>> WE HAVE A SUBSTITUTE TEACHER SPEAKING FOR HIM T. DR. RAMEY WILL NOT CHAIR THIS MORNING SO I'LL DO THAT TOO. WITHOUT FURTHER ADIEU, THANK YOU VERY MUCH FOR STEPPING IN. >> THANK YOU, IT'S GREAT TO BE ABLE TO PINCH HIT AND SHARE SOME OF OUR PERSPECTIVINGS ON CONTROVERSIES IN RED CELL TRANSFUSION AND NEONATES AND HIGHLIGHTING SOME POTENTIAL OPPORTUNITIES FOCUS OF THIS CONFERENCE IN THE ASSESSMENT OF TISSUE OXYGENATION, POST TRANSFUSION. AT THIS WITH A VIEW OF MORE VIEW OF EPIDEMIOLOGIST AND PHYSIOLOGIST AND IS TO SOME OF THE PERSPECTIVES WITH THE LENS IN MIND, I DON'T HAVE DISCLOSURES. HERE ARE SOME OF THE CONTROVERSIES AS A NEONATOLOGIST THAT WE ENCOUNTER IN RED CELL TRANSFUSION AND ONE BIG QUESTIONS IN OUR FIELD IS RESTRICTIVE TRANSFUSION PRACTICES RESULTING DEGREES OF VARYING DEGREE OF ANEMIA CAUSE LONG TERM NEW DEVELOPMENT IMPAIRMENT, NECROTIZING NEPHRITIS. AND THIS IS STILL UNANSWERED QUESTION IN OUR FIELD. ON THE DONOR SIDE WHAT ARE SOME OF THE AFFECTS OF PROCESSING RED CELLS TRANSFUSED, COMMON PRACTICES READIATION BEING ONE OF THEM THAT ARE FAIRLY WIDESPREAD, RADIATION -- AND THE EFFECTS OF RADIATION. I WILL TOUCH ON THAT AND FINALLY SOME OF THE MEASURES OF TISSUE OXYGENATION AND THIS TOPIC FOCUS ON SPECTROSCOPY OVER THE LAST DAY AND TODAY WE'LL HEAR OTHER OPPORTUNITIES FOR MONITORING. TO TAKE A PERSPECTIVE FROM MY VIEW, AS A CRITICAL CARE AND INTENSIVIST ON NEONATES, THE HABER TRIAL CHALLENGED HOW WE APPROACHED RED CELL TRANSFUSION. IN ADULTS BUT THE TWO MAIN TRIALS THAT TO THIS DAY WE HAVE TO GUIDE NEONATAL RED CELL TRANSFUSION, ADMINISTRATION OR THE IOWA TRIAL AND PINE TRIAL, THE TWO RANDOMIZED TRIALS THAT ALL PRACTICES IN OUR FIELD ARE CURRENTLY INFORMED BY. THESE WERE AS MANY OF THE TRIALS OTHER POPULATIONS RESTRICTIVE VERSUS LIBERAL TRANSFUSION THRESHOLD TRIAL. YOU CAN SEE HERE THAT THE DIFFERENT TRIGGERS THESE TRIALS DID USE DIFFERENT TRIGGERS DEPENDING ON AGE AND SEVERITY OF ILLNESS WHICH MAY EXPLAIN DIFFERENCES OBSERVED IN THE RESULTS. THE UNIVERSITY OF IOWA TRIAL OR THE IOWA TRIAL IT WAS A SINGLE CENTER TRIAL ENROLLED 100 INFANTS. THE PRIMARY OUTCOME WAS REDUCTION IN RED CELL TRANSFUSION EXPOSURE BUT THEY ALSO LOOK AT SHORT TERM OUTCOMES AND SHORT TERM ASSESSMENT THERE'S A SUGGESTION THAT THERE ARE MORE ADVERSE OUTCOMES, INTRACRANIAL PATHOLOGY, HEMORRHAGES IN THOSE INFANTS THAT RECEIVED MORE RESTRICTIVE TRANSFUSIONS BUT AT FOLLOW-UP IN THIS GROUP FOLLOWS UP TO 12 YEARS OF AGE FOUND THE OPPOSITE THAT LONG TERM FOLLOW-UP THEY WERE BETTER NEURAL COGNITIVE OUTCOMES IN THOSE LIBERALLY TRANSFUSED. THE PREMATURE NEOTRAN FUSION TRIAL WAS A TRANSFUSION TRIAL MULTI-CENTER TRIAL IN CANADA, THIS WAS A TRIAL IN 451 INFANTS LESS THAN A THOUSAND GRAMS. AND THE PRIMARY OUTCOME WAS A COMPOSITE SHORT TERM MORTALITY MORBIDITY THAT OCCURRED IN THE HOSPITAL. AND THIS TRIAL FOUND NO SIGNIFICANT DIFFERENCES BETWEEN GROUPS THOUGH LONGER TERM FOLLOW-UP THERE WAS AS I'LL SHOW IN THE NEXT SLIDE A SUGGESTION OF BETTER NEUROCOGNITIVE OUTCOMES WITH THOSE INFANTS MORE LIBERALLY TRANSFUSED. CLINICS IN OUR FIELD HAVE TAKEN THE RESULTS OF THE PINE TRIAL AND THE LACK OF A DIFFERENCE IN SHORT TERM MORBIDITY WHICH WAS A PRIMARY OUTCOME OF THE TRIAL. AS THE EVIDENCE SUPPORT MORE RESTRICTIVE TRANSFUSION PRACTICES WHICH IN OUR FEEL MANY TIME IN OUR CENTERS HAVE BECOME MORE COMMON. THE LONG TERM -- THIS IS THE TWO YEAR DATA FROM THE PINE TRIAL FOLLOW-UP IN OUR FIELD THE GOLD STANDARD OUTCOME FOR MANY STUDIES IS DEATH OR DISABILITY AT A PERIOD OF ASSESSMENT LONG TERM FOLLOW-UP TWO YEARS OR LATER AND HERE LOOKING AT TWO YEAR OUTCOME OF DEATH OR DISABILITY IN THESE PRETERM INFANTS THERE WAS NO DIFFERENCE IN APRIORI DEFINED COMPOSITE OUTCOME. THIS INCLUDED COGNITIVE IMPAIRMENT TWO STANDARD DEVIATIONS BELOW THE MEAN. BUT WHEN YOU USE A LITTLE LESS RESTRICTIVE MEASURE OF STANDARD DEVIATION BELOW THE MEAN, WHAT THE AUTHOR FOUND IN POST-DOC ANALYSIS IS HIGHER ODDS OF THIS COMPOSITE OUTCOME OF DEATH OR NEUROCOGNITIVE IMPAIRMENT AMONG INFANTS THAT HAD MORE RESTRICTIVE RANDOMIZED TRAN FUSION ARM AND -- TRANSFUSION ARM AND THIS FAVORED HIGHER HEMOGLOBIN THRESHOLDS. THIS WAS HYPOTHESIS GENERATING AND IS PART OF WHAT IS BEING TESTED OUT CURRENTY IN THE TRANSFUSION OF PREMATURE TRIAL THAT I'LL MENTION BUT THIS DOES SUGGEST THE UNCERTAINTY PARTICULARLY WITH NEUROCOGNITIVE OUTCOME CONSIST OF EFFECTS OF MORE RESTRICTIVE TRANSFUSION PRACTICES AND LOWER HEMOGLOBIN THRESHOLDS. THE OTHER ONE WITH TRANSFUSION IS NECROTIZING COLITIS, A PRIMARY INTEREST OF MINE. IT'S A MULTI-FACTORIAL DISEASE IN LAST TEN YEARS WE IMPROVED UNDERSTANDING, THERE ARE DIFFERENT FACTORS CONTRIBUTE DISBIOSIS BEING ONE OF THEM. THE OTHER FACTOR, SUPPORTED BY DATA RANDOMIZED TRIALS LOOKING AT HIGH VERSUS LOW OXYGEN SATURATION TARGETING, INFANTS RANDOMIZED TO LOWER OXYGEN SATURATION TARGETING AS YOU HEARD FROM YESTERDAY HAVE HIGHER LIST OF NECROTIZING COLITIS, THERE'S SOMETHING ABOUT OXYGEN DELIVERY THAT'S PART OF THE MULTI-FACTOR ETIOLOGY. IT'S A HIGH CASE FATALITY, THEY PRESENT WITH DISTENSION, FEEDING INTOLERANCE, OF THE INFANTS THAT REQUIRE SURGERY, MORTALITY IS 50%, SUBSTANTIAL LONG TERM MORBIDITY, CANCER ONE IN TEN DEATHS IN THE NEONATAL INTENSIVE CARE UNIT. THIS IS A STUDY AT COST SPECIFIC MORTALITY, TO NEONATAL RESEARCH NETWORK. I POINT THIS OUT BECAUSE THIS IS A DISEASE THAT TYPICALLY HAPPENS WEEKS INTO THE POSTNATAL HOSPITAL COURSE, MOST COMMON CAUSE OF DEATH BETWEEN TWO WEEKS AND TWO MONTHS OF AGE BUT IT ALLOWS FOR GOOD ASSESSMENT OF INCIDENT DISEASE BECAUSE THIS IS A RARE OCCURRENCE EARLY ON AND THE NEONATES THAT ARE CAPTIVE AUDIENCE ALLOWS FOR EARLY MONITORING AT PERIOD THESE INFANTS ARE AT RISK BUT DON'T DEVELOP DISEASE OPPOSED TO SOME OF THE INTERCRANIAL INJURY THAT WE OCCUR THAT HAPPENS -- CAN HAPPEN EARLY ON. THIS IS A DISEASE THAT TYPICALLY STRIKES LATER ON IN THE COURSE OF THESE INFANTS. SO WHAT ARE THE RED CELL TRANSFUSION TRIALS WITH REGARDS TO NECK? THE PINE, IOWA TRIAL BY BELL SHOWED NO SIGNIFICANT DIFFERENCE WHEN HE PULLED THE ESTIMATES, SMALL NUMBERS OF INFANTS AND RELATIVELY IMPRECISE ESTIMATES OF THE EFFECT THOUGH THE POINT SUGGESTS THERE WAS MORE NECK IN RESTRICTIVE TRANSFUSION PRACTICES IN INFANTS RANDOMIZED TO MORE RESTRICTIVE TRANSFUSION THRESHOLD THAN MORE LIBERAL. THERE ARE -- THESE TRIALS WERE PUBLISHED IN THE MID 2000s AND OVER THE LAST TEN YEARS OR SO THERE OOHs BEEN THIS REALLY RELATIVELY FREQUENT REPORTING OF LARGELY OBSERVATIONAL STUDIES SHOWING THIS ASSOCIATION BETWEEN REEL YESTERDAY TRANSFSION AND NECROTIZING COLITIS, EXPOSURE, THERE'S 17 STUDIES THAT EVALUATED THAT. IN 2012 THERE WAS A META ANALYSIS DONE, BASED ON ADJUSTED ESTIMATES FROM OBSERVATIONAL STUDIES SUGGESTING THAT INFANTS EXPOSED TO TRANSFUSION HAD TWO FOLD HIGHER NECROTIZING COLITIS WITH SOME CONFOUNDING. THAT LED SOME TO THINK OF THIS AS TRANSFUSION RELATED COMPLICATION, IN SOME THIS IS ONE OF THOSE EVENTS THAT PEOPLE CONSIDER POTENTIALLY RELATED TO TRANSFUSION. BUT THEN AS WITH ALL STUDIES IN PUBLICATION, THERE HAS BEEN MORE RECENTLY STUDIES THAT SHOW OPPOSITE AND NO ASSOCIATION OR RED CELL TRANSFUSION IS PROTECTIVE. THE QUESTION IS, IS IT THE RED CELL TRANSFUSION OR UNDERLYING ANEMIA AS RED CELL TRANSFUSION IS OFTEN TREATMENT FOR ANEMIA. YOU HEARD YESTERDAY BOTH MAY BE BAD FOR PATIENTS IN GENERAL, THIS IS A STUDY OUT OF BAY STATE LOOKING AT AS HEMATOCRIT DECREASES THE PARTICULAR PROBABILITY, MODEL PROBABILITY YOU SEE INCREASES AND THIS ASSOCIATION BETWEEN INFANTS HAVING MORE SEVERE ANEMIA HAVING HIGHER RISK OF NECROTIZING COLITIS BASED ON OBSERVATIONAL STUDIES. THAT LED US TO LOOK AT THIS QUESTION A LITTLE MORE CAREFULLY, THIS IS A PROSPECTIVE COHORT STUDY PUBLISHED TWO YEARS AGO THAT SPECIFICALLY LOOKED AT TRYING TO UNDERSTAND THESE TWO EXPOSURES WHICH IS RED CELL TRANSFUSION AND ANEMIA AND INFLUENCE ON NECROTIZING COLITIS, THE GOAL IS TO TEST HYPOTHESIS IF EXPOSURE WAS ASSOCIATED WITH DEVELOPMENT OF LONGITUDINAL COHORT BUT ALSO THEN TO LOOK AT THE INDEPENDENT CONTRIBUTION OF THE SEVERITY OF ANEMIA WHICH WE DEFINED USING A HEMOGLOBIN THRESHOLD LESS THAN 80-GRAM FOR -- DECALITER. WE TREAT THESES TWO EXPOSURES IN WEEKLY INTERVALS THAT ALLOWED US TO ACCOUNT FOR EXPOSURES IN RED CELL TRANSFUSIONS THAT INFANTS RECEIVE IN A GIVEN WEEK. WHAT WE FOUND IS THAT RED CELL TRANSFUSION WAS NOT ASSOCIATED WITH DEVELOPMENT OF ANY C, HAZARD RATIO THERE. AND RATIO DIRECTION OF THAT CONSISTENT WITH THE DATA WE SEE FROM THE TWO RANDOMIZED TRIALS THAT HAVE BEEN DONE TODAY. WE FOUND ASSOCIATION BETWEEN SEVERE ANEMIA IN GIVEN WEEK AND HIGHER RISK OF NECROTIZING COLITIS. THIS IS IMPRECISE ESTIMATED RELATIONSHIP BUT ONE WHEN WE LOOKED IN A NUMBER OF BOOT STRAP MODELS, A THOUSAND MODELS LOOKING HOW OFTEN THIS RISK FACTOR APPEARED, ABOUT 70% OF THE TIME WHICH MADE US THINK THIS IS A RELIABLE RISK FACTOR AND THIS IS OBSERVATIONAL JUST ASSOCIATION BUT DATE ACCOUNT FOR TEMPORALITY BETWEEN DEVELOPING SEVERE ANEMIA AND SUBSEQUENTLY DEVELOPING THE OUTCOME OF INTEREST WHICH IS NECROTIZING COLITIS. SO WHAT'S HAPPENING, THIS IS UPDATED ANALYSIS OUT OF INVESTIGATORS AT UNIVERSITY OF ALABAMA BIRMINGHAM. LOOKING AT NOW THE 17 OBSERVATIONAL STUDIES, A LITTLE OVER 10,000 INFANTS STUDIED. ALL OBSERVATIONAL LOOKING ASSOCIATIONS BETWEEN IS THERE ASSOCIATION BETWEEN EXPOSURE OF RED CELL TRANSFUSION AND HIGHER RISK AND YOU CAN SEE THE PULLED POINT ESTIMATE REALLY RELIES AROUND ONE BUT I THINK WHAT'S MORE STRIKING IS THE AMOUNT OF HETEROGENEITY, THE FORCE PLOT ABOUT 93%. LARGELY MOST STUDIES DON'T ACCOUNT FOR THE CHARACTERISTICS OF THOSE RED CELLS THAT ARE TRANSFUSED TO THE INFANTS. SOME OF THIS HETEROGENEITY IS EXPLAINED BY STUDY DESIGN IF YOU STRATIFY BY CASE CONTROL VERSUS COHORT STUDIES BUT A LOT OF HETEROGENEITY IS UNEXPLAINED AND I THINK HIGHLIGHTS SOME OF WHAT WE DON'T KNOW IN TERMS OF JUST STUDIES SHOWING PROTECTIVE OR ASSOCIATION BETWEEN RED CELLS. SO I THINK WHERE IS THE FIELD GOING? WE'RE EAGERLY ANTICIPATING THE RESULTS OF THE TRANSFUSIONS OF PREMATURE TRIAL WHICH WE'RE HOPING TO HAVE THE NEXT ONE TO TWO YEARS, ONE OF THE SITES, THIS IS IN THE TRIAL CONDUCTED IN NEONATAL RESEARCH SUPPORTED BY THE NHLBI LED BY TWO PRINCIPAL INVESTIGATORS THE IOWA AND PINE TRIAL COME TOGETHER TOO. TO LOOK AND TO ASSESS AFFECTS OF HIGH THRESHOLD WHICH INFANTS AREN'T ALLOWEDDED TO HAVE A HEMOGLOBIN BELOW SEVEN AS A TARGET COMPARED TO ONE THAT ALLOWS THEM TO FALL LESS TO LOW AS SEVEN DEPENDING HOW OLD THEY ARE AND LEVEL. THIS SEPARATION MAY ALLOW US TO HAVE EXPERIMENTAL EVIDENCE TO UNDERSTAND EFFECT OF THESE MORE RESTRICTIVE THAT ALLOW INCREASE TOLERANCE ANEMIA, PRIMARY OUTCOME IS DEATH NEUROCOGNITIVE IMPAIRMENT TWO YEARS AND NOW WITH FUNDING THROUGH FIVE YEARS OF AGE. THIS IS A COMMON PRACTICE, AS MANY OF YOU KNOW IN OUR FIELD. THIS WE HOPE WILL PROVIDE M DATA BUT I WOULD SAY THIS IS STILL RELYING ON HEMOGLOBIN THRESHOLDS IS IMPRECISE AND THIS IS BY HARVEY KLINE AND OTHERS HERE AT THE NIH AND IT'S A NICE VIEWPOINT ABOUT WE'RE STILL FAIRLY IMPRECISE JUST USING HEMOFLOW BIN THRESHOLDS AN EVEN WITH THE DATA FROM TRANSFUSION OF PREMATURE TRIAL WE WON'T IN WHOLE GROUP I THINK THAT WILL INFORM TARGETS BUT FOR INDIVIDUAL PATIENT IT'S RELATIVELY IMPRECISE MEASURE, YOU HEARD BY OTHERS YESTERDAY. THIS IS ONE EXAMPLE OF THAT. THIS IS OBSERVATIONAL STUDY FROM BOSTON LAST YEAR LOOKING AT THE NEONATES THE DEGREE THEY HAD PRE-OPERATIVE ANEMIA, THE RISK OF POST-OPERATIVE MORTALITY IN A COHORT OF DATA FROM MULTI-CENTER SURGICAL DATA AND REASONABLE NUMBER OF INFANTS, THEY FOUND AFTER ACCOUNTING FOR DIFFERENT CHARACTERISTICS OF CASE MIX IS THAT INFANTS MADE A RELATIVELY USING A RELATIVE WILL I HIGH CUT OFF HEMATOCRIT LESS THAN 40 HAD HIGHER ODDS OF MORTALITY. AND WE TALKED YOU HEARD YESTERDAY ABOUT STRESS, I THINK IN THE NEONATE UNDERGOING SURGERY, THAT IS A -- REALLY DOES -- IS A SUBSTANTIAL STRESSOR FOR RESERVE AND WHAT'S THE THRESHOLD FOR THAT NEONATE. IN PARTICULAR ARE PREMATURE INFANTS, THOSE THAT HAVE A BIRTHRATE LESS THAN TWO KILOGRAMS. IF YOU LOOK THESE INVESTIGATORS WENT TO MODEL THE PREDICTIVE PROBABILITY OF MORTALITY LOOKING AT INFANTS WHO HAD ALL THESE FACTORS THE POSTOP MORTALITY WAS 43%, IF YOU CHANGE AND SWITCH TO HEMATOCRIT GREATER THAN 40% THE PROBABILITY WAS STILL HIGH BUT DECLINED 23%. AND SO I THINK EVEN WITH TARGETED HEMOGLOBIN TRANSFUSION THRESHOLDS FOR INDIVIDUAL IN STRESS SETTINGS RECEIVING SUPPORT ON MECHANICAL VENTILATION WAS THE RIGHT TRIGGER. I THINK THAT TRANSITIONS TO WHERE THE ROLE OF ASSESSING REGIONAL OXYGEN SATURATION MAY -- THE OPPORTUNITY AS RELATES TO GUIDANCE FOR TRANSFUSION, YOU HAVE HEARD A LOT ABOUT NEONATE SPECTROSCOPY SO I WON'T REPEAT BUT THIS IS AN EXAMPLE OF AN INFANT, HIPAA COMPLIANT PICTURE OF ONE INFANT. AND THIS IS THE TWO TISSUE BEDS I THINK THAT ARE RELEVANT TO OUR PATIENTS WHICH SURGICAL TIERS AND MESOTERIC GUT OUTCOMES NECROTIZING COLITIS, THIS IS FROM A COHORT STUDY FROM TERRY AND CASSANDRA JOSEPHSON, A SMALL COHORT STUDY IN OUR CENTER OF 17 PRETERM INFANTS RELATIVELY WELL SEVERAL WEEKS INTO POST COURSE LARGE HEMOGLOBIN DRIVEN TRANSFUSION DECISIONS SO MONDAY THEY WOULD HAVE A HEMOGLOBIN THAT WOULD GUIDE THE DECISION TO TRANSFUSION OR NOT, MOSTLY NO RESPIRATORY SUPPORT, MOSTLY FEEDING. SO TAKE INFANT AND PLACE MESOTERIC THIS IS WHAT YOU SEE PRE-TRANSFUSION. SO LOOK AT CEREBRAL IN THIS PRE-TERM POPULATION THE RANGE IS 50 TO 85 PERCENT IS WHAT'S THOUGHT OF THE NORMATIVE RANGE OF NEARS AND WHEN YOU PLACE A MESOTERIC MEASURE YOU SEE VERY LOW SOME DATA LOWER LIMITS OF PROTECTION. WE FIRST STARTED THINKING THIS IS A PROBLEM WITH INAPPROPRIATE SIGNAL. BUT TRANSFUSION THAT INFANT WITH RED CELLS AND YOU SEE WITHIN A 40 HOUR PERIOD FOLLOWING RED CELL TRANFUSION THE MESOTERIC TISSUE OXYGEN SATURATION INCREASE AS ONE EXPECTS F. WHAT'S THE -- THIS IS SOMETHING I THINK NOW SHOWN BY OTHER GROUPS IN PARTICULAR VERY PRETERM INFANTS VERY LOW TISSUE OXYGENATION BY SATURATION IN THE MESS TEARIC REGION. BUT AS CONSEQUENCE OF IS THAT, THAT'S STILL A QUESTION WE DON'T KNOW THE ANSWER TO. BUT WHAT WE ALSO SEE ARE INFANTS WITH THIS CHANGE, THIS TYPE OF PROFILE WHERE THEY HAVE A LOW BASELINE YOU ADMINISTER TRANSFUSED RED CELLS, YOU DON'T SEE A CHANGE. WE USE A MEASURE WHERE WE LOOK AT THE AREA UNDER A FITTED SUPPLY CURVE, ACCOUNTING FOR SOME ISSUES WITH SIGNAL, LOSS BELOW DETECTION THRESHOLD BY INVITATION. AND WHEN YOU LOOK AT THIS YOU DON'T SEE -- IS THIS BECAUSE OF INCORRECT DOSE OR CHARACTERISTICS AS YOU HEARD YESTERDAY ABOUT PARTICULAR RED CELLS THAT INNUANCE THE LACK OF RESPONSE. WHAT WE HAVE SEEN IN THIS COHORT 17 INFANTS IS SUBSTANTIAL VARIABILITY IN RESPONSES TO RED CELL TRANSFUSION. SO RED CELL CHARACTERISTICS, SOME OF THE VARIABILITY MAYBE EXPLAINED BY PATIENT SPECIFIC FACTORS BUT IT'S IMPORTANT TO CONSIDER ALSO THE DONOR FACTORS. ONE YOU HEARD JOHN AND OTHERS TALK ABOUT YESTERDAY, AT LEAST BICRON LOGICAL AGE OF ASSESS -- BY CHRONOLOGICAL AGE, IS RELATIVELY WELL STUDIED IN TRIALS, AND I THIS THE DATA AT LEAST IN MY INTERPRETATION IS NOT CLEAR THAT PROLONGED BY CHRONOLOGICAL AGE OF STORAGE EFFECTS -- RELATES TO ADVERSE EFFECTS OF OUTCOMES, THIS IS META ANALYSIS 2016, THERE'S MORE RECENT DATA INCLUDING THE TRIAL NANCY AND OTHERS THAT THERE'S NOT CLEAR EFFECT, THIS LARGELY IS DRIVEN -- LARGELY THESE STUDIES ACCOUNT FOR ADULT SOME NEONATES INFANTS AND CHILDREN BUT MAJORITY INFANTS STUDIED IN THESE TRIALS ARE ADULTS. WE HAVE BEEN INTERESTED IN MORE SPECIFICALLY THE EFFECT OF RADIATION, THIS IS A COMMON PRACTICE IN FOR TRANSFUSION NEONATES TO PREVENT GRAFT VERSUS HOST DISEASE. THERE'S SOME VARIABILITY HOW IN THE CLINICAL SETTING IS APPLIED IN TERMS OF WHERE THE UNIT IS RADIATED, HOW LONG IT STAYINGS THIS IS ONE ASPECT OF VARIATION, YOU HEARD THE INFORMATION ON THE AGE AND GENDER. THIS IS SURVEY OF HOSPITALS BY DR. LUBAN AND DR. JOSEPHSON LOOKING WHAT WERE THE PRACTICES IN THIS GROUP OF HOSPITALS PARTICIPATING IN THE MATURES TRIAL MOST OF THESE HOSPITALS ROUTINELY IRRADIATE RED CELLS, THOUGH SOME DO RIGHT BEFORE ISSUE SO THERE'S LIMITED AMOUNTS OF STORAGE AFTER RADIATION WHEREAS OTHER HOSPITALS ALLOW THESE RED CELLS TO BE STORED AFTER RADIATION UP TO 28 DAYS. THIS IS I THINK JUST SOME INITIAL WORK TRYING TO UNDERSTAND WHAT ARE THE EFFECTS OF RADIATION PARTICULARLY WITH STORAGE RADIATION, THIS IS WORK WE DID WITH JOHN ROBACK AND BIOMARKER GROUP AT EMORY DEAN JONES, DONORS CAME IN AND DONATED BLOOD AND SAME UNITED WAS SPLIT, RADIATED AND STORED UNDER STANDARD BLOOD BANKING CONDITIONS THROUGH SAMPLE IN 35 DAYS OF STORAGE. TRYING TO UNDERSTAND THE METABOLIC ALTERATIONS WITH STORAGE FOLLOWING IRRADIATION. AND THIS IS I THINK CAN BE VIEWED AS A PRINCIPLE COMPONENT ANALYSIS THOUGH IT'S A DIFFERENT TECHNIQUE MULTI-LEVEL PARTIALLY SQUARED DISCRIMINANT ANALYSIS. THE POINT HERE IS THAT AN EARLY LIMITED STORE RAGES YOU SEE -- STORAGE YOU SEE METABOLIC PROFILE OF DONOR RED CELL UNITS TO BE SIMILAR, AT SEVEN DAYS YOU SEE A DIFFERENCE BETWEEN WITH THE RADIATED IN TERMS OF BETTER METABOLITES COMPARED TO THOSE NOT IRRADIATED BUT BEYOND SEVEN DAYS STARTING AT TEN UP TO 35 DAYS WE SEE THIS DIFFERENCE IN TERMS OF IRRADIATED AND CONTROL RBCs. SO WE THINK THAT IRRADIATION MAYBE ONE AND THERE'S DATA SHOW EFFECTS ON RED CELL MEMBRANE VISUALIZED BY RADIATION BUT THAT MAYBE ONE ASPECT OF VARIABILITY IN DONOR RED CELLS THAT IS AN OPPORTUNITY TO STUDY. IN CLUSTERING WE DID TWO CLUSTERS YOU SEE CLUSTERS THAT SEPARATED BY STORAGE AGE PARTICULARLY WITH THRESHOLD OF SEVEN TO TEN DAYS IN TERMS OF DIFFERENCES IN PATTERNS AND THEN ALSO CLUSTERS THAT SEPARATE BY RADIATION STATS. IZ PATHWAY ANALYSIS, THESE ARE LOOKING AT WHAT ARE THE PATHWAYS THAT ARE LARGELY EFFECTED AND GO ALONG WITH WHAT ONE EXPECTS WHICH IS PATHWAYS RELATED TO THE RED CELL MEMBRANE CONSISTENT WITH THE DATA ON EFFECTS OF IRRADIATION ON RED CELL MEMBRANE. THIS IS SOMETHING WE ARE LOOKING AT FURTHER, LED BY CASSANDRA JOSEPHSON, A PROSPECTIVE COHORT STUDY LOOKING AT UNDERSTANDING THE METABOLIC FINGERPRINTS OF BLOOD CELLS AND RESPONSE TO HOW INFANTS RESPOND TO TRAININGS FUSION SITING THE OPPORTUNITY FOR USING SATURATION AS MEASURE TO ASSESS THE RESPONSES TO RED CELL TRANSFUSION. YOU SAW EXAMPLEPS OF TWO PROFILES OF RESPONSES TO RED CELL TRANSFUSION. IN EACH OF THESE UNITS WILL HAVE A METABOLIC FINGERPRINT, THE PRIMARY EXPOSURE IS THE POST IRRADIATION STORAGE DURATION OF THESE RED CELLS TRANSFUSED TO PRE-TERM INFANTS. THE END POINT HERE BEING LOOK AT NEARS, WE ENROLLED 80 OUT OF 220 PLANNED INFANTS, WE HAVE BEEN ENROLLING FOR A YEAR. THE OTHER ASPECT IS BACK TO THE QUESTION ABOUT ANEMIA. AND HOW DOES ANEMIA SPECIFICALLY INFLUENCE THE -- IN THIS CASE OUR PARTICULAR INTEREST IS WITH MESS TEARIC OXYGENATION AND LOOKING LONGITUDINALLY, PRE-TERM INFANTS ARE IDEAL COHORT BECAUSE THEY ARE CAPTIVE AUDIENCE FOR 60 TO 90 DAYS CONSISTENTLY AND OFFER OPPORTUNITIES FOR LONGITUDINAL ASSESSMENTS SO THIS IS WHERE INFANTS ARE GETTING ASSESSED LONGITUDINALLY AS THEY GO THROUGH AND DEVELOP ANEMIA TO UNDERSTAND HOW THE LEVELS OF ANEMIA RELATE TO THESE DIFFERENCES IN MESOTERIC OXYGENATION AND HOPEFULLY THIS WILL ALLOW US MORE ABILITY TO UNDERSTAND THE RELATIONSHIPS BETWEEN THESE THAT YOU CAN'T DO IN A SMALL COHORT. SO NEW TECHNOLOGIES ARE REALLY NEEDED TO IDENTIFY SAFE LEVEL OF ANEMIA TOLERATEDDED IN PRE-TERM INFANTS. THRESHOLD TRIALS ARE IMPORTANT TO GUIDE GENERAL PRACTICE BUT CHALLENGE IN STRESS NEONATES ABOUT WHAT IS THE RIGHT LEVEL OF ANEMIA STILL WITH THE INFORMATION WE HAVE MAY NOT BE ANSWERED. AND THERE'S OPPORTUNITIES. WE HAVE BEEN SURPRISED HOW OFTEN WE PLACE A MESOTERIC OXYGENATION MEASURE ON NEONATES AND WE SEE LOW LEVELS OF MESOTERIC OXYGENATION. THE GAP IS TO UNDERSTAND WHAT DOES THAT MEAN RELATED TO THE IMPORTANT CLINICAL OUTCOMES RELATIVE PRE-TERM INFANTS, SAME WITH CEREBRAL OXYGENATION. THERE'S SOME STUDIES LOOKING AT THOSE OUT I DON'T MEANS. HOW DONOR RED CELL CHARACTERISTICS INFLUENCE TISSUE OXYGENATION. THERE'S RECIPIENT FACTORS THAT AFFECT RESPONSES, PARTICULARLY THE SEVERITY OF UNDERLYING ANEMIA PRIOR TO TRANSFUSION BUT WE THINK THAT DONOR RED CELL DARK TICKS THAT LOOKING AT TISSUE OXYGENATION RESPONSES USING IN THIS CASE SPECTROSCOPY MAY ALLOW HOW TO ASSESS CHARACTERISTICS IN PRE-POST TRANSFUSION CAN ALLOW FOR SOME LOOK AT THE DIFFERENT MODIFICATIONS THAT RED CELLS UNDERGO WITH PROCESSING THAT MAYBE A LITTLE LESS THAN SOME OF THE DIFFICULTY WITH LABEL, OTHER STUDIES THAT REQUIRES RECOVERY AND IMPORTANTLY HOW THESE MEASURES EFFECT IMPORTANT CLINICAL COMES IN PRE-TERM INFANTS. THANK YOU VERY MUCH FOR THE OPPORTUNITIES TO TALK. [APPLAUSE] WANT TO ACKNOWLEDGE COLLABORATORS CASSANDRA JOSEPHSON AT EMORY, PI IN THESE STUDIES, JOHN ROBAC AND BLOOD BANKING SURVEY ANALYSIS AS PART OF THE TRIAL. T >> THANK YOU, LIKE YESTERDAY TO KEEP ON TIME WE'LL SAVE QUESTIONS AND DISCUSSION FOR THE DISCUSSION PERIOD. MY UNDERSTANDING IS DR. HUTES HAS ARRIVED. MY UNDERSTANDING IS HE'LL HAVE A FEW WORDS. THANK YOU, KEITH. >> GOOD MORNING, I'M SORRY I ALMOST MADE IT IN TIME TO DO WHAT THE SCHEDULE SAID I WAS GOING TO DO. I AM LOOKING FORWARD TO HEARING ALL THE PRESENTATIONS TODAY, I'M SORRY, I WAS OUT OF STATE YESTERDAY AND EARLY FLIGHT ALMOST GOT ME HERE IF THE COMMUTE WAS A LITTLE BIT LONGER THAN I HOPED BUT IT ALMOST WORKED OUT. I WAS HERE AT THE