>> GOOD AFTERNOON, AND THANK YOU FOR COMING TO THE BSSR LECTURE SERIES. MY NAME IS MIKE SPITTLE AND I'M AT OBSSR AND IT IS MY GREAT PLEASURE TO INTRODUCE YOU TO DR. TOM McDADE. BRIEFLY, DR. TOM McDADE IS A BIOLOGICAL ANTHROPOLOGIST THAT CONDUCTS RESEARCH ON HEALTH AND HUMAN DEVELOPMENT IN RELATION TO SOCIAL. HE RECEIVED A„i B.A. AT POMONA COLLEGE, AND Ph.D. AT EMERY UNIVERSITY AND WAS A POST DOC RAL FELLOW AT UNC CHAPEL HILL. HIS WORK FOCUSES ON THREE TOPICS. LSH LIFE COURSE PERSPECTIVE ON IMMUNE FUNCTION AND THE REGULATION OF -- AND THE --. IT IS MY GREAT PLEASURE TO BE ABLE TO INTRODUCE YOU TO HIM AND HIS TALK IS CALLED ENVIRONMENTS, INFLAMMATION, TRANSGENERATIONAL PERPETUATION OF DISPARITIES IN HEALTH THANK YOU. >> THANK YOU ALL. CAN YOU HEAR ME? IS THIS WORKING? OKAY. PLEASE TO BE HERE. THANKS VERY MUCH FOR THE INVITATION, AND IT'S GREAT TO SEE SOME FAMILIAR FACES AND MEET SOME NEW ONES THAT I'VE KNOWN OVER E-MAIL OR THE PHONE. WHAT I'M GOING TO TRY TO DO TODAY IS TALK ABOUT REALLY ONE OF THOSE THREADS OF MY WORK BUT THEY ACTUALLY COME TOGETHER A BIT IN THIS PROJECT, AND TALK ABOUT A LIFE COURSE AND WHAT I'M MOVING TOWARDS AS AN INTERGENERATIONAL PERSPECTIVE ON INFLAMMATION AND SOCIAL DETERMINANTS OF HEALTH. SO MUCH OF WHAT WE UNDERSTAND ABOUT HUMAN PHYSIOLOGY, BIOLOGY DEVELOPMENT AND HEALTH IS DONE WITH RESEARCH ON LABORATORY ANIMALS, ANIMAL MODELS AND CLINICAL SETTINGS IN THE UNIVERSITY AND OTHER INDUSTRIALIZED SETTINGS. AS AN ANTHROPOLOGIST I'M INTERESTED IN A BROADER PERSPECTIVE ON HUMAN VARIATIONS AND HOW THAT MATTERS. I HOPE YOU'LL TAKE HOME A COMPARATIVE APPROACH TO UNDERSTANDING HUMAN BIOLOGY IS GENERATE INSIGHTS INTO THOSE BASIC PATHOPHYSIOLOGICAL PROCESSES THAT WE'RE INTERESTED IN. AS AN ANTHROPOLOGISTS IT'S ONE OF MY PRIVILEGES TO BE ABLE TO GO TO SOME OF THE PLACES AND DO THINGS IN INTERESTING PART OF THE WORLD. YOU'RE ALL FAMILIAR ABOUT THIS MINOR REVOLUTION AND OUR UNDERSTANDING OF HEALTH AND OUR INCREASING EMPHASIS IN UNDERSTANDING OF THE EARLY LIFE ORIGINS OF HALE AND ADULTHOOD. IT'S BEEN ALMOST 100 YEARS THAT WE'VE KNOWN FROM DATA COMING OUT OF THE UK THAT ENVIRONMENTS IN INFANCY PREDICT LONGEVITY, LIFE EXPECTANCY, AND OBESE RISK IN ADULTHOOD. OVER THE PAST 20 YEARS DAVID BARKER COMING OUT OF ENGLAND HAS MOST SUCCESSFUL IN PROMOTING THIS AS AN IMPORTANT AREA OF STUDY. AND THIS IS MORE RECENTLY CAPTURED PUBLIC IMAGINATION WITH A COUPLE OFKz MORE PUBLIC PIECES ON THIS ISSUE. THE WAY THE PARADIGM WORKS, WHICH I'M SURE IS FAMILIAR TO MOST OF YOU, YOU KNOW, WE USED TO THINK OF HEALTH IN ADULTHOOD AS PRIMARILY A PRODUCT OF OUR INDIVIDUAL GENETIC ENDOWMENT, OUR CURRENT ENVIRONMENTS AND OUR LIFESTYLES AND PERHAPS THEIR INTERACTION, BUT NOW WE'RE INCREASINGLY COMING TO APPRECIATE THE IMPORTANT ROLE THAT ENVIRONMENTAL EXPOSURES EARLY IN LIFE HAVE IN TERMS OF PROGRAMMING KEY PHYSIOLOGICAL SYSTEMS WHICH HAVE SDREKT DIRECT IMPLICATIONS FOR ADULTHOOD AND MODERATE THE EFFECTS OF GENES IN ADULTHOOD. THE VAST MAJORITY OF THIS RESEARCH HAS FOCUSED ON EARLY NUTRITIONAL EXPOSURES AND SUCH, BUT WE'RE MOVING BEYOND THAT QUICKLY. RELATED TO THAT, WE HAVE A LONG-STANDING TRADITION IN THE SOCIAL AND BEHAVIORAL SCIENCES IN APPRECIATING THE IMPACT OF EARLY ENVIRONMENTAL QUALITY, EARLY CHILDHOOD ENVIRONMENTS ON HEALTH, BUT ALSO ON COGNITIVE FUNCTION, ON SOCIAL FUNCTION AND EMOTIONAL FUNCTION. THINGS THAT MATTER TO SOCIAL ATTAINMENTS THAT WE CARE ABOUT. FOLKS LIKE JIM PECKMAN, JACK AND OTHERS HAVE BEEN AGGRESSIVELY PROMOTING A POLICY AJEB DA BASED ON THIS LONG-STANDING BODY OF RESARGE, EMPATHIZING THAT INVESTMENTS EARLY IN LIFE HAVE GREATER IMPACT, CREATE GREATER RETURNS THAN INVESTMENTS LATER IN LIFE. THESE FIELDS ARE CONVERGING AND IT'S A VERY EXCITING TIME, I THINK, TO BE INVOLVED IN LIFE COURSE AND INTERGENERAL RESEARCH RELATED TO HEALTH AND ITS SOCIAL DETERMINANTS. THIS IS AN AREA THAT I'M MOVING TOWARDS AND IF THERE'S TIME AT THE END I'LL TALK ABOUT TWO NEW PROJECTS I'M LAUNCHING THAT ARE RELATED TO THIS. WE CAN START TO THINK ABOUT SOCIAL ENVIRONMENTS AND INEQUALITY OR VARIATION IN THOSE ENVIRONMENT AND HOW THEY IMPACT HEALTH IN THAT GENERATION AND THE FUTURE GENERATION AND THEN HEALTH ENDOWMENTS AND ACHIEVEMENTS AND DEVELOPMENTS THAT ONE GENERATION CAN THEN HAVE IMPACT ON SOCIAL IMPACT ON THAT GENERATION AND FOLLOWING GENERATIONS. OKAY. I'M GOING MOVE TOWARD MY INTEREST IN IMMUNE FUNCTION AND INFLAMMATION, BUT START BY TALKING ABOUT A RELATIVELY LARGE BODY OF RESEARCH ON THE HYGIENE HYPOTHESIS WHICH HAS SHOWN BOTH EPIDEMIOLOGICALLY AS WELL AS MECHANISTICALLY EXPERIMENTALLY THAT INDIVIDUALS AS ADULTS ARE HIGHER RISK FOR ALLERGY DISEASES THAT ARE RELATED TO THE DISREGULAR LAG OF IMMUNE PROCESSES AND THAT INDIVIDUALS WHO HAVE IMPOVERISHED NUTRITION EARLY IN LIFE AND WHO HAVE LOWER LEVELS OF MICROBIAL EXPOTION MOSTLY PROXIED BY THINGS WHETHER YOU LIVED ON A FARM OR HAVE OLDER SIBLINGS, THESE KINDS OF EXPOSURES ACTUALLY PROTECT YOU AGAINST THESE KINDS OF DISEASES. THE WORK IS REALLY FOCUSED ON THOSE TYPES OF ATOPIC DISEASES AND THE QUESTION I'M GOING TALK TO YOU TODAY IS WHETHER THIS MAY MATTER TO INFLAMMATION AND HOW WE REGULATE THAT. TEN YEARS AGO THIS WOULD BE A NICHE QUESTION, BUT RIGHT NOW WE ARE CURRENTLY OBSESSED WITH INFLAMMATION I THINK BOTH AT RESEARCHERS AND IN THE PUBLIC EYE BECAUSE INFLAMMATION SEEMS TO BE THE THING THAT'S GOING TO DO US ALL IN. IT'S RELATED TO CARDIOVASCULAR DISEASE, DIABETES, DEMENTIA, CANCER, A NUMBER OF LARGE STUDIES HAVE SHOWN THIS AND CLINICALLY IT'S STARTING TO BE EVALUATED AS WELL. INFLAMMATION IS SOMETHING WE NEED TO BE CONCERNED ABOUT BECAUSE 15 YEARS AGO OUR UNDERSTANDING OF IT WAS SUCH THAT IF YOU DID NOT HAVE AN INFLAMMATORY SYSTEM YOU WOULD DIE BECAUSE YOU NEED IT TO HELP PROTECT YOU FROM