1 00:00:06,473 --> 00:00:06,973 GOOD MORNING. 2 00:00:07,040 --> 00:00:08,742 MY NAME IS JOSEPH BREEN. 3 00:00:08,808 --> 00:00:10,410 I'M A PROGRAM OFFICIAL IN THE 4 00:00:10,477 --> 00:00:11,978 NATIONAL INSTITUTES OF ALLERGY 5 00:00:12,045 --> 00:00:15,915 AND INFECTIOUS DISEASE, AND I 6 00:00:15,982 --> 00:00:18,351 WANT TO WELCOME YOU TO THE 7 00:00:18,418 --> 00:00:20,854 ADVANCING ME/CFS RESEARCH, 8 00:00:20,920 --> 00:00:21,621 IDENTIFYING TARGETS FOR 9 00:00:21,688 --> 00:00:22,822 INTERVENTION AND LEARNING FROM 10 00:00:22,889 --> 00:00:23,256 LONG COVID. 11 00:00:23,323 --> 00:00:25,792 THIS MEETING, ONE VERY MUCH LIKE 12 00:00:25,859 --> 00:00:29,496 IT, WAS STARTED IN 2019, AND WE 13 00:00:29,562 --> 00:00:31,164 BROUGHT PEOPLE TOGETHER HERE IN 14 00:00:31,231 --> 00:00:32,365 THE CLINICAL CENTER WITH THE 15 00:00:32,432 --> 00:00:37,937 IDEA THAT WE WOULD TRY AND 16 00:00:38,004 --> 00:00:38,938 ACCELERATE THE PROGRESS OF 17 00:00:39,005 --> 00:00:39,906 RESEARCH FOR ME/CFS AND REALLY 18 00:00:39,973 --> 00:00:41,107 START TO HIGHLIGHT SOME OF THE 19 00:00:41,174 --> 00:00:42,275 COLLABORATIVE RESEARCH CENTERS 20 00:00:42,342 --> 00:00:45,678 THAT WERE FUNDED OUT OF THE NIH 21 00:00:45,745 --> 00:00:48,748 ME/CFS WORKING GROUP. 22 00:00:48,815 --> 00:00:51,951 THINGS HAVE CHANGED SINCE 2019. 23 00:00:52,018 --> 00:00:55,321 SO THIS MEETING IS REALLY A 24 00:00:55,388 --> 00:00:56,089 LITTLE DIFFERENT. 25 00:00:56,156 --> 00:00:57,957 I THINK WE'LL FIND THAT THE 26 00:00:58,024 --> 00:01:01,127 SCIENCE HAS MOVED TO MUCH MORE 27 00:01:01,194 --> 00:01:02,529 ABOUT MECHANISMS AND THE IDEA OF 28 00:01:02,595 --> 00:01:05,832 THIS MEETING IS TO TRY AND 29 00:01:05,899 --> 00:01:09,569 IDENTIFY PATHWAYS THAT WILL BE 30 00:01:09,636 --> 00:01:12,038 TREATABLE AND DRUGGABLE, AND 31 00:01:12,105 --> 00:01:13,373 REALLY MAKE AN IMPACT FOR 32 00:01:13,440 --> 00:01:15,108 PATIENTS BASED ON THE THINGS 33 00:01:15,175 --> 00:01:19,045 THAT WE'VE LEARNED OVER THE LAST 34 00:01:19,112 --> 00:01:21,881 NUMBER OF YEARS, AND INCLUDING, 35 00:01:21,948 --> 00:01:23,516 FORTUNATELY OR UNFORTUNATELY, 36 00:01:23,583 --> 00:01:24,851 THE HUGE NUMBER OF PEOPLE WHO 37 00:01:24,918 --> 00:01:28,254 ARE SUFFERING FROM LONG COVID, 38 00:01:28,321 --> 00:01:29,989 WHERE THE SYMPTOMS OVERLAP SO 39 00:01:30,056 --> 00:01:31,624 MUCH WITH THOSE THAT HAVE BEEN 40 00:01:31,691 --> 00:01:33,827 SUFFERING FOR A LONG TIME WITH 41 00:01:33,893 --> 00:01:34,694 ME/CFS. 42 00:01:34,761 --> 00:01:39,299 BOTH SHORT TERM AND LONG TERM. 43 00:01:39,365 --> 00:01:40,366 SO THE IDEA IS THAT WE'LL 44 00:01:40,433 --> 00:01:41,935 LEVERAGE THE UNDERSTANDING FROM 45 00:01:42,001 --> 00:01:45,872 LONG COVID AND TRY AND APPLY TO 46 00:01:45,939 --> 00:01:47,273 ME/CFS TO REALLY BENEFIT PEOPLE 47 00:01:47,340 --> 00:01:49,442 WHO ARE SUFFERING. 48 00:01:49,509 --> 00:01:51,544 SO THAT'S WHAT WE'VE ASSEMBLED. 49 00:01:51,611 --> 00:01:52,745 THE OTHER THING WE'VE DONE A 50 00:01:52,812 --> 00:01:54,380 LITTLE BIT DIFFERENT IS TO 51 00:01:54,447 --> 00:01:57,984 REALLY HELP US UNDERSTAND HOW 52 00:01:58,051 --> 00:02:00,720 THIS IMPACTS LIVED EXPERIENCE 53 00:02:00,787 --> 00:02:03,256 INDIVIDUALS, WE HAVE THROUGHOUT 54 00:02:03,323 --> 00:02:04,657 THE CONFERENCE AND THE PROGRAM 55 00:02:04,724 --> 00:02:05,658 LIVED EXPERIENCE FOLKS TO 56 00:02:05,725 --> 00:02:09,796 PROVIDE THEIR PERSPECTIVE, AND 57 00:02:09,863 --> 00:02:10,763 THEY'LL BE DIFFERENT, WHICH 58 00:02:10,830 --> 00:02:13,733 REPRESENTS THE HETEROGENEOUS 59 00:02:13,800 --> 00:02:15,602 NATURE OF ME/CFS. 60 00:02:15,668 --> 00:02:17,337 MOST LIKELY, THE BIOLOGY DRIVING 61 00:02:17,403 --> 00:02:19,672 IT AS WELL AS THE VARIED HOST 62 00:02:19,739 --> 00:02:22,575 RESPONSE. 63 00:02:22,642 --> 00:02:24,110 THIS EFFORT IS A TRANS-NIH 64 00:02:24,177 --> 00:02:26,412 EFFORT LED BY DR. WALTER 65 00:02:26,479 --> 00:02:28,414 KOROSHETZ AND VICKY WHITTEMORE 66 00:02:28,481 --> 00:02:29,482 AND YOU'RE GOING TO HEAR FROM 67 00:02:29,549 --> 00:02:31,084 THEM SHORTLY, AND HISTORICALLY 68 00:02:31,150 --> 00:02:33,419 HAS BEEN SUPPORTED BY A NUMBER 69 00:02:33,486 --> 00:02:36,489 OF INSTITUTES AT NIH, INCLUDING 70 00:02:36,556 --> 00:02:38,691 MINE, NIAID, AND WE HAVE A NEW 71 00:02:38,758 --> 00:02:41,094 DIRECTOR, WHO'S HERE TODAY TO 72 00:02:41,160 --> 00:02:43,263 SHOW HER SUPPORT AND THE KIND OF 73 00:02:43,329 --> 00:02:45,231 SUPPORT THAT WE'VE GIVEN FROM 74 00:02:45,298 --> 00:02:48,835 NIAID OVER THE PAST AS WELL, DRL 75 00:02:48,902 --> 00:02:51,905 COME UP AND SAY A FEW WORDS. 76 00:02:51,971 --> 00:03:02,115 JEANNE? 77 00:03:03,216 --> 00:03:05,385 >> THANKS SO MUCH, JOE. 78 00:03:05,451 --> 00:03:06,653 IT'S A REAL HONOR TO BE HERE 79 00:03:06,719 --> 00:03:07,120 TODAY. 80 00:03:07,186 --> 00:03:08,955 I'VE BEEN AT NIH NOW AS DIRECTOR 81 00:03:09,022 --> 00:03:11,257 OF NIAID FOR JUST A LITTLE OVER 82 00:03:11,324 --> 00:03:13,092 TWO MONTHS, HAVING COME FROM THE 83 00:03:13,159 --> 00:03:14,861 UNIVERSITY OF ALABAMA AT 84 00:03:14,928 --> 00:03:16,563 BIRMINGHAM, WHERE I WAS, 85 00:03:16,629 --> 00:03:17,730 INCIDENTALLY, THE CONTACT 86 00:03:17,797 --> 00:03:19,032 PRINCIPAL INVESTIGATOR FOR THE 87 00:03:19,098 --> 00:03:20,667 RECOVER STUDY THERE, SO I AM 88 00:03:20,733 --> 00:03:24,270 FAMILIAR CERTAINLY WITH THAT 89 00:03:24,337 --> 00:03:28,007 ASPECT OF LONG COVID RESEARCH. 90 00:03:28,074 --> 00:03:29,409 A COUPLE OF THINGS I JUST WANTED 91 00:03:29,475 --> 00:03:31,277 TO MEX BEFORE GETTING JOE BACK 92 00:03:31,344 --> 00:03:32,278 TO INTRODUCE VICKY. 93 00:03:32,345 --> 00:03:33,746 AS JOE MENTIONED, HE'S BEEN THE 94 00:03:33,813 --> 00:03:34,914 POINT PERSON, HE DIDN'T SAY THAT 95 00:03:34,981 --> 00:03:35,949 BUT HE HAS BEEN THE POINT PERSON 96 00:03:36,015 --> 00:03:42,121 AND I WANT TO PUBLICLY THANK HIM 97 00:03:42,188 --> 00:03:43,523 AS OUR NIAID STAFF WORK CLOSELY 98 00:03:43,590 --> 00:03:45,625 WITH THE WORKING GROUP UNDER THE 99 00:03:45,692 --> 00:03:47,026 LEADERSHIP OF DR. KOROSHETZ AND 100 00:03:47,093 --> 00:03:48,227 VICKY WHITTEMORE, BOTH WHOM 101 00:03:48,294 --> 00:03:49,729 YOU'RE GOING TO HEAR FROM IN A 102 00:03:49,796 --> 00:03:49,963 MOMENT. 103 00:03:50,029 --> 00:03:52,932 AND I THINK THE THING I WOULD 104 00:03:52,999 --> 00:03:56,202 EMPHASIZE ABOUT NIAID'S 105 00:03:56,269 --> 00:03:57,236 INVOLVEMENT IS THAT WE ARE 106 00:03:57,303 --> 00:03:58,438 PARTICULARLY INTERESTED IN SOME 107 00:03:58,504 --> 00:03:59,505 AREAS I KNOW THAT MANY 108 00:03:59,572 --> 00:04:00,206 SCIENTISTS AND COMMUNITIES IN 109 00:04:00,273 --> 00:04:03,109 THE ROOM AND ONLINE ARE VERY 110 00:04:03,176 --> 00:04:05,979 FOCUSED ON, INCLUDING POST 111 00:04:06,045 --> 00:04:08,047 INFECTIOUS DISEASE ETIOLOGIES, 112 00:04:08,114 --> 00:04:12,619 HERPES VIRUSES IN PARTICULAR, 113 00:04:12,685 --> 00:04:15,154 IMMUNE DYSREGULATION, BOTH 114 00:04:15,221 --> 00:04:17,123 ADAPTIVE AND -- THAT CHANGE IN 115 00:04:17,190 --> 00:04:18,191 THIS SYNDROME OR THESE SYNDROMES 116 00:04:18,257 --> 00:04:20,059 AND IN GREAT INTEREST TO ME IN 117 00:04:20,126 --> 00:04:23,563 PARTICULAR AS A MICROBIOME 118 00:04:23,630 --> 00:04:28,735 ENTHUSIAST, THE GUT MICRO BUY 119 00:04:28,801 --> 00:04:30,103 AM -- THE BOTTOM LINE IS THAT 120 00:04:30,169 --> 00:04:31,537 THERE ARE I THINK INCREDIBLE 121 00:04:31,604 --> 00:04:33,840 ADVANCES HAPPENING IN THIS 122 00:04:33,906 --> 00:04:35,375 SPACE, AND WE ARE REALLY 123 00:04:35,441 --> 00:04:36,576 THRILLED TO BE ABLE TO WORK WITH 124 00:04:36,643 --> 00:04:38,344 NINDS TO SUPPORT THEM. 125 00:04:38,411 --> 00:04:40,780 I WANT TO JUST QUOTE SOMETHING 126 00:04:40,847 --> 00:04:44,017 VERY QUICKLY, I'M NOT SURE IF 127 00:04:44,083 --> 00:04:46,452 EVERYBODY SAW ED YOUNG'S PIECE 128 00:04:46,519 --> 00:04:46,953 IN THE "NEW YORK TIMES" 129 00:04:47,020 --> 00:04:48,621 YESTERDAY ABOUT HOW REPORTING ON 130 00:04:48,688 --> 00:04:51,257 LONG COVID, BUT ALSO ON THE 131 00:04:51,324 --> 00:04:54,661 FIELD OF M.E. AND CFS MADE HIM A 132 00:04:54,727 --> 00:04:55,028 BETTER REPORTER. 133 00:04:55,094 --> 00:04:56,162 THERE ARE JUST A COUPLE OF 134 00:04:56,229 --> 00:04:57,563 SENTENCES THAT I THOUGHT FOR ME 135 00:04:57,630 --> 00:05:01,401 REALLY CAPTURED SO MUCH ABOUT 136 00:05:01,467 --> 00:05:02,535 WHERE THIS MEETING IS GOING FROM 137 00:05:02,602 --> 00:05:04,237 WHERE IT STARTED IN 2019, AND 138 00:05:04,303 --> 00:05:06,572 WHAT HE SAYS IS, COVERING LONG 139 00:05:06,639 --> 00:05:07,840 COVID SOLIDIFIED MY VIEW THAT 140 00:05:07,907 --> 00:05:09,809 SCIENCE IS NOT THE OBJECTIVE 141 00:05:09,876 --> 00:05:11,044 NEUTRAL FORCE, IT IS OFTEN 142 00:05:11,110 --> 00:05:13,546 MISCOCONSTRUED AS. 143 00:05:13,613 --> 00:05:16,849 IT IS INSTEAD A HUMAN ENDEAVOR 144 00:05:16,916 --> 00:05:18,151 BUFFERED BY OUR CULTURE, VAL YOU 145 00:05:18,217 --> 00:05:20,687 OOS AND POLITICS, AS ENERGY 146 00:05:20,753 --> 00:05:22,755 DEPLETING ILLNESSES THAT 147 00:05:22,822 --> 00:05:24,357 DISPROPORTIONATELY AFFECT WOMEN, 148 00:05:24,424 --> 00:05:26,225 LONG COVID AND ME/CFS ARE EASILY 149 00:05:26,292 --> 00:05:27,994 BELITTLED BY A SEXIST SOCIETY 150 00:05:28,061 --> 00:05:30,163 THAT TRIVIALIZES WOMEN'S PAIN 151 00:05:30,229 --> 00:05:32,065 AND A CAPITALIST ONE THAT VALUES 152 00:05:32,131 --> 00:05:33,332 PEOPLE ACCORDING TO THEIR 153 00:05:33,399 --> 00:05:36,302 PRODUCTIVITY. 154 00:05:36,369 --> 00:05:39,238 SOCIETAL DISMISSAL LEADS TO 155 00:05:39,305 --> 00:05:41,541 SCIENTIFIC NEGLECT AND A LACK OF 156 00:05:41,607 --> 00:05:44,177 RESEARCH GU BECOMES FODDER FOR 157 00:05:44,243 --> 00:05:44,811 FURTHER SKEPTICISM. 158 00:05:44,877 --> 00:05:48,548 I THOUGHT THAT WAS A BEAUTIFUL 159 00:05:48,614 --> 00:05:49,649 CAPSULISM ABOUT HOW PEOPLE'S 160 00:05:49,716 --> 00:05:50,750 EXPERIENCES DOES LEAD TO 161 00:05:50,817 --> 00:05:52,385 DISMISSAL WHICH THEN DOES 162 00:05:52,452 --> 00:05:53,119 UNDERMINE THE ABILITIES TO DO 163 00:05:53,186 --> 00:05:54,554 THE SCIENCE THAT WE NEED TO DO 164 00:05:54,620 --> 00:05:55,288 TO UNDERSTAND WHAT WAS GOING ON 165 00:05:55,354 --> 00:05:56,756 IN THE FIRST PLACE, AND I THINK 166 00:05:56,823 --> 00:05:59,058 THIS MEETING IS A FANTASTIC 167 00:05:59,125 --> 00:06:01,661 EXAMPLE OF NOW MOVING INTO THIS 168 00:06:01,728 --> 00:06:02,662 AREA WHERE PROGRESS IS GOING TO 169 00:06:02,729 --> 00:06:03,629 BE HIGHLIGHTED AND YOU'RE GOING 170 00:06:03,696 --> 00:06:05,098 TO BE LOOKING AT POTENTIAL 171 00:06:05,164 --> 00:06:06,165 AVENUES FOR DIAGNOSIS AND 172 00:06:06,232 --> 00:06:06,432 TREATMENT. 173 00:06:06,499 --> 00:06:07,467 SO I REALLY WANT TO THANK YOU 174 00:06:07,533 --> 00:06:09,335 FOR THE OPPORTUNITY TO BE HERE 175 00:06:09,402 --> 00:06:10,636 AND MORE IMPORTANTLY, THANK YOU 176 00:06:10,703 --> 00:06:13,272 FOR YOUR DEDICATION TO THIS 177 00:06:13,339 --> 00:06:13,506 WORK. 178 00:06:13,573 --> 00:06:22,615 [APPLAUSE] 179 00:06:22,682 --> 00:06:29,255 >> THANK YOU, DR. JEANNE 180 00:06:29,322 --> 00:06:30,189 MARRAZZO. 181 00:06:30,256 --> 00:06:31,524 BEFORE WE MOVE AHEAD I WANT TO 182 00:06:31,591 --> 00:06:33,292 THANK THE ORGANIZING COMMITTEE 183 00:06:33,359 --> 00:06:35,161 THAT PUT TOGETHER THE PROGRAM, 184 00:06:35,228 --> 00:06:38,898 PARTICULARLY THE TWO CO-CHAIRS, 185 00:06:38,965 --> 00:06:42,268 AND A GROUP OF FOLKS WHO INCL 186 00:06:42,335 --> 00:06:44,771 INCLUDED SOME OF OUR PRIVATE 187 00:06:44,837 --> 00:06:46,873 PARTNERS, AS WELL AS OTHER 188 00:06:46,939 --> 00:06:48,941 RESEARCHERS WHO HELPED PUT 189 00:06:49,008 --> 00:06:49,776 TOGETHER THE PROGRAM SO THANK 190 00:06:49,842 --> 00:06:50,676 YOU FOR YOUR EFFORTS TO PUT 191 00:06:50,743 --> 00:06:51,511 TOGETHER WHAT WE'RE GOING TO SEE 192 00:06:51,577 --> 00:06:53,946 IN THE NEXT TWO DAYS. 193 00:06:54,013 --> 00:06:56,249 IT'S MY PLEASURE TO INTRODUCE 194 00:06:56,315 --> 00:06:57,784 DR. VICKY WHITTEMORE, WHO'S 195 00:06:57,850 --> 00:07:00,186 REALLY BEEN A LEADER AT NIH IN 196 00:07:00,253 --> 00:07:01,921 DRIVING A LOT OF WHAT HAPPENS 197 00:07:01,988 --> 00:07:07,126 WITH THE NIH ME/CFS WORKING 198 00:07:07,193 --> 00:07:09,095 GROUP AND I TELL THEM MY PARTNER 199 00:07:09,162 --> 00:07:10,897 IN CRIME, GREAT COLLEAGUE. 200 00:07:10,963 --> 00:07:11,597 VICKY? 201 00:07:11,664 --> 00:07:21,841 [APPLAUSE] 202 00:07:23,843 --> 00:07:24,610 >> THANK YOU, JOE. 203 00:07:24,677 --> 00:07:26,646 IT'S MY PLEASURE TO WELCOME YOU 204 00:07:26,712 --> 00:07:27,647 ALL TO NIH AND TO THE 205 00:07:27,713 --> 00:07:28,281 CONFERENCE. 206 00:07:28,347 --> 00:07:30,716 WE HAD AN ABSOLUTELY FANTASTIC 207 00:07:30,783 --> 00:07:32,151 WORKSHOP YESTERDAY WITH ALL THE 208 00:07:32,218 --> 00:07:34,453 YOUNG INVESTIGATORS, WITH 209 00:07:34,520 --> 00:07:35,321 INDIVIDUALS FROM A HIGH SCHOOL 210 00:07:35,388 --> 00:07:36,923 STUDENT ALL THE WAY UP THROUGH 211 00:07:36,989 --> 00:07:38,724 TO JUNIOR FACULTY. 212 00:07:38,791 --> 00:07:40,026 SO THANK YOU ALL FOR 213 00:07:40,092 --> 00:07:41,327 PARTICIPATING IN THAT MEETING 214 00:07:41,394 --> 00:07:43,830 THAT WE HAD A GREAT TIME AND 215 00:07:43,896 --> 00:07:46,432 HOPE TO CONTINUE THAT NETWORKING 216 00:07:46,499 --> 00:07:48,868 AND REALLY HELP TO FOSTER THOSE 217 00:07:48,935 --> 00:07:51,037 YOUNG INVESTIGATORS TO BECOME 218 00:07:51,103 --> 00:07:51,938 ESTABLISHED INVESTIGATORS IN 219 00:07:52,004 --> 00:07:56,843 THIS FIELD. 220 00:07:56,909 --> 00:07:58,177 I JUST WANT TO SAY THAT IT HAS 221 00:07:58,244 --> 00:08:00,012 BEEN MY PLEASURE TO WORK WITH 222 00:08:00,079 --> 00:08:02,582 DR. KOROSHETZ AND JOE TO REALLY 223 00:08:02,648 --> 00:08:04,951 ADVANCE ME/CFS RESEARCH HERE AT 224 00:08:05,017 --> 00:08:07,687 NIH, AS WELL AS TO WORK WITH THE 225 00:08:07,753 --> 00:08:09,088 COMMUNITY, WITH INDIVIDUALS WITH 226 00:08:09,155 --> 00:08:11,490 LIVED EXPERIENCE, WITH THE 227 00:08:11,557 --> 00:08:12,491 NON-PROFIT ORGANIZATIONS TO 228 00:08:12,558 --> 00:08:14,460 REALLY WORK TOGETHER TO MOVE THE 229 00:08:14,527 --> 00:08:15,361 FIELD FORWARD. 230 00:08:15,428 --> 00:08:19,031 SO I HOPE THAT YOU ENJOY THE 231 00:08:19,098 --> 00:08:19,932 CONFERENCE, AND I REALLY THINK 232 00:08:19,999 --> 00:08:21,100 THAT YOU'RE GOING TO HEAR SOME 233 00:08:21,167 --> 00:08:23,102 GREAT SCIENCE. 234 00:08:23,169 --> 00:08:26,505 SO IT'S MY PLEASURE TO INTRODUCE 235 00:08:26,572 --> 00:08:31,844 MY BOSS, MY BOSS AT THE NIH, DRE 236 00:08:31,911 --> 00:08:35,181 DIRECTOR OF NINDS, WHO IS BY FAR 237 00:08:35,248 --> 00:08:37,650 ONE OF THE MOST STEADFAST 238 00:08:37,717 --> 00:08:39,485 CHAMPIONS FOR RESEARCH ON ME/CFS 239 00:08:39,552 --> 00:08:40,953 AND REALLY SUPPORTIVE OF 240 00:08:41,020 --> 00:08:42,822 EVERYTHING THAT THE TRANS-NIH 241 00:08:42,889 --> 00:08:44,757 ME/CFS WORKING GROUP HAS BEEN 242 00:08:44,824 --> 00:08:45,658 ATTEMPTING TO DO TO REALLY 243 00:08:45,725 --> 00:08:46,959 ADVANCE THE FIELD. 244 00:08:47,026 --> 00:08:47,727 SO WELCOME, WALTER. 245 00:08:47,793 --> 00:08:53,199 [APPLAUSE] 246 00:08:53,266 --> 00:08:54,533 >> THANKS, AND THANKS, JEANNE. 247 00:08:54,600 --> 00:08:56,669 IT WAS REALLY GOOD TO HAVE YOU 248 00:08:56,736 --> 00:08:59,005 HERE, AND LOOKING FORWARD TO 249 00:08:59,071 --> 00:09:02,041 WORKING TOGETHER. 250 00:09:02,108 --> 00:09:04,310 NIAID AND NINDS HAVE BEEN GREAT 251 00:09:04,377 --> 00:09:07,146 PARTNERS IN THIS, SO WELL, GOOD 252 00:09:07,213 --> 00:09:07,647 MORNING, FOLKS. 253 00:09:07,713 --> 00:09:11,317 HOW DO YOU FEEL? 254 00:09:11,384 --> 00:09:17,690 HOW DO YOU KNOW HOW YOU FEEL? 255 00:09:17,757 --> 00:09:19,859 SO START OFF WITH A LITTLE 256 00:09:19,926 --> 00:09:21,060 HUMOR, BUT AN ACTUAL FACT, I 257 00:09:21,127 --> 00:09:23,462 THINK THIS CUTS -- THE QUESTION 258 00:09:23,529 --> 00:09:26,766 CUTS RIGHT TO THE ISSUE OF 259 00:09:26,832 --> 00:09:27,400 ME/CFS. 260 00:09:27,466 --> 00:09:30,503 EVERY DAY WE WAKE UP, WE FEEL 261 00:09:30,569 --> 00:09:30,836 DIFFERENTLY. 262 00:09:30,903 --> 00:09:32,672 THERE'S A REASON WHY WE FEEL 263 00:09:32,738 --> 00:09:33,005 DIFFERENTLY. 264 00:09:33,072 --> 00:09:34,640 WHEN WE GET AN INFECTION OR A 265 00:09:34,707 --> 00:09:36,943 COLD, WE DON'T FEEL SO GOOD. 266 00:09:37,009 --> 00:09:39,545 WHAT'S THAT ALL ABOUT? 267 00:09:39,612 --> 00:09:45,685 IT COMES UNDER THE TERM OF 268 00:09:45,751 --> 00:09:46,452 ENTEROSEPTION, WHICH IS HOW THE 269 00:09:46,519 --> 00:09:47,787 BRAIN IS TAKING ALL THE INPUTS 270 00:09:47,853 --> 00:09:52,458 FROM AROUND THE BODY AND 271 00:09:52,525 --> 00:09:53,993 INPUTTING INTO WHATEVER THESE 272 00:09:54,060 --> 00:09:54,894 MYSTERIOUS CENTERS ARE TO GIVE 273 00:09:54,961 --> 00:09:57,396 US THIS PERCEPTION OF HOW WE 274 00:09:57,463 --> 00:09:58,998 FEEL. 275 00:09:59,065 --> 00:10:00,466 HOW MUCH ENERGY WE HAVE. 276 00:10:00,533 --> 00:10:02,535 ARE WE IN A GOOD MOOD, ARE WE IN 277 00:10:02,601 --> 00:10:06,672 A BAD MOOD, AND WE DON'T REALLY 278 00:10:06,739 --> 00:10:09,075 UNDERSTAND EXACTLY HOW THAT IS 279 00:10:09,141 --> 00:10:09,408 HAPPENING. 280 00:10:09,475 --> 00:10:11,711 BUT WE DO KNOW THAT THERE'S SO 281 00:10:11,777 --> 00:10:13,279 MANY DIFFERENT THINGS THAT 282 00:10:13,346 --> 00:10:16,015 INFLUENCE HOW WE FEEL AND SO I 283 00:10:16,082 --> 00:10:21,020 WOULD SAY THAT TH UNDERSTANDING 284 00:10:21,087 --> 00:10:22,221 ME/CFS IS KIND OF ONE OF THE 285 00:10:22,288 --> 00:10:24,724 LAST MEDICAL MYSTERIES THAT ARE 286 00:10:24,790 --> 00:10:29,962 OUT THERE, BUT IT CUTS ACROSS SO 287 00:10:30,029 --> 00:10:34,467 MUCH OF BASICALLY HEALTH, AND SO 288 00:10:34,533 --> 00:10:38,437 I THINK IT'S INCREDIBLY -- AN 289 00:10:38,504 --> 00:10:39,171 INCREDIBLY IMPORTANT FIELD, 290 00:10:39,238 --> 00:10:41,140 THERE'S A LOT TO BE LEARNED, 291 00:10:41,207 --> 00:10:45,511 WE'RE KIND OF -- WE'VE BEEN KIND 292 00:10:45,578 --> 00:10:47,146 OF REACHING IN THE DARK BUT 293 00:10:47,213 --> 00:10:49,749 THERE ARE SOME LITTLE BURSTS OF 294 00:10:49,815 --> 00:10:52,385 LIGHT THAT I THINK WE CAN 295 00:10:52,451 --> 00:10:54,053 FOLLOW, AND WE REALLY NEED TO 296 00:10:54,120 --> 00:10:56,989 BUILD THE WORKFORCE TO GIVE THEM 297 00:10:57,056 --> 00:10:59,625 THE TOOLS THAT THEY NEED, FEED 298 00:10:59,692 --> 00:11:02,595 THEM WITH IDEAS THAT THEY CAN 299 00:11:02,661 --> 00:11:04,330 FOLLOW UP ON, AND HOPEFULLY WE 300 00:11:04,397 --> 00:11:08,167 CAN REALLY GET SOME ANSWERS THAT 301 00:11:08,234 --> 00:11:09,668 ARE GOING TO LEAD TO TREATMENTS, 302 00:11:09,735 --> 00:11:13,539 AS JOE SAID. 303 00:11:13,606 --> 00:11:17,943 SO NIAID AND NINDS WERE KIND OF 304 00:11:18,010 --> 00:11:19,311 INSTRUCTED BY DR. FRANCIS 305 00:11:19,378 --> 00:11:20,413 COLLINS TO GET TOGETHER AND 306 00:11:20,479 --> 00:11:21,480 REALLY TRY AND MAKE A DIFFERENCE 307 00:11:21,547 --> 00:11:23,549 IN THIS FIELD A NUMBER OF YEARS 308 00:11:23,616 --> 00:11:24,116 AGO. 309 00:11:24,183 --> 00:11:25,885 AND WE'VE BEEN WORKING HARD 310 00:11:25,951 --> 00:11:28,854 WITH, YOU KNOW, I WOULD SAY SOME 311 00:11:28,921 --> 00:11:30,256 SUCCESS BUT CLEARLY NOT THE KIND 312 00:11:30,322 --> 00:11:33,192 OF SUCCESS WE WANTED. 313 00:11:33,259 --> 00:11:38,030 WE HAVE -- BECAUSE THE ISSUES OF 314 00:11:38,097 --> 00:11:38,998 ME/CFS, THE SYMPTOMS ARE SO 315 00:11:39,065 --> 00:11:41,700 BROAD AND ACROSS MULTIPLE 316 00:11:41,767 --> 00:11:43,035 INSTITUTES, THERE'S INTEREST AND 317 00:11:43,102 --> 00:11:45,471 NEED FROM EXPERT FROM MULTIPLE 318 00:11:45,538 --> 00:11:47,640 DIFFERENT INSTITUTES TO BE 319 00:11:47,706 --> 00:11:50,576 INVOLVED IN ME/CFS RESEARCH. 320 00:11:50,643 --> 00:11:52,878 TAKE FOR EXAMPLE, TACHYCARDIA 321 00:11:52,945 --> 00:11:54,947 SYNDROME, THAT'S CLEARLY IN THE 322 00:11:55,014 --> 00:11:57,483 MISSION OF NHLBI, SO GETTING THE 323 00:11:57,550 --> 00:12:00,352 EXPERTISE FROM THAT SPACE IS 324 00:12:00,419 --> 00:12:03,255 ALSO IMPORTANT, BUT MANY OTHER 325 00:12:03,322 --> 00:12:06,025 INSTITUTES AS WELL. 326 00:12:06,092 --> 00:12:06,459 HAVE THESE 327 00:12:06,525 --> 00:12:08,527 REALLY SEVERE PROBLEMS WHICH 328 00:12:08,594 --> 00:12:10,463 LEAD TO CHRONIC FATIGUE IF NOT 329 00:12:10,529 --> 00:12:13,933 ME/CFS ITSELF. 330 00:12:13,999 --> 00:12:16,836 SO WE HAVE THIS WORKING GROUP OF 331 00:12:16,902 --> 00:12:18,204 21 INSTITUTES THAT HAVE EQUITIES 332 00:12:18,270 --> 00:12:20,005 IN THE SPACE AND WE TRY AND 333 00:12:20,072 --> 00:12:22,408 COORDINATE A ACTIVITIES AMONG EH 334 00:12:22,475 --> 00:12:24,176 OTHER AND GET EXPERTISE FROM 335 00:12:24,243 --> 00:12:24,910 MULTIPLE DIFFERENT INSTITUTES TO 336 00:12:24,977 --> 00:12:26,245 BEAR ON THIS PROBLEM. 337 00:12:26,312 --> 00:12:29,748 WE ALSO HAVE BEEN WORKING WITH A 338 00:12:29,815 --> 00:12:32,051 LOOSE INTERAGENCY GROUP OF OTHER 339 00:12:32,118 --> 00:12:33,886 FEDERAL AGENCIES THAT HAVE 340 00:12:33,953 --> 00:12:36,422 EQUITIES IN ME/CFS, PARTICULARLY 341 00:12:36,489 --> 00:12:39,592 THE CDC, WHICH HAS LONG TERM 342 00:12:39,658 --> 00:12:41,327 INTEREST. 343 00:12:41,393 --> 00:12:45,698 WE'VE BEEN TRYING TO KIND OF 344 00:12:45,764 --> 00:12:46,832 IMPROVE AND INCREASE THE AMOUNT 345 00:12:46,899 --> 00:12:49,335 OF RESEARCH GOING ON IN THIS 346 00:12:49,401 --> 00:12:51,070 SPACE WITH A NUMBER OF DIFFERENT 347 00:12:51,137 --> 00:12:52,371 MECHANISMS, AND ALTHOUGH YOU CAN 348 00:12:52,438 --> 00:12:54,240 SEE THERE'S BEEN SOME SUCCESS IN 349 00:12:54,306 --> 00:12:56,375 TERMS OF THE NUMBERS GOING UP, 350 00:12:56,442 --> 00:12:58,644 IF YOU THINK ABOUT THE SEVERITY 351 00:12:58,711 --> 00:12:59,845 OF THE DISEASE AND THE NUMBER OF 352 00:12:59,912 --> 00:13:02,348 PEOPLE AFFECTED, THERE'S A PAUL 353 00:13:02,414 --> 00:13:05,951 TRI AMPALTRY AMOUNT OF FUNDING. 354 00:13:06,018 --> 00:13:08,120 THIS IS OF COURSE WHAT WE GET 355 00:13:08,187 --> 00:13:09,255 CRITICIZED FOR ALL THE TIME BY 356 00:13:09,321 --> 00:13:10,523 THE PATIENTS WHO ARE SUFFERING 357 00:13:10,589 --> 00:13:12,858 AND RIGHTLY SO. 358 00:13:12,925 --> 00:13:15,060 I THINK THEY ARE VERY, VERY 359 00:13:15,127 --> 00:13:15,995 FRUSTRATED, PARTICULARLY, YOU 360 00:13:16,061 --> 00:13:17,263 KNOW, PEOPLE HAVE BEEN SUFFERING 361 00:13:17,329 --> 00:13:21,066 FOR DECADES AND STILL NO ANSW 362 00:13:21,133 --> 00:13:21,300 ANSWERS. 363 00:13:21,367 --> 00:13:22,902 BUT TO MOVE THIS DIAL, WE REALLY 364 00:13:22,968 --> 00:13:25,504 NEED THE SCIENCE TO KIND OF COME 365 00:13:25,571 --> 00:13:27,273 IN AND COMPETE FOR NIH GRANTS 366 00:13:27,339 --> 00:13:31,110 THAT ARE GOING TO MAKE A 367 00:13:31,177 --> 00:13:32,211 DIFFERENCE IN THE FIELD. 368 00:13:32,278 --> 00:13:34,947 SO I THINK THAT'S WHY WE REALLY 369 00:13:35,014 --> 00:13:37,016 ARE VERY INTERESTED IN HEARING 370 00:13:37,082 --> 00:13:39,552 FROM YOU, HAD A REALLY GREAT 371 00:13:39,618 --> 00:13:43,122 SESSION YESTERDAY WITH EARLY 372 00:13:43,189 --> 00:13:44,356 INVESTIGATORS, NEW INVESTIGATORS 373 00:13:44,423 --> 00:13:46,292 TO THE FIELD, AND SO WE WILL DO 374 00:13:46,358 --> 00:13:48,494 ANYTHING WE CAN TO TRY AND BUILD 375 00:13:48,561 --> 00:13:51,664 THIS FIELD UP. 376 00:13:51,730 --> 00:13:57,036 WE HAVE AN INTRAMURAL PROGRAM, 377 00:13:57,102 --> 00:13:58,771 DR. AVI NATH TOOK THIS ON, 378 00:13:58,837 --> 00:14:01,173 AGAIN, WHEN FRANCIS BROUGHT US 379 00:14:01,240 --> 00:14:03,809 INTO THIS AREA, DEVELOPED AN 380 00:14:03,876 --> 00:14:08,414 ME/CFS DEEP PHENOTYPING STUDY. 381 00:14:08,480 --> 00:14:11,116 SOME OF THE RESULTS ARE STILL IN 382 00:14:11,183 --> 00:14:13,452 PREPARATION FOR PUBLICATION 383 00:14:13,519 --> 00:14:13,953 PHASE. 384 00:14:14,019 --> 00:14:16,422 THERE'S THIS ONE ARTICLE THAT 385 00:14:16,488 --> 00:14:21,393 CAME OUT LOOKING AT MUSCLE AND 386 00:14:21,460 --> 00:14:24,797 FINDING WASF-3, A PROTEIN 387 00:14:24,863 --> 00:14:27,199 INVOLVED IN ER STRESS AND 388 00:14:27,266 --> 00:14:29,935 AUTOPHAGY AS POTENTIALLY 389 00:14:30,002 --> 00:14:33,138 SOMETHING THAT IS PRESENT IN 390 00:14:33,205 --> 00:14:34,807 PEOPLE WITH ME/CFS AS COMPARED 391 00:14:34,873 --> 00:14:38,811 TO CONTROLS. 392 00:14:38,877 --> 00:14:39,878 IN THESE FIELDS, THE MAIN 393 00:14:39,945 --> 00:14:41,347 QUESTION IS GETTING TO 394 00:14:41,413 --> 00:14:41,814 CAUSALITY. 395 00:14:41,880 --> 00:14:43,949 THERE'S GOING TO BE LOTS OF 396 00:14:44,016 --> 00:14:46,118 ABNORMALITIES, AND HERE AGAIN, I 397 00:14:46,185 --> 00:14:47,686 THINK WE NEED FURTHER WORK TO 398 00:14:47,753 --> 00:14:50,556 KNOW WHAT'S CAUSE AND EFFECT, 399 00:14:50,623 --> 00:14:51,724 PARTICULARLY WE HAVE THIS ISSUE 400 00:14:51,790 --> 00:14:53,726 OF DECONDITIONING, WHICH IS 401 00:14:53,792 --> 00:14:56,729 GOING TO AFFECT MUSCLE, BUT WE 402 00:14:56,795 --> 00:14:59,898 REALLY NEED TO FIND SOMETHING 403 00:14:59,965 --> 00:15:01,934 THAT HAS -- IN A CONTROL GROUP 404 00:15:02,001 --> 00:15:02,868 THAT'S DECONDITIONED, YOU'RE NOT 405 00:15:02,935 --> 00:15:03,836 GOING TO SEE THE SAME THING. 406 00:15:03,902 --> 00:15:05,170 BUT THIS IS SOMETHING TO FOLLOW 407 00:15:05,237 --> 00:15:08,440 UP ON, AND MAY PROVE TO BE 408 00:15:08,507 --> 00:15:11,410 SOMETHING SPECIFIC TO ME/CFS, 409 00:15:11,477 --> 00:15:15,447 BUT TIME WILL TELL. 410 00:15:15,514 --> 00:15:19,151 DR. NATH ALSO, WITH BRIAN 411 00:15:19,218 --> 00:15:20,185 WALLEN, WHO HAS BEEN WORKING IN 412 00:15:20,252 --> 00:15:21,253 THE ME/CFS FIELD A LONG TIME, 413 00:15:21,320 --> 00:15:25,057 HAD A PROGRAM IN LONG COVID DEEP 414 00:15:25,124 --> 00:15:27,826 PHENOTYPING, AND AGAIN, THEY 415 00:15:27,893 --> 00:15:30,329 HAVE BASICALLY THE SAME 416 00:15:30,396 --> 00:15:31,697 PROTOCOLS WITH ME/CFS, NOW 417 00:15:31,764 --> 00:15:33,599 TRANSLATED TO COVID, SO THEY'LL 418 00:15:33,666 --> 00:15:35,567 BE ABLE TO GET A COMPARISON TO 419 00:15:35,634 --> 00:15:37,503 THE LONG COVID AND THE ME/CFS 420 00:15:37,569 --> 00:15:39,505 GROUP THAT THEY HAVE BEEN 421 00:15:39,571 --> 00:15:39,838 INVESTIGATING. 422 00:15:39,905 --> 00:15:41,473 AND THEY'RE ALSO LOOKING AT 423 00:15:41,540 --> 00:15:44,043 ANOTHER KIND OF MYSTERIOUS 424 00:15:44,109 --> 00:15:46,879 ILLNESS THAT GULF WAR ILLNESS, 425 00:15:46,945 --> 00:15:49,782 WHICH HAS SOME OVERLAP WITH 426 00:15:49,848 --> 00:15:52,851 ME/CFS, SO THEY'RE GETTING THESE 427 00:15:52,918 --> 00:15:54,086 GROUPS, DEEP PHENOTYPING THEM 428 00:15:54,153 --> 00:15:55,821 AND ALLOWING COMPARISONS TO SEE 429 00:15:55,888 --> 00:15:57,289 IF SOMETHING FALLS OUT FROM ALL 430 00:15:57,356 --> 00:16:01,060 THREE. 431 00:16:01,126 --> 00:16:03,462 WE HAVE, OVER THE YEARS NOW, 432 00:16:03,529 --> 00:16:06,398 BEEN WORKING TO DEVELOP A 433 00:16:06,465 --> 00:16:07,633 CONSORTIUM OF WHAT WE CALL 434 00:16:07,700 --> 00:16:10,135 CENTERS OF EXCELLENCE FOR ME/CFS 435 00:16:10,202 --> 00:16:10,436 RESEARCH. 436 00:16:10,502 --> 00:16:15,474 THE IDEA THAT WE NEED CENTERS TO 437 00:16:15,541 --> 00:16:18,677 FORM THAT CAN TRAIN NEW 438 00:16:18,744 --> 00:16:20,646 INVESTIGATORS THROUGH RESEARCH, 439 00:16:20,713 --> 00:16:22,047 BUT THE MAIN THING IS TO DO IT 440 00:16:22,114 --> 00:16:24,917 IN A GROUP AND A TEAM SETTING AS 441 00:16:24,983 --> 00:16:27,219 OPPOSED TO ONE-OFFS. 442 00:16:27,286 --> 00:16:29,822 I THINK THE BANE OF A LOT OF 443 00:16:29,888 --> 00:16:31,290 ME/CFS RESEARCH IN THE PAST HAS 444 00:16:31,357 --> 00:16:34,626 BEEN A LOT OF PUBLICATIONS OF AN 445 00:16:34,693 --> 00:16:36,495 ABNORMALITY BUT VERY FEW THAT 446 00:16:36,562 --> 00:16:38,163 HAVE THEN BEEN REPRODUCED BY 447 00:16:38,230 --> 00:16:39,665 ANOTHER GROUP, SO IT'S BEEN 448 00:16:39,732 --> 00:16:41,467 REALLY HARD TO PUT YOUR HAND ON 449 00:16:41,533 --> 00:16:45,337 SOMETHING THAT YOU CAN BE SURE 450 00:16:45,404 --> 00:16:47,239 OF, BUT I THINK GROUPS WORKING 451 00:16:47,306 --> 00:16:49,174 TOGETHER DOING THINGS SIMILARLY, 452 00:16:49,241 --> 00:16:51,043 IF THEY'RE SEEING THE SAME THING 453 00:16:51,110 --> 00:16:52,845 IN MULTIPLE DIFFERENT PATIENT 454 00:16:52,911 --> 00:16:53,879 GROUPS, MORE LIKELY THIS IS 455 00:16:53,946 --> 00:16:55,781 GOING TO BE SOMETHING WE CAN 456 00:16:55,848 --> 00:16:59,551 SINK OUR TEETH INTO. 457 00:16:59,618 --> 00:17:02,788 WE HAVE A NUMBER OF INVESTIGATOR 458 00:17:02,855 --> 00:17:06,125 INITIATED RESEARCH PROGRAMS OUT 459 00:17:06,191 --> 00:17:07,760 THERE FOR PEOPLE TO APPLY TOMENT 460 00:17:07,826 --> 00:17:09,528 SOME OF THESE, THEY'RE ON FOR A 461 00:17:09,595 --> 00:17:11,063 COUPLE YEARS BUT THE PLAN IS TO 462 00:17:11,130 --> 00:17:16,535 REISSUE THEM. 463 00:17:16,602 --> 00:17:18,504 SO SO PLEASE LOOK FORWARD TO 464 00:17:18,570 --> 00:17:19,905 THOSE, TALK TO FOLKS THAT YOU 465 00:17:19,972 --> 00:17:20,873 MIGHT BE INTERESTED IN THIS 466 00:17:20,939 --> 00:17:22,174 FIELD EVEN IF THEY'RE IN ANOTHER 467 00:17:22,241 --> 00:17:23,208 FIELD TO KIND OF TEAM UP WITH 468 00:17:23,275 --> 00:17:24,843 YOU TO KIND OF LOOK AT A NEW AIR 469 00:17:24,910 --> 00:17:28,347 PROACH TNEWAPPROACH TO SOME OF E 470 00:17:28,414 --> 00:17:28,981 PROBLEMS. 471 00:17:29,048 --> 00:17:30,315 THE ONE CENTER THAT STILL WAS 472 00:17:30,382 --> 00:17:33,252 FUNDED IN THE GO-AROUND IS THE 473 00:17:33,318 --> 00:17:33,819 CORNELL GROUP. 474 00:17:33,886 --> 00:17:35,354 WE'RE HOPING -- AND YOU'LL 475 00:17:35,421 --> 00:17:36,522 PROBABLY HEAR FROM THEM TODAY, 476 00:17:36,588 --> 00:17:39,858 BUT WE'RE HOPING TO PUT THIS OUT 477 00:17:39,925 --> 00:17:42,694 AND FUND MORE CENTERS AND GET 478 00:17:42,761 --> 00:17:45,931 THAT TEAM APPROACH BACK, AND KEY 479 00:17:45,998 --> 00:17:49,635 TO THIS IS THE FACT THAT WE HAVE 480 00:17:49,701 --> 00:17:51,403 IN THE CENTER IDEA THE ABILITY 481 00:17:51,470 --> 00:17:53,372 TO BRING SAMPLES IN SO THAT 482 00:17:53,439 --> 00:17:56,542 OTHER INVESTIGATORS, EITHER 483 00:17:56,608 --> 00:17:58,877 WITHIN THE GROUP CAN HAVE ACCESS 484 00:17:58,944 --> 00:18:00,813 TO SAMPLES AND DO TESTS THAT 485 00:18:00,879 --> 00:18:02,114 THEY FIND ABNORMAL IN THEIR 486 00:18:02,181 --> 00:18:03,315 GROUP AND LOOK THE A SAMPLES 487 00:18:03,382 --> 00:18:04,550 FROM ANOTHER GROUP, SEE IF THEY 488 00:18:04,616 --> 00:18:06,318 CAN SEE THE SAME THING, AND ALSO 489 00:18:06,385 --> 00:18:07,152 THE HOPE IS TO MAKE THIS 490 00:18:07,219 --> 00:18:08,287 AVAILABLE TO INVESTIGATORS 491 00:18:08,353 --> 00:18:11,790 ACROSS THE COUNTRY. 492 00:18:11,857 --> 00:18:13,292 SO IF YOU'RE TRYING TO DO ME/CFS 493 00:18:13,358 --> 00:18:14,593 RESEARCH AND YOU NEED FIVE YEARS 494 00:18:14,660 --> 00:18:17,329 TO COLLECT SAMPLES, THAT'S BIG 495 00:18:17,396 --> 00:18:17,596 DOWNTIME. 496 00:18:17,663 --> 00:18:20,399 IF WE HAVE A REALLY GOOD, WELL 497 00:18:20,466 --> 00:18:21,500 ANNOTATED SAMPLE BANK, PEOPLE 498 00:18:21,567 --> 00:18:22,768 CAN TEST THEIR IDEAS POTENTIALLY 499 00:18:22,835 --> 00:18:25,604 IN THOSE SAMPLES WITHIN A YEAR 500 00:18:25,671 --> 00:18:28,807 AND GET ANSWERS. 501 00:18:28,874 --> 00:18:30,375 SO WE HAVE A NUMBER OF AWARDS 502 00:18:30,442 --> 00:18:32,678 AND I'LL JUST MENTION JUST THE 503 00:18:32,744 --> 00:18:33,645 TITLES TO GIVE YOU A SENSE OF 504 00:18:33,712 --> 00:18:35,180 WHAT THEY ARE. 505 00:18:35,247 --> 00:18:36,682 BUT THE GROUP AT COLUMBIA 506 00:18:36,748 --> 00:18:38,884 LOOKING IT THE NEUROLOGICAL POST 507 00:18:38,951 --> 00:18:41,820 SEQUELAE OF SARS-COV-2. 508 00:18:41,887 --> 00:18:43,589 A GROUP AT MASS GENERAL LOOKING 509 00:18:43,655 --> 00:18:46,125 AT NEUTROPHIL FUNCTION AND 510 00:18:46,191 --> 00:18:47,759 CYTOKINE PROFILES IN ME/CFS. 511 00:18:47,826 --> 00:18:49,928 A GROUP AT FLORIDA ATLANTIC 512 00:18:49,995 --> 00:18:52,831 LOOKING AT ENDOGENOUS 513 00:18:52,898 --> 00:18:55,834 RETROVIRUSES IN ME/CFS. 514 00:18:55,901 --> 00:18:59,671 A GROUP, AVIK ROY AND SIMMARON 515 00:18:59,738 --> 00:19:01,640 RESEARCH LOOKING AT ATG13, A 516 00:19:01,707 --> 00:19:03,842 FACTOR INVOLVED IN METABOLISM 517 00:19:03,909 --> 00:19:09,081 THROUGH THE MTOR PATHWAY IN 518 00:19:09,147 --> 00:19:10,983 ME/CFS. 519 00:19:11,049 --> 00:19:12,117 AN ANIMAL MODEL THAT LOOKS 520 00:19:12,184 --> 00:19:14,887 INTERESTING IN TERMS OF 521 00:19:14,953 --> 00:19:16,722 DEVELOPING WHAT SOME IN THE 522 00:19:16,788 --> 00:19:19,057 NEUROSCIENCE FIELD CALL SICKNESS 523 00:19:19,124 --> 00:19:19,525 BEHAVIOR. 524 00:19:19,591 --> 00:19:21,426 SO THE PEOPLE WHO ARE LOOKING AT 525 00:19:21,493 --> 00:19:23,195 THE EQUIVALENT OF ME/CFS IN 526 00:19:23,262 --> 00:19:25,464 ANIMALS ARE LOOKING IN THE 527 00:19:25,531 --> 00:19:28,534 HYPOTHALAMUS, TRYING TO FIND 528 00:19:28,600 --> 00:19:30,202 SOME EVIDENCE THAT THERE ARE 529 00:19:30,269 --> 00:19:31,870 CENTERS THERE THAT, WHEN TURNED 530 00:19:31,937 --> 00:19:34,006 ON BY WH WHATEVER, NOT CLEAR WHT 531 00:19:34,072 --> 00:19:35,541 TURNS THEM ON YET, BUT THERE ARE 532 00:19:35,607 --> 00:19:37,776 SEEMING LISTEN TERES THAT WILL 533 00:19:37,843 --> 00:19:39,611 CHANGE THE ANIMAL'S BEHAVIOR TO 534 00:19:39,678 --> 00:19:41,547 ONE THAT MIMICS WHAT HAPPENS 535 00:19:41,613 --> 00:19:43,248 WHEN, QUOTE-UNQUOTE, THE ANIMAL 536 00:19:43,315 --> 00:19:46,385 IS SICK. 537 00:19:46,451 --> 00:19:49,221 SO THESE MIGHT BE GOOD WAYS OF 538 00:19:49,288 --> 00:19:51,623 GETTING AT SOME MECHANISTIC 539 00:19:51,690 --> 00:19:53,058 PRINCIPLES AND SEE IF THEY APPLY 540 00:19:53,125 --> 00:19:53,825 TO THE HUMAN. 541 00:19:53,892 --> 00:19:57,129 THERE'S ANOTHER GROUP AT MOUNT 542 00:19:57,195 --> 00:20:00,065 SINAI LOOKING AT PROTEOMICS IN 543 00:20:00,132 --> 00:20:02,000 ME/CFS, AND ANOTHER GROUP AT 544 00:20:02,067 --> 00:20:05,103 MOUNT SINAI LOOKING AT HIGH 545 00:20:05,170 --> 00:20:08,373 FIELD MRI, BOTH STRUCTURAL AND 546 00:20:08,440 --> 00:20:12,411 LOOKING AT MR SPECTROSCOPY IN 547 00:20:12,477 --> 00:20:17,349 PATIENTS WITH ME/CFS. 548 00:20:17,416 --> 00:20:18,984 ANOTHER SET OF GRANTS LOOKING AT 549 00:20:19,051 --> 00:20:20,752 SINGLE CELL IMMUNE CELLS FROM 550 00:20:20,819 --> 00:20:24,990 RON DAVIS AT STANFORD. 551 00:20:25,057 --> 00:20:26,191 LEONARD JASON HAS BEEN STUDYING 552 00:20:26,258 --> 00:20:27,726 A LONG TIME PEOPLE WHO DEVELOP 553 00:20:27,793 --> 00:20:30,395 MONO AND THEN HAVE ME/CFS 554 00:20:30,462 --> 00:20:31,663 FOLLOWING MONO, WHICH WAS 555 00:20:31,730 --> 00:20:33,865 PROBABLY THE BEST MODEL UNTIL 556 00:20:33,932 --> 00:20:35,500 COVID CAME ALONG. 557 00:20:35,567 --> 00:20:36,802 MAYBE IT'S STILL THE BEST MODEL 558 00:20:36,868 --> 00:20:40,639 BUT WE'LL SEE. 559 00:20:40,706 --> 00:20:43,141 STUDIES OF HUMAN HERPES VIRUS IN 560 00:20:43,208 --> 00:20:45,677 ME/CFS, LOOKING AT 561 00:20:45,744 --> 00:20:48,880 CARDIOVASCULAR CHARACTERISTICS 562 00:20:48,947 --> 00:20:51,116 OF POST EXERTIONAL MALAISE, 563 00:20:51,183 --> 00:20:52,684 LOOKING AT LONG COVID AS A 564 00:20:52,751 --> 00:20:55,087 SUBTYPE OF CHRONIC FATIGUE 565 00:20:55,153 --> 00:20:56,822 SYNDROME, A GROUP AT UMASS 566 00:20:56,888 --> 00:20:59,324 LOOKING AT ALTERED T RESPONSES 567 00:20:59,391 --> 00:21:04,262 IN ME/CFS, A GROUP AT CORNELL 568 00:21:04,329 --> 00:21:08,300 LOOKING AT N ACETYLCYSTINE AS AN 569 00:21:08,367 --> 00:21:10,202 ANTIOXIDANT TO IMPROVE 570 00:21:10,268 --> 00:21:12,037 GLUTATHIONE LEVELS IN THE BRAIN, 571 00:21:12,104 --> 00:21:13,672 MEASURED BY SP SPECTROSCOPY, AND 572 00:21:13,739 --> 00:21:17,809 THEN ANOTHER ONE LOOKING AT 573 00:21:17,876 --> 00:21:20,912 MAGNETIC RESONANCE SPECTROSCOPY 574 00:21:20,979 --> 00:21:25,450 FOR SIGNS OF NEUROINFLAMMATION 575 00:21:25,517 --> 00:21:26,151 IN ME/CFS. 576 00:21:26,218 --> 00:21:28,220 AT NIH NOW, WE ARE INVOLVED IN 577 00:21:28,286 --> 00:21:31,423 DEVELOPING A ROAD MAP FOR ME/CFS 578 00:21:31,490 --> 00:21:34,226 RESEARCH. 579 00:21:34,292 --> 00:21:35,594 WHAT THIS MEANS IS THAT NIH 580 00:21:35,661 --> 00:21:38,930 CONVENES EXPERTS IN AN AREA IN 581 00:21:38,997 --> 00:21:40,165 HERE WE'RE TALKING ABOUT ME/CFS 582 00:21:40,232 --> 00:21:44,936 AND KIND OF DIVE DOWN INTO WHAT 583 00:21:45,003 --> 00:21:45,937 IS KNOWN AND WHAT THE 584 00:21:46,004 --> 00:21:47,172 OPPORTUNITIES ARE TO MOVE THE 585 00:21:47,239 --> 00:21:48,640 FIELD FORWARD, AND SO THIS GROUP 586 00:21:48,707 --> 00:21:52,511 HAS BEEN WORKING OVER THE YEAR, 587 00:21:52,577 --> 00:21:55,313 AND THIS IS A WORKING GROUP OF 588 00:21:55,380 --> 00:22:02,688 THE NINDS COUNCIL, AND A LOT OF 589 00:22:02,754 --> 00:22:04,089 WORK GOING INTO THIS. 590 00:22:04,156 --> 00:22:05,257 THEY HAVE GROUPS THAT ARE 591 00:22:05,323 --> 00:22:06,391 LOOKING AT ALL THESE DIFFERENT 592 00:22:06,458 --> 00:22:07,793 ASPECTS OF ME/CFS THAT YOU SEE 593 00:22:07,859 --> 00:22:09,995 HERE IN THE BLUE. 594 00:22:10,062 --> 00:22:11,630 THEY'RE HAVING MULTIPLE 595 00:22:11,697 --> 00:22:13,632 WORKSHOPS, INCLUDING PEOPLE WITH 596 00:22:13,699 --> 00:22:17,002 ME/CFS IN THE PLANNING AND THE 597 00:22:17,069 --> 00:22:19,304 EVALUATION PROCESS, AND WILL PUT 598 00:22:19,371 --> 00:22:21,440 TOGETHER A REPORT TO THE NINDS 599 00:22:21,506 --> 00:22:24,109 ADVISORY COUNCIL, WHICH I HOPE 600 00:22:24,176 --> 00:22:25,510 WILL BE ACCEPTED BY THE COUNCIL 601 00:22:25,577 --> 00:22:30,015 AND THEN USEFUL TO NOT JUST NIH 602 00:22:30,082 --> 00:22:32,317 BUT ALSO TO INVESTIGATORS AROUND 603 00:22:32,384 --> 00:22:33,852 THE WORLD IN TERMS OF TRYING TO 604 00:22:33,919 --> 00:22:35,487 MOVE THIS FIELD FORWARD, GETTING 605 00:22:35,554 --> 00:22:38,290 A SENSE OF WHAT THE EXPERTS HAVE 606 00:22:38,356 --> 00:22:40,759 SEEN AS THE MAJOR OPPORTUNITIES 607 00:22:40,826 --> 00:22:46,431 GOING FORWARD. 608 00:22:46,498 --> 00:22:47,799 THEN THE ELEPHANT IN THE ROOM, 609 00:22:47,866 --> 00:22:50,469 OF COURSE, IS THE FACT THAT LONG 610 00:22:50,535 --> 00:22:54,072 COVID HAS REALLY KIND OF 611 00:22:54,139 --> 00:22:55,407 CHANGED, I THINK, THE SPECTRUM 612 00:22:55,474 --> 00:22:58,410 FOR ME/CFS ON THE DOWNSIDE, YOU 613 00:22:58,477 --> 00:23:00,078 KNOW, PROBABLY HUNDREDS OF 614 00:23:00,145 --> 00:23:03,281 THOUSANDS OF PEOPLE NOW HAVE A 615 00:23:03,348 --> 00:23:04,916 SYNDROME THAT IS PROBABLY 616 00:23:04,983 --> 00:23:06,518 IDENTICAL TO ME/CFS. 617 00:23:06,585 --> 00:23:09,521 IT IS MAYBE ME/CFS ITSELF. 618 00:23:09,588 --> 00:23:13,892 AND IT CAME AFTER ACUTE COVID 619 00:23:13,959 --> 00:23:15,627 INFECTION. 620 00:23:15,694 --> 00:23:19,231 AND THAT PUTS THE PRIORITY FOR 621 00:23:19,297 --> 00:23:20,432 FINDING TREATMENTS WAY UP HIGH 622 00:23:20,499 --> 00:23:22,868 ON THE LIST, BECAUSE THE NUMBERS 623 00:23:22,934 --> 00:23:24,402 ARE JUST ASTRONOMICAL. 624 00:23:24,469 --> 00:23:26,338 IT WAS BAD BEFORE COVID, IT'S SO 625 00:23:26,404 --> 00:23:30,942 MUCH WORSE NOW. 626 00:23:31,009 --> 00:23:32,010 YOU CAN SEE HERE THE SYMPTOMS 627 00:23:32,077 --> 00:23:34,112 THAT PEOPLE WITH LONG COVID HAVE 628 00:23:34,179 --> 00:23:37,849 COMPLAINED OF AND YOU CAN 629 00:23:37,916 --> 00:23:39,117 RECOGNIZE THAT MANY OF THESE ARE 630 00:23:39,184 --> 00:23:41,453 ALSO VERY COMMON IN ME/CFS. 631 00:23:41,520 --> 00:23:44,823 SO THE OVERLAP IS REALLY QUITE 632 00:23:44,890 --> 00:23:46,558 STRIKING. 633 00:23:46,625 --> 00:23:53,031 IN ADDITION, MANY PEOPLE -- 634 00:23:53,098 --> 00:23:55,767 ME/CFS OCCURS AFTER SOME KIND OF 635 00:23:55,834 --> 00:23:56,835 STRESS, PARTICULARLY AN 636 00:23:56,902 --> 00:23:58,270 INFECTIOUS CONDITION, BUT IN THE 637 00:23:58,336 --> 00:24:01,106 PAST, PEOPLE WOULD SHOW UP YEARS 638 00:24:01,173 --> 00:24:02,641 AFTER THEY'VE HAD TROUBLES AND 639 00:24:02,707 --> 00:24:03,942 IT WAS VERY HARD TO UNDERSTAND 640 00:24:04,009 --> 00:24:05,710 WHAT'S GOING ON, WHAT TRIGGERED 641 00:24:05,777 --> 00:24:06,812 THIS IN THE BEGINNING, ALTHOUGH 642 00:24:06,878 --> 00:24:08,880 THEY MIGHT HAVE TALKED ABOUT AN 643 00:24:08,947 --> 00:24:10,649 INFECTIOUS ILLNESS, THE EPSTEIN 644 00:24:10,715 --> 00:24:12,317 BARR VIRUS AND MONONUCLEOSIS WAS 645 00:24:12,384 --> 00:24:14,252 KIND OF A GOOD WAY OF GOING 646 00:24:14,319 --> 00:24:16,421 AFTER THAT, BUT THAT WAS 647 00:24:16,488 --> 00:24:19,391 PROBABLY A MINORITY OF FOLKS. 648 00:24:19,457 --> 00:24:20,659 SO -- BUT HERE WITH COVID, WE 649 00:24:20,725 --> 00:24:21,893 KNOW EXACTLY WHAT THE INFECTION 650 00:24:21,960 --> 00:24:24,863 IS, WE KNOW EXACTLY WHEN IT 651 00:24:24,930 --> 00:24:28,333 OCCURRED, AND WITH THE RECOVER 652 00:24:28,400 --> 00:24:30,368 PROGRAM, WE HAVE $1.15 BILLION 653 00:24:30,435 --> 00:24:31,636 THAT WE PUT IN TO TRY AND 654 00:24:31,703 --> 00:24:34,706 UNDERSTAND THIS PROCESS. 655 00:24:34,773 --> 00:24:36,208 AND I THINK THERE'S HOPEFULLY 656 00:24:36,274 --> 00:24:37,676 GOING TO BE SOME ANSWERS THAT 657 00:24:37,742 --> 00:24:39,477 COME OUT OF THIS THAT ARE 658 00:24:39,544 --> 00:24:40,512 RELEVANT NOT JUST TO LONG COVID 659 00:24:40,579 --> 00:24:43,548 BUT TO ME/CFS IN GENERAL. 660 00:24:43,615 --> 00:24:46,284 SO WE HAVE COHORTS AND WE HAVE 661 00:24:46,351 --> 00:24:48,820 TO JUST BE SO GRATEFUL TO PEOPLE 662 00:24:48,887 --> 00:24:51,990 WHO VOLUNTEERED TO BE POKED AND 663 00:24:52,057 --> 00:24:53,325 TESTED. 664 00:24:53,391 --> 00:24:55,126 WE HAVE -- I THINK IT'S UP TO 665 00:24:55,193 --> 00:24:58,029 16,000 PEOPLE NOW HAVE ENROLLED 666 00:24:58,096 --> 00:24:58,864 IN THE COHORT STUDY. 667 00:24:58,930 --> 00:25:00,899 THIS INCLUDES PEOPLE WHO ARE 668 00:25:00,966 --> 00:25:04,135 ACUTELY INFECTED, AND THEN WERE 669 00:25:04,202 --> 00:25:05,337 RECRUITED INTO THE STUDY WITHIN 670 00:25:05,403 --> 00:25:07,072 30 DAYS OF THEIR ACUTE 671 00:25:07,138 --> 00:25:07,339 INFECTION. 672 00:25:07,405 --> 00:25:08,673 SOME OF THOSE ARE GOING TO MAKE 673 00:25:08,740 --> 00:25:10,342 A GOOD RECOVERY. 674 00:25:10,408 --> 00:25:13,178 TURNS OUT FROM WHAT WE'VE HEARD, 675 00:25:13,245 --> 00:25:14,512 ABOUT 70% OF THEM MAKE A GOOD 676 00:25:14,579 --> 00:25:15,180 RECOVERY. 677 00:25:15,247 --> 00:25:17,315 30% HAVE PERSISTENT SYMPTOMS AT 678 00:25:17,382 --> 00:25:20,418 THREE MONTHS AFTER. 679 00:25:20,485 --> 00:25:23,221 SO THIS IS NOT REPRESENTATIVE OF 680 00:25:23,288 --> 00:25:24,356 THE INCIDENCE BECAUSE MY 681 00:25:24,422 --> 00:25:27,525 SUSPICION IS THAT THE PEOPLE ARE 682 00:25:27,592 --> 00:25:28,860 MORE LIKELY TO ENROLL IF THEY 683 00:25:28,927 --> 00:25:30,395 WERE HAVING SYMPTOMS THREE OR 684 00:25:30,462 --> 00:25:32,998 FOUR WEEKS LATER, SO I THINK WE 685 00:25:33,064 --> 00:25:34,299 GOT AN ENRICHED POPULATION, BUT 686 00:25:34,366 --> 00:25:35,700 THAT'S REALLY GREAT FOR THE 687 00:25:35,767 --> 00:25:38,236 STUDY BECAUSE W WHAT WE REALLY 688 00:25:38,303 --> 00:25:40,005 WANTED WAS A GROUP THAT WAS 689 00:25:40,071 --> 00:25:41,006 ACUTELY INFECTED AT THE SAME 690 00:25:41,072 --> 00:25:42,407 TIME, SOME OF WHICH GOT BETTER, 691 00:25:42,474 --> 00:25:44,042 SOME OF WHICH DIDN'T. 692 00:25:44,109 --> 00:25:45,343 SO WE CAN COMPARE THE TWO GROUPS 693 00:25:45,410 --> 00:25:48,313 AND SEE WHAT HAPPENED OVER TIME. 694 00:25:48,380 --> 00:25:51,082 IF WE GOT TO, SAY, 5% PEOPLE 695 00:25:51,149 --> 00:25:51,816 DEVELOPING TROUBLE, WE WOULDN'T 696 00:25:51,883 --> 00:25:53,885 REALLY HAVE A LOT TO COMPARE BUT 697 00:25:53,952 --> 00:25:57,155 IT TURNS OUT THE STUDY IS ABOUT 698 00:25:57,222 --> 00:25:58,857 30% OF THOSE ACUTELY ENROLLED 699 00:25:58,924 --> 00:26:04,195 ARE CURRENTLY HAVING SYMPTOMS. 700 00:26:04,262 --> 00:26:05,163 THEN THERE'S THOUSANDS OF PEOPLE 701 00:26:05,230 --> 00:26:06,264 WHO HAVE HAD SYMPTOMS AND THEY 702 00:26:06,331 --> 00:26:07,766 ARE ENROLLED ALONG WITH A 703 00:26:07,832 --> 00:26:12,404 CONTROL GROUP, AND THIS ALLOWS 704 00:26:12,470 --> 00:26:15,006 THESE CONSORTIA ACROSS THE 705 00:26:15,073 --> 00:26:18,510 COUNTRY TO STUDY THIS IN LARGE 706 00:26:18,576 --> 00:26:19,311 DETAIL, MULTIPLE PATIENTS, 707 00:26:19,377 --> 00:26:20,378 DIFFERENT TIERS OF TESTS, AND 708 00:26:20,445 --> 00:26:21,813 ALSO SAMPLES ARE BEING COLLECTED 709 00:26:21,880 --> 00:26:26,584 AND STORED AT MAYO CLINIC SO 710 00:26:26,651 --> 00:26:28,453 THAT WE'LL HAVE A GREAT 711 00:26:28,520 --> 00:26:29,454 COLLECTION, IF WE DON'T FIGURE 712 00:26:29,521 --> 00:26:30,422 THIS OUT IN THE SHORT TERM, 713 00:26:30,488 --> 00:26:31,556 THOSE SAMPLES WILL BE AVAILABLE 714 00:26:31,623 --> 00:26:36,361 FOR LONGER FUTURE STUDIES. 715 00:26:36,428 --> 00:26:38,496 WE HAVE STUDIES GOING ON NOW TO 716 00:26:38,563 --> 00:26:41,199 GET AT THE PATHOBIOLOGY OF THE 717 00:26:41,266 --> 00:26:45,236 LONG COVID SITUATION IN PATIENTS 718 00:26:45,303 --> 00:26:46,438 AND IN ANIMAL MODELS. 719 00:26:46,504 --> 00:26:49,107 WE HAVE AUTOPSY STUDIES, WHICH 720 00:26:49,174 --> 00:26:52,711 ARE LOOKING FOR EVIDENCE OF 721 00:26:52,777 --> 00:26:54,713 TISSUE DAMAGE OR POTENTIALLY 722 00:26:54,779 --> 00:26:58,850 PERSISTENT VIRUS OR IMMUNE 723 00:26:58,917 --> 00:26:59,918 ABNORMALITIES IN DIFFERENT 724 00:26:59,985 --> 00:27:02,354 IMMUNE AREAS OF THE BODY. 725 00:27:02,420 --> 00:27:05,190 THIS IS SOMETHING THAT'S 726 00:27:05,256 --> 00:27:08,393 TERRIBLY LACKING IN ME/CFS. 727 00:27:08,460 --> 00:27:09,461 WHERE WE DON'T KNOW THAT THERE 728 00:27:09,527 --> 00:27:10,895 COULD BE SOMETHING HIDING THERE 729 00:27:10,962 --> 00:27:12,864 THAT NO ONE'S EVER SEEN BEFORE, 730 00:27:12,931 --> 00:27:14,566 BECAUSE NO ONE HAS EVER DONE A 731 00:27:14,632 --> 00:27:17,669 REALLY CAREFUL AUTOPSY STUDY IN 732 00:27:17,736 --> 00:27:19,871 PEOPLE THAT HAVE DIED FROM 733 00:27:19,938 --> 00:27:20,305 ME/CFS. 734 00:27:20,372 --> 00:27:22,273 I THINK NOW THEY HAVE 120 735 00:27:22,340 --> 00:27:24,676 AUTOPSIES IN THE LONG COVID 736 00:27:24,743 --> 00:27:25,543 STUDY. 737 00:27:25,610 --> 00:27:27,946 SOME OF THEM ARE CONTROLS, SOME 738 00:27:28,013 --> 00:27:29,247 ACUTELY INFECTED AND SICK, AND 739 00:27:29,314 --> 00:27:33,018 SOME OF THEM ARE PEOPLE WITH 740 00:27:33,084 --> 00:27:35,520 PASC OUT PAST AN INFECTION, SOME 741 00:27:35,587 --> 00:27:42,494 NORMALS OUT PAST INFECTION. 742 00:27:42,560 --> 00:27:43,695 THIS IS JUST AN INTERESTING 743 00:27:43,762 --> 00:27:44,662 POINT TO MAKE, IS THAT WHEN THE 744 00:27:44,729 --> 00:27:46,264 GROUP LOOKED AT THESE THOUSANDS 745 00:27:46,331 --> 00:27:50,468 OF PEOPLE IN THE COHORT STUDY, 746 00:27:50,535 --> 00:27:52,237 THE QUESTION IS ALWAYS WHAT'S 747 00:27:52,303 --> 00:27:54,406 THE DEFINITION, AND CERTAINLY 748 00:27:54,472 --> 00:27:55,507 ME/CFS HAS BEEN, YOU KNOW, 749 00:27:55,573 --> 00:27:57,075 INVOLVED IN TRYING TO DEFINE 750 00:27:57,142 --> 00:27:59,544 WHAT IT IS FOR DECADES. 751 00:27:59,611 --> 00:28:01,746 THIS IS BASICALLY A STATISTICAL 752 00:28:01,813 --> 00:28:03,314 ANALYSIS, SO IT'S NOT REALLY -- 753 00:28:03,381 --> 00:28:05,116 IT'S NOT A CLINICALLY USEFUL 754 00:28:05,183 --> 00:28:07,552 TOOL, BUT I THINK IT GIVES US 755 00:28:07,619 --> 00:28:08,453 SOME LESSONS. 756 00:28:08,520 --> 00:28:12,323 SO WHAT THEY DID IS, BECAUSE THE 757 00:28:12,390 --> 00:28:15,760 SYMPTOMS ARE SO COMMON IN THE 758 00:28:15,827 --> 00:28:16,327 NON-COVID POPULATION, IT'S 759 00:28:16,394 --> 00:28:18,830 REALLY HARD TO KNOW WHAT IS 760 00:28:18,897 --> 00:28:22,033 EXACTLY LONG COVID VERSUS THE 761 00:28:22,100 --> 00:28:26,237 USUAL, YOU KNOW, FATIGUE, 762 00:28:26,304 --> 00:28:27,472 EXERCISE INTOLERANCE, AND THAT 763 00:28:27,539 --> 00:28:29,641 APPLIES TO ME/CFS AS WELL. 764 00:28:29,707 --> 00:28:31,376 BUT STATISTICALLY, THEY LOOKED 765 00:28:31,443 --> 00:28:32,410 AND THEY SAID, WELL, WHAT ARE 766 00:28:32,477 --> 00:28:33,678 THE THINGS THAT REALLY TURN OUT 767 00:28:33,745 --> 00:28:36,648 TO BE REALLY DIFFERENT, AND IT 768 00:28:36,714 --> 00:28:38,149 TURNS OUT THAT THE NUMBER OF 769 00:28:38,216 --> 00:28:40,452 SYMPTOMS AND THE TYPE OF 770 00:28:40,518 --> 00:28:42,120 SYMPTOMS ARE THE ONES THAT RISE 771 00:28:42,187 --> 00:28:45,490 TO THE TOP, AND AT THE TOP IS A 772 00:28:45,557 --> 00:28:47,058 LOSS OF SMELL AND TASTE, AND OF 773 00:28:47,125 --> 00:28:49,861 COURSE THAT'S RELATED TO COVID 774 00:28:49,928 --> 00:28:54,799 SO TH THAT WAS BE EXPECTED 775 00:28:54,866 --> 00:28:56,768 DIFFERENT FROM CONTROLS, BUT 776 00:28:56,835 --> 00:28:58,169 POST EXERTIONAL MALAISE WAS 777 00:28:58,236 --> 00:28:58,470 NUMBER TWO. 778 00:28:58,536 --> 00:29:00,038 THAT WAS THE SECOND MOST 779 00:29:00,105 --> 00:29:01,906 IMPORTANT DISTINGUISHING FACTOR, 780 00:29:01,973 --> 00:29:05,310 AND OF COURSE THAT'S WHAT ONE OF 781 00:29:05,376 --> 00:29:06,644 THE REAL SIGNATURES OF ME/CFS 782 00:29:06,711 --> 00:29:07,045 ARE. 783 00:29:07,112 --> 00:29:10,215 BRAIN FOG, FATIGUE ARE ON THAT 784 00:29:10,281 --> 00:29:10,882 LIST. 785 00:29:10,949 --> 00:29:12,417 FATIGUE IS SO COMMON, IT DOESN'T 786 00:29:12,484 --> 00:29:15,687 DISTINGUISH AS WELL AS A SYMP 787 00:29:15,753 --> 00:29:16,454 SYMPTOM. 788 00:29:16,521 --> 00:29:18,089 THEN AS YOU CAN SEE, THE NUMBER 789 00:29:18,156 --> 00:29:20,959 OF SYMPTOMS CORRELATES WITH A 790 00:29:21,025 --> 00:29:22,460 DIFFERENCE FROM WHAT YOU WOULD 791 00:29:22,527 --> 00:29:24,863 EXPECT IN NORMALS. 792 00:29:24,929 --> 00:29:27,165 WE DON'T KNOW WHAT HAS CAUSED 793 00:29:27,232 --> 00:29:27,599 LONG COVID. 794 00:29:27,665 --> 00:29:30,034 WE WERE HOPING WE'D HAVE SOME 795 00:29:30,101 --> 00:29:31,302 BETTER EVIDENCE BY NOW BUT WE 796 00:29:31,369 --> 00:29:31,769 DON'T. 797 00:29:31,836 --> 00:29:35,940 THERE'S A LOT OF PAPERS OUT 798 00:29:36,007 --> 00:29:37,876 THERE TAUTING OR GOING AFTER 799 00:29:37,942 --> 00:29:39,444 CERTAIN MECHANISMS, BUT NONE OF 800 00:29:39,511 --> 00:29:42,180 THEM ARE TOTALLY NAILED DOWN. 801 00:29:42,247 --> 00:29:44,716 BUT THESE ARE THE ONES THAT ARE 802 00:29:44,782 --> 00:29:47,752 STICKING TO THE TOP AND WE HAVE 803 00:29:47,819 --> 00:29:48,920 DEVELOPED CLINICAL TRIALS. 804 00:29:48,987 --> 00:29:50,088 SOME OF THEM ARE TRYING TO GET 805 00:29:50,155 --> 00:29:51,589 AT THE PATHOPHYSIOLOGY, SO FOR 806 00:29:51,656 --> 00:29:53,625 INSTANCE, WE HAVE TRIALS TO 807 00:29:53,691 --> 00:29:58,229 START USING IVIG IN PEOPLE WITH 808 00:29:58,296 --> 00:29:59,764 AUTONOMIC DYSFUNCTION AFTER LONG 809 00:29:59,831 --> 00:30:03,501 COVID. 810 00:30:03,568 --> 00:30:04,836 POTS SYNDROME IS A REALLY 811 00:30:04,903 --> 00:30:06,638 PROMINENT ONE, AND THEN WE HAVE 812 00:30:06,704 --> 00:30:09,707 A PROLONGED ANTIVIRAL TREATMENT 813 00:30:09,774 --> 00:30:12,677 ON THE IDEA THAT THERE COULD BE 814 00:30:12,744 --> 00:30:14,412 PERSISTENT ACTIVE VIRUS IN 815 00:30:14,479 --> 00:30:15,947 FOLKS, AND THEN WE HAVE A NUMBER 816 00:30:16,014 --> 00:30:19,317 OF SYMPTOMATIC TRIALS LOOKING AT 817 00:30:19,384 --> 00:30:21,853 SLEEP, LOOKING AT COGNITION, TO 818 00:30:21,920 --> 00:30:26,024 TRY AND IMPROVE PATIENTS -- THE 819 00:30:26,090 --> 00:30:27,759 SUFFERING THE PATIENTS ARE 820 00:30:27,825 --> 00:30:28,193 UNDERGOING NOW. 821 00:30:28,259 --> 00:30:31,462 SO I THINK THERE'S -- I THINK 822 00:30:31,529 --> 00:30:34,032 WHAT COVID DID IS, I THINK IT 823 00:30:34,098 --> 00:30:36,301 MADE ALL THE WORK THAT PEOPLE IN 824 00:30:36,367 --> 00:30:37,702 ME/CFS HAVE BEEN DOING OVER THE 825 00:30:37,769 --> 00:30:40,004 YEARS, KIND OF RAISED IT IN 826 00:30:40,071 --> 00:30:41,206 PROMINENCE. 827 00:30:41,272 --> 00:30:42,407 THE PROBLEM OF ME/CFS IS STILL 828 00:30:42,473 --> 00:30:44,075 WITH US, THE PROBLEM OF LONG 829 00:30:44,142 --> 00:30:48,213 COVID IS WITH US, BUT WE HAVE A 830 00:30:48,279 --> 00:30:49,781 GREATER ARMY OF PEOPLE STUDYING 831 00:30:49,847 --> 00:30:51,716 THIS WITH GREATER TOOLS, 832 00:30:51,783 --> 00:30:53,451 HOPEFULLY GREATER SAMPLES, AND I 833 00:30:53,518 --> 00:30:55,987 THINK WORKING TOGETHER IS OUR 834 00:30:56,054 --> 00:30:58,957 BEST CHANCE AT REALLY DOING 835 00:30:59,023 --> 00:31:01,893 SOMETHING THAT TURNED THE CORNER 836 00:31:01,960 --> 00:31:02,860 AND GETS US TO IMPORTANT 837 00:31:02,927 --> 00:31:04,295 TREATMENTS FOR PEOPLE WHO ARE 838 00:31:04,362 --> 00:31:06,164 SUFFERING WITH ME/CFS. 839 00:31:06,231 --> 00:31:07,265 SO REALLY APPRECIATE THE WORK 840 00:31:07,332 --> 00:31:09,000 YOU'RE DOING. 841 00:31:09,067 --> 00:31:11,936 NIH IS HERE TO KIND OF MOVE THIS 842 00:31:12,003 --> 00:31:15,006 FORWARD AS BEST WE CAN, BUT THIS 843 00:31:15,073 --> 00:31:17,508 IS A TOUGH PROBLEM, AND WE HAVE 844 00:31:17,575 --> 00:31:18,943 TO BE CLEVER. 845 00:31:19,010 --> 00:31:19,310 THANKS. 846 00:31:19,377 --> 00:31:29,554 [APPLAUSE] 847 00:31:35,326 --> 00:31:38,029 >> THANK YOU, DR. KOROSHETZ. 848 00:31:38,096 --> 00:31:41,399 SO WE'RE GOING TO MOVE INTO OUR 849 00:31:41,466 --> 00:31:43,568 FIRST SESSION, IMMUNOLOGY OF 850 00:31:43,635 --> 00:31:45,003 ME/CFS AND LONG COVID. 851 00:31:45,069 --> 00:31:47,772 WE HAVE THREE SPEAKERS IN THIS 852 00:31:47,839 --> 00:31:48,006 SESSION. 853 00:31:48,072 --> 00:31:52,143 BUT WE'RE GOING TO START WITH 854 00:31:52,210 --> 00:31:53,945 LIVED EXPERIENCE SPEAKER VOX JO 855 00:31:54,012 --> 00:31:54,312 HSU. 856 00:31:54,379 --> 00:31:55,580 AND IT'S OUR PLEASURE TO 857 00:31:55,647 --> 00:31:56,414 INTRODUCE YOU AND PLEASE COME UP 858 00:31:56,481 --> 00:32:06,724 TO THE PODIUM. 859 00:32:22,140 --> 00:32:23,875 >> CAN YOU HEAR ME OKAY? 860 00:32:23,941 --> 00:32:24,142 FANTASTIC. 861 00:32:24,208 --> 00:32:24,642 THANK YOU. 862 00:32:24,709 --> 00:32:25,843 SO I APPRECIATE THE OPPORTUNITY 863 00:32:25,910 --> 00:32:27,912 TO SPEAK WITH YOU TODAY. 864 00:32:27,979 --> 00:32:34,018 I'LL JUST JUMP RIGHT INTO IT. 865 00:32:34,085 --> 00:32:35,219 "TO HAVE PAIN IS TO HAVE 866 00:32:35,286 --> 00:32:35,653 CERTAINTY. 867 00:32:35,720 --> 00:32:38,523 TO HEAR ABOUT PAIN IS TO HAVE 868 00:32:38,589 --> 00:32:38,756 DOUBT." 869 00:32:38,823 --> 00:32:40,191 THIS IS THE WILD PART ABOUT 870 00:32:40,258 --> 00:32:42,226 LIVING WITH A POORLY UNDERSTOOD 871 00:32:42,293 --> 00:32:42,894 ILLNESS. 872 00:32:42,960 --> 00:32:45,296 YOU WAKE EVERY DAY TO THE DREAD 873 00:32:45,363 --> 00:32:47,265 OF SUFFERING WHILE STRUGGLING TO 874 00:32:47,332 --> 00:32:50,435 PROVE TO OTHERS, WHILE MEDICAL 875 00:32:50,501 --> 00:32:51,502 AUTHORITIES SPEND TIME, ENERGY 876 00:32:51,569 --> 00:32:52,737 AND MONEY TRYING TO CONFIRM WHAT 877 00:32:52,804 --> 00:32:55,907 YOU ALREADY KNOW TO BE TRUE. 878 00:32:55,973 --> 00:32:57,442 SO I'M SPEAKING TO YOU AS A 879 00:32:57,508 --> 00:32:59,977 PERSON WITH M.E., WHICH COLLIDED 880 00:33:00,044 --> 00:33:01,045 WITH COVID-19 AND LONG COVID 881 00:33:01,112 --> 00:33:02,146 LAST YEAR. 882 00:33:02,213 --> 00:33:04,749 I'M ALSO SPEAKING TO YOU AS A 883 00:33:04,816 --> 00:33:05,116 RESEARCHER. 884 00:33:05,183 --> 00:33:06,150 I'M A PROFESSOR AT THE 885 00:33:06,217 --> 00:33:07,618 UNIVERSITY OF TEXAS AT AUSTIN, 886 00:33:07,685 --> 00:33:10,555 WHERE I STUDY THE POLITICAL 887 00:33:10,621 --> 00:33:11,889 EMBODIED IMPACT OF STORYTELLING, 888 00:33:11,956 --> 00:33:13,524 THE WAYS THAT NARRATIVE SHAPE 889 00:33:13,591 --> 00:33:15,360 POLICY, SOCIAL NORMS AND 890 00:33:15,426 --> 00:33:16,694 PERSONAL AND PUBLIC HEALTH. 891 00:33:16,761 --> 00:33:18,996 AND WE TELL STORIES EVERYWHERE, 892 00:33:19,063 --> 00:33:20,965 THROUGH NEWS MEDIA, POLITICAL 893 00:33:21,032 --> 00:33:21,833 BRIEFINGS, AND SCIENTIFIC 894 00:33:21,899 --> 00:33:23,134 STUDIES. 895 00:33:23,201 --> 00:33:25,670 MORE RECENTLY, I FOCUSED ON HOW 896 00:33:25,737 --> 00:33:28,272 DISCRIMINATORY STORIES 897 00:33:28,339 --> 00:33:29,073 INFILTRATE MEDICAL RESEARCH AND 898 00:33:29,140 --> 00:33:30,641 HOW THAT RESEARCH GETS TAKEN UP 899 00:33:30,708 --> 00:33:31,676 TO DO FURTHER DAMAGE. 900 00:33:31,743 --> 00:33:36,481 ALMOST EXACTLY A YEAR AGO, 901 00:33:36,547 --> 00:33:39,350 NATALIE SHORE PUBLISHED AN 902 00:33:39,417 --> 00:33:41,586 ARTICLE TITLED WE MIGHT HAVE 903 00:33:41,652 --> 00:33:42,286 LONG COVID ALL WRONG. 904 00:33:42,353 --> 00:33:43,921 IT OPENS WITH A STORY OF A WOMAN 905 00:33:43,988 --> 00:33:46,257 WITH FUNCTIONAL NEUROLOGICAL 906 00:33:46,324 --> 00:33:47,959 DISORDER WHICH WAS MISDIAGNOSED 907 00:33:48,025 --> 00:33:49,494 AS DEGENERATIVE DEMENTIA. 908 00:33:49,560 --> 00:33:51,996 SHE MIRACULOUSLY RECOVERS BY 909 00:33:52,063 --> 00:33:53,865 RETRAINING HER THINKING. 910 00:33:53,931 --> 00:33:55,066 SHORE DOES NOT DIRECTLY ACCUSE 911 00:33:55,133 --> 00:33:56,367 LONG COVID OF BEING 912 00:33:56,434 --> 00:33:57,568 PSYCHOSOMATIC. 913 00:33:57,635 --> 00:33:58,803 INSTEAD SHE CITES AN NIH STUDY 914 00:33:58,870 --> 00:34:00,505 THAT FOUND INCREASED RISK FOR 915 00:34:00,571 --> 00:34:01,773 LONG COVID AMONG, QUOTE, WOMEN 916 00:34:01,839 --> 00:34:03,174 AND THOSE WITH A HISTORY OF 917 00:34:03,241 --> 00:34:05,376 ANXIETY DISORDER. 918 00:34:05,443 --> 00:34:08,112 SHE EXPLAINS ANXIETY FREQUENTLY 919 00:34:08,179 --> 00:34:08,980 CAUSES SYMPTOMS MOST PEOPLE 920 00:34:09,046 --> 00:34:10,181 WOULD DESCRIBE AS PHYSICAL. 921 00:34:10,248 --> 00:34:11,582 BY LAYERING THESE STORIES ON TOP 922 00:34:11,649 --> 00:34:13,918 OF EACH OTHER, SHE'S BUILDING AN 923 00:34:13,985 --> 00:34:14,252 ARGUMENT. 924 00:34:14,318 --> 00:34:15,887 ANXIETY IS MISDIAGNOSED AS 925 00:34:15,953 --> 00:34:17,088 BIOMEDICAL ILLNESS, LONG COVID 926 00:34:17,155 --> 00:34:19,056 IS COMMONLY ASSOCIATED WITH 927 00:34:19,123 --> 00:34:20,224 ANXIETY, ANXIETY CAN BE CURED 928 00:34:20,291 --> 00:34:22,126 WITH THERAPY. 929 00:34:22,193 --> 00:34:23,628 THIS IS A PARTICULAR SELECTION 930 00:34:23,694 --> 00:34:26,497 OF EVENTS THAT SUGGESTS A COULD 931 00:34:26,564 --> 00:34:27,665 CONCLUSION, THAT M.E. AND LONG 932 00:34:27,732 --> 00:34:29,033 COVID COULD BE EFFECTIVE TREATED 933 00:34:29,100 --> 00:34:30,735 WITH PSYCHOLOGICAL APPROACHES. 934 00:34:30,802 --> 00:34:32,970 SHORE'S ARTICLE CLOSES WITH THE 935 00:34:33,037 --> 00:34:33,704 WOMEN'S PSYCHIATRIC 936 00:34:33,771 --> 00:34:35,239 REHABILITATION WHICH INVOLVES 937 00:34:35,306 --> 00:34:36,574 STRESS MANAGEMENT AND HABIT 938 00:34:36,641 --> 00:34:37,074 BUILDING. 939 00:34:37,141 --> 00:34:38,509 OF COURSE MEDIA WRITEUPS LACK 940 00:34:38,576 --> 00:34:40,077 THE NUANCE OF SCIENTIFIC 941 00:34:40,144 --> 00:34:41,245 LITERATURE BUT SHORE'S FRAMING 942 00:34:41,312 --> 00:34:42,447 PARALLELS THAT OF THE STUDY 943 00:34:42,513 --> 00:34:44,348 WHICH IDENTIFIES FEMALE GENDER 944 00:34:44,415 --> 00:34:46,617 AND ANXIETY AND DEPRESSION AS 945 00:34:46,684 --> 00:34:48,052 RISK FACTORS FOR LONG COVID. 946 00:34:48,119 --> 00:34:49,487 QUITE FRANKLY, IT DOESN'T MATTER 947 00:34:49,554 --> 00:34:50,922 WHETHER SHORE OR ANY OF THE 948 00:34:50,988 --> 00:34:52,657 RESEARCHERS WHOSE ARGUMENTS 949 00:34:52,723 --> 00:34:54,292 SUPPORT HER ARGUMENT BELIEVE 950 00:34:54,358 --> 00:34:57,395 THAT LONG COVID IS ALL IN ONE'SS 951 00:34:57,462 --> 00:34:57,895 HEAD. 952 00:34:57,962 --> 00:34:59,997 THEIR ARGUMENTS ENTER A CULTURAL 953 00:35:00,064 --> 00:35:00,965 CONTEXT WHERE DISABLED PEOPLE 954 00:35:01,032 --> 00:35:02,066 ARE ALREADY TREATED WITH 955 00:35:02,133 --> 00:35:03,501 SUSPICION, WHERE PSYCHIATRIC 956 00:35:03,568 --> 00:35:04,735 DIAGNOSES ARE ALREADY WEAPONIZED 957 00:35:04,802 --> 00:35:07,305 TO INVALIDATE A PERSON'S 958 00:35:07,371 --> 00:35:07,672 SELF-KNOWLEDGE. 959 00:35:07,738 --> 00:35:09,273 LET ME BE CLEAR. 960 00:35:09,340 --> 00:35:11,242 WHETHER OR NOT YOU ACTUALLY 961 00:35:11,309 --> 00:35:12,777 BELIEVE A DISCRIMINATORY 962 00:35:12,844 --> 00:35:13,778 NARRATIVE, YOUR WORDS CAN 963 00:35:13,845 --> 00:35:14,345 ENDORSE IT. 964 00:35:14,412 --> 00:35:16,514 WITH ALL THE AUTHORITY OF YOUR 965 00:35:16,581 --> 00:35:17,748 POSITION. 966 00:35:17,815 --> 00:35:19,116 STORIES ARE ALGORITHMIC. 967 00:35:19,183 --> 00:35:21,085 THEY PROVIDE A SET OF RULES FOR 968 00:35:21,152 --> 00:35:22,186 ANSWERING A QUESTION. 969 00:35:22,253 --> 00:35:24,255 WHEN WE SEE A MARVEL MOVIE, WE 970 00:35:24,322 --> 00:35:25,790 EXPECT FLASHY ACTION SEQUENCES. 971 00:35:25,857 --> 00:35:27,658 WHEN WE SEROMID-ATLANTIC 972 00:35:27,725 --> 00:35:29,427 COMEDIES WE ANTICIPATE HAPPILY 973 00:35:29,494 --> 00:35:31,596 EVER AFTERS, WHEN WE ENCOUNTER A 974 00:35:31,662 --> 00:35:32,797 PATIENT WITH ANXIETY, WE 975 00:35:32,864 --> 00:35:34,565 PRESCRIBE PSYCHOTHERAPY AND 976 00:35:34,632 --> 00:35:36,200 MAYBE EXERCISE AND SSRIs. 977 00:35:36,267 --> 00:35:37,401 LIKE THE ALGORITHMS THAT 978 00:35:37,468 --> 00:35:38,503 GENERATE OUR SOCIAL MEDIA FEEDS 979 00:35:38,569 --> 00:35:41,038 AND OUR GOOGLE SEARCH RESULTS, 980 00:35:41,105 --> 00:35:42,840 STORIES CAN DISCRIMINATE. 981 00:35:42,907 --> 00:35:43,474 THROUGHOUT WESTERN MEDICINE, THE 982 00:35:43,541 --> 00:35:46,577 STORE HE OOO OF HYSTERIA WHICH 983 00:35:46,644 --> 00:35:48,312 LIVES ON HAS PRESUMED THAT WOMEN 984 00:35:48,379 --> 00:35:49,814 ARE UNRELIABLE NARRATORS OF 985 00:35:49,881 --> 00:35:51,082 THEIR OWN BODIES. 986 00:35:51,148 --> 00:35:52,250 I DON'T NEED TO TELL MOST FOLKS 987 00:35:52,316 --> 00:35:53,584 IN THIS ROOM THAT THIS IS A 988 00:35:53,651 --> 00:35:55,353 STORY THAT HAS HAUNTED M.E. AS 989 00:35:55,419 --> 00:35:57,421 WELL AS CONDITIONS SUCH AS 990 00:35:57,488 --> 00:35:59,690 ASTHMA, ENDOMETRIOSIS, AND MS. 991 00:35:59,757 --> 00:36:02,226 THIS IS THE STORY INVOKED WHEN 992 00:36:02,293 --> 00:36:03,127 MEDICAL EXPERTS, WHEN THE 993 00:36:03,194 --> 00:36:04,529 NATION'S LEADING HEALTH 994 00:36:04,595 --> 00:36:06,163 AUTHORITY DECIDES TO ASK, IS 995 00:36:06,230 --> 00:36:07,698 ANXIETY A RISK FACTOR FOR LONG 996 00:36:07,765 --> 00:36:08,900 COVID? 997 00:36:08,966 --> 00:36:11,235 RATHER THAN ASKING, WHAT COMMON 998 00:36:11,302 --> 00:36:12,770 FACTORS MIGHT MAKE PARTICULAR 999 00:36:12,837 --> 00:36:14,672 PEOPLE MORE VULNERABLE TO 1000 00:36:14,739 --> 00:36:15,873 ANXIETY AND LONG COVID? 1001 00:36:15,940 --> 00:36:17,241 WHAT FORMS OF TREATMENT ARE 1002 00:36:17,308 --> 00:36:18,509 ALREADY AVAILABLE FOR THE 1003 00:36:18,576 --> 00:36:19,710 PHYSIOLOGICAL SYMPTOMS WE FOUND 1004 00:36:19,777 --> 00:36:21,279 IN M.E. AND LONG COVID AND WHAT 1005 00:36:21,345 --> 00:36:22,580 MIGHT WE INVESTIGATE TO IMPROVE 1006 00:36:22,647 --> 00:36:23,781 PATIENT OUTCOMES AND CURRENT 1007 00:36:23,848 --> 00:36:26,817 QUALITY OF LIFE? 1008 00:36:26,884 --> 00:36:28,719 M.E. HAS BEEN NAMED FOR OVER A 1009 00:36:28,786 --> 00:36:29,353 HALF CENTURY. 1010 00:36:29,420 --> 00:36:31,322 IF TRADITIONAL METHODS FOR 1011 00:36:31,389 --> 00:36:32,757 ADDRESSING ANXIETY AND 1012 00:36:32,823 --> 00:36:33,925 DEPRESSION WERE TENABLE 1013 00:36:33,991 --> 00:36:35,693 SOLUTIONS WE'D BE OVERRUN WITH 1014 00:36:35,760 --> 00:36:36,928 MIRACULOUS RECOVERY STORIES AND 1015 00:36:36,994 --> 00:36:37,328 WE'RE NOT. 1016 00:36:37,395 --> 00:36:38,996 BUT THIS STORY REMAINS 1017 00:36:39,063 --> 00:36:40,531 PERSUASIVE BECAUSE IT FEEDS ON 1018 00:36:40,598 --> 00:36:41,832 EXISTING STEREOTYPES ABOUT 1019 00:36:41,899 --> 00:36:43,034 WOMEN, ABOUT DISABILITY AND 1020 00:36:43,100 --> 00:36:46,637 ABOUT WHOSE PAIN NEEDS TO BE 1021 00:36:46,704 --> 00:36:47,171 TAKEN SERIOUSLY. 1022 00:36:47,238 --> 00:36:48,973 LET ME TRY A DIFFERENT STORY. 1023 00:36:49,040 --> 00:36:51,409 I GET SICK AT 19 YEARS OLD. 1024 00:36:51,475 --> 00:36:52,777 I SPEND WEEKS IN BED SAMPLING 1025 00:36:52,843 --> 00:36:54,145 ALL THE SOUPS THAT HOUSTON HAS 1026 00:36:54,211 --> 00:36:56,480 TO OFFER, BECAUSE IT TAKES TOO 1027 00:36:56,547 --> 00:37:00,084 LONG FOR ME TO GET BETTER, I 1028 00:37:00,151 --> 00:37:05,690 TODDER TO MY JOB, I DIGITIZE VHS 1029 00:37:05,756 --> 00:37:07,158 TAPES, I DO THIS OVER AND OVER 1030 00:37:07,224 --> 00:37:09,427 AGAIN IN THE COMING YEARS, 1031 00:37:09,493 --> 00:37:11,629 CHOOSE WORK OVER THE CRY OF MY 1032 00:37:11,696 --> 00:37:11,963 BODY. 1033 00:37:12,029 --> 00:37:14,265 AFTER THE GIRLFRIEND AND I BREAK 1034 00:37:14,332 --> 00:37:15,900 UP, AFTER MY FRIENDS STOP ASKING 1035 00:37:15,967 --> 00:37:17,301 ME TO COME OUT, AFTER I STOP 1036 00:37:17,368 --> 00:37:18,502 TALKING TO MY PARENTS BECAUSE 1037 00:37:18,569 --> 00:37:20,338 THEY SUSPECT I AM FAKING MY 1038 00:37:20,404 --> 00:37:21,238 PAIN, BECAUSE THEY ARE RELIEVED 1039 00:37:21,305 --> 00:37:22,873 WHEN THE GIRLFRIEND AND I BREAK 1040 00:37:22,940 --> 00:37:24,308 UP, BECAUSE THEY AND I HAVE BEEN 1041 00:37:24,375 --> 00:37:27,478 LOOKING FOR AN EXCUSE THROUGHOUT 1042 00:37:27,545 --> 00:37:28,346 MY LIFE ANYWAY. 1043 00:37:28,412 --> 00:37:29,647 I GO TO WORK BECAUSE I NEED THE 1044 00:37:29,714 --> 00:37:30,047 MONEY. 1045 00:37:30,114 --> 00:37:31,215 BECAUSE I HAVE BEEN TAUGHT THAT 1046 00:37:31,282 --> 00:37:33,284 MY VALUE LIES IN MY ABILITY TO 1047 00:37:33,351 --> 00:37:34,585 OUT WORK, THAT I CAN BREAK 1048 00:37:34,652 --> 00:37:36,787 MYSELF FOR WHAT OTHERS WILL NOT. 1049 00:37:36,854 --> 00:37:38,556 I WONDER IF THIS IS WHAT 1050 00:37:38,623 --> 00:37:40,424 RESIGNED ME TO A LIFE OF ILLNESS 1051 00:37:40,491 --> 00:37:42,593 AND HOW MUCH OF IT IS MY FAULT. 1052 00:37:42,660 --> 00:37:44,161 HOW AS A NOT YET OUT TRANS 1053 00:37:44,228 --> 00:37:45,563 PERSON OF COLOR I BECAME SO 1054 00:37:45,630 --> 00:37:48,065 PRACTICED IN HEATING MY BODY 1055 00:37:48,132 --> 00:37:49,166 WISHING AWAY I PRESUMED IT 1056 00:37:49,233 --> 00:37:50,601 SHOULD HURT THIS BAD. 1057 00:37:50,668 --> 00:37:52,003 BUT JUST AS I ABSORBED THE 1058 00:37:52,069 --> 00:37:53,571 STORIES THAT EXPECT MY PAIN, SO 1059 00:37:53,638 --> 00:37:55,506 TOO HAVE MY PHYSICIANS, SO TOO 1060 00:37:55,573 --> 00:37:57,074 HAVE ENTIRE SCIENTIFIC 1061 00:37:57,141 --> 00:37:57,708 DISCIPLINES THAT ALMOST NEVER 1062 00:37:57,775 --> 00:37:59,043 THINK TO ASK ABOUT THE GENERAL 1063 00:37:59,110 --> 00:38:00,277 HEALTH NEEDS OF TRANS PEOPLE OR 1064 00:38:00,344 --> 00:38:02,613 ABOUT THE HEALTH INEQUITIES 1065 00:38:02,680 --> 00:38:03,914 EXPERIENCED BY ASIAN AMERICANS, 1066 00:38:03,981 --> 00:38:04,849 SO TOO HAVE THE INSTITUTIONS 1067 00:38:04,915 --> 00:38:06,050 THAT HAVE BEEN CONTENT TO LET 1068 00:38:06,117 --> 00:38:08,019 PEOPLE WITH M.E. AND LONG COVID 1069 00:38:08,085 --> 00:38:11,055 DISAPPEAR FROM PUBLIC LIFE. 1070 00:38:11,122 --> 00:38:14,091 IN 2020, I FINALLY LEARNED WHAT 1071 00:38:14,158 --> 00:38:14,825 I HAVE AS ME/CFS. 1072 00:38:14,892 --> 00:38:15,926 I LEARNED THAT IN THE 1073 00:38:15,993 --> 00:38:17,228 INTERVENING YEARS THAT I SPENT 1074 00:38:17,294 --> 00:38:18,663 TRYING TO PROVE MY VALUE IN A 1075 00:38:18,729 --> 00:38:20,831 WORLD WHERE TRANS AND DISABLE 1076 00:38:20,898 --> 00:38:22,800 AND BLACK AND BROWN LIVES ARE 1077 00:38:22,867 --> 00:38:23,834 PRESUMED DISPOSABLE, IN THE 1078 00:38:23,901 --> 00:38:25,002 YEARS WHEN EVERY DOCTOR I SAW 1079 00:38:25,069 --> 00:38:26,237 INSISTED THAT I WAS FINE, THAT I 1080 00:38:26,303 --> 00:38:29,173 COULD PUSH THROUGH, I MIGHT HAVE 1081 00:38:29,240 --> 00:38:32,276 IRREVERSIBLY WORSENED MY DISE 1082 00:38:32,343 --> 00:38:32,510 DISEASE. 1083 00:38:32,576 --> 00:38:33,344 I WATCH FROM THE BED WHERE I 1084 00:38:33,411 --> 00:38:34,445 SPEND HOURS OF EACH DAY FIGHTING 1085 00:38:34,512 --> 00:38:36,080 TO SIT UP A VIRAL PANDEMIC STORM 1086 00:38:36,147 --> 00:38:37,314 ACROSS THE COUNTRY. 1087 00:38:37,381 --> 00:38:38,616 WHILE THE U.S. PRESIDENT BLAMES 1088 00:38:38,683 --> 00:38:40,151 PEOPLE WHO LOOK LIKE ME FOR THE 1089 00:38:40,217 --> 00:38:42,920 OUTPOURING OF SUFFERING. 1090 00:38:42,987 --> 00:38:45,022 BY THE TIME THERE'S DATA ON LONG 1091 00:38:45,089 --> 00:38:45,990 COVID, IT CONFIRMS WHAT I 1092 00:38:46,057 --> 00:38:47,758 ALREADY KNEW. 1093 00:38:47,825 --> 00:38:49,060 WHAT M.E. PATIENT ACTIVISTS HAVE 1094 00:38:49,126 --> 00:38:50,161 ALREADY BEEN SCREAMING FROM 1095 00:38:50,227 --> 00:38:51,662 THEIR SICK BEDS, THAT MANY 1096 00:38:51,729 --> 00:38:52,763 PEOPLE WITH COVID-19 WILL FIND 1097 00:38:52,830 --> 00:38:54,398 THAT SOME SYMPTOMS, SOMETIMES 1098 00:38:54,465 --> 00:38:56,400 MANY SYMPTOMS, SOMETIMES 1099 00:38:56,467 --> 00:38:57,501 DEVASTATING NEW LIFE LIMITATIONS 1100 00:38:57,568 --> 00:38:59,670 HAVE COME TO STAY. 1101 00:38:59,737 --> 00:39:01,872 BY THE TIME POST EXERTIONAL 1102 00:39:01,939 --> 00:39:03,307 MALAISE IS A TERM MY PHYSICIANS 1103 00:39:03,374 --> 00:39:04,508 RECOGNIZE, IT IS A CERTAINTY MY 1104 00:39:04,575 --> 00:39:05,743 BODY HAS HELD FOR YEARS. 1105 00:39:05,810 --> 00:39:07,578 IT IS A PITFALL I HAVE RUN HEAD 1106 00:39:07,645 --> 00:39:09,046 LONG INTO OVER AND OVER AGAIN, 1107 00:39:09,113 --> 00:39:11,749 UNDER THE REASSURANCE THAT TALK 1108 00:39:11,816 --> 00:39:13,050 THERAPY AND EXERCISE WOULD CARRY 1109 00:39:13,117 --> 00:39:13,718 ME TO FREEDOM. 1110 00:39:13,784 --> 00:39:15,052 BY THE TIME YOU ARE LISTENING TO 1111 00:39:15,119 --> 00:39:16,353 ME SPEAK, I HAVE BEEN SICK FOR 1112 00:39:16,420 --> 00:39:18,589 ALL OF MY ADULTHOOD. 1113 00:39:18,656 --> 00:39:20,725 I TURN 35 THIS YEAR. 1114 00:39:20,791 --> 00:39:21,625 I'M RECOGNIZING THAT I'M GOING 1115 00:39:21,692 --> 00:39:23,027 TO AGE INTO THIS DISEASE. 1116 00:39:23,094 --> 00:39:24,829 THAT I MAY NEVER AGAIN FEEL ANY 1117 00:39:24,895 --> 00:39:26,030 BETTER THAN I DO RIGHT NOW, 1118 00:39:26,097 --> 00:39:27,431 STANDING IN FRONT OF YOU WITH MY 1119 00:39:27,498 --> 00:39:29,967 DIZZY THOUGHTS AND ACHING BODY. 1120 00:39:30,034 --> 00:39:32,603 BUT THIS IS NOT JUST MY STORY. 1121 00:39:32,670 --> 00:39:34,505 IT'S A STORY OF MEDICAL NEGLECT, 1122 00:39:34,572 --> 00:39:37,641 WELL DOCUMENTED IN UNREST AND 1123 00:39:37,708 --> 00:39:38,509 THE FORGOTTEN PLAGUE. 1124 00:39:38,576 --> 00:39:41,245 IT'S A STORY ABOUT MEDICAL 1125 00:39:41,312 --> 00:39:42,880 RACISM BETTER DESCRIBED BY BLACK 1126 00:39:42,947 --> 00:39:44,548 WOMEN ACTIVISTS INCLUDING 1127 00:39:44,615 --> 00:39:48,185 WILHELMINA JENKINS, ASIAN 1128 00:39:48,252 --> 00:39:49,720 DEDANIEL, SAMIR SMITH SWEENEY. 1129 00:39:49,787 --> 00:39:53,524 IT'S A STORY OF HOSTILITY THAT 1130 00:39:53,591 --> 00:39:57,795 ERODES TRANS AND QUEER LIVES 1131 00:39:57,862 --> 00:39:58,462 COMBATED THROUGH CAREERS. 1132 00:39:58,529 --> 00:40:00,231 IN THIS WAY, M.E. AND LONG COVID 1133 00:40:00,297 --> 00:40:01,966 ARE NOT EXCEPTIONAL. 1134 00:40:02,032 --> 00:40:03,300 THEY BELONG TO A LITANY OF 1135 00:40:03,367 --> 00:40:04,602 MEDICAL COMPLISSITIES THAT 1136 00:40:04,668 --> 00:40:07,204 INCLUDE NOT ONLY HYSTERIA BUT 1137 00:40:07,271 --> 00:40:08,272 ALSO SCHIZOPHRENIA, A DIAGNOSIS 1138 00:40:08,339 --> 00:40:09,573 THAT WAS USED TO 1139 00:40:09,640 --> 00:40:10,775 INSTITUTIONALIZE BLACK CIVIL 1140 00:40:10,841 --> 00:40:12,743 RIGHTS ACTVISTS. 1141 00:40:12,810 --> 00:40:14,145 CHINESE MIGRANTS WERE EXILED 1142 00:40:14,211 --> 00:40:15,679 THROUGH ACCUSATIONS OF SMALLPOX, 1143 00:40:15,746 --> 00:40:18,115 SYPHILIS AND PLAGUE, A STRATEGY 1144 00:40:18,182 --> 00:40:20,384 REPEATED WITH COVID-19. 1145 00:40:20,451 --> 00:40:22,353 AND TRANS AND QUEER COMMUNITIES, 1146 00:40:22,419 --> 00:40:22,920 PARTICULARLY COMMUNITIES OF 1147 00:40:22,987 --> 00:40:24,121 COLOR, WERE DEVASTATED BY 1148 00:40:24,188 --> 00:40:24,989 GOVERNMENTAL AND SOCIAL 1149 00:40:25,055 --> 00:40:27,191 RESPONSES TO HIV/AIDS. 1150 00:40:27,258 --> 00:40:29,059 THIS IS A STORY WE'VE BEEN 1151 00:40:29,126 --> 00:40:30,861 SCREAMING FOR CENTURIES ACROSS 1152 00:40:30,928 --> 00:40:33,764 GENERATIONS. 1153 00:40:33,831 --> 00:40:35,966 IN RECENT YEARS, M.E. RESEARCH 1154 00:40:36,033 --> 00:40:39,270 HAS SEEN SIGNIFICANT PROGRESS. 