PREDOMINANCE OF THE PREVIOUS TALK WHICH I THOUGHT ADS PEDIATRICIAN WAS VERY COMPELLING. I LOOK FORWARD TO THE REST OF THE DISCUSSION AND GETTING -- BEING BROUGHT UP TO DATE WITH DISCUSSION FROM YESTERDAY. I WILL TRY TO KEEP US ON TIME. SO AGAIN, A VERY BELATED WELCOME BUT I'M REALLY PLEASED THAT -- ABOUT WHAT MARGARET AND HER& COLLEAGUES HAVE PUT TOGETHER HERE AND CHAIRS FOR THEIR WONDERFUL LEADERSHIP OF THIS MAGNIFICENT SYMPOSIUM. I WILL MOVE FORWARD NOW TO TURN IT BACK OVER TO DR. -- >> THANK YOU VERY MUCH. I WILL SAY FOR THOSE OF US IN THE TRANSFUSION MEDICINE COMMUNITY, THE SUPPORT OF DR. HUTES AND SIMONE HAS BEEN REALLY SPECTACULAR. WE GREATLY APPRECIATE IT. SO OUR NEXT TALK IS ABOUT BREEZING. THERE YOU ARE. ERICA FORZANI WILL TALK ABOUT NON-INVASIVE DEVICE FOR MEASURING METABOLISM. WELCOME. OKAY. LET'S SEE WHAT IS BREEZY. A LITTLE BIT OF STORY ABOUT THIS DEVICE. AND I WOULD LIKE TO SHARE. I HAVE BEEN THINKING HOW TO CONNECT THE DEVICE. THE PROPOSAL OF THE DEVICE EMERGING TECHNOLOGY WAS MOSTLY FOR WEIGHT MANAGEMENT. SO SINCE I WAS INVITED TO THIS WORKSHOP I WAS THINKING, OKAY, HOW WE CAN CONNECT WITH TISSUE OXYGENATION. BUT IN FACT I FOUND THERE IS A BIG CONNECTION. IT HAS BEEN A LEARNING EXPERIENCE FOR ME. SO IF WE LOOK AT THE TISSUE OXYGENATION PROCESS, WE BRING OXYGEN AND THEN WE EXCHANGE AT THE LEVEL THIS OXYGEN FROM GAS PHASE INTO THE BLOOD AND THEN THE HEART PUMPS THE BLOOD INTO THE TISSUE, THE MUSCLES, WHERE THE OXYGEN IS USED FOR THE ATP PRODUCTION. THE ENERGY PRODUCTION THAT SUSTAINS ALL OUR METABOLIC FUNCTIONS AND THEN AS A CONSEQUENCE OF THIS PROCESS, WE HAVE A INCORPORATION OF OX GENERAL AND RELEASE OF CARBON DIOXIDE, THAT IS TAKEN OUT OF THE BODY, AGAIN, AT THEIR LEVEL. SO BASICALLY THE TISSUE OXYGENATION PROCESS IS A GAS EXCHANGE PROCESS WHERE WE INCORPORATE OXYGEN AND WE RELEASE CARBON DIOXIDE. WE PRODUCE ENERGY IN THIS PROCESS. SO THE MAIN FUNCTION IS THIS PRODUCTION OF ENERGY AND BASICALLY IT COMES TO THE POINT WHERE WE LOOK AT THE END OF THE ENERGY BALANCE BECAUSE THIS ENERGY COMES FROM THE -- OUR INTAKE OUR CALORIE INTAKE. BASICALLY WE FUNCTION AS COME BUST SHUN ENGINE, WE TAKE FOOD, CONSUME OXYGEN TO PRODUCE CARBON DIOXIDE AND MOSTLY ATP. THAT ATP IS USED TO SUSTAIN THE DIFFERENT METABOLIC FUNCTIONS AROUND 20% IS USED FOR LIVER FUNCTIONS, ANOTHER 20% FOR THE BRAIN, 10% IN DIGESTION, 2347% IN HEART, 7 TO 10% AND SO ON. IF WE DON'T USE THE ENERGY STORAGE AS FAT TISSUE. THIS IS -- OKAY, THE CONNECTION BETWEEN A TISSUE OXYGENATION PROCESS AND ENERGY BALANCE. THIS PROCESS IS VERY IMPORTANT TO US WHO ARE IN THE ENERGY BALANCE SIZE AND LOOKING AT HOW THE INTAKE CALORIES CAN AFFECT THE ENERGY STORAGE BUT THE MAIN POINT HERE IS THAT IS IT POSSIBLE, IT HAS BEEN DEMONSTRATED THAT THIS OXYGEN CONSUMPTION, WHAT IS WE WERE DISCUSSING YESTERDAY IS THE OXYGEN CONSUMPTION RATE. AND THE CARBON DIOXIDE RATE, CAN BE RELATED TO THE ENERGY EXPENDITURE. THROUGH THIS FAMOUS EQUATION USED FOR A HUNDRED YEARS INITIALLY VALIDATED AGAINST THE CALORIC LEVEL, THE CONCLUSION WAS THE CALORIE METRY WAS EQUIVALENT TO THE CALORIE METRY. SO WE CAN GET ENERGY MEASUREMENTS MEASURED IN THE CHANGES IN TEMPERATURE OF THE HUMAN BODY INSIDE CALORIE METRIC CHAMBER OR MEASURED IN EXCHANGE OF GASES IN THE BODY. SO THIS WAS APPROVED IN THE 1900s BY EDWARD AND ROW IS A, THE RESEARCH PROVED THESE TWO METHOD WERE EQUIVALENT AND OTHERS DEMONSTRATED THE EQUIVALENCY BETWEEN TWO METHODS OVER TIME. SO THIS IS THE HISTORY SUMMARIZED. SO IF YOU LOOK HERE THE ENERGY EXPENDITURE COMES DOWN TO THE FIRST LAW OF THERMODYNAMIC. THE CONSERVATION OF ENERGY LAW. FROM THERE -- WAS THE FIRST ONE DOING THE HUMAN CALORIE METRY FROM THERE EDWARD AND ROW IS A GAVE GREAT CONTRIBUTIONS AND MANY OTHERS THROUGHOUT HISTORY. IF WE COME DOWN TO OUR TIMES 2000, YOU CAN SEE NOWADAYS WE HAVE PORTABLE BREAST BY BREAST INSTRUMENTATION THAT CAN BE AS LOW AS $5,00 AND THEY MEASURE ONLY OXYGEN, NOT CARBON DIOXIDE& BECAUSE INCORPORATING CARBON DIOXIDE REQUIRES SECOND TECHNOLOGY USED DIFFERENT FROM OXYGEN FOR OXYGEN TYPICALLY ELECTROCHEMICAL OR PARAMAGNETIC DETECTION. AND EQUIPMENT WITH OXYGEN AND CARBON DIOXIDE IS SLIGHTLY SIX TIME MORE EXPENSIVE BASICALLY, SO IF WE WANT TO BRING TOOLS TO THE REAL WORLD, THAT CAN PERFORM THESE MEASUREMENTS OF OXYGEN CONSUMPTION VO 2 AND CARBON DIOXIDE PRODUCTION BCL 2 BASICALLY GENERATE A PORTABLE CALORIE METRY TO BRING THE TWO MEASUREMENTS THAT ARE ESSENTIAL TO LOOK AT THE TISSUE OXYGENATION PROCESS. WE NEED TO COVER A GAP. BECAUSE IN THE REAL WORLD AS YOU KNOW WE HAVE ENERGY EXPENDITURE DEVICES THAT WE CAN BE PROBABLY NOWADAYS, ANY OTHER DEVICE BASED ON RATE BUT THIS NOT TRUE DIRECT MEASUREMENT OF THESE TWO PARAMETERS WE NEED. ON THE OTHER SIDE IN THE RESEARCH WE HAVE A GREAT INSTRUMENTATION FOR THESE TWO PARAMETERS BUT AS WE SAID, THIS IS EXPENSIVE AND DIFFICULT TO APPLY IN THE FIELD. IF WE WANT TO EXTEND AND GET TO LEARN MORE ABOUT WHAT'S GOING ON IN THE TISSUE OXYGENATION AND MASSIVE LEVEL AND FREE LIVING CONDITIONS. SO OKAY, WHAT ARE THE CHALLENGE FOR DEVELOPING NON-INVASIVE APPROACHES TO ASSESS THESE TISSUE OXYGENATION. THE CHALLENGE IS BASICALLY IF WE ARE LOOKING AT DETECTION OF OXYGEN AND CARBON DIOXIDE SIMULTANEOUSLY IN BLOOD IN CALORIE METRY WELL ACCEPTED METHODS, THE BREAST IS VERY COMPLEX SAMPLE WITH THOUSANDS OF MANY ADDED MOLECULES, PLUS IT'S HOT AND HUMID. SO HUMIDITY AND TEMPERATURE ARE WORSE ENEMIES OF TOOL MAKERS. SO BASICALLY THE PROBLEM IS SIMILAR TO THE WILLING TO DETECT A BIOMARKER IN BLOOD WHERE THERE'S OTHER MOLECULES AROUND. AND IT COMES DOWN TO FIND A NEEDLE IN THE HAY STACK. SO IS A CHALLENGING PROBLEM. WE CAN DEDICATE OUR ENERGY TO FIND OUT THE SOLUTIONS AND HERE IS HOW WE APPROACH IN ELECTROBIOSENSORS IN THESE KIND OF PROBLEMS SO WE BASICALLY CREATE SYSTEMS WHERE NOT ONLY THE SENSOR COMPONENT IS RELEVANT COMPONENT BUT ALSO WE TRY TO MERGE METHODS FOR COLLECTION FOR CONDITIONING OF SAMPLE TOGETHER WITH A SMART DETECTION MODE SIGNAL PROCESSING AND SO THAT WE CAN OBTAIN RESULTS EASY TO INTERPRET, EASY TO UNDERSTAND BUT SOMEONE THAT DOESN'T HAVE MUCH EXPERTISE. WITH THIS APPROACH WE HAVE BEEN ABLE TO CREATE SEVERAL DEVICES, ONE OF THEM IS A DEVICE THAT WE ARE TALKING TODAY ABOUT. WE BOUGHT BREEZY IN 2014 SO IT WAS THE FIRST METABOLIC RATE TRACKER. SO THE FIRST QUESTION WAS HOW ACCURATE IS THIS TRACKER? SO WE CONDUCTED A VALIDATION REQUEST GOLD STANDARD METHOD WHICH IS DOUGLAS METHOD AND WE FOUND IT WAS A GOOD CORE FOR VO 2 VCO 2 AND ENERGY EXPENDITURE AND RESPIRATORY PORTION WE TALK ABOUT THIS LATER. IN A FEW MINUTES. ASK SO WE WERE PRETTY SATISFIED SO THE ACCURACY WAS ALMOST 100% WITH THAT GOLD STANDARD METHOD. THEN THE QUESTION WAS THE SECOND QUESTION OF THIS WORKSHOP. TO PROGRESS IN THIS RESEARCH AREA. SO WHAT WE FOUND, IT WAS VERY ESSENTIAL FOR THE SCIENTIFIC COMMUNITY TO BE LIVING IN THIS DEVICE, THE DEVICE SHOULD BE CALIBRATED BY OTHERS. SO WE FOUND FOR EXAMPLE INTEREST IN THE HOSPITAL, THEY DID VALIDATION WITH THESE INSTRUMENT THAT MEASURE CARBON DIOXIDE WITH INFRARED AND OXYGEN, WITH ELECTROCHEMICAL METHOD YOU CAN SEE THE AVERAGE AND DIFFERENCE IS 3%, PRETTY GOOD IN TERMS OF THE ERROR. OF BREEZY VERSUS THESE INSTRUMENT. HERE YOU CAN SEE THAT THERE IS -- THIS IS MONEY INVOLVED HERE SO YOU CAN SEE THERE IS LESS ZEROS IN THAT MONEY THERE. SO I THINK THAT WAS THE -- OUR FIRST ACCOMPLISHMENT THAT IS A VIDEO HERE. SHOW ACCOMPLISHMENT AND THEN OTHERS FOLLOW MEXICAN GROUP VALIDATION WITH COHORT METABOLIC ARGENTINA, THERE WAS VALIDATION AGAINST -- AND THEN SAID I'M INTERESTED TO SEE IF WE DO A BIG STUDY WITH MANY SUBJECTS AS WE DID IN THE PAST WHERE WE CREATED EQUATION FORESTING METABOLIC RATE, WHAT HAPPENED WITH THE AVERAGE COMING FROM YOUR DEVICE AND SO ON. SO SHE CONDUCTED A STUDY AND CONCLUDE THAT WHICH IS VERY RELEVANT FOR US. OTHER INSTITUTIONS FOLLOW. WE ARE QUITE SATISFIED. I WILL SHARE A COUPLE OF STUDIES IN THIS DEVICE THAT ARE MORE RELATED TO THE DISCUSSION OF THIS TOPIC. BUT BEFORE SWITCHING SHOW YOU ALSO RESPIRATORY PORTION BECAUSE WE ARE GETTING HERE OXYGEN CONSUMPTION RATE AND CAR DON DIOXIDE PRODUCTION RATE AND THE RATIO OF THESE TWO IS PORTION BASICALLY TELLING US ABOUT THE STOICHIOMETRY OF THE COME BUST SHUN IN GENE OF THE BODY. SO WE CAN KNOW WHAT SUBSTRATE WE ARE TAKING, AS A SOURCE OF ENERGY, BASED ODDEN RATIO OF TWO COMPONENTS. IF WE'RE IN THIS RANGE .6 TO .75, WE ARE CONSUMING MORE OXYGEN THAN CARBON DIOXIDE SO TAKING SUBSTRATES WITH LITTLE OXYGEN AND THAT IS -- WE WILL BURNING MORE FAT, OXIDIZING MORE FAT THAN CARBS. ON THE OTHER SIDE IF WE HAVE A NUMBERS CLOSE TO ONE MEANS WE ARE TAKING ONE OXYGEN PER CARBON DIOXIDE PRODUCED AND WE ARE USING MOSTLY CARBOHYDRATES AS A SOURCE OF ENERGY. AND ANY NUMBER IN BETWEEN IS A SOURCE. THIS IS VERY VALUABLE TO ASSESS ACTUALLY WHAT IS THE BALANCE BETWEEN THE FATTY ACID OXIDATION AND THE GLUCOSE OXIDATION AT CELLULAR LEVEL. THAT'S ALSO TAKEN AND ANALYZE IN THE STUDIES. SO -- ALL RIGHT. LET'S SEE THIS ABILITY OF THIS PARAMETER AS A FUNCTION OF TIME, HERE IS AN EXAMPLE, THAT KEPT THE DIET AND KEPT WEIGHT MAINTENANCE TO AVOID ANY FLUCTUATIONS, MEASUREMENTS FOR A HUNDRED DAYS SO YOU CAN SEE THE AVERAGE AND THE PERCENTAGE ERROR IS AROUND 7% FOR VO 2 AND BCL 2, TRANSLATED IN SIMILAR PERCENTAGE ERROR FOR THE ENERGY EXPENDITURE AND RESPIRATORY PORTION. IN THIS CASE THE PERSON WAS TRYING TO ASSESS WHETHER THE AVERAGE RESTING RESPIRATORY PORTION WAS CORRELATED WITH INTAKE. IT WAS A HEALTHY INDIVIDUAL. SO HERE HERE STARTED CLINICAL STATUS. ANOTHER EXAMPLE, SO THE QUESTION IS, OKAY, WE CAN RELY ON THIS VALUE, TAKEN AT FASTING CONDITIONS IN THE FIRST THING IN THE MORNING BUT WHAT HAPPENED DURING THE DAY HOW DYNAMIC, IT WAS A CAPABILITY TO FOLLOW DYNAMIC CHANGES. SO FOR THAT DYNAMIC EXPERIMENTS PERFORMED OVER SIX HOURS IN A DAY ON AN INDIVIDUAL THAT WAS INITIALLY FASTING. SO THIS IS THE RQ AND INITIALLY WAS LOW. SO IT WAS OXIDIZE ADVERTISING LIPIDS AND THEN INDIVIDUAL CONDUCTED HIGH INTENSITY INTERVAL TRAINING WHERE THE CARBOHYDRATE UTILIZATION COMES UP AND WE CAN FOLLOW THESE CHANGE. THEN THE RESTORATION TO LOWER VALUES AFTER THE EXERCISE AND THEN AGAIN INCREASE IN ANOTHER BOUGHT OF EXERCISE UNTIL IT CAME DOWN. SO BASICALLY THIS WAS ONE OF THE PROOFS THE RESPIRATORY PORTION IS VERY DYNAMIC AND IS POSSIBLE TO FOLLOW IN RELATIVELY SHORT PERIOD OF TIME. THE MAIN INTEREST WITH RESPIRATORY PORTION, IT HAS BEEN SO FAR FROM THE NUTRITIONAL STANDPOINT AND NUTRITION, DIETITIAN ESPECIALLY MAKE SPECIALIST IN NUTRITION ARE INTERESTED IN LOOKING AT CHANGES OF RQ WITH DIET. SO HERE YOU CAN SEE IN THIS PLOT HOW THE AVERAGE IQ CHANGE FROM THIS PERIOD TO THIS PERIOD AND IT WAS CLEARLY DUE TO DIET COMPOSITION CHANGE. SORRY. SO THE DYNAMIC AND THE INSTABILITY OF THE RESPIRATORY PORTION WAS -- SO NOW IF WE GO MORE INTO GENERAL OVERVIEW OF CLINICAL STUDIES RELATED TO RESTING ENERGY EXPENDITURE, VO 2 VCO 2 WE CAN SEE MANY FACTORS INFLUENCING THESE MEASURES AND THERE ARE MANY INCLUDING BEHAVIOR IN VITAMIN EXERCISE, DIFFERENT CONDITIONS, HORMONES, PREGNANCYIES, ET CETERA. SO WE HAVE CONDUCTED CLINICAL ANALYSIS IN THESE DIFFERENT AREAS, BUT I WANT TO SHARE A LITTLE BIT ABOUT HUMAN MA SEN TA, THIS STUDY BY DR. -- SCHOOL OF NUTRITION AT ARIZONA STATE UNIVERSITY WAS QUITE AN INTERESTING. SO SHE LOOK AT CHANGES OF RESTING ENERGY EXPENDITURE WITH BREEZY THROUGHOUT PREGNANCY, 40 WEEKS OF PREGNANCY AS THE PREGNANT WOMAN GAINED WEIGHT, THESE WERE ALL CASES OF HEALTHY WEIGHT GAIN BECAUSE WHAT THEY WERE TRYING TO DO IS ADJUST THE GAIN TO ONE PUMP A WEEK IN THE SECOND AND THIRD TRIMESTER BASED ON THE CALORIES, RECOMMENDATION FOR -- FROM THE TRACKER, THAT THAT IS POSSIBLE. SO THE GOAL, IN FACT THIS PREGNANT LADIES WERE ABLE TO RESTORE THE PREPREGNANCY WEIGHT VERY FAST. BUT THE MOST INTERESTING THING HERE WAS THAT OKAY WE HAVE A PREGNANT LADY IN THE ROOM AND WE PROBABLY SEE SHE CAN TELL FROM EXPERIENCE ON WHAT SHE HAS BEEN EXPERIENCING. IN TERMS OF INTAKE. LADIES THINK I'M HAVING A BABY, I CAN EAT FOR TWO. THE DOCTOR SAYS IT'S NOT TWO, YOU MUST TAKE 600-KILO CALORIES PER DAY MORE. IF WE LOOK AT THIS CASE IT WAS THE CASE, IT WAS INCREASE OF 50, 60% DEPENDING ON THE STATE, THEN THERE WAS A FLU, RESTING METABOLIC RATE BUT THERE WAS MORE OR LESS THAT RECOMMENDATION. THE INTERESTING THING IS THAT IF WE FOLLOW -- IF WE USE AN EQUATION FOR ESTIMATING BASE ON WEIGHT HEIGHT GENDER AND AGE U YOU CAN SEE IN GRAY THE EQUATION PREDICTS LOWER VALUES THAN NECESSARY ONES, IN SOME PERIODS OF PREGNANCY AND HIGHER VALUES AND OTHERS. BASICALLY WE COULD BE UNDERFEEDING THE BABY OR OVERFEEDING THE BABY. IF WE FOLLOW THIS. SO NOT NECESSARY A HIGHER MASS IN WEIGHT MEANS A HIGHER ENERGY EXPENDITURE. THAT WAS THE FIRST CONCLUSION. SECOND CONCLUSION, IF WE TOOK ACROSS DIFFERENT CASES WERE ALL HEALTHY PREGNANCYIES, SO YOU CAN SEE THERE WAS AN INCREASE THROUGHOUT PREGNANCY FROM THE BASELINE OF 1200. IN THIS CASE THE BASELINE WAS 1520. IF WE TAKE VALUES DURING THE 40 WEEKS OF PREGNANCY, WITH REPETITIONS AND SO ON, THE AVERAGE COMES EXACTLY TO THE SAME. THAT'S UNBELIEVABLE. PLUS MINUS -- YOU CAN SEE IN THIS CASE, IT DIDN'T CHANGE. A THIRD CASE HERE IS SHOWING THAT A PERSON THAT HAS A VERY GOOD AMOUNT OF MUSCLE MASS BUT DROP WEIGHT IN INITIAL PERIOD, PROBABLY MUSCLE WEIGHT THE METABOLIC RATE DECREASE AROUND 1600 TO A LEVEL LESS THAN 1200, REMAIN CONSTANT THROUGHOUT PREGNANCY. SO IN THIS CASE THE RESTING ENERGY EXPENDITURE DECREASED PROBABLY BECAUSE OF MUSCLE MASS LOST. YOU CAN SEE THE POWER OF THE MEASUREMENT, THE MEASUREMENT HELPED SUSTAIN HEALTHY WEIGHT GAIN DURING PREGNANCY, BABIES ARE NORMAL AND HEALTHY BUT THE CHANGES WERE UNEXPECTED IN SOME CASES. THIS IS THE POWER -- WE CAN BRING SOMETHING TO THE FIELD NOW WITH THIS NEW DEVICE. THIS IS CASE TO RELATE TO HUMAN PLACENTA. SO THIS IS A CASE THAT I WANTED TO BRING AS A DEMONSTRATION ON HOW PORTABILITY EASIER USE CAN BRING NEW INSIGHT. A SECOND CASE WAS HERE, IS DOWN IN -- WAS MADE THIS CASE WAS PERFORM IN ARGENTINA IN A HOSPITAL WHERE THEY TREAT ACUTE CASES. AND IN THIS CASE WAS DIALYSIS WITH PEOPLE THAT HAS DIALYSIS THREE TIMES A WEEK AND WENT ON DIALYSIS MORE THAN TWO MONTHS. THEN THEY PAIRED THE SUBJECTS, 30 SUBJECTS WITH SUBJECTS THAT HAD SAME WEIGH AGE, GENDER AND HAVE NO FUNCTION, THEY COMPARE THE RESTING ENERGY EXPENDITURE ON THIS VERSUS INTERVENTION GROUP AT PRE-DIALYSIS LEVEL AND IF YOU'RE INTERESTED I CAN HANDLE THE ORIGINAL WORK BUT BASICALLY THE CONCLUSION WAS THAT THERE WASN'T SIGNIFICANT DIFFERENCE IN BETWEEN THESE TWO, THE PRE-DIALYSIS STAGE IN THE INTERVENTION GROUP, DIDN'T HAVE DIFFERENCE IN RESTING ENERGY EXPENDITURE WITH CONTROL GROUP. THE INTERESTING PART HERE CAME THROUGH HERE. THE PRE-DIALYSIS AND DIALYSIS PARAMETERS, THESE WERE MEASURED AND ANALYZED. AND HERE THEY FOUND SIGNIFICANT DIFFERENCE. AND HERE IS MORE DETAIL, THE SPECIFIC SIGNIFICANT DIFFERENCE, THE AVERAGE WAS SIGNIFICANTLY DIFFERENT, OF THE PRE-DIALYSIS VALUE VERSUS DIALYSIS VALUE. WHAT IS MORE IMPORTANT TO ME SINCE WE HAVE THESE 2002 TOOL THAT CAN BE USED INDIVIDUALLY AND WE CAN FOLLOW AND TRACK CHANGES AT PERSONAL LEVEL IS WHAT HAPPEN WITH EACH INDIVIDUAL HERE IS THE DIFFERENCE DURING THE DIALYSIS WITH RESPECT TO THE PRE-DIALYSIS, YOU CAN SEE THAT THESE CHANGES RANGE FROM 820-KILO CALORIES HIGHER DURING DIALYSIS DOWN TO LOWER VALUES WITH RESPECT TO PREDIALYSIS. MOST CASES HAD POSITIVE EFFECT. SO THE DIALYSIS INDUCED AND INCREASE OF RESTING ENERGY EXPENDITURE, OXYGEN CONSUMPTION AND CARBON DIOXIDE PRODUCTION. THAT WAS THE CONCLUSION. THERE WAS SOME INTERESTING FACTS, SMOKERS ARE MARKED HERE WITH THIS START AND YOU CAN SEE THERE WAS IN THIS GROUP HERE, THE ONES THAT DIDN'T HAVE POSITIVE AFFECT THERE WERE THREE SMOKERS AND THREE FROM FIVE THAT DIDN'T HAVE MAIN IMPACT OR OPPOSITE IMPACT. WERE SMOKERS. THIS IS OTHERALL, IF WE LOOK AT NOW PEOPLE THAT HAD SAME GENDER, SIMILAR AGE AND SIMILAR SAME TIME OF DIALYSIS TIME THROUGHOUT LIFE, THREE YEARS OF DIALYSIS, YOU CAN SEE THESE TWO CASES ONE HAD INCREASE OF 600-KILO CALORIES PER DAY. THE OTHER ALMOST NO EFFECT WITHIN THE ERROR. SO IT'S REALLY COME DOWN AGAIN TO THE PERSONAL LEVEL AND HOW IMPORTANT TO DO MEASUREMENTS AND DO INDIVIDUAL LEVEL SO SEEMS THE DIALYSIS IN THIS INDIVIDUAL HAD A POSITIVE EFFECT IN TERMS OF OXYGEN CONSUMPTION BUT IN THIS ONE NOT MUCH. NOW THE QUESTION IS HOW COULD THE TECHNOLOGY BE APPLIED IN CONTEXT OF TISSUE OXYGENATION. ASSESSMENT PRE- OR POST TRANSFUSION. I THINK THE ANSWER IS QUITE STRAIGHT FORWARD AFTER THIS DIALYSIS STUDY, WE CAN DO PRE-AND POST TRANSFUSION ANALYSIS OF THESE PARAMETERS ABOUT THE DEVICE AND GET TO KNOW WHETHER THERE'S BETTER OXYGENATION, BETTER DETOXIFICATION BECAUSE CARBON DIOXIDE RELEASE IS ALSO IMPORTANT. FIND WHETHER METABOLIC RATE IS HIGHER OR LOWER OR IF THERE'S LESS TIME OF ISCHEMIA, THAT'S ANOTHER QUESTION. SINCE WE ARE MEASURING AS WE MENTION RESPIRATORY PORTION, THE RESPIRATORY PORTION COULD BE INDICATION OF ACIDOSIS. SO THE CONCLUSION IS THAT OKAY WITH THIS TOOL WE CAN TRACK THE TISSUE OXYGENATION PROCESS, AND GET TO KNOW WHAT IS GOING ON WITH METABOLIC RATE AND RESTING ENERGY EXPENDITURE DURING THIS PROCESS. AND ALSO GET TO KNOW ABOUT THE SOURCE OF ENERGY AND UTILIZATION IF I HAVE TIME I WOULD LIKE TO DO A DEMO OF THE DEVICE. I DON'T KNOW IF I CAN. TWO MINUTES. LET ME DO A PRETEND. IF YOU'RE INTERESTED IN THE MEASUREMENT WE CAN DO IT DURING THE BREAK. THE DEVICE IS HERE, IT'S PORTABLE, IT HAS A MOUTHPIECE AND NOSE CLIP. SO WE SET THE DEVICE TO USE WITH A CARTRIDGE TO MEASURE OXYGEN AND CARBON DIOXIDE. IT'S A SENSORY STRIP YOU INSERT. THIS ONE TIME USE. THEN YOU GO TO THE APPLICATION YOU CAN SET FOR EACH USER PROFILE. THEN PROCEED TO MEASUREMENT. NEW RESTING METABOLIC RATE. MEASUREMENTS COULD BE THE CASE OF PRE- AND POST TRANSFUSION. ONCE THE MEASUREMENT IS PERFORMED, YOU GET THESE VALUES. YOU GET METABOLIC RATE VALUE, ENERGY SOURCE WHICH IS THE FIFTH ROAD THERE. YOU CAN SEE THAT WE CAN IMMEDIATELY KNOW ABOUT THE ENERGY EXPENDITURE AND WHAT IS THE IN THIS CASE WHAT WAS OXIDATION MOST USED SOURCE. WE CAN ALSO SEE HERE (OFF MIC) YOU CAN GET THE VCO 2. THIS IS THE MOST RELEVANT INFORMATION IN THE FIELD OF WEIGHT MANAGEMENT, FIRST PROPOSED INSTRUMENT. SINCE IT WAS THE FIRST PROPOSED, HERE IS HOW YOU CAN SELECT TARGET WAY TARGET EXERCISE, INTENSITY, DEPENDING ON WHAT YOU DO. HOURS YOU CAN DEDICATE TO EXERCISE PER WEEK AND AFTER THAT YOU CAN ASSESS CALORIE INTAKE TO REACH TARGET WAY WITH ESTIMATED TARGET DAY. YOU CAN SEE OVER THERE. WE HAVE HERE A PREGNANT LADY WITH 1330. ONE THOUSAND 330-KILO CALORIES PER DAY, AND WE NEED TO KNOW HOW MUCH SHE WOULD NEED TO EAT TO KEEP ONE POUND INCREASE PER WEEK. THAT IS EQUIVALENT TO 250-KILO CALORIES PLUS IN THE SECOND ROAD THERE. AND THIS LADY CAN DO TWO HOURS OF MODERATE EXERCISE BRISK WALK PER WEEK. HERE IS -- WE SHOULD BE AROUND 1900-KILO CALORIES TO SUSTAIN THIS HEALTHY WEIGHT GAIN. THIS IS PERSONALIZED. SO COMING BACK TO PRE-AND POST TRANSFUSION, THE IMPORTANCE OF THIS TOOL IS THAT IT COULD BE USED ANYWHERE BY ANYONE IN THE FIELD, ALL THE MEASUREMENTS ARE SAFE, IT CAN BE SHARED SO YOU CAN SHARE THROUGH EMAIL AND THE EMAIL WILL CONTAIN A CSV FILE WITH TIME STAMP INFORMATION THAT CAN BE EVALUATED LATE. SO THIS IS ALL. THANK YOU VERY MUCH FOR YOUR ATTENTION. YOU CAN TRY IT IF YOU WANT LATER. >> I DON'T KNOW ABOUT YOU GUYS, SCREW TRANSFUSION I NEED THIS FOR MY WEIGHT. THERE WILL BE A LINE OVER THERE, ANYONE WHO WANTS TO HAVE THEIR MEASUREMENTS DONE. I WANT ONE OF THOSE. OUR NEXT SPEAKER IS ELLIOT GERRERO WHO HAS MADE MANY VERY IMPORTANT CONTRIBUTIONS OVER THE YEARS, IN TRANSFUSION MEDICINE AND HE'S ANESTHESIOLOGIST WHO LIVES IN NEW YORK STATE NEAR US SO WELCOME, ELLIOT. LOOK FORWARD TO YOUR TALK. >> THANK YOU VERY MUCH, PLEASURE TO BE HERE. I HAVE NO DISCLOSURES TODAY. SO BECAUSE THIS MEETING INCLUDES DEVICE INNOVATORS AND CLINICIANS, I REALLY TRIED TO TAILOR THIS PRESENTATION TO PRESENT THE POTENTIAL ROLE OF NEARS WITHIN A CLINICAL SETTING SO FOCUS ON KIND OF THAT CLINICAL ISSUES, AND ALSO DISCUSS HOW IT AIDS TESTING QUALITY OF RED BLOOD CELLS. I WILL ALSO FOCUS ON ADULT PATIENTS THOUGH WE HAVE SEEN PROPREVIOUS TALKS THERE CLEARLY ARE POTENTIAL APPLICATIONS FOR NEARS AND SOME OF THESE ARE TECHNOLOGIES IN NEONATES. SO BRIEFLY WHY DO WE TRANSFUSE RED BLOOD CELLS? OUR GOAL IS TO GET ENOUGH OXYGEN TO CELLS SO THEY FUNCTION WELL AND DON'T DIE, THAT'S SIMPLE. THE GOAL IS SIMPLE BUT ACHIEVING THIS IS COMPLICATED. HOW DO WE GET THE OXYGEN TO THE CELLS? WE NEED FLOW, CARDIAC OUTPUT, PRESSURE WHICH A LOT OF PEOPLE DON'T THINK ABOUT. THINK A PATIENT SEPTIC WITH MEAN ARTERIAL PRESSURE OF 30, MAY HAVE A CARDIAC OUTPUT OF 15-LITERS BUT NOT ENOUGH PRESSURE DRIVING RED CELLS AND FLUIDS THROUGH THESE TISSUES AND WE NEED ARTERIAL OXYGEN CONTENT, LARGELY HEMOGLOBIN BEING SATURATED. SO I WAS -- WHEN I TALK TO THE MEDICAL STUDENTS AND RESIDENTS, IN THIS LECTURE I GIVE THEM TRICK QUESTIONS. WHAT IS AN ADEQUAE CARDIAC OUTPUT? THEY SAY FIVE OR THIS OR THAT. THEN I SHOW THIS SLIDE. IT TOTALLY DEPENDS. IF YOU'RE TRYING TO WIN THE BOSS IS TO BE MARATHON, FIVE LITTERS A MINUTE IS NOT GOING TO CUT IT. BUT MOREOVER TO OUR DISCUSSION, IF YOU'RE SITTING IN A HOSPITAL BED FIVE LITTERS A MINUTE MAYBE A LUXURY FLOW, PROBABLY FOR A LOT OF THESE