INFECTION DISEASE. THERE'S BEEN A CHANGE IN OUR CONCEPTUALIZATION OF INFLAMMATION THAT'S GOING TO FEATURE PROMINENTLY IN THE STORY I'LL TELL TODAY. WHAT HAS LED TO THIS? SOME OBSERVATIONS COMING OUT OF CARDIOVASCULAR EPIDEMIOLOGY WHICH HAS SHOWN THAT IF YOU MEASURE A KEY BIO MARKER OF INFLAMMATION, IF UH YOU MEASURE IT AND DETECT IT AT LEVELS THAT WERE CONSIDERED UNDETECTABLE BUT WITH NEW ASSAYS THAT ARE SENSITIVE WE CAN MEASURE IT, IT PROVIDE ADDITIONAL PREDICTIVE RISK FOR CARDIO VAS YOU CAR DISEASE THAN TRADITIONAL MEASURES. HERE YOU HAVE YOUR RATIO CHOLESTEROL TO HDL. AS THIS GOES DOWN, YOUR RISK OF HEART ATTACK GOES DOWN, BUT ALSO YOUR LEVEL OF CRP INDEPENDENTLY OF YOUR LIPID LEVEL HIGHER LEVEL ASSOCIATED WITH HIGHER RISK. THAT'S A KEY FEATURE OF THIS. IN THE POPULATION IN DEMOGRAPHIC SCIENCES INFLA MAKS HAS ALSO GOTTEN ATTENTION BECAUSE A PAPER HAS HAVE PROPOSED THAT LIFE EXPECTANCY IS DUE TO REDUCTIONS IN INFECTION DISEASE, MORBIDITY WHICH IS IN TURN LOWERED BURDENS OF INFLAMMATION THROUGHOUT AN INDIVIDUAL IS'S LIFE COURSE AND WHAT THEY CALL HAS LED TO THE DEVELOPMENT OF A COHORT MORBIDITY PHENOTYPE. IF YOU REDUCE IN CHILDHOOD YOU REDUCE THE OVERALL LIFETIME BURDEN OF INFLAMMATION AND THEREFORE SINCE INFLAMMATION IS CONTRIBUTOR TO CARDIO VASULAR VASCULAR DISEASE -- THOSE DATA ARE NOT WITHOUT SOME CONTROVERSY. NO MEANS A DONE DEAL. NONETHELESS, IT'S AN IMPORTANT PART OF OUR CURRENT UNDERSTANDING OF INFLAMMATION. THIS IS WHAT I'M CALLING THE CHRONIC LOW-GRATE FLAN MAGS x INFLAMMATION MODEL. MOD --¨V WITH THIS IS A STUDY OF CR BIO VESHLT. IT'S HEAVILY CITED -- THESE ARE A SET OF FOUR INDIVIDUALS WHO ARE SAMPLED AT THREE OR FOUR DAY INTERVALS OVER SEVEN WEEK PERIOD AND THE DOTS JUST CONNECT THEIR VALUES. SO WHAT YOU SEE, THE INDIVIDUALS HERE AT THE BOTTOM THERE'S A LITTLE BIT OF NOISE BUT PRETTY CONSISTENTLY THEY'RE LOW AND LOWER THAN THESE TWO INDIVIDUAL AT THE TOP. IF YOU JUST DO ONE SNAPSHOT IN TIME YOU'LL BE ABLE TO DIFFERENTIATE THESE TWO. THIS MEASURE SHOULD HAVE SOME PROGNOSTIC VALUE. THE ASSUMPTION IS THAT ONE INDIVIDUAL MEASURE OF CRP WILL IDENTIFY AND SEPARATE THESE INDIVIDUALS. THAT'S AN IMPORTANT PART OF THE PHYSIOLOGY OF THE SYSTEM AS WELL AS HOW WE LOSE USE IT EPIDEMIOLOGICALLY. IN TERMS OF PHYSIOLOGY, HERE'S HOW THE MODEL WORKS. BODY FAT IS VERY IMPORTANT SOURCE OF PROINFLAMMATION CYTOKINES. THOSE ENTER GENERAL CIRCULATION AND THEN THEY GO THE LIVER, CELLS IN THE LIVER PRODUCE -- -- IN TURN PROMOTE THE PRODUCTION OF CRP. CRP ENTERS GENERAL CIRCULATION AND THEN IT HAS THESE EFFECTS THAT ALL LEAD TO THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS. THESE PROCESSES ARE INDEPENDENT OF OTHER PATH PHYSIOLOGICAL PROCESSES RELATED TO LIPIDS AND -- THIS IS THE MODEL THAT UNDERLIES MUCH OF THIS RESEARCH. OKAY. WHAT DO THESE TWO HAVE IN COMMON? FROM THE LOOK OF HIM AROUND THE MIDDLE, UM, PROBABLY HAS PRETTY HIGH LEVELS OF CRP. VISCERAL ATA POST TISSUE AROUND THE MIDDLE IS MOST IMPORTANT -- HE PROBABLY HAS ELEVATED CRP, SHOULD BE INCREASING HIS RISK FOR CARDIOVASCULAR DISEASE AS WELL AS OTHER BAD THINGS. THIS IS A HORSESHOE CRAB. BEEN ON THE PLANET SINCE THE DAYS OF THE DINOSAURS, ALSO HAS VERY HIGH CONCENTRATIONS OF CRP AND THAT'S BECAUSE THE IMMUNE SYSTEM OF THE HORSESHOE CRAB DEPENDS ON PATTERN RECOGNITION MOLECULES AS A FIRST-LINE DEFENSE AGAINST INFECTIONS. IT DOES NOT HAVE AN ELABORATED, SPECIFIC HUMERAL AND LYMPHOCYTE-DRIVEN SYSTEM LIKE MAMMALS DO. C REACTIVE PROTEIN WAS DISCOVERED IN 1930 FOR ITS ABILITY TO BIND TO [INDISCERNIBLE] REGION. IT WAS FIRST DISCOVERED AS -- IT PLAYS AN IMPORTANT ROLE IN ALL ORGANISMS THAT HAVE IT. THIS IS WHAT THE MODEL LOOKS LIKE. IT'S NOT A CHRONIC ACTIVATION, IT'S A ACUTE PHASE OR A CUTELY RESPONSIVE MODEL WHERE YOU HAVE BASICALLY UNDETECTIBLE LEVELS OF C REACTOR PROTEIN. YOU GET CHALLENGED WITH A BACTERIUM, A VIRUS, OR AN INJURY THAT HAS TO BE DEALT WITH, AND LEVELS OF CRP INCREASE BY THREE OR FOUR ORDERS OF MAGNITUDE WITHIN 24-48 HOURS AFTER EXPOSURE. THAT PROVIDES A VERY RAPID FRONTLINE OF DEFENSE AGAINST THE INFECTION AGENT, AND THEN AS THE INFECTION STARTS TO RESOLVE AND IS MORE SPECIFIC IMMUNE DEFENSES START TO COME ONLINE WHICH CAN TAKE FOUR, FIVE DAYS TO COME ON, THE CONCENTRATION OF C REACTIVE PROTEIN DROP DOWN TO BASELINE. THAT'S AN ACUTE PHASE MODEL. THEN, AGAIN, IN TERMS OF MECHANISM AND PHYSIOLOGY, YOU HAVE A PATHOGENIC CHALLENGE, PROINFLAMMATORY MEDIATORS LIKE IL 6. THESE INDUCE THE LIVER TO PRODUCE MORE CRP. THEY ALSO CROSS THE BLOOD BRAIN BARERIER AND IP DEUCE THE SYMPTOMS WE ASSOCIATE WITH INFLAMMATION LIKE FEVER OR TIREDNESS. CRP ACTIVATES COMPLIMENTS, PROMOTES THE ACTIVITY OF [INDISCERNIBLE] CELL WHICH IS CAN CLEAR YOUR BODY OF THESE INFECTION DISEASES AND IT TAGS THEM SO THEY'RE RECOGNIZED BY THE BODY OF BEING FOREIGN AND HELPS US CLEAR OUR BODY OF THINGS LIKE THIS. THAT'S THE ACUTE PHASE MODEL. WE HAVE THIS SITUATION WHERE WE HAVE A PHYSIOLOGICAL SYSTEM THAT IS RESPONSIVE TO TWO DOMAINS OF STIMULI. ONE BEING PATHOGENS AND THE OTHER BEING BODY FAT, AND THEY SHARE A COMMON PHYSIOLOGICAL PATHWAYS WE RELATED TO CYTOKINES WHICH LEAD TO THE ACTIVATION OF INNATE IMMUNE PATHWAYS AS WELL AS PERHAPS INCREASING RISK FOR CARDIOVASCULAR DISEASE. NOW THE PROBLEM IS, WE ONLY STUDY THE SYSTEM IN PEOPLE LIKE THIS, RIGHT? SO WE WERE LOOKING AT THIS PATHWAY, BUT THE WAY THE SYSTEM FUNCTIONS, THE WAY IT HAS EVOLVED T WAY IT FUNCTIONS IN OTHER MAMMALS AND VERTEBRAS INVOLVES PRIMARILY THESE KINDS OF" IN STUDYING THIS SYSTEM ONLY INN> RELATIVELY PRIVILEGED AFFLUENT POST EPIDEMIOLOGICAL TRANSITION SETTINGS WITHOVER NUTRITION AND LOW LEVELS OF ARTIFICIAL DISEASE WE CONSTRAIN THE RANGE OF ENVIRONMENTAL VARIATION WHICH MAY BE CRITICAL IN UNDERSTANDING THIS SYSTEM IN A MORE COMPREHENSIVE