1155 00:40:39,336 --> 00:40:40,671 HOWEVER, THIS PROGRESS IS LITTLE 1156 00:40:40,738 --> 00:40:41,539 COMFORT FOR PEOPLE WHO HAVE 1157 00:40:41,605 --> 00:40:43,908 LIVED WITH M.E. FOR SO LONG. 1158 00:40:43,974 --> 00:40:45,409 WHAT'S CONSIDERED PROGRESS IS 1159 00:40:45,476 --> 00:40:47,144 OFTEN WHAT WE'VE ALREADY KNOWN. 1160 00:40:47,211 --> 00:40:49,580 FOR EXAMPLE, WHEN WHITE 1161 00:40:49,647 --> 00:40:50,481 RESEARCHERS DISCOVER THAT PEOPLE 1162 00:40:50,548 --> 00:40:51,816 OF COLOR RECEIVE POORER 1163 00:40:51,882 --> 00:40:52,883 TREATMENT FOR COMPLEX CHRONIC 1164 00:40:52,950 --> 00:40:54,485 DISEASES. 1165 00:40:54,552 --> 00:40:56,253 WHAT'S CONSIDERED PROGRESS IS 1166 00:40:56,320 --> 00:40:57,254 SOMETIMES OBSERVATIONAL STUDIES 1167 00:40:57,321 --> 00:40:58,355 THAT LITERALLY QUANTIFY THE 1168 00:40:58,422 --> 00:41:00,090 KNOWLEDGE OF OUR BODIES. 1169 00:41:00,157 --> 00:41:01,792 WHAT'S CONSIDERED PROGRESS IS 1170 00:41:01,859 --> 00:41:03,194 SOMEONE ELSE'S CAREER 1171 00:41:03,260 --> 00:41:04,295 ADVANCEMENT FOR NAMING OUR 1172 00:41:04,361 --> 00:41:05,796 SUFFERING. 1173 00:41:05,863 --> 00:41:08,866 IT IS THE SAME INSTITUTIONS THAT 1174 00:41:08,933 --> 00:41:10,100 ONCE NEGLECTED OUR DISEASES 1175 00:41:10,167 --> 00:41:11,168 TAKING CREDIT FOR IDENTIFYING 1176 00:41:11,235 --> 00:41:12,803 OUR PAIN. 1177 00:41:12,870 --> 00:41:15,039 I'M ASKING YOU TO UNDERSTAND OUR 1178 00:41:15,105 --> 00:41:16,907 STORIES AS MORE THAN DISCRETE 1179 00:41:16,974 --> 00:41:18,108 ANECDOTES, BUT AS POINTS IN A 1180 00:41:18,175 --> 00:41:19,977 MUCH LARGER CONSTELLATION OF 1181 00:41:20,044 --> 00:41:20,845 KNOWLEDGE. 1182 00:41:20,911 --> 00:41:22,813 ONE THAT HONORS BOTH PEER 1183 00:41:22,880 --> 00:41:24,682 REVIEWED STUDIES AND THE 1184 00:41:24,748 --> 00:41:25,649 EXPERIENTIAL WISDOM OF LIVING A 1185 00:41:25,716 --> 00:41:26,650 DISEASE. 1186 00:41:26,717 --> 00:41:28,485 I'M SPEAKING TO YOU AS BOTH A 1187 00:41:28,552 --> 00:41:30,354 PATIENT AND A RESEARCHER, AS 1188 00:41:30,421 --> 00:41:31,822 SOMEONE WHO HAS SPENT MY CAREER 1189 00:41:31,889 --> 00:41:33,023 THINKING ABOUT WHICH COMMUNITIES 1190 00:41:33,090 --> 00:41:35,092 ARE MOST IMPACTED BY MY WORK AND 1191 00:41:35,159 --> 00:41:36,560 HOW I HOLD MYSELF ACCOUNTABLE TO 1192 00:41:36,627 --> 00:41:39,463 THEM. 1193 00:41:39,530 --> 00:41:40,898 IF TO HAVE PAIN IS TO HAVE 1194 00:41:40,965 --> 00:41:42,433 CERTAINTY, THEN TO HEAR ABOUT 1195 00:41:42,499 --> 00:41:44,235 PAIN IS TO BE ENTRUSTED WITH 1196 00:41:44,301 --> 00:41:46,270 SOMEONE ELSE'S TRUTH. 1197 00:41:46,337 --> 00:41:47,605 WHAT WILL YOU DO WITH THAT 1198 00:41:47,671 --> 00:41:49,006 TRUST? 1199 00:41:49,073 --> 00:41:49,573 THANK YOU. 1200 00:41:49,640 --> 00:41:59,817 [APPLAUSE] 1201 00:42:10,027 --> 00:42:10,561 >> THANK YOU. 1202 00:42:10,628 --> 00:42:13,731 THAT WAS IMPORTANT AND MOVING. 1203 00:42:13,797 --> 00:42:17,134 AND REALLY SETS THE STAGE FOR 1204 00:42:17,201 --> 00:42:18,669 OUR SESSION. 1205 00:42:18,736 --> 00:42:21,739 I'M GOING TO INTRODUCE DR. MARK 1206 00:42:21,805 --> 00:42:24,241 DAVIS FROM STANFORD, WHO'S GOING 1207 00:42:24,308 --> 00:42:26,577 TO TALK ABOUT OXIDATIVE STRESS 1208 00:42:26,644 --> 00:42:28,012 AND A SHARED CHARACTERISTIC 1209 00:42:28,078 --> 00:42:30,814 BETWEEN ME/CFS AND LONG COVID. 1210 00:42:30,881 --> 00:42:40,991 MARK? 1211 00:42:57,241 --> 00:43:00,244 >> OKAY. 1212 00:43:00,311 --> 00:43:07,051 HOPE ALL THIS IS WORKING. 1213 00:43:07,117 --> 00:43:08,686 SO I DON'T THINK I NEED TO TELL 1214 00:43:08,752 --> 00:43:11,121 THIS AUDIENCE BUT NUMBERS JUST 1215 00:43:11,188 --> 00:43:12,723 CAME OUT ESTIMATED 3 MILLION 1216 00:43:12,790 --> 00:43:14,625 PEOPLE IN THE U.S. ALONE 1217 00:43:14,692 --> 00:43:17,695 SUFFERING FROM ME/CFS. 1218 00:43:17,761 --> 00:43:19,863 MANY MILLIONS MORE SUFFERING 1219 00:43:19,930 --> 00:43:23,267 FROM LONG COVID. 1220 00:43:23,334 --> 00:43:26,337 AND THERE'S JUST MANY MYSTERIES. 1221 00:43:26,403 --> 00:43:29,273 THE LACK OF A REAL DIAGNOSTIC, 1222 00:43:29,340 --> 00:43:34,745 THE LACK OF ANY MECHANISTIC 1223 00:43:34,812 --> 00:43:36,213 POTENTIAL CLUES AS TO WHAT'S 1224 00:43:36,280 --> 00:43:39,149 ACTUALLY GOING ON. 1225 00:43:39,216 --> 00:43:42,419 BUT THIS IS ALSO A GREAT STORY 1226 00:43:42,486 --> 00:43:46,123 ABOUT A YOUNG STUDENT OF MINE 1227 00:43:46,190 --> 00:43:48,659 WHO STARTED IN MY LAB AS AN 1228 00:43:48,726 --> 00:43:52,162 UNDERGRADUATE, STARTING IN 1229 00:43:52,229 --> 00:43:53,797 COMPUTATION, BUT ALONG THE WAY, 1230 00:43:53,864 --> 00:43:57,134 HE READ THIS BOOK, "THE PUZZLE 1231 00:43:57,201 --> 00:43:59,403 SOLVER," BY TRACIE WHITE WITH 1232 00:43:59,470 --> 00:44:02,239 RON DAVIS, AND REALLY WAS MOVED 1233 00:44:02,306 --> 00:44:05,542 BY THE STORY AND THE SUFFERING 1234 00:44:05,609 --> 00:44:06,977 THAT WE JUST HEARD ABOUT 1235 00:44:07,044 --> 00:44:10,247 ACTUALLY. 1236 00:44:10,314 --> 00:44:16,120 AND IT'S TALENTED YOUNG 1237 00:44:16,186 --> 00:44:17,888 SCIENTISTS LIKE VISHNU WHO TAKE 1238 00:44:17,955 --> 00:44:18,689 ON THE CHALLENGE. 1239 00:44:18,756 --> 00:44:21,325 AND MANY PEOPLE TAKE ON THE 1240 00:44:21,392 --> 00:44:22,760 CHALLENGE AND ONLY A FRACTION 1241 00:44:22,826 --> 00:44:26,397 SUCCEED. 1242 00:44:26,463 --> 00:44:28,132 BUT I THINK HE'S SUCCEEDED IN A 1243 00:44:28,198 --> 00:44:28,999 REALLY IMPORTANT WAY THAT GIVES 1244 00:44:29,066 --> 00:44:30,567 US AN OPENING INTO THE DISEASE 1245 00:44:30,634 --> 00:44:33,404 THAT WE NEVER HAD BEFORE, AND 1246 00:44:33,470 --> 00:44:35,906 THE PROSPECT OF AN ACTUAL 1247 00:44:35,973 --> 00:44:37,241 DIAGNOSTIC THAT WE'D NEVER HAD 1248 00:44:37,307 --> 00:44:40,344 BEFORE. 1249 00:44:40,411 --> 00:44:43,047 THIS DOESN'T OCCUR IN A VACUUM. 1250 00:44:43,113 --> 00:44:47,351 IT'S REALLY IMPORTANT THAT 1251 00:44:47,418 --> 00:44:50,821 PEOPLE GATHER THAT PATIENTS 1252 00:44:50,888 --> 00:44:55,426 DONATE BLOOD SAMPLES AND THAT 1253 00:44:55,492 --> 00:44:57,628 INVESTIGATORS COLLECT THOSE AND 1254 00:44:57,694 --> 00:44:58,829 STORE THOSE. 1255 00:44:58,896 --> 00:45:00,130 THERE ARE VERY GOOD WAYS TO 1256 00:45:00,197 --> 00:45:01,031 STORE BLOOD SAMPLES NOW. 1257 00:45:01,098 --> 00:45:02,800 YOU CAN STORE SAMPLES FOR 1258 00:45:02,866 --> 00:45:03,667 10-PLUS YEARS. 1259 00:45:03,734 --> 00:45:07,371 AND THIS IS A CRITICAL VARIED 1260 00:45:07,438 --> 00:45:08,739 ENTRY, BECAUSE IF YOU HAVE TO 1261 00:45:08,806 --> 00:45:11,475 START FROM SCRATCH, IT CAN TAKE 1262 00:45:11,542 --> 00:45:13,410 YEARS TO ACCUMULATE THE SAMPLES. 1263 00:45:13,477 --> 00:45:16,513 BUT IF THE SAMPLES FOR A DISEASE 1264 00:45:16,580 --> 00:45:18,916 LIKE ME/CFS ARE ALREADY THERE IN 1265 00:45:18,982 --> 00:45:20,350 THE BANK, YOU CAN TEST THINGS 1266 00:45:20,417 --> 00:45:22,853 MUCH MORE EASILY, MUCH MORE 1267 00:45:22,920 --> 00:45:26,590 QUICKLY, AND THAT'S BEEN A KEY 1268 00:45:26,657 --> 00:45:29,426 TO ALL SORTS OF DISEASE ANALYSIS 1269 00:45:29,493 --> 00:45:32,496 IN HUMANS. 1270 00:45:32,563 --> 00:45:34,198 SO BANKS ESTABLISHED YEARS AGO 1271 00:45:34,264 --> 00:45:35,599 BY RON DAVIS AND MORE RECENTLY 1272 00:45:35,666 --> 00:45:38,669 BY HECTOR BONILLA, WHO IS THE 1273 00:45:38,735 --> 00:45:41,538 HEAD OF THE ME/CFS/LONG COVID 1274 00:45:41,605 --> 00:45:45,476 CLINIC AT STANFORD AND MYSELF 1275 00:45:45,542 --> 00:45:48,312 HAVE BEEN BANKING SAMPLES FOR 1276 00:45:48,378 --> 00:45:49,580 YEARS IN SOME CASES. 1277 00:45:49,646 --> 00:45:53,150 AND THAT REALLY ENABLES IDEAS 1278 00:45:53,217 --> 00:45:55,886 LIKE VISHNU'S TO BE TESTED 1279 00:45:55,953 --> 00:45:56,120 QUICKLY. 1280 00:45:56,186 --> 00:45:57,921 SO I WANT TO JUST GIVE A PLUG 1281 00:45:57,988 --> 00:46:01,725 FOR THAT. 1282 00:46:01,792 --> 00:46:03,393 THERE'S ALSO, OF COURSE, HUGE 1283 00:46:03,460 --> 00:46:06,396 INTEREST IN LONG COVID, AND 1284 00:46:06,463 --> 00:46:08,265 THESE ARE OFTEN CO-DIAGNOSED 1285 00:46:08,332 --> 00:46:11,869 BECAUSE THEY HAVE SUCH SIMILAR 1286 00:46:11,935 --> 00:46:14,037 CHARACTERISTICS, ESPECIALLY 1287 00:46:14,104 --> 00:46:18,275 FATIGUE AND GETTING WORSE AFTER 1288 00:46:18,342 --> 00:46:21,111 EXERCISE AND ALL SORTS OF OTHER 1289 00:46:21,178 --> 00:46:27,084 UNPLEASANT THINGS. 1290 00:46:27,151 --> 00:46:28,552 IT'S NOT JUST ABOUT ME/CFS OR 1291 00:46:28,619 --> 00:46:30,053 LONG COVID THAT HAS THESE 1292 00:46:30,120 --> 00:46:30,921 SYMPTOMS. 1293 00:46:30,988 --> 00:46:32,256 THERE'S LYME DISEASE, FOR 1294 00:46:32,322 --> 00:46:34,324 EXAMPLE, VERY SIMILAR, AND ALSO 1295 00:46:34,391 --> 00:46:37,961 THERE'S A KNOWN INFECTIOUS 1296 00:46:38,028 --> 00:46:39,830 AGENT, AND THERE'S THIS REALLY 1297 00:46:39,897 --> 00:46:45,502 EXCELLENT REVIEW BY AKIKO 1298 00:46:45,569 --> 00:46:47,171 YOVASAKI POINTING OUT THAT MANY 1299 00:46:47,237 --> 00:46:51,775 INFECTIOUS DISEASES HAVE 1300 00:46:51,842 --> 00:46:54,478 SYNDROMES INCLUDING FATIGUE LONG 1301 00:46:54,545 --> 00:46:58,315 AFTER THE BUG IS GONE. 1302 00:46:58,382 --> 00:47:00,050 AND IN OUR OWN WORK, WE TOUCHED 1303 00:47:00,117 --> 00:47:02,886 ON THIS SOME YEARS AGO, WE SAW 1304 00:47:02,953 --> 00:47:05,122 THAT PATIENTS THAT HAD HEPATITIS 1305 00:47:05,189 --> 00:47:10,127 C THAT WERE CURED PROFOUNDLY 1306 00:47:10,194 --> 00:47:11,595 WITH A NEW DRUG THAT BECAME 1307 00:47:11,662 --> 00:47:18,101 AVAILABLE A FEW YEARS AGO, STILL 1308 00:47:18,168 --> 00:47:19,469 A YEAR AFTER THE VIRUS WAS GONE, 1309 00:47:19,536 --> 00:47:21,471 THEY HAD DAMAGE TO THEIR IMMUNE 1310 00:47:21,538 --> 00:47:22,973 SYSTEM IN PARTICULAR WAYS. 1311 00:47:23,040 --> 00:47:27,077 AND EVEN MORE RECENTLY, LOOKING 1312 00:47:27,144 --> 00:47:29,913 AT SARS-COV-2 VACCINATION AND 1313 00:47:29,980 --> 00:47:32,983 INFECTION, WE FOUND THAT PEOPLE 1314 00:47:33,050 --> 00:47:35,953 THAT GOT THE PFIZER VACCINE BUT 1315 00:47:36,019 --> 00:47:38,355 HAD HAD COVID PREVIOUSLY HAD A 1316 00:47:38,422 --> 00:47:42,492 MUCH REDUCED CD8 T-CELL RESPONSE 1317 00:47:42,559 --> 00:47:43,760 COMPARED TO PEOPLE THAT WERE 1318 00:47:43,827 --> 00:47:46,163 NAIVE TO THE DISEASE. 1319 00:47:46,230 --> 00:47:47,664 SO THERE'S MORE AND MORE 1320 00:47:47,731 --> 00:47:48,699 EVIDENCE THAT THERE'S SOMETHING 1321 00:47:48,765 --> 00:47:54,838 THAT HAPPENS DURING A SEVERE 1322 00:47:54,905 --> 00:47:56,273 DISEASE THAT EVEN WHEN THE 1323 00:47:56,340 --> 00:47:59,843 PATHOGEN IS GONE, THERE'S LONG 1324 00:47:59,910 --> 00:48:02,813 TERM DAMAGE TO THE IMMUNE SYSTEM 1325 00:48:02,879 --> 00:48:05,582 THAT CAN MANIFEST ITSELF IN 1326 00:48:05,649 --> 00:48:10,287 FATIGUE AN AND IN OTHER WAYS. 1327 00:48:10,354 --> 00:48:11,822 IT'S STILL SUCH AN EMERGING 1328 00:48:11,888 --> 00:48:16,226 AREA, IT HASN'T BEEN STU STUDIT 1329 00:48:16,293 --> 00:48:17,661 ALL MUCH, AND WE HAVE A LOT 1330 00:48:17,728 --> 00:48:19,296 BETTER TOOLS NOW THAN WE DID A 1331 00:48:19,363 --> 00:48:22,933 FEW YEARS AGO. 1332 00:48:23,000 --> 00:48:25,002 SO I THINK THERE'S GOING TO BE 1333 00:48:25,068 --> 00:48:29,039 SOME RAPID PROGRESS. 1334 00:48:29,106 --> 00:48:33,644 BUT VISH NA STARTE VISHNU STARTA 1335 00:48:33,710 --> 00:48:35,779 KIND OF A NAIVE BUT PENETRATING 1336 00:48:35,846 --> 00:48:39,583 IDEA FOCUSING ON FATIGUE. 1337 00:48:39,650 --> 00:48:40,150 , THAT 1338 00:48:40,217 --> 00:48:46,523 IF FATIGUE IS THE MAIN ESTIMATE, 1339 00:48:46,590 --> 00:48:49,593 DOESN'T THAT SUGGEST AN 1340 00:48:49,660 --> 00:48:50,927 ENERGETIC DEFECT, SOMETHING 1341 00:48:50,994 --> 00:48:57,067 GOING WRONG WITH THE METABOLISM, 1342 00:48:57,134 --> 00:48:58,635 SPECIFICALLY MITOCHONDRIAL 1343 00:48:58,702 --> 00:49:00,003 METABOLISM, WHICH IS THE SOURCE 1344 00:49:00,070 --> 00:49:02,406 OF ENERGY AT THE POWERHOUSE OF 1345 00:49:02,472 --> 00:49:02,973 THE CELL. 1346 00:49:03,040 --> 00:49:07,678 AS YOU MAY REMEMBER, ALMOST ALL 1347 00:49:07,744 --> 00:49:10,447 CELLS HAVE MIGHT MITOCHONDRIA. 1348 00:49:10,514 --> 00:49:13,083 IF THEY USE A LOT OF ENERGY LIKE 1349 00:49:13,150 --> 00:49:13,750 MUSCLE CELLS THEY CAN USE 1350 00:49:13,817 --> 00:49:15,052 HUNDREDS OF MITOCHONDRIA, AND 1351 00:49:15,118 --> 00:49:17,020 THIS PROVIDES THE ATP THAT 1352 00:49:17,087 --> 00:49:18,922 REALLY RUNS A LOT OF THE 1353 00:49:18,989 --> 00:49:23,393 MACHINERY AND ACTIVITY OF THE 1354 00:49:23,460 --> 00:49:23,927 CELL. 1355 00:49:23,994 --> 00:49:27,130 SO HE SPENT A YEAR ACTUALLY IN 1356 00:49:27,197 --> 00:49:33,270 HIS ROTATIONS AS AS A STARTING 1357 00:49:33,337 --> 00:49:34,705 IMMUNOLOGY STUDENT TWO YEARS AGO 1358 00:49:34,771 --> 00:49:36,807 AT STANFORD, AND HE ROTATED 1359 00:49:36,873 --> 00:49:38,875 HIMSELF THROUGH EVERY LAB HE 1360 00:49:38,942 --> 00:49:42,512 COULD FIND THAT STUDIED ENERGY 1361 00:49:42,579 --> 00:49:46,316 OR STUDIED MITOCHONDRIA. 1362 00:49:46,383 --> 00:49:47,551 SO REALLY LEARNED ALL THE WAYS 1363 00:49:47,617 --> 00:49:52,055 YOU CAN ANALYZE MITOCHONDRIA. 1364 00:49:52,122 --> 00:49:54,491 THEN WHAT SYSTEM, IT SEEMS LIKE 1365 00:49:54,558 --> 00:49:57,327 A NEUROLOGICAL DISEASE, SO YOU 1366 00:49:57,394 --> 00:50:01,365 CALL YOUR NEUROLOGIST IN, AND 1367 00:50:01,431 --> 00:50:03,133 TALKING TO HECTOR, NO, HE'S 1368 00:50:03,200 --> 00:50:04,568 TRIED TO CALL THE NEUROLOGISTS 1369 00:50:04,634 --> 00:50:06,436 BUT THEY DON'T ANSWER. 1370 00:50:06,503 --> 00:50:09,506 THEY'RE BUSY TRYING TO 1371 00:50:09,573 --> 00:50:12,142 UNDERSTAND HOW THE BRAIN WORKS. 1372 00:50:12,209 --> 00:50:18,382 AND SO ACTUALLY SINCE WE'RE 1373 00:50:18,448 --> 00:50:19,116 IMMUNOLOGISTS, IT WAS NATURAL TO 1374 00:50:19,182 --> 00:50:20,817 LOOK AT THE IMMUNE SYSTEM. 1375 00:50:20,884 --> 00:50:22,052 AND THE IMMUNE SYSTEM USES AS 1376 00:50:22,119 --> 00:50:24,554 MUCH ENERGY AS THE BRAIN. 1377 00:50:24,621 --> 00:50:26,656 IT USES AN ESTIMATED 20 TO 30%. 1378 00:50:26,723 --> 00:50:28,291 AND IF YOU'RE INFECTED, IT USES 1379 00:50:28,358 --> 00:50:29,292 A LOT MORE, BECAUSE YOU'RE 1380 00:50:29,359 --> 00:50:33,530 TRYING TO FIGHT OFF THE 1381 00:50:33,597 --> 00:50:36,633 INFECTION, YOUR CELLS ARE 1382 00:50:36,700 --> 00:50:37,601 DIVIDING LIKE CRAZY IMMUNE CELLS 1383 00:50:37,667 --> 00:50:40,904 TO TRY TO FIGHT OFF THE PATHO 1384 00:50:40,971 --> 00:50:42,672 PATHOGEN. 1385 00:50:42,739 --> 00:50:47,611 SO THAT'S HOW WE GOT TO THE 1386 00:50:47,677 --> 00:50:49,279 IMMUNE SYSTEM. 1387 00:50:49,346 --> 00:50:51,014 THE OTHER HUGE ADVANTAGE OF THE 1388 00:50:51,081 --> 00:50:52,516 IMMUNE SYSTEM IS IT'S 1389 00:50:52,582 --> 00:50:54,084 ACCESSIBLE, IT'S RIGHT THERE IN 1390 00:50:54,151 --> 00:50:54,951 YOUR BLOOD SAMPLE. 1391 00:50:55,018 --> 00:50:57,921 SO YOUR BLOOD SAMPLE IS FULL OF 1392 00:50:57,988 --> 00:50:59,256 RED CELLS WHICH PROVIDE OXYGEN 1393 00:50:59,322 --> 00:51:01,725 BUT ALSO WHITE CELLS, WHICH ARE 1394 00:51:01,792 --> 00:51:04,294 A MYRIAD, DOZENS AND DOZENS OF 1395 00:51:04,361 --> 00:51:05,162 DIFFERENT IMMUNE CELLS THAT DO 1396 00:51:05,228 --> 00:51:07,063 IMPORTANT THINGS LIKE MAKE 1397 00:51:07,130 --> 00:51:08,331 ANTIBODIES OR KILL INFECTED 1398 00:51:08,398 --> 00:51:09,132 CELLS. 1399 00:51:09,199 --> 00:51:11,435 AND WE SAW A HINT OF THIS SOME 1400 00:51:11,501 --> 00:51:14,004 YEARS AGO IN WORK WITH JOSE 1401 00:51:14,070 --> 00:51:18,375 MONTOYA, WHERE THERE SEEMED TO 1402 00:51:18,442 --> 00:51:20,911 BE A CERTAIN INFLAMMATORY 1403 00:51:20,977 --> 00:51:21,878 CYTOKINES IN THE BLOOD OF 1404 00:51:21,945 --> 00:51:23,113 CHRONIC FATIGUE PATIENTS. 1405 00:51:23,180 --> 00:51:24,347 SO THAT WAS KIND OF A STARTING 1406 00:51:24,414 --> 00:51:28,919 POINT, BUT NOT A -- THE REAL 1407 00:51:28,985 --> 00:51:32,589 DEAL WAS LOOKING AT REACTIVE 1408 00:51:32,656 --> 00:51:33,890 OXYGEN SPECIES, WHICH ARE 1409 00:51:33,957 --> 00:51:37,661 PRIMARILY IN THE MITOCHONDRIA, 1410 00:51:37,727 --> 00:51:42,299 AND REACTIVE OXYGEN SPECIES ARE 1411 00:51:42,365 --> 00:51:43,266 BASICALLY OXYGEN RADICALS. 1412 00:51:43,333 --> 00:51:45,235 IF YOU KNOW SOME CHEMISTRY, 1413 00:51:45,302 --> 00:51:49,873 RADICALS ARE DANGEROUS ENTITIES 1414 00:51:49,940 --> 00:51:51,508 THAT THEY CAN FORM THINGS LIKE 1415 00:51:51,575 --> 00:51:52,943 HYDROGEN PEROXIDE, PARTICULARLY 1416 00:51:53,009 --> 00:51:54,478 ARE JUST HUGELY REACTIVE. 1417 00:51:54,544 --> 00:51:58,348 THEY'RE UNSTABLE, AND THEY'RE 1418 00:51:58,415 --> 00:51:59,716 LACKING FOR SOMETHING TO BIND 1419 00:51:59,783 --> 00:52:01,051 TO, AND THAT MAY NOT BE 1420 00:52:01,117 --> 00:52:03,520 SOMETHING YOU WANT THEM TO BIND 1421 00:52:03,587 --> 00:52:06,156 TO. 1422 00:52:06,223 --> 00:52:07,190 BUT THEY ARE AN IMPORTANT 1423 00:52:07,257 --> 00:52:09,759 COMPONENT OF T-CELL ACTIVATION. 1424 00:52:09,826 --> 00:52:12,863 SO YOU NEED TO ELEVATE ROS 1425 00:52:12,929 --> 00:52:14,364 LEVELS IN THE MITOCHONDRIA AS 1426 00:52:14,431 --> 00:52:17,133 PART OF -- AND I'LL SHOW YOU A 1427 00:52:17,200 --> 00:52:19,369 MORE DETAILED ROUNDUP IN A 1428 00:52:19,436 --> 00:52:19,903 MINUTE. 1429 00:52:19,970 --> 00:52:22,506 IT'S A KEY PART OF THE 1430 00:52:22,572 --> 00:52:24,841 ACTIVATION STEP IN ACTIVATING 1431 00:52:24,908 --> 00:52:28,945 T-CELLS TO RESPOND TO INFECTION. 1432 00:52:29,012 --> 00:52:31,248 BUT TOO MUCH ROS IS DAMAGING. 1433 00:52:31,314 --> 00:52:34,317 IT'S GOING TO DEGRADE YOUR 1434 00:52:34,384 --> 00:52:37,521 MITOCHONDRIA AND DAJ ITS ABILITY 1435 00:52:37,587 --> 00:52:40,357 TO MAKE ENERGY. 1436 00:52:40,423 --> 00:52:45,161 SO THAT'S THE LEAD-IN TO THIS 1437 00:52:45,228 --> 00:52:48,365 ACTUAL DATA, WHERE WITH ME/CFS 1438 00:52:48,431 --> 00:52:52,202 PATIENTS, THAT WE LOOKED AT 1439 00:52:52,269 --> 00:52:53,203 COMPARED -- ORIGINALLY LOOKED AT 1440 00:52:53,270 --> 00:52:55,972 COMPARED TO HEALTHY CONTROLS ARE 1441 00:52:56,039 --> 00:53:00,744 BLUE, ME/CFS ARE RED. 1442 00:53:00,810 --> 00:53:06,249 IN CD19B CELLS, CD4 ARE T-CELLS, 1443 00:53:06,316 --> 00:53:08,018 CD8 ARE ANOTHER FORM OF T-CELL. 1444 00:53:08,084 --> 00:53:09,886 SO YOU CAN SEE THERE'S IN 1445 00:53:09,953 --> 00:53:12,389 GENERAL HIGH LEVELS OF ROS 1446 00:53:12,455 --> 00:53:14,090 LEVELS, REACTIVE OXYGEN SPECIES 1447 00:53:14,157 --> 00:53:15,292 LEVELS, BUT IT'S MORE COMPLEX 1448 00:53:15,358 --> 00:53:19,095 THAN THAT BECAUSE IF YOU NOTICE 1449 00:53:19,162 --> 00:53:21,197 THE SPOTS HERE, THERE'S SORT OF 1450 00:53:21,264 --> 00:53:21,898 TWO CATEGORIES. 1451 00:53:21,965 --> 00:53:25,368 THERE'S A HIGH COLLECTION AND A 1452 00:53:25,435 --> 00:53:26,369 LOW COLLECTION. 1453 00:53:26,436 --> 00:53:31,675 IT TURNS OUT THIS IS -- SORRY. 1454 00:53:31,741 --> 00:53:32,642 THIS IS A DIFFERENCE BETWEEN 1455 00:53:32,709 --> 00:53:33,410 MALES AND FEMALES. 1456 00:53:33,476 --> 00:53:36,813 SO IT TURNS OUT THAT FEMALES 1457 00:53:36,880 --> 00:53:39,049 WITH ME/CFS HAVE THE HIGH ROS 1458 00:53:39,115 --> 00:53:45,989 LEVELS, BUT THE MALES DO NOT. 1459 00:53:46,056 --> 00:53:46,957 IF WE LOOK -- IT SHOULD HAVE 1460 00:53:47,023 --> 00:53:48,024 BEEN THE OTHER WAY AROUND. 1461 00:53:48,091 --> 00:53:49,759 IF WE LOOK AT LONG COVID 1462 00:53:49,826 --> 00:53:51,161 TOGETHER WITH ME/CFS, WE ALSO 1463 00:53:51,227 --> 00:53:54,798 SEE ELEVATION OF ROS LEVELS, AND 1464 00:53:54,864 --> 00:53:58,234 THESE ALSO RESOLVE INTO MALE AND 1465 00:53:58,301 --> 00:54:01,705 FEMALE DIFFERENCES. 1466 00:54:01,771 --> 00:54:03,139 SO IT SEEMS LIKE THE DISEASE IS 1467 00:54:03,206 --> 00:54:04,240 MANIFESTING ITSELF VERY 1468 00:54:04,307 --> 00:54:09,179 DIFFERENTLY IN WOMEN VERSUS MEN. 1469 00:54:09,245 --> 00:54:15,852 AND SO THAT'S A WAY I'M ABLE 1470 00:54:15,919 --> 00:54:18,054 TO -- OKAY. 1471 00:54:18,121 --> 00:54:21,891 SO HERE IS WOMEN HERE ON THIS 1472 00:54:21,958 --> 00:54:23,560 SIDE. 1473 00:54:23,627 --> 00:54:26,196 AND IF YOU LOOK AT, SAY, 1474 00:54:26,262 --> 00:54:26,997 CD8 T-CELLS, HEALTHY CONTROLS 1475 00:54:27,063 --> 00:54:31,368 ARE HERE, VERY LOW. 1476 00:54:31,434 --> 00:54:32,602 AND ME/CFS, WOMEN ARE WAY UP 1477 00:54:32,669 --> 00:54:35,005 HERE. 1478 00:54:35,071 --> 00:54:35,739 SIMILARLY, LONG COVID ARE ALSO 1479 00:54:35,805 --> 00:54:36,740 UP HERE. 1480 00:54:36,806 --> 00:54:40,210 AND THEN IF YOU LOOK AT MALES, 1481 00:54:40,276 --> 00:54:42,545 IT'S REALLY NOT DISTINGUISHABLE 1482 00:54:42,612 --> 00:54:43,246 FROM NORMAL. 1483 00:54:43,313 --> 00:54:46,416 NOW, THAT DOESN'T SAY THAT THERE 1484 00:54:46,483 --> 00:54:51,054 ISN'T A STRESS PROBLEM IN MALES. 1485 00:54:51,121 --> 00:54:51,588 THERE IS. 1486 00:54:51,655 --> 00:54:55,558 IT'S JUST COMING UP DIFFERENTLY. 1487 00:54:55,625 --> 00:54:57,727 AND SO PART. 1488 00:54:57,794 --> 00:55:00,730 ROS PATHWAY, HOW DO YOU 1489 00:55:00,797 --> 00:55:01,931 DOWNREGULATE ROS? 1490 00:55:01,998 --> 00:55:03,600 ROS LEVELS ARE OBVIOUSLY 1491 00:55:03,667 --> 00:55:05,201 DANGEROUS, AND YOU NEED TO 1492 00:55:05,268 --> 00:55:05,935 REGULATE THEM. 1493 00:55:06,002 --> 00:55:07,804 AND ONE WAY YOU REGULATE THEM IS 1494 00:55:07,871 --> 00:55:12,809 WITH REDUCED GLUTATHIONE. 1495 00:55:12,876 --> 00:55:16,379 AND SO -- YEAH, SO JUST LOOKING 1496 00:55:16,446 --> 00:55:20,850 AT GLUTATHIONE, REDUCE 1497 00:55:20,917 --> 00:55:22,052 GLUTATHIONE LEVELS, THEN WE CAN 1498 00:55:22,118 --> 00:55:23,753 SEE ACTUALLY BOTH MALES AND 1499 00:55:23,820 --> 00:55:26,156 FEMALES HAVE ELEVATED, 1500 00:55:26,222 --> 00:55:30,226 ESPECIALLY ME/CFS HAS ELEVATED 1501 00:55:30,293 --> 00:55:32,128 GLUTATHIONE, LONG COVID TO A 1502 00:55:32,195 --> 00:55:34,464 LESSER EXTENT BUT STILL 1503 00:55:34,531 --> 00:55:36,433 SIGNIFICANTLY ABOVE BACKGROUND. 1504 00:55:36,499 --> 00:55:40,804 AND THIS IS -- WE DON'T HAVE 1505 00:55:40,870 --> 00:55:44,140 ENOUGH DATA WITH THE MALES JUST 1506 00:55:44,207 --> 00:55:47,844 YET, BUT THE TREND IS CLEAR THAT 1507 00:55:47,911 --> 00:55:49,813 WITH THESE DIFFERENT 1508 00:55:49,879 --> 00:55:51,815 LYMPHOCYTES, WE ARE SEEING 1509 00:55:51,881 --> 00:55:52,816 ELEVATED GLUTATHIONE LEVELS IN 1510 00:55:52,882 --> 00:55:59,155 BOTH FEMALES AND MALES. 1511 00:55:59,222 --> 00:56:00,690 SO THAT SAYS THAT THESE ARE 1512 00:56:00,757 --> 00:56:01,191 RELATED. 1513 00:56:01,257 --> 00:56:02,292 THEY'RE NOT DIFFERENT DISEASES. 1514 00:56:02,358 --> 00:56:03,560 IT'S JUST THAT PROBABLY THERE 1515 00:56:03,626 --> 00:56:05,995 WERE HIGH ROS LEVELS EARLIER IN 1516 00:56:06,062 --> 00:56:08,998 MALES BUT THEN SOMEHOW MALES ARE 1517 00:56:09,065 --> 00:56:10,834 ABLE TO REDUCE THOSE LEVELS, BUT 1518 00:56:10,900 --> 00:56:12,469 THEY STILL HAVE SIGNS OF A 1519 00:56:12,535 --> 00:56:17,373 PROBLEM IN THEIR -- IN THIS 1520 00:56:17,440 --> 00:56:20,643 PATHWAY AND IN THE 1521 00:56:20,710 --> 00:56:21,611 MITOCHONDRIAL -- IN THE ENERGY 1522 00:56:21,678 --> 00:56:24,347 GENERATION. 1523 00:56:24,414 --> 00:56:26,516 SO THIS IS JUST A TECHNICAL 1524 00:56:26,583 --> 00:56:29,219 EXPLANATION OF WHERE ROS COMES 1525 00:56:29,285 --> 00:56:32,355 IN IN TERMS OF THE T-CELL 1526 00:56:32,422 --> 00:56:33,823 ACTIVATION PATHWAY, SOMEWHERE IN 1527 00:56:33,890 --> 00:56:37,794 HERE. 1528 00:56:37,861 --> 00:56:41,397 AND WE CAN EVEN SEE NOW, IF WE 1529 00:56:41,464 --> 00:56:44,567 STIMULATE T-CELLS FROM ME/CFS 1530 00:56:44,634 --> 00:56:46,336 PATIENTS, VERSUS HEALTHY 1531 00:56:46,402 --> 00:56:47,470 CONTROLS, WE CAN SEE THAT 1532 00:56:47,537 --> 00:56:49,205 THERE'S A RELATIONSHIP BETWEEN 1533 00:56:49,272 --> 00:56:53,576 THE ROS LEVELS AND T-CELL 1534 00:56:53,643 --> 00:56:56,613 ACTIVATION, NAMELY LACKING AT 1535 00:56:56,679 --> 00:56:58,748 T-CELL DIVISION, T-CELL 1536 00:56:58,815 --> 00:56:59,082 PROLIFERATION. 1537 00:56:59,149 --> 00:57:00,150 SO WHAT DOES THAT MEAN? 1538 00:57:00,216 --> 00:57:02,519 THAT MEANS THAT YOUR T-CELLS AND 1539 00:57:02,585 --> 00:57:08,958 B CELLS ARE PRONE TO DIVIDE MUCH 1540 00:57:09,025 --> 00:57:10,260 MORE READILY THAN HEALTHY 1541 00:57:10,326 --> 00:57:11,327 CONTROLS, THAT HEALTHY CONTROLS 1542 00:57:11,394 --> 00:57:15,365 HAVE A CERTAIN BALANCE, BUT THAT 1543 00:57:15,431 --> 00:57:16,766 WITH ELEVATED ROS LEVELS OR 1544 00:57:16,833 --> 00:57:19,669 OTHER ASPECTS OF THIS 1545 00:57:19,736 --> 00:57:21,404 PHENOMENON, YOUR T-CELLS ARE 1546 00:57:21,471 --> 00:57:22,939 GOING TO PROLIFERATE MORE THAN 1547 00:57:23,006 --> 00:57:24,140 THEY SHOULD, WHICH MEANS THEY'RE 1548 00:57:24,207 --> 00:57:28,912 GOING TO USE MORE ENERGY THAN 1549 00:57:28,978 --> 00:57:30,446 THEY SHOULD, BUT THEN ALSO 1550 00:57:30,513 --> 00:57:32,382 YOU'RE DAMAGING THE 1551 00:57:32,448 --> 00:57:33,683 MITOCHONDRIA, SO YOU'RE GOING TO 1552 00:57:33,750 --> 00:57:35,652 BE LESS EFFICIENT AS PRODUCING 1553 00:57:35,718 --> 00:57:36,920 ENERGY. 1554 00:57:36,986 --> 00:57:38,488 SO YOU'RE REALLY HEADED TO AN 1555 00:57:38,555 --> 00:57:43,526 ENERGY DEFICIT. 1556 00:57:43,593 --> 00:57:44,761 AND THIS IS CONSISTENT WITH A 1557 00:57:44,828 --> 00:57:45,728 PAPER THAT WAS PUBLISHED A 1558 00:57:45,795 --> 00:57:50,767 LITTLE WHILE AGO LOOKING AT 1559 00:57:50,834 --> 00:57:52,468 INFLUENCE OF VACCINATION. 1560 00:57:52,535 --> 00:57:53,970 AND THEY SAW THAT THERE WAS 1561 00:57:54,037 --> 00:57:57,841 INCREASED CELLULAR PROLIFERATION 1562 00:57:57,907 --> 00:57:59,275 IN CFS PATIENTS VERSUS HEALTHY 1563 00:57:59,342 --> 00:58:02,645 CONTROLS. 1564 00:58:02,712 --> 00:58:04,013 AND THEN THE REALLY EXCITING 1565 00:58:04,080 --> 00:58:07,283 THING IS, CAN WE TREAT THIS? 1566 00:58:07,350 --> 00:58:10,220 ANOTHER ADVANTAGE OF WORKING 1567 00:58:10,286 --> 00:58:13,690 WITH IMMUNE CELLS IS WE'VE HAD 1568 00:58:13,756 --> 00:58:15,425 50, 60 YEARS OF WAYS TO 1569 00:58:15,491 --> 00:58:18,394 MANIPULATE IMMUNE CELLS AND TO 1570 00:58:18,461 --> 00:58:19,762 GET THEM TO PROLIFERATE, GET 1571 00:58:19,829 --> 00:58:21,631 THEM TO RESPOND, GET THEM TO DO 1572 00:58:21,698 --> 00:58:26,369 ALL KINDS OF TRICKS. 1573 00:58:26,436 --> 00:58:28,037 WHICH MEANS THAT THIS 1574 00:58:28,104 --> 00:58:28,705 HYPERPROLIFERATION PHENOMENON, 1575 00:58:28,771 --> 00:58:31,841 WE CAN TREAT THAT IN CULTURE. 1576 00:58:31,908 --> 00:58:36,246 AND SO VISHNU HAS. 1577 00:58:36,312 --> 00:58:37,513 THIS IS A BIT COMPLICATED, BUT 1578 00:58:37,580 --> 00:58:41,417 THE BOTTOM LINE IS THAT IF YOU 1579 00:58:41,484 --> 00:58:46,022 STIMULATE T-CELLS FROM A ME/CFS 1580 00:58:46,089 --> 00:58:49,359 PATIENT WITH NONSPECIFIC WAYS OF 1581 00:58:49,425 --> 00:58:51,327 STIMULATING THE T-CELL 1582 00:58:51,394 --> 00:58:56,032 PROLIFERATION, YOU GET A HUGE 1583 00:58:56,099 --> 00:59:00,904 BUNCH OF SIMULA STIMULATED T-CES 1584 00:59:00,970 --> 00:59:02,305 SHOWN HERE, BUT IF YOU LOWER THE 1585 00:59:02,372 --> 00:59:07,477 ROS LEVELS WITH N ACETYLCYSTEINE 1586 00:59:07,543 --> 00:59:12,415 OR METFORMIN OR LIP ROWXSTATIN, 1587 00:59:12,482 --> 00:59:14,550 YOU CAN GET A MUCH MORE NORMAL 1588 00:59:14,617 --> 00:59:15,518 DISTRIBUTION. 1589 00:59:15,585 --> 00:59:16,119 NOW, THIS DOESN'T SAY YOU'RE 1590 00:59:16,185 --> 00:59:18,187 GOING TO CURE ME/CFS WITH ANY OF 1591 00:59:18,254 --> 00:59:21,224 THESE DRUGS. 1592 00:59:21,291 --> 00:59:23,793 BUT IT PROVIDES A WAY, A TEST 1593 00:59:23,860 --> 00:59:27,964 TABLEHYPOTHESIS THAT MAYBE THISA 1594 00:59:28,031 --> 00:59:29,332 WAY TO HELP AND ALSO, MORE 1595 00:59:29,399 --> 00:59:30,633 GENERALLY, THIS IS A WAY TO 1596 00:59:30,700 --> 00:59:34,337 DISCOVER BETTER DRUGS. 1597 00:59:34,404 --> 00:59:36,105 THE MORE SOPHISTICATED WE CAN DO 1598 00:59:36,172 --> 00:59:39,776 THESE ASSAYS, THE MORE OPEN FOR 1599 00:59:39,842 --> 00:59:41,177 DRUG DISCOVERY. 1600 00:59:41,244 --> 00:59:42,612 DRUG DISCOVERY, YOU CAN DO IN 1601 00:59:42,679 --> 00:59:44,314 LAB DISH. 1602 00:59:44,380 --> 00:59:46,382 IT'S WAY FASTER AND MORE 1603 00:59:46,449 --> 00:59:47,583 EFFICIENT THAN DRUG DISCOVERY IN 1604 00:59:47,650 --> 00:59:48,051 LIVE PEOPLE. 1605 00:59:48,117 --> 00:59:49,385 YOU DON'T WANT TO GET TO LIVE 1606 00:59:49,452 --> 00:59:50,920 PEOPLE UNTIL YOU'RE PRETTY SURE 1607 00:59:50,987 --> 00:59:53,222 THAT YOU'RE DOING SOMETHING 1608 00:59:53,289 --> 00:59:58,828 USEFUL. 1609 00:59:58,895 --> 00:59:59,929 I THINK THIS IS -- WE'RE GETTING 1610 00:59:59,996 --> 01:00:03,166 BOTH A USEFUL DIAGNOSTIC ASSAY, 1611 01:00:03,232 --> 01:00:07,003 WHICH IS -- WHICH THERE'S BEEN A 1612 01:00:07,070 --> 01:00:08,438 HUGE NEED FOR AND A WAY FORWARD 1613 01:00:08,504 --> 01:00:11,541 IN TERMS OF DRUG TESTING AND 1614 01:00:11,607 --> 01:00:11,975 DRUG DISCOVERY. 1615 01:00:12,041 --> 01:00:13,309 I THINK IT'S VERY EXCITING. 1616 01:00:13,376 --> 01:00:16,045 THIS ALSO CORRELATES WITH A 1617 01:00:16,112 --> 01:00:19,449 RECENT PAPER THAT TREATED LONG 1618 01:00:19,515 --> 01:00:21,084 COVID PATIENTS WITH METFORMIN 1619 01:00:21,150 --> 01:00:26,356 AND FOUND THAT ALMOST HALF, 42%, 1620 01:00:26,422 --> 01:00:28,424 RESPONDED TO THIS TREATMENT. 1621 01:00:28,491 --> 01:00:31,160 SO IT'S SORT OF VERY HOPEFUL 1622 01:00:31,227 --> 01:00:33,029 THAT -- AND THIS IS AN 1623 01:00:33,096 --> 01:00:33,663 FDA-APPROVED DRUG. 1624 01:00:33,730 --> 01:00:35,865 IT'S ACTUALLY ALMOST A MIRACLE 1625 01:00:35,932 --> 01:00:36,165 DRUG. 1626 01:00:36,232 --> 01:00:40,670 I THINK IT PREVENTS AGING AND 1627 01:00:40,737 --> 01:00:42,472 MAKES YOU BREAKFAST IN BED. 1628 01:00:42,538 --> 01:00:44,240 I'M NOT SURE WHAT ELSE. 1629 01:00:44,307 --> 01:00:46,509 [LAUGHTER] 1630 01:00:46,576 --> 01:00:50,813 SO TO SUMMARIZE, WE SEE GREATLY 1631 01:00:50,880 --> 01:00:54,884 ELEVATED ROS LEVELS IN ME/CFS 1632 01:00:54,951 --> 01:00:57,520 WOMEN, ALSO IN LONG COVID WOMEN. 1633 01:00:57,587 --> 01:01:01,791 BUT NOT IN MEN. 1634 01:01:01,858 --> 01:01:03,092 AND I WOULD EXPECT WE'RE GOING 1635 01:01:03,159 --> 01:01:05,895 TO SEE THIS IN OTHER POST 1636 01:01:05,962 --> 01:01:11,801 INFECTION SYNDROMES. 1637 01:01:11,868 --> 01:01:13,870 THE MALE SEQUELAE IS MORE 1638 01:01:13,936 --> 01:01:15,571 COMPLEX, BUT WE CAN SEE CLEAR 1639 01:01:15,638 --> 01:01:17,206 EVIDENCE, I'M NOT SHOWING ALL 1640 01:01:17,273 --> 01:01:19,776 THE EVIDENCE, THAT OXIDATIVE 1641 01:01:19,842 --> 01:01:20,743 STRESS HAS BEEN THERE. 1642 01:01:20,810 --> 01:01:23,246 IT'S NOT THERE NOW. 1643 01:01:23,312 --> 01:01:25,148 IT SEEMS LIKE MALES CAN RESOLVE 1644 01:01:25,214 --> 01:01:26,582 THE HIGH ROS LEVELS MORE 1645 01:01:26,649 --> 01:01:29,652 EFFICIENTLY THAN FEMALES. 1646 01:01:29,719 --> 01:01:31,621 BUT THERE'S STILL SIGNS OF 1647 01:01:31,687 --> 01:01:34,657 MITOCHONDRIAL DAMAGE, AND ENERGY 1648 01:01:34,724 --> 01:01:39,262 DEFICIT. 1649 01:01:39,328 --> 01:01:40,663 I MENTIONED, AT LEAST FROM THE 1650 01:01:40,730 --> 01:01:43,900 FEMALE PATIENTS, THE T-CELLS 1651 01:01:43,966 --> 01:01:44,300 HYPERPROLIFERATE. 1652 01:01:44,367 --> 01:01:45,735 I'M NOT SURE IF THAT'S GOING TO 1653 01:01:45,802 --> 01:01:46,836 HAPPEN, WE DON'T HAVE ENOUGH 1654 01:01:46,903 --> 01:01:48,871 MALE PATIENTS THAT WE'VE STUDIED 1655 01:01:48,938 --> 01:01:50,640 YET, BUT WE WILL. 1656 01:01:50,706 --> 01:01:52,408 AND THAT WE CAN SUPPRESS THIS 1657 01:01:52,475 --> 01:01:54,110 WITH DRUGS LIKE METFORMIN AND 1658 01:01:54,177 --> 01:01:57,246 THERE'S SOME EVIDENCE THAT 1659 01:01:57,313 --> 01:02:03,519 METFORMIN MIGHT BE USEFUL TO AN 1660 01:02:03,586 --> 01:02:04,720 INTACT HUMAN BEING AS WELL. 1661 01:02:04,787 --> 01:02:06,189 SO AS I MENTIONED THIS IS A WAY 1662 01:02:06,255 --> 01:02:07,924 FORWARD TO OPTIMIZE DRUG 1663 01:02:07,990 --> 01:02:11,661 TREATMENTS AND DRUG DISCOVERY. 1664 01:02:11,727 --> 01:02:14,497 AND THEN IN THE WILD SPECULATION 1665 01:02:14,564 --> 01:02:20,069 DEPARTMENT, WHAT DOES THIS MEAN, 1666 01:02:20,136 --> 01:02:24,373 AND HOW CAN WE UNDERSTAND THIS 1667 01:02:24,440 --> 01:02:25,608 AT A DEEPER LEVEL? 1668 01:02:25,675 --> 01:02:27,577 AND WHY IS IT THAT THIS DEFECT 1669 01:02:27,643 --> 01:02:30,279 IN YOUR IMMUNE SYSTEM WOULD 1670 01:02:30,346 --> 01:02:33,916 CAUSE YOU FATIGUE? 1671 01:02:33,983 --> 01:02:36,919 AND NEUROLOGICAL SYMPTOMS? 1672 01:02:36,986 --> 01:02:41,257 AND SO THE WILD SPECULATION HERE 1673 01:02:41,324 --> 01:02:43,693 IS THAT IF YOUR IMMUNE SYSTEM IS 1674 01:02:43,759 --> 01:02:45,528 USING UP TOO MUCH ENERGY, IT 1675 01:02:45,595 --> 01:02:48,998 COULD ACT AS AN ENERGY SINK, 1676 01:02:49,065 --> 01:02:50,199 MEANING IT CAN DRAIN ENERGY THAT 1677 01:02:50,266 --> 01:02:53,469 YOU WOULD NORMALLY USE FOR 1678 01:02:53,536 --> 01:02:55,004 NEUROLOGICAL FUNCTION. 1679 01:02:55,071 --> 01:02:56,706 AND THIS MAKES SOME SENSE IN 1680 01:02:56,772 --> 01:02:57,573 TERMS OF WHAT HAPPENS WHEN YOU 1681 01:02:57,640 --> 01:03:01,844 HAVE A SEVERE INFECTION, ACTIVE 1682 01:03:01,911 --> 01:03:03,980 INFECTION, YOU FEEL LIKE CRAP. 1683 01:03:04,046 --> 01:03:09,018 YOU'RE NOT FEELING GOOD. 1684 01:03:09,085 --> 01:03:10,219 AND SOME OF THE THINGS THAT 1685 01:03:10,286 --> 01:03:12,188 WE'RE SEEING IN ME/CFS AND OTHER 1686 01:03:12,255 --> 01:03:15,525 THINGS IS JUST THAT WHAT ENERGY 1687 01:03:15,591 --> 01:03:17,160 YOU HAVE IS BEING DEVOTED TO 1688 01:03:17,226 --> 01:03:18,494 YOUR IMMUNE SYSTEM BECAUSE YOU 1689 01:03:18,561 --> 01:03:21,063 MIGHT DIE FROM THE INFECTION. 1690 01:03:21,130 --> 01:03:23,599 THAT'S THE SORT OF EMERGENCY 1691 01:03:23,666 --> 01:03:28,504 RESPONSE. 1692 01:03:28,571 --> 01:03:29,839 SO I DON'T THINK -- I MEAN, THE 1693 01:03:29,906 --> 01:03:31,307 QUESTION HAS COME UP AND IT'S A 1694 01:03:31,374 --> 01:03:33,142 GOOD QUESTION, ARE WE GOING TO 1695 01:03:33,209 --> 01:03:34,677 SEE -- IF WE COULD GET BRAIN 1696 01:03:34,744 --> 01:03:38,080 TISSUE FROM ME/CFS PATIENTS, 1697 01:03:38,147 --> 01:03:43,486 WOULD WE SEE HIGH ROS LEVELS OR 1698 01:03:43,553 --> 01:03:44,053 MITOCHONDRIAL DYSFUNCTION. 1699 01:03:44,120 --> 01:03:47,557 MY GUESS IS, NO, THAT IT ALL 1700 01:03:47,623 --> 01:03:50,126 CONNECTED, AND IF YOU'RE 1701 01:03:50,193 --> 01:03:52,762 DEVOTING ENERGY, AN INORDINATE 1702 01:03:52,828 --> 01:03:55,965 AMOUNT OF ENERGY TO YOUR IMMUNE 1703 01:03:56,032 --> 01:03:57,200 SYSTEM TO DO WHAT YOU THINK 1704 01:03:57,266 --> 01:03:58,868 YOU'RE FIGHTING OFF AN INFECTION 1705 01:03:58,935 --> 01:03:59,936 EVEN THOUGH THE PATHOGEN MIGHT 1706 01:04:00,002 --> 01:04:02,405 NOT BE THERE ANYMORE, THAT COULD 1707 01:04:02,471 --> 01:04:05,274 BE WHAT'S HAPPENING. 1708 01:04:05,341 --> 01:04:07,143 BUT WE'RE JUST THINKING ABOUT 1709 01:04:07,210 --> 01:04:08,711 THIS AND IT DOESN'T MEAN WE 1710 01:04:08,778 --> 01:04:10,680 REALLY KNOW ANYTHING. 1711 01:04:10,746 --> 01:04:12,081 AND THEN THE OTHER QUESTION IS, 1712 01:04:12,148 --> 01:04:16,886 WHY IS IT THAT SOME PEOPLE ARE 1713 01:04:16,953 --> 01:04:21,557 GETTING THIS SYNDROME AFTER AN 1714 01:04:21,624 --> 01:04:23,125 INFECTION OF LONG COVID OR 1715 01:04:23,192 --> 01:04:25,528 WHATEVER IS HAPPENING IN ME/CFS 1716 01:04:25,595 --> 01:04:28,564 OR SOME OF THESE OTHER THINGS? 1717 01:04:28,631 --> 01:04:31,601 WHY IS IT HAPPENING TO YOU IS 1718 01:04:31,667 --> 01:04:33,869 WHAT YOU PROBABLY WANT TO KNOW. 1719 01:04:33,936 --> 01:04:37,240 AND THERE, I THINK IT MIGHT HAVE 1720 01:04:37,306 --> 01:04:43,145 TO DO WITH PEOPLE'S IMMUNE 1721 01:04:43,212 --> 01:04:44,247 SYSTEMS HAVE VARIABLE RESPONSES 1722 01:04:44,313 --> 01:04:46,616 TO INFECTION. 1723 01:04:46,682 --> 01:04:49,018 AND THE IMMUNE SYSTEM USES UP AN 1724 01:04:49,085 --> 01:04:50,853 ENORMOUS NUMBER OF GENES, 1725 01:04:50,920 --> 01:04:53,823 THOUSANDS OF GENES, AND THESE 1726 01:04:53,889 --> 01:04:58,294 ARE ALL TARGETS FOR MUTATION, 1727 01:04:58,361 --> 01:05:01,197 AND THOSE MUTATIONS MAY NOT BE 1728 01:05:01,264 --> 01:05:07,003 CLINICALLY EVIDENT, EXCEPT WHEN 1729 01:05:07,069 --> 01:05:10,873 YOU GET SOME OF THESE DISEASES. 1730 01:05:10,940 --> 01:05:12,441 AND THEN IF YOUR IMMUNE SYSTEM 1731 01:05:12,508 --> 01:05:15,378 IS NOT VERY EFFICIENT AT GETTING 1732 01:05:15,444 --> 01:05:17,880 RID OF A VIRUS OR OTHER 1733 01:05:17,947 --> 01:05:19,282 PATHOGEN, YOU MIGHT HAVE A 1734 01:05:19,348 --> 01:05:22,018 PROLONGED PERIOD OF T-CELL 1735 01:05:22,084 --> 01:05:23,219 ACTIVATION, B CELL ACTIVATION 1736 01:05:23,286 --> 01:05:25,354 AND ELEVATED ROS LEVELS, AND 1737 01:05:25,421 --> 01:05:29,292 THEN IT BECOMES A QUESTION OF, 1738 01:05:29,358 --> 01:05:32,628 OKAY, ARE YOU DAMAGING YOUR 1739 01:05:32,695 --> 01:05:33,829 ENERGY METABOLISM IN TRYING TO 1740 01:05:33,896 --> 01:05:35,631 FIGHT THIS OFF. 1741 01:05:35,698 --> 01:05:38,000 AND ACTUALLY JUST FRIDAY, WE 1742 01:05:38,067 --> 01:05:42,471 HEARD A TALK WHERE THERE'S 1743 01:05:42,538 --> 01:05:46,075 EVIDENCE THAT SOME INDIVIDUALS 1744 01:05:46,142 --> 01:05:46,942 WITH LONG COVID STILL HAVE A 1745 01:05:47,009 --> 01:05:49,545 VERY ACTIVE T-CELL RESPONSE 1746 01:05:49,612 --> 01:05:51,414 AGAINST THE SARS-COV-2 VIRUS. 1747 01:05:51,480 --> 01:05:53,316 SO THAT'S CONSISTENT WITH THE 1748 01:05:53,382 --> 01:05:54,650 HYPOTHESIS THAT THESE SYNDROMES 1749 01:05:54,717 --> 01:05:57,820 ARE COMING ABOUT BECAUSE YOUR 1750 01:05:57,887 --> 01:05:59,655 IMMUNE SYSTEM IS NOT WORKING AS 1751 01:05:59,722 --> 01:06:04,026 WELL AS IT COULD TO CLEAR THE 1752 01:06:04,093 --> 01:06:05,828 VIRUS OR PATHOGEN, AND THAT PUTS 1753 01:06:05,895 --> 01:06:07,330 A LOT MORE STRESS AND THEN THAT 1754 01:06:07,396 --> 01:06:12,935 COULD LEAD TO DAMAGE TO 1755 01:06:13,002 --> 01:06:13,969 MITOCHONDRIA THROUGH ELEVATED 1756 01:06:14,036 --> 01:06:15,104 ROS LEVELS AND MAYBE OTHER 1757 01:06:15,171 --> 01:06:19,108 THINGS AS WELL. 1758 01:06:19,175 --> 01:06:22,411 SO THESE ARE SPECULATIONS AND 1759 01:06:22,478 --> 01:06:25,681 OUR WORKING HYPOTHESIS. 1760 01:06:25,748 --> 01:06:28,417 SO IT'S THINKING ABOUT HOW DO WE 1761 01:06:28,484 --> 01:06:30,486 GO FORWARD IN UNDERSTANDING 1762 01:06:30,553 --> 01:06:33,622 THIS, AND THESE ARE JUST 1763 01:06:33,689 --> 01:06:34,924 POSSIBILITIES WE'RE THINKING 1764 01:06:34,990 --> 01:06:35,358 ABOUT. 1765 01:06:35,424 --> 01:06:38,160 SO WITHOUT FURTHER ADO, I WANT 1766 01:06:38,227 --> 01:06:39,495 TO ACKNOWLEDGE ESPECIALLY 1767 01:06:39,562 --> 01:06:43,632 VISHNU, WHO'S JUST BEEN 1768 01:06:43,699 --> 01:06:45,301 INCREDIBLE IN FIGURING OUT WHAT 1769 01:06:45,368 --> 01:06:47,236 WERE TO DO IN THIS. 1770 01:06:47,303 --> 01:06:48,904 WE'VE BEEN WORKING ON CHRONIC 1771 01:06:48,971 --> 01:06:50,539 FATIGUE FOR SIX OR SEVEN YEARS, 1772 01:06:50,606 --> 01:06:52,608 AND WITHOUT REALLY ANY SUCCESS. 1773 01:06:52,675 --> 01:06:56,379 AND IT'S ONLY THESE IDEAS OF 1774 01:06:56,445 --> 01:06:58,013 VISHNU'S AND CARRYING THEM 1775 01:06:58,080 --> 01:07:02,485 THROUGHTHROUGH WITH THE KIND OFE 1776 01:07:02,551 --> 01:07:03,886 MINDEDNESS AND PASSION THAT IS 1777 01:07:03,953 --> 01:07:10,226 JUST FANTASTIC. 1778 01:07:10,292 --> 01:07:13,195 OF COURSE EASE HAD SOME HELP 1779 01:07:13,262 --> 01:07:16,866 FROM PEOPLE IN OUR GROUP, RON 1780 01:07:16,932 --> 01:07:20,369 DAVIS, HECTOR BONILLA HAS BEEN A 1781 01:07:20,436 --> 01:07:22,638 FANTASTIC CLINICAL COLLABORATOR, 1782 01:07:22,705 --> 01:07:24,039 RON DAVIS REALLY HELPED US GET 1783 01:07:24,106 --> 01:07:25,241 STARTED ON THIS AND HELPED FUND 1784 01:07:25,307 --> 01:07:25,941 SOME OF THE WORK. 1785 01:07:26,008 --> 01:07:31,113 WE'VE ALSO HAD INPUT FROM MIKE 1786 01:07:31,180 --> 01:07:39,922 SNYDER, VISHNU'S DAD SADASIVAN 1787 01:07:39,989 --> 01:07:41,123 SHANKAR, AND GENEROUS FUNDING 1788 01:07:41,190 --> 01:07:46,662 FROM BOTH THE KHOSLA FAMILY 1789 01:07:46,729 --> 01:07:49,198 FOUNDATION, HHMI INSTITUTE AND 1790 01:07:49,265 --> 01:07:49,632 NIAID. 1791 01:07:49,698 --> 01:07:50,232 SO I'LL STOP THERE. 1792 01:07:50,299 --> 01:07:50,533 THANK YOU. 1793 01:07:50,599 --> 01:08:00,776 [APPLAUSE] 1794 01:08:09,118 --> 01:08:12,455 >> THERE'S A SUBSTANTIAL ONLINE 1795 01:08:12,521 --> 01:08:16,192 PRESENCE SO I'M GOING TO TRY AND 1796 01:08:16,258 --> 01:08:18,527 GO THROUGH A FEW QUESTIONS. 1797 01:08:18,594 --> 01:08:25,100 [SPEAKER O OFF MIC] 1798 01:08:25,167 --> 01:08:31,574 [INAUDIBLE] 1799 01:08:31,640 --> 01:08:37,713 >> WHAT ARE PDEM? 1800 01:08:37,780 --> 01:08:39,348 >> POST EXERTIONAL MALAISE. 1801 01:08:39,415 --> 01:08:41,517 >> IN TERMS OF SURVEYS OF 1802 01:08:41,584 --> 01:08:44,487 FATIGUE, THERE WAS NOT A 1803 01:08:44,553 --> 01:08:46,889 CORRELATION. 1804 01:08:46,956 --> 01:08:47,990 WE LOOKED AT THAT. 1805 01:08:48,057 --> 01:08:49,625 BUT I THINK FATIGUE IS A TRICKY 1806 01:08:49,692 --> 01:08:51,227 THING IN TERMS OF IF YOU HAVE A 1807 01:08:51,293 --> 01:08:53,195 SUDDEN ONSET OF FATIGUE, I THINK 1808 01:08:53,262 --> 01:08:56,999 YOU'LL NOTICE IT, BUT IF IT'S A 1809 01:08:57,066 --> 01:08:59,735 SLOW, CRAWLING THING, YOU WOULD 1810 01:08:59,802 --> 01:09:01,937 HAVE A HARD TIME NOTICING IT. 1811 01:09:02,004 --> 01:09:03,606 SO WE DEFINITELY LOOKED AT THAT, 1812 01:09:03,672 --> 01:09:07,009 BUT WE DIDN'T SEE A CLEAR 1813 01:09:07,076 --> 01:09:09,778 CORRELATION. 1814 01:09:09,845 --> 01:09:10,913 >> ONE MORE QUESTION. 1815 01:09:10,980 --> 01:09:13,182 >> SURE. 1816 01:09:13,249 --> 01:09:16,619 >> YOU TALKED ABOUT POTENTIALLY 1817 01:09:16,685 --> 01:09:17,553 [INAUDIBLE] I'M WONDERING IF YOU 1818 01:09:17,620 --> 01:09:23,058 HAVE ANY COMMENTS ON WHETHER THE 1819 01:09:23,125 --> 01:09:24,026 PRODUCTION CHANGE [INAUDIBLE] 1820 01:09:24,093 --> 01:09:26,395 >> COULD YOU GET CLOSER TO THE 1821 01:09:26,462 --> 01:09:26,695 MICROPHONE? 1822 01:09:26,762 --> 01:09:28,397 >> YOU TALKED ABOUT AN ENERGY 1823 01:09:28,464 --> 01:09:31,433 SINK WITHIN THE IMMUNE SYSTEM AS 1824 01:09:31,500 --> 01:09:34,303 POTENTIALLY ONE WAY AROUND SOME 1825 01:09:34,370 --> 01:09:36,805 OF THESE -- ENERGY -- I WAS 1826 01:09:36,872 --> 01:09:37,573 WONDERING IF YOU HAD ANY 1827 01:09:37,640 --> 01:09:39,542 COMMENTS OR IF YOU LOOKED AT -- 1828 01:09:39,608 --> 01:09:43,479 LOOKING AT GLYCOLYSIS VERSUS 1829 01:09:43,546 --> 01:09:46,315 PERHAPS [INAUDIBLE] PRODUCTION 1830 01:09:46,382 --> 01:09:46,949 INSTEAD OF SINK? 1831 01:09:47,016 --> 01:09:49,218 >> I THINK WE LOOKED A LITTLE AT 1832 01:09:49,285 --> 01:09:51,654 THAT BUT DIDN'T SEE ANYTHING 1833 01:09:51,720 --> 01:09:52,655 OBVIOUS, BUT OF COURSE THAT'S A 1834 01:09:52,721 --> 01:09:55,991 BIG DEAL IN CANCER AND HOW YOU 1835 01:09:56,058 --> 01:10:00,129 USE THE ENERGY. 1836 01:10:00,195 --> 01:10:01,864 WE HAVE LOOKED AT ATP PRODUCTION 1837 01:10:01,931 --> 01:10:03,365 AND THERE DEFINITELY IS A 1838 01:10:03,432 --> 01:10:05,634 REDUCED ATP PRODUCTION IN MOST 1839 01:10:05,701 --> 01:10:09,071 OF THE PATIENTS. 1840 01:10:09,138 --> 01:10:15,010 BUT IT HASN'T GOTTEN TO THE 1841 01:10:15,077 --> 01:10:16,478 SUGAR QUESTION YET, AND I DON'T 1842 01:10:16,545 --> 01:10:18,581 THINK SUGAR IS GOING TO BE THE 1843 01:10:18,647 --> 01:10:18,814 ANSWER. 1844 01:10:18,881 --> 01:10:22,551 THERE WAS A QUESTION OVER HERE? 1845 01:10:22,618 --> 01:10:24,320 >> I JUST WANTED TO SAY THAT 1846 01:10:24,386 --> 01:10:25,988 PEOPLE ONLINE CAN'T HEAR THE 1847 01:10:26,055 --> 01:10:27,256 QUESTIONS, SO IF YOU COULD 1848 01:10:27,323 --> 01:10:30,125 REPEAT THEM. 1849 01:10:30,192 --> 01:10:32,928 >> WHAT WAS IT? 1850 01:10:32,995 --> 01:10:33,128 SORRY? 1851 01:10:33,195 --> 01:10:35,230 >> PEOPLE ONLINE CAN'T HEAR THE 1852 01:10:35,297 --> 01:10:35,497 QUESTIONS. 1853 01:10:35,564 --> 01:10:37,199 >> O I HAVE TO REPEAT THE 1854 01:10:37,266 --> 01:10:37,733 QUESTION. 1855 01:10:37,800 --> 01:10:37,933 OKAY. 1856 01:10:38,000 --> 01:10:38,834 SURE. 1857 01:10:38,901 --> 01:10:41,136 YEAH, THERE WAS JUST A QUESTION 1858 01:10:41,203 --> 01:10:42,705 ABOUT HAVE WE LOOKED AT 1859 01:10:42,771 --> 01:10:46,208 GLYCOLYSIS AND BASICALLY SUGAR 1860 01:10:46,275 --> 01:10:48,310 AS THE MAIN FUEL FOR THE 1861 01:10:48,377 --> 01:10:51,213 MITOCHONDRIA TO MAKE ATP, AND 1862 01:10:51,280 --> 01:10:52,748 NOTHING OBVIOUS CAME OUT OF 1863 01:10:52,815 --> 01:10:53,449 THAT. 1864 01:10:53,515 --> 01:10:55,184 WE HAVEN'T LOOKED AT IT 1865 01:10:55,250 --> 01:10:57,152 EXTENSIVELY, BUT NOTHING OBVIOUS 1866 01:10:57,219 --> 01:10:58,921 WAS THERE. 1867 01:10:58,988 --> 01:10:59,989 >> HI, MARK. 1868 01:11:00,055 --> 01:11:02,725 VERY BRIEFLY, IS THIS EFFECT 1869 01:11:02,791 --> 01:11:04,026 SPECIFIC TO B AND T-CELLS OR 1870 01:11:04,093 --> 01:11:06,095 HAVE YOU LOOKED AT OTHER IMMUNE 1871 01:11:06,161 --> 01:11:06,295 CELLS? 1872 01:11:06,362 --> 01:11:09,231 >> YEAH, SO THE QUESTION IS, 1873 01:11:09,298 --> 01:11:11,400 HAVE WE JUST LOOKED AT T-CELLS 1874 01:11:11,467 --> 01:11:13,135 OR HAVE WE LOOKED AT OTHER 1875 01:11:13,202 --> 01:11:13,469 CELLS. 1876 01:11:13,535 --> 01:11:15,771 AND THE ANSWER IS WE LOOKED AT B 1877 01:11:15,838 --> 01:11:17,272 CELLS AND T-CELLS. 1878 01:11:17,339 --> 01:11:18,574 AND WE'RE SEEING THE SAME 1879 01:11:18,641 --> 01:11:18,907 THINGS. 1880 01:11:18,974 --> 01:11:20,876 WE HAVEN'T LOOKED AT SOME OF THE 1881 01:11:20,943 --> 01:11:23,178 OTHER WHITE BLOOD CELLS LIKE 1882 01:11:23,245 --> 01:11:25,214 MACROPHAGES AND SO FORTH. 1883 01:11:25,280 --> 01:11:35,791 BUT WE'LL DO THAT EVENTUALLY. 1884 01:11:37,493 --> 01:11:38,560 >> THANKS VERY MUCH. 1885 01:11:38,627 --> 01:11:43,699 I'D LIKE TO INTRODUCE OUR NEXT 1886 01:11:43,766 --> 01:11:45,768 SPEAKER, DR. DERYA UNUTMAZ FROM 1887 01:11:45,834 --> 01:11:49,471 JACKSON LABS. 1888 01:11:49,538 --> 01:11:51,507 ONE OF THE ME/CFS CENTERS FOR 1889 01:11:51,573 --> 01:11:53,375 COLLABORATED RESEARCH FUNDED BY 1890 01:11:53,442 --> 01:11:55,344 NIH. 1891 01:11:55,411 --> 01:12:05,654 DEDERYA? 1892 01:12:33,415 --> 01:12:36,018 >> OKAY. 1893 01:12:36,085 --> 01:12:37,119 FIRST OF ALL, THANKS VERY MUCH 1894 01:12:37,186 --> 01:12:40,622 FOR REMIND RE -- FOR INVITING MO 1895 01:12:40,689 --> 01:12:42,257 THIS REALLY WONDERFUL MEETING. 1896 01:12:42,324 --> 01:12:44,426 I'D LIKE TO THANK JOE AND VICKY 1897 01:12:44,493 --> 01:12:48,030 AND ALL NIH. 1898 01:12:48,097 --> 01:12:49,465 SO WHAT I'M GOING TO TRY TO DO 1899 01:12:49,531 --> 01:12:54,369 IS, I'M THE P.I. OF THE JACKSON 1900 01:12:54,436 --> 01:12:56,638 LABORATORY CHRONIC FATIGUE 1901 01:12:56,705 --> 01:12:58,273 SYNDROME CENTER SUPPORTED BY 1902 01:12:58,340 --> 01:13:00,242 NIH, AND WE'VE BEEN DOING A LOT 1903 01:13:00,309 --> 01:13:01,643 OF WORK IN THE LAST FIVE YEARS 1904 01:13:01,710 --> 01:13:04,346 AND I'M GOING TO TRY TO CONDENSE 1905 01:13:04,413 --> 01:13:06,081 ALL OF THAT AND MAKE SOME SENSE 1906 01:13:06,148 --> 01:13:07,983 OUT OF IT. 1907 01:13:08,050 --> 01:13:13,021 I HOPE I CAN SUCCEED. 1908 01:13:13,088 --> 01:13:15,524 I'M AN IMMUNOLOGIST, SO MY FOCUS 1909 01:13:15,591 --> 01:13:17,459 HAS BEEN IN IMMUNOLOGY BUT AS I 1910 01:13:17,526 --> 01:13:19,294 WILL SHOW YOU, A LOT OF THE DATA 1911 01:13:19,361 --> 01:13:24,299 IS NON-IMMUNOLOGICAL, BECAUSE WE 1912 01:13:24,366 --> 01:13:26,602 WANTED TO UNDERSTAND TWO KEY 1913 01:13:26,668 --> 01:13:28,437 QUESTIONS AS IT RELATES TO 1914 01:13:28,504 --> 01:13:29,638 IMMUNE SYSTEM AND ME/CFS. 1915 01:13:29,705 --> 01:13:32,474 SO WE KNOW THERE'S OVERWHELMING 1916 01:13:32,541 --> 01:13:33,842 EVIDENCE THAT MULTIPLE PARTS OF 1917 01:13:33,909 --> 01:13:36,945 THE IMMUNE SYSTEM ARE PERTURBED 1918 01:13:37,012 --> 01:13:40,015 IN ME/CFS, BUT WE DON'T YET 1919 01:13:40,082 --> 01:13:41,183 UNDERSTAND HOW AND WHY THE 1920 01:13:41,250 --> 01:13:43,485 IMMUNE SYSTEM IS PERTURBED 1921 01:13:43,552 --> 01:13:53,962 DURING THE DISEASE, AND 1922 01:14:00,135 --> 01:14:02,638 IMPORTANTLY, WE ASK WHETHER THIS 1923 01:14:02,704 --> 01:14:04,573 KNOWLEDGE CAN HELP US UNDERSTAND 1924 01:14:04,640 --> 01:14:05,774 ME/CFS PATHOGENESIS AND 1925 01:14:05,841 --> 01:14:08,143 HOPEFULLY LEAD TO SOME 1926 01:14:08,210 --> 01:14:12,881 ACTIONABLE TARGETS FOR THE 1927 01:14:12,948 --> 01:14:14,483 TREATMENT. 1928 01:14:14,550 --> 01:14:16,451 SO JUST A VERY BRIEF BACKGROUND 1929 01:14:16,518 --> 01:14:19,188 ON THE IMMUNE SYSTEM, IMMUNE 1930 01:14:19,254 --> 01:14:19,454 RESPONSE. 1931 01:14:19,521 --> 01:14:22,024 IN THE MOST SIMPLISTIC WAY, WHEN 1932 01:14:22,090 --> 01:14:23,425 YOU'RE EXPOSED TO AN INFECTION, 1933 01:14:23,492 --> 01:14:25,594 YOUR T-CELLS OR YOUR B CELLS ARE 1934 01:14:25,661 --> 01:14:27,930 ACTIVATED BY AN ANTIGEN 1935 01:14:27,996 --> 01:14:29,965 PRESENTED BY THESE CELLS CALLED 1936 01:14:30,032 --> 01:14:31,633 ANTIGEN PRESENTING CELLS THAT 1937 01:14:31,700 --> 01:14:34,136 ARE DERIVED FROM VIRUSES OR 1938 01:14:34,203 --> 01:14:35,537 BACTERIA, THE CELLS GET 1939 01:14:35,604 --> 01:14:39,241 ACTIVATED, THEY EXPAND, THEY 1940 01:14:39,308 --> 01:14:42,544 CREATE AN ARMY, THEY 1941 01:14:42,611 --> 01:14:43,712 DIFFERENTIATE, THEY PRODUCE 1942 01:14:43,779 --> 01:14:45,347 ANTIBODIES THAT BLOCK 1943 01:14:45,414 --> 01:14:46,648 NEUTRALIZING VIRUSES OR THEY 1944 01:14:46,715 --> 01:14:48,617 BECOME A VARIETY OF EFFECTOR 1945 01:14:48,684 --> 01:14:51,019 T-CELLS THAT SWORD OF COMMENDS 1946 01:14:51,086 --> 01:14:52,221 TO OTHER IMMUNE PARTS TO CLEAR 1947 01:14:52,287 --> 01:14:53,322 OFF THE INFECTION. 1948 01:14:53,388 --> 01:14:54,623 ONCE THE INFECTION IS GONE, MOST 1949 01:14:54,690 --> 01:14:58,093 OF THESE CELLS ARE ALSO GONE. 1950 01:14:58,160 --> 01:14:59,628 A FEW OF THEM REMAIN ALIVE AND 1951 01:14:59,695 --> 01:15:02,364 THEY BECOME WHAT WE CALL MEMORY 1952 01:15:02,431 --> 01:15:04,266 CELLS. 1953 01:15:04,333 --> 01:15:05,667 THAT'S ACTUALLY THE BASIS OF HOW 1954 01:15:05,734 --> 01:15:07,669 WE HAVE IMMUNITY AFTER 1955 01:15:07,736 --> 01:15:10,806 VACCINATION OR INFECTIONS. 1956 01:15:10,873 --> 01:15:12,574 BUT SOMETIMES THIS DOESN'T 1957 01:15:12,641 --> 01:15:13,442 ALWAYS WORK THIS WAY. 1958 01:15:13,508 --> 01:15:18,146 EITHER THE IMMUNE SYSTEM SORT OF 1959 01:15:18,213 --> 01:15:19,481 RESPONSE TO SELF-ANTIGENS OR 1960 01:15:19,548 --> 01:15:21,850 THREATS THAT ARE NOT REALLY 1961 01:15:21,917 --> 01:15:24,586 THREATS, OR AFTER THE INFECTION, 1962 01:15:24,653 --> 01:15:26,788 THE SYSTEM DOES NOT RETURN TO 1963 01:15:26,855 --> 01:15:28,090 ITS STEADY STATE. 1964 01:15:28,156 --> 01:15:32,661 AND WE THINK SOME OF NIECE OF TE 1965 01:15:32,728 --> 01:15:34,963 THINGS ARE HAPPENING IN ME/CFS. 1966 01:15:35,030 --> 01:15:36,064 OBVIOUSLY THIS IS VERY COMPLEX. 1967 01:15:36,131 --> 01:15:37,466 IF YOU THINK OF THE IMMUNE 1968 01:15:37,532 --> 01:15:39,334 SYSTEM AS AN ARMY, YOU HAVE 1969 01:15:39,401 --> 01:15:41,103 MANY, MANY DIFFERENT DIVISIONS. 1970 01:15:41,169 --> 01:15:43,338 I'VE BEEN STUDYING T CELLS FOR 1971 01:15:43,405 --> 01:15:44,306 THE PAST 30 YEARS. 1972 01:15:44,373 --> 01:15:46,174 WE'VE IDENTIFIED SOME OF THESE 1973 01:15:46,241 --> 01:15:48,577 TARGETS, BUT THERE ARE MANY 1974 01:15:48,644 --> 01:15:50,178 DIFFERENT SUBPOPULATIONS. 1975 01:15:50,245 --> 01:15:51,747 THERE'S A DIFFERENT LABOR OF 1976 01:15:51,813 --> 01:15:52,848 DIVISION WITHIN THE IMMUNE 1977 01:15:52,915 --> 01:15:53,348 SYSTEM. 1978 01:15:53,415 --> 01:15:56,385 THERE ARE CELLS SUCH AS TH17 1979 01:15:56,451 --> 01:15:59,688 CELLS THAT RESPOND TO BACTERIA, 1980 01:15:59,755 --> 01:16:00,789 FUNGI, THERE ARE OTHERS THAT 1981 01:16:00,856 --> 01:16:02,124 RESPOND TO PARASITES. 1982 01:16:02,190 --> 01:16:05,494 WE HAVE THESE T-REGS, REGULATORY 1983 01:16:05,560 --> 01:16:07,029 CELLS THAT ACTUALLY ARE SORT OF 1984 01:16:07,095 --> 01:16:08,130 LIKE BUREAUCRATS THAT TRY TO 1985 01:16:08,196 --> 01:16:09,965 CONTROL THE IMMUNE RESPONSES. 1986 01:16:10,032 --> 01:16:12,935 THEY CAN BE GOOD OR BAD. 1987 01:16:13,001 --> 01:16:15,003 THEY'RE GOOD TO RESOLVING 1988 01:16:15,070 --> 01:16:16,471 RESPONSES BUT THEY COULD BE BAD 1989 01:16:16,538 --> 01:16:19,975 IF THERE'S TOO MUCH BUREAUCRACY, 1990 01:16:20,042 --> 01:16:21,410 AS YOU KNOW, YOU DON'T GET WORK 1991 01:16:21,476 --> 01:16:23,545 DONE, SO THERE ARE CELLS THAT 1992 01:16:23,612 --> 01:16:25,213 HEP B CELLS MAKE ANTIBODIES AND 1993 01:16:25,280 --> 01:16:27,082 SO ON AND SO FORTH. 1994 01:16:27,149 --> 01:16:29,584 CELLS THAT KILL VIRAL INFECTED 1995 01:16:29,651 --> 01:16:31,687 CELLS, WHICH WE CALL CYTOTOXIC 1996 01:16:31,753 --> 01:16:32,988 CELLS, AND I'M GOING TO MENTION 1997 01:16:33,055 --> 01:16:34,723 ABOUT THESE POPULATIONS OF CELLS 1998 01:16:34,790 --> 01:16:37,125 THAT ARE SO-CALLED NON-CLASSICAL 1999 01:16:37,192 --> 01:16:38,427 T CELLS. 2000 01:16:38,493 --> 01:16:39,962 AND THEN YOU HAVE DIFFERENT 2001 01:16:40,028 --> 01:16:42,831 FLAVORS OF THESE SUBSETS. 2002 01:16:42,898 --> 01:16:45,100 WHAT THESE FLAVORS MEANS IS THAT 2003 01:16:45,167 --> 01:16:46,935 FUNCTIONALLY, THESE CELLS CAN 2004 01:16:47,002 --> 01:16:47,269 CHANGE. 2005 01:16:47,336 --> 01:16:49,771 THEY ARE DYNAMIC AND FLEXIBLE. 2006 01:16:49,838 --> 01:16:52,841 FOR EXAMPLE, CELLS THAT PRODUCE 2007 01:16:52,908 --> 01:16:55,877 IL-17 AT SOME POINT CAN ALSO 2008 01:16:55,944 --> 01:16:57,379 PRODUCE IL22. 2009 01:16:57,446 --> 01:17:02,084 WE EITHER CALL THEM TH22 OR T 2010 01:17:02,150 --> 01:17:02,551 TH22TH17.22. 2011 01:17:02,617 --> 01:17:04,586 THEY CAN HAVE DIFFERENT 2012 01:17:04,653 --> 01:17:05,821 CHEMOKINE RECEPTORS ON THEIR 2013 01:17:05,887 --> 01:17:08,757 SURFACE THAT USUALLY ASSOCIATES 2014 01:17:08,824 --> 01:17:10,192 WITH THEIR EFFECTOR FUNCTION AND 2015 01:17:10,258 --> 01:17:13,028 THIS IS VERY IMPORTANT BECAUSE 2016 01:17:13,095 --> 01:17:15,097 KEEP KINE RECEPTORS ARE LIKE ZIP 2017 01:17:15,163 --> 01:17:16,198 CODES, THE CELLS HAVE TO KNOW 2018 01:17:16,264 --> 01:17:17,199 WHERE TO GO. 2019 01:17:17,265 --> 01:17:18,500 BECAUSE IF YOUR CELLS ARE GOING 2020 01:17:18,567 --> 01:17:19,401 TO LUNG INSTEAD OF LIVER, YOU'RE 2021 01:17:19,468 --> 01:17:20,702 GOING TO HAVE PROBLEMS. 2022 01:17:20,769 --> 01:17:21,603 BECAUSE THE INFECTION IS IN THE 2023 01:17:21,670 --> 01:17:24,206 WRONG PLACE. 2024 01:17:24,272 --> 01:17:26,708 AS I SAID, THIS CAN BE BOTH 2025 01:17:26,775 --> 01:17:28,343 SOMEWHAT IMPRINTED DURING 2026 01:17:28,410 --> 01:17:29,244 DIFFERENTIATION BUT ALSO 2027 01:17:29,311 --> 01:17:34,950 FLEXIBLE, SO THE CELLS ON ONE 2028 01:17:35,017 --> 01:17:35,617 EFFECTOR POPULATION CAN BE 2029 01:17:35,684 --> 01:17:37,052 RECRUITED TO ANOTHER SUBSET. 2030 01:17:37,119 --> 01:17:38,587 OF COURSE THE REASON I'M 2031 01:17:38,653 --> 01:17:41,623 PRESENTING THIS IS BECAUSE THIS 2032 01:17:41,690 --> 01:17:45,327 COMPLEXITY REQUIRES A VERY CLOSE 2033 01:17:45,394 --> 01:17:46,995 COMMANDING REGULATION BECAUSE IF 2034 01:17:47,062 --> 01:17:48,330 ANY OF THESE THINGS GO WRONG, 2035 01:17:48,397 --> 01:17:49,698 THEN YOU'RE GOING TO HAVE MAJOR 2036 01:17:49,765 --> 01:17:52,968 PROBLEMS. 2037 01:17:53,035 --> 01:17:55,037 THEN YOU HAVE WHAT WE CALL 2038 01:17:55,103 --> 01:17:56,271 NON-CLASSICAL T CELLS BECAUSE 2039 01:17:56,338 --> 01:17:57,873 THEY DON'T RECOGNIZE PEPTIDES. 2040 01:17:57,939 --> 01:18:01,510 THEY RECOGNIZE, FOR EXAMPLE, 2041 01:18:01,576 --> 01:18:03,478 THESE CELLS RECOGNIZE SMALL 2042 01:18:03,545 --> 01:18:06,448 MOLECULES, METABOLITES FROM 2043 01:18:06,515 --> 01:18:08,250 VITAMIN BQ PATHWAY, FOR EXAMPLE. 2044 01:18:08,316 --> 01:18:10,786 THERE ARE OTHERS THAT ARE CALLED 2045 01:18:10,852 --> 01:18:13,422 NK T CELLS THAT RECOGNIZE 2046 01:18:13,488 --> 01:18:13,789 GLYCOLIPIDS. 2047 01:18:13,855 --> 01:18:16,458 THERE ARE CELLS WHAT WE CALL 2048 01:18:16,525 --> 01:18:17,559 GAMMA-DELTA CELLS THAT CAN 2049 01:18:17,626 --> 01:18:20,495 ACTUALLY RESPOND TO MOLECULES 2050 01:18:20,562 --> 01:18:23,098 INDUCED BY STRESS. 2051 01:18:23,165 --> 01:18:25,500 THESE THINGS ARE ACTUALLY 2052 01:18:25,567 --> 01:18:27,202 MOLECULES EXPRESSED BY OUR CELLS 2053 01:18:27,269 --> 01:18:28,670 BUT THEY ARE INDUCED BY STRESS 2054 01:18:28,737 --> 01:18:30,639 AND THEY COULD BE SENSED BY 2055 01:18:30,705 --> 01:18:31,406 THESE GAMMA-DELTA CELLS. 2056 01:18:31,473 --> 01:18:34,209 SO THE IMMUNE SYSTEM IS TRYING 2057 01:18:34,276 --> 01:18:35,911 TO SENSE ANY SORT OF STRESS, ANY 2058 01:18:35,977 --> 01:18:38,280 SORT OF DANGER AND THREAT THAT'S 2059 01:18:38,346 --> 01:18:41,249 NOT NECESSARILY HAVE TO BE A 2060 01:18:41,316 --> 01:18:44,519 VIRAL OR BACTERIAL OR 2061 01:18:44,586 --> 01:18:45,120 PATHOGEN-ASSOCIATED MOLECULE. 2062 01:18:45,187 --> 01:18:47,789 IT COULD JUST BE COMING FROM THE 2063 01:18:47,856 --> 01:18:48,423 CELLS. 2064 01:18:48,490 --> 01:18:50,392 THEY CAN RECOGNIZE 2065 01:18:50,459 --> 01:18:52,027 PHOSPHOANTIGENS THAT ARE DERIVED 2066 01:18:52,094 --> 01:18:53,328 FROM BACTERIA OR VIRUSES. 2067 01:18:53,395 --> 01:18:55,997 SO THERE'S A LOT OF, AS I SAID, 2068 01:18:56,064 --> 01:18:59,000 LABOR OF DIVISION, LOTS OF 2069 01:18:59,067 --> 01:19:00,769 DIFFERENT POPULATIONS. 2070 01:19:00,836 --> 01:19:03,839 SO HOW DO WE STUDY THIS IN THE 2071 01:19:03,905 --> 01:19:05,040 CONTEXT OF A DISEASE LIKE 2072 01:19:05,107 --> 01:19:07,976 ME/CFS, WHICH IS ALREADY A VERY 2073 01:19:08,043 --> 01:19:09,778 COMPLEX DISEASE, AND ABOUT SIX 2074 01:19:09,845 --> 01:19:12,447 YEARS AGO, WHEN WE INITIATED 2075 01:19:12,514 --> 01:19:15,517 THIS PROJECT, WE PROPOSED SORT 2076 01:19:15,584 --> 01:19:18,320 OF A MULTI-OMICS TOPOLOGICAL 2077 01:19:18,386 --> 01:19:18,720 ANALYSIS. 2078 01:19:18,787 --> 01:19:20,522 WHAT I MEAN BY TOPOLOGICAL? 2079 01:19:20,589 --> 01:19:21,923 SO IF YOU WANT TO UNDERSTAND THE 2080 01:19:21,990 --> 01:19:22,924 IMMUNE SYSTEM, OBVIOUSLY YOU 2081 01:19:22,991 --> 01:19:24,993 HAVE TO ANALYZE DOZENS OR 2082 01:19:25,060 --> 01:19:26,661 HUNDREDS OF DIFFERENT 2083 01:19:26,728 --> 01:19:28,063 POPULATIONS OF IMMUNE CELLS, BUT 2084 01:19:28,130 --> 01:19:30,899 THAT DOESN'T GET YOU TO THE 2085 01:19:30,966 --> 01:19:33,001 ANSWER WHY ARE THOSE POPULATIONS 2086 01:19:33,068 --> 01:19:34,569 CHANGING, WHAT'S CAUSING THAT. 2087 01:19:34,636 --> 01:19:37,372 SO WE HYPOTHESIZE THAT THIS MUST 2088 01:19:37,439 --> 01:19:38,773 BE -- HAVE TO DO SOMEHOW WITH 2089 01:19:38,840 --> 01:19:40,709 THE METABOLISM, BECAUSE 2090 01:19:40,775 --> 01:19:44,446 METABOLITES ACT ON THE IMMUNE 2091 01:19:44,513 --> 01:19:45,680 SYSTEM, AND AS YOU HEARD IN THE 2092 01:19:45,747 --> 01:19:46,982 PREVIOUS TALK, THEY REALLY 2093 01:19:47,048 --> 01:19:52,220 AFFECT THE ENERGETICS, NERVE 2094 01:19:52,287 --> 01:19:54,055 FUNCTION, EVERYTHING, AND ONE OF 2095 01:19:54,122 --> 01:19:55,824 THE MAIN SOURCES OF THE 2096 01:19:55,891 --> 01:19:56,925 METABOLITES ARE THE BACTERIA 2097 01:19:56,992 --> 01:19:59,995 THAT LIVE IN THE GUT, NAMELY THE 2098 01:20:00,061 --> 01:20:01,396 MICROBIOTA OR WE CALL IT THE 2099 01:20:01,463 --> 01:20:02,297 MICROBIOME. 2100 01:20:02,364 --> 01:20:04,266 SO THERE MUST HAVE SOME KIND OF 2101 01:20:04,332 --> 01:20:05,534 LINK BETWEEN THESE DIFFERENT 2102 01:20:05,600 --> 01:20:06,201 SPACES, AND OF COURSE YOU HAVE 2103 01:20:06,268 --> 01:20:07,235 TO LINK THAT TO THE CLINICAL 2104 01:20:07,302 --> 01:20:07,636 SYMPTOM. 2105 01:20:07,702 --> 01:20:09,971 IF ANYTHING WE OBSERVE DISTURBED 2106 01:20:10,038 --> 01:20:11,339 HAS ANYTHING TO DO WITH ME/CFS 2107 01:20:11,406 --> 01:20:16,144 SYMPTOMS, THAT'S ANOTHER POORN 2108 01:20:16,211 --> 01:20:17,012 IMPORTANT QUESTION BECAUSE THEY 2109 01:20:17,078 --> 01:20:19,514 COULD BE JUST BYSTANDER EFFECTS. 2110 01:20:19,581 --> 01:20:20,482 YOU HAVE THESE DIFFERENT STATES 2111 01:20:20,549 --> 01:20:21,716 THAT YOU CAN IMAGINE, AND WE 2112 01:20:21,783 --> 01:20:23,218 WANTED TO ANALYZE THEM WITHIN 2113 01:20:23,285 --> 01:20:24,753 EACH SPACE AND THEN TOAP 2114 01:20:24,819 --> 01:20:26,521 LOGICALLY WE WANT TO CREATE 2115 01:20:26,588 --> 01:20:28,390 THESE LINKS SO THAT WE CAN SEE 2116 01:20:28,456 --> 01:20:30,358 THE WHOLE PICTURE. 2117 01:20:30,425 --> 01:20:34,162 AND SORT OF A HOLISTIC APPROACH 2118 01:20:34,229 --> 01:20:35,830 TO UNDERSTAND WHAT'S GOING ON. 2119 01:20:35,897 --> 01:20:38,900 AND IMPORTANTLY, WHEN WE DESIGN 2120 01:20:38,967 --> 01:20:42,070 THESE STUDIES, THANKS TO CINDY 2121 01:20:42,137 --> 01:20:44,639 BAITMAN, SHE HAD PROPOSED THAT 2122 01:20:44,706 --> 01:20:46,841 WE SHOULD DIVIDE THE PATIENTS 2123 01:20:46,908 --> 01:20:49,578 INTO SHORT TERM AND LONG TERM 2124 01:20:49,644 --> 01:20:49,844 PATIENTS. 2125 01:20:49,911 --> 01:20:52,247 AS YOU WILL SEE, THAT TURNED OUT 2126 01:20:52,314 --> 01:20:54,449 TO BE A REALLY, REALLY GREAT 2127 01:20:54,516 --> 01:20:55,116 IDEA AND VERY IMPORTANT. 2128 01:20:55,183 --> 01:20:56,551 SHORT TERM, PEOPLE WHO HAD THE 2129 01:20:56,618 --> 01:20:59,287 DISEASE LESS THAN FOUR YEARS, 2130 01:20:59,354 --> 01:21:00,689 LONG TERM, PEOPLE WHO HAVE THE 2131 01:21:00,755 --> 01:21:02,057 TEASE MORE THAN 10 YEARS. 2132 01:21:02,123 --> 01:21:03,425 BECAUSE CINDY HYPOTHESIZED THAT 2133 01:21:03,491 --> 01:21:05,060 THERE MUST BE SOME DIFFERENCES 2134 01:21:05,126 --> 01:21:07,796 IN THEIR BIOLOGY, AND SHE WAS 2135 01:21:07,862 --> 01:21:09,531 ALSO OBSERVING DIFFERENCES IN 2136 01:21:09,598 --> 01:21:12,901 THEIR SYMPTOMATOLOGY, FOR 2137 01:21:12,968 --> 01:21:13,602 EXAMPLE. 2138 01:21:13,668 --> 01:21:15,303 AND LASTLY BUT NOT LEASTLY, WE 2139 01:21:15,370 --> 01:21:20,942 ALSO HAD A TEMPORAL SUBJECTS, 2140 01:21:21,009 --> 01:21:22,043 TEMPORAL MEANING THAT WE 2141 01:21:22,110 --> 01:21:23,678 COLLECTED THESE SUBJECTS, NAMELY 2142 01:21:23,745 --> 01:21:26,314 FECAL SAMPLES, PLASMA AND IMMUNE 2143 01:21:26,381 --> 01:21:28,917 CELLS, AT THREE DIFFERENT TIME 2144 01:21:28,984 --> 01:21:29,951 POINTS. 2145 01:21:30,018 --> 01:21:31,453 YEAR ONE, YEAR TWO AND YEAR 2146 01:21:31,519 --> 01:21:31,653 THREE. 2147 01:21:31,720 --> 01:21:33,955 BECAUSE WE WANTED TO SEE HOW 2148 01:21:34,022 --> 01:21:35,390 THINGS CHANGE, OR ARE THEY 2149 01:21:35,457 --> 01:21:39,227 CONSISTENT OVER TIME. 2150 01:21:39,294 --> 01:21:40,528 SO OF COURSE THIS IS LOTS OF 2151 01:21:40,595 --> 01:21:43,465 LOTS OF DATA, AND I'M GOING TO 2152 01:21:43,531 --> 01:21:45,333 TRY TO SHOW YOU SOME OF IT IN A 2153 01:21:45,400 --> 01:21:45,867 CONDENSED FORM. 2154 01:21:45,934 --> 01:21:47,335 SO AS I SAID, THE WHOLE 2155 01:21:47,402 --> 01:21:49,170 FRAMEWORK HERE IS THAT WE WANTED 2156 01:21:49,237 --> 01:21:53,642 TO LINK THE MICROBIOME, WHICH 2157 01:21:53,708 --> 01:21:55,343 PRODUCES PROBABLY ABOUT 20, 30% 2158 01:21:55,410 --> 01:21:56,845 OF THE METABOLITES IN YOUR 2159 01:21:56,911 --> 01:21:58,113 BLOOD, IT AFFECTS ALL YOUR 2160 01:21:58,179 --> 01:22:00,115 PHYSIOLOGY, AND WHETHER THESE 2161 01:22:00,181 --> 01:22:02,050 METABOLITES CAN IMPACT THE 2162 01:22:02,117 --> 01:22:04,152 IMMUNOLOGY AND, IN TURN, THIS 2163 01:22:04,219 --> 01:22:07,088 COULD IMPACT THE PHENOTYPE, THE 2164 01:22:07,155 --> 01:22:09,824 SYMPTOMS OR THE PHYSIOLOGY OR 2165 01:22:09,891 --> 01:22:16,498 PATHOLOGY. 2166 01:22:16,564 --> 01:22:18,400 SO THIS IS JUST A SAMPLE OF THE 2167 01:22:18,466 --> 01:22:22,404 TYPES OF TATA DATA WE USE. 2168 01:22:22,470 --> 01:22:24,039 WHEN WE SAMPLED THE IMMUNE CELLS 2169 01:22:24,105 --> 01:22:25,440 WE SAW LOTS OF DIFFERENT 2170 01:22:25,507 --> 01:22:25,774 DISRUPTIONS. 2171 01:22:25,840 --> 01:22:26,875 I'M GOING TO SHOW YOU TWO 2172 01:22:26,941 --> 01:22:28,510 EXAMPLES OF THIS, BUT THERE WERE 2173 01:22:28,576 --> 01:22:30,478 MANY ESPECIALLY EFFECTOR CELLS, 2174 01:22:30,545 --> 01:22:30,912 EFFECTOR T CELLS. 2175 01:22:30,979 --> 01:22:34,416 WHEN I SAY EFFECTOR, CELLS THAT 2176 01:22:34,482 --> 01:22:36,051 PRODUCE A DIFFERENT SET OF 2177 01:22:36,117 --> 01:22:36,551 CYTOKINES, FOR EXAMPLE. 2178 01:22:36,618 --> 01:22:38,787 SO NAIVE CELLS, THEY'RE 2179 01:22:38,853 --> 01:22:39,554 UNEDUCATED, RIGHT, SO THEY DON'T 2180 01:22:39,621 --> 01:22:40,855 KNOW WHAT TO BECOME. 2181 01:22:40,922 --> 01:22:42,524 WHEN THE CELLS BECOME EFFECTOR 2182 01:22:42,590 --> 01:22:45,560 AND MEMORY, THEY ACQUIRE CERTAIN 2183 01:22:45,627 --> 01:22:45,994 FUNCTIONS. 2184 01:22:46,061 --> 01:22:47,729 THOSE FUNCTIONS CAN BE VERY 2185 01:22:47,796 --> 01:22:49,397 USEFUL OR THEY CAN BE VERY 2186 01:22:49,464 --> 01:22:51,833 DANGEROUS IF IT'S NOT CONTROLLED 2187 01:22:51,900 --> 01:22:55,170 PROPERLY, AND IN FACT WE SAW 2188 01:22:55,236 --> 01:22:58,139 THOSE CHANGES HAPPENING. 2189 01:22:58,206 --> 01:23:00,975 BUT IMPORTANTLY, WE ALSO SAW 2190 01:23:01,042 --> 01:23:02,010 DIFFERENCES BETWEEN THESE TWO 2191 01:23:02,077 --> 01:23:04,512 PATIENT GROUPS. 2192 01:23:04,579 --> 01:23:05,914 THE LONG TERM AND THE SHORT TERM 2193 01:23:05,980 --> 01:23:08,516 PATIENTS HAD SIGNIFICANT 2194 01:23:08,583 --> 01:23:10,518 DIFFERENCES IN THEIR IMMUNE 2195 01:23:10,585 --> 01:23:12,587 PROFILING, WHICH WERE ALSO 2196 01:23:12,654 --> 01:23:13,988 DIFFERENT FROM HEALTHY CONTROLS, 2197 01:23:14,055 --> 01:23:17,058 BUT EVEN WITHIN THOSE TWO GRO 2198 01:23:17,125 --> 01:23:19,160 GROUPS, WHEN WE AGE-MATCH AND 2199 01:23:19,227 --> 01:23:19,994 SEX-MATCH, THERE WERE 2200 01:23:20,061 --> 01:23:21,463 SIGNIFICANT DIFFERENCES. 2201 01:23:21,529 --> 01:23:25,200 SO THIS WAS VERY IMPORTANT DATA. 2202 01:23:25,266 --> 01:23:27,168 I JUST WANT TO SHOW YOU TWO 2203 01:23:27,235 --> 01:23:28,002 EXAMPLES OF THIS BECAUSE THEY 2204 01:23:28,069 --> 01:23:29,437 ARE RELEVANT FOR THE REST OF THE 2205 01:23:29,504 --> 01:23:30,772 STORY THAT I'M GOING TO TELL 2206 01:23:30,839 --> 01:23:31,106 YOU. 2207 01:23:31,172 --> 01:23:33,375 ONE OF THEM IS THAT WE'VE FOUND 2208 01:23:33,441 --> 01:23:35,043 DESTRUCTION IN THIS POPULATION 2209 01:23:35,110 --> 01:23:36,478 CALLED TH17 CELLS. 2210 01:23:36,544 --> 01:23:37,679 THE NAME COMES FROM THE FACT 2211 01:23:37,746 --> 01:23:39,547 THAT THEY PRODUCE IL-17, WHICH 2212 01:23:39,614 --> 01:23:42,350 IS A VERY IMPORTANT CYTOKINE, 2213 01:23:42,417 --> 01:23:44,686 HAS LOTS OF LOTS OF FUNCTION, 2214 01:23:44,753 --> 01:23:48,923 AND WE FOUND THAT IN PARTICULAR, 2215 01:23:48,990 --> 01:23:50,558 PATIENTS WITH MORE THAN 10 YEARS 2216 01:23:50,625 --> 01:23:53,294 OF DISEASE HAD FUNCTIONAL 2217 01:23:53,361 --> 01:23:57,599 DEFECTS IN THESE TH17 CELLS, IN 2218 01:23:57,665 --> 01:23:59,734 OTHER WORDS, THEY PRODUCED LESS 2219 01:23:59,801 --> 01:24:02,137 IL-17 OR LESS INTERFERON GAMMA 2220 01:24:02,203 --> 01:24:06,107 AND LESS IL-17 TOGETHER, AND WE 2221 01:24:06,174 --> 01:24:07,509 THOUGHT THAT THIS WAS VERY 2222 01:24:07,575 --> 01:24:08,410 EXCITING BECAUSE WE WERE 2223 01:24:08,476 --> 01:24:09,611 ACTUALLY WORKING ON THESE 2224 01:24:09,677 --> 01:24:11,546 POPULATIONS FOR MANY YEARS, AND 2225 01:24:11,613 --> 01:24:15,984 WE KNEW THAT TH17 CELLS WERE 2226 01:24:16,050 --> 01:24:18,319 LINKED TO TWO IMPORTANT 2227 01:24:18,386 --> 01:24:18,586 PHENOMENA. 2228 01:24:18,653 --> 01:24:22,624 ONE IS THAT THEY WERE LINKED TO 2229 01:24:22,690 --> 01:24:22,957 AUTOIMMUNITY. 2230 01:24:23,024 --> 01:24:24,692 A LOT OF AUTOIMMUNE DISEASES ARE 2231 01:24:24,759 --> 01:24:26,327 ASSOCIATED WITH TH17 CELLS, SO 2232 01:24:26,394 --> 01:24:28,730 THEY CAN BE BAD MOSTLY. 2233 01:24:28,797 --> 01:24:29,831 THE SECOND IS THAT THEY WERE 2234 01:24:29,898 --> 01:24:32,233 ALSO LINKED TO THE MICROBIOME. 2235 01:24:32,300 --> 01:24:35,737 THE BACTERIA THAT LIVE IN YOUR 2236 01:24:35,804 --> 01:24:38,339 GUT MOSTLY BUT ALSO IN YOUR 2237 01:24:38,406 --> 01:24:38,673 SKIN. 2238 01:24:38,740 --> 01:24:40,208 SO THERE WAS A VERY INTIMATE 2239 01:24:40,275 --> 01:24:42,744 RELATIONSHIP BETWEEN THE 2240 01:24:42,811 --> 01:24:43,945 MICROBIOTA WHICH PRODUCED 2241 01:24:44,012 --> 01:24:46,815 METABOLITES THAT ACTUALLY SHAPED 2242 01:24:46,881 --> 01:24:47,916 TH17 CELLS, WHICH, IN TURN, 2243 01:24:47,982 --> 01:24:49,751 COULD BE RESPONSIBLE FOR 2244 01:24:49,818 --> 01:24:50,852 AUTOIMMUNE DISEASES OR SOME 2245 01:24:50,919 --> 01:24:52,387 CHRONIC DISEASES. 2246 01:24:52,454 --> 01:24:53,455 OBVIOUSLY THEY HAVE ALSO SOME 2247 01:24:53,521 --> 01:24:55,557 VERY IMPORTANT FUNCTIONS IN 2248 01:24:55,623 --> 01:24:57,826 DEFENDING US AGAINST FUNGAL OR 2249 01:24:57,892 --> 01:25:00,128 BACTERIAL DISEASES. 2250 01:25:00,195 --> 01:25:01,129 THE SECOND POPULATION THAT WE 2251 01:25:01,196 --> 01:25:02,964 THOUGHT WAS VERY INTERESTING 2252 01:25:03,031 --> 01:25:07,569 THAT WE FOUND DIFFERENT IS CAL 2253 01:25:07,635 --> 01:25:09,671 CALLED -- I SHOWED YOU THESE 2254 01:25:09,737 --> 01:25:12,073 CELLS ARE SO-CALLED 2255 01:25:12,140 --> 01:25:13,074 NON-CLASSICAL CELLS. 2256 01:25:13,141 --> 01:25:14,909 THEY RECOGNIZE BACTERIAL 2257 01:25:14,976 --> 01:25:17,545 METABOLITES, SO BACTERIAL 2258 01:25:17,612 --> 01:25:19,948 METABOLITES DERIVED FROM THIS 2259 01:25:20,014 --> 01:25:21,483 PATHWAY WHICH TURNS OUT TO BE 2260 01:25:21,549 --> 01:25:23,084 PRODUCED BY THE BACTERIA, THE 2261 01:25:23,151 --> 01:25:26,387 VITAMIN B2 IN YOUR GUT, AND THE 2262 01:25:26,454 --> 01:25:27,355 METABOLITES FROM THE PATHWAY CAN 2263 01:25:27,422 --> 01:25:28,423 ALSO ASSOCIATE WITH THIS 2264 01:25:28,490 --> 01:25:31,526 MOLECULE CALLED MR1, WHICH THEN 2265 01:25:31,593 --> 01:25:32,727 ACTIVATES THESE T CELLS JUST 2266 01:25:32,794 --> 01:25:36,264 LIKE OTHER T CELLS. 2267 01:25:36,331 --> 01:25:39,167 THAT'S WHY WE CALLED THEM 2268 01:25:39,234 --> 01:25:41,703 ESPECIALLY -- THEY ALSO HAVE 2269 01:25:41,769 --> 01:25:44,239 THEM IN T-CELL RECEPTOR. 2270 01:25:44,305 --> 01:25:46,074 THESE CAN ALSO BE POTENT 2271 01:25:46,140 --> 01:25:48,042 PRODUCERS OF INFLAMMATORY 2272 01:25:48,109 --> 01:25:48,376 CYTOKINES. 2273 01:25:48,443 --> 01:25:50,245 SUCH AS INTERFERON GAMMA, SOME 2274 01:25:50,311 --> 01:25:55,049 OF THEM EXPRESSED IL-17 AND SOME 2275 01:25:55,116 --> 01:25:57,785 EXPRESS GZA, A MEDIATOR WHICH 2276 01:25:57,852 --> 01:25:59,988 CAN ACTUALLY KILL BACTERIA 2277 01:26:00,054 --> 01:26:00,855 INFECTED CELLS AND SO ON. 2278 01:26:00,922 --> 01:26:05,026 SO WHAT WE FOUND IS THAT THE 2279 01:26:05,093 --> 01:26:06,361 OPPOSITE OF WHAT I JUST SHOWED 2280 01:26:06,427 --> 01:26:09,197 YOU, IN THE SHORT TERM PATIENT, 2281 01:26:09,264 --> 01:26:10,398 FUNCTIONALLY THESE CELLS WERE 2282 01:26:10,465 --> 01:26:13,801 ALSO DISRUPTED. 2283 01:26:13,868 --> 01:26:16,871 SO THE GZA CAPACITY WAS 2284 01:26:16,938 --> 01:26:19,274 PERTURBED, EITHER DECREASED OR 2285 01:26:19,340 --> 01:26:20,241 INCREASED IN THE PATIENTS THAT 2286 01:26:20,308 --> 01:26:21,776 HAD THE DISEASE LESS THAN FOUR 2287 01:26:21,843 --> 01:26:23,578 YEARS, BUT NOT MORE THAN 10 2288 01:26:23,645 --> 01:26:24,512 YEARS. 2289 01:26:24,579 --> 01:26:26,281 SO AGAIN, THESE CELLS ARE ALSO 2290 01:26:26,347 --> 01:26:29,684 LINKED TO THE MICROBIOME. 2291 01:26:29,751 --> 01:26:33,187 WE THINK THEY'RE SORT OF THE 2292 01:26:33,254 --> 01:26:37,125 GUARDIANS OF THE ECOSYSTEM. 2293 01:26:37,191 --> 01:26:38,359 WE'VE DONE SOME STUDIES ON THAT, 2294 01:26:38,426 --> 01:26:40,194 THEY CAN DISCRIMINATE BETWEEN 2295 01:26:40,261 --> 01:26:43,798 DIFFERENT BACTERIA SPECIES, 2296 01:26:43,865 --> 01:26:45,533 BASED ON THE METABOLITES THEY 2297 01:26:45,600 --> 01:26:47,101 PRODUCE, AND SO ON AND SO FORTH, 2298 01:26:47,168 --> 01:26:48,436 SO WE THINK THAT THEY PLAY A 2299 01:26:48,503 --> 01:26:51,172 VERY IMPORTANT ROLE IN SENSING 2300 01:26:51,239 --> 01:26:52,574 THIS DIVERSITY OR HETEROGENEITY 2301 01:26:52,640 --> 01:26:54,642 OF THE MICROBIOME AND THEY SEEM 2302 01:26:54,709 --> 01:26:56,711 TO BE REALLY AFFECTED ESPECIALLY 2303 01:26:56,778 --> 01:26:57,712 IN THE SHORT TERM PATIENTS. 2304 01:26:57,779 --> 01:27:00,048 JUST KEEP THAT IN MIND. 2305 01:27:00,114 --> 01:27:04,953 SO THAT IS A SEGUE TO THE NEXT 2306 01:27:05,019 --> 01:27:06,487 SPACE, WHICH IS THE MICROBIOME. 