PATIENTS IF IT WAS THREE LITEDDERS A MINUTE THE OXYGEN CONSUMPTION IS QUITE LOW GLOBALLY IN MOST OF OUR PATIENTS. SO JUST SOMETHING THAT'S FOOD FOR THOUGHT AND FOR US TO CONSIDER. SO WHAT ARE ADEQUATE HEMOGLOBIN VALUES? AGAIN, YOU'RE NOT GOING TO WIN A MARATHON IF YOU'RE HEMOGLOBIN IS NOT UP AROUND 15. IN OUR ICU PATIENTS CONTROVERSY SURROUNDED SEVEN VERSUS TEN, KIND OF IN THIS RANGE. THOUGH PROBABLY MANY PATIENTS CAN TOLERATE LOWER HEMOGLOBIN LEVELS. AND WHAT ABOUT THE PATIENT ON THE FLOOR WHO IS NOT CRITICALLY ILL, THEY'RE NOT DYING, MAYBE AT RISK FOR DEVELOPING ISCHEMIA. SEVEN, EIGHT, PROBABLY A LOT OF THEM CAN TOLERATE THREE OR FOUR GRAMS PER DECEMBER-LITER, I'M NOT ADVOCATING THAT, WE WANT ENOUGH RESERVE IN PATIENTS SO THEY CAN WITHSTAND POTENTIAL INSOLES BUT FOOD FOR THOUGHT IN TERMS OF REALLY THE PROBLEMS THAT WERE FACED IN THE HOSPITAL LOOKING AT A PARTICULAR PATIENT TRYING TO DECIDE WHAT IS A FLOW, WHAT IS ENOUGH HEMOGLOBIN. AND FINALLY WHAT IS ENOUGH OXYGEN? SO WE KNOW OXYGEN FLOWS KIND OF LIKE WATER, GOES DOWN DIFFUSION. THE THING THAT'S SURPRISING TO MOST CLINICIANS, I SPEAK TO IS WHEN I SAY WOW, THE MITOCHONDRIAL PO2 IS 1 TO 5 MILL LITTERS OF MERCURY, YOU NEED VERY LITTLE OXYGEN TO DIFFUSE AND TO GET INTO THE MITOCHONDRIA. SO THIS IS -- SO BASED ON THIS, YOU WOULD THINK WELL, A PAO2 YOUR PO2 DOESN'T NEED TO BE 70 OR 80 OR 90 FOR SURVIVE. WE KNOW IN MOST PEOPLE THIS IS THE CASE. IF YOU LOOK AT SOME STUDIES WHERE YOU LOOK AT BLOOD GASES IN NORMAL VOLUNTEERS, 29,000 FEET. HERE ARE TWO STUDIES ONE COLLEAGUES OF MINE WHO DID THE HE WAS STUDY LOOKING AT BLOOD GASES BELOW THE SUMMIT AND PEOPLE GOING INTO A HYPOBARIC CHAMBER TO SIMULATE HIGH ALTITUDE. VOLUNTEERS ARE TOLERATING PAO2s OF 25 OR 30 AND SAO 2s IN THE 50 TO 60 RANGE. OBVIOUSLY THIS IS THE DEATH ZONE, YOU DON'T LIVE LONG LIKE THIS, I'M NOT ADVOCATING THAT OUR PATIENTS SHOULD BE LEFT WITH A PAO2 OF 55. BUT I HAD A PATIENT WITH DIFFERENT HOSPITAL WITH ECMO, HE WAS LIKE 80-YEAR-OLD GENTLEMAN ON VENTILATOR WITH LUNG INJURY. THE PAO2 WAS 38. VERY, VERY LOW. AND HE HAD ZERO LACTIC MEDICAL ACIDOSIS. GLOBALLY BASED ON HIS OXYGEN CONSUMPTION, THAT WAS MORE THAN ENOUGH OXYGEN OR ARTERIAL OXYGEN CONTENT. THESE NUMBERS ARE NOT THAT FAR OFF OR CRAZY FROM WHAT ACTUALLY MANY PATIENTS REQUIRE THOUGH NOT ADVOCATING SUCH LOW VALUES, SPO 2s OF VOLUNTEERS YOU CAN SEE AROUND 60% RANGE. IN TERMS OF SPECTROSCOPY, THIS WAS COVERED IN SEVERAL TALKS YESTERDAY SO I WON'T GO INTO DETAIL, JUST TO LET YOU KNOW IT'S AN OLD TECHNOLOGY THAT'S BEEN AROUND SINCE 1977 IN TERMS OF BEING DESCRIBED IN COMMERCIALLY VALUABLE IN THE '90s. NEAR INFRARED LIGHT IN ROUGHLY 7 TO 900 NANOMETER RANGE. MOST IMPORTANTLY, IT'S A WEIGHTED AVERAGE OF OXYGEN IN THE VEINS. SO IT'S -- AND THE ARTERIES. I'M SORRY, I HAVE THIS -- SO IT'S BACKWARDS. SO IT'S -- THIS IS SOMETHING BY SOME PEOPLE HAVE ARGUED IS A STRENGTH BUT I ARGUE IS A WEAKNESS. BECAUSE I THINK THAT FOR A LOT OF CLINICIANS, IT'S KIND OF A BLACK BOX HOOKING AT MIXTURE OF VENOUS AND ARTERIAL, CONFUSING WHAT THAT MEANS. IN CONTRAST IF I HAVE A PATIENT WITH A PA CATHETER AND THEIR SAO 2 IS 95%, I KNOW WHAT THAT MEANS AND WHAT I'M MEASURING IF SPO 2 IS 50 OR 60%, I KNOW WHAT THAT MEANS. HOW I INTERPRET WHAT TO DO WITH THAT IS A DIFFERENT QUESTION BUT I KNOW WHAT IT'S MEASURING. AND I THINK THE THING THAT MAKES PEOPLE UNCOMFORTABLE WITH NEARS IS IT'S NOT CLEAR EXACTLY WHAT YOUR MEASURING. HERE JUST SOME EXAMPLES OF SOME COMMERCIALLY AVAILABLE DEVICES, THERE'S SEVERAL LARGELY FOCUSED ON MEASURING OX SYMMETRY IN THE BRAIN AND ONE'S MEASURING IT IN THE PERIPHERAL TISSUES. SO JUST QUICKLY, IN TERMS OF GENERAL APPROACHES TO THE DEVICE DEVELOPMENT, I SAY THIS HAVING SPENT 30 YEARS, I'M AN ANESTHESIOLOGIST, INTENSIVE CARE PHYSICIAN, SO DEALING WITH A LOT OF DEVICES, MONITORING DEVICE MANAGERS TRYING TO BRING NEW PRODUCTS OVER THE YEARS. TWO GENERAL APPROACHES. ONE START WITH THE NEW TECHNOLOGY AND ASK WHAT IS IT GOOD FOR. WE SEE A LOT OF THAT IN THIS MEETING HERE WHERE WE HAVE REALLY BRILLIANT ENGINEERS INNOVATORS WITH CREATING NEW TECHNOLOGY AND TRYING TO FIGURE OUT WHAT'S THE BEST APPLICATION FOR IT. SOMETHING I'M MORE COMFORTABLE WITH AND FAMILIAR WITH, IS STARTING WITH THIS UNMET CLINICAL NEED AND SEARCHING FOR EXISTING TECHNOLOGY THAT CAN ADDRESS THAT NEED OR DEVELOPING NEW TECHNOLOGY TO ADDRESS IT. WHAT IS ROLE IN TRANSFUSION MEDICINE? TO TEST QUALITY OF RED CELLS IN VOLUNTEERS I WOULD SAY PROBABLY YES. I WILL GET TO THAT LATER ON. AND THEN FOR CLINICAL CARE TO OPTIMIZE TRANSFUSION AND OTHER DETERMINANTS OF OXYGEN DELIVERY, SO I WOULD SAY IN SOME CASES YES. BUT I THINK IT DEPENDS AND I THINK UNFORTUNATELY IT'S TOO BROAD A QUESTION. I THINK WE HAVE TO BE VERY FOCUSED ABOUT WHAT THE ACTUAL CLINICAL SETTING IS AND WHAT'S THE SPECIFIC QUESTION THAT WE ARE TRYING TO ADDRESS. JUST GOING TO GO THROUGH THESE POTENTIAL UNMET NEEDS WHERE NEARS MIGHT BE USEFUL. THIS IS NOT MEANT TO BE A COMPREHENSIVE LIST, THERE'S OTHER THINGS I'M SURE ONE CAN THINK OF BUT THESE ARE THINGS I THOUGHT OF WHILE PREPARING THIS PRESENTATION. SO UNILATERAL CEREBRAL ISCHEMIA IN CARDIAC AND VASCULAR SURGERY. IN MANY, MANY CENTERS, WE PLACE OXIMETRY NEARS ON THE FOREHEAD AND ON BOTH SIDES OF THE HEAD. ONE NEAT THING IS WE CAN USE THE PATIENT AS THEIR OWN CONTROL BECAUSE ONE OF THE BIG PROBLEMS WITH NEARS ANALYSIS, THE VALUE 70%. IT'S 30%, OKAY, THAT'S REALLY LOW. BUT MOST OF THE PATIENTS ARE KIND OF IN A RANGE, IT'S 50, 60, 70, 80, QUESTION REQUEST IS WHAT DOES THAT MEAN? ONE OF THE GREAT THINGS ABOUT THIS SETTING IS IF YOU'RE PUTTING ON BOTH SIDES OF THE HEAD, WHAT WE'RE TRYING TO DO IN CARDIAC SURGERY OR VASCULAR A SURGERY IS TRY TO DETERMINE IF THERE IS A PROBLEM MECHANICALLY WITH FLOW. BLOCKED OFF FLOW TO ONE SIDE OF THE BRAIN AND PATIENTS UNDER ANESTHESIA, HAVING A MASSIVE STROKE. THE BEAUTIFUL THING HERE IS THAT WE HAVE THE PATIENTS ON CONTROL. SO IF YOU SEE THAT OVER THE COURSE OF SURGERY, THE LEFT SIDE IS MAINTAINED BUT RIGHT SIDE PLUM METS, YOU DO NOT NEED -- THIS IS ALMOST LIKE THE PARACHUTE WITH REGARD TO RANDOMIZE TRIALS. YOU DON'T NEED RANDOMIZED TRIALS TO PROVE PARACHUTES WORK. IF YOU'RE CARDIAC SURGEON OR ANESTHESIOLOGIST, THIS IS AN UNMET NEED AND THIS IS AN AREA WE DON'T REALLY NEED A LOT OF OUTCOME DATA TO PROVE THIS IS USEFUL. IT SPEAKS FOR ITSELF. WHEN IT CORRELATES WITH CANNELLA POSITION AND YOU MOVE IT AND SEE THE STATS COME UP SO THIS IS ONE AREA WHERE THERE'S A COMPELLING USE TO USE IT AND FOR THIS REASON MANY SITES USE IT. SO WHAT ABOUT OPTIMIZATION OF FLATS IN THE OPERATING ROOM AND POST-OPERATIVELY? SO JUST TO SHOW YOU SOME EXAMPLES OF FLAT, I KNOW WE TALK ABOUT IT BUT THESE ARE PRETTY BIG INVASIVE TYPE OF PROCEDURES, IT'S A REAL CATASTROPHE WHEN THEY FAIL. SO THERE'S BEEN A LOT OF DISCUSSION, BY SOME OF THE DEVICE INNOVATORS ABOUT USING THEIR DEVICES BECAUSE YOU ARE LOOKING AT TISSUE THAT'S ON THE SURFACE SO AMENABLE TO SOMETHING APPLIED OUTSIDE. THIS IS USE OF NEARS WITH EXAMPLE FOR THE BREAST, OTHER AREAS. I'M NOT GOING TO GO THROUGH, THIS IS AN EXAMPLE, YOU CAN SEE FLAPS HERE LOOKING AT LACTATE AS WELL. SO THE POINT I JUST WANTED TO RAISE HERE, I WON'T GO INTO A LOT OF DATA HERE, IS I DO THINK THERE IS POTENTIAL APPLICATION FOR USING NEARS, IT'S NOT AS RELEVANT TO TRANSFUSION MEDICINE BECAUSE I THINK THAT ALTHOUGH TRANSFUSION IS OFTEN TIMES A FACTOR IN DETERMINING THE FLAP LIABILITY WE THINK ABOUT OTHER THINGS LIKE PROFUSION PRESSURE AND OTHER FACTORS. ANOTHER THING THAT I WANT TO RAISE BUT NOT GOING TO TALK MUCH ABOUT IT IS THIS CONCEPT OF PROBLEMS WITH -- ANASTHEMOSES DURING SURGERY. YOU HAVE ESOPHAGEAL SURGERY WHERE YOU PUT THE ESOPHAGUS BACK TOGETHER AND COLORECTAL SURGERY PUTTING INTESTINES BACK TOGETHER. ONE OF THE PROBLEMS WHERE IT CAN FAIL IS BECAUSE OF ISCHEMIA. SO THERE'S BEEN THOUGHTS OVER THE LAST TEN, 20 YEARS IN THE OPERATING ROOM KIND OF MEASURING THE OXYGENATION IN THE ACTUAL AREA WHERE YOU'RE DOING ANASTHEMOSIS TO DETERMINE IF THERE'S ADEQUATE OXYGENATION TO PREVENT THINGS FROM FALLING APART, WHICH IS A CATASTROPHIC PROBLEM. I WON'T TALK MORE ABOUT THIS. ANOTHER AREA THAT'S INTERESTING FOR USE OF NEARS IS MANAGEMENT OF PATIENTS WITH CHRONIC NON-HEALING WOUNDS. THESE THINGS ARE AWFUL. I THINK IT'S -- WE HAVE ALREADY HEARD SOME OF THE SPEAKERS PREVIOUSLY TALK ABOUT POTENTIAL APPLICATIONS. AGAIN, THIS IS ON THE SURFACE, IT'S NOT INSIDE OF THE BODY. AND SO IT MAKES SENSE INTUITIVELY THAT APPLYING THIS TECHNOLOGY WHERE YOU CAN LOOK AT TISSUE OXYGENATION MAYBE USEFUL, I'M NOT AWARE OF LARGE OUTCOME STUDIES THAT USED THIS TO GUIDE THERAPY, AND SHOW THE OUTCOME IS BETTER. AGAIN, I THINK TRANSFUSION WOULD BE ONE ASPECT, THERE'S OTHER TYPE OF INTERVENTIONS THAT WE USE TO TRY TO OPTIMIZE FLOW AND OXYGENATION IN THESE PATIENTS. BUT AGAIN, I THINK THERE CLEARLY IS A ROLE FOR IT. SO WHAT ABOUT EARLY WARNING FOR IMPENDING DECOMPENSATION IN BLEEDING PATIENTS? WE HEARD ABOUT THIS YESTERDAY. THIS IS THE IDEA WHERE AS I'M BLEEDING, THE BODY HAS VERY GOOD COMPENSATORY MECHANISMS. OFTENTIMES IT'S HARD TO SEE, TO DETECT PATIENTS WHO HAVE SIGNIFICANT BLEEDING OR HYPOBOLEMIA AND WHEN YOU CAN'T COMPENSATE YOU FALL OFF CLIFF AND YOU BECOME EXTREMELY UNSTABLE. SO I DOUBT THAT NEARS WILL EVER BE USEFUL TRAUMA HEMORRHAGE MONITOR IN THIS SETTING. YES, I DO THINK THAT IT CAN DETECT SHOCK STATES. SO I THINK IF YOU PUT SOMEONE EXPOSE SOMEBODY TO HEMORRHAGE LOWER BODY PRESSURE, YOU'RE GOING TO SEE EVIDENCE OF THE TISSUE OXYGENATION DROPPING. I JUST DON'T KNOW WHAT THE INCREMENTAL BENEFIT IS FOR THIS TECHNOLOGY IN PATIENTS ALREADY HIGHLY MONITORED. SO PATIENTS IN WHOM WE HAVE ARTERIAL CATHETERS OFTEN TIMES WITH CONTINUOUS BLOOD PRESSURE, FREQUENT BLOOD GASES LOOKING FOR METABOLIC ACIDOSIS. ABILITY TO DO SERIAL LACTATES WHICH IS ANOTHER VERY ESTABLISHED MEASURE OF GLOBAL TISSUE HYPOPRO FUSION. YOU'RE OUTPUT CONTINUOUS SPO 2, WE HAVE ONE TO ONE NURSING EXPERIENCE CLINICIANS AD TO ADD TO THAT, THERE'S ALWAYS A CONCERN, WHAT IS THE CLINICAL RELEVANCE OF MEASURING TISSUE OXYGENATION IN THE SKIN OR THE MUSCLE. SO I HAVE NO DOUBT, IF I PUT IT ON YOU AND I SHOCK YOU, YES, THE VALUE WILL GO DOWN AND THEN WHEN I RESUSCITATE YOU THE VALUE WILL GO UP SO THE TECHNOLOGY WORKS. IN THAT RESPECT BUT I DON'T KNOW REALLY WHAT THE CLINICAL RELEVANCE OF THAT IS IN TERMS OF ADDING IT ADS AN INCREMENTAL -- ADDITIONAL MONITOR IN THESE PATIENTS. WHAT ABOUT USING NEARS AS A SPOT CHECK? FOR SURVEILLANCE IN LOW RISK HOSPITALIZED PATIENTS? SO PATIENTS ON THE FLOOR, NOT IN THE ICU, PATIENTS WHO COME INTO THE EMERGENCY ROOM AND WE HAVE TENS OF THOUSANDS OF THESE PATIENTS COMING THROUGH, MOST HOSPITALS EVERY YEAR. SO WHEN I'M TALKING ABOUT HERE IS THESE CONNOTATIONS, THEY'RE NOT CRITICALLY ILL, THEY'RE SITTING IN A BED, THEY LOOK OKAY, AND SO HOW DO WE NORMALLY MANAGE THOSE PATIENTS OR DO SURVEILLANCE? ONCE EVERY FOUR HOURS OR EVERY NURSING OR EVERY SHIFT. STANDARD OF CARE IS MEASURE HEART RATE BLOOD PRESSURE SPO 2 AND HEMOGLOBIN IS NOT MEASURED FREQUENTLY BUT REALLY, THESE ARE THE CORNERSTONE OF A LOT OF MEASUREMENTS OF HOSPITALIZED PATIENTS BECAUSE YOU CAN SEE WE HAVE ARTERIAL OXYGEN CONTENT MEASURED HERE, THESE ARE GOOD SURROGATES FOR ADEQUATE CARDIAC OUTPUT AND BLOOD PRESSURE. SO MOST PATIENTS, IF THE HEART RATE IS 90, BLOOD PRESSURE 120 OVER 80, SPO 2 IS 97%, HEMOGLOBIN IS 12, WE ASSUME PROBABLY ADEQUATE OXYGEN DELIVERY. WE'RE NOT MEASURING IT AND WE OBVIOUSLY MEASURE RESPIRATORY RATE AND TEMPERATURE. THE NEW SCORE MODIFIED EARLY WARNING SCORE, IS ESTABLISHED MEASURE USED IN MOST HOSPITALS. WHICH BASICALLY THEN TAKES SOME OF THESE AND CREATES A COMPOSITE SCORE ADDING IN MENTAL STATUS TO ASK THE QUESTION, IS THIS A PATIENT WHO MIGHT BE AT RISK. SO PATIENT HAS MU SCORE OVER FOUR IN MANY HOSPITALS THEY WILL THEN DEVOTE ADDITIONAL RESOURCES TO FIGURE OUT WHAT'S GOING ON WITH THIS PATIENT. SO YOU COULD MAKE AN ARGUMENT ABOUT ADDING IN SPOT CHECKS OF NEARS TO THESE PATIENTS. I'M NOT ADVOCATING THAT, I'M SAYING THAT'S SOMETHING THAT COULD BE DONE, SOME OF THE COMPANIES LIKE INSPECT TROUGH HUTCHINSON WITH IN SPECTRA AND INTRA-OX DEVICE, I HAVE CREATED THESE DEVICES THAT ENABLE ONE TO DO SPOT CHECKS P THERE ARE SOME DATA ON THIS, A 500 PATIENT STUDY TO PREDICT PATIENTS DEVELOPING SEXES BUT TO MY KNOWLEDGE, THERE AREN'T LARGE STUDIES THAT ASSESS UTILITY AND SENSITIVITY AND SPECIFICITY FOR DETERMINING WHETHER PATIENTS ARE GETTING ADEQUATE OXYGEN IN BRAIN. YOU HAVE THOUSANDS OF PATIENTS SO YOU'RE BASICALLY DOING THIS ON PATIENTS WHO ARE TOTALLY FINE. THE QUESTION IS, CAN YOU DETECT THOSE PATIENTS, WHERE THE VITALS, EVERYTHING ELSE IS OKAY, BUT THEY HAVE SUBOPTIMAL OXYGEN DELIVERY, IF YOU CATCH THAT EARLIER YOU CAN INTERVENE AND IMPROVE OUTCOME. IT MAKES SENSE, THEORETICALLY IT'S POSSIBLE BUT I THINK IT'S A HEAVY LIFT IN TERMS OF DOING STUDIES TO DEMONSTRATE UTILITY. WHAT ABOUT USING NEERS TO MONITOR ICU PATIENTS. THIS IS WHERE IN SPECTRA, HUTCHINSON WHERE THESE COMPANIES STARTED OUT. SO AGAIN, NOW WE ARE TALKING THESE PATIENTS HERE, SO TALKING CRITICALLY ILL PATIENTS WHO ARE ALL ALREADY HIGHLY MONITORED. AND SIMILAR TO THE BLEEDING TRAUMA ARGUMENT THAT I MADE, I DOUBT MIIRS WILL HAVE A ROLE, PERIPHERAL TISSUE LIKE MUSCLE OR SKIN, CEREBRAL OXIMETRY CAN BE VALUABLE IN CERTAIN PATIENTS, FOR EXAMPLE WE ROUTINELY USE IT IN PATIENTS ON ECMO IN ICU BUT IN TERMS OF LOOKING AT MEERS FOR PERIPHERAL TISSUE SKIN, MUSCLE, I DOUBT IT WILL TAKE OFF AND CONFIRMED BY LACK OF TRACTION OFFER THESE COMPANIES TO SELL THEIR PRODUCT IN ICUs. SIMILAR ARGUMENTS TO WHAT I ALREADY MADE BEFORE WITH HIGHLY MONITORED SETTING, ONE, IICALLY CLINICIANS WONDER WHAT'S THE RELEVANCE OF MONITORING SKIN OR MUSCLE, WE HAVE SERIAL LACTATE, MANY PATIENTS HAVE PA CATHETERS SO I CAN MONITOR CARDIAC INDEX, MEASURE SPO 2 AND AGAIN URINE OUTPUT SPO 2, ONE TO ONE NURSING, EXPERIENCED CLINICIANS. SO THAT'S MY OPINION ON THAT ISSUE. SO FINALLY, WHAT ABOUT USING TO TEST RED BLOOD CELL QUALITY? I WOULD SAY QUALITY IS THREE THINGS. QUALITY IS AVOID DANCE OF SAFETY ISSUES. SO MAKING SURE IT'S SAFE, MAKING SURE THAT IT'S EFFECTIVE. IN TERMS OF THAT IT ACTUALLY DELIVERS OXYGEN. THAT HAS CAN IT BE USED? SO I WOULD SAY USE OF MEERS IS UNLIKELY IN NONE THEMIC NON-STRESSED HEALTHY VOLUNTEERS. THERE'S POTENTIALLY APPLICATION IN STRESSED HEALTHY VOLUNTEERS. AND WHY DO I SAY THIS? SO YOU LOOK AT THE DATA SHOWN BY DR. ZEKE YESTERDAY, A BEAUTIFUL STUDY LOOKING AT CHILDREN WITH SEVERE ANEMIA. SO SOMETHING WE DON'T -- RARELY ENCOUNTER IN THE UNITED STATES. THESE ARE CHILDREN WITH ELEVATED LACTATE, WHERE WHEN THEY INTERVENE THEY COULD SHOW THAT THEY COULD GET THE LACTATE TO NORMALIZE AND ALSO THEY SHOW ASSOCIATED WITH THAT, IMPROVEMENT IN TISSUE OXYGENATION. YOU CAN SIGH THERE IS A SINGLE HERE BUT IT'S VERY NOISY. THERE'S A LOT OF VARIABILITY BETWEEN DIFFERENT PATIENTS. SO CLEARLY, IN A SETTING WHERE YOU HAVE SEVERE ANEMIA, YOU CAN SEE THAT THE STO 2 OR CEREBRAL OXIMETRY IMPROVES WITH TRANSFUSION. WE HAVE SOME LITERATURE FROM ICU, A STUDY BY CARALLI AND COLLEAGUES WHERE THEY LOOKED AT PATIENTS IN A TRAUMA ICU, WAS OBSERVATIONAL STUDY WHERE SOME OF THE PATIENTS, RECEIVE NEW BLOOD, OLD BLOOD, YOU CAN SEE THE STO 2 YOU CAN SEE VERY NOISY, BUT YOU CAN SEE ABLE TO DETECT SOME DIFFERENCES BETWEEN THESE TYPES OF BLOOD PRODUCTS. THEN IN A RANDOMIZED STUDY, THIS IS JUST ANOTHER EXAMPLE, LOOKING AT STO 2, IN PATIENTS RANDOMIZED TO CRYOPRESERVE VERSUS STORED RED CELLS, IN THIS STUDY ABLE TO DETECT A DIFFERNCE. SEW YOU MIGHT SAY THIS LOOKS PROMISING TO SEE IF A RED CELL BAG IS BETTER THAN ANOTHER. IF WE'RE TESTING NEW INNOVATIONS. UNFORTUNATELY IN SOME DATA WE GENERATED, I'M LESS CONFIDENT THAT IT IS USEFUL IN THAT WAY. IN THE -- WE LOOKED AT TWO DEVICES THE FORESIGHT DEVICE USING CEREBRAL OXIMETRY AND THEN THE INSPECT TRADE VICE LOOKING AT TISSUE -- SPECTRA DEVICE. WE LOOKED AT NUMEROUS MEASURES OF TISSUE OXYGENATION AND HOW THEY RESPONDED AFTER TRANSFUSION BUT YOU CAN SEE VERY NOISY UNCLEAR PLOT, NOT CLEAR THAT WHEN YOU'RE GIVING THE TRANSFUSIONS, THESE PATIENTS RECEIVE THREE, FOUR FIVE UNITS OF BLOOD, A CLEAR CHANGE IN THE STO 2. PART OF THAT IS BECAUSE THERE'S SO MANY OTHER THINGS THAT INFLUENCE US AS WELL. THERE'S THE OXYGEN LEVELS IN THE BLOOD, ARTERIAL OXYGEN WHICH CAN BE QUITE DIFFERENT IN CERTAIN PATIENTS, THERE'S ALSO THE CARDIAC OUTPUT FLOW, USE OF VASOCONSTRICTORS, WE HAD DONE THE TASER IS THE STUDY, A SMALL STUDY, I DID THIS WITH ONE OF THE DUKE AWE NECESSARY THESEIA RESIDENTS, WE' ANESTHESIA RESIDENCES. WE TOOK TWO UNITS OF BLOOD WITH APHERESIS AND WE GAVE THEM 42 DAY BLOOD CELLS AT DIFFERENT TIME POINTS AND MEASURED CEREBRAL NEARS AND THE STO 2 WITH THE SAME DEVICES THAT I DESCRIBE BEFORE AND YOU CAN SEE THAT SMALL STUDY, BUT AGAIN, A LOT OF VARIABILITY BUT WE WERE ONLY ABLE TO SHOW THE CEREBRAL OXIMETRY, INCREASED A LITTLE BIT. A LITTLE BIT. JUST FROM 70.4 TO 71.8 WITH SEVEN DAY BLOOD BUT NOT INCREASE SIGNIFICANTLY ON AVERAGE WITH 42 DAY BLOOD AND TISSUE OXYGENATION WAS WORSE. YOU CAN SEE A LOT OF VARIABILITY AND WE DID NOT SEE ANY SIGNIFICANT SIGNAL IN TERMS OF BEING ABLE TO DEMONSTRATE IF YOU GIVE ONE UNIT OF BLOOD YOU CAN SEE THIS THING SHOOTING UP. IN PART WAS NOT SURPRISING, THESE ARE NOT ANEMIC, NOT STRESSED, THEY'RE NOT AT A POINT IN THEIR OXYGEN SHOOFLY CURVE WHERE THEY NEED THAT ADDITIONAL UNIT OF BLOOD. SO WHAT ABOUT ADDING HYPOXIA AS WAY STRESSING PEOPLE? THERE'S TWO WAYS YOU CAN DO THIS MODEL. ONE IS YOU CAN TAKE FOUR UNITS OF BLOOD OFF SOMEBODY, MAKE THEM MORE ANEMIC AND THEN GIVE THEM BACK FOUR UNITS OF BLOOD PRODUCT A VERSUS BLOOD PRODUCT B AND C IF THERE'S A DIFFERENCE IN THE QUALITY OF THOSE. BUT THAT'S A LIT MORE CHALLENGING AND SOMEBODY SOME ETHICAL CONCERNS TAKING OFF SO MUCH BLOOD AND GIVING BACK AT THE SAME TIME, THAT COULD BE PERFECTLY SAFE. BUT WHAT ABOUT POTENTIALLY ADDING HYPOXIA? I HAVE NOT ACTUALLY DONE THIS MODEL BUT MY COLLEAGUE DAVID MCCLEOD AT DUKE HAS DONE THIS FOR MANY, MANY YEARS, IT'S VERY SAFE, IT'S BEEN USED A LOT OF OTHER APPLICATION CONSIST. WE KNOW THAT WHEN YOU EXPOSE VOLUNTEERS TO HYPOXIA, THIS WAS A STUDY DONE PUBLISHED BACK IN 1990, YOU CAN SEE THAT THE SAO 2 DROP DOWN INTO THE 70s, YOUR VENTILATION GOES UP SO YOUR COMPENSATING SO THESE VOLUNTEERS ARE GETTING STRESS, THEY'RE BREATHING HEAVIER IF THEY WERE AT THE TOP OF MOUNT EVEREST. THE VENTILATION AND THE TITLE VOLUMES GOES UP, THEY BREATHE MORE QUICKLY. AND CO 2 GOES DOWN SO DAVE MCLOUD AND OTHERS WHO USED THIS MODEL USED A HYPOXIA MODEL YOU CAN BASICALLY GIVE VOLUNTEERS 11% OXYGEN AND INDUCE HYPOXIA FOR TEN MINUTES OR SO, FROM ONE OF THE STUDIES, BRIEF PROFOUND HYPOXIA, DEFINED AS SAO 250 TO 70% FOR TEN MINUTES IS NOT ASSOCIATED WITH CARDIOVASCULAR -- AND IS TOLERATED WITHOUT ANY ILL EFFECTS. MANY STUDIES SHOWING THIS. THIS IS FROM ONE OF THE STUDIES THAT DAVE AND COLLEAGUES PUBLISH YOU CAN SEE HIGH POTIA IN HEALTHY VOLUNTEER, SPO 2 IN THE DASH LINE AND THEN THE SOLID SQUARES ARE THE SAO 2 FROM BLOOD GAS YOU CAN SEE CORRELATING VERY WELL. YOU CAN SEE REPRODUCIBLY DECREASE YOUR SA AND SPO 2 DOWN INTO THE UPPER 70s AND THEN YOUR JUGULAR VENUS SACK, THE BLOOD COMING BACK FROM THE HEAD YOU CAN SEE ALSO DROPS AND THIS IS THE NEARS SIGNAL. WITH OXIMETRY YOU CAN SEE THAT SINCE IT'S A MIXTURE OF THESE TWO, THE OXYGEN AND THE VENUS BLOOD ALSO DROPPED AND THEN COMES BACK UP. ONE COULD CONSIDER THE FOLLOWING WHERE YOU GET INFORMED CONSENT, SCREENING TESTS YOU DO DOUBLE APHERESIS DONATION FROM VOLUNTEERS THEN ON MONDAY YOU DO HYPOXIA NEARS TEST, WEDNESDAY YOU GIVE THEM TWO UNITS OF BLOOD. I WOULD BE CONCERNED ABOUT GIVING ONE UNIT AND THAT BE ENOUGH TO SEE SIGNAL. DEVIL IN THE DETAIL WITH TRIAL DESIGN. YOU CAN DO A HYPOXIA TEST, THE PROBLEM IS THAT WILL REFLECT GIVING BLOOD BUT ALSO VOLUME FROM THE BLOOD. EACH SUBJECT IS THEIR OWN CONTROL AND THE PRIMARY END POINT IS COMPARING THE FRIDAY VERSUS MONDAY BECAUSE NOW THERE'S NO VOLUME EFFECT OF THE BLOOD. MERELY LOOKING AT IS THERE A DIFFERENT HOW HYPOXIC TISSUES GET BASED ON TWO UNITS OF WHATEVER RED CELLS YOU GAVE, THIS IS THE PRIMARY END POINT FOR NIH FUNDED STUDY USING MAX TESTING NOW. AND YOU CAN LOOK AT THENATER VALUE OF SE TO 2 OR PERCENT DROP FROM BASELINE FOR EACH TEST. FOOD FOR THOUGHT IF THINKING POTENTIAL -- I HAVEN'T DONE THIS HYPOXIA MODEL BUT IT WOULD BE QUITE FEASIBLE. SO IN SUMMARY, I THINK THAT NEARS CAN LIKELY PLAY A ROLE IN OPTIMIZATION OF TISSUE OXYGENATION SOME SETTINGS, FLATS, CHRONIC GROUND, THINGS THAT ARE CLOSER TO THE SKIN. I THINK THE ROLE OF EARLY DETECTION OF SHOCK IS UNCLEAR IN TERMS OF ACTUAL CLINICA UTILITY AND UPTAKE BY CLINICIANS, AS WELL AS I THINK THE ROLE FOR ITS USE IN ICU MONITORING IS LESS PROMISING, AND BUT I THINK THERE IS A POTENTIAL ROLE FOR USING IT IN A MODEL OF RBC QUALITY TESTING BUT AGAIN UNLIKELY IN NON-ANEMIC NON-STRESSED HEALTHY VOLUNTEERS GETTING ONE UNIT OF BLOOD. THANK YOU VERY MUCH. >> THANK YOU, ELLIOT. OUR LAST SPEAKER BEFORE THE BREAK IS DR. LEE FROM CAL TECH WHO WILL TALK ABOUT SOMETHING I HAVE NO IDEA WHAT IT'S ABOUT AND HOPEFULLY I'LL UNDERSTAND WHEN IT'S DONE. PHOTO ACOUSTIC METHODS OF INVESTIGATION. >> GOOD MORNING, EVERYONE, FIRST I WOULD LIKE TO THANK FOR MY INVITATION. I'M LEI FROM CAL TECH. IT'S MY