WAY. FOR THAT REASON, I'VE BEEN LOOKING AT INFLAMMATION AND ITS CORE LETS IN BOW LI YEAH, PHILIPPINES AND ECUADOR AS WELL AS THE UNITED STATES, AND I'M GOING TO BE TALKING ABOUT TWO STUDY WE'VE BEEN DOING ONE IN PHILIPPINES AND ONE IN ECUADOR. THIS SURVEY BEGAN IN THE EARLY 80s. INITIALLY STARTED AS AN INVESTIGATION OF MA TERRIBLE AND CHILD HEALTH AND THE PREDICTORS OF CHILD SURVIVAL AND BREAST FEEDING AND GROWTH IN LOW-INCOME DEVELOPING WORLD SETTINGS LIKE THE PHILIPPINES. IT DID THAT VERY WELL, WAS AN IMPORTANT STUDY IN DEMONSTRATING THE HEALTH BENEFITS OF BREAST FEEDING AT A TIME WHEN FORMULA USE WAS ON THE RISE ARNGSD THEN THE STUDY ENDED. IT WAS DESIGNED TO -- IT BEGAN WITH A RECRUITMENT OF MORE THAN THREE THOUSAND WOMEN FROM 30 RANDOMLY-SELECTED NEIGHBORHOODS AROUND SABU CITY WHICH WAS THE SECOND LARGEST METROPOLITAN AREA IN THE PHILIPPINES. EVERY WOMAN IN THIS WHO WAS PREGNANT DURING A FIXED WINDOW OF ENROLLMENT WAS ASKED TO PARTICIPATE AND OVER 95% OF THEM DID SIGN UP. THEY WERE INTERVIEWED, MEASUREMENTS WERE TAKEN OF THEM AND THEIR HOMES AND THEIR NEIGHBORHOODS AND THEN AT THE DELIVERY OF THEIR BABY, THEY WERE WEIGHED AND THEN EVERY TWO MONTHS FOR THE FIRST TWO YEARS OF THEIR OFFSPRING'S WERE VISITED IN THE HOME, BABY WAS A BIGGED, LENGTH WAS MEASURED, INFORMATION COLLECTED ON BRAETS FEEDING, DIET, HOW THE MOM WAS DOING, LEVELS OF INFECTION DISEASE. STUDY WAS DESIGNED TO END THERE, BUT ST THE STUDY WAS DONE IN COLLABORATIVE WITH COLLEAGUES C TOUCH WITHES, THE AND THEY KEPT. PARTICIPANTS TO SEE HOW THE KIDS WERE DOING. THEN HERE IN 98 AND 99 WHEN THE KIDS WERE 14 AND 15 I WAS DOING A POST DOC AT UNC CHAPEL HILL. IT WAS ABOUT THE TIME THAT THIS IDEA THAT WE NEEDED TO PAY MORE ATTENTION TO EARLY ENVIRONMENTS AS PREDICTORS OF HEALTH AND PHYSIOLOGICAL FUNCTIONS OF ADULTHOOD STARTED TO COME ONLINE. WE REALIZED THIS DATASET WAS THE BEST IN THE WORLD FOR LOOKING AT THESE KINDS OF QUESTIONS GIVEN THE HIGH RESOLUTION OF PROSE PROTECTIVELY COLLECTED DATA WE HAVE IN INFANCY. WE DID A LITTLE BIT OF WORK HERE, BUT, UM, GENERATED A BUNCH OF PROJECTS TO DO A MAJOR FOLLOW-UP AT 2005 WHERE WE COULD FIND 1885 OF THE ORIGINAL PARTICIPANTS WHO WERE IN THEIR EARLY 20s AT THE TIME. WE DID A FULL SEX SOCIAL DEMOGRAPHIC SURVEY OF THEM AND WE ALSO COLLECTED BLOOD AND SALIVA SAMPLES. THESE ARE THINGS WE MEASURED IN THOSE SAMPLES. I'LL TALK ABOUT THOSE IN A MOMENT. OKAY. SO THIS IS WHAT CRP LOOKS LIKE IN THE PHILIPPINES COMPARED TO ANN HAEN'S DATA. I'M SHOWING YOU HERE IS DATA FROM ANN HAENS AGE AND SEX MATCH. THESE ARE YOUNG ADULTS IN THE UNITED STATES AND OVERALL THE LEVEL OF CRP IN FILIPINO YOUNG ADULTS IS.2 OR.3 MILLIGRAMS PER LITTER COMPARED TO.9 MILLIGRAMS PER LITTER THE UNITED STATES. CONSISTENTLY IN THE U.S. WE SEE WOMEN TEND TO HAVE HIGHER THAN MEN, THAT'S NOT SO IN THE PHILIPPINES. THIS SEEMS COUNTERINTUITIVE TO US. HERE WE HAVE THE PHILIPPINES WHICH HAS MORE INFECTION DISEASE. THE UNITED STATES IS IN THE -- INFECTION DISEASE STILL THE NUMBER TWO SOURCE OF MORTALITY IN THE PHILIPPINES, SO THERE WAS A BURDEN OF INFECTION THAT IS HIGHER THAN IN THE UNITED STATES. SO IF CRP IS INVOLVED IN INFLAMMATION, MAYBE YOU MIGHT EXPECT IT TO BE HIGHER BUT THAT WAS NOT THE CASE. ONE OBVIOUS POSSIBILITY BASED ON WHAT I'VE SAID BEFORE ABOUT THE ROLE OF BODY FAT IN PROMOTING THE PRODUCTION OF CRP IN ACTIVATING INFLAMMATION PATHWAYS IS DIFFERENCES IN BODY FAT DISTRIBUTION. AMERICANS ARE HEAVIER THAN FILL PIN KNOWS. IN 2005, THE AVERAGE WAIST SIR KIM FRENS WAS 70 COMPARED TO ALMOST 89 CENTIMETERS IN THE UNITED STATES. MAYBE THAT EXPLAINS THE POPULATION DIFFERENCE. HERE WE HAVE THAT COMPARISON BASED ON WEIGHT SUR CIRCUMFRANCE GROUP. AMERICANS PRODUCE MORE CRP THAN FOLKS IN THE PHILIPPINES DO. THERE'S SOMETHING ELSE GOING ON HERE, AND MY$(D WHETHER EARLY ENVIRONMENTAL FACTORS MIGHT EXPLAIN THAT THIS. THERE IS ANOTHER POSSIBILITY AND I ALWAYS USED TO GET THIS QUESTION AND I'M HAPPY TO HAVE AN ANSWER THAT GENETIC DIFFERENCES ACROSS THE POPULATIONS CAN NOT EXPLAIN THE DIFFERENCES IN CRP. INFLAMMATION THERE ARE SNPs AND ALLELES THAT MATTER TO INDIVIDUAL DIFFERENCES AND INFLAMMATION. I HAVE A COLLEAGUE IN UNC CHAPEL HILL WHO DOES GENETIC COMPLEX DISEASES AND BECAME A COLLABORATOR ON THIS PROJECT AND IN 2005 SHE USED THE DNA CAMP V SAMPLE AND LOOKS AT -- THESE ARE DISEASES, GENES THAT HAVE BEEN PREVIOUSLY ASSOCIATED IN THE UNITED STATES AND IN WESTERN EUROPE WITH HIGHER OR LOWER LEVELS OF CRP AND WE FIND A VERY SIMILAR PATTERN OF ASSOCIATION WITH N THE PHILIPPINES. WE EXPLAIN SMALL AMOUNTS OF VARIANCE IN CRP, FOUR OR FIVE PERCENT AND THEY'RE NOT DRAMATIC POPULATION DIFFERENCES IN THE LEVEL OF PROAND ANTIINFLAMMATION SNPs ACROSS THE TWO SETTINGS. THE GENES MATTER BUT NOT TO THE STORY I'M TELLING YOU HERE TODAY. ALL RIGHT. SO NEW EARLY ENVIRONMENTS MATTER? SO DO EARLY ENVIRONMENTS MATTER? SO THE MODEL IS THAT I'M GOING TAKE YOU THROUGH SHEER THAT WE KNOW AS AN ADULT YOUR LEVEL OF BODY FAT, YOUR LEVEL OF PATHOGENIC EXPOSURES, BOTH THESE THINGS MATTER TO YOUR CONCENTRATION OF CRP AS WELL AS BEHAVIORAL THINGS. MIGHT THERE BE ANALOGOUS EXPOSURES EARLY IN LIFE IN INFANCY THAT MAY PROGRAM THE SYSTEM OR HAVE A DIRECT EFFECT IN THE SYSTEM ON SOME MEANINGFUL WAY? THIS IS A MODEL THAT'S GUIDING MY SELECTION OF VARIABILITIES AND IN TERMS OF TIMING WHEN WE'RE LOOKING AT THESE EXPOSURES, A PRIORITY THERE ARE VERY GOOD REASONS TO THINK THAT THE FIRST YEAR IN PARTICULAR BUT PROBABLY THE FIRST TWO YEARS OF LIFE IN INFANCY ARE CRITICAL PERIODS OF DEVELOPMENT OF THE IMMUNE SYSTEM. THIS FIGURE SHOWS YOU THAT. THIS IS THE POINT TO TAKE AWAY. WHAT THE TOP FIGURE IS AN E NUM RATIVE REPRESENTATION OF WHERE ASPECT OF THE IMMUNE SYSTEM ARE THROUGHOUT THE LIFE COURSE AND THIS IS A FUNCTIONAL