WELCOME DAY TWO OF THE NIAAA 50th SYMPOSIUM. YESTERDAY HAD WONDERFUL PRESENTATIONS BY DR. CATHERINE KEYS, AND SUSAN TAPER AND MARK SHUCK ET. IF YOU WERE NOT ABLE TO JOIN US, PLEASE NOTE THAT THOSE PRESENTATIONS WILL BE ARCHIVED AND WE'LL SHARE THE URL WHEN THE RENTATION IPRESENTATION IS POSTED. TODAY'S AGENDA IS PRESENTATIONS ON FOUR FEMALE ALCOHOL SPECTRUM DISORDERS AND ALCOHOL ASSOCIATED DELIVER DISEASE. LIKE YESTERDAY, WE'LL HAVE A 20-MINUTE QUESTION AND ANSWER SESSION AND INSTRUCTIONS ABOUT SUBMITTING QUESTIONS ABOUT APPEAR ON YOUR SCREEN DURING THOSE SEGMENTS. SO NOW I'D LIKE TO INTRODUCE OUR FIRST PRESENTER TODAY. DR. RAJITA SIN SINHA FESS OR AT YALE UNIVERSITY AND CHIEF OF THE PSYCHOLOGY SECTION AND PSYCHIATRY AT THE YALE CENTER FOR CLINICAL INVESTIGATIONS AND THE UNIVERSITY WIDE CENTER THAT FOCUSES ON UNDERSTANDING STRESS MECHANISMS EFFECTING MOOD, EMOTION, AND HEALTH BEHAVIOR SUCH AS ALCOHOL INTAKE AND CHRONIC DISEASE RISK. WE'LL BEGIN OUR PRE RECORDED LECTURE AND WE'LL RETURN FROM A LIVE QUESTION AND ANSWER SESSION WITH DR. SINHA. TAKE IT AWAY, DR. SINHA. >> IT'S MY REAL PLEASURE AND HONOR TO BE SPEAKING AT THE NIAAA 50th 50th ANNIVERSARY CELEBRATIONS. THANK YOU DR. KOOB. I'M GOING TO SPEAK ABOUT ALCOHOL'S DARK SIDE AND THE ROLE THAT STRESS PLAYS, FORECASTLY STRESS NEUROBIOLOGY IN DEVELOPING ALCOHOL RISK DOES ORDER AND THE RECOVER RYE FROM ALCOHOL USE DISORDERS. SO OF COURSE, YOU LOOK AT THESE IMAGES HERE. THESE ARE ALL IMAGES OF PARTYING, FUN, PLEASURE, REWARD, THESE ARE WORDS THAT COME UP WHEN PEOPLE THINK ABOUT THE WORD ALCOHOL OR HAVE TO IDENTIFY WHAT IS COMMONLY ASSOCIATED WITH ALCOHOL. PARTYING AND FUN COMES UP RIGHT AWAY AND THOSE ARE THE IMAGES ABOUT ALCOHOL THAT COME UP. YET, THERE'S THE OTHER SIDE. THE SIDE WHERE ANXIETY. PAIN, DISTRESS, DEPRESSION AND DRINKING UNDER THOSE CONDITIONS COME UP. THE QUESTION, THE TOGGLE BETWEEN THESE TWO SIDES, THE TWO OPPOSITE SIDES OF ALCOHOL ARE THE PLEASURE OF FUN REWARD AND THE DISTRESS, ANXIETY, PAIN SIDE OF IT. AND THE SHIFT FROM ONE TO THE OTHER, PARTICULARLY GOING TOWARDS AS DR. KOOB HAS SO BEAUTIFULLY IDENTIFIED, GOING TOWARDS THE DARK SIDE, IS THE BUILDING FROM DESIRE, HEALTHY, NORMAL DESIRE TO CRAVING AND COMPULSION STRESS OR TRAUMA MAY ALTER HOW MUCH REWARD WE FEEL AND THE RESPONSE TO STRESS THAT WE MAY HAVE. SO THERE'S THIS BIO DIRECTIONAL RELATIONSHIP. IN FACT, THERE ARE DATA THAT SHOW THAT HIGH STRESS AND ANXIETY MAY ENHANCE THE FEELING FOR REWARD AND NEED FOR REWARD AND IT ENHANCES STRESS. HOW DOES THAT RELATIONSHIP BREAKDOWN AND PLAY OUT? WE ARE IN THE MIDDLE OF THE CORONAVIRUS CRISIS. CURRENTLY, HERE IN THE UNITED STATES, AND THERE'S BEEN QUITE A BIT OF ATTENTION ON HOW COVID STRESS HAS BEEN INCREASING ALCOHOL USE. HERE IS A U.S.A. TODAY ARTICLE, REPORTING ON THE FACT AMERICANS ARE DRINKING MORE AMID OF COVID-19 PANDEMIC. BUT EXPERTS AND ALL OF US HAVE TALKED ABOUT HOW THIS COULD BE ANY RELIEF FROM THAT COULD BE TEMPORARY. IN FACT, ON SIDE SALES OF ALCOHOL ARE DOWN, AS PLACES HAVE BEEN CLOSED DOWN AND RESTAURANTS HAVE BEEN CLOSED DOWN. ECOMMERCE IS NOW ALLOWED. ECOMMERCE PROFITS HAVE INCREASED OVER 70% DURING THE COVID-19 PANDEMIC. THE BEVERAGE INDUSTRY SAYS THEIR SALES HAVE NOT INCREASED. SO WHAT IS GOING ON HERE? AGAIN, THE QUESTION COULD BE, WHO IS MOST SUSCEPTIBLE TO THESE INCREASED DRINKING EPISODES DURING COVID-19 STRESS. RIGHT HERE IN THIS YEAR, IN THE PANDEMIC YEAR, WE SEE THAT IN FACT THIS BY DIRECTIONAL RELATIONSHIP BETWEEN STRESS IN THIS CASE COVID RELATED STRESS, THE ISOLATION FROM COVID, THE CHANGE IN OUR LIFESTYLE, THE BREAK OF OUR REGULAR LIFESTYLE AND HABITS, SO TO DRIVING CERTAIN INDIVIDUALS AND CERTAIN GROUPS OF PEOPLE TOWARDS INCREASE LEVELS OF DRINKING AND GREATER RISK. SO, I'M GOING TO FOCUS ON ALCOHOL EFFECTS AND REWARD. WHAT MAY BE THE LINK TO STRESS AND PARTICULARLY TO HOW WE COPE WITH STRESS. AND THE POSITIVE OR THE RESILIENT COPING MECHANISMS THAT ARE HARD-WIRED IN OUR BRAIN. THERE ARE SEX DIFFERENCES IN STRESS RESPONSES THAT CAN BE SHOWN DURING DEVELOPMENT AND REALLY IN ADULTHOOD SO ACROSS THE LIFESPAN SO I'LL TALK ABOUT THAT AND TALK ABOUT OUT BINGE AND HEAVY DRINKING AND ALCOHOL CAN ALTER PATHWAYS IN THE BRAIN AS WELL AS IN THE PERIPHERY AND OUR BODIES AND THAT IS TIED TO INCREASING RISK FOR ALCOHOL USE DISORDER AND TO RELAPSE AND JEOPARDIZING RECOVERY FROM ALCOHOL USE DISORDER AND I WILL ACCEPTED WITH ASKING THE QUESTION AND SHOWING HOW WE ARE TARGETING WHETHER WE CAN PROMOTE RECOVERY BY TARGETING THIS ALCOHOL RELATED PHYSIOLOGY IN THE STRESS COPING CIRCUIT. I'D LIKE TO CALL THIS THE STRESS PATH OF PHYSIOLOGY OF ALCOHOL USE DISORDERS AND WHO DO WE IMPROVE OUR TREATMENT OUTCOMES. SO, HERE IS A CARTOON OF A FACE WITH THE BRAIN, A SECTION OF THE BRAIN AND WHAT YOU SEE IS THE DOPAMINE RICH REGIONS. I CALL IT THE MOTIVATIONAL CHECK CAL AND IT'S INVOLVED IN REWARD OR IN MOTIVATION. IT HEARS THE MENTAL AREA, THE REWARD REGION AND THEN THIS FRONTAL SYSTEM, THE PRE FRONTAL CORTEX THAT HELPS US REGULATE OUR REWARD IMPULSES AND THE NEED FOR PLEASURE, WITH SORT OF BALANCING IT WITH SELF-CONTROL. NOW, BEFORE WE HAD ALL OF THESE REWARDING SUBSTANCES THAT STIMULATE THIS PATHWAY IN THE BRAIN, THE QUESTION WE RAISE IN OUR LAB IS WHAT ABOUT STRESS RELATED MOTIVATION. WHAT ABOUT WHEN WE ARE UNDER STRESS, THE NEED FOR REWARD OR THE NEED FOR SAVING OURSELVES OR TO SURVIVE TO IMPROVE OUR CERTAIN STATE IN THE MOMENT? BEFORE WE HAD ALL OF THESE REWARDING SUBSTANCES, WE WERE HARD-WIRED TO DEAL WITH STRESS AND TO SAVE OURSELVES OR ADAPT UNDER CONDITIONS OF STRESS SO THAT WE CAN COME OUT ON THE OTHER SIDE LEARNING FROM THE STRESSFUL EXPERIENCE AND NOT HAVING TO GO THROUGH IT AGAIN. ONE OF THE STUDIES THAT WE DID A FEW YEARS AGO WAS TO LOOK AT THE NURRAL MECHANISMS OF RESILIENT COPING UNDER STRESS. WE ARE ALL FACED WITH STRESS EVERYDAY OF OUR LIVES, IN FACT, WE'RE IN THE MIDDLE OF A PANDEMIC. YET, PEOPLE ARE COPING. A LOT OF FOLKS ARE DRINKING AND HAVING DIFFICULTIES BUT THERE ARE OTHERS WHO ARE COPING EVERYDAY IN AN ACTIVE WAY AND DOING THE BEST THEY CAN. WE WANTED TO UNDERSTAND WHAT WE CALLED THE RESILIENT COPING MECHANISMS IN THE BRAIN THAT DRIVE THIS RESPONSE TO STRESS. WE EXPOSED A GROUP OF 30 INDIVIDUALS TO A BUNCH OF STRESSFUL IMAGES. THESE WERE REALLY THREATENING CHALLENGING, VERY GREW SOME AS WELL AS FEARFUVERY GRUESOME ANDNEUTRAL, RE LAXING, CALMING IMAGES AND THAT'S THE SECOND BLOCK. PEOPLE WERE EXPOSED AND WE ALSO ASSESSED THE STRESS HORMONE CORTISOL, STRESS AROUSAL DURING THIS PERIOD. WHAT WE IDENTIFIED FIRST, WAS WHEN LOOKING AT THESE IMAGES, WE FIND THAT THE LEVEL OF SUBJECTIVE STRESSFULNESS GOES UP PRETTY SIGNIFICANTLY ON A NINE-POINT SCALE GOING FROM 0-9, YOU HAVE PRETTY MODERATE TO HIGH LEVELS OF STRESS THAT REMAIN SUSTAINED. SO THESE IMAGES ARE COMING AT YOU AND THERE'S A HIGH LEVEL OF STRESS, THERE'S ALSO HIGH LEVEL OF SUBJECTIVE OR PEOPLE FEEL THE STRESS AND AROUSED AND CORTISOL LEVELS ARE GOING UP RELATIVE TO THE NEUTRAL CONDITION. WHAT IS HAPPENING IN THE BRAIN HERE, THIS IS A FUNCTIONAL MRI SCAN THAT THESE INDIVIDUALS PARTICIPATED IN WHERE THEY GO IN AND YOU SAW THE IMAGES THEY'RE LOOKING AND THEIR BRYN IS RESPONDING TO IMAGES AND THEIR BODY IS RESPONDING TO IT. WHEN YOU SEE A RED AND YELLOW, IT MEANS INCREASED ACTIVATION AND WHEN YOU SEE BLUE-PURPLE THOSE REGIONS OF THE BRAIN ARE SHOWING DECREASED A ACTIVATION RELATIVE TO BASELINE. THE EMOTIONAL CIRCUIT, LIKE THE HYPOTHALIMUS ARE GETTING ACTIVATED UNDER STRESS CONDITIONS. WE ALSO SEE THAT THE PRE FRONTAL CORTEX, WHEN IT'S BLUE, IT ACTUALLY THE REGULATORY REGIONS DON'T HAVE ENOUGH TIME, THEY ARE ACTUALLY BLUNTED. THEY'RE NOT RESPONDING SO THAT WE ARE GETTING GREAT STRESS RESPONSE HERE AND LESS AMOUNT OF REGULATION. THE IMPORTANT THING HERE THAT I WANT TO POINT OUT ARE THE REWARD REGIONS ARE ALSO HIGHLY AK TA RATE ISED AND THAT'S POINTED RIGHT HERE WHAT WE CALL THE STRAITUM. WE HAVE EMOTIONAL AS WELL AS REWARD REGIONS ACTIVATED. WHEN YOU LOOK AT THE RISE IN CORTISOL WE DO A BRAIN WITH CORTISOL WE SEE IN FACT THAT SORT COL IS INFLUENCING NOT THIS IS THE RESPONSE IN THE REGIONS AND THE HIPPOCAMPUS AND THE HYPOTHALIMUS, THE VERY TIGHT CORRELATION WITH CORTISOL RESPONSE IN FACT, THE REWARD REGIONS AND OUR PRE FRONTAL CORTEX ARE ASSOCIATED WITH CORTISOL WITH OUR STRESS RESPONSE AND THE FRONTAL REGIONS, THE BLUNTING IS ASSOCIATED WITH SOR CORTISOL. IT DOESN'T MEAN IT'S A PERFECT RELATIONSHIP, THIS IS JUST A CORRELATION AND NOT A CAUSAL CONNECTION. BUT MORE IMPORTANTLY, WHAT WE FOUND IS THAT IN THESE INDIVIDUALS, WE ASK THEM, ON A SEPARATE DAY, HOW THEY COPE WITH STRESS. AND WHAT ARE THE THINGS THAT THEY DO WHEN THEY'RE UNDER STRESS. WE LOOKED AT THE BRAIN RESPONSE. WHAT WHICH FOUND IS DURING THOSE FIVE MINUTES OF EXPOSURE TO THESE IMAGES, IS REALLY AWFUL ADVERSE IMAGES. THE BRAIN STARTS TO MOBILIZE AND ESPECIALLY THE PRE FRONTAL CORTEX AND THE TRY EIGHTAL AND THIS IS ASSOCIATED WITH ACTIVE COPING. IN FACT, THOSE INDIVIDUALS WHO DON'T SHOW A FLEXIBLOR A DYNAMIC RESPONSE DURING THE STRESS, TEND TO BE PEOPLE WHO ARE EMOTIONAL EATERS, THEY ARE THOSE WHO TEND TO HAVE NOT A LOT OF FIGHTS, OR HAVE EMOTION DISREGULATIONS, EMOTIONAL DISREGULATION IRRITABILITY, FRUSTRATION AND FOR THE TALK TODAY, THEY ARE BINGE DRINKING IN A SITTING DRINKING SIX OR PLUS DRINKS. THIS IS IMPORTANT TO IDENTIFY THAT IN FACT THERE'S STRESS RESILIENT COPING CIRCUIT THAT OVERLAPS WITH OUR REWARD REGIONS AND OUR IMPORTANT IN OUR COPING WITH STRESS AS WELL AS PERHAPS AS WE THOUGHT, IT COULD BE IMPORTANT IN COPING WITH HAVING A DRINK AND KNOWING WHEN TO STOP. SO GENERALLY HAVING A SENSE OF SELF-CONTROL AND BEING RESILIENT UNDER THE CHALLENGE OF ALCOHOL-RELATED STIMULATION. WHICH WE NOW THINK IS A CRITICAL RESILIENT COPING CIRCUIT INVOLVED IN ACTIVE COPING, MOTIVATION, AND FLEXIBLE CONTROL OF BEHAVIOR. NOW IT'S IMPORTANT TO TAKE A STEP BACK AND SAY THAT THERE ARE INDIVIDUAL DIFFERENCES IN HOW WE RESPOND TO STRESS AND MOST IMPORTANTLY, IF WE CAN THINK ABOUT THERE ARE SOME VERY BASIC HARD-WIRE DIFFERENCES BETWEEN A FEMALE BRAIN AND A MALE BRAIN. SO IF WE JUST LOOK AT GRAY MATTER VOLUME, THIS IS NOT FUNCTIONAL SPONSOR HOW DYNAMICALLY OUR BRAINS ARE RESPONDING TO DIFFERENT STIMULI, THIS IS JUST GRAY MATTER. THE CELL S VOLUME. FEMALES HAVE LESS GRAY MATTER IN EMOTIONAL AND STRESS REGIONS. WE HAVE THE HIPPOCAMPUS REGIONS BY LITERALLY THAT ARE DIFFERENT. BOTH IN THE ADOLESCENTS AS WELL AS IN THE ADULTS. AND SO THESE ARE SEPARATE GROUPS OF SUBJECTS AND WE SEE-THROUGH OUT THE LIFESPAN, THERE ARE SEX DIFFERENCES AND HOW OUR BRAINS ARE WIRED, PARTICULARLY IN EMOTION AND REWARD REGIONS. EMOTION AND STRESS REGIONS. THESE ARE THE HIPPOCAMPUS AND PARA HIPPO CAMPAL AND CEREBELLUM, THE MOTOR ROUTINE REGIONS. THE THAT WILL A MUSS. SO THIS IS AN POR IMPORTANT CONSIDERATION THAT WE'LL COME BACK TO AGAIN. THIS IS A GROUP OF YOUNG ADULT INDIVIDUALS WHO ARE SOCIAL DRINKERS. WE LOOKED AT THEIR BRAIN'S RESPONSES TO STRESS AND ALCOHOL QUEUES. THIS IS JUST TELLING US THAT THIS IS WHERE THE HOTSPOTS ARE. WHEN WE BREAK IT DOWN AND DIRECTLY COM MALES VERSUS FEMALES, MALES HAVE A HIGHER RESPONSE AND IN THE INSUL AR REGIONS THESE ARE LIMBIC REGIONS AS WELL AS IN PRE FRONTAL REGIONS, HOWEVER, FEMALES ARE MUCH HIGHER IN THAT PRE FRONTAL CORTEX REGION, WHICH IS VERY IMPORTANT IN HELPING US REGULATE STRESS AS WELL AS REGULATE OUR RESPONSES TO ALCOHOL-RELATED STIMULATION. SO, NOT ONLY ARE WE STRUCTURALLY DIFFERENT IN MALES VERSUS FEMALES, WHAT I'M SHOWING YOU HERE IS THAT THERE'S A DIFFERENT RESPONSE TO STRESS AND TO ALCOHOL CUES IN MEN VERSUS WOMEN. SO SEX DIFFERENCES ARE CRITICAL. WHEN WE THEN THINK ABOUT WHAT ALCOHOL DOES, JUST LEVELS OF HEAVIER DRINKING, BINGE DRINKING HERE IS FIVE OR MORE DRINKS IN A SITTING FOR MEN, FOUR OR MORE FOR WOMEN, AND AS WELL AS WEEKLY 15 OR MORE DRINKS PER WEEK FOR MEN AND EIGHT OR MORE FOR WOMEN. THE NATIONAL INSTITUTE OF ALCOHOLISM AND ALCOHOL ABUSE HAS CLEARLY IDENTIFIED THESE THRESHOLDS FOR BINGE DRINKING AND WHAT WE FIND IS THAT INDIVIDUALS WHO ARE ROUTINELY BINGE DRINKING, THEY ACTUALLY HAVE AN INCREASE IN THEIR BASIL CORTISOL LEVEL. THIS IS TWO SEPARATE STUDIES WE FIND THAT COMPARED TO LIGHT, MODERATE DRINKERS, CORTISOL LEVELS AT BASIL LEVELS, THIS IS AT SPECIFIC TIMES OF DAY, THE BINGE-HEAVY FOLKS HAVE A HIGHER BASIL LEVEL OF CORTISOL. AND SO WHEN YOU START TODAY SAY, WELL, I WONDER IF THIS CHANGES THEIR RESPONSE, THE CORTISOL RESPONSE TO ALCOHOL AS WELL AS TO THEIR RESPONSE TO STRESS. SO, IN A STUDY, WHERE WE WANTED TO LOOK AT THE EFFECTS OF CORTISOL AND ALCOHOL, WE CALL IT UNDER IMPLICIT ALCOHOL MOTIVATION CONDITIONS, THIS IS A THREE-DAY STUDY WITH SOCIAL DRINKERS, WHO WERE EITHER LIGHT TO MODERATE, NEVER BINGERS OR BINGE HEAVY DRINKERS AND THEY WERE EXPOSED TO EITHER ALCOHOL CUES OR NEUTRAL RELAXING CUES OR STRESS CUES AND THEY GOT TO DO THIS IMPLICIT ALCOHOL MOTIVATION TEST WHICH IS THE ALCOHOL TASTE TEST. IT'S BEEN AROUND FOR A LONG TIME AND THEY GET ON A TRAY TWO GLASSES OF BEER, TWO 12-OUNCE BEERS IN EACH MUG AND THEY'RE ASKED TO TASTE EACH ONE AND SAY WHETHER THEY'RE THE SAME OR DIFFERENT. THEY GET TO DRINK AS MUCH AS THEY NEED TO TO DECIDE WHETHER THEY'RE THE SAME TYPES OF BEER. THEY HAVE A PERIOD FOR 10 MINUTES AND WE'RE LOOKING AT THEIR BODY'S RESPONSE AND THEIR SUBJECTIVE RESPONSE TO THE DRINKING. YOU CAN SEE IN MAKING THAT DETERMINATION OF WHETHER THE BEERS ARE SAME OR DIFFERENT, THIS IS I AM POLIC MOTIVATION NATURALLY. THE BINGE-HEAVY INDIVIDUAL SOCIAL DRINKERS DRANK MORE. THEY FELT LIKE THEY HAD TO CONSUME MORE ALCOHOL TO MAKE THAT DETERMINATION COMPARED TO THE MODERATE DRINKERS. AND THEN, WHAT WE FIND OF COURSE THEY CONSUMED MORE AND THEY HAD A HIGHER CORTISOL RESPONSE. BUT THAT'S UNDERSTOOD BECAUSE THAT'S EXPECTED BECAUSE IN FACT, ALCOHOL WILL INCREASE CORTISOL RESPONSES, IT DID SO IN BOTH GROUPS HERE AND WE SEE THERE'S A HIGHER AND QUICKER RESPONSE IN THE BINGE HEAVY INDIVIDUALS. CORTISOL IS SENSITIVE TO ALCOHOL-RELATED INCREASES. WHAT WE ALSO FOUND, BEFORE THEY GET TO DRINK, THEY WERE EXPOSED TO STRESS AND NEUTRAL AND ALCOHOL CUES. WHAT WE FIND IS DESPITE THE FACT THAT THEY HAD A HIGHER COURT SAL RESPONSE BASILY, THEY HAD A BLUNTED RESPONSE TO STRESS. WHEN WE STRESS PEOPLE OUT LIKE I SHOWED YOU IN THE FIRST STUDY, CORTISOL GOES UP. AND MODERATE DRINKERS SHOWED AN INCREASE IN CORTISOL BUT BINGE-HEAVY DRINKERS HAD A BLUNTED RESPONSE IN THE STRESS CONDITION AND THE CUE CONDITION, NO DIFFERENCE IN THE NEUTRAL CONDITION. AND MORE IMPORTANTLY, THE MORE BLUNTED THEIR RESPONSE WAS, THE MORE THEY DRINK ALCOHOL. WHICH IS REALLY INTERESTING. IT WASN'T HIGH LEVELS OF ALCOHOL BUT IN FACT, A BLUNTED RESPONSE TO STRESS WAS MOST SENSITIVE IN PREDICTING HOW MUCH ALCOHOL THEY WOULD DRINK RIGHT AFTER. AND SO, THIS ALLOWED US TO COME UP WITH A MODEL THAT WE ARE TESTING AND WAY OF UNDERSTANDING THIS DATA WHICH IS REALLY IDENTIFYING A ROLE FOR GLUECOCORTICOIDS IN DRINKING. WHAT YOU SEE HERE IS THAT HERE ARE THE MODERATE DRINKERS, HERE THE BLINK-HEAVY DRINKER AND WE SOOT THE BLINK HEAVY DRINKERS ARE HIGHER SO RISK LEVEL IS GOING UP AND THEN, WHEN WE GIVE THEM ALCOHOL, THEY DON'T GET AS MUCH OF A RESPONSE. SO THEY HAVE TO DRINK MORE IN SOME WAYS IF YOU THINK ABOUT IT, TO GET THEIR SOR CORTISOL LEVELS BACK UP AT A CHALLENGE-RESPONSIVE LEVEL. SO THIS IS OUR MODEL THAT IF FACT THERE'S A DISRUPTION AND A NEED TO DRIVE THAT HOMEY OWE STATIC BASELINE UP TO NORMAL IN SOME WAYS IN BINGE-HEAVY DRINKERS AND THOSE WHO HAVE THE HIGHER LEVEL OF RISK. LET'S MAKE A SHIFT AND THINK ABOUT ALCOHOL USE DISORDER. SO, THE PERSON OR INDIVIDUALS WHO HAVE BEEN DRINKING AND BINGE DRINKING AND NOW ARE DRINKING MORE FREQUENTLY AND AT HIGHER LEVELS, AND HAVE DEVELOPED ALCOHOL USE DISORDER AND EPISODE OF ALCOHOL USE DISORDER. THE QUESTION WE ASKED IS WHEN THEY INITIATE TREATMENT AND THEY START TO THINK ABOUT CUTTING BACK OR ABSTAINING, WHAT ARE THE CHALLENGES OF MAINTAINING THAT ABSTINENCE OR MAINTAINING RECOVERY? WE KNOW THAT WHEN PEOPLE ENGAGE IN TREATMENT, THERE IS A RISK FOR EARLY DROP OUT. THERE'S A RISK FOR EARLY RELAPSE AND THOSE FACTORS JEOPARDIZE RECOVERY. I'M GOING TO SHOW YOU SOME DATA FROM OUR LARGE PUBLICLY-FUNDED SUBSTANCE ABUSE TREATMENT UNIT, THIS IS ONE YEAR DATA OF 878 OUT PATIENTS WHO HAVE PRIMARY SUBSTANCE USE DISORDERS EITHER WITH COCAINE, MARIJUANA, OPIOID OR ALCOHOL. IF YOU LOOK AT THE ALCOHOL, WHAT YOU SEE HERE ON THE X AXIS IS TIME TO DISCHARGE. HOW LONG DID THEY STAY AT THE CLINIC FOR TREATMENT? ON THE Y AXIS YOU SEE THEIR SURVIVAL. HOW LONG DID THEY LAST OR WHAT WAS RATHER ITS MUCH MORE THE PREPORTION WHO STAYED ABSTINENT. NOT ONLY DID THEY LAST IN TREATMENT ON THE X AXIS BUT REALLY WERE THEY ABSTINENTS. YOU START TO SEE PEOPLE FALLING OFF THE WAGON. EVERYBODY IS ABSTINENT IN THE BEGINNING WHEN THEY COME IN. THEY CAN CON JUS CONJURE UP ONE OR TWO DAYS AND THEY FALL OFF THE WAGON. IN THE CASE OF ALCOHOL, WE USE THE ALCOHOL USE DISORDER MEDICATIONS THAT HAVE BEEN APPROVED BY THE FDA AND IT'S STILL PEOPLE STAYING ABSTINENT AND YOU START TO SEE THIS DROPPING OFF. I WANTED TO SHOW YOU THIS IS A VERY DYNAMIC PHASE CAN WE IDENTIFY MARKERS THAT CAN TELL US WHAT GETS IN THE WAY GOING BELOW THE 50% USE FOR DISORDERS. I WANT TO STEP BACK AND THINK ABOUT A AT EIGHT WEEKS I'M LIVING ON LESSON INSTINCT AND HABIT. I CAN THINK CLEARLY AND TAKE TIME TO PROCESS THOUGHTS. BEFORE ACTING I NOTICE I'M TALKING LESS. I HAVEN'T HAD FULLY FORMED THOUGHTS FOR SO VERY LONG, IT'S KIND OF NICE TO HAVE MY FACULTIES BACK AGAIN JUST TO KEEP UP THE VAINER OF BEING A FULL HUMAN BUT UNDERNEATH, I WAS A SLAVE TO THE BOTTLE. A KNEE JERK REACTION. BUT NOW, I'M NO LONGER FEELING SILENCES. NAGGING AT MY KIDS, INTERRUPTING PEOPLE WHILE THEY TALK, I'M JUST LISTENING. NOT EVEN PLANNING HOW TO REACT, JUST SITTING WITH THE MOMENTS AND OBSERVING, HEARING, FEELING QUIET AND CONTEMPT IN MYSELF. I'VE SEEN THINK THAT I FOUND MY KHI. WOULD YOU EVEN KNOWING WHAT THAT WORD MEANT A WEEK AGO, I FELT SOMETHING. LIKE A PLACE INSIDE MY SOUL. SOMETHING I THINK I REMEMBER DISCOVERING AS A CHILD, AND TEEN, BEFORE ALCOHOL SMOOTHERS IT, A PRESENCE OF MYSELF. WE CAN COME UP WITH DATA AND ANALYSIS BUT I THINK THIS IS SO BEAUTIFULLY ARTICULATED BY THE PATIENT WHO IS AN EARLY RECOVERY BY SOMEONE WHO WITH ALCOHOL USE DISORDERS LEAVES AN EARLY RECOVERY AND HAS MANAGED TO NAR NARRATE HER EXPERIENCE OF THOSE INITIAL EIGHT WEEKS. BEAUTIFULLY WRITTEN. WHAT WE DID IN THE LABORATORY, WE WANTED TO UNDERSTAND THIS EARLY PERIOD. WE HAD PEOPLE COME BACK INTO THE LAB AND EXPERIMENTALLY PROVOKED THEIR EXPOSURE TO STRESS, TO NEUTRAL RELAX CUES AND TO ALCOHOL CUES IN THE CASE OF ALCOHOL PATIENTS. AND WHAT WE WERE ABLE TO DO IN THE LAB, IS EXPERIMENTALLY INDUCE AN INCREASE CRAVING OR COMPULSION FOR DRUGS. THEY'RE