HONTOR TO BE HERE TO SHARE REASONABLE RESULTS FROM ME AND MY COLLEAGUES IN -- THE TITLE OF TODAY'S PRESENTATION SUBPOENA TISSUE OXYGENATION. SO COMPARED TO THE OTHER MODALITIES SUCH AS NEARS, THIS IS A NEW TECHNOLOGY, SO I HOPE WE CAN INTRODUCE THIS TO EVERYONE TODAY. I WILL START WITH THE MOTIVATION AND INTRODUCE TOMOGRAPHY, IMAGING SKILL TECHNOLOGY AND I WILL END THIS DISCUSSION. WHY WE USE LIGHT? FIRST OF ALL YOU HAVE CTR PATH, RECEIVE SO PHOTO ENERGY IS GENTLE, ONLY UV IN GENERAL, WHICH IS NOT HIGH ENOUGH TO IONIZE THE MOLECULE, OCCUPIED TINY PORTION OF THE SPECTRUM. SO A FUNCTIONAL MRI PROVIDE FUNCTIONAL INFORMATION OF THE BRAIN SO DOES LIGHT. PROVIDE METABOLIC IMAGING, CAN PROVIDE IMAGING LIGHT TO THAT AS WELL. LIGHT DO ALSO PROVIDE HISTOLOGICAL MOLECULAR INFORMATION. FUNDAMENTALLY SPEAKING LIGHT INTERACT WITH TISSUE AT THE MOLECULAR LEVEL, LIGHT ALLOWED US TO PROBE ALL MOLECULES DIRECTLY. SO LIGHT ALSO FACE GRAND CHALLENGES IN PENETRATION DUE TO STRONG TISSUE SCATTERING SO ABERRATION LIMITS THE CLASSICAL WILD FIELD MICROSCOPY -- AND THE MICROSCOPY TWO PHOTON LIMITED DIFFUSION LIMIT TO ONE MILLIMETER OF PENETRATION. FOR TOMOGFIN COLLUDING COMPUTER TOMOGRAPHY AND BEATS DIFFUSION LIMIT AND REACHES SEVERAL CENTIMETERS OF PENETRATION BUT LIMITED BY THE PARTICIPATION TWO CENTIMETERS OF PENETRATION. WITH INTERNAL ARTICLES POTENTIALLY BECOME LIMIT AND REACH WHOLE BODY IMAGING. SO WHAT IS PHOTO ACOUSTIC? WHEN TISSUE IS ELIMINATED BY LIGHT, OBSERVED PHOTONS ELEVATES THE TO TON TO EXCITED STATE IT CAN GO THROUGH ONE OR TWO PHOTON PROCESS AND FLUORESCENCE PHOTONS WORKS IN TISSUE AND WE LOSE TRACK OF THEM AFTER SEVERAL SCHEDULE EVEN. THE ABSORB PHOTONS GO THROUGH ANOTHER CHANNEL SO NON--- TRANSFER OF ENERGY -- OTHER ENERGY TO HEAT SO THERMAL EXPANSION WILL GENERATE SOUND WAVE PROPAGATION, IT PROPAGATESSINGS WITH LOWER ABSORPTION IN THE TISSUE. WE CAN TRACE BACK THE OBSERVER BY DETECTING (INAUDIBLE). SO THE PHOTO ACOUSTIC ENERGY AND FLUORESCENCE ENERGY ARE LINKED BY THE QUANTUM YIELD. ROUGHLY SPEAKING COMPLIMENTARY TO EACH OTHER. SO CHEMISTS ARE WORKING HARD TO IMPROVE THEIR DYES OR BIOMOLECULES TO GET HIGHER QUANTUM YIELD. TAKE HOME MESSAGE TO IMPROVE THE AMOUNT YIELD. IF YOU HAVE 10%, 15%, WHICH MEANS 90 PEST HEAT CHANNEL GO TO -- 90% HEAT CHANNEL GO TO PHOTO ACOUSTIC CHANNEL, WE ARE PRETTY HAPPY ABOUT THAT. SO PHOTO ACOUSTIC TOMOGRAPHY HAVE TWO INCARNATIONS, ONE IS DIGITAL RECONSTRUCTION BASE COMPUTER TOMOGRAPHY, THE OTHER IS POINT BY POINT SCANNING BASE PHOTON MICROSCOPY SO TYPICALLY BEGINS WITH -- TISSUE IMAGE, AS PHOTON PROPAGATE INSIDE TISSUE, SOME OF THEM ARE ABSORBED BY THE MOLECULES AND CREATE LOCAL TEMPERATURE -- THROUGH LOCAL TEMPERATURE INDUCE CONSEQUENT PRESSURE RISE THROUGH THERMAL EXPANSION. PRESSURE RISE PROPAGATES INSIDE TISSUE AND DETECTED BY THE TRANSDUCER, PHOTO SIGNAL PROCESS BY THE COMPUTER TO FORM IMAGE WHICH MAPS THE ORIGINAL ENERGY POSITION INSIDE THE BIOLOGICAL TISSUE. FIRST PUBLISHED IN 2003, FUNCTIONAL PHOTO ACOUSTIC TOMOGRAPHY IMAGE BRAIN FUNCTION OF RODENTS THROUGH INTACT SCALP. THIS PAIR OF EARLY IMAGE SHOWS ONE SIDE SIMULATION DYNAMICALLY ACTIVATED THE CONTRALATERAL SIDE OF THE BRAIN. SO THIS NON-INVASIVE FUNCTIONAL IMAGING TO EXPONENTIAL GROWTH SINCE THEN. SO THE DEVELOPMENT OF PHOTO ACOUSTIC TAKES OFF WITH THE DEVELOPMENT OF SHORT LASER BROADBAND TRACK DEUCER AND RECONSTRUCTION AL GOSH RHYTHM. ALGORITHM. THE SIZE DOUBLE EVERY THREE YEAR, EVERY SINCE 2010 THIS CONFERENCE HAS BECOME THE LARGEST (INAUDIBLE). THE GROWTH IS DRIVEN LARGELY BY (INAUDIBLE) WHILE ORGANS -- ORGANELLES OF CELLS ARE IMAGED USING OPTICAL MICROSCOPY WITH OPTIMAL CONTRAST, TISSUES ARE IMAGED BY MRI ULTRASOUND IMPEDING IMAGE CORRELATION. ORGANELLES TO ORGANS IMPACT BIOLOGY AND CLINICAL TRANSLATION ACROSS SCALES, FIRST I'LL TALK ABOUT USING SPECIAL SKILLS. RECENT DEVELOPMENT WE CALL SINGLE IMPULSE PANEL PSAT. HERE IS A MOTIVATION TO BUILD SMALL ANIMAL IMAGING, ESPECIALLY RODENTS ARE ESSENTIAL MODELS FOR CLINICAL STUDIES, THEY PLAY IMPORTANT ROLE IN MODELING METHODOLOGY AND STUDY OF HUMAN DISEASE. THIS IS A COMPARISON OF SMALL ANIMAL WHOLE BODY IMAGING MODALITIES. USING IONIZING RADIATION. MRI LOW FOR IMAGING AND ULTRA SOUND DOES NOT IMAGE BLOOD OXYGENATION OR EXTRA MOLECULAR CONTRAST. THOUGH PROVIDE CENTIMETERS PENETRATION, ONLY ONE-THIRD OF THE PENETRATION DAMPS. SO DEVELOP A CPAT SIMULTANEOUSLY INTEGRATED HIGH SPATIAL TEMPORAL RESOLUTION, HIGH SENSITIVITY AND HIGH PENETRATION GAPS. WITH OPTICAL CONTRAST HARM ION SIZING RADIATION. SO I WILL BRIEFLY DESCRIBE THE SCHEMATIC OF THE SYSTEM. SO LIGHT FROM LASER IS CLINICAL LENS TO FORM PARTICLE THIS IS A CLOSE OUT. SO LIGHT IS I ILLUMINATEED FROM THE SIDE TO ANIMAL AND WE GENERATE ULTRASOUND FROM THE SIDE AS WELL. A RANDOM CONFOCAL MAXIMIZE DETECTION SENSITIVITY AND TRANSDUCER AND AMPLIFIED THEN DIGITIZE CONSTRUCTION. THIS IS THE ROUGHLY THE PERFORMANCE WE CAN GET ABOUT MICRON RESOLUTION AND THE 50 MICROSECOND DATA ACQUISITION. AS WE USE OTHER TOMOGRAPHY IMAGING MODALITIES SUCH AS MRI AFTER SCAN ANIMAL VERTICALLY THROUGH PLAN AND ALL THE SLICE OF THE CROSS SECTIONAL IMAGES, WE CAN COMPILE DETAILS OF ORGAN STRUCTURES ARE A CLEAR RESULT, BASED ON PURE BLOOD ON SORPTION, NO CONTRAST AGENT, TOTALLY NON-INVASIVE. WE CAN ALSO KEEP THE MOUSE AT CERTAIN POSITION AND LASERS AND THIS IS A REAL TIME IMAGE OF THE MOUSE LIVER. IMAGING READ OF 50 HERTZ RATE DURATION MOTION AND CARDIAC RELATED MOTIONS WERE FULLY CAPTURED. SO SO THIS IS LIVER, WHICH IS A BLOOD GENERATING ORGAN HAS A LOT OF BLOOD VESSEL INSIDE, ALSO BRACING THE MOVEMENT WE CAN SEE THE VESSELS BECOME BLURRY BECAUSE THEY ARE MOVING OUT OF ENDOCRINE AND BECOME CLEAR AGAIN WHEN THEY MOVE OUT. THIS IS A REAL TIME IMAGE OF THE UPPER ABDOMINAL CAVITY, IMAGING PERFORMANCE, AND TEST MEMORY, WITHOUT HARM OF RADIATION. SO UPPER THORACIC CAVITY MOTION ON -- ARE DISPLAYED HERE. SO BY RECORDING THE SIGNALS FROM -- AND SIGNAL FROM THE RESERVATION MOTION CAN BE TRACKED AND IDENTIFIED SO VERY SIMPLE, WILL SHOW US THE MOTION FROM RESERVATION IS BOUND TO ONE HERTZ AND THE MOTION FROM -- BOTH RESPIRATION FREQUENCY AND HEART RATE FREQUENCY WHICH IS 5.2-HERTZ. SO THE SIGNAL FROM TEMPORARILY CORRELATED TO THE HEART, THE HIGH SPEED AND SINGLE IMPULSE ENABLE TO SELECTIVELY HIGHLIGHT ARTERIES. BY AMPLITUDE, TO THE HEART FREQUENCY, THE ARTERIAL NETWORK IS MAPPED ON WHOLE BODY CROSS SECTIONAL IMAGE. SO THE -- DILATES DUE TO EJECTION OF BLOOD FROM THE CONTRACTED LEFT VENTRICLE, ALONG THE ARTERIAL -- WE SELECTED TWO VERTICALLY DISTRIBUTED FROM ARTERY NETWORK TO COMPUTER THE CHANGES OF THE CROSS SECTIONAL AREAS SO WE CAN SEE THIS CROSS SECTIONAL AREA OFTEN AS A FREQUENCY BECAUSE THEY'RE ON ONE ANIMAL CONNECTED TO THE SAME HEART BUT THERE IS A -- INDICATE CHANGE OF CROSS SECTIONAL AREA RESULT OF -- SO TRACKING THE IS IMPORTANT FOR CANCER STUDY IN THIS EXPERIMENT WE STRONGER OPTICAL ABSORPTION THAN HEMOGLOBIN DOES SO WE USE 80 NANOMETER LIGHT TO CAPTURE THIS CIRCULATING TUMOR CELLS, WHICH IS INJECTED ALONG CORTICAL VESSELS IN REAL TIME WITH HIGH CONTRAST WITHOUT LEVELING. BY ELIMINATING THE MOUSE BRAIN FROM THE TOP, WE -- CORTICAL VASCULATURE AND SO 2. THIS EXPERIMENT A MIX CHU OF 95% OXYGEN AND 5% NITROGEN WAS USED. DURING THE OXYGEN CHALLENGE THE MIXTURE WAS SWITCH TO 5% OXYGEN, 95% NITROGEN. AND THIS BACK TO THE INITIAL CONCENTRATION. VARIATION IS IN THE SO 2 DERIVED FROM THE CHANGES OF POST OXY AND DEOXYHEMOGLOBIN CONCENTRATION. FOLLOWING MANIPULATION OF OXYGEN CONCENTRATION. SO USING A SINGLE DEOXYHEMOGLOBIN FOR -- WE MAPPED BROOKS OXYGEN RESPONSES TO THE CHANGE OXYGEN SUPPLY AFTER WHICH OXYGEN CONCENTRATION FROM 95% TO 5% THE WHOLE BODY OXYGEN LEVEL CHANGED ACCORDINGLY. IMAGING DEMONSTRATING CAPABILITY FOR FUNCTIONING BRAIN IMAGING, WE NOW HAVE FURTHER EXCHANGED THE BRAIN IMAGE GAPS TO THE RAT WHOLE BRAIN. THIS IS A SET UP FOR RAT BRAIN IMAGE WE ALIGN THE PLAN OF THE RAT OF THE RAT BRAIN PARALLEL TO THE RATE AND THE LINE WAS FROM THE SIDE ON TO THE -- THIS IS A -- VASCULATURE RESULT EMPLOYING A -- FUNCTIONAL CONNECTIVITY. WHEN ANIMAL IS SLEEPING, BRAIN RESPONSES ON -- READ OUTS SHOW A CLEAR CORRELATION BETWEEN CORRESPONDING REGIONS OF LEFT AND RIGHT HEMISPHERES AS WELL AS CORRELATION BETWEEN REGIONS IN YOUR CORTEX. MOST INTERESTING, WE IDENTIFY DEEP LEFT AND RIGHT, WHICH IS.-- CENTIMETERS, ALSO IDENTIFY 16 FUNCTIONAL REGIONS IN THE BRAIN. AND THEY CORRELATION CO-EFFICIENT OF REPAIR. CORRELATION METRICS OF THE 16 FUNCTIONAL REGION IS SHOWN HERE. SO FROM TOP LEFT TO RIGHT BOTTOM I DO I CAN'T GONAL SHOW IT IS OUTER CORRELATION -- DIAGONAL SHOWS THE CORRELATION AND THE RIGHT TOP TO LEFT BOTTOM SHOWS CROSS CORRELATION BETWEEN LEFT AND RIGHT HEMISPHERE, THERE'S CORRELATIONS HERE ON THE CORNER, SHOWS CORRELATIONS ACROSS DIFFERENT REGIONS IN THE NEOCORTEX. SO JUST WHAT I SAID, THIS SYSTEM EMPLOYS TRANSDUCER ARRAY FOR ILLUMINATION, 100-MICRON. SO AS ULTRASOUND SIGNAL, CAN REACH ABOUT 200. AND THE MOUSE BRAIN SIX MILLIMETER SO THE -- 30-MICRONS. HERE IS A NEW SYSTEM WE DEVELOPED SO WITH HIGH FREQUENCY LINEAR TRANSDUCER AND LOW ROE AT A TIME IN AKRON KNOW PLAIN TO COVER THE WHOLE BRAIN AND FINALLY IN THIS SYSTEM REACH ABOUT 40-MICRON RESOLUTION. SO AFTER COMBINING SINGLE VIEW IMAGES TOGETHER WE REVIEW DETAIL VASCULATURE OF THE WHOLE MOUSE BRAIN. AND TO DEMONSTRATE THE IMAGING WE STUDIED EPILEPSY IN A MOUSE MODEL, SO SEIZURE IN A MOUSE WAS INDUCED BY INJECT THE FULL AP AFTER INJECTION THE NEUROACTIVITIES WAS IMAGED WITH A LIFT LINEAR AT 30-DEGREE ANGLE AND DIFFERENT TIME AFTER INJECTION SHOWN HERE. SO AS INDICATED THE INCREASE OF P AMPLITUDE WAS INITIALLY OBSERVED INTO THE INJECTION SITE THEN SPREAD OUT. SO THIS IS A MOVIE SHOWING THAT PROCESS, MORE INTERESTING IS SHOWING THE AROUND THE INJECTION SITE SPREAD OUT, SO FROM THIS SITE THEN SPREAD OUT ON THIS SIDE OF THE HEMISPHERE. NOW WE SCALE DOWN THE SYSTEM AND BUILD SECOND GENERATION FOR HUMAN BREAST IMAGING, THIS IS THE SET UP IN THE HOSPITAL WE USE FOR IMAGING BREAST CANCER PATIENT. THE PATIENT LIE DOWN IN PRONE POSITION IN A DONUT T ELIMINATEED FROM THE BOTTOM. AND THIS IS THE BREAST IMAGE THIS IS IMAGE FROM TUMOR OUTSIDE BREAST FROM A PATIENT AND THE ANGIOGENESIS IS THE HALLMARK TO DIFFERENTIATE THE LESION FROM NORMAL BREAST TISSUE. CROSS SECTION, WHERE THE HIGHER PEAK AMPLITUDE IS SHOWN HERE, RESPONDING WELL WITH THIS PART AND THE MAP FURTHER CONFIRM THAT THERE -- THE TUMOR EXISTS HERE. NOW MOVING ON TO ANOTHER MODALITY. WE CALL IT PHOTO MICROSCOPY, INSTEAD OF RECONSTRUCTING THE IMAGE DIGITALLY, OF FOLKS AUTO TRANSDUCER IS USED FOR ANALOG -- AS ANALOG FOR RECONSTRUCTION UPON LASER LIGHT EXITATION PICK UP THE P SIGNAL VERSUS TIME, WHILE TIME OF FLIGHT PROVIDES ACTUAL -- TRANSVERSE RESOLUTION, A SINGLE PAUSE WITH ONE DAY IMAGE AND SCANNING GET US 3-D IMAGE TO THE MICROSCOPIC IMAGING THIS 3-D PHOTO MICROSCOPY WAS FIRST BUILT AND OPT SCHEME IS DONUT SHAPE TO MINIMIZE THE SKIN INTERFERENCE AND ULTRASOUND TRANSDUCER IS TO MAXIMIZE DETECTION SENSITIVITY AND THE -- SCANNING PRODUCE IMAGES. THIS SYSTEM SKILL REGION MICRON RESOLUTION AND ABOUT THREE TO FOUR MILLIMETER PENETRATION. WE HAVE APPLIED THIS MICROSCOPE FOR HUMAN IMAGING, IT CAN MAP THE BLOOD VESSEL NETWORK. THE TYPICAL SCAN STRUCTURE BASE SCAN IMAGING, WAS ACQUIRED WITHOUT ANY CONTRAST AGENT. BASED ON PURE BLOOD ABSORPTION. IN THE DIFFUSION LIMIT PENETRATION ABOUT ONE MILLIMETER, WITHIN THE DIFFUSION LIMIT IS STILL EFFECTIVE AND USED FOR PROVIDING TRANSVERSE RESOLUTION. WHILE THE -- PROVIDES ACTUAL RESOLUTION THE KEY IN THIS SET UP IS OPTICAL COMBINER. TUMOR OPT TICKS AND ACOUSTIC ENERGY. HERE IS A SINGLE -- WE GET A ONED IMAGE AND SCANNING GET US 3-D IMAGE. THIS SYSTEM OPERATE -- EVEN THE TINIEST BLOOD VESSEL CAN (INAUDIBLE) CLOSE UP REVIEW -- ANNOTATION BY USING TWO DIFFERENT -- OXYGEN SATURATION MAP, MAP HERE, VESSEL THE WHOLE OXYGEN SATURATION IS MAPPING VESSEL PROVIDE VESSEL BY OXIMETRY AND WE CAN SEE HERE GIVEN A SINGLE -- HERE. WE RECENTLY BUILT FUNCTIONAL PANEL SYSTEM TO MOUSE BRAIN HEMODYNAMICS TO ELECTRICAL STIMULATION. ON THE LEFT, THIS IS OXYGEN SATURATION MAP OF BRAIN CORTEX, WHERE THIS BLUE COLOR INDICATES THE MEAN AND THE RED COLOR INDICATES ARTERIES. THIS SIDE OF THE MOVIE HIGH MOW DYNAMIC RESPONSE RESPOND ELECTRICAL STIMULATION WE CAN SEE ELECTRICAL STIMULATION ON THE LEFT, GIVES US A HIGH SIGNAL ON THE RIGHT HEMISPHERE AND SIMULATION ON THE LEFT -- RIGHT INCREASE SIGNAL ON THE CONTRALATERAL SIDE OF THE BRAIN. THIS IS USING THE SYSTEM WE IMAGE THE CORTICAL BRAIN SO 2 CHANGES UPON THE ELECTRICAL STIMULATION. THIS IS ANOTHER INTERESTING PHENOMENA OBSERVED DURING THE TUMOR STUDY, SIMILAR TO CONFLUENCE SO HAD DIFFERENT CO 2 CONCENTRATION BUT WHEN THEY EMERGE AFTER CONFLATION, IT WILL FLOW FORWARD IN PARALLEL WITH REAL MIXING. SO THIS IS BASELINE IMAGE ON MOUSE EAR, THE BLUE AND RED ARTERIES. SO INDUCE A TUMOR AND -- GIVE VEST IMAGE. WE OBSERVE THE BLOOD FLOW ELEVATED DUE TO -- LOW OXYGEN BLOOD, HIGH OXYGEN BLOOD MOVING FORWARD IN PARALLEL. SO AS DEMONSTRATED BEFORE THE TOTAL CONCENTRATION OXYGEN SATURATION, ALSO CAN MAP THE BLUFF USE THE DOPPLER EFFECT SO THIS CROSS SECTION PARABOLLIC FLOWS OF BOTH VEINS AND ARTERY. WE ALSO ADVANCE OXIMETRY TO AUTOMATE A SINGLE CELL RESOLUTION, HERE IS A DEMONSTRATION AT ONE HERTZ SCAN, AND 200-HERTZ. AT 200-HERTZ THE SINGLE BLOOD CELL IN REAL TIME, IT'S TRAPPED ON THE FLY AS WELL ENABLE FUNCTIONAL STUDY OF OXYGEN DELIVERED ON THE CELL BY CELL BASIS. WE CAN APPLY THIS TO HUMAN AS WELL. HUMAN IF I CANNER CODING SO THIS OXYGEN SAT RAYING MAPS SHOWS THE -- SATURATION MAP SHOWS TRANSPORT OF OXYGEN INDICATING MOST IS FROM HEMOGLOBIN SO YOU CAN SEE THIS HIGH OXYGEN AND LOW OXYGEN OUT. THIS IS THE LAST SLIDE. SO THIS IS THE CAPILLARY LOOP AT THE END OF THE FINGER COATED TIP. RELEASING OXYGEN DURING THEIR -- MOVING INSIDE THIS -- FINALLY I WOULD LIKE TO THANK THE GENEROUS SUPPORT FROM NIH. THAT'S OOH ALL. WE CAN DISCUSS MORE IF YOU HAVE MORE INTEREST. [APPLAUSE] >> THANK YOU VERY MUCH. SO IT'S NOW TIME FOR A BREAK. WE'RE A FEW MINUTES BEHIND TIME. WE'RE COMMITTED TO FINISHING THE WHOLE THING BY ONE O'CLOCK SO PLEASE, THAT CLOCK THERE SAYS 5 MINUTES AFTER TEN, PLEASE COME BACK AT 10:20 AND WE WILL START PROMPTLY THEN. THANK YOU VERY MUCH. OUR FIRST SPEAKER IN THIS SESSION IS DR. HARLED SCHWARZ WHO WILL SPEAK BY SITTING DOWN -- HAROLD SCHWARZ AND WE WILL SHOW THE SLIDES FOR HIM. >> THANK YOU VERY MUCH. I DON'T USUALLY HAVE TO SIT BUT I -- SOMETHING I ATE I THINK DISAGREED WITH ME. SO I THOUGHT I WOULD NOT PUT ON A SHOW OF THE FALLING PERSON. MY FEAR IS THERE ARE TOO MANY PHYSICIANS HERE. THIS IS THE FIRST OF THREE INTERRELATED TALKS, USING A TUCK MEEK CALLED NPR SO I'M GOING TO GIVE A FAIRLY GENERAL TALK TO GIVE A LITTLE INTRODUCTION TO EPR, I'M THEN GOING TO -- I HAVE BEEN PROFESSOR FOR TOO MANY YEARS AND SO I'M GOING TO THEN REVERT INTO THE PROFESSOR AND TRY TO LECTURE YOU A LITTLE ABOUT BASIC OXYGEN, I HAVE BEEN BEEN INVOLVED WITH OXYGEN FOR A FEW YEARS. AND SHOW YOU WHAT I THINK ARE VERY EXCITING DATA OF USING THIS TECHNIQUE TO MEASURE TISSUE OXYGEN. THE FOCUS IS THOUSAND MEASURE EFFECTIVENESS BY MEASURING OXYGENATION OF THE TARGET TISSUES. THAT'S ME, THEY LEFT OFF MY M.D.. I'M THE PROGRAM, I WORKED HARD FOR THAT M.D., I DON'T WANT TO GIVE IT UP. I'M AT THE GUY SELL SCHOOL OF MEDICINE. WHICH DOESN'T MEAN VERY MUCH UNTIL YOU REALIZE THAT IT'S THEODORE SUSGEISELL, THAT HE WANTS THE NAME OF OUR MEDICAL SCHOOL AND PERHAPS THE ADMINISTRATIVE ORGANIZATION OF OUR MEDICAL SCHOOL. JUST TO REMIND YOU WHILE HERE IN THE FLOWERS WE STILL HAVE A LITTLE SNOW IN NEW HAMPSHIRE, NOT THIS MUCH BUT WINTER HASN'T QUITE LEFT US SO DISCLOSURES, I DO HAVE A LITTLE COMPANY WHICH WE DEVELOPED IN ORDER TO DISSEMINATE OUR TECHNOLOGY -- THOUGH IT DOESN'T INVOLVE RESEARCH, THE TECHNIQUES I'M PRESENTING AND WILL TRY TO GET YOU EXCITED YOU WOULD HAVE TO BUY FROM IT SO THIS IS CLEARLY A CONFLICT OF INTEREST WHICH YOU SHOULD BE AWARE. THE -- WE HAVE A LITTLE BIT OF IP RELATED -- NOT REALLY NOT A REAL COMPANY IN THE SENSE THAT ANY MONEY WE MAKE WE THEN GIVE BACK TO THE LABORATORIES. SO IT'S -- IT IS TECHNICALLY A COMPANY. ADDITIONAL DISCLOSURES. I HAVE REALLY -- YOU WAS TRYING TO COME BACK WHEN I DID MY FIRST PAPER ON OXYGEN MORE THAN 40 YEARS. THIS IS NOT A DISINTERESTED PRESENTATION, IT IS SLANTED BY MY EXPERIENCE AND MY INTEREST. AND I'M OVERTLY TRYING TO PUSH FURTHER COLLABORATIONS. UNMORE DISCLOSURE SPEND TIME PHOTOGRAPHING BIRDS, I DON'T GET INVITATIONS TO TALK ABOUT -- TO PRESENT MY BIRDS. SO AS A COMPROMISE IN ORDER TO SEPARATE SECTIONS, I WILL SHOW YOU PICTURES OF BIRDS. TO POINT OUT THAT THE WORK THAT I'M GOING TO TALK ABOUT IS A PRODUCT OF A LOT OF PEOPLE OVER MANY YEARS. INVOLVED IN A VARIETY OF THINGS THAT INVOLVE CLINICAL PRE-CLINICAL BIOLOGICAL APPLICATIONS OF EPR. THERE'S A BIRD SEEING THIS IS CHERRY BLOSSOM TIME, MOST BIRDS ARE FROM SOUTHEAST ASIA. WHAT SHOULD WE MEASURE TO DETERMINE EFFECTIVENESS OF RED CELL BASED THERAPY? IN OOH SIMPLISTIC WAY WE GIVE BLOOD TO RAISE OXYGEN IN TISSUES SO ONE WAY, NOT THE ONLY WAY, ONE FACT DOOR IS WHAT IS THE OXYGEN IN THE TISSUE IN THE EXPECTATION THAT THIS WILL EFFECT OUTCOMES. SO WE DO THIS BY MEASURING OXYGEN AT THE SITE AND SOMETHING DISTRUSS, NOTHING TO DO WITH OUR EXPERIMENTS BUT BACK IN THE LECTURING MODE, IS ONE OF OUR REAL CHALLENGES IS TYPE OF POPULATION WHICH THERAPY IS INTENDED. ONE OF THE CHALLENGES FOR THE INSTITUTE BECAUSE NOBODY ELSE IS GOING TO DO IT, IS TO INVEST AND ENCOURAGE THE PROPER MODEL SYSTEM THAT WILL GIVE US SO WE CAN TEST. THAT'S A CHALLENGE. IT IS A REAL CHALLENGE TO DO BUT NOT WITHOUT SOME SUPPORT BECAUSE COMPANIES AREN'T GOING TO -- AREN'T GOING TO INVEST IN THIS. WE LIKE TO BE ABLE IF YOU'RE GOING TO MEASURE OXYGEN AND TISSUE YOU WANT TO MEASURE BEFORE AND AFTER -- YOU LIKE TO MEASURE IN INDIVIDUAL PATIENTS AND IT WILL BE IMPORTANT TO GET THE INFORMATION DYNAMICALLY THAT IS OVER MINUTES, SECONDS AND THEN REPEATEDLY ON DIFFERENT DAYS. MOST TECHNIQUES, THOUGH THERE ARE SOME EXCITING THINGS THAT HAVE BEEN SHOWN AT THIS WORKSHOP FELL SHORT OF MEASURING OXYGEN IN TISSUES. OXYGEN AND TISSUES REAL OXYGEN, IS WHAT WE NEED TO KNOW. SO I HAVE MODULATED MY TALK ON PRIOR -- BASED ON PRIOR PRESENTATION JUST TO PUT, -- TO EMPHASIZE MORE THAN I REALLY REALIZED WHEN I CAME HERE, THE OXYGEN TISSUE CLEARLY ISN'T ALL THE INFORMATION THAT WE NEED. BUT IT IS AN ESSENTIAL BIT OF THE INFORMATION SO I'M GOING TO FOCUS ON ONE OF THE IMPORTANT THINGS WHICH IS OXYGEN TISSUE. AND BUT IF WE'RE TRYING TO SEE WHETHER OTHER METABOLIC FACTORS ARE IMPORTANT,, WE HAVE TO KNOW WHAT HAPPENED TO THE OXYGEN, IF THIS TECHNIQUE WHICH MODIFIED SOMETHING ELSE SEEMED TO HELP WE STILL CAN'T REALLY UNDERSTAND THAT UNLESS WE KNOW DID IT OR DID IT NOT CHANGE THE OXYGEN. SO WE KNOW THE ROLE OF THE OXYGEN. I'M FOCUSING AT THIS SECTION ABOUT CLINICAL APPLICATIONS BUT THEY REALLY APPLY TO PRE-CLINICAL STUDIES TO SOME EXTENT. JUST A FEW COMMENTS, BOLD JUST TO EMPHASIZE WHAT YOU MEASURE WITH BOLD IS TOTAL DEOXYHEMOGLOBIN. SO WHEN BOLD CHANGES IT DOESN'T NECESSARILY MEAN YOU HAVE CHANGED SATURATION, BECAUSE IF YOU'VE CHANGED PRO FUSION, CHANGED VOLUME YOU WILL CHANGE THE AMOUNT OF THEOXI HEMOGLOBIN. SO THERE ARE -- BOLD IS A POWERFUL USEFUL TECHNIQUE BUT YOU HAVE TO UNDERSTAND THAT IT'S NOT -- IT IS ANYTHING WE'RE INTERESTED IN IS LIKELY TO CHANGE PROFUSION AND VOLUME PATHOPHYSIOLOGY CHANGES IT. OXYGEN CONCENTRATION IS DIFFERENT FROM PARTIAL PRESSURE AND JUST TO REMIND I NOTICED A COUPLE OF STUDIES WHERE PEOPLE MEASURING ANIMALS BREATHING ROOM AIR WHEN YOU ANESTHETIZE AN ANIMAL, IF YOU BREATHE ROOM AIR YOU WILL MAKING YOUR ANIMAL HYPOXIC YOU HAVE TO ENRICH THE AIR. OFF THE LECTURE PLATFORM, MOVING ON. THE ULTIMATE DETERMINANT OF EFFICACY IS OUTCOMES. SO WE HAVE TO TIE THINGS TO OUTCOMES. THIS THINGS IS NOT WORKING. HE GAVE IT UP READILY. EXISTING METHS TO MEASURE OXYGEN IN VIVO WE SHOULD DIFFERENTIATE, THEY'RE POTENTIALLY VALUABLE BUT THEY DO DIFFERENT THINGS SO METHODS THAT MEASURE OXYGEN, METHODS THAT MEASURE OXYGEN IN VASCULAR SYSTEM WHICH DOESN'T TELL YOU WHAT'S IN THE TISSUES THAT AFFECTS IT. THERE ARE METHODS THAT MEASURE PARAMETERS BY PLAUSIBLE MECHANISMS AND SO LET'S LOOK AT THESE DIFFERENT ONES AND WE HAVE TO THINK ABOUT TO WHAT EXTENT CAN THEY BE USED. ARE THEY AVAILABLE CLINICALLY AND CAN THE MEASUREMENTS BE MADE UNDER CLINICAL CONDITIONS. IT'S ALSO USEFUL IF YOU YOUS -- USE METHODS IN ANIMAL MODELS SO YOU CAN TRANSLATE. WHAT ARE THE METHODS THAT MEASURE PARAMETERS THAT REFLECT OXYGEN VIA PLAUSIBLE MECHANISM. SO THERE'S HYPOXIC MARKERS THAT ARE USEFUL, WHAT THEY TELL YOU IS THAT ONE TIME, ONE PLACE, THERE WAS HYPOXIA, DOESN'T TELL YOU HOW MUCH HYPOXIA, IT DOESN'T TELL YOU BUT IT'S VERY NICE MARKER THAT HYPOXIA OCCURRED AT THE TIME YOU ADMINISTERED THERE ARE INDICATORS OF REDOX STATE WHICH AGAIN ARE RELATED TO OXYGEN BUT DON'T TELL YOU OXYGEN PET TELLS YOU METABOLISM OF GLUCOSE ANALOGS, DOESN'T TELL YOU OXYGEN BUT IT'S POWERFUL, BOLD MRI IS POWERFUL, MRI PROFUSION AND DIFFUSION, ADD VERY IMPORTANT INFORMATION WE LIKE TO RELATE TO OXYGEN, SIMILARLY MRI SPECTROSCOPY, THESE ARE ONES THAT ARE MOST LIKELY TO BE AVAILABLE CLINICALLY AND PRE-CLINICALLY, SO