MEASURE. I'LL TALK YOU THROUGH IT. ON THE X AXIS IS AGE GOING FROM BIRTH TO 20 YEARS. THE Y AXIS IS PERCENT OF ADULT LEVEL. THIS IS WHERE YOU'RE AT, AT AGE 20. AS AN INFANT YOUR NUMBER OF T AND B CELLS ARE TWO TO THREE TO FOUR TIMES HIGHER DESPITE THE FACT THAT YOU ONLY WEIGH TEN POUNDS THE ABSOLUTE NUMBER OF CELLS ARE HIGHER. THE SIZE OF THE THYMUS IS DOUBLE IN INFANCY THAN WHAT IT IS FOR US IN THE ROOM RIGHT NOW. THE FUNCTION OF THESE CELLS, OF THE LYMPHOCYTES IS UP REGULATED. THEY'RE SENSITIVE TO ACTIVATION AND THAT'S WHAT THIS IS SHOW YOU. IF YOU XROOIM PRIME THESE CELLS THEY WILL REPLICATE AND DIVIDE. THERE ARE ASPECTS OF THE IMMUNE SYSTEM OF THE SPECIFIC IMMUNE SYSTEM THAT ARE VERY ACTIVE IN INFANCY. THIS MAKES SENSE IF YOU THINK ABOUT WHAT THE IMMUNE SYSTEM HAS TO ACHIEVE. YOU'RE BEING BORN INTO AN INFECTION DISEASE ECOLOGY THAT YOU CAN NEVER ANTICIPATE BECAUSE MICROORGANISMS EVOLVE SO QUICKLY ON THE ORDER OF DAYS OR PERHAPS WEEKS OR HUMANS EVOLVED ACROSS GENERATIONS THAT ARE 15-30 YEARS LONG. WE CAN'T COMPETE ON THAT LEVEL. WE HAVE TO LEARN THROUGH A SERIES OF VERY COOL PROCESSES THAT SORT OF EMBODY DARWINIAN PROCESSES WITHIN OUR OWN BODIES, WE HAVE TO LEARN ABOUT OUR INFECTION DISEASE ECOLOGY AND THAT'S WHAT'S GOING ON IN INFANCY. THAT'S WHY THESE PROCESSES ARE UP REGULATED. THIS POINTS TO INFANCY AS A CRITICAL PERIOD OF EDUCATION OF THE IMMUNE SYSTEM WHERE ENVIRONMENTS MAY HAVE DISAPPROPRIATIONAL LONG-TERM IP PACT. THAT'S THE PART WHERE I'M LOOKING IN INFANCY. ALSO I HAVE DATA FOR THE FIRST TWO YEARS, SO THAT'S THE IMPORTANT PART OF WHY I'M DOING THAT. THIS IS WHAT WE HAVE IN TERMS OF OPERATIONALIZING AND TESTING SOME OF THESE PIE POT CEASE. FROM THIS STUDY WE HAVE MEASURES OF BIRTH WEIGHTS MEASURED, LENGTH OR WEIGHTS, WHETHER THE GESTATIONAL AGE AND WHETHER THE BABY WAS DELIVERED PRETERM OR NOT. SOCIO ECONOMIC STATUS FOR PEOPLE. WE HAVE WEIGHT GAIN AND LENGTH GAIN OF THE INFANT, DURATION AND PATTERN OF BREAST FEEDING. MULTIPLE LEVELS OF CLEANLINESS AND SANITATION AND SELF-RECORDED OR MOM-REPORTED SYMPTOMS OF INFECTION DMZ THE INFANT. COMPARABLE MEASURES IN ADULTHOOD THAT PRIOR RESEARCH IN THE U.S. AND MATTER TO INFLAMMATION THAT WE CAN CONTROL FOR. SOME OF THESE MAY BE ON THE CAUSAL PATHWAY BUT THE RESULTS DON'T CHANGE WHETHER WE INCLUDE THESE OR NOT. THIS IS WHAT WE FOUND5 RESPECT TO BIRTH WAITHD AND CRP IN ADULTHOOD. INDIVIDUALS WHO WERE BORN WITH LARGER BIRTHWEIGHTS HAVE LOWER CRP AS YOUNG ADULTS. I'M MODELLING HERE THE PROBABILITY OF ELEVATED CRP. THE RESULTS ARE THE SAME IF I PRESENT THE ACTUAL CRP CONCENTRATIONS. LIKE IF THERE'S A QUESTION I CAN TELL YOU WHY I DECIDED TO -- IT HAS TO DO WITH DISTRIBUTION BUT THE RESULTS ARE ESSENTIALLY THE SAME. AS BIRTH WEIGHT GOES UP, PROBABILITY OF HIGH CR P P GOES DOWN. THIS IS IMPORTANT BECAUSE THERE ARE LOTS OF STUDIES THAT HAVE SHOWN THAT BIRTH WEIGHT IS ASSOCIATED WITH CARDIOVASCULAR RISK IN ADULTHOOD. THIS SUGGESTS THAT INFLAMMATION COULD BE A MECHANISM THROUGH THAT WHICH THAT -- THIS CANNOT EXPLAIN THE POPULATION DIFFERENCES IN CRP ACROSS THE U.S. AND PHILIPPINES. FILIPINOS IN GENERAL GIVE BIRTH TO LOWER BIRTH WEIGHT BABIES. SO IF ANYTHING SHE SHOULD HAVE HIGHER CONCENTRATIONS OF CRP COMPARED TO AMERICANS THIS IS NOT PART OF THE BIGGER STORY THAT I'M TRYING TO TELL YOU HERE. ALTHOUGH I THINK IT IS IMPORTANT. RI YEAH MORBIDITY IN INFANCY IS AN IMPORTANT PREDICTOR OF CRP. THIS IS, I THINK, MORE INTERESTING, AND WHAT I'M SHOWING YOU HERE IS THAT THIS IS THE NUMBER OF INTERVALS, THE INTERVIEWER WENT INTO THE MOM'S HOME AND ASKED THE MOM OVER THE PREVEEDING SEVEN DAYS HAS YOUR BABY EXPERIENCED SYMPTOMS OF DIARRHEA INFECTION. THIS IS THE NUMBER OF INTERVALS IN INFANCY DURING WHICH THE MOM SAID YES. IT'S NOT A COMPLETE CENSUS OF DIARRHEA MORBIDITY IN INFANCY BUT IT'S HIGHLY CORRELATED WITH THAT. BABIES WHO HAD HIGHER LEVELS OF DIARY YEAH IN INFANCY HAVE LOWER LEVEL OF CRP AS AN ADULT. INTERVIEWERS WENT INTO THESE HOMES AND OBSERVED THE HOMES. ONE OF THE THINGS THEY LOOKED FOR WAS WHETHER BABIES WERE AT A STAGE OF CRAWLING AND WHETHER ANIMAL FEE IS IS WAS PRESENT ON THE HOME. MANY OF THESE HOMES WERE OPEN. THIS IS A TROPICAL ENVIRONMENT. PIGS, FOWL, DOGS WERE ALOUD TO ROAM FREELY IN AND OUT OF THE HOME. IT WAS NOT UNLIKELY THAT BABIES WOULD COME IN CONTACT WITH ANIMAL FEE IS I FI IS IS. THE NUMBER OF TIMES THE INTERVIEWER CAME INTO THE HOME AND SAW THAT THIS SITUATION WAS HAPPENING. A HIGHER FREQUENCY OF CONTACT WITH FEE CALL MATERIAL, LOWER CRP AS AN ADULT. ALSO A HIGHER SEASONAL ENVIRONMENT WITH A RAINY SEASON AND DRY SEASON. THAT SEASONALITY IS ALSO ASSOCIATED WITH SEASONALITY INFECTION DISEASE BURDEN. A LOT OF THE EARLY WORK ON THIS STUDY WAS ASSOCIATED WITH SEASONALITY AND TRANS AND INFECTION DIARRHEA AND HOW BREAST FEEDING CAN BUFFER INFANTS FROM THAT SITUATION. INFANT BORN IN THE DRY SEASON ACTUALLY EXPERIENCE MORE INFECTION DISEASES IN THEIR FIRST YEAR OF LIFE BECAUSE THE ALIVE FOR MORE OF THE NON-DRY SEASON, RIGHT. LITTLE COUNTERINTUITIVE. KIDS BORN IN THE DRY SEASON IF YOU LOOK AT HOW THAT ASSOCIATED WITH INFECTION DISEASE EXPOSURE, THEY HAVE MORE AND THEY ALSO HAVE LOWER CRP AS AN ADULT. SO WE HAVE THREE MEASURES OF MICROBIAL EXPOSURE IN INFANCY. EACH ON ITS OWN I WOULDN'T PUT TOO MUCH STOCK IT BUT EACH HAVE DIFFERENT LEVELS AND STRENGTHS TO THEM AS MEASUREMENT CONSTRUCTS AND THEY SUGGEST THAT LOWER LEVELS OF MICROBIAL EXPOSURE ASSOCIATED WITH HIGHER CRP AND THAT'S INDEPENDENT OF PRENATAL UNDERNUTRITION OR LOWER BIRTH WEIGHT. THE MECHANISMS ARE NOT KNOWN. THIS IS SOMETHING THAT WE'RE STARTING TO LOOK AT AND I'LL TALK ABOUT IN A MOMENT, BUT ONE POSSIBILITY IS THAT THERE'S HIGHER LEVEL OF PROINFLAMMATORY SIGNALING, IL 6 IN PARTICULAR. IL 10 DISRUPTS IL 6. THERE ALSO