIS IS A PUBLICLY WEBCAST CONFERENCE SO I HOPE THAT PEOPLE IN THE MFN NETWORK ARE WATCHING IT, IFER THERE NOT -- >> THEY SHOULD BE. >> WE NEED TO SEND AN ANNOUNCEMENT TO THE COLLEAGUES. [APPLAUSE] >> WE WOULD LIKE TO BEGIN OUR RESEARCH TALKS. THE FIRST IS PLACENTA MULTIPARAMETRIC MRI AND POTENTIAL IMPACT OF AIR POLLUTION BY DR. DEVASKAR AND DR. SUNG. >> GOOD MORNING, EVERYONE. I WANT TO FIRST BEGIN BY THANKING THE NICHD LEADERSHIP, CATHY SPONG PREVIOUSLY AND DIANA BIANCHI RIGHT NOW FOR THE SUPPORT FOR THE WORK WE'LL BE SHOWING TODAY INCLUDNG OUR GROUP. I WOULD LIKE TO THANK DAVID WEINBERG FOR INVITING US. AND FOR AFROUZ ANDERSON WHO I JUST MET, FOR ALSO PLAYING A MAJOR ROLE OVER HERE. I WOULD LIKE TO BEGIN BY THANKING MISS HANLEY FOR SHARING HER STORY WITH US. IT IS INCREDIBLY MOTIVATING TO MANY OF US, INCLUDING ALL THE SUBJECTS THAT HAVE PARTICIPATED IN THE VARIOUS STUDIES THAT WILL BE PRESENTED HERE TODAY. SO WITH THAT, I'LL START MY TALK WHICH IS LISTED UP THERE. I WANT TO INTRODUCE THAT I'VE GOT DR. KYUNG SUNG WITH ME WHO WILL BE DOING A MAJOR PORTION OF THE PRESENTATION. WE'VE GOT CARLA JENSON FROM OB/ GYN SITTING RIGHT THERE AND BIATA RITZ, OUR EPIDEMIOLOGY EXPERT. SO, WE COMPLETED THE THIRD YEAR OF THE IMAGING INNOVATIONS RFA THAT HAD COME OUT. HYPOTHESIS CHRONIC EXPOSURE TO HIGH RATES OF ENVIRONMENTAL POLLUTION INCREASES RISK OF PLACENTAL INSUFFICIENCY DUE TO EARLY GESTATIONAL DEVELOPMENT OF ADVERSE PLACENTAL STRUCTURE AROUND FUNCTION, AS DETECTED BY MULTIPARAMETRIC MRI TECHNOLOGIC ADVANCES. SO THE AIMS WE DEVELOPED, I WON'T READ THEM, WE WANTED TO DEVELOP THESE MULTIPARAMETRIC MRI TECHNIQUES THROUGH EARLY TRIMESTERS, TO COMPARE IT TO STANDARD DOPPLER TECHNOLOGY, PARTICULARLY AS PREDICTIVE MARKER OF PLACENTAL INSUFFICIENCIES AND DETERMINE ENVIRONMENTAL TO THESE FACTORS, IMPORTANT GIVEN THE FIRES WE'RE FACING IN CALIFORNIA RIGHT NOW. IN OUR PRESENTATION, THE FOCUS WOULD BE ON THE FIRST ONE, DEVELOPMENT OF THE TECHNOLOGY, AND PERHAPS A HINT OF WHAT'S GOING ON WITH THE TOOLS THAT WE HAVE FOR THE ENVIRONMENTAL EXPOSURES. BEFORE I GET INTO THE STUDY DESIGN AS YOU HEARD FROM DR. BIANCHI ABOUT THE SILOS AT NICHD AND NIH, WE HAVE TO BREAK DOWN A LOT OF SILOS AT UCLA, AND WE BROUGHT TO BEAR MULTIPLE DEPARTMENTS, MULTIPLE SCHOOLS AS YOU CAN SEE HERE, AND MULTIPLE INVESTIGATORS TO BRING ABOUT WHAT WE WILL BE PRESENTING PRETTY QUICKLY TO YOU. THE NAMES IN RED ARE THE ONES HERE TODAY. A FEEL FOR CLINICAL STUDY DESIGN, THIS WAS PROSPECTIVE PRIOR TO COMPLICATIONS, BEGAN AS SOON AS WOMEN CAME INTO THE ANTENATAL CLINIC. WE'RE GRATEFUL TO THE SUBJECTING. A LOT OF STUDIES AND PROCEDURES WERE UNDERTAKEN. FOCUS ON THE MRIs, THE TALK THAT WILL BE PRESENTED TODAY, WE HAD TWO DONE. ONE AT 14 TO 16 WEEKS, THE SECOND ONE WAS FROM 19 TO 22 WEEKS, 20 SUBJECTS, PART OF A PILOT, ULTIMATE GOAL IS TO RECRUIT 300 SUBJECTS BASED ON POWER ANALYSIS. WE UNDERTOOK BLOOD AROUND URINE STUDIES, PLACENTAL PATHOBIOLOGY. WHAT YOU SEE ARE RED ARROWS WHICH SHOW THE TIMING WHEN THESE BLOODS WERE DRAWN AS WE LEVERAGING OMICS GRANTS THAT CAME OUT TOWARDS THE STUDY AS WELL. AND FINALLY THE ENVIRONMENTAL RISK FACTOR ASSESSMENT WAS UNDERTAKEN, FOUR SURVEYS GIVEN TO THE SUBJECTS, AND AIR MONITORS DEPLOYED TO THEIR HOMES SO WE COULD MONITOR THEIR EXPOSURE TO AIR POLLUTION ALONG WITH WHAT WAS PRESENT IN THE STATE OF CALIFORNIA AS AIR MONITORING STATIONS THAT ARE ACROSS OUR REGION AS WELL. ULTIMATELY MULTIPLE STUDIES ARE ONGOING AND JUST TO GIVE YOU A FEEL WE NOW HAVE A DATABASE ON THE CLINICAL OUTCOMES ENVIRONMENT, I'M LISTED THEM ALL THERE. WE'VE GOT PLACENTA GROSSE PATHOLOGY, A LOT OF OMICS WORK AND DNA, EPIGENETICS, AND RNA SEQUENCING EXOME AND BIOSENSOR DEVELOPMENT WHICH HAS JUST BEGUN. THE FOCUS OF OUR TALK TODAY TRULY IS ON THE IMAGING AND MRI DEVELOPMENT WHICH DR. SUNG WILL OUTLINE FOR ALL OF US. >> THANK YOU. LIKE SHERIN SAID WE'LL FOCUS ON IMAGING DEVELOPMENT. PLACENTA IS AN INTERESTING ORGAN. OVER TIME IT CHANGES THE FUNCTIONAL AND ALSO ANATOMICAL STRUCTURE AND MOTION IS ALSO CHANGING OVER TIME. SO WE HAVE TO CONSIDER THOSE CHANGES AND THE IMAGING HAS TO BE DEVELOPED BASED ON THOSE CHANGES OVER TIME. SO, OUR PLACENTA IMAGING PROTOCOL, STREAMLINE, LESS THAN 30 MINUTES, ACCOUNTS FOR PLACENTAL AND MATERNAL MOTION AND TRIED TO BE VOLUMETRIC, WE WANT A MULTI-PARAMEDIC IMAGING INCLUDING T2 WEIGHTED IMAGING, PERFUSION USING ASL AND MULTI-STAR WITH THE FREE BREATHING AND 3D VOLUMETRIC ENABLE. THIS IS AN EXAMPLE OF THE T2-WEIGHTED IMAGING, WE USE T2 HASTE TECHNIQUE WITH A NICE CONTRAST AND ALSO RESOLUTION AND HAS SOME LIMITATIONS IN THE THROUGH-PLANE RESOLUTION. WE ACQUIRED AXIAL, SAGITTAL, TO COVER ANATOMIC PLACENTA INFORMATION, TWO-MINUTE FREE BREATHING. RESOLUTION FOR IS 1 X 1 MILLIMETER. BASED ON THAT WE WERE ABLE TO MEASURE -- OH, SORRY -- WERE ABLE TO MEASURE PLACENTAL VOLUME OVER TIME, SO PARTICULARLY BECAUSE THE T2 HASTE HAD A THICK SLICE IN, MEASURE THE PLACENTAL FOR EACH ORTHOGONAL PLANE AND EVERYTHING ELSE, THE VOLUME, TO CALCULATE THE PLACENTAL VOLUME AT SPECIFIC WEEKS OF GESTATION. ANOTHER ONE IS CALLED PLACENTA PERFUSION USING ASL, ARTERIAL SKIN LABELING, IN PARTICULAR WE'RE UTILIZING THE PSEUDOCONTINUOUS ASL WHICH COMBINES ADVANTAGE OF PULSE ASL AND CONTINUOUS ASL. THE MAIN ADVANTAGE IS THE SNR, SIGNAL TO NOISE RATIO IMPROVEMENT, TWO TO THREE TIMES HIGHER. THE TECHNIQUE WE UTILIZE IN THE PLACENTA, PUT THE LABELING PLANE AT THE AORTIC BIFURCATION, THE MAIN REASON TO AVOID IMAGING PLANE, NOT ONLY THAT, IT CAN CREATE A VERY CONSISTENT LABELING POSITION. AND ALSO WE UTILIZE THE FREE BREATHING MULTI-DELAY SUED ASL TECHNIQUE WITH 3D READOUT, WE CAN ACHIEVE THE 3 X 3 RESOLUTION WITH EIGHT SLICES SO THE WHOLE POINT WITH THE 2-MINUTE FREE-BREATHING FOR EACH LABELING COULD GET A VERY VOLUMETRIC PLACENTA PERFUSION MEASUREMENT, SO EACH LABEL AND CONTROL IS ABOUT 4 SECONDS APART AND WE REPEAT 14 TIMES, TO MEASURE THE PLACENTA PERFUSION, AND THIS ABSTRACTION OF LABEL AND CONTROL CREATES CONTRAST OF PERFUSION. WE SIMULATED LABELING EFFICIENCY, CRITICAL FOR ASL MEASUREMENT ACCURACY, IT WAS ABOUT 63 OR 64%, WHICH GUARANTEES GOOD ACCURACY OF THE MEASUREMENT AS WELL. AND ALSO BECAUSE WE'RE LABELING IN MATERNAL AORTIC BIFURCATION THIS ACCOUNTINGS THE MATERNAL PERFUSION, NOT FETAL PERFUSION, SO WE CAN COMPLETELY SEPARATE THE MATERNAL AND FETAL PERFUSION DIFFERENCES. SO THIS TECHNIQUE WAS PUBLISHED, THIS YEAR'S YOUNG INVESTIGATOR AWARD FINALIST, LEFT SIDE SHOWING 3D PERFUSION IMAGING, RIGHT SHOWING MAXIMUM INTENSITY, YOU CAN APPRECIATE A VERY HETEROGENEOUS PERFUSION AND IN PARTICULAR WE'RE INVESTIGATING MORE INTO THAT BECAUSE IT LOOKS VERY INTERESTING. SO, TO LOOKING AT THE PLACENTA HETEROGENEITY, WE ACTUALLY LOOK AT THE THRESHOLDING AND ALSO PARTICULAR REGION OF INTEREST THAT HAS THE HIGH PERFUSION, AND THEN TRY AVERAGE OUT THOSE VALUES. SO THE KEY POINT HERE IS ACTUALLY PARTICULARLY LOOKING AT HIGH PERFUSION RELATED PARAMETER AND TRYING TO AVERAGE OUT, TO ACCOUNT FOR THE PLACENTA FUNCTION. ANOTHER THING IS R2* MEASUREMENT, WE CAN GET ABOUT 5 MILLIMETER, 2.2-MILLIMETER IN-PLANE RESTITUTION, FREE BREATHING, MEASURE VOLUMETRIC R2*. THE FIRST IS AROUND 14 TORE 18 WEEKS, AND THEN THE SECOND MRI IS AROUND 19 TO 24 WEEKS, AND THEN BASED ON THAT, AFTER THAT WE CAN GET THE PRIMARY BIRTH OUTCOME AND TRY TO ASSOCIATE IMAGING INTO THE BIRTH OUTCOME AS WELL. HERE ARE SOME EXAMPLES OF THE MULTIPARAMETRIC MRI, VOLUME, PLACENTA PERFUSION, R2*, AND HIGH PERFUSION-RELATED PARAMETER. AND THOSE ARE QUANTITATIVE NUMBERS LIKE I SAID, WE HAVE SCAN 1, SCAN 2 AND QUANTITATIVE FEATURES AS WELL. ALSO, WE LOOKED AT PRIMARY BIRTH OUTCOMES, SO ISCHEMIC PLACENTA DISEASE OR IPD, AND THEN IPD CONSISTS OF ANY OF FOUR FOLLOWING CONDITIONS, GESTATIONAL HYPERTENSION, PREECLAMPSIA, PRE--TERM BIRTH OR IGR, SMALL GESTATIONAL AGE, PLACENTAL ABRUPTION, OR ISCHEMIA. 118 WOMEN RECRUITED SO FAR, 13 CASES DO NOT HAVE THE TWO LONGITUDINAL MRI, 21 CASES WE DON'T HAVE EITHER BIRTH OUTCOMES OR RATING FOR BIRTH OUTCOMES. AND 10 CASES EXCLUDED BECAUSE OF ARTIFACT. 54 NORMAL AND IPD, ISCHEMIC PLACENTAL DISEASE OF 15 SUBJECTS. OUT OF 15 SUBJECTS WE HAVE ABOUT 3 IUGR AND THREE GESTATIONAL HYPERTENSION, 5 PREECLAMPSIA, AND 2 PRE--TERM BIRTH AND 3 COMBINATION OF EACH CONDITION, SOME OF THE CONDITIONS. HERE IS THE LONGITUDINAL ANALYSIS BETWEEN 16 AND 20 WEEKS OF GESTATION. YOU CAN CLEARLY SEE THAT THE PLACENTAL VOLUME CHANGES OVER TIME, VERY STATISTICALLY SIGNIFICANT, MILD BUT WE CAN SEE SOME STATISTICAL DIFFERENCES BETWEEN THE FIRST AND SECOND MRI IN PLACENTA PERFUSION. AND PLACENTA PERFUSIONING IS -- OOPS. PLACENTA PERFUSION -- OOPS, SORRY. I GUESS THIS IS SHOWING THE PERFUSION HETEROGENEITY FOR THE FIRST MRI AND THE SECOND MRI, YOU CAN CLEARLY SEE THAT THE FIRST MRI IN ISCHEMIC PLACENTAL DISEASE CASE THE PERFUSION IS MUCH LOWER THAN THE OTHER CASES, SO THIS CAN BE PURELY OCCURRED AT THE FIRST MRI AND THE SECOND MRI IT'S A LITTLE BIT LESS DIFFERENCE. SO WE ACTUALLY COMPARE THE HIGH PERFUSION-RELATED PARAMETER, PARTICULARLY LOOKING AT THE DIFFERENCE BETWEEN IPD OR ISCHEMIC PLACENTA DISEASE AND NORMAL CASES AND CAN CLEARLY SEE THAT CLEAR STATISTICAL DIFFERENCE BETWEEN TWO GROUPS AT THE EARLY STAGE, AND ALSO LATER, IT'S A LITTLE BIT LESS BUT STILL CAN FIND A VERY GOOD DIFFERENCE BETWEEN THE NORMAL AND IPD GROUP. IN THIS CASE WE'RE ACTUALLY LOOKING AT LEFT ONE IS HIGH PERFUSION RELATED PARAMETER, AND THE RIGHT ONE IS ACTUALLY MORE THE RELATIVE CHANGES IN HIGH PERFUSION RELATED PARAMETER. WE PLOT THE SCATTER PLOT FOR EACH SUBJECT. YOU CAN CLEARLY SEE THAT THE RED ONE IS THE IPD GROUP AND BEHAVES DIFFERENTLY THAN THE NORMAL SUBJECTS. PARTICULARLY AS I SAID BEFORE THOSE EARLY GESTATION, 16 WEEKS OF GESTATION, AND IPD GROUP IS COMPLETELY DIFFERENT FROM THE NORMAL SUBJECTS. AND ALSO WE LOOKED AT EACH ABNORMAL PREGNANCY PARTICULARLY DIFFERENCE BETWEEN NORMAL AND IUGR OR SGA OR NORMAL VERSUS GESTATIONAL HYPERTENSION OR PREECLAMPSIA, AND NORMAL VERSUS PRE--TERM BIRTH. INTERESTINGLY, WE CAN SEE SOME GROUPING AND BEHAVING DIFFERENTLY, BUT UNFORTUNATELY WE DON'T HAVE ENOUGH NUMBERS TO CONCLUDE AT THE MOMENT BUT IT'S VERY INTERESTING KIND OF OBSERVATION AT THE MOMENT. WE ALSO LOOK AT THE FETAL SEX AND ALSO PLACENTA POSITION, JUST LOOKING AT NORMAL PREGNANCIES ONLY, WE DON'T REALLY SEE ANY DIFFERENCES IN PLACENTA PERFUSION, FEMALE OR MALE OR ANTERIOR OR POSTERIOR PLACENTA. WE LOOK SPATIAL HYPER GENETY, CLASSIFY BETWEEN NORMAL AND IPDING WITH HIGH CURVE, AREA UNDER CURVE WAS GOOD IN TERMS OF SEPARATION BETWEEN NORMAL AND IPD SO IN THIS CASE WE WERE USING A T2 AND PERFUSION IMAGING. IN PARALLEL LOOKED AT AIR POLLUTION MONITORING, PARTICULARLY EACH SUBJECT HAS PURPLE AIR SENSOR, INDOOR AND OUTDOOR. WE'RE MONITORING BOTH INDOOR AND OUTDOOR AIR POLLUTION. IF YOU LOOK AT THIS MAP, SO THE PURPLE AIR COMPANY PROVIDED OUTDOOR MONITORING AND ALSO PURPLE TRIANGLES ARE SHOWING THAT THE SUBJECT THAT HAS THE PURPLE AIR MONITORING AND WE CAN MONITOR INDOOR AND OUTDOOR AIR POLLUTION. HERE IS AN EXAMPLE OF THE -- THAT THE INDOOR AIR POLLUTION IS HIGHER THAN OUTDOOR, PARTICULARLY THE HOUSEHOLD CHARACTERISTICS, THERE'S NO VENT IN THE KITCHEN, THERE'S A SMOKER IN THE HOUSE. OCCASIONALLY HIGH PEAK IN BLUE LINE, INDOOR AIR POLLUTION. IT CREATES MORE AIR POLLUTION THAN THE OUTDOOR. ANOTHER EXAMPLE IN THIS CASE OUTDOOR AIR POLLUTION IS HIGHER THAN INDOOR. THE HOUSEHOLD, THERE'S NO VENT, ALSO NO SMOKERS, BUT INTERESTINGLY THIS IS DECEMBER 2017, AND YOU CAN SEE THAT IT WELL CORRELATES WITH THE SOUTHERN CALIFORNIA WILDFIRES, INTERESTING OBSERVATION AS WELL. ASSOCIATION BETWEEN IMAGING AND INDOOR AND OUTDOOR AIR POLLUTION. SO, WITH THAT, WE ACTUALLY DEVELOPED A PLACENTAL MULTIPARAMETRIC MRI INCLUDING VOLUME PERFUSION AND ALSO R 2 STAR, OUR OBSERVATION SHOWS INTERESTING BEHAVIOR, CLEAR DIFFERENCE BETWEEN THE IPD AND NORMAL GROUP, AND THIS DEVELOPMENT IS WELL SHARED WITH OTHER GROUPS, INCLUDING SHARING WITH UNIVERSITY OF WISCONSIN, AND PERFUSION IMAGING WITH OREGON HEALTH SCIENCE UNIVERSITY, AND R2* MAPPING, THEY CAN REQUEST THROUGH AND GET THE R2* MAPPING AS WELL. THIS IS PRETTY MUCH OPEN FOR EVERYONE. WHOEVER WANTS THAT WE'RE HAPPY TO SHARE THE INFORMATION TOGETHER. WITH THAT, WE ACTUALLY DEVELOPED THE PLACENTA PERFUSION AND ALSO AIR POLLUTION MONITORING, NEXT STEP HAS TO BE THE ARTIFICIAL INTELLIGENCE. TO DO THAT, TO MY MIND, THE STANDARDIZED IMAGING DATA SET AND DATA SHARING IS KEY, ALSO THE CLEAR DEFINITION OF THE ABNORMAL PREGNANCIES ARE VERY IMPORTANT, NOT ONLY THAT I THINK THE MAIN LIMITATION OR THE MAIN REQUIREMENT FOR THE ARTIFICIAL INTELLIGENCE IS THE NUMBER OF THE DATASETS SO WE NEED TO INCREASE NUMBER OF DATASETS AND ONCE YOU HAVE THAT DEFINITELY CAN HAVE THE -- CAN BUILD THE ARTIFICIAL INTELLIGENCE TO PREDICT THE ABNORMAL PREGNANCIES. SO THANKS. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> SO QUESTIONS FROM THE AUDIENCE? WE'D BE HAPPY TO TAKE QUESTIONS, AND OUR COLLABORATORS MIGHT EVEN HELP US WITH SOME OF THE ANSWERS. >> IAN BIRD, WISCONSIN, NICE DATA AND NICE TO SEE THE GROUP OF PREGNANCIES WHERE YOU'RE SEEING IUGR, THE LOWER LOWER PERFUSION AT THE BEGIN. DO YOU HAVE ANY INFORMATION ON THE BLOOD WORK? DO YOU HAVE ANY MARKERS OF HYPOXIA OR INFLAMMATION OR OTHER ENVIRONMENTAL IRRITANTS REFLECTED IN THE BLOOD WORK? >> YEAH, SO THAT'S IN PROGRESS. I THINK WE'LL HAVE THAT INFORMATION PRETTY SOON. SINCE IT WAS NOT PART OF THE PRESENTATION TODAY, WE HAVEN'T BROUGHT IT HERE. >> I THINK I SAW PATHOLOGY ON THERE, FROM UC SAN DIEGO. I WANTED MAKE SURE, YOU HAVE A CATEGORY OVER THERE OF IUGR, WITHOUT PREECLAMPSIA IT'S A CLINICAL CATEGORY HAVE YOU BUT CONSIDERING OTHER PATHOLOGICAL FINDINGS THAT MAY NOT BE NOTED. >> YES, THANK YOU FOR THAT QUESTION. WE'RE ACTUALLY VERY MUCH TUNED INTO THAT, LOOKING AT MILLETUS. >> A QUESTION BETWEEN CONTROL AND EXPERIMENTAL GROUP, WHY DO YOU THINK THERE'S A DIFFERENCE EARLY ON VERSUS LATER IN THE DEVELOPMENT USING METRICS FOR PERFUSION? >> DO YOU WANT TO ANSWER THAT? >> THE ANSWER IS WE DON'T KNOW YET BUT DEFINITELY IT SEEMS LIKE THERE ARE SOME COMPENSATION GOING ON DURING PARTICULARLY FROM 16 TO 20 AND LATER. WE SAW A COUPLE CASES WITH HIGHER PERFUSION BUT LATER IT GOES DOWN, LOWER, AND GOING UP. SO DEFINITELY WE NEED MORE CASES CONCLUSIVE BUT THERE'S SOMETHING GOING ON. >> IF I MAY ADD TO THAT, I THINK IF THAT PANS OUT WITH MORE NUMBERS, IT DOES PROVIDE A WINDOW FOR ANY PLANNING OF INTERVENTIONS AS YOU JUST HEARD FROM THE SADI GROUP. >> ONE LAST QUICK FOLLOW-UP, ARE THERE ANY PLANS LOOKING AT ADDITIONAL TIME POINTS THROUGHOUT GESTATION? >> WE'D LOVE TO DO IT. IT ALL DEPENDS ON WHETHER THE FUNDING ALLOWS OR THE FUTURE BUDGET ALLOWS. >> THANK YOU VERY MUCH. >> FROM NICHD, VERY NICE WORK. A FOLLOW-UP ON THE SAME LINE OF THOUGHT, I ALSO WAS INTERESTED BY HOW DIFFERENT IN THE LATER AND SECOND STUDIES YOU DID. WERE THERE CORRELATIONS BETWEEN THE CHANGES IN THE BLOOD AND THE BABY'S OUTCOME? ARE THEY STILL PREGNANT, DO YOU KNOW WEIGHTS? >> YEAH, SO WE ARE FOLLOWING THOSE INFANTS IN OUR STUDY, AND I WOULD VENTURE TO SAY MANY WERE IUGR, SO BUT THE NUMBERS ARE SMALL AT THIS POINT. >> THANK YOU. >> HI, LUISE, UCSD. IN TERMS OF WHAT YOU'RE SEEING, IS IT MATERNAL PERFUSION ON THE MATERNAL SIDE, FETAL, BOTH, HOW CAN YOU TELL? CAN YOU DISTINGUISH? >> I'LL HAVE KYUNG ANSWER THAT. >> THIS IS BASED ON P CASTLE, SO WE DON'T TAG ANYTHING ON THE FETAL, PURELY MATERNAL. SOME TECHNIQUES ARE MIXED, BUT OUR TECHNIQUE IS NOT. >> OKAY. DOES IT MAKE SENSE TO DESIGN SOMETHING THAT YOU CAN KIND OF SUBTRACT OUT, IS THAT POSSIBLE? >> WHAT DO YOU MEAN? >> COULD YOU IMAGINE A TECHNIQUE WHERE YOU COULD POTENTIALLY LOOK AT THE TOTAL PERFUSION, MATERNAL TO TRACK IT OUT -- >> IF YOU'RE INTERESTED IN FETAL PERFUSION, IT IS POSSIBLE, ALTHOUGH THE ASL TECHNIQUES ARE VERY VARIOUS I WOULD SAY SO I'M NOT SURE IT'S GOING TO BE EASILY SUBTRACTIBLE. ALTHOUGH-- ANOTHER TECHNIQUE CAN COMBINE MATERNAL AND FETAL PERFUSION TOGETHER BUT THAT'S NOT PURELY A PLUS B AND WE'RE PLEASURING A. >> THANK YOU. >> I'M SORRY, WE HAVE TO GO WITH THE SCHEDULE. ALL RIGHT. THANK YOU VERY MUCH FOR A GREAT TALK. THE NEXT SPEAKER IS DR. SLED, THE TITLE IS WAVE REFLEX IN THE UMBILICAL ARTERY. >> THANK YOU FOR THIS OPPORTUNITY TO PRESENT OUR WORK ON WAVE REFLECTION AND UMBILICAL ARTERY, ONE OF THE YEAR ONE GRANTS. THE MOTIVATION FOR THIS WORK WAS THE USE OF DOPPLER ULTRASOUND AS SCREENING TECHNIQUE TO LOOK FOR PREGNANCIES WHICH ARE AT RISK OF GROWTH RESTRICTION, AND THE MOTIVATION IS THE OBSERVATION THAT THESE WAVE FORMS CAN BE ASSOCIATED WITH PLACENTAL PATHOLOGY, AND SO WHEN AN OBSTETRICIAN LOOK AT THE DOPPLER ULTRASOUND WAVE FORMS RATHER THAN FOCUSING ON TOTAL THEY WOULD LOOK AT THE SHAPE OF THE WAVE FORM, PARTICULARLY ASKING WHAT THE PEAK SYSTOLIC VELOCITY WAS, END DIASTOLIC AND TAKE A RATIO TO MEAN VELOCITY AND REPORT PULSEATILITY INDEX, YOU IN HEALTHY PLACENTA YOU EXPECT A WELL DEVELOPED VASCULAR NETWORK DOWNSTREAM, PATHOLOGIC PLACENTAS HAVE LONG STRINGILY VILLI, ASSOCIATED WITH ANOTHER PATTERN, ABSENCE OF END DIASTOLIC FLOW, YOU CAN HAVE A USEFUL METRIC DOWNSTREAM. THERE HAVE BEEN A NUMBER OF HEMODYNAMIC EXPLANATIONS PUT FORTH AS TO WHY THERE SHOULD BE THIS RELATIONSHIP BETWEEN THE SHAPE OF THE WAVE FORMS AND THE PLACENTAL MORPHOLOGY. ONE OF THE MORE INTRIGUING IS THE IDEA WHAT WE'RE ACTUALLY SEEING IS REFLECTION PHENOMENA. IN THIS IDEA, WE HAVE THE FETAL HEART WHEN IT CONTRACTS, GENERATES A PRESSURE PULSE, TRAVELS THROUGH CIRCULATION DOWN THE UMBILICAL ARTERY FASTER THAN THE BLOOD IS TRAVELING. WHEN THE PRESSURE PLUS REACHES PLACENTA IT COMES BACK UP, WE'RE SEEING SUPER POSITION OF THESE TWO WAVES, ESSENTIALLY FORWARD WAVE IN DARK GREEN, TRAVELING DOWN THE ARTERY, SHORT TIME LATER THERE'S REFLECTED WAVE, AND WHEN YOU ADD THOSE TOGETHER IF THIS REFLECTED WAVE IS SIGNIFICANT YOU MIGHT SEE AN ABSENCE OF END DIASTOLI PHILOSOPHY. IF WE HAD A WAY OF OBSERVING THIS REFLECTED WAVE DIRECTLY, IT MIGHT BE MORE SPECIFIC TO WHAT'S GOING ON IN THE PLACENTA BECAUSE REFLEXES ARE PRESUMABLY OCCURRING IN THE PLACENTA. THIS IS THE BEGINNING OF OUR STORY. TO GET STARTED WE LOOKED FIRST IN THE MOUSE, WE CAN MEASURE UMBILICAL ARTERY, DOPPLER WAVE FORMS, HIGHER FREQUENCY OF ULTRASOUND, PLAUSIBLE LOOKING PULSATION PATTERN THAT CHANGES AS GESTATION PROGRESSES. AND SO OUR IDEA TO GET BEYOND JUST LOOKING AT WAVE FORMS WAS TO THINK ABOUT HOW THEY AROSE, AND SO FOR THIS OUR IDEA WAS TO MAKE TWO MEASUREMENTS. WE RECORD VELOCITY AS WE DID BEFORE, PROPOSING THIS CONSISTENT WITH THE FORWARD AND REFLECTED WAVE AND LOOKED AT DIAMETER AS A FUNCTION OF TIME. WE EXPECT IT TO PULSATE AS IT PASSES BY AND BECAUSE OF THE PHYSICS OF HOW THE WAVES REFLECT, EXPECTATION IS A PRESSURE PULSE WOULD BE A POSITIVE WAVE IN CASES WHERE THE VELOCITY WAVE IS NEGATIVE. AND SO WHEN WE LOOK AT THE PULSE ATION OF THE ARTERY, EXPECT TO SEE A DIP IN VELOCITY, EXPECT A LUMP IN DIAMETER WAVE FORM, CROSS-SECTIONAL AREA. OUR IDEA IF WE PUT TWO MEASUREMENTS TOGETHER, IF THE TWO WAVE FORMS DIDN'T LOOK THE SAME THERE MUST BE A REFLECTION. TO GIVE A SENSE OF THE DATA, HERE IS THE MEASUREMENTS OF THE DIAMETER AS A FUNCTION OF TIME AMENDER BY N MODE ULTRASOUND, YOU CAN SEE ACCELERATION, DECELERATION OF BLOOD FROM SPECKLE PATTERNS CHANGEE HERE IS CORRESPONDING VELOCITY MEASURED BY DOPPLER, COMBINE TOGETHER TO COME UP WITH COMMON FLOW WAVE FORM WHICH WE DECOMPOSE INTO THIS FORWARD REFLECTED WAVE AND SUMMARIZE THAT HERE AS REFLECTION COEFFICIENT, PEAK TO PEAK AMPLITUDE OF WHAT'S REFLECTED COMPARED TO PEAK TO PEAK AMPLITUDE OF WHAT WAS DEVELOPED BY THE FETAL HEART. TO TRY AND ASK THE QUESTION, WELL, ARE THESE PRESENT IN THE MOUSE, WE WENT ON AND DID A PROOF OF CONCEPT STUDY, LOOKED AT TWO STRAINS OF MICE WHERE WE KNEW THAT THE ARCHITECTURE OF THE PLACENTA DIFFERED IN LATE GESTATION AND MEASURED VELOCITY AND DIAMETER, USED ULTRASOUND PROBES, EIGHT TIMES HIGHER THAN THE CLINIC, BETWEEN 8 AND 14 FETUSES IN THE GROUP. ONE THING THAT SURPRISED US REFLECTIONS WERE COMMON, ALMOST EVERY MOUSE THAT WE LOOKED AT HAD A SIGNIFICANT REFLECTION ON THE ORDER OF 35 TO 50%, AND THAT THEY WERE VERY CONSISTENT AT THE EARLY GESTATION BUT THERE WAS A DIVERGENCE IN LATE GESTATION, FITTING WITH THINGS WE ALREADY NEW, THERE WAS A GROWTH SPURT IN UMBILICAL ARTERY OR FETAL PLACENTAL ARTERY, YOU CAN GET A SENSE OF THAT FROM THESE MICRO CT IMAGES. THE OTHER THING THAT INTERESTED US THE DELAY BETWEEN THE FORWARD WAVE AND ARRIVAL OF THE REFLEX WAS LONG HERE ON THE ORDER OF 50 MILLISECONDS IN MOUSE, IT TAKES A FEW MILLISECONDS, MUST MEAN REFLECTION IS COMING FROM DEEP WITHIN THE PLACENTA. WITH THIS DATA IN HAND WE ASKED A MORE CLINICALLY FOCUSED QUESTION, WHAT IF WE HAD A PATHOLOGICAL PLACENTA AND TURNED TO THE MODEL WHICH WE LOOKED AT PREVIOUSLY WHERE WE USED COMBINATION ANTIRETROVIRAL THERAPY USED IN TREATMENT OF HIV, CONCOMITANTLY PRESCRIBED TO WOMEN WITH HIV, THIS WOULD LEAD TO ABNORMAL PLACENTA, PUT MOUSE ON A DIET USING A COMMON COCKTAIL OF DRUGS THAT TRIED TO SIMULATE WHAT A WOMAN MIGHT BE EXPOSED TO AND SO AGAIN WE LOOKED AT MICE AT 125 R. 15 15 -- AT 15 1/2 AND 17 1/2, ABOUT 18 DAYS, WE LOOKED AT VASCULAR ARCHITECTURE OF PLACENTAS, BETWEEN 11 AND 24 FETUSES PER GROUP. AND SO WHEN WE COLLECTED THE FETUSES AND PLACENTAS, WE SAW THAT FETUS IS GROW WITH GESTATIONAL AGE BUT THERE'S A SIGNIFICANT REDUCTION IN FETAL WEIGHT, CAUSED BY EXPOSURE TO THESE DRUGS. THERE'S ALSO A REDUCTION IN THE WEIGHT OF THE PLACENTA, AND SOMETHING THAT WE HAD NOT ANTICIPATED WAS THERE WOULD ALSO BE A THICKENING OF THE UMBILICAL ARTERY WALL, CAUSED BY THIS EXPOSURE. SO, FROM THERE WE LOOKED AT OUR ULTRASOUND MEASUREMENTS, WHEN WE RECORDED REFLECTION WE SAW AS WE HAD IN THE PREVIOUS STUDY THAT REFLECTION ROSE AS GESTATION PROGRESSED, BUT THAT IT ROSE BY GREATER AMOUNT IN THESE EXPOSED ANIMALS SO REACHING AT THE LAST TIME POINT REFLECTION ARTERY AT 50% OF FORWARD WAVE. THE OTHER THING WE OBSERVED IS THE TIME DELAY FOR THIS WAVE TO RETURN GOT SHORTER WHICH MIGHT BE CONSISTENT WITH THE THICKENING OF THE UMBILICAL ARTERY WALL. AND CONTRARY TO OUR EXPECT, PULSATILITY WENT DOWN, IT WAS LOW IN THIS EXPERIMENT. WE ASKED WHAT PLACENTAS LOOKED LIKE, LIGHTER, SMALLE REFLECTED IN THE VASCULAR VOLUME SO EXPOSED HOUSE HAD SMALLER VASCULAR VOLUME BUT MORE COMPLEX PLACENTA, YOU CAN SEE IT IN THE PICTURE, COLOR CODED BY DIAMETERS, ADDING ON THE ORDER OF A THOUSAND VESSEL SEGMENTS BY EXPOSURE TO THIS DRUG, SMALLER BUT MORE COMPLEX PLACENTA. SO WITH THESE TWO TIMES OF DATA IN HAND WE WENT ON AND ASKED THE QUESTION, SO, WHAT IS THE CONNECTION BETWEEN THESE FLOW WAVE FORMS WE'RE OBSERVING AND STRUCTURE OF THE PLACENTA? THIS IS THE COMPLICATED QUESTION. WE HAD SOME INTUITION. ONE OF THEM IS THAT THE THEORY PREDICTED WHEN BLOOD HAS HAD SPEEDUP OR SLOWDOWN THAT'S A POINT REFLECTION IS GENERATED, SO WE ASKED THE QUESTION AS THE UMBILICAL ARTERY ENTERS INTO THE PLACENTA AND BRANCHES INTO THE PLATE VESSELS DOES THE DOWNSTREAM CROSS-SECTIONAL AREA OF BRANCHES EXCEED UPSTREAM CROSS-SECTIONAL AREA OF UMBILICAL ARTERY, IF IT DID THE BLOOD WOULD NEED TO SLOW DOWN OR IF IT WAS SMALLER WOULD NEED TO SPEED UP AND IF THEY WERE MAGNIFIED THERE WOULD BE NO CHANGE. AND SO WHEN WE PLOTTED REFLECTION COEFFICIENT VERSUS THIS AREA RATIO, WE OBSERVED A U-SHAPED PATTERN, ESSENTIALLY WHEN AIR OF RATIO IS 1, FOR LARGER AND SMALLER RATIOS WE SEE ELEVATED REFLECTION. SO, THIS WAS ENCOURAGING. BUT I KNOW THAT ONLY EXPLAINS 35% OF THE VARIATION IN OUR REFLECTION COEFFICIENT SO I THINK THERE'S A LOT MORE TO DISCOVER ON THIS FRONT AND WE HAVE A POSTER HERE TODAY THAT'S PRESENTED BY LINDSAY, SPEAK TO HER ABOUT THIS WORK. LET'S RETURN TO THE QUESTION OF THE HUMAN. WE THOUGHT THERE MUST BE THE SIMILAR PHENOMENA WE COULD MEASURE IN HUMAN PREGNANCY. THERE ARE SOME CHALLENGES BECAUSE OUR IDEA THAT WE COULD OBSERVE PULSATIONS IN THE UMBILICAL ARTERY DOESN'T WORK WITH CLINICAL ULTRASOUND, DOESN'T HAVE THE RESOLUTION TO SEE THE ARTERY PULSE. BUT THERE ARE OTHER DIFFERENCES THAT ARE QUITE IMPORTANT BETWEEN THE MOUSE AND HUMAN, ONE IS THAT THE HUMAN UMBILICAL CORD IS LONG, THAT PULSE COULD TRAVEL DOWN THAT UMBILICAL ARTERY IN THE MOUSE IN 2 MILLISECONDS, IT WOULD TAKE 10 TO REVERSE THE HUMAN ARTERY, PERHAPS WE COULD UNDERSTAND WHERE THERE WAS REFLECTIONS IN THE HUMAN UMBILICAL ARTERY BY LOOKING AT DIFFERENT PLACES. IF WE LOOK AT THE FETAL END OF THE CORD, WHERE THERE'S A RELATIVELY LONG DELAY, FORWARD WAVE ARRIVES FIRST, REFLECTION LATER, THESE WOULD COMBINE TO CREATE THIS PULSATILE WAVE FORM. AT THE PLACENTAL SIDE YOU SHOULD GET A MORE SMOOTH WAVE FORM THAT'S LESS PULSATILE, OUR IDEA FOR HOW TO DETERMINE