ALL INPATIENTS IN THIS CASE OF THE ALCOHOL PATIENTS. WE SEE STRESS PROVOKES CRAVING AS DOES ALCOHOL RELATED CUES COMPARED TO NEUTRAL CUES. IN FACT, INCREASE LEVELS PREDICTS WHAT HAPPENS TO THEM WHEN THEY'RE DISCHARGED AND THEY TEND, THOSE WHO HAD HIGHER CRAVINGS INTENDED TO RELAPSE MORE QUICKLY. THAT SLIDE IS NOT IN HERE. WHAT YOU DO SEE IS THAT UNDER THOSE CONDITIONS OF STRESS, PROVOCATION OR CUE PROVOCATION, COMPARED TO NEUTRAL, FOLKS ALSO HAD AN INCREASE IN CORTISOL OR A BLUNTED RESPONSE TO CORTISOL IN THE CASE OF PATIENTS AND WHAT WE FIND IS THAT CORTISOL HORMONE RATIO WHICH IS A RATIO OF A DRONAAUDRINA SENSITIVITY. THE HIGHER THE GREATER THE LIKELIHOOD OF RELAPSE. IT'S TIME TO RELAPSE DISCHARGE AND SURVIVAL, HOW MANY PEOPLE SURVIVED WITHOUT RELAPSING ON THE Y ACTION I GUESS AN AXIS. THE RATIO IS A PREDICTER WITH THE COURT/ACTH, THE HIGHER THE COURT/ACTH RATIO THE QUICKLY THEY DROP OFF THE WAGON AND RELAPSING. BY DAY 20 HERE, YOU'VE GOT MOST OF THOSE WITH THE HIGHEST LEVELS OF COURT/ACTH RATIO RELAPSING. THERE'S A RANGE. WE'RE SEEING THAT HEAVY LEVELS OF DRINKING DOES ALTER THE CORTISOL AND PERIPHERAL SO IT IS IMPORTANT TO UNDERSTAND THE INDIVIDUAL VARIATION AND IDENTIFY THOSE WHO ARE MOST AT RISK FOR THIS STRESS RELATED PATH OWE PHYSIOLOGY. ONE OF THE FACTORS THAT ARE IMPORTANT IS SEX DIFFERENCES AND ACTA HORMONE AND IT STIMULATES CORTISOL IN OUR AUDRINA AND WE SEE FEMALES HAVE A MORE BLUNTED LEVEL AND THAT BASAL RESPONSE EFFECTS THEIR RESPONSE TO STRESS AND CUES. WE ALSO FIND THAT THIS IS GRAY MATTER VOLUME SO THIS IS JUST STRUCTURALLY THE NUMBER OF CELLS AND THIS SHOWS THIS FREE FRONTAL REGULATE OUR ACTIONS, OUR EMOTIONS AS WELL AS OUR REWARD RESPONSES IS MORE BLUNTED MEANING, THAT THERE'S JUST LOWER VOLUME, LOWER GRAY MATTER AMONG THOSE WHO ARE ABSENT INDIVIDUALS WITH MORE DISORDERS COMPARED TO CONTROLS. THOSE WHO HAVE THE LOWEST GRAY MATTER VOLUME TEND TO HAVE THE GREATEST RISK FOR RELAPSE, THE GREATEST RISK FOR JEOPARDIZING RECOVERY AND NOT DOING WELL IN TREATMENT POST INPATIENT STAY AND INPATIENT TREATMENT. WHEN WE LOOK AT FUNCTIONAL RESPONSE, BOTH TO STRESS AND TO ALCOHOL CUES, WHAT WE SEE IS THAT THERE'S A DISRUPTED FREE PRE FRONTAL AND REWARD REGION RESPONSE IN INDIVIDUALS WITH ALCOHOL USE DISORDER COMPARED TO HEALTHY CONTROLS IN THE GRAY BAR. WE SEE THAT INDIVIDUALS WITH ALCOHOL USE DISORDER ACTUALLY HAVE A HYPER ACTIVE RESPONSE TO THE RELAX STATE IF YOU ARE RELAXING, YOUR BRAIN ACTUALLY TENDS TO DEACTIVATE AND GO INTO BLUE FOR US IN AMONG THE HEALTHY CONTROLS BUT NOT SO FOR THOSE WITH ALCOHOL USE DISORDERS. THEY HAVE A HIGHER BASSAL STATE THAT IS REMNANT IN THIS COPING RESPONSE. THE STRESS AND CHALLENGE COPING CIRCUIT. WE WANT THIS TO MOBILIZE AND RESPOND TO STRESS IN AN ACTIVE WAY, IN A RESILIENT WAY AND IT SHOWS A RESPONSE AND MORE IMPORTANTLY, BOTH THE NEUTRAL RESPONSE IN THIS FRONTAL REGION, AS WELL AS THIS STRESS RESPONSE IN THIS FRONTAL REGION, IS PREDICTIVE OF FUTURE RELAPSE SO TIME TO RELAPSE POST INPATIENT STAY IS EFFECTED, CAN BE PREDICTED, BY THIS DISRUPTION IN THE FRE PRO FRONTAL CORTEX. SO THOSE WHO HAVE MORE CONDITIONS OR GREATER HYPER ACTIVITY UNDER NEUTRAL CONDITIONS RELAPSE MUCH MORE QUICKLY. AND SO, WHAT WE THINK WE'VE BEEN STUDYING AND IDENTIFYING WITH NIAAA'S WONDERFUL SUPPORT, IS REALLY COMING UP WITH A PROFILE, A RISK PROFILE FOR ALCOHOL RELAPSE. WHAT IS IT THAT JEOPARDIZES RECOVERY AND INCREASES THE RISK OF RELAPSE? INCREASED ANXIETY AND PROVOKED ALCOHOL CRAVINGS INCREASES THE RISK OF RELAPSE THAT HIGHER BASAL COURT ACTH RATIO OR HIGHER AUDRINA SENSITIVITY AND A UNABLE TO WHEN WE NEED STRESS OR CUE-RELATED ALCOHOL-RELATED STIMULI BEING PRESENTED. JUST HAVING LESS GRAY MATTER. HAVING SOME SHRINKING OR REDUCED VOLUME OF THE FRONTAL REGIONS OF THE BRAIN, ALSO ARE PREDICTIVE OF RELAPSE RISK. THIS STARTS TO TELL US THAT IN FACT, WE CAN BEGIN TO UNDERSTAND NOT ONLY THE EFFECTS OF HEAVY ALCOHOL USE ON THE BRAIN AND THE BODY, THAT IMPAIRS OUR FUNCTIONING JUST AS OUR PATIENTS IDENTIFY, BUT IN FACT, ALSO SHOW THAT WHICH IDENTIFY WHICH MEASURES, WHICH OF THOSE BIO BEHAVIORAL MEASURES ARE MOST SENSITIVE IN PREDICTING OR TELLING US THEY'RE GOING TO HAVE DIFFICULTY DURING THE EARLY PHASES OF TREATMENT. WHAT ABOUT CLINICAL TRANSLATION? THE LAST PART OF MY TALK I WANT TO SPEND JUST A FEW MINUTES ON CLINICAL TRANSLATION. BOTH IN TERMS OF IDENTIFYING THINKING ABOUT WHO IS MOST VULNERABLE TO THESE CHANGES, JUST LIKE DATA THAT I WAS SHOWING YOU IN TERMS OF THE SPREAD OF EACH OF THOSE MARKERS AND CAN THESE BIO BEHAVIOURAL MARKERS IDENTIFY THOSE WHO ARE MOST VULNERABLE CLINICALLY AND COULD SOME TREATMENT HELP WITH REVERSING THAT RISK PATTERN IN THE EARLY PHASE? THOSE WHO HAVE ACUTE WITHDRAWAL SYMPTOMS VERSUS THOSE WHO DO NOT. HOW MANY DAYS OF ABSTINENCE CAN YOU CONJURE UP? DO THOSE IMPACT THIS EARLY PHASE OF RECOVERY? IF A HISTORY OF TRAUMA AND CHRONIC STRESS IMPACTS THE EARLY PHASE OF RECOVERY, I'VE SHOWN YOU THERE ARE SEX DIFFERENCES IN THE BRAIN AND BODY'S RESPONSE TO STRESS AND ALCOHOL AND IT COULD HAVE AN IMPACT AS COULD BE THOSE WHO STARTED EARLY DRINKING IN THEIR TEEN YEARS VERSUS THOSE WHO START IN THE LATER YEARS. OTHER CO OCCURRING ILLNESSES AS WELL AS GENETICS AND HAVING A MORE VULNERABLE GENETIC PROFILE. I'M NOT GOING TO HAVE TIME TO CONSIDER EACH OF THESE MODERATORS OF THOSE RELAPSE MARKERS BUT I'M JUST GOING TO PAY ATTENTION TO THE VERY FIRST ONE AND TALK ABOUT ABSTINENCE DAYS AS WELL AS DISEASE SEVERITY. SO WE USED A DIFFERENT PROVOCATION METHOD TO ONCE AGAIN DO SOME EXPERIMENTS IN THIS SCANNER USING MRI TO PROVOKE STRESS AND CUES SO AGAIN, BLOCKS OF STRESSFUL IMAGES BUT THIS TIME WE ADDED ALCOHOL RELATED IMAGES AND ALSO NEUTRAL IMAGES AND YOU SEE THIS REALLY NICE THREE CONDITIONS DESIGN. THERE ARE COUNTER BALANCED AND RANDOMLY PRESENTED IN BLOCKS. SO IT ALLOWS US TO LOOK AT WHAT IS THE BRAIN'S RESPONSE TO ALCOHOL-RELATED STIMULATE AND STRESS RELATED STIM YOU LA STIMULI AND STRESS. WE ASKED THEM ABOUT HOW SUBJECTIVELY STRESSED THEY'RE FEELING AND HOW MUCH CRAVINGS THEY HAVE. I WANT TO SHOW YOU WHAT HAPPENED, WE HAVE DIFFERENT GROUPS OF INDIVIDUALS. THEY NEVER BINGE AND NEVER BINGED AND THESE ARE OUR BINGE HEAVY SOCIAL DRINKERS AND HERE OR THE INDIVIDUALS WITH ALCOHOL USE DISORDER. UNDER CONDITIONS OF BEING EXPOSED TO STRESS, IN FACT PEOPLE ARE REPORTING HIGH LEVELS OF STRESS IN THE PREVIOUSLY STUDY AND BOTH GROUPS HERE, THE LIGHT, MODERATE AND BINGE HEAVY SOCIAL DRINKERS SHOW THAT. LOOK AT OUR PATIENTS WHO ARE ENTERING TREATMENT. THEY HAVE A HIGHER LEVEL OF DISTRESS BASALLY. THERE'S A SHIFT IN THEIR STRESS BIOLOGY THAT MAKES THEM FEEL MORE DISTRESSED. THIS IS THE DARK SIDE DR. COOP KOOB. THIS IS THE STATE OF INDIVIDUALS SUFFERING FROM ALCOHOL USE DISORDER AND OF COURSE WHEN THEY'RE PROVOKED WITH STRESSFUL IMAGES, THEY ALSO GO UP IN THEIR REPORTING OF STRESS. WHAT ABOUT CRAVING. WE SEE THAT UNDER ALCOHOL CUE CONDITIONS, YOU SEE IMAGES OF NICE ALCOHOL AND WE ALL TEND TO HAVE A LIGHT INCREASE IN DESIRE FOR ALCOHOL. THAT IS IN THE MODERN DRINKERS AND THAT IS MUCH HIGHER AND CRAVING THOSE WHO ARE BINGE HEAVY DRINKER DRINKERS. WHAT ABOUT PATIENTS COMING INTO TREATMENT? THEY ARE SHIFTED. THEY'RE JUST NATURALLY CRAVING MORE BASALLY AND THEY START TO GET STRESSED OR STRESS IN THE RED LINE OR THEY GET EXPOSED TO ALCOHOL CUES, THEY HAVE GREATER CRAVINGS. SO CRAVINGS IS IN FACT A RISK MARKER FOR CONTINUED DRINKING AND WE HAVE SHOWN THAT IN DIFFERENT WAYS. THESE ARE TREATMENT ENTERING INDIVIDUALS WHO MAY HAVE HAD FIVE NUMBER OF DAYS OF AB ABSTINENCE AND THEIR STRESS, BRAIN STRESS CONSTRUCTOR COMPARED TO NEUTRAL AND WHEN IT'S BLUE IT'S BLUNT AND WHEN IT'S RED AND YELLOW THEY'RE AK TA RATE ISED AND W RATE RATE RATEACTIVATED AND WE SEE THE REGION FROM THE BRAIN UP INTO THE PRE FRONTAL CORTEX IS BLUNTED UNDER STRESS CONDITIONS AND UNDER ALCOHOL CUE CONDITIONS IN OUR PATIENTS COMPARED TO THE SOCIAL DRINKERS AND THEY SHOW A TYPIER ACTIVITY AT THE BASAL STATE SO THEIR NEUTRAL RELAXING STATE IS HYPER ACTIVE AND IT'S AS IF THERE'S THIS DISRUPTED PRESENTATION OF THE BRAIN'S CIRCUIT PARTICULARLY THE COPING THE RESILIENT COPING CIRCUIT AND IT'S UNDER SEIGE AND IS DISRUPTED THEY JUST DRINK TWO OR THROW DAYS AGO THERE'S A DIFFERENCE IN OUT THEY'RE RESPONDING AND THE EARLY DAYS OF TREATMENT AND THOSE WHO HAVE A LONG PERIOD CAN STAY SO THEY'RE PROBABLY HAVING NO HEAVY DRINKING DAYS IS HIGH. THOSE WHO HAVE A SHORT ABSTINENCE DAY PERIOD AS THEY ENTER. THEY GO BACK TO HEAVY BINGING DAYS. THEIR BRAIN IS BLUNTED FREE FRONTAL RESPONSE TO STRESS AND CUES IS PREDICTING A RETURN TO HEAVY DRINKING DAYS SO A NUMBER OF DAYS AND WHAT ABOUT WITHDRAWAL PEOPLE HAVE TYPES OF ALCOHOL RELATED SYMPTOMS AND THEY'RE ALL LISTED HERE WHETHER IT'S CRAVING AND IRRITABILITY, SLEEP DIFFICULTY, AGGRESSION, TENSION AND ANXIETY OF COURSE AND HEADACHES, THERE'S A RANGE OF SYMPTOMS. WHAT WE DECIDED TO DO WAS TO REALLY TRY TO UNDERSTAND WHETHER THIS EARLY SYMPTOM IS A IMPORTANT FACTOR IN IDENTIFYING THOSE WHO ARE GOING TO BOTH HAVE THE STRESS RELATED DISRUPTIONS THAT I'VE BEEN SHOWING YOU, AS WELL AS HAVE ACHIEVING RECOVERY IN THE EARLY PHASES OF TREATMENT. THOSE WITH ALCOHOL WITHDRAWAL SYMPTOMS, WHICH I SHOWED YOU IN THE PREVIOUS SLIDE, REPORT GREATER HIGHER THE ALCOHOL WITHDRAWAL SYMPTOMS HERE IS SHOWN HIGHER THE ANXIETY DEPRESSION CRAVEING AND SLEEP PROBLEMS AND IF YOU JUST DIVIDE THAT BASED ON THE SPLIT OF THE ALCOHOL WITHDRAWAL LEVELS, THOSE WITH HIGHER ALCOHOL WITHDRAWAL AND IN FACT HAVE GREATER NEGATIVE EFFECT DEPRESSION ANXIETY SYMPTOMS AND GREATER CRAVINGS AND WE DECIDED THERE WAS A HYPER ACTIVE STEVE PAIKIN AND IT COULSTATE ANDTHERE'S BASIC SCIENCE DATA THAT SHOWS THE FREE FRONTAL CONTEXT AND THIS INSTRUMENT COPING CIRCUIT TREE IS VERY EFFECT I HAVED BY NOR EP NIH RIN AND IT CAN BE RECEIPT RESCUED BY AGENTS THAT IN FACT WE USE IF ALL THE AGENT-LIKE AND IT'S AN ANTI HYPER TENSE I HAVE AGENT AND WITH THE HELP OF NIAAA CONDUCTED A PROVE OF 12-WEEK TRIAL WITH 100 PATIENTS WHO ENROLLED IN THE TRIAL, WE MEASURED DRINKING OUTCOMES EVERY DAY FOR THE 12 WEEKS AND THE LEVEL OF PRAZOSIN WAS 16 VERSUS PLACEBO AND DOUBLE BLIND TRIAL AND MOST IMPORTANTLY PEOPLE WERE ABLE TO GO INTO THIS TRIAL WITH NO ABSTINENCE DAYS REQUIRED. SO THOSE WHO WERE HAVING DIFFICULTIES IN STAYING ABSENT WERE STILL ALLOWED TO COME TO TREATMENT. WE DID NOT ASK THEM TO BE FIVE OR THREE DAYS ABSTINENT. THOSE WHO HAD HIGH LEVELS OF ALCOHOL WITHDRAWAL MAY HAVE GONE FOR DETOX BUT CAME BACK AND STARTED TREATMENT RIGHT AFTER -- STARTED TREATMENT AFTER DETOX. WE FOUND THAT ALCOHOL WITHDRAWALS SYMPTOMS SHOWED HERE MODERATED. IT WAS A SIGNIFICANT FACTOR IN HOW PEOPLE DID WITH PRAZOSIN. IN RED IS THE PLACEBO GROUP. THIS IS ACROSS THE THREE TO 12 WEEK PERIOD. AVERAGE LEVELS OF DRINKING. HEAVY DRINKING DAYS AND ANY DRINKING DAY. WHAT YOU SEE ON THOSE ON PLACEBO JUST RAMPING UP THEIR DRINKING IF THEY HAD GREATER ALCOHOL SEVERITY. THIS MAKES SENSE TO US. IF YOU HAVE GREATER WITHDRAWAL AND NEGATIVE EFFECT, YOU ARE IN FACT GOING TO BE RELAPSING OR YEP OR DIEING YOUR RECOVERY. LOOK AT WHAT PRAZOSIN. IT REVERSED THAT IN THOSE WITH HEAVY OR HIGHER LEVELS ALCOHOL WITHDRAWAL. WHAT DO I MEAN BY THAT? THIS IS JUST IN THE HIGH ALCOHOL WITHDRAWAL GROUP YOU SEE THAT DRINKING DAYS, ANY DRINKING DAYS PERCENT HEAVY DRINKING DAYS WAS MUCH LOWER, SIGNIFICANTLY LOWER IN THE PRAZOSIN GROUP HERE AND AS WELL AS AT WEEK 12. YOU SEE MUCH LOWER ALMOST DOWN TO ZERO. THIS IS 7% BY WEEK 12 IN THOSE TREATED WITH PRACTICES OWE SIN. THEY SHOWED IMPROVEMENTS IN ANXIETY AND ALCOHOL CRAVING AND THEIR MOOD LEVEL AS WELL. SO PRAZOSIN WAS HAVING THIS BENEFIT BUT REALLY ONLY FOR THOSE WITH HIGHER LEVELS OF ALCOHOL WITHDRAWAL. WE TOOK A PEEK IN THEIR BRAIN AND WE EXPOSED THEM TO ALCOHOL CUES AND STRESS CONDITIONS AND JUST LOOKED AT HOW THEY DID FROM BASELINE COMPARED TO WEEK NINE OF TREATMENT. SO WITH CHRONIC PRAZOSIN VERSUS CHRONIC PLACEBO. WE SEE RED AND YELLOW AND THE BRAIN IS COMING BACK AND GETTING ACTIVE AND WE SEE THE FRONTAL CORTEX GETTING BACK AND ACTIVE UNDER STRESS CONDITIONS AND ON THE OTHER HAND IN THE CUE CONDITION, WE SEE THIS STRIATAL RESPONSE IN THE PLACEBO OVERLY ACTIVE AND THAT'S DRIVING COMPULSION AND DRIVING CRAVING. I HOPE I HAVE SHOWN YOU THERE ARE POTENT CHRONIC ALCOHOL RELATED ADAPTATIONS WHEN WE LOOK AT THE BRAIN AS WELL AS IN THE STRESS HORMONAL SYSTEM WHICH IS IN THE PERIPHERY AND IN THE AUTO KNOT I CAN SYSTEM OR OUR ACROSSAAROUSALSYSTEM. THESE CHANGES RELATE TO THE REWARD AND MOTIVATION AND INSTRUMENTAL LEARNING CIRCUITS WHICH ARE PART OF OUR STRESS RESIL YEN CIRCUITRY. IT'S PART OF OUR COPING. HEAVY LEVELS OF ALCOHOL AND ALCOHOL DISTRESS TARGETS OUR ABILITY TO COPE WITH STRESS AND WITH CHALLENGE AND IN FACT, THAT'S ONE MAJOR PATHWAY BY WHICH ALCOHOL RECOVERY MAY BE JEOPARDIZED. SO WHAT IS IT THAT WE WOULD LIKE TO DO AS WE THINK ABOUT ALL OF THESE BIOBEHAVIOR MARKERS. WE WANT TO IDENTIFY THOSE WHO HAVE THE MOST VULNERABILITY IN TERMS OF ALCOHOL DEFECTS ON DISTRESS PATHWAYS. WE WANT TO DEVELOP THESE MARKERS THAT CAN BE USED IN EARLY TREATMENT AS PEOPLE ARE ENTERING TREATMENT. WE GET TO ASSESS THAT AND SAY OH, THIS LEVEL IS LOOKING TOO HIGH FOR YOU OR YOUR WITHDRAWAL SYMPTOMS ARE TOO HIGH. WE CAN'T JUST GIVE YOU ONE TYPE OF TREATMENT WE'LL GIVE YOU ANOTHER TYPE OF TREATMENT SO THE NEXT GOAL WOULD BE TO HAVE A PERSONALIZED PRECISION MEDICINE GOAL AND APPLYING A BIO BEHAVIORAL MARKER TO THE CLINICAL SETTING. HOW SEVERE ARE YOU AND WHAT IS THE THRESHOLD FOR CORTISOL PERHAPS, WHAT IS YOUR BRAIN'S RESPONSE OF HYPER WHO IS VULNERABLE TO RELAPSE AND JEOPARDIZING THEIR RECOVERY AND THEN WE WANT TO HAVE SPECIFIC TREATMENTS, SPECIFIC MEDICATIONS OR STRATEGIES THAT CAN TARGET THAT PARTICULAR PATH OF PHYSIOLOGY AND HELP INDIVIDUALS WHO ARE MOST VULNERABLE TO THIS EARLY PHASE OF RELAPSE AND JEOPARDIZING OF THEIR RECOVERY. SO THAT'S WHERE WE ARE HEADED WITH OUR WORK AND I WANT TO GO AHEAD AND ACKNOWLEDGE ALL OF THE FOLKS AT THE CENTER CENTER WHO HAVE BEEN PART OF DEVELOPING ALL OF THESE EXPERIMENTS AND THE RESEARCH AND A WHOLE GROUP HAVE CONTRIBUTED TO THIS WORK AND NONE OF THIS WOULD HAVE BEEN POSSIBLE WITHOUT THE SUPPORT OF THE NATIONAL INSTITUTE OF ALCOHOLISM AND ALCOHOL ABUSE. WE HAVE A GREAT DEBT OF THANKS TO THE INSTITUTE FOR SUPPORTING THIS WORK AND FOR REALLY PUTTING FOURTH KNOWLEDGE THAT WE THINK IS MOVING THE FIELD FORWARD IN IMPROVING OUR UNDERSTANDING OF WHAT LEADS TO GREATER RISK OF DEVELOPING ALCOHOL USE DISORDERS AS WELL AS WHAT GETS IN THE WAY OF THE RECOVERY IN THE EARLY PHASES AND HOW WE CAN TURN THE COURSE OF THAT AND IMPROVE OUR TREATMENT OUTCOMES. THANK YOU SO MUCH FOR YOUR ATTENTION. >> THANK YOU, THAT WAS A BRILLIANT TALK. IT'S SO GRATIFYING TO SEE THAT YOU BROUGHT THE STRESS AK SI AXIS TO THE HUMAN BRAIN AND THE STUDIES ON RESILIENCE ARE SO TIMELY AND IMPORTANT AND WITH, HOPEFULLY, YOU WILL BE ABLE TO HELP US WHEN WE FLOAT OUR DEFINITION OUT TO THE WORLD AND WITH SOME OF YOUR WONDERFUL, CLINICAL STUDIES. SO THERE ARE A COUPLE OF QUESTIONS ALREADY COMING IN AND WE'LL DO QUESTIONS AS LONG AS WE CAN HERE BEFORE WE HAVE TO MOVE ON AND SO THE FIRST FROM DEB IS CONSIDERING THE PATIENT COMMENTS IT SEEMS THAT PATIENT IS BECOMING MORE ROW FLECK TIVE OR CENTERS AND THIS TRANSITION IS WELL COME WITH THE PATIENTS WITH TRAINING IN BEHAVIORAL EXERCISES HELP BRING ABOUT THE CHANGE FROM BEING REACTIVE TO MORE CONTEMPLATE TIVE AND PURPOSEFUL DURING THE RECOVERY PERIOD CAN DIFFERENCES BE MEASURED BY FUNCTIONAL MRI? >> WE ABSOLUTELY CAN MEASURE BRAIN CHANGES, FUNCTIONAL CHANGES AS IN RESPONSE TO MINDFULNESS TRAINING AND IT'S A GREAT IDEA. IN FACT, THERE HAS BEEN A LARGE STUDY SHOWING THAT A MINDFULNESS BASE INTERVENTION DURING THE RECOVERY PHASES WAS EFFECTIVE IN COMPARISON TO CBT AND 12-STEP COUNSELING, PARTICULARLY IN THE LATER PHASES OF OUR RECOVERY AND SUSTAINING RECOVERY FOR THE LONG HALL. WHEN WE'VE DONE STUDIES LOOKING IN THE BRAIN, WE'VE ACTUALLY FOUND THAT MINDFULNESS TRAINING CAN DECREASE THE LIMBIC REWARD REGION REACTIVITY. INSUL A REACTIVITY WHEN FACED WITH STRESS AS A FUNCTION OF MINDFULNESS TRAINING RELATIVE TO COGNITIVE BEHAVIORAL THERAPY. WE THINK IT ACTUALLY MAY BE HELPING NOT ONLY IMPROVING PRE FRONTAL REGIONAL ACTIVATION BUT ALSO IN DECREASING SORT OF BASAL STATE IN EMOTION REGIONS. >> GREAT. I HAVE A QUESTION AND I'M EQUALLY INTERESTED. SO, WE KNOW THAT BINGE DRINKING CAN PRODUCE ANNALGESIA BUT DURING WITHDRAWAL THERE'S HYPER ALGESIA AND INCREASED PAIN RESPONSES IN YOUR SUBJECTS. MARK AND I WOULD BE VERY INTERESTED. >> YEAH, THAT'S A GREAT IDEA, GEORGE. WE HAVE LOOKED AT THAT AND WE ARE STARTING TO SEE THAT THIS IS A SHIFT IN PAIN THRESHOLD IN THE RIGHT WITH BINGE-HEAVY DRINKING. WE'RE VERY INTERESTED IN WHAT HAPPENS IN THE LATER STAGES, WHEN YOU ARE FACED WITH A CURRENT ALCOHOL-USE DISORDER AND AS YOU POINT OUT DURING THE WITHDRAWAL PHASE. SO WE HAVE A DIFFERENT EXPERIMENTAL PARADIGM WHICH WE'RE STARTING UP AND WE'RE LOOKING AT THAT MORE SYSTEMATICALLY. VERY CLOSE IN THE FUTURE WE SHOULD HAVE SOME FINDINGS FROM THAT BUT I DON'T HAVE THE DATA TO SHOW YOU YET. >> ANOTHER QUESTION THAT HAS COME OUT IS I'M CURIOUS TOO, YOU MAY NOT HAVE GOTTEN TO ANALYZE THIS BUT ARE THERE GENDER DIFFERENCES? IT WOULD BE INTERESTING. >> THAT'S A GREAT QUESTION. WE HAVE NOT BEEN ABLE TO LOOK AT THAT YET. WE HAD ABOUT 35% OF THE SAMPLE WERE WOMEN SO WE COULD DO A PILOT ANALYSIS AND WE HAVE A SENSE THERE WOULD BE SOME SEX DIFFERENCES BUT THE SAMPLES WERE SMALL SO WE'VE NOT BEEN ABLE TO LOOK AT THAT YET. WE'RE HOPING TO DO THAT IN THE NEXT PHASE O OF THIS LINE OF WORK. >> LET'S SEE IF THERE ARE OTHER QUESTIONS HERE. DO SEX DIFFERENCES CHANGE WITH AGE? IT'S A QUESTION I HAVEN'T HEARD ASKED BEFORE. YOU MAY NOT HAVE ANY DATA ON THAT YET BUT, CERTAINLY A QUESTION FOR THE FIELD? DO SEX DIFFERENCES CHANGE WITH AGE? >> YEAH, IT'S A GOOD QUESTION. WE DON'T HAVE DATA ON THAT AND WE REALLY NEED SOME GOOD DATA. THERE ARE SOME FINDINGS OUT THERE THAT OLDER FINDINGS AS YOU KNOW AND POST MENOPAUSAL WOMEN HAVE A MAJOR SHIFT IN THEIR HORMONE STATE AND THE IMPACT ON CORTISOL THOUGH AND PARTICULARLY THE VARIATION AS WELL AS UNDER STRESS CHALLENGE AND IT'S NOT BEEN REALLY LOOKED AT PARTICULARLY IN OUR WOMEN WHO ARE EARLY RECOVERY OR IN THOSE DRINKING MORE HEAVILY VERSED LIGHT DRINKERS. ESPECIALLY AS ALCOHOL INTAKE LEVELS HAVE GONE UP SO MUCH MORE IN WOMEN COMPARED TO MEN IN THE LAST LAST DECADE. >> MY QUESTION WHICH I ASK MORE OR LESS EVERYONE, COMES FROM CATHERINE KEYS LECTURE OF OUR SERIES AND THIS SCIENTIFIC SYMPOSIUM. SHE RAISED THE QUESTION OF HOW DO WE GLOBALLY, THIS THE ADDICTION THAT EVERYBODY KNOWS ABOUT AND NO ONE WANTS TO TALK ABOUT SO, WHAT WOULD BE YOUR GLOBAL HEALTH CONTRIBUTION FROM THE WORK YOU'VE BEEN DESCRIBING, HOW