2307 01:27:06,554 --> 01:27:08,656 AS I SAID, THERE'S TRILLIONS OF 2308 01:27:08,723 --> 01:27:10,191 BACTERIA THAT LIVE IN YOUR GUT, 2309 01:27:10,258 --> 01:27:11,526 AND THESE ARE REALLY, REALLY 2310 01:27:11,593 --> 01:27:14,262 IMPORTANT IN OUR BIOLOGY AND 2311 01:27:14,329 --> 01:27:15,163 PHYSIOLOGY, BUT IF THEY ARE 2312 01:27:15,229 --> 01:27:17,332 PERTURBED OR WHAT WE CALL 2313 01:27:17,398 --> 01:27:20,268 DYSBIOSIS HAPPENS, THEIR 2314 01:27:20,335 --> 01:27:21,502 PROPORTIONS CHANGE, THEIR 2315 01:27:21,569 --> 01:27:24,339 DIVERSITY GETS SMALLER, THERE'S 2316 01:27:24,405 --> 01:27:25,640 THOUSANDS OF DIFFERENT STRAINS, 2317 01:27:25,707 --> 01:27:28,176 THEN YOU GET ALL KINDS OF 2318 01:27:28,242 --> 01:27:31,012 PROBLEMS, CHRONIC DISEASES, 2319 01:27:31,079 --> 01:27:32,647 ACCELERATES AGING, IT EVEN 2320 01:27:32,714 --> 01:27:34,282 IMPACTS THE DRUGS WE TAKE DURING 2321 01:27:34,349 --> 01:27:35,850 CANCER LIKE IMMUNOTHERAPY DRUGS, 2322 01:27:35,917 --> 01:27:38,920 AND THIS COULD HAPPEN BY A 2323 01:27:38,987 --> 01:27:39,754 VARIETY OF REASONS. 2324 01:27:39,821 --> 01:27:42,824 YOUR DIET, USE OF TOO MUCH 2325 01:27:42,890 --> 01:27:43,791 ANTIBIOTIC, PATHOGEN INVASION, 2326 01:27:43,858 --> 01:27:45,526 SO ON AND SO FORTH, SO THEY PLAY 2327 01:27:45,593 --> 01:27:47,195 A REALLY MAJOR ROLE, AND THEY 2328 01:27:47,261 --> 01:27:52,133 ARE TIGHTLY LINKED TO THIS 2329 01:27:52,200 --> 01:27:55,169 IMMUNE PATHWAYS OR IMMUNE 2330 01:27:55,236 --> 01:27:57,305 ACTIVATION BECAUSE OBVIOUSLY THE 2331 01:27:57,372 --> 01:27:58,806 IMMUNE SYSTEM ALSO HAS TO KEEP 2332 01:27:58,873 --> 01:28:00,675 THEM IN THE LUMEN OF THE 2333 01:28:00,742 --> 01:28:01,676 INTESTINE, BUT AT THE SAME TIME, 2334 01:28:01,743 --> 01:28:05,947 THOSE BACTERIA PRODUCE A LOT OF 2335 01:28:06,014 --> 01:28:06,981 PRODUCTS THAT HELP THE IMMUNE 2336 01:28:07,048 --> 01:28:08,916 SYSTEM TO RESPOND TO THE 2337 01:28:08,983 --> 01:28:11,853 PATHOGENIC BACK TIER Y BACTERIA. 2338 01:28:11,919 --> 01:28:12,954 ONE PROBLEM IS THAT JUST LIKE 2339 01:28:13,021 --> 01:28:14,722 THE IMMUNE SYSTEM, THE 2340 01:28:14,789 --> 01:28:16,190 MICROBIOME IS ALSO PERSONALIZED. 2341 01:28:16,257 --> 01:28:18,226 SO EVERYONE IN THIS ROOM HAS 2342 01:28:18,292 --> 01:28:19,527 SOMEWHAT DIFFERENT MICROBIOTA 2343 01:28:19,594 --> 01:28:20,261 BECAUSE YOU HAVE DIFFERENT 2344 01:28:20,328 --> 01:28:20,862 STRAINS. 2345 01:28:20,928 --> 01:28:23,064 HOWEVER, THE BIGGER SORT OF WHAT 2346 01:28:23,131 --> 01:28:25,700 WE CALL PHYLA, THE BIGGER GROUPS 2347 01:28:25,767 --> 01:28:28,202 CAN BE QUITE SIMILAR, LIKE THE 2348 01:28:28,269 --> 01:28:34,108 RATIORAISH CARATIO CAN BE SIMILU 2349 01:28:34,175 --> 01:28:35,243 MIGHT HAVE DIFFERENT SUBSTRAINS 2350 01:28:35,309 --> 01:28:35,877 UNDERNEATH THAT. 2351 01:28:35,943 --> 01:28:40,682 SO TO GET AROUND THAT PROBLEM, 2352 01:28:40,748 --> 01:28:42,483 JULIO AT JACKSON LAB DESIGNED 2353 01:28:42,550 --> 01:28:44,752 THIS PROJECT WHERE WE, AGAIN, 2354 01:28:44,819 --> 01:28:47,155 TOOK FECAL SAMPLES THIS TIME 2355 01:28:47,221 --> 01:28:48,890 FROM EARLY, LATE ME/CFS 2356 01:28:48,956 --> 01:28:50,658 PATIENTS, AS WELL AS HEALTHY 2357 01:28:50,725 --> 01:28:52,527 CONTROLS, AND THEN WE SEQUENCED 2358 01:28:52,593 --> 01:28:55,363 ALL THESE BACTERIA IN THEIR 2359 01:28:55,430 --> 01:28:57,231 FECAL SAMPLES, WHICH KIND OF 2360 01:28:57,298 --> 01:29:03,905 REFLECTS WHAT'S IN THEIR GUT AND 2361 01:29:03,971 --> 01:29:05,206 PERFORMED A REALLY MASSIVE 2362 01:29:05,273 --> 01:29:06,140 ANALYSIS ON THAT. 2363 01:29:06,207 --> 01:29:07,809 THIS DATA WAS PUBLISHED 2364 01:29:07,875 --> 01:29:09,644 RECENTLY, WHICH I THINK IS 2365 01:29:09,711 --> 01:29:13,481 REALLY A FANTASTIC PAPER. 2366 01:29:13,548 --> 01:29:19,487 IT WAS BACK TO BACK WITH LIEN WN 2367 01:29:19,554 --> 01:29:20,788 LIPKIN'S GROUP WHICH CLEARLY 2368 01:29:20,855 --> 01:29:22,156 SHOWS THERE IS A MAJOR PROBLEM 2369 01:29:22,223 --> 01:29:23,458 IN THE MICROBIOME. 2370 01:29:23,524 --> 01:29:24,559 HOWEVER, GOING BACK TO OUR 2371 01:29:24,625 --> 01:29:28,329 PATIENT COHORTS, NOW WE REALIZED 2372 01:29:28,396 --> 01:29:32,366 THE WISDOM OF CINDY BAITMAN THAT 2373 01:29:32,433 --> 01:29:36,404 WE FOUND THAT THE MICROBIAL 2374 01:29:36,471 --> 01:29:37,271 DYSBIOSIS WAS HAPPENING MOSTLY 2375 01:29:37,338 --> 01:29:38,906 IN THE SHORT TERM ME/CFS 2376 01:29:38,973 --> 01:29:39,173 PATIENTS. 2377 01:29:39,240 --> 01:29:41,542 THIS WAS RATHER SURPRISING TO US 2378 01:29:41,609 --> 01:29:42,677 BECAUSE THE LONG TERM PATIENTS 2379 01:29:42,744 --> 01:29:45,613 CAN HAVE MORE SIGNIFICANT 2380 01:29:45,680 --> 01:29:50,351 SYMPTOMS AS WELL, AND THE GUT 2381 01:29:50,418 --> 01:29:51,552 MICROBIOME ON LONG TERM PATIENTS 2382 01:29:51,619 --> 01:29:52,587 WERE MORE SIMILAR TO CONTROLS 2383 01:29:52,653 --> 01:29:53,821 BUT THEY WERE NOT LIKE THE 2384 01:29:53,888 --> 01:29:54,922 HEALTHY CONTROLS BECAUSE THEY 2385 01:29:54,989 --> 01:29:59,527 ALSO HAD LOW ABUNDANCE OF 2386 01:29:59,594 --> 01:30:01,195 SPECIES AND DIFFERENCES IN THEIR 2387 01:30:01,262 --> 01:30:02,063 HETEROGENEITY. 2388 01:30:02,130 --> 01:30:03,164 HOWEVER, THEY WERE SORT OF NOT 2389 01:30:03,231 --> 01:30:07,201 AS BAD AS THE SHORT TERM ME/CFS 2390 01:30:07,268 --> 01:30:08,202 PATIENT MICROBIOME. 2391 01:30:08,269 --> 01:30:10,872 SO WHAT MIGHT BE GOING ON HERE? 2392 01:30:10,938 --> 01:30:12,573 AND SO I'M JUST GOING TO READ 2393 01:30:12,640 --> 01:30:14,542 THESE BECAUSE I THINK THESE ARE 2394 01:30:14,609 --> 01:30:15,743 VERY INTERESTING CONCLUSIONS 2395 01:30:15,810 --> 01:30:18,279 FROM THIS STUDY. 2396 01:30:18,346 --> 01:30:20,481 SO THE ABNORMALITIES IN SHORT 2397 01:30:20,548 --> 01:30:22,150 TERM COHORT COULD RESULT IN 2398 01:30:22,216 --> 01:30:29,457 POTENTIAL INCREASES IN ABERRANT 2399 01:30:29,524 --> 01:30:31,459 TRANSLOCATION OF MICROBIAL 2400 01:30:31,526 --> 01:30:32,827 METABOLITES THAT COULD AFFECT 2401 01:30:32,894 --> 01:30:34,495 HOST IMMUNE AND METABOLIC 2402 01:30:34,562 --> 01:30:35,363 PROCESSES. 2403 01:30:35,429 --> 01:30:38,566 IF THE IMMUNE ECOSYSTEM IS 2404 01:30:38,633 --> 01:30:42,603 PERTURBED, THAT COULD AFFECT 2405 01:30:42,670 --> 01:30:44,739 IMMUNE AND METABOLIC. 2406 01:30:44,806 --> 01:30:46,240 BUT WITHIN EXAMPLE IS THESE 2407 01:30:46,307 --> 01:30:53,981 SHORT CHAIN FATTY ACIDS SUCH AS 2408 01:30:54,048 --> 01:30:57,518 BUTYRATE AND TRYPTOPHAN 2409 01:30:57,585 --> 01:30:59,053 PRODUCERS. 2410 01:30:59,120 --> 01:31:02,657 IN SOME WAYS THE LONG TERM 2411 01:31:02,723 --> 01:31:04,525 PATIENT, THE DAMAGE HAS BEEN 2412 01:31:04,592 --> 01:31:06,060 DONE, SO THE PROGRESSION MAY 2413 01:31:06,127 --> 01:31:08,696 BEGIN WITH A LOSS OF BENEFICIAL 2414 01:31:08,763 --> 01:31:09,997 MICROBES, PARTICULARLY THESE 2415 01:31:10,064 --> 01:31:13,634 SHORT CHAIN FAT FATTY ACID PRODS 2416 01:31:13,701 --> 01:31:16,470 RESULTING IN MORE PERVASIVE GI 2417 01:31:16,537 --> 01:31:18,773 PHENOTYPES LATER REFLECTED IN 2418 01:31:18,840 --> 01:31:24,812 PLASMA METABOLITE LEVELS, THIS 2419 01:31:24,879 --> 01:31:26,581 IN TURN MAY LEAD TO MORE 2420 01:31:26,647 --> 01:31:28,683 ESTABLISHED METABOLIC AND 2421 01:31:28,749 --> 01:31:30,918 PHENOTYPIC CHANGES IN LONG TERM 2422 01:31:30,985 --> 01:31:32,253 ME/CFS PATIENTS. 2423 01:31:32,320 --> 01:31:33,354 THE DAMAGE HAS BEEN DONE, THE 2424 01:31:33,421 --> 01:31:36,524 DAMAGE HAS BEEN DONE THROUGH THE 2425 01:31:36,591 --> 01:31:37,625 METABOLISM, METABOLIC SYSTEM AND 2426 01:31:37,692 --> 01:31:40,795 THE I MEUP SYSTEM. 2427 01:31:40,862 --> 01:31:41,362 IMMUNE SYSTEM. 2428 01:31:41,429 --> 01:31:42,029 SO IS THAT THE CASE? 2429 01:31:42,096 --> 01:31:43,364 THAT COMES TO THE NEXT SPACE. 2430 01:31:43,431 --> 01:31:44,732 AND THE NEXT SPACE IS THE 2431 01:31:44,799 --> 01:31:45,099 METABOLISM. 2432 01:31:45,166 --> 01:31:46,767 THIS IS ACTUALLY A VERY BIG 2433 01:31:46,834 --> 01:31:47,201 SPACE. 2434 01:31:47,268 --> 01:31:48,469 THERE ARE THOUSANDS OF 2435 01:31:48,536 --> 01:31:49,370 METABOLITES THAT MOST OF THEM 2436 01:31:49,437 --> 01:31:53,107 ARE NOT EVEN IDENTIFIED YET. 2437 01:31:53,174 --> 01:31:54,642 I JUST MENTIONED SHORT CHAIN 2438 01:31:54,709 --> 01:31:58,179 FATTY ACIDS, THERE ARE ALL KINDS 2439 01:31:58,246 --> 01:31:59,347 OF METABOLITES THAT COME FROM 2440 01:31:59,413 --> 01:32:00,915 THE DIET THAT, COME FROM THE 2441 01:32:00,982 --> 01:32:02,583 BACTERIA, BUT ALSO PRODUCED BY 2442 01:32:02,650 --> 01:32:06,587 YOUR CELLS THAT ARE HAVING 2443 01:32:06,654 --> 01:32:09,757 DIFFERENT TYPES OF EFFECTS, FROM 2444 01:32:09,824 --> 01:32:12,193 BILE ACIDS TO LIPIDS, SUGARS AND 2445 01:32:12,260 --> 01:32:13,194 SO ON AND SO FORTH. 2446 01:32:13,261 --> 01:32:14,695 SO TO GET AROUND THAT PROBLEM IN 2447 01:32:14,762 --> 01:32:16,464 THIS FINAL SPACE, WE TOOK SORT 2448 01:32:16,530 --> 01:32:19,667 OF A SIMILAR APPROACH WHERE WE 2449 01:32:19,734 --> 01:32:21,302 TOOK THE PLASMA OF THE PATIENT 2450 01:32:21,369 --> 01:32:22,403 SAMPLES, THE SAME PATIENTS THAT 2451 01:32:22,470 --> 01:32:23,838 WE HAVE DONE THE IMMUNE 2452 01:32:23,905 --> 01:32:25,339 PROFILING WHERE WE HAD HUNDREDS 2453 01:32:25,406 --> 01:32:27,808 OF IMMUNE PROFILE DATA, WHERE WE 2454 01:32:27,875 --> 01:32:31,078 HAD THOUSANDS OF MICROBIAL 2455 01:32:31,145 --> 01:32:36,217 SPECIES IDENTIFIED, AND WE TRIED 2456 01:32:36,284 --> 01:32:37,685 TO IDENTIFY AS MANY METABOLITES 2457 01:32:37,752 --> 01:32:39,420 AS WE CAN. 2458 01:32:39,487 --> 01:32:42,623 WE DID THAT THROUGH A COMPANY 2459 01:32:42,690 --> 01:32:45,593 TALLED METABOLOME, WE THIS HAD 2460 01:32:45,660 --> 01:32:46,894 THOUSANDS OF METABOLITES THEY 2461 01:32:46,961 --> 01:32:47,328 COULD IDENTIFY. 2462 01:32:47,395 --> 01:32:49,096 THE REAL NUMBER IS PROBABLY MUCH 2463 01:32:49,163 --> 01:32:51,198 HIGHER THAN THAT, BUT THOSE WE 2464 01:32:51,265 --> 01:32:53,167 CAN SAY IN A REPRODUCIBLE 2465 01:32:53,234 --> 01:32:54,402 FASHION WE CAN IDENTIFY THEM AND 2466 01:32:54,468 --> 01:32:56,671 WE'VE PERFORMED THESE 2467 01:32:56,737 --> 01:32:58,005 METABOLOMICS ON ALL OF THESE 2468 01:32:58,072 --> 01:32:58,639 PATIENTS, SHORT TERM AND LONG 2469 01:32:58,706 --> 01:32:59,206 TERM. 2470 01:32:59,273 --> 01:33:01,509 AND AGAIN, WE FOUND LOTS OF 2471 01:33:01,575 --> 01:33:02,843 DIFFERENCES BETWEEN PATIENTS. 2472 01:33:02,910 --> 01:33:04,011 AND HEALTHY CONTROLS. 2473 01:33:04,078 --> 01:33:06,647 I'M JUST SHOWING YOU A VERY 2474 01:33:06,714 --> 01:33:08,416 SMALL EXAMPLE HERE. 2475 01:33:08,482 --> 01:33:09,951 I'LL SHOW YOU MORE DATA ON IT. 2476 01:33:10,017 --> 01:33:12,153 BUT AGAIN IMPORTANTLY, WE FOUND 2477 01:33:12,219 --> 01:33:13,354 DIFFERENCES BETWEEN THE SHORT 2478 01:33:13,421 --> 01:33:17,525 TERM AND THE LONG TERM PATIENTS. 2479 01:33:17,591 --> 01:33:18,993 SHORT TERM IN BLUE AND LONG TERM 2480 01:33:19,060 --> 01:33:19,927 IN RED. 2481 01:33:19,994 --> 01:33:23,130 YOU CAN SORT OF APPRECIATE THAT 2482 01:33:23,197 --> 01:33:25,766 THERE IS A BIGGER DIFFERENCE 2483 01:33:25,833 --> 01:33:26,901 BETWEEN THE LONG TERM PATIENTS 2484 01:33:26,968 --> 01:33:29,203 AND HEALTHY CONTROLS THAN THE 2485 01:33:29,270 --> 01:33:30,371 SHORT TERM AND THE HEALTHY 2486 01:33:30,438 --> 01:33:30,805 CONTROLS. 2487 01:33:30,871 --> 01:33:33,007 ALTHOUGH THERE WERE DIFFERENCES 2488 01:33:33,074 --> 01:33:34,742 IN BOTH GROUPS COMPARED TO THE 2489 01:33:34,809 --> 01:33:35,209 HEALTHY CONTROL. 2490 01:33:35,276 --> 01:33:36,010 OF COURSE THERE'S LIKE A 2491 01:33:36,077 --> 01:33:39,580 THOUSAND OF THESE, RIGHT? 2492 01:33:39,647 --> 01:33:40,581 SEVERAL HUNDRED OF THEM CAN BE 2493 01:33:40,648 --> 01:33:41,215 DIFFERENT FROM PATIENT TO 2494 01:33:41,282 --> 01:33:42,516 PATIENT, SO IT'S VERY DIFFICULT 2495 01:33:42,583 --> 01:33:46,087 TO LOOK AT THESE GRAPHS AND SAY 2496 01:33:46,153 --> 01:33:46,520 WHAT'S GOING ON. 2497 01:33:46,587 --> 01:33:48,255 YOU REALLY NEED TO SEE THE WHOLE 2498 01:33:48,322 --> 01:33:49,690 PICTURE, AND SORT OF THIS HEAT 2499 01:33:49,757 --> 01:33:53,227 MAP HELPS A BIT. 2500 01:33:53,294 --> 01:33:54,261 AGAIN, EACH OF THESE ARE 2501 01:33:54,328 --> 01:33:55,162 DIFFERENT METABOLITES. 2502 01:33:55,229 --> 01:33:56,897 YOU HAVE PATIENTS LESS THAN 2503 01:33:56,964 --> 01:33:58,799 4 YEARS, MORE THAN 10 YEARS, AND 2504 01:33:58,866 --> 01:33:59,667 HEALTHY CONTROLS. 2505 01:33:59,734 --> 01:34:02,670 YOU COULD SORT OF GET A FEEL 2506 01:34:02,737 --> 01:34:05,473 THAT IF YOU LOOK AT, FOR 2507 01:34:05,539 --> 01:34:08,576 EXAMPLE, XENOBIOTICS, THE 2508 01:34:08,642 --> 01:34:09,977 BACTERIA COMING FROM THE OUTSIDE 2509 01:34:10,044 --> 01:34:14,482 ARE MORE DIFFERENT IN THE LESS 2510 01:34:14,548 --> 01:34:16,484 THAN 4 YEAR GROUP THAN COMPARED 2511 01:34:16,550 --> 01:34:18,085 TO THE MORE THAN 10 YEAR GROUP, 2512 01:34:18,152 --> 01:34:19,420 BECAUSE THE MORE THAN 10 YEAR 2513 01:34:19,487 --> 01:34:20,388 GROUP SOMEWHAT LOOKS SIMILAR TO 2514 01:34:20,454 --> 01:34:22,556 THE HEALTHY CONTROL. 2515 01:34:22,623 --> 01:34:24,258 BUT THESE LOOK VERY DIFFERENT. 2516 01:34:24,325 --> 01:34:26,227 SO RED BECOMES BLUE, BLUE 2517 01:34:26,293 --> 01:34:28,963 BECOMES RED HERE. 2518 01:34:29,030 --> 01:34:30,364 IN THAT SORT OF DISEASE SCORE. 2519 01:34:30,431 --> 01:34:31,766 WHEREAS THE LIPIDS, IT'S THE 2520 01:34:31,832 --> 01:34:33,100 OTHER WAY AROUND, THAT YOU SEE 2521 01:34:33,167 --> 01:34:35,836 THAT THERE'S A BUNCH OF LIPIDS 2522 01:34:35,903 --> 01:34:37,805 THAT ARE SORT OF MORE DIFFERENT 2523 01:34:37,872 --> 01:34:39,340 IN MORE THAN 10 YEARS AND LESS 2524 01:34:39,407 --> 01:34:39,774 THAN 4 YEARS. 2525 01:34:39,840 --> 01:34:46,347 IN FACT, IN JULIO' O'S PAPER WE 2526 01:34:46,414 --> 01:34:47,148 HAD A HINT OF THAT. 2527 01:34:47,214 --> 01:34:48,949 WHEN YOU LOOK AT SEVERAL LIPIDS, 2528 01:34:49,016 --> 01:34:49,884 THERE WERE MORE DIFFERENTIAL 2529 01:34:49,950 --> 01:34:51,318 COUNTS OF LIPIDS IN THE LONG 2530 01:34:51,385 --> 01:34:53,054 TERM PATIENTS THAN THE SHORT 2531 01:34:53,120 --> 01:34:54,822 TERM PATIENTS, WHICH KIND OF 2532 01:34:54,889 --> 01:34:58,225 SUPPORTED THE HYPOTHESIS WE HAD 2533 01:34:58,292 --> 01:35:01,629 MADE IN THAT PAPER, THAT 2534 01:35:01,695 --> 01:35:03,464 SOMETHING IS GOING DIFFERENTLY. 2535 01:35:03,531 --> 01:35:04,799 BOTH PATIENT GROUPS ARE 2536 01:35:04,865 --> 01:35:08,436 DISRUPTED FOR THESE METABOLITES, 2537 01:35:08,502 --> 01:35:10,171 BUT THERE ARE MAJOR DIFFERENCES 2538 01:35:10,237 --> 01:35:11,439 BETWEEN THE SHORT TERM AND THE 2539 01:35:11,505 --> 01:35:12,406 LONG TERM PATIENTS. 2540 01:35:12,473 --> 01:35:14,375 SO THE NEXT QUESTION WAS, HOW DO 2541 01:35:14,442 --> 01:35:17,111 WE NOW START TO LINK THIS 2542 01:35:17,178 --> 01:35:17,978 TOGETHER? 2543 01:35:18,045 --> 01:35:19,547 SO YOU HAVE DIFFERENCES IN THE 2544 01:35:19,613 --> 01:35:21,382 IMMUNE SYSTEM, IN THE 2545 01:35:21,449 --> 01:35:21,682 METABOLISM. 2546 01:35:21,749 --> 01:35:23,217 HOW DO WE BRING THOSE TWO SPACES 2547 01:35:23,284 --> 01:35:23,651 TOGETHER? 2548 01:35:23,717 --> 01:35:28,422 SO WE STARTED TO DO THAT AND 2549 01:35:28,489 --> 01:35:29,824 THEY'VE DONE REALLY PHENOMENAL 2550 01:35:29,890 --> 01:35:30,357 WORK ON THIS. 2551 01:35:30,424 --> 01:35:32,359 WE'RE JUST PREPARING A PAPER TO 2552 01:35:32,426 --> 01:35:34,028 SUBMIT, THAT HE WAS ABLE TO LINK 2553 01:35:34,095 --> 01:35:39,600 A VARIETY OF IMMUNE SUBSETS TO 2554 01:35:39,667 --> 01:35:40,568 DIFFERENT METABOLITES THAT ARE 2555 01:35:40,634 --> 01:35:41,402 FOUND IN THE BLOOD. 2556 01:35:41,469 --> 01:35:44,438 OBVIOUSLY THIS IS A VERY 2557 01:35:44,505 --> 01:35:47,842 COMPUTATIONALLY RICH AND INTENSE 2558 01:35:47,908 --> 01:35:50,644 ANALYSIS, AND HE WAS ABLE TO 2559 01:35:50,711 --> 01:35:53,981 COME UP WITH MANY DIFFERENT 2560 01:35:54,048 --> 01:35:56,550 SUBPOPULATIONS, EACH OF WHICH 2561 01:35:56,617 --> 01:35:58,552 LINK TO DIFFERENT METABOLITES IN 2562 01:35:58,619 --> 01:36:00,187 THE SAME PATIENTS' BLOOD. 2563 01:36:00,254 --> 01:36:01,455 WHAT WAS INTERESTING IS THAT IN 2564 01:36:01,522 --> 01:36:04,091 HEALTHY CONTROLS, THERE WAS MUCH 2565 01:36:04,158 --> 01:36:05,392 FEWER ASSOCIATION, SO THERE 2566 01:36:05,459 --> 01:36:08,295 SEEMS TO BE MUCH GREATER 2567 01:36:08,362 --> 01:36:10,598 ASSOCIATION BETWEEN METABOLIC 2568 01:36:10,664 --> 01:36:14,969 PER TURBANS AND IMMUNE CELL 2569 01:36:15,035 --> 01:36:18,139 FREQUENCIES OR FUNCTIONALITY IN 2570 01:36:18,205 --> 01:36:19,740 THE PATIENT POPULATION. 2571 01:36:19,807 --> 01:36:22,810 SO THAT WAS VERY SATISFYING. 2572 01:36:22,877 --> 01:36:24,311 WE THINK THIS IS PROBABLY ONE OF 2573 01:36:24,378 --> 01:36:29,416 THE FIRST SUCH DATASETS EVER TO 2574 01:36:29,483 --> 01:36:31,585 BE GRADED AT LEAST AT THIS SCALE 2575 01:36:31,652 --> 01:36:33,687 BECAUSE IT ALSO GIVES YOU WAYS 2576 01:36:33,754 --> 01:36:35,089 TO HYPOTHESIZE OR IDENTIFY SOME 2577 01:36:35,156 --> 01:36:39,793 NEW PATHWAYS, HOW ONE METABOLITE 2578 01:36:39,860 --> 01:36:40,694 MIGHT LINK TO A PARTICULAR 2579 01:36:40,761 --> 01:36:41,795 POPULATION AND WHAT THAT MIGHT 2580 01:36:41,862 --> 01:36:43,531 MEAN AS ACTIONABLE TARGETS, 2581 01:36:43,597 --> 01:36:45,132 WHICH I WILL COME AT THE VERY 2582 01:36:45,199 --> 01:36:45,533 END. 2583 01:36:45,599 --> 01:36:46,000 OKAY. 2584 01:36:46,066 --> 01:36:50,371 SO THIS IS ALL GREAT BUT NOW WE 2585 01:36:50,437 --> 01:36:51,839 WANTED TO LINK EVERYTHING. 2586 01:36:51,906 --> 01:36:53,374 SO WE WANT ALL THESE DIFFERENT 2587 01:36:53,440 --> 01:36:55,309 SPACES, THE SYMPTOMS, 2588 01:36:55,376 --> 01:36:57,011 METABOLISM, MICROBIOME, IMMUNE 2589 01:36:57,077 --> 01:36:58,779 SPACES, ALL TOPICOLOGICALLY 2590 01:36:58,846 --> 01:36:59,146 LINKED TOGETHER. 2591 01:36:59,213 --> 01:37:02,683 SO OBVIOUSLY A HUMAN MIND CANNOT 2592 01:37:02,750 --> 01:37:06,220 POSSIBLY DO THAT SO WE TURNED TO 2593 01:37:06,287 --> 01:37:06,720 A.I. 2594 01:37:06,787 --> 01:37:07,655 WE ARE FORTUNATE IN THE RECENT 2595 01:37:07,721 --> 01:37:09,523 YEARS, THERE'S BEEN TREMENDOUS 2596 01:37:09,590 --> 01:37:11,192 ADVANCE ESPECIALLY IN THE DEEP 2597 01:37:11,258 --> 01:37:16,430 LEARNING, SO AGAIN, JULIO AT 2598 01:37:16,497 --> 01:37:20,501 JAX, SHE APPLIED THIS A.I. 2599 01:37:20,568 --> 01:37:21,268 ANALYSIS. 2600 01:37:21,335 --> 01:37:25,105 AGAIN, A PAPER THAT'S IN 2601 01:37:25,172 --> 01:37:26,340 PREPARATION. 2602 01:37:26,407 --> 01:37:28,509 WHERE IN A VERY SIMILAR PUSH TO 2603 01:37:28,576 --> 01:37:30,411 DEEP LEARNING WITH NEURAL 2604 01:37:30,477 --> 01:37:32,580 NETWORKS, WE UPLOADED THESE 2605 01:37:32,646 --> 01:37:34,248 DIFFERENT IMMUNE DATASETS, SOME 2606 01:37:34,315 --> 01:37:37,218 OF WHICH WAS ALREADY IN THE 2607 01:37:37,284 --> 01:37:38,752 DATABASES, BUT MOST OF IT IS OUR 2608 01:37:38,819 --> 01:37:40,588 DATA BECAUSE WE USE THE PREVIOUS 2609 01:37:40,654 --> 01:37:43,991 DATA TO SORT OF VALIDATE WHAT 2610 01:37:44,058 --> 01:37:45,125 WE'RE FINDING OR TRAIN THE SETS 2611 01:37:45,192 --> 01:37:49,964 AS THEY WOULD CALL IN THE A.I. 2612 01:37:50,030 --> 01:37:52,833 FIELD AND SEE WHAT WOULD COME 2613 01:37:52,900 --> 01:37:53,534 UP. 2614 01:37:53,601 --> 01:37:55,102 SO I'M REALLY VERY EXCITED ABOUT 2615 01:37:55,169 --> 01:37:57,271 THIS BECAUSE THIS REALLY SORT OF 2616 01:37:57,338 --> 01:37:59,573 WAS OUR DREAM WHEN WE STARTED 2617 01:37:59,640 --> 01:38:02,576 THIS PROJECT SIX YEARS AGO, THAT 2618 01:38:02,643 --> 01:38:03,978 WE WILL BE ABLE TO SOMEHOW BRING 2619 01:38:04,044 --> 01:38:05,946 TOGETHER THIS MASSIVE DATASETS 2620 01:38:06,013 --> 01:38:08,115 TOGETHER AND LINK THEM AT 2621 01:38:08,182 --> 01:38:10,918 DIFFERENT SPACES, BUT WE DIDN'T 2622 01:38:10,985 --> 01:38:12,319 KNOW HOW WE'D BE ABLE TO DO IT, 2623 01:38:12,386 --> 01:38:17,124 YOU KNOW, LOOKING FORWARD TO 2624 01:38:17,191 --> 01:38:18,425 FIVE YEARS OR SIX YEARS IN 2625 01:38:18,492 --> 01:38:18,826 ADVANCE. 2626 01:38:18,892 --> 01:38:20,894 BUT THE A.I.-DRIVEN APPROACH 2627 01:38:20,961 --> 01:38:22,997 REALLY ENABLES THIS BECAUSE IT 2628 01:38:23,063 --> 01:38:27,701 ALLOWS YOU, VERY ROBUST 2629 01:38:27,768 --> 01:38:29,236 ASSOCIATIONS, DEEP INTEGRATIONS, 2630 01:38:29,303 --> 01:38:31,538 AND ALLOWS YOU TO MAKE 2631 01:38:31,605 --> 01:38:32,573 HYPOTHESES, WHICH I THINK IS 2632 01:38:32,640 --> 01:38:36,610 VERY, VERY IMPORTANT, AND ALSO 2633 01:38:36,677 --> 01:38:38,579 OBVIOUSLY PREDICT DISEASE 2634 01:38:38,646 --> 01:38:39,747 BIOMARKERS, CLINICAL PHENOTYPES, 2635 01:38:39,813 --> 01:38:44,084 BECAUSE THE MORE RICH TH THE DAA 2636 01:38:44,151 --> 01:38:45,519 IS FROM DIFFERENT SPACES, THE 2637 01:38:45,586 --> 01:38:46,754 BETTER YOUR BIOMARKERS ARE GOING 2638 01:38:46,820 --> 01:38:48,289 TO BE, AND REALLY, MAYBE THE 2639 01:38:48,355 --> 01:38:50,391 MOST IMPORTANT IS THIS LAST 2640 01:38:50,457 --> 01:38:52,126 POINT, ADDRESS THE HETEROGENEITY 2641 01:38:52,192 --> 01:38:54,428 OF THIS SUCH COMPLEX DISEASE. 2642 01:38:54,495 --> 01:38:56,830 OBVIOUSLY NOT EVERY ME/CFS 2643 01:38:56,897 --> 01:38:58,465 PATIENTS HAVE THE SAME PROBLEM. 2644 01:38:58,532 --> 01:38:59,700 THEY HAVE DIFFERENT PROBLEMS. 2645 01:38:59,767 --> 01:39:01,035 IT MIGHT BE DUE TO THE AGE. 2646 01:39:01,101 --> 01:39:02,970 I JUST SHOWED YOU LESS THAN FOUR 2647 01:39:03,037 --> 01:39:04,071 YEARS, MORE THAN 10 YEARS 2648 01:39:04,138 --> 01:39:05,539 ALREADY HAVE HUGE DIFFERENCES 2649 01:39:05,606 --> 01:39:08,942 BETWEEN THEM, EVEN WITHIN THOSE 2650 01:39:09,009 --> 01:39:10,044 GROUPS, THERE ARE OBVIOUSLY 2651 01:39:10,110 --> 01:39:13,147 MANY, MANY DIFFERENCES. 2652 01:39:13,213 --> 01:39:14,982 SO THIS MIGHT BE THE MOST 2653 01:39:15,049 --> 01:39:15,549 EXCITING SLIDE. 2654 01:39:15,616 --> 01:39:19,620 SO WE WERE ABLE TO DO THIS DEEP 2655 01:39:19,687 --> 01:39:23,991 ME/CFS AND REALLY LINK THE 2656 01:39:24,058 --> 01:39:25,993 MICROBIOME, THE METABALOME AND 2657 01:39:26,060 --> 01:39:28,896 THE IMMUNE CELLS ACROSS THESE 2658 01:39:28,962 --> 01:39:30,564 SPACES. 2659 01:39:30,631 --> 01:39:32,766 I WON'T GO INTO DETAILS, THE 2660 01:39:32,833 --> 01:39:34,101 PAPER IS IN PREPARATION, BUT WE 2661 01:39:34,168 --> 01:39:35,969 COULD DO THAT, WE CAN CREATE 2662 01:39:36,036 --> 01:39:39,707 THESE SIGNATURES OF TOPOLOGICAL 2663 01:39:39,773 --> 01:39:43,777 ANALYSIS FOSH ME/ FOR ME/CFS VES 2664 01:39:43,844 --> 01:39:44,511 HEALTHY DONORS. 2665 01:39:44,578 --> 01:39:46,013 NOT EVEN THAT, WE CAN ACTUALLY 2666 01:39:46,080 --> 01:39:47,581 GO EVEN DEEPER, WE CAN LOOK AT 2667 01:39:47,648 --> 01:39:48,816 THE MALE PATIENTS, THE ELDERLY, 2668 01:39:48,882 --> 01:39:50,250 THOSE WHO HAD INFECTION, THOSE 2669 01:39:50,317 --> 01:39:55,656 WHO HAD LONG COVID OR PART OF 2670 01:39:55,723 --> 01:39:56,790 LONG DISEASE OR SHORT DISEASE, 2671 01:39:56,857 --> 01:39:58,926 WE ALSO HAVE LONG COVID AS WELL, 2672 01:39:58,992 --> 01:40:00,194 FEMALE, SO ON AND SO FORTH. 2673 01:40:00,260 --> 01:40:02,796 AND THEN YOU CAN EVEN GO 2674 01:40:02,863 --> 01:40:05,099 EVENTUALLY AT THIS SINGLE-PERSON 2675 01:40:05,165 --> 01:40:06,100 INDIVIDUAL LEVEL, WHICH WOULD BE 2676 01:40:06,166 --> 01:40:08,969 SORT OF THE HOLY GRAIL OF 2677 01:40:09,036 --> 01:40:10,104 PERSONALIZED PRECISION MEDICINE, 2678 01:40:10,170 --> 01:40:12,172 I GUESS. 2679 01:40:12,239 --> 01:40:14,441 SO FINALLY, I JUST WANT TO SHOW 2680 01:40:14,508 --> 01:40:16,577 YOU ONE VERY IMPORTANT SLIDE, 2681 01:40:16,643 --> 01:40:19,413 WHERE USING THIS DEEP ME/CFS 2682 01:40:19,480 --> 01:40:23,117 ANALYSIS, WE WERE ABLE TO 2683 01:40:23,183 --> 01:40:25,452 IDENTIFY OR CONFIRM -- REMEMBER 2684 01:40:25,519 --> 01:40:29,289 I MENTIONED TO YOU ABOUT THIS 2685 01:40:29,356 --> 01:40:30,924 BUTYRATE AND TRYPTOPHAN BEING 2686 01:40:30,991 --> 01:40:32,926 DISRUPTED IN THE MICROBIOME 2687 01:40:32,993 --> 01:40:34,128 PATHWAY, BUT THIS TIME WE 2688 01:40:34,194 --> 01:40:35,229 ACTUALLY BROUGHT ALL THE DATA 2689 01:40:35,295 --> 01:40:36,630 TOGETHER, AND WE WERE ABLE TO 2690 01:40:36,697 --> 01:40:38,532 LINK DIFFERENT SUBPOPULATIONS OF 2691 01:40:38,599 --> 01:40:40,634 IMMUNE CELLS, DIFFERENT 2692 01:40:40,701 --> 01:40:43,070 METABOLITES, MICROBIOME, SHORT, 2693 01:40:43,137 --> 01:40:46,573 LONG TERM, AND ACTUALLY CONFIRM 2694 01:40:46,640 --> 01:40:50,277 THAT THE BUTYRATE AND TRYPTOPHAN 2695 01:40:50,344 --> 01:40:51,612 WERE RELEVANT TARGETS. 2696 01:40:51,678 --> 01:40:52,746 IT WAS NOT JUST A BYSTANDER 2697 01:40:52,813 --> 01:40:53,947 EFFECT OR RANDOM EFFECT, THAT 2698 01:40:54,014 --> 01:40:55,916 THERE WAS A MECHANISTIC LINK 2699 01:40:55,983 --> 01:40:56,850 BETWEEN THESE POPULATIONS. 2700 01:40:56,917 --> 01:40:59,453 AND IN FACT, WE KNEW THAT 2701 01:40:59,520 --> 01:41:00,988 BUTYRATE AND TRYPTOPHAN AFFECTS 2702 01:41:01,054 --> 01:41:04,358 THE IMMUNE SYSTEM TREMENDOUSLY, 2703 01:41:04,425 --> 01:41:06,427 THESE TH17 CELLS THAT I SHOWED 2704 01:41:06,493 --> 01:41:07,628 YOU, BUT FOR THE FIRST TIME, WE 2705 01:41:07,694 --> 01:41:09,997 WERE ABLE TO SEE THAT BY 2706 01:41:10,063 --> 01:41:11,832 BRINGING ALL THIS DATA TOGETHER, 2707 01:41:11,899 --> 01:41:13,167 OBVIOUSLY THIS IS KIND OF A GOLD 2708 01:41:13,233 --> 01:41:14,735 MINE WHERE WE COULD HOPEFULLY 2709 01:41:14,802 --> 01:41:15,836 IDENTIFY OTHER ACTIONABLE 2710 01:41:15,903 --> 01:41:18,472 TARGETS THAT COULD BE IMPORTANT 2711 01:41:18,539 --> 01:41:21,175 FOR THERAPEUTICS. 2712 01:41:21,241 --> 01:41:23,710 SO I'M GOING TO STOP THERE AND 2713 01:41:23,777 --> 01:41:26,713 REALLY CITE ALL THE PEOPLE WHO 2714 01:41:26,780 --> 01:41:28,348 DID THE WORK. 2715 01:41:28,415 --> 01:41:30,517 MY TEAM AT JAX, WE WERE 2716 01:41:30,584 --> 01:41:33,187 RESPONSIBLE FOR THE IMMUNE 2717 01:41:33,253 --> 01:41:33,620 SYSTEM. 2718 01:41:33,687 --> 01:41:34,621 WE COULDN'T DO ANY OF THIS 2719 01:41:34,688 --> 01:41:37,491 WITHOUT THE CLINICAL TEAM. 2720 01:41:37,558 --> 01:41:39,560 CINDY BAITMAN AND SUZANNE 2721 01:41:39,626 --> 01:41:42,095 VERNON, WHO PROVIDED ALL OF THE 2722 01:41:42,162 --> 01:41:43,997 SAMPLES AND THE QUALITY OF THE 2723 01:41:44,064 --> 01:41:44,998 SAMPLES WAS SO IMPORTANT BECAUSE 2724 01:41:45,065 --> 01:41:47,601 THEY HAD TO BE REALLY WELL 2725 01:41:47,668 --> 01:41:51,672 DIAGNOSED AND I THINK THAT MADE 2726 01:41:51,738 --> 01:41:53,106 THE QUALITY OF THE DATA 2727 01:41:53,173 --> 01:41:53,774 TREMENDOUSLY BETTER. 2728 01:41:53,841 --> 01:41:56,243 WE REALLY ARE GRATEFUL TO THEM. 2729 01:41:56,310 --> 01:41:58,946 JULIA OH, WHO'S A STAR IN THE 2730 01:41:59,012 --> 01:42:01,415 MICROBIOME FIELD, DID ALL THE 2731 01:42:01,482 --> 01:42:06,987 MICROBIOME WORK AND A.I. WORK. 2732 01:42:07,054 --> 01:42:11,692 SHUZHAO LI DID ALL THE 2733 01:42:11,758 --> 01:42:13,727 METABOLOMICS. 2734 01:42:13,794 --> 01:42:19,166 XUDO -- IDENTIFICATION OF THE 2735 01:42:19,233 --> 01:42:19,766 MICROBIOME FROM THE PATIENTS. 2736 01:42:19,833 --> 01:42:20,667 OF COURSE I WANT TO ACKNOWLEDGE 2737 01:42:20,734 --> 01:42:26,907 ALL OUR FUNDING SOURCE, NIH, 2738 01:42:26,974 --> 01:42:28,141 NINDS AND NIAID. 2739 01:42:28,208 --> 01:42:28,408 THANK YOU. 2740 01:42:28,475 --> 01:42:38,652 [APPLAUSE] 2741 01:42:42,289 --> 01:42:45,025 >> HELLO. I HAD A COMMENT TO 2742 01:42:45,092 --> 01:42:45,225 MAKE. 2743 01:42:45,292 --> 01:42:47,628 >> I CAN BARELY HEAR YOU. 2744 01:42:47,694 --> 01:42:51,698 >> WITH ADEQUATE EFFORT, ONE 2745 01:42:51,765 --> 01:42:54,101 CAN -- DAMAGING VIRUSES FROM 2746 01:42:54,167 --> 01:42:56,537 CHRONIC FATIGUE SYNDROME 2747 01:42:56,603 --> 01:42:56,870 PATIENTS. 2748 01:42:56,937 --> 01:42:59,072 WE'VE DONE THAT, AND THE BEST 2749 01:42:59,139 --> 01:43:00,073 CHARACTERIZED VIRUS HAS THE 2750 01:43:00,140 --> 01:43:01,008 INTERESTING ASPECT THAT -- 2751 01:43:01,074 --> 01:43:02,409 >> I STILL CAN'T HEAR YOU. 2752 01:43:02,476 --> 01:43:03,644 CAN YOU GET CLOSER TO THE 2753 01:43:03,710 --> 01:43:04,711 MICROPHONE? 2754 01:43:04,778 --> 01:43:04,912 SORRY. 2755 01:43:04,978 --> 01:43:08,181 >> I'LL SPEAK AS LOUD AS I CAN. 2756 01:43:08,248 --> 01:43:11,985 SO WHAT WE'VE GOT IS DNA 2757 01:43:12,052 --> 01:43:16,723 SEQUENCED DATA OF A VIRUS 2758 01:43:16,790 --> 01:43:17,791 REPEATEDLY CULTURED FROM A 2759 01:43:17,858 --> 01:43:20,961 CHRONIC FATIGUE SYNDROME PATI 2760 01:43:21,028 --> 01:43:21,194 PATIENT. 2761 01:43:21,261 --> 01:43:25,132 WE'VE CLONED THAT, AND OF 249 2762 01:43:25,198 --> 01:43:29,836 CLONES, WHAT'S FASCINATING, 34 2763 01:43:29,903 --> 01:43:31,838 OF THE CLONES HAVE BACTERIAL 2764 01:43:31,905 --> 01:43:32,606 SEQUENCES. 2765 01:43:32,673 --> 01:43:35,909 THE BACTERIAL SEQUENCES ARE NOT 2766 01:43:35,976 --> 01:43:37,678 REPRESENTED IN ORDINARY 2767 01:43:37,744 --> 01:43:40,447 BACTERIAS, EXCEPT FOR MYCOPLASMA 2768 01:43:40,514 --> 01:43:42,549 FER MEN TINS THAT HAD BEEN 2769 01:43:42,616 --> 01:43:46,386 LINKED AS A POSSIBLE CO-FACTOR. 2770 01:43:46,453 --> 01:43:50,324 BUT THE OTHER ONES ARE ALSO 2771 01:43:50,390 --> 01:43:54,194 BASICALLY ALPHA PROTEOBACTERIA 2772 01:43:54,261 --> 01:43:55,829 WITH NUCLEOTIDE PLASMID, THERE'S 2773 01:43:55,896 --> 01:43:57,998 STILL NO DIRECT MATCHING ON GEN 2774 01:43:58,065 --> 01:44:01,134 BANK, BUT WHAT THIS IMPLIES 2775 01:44:01,201 --> 01:44:02,769 IMPORTANTLY, THE ATYPICAL 2776 01:44:02,836 --> 01:44:05,072 VIRUSES THAT INFECT CHRONIC 2777 01:44:05,138 --> 01:44:07,608 FATIGUE SYNDROME PATIENTS, WHICH 2778 01:44:07,674 --> 01:44:09,810 I REFER TO AS STEALTH ADAPTED 2779 01:44:09,876 --> 01:44:12,112 VIRUSES, BECAUSE IN THE 2780 01:44:12,179 --> 01:44:14,514 SEQUENCING, THEY'VE LOST OR 2781 01:44:14,581 --> 01:44:19,252 MUTATED THE GENES, COATI CODINGR 2782 01:44:19,319 --> 01:44:22,556 THE RELATIVELY FEW TARGETS, THE 2783 01:44:22,623 --> 01:44:23,890 IMMUNE SYSTEM IS TAKEN AWAY FROM 2784 01:44:23,957 --> 01:44:25,459 THE EQUATION, AT LEAST THE 2785 01:44:25,525 --> 01:44:26,860 CELLULAR IMMUNE SYSTEM. 2786 01:44:26,927 --> 01:44:31,064 WHERE THE VIRUS REGAINS ITS 2787 01:44:31,131 --> 01:44:34,501 INFECTIVITY IS PICKING UP 2788 01:44:34,568 --> 01:44:35,669 ADDITIONAL SEQUENCES. 2789 01:44:35,736 --> 01:44:37,304 THEY CAN PICK THEM UP FROM THE 2790 01:44:37,371 --> 01:44:38,305 CELLULAR GENOME OR THEY CAN PICK 2791 01:44:38,372 --> 01:44:40,107 THEM UP FROM OTHER MICROBES. 2792 01:44:40,173 --> 01:44:41,441 THE FACT THAT THEY CAN PICK THEM 2793 01:44:41,508 --> 01:44:46,647 UP FROM BACTERIAL SPECIES 2794 01:44:46,713 --> 01:44:50,651 IMPLIES THAT THESE VIRUSES CAN 2795 01:44:50,717 --> 01:44:52,653 ACTUALLY INFECT THE BACTERIA. 2796 01:44:52,719 --> 01:44:55,522 AND WE KNOW THAT IF VIRUSES 2797 01:44:55,589 --> 01:44:57,924 BECOME SIMPLE ENOUGH, THEY 2798 01:44:57,991 --> 01:44:59,559 BECOME LIKE PLASMIDS AND THEY 2799 01:44:59,626 --> 01:45:01,428 CAN INFECT BACTERIA. 2800 01:45:01,495 --> 01:45:05,432 SO THE ALTERED MICROBIOME YOU'RE 2801 01:45:05,499 --> 01:45:06,433 IDENTIFYING IN THESE PATIENTS 2802 01:45:06,500 --> 01:45:11,471 COULD BE A RESULT OF VIRUS 2803 01:45:11,538 --> 01:45:13,306 INFECTION INTO THE BACTERIA. 2804 01:45:13,373 --> 01:45:16,176 WHAT THIS IS HUGELY IMPORTANT 2805 01:45:16,243 --> 01:45:19,112 FOR, EVEN THOUGH THE BACTERIA 2806 01:45:19,179 --> 01:45:22,249 WERE IDENTIFIED, PROTEOBACTERIA 2807 01:45:22,315 --> 01:45:23,684 AND OTHER UNUSUAL BACTERIA, WHEN 2808 01:45:23,750 --> 01:45:26,620 YOU HAVE ILLNESSES LIKE CHRONIC 2809 01:45:26,687 --> 01:45:29,322 LYME DISEASE, IT'S PERFECTLY 2810 01:45:29,389 --> 01:45:33,660 CONSISTENT WB THE FACT THAT THEY 2811 01:45:33,727 --> 01:45:35,395 HAVE THESE STEALTH-ADAPTED 2812 01:45:35,462 --> 01:45:41,368 VIRUSES BUT IN A CELL THAT HAS 2813 01:45:41,435 --> 01:45:43,070 BARILLIA INVOLVED IN THE SAME 2814 01:45:43,136 --> 01:45:46,573 CELL, THE VIRUS CAN ACQUIRE SOME 2815 01:45:46,640 --> 01:45:49,309 BARILLIA VIRUS. 2816 01:45:49,376 --> 01:45:51,311 PEOPLE ARE IDENTIFYING 2817 01:45:51,378 --> 01:45:52,045 STREPTOCOCCAL TYPE GENES -- 2818 01:45:52,112 --> 01:45:52,946 >> DO YOU HAVE A QUESTION 2819 01:45:53,013 --> 01:45:53,647 BECAUSE I THINK -- 2820 01:45:53,714 --> 01:45:56,349 >> NO, THE QUESTION WAS 2821 01:45:56,416 --> 01:45:58,652 BASICALLY, I GUESS -- THE 2822 01:45:58,719 --> 01:46:00,454 COMMENT, PLEASE CONSIDER THE 2823 01:46:00,520 --> 01:46:03,590 FACT THAT THE ALTERED MICROBIOME 2824 01:46:03,657 --> 01:46:07,728 IS A SECONDARY EFFECT OF STEALTH 2825 01:46:07,794 --> 01:46:10,163 ADAPTED VIRUS INFECTION, AND 2826 01:46:10,230 --> 01:46:11,798 PLEASE CONSIDER THAT IN TERMS OF 2827 01:46:11,865 --> 01:46:13,867 NOT YOUR OWN WORK BUT THE OTHER 2828 01:46:13,934 --> 01:46:16,536 PEOPLE'S WORK IN TERMS OF THE 2829 01:46:16,603 --> 01:46:19,840 TRANSMISSION OF THESE ATYPICAL 2830 01:46:19,906 --> 01:46:21,441 VIRUSES BECAUSE IF THEY ARE 2831 01:46:21,508 --> 01:46:25,011 INFECTING BACTERIA, THAT POSES A 2832 01:46:25,078 --> 01:46:28,181 TOTALLY NEW UNDERSTANDING OF HOW 2833 01:46:28,248 --> 01:46:30,951 THE DISEASE COULD BE TRANSMI 2834 01:46:31,017 --> 01:46:31,251 TRANSMITTED. 2835 01:46:31,318 --> 01:46:32,686 THANK YOU FOR YOUR TALK. 2836 01:46:32,753 --> 01:46:33,420 >> I APPRECIATE THAT. 2837 01:46:33,487 --> 01:46:35,355 I MEAN, THERE'S OBVIOUSLY A 2838 01:46:35,422 --> 01:46:39,659 WHOLE UNIVERSE OF PHAGES THAT 2839 01:46:39,726 --> 01:46:41,094 INFECT THESE BACTERIA AND WE 2840 01:46:41,161 --> 01:46:42,529 DON'T KNOW MUCH ABOUT THEM, BUT 2841 01:46:42,596 --> 01:46:43,830 I'M NOT THE VIRUS EXPERT AND 2842 01:46:43,897 --> 01:46:45,766 MAYBE THE NEXT SPEAKER CAN 2843 01:46:45,832 --> 01:46:46,166 RESPOND TO THAT. 2844 01:46:46,233 --> 01:46:50,804 THANK YOU. 2845 01:46:50,871 --> 01:46:54,374 >> SO I THINK IF WERE YOU A COME 2846 01:46:54,441 --> 01:46:56,076 POSER, I WOULD CALL THAT AN 2847 01:46:56,143 --> 01:46:56,643 OPUS. 2848 01:46:56,710 --> 01:46:58,044 WHAT GREAT WORK, FAN TAS FICK 2849 01:46:58,111 --> 01:46:58,678 WORK. 2850 01:46:58,745 --> 01:46:59,279 CONGRATULATIONS. 2851 01:46:59,346 --> 01:47:00,480 I'M GOING TO HAVE TO BE NARROW 2852 01:47:00,547 --> 01:47:02,015 BECAUSE THERE WAS SO MUCH TO 2853 01:47:02,082 --> 01:47:05,185 ADDRESS THERE AND I HAVE NO MANY 2854 01:47:05,252 --> 01:47:06,219 QUESTIONS, BUT THERE'S BEEN SOME 2855 01:47:06,286 --> 01:47:08,555 WORK IN SONIA MARSHAL'S GROUP, 2856 01:47:08,622 --> 01:47:09,856 OUR GROUP REALLY, REALLY EARLY 2857 01:47:09,923 --> 01:47:13,627 THAT SUGGESTED THAT TO USE THE 2858 01:47:13,693 --> 01:47:16,997 MARKER -- USE THE INTRACELLULAR 2859 01:47:17,063 --> 01:47:18,431 GZA CONTENT, NOT ALL THE 2860 01:47:18,498 --> 01:47:21,101 BEAUTIFUL WORK SINCE THEN THAT 2861 01:47:21,168 --> 01:47:27,641 HAD SINGLE CELL GENOMICS, BUT 2862 01:47:27,707 --> 01:47:28,742 RATHER USING THE ACTUAL CONTENT 2863 01:47:28,809 --> 01:47:31,144 OF FLOW CYTOMETRY TO PREDICT THE 2864 01:47:31,211 --> 01:47:32,913 FUNCTION OF THE CYTOTOXIC T-CELL 2865 01:47:32,979 --> 01:47:35,715 AS WELL AS THE NK CELL, SOME 2866 01:47:35,782 --> 01:47:37,751 WORK SAYS THEY'RE BOTH BROKEN 2867 01:47:37,818 --> 01:47:40,053 AND IT'S NOT JUST NK CELLS, VERY 2868 01:47:40,120 --> 01:47:42,022 IMPORTANT I THINK OBSERVATION TO 2869 01:47:42,088 --> 01:47:45,659 UNDERSTAND SOME OF THE VIRAL 2870 01:47:45,725 --> 01:47:46,693 THINGS CONSIDERING AS WELL AS 2871 01:47:46,760 --> 01:47:46,927 OTHERS. 2872 01:47:46,993 --> 01:47:48,128 SO I'M WONDERING IN YOUR WORK, 2873 01:47:48,195 --> 01:47:50,096 THE WAY YOU APPROACHED IT, WILL 2874 01:47:50,163 --> 01:47:53,200 YOU BE ABLE TO TELL US WHETHER 2875 01:47:53,266 --> 01:47:55,535 OR NOT THERE WAS A QUANTITATIVE 2876 01:47:55,602 --> 01:47:58,271 DIFFERENCE IN PREFERENCING 2877 01:47:58,338 --> 01:48:01,975 GRANZYMES, AND WHAT YOU THINK IS 2878 01:48:02,042 --> 01:48:03,176 GOING ON THERE. 2879 01:48:03,243 --> 01:48:04,177 WE WERE THINKING IT WAS 2880 01:48:04,244 --> 01:48:05,512 EXHAUSTION, USING IT UP, NOT 2881 01:48:05,579 --> 01:48:06,146 NECESSARILY THAT YOU WEREN'T 2882 01:48:06,213 --> 01:48:06,813 MAKING IT. 2883 01:48:06,880 --> 01:48:07,814 BUT THAT'S HYPOTHESIS. 2884 01:48:07,881 --> 01:48:08,915 >> DEFINITELY. 2885 01:48:08,982 --> 01:48:11,351 IN FACT, GRANZYME A ESPECIALLY 2886 01:48:11,418 --> 01:48:14,421 BUT ALSO B WERE SOME OF THE 2887 01:48:14,487 --> 01:48:15,989 MAJOR DIFFERENCES THAT WE FOUND, 2888 01:48:16,056 --> 01:48:17,657 BOTH IN MAI T CELLS THAT I 2889 01:48:17,724 --> 01:48:19,993 SHOWED BUT ALSO IN CYTOTOXIC T 2890 01:48:20,060 --> 01:48:20,327 CELLS. 2891 01:48:20,393 --> 01:48:23,396 SO IF YOU LOOK AT GRANZYME A 2892 01:48:23,463 --> 01:48:25,732 EXPRESSING CD8s, YOU DON'T SEE 2893 01:48:25,799 --> 01:48:27,934 A DIFFERENCE IN THE TOTAL 2894 01:48:28,001 --> 01:48:29,035 CYTOTOXIC T CELLS, BUT 2895 01:48:29,102 --> 01:48:32,572 FUNCTIONALLY THOSE WERE 2896 01:48:32,639 --> 01:48:36,176 DIFFERENT. 2897 01:48:36,243 --> 01:48:38,144 SO YOUR POINT IS WELL TAKEN. 2898 01:48:38,211 --> 01:48:39,179 THERE'S SOMETHING GOING ON WITH 2899 01:48:39,246 --> 01:48:40,180 THE GRANZYME. 2900 01:48:40,247 --> 01:48:41,915 THOSE ARE INVOLVED IN BACTERIAL 2901 01:48:41,982 --> 01:48:43,116 DEFENSE AS WELL AND THEY HAVE 2902 01:48:43,183 --> 01:48:46,553 OTHER FUNCTIONS IN THE 2903 01:48:46,620 --> 01:48:47,420 CYTOTOXICITY AS WELL SO IT'S A 2904 01:48:47,487 --> 01:48:48,088 VERY INTERESTING LINK. 2905 01:48:48,154 --> 01:48:51,057 THERE'S PROBABLY BURIED DATA 2906 01:48:51,124 --> 01:48:52,425 HERE, WE MIGHT BE ABLE TO MAKE 2907 01:48:52,492 --> 01:48:54,394 SOME LINKS TO THE METABOLISM AS 2908 01:48:54,461 --> 01:48:54,594 WELL. 2909 01:48:54,661 --> 01:48:56,630 >> I THINK I'M GOING TO HAVE TO 2910 01:48:56,696 --> 01:49:03,370 STOP THERE. 2911 01:49:03,436 --> 01:49:04,504 >> THANK YOU. 2912 01:49:04,571 --> 01:49:05,605 APOLOGIZE IN ADVANCE THAT WE 2913 01:49:05,672 --> 01:49:08,275 CAN'T ADDRESS ALL THE QUESTIONS, 2914 01:49:08,341 --> 01:49:12,112 BUT WE ARE HEADED TO A BREAK. 2915 01:49:12,178 --> 01:49:13,546 WE ARE GOING TO CATCH UP A 2916 01:49:13,613 --> 01:49:14,848 LITTLE BIT, WE'RE GOING TO GIVE 2917 01:49:14,915 --> 01:49:15,882 15 MINUTES FOR OUR BREAK, SO 2918 01:49:15,949 --> 01:49:17,751 PLEASE COME BACK AT 11:05. 2919 01:49:17,817 --> 01:49:20,954 AND I WANT TO MAKE SURE THAT YOU 2920 01:49:21,021 --> 01:49:23,089 KNOW THAT IN POSTERS FROM THE 2921 01:49:23,156 --> 01:49:27,794 YOUNG INVESTIGATOR IN ME/CFS, 2922 01:49:27,861 --> 01:49:29,095 THE SPARK MEETING CAN BE VIEWED 2923 01:49:29,162 --> 01:49:30,363 AT THE BREAKS AND CERTAINLY AT 2924 01:49:30,430 --> 01:49:32,098 THE LUNCH, WHICH IS WHERE LUNCH 2925 01:49:32,165 --> 01:49:35,435 WILL ALSO BE, WHICH IS PROVIDED 2926 01:49:35,502 --> 01:49:37,704 BY THE OPEN MEDICINE FOUNDATION 2927 01:49:37,771 --> 01:49:40,173 FOR NETWORKING PURPOSES. 2928 01:49:40,240 --> 01:49:43,109 IF YOU GO OUT THESE DOORS, TURN 2929 01:49:43,176 --> 01:49:44,411 RIGHT AT THE COFFEE SHOP, THAT'S 2930 01:49:44,477 --> 01:49:47,113 WHERE THE TERRACE IS. 2931 01:49:47,180 --> 01:49:48,949 I SHOULD NOTE THAT'S ALSO WHERE 2932 01:49:49,015 --> 01:49:50,050 THE QUIET ROOMS ARE. 2933 01:49:50,116 --> 01:49:51,851 THERE ARE TWO QUIET ROOMS THERE 2934 01:49:51,918 --> 01:49:52,752 IF ANYBODY NEEDS A QUIET SPACE. 2935 01:49:52,819 --> 01:49:53,286 THANK YOU. 2936 01:49:53,353 --> 01:49:59,693 I'LL SEE YOU AT 11:05. 2937 01:49:59,759 --> 01:50:01,661 GOOD MORNING AGAIN. 2938 01:50:01,728 --> 01:50:02,862 WE'RE GOING TO GET STARTED WITH 2939 01:50:02,929 --> 01:50:07,467 OUR NEXT SESSION. 2940 01:50:07,534 --> 01:50:10,503 WHICH IS CALLED THE VIROLOGY OF 2941 01:50:10,570 --> 01:50:14,407 ME/CFS AND LONG COVID. 2942 01:50:14,474 --> 01:50:15,642 ONE OF THOSE WE THINK WE KNOW 2943 01:50:15,709 --> 01:50:17,377 THE VIRUS, THE OTHER, WE'RE 2944 01:50:17,444 --> 01:50:19,746 STILL LACKING. 2945 01:50:19,813 --> 01:50:20,146 LOOKING. 2946 01:50:20,213 --> 01:50:20,914 YOU'RE GOING TO HEAR ABOUT SOME 2947 01:50:20,981 --> 01:50:22,782 OF THAT IN THIS SESSION. 2948 01:50:22,849 --> 01:50:25,385 AND ACTUALLY IN OTHER TALKS 2949 01:50:25,452 --> 01:50:28,655 DURING THIS. 2950 01:50:28,722 --> 01:50:30,757 AS SIMILAR TO THE LAST SESSION, 2951 01:50:30,824 --> 01:50:31,825 WE'RE GOING TO START WITH A 2952 01:50:31,891 --> 01:50:32,892 LIVED EXPERIENCE PERSPECTIVE AND 2953 01:50:32,959 --> 01:50:34,861 WE'RE REALLY FORTUNATE TO HAVE 2954 01:50:34,928 --> 01:50:37,564 WITH US TODAY ASHANTI DANIEL, 2955 01:50:37,630 --> 01:50:39,666 WHO'S GOING TO TELL US HER 2956 01:50:39,733 --> 01:50:41,668 PERSPECTIVE, TO HELP FRAME OUR 2957 01:50:41,735 --> 01:50:42,969 SCIENTIFIC SESSION. 2958 01:50:43,036 --> 01:50:46,172 ASHANTI? 2959 01:50:46,239 --> 01:50:47,440 >> ALL RIGHTY. 2960 01:50:47,507 --> 01:50:48,341 GOOD MORNING. 2961 01:50:48,408 --> 01:50:50,677 AS JOE STATED, I'M ASHANTI 2962 01:50:50,744 --> 01:50:52,012 DANIEL, A DISABLED REGISTERED 2963 01:50:52,078 --> 01:50:55,949 NURSE AND PERSON WITH POST VIRAL 2964 01:50:56,016 --> 01:50:58,184 MYALGIC ENCEPHALOMYELITIS, AKA 2965 01:50:58,251 --> 01:50:59,486 ME/CFS, OR JUST M.E., WHICH I 2966 01:50:59,552 --> 01:51:01,888 PREFER. 2967 01:51:01,955 --> 01:51:05,125 PLUS, POTS, AUTOIMMUNE AUTONOMIC 2968 01:51:05,191 --> 01:51:06,459 NEUROPATHY AND MAST CELL 2969 01:51:06,526 --> 01:51:07,660 ACTIVATION SYNDROME. 2970 01:51:07,727 --> 01:51:09,362 I'M ALSO A SINGLE MOTHER OF TWO, 2971 01:51:09,429 --> 01:51:12,532 A FORMER FITNESS ENTHUSIAST AND 2972 01:51:12,599 --> 01:51:14,734 IN CASE YOU HADN'T NOTICED, A 2973 01:51:14,801 --> 01:51:15,368 BLACK WOMAN. 2974 01:51:15,435 --> 01:51:16,536 YOU MAY BE WONDERING WHY I 2975 01:51:16,603 --> 01:51:17,237 POINTED OUT MY RACE. 2976 01:51:17,303 --> 01:51:19,039 STAY TUNED AND YOU'LL FIND OUT. 2977 01:51:19,105 --> 01:51:20,206 BUT FIRST, LET ME START BY 2978 01:51:20,273 --> 01:51:23,043 TAKING YOU BACK TO AUGUST 2016. 2979 01:51:23,109 --> 01:51:25,011 I WAS LIVING MY BEST LIFE, 2980 01:51:25,078 --> 01:51:27,380 WORKING IN MY DREAM CAREER AS A 2981 01:51:27,447 --> 01:51:30,116 NEONATAL AND CONGENITAL CARDIAC 2982 01:51:30,183 --> 01:51:30,683 ICU NURSE. 2983 01:51:30,750 --> 01:51:32,585 I WAS AN ACTIVE SINGLE PARENT 2984 01:51:32,652 --> 01:51:34,320 AND WORKING OUT VIGOROUSLY FIVE 2985 01:51:34,387 --> 01:51:35,422 TO SIX DAYS A WEEK. 2986 01:51:35,488 --> 01:51:38,491 I WAS LITERALLY "THE" PICTURE OF 2987 01:51:38,558 --> 01:51:43,129 HEALTH. 2988 01:51:43,196 --> 01:51:46,533 WHEN COXSACKIE B VIRUS BLIND 2989 01:51:46,599 --> 01:51:48,334 SIGHTED ME, TAKING MY LIFE AND 2990 01:51:48,401 --> 01:51:49,302 CAREER AS I KNEW IT. 2991 01:51:49,369 --> 01:51:51,071 NOW IS THE MOMENT YOU ALL HAVE 2992 01:51:51,137 --> 01:51:52,372 BEEN WAITING FOR. 2993 01:51:52,439 --> 01:51:53,973 STRUCTURAL RACISM AND ITS IMPACT 2994 01:51:54,040 --> 01:51:55,942 ON PATIENTS WITH COMPLEX CHRONIC 2995 01:51:56,009 --> 01:51:57,577 DISEASES SUCH AS M.E. AND LONG 2996 01:51:57,644 --> 01:51:58,344 COVID. 2997 01:51:58,411 --> 01:52:00,880 FOR CLARITY, STRUCTURAL RACISM 2998 01:52:00,947 --> 01:52:03,650 IS SIMPLY THE HISTORICAL AND 2999 01:52:03,716 --> 01:52:04,651 CONTEMPORARY PRACTICES AND NORMS 3000 01:52:04,717 --> 01:52:06,286 THAT CREATE AND MAINTAIN WHITE 3001 01:52:06,352 --> 01:52:08,354 SUPREMACY. 3002 01:52:08,421 --> 01:52:09,889 NOW, IMAGINE NAIVELY THINKING 3003 01:52:09,956 --> 01:52:11,858 BECAUSE YOU'RE A NURSE, WITH 3004 01:52:11,925 --> 01:52:12,859 INSIDE KNOWLEDGE ON HOW TO 3005 01:52:12,926 --> 01:52:15,495 NAVIGATE THE HEALTHCARE SYSTEM, 3006 01:52:15,562 --> 01:52:17,363 THAT YOU WILL BE IMMUNE TO THE 3007 01:52:17,430 --> 01:52:18,131 STRUCTURAL RACISM WITHIN IT. 3008 01:52:18,198 --> 01:52:20,633 THAT JOKE WAS DEFINITELY ON ME. 3009 01:52:20,700 --> 01:52:22,469 BEING A NURSE DID NOT SAVE ME 3010 01:52:22,535 --> 01:52:23,803 FROM PHYSICIANS WHO DIDN'T TAKE 3011 01:52:23,870 --> 01:52:26,106 ME SERIOUSLY, NOR DID IT SAVE ME 3012 01:52:26,172 --> 01:52:27,373 FROM HEALTHCARE PROFESSIONALS 3013 01:52:27,440 --> 01:52:29,742 WHO DIDN'T APPRECIATE ME 3014 01:52:29,809 --> 01:52:31,177 EXERCISING AUTONOMY OVER MY 3015 01:52:31,244 --> 01:52:32,045 BLACK BODY. 3016 01:52:32,112 --> 01:52:33,880 HOW DARE I HAVE THE AUDACITY TO 3017 01:52:33,947 --> 01:52:35,048 DO THAT, RIGHT? 3018 01:52:35,115 --> 01:52:36,983 THOSE MOMENTS QUICKLY REMINDED 3019 01:52:37,050 --> 01:52:39,185 ME THAT DUE TO IMPLICIT BIAS, 3020 01:52:39,252 --> 01:52:41,588 WHICH IS SUBCONSCIOUS PREJUDICE 3021 01:52:41,654 --> 01:52:43,256 AND STRUCTURAL RACISM IN 3022 01:52:43,323 --> 01:52:44,657 HEALTHCARE, I AMFAR LESS LIKELY 3023 01:52:44,724 --> 01:52:46,826 TO BE BELIEVED AND PROPERLY 3024 01:52:46,893 --> 01:52:48,795 CARED FOR THAN WHITE MEN AND 3025 01:52:48,862 --> 01:52:50,263 EVEN WHITE WOMEN, REGARDLESS OF 3026 01:52:50,330 --> 01:52:52,065 MY PROFESSION. 3027 01:52:52,132 --> 01:52:53,867 AFTER MULTIPLE HOSPITALIZATIONS, 3028 01:52:53,933 --> 01:52:56,736 IT STILL TOOK THREE MONTHS OF ME 3029 01:52:56,803 --> 01:52:58,037 RELENTLESSLY ADVOCATING FOR 3030 01:52:58,104 --> 01:53:00,306 MYSELF TO FINALLY CONVINCE MY 3031 01:53:00,373 --> 01:53:02,242 PULMONOLOGIST THAT MY PROFOUND 3032 01:53:02,308 --> 01:53:04,978 MUSCLE WEAKNESS, VOICE 3033 01:53:05,044 --> 01:53:06,045 HOARSENESS, COGNITIVE 3034 01:53:06,112 --> 01:53:08,114 DYSFUNCTION, WHAT I NOW KNOW WAS 3035 01:53:08,181 --> 01:53:09,649 POST EXERTIONAL MALAISE, AND 3036 01:53:09,716 --> 01:53:11,284 BONE CRUSHING FATIGUE WAS MORE 3037 01:53:11,351 --> 01:53:13,920 THAN JUST A, QUOTE, SEVERE 3038 01:53:13,987 --> 01:53:14,988 ASTHMA EXACERBATION, AND THAT I 3039 01:53:15,054 --> 01:53:16,589 NEEDED TO BE REFERRED TO OTHER 3040 01:53:16,656 --> 01:53:17,657 SPECIALISTS TO FIGURE OUT WHAT 3041 01:53:17,724 --> 01:53:21,628 WAS MAKING ME SO SICK. 3042 01:53:21,694 --> 01:53:23,129 UNFORTUNATELY, THAT EXAMPLE OF 3043 01:53:23,196 --> 01:53:28,234 STRUCTURAL RIS RACISM I DIERNEDS 3044 01:53:28,301 --> 01:53:30,770 MINUSCULE COMPARED TO EGREGIOUS 3045 01:53:30,837 --> 01:53:31,838 EXAMPLE I'M GOING TO SHARE NOW. 3046 01:53:31,905 --> 01:53:34,240 THREE YEARS INTO MY ILLNESS 3047 01:53:34,307 --> 01:53:35,642 AFTER A TWO-WEEK STAY IN THE 3048 01:53:35,708 --> 01:53:36,776 HOSPITAL, A NURSE WAS DETERMINED 3049 01:53:36,843 --> 01:53:39,012 TO STRIP ME OF MY AUTONOMY. 3050 01:53:39,078 --> 01:53:42,048 I HAVE A PORT A CATH IN MY CHEST 3051 01:53:42,115 --> 01:53:44,284 AND DID AT THE TIME OF THIS 3052 01:53:44,350 --> 01:53:44,551 ADMISSION. 3053 01:53:44,617 --> 01:53:46,719 SINCE I WAS STILL INCREDIBLY 3054 01:53:46,786 --> 01:53:48,254 WEAK, I DECIDED TO BE DISCHARGED 3055 01:53:48,321 --> 01:53:50,790 FROM THE HOSPITAL WITH MY PORT 3056 01:53:50,857 --> 01:53:51,824 STILL ACCESS. 3057 01:53:51,891 --> 01:53:52,959 WELL, THIS NURSE, A CHARGE NURSE 3058 01:53:53,026 --> 01:53:54,794 NO LESS, WAS ABSOLUTELY NOT 3059 01:53:54,861 --> 01:53:55,528 HAVING THAT. 3060 01:53:55,595 --> 01:53:57,163 SO MUCH SO THAT SHE LITERALLY 3061 01:53:57,230 --> 01:53:59,232 THREATENED TO CALL PEOPLE TO 3062 01:53:59,299 --> 01:54:01,935 HOLD ME DOWN TO DEACCESS MY PORT 3063 01:54:02,001 --> 01:54:02,835 AGAINST MY WILL, AND IT DIDN'T 3064 01:54:02,902 --> 01:54:03,603 STOP THERE. 3065 01:54:03,670 --> 01:54:05,371 HELL BENT ON EXERCISING CONTROL 3066 01:54:05,438 --> 01:54:07,840 OVER MY BLACK BODY AND 3067 01:54:07,907 --> 01:54:08,474 UNFORTUNATELY COMMON EXPERIENCE 3068 01:54:08,541 --> 01:54:10,109 FOR BLACK PEOPLE IN AMERICA, THE 3069 01:54:10,176 --> 01:54:11,411 NURSE WENT SO FAR AS TO STAND IN 3070 01:54:11,477 --> 01:54:13,546 FRONT OF MY WHEELCHAIR AND PLACE 3071 01:54:13,613 --> 01:54:16,082 HER FOOT ON TO PREVENT ME AND MY 3072 01:54:16,149 --> 01:54:17,483 MOTHER, ANOTHER BLACK WOMAN, 3073 01:54:17,550 --> 01:54:19,052 FROM EXITING THE ELEVATOR TO 3074 01:54:19,118 --> 01:54:19,986 LEAF THE HOSPITAL. 3075 01:54:20,053 --> 01:54:22,288 SHE DID ALL OF THIS KNOWING I 3076 01:54:22,355 --> 01:54:25,124 HAD MY DISCHARGE PAPERS IN HAND 3077 01:54:25,191 --> 01:54:27,493 TO SAY THAT WAS A HORRIFYING AND 3078 01:54:27,560 --> 01:54:29,128 TRAUMATIC ORDEAL THAT RESULTED 3079 01:54:29,195 --> 01:54:30,530 IN NEGATIVE SEQUELAE FOR MY 3080 01:54:30,597 --> 01:54:32,165 HEALTH WOULD BE A GROSS 3081 01:54:32,232 --> 01:54:32,632 UNDERSTATEMENT. 3082 01:54:32,699 --> 01:54:34,801 THE POST EXERTIONAL MALAISE I 3083 01:54:34,867 --> 01:54:36,236 ENDURED AFTER THAT DEBACLE 3084 01:54:36,302 --> 01:54:37,971 ALMOST RESULTED IN A HOSPITAL 3085 01:54:38,037 --> 01:54:39,672 READMISSION. 3086 01:54:39,739 --> 01:54:41,841 THIS IS JUST ONE EXAMPLE OF 3087 01:54:41,908 --> 01:54:43,610 MANY, DEMONSTRATING WHAT CAN 3088 01:54:43,676 --> 01:54:45,411 HAPPEN WHEN BIASES GO UNCHECKED, 3089 01:54:45,478 --> 01:54:47,513 AND HOW IT IMPACTS PEOPLE OF 3090 01:54:47,580 --> 01:54:48,948 COLOR, PARTICULARLY BLACK WOMEN, 3091 01:54:49,015 --> 01:54:50,550 WHILE ACCESSING HEALTHCARE. 3092 01:54:50,617 --> 01:54:52,218 WITH THAT BEING SAID, LET ME 3093 01:54:52,285 --> 01:54:55,388 LEAVE YOU WITH THIS: STRUCTURAL 3094 01:54:55,455 --> 01:54:57,290 RACISM IS A PUBLIC HEALTH 3095 01:54:57,357 --> 01:54:58,057 CRISIS, AND EACH AND EVERY ONE 3096 01:54:58,124 --> 01:55:00,126 OF YOU HERE HAS THE POWER TO DO 3097 01:55:00,193 --> 01:55:02,228 SOMETHING ABOUT IT. 3098 01:55:02,295 --> 01:55:04,597 FOR HEALTHCARE PROFESSIONALS IN 3099 01:55:04,664 --> 01:55:05,898 ATTENDANCE, THOSE OF US WITH 3100 01:55:05,965 --> 01:55:07,900 COMPLEX CHRONIC ILLNESSES DES 3101 01:55:07,967 --> 01:55:09,168 DESPERATELY NEED YOU TO CHECK 3102 01:55:09,235 --> 01:55:10,436 YOUR IMPLICIT BIASES AT THE 3103 01:55:10,503 --> 01:55:11,104 DOOR. 3104 01:55:11,170 --> 01:55:11,971 BELIEVE PATIENTS WHEN THEY 3105 01:55:12,038 --> 01:55:13,206 DESCRIBE WHAT IS HAPPENING TO 3106 01:55:13,273 --> 01:55:14,140 THEIR BODIES. 3107 01:55:14,207 --> 01:55:15,975 NO MATTER HOW OUTLANDISH IT 3108 01:55:16,042 --> 01:55:16,876 SOUNDS. 3109 01:55:16,943 --> 01:55:18,177 AND DON'T BE SO QUICK TO BLAME 3110 01:55:18,244 --> 01:55:20,313 THEIR SYMPTOMS ON ANXIETY, 3111 01:55:20,380 --> 01:55:21,948 WEIGHT, THEIR SKIN COLOR, 3112 01:55:22,015 --> 01:55:23,616 GENDER, OR ANYTHING OTHER THAN 3113 01:55:23,683 --> 01:55:25,118 SOMETHING PHYSIOLOGICAL. 3114 01:55:25,184 --> 01:55:27,453 EVEN IF YOU DON'T HAVE THE 3115 01:55:27,520 --> 01:55:29,155 ANSWERS TO WHAT IS AILING THEM, 3116 01:55:29,222 --> 01:55:30,356 SIMPLY BELIEVING YOUR PATIENTS 3117 01:55:30,423 --> 01:55:32,125 AND BEING COGNIZANT OF WHAT YOU 3118 01:55:32,191 --> 01:55:35,461 CHART IN THEIR NOTES GOES SUCH A 3119 01:55:35,528 --> 01:55:36,462 LONG WAY. 3120 01:55:36,529 --> 01:55:37,664 ADDITIONALLY, I URGE AND 3121 01:55:37,730 --> 01:55:39,399 ENCOURAGE YOU TO CONSIDER 3122 01:55:39,465 --> 01:55:41,401 BECOMING INFECTION ASSOCIATED 3123 01:55:41,467 --> 01:55:43,002 CHRONIC CONDITION SPECIALISTS. 3124 01:55:43,069 --> 01:55:46,039 AS IT IS, THERE ARE TOO FEW 3125 01:55:46,105 --> 01:55:47,573 SPECIALISTS IN THE COUNTRY WHICH 3126 01:55:47,640 --> 01:55:48,775 LIMITS ACCESS TO CARE DUE TO 3127 01:55:48,841 --> 01:55:50,143 FINANCIAL CONSTRAINTS, LOGISTICS 3128 01:55:50,209 --> 01:55:52,712 IN TERMS OF TRAVELING TO A 3129 01:55:52,779 --> 01:55:54,280 SPECIALIST, AND VERY LENGTHY, UP 3130 01:55:54,347 --> 01:55:57,183 TO A YEAR IF NOT MORE, WAITS TO 3131 01:55:57,250 --> 01:55:58,618 GET NEW PATIENT APPOINTMENTS 3132 01:55:58,685 --> 01:56:00,987 WITH THE CURRENT SPECIALISTS. 3133 01:56:01,054 --> 01:56:02,455 CHRONIC ILLNESS WARRIORS NEED 3134 01:56:02,522 --> 01:56:04,190 APPROPRIATE MEDICAL 3135 01:56:04,257 --> 01:56:05,191 INTERVENTIONS AND TREATMENTS, SO 3136 01:56:05,258 --> 01:56:07,126 WE CAN GET BACK TO OUR 3137 01:56:07,193 --> 01:56:07,527 PRE-ILLNESS LIVES. 3138 01:56:07,593 --> 01:56:10,163 WE WERE NURSES, DOCTORS, 3139 01:56:10,229 --> 01:56:13,766 TEACHERS, LAWYERS, SCIENTISTS, 3140 01:56:13,833 --> 01:56:14,767 PARENTS, PARTNERS AND ALMOST 3141 01:56:14,834 --> 01:56:16,069 ANYTHING ELSE YOU CAN THINK OF 3142 01:56:16,135 --> 01:56:17,704 BEFORE THESE DISEASES BULLDOZED 3143 01:56:17,770 --> 01:56:18,805 OUR LIVES. 3144 01:56:18,871 --> 01:56:22,608 PLEASE HELP MAKE OUR DREAM OF A 3145 01:56:22,675 --> 01:56:23,910 FUTURE WITHOUT COMPLEX CHRONIC 3146 01:56:23,976 --> 01:56:25,778 DISEASES A REALITY. 3147 01:56:25,845 --> 01:56:28,047 OUR LOVED ONES NEED US, SOCIETY 3148 01:56:28,114 --> 01:56:30,817 NEEDS US. 3149 01:56:30,883 --> 01:56:41,060 [APPLAUSE] 3150 01:56:41,327 --> 01:56:51,537 THANK YOU, GUYS. 3151 01:56:57,243 --> 01:57:01,547 >> THANK YOU SO MUCH, ASHANTI. 3152 01:57:01,614 --> 01:57:04,350 THAT WAS REALLY ELOQUENT AND 3153 01:57:04,417 --> 01:57:06,652 MOVING. 3154 01:57:06,719 --> 01:57:09,055 AND A REALLY IMPORTANT REMINDER 3155 01:57:09,122 --> 01:57:10,156 OF SOME THINGS THAT ARE NOT 3156 01:57:10,223 --> 01:57:12,191 ALWAYS SO OBVIOUS, BUT ARE SUPER 3157 01:57:12,258 --> 01:57:14,827 IMPORTANT. 3158 01:57:14,894 --> 01:57:16,796 OBVIOUS TO EVERYONE IN THE 3159 01:57:16,863 --> 01:57:18,998 RESEARCH ENTERPRISE. 3160 01:57:19,065 --> 01:57:21,667 I WANT TO INTRODUCE OUR NEXT 3161 01:57:21,734 --> 01:57:23,536 SPEAKER, DR. IAN LIPKIN, FROM 3162 01:57:23,603 --> 01:57:25,571 COLUMBIA, WHO'S GOING TO GIVE US 3163 01:57:25,638 --> 01:57:27,974 INSIGHTS AND FORESIGHTS INTO THE 3164 01:57:28,040 --> 01:57:28,641 MICROBIOLOGY, IMMUNOLOGY OF 3165 01:57:28,708 --> 01:57:29,742 ME/CFS. 3166 01:57:29,809 --> 01:57:34,680 IAN? 3167 01:57:34,747 --> 01:57:36,582 >> THANK YOU, JOE. 3168 01:57:36,649 --> 01:57:42,622 THAT WAS REALLY QUITE MOVING. 3169 01:57:42,688 --> 01:57:43,823 I'M GOING TO HOPE THAT THIS 3170 01:57:43,890 --> 01:57:49,295 WORKS. 3171 01:57:49,362 --> 01:57:59,839 SO WE WERE WORKING EARLIER. 3172 01:58:00,106 --> 01:58:02,708 WHILE WE'RE GETTING SET UP, I 3173 01:58:02,775 --> 01:58:05,111 REALLY SPEND MOST OF MY CAREER 3174 01:58:05,178 --> 01:58:06,813 DOING WHAT WE CALL PATHOGEN 3175 01:58:06,879 --> 01:58:07,880 DISCOVERY. 3176 01:58:07,947 --> 01:58:12,084 THOUGH I REALLY BEGAN WITH NINDS 3177 01:58:12,151 --> 01:58:14,053 AND THEN WITH NIAID FOR MANY 3178 01:58:14,120 --> 01:58:15,288 YEARS. 3179 01:58:15,354 --> 01:58:22,128 >> CAN'T HEAR YOU, IAN. 3180 01:58:22,195 --> 01:58:25,798 >> I SPINT SPENT MOST OF MY LIG 3181 01:58:25,865 --> 01:58:28,000 ON PATHOGEN DISCOVERY, CHIEFLY 3182 01:58:28,067 --> 01:58:29,635 AROUND OUGHTBREAKS GLOBAL IN 3183 01:58:29,702 --> 01:58:31,504 SCOPE BUT NOTHING HAS BEEN QUITE 3184 01:58:31,571 --> 01:58:33,339 AS CHALLENGING AS ME/CFS, AND IF 3185 01:58:33,406 --> 01:58:36,275 WE CAN GET THIS TO RUN, I'LL 3186 01:58:36,342 --> 01:58:37,977 HAVE A CHANCE TO SHOW YOU WHAT 3187 01:58:38,044 --> 01:58:38,978 OUR THINKING IS. 3188 01:58:39,045 --> 01:58:41,080 THE HISTORY OF INFECTION WITH 3189 01:58:41,147 --> 01:58:44,150 ME/CFS GOES BACK A VERY, VERY 3190 01:58:44,217 --> 01:58:45,985 LONG TIME. 3191 01:58:46,052 --> 01:58:47,587 SEVERAL DECADES, AND THERE HAVE 3192 01:58:47,653 --> 01:58:49,255 BEEN A NUMBER OF OUTBREAKS THAT 3193 01:58:49,322 --> 01:58:51,524 HAVE BEEN DESCRIBED. 3194 01:58:51,591 --> 01:58:52,592 THE ONE WHICH I THINK IS 3195 01:58:52,658 --> 01:58:55,495 PROBABLY THE MOST USEFUL FOR US, 3196 01:58:55,561 --> 01:58:57,396 I'LL TALK ABOUT IN JUST A 3197 01:58:57,463 --> 01:58:59,298 MOMENT, BUT CAN YOU HEAR ME NOW? 3198 01:58:59,365 --> 01:59:04,437 GREAT. 3199 01:59:04,504 --> 01:59:05,605 SO THERE ARE ESTIMATES OF THE 3200 01:59:05,671 --> 01:59:08,241 NUMBER OF PATIENTS WHO HAVE 3201 01:59:08,307 --> 01:59:13,179 REPORTS OF INFECTION PRECEDING 3202 01:59:13,246 --> 01:59:14,046 CHARACTERIZING -- PRIOR TO 3203 01:59:14,113 --> 01:59:14,480 ME/CFS. 3204 01:59:14,547 --> 01:59:15,648 MY OWN MOVEMENT INTO THIS FIELD 3205 01:59:15,715 --> 01:59:17,950 REALLY BEGAN WITH WORK WITH THE 3206 01:59:18,017 --> 01:59:20,953 CDC, WHEN THERE WAS TALK ABOUT 3207 01:59:21,020 --> 01:59:22,288 BORNA DISEASE VIRUS BEING 3208 01:59:22,355 --> 01:59:23,389 IMPLICATED AS THE CAUSE OF 3209 01:59:23,456 --> 01:59:25,458 ME/CFS, AND THERE WERE TWO VERY 3210 01:59:25,525 --> 01:59:26,526 PROMINENT PAPERS THAT CAME OUT 3211 01:59:26,592 --> 01:59:28,394 THAT SUGGESTED THAT THIS WAS THE 3212 01:59:28,461 --> 01:59:29,695 CASE, AND WE WERE ASKED TO LOOK 3213 01:59:29,762 --> 01:59:30,730 INTO THIS. 3214 01:59:30,796 --> 01:59:31,998 AT THIS TIME, THERE WERE MANY 3215 01:59:32,064 --> 01:59:33,866 PEOPLE WHO WERE TALKING ABOUT 3216 01:59:33,933 --> 01:59:36,669 THIS BEING A PRIMARILY 3217 01:59:36,736 --> 01:59:39,705 PSYCHOLOGICAL ILLNESS WE DIDN'T 3218 01:59:39,772 --> 01:59:41,674 FIND ANY EVIDENCE FOR BORNA 3219 01:59:41,741 --> 01:59:42,942 VIRUSES BUT WHAT WE DID FIND WAS 3220 01:59:43,009 --> 01:59:44,944 THAT THE MAJORITY OF PATIENTS WE 3221 01:59:45,011 --> 01:59:46,913 STUDIED IN THE SWEDISH COHORT 3222 01:59:46,979 --> 01:59:48,314 HAD ANTIBODIES THAT REACTED WITH 3223 01:59:48,381 --> 01:59:50,249 A WIDE RANGE OF DIFFERENT 3224 01:59:50,316 --> 01:59:50,516 EPITOPES. 3225 01:59:50,583 --> 01:59:51,784 SO THERE WAS CLEARLY SOME SORT 3226 01:59:51,851 --> 01:59:56,722 OF IMMUNE SYSTEM DYSREGULATION. 3227 01:59:56,789 --> 02:00:00,359 NOW, MAUREEN HANSON AND JOHN CHI 3228 02:00:00,426 --> 02:00:02,495 AND OTHERS HAVE TALKED ABOUT 3229 02:00:02,562 --> 02:00:03,829 ENTEROVIRUSES IN ME/CFS. 3230 02:00:03,896 --> 02:00:05,464 WE HAVE FOUND NO EVIDENCE TO 3231 02:00:05,531 --> 02:00:07,934 SUPPORT THAT AS YET. 3232 02:00:08,000 --> 02:00:09,368 BUT THAT DOESN'T MEAN IT'S NOT 3233 02:00:09,435 --> 02:00:10,236 THE CASE. 3234 02:00:10,303 --> 02:00:11,203 THIS IS SOMETHING THAT I THINK 3235 02:00:11,270 --> 02:00:12,405 NEEDS TO BE STUDIED 3236 02:00:12,471 --> 02:00:14,173 APPROPRIATELY. 3237 02:00:14,240 --> 02:00:15,374 USING A VARIETY OF DIFFERENT 3238 02:00:15,441 --> 02:00:17,143 TYPES OF TECHNIQUES. 3239 02:00:17,209 --> 02:00:19,779 AND I WILL TELL YOU SOMETHING 3240 02:00:19,845 --> 02:00:20,079 ABOUT THIS. 3241 02:00:20,146 --> 02:00:21,581 WE ORIGINALLY BECAME INVOLVED IN 3242 02:00:21,647 --> 02:00:23,883 LOOKING AT ENTEROVIRUSES AND 3243 02:00:23,950 --> 02:00:24,984 CHRONIC DISEASES BECAUSE THERE 3244 02:00:25,051 --> 02:00:26,953 WERE REPORTS LINKING 3245 02:00:27,019 --> 02:00:28,187 ENTEROVIRUSES TO ALS. 3246 02:00:28,254 --> 02:00:31,223 WHICH AS YOU ALL KNOW IS LOU 3247 02:00:31,290 --> 02:00:32,425 GEHRIG DISEASE, MOTOR NEURON 3248 02:00:32,491 --> 02:00:32,725 DISEASE. 3249 02:00:32,792 --> 02:00:34,927 WE FOUND NO EVIDENCE FOR THAT 3250 02:00:34,994 --> 02:00:35,661 WHATSOEVER. 3251 02:00:35,728 --> 02:00:37,330 AND WE'VE DONE SIMILAR KINDS OF 3252 02:00:37,396 --> 02:00:40,700 WORK WITH MMR VACCINE AND 3253 02:00:40,766 --> 02:00:43,002 AUTISM, BORNA VIRUSES AND 3254 02:00:43,069 --> 02:00:43,869 NEUROPSYCHIATRIC DISEASES, AND 3255 02:00:43,936 --> 02:00:47,206 THEN MORE RECENTLY, XMRV AND 3256 02:00:47,273 --> 02:00:49,275 PMLV IN ME/CFS, WHERE WHAT WAS 3257 02:00:49,342 --> 02:00:51,811 REQUIRED TO REFUTE THIS 3258 02:00:51,877 --> 02:00:52,912 HYPOTHESIS WAS TO GET THE 3259 02:00:52,979 --> 02:00:55,081 ORIGINAL INVESTIGATORS TO LOOK 3260 02:00:55,147 --> 02:00:56,716 VERY CLEARLY AT NEW SAMPLES 3261 02:00:56,782 --> 02:00:58,451 USING RIGOROUS TECHNIQUES THAT 3262 02:00:58,517 --> 02:01:00,620 THEY ALONE WOULD DETERMINE, AND 3263 02:01:00,686 --> 02:01:02,188 USING THAT APPROACH, THEY WERE 3264 02:01:02,254 --> 02:01:05,124 UNABLE TO REPLICATE THEIR OWN 3265 02:01:05,191 --> 02:01:06,659 WORK. 3266 02:01:06,726 --> 02:01:08,294 NOW DO I THINK INFECTIONS ARE 3267 02:01:08,361 --> 02:01:10,029 IMPLICATED IN ME/CFS AS THE 3268 02:01:10,096 --> 02:01:11,797 TRIGGER OR EXACERBATING FACTOR? 3269 02:01:11,864 --> 02:01:13,299 THE ANSWER THERE IS PROBABLY 3270 02:01:13,366 --> 02:01:13,633 YES. 3271 02:01:13,699 --> 02:01:15,468 IF YOU JUST LOOK AT THE 3272 02:01:15,534 --> 02:01:17,570 PROTEOMIC EVIDENCE, WE SEE 3273 02:01:17,637 --> 02:01:19,205 EXAMPLES WHERE PEOPLE HAVE 3274 02:01:19,271 --> 02:01:24,210 CERTAIN KINDS OF CLONAL RYE 3275 02:01:24,276 --> 02:01:26,078 RESPONSES TO B CELLS SUGGESTING 3276 02:01:26,145 --> 02:01:27,480 THERE'S SOME SORT OF A TARGET. 3277 02:01:27,546 --> 02:01:29,015 THERE'S NO PROOF THAT'S CLEAR, 3278 02:01:29,081 --> 02:01:33,786 BUT AS DAR YA CAYA CAME UP WITHD 3279 02:01:33,853 --> 02:01:35,221 DESCRIBED IN HIS LAST TALK, WE 3280 02:01:35,287 --> 02:01:36,889 DO HAVE CLEAR EVIDENCE OF 3281 02:01:36,956 --> 02:01:38,557 DYSBIOSIS IN THE GI MICROBIOME. 3282 02:01:38,624 --> 02:01:39,692 AND SOME OF THE WORK THAT'S COME 3283 02:01:39,759 --> 02:01:43,095 OUT AS A RESULT OF THIS HAS BEEN 3284 02:01:43,162 --> 02:01:44,964 TO SUGGEST THAT THERE MAY BE 3285 02:01:45,031 --> 02:01:46,298 SOME SORT OF LEAKINESS IN THE 3286 02:01:46,365 --> 02:01:49,201 GUT WHICH RESULTS IN TRANSFER OF 3287 02:01:49,268 --> 02:01:51,737 PRODUCTS FROM THE INSIDE OF THE 3288 02:01:51,804 --> 02:01:54,940 INTESTINE INTO THE SYSTEMIC 3289 02:01:55,007 --> 02:01:56,409 CIRCULATION WHICH CAN THEN HAVE 3290 02:01:56,475 --> 02:01:57,610 EXTRAORDINARY IMPACT, NOT ONLY 3291 02:01:57,677 --> 02:02:01,614 ON THE IMMUNE SYSTEM, BUT ON 3292 02:02:01,681 --> 02:02:01,947 MITOCHONDRIA. 3293 02:02:02,014 --> 02:02:03,115 AS I'LL GO INTO IN JUST A 3294 02:02:03,182 --> 02:02:06,052 MOMENT. 3295 02:02:06,118 --> 02:02:08,454 SO WE AND OTHERS HAVE FOUND 3296 02:02:08,521 --> 02:02:14,126 ELEVATED LEVELS OF LPS/LBP 3297 02:02:14,193 --> 02:02:19,165 BINDING RECEPTOR, S CD14 AND SO 3298 02:02:19,231 --> 02:02:19,699 FORTH. 3299 02:02:19,765 --> 02:02:21,333 WHAT THIS IS LEADING TO IS SOME 3300 02:02:21,400 --> 02:02:23,502 ROLE FOR THE INNATE IMMUNE 3301 02:02:23,569 --> 02:02:24,937 SYSTEM IN THE PATHOGENESIS OF 3302 02:02:25,004 --> 02:02:25,705 THESE DISORDERS. 3303 02:02:25,771 --> 02:02:28,074 NOW WE HAVE PURSUED 3304 02:02:28,140 --> 02:02:29,942 CROSS-SECTIONAL MICROBIAL 3305 02:02:30,009 --> 02:02:31,377 STUDIES IN PATIENTS WITH ME/CFS. 3306 02:02:31,444 --> 02:02:34,346 WHAT I MEAN BY CROSS-SECTIONAL 3307 02:02:34,413 --> 02:02:35,848 IS THAT WE COLLECT SAMPLES FROM 3308 02:02:35,915 --> 02:02:39,018 PEOPLE AT VARIOUS STAGES OF 3309 02:02:39,085 --> 02:02:39,985 DISEASE AND LOOK FOR WHETHER OR 3310 02:02:40,052 --> 02:02:42,621 NOT WE CAN FIND VIRUSES, BACK 3311 02:02:42,688 --> 02:02:43,355 BACTERIA OR FUNGI. 3312 02:02:43,422 --> 02:02:44,724 TO DATE, THIS HAS BEEN 3313 02:02:44,790 --> 02:02:46,325 DISAPPOINTING, BUT THIS DOES NOT 3314 02:02:46,392 --> 02:02:49,829 EXCLUDE A ROLE FOR MICROBIAL 3315 02:02:49,895 --> 02:02:51,797 PATHOGENS IN THE PATHOGENESIS OF 3316 02:02:51,864 --> 02:02:52,031 ME/CFS. 3317 02:02:52,098 --> 02:02:53,699 BECAUSE WE MAY HAVE HIT-AND-RUN 3318 02:02:53,766 --> 02:02:56,168 VIRAL EXPOSURES, AND WE MAY ALSO 3319 02:02:56,235 --> 02:02:57,737 HAVE CRYPTIC OR INACCESSIBLE 3320 02:02:57,803 --> 02:02:59,305 SITES. 3321 02:02:59,371 --> 02:03:01,107 IF WE'RE SUPPORTED DURING THE 3322 02:03:01,173 --> 02:03:03,976 NEXT CYCLE OF THE CENTERS 3323 02:03:04,043 --> 02:03:05,845 APPLICATIONS, WE HAVE TWO 3324 02:03:05,911 --> 02:03:08,447 PROJECTS WHICH WILL SPECIFIC 3325 02:03:08,514 --> 02:03:08,848 FOCUS ON THIS. 3326 02:03:08,914 --> 02:03:10,850 ONE OF THESE, WE REFER TO AS THE 3327 02:03:10,916 --> 02:03:12,518 GOOD DAY/BAD DAY PROJECT THAT'S 3328 02:03:12,585 --> 02:03:15,554 LED BY TONY, WHO'S HERE NOW. 3329 02:03:15,621 --> 02:03:18,691 THE IDEA IS THAT AS PATIENTS 3330 02:03:18,758 --> 02:03:20,226 DEVELOP CHANGES IN THEIR 3331 02:03:20,292 --> 02:03:22,762 CLINICAL COURSE, WE WILL ACCESS 3332 02:03:22,828 --> 02:03:26,132 MATERIALS AND ASK QUESTIONS 3333 02:03:26,198 --> 02:03:26,432 RIGOROUSLY. 3334 02:03:26,499 --> 02:03:29,535 THE THIRD PROJECT FOCUSED ON 3335 02:03:29,602 --> 02:03:31,137 PATHOGEN DISCOVERY USING SAMPLES 3336 02:03:31,203 --> 02:03:33,906 THAT WE OBTAIN FROM THE SERUM 3337 02:03:33,973 --> 02:03:34,707 REPOSITORY AT THE DEPARTMENT OF 3338 02:03:34,774 --> 02:03:35,541 DEFENSE. 3339 02:03:35,608 --> 02:03:37,176 MORE ON THAT SHORTLY. 3340 02:03:37,243 --> 02:03:40,012 SO THIS IS THE CONSTRUCTION OF 3341 02:03:40,079 --> 02:03:43,048 THE SECOND CYCLE OF THE CENTER 3342 02:03:43,115 --> 02:03:45,584 FOR ME/CFS, WHICH IS A NATIONAL 3343 02:03:45,651 --> 02:03:48,120 PROGRAM, AND NOW ALSO INCLUDES 3344 02:03:48,187 --> 02:03:49,488 AN INDIVIDUAL IN SCOTLAND WHO 3345 02:03:49,555 --> 02:03:51,257 WILL DO GENETICS ABOUT WHICH I 3346 02:03:51,323 --> 02:03:53,759 WON'T SPEAK. 3347 02:03:53,826 --> 02:03:56,162 SO PROJECT ONE WILL LOOK AT 60 3348 02:03:56,228 --> 02:03:59,865 ME/CFS SUBJECTS AND 60 HEALTHY 3349 02:03:59,932 --> 02:04:02,201 MATCH CONTROLS, AND FOR NURSE 3350 02:04:02,268 --> 02:04:04,003 DANIELS, WE ARE SPECIFICALLY 3351 02:04:04,069 --> 02:04:07,306 TRYING TO FOCUS ON COLLECTING 3352 02:04:07,373 --> 02:04:09,475 SAMPLES FROM PATIENTS WHO ARE 3353 02:04:09,542 --> 02:04:10,876 NOT WHITE AND ARE NOT WEALTHY 3354 02:04:10,943 --> 02:04:13,479 AND SO ON. 3355 02:04:13,546 --> 02:04:14,713 AND THIS WILL REQUIRE SOME 3356 02:04:14,780 --> 02:04:16,348 ADDITIONAL SUPPORT FROM NIH. 3357 02:04:16,415 --> 02:04:18,551 BUT WE'RE GOING TO LOOK AT EVERY 3358 02:04:18,617 --> 02:04:20,286 ACCESSIBLE SAMPLE WE CAN 3359 02:04:20,352 --> 02:04:20,920 POSSIBLY COLLECT. 3360 02:04:20,986 --> 02:04:22,788 WE'LL LOOK ON BAD DAYS, WE'LL 3361 02:04:22,855 --> 02:04:24,323 LOOK THREE WEEKS LATER TO SEE IF 3362 02:04:24,390 --> 02:04:26,692 THERE'S SOME SORT OF AN INTERVAL 3363 02:04:26,759 --> 02:04:29,762 CHANGE, EITHER WITH PROTEOMICS, 3364 02:04:29,829 --> 02:04:30,863 METABOLOMICS, TRANSCRIPTOMICS OR 3365 02:04:30,930 --> 02:04:32,064 SEROLOGY, WHICH WILL GIVE US 3366 02:04:32,131 --> 02:04:34,366 CLUES AS TO WHAT MIGHT HAVE 3367 02:04:34,433 --> 02:04:35,134 CHANGED THE CONSEQUENCE. 3368 02:04:35,201 --> 02:04:36,836 WE WILL BE USING A PHONE APP, 3369 02:04:36,902 --> 02:04:38,938 WHICH ASKS VERY SPECIFIC 3370 02:04:39,004 --> 02:04:40,239 QUESTIONS THAT PATIENTS CAN 3371 02:04:40,306 --> 02:04:41,440 ANSWER FROM THE COMFORT OF THEIR 3372 02:04:41,507 --> 02:04:42,875 OWN HOMES. 3373 02:04:42,942 --> 02:04:45,144 THAT THEN LEADS TO A TRIGGER FOR 3374 02:04:45,211 --> 02:04:46,812 A COORDINATOR WHO GOES THEN AND 3375 02:04:46,879 --> 02:04:47,446 COLLECTS THE APPROPRIATE 3376 02:04:47,513 --> 02:04:48,080 SAMPLES. 3377 02:04:48,147 --> 02:04:50,349 I DON'T HAVE TIME TO TALK ABOUT 3378 02:04:50,416 --> 02:04:54,787 GIGENOTYPIC ANALYSIS BUT WE'RE 3379 02:04:54,854 --> 02:04:55,855 VERY EXCITED ABOUT THIS BECAUSE 3380 02:04:55,921 --> 02:04:58,490 IT'S A COLLABORATION THAT WOULD 3381 02:04:58,557 --> 02:04:59,658 DECODE ME WITHIN THE U.K. GROUP. 3382 02:04:59,725 --> 02:05:01,527 I TALKED A LITTLE BIT ABOUT THE 3383 02:05:01,594 --> 02:05:03,062 DEPARTMENT OF DEFENSE PROGRAM. 3384 02:05:03,128 --> 02:05:04,563 THERE ARE TENS OF MILLIONS OF 3385 02:05:04,630 --> 02:05:06,899 SAMPLES THAT HAVE BEEN COLLECTED 3386 02:05:06,966 --> 02:05:08,400 PRIMARILY FOR HIV SEROLOGY TO 3387 02:05:08,467 --> 02:05:13,539 LOOK AT ZERO CONVERSION. 3388 02:05:13,606 --> 02:05:16,242 SEROCONVERSION. 3389 02:05:16,308 --> 02:05:18,143 THIS ALLOWS US TO SEE WHETHER 3390 02:05:18,210 --> 02:05:20,446 THERE ARE CHANGES IN ANTIBODY 3391 02:05:20,512 --> 02:05:22,114 TITE RMENT S DIRECTED AGAINST 3392 02:05:22,181 --> 02:05:23,682 SPECIFIC ANTIGENS REPRESENTED BY 3393 02:05:23,749 --> 02:05:24,884 DIFFERENT BACTERIA, WHICH WILL 3394 02:05:24,950 --> 02:05:26,452 THEN ALLOW US TO GO BACK AND SAY 3395 02:05:26,518 --> 02:05:27,419 THERE IS OR IS NOT SOME SORT OF 3396 02:05:27,486 --> 02:05:27,953 A LINK. 3397 02:05:28,020 --> 02:05:30,689 NOW WE'RE USING ICD10 3398 02:05:30,756 --> 02:05:32,324 CATEGORIES, AND ICD-9 3399 02:05:32,391 --> 02:05:33,759 CATEGORIES, AND UNFORTUNATELY, 3400 02:05:33,826 --> 02:05:35,794 WE'RE NOT GOING TO BE ABLE TO 3401 02:05:35,861 --> 02:05:37,196 USE ME/CFS DIRECTLY. 3402 02:05:37,263 --> 02:05:40,733 WE'RE GOING TO HAVE TO RELY ON 3403 02:05:40,799 --> 02:05:42,234 CHRONIC FATIGUE UNSPECIFIED BUT 3404 02:05:42,301 --> 02:05:44,770 WE THINK THIS WILL BE USEFUL 3405 02:05:44,837 --> 02:05:46,171 NONETHELESS. 3406 02:05:46,238 --> 02:05:47,172 I'M GOING TO TALK A LITTLE ABOUT 3407 02:05:47,239 --> 02:05:48,374 THE METHODS THAT WE USE. 3408 02:05:48,440 --> 02:05:51,110 THESE WERE REALLY DEVELOPED 3409 02:05:51,176 --> 02:05:52,845 PRIMARILY FOR LOOKING AT 3410 02:05:52,912 --> 02:05:53,746 OUTBREAKS, BUT THEY'RE NOW BEING 3411 02:05:53,812 --> 02:05:55,981 USED IN ME/CFS. 3412 02:05:56,048 --> 02:05:57,449 CAPTURE SEQUENCING, WHICH IS 3413 02:05:57,516 --> 02:05:59,018 EXTRAORDINARILY POWERFUL, AND IS 3414 02:05:59,084 --> 02:06:00,486 NOW BEING USED CLINICALLY AS 3415 02:06:00,552 --> 02:06:02,254 WELL AS FOR RESEARCH, ALLOWS YOU 3416 02:06:02,321 --> 02:06:04,123 TO GET A THREE ORDER OF 3417 02:06:04,189 --> 02:06:07,059 MAGNITUDE ENRICHMENT, WHICH 3418 02:06:07,126 --> 02:06:08,527 SIMPLIFIES BIOINFORMATICS, GIVES 3419 02:06:08,594 --> 02:06:09,828 YOU THE SENSITIVITY THAT YOU 3420 02:06:09,895 --> 02:06:11,563 NEED TO LOOK FOR AGENTS THAT 3421 02:06:11,630 --> 02:06:13,198 MIGHT BE PRESENT. 3422 02:06:13,265 --> 02:06:14,500 THERE'S A BACTERIAL CORRELATE 3423 02:06:14,566 --> 02:06:16,802 WHICH HAS SIMILAR KINDS OF 3424 02:06:16,869 --> 02:06:18,971 PERFORMANCE CHARACTERISTICS. 3425 02:06:19,038 --> 02:06:21,273 WE ALSO USE VERY GRANULAR 3426 02:06:21,340 --> 02:06:22,808 APPROACHES FOR SEROLOGY, AND 3427 02:06:22,875 --> 02:06:25,077 THIS AS YOU'LL SEE IS EXTREMELY 3428 02:06:25,144 --> 02:06:25,344 IMPORTANT. 3429 02:06:25,411 --> 02:06:27,413 WE BEGAN BY USING MICRO ARRAYS 3430 02:06:27,479 --> 02:06:31,216 WITH OVERLAPPING PEPTIDES, AND 3431 02:06:31,283 --> 02:06:32,751 UNFORTUNATELY, WE CAN NO LONGER 3432 02:06:32,818 --> 02:06:34,920 ACCESS THOSE ARRAYS. 3433 02:06:34,987 --> 02:06:38,424 SO WE'VE NOW TURNED TO SORT OF A 3434 02:06:38,490 --> 02:06:41,593 GRANULAR PHASE DISPLAY APPROACH 3435 02:06:41,660 --> 02:06:43,128 WHICH I'LL DESCRIBE FOR YOU IN A 3436 02:06:43,195 --> 02:06:43,462 MOMENT. 3437 02:06:43,529 --> 02:06:44,964 I'M GOING TO GIVE YOU ONE 3438 02:06:45,030 --> 02:06:46,398 EXAMPLE OF HOW WE USE SEROLOGY 3439 02:06:46,465 --> 02:06:49,234 TO IMPLICATE A SPECIFIC VIRUS IN 3440 02:06:49,301 --> 02:06:50,135 ACUTE FLACCID MY LIGHTS. 3441 02:06:50,202 --> 02:06:58,877 MYELITIS.AS YOU CAN SEE, THERE S 3442 02:06:58,944 --> 02:07:01,313 DISEASE THAT TENDS TO GO UP 3443 02:07:01,380 --> 02:07:03,182 EVERY YEAR UNTIL THE ONSET OF 3444 02:07:03,248 --> 02:07:06,051 THE PANDEMIC, WHEN PEOPLE BECAME 3445 02:07:06,118 --> 02:07:07,453 ISOLATED AND USING MASKING AND 3446 02:07:07,519 --> 02:07:12,791 SO FORTH TO REDUCE TRANSMISSION. 3447 02:07:12,858 --> 02:07:14,760 WE WERE ABLE TO FIND A REGION 3448 02:07:14,827 --> 02:07:19,798 THAT CORRELATED WITH ENTEROVIRUS 3449 02:07:19,865 --> 02:07:21,967 D68, SAME TAIN JUSTLY EVALUATING 3450 02:07:22,034 --> 02:07:22,868 ALL THE VIRUSES KNOWN TO 3451 02:07:22,935 --> 02:07:24,103 SCIENCE, AND WE HAVE A SIMILAR 3452 02:07:24,169 --> 02:07:25,404 SORT OF APPROACH WHICH CAN BE 3453 02:07:25,471 --> 02:07:29,641 USED FOR OTHER VIRUSES AS WELL. 3454 02:07:29,708 --> 02:07:31,143 BECAUSE WE CAN NO LONGER ACCESS 3455 02:07:31,210 --> 02:07:33,979 THESE ARRAYS, WE NOW USE PHAGE 3456 02:07:34,046 --> 02:07:35,614 DISPLAY BUT IT'S NOT THE PHAGE 3457 02:07:35,681 --> 02:07:36,915 DISPLAY THAT MANY OF YOU WILL BE 3458 02:07:36,982 --> 02:07:37,616 FAMILIAR WITH. 3459 02:07:37,683 --> 02:07:40,753 IT IS MUCH MORE GRANULAR. 