COULD BE CHANGES IN THE PHENOTYPES OF T CELLS IN PARTICULAR LIKE P REGULATORY CELLS THAT PRODUCE A LOOT OF ANTI-INFLAMMATORY ACTION. SO MEK NISICALLY WE DON'T KNOW EXACTLY WHAT'S GOING ON, IF THERE'S ANY IMMUNOLOGISTS OR MOLECULAR BIOLOGISTS IN THE AUDIENCE, MAYBE YOU HAVE IDEAS. CONCEPTUALLY, THIS IS WHAT I THINK IS GOING ON. IN A HIGH PATHOGEN ENVIRONMENT, YOU CAN IMAGINE THESE RED ARROWS AS KROEB Y'ALL CHALLENGES AND EXPOSURE IN INFANCY DURING THIS CRITICAL PERIOD OF IMMUNE DEVELOPMENT, AND SO YOU GET A CHALLENGE, THE SYSTEM BECOMES ACTIVATED AND THEN IT TURNS ITSELF OFF, AND YOU DO THAT OVER AND OVER AND OVER AGAIN. SO YOU HAVE LOTS OF OPPORTUNITIES, LOTS OF EDUCATIONAL OPPORTUNITIES FOR YOUR SYSTEM TO.COM IN RESPONSE TO THE LOCAL INFECTION DISEASE ECOLOGY. TO THE EXTENT THIS IS A SENSITIVE PERIOD PHENOMENON, THOSE PATHWAYS CARRY FORWARD INTO ADULTHOOD AND THEN WHEN YOU'RE EXPOSED TO A PROINFLAMMATORY STRESSOR IN ADULTHOOD, YOU NOUNT A QUICK AND EFFICIENT RESPONSE THAT THEN BECOMES SHUTDOWN WHEN THE INFECTION HAS RESOLVED OR THE ISSUE IS RESOLVED. SO IT'S A VERY EFFICIENT ON AND OFF KIND OF DYNAMIC. IF YOU'RE IN A MORE SANITARY HIGH GEE NICK LOW PATHOGEN ENVIRONMENT, YOU HAVE FAR FEWER OPPORTUNITIES FOR THIS KIND OF EDUCATIONAL PROCESS TO UNFOLD AND THEN PERHAPS AS AN ADULT LACKING THOSE WHILE EDUCATED REGULATORY PATHWAYS WHEN THERE'S AN INFLAMMATORY STIMULUS T SYSTEM ACTIVATES, BECOMES OVERACTIVATED OR BECOMES SLOW TORE TURN ITSELF OFF OR KIND OF MEANDERS IS IS NOT VERY ACUTELY REGULATED, IT'S SORT OF ALWAYS ON AT A CHRONIC LEVEL. SO WAS THERE ANY EVIDENCE FOR THIS? THIS IS MY INTERPRETATION OF WHY THERE MAY BE LOWER CP IN THE PHILIPPINES BUT DO WE HAVE ANY EVIDENCE TO SUPPORT THAT? SO ONE SOURCE OF EVIDENCE IS THAT IN THOSE 2005 BLOOD SAMPLES WE MEASURED THE CRP IN AND I JUST TOLD YOU ABOUT, WE ALSO MEASURED IL 6 AND IL 10 AS PROAN ANTI-INFLAMMATORY CYTOKINES, RESPECTIVELY. THE DOTS SHOW YOU PREVIOUSLY PUBLISHED VALUES FOR POPULATIONS ALL OVER THE WORLD BUT MOSTLY IN WESTERN EUROPE AND THE UNITED STATES. THESE ARE VALUES FROM HEALTHY ADULTS. THERE'S A TON OF WORK USING CLINICAL POPULATIONS, SO WE GRADUATE OPPORTUNITY SPENT A LOT OF TIME MINING THE LITERATURE AND FINDING STUDIES THAT HAD HEALTHY CONTROLS AND WE SUMMARIZED THAT AND THE AVERAGE IL 6 CONCENTRATION ACROSS THESE STUDIES IS 1.9 MILLIGRAMS PER LITTER AND AVERAGE IL 10 IS 3.17. IN THE PHILIPPINES IL 6 IS LOWER AND IL 10 IS HIGHER. THIS IS PARTICULARLY INTERESTING. THIS IS QUITE A BIT HIGHER. THERE COULD BE A DIFFERENT AMBULANCE OF PROTOANTI-INFLAMMATORY CRY TOE KIND SIGNALLING IN THE PHILIPPINES THAT MAY EXPLAIN THE TYPE CONTROL IN THE LOWER LEVELS OF C REACTIVE PROTEIN. THAT'S MY INTERPRETATION FOR THIS MODEL. GOING FORWARD, WE WANTED TO DO A STUDY OF CRP BIO VARIABILITY IN ENVIRONMENT CHARACTERIZE BID HIGHER LEVELS OF INFECTION DISEASE. WE DID THIS IS ECUADOR LAST SUMMER. THIS IS THE MOD UNTIL THE UNITED STATES T CHRONIC LOW-GRADE INFLAMMATION MODEL I WAS TELLING YOU ABOUT. IF YOU ARE BORN INTO A VERY SANITARY ENVIRONMENT, WHEN THEN WE KNOW AT LEAST CORRELATIONALLY AS AN ADULT YOU'RE A PATTERN OF CRP PRODUCTION LIKE THIS WITH BETWEEN VARIATION AND RELATIVELY STABLE WITH INDIVIDUAL VARIATION OVERTIME. WE HAVE NO IDEA WHAT THOSE DYNAMICS LOOK LIKE IN A PREEPI TRANSITION POPULATION THP. THERE ARE TWO STUDIES THAT HAVE LOOKED THAT IN THE UNITED STATES. TWO STUDIES OF CRP BIO VARIABILITY PERIOD BOTH IN THE UNITED STATES BOTH WITH THE SAME CONCLUSION, BUT WHAT DOES IT LOOK LIKE IN THE EK DOR YAN AMAZON? WE DON'T KNOW. IT COULD BE WE GET A PATTERN LIKE THIS OR THIS, OR THIS PATTERN BUT EVERYTHING IS SHIFTED UP WHICH IS IN FACT WHAT THE COHORT MORBIDITY HYPOTHESIS WOULD SUGGEST. WE WANTED TO FIGURE THAT OUT. WE DESIGNED A STUDY AND IMPLEMENTED IT IN ECUADOR. I'M GOING TO SHOW YOU THE RESULTS IN A MINUTE. THIS IS FROM ONE OF THE STUDIES OF CRP BIOVARIABILITY IN THE UNITED STATES. THESE ARE INDIVIDUALS ON THE X AXIS AND THEIR CRP. THIS IS OVERzL EACH DOT REPRESENTS A CRP VALUE FOR THAT INDIVIDUAL. EACH INDIVIDUAL HAS MULTIPLE SAMPLES AND THIS LINE REPRESENTS THREE MILLIGRAMS PER LITTER. THAT'S THE COMMONLY USED CUT POINT TO IDENTIFY RYE HIE RISK CRP CONCENTRATION. YOU SEE THERE'S SEPARATION HERE. THERE ARE INDIVIDUALS FOR WHOM CRP IS CONSISTENTLY ABOVE THIS THREE MILLIGRAM PER LITTER THRESHOLD AND A NUMBER OF INDIVIDUAL WHO IS FLIRT WITH THAT LINE DOWN HERE. THERE'S A LOT OF AGAIN BETWEEN INDIVIDUAL VARIATION AND NOT AS MUCH WITHIN. SO WHAT DO WE SEE IN LOW LAND ECUADOR. THE STUDY WE DID WITH THE SHOAR, THEY'RE IN THE AMAZON BASIN -- ANDES MOUNTAINS RUN HERE, BUT THE ACTUAL BASIN OF SOUTH AMERICA BEGINS ON THE EAST COAST OF THESE MOUNTAINS. TROPICAL RAIN FOREST, THEY LIVE IN A SYSTEM OF „iRIVERS, VERY FEW ROADS, NO RUNNING WATER, NO ELECTRICITY AND HYPER INFECTION DISEASE. THEY'RE HORTICULTURAL LIST, LITTLE BIT OF HUNTING AND FISHING. HIGH DEGREE OF CHILD DEATH DUE TO INFECTION DISEASES AND THE MAIN SOURCE OF ILLNESS ARE [INDISCERNIBLE]. WE DID THIS STUDY WITH 52 ADULTS, 18-50 YEARS OF AGE. FOUR WEEKLY SAMPLING INTERVALS. WE VISITED THEM EVERY WEEK TO THE DAY AND WE COLLECTED A DRY BLOOD SPOT SAMPLE. THIS IS RELATED TO ONE OF THE MAJOR AREAS OF MY RESEARCH WHICH IS THE DEVELOPMENT OF MINIMALLY INVASIVE METHODS THAT ALLOW US TO STUDY HUMAN PHYSIOLOGY IN THE AMAZON. WE COLLECT THE SAMPLE BY NICKING THE PERSON'S FING FINGER WITH THE LAN SET AND WE PUT THE BLOOD ON TO THIS FILTER PAPER. THE BLOOD DRYS ON THE CARD AND BECOMES PRESERVED EVEN AT TROPICAL TEMPERATURES. WE SHIP THE SAMPLES BACK TO THE LAB OR PUNCH THEM OUT AND PUT IN THE BUFFER. WE MAKE WHOLE BLOOD AGAIN AND THEN ADD THEM TO AN ASSAY PLATE AND DO A SANDWICH [INDISCERNIBLE] AND THEN WE GENERATE A CALIBRATION CURVE AND