WOULD YOU SEE WHAT YOU ARE DOING COULD HELP US AT NIAAA IN THAT DOMAIN? >> >> WELL, THAT'S A REALLY IMPORTANT AND A LITTLE BIT QUESTION REALLY. I WOULD THINK ON MULTIPLE LEVELS MANY OF WHICH OF COURSE YOU ARE PURSUING WE SNEED TREATMENTS AND I HOPE IT TELL TELLS US THERE'S A VARIATION. HOW WE USE THOSE NEW MEDICATION TARGETS AND IN FACT HOW WE TEST THEM COULD BECOME MORE REFINED. OUR DATA ARE SHOWING THAT WE COULD ACTUALLY REFINE THE TESTING AND DEVELOPMENT OF THAT SO IN THE TREATMENT ARENA I WANT TO DO THAT. IT REALLY OPENS UP THE WINDOWS THAT DRINKING IS PRETTY DYNAMIC, PEOPLE DRINK AT CERTAIN PERIODS SUCH AS DURING COVID OR THEY DECREASE IT. IT'S REALLY IMPORTANT TO START TO THINK ABOUT HOW WE'RE GOING TO PROTECT OUR RESILIENT CIRCUIT. ONE PREVENTION STRATEGY IS TO THINK ABOUT INTERVENTIONS LIKE MINDFULNESS, WHICH ARE COMMUNITY-BASED AS WELL AS MORE SPECIALIZED WHEN THEY'RE APPLIED TO RISK GROUPS SO THERE ARE INTERVENTIONS SUCH AS THAT AND EVEN PUBLIC-HEALTH AND HELPING PEOPLE BEGIN TO IDENTIFY WHAT IS THEIR THRESHOLD WHERE THEY FEEL LIKE THEY'RE GOING MUCH MORE HABITUALLY TO THE DRINK AS OPPOSED TO TAKING A STEP BACK FOR A MOMENT AND SAYING WAIT, IS THERE ANOTHER OPTION S. THERE ANOTHER WAY OF HANDLING THIS PARTICULAR STRESS CHALLENGE OR THIS PARTICULAR DEMAND FOR THAT NEXT DRINK? SO I THINK WE STILL NEED TO KNOW QUITE A BIT ABOUT ALCOHOL'S EFFECTS DURING THE PHASE AND PARTICULARLY HOW IT'S INTERACTING WITH THE DYNAMIC CHANGES IN THE STRESS AXIS AS A FUNCTION OF ALCOHOL. CERTAINLY IN BOTH IN THE PREVENTION AND TREATMENT ARENA, THERE'S THESE DATA REALLY SPEAK TO THAT IN TERMS OF MOVING FORWARD. >> YOUR DATA WITH THE CORTEX SPEAKS TO THIS ISSUE AND IT'S WONDERFUL IF WE COULD HAVE -- WOULDN'T IT BE WONDERFUL IF WE CAN HAVE SOME DEVIS THAT WE CAN PUT ON THE FRONT OF THE HEAD AND SAY IT'S WORKING OR IT'S NOT WORKING BECAUSE IT'S CLEARLY CORRELATING WELL WITH THE COPING RESPONSES AND THE RESILIENCE RESPONSES. I'LL NEVER BE ABLE TO PRONOUNCE THAT WORD RESILIENCE BUT I'M WORKING ON IT. WE'RE REACHING THE TIME POINT WHERE IT'S TIME TO MOVE TO NEXT PRESENTATION. SO, THEY'LL PROBABLY BE QUESTIONS COMING IN FROM THE CHATBOX WHEN THEY WORKOUT THE LIVE FEEDBACK BUTTON ISSUE. AND I'M GOING TO MOVE ON AND I'M GOING TO THANK YOU AGAIN FOR DOING THIS AND A WONDERFUL PRESENTATION AND WE REALLY APPRECIATE YOU PARTICIPATING IN THIS SYMPOSIUM. THANK YOU, AGAIN, AND CONGRATULATIONS ON A GREAT TALK. >> THANK YOU SO MUCH. >> IT'S A TIME THAT WE MOVE ON. IT'S WITH GREAT PLEASURE THAT I INTRODUCE OUR NEXT SPEAKER, DR. BARBRA MAYSON. DR. MAYSON IS PROFESSOR AND CO DIRECTOR OF THE ADDICTION RESEARCH AT THE SCRIPPS RESEARCH. SHE'S ALSO THE PRINCIPLE INVESTIGATOR FOR THE SCRIPPS RESEARCH INSTITUTE ALCOHOL RESEARCH CENTER OF EXCELLENCE AND DIRECTOR OF LAB TO BE EVE CLINICAL PSYCHO PHARMACOLOGY FOCUSING ON CLINICAL RESEARCH FOR ALCOHOL USE DISORDER AND OTHER SUBSTANCE USE DISORDERS AND YOU MIGHT WANT TO POINT THAT DR. MAYSON DID THE ORIGINAL PUBLICATION ON THE LEADER OF THE U.S. CLINICAL TRIALS AND THE APPROVAL FOR THE FDA AND SO HER TALK IS GOING TO BE LOOKING BACK AND AHEAD AND CURRENT MEDICATIONS FOR THE TREATMENT OF ALCOHOL USE DISORDER. IT'S ALL YOURS, BARBRA. >> I'M SO HONORED TO BE PARTICIPATING IN THE 50th ANNIVERSARY CELEBRATION AND BY PRESENTING TO YOU A LOOK BACK AND AN LOOK FORWARD AT MEDICATIONS FOR THE TREATMENT OF ALCOHOL USE DISORDERS AND TODAY I'M GOING TO COMPARE THE RISKS AND BENEFITS OF IMPROVED MEDICATIONS AND USE DISORDERS AND EVALUATES THE RISK AND BENEFITS OF NOVEL DRUGS AND AND TARGETS FOR THERAPEUTIC POTENTIAL AND PIPELINE. I WAS INTERESTED IN COMPARING THE PREVALENCE AND MORTALITY AND MORBIDITY OF ALCOHOL AND OPIOIDS BECAUSE WE HEAR A LOT ABOUT THE OPIOID CRISIS YET ON ANY METRICS AND USE OR MISUSE, PREVALENCE OF THE DISORDER AND THE MORBIDITY OF EMERGENCY ROOM VISITS AND MORTALITY DEATH AND THE RATES ASSOCIATED WITH ALCOHOL FAR OUTWEIGH THE RATES WITH OPIOIDS, HOWEVER, AS THE ELEPHANT SAID TO THE PSYCHIATRIST, I'M RIGHT THERE IN THE ROOM AND NO ONE EVEN ACKNOWLEDGES ME. THE GENERAL LACK OF RECOGNITION OF ALCOHOL USE DISORDER AND EFFECTS THE INDIVIDUAL AFFLICTED WITH THAT IN THAT FEWER THAN 10% ARE ESTIMATED TO GET ANY TREATMENT. THE 4% OF PATIENTS IN FDA APPROVED TREATMENT ALCOHOL DISORDER. DRUG DEVELOPMENT TO TREAT AUD HAS BEEN LARGELY IGNORED BY THE PHARMACEUTICAL INDUSTRY AND INSTEAD BE DRIVEN BY NIAAA GRANTS TO ACADEMIC SCIENTISTS AS WELL AS WORK DONE BY THEIR OWN CLINICAL AND AND RESEARCH PROGRAMS. IT HAS DIFFERENT MECHANISMS OF ACTION BUT THEY SHARE SOME KEY CHARACTERISTICS IN COMMON. THEY'VE ALL BEEN SHOWN TO HAVE BETTER DRINKING OUTCOMES WITH COUNTING AND PLACEBO WITH COUNSELING AND I SAY THAT BECAUSE THE CLINICAL TRIALS MADE FOR APPROVAL HAVE INVOLVED BEHAVIORAL COUNSELING FOR ALL THEIR PARTICIPANTS SO THE DRUGS SHOWS A BENEFIT WITH COUNSELING ABOVE AND BEYOND THAT AND SHOWN WITH COUNSELING ALONE OR WITH PLACEBO. THESE MEDICATIONS ARE TO BE USED AS PART OF A COMPREHENSIVE TREATMENT PLAN BASED ON A CHRONIC CARE MODEL THAT SUGGESTS IN THE SURGEON GENERAL'S REPORT ON ALCOHOL AND HEALTH. THEY ARE ALL A TREATMENT AS IS BEHAVIORAL COUNSELING IS NOT A CURE FOR ALCOHOL DISUSE DISORDER. THEY'RE NOT A TREATMENT FOR ALCOHOL WITHDRAWAL WHICH TAKES ITS OWN TYPE OF MEDICATION NOR THE ALCOHOL SUBSTITUTION DRUGS THAT USED FOR HEROINE. NONE OF THEM ARE ADDICTIVE OR HABIT FORMING. YOU DON'T NEED INCREASES DOSES TO ACHIEVE THE DESIRED EFFECT. STOPPING THE DRUG DOESN'T RESULT IN REBOUND DRINKING OR CRAVING TO DRINK. THEY HAVE NO STREET VALUE FOR DRUGS. YOU WON'T GET A PENNY FOR THEM. IN TERMS OF ACHIEVING FDA APPROVAL FOR A MEDICATION TO TREAT AUD, AFTER A SEM BEING AND AND TYPICALLY, YOU ARE REQUIRED TO HAVE TWO PIVOTAL TRIALS AND MULTI-CENTERED TRIALS THAT HOPEFULLY REPRESENT THE FOUR QUAD RANTS OF THE COUNTRY AND THEY'RE SIX MONTHS IN DURATION, MEDICATION GIVEN IN CONJUNCTION WITH BEHAVIORAL COUNSELING AND THE PRIMARY OUTCOMES ARE EITHER RATES OF NO DRINKING OR NO HEAVY DRINKING. AND NO HEAVY DRINKING IS DEFINED AS FOUR MORE DRINKS A DAY FOR WOMEN, FIVE OR MORE DRINKS A DAY FOR MEN. AND WHAT IS A DRINK? A DRINK IS PURE ALCOHOL. IT'S AN OUNCE AND AND A HALF OF DISTIL SPIRITS OR FIVE OUNCE OUNCES OF WINE. IT HAS A BIO CHEMICAL MEASURE AND BREATH ALLIESERS LIKE THE STATE TROOPER USES BUT THAT REALLY ONLY CAPTURES DRINKING AT THE TIME OF THE STUDY VISIT. AND ALCOHOL TIP STICK, AND THERE ARE AND IT MAY HAVE OCCURRED AMONG THREE WEEKS. PRIOR TO THE VISIT. SMARTPHONE APPS FOR REAL TIME DISTRICTING AND NON EVASIVE TRANCTRANS DETERMINEAL WRIST. THE MECHANISM OF ACTION INVOLVES THE INTERACTION BETWEEN THE DRUG AND ALCOHOL. IF YOU DRINK, WHEN DISULFIRAM IS IN YOUR SYSTEM. THE DRUG WILL INHIBIT OF METABOLISM OF ALCOHOL SO A BY-PRODUCT QUICKLY BUILDS UP WITH THE RAPID ONSET OF FLUSHING, PALPITATIONS, AND OTHER SYMPTOMS THAT CAN BECOME QUITE SEVERE AND TIMES LIFE-THREATENING. SO, IT'S MECHANISM OF ACTION HAS A PSYCHOLOGICAL DETERRENT TO ALCOHOL USE. MEDICATIONS COMPLIANCE TENDS TO BE POOR RESULTS ARE OPTIMIZED WHEN YOU HAVE A COMPLIANT PATIENT WHO REALLY WANTS TO QUIT DRINKING AND IT INVOLVED PARTNER WHO WILL SUPERVISE THE DAILY ADMINISTRATION. IT SHOULD NEVER BE GIVEN TO SOMEONE IN A STATE OF ALCOHOL INTOXICATION OR WITHOUT THEIR FULL KNOWLEDGE, BECAUSE IT WILL INDUCE THE ALCOHOL DIE SUL FIR AM IF THEY DRINK. NOW, IT WAS APPROVED IN 1984 FOR OPIOID ADDICTION AND IT IS A PURE NEW OPIOID RECEPTORS ANTAGONIST AND IT LINES TO THE RECEPTORS AND BLOCKS SOME OF THE REWARDING EFFECTS OF DRINKING AND THE HYPOTHESIS FOR USING IT IN A AUD IS THAT IF ALCOHOL CONSUMPTION IS LESS REWARDING DRINKING WILL DECREASE. AND IN FACT, META ANALYSIS OF THE MANY NALTREXONE STUDY HAS SHOWN IT DOES DECREASE HEAVY DRINKING. COMPLIANCE PROBLEMS HAVE NOTED WITH ORAL DOSING AND A ONCE-MONTHLY EXTENDED RELEASE INTRA MUSCULAR INJECTION HAS BEEN DEVELOPED TO OFFSET THE COMPLIANCE PROBLEMS. BECAUSE OF IT HAS SUCH A SPECIFIC MECHANISM OF ACTION, PEOPLE HAVE LOOKED AT GENETIC PREDICTORS A GROUP AND THE RESULTS HAVE NOT BEEN RELIABLE AND THE MOST RECENT ANALYSIS HAS CONCLUDED THIS APPROACH IS NOT AND STAY TUNED. WITH THE TREATMENT OF AUD YOU HAVE TO THAT RESULTED IN A PURPOSE FOR ALCOHOL USE DISORDER AND AS WELL AS STEPHANIE BECAUSE ALCOHOL ITSELF IS A BETTER TOXIN AND AND INDUCING ALCOHOL AND AND IMPROVE FUNCTION AND SO, YOU HAVE THE TWO DRUGS THAT WORK BY EITHER MAKING YOU SICK OR REDUCING THE REWARDING EFFECTS OF ALCOHOL SO THEY'RE VERY ORIENTED TOWARDS THE REWARDING STOPPING THE REWARDING EFFECTS OF DRINKING AND ACAMPROSATE DOESN'T BLOCK A REPLACE ALCOHOL EFFECT AND RATHER, IT BUILDS ON THE OBSERVATIONS THE HEAVY DRINKING DIS REGULATES THE AND THE INHIBIT SYSTEM AND IN THE BRAIN AND IT RESTORES HOMEY OWE HOME HOME YO STATHATIS DIS-REGULATED AND IT HAS BEEN SHOWN TO INCREASE WITH RESULTS PERSISTING FOR AS LONG AS A YEAR AFTER THE LAST DOSE OF MEDICATION. SO UNLIKE THE EARLIER DRUGS, THIS DRUG DOES SEEM TO MAKE PERSISTING CHANGES AND DO HAVE PERSISTING EFFECTS IN TERMS OF TREATING AUD. BENEFIT OF THE MORE RESTORATIVE APPROACH THAT ACAMPROSATE HAS WHICH IS SLEEP DISTURBANCES WHICH CAN BE EARLY ABSTINENCE AND TO ROW LAPSE TO DRINKING. A GROUP AT THE MAYO CLINIC HAS BEEN ACTIVE IN IDENTIFYING PREDICTORS OF SUBGROUPS OF PATIENTS HIGHLY AND CONCENTRATION SHE SHOWED THE GREATEST REDUCTION AND BASELINE AND AT THE END OF THE TREATMENT, AND ON LIKE DRUGS IT'S NOT IN THE LIVER IT'S SAFE IN PATIENTS WITH LIVER IMPAIRMENT AND IT GOES THROUGH THE KIDNEYS SO YOU CANNOT HAVE SEVERE RENAL IMPAIRMENT. THEY HAVE PRACTICE GUIDELINES FOR THE PHARMACOLOGICAL FOR PATIENTS OF MODERATE TO SEVERE ALCOHOL USE DISORDER AND PATIENTS WHO WISH TO QUIT DRINKING OR PREFER MEDICATION OR IF NOT RESPONDED TO NON-PHARMACOLOGICAL TREATMENTS AND WHO HAVE NO INDICATIONS TO THEIR USE MEDICALLY. THEY DO NOT RECOMMEND DIE SUL PROGRAM AND DRINKING. THEY RECOMMEND A ANTIDEPRESSANT MEDICATION NOT USED FOR AUD UNLESS THERE'S A CONCURRENT DISORDER FOR WHICH THESE MEDICATIONS ARE INDICATED AND THEY ARE USED TO MANAGE ACUTE ALCOHOL WITHDRAWAL AND LASTS FOR ONLY UP TO FIVE DAYS BUT BEYOND THAT TIME THERE'S NOT SUPPORT FOR ITS USE IN THE TREATMENT OF AUD BECAUSE IT ITSELF HAS ABUSED POTENTIAL AND IS CROSS TOLERANT WITH ALCOHOL. A FOURTH DRUG IS APPROVED THROUGHOUT EUROPEAN UNION. IT'S DISCOVERY FOR AUD WAS SUPPORTED BY A GRANT FROM NIAAA. IT BINDS MORE POET APTLY TO NEW DELTA AND KAPPA OPIOID RECEPTORS AND THIS IS OF INTEREST BECAUSE LIKE THE NEW RECEPTORS ASSOCIATED WITH THE REWARDING EFFECTS OF ALCOHOL, THE KAPPA RECEPTORS IS THE MISERY RECEPTORS AND STIMULATION OF THE KAPPA RECEPTORS INCREASES ANXIETY SO BY BLOCKING THAT, AT THE SAME TIME YOU ARE BLOCKING SOME OF THE REWARDING EFFECTS OF DRINKING. IT FUNCTIONS AS A PARTIAL WHERE SOME PLEASURE IS ALLOWED THROUGH BUT NOT ALCOHOL RELATED. AND IT'S GIVEN IN A DIFFERENT WAY THAN THE EARLIER DRUGS WHICH YOU HAVE TAKEN DAILY. IT'S TAKEN ONE TO TWO HOURS PRIOR TO DRINKING OCCASIONS AND IT'S BEEN SHOWN TO DECREASE HEAVY DRINKING AND STUDIES UP TO ONE YEAR IN DURATION. THE EUROPEAN MEDICINE AGENCY USED A SLIGHTLY DIFFERENT CRITERIA THAN THE FDA USES. IT STIMULATED A TWO-LEVEL REDUCTION WORLD HEALTH ORGANIZATION DRINKING RISK LEVELS AND RISK LEVELS ARE THE LARGE DATASETS THAT CAN LOOK AT REDUCTION IN DRINKING AND ASSOCIATED BENEFITS DO SUPPORT THE BROAD CLINICAL RELEVANCE OF THE FDA APPROVED OUTCOMES AND THE WHO OUTCOMES. SO, THE EARLY MEDICATIONS FOCUSED ON REDUCING THE REWARDING EFFECTS OF DRINKING. THE DISULFIRAM AND THE REWARDING EFFECTS AND I DO THINK THAT PEOPLE ARE ORIGINALLY FELT THAT PEOPLE DRANK TO FEEL REWARDED. AS WE LEARN MORE ABOUT THE NEUROBIOLOGY ABOUT THE DISORDER WE'VE COME TO APPRECIATE, RATHER THAN POSITIVE REINFORCEMENT, DRINKING, MANY PEOPLE DRINK BECAUSE OF NEGATIVE REINFORCEMENT OF DRINKING AND BY THAT I MEAN, AFTER YOU DISCONTINUE DRINKING, IT'S A STRESS IN THE BRAIN THAT HAS BECOME USED TO HAVING CHRONIC ALCOHOL PRESENT AND -- AND ALL OF THESE NEUROPEPTIDES THAT HAVE BEEN IDENTIFIED HAS BECOME DIS-REGULATED AND ASSOCIATED WITH THE SYMPTOMS OF PROTRACTED WITHDRAWAL. THEY CAN SERVE AS DRUG TARGETS TO DEVELOP NOVEL MEDICATIONS THAT INTERRUPT THE CYCLE BEFORE YOU GET INTO THE STRONG CRAVING AND BINGE INTOXICATION RELAPSE PART OF THE SICKEL. THIS IS WHERE A LOT OF WORK, IN MY LAB AT NIAAA IS TAKING PLACE. BUILDING ON WHAT WE'VE LEARNED RECENTLY ABOUT THE NEUROBIOLOGY OF ALCOHOL USE DISORDERS AND AK TAIZATION OF THE STRESS RESPONSE IN EARLY ABSTINENCE DRIVING THE CYCLE FORWARD TO RELAPSE AND SEEKING TO NORMALIZE THOSE SYSTEMS AS A WAY OF SUPPORTING RECOVERY IN A WAY THAT IS ACCEPTABLE AND RELIEVING TO PATIENTS. SO, WE DIDN'T HAVE AN FDA APPROVED DRUG THAT WE COULD WORK WITH AND USE AS A MODEL. SO, GEORGE KOOB AND I, 20 YEARS AGO, RECEIVED A GRANT FROM NIAAA TO DEVELOP PARALLEL ANIMAL AND HUMAN LO LAB MODELS RISKS OF RELAPSE AND PROTRACTED WITHDRAWAL. PULLING IN TECHNIQUES THAT EXISTED FOR OTHER PURPOSES IN THE FIELD SUCH AS EFFECTIVE PRIMING TO INDUCE SOME OF THE INTERNAL RISK FACTORS FOR RELAPSE AND NEGATIVE EFFECT OF STATES THAT WE TALKED ABOUT AND AS WELL AS EXTERNAL RISK FACTORS FOR RELAPSE, WHICH IS EXPOSURE TO YOUR FAVORITE ALCOHOLIC BEVERAGE, BOTTLE OF YOUR FAVORITE BRAND IS THERE AND IT'S IN YOUR GLASS AND IT'S UNDER YOUR NOSE. SO YOU HAVE THE WHOLE FACTORY AND VISUAL CUES. WE USE NON TREATMENT SEEKING VOLUNTEERS, MEN AND WOMEN, WITH AUD WHO ARE ABSTINENT FOR THROW THREE DAYS PRIOR TO TESTING. WE'RE GETTING THE AK TAIZATION OF THACTIVATION OFTHE STRESS RESPONSE AND IT'S TO THE DRUG UNDER STUDY THIS IS A CREANING MODEL OF MEDICATIONS FOR THOSE NOVEL DRUG TARGETS TO SEE IF THEY HAVE POTENTIAL FOR AUD AND NEED TODAY ACHIEVE STUDY STATE OR MAINTENANCE AND IT CAN BE BETWEEN ONE TO TWO WEEKS. AND THEY'RE TESTED ON THE LAST DAY OF DOSING AND WE HAVE BOTH SEC TIVE AND OBJECTIVE MEASURES OF RESPONSIVE TEE TO ALCOHOL AND WE ALSO DO EXTENSIVE SAFETY MEASURES TO WHERE THE CONTROL BOTTLED WATER ARE PRESENTED IN RANDOM ORDER FOR 90 SECONDS FOLLOWING THE MOOD INDUCTION AND THE SUBJECT IS TOLD IF YOU SMELL THE BEVERAGE FOR 90 SECONDS AND TO NOT DRINK IT, AND THEN FOR VISUAL ITEMS APPEAR ONE BY ONE ON THE FLAT SCREEN IN FRONT OF THEM AND THEY CLICK THE MOUSE ON THE LINE TO INDICATE HOW STRONG IS YOUR CRAVING. IF I COULD DRINK ALCOHOL NOW, I WOULD DRINK IT. YOU WOULD BE HARD TO TURN DOWN AND DRINK RIGHT NOW. HAVING A DRINK WOULD MAKE THINGS JUST PERFECT. THE SCALE GOES FROM 0 TO 20 WHICH IS EXTREMELY STRONG. SO THE FIRST DRUG THAT WE STUDIED, IN OUR MODELS, WAS GAB A PENTON. IT WAS AVAILABLE AND IT'S WHAT WE USED IN THE TREATMENT OF NEURO PATHIC PAIN. AND RELEVANCE FOR ALCOHOL USE DISORDER BECAUSE IT WAS ASSOCIATED WITH MAUD ULIS OF GABAERGIC ACTIVITY VIA ACTION TO VOLTAGE SYSTEMS THAT BECOME ACTIVATED IN EARLY ABSTINENCE. AND DEPRESSION, ANXIETY AND INSOMNIA AND IN FACT, THERE'S A LITERATURE AROUND GABAPENTIN BEING INFECTIVE FOR IN SOMNIA, INCLUDING ALCOHOL-RELATED INSOMNIA. IT'S NOT METABOLIZED IN THE LIVER AND HAS ACCEPTABLE SAFETY AND TOLLER ABILITY. FOR ALL THEIR BA NINE AND HELPFUL CHARACTERISTICS HAVE PEOPLE HAVE HAVE PILL TRAYS THAT TELL YOU THE DAY OF THE WEEK AND THE TIME OF THE DAY AND THEN YOU KNOW WHERE YOU ARE AT AND YOU ARE GOOD TO GO. WE RANDOMIZED OUR VOLUNTEERS TO RECEIVE SEVEN DAYS OF GABAPENTIN AND TESTED THEM ON THE LAST DAY OF DOSING. WE FOUND THAT THOSE TREATED WITH GAB APENTIN HAD SIGNIFICANTLY LESS STRENGTH OF CRAVING, A LOWER IMPULSE TO DRINK, LESS FEELINGINGS OF LOSS OF CONTROL OVER DRINKING AND THEY ALSO SHOWED BENEFITS ACROSS MULTIPLE DIMENSIONS OF SLEEP INCLUDING SLEEP EFFICIENCY, TIME IT TAKES TO FALL ASLEEP, NO COMPLAINTS AT ALL ABOUT SLEEP QUALITY RELATIVE TO PLACEBO AND WHAT IS IMPORTANT THEY DID NOT REPORT NEXT-DAY DYSFUNCTION OR INSOMNIA. WE THEN CONDUCTED A DOUBLE PLY PLACEBO IN CLINICAL DRIVE OF GABAPENTIN IN OUT PATIENTS SEEKING TREATMENT FOR AUD. WE RANDOMIZED 150 PATIENTS TO 12 WEEKS OF TREATMENT WITH EITHER A HIGH FDA APPROVED DOSE OF GABAPEN TIN AND THE LOWEST DOSE 900 MILL A GRAMS A DAY OR PLACEBO AND ALL PATIENTS RECEIVED WEEKLY ABSTINENCE ORIENTED COUNSELING OVER THE 12-WEEK TREATMENT PERIOD. AND WE FOUND OVER THE 12-WEEK TREATMENT PERIOD THAT THOSE TREATED WITH THE HIGHEST DOSE OF GAB A PEN TIN HAD LESS ROW LAPSED TO DRINKING HIGHER RATES OF COMPLETE ABSTINENCE AND RELATIVE TO PLACEBO IN GROWN WITH 900 MILLIGRAM FALLING IN BETWEEN AND SIMILARLY IN TERMS OF THE RATES OF NO HEAVY DRINKING, YOU HAVE THE HIGHEST PREPORTION OF PATIENTS JUST ABOUT HALF THE SAMPLE, REPORTING NO HEAVY DRINKING AT ALL OVER THE COURSE OF THE STUDY. ABOUT TWICE AS MANY OF THOSE TREATED WITH PLACEBO. THE 900 MILL A GRAM GROUP FALLING IN BETWEEN. WE ALSO ACHIEVED SIMILAR RESULTS FOR QUANTITY AND FREQUENCY MEASURES OF DRINKING AND IN TERMS OF THE EFFECTS OF GABAPENTIN, THE 18 MILL A GRAM DOSE WHICH IS IN PURPLE, SHOWED THE GREATEST REDUCTION IN NEGATIVE EFFECT OF SYMPTOMS, SOME HAVE DEPRESSION AND CRAVINGS AND THE ALCOHOL CRAVING QUESTIONNAIRE, THIS IS OVER THE 12-WEEK TREATMENT PERIOD AND LIKEWISE, SLEEP COMPLAINTS ON THE PITTSBURGH SLEEP QUALITY INDEX, WHICH WE SAW EARLIER IN THE LAB STUDY AS WELL. SO, THOSE FINDINGS WERE REPLICATED AND WE CONCLUDED THAT GABAPENTIN DOSE IMPROVED BOTH RATES OF COMPLETE ABSTINENCE AND NO HEAVY DRINKING AS WELL AS DRINKING QUANTITY AND FREQUENCY. WE'VE SEEN THAT TIMELINE FOLLOW BACK. WE ALSO OBTAINED SIGNIFICANT REDUCTIONS IN GGT. LIVER MARKER OF RECENT ALCOHOL USE AND A REDUCTION IN THE PROTRACTED WITHDRAWAL SYMPTOMS OF CRAVING, SLEEP DISTURBANCE AND NEGATIVE AFFECTIVE SIM OPTION. TOMORROW'S. GABAPENTIN HAD NO DRUG RELATED ADVERSE EVENTS OR EVIDENCE OF ABUSE POTENTIAL AND GABAPENTIN FOR ALCOHOL USE DISORDER, HAS BEEN. NOT ONE REPORT HAS A SIGNAL OF ABUSE POTENTIAL. THERE WAS A FORMAL STUDY SHOWING THAT GABAPENTIN DOES NOT INTERACT FROM A CO DYNAMICALLY WITH ALCOHOL BUT GABAPENTINNOIDS AS A CLASS, MAY BE ABUSED BY OPIOID ADDICTS IN WITHDRAWAL, RECREATIONAL PRESCRIPTION DRUG ABUSERS AND PRISONERS AND AND IT HAS VALUE APPARENTLY. THE RISK OF IT'S FROM A DIFFERENCE THAT GIVE IT A STRONGER ABUSE SIGNAL. THE AMERICAN PSYCHIATRIC ASSOCIATION HAS INCLUDED GABAPENTIN AND ANOTHER ANTI CONVULSE ANT IN THEIR PRACTICE GUIDELINES FOR THE PHARMACOLOGICAL TREATMENT OF PATIENTS DISORDER AND RECOMMENDING THAT GABAPENTIN OR ITS PURE CAN BE USED IN PATIENT WITH A GOAL OF DECREASING OR QUITTING DRINKING OR PREFER GABAPENTIN OR TOLERANT NOT HAVE NOT RESPONDED. AND NOW I'M GOING TO TALK ABOUT ANOTHER DRUG THAT ACTS IN THAT PHASE OF THE ALCOHOL USE DISORDERS CYCLE. PROTRACTED WITHDRAWAL AND IT'S BEEN WELL DOCUMENTED THAT HEAVY ALCOHOL USE BLUNTS AND DRIVES RELEASING FACTOR THE IS ASSOCIATED WITH THE MISS ROW OF NOT DRINKING AND MIFEPRISTON IS