WHETHER THERE'S REFLECTION OR NOT WE COLLECT DATA SETS AND USE COMPUTER ALGORITHM TO ESTIMATE A FORWARD AND REFLECTED WAVE THAT COULD EXPLAIN ALL OF THESE DATA. AND SO TURNS OUT THIS PROBLEM IS SOLVABLE IF YOU HAVE THREE MEASUREMENTS, JUST ENOUGH TO CONSTRAIN ALL OF THE FREE PARAMETERS. ADDITIONAL COMPLEXITY, UNLIKE THE MOUSE, THE HUMAN HAS TWO UMBILICAL ARTERIES. YOU GO MEASURE BY ULTRASOUND YOU'RE NEVER SURE WHAT YOU'RE LOOKING AT, IN ADDITION TO FIGURING OUT WHAT WAVE FORMS EXPLAIN THIS DATA WE HAD THIS PERMUTATION PROBLEM TRYING TO DECIDE WHICH COMBINATIONS OF MEASUREMENT FIT TOGETHER. WE HAVE AN ALGORITHM THAT ADDRESSES THAT, A POSTER IS PRESENTED BY GREG TODAY ABOUT THIS METHODOLOGY. I'LL SHOW YOU WHAT WE SAW WHEN WE APPLIED IT. HERE IS TWO EXAMPLES WE LOOKED AT. ONE WAS EXAMPLE WHERE THE DIASTOLIC FLOW WAS RELATIVELY HIGH, AND HERE AS WE MOVE FROM THE FETAL END OF THE CORD TO THE PLACENTAL END THE WAVE FORMS LOOK ALMOST THE SAME, THAT'S BORNE OUT BY OUR CALCULATION. HERE'S THE ESTIMATE FORWARD WAVE AND THEN NEARLY NEGLIGIBLE CORRESPONDING REFLECTION. BUT A DIFFERENT CASE WE LOOKED AT WAS ONE WHERE WE SAW LOW DIASTOLIC VELOCITY AT FETAL END, HIGHER DIASTOLIC AT THE PLACENTAL END. EXPLAINED BY OUR MODEL, WE HAD TO GENERATE A WAVE FORM WHERE WE HAVE A FORWARD WAVE AND REFLECTED WAVE, WHICH IS QUITE SIGNIFICANT MAGNITUDE AND DELAY SO THE TWO COMBINE TO CREATE THIS CHANGE IN DIASTOLIC VELOCITY, AN INTERESTING CASE BECAUSE FOUR DAYS AFTER WE LOOKED AT THIS WOMAN, THE BABY WAS DELIVERED, AND PLACENTAL PATHOLOGY WAS DONE, THERE WAS EVIDENCE OF MATERNAL VASCULAR MAL PERFUSION, WE THOUGHT WE'RE ON THE RIGHT TRACK. WE WENT ON AND CONDUCTED A STUDY TO ASK HOW COMMON ARE THESE REFLECTED WAVE FORMS IN HUMAN PREGNANCY AND CAN WE RELIABLY MEASURE THEM SO FOR THIS RECRUITED 95 WOMEN IN TORONTO AND IN BALTIMORE BETWEEN 25 AND 37 WEEKS GESTATION, AND WE HAD TO PLACE FAIRLY STRINGENT CRITERIA ON QUALITY OF THE DATA TO MAKE SIX MEASUREMENTS, THEY HAVE TO BE CONSISTENT, WE COULDN'T HAVE FETAL HEART RATE VARY, SO BY THE TIME WE PLOTTED RESTRICTIONS WE WERE LEFT WITH 77 WOMEN WHOSE DATA SETS WE COULD WORK WITH, AND THAT GAVE US 130 ARTERIES THAT WE COULD ACTUALLY ANALYZE. WHEN WE TOOK 130 ARTERIES AND APPLIED WAVE REFLECTION MODEL TO THEM, WE COULD FIT 93 OF THOSE 130 ARTERIES, SO 72%, TO WITHIN 1.5% ACCURACY SO VERY HIGH DEGREE OF PRECISION AND EXPLAINING THE DATA BY THIS WAVE REFLECTION PHENOMENON. IF WE RELAXED CRITERIA COULD FIT A LARGER PROPORTION OF DATA. WE WERE INTERESTED IN WHETHER THE MOST OBVIOUS ALTERNATIVE HYPOTHESES WITH PLAUSIBLE. ONE FLOATED WAS VARIATIONS COULD BE JUST EXPLAINED BY THE VISCOUS ELASTIC PROPERTIES, LOSING ENERGY AS THEY MOVE DOWN THE CORD. PUT TO THE TEST, NONE OF THE DATA COULD BE EXPLAINED BY THAT MODEL. SO WE FELT STRONGLY THAT THIS WAS REALLY A WAVE REFLECTION PHENOMENON WE WERE OBSERVING. SO ONE OF THE THINGS WE WANTED TO KNOW, WHAT'S THE CONNECTION BETWEEN THIS AND THE PULSEATILITY INDEX? HERE ARE THE DATA. HERE ARE MEASUREMENTS MADE, TWO ARTERIES MEASURED, CONNECTED BY A LINE. THERE'S A RELATIONSHIP BETWEEN THE TWO. SO THE WEAK NEGATIVE RELATIONSHIP BETWEEN THE FETAL AND PULSEATILITY COULD INEXPLAIN SOME VARIATION. THERE'S LOTS OF EXAMPLES ON THE LEFT OF WHERE THE REFLECT COEFFICIENT IS NEGATIVE, CORRESPONDING TO THIS CARTOON WHERE WE HAVE A NEGATIVE REFLECTED WAVE. HALF THE DATA POINTS ON THE RIGHT SIDE CORRESPOND TO POSITIVE REFLECTION, MEANING REFLECTED WAVE FORM WHERE IT RISES RAPIDLY AND FALLS OFF. THIS CAUSED US TO RETHINK. INITIALLY I SAID THAT IN OUR EXPECTATION WAS THAT THE COMBINATION OF THESE WAVES AT THE FETAL END WOULD CAUSE PULSEATILITY TO GO UP AND PLACENTAL END TO BE DECREASED, A POSITIVE WAVE, THE EFFECT OF POSITIVE WAVE WOULD TEND TO SMOOTH WAVE FORMS, WHEREAS THE FETAL END -- OR PLACENTAL END THE OPPOSITE EFFECT, PULSEATILITY GOES UP. WE LOOKED AT PULSEATILITY INDEXES, WE SUBTRACTED PULSEATILITY INDEX AT THE FETAL END FROM PLACENTAL END, ASKED HOW THAT WOULD RELATE TO REFLECTION COEFFICIENT. WE SEE VERY STRONG RELATIONSHIP, REFLECTION COEFFICIENT EXPLAINED 79%. REFLECT COEFFICIENT IS CHALLENGING TO MEASURE, WHEREAS THE DIFFERENCE IN PULSEATILITY BETWEEN THE TWO ENDS IS A METRIC THAT COULD BE MEASURED IN ANY OBSTETRIC CLINIC, SO IT'S POTENTIALLY INTERESTING AS A BIOMARKER. AT THE SAME TIME REFLECTION IS MORE THAN JUST THIS REFLECTION COEFFICIENT, THERE'S LOTS OF DATA, WE DON'T KNOW WHAT IT MEANS BUT SOME PIECES ARE STARTING TO FIT TOGETHER. I'D LIKE TO CONCLUDE. I HOPE I PERSUADED YOU WAVE REFLECTIONS ARE PRESENT IN THE UMBILICAL ARTERY, WE BELIEVE THEY WERE RELATED TO MORPHOLOGY OF PLACENTAL ARTERIES, AT THIS POINT WE DON'T KNOW WHERE WITHIN THE PLACENTA REFLECTIONS ARE COMING FROM AND I MEAN IN PRACTICE THATTER LIKELY COMING FROM EVERYWHERE BECAUSE EVERY BIFURCATION SHOULD GENERATION SUCH A REFLECTION. WE DON'T KNOW IS THERE A CONNECTION BETWEEN THIS AND PLACENTAL PATHOLOGY, WE'RE DETERMINED TO FIND OUT. WE HAVE A LONGITUDINAL STUDY STUDYING WAVE REFLECTION AND HOPE TO PROVIDE IN THE FUTURE INSIGHT WHETHER THIS IS A NEW DIAGNOSTIC PROCEDURE OR JUST AN INTERESTING UNDERSTANDING OF HOW THE PLACENTA WORKS. EITHER WAY, WE WILL HOPEFULLY REPORT BACK IN THE NEAR FUTURE. AND SO WITH THAT I'D LIKE TO THANK MANY PEOPLE, INCLUDING MY COLLEAGUES, CHRIS McGOWAN, MATT WHO LED HUMAN STUDIES, LINDSAY CATHILL WHO IS PRESENTING A POSTER TODAY AND GREG SCHWARTZ WHO DEVELOPED COMPUTATIONAL PROCEDURES WE HAVE THAT I'VE PRESENTED. THE FUNDING OF COURSE OF THE HUMAN PLACENTA PROJECT WHICH MADE THIS POSSIBLE AND WITHOUT WHICH WE WOULDN'T HAVE BEEN ABLE TO DO ANY OF THESE EXPERIMENTS, SO THANK YOU. [APPLAUSE] >> NICE TALK, JOHN. TERRY MORGAN, OREGON. I'M GOING TO PITCH OUT MY RECOLLECTION IS THAT ABSENT END DIASTOLIC FLOW IN HUMANS MAY BE ASSOCIATED AND AMELIORATED DOWNSTREAM, HAVE YOU TRIED TO DO HUMAN STUDIES IN THE HUMAN STUDIES LIKE YOU DID WITH THE MOUSE, PERFUSION CT? >> NOT IN CONNECTION WITH THIS STUDY. SOME YEARS AGO DID X-RAY EXAMS OF PLACENTAS. I HOPED TO HAVE POTENTIAL PARTNERSHIPS COME OUT OF THIS MEETING, THERE'S A LOT OF INTERESTING THINGS WE COULD DISCOVER IF WE HAD THE CORRESPONDING HUMAN VASCULAR ARCHITECTURE, ALSO A PROJECT TO DO COMPUTATIONAL MODELING FROM FIRST PRINCIPLES. >> CORE ANGIO SIS IS REPRODUCIBLE. LOOK FORWARD TO SEEING IT. >> IAN BIRD, WISCONSIN. THE CORD TO BE AFFECTED, THICKNESS, LENGTH, COMPOSITION OF GEL VERSUS VESSEL. COULD THAT IMPACT? >> WE DON'T YET KNOW BUT PART OF THE STUDY SPECIFICALLY COLLECTED DATA FROM A NUMBER OF SUBGROUPS LIKE THAT SO WE HAVE A NUMBER OF CASES OF WOMEN WITH SINGLE UMBILICAL ARTERY AND WE HAVE EXAMPLES OF HYPOAND HYPER COILED CORDS. I DON'T HAVE AN ANSWER YES. >> FASCINATING WORK. DINESH FROM WISCONSIN. IT WAS IMPRESSIVE THAT IT WAS THE VASCULAR ARCHITECTURE WHAT YOUR WAVE FORM IS REFLECTING, I ABOUT THE FIRST BRANCHING ON THE PLACENTA SURFACE, BUT DOES IT ALTER THE NUMBER OF BRANCHING IN TERMS OF IN YOUR MOUSE PLACENTA? BECAUSE I SAW MULTIPLE SMALL BRANCHES BUT THE QUESTION IS ARE THERE REPEATED BRANCHING OCCURRING AND WHAT IS DRIVING THAT? >> SO THE -- YOU MEAN IN THE TREATED PLACENTA, THE FACT THERE WAS MANY MORE BRANCHES? YEAH, SO -- >> MANY MORE VESSELS BUT ARE THEY BECAUSE ONE BRANCH MAKES MULTIPLE BRANCHES OR THERE BE MULTIPLE STAGES? >> I WOULD SAY MULTIPLE STAGES. WE HAVEN'T SPENT A LOT OF TIME LOOKING AT THAT DATA BUT IT HAS A NORMAL HIERARCHICAL STRUCTURE, OTHER THAN WHERE YOU HAVE A SINGLE WITH MANY HAIRS HANGING OFF OF IT. >> OKAY. >> THANK YOU SO MUCH. THAT WAS GREAT. I'M WONDERING IF YOU ALLUDED TO YOU HAVE A CONTROL FOR FETAL HEART RATE CONSISTENCY, I GUESS THAT WAS WITHIN SUBJECT AND ALSO FETAL AND MATERNAL CONDITIONS THAT CHANGE THAT SO I DIDN'T KNOW IF HAD YOU TO EXCLUDE SOME OUTLIERS IN TERMS OF LOWER OR HIGHER HEART RATES, THAT'S ONE QUESTION. THE THE OTHER IS HOW DID YOU FEEL WITH THE FACT THE MOUSE HEART RATES -- THEY ARE THREE OUR FOUR TIMES HIGHER, IS THE PHYSICS FOR THE REFLECTION, UMBILICAL CORD AND HEART RATE CHANGES AT THE POINTS ON THE REFLECTION LINE? >> WE HAD TO EXCLUDE CASES WHERE IT WAS INCONSISTENT, WE WOULD PROCEED IF IT WAS CONSISTENTLY LOW OR CONSISTENTLY HIGH. THE FACT THAT THE MOUSE HEART RATE IS HIGH DIDN'T ADVERSELY AFFECT MEASUREMENTS, I MEAN THERE'S A WINDOW OF OPPORTUNITY, IF THE REFLECTION ARRIVES SO LATE IT OVERLAPS THE NEXT CARDIAC CYCLE THE SOLUTION BECOMES AMBIGUOUS BUT BECAUSE REFLECTIONS ARRIVE RELATIVELY SOONER AND CARDIAC CYCLE IS NOT SO MUCH SHORTENED PARTICULARLY UNDER ANESTHESIA IT'S STILL -- THE MOUSE LANDS IN THE SWEET SPOT WHERE YOU CAN MAKE A MEASUREMENT. >> THANK YOU. WONDERFUL PRESENTATION. HAVE YOU -- ALFRED FROM NORFOLK, VIRGINIA. IF YOU FOUND DIFFERENCE BETWEEN ANTERIOR AND POSTERIOR PLACENTA, I ASK BECAUSE WHETHER THE MATERNAL REFLECTIONS OF THE AORTA FOR INSTANCE ARE TRANSMITTED THROUGH THE PLACENTA INTO THE FETUS, AND COMPOUND THE RESULTS. >> THAT'S A FASCINATING QUESTION. WE HAVE THAT DATA BUT IT'S NOT SOMETHING WE THOUGHT TO ASK. I'LL FIND OUT. THANKS. >> NICHD. VERY NICE PRESENTATION. THERE'S A CHANGE IN THE ARCHITECTURE OF UMBILICAL CORD IN PRE-TERM VERSUS TERM. THE COILING INCREASES, THE COIL INDEX. INCREASING COIL, DOES IT MAKE DIFFERENCE IN TERMS OF REFLECTIVE WAVES? >> YEAH, SO IT'S TOO SOON FOR US TO SAY. ALL OF THOSE PARAMETERS ARE CHANGING THROUGH GESTATION BUT WHETHER THE COILING ITSELF IS ALTERING IT I CAN'T SAY AT THIS POINT. MY INTUITION IS NO, BUT THE COILING IS NOT AN IMPORTANT FACTOR IN THIS PHENOMENON, BUT WE'LL FIND OUT. THANK YOU. [APPLAUSE] AFROUZ KNOWS EVEN THOUGH I TELL HER SHE'S DOING SPEAKER INTRODUCTION, I CAN'T HELP IT. I NEED TO BE UP HERE AND LOOK AT EVERYBODY. I LOVED THE FIRST TALKS. I THINK THAT THERE'S A LOT OF ENERGY AND EXCITEMENT, AND I COULDN'T BE HAPPIER SO FAR. WE'LL SEE IF IT KEEPS GOING. >> ALL RIGHT. THE TITLE OF THE NEXT TALK IS THE IMPACT OF FETAL SEX ON THE PLACENTA BY DR. PISARSKA DR. GONZALEZ AND DR. SUN. >> GOOD MORNING, EVERYONE. AGAIN, I ALSO HAVE TO ECHO AND THANK YOU ALL FOR, A, GIVING US THE OPPORTUNITY TO PRESENT THE WORK WE'RE DOING THAT IS IN LARGE PART FUNDED THROUGH THE HPP, AND THE NICHD. SO, WE'RE GOING TO SPEAK ABOUT THE IMPACT OF FETAL SEX ON THE PLACENTA, BUT AS THERE ARE MANY PLACENTAL BIOLOGISTS HERE WE SHOULD CHANGE IT TO THE IMPACT OF PLACENTAL SEX ON OUTCOME. SO I'D LIKE TO THANK MY TWO POSTDOCTORAL FELLOWS PRESENTING TODAY, DR. GONZALEZ AND DR. SUN. SEX DIFFERENCES IMPACT PREGNANCY OUTCOMES. THEY IMPACT FETAL GROWTH AND DEVELOPMENT. FEMALES ARE SMALLER THAN MALES AS EARLY AS 8 TO 12 WEEKS GESTATION, CONTINUING THROUGH GESTATION. FETAL SURVIVAL IS ALSO IMPACTED BY SEX. MALE FETUSES HAVE A TWO TO FIVE-FOLD HIGHER RISK OF SPONTANEOUS ABORTION IN THE FIRST TRIMESTER AND BEFORE 23 WEEKS. COMPLICATIONS ARE AFFECTED BY SEX, PREECLAMPSIA IS MORE COMMON IN PREGNANCIES WITH MALE FETUSES, AND MATERNAL ASTHMA IMPACTS FEMALE FETAL GROWTH MORE THAN MALES. COMMON ADULT DISEASE WAS FETAL ORIGINS ARE SEXUALLY DIE MORPHIC INCLUDING HYPERTENSION, CORONARY HEART DISEASE, TYPE 2 DIABETES AND DEPRESSION. EARLY THROUGHOUT GESTATION, AS WELL AS PAST PREGNANCY LED US TO HAVE INTEREST IN LOOKING AT SEX DIFFERENCES IN THE PLACENTA. SO WE HAVE THE OPPORTUNITY TO LOOK AT FIRST TRIMESTER CHORIONIC VILLI OF OP GOING PREGNANCY, THIS GIVES US THE OPPORTUNITY TO NOT ONLY IDENTIFY THE CHANGES THAT OCCUR IN THE FIRST TRIMESTER IN THE PLACENTA BUT WE ALSO CAN ASSOCIATE TO MATERNAL PLACENTAL AND FETAL HEALTH BECAUSE THESE PREGNANCIES ARE ONGOING SO WE COULD LOOK AT OUTCOMES OF THE PREGNANCIES AS WELL AS BEYOND. SO, WE STARTED LOOKING AT FIRST TRIMESTER TRANSCRIPTOME AND IDENTIFIED THAT THERE ARE OVER 14,000 EXPRESSED GENES IN THE PLACENTA IN THE LATE FIRST TRIMESTER, 10 TO 13 WEEKS GESTATION. AND WE ALSO FIND THAT THE MAJORITY, 34% OF GENE EXPOS EXPRESSED ON CHROMOSOME 19 ARE A CONTRIBUTOR TO THOSE IN THE FIRST TRIMESTER, AND Y CHROMOSOME CONTRIBUTES 2.8% TO GENES EXPRESSED. SO WE LOOKED AT THOSE HIGHLY EXPRESSED PLACENTA ENRICHED GENES IN THE FIRST TRIMESTER, 17 ARE HIGHLY EXPRESSED IN THE FIRST TRIMESTER, OF INTEREST WE FIND THAT THE XAGE 3 IS PLACENTA SPECIFIC, THAT IS ONLY EXPRESSED IN THE PLACENTA, WHEREAS MANY OF THESE HIGHLY EXPRESSED GENES ARE ALSO PLACENTA ENRICHED AND ALSO PRETTY SELECTIVE FOR THE PLACENTA BECAUSE THEY ARE ONLY EXPRESSED IN VERY FEW OTHER TISSUES. IN ADDITION, ONE OF THE HISTONE ENCODING GENES IS ALSO EXPRESSED EXCLUSIVELY IN THE PLACENTA AND IT'S ONLY EXPRESSED IN THE FIRST TRIMESTER PLACENTA AND NOT AT TERM. THIS PLUS 11 OTHERS OF HISTONE ENCODING PROTEINS ARE EXPRESSED EXCLUSIVELY IN THE FIRST TRIMESTER PLACENTA, NOT IN TERM, WE THINK IT PLAYS A ROLE WITH TRANSCRIPTIONAL REGULATION IN THE EARLY FIRST TRIMESTER. SO WE LOOKED AT SEX DIFFERENCES IN THE FIRST TRIMESTER PLACENTA AND FIND THERE'S 58 DIFFERENTIALLY EXPRESSED GENES BETWEEN MALES AND FEMALES. SO WE FIND ON THE X CHROMOSOME 25 DIFFERENTIALLY EXPRESSED GENES, 15 DIFFERENTIALLY EXPRESSED GENES ON THE Y CHROMOSOME AND 18 DIFFERENTIALLY EXPRESSED GENES ON AUTOSOMES. LOOK AT UPREGULATED GENES IN FEMALES, ON THE X CHROMOSOME THE MAJORITY OF THESE X GENES ARE UPREGULATED AND THESE ESCAPE INACTIVATION, SIGNIFICANTLY GREATER THAN IN OTHER TISSUES WHERE GENES THAT ESCAPE IS 12 TO 20%. WE THINK THERE MIGHT BE A ROLE WHETHER IT IS A DOUBLE DOSE, UPREGULATED, AND COULD BE COMING NOT -- COMING FROM BOTH CHROMOSOMES, FROM THE MOTHER AND FATHER, SOMETHING THAT WE'RE CURRENTLY INVESTIGATING. WE FIND THAT MANY OF THE Y RANK GENES ARE ANCESTRAL Y GENES, ULTIMATELY ENDED UP ON THE Y CHROMOSOME. OF INTEREST THE MAJORITY OF THOSE GENES THAT ARE ANCESTRAL ARE EXPRESSED IN THE FIRST TRIMESTER PLACENTA. AND IN ADDITION THEY HAVE X HOMOLOGS, SO THESE GENES ARE TYPICALLY EXPRESSED ON THE PSEUDOAUTOSOMAL REGIONS WE THINK PLAYING A ROLE IN TERMS OF ALSO SIGNIFICANT CONTRIBUTORS TO SEX DIFFERENCES. SO WHEN WE LOOK AT AUTOSOME GENES 1/3 OF THE GENES DIFFERENTIALLY COMPRESSED WERE AUTOSOMAL, MORE UPREGULATED IN FEMALES THAN MALES. WHEN WE LOOK AT FUNCTIONAL SIGNIFICANCE OF THE UPREGULATED GENES, WE SEE THAT THERE ARE MORE UPREGULATED GENES IN FEMALE THAT PLAY A ROLE IN SIGNAL TRANSDUCTION, IN DNA REPLICATION, AS WELL AS CELL CYCLE REGULATION AND METABOLISM. WHEREAS THE UPREGULATED GENES IN MALE IN ADDITION TO THOSE ANCESTRAL GENES HAVE OTHER GENES THAT HAVE UNKNOWN FUNCTION AT THE PRESENT TIME. SO WHAT WE'RE TRYING TO UNDERSTAND AS WELL IS WHEN WE DID UPSTREAM ANALYSIS TO LOOK AT FUNCTIONAL REGULATORS THAT MIGHT BE CONTRIBUTING TO THESE DIFFERENCES PARTICULARLY IN THE AUTOSOME GENES WE COULDN'T REALLY FIND ANYTHING THAT'S EXPRESSED ON THE SEX CHROMOSOMES AND ALSO CANNOT FIND ANY TYPE OF HORMONAL REGULATORS THAT MIGHT BE CONTRIBUTING SO WE'RE STARTING TO LOOK AT OTHER AREAS AND THAT INCLUDES SOME OF THE microRNA STUDIES THAT DR. GONZALEZ WILL SPEAK ABOUT. >> HELLO, EVERYONE. WE PERFORMED microRNA SEQUENCING, SET EXPRESSION THRESHOLD OF AVERAGE OF ONE NORMALIZED COUNT PER SAMPLE OR BETTER AND FOUND 386 microRNAs EXPRESSED IN FIRST TRIMESTER PLACENTA. YOU CAN SEE THE CHROMOSOME DISTRIBUTION OF THESE microRNAs. WE FOUND THAT CHROMOSOMES 14 AND 19 EXPRESS A LARGE PORTION OF THESE microRNAs. THESE CHROMOSOMES HAVE KNOWN microRNA CLUSTERS, 14 CLUSTER IS MAMMALIAN SPECIFIC, CHROMOSOME 19 CLUSTER IS PRIMATE SPECIFIC, AND ENCODES A LOT OF microRNAS WHICH ARE PLACENTAL SPECIFIC. HERE I SHOW YOU THE MOST ABUNDANT microRNAS IN CVS TISSUE. SEVERAL OF THESE microRNAs ARE PLACENTAL SPECIFIC FROM THE CHROMOSOME 19 CLUSTER, WE ALSO SEE A LOT WHICH ARE EXPRESSED IN MATERNAL CIRCULATION, AND LOW LEVELS OF SOME microRNAS DIFFERENT POINTS OF GESTATION ASSOCIATED WITH FETAL GROWTH RESTRICTION. WE THINK A LOT OF THESE microRNAS ARE IMPORTANT IN EARLY PREGNANCY BECAUSE FETAL GROWTH IS ACTUALLY DIMORPHIC, WE NEED TO STUDY SEX DIFFERENCES. SO ANALYSIS IDENTIFIED TEN microRNAS, FOUR UPREGULATED IN FEMALES, I'M SORRY, SIX UPREGULATED IN FEMALES, FOUR UPREGULATED IN MALES. MIR 5171P WHEN LOW IN TERM PLACENTA IS ASSOCIATED WITH HIGHER RATES OF GESTATIONAL HYPERTENSION, PREECLAMPSIA AND FETAL GROWTH RESTRICTION. IN FEMALES 126-3P WHEN ADMINISTERED TO PREGNANT RATS LOWERS HYPERTENSION IN RAT PREECLAMPSIA MODEL. MIR-10A-5P WHEN LOW IN SECOND TRIMESTER SERUM IS ASSOCIATED WITH FETAL GROWTH RESTRICTION. LET-7A-5P REGULATES SEVERAL PLACENTA GROWTH FACTORS AND REGULATES A LOT OF GENES THAT AFFECT CELL GROWTH AND CELL PROLIFERATION. AND HAS GENERAL TUMOR SUPPRESSOR FUNCTION. SO AS YOU CAN SEE HERE, SEVERAL microRNAs, ALL OF THESE SIGNIFICANT microRNAs COME FROM AUTOSOMES, SOMETHING WE FOUND IN SEVERAL STUDIES WHERE SEX DIFFERENCES DON'T ONLY COME FROM SEX CHROMOSOMES SO IN ORDER TO UNDERSTAND HOW FETAL SEX AFFECTS DIFFERENT CELL TIMES IN THE PLACENTA, WE ALSO DID SINGLE CELL SEQUENCING AND TO MY COLLEAGUE TIAN WILL DISCUSS THESE RESULTS. >> SO, WE'VE LOOKED AT SINGLE CELL TRANSCRIPTOME PROFILES FROM THE FIRST TRIMESTER VILLI FROM HEALTHY SINGLETON PREGNANCIES, USED A CHROMIUM SYSTEM AND MORE THAN 7,000 CELLS WERE INCLUDED IN OUR FINAL ANALYSES. AND WITH THE UNSUPERVISED CLUSTERING WE WERE ABLE TO VISUALIZE FIVE MAIN CLUSTERS, AND WE IDENTIFIED THEM AS TROPHOBLAST CELLS, STROMAL CELLS HERE AND MACROPHAGES, DENDRITIC CELLS AND ENDOTHELIAL CELLS. AND THESE ARE SOME OF THE MARKERS THAT WE USED FOR THE CLUSTER IDENTIFICATION, SO YOU CAN SEE IN THE TOP PANEL THESE ARE THE TROPHOBLAST CELL MARKERS, AND THESE ARE THE STROMAL CELL MARKERS, AND THEN THE MACROPHAGE MARKERS, DENDRITIC CELL MARKERS AND TOWARDS THE END ARE THE ENDOTHELIAL MARKERS. SO WE'RE INTERESTED IN LOOKING AT THE SEX DIFFERENCE SO IN GENERAL THE CELLS FROM FEMALE AND MALE VILLI ARE EVENLY DISTRIBUTED IN ALL THE FIVE CLUSTERS. SO HERE ARE SOME OF OUR DATA. THE XY GENES DIFFERENTIALLY EXPRESSED BETWEEN SEXES IN EACH CLUSTER, AS YOU CAN SEE NOT SURPRISINGLY SOME Y GENES ARE UPREGULATED IN MALES, BUT THERE'S A CLUSTER SPECIFIC, SO FOR INSTANCE THESE TOP TWO Y GENES ARE MALE BIASED IN TROPHOBLAST CELLS, STROMAL CELLS AND MICRO RAGES. RPS 4Y IS UPREGULATED IN MALES ACROSS CLUSTERS. INTERESTINGLY, RPL 36A, IS UPREGULATED IN MALES IN THE EPITHELIAL POPULATION. THESE FOUR GENES ARE PROTEIN CODING GENES, IMPORTANT FOR TRANSLATIONAL REGULATION. AND THEN WE FOUND THREE X GENES UPREGULATED IN CELLS FROM FEMALE VILLI, AND TWO OF THEM ARE SPECIFIC IN THE TROPHOBLAST CELLS INDICATING THE DIFFERENT ROLES OF THESE GENES BETWEEN SEXES IN THIS PARTICULAR CELL TYPE. OKAY. SO WE ALSO FOUND AUTOSOMAL GENES DIFFERENTIALLY EXPRESSED BETWEEN SEXES ARE MORE THAN THE XY CHROMOSOME GENES, 27 BEING UPREGULATED IN MALES, 17 IN FEMALES. THIS SLIDE SHOWS MALES. FIVE GENES ARE SPECIFIC IN TROPHOBLAST CELLS THAT HAVE THE DIMORPHISM, AND FOUR THAT ARE SPECIFIC TO STROMAL CELLS, AND THEN THE TWO IMMUNE CELL POPULATION SHARED SEXUAL DIMORPHISM AT THESE FIVE GENES, AND THERE'S ONE GENE THAT IS SHARED, AND FOUR TO ENDOTHELIAL CELLS. MANY GENES MIGHT BE FAMILIAR BECAUSE MANY OF THEM HAVE INDICATED IN CERTAIN PREGNANCY COMPLICATIONS, FOR INSTANCE HLAC, STC 1, MMP 1 HAVE BEEN INDICATED FROM PREECLAMPSIA, ANOTHER EXAMPLE IS IGF1 SMALL GESTATIONAL AGE, AND PRE-TERM DELIVERY ASSOCIATION. BUT THERE ARE SOME GENES THAT WE DON'T KNOW THE DEFINED -- DON'T KNOW THE FUNCTION IN THE PREGNANCY CONTEXT OR DEFINED FUNCTION IN GENERAL SUCH AS SOME PROTEIN CODING GENES SUCH AS THE ONE MENTIONED. HERE IS THE LIST FOR THE GENES THAT ARE UPREGULATED IN FEMALES, CLUSTER SPECIFIC. AND FIVE GENES THAT ARE SPECIFIC TO TROPHOBLAST CELLS, HBG 2 IS SHARED BETWEEN STROMAL CELLS AND ENDOTHELIAL, AND G-PROTEIN COUPLED RECEPTORS SHARED BETWEEN THE TWO IMMUNE CELL POPULATIONS. IT'S INTERESTING TO SEE THAT SEVERAL CHEMOKINES ARE UPREGULATED IN THE FEMALE CELLS. AND ALSO THIS SEXUAL DIMORPHISM EXISTS IN CELL TYPES OTHER THAN IMMUNE CELLS. OKAY. SO BESIDES THE SEX DIFFERENCE PIECE FROM THIS SINGLE CELL TRANSCRIPTOME INFORMATION WE WERE ALSO ABLE TO DISSECT THE HETEROGENEITY WITHIN THE TROPHOBLAST CELL POPULATION AND WE FOUND THAT THERE ARE AS MANY AS SEVEN CELL SUBTYPES IN THE TROPHOBLAST, SHOWN HERE IN GREEN, PURPLE EBT CELL POPULATION, RED IS TROPHOBLASTS, AND THEN WE ALSO FOUND FOUR NEW SUBTYPES, IN ORDER TO KNOW WHAT THEY MIGHT BE AND WHAT THEIR RELATIONSHIP IS WITH THE SUBTYPES WE ALREADY KNOW, WE DID THE RECONSTRUCTION OF THE DEVELOPMENTAL TRAJECTORY BY DOING ANALYSIS, TWO BRANCHES, DEVELOPMENTAL BRANCHES FOR TROPHOBLAST CELLS ORIGINATE FROM CYTOTROPHOBLASTS, ONE BRANCH ENDS WITH EVT, THE OTHER ENDS WITH SYNCYTIOTROPHOBLASTS. SOME ARE LOCATED IN THE MIDDLE, EARLIER AT THE PSEUDOTIME AXIS OR LATER ON WHICH SUGGESTS THEY MIGHT BE NEW POPULATION ALSO THAT TRANSITION FROM CYTOTROPHOBLASTS TO SYNCYTIOTROPHOBLASTS. NEXT WE'LL TALK ABOUT FUTURE DIRECTION. >> TO THINK ABOUT WHAT'S GOING ON WITH THE TECHNOLOGY THAT WE HAVE NOW THAT'S AVAILABLE TO US AND WHAT FUTURE DIRECTIONS WE CAN LOOK TOWARDS, AS WE KNOW PEOPLE AND OTHERS AS WELL AS OURSELVES ARE TRYING TO DEVELOP NON-INVASIVE DIAGNOSTICS. THIS RECENT PAPER COME OUT IN "SCIENCE" WHERE THEY LOOKED AT CIRCULATING CELL FREE RNA OF NINE PLACENTA-SPECIFIC MARKERS, ABLE TO PREDICT GESTATIONAL AGE AT DELIVERY. OF THOSE CGA WHICH ENCODES ALPHA SUBUNIT IS AMONG THOSE NINE GENES. BUT WE ALSO FOUND CGA IS SEXUALLY DIMORPHIC IN SINGLE CELL STUDIES, STUDIES FOUND HCG IS HIGHER IN FEMALES COMPARED TO MALE FETUSES IN THE FIRST AND SECOND TRIMESTER. SO THE THINGS THAT ARE IMPORTANT FROM THE STUDIES IS THAT WE HAVE THE POTENTIAL OPPORTUNITY TO LOOK AT THE TRANSCRIPTOME, BOTH CODING AND NON-CODING, IN ORDER TO DEVELOP NON-INVASIVE DIAGNOSTIC STUDIES FOR MATERNAL PLACENTAL FETAL HEALTH, BUT THE OTHER THING THAT'S ALSO IMPORTANT IS WE START MOVING FORWARD WITH THESE TECHNOLOGIES, THAT SEX DOES MATTER AND WE REALLY HAVE TO TAKE THAT INTO CONSIDERATION WHEN WE DO THESE DEVELOPMENTAL DIAGNOSTIC TESTS IS INCLUDE SEX AS FACTOR THAT MIGHT INFLUENCE SOME OF THE RESULTS. SOME OF THE OTHER PRENATAL DIAGNOSTICS IS FOCUSING ON TROPHOBLAST CELLS AS WELL. AND WHAT WE'RE USING IS A RARE CELL SORTING DEVICE KNOWN AS NANOVELCRO CHIP IN COLLABORATION WITH DR. SING AT THE INSTITUTE AT UCLA AND USE A CHIP IMPRINTED WITH PLGA NANOSTRUCTURES THAT CAN CAPTURE THESE CELLS. AND WE'VE BEEN ABLE TO DO VARIOUS DOWNSTREAM ANALYSES, AND IN ADDITION WE CAN DO THAT WITH 8 mLs OF BLOOD, AS WELL AS DO SGR FINGERPRINT CONFIRMING FETAL PLACENTAL RELATIONSHIP AS WELL AS SHORT DELETIONS AND DUPLICATIONS. WE'RE STRUGGLING WE WOULD LIKE TO CAPTURE MORE CELLS AND SO AS DR. SUN MENTIONED THESE EXTRA-VILLOUS TROPHOBLAST CELLS, OTHERS ARE EXTRAVILLOUS AND WE WANT TO LOOK AT ANTIGENS TO CAPTURE MORE CELLS AND PERHAPS FIND NEW POPULATIONS IN THE CIRCULATION. SO THINGS TO KEEP IN MIND IS THAT PLACENTA DOES CHANGE GESTATION AS WE'VE SHOWN, SEX DIFFERENCES EXIST IN THE PLACENTAL AND FETAL DEVELOPMENT, AND THE CODING AND NON-CODING TRANSCRIPTOME MAY BE USED FOR NON-INVASIVE DIAGNOSTICS, AS WELL AS CIRCULATING TROPHOBLAST CELLS CAN POSSIBLY BE USED AS WELL. AND THAT NEW POPULATIONS OF CELLS AND OTHER SECRETED PLACENTAL FACTORS MAY BE IDENTIFIED TO IMPROVE AND DEVELOP NEW DIAGNOSTIC TOOLS FOR MATERNAL PLACENTAL AND FETAL HEALTH. SO I HAVE TO THANK ALL OF MY LAB MEMBERS INCLUDING THE TWO HERE WHO PRESENTED MUCH OF THE WORK ON SEX DIFFERENCES AND TO POINT OUT THE BABY IN THE PICTURE ON THE FIRST SLIDE IS STILL MY BABY, BUT NOT A BABY ANYMORE, IN OTHERS' EYES. OF COURSE I HAVE TO THANK MY COLLABORATORS AT LA BIOMED, UCLA, UNIVERSITY OF VIRGINIA AND JOHN WILLIAMS WHO DID 30,000 CHORIONIC VILLOUS SAMPLES FOR THE BIOREPOSITORY AND HPP FOR FUNDING. THANK YOU. [APPLAUSE] >> OUTSTANDING. NICE TO SEE YOU. I WANT TO BRING UP THE PLUGIN CELLS IN THE TROPHOBLAST, FIRST SEMESTER, PULLING OUT CTCs, CD56 IS UPREGULATED IN THESE CELLS. THAT WOULD BE FUN, THE PLUGGING CELLS PLAY A PIVOTAL ROLE ESPECIALLY TOWARDS THE END OF THE FIRST TRIMESTER. JUST AN IDEA. >> YEAH, GREAT. THANKS. >> OKAY. ALL RIGHT. THANK YOU. [APPLAUSE] >> THANK YOU SO MUCH FOR A GREAT TALK. THE TOPIC OF NEXT TALK IS TRENDS IN PLACENTAL BOLD MEASUREMENT OVER GESTATION, PRELIMINARY RESULTS FROM MULTI-SITE TRIAL, DR. FRIAS AND DR. SCHABEL FROM OREGON HEALTH AND SCIENCE UNIVERSITY. >> GOOD MORNING. WE'RE SO HAPPY TO BE HERE. IT'S ENCOURAGING AND EXCITING TO SEE THE PROGRESS THAT'S OCCURRED AS A RESULT OF FUNDING FROM THE HUMAN PLACENTA PROJECT. WE WANTED TO SHARE MEASUREMENTS LONGITUDINALLY IN PREGNANCY FOCUSING ON MULTI-SITE TRIAL. SO I DON'T NEED TO SHOW THIS SLIDE TO EVERYONE HERE BUT THIS IS JUST A REMINDER OF THE UNIT THAT WE'RE FOCUSING ON IN OUR MEASUREMENT. SO THERE ARE TWO VASCULAR COMPARTMENTS, MATERNAL WITH SPIRAL AND