3460 02:07:40,819 --> 02:07:42,721 IT APPLIES VERY SHORT PEPTIDE 3461 02:07:42,788 --> 02:07:45,257 SEQUENCES THAT ALLOWS US TO 3462 02:07:45,324 --> 02:07:50,396 DISCRIMINATE BETWEEN DIFFERENT 3463 02:07:50,462 --> 02:07:50,696 SEROTYPES. 3464 02:07:50,763 --> 02:07:51,897 THUS FAR WE'VE BEEN ABLE TO 3465 02:07:51,964 --> 02:07:53,332 COMPARE THE RESULTS WE OBTAINED 3466 02:07:53,399 --> 02:07:55,300 WITH MICRO ARRAYS VERSUS PHAGE 3467 02:07:55,367 --> 02:07:56,702 DISPLAY AND THERE'S VERY GOOD 3468 02:07:56,769 --> 02:07:58,470 OVERLAP WHEN WE'RE LOOKING AT 3469 02:07:58,537 --> 02:08:02,608 HERPES VIRUS AND WHEN WE'RE 3470 02:08:02,674 --> 02:08:03,942 REVIEWING PATIENTS WITH COVID-19 3471 02:08:04,009 --> 02:08:07,980 AND LOOKING AT CORONAVIRUS. 3472 02:08:08,047 --> 02:08:09,515 I'M GOING TO MOVE NOW TO THE 3473 02:08:09,581 --> 02:08:11,717 SPECULATIVE PORTION OF MY TALK, 3474 02:08:11,784 --> 02:08:13,018 WHERE I'M GOING TO DESCRIBE FOR 3475 02:08:13,085 --> 02:08:14,820 YOU WHY I THINK THE INNATE 3476 02:08:14,887 --> 02:08:15,654 IMMUNE SYSTEM IS GOING TO BE 3477 02:08:15,721 --> 02:08:16,755 IMPORTANT. 3478 02:08:16,822 --> 02:08:18,924 I REFERENCED EARLY ON THE PAPER 3479 02:08:18,991 --> 02:08:23,095 THAT WAS DESCRIBED BY DERYA 3480 02:08:23,162 --> 02:08:26,932 UNUTMAZ, WORK LED BY JULIA O AND 3481 02:08:26,999 --> 02:08:28,767 BY BRENT WILLIAMS AT OUR CENTER, 3482 02:08:28,834 --> 02:08:29,768 WHERE WE FOUND THAT THERE WERE 3483 02:08:29,835 --> 02:08:32,171 DIFFERENCES IN POPULATIONS OF 3484 02:08:32,237 --> 02:08:35,574 BACTERIA IN FECES OF INDIVIDUALS 3485 02:08:35,641 --> 02:08:36,809 WITH ME/CFS VERSUS MATCHED 3486 02:08:36,875 --> 02:08:37,443 CONTROLS. 3487 02:08:37,509 --> 02:08:41,513 AND THE IMPORTANT POINT THAT 3488 02:08:41,580 --> 02:08:43,449 DERYA HIGHLIGHTED EARLIER WAFS 3489 02:08:43,515 --> 02:08:46,518 THAT THERE WAS A REDUCTION IN A 3490 02:08:46,585 --> 02:08:48,921 FATTY ACID KNOWN ATTRIBUTE RATE 3491 02:08:48,987 --> 02:08:50,923 WHICH HAS IMPORTANT IMMUNE 3492 02:08:50,989 --> 02:08:51,690 REGULATORY PROPERTIES. 3493 02:08:51,757 --> 02:08:52,891 THERE'S ANOTHER FEATURE WHICH I 3494 02:08:52,958 --> 02:08:54,093 THINK IS ALSO IMPORTANT AND THAT 3495 02:08:54,159 --> 02:08:57,029 IS THAT THIS PARTICULAR MOLECULE 3496 02:08:57,096 --> 02:08:58,697 IS EXTREMELY IMPORTANT IN 3497 02:08:58,764 --> 02:09:00,199 MAINTAINING TIGHT JUNCTIONS IN 3498 02:09:00,265 --> 02:09:03,902 THE COLON SO THAT MOLECULES 3499 02:09:03,969 --> 02:09:05,704 DON'T TRANSIT IT EASILY FROM THE 3500 02:09:05,771 --> 02:09:07,840 UNSIDE OF THE GUT INTO THE 3501 02:09:07,906 --> 02:09:09,174 SYSTEMIC CIRCULATION WHERE THEY 3502 02:09:09,241 --> 02:09:11,043 MIGHT TRIGGER IMMUNE RESPONSES. 3503 02:09:11,110 --> 02:09:12,945 AND THESE ARE THE KEY PAPERS 3504 02:09:13,011 --> 02:09:15,714 THAT I THINK GIVE US INSIGHT 3505 02:09:15,781 --> 02:09:18,450 INTO THIS LEAKY GUT HYPOTHESIS. 3506 02:09:18,517 --> 02:09:21,153 THE INCREASED LEVELS OF LPS, THE 3507 02:09:21,220 --> 02:09:23,489 BINDING PROTEIN ST14, TWO 3508 02:09:23,555 --> 02:09:26,625 DIFFERENT GROUPS O HAVE REPORTED 3509 02:09:26,692 --> 02:09:27,826 VERY, VERY SIMILAR SORTS OF 3510 02:09:27,893 --> 02:09:28,093 FINDINGS. 3511 02:09:28,160 --> 02:09:31,029 NOW THE OTHER ASPECT, THE OTHER 3512 02:09:31,096 --> 02:09:31,997 SIDE OF THE COIN, IF YOU WILL, 3513 02:09:32,064 --> 02:09:33,432 IS THE HEIGHTENED SENSITIVITY 3514 02:09:33,499 --> 02:09:34,733 THAT WE SEE TO SOME OF THESE 3515 02:09:34,800 --> 02:09:36,101 AGENTS. 3516 02:09:36,168 --> 02:09:37,469 SO HERE IS AN EXAMPLE WHERE 3517 02:09:37,536 --> 02:09:39,138 WE'VE TAKEN SAMPLES DIRECTLY OUT 3518 02:09:39,204 --> 02:09:43,175 OF A PATIENT'S ARM, HAVE PLACED 3519 02:09:43,242 --> 02:09:44,843 THEM IN INCUBATION CHAMBERS 3520 02:09:44,910 --> 02:09:46,211 WHERE THEY'RE EXPOSED TO 3521 02:09:46,278 --> 02:09:48,514 SPECIFIC CYTOKINES, AND THEN WE 3522 02:09:48,580 --> 02:09:53,018 MEASURE IN THE SUPERNATENT WHAT 3523 02:09:53,085 --> 02:09:55,320 HAS ALLUDED INTO THAT OVER A 3524 02:09:55,387 --> 02:09:56,221 PERIOD OF 48 HOURS. 3525 02:09:56,288 --> 02:09:58,490 WHEN WE LOOK AT PRO-INFLAMMATORY 3526 02:09:58,557 --> 02:09:59,925 CYTOKINES, THE MOST ROBUST 3527 02:09:59,992 --> 02:10:01,560 RESPONSES AS YOU CAN SEE ON THE 3528 02:10:01,627 --> 02:10:05,497 FAR LEFT ARE IN WOMEN. 3529 02:10:05,564 --> 02:10:07,032 PRIMARILY WOMEN OVER THE AGE OF 3530 02:10:07,099 --> 02:10:09,034 45, AND THIS IS LINKED TO 3531 02:10:09,101 --> 02:10:10,102 CHANGES IN ESTROGEN. 3532 02:10:10,169 --> 02:10:14,606 BUT IN MALES, OLDER MALES AS 3533 02:10:14,673 --> 02:10:16,308 WELL, YOU SEE THERE'S AN 3534 02:10:16,375 --> 02:10:18,877 INCREASED RESPONSE TO THIS 3535 02:10:18,944 --> 02:10:19,711 SUPERANTIGEN TRIGGER OF 3536 02:10:19,778 --> 02:10:19,978 IMMUNITY. 3537 02:10:20,045 --> 02:10:22,781 SO AGAIN, IF YOU HAVE POROSITY 3538 02:10:22,848 --> 02:10:27,853 OF THE CLON COLON IK EPITHELIUMH 3539 02:10:27,920 --> 02:10:30,756 ALLOWS EXPOSURE AND YOU HAVE AN 3540 02:10:30,822 --> 02:10:31,924 IMMUNE SYSTEM THAT'S PRIMED IN 3541 02:10:31,990 --> 02:10:32,925 THIS WAY, YOU CAN GET THE SORT 3542 02:10:32,991 --> 02:10:34,259 OF SICKNESS BEHAVIOR THAT MANY 3543 02:10:34,326 --> 02:10:38,597 OF US ARE TALKING ABOUT. 3544 02:10:38,664 --> 02:10:39,998 SO I DESCRIBE VERY BRIEFLY, 3545 02:10:40,065 --> 02:10:41,533 BECAUSE I'M NOT AN IMMUNOLOGIST, 3546 02:10:41,600 --> 02:10:42,868 WHAT I UNDERSTAND ABOUT THE 3547 02:10:42,935 --> 02:10:44,169 INNATE IMMUNE SYSTEM AND WHY I 3548 02:10:44,236 --> 02:10:47,339 THINK THIS IS LIKELY TO BE 3549 02:10:47,406 --> 02:10:47,673 IMPORTANT. 3550 02:10:47,739 --> 02:10:49,808 THERE ARE A WHOLE SERIES OF 3551 02:10:49,875 --> 02:10:51,877 RECEPTORS IN HUMANS AND OTHER 3552 02:10:51,944 --> 02:10:53,512 MAMMALS THAT ARE CALLED TOLL 3553 02:10:53,579 --> 02:10:54,513 LIKE RECEPTORS. 3554 02:10:54,580 --> 02:10:55,581 ACTUALLY HIGHLY CONSERVED, YOU 3555 02:10:55,647 --> 02:10:57,649 CAN EVEN FIND THEM IN 3556 02:10:57,716 --> 02:10:58,116 INVERTEBRATES. 3557 02:10:58,183 --> 02:10:59,418 THEY RESPOND TO A WIDE VARIETY 3558 02:10:59,484 --> 02:11:01,286 OF DIFFERENT TYPES OF PATHOGENS. 3559 02:11:01,353 --> 02:11:03,622 THE ACTIVATION OF THESE 3560 02:11:03,689 --> 02:11:05,457 RECEPTORS LEADS TO THE 3561 02:11:05,524 --> 02:11:07,192 PRODUCTION TO THE RECRUITMENT OF 3562 02:11:07,259 --> 02:11:08,327 INTERMEDIATE MOLECULES, WHICH 3563 02:11:08,393 --> 02:11:10,929 TRAVEL INTO THE NUCLEUS ITSELF 3564 02:11:10,996 --> 02:11:12,664 AN INCREASE TRANSCRIPTION 3565 02:11:12,731 --> 02:11:15,067 ULTIMATELY RESULTING IN THE 3566 02:11:15,133 --> 02:11:16,401 EXPRESSION OF VARIOUS CYTOKINES. 3567 02:11:16,468 --> 02:11:20,339 NOW THIS IS A VERY SIMPLE SORT 3568 02:11:20,405 --> 02:11:21,506 OF DIAGRAM OF WHAT THIS LOOKS 3569 02:11:21,573 --> 02:11:24,109 LIKE, BUT YOU CAN SEE THE 3570 02:11:24,176 --> 02:11:24,843 OUTSIDE OF THE CELL AT THE TOP 3571 02:11:24,910 --> 02:11:26,345 AND YOU CAN SEE HERE THE 3572 02:11:26,411 --> 02:11:29,181 INTERNAL ORGANELLES. 3573 02:11:29,248 --> 02:11:30,616 I'D LIKE TO DRAW YOUR ATTENTION 3574 02:11:30,682 --> 02:11:32,818 TO THE FACT THAT THE TOLL-FREE 3575 02:11:32,884 --> 02:11:33,919 RECEPTOR, WHICH IS THE ONE WE 3576 02:11:33,986 --> 02:11:35,020 TYPICALLY SEE WITH VIRAL 3577 02:11:35,087 --> 02:11:37,322 INFECTIONS, AND THE TOLL 3578 02:11:37,389 --> 02:11:38,957 4 RECEPTOR WHICH IS THE ONE 3579 02:11:39,024 --> 02:11:40,692 THAT'S ACTIVATED WITH BACTERIAL 3580 02:11:40,759 --> 02:11:42,227 INFECTIONS, BOTH ACT THROUGH A 3581 02:11:42,294 --> 02:11:43,562 CONVERGENT PATHWAY, WHICH IS 3582 02:11:43,629 --> 02:11:46,064 THIS FACTOR NF KB. 3583 02:11:46,131 --> 02:11:47,165 AND ONE HYPOTHESIS THAT WE WOULD 3584 02:11:47,232 --> 02:11:50,435 LIKE TO ENTERTAIN IS THAT VIRAL 3585 02:11:50,502 --> 02:11:52,437 INFECTION INCREASES THE 3586 02:11:52,504 --> 02:11:54,306 SENSITIVITY TO THESE BACTERIAL 3587 02:11:54,373 --> 02:11:56,341 PRODUCTS WHICH MAY TRAFFIC FROM 3588 02:11:56,408 --> 02:11:58,076 THE INSIDE OF THE INTESTINE. 3589 02:11:58,143 --> 02:12:01,513 SO THE QUESTION THEN IS, CAN ABV 3590 02:12:01,580 --> 02:12:04,416 OR OTHER VIRAL INFECTIONS, 3591 02:12:04,483 --> 02:12:05,183 COXSACKIE WAS SOMETHING WE HEARD 3592 02:12:05,250 --> 02:12:08,920 ABOUT JUST A MOMENT AGO, ACT TO 3593 02:12:08,987 --> 02:12:11,056 RESET THE SET POINT FOR 3594 02:12:11,123 --> 02:12:14,826 PRO-INFLAMMATORY RESPONSES IN 3595 02:12:14,893 --> 02:12:15,827 INNATE IMMUNITY. 3596 02:12:15,894 --> 02:12:16,662 AND THAT, OF COURSE, WILL LEAD 3597 02:12:16,728 --> 02:12:17,763 TO A CORRELATE QUESTION. 3598 02:12:17,829 --> 02:12:19,731 CAN WE MODULATE THE ACTIVITY, 3599 02:12:19,798 --> 02:12:23,902 AND WOULD SUCH MODULATION IMPACT 3600 02:12:23,969 --> 02:12:26,338 THE CLINICAL COURSE OF ME/CFS? 3601 02:12:26,405 --> 02:12:27,539 THE OTHER THING I THINK WE 3602 02:12:27,606 --> 02:12:29,941 SHOULD CONSIDER WHEN WE'RE 3603 02:12:30,008 --> 02:12:31,443 THINKING ABOUT VIRAL INFECTIONS 3604 02:12:31,510 --> 02:12:33,945 OF THE CELL IS THE IMPACT ON THE 3605 02:12:34,012 --> 02:12:34,513 MITOCHONDRIA. 3606 02:12:34,579 --> 02:12:35,981 THIS GETS TO WHAT MARK DAVIS WAS 3607 02:12:36,048 --> 02:12:38,116 TALKING ABOUT EARLIER. 3608 02:12:38,183 --> 02:12:40,152 SO THERE IS EVIDENCE FROM A 3609 02:12:40,218 --> 02:12:42,020 NUMBER OF DIFFERENT GROUPS NOW 3610 02:12:42,087 --> 02:12:45,424 THAT INTERACTIONS BETWEEN VIRAL 3611 02:12:45,490 --> 02:12:46,958 PROTEINS AND ITS WIDE RANGE OF 3612 02:12:47,025 --> 02:12:49,895 TUMOR VIRUSES AND THE 3613 02:12:49,961 --> 02:12:51,997 MITOCHONDRIA WHICH FACILITATE 3614 02:12:52,064 --> 02:12:53,532 IMMUNE SURVEILLANCE ESCAPE, IF 3615 02:12:53,598 --> 02:12:56,034 YOU WILL, HAVE AN IMPACT ON 3616 02:12:56,101 --> 02:12:59,004 MITOCHONDRIAL FUNCTION. 3617 02:12:59,071 --> 02:13:00,772 AND THIS IS NOT OUR WORK BUT I 3618 02:13:00,839 --> 02:13:02,741 FOUND IT VERY, VERY EXCITING. 3619 02:13:02,808 --> 02:13:06,211 SO WITH EPSTEIN-BARR VIE RU YOU 3620 02:13:06,278 --> 02:13:08,413 CAN OVEREXPRESS THIS PROTEIN 3621 02:13:08,480 --> 02:13:10,515 LMP2, OR YOU CAN LOOK AT A 3622 02:13:10,582 --> 02:13:12,250 NATURAL INFECTION AND YOU CAN 3623 02:13:12,317 --> 02:13:17,289 SEE AS A RESULT OF THAT FISSION 3624 02:13:17,356 --> 02:13:19,791 WHICH OCCURS INSIDE THE 3625 02:13:19,858 --> 02:13:20,959 MITOCHONDRIA WHICH MIGHT HAVE AN 3626 02:13:21,026 --> 02:13:22,527 IMPACT ON THE ABILITY OF THOSE 3627 02:13:22,594 --> 02:13:23,061 MITOCHONDRIA TO FUNCTION. 3628 02:13:23,128 --> 02:13:24,963 NOW AS WE GO LOOKING FOR 3629 02:13:25,030 --> 02:13:25,630 TRIGGERS OF INFECTION, IT'S 3630 02:13:25,697 --> 02:13:26,732 IMPORTANT TO RECOGNIZE THAT NOT 3631 02:13:26,798 --> 02:13:28,800 ALL THE ASSAYS THAT WE USE ARE 3632 02:13:28,867 --> 02:13:30,235 GOING TO BE EQUAL IN TERMS OF 3633 02:13:30,302 --> 02:13:31,236 THEIR POTENCY AND 3634 02:13:31,303 --> 02:13:33,772 CHARACTERISTICS. 3635 02:13:33,839 --> 02:13:37,676 SO IF YOU USE THE COMMERCIAL EBV 3636 02:13:37,743 --> 02:13:39,344 ASSAYS FOR EXAMPLE AGAINST THOSE 3637 02:13:39,411 --> 02:13:41,179 TARGETS SEEN BELOW, YOU DON'T 3638 02:13:41,246 --> 02:13:43,815 SEE ANY DIFFERENCE BETWEEN 3639 02:13:43,882 --> 02:13:45,684 IMMUNOACTIVITY PROFILES CASES 3640 02:13:45,751 --> 02:13:48,553 VERSUS CONTROLS. 3641 02:13:48,620 --> 02:13:50,389 WE CREATED THIS PEPTIDE ARRAY 3642 02:13:50,455 --> 02:13:52,357 THAT I ALLUDED TO EARLIER, WHICH 3643 02:13:52,424 --> 02:13:54,893 ALLOWS US TO LOOK IN A MUCH MORE 3644 02:13:54,960 --> 02:13:57,829 GRANULAR FASHION AT 3645 02:13:57,896 --> 02:13:59,398 IMMUNOREACTIVITY. 3646 02:13:59,464 --> 02:14:02,901 THIS ALLOWED UTI US TO DESCRIBE 3647 02:14:02,968 --> 02:14:05,437 DIFFERENT PEPTIDE PATTERNS IN 3648 02:14:05,504 --> 02:14:07,038 ME/CFS CASES VERSUS CONTROLS. 3649 02:14:07,105 --> 02:14:09,241 NOW, WE HAVE FOCUSED PRIMARILY 3650 02:14:09,307 --> 02:14:11,309 ON WHAT WE'VE SEEN THUS FAR, 3651 02:14:11,376 --> 02:14:12,411 WHICH HAS BEEN WITH A WIDE RANGE 3652 02:14:12,477 --> 02:14:16,715 OF DIFFERENT HERPES VIRUSES, 3653 02:14:16,782 --> 02:14:21,019 CHIEFLY HSV-1, EBV, HHV-6. 3654 02:14:21,086 --> 02:14:22,187 WE HAVE NOT SEEN ANY DIFFERENCES 3655 02:14:22,254 --> 02:14:23,622 WITH RESPECT TO TICK-BORNE 3656 02:14:23,688 --> 02:14:28,727 DISEASE AGENTS OR TO ANTIVIRUS. 3657 02:14:28,794 --> 02:14:30,228 NOW DOES THIS MEAN THAT THEY 3658 02:14:30,295 --> 02:14:31,430 CAN'T BE IMPLICATED? 3659 02:14:31,496 --> 02:14:32,631 I'M NOT CERTAIN BUT IT'S NOT 3660 02:14:32,697 --> 02:14:34,266 LEADING US IN THAT WAY. 3661 02:14:34,332 --> 02:14:38,870 NOW, IF WE USE INSTEAD THINGS 3662 02:14:38,937 --> 02:14:40,605 THAT SEPARATE WITHIN EBV AND 3663 02:14:40,672 --> 02:14:44,042 OTHER HERPES VIRUSES THOSE 3664 02:14:44,109 --> 02:14:45,210 PROTEINS WHICH ARE ASSOCIATED 3665 02:14:45,277 --> 02:14:46,645 WITH REACTIVATION VERSUS THOSE 3666 02:14:46,711 --> 02:14:49,381 THAT ARE CONSTITUTIVELY 3667 02:14:49,448 --> 02:14:51,516 EXPRESSED, WE DO BEGIN TO SEE 3668 02:14:51,583 --> 02:14:53,018 DIFFERENCES. 3669 02:14:53,084 --> 02:14:56,087 SO IF YOU LOOK AT THE LEFT, 3670 02:14:56,154 --> 02:14:57,756 EBNA-1, EBNA-2, THERE'S NO 3671 02:14:57,823 --> 02:14:58,723 DIFFERENCE REALLY BETWEEN THE 3672 02:14:58,790 --> 02:14:59,424 CASES AND CONTROLS. 3673 02:14:59,491 --> 02:15:01,293 HOWEVER, WHEN YOU LOOK AT THESE 3674 02:15:01,359 --> 02:15:04,262 OTHER PROTEINS LIKE THE DNA 3675 02:15:04,329 --> 02:15:07,265 POLYMERASE OR BZLF1, YOU BEGIN 3676 02:15:07,332 --> 02:15:07,933 TO SEE DIFFERENCES. 3677 02:15:07,999 --> 02:15:10,368 NOW THEY'RE NOT SIGNIFICANT YET. 3678 02:15:10,435 --> 02:15:12,571 BUT THE NUMBERS REMAIN SMALL, 3679 02:15:12,637 --> 02:15:15,307 AND WE HAVEN'T USED A TRULY 3680 02:15:15,373 --> 02:15:17,776 QUANTITATIVE ASSAY LIKE AN ELI 3681 02:15:17,843 --> 02:15:23,849 ELIZABUT I THINK THERE'S LIKELYE 3682 02:15:23,915 --> 02:15:24,216 SOME FRUIT HERE. 3683 02:15:24,282 --> 02:15:25,951 IF YOU LOOK AT THIS MOLECULE IN 3684 02:15:26,017 --> 02:15:28,320 TERMS OF EPSTEIN-BARR VIRUS, IF 3685 02:15:28,386 --> 02:15:30,622 YOU LOOK AT THE TOP PANEL FOUR 3686 02:15:30,689 --> 02:15:31,957 OVER, YOU CAN SEE A VERY, VERY 3687 02:15:32,023 --> 02:15:32,991 DIFFERENT PATTERN THAN YOU SEE 3688 02:15:33,058 --> 02:15:35,360 IN THE NORMAL CONTROLS. 3689 02:15:35,427 --> 02:15:36,928 THIS SUGGESTS TO US THAT THERE 3690 02:15:36,995 --> 02:15:39,731 MAY BE SOME EVIDENCE OF 3691 02:15:39,798 --> 02:15:42,400 REACTIVATION OF SOME SORT WITH 3692 02:15:42,467 --> 02:15:43,835 EPSTEIN-BARR VIRUS IN 3693 02:15:43,902 --> 02:15:45,237 ASSOCIATION WITH DISEASE. 3694 02:15:45,303 --> 02:15:48,206 NOW, MIND YOU WE HAVE NOT LOOKED 3695 02:15:48,273 --> 02:15:50,175 AT ALL AT WHETHER OR NOT THESE 3696 02:15:50,242 --> 02:15:54,880 FINDINGS CAN BE LINKEDIN LINKEE 3697 02:15:54,946 --> 02:15:56,214 FATION TO AN INCREASE OF 3698 02:15:56,281 --> 02:15:57,415 SEVERITY OF DISEASE OR SOME SORT 3699 02:15:57,482 --> 02:15:58,316 OF IMPROVEMENT. 3700 02:15:58,383 --> 02:16:00,418 AND THIS GOOD DAY/BAD DAY 3701 02:16:00,485 --> 02:16:01,720 PROJECT, WHICH IS NUMBER ONE IN 3702 02:16:01,786 --> 02:16:04,055 OUR NEXT CENTER PROPOSAL, WILL 3703 02:16:04,122 --> 02:16:06,324 ALLOW US TO DO THIS. 3704 02:16:06,391 --> 02:16:07,626 NOW, AS I WAS THINKING MORE AND 3705 02:16:07,692 --> 02:16:10,729 MORE ABOUT INNATE IMMUNITY, I 3706 02:16:10,795 --> 02:16:14,099 CAME ACROSS WORK TALKING ABOUT 3707 02:16:14,165 --> 02:16:15,534 IL37, AND IT'S REALLY 3708 02:16:15,600 --> 02:16:16,067 INTRIGUING. 3709 02:16:16,134 --> 02:16:19,704 THIS IS A MEMBER OF THE IL-1 3710 02:16:19,771 --> 02:16:20,105 SUPERFAMILY. 3711 02:16:20,171 --> 02:16:21,573 IT IS BROADLY DISTRIBUTED BY 3712 02:16:21,640 --> 02:16:24,276 ORGANS AND BY CELLS AND HAS THE 3713 02:16:24,342 --> 02:16:25,977 ABILITY TO INTERFERE WITH INNATE 3714 02:16:26,044 --> 02:16:28,580 IMMUNITY. 3715 02:16:28,647 --> 02:16:30,348 AND WHAT HE AND HIS COLLEAGUES 3716 02:16:30,415 --> 02:16:33,418 HAVE DONE IS TO EXAMINE THIS LPS 3717 02:16:33,485 --> 02:16:34,619 MODEL. 3718 02:16:34,686 --> 02:16:36,254 THIS IS A COMPOUND THAT'S 3719 02:16:36,321 --> 02:16:38,156 RELEASED BY GRAM-NEGATIVE 3720 02:16:38,223 --> 02:16:40,692 BACTERIA, AND YOU CAN SEE IN 3721 02:16:40,759 --> 02:16:42,961 PANEL A THAT IF YOU TAKE ANIMALS 3722 02:16:43,028 --> 02:16:46,598 THAT ARE EXPOSED TO LPS AND YOU 3723 02:16:46,665 --> 02:16:49,000 PRE-TREAT THEM WITH IL-37, THEY 3724 02:16:49,067 --> 02:16:52,304 DON'T HAVE A ROBUST RESPONSE IN 3725 02:16:52,370 --> 02:16:57,075 TERMS OF EXPRESSION OF IL-6 AND 3726 02:16:57,142 --> 02:16:58,009 YOU CAN ACTUALLY SHOW THAT 3727 02:16:58,076 --> 02:16:59,744 THERE'S A DRAMATIC IMPROVEMENT 3728 02:16:59,811 --> 02:17:00,612 IN THEIR MOBILITY. 3729 02:17:00,679 --> 02:17:05,584 SO THEIR RUNNING TIME REDUCTION 3730 02:17:05,650 --> 02:17:07,152 IS LARGELY ABROGATED AS A RESULT 3731 02:17:07,218 --> 02:17:09,054 OF THE EXPOSURE TO IL-37. 3732 02:17:09,120 --> 02:17:12,591 IT SEEMS TO PROTECT THE MICE. 3733 02:17:12,657 --> 02:17:13,792 WE ALSO SEE THAT IN HEALTHY 3734 02:17:13,858 --> 02:17:16,494 MICE, WHICH IS IN FIGURE 2, 3735 02:17:16,561 --> 02:17:18,096 THERE IS ALSO AN IMPROVEMENT IN 3736 02:17:18,163 --> 02:17:19,598 THE ENDURANCE OF THESE ANIMALS. 3737 02:17:19,664 --> 02:17:20,799 SO THIS IS REALLY EXCITING 3738 02:17:20,865 --> 02:17:23,001 BECAUSE IT'S CORRELATED WITH AN 3739 02:17:23,068 --> 02:17:24,869 INCREASE IN OXYGEN CONSUMPTION. 3740 02:17:24,936 --> 02:17:26,838 SO I'VE NEVER ACTUALLY SEEN 3741 02:17:26,905 --> 02:17:29,441 ANYTHING BEFORE THIS WHERE 3742 02:17:29,507 --> 02:17:30,909 THERE'S BEEN ONE MOLECULE THAT'S 3743 02:17:30,976 --> 02:17:33,511 BEEN ABLE TO SOMEHOW TRANSFORM 3744 02:17:33,578 --> 02:17:36,381 THIS RESPONSE TO INNATE IMMUNE 3745 02:17:36,448 --> 02:17:38,350 STIMULI AND PREVENT THE SICKNESS 3746 02:17:38,416 --> 02:17:38,617 BEHAVIOR. 3747 02:17:38,683 --> 02:17:40,018 AND I'LL COME BACK TO THAT AT 3748 02:17:40,085 --> 02:17:44,589 THE VERY END. 3749 02:17:44,656 --> 02:17:46,491 NOW, I DON'T ACTUALLY PRACTICE 3750 02:17:46,558 --> 02:17:47,592 CLINICAL MEDICINE ANYMORE, BUT I 3751 02:17:47,659 --> 02:17:50,428 WORK VERY CLOSELY WITH A NUMBER 3752 02:17:50,495 --> 02:17:51,863 OF CLINICIANS. 3753 02:17:51,930 --> 02:17:54,833 AND I WANT TO JUST REFERENCE TWO 3754 02:17:54,899 --> 02:17:55,834 OF THEM IN PARTICULAR. 3755 02:17:55,900 --> 02:17:58,236 ONE WAS VANESSA LI, WHO WAS THE 3756 02:17:58,303 --> 02:18:00,105 CO-FOUNDER OF THE MICROBE 3757 02:18:00,171 --> 02:18:01,239 DISCOVERY PROJECT WHICH LAUNCHED 3758 02:18:01,306 --> 02:18:03,375 MUCH OF OUR WORK. 3759 02:18:03,441 --> 02:18:05,076 SADLY, WE LOST HER TO SUICIDE IN 3760 02:18:05,143 --> 02:18:06,845 2015. 3761 02:18:06,911 --> 02:18:08,079 THERE'S ANOTHER YOUNG WOMAN, 3762 02:18:08,146 --> 02:18:10,348 THIS IS HER PSEUDONYM, 3763 02:18:10,415 --> 02:18:10,782 CHRISTINA. 3764 02:18:10,849 --> 02:18:13,184 I'VE BEEN FOLLOWING HER FOR AT 3765 02:18:13,251 --> 02:18:16,154 LEAST FOUR YEARS, AND I'VE 3766 02:18:16,221 --> 02:18:18,790 WORKED WITH YAN PETERSON IN 3767 02:18:18,857 --> 02:18:20,025 GETTING HER TREATMENT. 3768 02:18:20,091 --> 02:18:23,461 SHE INITIATED AMPLIGEN TREATMENT 3769 02:18:23,528 --> 02:18:25,230 IN 2022, AND OVER A PERIOD OF 3770 02:18:25,296 --> 02:18:26,398 MONTHS, SHE'S BEEN ABLE TO GET 3771 02:18:26,464 --> 02:18:28,299 TO THE POINT WHERE SHE'S LEFT A 3772 02:18:28,366 --> 02:18:28,600 DARKROOM. 3773 02:18:28,667 --> 02:18:30,702 FIRST SHE SAT UP, NOW SHE CAN GO 3774 02:18:30,769 --> 02:18:32,370 OUTSIDE AND SHE'S ABLE TO 3775 02:18:32,437 --> 02:18:34,005 TOLERATE FAR MORE IN THE WAY OF 3776 02:18:34,072 --> 02:18:36,107 NOISE AND STIMULI. 3777 02:18:36,174 --> 02:18:38,943 THIS HAS BEEN AN ABSOLUTELY 3778 02:18:39,010 --> 02:18:40,812 EXTRAORDINARY ROWRY SPONS. 3779 02:18:40,879 --> 02:18:45,417 -- RESPONSE.AGAIN WE NEED TO TE 3780 02:18:45,483 --> 02:18:46,651 INNATE IMMUNE SYSTEM AND THE 3781 02:18:46,718 --> 02:18:48,186 WAYS IN WHICH YOU MIGHT INTERACT 3782 02:18:48,253 --> 02:18:48,920 WITH SOME OF THESE DIFFERENT 3783 02:18:48,987 --> 02:18:49,387 DRUGS. 3784 02:18:49,454 --> 02:18:50,588 NOW, THOSE OF YOU WHO KNOW ME 3785 02:18:50,655 --> 02:18:51,956 WELL KNOW THAT OVER THE PAST 3786 02:18:52,023 --> 02:18:54,592 YEAR, I'VE HAD A LOT OF HEALTH 3787 02:18:54,659 --> 02:18:54,926 DIFFICULTIES. 3788 02:18:54,993 --> 02:18:57,662 AND WHAT THIS HAS ACTUALLY DONE 3789 02:18:57,729 --> 02:19:00,498 FOR ME IS TO GIVE ME A MUCH 3790 02:19:00,565 --> 02:19:02,834 DEEPER APPRECIATION OF THE 3791 02:19:02,901 --> 02:19:05,003 URGENCY OF GETTING TO SOLUTIONS 3792 02:19:05,070 --> 02:19:08,306 FOR ME/CFS. 3793 02:19:08,373 --> 02:19:10,008 MY PROBLEMS STARTED STRUCTURAL 3794 02:19:10,075 --> 02:19:12,243 BUT THEY'VE BECOME METABOLIC AS 3795 02:19:12,310 --> 02:19:12,877 WELL. 3796 02:19:12,944 --> 02:19:13,978 CONGESTIVE HEART FAILURE, A 3797 02:19:14,045 --> 02:19:14,979 VARIETY OF OTHER SORTS OF 3798 02:19:15,046 --> 02:19:15,714 PROBLEMS. 3799 02:19:15,780 --> 02:19:17,382 I TAKE A WIDE RANGE OF DRUGS AT 3800 02:19:17,449 --> 02:19:18,016 THIS POINT. 3801 02:19:18,083 --> 02:19:20,685 KEY IN MANAGING MY MEDICAL 3802 02:19:20,752 --> 02:19:22,320 THERAPY HAS BEEN THE 3803 02:19:22,387 --> 02:19:23,955 AVAILABILITY OF A BIOMARKER. 3804 02:19:24,022 --> 02:19:29,360 IN THIS CASE, B TYPE NATRIATIC 3805 02:19:29,427 --> 02:19:30,028 PEPTIDE. 3806 02:19:30,095 --> 02:19:33,965 SO IT STARTED EXTREMELY HIGH, IT 3807 02:19:34,032 --> 02:19:35,700 DROPPED WITH DRUG THERAPY, IT 3808 02:19:35,767 --> 02:19:36,901 WENT UP AFTER A COUPLE OF 3809 02:19:36,968 --> 02:19:38,503 OPERATIONS AND NOW IT'S COMING 3810 02:19:38,570 --> 02:19:39,137 BACK TOWARDS NORMAL. 3811 02:19:39,204 --> 02:19:40,572 SO I HAVE A DEEPER APPRECIATION 3812 02:19:40,638 --> 02:19:43,508 FOR THE IMPACT OF AUTO MO MIBG 3813 02:19:43,575 --> 02:19:45,143 DYSFUNCTION AND FATIGUE ON DAILY 3814 02:19:45,210 --> 02:19:47,445 LIFE, AS WELL AS AN APPRECIATION 3815 02:19:47,512 --> 02:19:48,646 FOR THE IMPORTANCE OF 3816 02:19:48,713 --> 02:19:49,781 BIOMARKERS. 3817 02:19:49,848 --> 02:19:52,817 SO I'M GOING TO SUMMARIZE MY 3818 02:19:52,884 --> 02:19:54,486 TALK VERY, VERY RAPIDLY BY 3819 02:19:54,552 --> 02:19:56,654 SIMPLY TELLING YOU THAT I DO 3820 02:19:56,721 --> 02:19:59,524 THINK THERE'S LIKELY TO BE AN 3821 02:19:59,591 --> 02:20:02,060 IMPORTANT ROLE FOR INFECTION IN 3822 02:20:02,127 --> 02:20:04,262 TRIGGERING AND EXACERBATING 3823 02:20:04,329 --> 02:20:06,631 DISEASE WITH ME/CFS. 3824 02:20:06,698 --> 02:20:08,433 WE JUST HAVEN'T CLARIFIED WHAT 3825 02:20:08,500 --> 02:20:10,301 IT IS, AND IT'S UNLIKELY THAT 3826 02:20:10,368 --> 02:20:12,737 IT'S GOING TO BE A SINGLE AGENT. 3827 02:20:12,804 --> 02:20:16,775 AND I THINK SARS-COV-2 EXPOSURE 3828 02:20:16,841 --> 02:20:18,009 AND LONG COVID GIVES BETTER 3829 02:20:18,076 --> 02:20:19,944 CREDENCE TO THIS SORT OF 3830 02:20:20,011 --> 02:20:20,245 HYPOTHESIS. 3831 02:20:20,311 --> 02:20:21,179 WE'VE NOT YET BEEN ABLE TO 3832 02:20:21,246 --> 02:20:22,380 IDENTIFY THE AGENT OR AGENTS 3833 02:20:22,447 --> 02:20:25,350 THAT ARE RESPONSIBLE FOR THIS. 3834 02:20:25,416 --> 02:20:27,318 HOWEVER, WE HAVEN'T LINKED 3835 02:20:27,385 --> 02:20:29,554 SAMPLE COLLECTION TO CHANGES IN 3836 02:20:29,621 --> 02:20:31,389 CLINICAL STATUS, NOR HAVE WE 3837 02:20:31,456 --> 02:20:33,458 USED HIGH RESOLUTION SEROLOGY. 3838 02:20:33,525 --> 02:20:37,262 BOTH OF THESE ARE NOW PLAUSIBLE. 3839 02:20:37,328 --> 02:20:39,097 WE BELIEVE THAT DYSREGULATION OF 3840 02:20:39,164 --> 02:20:42,066 THE GUT MICROBIOME BASED ON SOME 3841 02:20:42,133 --> 02:20:47,806 OF THE DA DATA THAT DERY. 3842 02:20:47,872 --> 02:20:48,540 A SHOWED US 3843 02:20:48,606 --> 02:20:49,707 LATER IS GOING TO BE IMPORTANT 3844 02:20:49,774 --> 02:20:50,909 BECAUSE IT MOD LATES 3845 02:20:50,975 --> 02:20:52,043 INFLAMMATION AND IT'S ALSO 3846 02:20:52,110 --> 02:20:53,711 ASSOCIATED WITH POROSITY OF THE 3847 02:20:53,778 --> 02:20:56,581 BACTERIAL CELL WALL TO THE 3848 02:20:56,648 --> 02:20:59,017 TRANSFER OF PRODUCTS THAT CAN 3849 02:20:59,083 --> 02:21:00,785 IMPACT INNATE IMMUNITY. 3850 02:21:00,852 --> 02:21:02,854 AND I WOULD SAY THAT ALTHOUGH WE 3851 02:21:02,921 --> 02:21:04,756 DON'T FULLY UNDERSTAND THE 3852 02:21:04,823 --> 02:21:07,959 PATHOPHYSIOLOGY OF ME/CFS, IT IS 3853 02:21:08,026 --> 02:21:09,961 NOT PREMATURE TO ASK WHETHER OR 3854 02:21:10,028 --> 02:21:12,964 NOT THERE'S SOMETHING WE SHOULD 3855 02:21:13,031 --> 02:21:14,766 CONSIDER, AS LONG AS IT DOESN'T 3856 02:21:14,833 --> 02:21:17,368 HAVE PROFOUND ADVERSE EFFECTS 3857 02:21:17,435 --> 02:21:20,705 AND AS LONG AS IT'S UNDERTAKEN 3858 02:21:20,772 --> 02:21:22,507 THROUGH SOME SORT OF A 3859 02:21:22,574 --> 02:21:23,875 RANDOMIZED CLINICAL TRIAL. 3860 02:21:23,942 --> 02:21:27,345 SO THESE WOULD BE PRE AND 3861 02:21:27,412 --> 02:21:29,781 PROBIOTICS THAT ADDRESS 3862 02:21:29,848 --> 02:21:30,448 DYSBIOSIS AND RESULT IN AN 3863 02:21:30,515 --> 02:21:31,716 INCREASE IN LEVELS OF BUTYRATE 3864 02:21:31,783 --> 02:21:34,619 IN THE GUT, AS WELL AS DRUGS 3865 02:21:34,686 --> 02:21:37,155 THAT MODULATE INNATE IMMUNE 3866 02:21:37,222 --> 02:21:40,425 RESPONSES SUCH AS POLYIC, ALSO 3867 02:21:40,491 --> 02:21:43,628 KNOWN AS AMPLIGEN OR IL37. 3868 02:21:43,695 --> 02:21:45,597 I WILL SAY THAT THE COST RIGHT 3869 02:21:45,663 --> 02:21:51,769 NOW FOR POLY I-:C IS ABSURD. 3870 02:21:51,836 --> 02:21:53,938 THIS IS A VERY CHEAP MOLECULE TO 3871 02:21:54,005 --> 02:21:54,939 MAKE AND THERE'S NO REASON IT 3872 02:21:55,006 --> 02:21:56,474 SHOULDN'T BE AVAILABLE AT A FAR 3873 02:21:56,541 --> 02:21:57,375 LOWER COST. 3874 02:21:57,442 --> 02:21:58,576 AND FROM MY OWN PERSONAL 3875 02:21:58,643 --> 02:22:00,111 EXPERIENCE WITH CONGESTIVE HEART 3876 02:22:00,178 --> 02:22:01,880 FAILURE, I CAN TELL YOU THAT IF 3877 02:22:01,946 --> 02:22:04,849 WE WANT TO PURSUE PRECISION 3878 02:22:04,916 --> 02:22:07,151 MEDICINE, WE ARE GOING TO NEED 3879 02:22:07,218 --> 02:22:08,453 BIOMARKERS THAT ALLOW YOU TO 3880 02:22:08,519 --> 02:22:11,322 FORECAST CHANGES IN CLINICAL 3881 02:22:11,389 --> 02:22:12,190 STATUS, BECAUSE THE CHANGES AS 3882 02:22:12,257 --> 02:22:13,858 THEY OCCUR TOWARD IMPROVEMENT 3883 02:22:13,925 --> 02:22:16,261 ARE GOING TO BE VISUALIZED ON A 3884 02:22:16,327 --> 02:22:18,162 TIME SCALE PROBABLY ONE TO TWO 3885 02:22:18,229 --> 02:22:18,897 YEARS. 3886 02:22:18,963 --> 02:22:19,597 THANK YOU. 3887 02:22:19,664 --> 02:22:27,538 [APPLAUSE] 3888 02:22:27,605 --> 02:22:29,507 DO I HAVE TIME FOR QUESTIONS? 3889 02:22:29,574 --> 02:22:30,842 I CAN TAKE TWO QUESTIONS 3890 02:22:30,909 --> 02:22:33,912 APPARENTLY. 3891 02:22:33,978 --> 02:22:35,513 I THINK WE HEARD FROM JOHN 3892 02:22:35,580 --> 02:22:36,347 MARTIN EARLIER. 3893 02:22:36,414 --> 02:22:42,887 IF HE'S STILL HERE. 3894 02:22:42,954 --> 02:22:43,955 >> IS THIS ON? 3895 02:22:44,022 --> 02:22:44,489 OKAY. 3896 02:22:44,555 --> 02:22:44,956 HI. 3897 02:22:45,023 --> 02:22:47,992 I WAS CURIOUS IF YOU COULD SPEAK 3898 02:22:48,059 --> 02:22:51,095 TO -- I DON'T FOLLOW, YOU KNOW, 3899 02:22:51,162 --> 02:22:53,197 THE AMPLIGEN TRIALS PARTICULARLY 3900 02:22:53,264 --> 02:22:54,866 IN DETAIL, BUT ONE OF THE THINGS 3901 02:22:54,933 --> 02:22:58,269 I HAD TROUBLE RECONCILING IS HOW 3902 02:22:58,336 --> 02:23:00,672 THAT COULD IMPROVE SYMPTOMS IN 3903 02:23:00,738 --> 02:23:03,374 PEOPLE WITH CFS, ESPECIALLY IF 3904 02:23:03,441 --> 02:23:05,510 ONE OF THE THOUGHTS IS THERE'S 3905 02:23:05,576 --> 02:23:10,248 OVERACTIVE INNATE IMMUNITY, TLRT 3906 02:23:10,315 --> 02:23:11,215 IT'S CLEARING SOME RESIDUAL 3907 02:23:11,282 --> 02:23:12,884 VIRUS AND DO YOU HAVE ANY 3908 02:23:12,951 --> 02:23:14,852 INTEREST IN EXAMINING THOSE 3909 02:23:14,919 --> 02:23:15,987 RESPONDERS PRE AND POST TO SEE 3910 02:23:16,054 --> 02:23:18,289 WHAT EXACTLY IT'S DOING? 3911 02:23:18,356 --> 02:23:20,692 >> SO THERE ARE ACTUALLY TWO 3912 02:23:20,758 --> 02:23:21,292 QUESTIONS THERE. 3913 02:23:21,359 --> 02:23:23,061 ONE OF THEM HAS TO DO WITH HOW 3914 02:23:23,127 --> 02:23:25,096 DO YOU RECONCILE IN ONE INSTANCE 3915 02:23:25,163 --> 02:23:26,297 WHERE YOU'RE TRYING TO RAMP UP 3916 02:23:26,364 --> 02:23:27,465 THE IMMUNE SYSTEM AND THE OTHER, 3917 02:23:27,532 --> 02:23:28,700 YOU'RE TRYING TO DAMPEN IT, AND 3918 02:23:28,766 --> 02:23:30,501 HOW YOU CAN RECONCILE THOSE TWO. 3919 02:23:30,568 --> 02:23:32,136 I DON'T THINK ME/CFS IS A SINGLE 3920 02:23:32,203 --> 02:23:33,237 DISEASE. 3921 02:23:33,304 --> 02:23:35,206 I THINK THERE ARE PROBABLY 3922 02:23:35,273 --> 02:23:37,976 MULTIPLE PHENOTYPES AND MAY ALSO 3923 02:23:38,042 --> 02:23:39,077 BE DIFFERENCES. 3924 02:23:39,143 --> 02:23:40,611 OVER THE COURSE AS YOU SAW 3925 02:23:40,678 --> 02:23:41,713 EARLIER, THERE ARE DIFFERENCES 3926 02:23:41,779 --> 02:23:42,914 IN THE FIRST THREE TO FOUR YEARS 3927 02:23:42,981 --> 02:23:44,716 OF DISEASE VERSUS LATER. 3928 02:23:44,782 --> 02:23:46,217 SO ONE THING THAT MIGHT BE 3929 02:23:46,284 --> 02:23:47,852 USEFUL EARLY IN THE COURSE MAY 3930 02:23:47,919 --> 02:23:51,189 NOT BE USEFUL LATER ON. 3931 02:23:51,255 --> 02:23:55,460 THE OTHER ISSUE IS, IF YOU THINK 3932 02:23:55,526 --> 02:23:56,761 BACK TO THE EARLY DAYS OF 3933 02:23:56,828 --> 02:23:58,563 HEPATITIS C, WE USED TO TREAT 3934 02:23:58,629 --> 02:24:02,600 PATIENTS WITH INTERFERONS AND 3935 02:24:02,667 --> 02:24:05,436 WITH RIBOVIRIN, A DRUG THAT 3936 02:24:05,503 --> 02:24:07,572 CAUSES MUTATIONS IN THE HVC 3937 02:24:07,638 --> 02:24:07,805 GENOME. 3938 02:24:07,872 --> 02:24:08,973 NOW WE HAVE SPECIFIC DRUGS. 3939 02:24:09,040 --> 02:24:11,075 SO I CAN ENVISION A SITUATION 3940 02:24:11,142 --> 02:24:12,543 WHERE YOU HAVE CRYPTIC INFECTION 3941 02:24:12,610 --> 02:24:14,612 WITH SOME HERPES VIRUS OR ANY 3942 02:24:14,679 --> 02:24:16,681 VIRUS FOR THAT MATTER, AND AS A 3943 02:24:16,748 --> 02:24:19,417 FUNCTION OF BEING EXPOSED TO 3944 02:24:19,484 --> 02:24:20,318 AMPLIGEN, YOU MIGHT SOMEHOW 3945 02:24:20,385 --> 02:24:21,552 INTERFERE WITH THE ABILITY OF 3946 02:24:21,619 --> 02:24:23,187 THAT VIRUS TO REPLICATE. 3947 02:24:23,254 --> 02:24:25,490 BUT THAT'S PURELY SPECULATIVE. 3948 02:24:25,556 --> 02:24:27,291 IT'S SOMETHING THAT WE HOPE TO 3949 02:24:27,358 --> 02:24:30,028 GET INTO WITH THIS GOOD DAY/BAD 3950 02:24:30,094 --> 02:24:30,495 DAY PROJECT. 3951 02:24:30,561 --> 02:24:30,828 >> THANK YOU. 3952 02:24:30,895 --> 02:24:38,236 >> THANKS FOR YOUR QUESTION. 3953 02:24:38,302 --> 02:24:48,413 OKAY. 3954 02:24:49,647 --> 02:24:51,516 >> THANKS VERY MUCH, DR. LIPKIN. 3955 02:24:51,582 --> 02:24:59,090 I'D LIKE TO INTRODUCE DR. AVI 3956 02:24:59,157 --> 02:25:00,391 NATH FROM THE NATIONAL INSTITUTE 3957 02:25:00,458 --> 02:25:01,392 OF NEUROLOGICAL DISORDERS AND 3958 02:25:01,459 --> 02:25:02,493 STROKE WHO ACTUALLY AT THIS 3959 02:25:02,560 --> 02:25:06,664 MEETING IN 2019, BRIAN WALLIN 3960 02:25:06,731 --> 02:25:09,100 AND AVI TOLD US ABOUT A 3961 02:25:09,167 --> 02:25:10,401 LONGITUDINAL ME/CFS STUDY THIS 3962 02:25:10,468 --> 02:25:11,869 THEY WERE STARTING, AND THEN THE 3963 02:25:11,936 --> 02:25:13,404 PANDEMIC HAPPENED AND THEY 3964 02:25:13,471 --> 02:25:15,473 SUBSEQUENTLY SET UP A 3965 02:25:15,540 --> 02:25:16,374 LONGITUDINAL STUDY FOR LONG 3966 02:25:16,441 --> 02:25:17,075 COVID, AND I'M SURE OTHERS THAT 3967 02:25:17,141 --> 02:25:18,476 I DON'T KNOW ABOUT. 3968 02:25:18,543 --> 02:25:21,446 SO TODAY, AVI IS GOING TO TALK 3969 02:25:21,512 --> 02:25:22,880 TO US ABOUT CLINICAL PHENOTYPES 3970 02:25:22,947 --> 02:25:24,515 OF LONG COVID, 3971 02:25:24,582 --> 02:25:25,283 PATHOPHYSIOLOGICAL MECHANISMS 3972 02:25:25,349 --> 02:25:35,660 AND INTERVENTIONS. 3973 02:25:37,995 --> 02:25:42,500 >> THANKS, DR. BREEN. 3974 02:25:42,567 --> 02:25:44,035 IAN'S TALK IS ALWAYS A HARD ACT 3975 02:25:44,102 --> 02:25:44,802 TO FOLLOW. 3976 02:25:44,869 --> 02:25:46,604 HE DOES SUCH A SUPERB JOB AND 3977 02:25:46,671 --> 02:25:47,472 REALLY NICE WORK. 3978 02:25:47,538 --> 02:25:48,339 SO I'M GOING TO TELL YOU A 3979 02:25:48,406 --> 02:25:49,874 LITTLE BIT ABOUT WHERE WE STAND 3980 02:25:49,941 --> 02:25:52,910 WITH LONG COVID. 3981 02:25:52,977 --> 02:25:54,912 AND YOU'LL SEE THAT THERE ARE 3982 02:25:54,979 --> 02:25:56,347 PARALLELS BETWEEN THE TWO 3983 02:25:56,414 --> 02:26:00,551 DISEASES. 3984 02:26:00,618 --> 02:26:01,552 ONE GOOD THING ABOUT WORKING 3985 02:26:01,619 --> 02:26:02,887 WITH THE GOVERNMENT IS YOU NEVER 3986 02:26:02,954 --> 02:26:05,756 HAVE ANY DISCLOSURES. 3987 02:26:05,823 --> 02:26:06,290 [LAUGHTER] 3988 02:26:06,357 --> 02:26:10,695 SOMETIMES I WISH I HAD SOME. 3989 02:26:10,761 --> 02:26:11,362 OKAY. 3990 02:26:11,429 --> 02:26:12,997 SO FIRST OF ALL, WE ALL THINK WE 3991 02:26:13,064 --> 02:26:14,532 KNOW WHAT LONG COVID IS. 3992 02:26:14,599 --> 02:26:15,766 THE THING IS, NOBODY REALLY 3993 02:26:15,833 --> 02:26:17,735 KNOWS WHAT IT ACTUALLY IS. 3994 02:26:17,802 --> 02:26:20,238 THE TERM LONG COVID ITSELF WAS 3995 02:26:20,304 --> 02:26:22,540 COINED BY PATIENTS. 3996 02:26:22,607 --> 02:26:24,175 AND IT WAS LIKE, WELL, I GOT 3997 02:26:24,242 --> 02:26:25,977 COVID AND I'M NOT GETTING ANY 3998 02:26:26,043 --> 02:26:28,279 BETTER, I GOT LONG COVID. 3999 02:26:28,346 --> 02:26:29,647 IT'S AS SIMPLE AS THAT. 4000 02:26:29,714 --> 02:26:31,048 NIH CAME UP WITH ANOTHER 4001 02:26:31,115 --> 02:26:32,183 DEFINITION. 4002 02:26:32,250 --> 02:26:34,685 POST-ACUTE SEQUELAE OF COVID-19. 4003 02:26:34,752 --> 02:26:37,255 THAT'S A MOUTHFUL. 4004 02:26:37,321 --> 02:26:39,857 AND THEN THE WHO TRIED TO 4005 02:26:39,924 --> 02:26:41,492 SIMPLIFY IT, THEY CALL IT 4006 02:26:41,559 --> 02:26:42,226 POST-COVID. 4007 02:26:42,293 --> 02:26:44,829 SO IF YOU LOOK AT THE WHO 4008 02:26:44,896 --> 02:26:46,297 DEFINITION, IT IS THE 4009 02:26:46,364 --> 02:26:47,565 CONTINUATION OF OR DEVELOPMENT 4010 02:26:47,632 --> 02:26:50,168 OF NEW SYMPTOMS THREE MONTHS 4011 02:26:50,234 --> 02:26:52,770 AFTER INITIAL SARS-COV-2 4012 02:26:52,837 --> 02:26:54,505 INFECTION WITH THESE SYMPTOMS 4013 02:26:54,572 --> 02:26:56,174 LASTING FOR MORE THAN -- FOR AT 4014 02:26:56,240 --> 02:26:57,441 LEAST TWO MONTHS, WITH NO OTHER 4015 02:26:57,508 --> 02:26:58,342 EXPLANATION. 4016 02:26:58,409 --> 02:27:00,011 THE PROBLEM WITH THIS DEFINITION 4017 02:27:00,077 --> 02:27:02,647 IS THAT IT ENCOMPASSES ALMOST 4018 02:27:02,713 --> 02:27:05,416 EVERYTHING THAT'S GOING ON WITH 4019 02:27:05,483 --> 02:27:07,385 YOU AFTER THREE MONTHS OF 4020 02:27:07,451 --> 02:27:09,921 INFECTION. 4021 02:27:09,987 --> 02:27:11,789 AND SO WHAT IT DOESN'T ACCOUNT 4022 02:27:11,856 --> 02:27:13,558 FOR ARE THESE TWO DIFFERENT 4023 02:27:13,624 --> 02:27:16,294 POSSIBILITIES. 4024 02:27:16,360 --> 02:27:17,862 FIRST, IF YOU'RE ADMITTED IN THE 4025 02:27:17,929 --> 02:27:19,397 HOSPITAL, YOU HAVE ACUTE COVID, 4026 02:27:19,463 --> 02:27:21,232 IT IS NO SURPRISE THAT WHEN YOU 4027 02:27:21,299 --> 02:27:22,934 COME OUT, YOU'RE NOT GOING TO BE 4028 02:27:23,000 --> 02:27:23,267 FULLY BETTER. 4029 02:27:23,334 --> 02:27:24,569 IT'S GOING TO TAKE A WHILE. 4030 02:27:24,635 --> 02:27:26,204 BUT IT'S THE END ORGAN DAMAGE 4031 02:27:26,270 --> 02:27:28,139 THAT OCCURRED AS A SINGLE EVENT 4032 02:27:28,206 --> 02:27:28,940 DURING THE HOSPITALIZATION THAT 4033 02:27:29,006 --> 02:27:31,209 IS THE CAUSE OF YOUR SYMPTOMS. 4034 02:27:31,275 --> 02:27:32,944 SO THAT CATEGORY HAS TO BE 4035 02:27:33,010 --> 02:27:34,111 SEPARATED. 4036 02:27:34,178 --> 02:27:35,513 THEN YOU HAVE THE SECOND 4037 02:27:35,580 --> 02:27:36,547 CATEGORY OF INDIVIDUALS WHO 4038 02:27:36,614 --> 02:27:37,949 SAID, YOU KNOW, I NEVER WENT TO 4039 02:27:38,015 --> 02:27:40,284 THE HOSPITAL, ACTUALLY I GOT 4040 02:27:40,351 --> 02:27:42,220 SICK, I NEVER EVEN SAW A DOCTOR. 4041 02:27:42,286 --> 02:27:45,323 I GOT BETTER, I ESCAPED IT. 4042 02:27:45,389 --> 02:27:47,291 AND THEN A FEW DAYS OR WEEKS GO 4043 02:27:47,358 --> 02:27:48,426 BY AND THEY SAY, YOU KNOW WHAT, 4044 02:27:48,492 --> 02:27:50,094 I DON'T KNOW, I GOT THIS CHEST 4045 02:27:50,161 --> 02:27:51,195 PAIN, I CAN'T REALLY THINK 4046 02:27:51,262 --> 02:27:52,496 PROPERLY, I WENT BACK TO WORK 4047 02:27:52,563 --> 02:27:54,365 AND I CAN'T CONCENTRATE. 4048 02:27:54,432 --> 02:27:55,600 SOMETHING IS REALLY WRONG WITH 4049 02:27:55,666 --> 02:27:56,067 ME. 4050 02:27:56,133 --> 02:27:57,835 NOW I'M GETTING TIRED. 4051 02:27:57,902 --> 02:27:59,904 SO THOSE ARE TOTALLY DIFFERENT 4052 02:27:59,971 --> 02:28:03,207 CATEGORIES OF PATIENTS WHERE THE 4053 02:28:03,274 --> 02:28:04,342 PATHOPHYSIOLOGY OF BOTH OF THEM 4054 02:28:04,408 --> 02:28:05,509 ARE GOING TO BE DIFFERENT AND I 4055 02:28:05,576 --> 02:28:07,345 DON'T HAVE A GOOD TERM FOR THE 4056 02:28:07,411 --> 02:28:08,512 SECOND CLASS BUT WE'VE GOT TO 4057 02:28:08,579 --> 02:28:11,115 SEPARATE THESE TWO. 4058 02:28:11,182 --> 02:28:11,549 OKAY. 4059 02:28:11,616 --> 02:28:12,884 PEOPLE HAVE TALKED ABOUT 4060 02:28:12,950 --> 02:28:14,151 INCIDENCE OF ME/CFS AND COVID, 4061 02:28:14,218 --> 02:28:16,420 AND HERE'S DATA FROM THE CDC 4062 02:28:16,487 --> 02:28:18,723 SHOWING THAT IF YOU JUST LOOK AT 4063 02:28:18,789 --> 02:28:20,191 ADULTS ACROSS UNITED STATES 4064 02:28:20,258 --> 02:28:23,794 RIGHT NOW, ABOUT 6% OF ALL 4065 02:28:23,861 --> 02:28:26,864 ADULTS HAVE LONG COVID. 4066 02:28:26,931 --> 02:28:28,866 AND IF YOU WERE TO LOOK AT THOSE 4067 02:28:28,933 --> 02:28:30,835 INDIVIDUALS WHO HAD COVID AND 4068 02:28:30,901 --> 02:28:32,003 NOW HAVE LONG COVID IN THE 4069 02:28:32,069 --> 02:28:33,804 UNITED STATES, YOU'RE LOOKING AT 4070 02:28:33,871 --> 02:28:34,672 ABOUT 11% OR SO. 4071 02:28:34,739 --> 02:28:37,575 SO THAT'S A HUGE POPULATION. 4072 02:28:37,642 --> 02:28:38,442 THAT'S SUFFERING FROM THIS 4073 02:28:38,509 --> 02:28:39,243 DISEASE. 4074 02:28:39,310 --> 02:28:40,778 AND IT AFFECTS INDIVIDUALS IN 4075 02:28:40,845 --> 02:28:42,613 THE AGE GROUP WHERE THEY'RE MOST 4076 02:28:42,680 --> 02:28:47,051 PRODUCTIVE. 4077 02:28:47,118 --> 02:28:50,221 IF WE LACK AT LOOK AT THE SYMPS 4078 02:28:50,288 --> 02:28:51,422 PEOPLE DEVELOP DURING EARLY 4079 02:28:51,489 --> 02:28:52,356 COVID THERE'S A WHOLE LIST OF 4080 02:28:52,423 --> 02:28:52,623 SYMPTOMS. 4081 02:28:52,690 --> 02:28:54,325 SOME OF THEM GET BETTER, SOME OF 4082 02:28:54,392 --> 02:28:56,160 THEM DON'T GET BETTER, SOME OF 4083 02:28:56,227 --> 02:28:56,694 THEM GET WORSE. 4084 02:28:56,761 --> 02:28:58,996 IF YOU LOOK AT THE NEUROLOGICAL 4085 02:28:59,063 --> 02:29:00,331 SYMPTOMS THAT I'VE BOXED AT THE 4086 02:29:00,398 --> 02:29:01,666 BOTTOM, THEY ACTUALLY GET WORSE 4087 02:29:01,732 --> 02:29:02,800 OR DON'T GET BETTER OVER A 4088 02:29:02,867 --> 02:29:04,201 PERIOD OF TIME. 4089 02:29:04,268 --> 02:29:07,705 AND IN THIS GRAPH, LET ME SEE IF 4090 02:29:07,772 --> 02:29:09,273 THIS POINTER WORKS. 4091 02:29:09,340 --> 02:29:11,175 SORRY, MESSED THAT ONE UP. 4092 02:29:11,242 --> 02:29:13,010 OKAY. 4093 02:29:13,077 --> 02:29:17,515 GOOD. 4094 02:29:17,581 --> 02:29:18,049 THIS DOES WORK. 4095 02:29:18,115 --> 02:29:20,318 SO YOU SEE THE BOTTOM SYMPTOMS, 4096 02:29:20,384 --> 02:29:21,619 THEY SEEM TO GET WORSE OR 4097 02:29:21,686 --> 02:29:22,586 PERSIST COMPARED TO WHERE THEY 4098 02:29:22,653 --> 02:29:23,921 WERE. 4099 02:29:23,988 --> 02:29:25,956 SO THAT TELLS YOU THAT THE 4100 02:29:26,023 --> 02:29:28,125 NEUROLOGICAL SYMPTOMS REALLY ARE 4101 02:29:28,192 --> 02:29:30,561 THE MAJOR SEQUELAE OF LONG 4102 02:29:30,628 --> 02:29:32,196 COVID. 4103 02:29:32,263 --> 02:29:33,698 OKAY. 4104 02:29:33,764 --> 02:29:36,701 SO IF YOU LOOK AT THESE 4105 02:29:36,767 --> 02:29:37,368 INDIVIDUALS, THE SECOND CATEGORY 4106 02:29:37,435 --> 02:29:38,035 OF INDIVIDUALS, WHAT YOU CAN DO 4107 02:29:38,102 --> 02:29:40,371 IS YOU CAN ACTUALLY DIVIDE THEM 4108 02:29:40,438 --> 02:29:41,072 INTO FOUR DIFFERENT BUCKETS. 4109 02:29:41,138 --> 02:29:42,840 THEY OVERLAP WITH ONE ANOTHER. 4110 02:29:42,907 --> 02:29:44,208 DEPENDING ON WHAT THE 4111 02:29:44,275 --> 02:29:45,509 PREDOMINANT SYMPTOM IS. 4112 02:29:45,576 --> 02:29:47,978 SO THE FIRST IS SOME INDIVIDUALS 4113 02:29:48,045 --> 02:29:49,747 DEVELOP EXERCISE INTOLERANCE, 4114 02:29:49,814 --> 02:29:54,318 AND THAT IS IT'S -- ONE 4115 02:29:54,385 --> 02:29:56,787 CARDIOLOGIST I REMEMBER FROM 4116 02:29:56,854 --> 02:29:58,089 NEW YORK, WHAT SHE TOLD ME WAS 4117 02:29:58,155 --> 02:30:00,091 THAT, DOC, AFTER I GOT COVID, 4118 02:30:00,157 --> 02:30:01,559 NOW IT'S BEEN A MONTH OR TWO 4119 02:30:01,625 --> 02:30:03,627 GONE BY, AND I TAKE ONE FLIGHT 4120 02:30:03,694 --> 02:30:06,030 OF STAIRS AND I GET SO EXHAUSTED 4121 02:30:06,097 --> 02:30:07,832 THAT I CAN'T EVEN DO 4122 02:30:07,898 --> 02:30:09,266 TELEMEDICINE ANY LONGER. 4123 02:30:09,333 --> 02:30:13,304 SO IT CAN BE SO DEVASTATING. 4124 02:30:13,371 --> 02:30:15,272 SOME DEVELOP DIFFICULTIES WITH 4125 02:30:15,339 --> 02:30:16,674 COGNITION, MOOD AND SLEEP 4126 02:30:16,741 --> 02:30:17,742 DISORDERS, AND THERE'S ONE 4127 02:30:17,808 --> 02:30:22,680 EMPLOYEE HERE AT NIH THAT I SAW, 4128 02:30:22,747 --> 02:30:24,181 NO REASON TO BE DEPRESSED OR 4129 02:30:24,248 --> 02:30:25,683 ANYTHING, HE SAYS HE GOT COVID, 4130 02:30:25,750 --> 02:30:27,218 AND AFTER THAT, HE GOT AFRAID OF 4131 02:30:27,284 --> 02:30:28,052 HIMSELF. 4132 02:30:28,119 --> 02:30:29,553 SO HE ACTUALLY WENT TO A 4133 02:30:29,620 --> 02:30:31,021 SUBURBAN HOSPITAL, GOT ADMITTED 4134 02:30:31,088 --> 02:30:31,856 THERE FOR ABOUT A MONTH. 4135 02:30:31,922 --> 02:30:33,391 HE CAME OUT, NOW HE'S DOING 4136 02:30:33,457 --> 02:30:34,225 FINE. 4137 02:30:34,291 --> 02:30:36,727 BUT ACUTE EPISODE OF MAJOR 4138 02:30:36,794 --> 02:30:37,828 DEPRESSION CAN BE A 4139 02:30:37,895 --> 02:30:40,297 MANIFESTATION. 4140 02:30:40,364 --> 02:30:41,165 ANOTHER WOMAN, I'LL GIVE YOU AN 4141 02:30:41,232 --> 02:30:42,666 EXAMPLE OF COGNITIVE DISORDER. 4142 02:30:42,733 --> 02:30:44,201 SHE WORKS IN CONGRESS AND HER 4143 02:30:44,268 --> 02:30:48,339 JOB IS TO TAKE MINUTES. 4144 02:30:48,406 --> 02:30:50,040 SHE RECOVERED FROM COVID. 4145 02:30:50,107 --> 02:30:51,575 SHE DIDN'T REALIZE THERE WAS 4146 02:30:51,642 --> 02:30:52,576 ANYTHING WRONG WITH HER. 4147 02:30:52,643 --> 02:30:53,911 SHE ACTUALLY GOES THERE AND 4148 02:30:53,978 --> 02:30:55,446 REALIZES SHE CAN'T MULTITASK ANY 4149 02:30:55,513 --> 02:30:55,880 LONGER. 4150 02:30:55,946 --> 02:31:00,050 SHE COULDN'T TAKE NOTES. 4151 02:31:00,117 --> 02:31:02,086 SO THEY CAN BE SUBTLE AND THEY 4152 02:31:02,153 --> 02:31:03,954 CAN BE QUITE DRAMATIC. 4153 02:31:04,021 --> 02:31:08,392 SOME INDIVIDUALS CAN HAVE 4154 02:31:08,459 --> 02:31:09,393 DYSAUTONOMIA. 4155 02:31:09,460 --> 02:31:11,762 AN ONCOLOGIST IN VIRGINIA, SHE 4156 02:31:11,829 --> 02:31:12,863 CALLED ME AND SAYS YOU KNOW 4157 02:31:12,930 --> 02:31:14,832 WHAT, AFTER I GOT COVID NOW, I'M 4158 02:31:14,899 --> 02:31:16,100 ACTUALLY LYING DOWN AND TALKING 4159 02:31:16,167 --> 02:31:18,502 TO YOU BECAUSE EVEN IF I SIT UP, 4160 02:31:18,569 --> 02:31:19,804 I GET DIZZY. 4161 02:31:19,870 --> 02:31:21,238 AND SHE COULDN'T GO BACK TO HER 4162 02:31:21,305 --> 02:31:21,505 PRACTICE. 4163 02:31:21,572 --> 02:31:23,374 THEN THERE ARE A VARIETY OF PAIN 4164 02:31:23,441 --> 02:31:24,241 SYNDROMES THAT PEOPLE CAN 4165 02:31:24,308 --> 02:31:26,310 DEVELOP AS WELL. 4166 02:31:26,377 --> 02:31:31,849 SO WE BROUGHT IN A COHORT OF 17D 4167 02:31:31,916 --> 02:31:33,417 FINALLY ENROLLED 12 PATIENTS 4168 02:31:33,484 --> 02:31:37,688 THAT WE STUDIED EXTENSIVELY. 4169 02:31:37,755 --> 02:31:39,123 WE HAD ALL THESE CRITERIA, 4170 02:31:39,190 --> 02:31:40,224 THEY'RE ALL PUBLISHED. 4171 02:31:40,291 --> 02:31:41,792 BUT WHAT I WANT TO TELL YOU, WE 4172 02:31:41,859 --> 02:31:42,693 ARE LOOKING FOR THOSE 4173 02:31:42,760 --> 02:31:44,228 INDIVIDUALS THAT WE CALL 4174 02:31:44,295 --> 02:31:45,429 NEUROPATHS, WHICH MEANS THEY 4175 02:31:45,496 --> 02:31:46,864 CLEARLY HAVE NEUROLOGICAL 4176 02:31:46,931 --> 02:31:48,666 SYMPTOMS AFTER DEVELOPING COVID. 4177 02:31:48,732 --> 02:31:51,936 100% OF THEM HAD CHRONIC -- IT 4178 02:31:52,002 --> 02:31:53,904 COGNITIVE DIFFICULTIES AND 4179 02:31:53,971 --> 02:31:55,606 FATIGUE, AND THEN OTHERS HAD 4180 02:31:55,673 --> 02:32:00,744 OTHER VARIETY OF SYMPTOMS THERE. 4181 02:32:00,811 --> 02:32:01,645 WHAT ABOUT THE AGE GROUPS? 4182 02:32:01,712 --> 02:32:03,347 THIS IS AN INTERESTING STUDY. 4183 02:32:03,414 --> 02:32:04,615 THEY COMPARED INDIVIDUALS WHO 4184 02:32:04,682 --> 02:32:06,817 HAD ANY KIND OF RESPIRATORY 4185 02:32:06,884 --> 02:32:08,552 INFECTION OR IF THEY DEVELOPED 4186 02:32:08,619 --> 02:32:08,986 COVID. 4187 02:32:09,053 --> 02:32:09,920 COVID IS IN BLUE. 4188 02:32:09,987 --> 02:32:12,456 SO YOU CAN SEE AT ALL AGE 4189 02:32:12,523 --> 02:32:14,225 GROUPS, IF YOU DEVELOP COVID, 4190 02:32:14,291 --> 02:32:16,126 YOUR CHANCES OF DEVELOPING 4191 02:32:16,193 --> 02:32:16,894 COGNITIVE DIFFICULTIES ARE MUCH, 4192 02:32:16,961 --> 02:32:20,498 MUCH GREATER. 4193 02:32:20,564 --> 02:32:23,234 EXCEPT IF YOU'RE 70 YEARS OF 4194 02:32:23,300 --> 02:32:25,436 AGE, IT BAD NEWS, IT DOESN'T 4195 02:32:25,503 --> 02:32:26,470 MATTER WHAT INFECTION YOU GET, 4196 02:32:26,537 --> 02:32:27,271 YOU'RE DONE. 4197 02:32:27,338 --> 02:32:28,005 UNFORTUNATELY I'M GETTING CLOSER 4198 02:32:28,072 --> 02:32:30,474 TO THAT EVERY DAY. 4199 02:32:30,541 --> 02:32:32,977 OKAY. 4200 02:32:33,043 --> 02:32:36,046 THIS IS AN INTERESTING PET 4201 02:32:36,113 --> 02:32:36,480 STUDY. 4202 02:32:36,547 --> 02:32:39,450 HERE WHAT THEY DID IS THEY 4203 02:32:39,517 --> 02:32:41,685 LOOKED AT THE BRAIN AND THEY 4204 02:32:41,752 --> 02:32:42,786 AVERAGED THE INDIVIDUALS IN THAT 4205 02:32:42,853 --> 02:32:46,156 STUDY, SO THIS IS A CONSENSUS 4206 02:32:46,223 --> 02:32:49,193 SCAN HERE, AND IF YOU LOOK AT 4207 02:32:49,260 --> 02:32:49,960 THE COVID PATIENTS HERE, YOU CAN 4208 02:32:50,027 --> 02:32:51,929 SEE THAT THE ENTIRE BRAIN 4209 02:32:51,996 --> 02:32:53,764 ACTUALLY IS HYPOMETABOLIC. 4210 02:32:53,831 --> 02:32:55,366 AND MORE SO IN THE FRONTAL PARTS 4211 02:32:55,432 --> 02:32:56,767 OF THE BRAIN AS WELL AS THE 4212 02:32:56,834 --> 02:32:58,302 BASAL GANGLIA. 4213 02:32:58,369 --> 02:32:59,770 RELATIVELY THE POSTERIOR PARTS 4214 02:32:59,837 --> 02:33:00,871 ARE RELATIVELY SPARED. 4215 02:33:00,938 --> 02:33:01,772 THERE'S ANOTHER STUDY THAT 4216 02:33:01,839 --> 02:33:04,842 LOOKED AT THIS IN MORE DETAIL 4217 02:33:04,909 --> 02:33:06,243 AND WHAT THEY FOUND IS THAT IF 4218 02:33:06,310 --> 02:33:07,511 YOU LOOK AT THE HIND PART OF THE 4219 02:33:07,578 --> 02:33:08,879 BRAIN, YOU SEE MORE 4220 02:33:08,946 --> 02:33:09,713 ABNORMALITIES THERE THAN OTHER 4221 02:33:09,780 --> 02:33:12,349 PARTS OF THE BRAIN. 4222 02:33:12,416 --> 02:33:15,252 SO WHAT ARE THE UNDERLYING 4223 02:33:15,319 --> 02:33:16,887 POSSIBLE PATHOPHYSIOLOGICAL 4224 02:33:16,954 --> 02:33:18,422 MECHANISMS? DR. LIPKIN TALKED 4225 02:33:18,489 --> 02:33:19,890 ABOUT VIRAL REACTIVATION, SO 4226 02:33:19,957 --> 02:33:20,491 THAT'S CERTAINLY A POSSIBILITY 4227 02:33:20,558 --> 02:33:20,991 HERE. 4228 02:33:21,058 --> 02:33:23,394 COULD BE PERSISTENT VIRAL 4229 02:33:23,460 --> 02:33:25,596 INFECTION THAT YOU NEVER GOT RID 4230 02:33:25,663 --> 02:33:27,398 OF, OR IT COULD BE IMMUNE 4231 02:33:27,464 --> 02:33:28,299 DYSREGULATION OR SOMEHOW THEY 4232 02:33:28,365 --> 02:33:32,603 ALL MAY BE INTERLINKEDIN LINKEDE 4233 02:33:32,670 --> 02:33:38,943 WAY OR ANOTHER. 4234 02:33:39,009 --> 02:33:40,477 SO THIS STUDY JUST PUBLISHED 4235 02:33:40,544 --> 02:33:45,115 FROM YALE, AND THEY LOOKED AT 4236 02:33:45,182 --> 02:33:45,683 EBV REACTIVATION. 4237 02:33:45,749 --> 02:33:47,017 WHAT THEY FOUND WAS THAT, YES, 4238 02:33:47,084 --> 02:33:49,286 IN PATIENTS WITH LONG COVID, YOU 4239 02:33:49,353 --> 02:33:51,088 CAN FIND EVIDENCE OF 4240 02:33:51,155 --> 02:33:52,957 REACTIVATION OF EPSTEIN-BARR 4241 02:33:53,023 --> 02:33:57,561 VIRUS. 4242 02:33:57,628 --> 02:33:59,530 WHAT ABOUT PERSISTENT INFECTION? 4243 02:33:59,597 --> 02:34:01,131 SO WE KNOW AT LEAST WITH COVID, 4244 02:34:01,198 --> 02:34:02,299 IT'S ALL IN THE NOSE. 4245 02:34:02,366 --> 02:34:04,702 THE VIRUS GETS UP THERE, AND IT 4246 02:34:04,768 --> 02:34:05,903 INFECTS -- WE THOUGHT IT WOULD 4247 02:34:05,970 --> 02:34:07,638 BE PRETTY SIMPLE, WHAT WILL 4248 02:34:07,705 --> 02:34:09,473 HAPPEN IS YOU INFECT THE NASAL 4249 02:34:09,540 --> 02:34:11,942 MUCOSA AND THEN IT WILL JUST GO 4250 02:34:12,009 --> 02:34:13,944 UP THE CURB FORM PLATE AND 4251 02:34:14,011 --> 02:34:15,145 ENTERS THE BRAIN, OBVIOUSLY ALL 4252 02:34:15,212 --> 02:34:16,347 KINDS OF STUFF COMING IN FROM 4253 02:34:16,413 --> 02:34:18,382 THE NOSE INTO THE BRAIN. 4254 02:34:18,449 --> 02:34:19,883 AND YOU HAVE THE OLFACTORY NERVE 4255 02:34:19,950 --> 02:34:23,287 THAT GOES UP THERE. 4256 02:34:23,354 --> 02:34:24,355 INTERESTINGLY, YOU CAN FIND A 4257 02:34:24,421 --> 02:34:26,357 LOT OF VIRUS HERE IN THE NASAL 4258 02:34:26,423 --> 02:34:28,425 MUCOSA, AS YOU CAN SEE HERE IN 4259 02:34:28,492 --> 02:34:30,027 THIS ELECTRON MICROGRAPH. 4260 02:34:30,094 --> 02:34:31,228 ALL THESE BLACK DOTS ARE VIRAL 4261 02:34:31,295 --> 02:34:31,762 PARTICLES. 4262 02:34:31,829 --> 02:34:33,864 HOWEVER, IF YOU WERE TO LOOK AT 4263 02:34:33,931 --> 02:34:36,000 THE OLFACTORY BULB OR THE 4264 02:34:36,066 --> 02:34:37,101 OLFACTORY TUBERCLE, THERE'S 4265 02:34:37,167 --> 02:34:39,436 HARDLY ANY VIRUS THERE. 4266 02:34:39,503 --> 02:34:40,871 SO THE VIRUS DOESN'T GO UP THE 4267 02:34:40,938 --> 02:34:42,339 NOSE AND THE REASON FOR THAT IS, 4268 02:34:42,406 --> 02:34:44,208 IT DOESN'T INFECT THE OLFACTORY 4269 02:34:44,274 --> 02:34:45,175 NERVE. 4270 02:34:45,242 --> 02:34:47,544 WHAT IT AFFECTS ARE THE SUPPORT 4271 02:34:47,611 --> 02:34:52,249 CELLS, THE SUSTENTACULAR CELLS. 4272 02:34:52,316 --> 02:34:53,684 YOU GET THIS INFLAMMATION AND 4273 02:34:53,751 --> 02:34:54,618 THAT'S WHAT LEADS TO LOSS OF 4274 02:34:54,685 --> 02:34:54,852 SMELL. 4275 02:34:54,918 --> 02:34:57,254 WE LOOKED FOR THE VIRUS IN THE 4276 02:34:57,321 --> 02:34:59,423 BRAIN, AND BY MULTIPLE DIFFERENT 4277 02:34:59,490 --> 02:35:00,290 TECHNIQUES, WE DIDN'T FIND IT. 4278 02:35:00,357 --> 02:35:02,159 MOST PEOPLE AGREE WITH US, THERE 4279 02:35:02,226 --> 02:35:04,228 ARE SOME FEW REPORTS WHERE 4280 02:35:04,294 --> 02:35:08,866 PEOPLE HAVE FOUND RARELY 4281 02:35:08,932 --> 02:35:10,634 DETECTED VIRUS AND IF THEY HAVE, 4282 02:35:10,701 --> 02:35:11,502 IN VERY SMALL QUANTITIES. 4283 02:35:11,568 --> 02:35:13,937 MY COLLEAGUES HERE AT NIH 4284 02:35:14,004 --> 02:35:15,939 PUBLISHED THIS FABULOUS PAPER 4285 02:35:16,006 --> 02:35:18,008 WHERE THEY -- REALLY NICE WORK 4286 02:35:18,075 --> 02:35:19,777 LOOKING FOR SARS-COV-2, AND IF 4287 02:35:19,843 --> 02:35:21,645 YOU LOOK AT IT, THEY FOUND VIRUS 4288 02:35:21,712 --> 02:35:24,415 IN THE RESPIRATORY TRACT, LESS 4289 02:35:24,481 --> 02:35:24,948 THAN 14 DAYS. 4290 02:35:25,015 --> 02:35:27,651 YOU CAN FIND 9,000 COPIES, EVEN 4291 02:35:27,718 --> 02:35:29,353 BY ONE MONTH IT'S LESS THAN 1. 4292 02:35:29,420 --> 02:35:30,921 IF YOU LOOK AT THE BRAIN HERE, 4293 02:35:30,988 --> 02:35:34,792 LESS THAN 14 DAYS YOU HAVE 32, 4294 02:35:34,858 --> 02:35:35,826 BY ABOUT GREATER THAN A MONTH, 4295 02:35:35,893 --> 02:35:36,460 IT'S ALREADY GONE. 4296 02:35:36,527 --> 02:35:38,028 SO THIS ALONE CANNOT EXPLAIN 4297 02:35:38,095 --> 02:35:38,762 LONG COVID. 4298 02:35:38,829 --> 02:35:41,932 IT'S NOT A VIRAL ENCEPHALITIS. 4299 02:35:41,999 --> 02:35:42,966 HOWEVER, THERE ARE RARE 4300 02:35:43,033 --> 02:35:44,702 INSTANCES IN WHICH THE VIRUS CAN 4301 02:35:44,768 --> 02:35:45,335 INFICT FEK THE BRAIN. 4302 02:35:45,402 --> 02:35:46,737 THERE ARE TWO CASE REPORTS IN 4303 02:35:46,804 --> 02:35:48,038 THE LITERATURE OF CHILDREN WHERE 4304 02:35:48,105 --> 02:35:51,875 THEY CLAIM THAT THE VIRUS WENT 4305 02:35:51,942 --> 02:35:53,977 TRANSPLACENTALLY AND CAUSES 4306 02:35:54,044 --> 02:35:56,480 DEVASTATING NEUROLOGICAL 4307 02:35:56,547 --> 02:35:57,181 MANIFESTATION IN THESE CHILDREN, 4308 02:35:57,247 --> 02:35:59,316 AND THEY COULD FIND VIRUS AT 4309 02:35:59,383 --> 02:36:00,684 AUTOPSY AT LEAST IN THIS ONE 4310 02:36:00,751 --> 02:36:02,886 CHILD. 4311 02:36:02,953 --> 02:36:05,189 AND DR. EGAN FROM THE NATIONAL 4312 02:36:05,255 --> 02:36:06,090 INSTITUTES OF AGING JUST 4313 02:36:06,156 --> 02:36:07,124 PUBLISHED THIS PAPER WHERE SHE 4314 02:36:07,191 --> 02:36:08,959 DID FIND SOME EVIDENCE OF VIRAL 4315 02:36:09,026 --> 02:36:11,095 ANTIGEN IN THE PAPILLA OF THE 4316 02:36:11,161 --> 02:36:13,363 TONGUE. 4317 02:36:13,430 --> 02:36:14,732 AND THERE ARE THESE REPORTS 4318 02:36:14,798 --> 02:36:19,002 CLAIMING THAT THEY CAN FIND SOME 4319 02:36:19,069 --> 02:36:23,173 VIRAL ANTIGEN IN PATIENTS IN THE 4320 02:36:23,240 --> 02:36:25,409 SERUM TO THE SPIKE PROTEIN HERE, 4321 02:36:25,476 --> 02:36:26,844 BUT THIS STILL NEEDS TO BE 4322 02:36:26,910 --> 02:36:31,315 REPRODUCED BY OTHER LABS. 4323 02:36:31,381 --> 02:36:32,716 BUT WE KNOW THE PRESENCE OF 4324 02:36:32,783 --> 02:36:34,017 VIRAL ANTIGEN ALONE DOESN'T 4325 02:36:34,084 --> 02:36:35,018 NECESSARILY MEAN THAT'S THE 4326 02:36:35,085 --> 02:36:36,320 CAUSE OF DISEASE. 4327 02:36:36,386 --> 02:36:38,155 YOU HAVE LOTS OF OTHER DISEASES 4328 02:36:38,222 --> 02:36:39,223 WHERE ANTIGEN CAN PERSIST FOR A 4329 02:36:39,289 --> 02:36:40,324 LONG PERIOD OF TIME AND MAY OR 4330 02:36:40,390 --> 02:36:44,595 MAY NOT DRIVE ANY IMMUNE 4331 02:36:44,661 --> 02:36:46,396 DYSFUNCTION OR SYMPTOMS ALONE. 4332 02:36:46,463 --> 02:36:48,265 SO WHAT ABOUT IMMUNE 4333 02:36:48,332 --> 02:36:50,000 DYSREGULATION? 4334 02:36:50,067 --> 02:36:54,037 SO THIS IS A REALLY NICE PAPER 4335 02:36:54,104 --> 02:36:56,006 WHERE THEY AGAIN PUBLISHED 4336 02:36:56,073 --> 02:36:58,275 EARLIER THIS YEAR, AND WHAT THEY 4337 02:36:58,342 --> 02:36:59,510 SHOWED WAS THAT THEY USED THIS 4338 02:36:59,576 --> 02:37:04,915 MARKER CALLED TSPO, A LIGAND 4339 02:37:04,982 --> 02:37:07,751 THAT BINDS TO ACTIVATED 4340 02:37:07,818 --> 02:37:08,619 MICROGLIA IN THE BRAIN. 4341 02:37:08,685 --> 02:37:10,921 SO IT'S AN EVIDENCE OF -- CELL 4342 02:37:10,988 --> 02:37:11,755 ACTIVATION. 4343 02:37:11,822 --> 02:37:13,724 THEY FOUND THOSE INDIVIDUALS WHO 4344 02:37:13,791 --> 02:37:15,058 WERE COMPLAINING OF DEPRESSION 4345 02:37:15,125 --> 02:37:16,994 OR COGNITIVE DYSFUNCTION HAD 4346 02:37:17,060 --> 02:37:19,363 MORE EVIDENCE OF ACTIVATION 4347 02:37:19,429 --> 02:37:22,132 OF -- CELLS WITHIN THE BRAIN. 4348 02:37:22,199 --> 02:37:24,401 AND THIS IS ANOTHER STUDY FROM 4349 02:37:24,468 --> 02:37:25,502 THE NETHERLANDS, WHERE HERE THEY 4350 02:37:25,569 --> 02:37:27,104 SHOW WITH THAT SAME LIGAND, YOU 4351 02:37:27,171 --> 02:37:29,072 CAN SEE MASSIVE UPTAKE IN THE 4352 02:37:29,139 --> 02:37:30,474 BRAIN, WHILE THE NORMAL BRAIN IS 4353 02:37:30,541 --> 02:37:32,876 ALL RELATIVELY COLD. 4354 02:37:32,943 --> 02:37:34,812 AND WE LOOKED AT IT AT AUTOPSY 4355 02:37:34,878 --> 02:37:36,380 AND WE DO FIND THAT IN THESE 4356 02:37:36,446 --> 02:37:41,652 PATIENTS, YOU CAN FIND A 4357 02:37:41,718 --> 02:37:42,319 MICROGLIAL CELL ACTIVATION BOTH 4358 02:37:42,386 --> 02:37:43,854 IN THE GREY AND WHITE MATTER OF 4359 02:37:43,921 --> 02:37:45,088 PATIENTS WITH COVID. 4360 02:37:45,155 --> 02:37:48,692 BUT THESE ARE INDIVIDUALS WHO 4361 02:37:48,759 --> 02:37:52,129 HAD DIED LITERALLY ACUTELY FROM 4362 02:37:52,196 --> 02:37:52,863 THE INFECTION. 4363 02:37:52,930 --> 02:37:54,832 ALTHOUGH I DO BELIEVE THAT THESE 4364 02:37:54,898 --> 02:37:56,233 FINDINGS ARE RELEVANT FOR LONG 4365 02:37:56,300 --> 02:38:00,537 COVID AND I'LL TELL YOU WHY. 4366 02:38:00,604 --> 02:38:01,605 SO ONE OF THE THINGS YOU CAN DO 4367 02:38:01,672 --> 02:38:03,907 AT NIH IS HIGH RESOLUTION MRI 4368 02:38:03,974 --> 02:38:06,143 SCANS, AND WE CAN DO IT ON 4369 02:38:06,210 --> 02:38:08,779 AUTOPSY TISSUE. 4370 02:38:08,846 --> 02:38:10,981 SO WE WERE ABLE TO GET TISSUE 4371 02:38:11,048 --> 02:38:12,449 FROM THE MEDICAL EXAMINER'S 4372 02:38:12,516 --> 02:38:14,084 OFFICE IN NEW YORK OF 4373 02:38:14,151 --> 02:38:15,652 INDIVIDUALS WHO HAD DIED 4374 02:38:15,719 --> 02:38:17,387 SUDDENLY AT HOME, SO THESE WERE 4375 02:38:17,454 --> 02:38:19,556 NOT INDIVIDUALS WHO HAD MASSIVE 4376 02:38:19,623 --> 02:38:20,224 RESPIRATORY INFECTIONS. 4377 02:38:20,290 --> 02:38:21,758 MOST OF THEM DIDN'T EVEN REALIZE 4378 02:38:21,825 --> 02:38:22,693 THEY HAD ANYTHING WRONG WITH 4379 02:38:22,759 --> 02:38:23,026 THEM. 4380 02:38:23,093 --> 02:38:24,461 THIS IS EARLY IN THE PANDEMIC, 4381 02:38:24,528 --> 02:38:25,963 THEY WERE FOUND DEAD, EITHER IN 4382 02:38:26,029 --> 02:38:27,130 THE SUBWAY IN NEW YORK OR AT 4383 02:38:27,197 --> 02:38:29,466 HOME. 4384 02:38:29,533 --> 02:38:31,768 AND SO THESE INDIVIDUALS, HAD 4385 02:38:31,835 --> 02:38:33,337 THEY SURVIVED, THEY PROBABLY 4386 02:38:33,403 --> 02:38:35,005 WOULD HAVE DEVELOPED LONG TERM 4387 02:38:35,072 --> 02:38:35,739 SYMPTOMS BECAUSE I'LL SHOW YOU 4388 02:38:35,806 --> 02:38:37,207 THE PATHOLOGY WHEN YOU LOOK AT 4389 02:38:37,274 --> 02:38:37,908 THE BRAIN. 4390 02:38:37,975 --> 02:38:40,878 WE DID AN MRI SCAN, WE FOUND 4391 02:38:40,944 --> 02:38:42,379 THEIR BLOOD VESSELS WERE 4392 02:38:42,446 --> 02:38:43,680 ABNORMAL AND IN THE BLOOD 4393 02:38:43,747 --> 02:38:45,449 VESSEL, YOU CAN FIND THREE TYPES 4394 02:38:45,515 --> 02:38:47,184 OF PATHOLOGY IN THE SAME BLOOD 4395 02:38:47,251 --> 02:38:47,651 VESSEL. 4396 02:38:47,718 --> 02:38:49,486 SO YOU'VE GOT THICKENING HERE, A 4397 02:38:49,553 --> 02:38:51,455 SMALL CLOT OVER HERE, YOU MAKE A 4398 02:38:51,521 --> 02:38:52,990 SECTION FROM THAT BLOOD VESSEL 4399 02:38:53,056 --> 02:38:55,359 HERE AND YOU CAN SEE A MICRO 4400 02:38:55,425 --> 02:38:57,561 HEMORRHAGE AS WELL. 4401 02:38:57,628 --> 02:38:59,096 SO THERE'S VAST MICROVASCULAR 4402 02:38:59,162 --> 02:39:00,564 PATHOLOGY IN THESE PATIENTS. 4403 02:39:00,631 --> 02:39:03,400 AND WHEN WE LOOK FOR FIBRINOGEN 4404 02:39:03,467 --> 02:39:04,835 IN THE BRAIN THIS, IS A SMALL 4405 02:39:04,902 --> 02:39:06,803 BLOOD VESSEL HERE AND THE DARK 4406 02:39:06,870 --> 02:39:09,106 STAINING IS FIBRINOGEN, THIS IS 4407 02:39:09,172 --> 02:39:10,741 A VERY LARGE PROTEIN THAT SHOULD 4408 02:39:10,807 --> 02:39:11,909 NEVER ENTER THE BRAIN UNLESS THE 4409 02:39:11,975 --> 02:39:13,644 BLOOD VESSELS ARE DAMAGED. 4410 02:39:13,710 --> 02:39:15,646 YOU CAN SEE THERE IS LEAKAGE OF 4411 02:39:15,712 --> 02:39:17,714 FIBRINOGEN AROUND THE BLOOD 4412 02:39:17,781 --> 02:39:19,650 DEVELOPS AND EVEN IN THE 4413 02:39:19,716 --> 02:39:20,384 OLFACTORY BULB, YOU CAN SEE THIS 4414 02:39:20,450 --> 02:39:22,052 HERE, THIS IS IN THE PONS, AND 4415 02:39:22,119 --> 02:39:23,854 YOU CAN SEE THESE HIGH 4416 02:39:23,921 --> 02:39:25,088 RESOLUTION MRI IMAGES AT 11 4417 02:39:25,155 --> 02:39:27,357 TESLA THAT HAVE NEVER BEEN DONE 4418 02:39:27,424 --> 02:39:29,726 BEFORE IN THE HUMAN BRAIN. 4419 02:39:29,793 --> 02:39:32,262 SAME THING YOU CAN LOOK AT THE 4420 02:39:32,329 --> 02:39:32,930 SUBSTANTIA NIGRA HERE AND YOU 4421 02:39:32,996 --> 02:39:36,099 CAN SEE THERE'S LOSS OF SIGNAL 4422 02:39:36,166 --> 02:39:37,801 HERE IN THE SUBSTANTIA NIGRA AS 4423 02:39:37,868 --> 02:39:39,336 WELL IN THESE INDIVIDUALS, AND 4424 02:39:39,403 --> 02:39:42,205 THERE'S LEAKAGE OF FIBRINOGEN, 4425 02:39:42,272 --> 02:39:43,674 HERE IT'S RED INSTEAD OF BROWN. 4426 02:39:43,740 --> 02:39:45,342 SO WE LOOKED AT THE CELL 4427 02:39:45,409 --> 02:39:46,009 INFILTRATION OF THE BRAIN AND 4428 02:39:46,076 --> 02:39:48,946 WHAT WE FOUND, YOU FIND A LOT OF 4429 02:39:49,012 --> 02:39:50,981 MACROPHAGES BUT THAT'S NO 4430 02:39:51,048 --> 02:39:52,950 SURPRISE BECAUSE IF THERE ARE 4431 02:39:53,016 --> 02:39:54,384 THINGS LEAKING FROM THE BLOOD 4432 02:39:54,451 --> 02:39:56,119 VESSEL, THEN YOU WILL HAVE 4433 02:39:56,186 --> 02:39:56,753 MACROPHAGES THAT WILL COME AND 4434 02:39:56,820 --> 02:39:58,055 TRY TO CHEW IT UP AND TAKE IT 4435 02:39:58,121 --> 02:39:58,388 AWAY. 4436 02:39:58,455 --> 02:40:00,023 BUT ONCE THEY GET IN THERE, 4437 02:40:00,090 --> 02:40:04,828 THEY'RE YOUR BADDIESTS, THEY BAD 4438 02:40:04,895 --> 02:40:07,197 GUESTS, THEY JUST NEVER LEAVE. 4439 02:40:07,264 --> 02:40:08,498 WHEN THEY'RE ACTIVATED, THEY 4440 02:40:08,565 --> 02:40:09,700 CAUSE ALL KINDS OF DAMAGE AROUND 4441 02:40:09,766 --> 02:40:10,834 THEM. 4442 02:40:10,901 --> 02:40:12,970 WE FIND OTHER ASTROCYTES WHICH 4443 02:40:13,036 --> 02:40:15,038 ARE ACTIVATED, WHAT WE NEVER 4444 02:40:15,105 --> 02:40:16,239 FIND ARE T CELLS IN THE BRAIN. 4445 02:40:16,306 --> 02:40:18,075 IF THIS WAS A VIRAL 4446 02:40:18,141 --> 02:40:18,875 ENCEPHALITIS, YOU WOULD FIND T 4447 02:40:18,942 --> 02:40:19,943 CELLS ALL THROUGHOUT THE BRAIN. 4448 02:40:20,010 --> 02:40:22,245 YOU CANNOT GET VIRAL 4449 02:40:22,312 --> 02:40:23,113 ENCEPHALITIS AND NOT GET T 4450 02:40:23,180 --> 02:40:23,613 CELLS. 4451 02:40:23,680 --> 02:40:25,148 SO THE ABSENCE OF T CELLS TELLS 4452 02:40:25,215 --> 02:40:27,017 ME THAT THIS IS NOT A VIRAL 4453 02:40:27,084 --> 02:40:28,418 ENCEPHALITIS. 4454 02:40:28,485 --> 02:40:30,487 BUT WHAT YOU DO FIND IS YOU FIND 4455 02:40:30,554 --> 02:40:31,922 ACTIVATED PLATELETS SITTING 4456 02:40:31,989 --> 02:40:33,657 RIGHT ALONG THE BLOOD VESSEL AND 4457 02:40:33,724 --> 02:40:35,158 OCCLUDING SOME OF THESE BLOOD 4458 02:40:35,225 --> 02:40:38,528 VESSELS. 4459 02:40:38,595 --> 02:40:40,630 AGAIN WHEN WE QUANTIFIED THESE 4460 02:40:40,697 --> 02:40:41,765 THINGS, WE FIND MOST OF THE 4461 02:40:41,832 --> 02:40:42,833 PATHOLOGY IS PREDOMINANTLY THE 4462 02:40:42,899 --> 02:40:43,967 IN LOWER PARTS OF THE BRAIN, BUT 4463 02:40:44,034 --> 02:40:45,402 YOU DO FIND IT IN ALMOST ALL 4464 02:40:45,469 --> 02:40:48,805 PARTS OF THE BRAIN. 4465 02:40:48,872 --> 02:40:50,741 WE LOOKED AT THE BLOOD VESSELS 4466 02:40:50,807 --> 02:40:51,208 MORE CLOSELY. 4467 02:40:51,274 --> 02:40:52,376 WHAT WE FOUND IS THERE'S 4468 02:40:52,442 --> 02:40:55,112 ACTIVATION OF ADHESION MOLECULES 4469 02:40:55,178 --> 02:40:58,248 THERE, THERE'S -- WE FOUND MORE 4470 02:40:58,315 --> 02:41:00,684 IGM THAN IGG, BUT WE FOUND ALL 4471 02:41:00,751 --> 02:41:01,418 THESE ANTIBODIES. 4472 02:41:01,485 --> 02:41:03,587 SO WE THINK IT'S AN 4473 02:41:03,653 --> 02:41:05,756 ANTIBODY-MEDIATED PROCESS THAT 4474 02:41:05,822 --> 02:41:07,190 IS CAUSING DESTRUCTION OF THE 4475 02:41:07,257 --> 02:41:09,126 BLOOD VESSELS, MAKING THEM 4476 02:41:09,192 --> 02:41:09,993 LEAKY, AND THEN THINGS ARE 4477 02:41:10,060 --> 02:41:11,862 LEAKING INTO THE BRAIN. 4478 02:41:11,928 --> 02:41:13,397 AND I WANT TO BRING YOU BACK TO 4479 02:41:13,463 --> 02:41:15,866 THE COHORT OF PATIENTS THAT WE 4480 02:41:15,932 --> 02:41:17,734 BROUGHT HERE AT NIH, AND WHAT WE 4481 02:41:17,801 --> 02:41:19,269 FOUND WAS THAT IN ALL OF THEM, 4482 02:41:19,336 --> 02:41:21,872 WHEN WE LOOKED AT THE SPINAL 4483 02:41:21,938 --> 02:41:22,973 FLUID, THERE WERE ACTIVATED B 4484 02:41:23,040 --> 02:41:24,941 CELLS. 4485 02:41:25,008 --> 02:41:27,644 AND THE ANTIBODY PRODUCING B 4486 02:41:27,711 --> 02:41:28,612 CELLS, THAT AGAIN GOES REALLY 4487 02:41:28,678 --> 02:41:30,047 WELL WITH THE PATHOLOGY THAT I 4488 02:41:30,113 --> 02:41:32,516 SHOWED YOU THAT WAS AN 4489 02:41:32,582 --> 02:41:33,216 ANTIBODY-MEDIATED PROCESS. 4490 02:41:33,283 --> 02:41:34,951 AND THIS IS A STUDY FROM 4491 02:41:35,018 --> 02:41:35,252 HOPKINS. 4492 02:41:35,318 --> 02:41:38,221 THEY LOOKED AT PATIENTS AFTER 4493 02:41:38,288 --> 02:41:39,656 COVID AND WHAT THEY FOUND WAS 4494 02:41:39,723 --> 02:41:43,927 THAT THERE WAS A LOSS OF 4495 02:41:43,994 --> 02:41:45,529 ANTIBODIES DIRECTED AGAINST 4496 02:41:45,595 --> 02:41:48,999 H2 WHICH IS A RECEPTOR FOR 4497 02:41:49,066 --> 02:41:49,866 SARS-COV-2, THEY FOUND NOT ONLY 4498 02:41:49,933 --> 02:41:51,935 WERE THE ANTIBODIES ELEVATED BUT 4499 02:41:52,002 --> 02:41:53,070 THERE WAS A LOSS OF SWITCHING 4500 02:41:53,136 --> 02:41:55,772 FROM IGM TO IGG. 4501 02:41:55,839 --> 02:41:57,040 SO OVER A PERIOD OF THREE WEEKS 4502 02:41:57,107 --> 02:41:59,176 OR SO, YOU WOULD THINK THAT 4503 02:41:59,242 --> 02:42:00,777 THERE SHOULD BE CLASS SWITCHING 4504 02:42:00,844 --> 02:42:02,212 BUT IT NEVER REALLY OCCURRED. 4505 02:42:02,279 --> 02:42:03,613 SO HOW DO YOU ALL PUT THIS 4506 02:42:03,680 --> 02:42:05,315 TOGETHER I? 4507 02:42:05,382 --> 02:42:10,353 ONE WAY TO THINK ABOUT IT IS -- 4508 02:42:10,420 --> 02:42:11,655 WE FIND ANTIBODIES THERE AND 4509 02:42:11,721 --> 02:42:13,056 THEY'RE STICKING TO THE BLOOD 4510 02:42:13,123 --> 02:42:14,057 VESSEL. 4511 02:42:14,124 --> 02:42:16,026 THE H2 IS EXPRESSED ON THE BLOOD 4512 02:42:16,093 --> 02:42:16,326 VESSEL. 4513 02:42:16,393 --> 02:42:19,062 IF YOU GET AN ANTIBODY AGAINST 4514 02:42:19,129 --> 02:42:20,797 AN ANTIBODY, THAT COULD 4515 02:42:20,864 --> 02:42:21,665 POTENTIALLY EXPLAIN THE 4516 02:42:21,731 --> 02:42:25,035 OBSERVATIONS THAT YOU SEE HERE. 4517 02:42:25,102 --> 02:42:26,203 THERE ARE A LOT OF BLOOD VESSELS 4518 02:42:26,269 --> 02:42:26,870 IN THE BRAIN. 4519 02:42:26,937 --> 02:42:28,839 THIS JUST SHOWS YOU THAT IF YOU 4520 02:42:28,905 --> 02:42:32,242 INVOLVE THE BLOOD VESSEL, ALMOST 4521 02:42:32,309 --> 02:42:33,510 ALL ASPECTS OF THE BRAIN. 4522 02:42:33,577 --> 02:42:34,711 BECAUSE THE ENTIRE BRAIN IS JUST 4523 02:42:34,778 --> 02:42:36,813 FULL OF BLOOD VESSELS. 4524 02:42:36,880 --> 02:42:38,215 AND THERE ARE CONSEQUENCES OF 4525 02:42:38,281 --> 02:42:40,183 ALL THIS, AND THAT RESULTS IN 4526 02:42:40,250 --> 02:42:40,851 NEURONAL DAMAGE. 4527 02:42:40,917 --> 02:42:47,591 HERE I'M SHOWING YOU -- IN THE 4528 02:42:47,657 --> 02:42:48,558 CEREBELLUM, THAT'S BECAUSE 4529 02:42:48,625 --> 02:42:50,160 THERE'S LOSS OF PURKINJE CELLS 4530 02:42:50,227 --> 02:42:51,962 SO ALL OF THESE NEURITES ARE 4531 02:42:52,028 --> 02:42:55,198 LOST AS WELL. 4532 02:42:55,265 --> 02:42:56,099 AGAIN LOOKING AT THE BRAINSTEM 4533 02:42:56,166 --> 02:42:57,767 HERE, 11 TESLA MRI SCANNING, YOU 4534 02:42:57,834 --> 02:42:59,603 CAN SEE THE MEDULLA OF THE 4535 02:42:59,669 --> 02:43:00,904 BRAIN, BEAUTIFULLY WITH ALL THE 4536 02:43:00,971 --> 02:43:01,872 NUCLEI THAT YOU CAN MAP. 4537 02:43:01,938 --> 02:43:03,406 AND SO I REALLY WANTED TO LOOK 4538 02:43:03,473 --> 02:43:04,741 AT THAT AND THE REASON IS THAT I 4539 02:43:04,808 --> 02:43:07,010 TOLD YOU THESE PATIENTS HAD DIED 4540 02:43:07,077 --> 02:43:08,545 SUDDENLY, WAS NOT ENTIRELY CLEAR 4541 02:43:08,612 --> 02:43:10,180 WHY THEY DIED. 4542 02:43:10,247 --> 02:43:12,249 ONE WOULD THINK IT WAS A CARDIAC 4543 02:43:12,315 --> 02:43:13,250 ARRHYTHMIA BUT THERE WAS NOTHING 4544 02:43:13,316 --> 02:43:14,417 REALLY WRONG WITH THEIR HEART, 4545 02:43:14,484 --> 02:43:16,586 BUT THERE IS A RESPIRATORY 4546 02:43:16,653 --> 02:43:20,757 CENTER, CALLED THE PREBOTZINGER 4547 02:43:20,824 --> 02:43:21,258 COMPLEX. 4548 02:43:21,324 --> 02:43:22,459 THIS ALLOWED ME TO LOOK AT THAT. 4549 02:43:22,526 --> 02:43:24,094 WHEN WE LOOKED AT IT, WHAT WE 4550 02:43:24,161 --> 02:43:30,567 FOUND WAS THAT THERE'S NEURON 4551 02:43:30,634 --> 02:43:33,136 NEURONAL -- MOST LIKELY THESE 4552 02:43:33,203 --> 02:43:34,404 PATIENTS HAD CENTRAL 4553 02:43:34,471 --> 02:43:36,439 HYPOVENTILATION, WHICH IS ALSO 4554 02:43:36,506 --> 02:43:40,610 TERMED -- CURSE, AND THAT'S HOW 4555 02:43:40,677 --> 02:43:42,245 I THINK MOST LIKELY THESE 4556 02:43:42,312 --> 02:43:49,986 PATIENTS DIED. 4557 02:43:50,053 --> 02:43:52,289 SO THERE ARE TWO STUDIES 4558 02:43:52,355 --> 02:43:54,824 RECENTLY PUBLISHED. 4559 02:43:54,891 --> 02:43:57,627 THE GUT MICROBIOME AND ISSUES 4560 02:43:57,694 --> 02:44:00,664 WITH -- IN PATIENTS WITH ME/CFS. 4561 02:44:00,730 --> 02:44:02,566 THIS SUBSCRIBES TO THE SAME 4562 02:44:02,632 --> 02:44:04,401 HYPOTHESIS EXCEPT WHAT IT'S 4563 02:44:04,467 --> 02:44:05,802 SAYING IS THAT BECAUSE OF ALL 4564 02:44:05,869 --> 02:44:08,004 THOSE THINGS, TRYPTOPHAN IS NOT 4565 02:44:08,071 --> 02:44:10,540 BEING ABSORBED AND NOT BEING 4566 02:44:10,607 --> 02:44:11,942 CONVERTED TO SEROTONIN, AND 4567 02:44:12,008 --> 02:44:14,878 THAT'S HOWL SOME OF THESE -- HOE 4568 02:44:14,945 --> 02:44:17,347 OF THESE CASCADE OF EVENTS HAVE 4569 02:44:17,414 --> 02:44:19,015 BEEN OCCURRING. 4570 02:44:19,082 --> 02:44:19,983 NONETHELESS, IT'S INTRIGUING 4571 02:44:20,050 --> 02:44:21,451 THAT THERE MAY BE SOMETHING 4572 02:44:21,518 --> 02:44:21,651 THERE. 4573 02:44:21,718 --> 02:44:23,587 A LOT OF THESE PATIENTS ARE ON 4574 02:44:23,653 --> 02:44:24,821 SSRIs AND IT DOESN'T SEEM TO 4575 02:44:24,888 --> 02:44:26,089 MAKE A DIFFERENCE, BUT IT 4576 02:44:26,156 --> 02:44:27,490 DOESN'T MEAN THAT TRYPTOPHAN MAY 4577 02:44:27,557 --> 02:44:28,925 NOT BE INVOLVED IN SOME WAY. 4578 02:44:28,992 --> 02:44:31,094 AND THIS IS ANOTHER STUDY THAT 4579 02:44:31,161 --> 02:44:32,662 JUST CAME OUT FROM YALE WHERE 4580 02:44:32,729 --> 02:44:35,065 THEY LOOKED AT THE EVV ANTIBODY, 4581 02:44:35,131 --> 02:44:36,132 BUT ANOTHER IMPORTANT 4582 02:44:36,199 --> 02:44:37,234 OBSERVATION THEY MADE WAS THAT 4583 02:44:37,300 --> 02:44:38,835 THERE WAS DECREASED LEVELS OF 4584 02:44:38,902 --> 02:44:40,704 CORTISOL IN THIS PATIENT 4585 02:44:40,770 --> 02:44:41,271 POPULATION. 4586 02:44:41,338 --> 02:44:42,672 SO THAT'S ANOTHER THING TO KEEP 4587 02:44:42,739 --> 02:44:46,142 A CLOSE WATCH ON. 4588 02:44:46,209 --> 02:44:48,878 OKAY. 4589 02:44:48,945 --> 02:44:50,747 WHAT ABOUT NEURODEGENERATIVE 4590 02:44:50,814 --> 02:44:51,748 DISEASES? 4591 02:44:51,815 --> 02:44:56,620 CAN SARS-COV-2 ACCELERATE IN 4592 02:44:56,686 --> 02:44:57,187 NEURODEGENERATIVE DISEASE? 4593 02:44:57,254 --> 02:45:00,323 IT'S POSSIBLE, BUT HERE IS 4594 02:45:00,390 --> 02:45:01,424 EVIDENCE FOR THAT. 4595 02:45:01,491 --> 02:45:06,329 AND THAT IS THE -- BIOBANK HAS 4596 02:45:06,396 --> 02:45:07,130 PATIENTS THEY'VE BEEN FOLLOWING 4597 02:45:07,197 --> 02:45:09,299 FOR A LONG TIME WITH MRI SCANS 4598 02:45:09,366 --> 02:45:13,103 BEFORE AND AFTER COVID, AND SO 4599 02:45:13,169 --> 02:45:14,971 THEY HAD AN OPPORTUNITY TO 4600 02:45:15,038 --> 02:45:16,640 STRATIFY THE POPULATION BY AGE 4601 02:45:16,706 --> 02:45:18,341 AND THEY LOOKED AT THE BRAIN 4602 02:45:18,408 --> 02:45:20,777 VOLUME AND THEY FOUND THAT HERE 4603 02:45:20,844 --> 02:45:22,312 THE BOTTOM LINE IS INDIVIDUALS 4604 02:45:22,379 --> 02:45:26,316 WITH COVID, THAT THERE WAS 4605 02:45:26,383 --> 02:45:30,053 EVIDENCE OF BRAIN ATROPHY IN 4606 02:45:30,120 --> 02:45:34,524 INDIVIDUALS AT LATER AGES OF 4607 02:45:34,591 --> 02:45:35,925 LIFE AND THEY ALSO HAD INCREASED 4608 02:45:35,992 --> 02:45:36,760 DIFFICULTY WITH COGNITIVE 4609 02:45:36,826 --> 02:45:37,127 FUNCTION. 