GENERATE THE CONCENTRATION OF CRP IN EACH OF THESE SAMPLES. THIS KIND OF DATA COLLECTION OR SAMPLE COLLECTION APPROACH ALLOWS US TO GAIN ACCESS SESZ TO PEOPLE IN PLACES LIKE THE EK ECUADOR AMAZON AND GET A SAMPLE EVERY WEEK. HERE'S WHAT WE FOUND. SO AGAIN WE HAVE PARTICIPANT ON THE X AXIS, CRP CONCENTRATION ON THE Y. HERE'S THE THREE MILLIGRAM PER LITTER THRESHOLD AND EACH DIAMOND REPRESENTS A VALUE FOR THAT PARTICIPANT. PARTICIPANT OVER HERE ON THE RIGHT HAS VALUES STACKED UP LIKE THIS. SORTED BY OVERALL AVERAGE ACROSS VIMGS. DOES THIS LOOK DIFFERENT TO YOU? THERE ARE NONE OF THOSE, RIGHT? THERE ARE NO INDIVIDUALS WHO CONSISTENTLY PRODUCE CRP ABOVE THREE MILLIGRAMS PER LITTER. IN FACT, ONLY A THIRD OF THE INDIVIDUAL, 17 PEOPLE, PRODUCED ONE CRP VALUE ABOVE THIS THRESHOLD, AND ON THE OTHER WEEKLY INTERVALS THEY PRODUCED VALUES THAT WERE VERY LOW, IN MOST CASES LESS THAN ONE MILLIGRAM PEARLY LITTER. VERY DIFFERENT PATTERN OF VARIATION. THERE IS NO CHRONIC LOW-GRADE MAGS IN THIS SETTING. THERE'S ANOTHER WAY TO REPRESENT THIS. THIS IS GOING ACROSS TIME. SO WEEK THESE ARE THE 17 INDIVIDUALS FOR WHOM AT LEAST ONE SAMPLING INTERVAL HAD AN ELEVATED CRP. WEEK TWO, THERE ARE ABOUT SIX INDIVIDUAL WHO IS HAVE ELEVATED CRP, BUT THE NEXT WEEK EVERY SINGLE ONE OF THOSE HAS A LUE LESS THAN THAT HIGH-RISK THRESHOLD. IF YOU WERE DOING A CROSS SECTIONAL STUDY AND SAMPLED AT WEEKLY TWO, YOU WOULD SAY ABOUT A THIRD OF THIS POPULATION HAS HIGH-RISK CRP, THAT MATCHES TO THE U.S. BUT YOU WOULD MISCLASSIFY EVERY SINGLE ONE OF THOSE INDIVIDUALS BY VIRTUE OF DOING CROSS SECTIONAL STUDY DESIGN. SO TO MY MIND THAT IS ACTUALLY PRETTY COMPELLING EVIDENCE FOR A DIFFERENT SET OF REGULATORY DYNAMICS THAT INDIVIDUALS IN THE EK DOR YAN AMAZON CAN PRODUCE HIGH CRP BUT ALSO VERY LOW CRP. THE UNITED STATES IT SEEMS LIKE PEOPLE CAN PRODUCE HIGH CRP BUT A LOT OF PEOPLE CANNOT PRODUCE THAT LOW VALUE AND THOSE ARE THE INDIVIDUALS WHO ARE PROBABLY AT ELEVATED RISK FOR CARDIOVASCULAR DISEASE. I TRACE THAT BACK TO EXPOSURES EARLY IN LIFE. SETTING UP THE DYNAMICS OF THIS SYSTEM. THIS DOES HAVE SOME IMPLICATIONS FOR HOW WE UNDERSTAND INFLAMMATION AS IMPLICATIONS FOR OTHER THINGS WE CARE ABOUT. MAYBE WE SHOULDN'T THINK ABOUT EARLY ENVIRONMENTS MATTERING DIRECTLY TO INFLAMMATION IN ADULTHOOD BUT THINK ABOUT HOW EARLY ENVIRONMENTS SET UP THE DYNAMICS OF A SYSTEM, HOW THEY SET UP HOW THE SYSTEM IS REGULATE AND THE CONSEQUENCES OF DIFFERENTIAL PHENOTYPES, DIFFERENTIAL PATTERNS OF REGULATION MATTER IN RESPONSE TO STRESSORS IN ADULTHOOD, AND IN ORANGE HERE, WE HAVE A SET OF PROINFLAMMATORY STIMULI THAT ARE WELL-ESTABLISHED AND IN MANY CASES OF HIGH INTEREST TO SOME OF US. BODY FAT, I TALKED ABOUT, PRODUCED ABOUT UP REGULATED INFLAMMATION. SMOKING IS A STRESSOR, VACCINE IS A VERY NICE EXPERIMENTAL PAR TIME FOR ACTIVATING AN INFLAMMATORY RESPONSE. INFECTION ACTIVATED INFLAMMATION, PREGNANCY IS AN INFLAMMATION EVENT. THERE'S A LOT OF INTEREST IN PSYCHOSOCIAL STRESSOR AND THEIR IMPACT ON INFLAMMATION. PERHAPS ALL THESE THINGS ARE MODERATE, THEIR IMPACT ON THE INFLAMMATION RESPONSE AND IMPLICATIONS FOR DISEASE MAY BE MODERATED BY HOW YOUR BODY REGULATES INFLAMMATION IN RESPONSE TO EARLY ENVIRONMENT. I'M GOING TO SHOW YOU SOME PRELIMINARY DATA THAT SUGGESTS THAT'S THE CASE. GOING BACK TO THIS ORIGINAL OBSERVATION THAT IN THE UNITED STATES WE PRODUCE MORE CRP THAN FILIPINOS DO PER UNIT OF BODY FAT. IT COULD BE THAT IN THE PHILIPPINES BASED ON HIGHER LEVELS OF EXPOSURE TO MICROBES THERE ARE MORE ROBUST SET OF ANTIINFLAMMATION -- EVERYBODY THOUGH BODY FAT IS A PROINFLAMMATORY INPUT YOUR BODY IS BETTER ABLE TO KEEP THAT STIMULATION IN CHECK. PERHAPS THAT'S WHY WE HAVE LOWER CRP THERE ETCH AT THE SAME LEVEL ODD BODY FAT. IN ECUADOR, WE FIND THE SAME THING. SMALLER SAMPLE HERE. ONLY 50 PEOPLE TOTAL TO 10-15 PEOPLE IN EACH OF THESE CELLS AND AGAIN AT EVERY LEVEL OF WEIGHT CIRCUMFERENCE WE HAVE LOWER LEVELS OF CRP IN ECUADOR THAN THE UNITED STATES. WHAT ABOUT STRESS? SO I'VE DONE SOME WORK ON STRESS AND INFLAMMATION AND PUBLISHED A PAPER WITH JOHN AND COLLEAGUES R– ADULTS IN C HICAGO. OF OLDERV WE FOUND STRESS [INDISCERNIBLE] HIGHER CRP AMONG OLDER ADULTS CONTROLLING FOR EVERYTHING. OKAY. SO THAT'S INTERESTING. THERE ARE SOME GOOD REASONS TO UNDERSTAND HOW THIS MAY HAPPEN, WHICH I CAN GET INTO IF THERE ARE QUESTIONS. WE ALSO HAVE A PSS. WEED A ADMINISTERED IT TO OUR FILIPINO PARTICIPANTS. PUTTING ASIDE THE QUESTION ABOUT THE -- I CAN STILL ANALYZE THE ASSOCIATION BETWEEN VARIATION AND PERCEPTIONS OF STRESS AND CRP IN THE PHILIPPINES AND I'VE DONE THAT HERE. THERE IS A POSITIVE ASSOCIATION BUT IT'S VERY WEAK AND IT'S NOT STATISTICALLY SIGNIFICANT. SO THAT'S INTERESTING, BUT WHAT IF THIS OTHER ISSUE OF EARLY ENVIRONMENT MODERATING THE IMPACT OF STRESSORS IN ADULTHOOD, HOW MIGHT THAT INFORM WHAT WE DO HERE? I TRIED TO TEST THAT EXPLICITLY. I DID THIS LAST WEEK SO IT'S NOT FULLY FLESHED OUT. I JUST TOOK ONE OF THE VARIABLES THEY SHOWED BEFORE, MATTER TO CRP IN ADULTHOOD AND RAN AN INTERACTION. SO HERE WE HAVE PERCEIVED STRESS IN INTERACTION WITH SEASON OF BIRTH PREDICTING CRP. IF YOU WERE BORN NOT IN THE DRY SEASON -- THIS MEANS YOU HAVE LOWER LEVELS OF INFECTION EXPOSURE IN THE FIRST YEAR OF INFANCY -- THEN YOU START TO SEE A PATTERN OF ASSOCIATION THAT LOOKS LIKE CHICAGO. HIGHER STRESS, HIGHER CRP. IF YOU WERE BORN IN THE DRY SEASON, HIGHER LEVEL OF MICROBIAL EXPOSURE IN INFANCY, PERHAPS ROBUST„i ANTIINFLAMMATION IN PLACE THERE'S NO ASSOCIATION AND IF ANYTHING IT'S NEGATIVE. ON THEIR OWN NEITHER OF THESE LINES ARE SIGNIFICANT BUT THE INTERACTION IS. THERE IS IS DIFFERENT PATTERN OF ASSOCIATION BETWEEN THESE VARIABLES. THEY COULD TRACE THIS BACK TO EARLY ENVIRONMENTS. PREGNANCY. PREGNANCY INDUCES A