FETAL WITH FETAL VILLI, BLOOD FLOW INTO THE INTERVILLOUS SPACE, PERFUSES OVER THE VILLI, LIKE LEAVES IN A TREE. THE TWO COMPARTMENTS DEVELOP INDEPENDENTLY TO MAXIMIZE SURFACE AREA FOR EXCHANGE SO AT TERM THE SURFACE AREA FOR THE VILLI IS 13 METERS SQUARED, KING SIZE BED IS 5 METERS SQUARED, FOR PERSPECTIVE. AS JOHN SLED AND OTHERS HINTED AT EARLIER, ONE OF THE MOTIVATIONS TRYING TO FIND BETTER DIAGNOSTICS IS WE'RE LIMITED TO LOOKING AT THINGS EITHER PROXIMAL, BLOOD VESSELS THAT ARE PROXIMAL TO THE PLACENTA OR DISTAL TO THE PLACENTA. WHILE ALL THE FUNCTION IS HAPPENING IN THIS SPACE. AND SO THAT MOTIVATED US A WHILE AGO TO LOOK AT USING MRI TO TRY AND CHARACTERIZE FUNCTION IN THEIR INTERVILLOUS SPACE. OUR PROJECT WAS TO OPTIMIZE BOLD MRI ACQUISITION PROTOCOLS FOR HUMAN PREGNANCY, ADAPT 3D ANALYSIS TOOLS WE HAD DEVELOPED IN NON-HUMAN PRIMATE, AND ASCERTAIN WHETHER FUNDAMENTAL DATA -- ASCERTAIN FUNDAMENTAL DATA NECESSARY TO EXPLAIN HOW THIS SIGNAL CHANGES DURING PREGNANCY, WHAT'S THE NORMAL VARIANCE, AND THEN SEE ARE THERE DIFFERENCES IN AT-RISK PREGNANCIES OR PREGNANCIES THAT DEVELOP COMPLICATIONS. THE REASON WE THOUGHT THAT THIS WAS A GOOD PLACE TO FOCUS IS SHOWN HERE IN THIS GOOGLE EARTH VIEW OF THE PLACENTA, REPRESENTATIVE OF THE SPATIAL MODELING WE DEVELOPED. THE MOST IMPORTANT THING HERE IS THAT WE IDENTIFIED THIS ENDOGENOUS CONTRAST AGENT, ITS SPATIAL RELATIONSHIP TO SPIRAL ARTERY ALLOWED US TO EXPLAIN WHAT HAPPENED TO THAT SIGNAL AS DISTANCE FROM SPIRAL ARTERY AND ALLOWED US TO MODEL PLACENTA IN A WAY THAT WAS PHYSIOLOGICALLY RELEVANT BUT SPATIALLY RELEVANT FOR THE LOBULAR DOMAINS IN THE PRIOR SLIDE. OUR APPROACH WAS STRAIGHTFORWARD. WE'RE GOING TO ENROLL 300 WOMEN AT TWO SITES, OHSU AND OUR COLLEAGUES AT THE UNIVERSITY OF UTAH BECAUSE NUMBER ONE THEY ARE SO GREAT AT RUNNING CLINICAL TRIALS AND WE HAVE A LONG HISTORY OF COLLABORATING WITH THEM, AND WE WERE GOING TO HAVE THREE COHORTS, LOW RISK CONTROL GROUP, SMOKERS, WHICH IN OREGON HAVE A LOT OF MARIJUANA EXPOSURE SO IT'S SMOKER/MARIJUANA EXPOSURE GROUP. AND HIGH RISK GROUP DEFINED BY PRIOR COMPLICATIONS AND PREGNANCY HISTORY, SEVERE PREECLAMPSIA REQUIRING PRE--TERM DELIVERY PRIOR TO RESTRICTION AND STILLBIRTH. ENROLLED FOR THREE MRI SCANS, 12 TO 16 WEEKS, 26 TO 28 AND 32 TO 34 WEEKS. SIMPLE IN TERMS OF COULD WE IDENTIFY WITH MEASUREMENTS AN IMAGING PHENOTYPE ASSOCIATED WITH ADVERSE OUTCOME, AND THEN LONG TERM USE THAT IMAGING PHENOTYPE TO HELP US SEARCH FOR BIOMARKERS. OUR COLLABORATORS TERRY MORGAN IS HERE AND WOULD BE HAPPY TO TALK ABOUT THE WORK WITH EXOSOMES, USING HPP FUNDS TRYING TO DESCRIBE WHAT THOSE THINGS ARE BUT COULD THEY BE RELATED TO IN VIVO FUNCTION. WE'VE ENROLLED 162 PATIENTS AND MATHIAS WILL PRESENT THAT DATA AT THAT TIME >> THANK YOU. MOSTLY FOR THE NON-MRI PEOPLE I'LL REVIEW TERMINOLOGY. THERE'S LOT OF VERNACULAR. I TOLD ABOUT BOLD. BOLD IS A PHYSICAL EFFECT IN MRI WHETHER DEOXYGENATED HEMOGLOBIN SUPPRESSES SIGNALS IN CERTAIN TYPES OF ACQUISITIONS RELATIVE TO OXYGENATED HEMOGLOBIN SO YOU'RE SENSITIVE TO THE OXYGEN LEVEL WITHIN THE BLOOD, AND IT'S HISTORICALLY ASSOCIATED WITH FUNCTIONAL MRI IN THE BRAIN WHERE PEOPLE LOOK AT ACTIVATION OR PERTURBATION WHERE YOU TRY TO LOOK AT A CHANGE AND LOOK AT CHANGES IN BLOOD OXYGENATION, ASSOCIATED WITH CHANGES IN BLOOD FLOW. IN THIS CASE, WE ARE NOT DOING fMRI. THERE'S NO ACTIVATION HERE. IN SOME WAYS EVEN THOUGH THE PLACENTA IS COMPLEX FROM BIOLOGICAL AND GENETIC PERSPECTIVE IT'S SIMPLE PHYSIOLOGICALLY. HAVE SIMPLE SPATIAL STRUCTURES, YOU CAN RESOLVE THEM WITH MRI INDIVIDUALLY AND LOOK AT LOBULES AND SEE GRADIENT AS BLOOD COMING IN THE SPIRAL ARTERY FLOWS FROM THE MATERNAL SORT OF SIDE OF THE CIRCULATION THROUGH TO THE VENOUS DRAINAGE AND IS TAKEN UP BY THE FETUS, SO THE FETUS IS CONSUMING THAT OXYGEN, THAT GIVES A SENSE BOTH OF THE MATERNAL SUPPLY AND MAYBE MORE IMPORTANTLY BALANCE BETWEEN THE MATERNAL SUPPLY OF OXYGENATED BLOOD AND FETAL DEMAND. SO, IN THE PLACENTA IN PARTICULAR THE SPATIAL PATTERNS ARE SIGNIFICANT, AND WE FIRST SORT OF DEMONSTRATED THIS IN A PRIMATE MODEL OF PREGNANCY. AGAIN WERE DOING CONTRAST STUDIES WHICH SHOW WHERE THE SPIRAL ARTERIES ARE, SO THE SPIRAL ARTERIES I GUESS WE'VE GOT A POINTER HERE, IN CONTRAST STUDY YOU INJECT AN EXOGENOUS AGENT. WE MAPPED T2 STAR, INDICATES HIGHLY OXYGENATEDDED BY. WE FOUND 1:1 CORRELATION BETWEEN SPIRAL ARTERIES AND BRIGHT REGIONS IN THE PLACENTA AND T2 STAR MAPPING. WE THOUGHT WE WOULD LIKE TO NOW APPLY THIS IN A WAY IDEALLY TO BE CLINICAL TRANSLATED, WE SAW PROMISING RESULTS IN OUR PRIMATE MODELS. AND RATHER THAN DOING A CUSTOM ACQUISITION WE OPTED TO PICK A VERY OFF-THE-SHELF SET OF DATA ACQUISITION PROTOCOLS, USING COMPLETELY STANDARD PULSE SEQUENCES THAT YOU CAN GET ON ALMOST ANY MODERN SCANNER, THIS COULD BE IMPLEMENTED WITH NO SPECIAL SUPPORT AND REALLY IN A BROAD RANGE OF PLACES, AND WE SCANNED PATIENTS AT THREE TIME POINTS AND LOOKED AT PLACENTAL T2 STAR TO CORRELATE WITH THE PREGNANCY OUTCOMES. I'M GOING TO SHOW YOU AT THE FIRST GESTATIONAL TIME POINT, A MAP OF T2 STAR, AGAIN OUTLINE PLAS IN BLUE. ARE VALUES TO 0 TO 100 OR 120 MILLISECONDS. EARLY IN PREGNANCY PLACENTA IS HIGHLY OXYGENATED. THAT'S NOT A BIG SURPRISE. FETUS IS SMALL. IN THIS CASE THE MATERNAL SUPPLY EXCEEDS THE FETAL DEMAND OF OXYGEN. SO OXYGEN HAS TO GO SOMEWHERE, IF IT DOESN'T GO INTO THE FETUS IT ENDS UP STAYING IN THE MATERNAL CIRCULATION, TAKEN UP IN THE VENOUS BLOOD. AN ASIDE, I PLOT HERE THE MAPS OF OUR MEASUREMENT UNCERTAINTY, AS A PERCENTAGE. WE'RE TALKING ABOUT MOSTLY 5 TO 10% ERROR SO ANY VARIABILITY IN THESE MEASUREMENTS ESPECIALLY WHEN YOU ACCOUNT FOR THE FACT YOU HAVE TENS OF THOUSANDS OF VOXELS IN THE PLACENTA UNLIKELY TO BE MEASUREMENT ERROR DRIVEN BUT BY INTRINSIC. YOU START SEEING MORE SPATIAL STRUCTURE AND SLIGHTLY LOWER VALUES. THE ERRORS OF COURSE DON'T REALLY CHANGE OTHER THAN AS THE MOM GETS BIGGER THERE'S SOME INCREASE IN ERROR IN THE MIDDLE OF THE BODY FOR TECHNICAL REASONS. AND THEN AT THE THIRD TIME POINT YOU REALLY START TO SEE THE LOBULAR STRUCTURE EMERGING. YOU HAVE THE BRIGHT REGION SURROUNDED BY LOWER VALUES OF T2 STAR, THE LOBULE WHERE THE FETUS IS BIG ENOUGH IT'S CONSUMING MOST OR ALL OF THE OXYGENATED BLOOD THE MOM IS PROVIDING. SO, WHAT HAPPENS NOW IN PATHOLOGIC OR ABNORMAL PREGNANCIES, HERE A CASE OF SEVERE PREECLAMPSIA THAT UNFORTUNATELY WE DIDN'T CATCH UNTIL THE SECOND GESTATIONAL TIME POINT. YOU SEE COMPARING ACROSS THE TWO GESTATIONAL AGES THAT ALREADY HERE THIS PLACENTA IN THE CASE OF PREECLAMPSIA LOOKS LIKE TIME POINT THREE, SUBSTANTIALLY LOWER IN OXYGENATED BLOOD AND BY GESTATIONAL TIME POINT THREE HAVING A HARD TIME PROVIDING ADEQUATE OXYGEN TO THE FETUS. IF WE NOW LOOK AT HISTOGRAMS, THIS IS FOR THE SAME TWO PATIENTS IN THIS CASE, HISTOGRAMS OF T2 STAR VALUES AT THREE GESTATIONAL TIME POINTS TREND TOWARD LOWER VALUES, CONSISTENT DISTRIBUTION OF T2 STARS. IF WE NOW OVERLAY ON THAT THE PREECLAMPSIA PATIENT, IT'S VERY, VERY STARK. THERE'S NO QUESTION WE'RE DIFFERENTIATING BETWEEN PREECLAMPSIA AT GESTATIONAL TIME POINT TWO AND THREE, PLACENTA IS BORDERLINE HYPOXIC COMPARED TO NORMAL UNCOMPLICATED PLACENTA. NOW I'VE AVERAGED HISTOGRAMS OVER ALL NORMAL PREGNANCY, UNCOMPLICATED PREGNANCIES, SIMILAR BUT SMOOTHER HISTOGRAMS THAT GIVE A NATURAL HISTORY AT THREE TIME WINDOWS OF WHAT ONE COULD EXPECT T2 STAR TO LOOK LIKE, AND THEN HERE I'M OVERLAYING IT ON ALL OF THE CASES IN OUR STUDY WHERE WE HAD FETAL GROWTH RESTRICTION SO THE DASHED CURVES ARE COLOR CODED THE SAME WAY AT GESTATIONAL TIME POINTS, NOW I'VE GENERATED HISTOGRAMS FOR LOW BIRTH WEIGHT AND FGR IDENTIFIED BY ULTRASOUND. THERE'S A CLEAR AND UNMISTABLABLE SHIFT IN PLACENTAL T2 STAR VALUES AND DOWNWARD. THIS IS BASICALLY THE RAW DATA, I'M SHOWING YOU ACROSS SITES AS WELL, HERE THE THREE TIME POINTS, GESTATIONAL DAYS, 180, 220, BLUE AT UHSU, RED AT UNIVERSITY OF UTAH. YOU SEE THAT IT'S A RELATIVELY TIGHT DISTRIBUTION OF VALUES BUT THERE'S SOME VARIABILITY, AT ALL THE TIME POINTS. YOU ALSO SEE THE DERIVATIVES ARE QUITE CONSISTENT. IT'S NOT -- THIS GIVES I'D SAY MORE CONFIDENCE MEASUREMENTS ARE MEASURING SOMETHING BECAUSE WE DON'T SEE RANDOM JUMPING, TRENDS ARE CONSISTENT ACROSS PATIENTS AND SITES. AND HERE I'VE OVERLAID ALL OF THE ADVERSE PREGNANCY OUTCOMES THAT WE'VE HAD SO FAR. SO IT'S A LITTLE BIT BUSY. I APOLOGIZE FOR THAT. ONE CASE OF EARLY FETAL DEMISE. AND THAT WAS NOT AN OUTLIER, THE FIRST GESTATIONAL TIME POINT. WE HAVE TWO CASES OF PRE-TERM DELIVERY, HERE WE HAVE CASES OF IUGR, DOWN HERE THE THIRD TIME POINT, PREECLAMPSIA HERE, SEVERE MATERNAL HYPERTENSION, ANOTHER CASE OF PREECLAMPSIA WITH NEONATAL DEMISE, AND THE POINT I'D LIKE TO BRING UP HERE IS NOT EVERY ADVERSE OUTCOME IN THE SORT OF RELATIVELY BROAD DEFINITION IS ASSOCIATED WITH BAD T2 STAR VALUES ESPECIALLY AT THE EARLY STAGES, BUT THERE'S A VERY CLEAR TREND, THESE ARE ALL KIND OF HOVERING AT THE LOW END OF NORMAL OR AT THE REALLY VERY LOW END AND THE WORST CASES MOSTLY SEEM TO HAVE MUCH LOWER PLACENTAL OXYGEN LEVELS. SO IT'S CLEARLY A PREDICTIVE MEASUREMENT, AND SO THEN WE WANT TO LOOK AND SEE, IN TERMS OF OUR INNER SITE CORRELATIONS HOW GOOD ARE THEY? IS THIS SOMETHING THAT COULD BE DONE EASILY, DO WE GET CONSISTENT MEASURE. S? UTAH IS HIGHER ELEVATION, MAYBE LEVELS ARE DIFFERENT. WE HAD 30 AT OHSU UTAH 14 AND 12. NO STATISTICALLY SIGNIFICANT DIFFERENCE, AT ALL TIME POINTS, AT THE FIRST TIME POINT UTAH MEASUREMENTS WERE BORDERLINE, LIKE .08, THE OTHER WAS NO OBVIOUS SIGNIFICANCE. MAYBE BETTER IF WE NOW LOOK AT GESTATIONAL TRENDS, THE SLOPE BETWEEN TIME POINTS 1 AND 2 AND TIME POINTS 2 AND 3 ARE CONSISTENT ACROSS SITES SO WE'RE SEEING IN TERMS OF THIS NATURAL HISTORY THAT WE CAN MEASURE IT, WITH CLINICALLY USEFUL SEQUENCE, IT'S NOT EXCESSIVELY LONG, PROTOCOL CAN RUN 35 MINUTES ON A TYPICAL COOPERATIVE PATIENTS, MOST WOMEN DO FINE. IT GIVES HIGH LEVEL OF CONSISTENCY ACROSS THE SITES. ONE OTHER THING WE WANTED TO LOOK AT NOW IS HOW DO THESE T2 STAR MEASUREMENTS CORRELATE WITH WHAT -- WITH BIRTH WEIGHT PERCENTILES, SO WE COMPUTED THE BIRTH WEIGHT PERCENTILE FOR GESTATIONAL AGE AT DELIVERY FOR ALL PATIENTS FOR WHICH WE HAD T2 STAR MEASUREMENTS AND LIVE BIRTHS AND PLOTTED AND FIT TO A LINEAR CURVE, BIRTH WEIGHT, T2 STARS IS FUNCTION OF BIRTH WEIGHT PERCENTILE AT EACH GESTATIONAL TIME POINT. WE SEE WEAK CORRELATION AT FIRST GESTATIONAL TIME POINT, A COUPLE BAD CASES DID HAVE VERY LOW BIRTH WEIGHT, WERE ALREADY VISIBLE AT FIRST TIME POINT. A PRETTY CLEAR LINEAR CORRELATION BY TIME POINT 2, STRONGER AT TIME POINT 3. SO WE HAVE THIS STRONG CORRELATIVE RELATIONSHIP BETWEEN THE BIRTH WEIGHT PERCENTILE OF THE FETUSES AND THEIR T2 STAR VALUES IN THE PLACENTA, EVEN AT MID-GESTATION. SO, THE FINAL SLIDE, I'LL GO BACK TO PRIMATE DATA, JUST TO POINT OUT ONE OF THE INTERESTING THINGS TO US ABOUT THE T2 STAR MEASUREMENT IS IT'S A VERY RELEVANT PHYSIOLOGICAL MEASUREMENT OF SOMETHING SPECIFICALLY MEANINGFUL, AND IT TURNS OUT THAT LOW T2 STAR IS NOT THE ONLY THING THAT IS POTENTIALLY INDICATIVE OF PATHOLOGY, SO LOW T2 STAR SUGGESTS HYPO PERFUSION, HYPOXIA. IN OUR PRIMATE STUDIES HERE I'VE AVERAGED OVER CONTROL ANIMALS IN LATE GESTATION, BLUE CURVE IS THE CONTROL SET, PINK CURVE IS ANIMALS ON A HIGH FAT DIET THAT SHOWED SUPPRESSION IN THE T2 STAR VALUES, SOME NEGATIVE EFFECT. AND ALSO BABIES THAT WERE EXPOSED TO ETHANOL, MOMS WERE GIVEN ETHANOL, SHOWED A SIMILAR SUPPRESSION, SLIGHT DOWNWARD SHIFT IN T2 STAR. BUT WHAT'S INTERESTING IS WE RECENTLY PUBLISHED A STUDY ON ZIKA VIRUS INFECTIONS IN PREGNANT MACAQUES, AND WHAT WE FOUND THERE WAS EXACTLY THE OPPOSITE, THAT AT THE SAME GESTATIONAL TIME POINT WE HAD A HIGHER T2 STAR IN THE PLACENTA. WHAT IT MEANS, THE OXYGEN IN THE PLACENTA HAS TO GO SOMEWHERE SO EITHER IT'S CONSUMED BY THE FETUS OR RETURNED TO THE MATERNAL CIRCULATION. SO WHAT THIS IS TELLING YOU IS THAT THE MOM IS PROVIDING PLENTY OF OXYGEN TO THE FETUS IN THE ZIKA-INFECTED MONKEYS, BUT NOT GETTING THROUGH. THIS CORRELATED WITH OUR PATHOLOGIC RESULTS WHICH SHOWED INFLAMMATION, VASCULITIS OF THE FETAL VESSELS, ESSENTIALLY PERMEABILITY WENT DOWN, AND AS A RESULT THAT OXYGEN COULDN'T GET INTO THE FETUS EVEN THOUGH THE MOM WAS PROVIDING AN ADEQUATE SUPPLY OF OXYGENATED BLOOD. SO I THINK PLACENTAL T2 STAR MAPPING CAN BE DONE NOW, YOU KNOW, IN AN ALMOST CLINICAL SETTING. IT'S QUITE PROMISING QUANTITATIVE WAY OF LOOKING AT THE PLACENTA, PROVIDES QUANTITATIVE MOSTLY MEASURED DELIVERY OF OXYGENATED BLOOD TO PLACENTA, SPATIAL PATTERNS REFLECT PHYSIOLOGIC VARIABLES OF INTEREST, FETAL OXYHEMOGLOBIN, MATERNAL OXYGEN DELIVERY, AND PATHOLOGIC STATES CAN BE INDICATED BY DECREASED PLACENTAL T2 STAR OR INCREASED PLACENTAL T2 STAR AND WE'RE AT THIS POINT STARTING TO DEVELOP A RELATIVELY COHERENT SENSE OF WHAT THE NATURAL HISTORY IS LOOKING LIKE AND WE -- GOING FORWARD WILL BROADEN THE TIME WINDOWS OF OUR PATIENT ENROLLMENT TO FILL IN SOME GAPS IN GESTATIONAL AGE. AND HOPEFULLY GET A LITTLE MORE COMPLETE PICTURE OF HOW PLACENTAL T2 STAR EVOLVES OVER PREGNANCY. THESE ARE THE COLLABORATORS, A NUMBER AT UTAH WHO WORK ON THE PROJECT AND WE WOULD LIKE TO THANK THE NIH FOR SUPPORTING US BOTH IN THE PRIMATE AND HUMAN STUDIES. [APPLAUSE] CURIOUS WHETHER YOU THOUGHT BY LOOKING AT DISTRIBUTIONS YOU MIGHT BE ABLE TO COME UP WITH A MEASURE OF OXYGEN EXTRACTION BECAUSE, YOU KNOW, AS THAT INITIAL MODEL YOU SHOWED, SHOWED GRADIENT, IF YOU COULD IDENTIFY THE TWO ENDS OF THAT GRADIENT PERHAPS YOU COULD -- >> RIGHT. WE'RE WORKING ON THAT. SO OUR ORIGINAL WORK IN PRIMATES WE WERE LOOKING AT SPATIAL MODELING WHERE YOU CAN GET INFORMATION ON OXYGEN EXTRACTION AND ON FETAL OXYGEN SATURATION. SO THEN THE QUESTION IS GOING FROM THE SORT OF RELATIVELY -- IT'S SIMPLE BUT IT'S STILL SOPHISTICATED ENOUGH IT WOULDN'T BE A CLINICAL MODEL OF LOOKING AT THE SPATIAL EXCHANGE IN INDIVIDUAL LOCK ALLS -- LOBULES TO THE MORE STATISTICAL ANALYSIS, POSSIBLE TO GOT MORE OF THE HISTOGRAM. >> GREAT. >> WHEN YOU ANALYZE THE SITE COMPARISON OR THE TEMPORAL POINTS COMPARISON DID YOU NORMALIZE THE WEEKS OF GESTATION? >> OH -- >> BECAUSE WE HAVE -- >> VARIABILITY YOU MEAN? >> YEAH. >> WE DID NOT NORMALIZE TO WEEKS OF GESTATION IN PART BECAUSE THERE WERE NO STATISTICALLY SIGNIFICANT DIFFERENCES IN THE DISTRIBUTIONS OF THE GESTATIONAL TIME POINTS ACROSS SITES. SO IN PRINCIPLE WE COULD TRY TO CORRECT FOR THE SPECIFIC GESTATIONAL TIME POINTS OF THE ACTUAL STUDIES BUT BECAUSE BOTH SITES HAD SOME VARIABILITY IN BOTH T2 STAR AND GESTATIONAL AGE AND DIFFERENCES IN THE GESTATIONAL AGES WEREN'T SIGNIFICANT SO WE'RE SAMPLING EFFECTIVELY AT THE SAME TIMES. >> OKAY. JUST ONE MORE QUESTION. WHEN I LOOK AT THE HISTOGRAM IT LOOKS PRETTY SMOOTH BUT THEN THE SPATIAL DISTRIBUTION LOOKS HETEROGENEOUS. DO YOU HAVE ANY INSIGHTS ON WHY THE HISTOGRAM LOOKS QUITE SMOOTH EVEN THOUGH -- >> TENS OF THOUSANDS OF MEASUREMENTS, IT'S JUST A LOT OF DATA AND THERE'S A CONTINUOUS DISTRIBUTION OF T2 STAR VALUES UP TO THE UPPER LIMIT WHICH IS, YOU KNOW, 150 TO 200 MILLISECONDS FOR FULLY OXYGENATED BLOOD, SO -- >> WHAT I'M ASKING IS SOMETIMES WHEN YOU HAVE A HIGH VERSUS LOW CLEARLY YOU HAVE TWO DIFFERENT -- >> IT'S NOT -- IT'S STILL CONTINUOUS. I THINK SOMETIMES WHEN YOU APPLY COLOR MAPS TO IMAGES YOU CAN FOOL YOURSELF INTO THINKING IT'S MORE DISCREET, AND I THINK IT'S NOT. THAT'S CONSISTENT WITH WHAT WE'VE SEEN IN THE PRIMATES AS WELL, THAT THE DISTRIBUTIONS ARE CONTINUOUS, EVEN THOUGH YOU HAVE SPATIAL HETEROGENEITY IN THE PLACENTA. >> ALL RIGHT. THANK YOU. >> A QUESTION ABOUT SPECIFICITY OF T2 STAR MEASUREMENT, NOT JUST DUE TO OXYGEN CONTENT, COULD BE EDEMA, SO, FOR EXAMPLE, IN SOME CASES IT MAY NOT BE LESS OXYGEN SUPPLY, THERE MAY JUST BE MORE FIBROTIC CHANGE IN THE EDEMA CASE WITH ZIKA IT COULD BE EDEMA DRIVING THE CHANGE IN T2 STAR VALUES NOT NECESSARILY CHANGES IN OXYGEN CONTENT. HOW DO YOU PROPOSE TO TEASE THEM APART AND DETERMINE WHAT IS OXYGEN VERSUS OTHER FACTORS? >> SO EDEMA, FLUIDS CAN HAVE HIGH T2 STAR VALUES, IF YOU LOOK CAREFULLY AT IMAGES YOU'LL SEE AMNIOTIC FLUID IS HIGH, THAT'S A POTENTIAL ISSUE IF YOU HAD EXTENSIVE DIFFUSE EDEMA THAT CULD MASQUERADE AS SOMETHING THAT ELEVATED T2 STAR. ONE OF THE THINGS WE'VE DONE IN THE PRIMATE STUDIES, WE'VE INDUCED MATERNAL HYPOXIA, YOU CAN LOOK SPECIFICALLY AT SORT OF INVERSE OF WHAT'S COMMONLY DONE IN BOLD, BUT YOU CAN LOOK AT CHANGE, AND THOSE CHANGES WILL NOT AFFECT EDEMA SO WE HAVE A SOLID SENSE BY DOING PERTURBATION. MOST TISSUES HAVE LOW T2 STAR VALUES COMPARED TO OXYGENATED BLOOD SO THE ACTUAL CONTRIBUTION OF THAT, IF YOU HAVE A FIBROTIC FRACTION, IT'S PROBABLY, YOU KNOW, LESS IMPACTFUL THAN CHANGES IN OXY VERSUS DEOXYHEMOGLOBIN. >> DID YOU TRY GIVING INSTEAD OF DEPRIVING OXYGEN? THAT COULD INCREASE SIGNAL INTENSITY, CORRECT? >> WHEN WE'RE DOING PRIMATES WE DO AT BASELINE 100% SO THEY START HYPEROXIC OR FULLY OXYGENATED AND STEP THEM DOWN IN INCREMENTS. THERE ARE CHANGES, CERTAINLY THERE ARE BIG CHANGES GOING FROM 100% O2 TO 95% O2. BUT WE DON'T HAVE, YOU KNOW, A BASELINE OF HYPEROXAI. >> DAVID WEINBERG, NICHD. THIS IS AN OPPORTUNITY TO TELL THE GROUP IN RESPONSE TO SOME THINGS DR. BIANCHI HEARD AFTER HER TALK THIS IS A PERFECT EXAMPLE OF HOW IN SUPPORT OF THE HUMAN PLACENTA PROJECT ANIMAL MODELS AND AN MOL ANIMAL WORK IS INSTRUMENTAL AND WHY NICHD SUPPORTS IT, THAT LAID DOWN THE FOUNDATIONAL WORK. I HAVE A CHALLENGE FOR THE GROUP BECAUSE I NOTICE IN JOHN SLED'S TALK AND NOTICED HERE IS THAT IF YOU LOOK AT POPULATIONS, YOU CAN SEE GOOD DIFFERENTIATION BETWEEN NORMAL AND PATHOLOGICAL BUT WHEN YOU ARE WITH AN N OF ONE WOMAN IN FRONT OF YOU IT'S DIFFICULT, I SEE AT THE EXTREMES IT WORKS, SO I CHALLENGE THE GROUP TO FIGURE OUT HOW WE CAN MAYBE COMBINE TECHNIQUES SO WE HAVE THAT SORT OF n-OF-1 RESOLUTION. THE LAST THING IS THE THING ABOUT MARGARETA PISARSKA'S TALK, IT WOULD BE INTERESTING TO LOOK AT SEX DIFFERENCES ON YOUR DATA. YOU DON'T HAVE TO ANSWER NOW BECAUSE I'M GETTING THAT LOOK. >> ALL RIGHT. I WANT TO THANK DAVID FOR SETTING UP MY QUESTION, IT'S A QUESTION THAT RELATES TO n-OF-1 ONE IN THE MIDDLE OF THE NIGHT. THERE'S A DEBATE RAGING FROM A WHOLE DIFFERENT -- A RANGE OF SOURCES, TRANSCRIPTOMIC OR THE PLACENTA OR GENERAL PHYSIOLOGY OR THE STUDIES HERE SHOWING, THAT THE CAUSES OF PREECLAMPSIA ARE MANY AND THERE MAY BE THOSE PRIMARILY FAILURE OF ANTIGENESIS, HYPOXIA FROM THE SITE, AND INITIAL INSULT IS INFLAMMATION WHICH CAN PROMOTE SECONDARY HYPOXIA. HAVE YOU LOOKED AT THOSE CASES OF ADVERSE PREGNANCY OUTCOME THAT MATCHED YOUR CONTROL LINES VERSUS THOSE WELL BELOW THE CONTROL LINES FOR INFLAMMATORY MARKERS, DO YOU KNOW IF YOU CAN DISCRIMINATE FROM INFLAMMATION MARKERS, PARTICULARLY TNF AND INTERLEUKIN? >> GREAT QUESTION. WE HAVEN'T DONE IT YET, IT'S A SMALL SUBSET. WE COLLECT MORE PATHOLOGIC CONDITIONS, WE'D LIKE TO DO THAT TOGETHER. >> YEAH. >> BUT CLEARLY THAT'S THE MOST IMPORTANT POINT, GIVES US ONE COMPONENT, POTENTIALLY OF ADVERSE PHYSIOLOGY, BUT THE VARIABLES IMPACTING THAT AND DIFFERENTIALING SOME MAY NOT PLACENTA DIRECTLY MEDIATED, SO THE TEST WOULDN'T SEE THAT, BUT THERE ARE MANY THAT ARE AND LEARNING ABOUT WHICH THOSE ARE WILL HELP US DEFINE BIOLOGIC SIGNATURES FOR THOSE IMAGING PHENOTYPES. >> THANK YOU. >> I'M (INAUDIBLE) IN NICHD. I I WANT TO UNDERSTAND YOUR TAKEHOME MESSAGE ABOUT OXYGENATION, OXYGENATION GOES DOWN? >> YES. >> TWO FOLD? >> QUITE A LOT. T2 STAR IS NOT LINEARLY RELATED TO OXYGENATION, YOU HAVE TO TAKE THE INVERSE, FOR EXAMPLE, THEY TALKED ABOUT R2*, MORE DIRECTLY LINEARLY RELATED, IF YOU WANTED TO SAY YOU HAVE TO DO SOME COMPUTATIONS TO ESTIMATE WHAT YOUR OXYGEN LEVELS ARE BUT THEY DECREASE SUBSTANTIALLY OVER PREGNANCY. >> AND THEN WHAT IS THE RELATIONSHIP OF THIS OXYGENATION WITH MATERNAL OXYGENATION, IN THE TISSUE, SORRY, MATERNAL TISSUE VERSUS THE PLACENTA? >> WE CAN'T EASILY -- WE MEASURE MATERNAL SPO 2s, ALL GENERALLY IN THE NORMAL RANGE, BUT THE MATERNAL TISSUES DON'T HAVE THE SAME ANATOMIC FEATURES THE PLACENTA DOES, YOU CAN'T DIRECTLY COMPARE THEM TO THE PLACENTA. >> THAT MEANS THE NUMBERS YOU ARE GIVING BECAUSE OF THE HETEROGENEITY OF THE PLACENTA? >> YEAH, RIGHT, SO THE PLACENTA HAS A SPATIAL STRUCTURE WHERE THERE'S A GRADIENT AND OXYGEN -- BLOOD OXYGEN LEVEL COMING FROM THE MOM, SO THERE'S THE INLET FULLY OXYGENATED, GRADUALLY BECOMES DEOXYGEN RATION, OXYGENATION, LATER IN PREGNANCY THE FETUS IS CONSUMING MORE OXYGEN. THE PLACENTA WE CAN'T SEPARATE, I DON'T THINK. >> WE HAVE MATERNAL OXYGEN SATURATION, WE HAVE MATERNAL HEMOGLOBIN BUT DIRECT TISSUE MEASUREMENT OF NEARBY OXYGENATION WE DON'T HAVE A DIRECT MEASUREMENT. WE DON'T HAVE AN ARTERIAL LINE IN GETTING A CONTINUOUS MEASURE OF WHAT THE SATURATION IS DOING. >> THIS IS EXACTLY WHAT'S THE POINT, DIFFERENT OXYGENATION, THE THING YOU'RE MEASURING WITH YOUR BOLD SIGNAL IS NOT EXACTLY THE SAME. >> ALL RIGHT. [APPLAUSE] >> YOU HAVE GREAT QUESTIONS, YOU CAN TALK TO ALL THE PRESENTERS DURING LUNCH TIME AND NETWORKING. THE NEXT TALK TOTAL UTERINE BLOOD FLOW AND PERFUSION BY ULTRASOUND AND MRI BY DR. DINESH SHAW AND DR. WIEBEN FROM UNIVERSITY OF WISCONSIN MEDICAL SCHOOL. >> GOOD MORNING. THANK YOU FOR THE OPPORTUNITY TO PRESENT AND THANKS TO NICHD FOR THIS OPPORTUNITY TO DO THIS WORK. AND TO DAVID'S POINT, THE ONLY U01 FUNDED WITH ANIMAL WORK THAT WAS DESIGNED TO REALLY DO DEVELOPMENTAL WORK THAT WE CAN APPLY TO HUMANS. SO, WHAT I'M GOING TO TELL YOU IS THE MOST IMPORTANT THING ABOUT OUR PRESENTATION. THE OVERALL OVERARCHING CONCEPT. AND ONCE YOU HEARD IT, IF YOU SPACE OUT WHEN YOU COME BACK YOU'LL BE ABLE TO FOLLOW. BECAUSE I'M COUNTING ON MANY OF US TO SPACE OUT. SO HERE IS THE CONCEPT. FUNCTION OF AN ORGAN DEPENDS ON TOTAL UTERINE -- TOTAL BLOOD FLOW. WE FIGURED OUT THE CONCEPT WHAT IS TOTALLY UTERINE FLOOD FLOW. THE FUNCTION OF THE ORGAN DEPENDS ON PERFUSION. WE'RE DOING PERFUSION MAPPING. NEXT IS OXYGENATION, WE'RE DOING MAPPING OF OXYGENATION IN THE PLACENTA. AND THE QUESTION WE ASKED WHAT IS THE NEXT STAGE? AND THE NEXT STAGE IS INFLAMMATORY EVENT THAT OCCURS IN HIGH RISK PREGNANCIES WHERE MACROPHAGES ARE RECRUITED, AND WE CAME UP WITH A VERY CREATIVE WAY TO APPROACH THAT AND THAT WAS IF WE INJECT IRON CONTAINING COMPOUND, IT IS PICKED UP BY MACROPHAGES AND THEREFORE WE CAN ACTUALLY IN LIVE HUMAN BEINGS IMAGE MACROPHAGES BEING RECRUITED IN THE PLACENTA INTERFACE. TO DO THAT WE HAD TO HAVE A PRIMATE MODEL TO DO THE DEVELOPMENT WORK SO WE'RE GOING TO TELL YOU ABOUT SOME OF THE PRIMATE WORK, AND SOME OF OUR WORK RELATED TO TOTAL UTERINE BLOOD FLOW AND PERFUSION. WE'RE NOT ABLE TO MOVE IT. OKAY. SO THIS IS PART OF OUR TEAM. WE HAVE MRI PHYSICISTS, MRI RADIOLOGISTS, WE HAVE PLACENTAL BIOLOGISTS, PEOPLE WITH PRIMATE BIOLOGY EXPERT, IMMUNOLOGY EXPERT, MATERNAL-FETAL MEDICINE, CLINICAL MEDICINE EXPERTISE, THIS IS LIKE PROBABLY THE LARGEST TEAM OF ANY OF THE U01 GROUPS. SO, AS FAR AS THE TOTAL UTERINE BLOOD FLOW IS CONCERNED, THE QUESTION IS WHY WE NEED TO LOOK AT IT, SO ALL THE UTERINE ARTERY VASCULAR DOPPLER WORK GIVES YOU MEASUREMENTS OF VASCULAR RESISTANCE OF STRAIN WHILE WE WOULD LIKE TO ACTUALLY KNOW WHAT IS THE TOTAL BLOOD FLOW TO THE UTERUS, AND SINCE VAST MAJORITY OF IT ACTUALLY GOES TO THE PLACENTA, WE THOUGHT THAT WE CAN -- EVEN IF WE DON'T DIFFERENTIATE HOW MANY GOES TO UTERINE AND HOW MUCH TO PLACENTA WE STILL HAVE A GOOD HANDLE ON WHAT WE'RE LOOKING AT, WOULD DO IT WITH ULTRASOUND APPROACH AND DO IT WITH 4D FLOW WITH MRI AND THE PERFUSION WITH RHESUS MODEL AND RESULTS AND TELL YOU ABOUT SAFETY RELATED TO FERUMOXYTOL USE. THIS IS THE FIGURE WHEN WE EXPLAINED TO THE RADIOLOGIST WHAT WE'RE REALLY TALKING ABOUT AS FAR AS WHICH PARTICULAR BLOOD VESSELS WE'RE REFERRING TO. SO IF YOU LOOK AT THE UTERINE BLOOD FLOW, THE INFLUENCE FROM FOUR VESSELS, UTERINE ARTERIES, TWO UTERINE BRANCHES OF THE OVARIAN ARTERY, SO AFTER THE OVARIAN ARTERY SUPPLIES TO THE OVARY, THERE IS A OVARIAN STEM ARTERY THAT TRAVELS IN ANAYS THAT -- ANASTAMOSIS. BLOOD FLOW IN NON-PREGNANT STATE, BUT OVARIAN STEM ARTERY BLOOD FLOW INCREASES IN PREGNANCY, PRIMARY DATA SHOWS ORIGIN DEVELOPED IN WISCONSIN FROM 17 TO 34% OF THE BLOOD FLOW TO THE UTE RESISTANCE DURING PREGNANCY COMES HAVE OVARIAN BRANCHES, SO WE WANTED TO FOCUS ON THESE VESSELS, AND THIS FIGURE SIMPLY SHOWS THAT THIS IS THE BRANCH WE'RE REALLY REFERRAL TO, THAT THE ANATOMY IS VARIABLE. WE FIGURED OUT WITH DOPPLER ULTRASOUND WE CAN SEE THE OVARY, OVARIAN VASCULATURE AND TRY TO IDENTIFY ARTERY FLOWING AND ANASTAMOSING, HELPING US FIGURE OUT WE'RE IN THE CORRECT LOCATION. SO WE MEASURE THIS AT FOUR VESSELS AS WE POINTED OUT, AND IN THE YOU -- ULTRASOUND AND CONVENTIONAL APPROACH AS I POINTED OUT HAS BEEN WITH THIS DOPPLER FLOW STUDIES WHERE YOU LOOK AT THERE'S A GOOD DIASTOLIC FLOW IN THE UTERINE ARTERY AND PATHOLOGIC PREGNANCIES HAVE POOR DIASTOLIC FLOW AND NOTCH AND ELEVATED P.I. BUT THAT DOESN'T STILL TELL US ABOUT WHAT WE REALLY OUGHT TO KNOW FROM POINT OF VIEW OF FUNCTION OF AN ORGAN. IF WE USE THE POINT, EQUIPMENT AND PARK THE DATA IN THE VIEWPOINT SYSTEM, MEASURE TWO UTERINE ARTERIES AND BRANCHES, IF YOU'RE INTERESTED IN TECHNICAL DETAILS WE HAVE A POSTER TODAY, 9, 10, 11, YOU CAN GO BY AND WE CAN EXPLAIN HOW THAT'S DONE. WE DO DOPPLER FLOW MEASUREMENT AND DERIVE ALL THE INDICES THAT COME OUT BUT TWO WE'RE FOCUSED ON FOR MEASURING BLOOD FLOW WAS TIME AVERAGE VELOCITY MAXIMUM AND TIME AVERAGE VELOCITY MEAN. WE ALSO UPDATE DATA ON VESSEL LENGTH, VESSEL DIAMETER, IN ORDER TO CALCULATE FLOW, AND HAVE THE DATA ON HEARTRATE TO CALCULATE FLOW PER MINUTE, ANALYSIS OF FLOW BY TWO METHODS, BY USING TAVMAX WE'RE APPLYING PRINCIPLES OF FLUID DYNAMICS SO WE CALCULATE THE CONSTANT, THE IDEA IS AS THE FLOW TRAVELS FURTHER DOWNSTREAM IN A VESSEL, THAT THE VELOCITIES ACTUALLY CHANGE SO YOU NEED THESE MODIFICATIONS TO REALLY ARRIVE AT WHAT, QUOTE/UNQUOTE, THE TRUE VELOCITIES MIGHT BE AND APPLY VESSEL DIMENSIONS TO CALCULATE FLOW. TAVMEAN, AVERAGE VELOCITY, SORT OF ACCOUNTED FOR IT SO YOU CAN DIRECTLY TAKE THE CROSS-SECTION AREA AND DETERMINE THE FLOW DONE PRECISELY IN MRI. THIS IS TIME POINTS. WE WERE CAUTIOUS ABOUT NOT PROPOSING TO DO MRI IN THE FIRST TRIMESTER AND TIME POINTS IS VERY SIMILAR TO THE UCLA GROUP, AND ANTONIO'S GROUP, FIRST ULTRASOUND AND MRI BETWEEN 14 AND 16 WEEKS, SECOND BETWEEN 20 AND 22 WEEKS LIKE 20 AND 6/7, YOU CAN'T GO BEYOND. PILOT STUDIES, MAKE SURE WHAT WE LEARN FROM RESEARCH WORK, APPLICABLE FOR METHODOLOGIES, FOR PERFUSION, FOR BOLD, AND FOR PV VIPER TO DETERMINE THE FLOW AND SO WE DID THAT AND OUR DATA IS ABOUT SUBJECTS, FOCUS ON LET'S GET NORMATIVE DATA. COMPARISON GROUP IS ATOB SUBJECTS, DOING DISCRETE GROUPS WAS COMPLICATED, USING BMI AS THE VARIABLE, AND WE HAVE RECRUITED OB SUBJECTS BUT FOCUSING ON 47 LEAN SUBJECTS OUT OF WHICH WE ANALYZED DATA COMPLETE FOR ALL THE VESSELS ON 37 SUBJECTS. SO THIS GIVES YOU SOME INFORMATION ON WHAT IS REALLY -- WHAT ARE WE FINDING. IF YOU USE -- THIS IS LISTED AT 14 WEEKS, THIS IS 20, 22 WEEK WINDOW. MEAN STANDARD DEVIATION. MEAN GAVE US LOWER VALUES THAN TAVMAXINE THOUGH WE APPLIED PRINCIPLES OF FLUID DYNAMICS. WE HAVE THOUGHTS AS TO WHAT IT COULD BE. WE'RE GOING DO CONSULT WITH JOHN SLED AS TO HOW DO WE REALLY FIGURE OUT WHAT'S ACTUALLY TRUE FLOW. AT ANY RATE, IF THAT'S THE APPROACH YOU TAKE WE'RE USING CONVENTIONAL COMMERCIALLY AVAILABLE EQUIPMENT, WHAT IS THE NUMBER THAT WE SHOULD LOOK AT? AND THIS IS WHAT WE'RE COMING UP WITH SO THAT THE 20 TO 22 WEEK WINDOW, 5th AND 10th PERCENTILE, 174 MILLIMETERS PER LIMIT, CALCULATION DERIVED BY THIS METHOD FOR ALL THE FOUR VESSELS OUGHT TO BE TREATED AS THIS IS THE CUTOFF AND ANYTHING BELOW SHOULD BE TREATED AS HAVING LOW UTERINE BLOOD FLOW. WE HAVE SLIGHTLY DIFFERENT APPROACH IN THE MRI, AND I'M GOING TO LET OLIVER TELL YOU ABOUT IT. WE WERE MINDFUL OF IT, THAT BODY SIZE CAN MAKE A DIFFERENCE, CARDIAC OUTPUT CAN MAKE A DIFFERENCE, AND WE REALIZE WE DON'T HAVE A GOOD WAY OF ACTUALLY CAPTURING THE CARDIAC OUTPUT SO WE DECIDED WE'RE GOING TO TAKE THE INFERIOR AORTIC FLOW. WE'VE STARTED DOING THAT NOW. BUT WE WERE COLLECTING BMI DATA AND BMI DOES NOT ACTUALLY AFFECT THE TOTAL UTERINE BLOOD FLOW, SO FAR WITHIN THIS RANGE OF NORMAL BMI WOMEN ARE ABLE TO ACLEAVE -- ACHIEVE AS FAR AS NORMAL. WHEN WE LOOK AT RELATIONSHIP BETWEEN THE TAVMAX AND TAVMEAN VALUES, THEY CORRELATE BECAUSE THEY ARE DERIVED FROM SAME DATA, USING TWO METHODS FOR COMPUTING BUT WHEN WE LOOK AT ABSOLUTE VALUES I THINK WE BECAME A LITTLE CAUTIOUS LIKE TAVMAX IS PROBABLY VERY OVERESTIMATING. WE TAVMEAN IS OVERESTIMATING, WE HAVE A CUTOFF FOR DETERMINING WHO HAS LOW UTERINE BLOOD FLOW. THESE ARE MEAN AND 10th PERCENTILE, 20 TO 22 WEEK WINDOW, 174 MILLILITERS PER MINUTE OUGHT TO BE THE CRITERIA WE USE IN OUR OBESE SUBJECTS TO IDENTIFY HIGH RISK POPULATIONS WHO WOULD THEN DOWN THE ROAD MAYBE OFFER FERUMOXYTOL INJECTION FOR US TO MAP THE UTERINE INTERFACE. WE'RE ACTUALLY, AS WE GET HOME, THE FIRST TASK TO SUBMIT THE APPLICATION, VOLUMINOUS DATA ON ALL THE THINGS WE CAN APPLY TO FDA FOR GETTING APPROVAL FOR FERUMOXYTOL USE. OLIVER? >> SURE. THANK YOU, DINESH. I'M SWITCHING GEARS FROM ULTRASOUND TO MRI, MY AREA OF EXPERTISE, WELL SUITED TO DO FLOW MEASUREMENT FOR CARDIOVASCULAR IMAGING, USED FOR PLACENTA FLOW ASSESSMENT IN SMALLER PILOT STUDIES, A DECENT 2D STUDY LOOKED AT MIMICKING ULTRASOUND, FROM 2016, THE SAME CONCEPT OF INCORPORATING TOTAL UTERINE BLOOD FLOW, NOT JUST CONCENTRATING ON UTERINE CONTRIBUTIONS. MIXED SUCCESS IN THAT STUDY. IN ORDER TO PLACE THE PLANES OR MEASURE 2D FLOWS YOU NEED A GOOD ANGIOGRAM. WE DON'T GIVE CONTRAST, THE TIME OF FLIGHT ANGIOGRAMS TURNED OUT TO BE NOT SUFFICIENT, ONLY IN 20% OF PATIENTS I COULD FIND OVARIAN ARTERIES. SO WE TRIED TO ADDRESS THAT WITH ANOTHER APPROACH, 4D FLOW MRI, WE'LL SHOW YOU IMAGES TO EXPLAIN WHAT THAT MEANS, VOLUMETRIC ACQUISITION WHERE YOU DO ANALYSIS OF THE FLOW RETROSPECTIVELY. SO WHAT WE SET OUT TO LOOK AT UTERINE CONTRIBUTIONS, OVARIAN, OVARIAN STEM IN ARTERIES AND VEINS, IN THE SAME POPULATION THAT DINESH HAS MENTIONED, EARLY AND MID-SECOND SEMESTER. THE REASON, WHAT WE WOULD LIKE TO IMAGE IS OVARIAN STEM ARTERIES, WE OFTEN HAD PROBLEMS WITH THAT BECAUSE OF LIMITS IN SPATIAL RESOLUTION AND THEREFORE WE HAD TO GO BLOODSTREAM, OVARIAN ARTERIES AND OVARIAN VEINS. THIS WAS OUR FIRST RESEARCH PROJECT IN TERMS OF MRI GROUP, AND IMAGING AND PREGNANCY AND WE STARTED WITH ANIMAL MODEL, RHESUS MACAQUE MODEL THAT WAS A VERY GOOD CHOICE FOR US. THE ADVANTAGES OF IMAGING IN SUCH A MODEL IS THAT WE HAVE MUCH BIGGER PARAMETER SPACE TO EXPLORE. WE CAN DO LONGER SCAN SESSIONS, WE CAN VARY PARAMETERS TO COMPARE, STABILITY STUDIES, SERIAL STUDIES LIKE DAY TO DAY VARIABILITY, HARD TO JUSTIFY IN HUMANS AND FOR INITIAL GROUND WORK DRAMATICALLY REDUCES MOTION ON MATERNAL AND FETAL SIDE, MOM IS ANESTHETIZED, SO IS THE FETUS, YOU ELIMINATE RANDOM MOTION OF THE FETUS. USING OVERVIEW OF THE 4D FLOW MRI PROVIDES BOTH ANATOMIC REPRESENTATION, ANGIOGRAM AND FLOW MEASURES FROM THE RHESUS MACAQUE WITHOUT CONTRAST AGENT, BEAUTIFUL VASCULATURE INCLUDING FETAL VASCULATURE AND UMBILICAL CORD WHICH WE DON'T SEE IN HUMANS BECAUSE THE FEET SUSS NOT ANESTHETIZED. RETROSPECTIVELY YOU CAN ANALYZE VELOCITY AND FLOW PROFILES. WE'VE LEARNED THAT WE SAW UTERINE ARTERIES IN THE MONKEYS WE IMAGING, OVARIAN ARTERIES WERE NEVER VISIBLE, A SURPRISE. MAIN DRAINAGE WAS OVARIAN VEINS, REPEATABLE IN 70%, WORSE THAN OTHER AREAS LIKE AORTA CRANIAL SCANS, MORE IN THE 10% RANGE BUT STILL SOMEWHAT ACCEPTABLE. SO NOW PRESENTING OUR FIRST DATA ON THE HUMAN STUDY, SUBSET OF 20 SUBSETS, AT 14 AND 20 WEEKS, ALWAYS IMAGE IN SUPINE POSITION. THREE OBESE, TEN NON-OBESE, LARGE IMAGING VOLUME WE CAN PRESCRIBE, 4D ACQUISITION. LET ME SEE, THE YELLOW BOX, IT'S NOT DIFFICULT TO TARGET THE VESSEL THAT YOU'RE IMAGING, THEY ARE INCLUDED IN IMAGING VOLUME. . HERE ARE RESULTS SHOWING VISIBILITY OF VESSELS, ANGIOGRAMS CONSTRUCTED WHERE WE HAVE THE LARGE MAJORITY OF THOSE SUBJECTS WE SAW UTERINE ARTERIES, NO OVARIAN ARTERIES, OR OR BOTH OVARIAN ARTERIES. AND THEN WE HAD A FEW CASES, NO UTERINE ARTERIES BUT EITHER ONE OR TWO OVARIAN ARTERIES, DIFFERENT FROM THE MONKEYS WHERE WE NEVER SAW THE OVARIAN ARTERIES. HERE IS THE DISTRIBUTION OF THE FLOW LOOKING AT 14 AND 20 WEEKS FOR THE UTERINE OVARIAN ARTERIES. THOSE ARE NOT AVERAGES OVER ALL SUBJECTS, THIS IS OVER FOUR SUBJECTS, ON THE LEFT SIDE FOR 14 WEEKS, THAT ACTUALLY HAD OVARIAN CONTRIBUTIONS. SO WHAT I'M TRYING TO TELL YOU HERE IS THAT IN THE CASES THAT THERE WERE OVARIAN ARTERIES THERE WERE SIGNIFICANT CONTRIBUTIONS, A LITTLE UNEXPECTED FOR US. AND FROM THE LIMITED DATA WE HAVE HERE MOST OF THE BLOOD FLOW THAT INCREASED FROM 14 WEEKS TO 20 WEEKS WAS GOING THROUGH THE OVARIAN ARTERIES. WE ALSO TRIED TO LINK THE BLOOD FLOW TO THE PRESENTATION SIDE. WE THOUGHT IT MIGHT BE RATIONAL, OVARIAN, UTERINE ARTERIES MIGHT BE MORE INVOLVED IN BLOOD FLOW CONTRIBUTIONS, WE BASICALLY DIVIDED THE PLACENTA, SEGMENTATION INTO EIGHT, EIGHT VOLUMES, ANTERIOR, POSTERIOR, INFERIOR, TRIED TO LINK PREDOMINANT SITE OF PRESENTATION OF FLOW BUT DID NOT SEE IN THE LIMITED SET ANY CORRELATION, SO THAT HYPOTHESIS SO FAR HAS NOT WORKED OUT. SUMMARIZING RESULTS IN THE HUMANS WE THOUGHT IT WAS FEASIBLE, IN THE UTERINE ARTERIES IT WAS NOT FEASIBLE, IN THE OVARIAN STEM ARTERIES AT ALL. LIMITED VISUALIZATION OF OVARIAN ARTERIES, ISSUES WITH TECHNIQUE OR MORE LIKELY WE MISSED OVARIAN ARTERIES THAT HAD LOW FLOW CONTRIBUTION, THEREFORE WERE NOT VISIBLE IN ANGIOGRAM. AND SIMILAR TO THE MONKEYS, STILL NOTEWORTHY, WE SEE OUTFLOW MORE DOMINANT TO OVARIAN VEINS, ANECDOTAL EVIDENCE FROM RADIOLOGISTS WHO SAY THEY OFTEN SEE OVARIAN VEINS BUT HARDLY EVER SEE UTERINE VEINS. WE'RE RUNNING OUT OF TIME. THE FERUMOXYTOL STUDIES, THAT'S A CONTRAST AGENT THAT HAS PROMISED TO BE USED IN PREGNANCY, IRON SUPPLEMENT GIVEN IN PREGNANCY AS IT IS. AND VERSUS GADOLINIUM, WE USED TO DO HIGH RESOLUTION ANGIOGRAM AND PERFUSION STUDIES. SO HERE YOU SEE EXAMPLE, HIGH SPATIAL RESOLUTION, .5-MILLIMETER ISOTROPIC, YOU SEE A LOT OF SEGMENTAL BRANCH VESSELS, WITHIN THE PLACENTA. HERE'S DATA SEGMENTED. AND COLOR CODED FOR ARTERIES, VEINS, HERE IS DATA ON PLACENTA PERFUSION, WE'VE SEEN GROUPS PRESENTING ON PERFUSION, WHAT WE DO IN HUMANS, ASL PERFUSION, THAT PUTS CONTRAST IN HAND METHODS YOU CAN GET BETTER AND MORE DETAILED INFORMATION ON PERFUSION, AXIAL AND CORONAL PLANE AND DISTANCE. THERE'S TIME DELAY UP TO 50 SECONDS BETWEEN ARRIVAL AND LOBULES, ASL WOULD BE SENSITIVE IN THOSE IN FLOW ZONES, AFTER THAT SIGNAL IS LONG GONE BEFORE WE CAN SEE IT ON THE MRI. SO WE WERE INSPIRED BY THE WORK FROM THE OHSU GROUP WE JUST SAW IN THE PREVIOUS PRESENTATION, TO GO INTO LEVEL WHERE WE LOOK AT FUNCTIONAL UNITS, LOBULES AND COUNT THEM. I DON'T HAVE ENOUGH DATA BUT THAT'S THE DIRECTION, TO TRANSLATE TO HUMANS LOOKING FOR APPROVAL FOR FERUMOXYTOL, DINESH WILL SHOW A LITTLE BIT ON THE SAFETY OF THE DATA. >> I'M BETWEEN YOU AND LUNCH, I'M NOT GOING TO LET THAT HAPPEN TO YOU. OKAY. SO THIS WAS DEVELOPED REALLY -- FERUMOXYTOL WAS DEVELOPED FOR INSUFFICIENCY PATIENTS, ONE OF THE SAFEST IRON COMPOUNDS FOR GIVING INTRAVENOUSLY. IT HAS A LARGE CARBOHYDRATE MOIETY AROUND IRON, HENCE TAKEN UP BY MACROPHAGES, AND THEY ARE LOOKING AT ALL THESE CARBOHYDRATES AND QUEUE THAT UP AND RELEASE IRON INTO CIRCULATION. IT'S BEEN USED AND NOW ALSO USED FOR ANEMIA PATIENTS, THAT ARE REFRACTORY TO CONVENTIONAL TREATMENT, LOW SIDE EFFECTS, IT'S A ROBUST MRI CONTRAST AGENT DUE TO IRON RESPONSE TO MAGNETISM. WE TESTED WILL MACROPHAGES IN RHESUS WILL PICK UP THAT, AN IN VITRO STUDY SHOWING MONOCYTES WILL NOT, MACROPHAGES DO PICK UP. THIS IS BLUE STAINING. AND WHAT WE DID WAS IN VIVO STUDY, EXPOSING FERUMOXYTOL TO FIRST, SECOND, THIRD TRIMESTER TISSUES, THERE'S NO UPTAKE OF FERUMOXYTOL INTO THE PLACENTAL TISSUE. WE ALSO HAVE THIS IN VITRO -- IN VIVO DATA WHERE WE DID FERUMOXYTOL INJECTIONS, TOOK TISSUES AND LOOKED AT FERUMOXYTOL ACTUALLY IRON DOES NOT SHOW UP ON THE FETAL SIDE, OTHER THAN WHAT THE NORMAL AMOUNT OF IRON WOULD BE THERE ON THE FETAL SIDE. THE FETAL GROWTHS WERE NOT AFFECTED IN THE RHESUS MACAQUES EXPOSED TO FERUMOXYTOL, THIS TELLS YOU ABOUT TISSUE HISTOPATHOLOGY SCORING FOR THE PLACENTA, FETAL MEMBRANE, PLACENTAL BED, MATERNAL SPLEEN, MATERNAL LIVER, BLINDED PATHOLOGY SCORING, DO YOU SEE PATHOLOGY, NO DIFFERENCE BETWEEN ANIMALS THAT RECEIVE FERUMOXYTOL AND ANIMALS THAT DID NOT RECEIVE FERUMOXYTOL. AND THIS IS ACTUALLY ACTUAL IRON MEASUREMENTS IN THE TISSUE WHICH IS DONE WITH INDUCTION COUPLING, SPECTROSCOPY, AND LAB IN WISCONSIN CAN DO THAT FOR US, AND THIS SHOWS IRON IN DIFFERENT ORGANS. MATERNAL LIVER PICKS UP MOSTLY, KNOWN THE MATERNAL LIVER HAS LOTS OF MACROPHAGES AND WILL PICK UP THE IRON THAT IS FERUMOXYTOL THAT IS INJECTED IN THESE ANIMALS. WE ALSO LOOKED AT INFLAMMATION MODEL, I'M NOT PRESENTING THAT DATA BUT WE DID IL-6 INJECTIONS AND CREATED INFLAMMATION, AND IL-6 INJECTIONS WILL NOT INDUCE MACROPHAGE RECRUITMENT WHICH WE KIND OF KNEW ABOUT IT BUT THAT WOULD BE A PROBLEM. SO WE HAD ALREADY PROPOSED ALTERNATIVES, WORKING ON ALTERNATIVES TO RECRUIT MACROPHAGES IN THE PLACENTAL BED. HERE IS THE TEAM FROM OBSTETRICS AND GYNECOLOGY. THEY HAD TO LOOK AT EVERY ANGIOGRAM TO DECIDE WHICH VESSEL IS WHICH. ALEJANDRO WAS VERY INSTRUMENTAL IN GETTING US SORT OF CONNECTED TO THIS TEAM, AND DR. GOLUS WAS IN CHARGE OF THE PRIMATE PROJECTS AND THESE ARE THE POST DOCS, STUDENTS AND GRADUATE STUDENTS. THANK YOU VERY MUCH. [APPLAUSE] >> I DON'T THINK WE HAVE TIME FOR QUESTIONS. MAYBE ONE. ONE VERY SHORT QUESTION. JUST ONE. AND YOU CAN GRAB THEM DURING THE LUNCH. AND YOU SHOULD. >> DID YOU LOOK AT THE CORRELATION BETWEEN YOUR ULTRASOUND AND MRI MEASUREMENTS OF FLOW? >> SO, WHAT WE'RE FINDING IS BY MRI WE'RE GETTING MEASUREMENTS THAT ARE FAR DIFFERENT, MUCH LOWER THAN EVEN WITH TAVMEAN, AND PRAGMATICALLY, THAT'S THE NONE YOU GET IF THIS IS THE TECHNIQUE YOU USE. AND WE THOUGHT ABOUT WHY THAT IS SO, BECAUSE THE PC VIPER HAD TO BE SET UP, SUPPRESSING LATERAL SIGNALS AND INCREASING LONGITUDINAL SIGNALS, WE CAN SEE A LOT MORE VELOCITIES, YOU CAN SET SENSITIVITY OF THOSE VELOCITIES SO THE ONES WE SET UP FOR DETECTING VESSELS GIVES US TECHNICALLY LOWER FLOW IN MRI STUDY THAN IN ULTRASOUND. >> FOR THE SAME PERSON, IF A PERSON HAS HIGH FLOW WITH ONE MODALITY DO THEY HAVE HIGH FLOW WITH THE OTHER MODALITY? >> THERE'S CONSISTENCY BETWEEN THE TWO, RIGHT. >> ALL RIGHT. BEFORE WE LEAVE FOR LUNCH, THANK YOU SO MUCH. THANK YOU FOR A GREAT TALK WE ALL ENJOYED AND THE IMAGES. SPEAKER IS DR. ODIBO, PLACENTAL VASCULAR FLOW AND FETAL GROWTH RESTRICTION. >> GOOD AFTERNOON. I WANT TO THANK THE NICHD FOR THE OPPORTUNITY TO DO THIS WORK AND SUPPORTING US THE LAST THREE YEARS. THE ASSOCIATION BETWEEN FETAL GROWTH RESTRICTION AND PERINATAL MORBIDITY AND MORTALITY IS KNOWN WORLDWIDE, OVER THE YEARS IN THE U.S. ESPECIALLY WE KNOW THAT EVERY YEAR UP TO HALF A MILLION BABIES ARE BORN THAT ARE GROWTH RESTRICTED, SO THIS IS A SIGNIFICANT ECONOMIC IMPACT TO THE U.S. THE ROLE OF PLACENTA INSUFFICIENCY HAS BEEN UNDERSTOOD BUT WE HAVE NO RELIABLE WAY OF REPORTING VASCULARIZATION IN A NON-UNVASIVE MANNER OF THE PLACENTA. MANY YEARS AGO, THE FIRST ATTEMPTS AT LEAST CLINICALLY TRYING TO UNDERSTAND VASCULAR FLOW IN RELATIONSHIP WITH GROWTH RESTRICTION USING DOPPLER WAS DESCRIBED [ NO AUDIO ] PLACENTA GROWTH FACTOR, MANY FOUND WERE USEFUL AND ASSOCIATED WITH PREECLAMPSIA AND GROWTH RESTRICTION. HOWEVER, WHEN YOU LOOK AT SENSITIVITY OF THE AREA, AT MOST ABOUT 0.7, NOT GOOD ENOUGH FOR CLINICAL USE. SO THIS IS THE SLIDE SHOWING DIFFERENT STORIES, TRYING TO COMBINE DOPPLER AND SERUM MARKERS, AND TO TRY AND IMPROVE PREDICTION OF ADVERSE PREGNANCY OUTCOMES. THE GROUP FOUND IF YOU LOOK WITH THE FIXED FORCED POSITIVE RATE OF 10% COULD GO TO 78% WITH DETECTION OF PREECLAMPSIA. SIMILARLY, 90% WITH SIX FORCED POSITIVE RATE OF 10%, BUT WHEN YOU LOOK AT LEAL ET AL., GROWTH RESTRICTION, SENSITIVITY WAS 36%. UTERINE ARTERY DOPPLER OR OTHER SERUM MARKERS COMBINED DID NOT HELP US VERY MUCH. WE STARTED LOOKING, TRYING TO LOOK AT VASCULAR FLOW IN THE PLACENTA TO SEE HOW THIS WILL IMPROVE OUR PREDICTION OF ADVERSE PREGNANCY OUTCOME. A FEW YEARS BACK PEOPLE DESCRIBED ASSOCIATION BETWEEN LOW PLACENTA VOLUME AND POOR INNOVATION BY TROPHOBLAST. NOW IT'S POSSIBLE TO ACTUALLY DO THIS IN -- NOT IN REAL TIME BUT POST-PROCESSING TO BE ABLE TO MEASURE AND QUANTIFY THE PLACENTA VOLUME AND TO SEE IF THIS CAN BE USED TO PREDICT ADVERSE OUTCOMES. THIS IS THE TECHNOLOGY PREVIOUSLY -- THAT WAS DESCRIBED BY G.E., THIS IS LOOKING AT THE VOCAL TECHNOLOGY, AFTER YOU TRACED THE PLACENTA YOU CAN THEN USE TRACING TO GET THE PLACENTA VOLUME. AND USING PLACENTA VOLUME, MOST OTHERS WERE ABLE TO DESCRIBE AN ASSOCIATION BETWEEN PLACENTA VOLUME AND ADVERSE OUTCOMES INCLUDING FETAL GROWTH RESTRICTION. OUR GROUP ALSO WERE ABLE TO SHOW THIS WHEN I WAS AT WASH-U, AND ASSOCIATION BETWEEN SMALL PLACENTA ON PLACENTA VOLUME, USING ULTRASOUND AND GROWTH RESTRICTION. HOWEVER, SIMILAR TO WHAT WE FOUND UTERINE ULTRA DOPPLER, SERUM MARKERS, SENSITIVITIES WERE ALSO VERY LOW. IT MAKES US FEEL WE HAVE TO LOOK FOR OTHER INDICES. SOME OTHER INDICES WE LOOKED AT, WE'RE LOOKING AT VASCULAR INDICES IN THE PLACENTA, USING TECHNOLOGY FROM G.E. CALLED VOCAL AND VASCULARIZATION INSEX, VI, THE FLOW INDEX, FI, AND VOSS -- VASCULARIZATION FLOW, A COMBINATION OF THE TWO. PREECLAMPSIA AND GROWTH RESTRICTION WERE AGAIN MODEST, AT BEST. SO AT THIS POINT, WHAT WAS THE LIMITATION WITH LOOKING AT VASCULAR INDICES USING VOCAL, THE SETTINGS OF THE ULTRASOUND MACHINE WERE AFFECTING VASCULAR FLOW INDICES WE WERE GETTING FROM VOCAL. THE SECOND ISSUE WAS IN RECONSTRUCTING PLACENTA VOLUME, SOMETIMES THE EDGES OF THE PLACENTA ON ULTRASOUND LOOK VERY VAGUE AND VERY -- THEY LOOK VERY DULL. WHEN YOU PUT IN YOUR TRACING, YOU MAY BE FALSELY INCREASING THE VOLUME AND SO IT'S NOT AS PRECISE AS YOU REALLY WANT IT TO BE TO USE THIS FOR CLINICAL CARE. SO, COULD THIS BE -- THIS THESE PROBLEMS BE ALLEVIATED USING SOFTWARE, POSSIBLY THIS IS WHERE DR. COLLINS FROM OXFORD AND HER COLLEAGUES IN NEW JERSEY ARE WORKING ON LOOKING AT AUTOMATED SOFTWARE, TRYING TO USE THESE SO DEPENDENT ON HUMAN TRACING. AND SO UNTIL WE HAVE THOSE RESULTS WE DON'T KNOW. BUT SIMILARLY THIS PART OF THE TALK I CALL THE SALLY COLLINS SLIDES BECAUSE THIS NEXT SLIDE IS A PAPER THAT WAS REPORTED BY SALLY AND HER GROUP FROM OXFORD, A FEW YEARS BACK. BASICALLY DESCRIBING THE SPIRAL (INDISCERNIBLE). IF WE CANNOT USE 3D VOLUME IN PREDICTING ADVERSE OUTCOME, CAN WE USE A 2D ULTRASOUND TECHNOLOGY THAT EVERYBODY CAN USE, AND USE THIS TO PREDICT OUTCOMES? SO, WE'RE INTERESTING IN USING 2D TO LOOK AT THE SPIRAL ARTERY AND SOME PLACENTA VESSELS. SO, THIS WAS A VERY BEAUTIFUL PICTURE, AND WE TRIED TO REPRODUCE THESE, AND IT WAS SOMETIMES PRETTY DIFFICULT, THIS IS JUST LOOKING AT A FLOW HERE AND LOOKING AT I THINK -- I'LL USE THE POINTER HERE. YOU CAN SEE IF YOU LOOK HERE, THE SPIRAL ARTERY THAT YOU CAN SEE HERE, THE JETS ARE REALLY SMALL. IT COULD BE WE'RE UNLOCKING MOST OF THE PATIENTS, BUT I'M SURE SALLY WILL AGREE THAT TO REALLY GET A GOOD SPIRAL ARTERY JET LIKE THEY DID IN THOSE PAPERS TAKES A LOT OF TIME AND A LOT OF EFFORT. SO, WE WERE REALLY IMPRESSED WHEN WE LOOKED IN THE LITERATURE AND TRIED TO LOOK ON THE INTERNET AND SAW THIS TECHNOLOGY THAT WAS DESCRIBED BY SHEBA, NOW CANNON, CALLED THE SUPERB MICROVASCULAR IMAGING, SMI. WE HAVE NO RELATIONSHIP, NO CONNECTION WITH TOSHIBA, WE HAD TO BUY THE MACHINE FOR THIS STUDY. AND BASICALLY CONVENTIONAL DOPPLER, WHAT DOPPLER DOES IS THAT IT REMOVES THE CLUTTER AND MOTION ARTIFACTS AROUND YOUR ULTRASOUND WAVES, AND YOUR SOUND AND COLOR DOPPLER WAVES AND GIVES YOU A VERY GOOD PICTURE. BUT IN DOING THAT, IT ALSO RESULTS IN LOSS OF SOME OF THE LOW COMPONENTS WITHIN THE PLACENTA. SO THE IMAGE I SHOWED YOU A MINUTE AGO WHERE WE CANNOT REALLY SEE THE SPIRAL JETS VERY CLEARLY COULD BE BECAUSE OF THE FILTER IN THE ULTRASOUND MACHINE GETTING RID OF THE CLUTTER, ALSO GETTING RID OF SOME OF THE BLOOD FLOW WE SHOULD BE ABLE TO SEE WITHIN THE PLACENTA. BUT THE SMI TECHNOLOGY USES THE VERY HIGH ENERGY DISTRIBUTION OR HIGH DENSITY DISTRIBUTION WITHIN THE AREA OF YOUR REGION OF INTEREST AND IDENTIFIES AND REMOVES BOTH GLOBAL MOTIONS AND YET PRESENTS THE LOW CAPACITY VESSELS WITHIN THE PLACENTA. SO, THIS GOT US INTERESTED IN TRYING TO SEE IF WE CAN USE THIS TECHNOLOGY IN PREDICTING ADDRESS OUTCOMES. THERE ARE TWO TIMES OF WAYS THE SMI TECHNOLOGY IS USED. ONE IS JUST USING COLOR WHICH IS THE IMAGE ON YOUR LEFT-HAND SIDE, AND ON THE RIGHT I WAS SHOWING BOTH THE COLOR AND COMBINATION OF WHAT WE CALL THE MONOCHROME, WHICH IS THE NEXT SLIDE HERE. SO THE MONOCHROME IS ABLE TO SHOW ALL OF THE VESSELS. THIS IS ON THE SAME PATIENT, I SHOWED EARLIER ON, WHERE WE TRIED TO USE CONVENTIONAL DOPPLER TO SEE THESE SPIRAL ARTERY JETS, AND WERE NOT ABLE TO VISUALIZE, BUT ON MONOCHROME YOU'RE ABLE TO VISUALIZE THE SPIRAL ARTERY JETS, DID BETTER, AND SO THIS IS VERY PROMISING. SO, THE OTHER THING, WHEN WE COMPARE THE COLOR VERSUS THE MONOCHROME WE FEEL THAT THE MONOCHROME IS BETTER BECAUSE IT'S REALLY HIGHLIGHTS THE SMALL VESSELS BETTER THAN THE COLOR. THIS IS ALL LOOKING AT SMI NOW. BUT ALSO PRESERVES THE SLOW VESSELS SUCH AS SPIRAL ARTERIES. SO, AFTER IT WAS DESIGNED WITH THREE DIFFERENT AIMS, THE FIRST AIM REALLY WAS TO LOOK AT PLACENTA STRUCTURE ITSELF, AND THEN LOOK AT VASCULAR FLOW AND TO SEE THE CORRELATION BETWEEN THAT AND GROWTH RESTRICTION, BOTH IN NORMAL AND THOSE GROWTH RESTRICTED PREGNANCIES. SO WE STARTED THESE PATIENTS AT THREE DIFFERENT TIME POINTS. FIRST TRIMESTER BETWEEN 11 TO 13 WEEKS, SECOND TRIMESTER 18 TO 22, AND THIRD 28 TO 32. AT EACH WE LOOK AT -- USE THE SMI TO IDENTIFY THE VESSELS IN THREE REGIONS OF EACH PLACENTA, AND WE QUANTIFY THE NUMBER AND SIZE INCLUDING THE LENGTH OF THE SPIRAL ARTERY JETS. WE ALSO LOOK AT THE DEPTH OF PENETRATION, WHICH IS REALLY THE LENGTH OF THE SPIRAL ARTERY JETS WE'RE TALKING ABOUT. WE ALSO MEASURED POSITIVITY INDEX AND V MAX OF THE SPIRAL ARTERY, SAME INDICES FOR INTRAVILLOUS ARTERIALS AND ALSO LOOK FOR NUMBER OF BRANCHING WITHIN THE ARTERIALS. AND WE THEN FOR EACH PLACENTA, BASED ON WHAT WE FIND IN THE THREE REGIONS OF EACH PLACENTA, START WITH UMBILICAL CORD, THREE CENTIMETERS ON EACH SIDE. REPRODUCIBILITY STUDIES, SONOGRAPHERS I TRAINED ARE COMPARING, BY TAKING THE SAME MEASUREMENTS BY EACH OF THEM. SO THIS IS JUST AN EXAMPLE OF THE SPIRAL ARTERY JETS WITH T-I AND INDICES SHOWN IN THIS AREA HERE. WITH THE INTRA-VILLOUS ARTERIOLES, CAN YOU SEE THE SAME IN THE BOX. SIMILAR TO OLD STUDIES CAPTURING UTERINE ARTERY DOPPLER, ALSO CAPTURING UMBILICAL ARTERY VESSELS AND FINALLY LOOKING AT UMBILICAL VEIN DOPPLERS ACROSS GESTATION. THE SECOND AIM OF OUR STUDY NESTED CASE CONTROL STUDY LOOKING AT 40 CASES WITH GROWTH RESTRICTION FOR GESTATIONAL AGE AND SMOKING STATUS, AND COMPARING THEM WITH NORMAL PREGNANCIES. YOU'VE HEARD ABOUT BOLD MRI EARLIER IN THE PREGNANCY, THAT'S ONE OF THE TECHNOLOGIES WE'RE LOOKING AT AND TRYING TO CORRELATE THE FINDINGS FROM OUR ULTRASOUND VESICULARIZATION STUDIES, DEFINED ON BOLD MRI AND VIIN STUDIES. THE FIRST FIVE PATIENTS, NORMAL PREGNANCIES LOOKING AT THE BOLD MRI TIME OF NORMAL BREATHING VERSUS HIGH OXYGEN FLOW, 100% OXYGENATION. YOU CAN SEE GOOD SUPPRESSION BETWEEN TIME OF OXYGENATION AND THE TIME OF ROOM AIR BREATHING, THE GOAL TO OVERLAP AND SEE IF WE CAN SEE SIGNIFICANT DIFFERENCES. THE THIRD AIM OF THE STUDY IS TO LOOK AT SOME OF TRADITIONAL CELLULAR, MOLECULAR LEVEL MARKERS AND CORRELATE THEM BOTH WITH THE DOPPLER FINDINGS AS WELL AS WITH MRI FINDINGS. SOME OF THE SERUM MARKERS WE'RE LOOKING AT ARE LISTED IN THE SLIDE. WE ALSO ARE LOOKING AT SOME GENOME-WIDE METHYLATION STUDIES, AND FINALLY WE'RE ALSO LOOKING AT HISTOLOGICAL AND MORPHOLOGICAL CHANGES IN THE PLACENTA. SO, WHERE ARE WE CURRENTLY? WE'VE ALREADY RECRUITED ABOUT 371 PATIENTS. WE HAVE AN N OF 491 IN MIND. AND THE TWO CENTERS INVOLVED IN THE STUDIES ARE WILLIAM BEAUMONT AND MY CENTER IN TAMPA. THIS IS ETHNICITY OF EACH PATIENT. MAJORITY ARE CAUCASIANS. WE HAVE MRI FINDINGS, MRI STUDIES IN 18 CURRENTLY, WE'RE STILL COLLECTING MORE. WE HAVE AN N OF 40 IN MIND SO WE STILL HAVE SOME WAYS TO GO WITH THE MRI. AND WE HAVE SERUM COLLECTING IN EVERY PATIENT RECRUITED SO FAR. AND ONE OF THE QUESTIONS CAME UP LAST YEAR WHEN STUDIES WERE PRESENTED SIMILAR TO THIS ON DOPPLER, THE FIRST TRIMESTER, THE ISSUE OF SAFETY. AS WE KNOW, WE'RE TRYING TO FOLLOW THE ELARA PRINCIPAL, KEEPING THE ENERGY AS LOW AS NECESSARY. WE LOOK AT THE THERMAL AND MECHANICAL INDEX IN THE MACHINES, DOPPLER CAN INCREASE INDICES SLOWLY, BUT IN USING THE SMI WE'VE NOT SEEN ANY INCREASE IN THE T.I. OR M.I. COMPARED WITH CONVENTIONAL DOPPLER. JUST TO NOTE AS WE STAND HERE THERE'S NO EVIDENCE TO DATE THAT THE DOPPLER, THE ENERGY AND FREQUENCY WE USE HAS ANY HARM ASSOCIATED WITH THEM IN PREGNANCY. SO FINALLY I WANT TO ACKNOWLEDGE THE NICHD FOR SUPPORTING OUR WORK, THERE'S STILL A LOT OF ANALYSIS GOING ON HERE, A LOT OF BASIC SCIENCE WORK THAT'S BEING DONE, NOT PRESENTED TODAY BECAUSE MY COLLEAGUE, THE CO-P.I. FROM DR. LOCKWOOD'S LAB, COULD NOT MAKE IT. I ALSO WANT TO ACKNOWLEDGE MY OTHER SO INVESTIGATORS INCLUDING DR. KADA FROM RADIOLOGY WHO IS HERE TODAY AND OTHER RADIOLOGISTS FROM BEAUMONT AND SOME HAVE MOVED ON NOW TO ARIZONA BUT STILL COLLABORATING WITH US IN THE STUDY. I WANT TO THANK YOU AND TAKE ANY QUESTIONS. THANK YOU. [APPLAUSE] YES, SALLY. >> SALLY COLLINS, OXFORD. THANK YOU VERY MUCH FOR THE SHOUT-OUT. I'M FASCINATED BECAUSE AS YOU ARE AWARE I'VE SPENT A LOT OF TIME IN A DARKENED ROOM LOOKING FOR THESE JETS. WHAT EXACTLY IS IT YOU'RE LOOKING AT WITH THESE ARTERIOLES, I'M REALLY EXCITED ABOUT THIS, I DON'T USE VASCULAR IMAGING, WHAT ARE YOU SEEING? FROM SAYING INTRAVILLOUS ARTERIOLES, IT MAKES IT SOUND LIKE THE FETAL ASPECT. >> WE'RE LOOKING AT MATERNAL, ALSO FETAL, REALLY CALL IT ARTERIOLE, IT'S COMING FROM THE UMBILICAL VEIN, THE GOAL SEE ALSO WHETHER VERY EARLY IN PREGNANCY OR PREGNANCY PROGRESSES IS THERE ANY DERANGEMENT IN INDICES THAT COULD TELL US VERY EARLY THOSE PREGNANCIES THAT WOULD BE AT RISK FOR GROWTH RESTRICTION. >> WHERE ARE YOU ACTUALLY MANAGING TO MEASURE THESE ARTERIOLES? THEY ARE JUST NOT EVIDENT USING YOUR STANDARD COLOR DOPPLER, POWER DOPPLER, I'VE NEVER SEEN ANYTHING ON THE FETAL SIDE WITHIN THE INTRAVILLOUS SPACE, FROM WHAT I UNDERSTAND FROM HISTOPATHOLOGY YOUR FLOW THERE IS SO LOW, I MEAN IT'S ACTUALLY A SINGLE FILE OF RED CELLS. SO I JUST AM NOT AWARE OF IMAGING TECHNIQUE THAT CAN CAN PICK UP FLOW FROM SLOW. >> YOU WERE NOT CONVINCED FROM THE IMAGES, I CAN SHARE THEM IN THE MEETING TOMORROW. I DON'T KNOW IF YOU CAN SEE. IF YOU LOOK -- SO THIS IS THE MATERNAL SIDE, BUT THIS IS FETAL SIDE. THIS DOESN'T CAPTURE -- I THINK I HAD ONE EARLIER ON. >> ARE YOU ACTUALLY ABLE TO TRACE IT FROM UMBILICAL VESSELS, YOU SHOULD BE ABLE TRACE THE FLOW TO THE INTRAVILLOUS SPACE WHICH WOULD POTENTIALLY DEMONSTRATE THAT'S WHAT YOU'VE DEFINITELY GOT. >> YES, DEFINITELY WE SEE THEM COME OUT FROM THE UMBILICAL ARTERY, INTO THE PLACENTA, AND THEN SPREAD OUT. AND THAT'S WHERE WE ARE MEASURING THEM BUT DEFINITELY ARE SEEING THEM. >> OBVIOUSLY ONE OF THE DIFFICULTS MEASURING VESSELS AT DIFFERENT PLACES IN PLACENTA IS FINDING ANATOMICAL PLACE THAT'S REPRODUCIBLE. SPIRAL JETS, WE'RE GOING TO MEASURE WHERE WE SEE THE UTERO PLACENTAL INTERFACE, THE VELOCITY DROPS UP INTO THE SPACE, AND WE USE THAT AS AN ANATOMICAL LOCATION SO THAT NO MATTER WHAT JET YOU WERE MEASURING IN WHATEVER PLACENTA YOU WERE MEASURING AT THE SAME PLACE, LIKE THE UTERINE ARTERY AT THE POINT IT BIFURCATES, THAT STANDARDIZED WAY. >> WE STANDARDIZE TO BE VERY, VERY CLOSE TO JUST THE EDGE OF THE PLACENTA, AS YOU GET IN, BECAUSE YOU GO TOO FURTHER IN YOU'RE NOT SURE YOU GET DIFFERENT TYPES OF INTRAVILLOUS VESSELS THAT ARE NOT FETAL ORIGIN SO THAT'S WHERE WE'RE MEASURING ALL THE TIME. >> IS THAT A PARTICULAR DISTANCE FROM THE UMBILICAL CORD? >> OUR TEST POINT IS THE UMBILICAL CORD INSERTION, THREE CENTIMETERS ON EITHER SIDE PAST IT. >> THANK YOU VERY MUCH. >> I WANT TO ADD A COMMENT, THANKS ON A GREAT PRESENTATION, WE'RE USING THE SAME TECHNOLOGY JUST TO RESPOND TO THE PREVIOUS COMMENT, WE ARE ABLE TO SEE ABOUT 8 TO 10 SPIRAL ARTERIES AT 13 WEEKS, 8 TO 10 PLACENTAL ARTERIOLES, QUANTITATE P.I.S, TECHNOLOGY ALLOWS EXTENSIVE EVALUATION OF THE PLACENTA IN THE FIRST TRIMESTER. >> IS THERE TIME FOR ONE MORE? >> ONE MORE. >> BIG PICTURE QUESTION. TERRY FROM OREGON. IN THE MOUSE, JOHN WILL BACK ME UP ON THIS, THE "THEY" GROW SPIRAL ARTERIES DE NOVO, CLEARLY ABLE TO FUNCTION, GROW THEM EVOLVE THE END OF THE RADIAL AND OFTEN WILL BE VARIABLE NUMBER OF SPIRAL ARTERIES PER POD, THE HUMAN THEY WERE GROWN BEFORE SHE GETS PREGNANT BUT YOU COULD HYPOTHESIZE DIFFERENT HUMANS HAVE DIFFERENT DENSITY. YOU COULD COULDN'T ARTERIES IN THE PLACENTAL BED, DO YOU HAVE A SENSE YET OF HOW MANY SPIRAL ARTERIES FEED THE PLACENTA, WHAT VARIATION THERE IS BETWEEN INDIVIDUALS AND WHAT WOULD HYPOTHESIZE SIGNIFICANT DIFFERENCE BETWEEN PARITY, FOR EXAMPLE, OR ANY OTHER THING THAT MIGHT AFFECT THE ANGIOGENIC PROFILE, I'M INTERESTED IN THE SOIL BEFORE THE PLACENTA IMPLANTS. >> THIS IS A VERY GOOD QUESTION. THAT'S SOMETHING WE'VE NOT DONE. I'M GLAD THIS IS VIDEOS SO WHEN I WATCH BACK I CAN TAKE NOTES OF THE QUESTIONS AND LOOK AT IT. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH. WHAT A GREAT TALK. THE NEXT TITLE IS PLACENTA MRI, DEVELOPING ACCURATE QUANTITATIVE MEASURES OF THE PLACENTAL PHYSIOLOGY TO GUIDE INDIVIDUAL CARE, BY DR. GRANT AND DR. ABACI TURK FROM HARVARD UNIVERSITY. >> I'D LIKE TO ALSO THANKS THE NICHD AND DIANA BIANCHI FOR SUPPORT AND HPP AND DAVE WEINBERG WHO HAS GIVEN US TREMENDOUS MORAL SUPPORT THROUGH THE PROJECT, THE HPP COMMUNITY. THIS IS NOT EASY. AND SO IT'S FLIES -- NICE TO COME TO A MEETING AND SEE PEOPLE FROM SIMILAR NUMBERS AND CHALLENGES. I ENJOYED THE COMMUNITY AND QUESTIONS AND IDEAS FLOATING AROUND. SO, FOR THIS TALK HERE, OUR APPROACH, THE WAY WE DECIDED DO THINK ABOUT THIS WAS MORE FROM THE CONCEPT OF PRECISION MEDICINE. SO JUST LIKE IN GENETIC OR MOLECULAR PROFILING YOU USE THAT TO UNDERSTAND INDIVIDUAL VARIABILITIES, TO TRY TO PREDICT WHAT ARE THE BEST INDIVIDUAL THERAPIES FOR AN INDIVIDUAL. SO IT'S ALL ABOUT THE INDIVIDUAL. SO CAN WE USE THESE CONCEPTS AND MOVE THEM OVER TO MRI AND USE MRI TO UNDERSTAND INDIVIDUAL VARIABILITY AND PLACENTAL FUNCTION AND QUANTIFY DISTURBANCES AND SEE IF WE CAN DETECT CHANGES WITH RESPONSES IN EACH INDIVIDUAL. SO WE'RE VERY MUCH AFTER THAT INDIVIDUAL CHANGE TO DEVELOP BEDSIDE TOOLS THAT INFORM DECISION MAKING BASED ON PHYSIOLOGY. SO WHERE TO START? YOU'VE HEARD A LOT OF TALKS TODAY ABOUT DIFFERENT PLACES PEOPLE HAVE FOCUSED. IF YOU THINK ABOUT MATERNAL SUPPLY, OLIVER SHOWED IT'S HARD TO GET ALL THE MATERNAL ARTERIAL SUPPLY, YOU HEARD THE CHALLENGES OF PENETRATING VESSELS. IF WE LOOK AT UMBILICAL CORD TRANSCRIPTOME VILLOUS SPACE, I HAVE NO IDEA WHAT THE FLOW IS LIKE SO I DON'T KNOW WHAT MODEL TO USE TO CAPTURE IT ACCURATELY. IF WE WANT TO DO FLOW FROM THE FETAL SIDE WE HAVE TO BE ABLE TO GATE BY THE FETAL HEART RATE. RIGHT NOW FOR MRI WE USE EKG SYSTEMS TO GATE WITH ADULTS AND YOUNG CHILDREN BUT IT DOESN'T GO THROUGH THE ARE -- PICK UP HEART RATE OF THE FETUS. WE CANNOT GET ACCURATE MEASURES OF FETAL FLOW THROUGH THE PLACENTA. SIMILAR TO ANTONIO WE THOUGHT LET'S STEP BACK AND THINK ABOUT BASIC FUNCTION, ROLE OF THE PLACENTA. IT'S TO SUPPLY OXYGEN AND NUTRIENTS TO THE FETUS, AND TO REMOVE CARBON DIOXIDE AND WASTE. WE CAN USE USE BODY IMAGING. PROBLEMS THAT IMPAIR TRANSPORT CAN RESULT IN IUGR. WE MEASURE TRANSPORT USING BOLD IMAGING IMAGING AND OXYGEN EXPOSURE. WE TRIED TO CONTROL AS MANY FACTORS AS POSSIBLE. WE CHOSE MONOCHORIONIC DIAMNIOTIC TWINS, WE DIDN'T REALIZE HOW MUCH HE SAVED US BY SUGGESTING THIS, IT GETS FAR MORE COMPLICATED QUICKLY. THIS CONTROLS FOR MATERNAL ENVIRONMENT, GESTATIONAL AGE, SEX, GENETIC GROWTH PRO -- POTENTIAL, CHOOSING DISCORDANT TWINS, ONE DIAGNOSED WITH IUGR. OXYGEN EXPOSURE, MOTHER BRINGS ROOM AIR AND 100% OXYGEN, ROOM AIR FOR 10 MINUTES EACH. WE TRACK OXYGEN CHANGES WITH CHANGES IN BOLD MRI. WE'VE GOT BASELINE AND WE'RE LOOKING AT CHANGES OVER TIME, ATTRIBUTABLE TO OXYGEN BECAUSE THAT'S WHAT WE PROVIDED THE MOTHER. >> TO PERFORM HEMODYNAMIC ANALYSIS WE NEED TO ELIMINATE FETAL AND MATERNAL MOTION. YOU'VE SEEN SEVERAL MRIs, JUST TO INTRODUCE YOU WHAT WE'RE SEEING IN THE M.R. IMAGE, SO THIS IS THE UTERUS WALL, YOU CAN SEE THE FETUS AND PLACENTA REGION HERE. WATCH THE SAME SLIDES A LONG TIME YOU CAN OBSERVE HOW THE FETUS MOVING A LONG TIME, ALSO THE MATERNAL MOTION, HOW IT'S RESPONSE, LIKE HOW IT AFFECTS THE PLACENTAL REGIONAL CHANGE, MANAGE IT, WHICH IS -- CAN WE DEFINE AS (INDISCERNIBLE) MOTION. AFTER WE APPLY MOTION CORRECTION PATH LINE TO THE MRI TIME SERIES ACHIEVE SUCCESS UNTIL ALIGNMENT, TIME FRAMES TO REFERENCE FRAME, AND MANAGE TO SUCCESSFULLY PERFORM HEMODYNAMIC IN THE PLACENTA. RECENTLY OUR MIT COLLABORATORS ARE WORKING ON APPROACH TO TRACK IN PLACENTA IN MRI TIME SERIES, THERE WILL BE A POSTER ABOUT THAT IN THE POSTER SESSION. AND AFTER THE PREPARED DATA, MAKE THEM MOTION FREE, WE SUCCESSFULLY VISUALIZE BOTH CHANGE, MODIFY MATERNAL OXYGENATION, SO AS YOU SEE HERE MATERNAL OXYGENATION FROM AIR TO 100% OXYGEN MOST SIGNAL IN TERMS OF FIRST INCREASE STARTING FROM MATERNAL SIDE MOVING TO FETAL SIDE. LET ME TURN BACK TO THE 100% OXYGEN TO THE AIR, THEN THE SIGNAL STARTS TO DECAY SLOWLY, SLOWER THAN THE INCREASE IN SIGNAL INTENSITY. IF YOU LOOK AT AVERAGE VOLUMES, AS LIKE COMPUTER USING RESTING STATE, MAXIMUM SIGNAL STATE VOLUMES AND ALSO RESIDUE VOLUMES, YOU CAN OBSERVE THE SIGNAL IN TERMS OF DIFFERENCE BETWEEN EACH DIFFERENT STATE. USING THIS PLACENTAL BOLD SIGNAL WE WANT TO QUANTIFY PLACENTAL OXYGEN TRANSPORT, TO DO THAT WE COME UP WITH A MEASURE TIME, ACHIEVE USING BOLD SIGNAL INTENSITY CHANGE A LONG TIME AND GAMMA FUNCTION FITTING, ALSO COMPUTE BRAIN AND LIVER VOLUMES USING MR SPECTRAL IMAGE, AND CHECK THE CORRELATION BETWEEN CT AND FETAL GROWTH MEASURES, BRAIN VOLUME, LIVER VOLUME, BIRTH SPACE. AS A RESULT, BEFORE THAT LET ME INTRODUCE PLOTS, EACH COLOR, THE PAIRS ARE CONNECTED WITH SOLID LINE. HOLLOW CIRCLES INDICATE FETUSES DIAGNOSED WITH SMALL GESTATIONAL AGE AT TIME OF BIRTH. WE OBSERVED FROM THESE DATA, OBSERVED HIGHLY CORRELATED WITH FETAL BRAIN VOLUME, FETAL LIVER VOLUME AND BIRTH RATE. IN ANOTHER LONGER TTP VALUES ASSOCIATED WITH SMALLER BRAIN VOLUME, LIVER VOLUME AND LOWER BIRTH WEIGHT. ALSO IN PAIRS OBSERVE CORRELATION BETWEEN TTP MEASURES AND BIRTH RATE. >> WHAT DID WE LEARN FROM THE FIRST EXPERIENCE? WE CONTROL FOR MANY FACTORS, MATERNAL ENVIRONMENT, GESTATIONAL, GENETIC GROWTH POTENTIAL, BOLD MEASURES OF OXYGEN TRANSPORT ARE HIGHLY CORRELATED TO FETAL GROWTH, THAT MEANS SOMETHING IMPORTANT, FETAL GROWTH. HOW DO WE USE THAT, TAKE THAT AND USE IT AS A MEASURE OF AN INDIVIDUAL, IN SINGLETONS, WE WANT TO UNDERSTAND AGAIN INDIVIDUAL VARIABILITY. WE WANT TO TAKE ANOTHER FACTOR AND CHANGE ONE OTHER FACTOR. SO WHAT WE THOUGHT ABOUT IS WE COULD TAKE A SINGLE MOTHER AND CHANGE POSITION AND ALTER MATERNAL ENVIRONMENT, SO WE STILL KEEP GESTATIONAL AGE, SEX, GENETIC POTENTIAL THE SAME, CONTROL FOR THOSE F ACTORS BUT TILT THE MOTHER. THE SUPINE POSITION COMPLEXES AORTA AND VENA CAVA, WE THOUGHT WE COULD SEE CHANGES IN OXYGEN TRANSPORT WITH DIFFERENCES IN POSITION. M.R. PROTOCOL, RANDOMIZE MOTHERS TO LEFT LATERAL OR SUPINE FIRST, A 20-MINUTE BREAK, AND THEN TRACK THE OXYGEN CHANGES THROUGH THE TIME COURSE WITH OUR BOLD IMAGING. >> FOR THIS STUDY, THREE SUBJECTS DUE TO DISCOMFORTS IN SPINE POSITION, WE HAVE TO EXCLUDE BECAUSE OF UTERINE CONTRACTION AND DELAY TO SIGNAL DROP, ANALYZED SEVERAL SUBJECTS AT THE END, GROUP BOLD SIGNAL TIME HOURSES SPINE POSITION BASED ON MATERNAL POSITION, OBSERVED THAT, SIGNAL INCREASE AT END OF HYPER OXYGENATION IS MUCH HIGHER. WE SPECULATE IT MIGHT BE RELATED BETWEEN LOWER BASELINE OXYGENATION IN PLACENTA, SPINE POSITION, MAYBE BECAUSE OF THE ARTERIOLE COMPRESSION. WE CHECKED BETWEEN BOLD SIGNAL CHANGE, MAXIMUM SIGNAL CHANGE IS INCREASING WITH GESTATIONAL AGE. WHICH MIGHT BE ALSO EXPLAINED WITH LOWER OXYGENATION LEVEL IN THE HIGHER GESTATION AGE. >> WHAT DID WE LEARN, IF YOU USE TIME TO PEAK THERE'S A LOT OF THINGS TO CONTROL FOR. TO NAME A FEW, MATERNAL POSITION HAS AN IMPACT ON THE DYNAMICS OF OXYGEN TRANSPORT, FIGURE OUT HOW TO CONTROL OR COMPENSATE FOR THAT. AS ESRA MENTIONED WE SUSPECT THE REASON WE HAD BIGGER CHANGES SUPINE RATHER THAN IN LEFT LATERAL, IN SUPINE BASE OXYGEN LEVEL MAY BE LOWER SO WE'LL GET A BIGGER JUMP WHEN WE GIVE THE MOTHER THE OXYGEN. TO KNOW THAT WE HAVE TO MEASURE BASELINE OXYGEN SATURATION. IN ADDITION WE NEED TO UNDERSTAND REGIONAL PLACENTAL PERFUSION AND PLACENTA CONSUMPTION BECAUSE WE DIDN'T TALK ABOUT THAT HERE BUT WE SEE EVIDENCE THE PLACENTA CONSUMES OXYGEN SO WE HAVE TO ACCOUNT FOR THAT AS WELL TOO WHEN WE'RE DOING OUR OXYGEN TRANSPORT MEASURES. IN ADDITION, EVERYTHING HAS A SILVER LINING, NON-LABOR CONTRACTION RESULT IN 2/3 OF THE DATASET NOT USED FOR TIME TO PEAK ANALYSIS BECAUSE CONTRACTION OCCURS PART WAY THROUGH THE TIME COURSE, THAT'S 2/3 OF THE PATIENTS WE HAD, WE NEED TO FIGURE OUT HOW TO USE THAT DATA OR COMPENSATE FOR UTERINE CONTRACTIONS, MOST OF THESE WERE NOT FELT BY THE MOTHER SO IT WASN'T THEY WERE SAYING THEY WERE HAVING UTERINE CONTRACTION. FETAL MOTION PLAYS A ROLE TOO. ESRA DIDN'T MENTION THE FETUSES MOVED LESS WHEN THE MOTHERS WERE SUPINE THAN WHEN IN THE LEFT LATERAL POSITION. AGAIN, WE THINK THAT'S BECAUSE OF THE LOWER OXYGEN CONTENT THAT THE FETUS IS RESPONDING TO THAT BUT OTHER TIMES FETAL MOTION MAY BE INCREASING AND DRIVING UP THE FETAL OXYGEN CONSUMPTION SO WE NEED TO UNDERSTAND FETAL MOTION AND TO BE ABLE TO CAPTURE IT AND QUANTITY FIGHT IT TO PUT METRICS INTO THE RIGHT CONTEXT. >> SO ALL THESE STUDIES, BOLD MRI STUDIES, T2* MEASUREMENTS, WE KNOW T2* MEASUREMENTS ARE AFFECTED BY INDIVIDUALS, SPECIFICALLY (INDISCERNIBLE) IT'S NOT DIRECT MEASURE OF OXYGENATION. SO WE'RE MORE INTERESTED IN THE INDIVIDUAL BLOOD AND TISSUE OXYGENATION WITH T1 AND T2 MEASUREMENTS, AND OUR COLLEAGUES APPLIED FINGERPRINTING APPROACH TO ESTIMATE T1 AND T2 VALUES AND ACHIEVED FOR TEN DIFFERENT SUBJECTS, AND HE ALSO OBSERVED SOME RESPONSE, DIFFERENCES WITH GESTATIONAL AGE THAT HE WILL PRESENT DURING THE POSTER SESSION, PLEASE VISIT HIS POSTER FOR MORE DETAILS. BESIDES REGIONAL INFORMATION FROM OXYGENATION WE'RE INTERESTED IN THE PLACENTAL PERFUSION AND WE KNOW FROM THE LITERATURE INTRAVOXEL AND CURRENT MODSEL IMAGING CAN RELATE TO PERFUSION IN MATERNAL AND FETAL COMPARTMENTS, AND IN LITERATURE THERE ARE SEVERAL STUDIES CONTAINING PREECLAMPSIA WITH CONTROL SUBJECTS, SHOWING DIFFERENCE IN PERFUSION VALUES IN THE TWO GROUPS. WE WANT TO MOVE ONE STEP FURTHER AND IMPROVE REGIONAL PERFUSION USING DIFFUSION IMAGING. IN THAT METHOD IVIM MEASURES, AND SLOW MEASURES DIFFUSION COMPONENT, AND WE WANT TO DO JOINT, MORE ACCURATE ABSTRACTION OF DIFFUSION COMPONENT AND BETTER ESTIMATION OF THE PERFUSION. OUR ULTIMATE AIM IS TO ESTIMATE REGIONAL PLACENTAL OXYGEN CONSUMPTION. IT WAS DEMONSTRATED WE CAN ESTIMATE WHOLE, FETAL USING T1 AND T2 MEASUREMENTS AND FLOW MEASUREMENTS BUT WE WANT TO DO LIKE REGIONAL, HOW WE CAN MOVE FORWARD. WE CAN MEASURE T1 AND T2 VALUES FOR THE SPECIFIC REGION AND MEASURE THE FLOW USING FACE CONTRAST IMAGING, USING FETAL CARDIAC GATING WITH M.R. COMPATIBLE ULTRASOUND DEVICE DEVELOPED WE OUR COLLEAGUES AND WE CAN ESTIMATE FETAL PLACENTAL OXYGEN CONSUMPTION AND MOVE ONE STEP FURTHER AND WITH USING THE T1 AND T2 MEASUREMENTS AND PERFUSION CAN ESTIMATE REGIONAL PLACENTAL OXYGENATION METABOLISM. >> CAN WE GET THE LIGHTS DOWN TO SEE THE VIDEO? I JUST WANT TO MAKE SURE. >> SORRY. >> THANKS. >> SO HERE WE ARE TALKING ABOUT UTERINE CONTRACTION, SUFFERING FROM UTERINE CONTRACTION, NOT DOING TTP ANALYSIS IN THAT SUBJECT. WHY WE ARE NOT DOING THIS? BECAUSE UTERINE CONTRACTION SOMETIMES AFFECT THE WHOLE PLACENTA, AND IF YOU LOOK AT LIKE PLACENTAL BOLD SIGNAL CHANGE, DURING THE CONTRACTION, YOU CAN SEE A HUGE DECAY IN THE SIGNAL. ALSO AT THE SAME TIME YOU CAN SEE PLACENTAL VOLUME CHANGE, UTERINE VOLUME CHANGE, AND ALSO AT THE SAME TIME CAN SEE PLACENTAL SIGNAL CHANGE.& BUT IF YOU LOOK AT NOT OVERALL SIGNAL CHANGE BUT REGIONAL CHANGE, YOU CAN SAY THAT -- YOU CAN SEE THAT IT'S EFFECT IS MORE HETEROGENUS. MAXIMUM SIGNAL CHANGE IS LOWER COMPARED TO THE OTHER REGIONS. AND ALSO, UTERINE CONTRACTION SOMETIMES NOT AFFECT ALL SIGNALS BUT JUST REGIONAL SIGNALS. THIS EXAMPLE, IF YOU LOOK AT THE OVERALL SIGNAL CHANGE, IT'S HARD TO PREDICT THAT WHETHER THERE'S JUST THE FLUCTUATION OR THERE'S CONTRACTION, BUT IF YOU LOOK AT A SMALLER REGION AFFECTED WITH CONTRACTION YOU CAN SEE SIGNIFICANT DROP IN THE SIGNAL. SO WE DID SEVERAL OTHER LIKE NON-LABOR CONTRACTION, PLEASE VISIT OUR POSTER ABOUT THAT. >> AGAIN, WE MENTIONED WE NEED TO ACCOUNT FOR OR TRACK FETAL MOTION. WE WANT TO BE ABLE TO CORRECT FOR IT OR PREDICT IT TO GET BETTER IMAGES AND CAPTURE AND QUANTIFY TO SEE GESTATIONAL AGE AND PLACENTAL FUNCTION, WE KNOW FROM MSN COLLEAGUES THAT THE STRESS TEST FOR EXAMPLE FETAL MOTION IS A KEY COMPONENT. A COLLEAGUE FROM M.I.T., WE HAD STUDENTS THAT PAINSTAKINGLY LABELED EYES, WRIST, ELBOW, SHOULDERS, KNEES, HIP, ANKLE, IN THESE FRAMES. WE'VE GOT NOW, OH, THOUSANDS OF DATA SETS OR FRAMES OF THIS TIME COURSE AFTER DOING MULTIPLE EXPERIMENTS SO THEY HAVE DONE A SUBSET OF THOSE, CIRCLING EACH OF THEM, AND WE CAN ACTUALLY VISUALIZE THE MOTION ON THESE VIDEOS SO THAT'S THE SAME FETUS ACTUALLY. NOW CHARACTERIZED IN TEMPORAL TIME COURSE. WE CAN START TO GATHER METRICS AND SEE THE FIELD MOTION, SOME FETUSES, THE FETUS LIES IN, ANOTHER FETUS IT'S RANDOM ALL OVER THE PLACE, THERE'S A HUGE AMOUNT OF INFORMATION IN THE METRICS OF MOTIONS WE CAN CAPTURE MOVING FORWARD. TWO APPROACHES, ONE TO PREDICT IMAGING FOR THE NEXT SLICE AND NEXT CHARACTERIZE KINEMATICS. WHAT DID WE LEARN FROM THE LAST EXPERIENCE IN MUCH WORK IS LEFT TO BE DONE TO QUANTIFY PLACENTAL OXYGEN TRANSPORT, IN REAL TIME, AND TO UNDERSTAND WHAT GIVES RISE TO INDIVIDUAL VARIABILITY, AND THAT'S WHAT WE WORKED HARD TO HAVE MOTION CORRECTION, WHATEVER WE CAN CONTROL AND CORRECT FOR WE TRY TO DO THAT. MOVE STEP BY STEP, CHANGING ANOTHER VARIABLE TO SEE WHAT IMPACT THAT HAS ON OXYGEN CONSUMPTION, OR OXYGEN TRANSPORT. THERE'S STILL MUCH TO DO. BUT WE'VE COME A LONG WAY, AT LEAST I PERSONALLY CAN SAY I'VE COME A LONG WAY FROM UNDERSTANDING THE PLACENTA, FIRST I THOUGHT OF IT AS A BIG ROUND DEAD BLOB THAT DIDN'T REALLY DO MUCH. AND NOW WE'RE BEGINNING TO REALIZE WE CAN BEGIN TO SEE IN VIVO PLACENTAL FUNCTIO IN REAL TIME. WHAT I'M SHOWING YOU HERE IS ONE OF THOSE EXPERIMENTS WE DID WITH THE MONOCHORIONIC TWINS, PLACENTA FLATTENED, SHOWING TIME COURSE ON FLATTENED PLACENTA. INSTEAD OF BEING CURVED AND HARD TO SEE WE'VE FLATTENED SO YOU CAN SEE THE TIME COURSE. AND WHAT YOU SEE HERE, THERE'S AN ALTERNATIVE EXPOSURE GIVEN THROUGH THE TIME COURSE, YOU'LL SEE CHANGES IN SIGNAL INTENSITY, WE NEED TO CAPTURE DYNAMICS, THAT HAS TO DO WITH HEALTH OF THE PLACENTA, NOT JUST WHOLE VOLUME AVERAGES. THE TOP IS MORE HYPERINTENSE WITH HIGHER OXYGEN CONTENT, THAT'S THE PART OF THE PLACENTA THAT'S SUPPLYING TWIN A, THE LARGER TWIN, AND DARKER PLACENTA IS THE ONE THAT'S SUPPLYING THE SMALLER TWIN, TWIN B. I'M A RADIOLOGIST. WE HAVE TO HAVE METRICS VISIBLE TO SEE THEM, FLATTENING ALLOWS TO US LOOK AT THESE DATASETS AND ANYTHING OUT THE NEXT METRIC TO CAPTURE WHAT WE'RE SEEING VISUALLY. IF YOU WANT TO CATCH A MOST OTHER THAT, THERE'S ONE SHOWING THE FLATTENING TECHNIQUE, CORRELATING WITH BIOPSY SPECIMENS TO TO ALIGN TO PLACENTA EX VIVO. IT DOESN'T JUST TAKE A VILLAGE, IT TAKES A CITY TO DO PLACENTA IMAGING. WE'LL HAVE A HUGE ARRAY OF PEOPLE WE WORK WITH, MOST ARE NOT FUNDED ON THE U01 BUT HPP, BUT THEY ARE ALWAYS THERE TO HELP AND GIVE ADVICE. WE HAVE A TOTAL OF SIX MFMs FROM THREE DIFFERENT HOSPITALS, WE'RE ALWAYS GATHERING DIFFERENT OPINIONS. WE HAVE A TECHNICAL TEAM, THE PROJECT CO-LED BY ALFOUR AND LARRY, THE TEAMS PLAY A BIG ROLE. A SHOUT OUT, NATALIE IS A RESEARCH ASSISTANT WHO DOES A PHENOMENAL JOB RECRUITING AND ORGANIZIN US. JEFF STOUT IS ALSO IN THERE TOO. WHERE IS HIS PICTURE? RIGHT HERE, JEFF STOUT IS HERE. MASA IS HERE AND RAY IS HERE. I WANT TO THANK EVERYBODY FOR THEIR ATTENTION AND FOR THE PRIVILEGE OF BEING PART OF THIS WHOLE COMMUNITY. AND I FORGOT, ESRA, LEAD POSTDOC ON THE PROJECT. SHE GAVE THE TALK BECAUSE SHE KNOWS THIS FAR MORE THAN I DO AND REALLY PUSHES A LOT OF THIS WORK FORWARD AND MAKES SURE WE KEEP OURSELVES ORGANIZED AND OUR EYE ON THE TARGET. THANK YOU, ESRA, FOR ALL YOUR WORK. [APPLAUSE] >> WE HAVE TIME FOR QUESTIONS. >> REALLY FASCINATING. I WANTED TO ASK ABOUT THE TIME COURSE OF YOUR OXYGEN CHALLENGE STUDY AND SEEMED LIKE IT DIDN'T RETURN TO BASELINE, I'VE SEEN THAT IN ANN SORENSON'S WORK, WONDERING HOW YOU INTERPRET THAT RESULT. >> CAN I GO FIRST? THIS IS SOMETHING WE THINK IS REALLY FASCINATING. WE THINK A LOT IS WITHIN THE MATERNAL LAKES, NOT -- THERE'S A LOT OF DISSOLVED OXYGEN THAT STAYS WITHIN THE PATERNAL LAKES AND DOESN'T GET TAKEN TO THE FETUS. IN SOME CASES, IN SOME ORGANS THE DIP IS BELOW BASELINE, IN THE FETAL ORGANS, SOMETIMES THE PLACENTA IS RETAINING OR CONSUMING SOME OXYGEN TOO. THERE'S A HUGE AMOUNT OF INFORMATION IN THE SECONDS TIME COURSE AND WE'VE TRACKED IT FOR 30 MINUTES I THINK MAX, IT HAS NOT GONE BACK TO BASELINE. WE'RE INTERESTED IN UNDERSTANDING THAT DYNAMIC TOO. DO YOU WANT TO ADD? >> YEAH, I THINK BECAUSE OF THAT INFORMATION THAT WE GATHER, IT'S VERY IMPORTANT TO MEASURE T1 AND T2 CHANGE, LIKE OXYGENATION CHANGE WHEN YOU MATERNAL OXYGEN, I THINK IT'S SHOWN IMPORTANT TO GET REAL MEASUREMENTS. >> THANK YOU. REALLY FASCINATING. >> JOHN ASKED MY QUESTION. A SECOND ONE, YOU OBVIOUSLY HAVE SOME NICE-LOOKING PLACENTAL T2* MAPS, TRYING TO DO T2 FOR REASONABLE TECHNICAL REASONS. IS THERE ANY CORRELATION BETWEEN THOSE TWO? HAVE YOU LOOKED TO COMPARE THE T2 AND T2* VALUES? BECAUSE THE NUMBERS THAT YOU'RE SHOWING FOR T2 ARE QUITE LOW. YOU'D EXPECT THEM TO BE HIGHER THAN THE T2*. >> FOR THIS PROJECT, WE HAVE ALSO T2* MEASUREMENTS AND WE OBSERVE LIKE GOOD CORRELATION BETWEEN T2 AND T2* MEASUREMENTS, BUT WE DIDN'T LIKE DO ANY VISUALIZATION, WE COMPARED, VALUES ARE ALIGNED WITH THIS REPORTED IN THE LITERATURE AS WELL, AND THEY ARE VERY -- T2* MEASUREMENTS ARE WELL CORRELATED WITH T2 MEASUREMENTS. I HAVEN'T SHOWN HERE. >> I HAD A QUESTION ABOUT THE RIGID BODY MOTION, RIGID MOTION CORRECTION. ARE YOU FITTING THAT TO A MODEL FOR DISPLACEMENT OR IS THERE ANOTHER METHOD YOU'RE USING? >> CAN YOU REPEAT THE QUESTION? >> SURE. FOR THE RIGID MOTION CORRECTION, IS THERE A MODEL THAT YOU'RE FITTING IT TO ACROSS THE TIME POINTS? OR IS THERE ANOTHER METHOD YOU'RE USING? >> SO I'M USING THE MOTION CORRECTION, CHOOSING ONE REFERENCE FRAME, ALIGN ALL THE OTHER FRAMES WITH THIS REFERENCE FRAME SO THIS IS LIKE WE'RE USING PAIRWISE MOTION CORRECT, BUT BEFORE THIS KNOWLEDGE OF MOTION CORRECTION WE'RE ALSO DOING INTRAVOLUME TO CORRECT MOTION BETWEEN SLICES. >> THANK YOU VERY MUCH. >> WHEN WE DO DIFFERENT BODY PARTS WE HAVE DIFFERENT CORRECTIONS SO WE USE RIGID CORRECTION FOR THE BRAIN BUT NON-RIGID FOR OTHERS. >> LES, OREGON HEALTH SCIENCE UNIVERSITY. I DESCRIBED MYSELF AS A CARD-CARRYING PLACENTOLOGIST, IT'S NOT JUST A CONDUIT IN A SUPPLIES STUFF TO THE FETUS. THE PLACENTA HAS APPRECIABLE METABOLISM OF ITS OWN, AND FROM ANIMAL MODELS 40 TO 50% OF ALL THE OXYGEN SUPPLIED BY THE UTERO PLACENTA VESSELS IS CONSUMED BY THE PLACENTA ITSELF. >> YEAH. >> THERE'S A PHENOMENA CALLED METABOLIC REPROGRAMMING, THIS IS A GOOD EXAMPLE, HIGH ALTITUDE, FOR EXAMPLE, WOMEN LIVING IN THE ANDES, THE PLACENTA CAN CUT DOWN ITS OXYGEN CONSUMPTION TO ENSURE THAT THE FETUS STAYS NORMOXIC. THAT MIGHT AFFECT THE AMOUNT OF OXYGEN AVAILABLE FOR THE FETUS, SO IT COULD BE NOT WHAT THE FETUS WANTS, IT'S ACTUALLY WHAT THE PLACENTA GIVES IT. >> ABSOLUTELY. >> TO ITS OWN METABOLISM WE'VE GOT TO CONSIDER. AGAIN, THIS LACK OF DISAPPEARANCE OF THE BOLD SIGNAL WHEN YOU HYPEROXYGEN HYPEROXYGENNATE, I'VE GOT ENOUGH. WE'VE GOT TO THINK ABOUT IT'S NOT JUST THE FETUS THAT'S GETTING OXYGENATED, IT'S THE PLACENTA AS WELL AS THE FETUS AND THE TWO INTERACT SOMEHOW. >> SO DOES THE VILLI AND LAKE, METABOLISM IN BETWEEN. THE CORRELATIVE OF FETAL MOTION, IF YOU HAVE HIGH -- YOU THINK YOU'RE RETAINING OXYGEN AND FETAL MOTION GOES DOWN, THAT SUPPORTS THAT HYPOTHESIS. WE HAVE ANOTHER WAY TO PROBE AT THAT AS WELL AS IF WE CAN MEASURE UMBILICAL FLOW. NOW WITH DOPPLER ULTRASOUND WE'LL PICK UP IMBULL TILL FLOW TO SEPARATE MATERNAL CIRCULATION -- FETAL CIRCULATION FROM WHAT'S HAPPENING IN THE PLACENTA. WHEN WE LOOKED AT THE IUGR TWINS, THE PLACENTA WITH THE IUGR FETUS WE INTERPRETED THAT AS HIGH ALTITUDE PLACENTA, IT WAS THE ONE THAT WOULD KEEP THE OXYGEN LONGER AND TO THE DETRIMENT OF THE FETAL ORGANS, SO THERE IS -- WE'VE SEEN EVIDENCE OF THAT KIND OF BEHAVIOR. >> THANKS. >> DINESH. FANTASTIC WORK. AND I WAS GOING TO COMMENT ON THAT IN A SLIGHTLY DIFFERENT WORDS. PLACENTA FUNCTIONS AT OPTIMAL EFFICIENTCY FOR EXTRACTING OXYGEN, EFFICIENCILY OF DELIVERY, YOU'RE SEEING BECAUSE OXYGEN SATURATION YOU'RE MEASURING IN THE BLOOD WITHIN THE PLACENTA, AND WHEN THE PLACENTA HAS GOTTEN ENOUGH IT DOESN'T SEE A NEED TO EXTRACT ANY MORE. AND THAT'S WHY IT'S STAYING THERE FOR A LONGER TIME. >> DEPENDS WHERE IT IS, WHETHER IT'S IN THE MATERNAL LAKES BECAUSE BEING SUPPLIED BY MATERNAL SIDE BUT HASN'T GONE ANYWHERE OR IN THE INTERSTITIAL PACE OR TRANSPORTED ACROSS TO THE FETUS, WE'RE TRYING TO UNDERSTAND THAT DYNAMIC TO BETTER UNDERSTAND WHICH STATE IT'S OPERATING IN. DO YOU WANT TO COMMENT? I LOVE THE ENERGY