4610 02:45:37,193 --> 02:45:39,329 SO THE BOTTOM LINE OF THIS STUDY 4611 02:45:39,396 --> 02:45:41,097 IS THAT WHATEVER YOU DO, JUST 4612 02:45:41,164 --> 02:45:43,600 DON'T GET OLD. 4613 02:45:43,667 --> 02:45:48,938 [LAUGHTER] 4614 02:45:49,005 --> 02:45:51,875 IN STUDY LOOKED AT CMF 4615 02:45:51,941 --> 02:45:52,742 NEUROFILAMENT LEVELS AND THEY 4616 02:45:52,809 --> 02:45:54,711 SHOWED INDIVIDUALS WHO HAD COVID 4617 02:45:54,778 --> 02:45:59,316 AND WE HAD HIGHER LEVELS OF 4618 02:45:59,382 --> 02:46:00,750 NEUROFILAMENT AND LOWER LEVELS 4619 02:46:00,817 --> 02:46:03,320 OF AMYLOID BETA IN THEIR CSF, 4620 02:46:03,386 --> 02:46:05,355 AND THAT IS A HALLMARK OF 4621 02:46:05,422 --> 02:46:08,391 ALZHEIMER'S DISEASE. 4622 02:46:08,458 --> 02:46:10,860 I'M GOING TO SKIP THIS SLIDE 4623 02:46:10,927 --> 02:46:14,831 HERE. 4624 02:46:14,898 --> 02:46:17,634 AND SOME PATIENTS DEVELOP 4625 02:46:17,701 --> 02:46:20,470 AUTONOMIC DYSFUNCTION, POTS, 4626 02:46:20,537 --> 02:46:21,571 DYSAUTONOMIA. 4627 02:46:21,638 --> 02:46:23,106 THIS IS EVIDENCE FOR THAT 4628 02:46:23,173 --> 02:46:24,074 SHOWING INDIVIDUALS STAND UP, 4629 02:46:24,140 --> 02:46:25,375 SUDDENLY THEIR HEART RATE GOES 4630 02:46:25,442 --> 02:46:26,810 UP AND THE BLOOD PRESSURE FALLS. 4631 02:46:26,876 --> 02:46:28,311 THERE ARE MANY DIFFERENT 4632 02:46:28,378 --> 02:46:29,179 ITERATIONS OF THIS THAT CAN 4633 02:46:29,245 --> 02:46:30,714 OCCUR IN THESE INDIVIDUALS. 4634 02:46:30,780 --> 02:46:32,816 AND WE LOOKED AT THAT HERE AS 4635 02:46:32,882 --> 02:46:35,318 WELL, WITH DR. GOLDSTEIN, AND 4636 02:46:35,385 --> 02:46:37,821 SEVERAL OF OUR PATIENTS HAVE A 4637 02:46:37,887 --> 02:46:39,689 SIMILAR KIND OF A SYNDROME HERE. 4638 02:46:39,756 --> 02:46:41,858 AND SOME PATIENTS WILL DEVELOP A 4639 02:46:41,925 --> 02:46:43,960 SMALL FIBER POLYNEUROPATHY, AND 4640 02:46:44,027 --> 02:46:47,130 YOU CAN DIAGNOSE THAT BY -- ON 4641 02:46:47,197 --> 02:46:48,098 SKIN BIOPSY. 4642 02:46:48,164 --> 02:46:49,933 THIS IS AN INTERESTING STUDY 4643 02:46:49,999 --> 02:46:51,801 SHOWING VARIOUS KINDS OF PAIN 4644 02:46:51,868 --> 02:46:52,569 SYNDROMES THAT OCCUR IN 4645 02:46:52,635 --> 02:46:52,869 INDIVIDUALS. 4646 02:46:52,936 --> 02:46:54,437 I'D LIKE TO POINT OUT TO YOU 4647 02:46:54,504 --> 02:46:56,139 HEADACHES, SO WE'VE SEEN A LOT 4648 02:46:56,206 --> 02:46:56,906 OF INDIVIDUALS WITH VARIOUS 4649 02:46:56,973 --> 02:46:57,807 KINDS OF HEADACHES. 4650 02:46:57,874 --> 02:46:59,209 SOME OF THEM HAVE UNDERLYING 4651 02:46:59,275 --> 02:46:59,909 CAUSES FOR IT. 4652 02:46:59,976 --> 02:47:05,415 THEY CAN HAVE THROM BEE SEES OFE 4653 02:47:05,482 --> 02:47:07,217 VENOUS SIGHNESSES, SO ONE NEEDS 4654 02:47:07,283 --> 02:47:08,485 TO MAKE SURE THERE AREN'T OTHER 4655 02:47:08,551 --> 02:47:10,620 CAUSES FOR THE HEADACHE, BUT 4656 02:47:10,687 --> 02:47:12,222 THAT'S A MAJOR CAUSE FOR PAIN IN 4657 02:47:12,288 --> 02:47:13,390 THIS PATIENT POPULATION. 4658 02:47:13,456 --> 02:47:15,592 SO WHAT CAN WE DO ABOUT THESE 4659 02:47:15,658 --> 02:47:16,493 PATIENTS? 4660 02:47:16,559 --> 02:47:18,795 CERTAINLY THEY SHOULD RECEIVE 4661 02:47:18,862 --> 02:47:19,562 SYMPTOMATIC TREATMENT. 4662 02:47:19,629 --> 02:47:21,731 A LOT OF THESE THINGS ARE 4663 02:47:21,798 --> 02:47:24,033 AMENABLE TO VARIOUS KINDS OF 4664 02:47:24,100 --> 02:47:25,235 SYMPTOMATIC TREATMENTS. 4665 02:47:25,301 --> 02:47:26,202 I'M NOT GOING TO GO OVER EACH 4666 02:47:26,269 --> 02:47:27,337 ONE OF THEM IN DETAIL. 4667 02:47:27,404 --> 02:47:29,639 AND THEN PEOPLE HAVE TALKED 4668 02:47:29,706 --> 02:47:36,179 ABOUT IMMUNE THERAPIES, IT JUST 4669 02:47:36,246 --> 02:47:38,481 DEPENDS ON WHAT WE THINK IS THE 4670 02:47:38,548 --> 02:47:39,783 UNDERLYING IMMUNE ABNORMALITY. 4671 02:47:39,849 --> 02:47:41,818 ONE CAN USE NONSPECIFIC THINGS, 4672 02:47:41,885 --> 02:47:45,789 FOR EXAMPLE, CORTICOSTEROIDS, 4673 02:47:45,855 --> 02:47:50,927 PLASMA PHORESIS, WE'RE CURRENTLY 4674 02:47:50,994 --> 02:47:54,297 DOING A TRIAL HERE ON IVIG. 4675 02:47:54,364 --> 02:47:56,065 ONE CAN ACTIVATE THE INNATE 4676 02:47:56,132 --> 02:47:59,269 IMMUNE SYSTEM IN MANY WAYS, AND 4677 02:47:59,335 --> 02:48:02,272 ONE WOULD THINK T CELLS WOULD BE 4678 02:48:02,338 --> 02:48:05,008 EXHAUSTED BUT YOU CAN REVERSE 4679 02:48:05,074 --> 02:48:05,575 THAT AS WELL. 4680 02:48:05,642 --> 02:48:07,677 WE NEED TO STRATIFY PATIENT 4681 02:48:07,744 --> 02:48:08,845 POPULATIONS AND LOOK AT THEM. 4682 02:48:08,912 --> 02:48:10,346 ANOTHER THING YOU CAN DO IS GET 4683 02:48:10,413 --> 02:48:11,080 VACCINATED. 4684 02:48:11,147 --> 02:48:13,082 YOU CAN PREVENT LONG COVID. 4685 02:48:13,149 --> 02:48:15,051 AND SO THIS IS AN INTERESTING 4686 02:48:15,118 --> 02:48:16,319 META-ANALYSIS THAT LOOKED AT ONE 4687 02:48:16,386 --> 02:48:18,221 DOSE OF THE VACCINE, DIDN'T MAKE 4688 02:48:18,288 --> 02:48:19,088 A HUGE DIFFERENCE. 4689 02:48:19,155 --> 02:48:21,524 YOU LOOK AT TWO DOSAGES, STARTS 4690 02:48:21,591 --> 02:48:23,660 SHIFTING TO THE LEFT, THAT'S 4691 02:48:23,726 --> 02:48:24,327 PROTECTING YOU AGAINST LONG 4692 02:48:24,394 --> 02:48:24,661 COVID. 4693 02:48:24,727 --> 02:48:27,931 LOOK AT THREE DOSAGES, AND IT'S 4694 02:48:27,997 --> 02:48:29,032 WAY DOWN TO THE LEFT. 4695 02:48:29,098 --> 02:48:32,402 I'VE HAD FIVE, OKAY? 4696 02:48:32,469 --> 02:48:33,937 ALL RIGHT. 4697 02:48:34,003 --> 02:48:35,038 SO CLINICAL TRIALS THAT WE'RE 4698 02:48:35,104 --> 02:48:37,106 DOING HERE, NATURAL HISTORY 4699 02:48:37,173 --> 02:48:37,574 STUDY. 4700 02:48:37,640 --> 02:48:38,741 WE'RE IN THE PROCESS OF DOING A 4701 02:48:38,808 --> 02:48:41,377 VIRAL RESERVOIR STUDY. 4702 02:48:41,444 --> 02:48:44,848 AND I TOLD YOU ABOUT IVIG STUDY. 4703 02:48:44,914 --> 02:48:46,483 SO I'D LIKE TO CONCLUDE THAT 4704 02:48:46,549 --> 02:48:48,151 SAYING DIRECT INVASION OF THE 4705 02:48:48,218 --> 02:48:49,285 BRAIN BY SARS-COV-2 IS RARE AND 4706 02:48:49,352 --> 02:48:51,855 DOES NOT EXPLAIN THE 4707 02:48:51,921 --> 02:48:54,824 NEUROLOGICAL COMPLICATIONS. 4708 02:48:54,891 --> 02:48:57,293 -- IMMUNE EXHAUSTION AND 4709 02:48:57,360 --> 02:48:58,361 ANTIBODY-MEDIATED PHENOMENON. 4710 02:48:58,428 --> 02:49:00,196 CLINICAL TRIALS WITH I KNEW KNOW 4711 02:49:00,263 --> 02:49:01,631 THERAPIES COULD BE CONSIDERED IN 4712 02:49:01,698 --> 02:49:02,265 PATIENTS WITH LONG COVID. 4713 02:49:02,332 --> 02:49:04,868 I'D LIKE TO ACKNOWLEDGE A NUMBER 4714 02:49:04,934 --> 02:49:09,472 OF PEOPLE WHO DID THIS WORK. 4715 02:49:09,539 --> 02:49:12,976 SO WE GOT THE BRAINS MAINLY FROM 4716 02:49:13,042 --> 02:49:14,511 REBECCA IN NEW YORK AND ALSO A 4717 02:49:14,577 --> 02:49:17,680 FEW BRAINS FROM MARCOUX HEFTY, 4718 02:49:17,747 --> 02:49:21,784 DANIEL PEARL, ELI EYE SER, OUR 4719 02:49:21,851 --> 02:49:22,652 NEUROPATHOLOGISTS WHO HELPED 4720 02:49:22,719 --> 02:49:25,021 WITH INTERPRETATION OF OUR 4721 02:49:25,088 --> 02:49:26,422 STUDIES. 4722 02:49:26,489 --> 02:49:28,124 SERENA WROTE A REVIEW PAPER ON 4723 02:49:28,191 --> 02:49:29,659 ALL THESE FINDINGS, AND THESE 4724 02:49:29,726 --> 02:49:31,528 ARE MY COLLEAGUES WHO DID ALL 4725 02:49:31,594 --> 02:49:33,263 THE IMMUNOSTAINING AND ALL THE 4726 02:49:33,329 --> 02:49:33,930 PATHOLOGY HERE. 4727 02:49:33,997 --> 02:49:37,100 THIS IS THE TH GROUP THAT DID AL 4728 02:49:37,166 --> 02:49:38,635 THE MRI WORK OVER HERE AT THE 4729 02:49:38,701 --> 02:49:39,402 BOTTOM. 4730 02:49:39,469 --> 02:49:42,005 AND THIS WAS OUR CLINICAL TEAM 4731 02:49:42,071 --> 02:49:46,376 OVER HERE, AND OUR NURSES, AND 4732 02:49:46,442 --> 02:49:47,010 DR. KOROSHETZ, WHO HAS SUPPORTED 4733 02:49:47,076 --> 02:49:48,278 OUR STUDIES ALL THE WAY FROM THE 4734 02:49:48,344 --> 02:49:48,678 BEGINNING. 4735 02:49:48,745 --> 02:49:50,547 SO I'LL STOP HERE AND IF THERE'S 4736 02:49:50,613 --> 02:49:51,014 TIME, TAKE QUESTIONS. 4737 02:49:51,080 --> 02:49:57,887 [APPLAUSE] 4738 02:49:57,954 --> 02:50:01,124 WE[APPLAUSE] 4739 02:50:02,158 --> 02:50:04,227 ONE QUESTION. 4740 02:50:04,294 --> 02:50:07,997 >> FRANCISCO. 4741 02:50:08,064 --> 02:50:09,098 ONE OF THE GRAPHS HINTED AT IT, 4742 02:50:09,165 --> 02:50:10,633 BUT DID YOU CONSISTENTLY 4743 02:50:10,700 --> 02:50:12,502 SEGREGATE OR ANALYZE YOUR DATA 4744 02:50:12,569 --> 02:50:14,337 BY SEX ALSO FOR ALL THE 4745 02:50:14,404 --> 02:50:16,306 PARAMETERS THAT YOU MEASURED? 4746 02:50:16,372 --> 02:50:17,874 AND DID YOU SEE DIFFERENCES? 4747 02:50:17,941 --> 02:50:19,275 >> THERE'S TOO MUCH OF AN ECHO. 4748 02:50:19,342 --> 02:50:24,881 CAN YOU REPEAT THE QUESTION? 4749 02:50:24,948 --> 02:50:27,951 >> SO IT APPEARS THAT LONG COVID 4750 02:50:28,017 --> 02:50:28,785 IS MORE COMMON IN WOMEN AS 4751 02:50:28,851 --> 02:50:31,287 COMPARED TO MEN. 4752 02:50:31,354 --> 02:50:32,522 NUMBER OF STUDIES HAVE POINTED 4753 02:50:32,589 --> 02:50:34,791 THAT OUT. 4754 02:50:34,857 --> 02:50:35,758 WHY THAT IS THE CASE, I DON'T 4755 02:50:35,825 --> 02:50:36,859 THINK IT'S QUITE EVIDENT TO US 4756 02:50:36,926 --> 02:50:43,333 AT THE MOMENT. 4757 02:50:43,399 --> 02:50:44,067 >> [INAUDIBLE] 4758 02:50:44,133 --> 02:50:45,735 >> EPIDEMIOLOGICALLY YOU SEE 4759 02:50:45,802 --> 02:50:46,603 MORE LONG COVID IN WOMEN 4760 02:50:46,669 --> 02:50:47,270 COMPARED TO MEN. 4761 02:50:47,337 --> 02:50:48,805 THAT'S WHAT I'M SAYING. 4762 02:50:48,871 --> 02:50:51,207 THAT'S ALL I KNOW. 4763 02:50:51,274 --> 02:50:53,643 >> HI. 4764 02:50:53,710 --> 02:50:56,346 I JUST HAD A QUESTION ABOUT THE 4765 02:50:56,412 --> 02:50:57,413 CORRELATIONS BETWEEN THE LONG 4766 02:50:57,480 --> 02:51:00,283 COVID AND NEURODEGENERATIVE 4767 02:51:00,350 --> 02:51:00,917 DISEASES. 4768 02:51:00,984 --> 02:51:03,686 DO THE RESULTS SUGGEST THAT IT'S 4769 02:51:03,753 --> 02:51:05,421 KIND OF EXACERBATING THE 4770 02:51:05,488 --> 02:51:07,957 PRE-EXISTING FORMATION OF THE 4771 02:51:08,024 --> 02:51:11,995 NEUROFIB LEAR TANFIBRILLARY TANT 4772 02:51:12,061 --> 02:51:13,096 CAUSING THE DIRECT FORMATION OF 4773 02:51:13,162 --> 02:51:14,631 NEW ONES LIKE CREATING THIS NEW 4774 02:51:14,697 --> 02:51:16,366 SOURCE OF THE NFTs? 4775 02:51:16,432 --> 02:51:19,035 >> SO WE DON'T KNOW FOR █SURE, 4776 02:51:19,102 --> 02:51:24,073 BUT I THINK IT WOULD BE EASY TO 4777 02:51:24,140 --> 02:51:25,908 IMAGINE THAT YOU ARE 4778 02:51:25,975 --> 02:51:26,776 PRECIPITATING AN UNDERLYING 4779 02:51:26,843 --> 02:51:29,178 DISEASE AND JUST EXACERBATING 4780 02:51:29,245 --> 02:51:30,713 IT: THERE ARE IN VITRO STUDIES 4781 02:51:30,780 --> 02:51:33,983 SHOWING THAT YOU CAN TAKE THE 4782 02:51:34,050 --> 02:51:37,687 SPIKE PROTEIN, TAKE SYNUCLEIN, 4783 02:51:37,754 --> 02:51:39,055 AMYLOID OR TAU AND ACTUALLY 4784 02:51:39,122 --> 02:51:39,989 CAUSING A GAITIONS. 4785 02:51:40,056 --> 02:51:41,858 ONCE THOSE AGGREGATES FORM THEY 4786 02:51:41,924 --> 02:51:43,593 PERFORM LIKE A PRION-LIKE 4787 02:51:43,660 --> 02:51:45,228 BEHAVIOR AND CAUSE MORE AND MORE 4788 02:51:45,294 --> 02:51:45,528 AGGREGATION. 4789 02:51:45,595 --> 02:51:48,197 SO ANY KIND OF RESPIRATORY 4790 02:51:48,264 --> 02:51:49,932 ILLNESS CAN TRIGGER THESE KINDS 4791 02:51:49,999 --> 02:51:50,600 OF THINGS. 4792 02:51:50,667 --> 02:51:54,771 IT'S NOT UNCOMMON, EVEN BEFORE 4793 02:51:54,837 --> 02:51:57,073 COVID, GRANDMA COMES IN THE 4794 02:51:57,140 --> 02:51:58,608 HOSPITAL, ADMITTED TO ICU, SHE 4795 02:51:58,675 --> 02:52:00,109 COMES OUT AND SHE'S NOT THE SAME 4796 02:52:00,176 --> 02:52:00,410 GRANDMOTHER. 4797 02:52:00,476 --> 02:52:01,644 SO I THINK THIS CHRONIC 4798 02:52:01,711 --> 02:52:02,979 INFLAMMATION CAN PRECIPITATE 4799 02:52:03,046 --> 02:52:03,413 THESE THINGS. 4800 02:52:03,479 --> 02:52:09,252 >> THANK YOU. 4801 02:52:09,318 --> 02:52:11,320 >> THANK YOU, DR. NATH. 4802 02:52:11,387 --> 02:52:16,726 [APPLAUSE] 4803 02:52:16,793 --> 02:52:20,296 >> IT'S TIME FOR LUN MP. 4804 02:52:20,363 --> 02:52:20,630 LUNCH. 4805 02:52:20,697 --> 02:52:22,365 AGAIN I MENTIONED LUNCH IS DOWN 4806 02:52:22,432 --> 02:52:24,133 IN THE TERRACE, SO GO OUT THESE 4807 02:52:24,200 --> 02:52:25,468 DOORS, GO TO THE RIGHT. 4808 02:52:25,535 --> 02:52:27,303 AT THE COFFEE SHOP, THERE WILL 4809 02:52:27,370 --> 02:52:30,073 BE SIGNS AND LUNCH HAS BEEN VERY 4810 02:52:30,139 --> 02:52:31,808 GRACIOUSLY PROVIDED BY THE OPEN 4811 02:52:31,874 --> 02:52:32,675 MEDICINE FOUNDATION TO SORT OF 4812 02:52:32,742 --> 02:52:34,610 TRY AND FOSTER SOME NETWORKING 4813 02:52:34,677 --> 02:52:36,212 SO YOU DON'T HAVE TO GO -- THERE 4814 02:52:36,279 --> 02:52:37,613 ARE CAFETERIAS, OF COURSE, IN 4815 02:52:37,680 --> 02:52:39,582 THIS BUILDING, BUT HAVING FOOD 4816 02:52:39,649 --> 02:52:41,084 THERE, AND THE POSTERS FROM THE 4817 02:52:41,150 --> 02:52:43,119 YOUNG INVESTIGATOR SYMPOSIUM 4818 02:52:43,186 --> 02:52:43,519 YESTERDAY. 4819 02:52:43,586 --> 02:52:47,323 SO I'D ENCOURAGE YOU TO GO THERE 4820 02:52:47,390 --> 02:52:50,093 AND VISIT WITH THE YOUNG 4821 02:52:50,159 --> 02:52:51,594 INVESTIGATORS, AND THERE ARE 4822 02:52:51,661 --> 02:52:54,230 LUNCHES PROVIDED THERE. 4823 02:52:54,297 --> 02:52:57,100 THERE'S ALSO A FEW TABLES FROM 4824 02:52:57,166 --> 02:52:58,935 OTHER PRIVATE FOUNDATIONS, AND 4825 02:52:59,001 --> 02:53:02,538 ALSO A TABLE FROM RTI, WHICH IS 4826 02:53:02,605 --> 02:53:05,475 THE DMCC, THE DATA MANAGEMENT 4827 02:53:05,541 --> 02:53:07,543 COORDINATING CENTER FOR THE NIH 4828 02:53:07,610 --> 02:53:08,678 ME/CFS NETWORK, WHERE THEY'RE 4829 02:53:08,745 --> 02:53:11,948 GOING TO SHOW YOU THEIR MAP 4830 02:53:12,014 --> 02:53:13,349 ME/CFS AND OTHER THINGS THAT 4831 02:53:13,416 --> 02:53:16,886 THEY'VE BUILT TO INCREASE THE 4832 02:53:16,953 --> 02:53:19,055 SHARING IN THE COMMUNITY OF DATA 4833 02:53:19,122 --> 02:53:20,490 ACROSS MANY, MANY DIFFERENT 4834 02:53:20,556 --> 02:53:21,457 STUDIES. 4835 02:53:21,524 --> 02:53:24,060 AND PLEASE COME BACK BY 1:05. 4836 02:53:24,127 --> 02:53:25,661 WE'RE GOING TO CUT A LITTLE TIME 4837 02:53:25,728 --> 02:53:28,231 SHORT AND TRY AND CATCH UP. 4838 02:53:28,297 --> 02:53:28,765 1:05. 4839 02:53:28,831 --> 02:53:38,541 THANK YOU. 4840 02:53:38,608 --> 02:53:46,215 >> GOOD AFTERNOON. 4841 02:53:46,282 --> 02:53:50,253 TODAY WE'RE GOING TO HAVE A TALK 4842 02:53:50,319 --> 02:53:53,756 FROM DR. MIKE SNELLER FROM NIAID 4843 02:53:53,823 --> 02:53:55,725 THAT ACTUALLY FITS AS THE FINAL 4844 02:53:55,792 --> 02:53:57,393 TALK IN THE SESSION THAT ENDED 4845 02:53:57,460 --> 02:54:02,632 RIGHT BEFORE LUNCH, AND 4846 02:54:02,698 --> 02:54:04,066 DR. SNELLER WAS VERY KIND TO 4847 02:54:04,133 --> 02:54:05,234 COME AND GIVE THIS TALK EVEN 4848 02:54:05,301 --> 02:54:07,003 THOUGH HE'S ON CLINICAL SERVICE, 4849 02:54:07,069 --> 02:54:08,204 SO THANK YOU SO MUCH FOR MAKING 4850 02:54:08,271 --> 02:54:09,405 THE TIME. 4851 02:54:09,472 --> 02:54:11,474 HIS TITLE IS LONGITUDINAL STUDY 4852 02:54:11,541 --> 02:54:14,010 OF COVID-19 SEQUELAE AND 4853 02:54:14,076 --> 02:54:24,253 IMMUNITY. 4854 02:54:28,191 --> 02:54:29,692 >> THANK YOU, JOE, FOR INVITING 4855 02:54:29,759 --> 02:54:30,927 ME TO GIVE THIS TALK. 4856 02:54:30,993 --> 02:54:32,562 WHAT I'M GOING DO IS BASICALLY, 4857 02:54:32,628 --> 02:54:34,897 AFTER GIVING A FEW BACKGROUND 4858 02:54:34,964 --> 02:54:36,098 POINTS, BRIEFLY DESCRIBE THE 4859 02:54:36,165 --> 02:54:39,468 STUDY THAT WE'RE DOING LOOKING 4860 02:54:39,535 --> 02:54:43,639 AT BOTH CLINICAL FEATURES AND 4861 02:54:43,706 --> 02:54:45,374 IMMUNOPATHOGENESIS OF POST COVID 4862 02:54:45,441 --> 02:54:46,576 SYNDROME, REVIEW THE DATA WE'VE 4863 02:54:46,642 --> 02:54:48,144 GOT SO FAR, MOST OF WHICH WAS 4864 02:54:48,211 --> 02:54:49,979 PUBLISHED ABOUT A YEAR AGO IN 4865 02:54:50,046 --> 02:54:52,815 THE ANNALS OF INTERNAL MEDICINE 4866 02:54:52,882 --> 02:54:54,450 AND THEN LET YOU KNOW WHERE THE 4867 02:54:54,517 --> 02:54:55,885 STANDING OF THE PROTOCOL IS NOW 4868 02:54:55,952 --> 02:54:56,953 AND WHAT OUR FUTURE DIRECTIONS 4869 02:54:57,019 --> 02:55:02,024 ARE AS OF NOW. 4870 02:55:02,091 --> 02:55:03,025 FIRST JUST A WORD ABOUT 4871 02:55:03,092 --> 02:55:04,060 TERMINOLOGY. 4872 02:55:04,126 --> 02:55:05,494 SO OBVIOUSLY THERE'S A NUMBER OF 4873 02:55:05,561 --> 02:55:07,530 TERMS THAT HAVE BEEN USED FOR 4874 02:55:07,597 --> 02:55:10,032 PERSISTENT SYMPTOMS IN PEOPLE 4875 02:55:10,099 --> 02:55:11,534 WHO HAVE BEEN INFECTED WITH 4876 02:55:11,601 --> 02:55:12,401 SARS-COV-2. 4877 02:55:12,468 --> 02:55:13,936 WHEN WE INITIALLY WROTE THIS 4878 02:55:14,003 --> 02:55:15,805 PROTOCOL IN THE SPRING OF 2020, 4879 02:55:15,872 --> 02:55:19,208 THE TERM LONG COVID HAD NOT BEEN 4880 02:55:19,275 --> 02:55:21,811 COINED YET, SO WE ENDED UP 4881 02:55:21,878 --> 02:55:28,251 CALLING IT POST-ACUTE SCWEA LAYE 4882 02:55:28,317 --> 02:55:34,390 OF SARS-COV-2 OR PASC. 4883 02:55:34,457 --> 02:55:35,925 I MAY LAPSE INTO USING ONE OF 4884 02:55:35,992 --> 02:55:38,427 THESE OTHER TERMS DURING THE 4885 02:55:38,494 --> 02:55:39,528 TALK, BUT BASICALLY THESE ALL 4886 02:55:39,595 --> 02:55:43,566 REFER TO THE SAME ENTITY. 4887 02:55:43,633 --> 02:55:46,502 THE SECOND POINT I WANT TO MAKE 4888 02:55:46,569 --> 02:55:49,805 IS ABOUT WHETHER YOU TALK ABOUT 4889 02:55:49,872 --> 02:55:52,875 POST COVID SEQUELAE, THEY FALL 4890 02:55:52,942 --> 02:55:55,311 INTO TWO BROAD GROUPS. 4891 02:55:55,378 --> 02:55:56,579 FORTUNATELY ONLY ABOUT 5 TO 10% 4892 02:55:56,646 --> 02:55:58,648 OF PEOPLE WHO CONTRACT 4893 02:55:58,714 --> 02:55:59,448 SARS-COV-2 INFECTION DEVELOP 4894 02:55:59,515 --> 02:56:01,150 VERY SEVERE LIFE-THREATENING 4895 02:56:01,217 --> 02:56:03,819 DISEASE THAT REQUIRES INTENSIVE 4896 02:56:03,886 --> 02:56:06,455 CARE UNIT ADMISSION, MECHANICAL 4897 02:56:06,522 --> 02:56:07,623 VENTILATION, ALL SORTS OF OTHER 4898 02:56:07,690 --> 02:56:10,893 THINGS AND IS OFTEN ASSOCIATED 4899 02:56:10,960 --> 02:56:12,795 WITH NOT ONLY PULMONARY FAILURE 4900 02:56:12,862 --> 02:56:14,230 BUT OTHER MULTISYSTEM ORGAN 4901 02:56:14,297 --> 02:56:14,664 FAILURE. 4902 02:56:14,730 --> 02:56:15,831 OVER HALF OF THOSE PATIENTS WILL 4903 02:56:15,898 --> 02:56:17,600 DEVELOP SOMETHING THAT HAS 4904 02:56:17,667 --> 02:56:19,435 PREVIOUSLY BEEN TERMED POST ICU 4905 02:56:19,502 --> 02:56:20,369 SYNDROME AND IS IDENTICAL TO 4906 02:56:20,436 --> 02:56:23,706 WHAT HAS BEEN DESCRIBED AS POST 4907 02:56:23,773 --> 02:56:25,908 ICU SYNDROME THAT INVOLVES 4908 02:56:25,975 --> 02:56:28,311 RESIDUAL SEQUELAE FROM ORGAN 4909 02:56:28,377 --> 02:56:30,613 SYSTEM DAMAGE DONE DURING ACUTE 4910 02:56:30,680 --> 02:56:31,914 ILLNESS, LUNG DAMAGE FIBROSIS 4911 02:56:31,981 --> 02:56:33,215 FROM BEING ON A VENTILATOR FOR 4912 02:56:33,282 --> 02:56:35,751 MANY WEEKS TO MONTHS, END ORGAN 4913 02:56:35,818 --> 02:56:38,054 DAMAGE TO THE KIDNEYS, LIVER, 4914 02:56:38,120 --> 02:56:40,323 HEART AND SO FORTH, STROKES, AND 4915 02:56:40,389 --> 02:56:41,991 COGNITIVE AND PSYCHIATRIC 4916 02:56:42,058 --> 02:56:42,792 CONSEQUENCES THAT PROBABLY 4917 02:56:42,858 --> 02:56:45,928 RELATE TO PROLONGED SEDATION AND 4918 02:56:45,995 --> 02:56:56,505 PROBABLY ANOXIC BRAIN INJURY. 4919 02:56:56,772 --> 02:56:57,773 I'LL TRY TO TALK A LITTLE 4920 02:56:57,840 --> 02:57:01,210 LOUDER. 4921 02:57:01,277 --> 02:57:03,179 SO THAT SYNDROME, AGAIN, HAS 4922 02:57:03,245 --> 02:57:04,647 PREVIOUSLY BEEN RECOGNIZED AND 4923 02:57:04,714 --> 02:57:08,017 IT OCCURS IN ALL CRITICAL 4924 02:57:08,084 --> 02:57:09,852 ILLNESSES AND OCCURS IN CRITICAL 4925 02:57:09,919 --> 02:57:10,987 ILLNESS FROM SARS-COV-2 4926 02:57:11,053 --> 02:57:11,454 INFECTION. 4927 02:57:11,520 --> 02:57:13,556 FORTUNATELY ONLY ABOUT 10% OF 4928 02:57:13,622 --> 02:57:16,425 PEOPLE AT LEAST BACK IN 2020 4929 02:57:16,492 --> 02:57:18,160 WOULD GET THAT SEVERE DISEASE. 4930 02:57:18,227 --> 02:57:19,362 I SUSPECT THAT'S MUCH LESS NOW 4931 02:57:19,428 --> 02:57:20,596 WITH ALL THE VACCINATION AND 4932 02:57:20,663 --> 02:57:24,200 IMMUNITY IN THE POPULATION. 4933 02:57:24,266 --> 02:57:26,535 THE SECOND SYNDROME, THE VAST 4934 02:57:26,602 --> 02:57:27,370 MAJORITY OF PATIENTS DON'T GET 4935 02:57:27,436 --> 02:57:29,972 THIS SEVERE CRITICAL DISEASE, 4936 02:57:30,039 --> 02:57:31,540 THEY GET MILD/MODERATE DISEASE 4937 02:57:31,607 --> 02:57:34,377 THAT DOES NOT REQUIRE 4938 02:57:34,443 --> 02:57:36,112 HOSPITALIZATION OR SUM PLEN 4939 02:57:36,178 --> 02:57:36,545 TAITION. 4940 02:57:36,612 --> 02:57:37,646 SOMEWHERE REPORTED BETWEEN 10 4941 02:57:37,713 --> 02:57:39,515 PROBABLY AT THE HIGH END 50% OF 4942 02:57:39,582 --> 02:57:41,050 INDIVIDUALS WHO HAVE MILD TO 4943 02:57:41,117 --> 02:57:42,284 MODERATE DISEASE WILL HAVE ONE 4944 02:57:42,351 --> 02:57:44,253 OR MORE PERSISTENT SYMPTOMS 4945 02:57:44,320 --> 02:57:45,521 AFTER RECOVERY FROM THE ACUTE 4946 02:57:45,588 --> 02:57:46,422 ILLNESS. 4947 02:57:46,489 --> 02:57:49,158 NOW THIS SYNDROME, LONG COVID, 4948 02:57:49,225 --> 02:57:51,327 OR WHATEVER YOU WANT TO CALL IT, 4949 02:57:51,394 --> 02:57:52,762 BEARS CERTAIN FEATURES TO OTHER 4950 02:57:52,828 --> 02:57:57,233 POST INFECTIOUS NON-CRITICAL 4951 02:57:57,299 --> 02:57:58,734 POST INFECTIOUS SYNDROMES, 4952 02:57:58,801 --> 02:58:01,604 INCLUDING POST INFECTIOUS ME/CFS 4953 02:58:01,670 --> 02:58:04,907 AND POST TREATMENT LYME DISEASE. 4954 02:58:04,974 --> 02:58:08,844 SO OUR PROTOCOL ENROLLED 4955 02:58:08,911 --> 02:58:10,646 PATIENTS IN THIS PRETTY MUCH 4956 02:58:10,713 --> 02:58:12,048 EXACT PROPORTION, ABOUT 90% OF 4957 02:58:12,114 --> 02:58:13,349 THE PATIENTS CURRENTLY ON OUR 4958 02:58:13,416 --> 02:58:15,184 PROTOCOL HAD MILD TO MODERATE 4959 02:58:15,251 --> 02:58:16,419 DISEASE THAT DID NOT REQUIRE 4960 02:58:16,485 --> 02:58:16,952 HOSPITALIZATION. 4961 02:58:17,019 --> 02:58:19,488 AND ONLY ABOUT 10% WERE 4962 02:58:19,555 --> 02:58:21,223 CRITICALLY ILL IN AN INTENSIVE 4963 02:58:21,290 --> 02:58:22,525 CARE UNIT REQUIRING MECHANICAL 4964 02:58:22,591 --> 02:58:24,593 VENTILATION. 4965 02:58:24,660 --> 02:58:26,028 SO THE OBJECTIVES OF THIS STUDY 4966 02:58:26,095 --> 02:58:27,663 WHEN WE FIRST STARTED OUT IN THE 4967 02:58:27,730 --> 02:58:29,131 SPRING OF 2020 WERE TO 4968 02:58:29,198 --> 02:58:30,332 CHARACTERIZE THE MEDICAL AND 4969 02:58:30,399 --> 02:58:32,168 MENTAL HEALTH SEQUELAE FOLLOWING 4970 02:58:32,234 --> 02:58:35,638 RECOVERY OF ADULTS FROM 4971 02:58:35,704 --> 02:58:36,205 COVID-19, AND ALSO TO 4972 02:58:36,272 --> 02:58:38,274 INVESTIGATE THE PATHOGENESIS OF 4973 02:58:38,340 --> 02:58:40,676 ANY IDENTIFIED CLINICAL 4974 02:58:40,743 --> 02:58:40,943 SEQUELAE. 4975 02:58:41,010 --> 02:58:42,445 SO AT THE TIME THIS PROTOCOL WAS 4976 02:58:42,511 --> 02:58:43,546 WRITTEN WE DIDN'T KNOW THAT MUCH 4977 02:58:43,612 --> 02:58:45,081 ABOUT LONG COVID, BECAUSE THE 4978 02:58:45,147 --> 02:58:46,148 DISEASE HAD ONLY BEEN IN THE 4979 02:58:46,215 --> 02:58:47,583 UNITED STATES FOR A FEW MONTHS. 4980 02:58:47,650 --> 02:58:51,954 THE ACUTE DISEASE. 4981 02:58:52,021 --> 02:58:53,722 SO WE MADE OUR INCLUSION 4982 02:58:53,789 --> 02:58:54,457 CRITERIA PRETTY LIBERAL. 4983 02:58:54,523 --> 02:58:56,592 THE ONLY THING WE INSISTED ON, 4984 02:58:56,659 --> 02:58:58,527 THIS WAS ALL DONE ON ADULTS, WAS 4985 02:58:58,594 --> 02:58:59,595 THAT WE WERE DEALING WITH 4986 02:58:59,662 --> 02:59:00,830 PATIENTS THAT CLEARLY HAD 4987 02:59:00,896 --> 02:59:03,232 COVID-19, SO WE REQUIRED 4988 02:59:03,299 --> 02:59:06,001 LABORATORY DOCUMENTATION OF 4989 02:59:06,068 --> 02:59:07,036 COVID-19 INFECTION THAT WE HAD 4990 02:59:07,103 --> 02:59:09,338 TO HAVE COPIES OF BEFORE WE 4991 02:59:09,405 --> 02:59:10,439 WOULD ENROLL THE INDIVIDUAL AND 4992 02:59:10,506 --> 02:59:11,841 THOSE CRITERIA ARE LISTED HERE, 4993 02:59:11,907 --> 02:59:14,577 BASICALLY A POSITIVE PCR OR 4994 02:59:14,643 --> 02:59:16,912 LATER ON ANTIGEN TESTS IN PEOPLE 4995 02:59:16,979 --> 02:59:18,848 WHO WERE UNABLE TO GET PCRs 4996 02:59:18,914 --> 02:59:20,382 BECAUSE OF LACK OF AVAILABILITY, 4997 02:59:20,449 --> 02:59:21,617 THEY COULD BE ELIGIBLE IF THEY 4998 02:59:21,684 --> 02:59:23,018 HAD A POSITIVE ANTIBODY TEST 4999 02:59:23,085 --> 02:59:24,353 THAT HAD BEEN APPROVED BY THE 5000 02:59:24,420 --> 02:59:26,822 FDA FOR EMERGENCY USE 5001 02:59:26,889 --> 02:59:27,857 AUTHORIZATION, AND A HISTORY 5002 02:59:27,923 --> 02:59:30,626 THAT WAS COMPATIBLE WITH 5003 02:59:30,693 --> 02:59:33,262 COVID-19 THAT OCCURRED AFTER 5004 02:59:33,329 --> 02:59:34,130 JANUARY 2020. 5005 02:59:34,196 --> 02:59:35,197 THE THIRD CRITERIA WAS THAT THEY 5006 02:59:35,264 --> 02:59:38,100 HAD TO BE AT LEAST SIX WEEKS 5007 02:59:38,167 --> 02:59:39,635 SINCE THE ONSET OF THEIR ACUTE 5008 02:59:39,702 --> 02:59:39,969 COVID ILLNESS. 5009 02:59:40,035 --> 02:59:41,637 WE DIDN'T REALLY WANT TO START 5010 02:59:41,704 --> 02:59:42,805 LOOKING AT PEOPLE UNTIL THEY'D 5011 02:59:42,872 --> 02:59:45,341 RECOVERED FROM THEIR ACUTE 5012 02:59:45,407 --> 02:59:47,076 ILLNESS. 5013 02:59:47,143 --> 02:59:48,477 IT TURNS OUT AS YOU'LL SEE MOST 5014 02:59:48,544 --> 02:59:49,812 PATIENTS WERE FAR BEYOND SIX 5015 02:59:49,879 --> 02:59:50,980 WEEKS BY THE TIME THEY ENROLLED 5016 02:59:51,046 --> 02:59:53,315 IN THE STUDY. 5017 02:59:53,382 --> 02:59:54,750 WE ALSO KNEW THERE WAS GOING TO 5018 02:59:54,817 --> 02:59:55,818 BE ESSENTIAL, SINCE WE WERE 5019 02:59:55,885 --> 02:59:57,353 GOING TO BE DOING A LOT OF 5020 02:59:57,419 --> 02:59:58,554 DIAGNOSTIC TESTING ON THESE 5021 02:59:58,621 --> 02:59:59,989 INDIVIDUALS, TO HAVE A CONTROL 5022 03:00:00,055 --> 03:00:03,025 GROUP WHO HAD NOT HAD COVID-19 5023 03:00:03,092 --> 03:00:04,026 AND IT WAS REASONABLY WELL 5024 03:00:04,093 --> 03:00:06,996 MATCHED WITH REGARDS TO AGE, 5025 03:00:07,062 --> 03:00:09,098 COMORBIDITIES, AND GENDER. 5026 03:00:09,165 --> 03:00:11,233 SO WE ENROLLED A CONTROL GROUP. 5027 03:00:11,300 --> 03:00:12,568 THE INCLUSION CRITERIA FOR THE 5028 03:00:12,635 --> 03:00:14,537 CONTROL GROUP, AGAIN, ONLY 5029 03:00:14,603 --> 03:00:15,604 ADULTS, WAS NO PAST KNOWN 5030 03:00:15,671 --> 03:00:17,573 DIAGNOSIS OF COVID-19 OR A 5031 03:00:17,640 --> 03:00:18,574 COVID-19-LIKE ILLNESS. 5032 03:00:18,641 --> 03:00:19,875 AND NO CURRENT SYMPTOMS THAT 5033 03:00:19,942 --> 03:00:21,644 WERE SUGGESTIVE OF COVID-19. 5034 03:00:21,710 --> 03:00:24,813 THEY ALSO HAD TO HAVE NEGATIVE 5035 03:00:24,880 --> 03:00:26,549 SEROLOGY FOR -- INITIALLY FOR 5036 03:00:26,615 --> 03:00:30,719 BOTH SPIKE ANTIGEN AND 5037 03:00:30,786 --> 03:00:31,921 SARS-COV-2 KNEW CLOA CAPSID 5038 03:00:31,987 --> 03:00:34,123 ANTIGEN BUT WITH THE ADVENT OF 5039 03:00:34,190 --> 03:00:37,259 VACCINATIONS, WE COULD ONLY LOOK 5040 03:00:37,326 --> 03:00:39,995 AT CAPSID ANTIGENS. 5041 03:00:40,062 --> 03:00:41,664 -- HAD NO HISTORY OF ANY 5042 03:00:41,730 --> 03:00:45,501 COVID-LIKE ILLNESS. 5043 03:00:45,568 --> 03:00:47,670 SO THIS WAS TRULY A 5044 03:00:47,736 --> 03:00:48,437 MULTIDISCIPLINARY STUDY WHEN WE 5045 03:00:48,504 --> 03:00:51,073 SET IT UP AND STILL IS. 5046 03:00:51,140 --> 03:00:53,676 FROM NIAID WE HAVE A NUMBER OF 5047 03:00:53,742 --> 03:00:55,311 INFECTIOUS DISEASE PHYSICIANS 5048 03:00:55,377 --> 03:00:56,946 BESIDES MYSELF, A STATISTICIAN 5049 03:00:57,012 --> 03:01:00,382 AND SEVERAL IMMUNOLOGISTS AND 5050 03:01:00,449 --> 03:01:01,450 IMMUNOLOGY LABORATORIES INVOLVED 5051 03:01:01,517 --> 03:01:06,589 TO HELP US LOOK AT PATHOGENESIS 5052 03:01:06,655 --> 03:01:08,557 AS WELL AS VIRAL SEROLOGY LAB, 5053 03:01:08,624 --> 03:01:10,459 WE ALSO APPROACHED INVESTIGATORS 5054 03:01:10,526 --> 03:01:12,194 FROM NIMH AND MADE SEVERAL OF 5055 03:01:12,261 --> 03:01:14,797 THEM CO-INVESTIGATORS. 5056 03:01:14,863 --> 03:01:17,633 INCLUDING TWO PSYCHIATRISTS AND 5057 03:01:17,700 --> 03:01:19,501 TWO PSYCHOLOGISTS TO HELP WITH 5058 03:01:19,568 --> 03:01:20,269 EVALUATING MENTAL HEALTH ASPECTS 5059 03:01:20,336 --> 03:01:23,138 OF THIS SYNDROME AND NEURAL 5060 03:01:23,205 --> 03:01:24,206 COGNITIVE FUNCTION IN THIS 5061 03:01:24,273 --> 03:01:24,540 SYNDROME. 5062 03:01:24,607 --> 03:01:28,277 AND WE ALSO HAD NHLBI 5063 03:01:28,344 --> 03:01:29,245 INVESTIGATORS THAT ARE 5064 03:01:29,311 --> 03:01:30,479 CARDIOLOGISTS AND PULMONOLOGISTS 5065 03:01:30,546 --> 03:01:31,747 WHO AGAIN HELPED US WITH THE 5066 03:01:31,814 --> 03:01:33,716 INTERPRETATION OF 5067 03:01:33,782 --> 03:01:34,416 CARDIOPULMONARY ABNORMALITIES 5068 03:01:34,483 --> 03:01:35,884 THAT WE EXPECTED TO SEE IN THESE 5069 03:01:35,951 --> 03:01:39,755 INDIVIDUALS. 5070 03:01:39,822 --> 03:01:42,258 SO THE STUDY PROCEDURES, SO 5071 03:01:42,324 --> 03:01:43,659 EVERYBODY AT THEIR BASELINE 5072 03:01:43,726 --> 03:01:46,095 EVALUATION STARTED WITH A 5073 03:01:46,161 --> 03:01:47,229 COMPREHENSIVE HISTORY AND 5074 03:01:47,296 --> 03:01:47,863 PHYSICAL EXAMINATION. 5075 03:01:47,930 --> 03:01:49,832 WE THEN RAN A WHOLE BATTERY OF 5076 03:01:49,898 --> 03:01:51,867 ROUTINE LABORATORY STUDIES TO 5077 03:01:51,934 --> 03:01:54,069 ASSESS MULTIPLE ORGAN FUNCTION, 5078 03:01:54,136 --> 03:01:57,573 KIDNEY, LIVER, EE MA TOPO HE 5079 03:01:57,640 --> 03:01:59,308 TICK FUNCTION, COAGULATION 5080 03:01:59,375 --> 03:01:59,642 PARAMETERS. 5081 03:01:59,708 --> 03:02:03,245 WE ALSO LOOKED AT 5082 03:02:03,312 --> 03:02:04,647 AUTOANTIBODIES, BIOMARKERS OF 5083 03:02:04,713 --> 03:02:07,716 INFLAMMATION AND TISSUE DAMAGE. 5084 03:02:07,783 --> 03:02:09,918 AGAIN REGARDLESS OF SYMPTOMS OF 5085 03:02:09,985 --> 03:02:11,320 WHETHER THEY HAD PERSISTENT 5086 03:02:11,387 --> 03:02:13,756 SYMPTOMS OR NOT. 5087 03:02:13,822 --> 03:02:15,291 ALSO THE PATIENTS FILLED OUT A 5088 03:02:15,357 --> 03:02:16,258 BATTERY OF QUESTIONNAIRES TO 5089 03:02:16,325 --> 03:02:17,893 ASSESS A VARIETY OF SYMPTOMS AS 5090 03:02:17,960 --> 03:02:18,994 WELL AS FUNCTIONAL STATUS. 5091 03:02:19,061 --> 03:02:20,763 WE DID SARS-COV-2 SEROLOGY AT 5092 03:02:20,829 --> 03:02:23,499 EVERY VISIT LOOKING AT BOTH 5093 03:02:23,565 --> 03:02:25,668 ANTIBODIES OF SPIKE PROTEIN AND 5094 03:02:25,734 --> 03:02:27,636 ANTICAPSID ANTIGEN AND THOSE WHO 5095 03:02:27,703 --> 03:02:28,937 HAD ADEQUATE ACCESS, WE ALSO DID 5096 03:02:29,004 --> 03:02:31,674 A PROCEDURE KNOWN AS 5097 03:02:31,740 --> 03:02:32,775 LEUKAPHORESIS THAT ALLOWS ONE TO 5098 03:02:32,841 --> 03:02:34,410 GET A LARGE AMOUNT OF MONO 5099 03:02:34,476 --> 03:02:36,478 NUCLEAR CELLS, LYMPHOCYTES AND 5100 03:02:36,545 --> 03:02:37,446 MONOCYTES WITHOUT HAVING TO TAKE 5101 03:02:37,513 --> 03:02:39,648 A LOT OF BLOOD VOLUME. 5102 03:02:39,715 --> 03:02:40,215 TO BE USE 5103 03:02:40,282 --> 03:02:42,284 FORD RESEARCH STUDIES ON THE 5104 03:02:42,351 --> 03:02:46,789 PATHOGENESIS OF THIS SYNDROME. 5105 03:02:46,855 --> 03:02:48,991 IT ALSO -- THE STUDY PROTOCOLS 5106 03:02:49,058 --> 03:02:51,360 INCLUDED A MENTAL HEALTH 5107 03:02:51,427 --> 03:02:52,661 EVALUATION, A SUBGROUP OF 200 5108 03:02:52,728 --> 03:02:54,229 INDIVIDUALS UNDERWENT FORMAL 5109 03:02:54,296 --> 03:02:55,731 PSYCHIATRIC INTERVIEWS BY THE 5110 03:02:55,798 --> 03:02:56,432 PSYCHIATRISTS ON THE STUDY. 5111 03:02:56,498 --> 03:02:57,566 THERE WERE ALSO A VARIETY OF 5112 03:02:57,633 --> 03:02:58,567 MENTAL HEALTH QUESTIONNAIRES 5113 03:02:58,634 --> 03:03:00,336 THAT WE ASKED PARTICIPANTS TO 5114 03:03:00,402 --> 03:03:02,905 FILL OUT. 5115 03:03:02,971 --> 03:03:04,073 AND NEUROCOGNITIVE TESTING 5116 03:03:04,139 --> 03:03:04,940 LOOKING SPECIFICALLY AT 5117 03:03:05,007 --> 03:03:07,009 PROCESSING SPEED, EPISODIC 5118 03:03:07,076 --> 03:03:09,845 MEMORY AND EXECUTIVE FUNCTION. 5119 03:03:09,912 --> 03:03:11,814 CARDIOPULMONARY EVALUATIONS 5120 03:03:11,880 --> 03:03:14,650 INCLUDED PULMONARY FUNCTION 5121 03:03:14,717 --> 03:03:17,519 TESTING, 6 MINUTE WALK TEST, ECG 5122 03:03:17,586 --> 03:03:19,855 AND ECHOCARDIOGRAM, WE DID A 5123 03:03:19,922 --> 03:03:21,323 CARDIAC MRI ON A SUBGROUP 5124 03:03:21,390 --> 03:03:22,658 INITIALLY, WE STOPPED DOING THAT 5125 03:03:22,725 --> 03:03:24,426 BECAUSE IT WAS VERY LABOR IN15 5126 03:03:24,493 --> 03:03:25,961 SIEVE AND WE WERE NOT FINDING 5127 03:03:26,028 --> 03:03:28,597 ANY HINT OF ABNORMALITIES IN OUR 5128 03:03:28,664 --> 03:03:29,665 PATIENTS. 5129 03:03:29,732 --> 03:03:31,200 FINALLY, WHEN WE WROTE THE 5130 03:03:31,266 --> 03:03:32,267 PROTOCOL, WE WEREN'T EXACTLY 5131 03:03:32,334 --> 03:03:35,771 SURE WHAT THE FULL SPECTRUM OF 5132 03:03:35,838 --> 03:03:38,974 POST COSYD SEQUELAE WOULD BE SO 5133 03:03:39,041 --> 03:03:40,476 WE WROTE STEPS THAT WE COULD DO 5134 03:03:40,542 --> 03:03:43,979 ANY DIAGNOSTIC TESTING NEEDED 5135 03:03:44,046 --> 03:03:45,614 NEEDED TO WORK UP SYMPTOMS OR 5136 03:03:45,681 --> 03:03:46,615 ABNORMAL FINDINGS IN EITHER 5137 03:03:46,682 --> 03:03:47,149 GROUP. 5138 03:03:47,216 --> 03:03:49,151 SO THIS PROTOCOL HAS FOLLOW-UP 5139 03:03:49,218 --> 03:03:50,119 VISITS EVERY SIX MONTHS AND 5140 03:03:50,185 --> 03:03:51,420 TOTAL DURATION IS THREE YEARS. 5141 03:03:51,487 --> 03:03:54,156 MOST OF THE BASELINE STUDIES AND 5142 03:03:54,223 --> 03:03:55,591 EVALUATIONS ARE REPEATED AT 5143 03:03:55,657 --> 03:03:57,226 EITHER THE SIX MONTH OR THE 5144 03:03:57,292 --> 03:03:59,495 12-MONTH FOLLOW-UP VISITS. 5145 03:03:59,561 --> 03:04:02,464 WE ALSO, DURING OUR LONGITUDAL 5146 03:04:02,531 --> 03:04:03,665 FOLLOW-UP, ARE COLLECTING DATA 5147 03:04:03,732 --> 03:04:06,735 ON SARS-COV-2 VACCINATION RATES, 5148 03:04:06,802 --> 03:04:07,403 REINFECTION RATES IN THE 5149 03:04:07,469 --> 03:04:08,570 COVID-19 GROUP, AND DEVELOPMENT 5150 03:04:08,637 --> 03:04:09,905 OF NEW INFECTION IN THE CONTROL 5151 03:04:09,972 --> 03:04:12,408 GROUPS WHO WERE INITIALLY 5152 03:04:12,474 --> 03:04:14,042 OBVIOUSLY NOT INFECTED OR HADN'T 5153 03:04:14,109 --> 03:04:15,144 BEEN INFECTED PRIOR TO 5154 03:04:15,210 --> 03:04:20,516 ENROLLMENT. 5155 03:04:20,582 --> 03:04:23,919 SO OF AFTER THE FIRST YEAR OF TE 5156 03:04:23,986 --> 03:04:26,188 STUDY, WE HAD ENROLLED OVER 300 5157 03:04:26,255 --> 03:04:27,523 PATIENTS AS PARTICIPANTS IN THIS 5158 03:04:27,589 --> 03:04:27,723 STUDY. 5159 03:04:27,790 --> 03:04:28,957 THE FINDINGS WE FELT WERE 5160 03:04:29,024 --> 03:04:31,560 IMPORTANT ENOUGH TO WARRANT 5161 03:04:31,627 --> 03:04:32,761 PUBLISHING A BASELINE PAPER OF 5162 03:04:32,828 --> 03:04:35,063 OUR BASELINE FINDINGS IN PEOPLE 5163 03:04:35,130 --> 03:04:36,198 WHO WERE RECRUITED DURING THE 5164 03:04:36,265 --> 03:04:37,199 FIRST YEAR OF THE STUDY. 5165 03:04:37,266 --> 03:04:38,934 SO THAT WAS JUNE 30TH, 2020 5166 03:04:39,001 --> 03:04:40,969 UNTIL JULY 1ST, 2021. 5167 03:04:41,036 --> 03:04:44,039 SO THIS IS A FLOW DIAGRAM OF THE 5168 03:04:44,106 --> 03:04:45,240 PATIENTS ENROLLED. 5169 03:04:45,307 --> 03:04:47,142 AS YOU SEE WE ASSESSED OVER 300 5170 03:04:47,209 --> 03:04:47,409 PATIENTS. 5171 03:04:47,476 --> 03:04:49,044 A FEW OF THEM DIDN'T MEET 5172 03:04:49,111 --> 03:04:50,045 INCLUSION CRITERIA OR DIDN'T 5173 03:04:50,112 --> 03:04:51,246 RETURN FOR THEIR FOLLOW-UP 5174 03:04:51,313 --> 03:04:51,480 VISITS. 5175 03:04:51,547 --> 03:04:54,650 WE ENDED UP ENROLLING 311 5176 03:04:54,716 --> 03:04:55,317 INDIVIDUALS. 5177 03:04:55,384 --> 03:04:57,853 122 IN THE CONTROL GROUP AND 189 5178 03:04:57,920 --> 03:04:59,688 IN THE COVID GROUP. 5179 03:04:59,755 --> 03:05:01,290 WE HAD TO EXCLUDE TWO PATIENTS 5180 03:05:01,356 --> 03:05:03,058 FROM THE CONTROL GROUP BECAUSE 5181 03:05:03,125 --> 03:05:05,594 THEIR ANTIBODY ASSAYS FOR 5182 03:05:05,661 --> 03:05:06,829 SARS-COV-2 ANTIBODIES CAME BACK 5183 03:05:06,895 --> 03:05:09,097 POSITIVE SO THE FINAL CONTROL 5184 03:05:09,164 --> 03:05:10,299 GROUP ANALYSIS GROUP FOR THE 5185 03:05:10,365 --> 03:05:13,836 CONTROLS WAS CONSISTENT OF 120 5186 03:05:13,902 --> 03:05:15,304 INDIVIDUALS WITH 189 POST COVID 5187 03:05:15,370 --> 03:05:19,208 PATIENTS. 5188 03:05:19,274 --> 03:05:22,311 SO FOR THE PROTOCOL, WE DEFINED 5189 03:05:22,377 --> 03:05:24,012 THE POST PASC OR LONG COVID, IF 5190 03:05:24,079 --> 03:05:25,481 YOU WILL, AT ANY SYMPTOM OR 5191 03:05:25,547 --> 03:05:27,249 MEDICAL CONDITION THAT BEGAN OR 5192 03:05:27,316 --> 03:05:29,751 WORSENED AFTER THE ONSET OF THE 5193 03:05:29,818 --> 03:05:30,652 ACUTE COVID-19 ILLNESS AND COULD 5194 03:05:30,719 --> 03:05:32,154 NOT BE EXPLAINED BY ANOTHER 5195 03:05:32,221 --> 03:05:33,355 DIAGNOSIS AND WAS STILL PRESENT 5196 03:05:33,422 --> 03:05:35,357 AT THE TIME OF THE ENROLLMENT OR 5197 03:05:35,424 --> 03:05:36,225 BASELINE VISIT. 5198 03:05:36,291 --> 03:05:38,494 AND FOR THIS -- TO THIS INITIAL 5199 03:05:38,560 --> 03:05:40,896 189 PATIENTS, THE MEANTIME 5200 03:05:40,963 --> 03:05:42,564 BETWEEN THE ONSET OF THEIR ACUTE 5201 03:05:42,631 --> 03:05:44,533 COVID SYMPTOMS AND WHEN THEY HAD 5202 03:05:44,600 --> 03:05:47,169 THEIR FIRST PROTOCOL VISIT WAS 5203 03:05:47,236 --> 03:05:49,338 162 DAYS. 5204 03:05:49,404 --> 03:05:50,205 SO FOR COMPARISON PURPOSES AND 5205 03:05:50,272 --> 03:05:51,640 TO MAKE IT FAIR WITH THE 5206 03:05:51,707 --> 03:05:53,709 CONTROLS, FOR SYMPTOMS WE ONLY 5207 03:05:53,775 --> 03:05:55,143 COUNTED SYMPTOMS FROM THE 5208 03:05:55,210 --> 03:05:58,180 CONTROLS THAT HAD AN ONSET OR 5209 03:05:58,247 --> 03:06:00,816 WORSENING WITHIN 162 DAYS OF 5210 03:06:00,883 --> 03:06:01,783 THEIR ENROLLMENT INTO THE 5211 03:06:01,850 --> 03:06:04,520 PROTOCOL. 5212 03:06:04,586 --> 03:06:06,822 SO THIS SLIDE WAS TAKEN 5213 03:06:06,889 --> 03:06:07,656 PARTIALLY FROM THE MANUSCRIPT 5214 03:06:07,723 --> 03:06:09,358 AND IT SHOWS SORT OF THE 5215 03:06:09,424 --> 03:06:12,961 BASELINE CHARACTERISTICS OF BOTH 5216 03:06:13,028 --> 03:06:13,729 GROUPS OF PARTICIPANTS. 5217 03:06:13,795 --> 03:06:16,131 SO THE CONTROLS ARE LISTED TO 5218 03:06:16,198 --> 03:06:19,868 THE LEFT, THE OVERALL COHORT OF 5219 03:06:19,935 --> 03:06:20,602 COVID-19 INDIVIDUALS IS SHOWN IN 5220 03:06:20,669 --> 03:06:22,237 THE NEXT COLUMN, AND THEN THE 5221 03:06:22,304 --> 03:06:24,540 LAST TWO COLUMNS ARE BROKEN DOWN 5222 03:06:24,606 --> 03:06:27,442 BY THOSE WITH AND WITHOUT 5223 03:06:27,509 --> 03:06:30,445 POST-ACUTE COVID SEQUELAE. 5224 03:06:30,512 --> 03:06:32,080 SO AS YOU CAN SEE, SLIGHTLY OVER 5225 03:06:32,147 --> 03:06:33,849 HALF OF THE COVID GROUP HAD ONE 5226 03:06:33,916 --> 03:06:38,086 OR MORE POST COVID SYMPTOMS. 5227 03:06:38,153 --> 03:06:40,622 LOOKING AT THE VARIOUS 5228 03:06:40,689 --> 03:06:41,290 CHARACTERISTICS, THIS WAS A 5229 03:06:41,356 --> 03:06:42,524 PRETTY WELL MATCHED COHORT. 5230 03:06:42,591 --> 03:06:45,093 YOU CAN SEE THE MEDIAN AGE AT 5231 03:06:45,160 --> 03:06:46,628 ENROLLMENT WAS VERY CLOSE IN THE 5232 03:06:46,695 --> 03:06:47,429 GROUPS. 5233 03:06:47,496 --> 03:06:48,830 51 IN THE CONTROL GROUPS AND 50 5234 03:06:48,897 --> 03:06:50,132 IN THE OVERALL COVID GROUP AND 5235 03:06:50,198 --> 03:06:51,466 DIDN'T REALLY DIFFER MUCH 5236 03:06:51,533 --> 03:06:54,002 BETWEEN THOSE WITH AND WITHOUT 5237 03:06:54,069 --> 03:06:55,070 PERSISTENT COVID -- POST COVID 5238 03:06:55,137 --> 03:06:56,805 SYMPTOMS. 5239 03:06:56,872 --> 03:06:58,540 COMPARING THE OVERALL COHORTS, 5240 03:06:58,607 --> 03:07:00,542 THEY WERE WELL MATCHED FOR 5241 03:07:00,609 --> 03:07:03,278 GENDER, BUT AS YOU CAN SEE, THE 5242 03:07:03,345 --> 03:07:06,448 PARTICIPANTS WHO HAD ONE OR MORE 5243 03:07:06,515 --> 03:07:08,283 PASCs TENDED TO BE -- HAD A 5244 03:07:08,350 --> 03:07:09,818 HIGHER RATE OF FEMALES IN THAT 5245 03:07:09,885 --> 03:07:11,920 GROUP. 5246 03:07:11,987 --> 03:07:14,556 IT IS PREDOMINANTLY CAUCASIAN 5247 03:07:14,623 --> 03:07:15,757 INDIVIDUALS, ALTHOUGH WE DID TRY 5248 03:07:15,824 --> 03:07:17,926 AS HARD AS WE COULD TO ENROLL 5249 03:07:17,993 --> 03:07:19,461 OTHER ETHNIC GROUPS AND RACIAL 5250 03:07:19,528 --> 03:07:24,066 GROUPS. 5251 03:07:24,132 --> 03:07:25,534 FINALLY IF WE LOOKED AT A NUMBER 5252 03:07:25,601 --> 03:07:28,437 OF PRE-EXISTING CONDITIONS, 5253 03:07:28,503 --> 03:07:30,505 AGAIN, THE CONTROLS WERE OBESE, 5254 03:07:30,572 --> 03:07:31,673 DIABETES, HYPERTENSION AND 5255 03:07:31,740 --> 03:07:34,042 MENTAL HEALTH PROBLEMS. 5256 03:07:34,109 --> 03:07:34,876 THE ONE THAT DID STAND OUT AS 5257 03:07:34,943 --> 03:07:36,211 YOU CAN SEE AND I'M SURE PEOPLE 5258 03:07:36,278 --> 03:07:39,681 HAVE HEARD OF IS THE LONG COVID 5259 03:07:39,748 --> 03:07:42,651 GROUP HAD A HIGHER PRE-COVID INS 5260 03:07:42,718 --> 03:07:44,419 KENS OF HISTORY OF HAVING 5261 03:07:44,486 --> 03:07:45,153 ANXIETY DISORDER. 5262 03:07:45,220 --> 03:07:46,455 BUT NOT OTHER MOOD DISORDERS 5263 03:07:46,521 --> 03:07:49,524 SUCH AS DEPRESSION OR BIPOLAR. 5264 03:07:49,591 --> 03:07:50,892 FINALLY AS I ALLUDED TO EARLIER, 5265 03:07:50,959 --> 03:07:51,927 THE MAJORITY OF THESE PATIENTS 5266 03:07:51,994 --> 03:07:53,895 WERE NOT HOSPITALIZED, ONLY A 5267 03:07:53,962 --> 03:07:56,298 LITTLE OVER 11% WERE 5268 03:07:56,365 --> 03:07:57,532 HOSPITALIZED FOR COVID-19 AND 5269 03:07:57,599 --> 03:07:58,934 HAD CRITICAL ILLNESS. 5270 03:07:59,001 --> 03:08:01,703 THE OTHER 89% HAD MILD ILLNESS 5271 03:08:01,770 --> 03:08:06,041 AND WERE NEVER HOSPITALIZED. 5272 03:08:06,108 --> 03:08:12,180 SO THIS IS A PLOT LOOKING AT 5273 03:08:12,247 --> 03:08:13,482 PRECOVID RISK FACTORS FOR THE 5274 03:08:13,548 --> 03:08:14,483 DEVELOPMENT OF PERSISTENT 5275 03:08:14,549 --> 03:08:15,350 SYMPTOMS OR LONG COVID AND WE 5276 03:08:15,417 --> 03:08:17,119 LOOKED AT ALL OF THE -- PRETTY 5277 03:08:17,185 --> 03:08:17,886 MUCH EVERYTHING IN THE PREVIOUS 5278 03:08:17,953 --> 03:08:18,086 TABLE. 5279 03:08:18,153 --> 03:08:20,155 YOU CAN SEE THE ONLY TWO, AGAIN, 5280 03:08:20,222 --> 03:08:22,791 ANY OF THE DOTS TO THE RIGHT OF 5281 03:08:22,858 --> 03:08:24,660 THIS -- OF THE DOTTED LINE ARE 5282 03:08:24,726 --> 03:08:26,628 ASSOCIATED WITH HIGHER ODDS OF 5283 03:08:26,695 --> 03:08:28,363 GETTING LONG COVID, THOSE TO THE 5284 03:08:28,430 --> 03:08:30,866 LEFT, LOWER ODDS OF GETTING LONG 5285 03:08:30,932 --> 03:08:32,501 COVID. 5286 03:08:32,567 --> 03:08:34,703 AND THE BARS ATTACHED TO EACH 5287 03:08:34,770 --> 03:08:36,672 CIRCLE ARE THE 95% CONFIDENCE 5288 03:08:36,738 --> 03:08:37,005 INTERVALS. 5289 03:08:37,072 --> 03:08:41,710 SO THERE ARE ONLY TWO FEATURES 5290 03:08:41,777 --> 03:08:43,478 OR PRECOVID RISK FACTORS THAT 5291 03:08:43,545 --> 03:08:44,079 WERE SIGNIFICANTLY ASSOCIATED 5292 03:08:44,146 --> 03:08:45,313 WITH THE DEVELOPMENT OF LONG 5293 03:08:45,380 --> 03:08:45,681 COVID. 5294 03:08:45,747 --> 03:08:47,949 ONE IS FEMALE GENDER AS YOU CAN 5295 03:08:48,016 --> 03:08:50,352 SEE THE ODDS RATIO WAS 2.34 AND 5296 03:08:50,419 --> 03:08:52,421 THE CONFIDENCE INTERVAL DID NOT 5297 03:08:52,487 --> 03:08:52,921 CROSS 1. 5298 03:08:52,988 --> 03:08:55,057 HISTORY OF A PRIOR ANXIETY 5299 03:08:55,123 --> 03:08:57,192 DISORDER WITH AN ODDS RATIO OF 5300 03:08:57,259 --> 03:08:59,928 2.78 AND, AGAIN, CONFIDENCE 5301 03:08:59,995 --> 03:09:05,867 INTERVAL NOT CROSSING 1. 5302 03:09:05,934 --> 03:09:07,269 THIS IS A SUMMARY OF THE 5303 03:09:07,335 --> 03:09:09,471 SYMPTOMS REPORTED IN BOTH 5304 03:09:09,538 --> 03:09:11,039 GROUPS, AND REALLY THESE ARE THE 5305 03:09:11,106 --> 03:09:12,340 SYMPTOMS THAT WERE REPORTED IN 5306 03:09:12,407 --> 03:09:14,843 MORE THAN 1% OF THE COVID GROUP. 5307 03:09:14,910 --> 03:09:17,312 AND AS YOU CAN SEE, ONLY ONE OF 5308 03:09:17,379 --> 03:09:20,882 THE BARS HAS A CONTROL GROUP 5309 03:09:20,949 --> 03:09:21,516 COLOR ON IT. 5310 03:09:21,583 --> 03:09:22,617 THAT'S BECAUSE THERE WERE NO 5311 03:09:22,684 --> 03:09:25,020 CONTROLS THAT IN THE LAST -- IN 5312 03:09:25,087 --> 03:09:27,989 THE PREVIOUS 162 DAYS PRIOR TO 5313 03:09:28,056 --> 03:09:29,057 ENROLLMENT HAD DEVELOPED ANY OF 5314 03:09:29,124 --> 03:09:31,026 THESE OTHER SYMPTOMS. 5315 03:09:31,093 --> 03:09:32,661 SO MOST OF THIS IS FOR THE COVID 5316 03:09:32,728 --> 03:09:33,562 GROUP, WHICH IS IN BLUE. 5317 03:09:33,628 --> 03:09:36,264 YOU CAN SEE THAT THERE IS THE 5318 03:09:36,331 --> 03:09:37,966 MOST PROMINENT SYMPTOM WAS 5319 03:09:38,033 --> 03:09:39,568 FATIGUE IN 26% OF THE WHOLE 5320 03:09:39,634 --> 03:09:41,236 COVID COHORT, AND COGNITIVE 5321 03:09:41,303 --> 03:09:43,605 DYSFUNCTION, ABOUT 20%, 5322 03:09:43,672 --> 03:09:45,841 SHORTNESS OF BREATH IN SOMEWHERE 5323 03:09:45,907 --> 03:09:49,377 AROUND 18%, SO ON ALL THE WAY 5324 03:09:49,444 --> 03:09:51,179 DOWN. 5325 03:09:51,246 --> 03:09:53,682 SO NOW MOST RECOGNIZED AND 5326 03:09:53,749 --> 03:09:54,983 COMMON SYMPTOM IN PEOPLE THAT 5327 03:09:55,050 --> 03:09:56,418 PERSIST FOLLOWING ACUTE ILLNESS. 5328 03:09:56,485 --> 03:09:57,486 THE ONLY ONE THAT SHOWED UP IN 5329 03:09:57,552 --> 03:09:58,954 THE CONTROL GROUP AT ALL WAS 5330 03:09:59,020 --> 03:10:00,355 ANXIETY THAT DEVELOPED WITHIN 5331 03:10:00,422 --> 03:10:01,556 162 DAYS OF ENROLLMENT BUT IT 5332 03:10:01,623 --> 03:10:03,859 WAS FAR LESS IN THE CONTROL 5333 03:10:03,925 --> 03:10:09,531 GROUP THAN IN THE COVID GROUP. 5334 03:10:09,598 --> 03:10:10,832 SO I DON'T REALLY HAVE TIME IN 5335 03:10:10,899 --> 03:10:12,200 THIS TALK TO GO THROUGH EVERY 5336 03:10:12,267 --> 03:10:13,802 SINGLE TEST WE DID AND COMPARE 5337 03:10:13,869 --> 03:10:15,537 IT WITH CONTROLS AND THE POST 5338 03:10:15,604 --> 03:10:17,606 COVID GROUP AND THE POST COVID 5339 03:10:17,672 --> 03:10:19,374 GROUP WITH AND WITHOUT PERSIST 5340 03:10:19,441 --> 03:10:20,475 10 SYMPTOMS SO I'M GOING TO 5341 03:10:20,542 --> 03:10:22,010 SUMMARIZE THOSE FINDINGS HERE. 5342 03:10:22,077 --> 03:10:23,044 PARTICIPANTS IN THE COVID-19 5343 03:10:23,111 --> 03:10:24,079 GROUP REPORTED MORE SYMPTOMS 5344 03:10:24,146 --> 03:10:25,781 COMPARED TO THE CONTROL GROUP. 5345 03:10:25,847 --> 03:10:26,915 OBVIOUSLY AS I SHOWED YOU IN THE 5346 03:10:26,982 --> 03:10:27,349 PREVIOUS SLIDE. 5347 03:10:27,415 --> 03:10:29,317 AND AGAIN THE MOST COMMON 5348 03:10:29,384 --> 03:10:31,086 SYMPTOMS ARE NOW WELL-KNOWN, I 5349 03:10:31,153 --> 03:10:34,356 THINK, TO MOST PEOPLE. 5350 03:10:34,422 --> 03:10:37,192 ABNORMAL FINDINGS ON PHYSICAL 5351 03:10:37,259 --> 03:10:42,230 EXAM OR LABORATORY TESTING 5352 03:10:42,297 --> 03:10:43,665 OCCURRED WITH SIMILAR FREQUENCY 5353 03:10:43,732 --> 03:10:44,966 IN BOTH THE COVID-19 GROUP AND 5354 03:10:45,033 --> 03:10:47,269 THE CONTROL GROUPS, AND WERE NOT 5355 03:10:47,335 --> 03:10:49,871 ASSOCIATED WITH ANY POST-ACUTE 5356 03:10:49,938 --> 03:10:53,308 SEQUELAE OF COVID-19. 5357 03:10:53,375 --> 03:10:54,576 THAT LATTER POINT IS ILLUSTRATED 5358 03:10:54,643 --> 03:10:56,478 HERE FOR THE SORT OF PASC AS A 5359 03:10:56,545 --> 03:10:57,179 WHOLE. 5360 03:10:57,245 --> 03:10:59,080 AGAIN, IN ANOTHER FOREST PLOT. 5361 03:10:59,147 --> 03:11:02,184 ON THE LEFT IS LISTED THE 5362 03:11:02,250 --> 03:11:04,986 DIAGNOSTIC TESTS THAT WE AN 5363 03:11:05,053 --> 03:11:06,955 ANALYZED, THE ODDS RATIO OF IT 5364 03:11:07,022 --> 03:11:09,491 BEING ASSOCIATED WITH ANY 5365 03:11:09,558 --> 03:11:11,526 POST-ACUTE COVID MANIFESTATION 5366 03:11:11,593 --> 03:11:14,095 ARE SHOWN IN THE DOTS, IN THE 5367 03:11:14,162 --> 03:11:14,629 COLUMN OVER HERE. 5368 03:11:14,696 --> 03:11:15,931 YOU CAN SEE THAT REALLY NOTHING, 5369 03:11:15,997 --> 03:11:20,302 NONE OF THESE ABNORMALITIES ON 5370 03:11:20,368 --> 03:11:22,103 ANY OF THESE TESTS OR LABORATORY 5371 03:11:22,170 --> 03:11:23,839 VALUES WAS SIGNIFICANTLY 5372 03:11:23,905 --> 03:11:25,040 ASSOCIATED WITH POST-ACUTE 5373 03:11:25,106 --> 03:11:27,909 SYMPTOMS OF COVID-19. 5374 03:11:27,976 --> 03:11:29,110 WE THEN BROKE THIS DOWN BY 5375 03:11:29,177 --> 03:11:29,978 INDIVIDUAL GROUPS OF SYMPTOMS SO 5376 03:11:30,045 --> 03:11:33,215 WE LOOKED AT FATIGUE, 5377 03:11:33,281 --> 03:11:35,383 CARDIOPULMONARY SYMPTOMS, AND 5378 03:11:35,450 --> 03:11:36,318 NEUROCOGNITIVE SYMPTOMS, AND DID 5379 03:11:36,384 --> 03:11:37,652 THE SAME ANALYSIS. 5380 03:11:37,719 --> 03:11:39,054 AND THE RESULTS WERE EXACTLY THE 5381 03:11:39,120 --> 03:11:40,622 SAME AND I'LL SHOW YOU AN 5382 03:11:40,689 --> 03:11:42,090 EXAMPLE JUST OF THE NEUROLOGIC 5383 03:11:42,157 --> 03:11:42,424 SYMPTOMS. 5384 03:11:42,490 --> 03:11:43,658 IN THIS CASE, NEUROLOGIC 5385 03:11:43,725 --> 03:11:44,960 SYMPTOMS INCLUDED COGNITIVE, ANY 5386 03:11:45,026 --> 03:11:46,728 KIND OF SYMPTOM OF COGNITIVE 5387 03:11:46,795 --> 03:11:51,867 IMPAIRMENT OR HEADACHE OR 5388 03:11:51,933 --> 03:11:52,200 PARESTHESIAS. 5389 03:11:52,267 --> 03:11:54,035 AGAIN IT LOOKS VERY SIMILAR TO 5390 03:11:54,102 --> 03:11:54,936 THE FIRST FOREST PLOT I SHOWED 5391 03:11:55,003 --> 03:11:57,239 YOU IN THAT NONE OF THE TESTING 5392 03:11:57,305 --> 03:12:00,408 WE DID CORRELATED WITH 5393 03:12:00,475 --> 03:12:01,376 NEUROCOGNITIVE OR NEUROLOGIC 5394 03:12:01,443 --> 03:12:01,710 SYMPTOMS. 5395 03:12:01,776 --> 03:12:02,477 SPECIFICALLY IF YOU LOOK AT THE 5396 03:12:02,544 --> 03:12:04,679 ONES THAT I'VE HIGHLIGHTED, A 5397 03:12:04,746 --> 03:12:08,250 BIOMARKER OF BRAIN INJURY WAS 5398 03:12:08,316 --> 03:12:11,052 NOT ASSOCIATED WITH ANY OF THE 5399 03:12:11,119 --> 03:12:11,887 NEUROLOGIC SYMPTOMS. 5400 03:12:11,953 --> 03:12:16,024 A 6 HAD B 6-MINUTE WALK TEST ISD 5401 03:12:16,091 --> 03:12:18,126 MEASURE OF STRENGTH AND BALANCE 5402 03:12:18,193 --> 03:12:19,761 AND CARDIOPULMONARY FUNCTION. 5403 03:12:19,828 --> 03:12:21,162 A AGAIN DISTANCE WALKED IN 5404 03:12:21,229 --> 03:12:22,364 6 MINUTES WAS NO SIGNIFICANTLY 5405 03:12:22,430 --> 03:12:25,267 DIFFERENT IN THOSE WITH OR 5406 03:12:25,333 --> 03:12:26,568 WITHOUT NEUROLOGIC SYMPTOMS. 5407 03:12:26,635 --> 03:12:29,037 PROBABLY MOST IMPORTANTLY, NONE 5408 03:12:29,104 --> 03:12:30,405 OF THE NEUROCOGNITIVE TESTING IN 5409 03:12:30,472 --> 03:12:32,974 ANY OF THE THREE DOMAINS WAS 5410 03:12:33,041 --> 03:12:38,914 SIGNIFICANTLY DIFFERENT OR 5411 03:12:38,980 --> 03:12:43,818 SIGNIFICANTLY ASSOCIATED IN AN 5412 03:12:43,885 --> 03:12:45,020 ODDS RATIO OF 1. 5413 03:12:45,086 --> 03:12:48,623 SO TO SUMMARIZE, PARTICIPANTS 5414 03:12:48,690 --> 03:12:52,794 WITH PASC SELF-REPORTED -- EVEN 5415 03:12:52,861 --> 03:12:54,829 THOUGH WE HAD A LACK OF SORT OF 5416 03:12:54,896 --> 03:12:57,165 OBJECTIVE FINDINGS IN THESE 5417 03:12:57,232 --> 03:12:57,933 INDIVIDUALS, CERTAINLY THE 5418 03:12:57,999 --> 03:12:59,801 PRESENCE OF THESE SYMPTOMS HAD A 5419 03:12:59,868 --> 03:13:01,002 MAJOR EFFECT ON THE QUALITY OF 5420 03:13:01,069 --> 03:13:02,537 LIFE IN THESE INDIVIDUALS. 5421 03:13:02,604 --> 03:13:04,039 AND THESE PATIENTS HAD 5422 03:13:04,105 --> 03:13:07,342 SIGNIFICANTLY LOWER SCORES ON 5423 03:13:07,409 --> 03:13:08,977 BOTH THE MENTAL HEALTH AND 5424 03:13:09,044 --> 03:13:11,579 PHYSICAL HEALTH PORTIONS OF THE 5425 03:13:11,646 --> 03:13:13,348 SF36 HEALTH SURVEY. 5426 03:13:13,415 --> 03:13:16,651 SELF-REPORTED ANXIETY WAS ALSO 5427 03:13:16,718 --> 03:13:19,387 INCREASED IN THE GROUP WITH 5428 03:13:19,454 --> 03:13:21,356 POST-ACUTE COVID -- SEQUELAE OF 5429 03:13:21,423 --> 03:13:21,690 COVID. 5430 03:13:21,756 --> 03:13:23,758 THIS IS PROBABLY LIKELY DUE TO 5431 03:13:23,825 --> 03:13:25,060 WORRY AND CONCERN AND ANXIETY 5432 03:13:25,126 --> 03:13:26,027 ABOUT SYMPTOMS THEY WERE HAVING 5433 03:13:26,094 --> 03:13:27,562 THAT WERE UNEXPLAINED. 5434 03:13:27,629 --> 03:13:29,297 AND FINALLY, EXPLORATORY STUDIES 5435 03:13:29,364 --> 03:13:31,099 WE DID IN THE LABORATORY LOOKING 5436 03:13:31,166 --> 03:13:34,769 AT A NUMBER OF BIOMARKERS OF 5437 03:13:34,836 --> 03:13:39,407 INFLAMMATION IN AUTOANTIBODIES 5438 03:13:39,474 --> 03:13:40,809 AND VIRAL ANTIGENS, WE COULD NOT 5439 03:13:40,875 --> 03:13:45,280 FIND ANY EVIDENCE OF ABNORMAL 5440 03:13:45,347 --> 03:13:47,682 SYSTEMIC IMMUNE ACTIVATION, 5441 03:13:47,749 --> 03:13:50,318 AUTOIMMUNE DISEASE OR PERSISTENT 5442 03:13:50,385 --> 03:13:54,923 VIRAL INFECTION. 5443 03:13:54,990 --> 03:13:57,759 SO LIKE ANY STUDY, THIS STUDY 5444 03:13:57,826 --> 03:13:58,626 HAS ITS STRENGTHS AND 5445 03:13:58,693 --> 03:13:58,960 WEAKNESSES. 5446 03:13:59,027 --> 03:14:00,362 I THINK THE STRENGTHS ARE THAT 5447 03:14:00,428 --> 03:14:03,131 IT REQUIRE LABORATORY-CONFIRMED 5448 03:14:03,198 --> 03:14:06,534 DEFINITE SARS-COV-2 INFECTION SO 5449 03:14:06,601 --> 03:14:09,137 WE ARE EVALUATING PATIENTS WHO 5450 03:14:09,204 --> 03:14:10,905 DID FOR SURE HAVE SARS-COV-2 5451 03:14:10,972 --> 03:14:11,639 INFECTIONS. 5452 03:14:11,706 --> 03:14:13,408 THE CONCURRENT ENROLLMENT OF 5453 03:14:13,475 --> 03:14:14,042 CONCURRENT CONTROL GROUP THAT 5454 03:14:14,109 --> 03:14:15,377 WAS SIMILAR TO THE COVID-19 5455 03:14:15,443 --> 03:14:17,679 GROUP IN AGE AND COMORBIDITIES 5456 03:14:17,746 --> 03:14:18,747 AND DEMOGRAPHIC CHARACTERISTICS 5457 03:14:18,813 --> 03:14:22,450 BUT HAD NO HISTORY OF OR 5458 03:14:22,517 --> 03:14:23,785 SEROLOGIC EVIDENCE OF PRIOR 5459 03:14:23,852 --> 03:14:24,552 SARS-COV-2 INFECTION WAS VERY 5460 03:14:24,619 --> 03:14:25,220 IMPORTANT BECAUSE WHEN YOU DO 5461 03:14:25,286 --> 03:14:27,055 ALL THIS DIAGNOSTIC TESTING IN 5462 03:14:27,122 --> 03:14:30,025 PEOPLE WHO DON'T REALLY HAVE 5463 03:14:30,091 --> 03:14:33,395 SYMPTOMS, WE DID CARDIOPULMONARY 5464 03:14:33,461 --> 03:14:35,530 TESTING IN PEOPLE WHO HAD NO 5465 03:14:35,597 --> 03:14:36,831 SYMPTOMS AND PEOPLE WHO HAD 5466 03:14:36,898 --> 03:14:38,533 SYMPTOMS OUTSIDE THE 5467 03:14:38,600 --> 03:14:40,101 CARDIORESPIRATORY SYSTEM, SAME 5468 03:14:40,168 --> 03:14:42,003 FOR NEUROCOGNITIVE TESTING, 5469 03:14:42,070 --> 03:14:43,405 EVERYBODY GOT THE SAME BATTERY 5470 03:14:43,471 --> 03:14:45,006 OF TESTS. 5471 03:14:45,073 --> 03:14:47,876 YOU'LL PICK UP SORT OF ALL MINOR 5472 03:14:47,942 --> 03:14:48,610 ABNORMALITIES THAT YOU'RE NOT 5473 03:14:48,676 --> 03:14:49,711 GOING TO KNOW WHETHER THESE ARE 5474 03:14:49,778 --> 03:14:52,580 DUE TO THE UNDERLYING INFECTION 5475 03:14:52,647 --> 03:14:55,050 OR JUST THE VARIABILITY OF THE 5476 03:14:55,116 --> 03:14:56,451 TESTING, ESPECIALLY WHEN YOU DO 5477 03:14:56,518 --> 03:14:58,019 SO MANY DIAGNOSTIC TESTS ON 5478 03:14:58,086 --> 03:14:59,087 PEOPLE, ESPECIALLY THE CONTROL 5479 03:14:59,154 --> 03:15:00,088 GROUP WHO DON'T HAVE AN 5480 03:15:00,155 --> 03:15:05,994 INDICATION FOR THOSE TESTS. 5481 03:15:06,061 --> 03:15:08,196 FINALLY, WE DID IN AN ORGANIZED 5482 03:15:08,263 --> 03:15:11,032 WAY PROTOCOL-DEFINED 5483 03:15:11,099 --> 03:15:12,200 PRESPECIFIED DIAGNOSTIC 5484 03:15:12,267 --> 03:15:13,268 EVALUATIONS ON ALL PARTICIPANTS, 5485 03:15:13,334 --> 03:15:15,070 INCLUDING CONTROLS, THOSE 5486 03:15:15,136 --> 03:15:16,571 WITH -- WHO HAD COVID AND DID 5487 03:15:16,638 --> 03:15:18,907 NOT HAVE ANY RESIDUAL SYMPTOMS 5488 03:15:18,973 --> 03:15:20,208 AND THOSE WHO HAD RESIDUAL 5489 03:15:20,275 --> 03:15:21,309 SYMPTOMS, THEY ALL GOT THE SAME 5490 03:15:21,376 --> 03:15:24,045 WORKUP. 5491 03:15:24,112 --> 03:15:25,280 SO LIMITATIONS. 5492 03:15:25,346 --> 03:15:27,749 ONE, AT LEAST AT THE TIME FOR 5493 03:15:27,816 --> 03:15:28,983 THIS PAPER AND TO A LESSER 5494 03:15:29,050 --> 03:15:30,518 EXTENT I HOPE NOW, IT IS A 5495 03:15:30,585 --> 03:15:31,586 RELATIVELY SMALL SAMPLE SIZE, 5496 03:15:31,653 --> 03:15:33,354 BUT AGAIN, IT'S HARD TO DO ALL 5497 03:15:33,421 --> 03:15:36,658 THIS DIAGNOSTIC TESTING AT ONE 5498 03:15:36,724 --> 03:15:38,493 CENTER IN ONE CLINIC ON A LARGE 5499 03:15:38,560 --> 03:15:40,128 NUMBER OF PATIENTS. 5500 03:15:40,195 --> 03:15:41,963 MOST -- AND AGAIN, MOST AS I'VE 5501 03:15:42,030 --> 03:15:42,664 MENTIONED, MOST OF THE 5502 03:15:42,730 --> 03:15:44,499 PARTICIPANTS IN THIS STUDY, 5503 03:15:44,566 --> 03:15:46,034 APPROXIMATELY 90% HAD MILD TO 5504 03:15:46,101 --> 03:15:47,135 MODERATE ACUTE ILLNESS THAT 5505 03:15:47,202 --> 03:15:48,236 DIDN'T REQUIRE HOSPITALIZATION, 5506 03:15:48,303 --> 03:15:49,537 SO THESE FINDINGS DON'T 5507 03:15:49,604 --> 03:15:51,940 NECESSARILY APPLY TO PEOPLE 5508 03:15:52,006 --> 03:15:53,208 WHOSE ACUTE ILLNESS WAS SEVERE 5509 03:15:53,274 --> 03:15:54,776 AND REQUIRED INTENSIVE CARE 5510 03:15:54,843 --> 03:15:56,077 TREATMENT. 5511 03:15:56,144 --> 03:15:58,446 AND FINALLY, AS I ALSO MENTIONED 5512 03:15:58,513 --> 03:15:59,714 AND ALLUDED TO, THE PREVALENCE 5513 03:15:59,781 --> 03:16:01,483 OF PASC THAT WE FOUND IN THIS 5514 03:16:01,549 --> 03:16:04,285 INITIAL COHORT WHICH WAS 55% 5515 03:16:04,352 --> 03:16:05,520 ALMOST CERTAINLY REPRESENTS A 5516 03:16:05,587 --> 03:16:06,087 MARKET OVERESTIMATION. 5517 03:16:06,154 --> 03:16:08,356 AS I THINK INDIVIDUALS WHO DO 5518 03:16:08,423 --> 03:16:10,792 SUFFER FROM POST COVID SYMPTOMS 5519 03:16:10,859 --> 03:16:13,061 WERE PROBABLY MORE MOTIVATED TO 5520 03:16:13,128 --> 03:16:14,395 ENROLL IN THE STUDY IN THE HOPES 5521 03:16:14,462 --> 03:16:15,797 WE WOULD FIND AN EXPLANATION FOR 5522 03:16:15,864 --> 03:16:21,136 THEIR SYMPTOMS. 5523 03:16:21,202 --> 03:16:22,370 SO THIS IS THE CURRENT STATUS OF 5524 03:16:22,437 --> 03:16:23,671 THE PROTOCOL AS OF A FEW WEEKS 5525 03:16:23,738 --> 03:16:24,105 AGO. 5526 03:16:24,172 --> 03:16:25,640 SO OUR TOTAL ENROLLMENT IS NOW 5527 03:16:25,707 --> 03:16:27,408 UP TO 530. 5528 03:16:27,475 --> 03:16:30,845 IN THE CONTROL GROUP, WE NOS NOW 5529 03:16:30,912 --> 03:16:32,413 HAVE 246 CONTROLS AND IN THE 5530 03:16:32,480 --> 03:16:33,515 COVID-19 GROUP, 284. 5531 03:16:33,581 --> 03:16:34,749 THE BREAKDOWN AS IT STANDS RIGHT 5532 03:16:34,816 --> 03:16:37,552 NOW IS, AGAIN, ABOUT 50/50 5533 03:16:37,619 --> 03:16:38,753 HAVING POST COVID SYNDROME AND 5534 03:16:38,820 --> 03:16:40,855 THE OTHER 50% HAVING NO RESIDUAL 5535 03:16:40,922 --> 03:16:45,193 SYMPTOMS. 5536 03:16:45,260 --> 03:16:46,561 SO WE'RE JUST NOW STARTING TO 5537 03:16:46,628 --> 03:16:49,597 LOOK AT THE ONE-YEAR DATA. 5538 03:16:49,664 --> 03:16:50,565 THERE'S 247 OF THE COVID-19 5539 03:16:50,632 --> 03:16:52,100 COHORT THAT HAVE COMPLETED THEIR 5540 03:16:52,167 --> 03:16:53,301 ONE-YEAR FOLLOW-UP. 5541 03:16:53,368 --> 03:16:54,936 AT LEAST THEIR ONE-YEAR 5542 03:16:55,003 --> 03:16:56,704 FOLLOW-UP AND SOME HAVE 5543 03:16:56,771 --> 03:16:57,772 COMPLETED MORE THAN THAT. 5544 03:16:57,839 --> 03:16:59,974 AND THIS LOOKS AT THE -- WHAT 5545 03:17:00,041 --> 03:17:01,176 HAPPENS TO THE SAME SYMPTOMS I 5546 03:17:01,242 --> 03:17:03,244 SHOWED YOU ON AN EARLIER SLIDE 5547 03:17:03,311 --> 03:17:05,213 BETWEEN BASELINE AND MONTH 12. 5548 03:17:05,280 --> 03:17:07,348 AND YOU CAN SEE WITH FATIGUE, 5549 03:17:07,415 --> 03:17:09,484 THERE'S WHAT I THOUGHT WAS A 5550 03:17:09,551 --> 03:17:11,219 RATHER SURPRISING RESOLUTION OF 5551 03:17:11,286 --> 03:17:14,355 FATIGUE IN THE PATIENTS -- NO 5552 03:17:14,422 --> 03:17:15,857 LONGER HAD IT AT ONE YEAR. 5553 03:17:15,924 --> 03:17:20,128 THE COGNITIVE SYMPTOMS WERE NOT 5554 03:17:20,195 --> 03:17:22,163 QUITE AS IMPRESSIVE A DROP BUT 5555 03:17:22,230 --> 03:17:24,265 VIRTUALLY EVERY SYMPTOM WITH THE 5556 03:17:24,332 --> 03:17:26,100 EXCEPTION OF ANXIETY WAS 5557 03:17:26,167 --> 03:17:27,435 DECREASED AT THE ONE-YEAR 5558 03:17:27,502 --> 03:17:29,938 FOLLOW-UP. 5559 03:17:30,004 --> 03:17:32,140 AND BY DECREASED, I MEAN THE 5560 03:17:32,207 --> 03:17:33,208 SYMPTOMS WERE GONE. 5561 03:17:33,274 --> 03:17:35,076 THEY SAID THEY WERE BETTER, THEY 5562 03:17:35,143 --> 03:17:38,146 STILL GOT COUNTED AS HAVING 5563 03:17:38,213 --> 03:17:39,681 FATIGUE, IT HAD TO COMPLETELY 5564 03:17:39,747 --> 03:17:42,984 RESOLVE TO BE PUT IN THE GREEN 5565 03:17:43,051 --> 03:17:49,090 BAR, OR A CONSIDERED RESULT. 5566 03:17:49,157 --> 03:17:51,059 SO DURING THE LAST YEAR AND A 5567 03:17:51,125 --> 03:17:52,794 HALF, SORT OF AN INTERESTING AND 5568 03:17:52,860 --> 03:17:54,229 I THINK A UNIQUE OPPORTUNITY HAS 5569 03:17:54,295 --> 03:17:56,831 COME ALONG IN THAT MEMBERS OF 5570 03:17:56,898 --> 03:17:58,366 OUR CONTROL GROUP STARTING ABOUT 5571 03:17:58,433 --> 03:18:00,668 IN DECEMBER OF '21, WHEN THE 5572 03:18:00,735 --> 03:18:02,003 OMICRON VARIANT SORT OF HIT THIS 5573 03:18:02,070 --> 03:18:07,008 AREA AND BECAME THE DO DOMINANT 5574 03:18:07,075 --> 03:18:08,343 VARIANT AND HAS REMAINED THE 5575 03:18:08,409 --> 03:18:10,211 DOMINANT VARIANT IN THIS AREA, 5576 03:18:10,278 --> 03:18:11,512 HALF OF OUR CONTROL GROUP HAS 5577 03:18:11,579 --> 03:18:15,116 NOW BECOME INFECTED WITH -- AT 5578 03:18:15,183 --> 03:18:17,085 LEAST ONCE WITH SARS-COV-2. 5579 03:18:17,151 --> 03:18:18,353 THESE ARE PEOPLE WHO AGAIN HAD 5580 03:18:18,419 --> 03:18:19,654 ONE OR MORE VISITS AS CONTROLS 5581 03:18:19,721 --> 03:18:21,489 WHO WERE NOT INFECTED BECAUSE WE 5582 03:18:21,556 --> 03:18:23,224 CHECK SEROLOGIES AT EVERY VISIT 5583 03:18:23,291 --> 03:18:26,194 AND LOOK FOR SEROCONVERSION BUT 5584 03:18:26,261 --> 03:18:30,131 THESE PEOPLE HAD SYMPTOMATIC -- 5585 03:18:30,198 --> 03:18:31,466 THIS OFFERS A UNIQUE OPPORTUNITY 5586 03:18:31,532 --> 03:18:32,834 SO YOU HAVE THE IDEAL SORT OF 5587 03:18:32,900 --> 03:18:33,434 CONTROL COHORT. 5588 03:18:33,501 --> 03:18:35,470 YOU HAVE A GROUP OF INDIVIDUALS 5589 03:18:35,536 --> 03:18:37,605 WHO HAD EXTENSIVE EVALUATION 5590 03:18:37,672 --> 03:18:40,275 PRIOR TO BECOMING INFECTED WITH 5591 03:18:40,341 --> 03:18:41,609 SARS-COV-2, AND ALL THESE PEOPLE 5592 03:18:41,676 --> 03:18:43,878 AGREED TO REMAIN ON THE PROTOCOL 5593 03:18:43,945 --> 03:18:45,413 AND CAN CONTINUE UNDERGOING 5594 03:18:45,480 --> 03:18:48,349 THESE SAME MANIFESTATIONS, SO 5595 03:18:48,416 --> 03:18:49,584 THEY'RE THE PERFECT CONTROL 5596 03:18:49,651 --> 03:18:51,986 GROUP AND IT GIVES YOU THE MOST 5597 03:18:52,053 --> 03:18:54,922 ACCURATE ESTIMATE OF PREVALENCE 5598 03:18:54,989 --> 03:18:56,691 OF LONG COVID, HOW MANY PEOPLE 5599 03:18:56,758 --> 03:18:59,861 THAT GET ACUTE COVID DEVELOP 5600 03:18:59,927 --> 03:19:01,262 PERSISTENT -- OR CONTINUE ON TO 5601 03:19:01,329 --> 03:19:02,797 HAVE PERSISTENT SYMPTOMS, SINCE 5602 03:19:02,864 --> 03:19:04,866 YOU KNOW THE COHORT BEFORE AND 5603 03:19:04,932 --> 03:19:06,501 AFTERWARDS, SO THERE'S NO BIAS 5604 03:19:06,567 --> 03:19:08,736 AS FAR AS REFERRAL BIAS OR 5605 03:19:08,803 --> 03:19:09,437 SELF-REFERRAL BIAS OR THINGS 5606 03:19:09,504 --> 03:19:10,138 LIKE THAT. 5607 03:19:10,204 --> 03:19:11,773 SO WHEN WE LOOKED AT THIS 5608 03:19:11,839 --> 03:19:14,509 COHORT, AND AGAIN, ALL THESE 5609 03:19:14,575 --> 03:19:15,410 INDIVIDUALS, NONE OF THESE 5610 03:19:15,476 --> 03:19:16,277 INDIVIDUALS REQUIRED 5611 03:19:16,344 --> 03:19:16,844 HOSPITALIZATION. 5612 03:19:16,911 --> 03:19:18,346 THEY ALL HAD MILD TO MODERATE 5613 03:19:18,413 --> 03:19:18,680 ILLNESS. 5614 03:19:18,746 --> 03:19:20,181 NONE OF THE INFECTED CONTROLS. 5615 03:19:20,248 --> 03:19:22,283 SO IF WE LOOK AT THE INCIDENCE 5616 03:19:22,350 --> 03:19:27,655 OF PO POST-ACUTE SEQUELAE OF CO, 5617 03:19:27,722 --> 03:19:28,990 ONLY ONE INDIVIDUAL OUT OF THE 5618 03:19:29,057 --> 03:19:32,427 134 DEVELOPED -- OR HAD 5619 03:19:32,493 --> 03:19:33,061 PERSISTENT SYMPTOMS FOLLOWING 5620 03:19:33,127 --> 03:19:33,761 INFECTION. 5621 03:19:33,828 --> 03:19:36,497 THE OTHER 133 COMPLETELY 5622 03:19:36,564 --> 03:19:38,166 RECOVERED AND HAVE NO LONG COVID 5623 03:19:38,232 --> 03:19:39,567 SYMPTOMS. 5624 03:19:39,634 --> 03:19:41,736 SO THAT WAS REALLY A STRIKING 5625 03:19:41,803 --> 03:19:44,572 FINDING AND I THINK THAT TELLS 5626 03:19:44,639 --> 03:19:46,541 YOU THAT THIS IS A MORE ACCURATE 5627 03:19:46,607 --> 03:19:49,277 WAY OF DETERMINING PREVALENCE 5628 03:19:49,344 --> 03:19:51,245 THAN JUST OPEN-ENDED SELF 5629 03:19:51,312 --> 03:19:52,680 REFERRAL OR PHYSICIAN REFERRAL. 5630 03:19:52,747 --> 03:19:58,619 AND I THINK IT GIVES YOU AN IDEA 5631 03:19:58,686 --> 03:20:00,722 OF WHAT THE CURRENT PICTURE OF 5632 03:20:00,788 --> 03:20:02,890 LONG COVID IS NOW AND WILL BE IN 5633 03:20:02,957 --> 03:20:04,826 THE FUTURE. 5634 03:20:04,892 --> 03:20:06,461 WHETHER IT'S AS LOW AS 1% OR 5635 03:20:06,527 --> 03:20:08,629 LESS, THE SAMPLE SIZE IS TOO 5636 03:20:08,696 --> 03:20:13,234 SMALL TO TELL BUT THIS SHOWS YOU 5637 03:20:13,301 --> 03:20:14,202 THE BASELINE CHARACTERISTICS I 5638 03:20:14,268 --> 03:20:15,837 WAS TRYING TO FIGURE OUT WHY 5639 03:20:15,903 --> 03:20:17,105 THERE'S ANYTHING IN THE 5640 03:20:17,171 --> 03:20:18,706 DEMOGRAPHICS OF THIS -- OF THE 5641 03:20:18,773 --> 03:20:20,475 INFECTED CONTROLS THAT WAS 5642 03:20:20,541 --> 03:20:21,542 DIFFERENT AND THAT MIGHT EXPLAIN 5643 03:20:21,609 --> 03:20:22,310 THIS HUGE DIFFERENCE. 5644 03:20:22,377 --> 03:20:23,644 SO THIS TABLE JUST COMPARES THE 5645 03:20:23,711 --> 03:20:25,480 ORIGINAL COHORT TO THE RIGHT, 5646 03:20:25,546 --> 03:20:27,782 THE 189 THAT I JUST DISCUSSED, 5647 03:20:27,849 --> 03:20:30,451 WITH THE 134 INFECTED CONTROLS 5648 03:20:30,518 --> 03:20:31,819 WHO GOT INFECTED AFTER ONE OR 5649 03:20:31,886 --> 03:20:34,355 MORE PROTOCOL VISITS. 5650 03:20:34,422 --> 03:20:35,923 SO THEY REALLY LOOKED VERY 5651 03:20:35,990 --> 03:20:37,759 SIMILAR AS FAR AS ALL THE 5652 03:20:37,825 --> 03:20:41,062 DEMOGRAPHICS, THE PRECOVID 5653 03:20:41,129 --> 03:20:42,397 CONDITIONS, PRECOMORBIDITIES, 5654 03:20:42,463 --> 03:20:43,531 BUT THE BIG DIFFERENCE IS SHOWN 5655 03:20:43,598 --> 03:20:45,133 AT THE BOTTOM, WHICH FIRST OF 5656 03:20:45,199 --> 03:20:46,601 ALL IS THAT ONLY TWO OF THE 5657 03:20:46,667 --> 03:20:48,269 INFECTED CONTROLS WERE INFECTED 5658 03:20:48,336 --> 03:20:49,670 PRIOR TO DECEMBER 2021, THAT 5659 03:20:49,737 --> 03:20:52,173 WOULD HAVE BEEN IN THE ALPHA OR 5660 03:20:52,240 --> 03:20:54,709 DELTA VARIANT STAGE, SO THE VAST 5661 03:20:54,776 --> 03:20:56,677 MAJORITY WERE INFECTED WITH 5662 03:20:56,744 --> 03:20:57,745 OMICRON VARIANTS. 5663 03:20:57,812 --> 03:20:58,746 SECOND, IF YOU LOOK AT THE 5664 03:20:58,813 --> 03:20:59,747 VACCINATION RATES, IN THE 5665 03:20:59,814 --> 03:21:01,816 INITIAL COHORT OF 189, ONLY ONE 5666 03:21:01,883 --> 03:21:03,885 OF THOSE INDIVIDUALS HAD BEEN 5667 03:21:03,951 --> 03:21:05,319 VACCINATED PRIOR TO CONTRACTING 5668 03:21:05,386 --> 03:21:05,953 COVID. 5669 03:21:06,020 --> 03:21:07,422 THAT'S BECAUSE MAINLY VACCINES 5670 03:21:07,488 --> 03:21:08,356 WEREN'T AVAILABLE DURING THAT 5671 03:21:08,423 --> 03:21:09,991 FIRST YEAR OF THE STUDY FOR MOST 5672 03:21:10,057 --> 03:21:12,860 INDIVIDUALS. 5673 03:21:12,927 --> 03:21:15,029 IN SHARP CONTRAST TO THAT IS 5674 03:21:15,096 --> 03:21:16,130 ONLY ONE INDIVIDUAL IN THE 5675 03:21:16,197 --> 03:21:17,698 INFECTED CONTROL GROUP WAS NOT 5676 03:21:17,765 --> 03:21:20,301 VACCINATED PRIOR TO CONTROL -- 5677 03:21:20,368 --> 03:21:22,670 SO VACCINATION RATE WAS 99%, AND 5678 03:21:22,737 --> 03:21:24,772 THAT'S RECEIVING AT LEAST TWO 5679 03:21:24,839 --> 03:21:27,175 VACCINES AND ONE BOOSTER, AT 5680 03:21:27,241 --> 03:21:31,145 LEAST ONE BOOSTER. 5681 03:21:31,212 --> 03:21:32,180 SO THERE'S SIGNIFICANT 5682 03:21:32,246 --> 03:21:33,848 DIFFERENCE IN THE INCIDENCE OF 5683 03:21:33,915 --> 03:21:35,716 POST-ACUTE SEQUELAE OF COVID 5684 03:21:35,783 --> 03:21:38,352 SEEING THESE INFECTED CONTROLS 5685 03:21:38,419 --> 03:21:40,655 IS PROBABLY LARGELY RELATED TO A 5686 03:21:40,721 --> 03:21:42,590 HIGH VACCINATION RATE AND 5687 03:21:42,657 --> 03:21:46,160 PERHAPS THE OMICRON VARIANT AND 5688 03:21:46,227 --> 03:21:47,328 THE FACT THAT THERE'S NO 5689 03:21:47,395 --> 03:21:48,196 REFERRAL BIAS IN THIS 5690 03:21:48,262 --> 03:21:50,598 POPULATION. 5691 03:21:50,665 --> 03:21:53,367 SO THE STUDY IS ONGOING. 5692 03:21:53,434 --> 03:21:55,203 WE STILL ARE ENROLLING PATIENTS. 5693 03:21:55,269 --> 03:21:56,938 THESE ARE SORT OF LISTED SORT OF 5694 03:21:57,004 --> 03:21:57,805 WHAT'S CURRENTLY GOING ON AND 5695 03:21:57,872 --> 03:21:59,774 WHAT SOME OF THE GOALS ARE. 5696 03:21:59,841 --> 03:22:00,875 SO WE'RE GOING TO CONTINUE TO 5697 03:22:00,942 --> 03:22:02,109 FOLLOW THE PREVALENCE OF PASC 5698 03:22:02,176 --> 03:22:03,711 OVER TIME. 5699 03:22:03,778 --> 03:22:07,648 WE'RE LOOKING AT LONGITUDAL 5700 03:22:07,715 --> 03:22:08,449 FOLLOW-UP, NEUROCOGNITIVE 5701 03:22:08,516 --> 03:22:10,284 FUNCTION AND SEE IF THERE'S ANY 5702 03:22:10,351 --> 03:22:11,486 CHANGE PAST ONE YEAR. 5703 03:22:11,552 --> 03:22:13,988 ONE YEAR AND BEYOND. 5704 03:22:14,055 --> 03:22:15,623 WE'RE LOOKING AT THE EFFECT OF 5705 03:22:15,690 --> 03:22:16,891 REINFECTION OF THE COVID-19 5706 03:22:16,958 --> 03:22:20,595 GROUP ON PERSISTENT SYMPTOMS 5707 03:22:20,661 --> 03:22:21,229 DUE -- LONG COVID SYMPTOMS AND 5708 03:22:21,295 --> 03:22:23,764 PEOPLE WHO HAVE THEM GET WORSE 5709 03:22:23,831 --> 03:22:24,599 AFTER RE-INFECTION. 5710 03:22:24,665 --> 03:22:27,235 UP TO THIS POINT, AS OF TODAY, 5711 03:22:27,301 --> 03:22:29,070 41% OF THE ENTIRE COVID CORE 5712 03:22:29,136 --> 03:22:31,205 HORT HAS EXPERIENCED ONE OR MORE 5713 03:22:31,272 --> 03:22:31,873 REINFECTIONS AND WE'RE IN THE 5714 03:22:31,939 --> 03:22:34,809 PROCESS OF ANALYZING HOW THAT 5715 03:22:34,876 --> 03:22:36,043 IMPACTS REPORTED SYMPTOMS THAT 5716 03:22:36,110 --> 03:22:37,612 THEY HAVE OR DON'T HAVE. 5717 03:22:37,678 --> 03:22:40,281 AND WE'RE LOOKING AT DOING 5718 03:22:40,348 --> 03:22:41,482 ADDITIONAL BIOMARKER STUDIES 5719 03:22:41,549 --> 03:22:42,884 LOOKING AT MORE BIOMARKERS. 5720 03:22:42,950 --> 03:22:45,052 IN FACT, WE'RE JUST FINISHING A 5721 03:22:45,119 --> 03:22:46,921 SET OF EXPERIMENTS INVOLVING 5722 03:22:46,988 --> 03:22:50,525 SEFERLG THOSEVERAL THOUSAND SAMM 5723 03:22:50,591 --> 03:22:52,393 THE ENTIRE COHORT LOOKING AT 5724 03:22:52,460 --> 03:22:54,695 EVERY CYTOKINE THAT IS REPORTED 5725 03:22:54,762 --> 03:22:56,097 HAVING BEEN ASSOCIATED IN OTHER 5726 03:22:56,163 --> 03:22:56,898 PUBLICATIONS WITH LONG COVID. 5727 03:22:56,964 --> 03:22:58,499 WE'RE ALSO GOING TO ANALYZE THAT 5728 03:22:58,566 --> 03:23:00,167 NOT JUST AS A WHOLE GROUP, BUT 5729 03:23:00,234 --> 03:23:02,570 BREAK IT DOWN BY GENDER, GIVEN 5730 03:23:02,637 --> 03:23:05,072 THE GENDER DIFFERENCES IN LONG 5731 03:23:05,139 --> 03:23:07,708 COVID SYMPTOMS. 5732 03:23:07,775 --> 03:23:09,677 WE'RE STARTING TO LOOK MORE AND 5733 03:23:09,744 --> 03:23:11,445 MORE AT VIRAL PERSISTENCE 5734 03:23:11,512 --> 03:23:15,349 LOOKING AT BOTH PLASMA 5735 03:23:15,416 --> 03:23:16,484 NUCLEOCAPSID AND SPIKE PROTEIN 5736 03:23:16,551 --> 03:23:19,287 LEVELS. 5737 03:23:19,353 --> 03:23:20,821 -- SHOW NOBODY'S POSITIVE FOR 5738 03:23:20,888 --> 03:23:22,490 THAT IN ANY GROUP, INCLUDING 5739 03:23:22,557 --> 03:23:23,791 CONTROLS OR NON-CONTROLS. 5740 03:23:23,858 --> 03:23:25,493 SPIKE PROTEIN LEVELS, THERE ARE 5741 03:23:25,560 --> 03:23:28,162 TWO MAIN ASSAYS BEING USED AND 5742 03:23:28,229 --> 03:23:29,864 WE'VE SENT BLINDED SAMPLES TO 5743 03:23:29,931 --> 03:23:38,673 TWO CABINETRIES THAT ARE LABORAS 5744 03:23:38,739 --> 03:23:41,742 ASSAY, TWO SAYING MARKEDLY 5745 03:23:41,809 --> 03:23:42,743 DISCREPANT. 5746 03:23:42,810 --> 03:23:44,145 STILL UP IN THE AIR WHAT THAT'S 5747 03:23:44,211 --> 03:23:45,112 REFERRING TO THERE. 5748 03:23:45,179 --> 03:23:46,747 AND WE'VE STOPPED RECRUITING 5749 03:23:46,814 --> 03:23:48,950 PEOPLE WHO HAVE HAD COVID IN THE 5750 03:23:49,016 --> 03:23:51,252 LAST YEAR AND BEEN FOCUSING ON 5751 03:23:51,319 --> 03:23:53,087 RECRUITING ONLY COVID-NEGATIVE 5752 03:23:53,154 --> 03:23:55,523 CONTROLS, AS FAR AS WE CAN TELL, 5753 03:23:55,590 --> 03:23:56,190 COVID-NEGATIVE CONTROLS, WITH 5754 03:23:56,257 --> 03:23:58,259 THE IDEA THEY'RE ALL GOING TO 5755 03:23:58,326 --> 03:23:59,026 CONTRACT SARS-COV-2 INFECTION, 5756 03:23:59,093 --> 03:24:00,428 AND THAT WILL BE, I THINK, A 5757 03:24:00,494 --> 03:24:02,196 VERY VALUABLE COHORT TO ENLARGE 5758 03:24:02,263 --> 03:24:05,266 AND TO STUDY TO GET A TRUE LOOK 5759 03:24:05,333 --> 03:24:08,402 AT WHAT THE PREVALENCE OF LONG 5760 03:24:08,469 --> 03:24:11,906 COVID IS IN 2023-2024 IN A 5761 03:24:11,973 --> 03:24:18,312 HIGHLY VACCINATED POPULATION. 5762 03:24:18,379 --> 03:24:19,447 SO THAT'S THE END OF MY TALK. 5763 03:24:19,513 --> 03:24:29,690 [APPLAUSE] 5764 03:24:37,898 --> 03:24:38,833 >> I HAVE ONE QUESTION. 5765 03:24:38,899 --> 03:24:39,433 CAN YOU HEAR? 5766 03:24:39,500 --> 03:24:40,167 >> BARELY. 5767 03:24:40,234 --> 03:24:41,802 >> HAVING FINALLY CONTRACTED 5768 03:24:41,869 --> 03:24:44,839 COVID ABOUT SIX WEEKS AGO, I'M 5769 03:24:44,905 --> 03:24:48,009 CURIOUS IF YOU HAVE DATA ON THE 5770 03:24:48,075 --> 03:24:49,110 CONTROLS, WHETHER THEY HAD 5771 03:24:49,176 --> 03:24:51,979 ACCESS TO ANTIVIRAL THERAPY LIKE 5772 03:24:52,046 --> 03:24:52,346 PAXLOVID. 5773 03:24:52,413 --> 03:24:55,016 >> I'M SORRY, I MISSED THE LAST 5774 03:24:55,082 --> 03:24:55,449 PART. 5775 03:24:55,516 --> 03:24:56,517 >> YOUR THOUGHT ON WHETHER OR 5776 03:24:56,584 --> 03:24:58,185 NOT THE CONTROLS HAD -- IF YOU 5777 03:24:58,252 --> 03:25:00,154 HAVE DATA ON WHETHER OR NOT THEY 5778 03:25:00,221 --> 03:25:02,790 RECEIVED ANTIVIRAL THERAPY. 5779 03:25:02,857 --> 03:25:03,124 PAXLOVID. 5780 03:25:03,190 --> 03:25:04,525 >> OH, PAXLOVID. 5781 03:25:04,592 --> 03:25:06,661 YEAH, WE RECORD -- OH, ACTUALLY 5782 03:25:06,727 --> 03:25:09,563 MOST OF THEM DIDN'T. 5783 03:25:09,630 --> 03:25:09,797 GET 5784 03:25:09,864 --> 03:25:10,164 PAXLOVID. 5785 03:25:10,231 --> 03:25:12,833 I DON'T KNOW, IT'S NOT -- MOST 5786 03:25:12,900 --> 03:25:15,803 OF THE REASONS -- WE RECORD THAT 5787 03:25:15,870 --> 03:25:17,104 DATA, BUT MOST OF THE PEOPLE SAY 5788 03:25:17,171 --> 03:25:18,773 I JUST DIDN'T FEEL SICK ENOUGH 5789 03:25:18,839 --> 03:25:19,974 TO GET IT. 5790 03:25:20,041 --> 03:25:20,941 SOME PEOPLE STARTED TAKING IT 5791 03:25:21,008 --> 03:25:22,143 AND DIDN'T LIKE THE SIDE 5792 03:25:22,209 --> 03:25:22,710 EFFECTS. 5793 03:25:22,777 --> 03:25:24,011 SOME PEOPLE HAD DRUG 5794 03:25:24,078 --> 03:25:25,112 INTERACTIONS THAT WERE HARD TO 5795 03:25:25,179 --> 03:25:26,647 GET AROUND LIKE WITH 5796 03:25:26,714 --> 03:25:27,381 ANTICOAGULANTS AND STUFF. 5797 03:25:27,448 --> 03:25:29,350 SO I THINK THE USE OF PAXLOVID, 5798 03:25:29,417 --> 03:25:31,452 AT LEAST MY EXPERIENCE ON THIS 5799 03:25:31,519 --> 03:25:32,987 STUDY, IS NOT VERY HIGH. 5800 03:25:33,054 --> 03:25:34,555 I THINK IT'S GOING TO BE EVEN 5801 03:25:34,622 --> 03:25:35,956 LESS NOW IF YOU HAVE TO PAY THE 5802 03:25:36,023 --> 03:25:38,559 INSURANCE CO-PAY FOR IT, WHICH 5803 03:25:38,626 --> 03:25:40,828 AT LEAST FOR MY INSURANCE, NIH 5804 03:25:40,895 --> 03:25:43,030 INSURANCE COVERAGE IS ABOUT $400 5805 03:25:43,097 --> 03:25:43,597 FOR A COURSE. 5806 03:25:43,664 --> 03:25:45,466 THAT'S THE CO-PAY. 5807 03:25:45,533 --> 03:25:47,101 >> I WAS VERY LUCKY MY INSURANCE 5808 03:25:47,168 --> 03:25:47,668 COVERED IT. 5809 03:25:47,735 --> 03:25:48,969 HOW ABOUT THE ONE PATIENT WHO 5810 03:25:49,036 --> 03:25:51,005 DEVELOPED PASC, DO YOU KNOW IF 5811 03:25:51,072 --> 03:25:51,639 THAT ONE GOT -- 5812 03:25:51,706 --> 03:25:53,541 >> I DON'T RECALL THAT THAT 5813 03:25:53,607 --> 03:25:54,875 INDIVIDUAL GOT -- BUT I DO KNOW 5814 03:25:54,942 --> 03:25:56,310 THAT ALL OF HER SYMPTOMS THAT 5815 03:25:56,377 --> 03:26:00,114 SHE HAD OF PASC CONCENTRATION 5816 03:26:00,181 --> 03:26:04,051 IMPAIRMENT AND FATIGUE WERE 5817 03:26:04,118 --> 03:26:04,819 PRESENT AS A CONTROL. 5818 03:26:04,885 --> 03:26:06,353 SHE JUST FELT THAT THEY WORSENED 5819 03:26:06,420 --> 03:26:07,254 AFTER THE INFECTION. 5820 03:26:07,321 --> 03:26:10,191 SO BY OUR DEFINITION, WE COUNTED 5821 03:26:10,257 --> 03:26:19,500 THAT AS IN THE LONG COVID GROUP. 5822 03:26:19,567 --> 03:26:25,539 [APPLAUSE] 5823 03:26:25,606 --> 03:26:26,640 THESE ARE TOUGH ACTS TO FOLLOW 5824 03:26:26,707 --> 03:26:29,043 WHEN YOU COME UP HERE. 5825 03:26:29,110 --> 03:26:32,012 SO OUR LATEBREAKING SESSION IS 5826 03:26:32,079 --> 03:26:33,314 THREE 10-MINUTE TALKS AND WE'RE 5827 03:26:33,380 --> 03:26:40,855 GOING TO BE LED OFF BY AGOSTINA 5828 03:26:40,921 --> 03:26:42,323 CASAMENTO-MORAN FROM JOHNS 5829 03:26:42,389 --> 03:26:43,491 HOPKINS, UNDERSTANDING THE 5830 03:26:43,557 --> 03:26:45,893 BEHAVIORAL FEATURES OF FA TEEK 5831 03:26:45,960 --> 03:26:48,529 IN LONG COVID. 5832 03:26:48,596 --> 03:26:55,236 AGOST? 5833 03:26:56,904 --> 03:26:58,439 >> GOOD AFTERNOON, EVERYBODY. 5834 03:26:58,506 --> 03:27:00,908 THANK YOU FOR GIVING ME THE 5835 03:27:00,975 --> 03:27:02,777 OPPORTUNITY TO PRESENT TODAY AND 5836 03:27:02,843 --> 03:27:04,311 SHARE PART OF OUR WORK, WHICH IS 5837 03:27:04,378 --> 03:27:06,480 AIMING TO UNDERSTAND THE 5838 03:27:06,547 --> 03:27:08,082 BEHAVIORAL FEATURES OF FATIGUE 5839 03:27:08,149 --> 03:27:09,250 IN LONG COVID. 5840 03:27:09,316 --> 03:27:14,789 BUT BEFORE I START, I WOULD LIKE 5841 03:27:14,855 --> 03:27:15,923 TO HIGHLIGHT THAT THE WORK THAT 5842 03:27:15,990 --> 03:27:17,224 I'M SHARING TODAY RESULTS FROM A 5843 03:27:17,291 --> 03:27:25,766 STRONG COLLABORATION WITH OTHERS 5844 03:27:25,833 --> 03:27:27,401 AS WELL AS THE HOPE REGISTRY AT 5845 03:27:27,468 --> 03:27:27,735 JOHNS HOPKINS. 5846 03:27:27,802 --> 03:27:28,936 TOGETHER WE HAVE WORKED 5847 03:27:29,003 --> 03:27:29,937 COLLABORATIVELY TO MAKE SURE 5848 03:27:30,004 --> 03:27:33,007 THAT OUR WORK IS INCLUSIVE, IT 5849 03:27:33,073 --> 03:27:34,108 TAKES INTO CONSIDERATION BOTH 5850 03:27:34,175 --> 03:27:35,309 THE SCIENTIFIC AND CLINICAL 5851 03:27:35,376 --> 03:27:36,410 PERSPECTIVE, AND THAT WE CAN 5852 03:27:36,477 --> 03:27:37,611 QUICKLY TRANSLATE WHAT WE LEARN 5853 03:27:37,678 --> 03:27:38,946 BOTH TO THE CLINIC AND THE 5854 03:27:39,013 --> 03:27:41,849 COMMUNITY. 5855 03:27:41,916 --> 03:27:43,217 SO FOR TODAY'S TALK, I WOULD 5856 03:27:43,284 --> 03:27:47,087 LIKE TO FIRST GIVE YOU A BRIEF 5857 03:27:47,154 --> 03:27:50,691 OVERVIEW ABOUT COVID FATIGUE. 5858 03:27:50,758 --> 03:27:52,960 I WILL SHARE OTHER FEATURES OF 5859 03:27:53,027 --> 03:27:54,728 FATIGUE WE'RE FINDING AT 5860 03:27:54,795 --> 03:27:56,831 BASELINE AND FINISH WITH A BRIEF 5861 03:27:56,897 --> 03:27:57,898 TAKE-HOME MESSAGE AND A QUICK 5862 03:27:57,965 --> 03:28:00,201 OVERVIEW OF WHAT ARE OUR NEXT 5863 03:28:00,267 --> 03:28:02,837 STEPS. 5864 03:28:02,903 --> 03:28:05,806 SO AS WE ALL KNOW, DEBILITATING 5865 03:28:05,873 --> 03:28:06,774 FATIGUE IS THE MOST COMMON 5866 03:28:06,841 --> 03:28:09,510 SYMPTOM IF LONG COVID. 5867 03:28:09,577 --> 03:28:09,977 IN LONG COVID. 5868 03:28:10,044 --> 03:28:11,946 IN ADDITION, 1 IN 4 INDIVIDUALS 5869 03:28:12,012 --> 03:28:13,480 WITH LONG COVID WILL MEET THE 5870 03:28:13,547 --> 03:28:16,851 DIAGNOSIS CRITERIA FOR ME/CFS, 5871 03:28:16,917 --> 03:28:17,985 WHICH IS IN ITSELF A CONDITION 5872 03:28:18,052 --> 03:28:20,187 THAT IS CHARACTERIZED BY 5873 03:28:20,254 --> 03:28:22,690 DEBILITATING FATIGUE. 5874 03:28:22,756 --> 03:28:24,124 HOWEVER, THE EXACT CLINICAL 5875 03:28:24,191 --> 03:28:25,226 PRESENTATION OF FATIGUE IN LONG 5876 03:28:25,292 --> 03:28:26,760 COVID AND ITS MECHANISMS REMAINS 5877 03:28:26,827 --> 03:28:28,963 UNKNOWN. 5878 03:28:29,029 --> 03:28:30,664 BUT BEFORE TRYING TO UNDERSTAND 5879 03:28:30,731 --> 03:28:31,999 FATIGUE IN LONG COVID, WE NEED 5880 03:28:32,066 --> 03:28:34,001 TO TAKE A STEP BACK AND ASK 5881 03:28:34,068 --> 03:28:35,402 OURSELF WHY DO WE HAVE SUCH A 5882 03:28:35,469 --> 03:28:36,971 LIMITED UNDERSTANDING OF FATIGUE 5883 03:28:37,037 --> 03:28:37,504 IN GENERAL? 5884 03:28:37,571 --> 03:28:39,807 AND THIS IS EVEN THOUGH FATIGUE 5885 03:28:39,874 --> 03:28:41,542 IS ONE OF THE MOST COMMON AND 5886 03:28:41,609 --> 03:28:42,877 DEBILITATING SYMPTOMS ACROSS THE 5887 03:28:42,943 --> 03:28:45,613 HEALTHCARE SYSTEM. 5888 03:28:45,679 --> 03:28:47,381 BECAUSE FATIGUE HAS A BROAD 5889 03:28:47,448 --> 03:28:48,482 CLINICAL PRESENTATION ACROSS 5890 03:28:48,549 --> 03:28:50,484 INDIVIDUALS AND ILLNESSES, IT 5891 03:28:50,551 --> 03:28:56,423 HAS BEEN BROADLY DEFINED AS -- 5892 03:28:56,490 --> 03:28:58,959 AWARENESS, INCREASE OF -- OR 5893 03:28:59,026 --> 03:28:59,360 EXHAUSTION. 5894 03:28:59,426 --> 03:29:01,395 IT IS THIS IMPRECISE DEFINITION 5895 03:29:01,462 --> 03:29:03,764 AND THE ABSENCE OF QAWBT TAITIVE 5896 03:29:03,831 --> 03:29:04,765 METHODS TO DISTINGUISH BETWEEN 5897 03:29:04,832 --> 03:29:06,634 ASPECTS OF FATIGUE WHICH LIMITS 5898 03:29:06,700 --> 03:29:07,935 OUR ABILITY TO DEEP LE 5899 03:29:08,002 --> 03:29:09,570 UNDERSTAND IT AND HINDERS THE 5900 03:29:09,637 --> 03:29:10,804 DEVELOPMENT OF EVIDENCE-BASED 5901 03:29:10,871 --> 03:29:12,139 TREATMENT. 5902 03:29:12,206 --> 03:29:15,409 SO TO UNDERSTAND FATIGUE IN LONG 5903 03:29:15,476 --> 03:29:16,744 COVID, WE HAVE DEVELOPED AN 5904 03:29:16,810 --> 03:29:18,479 EXPERIMENTAL APPROACH THAT 5905 03:29:18,545 --> 03:29:21,248 ALLOWS US TO QUANTITATIVELY 5906 03:29:21,315 --> 03:29:22,549 DESCRIBE THREE FEATURES OF 5907 03:29:22,616 --> 03:29:22,850 FATIGUE. 5908 03:29:22,917 --> 03:29:24,952 WE USE FATIGUE RATINGS TO 5909 03:29:25,019 --> 03:29:27,821 UNDERSTAND THE FEELINGS OF 5910 03:29:27,888 --> 03:29:29,223 TIREDNESS, AND EFFORT ASSESSMENT 5911 03:29:29,290 --> 03:29:32,426 TASK TO UNDERSTAND FATIGUE 5912 03:29:32,493 --> 03:29:36,130 PERCEPTION AND DECISION-MAKING 5913 03:29:36,196 --> 03:29:37,865 TASK -- LET ME WALK YOU THROUGH 5914 03:29:37,932 --> 03:29:38,966 THESE THREE METRICS IN MORE 5915 03:29:39,033 --> 03:29:42,636 DETAIL. 5916 03:29:42,703 --> 03:29:46,774 SO TO UNDERSTAND, WE ASK 5917 03:29:46,840 --> 03:29:48,375 INDIVIDUALS TO RATE THE LEVEL OF 5918 03:29:48,442 --> 03:29:50,277 TIREDNESS THAT THEY FEEL BY 5919 03:29:50,344 --> 03:29:53,647 MOVING THE CURSOR IN A COMPUTER 5920 03:29:53,714 --> 03:29:54,415 SCREEN. 5921 03:29:54,481 --> 03:29:57,384 THIS IS A SUBJECTIVE SELF-REPORT 5922 03:29:57,451 --> 03:29:59,787 METRIC, AND OUR WORKING 5923 03:29:59,853 --> 03:30:03,757 HYPOTHESIS REFLECTS AN EFFECTIVE 5924 03:30:03,824 --> 03:30:06,493 RESPONSE TO HOMEOSTASIS. 5925 03:30:06,560 --> 03:30:09,430 SO UNDERSTAND EFFORT PERCEPTION, 5926 03:30:09,496 --> 03:30:11,198 WE USE AN EFFORT ASSESSMENT TASK 5927 03:30:11,265 --> 03:30:14,468 IN WHICH WE ASK INDIVIDUALS TO 5928 03:30:14,535 --> 03:30:18,872 EXERT A -- TARGET FORCE AND THEN 5929 03:30:18,939 --> 03:30:19,540 RETROSPECTIVELY ASSESS HOW MUCH 5930 03:30:19,606 --> 03:30:20,607 EFFORT THEY FELT TO HAVE 5931 03:30:20,674 --> 03:30:20,941 EXERTED. 5932 03:30:21,008 --> 03:30:22,376 THIS IS A HYBRID METRIC BECAUSE 5933 03:30:22,443 --> 03:30:24,778 WE'RE ASKING PARTICIPANTS TO 5934 03:30:24,845 --> 03:30:26,847 SUBJECTIVELY ASSESS AND 5935 03:30:26,914 --> 03:30:27,982 OBJECTIVELY EXERT THE FORCE, AND 5936 03:30:28,048 --> 03:30:29,950 OUR WORKING HYPOTHESIS IS THAT 5937 03:30:30,017 --> 03:30:32,152 IT REFLECTS A SENSORY MOTOR 5938 03:30:32,219 --> 03:30:33,687 UNDERSTANDING OF THE EXERTED 5939 03:30:33,754 --> 03:30:36,523 EFFORT. 5940 03:30:36,590 --> 03:30:38,392 LASTLY, TO UNDERSTAND 5941 03:30:38,459 --> 03:30:39,159 INDIVIDUALS' WILLINGNESS TO 5942 03:30:39,226 --> 03:30:43,731 EXERT EFFORT, WE USE AN EFFORT 5943 03:30:43,797 --> 03:30:45,366 DECISION-MAKING -- TO MAKE A 5944 03:30:45,432 --> 03:30:46,834 CHOICE TO EITHER EXERT A CERTAIN 5945 03:30:46,900 --> 03:30:50,004 AMOUNT FOR SURE OR TAKE A 5946 03:30:50,070 --> 03:30:51,739 GAMBLE, IN WHICH THEY CAN HAVE A 5947 03:30:51,805 --> 03:30:53,173 50/50 CHANCE OF EXERTING A 5948 03:30:53,240 --> 03:30:54,608 HIGHER AMOUNT OR NO EFFORT AT 5949 03:30:54,675 --> 03:30:56,443 ALL. 5950 03:30:56,510 --> 03:30:57,678 THIS METRIC IS THE MOST 5951 03:30:57,745 --> 03:30:58,645 OBJECTIVE METRIC THAT WE HAVE 5952 03:30:58,712 --> 03:30:59,747 BECAUSE PARTICIPANTS UNDERSTAND 5953 03:30:59,813 --> 03:31:01,615 WHAT THEY ARE DOING BUT THEY 5954 03:31:01,682 --> 03:31:03,017 DON'T KNOW WHY WE ARE DOING IT. 5955 03:31:03,083 --> 03:31:07,654 AND OUR WORKING HYPOTHESIS IS IT 5956 03:31:07,721 --> 03:31:09,056 REFLECTS INDIVIDUALS' DECISION 5957 03:31:09,123 --> 03:31:10,491 TO ENGAGE IN ACTION AS A 5958 03:31:10,557 --> 03:31:11,625 BEHAVIORAL STRATEGY THAT COULD 5959 03:31:11,692 --> 03:31:14,228 ALLOW US TO ACT OR REST IN ORDER 5960 03:31:14,294 --> 03:31:16,196 TO RECOVERY. 5961 03:31:16,263 --> 03:31:18,799 SO OUR GOAL IS TO USE THESE 5962 03:31:18,866 --> 03:31:20,367 THREE QUANTITATIVE METRICS TO 5963 03:31:20,434 --> 03:31:20,934 CHARACTERIZE FATIGUE IN LONG 5964 03:31:21,001 --> 03:31:23,537 COVID. 5965 03:31:23,604 --> 03:31:27,041 SO WHAT DID WE FIND? 5966 03:31:27,107 --> 03:31:29,710 SO FIRST WE HAD 34 LONG COVID 5967 03:31:29,777 --> 03:31:33,447 PARTICIPANTS AND 34 HEALTHY AGE, 5968 03:31:33,514 --> 03:31:36,050 SEX, RACE AND FITNESS MATCHED 5969 03:31:36,116 --> 03:31:37,885 CONTROLS. 5970 03:31:37,951 --> 03:31:39,653 THIS IS A BIG TABLE WITH A 5971 03:31:39,720 --> 03:31:40,988 SUBSET OF MY LONG COVID 5972 03:31:41,055 --> 03:31:42,056 PARTICIPANTS, BUT THE GOAL HERE 5973 03:31:42,122 --> 03:31:44,591 IS TO SHOW YOU THEY'RE PRIMARILY 5974 03:31:44,658 --> 03:31:46,226 WOMEN, THAT THEY HAVE ALL 5975 03:31:46,293 --> 03:31:47,661 REPORTED THAT THE PERCEIVED 5976 03:31:47,728 --> 03:31:48,996 PHYSICAL AND COGNITIVE STATUS IS 5977 03:31:49,063 --> 03:31:50,731 LOWER THAN THEIR PRECOVID 5978 03:31:50,798 --> 03:31:51,231 ESTIMATE. 5979 03:31:51,298 --> 03:31:53,167 AND THAT THEY ALL REPORT FATIGUE 5980 03:31:53,233 --> 03:31:55,135 BEING ONE OF THE MOST COMMON AND 5981 03:31:55,202 --> 03:31:55,903 DEBILITATING SYMPTOMS THAT THEY 5982 03:31:55,969 --> 03:31:57,771 EXPERIENCE. 5983 03:31:57,838 --> 03:31:59,506 SO WHAT DID WE FIND 5984 03:31:59,573 --> 03:32:00,674 EXPERIMENTALLY? 5985 03:32:00,741 --> 03:32:02,409 SO LOOKING AT FEELINGS OF 5986 03:32:02,476 --> 03:32:04,078 TIREDNESS, NOT SURPRISINGLY, WE 5987 03:32:04,144 --> 03:32:05,512 SEE THAT INDIVIDUALS WITH LONG 5988 03:32:05,579 --> 03:32:07,915 COVID DEPICTED IN BLACK 5989 03:32:07,981 --> 03:32:09,416 EXPERIENCED HIGHER FATIGUE 5990 03:32:09,483 --> 03:32:13,053 RATINGS THAN HEALTHY CONTROLS. 5991 03:32:13,120 --> 03:32:15,355 IMPORTANTLY, THIS INITIAL METRIC 5992 03:32:15,422 --> 03:32:16,824 RELATES TO PERCEIVED PHYSICAL 5993 03:32:16,890 --> 03:32:17,758 STATUS AND THE NUMBER OF 5994 03:32:17,825 --> 03:32:18,759 SYMPTOMS. 5995 03:32:18,826 --> 03:32:20,928 SO ON THE Y AXIS, YOU HAVE 5996 03:32:20,994 --> 03:32:23,464 PERCEIVED PHYSICAL STATUS AS A 5997 03:32:23,530 --> 03:32:25,132 FUNCTION OF FATIGUE RATINGS, 5998 03:32:25,199 --> 03:32:26,767 THOSE WHO REPORT HIGHER FATIGUE 5999 03:32:26,834 --> 03:32:28,202 ARE ALSO THE ONES WHO ARE 6000 03:32:28,268 --> 03:32:29,303 REPORTING LOWER PERCEIVED 6001 03:32:29,369 --> 03:32:31,271 PHYSICAL STATUS. 6002 03:32:31,338 --> 03:32:32,806 THE SAME TREND YOU CAN SEE NOW 6003 03:32:32,873 --> 03:32:34,575 WITH HAVING THE NUMBER OF 6004 03:32:34,641 --> 03:32:35,976 SYMPTOMS OR THE SYMPTOM COUNT ON 6005 03:32:36,043 --> 03:32:38,078 THE Y AXIS, WHICH WE ASSESS WITH 6006 03:32:38,145 --> 03:32:39,279 A VERY COMPREHENSIVE CHECKLIST 6007 03:32:39,346 --> 03:32:41,815 IN WHICH WE TRY TO CHARACTERIZE 6008 03:32:41,882 --> 03:32:44,551 HOW IS THE FATIGUE 6009 03:32:44,618 --> 03:32:45,886 MANIFESTING -- THE DISEASE 6010 03:32:45,953 --> 03:32:46,420 MANIFESTING IN THESE 6011 03:32:46,487 --> 03:32:47,087 INDIVIDUALS. 6012 03:32:47,154 --> 03:32:48,055 I THINK THESE RESULTS SPEAK TO 6013 03:32:48,122 --> 03:32:50,824 THE IDEA THAT THIS METRIC IS -- 6014 03:32:50,891 --> 03:32:53,026 COULD INDEED BE CAPTURING AN 6015 03:32:53,093 --> 03:32:55,362 EFFECTIVE RESPONSE TO SOME LEVEL 6016 03:32:55,429 --> 03:32:58,732 OF BODY DISHOMEOSTASIS. 6017 03:32:58,799 --> 03:33:00,634 NEXT, LOOKING AT EFFORT 6018 03:33:00,701 --> 03:33:02,269 ASSESSMENT, BUT PARTICULARLY THE 6019 03:33:02,336 --> 03:33:05,873 EXERT COMPONENT, WHAT WE SEE IS 6020 03:33:05,939 --> 03:33:08,275 SIMILAR MODEL CONTROL BETWEEN 6021 03:33:08,342 --> 03:33:08,609 THE GROUPS. 6022 03:33:08,675 --> 03:33:10,043 SO WHAT YOU HAVE IS EXERTED 6023 03:33:10,110 --> 03:33:11,345 FORCE ON THE Y AXIS AS A 6024 03:33:11,411 --> 03:33:12,880 FUNCTION OF THE TARGET FORCE. 6025 03:33:12,946 --> 03:33:14,181 YOU HAVE LONG COVID IN BLACK, 6026 03:33:14,248 --> 03:33:15,082 HEALTHY CONTROLS IN GREY. 6027 03:33:15,149 --> 03:33:16,884 AND YOU CAN SEE THAT BOTH GROUPS 6028 03:33:16,950 --> 03:33:19,887 ARE COMPLETELY OVERLAPPING. 6029 03:33:19,953 --> 03:33:23,457 HOWEVER, DESPITE SIMILAR MOTOR 6030 03:33:23,524 --> 03:33:24,825 CONTROL BETWEEN THE GROUPS, 6031 03:33:24,892 --> 03:33:25,959 LOOKING NOW AT THE ASSESSED 6032 03:33:26,026 --> 03:33:27,561 COMPONENT OF THE TASK, WHAT WE 6033 03:33:27,628 --> 03:33:29,129 SEE IS HEIGHTENED EFFORT 6034 03:33:29,196 --> 03:33:31,198 PERCEPTION IN LONG COVID. 6035 03:33:31,265 --> 03:33:32,332 SO NOW YOU HAVE EFFORT 6036 03:33:32,399 --> 03:33:33,834 PERCEPTION ON THE Y AXIS AS A 6037 03:33:33,901 --> 03:33:34,701 FUNCTION OF THE TARGET FORCE AND 6038 03:33:34,768 --> 03:33:36,470 NOW YOU CAN SEE THAT INDIVIDUALS 6039 03:33:36,537 --> 03:33:37,471 WITH LONG COVID DISASSOCIATE 6040 03:33:37,538 --> 03:33:39,773 FROM THE HEALTHY COUNTERPART AND 6041 03:33:39,840 --> 03:33:41,875 SHOW A HEIGHTENED ASSESSMENT OF 6042 03:33:41,942 --> 03:33:43,410 EFFORT. 6043 03:33:43,477 --> 03:33:44,611 SUGGESTING POTENTIALLY THAT IN 6044 03:33:44,678 --> 03:33:46,780 THIS POPULATION, THERE IS SOME 6045 03:33:46,847 --> 03:33:48,415 ALTERATIONS THAT CHANGE THE 6046 03:33:48,482 --> 03:33:49,583 SENSORY MOTOR UNDERSTANDING OF 6047 03:33:49,650 --> 03:33:51,852 WHAT'S THE EFFORT THAT THEY ARE 6048 03:33:51,919 --> 03:33:54,254 ACTUALLY EXERTING. 6049 03:33:54,321 --> 03:33:57,357 LASTLY, LOOKING AT THE EFFORT 6050 03:33:57,424 --> 03:34:01,528 BASED DECISION, THIS REFLECTS 6051 03:34:01,595 --> 03:34:03,463 THE ACCEPTANCE RATE OF THE FLIP 6052 03:34:03,530 --> 03:34:04,231 OPTION. 6053 03:34:04,298 --> 03:34:05,699 SUCH THAT THE WARMER THE COLOR, 6054 03:34:05,766 --> 03:34:08,869 THE MORE LIKELY YOU ARE TO 6055 03:34:08,936 --> 03:34:10,170 ACCESS THE FLIP OPTION, THE 6056 03:34:10,237 --> 03:34:11,605 COOLER THE COLORS, THE LESS 6057 03:34:11,672 --> 03:34:12,839 LIKELY THAT YOU ARE TO ACCEPT 6058 03:34:12,906 --> 03:34:14,575 THE FLIP OPTION. 6059 03:34:14,641 --> 03:34:17,411 AND WHAT WE SEE IS THAT NOT 6060 03:34:17,477 --> 03:34:20,714 SURPRISINGLY, IN HEALTHY 6061 03:34:20,781 --> 03:34:23,350 CONTROLS, THE THE LOWER THE 6062 03:34:23,417 --> 03:34:24,551 VALUE OF THE FLIP OPTION ARE NOT 6063 03:34:24,618 --> 03:34:25,452 LIKELY WE ARE TO ACCEPT IT. 6064 03:34:25,519 --> 03:34:26,887 THIS IS PARTICULARLY TRUE WHEN 6065 03:34:26,954 --> 03:34:28,622 WE ARE PRESENTED WITH HIGHER 6066 03:34:28,689 --> 03:34:30,390 VALUES OF THE SURE OPTION, 6067 03:34:30,457 --> 03:34:33,193 SHIFTING FROM LEFT TO RIGHT. 6068 03:34:33,260 --> 03:34:35,662 HOWEVER, THIS PATTERN IS NOT AS 6069 03:34:35,729 --> 03:34:37,097 CLEAR IN LONG COVID. 6070 03:34:37,164 --> 03:34:39,166 SO A WAY FOR US TO QUANTIFY THE 6071 03:34:39,233 --> 03:34:40,267 DIFFERENCES BETWEEN THE GROUPS 6072 03:34:40,334 --> 03:34:42,803 IS TO SUBTRACT THESE TWO 6073 03:34:42,869 --> 03:34:44,004 MATRICES AND SEE WHAT IS THE 6074 03:34:44,071 --> 03:34:45,105 DIFFERENCE IN DECISIONS TO 6075 03:34:45,172 --> 03:34:45,872 ENGAGE BETWEEN THE GROUPS. 6076 03:34:45,939 --> 03:34:47,407 AND THIS IS WHAT I'M SHOWING YOU 6077 03:34:47,474 --> 03:34:49,109 HERE. 6078 03:34:49,176 --> 03:34:52,279 THIS IS THE SAME HEAT MAP, BUT 6079 03:34:52,346 --> 03:34:54,014 THIS TIME THE WARMER THE COLOR 6080 03:34:54,081 --> 03:34:55,616 REFLECTS A HIGHER LIKELIHOOD OF 6081 03:34:55,682 --> 03:34:58,652 LONG COVID PARTICIPANTS CHOOSING 6082 03:34:58,719 --> 03:35:01,188 THE FLIP OPTION RED THAN THE 6083 03:35:01,255 --> 03:35:01,922 HEALTHY COUNTERPARTS. 6084 03:35:01,989 --> 03:35:03,390 THE INDIVIDUALS WITH LONG COVIDD 6085 03:35:03,457 --> 03:35:08,629 HAVE A MUCH RISKIER BASE TO MAKE 6086 03:35:08,695 --> 03:35:09,062 DECISION. 6087 03:35:09,129 --> 03:35:10,063 THESE INDIVIDUALS ARE NORMALLY 6088 03:35:10,130 --> 03:35:12,165 WILLING TO EXERT EFFORT TO 6089 03:35:12,232 --> 03:35:14,568 COMPARED TO THE STIGMA THAT YOU 6090 03:35:14,635 --> 03:35:16,870 FEEL FAT BECAUSE YOU'RE LAZY, 6091 03:35:16,937 --> 03:35:19,406 BUT ALSO MAYBE THEY ARE SO 6092 03:35:19,473 --> 03:35:20,841 DESPERATE TO GET THE ZERO OPTION 6093 03:35:20,907 --> 03:35:23,443 THAT THEY NEED TO REST, THAT 6094 03:35:23,510 --> 03:35:25,545 THEY ARE WILLING TO TAKE THAT 6095 03:35:25,612 --> 03:35:26,980 GAMBLE. 6096 03:35:27,047 --> 03:35:29,383 SO AS A SUMMARY, OUR DATA 6097 03:35:29,449 --> 03:35:31,652 SUGGESTS THAT INDIVIDUALS WITH 6098 03:35:31,718 --> 03:35:35,756 LONG COVID EXHIBIT HIGHER -- AND 6099 03:35:35,822 --> 03:35:37,691 RISKIER BASED DECISION-MAKING. 6100 03:35:37,758 --> 03:35:39,059 BUT IF THERE IS ONE THING THAT I 6101 03:35:39,126 --> 03:35:42,996 WOULD LIKE ALL OF US TO REMEMBER 6102 03:35:43,063 --> 03:35:44,898 OR TO TAKE FROM THIS TALK IS 6103 03:35:44,965 --> 03:35:46,233 THAT IF WE REALLY WANT TO 6104 03:35:46,300 --> 03:35:47,167 UNDERSTAND FATIGUE, WE NEED TO 6105 03:35:47,234 --> 03:35:48,869 USE A BATTERY OF BEHAVIORAL 6106 03:35:48,935 --> 03:35:50,070 TASKS THAT WILL ALLOW US TO 6107 03:35:50,137 --> 03:35:51,772 CAPTURE THE MULTIDISCIPLINARY 6108 03:35:51,838 --> 03:35:53,106 NATURE OF FATIGUE, NOT ONLY IN 6109 03:35:53,173 --> 03:35:59,413 LONG COVID AND MESOPOTAMIA BUT O 6110 03:35:59,479 --> 03:36:00,147 OTHER CONDITIONS. 6111 03:36:00,213 --> 03:36:02,616 SO TO CONCLUDE, I SHOW YOU ONLY 6112 03:36:02,683 --> 03:36:03,183 BASELINE DATA. 6113 03:36:03,250 --> 03:36:05,452 OUR GOAL IS TO -- ACTUALLY -- 6114 03:36:05,519 --> 03:36:08,121 WORKING ON UNDERSTANDING THE 6115 03:36:08,188 --> 03:36:09,323 NEUROMUSCULAR MECHANISMS OF 6116 03:36:09,389 --> 03:36:10,290 THESE DATA, AND WE'RE GOING TO 6117 03:36:10,357 --> 03:36:13,260 BE USING OTHER NEUROIMAGING AND 6118 03:36:13,327 --> 03:36:14,161 PHYSIOLOGICAL TECHNIQUES TO 6119 03:36:14,227 --> 03:36:15,595 REALLY GET AT THE MECHANISMS. 6120 03:36:15,662 --> 03:36:17,664 BUT ALSO, MY NEXT PROJECT WILL 6121 03:36:17,731 --> 03:36:19,766 BE AIMING TO CHARACTERIZE 6122 03:36:19,833 --> 03:36:24,037 FATIGUE AND ME C NISMS DURING PT 6123 03:36:24,104 --> 03:36:25,505 EXERTIONAL MALAISE, I REALLY 6124 03:36:25,572 --> 03:36:27,240 BELIEVE TO UNDERSTAND WHAT'S 6125 03:36:27,307 --> 03:36:28,208 HAPPENING IN LONG COVID WE NEED 6126 03:36:28,275 --> 03:36:28,975 TO GO AFTER THEM. 6127 03:36:29,042 --> 03:36:30,877 THE IDEA IS TO LOOK AT THESE 6128 03:36:30,944 --> 03:36:31,978 METRICS DURING AND IMMEDIATELY 6129 03:36:32,045 --> 03:36:37,751 AFTER REPEATING A SUBMAXIMAL 6130 03:36:37,818 --> 03:36:38,652 EXERTION -- AND AFTER TWO DAYS 6131 03:36:38,719 --> 03:36:40,420 AND SO FORTH, WORK WE HAVE BEEN 6132 03:36:40,487 --> 03:36:42,489 WORKING VERY CLOSELY WITH ALLA 6133 03:36:42,556 --> 03:36:43,256 IN TRYING TO CAPTURE IT. 6134 03:36:43,323 --> 03:36:45,058 SO WITH THAT, I THANK YOU FOR 6135 03:36:45,125 --> 03:36:46,259 YOUR ATTENTION, AND I'M HAPPY TO 6136 03:36:46,326 --> 03:36:46,927 TAKE ANY QUESTIONS. 6137 03:36:46,993 --> 03:36:57,170 [APPLAUSE] 6138 03:37:08,515 --> 03:37:11,451 >> THANK YOU, AGOST. 6139 03:37:11,518 --> 03:37:14,654 OUR NEXT SPEAKER IS FROM 6140 03:37:14,721 --> 03:37:18,158 COLUMBIA, COMPREHENSIVE PLASMA 6141 03:37:18,225 --> 03:37:25,265 METABOLOMICS ANALYSIS WITH 6142 03:37:25,332 --> 03:37:32,606 EXERCISE TOLERANCE TEST. 6143 03:37:52,993 --> 03:37:54,528 >> HI. 6144 03:37:54,594 --> 03:37:56,363 MY NAME IS XIAOYU CHE, AS 6145 03:37:56,430 --> 03:37:57,564 TONIGHT PROFESSOR OF 6146 03:37:57,631 --> 03:37:58,665 BIOSTATISTICS FOR THE CENTER FOR 6147 03:37:58,732 --> 03:38:00,434 INFECTION IMMUNITY AT COLUMBIA 6148 03:38:00,500 --> 03:38:01,067 UNIVERSITY. 6149 03:38:01,134 --> 03:38:02,202 AND TODAY I'LL BE PRESENT DATA 6150 03:38:02,269 --> 03:38:05,372 FROM A COMPREHENSIVE PLASMA 6151 03:38:05,439 --> 03:38:06,706 METABOLOMICS ANALYSIS IN 6152 03:38:06,773 --> 03:38:17,784 MESOPOTAME/CFSWITH EXERCISE TOL. 6153 03:38:21,488 --> 03:38:23,390 TWO SITES, CLINIC IN NEW YORK 6154 03:38:23,457 --> 03:38:25,425 CITY AND STANFORD UNIVERSITY 6155 03:38:25,492 --> 03:38:26,793 SCHOOL OF MEDICINE. 6156 03:38:26,860 --> 03:38:30,096 THERE WERE 47 ONE TO ONE MATCHED 6157 03:38:30,163 --> 03:38:30,931 CASE CONTROL PAIRS. 6158 03:38:30,997 --> 03:38:33,266 THE PLASMA SAMPLES WERE 6159 03:38:33,333 --> 03:38:35,035 COLLECTED AT TWO TIME POINTS. 6160 03:38:35,101 --> 03:38:37,971 THERE IS IMMEDIATELY BEFORE AND 6161 03:38:38,038 --> 03:38:41,508 24 HOURS AFTER THE ETT. 6162 03:38:41,575 --> 03:38:42,809 KNOWN PARTICIPANTS WERE REQUIRED 6163 03:38:42,876 --> 03:38:44,578 TO GO TO 12-HOUR FASTING BEFORE 6164 03:38:44,644 --> 03:38:46,213 BLOOD DRAW. 6165 03:38:46,279 --> 03:38:48,548 THE METABOLOMICS ASSAYS WERE 6166 03:38:48,615 --> 03:38:52,385 PERFORMED AT DR. OLIVER FINN'S 6167 03:38:52,452 --> 03:38:54,254 METABOMIBG CENTER AT U.C. DAVIS 6168 03:38:54,321 --> 03:38:58,124 AND GENERATED DAY TAI FOR 935 6169 03:38:58,191 --> 03:39:02,162 ANNOTATED METABOLITES FROM FOUR 6170 03:39:02,229 --> 03:39:04,164 SEPARATE PANELS. 6171 03:39:04,231 --> 03:39:06,500 WE COMPARED LEVELS OF 6172 03:39:06,566 --> 03:39:08,768 METABOLITES FOR THE 6173 03:39:08,835 --> 03:39:09,970 DIFFERENCES -- THE BETWEEN-GROUP 6174 03:39:10,036 --> 03:39:11,671 DIFFERENCES AT TWO TIME POINTS, 6175 03:39:11,738 --> 03:39:14,407 AND ALSO THE WITHIN-GROUP 6176 03:39:14,474 --> 03:39:16,810 TRAJECTORIES IN CASES AND 6177 03:39:16,877 --> 03:39:17,711 CONTROLS, AS WELL AS 6178 03:39:17,777 --> 03:39:19,379 INTERACTIONS WHICH WILL INDICATE 6179 03:39:19,446 --> 03:39:23,617 A CROSSOVER EFFECT. 6180 03:39:23,683 --> 03:39:25,485 WE RECENTLY PUBLISHED A PAPER ON 6181 03:39:25,552 --> 03:39:28,321 THE UTILITY OF BAYESIAN 6182 03:39:28,388 --> 03:39:30,023 INFERENCE IN HUMAN ME TACK LOW 6183 03:39:30,090 --> 03:39:31,658 MIX DATA ANALYSIS AND SHOW THAT 6184 03:39:31,725 --> 03:39:33,326 EXHIBIT GRATING DATA FROM 6185 03:39:33,393 --> 03:39:35,529 SIMILAR STUDY DESIGN AS PRIOR 6186 03:39:35,595 --> 03:39:38,064 INFORMATION CAN SIGNIFICANTLY 6187 03:39:38,131 --> 03:39:39,366 IMPROVE THE INTERPRETABILITY. 6188 03:39:39,432 --> 03:39:44,004 AND, THEREFORE, WHERE REQUIRED 6189 03:39:44,070 --> 03:39:45,539 DATA -- INDEPENDENT STUDY WITH A 6190 03:39:45,605 --> 03:39:48,275 SIMILAR STUDY DESIGN FROM 6191 03:39:48,341 --> 03:39:49,910 CORNELL UNIVERSITY INDEED 6192 03:39:49,976 --> 03:39:51,211 DR. MAUREEN HANSON'S RECENT 6193 03:39:51,278 --> 03:39:54,814 PUBLICATION. 6194 03:39:54,881 --> 03:39:57,551 THE DIFFERENCE IS THEY CONDUCTED 6195 03:39:57,617 --> 03:40:00,287 TWO EXERCISE TESTS ON TWO 6196 03:40:00,353 --> 03:40:03,256 CONSECUTIVE DAYS, WHERE WE ONLY 6197 03:40:03,323 --> 03:40:05,325 CONDUCTED ONE EXERCISE TEST. 6198 03:40:05,392 --> 03:40:08,995 BUT OUR PRE-ETT TIME POINT 6199 03:40:09,062 --> 03:40:13,066 CORRESPONDED TO THEIR D1 PRE AND 6200 03:40:13,133 --> 03:40:16,202 OUR POST TIME POINT CORRESPONDED 6201 03:40:16,269 --> 03:40:19,539 TO THEIR D2 PRE. 6202 03:40:19,606 --> 03:40:21,074 MATCHING FOR METABOLITES WERE 6203 03:40:21,141 --> 03:40:22,809 NOT IDEAL. 6204 03:40:22,876 --> 03:40:24,144 ONLY 220 METABOLITES WERE 6205 03:40:24,210 --> 03:40:24,644 MATCHED. 6206 03:40:24,711 --> 03:40:26,680 BETWEEN THE TWO STUDIES, 6207 03:40:26,746 --> 03:40:28,882 INCLUDING 60% OF PRIMARY 6208 03:40:28,949 --> 03:40:34,955 METABOLITES IN OUR ASSAY, 37% OF 6209 03:40:35,021 --> 03:40:37,591 BIOGENIC AMINES. 6210 03:40:37,657 --> 03:40:41,328 THE LIPIDS AND OXYLIPINS WERE 6211 03:40:41,394 --> 03:40:42,495 PROTEIN MATCHED. 6212 03:40:42,562 --> 03:40:45,332 IT WAS STILL SUCCESSFULLY 6213 03:40:45,398 --> 03:40:46,232 PERFORMED, INTEGRATING CORNELL'S 6214 03:40:46,299 --> 03:40:50,337 DATA ON THIS 220 METABOLITES 6215 03:40:50,403 --> 03:40:53,940 MOSTLY ESSENTIAL COMPOUNDS. 6216 03:40:54,007 --> 03:40:56,142 SORE THE RESULTS, FIRST WE FOUND 6217 03:40:56,209 --> 03:41:02,849 ELEVATED LEVELS AT BOTH PRE AND 6218 03:41:02,916 --> 03:41:03,817 POST ETT TIME POINTS. 6219 03:41:03,883 --> 03:41:08,254 IT IS RECOGNIZED BY THE -- 6220 03:41:08,321 --> 03:41:10,724 ADJUST THE P VALUE AND BAYESIAN 6221 03:41:10,790 --> 03:41:11,992 ANALYSIS NOT INCLUDING DATA FROM 6222 03:41:12,058 --> 03:41:14,194 OTHER STUDIES AS WELL AS 6223 03:41:14,260 --> 03:41:17,163 COMBINED ANALYSIS INCORPORATING 6224 03:41:17,230 --> 03:41:17,697 DATA. 6225 03:41:17,764 --> 03:41:23,003 ALSO THE PLASMA LEVELS OF PRO WE 6226 03:41:23,069 --> 03:41:26,506 UPREGULATED AT THE POST-ETT TIME 6227 03:41:26,573 --> 03:41:30,310 POINT. 6228 03:41:30,377 --> 03:41:31,745 SO AROUND A QUARTER OF THE 6229 03:41:31,811 --> 03:41:34,648 RESIDENT BACTERIA SPECIES IN 6230 03:41:34,714 --> 03:41:40,420 HUMAN GUT PRODUCE BETA -- OF 6231 03:41:40,487 --> 03:41:42,088 CHRONIC ACID. 6232 03:41:42,155 --> 03:41:45,392 THE PROPIONIC ACID IS A SHORT 6233 03:41:45,458 --> 03:41:47,827 CHAIN FATTY ACID PRODUCED BY GUT 6234 03:41:47,894 --> 03:41:48,261 BACTERIA. 6235 03:41:48,328 --> 03:41:50,597 SO THESE DATA MAY PROVIDE ACTUAL 6236 03:41:50,664 --> 03:41:54,467 EVIDENCE OF THE GUT MICROBIOTA 6237 03:41:54,534 --> 03:42:02,442 DYSBIOSIS IN T IN ME/CFS PRESEND 6238 03:42:02,509 --> 03:42:03,009 PREVIOUSLY IN THE MORNING. 6239 03:42:03,076 --> 03:42:04,511 SO ONE OF THE KEY FINDINGS IN 6240 03:42:04,577 --> 03:42:06,146 THE METABOLOMICS ANALYSIS WE 6241 03:42:06,212 --> 03:42:10,884 FOUND IS IN THE LEVELS OF -- 6242 03:42:10,950 --> 03:42:11,217 ACID. 6243 03:42:11,284 --> 03:42:16,589 HERE THE LEVELS IN ME/CFS 6244 03:42:16,656 --> 03:42:17,991 DECREASED FROM BEFORE TO AFTER 6245 03:42:18,058 --> 03:42:20,026 EXERCISE WHERE THE LEVELS IN 6246 03:42:20,093 --> 03:42:23,296 CONTROLS -- NO, THE LEVELS IN 6247 03:42:23,363 --> 03:42:25,498 ME/CFS INCREASED FROM BEFORE TO 6248 03:42:25,565 --> 03:42:27,200 AFTER EXERCISE, WHILE THE LEVELS 6249 03:42:27,267 --> 03:42:29,803 AND CONTROLS MARGINALLY 6250 03:42:29,869 --> 03:42:30,770 DECREASED. 6251 03:42:30,837 --> 03:42:35,508 SO HERE WE HAVE THE LEVELS OF 6252 03:42:35,575 --> 03:42:36,309 PHOSPHATE DECREASED FROM BEFORE 6253 03:42:36,376 --> 03:42:39,012 TO AFTER EXERCISE IN HEALTHY 6254 03:42:39,079 --> 03:42:43,283 CONTROLS, BUT NO CHANGE IN THE 6255 03:42:43,349 --> 03:42:43,616 ME/CFS. 6256 03:42:43,683 --> 03:42:45,618 SO THIS DATA TOGETHER SHOWS THAT 6257 03:42:45,685 --> 03:42:50,323 THE FIRST CONTROLS ARE UTILIZ 6258 03:42:50,390 --> 03:42:53,359 UTILIZING - CITRIC ACID TO PRODE 6259 03:42:53,426 --> 03:42:55,228 MOLECULES, WHILE THIS PUNKS IS 6260 03:42:55,295 --> 03:42:56,896 IMPAIRED LEADING TO ACCUMULATION 6261 03:42:56,963 --> 03:42:59,966 OF SUCH AN ACID. 6262 03:43:00,033 --> 03:43:02,168 THE PHOSPHATE DYSREGULATION MAY 6263 03:43:02,235 --> 03:43:05,004 HAVE MANY IMPLICATIONS BUT MOST 6264 03:43:05,071 --> 03:43:06,639 ARE INVOLVED IN ENERGY 6265 03:43:06,706 --> 03:43:07,674 METABOLISM, INCLUDING GENERATION 6266 03:43:07,741 --> 03:43:10,310 AND CONSUMPTION OF ATP MOLECULES 6267 03:43:10,376 --> 03:43:13,346 AND THE GLYCOLYSIS AND OXIDATIVE 6268 03:43:13,413 --> 03:43:17,016 PHOSPHORYLATION. 6269 03:43:17,083 --> 03:43:20,386 WE ALSO FOUND DYSREGULATION IN 6270 03:43:20,453 --> 03:43:24,224 THE RATIOS WHERE THEY WERE 6271 03:43:24,290 --> 03:43:31,264 ELEVATED IN ME/CFS BUT DECREASED 6272 03:43:31,331 --> 03:43:32,565 IN RESPONSE TO ETT. 6273 03:43:32,632 --> 03:43:34,134 THIS IS A KEY INDEX TO ASSESS 6274 03:43:34,200 --> 03:43:37,237 THE METABOLIC ACTIVITY IN THE 6275 03:43:37,303 --> 03:43:38,438 UREA CYCLE. 6276 03:43:38,505 --> 03:43:44,444 A JAPANESE STUDY -- IT ALSO 6277 03:43:44,511 --> 03:43:45,712 CONNECTS WITH THE ENERGY 6278 03:43:45,779 --> 03:43:47,580 METABOLISM BY SHARING SOME 6279 03:43:47,647 --> 03:43:52,485 INTERMEDIATES WITH THE TC CYCLE. 6280 03:43:52,552 --> 03:43:54,587 THEY ALSO FOUND EVIDENCE OF THE 6281 03:43:54,654 --> 03:43:57,991 IMPAIRED UREA CYCLE IN PLASMA 6282 03:43:58,057 --> 03:44:00,627 AND URA METABOLOMICS. 6283 03:44:00,693 --> 03:44:07,901 ANOTHER RATIO WAS DOWN REGULATEE 6284 03:44:07,967 --> 03:44:09,435 BUT INCREASED IN RESPONSE TO 6285 03:44:09,502 --> 03:44:10,336 EXERCISE. 6286 03:44:10,403 --> 03:44:14,574 AND THAT INDICATES ABNORMALITIES 6287 03:44:14,641 --> 03:44:16,376 IN THE PATHWAY AND TRYPTOPHAN 6288 03:44:16,442 --> 03:44:17,076 METABOLISM. 6289 03:44:17,143 --> 03:44:19,746 AND THAT CAN INFLUENCE 6290 03:44:19,813 --> 03:44:20,947 MITOCHONDRIAL FUNCTIONING AND 6291 03:44:21,014 --> 03:44:24,050 ALSO INDUCE COGNITIVE IMPAIRMENT 6292 03:44:24,117 --> 03:44:26,352 IN ADDITION, THERE ARE ALSO 6293 03:44:26,419 --> 03:44:31,291 LINKS TO INFLAMMATION. 6294 03:44:31,357 --> 03:44:33,426 THE CHEMICAL ENRICHMENT ANALYSIS 6295 03:44:33,493 --> 03:44:35,061 ALSO REVEALED SOME ALTERED 6296 03:44:35,128 --> 03:44:38,431 CHEMICAL CLUSTERS. 6297 03:44:38,498 --> 03:44:41,868 FIRST, DERIVED FROM ACIDS, AND 6298 03:44:41,935 --> 03:44:43,636 FUNCTION AS INFLAMMATORY 6299 03:44:43,703 --> 03:44:46,172 REGULATORS WERE REDUCED IN 6300 03:44:46,239 --> 03:44:48,041 ME/CFS BEFORE EXERCISE. 6301 03:44:48,107 --> 03:44:51,444 AND TERPENES, MAINLY THE 6302 03:44:51,511 --> 03:44:53,513 ANTI-INFLAMMATORY LINALOU WERE 6303 03:44:53,580 --> 03:45:03,857 ALSO DOWN THE -- IN ME/CFS. 6304 03:45:03,923 --> 03:45:05,725 NEXT, ELEVATED IN ME/CFS BEFORE 6305 03:45:05,792 --> 03:45:08,461 AND AFTER EXERCISE AND 6306 03:45:08,528 --> 03:45:09,863 ELEVATIONS WERE MORE SIGNIFICANT 6307 03:45:09,929 --> 03:45:12,198 AT A POST-ETT TIME POINT. 6308 03:45:12,265 --> 03:45:13,399 THESE COMPOUNDS ARE LIPIDS THAT 6309 03:45:13,466 --> 03:45:16,603 SERVE AS ENERGY SOURCE THAT CAN 6310 03:45:16,669 --> 03:45:18,605 RELEASE FREE FATTY ACIDS. 6311 03:45:18,671 --> 03:45:23,076 THE ELEVATIONS CAN ALSO 6312 03:45:23,142 --> 03:45:24,611 CONTRIBUTE TO ELEVATION. 6313 03:45:24,677 --> 03:45:25,879 LASTLY, LEVELS OF CARNITINES 6314 03:45:25,945 --> 03:45:28,381 WERE REDUCED IN ME/CFS AFTER 6315 03:45:28,448 --> 03:45:29,048 EXERCISE. 6316 03:45:29,115 --> 03:45:31,117 CARNITINES ARE CRITICAL BECAUSE 6317 03:45:31,184 --> 03:45:32,485 THEY'RE RESPONSIBLE FOR THE 6318 03:45:32,552 --> 03:45:33,920 TRANSPORTATION OF FREE FATTY 6319 03:45:33,987 --> 03:45:37,523 ACIDS INTO MITOCHONDRIA FOR 6320 03:45:37,590 --> 03:45:41,995 LATER OXIDATION. 6321 03:45:42,061 --> 03:45:44,163 WE ALSO FOUND SOME UNIQUE 6322 03:45:44,230 --> 03:45:45,665 METABOLIC PHENOTYPES IN 6323 03:45:45,732 --> 03:45:47,433 SUBGROUPS OF ME/CFS. 6324 03:45:47,500 --> 03:45:48,635 IN PATIENTS WITH LESS THAN THREE 6325 03:45:48,701 --> 03:45:50,003 YEARS OF ILLNESS DURATION, A 6326 03:45:50,069 --> 03:45:55,241 GROUP OF POS FOE LIPIDS, WERE 6327 03:45:55,308 --> 03:45:59,312 EITHER ELEVATED AFTER EXERCISE 6328 03:45:59,379 --> 03:46:00,546 OR INCREASED FROM BEFORE TO 6329 03:46:00,613 --> 03:46:05,351 AFTER EXERCISE. 6330 03:46:05,418 --> 03:46:09,289 SO THEIR DYSREGULATIONS WILL 6331 03:46:09,355 --> 03:46:10,256 INDICATE PEROXISOMAL 6332 03:46:10,323 --> 03:46:11,090 DYSFUNCTION. 6333 03:46:11,157 --> 03:46:15,762 ALSO THE CROSSTALK BETWEEN THEM 6334 03:46:15,828 --> 03:46:17,430 IS CRITICAL FOR MAINTAINING THE 6335 03:46:17,497 --> 03:46:20,934 ENERGY HOMEOSTASIS. 6336 03:46:21,000 --> 03:46:26,773 WE FIRST REVIEWED PEROXISOMAL 6337 03:46:26,839 --> 03:46:35,882 DYSFUNCTIONS IN -- ABUNDANT 6338 03:46:35,949 --> 03:46:38,418 NUMBER OF LIPID MEDIATORS WERE 6339 03:46:38,484 --> 03:46:42,021 ALL REDUCED IN FEMALE ME/CFS 6340 03:46:42,088 --> 03:46:44,090 PATIENTS YOUNGER THAN 45 6341 03:46:44,157 --> 03:46:46,559 COMPARED TO THEIR CORRESPONDING 6342 03:46:46,626 --> 03:46:46,859 CONTROLS. 6343 03:46:46,926 --> 03:46:49,195 SO DR. LIPKIN PRESENTED DATA 6344 03:46:49,262 --> 03:46:50,797 FROM THE TRUE CULTURE ASSAY IN 6345 03:46:50,863 --> 03:46:54,133 THE SAME COHORT THAT SHOW THAT 6346 03:46:54,200 --> 03:46:57,904 CYTOKINE RESPONSE ENTEROTOXIN 6347 03:46:57,971 --> 03:47:06,646 TYPE B WERE ELEVATED IN FEMALE 6348 03:47:06,713 --> 03:47:08,915 M.E. CFS AND CORRELATE WITH 6349 03:47:08,982 --> 03:47:09,582 ESTRADIOL LEVELS. 6350 03:47:09,649 --> 03:47:10,883 HERE WE FOUND FURTHER EVIDENCE 6351 03:47:10,950 --> 03:47:13,086 THAT AGE IS AN IMPORTANT FACTOR 6352 03:47:13,152 --> 03:47:15,254 THAT MAY CONTRIBUTE TO THE 6353 03:47:15,321 --> 03:47:18,491 SUBGROUPS OF ME/CFS, AT LEAST IN 6354 03:47:18,558 --> 03:47:19,025 FEMALES. 6355 03:47:19,092 --> 03:47:20,593 AND THESE SUBGROUPS HAVE UNIQUE 6356 03:47:20,660 --> 03:47:21,995 IMMUNE AND INFLAMMATORY 6357 03:47:22,061 --> 03:47:24,097 PROFILES. 6358 03:47:24,163 --> 03:47:25,765 AND WE HAVE MORE PROFOUND 6359 03:47:25,832 --> 03:47:27,100 EVIDENCE IN THE PLASMA 6360 03:47:27,166 --> 03:47:30,036 PROTEOMICS THAT SUPPORT THIS 6361 03:47:30,103 --> 03:47:32,939 SUBGROUPING. 6362 03:47:33,006 --> 03:47:37,710 SO TO SUM UP, WE KER CHARACTERIE 6363 03:47:37,777 --> 03:47:40,680 THE METABOLIC PROFILES IN ME/CFS 6364 03:47:40,747 --> 03:47:42,315 FOLLOWING EXERCISE TOLERANCE 6365 03:47:42,382 --> 03:47:47,220 TEST SHOWS ABNORMALITY IN THE -- 6366 03:47:47,286 --> 03:47:49,589 THE KI CHIMERA PATHWAY WAS ALSO 6367 03:47:49,655 --> 03:47:52,759 IMPAIRED AND CAN COMPROMISE 6368 03:47:52,825 --> 03:47:54,093 COGNITIVE FUNCTIONING. 6369 03:47:54,160 --> 03:47:55,795 CARNITINES WERE DEPLETED IN 6370 03:47:55,862 --> 03:47:57,997 ME/CFS AFTER EXERCISE, WHICH 6371 03:47:58,064 --> 03:48:00,433 INDICATE A LOSS OF CAPABILITY OF 6372 03:48:00,500 --> 03:48:02,835 TRANSPORTING FREE FATTY ACIDS 6373 03:48:02,902 --> 03:48:05,371 INTO MITOCHONDRIA FOR BETA 6374 03:48:05,438 --> 03:48:06,639 OXIDATION. 6375 03:48:06,706 --> 03:48:10,676 TRIGLYCERIDES AND DIGLIS RIDES S 6376 03:48:10,743 --> 03:48:12,478 ARE RESPONSIBLE FOR RELEASING 6377 03:48:12,545 --> 03:48:14,781 THESE FREE FATTY ACIDS AND THEY 6378 03:48:14,847 --> 03:48:23,322 WERE UPREGULATED IN ME/CFS. 6379 03:48:23,389 --> 03:48:28,628 TOGETHER THEY FORM A EXR 6380 03:48:28,694 --> 03:48:29,195 COMPREHENSIVE MODEL. 6381 03:48:29,262 --> 03:48:30,696 WE WILL INCORPORATE THE 6382 03:48:30,763 --> 03:48:32,331 PROTEOMICS DATA GENERATED FROM 6383 03:48:32,398 --> 03:48:35,268 THE SEROLOGIC PANEL FOR OUR 6384 03:48:35,334 --> 03:48:38,538 UPCOMING PUBLICATION. 6385 03:48:38,604 --> 03:48:41,107 AND OUR CENTER WILL ALSO 6386 03:48:41,174 --> 03:48:42,875 CONTRIBUTE TO IT. 6387 03:48:42,942 --> 03:48:45,244 SO LASTLY, THE WORK WAS FUNDED 6388 03:48:45,311 --> 03:48:46,679 BY NIH AND CHRONIC FATIGUE 6389 03:48:46,746 --> 03:48:47,013 INITIATIVE. 6390 03:48:47,080 --> 03:48:50,349 I WANT TO ACKNOWLEDGE DR. OLIVER 6391 03:48:50,416 --> 03:48:53,686 FINN'S GROUP AT U.C. DAVIS FOR 6392 03:48:53,753 --> 03:48:55,888 THE PERFORMANCE OF THE 6393 03:48:55,955 --> 03:48:56,756 METABOLOMICS ANALYSIS AND 6394 03:48:56,823 --> 03:49:00,793 SPECIAL THANKS TO THE DOCTORS 6395 03:49:00,860 --> 03:49:04,997 FOR SHARING THEIR DATA WITH US 6396 03:49:05,064 --> 03:49:07,333 FOR THE BAYESIAN ANALYSIS. 6397 03:49:07,400 --> 03:49:07,633 THANK YOU. 6398 03:49:07,700 --> 03:49:17,877 [APPLAUSE] 6399 03:49:22,014 --> 03:49:25,084 >> OUR NEXT SPEAKER IS JESSICA 6400 03:49:25,151 --> 03:49:26,519 MAYA FROM CORNELL, WHO'S GOING 6401 03:49:26,586 --> 03:49:27,854 TO TELL US ABOUT INVESTIGATING 6402 03:49:27,920 --> 03:49:30,056 T-CELL POPULATIONS FOR IMMUNE 6403 03:49:30,123 --> 03:49:40,600 CELL DYSFUNCTION IN ME/CFS. 6404 03:50:12,131 --> 03:50:13,266 >> THANK YOU SO MUCH FOR 6405 03:50:13,332 --> 03:50:15,768 INVITING ME TO BE HERE AND 6406 03:50:15,835 --> 03:50:18,070 PRESENTING MY WORK. 6407 03:50:18,137 --> 03:50:20,773 I'LL GO AHEAD AND GET STARTED. 6408 03:50:20,840 --> 03:50:23,176 SO TO BEGIN, I'LL INTRODUCE THE 6409 03:50:23,242 --> 03:50:24,377 IMMUNE CELL POPULATIONS UNDER 6410 03:50:24,443 --> 03:50:26,746 INVESTIGATION IN MY STUDY, WHERE 6411 03:50:26,812 --> 03:50:28,047 IN YOUR BLOOD, YOU HAVE YOUR 6412 03:50:28,114 --> 03:50:29,715 WHITE BLOOD CELLS THAT CONTAIN 6413 03:50:29,782 --> 03:50:32,752 YOUR IMMUNE CELLS LIKE 6414 03:50:32,818 --> 03:50:39,258 PERIPHERAL BLOOD CELLS. 6415 03:50:39,325 --> 03:50:40,359 THIS CONTAINS THE CELLS I WORK 6416 03:50:40,426 --> 03:50:40,726 WITH. 6417 03:50:40,793 --> 03:50:45,565 IN PARTICULAR, THIS INCLUDES CDR 6418 03:50:45,631 --> 03:50:49,001 CYTOTOXIC T CELLS AS WELL AS CD. 6419 03:50:49,068 --> 03:50:51,204 NOW THESE T CELLS CAN BE FURTHER 6420 03:50:51,270 --> 03:50:53,839 DIVIDED INTO THEIR STAGE OF 6421 03:50:53,906 --> 03:50:55,241 DIFFERENTIATION, SUCH ACINI EVE 6422 03:50:55,308 --> 03:50:58,277 CELLS THAT SURVEY THE BODY FOR 6423 03:50:58,344 --> 03:50:59,812 INFECTIONS, THE POST INFECTION 6424 03:50:59,879 --> 03:51:01,581 EFFECTOR OR HELPER CELLS THAT 6425 03:51:01,647 --> 03:51:04,050 CAN BE CYTOTOXIC, AND THEN 6426 03:51:04,116 --> 03:51:07,420 FINALLY MEMORY CELLS THAT STICK 6427 03:51:07,486 --> 03:51:09,488 AROUND, PROTECT THE BODY IF 6428 03:51:09,555 --> 03:51:12,725 THESE CELLS REENCOUNTER THAT 6429 03:51:12,792 --> 03:51:15,461 INFECTION LATER ON. 6430 03:51:15,528 --> 03:51:17,830 OFTEN EXAMINED PBMCs 6431 03:51:17,897 --> 03:51:19,298 COLLECTIVELY BUT CONSIDERING THE 6432 03:51:19,365 --> 03:51:20,566 DIVERSE CELL TYPES WITHIN THIS 6433 03:51:20,633 --> 03:51:22,101 GROUP, EACH WITH UNIQUE 6434 03:51:22,168 --> 03:51:23,402 METABOLISMS, FUNCTIONS AND 6435 03:51:23,469 --> 03:51:26,539 CYTOKINE PREFERENCES, IT'S 6436 03:51:26,606 --> 03:51:27,974 CRUCIAL TO ISOLATE IMMUNE CELLS 6437 03:51:28,040 --> 03:51:29,175 TO SUBSETS FOR ACCURATE 6438 03:51:29,242 --> 03:51:30,109 IDENTIFICATION OF ANY 6439 03:51:30,176 --> 03:51:31,510 ABNORMALITIES. 6440 03:51:31,577 --> 03:51:32,745 OTHERWISE CHANGES COULD BE 6441 03:51:32,812 --> 03:51:33,913 OBSCURED WHEN LOOKING AT THE 6442 03:51:33,980 --> 03:51:38,050 ENTIRE CELL POPULATION. 6443 03:51:38,117 --> 03:51:40,553 NOW PREVIOUSLY WE'VE SHOWN THAT 6444 03:51:40,620 --> 03:51:42,622 ME/CFS SITE TOXIC CD8 T CELLS 6445 03:51:42,688 --> 03:51:45,858 HAVE DECREASED GLYCOLYSIS, 6446 03:51:45,925 --> 03:51:49,128 DECREASED MITOCHONDRIAL MEMBRANE 6447 03:51:49,195 --> 03:51:50,896 POTENTIAL AS WELL AS 6448 03:51:50,963 --> 03:51:51,964 INCREASED -- IN IMMUNOLOGY 6449 03:51:52,031 --> 03:51:52,932 THERE'S MORE LIGHT BEING SHED ON 6450 03:51:52,999 --> 03:51:54,800 THE IMPORTANCE OF METABOLISM AS 6451 03:51:54,867 --> 03:51:57,069 WELL AS FUEL USAGE IN THESE CELL 6452 03:51:57,136 --> 03:51:58,304 TYPES SO THAT THEY CAN FUNCTION 6453 03:51:58,371 --> 03:51:59,372 PROPERLY. 6454 03:51:59,438 --> 03:52:01,941 AND BY FUNCTION, I MEAN HOW 6455 03:52:02,008 --> 03:52:03,376 RESPONSIVE ARE THEY TO 6456 03:52:03,442 --> 03:52:04,510 INFECTIONS, AND HOW WELL CAN 6457 03:52:04,577 --> 03:52:05,811 THEY FIGHT OFF ANY IMMUNE 6458 03:52:05,878 --> 03:52:07,246 CHALLENGES. 6459 03:52:07,313 --> 03:52:09,215 AND WHILE THIS WORK IS NOT THE 6460 03:52:09,282 --> 03:52:11,651 FOCUS OF TODAY'S TALK, THESE 6461 03:52:11,717 --> 03:52:13,386 METABOLIC CHANGES DID LEAD ME TO 6462 03:52:13,452 --> 03:52:14,887 INVESTIGATE WHAT THESE 6463 03:52:14,954 --> 03:52:16,322 ABNORMALITIES COULD TELL US 6464 03:52:16,389 --> 03:52:18,691 ABOUT ME/CFS T-CELL FUNCTION. 6465 03:52:18,758 --> 03:52:19,992 SPECIFICALLY, A PHENOMENON 6466 03:52:20,059 --> 03:52:23,029 CALLED T-CELL EXHAUSTION. 6467 03:52:23,095 --> 03:52:24,563 AND SO NORMALLY WHEN A T-CELL -- 6468 03:52:24,630 --> 03:52:26,098 WHEN A CELL ENCOUNTERS AN 6469 03:52:26,165 --> 03:52:28,901 INFECTED CELL, IT WILL ENGAGE 6470 03:52:28,968 --> 03:52:29,568 COSTIMULATORY RECEPTORS TO BEGIN 6471 03:52:29,635 --> 03:52:31,203 A SIGNALING CASCADE FOR EFFECTOR 6472 03:52:31,270 --> 03:52:32,638 FUNCTION. 6473 03:52:32,705 --> 03:52:34,640 HOWEVER, WHEN PD-1, WHICH IS A 6474 03:52:34,707 --> 03:52:36,075 MAJOR REGULATOR OF T-CELL 6475 03:52:36,142 --> 03:52:39,211 EXHAUSTION, IS ENGAGED ON A CELL 6476 03:52:39,278 --> 03:52:40,946 SURFACE, ITS SIGNALING WILL 6477 03:52:41,013 --> 03:52:41,881 DEPHOSPHORYLATE EFFECTOR 6478 03:52:41,947 --> 03:52:44,116 MOLECULES AND AS A RESULT, CAUSE 6479 03:52:44,183 --> 03:52:45,718 A DECREASE IN T-CELL 6480 03:52:45,785 --> 03:52:47,253 PROLIFERATION, SURVIVAL, 6481 03:52:47,320 --> 03:52:49,455 CYTOKINE PRODUCTION, AND PROTEIN 6482 03:52:49,522 --> 03:52:50,256 SYNTHESIS. 6483 03:52:50,323 --> 03:52:53,259 AND NOTABLY METABOLICALLY, 6484 03:52:53,326 --> 03:52:54,427 EXHAUSTED T CELLS ARE 6485 03:52:54,493 --> 03:52:55,728 CHARACTERIZED BY THE SAME 6486 03:52:55,795 --> 03:52:57,997 DYNAMICS THAT WE'VE REPORTED IN 6487 03:52:58,064 --> 03:53:02,268 ME/CFS T CELLS. 6488 03:53:02,335 --> 03:53:04,670 HOWEVER, IDENTIFYING AND 6489 03:53:04,737 --> 03:53:06,605 CONFIRMING AN EXHAUSTED STAY IN 6490 03:53:06,672 --> 03:53:07,573 ME/CFS HAS BEEN CHALLENGING DUE 6491 03:53:07,640 --> 03:53:09,108 TO LIMITATIONS IN SAMPLE 6492 03:53:09,175 --> 03:53:10,343 COLLECTION AS WELL AS VIRUS 6493 03:53:10,409 --> 03:53:12,044 SPECIFICITY. 6494 03:53:12,111 --> 03:53:13,512 HOWEVER, A NOTABLE STUDY FROM 6495 03:53:13,579 --> 03:53:15,815 2020 ELEGANTLY CHARACTERIZED 6496 03:53:15,881 --> 03:53:17,683 T-CELL EXHAUSTION INTO FOUR 6497 03:53:17,750 --> 03:53:19,618 DISTINCT DIFFERENTIATION STAGES. 6498 03:53:19,685 --> 03:53:21,687 STARTING WITH TWO PROGENITOR 6499 03:53:21,754 --> 03:53:22,455 STAGES. 6500 03:53:22,521 --> 03:53:24,557 NEXT DIFFERENTIATING INTO AN 6501 03:53:24,623 --> 03:53:25,691 INTERMEDIATE EXHAUSTIVE STATE, 6502 03:53:25,758 --> 03:53:27,393 AND THEN FINALLY DIFFERENTIATING 6503 03:53:27,460 --> 03:53:28,828 TO A TERMINAL STAGE. 6504 03:53:28,894 --> 03:53:30,262 NOW THE RESEARCHERS 6505 03:53:30,329 --> 03:53:31,564 CHARACTERIZED THESE PD-1 6506 03:53:31,630 --> 03:53:32,998 POSITIVE CELLS THAT WERE 6507 03:53:33,065 --> 03:53:34,200 EXHAUSTED BASED ON THE PRESENCE 6508 03:53:34,266 --> 03:53:37,470 OR ABSENCE OF MARKERS SUCH AS 6509 03:53:37,536 --> 03:53:40,206 CD69, AS WELL AS TRANSCRIPTION 6510 03:53:40,272 --> 03:53:44,310 FACTORS LIKE TOX, T-BET, TCF1. 6511 03:53:44,377 --> 03:53:46,846 DWTWO OF THESE STAGES ARE SPECIC 6512 03:53:46,912 --> 03:53:47,813 TO CIRCULATING CELLS WHICH IS 6513 03:53:47,880 --> 03:53:49,415 WHAT I WORK WITH, AND THEY HAVE 6514 03:53:49,482 --> 03:53:51,150 DISTINCT FEATURES COMPARED TO 6515 03:53:51,217 --> 03:53:53,119 HEALTHY, NON-EXHAUSTED PD-1 6516 03:53:53,185 --> 03:53:55,087 POSITIVE CELLS. 6517 03:53:55,154 --> 03:53:56,389 SO THIS CELL PHENOTYPING IS PART 6518 03:53:56,455 --> 03:53:58,557 OF THE BASIS OF MY STUDY TO THEN 6519 03:53:58,624 --> 03:54:01,761 ANSWER THE QUESTION, ARE ME/CFS 6520 03:54:01,827 --> 03:54:04,330 T CELLS IN AN EXHAUSTED STATE? 6521 03:54:04,397 --> 03:54:06,632 AND SO FOR THE STUDY, WE HAVE 15 6522 03:54:06,699 --> 03:54:08,467 PATIENTS AND 14 AGE MATCHED 6523 03:54:08,534 --> 03:54:10,636 HEALTHY SEDENTARY CONTROL 6524 03:54:10,703 --> 03:54:11,704 FEMALES, WHERE PATIENT ILLNESS 6525 03:54:11,771 --> 03:54:13,839 DURATION VARIED FROM 2 TO 30 6526 03:54:13,906 --> 03:54:15,941 YEARS, AND PARTICIPANTS PROVIDED 6527 03:54:16,008 --> 03:54:18,010 DETAILS ON THEIR ME/CFS 6528 03:54:18,077 --> 03:54:18,878 PRESENTATION AS WELL AS SYMPTOM 6529 03:54:18,944 --> 03:54:19,311 SEVERITY. 6530 03:54:19,378 --> 03:54:21,714 SO FOR EXAMPLE, THE LOWER BELL 6531 03:54:21,781 --> 03:54:23,015 ACTIVITY SCALE YOU SEE AT THE 6532 03:54:23,082 --> 03:54:25,551 BOTTOM IN THE PATIENT COHORT 6533 03:54:25,618 --> 03:54:26,952 HIGHLIGHTS MORE SEVERE HEALTH 6534 03:54:27,019 --> 03:54:28,320 IMPAIRMENTS COMPARED TO THE 6535 03:54:28,387 --> 03:54:30,289 HEALTHY CONTROL COHORT. 6536 03:54:30,356 --> 03:54:31,624 NOW OUR STUDY IS ALSO UNIQUE 6537 03:54:31,690 --> 03:54:32,925 BECAUSE WE ALSO ASKED ALL 6538 03:54:32,992 --> 03:54:35,394 PARTICIPANTS TO PERFORM THE 6539 03:54:35,461 --> 03:54:37,129 TWO-DAY CARDIOPULMONARY EXERCISE 6540 03:54:37,196 --> 03:54:38,130 TEST THAT WAS JUST MENTIONED IN 6541 03:54:38,197 --> 03:54:40,065 THE LAST TALK, AND THIS IS 6542 03:54:40,132 --> 03:54:41,901 TYPICALLY USED AS A DIAGNOSTIC 6543 03:54:41,967 --> 03:54:45,738 TOOL TO INDUCE THE HALLMARK POST 6544 03:54:45,805 --> 03:54:47,006 EXERTIONAL MALAISE STATE IN 6545 03:54:47,072 --> 03:54:47,807 INDIVIDUALS WITH ME/CFS. 6546 03:54:47,873 --> 03:54:49,642 AND SO THIS WAS ALSO DONE IN 6547 03:54:49,708 --> 03:54:51,076 THIS ATTEMPT TO KIND OF 6548 03:54:51,143 --> 03:54:53,446 STANDARDIZE OUR DISEASE STAILT N 6549 03:54:53,512 --> 03:54:55,214 OUR COHORT, SO WE COLLECTED 6550 03:54:55,281 --> 03:54:57,183 WHOLE BLOOD FOLLOWING THE 6551 03:54:57,249 --> 03:54:58,818 TWO-DAY CPE IT THE AND FROM 6552 03:54:58,884 --> 03:55:01,454 THERE ISOLATED PBMCs TO USE 6553 03:55:01,520 --> 03:55:03,823 MAGNETIC BEAD ISOLATION TO 6554 03:55:03,889 --> 03:55:05,391 SEPARATE OUT CD8 POSITIVE T 6555 03:55:05,458 --> 03:55:05,791 CELLS. 6556 03:55:05,858 --> 03:55:07,960 FROM THERE I EMPLOYED FLOW 6557 03:55:08,027 --> 03:55:09,829 CYTOMETRY TO ASSESS MARKERS 6558 03:55:09,895 --> 03:55:12,965 LINKED TO THE PHENOTYPES I 6559 03:55:13,032 --> 03:55:16,235 MENTIONED EARLIER, AND I ALSO 6560 03:55:16,302 --> 03:55:17,670 EXAMINED TRANSCRIPTION FACTORS 6561 03:55:17,736 --> 03:55:18,971 SUCH AS TOX, WHICH IS KNOWN TO 6562 03:55:19,038 --> 03:55:20,806 DRIVE T-CELL EXHAUSTION IN THE 6563 03:55:20,873 --> 03:55:25,077 CONTEXT OF PD-1 POSITIVE CELLS, 6564 03:55:25,144 --> 03:55:27,346 AS WELL AS TCF1 WHICH SUPPORTS 6565 03:55:27,413 --> 03:55:28,547 THE PROGENITOR STATE IN 6566 03:55:28,614 --> 03:55:29,748 CIRCULATING T-CELL EXHAUSTION, 6567 03:55:29,815 --> 03:55:31,684 AND THEN TBET, WHICH AGAIN IN 6568 03:55:31,750 --> 03:55:33,886 THE CONTEXT OF AN EXHAUSTED 6569 03:55:33,953 --> 03:55:35,654 T-CELL STATE CAN MAINTAIN A 6570 03:55:35,721 --> 03:55:38,357 BALANCE AMONG VARIOUS T-CELL 6571 03:55:38,424 --> 03:55:39,625 EXHAUSTED STAGES IN TISSUES 6572 03:55:39,692 --> 03:55:40,860 VERSUS CIRCULATION, AND ALSO 6573 03:55:40,926 --> 03:55:44,663 REGULATES THIS TRANSITION FROM 6574 03:55:44,730 --> 03:55:47,299 INTERMEDIATE TO LATE STAGES OF 6575 03:55:47,366 --> 03:55:47,900 EXHAUSTION. 6576 03:55:47,967 --> 03:55:49,101 AND SO HERE I'M SHOWING YOU THE 6577 03:55:49,168 --> 03:55:50,536 GATING STRATEGY USED TO DETECT 6578 03:55:50,603 --> 03:55:53,439 THESE EXHAUSTION MARKERS WHERE I 6579 03:55:53,506 --> 03:55:54,540 ANALYZED THESE MARKERS FOR THE 6580 03:55:54,607 --> 03:55:55,407 FREQUENCY OF POSITIVE 6581 03:55:55,474 --> 03:55:56,809 POPULATIONS IN TOTAL CELLS. 6582 03:55:56,876 --> 03:55:58,244 INDICATED BY THE BLACK BAR FOR 6583 03:55:58,310 --> 03:55:59,011 EACH MARKER. 6584 03:55:59,078 --> 03:56:02,081 AND NOW WITHIN THE PD-1 POSITIVE 6585 03:56:02,147 --> 03:56:04,416 CELLS, I AGAIN LOOKED AT ALL 6586 03:56:04,483 --> 03:56:06,852 THESE MARKERS SINCE WE'VE SEEN 6587 03:56:06,919 --> 03:56:07,653 TRANSCRIPTION FACTORS ARE 6588 03:56:07,720 --> 03:56:09,355 DISTINCT IN PD-1 POSITIVE 6589 03:56:09,421 --> 03:56:10,756 EXHAUSTED T CELLS COMPARED TO 6590 03:56:10,823 --> 03:56:12,391 PD-1 POSITIVE NORMAL HEALTHY 6591 03:56:12,458 --> 03:56:13,826 CELLS. 6592 03:56:13,893 --> 03:56:16,629 AND IT'S WITHIN THESE PD-1 6593 03:56:16,695 --> 03:56:17,496 POSITIVE CELLS THAT I THEN 6594 03:56:17,563 --> 03:56:19,265 DEFINE THE TWO EXHAUSTED 6595 03:56:19,331 --> 03:56:21,767 PHENOTYPES I CAN DETECT IN 6596 03:56:21,834 --> 03:56:23,702 CIRCULATION. 6597 03:56:23,769 --> 03:56:25,137 SO THEN FINALLY, I ALSO LOOKED 6598 03:56:25,204 --> 03:56:28,707 AT ALL OF THESE MARKERS AND 6599 03:56:28,774 --> 03:56:31,544 PHENOTYPES WITHIN SUBSETS OF 6600 03:56:31,610 --> 03:56:33,078 POPULATIONS TO IDENTIFY ANY 6601 03:56:33,145 --> 03:56:34,380 SUBPOPULATIONS WITH ALTERED 6602 03:56:34,446 --> 03:56:35,915 FREQUENCIES OF THESE INHIBITORY 6603 03:56:35,981 --> 03:56:36,782 RECEPTORS OR TRANSCRIPTION 6604 03:56:36,849 --> 03:56:38,083 FACTORS THAT WERE OTHERWISE 6605 03:56:38,150 --> 03:56:39,818 CONCEALED WITHIN OVERALL 6606 03:56:39,885 --> 03:56:43,322 CD8 T-CELL POPULATION ANALYSES. 6607 03:56:43,389 --> 03:56:44,857 THIS IS ALSO TO IDENTIFY ANY 6608 03:56:44,924 --> 03:56:47,059 SPECIFIC SUBSETS RESPONSIBLE FOR 6609 03:56:47,126 --> 03:56:49,895 OVERALL T-CELL CHANGES. 6610 03:56:49,962 --> 03:56:52,064 SO NOW STARTING WITH TOTAL 6611 03:56:52,131 --> 03:56:52,998 CD8 POSITIVE T CELLS, I SAW NO 6612 03:56:53,065 --> 03:56:53,766 DIFFERENCE IN THE TOTAL 6613 03:56:53,832 --> 03:56:54,900 FREQUENCY OF THE HALLMARK 6614 03:56:54,967 --> 03:56:56,735 EXHAUSTION MARKER PD-1, BETWEEN 6615 03:56:56,802 --> 03:56:58,337 PATIENTS AND CONTROLS FOLLOWING 6616 03:56:58,404 --> 03:57:00,205 THE TWO-DAY CPET. 6617 03:57:00,272 --> 03:57:04,043 BUT ONCE I ANALYZED CD1 POSITIVE 6618 03:57:04,109 --> 03:57:05,811 T CELLS I BEGAN TO NOTICE THE 6619 03:57:05,878 --> 03:57:07,413 DIFFERENCES. 6620 03:57:07,479 --> 03:57:09,481 SPECIFICALLY THIS ASSAY SHO 6621 03:57:09,548 --> 03:57:12,017 SHOWED -- IN TOTAL CD8 T CELLS 6622 03:57:12,084 --> 03:57:13,118 OF ME/CFS PATIENTS COMPARED TO 6623 03:57:13,185 --> 03:57:14,687 HEALTHY CONTROLS. 6624 03:57:14,753 --> 03:57:17,990 I WAS ALSO ABLE TO DETECT THE 6625 03:57:18,057 --> 03:57:19,959 RELATED CIRCULATING PROGENITOR 6626 03:57:20,025 --> 03:57:21,660 EXHAUSTED T-CELL PHENOTYPE AT 6627 03:57:21,727 --> 03:57:24,496 HIGHER PROPORTIONS IN TOTAL 6628 03:57:24,563 --> 03:57:25,497 CD8 POSITIVE ME/CFS T CELLS AS 6629 03:57:25,564 --> 03:57:26,498 WELL. 6630 03:57:26,565 --> 03:57:29,301 NOW, THIS PROGENITOR STAGE OF 6631 03:57:29,368 --> 03:57:30,636 QUIESCENT EXHAUSTED T CELLS 6632 03:57:30,703 --> 03:57:31,737 MAINTAINS T-CELL EXHAUSTION 6633 03:57:31,804 --> 03:57:33,105 DURING CHRONIC VIRAL INFECTIONS. 6634 03:57:33,172 --> 03:57:34,306 AND THIS IS THE STAGE OF 6635 03:57:34,373 --> 03:57:35,608 EXHAUSTION THAT CAN ACTUALLY BE 6636 03:57:35,674 --> 03:57:37,376 RESTORED TO PROPER FUNCTION BY 6637 03:57:37,443 --> 03:57:38,877 TREATMENT WITH PD-1 BLOCKADE 6638 03:57:38,944 --> 03:57:41,914 THERAPY. 6639 03:57:41,981 --> 03:57:43,882 AND SO THEN I ALSO FOUND A 6640 03:57:43,949 --> 03:57:45,150 SIGNIFICANTLY HIGHER FREQUENCY 6641 03:57:45,217 --> 03:57:46,652 OF THE EXHAUSTED IPT IMMEDIATE 6642 03:57:46,719 --> 03:57:48,253 CELL PHENOTYPE IN ME/CFS CELLS 6643 03:57:48,320 --> 03:57:49,488 COMPARED TO HEALTHY CONTROL 6644 03:57:49,555 --> 03:57:50,656 CELLS AS WELL. 6645 03:57:50,723 --> 03:57:52,458 AND SO ALL OF THESE 6646 03:57:52,524 --> 03:57:54,259 TRANSCRIPTIONALLY DIFFERENT 6647 03:57:54,326 --> 03:57:56,161 ME/CFS CD8 T CELLS INDICATE THAT 6648 03:57:56,228 --> 03:57:57,663 INDIVIDUALS WITH ME/CFS MAY HAVE 6649 03:57:57,730 --> 03:57:59,898 THESE MORE DISREGULATED 6650 03:57:59,965 --> 03:58:01,200 EXHAUSTED T CELLS THAN THE 6651 03:58:01,266 --> 03:58:02,301 HEALTHY SEDENTARY CONTROLS THAT 6652 03:58:02,368 --> 03:58:05,137 WE COMPARED THEM TO FOLLOWING 6653 03:58:05,204 --> 03:58:08,607 EXERCISE. 6654 03:58:08,674 --> 03:58:10,576 JUST TO GO THROUGH A FEW OF THE 6655 03:58:10,643 --> 03:58:14,847 EFFECTOR SUBSETS, I THEN SAW AN 6656 03:58:14,913 --> 03:58:16,515 INCREASE IN EARLY DIFFERENTIATED 6657 03:58:16,582 --> 03:58:16,782 T CELLS. 6658 03:58:16,849 --> 03:58:18,550 CLA SIBLY TOX IS NOT ESSENTIAL 6659 03:58:18,617 --> 03:58:20,085 FOR THE ESTABLISHMENT OF 6660 03:58:20,152 --> 03:58:22,921 EFFECTOR OR MEMORY CD8 POSITIVE 6661 03:58:22,988 --> 03:58:24,123 T CELLS, BUT THIS TRANSCRIPTION 6662 03:58:24,189 --> 03:58:26,291 FACTOR PLAYS A CRUCIAL ROLE IN 6663 03:58:26,358 --> 03:58:27,393 T-CELL EXHAUSTION BECAUSE IN THE 6664 03:58:27,459 --> 03:58:29,795 ABSENCE OF TOX EXHAUSTED T CELLS 6665 03:58:29,862 --> 03:58:32,297 ARE SIMPLY NOT PRODUCED. 6666 03:58:32,364 --> 03:58:33,832 I ALSO HERE OBSERVED A 6667 03:58:33,899 --> 03:58:36,135 REMARKABLY HIGHER FREQUENCY OF 6668 03:58:36,201 --> 03:58:37,970 THE INTERMEDIATE EXHAUSTED 6669 03:58:38,037 --> 03:58:39,838 T-CELL PHENOTYPE WITHIN THE 6670 03:58:39,905 --> 03:58:40,639 INTERMEDIATE POPULATION COMPARED 6671 03:58:40,706 --> 03:58:43,409 TO THE HEALTHY CONTROL GROUP. 6672 03:58:43,475 --> 03:58:44,843 THIS POPULATION SEEMS TO BE THE 6673 03:58:44,910 --> 03:58:46,812 LARGEST CONTRIBUTOR OF THIS 6674 03:58:46,879 --> 03:58:48,547 EXHAUSTED PHENOTYPE IN ME/CFS T 6675 03:58:48,614 --> 03:58:51,283 CELLS. 6676 03:58:51,350 --> 03:58:53,919 NOW, IN LATE EFFECTOR T-CELL 6677 03:58:53,986 --> 03:58:54,987 POPULATIONS, A DISTINCTIVE 6678 03:58:55,054 --> 03:58:56,188 PATTERN BEGINS TO EMERGE WHICH 6679 03:58:56,255 --> 03:58:58,590 IS THIS LOWER FREQUENCY OF T-BET 6680 03:58:58,657 --> 03:59:02,127 POSITIVE CELLS IN TOTAL EFFECTOR 6681 03:59:02,194 --> 03:59:02,961 POPULATIONS. 6682 03:59:03,028 --> 03:59:04,463 NOW, T-BET IS PIVOTAL NOT ONLY 6683 03:59:04,530 --> 03:59:06,098 IN EXHAUSTED CELLS BUT IN 6684 03:59:06,165 --> 03:59:06,465 GENERAL. 6685 03:59:06,532 --> 03:59:08,067 IT'S KNOWN FOR ITS ROLE IN 6686 03:59:08,133 --> 03:59:10,269 REGULATING THE EXPRESSION OF 6687 03:59:10,335 --> 03:59:12,304 GENES THAT BASICALLY ENCODE 6688 03:59:12,371 --> 03:59:13,172 EFFECTOR MOLECULES. 6689 03:59:13,238 --> 03:59:15,674 SO THESE RESULTS ALIGN WITH 6690 03:59:15,741 --> 03:59:17,776 PRIOR ME/CFS LITERATURE 6691 03:59:17,843 --> 03:59:20,045 REPORTING THE CYTOTOXIC IMMUNE 6692 03:59:20,112 --> 03:59:22,781 RESPONSE IN ME/CFS. 6693 03:59:22,848 --> 03:59:24,550 AKITION DIGSALLY, TOX POSITIVE 6694 03:59:24,616 --> 03:59:26,585 CELLS WERE OBSERVED AT HIGHER 6695 03:59:26,652 --> 03:59:28,353 PROPORTIONS IN TERMINALLY 6696 03:59:28,420 --> 03:59:29,755 DIFFERENTIATED POPULATIONS. 6697 03:59:29,822 --> 03:59:30,589 INTERESTING BECAUSE THIS 6698 03:59:30,656 --> 03:59:31,423 TRANSCRIPTION FACTOR MAINTAINS 6699 03:59:31,490 --> 03:59:33,759 THE EXHAUSTED T-CELL RESPONSE 6700 03:59:33,826 --> 03:59:36,295 BUT IT DOES SO IN PART BY 6701 03:59:36,361 --> 03:59:38,363 INHIBITING CLASSIC CD8 T-CELL 6702 03:59:38,430 --> 03:59:39,131 TERMINAL DIFFERENTIATION. 6703 03:59:39,198 --> 03:59:41,633 AND THIS IS IN AN ATTEMPT TO 6704 03:59:41,700 --> 03:59:44,336 PROTECT AGAINST T-CELL MEDIATED 6705 03:59:44,403 --> 03:59:45,003 IMMUNOPATHOLOGY. 6706 03:59:45,070 --> 03:59:46,939 SO THEN FINALLY, I CONTINUE TO 6707 03:59:47,005 --> 03:59:49,508 SEE THESE ELEVATED EXHAUSTED 6708 03:59:49,575 --> 03:59:51,343 CELL PHENOTYPE FREQUENCIES IN 6709 03:59:51,410 --> 03:59:52,678 LATE EFFECTOR AND PARTICULARLY 6710 03:59:52,745 --> 03:59:54,713 IN TERMINAL ME/CFS T CELLS, 6711 03:59:54,780 --> 03:59:56,682 COMPARED TO HEALTHY CONTROLS. 6712 03:59:56,749 --> 03:59:58,016 ALTHOUGH IT'S NOT AT THE SAME 6713 03:59:58,083 --> 03:59:59,485 HIGH PROPORTIONS AS WHAT WE SAW 6714 03:59:59,551 --> 04:00:01,754 IN THE PREVIOUS SLIDE IN THE 6715 04:00:01,820 --> 04:00:02,788 EARLY DIFFERENTIATED T-CELL 6716 04:00:02,855 --> 04:00:05,224 POPULATION. 6717 04:00:05,290 --> 04:00:07,292 AND SO THEN IN CONCLUSION, MU 6718 04:00:07,359 --> 04:00:08,727 STUDY REVEALS THE PRESENCE OF 6719 04:00:08,794 --> 04:00:10,229 THIS DISREGULATED IMMUNE CELL 6720 04:00:10,295 --> 04:00:12,297 STATE IDENTIFIED BY AN EXHAUSTED 6721 04:00:12,364 --> 04:00:13,665 T-CELL PHENOTYPE AND MULTIPLE 6722 04:00:13,732 --> 04:00:14,700 ME/CFS SUBSETS. 6723 04:00:14,767 --> 04:00:16,001 INDICATING A SUPPRESSED IMMUNE 6724 04:00:16,068 --> 04:00:17,202 RESPONSE IN THIS ILLNESS THAT 6725 04:00:17,269 --> 04:00:19,304 SUPPORTS THE IDEA OF A CHRONIC 6726 04:00:19,371 --> 04:00:21,907 VIRAL INFECTION IN THIS DISEASE. 6727 04:00:21,974 --> 04:00:24,309 AND OUR FINDINGS ARE PROMISING. 6728 04:00:24,376 --> 04:00:25,744 IT'S IMPORTANT TO NOTE THAT 6729 04:00:25,811 --> 04:00:26,712 T-CELL EXHAUSTION WHICH IS SEEN 6730 04:00:26,779 --> 04:00:27,913 IN VARIOUS MODELS INCLUDING 6731 04:00:27,980 --> 04:00:29,648 CANCER AND OTHER CHRONIC VIRAL 6732 04:00:29,715 --> 04:00:31,383 DISEASES HAS SHOWN REVERSIBILITY 6733 04:00:31,450 --> 04:00:33,252 WITH PD-1 BLOCKADE THERAPY, 6734 04:00:33,318 --> 04:00:35,420 RESULTING IN INCREASED CELL 6735 04:00:35,487 --> 04:00:37,189 PROLIFERATION AND FUNCTION. 6736 04:00:37,256 --> 04:00:39,024 AND AS THERE'S CURRENTLY NO 6737 04:00:39,091 --> 04:00:41,093 FDA-APPROVED TREATMENT FOR 6738 04:00:41,160 --> 04:00:42,427 ME/CFS, INVESTIGATING EXHAUSTION 6739 04:00:42,494 --> 04:00:44,596 AS A POTENTIAL MECHANISM AND 6740 04:00:44,663 --> 04:00:46,865 IDENTIFYING THERAPEUTIC TARGETS 6741 04:00:46,932 --> 04:00:47,766 HOLDS SUBSTANTIAL PROMISE FOR 6742 04:00:47,833 --> 04:00:49,067 INDIVIDUALS THAT ARE AFFECTED BY 6743 04:00:49,134 --> 04:00:51,570 THIS DISEASE. 6744 04:00:51,637 --> 04:00:52,771 AND SO WITH THAT, I'D LIKE TO 6745 04:00:52,838 --> 04:00:55,073 THANK MY LAB, THE CLINICIANS, MY 6746 04:00:55,140 --> 04:00:56,842 MENTORS, INCLUDING MY PI, 6747 04:00:56,909 --> 04:00:57,910 DR. MAUREEN HANSON, AND MY 6748 04:00:57,976 --> 04:00:59,478 FUNDING SOURCES AND RESOURCE 6749 04:00:59,545 --> 04:01:01,180 FACILITIES AT CORNELL. 6750 04:01:01,246 --> 04:01:01,480 THANK YOU. 6751 04:01:01,547 --> 04:01:11,723 [APPLAUSE] 6752 04:01:30,876 --> 04:01:32,244 >> ACTUALLY CAN I ASK YOU A 6753 04:01:32,311 --> 04:01:32,511 QUESTION? 6754 04:01:32,578 --> 04:01:32,878 >> SURE. 6755 04:01:32,945 --> 04:01:34,746 >> DO YOU THINK IF YOU USE THE 6756 04:01:34,813 --> 04:01:36,048 PD-1 THERAPY, WOULD IT BE 6757 04:01:36,114 --> 04:01:41,186 SOMETHING THAT WOULD HAVE TO BE 6758 04:01:41,253 --> 04:01:43,655 DONE CONTINUALLY, OR COULD BE 6759 04:01:43,722 --> 04:01:43,956 ONE TIME? 6760 04:01:44,022 --> 04:01:45,357 >> SO HE WAS ASKING ABOUT HOW 6761 04:01:45,424 --> 04:01:46,825 REALISTIC THE PD-1 BLOCKADE 6762 04:01:46,892 --> 04:01:48,527 THERAPY WOULD BE IN THE CONTEXT 6763 04:01:48,594 --> 04:01:49,361 OF ME/CFS. 6764 04:01:49,428 --> 04:01:51,129 SO IT'S CURRENTLY BEING USED AS 6765 04:01:51,196 --> 04:01:51,797 A CANCER THERAPY. 6766 04:01:51,864 --> 04:01:53,065 IT HASN'T BEEN APPROVED FOR 6767 04:01:53,131 --> 04:01:53,966 CHRONIC VIRAL INFECTIONS. 6768 04:01:54,032 --> 04:01:55,801 THERE HAVE BEEN A FEW STUDIES 6769 04:01:55,868 --> 04:01:57,236 WITH LIKE HIV THAT THEY'VE USED 6770 04:01:57,302 --> 04:01:59,538 IT IN COMBINATION AS CLINICAL 6771 04:01:59,605 --> 04:02:01,006 TRIALS AGAIN WITH ANTIVIRALS 6772 04:02:01,073 --> 04:02:03,876 THAT ARE SPECIFIC TO HIV WHERE 6773 04:02:03,942 --> 04:02:06,278 THEY'RE FLUSHING OUT THE 6774 04:02:06,345 --> 04:02:07,679 RESERVOIRS AND THEN DOING A 6775 04:02:07,746 --> 04:02:09,314 LOWER DOSE OF PD-1 BLOCKADE 6776 04:02:09,381 --> 04:02:10,749 THERAPY TO TRY TO GET AT THOSE 6777 04:02:10,816 --> 04:02:12,951 CELLS THAT ARE TYPICALLY HIDDEN. 6778 04:02:13,018 --> 04:02:13,852 SO IT WOULD HAVE TO BE SOMETHING 6779 04:02:13,919 --> 04:02:16,221 WHERE ONCE WE UNDERSTAND THE 6780 04:02:16,288 --> 04:02:17,890 MECHANISM, WE COULD DIRECT IT. 6781 04:02:17,956 --> 04:02:19,057 BASED ON WHAT ELSE WE KNOW ABOUT 6782 04:02:19,124 --> 04:02:20,959 THE DISEASE. 6783 04:02:21,026 --> 04:02:23,896 >> IT WOULDN'T BE ONE -- 6784 04:02:23,962 --> 04:02:27,232 >> IT WOULDN'T BE WITH. 6785 04:02:27,299 --> 04:02:28,934 >> THANK YOU. 6786 04:02:29,001 --> 04:02:32,604 >> SO OUR NEXT SESSION IS 6787 04:02:32,671 --> 04:02:35,240 ACTUALLY METABOLISM OF ME/CFS 6788 04:02:35,307 --> 04:02:36,508 AND LONG COVID, AND WE HAVE 6789 04:02:36,575 --> 04:02:40,879 THREE SPEAKERS, AND THE 6790 04:02:40,946 --> 04:02:46,885 MODERATOR IS DR. KARL-JOHAN 6791 04:02:46,952 --> 04:02:47,753 TRONSTAD ACTUALLY A SPEAKER IN 6792 04:02:47,819 --> 04:02:51,023 THE SESSION, WHICH IS WHY I'M 6793 04:02:51,089 --> 04:02:51,790 INTRODUCING FOLKS. 6794 04:02:51,857 --> 04:02:54,660 THE FIRST SPEAKER IS PAUL HWANG 6795 04:02:54,726 --> 04:02:56,595 FROM NHLBI WHO'S GOING TO TELL 6796 04:02:56,662 --> 04:02:58,597 US ABOUT HIS THOUGHTS ABOUT A 6797 04:02:58,664 --> 04:03:00,632 PAPER THAT HE RECENTLY PUBLISHED 6798 04:03:00,699 --> 04:03:03,135 AND THEN SOME ADDITIONAL 6799 04:03:03,201 --> 04:03:03,802 THINKING ABOUT ACTUALLY 6800 04:03:03,869 --> 04:03:04,937 SOMETHING DR. KOROSHETZ 6801 04:03:05,003 --> 04:03:08,407 MENTIONED THIS MORNING, WASF3 6802 04:03:08,473 --> 04:03:10,275 MAY MEDIATE BIOENERGETIC 6803 04:03:10,342 --> 04:03:11,043 DEFICIENCY OF ME/CFS. 6804 04:03:11,109 --> 04:03:21,219 PAUL? 6805 04:03:29,561 --> 04:03:32,064 >> THANK YOU. 6806 04:03:32,130 --> 04:03:35,400 THANKS VERY MUCH, JOE AND OTHER 6807 04:03:35,467 --> 04:03:37,602 ORGANIZING MEMBERS FOR THIS 6808 04:03:37,669 --> 04:03:38,203 INVITATION, OPPORTUNITY TO 6809 04:03:38,270 --> 04:03:41,707 PRESENT OUR WORK. 6810 04:03:41,773 --> 04:03:42,741 IT'S ALSO IMPORTANT FOR ME TO 6811 04:03:42,808 --> 04:03:45,911 THANK MEMBERS OF MY LABORATORY, 6812 04:03:45,978 --> 04:03:48,246 ESPECIALLY THOSE THAT DID MUCH 6813 04:03:48,313 --> 04:03:50,282 OF THE WORK THAT I'LL BE SHOWING 6814 04:03:50,349 --> 04:03:52,017 YOU. 6815 04:03:52,084 --> 04:03:53,952 SO WHAT I'D LIKE TO DO TODAY IS 6816 04:03:54,019 --> 04:03:55,721 SHARE WITH YOU A SHORT STORY 6817 04:03:55,787 --> 04:03:59,658 THAT WE'VE BEEN WORKING ON FOR 6818 04:03:59,725 --> 04:04:02,027 THE PAST FEW YEARS IN WHICH 6819 04:04:02,094 --> 04:04:04,262 WE'VE TRIED TO DETERMINE THE 6820 04:04:04,329 --> 04:04:08,867 MECHANISM FOR THE LACK OF ENERGY 6821 04:04:08,934 --> 04:04:10,669 IN THE SKELETAL MUSCLE OF 6822 04:04:10,736 --> 04:04:12,537 PATIENTS WITH CHRONIC FATIGUE 6823 04:04:12,604 --> 04:04:16,908 SYNDROME. 6824 04:04:16,975 --> 04:04:20,712 SO THIS PROJECT STARTS WITH A 6825 04:04:20,779 --> 04:04:25,550 PATIENT WHO ARE ACTUALLY IS A 6826 04:04:25,617 --> 04:04:26,952 PROJECT WE KIND OF STUMBLED UPON 6827 04:04:27,019 --> 04:04:31,423 BECAUSE OF A VERY PERSISTENT BUT 6828 04:04:31,490 --> 04:04:35,594 PLEASANT PATIENT WHO SHOWED UP 6829 04:04:35,660 --> 04:04:38,430 WITH THE SYMPTOM OF FATIGUE. 6830 04:04:38,497 --> 04:04:42,801 SO OUR LAB HAS BEEN WORKING ON 6831 04:04:42,868 --> 04:04:46,605 AN EARLY ONSET CANCER DISORDER 6832 04:04:46,671 --> 04:04:49,908 CAUSED BY INHERITED MUTATIONS OF 6833 04:04:49,975 --> 04:04:51,777 P53, WHICH IS ARGUABLY THE MOST 6834 04:04:51,843 --> 04:04:53,578 IMPORTANT TUMOR SUPPRESSOR GENE 6835 04:04:53,645 --> 04:04:58,316 IN THE HUMAN GENOME. 6836 04:04:58,383 --> 04:05:06,358 AND WE HAD LOOKED AT LI-FRAUMENI 6837 04:05:06,425 --> 04:05:09,928 SYNDROME BOTH IN IT'S FORMS AND 6838 04:05:09,995 --> 04:05:11,396 WE HAD REPORTED A NUMBER OF 6839 04:05:11,463 --> 04:05:15,667 YEARS AGO THAT INDIVIDUALS WITH 6840 04:05:15,734 --> 04:05:16,435 LI-FRAUMENI SYNDROME ACTUALLY 6841 04:05:16,501 --> 04:05:19,504 HAVE INCREASED MITOCHONDRIAL 6842 04:05:19,571 --> 04:05:25,544 METABOLISM. 6843 04:05:25,610 --> 04:05:26,745 THE PATIENT HAD SEEN THIS WORK 6844 04:05:26,812 --> 04:05:32,317 ON THE WEB AND CONTACTED ME AND 6845 04:05:32,384 --> 04:05:34,386 SAID, I HATE TO DO THIS TO YOU, 6846 04:05:34,453 --> 04:05:35,720 BUT I'M THE EXACT OPPOSITE OF 6847 04:05:35,787 --> 04:05:37,989 WHAT YOU REPORTED, WHICH IS -- 6848 04:05:38,056 --> 04:05:40,759 WE HAD REPORTED THAT P53 6849 04:05:40,826 --> 04:05:42,594 PROMOTES AEROBIC EXERCISE AND 6850 04:05:42,661 --> 04:05:44,129 ALL THAT, IN MOUSE MODEL IT 6851 04:05:44,196 --> 04:05:46,765 DOUBLES THE CAPACITY OF MICE. 6852 04:05:46,832 --> 04:05:49,601 BUT SHE'S THE EXACT OPPOSITE. 6853 04:05:49,668 --> 04:05:51,103 AND HAS BEEN FATIGUED FOR MANY 6854 04:05:51,169 --> 04:05:52,771 YEARS. 6855 04:05:52,838 --> 04:05:55,140 SO THIS IS THE CASE OF A 6856 04:05:55,207 --> 04:05:58,543 38-YEAR-OLD WOMAN WITH 6857 04:05:58,610 --> 04:05:59,044 LI-FRAUMENI SYNDROME WHO 6858 04:05:59,111 --> 04:06:01,279 PRESENTED WITH FATIGUE AGAIN 6859 04:06:01,346 --> 04:06:02,481 SINCE TEENAGE YEARS SINCE HAVING 6860 04:06:02,547 --> 04:06:07,185 A BOUT OF MONONUCLEOSIS, SHE 6861 04:06:07,252 --> 04:06:07,953 RECALLS. 6862 04:06:08,019 --> 04:06:10,122 SHE HAD EXTENSIVE CLINICAL 6863 04:06:10,188 --> 04:06:14,192 WORKUP OVER THE YEARS AND REALLY 6864 04:06:14,259 --> 04:06:15,727 IT WAS UNREMARKABLE IN TERMS OF 6865 04:06:15,794 --> 04:06:17,229 DIAGNOSIS AND SHE ACTUALLY ALSO 6866 04:06:17,295 --> 04:06:21,399 HAD A MITOCHONDRIAL DISEASE 6867 04:06:21,466 --> 04:06:23,468 WORKUP WHICH SEQUENCING WHICH 6868 04:06:23,535 --> 04:06:25,971 SHOWED NO MUTATIONS. 6869 04:06:26,037 --> 04:06:29,374 SO I THINK IN THIS AUDIENCE I 6870 04:06:29,441 --> 04:06:33,845 DON'T HAVE TO SAY MUCH ABOUT 6871 04:06:33,912 --> 04:06:36,915 ME/CFS, BY MAINLY THAT MANY 6872 04:06:36,982 --> 04:06:38,116 DIFFERENT MECHANISMS HAVE BEEN 6873 04:06:38,183 --> 04:06:39,417 PROPOSE AND THERE'S A HEAVY 6874 04:06:39,484 --> 04:06:41,153 FOCUS ON IMMUNE MECHANISM IN 6875 04:06:41,219 --> 04:06:42,921 THIS SESSION. 6876 04:06:42,988 --> 04:06:46,324 BUT THERE'S ALSO BEEN REPORTS OF 6877 04:06:46,391 --> 04:06:46,892 MITOCHONDRIAL DYSFUNCTION. 6878 04:06:46,958 --> 04:06:47,526 IT'S CLEAR THAT THERE'S 6879 04:06:47,592 --> 04:06:49,594 SOMETHING WRONG WITH THE 6880 04:06:49,661 --> 04:06:52,564 MITOCHONDRIA IN THESE PATIENTS, 6881 04:06:52,631 --> 04:06:54,099 BUT NO SPECIFIC GENE HAD BEEN 6882 04:06:54,166 --> 04:06:58,236 IDENTIFIED. 6883 04:06:58,303 --> 04:07:01,406 IN ANY EVENT, WE INVITED THE 6884 04:07:01,473 --> 04:07:03,508 PATIENT TO COME TO THE NIH AND 6885 04:07:03,575 --> 04:07:07,112 WE STUDIED HER. 6886 04:07:07,179 --> 04:07:11,883 AND WE DID THIS NONINVASIVE 6887 04:07:11,950 --> 04:07:17,689 EXERCISE TEST CALLED A P31MR 6888 04:07:17,756 --> 04:07:18,256 SPECTROSCOPY. 6889 04:07:18,323 --> 04:07:22,761 IT'S ACTUALLY A PHOSPHOCREATINE 6890 04:07:22,827 --> 04:07:23,595 DEPLETION TEST WHERE YOU DO THIS 6891 04:07:23,662 --> 04:07:26,865 KIND OF MILD FOOT EXERCISE TEST. 6892 04:07:26,932 --> 04:07:28,066 I'M HAVING TO LOOK UP HERE 6893 04:07:28,133 --> 04:07:29,935 BECAUSE I CAN'T SEE THE POINT ON 6894 04:07:30,001 --> 04:07:31,670 THE SCREEN HERE. 6895 04:07:31,736 --> 04:07:33,872 BUT WE DO THIS MILD EXERCISE 6896 04:07:33,939 --> 04:07:36,708 TEST WITH A FOOT PEDAL ON A 6897 04:07:36,775 --> 04:07:37,576 FIXED WEIGHT HERE AND YOU DO 6898 04:07:37,642 --> 04:07:39,544 KIND OF LIKE A REALTIME MRI 6899 04:07:39,611 --> 04:07:41,179 SCAN, AND YOU'RE IMAGING THE 6900 04:07:41,246 --> 04:07:43,481 LEVELS OF THIS VERY IMPORTANT 6901 04:07:43,548 --> 04:07:45,951 CHEMICAL CALLED PHOSPHOCREATINE 6902 04:07:46,017 --> 04:07:47,085 THAT'S THE ENERGY MOLECULE THAT 6903 04:07:47,152 --> 04:07:48,620 CELLS USE FOR MUSCLE 6904 04:07:48,687 --> 04:07:49,921 CONTRACTION. 6905 04:07:49,988 --> 04:07:51,790 AND WHAT YOU DO IS A MILD 6906 04:07:51,856 --> 04:07:52,824 EXERCISE FOR A FIXED PERIOD OF 6907 04:07:52,891 --> 04:07:54,626 TIME, YOU STOP EXERCISING, AND 6908 04:07:54,693 --> 04:07:57,362 THEN YOU LOOK AT THE RECOVERY OF 6909 04:07:57,429 --> 04:07:59,965 THIS ENERGY MOLECULE WHICH GETS 6910 04:08:00,031 --> 04:08:01,700 DEPLETED WITH EXERCISE. 6911 04:08:01,766 --> 04:08:04,236 AND YOU CAN DO A CALCULATION 6912 04:08:04,302 --> 04:08:06,938 LOOKING FOR THE TIME CONSTANT OF 6913 04:08:07,005 --> 04:08:08,506 RECOVERY OF PHOSPHOCREATINE, AND 6914 04:08:08,573 --> 04:08:12,010 THAT HAS BEEN SHOWN BY OTHER 6915 04:08:12,077 --> 04:08:14,980 RESEARCHERS THAT CAN BE A MARKER 6916 04:08:15,046 --> 04:08:17,882 OF -- A NONINVASIVE MARKER OF 6917 04:08:17,949 --> 04:08:18,984 MITOCHONDRIAL OXIDATIVE 6918 04:08:19,050 --> 04:08:20,619 PHOSPHORYLATION WHICH IS WHAT 6919 04:08:20,685 --> 04:08:22,387 MAKES ATP TO MAKE ENERGY FOR THE 6920 04:08:22,454 --> 04:08:23,054 CELLS TO USE. 6921 04:08:23,121 --> 04:08:25,457 AND WHAT WE SAW WAS RATHER 6922 04:08:25,523 --> 04:08:25,890 SURPRISING. 6923 04:08:25,957 --> 04:08:31,596 THIS IS SO THE PATIENT WITH 6924 04:08:31,663 --> 04:08:33,665 FATIGUE IS PATIENT S1, S STANDS 6925 04:08:33,732 --> 04:08:34,766 FOR SIBLING 1. 6926 04:08:34,833 --> 04:08:38,036 AND SHE HAD A VERY PROLONGED 6927 04:08:38,103 --> 04:08:39,804 RECOVERY TIME CONSTANT OF 6928 04:08:39,871 --> 04:08:40,338 80 SECONDS. 6929 04:08:40,405 --> 04:08:41,640 WE'VE NEVER SEEN ANYTHING THAT 6930 04:08:41,706 --> 04:08:43,975 PROLONGED. 6931 04:08:44,042 --> 04:08:46,244 NORMAL RANGE IS ABOUT 36 TO 6932 04:08:46,311 --> 04:08:48,546 40 SECONDS RECOVERY TIME 6933 04:08:48,613 --> 04:08:50,282 CONSTANT. 6934 04:08:50,348 --> 04:08:51,383 WE REPEATED THAT SIX MONTHS 6935 04:08:51,449 --> 04:08:51,616 LATER. 6936 04:08:51,683 --> 04:08:52,751 IT WAS PRETTY CONSTANT. 6937 04:08:52,817 --> 04:08:54,552 IT WAS 80 SECONDS. 6938 04:08:54,619 --> 04:08:59,057 WE ALSO INVITED THE PATIENT'S 6939 04:08:59,124 --> 04:09:00,692 BROTHER, SIBLING 2, S STANDS FOR 6940 04:09:00,759 --> 04:09:04,095 SIBLING 2, WHO ALSO HAD 6941 04:09:04,162 --> 04:09:06,064 LI-FRAUMENI SYNDROME, THE SAME 6942 04:09:06,131 --> 04:09:07,465 MUTATION, P53 MUTATION, BUT HE 6943 04:09:07,532 --> 04:09:10,635 DIDN'T HAVE FATIGUE SYMPTOMS. 6944 04:09:10,702 --> 04:09:14,773 AND WE FOUND THAT HIS RECOVERY 6945 04:09:14,839 --> 04:09:16,107 TIME CONSTANT WAS 30 SECONDS. 6946 04:09:16,174 --> 04:09:17,309 AND THAT'S ACTUALLY A LITTLE BIT 6947 04:09:17,375 --> 04:09:18,410 FAST, AND THAT'S EXACTLY WHAT 6948 04:09:18,476 --> 04:09:20,278 WE'RE SEEING IN OTHER 6949 04:09:20,345 --> 04:09:20,945 LI-FRAUMENI SYNDROME PATIENTS, 6950 04:09:21,012 --> 04:09:23,982 THAT IS THEY HAVE INCREASED 6951 04:09:24,049 --> 04:09:26,151 MITOCHONDRIAL -- SO IT APPEARED 6952 04:09:26,217 --> 04:09:28,820 THAT THE MUTATIONAL P53 DID NOT 6953 04:09:28,887 --> 04:09:30,422 SEEM TO DIRECTLY CORRELATE WITH 6954 04:09:30,488 --> 04:09:31,089 THIS TIME CONSTANT. 6955 04:09:31,156 --> 04:09:34,926 SO SOMETHING ELSE WAS HAPPENING. 6956 04:09:34,993 --> 04:09:36,561 THIS IS AGAIN RATHER PROFOUND, 6957 04:09:36,628 --> 04:09:37,996 SO WE'RE VERY CURIOUS AND WE 6958 04:09:38,063 --> 04:09:41,933 WANTED TO STUDY HER FURTHER. 6959 04:09:42,000 --> 04:09:43,902 SO WE TOOK SMALL SKIN BIOPSIES 6960 04:09:43,968 --> 04:09:46,504 FROM BOTH THE PATIENT AND HER 6961 04:09:46,571 --> 04:09:48,773 BROTHER AND MADE FIBROBLAST 6962 04:09:48,840 --> 04:09:51,543 CELLS AND JUST DID A SIMPLE 6963 04:09:51,609 --> 04:09:53,511 OXYGEN CONSUMPTION TEST TO LOOK 6964 04:09:53,578 --> 04:09:56,247 AT MITOCHONDRIAL RESPIRATION. 6965 04:09:56,314 --> 04:09:58,783 AGAIN WE SAW THAT THE PATIENT IS 6966 04:09:58,850 --> 04:10:01,586 IN RED, SHE HAD DIMINISHED 6967 04:10:01,653 --> 04:10:03,254 OXYGEN CONSUMPTION WITH 6968 04:10:03,321 --> 04:10:05,857 MITOCHONDRIAL ACTIVITY, BOTH IN 6969 04:10:05,924 --> 04:10:08,927 ITS BASAL AND STIMULATED STATE 6970 04:10:08,993 --> 04:10:10,462 IN THE UNCOUPLED STATE, WHILE 6971 04:10:10,528 --> 04:10:15,500 THE BROTHER, THE CONTROL, S2, 6972 04:10:15,567 --> 04:10:18,336 HAD NORMAL LEVELS OF OXYGEN 6973 04:10:18,403 --> 04:10:20,071 CONSUMPTION AND MITOCHONDRIAL 6974 04:10:20,138 --> 04:10:23,842 FUNCTION. 6975 04:10:23,908 --> 04:10:26,578 SO AT THIS POINT, I WILL 6976 04:10:26,644 --> 04:10:29,414 SUMMARIZE OUR WORK BY SAYING 6977 04:10:29,481 --> 04:10:33,451 THAT BY FOLLOWING RETROGRADE 6978 04:10:33,518 --> 04:10:37,322 ABERRANT SIGNALING INVOLVING P53 6979 04:10:37,389 --> 04:10:39,924 AND P38, WHICH IS JUST, AGAIN, 6980 04:10:39,991 --> 04:10:44,095 REGULATORY MOLECULES IN THE CE 6981 04:10:44,162 --> 04:10:46,398 CELL, WE TRACE THIS BACK TO 6982 04:10:46,464 --> 04:10:56,341 INCREASED LEVELS OF WA WASF3 6983 04:10:56,408 --> 04:10:57,642 EXPRESSION. 6984 04:10:57,709 --> 04:11:03,681 IT STANDS FOR WISKOTT-ALDRICH 6985 04:11:03,748 --> 04:11:05,216 SYNDROME PROTEIN FAMILY MEMBER 6986 04:11:05,283 --> 04:11:05,350 3. 6987 04:11:05,417 --> 04:11:07,051 THIS WAS A FAMILY MEMBER OF THE 6988 04:11:07,118 --> 04:11:08,586 GENE THAT MUTATED IN THAT 6989 04:11:08,653 --> 04:11:10,688 CONDITION. 6990 04:11:10,755 --> 04:11:11,656 AND WHAT WAS INTERESTING WAS 6991 04:11:11,723 --> 04:11:14,058 THAT THIS GENE HAD ACTUALLY BEEN 6992 04:11:14,125 --> 04:11:16,995 IDENTIFIED AS ONE OF THE TOP 6993 04:11:17,061 --> 04:11:20,298 CANDIDATE GENES IN ME/CFS IN A 6994 04:11:20,365 --> 04:11:21,499 BIOINFORMATICS STUDY PUBLISHED 6995 04:11:21,566 --> 04:11:24,135 PROBABLY OVER 10 YEARS AGO, AND 6996 04:11:24,202 --> 04:11:30,475 THIS WAS BASED ON PROTEOMICS SNP 6997 04:11:30,542 --> 04:11:33,211 AND GENE ANALYSIS, BUT NOT MUCH 6998 04:11:33,278 --> 04:11:38,049 MORE HAD BEEN DONE WITH WASF3. 6999 04:11:38,116 --> 04:11:39,551 HOWEVER, WASF3 IS A WELL-KNOWN 7000 04:11:39,617 --> 04:11:39,884 PROTEIN. 7001 04:11:39,951 --> 04:11:43,855 IT IS KNOWN TO BE AN ACTIN 7002 04:11:43,922 --> 04:11:45,690 INTERACTING PROTEIN, IT HELPS 7003 04:11:45,757 --> 04:11:47,225 POLYMERIZE ACTIN. 7004 04:11:47,292 --> 04:11:49,427 AND ALSO SERVES AS A SCAFFOLD 7005 04:11:49,494 --> 04:11:51,963 FOR PROTEIN COMPLEXES. 7006 04:11:52,030 --> 04:11:54,632 AND IT'S BEEN HIGHLY STUDIED IN 7007 04:11:54,699 --> 04:11:58,636 THE CELL MIGRATION FIELD AND IS 7008 04:11:58,703 --> 04:12:01,239 THOUGHT TO BE IMPORTANT FOR 7009 04:12:01,306 --> 04:12:03,241 METASTASIS, CANCER CELLS ABLE TO 7010 04:12:03,308 --> 04:12:09,681 MOVE AROUND. 7011 04:12:09,747 --> 04:12:13,184 SO WE DECIDE TO STUDY THIS 7012 04:12:13,251 --> 04:12:14,819 PROTEIN FURTHER, AND ONE OF THE 7013 04:12:14,886 --> 04:12:17,789 FIRST EXPERIMENTS WE DID WAS TO 7014 04:12:17,856 --> 04:12:18,923 SEE WHAT HAPPENS IF YOU KNOCK 7015 04:12:18,990 --> 04:12:25,129 DOWN -- AGAIN, WE FOUND HIGH 7016 04:12:25,196 --> 04:12:27,265 LEVELS OF WASF3. 7017 04:12:27,332 --> 04:12:29,667 WE CAN DO THAT SIMPLY BY DOING A 7018 04:12:29,734 --> 04:12:32,270 KNOCK DOWN EXPERIMENT USING THE 7019 04:12:32,337 --> 04:12:35,006 PATIENT'S CELLS, AND YOU CAN SEE 7020 04:12:35,073 --> 04:12:39,410 THAT WHEN WE KNOCK DOWN WASF3 7021 04:12:39,477 --> 04:12:43,114 PROTEIN USING SH RNA, THE 7022 04:12:43,181 --> 04:12:44,315 MITOCHONDRIAL RESPIRATION IN THE 7023 04:12:44,382 --> 04:12:52,323 PATIENT'S SKIN GUY SKIN FIBROBS 7024 04:12:52,390 --> 04:12:55,360 IMPROVED, SO IT HAD THE ABILITY 7025 04:12:55,426 --> 04:12:56,561 TO CONSUME OXYGEN BUT SOMETHING 7026 04:12:56,628 --> 04:12:57,362 WAS SUPPRESSING IT. 7027 04:12:57,428 --> 04:12:58,496 WHAT WAS ALSO INTERESTING WAS 7028 04:12:58,563 --> 04:13:01,299 THAT THE RESPIRATORY COMPLEX 7029 04:13:01,366 --> 04:13:03,234 4 PROTEIN, JUST LOOKING AT COX-1 7030 04:13:03,301 --> 04:13:05,336 AND COX-2 SUBUNIT PROTEINS, THE 7031 04:13:05,403 --> 04:13:09,173 PROTEIN LEVELS ACTUALLY ALSO 7032 04:13:09,240 --> 04:13:12,010 IMPROVED, SUGGESTING THAT WASF3 7033 04:13:12,076 --> 04:13:14,746 ARE SOMEHOW DOWNREGULATING THIS 7034 04:13:14,812 --> 04:13:16,981 COX, WHICH IS AGAIN ESSENTIAL 7035 04:13:17,048 --> 04:13:18,149 FOR RESPIRATION, AND I'LL SHOW 7036 04:13:18,216 --> 04:13:19,551 YOU HERE IN THE NEXT SLIDE THAT 7037 04:13:19,617 --> 04:13:21,553 WHEN WE DO THE CONVERSE 7038 04:13:21,619 --> 04:13:24,522 EXPERIMENT, SO NOW YOU 7039 04:13:24,589 --> 04:13:29,093 OVEREXPRESS WASF3 IN A C2C12 7040 04:13:29,160 --> 04:13:30,762 MOUSE MYOBLAST LIKE THE SKELETAL 7041 04:13:30,828 --> 04:13:31,930 MUSCLE CELLS IN TISSUE CULTURE, 7042 04:13:31,996 --> 04:13:33,464 SO WE WERE ABLE TO INTRODUCE 7043 04:13:33,531 --> 04:13:35,133 THIS PROTEIN, EXPRESS IT AT 7044 04:13:35,199 --> 04:13:37,101 HIGHER LEVELS, AND WHAT YOU CAN 7045 04:13:37,168 --> 04:13:40,805 SEE HERE IS THAT COMPARED TO 7046 04:13:40,872 --> 04:13:45,777 CONTROL, WHEN YOU EXPRESS WASF3 7047 04:13:45,843 --> 04:13:48,046 YOU CAN SUPPRESS OXYGEN 7048 04:13:48,112 --> 04:13:48,479 CONSUMPTION. 7049 04:13:48,546 --> 04:13:49,814 ASSOCIATED WITH THAT WE SO YOU 7050 04:13:49,881 --> 04:13:52,150 DOWN REGULATION WITH THE COMPLEX 7051 04:13:52,216 --> 04:14:01,426 FOUR SUBUNITS, COX-1 AND COX-5. 7052 04:14:01,492 --> 04:14:02,660 SOME OF THE OTHER SUBUNITS FROM 7053 04:14:02,727 --> 04:14:04,195 OTHER COMPLEXES SUCH AS COMPLEX 7054 04:14:04,262 --> 04:14:07,131 5 WHICH IS THE ATP SYNTHASE 7055 04:14:07,198 --> 04:14:08,366 COMPLEX 3 DID NOT APPEAR TO 7056 04:14:08,433 --> 04:14:10,368 CHANGE MUCH, COMPLEX 7057 04:14:10,435 --> 04:14:12,203 1 ESPECIALLY AND COMPLEX 2 IS 7058 04:14:12,270 --> 04:14:15,607 PROBABLY JUST A COMPENSATORY 7059 04:14:15,673 --> 04:14:18,109 INCREASE AND THAT'S PRETTY 7060 04:14:18,176 --> 04:14:22,814 WELL-KNOWN -- HYDROGENASE. 7061 04:14:22,880 --> 04:14:24,782 SO WE ARE VERY INTRIGUED BY 7062 04:14:24,849 --> 04:14:26,618 THESE FINDINGS AND WE WANTED TO 7063 04:14:26,684 --> 04:14:28,886 LOOK FURTHER INTO THE MECHANISM. 7064 04:14:28,953 --> 04:14:29,854 AND ONE OF THE OTHER THINGS WE 7065 04:14:29,921 --> 04:14:33,458 DID WAS WE OVEREXPRESSED WASF3 7066 04:14:33,524 --> 04:14:39,397 AGAIN IN THE C2C12 MYOBLASTS, TO 7067 04:14:39,464 --> 04:14:43,101 SEE IF WAS IF 3 LOCALIZES THE 7068 04:14:43,167 --> 04:14:43,434 MITOCHONDRIA. 7069 04:14:43,501 --> 04:14:47,372 THERE WAS SOME INDICATION IT 7070 04:14:47,438 --> 04:14:48,740 DOES BUT WE WANTED TO SEE IT 7071 04:14:48,806 --> 04:14:50,441 OURSELVES. 7072 04:14:50,508 --> 04:14:55,046 SO WE AGAIN TRANSFECTED C2C12 7073 04:14:55,113 --> 04:15:02,253 MYOBLASTS WITH THE GENEWATO 7074 04:15:02,320 --> 04:15:04,989 EXPRESS IT. 7075 04:15:05,056 --> 04:15:07,191 THE MITOCHONDRIAL FRACTION 7076 04:15:07,258 --> 04:15:15,600 ENRICHED FOR WA WAS IF3. 7077 04:15:15,667 --> 04:15:16,901 THERE'S AN UPPER BAND AND LOWER 7078 04:15:16,968 --> 04:15:17,902 BAND. 7079 04:15:17,969 --> 04:15:19,637 AND YOU CAN SEE THAT THE LOWER 7080 04:15:19,704 --> 04:15:22,106 BAND APPEARS TO BE WHAT 7081 04:15:22,173 --> 04:15:25,910 LOCALIZES THE MITOCHONDRIA. 7082 04:15:25,977 --> 04:15:32,050 AND EMPIRICALLY, WE TREATED THIS 7083 04:15:32,116 --> 04:15:34,886 CELL WITH ALKALINE PHOSPHATASE, 7084 04:15:34,952 --> 04:15:37,288 WHICH IS -- PHOSPHATE GROUPS 7085 04:15:37,355 --> 04:15:38,089 FROM PROTEINS. 7086 04:15:38,156 --> 04:15:41,025 AND YOU CAN SEE THAT THE BAND 7087 04:15:41,092 --> 04:15:43,861 SHIFTS FROM THIS LOW MOLECULAR 7088 04:15:43,928 --> 04:15:45,396 WEIGHT IN THE MITOCHONDRIA TO A 7089 04:15:45,463 --> 04:15:46,364 HIGHER MOLECULAR WEIGHT, 7090 04:15:46,431 --> 04:15:50,101 INDICATING TO US THAT, PERHAPS, 7091 04:15:50,168 --> 04:15:53,037 THE WASF3 FOUND IN THE 7092 04:15:53,104 --> 04:15:55,039 MITOCHONDRIA AT LEAST IN THE 7093 04:15:55,106 --> 04:15:58,643 C2C12 IS PHOSPHORYLATED AND 7094 04:15:58,710 --> 04:15:59,577 POTENTIALLY INDICATING THAT'S 7095 04:15:59,644 --> 04:16:04,382 MAYBE HOW IT'S TARGETED. 7096 04:16:04,449 --> 04:16:05,450 THESE ARE ONGOING STUDIES. 7097 04:16:05,516 --> 04:16:06,651 WE ALSO WONDERED ABOUT THE 7098 04:16:06,718 --> 04:16:10,788 MECHANISM AND HOW WASF3 DOWN 7099 04:16:10,855 --> 04:16:13,791 REGULATES THOSE COX RESPIRATORY 7100 04:16:13,858 --> 04:16:17,395 COMPLEX 4 PROTEINS. 7101 04:16:17,462 --> 04:16:18,596 BECAUSE IT PLAYS AN IMPORTANT 7102 04:16:18,663 --> 04:16:23,000 ROLE IN SCAFFOLDING AND HELPING 7103 04:16:23,067 --> 04:16:26,504 PROTEINS COMPLEX INTERACT, WE 7104 04:16:26,571 --> 04:16:28,873 WONDERED THE EFFECT OF 7105 04:16:28,940 --> 04:16:31,409 MITOCHONDRIAL SUPER -- 7106 04:16:31,476 --> 04:16:32,610 RESPIRATORY COMPLEXES ARE KNOWN 7107 04:16:32,677 --> 04:16:35,246 TO FUNCTION BY CLUSTERING 7108 04:16:35,313 --> 04:16:38,883 TOGETHER COMPLEX 1, 2, 3, 4 AND 7109 04:16:38,950 --> 04:16:41,753 IS THOUGHT TO PROMOTE MORE 7110 04:16:41,819 --> 04:16:44,355 EFFICIENT ELECTRON TRANSFER AND 7111 04:16:44,422 --> 04:16:45,556 MITOCHONDRIAL RESPIRATION. 7112 04:16:45,623 --> 04:16:49,527 WE PERFORMED DENATURING OF BLUE 7113 04:16:49,594 --> 04:16:56,868 NATIVE GELS -- TO INCREASE THE 7114 04:16:56,934 --> 04:17:00,938 WASF3 -- AND YOU CAN SEE HERE, 7115 04:17:01,005 --> 04:17:04,876 THESE ARE REALLY LARGE COMPLEKS. 7116 04:17:04,942 --> 04:17:06,544 720 KILODALTON PROTEIN COMPLEX, 7117 04:17:06,611 --> 04:17:12,083 YOU CAN SEE OVEREXPRESSED -- 7118 04:17:12,150 --> 04:17:13,718 IT'S KNOWN FROM THE SUPER 7119 04:17:13,785 --> 04:17:15,686 COMPLEX FIELD THAT THE 720 7120 04:17:15,753 --> 04:17:19,423 CORRESPONDS TO THE COMPLEX 7121 04:17:19,490 --> 04:17:20,858 3 DIMER SO WE'RE TALKING ABOUT 7122 04:17:20,925 --> 04:17:21,959 RESPIRATORY COMPLEX 3 WHICH IS 7123 04:17:22,026 --> 04:17:23,795 FORM BID MULTIPLE PROTEINS NOW 7124 04:17:23,861 --> 04:17:27,999 FORMING A DIMER AND INTERACTING 7125 04:17:28,065 --> 04:17:32,770 WITH COMPLEX 4, SO IT'S ACTUALLY 7126 04:17:32,837 --> 04:17:35,540 A HETEROOLIGOMER COMPLEX. 7127 04:17:35,606 --> 04:17:40,678 WHAT WE CAN SEE HERE IS THAT 7128 04:17:40,745 --> 04:17:46,818 WHEN YOU OVEREXPRESS WASF3, THIS 7129 04:17:46,884 --> 04:17:50,421 720 KILL DALTON APPEARS TO 7130 04:17:50,488 --> 04:17:51,289 DECREASE BUT IMPORTANTLY, IT'S 7131 04:17:51,355 --> 04:17:56,327 THE ACTIVITY OF COMPLEX 4 U 4 YU 7132 04:17:56,394 --> 04:18:01,699 CAN SEE THE ACTIVITY IS LOWER. 7133 04:18:01,766 --> 04:18:02,800 THAT SUGGESTS AGAIN WHAT YOU SAW 7134 04:18:02,867 --> 04:18:04,435 WITH OXYGEN CONSUMPTION, IT'S 7135 04:18:04,502 --> 04:18:06,404 REALLY EQUIVALENT OF OXYGEN 7136 04:18:06,470 --> 04:18:07,772 CONJUNCTION IN GEL CHEMICAL 7137 04:18:07,839 --> 04:18:08,206 REACTION SHOWN HERE. 7138 04:18:08,272 --> 04:18:12,577 SO AGAIN WE'RE SEEING COMPLEX 7139 04:18:12,643 --> 04:18:15,513 4 ACTIVITY DECREASE WHERE 7140 04:18:15,580 --> 04:18:16,614 COMPLEX 1 ACTIVITY DOESN'T SEEM 7141 04:18:16,681 --> 04:18:19,383 TO CHANGE VERY MUCH. 7142 04:18:19,450 --> 04:18:20,785 SO AGAIN SOMETHING IS POINTING 7143 04:18:20,852 --> 04:18:22,453 TO COMPLEX 4 AS BEING 7144 04:18:22,520 --> 04:18:22,787 DESTABILIZED. 7145 04:18:22,854 --> 04:18:25,189 THIS IS ACTUALLY VERY 7146 04:18:25,256 --> 04:18:29,126 INTERESTING BECAUSE THE COMPLEX 7147 04:18:29,193 --> 04:18:32,964 3 DIMER IS KNOWN TO BE VERY 7148 04:18:33,030 --> 04:18:34,465 IMPORTANT FOR HELPING STABILIZE 7149 04:18:34,532 --> 04:18:36,033 COMPLEX 46789 WITHOUT THIS 7150 04:18:36,100 --> 04:18:37,969 COMPLEX 3 DIMER FORMATION, 7151 04:18:38,035 --> 04:18:40,071 COMPLEX 4 GETS DESTABILIZED AND 7152 04:18:40,137 --> 04:18:40,905 DEGRADED, SUGGESTING MAYBE THAT 7153 04:18:40,972 --> 04:18:44,909 MIGHT BE THE MECHANISM BY WHICH 7154 04:18:44,976 --> 04:18:46,310 COX -- THE INITIAL WESTERN BLOTS 7155 04:18:46,377 --> 04:18:53,651 I SHOWED YOU WAS LOWER. 7156 04:18:53,718 --> 04:18:58,389 SO WE WONDERED -- WE MADE A 7157 04:18:58,456 --> 04:19:02,760 TRANSGENIC MOUSE AND WHAT WE 7158 04:19:02,827 --> 04:19:06,797 FOUND WAS RATHER DRAMATIC, ITS 7159 04:19:06,864 --> 04:19:08,332 EXERCISE CAPACITY ON A TREADMILL 7160 04:19:08,399 --> 04:19:10,201 WAS DRAMATICALLY REDUCED BY 7161 04:19:10,268 --> 04:19:12,937 ABOUT 50%, ABOUT HALF OF WHAT 7162 04:19:13,004 --> 04:19:14,372 ITS WILD TYPE LITTER MATES WERE 7163 04:19:14,438 --> 04:19:16,440 CAPABLE OF DOING, SO YOU'RE 7164 04:19:16,507 --> 04:19:19,644 SUPPRESSING EXERCISE CAPACITY. 7165 04:19:19,710 --> 04:19:21,812 ALSO ISOLATED SKELETAL MUSCLE 7166 04:19:21,879 --> 04:19:23,581 FROM THESE MICE AND WE'RE ABLE 7167 04:19:23,648 --> 04:19:26,250 TO SHOW DECREASED MITOCHONDRIAL 7168 04:19:26,317 --> 04:19:27,451 RESPIRATION, ALBEIT NOT AS 7169 04:19:27,518 --> 04:19:31,756 DRAMATIC AS 50% BUT IN VIVO IT'S 7170 04:19:31,822 --> 04:19:33,090 HARD TO TELL WHAT THE CORRELATES 7171 04:19:33,157 --> 04:19:34,458 ARE OF EXERCISE FUNCTION. 7172 04:19:34,525 --> 04:19:42,566 WE ALSO LOOKED AT EXPRESSION OF 7173 04:19:42,633 --> 04:19:43,301 WASF3 PROTEIN IN DIFFERENT 7174 04:19:43,367 --> 04:19:44,035 TISSUES. 7175 04:19:44,101 --> 04:19:46,737 WE WERE ABLE TO OVEREXPRESS 7176 04:19:46,804 --> 04:19:48,039 WASF3 PROTEIN HERE IN THE 7177 04:19:48,105 --> 04:19:49,040 TRANSGENIC MOUSE COMPARED TO 7178 04:19:49,106 --> 04:19:53,210 WILD TYPE MICE THERE. 7179 04:19:53,277 --> 04:19:55,012 YOU CAN SEE THERE ARE DIFFERENT 7180 04:19:55,079 --> 04:19:58,549 BASAL LEVELS OF WASF3 EVIDENT IN 7181 04:19:58,616 --> 04:20:00,451 DIFFERENT TISSUES, IT ACTUALLY 7182 04:20:00,518 --> 04:20:02,219 EXPRESSES A LOT OF WASF. 7183 04:20:02,286 --> 04:20:03,287 AND THAT MAY HAVE SOMETHING TO 7184 04:20:03,354 --> 04:20:05,089 DO WITH THE ACTIN. 7185 04:20:05,156 --> 04:20:07,058 ACTIN IS VERY IMPORTANT IN THE 7186 04:20:07,124 --> 04:20:08,592 BRAIN FOR NEURONAL STRUCTURE, 7187 04:20:08,659 --> 04:20:11,662 CELL STRUCTURE. 7188 04:20:11,729 --> 04:20:13,531 BUT IN ANY EVENT, YOU CAN SEE 7189 04:20:13,597 --> 04:20:15,099 THAT DIFFERENT LEVELS. 7190 04:20:15,166 --> 04:20:20,972 IN THE LIVER WE CAN OVEREXPRESS, 7191 04:20:21,038 --> 04:20:22,506 THE REASON IS UNCLEAR, BUT WHAT 7192 04:20:22,573 --> 04:20:24,075 IS CLEAR HERE IS WE CAN 7193 04:20:24,141 --> 04:20:25,276 OVEREXPRESS IT IN SKELETAL 7194 04:20:25,343 --> 04:20:28,579 MUSCLE AND THE MICE HAVE THIS 7195 04:20:28,646 --> 04:20:28,879 PHENOTYPE. 7196 04:20:28,946 --> 04:20:31,415 JUST LOOKING AT THE OTHER 7197 04:20:31,482 --> 04:20:32,817 COMPLEXES, AGAIN, YOU DON'T SEE 7198 04:20:32,883 --> 04:20:40,057 MUCH CHANGE IN COMPLEX 1. 7199 04:20:40,124 --> 04:20:41,258 COMPLEX 2 AS WELL AS COMPLEX 3. 7200 04:20:41,325 --> 04:20:43,427 BUT AGAIN, YOU SEE THAT THE 7201 04:20:43,494 --> 04:20:45,963 COMPLEX 4 SUBUNITS, COX-1, 7202 04:20:46,030 --> 04:20:47,932 COX-2, 5 AND 17, ARE ALL 7203 04:20:47,999 --> 04:20:48,799 DIMINISHED. 7204 04:20:48,866 --> 04:20:52,570 AND AGAIN, THE ATPASE THAT 7205 04:20:52,636 --> 04:20:54,405 ACTUALLY MAKES THE ATP IS 7206 04:20:54,472 --> 04:20:54,739 UNCHANGED. 7207 04:20:54,805 --> 04:21:05,316 SO AGAIN, THERE'S THIS -- 7208 04:21:05,383 --> 04:21:10,721 WITHOUT THAT, YOU CAN'T RESPIRE. 7209 04:21:10,788 --> 04:21:12,623 SO HAVING OBSERVED THIS IN A 7210 04:21:12,690 --> 04:21:14,125 SINGLE PATIENT, IT'S IMPORTANT 7211 04:21:14,191 --> 04:21:18,829 TO SEE IF THIS MIGHT ALSO APPLY 7212 04:21:18,896 --> 04:21:20,264 TO OTHER PATIENTS, SO WE ARE 7213 04:21:20,331 --> 04:21:26,203 VERY FORTUNATE TO BE HERE AT NIH 7214 04:21:26,270 --> 04:21:29,006 TO BE ABLE TO COLLABORATE WITH 7215 04:21:29,073 --> 04:21:30,574 AVI NATH, WHO ACTUALLY GAVE A 7216 04:21:30,641 --> 04:21:35,713 TALK JUST A LITTLE BIT EARLIER 7217 04:21:35,780 --> 04:21:37,381 AND BRYANT WALLIT. 7218 04:21:37,448 --> 04:21:39,016 THEY HAD DONE THIS ME/CFS STUDY 7219 04:21:39,083 --> 04:21:40,551 WHERE THEY COLLECTED PATIENT 7220 04:21:40,618 --> 04:21:42,319 SAMPLES AND THEY ACTUALLY HAD 7221 04:21:42,386 --> 04:21:43,954 TAKEN NEEDLE BIOPSIES OF 7222 04:21:44,021 --> 04:21:49,760 SKELETAL MUSCLE OF ME/CFS 7223 04:21:49,827 --> 04:21:50,828 PATIENTS AND STORED THEM AWAY. 7224 04:21:50,895 --> 04:21:52,430 WE WERE ACTUALLY ABLE TO CHECK 7225 04:21:52,496 --> 04:21:53,597 FOR LEVELS IN A SUBSET OF 7226 04:21:53,664 --> 04:21:54,932 PATIENTS THAT THEY HAD COLLECTED 7227 04:21:54,999 --> 04:21:56,133 SAMPLES, SO THIS WAS ACTUALLY -- 7228 04:21:56,200 --> 04:21:57,268 THIS IS JUST REPRESENTATIVE OF 7229 04:21:57,334 --> 04:21:59,003 HALF THE SAMPLES, SO THERE WERE 7230 04:21:59,070 --> 04:22:01,539 ACTUALLY 10 HEALTHY VOLUNTEERS, 7231 04:22:01,605 --> 04:22:04,008 CONTROLS AND 14 ME/CFS PATIENTS, 7232 04:22:04,075 --> 04:22:05,576 SO THIS IS REALLY JUST HALF. 7233 04:22:05,643 --> 04:22:07,344 BUT GENERALLY WE WERE ABLE TO 7234 04:22:07,411 --> 04:22:09,780 SHOW THAT THERE WAS 7235 04:22:09,847 --> 04:22:10,714 DIFFERENT DEGREES OF EXPRESSION 7236 04:22:10,781 --> 04:22:13,084 OF WASF3 PROTEIN BUT THEY TENDED 7237 04:22:13,150 --> 04:22:16,587 TO BE HIGHER IN THE ME/CFS 7238 04:22:16,654 --> 04:22:21,292 PATIENTS. 7239 04:22:21,358 --> 04:22:24,228 AGAIN HETEROGENEOUS COMPARED TO 7240 04:22:24,295 --> 04:22:25,229 CONTROLS. 7241 04:22:25,296 --> 04:22:28,099 CONTROLS VERSUS ME/CFS PATIENTS. 7242 04:22:28,165 --> 04:22:32,770 AND THIS IS JUST LOOKING AT THE 7243 04:22:32,837 --> 04:22:34,305 COMPLEX 4-G SUBUNITS AND A 7244 04:22:34,371 --> 04:22:36,474 CORRELATION BETWEEN WASF AND THE 7245 04:22:36,540 --> 04:22:41,112 SIGNIFICANT CORRELATION BETWEEN 7246 04:22:41,178 --> 04:22:43,747 WASF3 AND COMPLEX 4 SUBUNITS, 7247 04:22:43,814 --> 04:22:47,218 QUANTIFICATION OF THE DATA. 7248 04:22:47,284 --> 04:22:52,623 SO WHAT REGULATES WASF3, WHY IS 7249 04:22:52,690 --> 04:22:53,724 WASF3 INCREASED IN THE SAMPLES 7250 04:22:53,791 --> 04:22:57,128 AT LEAST THAT WE'VE LOOKED AT SO 7251 04:22:57,194 --> 04:22:57,795 FAR? 7252 04:22:57,862 --> 04:23:00,431 THERE WAS SOME INDICATION IN THE 7253 04:23:00,498 --> 04:23:02,032 WASF3 FIELD, AGAIN, IT'S A WELL 7254 04:23:02,099 --> 04:23:04,301 STUDIED PROTEIN IN THE CELL 7255 04:23:04,368 --> 04:23:06,237 MOTILITY AND ACTIN FIELD, AND 7256 04:23:06,303 --> 04:23:07,872 THE CANCER FIELD. 7257 04:23:07,938 --> 04:23:13,711 AND WASF3 CAN BE INDUCED BY ER 7258 04:23:13,777 --> 04:23:19,416 STRESS, AND WE TESTED IN THE 7259 04:23:19,483 --> 04:23:21,685 CELLS, ACTUALLY IT WAS SHOWN TO 7260 04:23:21,752 --> 04:23:25,089 BE BIP, A CHAPERONE PROTEIN THAT 7261 04:23:25,156 --> 04:23:26,090 STABILIZES PROTEIN FOLDING THAT 7262 04:23:26,157 --> 04:23:28,392 WAS ACTUALLY INVOLVED IN THAT 7263 04:23:28,459 --> 04:23:34,298 PROCESS, MIGHT ACTUALLY REGULATE 7264 04:23:34,365 --> 04:23:39,770 WASF3, SO WE TREATED SOME HUMAN 7265 04:23:39,837 --> 04:23:42,306 MYOBLASTS WITH TWO DIFFERENT 7266 04:23:42,373 --> 04:23:43,674 CHEMICALS THAT ARE KNOWN TO 7267 04:23:43,741 --> 04:23:44,875 INDUCE ER STRESS. 7268 04:23:44,942 --> 04:23:47,978 AND YOU CAN SEE THAT 7269 04:23:48,045 --> 04:23:48,746 WASF3 PROTEINS COMPARED TO 7270 04:23:48,812 --> 04:23:50,481 UNTREATED CONTROL WAS INDUCED BY 7271 04:23:50,548 --> 04:23:52,216 ER STRESS, AND IN PARALLEL, YOU 7272 04:23:52,283 --> 04:23:54,885 CAN SEE THE COMPLEX 4 SUBUNITS 7273 04:23:54,952 --> 04:23:57,488 ARE DECREASED. 7274 04:23:57,555 --> 04:24:02,092 AND PERK AND BIP ARE CHAPERONE 7275 04:24:02,159 --> 04:24:03,494 PROTEIN, JUST ER STRESS MARKERS. 7276 04:24:03,561 --> 04:24:06,297 SO YOU CAN SEE ASSOCIATED WITH 7277 04:24:06,363 --> 04:24:08,699 INCREASE IN ER STRESS, THERE WAS 7278 04:24:08,766 --> 04:24:10,801 A PARALLEL INCREASE IN 7279 04:24:10,868 --> 04:24:14,405 WASF3 WITH A DOWN REGULATION OF 7280 04:24:14,471 --> 04:24:15,406 RESPIRATORY COMPLEX. 7281 04:24:15,472 --> 04:24:19,143 WE ALSO USED LIPOPOLYSACCHARIDE 7282 04:24:19,210 --> 04:24:21,345 WHICH IS AN ENDO TOXIN, ALSO 7283 04:24:21,412 --> 04:24:23,314 KNOWN TO INDUCE ER STRESS, AND 7284 04:24:23,380 --> 04:24:25,349 SO WE TREATED MICE WITH THIS AND 7285 04:24:25,416 --> 04:24:27,718 YOU CAN SEE THAT WASF -- I 7286 04:24:27,785 --> 04:24:31,021 SHOULD ALSO MENTION THAT IT'S A 7287 04:24:31,088 --> 04:24:31,789 MODEL OF SEPSIS. 7288 04:24:31,855 --> 04:24:33,190 SEPSIS IS WELL-KNOWN TO BE 7289 04:24:33,257 --> 04:24:37,695 ASSOCIATED WITH FATIGUE AS WELL. 7290 04:24:37,761 --> 04:24:40,798 WE SAW WASF3 INDUCED IN THIS 7291 04:24:40,864 --> 04:24:43,334 PROTEIN OVER TIME, AND AGAIN, 7292 04:24:43,400 --> 04:24:44,735 THERE'S DECREASE IN COMPLEX 4, 7293 04:24:44,802 --> 04:24:45,970 INCREASE IN THE ER STRESS 7294 04:24:46,036 --> 04:24:48,038 MARKERS. 7295 04:24:48,105 --> 04:24:49,673 WE WENT BACK TO THE PATIENT'S 7296 04:24:49,740 --> 04:24:52,543 CELLS, THE FIBROBLASTS, AND WE 7297 04:24:52,610 --> 04:24:54,111 COMPARED THE BROTHER CONTROL 7298 04:24:54,178 --> 04:24:57,248 SUBJECT TO THE PATIENT S1 AT 7299 04:24:57,314 --> 04:25:01,518 BASELINE, YOU CAN SEE THAT THE 7300 04:25:01,585 --> 04:25:04,822 PATIENT'S CELL, GUY PRO BLASTS 7301 04:25:04,888 --> 04:25:06,390 HAS HIGHER PERK, AGAIN A MARKER 7302 04:25:06,457 --> 04:25:08,459 OF ER STRESS. 7303 04:25:08,525 --> 04:25:10,995 AND WE TRIED TO REVERSE THE ER 7304 04:25:11,061 --> 04:25:13,163 STRESS USING A NUMBER OF 7305 04:25:13,230 --> 04:25:14,498 DIFFERENT ER STRESS INHIBITORS. 7306 04:25:14,565 --> 04:25:20,971 ONE OF THEM IS TUDCA FOR 7307 04:25:21,038 --> 04:25:22,172 PATIENTS WITH BILE OR LIVER 7308 04:25:22,239 --> 04:25:23,374 DISORDERS, AND WE USE A MUCH 7309 04:25:23,440 --> 04:25:25,809 MORE POTENT ER STRESS INHIBITOR, 7310 04:25:25,876 --> 04:25:28,679 IT'S ACTUALLY A PHOSPHATASE 7311 04:25:28,746 --> 04:25:32,683 INHIBITOR, SALUBRINAL. 7312 04:25:32,750 --> 04:25:35,286 WE TREATED THE CELLS AND -- IN 7313 04:25:35,352 --> 04:25:36,253 THE PATIENT CELL, AND YOU CAN 7314 04:25:36,320 --> 04:25:37,554 SEE WE WERE ABLE TO DOWN 7315 04:25:37,621 --> 04:25:40,324 REGULATE THE ER STRESS MARKER, 7316 04:25:40,391 --> 04:25:43,294 AND ASSOCIATED WITH THAT WAS A 7317 04:25:43,360 --> 04:25:46,797 DOWN REGULATION OF WASF38 7318 04:25:46,864 --> 04:25:49,800 PROTEIN, AGAIN, MUCH MORE 7319 04:25:49,867 --> 04:25:53,337 POTENTLY WITH THE SALUBRINAL, A 7320 04:25:53,404 --> 04:25:54,638 HIGHLY POTENT DRUG ACTUALLY TO 7321 04:25:54,705 --> 04:25:57,074 THE LEVEL OF THE CONTROL LEVEL. 7322 04:25:57,141 --> 04:25:59,777 CONTROL PATIENT CELL LEVEL. 7323 04:25:59,843 --> 04:26:01,245 MOST IMPORTANTLY, WE WERE ABLE 7324 04:26:01,312 --> 04:26:04,281 TO SHOW USING THE SALUBRINAL, 7325 04:26:04,348 --> 04:26:05,516 WHICH AGAIN IS VERY SPECIFIC FOR 7326 04:26:05,582 --> 04:26:08,252 ER STRESS, WE BELIEVE, MORE 7327 04:26:08,319 --> 04:26:09,153 SPECIFIC THAN TUD. 7328 04:26:09,219 --> 04:26:11,455 C A, WE WERE ABLE TO IMPROVE THE 7329 04:26:11,522 --> 04:26:16,393 PATIENT'S BASAL RESPIRATION HE 7330 04:26:16,460 --> 04:26:18,929 HERE, WE HAD RECOVERY OF OXYGEN 7331 04:26:18,996 --> 04:26:20,431 CONSUMPTION IN THE PATIENT CELLS 7332 04:26:20,497 --> 04:26:22,866 WHEN WE DOWNREGULATED ER STRESS, 7333 04:26:22,933 --> 04:26:24,435 SUGGESTING PERHAPS THAT THAT'S A 7334 04:26:24,501 --> 04:26:26,503 STRATEGY THAT COULD BE USED TO 7335 04:26:26,570 --> 04:26:29,573 IMPROVE MITOCHONDRIAL FUNCTION, 7336 04:26:29,640 --> 04:26:30,708 AT LEAST IN THE PATIENT'S CELLS, 7337 04:26:30,774 --> 04:26:34,845 IT'S SUGGESTING THAT. 7338 04:26:34,912 --> 04:26:37,481 SO I'D LIKE TO SUMMARIZE BY 7339 04:26:37,548 --> 04:26:40,050 SAYING WE'VE IDENTIFIED WASF3 IN 7340 04:26:40,117 --> 04:26:41,685 A SINGLE PATIENT WHO HAPPENED TO 7341 04:26:41,752 --> 04:26:42,853 HAVE LI-FRAUMENI SYNDROME. 7342 04:26:42,920 --> 04:26:45,856 WE WERE INTRIGUED BY HER 7343 04:26:45,923 --> 04:26:46,523 MITOCHONDRIAL DYSFUNCTION AND 7344 04:26:46,590 --> 04:26:47,725 FOLLOWED UP ON THAT. 7345 04:26:47,791 --> 04:26:50,561 WE BELIEVE THAT WASF3 IS 7346 04:26:50,627 --> 04:26:51,528 SOMEHOW -- ACTUALLY I DIDN'T 7347 04:26:51,595 --> 04:26:52,796 SHOW YOU THE DATA HEE BUT WE 7348 04:26:52,863 --> 04:26:55,065 ACTUALLY HAVE EVIDENCE THAT 7349 04:26:55,132 --> 04:26:58,302 WASF3 PROTEIN ITSELF IS IN 7350 04:26:58,369 --> 04:26:59,703 PHYSICAL PROXIMITY TO A COUPLE 7351 04:26:59,770 --> 04:27:03,907 OF SUBUNITS OF THE COMPLEX 3, 7352 04:27:03,974 --> 04:27:04,775 RATHER SPECIFIC INTERACTION 7353 04:27:04,842 --> 04:27:06,210 GOING ON, AND THAT WHAT WE THINK 7354 04:27:06,276 --> 04:27:09,546 IS HAPPENING IS THAT WASF3 IS 7355 04:27:09,613 --> 04:27:11,715 PREVENTING WHEN IT BINDS THE 7356 04:27:11,782 --> 04:27:15,119 COMPLEX, IT'S PREVENTING COMPLEX 7357 04:27:15,185 --> 04:27:20,157 4 SUBUNITS FROM -- DESTABILIZES 7358 04:27:20,224 --> 04:27:20,691 COMPLEX 4 PROTEIN. 7359 04:27:20,758 --> 04:27:25,629 IF YOU DON'T HAVE THIS 7360 04:27:25,696 --> 04:27:27,831 SUPERCOMPLEX, THEN YOUR 7361 04:27:27,898 --> 04:27:30,033 EFFICIENCY OF RESPIRATION WOULD 7362 04:27:30,100 --> 04:27:32,569 BE DECREASED, AND IF YOU CAN'T 7363 04:27:32,636 --> 04:27:35,105 RE SPIRE, YOU CAN'T MAKE ATP AND 7364 04:27:35,172 --> 04:27:37,040 PERHAPS THAT CAN CONTRIBUTE TO 7365 04:27:37,107 --> 04:27:40,277 THE FATIGUE AND ENERGY 7366 04:27:40,344 --> 04:27:42,679 DEFICIENCY IN CHRONIC FATIGUE 7367 04:27:42,746 --> 04:27:44,014 SYNDROME. 7368 04:27:44,081 --> 04:27:46,950 SO I'D LIKE TO COMPLETE JUST BY 7369 04:27:47,017 --> 04:27:47,985 ACKNOWLEDGING AGAIN PEOPLE WHO 7370 04:27:48,051 --> 04:27:51,388 DID ALL THE WORK. 7371 04:27:51,455 --> 04:27:54,458 MY LAB MEMBERS, THE PATIENT WHO 7372 04:27:54,525 --> 04:27:56,093 MADE THIS STUDY POSSIBLE. 7373 04:27:56,160 --> 04:27:59,730 WITHOUT PATIENTS, PERSISTENT 7374 04:27:59,797 --> 04:28:03,934 PATIENTS, IT WOULD BE DIFFICULT 7375 04:28:04,001 --> 04:28:06,737 TO DISCOVERY, AND ALSO THE MANY 7376 04:28:06,804 --> 04:28:08,105 COLLABORATORS WHO HELPED US WITH 7377 04:28:08,172 --> 04:28:11,708 THIS STUDY, ESPECIALLY BRIAN 7378 04:28:11,775 --> 04:28:15,379 WALITT AND AVI NATH WHO AGAIN 7379 04:28:15,446 --> 04:28:16,680 HELPED US WITH THE SAMPLES AND 7380 04:28:16,747 --> 04:28:17,681 GAVE US GREAT ADVICE. 7381 04:28:17,748 --> 04:28:18,015 SO THAT'S IT. 7382 04:28:18,081 --> 04:28:18,382 THANK YOU. 7383 04:28:18,449 --> 04:28:28,625 [APPLAUSE] 7384 04:28:33,230 --> 04:28:34,531 >> HELLO. 7385 04:28:34,598 --> 04:28:36,633 FRANCISCO FROM SAN DIEGO. 7386 04:28:36,700 --> 04:28:37,601 QUESTION. 7387 04:28:37,668 --> 04:28:39,736 IN YOUR OVEREXPRESSING MICE, IF 7388 04:28:39,803 --> 04:28:42,806 YOU DO A SECOND TREADMILL TEST, 7389 04:28:42,873 --> 04:28:44,775 DO THEY DEVELOP LIKE A POST 7390 04:28:44,842 --> 04:28:46,009 EXERTIONAL MALAISE? 7391 04:28:46,076 --> 04:28:48,412 >> THAT'S A GREAT QUESTION. 7392 04:28:48,479 --> 04:28:51,482 THE QUESTION IS WHETHER -- IF 7393 04:28:51,548 --> 04:28:52,783 YOU EXERCISE TEST THE MICE, 7394 04:28:52,850 --> 04:28:55,953 AGAIN, DO THEY -- I GUESS IS 7395 04:28:56,019 --> 04:28:57,087 THERE A CHANGE, RIGHT? 7396 04:28:57,154 --> 04:28:58,856 WE ACTUALLY DEPARTMENT DO THAT, 7397 04:28:58,922 --> 04:29:02,359 BUT THAT'S A VERY, YOU KNOW, 7398 04:29:02,426 --> 04:29:04,528 INTERESTING POINT. 7399 04:29:04,595 --> 04:29:05,395 BUT WE DIDN'T DO THAT. 7400 04:29:05,462 --> 04:29:08,198 I MEAN, IT WAS A VERY DRAMATIC 7401 04:29:08,265 --> 04:29:08,632 DECREASE. 7402 04:29:08,699 --> 04:29:10,634 WE'RE JUST PROVING THAT -- WE'RE 7403 04:29:10,701 --> 04:29:12,803 JUST DEMONSTRATING THAT IF YOU 7404 04:29:12,870 --> 04:29:14,371 OVEREXPRESS IT IN VIVO, YOU CAN 7405 04:29:14,438 --> 04:29:16,840 HAVE AN IN VIVO PHYSIOLOGIC 7406 04:29:16,907 --> 04:29:18,141 PHENOTYPE. 7407 04:29:18,208 --> 04:29:19,576 THANKS. 7408 04:29:19,643 --> 04:29:23,514 >> ONE CORNELL QUESTION. 7409 04:29:23,580 --> 04:29:28,118 [LAUGHTER] 7410 04:29:28,185 --> 04:29:29,119 >> OKAY. 7411 04:29:29,186 --> 04:29:32,956 I WAS WONDERING IF YOUR CONTROLS 7412 04:29:33,023 --> 04:29:34,591 FOR THE SKELETAL MUSCLE BIOPSY 7413 04:29:34,658 --> 04:29:37,528 WERE SEDENTARY. 7414 04:29:37,594 --> 04:29:39,830 AND WERE THE CONTROLS SEDENTARY 7415 04:29:39,897 --> 04:29:41,198 THAT YOU WERE COMPARING THE 7416 04:29:41,265 --> 04:29:44,401 LEVELS OF WASF3 TO THE PATIENTS 7417 04:29:44,468 --> 04:29:47,404 WHO ARE SEDENTARY? 7418 04:29:47,471 --> 04:29:50,641 AND THE POINT BEING IS, IS IT 7419 04:29:50,707 --> 04:29:53,510 POSSIBLE THAT THERE'S A 7420 04:29:53,577 --> 04:29:56,113 DIFFERENCE IN WASF33 LEVELS IN 7421 04:29:56,179 --> 04:29:57,347 PEOPLE WHO ARE SEDENTARY VERSUS 7422 04:29:57,414 --> 04:29:58,148 PEOPLE WHO ARE ACTIVE? 7423 04:29:58,215 --> 04:29:59,316 >> THAT'S A GREAT POINT. 7424 04:29:59,383 --> 04:30:00,651 THAT'S A GREAT POINT. 7425 04:30:00,717 --> 04:30:04,821 THE QUESTION IS, DID WE CONTROL 7426 04:30:04,888 --> 04:30:06,557 FOR LEVEL OF ACTIVITY IN THE 7427 04:30:06,623 --> 04:30:08,091 HEALTHY VOLUNTEER MUSCLE 7428 04:30:08,158 --> 04:30:12,162 SAMPLES. 7429 04:30:12,229 --> 04:30:13,697 I ACTUALLY APOLOGIZE BUT I DON'T 7430 04:30:13,764 --> 04:30:17,367 KNOW THE ANSWER TO THAT. 7431 04:30:17,434 --> 04:30:18,435 I'M SURE BRIAN HAS THE ANSWER TO 7432 04:30:18,502 --> 04:30:21,171 THAT BECAUSE THEY TOOK A VERY 7433 04:30:21,238 --> 04:30:24,908 COMPREHENSIVE SURVEY OF THESE 7434 04:30:24,975 --> 04:30:25,909 PATIENTS SO I'M SURE THEY HAVE 7435 04:30:25,976 --> 04:30:28,645 THE ACTIVITY LEVELS OF THE 7436 04:30:28,712 --> 04:30:31,682 PATIENTS, BUT THAT'S A GOOD 7437 04:30:31,748 --> 04:30:33,617 QUESTION. 7438 04:30:33,684 --> 04:30:34,685 AND I THINK THE IMPORTANT 7439 04:30:34,751 --> 04:30:36,219 QUESTION IS DOES IT ALSO CHANGE 7440 04:30:36,286 --> 04:30:40,023 WITH EXERCISE, RIGHT, AS THE 7441 04:30:40,090 --> 04:30:41,058 PREVIOUS PERSON ASKED THE 7442 04:30:41,124 --> 04:30:42,826 QUESTION ABOUT WHAT HAPPENS 7443 04:30:42,893 --> 04:30:44,561 AFTER EXERCISE, DOES IT GET 7444 04:30:44,628 --> 04:30:45,128 WORSE. 7445 04:30:45,195 --> 04:30:49,533 BUT WE REALLY DON'T KNOW DOES IT 7446 04:30:49,600 --> 04:30:50,734 CHANGE WITH EXERCISE ACTIVITY. 7447 04:30:50,801 --> 04:30:53,904 I WOULD SUSPECT THAT IF YOU DO 7448 04:30:53,971 --> 04:30:55,205 ENDURANCE EXERCISE THAT THERE 7449 04:30:55,272 --> 04:30:57,441 WILL BE CHANGES IN ER STRESS 7450 04:30:57,507 --> 04:30:59,743 LEVELS IN SKELETAL MUSCLE. 7451 04:30:59,810 --> 04:31:00,944 SO I WOULD IMAGINE THAT THERE 7452 04:31:01,011 --> 04:31:04,147 WOULD BE ADAPTATIONS THAT MIGHT 7453 04:31:04,214 --> 04:31:04,381 CHANGE. 7454 04:31:04,448 --> 04:31:07,718 SO I THINK IT'S A GOOD QUESTION, 7455 04:31:07,784 --> 04:31:08,185 IMPORTANT QUESTION. 7456 04:31:08,251 --> 04:31:10,454 >> RELATED TO THAT, WAS THERE A 7457 04:31:10,520 --> 04:31:11,688 SEX DIFFERENCE IN THE PATIENTS 7458 04:31:11,755 --> 04:31:15,158 AND CONTROLS AND IS THERE ANY 7459 04:31:15,225 --> 04:31:17,260 EVIDENCE ABOUT MALES VERSUS 7460 04:31:17,327 --> 04:31:18,662 FEMALES ABOUT HAVING MORE OR 7461 04:31:18,729 --> 04:31:20,063 LESS WASF3. 7462 04:31:20,130 --> 04:31:21,698 >> OH, IT'S SO HARD TO HEAR FROM 7463 04:31:21,765 --> 04:31:23,667 UP HERE. 7464 04:31:23,734 --> 04:31:26,503 OH. 7465 04:31:26,570 --> 04:31:33,677 I THINK THERE ARE MORE WOMEN 7466 04:31:33,744 --> 04:31:35,078 SAMPLES BUT THERE ARE MALE 7467 04:31:35,145 --> 04:31:35,746 SAMPLES AS WELL. 7468 04:31:35,812 --> 04:31:37,047 WE ACTUALLY TRY TO BALANCE THAT 7469 04:31:37,114 --> 04:31:41,985 AS WELL. 7470 04:31:42,052 --> 04:31:43,453 BUT I'M PRETTY SURE IT'S 7471 04:31:43,520 --> 04:31:48,825 DEFINITELY MORE WOMEN THAN MEN. 7472 04:31:48,892 --> 04:31:50,560 >> SORRY I HAD TO CUT YOU OFF, 7473 04:31:50,627 --> 04:31:50,761 JEFF. 7474 04:31:50,827 --> 04:31:52,229 MAYBE YOU CAN ASK DURING THE 7475 04:31:52,295 --> 04:31:55,332 PANEL DISCUSSION. 7476 04:31:55,399 --> 04:31:57,701 WE'LL MOVE TO OUR NEXT SPEAKER, 7477 04:31:57,768 --> 04:32:00,170 METABOLIC INSIGHTS INTO ME/CFS, 7478 04:32:00,237 --> 04:32:01,905 PHENOTYPES AND UNDERLYING 7479 04:32:01,972 --> 04:32:04,207 MECHANISMS. 7480 04:32:04,274 --> 04:32:05,175 KARL-JOHAN TRONSTAD FROM 7481 04:32:05,242 --> 04:32:06,943 UNIVERSITY OF BERGEN. 7482 04:32:07,010 --> 04:32:08,879 PROBABLY TRAVELED THE FURTHEST 7483 04:32:08,945 --> 04:32:19,089 TO COME. 7484 04:32:20,924 --> 04:32:22,392 >> THANK YOU, AND THANK YOU FOR 7485 04:32:22,459 --> 04:32:25,262 THE INVITATION TO COME. 7486 04:32:25,328 --> 04:32:26,363 IT'S VERY GOOD TO BE HERE AND 7487 04:32:26,430 --> 04:32:30,200 LISTEN TO THE TALKS. 7488 04:32:30,267 --> 04:32:33,870 NIH IS INSTRUMENTAL IN INSPIRING 7489 04:32:33,937 --> 04:32:35,305 RESEARCH ALL OVER THE WORLD, I 7490 04:32:35,372 --> 04:32:36,573 THINK, EVEN IN SMALL CORNERS OF 7491 04:32:36,640 --> 04:32:38,008 THE WORLD. 7492 04:32:38,075 --> 04:32:41,445 WHERE I CAME FROM, COME FROM. 7493 04:32:41,511 --> 04:32:43,847 SO I'M GOING TO TALK ABOUT 7494 04:32:43,914 --> 04:32:47,784 METABOLIC STUDIES IN ME/CFS, AND 7495 04:32:47,851 --> 04:32:49,119 SOME OF THE THINGS WE HAVE BEEN 7496 04:32:49,186 --> 04:32:54,591 WORKING ON, BUT FIRST I'LL 7497 04:32:54,658 --> 04:32:56,793 INTRODUCE TO THE GROUP WE ARE 7498 04:32:56,860 --> 04:32:58,995 WORKING IN. 7499 04:32:59,062 --> 04:33:02,099 I WILL JUST HOLD THE POINTER. 7500 04:33:02,165 --> 04:33:03,767 AND I'M WORKING IN A 7501 04:33:03,834 --> 04:33:05,569 TRANSLATIONAL RESEARCH GROUP IN 7502 04:33:05,635 --> 04:33:10,307 BERGEN, IN NORWAY. 7503 04:33:10,373 --> 04:33:20,851 ANI COME FROM THE UNIVERSITY IN 7504 04:33:20,917 --> 04:33:22,352 THE DEPARTMENT OF BIOMEDICINE AT 7505 04:33:22,419 --> 04:33:25,655 THE UNIVERSITY OF BERGEN AND 7506 04:33:25,722 --> 04:33:27,224 COLLABORATE CLOSELY WITH THE 7507 04:33:27,290 --> 04:33:27,891 CLINIC. 7508 04:33:27,958 --> 04:33:30,193 TOGETHER WE INVESTIGATE 7509 04:33:30,260 --> 04:33:31,394 MECHANISMS AND DIFFERENCES 7510 04:33:31,461 --> 04:33:33,797 BETWEEN HEALTHY AND ME/CFS 7511 04:33:33,864 --> 04:33:36,099 PATIENTS. 7512 04:33:36,166 --> 04:33:39,436 THERE'S A BIOBANK -- WHICH WE 7513 04:33:39,503 --> 04:33:41,705 USE AS A RESOURCE FOR THESE 7514 04:33:41,772 --> 04:33:42,806 STUDIES. 7515 04:33:42,873 --> 04:33:47,878 SO THE HYPOTHESIS WE ARE 7516 04:33:47,944 --> 04:33:51,715 ADDRESSING IS THAT M.E. IS DUE 7517 04:33:51,782 --> 04:33:56,386 TO AN ACQUIRED IMMUNE SYSTEM 7518 04:33:56,453 --> 04:33:59,756 DEFECT THAT CAN BE CAUSED BY 7519 04:33:59,823 --> 04:34:01,958 AUTOIMMUNITY. 7520 04:34:02,025 --> 04:34:03,460 PROBABLY IN A SUBGROUP OF 7521 04:34:03,527 --> 04:34:03,794 PATIENTS. 7522 04:34:03,860 --> 04:34:07,030 AND BASED ON THIS HYPOTHESIS, MY 7523 04:34:07,097 --> 04:34:09,766 PARTNERS AT THE CLINIC, THEY ARE 7524 04:34:09,833 --> 04:34:11,067 TRYING TO TEST DIFFERENT 7525 04:34:11,134 --> 04:34:13,837 THERAPIES TO REBOOT PARTS OF THE 7526 04:34:13,904 --> 04:34:14,838 IMMUNE SYSTEM. 7527 04:34:14,905 --> 04:34:17,707 TO SEE IF THAT HAS BENEFICIAL 7528 04:34:17,774 --> 04:34:22,145 EFFECT. 7529 04:34:22,212 --> 04:34:24,347 NOW, THIS HISTORY, THE HISTORY 7530 04:34:24,414 --> 04:34:28,485 OF THIS RESEARCH STARTED AROUND 7531 04:34:28,552 --> 04:34:32,622 2007 WHERE MY TWO MAIN 7532 04:34:32,689 --> 04:34:36,893 COLLEAGUES AT THE CLINIC ARE 7533 04:34:36,960 --> 04:34:41,932 WORKING IN THE CANCER WORLD AND 7534 04:34:41,998 --> 04:34:43,433 THEY TREAT CANCER PATIENTS, 7535 04:34:43,500 --> 04:34:44,467 CANCER PATIENTS THAT HAD M.E. 7536 04:34:44,534 --> 04:34:46,636 FOR SEVERAL YEARS BEFORE THEY 7537 04:34:46,703 --> 04:34:48,071 GOT THEIR CANCER TREATMENT, AND 7538 04:34:48,138 --> 04:34:50,207 THEN THEY OBSERVED THAT SOME OF 7539 04:34:50,273 --> 04:34:51,308 THESE PATIENTS BECAME BETTER 7540 04:34:51,374 --> 04:34:54,144 AFTER THE CANCER TREATMENT. 7541 04:34:54,211 --> 04:34:59,316 SO THEN THEY GOT THIS IDEA OF -- 7542 04:34:59,382 --> 04:35:01,384 MAYBE THIS COULD BE SOME TYPE OF 7543 04:35:01,451 --> 04:35:03,053 AN AUTOIMMUNE MECHANISM. 7544 04:35:03,119 --> 04:35:05,689 AND THEY HAVE DONE SEVERAL 7545 04:35:05,755 --> 04:35:09,326 CLINICAL TRIALS TO TEST IMMUNE 7546 04:35:09,392 --> 04:35:11,394 MODULATING TREATMENTS IN THESE 7547 04:35:11,461 --> 04:35:12,495 PATIENT GROUPS AND THEY HAVE 7548 04:35:12,562 --> 04:35:14,831 ESTABLISHED THE BIOBANK AND ALSO 7549 04:35:14,898 --> 04:35:15,966 DONE OBSERVATIONAL STUDIES 7550 04:35:16,032 --> 04:35:18,134 RELATED TO THIS. 7551 04:35:18,201 --> 04:35:20,770 SO THE STATUS IS THAT THERE 7552 04:35:20,837 --> 04:35:22,339 MIGHT BE A SUBGROUP OF PATIENTS 7553 04:35:22,405 --> 04:35:26,643 THAT MAY BENEFIT FROM THIS. 7554 04:35:26,710 --> 04:35:31,314 BUT MORE EVIDENCE IS NEEDED. 7555 04:35:31,381 --> 04:35:33,149 NOW WE CAME IN AROUND 2015 AND 7556 04:35:33,216 --> 04:35:34,551 CONTRIBUTED IN THE MECHANISTIC 7557 04:35:34,618 --> 04:35:38,521 INVESTIGATIONS. 7558 04:35:38,588 --> 04:35:42,092 ALSO THE COMPREHENSIVE BLOOD 7559 04:35:42,158 --> 04:35:44,661 SAMPLE ANALYSIS THAT HAS BEEN 7560 04:35:44,728 --> 04:35:50,600 DONE UNDER THE BIOBANK SAMPLES. 7561 04:35:50,667 --> 04:35:55,739 TWO OF THE MAJOR CLINICAL TRIALS 7562 04:35:55,805 --> 04:36:05,615 TRIALS, THERE WERE MANY LEARNING 7563 04:36:05,682 --> 04:36:06,816 LESSONS AND MANY SAMPLE FROM 7564 04:36:06,883 --> 04:36:08,919 THAT STUDY WHICH HAS BEEN VERY 7565 04:36:08,985 --> 04:36:10,787 USEFUL AFTERWARDS. 7566 04:36:10,854 --> 04:36:17,060 THIS WAS A MULTICENTER RCT AND 7567 04:36:17,127 --> 04:36:20,563 IT NEGATIVE. 7568 04:36:20,630 --> 04:36:26,403 THE CYCLOME TRIAL DRUG WAS HARD 7569 04:36:26,469 --> 04:36:30,040 FOR THE PATIENT TS TO 50 THROUGH 7570 04:36:30,106 --> 04:36:31,574 THIS AND IT WAS AN OPEN LABEL 7571 04:36:31,641 --> 04:36:32,008 STUDY. 7572 04:36:32,075 --> 04:36:34,577 MORE THAN HALF OF THE PATIENTS 7573 04:36:34,644 --> 04:36:36,980 GOT CLINICAL BENEFIT FROM THIS 7574 04:36:37,047 --> 04:36:38,214 TREATMENT. 7575 04:36:38,281 --> 04:36:43,486 THE S.DUE TO SIDE EFFECTS, THISG 7576 04:36:43,553 --> 04:36:44,788 WILL NOT BE CONTINUED FOR 7577 04:36:44,854 --> 04:36:45,121 TESTING. 7578 04:36:45,188 --> 04:36:47,757 NOW BASED ON THESE OBSERVATIONS 7579 04:36:47,824 --> 04:36:53,163 AND THE OTHER ACTIVITY GOING ON, 7580 04:36:53,229 --> 04:36:56,032 WE HAVE THIS WORKING HYPOTHESIS. 7581 04:36:56,099 --> 04:36:57,867 IT'S ON THE IMMUNE DYSREGULATION 7582 04:36:57,934 --> 04:37:04,307 BEHIND THAT CAUSES AN EFFECTOR 7583 04:37:04,374 --> 04:37:06,276 MECHANISM, AND WE FIND VASCULAR 7584 04:37:06,343 --> 04:37:09,212 DYSREGULATION TO BE A POSSIBLE 7585 04:37:09,279 --> 04:37:10,780 AND LIKELY EFFECTOR MECHANISM. 7586 04:37:10,847 --> 04:37:12,549 AND THEN YOU HAVE ADAPTATION OF 7587 04:37:12,615 --> 04:37:14,985 CHANGES AFTERWARDS. 7588 04:37:15,051 --> 04:37:16,720 WE DIVIDED IN THREE STEPS TO TRY 7589 04:37:16,786 --> 04:37:27,063 TO KIND OF FIND THE PAT THAT PAT 7590 04:37:27,130 --> 04:37:29,566 MIGHT BE ASSOCIATED THROUGH 7591 04:37:29,632 --> 04:37:31,267 THESE THREE STEPS. 7592 04:37:31,334 --> 04:37:37,974 THERE YOU ALSO FIND SOME 7593 04:37:38,041 --> 04:37:39,009 SUGGESTIONS FOR THERAPEUTIC 7594 04:37:39,075 --> 04:37:42,178 STRATEGIES AND WHERE TO GO -- WE 7595 04:37:42,245 --> 04:37:42,912 COULD GO. 7596 04:37:42,979 --> 04:37:44,781 SO CURRENTLY THEY'RE TESTING 7597 04:37:44,848 --> 04:37:45,915 PLASMA CELL DIRECTED TREATMENT 7598 04:37:45,982 --> 04:37:47,817 IN A PILOT STUDY. 7599 04:37:47,884 --> 04:37:50,553 MAYBE THAT CAN BE A POSSIBLE 7600 04:37:50,620 --> 04:37:51,721 STRATEGY. 7601 04:37:51,788 --> 04:37:53,490 NOW, WHEN IT COMES TO THE STATUS 7602 04:37:53,556 --> 04:37:58,661 OF METABOLISM IN ME/CFS, STUDIES 7603 04:37:58,728 --> 04:38:01,731 HAVE FOUND CHANGES IN BLOOD 7604 04:38:01,798 --> 04:38:02,932 BIOCHEMISTRY AND THERE ARE MANY 7605 04:38:02,999 --> 04:38:04,634 THEORIES AND HYPOTHESES 7606 04:38:04,701 --> 04:38:07,904 DISCUSSED, BUT WE INTERPRET -- 7607 04:38:07,971 --> 04:38:10,340 TO KEEP IT SIMPLE, WE INTERPRET 7608 04:38:10,407 --> 04:38:13,043 THESE FINDINGS AS INDICATIONS -- 7609 04:38:13,109 --> 04:38:15,211 THERE ARE MANY FINDINGS, MANY 7610 04:38:15,278 --> 04:38:16,279 INDICATIONS OF ENERGY STRESS IN 7611 04:38:16,346 --> 04:38:19,015 THOSE FINDINGS. 7612 04:38:19,082 --> 04:38:21,184 AND WE ALSO THINK THERE IS 7613 04:38:21,251 --> 04:38:22,285 EVIDENCE OF HYPOXIA. 7614 04:38:22,352 --> 04:38:24,454 THIS HAS BEEN, OF COURSE, A 7615 04:38:24,521 --> 04:38:25,755 PARADIGM IN THE FIELD AS WELL, 7616 04:38:25,822 --> 04:38:28,658 THAT TISSUE HYPOXIA IS A 7617 04:38:28,725 --> 04:38:33,163 CHARACTER OF THIS PATIENT GROUP. 7618 04:38:33,229 --> 04:38:39,102 BUT THERE HAVE NOT BEEN TARA TAO 7619 04:38:39,169 --> 04:38:40,303 REALLY SHOW THIS IN MOST 7620 04:38:40,370 --> 04:38:42,072 PATIENTS. 7621 04:38:42,138 --> 04:38:43,573 WE THINK THERE ARE METABOLIC 7622 04:38:43,640 --> 04:38:46,076 SUBGROUPS THAT CAN ALSO BE OF 7623 04:38:46,142 --> 04:38:47,243 CLINICAL INTEREST, BUT WE NEED 7624 04:38:47,310 --> 04:38:50,580 MORE CLINICAL OR COMPREHENSIVE 7625 04:38:50,647 --> 04:38:56,719 STUDIES TO REALLY GET INTO THE 7626 04:38:56,786 --> 04:38:57,754 MOLECULAR ARCHITECTURE, AND 7627 04:38:57,821 --> 04:38:59,589 MAYBE FIND BIOMARKERS AND MAYBE 7628 04:38:59,656 --> 04:39:03,093 TARGETS FOR TREATMENT. 7629 04:39:03,159 --> 04:39:05,862 DIFFERENT MORE PRECISE 7630 04:39:05,929 --> 04:39:06,963 SUBGROUPS. 7631 04:39:07,030 --> 04:39:09,833 SO I WILL GO INTO THIS TISSUE 7632 04:39:09,899 --> 04:39:13,636 HYPOXIA TOPIC. 7633 04:39:13,703 --> 04:39:15,305 SO WE HAVE SOME INDICATIONS, AND 7634 04:39:15,371 --> 04:39:21,010 I THINK I DON'T NEED TO USE TIME 7635 04:39:21,077 --> 04:39:23,980 CONVINCING YOU THAT TISSUE 7636 04:39:24,047 --> 04:39:26,683 HYPOXIA IS IMPORTANT. 7637 04:39:26,750 --> 04:39:27,550 COMING AFTER ME, HE WILL TALK 7638 04:39:27,617 --> 04:39:28,818 MORE ABOUT THIS BUT THEY HAVE 7639 04:39:28,885 --> 04:39:29,652 CONTRIBUTED SOME OF THE MOST 7640 04:39:29,719 --> 04:39:32,188 IMPORTANT FINDINGS LIKELY THAT 7641 04:39:32,255 --> 04:39:36,693 THIS IS A VERY LIKELY EFFECT. 7642 04:39:36,759 --> 04:39:39,429 NOW, THIS IS DUE -- THIS LEADS 7643 04:39:39,496 --> 04:39:44,267 TO REDUCED OXYGEN OR A VASCULAR 7644 04:39:44,334 --> 04:39:46,703 EFFECT CAN LEAD TO REDUCED 7645 04:39:46,769 --> 04:39:49,205 OXYGEN DELIVERY ANDS BE 7646 04:39:49,272 --> 04:39:50,974 RESPONSIBLE FOR THE LACTATE 7647 04:39:51,040 --> 04:39:52,342 OVERPRODUCTION THAT THE PATIENTS 7648 04:39:52,408 --> 04:39:54,444 TALK ABOUT AND WE HAVE BEEN 7649 04:39:54,511 --> 04:39:59,249 ALSO -- OR SOME GROUPS -- THIS 7650 04:39:59,315 --> 04:40:01,518 STUDY FROM OSLO WHERE YOU SEE 7651 04:40:01,584 --> 04:40:04,888 THE RED LINES SHOWING AN EARLY 7652 04:40:04,954 --> 04:40:08,358 ELEVATION OF LACTATE IN PATIENTS 7653 04:40:08,424 --> 04:40:10,059 DURING THE TEST. 7654 04:40:10,126 --> 04:40:11,494 ALSO THESE EFFECTS CAN BE 7655 04:40:11,561 --> 04:40:12,428 RESPONSIBLE AT LEAST PARTLY FOR 7656 04:40:12,495 --> 04:40:17,400 THE PHYSICAL IMPAIRMENT AND 7657 04:40:17,467 --> 04:40:18,968 SYMPTOMS IN THE PATIENTS. 7658 04:40:19,035 --> 04:40:20,603 AND I WILL TAKE YOU BACK TO THE 7659 04:40:20,670 --> 04:40:22,505 CORE WHEN IT COMES TO ENERGY 7660 04:40:22,572 --> 04:40:25,341 METABOLISM AND WHAT KIND OF 7661 04:40:25,408 --> 04:40:30,013 EFFECTS TISSUE HYPOXIA WE WILL D 7662 04:40:30,079 --> 04:40:32,549 TO OR MAY LEAD TO OR EVEN A 7663 04:40:32,615 --> 04:40:33,850 PARTIAL ACTIVATION OF THIS 7664 04:40:33,917 --> 04:40:34,384 HYPOXIA M PRA. 7665 04:40:34,450 --> 04:40:35,752 SO HERE WE HAVE THE MAIN ACCESS 7666 04:40:35,818 --> 04:40:37,287 OF ENERGY METABOLISM IN THE 7667 04:40:37,353 --> 04:40:38,188 CELL. 7668 04:40:38,254 --> 04:40:43,826 WITH GLUCOSE BEING CONVERTED TO 7669 04:40:43,893 --> 04:40:46,329 PYRUVATE, IMPORTED INTO THE 7670 04:40:46,396 --> 04:40:49,499 MITOCHONDRIA AND CONVERTED TO 7671 04:40:49,566 --> 04:40:52,936 ACETYL COA, THEN YOU HAVE THE 7672 04:40:53,002 --> 04:40:56,005 TCA CYCLE, AND OXIDATIVE 7673 04:40:56,072 --> 04:40:57,640 PHOSPHORYLATION SYSTEM, WHICH 7674 04:40:57,707 --> 04:41:01,511 THEN ARE RESPONSIBLE FOR MAKING 7675 04:41:01,578 --> 04:41:03,613 ALL THAT ATP FROM THE 7676 04:41:03,680 --> 04:41:06,149 MITOCHONDRIAL FUNCTION. 7677 04:41:06,216 --> 04:41:10,453 NOW, WHAT HAPPENS IF WE HAVE 7678 04:41:10,520 --> 04:41:13,790 SOME ELEVATION OF -- OR 7679 04:41:13,856 --> 04:41:18,328 AMPLIFIED EFFECTS OF HYPOXIA? 7680 04:41:18,394 --> 04:41:21,064 SO TYPICALLY THIS LEADS TO 7681 04:41:21,130 --> 04:41:24,801 INCREASED GLYCOLYSIS. 7682 04:41:24,867 --> 04:41:29,405 AND INCREASED PRODUCTION OF 7683 04:41:29,472 --> 04:41:32,942 PYRUVATE, THIS IS WHERE NOW THE 7684 04:41:33,009 --> 04:41:34,377 CELL GETS MOST OF ITS ENERGY. 7685 04:41:34,444 --> 04:41:37,046 BUT SINCE WE HAVE A LACK OF 7686 04:41:37,113 --> 04:41:38,915 OXYGEN, THE MITOCHONDRIAL 7687 04:41:38,982 --> 04:41:40,683 MACHINERY WHICH WILL BE TURNED 7688 04:41:40,750 --> 04:41:46,522 OFF, OR IF YOU HAVE A CONDIT 7689 04:41:46,589 --> 04:41:47,957 CONDITION -- OF OXYGEN, WE CAN 7690 04:41:48,024 --> 04:41:52,228 THINK MAYBE MITOCHONDRIA ARE 7691 04:41:52,295 --> 04:41:59,002 PARTLY TURNED OFF. 7692 04:41:59,068 --> 04:42:00,169 NOW, WHAT ARE THE CONSEQUENCES 7693 04:42:00,236 --> 04:42:04,440 OF THIS? 7694 04:42:04,507 --> 04:42:07,076 THERE WILL BE METABOLIC 7695 04:42:07,143 --> 04:42:07,844 COMPROMISES. 7696 04:42:07,911 --> 04:42:09,879 THERE WILL BE MORE LACTATE, 7697 04:42:09,946 --> 04:42:12,382 THERE WILL BE A STRUGGLE FOR ATP 7698 04:42:12,448 --> 04:42:15,551 AND THIS CAN BE AMPLIFIED BY 7699 04:42:15,618 --> 04:42:16,753 ACTIVITY. 7700 04:42:16,819 --> 04:42:18,588 AND THIS IS SOMETHING THAT WE 7701 04:42:18,655 --> 04:42:19,789 EASILY CAN RELATE TO WHEN IT 7702 04:42:19,856 --> 04:42:24,060 COMES TO THE PATIENTS. 7703 04:42:24,127 --> 04:42:26,529 THE POSSIBLE CAUSES CAN THEN BE 7704 04:42:26,596 --> 04:42:29,265 THAT THERE IS LESS BLOOD TO THE 7705 04:42:29,332 --> 04:42:30,566 TISSUE, LESS PERFUSION. 7706 04:42:30,633 --> 04:42:31,668 AS I MENTIONED. 7707 04:42:31,734 --> 04:42:33,603 BUT IT CAN ALSO BE DUE TO 7708 04:42:33,670 --> 04:42:35,805 MITOCHONDRIAL DEFECTS, WHICH CAN 7709 04:42:35,872 --> 04:42:38,207 BE, FOR INSTANCE, GENETIC IN 7710 04:42:38,274 --> 04:42:39,575 MITOCHONDRIAL DISEASE AND 7711 04:42:39,642 --> 04:42:40,677 CONDITIONS LIKE THAT, BUT ALSO 7712 04:42:40,743 --> 04:42:43,313 IN SOME ACQUIRED METABOLIC 7713 04:42:43,379 --> 04:42:44,847 DISEASE, NOT ONLY ACQUIRED BUT 7714 04:42:44,914 --> 04:42:47,183 ALSO DIABETES AND OTHER 7715 04:42:47,250 --> 04:42:48,618 CONDITIONS, THIS SYSTEM CAN BE 7716 04:42:48,685 --> 04:42:49,519 ACTIVATED. 7717 04:42:49,585 --> 04:42:51,521 AND THEN THE NEGATIVE 7718 04:42:51,587 --> 04:42:53,289 PHYSIOLOGICAL IMPACT INVOLVES 7719 04:42:53,356 --> 04:42:55,792 BOTH LOWERED ANAEROBIC 7720 04:42:55,858 --> 04:42:57,560 THRESHOLD, EXERCISE INTOLERANCE, 7721 04:42:57,627 --> 04:43:00,530 AND MAYBE POST EXERTION MALAISE, 7722 04:43:00,596 --> 04:43:03,666 WHICH IS THE THING WE KNOW LESS 7723 04:43:03,733 --> 04:43:05,935 OF IN THIS CONTEXT. 7724 04:43:06,002 --> 04:43:10,807 NOW YOU HAVE THIS ACTIVATED 7725 04:43:10,873 --> 04:43:13,810 PROGRAM FOR -- ACTIVATED BECAUSE 7726 04:43:13,876 --> 04:43:15,178 THERE IS A LACK OF OXYGEN. 7727 04:43:15,244 --> 04:43:19,082 AND THIS CREATES A CONDITION OF 7728 04:43:19,148 --> 04:43:20,950 ENERGY STRESS, WHICH THE BODY 7729 04:43:21,017 --> 04:43:23,653 CAN TRY TO MITIGATE BY 7730 04:43:23,720 --> 04:43:24,754 ACTIVATING METABOLIC 7731 04:43:24,821 --> 04:43:26,222 ADAPTATIONS. 7732 04:43:26,289 --> 04:43:28,524 AND THIS CAN BE LONG TERM 7733 04:43:28,591 --> 04:43:31,627 ADAPTATIONS, AND THEY ARE 7734 04:43:31,694 --> 04:43:34,664 INHERENT PROGRAMS TO TRY TO 7735 04:43:34,731 --> 04:43:38,000 RESCUE THE SITUATION. 7736 04:43:38,067 --> 04:43:39,969 BUT THESE ARE ALSO ACTIVATED IN 7737 04:43:40,036 --> 04:43:41,738 DIFFERENT CONTEXTS. 7738 04:43:41,804 --> 04:43:45,108 SO THIS MAY LOOK VERY COMPLEX, 7739 04:43:45,174 --> 04:43:46,809 BUT IT'S IMPORTANT TO KNOW THAT 7740 04:43:46,876 --> 04:43:50,546 THIS IS CONTEXT-DEPENDENT 7741 04:43:50,613 --> 04:43:52,949 PATHWAYS WE ARE TALKING ABOUT. 7742 04:43:53,015 --> 04:43:56,185 SO THE PURPOSE OF THESE 7743 04:43:56,252 --> 04:44:00,890 ADAPTATIONS ARE TO RESCUE AND 7744 04:44:00,957 --> 04:44:05,261 MAINTAIN SUPPLY. 7745 04:44:05,328 --> 04:44:08,464 IN MOST CONTEXT DEPENDENT 7746 04:44:08,531 --> 04:44:10,032 PROGRAMS AND EXERCISE, IT 7747 04:44:10,099 --> 04:44:11,434 TYPICALLY INVOLVES FUEL 7748 04:44:11,501 --> 04:44:13,436 SWITCHING FROM GLUCOSE TO 7749 04:44:13,503 --> 04:44:15,838 ANOTHER OXIDATIVE -- OXIDIZED 7750 04:44:15,905 --> 04:44:18,408 FUEL, AND THIS ALSO HAS A 7751 04:44:18,474 --> 04:44:18,941 SYSTEMIC IMPACT. 7752 04:44:19,008 --> 04:44:22,311 IT'S NOT ONLY IN THE TISH EUM TE 7753 04:44:22,378 --> 04:44:24,947 WHERE YOU MAY FIND AMPLIFIED 7754 04:44:25,014 --> 04:44:26,382 HYPOXIA EFFECT BUT ALSO IN OTHER 7755 04:44:26,449 --> 04:44:31,521 ORGAN SYSTEMS. 7756 04:44:31,587 --> 04:44:37,994 SO THIS EFFECT OF HYPOXIA AND 7757 04:44:38,060 --> 04:44:40,396 STRESS ACTIVATES ALTERNATIVE 7758 04:44:40,463 --> 04:44:44,767 PATHWAYS, AND IT MAY, IN THE 7759 04:44:44,834 --> 04:44:47,470 CONTEXT OF ME/CFS, IT MAY SERVE 7760 04:44:47,537 --> 04:44:51,107 TO MITIGATE EFFECTS ON SYMPTOMS 7761 04:44:51,174 --> 04:44:53,276 AND TRY TO BE A POSITIVE 7762 04:44:53,342 --> 04:44:57,513 INFLUENCE ON THE CONDITION. 7763 04:44:57,580 --> 04:44:58,681 NOW, IN MOLECULAR TERMS, WHAT 7764 04:44:58,748 --> 04:45:00,616 HAPPENS HERE IS THAT THE LACK OF 7765 04:45:00,683 --> 04:45:02,985 OXYGEN, IT OF COURSE INHIBITS 7766 04:45:03,052 --> 04:45:05,755 MITOCHONDRIAL RESPIRATION 7767 04:45:05,822 --> 04:45:09,158 DIRECTLY BY INHIBITING 7768 04:45:09,225 --> 04:45:10,126 PHOSPHORYLATION SYSTEM, IN 7769 04:45:10,193 --> 04:45:11,594 ADDITION, IT ACTIVATES 7770 04:45:11,661 --> 04:45:12,962 TRANSCRIPTION FACTOR CALLED 7771 04:45:13,029 --> 04:45:15,565 HYPOXIA INDUCED FACTOR 1 ALPHA 7772 04:45:15,631 --> 04:45:20,069 WHICH REGULATES BOTH 7773 04:45:20,136 --> 04:45:21,471 ANGIOGENESIS BUT ALSO STEPS IN 7774 04:45:21,537 --> 04:45:23,873 THIS MAIN ENERGY PATHWAY. 7775 04:45:23,940 --> 04:45:26,142 AND THIS OCCURS THROUGH GENETIC 7776 04:45:26,209 --> 04:45:28,911 REGULATION. 7777 04:45:28,978 --> 04:45:32,348 SO HIF1 ALPHA TARGETS SPECIFIC 7778 04:45:32,415 --> 04:45:34,550 GENES WITH A RESPONSE ELEMENT IN 7779 04:45:34,617 --> 04:45:36,652 THE PROMOTER REGION, THEN YOU 7780 04:45:36,719 --> 04:45:39,522 HAVE INCREASED EXPRESSION OF 7781 04:45:39,589 --> 04:45:42,792 THESE DIFFERENT GENES. 7782 04:45:42,859 --> 04:45:47,630 WHERE SO IN OUR STUDY IN 2016, 7783 04:45:47,697 --> 04:45:54,704 THAT ONE TARGET, OR THAT THE 7784 04:45:54,770 --> 04:45:58,474 ACTIVITY OF THE PYRUVATE 7785 04:45:58,541 --> 04:45:59,575 HYDROGENASE SEEM TO BE INHIBITED 7786 04:45:59,642 --> 04:46:02,311 AND WE FOUND INCREASED 7787 04:46:02,378 --> 04:46:03,346 EXPRESSION OF SEVERAL PROTEINS 7788 04:46:03,412 --> 04:46:05,181 THAT HAVE AN INHIBITORY EFFECT 7789 04:46:05,248 --> 04:46:08,751 ON THIS ENZYME, AND THERE WERE 7790 04:46:08,818 --> 04:46:09,619 INCREASED EXPRESSION OF THIS IN 7791 04:46:09,685 --> 04:46:10,786 THE PATIENTS. 7792 04:46:10,853 --> 04:46:15,625 AND ONE OF THESE IS THE PD 7793 04:46:15,691 --> 04:46:17,760 PDK1 PART OF IT, WHICH IS A 7794 04:46:17,827 --> 04:46:19,295 TARGET OF HIF1 ALPHA. 7795 04:46:19,362 --> 04:46:22,465 SO THIS IS AN INDICATION THAT 7796 04:46:22,532 --> 04:46:24,834 THERE MAY BE AMPLIFIED HYPOXIA 7797 04:46:24,901 --> 04:46:26,836 EFFECT IN THE PATIENTS. 7798 04:46:26,903 --> 04:46:34,143 NOW, IN THIS CONTEXT, IT IS ALSO 7799 04:46:34,210 --> 04:46:37,280 POSSIBLE ACTUALLY THAT THERE WAS 7800 04:46:37,346 --> 04:46:39,448 A THREE PROTEIN, COULD BE A 7801 04:46:39,515 --> 04:46:43,419 MEDIATOR HERE, AND IT SUGGESTS 7802 04:46:43,486 --> 04:46:46,556 IT WAS VERY INTERESTING TO 7803 04:46:46,622 --> 04:46:52,828 LISTEN TO JUST THE PRESENTATION 7804 04:46:52,895 --> 04:46:58,834 OF DR.HWANG AND REALLY SHOWS 7805 04:46:58,901 --> 04:47:02,772 MOLECULAR MECHANISM WHEREBY -- 7806 04:47:02,838 --> 04:47:05,274 WHICH CAN REALLY EXPLAIN PARTS 7807 04:47:05,341 --> 04:47:08,444 OF THE MECHANISM INVOLVED IN 7808 04:47:08,511 --> 04:47:10,413 ME/CFS PATIENTS. 7809 04:47:10,479 --> 04:47:14,784 NOW THIS WAS A -- ALSO HAS 7810 04:47:14,850 --> 04:47:17,453 RESPONSE ELEMENT FOR HIF1 ALPHA 7811 04:47:17,520 --> 04:47:21,857 IN THE PROMOTED REGION, SO THIS 7812 04:47:21,924 --> 04:47:24,694 IS A SUGGESTION THAT MAYBE, IF 7813 04:47:24,760 --> 04:47:27,229 THERE IS A CONDITION OF HYPOXIA 7814 04:47:27,296 --> 04:47:31,701 IN THE PATIENTS' MUSCLES, THIS 7815 04:47:31,767 --> 04:47:37,807 COULD ALSO EXPLAIN WHY WASF3 SIN 7816 04:47:37,873 --> 04:47:39,308 CREASED IN THE PATIENTS. 7817 04:47:39,375 --> 04:47:40,409 BUT THIS HAS NOT BEEN 7818 04:47:40,476 --> 04:47:41,510 INVESTIGATED YET. 7819 04:47:41,577 --> 04:47:44,847 BUT IT COULD BE AN ALTERNATIVE 7820 04:47:44,914 --> 04:47:49,819 MECHANISM BUT THAT SAID, 7821 04:47:49,885 --> 04:47:52,955 WASF3 BEING A MEDIATOR TO 7822 04:47:53,022 --> 04:47:54,156 INHIBIT OXIDATIVE 7823 04:47:54,223 --> 04:47:55,224 PHOSPHORYLATION IN THE CONTEXT 7824 04:47:55,291 --> 04:47:57,293 OF HYPOXIA MAKES PERFECT SENSE 7825 04:47:57,360 --> 04:48:00,463 AS WELL, AND IT CAN EXPLAIN 7826 04:48:00,529 --> 04:48:04,867 MAYBE SOME OF THE EFFECTS. 7827 04:48:04,934 --> 04:48:06,369 I THINK FINDINGS LIKE THESE ARE 7828 04:48:06,435 --> 04:48:07,770 PARTICULARLY IMPORTANT, SINCE WE 7829 04:48:07,837 --> 04:48:11,841 HAVE SO FEW MOLECULAR TARGETS TO 7830 04:48:11,907 --> 04:48:13,042 REALLY TRANSLATE INTO THE IN 7831 04:48:13,109 --> 04:48:15,645 VITRO SETTING AND START STUDYING 7832 04:48:15,711 --> 04:48:17,480 THE MOLECULAR MECHANISMS 7833 04:48:17,546 --> 04:48:21,751 INVOLVED IN ME/CFS. 7834 04:48:21,817 --> 04:48:24,687 BECAUSE SUCH KIND OF DISCOVERIES 7835 04:48:24,754 --> 04:48:28,024 MAKES US ABLE TO DEVELOP IN 7836 04:48:28,090 --> 04:48:32,595 VITRO MECHANISTIC MODELS, AND 7837 04:48:32,662 --> 04:48:34,664 MAYBE -- EVEN PAUL AND HIS GROUP 7838 04:48:34,730 --> 04:48:37,700 MADE ANIMALS, AND WE ARE LACKING 7839 04:48:37,767 --> 04:48:45,574 ALSO ANIMAL MODELS IN THIS FIELD 7840 04:48:45,641 --> 04:48:47,410 THAT IN A -- MANNER REFLECTS THE 7841 04:48:47,476 --> 04:48:49,912 DISEASE MECHANISM. 7842 04:48:49,979 --> 04:48:51,781 BUT SUCH FINDING REALLY GIVES 7843 04:48:51,847 --> 04:48:53,516 HOPE THAT WE WILL BE ABLE TO 7844 04:48:53,582 --> 04:48:56,452 MAKE GOOD MECHANISTIC MODELS SO 7845 04:48:56,519 --> 04:49:01,824 WE CAN DO MECHANISTIC STUDIES. 7846 04:49:01,891 --> 04:49:04,260 NOW, HERE ARE SOME OF THE 7847 04:49:04,326 --> 04:49:07,229 EFFECTS OF THE ADAPTATION GOING 7848 04:49:07,296 --> 04:49:11,300 ON, UPON AMPLIFIED HYPOXIA. 7849 04:49:11,367 --> 04:49:15,871 TYPICALLY, GLYCOLYSIS WILL BE 7850 04:49:15,938 --> 04:49:19,341 DECREASED BY THIS INFLUENCE AND 7851 04:49:19,408 --> 04:49:25,581 THIS OCCURS PARTLY BECAUSE OF 7852 04:49:25,648 --> 04:49:28,918 PDH INHIBITION BY DIFFERENT 7853 04:49:28,984 --> 04:49:29,185 PATHWAYS. 7854 04:49:29,251 --> 04:49:31,120 THE PURPOSE IN THIS CASE IS TO 7855 04:49:31,187 --> 04:49:33,389 PROMOTE ALTERNATIVE FUELING BY 7856 04:49:33,456 --> 04:49:36,892 FATTY AND AMINO ACIDS THAT CAN 7857 04:49:36,959 --> 04:49:39,295 FUEL INTO THE TCA CYCLE AND 7858 04:49:39,361 --> 04:49:41,564 PROVIDE A FUEL FOR OXIDATIVE 7859 04:49:41,630 --> 04:49:43,199 PHOSPHORYLATION AS WELL. 7860 04:49:43,265 --> 04:49:45,801 BUT THIS, OSKT, OCCURS NOW IN 7861 04:49:45,868 --> 04:49:48,571 THE PRESENCE OF OXYGEN. 7862 04:49:48,637 --> 04:49:50,139 SO THIS CAN BE ACTIVATED IN 7863 04:49:50,206 --> 04:49:53,008 DIFFERENT CO CONTEXTS AND ALSO N 7864 04:49:53,075 --> 04:49:55,745 DIFFERENT CELL TYPES, AND SOME 7865 04:49:55,811 --> 04:49:58,347 OF THE FACTORS THAT CAN 7866 04:49:58,414 --> 04:50:01,951 CONTRIBUTE TO THIS HAVE SOME OF 7867 04:50:02,017 --> 04:50:03,786 THOSE THAT ARE MOST KNOWN, THEY 7868 04:50:03,853 --> 04:50:05,421 ARE KNOWN ENERGY SENSOR AND 7869 04:50:05,488 --> 04:50:06,956 METABOLIC REGULATOR, THEY ARE 7870 04:50:07,022 --> 04:50:09,458 KNOWN TARGETS FOR DIFFERENT 7871 04:50:09,525 --> 04:50:16,999 KINDS OF DRUGS AND TREATMENTS. 7872 04:50:17,066 --> 04:50:20,503 IN DIFFERENT CONTEXTS. 7873 04:50:20,569 --> 04:50:23,739 SO THEIR MAIN TASK IS TO RESTORE 7874 04:50:23,806 --> 04:50:25,074 ATP, CONSERVE GLUCOSE AND TO 7875 04:50:25,141 --> 04:50:26,375 PROVIDE ALTERNATIVE FUELING. 7876 04:50:26,442 --> 04:50:28,911 WHAT'S RELEVANT ALSO HERE IS 7877 04:50:28,978 --> 04:50:31,947 THERE CAN HAPPEN DEREGULATION IN 7878 04:50:32,014 --> 04:50:34,550 THE SYSTEM. 7879 04:50:34,617 --> 04:50:36,952 WHICH CAN CONTRIBUTE TO THINGS 7880 04:50:37,019 --> 04:50:39,355 LIKE DYSLIPIDEMIA AND INSULIN 7881 04:50:39,421 --> 04:50:41,323 RESISTANCE. 7882 04:50:41,390 --> 04:50:45,394 AND THIS ON TOP OF THE MECHANISM 7883 04:50:45,461 --> 04:50:50,032 OF ME/CFS CAN LEAD TO FURTHER 7884 04:50:50,099 --> 04:50:51,700 IMPAIRMENT OR NEGATIVE EFFECTS. 7885 04:50:51,767 --> 04:50:56,071 WE KNOW THAT SOME OF THESE 7886 04:50:56,138 --> 04:50:58,274 REGULATORY ELEMENTS ARE RELEVANT 7887 04:50:58,340 --> 04:50:59,041 ALSO IN ME/CFS. 7888 04:50:59,108 --> 04:51:03,145 AND I'M SUING SHOWING YOU AN EE 7889 04:51:03,212 --> 04:51:05,748 HERE, INCREASED EXPRESSION OF BD 7890 04:51:05,815 --> 04:51:07,082 K1 IN THE PATIENTS, WE ALSO 7891 04:51:07,149 --> 04:51:09,585 FOUND INCREASED EXPRESSION OF 7892 04:51:09,652 --> 04:51:13,055 PDK4, WHICH IS TYPICALLY A 7893 04:51:13,122 --> 04:51:14,690 FACTOR THAT'S ACTIVATED WHEN 7894 04:51:14,757 --> 04:51:17,893 FATTY ACID OXIDATION IS HIGH, 7895 04:51:17,960 --> 04:51:21,096 YOU HAVE AN ALTERNATIVE 7896 04:51:21,163 --> 04:51:24,433 FUELING OF THE SYSTEM. 7897 04:51:24,500 --> 04:51:27,837 SO THIS IS TYPICALLY AN ADAPTIVE 7898 04:51:27,903 --> 04:51:29,471 RESPONSE. 7899 04:51:29,538 --> 04:51:32,641 SO IN THE PATIENTS, THIS SEEMS 7900 04:51:32,708 --> 04:51:33,609 ACTIVATED AT THE SAME TIME, BOTH 7901 04:51:33,676 --> 04:51:36,445 THE HYPOXIC RESPONSE AND 7902 04:51:36,512 --> 04:51:39,949 ADAPTATION. 7903 04:51:40,015 --> 04:51:42,885 AND WE LACKED FURTHER INTO THE 7904 04:51:42,952 --> 04:51:51,060 METABOLIC -- IN ME/CFS AND IN 7905 04:51:51,126 --> 04:51:52,394 COMPREHENSIVE METABOLOMICS 7906 04:51:52,461 --> 04:52:01,971 STUDY, WE MENTIONED I WE FOUND 9 7907 04:52:02,037 --> 04:52:03,005 SIGNIFICANT DIFFERENCES BETWEEN 7908 04:52:03,072 --> 04:52:03,405 THE TWO GROUPS. 7909 04:52:03,472 --> 04:52:06,075 WE DID SEE DATA HETEROGENEITY, 7910 04:52:06,141 --> 04:52:08,210 AND WE USED THIS ACTUALLY AS A 7911 04:52:08,277 --> 04:52:11,480 RESOURCE TO CLUSTER THREE 7912 04:52:11,547 --> 04:52:12,448 SUBSETS OF PATIENTS. 7913 04:52:12,514 --> 04:52:15,584 WE CALL THEM METABOLIC 7914 04:52:15,651 --> 04:52:19,188 PHENOTYPES, AND ESPECIALLY IT 7915 04:52:19,255 --> 04:52:22,424 POINTED TO AMINO ACIDS AND 7916 04:52:22,491 --> 04:52:24,960 LIPIDS AND WHAT WE INTERPRETED 7917 04:52:25,027 --> 04:52:26,829 AS PATTERNS OF ENERGY STRESS 7918 04:52:26,896 --> 04:52:28,697 BECAUSE OF THIS ALTERNATIVE 7919 04:52:28,764 --> 04:52:29,098 METABOLISM. 7920 04:52:29,164 --> 04:52:34,770 I ARE NOT WILL NOT GO IN DETAILD 7921 04:52:34,837 --> 04:52:37,907 SEE UNIQUE UNIFORM EFFECT IN THE 7922 04:52:37,973 --> 04:52:39,008 GROUPS, WE SEE, FOR INSTANCE, 7923 04:52:39,074 --> 04:52:43,279 THE HEALTHY CONTROLS COMPARED TO 7924 04:52:43,345 --> 04:52:44,847 THE TOTAL M.E. GROUP, THERE WAS 7925 04:52:44,914 --> 04:52:47,316 AN ELEVATION IN GLYCEROL, AND WE 7926 04:52:47,383 --> 04:52:49,551 DID SEE SIMILAR LEVELS IN THE 7927 04:52:49,618 --> 04:52:52,054 THREE DIFFERENT SUBSETS. 7928 04:52:52,121 --> 04:52:58,460 GLYCEROL IS ACTUALLY COMING FROM 7929 04:52:58,527 --> 04:53:01,730 DS -- OF FATTY ACIDS FROM 7930 04:53:01,797 --> 04:53:04,667 TRIGLYCERIDES. 7931 04:53:04,733 --> 04:53:09,004 SO YOU HAVE MOBILIZATION OF FAT 7932 04:53:09,071 --> 04:53:11,040 AND THE RELEASE OF FREE FATTY 7933 04:53:11,106 --> 04:53:16,578 ACIDS IN BLOOD TO BE USIZ UTILID 7934 04:53:16,645 --> 04:53:19,081 FOR ENERGY PURPOSES. 7935 04:53:19,148 --> 04:53:20,749 SO MOBILIZATION IN ALL THE THREE 7936 04:53:20,816 --> 04:53:23,819 SUBSETS. 7937 04:53:23,886 --> 04:53:25,321 HERE IS ANOTHER EXAMPLE, WE DID 7938 04:53:25,387 --> 04:53:29,258 SEE HERE THAT THERE WAS A SMALL 7939 04:53:29,325 --> 04:53:31,093 INCREASE IN THE TOTAL M.E. 7940 04:53:31,160 --> 04:53:35,898 GROUP, BUT THERE WERE ALSO A 7941 04:53:35,965 --> 04:53:36,765 LARGE SPREAD IN THIS GROUP. 7942 04:53:36,832 --> 04:53:40,269 AND WHEN WE SUBDIVIDED BASED ON 7943 04:53:40,336 --> 04:53:43,339 THE DIFFERENT -- THREE DIFFERENT 7944 04:53:43,405 --> 04:53:45,040 GROUPS OF PATIENTS OR SUBGROUPS, 7945 04:53:45,107 --> 04:53:46,241 WE SAW THAT THIS WAS 7946 04:53:46,308 --> 04:53:48,177 PARTICULARLY DUE TO ELEVATION IN 7947 04:53:48,243 --> 04:53:50,946 ONE OF THE SUBSETS. 7948 04:53:51,013 --> 04:53:55,651 SO THIS METABOLITE, 7949 04:53:55,718 --> 04:53:57,086 3 HYDROXYBUTYRATE, IS THE SAME 7950 04:53:57,152 --> 04:53:58,487 AS -- IT'S A KETONE BODY, AND 7951 04:53:58,554 --> 04:54:01,724 THIS IS ACTIVATED OR ELEVATED 7952 04:54:01,790 --> 04:54:06,528 TYPICALLY UNDER ENERGY STARVED 7953 04:54:06,595 --> 04:54:08,163 CONDITIONS. 7954 04:54:08,230 --> 04:54:11,033 ANOTHER OBSERVATION WAS THAT 7955 04:54:11,100 --> 04:54:13,802 THESE THREE METABOLIC SUBSETS 7956 04:54:13,869 --> 04:54:15,037 WERE ALSO DIFFERENT WHEN IT CAME 7957 04:54:15,104 --> 04:54:17,806 TO THE PHYSICAL FUNCTION SCORE, 7958 04:54:17,873 --> 04:54:19,541 THE SF36 PHYSICAL FUNCTION 7959 04:54:19,608 --> 04:54:20,709 SCORE. 7960 04:54:20,776 --> 04:54:28,917 SO WHAT WE CALL THE MEM 7961 04:54:28,984 --> 04:54:29,785 MEM2 METABOTYPE SEEMED WORSE 7962 04:54:29,852 --> 04:54:30,786 COMPARED TO OTHER ONES. 7963 04:54:30,853 --> 04:54:32,688 SO THE METABOLIC PHENOTYPE SEEMS 7964 04:54:32,755 --> 04:54:35,891 TO BE A FUNCTIONAL EFFECT ON THE 7965 04:54:35,958 --> 04:54:36,325 PATIENTS. 7966 04:54:36,392 --> 04:54:39,361 WE DON'T KNOW, REALLY, IF IT'S 7967 04:54:39,428 --> 04:54:41,563 THE HEN AND THE EGG AND, YEAH, 7968 04:54:41,630 --> 04:54:43,966 WHICH IS THE -- ONE. 7969 04:54:44,033 --> 04:54:45,834 BUT IT IS INTERESTING TO SEE 7970 04:54:45,901 --> 04:54:50,372 THAT IT HAS CLINICAL IMPACT. 7971 04:54:50,439 --> 04:54:53,442 AND HERE THE CONCLUSION FROM 7972 04:54:53,509 --> 04:54:54,009 THAT STUDY. 7973 04:54:54,076 --> 04:54:55,644 WE DID SEE COMMON FEATURES OF 7974 04:54:55,711 --> 04:54:56,912 ENERGY STRAIN IN THE PATIENTS. 7975 04:54:56,979 --> 04:55:01,083 WE THINK THAT COULD BE DUE TO 7976 04:55:01,150 --> 04:55:03,519 TISSUE HYPOXIA OR AT LEAST SOME 7977 04:55:03,585 --> 04:55:07,122 UNDERLYING ENERGY STRESS AND IT 7978 04:55:07,189 --> 04:55:08,323 IS EXERTION-SENSITIVE. 7979 04:55:08,390 --> 04:55:11,927 THEN WE DID SEE CONTEXTUAL 7980 04:55:11,994 --> 04:55:17,366 DEFECTS, WHERE WE THINK MIRRORS 7981 04:55:17,433 --> 04:55:18,233 METABOTYPES, ONE SIMILAR TO 7982 04:55:18,300 --> 04:55:23,038 FASTING WITH HIGH FATTY ACIDS 7983 04:55:23,105 --> 04:55:25,674 AND HIGH KETONE BODIES. 7984 04:55:25,741 --> 04:55:28,744 THEY ARE STILL EXTREME LIE HIGH, 7985 04:55:28,811 --> 04:55:30,279 THERE IS A BIOLOGICAL SHIFT. 7986 04:55:30,345 --> 04:55:35,050 AND THE SAME FOR METABOTYPE 7987 04:55:35,117 --> 04:55:38,887 2 WHICH HAD SIMILARITY TO THIS 7988 04:55:38,954 --> 04:55:41,290 LIPIDEMIA WITH HIGH DRY GLIS 7989 04:55:41,356 --> 04:55:43,926 RIDES AND THEN YOU HAVE M3 WHICH 7990 04:55:43,992 --> 04:55:45,327 WAS SOMETHING IN BETWEEN AND 7991 04:55:45,394 --> 04:55:46,862 ALSO MORE SIMILAR TO THE 7992 04:55:46,929 --> 04:55:54,303 CONTROL. 7993 04:55:54,369 --> 04:55:55,838 SO HOW IS THIS CONNECTED AND HOW 7994 04:55:55,904 --> 04:55:58,574 IS IT CONECTED TO THE OTHER 7995 04:55:58,640 --> 04:56:04,346 FINDINGS SUPPORTING THAT THERE ? 7996 04:56:04,413 --> 04:56:06,181 WE STILL HAVE MUCH TO DO IN THAT 7997 04:56:06,248 --> 04:56:07,082 SENSE. 7998 04:56:07,149 --> 04:56:11,053 WE THINK THAT -- WE DON'T REALLY 7999 04:56:11,120 --> 04:56:13,889 KNOW IF IT IMPACTS OXYGEN 8000 04:56:13,956 --> 04:56:15,157 DELIVERY OR UPTAKE IN THE 8001 04:56:15,224 --> 04:56:15,824 TISSUES. 8002 04:56:15,891 --> 04:56:18,994 WE DON'T REALLY KNOW HOW THIS IS 8003 04:56:19,061 --> 04:56:20,496 EXACERBATED BY EXERTION, BUT 8004 04:56:20,562 --> 04:56:24,666 YOU'RE BEGINNING TO GET MUCH 8005 04:56:24,733 --> 04:56:25,667 KNOWLEDGE -- DAVID WILL TALK 8006 04:56:25,734 --> 04:56:27,402 ABOUT AFTERWARDS. 8007 04:56:27,469 --> 04:56:32,007 WHEN IT COMES TO POST EXERTION 8008 04:56:32,074 --> 04:56:33,842 MALAISE, THERE ARE STUDIES FROM 8009 04:56:33,909 --> 04:56:34,710 CORNELL AND OTHER GROUPS THAT 8010 04:56:34,776 --> 04:56:37,880 ARE DOING THAT, SO THAT'S VERY 8011 04:56:37,946 --> 04:56:38,847 GOOD BECAUSE THIS HAS BEEN A 8012 04:56:38,914 --> 04:56:41,183 BLACK HOLE FOR SO MANY YEARS. 8013 04:56:41,250 --> 04:56:42,818 AND WE ALSO NEED TO LOOK INTO 8014 04:56:42,885 --> 04:56:47,156 WHAT ARE THE LINKS TO THE IMMUNE 8015 04:56:47,222 --> 04:56:51,460 SYSTEM DYSREGULATION. 8016 04:56:51,527 --> 04:56:56,465 AND WHEN IT COMES TO SIMILARITY 8017 04:56:56,532 --> 04:57:03,138 WITH LONG COVID, THE GERMAN 8018 04:57:03,205 --> 04:57:04,206 ASSOCIATION A COUPLE YEARS AGO 8019 04:57:04,273 --> 04:57:06,642 MADE THIS NICE OVERVIEW OF 8020 04:57:06,708 --> 04:57:08,177 REPLICATED FINDINGS WHICH POINTS 8021 04:57:08,243 --> 04:57:13,882 TO SEVERAL OF THE KEY ELEMENTS 8022 04:57:13,949 --> 04:57:17,252 THAT HAVE BEEN MENTIONED SEVERAL 8023 04:57:17,319 --> 04:57:17,686 TIMES ALREADY. 8024 04:57:17,753 --> 04:57:19,755 SO I'VE NOT LOOKED INTO THE 8025 04:57:19,821 --> 04:57:21,390 EXACT REPLICATION IN THIS THING, 8026 04:57:21,456 --> 04:57:27,396 BUT I THINK MORE COMPREHENSIVE 8027 04:57:27,462 --> 04:57:28,630 STUDIES, THERE IS SO MUCH GOING 8028 04:57:28,697 --> 04:57:31,200 ON NOW IN THE LONG COVID FIELD 8029 04:57:31,266 --> 04:57:35,070 AND ALSO WE HAVE SOME DATASET 8030 04:57:35,137 --> 04:57:37,039 FROM THE M.E. FIELD, BUT WE NEED 8031 04:57:37,105 --> 04:57:40,075 LARGER STUDIES ALSO IN THE M.E. 8032 04:57:40,142 --> 04:57:41,877 FIELD, I THINK TO REALLY BE ABLE 8033 04:57:41,944 --> 04:57:43,445 TO LOOK INTO THE SUBGROUPS OF 8034 04:57:43,512 --> 04:57:44,880 PATIENTS AND TRYING TO 8035 04:57:44,947 --> 04:57:46,615 UNDERSTAND THE UNDERLYING 8036 04:57:46,682 --> 04:57:48,116 MECHANISMS. 8037 04:57:48,183 --> 04:57:51,920 WE KNOW ALSO LITTLE ABOUT THE 8038 04:57:51,987 --> 04:57:54,690 METABOLIC LANDSCAPE OF POST 8039 04:57:54,756 --> 04:57:56,091 EXERTIONAL MALAISE FROM 8040 04:57:56,158 --> 04:57:57,593 MAUREEN'S GROUP, THEY HAVE DONE 8041 04:57:57,659 --> 04:57:58,994 SEVERAL INTERESTING STUDIES, AND 8042 04:57:59,061 --> 04:58:02,631 COULD IT BE THAT THERE ARE SOME 8043 04:58:02,698 --> 04:58:04,333 TOXIC EFFECTS OR TOXIC FACTORS 8044 04:58:04,399 --> 04:58:06,301 THAT ARE RELEASED UNDER THIS 8045 04:58:06,368 --> 04:58:07,002 EXERCISE TESTING. 