LOT OF CHANGES IN A WOMAN'S IMMUNE SYSTEM AND HOW SHE REGULATES IMMUNE FUNCTION. THIS IS VERY IMPORTANT BECAUSE THE FETUS IS ONLY 50% GENETICALLICALLY RELATED TO HER. THERE HAS TO BE SUPPRESSION OF IMMUNE PROCESSES THAT WOULD OTHERWISE REJECT THE FETUS. CHANGES IN DYNAMICS ARE PART OF THIS PROCESS. IN 2005 WHEN WE COLLECTED OUR BLOOD SAMPLES, THERE WERE ABOUT 80 WOMEN WHO WERE PREGNANT AT THE TIME OF THIS SURVEY AND WE COLLECTED BLOOD FROM THEM BUT IN ALL THE ANALYSIS I'VE SHOWED YOU I'VE ELIMINATED THEM FROM THE SAMPLE BECAUSE THEIR CRP RZ UP AND THEIR DYNAMICS ARE DIFFERENT. IT'S A VERY INTERESTING SUBSET OF WOMEN TO LOOK AT. THESE ARE GOING FEATURE IN A GRANT APPLICATION TO JUSTIFY ADDITIONAL RESEARCH. VERY PRELIMINARY AND WHAT I'VE DONE HERE IS TAKEN WOMEN AND DIVIDED THEM JUST ON MEDIUM SPLIT ON WHETHER THEY HAD HIGH OR LOW CRP AT THE TIME OF THE BLOOD COLLECTION AND WHETHER THEY HAD HIGH OR LOW IL 10. I'M FEATURING IL 10 HERE BECAUSE PART OF THE STORY I'M DEVELOPING IS THAT IL 10 IS A VERY IMPORTANT AEN INFLAMMATORY SIGNAL. IT'S LIKE DRIVING 100 MILES PER HOUR WITH YOUR FOOT ON THE ACCELERATOR. IF BRAKES ARE WORKING YOU CAN SLOW DOWN AND KEEP THINGS IN CONTROL. BETTER THAN GOING 100 MILES PER HOUR DOWN THE HIGHWAY WITH NO BRAKES AND NO WAY TO KEEP THINGS IN CHECK. I'M GOING TO SHOW YOU A SLIDE ABOUT CARDIOVASCULAR DISEASE IN A MINUTE THAT HELPS ME JUSTIFY THIS APPROACH. HERE'S THE DISTRIBUTION AMONG WOMEN WHO ARE BORN INTO LOW MICROBE HOUSEHOLD. I TOOK THE VARIABLE I SHOWED YOU BEFORE AND DID A MEDIAN SPLIT. ABOUT A QUARTER HAVE LOW CRP. ABOUT A THIRD HAVE HIGH CRP AND LOW IL 10. SO I'M INTERPRETING THIS AS INCONTROLLED INFLAMMATORY STATE. A THIRD HAVE HIGH CRP AND HIGH IL 10. I'M INTERRUPTING THIS AS A CONTROLLED INFLAMMATORY STATE. NOW, IF WE LOOK AT WOMEN WHO WERE BORN INTO HOMES 20 YEARS AGO WITH A HIGHER LEVEL OF MICROBIAL EXPOTION THEY'RE MUCH MORE LIKELY TO BE IN THIS WELL CONTROLLED INFLAMMATORY STATE. SO DOES THIS MATTER? I MEAN, THIS IS INTERESTING. ONE OF THE THINGS THAT'S COOL ABOUT TO THIS TO ME THE S YOU'RE PERTURBING THE SYSTEM AND THE DYNAMICS OF THE RESPONSE IS VERY INTERESTING. DOES THIS HAVE ANY HEALTH CONSEQUENCES? THE THING THAT GOT ME THINKING IN THIS DIRECTION IS THE STUDY OF, UM, CARDIOVASCULAR DISEASE. THESE WERE PATIENT WHO IS PRESENTED TO HOSPITAL WITH A HEART ATTACK. THEIR BLOOD WAS DRAWN AND THEY WERE FOLLOWED FOR SIX MONTHS, AND THE OUTCOME IS DEATH OR SUBSEQUENT HEART ATTACK, AND AT BASELINE, INDIVIDUALS WHO HAD LOW IL 10 AND HIGH CRP HAD THE WORST OUTCOMES, FAR AND AWAY THE WORST. ONE IN FIVE OF THEM WAS DEAD. PEOPLE HAD THE BEST OUTCOMES HAD HIGH CRP. THIS IS CONSISTENT WITH THE IDEA THAT INFLAMMATION IS GOOD FOR YOU IN CERTAIN CIRCUMSTANCES. BUT THEY ALSO HAD HIGH IL 10. THE PEOPLE WHO DID BEST HAD INFLAMMATION BUT A CONTROLLED INFLAMMATORY STATE. SO MIGHT THIS APPLY ALSO TO AN IMPORTANT HEALTH YOUTH COME OUTCOME FOR ADULTHOOD IN WOMEN AND THE BIRTH WEIGHT OF YOUR BABY? INDIVIDUALS IN THIS WELL-CONTROLLED INFLAMMATORY STATE HAVE AN AVERAGE BIRTH WAIT WEIGHT THAT IS MORE THAN A HUNDRED GRAMS HIGHER THAN WOMEN IN POORLY CONTROLLED INFLAMMATORY STATE OR WOMEN WITH NO ACTIVE INFLAMMATORY ACTIVITY, AGAIN SUGGESTING THAT INFLAMMATION IS DOING STHIENG GOOD BUT YOU WANT TO CONTROL IT. ENOUGH TO MOTIVATE US TO PURSUE A MORE LIFE COURSE AND EVEN INTERGENERATIONAL APPROACH TO THE STUDY OF INFLAMMATION, AND THIS IS OUR WORKING MODEL, AND, UH, THIS IS THE LIFE COURSE HERE, AND WE HAVE AN INFLAMMATORY PHENOTYPE WHICH DEVELOPS IN INFANCY CHILDHOOD INTO ADULTHOOD AND A LOT OF INTEREST HOW N HOW THAT MATTERS TO AGING. INFLAMMATION IS KEY IN PREGNANCY AND IT CAN BE -- THAT SETS UP THE NEXT GENERATION WITH RESPECT TO THESE PROCESSES AS WELL. WE CAN TRACE AN INDIVIDUAL'S INFLAMMATORY PHENOTYPE BACK TO HER INFANCY AND PRENATAL NUTRITIONAL ENVIRONMENT, POST NATAL INFECTION ENVIRONMENT, AND THERE'S A LOT OF INTERESTING RESEARCH ON THE ROLE OF PSYCHOSOCIAL STRESSORS IN CHILDHOOD THAT I DIDN'T TALK ABOUT MATTERING TO THE DEVELOPMENT OF INFLAMMATION AS WELL. I HAVE BROADER INTERESTS IN SOCIAL DISPARITIES AND INEQUALITIES. THESE ARE ALL EXPO E SURES THAT ARE PARTITIONS IN DIFFERENT WAYS BY SOCIO ECONOMIC PROCESSES. I THINK I'LL PROBABLY END THERE. I HAVE TWO STUDY PUTTING IN MOTION THAT TESTS VARIOUS ASPECTS OF THIS MODEL. IF THERE ARE QUESTIONS ON THAT I'D BE HAPPY TO FEATURE THEM BUT I WANT TO LEAVE TIME FOR QUESTIONS SO MAYBE WE SHOULD DO THAT. THANK YOU. [APPLAUSE] >> [LOW AUDIO]. >> ALMOST ALL THE DELIVERIES WERE IN THE HOME OR A LOCAL BIRTH CENTER. >> [LOW AUDIO]. >> YEAH, VERY VIEW, VERY VIEW C-SECTIONS BUT THAT I THINK IS A VERY INTERESTING POSSIBLE ROUTE. THERE'S A LOT OF PARTICULARLY WITH RECENT INTEREST IN MICROBUY YOEMS AND CROSS GENERATIONS. DOING SOMETHING LIKE THIS IN THE UNITED STATES WOULD BE VERY INTEREST INTERESTING [INDISCERNIBLE]. YES. >> [LOW AUDIO]. >> MM-HMM. >> [LOW AUDIO]. >> MM-HMM. YEAH. >> [LOW AUDIO]. >> MM-HMM. YEAH. >> [LOW AUDIO]. >> SO I THINK THERE ARE TWO THINGS THERE. ONE IS THERE IS A LOT OF RESEARCH AND INTEREST IN THE UNITED STATES, IN PARTICULAR ON INFECTION AND THE REGULATION OF INFLAMMATION ON GESTATION PREDICTING PRETERM DELIVERY BUT ALSO LOWER BIRTH WEIGHT. IN THE UNITED STATES LOWER BIRTH WEIGHT IS ALMOST ALWAYS ASSOCIATED WITH EARLY BIRTH. WE DON'T HAVE THE DATA TO ADDRESS IT. BUT WITH RESPECTED TO LEVEL OF PRENATAL AND POST NATAL EXPOSURE THAT MIGHT MATTER TO US IN THE U.S. VERSUS THE PHILIPPINES. PHILIPPINES IN THE 80s, THE LEVEL OF EXPOSURE TO THE KINDS OF MICROBES PROBABLY ORDERS A MAGNITUDE GREATER THAN WHAT HAPPENS ON THE UNITED STATES EXCEPT ON A RURAL FARM WHERE YOU'RE ACTIVELY ENGAGED WITH ANIMALS. I DON'T THINK THIS WILL TRACK FOR DISADVANTAGE, BUT THAT'S A VERY