WE WANT TO USE THEM BUT UNDERSTAND WHAT WE'RE GIVING AND WHAT WE PARTICULARLY WOULD LIKE TO DO IS TO RELATE THEM TO THOSE CIRCUMSTANCES WHERE THEY REFLECT REAL TICKER SHOE OXYGEN. -- REAL TISSUE OXYGEN. WE HAVE METHODS THAT MEASURE OXYGEN IN VASCULAR SYSTEM, NEARS TELLS US OXYGEN SATURATION TOTAL HEMOGLOBIN VERY POWERFUL, IN THE VASCULAR SYSTEM, BLOOD GASES ARE THEY ARE AVAILABLE, THEY DON'T NECESSARILY RELATE TO THE OXYGEN IN THE TISSUE AND IT'S REALLY IMPORTANT TO UNDERSTAND WHAT PART OF THE VASCULATURE THEY REFLECT. THEY DON'T TELL YOU ALL VASCULATURE. THERE WAS A NICE COMMENT EARLIER PRESENTATION ABOUT MIXTURE OF SATURATION, IT DOESN'T GIVE YOU ALL THE ARTERY, AND VEINS, IT GIVES YOU DISPROPORTIONATELY THE MICROVASCULATURE BECAUSE YOU HAVE BIG CELLS AN BIG VESSELS. SO THE METHODS THAT DIRECTLY MEASURE OX GENERAL AND TISSUES -- OXYGEN AND TISSUES ARE THE OXYGEN ELECTRODE, THE OPTICAL METHODS WE HEARD A LOT OF AND EXCITING IMPORTANT. THERE WAS A BRIEF LOVE AFFAIR WITH FLUORINE HYDROCARBON NMR WHICH DIED AID WAY AND EPR OXIMETRIES SO THESE ARE WAYS ONE CAN MEASURE OXYGEN AND TISSUE. THE EPINDORF -- THESE METHODS ARE POTENTIALLY GOLD STANDARD THAT TELL YOU WHAT THE OXYGEN LEVEL IS IN TISSUE AND MAYBE YOU CAN RELATE THAT BUT IN ORDER TO UNDERSTAND THEM YOU NEED TO KNOW, YOU SAY THERE'S OXYGEN INISH THE SHOE, WHAT IS THE TISSUE YOU'RE MEASURING, WHAT'S THE VOLUME, AND WHAT IS LOCATION OF THAT VOLUME. AND YOU NEED TO KNOW WHETHER IT'S P O2 OR -- THESE COULD BE PARTICULARLY VALUABLE TO TELL YOU HOW THE MORE AVAILABLE LESS DIRECT METHODS UNDER WHAT CONDITIONS DO THEY PROVIDE DESIRED INFORMATION SO WE NEED MULTIPLE MEASUREMENTS OR WE NEED TO HAVE SOME SORT OF CALIBRATION IF USE IN VIVO. SO LET'S LOOK BRIEFLY AT THE OXYGEN ELECTRODE, THIS IS THE GOLD STANDARD, REMEMBER YOU GET THIS PATTERN YOU ARE INJURING THE TRANSFUSION AT THE SAME TIME. A MANY DECEMBER PERTURBATION BUT IT CAN BE SIGNIFICANT, YOU CAN'T MAKE REPEATED MEASUREMENTS BECAUSE YOU CAN'T MAKE MUSH OUT OF TISSUE. AND IT'S NO LONGER COMMERCIALLY AVAILABLE IF IT'S NOT -- SEEMS UNLIKELY TO BECOME COMMERCIALLY AVAILABLE FOR CLINICAL USE. THE OPTICAL METHODS WE HEARD ABOUT, IT'S REALLY EXCITING, I THINK, AND PEOPLE SEEM TO BE REALISTICALLY UNDERSTANDING VIRTUES AND POTENTIAL LIMITS, FLUORINE NMR, I WILL SKIP THIS H. SO EPR OXIMETRY IS BASED -- IT'S A PHYSICAL METHOD BASED ON OXYGEN, CHANGING THE LINE LIST EPR DETECTABLE SPECIES, I WILL GIVE YOU COUPLE OF MINUTES OF THAT. IT'S A PHYSICAL INTERACTION WITHOUT CONSUMPTION OF OXYGEN. SO THAT'S USEFUL, IF YOU USE SOLUBLE OXYGEN, SENSITIVE MOLECULES YOU CAN CARRY OUT IMAGING AND WE'LL SHOW YOU WONDERFUL DATA PARTICULATES YOU CAN PUT IN AND MAKE REPEATED MEASUREMENTS. I WILL TALK ABOUT DATA ON THIS AND MY COLLEAGUE COOPS WILL PRESENT SOME VERY EXCITING DEVELOPMENTS, IT'S BEEN WIDELY USED SUCCESSFULLY IN PRE-CLINICAL MODELS. EPR OXIMETRY BASED ON PARTICULATES REQUIRES A ONE TIME INJECTION OF OXYGEN SENSITIVE MATERIAL. WHICH RAISES CHALLENGES BECAUSE IF YOU DO IT IN PATIENTS YOU HAVE TO GET CLEARANCE TO DO THAT. ONE THERE YOU GET CONTINUOUS MEASUREMENTS AND REPEATED MEASUREMENTS OVER TIME. I WILL SHOW YOU CLINICALLY HOW EXTENSIVE THAT IS. THEY HAVE BEEN USED SUCCESSFULLY, THERE'S CLINICAL MEASUREMENTS UNDERWAY USING INDIA OR PDMS COATED, WHICH WE'LL TALK ABOUT. SEE ONLY NON-ASIAN BIRD THIS IS FROM HAWAII. SO EPR JUST MAGNETIC RESONANCE SPECIFIC SPECIES WITH UNPAIRED ELECTRONS SO ELECTRONS HAVE SPIN SO IF YOU HAVE UNPAIRED ELECTRON YOU HAVE A MAGNET. NOW YOU CAN TAKE THAT MAGNET AND FLIP IT, THAT'S WHAT YOU DO FOR EPR. MRI IS SO POWERFUL BECAUSE MRI IS BASED ON THE SPIN OF THE NUCLEUS IN WATER, WATER IS 100 MOLAR, 100 MOLAR, THOSE OF US THAT STRIKE NANOMOLARS AND MICROMOLAR CONCENTRATIONS, MRI WHICH IS VERY INSENSITIVE INHERENTLY IS EXTREMELY SENSITIVE FOR IMAGING BECAUSE OF THE WATER. EPR IS BEEN AROUND A LONG TIME, THE USUAL FREQUENCIES WE USE. YOU USE IN YOUR KITCHEN. YOU DID THE SAME THING IN ANIMALS, WE WOULD DO -- GET THE SAME THING, WE HAVE THE FAMOUS FOILED GERBIL WITH PEOPLE TALK ABOUT IN MICROWAVE SO WE HAVE TO GO DOWN IN FREQUENCY WHICH MAKES IT TECHNICALLY CHALLENGING. EPR CAN DO WONDERFUL THINGS, I SPENT MY LIFE USING IT BUT OXIMETRY IS WHAT WE'RE GOING TO TALK ABOUT BUT ALSO NICE FOR FREE RADICALS AND PHYSICAL ENVIRONMENT, REDOX STATE. ARE SO IT'S A POWERFUL TECHNIQUE. THIS IS WHAT EPR INSTRUMENT LOOKS LIKE FOR ANIMALS, MAGNET MICROWAVE FREQUENCY, PHYSIOLOGICAL CONDITIONS, YOU CAN MAKE BIGGER ONES GET BIGGER ANIMALS AND GREAT BIG ONES AND HAVE GREAT BIG ANIMALS. THE MACK NETTIC FIELD IS ABOUT 400 WE USE EQUIVALENT MAGNET THAT INVOLVES YOUR REFRIGERATOR. HOW MEASURE EFFICACY OF BLOOD PREPARATION? WE USED A -- A VERY WONDERFUL COLLABORATION WITH PAUL BHULLAR, WE USED DIRECT TRANSFUSION MODEL, WE PUT IN SOME PDMS COATED PARAMAGNETIC MATERIALS IN THE MUSCLE. THEN WE COULD MEASURE CONTINUOUSLY OVER BASELINE ACUTE HEMORRHAGE TRANSFUSION, POST TRANSFUSION USING AN ANIMAL AGED BLOOD PREPARATION, THESE ARE THE DATA WE GOT GENERALLY SO EXPERIMENT IS YOU PUT THE OXYGEN SENSITIVE MATERIAL IN THE MUSCLE AND THEN IT'S THERE, FOREVER. YOU GET BASELINE, YOU TAKE BLOOD OUT WHICH IS .2. SO NOW EACH POINT -- EACH OF THOSE IS SEPARATE MEASUREMENT SO THE TIME RESOLUTION IS GOOD, YOU CAN GET SOME FEELING FOR SCATTER AND LOOKING AT THAT. THEN YOU CAN FOLLOW THE OXYGEN CONTINUOUSLY. GIVE TRANSFUSION USING FRESH BLOOD AND YOU SEE WHAT HAPPENS. OVER POST TRANSFUSION PERIOD, THESE ARE CARRIED OUT THREE HOURS. WE HAVE THEM IN SCAN NUMBERS INSTEAD OF TIME, I APOLOGIZE. THEN USE RED BLOOD STORED 14 DAYS, I'M NOT A TRANSITION PERSON, EQUIVALENT TO 42 DAYS. YOU CAN SEE NOW WHEN YOU LOOK AT THE TISSUE OXYGEN, NOW YOU ARE LOOKING AT THE EFFECT OF THE ORGAN, MAYBE MAY OR MAY IN THE BE THE RIGHT ORGAN, LOOKING AT MUSCLE, WE'RE SEEING IT DOESN'T GO BACK AS WELL. THEN DOESN'T SEEM TO HOLD. AT YEAR C YOU'RE GETTING A DIRECT DEMONSTRATION SO THE TAKE HOME POINTS, I WILL SHOW YOU THE DATA, ARE THAT WE CAN MEASURE IT, THAT WE CAN MAKE CONTINUOUS MEASUREMENTS. WE COULD MAKE MEASUREMENTS IN A DIFFERENT EXPERIMENTAL TECHNIQUE, WE SACRIFICE THE ANIMALS FOR WHATEVER LENGTH OF TIME IS DESIRED. AND I WILL SHOW YOU COMPARABLE MEASUREMENTS MADE IN HUMANS. THIS IS THE SUMMARY OF A LOT OF VERY HARD GOTTEN DATA AND PAUL WAS A HERO IN GETTING THIS. SO WHAT WE SEE IS FOR FRESH BLOOD, THERE'S BASELINE IN THE MUSCLE, HEMORRHAGE, IT GOES DOWN, TRANSFUSE, IT GOES UP, AND THEN POST TRANSFUSION WENT DOWN A LITTLE BIT BUT GOT UP TO THE ORIGINAL LEVEL. STORED BLOOD ORIGINAL LEVEL, THE HEMORRHAGE WENT DOWN. IT DIDN'T GO BACK UP. SO PRETTY SIMPLE END POINT. BUT IT'S NOT SURPRISING RESULTS. BUT YOU CAN THINK IMMEDIATELY THAT GEE, HERE IS A TEST SYSTEM, WHICH MIGHT BE USEFUL FOR EXAMINING DIFFERENT RED CELL PREPARATIONS TO RADIATE -- WHAT HAPPENS TO RADIATION. WHAT DOES IT DO FOR THE OXYGENATION. WHAT IS OUR TAKE HOME FROM THE INITIAL STUDY, THIS IS A PILOT STUDY, 24 OR 30 ANIMAL, NOT DEFINITIVE BUT OUT SHOWS FEASIBILITY, IT APPEARED, THE BLOOD STORED 14 DAYS APPEARS TO HAVE LOST ITS ABILITY. WE WILL REPEAT IT IN MEASUREMENTS IN THE BRAIN. HEARSAY THE WHOLE STUFF, DIFFERENT BIRD. SO ONE OF OUR PEOPLE. SO ABOUT 15 YEARS AGO WE STARTED USING PARAMAGNETIC MATERIAL. HOW DO YOU -- IN A HUMAN AN SAFELY EFFECT TESTIFILY NOT SPEND THE REST OF YOUR LIFE TRYING TO MEET REQUIREMENTS OF THE FDA WHICH ARE REASONABLE REQUIREMENTS. SO WE USE INDIA INK. SO INDIA INK HAS UNPAIRED ELECTRONS. INDIA INK HAS BEEN USED IN PEOPLE SOMEWHAT OVER TEN THOUSAND YEARS. THE FDA HAS LOOKED AT THE -- AT INDIA INK AND SAID WE ARE NOT INTERESTED IN INDIA INK, IT'S GRANDFATHERED IN, IT'S NOT DRUG, IT'S SOMETHING PEOPLE HAVE DONE AND SO THERE IS NO FDA CLEARANCE FOR IT AS A NEW DRUG. SO WE CAN INJECT IT, YOU CAN GET NDA, INJECT IT NITA TOO PARLOR. HERE WE PUT THE INDIA INK. WE'RE INTERESTED IN THE DIABETIC FOOTED, WHERE PEOPLE MEASURE OXYGEN BECAUSE IT'S THE CRITICAL REGION BUT WHERE THEY CAN MEASURE IT. SO THAT'S WHERE WE PUT IT BUT WE COULD ALSO PUT IT AND WE DO MEASUREMENTS. THIS IS WHERE PATHOPHYSIOLOGY OF DIABETES OCCURS. UNDER THE SECOND METATARSAL, WHY THE SECOND METATARSAL? WHEN YOU STAND UP THAT'S WHERE THE MOST WEIGHT IS. SO THIS IS THIS INSTRUMENT THAT WE HAVE WITH A VOLUNTEER WHO RECEIVED THE INJECTION. T WE HAVE A BLOOD PRESSURE CUFF ON THE THIGH SO WE CAN DO A HYPOXIA YOU CAN ALSO DO HYPOXIA BY BREATHING WHICH IS EASIER. EASIER TO GET CLEARANCE. YOU CAN GET BASELINE, YOU CAN PRESS -- WHEN YOU DON'T HAVE AS MUCH OXYGEN THE LINE GETS NARROWER. THE SENSITIVITY IS MUCH HIGHER FOR LOW OXYGEN WE CAN TELL DIFFERENCE BETWEEN ONE AND TWO AND THREE. NOT VERY GOOD TELLING DIFFERENCE BETWEEN 200 AND 205. AND SO HERE IS A VOLUNTEER. JUST WHAT KIND OF DATA CAN YOU GET. THERE'S A BASELINE, YOU COMPRESS, THEN YOU GET THE DYNAMICS ON THE RECOVERY, THEN YOU GIVE OXYGEN. THERE'S AN AWFUL LOT OF PHYSIOLOGICAL INFORMATION THERE. THAT YOU CAN DISSECT OUT ON RATES OF RECOVERY, RATES OF INCREASE TWEAKING OUT DIFFERENCES BETWEEN CONSUMPTION AND DELIVERY. SO IT GIVES YOU A LOT OF DATA THAT YOU CAN WORK WITH. THE OTHER THING ABOUT THE HUMAN STUDIES, HERE THE ABSCESSA IS IN YEARS. SO THAT'S A SERIES OF EXPERIMENTS, DONE BUT I PUT IN JUST TO POINT OUT ONCE YOU PUT THIS MATERIAL IN, YOU HAVE GOT IT FOREVER. SO YOU CAN GO BACK AND MEASURE IT IN A VERY RUE TYPE WAY. SO TRYING TO KEEP US ON TIME, NICE BIRD. JUST TO SUMMARIZE IN VIVO USE OF E PPR OXIMETRY, HAS HAD A LOT OF USE IN PRE-CLINICAL STUDIES AN LABS ALL OVER WORLD. FROM MICE TO PIGS, HUMAN SUBJECTS HAVE BEEN DONE YOU BOTH USING EPR FOR DOSIMETRY AS WELL AS OXIMETRY. SEVERAL INSTITUTIONS IN THE U.S. AN LABS COLLABORATING WITH KOREA, JAPAN BELGIUM AND FRANCE. WE CAN MAKE MEASUREMENTS DON'T WOWSLY AND REPEATEDLY. WE THINK ONE OF THE NICHES WILL BE STAKE MORE VALUABLE TECHNIQUES SUCH AS MRI OR PET. WE PROVIDED INDIRECT INFORMATION THOSE SIXER WHERE THE INFORMATION DIRECTLY RELATES TO TISSUE OXYGEN THEN MORE WIDELY USED TOOLS CAN BE USED UNDER WELL DEFINED CIRCUMSTANCES. FOR TRANSFUSION JUST KIND OF THOUGHT THING WE CAN USE A BEDSIDE, EPR OXIMETER, WE CAN INJECT INDIA INK AND SUPERFICIAL SITES, AND MAKE THE MEASUREMENTS SO THAT YOU CAN DO IT IN INDIVIDUAL PATIENTS. WE HAVE TALKED ABOUT USING OXYGEN AND RESEARCH USERS I THINK ARE PRETTY BIG SO SUMMARIZING. ONE COULD ARGUE ADEQUATE EVALUATION OF RED CELL PREPARATIONS SHOULD INCLUDE DIRECT DEMONSTRATION OF OXYGEN IN TISSUES. YOU REALLY NEED THIS INFORMATION IN ORDER TO LOOK AT SOME OF THE MORE COMPLEX THINGS THAT HAVE BEEN VERY EXCITING TO TALK ABOUT SO WE NEED SOME SORT OF GOLD STANDARD USING DIRECT MEASUREMENTS OF OXYGEN IS -- WAS THE OXYGEN DELIVERED, NOT THE WHOLE STORY BUT ESSENTIAL PART OF THE STORY, STILL SO WE LIKE TO LOOK AT THE EFFECTIVENESS AS A TECHNICAL CHALLENGE, IT'S EXCITED TO SEE THAT THERE MAYBE A LOT OF TECHNIQUES I THINK EPR CAN DO THAT. DO THIS IN INDIVIDUAL SUBJECTS UNDER CLINICALLY APPLICABLE AND RESOLVE QUESTIONS. FINALLY WE'RE INTERESTED IN THE COLLABORATION WITH OTHERS TO MAKE EXPERIMENTAL MEASURES IN THEIR SYSTEMS AND THIS SEEMED PARTICULARLY APPROPRIATE -- IT'S NOW CALLED (INDISCERNIBLE) THANK YOU VERY MUCH. [APPLAUSE] AS A NON-BIRD WATCHER I'M JOYED HIM SAYING THAT'S A BIRD, THAT'S A BIRD, THAT'S A BIRD. THAT'S ABOUT THE LEVEL -- AFTER BLUE JAYS AND CARDINALS I'M LOST. NEXT SPEAKER IS DR. COOPERSAMI. ALSO TALK SAME BROAD TOPIC. >> THANK YOU. ALSO -- SCHOOL OF MEDICINE HAS GIVEN A NICE INTERACTION INTO EPR. EPR OXIMETRY. SO I'M GOING TO CONTINUE FROM WHERE I LEFT OFF. THIS IS -- JUST COUPLE OF MONTHS AGO TAKEN FEW YEARS AGO. THAT'S DARK MUSCLE, I ALSO HAVE SOMETHING TO DISCLOSE, THE TWO TECHNOLOGIES THAT I'M GOING TO TALK TODAY ARE PROTECTED AND I HAVE SIGNIFICANCE INTEREST IN PURSUING THEM FOR COMMERCIALIZATION. SO WITH THAT, AGAIN TECHNOLOGY IS EPR OXIMETRY THAT I'M GOING TO TALK ABOUT IS A PARTICULAR BASED TECHNOLOGY, NOT INDIA INK OR SOLUBLE MOLECULE NOW TALKING NEXT BUT THIS IS A SYNTHETIC PROBE WHICH OUR LABORATORY HAS DEVELOPED CONTINUOUS FUNDING 15 YEARS FROM NIBIB. I WILL SHOW YOU THE PROBE THAT'S CURRENTLY BEING DEVELOPED FOR HUMAN SUBJECT APPLICATION IN HUMAN MEASUREMENTS. SO EPR IS DIRECT, IT'S RELIABLE BECAUSE THERE'S NO BACKGROUND, YOU GET -- SOME BACK GROWN, ONE CAN DO REPEATED MEASUREMENTS WITHOUT HAVING TO READ THE VIEWS OR REINFUSE THE PROBE. THIS IS THE PROBE THAT WE ARE OPTIMIZE OVER THE YEARS. AND THIS CAN BE CRYSTALIZED SHOWN HERE YOU CAN ALSO FORM VERY FINE CRYSTALS, MICRON SIZE CRYSTALS, INFUSION BUT I'M NOT GOING TO TALK ABOUT IT. I'M GOING TO TALK ABOUT IMPLANT OR ON THE SKIN CONTINUOUSLY MEASURING OXYGEN. SO BANDAGE (INDISCERNIBLE) VERY GOOD SO VERY SMALL AMOUNT IMPLANTED, HIGHLY RESPONSIVE TO MOLECULAR OXYGEN AND SHOWN TO BE STABLE FOR MORE THAN TEN YEARS. WITHOUT CHANGING CALIBRATION. MORE IMPORTANTLY, THE CRYSTAL BY ITSELF IS NON-TOXIC AND STABLE IN TISSUE WHEN IMPLANTED. WE CARRIED OUT PRE-CLINICAL STUDIES OVER 10, 15 YEARS, MYOCARDIAL OXIMETRY, ISCHEMIA REPRO FUSION, BY INJECTS OR PLANNING CROCK CRYSTALS BUT WHEN IT COMES -- ROCK CRYSTALS BUT IN HUMAN SUBJECTS WE DON'T WANT TO DO IT FOR THE REASONS TOO, WE DON'T KNOW THE FULL TOXICITY PROFILE BECAUSE WE WANT TO LEAVE ANYTIME THE TISSUE. TUMOR GROWTH, OTHER THINGS YOU DON'T WANT -- TO MIGRATE AND BREAK DOWN THINGS LIKE THAT. SO WE WANT TO MAKE IT SAFE SO WE USE (INDISCERNIBLE) POLYMER WHICH IS KNOWN TO BE OXYGEN PERMEABLE, IF THEY APRO-FOR CLINICAL USE, WE USE THAT POLYMER TO IN CASE THIS CRYSTAL IS HOLDING THE CRYSTALS TOGETHER, THE PRODUCT THAT WE CALL ASOXI CHIP. SO BASICALLY CRYSTALS IN PDMS AND IT WORKS BY OXYGEN MOLECULAR OXYGEN DIFFUSING INTO THE POLYMER, INTO THE CRYSTAL AND MAKING THE PARAMAGNETIC EFFECT SO GAS BASED INTERACTION, OUTSIDE IN THE TISSUE THAT THE INTERACTIONS -- SO FEW MEASUREMENT DIRECT -- CONCENTRATION IT HAS NO EFFECT IT'S A PHENOMENA T 2 EFFECT BROADENING THAT GIVES YOU HUGE, DYNAMIC RANGE OF SOLUTION FOR OXYGEN MEASUREMENT AND IF YOU LOOK AT THE CALIBRATION, WHERE VICTIM MEASURED A FUNCTION EQUAL COLLABORATION IS ABSOLUTELY COLLABORATION THROUGHOUT AND AGAIN STABLE, DOESN'T CHANGE OVER TIME, LEFT IN THE TISSUE. SO WE ESTABLISHED, AGAIN BEFORE MOVING ON TO CLINICAL PLANNING IN HUMAN SUBJECTS, OF PATIENTS WE GET PRE-CLINICAL EVALUATION TO LOOK AT TOXICITY OVER LONG TERM AND ALSO ABILITY TO MAKE MEASUREMENTS SO WE TOOK RATS AND IMPLANTED IN THE RAT MUSCLE TISSUE AND WE CARRIED OUT THE MEASUREMENT FOR ONE YEAR. ON THE SAME AN MA'AMS. AND AGAIN AS YOU CAN SEE HERE THE RATE OF -- MEASUREMENT ON THE PARTICULAR TIME WHICH IS AROUND 25 MILLIMETER MERCURY, ALSO DO MUSCLE CONSTRICTION TO MAKE SURE IT IS REDUCING ANY DYNAMIC CHANGES IN THE OXYGEN SO WE DO THAT WHEN THE VALUE GOES DOWN, YOU CAN RESTRICT BLOOD FLOW TO MUSCLE, THEN WHEN YOU RELEASE IT GOES BACK AND WE CONTINUE THIS FOR ONE YEAR, YOU CAN SEE PRETTY MUCH THE DATA IS STABLE. THE DATA ANALYSIS TO LOOK AT THE TISSUE PRETTY MUCH THERE WAS NO TOXICITY OF ANYTHING. SO THAT'S CLINICAL EVALUATION, TO SUM UP. WHEN THE OXYGEN PROVIDES ABSOLUTE VALUE AND HIGHLY RELIABLE BECAUSE IT'S A SPECIFIC OXYGEN, THERE'S NOTHING ELSE IN THE BIOLOGICAL SYSTEM NITRIC OXIDE, BUT IT'S NOT LOW LEVEL, OTHER THAN THAT'S A VERY SPECIFIC MOLECULAR OXYGEN, RELIABLE, HIGHLY SENSITIVE TO HYPOXIA. IN THE ABSENCE OF OXYGEN NARROW PEAK, (OFF MIC) THIS METHOD HAS BETTER SENSITIVITY LOW PO2 WHICH IS PATHOPHYSIOLOGY SITUATIONS. ONE CAN DO REPEATED MEASUREMENTS SO ONCE IN THE TISSUES YOU CAN KEEP REPEATED SCANS AS LONG AS IT DOESN'T MOVE AWAY THINGS LIKE THAT, RESPONSIBLE TO DO IT, STABLE, PROVIDES ROBUST MEASUREMENT FOR LONGER PERIODS OF TIME. SO I'M GOING TO TALK ABOUT CLINICAL TRIAL GOING ON, (INDISCERNIBLE) HOSPITAL NOR THE PAST 200 YEARS OR SO. AGAIN, WE START OUT AND THINK ABOUT MANY APPLICATIONS, WE THINK ABOUT THIS RADIATION TUMOR RADIATION AS YOU MAY KNOW RADIATION DEPENDS ON TUMOR OXYGENATION, MOST SOLID TUMORS ARE HYPOXIC OR KNOWN MOSTLY HYPOXIC. HYPOXIA IN PIGS, RADIATION INDUCED DNA DAMAGE WHETHER I CLINICIANS RADIATION ONCOLOGISTS NEED TO KNOW, WHAT IS OXYGEN LEVEL, IS REASONABLE, REALLY BIOLOGICAL HYPOXIA SO YOU WANT TO KNOW WHAT THE LEVEL IS, SECOND, CAN WE INCREASE BY OXYGEN BY SOME OTHER THINGS AT THE TIME OF RADIATION, THIS IS A GROUP FORCE RADIATION CELL SO YOU NEED OXYGEN IN THE TUMOR AT SUFFICIENT LEVEL AT TIME OF RADIATION, NOT BEFORE OR NOT LATER. SO IT'S VERY IMPORTANT AT TIME OF RADIATION DOSE, WE TOOK THAT AS A PROJECT, WROTE IT UP SUBMITTED IT AND GOT FUNDING. AND THE FUNDING IS A PHASE 1 TRIAL, PHASE 1 SAFETY EFFICACY EPI GOOD FOR MEASURING OXYGEN CONCERN RATION IN THE TUMOR AND THEN -- CONCENTRATION IN THE TUMOR AND SAFE IMPLANTED PROBE TECHNOLOGY SUBSETS SO THAT'S OUR THINGS SO WE GOT IT FUNDED. ACCESSIBLE TUMORS BREAST HEAD AND NECK SARCOMA AND THINGS LIKE THAT. SO THAT'S HOW WE STARTED. AND AGAIN, THE CHIP THAT WE IMPLANT IN THE PATIENT IS SOMETHING LIKE A SOFT RUBBER BULLET BECAUSE ITEMED MOSTLY (INAUDIBLE) PDMS POLYMER, YOU CAN USE 18 GAUGE FOR EXAMPLE BRACHYTHERAPY NOODLE TO IMPLANT THE CRYSTAL IN DESIRED PART OF THE TUMOR, YET DO IT WITHOUT ANY GUIDANCE WE ALSO USE ULTRASOUND TO GUIDE FOR MACEMENT OF THE CHIP IN THE MIDDLE OF THE TUMOR. SO AGAIN IT'S A SMALL DENSITY, USING PULSE TECHNOLOGY, THE FREQUENCY WE USE, IS LIMITED 15-MILLIMETER DEPTH NOW SO IT'S A SUPER OFFICIAL MEASUREMENT SO IT'S POSSIBLE TO GO DEEPER THAN THAT. THIS SHAH WHAT WE'RE DOING NOW. WE PLANT THIS, AND HERE IS AN EXAMPLE HOW WE MEASURE USING EXISTING CLINICAL SCANNER IN THE LABORATORY SO WE PLACE PATIENT HERE SIGNED PREVIOUS TALK SO WE PLACE IT BY TUMOR. AND WE DO SCANNING OF OXYGEN. ADD IN FIVE SECONDS AND WE GO FIVE MINUTES TO LOOK AT THE BASE TUMOR PO2. ONCE WE KNOW THAT NEXT WE SEE WHETHER THE PO2 OF THE TUMOR RESPONSE TO HYPEROXYGEN GREETING. TEN MINUTES ACCORDING TO PROTOCOL AND YOU SEE WHETHER THERE'S EFFECT RESPONSE IN THIS CASE AS YOU CAN SEE ABOUT TWO TO THREE MILLIMETER MERCURY SEVERELY HYPOXIC. WHEN YOU GIVE OXYGEN BREATHING IT GOES UP. MORE THAN THERE'S A RESPONSIVE TUMOR HYPEROXYGENATION, THEN YOU STOP GIVING OXYGEN, IT SLOWS COMES BACK. THIS WILL GIVE A WINDOW OF PATIENT RADIATION HYPOXIA, YOU GIVE OXYGEN, THERE'S A WINDOW AFTER TURNING OFF THE -- WINDOW YOU CAN -- RADIATION. AN EXAMPLE THE MEASURE IS SO ACCURATE IN THESE VALUES BECAUSE IT'S HYPOXIA, SENSITIVITY IS HIGH, WHEREAS HIGH OXYGENATION YOU WILL SEE -- EACH ONE IS A SINGLE MEASUREMENT DOING CONTINUOUS SWEEP. SO THIS IS ANOTHER ONE IN MELANOMA. HYPOXIC, TWO MILLIMETER MERCURY, IN RESPONSE TO OXYGENATION, NOT AS MUCH AS OTHER TUMOR BUT YOU CAN SEE IT COMES BACK UP THERE. DO TUMORS ALWAYS RESPOND TO HYPEROXIA POSITIVELY? HERE IS AN EXAMPLE WHERE THERE'S ACC, WHERE IT IS HYPOXIC, SO THIS DOES NOT RESPOND TO HYPEROXYGEN IF YOU KNOW, THE CLINICIAN CAN THINK OF SOME OTHER MODALITY, INCREASE RADIATION DOSE SO THAT THAT WILL HELP GUIDE (INAUDIBLE). WHAT ABOUT THIS ONE? MELANOMA FOR EXAMPLE THIS TUMOR WHEN YOU GET HYPEROXYGENATION THERE'S A DROP IN TUMOR PO2 SO THIS IS GOING TO NEGATIVELY IMPACT THE OUTCOME OF RADIATION THERAPY SO IT'S USEFUL TO KNOW WHAT IS THE LEVEL AND HOW DOES IT RESPOND IN THE USUAL CASE AT EACH TIME SO THAT'S OUR FINDING WE WOULD LIKE THE MAKE UP FOR MAKE ALL THESE MEASUREMENTS. SO HERE IS REPEATED MEASURE. SAME PATIENT, SAME TUMOR, MEASURE WEEKLY BASIS EVERY TIME THE PATIENT COMES FOR RADIATION TREATMENT, SO WE LOOK AT IT USABILITY OF THE METHOD AS YOU CAN SEE HERE, THREE MEASUREMENT ON THREE DIFFERENT TIMES ON THE SAME CHIP BECAUSE IMPLANT ONCE, -- AND IN THIS CASE THE BASELINE IS STABLE, THE TUMOR RESPONDS TO HYPEROXYGENATION ALL THREE TIMES AND THAT'S WHAT YOU SEE HERE THAT SHOWS THE LIABILITY AND REPRODUCIBILITY FOR MULTIPLE TIMES. WE HAVE COMPLETED SO FAR 16 PATIENTS, 70 MEASUREMENTS AND SOME PATIENTS WE DID MULTIPLE MEASUREMENTS SO I WANT TO GIVE YOU AN IDEA CAN'T USE ONE SIZE FIT ALL APPROACH. YOU CAN SEE HERE THAT'S A RAID CROW BIOLOGICAL HYPOXIA. MOST TUMORS STUDY ACCEPT A FEW ARE HYPOXIC. NO DOUBT. LEVELS OF HYPOXIA. WHEN YOU GIVE OXYGEN THERE'S RESPONSE IN MOST TUMOR, BUT NOT ALL, SOME SORT OF VERY SMALL RESPONSE AND SOME EVEN NEGATIVE RESPONSE. ISM PRESSING THE POINT, YOU SHOULD -- IMPRESSING THE POINT YOU SHOULD MEASURE EACH TUMOR EACH TIME RADIATION THERAPY BUT THERE'S A SMALL COHORT NUMBER OF TUMORS BUT AT LEAST GIVES THE POINT, WE ARE CONTINUING THAT, STILL IN INITIAL PHASE OF RECRUITMENT, NUMBER, LEVELS OF HYPOXIA, AND HYPEROXYGENATION IS NOT PREDICTIVE. YOU CANNOT SAY BCC RESPOND, MELANOMA WILL NOT RESPOND, YOU CANNOT MAKE THOSE PREDICTIONS SO THIS DOES IMPORTANT OF HAVING A METHOD AND MEASUREMENT IN EACH TIME. WHEN THIS ADVANTAGE IS THAT YOU HAVE BEEN IMPLANTED SOMETHING SO IT BECOMES INVASIVE MINIMALLY INVASIVE, WHEN YOU PUT OXYGEN IN. THOUGH STABLE. REAL PO2 VALUE IN TYPE TISSUE. SO THAT'S GOOD. SO THE SECOND PART IS WE DEVELOP TECHNOLOGY FOR THOSE APPLICATIONS WE DON'T HAVE TO IMPLANT THE CHIP BUT RATHER LEAVE IT ON THE SKIN. I MISSED THE -- IN EVAN'S TALK, SO SIMILAR TO THAT BUT DEVELOPED TECHNOLOGY TRANSCUTANEOUS SO STICK THE CHIP, MEASURE IT AND PEEL IT OFF SO YOU GET OXYGEN MEASUREMENTS SO SHOW YOU A FEW SLIDES ON THAT, WHICH IS JUST COMPLETED, WE HAVE PRELIMINARY PATIENT STUDY VALUES I WANT TO SHOW