AVAILABLE FOR REPURCHASING AND IT'S FDA APPROVED IN CURBINGS PATIENTS AND CLINICALLY, WE HAVE HYPOTHESIZED THAT ADMINISTERING IT IN ALCOHOL USE DISORDER FOLLOWING ACUTE WITHDRAWAL MIGHT NORMALIZE THE HPA ACCESS DISREGULATION AND PROTECTING AGAINST RELAPSE DURING THE PROTRACTED WITHDRAWAL. SO, WE DID THE -- WE TESTED PATIENTS IN THE LAB MODEL OF RISK FACTORS FOR RELAPSE AND RANDOMIZING SUBJECTS TO 600 MILLIGRAMS A DAY OR MATCHED PLACEBO AND FOUND THAT NOT ONLY DID WE OBTAIN A SIGNIFICANT REDUCTION IN CRAVINGS RESPONSE TO THE ALCOHOL CUES, WE ALSO OBTAINED A SIGNIFICANT REDUCTION IN DRINKING BOTH DURING THE WEEK ON DRUG AND IN THE WEEK OFF DRUG. WE OBTAINED A BASELINE IN GGT THE MARKER OF LIVER FUNCTION THAT IS SENSITIVE TO ALCOHOL INTAKE AND IN ALTNAST AS WELL. OTHER LIVER FUNCTIONS MARKERS. AND THE CLINICAL STUDIES OF TOGETHER SHOWED REDUCTION IN CRAVINGS, DRINKING AND LIVER FUNCTION TEST VALUES RELATIVE TO PLACEBO SUGGESTING THERAPEUTIC POTENTIAL FOR AUD AND THEY WERE WELL TOLERATE REQUESTED NO TOLERATE WITH NON-COMPLIANCE REBOUND FOLLOWING DRUG DISCONTINUATION IN OUR SAMPLES OF PATIENTS WITH AUD. AND THESE FINDINGS PROVIDE CLINICAL VALIDATION OF EARLIER PRE CLINICAL STUDIES AND THE ANIMAL MODEL PROTRACTED WITHDRAWALS SHOWING THESE DRUGS SEEKING IT AND THEY LEND SUPPORT TO THE ROLE OF DRUGS, THE TARGET, ABSTINENCE RELATED TO REGULATION AND STRESS SYSTEMS AS A NOVEL TREATMENT APPROACH FOR AUD AND THEY MAY REDUCE THE NEGATIVE EFFECT IN INSOMNIA OF EARLY ABSTINENCE AND INCREASE MEDICATION ADHERENCE AND REDUCE THE NOT DRINKING IN EARLY ABSTINENCE. SO, IN ADDITION TO THE WORK OF MY EXTERNAL INVESTIGATORS, LARGELY FUNDED BY NIAAA, AND NIAAA ITSELF HAS AN ACTIVE RESEARCH PROGRAM. THE CLINICAL INVESTIGATIONS GROUP CONDUCTS MULTI-CENTERED TRIALS THAT HAVE SHOWN POSITIVE RESULTS FOR DRUGS WORKING BETTER RELEVANT TO PROTRACTED ABSTINENCE AND A ANTAGONIST AND NIAAA INTERMURAL RESEARCH PROGRAM HAS BEEN ACTIVE ALSO IN STUDY MOLECULES THAT MAY BE RELEVANT TO TREATING PROTRACTED ABSTINENCE WITH LORENZO'S TEAM LOOKING AT GHRELIN ROW SCEPTER ANTAGONIST AND MINERALOCOURTICOID AND LOOKING AT A MOLECULE THAT MAY SHOW EFFICACY FOR BOTH ALCOHOL USE DISORDER AND ALCOHOL ASSOCIATED DELIVER DISEASE. SO THIS GIVES YOU JUST A SENSE OF AND IF I HAVE A WISH LIST FOR MEDICATIONS IN THE FUTURE TO TREAT AUD I WOULD LOOK FOR SMALL MOLECULES THAT CAN CROSS THE BLOOD BRAIN BARRIER AND TARGET THE BRAIN REGIONS AND SYSTEMS THAT WE'VE IDENTIFIED AS BECOMING DIS-REGULATED IN A WAY THAT RELEVANT TO TREATING AUD. THE MOLECULES HAVE TO EITHER HAVE AN IND OR A WAIVER OF AN IND FROM THE FDA IN ORDER TO BE PERMITTED TO STUDY. DRUGS IN HUMANS, THROUGH THE TREATMENT OF AUD, THEY SHOULD NOT HAVE ABUSE POTENTIAL NOR THIS SHE INTERACT WITH ALCOHOL BECAUSE THERE'S ALWAYS A RISK OF RELAPSE. SUCH THAT ALERTNESS AND MOTOR COORDINATION BECOMES EVEN MORE IMPAIRED IN THE DRUG IS ON BOARD. IT WOULD BE WITH ALCOHOL ALONE. THE DRUG SHOULD HAVE A GOOD SAFETY PROFILE, NO MORE TOXICITY AND GOOD TOLERABILITY AND ADVERSE EVENTS AND BEING TYPICALLY MILD TO MODERATE AND NOT ASSOCIATED WITH DROPPING OUT OF TREATMENT AND THE MEDICATION SHOULD HAVE GOOD PATIENT ACCEPTABILITY IN TERMS OF ROOT OF ADMINISTRATION WHICH IS TYPICALLY ORAL AND THE DOSING REGIMENT THAT IS ACCEPTABLE TO THE PATIENT AND ADAPTIVE TO THEIR LIFESTYLE. I WANT TO POINT OUT THERE CAN BE SEX DIFFERENCES IN DRUG METABOLISM AND DIFFERENCES IN DRUG METABOLISM DUE TO ETHNICITY. WE'RE FAMILIAR WITH THE FLUSHING RESPONSE. CONSEQUENTLY, THESE DIFFERENCES IN DRUG METABOLISM MAY HAVE EFFECTS AND DRUG EFFICACY OR SAFETY AND THAT IS WHY IT'S SO IMPORTANT THAT WE HAVE ADEQUATE REPRESENTATION OF MINORITIES IN WOMEN AND CLINICAL TRIALS OF MEDICATIONS TO TREAT AUD AND ALL NEW MEDICATIONS AND VACCINES. DISULFIRAM HAVE NOT SYSTEMATIC STUDIES OF DIFFERENCES FOR MEN AND WOMEN ALTHOUGH, VIVIDEL TROLL DOES NOT EFFECT THE KEN ETICS. THE LONG ACTING FORMULATION OF NALTREXONE HE. BUT ONLY MEN RESPONDED AND THE PIVOTAL TRIAL, NOT WOMEN. THEY DON'T THINK THAT'S BEEN ADEQUATELY UNDERSTOOD. THEACAMPROSATE HAS BEEN IN A SEX SPECIFIC META ANALYSIS OF INDIVIDUAL RECORDS OBTAINED FROM 1300 WOMEN AND 4,000 MEN WHO PARTICIPATED IN 22ACAMPROSATE CLINICAL TRIALS AND THEY FOUND A SIGNIFICANT EFFECT TO PLACEBO AND BOTH RATES OF ABSTINENCE AND NO HEAVY DRINKING AND EFFECT SIZES DID NOT DIFFER BETWEEN MEN AND WOMEN. AND THE SIDE EFFECT AND TOLERABILITY PROFILE INCLUDING THE NUMBER, TYPE AND SEVERITY OF ADVERSE EFFECTS DID NOT DIFFER BETWEEN MEN AND WOMEN. AND ANOTHER FINDING OF THIS STUDY THAT I DO WANT TO POINT OUT IS THAT DESPITE A HISTORY OF SIGNIFICANTLY MORE ANXIETY, DEPRESSION, SUICIDE ATTEMPTS, DRUG ABUSE, INTERPERSONAL LOSS, GREATER LIVER IMPAIRMENT AT BASELINE, THEN MEN, WOMEN RESPONDED WELL TO AUD TREATMENT. IN TERMS OF THE USE OF THE MEDICATIONS TO TREAT AUD ACROSS THE LIFESPAN, IT IS NEVER TOO EARLY OR TOO LATE TO TREAT AUD. DRINKING IS ILLEGAL UNDER THE AGE OF 21 IN THE U.S. SO, MOST OF ALCOHOL MISUSE BUT THERE ARE CASES OF ALCOHOL USE DISORDERS THAT ARE SIGNIFICANT IN SOME TEENS AND THERE HAVE BEEN TWO SMALL DOUBLE BLIND PLACEBO CONTROL TRIALS IN TEENS THAT FOUND GOOD TOLERABILITY AND HIGHER RATES OF ABSTINENCE WITH THE RELATIVE TO PLACEBO AND? TERMS OF PEOPLE OVER THE AGE OF 65, THEY HAVE BEEN INCLUDED IN SOME TRIALS OF DISULFIRAM BUT NOT IN SUFFICIENT NUMBERS TO ANALYZE DIFFERENCES IN SAFETY AND ADVOCACY FROM YOUNGER PATIENTS. YOU KNOW, BASICALLY, YOU MAY NEED CLOSER MONITORING IF AN OLDER PERSON IS AT INCREASED RISK FOR LIVER OR CARDIAC PROBLEMS TO TREAT DISORDERS BUT UNLESS THERE'S SOME MEDICAL CONTRA INDICATION, ALCOHOL USE DISORDER IS VERY SERIOUS AND THE OLDER POPULATION FOR ALL THE USUAL REASONS PLUS RISKS OF FALLS, ET CETERA. SO NIAAA HAS CREATED A TREATMENT ADVOCATOR WEBSITE TO HELP PEOPLE FIND PRACTITIONERS IN THEIR AREAS THAT PROVIDE EVIDENCE-BASED TREATMENTS WHETHER IT'S BEHAVIORAL OR FORM LOGICAL FOR AUD AND CONTAINS A LOT OF INFORMATION ABOUT ALCOHOL USE DISORDER AND AS WELL AS ABOUT TREATMENT. I'D LIKE TO END BY ACKNOWLEDGING THE SUPPORT THAT NIAAA HAS PROVIDED FOR MY WORK, BOTH IN TERMS OF MEDICATION DEVELOPMENT AND MODEL DEVELOPMENT AND HAVE PROTRACTED ABSTINENCE AND I WOULD LIKE TO SAY A WHOLEHEARTED THANK YOU AND CONGRATULATION TO NIAAA ON THEIR 50th 50th ANNIVERSARY WITH BEST WISHES FOR MANY MORE E EXCITING ADVANCE AND THE TREATMENT OF ALCOHOL USE DISORDER IN YEARS TO COME. THANK YOU, VERY MUCH. >> SO, THANK YOU. AND IT'S NOW TIME FOR QUESTIONS. AND SO, I JUST WANT TO SAY AND MAKE ONE ANNOUNCEMENT BEFORE THE QUESTIONS WHICH IS AND FEEDBACK AND THE BUTTON IS UP AND RUNNING. FOR THOSE OF YOU WHO HAD QUESTIONS ABOUT DR. SINHA, SEND THEM ON BECAUSE WE'LL SEND THEM ON TO DR. SINHA. WE'RE OPEN FOR QUESTIONS FOR DR. MASON, WE 'LL LEAD OFF WITH THE FIRST QUESTION WHICH IS, WHAT ARE THE MAIN CHALLENGES IN DEVELOPING MEDICATIONS FOR AUD? WHY IS THE SUCCESS RATES SO LOW? HOW CAN WE OVERCOME THESE CHALLENGES AND WHY HAVE WE NOT BEEN SUCCESSFUL IN DOING SO? SO DR. MASON. >> VERY IMPORTANT QUESTION. WELL, AS WE'VE SEEN, IN THE HUNT FOR A COVID-19 VACCINE, BIG PHARMA IS DRAWN TO FOLLOWING THE MONEY AND WILL COMPETE VIGOROUSLY WHERE THEY BELIEVE A BIG NEED EXIST SO AND ANTIDEPRESSANT TO TREAT AND CLONES AND CLONES AND CLONES SO WHY NOT ALCOHOL USE DISORDER WHICH IS NATION WIDE SURVEY HAS SHOWN THEY DON'T HAVE THE FDA AND OTHER APPLICATIONS THAT PHYSICIANS AT LARGE WOULD BE FAMILIAR WITH SO THEY'RE SILOED AND AND THAT MAY BE ONE OF THE REASONS WHY THE FDA APPROVED MEDICATIONS FOR THE APA RECOMMENDED MEDICATIONS HAVE NOT BEEN WIDELY IMPLEMENTED THROUGHOUT AND DESPITE PRIMARY KING AND AND THE SURGEON GENERAL'S REPORT ON ALCOHOL AND HEALTH AND SUGGESTED THAT ALCOHOL USE DISORDER LIKE AND MEDICAL CONDITION WHERE IT'S IDENTIFIED IN THE CHART WHEN THE DIAGNOSIS WAS MADE AND THE I NOTED COMPROMISED LIVER FUNCTIONING AND JOB LOSS, ET CETERA AND THE TREATMENT PLAN DEVELOPED AND THE PATIENT FOLLOWED FOR ADHERENCE TO THE TREATMENT PLAN REACHING RISK OF RELAPSE AT EVERY SUBSEQUENT VISIT THAT THIS WOULD BE STIMULATED BY NOTATION IN THE NOW ELECTRONIC RECORD AND HOWEVER, BECAUSE THE MEDICATION DEVELOPMENT FEE HAS NOT BEEN A FOCUS FOR BIG AND THIS IS BEEN PICKED UP BY THE ACADEMIC RESEARCH COMMUNITY AND I REALLY WANT TO GIVE A SHOUT OUT TO RAY UNTIL AND I'M SHOWED THEIR SIGN I HAVE I CAN WORK AND OF IN THE PREVIOUS SLIDE WITH THE ANTAGONIST AND THE TREATMENT OF AUD BUT THEY HAVE RECEIVED AS THE PROGRAM OFFICER FOR THE MEDICATION DEVELOPMENT STUDIES CONDUCTED IN ACADEMIA FOR DECADES AND THEY HAVE WRITTEN COUNTLESS REVIEWS AND PROGRAM ANNOUNCEMENTS AND WORKS VERY HARD TO DEVELOP FUNDING MECHANISMS TO OVERCOME THE OBSTACLES AND BRING A MOLECULE FROM THE LAB TO THE BEDSIDE AND THAT ARE NOT INVOLVED. THEY ARE WORKED WITH SISTER AGENCIES LIKE THE DIVISION OF THE FDA THAT IS INVOLVED IN APPROVAL OF AUD MEDICATIONS AND THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES TO GAIN ACCESS TO NEW MOLECULES AND THEY MIGHT HAVE THERAPEUTIC POTENTIAL FOR AUD FOR ALCOHOL USE DISORDERS AND THE THAT YOU SAID ARE SO THIS GREAT DEAL DEAL OF WORK ON GOING AND I HAVE GREAT OPTIMISM AND IT'S IMPORTANT THAT BASIC SCIENTISTS AND CLINICAL RESEARCHERS IN HUMAN STUDIES AND I TOLD YOU MY WISH LIST FOR NOVEL MEDICATIONS AND THE WORK THAT'S GOING FORWARD TO USE THE SEND LIVE FEEDBACK LINK BUTTON YOU MAY HAVE TO REFRESH YOUR BROWSER AND I'VE BEEN TOLD THAT WE DO HAVE A MESSAGE FROM MUHAMMAD AKBAR. ARE THERE ANY COMPARABLE STUDIES TO DATE. IN TERMS OF POTENTIAL IT'S MORE POTENT AND I DON'T KNOW HOW IT WOULD STACK UP RELATIVE TO THE GABAPENTINNOIDS. >> SO FOR ANOTHER QUESTION HERE, MODELS HELP GUIDE THE IDENTIFICATION OF PHARMACOLOGICAL TARGETS FOR THE AUD LOST I LOST IN TRANSLATION OCCURS WHEN CLINICAL STUDY THAT'S SLOW THE RESEARCH PROCESS TO INFORM TREATMENT FOR AUD. A BETTER UNDERSTANDING TO PRE CLINICAL RESEARCHERS HOW TO MAKE ROBUST MODELS OF ALCOHOL USE, MISUSE AND ALCOHOL USE DISORDER AS WELL AS CO OCCURRING DISORDERS TO HELP WITH TRANCATION. >> THAT'S A VERY IMPORTANT QUESTION AND ONE THAT I'VE BEEN INVOLVED IN IN A NUMBER OF YEARS THAT'S A MEMBER OF THE CONSORTIUM WHERE I PROVIDE PROOF OF CONCEPT OR MOLECULES THAT IDENTIFIED BY BASIC RESEARCHERS AS HAVING THEIR SPEED US I CAN PO CONTINUE FO -- ASPART OF SCRIPPS ALCOHO L CENTER GRANT THE P60, FROM NIAAA WHERE WE HAVE TRANSLATE PRE CLINICAL TO MOVE DRUG FORWARD AND WE'VE LEARNED IMPORTANT LESSONS ABOUT DOSE EQUIVALENCE LIKE I MENTIONED TO YOU, BECAUSE OF THE WAY WE WORK TOGETHER AND I PROVIDE THE CLINICAL PROOF OF CONCEPT AND IT'S NOT JUST ME AND IN MY SETTING IT IS BUT, YOU KNOW, THERE ARE CENTERS ALL OVER THE WORLD DOING THIS. THE CLINICAL WORK PROVIDES BACK CHECK ON THE PRE CLINICAL MODELS SO WE'RE ALWAYS LOOKING FOR THAT CONCORDANCE AND WE FOUND THAT IN THE WORK IN THE WORK THAT I PRESENTED TO YOU, THAT CLINICAL WORK WAS ALSO VERIFIED IN MODEL MODELS. >> SO, AARON WILLIAMS ASKS, ANY RESEARCH ON THE BENEFITS OF USING APPROVED MEDICATIONS IN COMBINATION WITH EACH OTHER? >> YES, THERE HAVE BEEN STUDIES AND THE RESULTS ARE MIXED. SOME STUDIES HAVE FOUND A BENEFIT OF COMBINING DISULFIRAM AND IT WAS FOUND A BENEFIT OF COMBINING DRUGS AND A LARGE MULTI CENTER TRIAL DID NOT FIND TREATMENT EFFECTS AND THIS IS A QUESTION THAT'S STILL HAS TO BE ANSWERED BY THE TREATMENT PROVIDER AND ASSESSING WHETHER A RESPONSE TO ONE MEDICATION HAS RATHER THAN TAKING THE PERSON OFF THE MEDICATION BECAUSE THEY HAVE BENEFITS FROM THAT SO IT'S KIND OF TILL THINKING ABOUT THE MEDICAL CONDITION AND THE PROS AND CONS YOU START WITH AN ADD ON AND. >> WELL, THERE'S CERTAINLY INTEREST IN DOING SO. THERE ARE SOME PROBLEMS WITH THE MOLECULE HAVING A VERY, VERY LONG HALF LIFE AND TO MY KNOWLEDGE, THEY'RE NOT AVAILABLE AND I DO BELIEVE THAT THAT IS AN AREA OF INVESTIGATIONS THANK YOU FOR THE GREAT INFORMATION. IT SEEMS THAT WE OFTEN TIMES FOCUS ON ANTAGONIZING THE STRESS SYSTEM AND ANTAGONIST CRF FOR THE DARK SIDE TREATMENT ARE YOU AND AND ANTAGONIZE AND AND MAYBE COMBINING THE ANTAGONIST PLUS OXYTOCIN. >> THAT'S A VERY FORWARD-THINKING QUESTION. AND IT'S A GREAT HYPOTHESIS TO INVESTIGATE. ONE PROBLEM THAT WE HAVE IN CLINICAL RESEARCH IS THE BACK OF AVAILABILITY COMPOUNDS AND BASICALLY WE NEED AN ACCESS TO AN INVESTIGATIONAL COMPOUND FROM A PHARMACEUTICAL COMPANY THAT HAS AN IND THAT WE CAN CROSS REFERENCE AND OR IMPROVED DRUG FOR ANOTHER END INDICATION THAT WE CAN REPURPOSE AND THERE ARE NO ANTAGONIST APPROVED AND I HAVE NOT BEEN SUCCESSFUL NOT FOR LACK OF TRYING TO GAIN ACCESS TO AN INVESTIGATIONAL CRF ANTAGONIST TO DO THE KIND OF WORK YOU PROPOSED SO, IT'S WHERE WE'RE AT. >> VERY GOOD QUESTION. SO, FROM SHALU, I OFTEN USE THEM IN CONJUNCTION FOR LET ME START OFF. I OVER IT IN CONJUNCTION FOR ANTI CRAVING EFFECTS AND POST ACUTE WITHDRAWAL IS THERE ANY EVIDENCE USING TWO ANTI MEDICATIONS AT ONES FOR INCREASED EFFICACY? >> IN CHRONIC WHAT? >> IN CHRONICALLY LAPSES? >> INTERESTING. I KNOW THE GUIDANCE SAYS TO NOT BEGIN WITH POLICY PHARMACY BUT TO BEGIN WITH COLLECTING ONE MEDICATION AND CONSULTATION WITH THE PATIENT GOING OVER THE PROS AND CONS BECAUSE IT'S BEEN SHOWN WHEN THE PATIENT HAS INPUT INTO THE CHOICES OF MEDICATION, COMPLIANCE AND OUTCOME TEND TO BE SOMEWHAT OPTIMIZED AND SO, GIVEN THAT YOU KNOW THE PATIENT AND KNOW THEIR CHRONICALLY LAPSERS, YOU MIGHT WANT TO PROPOSE AND THE RISKS AND ROW LAPSED DRINKING OCCURS AND THERE IS A LITERATURE ABOUT MOST EVERY MEDICATION USED IN COMBINATION AND SO I THINK THAT YOU CAN HAVE THE SUPPORT OF THE LITERATURE AND GOING INTO THAT WITH THE QUESTION. >> THIS IS OUR LAST QUESTION AND YOU HAVE TO STOP BUT YOU CAN CONTINUE TO SEND YOUR QUESTIONS FOR ALL THE SPEAKERS AND WE WILL SEND THEM ONTO THE SPEAKERS. WE PROMISE. OK, I NOTICED YOU MENTIONED BIOCHEMICAL TESTING VERIFICATION AND YOU DIDN'T SEE PETH ON THE LIST. ARE CURRENT PHARMACEUTICAL THERAPY TRIALS USING THIS ASSAY AS AN OUTCOME? >> I BELIEVE THAT THE TRIALS MAY BE USING THIS OUT M I TRIED TO KEEP MY TALK ABOUT WHAT WOULD BE AVAILABLE TO PEOPLE USING LAB CORE OR COMMONLY AVAILABLE AND TESTING. F IS STILL REQUIRED A SPECIALIZED AUDITORY AND IT'S A WORTH WILE BIOMARKER RELAPSE TO ALCOHOL USE AND STUDIES ASK. >> THANK YOU FOR A GREAT TALK AND QUESTION SESSION. WE ARE NOW GOING TO TAKE A 10-MINUTE BREAK. I WANT TO THANK OUR SPEAKERS. WE HAVE TWO MORE GREAT TALKS COMING UP IN THE AFTERNOON SO WE'LL SEE YOU ABOUT IN MINUTES. >> THIS PRESENTATION TODAY IS FOR THAL ALCOHOL SPECTRUM DISORDERS AWARENESS TO IN SIGHT IN 50 YEARS. FOLLOWING HIS PRESENTATION BEING WE'LL RETURN FOR OUT QUESTION AND ANSWER SESSION WITH DR. CHARNESS. GOOD AFTERNOON. MY NAME IS MICHAEL CHARNESS AND I'M DELIGHTED TO BE HERE TO HELP CELEBRATE NIAAA'S 50th 50th ANNIVERSARY. THIS IS THE RIGHT DISORDER TO TALK ABOUT BECAUSE IT DIDN'T REALLY COME TO RECOGNIZE MISSION UNTIL THIS IS A SURPRISING HISTORICAL NOTE BECAUSE ALCOHOL HAS WITH THIS SINCE ANTIQUITY AND THE REAL RECOGNITION OF FETAL ALCOHOL SYNDROME IS THE INITIAL SYNDROME IS PART OF FETAL ALCOHOL SPECTRUM DISORDERS IS REALLY QUITE RECENT AND WITHIN NIAAA'S HALF CENTURY. YOU CAN SEE THREE PAPERS PHOTOGRAPHED. TWO IN ENGLISH AND ONE IN FRENCH. IN FACT, THE FIRST REAL DESCRIPTION OF FETAL ALCOHOL SYNDROME WAS BY LEMOINE AND IT WAS PUBLISHED AND NOT KNOWN TO READERS OF THE ENGLISH LANGUAGE LITERATURE UNTIL 1973 WHEN THERE WERE TWO PAPERS IN THE LANCE ET, WITHIN BY DEN JONES AND SMITH AND REALLY DESCRIBED FETAL ALCOHOL SYNDROME CLOSE TO HOW WE RECOGNIZE IT TODAY. HERE WE HAVE A DISORDER THAT SHOULD BE RECOGNIZABLE AND YET HAS NOT COME TO OUR ATTENTION UNTIL THE LAST HALF CENTURY AND WHAT IS REMARKABLE ABOUT THIS IS WE CAN FOLLOW THE DISCOVERY AND AWARENESS OF FETAL ALCOHOL SYNDROME TO OUR CURRENT STATE OVER THE ENTIRE LIFE OF NIAAA AND IN FACT, NIAAA HAS PLAYED THE LEAD ROLE IN FUNDING RESEARCH THAT HAS OPENED OUR EYES TO A DISORDER. SO, WE WANT TO GO BACK IN TIME TO THE LONDON EPIDEMIC 1690 TO 1752. THIS WAS ONE OF THE FIRST RECORDED INDICATIONS THAT ALCOHOL COULD ADVERSELY EFFECT THE FETUS. THERE WERE CHANGES AND TAX LAWS THAT MADE BEGIN CHEAP AND THERE WAS AN INCREASE IN DRINKING AND THE WOOD CUT OVER THE CORNER HERE IS A WOMAN ADMINISTERING BEGIGIN TO HER BABY. HOPEFULLY THINGS WERE NOT THIS BAD. SOMEWHERE AROUND 1725, THE LONDON COLLEGE OF PHYSICIANS PETITIONS THE HOUSE OF COMMONS TO REIMPOSE THE TAX AND THEY WERE OBSERVING AN INCREASE IN WEAK FEEBLE AND DIS TEMPERED CHILDREN. WE TODAY BY BY RESEARCH, MUCH OF IT FUNDED BY NIA, IT CAUSES BIRTH DEFECTS AND COGNITIVE BEHAVIOR IN MEDICAL DIS A LOTS THAT MANIFEST DIFFERENTLY ACROSS THE LIFESPAN AND THIS IS A PICTURE OF FOUR CHILDREN OF DIFFERENT RACES AND ETHNICITY WHO ALL SHOW COMMON FACIAL CHARACTERISTICS OF FETAL ALCOHOL SYNDROME AND I'LL SHOW YOU IN A LITTLE BIT MORE DETAIL A THIN UMER LIP, A SMOOTH NASAL FILTER AND SOMETHING YOU MAY NOT SEE BUT SHORT FISHERS. NOW, THERE'S NOT A SINGLE DIAGNOSTIC TEST AND PEOPLE IN DIFFERENT PLACES IN THE UNITED STATES AND DIFFERENT COUNTRIES IN THE WORLD HAVE APPROACHED THE DIAGNOSIS OF FETAL ALCOHOL SYNDROMES USING DIFFERENT FRAMES WORKS AND I'M NOT GOING TO DWELL MUCH ON THESE DIFFERENCES EXCEPT TO SAY THAT NIAAA IS CURRENTLY FACILITATING AN EFFORT TO TRY TO UNIFY AT LEAST THE RESEARCH CLASSIFICATION OF FETAL ALCOHOL DISORDERS. I WILL SHOW YOU ONE OF THE FRAMEWORKS AS AN EXAMPLE AND THIS WAS PUBLISHED BY COLLEAGUES IN PEDIATRICS IN 2016. THIS IS FETAL ALCOHOL SYNDROME ITSELF WHICH IS WITH OR WITHOUT ETHANOL EXPOSURE AND THE REASON FOR THAT IS AGAIN THAT THE FACIAL FEATURES THAT YOU SEE HERE AND IN UPPER LEVELS AND SMALL FISHERS AND IT WAS CONSIDERED SUFFICIENTLY SPECIFIC TO ALLOW A DIAGNOSIS IN THE ABSENCE OF A HISTORY OF ALCOHOL EXPOSURE AND I HAVE POINTED OUT THE SPECIFIC PATTERN OF MINOR FACIAL ANOMALIES AND WOOZY BRIEF OR POST SEE FISH TEE AND THERE'S EVIDENCE CENTRAL NERVOUS SYSTEM DYSFUNCTION AND IT'S STRUCTURAL BRAIN ABNORMALITY AND HEAD CIRCUMFERENCE OR SEIZURES. THE MOST DISABLING ASPECT OF THIS DISORDER IS THE NEURO BEHAVIOURAL IMPAIRMENT. NEURO COGNITIVE AND THESE ARE THE ELEMENTS OF FETAL ALCOHOL SYNDROME. ONCE AGAIN, THESE ARE THE FACIAL FEATURES ILLUSTRATED HERE AND IN LIGHTER FONT, THERE ARE SOME OTHER MINOR FACIAL ADD NORMAL TEASE AND THESE ARE A SUBJECT OF ON GOING RESEARCH TO SEE IF WE CAN UNDER IN THE ABSENCE OF THESE CLASSIC AND DEFINING FACIAL ABNORMALITIES, WHETHER FOR EXAMPLE, A FLAT MID-FACED AND SHORT NOSE, LOW NASAL BRIDGE AND MINOR ANOMALIES AND COULD WE BROUGHT TO BEAR IN THE DIAGNOSIS OF CHILDREN WHO ARE HAVING NEURO COGNITIVE ABNORMALITIES AND BEHAVIORAL DYSFUNCTION AND A CONSEQUENCE OF PRE-NATAL EXPOSURE. IT TOOK A LONG TIME FOR THE IDEA TO TAKE THAT ALCOHOL ITSELF WAS A AND IT WAS THIS CLASSIC PAPER BY KATHY AND PUBLISHED IN SCIENCE IN 1981 THAT MADE CLEAR THAT A SINGLE EXPOSURE TO ALCOHOL AT A PARTICULAR MOMENT IN GESTATION COULD LEAD TO ABNORMALITIES THAT MIRRORED CLOSELY TO THE FACIAL AND BRAIN AN NOMLIES THAT ARE OBSERVED IN CHILDREN WITH FETAL ALCOHOL SYNDROME. SO, HERE YOU SEE A CONTROL MOUSE FETUS, A MOUSE EXPOSED TO ALCOHOL AT DAY SEVEN OF GESTATION AND THE EYES ARE SMALLER, AND THAT THE AREA OF THE UPPER LIP IS LESS WELL DEVELOPED AND THE AREA IS DIFFERENT IN THE PRE-NATALLY EXPOSED MOUSE EMBRYO TO THE CONTROL MOUSE FETUS. THERE WERE A NUMBER OF REALIZATIONS THAT CAME ABOUT AS A RESULT OF DR. SULIK'S SEMINAL PAPER. ALCOHOL ALONE IS RESPONSIBLE FOR THE DEFINING FACIAL FEATURES OF FETAL ALCOHOL SYNDROME AND SECOND, THAT A SINGLE EXPOSURE IN A BINGE-DRINKING MODEL, COULD PRODUCE THE FETAL ALCOHOL SYNDROME PHENOTYPE. THIRD, THEY BEGAN IN THIS PAPER TO IDENTIFY SOME OF THE MECHANISM THAT'S WERE RESPONSIBLE FOR ALCOHOL'S EFFECTS ON FETAL DEVELOPMENT INCLUDING DISRUPTION OF DEVELOPMENT OF THE NEURO PLATE AND ITS DERIVATIVES WHICH ARE VERY IMPORTANT IN ULTIMATELY THE DEVELOPMENT TO THE FACE. I WANT TO READ TO YOU FOR THE CONCLUSION OF THIS PAPER BECAUSE IN SO MANY WAYS IT WAS IN SIGHTMENT AND IN CONCLUSION, ETHANOL, ONE OF THE HERITAGE HAS A IMAGINE OFFERING IN THE MOUSE IN HUMAN GESTATION AND MANY WOMEN ARE NOT AWARE OF THEIR PREGNANCY AT THIS STAGE AND THEY ARE RESPONSIBLE FOR SOME OF THE BEHAVIOR ABNORMALITIES AND LACK OF INHIBITION AND IMPAIRED LEARNING AND IMPAIRED HABITUATION ANHABITUATION. PEOPLE WHO ARE EXPOSES TO ALCOHOL SOMETIMES GROW UP IN CHAOTIC HOUSEHOLDS AND EXPOSED TO OTHER DRUGS IN PREGNANCY AND NICOTINE IN PARTICULAR AND HOW DOES ONE SEPARATE OUT THE EFFECTS OF ALL OF THOSE DIFFERENT CONDITIONS? RECOGNIZING ALL MODELS ARE BAD AND SOME ARE USEFUL THAT SOME OF THESE VERY SAME ABNORMALITIES CAN BE PRODUCED SO, I WANT TO GO BACK TO KATHY'S MODEL AND MAKE AN IMPORTANT POINT. WHICH IS THAT DAY SEVEN IN THE HOUSE, THE POINT IN THE MOUSE'S DEVELOPMENT WHEN THE EXPOSURE PRODUCES FETAL ALCOHOL SYNDROME CORRESPONDS TO DAY 17 IN HUMAN DEVELOPMENT AND DAY 17 IS JUST AND SO IF WOMEN ARE DRINKING AND NOT TRYING TO CONCEIVED, THIS IS A MOMENT WHEN FETAL ALCOHOL SYNDROME MAY OCCUR. IMPORTANTLY, IT IS THIS COINCIDENTAL HAPPENNEN DISTANCE OF ALCOHOL EXPOSURE AT DAY 17 THAT RESULTS IN THE SPECIFIC FACIAL ABNORMALITIES THAT ALLOW US TO RECOGNIZE FETAL ALCOHOL SYNDROME. AND OF COURSE, THERE MAY BE ALCOHOLIC EXPOSURE AT OTHER DAYS OF PREGNANCY AND THEY WILL NOT FETAL ALCOHOL SYNDROME IS A CONSEQUENCE OF OBSERVING A SPECIFIC PATTERN OF FACIAL ANOMALIES AT A SPECIFIC MOMENT IN FETAL DEVELOPMENT. SO, I MENTIONED THAT THE SENSITIVITY IN DEVELOPMENT AT EARLY STAGES OF DEVELOPMENT OF THE FETUS ALCOHOL AND IT'S IMPORTANT TO CONSIDER WHAT WE KNOW THEY WILL ACKNOWLEDGE ALCOHOL USE IN ALMOST 20% PEOPLE 3% BINGE DRINK AND 10% ACKNOWLEDGE ANY USE. WE KNOW THAT ALCOHOL FREELY CROSSED THE PLACENTA AND THE EMBRYO IS EXPOSED TO THE SAME LEVELS AS THE MOTHER. 64060% OF WOMEN WHO DRINK DO NOT RECOGNIZE THEIR PREGNANCY AFTER THE FOURTH WEEK AND THIS MOST SENSITIVE POINT IN FACIAL FEATURES, AND IT'S EARLIER THAN THE FOURTH WEEK AND THE ADVERSE EFFECTS OF FREE NATAL ALCOHOL CAN OCCUR BEFORE WOMEN KNOW SHE'S PREGNANT AND IF THERE ARE CONSEQUENCE TO THE FETAL, ON DAY 17, OR AT THIS STAGE THAT RESULTED IN THIS VERY RECOGNIZABLE FETAL ALCOHOL SYNDROME, THEN, WHAT ABOUT ALL OF THE EXPOSURES AND OTHER TIMES THAT DON'T INTRODUCE THIS AND IT'S RECOGNIZING FETAL ALCOHOL SYNDROME TO PARTIAL MEETAL ALCOHOL SYNDROME AND SOMETHING THAT SOME CALL ALCOHOL RELATED NEURO DEVELOPMENTAL DISORDER WHERE THERE IS NO FACIAL DIS MORPHOLOGY. ALCOHOL RELATED BIRTH DEFECTS. AND THERE MAY BE MANY CHILDREN WHO TEST IN THE NORMAL RANGE BUT PERHAPS NEVER REACH THEIR FULL POTENTIAL BECAUSE OF PRE-NATAL ALCOHOL EXPOSURE. AT OTHER TIMES IN PREGNANCY, THE SIZE IS REALLY STAGE OF GUEST RELATIONS AND THERE HAS BEEN AN EFFORT TO TRY TO UNDERSTAND AND TO ORGANIZE SOME OF THE NEURO COGNITIVE IN BEHAVIORAL ASPECTS OF PRE-NATAL ALCOHOL EXPOSURE TO SEE IF THERE ARE SPECIFIC RECOGNIZABLE SYNDROMES AND PROPOSED WITH ANY DSM5, AND NEURO ASSOCIATED WITH PRE-NATAL ALCOHOL EXPOSURE AND JULIE DESCRIBED THIS IN THE PAPER THAT'S IS REFERENCED BELOW AND THE THREE DOMAINS ARE ABNORMALITIES AND DISORDERS OF SELF-REGULATIONS AND HOW DO WE REALLY COME TO UNDERSTAND SOME OF THESE SYNDROMES WHEN IT'S ENORMOUS WHEN THERE'S DIFFERENCES ACROSS DIFFERENT ETHNIC AND RACIAL GROUPS IN AND IT MAYBE DIFFICULT IN ANY ONE PLACE OR CENTER TO BE ABLE TO STUDY ENOUGH INDIVIDUALS WHO ARE EFFECTED TO BE ABLE TO COME TO REALLY HARD CONCLUSIONS ABOUT PREVALENCE AND DIAGNOSIS AND THE CLINICAL MANIFESTATIONS AND NIAAA FUNDED FETAL ALCOHOL SPECTRUM DISORDERS PREVALENCE AND THIS WAS GOING INTO FIRST GRADE CLASSES IN THE COUNTRY AND THEY WERE THE PIS OF THIS STUDY AND THEY CONDUCTED THIS IN FOUR REGIONS OF THE COUNTRY AND FETAL ALCOHOL SYNDROME COULD BE DIAGNOSED AMONG FIRST GRADERS IN SIX TO NINE PER 1,000 LIVE BIRTH AND THIS BROADER SET OF DISORDERS WHERE YOU DON'T REQUIRE THE SPECIFIC FACIAL ABNORMALITY OF FETAL ALCOHOL EXPOSURE WAS DIAGNOSED IN 1 IF THE 1 TO 5% OF FIRST GRADERS. AND THIS PREVALENCE IS EQUAL TO OR GREATER THAN AUTISM SPECTRUM DISORDERS AND CHILDREN GROW UP TO BE ADULTS WITH FETAL ALCOHOL SPECTRUM DISORDERS AND IN THE UNITED STATES, THEY FALL OFF A CLIFF WHERE THEY ARE AWARE OF THESE DISORDERS AND THEY'RE NOT FOLLOWING THEM AND THEY ARE SEEN BY INTERNISTS, NEUROLOGISTS, PSYCHIATRISTS WHO MAY NOT BE FAMILIAR WITH THIS DIAGNOSIS. THEY'RE THEY'RE THERE IN NUMBERS. NIAAA FUNDED THE COLLABORATIVE INITIATIVES ON FETAL ALCOHOL SPECTRUM DISORDERS AND IT BEGAN IN 2003 AS AN ATTEMPT TO LOCK ACROSS PLACES IN THE WORLD AND THE UNITED STATES AND TO BETTER IDENTIFY CHILDREN WHO WERE EFFECTED BY PRE-NATAL EXPOSURE AND THIS USES VERY BASIC STUDIES AND I WILL TELL WHAT YOU HAS COME OUT OF THIS FUND AND COLLABORATIVE INITIATIVE. ADDRESSING TIME SPECIFICITY WITH A FACE WHICH IS FETAL ALCOHOL SYNDROME AND THIS IS WORK THAT WAS PUBLISHED BY ROB LA PIN SKI AND WORKING IN CATH'S' LAB AND YOU CAN SEE THREE COLUMNS THIS IS A NORMAL CHILD AND A NORMAL CONTROL AND MRI WAS DONE WITH FACIAL RECONSTRUCTION AND YOU SEE IT TO THE BRAIN AND THIS IS A CHILD WITH FOR THAL ALCOHOL SYNDROME THIS RESEARCH WOULD CAREFULLY TIMED EXPOSURE AND THIS VERY METICULOUS MRI STUDY WITH RACIAL RECONSTRUCTION RECONSTRUCTION OF THE BRAIN AND AND YOU SEE A HUGE RANGE AND FINDINGS UP TO THE SEVERE MALL FORMATIONS BOTH A FACE AND YOU CAN SEE HOW IT'S HUGE ON THE FACE AND WORK DONE BY SUSAN AT THE UNIVERSITY OF WASHINGTON AND THE SEVERITY OF THE FACIAL INVOLVEMENT AND YOU SEE THE RIGHT THALAMUS WHICH IS HONE HERE AND YOU CAN SEE THAT AT LEVELS OF FACIAL INVOLVEMENT THAT ARE NOT CONSIDERED DIAGNOSTIC, AND SO THE FACE DOES REFLECT THE BRAIN IN THAT THE SEVERITY OF INVOLVEMENT IS REFLECTIVE OF THE SEVERITY AND FABLE INVOLVEMENT AND YET THERE ARE DEVELOPS OF THE BRAIN THAT DON'T HAVE A FACIAL CORRESPONDING ABNORMALITY ABNORMALITY. AND EARLY IN OUR UNDERSTANDING OF FETAL ALCOHOL SYNDROME, STIRLING CLARREN AND COLLEAGUES PUBLISHED THESE PICTURES SHOWING A COUPLE OF CASES OF VERY SEVERE INVOLVEMENT AND IN AND FROM THESE, WE CAN LEARN WHAT SOME OF THE AND THE VEN TRICK ALS AND AND FAILING TO DEVELOP NORMALLY AND THESE AGAIN ARE SOME OF THE MORE SEVERE CASES AND WHAT WE KNOW FROM STUDYING THE BRAINS USING IMAGING IS THAT THE ABNORMALITIES ARE NOT AS OBVIOUS AND AS CLINICALLY APPARENT IN CLINICAL MRI STUDIES THAT MOST CHILDREN HAVE A BRAIN THAT REALLY WOULDN'T BE CALLED ABNORMAL BY A NEURO RADIOLOGIST BUT HERE IS AN EXAMPLE OF SOMETHING THAT YOU CAN SEE AT LEAST IN SOME CHILDREN AND THIS IS THE CORP IS COLOSAL THAT TRANSMITS INFORMATION FROM ONE SIDE OF THE BRAIN TO THE OTHER AND A LARGE WHITE MATTER BUNDLE AND YOU CAN SEE IN A CHILD THAT HAS MILDER EXPOSURE TO ALCOHOL, HYPO PLASTIC OR THINNER AND AN ABSENCE. TO POINT TO MAKE THIS IS NOT A UNUSUAL FINDING IN FETAL ALCOHOL SYNDROME BUT AN OCCASIONAL FINDING. HOWEVER, IF YOU USED MORE SOPHISTICATED IMAGING APPROACHES, THIS IS DIFFUSED TENSER IMAGING, LOOKING AT WHITE MATTER DEFECTS IN FETAL IN WHITE MATTER TRACTION IN FASD, YOU CAN SEE IN THE CONTROLS A VERY RICH ARRAY OF WHITE MATTER BUNDLES IN THE MID LINE AND HERE YOU CAN SEE REAL DEFECTS THAT CORRESPOND IN THIS CASE TO THE SMALLEST CORPIS. STHERE ARE EFFECTS OF PRE-NATAL ALCOHOL EXPOSURE THAT GO BEYOND WHAT YOU SEE AT A MOMENT IN TIME. PRE-NATAL ALCOHOL EXPOSURE EFFECTS THE TRAJECTORY OF POST NATAL BRAIN DEVELOPMENT SO THIS IS WORK AGAIN BY ELIZABETH'S GROUP AND YOU CAN SEE IN CONTROLS AND THERE IS INCREASE IN VOLUME OF BRAIN REGION? THIS CASE AND MEASURING THE AREA IN PURPLE AN AND IT DECREASES OVERTIME AND ONLY THE ACTIVELY FUNCTIONING SINAPSES ARE RETRAINED AND WHEN YOU LOOK AT THE SAME PAROLE FILE IN CHILDREN EXPOSED TO ALCOHOL IN, THERE'S NOT THE INCREASE IN DENSITY AND BRAIN VOLUME BUT RATHER A PROGRESSIVE DECREASE THAT REALLY IS A DIFFERENT TRAJECTORY. WHAT SOMEWHERE OF THE MECHANISM THAT'S ACCOUNT FOR ALCOHOL EFFECTS ON THE BRAIN. THIS IS WORK THAT WAS DONE IN MY LAB AND IT BEGAN MANY YEARS AGO WITH THE OBSERVATIONS THAT SOME OF THE ABNORMALITIES OBSERVED IN CHILDREN WITH FETAL ALCOHOL SYNDROME, SOME OF THE BRAIN ABNORMALITIES WERE ALSO SEEN IN CHILDREN WHO HAD MUTATIONS IN THE GENE FOR L1, A CELL ADHESION MOLECULE AND IT HELPED GUIDE SOME OF THE PROCESSES WE KNOW ARE ABNORMAL IN FETAL ALCOHOL SPECTRUM DISORDERS SPECIFICALLY THE ABILITY OF CELLS TO, AFTER THEIR BIRTH IN ONE PART OF THE BRAIN, MIGRATE SUCCESSFULLY TO OTHER PARTS AND MAKE THE APPROPRIATE CONNECTIONS AND WHAT WE DID WAS VERY SIMPLE. WE TOOK MOUSE AND TRANCE FACTED THEM WITH L1 AND SHOWS THE CELLS WERE STICKIER AND DID THE SAME ASSAY FOR THE STICKINESS OF THE CELL FOR THE CELL ADHESION AND THAT IN THE PRESENCE OF ENOUGH ALCOHOL THAT YOU WOULD HAVE IN YOUR BLOOD AFTER ONE DRINK, ONE COULD SEE SIGNIFICANT INHIBITIONS OF ADHESION BY L1 AND AT A LEVEL THAT'S COMPARABLE TO THE LEVEL THAT IS HIGHER FOR LEGAL INTOXICATION IN MANY STATES THAT THERE WAS QUITE REMARKABLE INHIBITION OF CELL ADHESION MEDIATED BY L1. IT STICKS OUT THROUGH THE CELL MEMBRANE AND CURLS IN THIS LOCATION RIGHT HERE AND IT'S THIS CURVATURE AND THE JOINING OF TWO REGIONS OF THE MOLECULE THAT ALLOW IT TO FUNCTION BEST IN CELL ADD MEDICATION. WADHESION.WE WERE ABLE TO SHOW THAT ALCOHOL WAS BINDING TO A SPECIFIC REGION ON THE L1 MOLECULE, ACROSS TWO DIFFERENT REGIONS THAT ARE VERY CLOSE TOGETHER HERE AND MAYBE PLAY AN IMPORTANT ROLE AS YOU SEE IN THIS EXPANDED PHOTOGRAPH OF JOINING THE TWO REGIONS OF THE MOLECULE TOGETHER TO FACILITATE THEIR FUNCTION. SO, THIS IS BUT ONE OF MANY MECHANISMS THAT UNDERLIES ALCOHOL'S EFFECTS ON THE DEVELOPING NERVOUS SYSTEM AND I WANT TO NOW TAKE A MOMENT AND TALK ABOUT ADDITIONAL WORK THAT WAS DONE AS PART OF CFAS. THIS BY EFFICIENT COLLEAGUES AND SCOTT PARNELL'S LAB SHOWING THAT ALCOHOL ALONE CAN PRODUCE CERTAIN EFFECTS. THIS IS NOW LOOKING AT MICE AND LOOKING AT OCULAR DEFECTS AND THAT THE EFFECTS OF COLOMBIA ARE SIGNIFICANTLY EXACERBATED BY CANNABINOIDS. YOU SEE THE ALCOHOL EXPOSURE THAT DOESN'T PRODUCE DEFECTS MUCH DIFFERENT THAN THE VEHICLE. IN THE PRESENCE OF CANNABINOIDS A GREATLY INCREASED EFFECT AND AS YOU INCREASE THE DOSE OF ETHANOL, THIS EFFECT OF CANNABINOIDS IS REMARKABLE. THIS IS DIFFERENT WITH SEVERAL CAN AB INOIDS THIS IS ALCOHOL'S EFFECT ON SONIC HEDGE DOG SIGNALING IN EFFECTS FURTHER DOWNSTREAM TO PRODUCE A COMBINED EFFECT THAT IS GREATER THAN THE EFFECT OF EITHER ONE ALONE. THE EFFECT IT TURNS OUT, IS ON A VERY IMPORTANT ASPECT OF DEVELOPMENT WHICH IS CILIA FUNCTION AND THE EFFECT OF ALCOHOL ON CILIA MAY BE CRITICAL TO NORMAL DEVELOPMENT. THIS HAS IMPORTANT POLICY IMPLICATIONS BECAUSE WE KNOW THAT AS CANNABIS IS LEGAL IT'S USED BY PEOPLE. MANY WOMEN ARE NOT AWARE OF THEIR PREGNANCY AT THE TIME THAT THEY MAY CHOSE TO USE CANNABIS, ALCOHOL OR THE TWO COMBINED. THERE'S ADDITIONAL WORK. THIS IS WORK DONE BY JOHAN IN HIS LAB. McCARTHY AND ALL PUBLISHED THIS WORK AND DEVELOPMENT AND IT SHOWS ANOTHER VERY IMPORTANT FINDING WHICH IS THE ROLE OF GENETICS IN ALCOHOL'S EFFECTS ON DEVELOPMENT AND THIS IS A CBC ARZEBRAFISH MODEL AND IT'S LOOKING AT CRANIAL FACIAL DEVELOPMENT AND WE'RE LOOKING AT DELETION OF ONE OR TWO PDGFRA WHICH IS A RECEPTORS FOR THE PDGFRA GROWTH FACTOR AND UNTREATED, THERE IS VERY LITTLE EFFECT COMPARED TO CONTROL BUT IN THE PRESENCE OF ETHANOL, THE EFFECT OF LOSING ONE OF THE PDGFRA IS GREATLY INCREASED AND OF COURSE, IN THE PRESENCE OF ALCOHOL, LOSING BOTH OF PDGFRA PRODUCES A DRAMATIC EFFECT ON CRANIAL FACIAL DEVELOPMENT AND INTERESTINGLY, THE COLLEAGUES ARE LOOKING AT THE COHORT COULD FIND SIMILAR PREDISPOSITIONS TO ALCOHOL WITH VARIANCE OF THE PDGFRA GENE IN THE COHORT. IT'S UP STREAM OF ANOTHER IMPORTANT SIGNALING PATHWAY WHICH IS M.T.O. R AND DOING A GENETIC ANNAL SITS, THIS IS PRELIMINARY WORK LOOKING AT HUMANS, BOTH AFRICAN AMERICANS AND EUROPEAN AMERICANS, WAS ABLE TO FIND GENES THAT SEEMED TO IDENTIFY A DIFFERENT SUSCEPTIBILITY TO NORMAL EFFECTS OF ALCOHOL EXPOSURE AND INTERESTINGLY, SEVERAL OF THESE GENES WERE INVOLVED EITHER IN CILIA OR THE M.T.O. R PATHWAY SO WORK DONE IN BASIC MODELS OF MICE AND ZEBRA FISH, SEEMED TO IDENTIFY GENES THAT WERE IMPORTANT IN A HUMAN COHORT. THIS IS WORK THAT NOW IS BEING EXPANDED AS MORE AND MORE GENETIC SAMPLES ARE BEING STUDIED AND AS TOLD GENOME SEQUENCES IS BEING APPLIED TO UNDERSTAND THIS. I MENTIONED EARLY IN MY DISCUSSION THAT ALCOHOL HAS LIFELONG EFFECTS ON COGNITION, DEVELOPMENT AND ALSO ON MEDICAL DISORDERS. ALCOHOL IS LIKE MANY OTHER EARLY EMBRYONIC AND FETAL EVENTS. SOMETHING THAT CAN CHANGE AND RESULT IN LONG-TERM EFFECTS THAT ARE MANIFEST ACROSS A LIFESPAN. THIS IS WORK THAT I'M GOING TO TELL YOU ABOUT THAT WAS DONE BY OLIVIA WEEKS IN HER DOCTORAL THESIS, LOOKING AT THE EFFECTS OF ALCOHOL ULTIMATELY ON THE MANIFESTATIONS IN ADULTHOOD AND WE KNOW MATERNAL CONDITIONS SPECIFICS POSE YOU'RE, DRUG EXPOSURE INCLUDING ALCOHOL, AND GESTATIONAL DIABETES MAY STRUCTURAL CHANGES AND STRESS. AND OBES OBESITY AND SO WHAT DR. WEEKS DID IS SHE LOOKED AT A POPULATION OF PATIENTS WHO WERE DIAGNOSED IN THE MASS GENERAL DATABASE WITH FETAL ALCOHOL SPECTRUM DISORDERS AND LOOKED AT ABNORMAL BMI AND HEIGHT MEASUREMENTS AND ALSO MEASURES OF METABOLIC FUNCTION. AND SHE FOUND INTERESTINGLY DIFFERENCES BETWEEN MALES AND FEMALES. MALES INTENDED TO BE UNDER WEIGHT, WHICH IS CONSISTENT WITH WHAT IS OBSERVED ALSO IN CHILDHOOD. YOU CAN SEE THAT THE MALES, IF ANYTHING, HAVE SLIGHTLY LOWER BMI BUT FEMALES INTENDED TOWARDS OVERWEIGHT AND OBESITY. THERE WAS, HOWEVER, NO CHANGE IN MALES AND FEMALES WITH FETAL ALCOHOL SPECTRUM DISORDERS IN TERMS OF STATURE THAT THEY HAD SHORT STATURE BOTH MALES AND FEMALES. NOW, AS A RESULT OF A VERY COMPLEX AND H ELEGANT SERIES, DR. WEEKS WAS ABLE TO SHOW IN ADULTHOOD, THAT MANY OF THE MALES AND FEMALES IN THE DATABASE HAD ELEMENTS OF METABOLIC SYNDROME. AND SHE COULD REPRODUCE SOME OF THE SAME FINDINGS IN ZEBRA FISH THAT WERE EXPOSED TO ALCOHOL IN UTERO. ELEVATED BMI, ABDOMINAL OBESITY, FASTING HYPER GLYCEMIA AND SHE WAS ABLE TO DISSECT THAT THEY WERE DUE TO CHANGES IN BEHAVIOR, GROWTH, TRANSCRIPTIONAL PROGRAMS OF DNA AND CHANGES IN METABOLISM AND THESE WERE MIRRORED IN SOME OF THESE LATER CHANGES IN ADULTHOOD. SO WHAT'S IS THE SIGNIFICANCE OF THESE FINDINGS THAT CHILDREN WHO ARE EXPOSED TO ALCOHOL IN UTERO NEED TO BE FOLLOWED ACROSS THE LIFESPAN AND SCREENED FOR METABOLIC ABNORMALITIES THAT WE'RE ONLY BEGINNING TO DISCERN AND FOR OTHER MEDICAL PROBLEMS AS WELL THAT WE'RE ONLY BEGINNING TO UNDERSTAND THAT IN ADDITION TO UNDERSTANDING THE COGNITIVE, SOCIAL, AND BEHAVIORAL DEVELOPMENTAL PROBLEMS, THAT AGAIN, WILL BE WITH THEM FOR THEIR LIFETIME AND THERE ARE MEDICAL EVENTS THAT NEED TO BE IDENTIFIED AND NEED TO BE BETTER UNDERSTOOD. SOME OF THESE ARE NOW BEING STUDIED AND THIS IS WORK THAT CLAIRE COALS HAS PROVIDED. VERY PRELIMINARY THAT SHE IS DOING IN COLLABORATION WITH INVESTIGATORS AT UNIVERSITY OF WASHINGTON AND JOANNE WINEBURG IN VANCOUVER AND THIS IS A SELF-REPORT, NOT A CHART REVIEW. DID YOU HAVE HEART PROBLEMS AS A CHILD? DO YOU HAVE HEART PROBLEMS NOW AND OF COURSE DO YOU HAVE HIGH BLOOD PRESSURE. YOU CAN SEE THAT THERE'S A QUITE STRIKING DIFFERENCE IN THE NUMBER OF ADULTS WHO ANSWERED YES VERSUS CONTROLS WITH DIAGNOSIS OF FETAL ALCOHOL SPECTRUM DISORDERS AND SAME FOR CURRENT HEART PROBLEMS NOW AND SAME FOR HIGH BLOOD PRESSURE IN ADULTS SO AGAIN, SOMETHING IMPORTANT THAT NEEDS TO BE BETTER STUDIED AND BETTER UNDERSTOOD THAT WILL TELL US HOW BETTER TO MANAGE THIS DISORDER WHICH EXISTS IN SUCH A HIGH PREVALENCE IN OUR POPULATION. THIS IS WORK DONE BY TAMMY BODNER AND JOANNE WINEBURG'S LAB, TAKING ADVANTAGE OF A LONGITUDINAL STUDY CONDUCTED IN UKRAINE. MATERNAL CYTOKINE SIGNATURES ARE LINKED TO ALCOHOL INTAKE AND NEURO DEVELOPMENTAL OUTCOMES WHEN THE STUDIES AND THE SAMPLES WERE OBTAINED IN THE SECOND TRIMESTER. THESE ARE DIFFERENT CYTOKINES AND THESE REFLECT ALCOHOL EXPOSURE AS WELL AS CHILDREN WHO HAD WORSE DEVELOPMENTAL OUTCOMES SO AGAIN, SOMETHING ABOUT THE CHANGE I IN CYTOKINE WAS ALCOHOL EXPOSURE AND PREDICTIVE OF NEURO DEVELOPMENT AND THIS REQUIRES MUCH GREATER STUDY. SO, I WANT TO CONCLUDE WITH WHAT I THINK IS ONE OF THE MOST SIGNIFICANT CHALLENGES IN THIS FIELD WHICH IS THAT GIVEN THE LARGE NUMBER OF CHILDREN THAT ARE EFFECTED, HOW DO WE MAKE THE DIAGNOSIS AND HOW DO WE PROVIDE INTERVENTIONS WHEN THE NUMBER OF SPECIALISTS AVAILABLE TO DO SO IS GREATLY UNDER REPRESENTED OR INSUFFICIENT. SO, DIAGNOSIS AND TREATMENT ARE REALLY UNAVAILABLE FOR MOST EFFECTED INDIVIDUALS. THERE ARE INSUFFICIENT NUMBERS OF SUFFICIENTLY TRAINED CLINICIANS AND THE GEOGRAPHY MAKES MANY OF THESE CLINICIANS IN ACCESSIBLE AND THEN OF COURSE THERE'S STIGMA. WHICH IS A HUGE PROBLEM IN OUR FIELD BECAUSE MANY PARENTS EITHER ADOPTIVE PARENTS OR BIOLOGICAL PARENTS OF CHILDREN WERE FASD MAY BE RELUCTANT TO COME FORWARD AND IN CERTAIN CULTURES, THEY MAY FACE CONSEQUENCES FOR DOING SO. AND AGAIN, WE DON'T NECESSARILY AGREE ON HOW TO DYING KNOW FASD SO HOW DO WE MOVE FORWARD IN DOING DIAGNOSIS AND TREATMENT THAT CAN OVERCOME SOME OF THESE GEOGRAPHICAL BARRIERS? WELL, ONE OF THE EFFORTS OF CFAS RIGHT NOW IS TO TAKE ADVANTAGE OF ONLINE OR MOBILE DIAGNOSIS AND TREATMENT. THIS WILL ALLOW PATIENTS AND FAMILIES TO ANONYMOUSLY ENGAGE WEB BASED ALGORITHMS FROM ANY LOCATION IN THE WORLD THAT HAS AN INTERNET CONNECTION. THIS REDUCES BARRIERS RELATED TO GEOGRAPHY AND STIGMA AND CLINICIAN AVAILABILITY. AS MIKE, WORKING WITH PETER HAMMOND, DID SOME OF THE WORK I'M GOING TO DESCRIBE NOW ON USING 3D FACIAL IMAGING FOR DIAGNOSIS. AND THIS IS WORK THAT'S ON GOING LOOKING AT VARIATION, NOT ONLY IN THE MORPHOLOGY OF THE FACE AND ALSO IN SOME BRAIN STRUCTURES SHOWN HERE MORPHING BETWEEN FETAL ALCOHOL SYNDROME AND A CONTROL CORPIS COLOSOM AND YOU CAN SEE THE STRUCTURES CORRELATE WITH THE FACE AS YOU DO THIS MORPHOLOGY AND ALSO IF YOU LOOK ACROSS HERE, A CHILD WITH FETAL ALCOHOL, WHEN YOU GET TO THIS SIDE OF THE SPECTRUM AND A CHILD WITH CONTROL WHEN YOU GET TO THIS SIDE ALLOWS YOU A REMARKABLE LOOK AT WHAT CHANGES IN THE FACE AS YOU MORPH BETWEEN THESE TWO CONDITIONS. AND THE ABILITY TO DO THIS ANALYSIS REALLY ALLOWS FOR ALMOST PERFECT DISCRIMINATION BETWEEN FETAL ALCOHOL AND CONTROLLED CHILDREN. IN ALSO ALLOWS YOU TO CLUSTER CLUSTER CHILDREN WHERE DUE HAVE THE CHARACTERISTICS FACE AND IDENTIFY GROUPS WHO ARE FETAL ALCOHOL LIKE WHOSE COGNITION VARIES FROM CHILDREN WHO ARE MORE CONTROL LIKE IN THEIR FACE. AND SO, AGAIN, WE SEE THE RELATIONSHIP BETWEEN FACE, BRAIN, AND COGNITION. THIS IS WORK BEING DONE BY SER A MATSON, ATTEMPTING TO USE WHAT HAS BEEN LEARNED ABOUT COGNITION AND BEHAVIOR TO REDUCE TO A DECISION TREE KNOWN HERE AS THE E-TREE AND JUST THE CRITICAL ELEMENTS FOR PREDICTION OF ALCOHOL EXPOSURE AND SHE'S BEEN ABLE TO DO THIS WITH RELATIVELY HIGH SENSITIVITY AND A RELATIVELY LOW RATE OF FALSE POSITIVES. AND THIS NOW MOVING THIS DIAGNOSTIC SYSTEM AND THIS E-TREE ONLINE SO IT CAN BE DONE REMOTELY AND BRAIN ONLINE WHICH IS UNDER DEVELOPMENT WILL BE COMPLETED IN THIS VALIDATION IS UNDERWAY. THIS WILL AGAIN ALLOW REMOTE TESTING WHERE CHILDREN MAY NOT HAVE ACCESS TO THE KIND OF TESTING FACILITIES THAT ARE AVAILABLE IN LARGE CITIES OR AREAS WITH SPECIALIZED SECTORS. AND THEN FINALLY, CHRISTIE AS PART OF CFAS ARE TAKING WHAT WAS A SUCCESSFUL PROGRAM, FAMILIES MOVING FORWARD, AND ADOPTING THE CONTENT PRINCIPLES AND METHODS TO FMS CONNECT AND FAMILIES MOVING FORWARD CONNECT, WHICH IS AN ONLINE VERSION THAT HAS AND WOULD PROVE VALUABLE AND OUR CURRENT SETTING WHERE PEOPLE ARE REALLY HAVING TO PHYSICALLY DISTANCE AND THIS JUST SHOWS YOU A LITTLE BIT ABOUT THE APPROACH THAT THEY'RE TAKING, MANY MODULES THAT FAMILIES CAN ACCESS AND WORK THROUGH IN COLLABORATION WITH A REMOTE THERAPIST. SO, THIS IS JUST AN ONGOING ATTEMPT BY THESE MANY OF THE PEOPLE FROM CFAS WHO ARE DOING THIS WORK OF TRYING TO BRIDGE BASIC BIOLOGY WITH AN ATTEMPT TO PROVIDE METHODS FOR ONLINE DIAGNOSIS AND ONLINE TREATMENT. I WANT TO CONGRATULATE NIAAA ON ITS 50th ANNIVERSARY AND THANK NIAAA FOR FUNDING THE FIELD OF FETAL ALCOHOL DISORDER RESEARCH AND FUNDING THAT REALLY IS RESPONSIBLE FOR MUCH OF WHAT WE KNOW ABOUT FASD TODAY AND WHAT WE EXPECT WE'LL LEARN IN THE COMING YEARS. THANK YOU. >> I WANT EVERYBODY TO UNDERSTAND THAT YOU CAN SEE ANY OF THE PRESENTATIONS BY VIDEO CAST AFTER THE SYMPOSIUM IS OVER AND AFTER THOSE HAVE BEEN UPLOADED AT NIH. I WOULD LIKE TO LEAD OFF WITH A COUPLE QUESTIONS. THERE'S ONE BEFORE EVEN INTO MIND THERE ARE SHOWING UP IN THE CHATBOX. MICHAEL, THAT WAS A SUPERB TALK AND REALLY SHOWING US WHERE WE HAVE BEEN AND HOPEFULLY WHERE WE MIGHT BE ABLE TOLL GO. SO GEORGE HAS A QUESTION. HE SAYS, GREAT TALK AND DOES HAVE THE SAME TIME OF VULNERABILITY AS IT DOES FOR ETHANOL? >> I CAN ONLY SAY THAT THE WORK DONE IN SCOTT PERSONNEL'S LAB DID USE TIME OF EXPOSURE AND I THINK THAT THERE'S A LOT TO BE LEARNED ABOUT THE RELATIVE EFFECTS OF ALCOHOL AND CANNABINOIDS IS THE DRUG ITSELF THAT IS RESPONSIBLE FOR THE EFFECTOR IS IT THE TIMING OF DISRUPTION OF DEVELOPMENT WHICH IS IMPORTANT AND WHAT KATHY DID, IS SHE EXPOSED FETUSES TO RETINO ACID ADD THE SAME TIME AS ALCOHOL IN THIS SEVEN-DAY EXPOSURE MODEL AND WHAT HE FOUND WAS VERY, VERY SIMILAR DEVELOPMENTAL ABNORMALITIES AND. >> THE QUESTION IS FROM IT IS THE FATHER ALSO EFFECT THE FETUS? >> THAT IS A QUESTION THAT BOTH BY OWE MEDICALLY IMPORTANT AND FILL OS I CANNILY IMPORTANT AND THERE IS DATA GOING BACK MANY YEARS THAT SUGGESTS THERE MAY BE A PATERNAL AND DATA HAS SUGGESTED A TRANCE GENERATIONAL PATERNAL EFFECT SO THERE'S MUCH MORE TO LEARN ABOUT THAT AS WELL. SO MEN ARE NOT OFF THE HOOK. >> IT WOULD BE IN DEED INTERESTING TO FIND OUT IF THERE'S ANY SYNERGISTIC EFFECT WITH MOTHER AND FATHER ROW HAM ADD, I ASKED COULD COVID-19 INFECTION WITH FASD EFFECT FETAL DEVELOPMENT, IN OTHER WORDS, IS THERE ANY INTERACTION OF COVID-19 WITH FASD AND WHAT DO YOU KNOW ABOUT THAT SO FAR? >> I CAN ONLY SPECULATE. ACTUALLY, WE'VE ONLY HAD COVID-19 FOR A GESTATIONAL PERIOD AND THERE MAY BE FINDINGS IN CHILDREN WHO HAVE BEEN EXPOSED TO COVID-19 TO SARS-CoV-2 ALONE THAT WE DON'T DISCOVER FOR FIVE YEARS WHEN CHILDREN REACH A CERTAIN DEVELOPMENTAL AGE WHERE IT'S MANIFESTED AND THERE IS EVIDENCE THAT SARS-CoV-2 THE VIRUS THAT CAUSE COVID, WE DON'T KNOW VERY MUCH ABOUT THE DEVELOPMENTAL ASPECT OF THAT AND THERE'S BEEN AN INCREASE IN DRINKING AND PEOPLE WHO ARE ISOLATED AND UNDER GREATER STRESS SO WE MAY SEE A POTENTIAL INTERACTION OF TWO IMPORTANT FACTORS AND THEN WE ALSO KNOW AND I ALLUDED TO THIS IN MY DISCUSSION, THAT THERE IS AN INCREASE IN THE ADVERSE CHILDHOOD EVENTS THAT MAY EFFECT DEVELOPMENT AND WE KNOW THAT THERE'S AN INTERNET CREASE IN PARTNER VIOLENCE AND IN IT BUSE AND IT REMAINS TO BE SEEN HOW LONG THIS PANDEMIC PLAYS OUT AND WHAT THOSE ADDITIONAL FACTORS WILL BE SO I THINK THAT THIS IS REALLY GOING TO BE A CASE WHERE IT'S GOING TO BE IMPORTANT AND THEY HAVE SIMPLE MODEL SYSTEMS TO UNDERSTAND EACH FACTOR AND UNDERSTANDING HOW THESE PLAY OUT WHEN THEY COEXIST TOGETHER. >> AND, THE PERENNIAL QUESTION, MICHAEL, WHAT IS THE IMPACT OF THE LOW OR LIGHT DRINKING DURING PREGNANCY IS THERE ANY LEVEL OF DRINKING SAFE? WHAT WOULD YOU SAY TO THAT ONE? >> SO, I WOULD GO ALONG WITH THE SURGEON GENERAL WHO ADVISES AGAINST ANY DRINKING AT ALL WHEN TRYING TO CONCEIVE OR DURING PREGNANCY. THE REASON FOR THAT IS THAT NEITHER BASIC PRE CLINICAL STUDIES OR CLINICAL STUDIES HAVE ESTABLISHED A SAFE THRESHOLD. INTERESTINGLY, THE ABCD STUDY JUST PRODUCED AN INTERESTING PAPER SHOWING EFFECTS OF QUITE LOW LEVELS OF EXPOSURE OF PREGNANCY ON COGNITIVE MEASURES AND THIS IS NOT THE ONLY PAPER TO HAVE DONE SO. I THINK THAT AGAIN, WORKING WITH HUMANS CAN BE MESSY AND ABCD STUDY HAS THE ADVANTAGE OF VERY LARGE NUMBERS AND A VERY ORGANIZED WAY OF UNDERSTANDING COGNITIVE AND BEHAVIORAL EFFECTS AS WELL AS CHANGES AND BRAIN MORPHOLOGY AND THEY WILL HELP US AND TO DATE BASIC BIOLOGY AND THE CLINICAL COHORTS AND SUGGESTED THE SURGEON GENERAL HAS IT RIGHT. >> THERE'S A QUESTION ABOUT DIAGNOSIS. CASES OF IT'S CALLED A HIDDEN OR ADVISABLVISIBILITY BECAUSE MOST ARE NOT DIAGNOSED UNTIL ADOLESCENTS, ADULTHOOD, IF AT ALL. IT'S JUST FROM BILL WHO YOU KNOW VERY . WHY DOES THIS OCCUR AND HOW CAN WE DO BETTER? >> I THINK IT'S JUST WHAT BILL'S QUESTION 'EM PLIED WHICH IS THAT THIS HAS BEEN AROUND FOR MILLENIA AND IT REALLY TOOK THE TEARING OF THE FACE WITH SOME OF THE BEHAVIORAL AND COGNITIVE ABNORMALITIES TO MAKE THIS A RECOGNIZABLE SYNDROME AND WE THOUGH THAT SYNDROME RESULTS ONLY FROM EXPOSURE DURING GESTATION. WE NEED TO FIND WAYS TO IDENTIFY EXPOSURE AT OTHER TIMES BECAUSE IT MAY TURNOUT THAT THE COGNITIVE AND ABNORMALITIES ARE NOT THEMSELVES SPECIFIC TO BE ABLE TO ALLOW A DIAGNOSIS. IT MAY BE THAT SOME OF THE WORK THAT I DESCRIBED THAT MIKE IS NOW PURSUING WITH SFAS, WILL HELP US IDENTIFY USING 3-D FACIAL IMAGING, AND SOME OF THEM MORE SUBJECT NOT THAT WILL HELP DRINK AND TO SOME OF THESE ADVERSE BEHAVIORAL AND COGNITIVE OUTCOMES. IT'S IMPORTANT TO RECOGNIZE THAT WE DON'T ALWAYS HAVE A RELIABLE HISTORY OF DRINKING AND SO, THERE ARE MANY, MANY CHILDREN, SOME ADOPTED AND SOME WITHOUT THE HISTORY AVAILABLE TO US, ESPECIALLY WHEN PEOPLE PRESENTED ADULTHOOD, TO ALLOW US TO MAKE A LINK BETWEEN A BEHAVIORAL OR COGNITIVE ABNORMALITY IN DRINKING AND EXPOSURE TO ALCOHOL DURING GESTATION. IF WE CAN DEVELOP BETTER BIOMARKERS BUT ULTIMATELY IT'S A COMBINATION OF HOW WELL WE CAN UNDERSTAND EXPOSURE AND INFORM WHAT EXTENT WE CAN TEASE OUT RELATIVELY SPECIFIC, NOT ABSOLUTELY SPECIFIC, COMBINATIONS OF ABNORMALITIES THAT WILL MAKE US MORE SOPHISTICATED AND MORE RELIABLE IN MAKING THIS DIAGNOSIS. SHE'S FROM BETTY FORWARD CAN YOU SUGGEST ANYTHING WE CAN DO FOR OUR PREGNANT PATIENTS WHO HAVE HAD ALCOHOL CANNABIS EXPOSURE COMING INTO TREATMENT TO HELP MITIGATE. >> THIS IS TRUE FOR ALCOHOL EXPOSURE ACROSS THE LIFESPAN AND MINIMIZING IT AT WHATEVER IT WILL MID GIT FURTHER ALCOHOL RELATED NEURO TOXICITY AND OPTIMIZING PREGNANCY BY OPTIMIZING PRE-NATAL CARE INCLUDING THE USE USE OF VITAMINS AND THERE'S ON GOING WORK LOOKING AT I THINK IT'S LIKE, AS I SAID, ALCOHOL EXPOSURE ACROSS THE LIFESPAN THAT AT SOME POINT A PERSON MAY PRESENT WITH SOME MILD OR MAYBE MODERATE INJURIES AT THAT POINT IN TIME, YOU STILL HAVE OPTIONS WHICH IS TO MITIGATE FURTHER INJURY OR REDUCE FURTHER JUDGE BY DECREASING DRINKING SO CARRYING THE MESSAGE THAT ALCOHOL MAY BE HARMFUL TO THE FETUS, IS AN IMPORTANT ONE FOR EVERYBODY WHO HAS CONTACT WITH PATIENTS WHO ARE PREGNANT. >> TO FOLLOW-UP, COULD YOU JUST SAY A FEW WORDS HOW THE FIELD THINKS CODING IS WORKING IN THIS DOMAIN? >> I WOULD SAY THAT THERE ARE A LOT OF REALLY GOOD IDEAS INCLUDING ONE THAT IT SUGGESTS THE ABILITY OF ALCOHOL TO CHANGE THE SUB CELLULAR DISTRIBUTION OF L1. THAT IS NOT THE ONLY EXPLANATION AND AT THIS POINT, AND THE AREA SO DESERVES A LOT MORE INVESTIGATION. >> FROM MARILYN FAUCET, IS THERE ANYWAY, AS A SCIENTIST, INCLUDED THE ISSUE OF SUFFERING THAT RESULTS TO THE INDIVIDUAL FAMILY IN SOCIETY? >> THAT'S A DIFFICULT QUESTION. I AM A PHYSICIAN AND AS A PHYSICIAN, ALLEVIATING HUMAN SUFFERING IS REALLY ONE OF OUR PRIMARY TASKS AND SO SUFFERING HAS BOTH A CONSEQUENCE TO THE PERSON WHO IS SUFFERING AND TO THE PERSON THAT THEY NURTURE AND I THINK IT'S GOING TO BE IMPORTANT FOR US TO BE ABLE TO IDENTIFY THE ADVERSE EFFECTS OF ALCOHOL ON FETAL DEVELOPMENT AND PROVIDE SUPPORT TO PEOPLE WHO ARE WORKING WITH THOSE CHILDREN AND CHAOTIC FAMILY CIRCUMSTANCES DIFFICULT CHALLENGES FACED BY PARENTS AND ADOPT TIP PARENTS AND THE SOCIAL GROUPS THAT THEY INTERACT WITH AND TO SUPPORT THE FAMILY AND TO SUPPORT THE CHILD. WHERE THEY DON'T RECOGNIZE THE IMPORTANCE OF ALCOHOL EXPOSURE ON LONG-TERM DEVELOPMENTAL OUTCOMES AND PROVIDE SUPPORT TO THE FAMILIES SO THAT THEY CAN WHETHER THIS AND ALLOW THEIR CHILDREN TO DEVELOP TO THEIR GREATEST POTENTIAL. >> SPEAKING OF THIS, MICHAEL, ONE OF THE QUESTIONS THAT HAS BEEN SUBMITTED IS, WHERE CAN SOMEONE FIND RESOURCES FOR INDIVIDUALS WITH FAS DID AND THEIR FAMILIES AND ANSWER YOU BEFORE, WE HAVE JUST UPDATED THE WEBSITE SO I GUESS ARE WE UPDATED ENOUGH IN THIS DOMAIN SO THAT PEOPLE CAN FIND THE RESOURCES THAT YOU MIGHT RECOMMEND BUT WHERE ELSE MIGHT THEY LOOK? DO THEY HAVE A WEBSITE? >> SO CFAS HAS A WEBSITE BUT THEY HAVE A VERY CLOSE WORKING RELATIONSHIP WITH NOFAS NATIONAL ORGANIZATION OF THE FETAL ALCOHOL SYNDROME AND THEY WORK CLOSELY WITH COMMUNITIES AND INDIVIDUALS TO HEIGHTEN AWARENESS ABOUT PRE-NATAL ALCOHOL EXPOSURE AND ITS CONSEQUENCES SO I THINK BETWEEN NIAAA, THE CFAS WEBSITE AND NOFAS, YOU HAVE A GOOD PLACE TO START. >> AND NOW THOSE LINKED TO OUR WEBSITE? DO YOU KNOW YET? >> MAYBE YOU COULD SEND US A MESSAGE AND LET ME KNOW. >> NOFACE LINKED TO NIAAA. >> YEAH, YEAH. >> OK. SO, HERE IS ANOTHER QUESTION. MICHAEL, ARE YOU TOO TIRED YET? ARE YOU OK? >> I'M GOOD. >> THANK YOU FOR YOUR PRESENTATION. TO FOLLOW-UP ON A PREVIOUS QUESTION ABOUT COVID, WE'RE SEEING A 41% INCREASE OF ALCOHOL USE BY WOMEN DURING THE PANDEMIC. WE, AND THE PREVENTION FIELD, ARE PREPARING FOR AN INCREASE ALCOHOL-EXPOSED PREGNANCIES. CAN YOU SPEAK TO THE WHAT NIAAA, NIH AND OTHER POWERS WILL BE DOING TO ADDRESS THE NORMALIZATION OF ALCOHOL USE IN SOCIETY, ESPECIALLY BEFORE WE TURN OUR ATTENTION TO THE USE OF CANNABIS? THIS IS FROM HENDRIX AT ARC AND C AND I'M NOT SURE WHERE THAT IS BUT MAYBE THEY CAN COMMUNICATE WITH YOU SEPARATELY ABOUT THESE ISSUES. THESE ARE BIG ISSUES. I'M HAPPY TO MAKE A FEW COMMENTS. I'M GOING TO LET YOU GO FIRST. >> I WOULD JUST HIGHLIGHT SOME OF THE URGENT QUESTIONS THAT NEED TO BE ADDRESSED. ONE OF THEM IS WHAT ARE THE EFFECTS OF SARS-CoV-2 AND DIFFERENT DEVELOPMENTAL OUTCOMES. A SECOND IS WHAT ABOUT BETWEEN ALCOHOL AND OTHER DRUGS ON EFFECTS OF CARS AND A THIRD IS HOW WILL WE MITIGATE THE EFFECTS OF ALCOHOL AND SARS SARS-CoV-2 ALONE IN TOGETHER AND WHEN WE CONFRONT A RISING TIDE OF FASD AND ANY OF THE EXACERBATING EFFECTS OF COVID-19. AND TO DO THAT IT WILL TAKE THE WORK OF NIH AND I WILL PASS THAT ON TO YOU TO ANSWER THE REST OF THAT QUESTION. >> I THINK THE PREN WHO WROTE IT WAS AMY HENDRIX, IT WILL TAKE A VILLAGE. WE ARE FACING NOT ONLY WOMEN, PREGNANT WOMEN, BUT ALSO OTHER INDIVIDUALS WHO ARE USING ALCOHOL TO COPE WITH STRESS AND SOME COVERED BY OUR PREVIOUS SPEAKERS AND WE'RE GOING TO NEED TO UP OUR GAME WITH PREVENTION AND TREATMENT AND ISSUES AROUND RECOVERY AND THEY ARE ALL HIGH PRIORITIES AND WE HAVE TO UP OUR GAME AND I KNOW THERE WE'RE ALREADY FUNDING GRANTS IN THIS DOMAIN ABOUT TELEHEALTH, TELEMEDICINE, REACHING OUT TO MORE RURAL COMMUNITIES AND EVEN WHEN THERE'S NOT A PANDEMIC WE STILL HAVE CHALLENGES AND TAKING TREATMENT OUT TO LA I TOURED ALASKA A YEAR AGO OR SO AND YOU KNOW, THIS WAS A BIG, BIG ISSUE AND I MIGHT ADD IT WAS A BIG ISSUE AROUND DIAGNOSIS OF FETAL ALCOHOL SPECTRUM DISORDER SO SOME OF THE THINGS THAT YOU SHOWED AT THE VERY END OF YOUR TALK ABOUT HOW WE MIGHT BE ABLE TO DO THIS WITH VIDEO IMAGES AND YOUR OWN iPHONE AND MAYBE LIKE SARAH MATSON'S NEUROPHYSIOLOGICAL TEST THAT COULD BE APPLIED THROUGH TELEMEDICINE, TELEHEALTH, THESE ARE ALL CHALLENGES THAT WE'RE DEFINITELY FACING. AND WE'LL BE FACING AS THE IT FADES IN THE NEXT YEAR. AND THEY HAVE CONFIRMED THAT THE NIAAA CURRENT VERSION AND LINKS TO AND A GOOD PLACE TO START FOR ANY QUESTIONS THAT YOU COME UP WITH DURING THIS SIM POSE YUS, SYMPOSIUM. WE CAN CHANGE THE WEBSITE AND ADDRESS SOME OF THE QUESTIONS THAT PEOPLE HAVE. SO, I THINK THEY'RE TELLING ME WITH SHOULD ASK THE BIG QUESTION, AND THAT IS HOW -- YOU CAN WAX ON ABOUT THIS. YOU HAVE FIVE MORE MINUTES IF YOU NEED IT. WHAT ARE THE BIG CHALLENGES FOR THE NEXT 50 YEARS OR TO PUT IT IN THE CONTEXT AS I REFER BACK TO CATHERINE KEY, A REGIONAL TALK TO OUR SYMPOSIUM YESTERDAY, AND SHE WAS DESCRIBING COHORT EFFECTS AND WHAT IS THE WAY WE CAN EFFECT THE COHORT OF PROBLEMS, PUBLIC-HEALTH WAY AND MOST EFFECTIVELY SO, PUT ON THE HAT AND TELL ME WHAT WE SHOULD BE DOING? >> >> LET ME POSE QUESTIONS THAT FURTHER RESEARCH WILL NEED TO ANSWER. HOW CAN WE PREVENT PRE-NATAL ALCOHOL EXPOSURE THROUGH CHANGES IN POLICY AND MESSAGING? HOW CAN WE UNDERSTAND HOW ALCOHOL EFFECTS THE DEVELOPING FETUS SO THAT WE CAN DESIGN AND INTERVENTIONS THAT ARE MORE TARGETED AND HOW CAN WE DIAGNOSE FETAL ALCOHOL SPECTRUM DISORDERS WHEN WE WORK WITH A DOZEN DIFFERENT DIAGNOSTIC SYSTEMS? HOW CAN WE ACHIEVE COHERENCE AND HARMONIZE THE SYSTEMS SO THE WORK WE DO IN ONE PART OF THE WORLD IS COMPREHENSIBLE TO PEOPLE IN AT PART OF THE WORLD. CAN WE UNDERSTAND EXACTLY WHAT ALCOHOL IS DOING TO THE DEVELOPING BRAIN AND USING TECHNIQUES OF BRAIN IMAGING AND CAN WE UNDERSTAND HOW ALCOHOL'S EFFECTS IN GESTATION PROGRAM THE ORGANISM FOR CHANGES THAT OCCUR IN PLAY OUT OVER THE LIFESPAN. WHAT ARE THE INTERVENTIONS THAT ARE GOING TO BE MOST SUCCESSFUL IN MITIGATING THE EFFECTS AND IN DEFERENCE TO THE PREVIOUS QUESTIONERS, THE EFFECTS BUT THE SUFFERING THAT IS EXPERIENCED BY THE INDIVIDUAL AND BY THEIR FAMILY AS A CONSEQUENCE TO THE DEFICITS CAUSED BY FETAL ALCOHOL SPECTRUM DISORDERS. HOW CAN WE AUD MATE, HOW CAN WE USE MACHINE LEARNING ARTIFICIAL INTELLIGENCE AND EVERYTHING THAT WE LEARN THROUGH THE RESEARCH THAT IS DONE ON THESE LARGE COHORTS TO MAKE DIAGNOSIS AVAILABLE TO EVERYBODY IN THE WORLD IN A CLOUD-BASED WAY. YOU JUST NEED ACCESS TO THE ENTERTAINMENT AND YOU DON'T NEED TO TRAVEL TO SAN DIEGO AND SEE KEN JONES. AND HOW CAN WE ALSO AUTOMATE TREATMENT AND USE CURRENT AND FUTURE TECHNOLOGY TO BE ABLE TO AAMPLIFY THE RELATIVELY FEW PROVIDERS THAT WE HAVE TO BE ABLE TO IMPACT COMMUNITIES EVERYWHERE IN THE WORLD. THESE ARE A FEW QUESTIONS BIOMARKERS AND THERE ARE MANY OTHERS AND I COULD FELT THE NEXT 25 YEARS OF NIAAA'S RESEARCH PORTFOLIO WITH IMPORTANT QUESTIONS THAT WE JUST NEED TO GET ABOUT AND BE BUSY TRYING TO ANSWER. >> THANK YOU, MIKE A THAT WAS GREAT. IF I MAY BE SO PRESUMPTUOUS, I WOULD ADD ON THAT WE NEED TO PUT ENERGY NO UNDERSTANDING STIGMA AND HOW TO MITIGATE THE EFFECTS OF STIGMA AS WELL, FOR THE MOTHERS IN PARTICULAR, AND I KNOW YOU AND I AND BILL DUNPHY HAVE ATTENDED SOME OF THEIR MEETINGS AND DONE THE BEST WE CAN, BUT I THINK IT'S STILL AN AREA THAT NEEDS SOME WORK. BY THE WAY, I MISS ATTRIBUTED ONE OF THE QUESTIONS TO AMY HENDRIX, THANK YOU FOR YOUR PREVIOUS QUESTION. ANY OTHER QUICK QUESTIONS WE HAVE ONE MINUTE LEFT BEFORE WE MOVE ON? ZEBA FISH HAVE NO UTERUS, I APOLOGIZE. [LAUGHTER] >> WELL. I WOULDN'T HAVE CAUGHT THAT ONE. I DON'T KNOW WHETHER ANYBODY WOULD. WE WON'T TALK ABOUT THAT EITHER. >> THE ONLY STUFF WHEN YOU SEE YOUR OWN TALK. >> THAT'S CORRECT. ANYWAY, THANK YOU SO MUCH, MICHAEL. GREAT TALKING AND GREAT DISCUSSION WITH EVERYONE. WE'RE GOING TO MOVE ON TO OUR NEXT SPEAKER AND THE LAST SPEAKER. THIS IS OUR LAST SPEAKER BECAUSE THIS IS BEEN SO MUCH FUN AND SO MUCH REALLY EXCITING INFORMATION BUT IT'S TO BE CONTINUED AT LEAST FOR ONE MORE TALK. I'M PLEASED TO INTRODUCE OUR NEXT IS DISTINGUISH GUEST SPEAKER, VIJAY SHAH IS A CHAIR OF THE GASTRO INTERROLOGY AND HELP CO TOLL GEE AT THE MAYO CLINIC IN MINNESOTA AND HE HAS INCOMPETENTER RELATED AREAS RELATING TO ALCOHOL ASSOCIATED LIVER DISEASE AND ITS COMPLICATIONS. HIS EXPERTISE IS LABORATORY-BASED STUDIES ON THE MECHANISMS OF DISEASE AND CLINICAL TRIALS RESEARCH AND HIS PRESENTATION IS TITLED "HOPE THROUGH DISCOVERY, ALCOHOL ASSOCIATED LIVER DISEASE" I MIGHT ADD THAT DR. SHAH IS ALSO A LEADER IN OUR LARGE HELP TOLL GEE CON OR SLUM AND I HOPE YOU WILL BE TELLING US ABOUT THAT AS WELL. >> IN THIS TALK I WILL INCORPORATE SOME ORIGINAL RESEARCH, IN ADDITION TO SOME DIE TACTIC INFORMATION ABOUT LIVER DES SEIZE WITH A FOCUS ON NEW CONCEPTS. AND ALSO, BEING INSURE TO ACCOMMODATE ISSUES RELATING TO DIVERSITY OF GENDER, IN ALCOHOL ASSOCIATED LIVER DISEASE AND LIFESPAN. SO, THE GLOBAL BURDEN OF ALCOHOL ASSOCIATED LIVER DISEASE IS SHOWN IN THIS SLIDE, WHICH IS AN ARTICLE THAT I CO AUTHORED, ALONG WITH A COUPLE OF MY COLLEAGUES, THAT WILL COME OUT IN HEL SOON. IT GIVES THE GLOBAL BURDEN OF ALCOHOL ASSOCIATED LIVER DISEASE. 2.4 BILLION PEOPLE USING ALCOHOL AND ALCOHOL USE DISORDERS YOU CAN SEE IS IN ABOUT 10% OF THOSE. COMPENSATED SIRROSIS IN ABOUT 10% OF THOSE PEOPLE AND THAT'S SHOWN HERE IN THE LAST GREEN BAR OF THE DEATHS FROM CANCER FOR 1% OF ALL WORLDWIDE DEATHS. SO, THIS SLIDE ADDRESSES LIFESPAN AND GENDER RELATED ISSUES OF ALCOHOL ASSOCIATED LIVER DISEASE. AND WHAT IS BECOMING CLEAR IN THIS PAPER, AND FROM SEVERAL OTHER PAPERS SINCE THEN, IS THAT THERE'S AN INCREASING MORTALITY DUE TO ALCOHOLIC ASSOCIATED LIVER DISEASE IN YOUNGER PEOPLE AND IN WOMEN. AND THIS IS SHOWN IN THIS SLIDE, ESPECIALLY THE ISSUES RELATED TO SEX IN THIS PANEL ON YOUR LOWER LEFT, AND YOU CAN SEE THAT ALCOHOL ASSOCIATED LIVER DISEASE IS ADVERSELY EFFECTING WOMEN EVEN MORE THAN MEN AND INCREASING IN INCIDENTS IN YOUNGER INDIVIDUALS JUST AGES 25-34. SO ALTHOUGH ALCOHOL ASSOCIATED LIVER DISEASE STILL OCCURS MORE IN MEN THAN WOMEN, THERE'S AN INCREASING INCIDENTS OF DISEASE BURDEN IN WOMEN IN THE CURRENT TIME. AND YOU CAN SEE ALSO, THAT AS I MENTIONED, INCREASES IN TOTAL AMOUNTS OF CIRRHOSIS DURING THIS PERIOD OF TIME AS WELL. SO, ALTHOUGH CARDIAC DISEASE AND PULMONARY DISEASE RECEIVE A GREAT DEAL OF ATTENTION AS CHRONIC CONDITIONS IN THIS COUNTRY AND APPROPRIATELY, THIS SLIDE SHOWS YOU THE BURDEN OF ALCOHOL ASSOCIATED LIVER DISEASE COMPARED TO THESE OTHER MORE STUDIED CONDITIONS. THIS IS SHOWN IN THE RED BARF ALCOHOL ASSOCIATED CIRRHOSIS AND ALCOHOL ASSOCIATED HEPATITIS AND THEIR OVER ALL BURDEN IN TERMS OF INPATIENT CHARGES FOR THESE CONDITIONS COMPARED TO CHRONIC CARDIAC AND PULMONARY DISEASES. SO, WITH THAT BACK DROP OF THE EPIDEMIOLOGY AND GLOBAL DISEASE BURDEN OF ALCOHOL ASSOCIATED LIVER DISEASE, I'LL MOVE TO ONE OF OUR RESENT DATASETS AND I WILL HAVE SOME DATASETS INTO SOME -- WHAT IS THE DEVELOPMENT OF FATTY LIVER DISEASE AND MORTALITY. WE KNOW THAT OBESITY IS AN INCREASING PROBLEM IN OUR COUNTRY FOR PAST SEVERAL DECADES AS WELL AS ALCOHOL CONSUMPTION. SO, WE EXPLORED THIS IN MAYO CLINIC USING OUR WORLD-RENOWNED DATASETS THAT WE HAVE AND THIS IS ONE OF OUR DATASETS WITH 18,000 PATIENTS WITHOUT KNOWN LIVER DISEASE WHO ARE ENROLLED IN A BOY OWE BAN A BIO BANK STUDY IN A PER IOD OF ABOUT SEVEN YEARS. THIS COHORT, WE WERE ABLE TO BREAK INTO GROUPS OF NON CRINGERS OR TEA T TODRINKERS AND MODERATE DRINKERS. ONE TO TWO DRINKS A DAY AND THEN HEAVY DRINKERS OF MORE THAN TWO DRINKS PER DAY. AND THEN THESE INDIVIDUALS WERE FOLLOWED FOR UP TO SIX YEARS AND THEN THESE ARE THE PRIMARY OUTCOMES WE LOOKED AT. FATTY LIVER DISEASE, BASED ON DYING KNOW TICK CODES AND CONFIRMED BY IMAGING STUDIES BY 684 INCIDENT CASES IS OUR PRIMARY OUTCOME FROM THIS GROUP OF PATIENTS. SECONDARY OUTCOMES AND ALL CAUSED MORTALITY AND CARDIOVASCULAR MORTALITY AND IN THE NEXT FEW SLIDES WHICH I WILL SHOW AS GRAPHS, I WILL SHOW YOU PRIMARY END POINT AND IT'S FATTY LIVER DISEASE AS WELL AS SECONDARY OUTCOMES IN THESE THREE CATEGORIES OF INDIVIDUALS LOOKING AT DIFFERENT LEVELS OF BMI TO UNDERSTAND THE RELATIONSHIP OF BMI WITH ALCOHOL CONSUMPTION ON THESE OUTCOMES. SO THIS IS THE FIRST SLIDE SHOWING THAT MODERATE ALCOHOL CONSUMPTION ACTUALLY HAS A PROTECTIVE EFFECT IN NORTHERLIAL BMI BUT A HARMFUL EFFECT IN OBESE INDIVIDUALS FOR FATTY LIVER DISEASE. AND THIS IS SHOWN HERE WHERE MODERATE ALCOHOL CONSUMPTION ACTUALLY HAS A PROTECTIVE EFFECT IN NORMAL BMI INDIVIDUALS AND NO EFFECT IN OVERWEIGHT INDIVIDUALS AND A HARMFUL EFFECT IN OBESE INDIVIDUALS. THIS PROTECTIVE EFFECTIVE MODERATE ALCOHOL CONSUMPTION FOR ALL CAUSE MORTALITY WAS DECREASED IN INDIVIDUALS WHO ARE OVER WEIGHT AND NOT OBSERVED IN INDIVIDUALS WHO ARE OBESE. SO THIS IS AGAIN SHOWN HERE WITH THE SAME GRAPH IN TERMS OF INDIVIDUALS BROKEN DOWN BY A AMOUNT OF ALCOHOL CONSUMPTION IN DIFFERENT BMI CATEGORIES. AND THERE'S A DECREASE IN INDIVIDUALS WHO ARE OVERWEIGHT AND THIS PROTECTIVE EFFECT IS NOT OBSERVED IN THOSE WHO ARE OBESE. AND THEN THE ADDITIONAL END POINT OF CARDIOVASCULAR MORTALITY THE SAME GRAPH PATTERN, WE'LL GO OVER THIS DATA, AND SHOW AS A PROTECTIVE EFFECT OF MODERN ALCOHOL CONSUMPTION AND IT WAS NOT OBSERVED IN OVERWEIGHT OR OBESE INDIVIDUALS. YOU CAN SEE THE PROTECTIVE EFFECT WAS NOT OBSERVED IN INDIVIDUALS WHO ARE OVERWEIGHT OR OBESE COMPARED TO INDIVIDUALS WITH A NORMAL BMI. SO, THIS LEADS US TO UNDERSTAND THAT THERE'S AN INTERACTION BETWEEN ALCOHOL CONSUMPTION AND OBESITY. AND THIS IS ACTUALLY LED US TO PROPOSE SOME DIFFERENT CUT POINTS PERHAPS FOR WHAT IS HAZARDOUS DRINKING AND INDIVIDUALS WHO HAVE A BMI LESS THAN 30 AS OPPOSED TO INDIVIDUALS WITH A BMI GREATER THAN 30 IN TERMS OF ALCOHOL CONSUMPTION. AND WHAT MAY LEAD TO HAZARDS. AND INDIVIDUALS WITH A HIGHER BMI AS WELL AS INDIVIDUALS WHO ARE WOMEN SHOULD HAVE A LOWER THRESHOLD FOR ALCOHOL CONSUMPTION BECAUSE OF THESE ADVERSE EFFECTS THAT ARE SHOWED YOU. THE EXACT AMOUNTS I'VE SHOWN YOU HERE TAKING INTO ACCOUNT GENETIC PREDISPOSITIONS AND FAMILY HISTORIES AND OTHER VARIABLES. SO, WE'LL MOVE FROM THAT DATA SET INTO THE NEXT ISSUE OF MANAGING EXCESS ALCOHOL CONSUMPTION IN INDIVIDUALS WITH ALCOHOL USE DISORDER AND I'M GOING TO FOCUS IN THESE NEXT SEVERAL SLIDES, ESPECIALLY ON INDIVIDUALS WITH COEXIST ANT ALCOHOL USE DISORDER AND ALCOHOL USE DISORDER. THIS SHOWS YOU A COUPLE OF GROUPS WITHIN THE POPULATION. THE GENERAL POPULATION AS WELL AS THE HIGH-RISK POPULATION. IN THE GENERAL POPULATION AND I'LL GO THROUGH THIS IN SEPARATE SLIDES. THERE ARE TACTICS THAT ARE EFFECTIVE. THIS INCLUDES ALCOHOL TAXATION, MINIMUM UNIT PRICING, AND LIMITING ALCOHOL AVAILABILITY. AND THEN IN THE GROUP THAT'S ALCOHOL ASSOCIATED LIVER DISEASE THERE'S COGNITIVE AND BEHAVIORAL THERAPIES AND WE'LL DISCUSS IN LATER SLIDES. SO, THIS SLIDE, TAKEN FROM THE ARTICLE I MENTIONED EARLIER WHICH I'LL SHOW YOU A FEW FIGURES FROM THIS ARTICLE, STARTS TO LOOK AT THIS COMBINATION OF ALCOHOL USE DISORDER AND ALCOHOL ASSOCIATED LIVER DISEASE AND RECOGNIZING HIGH-RISK PATIENTS AND HOW TO SCREEN AND RISKS GRATIFY THESE INDIVIDUALS AND THE NEXT SLIDE I WILL SHOW YOU WILL FOCUS ON POTENTIAL INTERVENTIONS AND THESE GROUPS. SO, FOR ALCOHOL USE DISORDER, RISK STRATIFICATION USES NIAAA RECOMMENDATIONS, AUDIT SCORE, BIOMARKERS, URINARY ETHANOL PAP TESTING AND FOR ALCOHOL ASSOCIATED LIVER DISEASE, NON INVASIVE SERUM BASED BIOMARKERS OR ALGORITHMS AND USING IMAGES STUDIES THAT ARE NON INVASIVE AND POSSIBLY I'VE SEEN SOME CASES LOOKING FOR THAT GROUP THAT MAY HAVE AUD AS WELL AS ALD KNOWING THAT THIS IS THE GROUP THAT REALLY WE NEED TO FOCUS MORE ATTENTION ON. AND SO, THAT IS WHERE WE HAVE THIS TARGETED SCREENING AND HIGH-RISK AUD AND ALD CANDIDATES AND IDENTIFYING THESE INDIVIDUALS FOR MORE IN-DEPTH ASSESSMENT FOR ALCOHOL USE DISORDER AND MORE IN-DEPTH ASSESSMENT FOR ALCOHOL ASSOCIATED LIVER DISEASE. AND WHAT TO DO IN THESE INDIVIDUALS? THIS IS A SLIDE FROM THE SAME ARTICLE LOOKING AT TREATMENT PARADIGMS FOR THESE INDIVIDUALS. AND HERE AGAIN, WE'LL TAKE IT FROM THE TOP OF THIS SLIDE. LIVER PATIENT PRESENTS TO THE PRIMARY CARE CLINIC AND GOES THROUGH WHAT I OUTLINED IN THE PRIOR SLIDE. ASSESS FOR ALCOHOL USE AND ALCOHOL ASSOCIATED LIVER DISEASE AND USING NON INVASIVE EVALUATIONS AND SIR LOGIC EVALUATIONS AND THEN CHARACTERIZING OR CATEGORIZING THE ALCOHOL ASSOCIATED LIVER DISEASE INTO THESE STAGES OF NON, JUST FAT IN THE LIVER, FAT PLUS INFLAMMATION, SCARRING, AND SCARRING WITH HEPATITIS AS WELL. AND POTENTIAL MANAGEMENT ALGORITHMS HERE OF WHO MIGHT BE WELL EQUIPPED TO TAKE CARE OF THESE PATIENTS. OFTEN INDIVIDUALS IN VERY EARLY STAGES ARE FINE WITH A PRIMARY CARE MANAGEMENT APPROACH. THEY WILL REQUIRE INPUT FROM HELPTOLOGISTS OR CO MANAGEMENT WITH HELPTOLOGISTS AND IN THE MOST EXTREME EXAMPLES, REQUIRE TRANSPLANT HEL HELP A TOLL GEE. THE ALCOHOL USE DISORDER, AGAIN, YOU CAN IMAGINE A SIMILAR SPECTRUM. MISUSE AND MILD AUD AND MORE SEVERE AUD AND AGAIN, SAME IDEA OF SCREENING PREVENTION AND EDUCATION AND THEN REFERRING TO A PROFESSIONAL. THIS IS REALLY WHERE WE HAVE A GREAT DEAL OF OPPORTUNITIES AND WE'VE BEEN PARTNERING WITH NIAAA TO EXPLORE MODELS WHERE WE MIGHT HAVE HELPTOLOGISTS BETTER UNDERSTAND ALCOHOL USE DISORDER AND WE KNOW RIGHT NOW THROUGH SURVEYS AND OTHER INSTRUMENTS THAT MOST HEPATOLOGISTS, EVEN THOUGH WHO ALCOHOL ASSOCIATED WITH LIVER DISEASE DON'T FEEL COMFORTABLE PRESCRIBING MEDICATIONS AND DON'T FEEL LIKE THEY HAVE THE SKILL FOR INTERVENTION SO THIS IS AN UNMET NEED. SO WITH THAT, I WILL MOVE INTO A PROPOSED TREATMENT ALGORITHM IN ALCOHOL ASSOCIATED HEPATITIS. SO THESE ARE PATIENTS WITH ALCOHOL ASSOCIATED HEPATITIS AND WE KNOW THAT THEY HAVE ALCOHOL USE DISORDERS BECAUSE OF THE SEVERE INJURY IN THEIR LIVER FROM ALCOHOL. AND SO THAT'S THE STAPLE IS IMPLEMENTING THERAPY FOR ALCOHOL USE DISORDER AND I'M GOING TO SHOW YOU A COUPLE SLIDES OF A STUDY WE DID ON THIS TOPIC. IN ADDITION TO THAT, THOSE WITH MILD DISEASE SHOULD RECEIVE NUTRITIONAL SUPPLEMENTATION AND TREATMENT OF COMPLICATIONS. WE CHARACTERIZE THE DISEASE AS MILD OR SEVERE USING THE FUNCTION AND MORE COMMONLY AND POPULARLY WE USE THE MEL SCORE AND THE MEL SCORE OVER 20 CAN SIGNIFY SEVERE ALCOHOL ASSOCIATED LIVER DISEASE OR ALCOHOLIC HEPATITIS. AND INDIVIDUALS WITH CONTRA INDICATIONS TO STEROIDS, YOU CAN BE EVALUATED FOR THIS AND IF THEY DON'T HAVE CONTRA INDICATIONS, THE STEROIDS CAN BE USED. AFTER ONE WEEK OF STEROID INTERVENTION WE CAN EVALUATE IF THEY'RE HAVING BENEFITS THROUGH A NUMBER OF DYNAMIC SCORES INCLUDING THE LIL SCORE WHICH ASSESSES BILLY RUBEN AND VARIABLES AND HOW THEY CHANGED IN PATIENTS. FOR NON RESPONDERS, WE LOOK AT WHETHER THE PATIENT IS A TRANSPLANT CANDIDATE. I'LL SHOW YOU A FEW SLIDES ABOUT TRANSPLANTATION LATER ON TO FINISH THE TALK. IT'S VERY IMPORTANT THAT INDIVIDUALS WHO ARE VERY ADVANCED IN DISEASE AND ARE NOT CANDIDATES FOR LIVER TRANSPLANTATION THAT PALLIATIVE CARE PATHS ARE PERSUADE BECAUSE OTHERWISE INDIVIDUALS ARE COMING BACK AND FOURTH FOR REPEATED HOSPITALIZATIONS, UTILIZING LARGE AMOUNTS OF RESOURCES AND OFTEN HAVE NO PATH TOWARDS ANY MEANINGFUL RECOVERY. SO THIS SLIDE GOES OVER SOME OF THE CURRENT FARM LOGIC TREATMENT OPTIONS FOR ADDICTION IN INDIVIDUALS WITH ALCOHOL USE DISORDER AND LIVER DISEASE. AND MANY OF YOU KNOW THESE DRUGS BETTER THAN ME. I WOULD SAY THAT THE DRUG THAT'S RECEIVED PROBABLY THE MOST ATTENTION AND IS USED MOST FREQUENTLY IN THIS GROUP OF PATIENTS WITH COEXISTING ALCOHOL USE DISORDER AND LIVER DISEASE IS BACKLAFIN AND LORENZO LEGGIO, WHO MIGHT BE ON THIS CALL, IS ONE OF THE WORLD EXPERTS IN THE USE OF THIS DRUG AND THE INDICATION IN DOSING IS PROVIDED HERE AND THE RED CIRCLE. I'LL REMIND YOU THAT OTHERS ARE FDA APPROVED FOR ALCOHOL USE DISORDER ALTHOUGH NOT NECESSARILY ALL APPROVED IN PATIENTS WITH ALCOHOL ASSOCIATED LIVER DISEASE AND FURTHERMORE, AS I MENTIONED, MANY HEPATOLOGISTS ARE NOT COMFORTABLE PRESCRIBING THESE MEDICATIONS AND FURTHERMORE, WE KNOW THAT WE NEED TO PROVIDE THERAPY, COGNITIVE, BEHAVIORAL THERAPIES IN COMBINATION WITH FARM LOGIC THERAPY AND THAT'S ALL LACKING RIGHT NOW. AND HERE, WE LOOKED AT INDIVIDUALS WHO WERE HOSPITALIZED WITH ALCOHOL ASSOCIATED LIVER DISEASE AND THOSE WHO RECEIVED ALCOHOL COUNSELING EARLY VERSUS THOSE WHO DID NOT RECEIVE ALCOHOL COUNSELING. AND YOU CAN SEE THAT IN TERMS OF BOTH IN A TEST COHORT AND A VALIDATION COHORT LOOKING AT BOTH 30-DAY READMISSION AS WELL AS 30-DAY ALCOHOL RELAPSE, THAT INDIVIDUALS WHO DID ATTEND EARLY ALCOHOL REHABILITATION HAD A MUCH LOWER 30-DAY READMISSION AND RELAPSE RATE COMPARED TO THOSE WHO DID NOT ATTEND. THIS IS CERTAINLY A CHALLENGE FOR US IN THE WARDS. IT'S CONVINCING PATIENTS TO UNDERGO REHABILITATION TO SEE A THERAPIST AND THEN ON THE FLIP SIDE, WE KNOW THAT MANY HEALTH SYSTEMS ARE STRESSED AND DO NOT HAVE THAT AVAILABILITY AND INSURANCE PRODUCTS AND MEMES ARE ALSO LIMITED FROM A BIN LADIN PERSPECTIVE. COMPARED TO THE RED LINE OF LOWS WHO DID NOT RECEIVE ALCOHOL REHABILITATION. SO SOME SUMMARY RECOMMENDATIONS THAT I'LL PROVIDE YOU. ALL PATIENTS WITH SHOULD BE EVALUATED BY ADDICTION SPECIALISTS DURING THE HOSPITAL STAY AND REFERRED FOR TREATMENT WITHIN 30 DAYS OF HOSPITAL DISCHARGE. NEXT WE'LL MOVE TO STRATEGIES TO MITIGATE THE IMPACT OF ALCOHOL ASSOCIATED LIVER DISEASE AT GLOBAL LOCAL REGIONAL AND INDIVIDUAL LEVELS. I'VE GONE OVER SOME OF THIS THROUGH THE PRIOR SLIDES AND THE A GLOBAL LEVEL WE NEED BROADER SOCIETY WIDE ALCOHOL REDUCTION AND MONITORING OF IDENTIFY INDIVIDUALS WHO ARE DRINKING IN SUCCESS AND SOME HAVE SHOWN HERE IN TERMS OF PRICEING AND I MENTIONED BY TAXATION AND IT'S NOT POPULAR BUT IT WORKS AND REDUCTION OF ALCOHOL AVAILABILITY AND BY GOVERNMENT REGULATIONS AND REGULATED HOURS OF SALES AND AGE LIMITS AND RESTRICTIONED PROMOTION BY LIMITING ACCESSIBILITY OF ADVERTISING TO YOUTH TARGETING AND AND THEN WARNING LABELS, ET CETERA. EARLY IDENTIFICATION OF ALCOHOL USE DISORDER AND ALCOHOL DISORDER LIVER DISEASE INDIVIDUALS WITH BOTH CONDITIONS COEXISTING AND I SHOWED YOU DATA ABOUT POPULATION SCREENING AND THIS IS AN OPPORTUNITY HERE IN TERMS OF OUTREACH PROGRAMS, TELEHEALTH EXTENDERS USING TECHNOLOGY TO HELP US REACH MORE PEOPLE. AND AN EXAMPLE OF THIS TECHNOLOGY IS PROJECT ECHO WHICH WAS IN THE PROJECT THAT WAS USED TO DES SEM NATURE INFORMATION ABOUT HEPATITIS C AND TREATMENT TO PROVIDERS IN HOLE RURAL AREAS PROVIDE CARE FOR PATIENTS WITH HEPATITIS C AND YOU CAN IMAGINE SIMILAR APPROACHES MIGHT BE EFFECTIVE FOR ALCOHOL USE DISORDER AND ALCOHOL ASSOCIATED LIVER DISEASE AS WELL. AND AT THE INDIVIDUAL LEVELS, INDIVIDUALIZED TREATMENT FOR ALCOHOL USE DISORDER AND ALCOHOL ASSOCIATED LIVER DISEASE AND HERE, I BLEAK OUT THE THERAPY AND AS WELL AS ALCOHOL USE DISORDERS AND THEN RECOGNIZING AN UNMET NEED IS IDENTIFYING INDIVIDUALS WHO CAN HELP PATIENTS WITH BOTH OF THESE CONDITIONS COEXISTING. SO I MADE A ILLUSION TO TECHNOLOGY AND WE KNOW THAT WITH THE IMPROVEMENTS IN BIO MONITORING, ARTIFICIAL INTELLIGENCE AND REMOTE MONITORING AND TELEHEALTH AND WEARABLES AND THAT WE ARE IN A POSITION TO REVOLUTIONIZE HOW WE TAKE CARE OF PATIENTS WITH ALCOHOL USE DISORDERS AND THOUSAND CONTINUED ENHANCEMENTS OF MEASURE COLOR LEVELS IN INDIVIDUALS AND THEN BEING ABLE TO RESPOND TO THEM THROUGH APSE OR COMPUTER-BASED ALGORITHM AND TECHNOLOGIES THAT MIGHT ALLOW US TO REACH PEOPLE THAN WE'VE BEEN REACHING. SO, THE SUMMARY OF THIS SECTION OF THE TALK THE HEALTHCARE BURDEN OF ALCOHOL LIVER DISEASE INCREASES AT LOCAL REGIONAL AND GLOBAL LEVELS AND ANY PROTECTIVE EFFECTS OF ALCOHOL ARE LOST AND OVER WEIGHT AND OBESE INDIVIDUALS AND ALL PATIENTS WITH ALCOHOL ASSOCIATED HEPATITIS SHOULD BE FORMALLY EVALUATED BY ADDICTIONS SPECIALISTS AND REFERRED FOR TREATMENT. WE NEED TO IMPROVE THE QUALITY OF ALCOHOL ASSOCIATED LIVER DISEASE DATA AND STANDARDIZE OUR REPORTING AND SUPPORT APPROACHES THAT ADDRESS BOTH ALCOHOL ASSOCIATED LIVER DISEASE AND ALCOHOL USE DISORDER AND DIGITAL TECHNOLOGIES FOR UNDERSERVED COMMUNITIES. AND IN THE LAST SECTION OF MY TALK I'LL TALK A LITTLE BIT ABOUT WHAT IS NEW IN SOME OF THE RESEARCH IN THIS AREA ESPECIALLY THE WORK FOR MAYO CLINIC, WHERE I WORK. FOCUS ON AREAS WHERE WE'RE EXPLORING AND AREAS OF HOW ALCOHOL DAMAGES LIVER CELLS AND WE KNOW THAT DAMAGE RELEASE THINKS WHICH HAVE A NUMBER OF OPPORTUNITIES THE ALCOHOL INJURY PARASITES I SHOULD SHOW AND I DIDN'T MEANING HERE AFTER THIS INJURY THEY RELEASED THESE AND THESE IN TURN RECRUIT CELLS SUCH AS MACRO FACT AND THEY RELEASE A NUMBER OF CYTOKINE AND LEAD TO INJURIES THAT WE SEE AND INFLAMMATION THAT WE SEE IN PATIENTS WITH ALCOHOL ASSOCIATED LIVER DISEASE. WE HAVE STUDIES GOING ON IN 22 AND THEY WERE PIONEERS AND BEN GAL AND WE HAVE TRIALS GOING ON IN INHIBITION THROUGH PRE CLINICAL STUDIES PIONEERED BY THAT ARE NOW ON GOING THROUGH THE NET WHICH I WILL SHOW YOU LATER. WE ARE LOOKING AT A NON ENFACE I HAVE APPROACH TO TRY TO UNDERSTAND THE LEVEL OF INJURIES BUY BROW SIS IN THE COVER AND FOR A LIVER BUY OLE SEE WHICH IS NEEDED TO MAKE THAT DYING KNOWING SIS SO I'LL SHOW YOU DATA FROM THAT LAST CARTOON SUT A COUPLE OF PIECES TO GIVE YOU A CONCERNED OF WHAT WE'RE DOING. THIS IS A RECENT PUBLICATION AND THAT I WILL SHOWED YOU DATA FROM WHETHER THEY COULD BE A BIO MARKER IN ALCOHOL ASSOCIATED LIVER DISEASE WE KNOW THEY HAVE PRE CLINICAL MODELS SUCH AS MICE, AS WELL AS IN HUMANS AND AS WELL AS IN INVITO MODELS WITH CELLS THAT INJURED RELEASE THESE VES I CANELS AND THEY CAN BE DETECTED FROM BLOOD AND MEASURED AND ANALYZED. SO THIS IS AN EXAMPLE OF A RECENT PUBLICATION FROM OUR GROUP LOOKING AT THE NUMBERS OF PATIENTS WITH ALCOHOL ASSOCIATED HEPATITIS AND IN DEED, INDIVIDUALS WITH HIGHER NUMBERS OF CIRCULATING WORSE SURVIVAL AND THOSE WITH HIGH EV COUNTS DO WORSE THAN INDIVIDUALS WITH LOW EV COUNTS SO THEY APPEAR TO PREDICT THE LEVEL OF SEVERITY OF THE DISEASE EX AND SO, THERE'S GREAT OPPORTUNITIES HERE WHICH WE CONTINUE TO EXPLORE AND ABOUT HOW THE LIVER MIGHT RELEASE THESE THESE AND THEY WE DETECT THE BLOOD THAT MIGHT BE LIVER SPECIFIC AND HOW WE USE THEM TO ANALYZE THEM FOR DIAGNOSIS AND DYNAMIC RISK PROFILING. AND SO I MENTIONED TO YOU THAT THERE'S A GREAT DEAL OF ACTIVITY IN THE FIELD THAT'S REALLY BEEN SPEARHEADED BY THE NIAAA THROUGH TARGETED INVESTMENTS TO ENERGIZE AND TRANSFORM THIS FIELD. AND SO THIS IS A SLIDE SHOWING THE NIAAA CONSORTIUM WHICH IS TO ADVANCE THE UNDERSTANDING AND CLINICAL MANAGEMENT OF ALCOHOL ASSOCIATED HEPATITIS TESTING NEW THERAPIES SUCH AS IL22 AND FOCUSING ON NEW DRUG ABLE DISEASE MECHANISMS. AND THE MANY OF STUDIES THROUGH THIS CONSORTIUM FOCUS ON HOW ALCOHOL AFFECTS THE INTESTINE, THE LIVER CELLS, AND AS WELL AS THE INFLAM A WHICH INJURY TO A CELL LEADS TO INFLAMMATORY CELL RECRUITMENT. AND A NUMBER OF MOLECULES RELEASED BY THESE VARIOUS CELLS ARE FOCUS ESPECIALLY I WILL SHOWED YOU A SLIDE ABOUT AND THIS INVOLVES CELL TYPES IN THE LIVER INCLUDING THE CELLS. I'LL SHOW YOU A SLIDE HERE. THIS IS A HOMEGROWN PRODUCT OF THE NIAAA AND IT'S PRODUCED FROM BLOOD CELLS AND IT PROMOTES LIVER REPAIR AND IT REDUCES FIBRO SIS AND IT'S NOT IMMUNO SUPPRESSIVE. THERE'S ACTIVE TRIALS AND WE'VE BEEN CONDUCTING TRIALS IN ALCOHOLIC HEPATITIS AS WELL. AND THIS IS SHOWN HERE. THE PROOF OF CONCEPT OF HOW THE DRUG SHOULD WORK AND IT'S TO REDUCE THE INJURY AND STIMULATE HEPATOCYTE AND THIS WAS A STUDY SHOWING THIS COM BOUND WHICH IS A FUSION PROTEIN OF HUMAN IS ABLE TO IMPROVE SURROGATE MARKERS OF LIVER INJURIES USING THE MEL SCORE, FOR EXAMPLE, AND THAT OVERTIME, INDIVIDUALS WITH ALCOHOL ASSOCIATED IT HAVE AN IMPROVEMENT IN THEIR MEL CORE MEL SCORE AND THIS OVER ONE MONTH AS WELL AS UP TO DAY 42 AND AN INDIVIDUALS WITH MODERATE AS WELL AS SEVERE ALCOHOL ASSOCIATED HEPATITIS. SO, FURTHER TRIALS ARE BEING PREPARED FOR A CONTROL GROUP AND A RANDOMIZED CONTROL TRIAL. AND FINALLY, THIS IS SOME ACTIVE WORK GOING ON IN OUR PROGRAM AS WELL. I MENTIONED THE CHEMO KINDS AND LOOKING AT HOW WE CAN ROCK THE PROCESS WHICH WHICH CYTOKINES SUCH AS AT THESE CHEMO COINS AND WE KNOW THEY'RE ABLE TO BY TARGETING A SUPER ENHANCER THROUGH A PATHWAY OF A TRANSCRIPTION FACTOR CALLED BRD4. SO, FINALLY I'M GOING TO WRAP-UP HERE WITH A COUPLE SLIDES ABOUT LIVER TRANSPLANTATION. WE KNOW THAT THERE'S OUTSTANDING TRANSPLANT OUTCOMES FOR ALCOHOL ASSOCIATED CIRRHOSIS AND THIS IS LED TO AN INCREASE IN THE AMOUNT OF TRANSPLANTS BEING DONE FOR ALCOHOL ASSOCIATED HEPATITIS. AND WE KNOW THAT THERE'S INCREASING NUMBER OF CENTERS DOING THIS NOW AND THERE'S A RECOGNITION THAT WE NEED TO PROVIDE SOME LEVELS OF STANDARDS OF CARE OF WHICH TYPES OF PATIENTS WITH ALCOHOL ASSOCIATED HEPATITIS SHOULD UNDERGO LIVER TRANSPLANTATION AND WHICH PATIENTS SHOULD NOT. AND SO A RECENT CONFERENCE BY SPONSORED BY THE COLLEAGUES AT BAYLOR, WENT OVER SOME PATIENT CRITERIA FOR LISTING AND RECOMMENDATIONS AND I REFER YOU TO THIS PAPER AS WELL AS ANOTHER PAPER THAT IS IN LIVER TRANSPLANTATION FOCUSED ON THE OUTCOMES FROM THIS CONFERENCE. >> THANK YOU. THAT WAS SUPERB AND GAVE ME A LOT OF NEW INFORMATION THAT I SORT OF NEW ABOUT BUT REALLY HELPED CONSOLIDATE IT AND I THINK THE EFFORT OF NOT ONLY FINDING NEW TREATMENTS FOR ALCOHOL ASSOCIATE THE LIVER DISEASE BUT ALSO TO EMPLOY WHAT WE ALREADY KNOW INTO MEDICAL CARE WAS SOME OF YOUR EFFORTS AT THE MAYO CLINIC ARE REALLY EXCELLENT. WE'RE OPEN FOR QUESTIONS. I HAVE MY PHILOSOPHICAL ONES LINED UP AND MICHAEL COLLINS IN CHICAGO, THANK YOU DR. FOR YOUR CLEAR PRESENTATION AND YOUR DATA INDICATES THAT MODERATE ALCOHOL ADD A PRO DETECTIVE AND CARDIO PROTECTIVE IN NORMAL BMI. WHAT IS JURY EXPLANATION FOR THIS FINDING IN SOME COGNITIVE STUDY AND DO YOU THINK BMI IS PROBABLY A POSSIBLE EXPLANATION. >> THANK YOU, GEORGE. THINGS WE SEE IN RESEARCH DOESN'T ALWAYS RESULT IN RECOMMENDATIONS AND PUBLIC POLICY SO BY THAT, I MEAN THAT WE DO SEE SOME STUDIES WHERE THERE'S A SIGNAL OF BENEFICIAL EFFECTS OF MODERATE ALCOHOL CONSUMPTION AND THIS IS SEEN THROUGH CARDIOVASCULAR SIGNAL BUT WE KNOW THAT THERE'S NO JAY-SHAPED CURVE FOR ALCOHOL CONSUMPTION AND CANCER IS AND WE ALSO KNOW THAT WHEN THE INDIVIDUALS START DRINKING SMALLER AMOUNTS IT CAN LEAD TO LARGER AMOUNTS OF ALCOHOL CONSUMPTION SO THIS IS WHAT WE FOUND. IT'S ANTI INCOMPETEN INTELLECTUAL TO NOT SHOW THE RESULT. I WOULDN'T RECOMMEND MODERATE ALCOHOL CONSUMPTION TO PEOPLE BUT IT'S EXACERBATED IF OWE BEE TEASE AND THIS IS STUDIES MANY YEARS BACK THE COMBINATION EFFECT OF OBESITY WITH ALCOHOL CONSUMPTION. >> FROM MY PERSPECTIVE IT'S A KEY PART OF THE FINDINGS IS THIS INTERACTION WITH BMI AND I THINK IT'S WELL WORTH MAKING THE POINT THAT EVEN IF THIS WAS DISCOVERED AEROMEXICO ON. ON ITS NEGLECTED IN OUR PERSPECTIVE. NIAAA RECOMMENDS THAT WE STICK WITH THE DIETARY GUIDELINES TWO DRINKS A DAY FOR MALES AND ONE DRINK DRINK A DAY FOR FEMALES. EVEN THERE, AS YOU POINT OUT, THE LIKELIHOOD OF INCREASED CANCER IS A REAL PHENOMENON AND IT STARTS WITH ANY DRINKING AND I REFER YOU TO THE NATIONAL CANCER WEBSITE. ANDRE ORRIS HAS THE FOLLOWING QUESTION. WHAT IS THE MECHANISM OF THE PROTECTIVE EFFECTS OF MODERATE DRINKING IN NORMAL BMI INDIVIDUALS. WHY NOT IN OVERWEIGHT OR OBESE PATIENTS? >> IT'S ALONG THE SAME LINES AS THE PRIOR QUESTION IF THE SENSE THERE MAY BE SOME BENEFICIAL CARDIO VAAS YOU LAR EFFECTS OF LOW LEVELS OF ALCOHOL AND THIS IS SEEN IN AV A VARIETY 6 OF STUDIES PREVIOUSLY. THAT MAY BE PART OF THE BASIS. SO, NON ALCOHOL HEPATITIS, OR NASH AS IT'S KNOWN AND GO UNDIAGNOSED BECAUSE THEY'RE A LARGELY ASYMPTOMATIC, DO YOU HAVE RECOMMENDATIONS FOR PRIMARY CARE PROVIDERS ON HOW TO DETECT EARLY DAMAGE AND IDENTIFIED HOW TO ADDRESS THEM WITH PATIENTS AND IF YOU CAN ANSWER THAT WITH A SOLID SUGGESTION, IT OF COURSE WOULD NOT GOING FAR TO WHAT YOU SPENT THE EARLY PART OF YOUR TALK TALKING ABOUT WHICH IS HOW CAN WE USE, IN FACT, LIVER PATHOLOGY AS A BIO MARKER FOR TREATMENT IN EFFECT. >> SO THERE ARE WAYS I CAN ANSWER THIS THAT ARE CURRENT STANDARDS OF CARE AND IN TERMS OF FUTURISTIC IDEAS AND THIS CURRENT STANDARDS OF CARE GENERALLY ARE GOING TO FOCUS ON NON INVASIVE TESTING, BECAUSE, INVASIVE TESTING DOESN'T HAVE A ROLE IN SCREENING PROCESSES. THE NON INVASIVE TESTING APPROACHES INCLUDE ALGORITHMS FROM BLOOD TESTS. MANY ARE OTHERS WIDE LIE IN PATIENTS WITH NON ALCOHOL ASSOCIATED LIVER DISEASE AND INVOLVE A COUPLE OF THE LIVER BLOOD TESTS SUCH ASDALT AND THE PLATELET COUNT AND DIFFERENT ALGORITHMS HAVE DIFFERENT VARIABLES IN IT AND OFTEN TIMES THE MOST COMMON BLOOD TEST THAT MIGHT BE IN A STANDARD SCREEN TEST WILL BE AN AST OR AN ALT AND IT'S OFTEN WHERE MANY OF THE CASES WILL BE REFERRED TO THE LIVER CLINIC FROM THERE AND THE NEXT STEP REALLY AFTER BLOOD TESTING, IS NON INVASIVE IMAGING AND MUCH OF THAT FOCUSES ON EITHER YOU WILL T ULTRASOUND SCREENING AND JUST LIKE WE KNOW WHEN THE LIVER GETS HARD AND IT'S STIFFER. WE CAN SENSE THAT FROM AN ULTRASOUND MACHINE AS WELL USING -- I SHOW ED YOU ONE IMAGE OF THE MR WHICH IS MORE ACCURATE BUT MORE EXPENSIVE AND NOT AS WIDELY AVAILABLE AT THIS TIME BUT I THINK THAT THE CEILING FOR TECHNOLOGY IMPROVEMENTS IN THE MR TECHNOLOGY IS MUCH HIGHER. SO WE'RE HOPEFUL THAT THAT WILL ALSO SERVE AS AN APPROACH. IN TEMPERATURES OF RESEARCH, THIS IS A VERY ACTIVE AREA OF NON ENFACE I HAVE TESTING. WE'RE DOING A LOT OF WORK IN THIS AREA AND HOW WE DETECT LIVER DISEASE EARLIER. I WON'T GO INTO TOO MUCH ABOUT WHAT WE'RE DOING RIGHT NOW. SUFFICE IT TO SAY, THERE'S A LOT OF PROMISING APPROACHES, USING WEARABLES AND DIGITAL TECHNOLOGY THAT COULD HELP US SCREEN LARGE, MUCH LARGER NUMBERS OF INDIVIDUALS WITH MUCH LESS COST. >> GREAT. SO, WE HAVE A QUESTION FROM LORENZO LEGGIO. HE SAYS DR. SHAH, THANK YOU FOR A WONDERFUL TALK. STIGMA HAS EFFECTS IN THE LIVER FIELD AND PATIENTS WHO ARE LESS LIKELY TO RECEIVE LIVER TRANSPLANT. CAN YOU COMMENT ON THIS. THANK YOU SO MUCH. >> HE IS CORRECT. IN THE LIVER FIELD, WE'RE ALL WORKING TO ENHANCE OUR INTERNET EVERINTERACTIONS WITH ALCOHOL USE DISORDER SPECIALISTS AND IN TURN AS I MENTIONED, THERE'S A SHORTAGE OR A LACK OF VEIL ABILITY AND LACK OF ACCESS TO ADDITION SPECIALISTS AND ESPECIALLY IN LIVER PATIENTS AND VARIETY OF REASONS FOR THIS AND PART OF THE SOLUTIONS ARE FOR LIVER SPECIALISTS TO START TO BETTER UNDERSTAND ALCOHOL USE DISORDER MANAGEMENT AND WE'RE WORKING WITH NIAAA RIGHT NOW TO TRY TO THINK ABOUT HOW WE MIGHT BE ABLE TO INCORPORATE COMPONENTS OF THIS INTO LIVER TRAINING, ESPECIALLY NOW WITH SO MUCH OF THE LIVER DISEASE BEING CAUSED FROM ALCOHOL-BASED IDEOLOGIES AND SO I THINK THAT SOME OF THAT STIGMA CAN BE RESOLVED TRYING TO GET TO THE QUESTION ITSELF BY PHYSICIAN, BY PATIENTS SEEING PHYSICIANS COMFORTABLE TALKING ABOUT ALCOHOL DISORDER RATHER THAN PASSING THE BUCK AND HAVING THAT DEALT WITH BY AN ADDICTION SPECIALIST AND IN WHICH CASE MANY OF THE PATIENTS DON'T EVEN WANT TO GO CENA INDIVIDUAL. AS YOU POINTED OUT IN THAT SLIDE AND THE GRAIN FROM ALCOHOL ASSOCIATED LIVER DISEASE AND LARGER AND CARDIOVASCULAR SO THEY HAVE A QUESTION AND THE COUNT IS ELEVATED AND MANY PATIENTS WITH ALCOHOL HEPATITIS WITH CIRRHOSIS SO THE NUMBER OF HELP AT SIGHTS ARE REDUCED AND SO WHAT ARE THE SOURCES OF THESE COMING FROM IN CIRRHOSIS. >> THIS IS PART OF THE COMPLEXITY OF THE FIELD OF VESICLES IS IDENTIFYING THEIR IDEOLOGY. WE'RE DOING STUDIES RIGHT NOW LOOKING IN SIP CODES ARE IS WE THINK THEY'RE COMING FROM HELP AT SIGHTS BUT PROBABLY MANY THOSE CIRCULATING IN THE BLOODY ARRIVE FROM PLATELETS AND WE NO CELLS ALSO MAKE VES I CAN ELSE AND I DIDN'T SHOW YOU ABOUT BENEFICIAL EFFECTS BUT THEY CAN ALSO BE A SOURCE OF CARRYING BENEFICIAL CARGO AND MANY THERAPIES ARE BEING EVALUATED IN TERMS OF PACKAGING DRUGS INTO VES I CAN ALS. >> IT'S COOL TO THINK OF BAR CODES ON EXTRA CELLULAR VESICLES. STAR WARS. KIM MILLER ASKS, DO YOU SEE CULTURAL DISPARITIES IN FAS AND LIVER DISEASE? IS NIAAA WORKING TO DECREASE ANY DISPARITIES? >> I'LL LET YOU ANSWER THE FIRST PART OF THAT ON THE LIVER DISEASE AND MAYBE I CAN SAY FEW WORDS ON THE OTHER PART. >> I THINK CLEARLY WE HAVE DISPARITIES IN LIVER DISEASE AND I MIGHT AND WE'RE LOOKING HEALTH EQUITY AND THERE'S MULTIPLE GROUPS THAT ARE THEY'RE DEVELOPING STRATEGIES TO ADDRESS THAT THERE'S ALSO LACK OF GOOD LIVER ACCESS FOR RURAL POPULATIONS AND AS WELL AS FOR ELDERLY POPULATIONS. SO THERE MAY BE APPROACHES THAT ARE COMMON THAT COULD ADDRESS MULTIPLE GROUPS AND SOME OF THEM ARE URBAN AND SETTINGS OF DISPARITIES AND SOME OF THEM ARE RURAL SETTINGS OF DISPARITIES BUT NONE THE LESS, WE NEED TUESDAUSETECHNOLOGIES TO REACH MORE INDIVIDUALS AND ALSO RECOGNIZING THAT ALL OF THE CURRENT TECHNOLOGIES MAY NOT BE AVAILABLE TO INDIVIDUALS WHO HAVE A LACK OF HEALTH EQUITY BUT THIS IS THE DIRECTION WE'RE GOING TO NEED TO GO GIVEN LIMITATIONS AND HEALTH PROVIDERS AND HOW MUCH DOCTORS CAN DO FACE-TO-FACE. >> I DID HAVE A SLIDE A LOT THE END OF MY PRESENTATION WITH SOME OF THE GOALS WE'VE OUTLINED ON DISPARITIES. WE DEFINITELY BELIEVE THAT A DIVERSE APPROACH TO SCIENCE IS THE BEST APPROACH FROM INNOVATION AND THE PERSPECTIVE OF ADVANCING SCIENCE AND MORE EFFECTIVE WAY. TO DO THAT, WE ALSO NEED DIVERSE RESO SEARCHERS AND WE NEED DIVERSE SUBJECTS IN OUR STUDIES AND WE NEED DIVERSE ADMINISTRATION OF THE RESULTS STAY TUNED, WE'LL COMING OUT WITH CONCRETE MOVEMENT IN THE NEW YEAR. SO, RAJITA, DO YOU KNOW IF ANYONE TRIED USING PATHOGEN TO ADDRESS LIVER PATHOLOGY ENNIS EFFECTS ON BPH, IS THAT BLOOD PRESSURE AND HEART? >> THAT'S A GOOD QUESTION. THERE WERE STUDIES RECOGNIZE PRAZOSIN AND JUST LIKE WE HAVE PRESSURE AND # THERE'S BLOOD CIRCULATION AROUND THE LIVER AND THERE ARE COMPLICATIONS THAT THEY'RE RELATED TO PORTAL HYPER TENSION WHICH IS THE HIGH PRESSURE BEHIND THAT LIVER. THERE WERE INITIAL STUDIES LOOKING AT THAT LONG TIME BACK ON PRAZOSIN THAT HASN'T BEEN PERSUADE BECAUSE OF SIDE EFFECTS AND LIMITED SIZE OF PRAZOSIN ON THE PRESSURE BEHIND THE LIVER. >> OUR DEPUTY DIRECTOR HAS A QUESTION. PATRICIA POWELL. DO THE NUMBER SIMPLY REPRESENT GREATER LIVER DAMAGE OR SOMETHING MORE NUANCED THAT THEY'RE REPORTING QUOTE-UNQUOTE THAT PREDICTS INMORTALITY. >> IT IS. THAT'S OUR CURRENT WORKING HYPOTHESIS IT IS LIVER INJURY AND STRESS OF HELP AT SIGHTS AND THEIR EFFORTS TO COMMUNICATE WITH OTHER CELLS THAT MIGHT HELP THEM AND SO THIS IS A SIGNAL OF THAT STRESS OF THE HELP AT A SIGHT AND WE DON'T HAVE A VERY GOOD HANDLE AROUND ALL THE DIFFERENT VESICLES AND WHO IS MAKING EACH VESICLES AND THAT WOULD BE NECESSARY TO PROVE THAT HYPOTHESIS. I WOULD ADD THAT IN ADDITION TO THE NUMBERS, I DIDN'T SHOW THE DATA IN THE SNIPPET OF DATA I SHOWED YOU DURING THE TALK BUT WE THINK THE CARGO IS A BIOMARKER, IT'S WHAT IS IN THE VESICLES AND WE SHOWED LIPIDS THAT WERE CONTAINED IN THE VESICLES AND THE AMOUNTS OF THOSE LIPIDS IN THE VESICLES WAS IMPORTANT IN TERMS OF THE PROGNOSIS OF THE DISEASE SEVERITY. >> SO WE HAVE A QUESTION FROM SETH FROM THE LAPPE LAND DOWN UNDER. THANK YOU AND IN AUSTRALIA WE'VE BEEN USING AN INTEGRATED MODEL OF CARE SINCE THE LAST TWO OR THREE YEARS FOR ALD PATIENTS WITH HEPATOLOGISTS TRANSPLANT ADDICTION SPECIALISTS ARE PART OF THE CARE TEAM FROM EARLY ON. I WOULD SAY SET, IF YOU CAN SEND US A PUBLICATION ON THIS WE WOULD BE GRATEFUL BUT VEEJAY, ANY THOUGHTS THERE? >> JEFF, THIS MODEL IS POPULAR UNTIL THE TRANCE PLANT SETTING. PART IS JUST THE HEALTHCARE MODEL. OUR HEALTHCARE MODEL, TRANSPLANT GENERATES A LARGE REVENUE AND SO THERE'S A LOT OF INVESTMENTS IN MAKING SURE THAT THAT SERVICE LINE FUNCTIONS PROPERLY AND HAS ALL THE RESOURCES, EVEN THAT, YOU KNOW, EVERY CENTER DOESN'T HAVE ADEQUATE RESOURCES BUT, THAT IS WHERE WE SEE IT MOST COMMONLY. IN THE EARLIER STAGES, OF DISEASE, THIS IS CERTAINLY THE BEST MODEL AND I THINK UNIVERSITY OF MICHIGAN, JESSICA MELINGER HAS A NICE MODEL. WITH LORENZO WAS IN ITALY HE IS A ALCOHOL USE DISORDER SPECIALIST ROUNDING AND INTEGRATED WITH THE TEAM. AT MAYO IN OUR TRANSPLANT GROUP, WE HAVE A NICE MODEL WITH VERY STRONG INTERACTIONS AND I THINK WE KNOW THAT THE TRANSPLANT IS ONLY THE TIP OF THE ICEBERG AND 99% OF THE PATIENTS AREN'T GETTING TRANSPLANTS AND THAT'S WHERE WE NEED THAT MODEL BUT IT'S IN A CAPITALIST HEALTHCARE MODEL THAT WE HAVE IN THIS COUNTRY WE'LL HAVE TO FIND OUT HOW TO GET SYSTEMS TO RECOGNIZE THAT THE COST SAVINGS THAT CAN STILL OCCUR FROM THESE TYPES OF MODELS. >> WE HAVE A QUESTION. THANK YOU FOR THE INSIGHTFUL LECTURE AND THE FRAMEWORK OF INTEGRATION OF AUD AND ALD MANAGEMENT AND TREATMENT IS QUITE NEW. WHAT DO YOU RECOMMEND FOR THE ROLE FOR NIAAA AND PROFESSIONAL SOCIETIES SUCH AS AAA, SLD AND APA IN MAKING THE FRAMEWORK WORK? >> WELL, I THINK WE'RE IN THE MIDST WHERE WE HAVE OUR SLEEVES ROLLED UP AND WE'RE IN THE MIDST OF THAT AND I THINK THAT THE ASDL WANTS TO PARTNER WITH NIAAA AND TRAINING SYSTEMS TO UNDERSTAND WHAT IS BEST FOR TRAINEES, WHAT IS BEST FOR PATIENTS AND WHAT CAN MOVE THE BALL IN TERMS OF THIS KIND OF COMBINED APPROACH. YOU CAN IMAGINE MAYBE THAT THERE WILL BE A DIFFERENT TYPE OF A SPECIALTY, WHICH IS JUST FOCUSED ON THESE PATIENTS. I DON'T KNOW HOW MANY IS THE RIGHT NUMBER. WE HAVE A SHORTAGE UNTIL THE COUNTRY BUT I THINK MORE AND MORE OF THEM ARE BECOMING INTEREST AND I IMAGINE SOME OF THEM MAY WANTED TO GO INTO A YEAR OF ALCOHOL USE DISORDER AND ALTERNATIVE PATH IS TO INTRODUCE MORE TRAINING OF PARMACOTHERAPY AND COUNSELING INTO THE LIVER CURRICULUM. THE FLIP SIDE IN PEOPLE WANT TO LEARN ABOUT LIVER DISEASE IT'S ANOTHER APPROACH. >> WHAT PATH FORWARD TO YOU SEE THAT HEPATOLOGISTS WILL BE COMFORTABLE ENOUGH TO SCREEN FOR ALCOHOL USE DISORDER AND FEEL COMFORTABLE REFERRING TO TREATMENT? I MEAN I THINK YOU'VE ANSWERED THAT. ONE OF OUR GOALS IS TO GET EVERYBODY SCREENED AND WE'RE QUESTIONING THAT AS KATHY KNOWS AND EVERY DOMAIN. ANY THOUGHTS FROM YOU ON THIS? >> AT LEAST SOME OF THE BASIC THINGS, THE AUDIT AND JUST NOT RUNNING THE OTHER WAY WHEN IT LOOKS LIKES IT'S GOING TO BE A MESSY CONVERSATION. BUT AGAIN, YOU KNOW, RIGHT NOW THE MODELS AROUND BUILT FOR EXTENDED BEHAVIORAL CONVERSATIONS. AT LEAST A MINIMUM OF AN ABILITY TO SCREEN AND AN ABILITY TO HAVE PARTNERS TO WORK WITH PATIENTS ON THEIR ADDICTION AS WELL AS THEIR LIVER DISEASE. >> YOU JUST TRIGGERED A THOUGHT IN MY BRAIN, THE MESSAGE THAT I WONDER IF A SILVER LINING IS TO FAKE THE MESSY PART OF IT SO YOU LOOK AT A SCREEN WITH QUESTIONS THAT WILL TELL THE COMPUTER TO SEND A MESSAGE TO YOUR PRIMARY CARE DOCTOR. MAYBE THERE'S A PROBLEM. SO, I'M GOING TO SKIP YOU ON THIS BECAUSE I WANT TO THE PEOPLE WHO ARE NOT NIAAA. DOM INEQUAL WANTS TO KNOW WHETHER YOU HAVE BEEN MICRO BIOTICS PROFILING WITH AUD LIVER DISEASE? >> I HAVEN'T DONE THAT BUT THERE'S A LOT OF WORK GOING ON IN THAT. IF I GAVE A COUPLE NAMES I WILL FORGIVE A LOT BUT I THINK BERN SHNABBLE ARE DYING QUIT DOING QUITE A BIT. BERN SHNABBLE HAS A PAPER IN NATURE ON TARGETING THE MICROBIOME AND USING FAGE THERAPY IS A WAY TO MANAGE ALCOHOL USE IN ANIMAL MODELS BUT I THOUGHT IT WAS AMAZING WHILE THE DISEASE IS THAT LEVEL AVENUE TENSION AND RECOGNITION TO END UP IN NATURE AND WITH REALLY FORWARD-LOOKING IDEAS AND THINKING SO, THERE'S A LOT GOING ON IN THAT SPACE AS I MENTIONED A LOT OF IT FOCUSES ON EITHER DIS BIO SIS OR GUT PERMEABILITY. >> FROM TULANE. THEY ASKED INTEREST AND INFORMATIVE PRESENTATION BASED ON YOUR DATA RELEASE OF EXTRA CELLULAR VESICLES IT'S NEGATIVELY IMPACT LIVER HEALTH. COULD YOU PROVIDE EXPLANATION FOR THAT OBSERVATION? >> THANK YOU. >> WELL, WE THINK THAT THE CONTENT OF THESE VESICLES WORKS IN SOME WAY LIKE THE RESPONSE AND WHEN THE VESICLE IS RELEASED IT CAN RECRUIT INFLAMMATORY CELLS THROUGH MEDIATOR WHICH THEY AK TA RATE IS THE MACRO FACT AND LEAD TO THE RELEASE OF CYTOKINES THAT WE KNOW ARE INVOLVED IN NEWTRO AND THE LIVER BIOPSY WITH WE KNOW THAT'S WHAT DRIVING S DRIVING THE DISEASE PROCESS OF KNEW TRA FILLS INTO THE LIVER. >> AND WE HAVE TO WRAP-UP AND I HAVE TWO MORE HERE. IT'S A CLINICAL DATA ON MODERATE ALCOHOL USE PROTECTING OR EXACERBATING NASH AND ARE THERE DIFFERENCES IN VARIOUS ETHNICITY. >> AGAIN, WHAT IS VERY CLEAR IS THAT THERE IS A INTER PLAY BETWEEN OBESITY AND ALCOHOL CONSUMPTION AND INDIVIDUALS AS THEY BECOME OVERWEIGHT OR OBESE, IT TAKES LESS AMOUNT OF LEADING TO LIVER INJURIES AND WHAT IS LESS CLEAR IN INDIVIDUALS WHO ARE NOT OBESE WHETHER SMALL AMOUNTS OF ALCOHOL ARE ININJURIOUS OR NOT AND WE WEPT OVER THAT EARLIER IN THE Q&A AND I WON'T REPEAT ALL ALL OF THAT. >> MY QUESTION IS, FROM MOHAMMAD AKBAR, CAN WE USE OMEGA THREE FATTY ACIDS AND DHA AND DP. >> Commissioner Safai: THERE ANY DATA THERE? >> THERE'S A LOT OF INFORMATION ON ANTI-OX TENTS AND I THINK THERE'S PROBABLY SOMETHING THERE WITH ANTI-OX DENTS THE PROBLEM IS THAT WE DON'T KNOW THE RIGHT AMOUNT AND WE DON'T KNOW THE RIGHT DOSE AND WE DON'T KNOW THE RIGHT ROUTES OF ADMINISTRATION AND THE SPECIFIC ONES TO GIVE SO, RIGHT NOW IT'S NOT EVIDENCE-BASED TO USE THOSE AND PROBABLY THE STRONGEST ANTIOXIDANT FOR BENEFICIAL EFFECTS IS ANNASITELSISTINE IN COMBINATION WITH STEROIDS CAN BE EFFECTIVE IN PATIENTS WITH SEVERE ALCOHOL ASSOCIATED HEPATITIS. >> THANK YOU. THANK YOU FOR VOGUE THIS EXTEND THE QUESTION AND ANSWER. WHICH YOU ARE PRESENTATION ALLOWED. I WANT TO THANK EVERYONE WHO PARTICIPATED IN THIS SYMPOSIUM. I WANT TO THANK EVERYONE. YOU ALL DID A SUPERB JOB AND THE QUESTIONS HAVE BEEN NONSTOP. I HOPE SOME OF OUR LITTLE IT GLITCHES DIDN'T DISSUADE YOU FROM DOING THIS AGAIN. HOPEFULLY YOU WILL BE HAPPY WITH THE SYMPOSIUMS WE PUT TOGETHER. THIS CONCLUDES OUR 50th 50th ANNIVERSARY SYMPOSIUM. THANK YOU AS WE CELEBRATE NIAAA LEGACY OF ADVANCING ALCOHOL RESEARCH. I THINK WE'VE MADE A LOT OF PROGRESS IN THE LAST 50 YEARS. I THINK THAT WAS EVIDENT BY ALL THE WONDERFUL PRESENTATIONS OF PAST AND WHERE WE'RE GOING IN THE FUTURE, WHICH I'M PLEASED TO THE SPEAKERS ADDRESSED. NIAAA IS POISE TO BUILD ON THE PROGRESS THAT'S BEEN MADE THROUGH EXTRAMURAL AND INTRAMURAL RESEARCH TO GAIN GREATER INSIGHTS IN THE FUTURE AND WOME WE WILL FOCUS ON REMAINING NIMBLE FOR RESEARCH NEEDS AND OPPORTUNITIES AS THE COVID PANDEMIC AND ENSURING DIVERSITY AND INCLUSION ARE REFLECTED WITHIN OUR RESEARCH AND OUR WORKFORCE AND I THINK EVEN FROM THE QUESTIONS THAT PEOPLE HAVE BEEN ASKING ABOUT ETHNIC DIFFERENCES, ABOUT GENDER DIFFERENCES, WE HAVE TO MAKE THIS A MAJOR FOCUS IN THE FUTURE. WE LOCK FORWARD TO KEEPING IN TOUCH WITH YOU TO LET YOU KNOW THROUGH THESE PLATFORMS WHEN THIS SYMPOSIUM BECOMES AVAILABLE IN A FEW DAYS AS AN ARCHIVE ON THE NIH VIDEO CAST SITE SO IF YOU MISSED ANYTHING, YOU CAN GO TO THE NIH VIDEO CAST SITE AND REVISIT SOME OF THESE PRESENTATIONS AND THE SLIDES THAT WERE PRESENTED. AGAIN, I WANT TO THANK ALL THE PRESENTERS AND ALL OF YOU FOR JOIN USING FOR THIS 50th 50th ANNIVERSARY CELEBRATION AND THANK OUR TEAM WHO PUT THIS TOGETHER. I'M GOING TO MENTION THREE OF THE PRIMARY PEOPLE HERE. FRED, IT WAS HIS DREAM SYMPOSIUM AND IT TURNED INTO A WONDERFUL DREAM. JOHN, GREG, FOR GETTING EVERYTHING ORGANIZED AND DEB FOR FEEDING ME MESSAGES AND KEEPING THE TRAINS RUNNING ON TIME. IT'S BEEN A WONDERFUL TWO DAY, I WISH I COULD DO IT THE REST OF THE WEEK. TIME TO GIT BACK TO THE REAL WORLD. SO, BYE AND THANK YOU.