TESTABLE HYPOTHESIS ON SOMETHING THAT I WOULD LIKE TO LOOK AT. A LOT OF LIT KRA RA CHUR ON THE HIGH JEEB HYPOTHESIS AND THE IMMUNE PATHWAYS RELATED TO THAT SUGGEST THAT IT'S NOT NECESSARILY OVER INFECTIONS. SO, OF COURSE, I HAVE A FOUR-AND-A-HALF YEAR OLD AND EVERY TIME HE CAME HOME WITH A COLD I WAS LIKE GREAT, ONE NOTCH DOWN ON THE RISK FOR ASTHMA. [LAUGHTER] IT'S PROBABLY NOT THAT. THOSE THINGS ARE CORRELATED BUT WHAT'S PROBABLY LACKING IS EXPOSURE TO COME ON MICROORGANISMS THAT ARE IN DIRT AND ROTTING VEGETABLE MATERIAL AND WATER THAT'S NOT BEEN BLEACHED. THINGS THAT HAVE BEEN PART OF THE MAMMALIAN ENVIRONMENT FOR MA LIN YEAH THAT IN POST EPIDEMIOLOGICAL POPULATIONS AND POST EPI HYPER HYGIENIC ENVIRONMENTS THAT WE'VE ELIMINATED FROM OUR DIETS, FROM OUR ENVIRONMENT. I THINK EVEN IN SOCIALLY DISADVANTAGED CIRCUMSTANCES IN THE UNITED STATES, PEOPLE ARE MOSTLY DRINKING TAP WATER, NOT ENGAGE SOIL THE WAY PEOPLE IN OTHER PARTS OF THE WORLD DO. THAT IS A TESTABLE HYPOTHESIS. >> [LOW AUDIO]. >> PROBABLY NOT MUCH. I DON'T THINK THAT THERE'S -- THIS'S NO EVIDENCE TO SUGGEST THAT VACCINES REALLY MATTER TO THE KINDS OF THINGS THAT I'M TALKING ABOUT BUT IF THEY DO MATTER THEY MAY PUT INDIVIDUALS AT RISK NOR HIGHER [INDISCERNIBLE] THE WAY THEY ACTIVATE THE IMMUNE RESPONSE IS BY [INDISCERNIBLE] WHICH HAVE BEEN ASSOCIATED WITH ALLERGY AND ASTHMA. WE DO HAVE INFORMATION ON VACCINES IN THIS STUDY BUT THEY DON'T SEEM TO EXPLAIN ANY VARIATION HERE. THEY DO MATTER. THEY, UM, ARE NOT EXPLAINING WHAT I'M SHOWING HERE, BUT INTERESTINGLY ALONG THOSE LINES SORT OF WHAT CAN WE DO TO PRIME SOME OF THESE PATHWAYS. THERE ARE CLINICAL TRIALS IN THE UK WHERE PEOPLE AS AN ADULT WHO SUFFER FROM EXTREME FORM OF ALLERGY OR ASTHMA HAVE BEEN GIVEN EXTRACTS OF PARASITES OR SOME OF THE MICROBES THAT I'M TALKING ABOUT AND IT'S SHOWN THAT IT'S ALLEVIATED SOME SYMPTOMS. I THINK THAT'S INTERESTING. MY CRITIQUE IN THAT WOULD BE IT'S PROBABLY TOO LATE. IF YOU WANT A BANG FOR YOUR BUCK I THINK YOU TO DO IT EARLIER IN LIFE. BUT THEY DO SHOW SMALL EFFECTS. >> QUESTIONS, ANYMORE QUESTIONS? >> YEAH. >> [LOW AUDIO]. >> YEAH. MM-HMM. [LAUGHTER] RIGHT. RIGHT. >> [LOW AUDIO]. >> THIS IS SOMETHING I WOULD LOVE TO DO. I THINK ANOTHER CLASS OF PEOPLE TO LOOK AT IN THIS REGARD OR IMMIGRANTS WHO MAY HAVE GROWN UP IN A CERTAIN ENVIRONMENT AND COME TO THE UNITED STATES. THAT WOULD BE VERY INTERESTING CASE STUDY. THERE'S GOOD OPPORTUNITY HERE BECAUSE THERE ARE A LOT OF STUDIES, A LOT OF DEMOGRAPHICS SOCIAL SCIENCE POPULATION STUDIES MOVING FORWARD OVER THE PAST FIVE YEARS AT HEALTH HRS, THAT ARE USING THIS BLOOD SPOT METHOD THAT ARE MEASURING CRP AND HAVE HISTORIES OF WHERE PEOPLE GREW UP, WHETHER THEY WENT TODAYCARE OR NOT, WHETHER OLDER SIBLINGS, WHETHER THEY WERE ON A FARM, IMMIGRANT. WE CAN TEST THESE HYPOTHESES. I'M WAITING FOR DATA SO I CAN DO SOME OF THOSE THINGS. >> [LOW AUDIO]. >> THERE ARE DEFINITELY SOME SELECTION. I DON'T WORRY SO MUCH ABOUT MORTALITY SELECTION IN THE PHILIPPINE STUDY. IT WASN'T AS HIGH AS THE ORIGINAL INVESTIGATORS THOUGHT IT MIGHT BE. I'M SURE YOU NOTICED THAT ORIGINAL END WAS 3,300 AND WE WERE AT 885 IN 2005. MOST OF THE LOSS HAPPENED IN THE FIRST TWO YEARS OF LIFE AND IT WAS DUE TO MIGRATION. IT WASN'T DUE TO LACK OF PARTICIPATION OR ENTHUSIASM FOR THE STUDY BUT A LOT OF PEOPLE MOVE OUT OF SABU, MOVED TO THE UNITED STATES, HONG KONG AND WE DIDN'T HAVE THE FUNDS TO FOLLOW THEM UP. THE BIAS IS THAT WE HAD PEOPLE THAT ARE MORE LIKELY TO STAY IN SABU, SO THEY WERE A LITTLE LESS EDUCATED AND NOBLE. YEAH. >> [LOW AUDIO]. >> HMM. MM-HMM. >> [LOW AUDIO]. >> YEAH. YEAH. >> [LOW AUDIO]. >> THAT'S GREAT. I THINK WE'RE ONE OF MY GOALS IS TO GET PEOPLE TO ASK THESE QUESTIONS AND TO GENERATE HYPOTHESES AND TEST THEM USING RESOURCES LIKE THAT WHICH I ACTUALLY WAS NOT AWARE OF. THERE'S A LOT OF RESEARCH ON THE HYGIENE HYPOTHESIS IN THE CONTEXT OF ALLERGY AND IMMUNOLOGY. I WANT TO EXPAND THAT OUT. IF INFLAMMATION REALLY MATTERS TO ALL OF THESE THINGS WE CARE ABOUT, THEN THESE SAME KINDS OF EXPOSURES EARLY IN LIFE SHOULD MATTER, AND SO WE SHOULD STUDY THEM. MAYBE IT ONLY APPLIES IN THE PHILIPPINES AND PLACES LIKE THAT NOT SO MUCH HERE, BUT WE SHOULD FIGURE THAT OUT OR TRY TO. >> [LOW AUDIO]. >> MANY MM-HMM. YEAH. >> [LOW AUDIO].MM-HMM. YEAH. >> [LOW AUDIO].MM-HMM. YEAH. >> [LOW AUDIO].MM-HMM. YEAH. >> [LOW AUDIO].MM-HMM. YEAH. >> [LOW AUDIO].-HMM. YEAH. >> [LOW AUDIO]. >> RIGHT. RIGHT. >> [LOW AUDIO]. >> YEAH. >> RIGHT. SO YES AND NO. SO, UM, IT'S BASED ON DATA FROM THE U.S., LARGE EPIDEMIOLOGIC COHORTS AND IT ALSO MAPS ON THE THIRD OF THE DISTRIBUTION -- THAT RECOMMENDS THE USE OF THAT [INDISCERNIBLE]. ONE OF THE REASONS THAT I USED THIS CUP POINT APPROACH IN THE PHILIPPINES IS THAT THE DISTRIBUTION HAS SHIFT SOD FAR LEFT THAT I DON'T THINK THREE MILLIGRAMS PER LITTER IS MEANINGFUL THERE. I USED THIRD TILES. THE CUT POINT FOR THAT WAS .7 MILLIGRAMS PER LITTER. THAT WAS A WAY TO THINK OF RELATIVE RISK. DO THINK THE LEVEL REALLY MATTERS AND THAT IS ONE OF THE THINGS THAT WE'VE JUST BEEN FUND BID NIA TO LOOK AT AMONG THE MOMS. SO THE MOMS WHO WERE ORIGINALLY RECRUITED INTO THE STUDY ARE NOW IN THEIR 50 AND 60s AND 70s AND THEY'RE AGEING IN THE CARDIOVASCULAR LIST. WE'VE MEASURED THEIR CRP BEFORE, WE'RE GOING TO MEASURE IT AGAIN AND WE'LL BE ABLE TO SEE WHAT THE IS CUT POINT THAT PREDICTS RISK IN THIS ENVIRONMENT, BUT WE'RE ALSO GOING TO GIVE THEM A VACCINE ARK FLU VACCINE ARK SUBSET OF THEM AND MEASURE THE DYNAMIC OF THE RESPONSE TO THE VACCINE AND SEE IF THAT'S A BETTER PREDICTOR OF CARDIOVASCULAR RISK THAN JUST YOUR ARCH CRP LEVEL. I'LL BE GOING TO THE PHILIPPINES IN ABOUT THREE WEEKS TO GET THAT OFF THE GROUND. >> THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU.