>> OKAY. I THINK WE'LL GET STARTED. GOOD AFTERNOON. I JUST HAVE TWO ANNOUNCEMENTS. SEVERAL PEOPLE ASKED ME ABOUT THE FINAL EXAM IN THIS COURSE BECAUSE WE'RE THUNNERRING DOWN THE HOME STRETCH, ONLY TWO MORE SESSIONS. NEXT WEEK IS THE SESSION ON ALZHEIMER'S DISEASE AND FEN THE FINALE IS A SYMPOSIUM ON OPPORTUNITIES IN THE WORLD FORMFk Ph.D. GRADUATES THESE DAYS. AND THERE'S A POSSIBILITY THAT THE DIRECTOR MAYBE WITH US TO DISCUSS PART OF THIS PROBLEM BUT WILL ALL POSTED. THE SECOND THING IS TO MENTION TO THOSE OF YOU WHO DONE KNOW, IF YOU JUST GOOGLE DEMISTFYING MEDICINE AND GO TO OUR WEBSITE YOU CAN SEE THE POWERPOINTS FOR ALL SESSIONS OF THE COURSE AS WELL AS REFERENCES AND EVERYTHING ELSE, NOT ONLY FOR THIS YEAR BUT FOR THE PREVIOUS NINE YEARS SO THERE'S A LOT OF MATERIAL THERE IF YOU WANT TO LOOK AT IT AND IF YOU WANT TO HEAR, THEN YOU HAVE TO GO TO THE NIH VIDEO ARCHIVE WHERE YOU CAN ACTUALLY WATCH AND LISTEN AND HEAR AT THE SAME TIME. THE OTHER THING IS TO REMIND YOU, BELIEVE IT OR NOT, THERE'S SOMEWHERE BETWEEN 150 AND 300 PEOPLE WHO WATCH THIS PROGRAM LIVE EACH WEEK JUST FROM THE NIH CAMPUS. SO WHEN THE TIME COMES, FEEL FREE, WE ENCOURAGE YOU TO ASK QUESTIONS OR MAKE BRIEF COMMENTS BUT UNFORTUNATELY WE ONLY HAVE ONE MICROPHONE HERE SO JUST WAIT A MINUTE UNTIL WE CAN GET THE MICROPHONE TO YOU BECAUSE PEOPLE SEND ME EMAILS AND SAY IT'S A BIT DISCONCERTING TO HEAR THE ANSWERS AND THEN TRY AN GUESS WHAT THE QUESTIONS ARE. SO THERE'S A FAMOUS BASEBALL SCENARIO FROM A LONG TIME AGO OF AN INFIELD WHERE THE LOGO WENT TINKERS TO EVERS TO CHANCE, THAT'S THE WAY THEY GET A DOUBLE PLAY, THE ST. LOUIS CARDINALS. AT ANY RATE I DON'T WANT TO BELABOR THE POINT BUT THAT'S WHAT'S GOING TO HAPPEN TODAY BECAUSE MY PLEASURE IS TO INTRODUCE JIM BATY TO YOU. HE IS THE DIRECTOR OF THE NATIONAL INSTITUTE OF DEAFNESS AND COMMUNICATIVE -- COMMUNICATION DISORDERS. AND HE WILL INTRODUCE OUR SPEAKERS AND OUR GUESTS AND WILL CARRY ON AT THAT POINT. DR. BATTY CAME TO NIH HAVING GOTTEN AN M.D. AND Ph.D. FROM STANFORD, HE THEN TRAINED IN PEDIATRIC AND WAS A FOAL LOW IN GENETICS AT HARVARD. AFTER COMING TO NIH AS HEAD LOODERSHIP AND PRODUCTIVE ACTIVITIES IN THE CANCER INSTITUTE NINDS BACK IN THE CANCER INSTITUTE HE ALSO SHEPHERDED THE STEM CELL TASKS FORCE FOR THE NIH AND BECAME DIRECTOR OF THE INSTITUTE. SO IT'S A PLEASURE TO HAVE YOU WITH US, THANK YOU VERY MUCH FOR COMING. >> THANKS, WIN. PLEASURE TO BE HERE. I WILL NOT TAKE A LOT OF YOUR TIME OTHER THAN TO GIVE YOU AN IDEA HOW THE PROGRAM IS GOING TO ROLL OUT TODAY. WE HAVE TWO OF OUR MOST OUTSTANDING SCIENTISTS WITH WITH US TODAY. WE HAVE DR. JOHNNY PAR CO, WHO IS HEAD OF THE DEPARTMENT OF AUTOLAIRN GOLG AT JOHNS HOPKINS MEDICAL SCHOOL WHO DROVE DOWN FROM BALTIMORE IN THE TRAFFIC TODAY TO HELP US OUT. AND THEN FROM OUR OWN INTRAMURAL PROGRAM WE HAVE DR. TOM FRIEDMAN WHO RUNS WHO IS ARGUABLY THE FINEST LAB IN THE WORLD STUDYING GENETICS OF HER RED TEAR HEARING IMPAIRMENT. IN ADDITION WE'RE ABSOLUTELY DELIGHTED TO WELCOME THE COWELLS. HER AND HER TWO DAUGHTERS GRACIE AND CARRIE. GRACIE HAS BEEN A PATIENT FOR A NUMBER OF YEARS AND AS AN INDIVIDUAL WHO USES AND BENEFITS FROM THE COCHLEAR IMPLANT. SO WITH NO FURTHER ADIEU, I WOULD LIKE TO LET JOHN GET THINGS GOING. >> GOOD AFTERNOON, EVERYONE. I TEND TO MUMBLE DURING MY NORMAL WORK DAY BECAUSE IT'S GOOD FOR BUSINESS SO IF YOU CATCH ME DOING THAT, PLEASE GIVE ME THE UP SIGN AND I'LL TRY TO INCREASE THE INTENSITY AND MAKE SURE THAT I'M DELIVERING THE SPEECH SIGNALS TO YOU AT THE PROPER INTENSITY. I OWE MY PROFESSIONAL CAREER TO THE TO HAVE THIS INVITATION AND BE WITH YOU THIS AFTERNOON. I'M GOING TO BE TALKING TO YOU A LITTLE BIT ABOUT SOME OF THE GENERAL CLINICAL PRINCIPLES THAT LAY BEHIND THIS PROBLEM OF HEARING LOSS. YOU'LL HEAR ABOUT THE UPDATED EPIDEMIOLOGY RELATED TO THIS DISORDER WHICH IS BECOMING ALMOST STAGGERING WB OUR SOCIETY -- WITHIN OUR SOCIETY. SO WE'LL TALK ABOUT HOW WE HEAR THE PHYSIOLOGY OF OUR AUDITORY PATHWAY, CAWS OF HEARING LOSS IN A GENERAL WAY, BUT WE'LL THEN TAKE A DEPARTURE FROM THE CLINICAL SIDE TO LOOK AT THE REMARKABLE INSIGHTS BROUGHT ABOUT BY DR. FREED MAP AND HIS COLLEAGUES -- FRIEDMAN AND HIS COLLEAGUES REGARDINGS THE UNDERPINNINGS OF HAIR CELL DYSFUNCTION. WE'LL TALK ABOUT THE CLINICAL ASPECTS OF HEARING LOSS AND HOW -- THANK YOU. HOW IT AFFECTS DAILY LIFE IN A WAY THAT CAN HAVE PROFOUND IMPLICATIONS AND THEN WE'LL FINISH THE REHABILITATION AN THOSE NEW TECHNOLOGIES THAT ARE MERGING TO MANAGE THIS VERY COMMON DISORDER. NOW, WE ARE GOING TO BE TALKING PREDOMINANTLY THIS AFTERNOON ABOUT SENSORY NEURAL HEARING LOSS. MANY CHILDREN, 80% BY THEIR FIFTH BIRTHDAY WILL EXPERIENCE SOME PERIOD OF HEARING LOSS RELATED TO ACCUMULATION OF FLUID IN THE MIDDLE EAR AND EAR INFECTIONS. THERE ARE MANY DISORDERS OF THE EAR CANAL RESOLVED WITH MEDICAL TREATMENT. WE WON'T FOCUS ON THOSE DISORDERS. WHAT WE WILL BE FOCUSING ON HOWEVER ARE JUST DISORDERS THAT INVOLVE THE REMARKABLE MACHINERY OF TRANSDUCTION THAT OCCURS WITHIN THE COKE COLLIEIA, WITHIN THE SPIRALIOUS SEE RIGHT HERE, LAYS THAT HOUSES THE TRANSDUCING ELEMENTS AS OUTER AND INNER HAIR CELLS SHOWN HERE THAT HAVE ABERRANT INNERVATION THAT CONVERT VIRAL MECHANICAL ENERGY INTO NEURAL TRAFFIC THAT HAS BEEN SENT TO OUR BRAIN FOR PROCESSING. THE WAY WE HEAR USES THIS REMARKABLE FRIF RAL TRANSDUCKTIVE MECHANISM T HAIR CELL SYSTEM THROUGH SEVERAL CHANNELS TO SEND INFORMATION TO A LARGE NUMBER OF SUBSTATIONS WITHIN THE AUDITORY BRAIN STEM AND TO THE AUDITORY CORTEX. THIS GIVES RISE TO MULTIPLE PATHWAYS, BOTH EXCITATORY AND INHIBITORY TO THE PERCEPTIONS OF HEARING. IN A SOUND SIGNATURE HAS BASICALLY THREE DIMENSIONS. SO I'M GOING TON FOCUSING A LITTLE BIT ABOUT HOW WE USE OUR PATHWAY TO UNDERSTAND SPEECH. AS YOU KNOW THERE ARE REMARKABLE -- THERE THERE'S A REMARKABLE SPECTRUM OF STIMULI THAT CAN BE PERCEIVED BY THE EAR. IN FACT, LET'S TRY TO FOCUS FOR THE CLINICAL PART OF THE TALK ON SPEECH PERCEPTION. THAT SIGNATURE CAN COME THROUGH AND BASICALLY IDENTIFY ITSELF THROUGH VARIATIONS INTENSITY AND WHILE VOW WELLS AN CONSONANTS HAVE DIFFERENT FREQUENCY SIGNATURES THEY HAVE DIFFERENT INTENSITY SIGNATURES SO THAT HAS AREAS EXPRESSED FROM THE LOWER AIR YEAHWAY TO -- AIRWAY TO PRODUCE A VOWEL THAT'S UNIMPEDE SOD THE VOWELS HAVE GREATER INTENSITY THAN DO THE COBS NANT SOUNDS. THIS AS WE'LL SEE HAS IMPLICATIONS FOR HIGH FREQUENCY SENSORY NEURAL HEARING LOSS AND IS PARTICULARLY AN ISSUE BECAUSE SPOKEN ENGLISH IS SO DEPENDENT ON CONSONANT RECOGNITION TO ALLOW FOR SPEECH USE. THERE'S A DIMENSION IN TIMING. AND THIS IS WHERE WE IDENTIFY SPEAKERS IN MANY CASES WE IDENTIFY WHERE THEY ARE FROM, SOME MAY RECOGNIZE I HAVE NEITHER A MID COAST OR MID ATLANTIC ACCENT, BORN IN DETROIT. YOU MAY HEAR THAT MICHIGAN TWAING AND A FEW VOWELS THAT STAY ON, HANG ON A LITTLE LONGER THAN THEY SHOULD. BUT YOU WILL IN FACT VARYING PERCEPTIONS OF SOMEONE'S SPEECH DEPENDING ON TIMING QUEUES. BUT IT IS FREQUENCY THAT PROVIDES OUR LIFELINE TO UNDERSTANDING THE BUILDING BLOCKS OF SPEECH AND IT IS FREQUENCY PERCEPTION THAT IS DISTORTED IN SENSORY NEURAL HEARING LOSS WHEN THOSE HAIR CELLS YOU GENERATE DON'T DO THEIR JOB. WE COULD HAVE TAKEN A COMMON INSTRUCTION IN SPOKEN ENGLISH TO SANDWICH AROUND A VOWEL TO CONSONANT SOUNDS AND WE CAN SEE BY PUTTING IN THE SANDWICH A DIFFERENT VOWEL SOUND TO HUD TO HAD TO HID. PROVIDING YOU WITH INFORMATION, VERY DIFFERENT SORTS OF MEANINGS THAT ARE CODED BY A SIGNATURE OF VOWELS PRODUCED BY TWO TONES COMING SIMULTANEOUSLY FROM MY TONETORY TRACK. BY MAKING VARIATIONS IN VOWEL SOUNDS YOU CAN CHANGE THE OTHER END RATHER DRAMATICALLY. LET'S LOOK AT VIDEO RECONSTRUCTION HOW THE AUDITORY PATHWAY PUTS THIS TOGETHER. >> I'M NOT GETTING SOUND FROM MY COMPUTER. >> YOU'RE GOING TO SEE THOSE SPEECH SOUNDS PLAY OUT AS MOVEMENTS IN THE MEMBRANE TO DEFLECT THE HAIR CELLS. SEE THE HAIR CELL APPARATUS THERE. >> FROM THE COCHLEAR THERE'S SPIRAL LAID OUT LINEARLY. (INDISCERNIBLE) >> HIT HAD HEARD HARD HID. >> SO THAT CO-CLEAR SPIRAL IS LAID OUT COKE CO-CLEAR SPIRAL IS LAID OUT IN THE CASH FLOW COCHLEA. WE WILL ENCODE HIGH FREQUENCY THAT'S THE TOAN TOPIC IMPLICATIONS FOR REHAB TECHNIQUES THAT WE'LL BE DISCUSSING LATER. SO LET'S TALK A LITTLE BIT ABOUT HEARING LOSS NOW. SENSORY NEURAL HEARING LOSS IS ONE OF THE MOST PREVALENT CONDITIONS TO AFFECT HUMANS. IT'S AFFECTS AS WE'LL SEE IN PREVALENCE FIGURES THE MAJORITY OF INDIVIDUAL WHOSE ARE OVER THE AGE OF 60 IN OUR SOCIETY. THE AGING EFFECT IS SUCH THAT IT SEEMS TO AFFECT MALES TO A HIGHER DEGREE THAN FEMALES. WE ARE AT A STAGE IN THE ELUTION OF OUR SOCIETY I SUPPOSE -- EVOLUTION WHERE HIGH FREQUENCY HEARING LOSS THAT YOU SEE HERE, THIS TAIL RIGHT HERE, IS AFFECTING YOUNGER MALES AT A RATE THAT IS UNPRECEDENTED PREVIOUSLY. AS WE SEE, AS WE GET INTO MIDDLE AGED POPULATIONS, IN FACT THOSE THAT ARE WELL-SCREENED AND HAVE HELLTIVELY LITTLE NOISE EXPOSURE, WE STILL SEE THIS ACCENT WAITION OF HIGH FREQUENCY HEARING LOSS THAT PREDOMINANTLY AFFECTS MALES AT EARLIER AGE, TYPICALLY 5 TO 10 YEARS EARLIER THAN FEMALES. THE SOURCE IS NOT CLEAR. THERE'S SOMETHING ABOUT OUR INDUSTRIALIZED SOCIETY THAT GIVES RISE TO THIS HIGH FREQUENCY HEARING LOSS AFFECT, HOWEVER. THIS MAYBE IN THE FORM OF SUBTLE EXPOSURES TO TRAUMA, TO NOISE, DAMAGING TRAUMATIC LEVELS OF ACOUSTIC ENERGY THAT CAN AFFECT THOSE HAIR CELLS, THE ACHILLES HEAL OF THE INNER EAR. MACHINE OR BLASTED BASED NOISE, CAN BE IMPACT NOISE, IN AN INDUSTRIAL SETTING, IT CAN BE RECREATIONAL SHOOTERS WE SEE THESE EFFECTS. MUSIC, THE STORY OF MUSIC IS MUDDLED. ONE WOULD THINK AT THIS POINT WE WOULD UNDERSTAND THE DYNAMICS OF MUSIC INDUCED INNER EAR DAMAGE AND WE DON'T AS YET. VERY CONFLICTING NOTIONS ON WHETHER PERSONAL ENTERTAINMENT DEVICES ARE RESPONSIBLE FOR THE SENSORY NEURAL HEARING LOSS WE SEE NOW. BUT IN FACT ONE THING -- ONE HAS TO BELIEVE THAT THAT'S HAVING SOME IMPACT ON OUR OVERALL PREVALENCE OF SENSORY NEURAL HEARING LOSS. APPLIANCES AN TRANSPORTATION, THE KINDS OF THINGS WHICH YOU MIGHT EXPERIENCE WHEN I WAS IN CHICAGO OVER THE WEEKEND WHEN THE TRAIN WOULD GO OVERHEAD. IT WAS VERY LOUD AND I WAS COMFORTED BY STUDIES THAT SHOW TRANSPORTATION-BASED NOISE BECAUSE IT'S RELATIVELY BRIEF IS NOT INJURIOUS TO THE HUMAN INNER EARCH I WASN'T SO SURE ABOUT IT IN A COUPLE OF INSTANCES BUT THESE ARE THE KINDS OF THINGS THAT ARE OUT THERE IN TERMS OF POTENTIAL EXPOSURES. ONE WOULD THINK THAT AS YOU AGE AND YOU LOSE SOME OF YOUR HEARING THAT YOU PERHAPS BECOME LESS VULNERABLE TO THE EFFECTS OF NOISE TRAUMA. UNFORTUNATELY THAT'S NOT THE CASE. THERE'S -- THEY SEEM TO BE ADDITIVE THERE. IS A COMPRESSION FACTOR HERE THAT MITIGATES THIS ADDITION A LITTLE BIT BUT IN FACT WE STILL MAINTAIN THAT OUR SENIORS WITH ADVANCED LEVELS OF HEARING LOSS NEED TO PRACTICE, STRIP NOISE AVOIDANCE IN ORDER TO MAINTAIN THE THE RESIDUAL HEARING. SO A COUPLE OF STUDIES RECENTLY PUBLISHED AND GAIN AD TREMENDOUS AMOUNT OF NOTORIETY RELATED TO THE PREVALENCE OF SENSORY NEURAL HEARING LOSS DEMONSTRATED IN SEVERAL NATIONAL SURVEYS, DATA SETS ON WHICH ARE AVAILABLE FOR ASSESSMENT. A COUPLE OF FIGURES FOR PERCENTAGES OF POPULATIONS FROM THESE AGE GROUPS THAT ARE SHOWING CLINICALLY SIGNIFICANT SENSORY NEURAL HEARING LOSS N THAT FIRST -- THE MIDDLE COLUMN THERE YOU SEE THE OVERALL PERCENT PREVALENCE OF A CLINICALLY SIGNIFICANT HEARING LOSS ACROSS ALL OF THE PRINCIPLE SPEECH FREQUENCIES. AND THE ALARMING STATISTIC THERE NOW IS THAT AS INDIVIDUALS AT OUR SOCIETY ARE REACHING THEIR 80th BIRTHDAY AT HIGHER RATES THAN EVER BEFORE, WE'RE SEEING A UNIVERSAL PRESENCE OF CLINICALLY SIGNIFICANT HEARING LOSS ACROSS KEY FREQUENCIES. THIS IS THE LEVEL OF HEARING LOSS THAT DOES REQUIRE SOME SORT OF INTERVENTION IN ORDER TO MAINTAIN THE NORMAL LEVEL OF SOCIAL CONTACT ONE WOULD EXPECT IN DAILY LIFE IN AMERICA. PERHAPS EVEN MORE ALARMING FACT NOW IS A PERCENT PREVALENCE OF 8.5 PERCENT% AMONG THE YOUNGEST POPULATION STUDIED IN THE NHANS STUDY WHICH IS INDIVIDUALS IN THEIR THIRD DECADE OF LIFE NOW SHOWING A CLOSE TO 10% INCIDENCE OF A HIGH FREQUENCY HEARING LOSS. THE PROBLEM IS THAT THIS HIGH FREQUENCY HEARING LOSS TENDS TO ERODE THE MID AND LOW FREQUENCIES OVER TIME SUCH THAT YOU CAN PREDICT FOR CERTAIN THAT THIS GROUP IS GOING TO RATHER QUICKLY MOVE INTO THIS GROUP OF A PAN FREQUENCY SENSORY NEURAL HEARING LOSS IN THE NEXT 10 TO 15 YEARS, THAT POPULATION IS GOING TO ACCUMULATE. SO ONE WOULD PREDICT BASED ON THESE NUMBERS AND WHERE WE WERE 30 YEARS AGO WHEN NHANES AND SIMILAR SURVEY DATA WERE STARTING TO BE COLLECTED, IS THAT WE'RE PROBABLY GOING TO GET THIS KIND OF INCIDENCE FIGURE LEADING DOWN INTO THIS AGE GROUP HERE IN THE NEXT 20 TO 30 YEARS. SO IT MAY WELL BE THAT OUR MIDDLE AGED POPULATION IS GOING TO HAVE A NEARLY UNIVERSAL PREVALENCE, CLINICALLY SIGNIFICANT SENSORY NEURAL HEARING LOSS, SOMETHING FOR US TO THINK ABOUT. WE'RE BECOMING AWARE OF THESE ISSUES AND IT BECOMES A MATTER OF EDUCATION AND DISTRIBUTION OF INFORMATION SUCH THAT WE CAN HOPEFULLY DO SOMETHING ABOUT THIS AND TAKE PREVENTIVE MEASURES. WE WANT TO THANK OUR SUPER BOWL CHAMPION FOR CHAMPIONING THE CAUSE OF NIDCD. MILLIONS AN MILLIONS OF PEOPLE WATCHING AFTER THE FLOWER LENS SAINTS WON A YEAR AND A HALF AGO. WE NEED TO FURTHER THOSE EFFORTS, FASCINATING TO THINK WHAT IT MIGHT BE ABOUT AMERICAN SOCIETY THAT'S GIVING RISE TO THIS PREVALENT PROBLEM OF SENSERY NEURAL HEARING LOSS. THE AFFECTS OF NOISE IN OUR SOCIETY, IS IT OUR DIET, CIGARETTE SMOKING WHICH WE NOW KNOW IS A MAJOR CONTRIBUTOR THE SENSORY NEURAL HEARING LOSS, DIABETES, WHICH IS CLEARLY ASSOCIATED AS WELL, CARDIOVASCULAR CORRELATES SHOW SENSORY NEURAL HEARING LOSS ASSOCIATE -- ASSOCIATION. BUT THERE ARE DRAMATIC DIFFERENCE TWOONS OUR PREVALENCE AND OTHER SOCIETIES. IN FACT THE EASTER ISLAND STORY IS INTERESTING. EASTERN ISLANDERS IF THEY LIVE MOST OF THEIR ISLANDS THEIR LIFE ON THE LAND SHOW EXQUISITELY SENSITIVE HEARING. SIMILARLY YOU SEE THIS IN CENTRAL AFRICA WITH TRIEBSMEN WHO SHOW VERY, VERY SENSITIVE HEARING. SOME OF THE FIELD STUDIES SUGGEST THAT THERE ARE 100-YEAR-OLD (INDISCERNIBLE) WITH PERFECT HEARING. THE PROBLEM IS IN THOSE POPULATIONS NOBODY KNOWS HOW OLD THEY REALLY ARE BECAUSE THEY DON'T SORT OF KEEP TRACK OF THEIR AGE, MAYBE SOMETHING VERY HEALTHY ABOUT THAT, I'M NOT SURE BUT THEY DO SHOW DRAMATIC DIFFERENCES FROM OUR SOCIETY. IN FACT, IT'S REASONABLE I THINK FOR US TO LOOK AT THESE MAJOR CONTRIBUTORS TO SENSORY NEURAL HEARING LOSS WHETHER RELATED TO THE AGE AFFECT, NOISE TRAUMA, TO INFLAMMATORY INTOXICANTS, WHETHER TOXIC MEDICATIONS OR CHEMOTHERAPEUTIC AGENTS THAT PRODUCE SENSORY NEURAL HEARING LOSS BUT THE EMERGING STORY AND ONE THAT'S BEEN COMING PREDOMINANTLY FROM THE N,DCD IN MANY TRAINEES THAT SPEND TIME ON CAMPUS HERE AND NOW IN THEIR LABS LOOKING TO THESE QUESTIONS, IT IS ABSOLUTELY CLEAR THAT THE GENETIC BACKGROUND IS HAVING A MARKED IMPACT ON OUR UNDERSTANDING OF THESE MECHANISMS OF AUTOTOXICITY AND SENSORY HEARING LOSS. WITH THAT PREAMBLE I'LL TURN IT TO DR. TOM FRIEDMAN WHO LIS L DISCUSS THE MOLECULAR BACKGROUND OF HEARING LOSS. TOM. >> THANK YOU JIM AND DR. NIPARKO. (OFF MIC) >> OKAY. GOOD. SO WHAT I WANT TO DO IS TELL YOU A LITTLE BIT ABOUT THE GENETICS OF HEARING LOSS AND I WANT TO START OFF WITH BASIC HUMAN GENETICS. FOR THOSE OF YOU WHO HAVE HAD THIS SINCE HIGH SCHOOL, BEAR WITH ME. SO FIRST OF ALL, HUMANS HAVE 22 AUTOSOMES AND YOU INHERIT A PAIR FROM MOM AND FROM DAD, SO YOU HAVE 44, THEN YOU HAVE GOT MALES HAVE AN X AN YRK AN FEMALES HAVE TWO X CHROMOSOMES SO WE HAVE A TOTAL OF 46. WHEN I STARTED HIGH SCHOOL I WAS 48 AND WITHIN FOUR YEARS HUMAN POPULATION AROUND THE WORLD LOST TWO CHROMOSOMES. LAUGH WILL HAVE HER RED TEAR HEARING LOSS HAS COME IN MANY FORMS AND THERE'S DOMINANTLY INHERITED HEARING LOSS AND THE SITUATION HERE IS A SINGLE MUTATION IS INHERITED FROM ONE OR THE OTHER PARENTS. THIS IS A PEDIGREE SHOWING SEVERAL GENERATIONS AND THE DEAFNESS ISN'T SKIPPING A GENERATION. FOR THOSE THAT DON'T KNOW PEDIGREES, FEMALES ARE ILLUSTRATED BY CIRCLES AND MALES BY SQUARES AND AFFECTED FEMALES AN MALES BY FILLED IN CIRCLES AND SQUARES. ALSO IN THIS PEDIGREE THERE'S A HORIZONTAL LINE AND THAT'S A MARRIAGE. AND THEN THE SIBLINGS ARE ON A HORIZONTAL LINE FROM THE OLDEST TO THE YOUNGEST. SO THIS IS A PEDIGREE SHOWING AUTOSOMAL INHERITED HEARING LOSS AND NOTICE THEY'RE BOTH MALES AN FEMALES AFFECTED AND BOTH MALES AND FEMALES AFFECTED CAN PASS IT ON TO BOTH FEMALE AND MALE CHILDREN. SO IT'S LIKELY TO BE ON AN AUTOSOME. ONE OF THOSE 22. RECESSIVELY INHERITED DEAFNESS SUGGEST BOTH PARENTS CONTRIBUTE A MUTANT ALEGAL. AN EXAMPLE IS THIS. THIS PARTICULAR PEDIGREE HAS MARRIAGES THAT HAS DOUBLE LINES. WHAT THAT MEANS IS THAT THE INDIVIDUALS ARE RELATED TO ONE ANOTHER IN THIS MARRIAGE. IN THIS CASE YOU CAN TELL THE YOU TRACE THE PARENTS, THIS WOMAN'S MOTHER AND FATHER HAVE -- SHE HAS GRANDPARENTS THAT ARE SHARED BY HER HUSBAND. SO SHE AND HER HUSBAND HAVE THE SAME GRANDPARENTS AND THIS IS LIKELY TO PRODUCE THE RECESSIVE DISORDERS IN WHICH THE SAME MUTANT ALLELE PRESENT ON THE TWO IN THIS CASE AUTOSOMES. SO HEARING LOSS HOWEVER ISN'T AS SIMPLE AS I INDICATED. ITIT ISN'T JUST ONE MUTATED COPY OF THE GENE, FOR SURE YOU'RE GOING TO HAVE DOMINANT INHERITED DEAFNESS OR IN THIS CASE TWO MUTATED COPIES OF RECESSIVE ALLELE, YOU WON'T EXPERIENCE HEARING LOSS, HER RED TEAR HEARING LOSS WITHIN THE SAME FAMILY SHOWS CONSIDERABLE VARIATION IN THE AGE OF ONSET. SEVERITY OR PENETRANT. WHAT I MEAN BY PENETRANT IS SOMETIMES INDIVIDUALS CAN INHERIT THE DOMINANT MUTATION AND TWO RECESSIVE MUTATIONS AND THEY DON'T HAVE HEARING LOSS. THEY ARE NON-PENETRANT. WHAT THAT MEANS IS THERE ARE OTHER FACTORS INFLUENCING THE OUTCOME. THOSE FACTORS OTHER GENES IN THE GENOME SO OTHER VARIANTS OF OTHER GENES, THEY'RE CALLED MODIFIERS, MODIFIER GENES AND THERE HAVE BEEN ENVIRONMENTAL FACTORS SO SOMETIMES 100% CON COR TANS BETWEEN THE GENOTYPE, WHAT THE STATUS OF THE GENE IS AND THE PHENOTYPE OR THE OUTCOME. SO WHAT I WANT TO DO WITH THE REMAINDER OF THE TIME THAT I HAVE IS TO TELL YOU AB HUMAN HER RED TEAR HEARING LOSS, MORE GAK GROUND INFORMATION AND I WANT TO ILLUSTRATE THIS WITH FOUR DIFFERENT GENES. SO WHAT WE'RE GOING TO DO IS FILL IN THIS TABLE. THE FOUR GENES I WANT TO TALK ABOUT ARE JGB-2, AND EACH ILLUSTRATES AN IMPORTANT POINT THAT I WANT TO MAKE. THEN THERE ARE THREE QUESTIONS THAT I WANT TO DEMYSTIFY, THAT IS, WHAT PORTION OF HEARING LOSS HAS ENVIRONMENTAL CAUSES AND HOW MUCH IS HEREDITY, HER RED TEAR. HOW MANY -- HEREDITARY. HOW MANY FUNCTIONING GENES CAUSE HEARING LOSS AND HOW DO YOU KNOW WHEN A DEAFNESS GENE IS IDENTIFIED? HOW DO YOU KNOW WHEN YOU FOUND ONE? SO AS DR. NIPARKO INDICATED, INDIVIDUALS THAT ARE 80 YEARS OLD AND OLDER MANY OF THEM HAVE SIGNIFICANT HEARING LOSS BUT WHAT I WANT TO FOCUS ON IS NOT HEARING LOSS IN OLD AGE, BY THE WAY, THERE'S A WONDERFUL REVIEW OF THIS BY GATE AND MILLS IN LANSETT. BUT WHAT I WANT TO FOCUS ON IS HEARING LOSS IN CHILDREN, 1 TO 3 IN A THOUSAND CHILDREN ARE BORN WITH SIGNIFICANT HEARING LOSS. JUST TO ILLUSTRATE THOUGH, THE HEARING LOSS IN THESE ADULTS SAY 36-DECIBEL HEARING LOSS MEANS THAT YOU'RE GOING TO BE MISSING A LOT OF LANGUAGE AND COMMUNICATION BETWEEN INDIVIDUALS. WHAT I HAVE DONE IS DIVIED HEARING LOSS TO TWO MAJOR CLASSES AND DR. NIPARKO INDICATED THERE ARE NON-HER RED TEAR CAUSES, INFECTIONS, AUTOTOXIC DRUG, NOISE EXPOE SHOWER AND TRAUMA. BUT I WANT TO FOCUS ON HER RED TEAR CAUSES AND DIVIDE THEM INTO SYNDROMIC AN NON-SYNDROMIC. THOUGH YOU'LL SEE THAT THAT'S NOT A CLEAR DISTINCTION. SO I SHADED IT TO INDICATE A GRAY ZONE BETWEEN SYNDROMIC AND NON-SYNDROMIC. WHAT I MEAN BY SYNDROMEIC IS THAT IN ADDITION TO DEAFNESS THERE ARE OTHER CLINICAL FEATURES SUCH AS A MALL FORMATION OR OTHER PROBLEM. THERE ARE ABOUT 400 SYNDROMES BY NAME THAN THE MENDELIAN INHERITED MAN DATABASE WHICH HEARING LOSS IS A COMPONENT. ABOUT 35 OF THOSE GENES HAVE BEEN IDENTIFIED. SO SYNDROMIC HEARING LOSS IS ABOUT 30% OF THE TOTAL HER -- HEREDITARY HEARING LOSS. SOME OF THE SYNDROMES COMMON, I'M ONLY GOING TO TALK ABOUT THE LAST TWO, BUT BRIEFLY WANT TO INDICATE PROGRESSIVE RENAL FAILURE, HEARING LOSS AND OCULAR ANOMALIES, DREW AND LANG NIELSEN LONG QT INTERVAL DUE TO VENTRICULAR ARRHYTHMIAS AND HIGH RISK OF SUDDEN DEATH. SO YOU CAN IMAGINE HEARING LOSS IS OBVIOUS BUT THE ARRHYTHMIAS MAY NOT BE. THERE'S A REASON WHY CHILDREN OUGHT TO SEE A PHYSICIAN AND HAVE THOROUGH CHECK UP. THEN THERE'S STICKLER'S SYNDROME, PRE-MATURE OSTEOARTHRITIS, CLEFT PALATE, CRANIOFACIAL ABNORMALITIES AND GARDENBERG SYNDROME, PIG MEN TEAR ABNORMALITIES LIKE WHITE FORE LOCKS OR IF YOU CAN SEE IT THERE ARE TWO DIFFERENT COLORED EYES. CONGENITAL SENSORY NEURAL HEARING LOSS THOUGH PENETRANTS ARE AS LOW AS 10 TO 20% OR AS HIGH AS 80%. THIS IS A DOMINANT FORM OF HEARING LOSS SYNDROME AND IN MANY FAMILIES THAT WE STUDIED YOU'LL HAVE AN INDIVIDUAL THAT WILL CARRY THE MUTATION BUT HAVE NORMAL HEARING. THEY HAVE OCULAR DISPLACEMENT OF THE INNER EYE AND AT THAT POINT IT SEEMS TO BE BROAD, NASAL ROUTE AND THERE'S MALFORMATION SO THAT THAT DISTANCE IS ENLARGED. THEN THERE'S (INDISCERNIBLE) SYNDROME THAT I WILL TELL YOU ABOUT NOW OR IN A FEW MINUTES. THERE'S NONSYNDROMIC HEARING LOSS WHICH IS HEARING LOSS UNTIL YOU DISCOVER OTHER FEATURES WITH THOROUGH MOUSE MODELS. NON-SYNDROMIC IS TENSETIVE UNTIL YOU STUDY THOROUGHLY. NON-SYNDROMIC HEARING LOSS INHERITED AS AN AUTOSOMAL RECESSIVE IS 56% OF ALL NON-SYNDROMIC HEARING LOSS AND DOMINANTLY INHERITED NON-SYNDROMIC HEARING LOSS, IS 12%, THEN THERE'S 2% X LINKED PERHAPS THERE'S A GENOME, THE Y CHROMOSOME AND THERE ARE ALSO MUTATIONS IN THE MITOCHONDRIA WHICH YOU INHERIT FROM YOUR MOM. AND I'LL HAVE A NOTE TO SAY ABOUT THAT IN THE LAST SLIDE. SO THIS SLIDE IS DESIGNED TO BE BUSY AND ILLUSTRATES ALL OF THE DEAFNESS GENES THAT HAVE BEEN MAPPED WHICH ARE GREEN AND BLACK AN THOSE IDENTIFYD WHERE WE KNOW THE GENE IN GREEN. YOU CAN SEE EVERY SINGLE AUTOSOME AND SEX CHROMOSOME IN THE MITOCHONDRIA IN MUTATIONS IN GENES THAT CAN CAUSE DEAFNESS. SO IMMEDIATELY YOU KNOW HEREDITARY DEAFNESS IS GENETICALLY HETEROGENEOUS, THERE'S MANY GENES THAT CAN CAUSE, THE FIRST ONE WAS MAPPED, REPORTED IN 1994, SO THESE ARE THE LOCI WHERE DEAFNESS GENES ARE LOCATED, THEY'RE PARTICULAR CHROMOSOMAL ADDRESSES AND THEN THERE'S A LAG AND IT TAKES A WHILE TO IDENTIFY THE GENE, TO FIND THE GENE. SO UP TO 60 OR 70 GENES REPORTED FOR INHERITED HEARING LOSS AND HALF IDENTIFIED OF. JUST THIS YEAR TWO MORE GENES IDENTIFIED. IRDL-1 AND MSRB-3. WE DON'T KNOW MUCH ABOUT THE FUNCTION OF EITHER OF THOSE GENES. SO WHAT IS THE EXPERIMENTAL ROUTE OF DEAFNESS SEGREGATING IN THE FAMILY TO FINING STUDYING THE FUNCTION OF THE CULPRIT GENE? FIRST IS WE HAVE TO AS CERTAIN THE LARGE FAMILY AND YOUR -- YOU NEED GOOD CLINICAL DATA, AND YOU NEED DNA FROM THESE INDIVIDUALS. YOU NEED TO GENETICALLY MAP THE LOCATION ON A CHROMOSOME WHERE THE MUTATED GENE IS LOCATED. NOT GOING TO TELL YOU HOW WE DO THAT. THEN YOU NEED TO FIND THE GENE AND I'M NOT GOING TO TELL YOU MUCH ABOUT THAT AS WELL. BUT THIS IS CHROMOSOME 9. AND THERE'S A NEW LOCUST DOWN HERE BUT THERE ARE OTHER LOCI FOR DEAFNESS WHICH HAVE ALSO BEEN MAPPED BY OTHER LAB -- BY MANY LABS, MANY LABS AROUND THE WORLD ARE DOING THIS. ONCE YOU'VE MAPPED IT, ONCE YOU HAVE IDENTIFIED THE GENE AND YOU'RE CONFIDENT YOU HAVE THE THE GENE THEN YOU HAVE TO BUILD ANIMAL MODELS TO FACILITATE YOUR UNDERSTANDING, THESE COULD BE MOUSE MODELS, ZEBRAFISH MODELS, OR MATHEMATICAL MODELS BUT YOU NEED SOME OTHER WAY OF STUDYING THE FUNCTION OF THESE GENES BECAUSE YOU CAN'T HAVE PEOPLE TO LEND YOU THEY'RE. THIS IS A MOUSE MODEL, WHEN MICE ARE DEAF THEY HAVE A TENDENCY TO RUN INTO CIRCLES BECAUSE IT AFFECTS THEIR VESTIBULAR SYSTEM AND THEY WONDER AROUND IN FIGURE AGOS OR CIRCLES SO I WANT TO FILL IN THIS TABLE AND THE FIRST GENE I WANT TO TELL YOU IS GJB-2. THE FIRST DEAFNESS LOCUST TO BE MAPPED SO IT WAS GIVEN DFNB-1. MUTATIONS IN THIS GENE CAN CAUSE NON-SYNDROMIC DEAFNESS AND THE PROTEIN THE CENEXIN 26, LOCATED ON CHROMOSOME 13 FLOOR THE CENTROMERE. KNEE THE CENTROMERE, THERE'S NOT ONLY THE GENE JGB-2, THERE'S JGB-6 AND GJA-3 BY DUPLICATION BECAUSE THEY'RE SIMILAR IN SEQUENCE BUT ALL THE MUTATIONS RESPONSIBLE FOR MOST OF THE MUTATIONS THAT ARE RESPONSIBLE FOR DFNB-1 DEAFNESS ARE IN THIS GENE CALLED GJB-2 THAT ENCODES KENEXIN 26. A PROTEIN OF ABOUT 226 AMINO ACIDS. LET'S IMAGINE THE INSIDE OF THE CELL, THIS IS THE MEMBRANE, THAT'S THE EXTRA CELLULAR AREA. THIS PROTEIN HAS FOUR TRANSMEMBRANE DOMAINS, SO IT SPANS THE MEMBRANE FOUR TIMESCH SIX OF THESE PROTEINS MAKE UP A CHANNEL. THERE IS A CHANNEL ON ONE CELL, A NEIGHBORING CELL THERE MAYBE ANOTHER CENEXIN CHANNEL SO THE 12 SUB UNIT GET TOGETHER AND ALLOW CELL TO CELL COMMUNICATION OF SMALL MOLECULES INDICATED BY THE LITTLE GREEN BALLS. MUTATIONS IN JGB-2 ACCOUNT FOR 20% OF NON-SYNDROMIC AUTOSOMAL RECESSIVE DEAFNESS IN EUROPE AND THE UNITED STATES. SO IF YOU WERE TO GUESS WHAT GENE WAS RESPONSIBLE FOR DEAFNESS IN A PARTICULAR INDIVIDUAL, THIS IS THE GENE THAT YOU WILL PICK. THERE ARE MANY DIFFERENT MUTATIONS OF THIS GENE, IN FACT THERE ARE HUNDREDS OF MUTATIONS OF THIS GENE RESPONSIBLE FOR DEAFNESS BUT TWO, THREE OR FOUR THAT EXPLAIN MUCH OF THE DEAFNESS. SO ONE OF THEM IS CALLED 35 DELG, THAT MEANS DELETION OF A G IN THE GENE AND THAT RESULTS IN A SHIFTING OF THE READING FRAME AND A TRUNCATION OF THE PROTEIN. SO YOU GET A LITTLE TINY PROTEIN THAT'S SIMPLY NON-FUNCTIONAL AND AS A CONSEQUENCE NO GAAP JUNCTION. THE OTHER MUTATION IS 167 DELL T, IT ACCOUNTS FOR 40 TO 60% OF NON-SYNDROMIC HEARING LOSS IN THE ASHKENAZI JEWISH POPULATION THRCH'S NO GREATER HEARING LOSS IN THIS POPULATION BUT MOST OF THE MUTATIONS RESPONSIBLE FOR DEAFNESS ARE THIS MUTATION 167 DELLT. IT LIKE 35 DELL G DELETES A T, CAUSES A READING SHIFT FRAME AND PREMATURE TRUNCATION OF THE PROTEIN DURING TRANSLATION. THIS TOO WOULD BE NON-FUNCTIONAL. SO THESE TWO ACCOUNT FOR A LARGE PROPORTION OF THE HEARING LOSS. AMONG NORMAL HEARING ASHKENAZIE JEWS THE HEARING FREQUENCY IS 4%. BUT WHAT IS REALLY INTERESTING IN THE SAME FAMILY WITH THE SAME MUTATIONS, TWO COPIES OF THIS MUTATION, THE HEARING LOSS CAN BE VERY DIFFERENT. YOU CAN HAVE ONE PERSON WHO WEARS HEARING AIDS AND IS A SPEECH THERAPIST. AND ANOTHER CHILD HAS A COCHLEAR IMPLANT AND WITHOUT BEING PROFOUNDLY DEAF. SO THERE'S A GREAT DEAL OF VARIATION AMONG SIBS IN THE SAME FAMILY, WE DON'T UNDERSTAND THAT. THOSE ARE THE TWO MUTATIONS AND THERE'S LITERALLY OVER 200 MUTATIONS OF THIS TINY GENE THAT HAS ONE EXON THAT'S CODING, EXON 2, THE FIRST EXON OF THIS GENE IS NON-CODING. SO HOW DO YOU GET THESE HIGH FREQUENCIES OF MUTATIONS IN A PARTICULAR POPULATION? THEY'RE VARIOUS EXPLANATIONS. ONE IS THERE COULD BE A SELECTED ADVANTAGE TO THE CARRIER. SOMETHING COMPLETELY UNRELATED TO HEARING. ANOTHER IS THE POSSIBILITY IS THE HIGH MUTATION RATE, THE GENE IS A HOT SPOT FOR MUTATIONAL EVENTS. BUT THE USUAL EXPLANATION IS THERE'S A POPULATION BOTTLENECK AND IT COULD BE THAT A FEW PEOPLE LEAVE A LARGE POPULATION AND ESTABLISH A NEW ONE AND IF ONE INDIVIDUAL IS A CARRIER, THEN IN A POPULATION EXPANDS THERE'S GOING TO BE A HIGH FREQUENCY OF THAT ALTERED GENE IN THE POPULATION. AND YOU CAN THINK OF VARIOUS REASONS WHY YOU WOULD HAVE A BOTTLE NECK IN A POPULATION. SO THE SECOND GENE I WANT TO BRIEFLY TELL YOU ABOUT IS DSNB-3, THE THIRD DEAFNESS GENE TO BE IDENTIFIED ON CHROMOSOME 17 ALONG WITH A DOMINANTLY INHERITED FORM OF DEAFNESS, DFNA-20 WHICH I WON'T TELL YOU ABOUT. DFNB-3 WAS MAPPED IN A POPULATION IN BALI. AND THERE WOULD BE TWO REASONS FOR WANTING TO STUDY THIS. ONE IS THAT EVERY TIME YOU IDENTIFY A NEW DEAFNESS GENE YOU FIND OUT SOMETHING NEW THAT YOU DIDN'T KNOW ABOUT HOW THE AUDITORY SYSTEM WORKS SO EVEN IF THIS WERE A PRIVATE MUTATION IN ONE LITTLE ISOLATED VILLAGE, IT WOULD BE WORTH STARTING BUT TURNS OUT THAT'S NOT THE CASE IN THIS ONE EXAMPLE THAT I'M GOING TO TELL YOU ABOUT. SO IN BALI IN NORTHERN BALI THERE'S A VILLAGE, IT HAS ABOUT 2200 PEOPLE THAT ARE VERY POOR. THIS IS AN EXAMPLE OF WHAT THE VILLAGE IS LIKE AND THEY TAKE GOOD CARE OF THEMSELVES. THIS IS A BABY BEING WEIGHED WHICH THEY -- THEY RECORD A LOT OF THEIR MEDICAL ISSUESCH THESE YOUNG MEN WHO LOOK VERY HEALTHY, THEIR MARSHALL ARTISTS, THEY'RE DANCERS AND THEY'RE ALL WATCHING THE THE DRUMMER AND THEY'RE FEELING WITH THEIR FEET BECAUSE THEY'RE ALL PROFOUNDLY DEAF, THEY HAVE A DANCE TRIP THAT GOES AROUND BALI PERFORMING. IN THIS VILLAGE 15 YEARS AGO 46 DEAF INDIVIDUALS AMONG THE 2200 AND YOU CAN DRAW A PEDIGREE SUCH THAT THEY ARE RELATED BACK TO ONE INDIVIDUAL THAT DIED SEVERAL GENERATIONS AGO. WHAT'S INTERESTING IS IF YOU TAKE A BLOOD SAMPLE FROM INDIVIDUAL WHOSE SAY THEY HAVE NO RELATIVES AS FAR BACK AS THEY CAN REMEMBER, THAT ARE HEARING IMPAIRED, THAT 25% OF THEM ARE CARRYING A MUTATION THAT CAUSE DEAFNESS IN THIS POPULATION. WE HAVE 25 OUT OF 100. SO THE GENE WAS KNOCKED TO CHROMOSOME 17 AND IT TURNS OUT CLONED AND UNCONVENTIONAL MYOSIN. UNLIKE JGB-2, THIS GENE INSTEAD OF ONE CODING EXON HAS 65 CODING EXONS. US Os A BIG JEAN. THE MUTATION THAT CAUSED DEAFNESS IN THIS VILLAGE IS CIRCLED HERE, AND ALL THESE OTHER MUTATIONS HAVE BEEN IDENTIFIED AND IT TURNS OUT THAT BECAUSE THIS IS SUCH A LARGE GENE AND NOBODY WANTED TO SEQUENCE UNTIL THE COST OF SEQUENCING WAS REDUCED, WE DIDN'T KNOW THAT THIS IS PROBABLY ABOUT THE FOURTH PERHAPS THE FIFTH MOST COMMON GENE MUTATIONS CAUSE DEAFNESS WERE APPLIED. SO MOVING ON THERE'S SLP-26A-4, MUTATIONS IN THIS GENE CALLED PENDIN SYNDROME AND THE PROTEIN IS PENDRIN. INDIVIDUALS WITH THIS SYNDROME FIRST DESCRIBED IN 1896 HAS A HEARING LOSS WHICH IS HIGHLY VARIABLE AND HAVE GREATER OR NOT. ALSO WE KNOW MUTATIONS OF THIS VERY SAME GENE CAN CAUSE NON-SYNDROMIC DEAFNESS DSM HB-4, A VERY INTERESTING PROTEIN THAT'S STUDIED SINCE ERIC GREEN'S LAB HERE IDENTIFIED IT A NUMBER OF YEARS AGO. SO MUTATIONS IN THIS GENE CAN CAUSE PENDRIN SYNDROME AND NON-SYNDROMIC DEAFNESS. WE DON'T FULLY UNDERSTAND WHY SOME INDIVIDUALS END UP WITH FULL BLOWN PENDRIN AND OTHERS ENUP WITH NON-SYNDROMIC DEAFNESS. SO THE LAST EXAMPLE THAT I WANT TO TELL YOU ABOUT IS USHER SYNDROME, IT COMES IN BASICALLY THREE VARIETIES, TYPE 1, AND 3. TYPE 1 IS THE MOST SEVERE. CHARACTERIZED BY CONGENITAL PROFOUND HEARING LOSS, RETINITIS PIGMENTOSA WHICH BEGINS TO BE DETECTED IN THE FIRST DECADE. AND LOSS OF PERIPHERAL VESTIBULAR REFLEXES SO THESE CHILDREN ARE LATE WALKING. THEN THIS ICE TYPE 2 AND 3, LESS SEVERE. SO THE REDUCED SEVERITY IS INDICATED HERE. SO THIS IS AN RP FUNDED PHOTOGRAPH PROVIDED BY DR. STEVEING. YOU CAN SEE THESE BLACK PIGMENTED CELLS THAT BEGIN AT THE PERIPHERY AND EVENTUALLY TAKE OVER THE RETINA UNTIL THE PERSON IS VIRTUALLY BLIND. (OFF MIC) >> WELL -- YES, YOU LOOSE CONES YOU LOSE RODS. OKAY. SO THE SLIGHTLY LESS SEVERE FORM OF USHER IS THE MOST COMMON CALLED USHER TYPE 2. THEN USHER TYPE 1, THE MOST SEVERE AND THEN USHER 3. SO IT'S ALSO INHERITED AS RECESSIVE. THIS IS A LITTLE FAMILY SO TWO UNAFFECTED PARENTS AND TWO AFFECTED CHILDREN. HERE ARE SOME UNAFFECTED PARENTS AND TWO AFFECTED SIBLINGS. THESE GENES WERE LARGELY MAPPED IN FAMILIES SO THESE TWO INDIVIDUALS ARE RELATED TO EACH OTHER AND NOTICE AGAIN TWO UNAFFECTED PARENTS, SEVERAL AFFECTED CHILDREN AN UNAFFECTED CHILDREN. THERE ARE A LARGE NUMBER OF GENES FOR USHER SYNDROME, AND INDICATED IN GREEN THE GENES MAPPED AND IDENTIFIED AND IN THIS PINK OR ORANGE THE LOCI FOR USHER SYNDROME THAT HAS BEEN MAPPED BUT THE GENES NOT YET IDENTIFIED OR REPORTED. SO THERE'S MANY DIFFERENCE MUTATED GENES THAT CAN CAUSE USHER SYNDROME DISTRIBUTED AROUND THE GENOME. AS YOU MIGHT EXPECT THERE ARE FOUNDER MUTATIONS, ONCE AGAIN THERE'S A MUTATION THAT ACCOUNTS FOR THE MAJORITY OF YOU SHALL E SYNDROME IN THE ASHKANAZIE JEW, ARGININE 245X, IN A GENE CALLED PCDH-15, RESPONSIBLE FOR USHER SYNDROME TYPE 1F. IN THE FRENCH CANADIANS FROM QUEBEC, THIS MUTATION IS LARGELY RESPONSIBLE FOR MOST OF THE USHER SYNDROME IN THE SWEDES, THERE'S A MUTATION OF CATION 23. IN THE FINS THIS MUTATION IS RESPONSIBLE. SO IF YOU WERE A PHYSICIAN AND YOU HAD A PATIENT WITH USHER SYNDROME YOU WANT TO KNOW IF THERE THEY'RE FROM SAY SWEDEN. YOU CAN PROBABLY FIND IN THE MAJORITY OF CASES THAT MUTATION IS RESPONSIBLE FOR THEIR USHER SYNDROME. SO AS WE LEARN MORE AND MORE ABOUT EACH OF THE VARIOUS POPULATIONS ON THE PLANET, IT WILL MAKE IT MUCH EASIER TO OBTAIN A MOLECULAR DIAGNOSIS FOR THE INDIVIDUAL. WHAT I WANT TO DO IS TELL YOU BRIEFLY ABOUT USHER SYNDROME TYPE 1, THE D LOCUST ON CHROMOSOME 10. AND I WON'T TALK ABOUT ITS NEIGHBOR WHICH IS USHER 1F. SO YOU SHALL 1D, THE GENE IS CALLED CADHERIN 23, AND MUTATIONS ARE IN CADHERIN 23, RESPONSIBLE FOR USHER SYNDROME SO IT'S SYNDROMIC BUT NOT ALWAYS. NOT ALWAYS. THE PROTEIN IS CALLED CADHERIN 23. AND THERE ARE VERY LARGE NUMBER OF MUTATIONS OF CAT HEREIN 23 OF CDH-23 ENCODING CADHERIN 23 WHICH ARE RESPONSIBLE FOR USHER SYNDROME, PROBABLY ONLY A QUARTER OF THE REPORTED MUTATIONS NOW. BUT SURPRISINGLY, THERE ARE ALMOST AN EQUAL NUMBER OF MUTATIONS OF THIS SAME GENE THAT ARE RESPONSIBLE FOR NON-SYNDROMIC DEAFNESS. THESE INDIVIDUALS DO NOT DEVELOP RP. WE DON'T FULLY UNDERSTAND WHY THESE MUTATIONS, THERE ARE MISSENSE MUTATIONS BUT THERE ARE SOME MISSENSE MUTATIONS, AMINO ACID SUBSTITUTIONS THAT CAUSE USHER SYNDROME, WE DON'T KNOW WHY THESE MISSENSE MUTATIONS DON'T CAUSE RP. WE THINK IT'S BECAUSE THEY HAVE A LITTLE BIT OF RESIDUAL ACTIVITY AND THAT'S ACTUALLY GOOD NEWS BECAUSE IF THAT WERE TRUE IT WOULD MEAN THAT THE RETINA CAN GET BUY WITH A SLIGHTLY DI IF HE CANTIVE PROTEIN OR MAYBE LOW LEVELS THE INNER EAR CAN'T. SINCE THE RP IS PROGRESSIVE, PERHAPS IF YOU SLOW DOWN THE RATE OF LOSS OF THE RP YOU MIGHT BE ABLE TO PRESERVE ENOUGH VISION. MUTATIONS OF CADHERIN 23 CAN CAUSE USHER TYPE 1D OR DFNB-12. SO THAT'S DOUBLE BOOKKEEPING. WHEN I TOLD YOU AT THE BEGINNING THAT THERE ARE LOTS OF SYNDROMES, AND THERE ARE LOTS OF GENES THERE'S NONSYNDROMIC DEAFNESS WE'RE COUNTING THE SAME GENE TWICE. BECAUSE MUTATIONS OF THE SAME GENE CAUSE EITHER SYNDROMIC OR NON-SYNDROMIC DEAFNESS. THAT BRINGS US A LITTLE EXAMPLE. THIS IS A LITTLE FAMILY, TWO CHILDREN, I'M GIVING IT AWAY BY SAYING THEY WERE INCOMPLETELY DIAGNOSED WITH NON-SYNDROMIC DEAFNESS. THE MOTHER INDICATED THERE WERE RELATIVES WHICH ALSO HAD DEAFNESS THAT LIVED IN A FAR AWAY PLACE AND THEY DIDN'T WANT US TO CONTACT THEM. SO THE FAMILY IS TOO SMALL TO GENETICALLY MAP THE DEAFNESS BUT WE CHECKED FOR MUTATIONS IN GJB-2 AND THERE WEREN'T ANY. TURNS OUT THERE'S THIS FAMILY IN THIS LITTLE PLACE IT HAPPENED ON AN TWO INDIVIDUALS HAVE USHER SYNDROME IN THAT OTHER CHROMOSOME 10 GENE THEY HAVE THIS R 245 MUTATION IN CADHERIN 15. REALIZE BOTH BOTH FAMILIES, WE FOUND BOTH SIDES OF FAMILY AND TURNS OUT THESE YOUNG CHILDREN HAVE MUTATIONS IN THIS GENE AND HAVE USHER SYNDROME. SO THIS IS ANOTHER FAMILY, IT'S GOING TO ILLUSTRATE THE LAST POINT THAT I WANT TO MAKE. SO WE HAVE A SMALL FAMILY SEGREGATING USHER SYNDROME TYPE 3. AND IT TURNS OUT THEY BOTH HAVE EXACTLY THE SAME HOMOZYGOUS MUTATION AND YET THIS INDIVIDUAL AT 29 HAS REALLY SEVERE TO PROFOUND HEARING LOSS. WHEREAS THIS INDIVIDUAL AT 38 HAS MILD TO MODERATE HEARING LOSS. SO KNOWING THE GENOTYPE DOES NOT GIVE YOU 100% ASSURANCE OF WHAT THE CLINICAL CHARACTERISTICS ARE GOING TO BE. WE NEED TO UNDERSTAND THE VARIOUS ENVIRONMENTAL AND GENETIC FACTORS THAT INFLUENCE THE PHENOTYPE, THE YOU COME. HEARING LOSS, PROGRESSIVE RETINAL VES TIBLATION. AND THERE'S NINE USHER GENES AND MORE TO BE IDENTIFIED. PROTEINS ENCODED BY THE USHER GENES WHICH DIDN'T TELL YOU ALL INTERACT WITH EACH OTHER AND FORM AN AGGREGATE A NETWORK AND WE DON'T FULLY UNDERSTAND THE -- LIKELY TO IDENTIFYING PENDING RP PRIR TO DETECTION BY ELECTRORETINA GRAM OR FUNDOSCOPY. SO EARLY DIAGNOSIS PERMITS TIMELY GENETIC COUNSELING FOR THE PARENTS AND THE OPTION FOR PRE-NATAL DIAGNOSIS AT RISK COUPLES. ENHANCE SOCIAL AN EMOTIONAL ADJUSTMENT. ORAL LANGUAGE MAYBE OPTIMAL MODE OF COMMUNICATION SINCE LIP READING IS VISUAL AND AUDITOR ORAL COMMUNICATION IS MORE SUCCESSFUL OF COCHLEAR IMPLANTS IN CONJUNCTION WITH SPEECH THERAPY IMPLEMENTED PRIOR TO ONSET OF RP. FOR USHER SUBJECTS, VISION LOSS DUE TO RP IS SLOW AND RIPE FOR RESEARCH ON THERAPEUTIC INTERVENTIONS. SO AS TO THOSE THREE QUESTIONS WHAT PROPORTION OF HEARING LOSS HAS ENVIRONMENTAL CAUSES AND HOW MUCH IS HEREDITARY? ABOUT 50/50. HOW MANY MALL FUNCTIONING GENES CAUSE NON-SYNDROMIC HEARING LOSS? WE THINK ABOUT A HUNDRED. HOW DO YOU KNOW WHEN A DEAFNESS GENE HAS BEEN IDENTIFIED IN THIS IS TRICKY BUSINESS. BECAUSE WHAT YOU'RE TRYING TO DO IS IDENTIFY FAMILIES THAT ARE SEGREGATED -- LARGE FAMILIES SEGREGATING HEARING LOSS, YOU'RE TRYING TO MAP THE GENE TO A PARTICULAR CHROMOSOME. SOMETIMES THERE ARE A HUNDRED GENES IN THAT INTERVAL AND YOU LAND ON A GENE WHERE YOU FIND A VARIANT. THAT VARIANT MAY OR MAY NOT BE CAUSAL SO IT'S NICE TO HAVE A LARGE NUMBER OF FAMILIES ALL WITH DEAFNESS SEGREGATING AND NOT BEING TO THAT SAME LOCATION. SO IT'S NICE TO HAVE MANY MUTATIONS THAT TRACK WITH THE HEARING LOSS IN LARGE FAMILIES, THE QUESTION IS DOES THE GENE MAKE BIOLOGICAL SENSE? DOES IT HAVE CRITICAL FUNCTION IN HEARING AND THE ONLY WAY YOU CAN FIGURE THAT OUT IS TO MAKE SOME KIND OF AN AL MODEL. WITH THE DEAFNESS GENE AND WHAT YOU HOPE IS IT CAPITULATE IT IS HEARING LOSS YOU OBSERVED IN THE HUMANS. FINALLY I WANT TO LEAVE YOU WITH GENERAL CONCLUSIONS ABOUT HEREDITARY HEARING LOSS. CLINICALLY AND GENETICALLY HETEROGENEOUS, THAT'S THE FIRST TAKE HOME MESSAGE. THE SECOND ONE IS MOLECULAR GENETIC EVALUATION PREVENTS HEARING LOSS. SO I DIDN'T TELL YOU ABOUT THIS MITOCHONDRIAL MUTATION, 1555 A TO G AND IT'S ASSOCIATED WITH INCREASED RISK OF HEARING LOSS IN THE PRESENCE OF AMINO GLIEK SITE ABTBIOTICS. SO INDIVIDUALS WITH THIS MUTATION CAN LOSE THEIR HEARING WITHOUT EXPOSURE TO IMMUNOGLYCO SITE ANTIBIOTICS BUT LOOSE IT IN THE PRESENCE OF IMMUNOGLYCOCYTE ANTIBIOTICS. IN ADDITION TO COCHLEAR IMPLANTS FUTURE POSSIBILITIES FOR CLINICAL TRIALS TO PREINVENTORY OR TWEAK GENETIC AS WELL AS OTHER CAUSES OF HEARING LOSS MAY SOME DAY INCLUDE GENE THERAPY, STEM CELLS, WHERE REGENERAL RA ACTIVE STRATEGIES TO RESTORE HEARING LOSS. SO WITH THAT I'M GOING TO TURN THE PODIUM BACK TO DR. NIPARKO. >> THERE'S A HOST OF MECHANISMS THAT CAN GIVE RISE TO HAIR CELL FUNCTION WHEN WE LOOK AT CLINICAL MANIFESTATION OF THAT HAIR CELL DYSFUNCTION, THE THE MOST OBVIOUS AND INTUITIVE CLINICAL EFFECT IS THAT IN FACT WILL HAVE REDUCED SENSITIVITY. THAT IN GENERAL THINGS SOUND A LITTLE BIT SOFTER. BUT FOR THOSE OF YOU WITH A HEARING LOSS YOU UNDERSTAND THAT THAT'S ONLY A VERY EARLY SYMPTOM AND A RELATIVELY MILD SYMPTOM OF SENSORY NEURAL HEARING LOSS. IN FACT, IS THE DISTORTIONS AND IMPAIRMENT OF PITCH RESOLUTION WHERE THERE SEEMS TO BE THIS SMEARING OF KEY FREQUENCIES PARTICULARLY IN THE HIGHER FREQUENCY AREA THAT GIVE RISE TO UNPLEASANT SOUNDS AND A COMPLETE INABILITY TO WHAT IS BEING SAID. IN MANY CASES YOU CAN HEAR A SPEECH SIGNAL. YOU SIMPLY CANNOT UNDERSTAND THE UTTERANCE, IT CAN BE FRUSTRATING TO BE SEATED ACROSS THE TABLE FROM SOMEONE AND EXPERIENCE THIS DISCONNECT. RECRUITMENT IS ANOTHER SERIOUS PHENOMENON WHERE HAIR CELLS IN A POPULATION, IN FACT, MAY HAVE A SIMPLY ELEVATED THRESHOLD SO THAT ONCE IN FACT THERE'S ENOUGH INTENSITY TO ACTIVATE THAT POPULATION OF HAIR CELLS, THERE'S THIS SURGE OF ACTIVITY THAT GIVES RISE TO A TACTILE SENSE, A VERY UNPLEASANT SENSE OF HEARING WITH LOUDER SOUNDS RELATIVE TO SONG. SO THIS PRESENTS A PROBLEM WHEN TRYING TO AMPLIFY SOUNDS IN A WAY THAT PROVIDES A COMFORTABLE SORT OF SENSATION, THIS IS WHERE SOFT SOUNDS NEED TO BE AMPLIFIED, LOUD SOUNDS DO NOT NEED TO BE AMPLIFIED. UNFORTUNATELY WITH ADAPTIVE TECHNOLOGY NOW WE'RE ABLE TO PROVIDE THIS SORT OF COMPRESSION OF AMPLIFICATION THAT CAN MANAGE RECRUITMENT. FINALLY TENITIS IS THE UNWANTED SENSATION THAT OCCURS CENTRALLY THAT IS BEEN TRACED TO PATHWAYS IN THE MID BRAIN IN PARTICULAR WHERE THERE SEEMS TO BE A HIGHER LEVEL OF INTERNALLY GENERATED ACTIVITY THAT IS SENLTLY SUBSTITUTING IN FOR THE INFORMATION NOT COMING FROM THE COCHLEA GIVING RISE TO A TYPICAL RINGING OR BUZZING OR HUMMING SOWN. SO OUR STRATEGIES CLINICALLY FOR THE VAST MAJORITY OF PEOPLE WITH SENSORY NEURAL HEARING LOSS IS TO AMPLIFY SOUNDS BY TAKING IN THE ACOUSTIC ENERGY THAT'S COMING IN TO THE SIDE OF THE HEAD OR TO THE INTERNAL -- EXTERNAL EAR CANAL AND TO AMPLIFY THAT ENERGY AND DRIVE A COLUMN OF AIR THAT WILL VIBRATE THE EARDRUM IN A WAY THAT WILL MAKE UP FOR THE HEARING LOSS. WHEN WE HAVE IMPAIRED PITCH RESOLUTION AS OCCURS IN THE VAST MAJORITY OF SENSORY NEURAL HEARING LOSS SUFFERERS, THERE ARE FILTERING TECHNIQUES WHERE IN FACT USING FILTERED BINS WE CAN DIRECT THE STIMULATION OF SOUND TO VARYING DEGREES DEPENDING ON THE FREQUENCY THAT IS WANTING. WE USE COMPRESSION, FOR SOFT SOUNDS IN LOWER REGISTRIES ARE GOING TO BE AMPLIFIED TO A GREATER DEGREE THAN WOULD A LOUD SOUND THAT COULD OVERSTIMULATE THE SYSTEM. FINALLY, TENITIS THERAPY IS COMING INTO ITS OWN IN TERMS OF EXPERIMENTAL MODELS THAT NOW ALLOW FOR SUBTOTAL MASKING. ONE WAY TO THINK ABOUT THIS IS IF YOU HAVE INTERNAL TENITIS, IF YOU NOTICE A RINGING SOUND IN YOUR EARS, INCREASINGLY WHAT WE'RE ASKING PATIENTS TO DO IS LISTEN TO TONAL STIMULI OR SOMETHING AROUND THAT SIMILAR TONE BAND AT A LEVEL THAT IS BELOW THEIR OWN INTERNAL DENY AT THIS. THIS IS TO SIMPLY MASK OVER AND SWAMP THE SENSATION WITH SOME TOTAL MASKING WE'RE INVITING THE BRAIN TO LISTEN THROUGH THE TENITIS TO THE SALIENT STIMULUS AND FOCUS ON THAT IN AN ATTEMPT TO CENTRALLY DEVELOPED IT HAS SHOWN SOME PROMISE THE VARIOUS STIMULI THAT ARE USE FORD THIS ARE SOMEWHAT STILL UNCERTAIN IN TERMS OF EFFICACY BUT WE'RE MAKING STRIDES I THINK IN BEING ABLE TO OFFER TENITIS THERAPY. DENYTIS. IT IS WOVEN THROUGHOUT THE NIDCD TO FIND STRATEGIES TO IMPROVE ONE'S SPEECH IN A NOISE CHALLENGED ENVIRONMENT. UNFORTUNATELY WHEN WE WANT OUR HEARING AT ITS BEST IN A SOCIAL SITUATION, LARGE ROOM, THAT MAY NOT BE AS ACOUSTICALLY FAVORABLE AS THIS ROOM, WE WANT OUR EARS TO BE AT THEIR BEST AND THEY IN FACT ARE AT THEIR WORST. THE REASON THAT IS IN TERMS OF HAIR CELL PATHOLOGY WE SEE ABOUT THE POPULATION OF HAIR CELLS IN OUR INNER EAR AND HOW THEY SUPPORT THE UNDERSTANDING AN CONSONANT AND VOWEL INFORMATION, WE CAN LAY OUT ACOUSTIC ENERGIES AN FIND THEIR PITCH INFORMATION, THEIR INTENSITY AND HOW THEY'RE PUT TOGETHER IN A WAY WITH TIMING OVER TIME TO PRODUCE SILL BILLS AND WORDS. IN A NORMAL HEARING SITION, IN A QUIET ENVIRONMENT THAT WORKS OUT, MAPS OUT BEAUTIFULLY ACROSS A LARGE GEOGRAPHY OF AUDITORY ENERGY. BUT IN FACT WHEN WE START TO IMPOSE NOISE YOU CAN SEE WE START TO CONSTRAIN THAT GEOGRAPHY. LOW FREQUENCIES IN PARTICULAR ARE GOING TO BE SATURATED BY BACKGROUND NOISE IN MANY NOISY ENVIRONMENTS AND ULTIMATELY WITH MULTI-TALKER ENVIRONMENTS FOR EXAMPLE WE START TO COME PRESS THE SITUATION EVEN MORE. THIS GETS TO BE A PROBLEM AS WE MOVE INTO AN AREA HERE OF THE AUDIOGRAM WHERE THERE IS A SENSORY NEURAL -- A SIGNAL TO NOISE RATIO FAVORABLE IN THAT RESTRICTED AREA. SHOWN OTHERWISE HERE, WHETHER ENWE PUT IN A NOISE FLAR AS EXISTS IN MANY SOCIAL SITUATIONS. WE THROW IN THE PROBLEM OF RECRUITMENT OF THAT SURGE OF ENERGY THAT COMES THROUGH THAT IS VERY UNPLEASANT AND REALLY CORRUPTS SPEECH PERCEPTION, WE SEE NOW THAT WE HAVE A FAVORABLE SIGNAL TO NOISE RATIO, IN A RELATIVELY SMALL AREA OF THAT AUDIO GRAM WHERE IT HAS A TREMENDOUS VOLUME TO UNDERSTAND WHAT IS SAID AND HOPEFULLY NOT TRIGGER TOO MUCH RECRUITMENT BY DOING SO. THIS UNDERSCORES THE PROBLEM THAT WE HAVE WITH AMPLIFICATION. BECAUSE WE HAVE TO TRY TO FIT ALL SPEECH INFORMATION COMING IN TO A RELATIVELY CONSTRAINED AREA OF ACOUSTIC ENERGY. SPEECH IS REMARKABLY RESISTANT TO CORRUPTION. THIS IS WHY WITH RELATIVELY FEW QUEUES, MOST INDIVIDUALS WHO WERE -- HAVE GROWN UP WITH HEARING ARE ABLE TO PUT TOGETHER A CONVERSATION DESPITE THE FACT THEY MAYBE HEARING RELATIVELY LITTLE OF THE SILL BILL INFORMATION THAT'S COMING IN IN A STREAM OF CONVERSATION. SO PARTICULARLY YOUNG LISTENERS ARE VERY GOOD IN A BAR SCENE WHERE THERE'S A MULTI-TALKER ENVIRONMENT BECAUSE OF SOME INNER -- ANY INTERMITTENCY AT ALL IN BACKGROUND NOISE WILL ALLOW A YOUNG LISTENER TO PICK OUT CERTAIN PIECES IT GETS HARDER TO DO AS YOU AGE FOR MIDDLE AGED AND OLDER LISTENERS CAN CHALLENGE OUR ABLE TO UNDERSTAND EVEN THOSE SPEECHES REMARKABLY RESISTANT TO CORRUPTION. BUT WHEN YOU THROW IN ACOUSTICALLY UNFAVORABLE ENVIRONMENTS AS EXISTS OFTENTIMES IN RESTAURANTS SETTINGS WE HAVE HARD SURFACES. THOSE HARD SURFACES ACTUALLY PRODUCE REVERBERATION THAT ARE GOING TO MODIFY THE SPEECH SIGNAL THAT IS COMING INTO YOUR EAR. SO YOU'RE NOT GIVING THE SAME THAT YOU GET IN ACQUIRED ENVIRONMENT THIS CREATES A MASKING EFFECT WHERE THE MULTI-TALKER BACKGROUND IN FACT CONTAMINATES THE SALIENT SPEECH SIGNAL IN SUCH A WAY THAT YOU ARE UNABLE TO UNDERSTAND WHAT IS BEING SAID. THIS IS WHERE SPATIAL SEPARATION IS ABSOLUTELY ESSENTIAL. WITH BILATERAL HEARING, WE ARE AT A GREAT ADVANTAGE IN A NOISY ENVIRONMENT BECAUSE WE CAN SEPARATE THAT SPEAKER WHO MAYBE THREE FEET AWAY FROM US FROM ALL OF THE OTHER SOURCES OF SPEECH SIGNALS THAT MAY COME TO US WITH A MULTI-TALKER ENVIRONMENT. THIS HAS BEEN THE FOCUS OF SOME DIRECTIONAL MICROPHONE TECHNOLOGY THAT REALLY AIM YOUR LISTENING FOR EXAMPLE WITH BILATERAL HEARING AIDS OR WITH COCHLEAR IMPLANTS AT A POINT THAT IS 3 TO 5 FEET IN FRONT OF YOU. THIS ALLOWS YOU TO EXCLUDE THAT ENVIRONMENTAL SOUND THAT IS CORRUPTING YOUR SPEECH UNDERSTANDING. SO GIVEN THIS SITUATION AND GIVEN THE HIGH-TECH SMART FAST AND SMALL TECHNOLOGY THAT WE HAVE IN 2011, WHY IS IT THAT ONLY ONE IN ABOUT 6 LISTENERS WITH A CLINICALLY SIGNIFICANT NEURAL HEARING LOSS DOES ANYTHING ABOUT IT? THIS IS ANOTHER AREA THAT IS RIPE FOR CLINICAL RESEARCH. THERE IS A WHOLE HOST OF ATTITUDES THAT HAVE BEEN DETERMINED BY SURVEY TECHNIQUES INCLUDING A PERCEIVED LOW LEVEL OF IMPAIRMENT THAT I HEAR WELL ENOUGH, I DON'T NEED TO HEAR EVERYTHING, I HEAR WHAT I WANT. FINE HEARING IS UNNECESSARY OR MY HEARING LOSS IS NOT DISRUPTIVE. IT MAY NOT BE DISRUPTIVE TO THE INDIVIDUAL WITH THE SENSORY NEURAL HEARING LOSS BUT EVERYONE AROUND THEM DOES FEEL A SENSE OF DISRUPTION. IN FACT STARTS TO MAKE JUDGMENTS ABOUT THAT INDIVIDUAL'S ENGAGEMENT, THEIR FOCUS, THEIR ABILITY TO REALLY PERFORM IN THE DAY TO DAY SOCIAL INTERACTIONS THAT OCCUR TYPICALLY IN WORKPLACES FOR EXAMPLE. THERE IS A PROBLEM OF PERCEIVED STIGMA AND ADMITTING THAT YOU HAVE A HEARING LOSS, THERE IS A PROBLEM WITH EXPERIENCES WITH AMPLIFICATION IN THAT HEARING AIDS DON'T DELIVER PARTICULARLY IN NOISY SETTINGS. THERE'S A PROBLEM OF COST, THIS TECHNOLOGY IS NOT CHEAP AND IS TYPICALLY NOT A COVERED BENEFIT. THERE IS A DEMOGRAPHIC INFLUENCE THAT INCREASINGLY BECOMES AN ISSUE FOR US AS A PUBLIC HEALTH MATTER. THAT IS THAT INCREASINGLY WE SEE LARGER AND LARGER SENIOR POPULATION THAT ADOPTS A COMMUNICATIVELY LESS ACTIVE LIFESTYLE. WE THINK THIS POTENTIALLY HAS PROFOUND IMPLICATIONS BECAUSE OUR CONCERN IS THAT THIS LISTENER HERE AT SOME POINT IS JUST GOING TO CHECK OUT OF THIS ENVIRONMENT. PSYCHOLOGICALLY, EMOTIONALLY, OTHERWISE, SHE WILL START TO WITHDRAW FROM THAT SCENARIO. ALTHOUGH I'M SHOWING A FEMALE FIGURE HERE, IN FACT TYPICALLY IS A MALE WHO IS IN THAT SCENARIO. AND THE MODEL OF THE SENSORY NEURAL HEARING LOSS RELATED SOCIAL WITHDRAWAL IS THAT THE GRADUAL ONSET AND THE PROGRESSION FOSTERS THE SENSE OF MINIMALIZATION AND DENIAL OF THE HEARING LOSS AND THEN ADOPTION OF THIS COMMUNICATIVELY LESS ACTIVE LIFESTYLE AND REDUCED SOCIAL CONNECTIVITY. YOU CAN SHOW IN SEEN YORS WHO DO NOT ENGAGE IN REGULAR SOCIAL INTERACTIONS A CHANGE IN THEIR IMMUNOLOGIC FUNCTION, THEIR WHITE CELL MIGRATION CAPACITY IS REDUCED. YOU CAN SHOW THERE ARE CARDIOVASCULAR EFFECTS THAT AS A POPULATION FOR THOSE WHO ARE NOT SOCIALLY CONNECTED IS FUNDAMENTALLY DIFFERENT THAN THOSE WHO REMAIN SOCIALLY ENGAGED. BUT AN AREA THAT I THINK IS GOING TO EMERGE AS A VERY IMPORTANT ONE FOR COGNITIVE DECLINE REMITS TO EFFECTS OF HEARING LOSS ON COGNITION. I WOULD LIKE THE SHARE WITH YOU SOME RECENT DATA FROM OUR GROUP THAT SUGGESTS THAT THE POSSIBILITY OF HEARING LOSS MAYBE ASSOCIATED WITH DEMENTIA, PERHAPS EVEN THROUGH A CAUSAL PATHWAY. AND THE MODEL HERE IS THAT THE BRAIN HAS TO DEDICATE IN MANY CASES GREATER RESOURCES TO PROCESSING AT THE EXPENSE OF COGNITIVE RESERVE. AS IS BECOMING I THINK THE MODEL FOR UNDERSTANDING DECLINES IN COGNITION. WE HAVE A COGNITIVE RESERVE THAT IDEALLY ALLOWS US TO ANY GAUCHEIATE OUR 6, 7 AND 8TH DECADES IN A WAY THAT ALLOWS US TO PUT TOGETHER THINGS, PERHAPS IN A DIFFERENT WAY FROM THE WAY WE DID IT WHEN WE WERE YOUNGER. BUT IN FACT GIVES US A RESERVE THAT ALLOWS US TO FUNCTION ON A DAILY BASIS. IF YOU START TO EXHAUST THAT COGNITIVE RESERVE WITH PROCESSING DEMANDS, THAT REQUIRE ADDITIONAL ATTENTION, ADDITIONAL PSYCHOLOGICAL ENERGY TO ENGAIBLG AND UNWHAT IS GOING ON IN THE WORD AROUND YOU, THERE MAYBE RISKS. AND I THINK THOSE RISK HAVE BEEN SUGGESTED BY LONGITUDINAL DATA THAT WE HAVE SEEN IN SEVERAL OF OUR SURVEYS. FRANK LYNN, ONE OF MY COLLEAGUES DEMONSTRATED IN A RECENT PUBLICATION THAT LOOKED AT THE BALTIMORE LONGITUDINAL AGING STUDY THAT, THE RISK OF DEMENTIA WAS LINEARLY RELATED TO THE SEVERITY OF HEARING LOSS. THIS IS AN UNADJUSTED CAP PLAN MIRE CURVE THAT DEMONSTRATES HOW A SEVERE HEARING LOSS FOR EXAMPLE, PUTS YOU AT SIGNIFICANT RISK FOR DEMENTIA. YOUR PROBABILITY OF REMAINING DEMENTIA FREE STARTS TO DECLINE RELATIVELY EARLY IN ADULT STAGES WITH A SEVERE HEARING LOSS. HEARING LOSS OF DEMENTIA ON THE ORDINANT, THAT AT THAT FLEX POINT 25 DB HEARING LOSS THERE'S A LINEAR GROWTH IN THE RISK OF DEMENTIA ASSOCIATED WITH GREATER LEVELS OF HEARING LOSS. SUGGESTIONS THAT PERHAPS THERE IS SOME CAUSAL EFFECT WHERE HEARING LOSS MAY TAP ONES COGNITIVE RESERVE. WE KNOW THAT THE PREVALENCE OF DIMENSION SHAH WILL DOUBLE EVERY 20 YEAR GOING FORWARD, BY 2050, ONE IN 30 AMERICANS WILL HAVE DIMENSION SHAH. BY MERELY DELAYING ONSET BAY YEAR WE WILL HAVE A SUBSTANTIAL DROP IN MY DIMEN SHAH PREVALENCE. THAT'S CURRENTLY NO TREATMENTS THAT SHOW THIS EFFECTIVE NSZ BUT OUR HOPE IS IN FACT IF HEARING LOSS IS SHOWN TO HAVE SOME CAUSAL RELATIONSHIP TO COGNITIVE DECLINE, EVEN IF IN A SUBPOPULATION, WE MAYBE ABLE TO MANAGE CRUBTING HEARING LOSS THROUGH EXUSING TECHNOLOGIES. THOSE EXISTING TECHNOLOGIES IN THE FORM OF AMPLIFICATION, IN FACT, SHOW MANY OF THE LARGER LIFE EFFECTS OF SENSORY NEURAL HEARING LOSS CAN BE REVERSED WITH ADEQUATE AMPLIFICATION. HEARING AIDS IMPROVE SCORES OF SOCIAL EMOTIONAL FUNCTION, COMMUNICATION, COGNITION AND DEPRESSION. IT IS PARTICULARLY THE PROBLEM OF DEPRESSION THAT NEEDS TO BE MANAGED WHEN IT EXISTS WITH HEARING LOSS BECAUSE IN MANY CASES THAT SEEMS TO BE AN ADDITIONAL BARRIER BY SEEKING INTERVENTION. WE SEE CO-EXISTING DEPRESSION IN OUR PATIENTS. BUT THE GAINS WE SEE WITH AMPLIFICATION APPEAR TO BE SUSTAINABLE WHEN USED PROPERLY FITTED HEARING AIDS. BOOM TECHNOLOGY IS QUITE IMPRESSIVE OVER THE PAST DECADE OR SO AS DEVICES HAVE BECOME SMALLER, FASTER AND SMARTER. IMPORTANTLY THOUGH WE HAVE FOUND WAYS TO MANAGE OUR PLACEMENT OF DEVICES IN THE EAR CANAL. OUR STRATEGY HAS BEEN TO MOVE AWAY FROM COMPLETE OCCLUSION OF THE EAR CANAL IN AN ATTEMPT TO KEEP HIGH FREQUENCY STIMULATION IN THE EAR AND RATHER GOING WITH A RELATIVELY COMFORTABLE AND FREE FITTING MODEL THAT ALLOWS FOR HIGH FREQUENCY INPUTS BY VIRTUE OF THE PROCESSING STRATEGY BUT NOT THE MOLD TECHNOLOGY. THIS IS A RELATIVELY LIGHT-WEIGH FEATHER WEIGHT BUTTON PLACED IN THE EAR CANAL ALLOWING FOR GREATER COMFORT, ALLOWING FOR THE KIND OF DIRECTIONALITY THAT WE GET WHEN WE PUT THINGS IN TO THE EAR CANAL. NOISE REDUCTIONS, NATURALNESS, FIDELITY, THESE THINGS HAVE COME ABOUT BY SMARTER AND FASTER PROCESSING. SO OUR HEARING AID TECHNOLOGY IS EMULATE OWRG CELL PHONES AN LAB TOP TECHNOLOGY AND BEING ABLE TO DO GREAT THINGS IN SMALLER PACKAGES. WE NEED TO NOTE THAT NORMAL HEARING IS NOT RESTORED WITH AMPLIFICATION AND DOES REQUIRE A PERIOD OF ADAPTATION WHEN USING HEARING AITS. THE TECHNOLOGY HAS I THINK EFFECTIVELY ADDRESSED THIS QUESTION OF COZ MEESIS, I WOULD CHALLENGE ANY BLUE TOOTH WEARER FIND A TECHNOLOGY THAT ALLOWS YOU THE USE BLUE TOOTH THAT LOOKS BETTER THAN CURRENT HEARING AID DESIGN. LET'S FINISH UP WITH A DISCUSSION OF PROFOUND HEARING LOSS, THIS BY DEFINITION IS A PROGRESSION OF HEARING LOSS THAT GOES TO THE LEVEL WHERE HEARING AID IS NOT GOING TO PROVIDE MEANINGFUL BENEFIT. THE PROBLEM HERE IS THAT AMPLIFICATION IS CAPABLE OF PROVIDING 30 TO 35 DB BUT WHEN A PROFOUND SENSORY NEURAL HEARING LOSS IS PRESENT, WHEN DEAFNESS IS PRESENT, YOU CAN SEE THAT WITH AMPLIFICATION YOU JUST DON'T ACCESS THE KEY BUILDING BLOCKS OF SPEECH AND PARTICULARLY THE HIGH FREQUENCY CONSONANT INFORMATION WHICH IS RESPONSIBLE FOR 75% OF SILL BILL UNDERSTANDING IN SPOKEN ENGLISH. THE ADVENT OF A COCHLEAR IMPLANT SERENDIPITOUSLY DISCOVERED IN 1954 REFINED THROUGH THE 1980s AND 1990s, TO NOW BEING AN INTERVENTION HAVING PLACED 200,000 INDIVIDUALS WORLD WIDE, HALF IN THE UNITED STATES, THIS TECHNOLOGY PLACES AN ARRAY OF CONTACTS IN TO THE COCHLEA, IT DISTRIBUTES THOSE ARRAYS, ARRAY OF CONTACTS ACROSS THE ABERRANT NERVE BUNDLE IN ORDER TO DIRECTLY STIMULATE THOSE NERVE FIBERS THAT ARE NOT BEING ACTIVATED BY HAIR CELLS BECAUSE THEY HAVE EITHER BEEN LOST OR ARE DEFECTIVE. THE TECHNOLOGY HAS BECOME INCREASINGLY REFINED SO THAT WE CAN SEPARATE CHANNELS AND WE CAN PROVIDE VERY DISCRETE STIMULATIONS ACROSS DIFFERENT ELECTRODE PAIRS. IN THE 19 0s WE HAD CRUDE TECHNOLOGY THAT DIDN'T PROVIDE THE KIND OF CHANNEL FUNCTIONING THAT WE NEED FOR NATURAL SOUND. IN THE 1980s WE WERE TOLD BY PATIENTS THAT IT SOUNDS GREAT, IT SOUNDS LIKE A RO BT. -- ROBOT. I CAN UNDERSTAND WHAT'S BEING SAID BUT IT SOUNDS LIKE A ROBOT. WE HEARD ROBOT. ONE CAN IMAGINE WHY THAT WOULD BE. IF YOU LOOK AT THE SPECTROGRAM HERE HOW THE FREQUENCIES LAID OUT, THE WORD OF THREE FULL NAME WORD LIKE CHOICE, CAME OUT OF CHOICE. AND YOU CAN SEE THAT THAT WAS NOT WOULD NOT GIVE RISE TO MUCH DIFFERENTIATION OF PITCH. THAT IMPROVED THROUGH THE 1990s AS WE ADDED MORE FILTERS, WE ADDED MORE CAPACITY TO STIMULATE ACROSS CHANNELS, TO GIVE US WHAT IS PROBABLY A MORE NATURAL SOUNDING INPUT TO NOW WHERE IN FACT YOU WILL HEAR SHORTLY FROM MS. GRACIE CAWAL THE SPEECH OF A MODERN COCHLEAR IMPLANT USER THAT REFLECTS IN FACT THE KIND OF TECHNOLOGY THAT IS CAPABLE OF PUTTING OUT A VERY HIGH FIDELITY SIGNAL. SO LET'S LOOK AT A QUICK EXAMPLE HOW THIS TECHNOLOGY FUNCTIONS. >> ACROSS THE ARRAY WE'RE GOING TO STIMULATE THE AUDITORY NERVE. THAT ARRAY IS IMPLANTED TO THE COCHLEA HERE. THOSE CURRENT INJECTIONS STIMULATE AUDITORY NERVE FIBER. NOW, WITH COCHLEAR IMPLANT ACTIVATION WITH ELECTRICAL HEARING WE CAN OVERCOME THE LARGE GAP MANY INTENSITY AND PROVIDE 70 TO 80-DECIBEL IMPROVEMENT IN THREB HOLE. WE CAN EASILY -- THRESHOLD. WE CAN GET THIS INDIVIDUAL'S HEARING INTO THAT THE AREA WHERE THEY CAN EASILY ACCESS SPEECH SIGNAL. AS A RESULT, WE HAVE SEEN THIS REMARKABLE STEADY IMPROVEMENT IN THE ABILITY TO UNDERSTAND SPEECH USING THIS TECHNOLOGY AS WE PROVIDED GREATER AMOUNTS OF FIDELITY THROUGH MULTIPLE CHANNELS STIMULATION OF AUDITORY NEURONS, ATTEMPTING TO DO IT IN THE SAME WAY THE 35,000 FIBERS ARE NORMALLY ACTIVATED BY HAIR CELLS. NOW, THERE'S NO PLACE WHERE THIS HAS PLAYED OUT MORE DRAMATICALLY THAN IN PROVIDING OPTIONS TO HEARING FAMILIES OF CHILDREN WHO ARE DEFENSE. AND -- DEAF. AND WHILE THERE ARE CULTURAL CONTROVERSIES RELATED TO THIS, THE VAST MAJORITY OF CHILDREN WHO ARE BORN DEAF ARE BORN TO A HEARING FAMILY. SO ONE CAN IMAGINE THAT THE FAMILIES ROLE IN ACULTURE ATING THE CHILD THROUGH THE USE OF NATIVE LANGUAGE IS POTENTIALLY IMPAIRED WHEN A HEARING FAMILY TRIES THE ADOPT SIGN LANGUAGE FOR A DEAF CHILD. STUDIES HAVE SHOWN THAT MOMS ON AVERAGE WILL FIND AT A 10 TO 12-YEAR-OLD LEVEL OF LANGUAGE. DADS AS YOU CAN GUESS 7 OR 8, LEVEL OF LANGUAGE SO YOU CAN IMAGINE THAT CHILD IS GOING TO BUMP UP INTO SOME ECTS OF THE LANGUAGE LEVEL AT HOME, IF SIGN LANGUAGE IS THE PRIMARY MODE. ONE OF THE MOST IMPRESSIVE THINGS ABOUT THIS TECHNOLOGY THEN IS THAT IT GIVES FAMILIES OF DEAF CHILDREN THE OPPORTUNITY TO PROVIDE ACOUSTIC AND TO NETTIC ACCESS FOR THEIR CHILDREN TO THE VERBAL COMMUNICATIONS ATS HOME. IN FACT, WHEN WE BUILD ON THOSE IN THE SCHOOL ENVIRONMENT WE CAN SEE THAT THERE MAYBE SCHOLASTIC ACHIEVEMENT IN SOCIAL VERSATILITY. FINALLY GOING ON HOPEFULLY TO THE FULL RANGE OF EDUCATIONAL AND VOCATIONAL OPTIONS, SOCIAL INDEPENDENCE AN NORMAL LIFE CHANCES. NOW, WE HAVE FELT ALL ALONG THAT THE EARLIER WE COULD PLACE THE DEVICE, THE MORE WE CAN LEVERAGE NEURONAL PLASTICITY CENTRAL PROCESSING CAPACITY TO ALLOW CHILDREN TO DEVELOP THEIR PERCEPTUAL REPERTOIRE AROUND THE IMPLANT EXPERIENCE IN ELECTRICAL HAIRING. IN THE 80s, WE THOUGHT PLANNING KIDS AT AGE 10 WOULD BE EARLY INTERVENTION AND WOULD BE VERY EFFECTIVE. IT WAS NOT. IT WAS A FAILURE. SO MANY OF THE INDIVIDUALS THAT WE SEE IMPLANNED IN CHILDHOOD IN THE 1980s HAVE BECOME USERS. A SULLIED REPUTATION BECAUSE OF THAT. BUT AS WE GAINED CONFIDENCE WITH EARLIER AND EARLIER INTERVENTION AS WE HAVE GONE THROUGH THE DECADES WE HAVE INTERVENED EARLIER. ONE QUESTION WE HAVE ASKED IN A MULTI-CENTER STUDY FUNDED BY THE NIDCD IS WHETHER THERE'S A POINT BEFORE WHICH IMPLANTATION IS LIKELY TO RESULT IN SUCCESS IN SPOKEN LANGUAGE USE BY PROVIDING EFFECTIVE HEARING. AND AFTER WHICH IF WE IMPLANT THAT CHILD IS THE OUTCOME CI MY NISHED. WITH EARLY DETECTION WITH UNIVERSAL NEWBORN SCREENING WE HAVE THE OPPORTUNITY TO IMPLANT CHILDREN UNDER THE AGE OF 15 TO 18 MONTHS QUITE ROUTINELY NOW, SO WE HAVE THE OPPORTUNITY TO LOOK AT THESE QUESTIONS. THE REAL DYNAMICS OF SPOKEN LANGUAGE LEARNING IS WE BEGIN WITH A PRECISE AN RELIABLE ENCODING THAT IS AT THE LEVEL OF DETECTION. THEN WE BUILD ON THAT DETECTION ABILITY TO DISCRIMINATE BETWEEN CELLS, TO IDENTIFY RECOGNIZABLE SOUNDS, RECOGNIZING SOUNDS IN A PARTICULAR COMBINATION LIKE CHOICE, MEANS SOMETHING AND THEY HAVE A PARTICULAR MEANING. THAT ALLOWS US THEN TO PUT ALL THIS TOGETHER TO PROVIDE US WITH THE ABILITY TO EXPRESS OURSELVES IN A REFINED NUANCED WAY USING SPOKEN LANGUAGE AND COMPREHENDING THAT LANGUAGE. SO ORAL LANGUAGE EMERGES AS SOUND IS ENCODED IN THE CONTEXT OF A SPEAKER'S THOUGHTS OVER AN EXPERIENCE. ONE WAY TO LOOK AT THE ABILITY TO ACCESS THAT HIERARCHY IS IN ANIMAL MODELS AND SOME WORK THAT WE DID -- WORK WE DID OVER THE PAST 15 YEARS IN THE LABORATORIES OF DR. DAVID RIUGO HAVE USED THE CONGENITALLY DEAF WHITE CAT, AN ANIMAL ANALOG OF THE THE WARDENBERG SYNDROME DR. FRIEDMAN MENTIONED. WE USED A IMPLANT SHOWN HERE WITH ARRAY OF CONTACTS THAT IS SHOWN RIGHT THERE PLACED IN TO THE INNER EAR. LET'S LOOK AT HOW THIS CAT BEHAVES IN RESPONSE TO SOUND. THIS CAT HAS BEEN TRAINED TO ATTEND TO ONE PARTICULAR STIMULUS USING A POSITIVE REINFORCEMENT PARADIGM. >> I'M NOT ABLE TO FIND THE ARROW, THE POINTER. THERE WE ARE. (INDISCERNIBLE) SO OUR CATS ARE NAMED AFTER THE CONDIMENTS YOU CAN GET OUT OF PIZZA, SO WE GO DOWN THE PIZZA LIVE IN THE LAB. THAT WAS ANCHOVY. AND ANCHOVY WAS TRAINED TO RESPOND TO A FINGER SNAP. AND WE USE DIFFERENT STIMULI. WE HAVE ONE THAT IS TRAINED ON BCH AND BAY BEETHOVEN DOES B WAKE HIM UP, IT'S AMAZING HOW IN FACT THESE CATS ARE ABLE TO DEVELOP PROBABLY SOMETHING WELL BEYOND SIMPLE PARADIGMS OF DETECTION AND DISCRIMINATION BUT THEY PRECISELY AN RELIABLY ENCODE SIGNALS THAT ARE REQUIRED FOR HIGHER OPENING -- FOR THE OPENING OF HIGHER LEVELS OF PROCESSING. COCHLEAR IMPLANTATION PROVIDES THIS IN CHILDREN. BUT THE RANGE OF VARIATION IS GREAT. SO TO CHARACTERIZE THAT VARIATION OUR MULTI-CENTER STUDY RECRUITED 188 CHILDREN FROM 6 CENTERS, 97 NORMAL HEARING CONTROLS. WE HAVE USED HIERARCHICAL TESTING OF SEVERAL DOMAINS OF COMMUNICATION AND IN THIS CASE WHAT YOU SEE BEFORE YOU LAID OUT IS THE HIERARCHICAL MEASURES OF LANGUAGE THAT GO FROM VERY SIMPLE CONSTRUCTS OF EARLY DEVELOPMENT TO MORE PRECISE MEASURES OF SPOKEN LANGUAGE SKILLS AND GIVE RISE ULTIMATELY. THESE WILL GIVE RISE TO SAT SCORES AND SO FORTH AS THESE KIDS ARE GROWING. TO HELP YOU EYE BALL THE DATA SETS THAT I'M GOING TO SHARE WITH YOU NOW, I'M GOING TO BREAK THEM UP INTO THREE GROUPINGS DEPENDING WHETHER CHILDREN WERE IMPLANTED UNDER AGE OF 18 MONTHS AND EARLY TODDLER STAGES BETWEEN ONE AND A HALF AND 3 YEARS OF AGE AND OVER THE AGE OF 3. WHAT WE SEE IS THAT THE EARLY IMPLANT GROUP SHOWS A TRAJECTORY OF DEVELOPMENT OF THEIR VERBAL LANGUAGE COMPREHENSION SKILLS THAT LOOKS LIKE THIS, THE OLDER -- YOUNGER TODDLERS LIKE THIS. AND THE OLDER TODDLERS, SOMETHING LIKE THIS. THEIR NORMAL HEARING DEPENDING ON THE TEST AGE WHEN THEY WERE IN FACT EVALUATED. IN THE ABSTRACT THAT PROBABLY DOESN'T MEAN AS MUCH AS SIMPLE REPRESENTATION OF MEANS ACROSS VARIOUS AGE GROUPS. YOU CAN SEE EARLY IMPLANTATION FOR THOSE CHILDREN UNDER AGE OF 18 MONTHS SHOWS A TRA WRECK TORRY THAT STAYS WITHIN ONE STANDARD DEVIATION OF NORMAL HEARING PEERS SHOWN IN WHITE. WHEREAS WE SEW A FALL OFF FOR THE KIDS IMPLANTED LATER IN THEIR TODDLER STAGES. THE VAST MAJORITY OF CHILDREN WHO RECEIVED AN IMPLANT IN THIS STUDY, 180 ARE ABOVE THIS LINE WHICH WOULD HAVE BEEN THEIR MEAN OF LANGUAGE LEARNING PROJECTED FROM BASELINE SCORE SO THEY BENEFITED AS A POPULATION IMMENSELY. ONE THING THAT HAS COME FROM THIS STUDY IS NEW INFORMATION IN THE FIELD, THERE ARE ROBUST EFFECTS OF SOCIOECONOMICS. WE KNOW THAT SOCIOECONOMICS AFFECTS LANGUAGE LEARNING BUT WE DIDN'T HAVE A SENSE FOR THE IMPORTANCE THAT THIS FACTOR, THIS MODIFIER MAY HAVE FOR COCHLEAR IMPLANTATION BUT IT DOES SEEM YOU SEE IN THE SOLID LINES THE TRAJECTORY OF KIDS FROM FAMILIES WITH INCOMES OVER $50,000 PER YEAR, THE DOLTED LINE -- DOTTED LINE UNDER $50,000 PER YEAR, THIS REHABILITATIVE STRATEGY TAXES A LOWER SOCIOECONOMIC FAMILY IN A WAY THAT PRODUCES THE VERY DIFFERENT RESULT. IF YOU'RE INTERESTED IN DETAILS I'LL REFER YOU TO AN ARTICLE IN JAMA A YEAR AGO THAT SUMMARIZES A GREAT NUMBER OF VARIABLES. I WOULD LIKE TO MOVE ALONG BECAUSE INTO SPEND THE LAST 15 MINUTES EXAMINING WHAT I CONSIDER TO BE THE MOST IMPORTANT ASPECT OF THIS STUDY WHICH IS OUR ASSESSMENT OF MATERNAL INPUT INTO LANGUAGE LEARNING OF A CHILD BORN WITHOUT HEARING WHO RECEIVED A CONVENTIONAL INTERVENTION LIKE A COCHLEAR IMPLANT. WE KNOW THAT EARLY LANGUAGE LEARNERS FIND THE LANGUAGE THEY NEED IN THE SPEECH OF THEIR PARENTS. THAT'S WELL RECOGNIZED IN HIGH SOCIOECONOMIC ENVIRONMENTS YOU SEE HIGHER EDUCATION LEVELS, MORE UTTERANCES PER YUN TIME BUT YOU ALSO SEE A QUALITATIVELY DIFFERENT TYPE OF UTTERANCE THAT IS PRODUCED IN THOSE HOUSEHOLD WHERE IS IT TEBDZ TO BE A MORE ENCOURAGING EXEMPLOYERTORY TYPE OF LANGUAGE USED THAN IS USED IN THOSE ENVIRONMENTS. UNFORTUNATELY IN LOWER SOCIOECONOMIC ENVIRONMENT CONVERSELY WE SEE A FORM OF DISCOURAGING LANGUAGE THAT IS OFTENTIMES PUNITIVE AND DOES NOT FOSTER SPOKEN LANGUAGE GROWTH. MA TERM SENSITIVITY IN EARLY LANGUAGE LEARNING IS THE CONSTRUCT WE EXPLORED IN OUR STUDY WHERE IN FACT A CARE GIVER USES A LINGUISTIC SYMBOL, SAY SOMETHING LIKE A HOUSE, A TOY OF A HOUSE, AND IN FACT SIGNALS THE SENT INTENT TO THE CHILD THAT HE OR SHE SHOULD SHARE ATTENTION TO THE CONCEPT OF A HOUSE. THIS ESTABLISHES A JOINT ATTENTIONAL FRAME, THE COMMUNICATIVE INTENT OF THE CARE GIVER AND OVER TIME ENCOURAGES THAT CHILD TO IN FACT TAKE AN IDEA LIKE A HOUSE AND SHARE BACK TO BEGIN THE IMITATIVE LEARNING PROCESS THAT GIVES RISE TO EFFECTIVE SPOKEN LANGUAGE USE. SO LET US TAKE A QUICK LOOK AT A MOM WHO IS ENGAGED IN THIS KIND OF INTERACTION. >> GRACIE, STAND UP. DO YOU KNOW WHO THAT LITTLE GIRL IS? COME ON OVER HEREMENT WHY DON'T YOUR MOM AN SISTER COME OVER AS WELL. WHY DONE YOU HOLD THIS, YOU CAN HAVE A SEAT THERE. THIS IS GRACIE AND HERRER KELLY AND HER MOM ANDY CRAWLEY KUWAL. GRAY SIRKS HOW HOLE WERE YOU WHEN YOU RECEIVED YOUR FIRST COCHLEAR IMPLANT. >> ONE. >> YOU WANT TO SPEAK INTO THE MIC. >> I WAS ONE YEARS OLE. >> WHEN DID YOU GET YOUR SECOND COCHLEAR IP PLANT IN THE OTHER EAR? >> I GOT IT IN -- I GOT THE SURGERY IN DECEMBER BUT I GOT ACTIVATED IN JANUARY. >> THIS PAST YEAR. >> YES. >> THIS YEAR SO YOU JUST HAD NOT QUITE A YEAR EXPERIENCE WITH THE SECOND COCHLEAR. >> THREE MONTHS. SO AFTER GRACIE RECEIVED HER COCHLEAR IMPLANT, YOU RECOGNIZE THIS YOUNG LADY AS WELL? SHE BECAME A BIT OF A POSTER CHILD FOR OUR PROGRAM, AT JOHNS HOPKINS. YOU CAN SEE WHY WE CHOSE HER. TBRAI SI, YOU STARTED SCHOOL AFTER YOU RECEIVED YOUR FIRST COCHLEAR IMPLANT WHERE? WHERE DID YOU GO TO SCHOOL IN >> AT THE BIB LER SCHOOL. >> WHERE DO YOU GO TO SCHOOL NOW? >> NEXT YEAR BECAUSE I'M GRADUATING. >> SOW YOU ARE ABOUT TO GRADUATE FROM THE RIVER SCL OF WASHINGTON D.C., IS THAT CORRECT? >> YES. >> CAN YOU TELL US ABOUT THE RIVER SCHOOL AT WASHINGTON D.C.? >> IT'S A GREAT SCHOOL FOR ME BECAUSE THE CLASSROOMS HAVE A SYSTEM WHERE A TEACHER WEAR AS MICROPHONE, IT KIND OF MAKES THE VOICE LOUDER, MAKES IT EASIER TO HEAR THEM. AND THE SCHOOLS ARE SMALL CLASSES ARE SMALL SO NOT A LOT GOING ON AT THE TIME. AND THERE ARE PEOPLE THERE WHO GUIDE ME ALONG TO HELP ME WITH MY KNEW EARS OR BOTH EARS. I'VE KIND OF SAD TO LEAVE IT BUT I KNOW IT WILL BE A GOOD CHANGE IN MY NEW SCHOOL. >> TIME TO GO OUT IN THE REAL WORLD. >> YES. >> KELLY, WHERE DO YOU GO TO SCHOOL? >> I GO TO THE SAME PLACE. >> HOW YOUR HEAR SOMETHING >> IT'S FINE. >> IT'S FINE. AND YOU HAVE GOB TO SCHOOL WITH KIDS WHO USE COCHLEAR IMPLANTS SINCE YOU WERE JUST A LITTLE GIRL, RIGHT? >> YES. >> WHAT'S THAT LIKE BEING IN A CLASSROOM WITH A CHILD WHO HAS GOT A COCHLEAR IMPLANT? WELL, SOMETIMES YOU JUST TALK A LOT AND IT'S LIKE WHEN YOU'RE DOING LIKE HOME WORK DOING AN ACTIVITY, WE -- TWO KIDS FROM MY CLASS THAT HAVE CIs AND THEY SOMETIMES HAVE TROUBLE SAYING SENTENCES AND LISTENING. SO IT'S ACTUALLY KIND OF SLOW IN MY CLASS. P >> DO YOU HELP THEM SOMETIMES IN >> YES. >> DO YOU HELP THEM UNDERSTAND WORDS AND HOW TO PUT A SENTENCE TOGETHER? >> UH-HUH. >> THAT'S GREAT. THAT WOULD BE AN INTERESTING EXPERIENCE BECAUSE YOU SORT OF BECOME THE TEACHER, DON'T YOU? >> A LITTLE BIT. >> TERRIFIC. >> ARE YOU THE DEMOB STRAITER IN YOUR CLASS? >> YES. -- DEMONSTRATOR. >> AND COULD YOU TELL US WHAT THE DEMONSTRATOR DOES? >> APPARENTLY IN KELLY'S CLASS SHE'S THE ONE WHO ACTS THINGS OUT TO HELP DEMONSTRATE THE DIFFERENCE BETWEEN TWO WORDS. SHE I SUPPOSE HAS A HAMMISH QUALITY TO HER PERSONALITY. IF THE CHILDREN IN THE CLASS WITH COCHLEAR IMPLANTS HAVE A HARD TIME DISCRIMINATING BETWEEN TWO DIFFERENT WORDS THEY'LL ASK KELLY TO ACT OUT THE DIFFERENCE BETWEEN THE TWO WORDS. >> AS I MENTIONED, WE HAVE A LARGE MULTI-CENTER STUDY GOING ON RIGHT NOW AND ONE OF THE THINGS THAT COMES FROM THAT STUDY IS THAT WE SEE WHEN MOMS ACT LIKE THIS, WE SEE A RESULT THAT THAT IS THE MOST PROFOUND EFFECT ON A CHILD'S LANGUAGE LEARNING ABILITY, NINE YEARS LATER AS WE SEE IN GRACIE, SO WE LITERALLY HAVE STATISTICALLY ANALYZED 70 VARIABLES, WE CAN FIND NOTHING THAT MATCHES THAT INPUT FOR LATER LANGUAGE NG. WHAT'S GOING ON IN THE MIND OF A YOUNG MOM WHO HAS HAD PERFECT HEARING WITH A DEAF CHILD THAT ALLOWS HER TO DO THAT? >> MY HEARING WAS PERFECT BACK THEN. I LOST A LOT OF IT ABOUT A YEAR AGO BUT YOU KIND OF ARE LOOKING DESPERATELY FOR WAY TO COMMUNICATE. WE LEARNED EARLY THAT GRACE WAS DEAF BUT IT FELT LIKE A LONG TIME HAD PASSED. SHE WAS FOUR AND A HALF MONTHS OLE WHEN SHE WAS DIAGNOSED WITH HER PROFOUND HEARING LOSS. AND AT THAT TIME IT SORT OF FELT LIKE EVERYTHING HAD BEEN WASTED, ALL THE -- SHE DIDN'T KNOW WHAT HER NAME WAS AND DIDN'T KNOW WHAT MY VOICE SOUNDED LIKE AND SHE DIDN'T HEAR ME SINGING TO HER AND YOU THINK ABOUT THOSE THINGIOUS EAR NEVER GOING TO HAVE AND I HAD NEVER HEARD OF A COCHLEAR IMPLAN WHEN WE FOUND OUT THAT SHE WAS DEAF. SO THEN YOU SORT OF VERY QUICKLY TRY TO FIGURE OUT HOW TO MAKE UP FOR THAT LOST TIME AN FIND A WAY TO COMMUNICATE. AND ACTUALLY HAVING ACCESS TO GALLUDET NEARBY AND LEARNING SIGN LANGUAGE AND TO BE ABLE TO OBSERVE OTHER DEAF FAMILIES WHO WERE SO VISUALLY STIMULATING WITH THEIR CHILDREN, WAS A REALLY IMPORTANT LESSON I THINK BECAUSE IT GAVE ME A MEANS FOR COMMUNICATING WITH HER. SO I COULD HAVE JUST KEPT TALKING TO HER AND SHE COULD HAVE SEEN MY LIPS MOVING AND SHE MIGHT HAVE GOTTEN SOMETHING OUT OF THAT BUT UP UNTIL SHE WAS ONE THIS WAS THE ONLY WAY THAT WE CAN COMMUNICATE WITH HER. I WAS ABSOLUTELY DETERMINED TO BE COMMUNICATING WITH HER IN ANY WAY THAT I CAN. SO SHE WAS MY FIRST AND YOU'RE PRETTY ATTACHED TO THE IDEA OF BEING ABLE TO GIVE THEM EVERYTHING. SO THAT WAS PRETTY -- I DIDN'T THINK ABOUT IT, JUST KIND OF HOW I FOUND WAY TO TALK TO HER. >> SO THAT WAS ONE MONTH BEFORE SHE RECEIVED HER FIRST COCHLEAR IMPLANT? >> SHE WAS TEN MONTHS OLD IN THAT ONE. >> GREAT. SO GRACIE, I VISITED YOUR SCHOOL RECENTLY AND WHEN I DID THEY GAVE ME A COPY OF A BOOK THAT YOU WROTE. AND THIS -- >> WHICH ONE? I WROTE TWO. >> TWO BOOKS? >> YES. WHICH ONE IS IT? >> THIS IS ALL ABOUT DEAF PEOPLE. IS THAT THE FIRST OR THE SECOND BOOK? >> THAT'S THE SECOND BOOK I WROTE IN SCHOOL. THE FIRST ONE THAT I WROTE I WAS A LITTLE BIT OLDER THAN MY SISTER WHO IS NOW 6 1/2, I WAS ABOUT 7 AND MY -- I COMPLETELY BROKE DOWN AND I KIND OF WROTE DOWN ONE WHAT IT WAS LIKE, IMMEDIATELY NOT BE ABLE TO HEAR ANYTHING FOR A LONG PERIOD OF TIME. IT KIND OF STARTLED ME THEN ALL OF A SUDDEN I'M NOT HEARING AND I WROTE A BOOK ABOUT IT THAT NIGHT BECAUSE I WAS KIND OF UPSET. I DIDN'T LIKE NOT BEING ABLE TO HEAR PEOPLE. >> SO YOU HAD TO FIND A WAY TO COMMUNICATE. YOU WROTE A BOOK. >> EXACTLY. AND MY MOM HELPED ME OUT WITH THAT. AND THE NEXT DAY (INDISCERNIBLE) WE STILL DONE KNOW AND I WAS FINE AGAIN. THAT'S MY SECOND. >> OKAY. THIS IS THE SECOND BOOK THEN. OKAY. THIS BOOK HAS SEVEN CHAPTERS. AND ONE OF THE CHAPTERS IS THE GOOD THINGS ABOUT BEING DEAF. NOW, I HAVE HEARD YOU TALK ABOUT BEFORE BUT COULD YOU SHARE WITH THIS AUDIENCE WHAT -- TELL US WHAT THE GOOD THINGS ABOUT BEING DEAF MIGHT BE OR GIVE US AN EXAMPLE OF THAT? >> OKAY. WELL, PRETEND THAT YOU'RE BEING REALLY ANNOYING, I CAN JUST BOP UP MY CI. >> SO YOU CAN JUST TAKE OFF YOUR CI. AND WHAT HAPPENS THEN? >> DISM SOMETIMES MY MOM IS SCREAMING AT ME AND I DON'T WANT TO HEAR HER. [LAUGHTER] >> BUT THERE'S SOME OTHER TIMES -- THERE ARE SOME OTHER TIMES WHEN THERE ARE NOISES THAT ANNOY ME OR BUG ME OR I FEEL AREN'T SUPPOSED TO BE THERE AND I JUST TAKE OFF MY CI, I CAN HEAR ANYTHING. >> SO WE DONE REALLY WANT TO HEAR EVERYTHING IN THE WORLD OUT THERE, IS THAT RIGHT? >> THAT'S KIND OF TRUE. YES. >> I UNDERSTAND RECENTLY YOU HAVE STUDIED SOMETHING AT SCHOOL CALLED THE PERIODIC TABLE OF ELEMENTS. >> OKAY. YEAH. I DID. >> WE HAVE A LOT OF SCIENTISTS IN THE ROOM WHO LEARNED ABOUT THAT A LONG TIME AGO. WHAT IS THAT ABOUT? WHAT IS THE PERIODIC TABLE OF ELEMENTS FOR? >> WHAT IS IT PURPOSE? >> THE MAKE UP THE WORLD OF 114 OF THEM, THEY COME IN COMBINATIONS LIKE SODIUM AL JENATE OR HYDROGEN PEROXIDE IS ONE. CARBON DIOXIDE. GOLD. SILVER, THERE ARE PLENTY. AND (INDISCERNIBLE) >> I JUST HEARD YOU WERE FASCINATED WITH THE PERIODIC TABLE OF ELEMENTS AND I CAN TELL YOU LEARNED A LOT FROM THAT SECTION OF YOUR SCIENCE TRAINING AND I THINK YOU'RE GETTING READY TO COME TO THE NIH TO WORK HERE FULL TIME. DON'T YOU? [LAUGHTER] >> SO -- >> I THINK YOU'RE ON YOUR WAY. CAN WE ASK IF THE AUDIENCE HAS ANY QUESTIONS AT ALL? >> SOUND GREAT. DO YOU GUY VERSUS ANY QUESTIONS? (OFF MIC) >> YES, IT TURNS OUT I LOVE MUSIC. I THINK THAT ME AND MY MOM REALLY, REALLY HAPPY. >> THEY WANT ME TO REPEAT THE QUESTION. GREAT QUESTION ABOUT GRACIE'S APPRECIATION OF MUSIC AND WHETHER SHE LIKES TO SING. HOW DO YOU LISTEN TO MUSIC? >> I LIKE PIANO AND I LIKE GUITAR. I LIKE NOT COMPLETELY ROCK AND ROLL BECAUSE I CAN'T MAKE A WORD OF WHAT THE SINGERS ARE SAYING BUT I PREFER NOT TOO MELLOW. >> DO YOU PLAY PIANO YOURSELF? >> YES. I TAKE LESSONS AND I HAVE TO TAKE GUITAR LESSONS. WHICH I PLAYED A LITTLE MORE OFTEN. >> WHO IS YOUR FAVORITE MUSIC ARTIST? >> (INAUDIBLE). >> SAY U IT AGAIN. >> REGINA SPECTOR. >> THAT'S A NEW ONE FOR ME, THEY'RE ALL NEW FOR ME THESE DAYS. (OFF MIC) >> SO THE QUESTION IS, WHAT DID YOU NOTICE THE MOST WHEN YOU RECEIVED THE SECOND IMPLANT? >> ACTUALLY IT IS -- I CAN FOCUS MORE EASILY ON PEOPLE AND EVERYTHING'S SLIGHTLY MORE AMPLIFIED. AND I CAN LIKE I WAS KIND OF TESTING IT DURING THE SPEECH THAT YOU WERE MAKING DR. DI PAR CO-AND I KEPT TAKING OFF MY RIGHT EAR AND THE SOUND WOULD TRAVEL FROM -- TO DROPPING DOWN. AND AS SOON AS I PUT IT BACK ON I WOULD FIND THE DIFFERENCE, IT WAS LOUDER. AND I (INAUDIBLE) FOR THREE MONTHS SO I'M KIND OF SURPRISED. AS THE AMPLIFICATION AND THE FOCUS. >> SO THAT'S CALLED BINORMAL SUMMATION. AND THAT'S WHERE TWO YEARS WE'LL HEAR THE SAME SIGNAL LOUDER THAN ONE EAR WOULD HEAR. BUT LET ME ASK YOU, IF CALI IS CALLING FOR YOU NOW WITH TWO IMPLANTS DO YOU KNOW WHERE SHE IS IN HOUSE, BETTER THAN BEFORE WHEN YOU JUST HAD ONE? >> YES, MUCH BETTER. STIEPS I GOT IT WRONG BUT IT WOULD BE LIKE 75%, ALWAYS CORRECT WHICH IS GREAT BECAUSE USUALLY I WOULD BE LIKE 10% CORRECT. >> OKAY. INTERESTING. OKAY. OTHER QUESTIONS? >> WHY DID WE WAIT SO LONG FOR THE SECOND IMPLANT? I THINK MAYBE WE ALL HAVE AN ANSWER FOR THAT. ALL BE A LITTLE BIT RESPONSIBLE BUT WHAT'S YOUR UNDERSTANDING? >> AT FIRST I DIDN'T REALLY SEE A REASON. I WAS LIKE WHY GET A SECOND EAR? I'M PERFECT WITH THE LEFT ONE. MY PARENTS AND MY AUDIOLOGIST KEEP CONVINCING ME TO TRY AND GET A SECOND ONE AND EVERY TIME I POINT THIS OUT THEY'RE LIKE NO WE'RE NOT CONVINCING YOU JUST GIVING YOU AN EXAMPLE. FINALLY IT WAS SOMETHING CHANGED MY MIND. WHY NOT? I MEAN, WHY DON'T I GET A SECOND EAR? IT MIGHT HELP ME AND MY FRIEND MY MY SHE GOT HER SECOND CICS A LITTLE BIT BEFORE ME, ALMOST LIKE A GUINEA PIG OR MOUSE, A DESCRIPTION. AND SHE PREFERS IT TO BE CALLED A CAT. SHE LIKES THEM BETTER. (OFF MIC) >> EXACTLY. BUT SHE KIND OF SHOWED A GOOD EXAMPLE FOR ME, SHE HAD BEEN IMPROVING A LOT WITH HER NEW CI AND SO I FINALLY DECIDED THAT I WOULD UP TO TAKING IT. THE REASON WHY IT TOOK ME SO LONG KIND OF I DIDN'T SEE THE REASON. BUT THINGS STARTED TO PIECE TOGETHER. >> YOUR IMPLANT CENTER HELD A CONSERVATIVE VIEW POINT OF THIS. WE FELT THAT IF LANGUAGE LEVELS WERE AGE APPROPRIATE WE REALLY DIDN'T HAVE GOOD EVIDENCE THAT BINEURAL INPUTS WOULD PROVIDE LOCALIZATION AND SPEECH AND NOISE HEARING BUT AS THAT LITERATURE STARTED TO SHOW EFFECTS IN FACT WE BECAME MUCH MORE OPEN TO THE POSSIBILITIES OF THAT AND OUR OWN RESEARCH WAS SHOWING IN FACT THAT THERE WERE SIGNIFICANT GAINS THAT WERE TAKING TWO TO THREE YEARS TO MANIFEST. SO IT WAS NOT AN EARLY EFFECT. BUT WE SAW DRAMATIC IMPROVEMENTS BILATERAL IMPLANTATION PARTICULARLY FOR KIDS IMPLANTED UNDER THE AGE OF 12 WITH THEIR SECOND IMPLANT. (OFF MIC) >> SOMETIMES. (OFF MIC) >> THE QUESTION IS WHETHER CALI HAS NOTICED DIFFERENCES IN GRAYSIS'S RESPONSE BEHAVIORS AND HOW SHE'S LISTENING WITH THAT SECOND IMPLANT. KALLEY, WHAT DO YOU THINK? YOU HAVE SEEN SOME CHANGES, HUH? >> SOMETIMES I JUST LIKE ONCE I WAS -- I USUALLY SEE THE DIFFERENCES BUT NOT ALWAYS. >> DEPENDING WHETHER SHE'S INTERESTED IN LISTENING TO YOU AT THAT TIME. I WONDER IF YOU CAN COMMENT ON THAT AS WELL. Q. SURE. THE LOCALIZATION IS -- HAS BEEN HUGE. BECAUSE SHE HAD NO THREE DIMENSIONAL -- NO TRIANGULATION. THAT HAS BEEN REALLY FAST. SO NOW WE CAN PLAY THIS GAME WHERE THERE'S FOUR OF US MINE HER AND WE MOVE AROUND TO DIFFERENT PLACES AND ONE OF US WILL CALL HER NAME AND SHE'LL GO LIKE THAT AND POINT TO WHERE WE ARE AND SHE COULDN'T DO THAT BEFORE. HER TEACHERS NOTICED WITHIN MAYBE TWO WEEKS OF THE ACTIVATION OF HER SECOND ONE THAT SHE WAS DOING MUCH, MUCH BETTER IN NOISY SITUATIONS. HONESTLY FOR ME AT HOME I HAVEN'T NOTICED THAT BIG OF A DIFFERENCE BUT IT'S NOT GENERALLY A CHALLENGING ENVIRONMENT AT HOME SO SHE'S DONE SO WELL WITH THE ONE WHICH WAS PART OF THE REASON THAT IT WAS A MORE DIFFICULT DECISION TO GO WITH THE SECOND ONE THAN IT WOULD HAVE BEEN FOR SOMEBODY WHO MAYBE WASN'T PERFORMING AS WELL AS PARENTS MIGHT HAVE HOPED SO WHEN YOU HAVE GOT A KID THAT'S TESTING SO HIGH AND THAT'S PERFORMING SO WELL AND IS SUCCEEDING SO WELL IN SCHOOL, GOING THROUGH THAT SURGERY IS A LITTLE BIT -- IT'S HARDER TO JUSTIFY. BUT GIVE ME BACK THE MIC SHE SAID. BUT SHE'S LEAVING THE SKOL WHICH IS A SUPPORTIVE ENVIRONMENT AND GOING TO A SCHOOL WHICH HAS SOME SUPPORTS IN PLACE BUT NOT THE SAME EXTENT AND I FELT IF WE CAN GIVE HER ANY BOOST TO SUPPORTER THE SOONER THE BETTER SO SHE WOULD HAVE THIS YEAR TO ADJUST AND HAVE THE AUDITORY THERAPY IN SCHOOL, HER CLASS HAS -- WITH A TEACHER AND SPEECH AND LANGUAGE PATHOLOGIST SO IT'S AN EXCELLENT WORLD FOR KIDS WITH A HEARING LOSS TO BE THERE. SO SHE'S NOW HAVING THE OPPORTUNITY TO ADJUST BEFORE MOVING INTO A TRICKIER ENVIRONMENT BUT WE NEEDED GRACE TO BUY INTO THAT BECAUSE SHE HAD TO DO ALL THE WORK. AND IT IS STARTING OVER AGAIN, SHE HADN'T BEEN IN SPEECH THERAPY SINCE SHE WAS 2 BUT SHE HAD TO START AGAIN BECAUSE SHE HAD TO TRAIN THE NEW EAR TO HEAR. SO UNLESS SHE WAS GOING TO BUY INTHE THAT THERE'S NO POINT DOING IT BUT WE GOT HER ON BOARD. HERE GRACE. >> ANY MORE QUESTIONS? >> YOU JUST WANTED THE MICROPHONE BACK. IS YOUR RIGHT HERE HEARING AS WELL AS YOUR FIRST EAR, YOUR LEFT EAR AT THIS POINT? IF YOU JUST TOOK YOUR LEFT IMPLANT OFF? >> I'M STARTING TO BE AUTOMOBILE TO HEAR VOICES BUT MAINLY IT'S KIND OF DEEP VOICE LIKE TOGETHER. IT'S NOT -- YOU COULDN'T CALL IT AN EXACT VOICE AND IT'S DEFINITELY NOT AD R AS GOOD BUT IT'S BEEN GETTING AROUND SO SAY THERE'S LIKE A PIE AND WHEN THE PIE IS ALL EATEN, IT'S FROM PRETTY MUCH ALL COVERED. MY LEFT EAR IS PRETTY MUCH -- MY LEFT EAR'S PIE IS PRETTY MUCH EATEN BUT THE RIGHT STILL HAS ABOUT LIKE 3 QUARTERS OF THE WAY. IT'S THREE QUARTERS EATEN. BE >> THAT'S PRETTY GOOD AFTER THREE OR FOUR MONTHS. ONE MORE QUESTION, PLEASE. (OFF MIC) >> DO YOU KNOW SIGN LANGUAGE? HOW MUCH SIGN LANGUAGE WOULD YOU USE IN AN AVERAGE DAY? >> SOMETIMES I USE MORE LIKE HAND MOTIONS THAN ACTUAL SIGN LANGUAGE BUT I USE IT SOMETIMES TO SECRETLY COMMUNICATE WITH MY FRIEND. >> WITH YOUR FRIENDS -- MY MY. >> YOUR FRIEND THAT HAS BILATERAL E >> IF SOMETHING IS REALLY BORENING A CLASS WE WOULD GO. THAT'S THE SIEB FOR BORING. I MADE TRIAL ON THAT ONE RIGHT AWAY. >> AND ANDY, HOW MUCH SIGN -- HOW MUCH SIGN LINK -- >> IT'S OUR BACK UP LANGUAGE AND WE DEFINITELY -- I WAS SIGNING TO THEM OVER HERE BECAUSE I DIDN'T WANT TO INTERRUPT ACROSS THE ROOM, I'LL OFTEN SIGN WITH HER BUT GRACE IS MORE A RECEPTIVE SIGNER BECAUSE EVEN WHEN HER CIs ARE OFF SHE STILL SPEAKS. SHE HAS REALLY BEAUTIFUL SPEECH EVEN WHEN SHE CAN'T HEAR HERSELF SO I'LL SIGN TO HER AND SHE'LL SPEAK BACK TO ME. DO YOU KNOW ANY SIGN LANGUAGE, CALI. >> A LITTLE BIT. I KNOW I KNOW STOP. THIS ONE IS STOP. THEY ALSO KNOW YES, NO, A. I CAN SPELL MY NAME. K A L I. >> THAT'S FANTASTIC. YOU HAVE TAUGHT US A WHOLE LOT TODAY. [APPLAUSE] >> I TOO WANT TO THANK YOU ON BEHALF OF ALL OF US, LOVELY YOUNG LADIES, FOR COMING TO BE WITH US. THANK YOU. BEST OF LUCK TO YOU. JIM, DO YOU WANT THE MAY ANY -- THANK YOU, VERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. 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WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. 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WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. WE APPRECIATE ALL OF OUR SPEAKERS AND WE LOOK FORWARD TO SEEING YOU NEXT WEEK. THANK ERY MUCH. THANK ERY MUCH.