IN THIS ROOM. I'M GLAD THAT YOU GUYS ARE SHOWING DR. BIANCHI THAT THE HPP IS A ROCKING EVENT, YOU KNOW, THAT WE HAVE A LOT OF REALLY SHARP PEOPLE, ALL VERY, VERY EXCITED, THINKING HARD. I THINK WE'VE SEEN SOME OF THE CHALLENGES AND WE'RE GOING TO HAVE A LITTLE DISCUSSION ABOUT THAT LATER. SO I WANT TO TURN IT BACK OVER TO AFROUZ. >> ALL RIGHT. THE NEXT TOPIC IS DEVELOPING TOOLS TO MEASURE PLACENTAL OXYGENATION, MRI AND NEAR INFRARED SPECTROSCOPY, DR. SCHWARTZ FROM UNIVERSITY OF PENNSYLVANIA. GOOD AFTERNOON. THANK EVERYONE. IT'S A GREAT SETUP, ALL THE OXYGEN TALK, HOPEFULLY THIS WILL BE ONE MORE PERSPECTIVE ON OUR APPROACH. I WANT TO THANK THE HPP, DAVID WEINBERG HAS BEEN A GREAT SHEPHERD THROUGH THE PROCESS, AND IN THIS PRESENTATION WHICH HAS BEEN DONE BY AN UNBELIEVABLE GROUP OF MRI AND BIOMEDICAL OPTIC PHYSICISTS. THE IMPORTANT THING TO NOTE, NONE OF THEM WORKED IN PLACENTA UNTIL THIS U01 CAME OUT. SO THANK YOU. WE'RE GOING TO TALK ABOUT TWO TOPICS RELATED OBVIOUSLY BUT TWO MECHANISMS OR STRATEGIES TO LOOK AT ASPECTS OF OXYGENATION IN THE FETAL PLACENTAL UNIT. FIRST WE'LL TALK ABOUT QUANTITATIVE MRI, DIFFERENT THAN WHAT YOU'VE BEEN HEARING ABOUT. AND THEY HAVE PROS AND CONS. WE'LL TALK ABOUT OUR APPROACH. SO WHEN YOU TALK ABOUT METABOLIC RATE OF OXYGEN CONSUMPTION WE WORK WITH FIXED PRINCIPLE, WHICH TELLS US UPTAKE OF A SUBSTANCE WILL BE EQUAL TO THE PRODUCT OF THE RATE OF ITS SUPPLY, AND DIFFERENTIAL CONCENTRATION OF THE SUBSTANCE IN INFLOW AND OUTFLOW. SO FOR OXYGEN, WE'LL BE ABLE TO SEE THAT IF YOU CAN MEASURE THE ARTERIAL AND VENOUS OUTFLOW, AND TRYING TO APPLY IN PREGNANCY, START WITH GRAVID UTERUS, WORK TO ISOLATE THE FETUS, ARTERIAL OXYGENATED BLOOD INFLOW, VENOUS DRAINAGE WITH DEOXYGENATED PLOD, OBTAIN THE P.M.RO2. WE TOOK MRI APPROACHES TO TARGET EACH PIECE OF THE PUZZLE IN THE IDEAL MANNER, EACH HAS ITS OWN CHALLENGES. HERE IS AN OVERVIEW. WE LOOKED AT FETAL MASS, TRACED OUT MASS AND SEGMENTS USING BAKERS EINVESTIGATORS TO GET VOLUME TO MASS, BLOOD THROUGH THROUGH UTERINE ARTERIES WE USED 4D FLOW, UMBILICAL WE USED 2D. SYSTEMIC ARTERIAL SATURATION 9 2%, OXIMETRY FORUM . WE USED MATERNAL HEMATOCRIT, BASED ON GESTATIONAL AGE, 25 WOMEN, SECOND AND THIRD TRIMESTER, SOME WITH BIRTH WEIGHT LESS THAN 10th PERCENTILE. MRI ESTIMATES OF FETAL WEIGHT, RED REPRESENTS DELIVERING SGA INFANT. UTERINE ARTERIES, FIRST TIME OF FLIGHT TO IDENTIFY VESSELS, AND 4D FLOW FROM TAKEOFF POINT OF ILIAC. TEMPORAL RESOLUTION OF 44 MILLISECONDS, MORE ROBUST QUANTIFICATION, MORE THINGS WE CAN DO WITH UTERINE ARTERY HEMODYNAMICS. HERE WE SEE OUR ESTIMATES OF UTERINE BLOOD FLOW, MIMICKING LITERATURE, USING DOPPLER TECHNIQUES. WE CROSS-VALIDATED 4D COMPARING WITH VELOCITY AND PULSATIVITY. ACQUIRED OVER 9 SECONDS OF A PATIENT BREATH-HOLD. WHEN WE LOOK AT BLOOD FLOW RATE THROUGH UMBILICAL VEIN DATA MIMICS LITERATURE, INCREASING WITH FETAL GROWTH. SO NOW T2 BASED OXIMETRY, THIS IS DIFFERENT THAN T2* AND R2 , WE'RE LOOKING AT BLOOD WITHIN THE LUMEN OF THE VESSEL AND T2 RELAXATION TIME. T2 BASED OXIMETRY REQUIRES CALIBRATION SPECIFIC TO SEQUENCE BEING UTILIZED, PERFORMING EX VIVO CALIBRATION EXPERIMENTS TO DEVELOP OUR CURVE MORE ROBUST TO OUR SEQUENCES AND PERFORMED WITH ADULT AND FETAL CORD BLOOD TO CONTROL FOR VARIATIONS. ANOTHER CHALLENGE IS UMBILICAL VEIN IS TORTUOUS AT EARLIER GESTATIONAL AGES, AS NUMBER OF PIXELS AND LUMEN IS LIMITED AND ANGLE OF ACQUISITION COULD BE VARIABLE YOU HAVE A PROBLEM WITH PARTIAL VOLUME EFFECT, SOME PIXELS MIGHT CONTAIN VESSEL WOMEN AND LACTATING OR WHARTON'S JELLY, YOU'RE NOT SURE WHAT YOU'RE MEASURING. A BACKGROUND SUPPRESSED TECHNIQUE WAS DEVELOPED TO BE ABLE TO REALLY LOOK AT THE T2 SIGNAL OF THE BLOOD ALONE AND THAT HELPS OUR SIGNAL TO NOISE RATIO, OUR SNR. HERE WE SEE VARIOUS EQUI TIMES, 23 WEEKS GESTATION, UMBILICAL VEIN, TARGET VESSELS. THE SIGNAL INTENSITY FOR EACH TARGET VESSEL IS PLOTTED AGAINST T2 RELAXATION, TO GET A NUMBER CONVERTED TO OXYGEN SATURATION USING CALIBRATION CURVES. WE SEE 109 MILLISECONDS, TRANSLATES INTO 70% OXYGEN SATURATION. SO NOW THESE OXYGEN MEASUREMENTS ARE DIFFICULT TO VALIDATE. WE CAN'T JUST COMPARE TO ULTRASOUND DOPPLER. THERE ARE A RANGE OF REPORTED pO2 VALUES BASED ON INVASIVE TECHNIQUES DONE IN THE PAST. THIS DIAGRAM IS TAKEN FROM REVIEW BY NY ET AL., REPORTED pO2 VALUES FROM 19 TO 43 MILLIMETERS OF MERCURY. USING FETAL HEMOGLOBIN DISASSOCIATION CURVE WE CAN CONVERT THAT. ON THE MATERNAL SITE, UTERINE VEIN, WE CAN SEE CONVERTED TO 64 TO 80 PER CENT OXYGEN SATURATION, JUST A RANGE. WE'VE SEEN IN OUR DATA FROM MRI, A MEAN VALUE OF 70% HEMOGLOBIN OXYGENATION IN UMBILICAL VEIN, SUPPLY TO THE FETUS. MEAN IS IN THE RANGE REPORTED BASED ON LITERATURE VALUES. WE GET A MEAN OF 60%, THE DATA CAME FROM UTERINE VEIN SAMPLING AFTER DELIVERY OF BABY OR AFTER DELIVERY OF THE PLACENT, AND SO ONCE THE METABOLIC ACTIVITY IS GONE OXYGEN SATURATION WILL BE INFLATED SO I THINK 60% MEAN IS PROBABLY WHAT IS MORE REASONABLY TO BE EXPECTED FROM A BIOLOGICAL PLAUSIBILITY STANDPOINT. SO NOW FOR DEOXYGENATED FETAL BLOOD, NATURAL TARGET SHOULD BE UMBILICAL ARTERY. THAT'S TOO CHALLENGING IN TERMS OF RESOLUTION NEEDED AND COILING OF ARTERY, BEYOND OUR CURRENT CAPABILITIES. WE TARGETED DESCENDING FETAL AORTA INSTEAD WHICH SUPPLIES UMBILICAL ARTERY THROUGH THE ILIAC AND GENERALLY HAS SIMILAR IF NOT SAME SATURATION. THE TYPICAL FETAL POSITION IS LONGITUDINAL LIE, THAT MEANS FETAL AORTA IS PARALLEL TO THE BORE OF THE SCANNER, MAKING THE METHOD TO QUANTIFY OXYGEN SATURATION WITHIN A BLOOD VESSEL, MORE IDEAL FOR THIS VESSEL, IF WE USE THIS FOR QUANTIFICATION OF DESCENDING AORTA. SO M.R. SUSCEPTOMETRY IS BASED ON FIELD MAPPING. AND THAT'S NOW PROPORTIONAL TO M.R. SUSCEPTIBILITY, DEOXYGENATED BLOOD HERE. ON THE RIGHT EXAMPLE OF DESCENDING FETAL AORTA, FIELD MAP MAGNIFIED HERE FOR YOU. GOING BACK TO OUR DIAGRAM ON THE SUMMARY OF THE LITERATURE WE SEE RANGE OF pO2 VALUES, UMBILICAL ARTERY, ONGOING GESTATION 16 TO 28 MILLIMETERS OF MERCURY, USING FETAL OXYGEN DISASSOCIATION CURVE CONVERTS TO 48 TO 75% SATURATION. AND SURE ENOUGH OUR M.R. ESTIMATES ARE WITHIN THAT RANGE. WE'VE GOT A MEAN OF 57% OXYGEN SATURATION IN DESCENDING FETAL AORTA. WITH THE INGREDIENTS WE'VE PRESENTED SO FAR WE HAVE THE ABILITY TO LOOK AT THE AV DIFFERENCE OF THE FETUS AND CAN CALCULATE OXYGEN BY THE FETUS AFTER BEING SUPPLIED BY THE PLACENTA, TO MOVE ON TO THE FETUS AND OUR BELOVED PLACENTA. THE CURVE SHOWS OXYGEN EXTRACTION GOES UP WITH GESTATIONAL AGE, WHICH MAKES SENSE, THE FETUS EXTRACTS MORE OXYGEN THE LARGER IT GETS. SO NOW WHEN CONVERTING TO FETAL MR O2, MILLILITERS OF OXYGEN PER MINUTE, IT GIVES MORE CONFIDENCE MEASURES ARE BIOLOGICALLY SENSIBLE AND PLAUSIBLE AND WE SEE HOW THEY MIMIC EACH OTHER. WE SEE THAT OF COURSE THIS IS A VERY PRELIMINARY DATA THAT SGA BABIES SEEM TO HAVE A SLIGHTLY LOWER OR DEPRESSED MRO2 CURVE. AS PLACENTA IS THE ROOT OF OXYGEN EXCHANGE AND WE WANT TO UNDERSTAND WHAT'S GOING ON IN THE PLACENTA IN TERMS OF ITS EXTRACTION, WE CAN TAKE THE UTERINE MRO2 AND FETAL MRO2 AND ARRIVE AT PLACENTAL MRO2. AS ALLUDED TO BEFORE WE HAVE TO UNDERSTAND WHAT'S EXPECTED OF THE PLACENTA IN ITS OWN OXYGEN CONSUMPTION. A LOT OF DATA ARE AS REFERRED TO BEFORE, ANIMAL DATA FROM SHEEP, JUST ONE EXAMPLE, IN SOME MODELS OF DISTRESS WE SEE IT'S BELIEVED PLACENTA IS ABLE TO CONTINUE USE OF ATP AND OXYGEN AT EXPENSE OF FETUS, IN OTHER MODELS THE PLACENTA OXYGEN EXTRACTION GETS DEPRESSED FAR FURTHER THAN THE FETUS, DIFFERENT MODELS OUT THERE, ANIMAL MODELS ARE USED TO HYPOTHESIS. OUR DATA IS PRELIMINARY. EARLY RESULTS SHED LIGHT ON THE FEASIBILITY OF USING M.R. TO TACKLE THIS PROBLEM IN A QUANTITATIVE WAY USING ROBUST METHODOLOGY SUCH AS MRI. THERE'S ALWAYS ROOM FOR IMPROVEMENT, A.K.A. MORE FUNDING. WE HAVE ISSUES RELATED TO FETAL AND MATERNAL MOTION, WE KEEP ACQUISITIONS SHORT, 10 TO 20 SECONDS AT A POP, PATIENTS TOLERATE IT WELL. WE ACQUIRE MULTIPLE ACQUISITION TO TRY TO ROOT OUT SIGNIFICANT MOTION ARTIFACT. WE DO 4D FLOW IS ROBUST, BUT THERE IS A TEMPORAL AND SPATIAL RESOLUTION THAT CAN BE IMPROVED AND OPTIMIZEDs AND USING POPULATION BASED OPTION, HEMATOCRIT, RED CELL PRODUCTION IS IN RESPONSE TO HYPOXIA, WE MAKE ASSUMPTION ON FETAL HEMATOCRIT, IT SHOULD BE LESS THAN 5% ERROR IN OXYGEN SATURATION ESTIMATION BUT SOMETHING WE WANT TO WORK ON IMPROVING FURTHER. SWITCHING GEARS TO A DIFFERENT TECHNOLOGY THAT YOU HAVEN'T HEARD MUCH ABOUT YET IN TERMS OF THIS PROGRAM, WE KNOW MRI IS VERY ROBUST, A LOT OF TEAMS ARE USING IT, IT HAS LOGISTICAL, FINANCIAL CHALLENGES, IT'S NOT A BEDSIDE TOOL. OUR TECHNIQUES IN MRI HAVE NOT BEEN FOCUSING ON PARENCHYMA, THE OPTICS TEAM IS LOOKING AT TISSUE OXYGENATION OF THE PLACENTA USING A BEDSIDE TOOL. OUR GOAL IS TO MEASURE OXY AND DEOXYHEMOGLOBIN IN A QUANTITATIVE AND NON-INVASIVE MANNER. LIGHT DIFFUSES THROUGH TISSUE, WE KNOW IT IS ABSORBED BY CHROMOPHORES. NOW, THE ABSORPTION IS CHARACTERIZED BY MU A. AND THE DIFFERENTIAL ABSORPTION OF EACH CHROMOPHORE ALLOWS QUANTIFY TO CONVERGE INTO TISSUE OXYGENATION, OVER HERE. THE THING TO NOTE IS THERE'S SIGNIFICANT SCATTERING OF LIGHT THROUGH TISSUE. BODY TISSUE IS HIGHLY SCATTERING. AS THAT SCATTERING NEEDS TO BE CONTROLLED FOR BECAUSE IT IMPACTS YOUR MEASUREMENT OF ABSORPTION, WITHOUT A GOOD MEASUREMENT YOU CAN'T GET AN ACCURATE OR PRECISE OXYGEN SATURATION MEASUREMENT. HOW DO WE DEAL WITH THE SCATTERING? SO, IN SETTING UP OUR APPROACH WE HAVE TO IDENTIFY OUR CHALLENGES. WE KNOW THE PLACENT IS GENERALLY AROUND FROM 2 TO 4 CENTIMETERS DEEP IN MOST PATIENTS, EXCLUDED MORBID OBESITY BUT MOST WE CAN REACH PLACENTA IF IT'S ANTERIOR AT 2 TO 4 CENTIMETERS AROUND. PHOTONS GENERALLY TRAVEL THROUGH THE TISSUE AND AMOUNT THAT GETS DETECTED AT DETECTOR IS AROUND 1/ 1/ 1/3 TO 1/2, HOW FAR AWAY IMPACTS WHAT THE DETECTOR WILL SEE. YOU NEED LARGE SEPARATIONS TO GET ENOUGH PHOTONS FROM A CERTAIN DEPTH. WE KNOW THE MORE LIGHT GOES THROUGH TISSUE, THE MORE IT GETS ATTENUATED, THERE'S A CHALLENGE DETECTING PHOTONS. ALSO WE KNOW THE HUMAN ABDOMEN IS NOT HOMOGENOUS. IT'S LAYERED. WE HAVE DIFFERENT TISSUE, ADIPOSE, RECTUS MUSCLE, DIFFERENT THICKNESS, IMPACT OF SCATTERING WE'LL TRY TO WORK THROUGH. A LOT OF PRIOR WORK USES CONTINUOUS WAVE NEAR INFRARED SPECTROSCOPY PUTTING OUT INPUT A LASER OF A GIVEN INTENSITY AND MEASURES WHAT INTENSITY IS OF THE LIGHT COMING BACK. YOU ONLY GET ONE VARIABLE HERE. THAT ONE VARIABLE CAN JUST BE ESTIMATED IN ABSORBANCE BUT CAN'T LOOK AT SCATTERING, LIMITED ACCESS TO PLACENTAL TISSUE, MACHINES HAVE REPORTED SEPARATIONS UP TO 4, 4 1/2 CENTIMETERS, NOT DEEP ENOUGH FOR MOST PLACENTAS, YOU DON'T KNOW WHAT'S GOING ON IN OVERLYING LAYERS. FREQUENCY DOMAIN MODULATES THE LIGHT AT A GIVEN FREQUENCY, YOU CAN MEASURE AMPLITUDE SHIFT AND FACE SHIFT, WITH THE TWO VARIABLES YOU SOLVE FOR OXY AND DEOXYHEMOGLOBIN, OVER LONG SOURCE OF SEPARATION AND DECIDED TO INTEGRATE TO ULTRASOUND MACHINE TO MAP OUT OVERLYING LAYERS AND DEVELOP ANATOMY-BASED MODELING. SO, THIS WAS GOING TO BE MY MOST COMPLICATED, I SAW THE RED SIGN. THIS IS ONE I LOST SLEEP OVER, SO IT'S ALL GOOD. [LAUGHTER] DON'T FEEL GUILTY. SO WE GENERATE -- YOU HAVE THE SOURCE GOING IN HERE, LIGHT TRAVELING THROUGH THE DETECTOR, BANANA-SHAPED PATH, LASER MODERATED WITH OVER 90% MODULATION DEPTH, GETS DETECTED SEVERAL CENTIMETERS AWAY BY THE DETECTOR, DOWN CONVERSION WITH REFERENCE SIGNAL, THAT GETS CONVERTED WITH AMPLIFIER TO DEFECT DIFFERENCE IN SHIFT AND AMPLITUDE. THAT'S THE CLINICIAN VERSION. WE DID PHANTOM STUDIES USING TRANSLATIONAL STAGE, WHERE OUR MACHINE WE BUILT WITH THREE WAVELENGTHS, TO IMPROVE OUR ACCURACY IN OUR MEASUREMENTS WITH 12 DETECTOR PAIRS, LOW LASER POWER, TO SHOW HIGH SIGNAL TO NOISE RATIO AT LARGE SOURCE DETECTOR SEPARATIONS, MORE THAN EVER REPORTED BEFORE. AND WE STILL MAINTAIN GREATER THAN 90% ACCURACY DETECTING OPTICAL PROPERTIES EVEN FOUR TO FIVE CENTIMETERS DEEP FROM THE SKIN, THE IMPORTANCE OF WHAT THAT MEANS FOR PLACENTAL WORK AND OTHER WORK THAT CAN USE THIS DEVICE I THINK CANNOT BE OVERSTATED IF IT WORKS. SO, WE INTEGRATED WITH OUR ULTRASOUND, WE HAVE THE PROBE AND BUILT THE OPTICAL PROBE AROUND IT, THIS IS THE DETECTOR, EACH IS A SOURCE DETECTOR SEPARATION THAT'S EXACT. EACH PAIRS FIRES AT A FRAME. ULTRASOUND ALLOWS US TO CREATE TWO-LAYER MODEL TO SEPARATE OVERLYING LAYERS AND UNDERSTAND THOSE OPTICAL PROPERTIES AND FOCUS ON THE DEEP PLACENTA AND TRY TO GET TISSUE PLACENTAL OXYGENATION, NON-INVASIVELY, TRANSABDOMINAL PROBE. THIS APPLIES TO HUMANS OVER THE LAST COUPLE MONTHS, TECHNICAL ADVANCE HAS TO HAPPEN, SEVEN MEASUREMENTS OF PLACENTA TISSUE OXYGENATION FROM 65% TO 77% OXYGEN SATURATION, ON THE Y-AXIS WE SEE THE CHANGES, WE DID REPRODUCIBILITY AND TOOK EACH MEASUREMENT THREE TIMES IN THE SAME SPOT, IN ALL CASES, SMALL SAMPLES, BUT SATURATION NUMBER AROUND 2.3% OF EACH OTHER SO WE'RE GETTING RELATIVELY REPRODUCIBLE NUMBERS WHICH WAS EXCITING FOR US. TO FURTHER THE REPRODUCIBILITY OR SHOW DIFFERENT WAY, ONE PATIENT WE DID THREE POSITIONS, RIGHT SIDE, LEFT SIDE, CENTRAL, THE SMALL VARIATIONS BETWEEN THE -- WITHIN EACH SITE. INTERESTINGLY, TOO EARLY TO CONCLUDE ANYTHING, INTERESTINGLY THE CENTRAL AREA, THIS SINGLE CASE, HAD A LOWER SATURATION IN THE PERIPHERAL AREAS. SO, AGAIN, WE DON'T KNOW -- VERY PRELIMINARY DATA BUT YOU CAN START USING THIS MACHINE IN A WAY THAT MIGHT BE EXCITING. WE TRIED TO DO MATERNAL OXYGEN HYPER OXIA EXPERIMENT, BASELINE SATURATIONS OF 68% OR SO, AND THEN IN THE FIRST 3 1/2 MINUTES OF 20-FRAME HYPEROXYGENATION 100% OXYGEN WE SEE 74%, 75%, UP TO 77% BEFORE THEY START TRENDING BACK DOWN, ONE INDIVIDUAL, IT'S OUR FRESHER DATA, WE'RE STARTING TO SEE THIS TRENDS UP AND DOWN IN THIS ONE SPOT. SO OVERALL THERE'S A LOT OF CHALLENGES TO THIS TECHNOLOGY. IT'S QUITE SOPHISTICATED, QUITE SENSITIVE. A LOT MORE WORK NEEDS TO BE DONE BUT THE HOPE IS IF WE CAN OVERCOME CHALLENGES WE CAN HAVE A NEW INNOVATIVE BEDSIDE TOOL TO LOOK AT TISSUE OXYGENATION OF PLACENTA AT THE BEDSIDE WITH NON-INVASIVE AND QUANTITATIVE MANNER. WE HAVE A LOT OF WORK TO DO WITH CALIBRATION, WE USE LIQUID CALIBRATION FOR EACH PATIENT, QUITE LABORIOUS, WE HAVE TO DECREASE FRAME TIME TO GET EVEN MORE DYNAMIC RESOLUTION, AND WE WANT TO WORK ON OUR MULTI-LAYERING MODELING APPROACHING, WE'RE EXCITED TO CONTINUE THIS WORK. SO CONCLUDING SLIDE, I THINK THAT, YOU KNOW, THIS WORK, QUANTITATIVE IMAGING MODALITIES CAN BE LEVERAGING INTO PLACENTA FUNCTION, MRO2 ASSESSMENTS ARE FEASIBLE. AND THAT THE HOPE IS WE CAN DEVELOP THIS FURTHER INTO A BEDSIDE TOOL TO REALLY FUNCTIONALLY ASSESS HUMAN PLACENTAL OXYGENATION. THANK YOU. I'LL TAKE ANY QUESTIONS. [APPLAUSE] THESE GUYS ARE THE BRAINS BEHIND THIS, NOUN HAVE WORKED ON PLACENTA, I'M NOT SURE THEY COULD SPELL PLACENTA UNTIL WE GOT THIS RFA, THIS SHOWS THE SUCCESS OF THE PROJECT SO THANK YOU TO THE NICHD. >> A QUESTION ABOUT THE WORK ON M.R. IN TERMS OF MEASUREMENTS OF OXYGEN SATURATION. IN MODELING PLACENTA IT'S AN ASSUMPTION OFTEN MADE IT'S A SLOW EXCHANGE CONDITION, ESSENTIALLY THE UMBILICAL VEIN, WITH THE BLOOD LEAVING PLACENTA BY UTERINE VEIN, TRYING TO DO THE NUMBERS IN MY HEAD TO SEE IF THAT -- IT SEEMS CLOSE BASED ON YOUR MEASUREMENTS, WONDERING IF THAT'S THE WAY YOU THINK OF YOUR DATA, ESSENTIALLY THAT -- >> YEAH, WE SEE THE SAME GRAPH, EQUILIBRATION, UMBILICAL VEIN AND OVARIAN VEIN SHOULD EQUILIBRATE. WE'RE SEEING LOWER IN OVARIAN VEIN, THERE'S A LOT OF METABOLIC ACTIVITY IN THE PLACENTA AND PROBABLY UTERUS ALSO, HARD TO IDENTIFY, IT MAKES MORE SENSE THAT OVARIAN VEIN WILL BE SLIGHTLY LOWER, ACCOUNTING FOR MUCH MORE OF THE OXYGEN EXTRACTION OF THE SYSTEM. IT'S HARD TO KNOW IF IT'S RELATED TO OUR IMPRECISION OR PHYSIOLOGIC BUT THAT'S WHY THESE TECHNIQUES ARE REFINED AND COMPLEMENT OTHERS WE SAW TODAY. >> REALLY BEAUTIFUL, I'M INTERESTED IN YOUR BIOPHOTONICS SYSTEM. I HAVE TWO COMMENTS. ONE, ON THE LAYERS THAT YOU EXPOSE ONE PARAMETER IS THE MELANIN CONTENT. >> I CAN'T HEAR YOU. >> MELANIN CONTENT, THE SKIN COLOR ABSORBS A LOT, YOU'RE DEALING WITH AFRICAN-AMERICAN AND SO OH AND SO FORTH, THAT'S A VERY INTERESTING THING THAT THE JAPANESE GROUP YOU REPORTED YOU KNOW WHEN YOU LOOK AT THEIR BMI THEY ARE REALLY LEAN WOMEN AND ALSO THE SKIN, THE COLOR ACTUALLY, YOU KNOW, CLEAR. AND THE OTHER COMMENT THAT I WANT TO MAKE, THE JAPANESE GROUP IS NOT USING CW BUT THEY WEREOME ONE SOURCE DETECTOR SEPARATION BUT THE WAY YOU'RE DOING THIS VERY CHALLENGING AND VERY NICE AND I HOPE YOU CAN TALK MORE. >> THANK YOU. I DON'T THINK THERE WAS A QUESTION IN THERE. >> NADAV, CONGRATULATIONS. THAT'S OUTSTANDING WORK. I HAVE A GENERAL QUESTION TO SEE IF YOU'VE LOOKED AT THIS. LIKE IN THE PRIOR PRESENTATION, AFTER THE HYPEROXIA CHALLENGE THAT SEEMED TO BE A DELAYED RECOVERY, GREATER THAN 10 MINUTES WHICH SEEMS DIFFICULT TO EXPLAIN PURELY BY MATERNAL VASCULAR DYNAMICS. IT SEEMS LIKE A POSSIBILITY, YOU'VE ALTERED FETAL CARDIOVASCULAR DYNAMICS BY HYPER OXYGENATION, RIGHT? SATURATING THE FETAL HEMOGLOBIN, PROBABLY CHANGE PERFUSION BECAUSE OF THAT. DID YOU MEASURE IN TERMS OF YOUR UMBILICAL VEIN FLOW BEFORE AND AFTER LIKE THE HYPEROXIA CHALLENGE, AND DID IT CHANGE AFTER MULTIPLE MULTIPLE ACQUISITIONS OF THAT DATA? >> I THINK IT'S AN EXCELLENT QUESTION. I WAS GOING ASK A SIMILAR QUESTION TO THE MRI TEAMS TO SEE IF THEY CAN SEE A DIFFERENCE. IT'S SENSITIVE TO MOTION. WE HAVE TO KEEP LAYERS THE SAME. I'M SITTING WITH MY HAND NOT MOVE FOR 10, 15, 20 MINUTES, WE CAN'T SCAN THE FETUS IN OTHER PLACES AT THE SAME TIME. WE'VE BEEN FOCUSING TO GET THAT SYSTEM WORKING IN A BELIEVABLE WAY. ONCE WE GET IT WORKING MORE THERE ARE SO MANY QUESTIONS SIMILAR TO THAT WE WANT TO UNDERSTAND. THE FEW PATIENTS SO FAR, WE'VE ANECDOTALLY SEEN THE FETUS STARTS MOVING MORE. DOES THAT EXTRACT MORE OXYGEN FROM THE PLACENTA? DOES THAT LEAD TO SOME HITCH WE'RE SEEING? DOES THE PLACENTA GET ACTIVATED TO REMAIN FOR OF A RESERVOIR BECAUSE OF SOME SORT OF REACTION TO THE HYPER OXYGENATION AND RETAINS MORE OF IT THAN IT WOULD IF OTHERWISE? THESE ARE ALL IMPORTANT QUESTIONS. WE NEED THE TOOLS TO START ANSWERING THEM. >> THANK YOU. BILL FIFER, COLUMBIA. VERY IMPRESSIVE. I WAS WONDERING ONCE YOU MOVED INTO THE FREQUENCY DOMAIN APPROACH DO YOU STILL INTEND TO MAYBE ALSO INCORPORATE THE AMPLITUDE DOMAIN MAYBE AT THE SAME TIME OR ALTERNATING? BECAUSE YOU CAN GET EVEN MORE INFORMATION PRESUMABLY FROM USING MORE THAN ONE UPTOTE, I DON'T KNOW IF THAT'S TRUE, YOU ALLUDED MAYBE NOW YOU CAN BE DEALING WITH MOTHERS WITH HIGHER BMIs WITH THE FREQUENCY DOMAIN, IS THAT TRUE? BECAUSE YOU CAN GET DEEPER AND MAYBE NOT WORRY ABOUT THE BMI OF YOUR SUBJECT? >> FREQUENCY DOMAINS YOU NEED BOTH TO GET ENOUGH VARIABLES TO SOLVE FOR BOTH EQUATIONS OF OXY AND DEOXY. WE'RE MEASURING AMPLITUDE AND FASCIA. PENETRATION, DO WE NEED A TOOL TO WORK IN MOST PATIENTS AS RESEARCH TOOL AND REFINE WITH BIGGER PATIENT. RIGHT NOW WE FEEL CONFIDENT WE'RE GETTING PHOTONS BACK FROM THE PLACENTA, EVEN IF IT'S 4 CENTIMETERS DEEP. PHANTOM UP TO 5 CENTIMETERS. BEFORE WE TOUT THIS AS SOMETHING WE'LL EXTRAPOLATE, WE WANT TO HONE IN ON PRECISION OF MEASUREMENTS, THE WORST THING IS BAD DATA, WE DON'T WANT TO PUT DATA OUT WE DON'T BELIEVE AND PEOPLE HAVE CONCLUSIONS. WE'RE TAKING BABY STEPS TO DO IT THE RIGHT WAY. >> THANKS. >> NADAV, EXCELLENT WORK ON OXIMETRY. I THINK YOUR VAIN DATA MAY BE REAL, EXITS INTO THE VEIN MORE PREFERENTIALLY COMPARED TO UTERINEVEIN. >> WE SEE THAT ALSO. IT'S EASIER TO GET BUT ANATOMICALLY AND PHYSIOLOGICALLY MAKES MORE SENSE. >> BEAUTIFUL WORK. A COUPLE QUESTIONS, INTERESTING COMPARISON, WE DID NEARS IN INFANTS, OUR SAMPLES ARE TEN SECONDS BECAUSE OF HIGHER SNR, HOW DO YOU COMPENSATE? >> THE FIRST POINT I WOULD SAY IN ORDER TO GET REALTIME MAPPING, I'M GETTING ULTRASOUND IMAGES EVERY FEW FRAMES, REMEASURING ALL THE LAYERS SO WE CAN FEED THE MODEL WITH UPDATED INFORMATION. IT'S STILL NOT REAL TIME BECAUSE WE HAVE TO GET STATIC FRAMES, IT'S AROUND 21 1/2 SECONDS FOR EACH FRAME. WE'RE MEASURING IN THE CENTER AS WELL AS EACH SIDE AND SWITCH TO LINEAR PROBE, INITIALLY USED CURVED PROBE THAT OBSTETRICIANS USED, SPECIFICALLY DID LINEAR PROBE TO DECREASE POTENTIAL IMPACT AT THE SKIN LAYER WHERE YOU'RE DEFORMING TO THE SKIN WHERE IT IMPACTS THE LIGHT. USING A FLAT PROBE MEASURING MORE THAN ONE SITE, USING THAT IN OUR MODEL. MORE WORK TO BE DONE. I'M SURE THEY THOUGHT OF DIFFUSION SPECTROSCOPY, THE TOOL THEY DECIDED WAS OPTIMAL, I'M GOING TO DEFER. A LOT OF SCIENTISTS ARE IN THE AUDIENCE, TWO RIGHT HERE, LYNN AND TIFFANY DID A LOT OF THE WORK IN THE LAB ALSO, THEY ARE OPEN FOR QUESTIONS OF COURSE AFTER FOR TECHNICAL STUFF. >> THANK YOU. [APPLAUSE] >> WONDERFUL TALK. THANK YOU. THE NEXT AND LAST RESEARCH TALK IS EXOSOME BASED PLACENTAL MATERNAL FETAL COMMUNICATION BY YOEL SADOVSKY FROM UPMC MAGEE WOMENS HOSPITAL. >> THANK YOU VERY MUCH. THANK YOU FOR ORGANIZING THIS MEETING. IT'S ALWAYS GREAT TO BE HERE TO JOIN AND SHARE DATA. I ALSO -- MY FIRST IMAGE IS ONE OF MY PICTURES OF PITTSBURGH. THIS IS THE TIME I WOULD MAKE A JOKE OR STORY, BUT UNFORTUNATELY PITTSBURGH WAS IN THE NEWS 2 1/2 WEEKS AGO FOR THE VERY TRAGIC SHOOTING THAT TOOK PLACE IN A SYNAGOGUE WHILE PEOPLE WERE PRAYING ON SATURDAY MORNING, SO I JUST CAN'T CONTINUE WITHOUT REMINDING ALL OF US THAT WE'RE SCIENTISTS, TIMES LIKE THESE HAVE TO REMIND OURSELVES ABOUT OUR COMMITMENT -- I'M NOT SURE WHAT'S HAPPENED. AT TIMES LIKE THIS WE HAVE TO REMIND OURSELVES OF OUR COMMITMENT TO THE TRUTH AND TO REAL FACTS, NOT FAKE FACTS, AND ALSO TO HUMANISM, GLOBAL HUMANISM. THANK YOU. [APPLAUSE] SO IN OUR RESEARCH, WE FOCUS ON COMMUNICATION BETWEEN THE MOTHER, THE PLACENTA, AND THE FETUS, TO TAKE PLACE BY SIGNALS THAT EMANATE FROM THE PLACENTA AND CAN BE SEEN, AND CAN BE SEEN EMERGING FROM THE PLACENTA, AFFECTING DIVERSE MATERNAL ORGANS AND FETAL ORGANS, ALSO POTENTIALLY MAY EMANATE FROM FETUS TO AFFECT THE PLACENTA AND VICE VERSA, EXAMPLES IN FETAL SELLS IN PLACENTAL VILLI. WE LOOK SIMPLISTICALLY AT THIS SYSTEM, THREE COMPONENTS, THE MOTHER, HERE, THE PLACENTA AND FETUS. AND WE'RE TRYING TO UNDERSTAND THE COMMUNICATION THAT TAKES PLACE PRIMARILY THROUGH THE MAIN COMMUNICATION SITE WHICH IS THE TROPHOBLAST, YOU CAN SEE A CARTOON OF A CROSS-SECTION OF VILLI, HERE THE TROPHOBLASTS, YOU CAN ALSO SEE HERE IN THE ELECTRON MICROSCOPE IMAGE WITH THE MOTHER BEING HERE, MOTHER BLOOD HERE, FETAL BLOOD HERE OR HERE, THIS COMMUNICATION INTERFACES THE KEY FUNCTIONS WE'RE INTERESTED IN. WE'VE BEEN STUDYING NUCLEIC ACID, IN THE PAST PROTEIN MOLECULES THAT MEDIATE FUNCTIONS ACROSS THIS INTERFACE, AND I WOULD LIKE TO JUST BRIEFLY SHARE WITH YOU WHAT WE'VE DONE, WHAT WE'RE DOING RIGHT NOW IN THAT CONTEXT. WE HAVE A FUNCTION FOR OUR ANALYTES. THESE ARE NOT JUST DESIGNED FOR DIAGNOSTICS BUT ALSO FOR POTENTIAL KEY FUNCTION IN HUMAN PLACENTAL -- DURING HUMAN PREGNANCY. ONE OF THE KEY FUNCTIONS WE'VE UNCOVERED IS ANTI-VIRAL EFFECT THAT YOU CAN SEE HERE, WHERE IF WE TAKE NON-TROPHOBLASTIC CELLS, IT WAS EASY TO INFECT NOT PLACENTAL CELLS WITH DIFFERENT VIRUSES BUT ALMOST IMPOSSIBLE TO INFECT PRIMARY HUMAN TROPHOBLAST CELLS WITH DIFFERENT VIRUSES. THIS IS THE KEY FUNCTION, WE'VE UNCOVERED, NOT ONLY THIS WE FOUND, I'LL ABBREVIATE THE DATA HERE, WE FOUND THIS FUNCTION CAN BE TRANSFERRED TO OTHER NON-PLACENTAL CELLS BY TRANSFERRING THE MEDIUM, THE CONDITION MEDIUM FROM TROPHOBLASTIC CELLS TO OTHER CELLS THAT USED TO BE SUSCEPTIBLE VIRUSES AND CAN CONFER TO NON-PLACENTAL CELL TYPES. HIGH THROUGHPUT ANALYSIS, AND OTHERS, WE FOUND THIS EFFECT IS MEDIATED BY PLACENTAL-PRODUCED microRNAs, AND THERE'S SPECIFIC FAMILIES microRNAs MENTIONED THIS MORNING, CHROMOSOME 19 microRNA CLUSTER, THIS IS A PICTURE OF JEAN CLAUDE, IN THE AUDIENCE, WHO HAS DONE THE WORK IN THE LAB. THE LARGEST ONES IN THE HUMAN BODY, CAN MEDIATE THIS EFFECT, INTERESTINGLY THESE microRNAS EXPRESSED IN THE PLACENTA, PRIMATE SPECIFIC, NOT EXPRESSED IN RED, ONLY IN PRIMATES AND HUMANS. INTERESTINGLY BUT NOT CRITICAL FOR THIS TALK, IMPRINTED FROM THE FATHER'S ALLELE. IF YOU TAKE JUST THE microRNAs, A MIX OF THESE MICRORNAS, WE CAN CAUSE RESISTANCE IN THE OTHER, MEDIATED BY AUTOPHAGY, IF WE BLOCK USING INHIBITION OR SILENCING ONE OF THE KEY AUTOPHAGIC PROTEINS CAN BLOCK THIS AND RESTORE SENSITIVITY TO VIRUSES. WE FOUND IN THE LAST SEVERAL YEARS AND PUBLISHED WHEN WE SCREEN PLACENTAL MEDIUM, SPECIFICALLY VESICLES MADE BY PLACENTAL TROPHOBLASTS, HUMAN PLACENTAL TROPHOBLASTS, HIGHLY EXPRESSED IN EVERY VESICLE MADE WITHIN THE -- BY HUMAN TROPHOBLAST CELLS IN THE PLACENTA, YOU CAN SEE APOPTOTIC BODIES, MICROVESICLES, SMALLER EXOSOMES WITHIN INTRALUMAL VESICLES TO BE RELEASED AS EXOSOMES, EACH CONVEYANCE CD19 