YOU THE DATA ON THAT. THIS IS WHAT IT IS. WE CALL IT SPOT CHIP BECAUSE IT MEASURES SKIN PROFUSION OXYGEN TENSION, SPOT YOU APPLY STICKER TO THE SPOT. UNDER SKIN, THE CHIP IS NOTHING BUT THE SAME CHIP BUT MEASURE -- ABOUT 16-MICRON, CHEN YOU HAVE AN OXYGEN LAY IT ON IT SO THE CHIP IS COMPOSED OF THE TWO, SO IT NOT ALLOW AMBIENT OXYGEN TO GO TO THE CHIP, THE CHIP WILL ONLY RESPOND BECAUSE CHIP WILL BE PLACED ON THE SKIN SO THE OXYGEN WILL GO ON AND USE THE LINE BROADENING, OVER ALL ON TO THE SKIN, ONCE PLACE ON THE SKIN IT'S STABLE, THE WHOLE DAY OR TWO, THREE DAY YOU CAN MEASURE THREE DAYS AND BACK. IT'S STABLE AND YOU CAN FILL IT UP AND DONE. SO THAT'S A CHIP. YOU CAN NOT PLACE THE STICKER ON THE SKIN, WE CAN DO ONE THREE OR AS MANY AS YOU WANT, EACH ONE USE ONE DATA POINT. THE SIZE OF THE CHIP, THREE MILLIMETER, 1, 2, 3, 6, ANYTHING YOU WANT DEPENDING ON HOW -- HOW MUCH DO YOU WANT, THREE MILLIMETER, ONE MULTIPLE SITES, ON THE SKIN. IT IS A DATA COLLECTED FROM 85 MEASUREMENTS. ABOUT TEN VOLUNTEER, EIGHT VOLUNTEERS, HUMAN SUBJECTS, WHERE TO COME OVER A PERIOD OF SIXER MONTHS, EACH TIME BUT NEW CHIP ON MAKE AN MEASUREMENT SO THE ONE TWO THREE SUBJECT NUMBER, SO THAT'S DISTRIBUTION OF OXYGEN ON SUBJECT NUMBER ONE, SUBJECT NUMBER TWO, THREE, ET CETERA. AS YOU CAN SEE THERE IS A VARIATION IN EACH SUBJECT OVER PERIOD OF SIX MONTHS, WE TRY TO& PLACE THE STICKER EXACTLY IN THE SAME LOCATION BUT NOT EXACTLY BUT CLOSE BY. WE ALSO FOUND OUT NOT MUCH VARIATION EVEN FEW MILLIMETERS OR CENTIMETERS OFF. THAT'S THE DATA. YOU CAN SEE THAT'S A LESS SELF-INTRAPERSON VARIATION THAN INTERPERSON VARIATION SUGGESTING THAT THE DIFFERENCES ARE NOT DUE TO THE MEASUREMENT TECHNOLOGY BUT RATHER IN PERSON, THERE'S A SMALL NUMBER WE DON'T HAVE THE INFORMATION ABOUT THE PATIENT TO CONNECT TO. BUT OVERALL THERE'S THE SAME -- SEEMS TO BE AGE INFLUENCE HERE, BUT THAT'S NOT THE PART OF THE STUDY RIGHT NOW SO THESE ARE THE MEAN VALUES. AND THE STANDARD DEVIATION THE VALUES ARE IN THE RANGE 10 TO 25, THAT'S CLOSE TO NOD TISSUE VALUE, SLIGHTLY LOW HE WERE AND SECOND THING MOST IMPORTANT THING THAT I DIDN'T MENTION IS THESE MEASUREMENTS WERE DONE AT ROOM TEMPERATURE. THAT'S USED IN THE CLINIC. YOU FEED THE SKIN TO 40 TO -- KEEP IT CONNECTED TO THE DEVICE ALL THE TIME. HERE THE PERSON IS FREE TO MOVE AROUND. MEASURED ROOM TEMPERATURE, NOT TEMPERATURE SO THERE'S NO PERTURBATION TO THE TRANSCUTANEOUS OXYGEN IN THIS CASE. WHAT ABOUT CHANGES TO THE FLOW? THAT'S WHERE THE GOAL OF THIS MEETING COMES WHEN INFUSE TRANSFUSE, THERE'S A CHANGE, WILL THIS BE ABLE TO RECOGNIZE FOR EXAMPLE WE PUT A CHIP IN HERE AND BASE IS AROUND 23-MILLIMETER MERCURY, AT THAT POINT WE DID CONSTRICTION USING -- THEY CAN SEE IMMEDIATELY THE VALUE GOES DOWN DEGREES. RESPONSE TO CONSTRICTION OF BLOOD FLOW TO THE LEG. AND AGAIN, AT THIS POINT YOU SEE INCREASE GOING BACK IN SOME CASES SO NICELY DEMONSTRATES THE OXYGENATION. BASE VALUES HERE, GOES DOWN WHEN YOU APPLY A CUFF AND INFLATE 180-MILLIMETER MERCURY AND WHEN THE FLOW IS -- CONSTRICTION IS RELEASED, IT SHOOTS UP, SOME HYPEREMIA, AGAIN AT THIS POINT WHEN THE SUBJECT WAS GIVEN 100% OXYGEN BREATHING YOU CAN SEE FURTHER INCREASE IN THE TRANSCUTANEOUS OXYGEN. THAT'S WHERE USING THE TECHNOLOGY CAN BE USED FOR THE PURPOSE THAT THIS MEETING IS FOR. WITHOUT RELIABILITY ON OXYGEN AND NO BACKGROUND. THIS IS ABOUT THE PROBES AND WHERE WE GO NOW. WE USE THE CLINICAL SCANNER IN THE EPR CENTER OR IN THAT ROOM, VOLUNTEER HAS TO BE TAKEN TO THAT ROOM, PLACED WITH A MAGNETIC -- ALSO WORKING ON THE TECHNOLOGY TO MINIATURIZE THE WHOLE THING, EVEN IMPLANTABLE DEVICE INCLUDING MAGNET, SO MEASUREMENTS ARE DONE BY THE WEBSITE OR OFFICE PROCEDURE ROOM, YOU DON'T HAVE TO TAKE SUBJECT TO EPR ROOM, THAT'S WORKING WITH FUNDING FROM NIBIB AND WE HAVE ALMOST GOT A PRODUCT WORKING PRODUCT FURTHER SPOT CHIP TRANSCUTANEOUS APPLICATION WILL BE CONDITION USING THE DEVICE THAT SIMPLE, SOMETHING ELSE NECESSARY, THAT HAS MAGNET ATTACHED TO THE SPOT. SO THAT'S WHAT WE'RE WORKING ON NOW, TO MINIATURIZE THE DEVICE BY READING OXYGEN CONCENTRATION. WITH THAT I THANK YOU FOR YOUR ATTENTION AND THANK THE FUNDING AGENCY FOR MAKING THIS POSSIBLE. THANK YOU. [APPLAUSE] >> LAST BUT NOT LEAST, THE LAST PRESENTATION BEFORE THE DISCUSSION IS BY DR. (INAUDIBLE). THANK YOU. >> THANK YOU FOR INCLUDING WORK IN THIS WORKSHOP. WE CAN GET MOPTORRING EFFICACY OF BLOOD TRANSFUSION. I'M FROM THE INTRAMURAL RESEARCH PROGRAM OF NCI WHERE OUR FOCUS IS JUST LIKE THE SPEAKERS BEFORE ME TO MONITOR TUMOR OXYGEN. THE DIFFERENCE BETWEEN MY AND THEIRS IS I INFUSE A PARAMAGNETIC PROBE WHICH DISTRIBUTES AND I OBTAIN THREE DIMENSIONAL MAPS, IN PARTICULAR TUMOR OXYGEN AND WITH TEMPORAL RESOLUTION AFTER TECHNIQUE WE HAVE DEVELOPED WE CAN ALSO PROBE SOME FLUCTUATIONS IN THE TUMOR AND ALSO RESPONSES TO MANIPULATIONS MAKE IN THE BREATHING GAS ON THE TUMOR OXYGENATION. ONE THING I WOULD LIKE TO ADD TO THE SPEAKERS BEFORE WE, IS I CALL IT LOW FIELD MAGNETIC RESONANCE WHICH IS EPR BUT ONLY DIFFERENCE AT GIVEN FREQUENCY WE PRACTICE EPR NMR MRI. THE MAGNETIC FIELD OF EPR HAS ABOUT 660 TIMES LOWER BECAUSE MAGNETIC MOMENT THAT MUCH STRONGER. SO FOR EXAMPLE, 300 MEG HERTZ NMR MRI YOU NEED A 7 TESLA MAGNET FROM EPR TESLA MAGNET INHERENTLY CAPABLE OF BEING MINIATURIZED. THIS IS MY GROUP, ALSO GO THROUGH MY DISCLOSURES. I'M A PI AND IN NCIG AND ALSO ISSUE PATENT WITH GER TRANSPORT MAGNET TO CARRY POLARIZE AND MAYBE PENDING APPLICATION WHERE WE HAVE AN ALGORITHM FOR -- MY TALK IS GOING TO BE DISCUSSING THE EPR IMAGING SYSTEM, WHICH IS GOING TO -- I DIDN'T PERSONALLY ATTEND THE WORKSHOP YESTERDAY OFFICE ALL THE TALKS. I SAW A LOT OF DISCUSSION USING LACTATE AS A SURROGATE FOR OXYGEN. WE HAVE A TECHNIQUE IN OUR LAB, PRE-CLINICAL AND CLINICAL. WHERE WE CAN MONITOR THE COMMERCIAL OF PYRUVATE LACTATE, WHICH WILL BE A SURROGATE OF THESE METHODS, WE PLAN TO STUDY NEURON ONCOLOGY NEUROLOGY AND CLINICAL CASES FOR THE GLYCOLYSIS WARBERG EFFECT AND DISTINGUISH SO THESE TOOLS TAKE MOST OF MY TIME, AND THEN PORTABLE EPR SYSTEM FOR LONG TERM PO2 MONITORING WHICH I HAVE A FEW SLIDES TO MAKE MYSELF RELEVANT TO THIS WORKSHOP. CANCER TREATMENT MOST OF IT IS THROUGH (INAUDIBLE) KEY TARGET AND PATHWAYS. NOWADAYS THERE'S ALSO A LOT OF INTEREST IN THERAPIES TARGETING THE TUMOR MICROENVIRONMENT, ESPECIALLY THE METABOLISM AND PHYSIOLOGY WHICH WE HAVE ACTIVE PROGRAMS, MY GROUP AN INTRAMURAL PROGRAM SO HERE MOLECULAR IMAMMING OFF THE TUMOR ENVIRONMENT CAN PLAY A ROLE SELECTING APPROPRIATE TREATMENT AND MONITORING TREATMENT RESPONSE. SO THIS IS WELL KNOWN DIAGRAM OF CELLS OF GLUCOSE TAKEN IN. AND WE CAN TAKE FEW STEPS DOWN YOU HAVE PYRUVATE WHICH CAN ENTER THE CENTS CYCLE AND GENERATE ATP AND THE BY-PRODUCT IS CARBON DIOXIDE OR THE WARBECK PHENOTYPE YOU GET LACTATE. IN MY LAB I CAN IMAGE OXYGEN, I CAN IMAGE THE KINETICS OF CONVERSION OF LABELED PYRUVATE, LAKE AT A TIME. I CAN MEASURE THE KINETIC IT IS OF PYRUVATE UTILIZED THROUGH THE PCO CYCLE, ATP AND THE BY-PRODUCT CARBON DIOXIDE IS SOMETHING I CAN MEASURE, I CAN MEASURE OXYGEN SO THESE ARE THE THREE TECHNIQUES IN MY LAB. SOME OF THEM CLINICAL AND PRE-CLINICAL, SOME OF THEM AT THE VERGE OF BEING TRANSLATED CRITICALLY. SO YOU ALL KNOW THAT IN WELL DIFFERENTIATED TISSUE, GLUCOSE IS BURNED TO THE PRESENCE OF OXYGEN TO GENERATE ATP AND YOU HAVE BY-PRODUCT OF CARBON DIOXIDE. BUT WHEN YOU HAVE NO OXYGEN, YOU HAVE MOSTLY AN AEROBIC GLYCOLYSIS WITH LACTATE AS BY-PRODUCT. BUT IN CANCER, ABOUT 85% OF GLUCOSE IN THE PRESENCE OF OXYGEN, IS CONVERTED TO LACTATE SO THIS IS WHAT IS WELL KNOWN AS THE WARBERG PHENOTYPE AND HOW CAN WE USE IMAGING ESPECIALLY CARBON LABELED MRI, DESCRIBE A TUMOR WHERE THE ENERGYETICS ARE GOING THROUGH AEROBIC OXIDATIVE PHOSPHORYLATION OR AEROBIC GLYCOLYSIS. SO MEASURING TISSUE, THIS IS TOPIC WELL PRESCRIBED BY THE SPEAKERS BEFORE ME. OXYGEN HAS TWO UNPAIRED ELECTRONS SO IT IMPOSES WHAT IS WELL KNOWN AS A T 2 CONTRAST ON A PARAMAGNETIC PROBE IF WE HAVE ONE ENDOGENOUS. UNFORTUNATELY, OR FORTNALLY WE DON'T HAVE ANY ENDOGENOUS PROBES WHICH I WILL GO FOR DETECTING IMAGING SO WE YOU HAVE ABUNDANT WATER, 55 MOLAR WALKER, 110 MOLAR PROTONS SO TISSUE PROTON HAS HIGHEST MAGNETIC AND VERY STABLE SO WE HAVE ABUNDANCE FOR MRI, FROM EPR, LEARNING FROM, MANYRI EXPERIENCE WE CANNOT USE METAL THERE IS IN THE BODY BUT BECAUSE OF SIGNALS YOU CAN RECOVER IN IN LIQUID TEMPERATURES. FREE RADICALS ARE THERE IN THE IMMUNE SYSTEM SO WE DON'T HAVE ENOUGH AND THEY DON'T LIVE LONG SO E NEED A TRACER SO WE NEED A TRACER EXOGENOUS, DESCRIBED 1900 BY CHEMIST IN MICHIGAN, EVEN WITHOUT AVAILABLE CHEMISTRY RESOURCES ENGINEIOUS CHEMIST, HE DESCRIBED ELECTRONIC STATE OF THIS MOLECULE AS FREE RADICAL. SAYING THE RESEARCH IN THIS FIELD WILL CONTINUE AND I RESERVE THE FIELD TO MYSELF BUT THE INDUSTRY DOESN'T READ PAPERS SO HE TOOK THIS MOLECULE, VARIED IT SIGNIFICANTLY SO ITs WATER SOMABLE AND THE TOXIS -- SOLUBLE AND THE TOXICITY IS AVAILABLE FOR HUMAN USE FOR DIFFERENT APPLICATION. IT'S LIKE THE PARTICLES DESCRIBED BY THE TWO SPEAKERS BEFORE ME, RESPONSE TO OXYGEN IN SIMILAR MANNER YOU HAVE BROADENING AND IF YOU CAN INJECT THIS MOLECULE AT DOSES WHICH ARE NON-TOXIC, AND USING THE MAGNETIC FIELD RADIUS LIKE MRI WE CAN FOLLOW THE DRIBS AND FROM THE DISTRIBUTION YOU CAN SEE HOW MUCH RADICAL AT EACH PLACE AND WHAT IS THE LANGUAGE AND FROM THAT LANGUAGE WE CAN CALIBRATE WITH CALCULATION TO GET ABSOLUTE PEER MEASUREMENT, BASED ON THAT MY LAB HAS COME POINT LEVEL MANUFACTURED EPR SYSTEM WORKK AT 300 MEGAHERTZ, THIS IS A RESONATOR EXPOSED TO MAGNET AND FREQUENCY 300 MEGAHERTZ, HERE IS THE TOOL BEARING LEG AND NORMAL LEG AND THESE ARE TWO TUBES CONTAINING RADICAL AS POSITIONAL MARKER. THIS SCALE IS ABSOLUTE PO2, JUST REALLY MAKING THE MERCURY, SIGH THE TUMOR HAS POOR HOMOGENATE IN PROFUSION REFLECTED IN HIGH AREAS OF HYPOXIA AND SOME REGIONS OF HIGH OXYGEN. SO WE DON'T HAVE ANATOMIC INFORMATION AVAILABLE FROM EPR SO WE PUT THE WHOLE THING IN ANOTHER -- TAKE IT TO SEVEN TESLA MAGNET WITH THE SAME FREQUENCY, SO WE DON'T HAVE TO REMOVE THE OBJECT BY IMAGING AND WE HAVE NOW ATOMIC IMAGE FROM MRI AND CAN FUSE THESE TWO IMAGES SO WE HAVE APPEAL ANATOMICALLY CORRECT. SO AFTER DOING THIS WE SAID WHAT ARE THE APPLICATIONS. ONE APPLICATION IS CAN THE CHANGES IN TISSUE OXYGENATION BY EPR WHERE THIS IS ANATOMY AND THIS IS A TUMOR BEARING LEG, NORMAL LEG, THIS IS WHEN THE MOUSE WAS BREATHING ROOM AIR WHERE WE CAN SEE THERE'S OXYGENATION, WHEN IN THE TUMOR BUT SOME REGIONS OF HYPOXIA. BUT WHEN WE MAKE THE MOUSE BREATHE CARBON, 95% OXYGEN WE HAVE SIGNIFICANTLY INCREASED THE OXYGENATION OF THE TUMOR AND CAN MAKE THE HISTOGRAM AND SEE BEFORE IT WAS BREATHING THIS IS THE HISTOGRAM, IT WAS BREATHING SHIFTED TO THE RIGHT. WE CAN ALSO MINIMIZING THE IMAGING, TAKING A SNAP SHOT EF THREE MINUTES WE CAN LOOK AT TRACER LEVEL MAPS IN TUMOR AFTER WE HAVE INJECTED ONCE THE TRACER AND WE CAN SELECT FOUR REGIONS SEE TRACER LEVEL CHANGES AND WHAT ARE OXYGEN FLUCTUATIONS IN TUMOR UX YOU CAN SEE THE TRACER LEVEL IN THIS TIME WINDOW IS FAIRLY UNIFORM, THOUGH DIFFERENT IN EACH REGION, THIS REGION, REGION 4 CENTRAL TUMOR IS DIFFUSION LIMITED HYPOXIA, WHEREAS REGION ONE YOU CAN SCENIC WEIGHS WHICH ARE WIDE, 52 HYPOXIA WHERE THE WHOLE TUMOR BIOLOGY IS DIFFERENT THAN THIS REGION COMPARED TO THE DIFFUSED LIMITED HYPOXIA. WE CAN ALSO LOOK AT CHALLENGES TO SEE IF WE CAN IMPROVE OXYGENATION DIFFUSION LIMITED REGION WHERE IS WE MAKE THE ANIMAL BREATHE AIR FOLLOWED BY CARBO GENERAL AND AIR AND WE CAN SEE WE CAN MAKE CHANGES AND ALSO DISTINGUISH WHICH ARE THE REGIONS WE ARE REAL DIFFUSION LIMITED HYPOXIA. SO THESE ARE SOME TYPICAL EXAMPLES WE CAN USE WITH EP, ARE. SO WE HAVE NOW THIS IS A SLIDE FROM MY CLEANING WHO COULDN'T BE AT THIS WORKSHOP. HOWARD -- FROM UNIVERSITY OF CHICAGO, RADIATION ONCOLOGIST AND SPECTROSCOPIST. HE USED THIS TO BOOST RADIATION THE REGION WHICH IS PRE-DETERMINED FROM EXMANGE EXPERIMENTS AS HYPOXIC AND BOOST RADIATION SURVIVAL IN THIS FROM THE KAPLAN MEYER ANALYSIS, HE SHOW THAT KNOWLEDGE OF HYPOXIA BEFORE TREATMENT IS VERY USEFUL IN PLANNING RADIATION THERAPY. SO NOW THE QUESTION IS CAN APRIORI TUMOR HYPOXIA TREATMENT IN THE CLINIC. I HAVE TAKEN METABOLIC MRI OF HYPERPOLARIZED PYRUVATE IN TESTING THE -- AND TREATMENT RADIATION HYPOXIA ACTIVATED -- THESE ARE THE THREE TUMOR WHERE IN VITRO WE HAVE DONE PROFILE USING THE EXTRA CELLULAR ACIDIFICATION RATE AND OXYGEN CONSUMPTION RATE AND WE FIND THAT THIS TUMOR LINE IN VITRO IS GLYCOLYTIC AND THIS IS AT LEAST OF THE THREE. IN VITRO, THIS IS THE MOST -- THIS IS THE LEAST. WE HAVE THIS INFORMATION, NOW WE IMPLANT TUMORS IN VIVO ON THE HIGHER WE GET ANATOMIC, YOU CAN TARGET OXYGEN IMAGE, YOU CAN SEE THE TUMOR HIGHLY GLYCOLYTIC AT CELL LANE AND LARGE AREA HYPOXIA, ABOUT 50 PERSONS FOR TUMOR IS HYPOXIC COMPARED TO THIS TUMOR THE HYPOXIC VOLUME IS 25%. WE CAN USE -- THIS SEQUENCE IS COMING OPPOSITE BUT WE CAN BASED ON THIS INFORMATION WE CAN TAKE WHERE WE HAVE A HYPOXIC SENSOR, WHICH IS CONVERTED TO THE ION RADICAL WHEN THERE'S OXYGEN IT GOES BACK AND INTEGRATES BUT WHEN THERE'S NO OXYGEN IT BREAKS DOWN TO RELEASE THE TOXIN AND YOU CAN SEE WHEN THERE'S LESS OXYGEN THERE'S FOUR LOGS OF IC 50 LOWER IC 50 WHEN THERE'S LESS OXYGEN SO WE USE THIS -- THE IDEA IS TO COMBINE WITH SEW TAKE CARE OF CANCER CELLS IMMEDIATELY NEXT TO THE CAPILLARY AND THIS MOLECULE SURVIVE FROM TRANSIT AND REACH THERE. SO OUR INFORMATION WHERE WE HAVE PRE-TREATMENT HYPOXIC VALUES IN THIS HYPOXIA VALUES THIS BEING MOST HYPOXIC POINTS WELL TO THE HYPOXIC ACTIVATED AND RADIATION (INAUDIBLE) SO WE HAVE THEREFORE A CAPABILITY OF IMAGING AND WHERE WE HAVE SHOWN BOOSTING RADIATION TO HYPOXIC REGENERALS REALIZE BETTER SURVIVAL AND THIS IS NOW ACCESSIBLE FOR HUMAN USE FOR LOCAL IMAGING OF PO2 AND PROSTATE BREAST HEAD AND MENTION. WHAT WE ARE TRYING IS TO SEE IF WE CAN GET DEEPER INSIDE ORGANS SUCH AS PANCREAS. NOW I -- I THINK I HAVE A FEW MORE MINUTES. SO THIS IS A TECHNIQUE WHICH IS NOW AVAILABLE IN THREE OR FOR LABS IN THE US. FROM WE CLICKLY TRANSLATED ITSELF TO HUMAN USE FROM PRE-CLINICAL AND NCI IS ONE OF THOSE PLACES WHERE MY LAB WE HAVE A PRE-CLINICAL SYSTEM AND CLINICAL SYSTEM. ONE MORE AT UCSF, ONE AT MEMORIAL SLOAN-KETTERING AND I THINK UCON HAS ONE AND UT SOUTH WESTERN. BUT BASICALLY, TO GIVE YOU AN IDEA OF WHAT ARE THE RELATIVE DIFFERENCES IN SENSITIVITY OF MRI FOR EXAMPLE, WATER AS WE ALL KNOW WORKS AS CARBON 13. YOU CAN SEE THIS COLUMN, FOR THE SAME CONCENTRATION WE HAVE FOUR ORDERS MAGNITUDE LOWER SENSITIVE TOY TO CARBON IMAGING, PUT IN THE CONCENTRATION 55 MOLAR VERSUS 100 MILLIMOLAR TRACER AND LOWER SENSITIVITY. SO TO IMAGE CARBON 13 LABELED MOLECULES, WE HAVE A GAP -- SENSITIVITY BUT ADVANTAGE OF IMAGING CARBON 13 AS YOU CAN SEE YOU CAN INJECT THE TRACER, OFTEN LABEL THE SPECIFIC SIDE AND YOU CAN MONITOR CONVERSION BASED ON DIFFERENCES BETWEEN ONE INJECTED AND VARIOUS METABOLITES. PROVIDED YOU CAN BRIDGE THIS GAP. SO PYRUVATE IS ONE MOLECULE, WHICH HAS -- I DON'T WANT TO GO INTO THE HYPERPOLARIZATION OF PHYSICS BUT TO LET YOU KNOW PYRUVATE ACID AT ONE OR TWO POSITION HAS IDEAL FEATURES FOR IT TO BE POLARIZED. SO HOW DO WE DO IT, BNP POLARIZATION, WHAT WE DO IS TAKE THE PYRUVATE ACID AT CERTAIN CONCENTRATION, ONE OR TWO MOLAR AND DISSOLVE ALONG WITH THE RADICAL I SHOWED YOU USED FOR EPR AND FREEZE IT SO A TEMPERATURE. KEEP IT THERE. FOR ABOUT ONE HOUR AND IN A MAGNETIC FIELD AND IRRADIATE WITH EPR FREQUENCY AT THE CORRESPONDING MAGNETIC FIELD RESONANCE AND IRRADIATE ONE HOUR. THAT IS SIMPLE, TRICK IS WE HAD TO DISSOLVE AFTER AN HOUR DISSOLVE -- WE HAVE TO TAKE THE FROZEN AND DISSOLVE WITH A BUFFER AND DIGESTING THE PH AND BRING IT BACK TO ROOM TEMPERATURE. AND PRESERVING THE HYPERPOLARIZED STATE. SO THIS IS THE TECHNOLOGY BARRIER OVERCOME BY G BUT IF YOU CAN DO THAT YOU CAN SEE THE SPECTRUM OF PYRUVATE WHICH IS IN BLUE. AND LACTATE WHICH IS HERE. AND BICARBONATE WHICH IS THERE AND ALANINE. SO BICARNATE REFLECTS OXIDATIVE PHOSPHORYLATION. SEW WE -- SO WE CAN DISTINGUISH THE PROCESSES BY SENSITIVITY GAP. THIS IS AN EXAMPLE SHOWING HOW POWERFUL THE HYPERPOLARIZATION TECHNIQUE IS. THIS IS UREA, A SIGNAL FIVE OR ABOUT -- 65 HOURS OF -- HYPERPOLARIZATION IN SAME SAMPLE, ONE SECOND YOU HAVE 10,000 FOLD ENHANCEMENT OF SIGNAL ODDS RATIO. THIS IS A PRE-CLINICAL HYPERPOLARIZE IN MY LAB, YOU HAVE TO DISSOLVE EVERYTHING AND QUICKLY TAKE THE SAMPLE TO THE MRS OTHERWISE WE USE THE POLARIZATION OF THE CARBON. SO IN SUCH CASE WE CAN FLOW WARBURG. ONCE YOU INJECT YOU HAVE TWO MINUTES TO IMAGE, ONCE DISSOLVED YOU NEED SOMEBODY TO RUN FAST TO THE SCANNER. SO WE CAN DO IT IN OUR CLINICAL SCANNER IN 17 SECONDS SO WE HAVE OFFERED A POSITION TO USAIN BOLT. SO THESE ARE ALL THE MOLECULES Z CANDIDATES BEING LOOKED AT, I DON'T WANT TO SPEND TOO MUCH TIME, VARIOUS PATHWAYS WHICH ARE POSSIBLE TO PROBE. BUT FDA APPROVAL PYRUVATE LEVEL AT ONE AND TWO POSITIONS THIS ENTERS THE KREB CYCLE AND REPORTS A FEW MORE STOPS. WARBERG EXIT IT IS CENTS CYCLE SO YOU -- AND HERE IS ONE STUDY WHERE WE HAVE TAKEN RENAL CELL FARCER CARCINOMA, AS A XENOGRAPH AND LOOKED AT THE LACTATE AND PYRUVATE BEFORE AND AFTER TREATMENT YOU CAN SEE IT HAS RESPONSE, BEFORE THEY SHARE TUMORS YOU CAN SEE A BICHEMICAL RESPONSE EARLY IN TREATMENT. SO FOR THE GROUPS INTEREST HERE, THAT HAVE TAKEN A PIG MODEL, WHERE THEY HAVE INJECTED -- WE HAVE -- WHERE THEY HAVE INDUCED FOCAL ISCHEMIA, AND YOU CAN SEE THIS LACTATE ALANINE. IF YOU SEE BICARBONATE, THE ISCHEMIC REGION IS YOU HAVE LOST THE BICARBONATE WHICH REFLECT IT IS MITOCHONDRIAL ACTIVITY AND WHEN THE ISCHEMIC PERIOD IS LONG YOU HAVE SEEN LOSS OF MITOCHONDRIAL ACTIVITY IN THE WHOLE REGION. ONE REGION CARDIOVASCULAR RESEARCH. WE HAVE TAKEN THE THREE TUMORS. ONE GLYCOLYTIC VERSUS OX AND WE HAVE EQUIVALENCE OF PO2 VERSUS LACTATE PRODUCTION SUGGESTING THAT C 13 MRI CAN REPORT HYPOXIA AS SURROGATE OF -- USING THE SURROGATE OF GLYCOLYSIS. THIS IS THE FIRST HUMAN STUDY AT UCSF, WHERE THIS IS A PROSTAE WHICH IS NORMAL AND THERE'S A PROSTATE WHICH HAS BEEN -- FROM BIOPSY CHARACTERIZED MALIGNANCY, YOU CAN SEE NOVEL PROSTATE PYRUVATE REMAINS WITHOUT BEING CONVERTED LACTATE AND HERE YOU CAN SEE THE LACTATE. SO THIS IS THE FIRST STUDY WHICH HAS BEEN PUBLISHED BY THE UCSF GROUP AND THIS IS ANOTHER STUDY WHERE (INAUDIBLE) LOOKS NORMAL, THIS WAS BIOLOGY SHY PROVEN PROSTATE ONCE SUBJECT IS SCANNED BY C 13 YOU CAN SEE ORGANS AND LATER BIOPSY SHOWED THIS IS IMAGE GUIDED, THIS ALSO HAS MALIGNANTS. SO SLIDE, I HAVE A FEW MORE MINUTES. WE HAVE COLLABORATED WITH A NEUROLOGY INSTITUTE IN OUR CAMPUS, WHERE THEY HAVE MADE A WIDE PROBE PARAMETRIC AMPLIFICATION WHICH IN PRINCIPAL MINIATURIZED TO SUBMILLIMETER -- WE PUT THE OXYGEN SENSING CRYSTAL DESCRIBEDDED BY THE TWO SPEAKERS BEFORE ME, PDMS AND WE HAVE STERILIZED THE WHOLE SYSTEM AND THERE ARE NO LEADS TAKEN OUT SO WE CAN PUT IT IN THE TISSUE AT THE REGION OF INTEREST AT ANY DEPTH BECAUSE THE RADIATION PENETRATES LIKE TESLA MRI. AND THE LINE THAT -- OF COURSE IN OXYGEN, BY HAVING A SURFACE, THIS IS A HARMONIC SURFACE PILE, AMPLIFIES 10 TO 15 FOLD. YOU CAN PUT A TINY CRYSTAL WITH WIRELESS AMPLIFIER AND WE CAN SEE THESE THAT THERE'S NO POST RESPONSE TO THIS IMPLANTATION OVER PERIOD OF TIME. WE CAN OVER SEVERAL WEEKS MONITOR OXYGEN WHEN READING ROOM AIR, SO WE CAN DO IT SEQUENTIALLY AND THIS WHAT WE LEARNED IS NEVER CAPABLE MALE MICE THE SAME OF THE FIGHT. SO SOME OF THIS MOUSE WAS KILLED BY OTHER -- SO YOU HAD TO TERMINATE THE STUDY T HAVE SPEAKERS BEFORE WE SHOWED, THIS CUB DONE OVER SEVERAL YEAR YODS, SEVERAL WEEKS OR YEARS AT A TIME. AND IN PRINCIPLE, EPR BEING LOW MAGNETIC FIELD TECHNIQUE WE CAN PUT A MAGNETIC BRICK WHICH IS A PERMANENT MAGNET, IMPLANT THE RESONATOR AND CRYSTAL LUNG AND WE CAN HAVE SIGNAL COMING TO THE EPR SYSTEM WHICH CAN BE MINIATURIZED, WE CAN READ THE SIGNAL AND SCOPE WHERE NARROW LINE SHOWS ISCHEMIA, HYPOXIA, NORM OXIC AND IT CAN BE INFERENCE OF MINIATURIZED. THANK YOU FOR THE INVITATION TO PARTICIPATE IN THIS WORKSHOP. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> IN CASE PEOPLE ARE HYPOGLYCEMIC WE'LL GIVE YOU SECH MINUTES TO GO TO CAFE AND GET COOKIES, WHATEVER YOU NEED THEN START AGAIN PROMPTLY AT 11:45. WE'LL HAVE THE FINAL DISCUSSION AND SEE WHAT IDEAS WE CAN COME UP WITH. THANK YOU. SEE YOU IN SEVEN MINUTES. I'M HOPING FOR AS ROBUST OR MORE ROBUST A CONVERSATION TODAY AS WE HAD YESTERDAY. I'M ALSO TAKING THE SPEAKERS OR THE CHAIR'S PREROGATIVE, SINCE MY CO-CHAIR FLEW THE COOP SHE CAN'T DISAGREE WITH ME. UNFORTUNATELY SIMONE HAD TO LEAVE EARLY AND SHE APOLOGIZES BUT I WILL TRY TO END BY 12:45 AT THE LATEST RATHER THAN END AT 1:00. BEFORE WE START THE CONVERSATION THERE'S A COUPLE OF THINGS TO SAY. ONE IS THE GOAL OF THE MEETING IS NOT TO BE THE END BUT TO BE THE BEGINNING. AND THE GOAL WAS TO STIMULATE PEOPLE'S THOUGHT PROCESSES, TO GET CROSS FERTILIZATION FROM PEOPLE WHO DON'T GO TO SAME MEETINGS AND TALK THE SAME THINGS. ALL OR AT LEAST INITIAL GOAL OF TRYING TO GIVE SOME IDEAS AND SOME ADVICE TO NHLBI TO WHAT MIGHT BE FRUITFUL AVENUES FOR FUTURE STUDIES. NOT JUST FROM THE SELFISH VIEW OF YOUR OWN STUDIES THE MOST IMPORTANT RFP FUNDS EXACTLY WHAT YOU DO. OR WHAT I DO. BUT TO STILL LATE CROSS FERTILIZATION TO SEE IF THERE CAN BE SOME SYNERGIES TO MOVE THE FIELD FORWARD. SECONDS THING, THE FOCUS OF THESE MEETINGS WAS THESE QUESTIONS WHICH I DON'T THINK HAVE BEEN ANSWERED WHICH IS FINE BUT WE HAVE HAD LOTS OF THOUGHTS ABOUT THEM AND AROUND THEM. THE SPEAKERS AND MARGARET AND SIMONE AND I WILL SPEND A LOT OF EFFORT TO SEE IF WE CAN GET SOME OF THESE IDEAS ON PAPER TO ADDRESS THESE QUESTIONS. THERE WILL BE A PAPER COMING OUT OF THIS BECAUSE WE'RE ALL ACADEMIC SO WHAT DO PRODUCE, PAPERS. BUT IT SHOULD FORM A BASIS FOR NHLBI RECOMMENDATIONS. AND IF THE SPEAKERS ARE WILLING WE EXPECT THEY WILL BE CO-AUTHOR ON THIS PAPER AND THE PRICE PRICE IS TO SEND HALF A PAGE AT MAXIMUM SUMMARY ADDRESSING WHAT YOU SAID HOPE ANY ADDRESSING THESE QUESTIONS WHICH MARGARET AND SIMONE AND I WILL EDIT AND SEND BACK TO PEOPLE FOR THEIR COMMENTS. I WOULD ALSO SUGGEST THAT IF ANYONE IN THE AUDIENCE -- WEE NOT TRYING TO BE EXCLUSIVE, IF YOU WANT TO PARTICIPATE IN THE PAPER, BY HELPING PROVIDE IDEAS EDITING OR THOUGHTS AND WE WELCOME THAT, EMAIL US AND TELL US YOU'RE INTERESTED. >> TELL US THE LENGTH. >> HALF A PAGE. WE HAVE 20 SOMETHING SPEAKERS AND WHETHER WE CON SUNDAY PUBLISHING TRANSFUSION MEDICINE REVIEWS OR RICK HAUFMAN PUBLISHING IN TRANSFUSION THERE'S PAGE LIMITATIONSES SO THE GOAL IS NOT PUBLISH 20 PAPERS IN A SPECIAL VOLUME, GOAL IS TO SUMMARIZE THE MEETING WITH RECOMMENDATIONS FOR FUTURE STUDIESES SO E WANT EACH OF YOU TO SUMMARIZE YOUR THOUGHTS ABOUT WHAT YOU DO, HOW IT RELATES TO QUESTIONS AND HALF A PAGE OR LESS. HARD FOR ACADEMIC TO FOCUS OUR THOUGHTS ON BUT THAT'S REQUIREMENT AND CHALLENGE IF YOU DON'T DO THAT I'LL DO IT FOR YOU. YOU PROBABLY WON'T LIKE THE WAY I WILL EDIT EXACTLY. BIRD BY BIRD. ARE THERE QUESTIONS OR COMMENTS ON THAT? MARGARET, DO YOU WANT TO ADD THE THAT? >> REGARDING THE PAPER YES WE WANT HALF A PAGE FOR SUMMARIES FROM YOUR PRESENTATIONS BUT THEN ALSO IN A DIGS AND BULLET POINT FORMAT RECOMMENDATIONS OR SOME OTHER SUGGESTIONS THAT COME TO MIND FROM EITHER DISCUSSION OR WHAT YOU WOULD LIKE TO GET ACROSS, THEN WE CAN ALSO USE THAT TO COLLATE AND MAKING THE RECOMMENDATIONS. THANK YOU. >> YES, MA'AM. USE YOUR MICROPHONE. >> ANY OF THE NEONATOLOGISTS PERINATOLOGISTS, FETAL MEDICINE, CRITICAL CARE FOLKS, WE ALSO HAVE BEEN INVITED TO SUBMIT TO PEDIATRIC RESEARCH. A SMALL COMMENTARY IN PARTICULAR THEY HAVE SUBSTANTIVE INTEREST IN OBVIOUSLY OXYGENATION IN THE NEONATAL AND CRITICAL CARE AREAS AND SO ANY WHO WANT TO PARTICIPATE, SEND ME AN EMAIL, I'M EASY TO FIND. >> SO THE DEE GOAL TO THIS IS -- KEY GOAL IS THIS IS A WORKSHOP NOT JUST SPEAKERS SO E WANT ANY POLICE WHO WANT TO BE INVOLVED IN NEXT STEPS, PLEASE VOLUNTEER. BEFORE GOING TO BROAD DISCUSSION OR TO BEGIN THE BROAD DISCUSSION I ASKED SONNY IF HE WOULD I DRESS ONE OF THE ISSUES THAT CAME UP YESTERDAY ABOUT STUDIES. SO I JUST WANT TO PUT THAT NOTION OF RED CELL QUALITY IF YOU WILL INTO PERSPECTIVE. >> WHAT I WANT TO DO IS SUMMARIZE THE LITTLE BIT I KNOW ISSUE OF RESTORATION OF TRANSFUSION. DPG DETERIORATES DURING STORAGE AND DEPENDING HOW YOU MANIPULATE BLOOD CAN DETEE YOUR RATE QUICKLY. SO A COMMON APPROACH IS OVERNIGHT HOLD DONOR DONATES BLOOD AND BLOOD MAYBE HELD OVERNIGHT. PRIOR TO BEING MADE INTO ITS COMPONENTS. IF YOU DO AN OVERNIGHT HOLD WHICH IS AN ADVANTAGE FOR THE BLOOD COLLECTORS, THEY DON'T HAVE TO RUSH BACK TO THE LAB TO MAKE COMPONENTS, THEY CAN BRING BACK THE WHOLE BLOOD LET IT SIT OVER NIGHT AND MAKE COMPONENT THE NEXT MORNING IF YOU DO THAT, THE NEXT MORNING THE DPD LEVELS ARE ZERO. SO VERY LARGE AMOUNT OF BLOOD BEING DISTRIBUTED CURRENTLY ALREADY STARTS OUT EVEN IF IT'S SO CALLED FRISCH WITH A LOW DPG. IF YOU DO IT THE OLD FASHIONED WAY BRING IT BACK QUICKLY AND MAKE YOUR COMPONENTS THE DPG LEVELS ARE HIGH AT DAY ONE, BUT WILL GO DOWN TO 0 BY DAY 14. THAT TAKES US THEN WHAT HAPPENS WHEN YOU TRANSFUSE, WE KNOW DPG RESTORES ITSELF AND ANDY STUDIED THIS CAREFULLY, PUBLISHED IN 19 # # AND HE DID A SIMPLE CLEVER THING HE TOOK GROUP A RECIPIENT, TRANSFUSED THEM BE STORED RED BLOOD CELLS THAT WERE GROUP O AND THEN FOLLOWING A TRANSFUSION AT SERIAL TIME INTERVALS BLED THE RECIPIENT AND YOU CAN SEPARATE THE A CELLS FROM THE O CELLS, PATIENTS NATIVE CELLS FROM THE TRANSFUSED CELLS, SEPARATE THEM JUST USING IN A TEST WITH ANTIBODY TO THE GROUP A BLOOD GROUP. VERY LOVELY FIGURE FROM THAT PAPER THAT SHOWS DPG LEVELS AT 12 MOLTS PER GRAM OF HEMOGLOBIN, NORMAL LEVEL IN THE RECIPIENTS MEMBERS THE GROUP A PERSON, AND THE A CELLS GO ALONG NORMALLY, AND THEN AT THE TIME THEY TRANSFUSION THEY TRANSFUSE O CELLS START AT ZERO AND THEY JUST RISE UP FOLLOWING TRANSFUSION AND REACH THE LEVEL OF 12. THE KINETICS OF THAT IN THE FIRST SEVEN HOURS DPG RESTORED ITSELF TO 50% OF NORMAL AT 24 HOURS IT WAS AT TWO-THIRDS OF NORMAL, AND AT 48 HOURS IT WAS COMPLETELY NORMAL. SO I THINK WE HAVE GOOD EVIDENCE, WE UNDERSTAND ESSENTIALLY THE KINETICS OF THE RECOVERY OF 2, 3 DPG FOLLOWING TRANSFUSION. >> HIGH LEVEL OF ADAPTATION TOO FROM C LEVEL TO HIGH LEVEL (INDISCERNIBLE) TAKES A DAY, DAY AND A HALF. >> I SEE. SO I ACTUALLY THINK THAT'S WELL UNDERSTOOD AND THE ONLY OTHER THING I WANT TO POINT OUT FROM THE PROJECT I DID IN UGANDA IS WE RANDOMIZED CHILDREN TO FRESH BLOOD, THAT BLOOD WAS MADE IN A TRADITIONAL WAY SO DPG PRESERVED IN THE FRESH BLOOD CASES VERSUS BLOOD STORED FOR 35 DAYS OR SO, SO THAT WAS ALL DEPLETED OF DPG. WHEN WE RANDOMLY ASSIGNED THE RECIPIENTS TO GET ONE BLOOD OR THE OTHER, THEN MEASURE LACTATE CLEARANCE, AND THE TIME PERIOD OF LACTATE CLEARANCE WE USE OVER THE FIRST EIGHT HOURS SO WE WERE FOCUSING ON A PERIOD OF TIME WHEN WE KNEW THE STORED BLOOD HAD NOT COMPLETELY REPLETED ITS 2, 3 DPG FROM DR. HEATON'S WORK. NEVERTHELESS THE STORED BLOOD WHICH HAD NOT YET REPLETED ITSELF WAS CAPABLE OF CAUSING THIS SAME DEGREE OF LACTATE CLEARANCE AS THE FRESH BLOOD, SUGGESTING THAT DEPLETED BLOOD INITIAL HOURS OF TRANSFUSION, THAT DIDN'T MATTER THAT MUCH WITH RESPECT TO LACTATE CLEARANCE IN THE RECIPIENT. >> DID HE MEASURE OPTION AFFINITY TOO? DPG IS IMPORTANT BUT NOT THE ONLY -- >> THIS WAS A TOTALLY IN VITRO THING HE MEASURED ATP AND DPG LEVELS, HE WASN'T MEASURING REALLY HEMOGLOBIN OXYGEN AANYONETY, THAT'S I THINK -- EXACTLY CORRECT, DEPENDS ON MULTIPLE FACTORS WHICH IS WHY WE THINK IN PATIENTS WHO HAD LACTIC ACIDEMIA, OFF LOADING, THAT'S WHY WE THINK DPG DIDN'T MATTER IN VIVO. SO WITH THE PATIENTS THAT WE WERE STUDYING IN THE CONTEXT THAT WE WERE STUDYING THEM. >> FLOOR IS OPEN. COMMENTS, QUESTIONS. (OFF MIC) >> THE ISSUE OF THE OXYGEN HEMOGLOBIN DISSOCIATION CARBON SICKLIERS IS VERY INTERESTING. ONE -- AGAIN I HAVE NO CONFLICT OF INTEREST SO I CAN COMPLIMENT COMPANIES THAT -- AT WILL. I THINK ONE OF THE INTERESTING MOLECULES CURRENTLY BEING WORKED OUT IS SOMETHING CALLED GBT 440 BY A COMPANY. IT WRITES -- IT -- I'M SORRY, IT LEFT SHIFTS THE HEMOGLOBIN OXYGEN ASSOCIATION CURVE MAKING THE HEMOGLOBIN MORE STINGY AND LESS WILLING TO GIVE UP OXYGEN WHICH MEANS THAT IF YOU'RE A RED CELL, A SICKLE RED CELL YOU STAY BETTER OXYGENATED. WHICH STILL IF YOU'RE SICKLE RED CELL THAT'S VERY MUCH TO YOUR ADVANTAGE. SLIGHTLY MORE OXYGENATED. YOU'RE LESS LIKELY TO UNDERGO THAT NUCLEATION EVENT AND THEN THE ENTIRE SICKLING CASCADE THAT IS WHY WE TRY TO INCREASE HEMOGLOBIN F LEVELS IN SICKLIERS BY USING HYDROXYUREA TO ACHIEVE THE SAME RESULT, MOVABLE THE CURVE TO THE LEFT AND KEEP THE RED BLOOD CELLS STINGY AND HOLDING ON TO OXYGEN SO IT'S RELEVANT FOR THE THAT POSITION OF THE CURVE IS EXTREMELY RELEVANT FOR SICKLIERS FOR THEIR OWN RED CELLS. I THINK WHEN YOU TRANSFUSE THEM, WITH TRANSFUSIONED BLOOD, THE DPG LEVEL DOESN'T MATTER AT ALL, SEPARATE CELL. FOR SICKLE CELLS HAVING A LEFT SHIFTED CURVE IS ATIVAN TRAIN YOUS. SO DPG IS NOT THE FRIEND OF A SICKLE CELL BECAUSE DPG HELPS OFF LOAD OXYGEN FROM THE SICKLE CELL MAKING IT HYPOXIC INSIDE THE RED BLOOD CELL. >> THERE IS SOME WORK THAT WAS DONE BY A PERSON WHOSE NAME I WON'T USE BECAUSE HE WAS AT NIH FOR MANY YEARS. I'LL LEAVE THAT ONE ALONE. ON SICKLE CELL DISEASE AND QUANTITATIVE 2, 3, INTRACELLULAR 2, 3 DPG. 'S PUBLISHED FROM BLOOD AND FROM 1972. ANYBODY WANT TO KNOW THE CITATION, COME SEE ME. >> OTHER THOUGHTS? >> MAYBE A SUGGESTION FOR THE CONVERSATION NOW AND THAT WOULD PERHAPS BE USEFUL FOR THE WORKSHOP REPORT. SEVERAL SPEAKERS DID THIS TO A DEGREE IN THEIR TALKS BUT I WONDER IF IT MIGHT BE WORTH CREATING AN ORGANIZING TABLE THAT IDENTIFIED IDEAL REQUIREMENTS OF THE -- A SUITE OF MONITORING APPROACHES FOR -- TO EVALUATE TRANSFUSION EFFICACY OR AND/OR RED CELL QUALITY. AS HOW WE MIGHT APPROACH THIS IF WE WEREN'T CONSTRAINED BY REALITY AND LIMITATIONS OF THE DEVICES THAT WE HAVE ACCESS TO, AND THEN ALSO PERHAPS TO CONSIDER A TABLE ALIGNING THE ACTUAL THINGS THAT ARE AVAILABLE AND WITH LITTLE CHECKS ABOUT WHAT THEY CAN AND CAN'T DO. WHILE EVERYBODY WILL GIVE THEIR OWN LITTLE PARAGRAPH IT WOULD BE USEFUL TO PERHAPS MAKE IT INTEGRATED. I DON'T KNOW IF YOU THINK >> GREAT IDEA MAYBE STEP BACK. IF I WAS LISTENING CAREFULLY TO ELLIOT HE WAS TRYING TO DEFINE RED CELL QUALITY AND IF I RECALL HE SAID THERE WERE THREE THINGS. I ONLY CAUGHT THE FIRST TWO. ONE WITH WAS SAFETY NOT GIVING HIV WITH RED CELLS IS IMPORTANT, MEASURE OF QUALITY. AND THE SECOND THING YOU SAID WAS DELIVERING OXYGEN. IF YOU GIVE A BAG OF BLOOD AND TWO DAYS LATER HALF THE CELLS ARE GONE DOESN'T ADDRESS SAFETY OR COULD ADDRESS SAFETY BUT IT'S A SEPARATE ISSUE. SOME OF US THINK IT RELEVANT TO SAFETY BUT I WILL LEAVE THAT ALONE. SO AT LEAST I WOULD POSIT THAT WE CAN READILY AGREE ABOUT SAFETY IN TERMS OF CERTAINLY HEMOGLOBIN TRANSFUSIONRY ACTIONS OR TROLLY OR TRANSFUSION TRANSMITTED INFECTIOUS DISEASE. >> IT'S ALSO OTHER THINGS WHICH ARE MORE THEORETICAL LIKE THE RED CELLS GETTING STUCK IN THE MICROCIRCULATION AND EXACERBATING ORGAN ISCHEMIA. THAT'S SOMETHING WE ALL THINK ABOUT, MANY MANY OF US BELIEVE IS PROBABLY A REAL PHENOMENON BUT ACTUALLY PROVING THAT >> I THINK ONE WAY TO PUT IT, THERE ARE COUNTER PRODUCTIVE FEATURES OF THE PHYSIOLOGY OF CELLS INDEPENDENT OF THE SAFETY, INDEPENDENT OF INFECTIOUS AND/OR NON-INFECTIOUS QUOTE HAZARDS OF FUSION, LIKE TROLLY, ET CETERA. FEATURES OF RED CELL PHYSIOLOGY COUNTER PRODUCTIVE TO BLOOD FLOW OR OXYGEN DELIVERY WHICH HAS TO DO WITH MICROPARTICLES OR ENCAPSULATED HEMOGLOBIN. ADHERENCE OR AGGREGATION OR VASOCONSTRICTION THAT PREVENT OXYGEN DELIVER BY NORMAL OR NATIVE RED CELLS. SO THAT WOULD BE AGER AN ASPECT OF SAFETY HIGHLY RELEVANT TO THIS WORKSHOP. >> I WANT TO MAKE SURE WE HAVE A PLACE HOLDER BECAUSE I WANT TO GET BACK TO EFFICACY EVENTUALLY BUT THIS IS A GOOD CONVERSATION WHAT WE MEAN BY SAFETY. SO YES. >> CARRY OVER FROM THE END OF THINGS NHLBI MIGHT BE INTERESTED TO SUPPORT IT RELATES TO STANDARDS. WHAT ARE THOSE STANDARD BLOOD TESTS THAT YOU WOULD DO ON THE BLOOD ITSELF? SEEMS LIKE A SIMPLE PROBLEM BUT IT'S LIKE WHEN YOU HAVE BLOOD AND YOU HAVE BLOOD AND YOU HAVE BLOOD AND I HAVE BLOOD, HOW DO WE CHARACTERIZE BASIC PHYSICAL AND FUNCTIONAL PROPERTIES ABOUT IT LIKE WE TALKED ABOUT DEFORMABILITY BUT WHAT IS DEFORMABILITY. HOW DO YOU CHARACTERIZE IT AND HAVING SOMETHING SET IN STONE SO WE ALL CHARACTER RIDES IT IN THE SAME WAY. SO IT'S THEN DATA IS MORE COMPARABLE JUST IN THE LAB HOW DO YOU CHARACTERIZE THE PROPERTIES OF BLOOD IN STANDARDIZED FASHION IT WOULD BE USEFUL. >> YOU WERE GOING TO SAY SOMETHING? >> WHEN YOU TALK ABOUT ALL THIS IN VITRO MEASUREMENTS LIKE MICROPARTICLES AND ALL THOSE THINGS, WE DON'T KNOW WHAT HAPPENS BECAUSE I CAN TELL YOU FOR A FACT THE MICROPARTICLES ARE CLEARED BY THE SPLEEN. IN THALASSEMIA PATIENTS, A LOT OF MICROPARTICLES, ORDER OF MAGNITUDE MORE OR LESS MICROPARTICLES SO ONE OF THE THINGSTY THINK WE NEED TO UNDERSTAND IS SO MUCH OF THIS OR THAT. WHAT I WOULD LIKE TO KNOW THERE'S RELEVANCE TOKER OUTCOMES OF TRANSFUSION, HOW LONG ARE THEY IN CIRCULATION? MORE THAN HALF HOUR OR SOMETHING LIKE THAT, DOESN'T MAKE A DIFFERENCE. OR COULD MAKE DIFFERENCE THESE ARE KINETICS IMPORTANT FOR THIS CORRELATION OF IN VITRO AND IN VIVO. THAT'S MY PERSONAL BIAS. >> EVEN THOUGH THEY'RE CLEAR SO THERE'S A LOT OF SIGNALING FROM THE MICROPARTICLES TOO, THAT MIGHT BE DISADVANTAGEOUS SO THOUGH NO LONGER CIRCULATING THEY HAVE DONE DAMAGE BY GETTING -- >> SOMETHING TO THINK ABOUT. >> I WOULD LIKE TO ADD, WHEN WE'RE DEALING WITH NEONATES AND PREMATURE INFANTS THERE'S A LOT MORE MANIPULATION THAT OCCURS TO THE RED CELLS SO'S A RED CELL IN A BAG BUT THAT BAG THEN GOES INTO A SYRINGE, THE SYRINGE GETS MOUNTED ON AN INFUSION DEVICE AN GOES THROUGH A TEE ANY TINY CATHETER OR NEEDLE. SO EXACTLY WHAT MOHANDRA IS SPEAKING ABOUT IS CRITICAL. NA WHAT'S IN T BAG AND GETS INTO THE BABY ARE VERY DIFFERENT. >> OTHER THING I WOULD SAY, (INDISCERNIBLE) FUNCTION IS NOT FULLY FUNCTIONAL HUMANS IN ABOUT SIX MONTHS IN TERMS OF REMODELING THE RED CELLS AND STUFF LIKE THAT, BECAUSE IN THE NEONATES FOR EXAMPLE, WITH THE BEST EXAMPLE IS -- CYTOSIS, THERE'S NOT -- THEY'RE IN THE ANEMIC AFTER BIRTH BUT BY THREE MONTHS THEY'RE FULLY ANEMIC BECAUSE SCREENING IS FUNCTION IS FULLY -- THREE MONTHS NEONATES, AGAIN WE NEED TO BE CAREFUL EXACTLY WHAT YOU SAID BUT ALSO SPLEEN NEONATES VERY DIFFERENT FROM OTHER PATIENTS. OTHER INDIVIDUALS. >> I WANT TO MAKE A QUICK COMMENT, WHAT'S BEEN VERY EXCITING THE LAST FEW DAYS IS THAT FOCUS ON IN IN VIVO MEASUREMENTS AND SO WHILE THERE'S MUCH TO BE LEARNED FROM THE LABORATORY IN SOME WAYS A LABORATORY CAN SEND US MISLEADING SIGNALS SOMETIMES THERE IS A LOT OF EXCITEMENT IN UNDERSTANDING NEW WAYS TO MEASURE EFFICACY IN VIVO SO I URGE YOU TO STICK TO THAT AND NOT OPEN UP A CAN OF WORMS WHAT ARE THE MANY WAYS YOU CAN DO LABORATORY TESTS ON BLOOD. THERE'S OTHER VENUE FOR THAT, AND AT THIS TIME ALSO DETRACTS FROM WHAT IS REALLY SPECIAL ABOUT WHAT WE HAVE HEARD THE LAST FEW DAYS. >> WE'LL GET TO EFFICACY SHORTLY. KEITH. >> SO I WANT TO ASK DR. LEE, ONE OF THE THINGS OBVIOUSLY THAT'S IMPORTANT AND WE BEGAN THE DAY TALKING ABOUT NEONATES AND PRE-TERM NEONATES, IN TERMS OF PHOTO TOE ACOUSTIC IMAGING, OBVIOUSLY YOU VERY ADEPTLY DESCRIBED HOW SIGNAL WAS GENERATED ON ACOUSTIC SIDE FOLLOWING THE LASER ON THE PHOTO SIDE. IS THERE -- IF WE WERE GOING TO APPLY THAT TECHNOLOGY THROUGH OPEN FONT NIL IN NEONATE TO LOOK AT PROFUSION IN THE BRAIN, IS ENERGY GENERATED OF SIGNIFICANT AMOUNT TO BE A WORRY TO EARLY NEURONAL DEVELOPMENT OR IS THAT OPINION LOOK AT IN NEONATAL MICE OR ANYTHING -- ANY OTHER MODEL THAT MIGHT GIVE INDICATION? DO YOU KNOW HOW MANY ERG OF ENERGY PER WHATEVER IS THERE. IS IT OF ANY CONCERN WHATSOEVER IN >> WHEN WE DO ALL THIS DATA THAT I SHOW ALWAYS LASER ON THE SURFACE OF THE SKIN. WE WELL UNDER THE LIMIT, THE AMERICAN STANDARD OF SAFETY LIMIT WHICH IS (INDISCERNIBLE) ALWAYS BELOW THAT. OUR PHOTO ACOUSTIC IS VERY SENSITIVE TO TEMPERATURE, IF WE INCREASE TEMPERATURE OUR SIGNAL GOES UP, SO SIGNAL CHANGE. WE KNOW HOW MUCH TEMPERATURE RISE WE INDUCED. ALSO WE USE SHORT PULSE LEADER FEW NANOSECOND SO THE TEMPERATURE RISES WITH SKILL, AFTER -- WE DID HAVE A SIGNAL. SO YOU -- MOST OF OUR CASES WE CAN GUARANTEE THERE'S NO DAMAGE BUT WE NEVER TRIED TO APPLY ANYTHING ON THE OPEN SKULL BUT I WOULD SAY ONCE THIS DOOR IS OPEN, THE ACOUSTIC POPULATION IS A STREET WAY. ALSO HAS VERY GOOD PENETRATION SO WE HAVE GOOD CONFIDENCE TO SEE (INDISCERNIBLE) DETECTION. >> MAKE A COMMENT THERE BASED ON MANY YEARS OF FAILING. IS THAT ONE OF THE MOST FRIGHTENING THINGS I HAVE -- ONE CAN HEAR AND YOU JUST SAID IT IS WE KNOW ENOUGH NOT TO WORRY. I WOULD STILL ENCYST ONE NEEDS TO MAKE THE MEASUREMENT IN THE APPROPRIATE ANIMAL MODEL. BECAUSE WE NEVER REALLY KNOW AS MUCH AS WE THINK WE KNOW. AND YOU STILL HAVE TO TEST BIOLOGICALLY. >> THAT'S FAIR. SO IT'S FAIR BUT WE DO MONITOR ANIMAL, WE DIDN'T SEE ANY DAMAGE BUT WE DIDN'T REALLY DO THE CASOLOGY BUT ANIMAL -- DIDN'T DO ANYTHING ON THERE. >> NIE MATES, HEAR FROM NAOMI AND PEDIATRICIANS THAT ALL BETS ARE OFF WITH FETUSES AND NEONATES AND KIDS AND SO IT IS A CONCERN THAT NEEDS TO BE ADDRESSED APPROPRIATELY. >> WELL SPOKEN. AS I'M SURE MY COLLEAGUES WILL AGREE THEY ARE NOT VERY GOOD NEONATAL ANIMAL MODELS, SAVE THE KIT TESTIMONY FOR ROP AND THE LAMB FOR COMPLEX CONGENITAL HEART DISEASE. ANYTHING ELSE? >> >> THERE'S ANOTHER ONE THAT HAS SIMILAR DEVELOPMENT TO BABIES. >> CNS AND EYE DEVELOPMENT OPEN FONTANEL CLOSE FONTANEL PARTIALLY CLOSED FONTANEL, LOTS OF THINGS TO THINK ABOUT. >> JUST TO SAY IT IS A GREAT MEETING AND I WAS VERY IMPRESSED WITH THE NEW TICKNOLOGIES BEING DEVELOPED. -- TECHNOLOGIES BEING DEVELOPED. NOT TO TAKE TOO SERIOUSLY FROM RED CELL AND TRY TO SEE HOW WE CAN USE THEM TO OUR ADVANTAGE IN THE FUTURE. NOT ALL WORK BUT THERE'S A LOT OF PROGRESS AND VERY TAKEN BY TECHNOLOGY THAT WE WERE PRESENTED THE LAST DAY AND A HALF, I WOULD LIKE THE THANK MARGARET AND NHLBI FOR EXPOSING REALLY EXCITING. I'M GOING TO TAKE MY PLANE AND THINK ABOUT OUR STUFF. THANK YOU SO MUCH. >> THANK YOU VERY MUCH. I WOULD LIKE TO ECHO HIS WORDS ABOUT THE FACT THAT THE UNIQUE ASPECT OF THIS MEETING IS COMBINATION OF CLINICS AND DEVICE INNOVATORS. SO ONE OF THE QUESTIONS HERE IS WE HAD ASKED FROM YOUR PERSPECTIVE HOW TECHNOLOGY CAN BE APPLIED TO TRANSFUSION BUT WE WOULD ALSO LIKE TO PERHAPS SWITCH THAT QUESTION TO THE PEOPLE THAT THE CUSTOMERS WITHIN THIS ROOM THAT ARE CLINICIANS, FAMILIAR WITH YOUR PARTICULAR AREA, HOW COULD TECHNOLOGIES YOU HEARD ABOUT DO YOU FEEL COULD BE USED IN YOUR RESEARCH SPACE, THAT WOULD ALSO BE HELPFUL FOR US. >> I THINK MAYBE WE CAN THANK YOU, I THINK WE CAN START WITH SAYING WELL, FOR THE PHYSICIANS IN THE ROOM IN PARTICULAR, WHAT DO WE MEAN BY EFFICACY? OR EFFECTIVENESS OR -- AND WHAT DO WE CARE ABOUT AND PARTICULARLY IN CONTEXT OF TRANSFUSION AS TO FORGET FRESH OLD ANYTHING ELSE, HOW DO WE KNOW THE TRAININGS FUSION WORKED OR NOT TRANSFUSION WORKED OR NOT. HOW WOULD WE DEFINE EFFICACY. >> MANY TIMES WE'RE GIVING PACK CELLS FOR EXAMPLE. TO TREAT SEVERE METABOLIC ACIDOSIS. THAT'S A SHORT TERM OUTCOME WE WOULD KNOW WITH LACTIC ACIDOSIS RESULTS WITH ATTENUATION BUT WE NEED MORE SENSITIVE MEASURES CLINICALLY, IT'S VERY DIFFICULT. WE NEED MORE SENSITIVE MEASURES THAT DETECTED INSUFFICIENT TISSUE OXYGEN DELIVERY. HOY THAT TISSUE OXYGEN DELIVERY IS IMPROVED WITH TRANSFUSION. THAT WOULD BE A CRITICAL ISSUE IN MANY PATIENTS. >> YOU'RE ABSOLUTELY RIGHT. SO I MEAN THE WAY I THINK ABOUT THIS, I THINK THERE'S THREE WAYS TOUT EVALUATE IT OR THREE SITUATIONS. WHERE ONE IS WHEN TALKING ABOUT WE'RE ALREADY THE BODY IS IN SOME SORT OF SUPPLY DEPENDENCY AND IT'S CRITICALLY CONSTRAINED BY OXYGEN CARRYING CAPACITY. IF THAT'S THE STATE OF AFFAIRS, WHAT YOU SHOULD SEE WITH -- BY INCREASING OXYGEN CARRYING CAPACITY, IS REDUCTION IN MEASURES OF AN AEROBIC METABOLISM. SO THAT'S IN A -- PATIENT IS IN A GLOBAL SUPPLY DIPENDENCY STATE. THERE'S ALSO A PRE-FAILURE STATE. WHERE THE INDICATION FORTRAN FUSION IS TO -- FOR TRANSFUSION IS TO RELIEVE THE STRESS OF ANEMIA, SO PATIENT T SHOE PO2 IS NORMAL. THAT'S NO AN AEROBIC METABOLISM, MOUNT EVEREST, DON'T MAKE LACTATE AND THEY'RE CLIMBING MOUNTAINSES FOR CHRIST SAKE. SO THE O2 CARRIES CAPACITY IS NOT THE PROBLEM BUT THEY MIGHT BE IN A PRE-FAILURE STATE IF EITHER OPTION EITHER THEY BLED MORE OR THEY OXYGEN CONSUMPTION CHANGED AND THE QUEUES THERE ARE I THINK IN THE COMPENSATORY PHYSIOLOGY SO THE SIGNAL THAT THE TRANSFUSION THAT IMPROVING OXYGEN CARRYING CAPACITY IS RELIEVED, IF THE REASON YOU GIVE BLOOD IS RELIEVE PHYSIOLOGIC STRESS OF ANEMIA, THEN YOU RECOLLECTED BE MEASURING THE STRESS. THAT'S THE INTEGRATED PHYSIOLOGY MEASURES WE TALKED ABOUT AND SO THERE HAS TO BE A WAY TO INDEX THE WORK ASSOCIATED WITH COMPENSATING FOR ANEMIA. WHEN YOU'RE IN A PRE-FAILURE STATE, AND I THINK FRANKLY THAT'S MOST OF THE TRANS FUGUES. AND THE THIRD IS WHEN THERE'S A SPECIFIC VITAL ORGAN UNDER THREAT, COULD BE INTESTIN IN A PREMATURE BABY, IT COULD BE SOMEBODY WITH A STROKE IN EVOLUTION, COULD BE SOMEBODY HAVING A HEART ATTACK, SOMEBODY WITH SKIN GRAPH WHATEVER IT IS. AND THEY ARE TISSUE SPECIFIC OR REGIONAL MEASURES OR BIOMARKERS, LIKE A TROPONIN EQUIVALENT FOR EACH ORGANS. THEY ARE ALL DIFFERENT. FOURTH CATEGORY, A COMPLEX SITUATION WHERE SOMEBODY IS IN ONE OF THOSE THREE STATES, OTHER COMPONENTS OF THE OXYGEN DELIVERY SYSTEM FLAWED SO YOU'RE ANEMIC WITH HEART FAILURE AND CYANOTIC. AND THE ATTRIBUTION TO ANEMIA ISN'T CLEAR YOU HAVE TO BE ABLE TO SEPARATE CONTRIBUTION FROM LOY CARDIAC OUTPUT FROM THE ANEMIA, SO THAT IF YOU GIVE BLOOD, AND SITUATION IMPROVES OR DOESN'T, YOU CAN FIGURE WHAT TO DO NEXT OR SEQUENCE INTERVENTIONS AND FRANKLY THAT'S -- THAT I THINK THE PRE-FAILURE STATE YOU'RE TRYING TO RELIEVE STRESS IN SOMEONE WITH STABLE OXYGEN DELIVERY AND THE SITUATION WHERE IF YOU'RE IN OXYGEN DELIVERY FAILURE, USUALLY THERE'S SOMETHING ELSE COMPLICATING THE ANEMIA. THOSE ARE TWO THINGS TO FOCUS ON, THE ONE MOST READILY PREPARE AD TO DO IS MEASURE OXYGEN, LACK AN TISSUE AND IN THE SETTING OF ONLY ANEMIA AND SEE IF IT GETS BACK. THAT'S THE SIMPLEST ONE BUT RAREST I THINK. >> TO WALLY'S POINT IN TERMS OF TARGETING THE SPECIFIC PARAMETERS OF TISSUE OXYGENATION AND LOOKING AT THE EFFICACY, DO RED CELLS IMPROVE AND HELP YOU GET WITHIN A RANGE IN THE TRIAL LOOKING AT TARGETING THE RANGE, 55, 75% CEREBRAL SATURATION AND YIELD IMPORTANT MEANINGFUL OUTCOMES. BETTER LONG TERM NEURO-DEVELOPMENTAL OUTCOMES. I THINK THAT SUPPORT UTILITY BUT IF IT DOES NOT, GETTING TO THE EFFICACY OF RED CELL TRANSFUSION IF YOU DO NOT ACHIEVE THOSE TARGETS, WHY NOT. WHAT IS THE LIMITATION? IS IT A PRODUCT ISSUE, IS IT RECIPIENT OR DOSE ISSUE. I THINK THAT WOULD BE AFFIRMATIVE GETTING TO QUESTION OF EFFICACY OF RED CELL TRANSFUSION AND ACHIEVING THAT. >> I'M SO GLAD YOU SAID THAT, I OBVIOUSLY LEFT THAT OUT. BABIES NEURAL DEFECTS NEURO-DEVELOPMENTAL OUTCOMES MISSION CRITICAL WHAT IS NOT NOTED IN THAT WISE CALF PAPER WITH ANEMIA TOLERANCE, THE ONLY SIGN OF ANEMIA IN TOLERANCE HE FOUND IN THOSE SUBJECT WERE NEUROCOGNITIVE IMPAIRMENT SO THIS WAS MEMORY IMPAIRMENT, THAT WAS TRANSIENT, RELEAVED WITH TRANSFUSION. BY THE WAY WASN'T -- IT WASN'T STORAGE DEPENDENT. BUT AND THERE WAS SOME OTHER TASK THEY WERE DOING, I DON'T REMEMBER BUT THERE WERE FUNCTIONAL NEUROCOGNITIVE REVERSIBLE NEUROCOGNITIVE DEFICITS WITH ADULTS IN ANEMIA WHO APPEARED TO BE TOLERATING ANEMIA, OF COURSE WE COULD BE NO WAY TO KNOW WHAT THE STORY IS IN BABIES, SO THERE ARE ACUTE -- UP IN OF IT WAS PRESENTED HERE. BUT BEYOND JUST CEREBRAL NEARS THE FUNCTIONAL STUDIES WITH NEURAL PHYSIOLOGY, INTEGRATED EEG. AND OTHERS THAT ARE USED TO DENOTE BRAIN HEALTH IN BABIES THAT MIGHT BE ACUTE SURROGATES FOR LATE EFFECTS AND THAT MIGHT BE APPROPRIATE TO INCLUDE TOO. >> I WANT TO ADD A LITTLE DETAIL. I LIKE ALAN'S FOUR CATEGORIES. CATEGORY 3 WAS TARGETED ISCHEMIC AREA. IF YOU'RE ASSESS EFFICACY IN THAT TARGETED SETTING, IT WOULD BE NICE TO KNOW DIRECT MEASUREMENTS OF OXYGEN LEVEL BUT ALSO A METABOLIC MEASUREMENT OF HEALTH OF THE CELL. SO I WOULD DEFINE EFFICACY NOT EXCLUSIVELY BY GETTING OXYGEN THERE, THOUGH THAT'S OBVIOUSLY CRITICAL. BUT ALSO METABOLIC PAIRING. THAT'S THAT TARGET. THAT'S CELLULAR HAPPINESS. WE'LL CHANGE THIS WELL CELL TO HAPPY CELL. >> THANKS FOR THAT COMMENT, I WANT TO ADD ON TO THAT, THERE'S SLIT LITERATURE AT LEAST SYSTEMIC LEVEL TO MEASURE RESIDUAL HYPOXEMIA AFTER ONE HAS DONE EVERYTHING TO INCREASE SPO 2 TO INCREASE CARDIAC OUTPUT, ET CETERA, PCO2 GAB OR COMBINATION OF OXYGEN DELIVERY OVER THE PCO2 GAP, THE CELLS RELEASE CO 2 WHEN METABOLICALLY ACTIVE. THE FACT WE CAN MEASURE THIS SYSTEMICALLY MAKES ME THINK BE THIS TECHNOLOGY WE CAN PAIR OXYGEN MEASUREMENTS TO PRODUCTION OF CO 2 AND COUPLE THOSE TWO THINGS TO ACTUALLY TARGET THAT. WHICH IS ON DELIVERING ARE OXYGEN BUT IS CELL REQUIRING IT AND IT GIVES YOU A MEASURE OF EFFICACY BECAUSE IF THAT NUMBER GETS BETTER THAT MEANS YOU'RE TRANSFUSION IS DOING WHAT IT'S SUPPOSED TO DO. SO THAT'S -- >> TO FOLLOW THAT IDEA, THERE IS AGAIN THIS HEMOGLOBIN BUT THE RED BLOOD CELL HAS A REALLY IMPORTANT CARBONIC ANHYDRASE INSIDE IT AND REALLY IS EXTREMELY ACTIVE PARTICIPANT IN THE REMOVAL OF CARBON DIOXIDE. THAT MAY IN FACT BE WHAT'S ACTUALLY DRIVING THE BUS IN MANY REGARDS. SO IT'S A RED CELLS RESPONSIBILITY TO BRING IN THE CO 2 THEN DO CHLORIDE SHIFT AND GET IT ALL OUT THERE. WE KIND OF IGNORE CARBONIC -- THE HEALTH OF THE RED BLOOD CELL CARBONIC ANHYDRASE, THE PERFORMANCE OF RED BLOOD CELL WE WERE KIND OF FIBRIL ITIC SYSTEM, STUFF WE DON'T LOOK AT. SO I THINK THAT THAT -- THE IDEA OF THAT METABOLIC PERFORMANCE RED CELL FOR CO 2 REMOVAL IS VERY, VERY -- GREAT OPPORTUNITY I THINK FOR US. ONE MORE COMMENT, WE HAVEN'T REALLY TOUCHED ON THE FACT THAT RED BLOOD CELLS HELP MICRO VASCULATURE TO DISTRIBUTE OXYGEN APPROPRIATELY. THAT WOULD BE SECOND ORDER MEASURE OF EFFICACY IF MICROCIRCULATION IS REDISTRIBUTING ADEQUATELY OXYGEN BECAUSE OF THE BLOOD TRAININGS FUSION BETTER THAN CRYSTALOIDS WHICH THERE'S A VAST LITERATURE BEHIND, WOULD BE ANOTHER MEASURE OF EFFICACY. >> ONE THING SONNY MENTIONED EARLIER THAT REGISTERED IN SIMONE'S NOTES, REGISTER -- THE ISSUE OF DYNAMIC TEST ORGANIZE STRESS TESTING OR TRYING TO GET, I'M SORRY, A DYNAMIC RESPONSE TO A CHANGE IN STATE. SO THAT EITHER DOBUTAMINE STRESS OR HYPOXIA STRESS OR SOME THING LIKE THAT THAT SEEMS ROUTINE IN SETTINGS BUT MAKES SOME PEOPLE'S TOES CURL IF THEY THINK ABOUT DOING IT IN ICO PATIENTS WHO ARE ALREADY ILL, IT WOULD BE REVEALING IF THERE WERE A WAY TO DO THAT WAS CONSIDERED SAFE AND REASONABLE. >> THANK YOU FOR RAISING THAT. TAKE IT IN A SLIGHTLY DIFFERENT DIRECTION IF OKAY WITH EVERYONE. THIS RELATES TO THAT DIRECTLY. IMAGINE FOR A MOMENT WE'RE THE FDA. I DON'T KNOW IF THERE'S FDA PEOPLE ROOM OR NOT GOING TO SPEAK ILL OF THE FDA. LET'S MAKE FIT WE'RE THE FDA THEY ARE CONCERNED ABOUT RED CELL QUALITY, EFFICACY, ET CETERA, TO DATE AS FAR AS I KNOW WITH RED CELL TRANSFUSION THE ONLY STUDIES RELEVANT ARE THE ONES WE DO IN HEALTHY VOLUNTEERS SO EITHER MEASURING WHAT GARBAGE IS RELEASED AND THEN MEASURING CIRCULATORY LIFE SPAN IN RECIPIENT POST TRANSFUSION RECIPIENTS HEALTHY VOLUNTEERS SO STORE REGULATORY PURPOSE THEY WOULD LIKE THE START WITH HOW DOES IT WORK IN HEALTHY VOLUNTEERS SO WHAT COULD WE ADD TO THE -- I'M PROMPTING YOU. WHAT CAN WE ADD TO HEALTHY VOLUNTEER STUDIES THAT WE DO THAT MIGHT BE A BETTER SURROGATE FOR EFFICACY IN A SICK PATIENT? >> HE ELLIOT LEFT UNFORTUNATELY, I'LL PLAY HIS ROLE. ELLIOT WOULD SAY YOU HAVE TO PUT A DEMAND ON THE SYSTEM EITHER BY CONSTRAINING OXYGEN AVAILABILITY OR INCREASING OXYGEN CON SOME SHUN AND -- CONSUMPTION AND SEE HOW DONOR TREND PERFORM. HE BEGAN WITH EXERCISE, RUBBING ON TREADMILL OR BIKE OR SOMETHING. AND HE IS ALSO NOW DOING HYPOXIA, THE DYNAMIC RESPONSE IN OXYGEN DELIVERY IN THAT SETTING OUGHT TO BE REFLECT THE QUALITY I WOULD ASSUME. >> DEVICE MAKERS IF WE WERE GOING TO DO THIS IN HEALTHY BONE YOU NODE A DEVICE SENSITIVE ENOUGH TO SEE DIFFERENCES IN PEOPLE OTHERWISE THEY THEY THEY WILLTHY, OTHERWISE THEY COULDN'T PARTICIPATE IN STUDIES, SO WHAT DO YOU PROPOSE? >> THEY WERE FROM ALAN E ELLIOT UNFORTUNATELY IS NOT HERE BUT HE COMMENDED AND EXPRESSION ASSOCIATION OF USING THESE HEALTHY VOLUNTEERS AN SEE HOW THE EFFECT OF RED BLOOD TRANSFUSION IS ON THE PERFORMANCE IN TERMS OF OXYGEN CONSUMPTION. AND HE HAS DONE SO FAR FOUR SUBJECTS AND MEASURE VO 2 MAX WHEN EXERCISING. BEFORE AND AFTER THE TRANSFUSION OF TWO UNITS. WHAT THEY ARE EXACTLY RECOVERING IN TERMS OF IMPROVED PERFORMANCE IS THAT OXYGEN CONSUMPTION THAT IS EQUIVALENT TO THE TWO UNITS OF RED BLOOD CELLS. SO THIS IS REALLY ENCOURAGING, ESPECIALLY FOR ME, WE ARE DOING THIS NON-INVASIVE VO 2 MEASUREMENTS AND THEN COMMENTS RELATED TO PCO2 RELEASE SYSTEM IS VERY INTERESTING ALSO. I WAS IN THE BREAK TALKING TO DR. TEAXAR FROM MAYO, INCREASE IN PATIENTS THAT I SHOW IS MOSTLY BECAUSE OF AFTER DIALYSIS THE PATIENTS BECOME WITH HIGHER BICARBONATE CONCENTRATIONS SO PROBABLY HIGHER RELEASE OF VCO 2 SO WE'RE GOING BACK AND WE WILL EMAIL THE PEOPLE IN TO LEAK INTO THOSE LEVELS MORE CAREFULLY. AND I THINK THAT FROM THE PERSPECTIVE OF CALORIE METRY THERE IS A WAY TO GO LOOKING AT OXYGEN CONSUMPTION AND CARBON DIOXIDE PRODUCTION INVASIVELY PRE-AND POST TRANSFUSION. SINCE I'M LISTENING HERE, AUDIENCE, THE PROBLEM NEEDS TO BE FOLLOWS SPECIALLY IN CRITICAL POPULATIONS PEDIATRIC POPULATIONS SO WE NEED TO DO ADAPTATIONS FOR THE BABIES. SOMETHING PLACED IN INCUBATOR TO FOLLOW NON-INVEIGH SAN FRANCISCOLY. -- NON-INVASIVELY. THIS IS MY POINT. >> OTHER DEVICE TOOL MAKERS? WHEN WE DO THESE HEALTHY VOLUNTEER STUDIES, REMEMBER THEIR HEMOGLOBIN IS NORMAL BEFORE WE TRANSFUSE SO THEY'RE ACTUALLY NORMAL HEALTHY PEOPLE WHO GET IF YOU WILL HYPERTRANSFUSED. FINDING INCREMENTS OF EFFICACY AND BENEFIT IS TRICKY. SO I OPEN FLOOR. BANDAGES OTHER THINGS. >> PUTTING THEM UNDER STRESS, WAY TO TEST THOSE LIMITS AND WITHOUT DOING THAT YOU PROBABLY WON'T SEE MUCH DIFFERENCE SO THAT'S THE RIGHT WAY TO DO IT. HEARING DISCUSSION, THINKING ABOUT LOCAL PRODUCTION OF CARBON DIOXIDE IN CONVERSATIONS ABOUT IF YOU ARE TAKING IN OXYGEN AND USING IT YOU WILL PRODUCE CARBON DIOXIDE. WE ALSO HAVE A TISSUE BASED CASH BONN DIOXIDE -- CARBON DIOXIDE SENSOR. IF YOUR BODY IS EFFECTIVELY CLEARING IT, MAYBE IT WON'T BE REFLECTED LOCALLY SO THERE'S TO BE LEARNED ABOUT OXYGEN CARBON DIOXIDE BALANCE AND PUT SIMULTANEOUSLY WITH A BREATH MONITOR WOULD BE INFORMATIVE, VERY INTERESTING TO SEE WHAT COMES OUT, WHAT'S PRODUCED IN LOCAL TISSUES PARTICULARLY IF THERE'S TISSUES AT RISK. TISSUES THAN I GUESS NUMBER THREE CATEGORY THAT YOU TALKED ABOUT. THERE'S ADMISSION TESTING AND IN FUEL QUALITY SO I THINK THAT -- SO -- BUT THE OTHER POINT ELLIOT WAS TREATING THE EXERCISE VERSUS HYPOXIA AS EITHER OR, I'M NOT SURE THEY REPORT THE SAME THING. SO I WOULD ASSUME BOTH EITHER MIGHT REVEAL A DIFFERENT FLAW IN THE RED CELLS AND THE OTHER TECHNIQUE SONNY MENTIONED WHERE YOU PRODUCE REGIONAL STRESS BY PARTIAL BRACHIAL ARTERY OCCLUSION AND MONITORING WHAT'S HAPPENING IN THE ARM IN BOTH THE OXYGENATION AND RECOVERY, THAT'S A THIRD WAY TO DO IT. WITH OBVIOUSLY NON-VITAL NO HEAD TOURNIQUETS BUT IT'S ANOTHER GOOD WAY TO EVALUATE RED CELL PERFORMANCE. >> IF JOHN WERE STILL HERE HE WOULD HAVE SAID THAT SORT OF THING. SO THANK YOU FOR BRINGING IT UP. >> ONE THING THAT PROBABLY IS NEED TO SAY JUST MAYBE EVERYONE ASSUMES THAT ALREADY, EVERY TIME WE TEST TECHNOLOGIES THE CORE IS TO DESIGN SOMETHING STUDY THAT INCORPORATES AS MANY OF THEM AS POSSIBLE. EVERY DEVICE WE TALKED ABOUT FROM PHOTO ACOUSTIC BASED TOOLS TO IMPLANTABLE SENSORS O TO SOME FILMS THEY SAY SOMETHING DIFFERENT. AT THE END. DAY I WOULDN'T BE SHOCKED COMBINATION IS NECESSARY. JUST LIKE TODAY YOU -- IF YOU NEED TO DO A DIAGNOSTIC YOU GET BLOOD AND WEIGHED AND MANY FACTORS THAT FALL IN, ONE THING IS NOT ENOUGH. THERE'S A SUGGESTION YESTERDAY BY DR. SCHWARZ THAT MAYBE SOMETHING COULD BE APPLIED IN HEALTHY VOLUNTEERS BUT PUTTING PEOPLE UNDER STRESS AND TESTING OUT TOOLS IS FINE. WONDERING IS IT ADEQUATE TO SAY TITRATE VARIOUS LEVELS OF BREATHED OXYGEN GASES, SO IF YOU GAVE THEM HIGHER OXYGEN BY 5%, 10% AND TITRATED UP AND FIND THOSE THRESHOLDS CAN WE WORK BACKWARDS THROUGH SOME KNOWLEDGE OF PHYSIOLOGY, TO UNDERSTAND WHERE THOSE CUT OFFS COULD BE. CHALLENGES IN HEALTHY HUMAN WITH REGULAR HEMOGLOBIN LEVELS, NON-ANEMIA, WE'RE ESSENTIALLY TACKLING THE HARDEST PROBLEM FIRST. IF A WAY OF INTRODUCING SOMETHING SIMPLE INTO BIASES OUR ABILITY TO PICK UP NET CHANGES THAT COULD BE SOMETHING DESIGN FAIRLY STRAIGHT FORWARD MANNER. >> I THINK WE NEED INPUT THE MAKE SURE WE'RE NOT REINVENTING THE WHEEL. BUT WE LOOKED AT -- HOW ABOUT ABOUT THIS BE OUR TECHNIQUES AND THERE'S TWO REASONABLE THINGS IF THEY FIT ONE CAN DO, ONE IS LOCAL CONSTRICTION, TOURNIQUET, THAT'S NOT A PROBLEM. THE OTHER IS BREATHING IN BOTH REDUCED OXYGEN AND INCREASED OXYGEN. BUT IT WOULD BE REALLY USEFUL TO GET SOME SORT OF GROUP INPUT EFFORTS T MAYBE SPECIFIC TASK WITHIN THE INSTITUTE OF DEFINING THESE MODELS IN HEALTHY VOLUNTEERS. DEFINING MODELS IN ANIMALS TO TRY TO SIMULATE THE REAL CLINICAL CONDITIONS WE USE. AND DEFINING GROUND RULES OF WHAT UNDER WHAT CIRCUMSTANCES WE CAN BE DOING THE TESTS IN THE INDIVIDUAL PATIENTS IN WHOM WE'RE THINKING OF INTERVENING. WHAT WOULD BE SAFE, OR REASONABLE TO DO. BUT I THINK ALL OF US KNOW THE ANSWERS TO ALL THOSE THINGS AND WE ALL HAVE DIFFERENT ANSWERS. AND THERE WOULD BE SOME BENEFIT IN AT LEAST BEING WRONG AS A GROUP INSTEAD OF BEING WRONG AS AN INDIVIDUAL. >> I WANT TO MAKE A COUPLE OF SIDE POINTS. I WOULD LIKE TO GET AWAY FROM NORMAL VOLUNTEERS. I FAIL TO SEE THEM AS THE BENCHMARK HERE. IF WE'RE TRYING TO SAY WELL, THE TASK IS TO IDENTIFY, WHAT ARE THE SPECIFIC CHARACTERISTICS OF TRANSFUSION, THE OUTCOMES, THE NATURE OF DIFFERENT KINDS OF BLOOD, I THINK I WOULD RATHER LOOK AT A POPULATION THAT'S GETTING REPEATEDLY TRANSFUSED IN PA WAY THAT IS NOT NORMAL. I THINK AS ELLIOT POINTED OUT TRANSFUSION TODAY ARE GIVEN FOR PEOPLE CONSIDERED AT RISK BECAUSE THEY'RE AGED, ANEMIA BUT NOT CLINICALLY ACUTELY ILL. I THINK THAT'S AN IDEAL POPULATION THAT SHOULD BE EXAMINED BOTH LOCAL AND FOCUS AREAS OF ISCHEMIA, THEY MIGHT HAVE PERIPHERAL SENSORS, CNS SENSORS AN REALLY IN RA CONTROLLED ENVIRONMENT WHAT ARE EFFECTS OF TRANSFUSION IN THAT GROUP. YOU LEARN MORE THAN TREATING PEOPLE THAT ARE HEALTHY VOLUNTEERS FOR REASONS WE HER, THEY'RE REALLY THE OTHER THING THAT COMES UP IS PEOPLE ARE REPEATEDLY GET TRANSFUSED FOR SYMPTOMS MEANING SICKLE CELL DISEASE OR OTHER KINDS OF ANEMIA, THAT PERIODICALLY BECOME SYMPTOM@MIC, THAT'S AN IDEA GROUP WHOA IS THE LEVEL OF ISCHEMIA BEFORE AND AT TIME OF TRANSFUSION. THAT'S AN AREA IF I WERE IN THE INVESTIGATING BUSINESS IN HEMATOLOGY I WOULD SAY THIS IS WHAT WE SHOULD BE USING THESE TOOLS FOR. FROM A CLINICIAN PERSPECTIVE. I THINK FOCUS ON PEOPLE THAT NEED TRANSFUSED AN WORK ON THOSE CASES. >> WHAT I MEANT BY HEALTHY VOLUNTEERINGS ISN'T THE USUAL COLLEGE AGE KIDS WHO GOD KNOWS WHAT THEY ARE TAKING IN ANYWAY. SO TWO TESTS WE NEED TO DO BOTH. ONE IS IN PEOPLE WHO AREN'T ACUTELY ILL BUT WHO MAY BE SOMEWHAT REASONABLE SURROGATES AGE DIABETES, WHATEVER, THE OTHER SET OF THINGS TO THINK ABOUT OF PATIENTS WHOSE ARE ILL AND WHAT CAN WE ETHICALLY SAFELY DO BEFORE WE TREAT TO TELL US WHETHER OR NOT TREATMENT IS GOING TO BE SUCCESSFUL. THAT'S A TOUGH ONE. ANIMAL MODELS ARE EVEN TOUGHER BUT STILL MIGHT BE WORTH PURSUING. >> I WANT TO MAKE A CASE FOR BENCH TESTING. SO IMAGINE THERE IS A DIFFERENCE IN QUALITY WITH IMAGINARY PROCESS A AND IMAGINARY PROCESS B AND WORKSHOP YOU DISCOVER THE WAY TO EVALUATE AND YOU SAY THIS UNIT ACHIEVING WHAT WE WOULD THINK IS THE RIGHT THING BETTER THAN THE OTHER ONE. HOW DO YOU TELL WHAT WAS THE FLAW? WE PRESUME THE AGING AS A FUNCTION OF TIME WAS A PRINCIPLE DETERMINANT OF QUALITY AND ITS APPARENT MAYBE, NOT THE ONLY THING. THERE HAS TO BE ATTEMPT TO MEASURE PHYSIOLOGY THAT WE KNOW HOW TO MEASURE IN RED CELLS, THAT WE THINK INFLUENCES OXYGEN DELIVERY SO WE CAN MAKE ATTRIBUTION ALL BEING DONE NOW IS SURVIVAL IN THE BAG AND YOU CAN EASILY THINK OF A SCENARIO WHERE THAT'S THE OPPOSITE. MAYBE CELLS THAT DIE WITH CERTAIN AMOUNT OF OSMOTIC RESILIENCE MORE EASILY THAN OTHERS YOU CLEAR BAD CELLS FASTER IN THAT UNIT AND REMAINING CELLS ARE BETTER THAN SOME OTHER UNIT WHERE CELLS DON'T DIE WHEN THEY SHOULD DIE. THOSE ARE DEFORMABILITY OR WHATEVER WORD WOULD CHOOSE. TO AFFINITY, ADHESION, AGGREGATION, SO THAT YOU HAVE A PROFILE OF THAT UNIT WHEN YOU EVENTUALLY FIND OUT IN VIVO IF WORKING OR NOT WHAT TO TRY TO FIX. >> WELL TAKEN. >> PHI AGREE WITH THAT SYSTEMATIC APPROACH BECAUSE OTHERWISE HOW TOW MAKE SENSE OF CLINICAL DATA WITHOUT METRICS. ONE OF THE COMMENTS DR. SCHWARZ MADE ABOUT A CONTROLLED OXYGEN MODULATION WITH TOURNIQUET MODEL, REALLY REINFORCED IN MY MIND THERE'S MULTIPLE COMPETING EFFECTS THAT IF YOU JUST MEASURE OXYGEN DELIVERY OR OXYGEN ITSELF, OR OXYGEN CARRYING CAPACITY, YOU'RE -- YOU MISS A CRITICAL COMPONENT OF FLOW. THAT IS A COMBINATION OF HOW MUCH IS FLOWING AS WELL AS WHAT IS CAPACITY TO DELIVER TRYING TO DESIGN MONITORING, HOW MUCH FLOW IS THERE. HOW MUCH BLOOD IS FLOWING AS WELL AS OXYGEN CONCENTRATION, COMPELLING THING TO TRY TO COUPLE THOSE METRICS TOGETHER. FOR ANY KIND OF LOCAL SYSTEMIC MEASUREMENTS TO TRY TO RUN MULTIPLE THINGS SIMULTANEOUSLY AND IT GOES BACK TO I THINK MAYBE YOU SONNY OR SOMEONE ON THIS SIDE OF THE TABLE WHO SAID HOW TO LOOK AT THE SYSTEM AS A WHOLE. NOT JUST OXYGEN CONCENTRATIONS OR FLUX. BUT AS A WHEEL I THINK WE'LL LEARN THE MOST -- WHOLE, WE'LL LEARN MOST FROM WHATEVER TRIAL OR EXPERIMENTS DONE IF WE KEEP CIVIL SYSTEM APPROACH IN THINKING. >> THANK YOU. STEVEN, I AGREE WHAT YOU SAID ABOUT HEALTHY VOLUNTEERS, THE REASON I HAVE RAISED IT IS BECAUSE AT THE MOMENT OR CONSTRAINTS WITH FDA FROM REGULATORY POINT OF VIEW OR SAW STUDIES IN HEALTHY VOLUNTEERS, MAYBE A FAULT EQUIVALENT WHAT'S GOOD IN HEALTHY VOLUNTEER IS IPSO FACTOR GOOD FOR A PATIENT IF YOU WANT TO MAKE A NEW BAG OR SOLUTION OR ANYTHING, THE GOLD STANDARD STUDIES ARE DONE IN HEALTHY VOLUNTEERS P SO ONE OF THE QUESTIONS IS CAN WE MAKE THOSE STUDIES MORE RELEVANT WHEN WE TAKE UNITS AND GIVE THEM TO PATIENTS. THAT IS WHY I RAISED IT BUT POINTS ARE WELL TAKEN. >> MAYBE I CAN MAKE A STRAW MAN AND EVERY CAN TAKE OUT PITCH FORKS AND DESTROY IT BUT AS OUTSIDER TO THE TRANSFUSION WORLD LOOKING IN, THERE SEEMS TO BE THREE KEY SETS LOCUST OF PROBLEM. THE QUESTIONS ABOUT BLOOD INTEGRITY, BLOOD QUALITY, THERE'S A QUESTION WHAT'S OCCURRING WITHIN THE ORGANS, BEING ABLE TO ACCESS THE ORGANS, THERE'S EXTRA QUESTION OF TECHNOLOGIES THAT LOOK PERIPHERALLY IN WHAT THEY DO INFER BASED ON THE FIRST TWO. MAYBE THE RECOMMENDATION IS TO THE NIH AND OTHERS IS PLEASE DON'T ROLE YOUR EYES BUT PERHAPS SET UP CONSORTIUM LIKE APPROACH THAT AIMS TO SOLVE AT ALL THESE IN CONCERT. IT SOUNDS TO ME LIKE FROM A TECH PERSON, THAT IF I WENT INTO A TRIAL WITH SOME OF THE TECHNOLOGIES I HAVE, CONNECT UP AND WE TRY SOMETHING, THAT WE'RE GOING TO BE LOOKING AT ONLY ONE CIRCLE IN THIS NINE CIRCLE VIN DIAGRAM AND LIKELY NOT GOING TO MAKE AN IMPACT. WE WILL SEE STUFF, WRITE A NICE PAPER AND AT THE END OF THE DAY I DON'T FEEL LIKE WE'RE -- THAT'S GOING TO NECESSARILY CONTRIBUTE TO THE PROBLEM AT HAND. MUCH MORE COMPREHENSIVE GROUP THAT ANALYZES BLOOD AND BLOOD QUALITY VIA DIFFERENT MEASUREMENTS THAT USES NEW TOOLS IN CONCERT WITH EXISTING METRICS FOR OUTCOME AND TRACKS ACROSS A COHORT OF PATIENTS I DON'T KNOW IF WE NEED DATA TO COLLECT DATA BUT THERE'S MISSING INFORMATION AND BRING TO BARE THE UNIQUE TALENTS OF EVERYONE IN THIS ROOM, AND BACKGROUND PEOPLE IN THIS ROOM AND LISTENING ON THE WEB AND ELSEWHERE, MIGHT BE A WORTHWHILE APPROACH TO TACKLING ALL THESE THINGS IF DONE PROPERLY COULD GENERATE DATA TO ALLOW US TO ANSWER SOME HYPOTHESES OR AT LEAST FROM WHERE I PEOPLE SITTING, ASK THE RIGHT QUESTIONS. MAYBE THAT'S NAIVE BUT SEEMS TO ME IF WE DON'T WORK TOGETHER WE ARE GOING SCATTER SHOT AND MISS THE BIG PICTURE. >> YOU'RE PROPOSING TWO ACADEMIC SENSE FOLLOW-UP MEETING TO -- I'M KIDDING. YOUR POINT IS WELL TAKEN. WHATEVER POPULATION WE HAVE OUR FAVORITE POPULATIONS INCLUDING THE WOMAN SITTING MENTION TO YOU TO STUDY. THE MORE YOU CAN STUDY PATIENTS THE FASTER YOU GET TO, ANSWER THE PROBLEM IS MORE YOU STUFF PATIENTS THE MORE DIFFICULT TO PERFORM CLINICAL TRIALS. SO IT'S A BALANCE. >> I HEARD A QUESTIONTOR DR. HUTES WHICH WAS WHAT IS THE LIKELIHOOD OF -- ARE THERE -- IS IT ACTUALLY FEASIBLE GIVEN CURRENT ENVIRONMENT THAT THERE'S A MECHANISM THROUGH WHICH YOU COULD SOLICIT APPLICATIONS FOR MULTI-PI INTEGRATED APPROACH TO ADDRESSING THE QUESTIONS RAISED IN THIS WORKSHOP. IS THAT WHAT YOU ARE -- I THIS I THAT'S WHAT YOU >> PPG PO 1. >> I WOULD RESPOND THAT IT SOUNDS LIKE WHAT YOU'RE TALKING ABOUT IF TALKING INVESTIGATOR INITIATED, IS A LARGE RO1. YOU HAVE TO GET PERMISSION TO COME IN BUT THAT'S THE WAY, BECAUSE REGARDLESS IT WILL BE EXPENSIVE. THE MESS UP TO INFRASTRUCTURE LICK PO 1 AND MORE INTO THE SCIENTIFIC QUESTIONS, THE BETTER. I WOULD SAY -- AGAIN, IT'S NOT SIMPLE AS CREATING A NEW COHORT BECAUSE THAT'S A WHOLE 'NOTHER KETTLE OF FISH. IF YOU CAN GET THE SCIENCE DOWN TO CIRCUMSCRIBED AREA WHERE EXPERTISE COULD FIT TOGETHER AND SAY WE WANT TO BIOLOGICALLY DEFINE THIS, THAT HE FIRST PASS, THAT WILL BE THE FASTEST BECAUSE FIRST IT DOESN'T REQUIRE CREATION OF INITIATIVE WHICH WILL BE PROBLEMATIC IN THIS ENVIRONMENT ANYWAY AND WE HAVE AS PEOPLE AROUND THIS TABLE KNOW WE HAVE INFRASTRUCTURE ALREADY THAT SUBSTANTIAL IN TRANSFUSION AND AUGMENT THAT DE NOVO IS NOT STRAIGHT FORWARD THINGS TO DO. SO I WOULD SAY DEFINE SCIENTIFIC QUESTIONS YOU WANT TO ASK AND COME IN WITH MULTI-EXPERTISE ACROSS AS YOU SAID ACROSS DISCIPLINES, PROBABLY YOUR BEST QUICKEST APPROACH FROM WHERE I SIT. >> BEFORE WE END I WANT TO GIVE THE PEOPLE AROUND TABLE ANOTHER CHANCE THINGS TO SAY OR BRING UP. OR QUESTIONS. COMMENTS. OKAY. WITH -- YES, MARGARET. >> I ALSO WANTEDDED TO ASK OUR NCE COLLEAGUES IF YOU HAVE ANY ADDITIONAL COMMENTS BECAUSE I KNOW THAT THE INITIAL IMPETUS TO INVITE WAS TO -- AGAIN WORKING WITH NON-NORMATIVE CONTROL POPULATION BUT ALSO PART OF THE OXYGEN CLUB WHICH CELEBRATED ITS 30th ANNIVERSARY SO THAT'S OOH A MOLECULE WE HAVE TALKING ABOUT TODAY IF YOU HAVE COMMENTS. >> ONE TECHNIQUE I THINK CAN SERVE WITH THIS, THE BAG LEVEL OR EVEN TISSUE LEVEL IS LOOKING AT THE KINETICS OF PRODUCTION OF LACTATE WHICH MAYBE A SURROGATE FOR THINGS OF IMPORTANCE. BUT THAT IS ONE THING WHICH IS NO -- A LIMITED NUMBER OF SITES INCREASING. I THINK WASU IS HAVING ONE -- GETTING ONE SO I CAN SEE WHAT (INDISCERNIBLE) IN A YEAR OR SO. HOW RELEVANT OR HOW NECESSARY IT IS, IS NOT MY AREA FOR ME TO SAY. ONE WAY OR THE OTHER BUT THE OXYGEN CHIPS OR INDIA INK ARE TECHNIQUES WHICH MAY -- NICELY WITH OTHER AREAS. OPTICAL METHODS ARE PHOSPHORUS. SO I THINK THEY ALL MAY TELL YOU SOMETHING DIFFERENT BUT PUTTING TOGETHER THE STORY OUR MEASUREMENTS ARE MORE GLOBAL IN TERMS OF INFUSING AND THAT WILL NEED REGULATORY APPROVAL BUT PARTICLES AND INDIA INK MAY NOT HAVE REGULATORY BURDEN COB RECEIVED FOR TIME FOR OTHER TECHNIQUES. >> WITH THAT I WOULD LIKE TO TAKE THE OPPORTUNITY TO THANK KEITH AND SIMONE AND MARGARET AND KATHERINE AND DILIA FOR COMING UP WITH THIS IDEA AND CONVENING THIS MEETING. I CERTAINLY FOUND IT STIMULATING AND EDUCATIONAL. I WOULD ALSO LIKE TO THANK ALL THE SPEAKERS WHO CAME AND PARTICIPATED ACTIVELY AND CERTAINLY GUESS WHO CAME INTO THE WORKSHOP, YOU WILL BE HEARING FROM US MORE ABOUT GOING FORWARD WITH THIS SO THANK YOU VERY MUCH.