microRNAS, WHEN WE TAKE VESICLES AND PUT THEM ON OTHER NON-PLACENTAL CELLS WE CAN CONFER RESISTANCE TO VIRUSES TO THESE CELLS. INTERESTINGLY, ALL OF THESE VESICLES CONTAIN microRNAs BY FAR THE MOST ACTIVE ONE WITH THE FUNCTION I SHOWED YOU, ANTI- VIRAL FUNCTION, BY FAR THE MOST ACTIVE ONES ARE EXOSOMES. WE ALREADY PUBLISHED THIS WORK. I WANT TO SUMMARIZE THAT WHAT WE SHOWED IS PLACENTAL TROPHOBLASTS CAN PRODUCE EXOMES, VERY LARGE AMOUNT , CAN BE FOUND IN TISSUE CULTURE MEDIUM, ADD THEM TO NON-PLACENTAL CELL TYPES THEY CAUSE AUTOPHAGY, HERE IS A CARTOON OF AUTOPHAGEOSOME, ONCE THEY PRODUCE VESICLES IT FUSES WITH THE VIRAL VESICLE AND SHUTTLE THE VIRAL VESICLE FOR DEGRADATION WITH THE LYSOSOMES. WE ALSO FOUND AND JUST PUBLISHED A YEAR AND A HALF AGO IN AN INDEPENDENT LINE OF INVESTIGATION THAT THERE'S ANOTHER ANTI-VIRAL MECHANISM THE PLACENTA PRODUCES, MEDIATED BY TYPE 3 INTERFERON, LAMBDA 1, LAMBDA 2, UNIQUE TO TROPHOBLASTS, ADDED OR WHEN THEY ARE NATURALLY PRODUCED WITH PLACENTA THEY CAUSE THE INDUCTION OF WHAT'S CALLED INTERFERON STIMULATED GENES OR ISGs, WHICH HAVE A CLASSICAL ANTI-VIRAL PROPERTIES WITHIN CELLS. SO FOR MY REMAINING TIME I WANT TO SHOW YOU OUR KEY QUESTIONS WE'VE BEEN ADDRESSING FOR THE LAST SEVERAL YEARS. WE CONTINUE TO ADDRESS THEM INCLUDING SOME UNPUBLISHED DATA. THIS IS JUST THE CARTOON, THE SAME ONE I SHOWED JUST NOW, TO SHOW YOU SOME KEY QUESTIONS IN THE FIELD, WHICH ONES WE'RE TARGETING IN OUR CURRENT RESEARCH. THE FIRST QUESTION YOU CAN SEE HERE WITHIN TROPHOBLASTS, THE QUESTION IS GENERAL WHAT MEDIATES THE UPLOAD OF ANY KIND OF CARGO INCLUDING SMALL RNAs AND microRNAS, WHAT MEDIATES UPLOAD OF THIS CAR GOING INTO WHAT WILL BECOME EXOSOMES RELEASED INTO CELLS. THIS IS ADDRESSED BY OBSERVED, INCLUDING A NOBEL LAUREATE FROM BERKELEY, STUDYING THIS PHENOMENON, IDENTIFIED RNA-BINDING PROTEINS THAT SEEM TO BE PREFERENTIALLY UPLOADING CERTAIN microRNAs INTO EXOSOMES. WE'VE NOT FOUND THIS TO BE HAPPENING IN TROPHOBLASTS, DID NOT FIND PREFERENTIAL UPREGULATION OR I'M SORRY UPLOADING OF THESE C19 MICRO SOMES INTO EXOSOMES. THERE'S A CORRELATION. WE'RE VERY MUCH INTERESTED IN THE SHUTTLING OF EXOSOMES, WE'RE INTERESTED IN THE UPTAKE AND WHERE IT GETS DEPOSITED AND HOW EXOSOMES GET INTO CELLS TO SHUTTLE CARGO WITHIN CELLS. AND ALSO WE'RE VERY MUCH INTERESTED IN ANY ENVIRONMENTAL MATERNAL AND DISEASE CONDITIONS MAY AFFECT THIS TRAFFICKING MECHANISM, WE'RE NOT PURSUING IT RIGHT NOW BUT IT'S ONE OF OUR FUTURE GOALS. I WANT TO STOP WITH THIS QUESTION, WHERE THE MICRORNA IS GOING IN THE BODY. WE TRIED TO UNTANGLE THIS QUESTION BY USING HIGH-THROUGHPUT SEQUENCING OF MOTHERS DURING PREGNANCY SO WE TOOK BLOOD FROM MOTHERS, FETUSES BY CORE BLOOD DELIVERY, ALSO PLACENTAL BIOPSIES. WE TOOK A LARGE NUMBER OF PATIENTS USING RNA-SEQ, QUANTIFIED ACROSS THREE COMPARTMENT, MOTHER, PLACENTA, FETUS, COULD NOT ALLS THE DATA TO DECIPHER BETWEEN THE MOTHER, PLACENTA AND FETUS. TO OVERCOME THIS ISSUE WE USED A MOUSE SYSTEM AND I TOLD YOU THAT THE microRNAs WE'VE BEEN WORKING ON EXPRESSED ON C-19 FAMILY OF microRNAs ARE NOT NATURALLY EXPRESSED IN THE MOUSE OR OTHER LOWER ORGANISMS. WE CLONED THE KILOBASE FRAGMENT, USING TRANSGENIC APPROACHES, ONE WHO IS SITTING HERE CREATED THE MICE, WITH THE HOPE WHEN PREGNANT THEY WILL RECAPITULATE THE HUMAN BIOLOGY. WE'RE LUCKY TO SEE WHEN THE MICE WERE NOT PREGNANT EXPRESSED A MAINLY IN THE TESTES AND OVARY. WE'RE PLEASED TO SEE LIKE THE HUMAN BIOLOGY, AS SOON AS THE FEMALE GOT PREGNANT, HER PLACENTA STARTED MAKING LARGE AMOUNT OF MICRORNAS, 40 TO 200 FOLD INCREASE, LIKE HUMAN PREGNANCY. INTERESTINGLY NOT ONLY EXPRESS PATTERN MIMICS HUMANS BIOLOGY BUT ALSO PATTERN OF INDIVIDUAL microRNA EXPRESSION MIMICKED SUCH THAT IF A microRNA WAS HIGH IN TROPHOBLAST CELLS IT WAS HIGH IN A HUMAN. REMEMBER, THESE MICE HAVE NEVER SEEN THOSE microRNAs NATURALLY IN THE BODY. WE'R QUITE PLEASED TO SEE THIS IS A FOREIGN PIECE OF DNA, THIS DNA WAS REGULATEED IN THE MANNER THAT MIMICKED THE HUMAN PLACENTA. NOW WE HAD A SYSTEM WE CAN STUDY TRAFFICKING BETWEEN THE MOTHER, PLACENTA AND FETUS, IN ONE PICTURE I WANT TO SUMMARIZE OUR DATA. THE FIRST EXPERIMENT WAS SIMPLY IF THERE'S TRAFFICKING FROM THE PLACENTA INTO THE MOTHER'S SIDE, THAT WAS VERY EASY EXPERIMENT. WE TOOK A WILDTYPE MOTHER AND TRANSGENIC FATHER, CROSSED THEM, HALF EMBRYOS ARE TRANSGENIC, WHATEVER WE FOUND IN MATERNAL TISSUES CAME FROM FETUS AND PLACENTA AND INDEED FOUND NON-EVEN DISTRIBUTION OF microRNAs IN DIVERSE MATERNAL ORGANS, I WON'T GET INTO THIS. WE PUBLISHED THIS LAST YEAR. WE LOOKED AT CAN WE DETECT TRAFFICKING FROM THE MOTHER INTO THE FETUS AND PLACENTA. WE DID THE OPPOSITE EXPERIMENT. HERE WHAT YOU SEE ON THE LEFT SIDE IS THE MOTHER IS TRANSGENIC, FATHER WAS WILDTYPE, HALF EMBRYOS ARE WILD TYPE, WE CAN DETECT TRAFFICKING FROM MATERNAL TISSUES INTO THE WILDTYPE FETUS, PLACENTA, AND FETAL TISSUES. WE DID EMBRYO TRANSFER, WILD TYPE INTO TRANSGENIC MOTHER AND CAN SEE THE SAME THING. IN THE THIRD AND LAST EXPERIMENT WERE ABLE TO USE TRANSGENIC APPROACHES USING LENTIVIRUS, AFFECT AT DAY 3.5, ONLY THE PLACENTA WILL EXPRESS microRNA, FETUS WILL NOT, ABLE TO FIND CLEAR TRAFFICKING FROM THE PLACENTA, NOT ONLY TO THE MOTHER BUT ALSO INTO THE FETUS. JUST TO SUMMARIZE THOSE DATA WE SEE NICE TRAFFICKING FROM THE PLACENTA INTO THE MOTHER, ALSO SOME FROM THE MOTHER TO THE FETUS, ALSO SOME TRAFFICKING FROM THE PLACENTA INTO THE FETAL SITE. THE NEXT QUESTION I SHOWED YOU IS CAN WE PROVE THAT THESE microRNAS ARE EXPRESSED AND HAVE SOME EFFECT CAN WE PROVE THEY GET INTO CELLS AND HOW. TO SHOW THEY GET INTO CELLS WE CAN DO SEVERAL THINGS. ONE THING YOU CAN SEE HERE ON THE LEFT IS BASICALLY JUST A WESTERN BLOT, THE SIMPLEST APPROACH FOR ONE OF THE PROTEINS THAT EXPRESS AN EXOSOME, SEE IT NICELY IN CELLS, NICE BUT NOT PROBABLY GOOD ENOUGH. THE OTHER THING MORE CONVINCING WE WANTED TO MAKE SURE THAT WHEN THE EXOSOMES GET INTO CELLS THEY SHUTTLE INTO THE RIGHT PATHWAY WITHIN CELLS. TO BE ABLE TO VISUALIZE THIS WE DID A TRICK, MADE A MUTATION IN ONE OF THE ENDOSOME MAL PROTEINS, FROM GLUTAMINE TO LEUCINE, LABELED WITH GFP, THE ENDOSOMES BECOME BIGGER, A CONTROL EXPERIMENT, NOW WE'RE ADDING EXOSOMES, YOU CAN SEE THE NICE EXOSOME, EXACTLY LOCATED WITHIN IN THE CELL WHERE IT SHOULD BE. WE HAVE DONE AND CONTINUE NOW TO DO SOME ADDITIONAL TIME COURSE STUDIES TO BE ABLE TO LOCALIZE EXOSOMES WITHIN ORGANELLES AND USING A FAIRLY SHORT TWO HOURS TIME COURSE CAN SEE NICE LOCALIZATION OF EXOSOMES LABELED WITH RED, AND EA1 PROTEIN AND CAN SEE CROSS-STAIN, LATE ENDOSOMES AND LYSOSOMES AND HAVE A GOOD HANDLE THEY ARE GETTING INTO CELLS AND SORTED THE WAY THEY ARE SUPPOSED TO BE SORTED. WHAT IS THE MECHANISM BY WHICH THESE EXOSOMES GET INTO CELLS? ANOTHER WHO IS IN THE AUDIENCE ALSO, SHOWN IN THIS PICTURE IS DOING THESE EXPERIMENTS NOW, HE HAS A POSTER THIS AFTERNOON, HOW HE PURSUES DIFFERENT PATHWAYS, BUT HAS BEEN STUDYING DIFFERENT PATHWAYS INCLUDING MACRO CYTOSIS, AND WE THINK WE'RE CLOSE TO HONE DOWN ON DIFFERENT PATHWAYS WHICH MAY NOT BE UNIFORM AMONG DIFFERENT CELL TYPES, STUDYING IN PLACENTAL FIBROBLASTS, ENDOTHELIAL CELLS AND OTHER CELL TYPES TO FULLY UNDERSTAND THE MECHANISM OF ACTION. AND HE HAS GENERATED CONSTRUCTS TO HELP US TRACE THE ENTRY OF THESE EXOSOMES INTO CELLS. IS IT POSSIBLE THAT SOME EXOSOMAL PROTEINS HAVE A BARCODE THAT SHUTTLES THEM INTO THE RIGHT CELLS IN THE MOTHER AND FETAL CIRCULATION? WE THINK THERE'S A BARCODE. IT'S A PROTEIN BARCODE, PHOSPHOLIPIDS ARE PROBABLY ALSO IMPORTANT BUT AS A PROOF OF PRINCIPLE WHAT WE DID USING A HIGH THROUGHPUT PROTEOMIC WE IDENTIFIED ONE OF THE FUSOGENIC PROTEINS IS EXPRESSED, USING CRISPR/CAS9 KNOCK OUT RECEPTOR FROM TARGET CELLS. WHEN WE KNOCK OUT THE RECEPTOR FROM THE TARGET CELLS NOT ONLY REDUCE UPTAKE OF EXOSOMES INTO CELLS AND ATTENUATED ANTI-VIRAL ACTIVITY, WE FEEL COMFORTABLE SAYING THERE'S A PROTEIN BARCODE, HIGH THROUGHPUT APPROACH TO TEASE OUT THE BARCODE ON THE SURFACE OF EXOSOMES AND TARGET CELLS TO UNDERSTAND THE INTERACTION. THESE ARE DATA FROM OTHERS FROM AUSTIN, TEXAS, FROM BERKELEY, FROM THAT GROUP, WHEN YOU USE RNA SEQUENCING ON DIFFERENT EXTRACELLULAR VESICLES THERE ARE SOME VERY INTERESTING FORMS OF microRNAs AND OTHER TYPES OF RNAs HIGHLY EXPRESSED AMONG SMALL RNA MOLECULES AND I THINK NOWADAYS USING HIGH THROUGHPUT TECHNOLOGY SEQUENCING AND WITH PROPER CONTROLS WE SHOULD BE ABLE TO IDENTIFY OTHER SIGNALS THAT EMANATE IN OUR CASE FROM THE PLACENTA AND CAN BE SHUTTLED TO OTHER CELL TYPES TO CARRY OUT THEIR AFFECTS, microRNA IS A SMALL PART OF THE PUZZLE, ALSO LEADS TO OTHER QUESTIONS THAT I WANT TO SHARE WITH YOU AS WE'RE THINKING ABOUT THESE QUESTIONS. FOR EXAMPLE, IF YOU CALCULATE THE NUMBER OF microRNAs IN TYPICAL EXOSOMES PEOPLE THINK THE NUMBERS CAN REACH A TOTAL IN BLOOD, THE DIAMETER OF EXOSOMES, AFTER YOU REDUCE PHOSPHOIPID LAYERS, 10 TO 70 NANOMETERS. IF YOU CALCULATE, THE CAR GO COULD BE UP TO 25,000. THE OTHER COUNTER-CALCULATION SUGGEST MAYBE THE NUMBER OF THOSE SMALL RNA PER EXOSOME MAY BE SMALLER. HOW CAN WE RECONCILE DATA TO FIND OUT THE NUMBER OF MOLECULES AND POTENTIAL EFFECT ON THEIR CELLS? I WANT TO SHARE OTHER KEY QUESTIONS WE'RE DEALING WITH RIGHT NOW. THIS IS NOT A PICTURE OF PITTSBURGH. I'M HAPPY THE LIZARD JOINS OUR CONVERSATION. HOW DO WE DEFINE EXTRACELLULAR VESICLES? THIS IS A BIG ARGUMENT IN LITERATURE. EXOSOMES ARE DEFINED BY THEIR SIZE, PROTEINS ON THE SURFACE. THE BEST WAY TO DEFINE IS ISOLATING VESICLES, REMAINS A TECHNICAL CHALLENGE FOR EVERYBODY IN THE FIELD. ARE ALL VESICLES MADE EQUAL? WE'RE TRYING TO UNDERSTAND DIVERSITY, VARIABILITY OF VESICLES. HOW DO THEY FIND THEIR TARGETS? WE'RE STUDYING THE BARCODE BUT WE DON'T KNOW. PACKAGED IN EXTRACELLULAR VESICLES, IT'S A VERY TOUGH QUESTION, WE DEALING WITH THIS TO TRY TO UNDERSTAND BUT IT ADDS TO THE QUESTION WHAT ARE THE OTHER FUNCTIONS OF EXTRACELLULAR VESICLES, IS IT POSSIBLE THEY ARE NOT INERT PACKAGES BUT SMALL FACTORIES THAT PROCESS MESSAGES TO BE ABLE TO CARRY THEM TO THE TISSUE? I WANT TO CONCLUDE BY A CLINICAL APPLICATION, THAT WE'RE WORKING ON RIGHT NOW WITH SEVERAL ENGINEERS. IF YOU'RE USING EXTRACELLULAR VESICLES AS NOT ONLY TO UNDERSTAND PLACENTAL BIOLOGY BUT AS MARKERS FOR DIAGNOSTICS, IN REAL TIME DURING PREGNANCY, ONE HAS TO HAVE A VERY EFFICIENCIES -- SYSTEM TO ISOLATE EXOSOMES. IF WE CAN DO A SIMPLE BLOOD TEST, IN A MOTHER, AND EXTRACT EXOSOMES AND RAPIDLY NOT DOING ONE TO TWO DAYS, EVEN THREE DAYS, RAPIDLY ISOLATE EXOSOMES, WORKING WITH THIS QUESTION WITH BIOENGINEERS FROM M.I.T., CARNEGIE MELLON AND DUKE UNIVERSITY, AND ESSENTIALLY WE CAME UP WITH A SYSTEM YOU CAN SEE WHICH IS A SMALL SYSTEM WHICH IS BASED ON ULTRASOUND, ACOUSTIC RESISTANT NODES, THAT YOU CAN SEE ONE HERE, ONE HERE, AND IN THIS VESICLE, WHOLE BLOOD, ACOUSTIC NODES ARE DESIGNED TO SEPARATE FIRST RED BLOOD CELLS, WHITE BLOOD CELLS, PLATELETS, AND THE SECOND ONE TO SEPARATE LARGER VESICLES, THE MICROVESICLES AND APOPTOTIC BODIES FROM THE EXOSOMES. MY LAST PICTURE, HOW IT ACTUALLY WORKS. HERE IS A LITTLE MOVIE, WHICH I HOPE WORKS. HERE YOU SEE WHOLE BLOOD COMING IN. THIS IS WHOLE BLOOD. COULD BE APPLIED TO THE BEDSIDE. FIRST NODE WE'RE SEPARATING RED BLOOD CELLS, WHITE BLOOD CELLS AND PLATELETS, VESICLES ARE SHUTTLING TO SECOND NODE YOU'LL SEE IN A SECOND, WE'RE GOING TO SEPARATE THE LARGER VESICLES, APOPTOTIC BODIES, AND MICROVESICLES, EXOSOMES HERE, COLLECT THEM ON THE OTHER SIDE USE THEM FOR DIAGNOSING PLACENTAL DIAGNOSTICS. SO THIS IS WHAT I WANTED TO TELL YOU TODAY. IF YOU'RE INTERESTED IN THIS TECHNOLOGY, THE INPUT IS 100 MICRO LITERS OF BLOOD, OUTPUT IS FAIRLY PURE, NOT 100% PURE BUT MORE THAN 95% PURE EXOSOMES, 25 MINUTES TO PERFORM. THESE ARE THE PEOPLE THAT CONTRIBUTED TO THE WORK. JEAN FRANCOIS AND WUI ARE HERE, THOSE ARE THE OTHERS I INTRODUCED ALONG THE WAY, COLLABORATORS FROM CELL BIOLOGY AND UNIVERSITY OF PITTSBURGH, THE ENGINEERING TEAM, WE WORK WITH NATHAN PRICE AND ALLISON PACKETT WHO IS HERE. THANK YOU VERY MUCH. [APPLAUSE] >> HI, Y'ALL. YOU ARE THE GOLD STANDARD BOTH AS SCIENTIST AND HUMAN BEING. THANK YOU FOR BEING OUR LEADER. I APPRECIATE THAT. MY QUESTION HAS TO DO WITH microRNAs AND VIRUS. PRIMARY CELL LINE FROM FLOATING VILLI, THINKING ABOUT ANCHORING VILLI, CMV MAY CRAWL UP THE TROPHOBLASTIC COLUMNS, HAVE YOU MAPPED microRNAs IN DIFFERENT CELL TYPES? >> NOT YET. WE DID MAP THEM TO OTHER -- WUI, WHO IS HERE, MAPPED THEM. SEEMS TO BE MANY OTHER CELL TIMES WITHIN THE PLACENTA, HUMAN PLACENTA, EXPRESSED MATURE C-19 microRNAs BUT WE THINK THEY ARE PROBABLY UPTAKING FROM TROPHOBLASTS. WUI DID NOT FIND THE PRECURSOR FOR THE microRNAS IN THE CELLS, THERE'S ONE PUBLICATION THAT SUGGESTS OTHER CELL TIMES -- TYPES MAY MAKE THEM, WE THINK THEY ARE PROBABLY UPTAKE. WHICH SUBTYPE OF TROPHOBLASTS? WHEN YOU INTRODUCE microRNAS IT SLOWS DOWN MIGRATION, WE DIDN'T TALK ABOUT THIS FUNCTION BUT PUBLISHED THAT. OTHER CELL TIMES WE -- -- OTHER CELL TYPES WE DON'T KNOW YET. >> NC STATE. THE POINT YOU MADE ABOUT SPECIFIC CELL TYPE, TROPHOBLAST MAKES THESE EXOSOMES, DO YOU SEE A BIAS BETWEEN WHAT IS SECRETED IN THE APICAL VERSUS BASAL, LIKE IF THE FETUS IS GETTING SOMETHING AND MOTHER IS GETTING SOMETHING, PRESUMABLY THEY ARE GETTING SOMETHING DIFFERENT AND WOULD YOU COMMENT ON THAT? >> IT'S A GREAT QUESTION. WE REALLY DON'T KNOW FOR SURE. BASED ON THE FLOW WE'RE SEEING THE FLOW SEEMS TO BE GREATER INTO THE MOTHER'S SIDE FROM THE MICROVILLOUS AREA. THINK ABOUT THE FETAL SIDE, IN VIVO THE microRNAS OR WHATEVER PACKAGE CONTENT MAY REVERSE BASE MEMBRANE. WE'VE BEEN ABLE TO SEE PASSAGING INTO THE FETAL SIDE BUT WE'VE NOT TRIED TO, USING TRANSFER SYSTEMS OR OTHERS, TO BE ABLE TO COMPARE THE RATE OF TRAFFICKING FROM THE TWO SURFACES. IT'S A GREAT QUESTION. THANK YOU. >> NICE PRESENTATION. I EXPECT NOTHING LESS, OF COURSE. THE QUESTION ON MY MIND IS THE MEMBRANE IN CLOSURE OF THE MICRO PARTICLES, WHAT ROLE THAT MAY PLAY IN TARGETING FUSION. SO, IS FUSION SUBJECT TO THE PRESENCE OF THINGS LIKE ANCHORING PROTEINS AND GET CARRIED IN CARGO? >> GREAT QUESTION. WE'RE INTERESTED IN WHAT DETERMINESES UPTAKE AND ENTRY INTO TARGET CELLS. I DIDN'T TALK ABOUT IT BUT WE'VE DONE A HIGH THROUGHPUT LIPID OMIC ANALYSIS, I CAN TELL YOU THE PLACENTAL EXOSOMES ARE DIFFERENT FROM MICROVESICLES IN APOPTOTIC BODIES, CONCENTRATION OF CHOLINE IS HIGHER COMPARED TO OTHERS WHERE THERE'S MUCH GREATER PRESENCE OF (INDISCERNIBLE), SUPPORTS GREATER RIGIDITY OF EXOSOMES BECAUSE OF THE NATURE OF CHOLINE. WE THINK THIS IS CRITICAL FOR THE EXACT INTERACTION OF EXOSOME OR OTHER VESICLE WITH PHOSPHOLIPID SURFACE OF A CELL. WHAT ACTUALLY ARE THE OTHER DETERMINANTS THAT DO IT WE'RE RIGHT NOW IN THE MIDDLE OF A WORK WE HOPE TO COMPLETE VERY SOON, TO TEST AND ALSO IMAGE INTERACTION USING LIVE-CELL IMAGING, FLUORESCENT LIVE CELL IMAGING AND OTHER IMAGING TECHNIQUES TO VISUALIZE AND DETERMINE WHAT ARE THE KEY CHARACTERISTICS THAT ALLOW THIS INTERACTION TO OCCUR. >> AND IS CHOLESTEROL IMPORTANT? >> CHOLESTEROL MAY BE IMPORTANT BUT THERE'S NO FREE GLYCEROL IN THE MEMBRANE. >> CHOLESTEROL. >> CHOLESTEROL MAY BE VERY IMPORTANT. WE'VE NOT TESTED YET. WE THINK CHOLESTEROL WOULD BE IMPORTANT, AS WELL AS AS YOU SUGGESTED EARLIER OTHER PROTEINS. >> THANK YOU. >> DUKE UNIVERSITY. THANK YOU FOR THE WONDERFUL TALK. A QUESTION. IN YOUR TALK YOU FOCUS ON EXOSOMES. WHAT ARE ABOUT LARGER SIZE MICROVESICLES, DO THEY HAVE ANTI-VIRUS EFFECT AS WELL? >> THANK YOU. WE THINK THE MICROVESICLES AND APOPTOTIC BODIES ARE CARRYING SIGNIFICANT CARGO AND MAY BE USED FOR DIAGNOSTICS. WE HAVE A FUNCTION, WE HAVE MORE THAN ONE FUNCTION, BUT ONE KEY FUNCTION, THAT KEY FUNCTION WAS MEDIATED MUCH MORE ROBUSTLY BY THE EXOSOMES, NOT TO SAY MICROVESICLES AND OTHER VESICLES ARE NOT EQUALLY IMPORTANT. >> THANK YOU. >> ONE MORE QUESTION. >> THANK YOU FOR THE TALK. I APPRECIATE YOUR DISCOVERY OF THESE WHAT WE USED TO CALL ENDOGENOUS RETROVIRUSES, BEFORE WE KNEW ANYTHING, WHEN WE LOOKED AT HIV EXPOSED PLACENTA, WE FOUND THEM. THE PLACENTA HAS AFFINITY FOR THESE MICROVESICLES AND GETS INFECTED, WE HAD CASES WHERE THE PLACENTA WAS INFECTED BY IMMUNOGOLD, WHAT ELSE DO WE DO? WE DO IN SITU PCR, LOOKED FOR ALL KINDS OF TESTS, AND ALL THESE CELLS IN THE PLACENTA ARE INFECTED BUT THE BABY WAS NOT INFECTED. SO THERE MAY BE SOME FUNCTIONAL CAPACITY OF THE PLACENTA TO ABSORB SOME OF THIS STUFF THAT EXPERIENCED IN THIS VERY SMALL EXPERIMENT BUT WE HAD VERY, VERY CONVINCING DATA. WE HAD AT LEAST 20 BABIES THAT WERE TOTALLY HIV FREE BUT WHEN YOU LOOKED AT THE PLACENTA WHAT YOU COULD SEE IS EXACT COPIES OF AN HIV VIRUS. >> IT'S A HUGE POINT THAT PROBABLY WAS REQUIRED A LONG TIME TO DISCUSS, BRIEFLY I AGREE WITH YOU 100%. THE PLACENTA IS THE FOREFRONT OF THE FETAL PLACENTAL UNIT INTERACTING WITH THE MOTHER AND EXTERNAL WORLD. IT'S NOT SURPRISING PLACENTA WOULD BE TARGET FOR ALL KINDS OF VIRAL ELEMENTS, OTHER TYPES OF RETRO ELEMENTS AND NUCLEIC ACID AND OTHER MOLECULES THAT MAY ENTER, AS THEY ENTER INTO THE FETUS POTENTIALLY THEY COULD AFFECT THE NEXT GENERATION OF HUMANS. SO IT'S NOT SURPRISING THE PLACENTA HAS DEVELOPED TECHNOLOGIES, ITS OWN INHERENT TECHNOLOGY, DESIGNED TO ATTENUATE EFFECT OF THOSE EXTRA RETRO ELEMENTS AND EXTERNAL PARTICLES. IT'S ALSO INTERESTING, WE DON'T KNOW WHY, NOBODY WHO SITS HERE KNOWS WHY THERE'S MUCH LESS SUPPRESSION IN THE GENOME OF THE PLACENTA COMPARED TO THE FETUS WHICH MAY SUGGEST THE PLACENTA FINDS A WAY TO SORT THESE ELEMENTS, SOME OF THEM AS WE KNOW ARE USED AS PLACENTAL ADVANTAGE, FOR EXAMPLE, SENSEITENE HAS BEEN USED FOR HUMAN PLACENTAL FOR CELL FUSION, ALSO C-19 CLUSTER SEEMS TO BE A RETRO ELEMENT AS WELL. WHY THESE ARE EXPRESSED IN THE PLACENTA AND CLEARLY EXPRESSED IN THE FETUS WE DON'T KNOW BUT THE PLACENTA HAS A UNIQUE WAY TO ADDRESS FOREIGN ELEMENTS INTRODUCED INTO THE BODY AND MAY POTENTIALLY AFFECT EVOLUTION. >> WELL, I SPOKE TO TONY FAUCI, WE GREW UP IN THE SAME NEIGHBORHOOD IN BROOKLYN. WANT TO LEARN HOW TO PUT AN HIV VIRUS TO SLEEP? TALK TO THE PLACENTA. >> THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH. IT WAS A VERY EXCITING TALK. NOW WE'RE GOING TO START OUR NEW SESSION, QUITE DIFFERENT, A PANEL DISCUSSION THAT WE'RE GOING TO HAVE ABOUT THE CHALLENGES OF THE CLINICAL TRANSLATION. I KNOW SOME OF YOU IN THIS ROOM ARE VERY INTERESTED IN THE TOPIC, AND WE REALLY WOULD LIKE YOUR INPUT HERE, WE WANT YOU TO BE INTERACTIVE, ASK QUESTIONS AND GET INVOLVED TO MAKE THIS PANEL BETTER. SO WITH THAT I WOULD LIKE TO HAVE DR. CATHY SPONG FROM UNIVERSITY OF TEXAS SOUTHWEST MEDICAL CENTER AS PANEL DISCUSSION. >> I CAN HAVE THE OTHER PANELISTS COME ON UP. FIRST I WANT TO SAY -- >> USE THE MICROPHONE. >> WONDERFUL. THANK YOU SO MUCH. WHAT AN INCREDIBLE DAY WE'VE HAD. I AM JUST THINKING BACK ON THE LAST FIVE YEARS, ALL OF THE ADVANCES THAT HAVE HAPPENED TO THE POINT WE NOW CAN ACTUALLY HAVE A PANEL LIKE THIS. AND IT'S REALLY EXCITING TO THINK THAT WE'VE REALLY MOVED THE NEEDLE TO BE ABLE TO START THINKING ABOUT NOW THAT SO MUCH HAS BEEN ACCOMPLISHED HOW DO WE MOVE FORWARD FROM HERB, -- HERE, WHAT ARE THE CHALLENGES, THE EASY THINGS, THE THINGS THAT WILL TAKE MORE TIME TO MOVE INTO CLINICAL TRANSLATION OF THE WORK WE'VE BEEN HEARING TODAY. I THANK NICHD, DR. BIANCHI FOR LEADERSHIP IN THE PROJECT. IT'S BEEN AN INCREDIBLE RIDE FOR FIVE YEARS SEEING WHAT'S HAPPENING. I THANK DAVID AND CHRISTY AND BRUCE FOR THEIR HARD WORK BRINGING THIS MEETING TOGETHER AND MAKING THIS PANEL HAPPEN. WE DID HAVE A COUPLE CONVERSATIONS, E-MAIL CONVERSATIONS WITH OUR PANELISTS. WE'RE GOING TO HAVE EACH GIVE A BRIEF PRESENTATION ON SOME OF THE ASPECTS THEY HAVE IN THINKING ABOUT TRANSLATING WHAT WE'VE BEEN HEARING IN THE HUMAN PLACENTA PROJECT TO CLINICAL WORK AND WE'LL HAVE ROBUST INTERACTIVE DISCUSSION. I FEEL THAT WILL HAPPEN BECAUSE WE'VE HAD SUCH GREAT DISCUSSION ALREADY WHICH MEANS WE'RE A LITTLE LATE ON TIME AND I APOLOGIZE FOR THAT. IF WE COULD GET STARTED, I'M GOING TO ASK JODI TO LEAD US OFF. >> IS THIS ON? OKAY. GOOD. WEARING MY CLINICAL HAT IN THE MIDDLE OF THE NIGHT OUR CHALLENGE TO TAKE THIS PHENOMENAL PLACENTAL STUFF, TRULY PHENOMENAL STUFF, AS IT RELATES TO CONDITIONS LIKE FETAL GROWTH RESTRICTION AND PREECLAMPSIA AND TO APPLY IT CLINICALLY AS A SCREENING TEST, FOR EXAMPLE, SOMETHING THAT'S COST EFFECTIVE, EASY TO USE IN DOCTORS' OFFICES, IDENTIFYING RISKS, IMPORTANT ENOUGH TO REALLY -- DISCRIMINATORY AND IMPORTANT ENOUGH TO WARRANT CLINICAL CARE. I REALIZE THIS IS A CHALLENGE. OR DIAGNOSTIC TEST, NOT DIAGNOSTIC OF GROWTH RESTRICTION OR PREECLAMPSIA NECESSARILY, DIAGNOSTIC FOR A PLACENTAL CONDITION OR PHENOTYPE OR SOME OF THE THINGS YOU'VE ALL BEEN STUDYING BUT IN A DISCRETE WAY WE CAN ALL AGREE UPON AND THEN MOVE FORWARD AND USE CLINICAL WHEN WE'RE THINKING ABOUT TREATMENT. AND HOW TO STANDARDIZE THIS AND HAVE IT NOT JUST BE AT ONE MAJOR MEDICAL CENTER BUT FOR EVERYONE. AND I CAME UP WITH A COUPLE CLINICAL SCENARIOS TO MAKE THIS MORE CONCRETE. SO SCREENING, FIRST TRIMESTER WOULD BE GREAT, EARLY ENOUGH TO CONSIDER THERAPY. WE HAVE -- THERE'S A PRECEDENT FOR LOOKING AT PLACENTAL DISEASE IN THE FIRST TRIMESTER BECAUSE IN THE MID-'90s AND THEN EARLY 2000s WHEN AMYPLOIDY CAME INTO ITS OWN, IN THE FIRST TRIMESTER, PAP A, WERE ASSOCIATED STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH FETAL LOSS, FETAL GROWTH RESTRICTION, PREECLAMPSIA AND THERE WAS A LOT OF RESEARCH INTEREST IN THAT AREA. STATISTICAL ASSOCIATIONS WERE NOT DISCRIMINATORY ENOUGH TO TRANSLATE INTO CLINICAL CARE AND SO MOVING FORWARD THAT'S GOING TO BE A REAL CHALLENGE BECAUSE, YOU KNOW, THE BENEFIT OF THOSE EVERYONE HAD ACCESS TO THEM, RELATIVELY EASY, IF ONLY WE COULD COME UP WITH DISCRIMINATORY STUFF TO USE MOVING FORWARD WE HAVE BETTER TOOLS, MAYBE WE COULD LEVERAGE THAT. SAY, FOR EXAMPLE, WE IDENTIFIED SOME SORT OF OMIC MARKER, THOSE PREGNANCIES COULD BE REFERRED FOR REALLY SPECIAL PLACENTAL IMAGING AND THEN WE MIGHT BE ABLE TO DETECT VASCULAR ABNORMALITIES OR OTHER FINDINGS EARLIER MOVING IT FORWARD. AND THEN ONE MAYBE FOR DIAGNOSTIC TEST, FETAL GROWTH RESTRICTION AS AN MFM IS A LITTLE BIT MORE OF A CONUNDRUM FOR ME. OF THE 4 MILLION PREGNANCIES PER YEAR, 400,000 AT OR BELOW THE 10th PERCENTILE. NOT AN ADVERSE OUTCOME FROM FETALLY OR NEONATEALLY. AT 39 WEEKS THE 10th PERCENTILE IS 6 POUNDS, 5 OUNCES. OB WORLD, TAKE-HOME BABY SIZE. THAT'S NOT A MINORITY OF FETUSES THAT ARE GROWTH RESTRICTED, ARE AT SIGNIFICANT RISK, WE WANT TO MINIMIZE ADVERSEOUT COMES AND IDENTIFY THEM EARLY, BUT ALSO THE MAJORITY, FETAL GROWTH RESTRICTION IS A RISK FACTOR, NOT OUTCOME. AND BECAUSE WE DON'T REALLY HAVE AN EFFECTIVE WAY TO DISCERN THOSE WHO WILL OR WON'T BE AFFECTED WE DON'T USE OUR RESOURCES VERY EFFECTIVELY. SO MORE AND MORE WE'RE DOING ROUTINE THIRD TRIMESTER ULTRASOUND, FINDINGS A FETUS THAT'S BELOW THE 10th PERCENTILE. IT HAS NORMAL UMBILICAL DOPPLERS AND NORMAL AMNIOTIC FLUID, AND WE DON'T -- WE DIDN'T FIND A PROBLEM SO WE CAN'T BE SURE SO WE KEEP WATCHING SO THAT PREGNANT WOMAN MAY BE VERY WORRIED, SHE MAY HAVE IN THE NEXT SIX WEEKS UPWARDS OF A DOZEN MORE VISITS FOR MONITORING OR TESTING USING ALL SORTS OF RESURCES BECAUSE WE DON'T KNOW THAT THERE WON'T BE A PROBLEM. WHAT IF WE COULD JUST TEST IT THEN? WE COULD AVOID A LOT OF HEARTACHE AND WASTED RESOURCES AND FOCUS EFFORTS ON THE ONES WHO NEED IT MOST. THOSE ARE SOME CHALLENGES I SEE. >> THANK YOU VERY MUCH, JODI. YOU'VE OUTLINED WHAT WE'RE FACING AS WE SEE THESE PATIENTS. GEORGE? >> LET ME THANK DAVID FOR INCLUDING ME IN THIS PANEL AND THANKING ALL THE PRESENTERS. SO FAR, VERY EXCITING PROJECTS THEY ALL HAVE. MY CHARGE WAS TO SUMMARIZE TO YOU THE PATH FROM WHAT WE'RE DOING CURRENTLY, TO CLINICAL USE IN PATIENTS. WHAT IS THE PURPOSE OF EVERYTHING WE'RE DOING? WE'RE DOING ALL OF THIS TO IMPROVE OUTCOME. HOWEVER, WE'RE NOT GOING TO IMPROVE OUTCOME UNLESS CLINICIANS AND BETTER IF PROFESSIONAL ORGANIZATIONS RECOMMEND THE USE OF SUCH A TEST. SO, I'VE BEEN INVOLVED FROM THE LAB TO THE EARLY RESEARCH TO THE CLINICAL RESEARCH, TO GUIDELINE DEVELOPMENT. WHAT WE WANT IS SOMEDAY ONE, TWO, THREE, FOUR OF THESE TESTS OR TECHNIQUES PRESENTED TO MAKE IT INTO AN ACOG OR SMFN GUIDELINE USING THESE TESTS WILL IMPROVE OUTLINE. THAT'S WHAT WE DESCRIBE FOR. WHAT I -- WHAT WE STRIFE FOR WHAT IS THE PATH FOR IT TO MAKE IT TO SUCH A GUIDELINE? PRIMARILY, IT'S THE NEED FOR LEVEL 1 EVIDENCE. LEVEL 1 EVIDENCE IS BASICALLY ROBUST CLINICAL TRIAL, BEST IF IT'S RANDOMIZED CLINICAL TRIAL, ALTHOUGH SOMETIMES IN A SCREENING TEST MAYBE IT'S NOT A RANDOMIZED CLINICAL TRIAL. BUT THAT'S WHAT WE REALLY SHOULD BE STRIVING FOR. SO WHAT IS THE FIRST STEP IN THAT PROCESS? THE FIRST STEP IS A VALIDATION STUDY. LET'S SAY AS JODI MENTIONED YOU HAVE A TEST THAT PREDICTS FETAL GROWTH RESTRICTION. OR DIAGNOSES FETAL GROWTH RESTRICTION, ALL THESE TESTS AND TECHNOLOGIES MOSTLY ARE GOING TO PREDICT OR DIAGNOSE SOME OUTCOME. SO LET'S SAY IT'S A PREDICTIVE TEST, OR DIAGNOSTIC TEST OF FETAL GROWTH RESTRICTION. THAT YOU HAVE DONE THE STUDIES FOR. NOW, THE NEXT STEP, YOU HAVE TO VALIDATE IN AN INDEPENDENT COHORT, IT'S NOT ENOUGH YOU SHOW IT'S PREDICTIVE MUCH -- OF DIAGNOSTIC. IT HAS TO BE VALIDATED BECAUSE THE INITIAL STEP WHEN YOU DEVELOP A PREDICTIVE TEST DATA WILL FIT BETTER IN YOUR DATA SET THAN IN ANOTHER DATA SET. SO YOU HAVE TO VALIDATE. THAT'S THE FIRST STEP. NOW, IN ORDER TO VALIDATE IT, YOU ALSO HAVE TO PICK AN ADEQUATE PRIOR OUTCOME TO VALIDATE, DIAGNOSTIC OR SCREENING. JODY MENTIONED, FETAL GROWTH RESTRICTION MAYBE BIRTH WEIGHT LESS THAN 10th PERCENTILE. WHY WOULD WE WANT TO PREDICT A BABY LESS THAN THE 10th PERCENTILE? WE WANT TO PREDICT ADVERSE OUTCOME. WHEN YOU PICK ADVERSE OUTCOME IT HAS TO BE CLINICALLY SIGNIFICANT, IT'S NOT ONLY APGAR SCORE LESS THAN 7, IT HAS TO INCLUDE MORBIDITY, ALSO MORTALITY, PROBABLY RARE. BUT THEN YOU ALSO HAVE TO DECIDE YOU WANT THE IMMEDIATE ADVERSE OUTCOME OR LONG-TERM OUTCOME, OBVIOUSLY IMMEDIATE OUTCOME LIKE IN THE NURSERY OR BEFORE DISCHARGE OF THE BABY, THAT'S AN EASIER STUDY THAN SOMETHING AT 2 YEARS OF AGE OR 5 YEARS OF AGE. BUT THE LONG-TERM OUTCOME IS THE MORE CLINICALLY SIGNIFICANT. SO WHAT YOU IMPROVE OR DETECT SOMETHING IN THE NURSERY, BUT THEN AT 2 YEARS OR 5 YEARS THE BABY IS COMPLETELY NORMAL. SO THESE ARE ALL DECISIONS THAT HAVE TO BE MADE IN THAT PATH, AND THAT'S WHY I'M TRYING TO MAKE SURE WE UNDERSTAND THAT IT'S A LITTLE BIT MORE COMPLEX THAN JUST SHOWING SOMETHING. NOW, THE OTHER THING THAT I SEE QUITE A LOT DONE, THAT AT THE END WILL NOT CONVINCE ANY CLINICAL BODY TO ADVOCATE FOR THAT TEST, IS TO DO THE APPROPRIATE PREDICTION ANALYSIS, OR DIAGNOSTIC ANALYSIS, BUT THEY ARE BOTH THE SAME, ALMOST THE SAME. VERY OFTEN WHAT WE DO AT THE BEGINNING IS WE TAKE THOSE WITH THE POSITIVE TEST AND THOSE WITH NEGATIVE TEST AND SHOW THERE'S A DIFFERENCE STATISTICALLY SIGNIFICANT DIFFERENCE IN BIRTH WEIGHT BETWEEN THE TWO GROUPS. OR WE SHOW STATISTICALLY SIGNIFICANT DIFFERENCE IN PREECLAMPSIA RATES OR PRE-TERM BIRTH RATE BETWEEN THE GROUPS. IN THE BEGINNING THAT'S FINE. THIS IS NOT A PREDICTION ANALYSIS. WHAT WE HAVE TO DO IS IT A PREDICTION ANALYSIS, DOES IT PREDICT, NOT THAT THE TWO GROUPS ARE DIFFERENT IN THE OUTCOME. DIFFERENCE IS GOOD BUT DOESN'T TRANSLATE CLINICALLY TO PREDICTION. FOR THAT PREDICTION STUDY YOU NEED LARGE SAMPLE SIZE BECAUSE IT'S BASED ON SENSITIVITY, SPECIFICITY, LIKELIHOOD RATIOS, ALL OF THESE REQUIRE MUCH LARGER SAMPLE SIZES THAN COMPARING OUTCOME RATE OR COMPARING SOME MEASURE BETWEEN THE TWO GROUPS. SO IT'S CRITICAL I THINK TO HAVE THE PLAN IN MIND AHEAD OF TIME AND NOT JUST SAY, OH, IT'S PREDICTIVE BECAUSE THE TWO GROUPS ARE SIGNIFICANTLY DIFFERENT. THAT'S NOT PREDICTIVE. NOW, ALSO, THE FIRST STEP NOW YOU VALIDATED THE TEST, YOU SHOWED ADEQUATELY POWERED STUDY, APPROPRIATE ANALYSIS IT IS PREDICTIVE. HAVE YOU SENSITIVITY OF 80%, SPECIFICITY OF 80%, LIKELIHOOD RATIO ABOVE 10, FOR POSITIVE, BELOW 0.5 FOR NEGATIVE PREDICTED LIKELIHOOD RATIO, FINE AND G HOWEVER, THAT DOESN'T MEAN IT'S GOING TO TRANSLATE INTO CLINICAL APPLICATION. THE NEXT STEP, IT'S A TWO-STEP PROCESS, THE NEXT STEP IS YOU HAVE TO SHOW THAT IT IS CLINICALLY BENEFICIAL TO PREDICT THIS OUTCOME OR DIAGNOSE THIS OUTCOME. LET'S TAKE GROWTH RESTRICTION, SO YOU HAVE A TEST THAT PREDICTS GROWTH RESTRICTION. OKAY. BUT THEN WHAT ARE YOU GOING TO DO WITH IT? OR PREDICTS PRE-TERM BIRTH OR PREECLAMPSIA, WEEKS BEFORE IT DEVELOPS. SO THE NEXT STEP IS WHAT ARE WE GOING TO DO WITH THIS RESULT. ARE WE JUST GOING TO WORRY THE PATIENT AND PROVIDER, OR IS THERE SOMETHING WE'RE GOING TO INTERVENE TO DO? AND THAT'S WHERE RANDOMIZED CLINICAL TRIALS INTERVENTION CLINICAL TRIALS COME IN. SO YOU RANDOMIZE PATIENTS WITH POSITIVE TEST TO SOME INTERVENTION, NO INTERVENTION, AND YOU SEE IF IT IMPROVES OUTCOME. NOW, GIVEN THAT WE HAVE TWO PEOPLE IN THE THIS EQUESTIONS, THE MOTHER AND BABY, IT'S ALSO IMPORTANT NOT TO SHOW IT JUST IMPROVES OUTCOME BUT ALSO THAT THE IMPROVEMENT OR THE BENEFIT OUTWEIGHS ANY RISKS. SO IF WE PREDICT SOMEBODY'S GOING HAVE A PREECLAMPSIA OR FETAL GROWTH RESTRICTION, THEN MAYBE THE INTERVENTION IS TO INDUCE THEM BEFORE THIS HAPPENS. HOWEVER, INDUCTION HAS SOME HARM IN IT TOO. YOU ARE HAVE TO BENEFIT BALANCE AND HARMS. IT'S IMPORTANT TO PICK YOUR OUTCOMES APPROPRIATELY BECAUSE THEN YOUR ULTIMATE GOAL IS CONVINCE CLINICIANS AND PROFESSIONAL ORGANIZATIONS TO RECOMMEND SUCH A TEST AND IT'S NOT GOING TO HAPPEN UNLESS THE BENEFIT OUTWEIGHS THE OUTCOMES. SO, HOPEFULLY I'M NOT DISCOURAGING ANYONE HERE FROM DOING THIS, RIGHT? BUT IT IS POSITIVE. IT'S NOT NEGATIVE. I THINK THERE ARE WAYS TO DO THIS. I KNOW -- IAN, THANK YOU FOR MENTIONING THE MSNU NETWORK BUT THERE ARE MULTIPLE NETWORKS AND OPPORTUNITIES TO DO THIS BUT IT HAS TO BE, AS YOU CAN SEE, LARGE SAMPLE SIZE, LONG-TERM OF OUTCOMES, ALL THIS MEANS IT'S MOST LIKELY GOING TO BE A MULTI-SITE STUDY IN CENTERS THAT CAN HAVE THIS INFRASTRUCTURE. BUT THERE ARE WAYS TO DO IT AND HOPEFULLY WHAT I'M HOPING AT LEAST IS THAT THROUGH THE HUMAN PLACENTA PROJECT WE CAN IDENTIFY MAYBE ONE, TWO, THREE, OR TOP CHOICES OF THESE TESTS, THEN WE CAN TAKE CLINICALLY INTO APPLICATION, CLINICAL APPLICATION WITH APPROPRIATE CLINICAL TRIALS. OTHER AREAS COULD BE ALSO INDUSTRY, INDUSTRY COULD TAKE ON SUCH A TRIAL AND COULD TAKE ON SUCH A TEST, OR SUCH TECHNIQUE, ULTRASOUND OR MRI TECHNIQUE AND MOVE IT FORWARD. THAT'S HOW THE PROCESS WORKS. YOU HAVE TO COME AS CLOSE AS POSSIBLE TO THE CLINICAL TRIAL. YOU HAVE TO DEVELOP THE INFORMATION AND RESEARCH TO CONVINCE THAT THERE IS GOOD POTENTIAL TO DO THE CLINICAL TRIAL, I CAN TELL YOU FROM HEARING TODAY AND I CAN'T WAIT FOR TOMORROW, I CAN TELL YOU THAT I HAVE AT LEAST -- I'VE SEEN AT LEAST THREE GOOD TESTS THAT PERSONALLY I WOULD PROPOSE TO THE NETWORK TOMORROW IF YOU LET ME SO I'M REALLY GLAD THAT WE'RE DOING THIS BECAUSE WE NEED WHAT WE'RE DOING HERE IN ORDER TO IMPROVE CARE AND IN ORDER TO IMPROVE CLINICAL APPROACHES TO OUR PREDICTION, PREVENTION, DIAGNOSIS AND IMPROVING OUTCOME. THANK YOU. >> THANK YOU, GEORGE. YOU MADE A GREAT SEGUE TO THE NEXT SPEAKER, VASUM FROM THE FDA. >> I'M NOT SURE I'LL HAVE MUCH TO ADD. I WAS GOING TO THANK DAVID FOR AFROUZ FOR INVITING ME. HOW DO I ADD VALUE TO THE CONVERSATIONING? FROM THE FDA PERSPECTIVE I THOUGHT PERHAPS I CAN TELL YOU A STORY. TALK ABOUT TRANSLATING TECHNOLOGY INTO MEANINGFUL APPLICATIONS AND CLINICAL USE THAT MAKE A DIFFERENCE FOR PATIENTS, THAT'S WHAT WE'RE INTERESTED IN AT THE AGENCY. HE WANT TO ENSURE PATIENTS IN THE U.S. HAVE ACCESS TO HIGH QUALITY SAFE AND EFFECTIVE MEDICAL DEVICES, THAT'S PUBLIC HEALTH IMPORTANCE FIRST IN THE WORLD. PERHAPS A STORY ABOUT TRANSLATION WOULD DRIVE HOME THE PERSPECTIVE I HAVE. SO, A FEW MONTHS AGO I WAS INVITED TO BE A VISITING PROFESSOR AT A PREMIER INSTITUTION ON THE WEST COAST. HOW MANY PEOPLE ARE HERE FROM STANFORD? I DIDN'T SAY THAT WAS THE INSTITUTION BUT I WANT TO MAKE SURE. I'M HOPING MY COLLEAGUES WON'T BE TOO UPSET WITH ME TO TELL THE STORY. AT THE END OF A LECTURE SOMEONE IN CARDIOLOGY TALKED TO ME ABOUT SOME TECHNOLOGY THEY ARE DEVELOPING. I WAS LIKE THIS IS AMAZING, INCREDIBLE WORK YOU'RE DOING, THIS TECHNOOGY HAS THE POTENTIAL TO MAKE A SIGNIFICANT DIFFERENCE, NOT JUST FOR CHILDREN BUT FOR ADULTS AS WELL. I SAID LET'S GET TOGETHER AND FIGURE OUT HOW I CAN HELP YOU WITH THIS. JUST TO GIVE BACKGROUND, THEY HAVE PUBLISHED IN "NATURE," "SCIENCE" AND "NEW ENGLAND JOURNAL," IT HAS GREAT POTENTIAL. I'M BACK ON CAMPUS AT THE FDA, A FEW MONTHS LATER, WE SET ALL MEETING. I GOT OUR SCIENTISTS AND REVIEWERS TO DEAL WITH THAT TYPE OF TECHNOLOGY TO BE ON THE PHONE CALL WITH THEM. WITH MY COLLEAGUES FROM STANFORD. AND THIS IS WHERE IT BECOMES HUMOROUS. IT'S AN HOUR AND 20-MINUTE CONVERSATION WE HAD SCHEDULED, 30 OR 40 MINUTES INTO THE CONVERSATION ONE OF THE P.I.s AT STANFORD, AGAIN, AS I MENTIONED, THE PINNACLE OF ACADEMIC ACCOMPLISHMENT IN TERMS OF WHAT HE'S DONE, HE ASKED THE QUESTION, REMIND ME AGAIN WHAT IS IT EXACTLY THAT THE FDA DOES? AND THE REASON THIS WAS IMPORTANT IS BECAUSE THERE IS A GREAT DEAL OF INCREDIBLE RESEARCH AND DEVELOPMENT OF TECHNOLOGIES AND TESTS THAT ARE GOING ON OUT THERE, AND YET SO FEW OF THEM GET TO THE POINT WHERE THEY BECOME COMMERCIALLY VIABLE, THEY ARE APPROVED BY THE FDA, AND CAN ACTUALLY MAKE A DIFFERENCE TO ALL THE PATIENTS OUT THERE. I'LL GIVE ONE OTHER EXAMPLE THAT'S MORE CLOSER TO HOME WITH NICHD AND COLLEAGUES THAT I'VE BEEN SPEAKING WITH. I WAS INVITED TO A LEADERSHIP MEETING AT NICHD, AND I WAS HAPPY TO COME AND FIGURE OUT WHAT'S GOING ON, WHAT PEOPLE ARE DOING. I DID A LITTLE BIT OF RESEARCH BEFORE COMING THERE TO GET SOME SENSE OF WHAT TYPES OF GRANTS HAVE BEEN PROVIDED THROUGH NICHD, DOING GREAT GRANT PROGRAMS. I DID RECOGNIZE THAT THERE IS A GREAT DEAL OF MONEY BEING INVESTED IN NEONATAL DEVICE DEVELOPMENT. AND PERINATAL DEVICE DEVELOPMENT, I THOUGHT IT WAS GREAT, WONDERFUL. I TOOK A LOOK AT HOW MANY NEONATAL DEVICES WE HAVE SEEN AT THE AGENCY, AT THE FDA, OVER THE PAST DECADE. I'LL PUT IT OUT THERE. HOW MANY DEVICES DO YOU THINK THE FDA HAS APPROVED IN THE NEONATAL POPULATION IN THE PAST DECADE? ONE. YES. YES, ONE. IT'S NOT TO SAY THAT THE FUNDING THAT IS BEING UTILIZED IS BAD BUT WE HAVE TO BE COGNIZANT TO CREATE PATHWAYS TO COMMERCIAL AND BUSINESS VIABILITY FOR TECHNOLOGIES THAT TRULY CAN MAKE A DIFFERENCE FOR PEOPLE BECAUSE THEY REALLY CAN SERVE ESPECIALLY THE NEONATAL POPULATION VERY WELL. YET WE'RE NOT GETTING THEM OUT TO THE BROADER PUBLIC BECAUSE THEY ARE NOT COMING THROUGH THE FDA AND PEOPLE AREN'T PERHAPS THINKING ABOUT THE BUSINESS ASPECTS OF IT AND CREATING A SUSTAINABILITY MODEL FOR DEVELOPING THAT TECHNOLOGY. AND THAT IS A LOT OF WORK I'M WORKING ON AT THE AGENCY, AS CHIEF MEDICAL CENTER FOR PEDIATRICS, SPECIAL POPULATIONS, TO FIGURE OUT HOW DO WE CREATE SYSTEMS THAT SUPPORT TECHNOLOGIES THAT SERVE THE COMPLEX NEEDS OF PATIENTS, ESPECIALLY PEDIATRIC AND PERINATAL PATIENTS AND HOW CAN WE ACTUALLY DEVELOP THAT SYSTEM THAT FOSTERS THOSE TECHNOLOGIES AND THERE BY ADVANCES DEVICE DEVELOPMENT AND NOVEL DEVICES FOR ALL POPULATIONS ACROSS THE U.S. SO HAPPY TO HOPEFULLY BE PART -- ADD SOME VALUE TO THE CONVERSATION AS WE MOVE FORWARD. >> THANK YOU SO MUCH. WHAT I'D LIKE TO DO IS OPEN IT TO AN OPEN DISCUSSION IN THE ROOM ON CHALLENGES THAT YOU SEE IN TRANSLATING SOME OF THIS WORK INTO CLINICAL APPLICATIONS, WHETHER THAT'S GOING TO CHANGE THE OUTCOME OR SIMPLY BE AN IDENTIFIER OF NORMAL VERSUS ABNORMAL TO BE ABLE TO TEST IN THE RANDOMIZED TRIAL OF INTERVENTIONS TO OPTIMIZE OUTCOME. WE'VE GOT LOTS OF PEOPLE WITH GREAT IDEAS, HELPFUL TO HAVE A DIALOGUE WITH EXPERTS HERE AND IN THE ROOM. >> AGAIN, IAN BIRD, WISCONSIN. SO MY WORK IS FOCUSED ON PREECLAMPSIA ALONG WITH MY COLLEAGUES FROM WISCONSIN, DINESH SHAH IS HERE. WORK FROM TORONTO, LEVI AND COX, CHARACTERIZED PLACENTAS OF PREECLAMPSIAIC WOMEN INTO TWO MAJOR SUBGROUPS, CON ONTICAL, ONE WAS INFLAMMATION. BASICALLY THOSE PLACEBOS SUGGESTED HISTORY OF HYPOXIA AND INFLAMMATION. AND IT'S A NEW APPROACH, REFLECTS THE DECADES-OLD DISPUTE OVER THE ORIGIN OF PREECLAMPSIA AND I THINK THIS IS AT THE HEART OF WHY IN THE MIDDLE OF THE NIGHT WHEN CONFRONTED WITH THAT PATIENT, YOU DON'T KNOW WHAT TO DO, THE FIRST QUESTION IS IS IT AN APPL OR AN ORANGE? EACH WOMAN IS UNIQUE AND YOU'VE GOT TWO ORIGINS. IF WE'RE GOING TO DO CLINICAL TRIALS WE HAVE TO BUILD IN MEASURES OF WHETHER WHAT WE'RE LOOKING AT ARE THE CONSEQUENCE OF WHAT ORIGINATED AS A HYPOXIC EPISODE THAT LED TO A PROBLEM OR INFLAMMATORY EPISODE THAT LED TO A PROBLEM, THIS IS WHY WOMEN WITH POOR ANGIOGENESIS AT BEGINNING OF PREGNANCY AND HYPERTENSION HAVE HAVE A COMMON OUTPUT, COMPLETELY DIFFERENT CAUSES, WE'VE GOT TO GET A HANDLE OR WE'RE GOING TO BE CONFUSED BY THE DATA. YOU'LL HAVE TO SEPARATE THE SUBGROUPS. >> I THINK THE POINT YOU'RE MAKING IS INCREDIBLY IMPORTANT, CERTAINLY ONE THAT IN OBSTETRICS WE HAVE LIVED OVER THE LAST COUPLE OF DECADES WHERE INITIALLY IT WAS A DESIRED TO HIT ANYTHING YOU COULD FOR PRE-TERM BIRTH OR PREECLAMPSIA WITH ONE INTERVENTION, REALLY TAILORING THAT THERAPY TO THE UNDERLYING ETIOLOGY IS ABSOLUTELY ESSENTIAL. ANY OTHER COMMENTS? >> I AGREE. THIS BASICALLY INDIVIDUALIZING THERAPY OR PREVENTIVE APPROACH IS BASED ON THE MECHANISM, ABSOLUTELY. BUT, AGAIN, NOT TO DISCOURAGE ANYBODY, BUT IN ORDER TO PROVE THAT THIS MECHANISM WORKS, THIS MECHANISM IS RESPONSIBLE FOR X, Y AND Z MORBIDITY, YOU STILL NEED THE LARGE PROSPECTIVE STUDIES THAT SHOW IF THE TEST SHOWS INFLAMMATION, HOPEFULLY EARLY ENOUGH THAT OF THAT YOU CAN INTERVENE, THEN YES, THE END RESULT IS INFLAMMATION. IF IT SHOWS HYPOXIA, THE END RESULT IS HYPOXIA. AND IT HAS TO BE A PREDICTIVE ANALYSIS, AS I SAID, NOT JUST SIGNIFICANT DIFFERENCE BETWEEN THE TWO GROUPS. AND THAT REQUIRES THOUSANDS OF PATIENTS. >> WELL CHARACTERIZED POPULATIONS. >> CAN I ASK, DO WE HAVE THE DIAGNOSTIC TOOLS TO DISCERN ONE VERSUS THE OTHER? >> CAN I ACTUALLY COMMENT ON THAT? THAT I THINK -- I'M GLAD YOU WENT AHEAD OF ME. MONICA FROM UC SAN DIEGO. PERINATAL PATHOLOGIST, EACH TIME I SIT AT THE MICROSCOPE LET'S USE IUGR AS EXAMPLE, IT'S MORE COMPLEX EVEN THAN PREECLAMPSIA. FROM AN ANATOMIC PATHOLOGY POINT OF VIEW, I'M LOOKING, I TEACH RESIDENTS YOU LOOK AT FOUR POSSIBLE PLACENTAL DIAGNOSES, ONE IS CLASSIC MATERNAL VASCULAR MAL PERFUSION, THE PATTERN, A SMALL PLACENTA WITH INFARCTS, EVIDENCE OF DECIDUAL VASCULOPATHY, VELLITUS IS COMMON ESPECIALLY WHEN SEVERE CAN CAUSE IUGR, SECOND IS FETAL VASCULAR MALPERFUSION, THE PLACENTA MAY NOT BE SMALL BUT THERE'S A PROBLEM WITH ONLY THE FETAL CIRCULATION AND PLACENTA WHICH RENDERS THE PLACENTA NOT FUNCTIONAL, ASSOCIATED WITH ISSUES OF UMBILICAL CORD, HYPERTWISTED, COULD INTERFERE WITH CIRCULATION, AND WHERE THE PLACENTA IS LARGE, FROM A PATHOLOGY PERSPECTIVE IF THESE ARE NOT DIAGNOSED GEORGE WAS SAYING WHEN WE DEFINE OUTCOMES WHAT ARE OUTCOMES. WE'RE TALKING ABOUT IUGR AS OUTCOME, THAT'S NOT SPECIFIC ENOUGH. YES, I THINK WHAT WE NEED IS WE NEED THE VERY GOOD CLINICAL ANNOTATION FOR THESE CASES, AND THEN WE DO NEED WHEN WE COLLECT SERUM, BLOOD, WE'RE GOING TO LOOK AT KIND OF MOLECULAR SIDE, LET'S NOT FORGET BEING ABLE TO LOOK AT PLACENTA UNDER THE MICROSCOPE CAN TELL US A LOT AS WELL. >> BEAUTIFUL. THANK YOU. >> HI. ADAM, N.C. STATE UNIVERSITY. I WANT TO HEAR YOUR COMMENTS. A LOT OF TIMES I FEEL LIKE WITH THE PLACENTA THERE'S THIS IMAGE PROBLEM, WITH THE GENERAL PUBLIC, THAT IT'S KIND OF SENSITIVE AREA. I'VE GIVEN TALKS AND HAVE GOTTEN ANGRY E-MAILS TALKING ABOUT HOW TROPHOBLASTS ARE INVASIVE AND THINGS LIKE THAT. CAN YOU TALK ABOUT HOW THE GENERAL PUBLIC KIND OF -- SORRY -- KIND OF FEELS ABOUT THIS KIND OF AREA OF RESEARCH AND WHY IT'S HAVING TROUBLE KIND OF TRANSITIONING TO A CLINICAL STUDY AS OPPOSED TO SOMETHING LIKE CANCER? >> YOU'RE SAYING IT HAS AN IMAGE PROBLEM? [LAUGHTER] >> YEAH, I THINK TALKING TO LIKE THE GENERAL PUBLIC, I THINK PEOPLE ARE WARY OF THE SUBJECT OF THE PLACENTA. THERE'S A REASON WHY IT'S ONE OF THE LEAST UNDERSOOD ORGANS, AND I THINK THERE'S A WARINESS IN THE GENERAL PUBLIC BEHIND IT. I KNOW THAT WE ALL THINK THERE ISN'T BECAUSE THIS IS WHAT WE STUDY, THIS IS WHAT WE, YOU KNOW, LOVE TO LEARN ABOUT, BUT I THINK IN GENERAL PEOPLE DON'T KNOW WHAT THE PLACENTA IS AS OPPOSED TO ANY OR OTHER ORGAN IN THE BODY. >> IT WAS CALLED THE AFTER BIRTH. IT DOESN'T HAVE A GREAT NAME, RIGHT? IT CLEARLY IS ONE THAT IS THIS MODEL ORGAN SYSTEM FOR SO MANY DIFFERENT THINGS, RIGHT? IF YOU LOOK AT THE INVASIVENESS OF THE PLACENTA, YOU CAN UNDERSTAND INVASION BY STUDYING IT. THERE'S SO MANY OPPORTUNITIES WITH THE PLACENTA. AD HOW WE TURN THAT AROUND I THINK IS SOMETHING THAT HAS BEEN A LONG TIME IN COMING. EVERYONE HAS SOMETHING TO SAY SO I'LL LET GEORGE GO AHEAD. >> THE PLACENTA FOR A LONG TIME WAS THOUGHT OF AS A DISCARDED SPECIMEN, RIGHT? I MEAN, WHAT DOES IT MATTER? THAT'S A PROBLEM, AS PEOPLE THINK BIT, NOW PEOPLE ARE EATING THE PLACENTA SO THAT MAY BE GOOD FOR THE PLACENTA. THE QUESTION REALLY AT THE END IS NOT ONLY ABOUT THE PLACENTA. IT'S ABOUT OBSTETRICAL RESEARCH IN GENERAL. AS DR. BIANCHI SHOWED EARLIER, IT TOOK AN ACT OF CONGRESS TO DO THE PRGLAC AND PROMOTE AND ADVOCATE FOR RESEARCH IN PREGNANCY. AND THAT'S A PROBLEM, COMPARED TO CANCER, COMPARED TO CARDIAC DISEASE, PREGNANCY IS BELIEVED TO BE A NORMAL PHYSIOLOGIC EVENT THAT MOST OF THE TIME ENDS UP IN A NORMAL OUTCOME. SURE, PEOPLE HAVE HEARD OF A BABY BORN PRE-TERM AND MOTHER WHO HAD A STROKE FROM PREECLAMPSIA AND ALL OF THAT. BUT THEY DON'T SEE THAT AS A BIG HEALTH PROBLEM IN THE GENERAL PICTURE. BUT WHAT'S IMPORTANT FOR US, THE ONUS IS ON US TO SHOW THAT PREGNANCY IS IMPACTFUL FOR THE FUTURE HEALTH OF BOTH THE MOTHER AND THE BABY, AND THAT'S I THINK WHAT DR. BIANCHI WAS SAYING THIS MORNING. IF YOU LOOK AT THE PLACENTA, THEN YOU CAN CONNECT THE PLACENTA TO THE FUTURE HEALTH OF THE BABY, BUT NOT ONLY THE BABY, THE MOTHER TOO BECAUSE EVERY PREGNANT MOTHER WITH PREECLAMPSIA, PRE-TERM BIRTH, GROW RESTRICTION OR STILLBIRTH IS AT RISK FOR CARDIOVASCULAR DISEASE LATER IN LIFE. WHY DO WE WAIT TILL THEY ARE 50 YEARS TO DO SCREENING TESTS WHEN WE HAVE THE BEST SCREENING TEST, WHICH IS THE PLACENTA, AND CAN YOU IMAGINE ANY TEST, PLACENTAL TEST YOU PRESENTED TODAY RELATING TO LONG-TERM HEALTH OF THE MOTHER AND THE BABY WILL MAKE IT MUCH MORE IMPACTFUL THAN JUST FOR THE PREGNANCY OUTCOME? >> I GUESS IT'S THE POINT I'M TRYING TO MAKE IS THAT THE GENERAL PUBLIC DOESN'T KNOW HOW BENEFICIAL LIKE THE KNOWLEDGE OF THE PLACENTA IS. THAT'S WHY I SAID IMAGE PROBLEM, I GOT PUSHED BACK FROM THAT. IT IS. MOST PEOPLE DON'T KNOW THE BENEFITS OF THIS KIND OF RESEARCH, AND IT'S KIND OF -- YOU GO TO A CANCER CONFERENCE, AND THERE'S SO MANY DIFFERENT PEOPLE THERE, AND I WISH THERE WAS JUST -- I DON'T KNOW, A BIGGER RESEARCH INTO THE PLACENTA BECAUSE I THINK EVERYONE BENEFITS FROM IT BECAUSE EVERYONE IS BORN. >> THAT'S OUR DUTY. IT'S OUR JOB TO DO THAT. I GUESS MY QUESTION IS HOW DO WE MAKE THAT MORE WELL KNOWN TO EVERYBODY. >> THE TEST HE SHOWED AT THE END SHOWS IF THEY HAVE PARTICLES OR WHATEVER X PARTICLE, THEN THE RISK OF CORONARY ARTERY DISEASE WHEN THEY ARE 50 IS TEN TIMES HIGHER THAN IF THEY DON'T HAVE IT, THEN PEOPLE WILL PAY ATTENTION. >> I THINK IT'S -- YOU KNOW, IT IS -- IT'S DIFFICULT TO GET THAT MESSAGE OUT THERE. WE'VE BEEN TRYING FOR YEARS, RIGHT, IF YOU CAN OPTIMIZE PREGNANCY OUTCOME YOU OPTIMIZE HEALTH OF THE WORLD. RIGHT? YOU GET A HEALTHIER MOM, HEALTHIER BABY, HEALTHIER FAMILY. HOW DO YOU DO THAT? BY OPTIMIZING THE PLACENTA. >> YOU BRING UP A VERY IMPORTANT ISSUE THAT ESPECIALLY TALKING ABOUT GOVERNMENT RESEARCH, SOCIOPOLITICAL PROCESS HERE ABOUT OPTICS. OPTICS, OPTICS, OPTICS. WHAT GEORGE MENTIONED IF YOU REALLY TRY TO CONTEXTUALIZE PLACENTAL RESEARCH, PLACENTAL EVALUATION IN THE CONTEXT OF SIGNIFICANT HEALTH OUTCOMES LIKE CARDIOVASCULAR DISEASE THAT IS GOING TO HELP CHANGE AND SHIFT OPTICS IN ONE WAY. I WILL ALSO MENTION THE SIMILAR ISSUE THAT I SAYS IN TERMS OF PEDIATRIC HEALTH CARE, CDRH PEDIATRICS IS THE DAY YOU'RE BORN UNTIL YOU'RE 21st YEAR OF LIFE BUT THERE'S A GREAT EVOLVING FIELD OF FETAL INTERVENTIONS, ESPECIALLY IN MY FIELD CONGENITAL HEART DISEASE IN TERMS OF FETAL CARDIAC INTERVENTIONS, FETAL CARDIAC INTERVENTIONS CAN MAKE A SIGNIFICANT DIFFERENCE IN NATURAL HISTORY AND LONG-TERM OUTCOMES OF WHAT WE PREVIOUSLY THOUGHT WERE NEARLY MORTALITY-PROVIDING DISEASES IN PEDIATRIC CARDIOLOGY. DESPITE THAT, WE'RE CURRENTLY UNABLE TO UTILIZE RESEARCH FUNDING BEING COMMITTED TO PEDIATRICS FOR FETAL INTERVENTIONS THAT ALTERNATE HISTORY IN CHILDREN. AND THAT, AGAIN, IS OPTICS. I WOULD JUST REITERATE AND MAYBE ECHO WHAT GEORGE MENTIONED ABOUT IT IS PARTLY OUR RESPONSIBILITY TO HELP PEOPLE UNDERSTAND, AND A GREAT DEAL OF WHAT I DO I FEEL LIKE -- I'VE ONLY BEEN WITH THE AGENCY A FEW YEARS BUT EVEN AT MEETINGS INSIDE THE AGENCY HELPING ALL THE DIFFERENT PEOPLE COMING FROM DIFFERENT PERSPECTIVES TO UNDERSTAND THE CONTEXT AND HELP CREATE THE MESSAGE WHERE THERE COULD BE POTENTIAL ALIGNMENT, WHERE EVERYBODY CAN UNDERSTAND WHY IT'S IMPORTANT, AND WHERE WE CAN ALL MOVE FORWARD TOGETHER. >> MIKE? >> MIKE VARNER, UTAH. I WANT TO SECOND GEORGE'S COMMENT, IMPORTANCE OF MEANINGFUL OUTCOMES FOR CLINICAL TRIALS. AND SPECIFICALLY AS IT RELATES TO ALL THE AMAZING STUFF WE'VE HEARD THIS MORNING I HOPE ALL THE INVESTIGATORS WILL HAVE THE WHETHER WITH ALL AND MECHANISM TO FOLLOW THE CHILDREN WHO ARE BEING STUDIED, WHOSE PLACENTAS ARE BEING STUDY TO THE POINT OF MEANFUL NEURODEVELOPMENTAL OUTCOME. WE OWE IT TO THEM. >> I DON'T WANT PEOPLE TO GET DISCOURAGED BECAUSE I MEAN WHAT MIKE SAID IS VERY IMPORTANT. HOWEVER THINGS ARE INCREMENTAL. IT'S NOT LIKE OH MY GOD, YOU'RE ALL SINKING. WHAT AM I GOING TO DO NOW? MY NEXT STEP IS FIND THE MEANINGFUL OUTCOME AND DO THE STUDY. IT'S ALL INCREMENTAL. WE HEARD THIS MORNING FROM A PATIENT WHO WAS ON A STUDY FOR STATINS. LET ME USE THAT BECAUSE I'M FAMILIAR WITH IT AS AN EXAMPLE. THE STATIN FIRST WAS SHOWN IN ANIMAL MODELS THAT IT PREVENTED WHATEVER THE PREECLAMPSIA-LIKE SYMPTOM IN THE ANIMAL. MULTIPLE PUBLICATIONS CONVINCED US IT'S TIME TO MOVE TO THE HUMAN. BUT WE DIDN'T MOVE TO THE HUMAN WITH A LARGE THOUSANDS OF PATIENTS STUDY. THE FIRST STUDY WAS REALLY A PROOF OF CONCEPT STUDY. IF YOU GIVE PLACEBO TO PATIENTS, CAN YOU CHANGE THE ANGIOGENIC MARKERS? IT WAS A SURROGATE OUTCOME, IT WAS NOT THE OUTCOME WE ALL BELIEVED IN AND WANT TO CHANGE CLINICAL OUTCOME. IT WAS A SURROGATE OUTCOME. THE NEXT STEP FOR PLACENTA PROJECT STUDY WOULD BE A SURROGATE OUTCOME. AND THEN YOU GET ENOUGH EVIDENCE WITH THE SURROGATE OUTCOME AND OTHER PILOT STUDIES, PROOF OF CONCEPT STUDIES, THEN TO CONVINCE PEOPLE TO MOVE TO THE MULTI-CENTER ONE WITH THE HARD OUTCOME, WITH THE LONG-TERM OUTCOME HOPEFULLY. IT'S A STEP-WISE PROCESS. >> THANK YOU. WE'VE GOT LONG LINES AND SHORT TIME. WE'LL KEEP MOVING. GO AHEAD. DINESH? >> A COUPLE QUICK POINTS. GEORGE, IAN AND I ARE TAKING TURNS PLUGGING FOR THE NETWORK, TO DR. BIANCHI, NOT TO SIMPLY FORM MFN NETWORK. NETWORKS NEED TO OPEN TO ALLOW SCIENTISTS TO BRING TRIALS FOR WHICH THEY HAVE ALREADY DONE VALIDATION. SO THAT'S JUST ONE POINT. SECOND POINT IS I'M SENDING MY APPLICATION FOR FERUMOXYTOL IN TWO WEEKS TO FDA. THE THIRD THING WHICH IS THE MAIN THING I WANTED TO SHARE WITH BOTH OF YOU, I THOUGHT IT WAS A GENIUS OF THE PEOPLE WHO SAT ON THE PANEL FOR THE ORIGINAL HPP PROPOSAL REQUIRING A CLINICIAN ON THE STUDY. IN OUR CASE, I ENDED UP BEING A P.I. AND CO-P.I. WITH OLIVER BECAUSE WE WERE DRIVING WHAT NEEDS TO BE DONE. WE HAVE BEEN DRIVING EXACTLY FROM THE POINT OF JODY AND GEORGE POINTED OUT, WHAT WOULD MAKE A DIFFERENCE? AND TO MAKE THAT DIFFERENCE, I DON'T THINK WE WANT TO MAKE A DIAGNOSIS OF FETAL GROWTH RESTRICTION. CLINICIANS GENERALLY DO A PRETTY GOOD JOB OF MAKING DIAGNOSIS OF FETAL GROWTH RESTRICTION. YOU WOULD THINK I SET UP MANNA TO COME IN FRONT OF ME BUT THE IDEA BUT HOW DO WE DEFINE BY ADVANCED IMAGING TECHNIQUE DIFFERENT PATTERNS OF PRESENTATIONS BEFORE IT BECOMES SO SEVERE, THAT THE CLINICIAN IS IN A BIND TO EITHER DO DELIVERY OR NOT TO DO DELIVER. THE GOAL OUGHT TO BE TO CREATE THIS TECHNOLOGY AT A TIME POINT AND WE'RE FOCUSING NOW BETWEEN 20-22 WEEK AND 24-WEEK WINDOW SO WE BRING TO CLINICIAN A TEST THAT IS THEN READY FOR APPLYING FOR A CLINICAL TRIAL OF ANY KIND OF INTERVENTION, BASED ON WHAT WE HAVE UNDERSTOOD ABOUT THE PATHOBIOLOGY. SO, YES, YOU'RE RIGHT, THAT'S THE WAY TO GO. OUR NEXT PHASE IS GROW TO GROWTH RESTRICTION, DEFINE PATTERNS OF PLACENTAL BIOLOGY, THEN CORRELATED WITH HISTOPATHOLOGY, AND BIOMARKERS. SO I WANTED TO SHARE WITH YOU THAT WE ARE THINKING IN THOSE TERMS, SO LOOK FOR THOSE GRANTS. >> DAVID WINE BERG. I LOOKED AT THE TIME. I WILL BE THE BAD GUY. THERE'S A LOT OF PEOPLE WHO BROUGHT POSTERS WHO WANT TO SHARE THEM. WE'RE ALREADY WAY OVER TIME. I APOLOGIZE. I'M GOING TO HAVE TO RETHINK THIS IF WE DO THIS AGAIN. PLEASE, THESE GUYS ARE NOT GOING ANYWHERE. >> I'M HERE. >> SO I WOULD LIKE PEOPLE TO TALK TO THEM. I'D LIKE THE AUDIENCE TO HEAR YOUR THOUGHTS BUT I JUST CAN'T FIGURE OUT HOW TO MAKE TIME COMPRESS FOR ME. SO I WANT TO THANK EVERYBODY FOR A GREAT DAY. PLEASE GO TO THE POSTERS. PLEASE NETWORK AND PLEASE TALK TO OUR PANELISTS. >> THANK YOU. THANKS, PANELISTS. [APPLAUSE] [END OF PROGRAM]