8046 04:58:07,069 --> 04:58:11,106 WE KNOW THAT TRAINING ITSELF 8047 04:58:11,173 --> 04:58:12,841 CREATES WAVES OF PROGRAMS THAT 8048 04:58:12,908 --> 04:58:16,345 ARE ACTIVATED GENE REGULATION 8049 04:58:16,411 --> 04:58:18,080 PROGRAMS AND THEN YOU HAVE A 8050 04:58:18,146 --> 04:58:19,948 GRADUAL ADAPTATION OF THE 8051 04:58:20,015 --> 04:58:21,149 METABOLISM IN THE MUSCLE WHICH 8052 04:58:21,216 --> 04:58:23,218 IS POSITIVE, BUT WE ALSO KNOW 8053 04:58:23,285 --> 04:58:25,621 THAT EXCESSIVE TRAINING CAN LEAD 8054 04:58:25,687 --> 04:58:29,358 TO MITOCHONDRIAL IMPAIRMENT, 8055 04:58:29,424 --> 04:58:32,728 THERE CAN BE SOME TOXIC FACTORS 8056 04:58:32,794 --> 04:58:34,563 RELEASED UNDER THESE CONDITIONS. 8057 04:58:34,630 --> 04:58:36,098 SEVERAL GROUPS HAVE ALSO SEEN, 8058 04:58:36,164 --> 04:58:37,733 INCLUDING OURSELF IN THIS STUDY, 8059 04:58:37,799 --> 04:58:41,670 WE SAW THAT IF WE COUNTED 8060 04:58:41,737 --> 04:58:43,071 HEALTHY MUSCLE CELLS IN THE 8061 04:58:43,138 --> 04:58:45,607 PRESENCE OF SERUM FROM PATIENTS, 8062 04:58:45,674 --> 04:58:49,745 WE COULD SEE SOMETHING THAT 8063 04:58:49,811 --> 04:58:50,512 RESEMBLES ENERGY STRESS IN THE 8064 04:58:50,579 --> 04:58:50,846 PATIENTS. 8065 04:58:50,912 --> 04:58:54,216 WE DID SEE BOTH INCREASED OXYGEN 8066 04:58:54,283 --> 04:58:55,951 CONSUMPTION AND INCREASED 8067 04:58:56,018 --> 04:58:57,386 LACTATE PRODUCTION UNDER THESE 8068 04:58:57,452 --> 04:58:57,719 OPINIONS. 8069 04:58:57,786 --> 04:59:02,557 SO THERE ARE SOME ACTIVE FACTORS 8070 04:59:02,624 --> 04:59:03,492 IN THE BLOOD OF THE PATIENTS. 8071 04:59:03,558 --> 04:59:05,127 WE DON'T REALLY KNOW IF IT'S IN 8072 04:59:05,193 --> 04:59:08,497 COCKTAIL EFFECT OR IF IT'S -- IF 8073 04:59:08,563 --> 04:59:11,366 THERE ARE SINGLE FACTORS THAT 8074 04:59:11,433 --> 04:59:13,435 ARE RESPONSIBLE FOR THESE KIND 8075 04:59:13,502 --> 04:59:17,039 OF EFFECTS. 8076 04:59:17,105 --> 04:59:19,441 AND SOME SPECULATION WHEN IT 8077 04:59:19,508 --> 04:59:20,709 COMES TO BIOMARKERS AND 8078 04:59:20,776 --> 04:59:21,243 TREATMENTS. 8079 04:59:21,310 --> 04:59:24,846 IF WE HAVE A KIND OF A MAP LIKE 8080 04:59:24,913 --> 04:59:29,017 THIS, WE CAN LOOK INTO WHAT CAN 8081 04:59:29,084 --> 04:59:30,419 BE DONE, SO IN HIS GROUP, THEY 8082 04:59:30,485 --> 04:59:32,821 CALL IT A TREATABLE 8083 04:59:32,888 --> 04:59:33,922 NEUROVASCULAR DYSREGULATION, AND 8084 04:59:33,989 --> 04:59:35,791 THIS OF COURSE WILL REPAIR THE 8085 04:59:35,857 --> 04:59:38,927 HYPOXIA EFFECTS. 8086 04:59:38,994 --> 04:59:40,228 WHERE ADAPTATION OF PROGRAMS CAN 8087 04:59:40,295 --> 04:59:44,299 BE ACTIVATED BY DIFFERENT 8088 04:59:44,366 --> 04:59:46,234 THERAPIES OR SUPPLEMENTS OR 8089 04:59:46,301 --> 04:59:47,436 STRATEGIES, BUT THEY ARE NOT 8090 04:59:47,502 --> 04:59:48,637 ALWAYS POSSIBLE TO DO. 8091 04:59:48,704 --> 04:59:51,573 FOR INSTANCE, WE NOPE THAT 8092 04:59:51,640 --> 04:59:53,542 PHYSICAL ACTIVITY IS POSITIVE 8093 04:59:53,608 --> 04:59:55,143 FOR THIS SITE, BUT THIS IS OF 8094 04:59:55,210 --> 04:59:56,144 COURSE NOT ALWAYS POSSIBLE TO 8095 04:59:56,211 --> 04:59:56,578 DO. 8096 04:59:56,645 --> 05:00:01,616 BUT IF WE HAVE A MAP WITH THE 8097 05:00:01,683 --> 05:00:03,418 RESPONSIBLE FACTORS LIKE THIS, 8098 05:00:03,485 --> 05:00:05,654 WE CAN KIND OF TRY TO BE 8099 05:00:05,721 --> 05:00:09,458 SPECIFIC WHEN WE MAKE HYPOTHESES 8100 05:00:09,524 --> 05:00:13,729 AND ALSO USE MODEL SYSTEM THAT 8101 05:00:13,795 --> 05:00:15,297 HAS ALREADY BEEN CREATED IN THE 8102 05:00:15,364 --> 05:00:17,332 LABORATORIES AROUND, BECAUSE 8103 05:00:17,399 --> 05:00:18,633 THEN YOU CAN REALLY LOOK INTO 8104 05:00:18,700 --> 05:00:24,639 THE MECHANISMS. 8105 05:00:24,706 --> 05:00:30,512 SO WE THINK STILL THAT IT IS A 8106 05:00:30,579 --> 05:00:34,049 VIABLE APPROACH TO TRY TO 8107 05:00:34,116 --> 05:00:35,984 CORRECT EFFECTS IN THE IMMUNE 8108 05:00:36,051 --> 05:00:38,120 SYSTEM, BUT IT IS -- ADD 8109 05:00:38,186 --> 05:00:42,791 CHALLENGE AS WELL SINCE WE DON'T 8110 05:00:42,858 --> 05:00:44,292 HAVE THE OBJECTIVE BIOMARKERS 8111 05:00:44,359 --> 05:00:49,664 FOR THE CONDITION AND ALSO FOR . 8112 05:00:49,731 --> 05:00:50,665 THIS IS A CHALLENGE, OF COURSE, 8113 05:00:50,732 --> 05:00:52,501 IN THE ENTIRE FIELD. 8114 05:00:52,567 --> 05:00:55,437 AND ALSO WE WILL HAVE TO WORK 8115 05:00:55,504 --> 05:00:56,638 HARD TO FIND THE MISSING LINKS 8116 05:00:56,705 --> 05:00:59,374 IN THE MECHANISM AND THAT 8117 05:00:59,441 --> 05:01:03,011 INCLUDES DEEP IMMUNE 8118 05:01:03,078 --> 05:01:04,846 CHARACTERIZATION AND 8119 05:01:04,913 --> 05:01:07,783 CHARACTERIZATION OF SUBGROUPS AS 8120 05:01:07,849 --> 05:01:08,884 WELL, DEFINED POSSIBLE 8121 05:01:08,950 --> 05:01:09,151 SUBGROUPS. 8122 05:01:09,217 --> 05:01:14,790 SO I WILL END THIS BY THANKING 8123 05:01:14,856 --> 05:01:18,727 MY GROUP AT BERGEN AND OUR 8124 05:01:18,794 --> 05:01:20,796 COLLEAGUES, AND THANK YOU FOR 8125 05:01:20,862 --> 05:01:21,062 LISTENING. 8126 05:01:21,129 --> 05:01:30,005 [APPLAUSE] 8127 05:01:30,071 --> 05:01:31,306 >> HI. 8128 05:01:31,373 --> 05:01:32,607 ALLAN CASH. 8129 05:01:32,674 --> 05:01:35,544 I'M WITH TERRA BIOLOGICAL SO I'M 8130 05:01:35,610 --> 05:01:37,179 FROM INDUSTRY HERE. 8131 05:01:37,245 --> 05:01:38,079 OOO! 8132 05:01:38,146 --> 05:01:38,380 [LAUGHTER] 8133 05:01:38,447 --> 05:01:45,053 HAVE YOU MEASURED HYPOXABLE 8134 05:01:45,120 --> 05:01:45,921 INDUCIBLE FACTOR IN THESE 8135 05:01:45,987 --> 05:01:46,455 PATIENTS? 8136 05:01:46,521 --> 05:01:48,290 HAVE YOU SEEN AN INCREASE IN 8137 05:01:48,356 --> 05:01:48,924 ME/CFS PATIENTS? 8138 05:01:48,990 --> 05:01:53,128 >> THE SHORT QUESTION, SO HOW DE 8139 05:01:53,195 --> 05:01:55,664 WE SEEN AN INCREASE IN 8140 05:01:55,730 --> 05:01:56,631 HIF1 ALPHA IN M.E. PATIENTS? 8141 05:01:56,698 --> 05:02:00,869 THE SHORT ANSWER IS NO. 8142 05:02:00,936 --> 05:02:02,604 AND THE REASON FOR THIS IS THAT 8143 05:02:02,671 --> 05:02:06,241 THIS WILL HAVE TO BE MEASURED IN 8144 05:02:06,308 --> 05:02:08,877 THE MUSCLE TISSUE OR TISSUE 8145 05:02:08,944 --> 05:02:11,246 WHERE YOU EXPECT THE HYPOXIC 8146 05:02:11,313 --> 05:02:11,480 EFFECT. 8147 05:02:11,546 --> 05:02:16,184 IT'S ACTUALLY REGULATED -- IT'S 8148 05:02:16,251 --> 05:02:19,354 CONTINUOUSLY EXPRESSED IN THE 8149 05:02:19,421 --> 05:02:21,656 PRESENCE OF OXYGEN IS DEGRADED 8150 05:02:21,723 --> 05:02:23,725 BUT IF OXYGEN DISAPPEARED, IT'S 8151 05:02:23,792 --> 05:02:24,059 STABILIZED. 8152 05:02:24,125 --> 05:02:25,794 SO IT'S QUITE QUICKLY STABILIZED 8153 05:02:25,861 --> 05:02:28,129 TO AN ACTIVE FORM. 8154 05:02:28,196 --> 05:02:32,167 BUT YOU DON'T FIND IT USUALLY IN 8155 05:02:32,234 --> 05:02:33,935 BLOOD CELLS CIRCULATING, 8156 05:02:34,002 --> 05:02:34,236 ACTIVATED. 8157 05:02:34,302 --> 05:02:36,404 SO YOU NEED THE TISSUE OR 8158 05:02:36,471 --> 05:02:37,005 SOMETHING. 8159 05:02:37,072 --> 05:02:41,042 >> AND SO FOLLOW-ON, ANOTHER WAY 8160 05:02:41,109 --> 05:02:44,646 INSTEAD OF USING OXYGEN TO BREAK 8161 05:02:44,713 --> 05:02:50,218 DOWN HIGH HYPOXABLE INDUCIBLE 8162 05:02:50,285 --> 05:02:56,858 FACTOR 1 ALPHA IS TO USE O 8163 05:02:56,925 --> 05:02:59,027 OXYLOACETATE, SHOWING INCREASING 8164 05:02:59,094 --> 05:03:02,330 THOSE LEVELS BREAKS DOWN 8165 05:03:02,397 --> 05:03:04,833 HIF1 ALPHA, AND IN CLINICAL 8166 05:03:04,900 --> 05:03:09,437 TRIALS, OXYLOACETATE TAKES 8167 05:03:09,504 --> 05:03:13,241 REDUCTIONS IN FATIGUE IN LONG 8168 05:03:13,308 --> 05:03:14,409 COVID AND CHRONIC FATIGUE 8169 05:03:14,476 --> 05:03:15,110 SYNDROME. 8170 05:03:15,176 --> 05:03:16,478 SO THAT WOULD SUPPORT YOUR 8171 05:03:16,545 --> 05:03:16,778 THEORY HERE. 8172 05:03:16,845 --> 05:03:23,051 >> SO IF YOU INJECT 8173 05:03:23,118 --> 05:03:23,385 OXYLOACETATE? 8174 05:03:23,451 --> 05:03:24,753 >> OR YOU CAN TAKE IT ORALLY. 8175 05:03:24,819 --> 05:03:26,087 >> ORALLY AS WELL, OKAY. 8176 05:03:26,154 --> 05:03:27,188 I DON'T KNOW ABOUT THAT. 8177 05:03:27,255 --> 05:03:33,528 I KNOW IN CANCER CELLS, IF YOU 8178 05:03:33,595 --> 05:03:37,799 HAVE DEFECT, A T CYCLE DEFECT, 8179 05:03:37,866 --> 05:03:39,968 YOU GET AN ACCUMULATION AND THIS 8180 05:03:40,035 --> 05:03:43,138 ACTUALLY ACTIVATES THE HYPOXIA 8181 05:03:43,204 --> 05:03:43,905 INDUCIBLE FACTOR. 8182 05:03:43,972 --> 05:03:46,308 YOU GET KIND AFTER SAW DOUGH 8183 05:03:46,374 --> 05:03:47,075 HYPOXIA. 8184 05:03:47,142 --> 05:03:51,246 BUT THIS OCCURS INVIED S. SIDE E 8185 05:03:51,313 --> 05:03:51,580 CELLS. 8186 05:03:51,646 --> 05:03:52,514 SO IT CAN BE DIFFERENT. 8187 05:03:52,581 --> 05:03:54,716 >> IN CANCER CELLS, THE WARBURG 8188 05:03:54,783 --> 05:03:56,818 EFFECT DOES THE SAME THING BY 8189 05:03:56,885 --> 05:03:57,485 INCREASING LACTATE LEVELS. 8190 05:03:57,552 --> 05:03:59,588 >> THIS IS DONE -- THE MECHANISM 8191 05:03:59,654 --> 05:04:00,956 OF THE WARBURG EFFECT IN THOSE 8192 05:04:01,022 --> 05:04:01,156 CELLS. 8193 05:04:01,222 --> 05:04:01,957 >> YES. 8194 05:04:02,023 --> 05:04:06,094 AND IN THE LAST THREE YEARS, 8195 05:04:06,161 --> 05:04:07,195 OXYLOACETATE HAS BEEN SHOWN TO 8196 05:04:07,262 --> 05:04:09,064 REVERSE THE WARBURG EFFECT. 8197 05:04:09,130 --> 05:04:18,273 >> YEAH. 8198 05:04:18,340 --> 05:04:22,510 >> APOLOGIZE, THERE WILL BE A 8199 05:04:22,577 --> 05:04:23,511 PANEL DISCUSSION, WE MIGHT 8200 05:04:23,578 --> 05:04:27,349 RETURN TO SOME OF THE THEMES. 8201 05:04:27,415 --> 05:04:31,586 THE LAST SPEAKER IN THIS SESSION 8202 05:04:31,653 --> 05:04:34,556 IS -- ACTUALLY HIS WORK WAS JUST 8203 05:04:34,623 --> 05:04:37,492 REFERENCED, DAVID SYSTROM. 8204 05:04:37,559 --> 05:04:40,462 NEUROVASCULAR DYSREGULATION 8205 05:04:40,528 --> 05:04:42,163 DURING EXERCISE IN ME/CFS. 8206 05:04:42,230 --> 05:04:43,264 SO LOOK FORWARD TO HEARING YOUR 8207 05:04:43,331 --> 05:04:53,441 WORK. 8208 05:05:00,582 --> 05:05:02,851 >> THANK YOU FOR THE IN INVITATN 8209 05:05:02,917 --> 05:05:04,519 AND I THINK EVEN I KNOW HOW TO 8210 05:05:04,586 --> 05:05:06,021 PLUG IN AN HDMI CABLE WITHOUT 8211 05:05:06,087 --> 05:05:10,859 HELP. 8212 05:05:10,925 --> 05:05:11,359 ALL RIGHT. 8213 05:05:11,426 --> 05:05:14,295 SO I WAS ACTUALLY HERE, 8214 05:05:14,362 --> 05:05:15,397 DR. BREEN, IN 2019. 8215 05:05:15,463 --> 05:05:18,033 I SAT IN FRONT OF RON TOMPKINS 8216 05:05:18,099 --> 05:05:19,801 OVER ON THE OTHER SIDE, AND IT 8217 05:05:19,868 --> 05:05:23,505 WAS AN AMAZING SESSION. 8218 05:05:23,571 --> 05:05:24,939 AND A LITTLE WATER UNDER THE 8219 05:05:25,006 --> 05:05:26,007 BRIDGE SINCE THEN, I GUESS, 8220 05:05:26,074 --> 05:05:32,013 CALLED A PANDEMIC. 8221 05:05:32,080 --> 05:05:33,782 SO IT'S A PLEASURE TO COME BACK 8222 05:05:33,848 --> 05:05:34,983 AND GIVE YOU GUYS A LITTLE 8223 05:05:35,050 --> 05:05:36,618 UPDATE ON WHAT WE'VE BEEN DOING 8224 05:05:36,685 --> 05:05:38,853 IN BOSTON, WATCHING THE PATRIOTS 8225 05:05:38,920 --> 05:05:49,230 GO DOWN IN SMOKE. 8226 05:06:40,181 --> 05:06:40,782 IT'S THERE. 8227 05:06:40,849 --> 05:06:42,684 SUCCESS. 8228 05:06:42,751 --> 05:06:47,021 PATIENCE IS A VIRTUE. 8229 05:06:47,088 --> 05:06:48,456 SO WHAT I HOPE TO CONVINCE SOME 8230 05:06:48,523 --> 05:06:50,291 OF YOU IN THE AUDIENCE OVER THE 8231 05:06:50,358 --> 05:06:53,695 NEXT 20, 25 MINUTES IS THAT 8232 05:06:53,762 --> 05:06:56,564 THERE IS SYSTEMIC VASCULAR 8233 05:06:56,631 --> 05:06:57,732 DYSREGULATION DURING EXERCISE 8234 05:06:57,799 --> 05:07:02,537 THAT'S AT PLAY IN BOTH ME/CFS 8235 05:07:02,604 --> 05:07:03,171 AND IN LONG COVID. 8236 05:07:03,238 --> 05:07:04,405 AND THERE ARE MANY WAYS TO 8237 05:07:04,472 --> 05:07:04,939 ATTACK THIS. 8238 05:07:05,006 --> 05:07:06,141 WE'VE GOT ONE PARTICULAR TOOL 8239 05:07:06,207 --> 05:07:07,475 THAT I'D LIKE TO INTRODUCE, 8240 05:07:07,542 --> 05:07:09,010 THOSE OF YOU WHO DON'T KNOW 8241 05:07:09,077 --> 05:07:11,613 ABOUT IT, THE INVASIVE 8242 05:07:11,679 --> 05:07:12,280 CARDIOPULMONARY EXERCISE TEST, 8243 05:07:12,347 --> 05:07:14,983 WHICH REALLY GIVES US A DEEP 8244 05:07:15,049 --> 05:07:16,618 DIVE INTO THE PATHOPHYSIOLOGY 8245 05:07:16,684 --> 05:07:18,720 DURING ACUTE EXERCISE. 8246 05:07:18,787 --> 05:07:20,455 A LITTLE BIT OF HISTORY HERE 8247 05:07:20,522 --> 05:07:22,991 FIRST JUST FOR FUN. 8248 05:07:23,057 --> 05:07:25,360 I WENT BACK A LITTLE WHILE AGO 8249 05:07:25,426 --> 05:07:26,194 AND LOOKED FOR EVIDENCE THAT 8250 05:07:26,261 --> 05:07:29,864 WE'VE BEEN HERE BEFORE, AND WE 8251 05:07:29,931 --> 05:07:31,533 IN FACT HAVE BEEN HERE BEFORE, 8252 05:07:31,599 --> 05:07:32,867 ACTUALLY EVEN BEFORE THE SPANISH 8253 05:07:32,934 --> 05:07:35,870 FLU, THE RUSSIAN FLU, DESCRIBED 8254 05:07:35,937 --> 05:07:38,640 AFTERWARDS SOMETHING SIMILAR TO 8255 05:07:38,706 --> 05:07:40,008 ME/CFS, AND AFTER THE SPANISH 8256 05:07:40,074 --> 05:07:42,410 FLU FOR ABOUT A DECADE, THERE 8257 05:07:42,477 --> 05:07:44,345 WERE -- THERE WAS ABOUT A DECADE 8258 05:07:44,412 --> 05:07:46,214 WORTH OF PAPERS WRITTEN, MOSTLY 8259 05:07:46,281 --> 05:07:48,049 CASE REPORTS THROUGH EUROPE OF 8260 05:07:48,116 --> 05:07:50,351 AN INTERESTING ENTITY CALLED 8261 05:07:50,418 --> 05:07:55,590 THIS ENCEPHALITIS LETH ARGICA. 8262 05:07:55,657 --> 05:08:00,428 THIS FELLOW, AN AUSTRIAN 8263 05:08:00,495 --> 05:08:01,296 ANATOMIST SCRIBED IT FIRST. 8264 05:08:01,362 --> 05:08:02,730 HE MET A LOT OF PUSHBACK. 8265 05:08:02,797 --> 05:08:03,665 DOES THIS SOUND FAMILIAR? 8266 05:08:03,731 --> 05:08:09,838 IT WAS CALLED POST-INFLUENZAL 8267 05:08:09,904 --> 05:08:10,104 HYSTERIA. 8268 05:08:10,171 --> 05:08:12,040 IT WAS ACTUALLY REVISITED IN A 8269 05:08:12,106 --> 05:08:13,575 REVIEW ARTICLE JUST RECENTLY, IF 8270 05:08:13,641 --> 05:08:14,776 YOU'RE INTERESTED. 8271 05:08:14,843 --> 05:08:16,277 THERE WAS ANOTHER PLACE, I WANT 8272 05:08:16,344 --> 05:08:18,379 TO GIVE YOU A LITTLE BIT OF 8273 05:08:18,446 --> 05:08:22,984 HISTORY ABOUT -- IT WAS A PLACE 8274 05:08:23,051 --> 05:08:25,253 EVEN THE DOCTOR IN THE FRONT ROW 8275 05:08:25,320 --> 05:08:27,222 WAS TOO YOUNG TO KNOW IN PERSON, 8276 05:08:27,288 --> 05:08:30,959 IT WAS THIS PLACE. 8277 05:08:31,025 --> 05:08:32,260 THE HARVARD FATIGUE LAB. 8278 05:08:32,327 --> 05:08:34,729 THEY MISSED THE BOAT, HOWEVER, 8279 05:08:34,796 --> 05:08:36,464 ON THE ME/CFS EQUIVALENT. 8280 05:08:36,531 --> 05:08:37,866 WHAT THEY WERE DOING WAS TRYING 8281 05:08:37,932 --> 05:08:39,167 TO TRAIN THE WORKERS OF THE 8282 05:08:39,234 --> 05:08:43,571 WORLD TO BE MORE PRODUCTIVE, AND 8283 05:08:43,638 --> 05:08:44,405 THE DEAN OF THE BUSINESS SCHOOL 8284 05:08:44,472 --> 05:08:46,374 AND THE MEDICAL SCHOOL GOT 8285 05:08:46,441 --> 05:08:48,576 TOGETHER AND STUDIED NORMAL 8286 05:08:48,643 --> 05:08:49,444 HUMAN EXERCISE PHYSIOLOGY. 8287 05:08:49,510 --> 05:08:51,613 MANY OF THE BASIC TENETS HAVE 8288 05:08:51,679 --> 05:08:54,449 WITHSTOOD THE TEST OF TIME HERE. 8289 05:08:54,515 --> 05:08:57,318 FLASH FORWARD A LITTLE BIT TO 8290 05:08:57,385 --> 05:08:58,553 THE BRIGHAM AND WOMEN'S HOSPITAL 8291 05:08:58,620 --> 05:08:58,987 WHERE I AM. 8292 05:08:59,053 --> 05:09:00,054 I DON'T KNOW WHERE THE QUESTION 8293 05:09:00,121 --> 05:09:01,522 MARK ENDS, DR. BREEN, BUT WE'LL 8294 05:09:01,589 --> 05:09:02,824 KEEP GOING FOR A WHILE YET. 8295 05:09:02,891 --> 05:09:04,225 SO WE'RE DOING SOME OF THE SAME 8296 05:09:04,292 --> 05:09:05,260 TESTING THEY DID BACK IN THE 8297 05:09:05,326 --> 05:09:08,263 DAY. 8298 05:09:08,329 --> 05:09:09,230 AND MORE RECENTLY, ABOUT HOF OF 8299 05:09:09,297 --> 05:09:11,432 OUR PATIENTS EITHER HAVE LONG 8300 05:09:11,499 --> 05:09:12,100 COVID OR ME/CFS. 8301 05:09:12,166 --> 05:09:15,503 THIS TEST WAS ORIGINALLY 8302 05:09:15,570 --> 05:09:18,006 DEVELOPED TO DETERMINE WHAT AILS 8303 05:09:18,072 --> 05:09:20,742 A PATIENT WITH HEART OR LUNG 8304 05:09:20,808 --> 05:09:21,109 DISEASE. 8305 05:09:21,175 --> 05:09:22,210 I'LL GIVE YOU JUST A LITTLE 8306 05:09:22,277 --> 05:09:25,546 MOVIE OF THIS, THIS GENTLEMAN 8307 05:09:25,613 --> 05:09:26,781 AGREED TO BE FILMED. 8308 05:09:26,848 --> 05:09:28,116 WE'VE GOT A FEW THINGS TO POINT 8309 05:09:28,182 --> 05:09:28,616 OUT. 8310 05:09:28,683 --> 05:09:37,825 WE'VE GOT A MOUTHPIECE IN PLACE. 8311 05:09:37,892 --> 05:09:39,494 IT'S CONNECT TODAY A METABOLIC 8312 05:09:39,560 --> 05:09:39,794 CART. 8313 05:09:39,861 --> 05:09:40,929 THAT'S THE NON-INNOVATIVE 8314 05:09:40,995 --> 05:09:42,330 PORTION. 8315 05:09:42,397 --> 05:09:48,136 IT'S QIE QUITE USEFUL. 8316 05:09:48,202 --> 05:09:49,971 THIS WAS DONE IN NEW YORK. 8317 05:09:50,038 --> 05:09:51,506 THE CATHETERS GIVE US SOME 8318 05:09:51,572 --> 05:09:52,006 ADDITIONAL INFORMATION. 8319 05:09:52,073 --> 05:09:54,776 THERE'S A PULMONARY ARTERY 8320 05:09:54,842 --> 05:09:56,811 CATHETER IN THIS GENTLEMAN'S 8321 05:09:56,878 --> 05:09:59,147 JUGULAR VEIN, THE TIP IS IN THE 8322 05:09:59,213 --> 05:10:01,683 PULMONARY ARTERY WHERE WE 8323 05:10:01,749 --> 05:10:04,319 MEASURE PRESSURE AND MIXED 8324 05:10:04,385 --> 05:10:05,520 VENOUS BLOOD GASES AND LACTATE 8325 05:10:05,586 --> 05:10:06,187 AND BIOMARKERS. 8326 05:10:06,254 --> 05:10:07,922 THEN IN HIS LEFT WRIST, CAN YOU 8327 05:10:07,989 --> 05:10:09,691 SEE RADIAL ARTERY CATHETER, WE 8328 05:10:09,757 --> 05:10:11,559 MEASURE ARTERIAL BLOOD GASES AND 8329 05:10:11,626 --> 05:10:15,063 LACTATE AND OTHER BIOMARKERS. 8330 05:10:15,129 --> 05:10:17,265 AND THIS IS WHAT WE END UP 8331 05:10:17,332 --> 05:10:18,766 MEASURING THAT'S IMPORTANT, 8332 05:10:18,833 --> 05:10:21,336 ESPECIALLY TO ME/CFS AND LONG 8333 05:10:21,402 --> 05:10:24,472 COVID. 8334 05:10:24,539 --> 05:10:28,743 TIME HO MO HONORED THINGS SHOWN. 8335 05:10:28,810 --> 05:10:31,245 THE VO2 IS WAY TO MEASURE HOW 8336 05:10:31,312 --> 05:10:32,714 IMPAIRED YOUR PATIENT IS, THE 8337 05:10:32,780 --> 05:10:34,549 CO2 OUTPUT AT THE MOUTH IS QUITE 8338 05:10:34,615 --> 05:10:37,185 USEFUL IN DETECTING METABOLISM. 8339 05:10:37,251 --> 05:10:38,086 MINUTE VENTILATION IS VE. 8340 05:10:38,152 --> 05:10:39,721 THEN WE MEASURE A BUNCH OF 8341 05:10:39,787 --> 05:10:40,054 PRESSURES. 8342 05:10:40,121 --> 05:10:41,189 YOU'LL SEE THAT FILLING 8343 05:10:41,255 --> 05:10:42,824 PRESSURES ARE QUITE IMPORTANT TO 8344 05:10:42,890 --> 05:10:45,660 BOTH M.E. AND LONG COVID. 8345 05:10:45,727 --> 05:10:47,628 THE RIGHT ATRIAL PRESSURE, THE 8346 05:10:47,695 --> 05:10:48,896 RIGHT VENTRICULAR PRESSURE 8347 05:10:48,963 --> 05:10:50,264 POTENTIALLY AND THEN DOWN BELOW, 8348 05:10:50,331 --> 05:10:52,567 THE MEAN PULMONARY ARTERY 8349 05:10:52,633 --> 05:10:55,169 PLEASURE AND THE PULMONARY 8350 05:10:55,236 --> 05:10:56,938 CAPILLARY EDGE PRESSURE. 8351 05:10:57,005 --> 05:10:58,573 THOSE THINGS PROSPECTIVELY RULE 8352 05:10:58,639 --> 05:11:00,441 OUT THINGS LIKE PULMONARY 8353 05:11:00,508 --> 05:11:01,743 HYPERTENSION AND HEART FAILURE 8354 05:11:01,809 --> 05:11:04,612 THAT CAN PLAGUE A PATIENT INTO 8355 05:11:04,679 --> 05:11:06,180 ACUTE LONG COVID. 8356 05:11:06,247 --> 05:11:08,349 DOWN AT THE LOWER LEFT IS MIXED 8357 05:11:08,416 --> 05:11:09,417 VENOUS O2 CONTENT. 8358 05:11:09,484 --> 05:11:11,853 THE MEASUREMENT OF VO2 AND THOSE 8359 05:11:11,919 --> 05:11:12,720 LATTER TWO MEASUREMENTS ALLOW US 8360 05:11:12,787 --> 05:11:14,789 TO GET A THICK CARDIAC OUTPUT 8361 05:11:14,856 --> 05:11:16,457 EVERY MINUTE DURING EXERCISE. 8362 05:11:16,524 --> 05:11:18,126 AND THIS IS OUR ALGORITHM. 8363 05:11:18,192 --> 05:11:20,194 I WON'T BELABOR ALL OF THESE 8364 05:11:20,261 --> 05:11:23,164 LITTLE PODS, BUT UP AT THE TOP, 8365 05:11:23,231 --> 05:11:24,532 WE GET THIS OVERALL ASSESSMENT 8366 05:11:24,599 --> 05:11:25,800 OF HOW SICK THE PATIENT IS WITH 8367 05:11:25,867 --> 05:11:27,335 A VO2 PEAK. 8368 05:11:27,402 --> 05:11:29,103 WE CAN RULE OUT A PULMONARY 8369 05:11:29,170 --> 05:11:30,438 MECHANICAL LIMIT OVER ON THE 8370 05:11:30,505 --> 05:11:33,174 LEFT UPPER LEFT, THAT'S A 8371 05:11:33,241 --> 05:11:34,909 NONINVASIVE MARKER AND I'VE 8372 05:11:34,976 --> 05:11:45,520 DISCOVERED A POINTER HERE MAYBE. 8373 05:11:45,787 --> 05:11:47,622 THIS WOULD BE GERMANE TO A 8374 05:11:47,688 --> 05:11:50,458 PATIENT WHO PERHAPS HAD ACUTE 8375 05:11:50,525 --> 05:11:52,293 COVID, WAS ON A VENTILATOR, 8376 05:11:52,360 --> 05:11:53,995 THESE ARE NOT BE THE PATIENTS I 8377 05:11:54,062 --> 05:11:54,762 WILL BE TALKING ABOUT TODAY. 8378 05:11:54,829 --> 05:11:56,164 THEY WILL BE THE PATIENTS WITH 8379 05:11:56,230 --> 05:11:57,632 LONG COVID WITHOUT HEART AND 8380 05:11:57,698 --> 05:11:58,966 LUNG DISEASE DENOTED BY THAT. 8381 05:11:59,033 --> 05:12:00,902 THEN IF YOU FOLLOW DOWN TO THE 8382 05:12:00,968 --> 05:12:02,437 LEFT, WE CAN MEASURE PEAK 8383 05:12:02,503 --> 05:12:03,571 CARDIAC OUTPUT. 8384 05:12:03,638 --> 05:12:06,474 WE CAN EXPRESS THAT AS A PERCENT 8385 05:12:06,541 --> 05:12:07,375 PREDICTED, AND IF THERE'S A 8386 05:12:07,442 --> 05:12:09,777 MATCH WITH THE VO2 PEAK, WE'VE 8387 05:12:09,844 --> 05:12:11,079 DENOTED A CARDIAC LIMIT. 8388 05:12:11,145 --> 05:12:12,713 WE CAN DIFFERENTIATE LEFT FROM 8389 05:12:12,780 --> 05:12:14,816 RIGHT HEART DISEASE, AND WHERE 8390 05:12:14,882 --> 05:12:16,150 YOU'LL SEE IN A FEW MINUTES, WE 8391 05:12:16,217 --> 05:12:18,386 END UP WITH MOST PATIENTS, IN 8392 05:12:18,453 --> 05:12:20,288 FACT, ALMOST ALL PATIENTS WITH 8393 05:12:20,354 --> 05:12:22,056 BOTH M.E. AND LONG COVID IS 8394 05:12:22,123 --> 05:12:24,225 SOMETHING WE CALL PRELOAD 8395 05:12:24,292 --> 05:12:25,193 FAILURE, IT'S DOWN AT THE 8396 05:12:25,259 --> 05:12:26,327 BOTTOM, AND I'M GOING TO SMEND 8397 05:12:26,394 --> 05:12:30,465 SSPENDSOME TIME EXPLAINING THAT. 8398 05:12:30,531 --> 05:12:31,666 WAY OVER TO THE RIGHT IS 8399 05:12:31,732 --> 05:12:33,434 SOMETHING ELSE. 8400 05:12:33,501 --> 05:12:35,069 THE LAST TWO TALKS WERE 8401 05:12:35,136 --> 05:12:35,436 FABULOUS. 8402 05:12:35,503 --> 05:12:39,707 THIS IS IMPAIRED SYSTEMIC OXYGEN 8403 05:12:39,774 --> 05:12:41,375 EXTRACTION, MEANING THE FAILURE 8404 05:12:41,442 --> 05:12:44,779 TO DEPRESS THE MIXED VENOUS 8405 05:12:44,846 --> 05:12:46,280 OXYGEN CONTENT DYNAMICALLY 8406 05:12:46,347 --> 05:12:47,148 DURING EXERCISE SHOULD FALL 8407 05:12:47,215 --> 05:12:47,682 ABOUT THREE FOLD. 8408 05:12:47,748 --> 05:12:49,917 WHEN IT FAILS TO DO SO, THERE 8409 05:12:49,984 --> 05:12:51,886 CAN BE CIRCULATORY ABNORMALITIES 8410 05:12:51,953 --> 05:12:53,387 IN THE PERIPHERY THAT I'LL TALK 8411 05:12:53,454 --> 05:12:55,056 ABOUT, BUT I SHOULD ALSO 8412 05:12:55,123 --> 05:12:56,924 ACKNOWLEDGE THAT INTRINSIC 8413 05:12:56,991 --> 05:12:57,558 MITOCHONDRIAL DISEASE COULD DO 8414 05:12:57,625 --> 05:12:59,227 THE SAME. 8415 05:12:59,293 --> 05:13:00,962 THIS IS WHERE WE GOT INTO THE 8416 05:13:01,028 --> 05:13:02,530 BUSINESS ABOUT SEVEN YEARS AGO. 8417 05:13:02,597 --> 05:13:05,032 WE WERE GETTING REFERRALS 8418 05:13:05,099 --> 05:13:07,902 INCREASINGLY FREQUENTLY OF 8419 05:13:07,969 --> 05:13:09,871 PATIENTS WHOSE EXERCISE 8420 05:13:09,937 --> 05:13:11,305 INTOLERANCE INCLUDING SHORTNESS 8421 05:13:11,372 --> 05:13:17,979 OF BREATH, THAT'S DYSPNEA, 8422 05:13:18,045 --> 05:13:19,714 FATIGUE, PALPITATIONS WERE NOT 8423 05:13:19,780 --> 05:13:21,282 EXPLAINED BY ANY INTRINSIC HEART 8424 05:13:21,349 --> 05:13:22,483 OR LUNG DISEASE, SO WE FOLLOWED 8425 05:13:22,550 --> 05:13:24,218 THAT ALGORITHM AND MADE SOME 8426 05:13:24,285 --> 05:13:25,319 PRELIMINARY DISCOVERIES. 8427 05:13:25,386 --> 05:13:26,187 AND THE FIRST ONE WE DISCOVERED 8428 05:13:26,254 --> 05:13:27,755 WAS SOMETHING WE'VE COME TO CALL 8429 05:13:27,822 --> 05:13:28,723 PRELOAD FAILURE. 8430 05:13:28,789 --> 05:13:30,491 YOU'LL FIND OTHER NAMES IN THE 8431 05:13:30,558 --> 05:13:32,994 LITERATURE NOW. 8432 05:13:33,060 --> 05:13:34,095 BUT WHAT WE DETERMINED WHEN WE 8433 05:13:34,162 --> 05:13:36,330 COMPARED TO A NORMAL COHORT, 8434 05:13:36,397 --> 05:13:37,765 THESE WERE PATIENTS WHO WERE 8435 05:13:37,832 --> 05:13:39,700 REFERRED TO US WITH EXERCISE 8436 05:13:39,767 --> 05:13:41,335 INTOLERANCE WHO DID NOT HAVE ANY 8437 05:13:41,402 --> 05:13:42,436 HEART OR LUNG DISEASE, 8438 05:13:42,503 --> 05:13:44,539 EVERYTHING WAS NORMAL, THEY WERE 8439 05:13:44,605 --> 05:13:48,042 PROBABLY AGE 60 RATHER THAN AGE 8440 05:13:48,109 --> 05:13:50,444 20. 8441 05:13:50,511 --> 05:13:51,846 SO THEY'RE THE NORMAL COHORT. 8442 05:13:51,913 --> 05:13:53,447 WHAT WE DETERMINED WHEN WE RULED 8443 05:13:53,514 --> 05:13:54,749 OUT HEART AND LUNG DISEASE AS A 8444 05:13:54,815 --> 05:13:57,919 CAUSE FOR EXERCISE INTOLERANCE, 8445 05:13:57,985 --> 05:13:59,754 WAS THAT PRELOAD FAILURE SEEMED 8446 05:13:59,820 --> 05:14:01,522 TO BE CAUSAL. 8447 05:14:01,589 --> 05:14:05,226 SO THAT'S SHOWN OVER ON THE LEFT 8448 05:14:05,293 --> 05:14:06,794 SIDE, RIGHT ATRIAL PRESSURE AN 8449 05:14:06,861 --> 05:14:08,129 SURROGATE FOR THE LEFT ATRIAL 8450 05:14:08,196 --> 05:14:09,730 PRESSURE IS THE PULMONARY 8451 05:14:09,797 --> 05:14:11,199 CAPILLARY WEDGE PRESSURE. 8452 05:14:11,265 --> 05:14:11,999 TWO IMPORTANT POINTS HERE, YOU 8453 05:14:12,066 --> 05:14:14,001 HAVE TO HAVE THE PATIENT IN THE 8454 05:14:14,068 --> 05:14:16,204 UPRIGHT POSITION. 8455 05:14:16,270 --> 05:14:18,506 MANY IN THE AUDIENCE KNOW 8456 05:14:18,573 --> 05:14:19,507 GRAVITY IS THE ENEMY HERE. 8457 05:14:19,574 --> 05:14:21,475 SO UPRIGHT IS WHERE WE SEE THE 8458 05:14:21,542 --> 05:14:23,110 SIGNAL, AND AT MAXIMUM EXERCISE, 8459 05:14:23,177 --> 05:14:24,545 THE SIGNAL IS NOT AS WELL SEEN 8460 05:14:24,612 --> 05:14:26,314 IN THE RESTING STATE. 8461 05:14:26,380 --> 05:14:28,516 SO LOWER FILLING PRESSURES ARE 8462 05:14:28,583 --> 05:14:30,818 WHAT SERVE TO DIFFERENTIATE 8463 05:14:30,885 --> 05:14:34,288 THESE PATIENTS HEMODYNAMICALLY 8464 05:14:34,355 --> 05:14:35,723 VERSUS THE NORMAL CONTROLS. 8465 05:14:35,790 --> 05:14:36,857 OVER ON THE RIGHT, WE'VE 8466 05:14:36,924 --> 05:14:38,593 ATTEMPTED TO REGRESS VO2 PEAK, 8467 05:14:38,659 --> 05:14:40,561 AND THEN CARDIAC OUTPUT PEAK 8468 05:14:40,628 --> 05:14:43,431 AGAINST THOSE FILLING PRESSURES 8469 05:14:43,497 --> 05:14:44,532 ON BOTH SIDES OF THE HEART, AND 8470 05:14:44,599 --> 05:14:46,701 YOU CAN SEE THERE'S AN 8471 05:14:46,767 --> 05:14:48,269 ASSOCIATION. 8472 05:14:48,336 --> 05:14:49,870 SO WE CALL THIS PRELOAD FAILURE. 8473 05:14:49,937 --> 05:14:51,739 WE LEARNED IN RETROSPECT THAT 8474 05:14:51,806 --> 05:14:53,741 MOST OF THESE PATIENTS MET THE 8475 05:14:53,808 --> 05:14:55,476 OLD IOM CRITERIA FOR ME/CFS, SO 8476 05:14:55,543 --> 05:14:57,111 THIS IS HOW THE LUNG DOCTOR WITH 8477 05:14:57,178 --> 05:14:58,879 A LITTLE BIT OF SERENDIPITY GOT 8478 05:14:58,946 --> 05:15:01,949 INTO THIS BUSINESS. 8479 05:15:02,016 --> 05:15:03,718 THIS IS WHERE THEY LANDED IN OUR 8480 05:15:03,784 --> 05:15:05,052 ALGORITHM, THE VO2 PEAK WAS 8481 05:15:05,119 --> 05:15:06,454 DOWN, THE CARDIAC OUTPUT WAS 8482 05:15:06,520 --> 05:15:09,724 DOWN, AND THE REASON FOR IT WAS 8483 05:15:09,790 --> 05:15:11,158 NOT HEART, LEFT OR RIGHT-SIDED 8484 05:15:11,225 --> 05:15:11,525 HEART DISEASE. 8485 05:15:11,592 --> 05:15:13,494 IT WAS FAILURE TO PRIME THE 8486 05:15:13,561 --> 05:15:14,128 PUMP. 8487 05:15:14,195 --> 05:15:16,764 SO THIS HAS BEEN UBIQUITOUS AND 8488 05:15:16,831 --> 05:15:17,898 HAS WITHSTOOD THE SEVEN YEARS OF 8489 05:15:17,965 --> 05:15:22,570 OUR STUDY, SO MY INTERIM 8490 05:15:22,637 --> 05:15:23,638 ANALYSIS IS THAT IN ME/CFS, 8491 05:15:23,704 --> 05:15:25,539 THERE IS EVIDENCE OF SYSTEMIC 8492 05:15:25,606 --> 05:15:26,240 VASCULAR DYSREGULATION IN THE 8493 05:15:26,307 --> 05:15:28,843 FORM OF FAILURE TO VENOCONSTRICT 8494 05:15:28,909 --> 05:15:30,144 AND PRIME THE PUMP ON BOTH SIDES 8495 05:15:30,211 --> 05:15:33,314 OF THE HEART. 8496 05:15:33,381 --> 05:15:34,649 WE TOOK A LITTLE DEEPER DIVE 8497 05:15:34,715 --> 05:15:35,983 INTO THIS WITH PHILIP JOSEPH 8498 05:15:36,050 --> 05:15:37,618 LEADING THE CHARGE TWO YEARS 8499 05:15:37,685 --> 05:15:40,721 AGO, AND WE DID TWO ADDITIONAL 8500 05:15:40,788 --> 05:15:41,689 THINGS. 8501 05:15:41,756 --> 05:15:43,357 WE HAD A LARGER DATABASE, WE 8502 05:15:43,424 --> 05:15:44,659 LOOKED AT ABOUT 1500 PATIENTS 8503 05:15:44,725 --> 05:15:46,394 WHO HAD UNDERGONE THIS TYPE OF 8504 05:15:46,460 --> 05:15:48,095 TESTING, AND ENDED UP WITH A 8505 05:15:48,162 --> 05:15:50,698 COHORT OF PATIENTS WITH 8506 05:15:50,765 --> 05:15:53,301 WELL-DEFINED CLINICAL ME/CFS AND 8507 05:15:53,367 --> 05:15:57,138 ADDITIONALLY THOSE HO H WHO HAD 8508 05:15:57,204 --> 05:15:59,874 UNDERGONE A SKIN BIOPSY, 8509 05:15:59,940 --> 05:16:01,208 SOMETHING YOU HEARD ALLUDED TO 8510 05:16:01,275 --> 05:16:01,876 EARLIER THIS MORNING. 8511 05:16:01,942 --> 05:16:06,614 AND THIS IS THE NEW VASCULAR 8512 05:16:06,681 --> 05:16:07,782 INFORMATION WE GOT. 8513 05:16:07,848 --> 05:16:10,084 WE BORROWED HEAVILY FROM THE POT 8514 05:16:10,151 --> 05:16:11,185 IS THE LET'S TOUR, WHICH 8515 05:16:11,252 --> 05:16:13,387 SUGGESTS THAT IN THE UPRIGHT 8516 05:16:13,454 --> 05:16:14,789 TILT TABLE TEST, THERE WAS A LOW 8517 05:16:14,855 --> 05:16:16,157 FLOW GROUP OVER TO THE LEFT IN 8518 05:16:16,223 --> 05:16:17,958 THE BLUE, AND A HIGH FLOW GROUP 8519 05:16:18,025 --> 05:16:22,797 OVER TO THE RIGHT, IN POTS AND 8520 05:16:22,863 --> 05:16:24,065 WE ASKED THE QUESTION DOES THE 8521 05:16:24,131 --> 05:16:25,866 SAME THING HAPPEN DURING UPRIGHT 8522 05:16:25,933 --> 05:16:26,867 EXERCISE IN ME/CFS. 8523 05:16:26,934 --> 05:16:32,206 AND THE ANSWER SEEMED TO BE YES, 8524 05:16:32,273 --> 05:16:33,774 THE CARDIAC OUTPUT WE MEASURE, 8525 05:16:33,841 --> 05:16:36,744 WE'RE LOOKING AT THIS AS A SLOPE 8526 05:16:36,811 --> 05:16:38,279 VERSUS INCREASING METABOLISM 8527 05:16:38,346 --> 05:16:39,747 DURING INCREMENTAL CYCLING. 8528 05:16:39,814 --> 05:16:41,716 THE CARDIAC OUTPUT WE MEASURE IS 8529 05:16:41,782 --> 05:16:42,450 PULMONARY BLOOD FLOW. 8530 05:16:42,516 --> 05:16:43,651 WHAT WE KNOW IS THAT THESE 8531 05:16:43,718 --> 05:16:48,189 PATIENTS HAVE A LOW VO2 PEAK, 8532 05:16:48,255 --> 05:16:50,024 BUT THE PULMONARY BLOOD FLOW IS 8533 05:16:50,091 --> 05:16:50,925 VERY HIGH. 8534 05:16:50,991 --> 05:16:52,293 THIS IS A HALLMARK IN CARDIOLOGY 8535 05:16:52,360 --> 05:16:53,627 OF LEFT TO RIGHT SHUNTING, AND 8536 05:16:53,694 --> 05:16:54,862 WE KNOW THAT NONE OF THESE 8537 05:16:54,929 --> 05:16:57,465 PATIENTS HAS A HOLE IN THE HEART 8538 05:16:57,531 --> 05:16:58,299 AND INTRACARDIAC LEFT TO RIGHT 8539 05:16:58,366 --> 05:16:58,733 SHUNT. 8540 05:16:58,799 --> 05:17:01,802 THIS IS PERIPHERAL LEFT TO RIGHT 8541 05:17:01,869 --> 05:17:02,903 SHUNTING. 8542 05:17:02,970 --> 05:17:05,005 AS A CONSEQUENCE, WHAT WE END UP 8543 05:17:05,072 --> 05:17:07,174 WITH, WITH THE FIC PRINCIPAL 8544 05:17:07,241 --> 05:17:09,276 WHICH IS SHOWN ABOVE IS A 8545 05:17:09,343 --> 05:17:10,845 DEPRESSED VO2 PEAK BECAUSE OF 8546 05:17:10,911 --> 05:17:12,480 FAILURE TO EXTRACT OXYGEN. 8547 05:17:12,546 --> 05:17:15,182 WE THINK THIS IS A PERIPHERAL 8548 05:17:15,249 --> 05:17:16,751 VASCULAR PHENOMENON WHERE THE 8549 05:17:16,817 --> 05:17:19,086 INDIVIDUAL WITH ME/CFS IS 8550 05:17:19,153 --> 05:17:21,021 PERFUSING ORGAN SYSTEMS THAT DO 8551 05:17:21,088 --> 05:17:24,625 NOT NEED THE OXYGENATED BLOOD 8552 05:17:24,692 --> 05:17:24,992 FLOW. 8553 05:17:25,059 --> 05:17:26,093 THINGS LIKE THE KIDNEY, THE GUT 8554 05:17:26,160 --> 05:17:26,627 AND THE SKIN. 8555 05:17:26,694 --> 05:17:28,262 AND WE HAVE SOME ADDITIONAL 8556 05:17:28,329 --> 05:17:29,597 EVIDENCE OF THAT. 8557 05:17:29,663 --> 05:17:31,031 SO HIGH FLOW GROUP IS WHAT I 8558 05:17:31,098 --> 05:17:33,868 WANT TO FOCUS ON FOR A SECOND 8559 05:17:33,934 --> 05:17:37,371 WITH IMPAIRED SYSTEMIC 8560 05:17:37,438 --> 05:17:37,805 O2 EXTRACTION. 8561 05:17:37,872 --> 05:17:39,440 WE TOOK A LOOK AT HOW MANY OF 8562 05:17:39,507 --> 05:17:41,776 THESE PATIENTS HAD SMALL FIBER 8563 05:17:41,842 --> 05:17:44,845 NEUROPATHY BY A SINGLE EPIDERMAL 8564 05:17:44,912 --> 05:17:48,315 SKIN BIOPSY AT MASS GENERAL, AND 8565 05:17:48,382 --> 05:17:51,819 THE ANSWER WAS ABOUT 45% EITHER 8566 05:17:51,886 --> 05:17:53,921 HAD DEFINITE SMALL FIBER 8567 05:17:53,988 --> 05:17:55,589 NEUROPATHY OR PROBABLE SMALL 8568 05:17:55,656 --> 05:17:58,526 FIBER NEUROPATHY. 8569 05:17:58,592 --> 05:18:00,728 THAT 45% IS ABOUT THE SAME AS 8570 05:18:00,795 --> 05:18:01,829 DESCRIBED IN THE LITERATURE IN 8571 05:18:01,896 --> 05:18:04,698 BOTH POTS AND IN FIBROMYALGIA 8572 05:18:04,765 --> 05:18:06,767 VERY MUCH RELATED TO ME/CFS, OF 8573 05:18:06,834 --> 05:18:08,235 COURSE, WITH A LOT OF OVERLAP 8574 05:18:08,302 --> 05:18:09,670 WITH THE VENN DIAGRAM. 8575 05:18:09,737 --> 05:18:14,141 SO WE BEGAN TO BELIEVE THAT WHAT 8576 05:18:14,208 --> 05:18:17,878 WE WERE OBSERVING WITH THE 8577 05:18:17,945 --> 05:18:19,180 VASCULAR DYSREGULATION BOTH ON 8578 05:18:19,246 --> 05:18:22,016 THE VENOUS SIDE, FAILURE TO 8579 05:18:22,082 --> 05:18:23,117 VENOCONSTRICT AND ON THE 8580 05:18:23,184 --> 05:18:25,119 ARTERIAL SIDE, FAILURE TO DIVERT 8581 05:18:25,186 --> 05:18:26,854 CARDIAC OUTPUT APPROPRIATELY TO 8582 05:18:26,921 --> 05:18:29,757 THTHE EXERCISING MUSCLE BED WASA 8583 05:18:29,824 --> 05:18:33,027 VASCULAR DYSREGULATION 8584 05:18:33,093 --> 05:18:34,328 PRIMARILY, THEN SECONDARILY 8585 05:18:34,395 --> 05:18:34,628 BLOOD FLOW. 8586 05:18:34,695 --> 05:18:36,096 SO THIS IS WHERE WE THINK WE END 8587 05:18:36,163 --> 05:18:37,665 UP WITH THAT HIGH FLOW GROUP 8588 05:18:37,731 --> 05:18:39,733 OVER TO THE RIGHT IN ADDITION TO 8589 05:18:39,800 --> 05:18:42,136 THE PRELOAD FAILURE. 8590 05:18:42,203 --> 05:18:44,472 NOW, HOW DO I KNOW ALL THIS IS 8591 05:18:44,538 --> 05:18:45,673 NEUROVASCULAR DYSREGULATION? 8592 05:18:45,739 --> 05:18:47,107 WE BEGIN TO MAKE A CASE FOR THE 8593 05:18:47,174 --> 05:18:50,077 REASONS I JUST GAVE YOU. 8594 05:18:50,144 --> 05:18:53,147 BUT WE ATTEMPTED TO TEST THIS 8595 05:18:53,214 --> 05:18:54,381 WITH SOMETHING THAT WAS JUST 8596 05:18:54,448 --> 05:18:55,349 MENTIONED A SECOND AGO. 8597 05:18:55,416 --> 05:18:57,885 A DRUG THAT IS THOUGHT TO 8598 05:18:57,952 --> 05:19:03,357 PRIMARILY AFFECT NEUROLOGIC 8599 05:19:03,424 --> 05:19:03,991 TRANSMISSION. 8600 05:19:04,058 --> 05:19:07,695 THIS IS PYRIDOSTIGMINE, 8601 05:19:07,761 --> 05:19:09,096 FDA-APPROVED SO THIS IS AN 8602 05:19:09,163 --> 05:19:12,466 OFF-LABEL COMMENT FOR MYASTHENIA 8603 05:19:12,533 --> 05:19:14,969 GRAVIS FOR N ACETYLCHOLINE AT 8604 05:19:15,035 --> 05:19:16,770 THE END PLATE FOR THE MUSCLE 8605 05:19:16,837 --> 05:19:18,205 WEAKNESS, AUTOIMMUNE DISEASE, IT 8606 05:19:18,272 --> 05:19:20,941 RETARDS THE DEGRADATION OF 8607 05:19:21,008 --> 05:19:21,275 ACETYLCHOLINE. 8608 05:19:21,342 --> 05:19:23,010 BUT WHAT WE WERE REMINDED OF AS 8609 05:19:23,077 --> 05:19:24,778 WE GOT INTO THIS, WE KNEW THIS 8610 05:19:24,845 --> 05:19:28,315 WAS ON THE LIST OF POTS DRUGS, 8611 05:19:28,382 --> 05:19:30,518 WE ANECDOTALLY TRIED IT AND THEN 8612 05:19:30,584 --> 05:19:31,418 SYSTEMATICALLY. 8613 05:19:31,485 --> 05:19:32,820 WE'RE REMINDED THERE'S A 8614 05:19:32,887 --> 05:19:34,288 CHOLINERGIC STEP OF THE 8615 05:19:34,355 --> 05:19:35,789 ADRENERGIC OUTFLOW TO BLOOD 8616 05:19:35,856 --> 05:19:38,192 VESSELS AT THE AUTO NO NICK 8617 05:19:38,259 --> 05:19:38,459 GANGLION. 8618 05:19:38,526 --> 05:19:40,628 SO THAT IS A CHOLINERGIC STEP. 8619 05:19:40,694 --> 05:19:42,096 WE THINK IT MAY BE WORKING THERE 8620 05:19:42,162 --> 05:19:45,032 IN POTS, AND PERHAPS IN M.E. 8621 05:19:45,099 --> 05:19:46,367 DURING UPRIGHT EXERCISE. 8622 05:19:46,433 --> 05:19:49,136 SO WE DID A RANDOMIZED PLACEBO 8623 05:19:49,203 --> 05:19:50,938 CONTROLLED STUDY AT THE BRIGHAM, 8624 05:19:51,005 --> 05:19:55,175 AND IT WENT AS FOLLOWS. 8625 05:19:55,242 --> 05:19:56,143 THESE PATIENTS WITH M.E. WERE 8626 05:19:56,210 --> 05:19:57,278 REFERRED TO US FOR CLINICAL 8627 05:19:57,344 --> 05:19:58,045 TESTING. 8628 05:19:58,112 --> 05:19:59,246 WE DID THE TESTING WITH THE 8629 05:19:59,313 --> 05:20:00,014 LINES IN PLACE. 8630 05:20:00,080 --> 05:20:02,383 WE IDENTIFIED PRELOAD FAILURE, 8631 05:20:02,449 --> 05:20:05,319 AND THEN WE GAVE THEM A SINGLE 8632 05:20:05,386 --> 05:20:10,124 DOSE OF ORAL DRUG 60 MILLIGRAMS. 8633 05:20:10,190 --> 05:20:12,560 REMEMBER THIS IS ACUTE, A SINGLE 8634 05:20:12,626 --> 05:20:14,061 DOSE, THEN WE ASKED THEM TO 8635 05:20:14,128 --> 05:20:16,163 RELAX FOR 45 MINUTES AND THEN 8636 05:20:16,230 --> 05:20:17,731 PEDAL AGAIN WITH THE LINES IN 8637 05:20:17,798 --> 05:20:18,399 PLACE. 8638 05:20:18,465 --> 05:20:19,600 SO PLACEBO CONTROLLED, AND THIS 8639 05:20:19,667 --> 05:20:22,236 IS WHAT WE FOUND. 8640 05:20:22,303 --> 05:20:24,071 THE VO2 PEAK, WHEN THEY GOT 8641 05:20:24,138 --> 05:20:25,973 DRUG, WHICH IS OVER ON THE 8642 05:20:26,040 --> 05:20:28,075 GREEN, IMPROVED. 8643 05:20:28,142 --> 05:20:30,144 IF THEY DIDN'T GET IT AND WERE 8644 05:20:30,210 --> 05:20:32,246 WONDERING IF THIS WAS EARLY PEM, 8645 05:20:32,313 --> 05:20:34,348 THEY ACTUALLY GOT WORSE. 8646 05:20:34,415 --> 05:20:36,317 THE EFFECT SIZE WAS SMALL BUT 8647 05:20:36,383 --> 05:20:38,752 PLEASE REMEMBER SINGLE DOSE MOST 8648 05:20:38,819 --> 05:20:40,154 FOLKS RESPOND CLINICALLY OVER 8649 05:20:40,220 --> 05:20:41,822 WEEKS TO MONTHS. 8650 05:20:41,889 --> 05:20:44,525 AND THE REASON THE VO2 PEAK WAS 8651 05:20:44,592 --> 05:20:45,893 IMPROVED WAS THAT THE CARDIAC 8652 05:20:45,960 --> 05:20:48,062 OUTPUT WAS HIGHER IF THEY GOT 8653 05:20:48,128 --> 05:20:50,164 ACTIVE DRUG, AND IT WAS RELATED 8654 05:20:50,230 --> 05:20:52,266 TO AN IMPROVEMENT IN RIGHT 8655 05:20:52,333 --> 05:20:53,567 ATRIAL PRESSURES, FILLING 8656 05:20:53,634 --> 05:20:54,768 PRESSURES. 8657 05:20:54,835 --> 05:20:56,070 AGAIN, EFFECT SIZE SMALL, BUT 8658 05:20:56,136 --> 05:20:59,840 MAYBE A SIGNAL THAT THIS IS 8659 05:20:59,907 --> 05:21:01,742 IMPROVED AUTONOMIC NERVOUS 8660 05:21:01,809 --> 05:21:02,109 SYSTEM FUNCTION. 8661 05:21:02,176 --> 05:21:03,677 SO WHAT I WOULD CONCLUDE HERE 8662 05:21:03,744 --> 05:21:06,580 BASED ON THAT LITTLE BIT OF DATA 8663 05:21:06,647 --> 05:21:09,083 IS THAT IN ME/CFS, WE HAVE SOME 8664 05:21:09,149 --> 05:21:11,185 EVIDENCE OF NEUROVASCULAR 8665 05:21:11,251 --> 05:21:12,753 DYSREGULATION IN PART BECAUSE A 8666 05:21:12,820 --> 05:21:14,688 DRUG THAT IS THOUGHT TO 8667 05:21:14,755 --> 05:21:16,757 FACILITATE AUTONOMIC NERVOUS 8668 05:21:16,824 --> 05:21:19,226 SYSTEM FUNCTION IMPROVES THE 8669 05:21:19,293 --> 05:21:19,560 HEMODYNAMICS. 8670 05:21:19,627 --> 05:21:21,195 THIS IS POTENTIALLY A NICE 8671 05:21:21,261 --> 05:21:23,397 EXAMPLE OF USING A DRUG TO DO A 8672 05:21:23,464 --> 05:21:25,599 DEEP DIVE INTO THE 8673 05:21:25,666 --> 05:21:26,834 PATHOPHYSIOLOGY OF A DISEASE 8674 05:21:26,900 --> 05:21:28,135 WITHOUT GOOD BIOMARKERS. 8675 05:21:28,202 --> 05:21:30,337 SO IF A DRUG WE KNOW HOW IT 8676 05:21:30,404 --> 05:21:33,374 WORKS, WORKS, THEN ERGO PERHAPS 8677 05:21:33,440 --> 05:21:35,042 THIS IS WHAT AILS THE PATIENT AT 8678 05:21:35,109 --> 05:21:38,212 LEAST IN PART. 8679 05:21:38,278 --> 05:21:39,246 PART TO BEGIN WITH. 8680 05:21:39,313 --> 05:21:41,882 A LITTLE BIT ON LONG COVID. 8681 05:21:41,949 --> 05:21:43,183 THIS IS A SMALL STUDY. 8682 05:21:43,250 --> 05:21:45,352 VERY SIMILAR IN FASHION USING 8683 05:21:45,419 --> 05:21:49,123 THAT INVASIVE CARDIOPULMONARY 8684 05:21:49,189 --> 05:21:50,124 EXERCISE TEST COMPARED TO 10 8685 05:21:50,190 --> 05:21:51,759 NORMAL CONTROLS, WE HAD 10 8686 05:21:51,825 --> 05:21:53,093 PATIENTS WITH LONG COVID AT 8687 05:21:53,160 --> 05:21:54,628 LEAST SIX MONTHS OUT FROM THEIR 8688 05:21:54,695 --> 05:21:55,329 ACUTE DISEASE. 8689 05:21:55,396 --> 05:21:57,898 THEY HAD NO HEART OR LUNG 8690 05:21:57,965 --> 05:21:58,232 DISEASE. 8691 05:21:58,298 --> 05:22:00,334 WHAT YOU CAN SEE IS THEIR 8692 05:22:00,401 --> 05:22:01,568 VO2 PEAKS AS A PERCENT PREDICTED 8693 05:22:01,635 --> 05:22:07,508 OR ABOUT 70% AND NORMAL CONTROLS 8694 05:22:07,574 --> 05:22:09,376 WERE SUPER IT IS NORMAL. 8695 05:22:09,443 --> 05:22:11,445 PULMONARY PLEASURE MEASURED BY 8696 05:22:11,512 --> 05:22:13,881 THE FIC PRINCIPLE WAS ACTUALLY 8697 05:22:13,947 --> 05:22:15,315 THE SAME AS THE CONTROLS IN THE 8698 05:22:15,382 --> 05:22:17,017 NORMAL RANGE BUT AGAIN VO2 PEAK 8699 05:22:17,084 --> 05:22:19,319 IS DOWN AND WHAT THEY HAVE IS 8700 05:22:19,386 --> 05:22:21,488 SEVERE IMPAIRMENT OF SYSTEMIC 8701 05:22:21,555 --> 05:22:22,623 OXYGEN EXTRACTION BY A DIFFERENT 8702 05:22:22,690 --> 05:22:24,258 NUMBER, BUT IT'S ABOUT HALF OF 8703 05:22:24,324 --> 05:22:25,993 THE NORMAL SHOWN IN THAT THIRD 8704 05:22:26,060 --> 05:22:27,227 ROW. 8705 05:22:27,294 --> 05:22:33,400 AND THEY LAKELY HAD PRELOAD LIKD 8706 05:22:33,467 --> 05:22:35,369 ERROR, LOW FILLING PRESSURES AND 8707 05:22:35,436 --> 05:22:36,570 IMPAIRED OXYGEN EXTRACTION. 8708 05:22:36,637 --> 05:22:39,039 SO AT LEAST IN OUR EXERCISE 8709 05:22:39,106 --> 05:22:40,641 WORLD, THIS FORM OF LONG COVID 8710 05:22:40,708 --> 05:22:42,409 LOOKS FRIGHTENINGLY SIMILAR. 8711 05:22:42,476 --> 05:22:45,312 IT LOOKS VERY CLOSE TO WHAT 8712 05:22:45,379 --> 05:22:46,380 WE'VE SEEN IN ME/CFS. 8713 05:22:46,447 --> 05:22:48,048 THEY LAND IN THE SAME PLACE. 8714 05:22:48,115 --> 05:22:52,753 SO I WOULD CONCLUDE BOTH IN M.E. 8715 05:22:52,820 --> 05:22:54,855 AND CFS AND LONG COVID, WE MAY 8716 05:22:54,922 --> 05:22:56,724 HAVE SOME EVIDENCE OF 8717 05:22:56,790 --> 05:22:58,225 NEUROVASCULAR DYSREGULATION. 8718 05:22:58,292 --> 05:23:00,794 WE PUBLISHED AS A RESULT OF SOME 8719 05:23:00,861 --> 05:23:02,563 COMBINED EFFORTS OF THE RECOVER 8720 05:23:02,629 --> 05:23:07,267 PROJECT THIS REVIEW A FEW MONTHS 8721 05:23:07,334 --> 05:23:09,536 AGO, A COMBINED EFFORT WHERE WE 8722 05:23:09,603 --> 05:23:09,903 CONCLUDED THIS. 8723 05:23:09,970 --> 05:23:11,672 I THINK IT'S ON REASONABLY SOLID 8724 05:23:11,739 --> 05:23:12,106 GROUND. 8725 05:23:12,172 --> 05:23:15,008 THERE MAY BE SUBSETS OF BOTH 8726 05:23:15,075 --> 05:23:16,110 DISEASES, BUT GENERALLY 8727 05:23:16,176 --> 05:23:22,149 SPEAKING, THE EXERCISE PATHOPHYS 8728 05:23:22,216 --> 05:23:23,417 SEEMS TO BE BOTH THE SAME IN 8729 05:23:23,484 --> 05:23:24,451 M.E. AND LONG COVID. 8730 05:23:24,518 --> 05:23:26,653 A LITTLE BIT OF A CALLOUT HERE 8731 05:23:26,720 --> 05:23:27,321 FOR TWO THINGS. 8732 05:23:27,387 --> 05:23:28,856 ONE IS THAT I THINK THE PRELOAD 8733 05:23:28,922 --> 05:23:31,625 FAILURE THAT WE SEE AND THE 8734 05:23:31,692 --> 05:23:33,360 ARTERIAL ABNORMALITIES LEFT TO 8735 05:23:33,427 --> 05:23:36,663 RIGHT SHUNTING DO HAVE A 8736 05:23:36,730 --> 05:23:38,565 DIFFERENTIAL DIAGNOSIS THAT IS 8737 05:23:38,632 --> 05:23:40,667 WORTHY OF FURTHER INVESTIGATION, 8738 05:23:40,734 --> 05:23:41,935 AND SOME IN THIS ROOM ARE DOING 8739 05:23:42,002 --> 05:23:42,503 EXACTLY THIS. 8740 05:23:42,569 --> 05:23:44,304 SO I'VE TALKED TO YOU ABOUT 8741 05:23:44,371 --> 05:23:44,838 DYSAUTONOMIA. 8742 05:23:44,905 --> 05:23:47,341 THERE ARE DATA THAT SUGGEST THAT 8743 05:23:47,407 --> 05:23:48,709 AS A RESULT OF THESE DISEASES, 8744 05:23:48,776 --> 05:23:51,078 THERE'S A SUBSET OF PATIENTS 8745 05:23:51,145 --> 05:23:52,412 WITH HYPOVOLEMIA. 8746 05:23:52,479 --> 05:23:54,214 THERE ARE EMERGING DATA, 8747 05:23:54,281 --> 05:23:56,450 ESPECIALLY IN LONG COVID, THAT 8748 05:23:56,517 --> 05:23:59,019 THE ENDOTHELIUM MAY BE INFLAMED 8749 05:23:59,086 --> 05:24:04,091 AND MAYBE EVEN INFECTED SO 8750 05:24:04,158 --> 05:24:04,858 ENDOTHELIITIS IS A NEW WORD I 8751 05:24:04,925 --> 05:24:05,959 HAD TO LEARN TO PRO MOWNS. 8752 05:24:06,026 --> 05:24:07,361 THERE ARE MICRO CLOTS THAT HAVE 8753 05:24:07,427 --> 05:24:09,296 BEEN DESCRIBED IN BOTH DISEASES. 8754 05:24:09,363 --> 05:24:10,697 A LITTLE PACKETS OF BLOOD CLOTS 8755 05:24:10,764 --> 05:24:15,002 WITH IP FL INFLAMMATORY CYTOKINT 8756 05:24:15,068 --> 05:24:16,470 SOLUBLE THEREFORE NOT MEASURABLE 8757 05:24:16,537 --> 05:24:17,638 OUT IN THE PERIPHERY, PERHAPS 8758 05:24:17,704 --> 05:24:18,839 DAMAGING THE SMALL VESSELS, AND 8759 05:24:18,906 --> 05:24:21,875 THERE ARE EVEN RED BLOOD CELL 8760 05:24:21,942 --> 05:24:22,810 ABNORMALITIES, THEY'RE TOO BIG, 8761 05:24:22,876 --> 05:24:23,911 THEY'RE TOO STIFF, THEY DON'T 8762 05:24:23,977 --> 05:24:26,280 EXHIBIT ACT WITH THE ENDOTHELIUM 8763 05:24:26,346 --> 05:24:27,114 NORMALLY DURING EXERCISE, THEY 8764 05:24:27,181 --> 05:24:29,883 MAY BE AT PLAY, AND A SPECIAL 8765 05:24:29,950 --> 05:24:32,686 CALLOUT HERE TO THE NIH ROAD MAP 8766 05:24:32,753 --> 05:24:35,189 WEBINAR, WHICH WE'RE PARTWAY 8767 05:24:35,255 --> 05:24:36,957 THROUGH OUR CIRCULATION VERSION 8768 05:24:37,024 --> 05:24:41,762 OF THIS WILL BE ON JANUA 8769 05:24:41,829 --> 05:24:42,830 JANUARY 11TH, A PLUG, SO PLEASE 8770 05:24:42,896 --> 05:24:44,998 TUNE IN, AND ALL OF THESE 8771 05:24:45,065 --> 05:24:49,236 SUBTITLES WILL BE COVERED. 8772 05:24:49,303 --> 05:24:50,504 SO WHAT I WANTED TO LEAVE YOU 8773 05:24:50,571 --> 05:24:51,605 WITH IS WHERE WE'RE GOING NEXT. 8774 05:24:51,672 --> 05:24:53,674 I KNOW JOE WANTED TO ADDRESS 8775 05:24:53,740 --> 05:24:55,609 POTENTIAL TREATMENT TRIALS, AND 8776 05:24:55,676 --> 05:24:57,110 WE DON'T CLAIM TO HAVE THE 8777 05:24:57,177 --> 05:24:58,645 ANSWER, BUT WE ARE GOING TO 8778 05:24:58,712 --> 05:25:03,383 LAUNCH A TREATMENT TRIAL WI WITH 8779 05:25:03,450 --> 05:25:05,252 GENEROUS HELP OF OPEN MEDICINE 8780 05:25:05,319 --> 05:25:07,421 FOUNDATION AND LINDA WHO'S HERE 8781 05:25:07,487 --> 05:25:08,856 IN THE AUDIENCE AT THE BRIGHAM. 8782 05:25:08,922 --> 05:25:11,425 IT'S CALLED THE LIFT TRIAL, THE 8783 05:25:11,491 --> 05:25:12,526 LIFE IMPROVEMENT TRIAL. 8784 05:25:12,593 --> 05:25:15,729 IT'S DEDICATED INITIALLY ANYWAY 8785 05:25:15,796 --> 05:25:16,196 TO ME/CFS PATIENTS. 8786 05:25:16,263 --> 05:25:17,931 IT'S A SMALLER TRIAL BUT IT WILL 8787 05:25:17,998 --> 05:25:20,701 BE RANDOMIZED AND PLACEBO 8788 05:25:20,767 --> 05:25:22,102 CONTROLLED AND WE THINK WE'VE 8789 05:25:22,169 --> 05:25:25,205 POWERED IT AT LEAST SUFFICIENTLY 8790 05:25:25,272 --> 05:25:25,939 TO ANSWER SOME QUESTIONS. 8791 05:25:26,006 --> 05:25:31,378 THIS WILL BE A TRIAL THAT I JUST 8792 05:25:31,445 --> 05:25:34,581 MENTIONED VERSUS LOW DOSE 8793 05:25:34,648 --> 05:25:35,549 NALTREXONE, MAYBE A TOPIC FOR 8794 05:25:35,616 --> 05:25:37,017 THE PANEL, VERSUS THE 8795 05:25:37,084 --> 05:25:39,119 COMBINATION OF THE TWO, VERSUS 8796 05:25:39,186 --> 05:25:39,353 PLACEBO. 8797 05:25:39,419 --> 05:25:41,688 SO IT WILL BE A PROPER 8798 05:25:41,755 --> 05:25:42,422 RANDOMIZED CLINICAL TRIAL, 40 8799 05:25:42,489 --> 05:25:45,492 PATIENTS IN EACH ARM, THREE 8800 05:25:45,559 --> 05:25:47,027 MONTHS OVERALL, AND THESE ARE 8801 05:25:47,094 --> 05:25:48,228 THE THINGS WE'RE GOING TO 8802 05:25:48,295 --> 05:25:50,130 MEASURE. 8803 05:25:50,197 --> 05:25:52,566 WE'VE GOT THREE MAJOR 8804 05:25:52,633 --> 05:25:56,003 QUESTIONNAIRES, ONE THAT'S COME 8805 05:25:56,069 --> 05:26:00,474 OUT OF NORWAY MORE RECENTLY, AND 8806 05:26:00,540 --> 05:26:04,177 DSQ PEM SHORT FORM THAT WILL BE 8807 05:26:04,244 --> 05:26:04,945 ADMINISTERED INTERMITTENTLY. 8808 05:26:05,012 --> 05:26:06,513 MOST OF THE DATA WILL BE 8809 05:26:06,580 --> 05:26:07,414 UPLOADED WITH OUR COMPUTATIONAL 8810 05:26:07,481 --> 05:26:07,948 GROUP. 8811 05:26:08,015 --> 05:26:11,218 WE'RE GOING TO HAVE THEM ALL 8812 05:26:11,285 --> 05:26:12,686 WEAR ONE OF THE NEWER GARMIN 8813 05:26:12,753 --> 05:26:13,553 WEARABLE DEVICES WHICH IS 8814 05:26:13,620 --> 05:26:15,455 REPORTED TO MEASURE ALL OF THESE 8815 05:26:15,522 --> 05:26:16,523 THINGS YOU SEE DOWN BELOW. 8816 05:26:16,590 --> 05:26:18,125 WE'RE GOING TO HAVE TO MEASURE 8817 05:26:18,191 --> 05:26:19,326 THESE THINGS, WEAR THEM 8818 05:26:19,393 --> 05:26:21,595 CONTINUOUSLY FOR THE THREE 8819 05:26:21,662 --> 05:26:23,430 MONTHS, IN HOPES OF CAPTURING 8820 05:26:23,497 --> 05:26:25,265 CRASHES AND PERHAPS SEEING WHAT 8821 05:26:25,332 --> 05:26:26,566 THE PATHOPHYSIOLOGY IS RELATED 8822 05:26:26,633 --> 05:26:28,869 TO CRASHES. 8823 05:26:28,936 --> 05:26:30,771 WE ARE ADDITIONALLY GOING TO DO 8824 05:26:30,837 --> 05:26:32,005 A PHYSIOLOGIC TEST. 8825 05:26:32,072 --> 05:26:35,375 THIS IS A BABY EXERCISE TEST. 8826 05:26:35,442 --> 05:26:36,710 IT'S CALLED THE SHAPE TEST. 8827 05:26:36,777 --> 05:26:40,280 IT'S A METABOLIC CART DEVELOPED 8828 05:26:40,347 --> 05:26:42,516 BY THE MEDICAL GRAPHICS 8829 05:26:42,582 --> 05:26:43,417 ENGINEERS. 8830 05:26:43,483 --> 05:26:45,085 IT'S A 3-MINUTE STEP TEST. 8831 05:26:45,152 --> 05:26:47,487 IT SHOULD NOT BE TOO ONEROUS FOR 8832 05:26:47,554 --> 05:26:51,425 OUR PATIENTS WITH ME/CFS. 8833 05:26:51,491 --> 05:26:53,994 IT IS SELF-PACED. 8834 05:26:54,061 --> 05:26:56,196 THESE ARE OUR EXERCISE 8835 05:26:56,263 --> 05:26:57,097 PHYSIOLOGISTS DOING THIS, SO 8836 05:26:57,164 --> 05:26:59,933 DON'T BE DISMAYED BY HOW FAST 8837 05:27:00,000 --> 05:27:01,068 JULIE TRACIE GOES. 8838 05:27:01,134 --> 05:27:02,602 THEY CAN GO AS SLOW AS THEY WANT 8839 05:27:02,669 --> 05:27:04,438 BUT ONLY FOR THREE MINUTES AS A 8840 05:27:04,504 --> 05:27:05,672 CONSTANT LOAD TEST. 8841 05:27:05,739 --> 05:27:07,274 WE GET MANY OF THE NONINVASIVE 8842 05:27:07,341 --> 05:27:09,443 VARIABLES THAT WE GET FROM AN 8843 05:27:09,509 --> 05:27:10,410 INCREMENTAL MEDICAL GRAPHICS 8844 05:27:10,477 --> 05:27:10,811 TEST. 8845 05:27:10,877 --> 05:27:13,013 SO THAT WILL BE ADMINISTERED AT 8846 05:27:13,080 --> 05:27:14,314 TIME ZERO AND AT THE END OF THE 8847 05:27:14,381 --> 05:27:17,084 STUDY, THE THREE-MONTH STUDY. 8848 05:27:17,150 --> 05:27:18,418 SO THAT'S ALL I HAD TO TELL YOU 8849 05:27:18,485 --> 05:27:19,553 TODAY. 8850 05:27:19,619 --> 05:27:23,390 I HOPE I MADE SOMEWHAT OF A CASE 8851 05:27:23,457 --> 05:27:25,692 FOR NEUROVASCULAR DYSREGULATION 8852 05:27:25,759 --> 05:27:27,427 IN ME/CFS AND LONG COVID. 8853 05:27:27,494 --> 05:27:28,962 I HAVE A LOT OF THANKS TO GIVE. 8854 05:27:29,029 --> 05:27:31,598 I MENTIONED SOME FOLKS ALREADY. 8855 05:27:31,665 --> 05:27:37,537 PHILIP JOSEPH AND INDY SINGH, 8856 05:27:37,604 --> 05:27:40,807 JOHANNA AND SARRA, I'VE GOT A 8857 05:27:40,874 --> 05:27:44,011 COMPUTATIONAL GROUP WITH 8858 05:27:44,077 --> 05:27:51,685 WENZHONG, JOSHUA AN OVER THERE. 8859 05:27:51,752 --> 05:27:57,157 RON DAVIS AT STANFORD, HELENE 8860 05:27:57,224 --> 05:27:58,959 AND MAUREEN HANSON WHOM YOU'VE 8861 05:27:59,026 --> 05:27:59,926 HEARD A LOT ABOUT TODAY, ALL 8862 05:27:59,993 --> 05:28:01,461 GOING TO BE COLLABORATING ON 8863 05:28:01,528 --> 05:28:03,096 THIS LIFT STUDY IN THE FUTURE, 8864 05:28:03,163 --> 05:28:04,765 AND I THANK THEM VERY MUCH AND 8865 05:28:04,831 --> 05:28:05,632 YOU FOR YOUR ATTENTION. 8866 05:28:05,699 --> 05:28:13,573 [APPLAUSE] 8867 05:28:13,640 --> 05:28:16,376 >> HOW ARE WE DOING FOR TIME? 8868 05:28:16,443 --> 05:28:17,411 ONE QUESTION? 8869 05:28:17,477 --> 05:28:19,846 SURE. 8870 05:28:19,913 --> 05:28:22,149 AND THERE WILL BE A PANEL LATER. 8871 05:28:22,215 --> 05:28:22,315 YES. 8872 05:28:22,382 --> 05:28:24,217 >> VERY INTERESTING. 8873 05:28:24,284 --> 05:28:28,121 I'M LEARNING A LOT HERE. 8874 05:28:28,188 --> 05:28:30,891 SO YOU SAID THAT MIXED VENOUS 8875 05:28:30,957 --> 05:28:35,562 OXYGEN SATURATION WAS HIGHER IN 8876 05:28:35,629 --> 05:28:39,933 THE CSF PATIENTS CONSISTENT WITH 8877 05:28:40,000 --> 05:28:42,502 OXYGEN -- SO THAT SEEMS TO BE IN 8878 05:28:42,569 --> 05:28:44,071 CONTRAST TO THE PREVIOUS SPEAKER 8879 05:28:44,137 --> 05:28:46,406 WHO TALKED ABOUT OXYGEN HYPOXIA 8880 05:28:46,473 --> 05:28:48,708 IN TISSUES, SO I DON'T KNOW HOW 8881 05:28:48,775 --> 05:28:51,611 YOU CAN RECONCILE THAT. 8882 05:28:51,678 --> 05:28:54,181 >> OKAY. 8883 05:28:54,247 --> 05:28:56,149 I CAN DEFER TO YOU, IT'S HARD TO 8884 05:28:56,216 --> 05:28:57,717 HEAR FROM UP HERE THE QUESTION, 8885 05:28:57,784 --> 05:28:59,453 BUT I THINK IT SOUNDS LIKE 8886 05:28:59,519 --> 05:29:01,555 THERE'S THE QUESTION ABOUT 8887 05:29:01,621 --> 05:29:03,323 WHETHER VENOUS OXYGEN LEVELS 8888 05:29:03,390 --> 05:29:05,525 DURING EXERCISE ARE HIGHER OR 8889 05:29:05,592 --> 05:29:08,261 LOWER IN THESE DISEASES. 8890 05:29:08,328 --> 05:29:10,464 WE FIND PRETTY UNIFORMLY, AT 8891 05:29:10,530 --> 05:29:12,265 LEAST, DURING WHOLE BODY 8892 05:29:12,332 --> 05:29:14,267 EXERCISE AND MIXED VENOUS OXYGEN 8893 05:29:14,334 --> 05:29:17,337 CONTENT FROM THE TIP OF THE PA 8894 05:29:17,404 --> 05:29:18,238 CATHETER THAT THEY'RE 8895 05:29:18,305 --> 05:29:19,106 INAPPROPRIATELY HIGH. 8896 05:29:19,172 --> 05:29:20,440 IT'S NOT EVERYBODY, IT'S THAT 8897 05:29:20,507 --> 05:29:22,609 RED GROUP, THE HIGH FLOW GROUP 8898 05:29:22,676 --> 05:29:23,677 THAT ARE LIKE THAT. 8899 05:29:23,743 --> 05:29:26,713 AND THEN LIMITED NUMBER OF LONG 8900 05:29:26,780 --> 05:29:28,281 COVID PATIENTS HAVE THE SAME. 8901 05:29:28,348 --> 05:29:30,917 I WOULD JUST ADD THAT I THINK WE 8902 05:29:30,984 --> 05:29:34,221 ARE VERY MUCH CONCORDANT AND ONE 8903 05:29:34,287 --> 05:29:35,388 OTHER THING I DIDN'T TALK ABOUT 8904 05:29:35,455 --> 05:29:37,457 TODAY TO ANY DEGREE, THAT IS 8905 05:29:37,524 --> 05:29:40,927 THAT IMPAIRED OXYGEN EXTRACTION 8906 05:29:40,994 --> 05:29:43,997 DURING EXERCISE CAN BE 8907 05:29:44,064 --> 05:29:44,598 O2 SUPPLY-RELATED. 8908 05:29:44,664 --> 05:29:48,435 WE KNOW IT'S NOT A PROBLEM WITH 8909 05:29:48,502 --> 05:29:49,169 GLOBAL CARDIAC OUTPUT. 8910 05:29:49,236 --> 05:29:51,471 WE KNOW IT'S NOT A PROBLEM WITH 8911 05:29:51,538 --> 05:29:53,740 ARTERIAL OXYGEN CONTENT, BUT WE 8912 05:29:53,807 --> 05:29:55,709 BELIEVE THERE MAY BE AN 8913 05:29:55,775 --> 05:29:57,210 O2 SUPPLY PROBLEM AT THE 8914 05:29:57,277 --> 05:29:58,778 MICROVASCULAR LEVEL. 8915 05:29:58,845 --> 05:30:02,849 BUT THE OTHER THING THAT 8916 05:30:02,916 --> 05:30:03,817 IMPAIRED OXYGEN EXTRACTION COULD 8917 05:30:03,884 --> 05:30:06,586 BE RELATED TO IS INTRINSIC 8918 05:30:06,653 --> 05:30:09,089 SKELETAL MUSCLE MITOCHONDRIAL 8919 05:30:09,156 --> 05:30:10,257 DYSFUNCTION AND THE TWO MAY 8920 05:30:10,323 --> 05:30:11,791 COEXIST. 8921 05:30:11,858 --> 05:30:13,827 >> I HAD TWO QUESTIONS. 8922 05:30:13,894 --> 05:30:14,427 >> YES, SIR. 8923 05:30:14,494 --> 05:30:19,366 >> WHAT HAPPENS TO THE PULSE 8924 05:30:19,432 --> 05:30:20,267 RATE WITH THE DRUG? 8925 05:30:20,333 --> 05:30:22,302 COULD THAT HAVE AN IMPACT ON THE 8926 05:30:22,369 --> 05:30:22,536 FILLING? 8927 05:30:22,602 --> 05:30:26,339 AND THE SECOND QUESTION IS, THE 8928 05:30:26,406 --> 05:30:27,440 O2 CONSUMPTION DIFFERENCES AS 8929 05:30:27,507 --> 05:30:29,242 YOU'RE MENTIONING, YOU TALKED 8930 05:30:29,309 --> 05:30:31,111 ABOUT MICROVASCULAR CHANGES AS 8931 05:30:31,178 --> 05:30:31,545 WELL. 8932 05:30:31,611 --> 05:30:33,713 HOW ABOUT VENTILATION PERFUSION 8933 05:30:33,780 --> 05:30:34,080 MISMATCH? 8934 05:30:34,147 --> 05:30:35,148 >> OKAY. 8935 05:30:35,215 --> 05:30:37,050 LET ME ANSWER THE LATTER, 8936 05:30:37,117 --> 05:30:40,053 BECAUSE IT'S EASIER. 8937 05:30:40,120 --> 05:30:42,222 THERE IS -- WE HAVE VIRTUALLY NO 8938 05:30:42,289 --> 05:30:44,090 EVIDENCE, AGAIN, THE TYPES OF 8939 05:30:44,157 --> 05:30:45,325 PATIENTS I'VE DESCRIBED HERE 8940 05:30:45,392 --> 05:30:48,094 FREE OF HEART AND LUNG DISEASE. 8941 05:30:48,161 --> 05:30:50,597 A V/Q MISMATCH, VENTILATION 8942 05:30:50,664 --> 05:30:51,631 PERFUSION MISMATCH. 8943 05:30:51,698 --> 05:30:54,167 THE ALVEOLAR ARTERIAL OXYGEN 8944 05:30:54,234 --> 05:30:56,269 DIFFERENCE AT PEAK EXERCISE IS 8945 05:30:56,336 --> 05:30:57,704 PERFECTLY NORMAL. 8946 05:30:57,771 --> 05:31:00,974 AND THE PHYSIOLOGIC DEAD SPACE 8947 05:31:01,041 --> 05:31:02,375 TO -- IS NORMAL, THOSE ARE THE 8948 05:31:02,442 --> 05:31:04,077 TWO EXTREMES OF LOW AND HIGH 8949 05:31:04,144 --> 05:31:04,778 V/Q. 8950 05:31:04,844 --> 05:31:07,447 SO THEY ARE NORMAL IN THESE 8951 05:31:07,514 --> 05:31:08,748 PATIENTS WE'RE STUDYING, IT'S 8952 05:31:08,815 --> 05:31:11,151 NOT LUNG DISEASE OR PULMONARY 8953 05:31:11,218 --> 05:31:13,253 VASCULAR DISEASE. 8954 05:31:13,320 --> 05:31:14,087 SO HEART RATE IS INTERESTING, 8955 05:31:14,154 --> 05:31:16,456 THERE ARE A FEW PATIENTS, I 8956 05:31:16,523 --> 05:31:18,191 BELIEVE, AND I KNOW SOME DIFFER 8957 05:31:18,258 --> 05:31:23,597 ON THIS, WITH KRO KNOW TROPIC 8958 05:31:23,663 --> 05:31:25,699 IMCOMPETENCE IN M.E. AND LONG 8959 05:31:25,765 --> 05:31:27,334 COVID, BUT IT DOESN'T SEEM TO 8960 05:31:27,400 --> 05:31:29,035 ACUTELY OR CHRONICALLY AFFECT 8961 05:31:29,102 --> 05:31:29,736 IT. 8962 05:31:29,803 --> 05:31:31,204 RESTING HEART RATES OCCASIONALLY 8963 05:31:31,271 --> 05:31:33,073 AT NIGHT WITH WEARABLE DEVICES 8964 05:31:33,139 --> 05:31:36,810 GO LOWER ON IT, SO ONE HAS TO 8965 05:31:36,876 --> 05:31:38,278 BEA WEAR OF THAT ONE, BUT AT 8966 05:31:38,345 --> 05:31:40,013 PEAK EXERCISE, IT SEEMS NOT TO 8967 05:31:40,080 --> 05:31:40,580 HAVE ANY DIFFERENCE. 8968 05:31:40,647 --> 05:31:41,848 >> SO THE HEART RATES ARE 8969 05:31:41,915 --> 05:31:42,148 EQUIVALENT? 8970 05:31:42,215 --> 05:31:43,049 >> CORRECT. 8971 05:31:43,116 --> 05:31:43,283 CORRECT. 8972 05:31:43,350 --> 05:31:44,584 >> ON AND OFF THE DRUG? 8973 05:31:44,651 --> 05:31:46,353 >> YES. 8974 05:31:46,419 --> 05:31:52,626 >> THANKS, JOE. 8975 05:31:52,692 --> 05:31:54,294 >> SO WE HAVE A SHORT BREAK, 8976 05:31:54,361 --> 05:31:57,097 WHICH IS GOING TO BE MADE 8977 05:31:57,163 --> 05:31:58,865 SHORTER. 8978 05:31:58,932 --> 05:32:01,034 RETURN AT 4:05, JUST A BIOBREAK 8979 05:32:01,101 --> 05:32:02,002 SO WE CAN STAY ON TIME. 8980 05:32:02,068 --> 05:32:08,575 THANK YOU. 8981 05:32:08,642 --> 05:32:10,877 >> OKAY, I THINK WE HAVE TO 8982 05:32:10,944 --> 05:32:15,749 START THE SESSION. 8983 05:32:15,815 --> 05:32:16,916 WE HAVE 25 MINUTES FOR SOME 8984 05:32:16,983 --> 05:32:21,688 DISCUSSION. 8985 05:32:21,755 --> 05:32:23,423 AND SO THERE MIGHT BE SOME 8986 05:32:23,490 --> 05:32:31,765 QUESTIONS THAT HAVE ACCUMULATED. 8987 05:32:31,831 --> 05:32:35,135 BUT BEFORE WE OPEN THE 8988 05:32:35,201 --> 05:32:36,102 POSSIBILITY FOR QUESTIONS, MAYBE 8989 05:32:36,169 --> 05:32:38,571 WE SHOULD HAVE SOME -- IF THERE 8990 05:32:38,638 --> 05:32:39,873 ARE SOME SUMMARY THOUGHTS FROM 8991 05:32:39,939 --> 05:32:45,445 THE PANEL HERE. 8992 05:32:45,512 --> 05:32:52,552 SO WE HAVE BEEN THROUGH -- 8993 05:32:52,619 --> 05:32:53,853 TOPIC OF THIS SESSION IS 8994 05:32:53,920 --> 05:32:54,754 METABOLISM AND METABOLIC 8995 05:32:54,821 --> 05:32:55,455 FUNCTION. 8996 05:32:55,522 --> 05:32:56,790 SO MAYBE I CAN ASK -- START BY 8997 05:32:56,856 --> 05:32:59,192 ASKING A QUESTION TO MY TWO 8998 05:32:59,259 --> 05:33:01,695 COLLEAGUES HERE, IF THEY THINK 8999 05:33:01,761 --> 05:33:04,264 ME/CFS IS A METABOLIC DISEASE, 9000 05:33:04,331 --> 05:33:09,102 OR IF WHAT WE ARE SEEING IS 9001 05:33:09,169 --> 05:33:10,303 SIMPLY -- OR NOT SIMPLY BECAUSE 9002 05:33:10,370 --> 05:33:15,275 IT'S COMPLEX, BUT IF IT IS 9003 05:33:15,342 --> 05:33:17,711 SOMETHING ELSE THAT CAUSES THE 9004 05:33:17,777 --> 05:33:23,817 METABOLIC EFFECT. 9005 05:33:23,883 --> 05:33:25,885 >> I THINK I'M THE LEAST 9006 05:33:25,952 --> 05:33:26,820 KNOWLEDGEABLE ABOUT ME/CFS 9007 05:33:26,886 --> 05:33:28,021 BECAUSE I'M REALLY COMPLETELY 9008 05:33:28,088 --> 05:33:32,559 NEW TO THE FIELD. 9009 05:33:32,625 --> 05:33:33,860 BUT YOU KNOW, IT SEEMS LIKE 9010 05:33:33,927 --> 05:33:35,795 DEFINITELY THERE'S SOME 9011 05:33:35,862 --> 05:33:37,297 IMMUNE -- THERE'S SO MUCH STUFF 9012 05:33:37,364 --> 05:33:43,236 ON THE IMMUNE SYSTEM HERE. 9013 05:33:43,303 --> 05:33:47,073 SO I THINK AT ONE LEVEL, AT 9014 05:33:47,140 --> 05:33:49,309 LEAST EVERYTHING FOR ME REVOLVES 9015 05:33:49,376 --> 05:33:52,278 AROUND THE MITOCHONDRIA AND THE 9016 05:33:52,345 --> 05:33:53,213 SUPERCOMPLEXES, SO IT SEEMS TO 9017 05:33:53,279 --> 05:33:54,681 ME THAT AT LEAST WHAT WE'VE 9018 05:33:54,748 --> 05:33:57,150 FOUND IS JUST A -- IT'S 9019 05:33:57,217 --> 05:33:58,718 CERTAINLY NOT THE CAUSE OF 9020 05:33:58,785 --> 05:34:00,120 ME/CFS, I THINK ME/CFS OBVIOUSLY 9021 05:34:00,186 --> 05:34:07,527 IS VERY HETEROGENEOUS AND THE 9022 05:34:07,594 --> 05:34:08,828 WASF GENE WE'VE IDENTIFIED I 9023 05:34:08,895 --> 05:34:11,131 THINK MAY EXPLAIN MAYBE IN A 9024 05:34:11,197 --> 05:34:13,600 SUBSET OF THE PATIENTS WITH 9025 05:34:13,666 --> 05:34:18,071 ME/CFS, IT COULD BE A SUBSET, 9026 05:34:18,138 --> 05:34:19,806 AND IS REALLY A -- SOME SORT OF 9027 05:34:19,873 --> 05:34:21,775 A STRESS RESPONSE OF THE CELLS, 9028 05:34:21,841 --> 05:34:24,911 IT'S A METABOLIC ADAPTATION, 9029 05:34:24,978 --> 05:34:25,912 SOMETHING TELLING THE CELL TO 9030 05:34:25,979 --> 05:34:28,314 TURN DOWN ITS MITOCHONDRIA, SO I 9031 05:34:28,381 --> 05:34:33,853 THINK IT REALLY A MEDIATOR OF 9032 05:34:33,920 --> 05:34:34,421 MITOCHONDRIAL FUNCTION. 9033 05:34:34,487 --> 05:34:37,223 FOR SOME REASON, THE CELL WANTS 9034 05:34:37,290 --> 05:34:42,162 TO DO THIS, AND STRESS RESPONSE 9035 05:34:42,228 --> 05:34:43,997 OR ADAPTIVE RESPONSE, I THINK, 9036 05:34:44,063 --> 05:34:45,598 THAT'S MY IMPRESSION, TO SOME 9037 05:34:45,665 --> 05:34:47,033 PRIMARY INSULT, WHICH I THINK 9038 05:34:47,100 --> 05:34:48,268 MUST HAVE SOMETHING TO DO WITH 9039 05:34:48,334 --> 05:34:52,272 THE IMMUNE SYSTEM. 9040 05:34:52,338 --> 05:34:53,540 THAT'S ALL I CAN SAY. 9041 05:34:53,606 --> 05:34:55,008 >> I GUESS I WOULD ECHO ALL OF 9042 05:34:55,074 --> 05:34:55,442 THOSE THOUGHTS. 9043 05:34:55,508 --> 05:34:57,410 I THINK THE THEMES THAT WE THINK 9044 05:34:57,477 --> 05:34:59,779 ABOUT REPEATEDLY ARE, OF COURSE, 9045 05:34:59,846 --> 05:35:04,484 POST INFECTIOUS AUTOIMMUNITY, 9046 05:35:04,551 --> 05:35:06,986 INFLAMMATION, AND WHERE THERE'S 9047 05:35:07,053 --> 05:35:10,056 INFLAMMATION THAT'S UNCHECKED, 9048 05:35:10,123 --> 05:35:11,324 ONGOING, THERE ARE OFTEN -- 9049 05:35:11,391 --> 05:35:12,859 THERE'S METABOLISM PROBLEMS, AND 9050 05:35:12,926 --> 05:35:18,097 WE'VE HAD THIS DISCUSSION, KARL 9051 05:35:18,164 --> 05:35:19,499 AND I, ACTUALLY ON THE BUS OVER 9052 05:35:19,566 --> 05:35:20,834 HERE THIS MORNING, TALKING ABOUT 9053 05:35:20,900 --> 05:35:22,769 METABOLIC EFFECTS OF O2 SUPPLY, 9054 05:35:22,836 --> 05:35:25,205 WHICH MAY BE A SUSPECT, AND ITS 9055 05:35:25,271 --> 05:35:27,907 DEMAND, WHICH WOULD BE INTRINSIC 9056 05:35:27,974 --> 05:35:28,541 MITOCHONDRIAL DYSFUNCTION. 9057 05:35:28,608 --> 05:35:30,410 AND I BELIEVE BOTH CAN BE AT 9058 05:35:30,477 --> 05:35:32,378 PLAY IN ANY GIVEN PATIENT. 9059 05:35:32,445 --> 05:35:34,981 THEY'RE NOT MUTUALLY EXCLUSIVE. 9060 05:35:35,048 --> 05:35:39,352 SO O2 SUPPLY ISSUES RELATED TO 9061 05:35:39,419 --> 05:35:42,722 VASCULAR DYSREGULATION IN 9062 05:35:42,789 --> 05:35:44,991 INTRINSIC MITOCHONDRIAL PROBLEMS 9063 05:35:45,058 --> 05:35:46,192 CAN COEXIST, AND THEIR 9064 05:35:46,259 --> 05:35:50,697 TREATMENTS ARE LIKELY VERY, VERY 9065 05:35:50,763 --> 05:35:51,331 DIFFERENT. 9066 05:35:51,397 --> 05:35:52,765 ALTHOUGH THERE MAY BE A SILVER 9067 05:35:52,832 --> 05:35:53,900 BULLET WAY AT THE TOP OF ALL 9068 05:35:53,967 --> 05:35:55,001 THIS, AT LEAST GIVEN WHAT WE 9069 05:35:55,068 --> 05:35:58,271 KNOW RIGHT NOW, IF WE TREAT 9070 05:35:58,338 --> 05:36:00,206 GENETIC FORMS OF MITOCHONDRIAL 9071 05:36:00,273 --> 05:36:02,709 DISEASE WITH THE MYTO COCKTAIL 9072 05:36:02,775 --> 05:36:06,212 RECOMMENDED BY THE MITOCHONDRIAL 9073 05:36:06,279 --> 05:36:07,881 SOCIETY, IT'S THREE VITAMINS. 9074 05:36:07,947 --> 05:36:09,949 IF WE TREAT THE BLOOD FLOW 9075 05:36:10,016 --> 05:36:11,017 ABNORMALITIES AS YOU TALKED 9076 05:36:11,084 --> 05:36:13,553 ABOUT, KARL, WE BORROW HEAVILY 9077 05:36:13,620 --> 05:36:16,923 FROM THE POTS LITERATURE AND 9078 05:36:16,990 --> 05:36:17,690 CONSERVATIVE MEASURES. 9079 05:36:17,757 --> 05:36:18,892 AND THEY'RE NOT MUTUALLY 9080 05:36:18,958 --> 05:36:22,195 EXCLUSIVE. 9081 05:36:22,262 --> 05:36:31,137 >> SO THIS LOW ANAEROBIC 9082 05:36:31,204 --> 05:36:33,439 THRESHOLD, THIS VERY QUICKLY 9083 05:36:33,506 --> 05:36:35,575 ACTIVATED LACTATE PRODUCTION, 9084 05:36:35,642 --> 05:36:37,911 LACTATE WE USE AS KIND OF -- AS 9085 05:36:37,977 --> 05:36:42,916 VERY SIMPLE A MEASURE FOR THE 9086 05:36:42,982 --> 05:36:43,850 ANAEROBIC THRESHOLD. 9087 05:36:43,917 --> 05:36:44,951 YOU CAN MEASURE IT INDIVIDUALLY 9088 05:36:45,018 --> 05:36:46,152 AND EVERYBODY CAN DO IT MORE OR 9089 05:36:46,219 --> 05:36:47,020 LESS. 9090 05:36:47,086 --> 05:36:49,822 IT'S DIFFICULT TO REALLY BASE A 9091 05:36:49,889 --> 05:36:53,660 PATHOLOGICAL MECHANISM ON THAT 9092 05:36:53,726 --> 05:36:56,930 ALONE BECAUSE IT'S A PART OF THE 9093 05:36:56,996 --> 05:36:58,031 PROGRAM, IT'S AFFECTED BY SO 9094 05:36:58,097 --> 05:36:59,299 MANY FACTORS. 9095 05:36:59,365 --> 05:37:01,734 BUT IT CAN RESONATE A LITTLE BIT 9096 05:37:01,801 --> 05:37:02,902 AROUND LACTATE IN YOUR SETTING, 9097 05:37:02,969 --> 05:37:05,405 WHAT IT MEANS FOR THE INDIVIDUAL 9098 05:37:05,471 --> 05:37:10,577 PATIENTS. 9099 05:37:10,643 --> 05:37:14,080 >> ANAEROBIC METABOLISM, THE 9100 05:37:14,147 --> 05:37:16,249 THRESHOLD, THE PEAK LACTATE, THE 9101 05:37:16,316 --> 05:37:18,084 RECOVERY LACTATE, THEY'RE ALL -- 9102 05:37:18,151 --> 05:37:20,153 THEY ALL CAN BE TRACED BACK TO 9103 05:37:20,219 --> 05:37:23,122 EITHER OF THE PROBLEMS. 9104 05:37:23,189 --> 05:37:24,724 O2 SUPPLY OR MITOCHONDRIAL 9105 05:37:24,791 --> 05:37:26,693 MACHINERY PROBLEMS. 9106 05:37:26,759 --> 05:37:27,594 EXOWB OR A COMBINATION OF THE 9107 05:37:27,660 --> 05:37:28,027 TWO. 9108 05:37:28,094 --> 05:37:30,029 AND I THINK AT LEAST IN OUR 9109 05:37:30,096 --> 05:37:33,666 WORLD, WE ROUTINELY MEASURE 9110 05:37:33,733 --> 05:37:35,168 LACTATING ONE HOUR AFTER OUR 9111 05:37:35,234 --> 05:37:37,270 INCREMENTAL EXERCISE TEST, AND 9112 05:37:37,337 --> 05:37:39,405 WE FIND THEM ELEVATED, SOMETIMES 9113 05:37:39,472 --> 05:37:40,740 AT REST BEFORE THE TEST, WHICH 9114 05:37:40,807 --> 05:37:43,543 IS PURPORTED TO BE AN INDEX OF 9115 05:37:43,610 --> 05:37:46,079 MITOCHONDRIAL DYSFUNCTION, AND 9116 05:37:46,145 --> 05:37:47,914 THEN MORE OFTEN ELEVATED ONE 9117 05:37:47,981 --> 05:37:49,682 HOUR POST. 9118 05:37:49,749 --> 05:37:52,018 BUT I'VE SEEN THIS IN OTHER 9119 05:37:52,085 --> 05:37:53,052 DISEASES AS WELL THAT HAVE 9120 05:37:53,119 --> 05:37:56,122 NOTHING TO DO WITH ME/CFS, 9121 05:37:56,189 --> 05:37:58,491 MEANING A LACTATE OF 4 MILIMOLAR 9122 05:37:58,558 --> 05:37:59,826 ONE HOUR AFTER EXERCISE AFTER 9123 05:37:59,892 --> 05:38:01,327 HEART FAILURE OR PULMONARY 9124 05:38:01,394 --> 05:38:02,629 HYPERTENSION, AND THEN THE OTHER 9125 05:38:02,695 --> 05:38:04,263 INFLUENCE IS THE PEAK LACTATE, 9126 05:38:04,330 --> 05:38:07,000 WHICH IS DRIVEN BY YOUR MOTHER, 9127 05:38:07,066 --> 05:38:08,601 AND HOW MANY FAST TWITCH MUSCLE 9128 05:38:08,668 --> 05:38:11,571 FIBERS YOU'VE INHERITED, 9129 05:38:11,638 --> 05:38:12,605 GLYCOLYTIC FIBERS, THAT'S THE 9130 05:38:12,672 --> 05:38:14,707 SOURCE OF MUSCLE LACTATE. 9131 05:38:14,774 --> 05:38:16,476 SO IF THE SPRINTER OF THE WORLD 9132 05:38:16,542 --> 05:38:20,046 AS WE TALKED ABOUT THIS MORNING 9133 05:38:20,113 --> 05:38:21,447 IS 14 MILIMOLAR AT PEAK 9134 05:38:21,514 --> 05:38:24,083 EXERCISE, THEY MAY BE 4 1 HOUR 9135 05:38:24,150 --> 05:38:25,585 POST AND IT HAS NOTHING TO DO 9136 05:38:25,652 --> 05:38:27,353 WITH MITOCHONDRIAL DYSFUNCTION 9137 05:38:27,420 --> 05:38:28,755 OR POTENTIALLY O2 DELIVERY. 9138 05:38:28,821 --> 05:38:30,356 SO I THINK THE LACTATES, IT'S A 9139 05:38:30,423 --> 05:38:34,060 BIT OF A MURKY NONSPECIFIC 9140 05:38:34,127 --> 05:38:39,332 BIOMARKER. 9141 05:38:39,399 --> 05:38:40,867 GOT SOME QUESTIONS OUT THERE. 9142 05:38:40,933 --> 05:38:42,368 >> WE CAN START HERE. 9143 05:38:42,435 --> 05:38:44,170 >> COULD I INTRODUCE ONE OTHER 9144 05:38:44,237 --> 05:38:45,638 VARIABLE INTO THE EQUATION, 9145 05:38:45,705 --> 05:38:47,040 WHICH IS THE BLOOD VOLUME, 9146 05:38:47,106 --> 05:38:49,776 BECAUSE WE HAVE DATA IN THE 9147 05:38:49,842 --> 05:38:54,147 FIELD DATING BACK TO STRAYER'S 9148 05:38:54,213 --> 05:38:55,982 WORK, OUR GROUP, SHOWED THE 9149 05:38:56,049 --> 05:38:58,051 BLOOD VOLUME TO BE LOW IN 9150 05:38:58,117 --> 05:38:59,686 ME/CFS, EVEN AS MUCH AS A LITER 9151 05:38:59,752 --> 05:39:00,019 LOW. 9152 05:39:00,086 --> 05:39:01,988 SO THAT GOES TO YOUR PRELOAD 9153 05:39:02,055 --> 05:39:02,522 FAILURE. 9154 05:39:02,588 --> 05:39:03,956 SO I'M WONDERING IF THERE'S JUST 9155 05:39:04,023 --> 05:39:05,458 NOT ENOUGH CELLS AND THERE'S NOT 9156 05:39:05,525 --> 05:39:08,628 ENOUGH PRELOAD, HOW MUCH OF THIS 9157 05:39:08,695 --> 05:39:10,363 HYPOXIA-DRIVEN HYPOTHESIS IS 9158 05:39:10,430 --> 05:39:11,464 BEING DRIVEN BY THAT? 9159 05:39:11,531 --> 05:39:12,765 AND I'M GOING TO ADD ONE MORE 9160 05:39:12,832 --> 05:39:13,199 QUESTION. 9161 05:39:13,266 --> 05:39:16,135 WHY WOULD THE DARN VOLUME BE 9162 05:39:16,202 --> 05:39:16,569 LOW? 9163 05:39:16,636 --> 05:39:19,739 THE EPO LEVELS ARE NORMAL. 9164 05:39:19,806 --> 05:39:29,015 THEIR ERYTH ERYTH ERYTHROPOIETE. 9165 05:39:29,082 --> 05:39:33,152 >> WE HEARD THE FIRST PART. 9166 05:39:33,219 --> 05:39:34,454 >> RIGHT, AND THE SECOND PART IS 9167 05:39:34,520 --> 05:39:38,257 WHAT IS DRIVING HYPOVOLEMIA. 9168 05:39:38,324 --> 05:39:42,195 IN THE SETTING OF A NORMAL 9169 05:39:42,261 --> 05:39:49,268 ERYTHERYTHROPOITEN LEVEL. 9170 05:39:49,335 --> 05:39:52,872 >> WHAT AS LED ME TO LEAN TOWARD 9171 05:39:52,939 --> 05:39:54,273 THE COMPONENT OF THE 9172 05:39:54,340 --> 05:39:55,508 PYRIDSTIGMINE STUDY I PRESENTED 9173 05:39:55,575 --> 05:39:55,908 TODAY. 9174 05:39:55,975 --> 05:39:57,443 NOW IN FAIRNESS, COULD THERE BE 9175 05:39:57,510 --> 05:40:01,581 A PATIENT WITH HYPOVOLEMIA WHOSE 9176 05:40:01,647 --> 05:40:03,082 PRELOAD FAILURE IS SOMEWHAT 9177 05:40:03,149 --> 05:40:04,851 OVERCOME, A BAND-AID, AS IT 9178 05:40:04,917 --> 05:40:08,554 WERE, BY IMPROVING NERVE 9179 05:40:08,621 --> 05:40:10,056 TRANSMISSION, MAYBE. 9180 05:40:10,123 --> 05:40:12,592 AND SO I WOULD SUGGEST, TUNE IN 9181 05:40:12,658 --> 05:40:16,829 TO THE CIRCULATION WEBINAR ON 9182 05:40:16,896 --> 05:40:17,463 JANUARY 11TH, WHEN WE'RE GOING 9183 05:40:17,530 --> 05:40:19,665 TO HAVE THAT VERY ENTITY 9184 05:40:19,732 --> 05:40:24,270 PRESENTED BY OUR AMSTERDAM 9185 05:40:24,337 --> 05:40:25,505 COLLEAGUES, HYPOVOLEMIA AS A 9186 05:40:25,571 --> 05:40:26,606 COMPONENT, AND I PUT IT UP THERE 9187 05:40:26,672 --> 05:40:28,474 AS A DIFFERENTIAL DIAGNOSIS. 9188 05:40:28,541 --> 05:40:29,709 SECOND PART WAS? 9189 05:40:29,776 --> 05:40:33,212 >> WHAT COULD DRIVE A LOW VOLUME 9190 05:40:33,279 --> 05:40:33,412 STAY? 9191 05:40:33,479 --> 05:40:34,147 >> DON'T KNOW. 9192 05:40:34,213 --> 05:40:36,816 THERE ARE SOME OLDER DATA THAT 9193 05:40:36,883 --> 05:40:38,818 SUGGEST, AND HATE TO GET INTO 9194 05:40:38,885 --> 05:40:40,153 DECONDITIONING BECAUSE I DO NOT 9195 05:40:40,219 --> 05:40:43,556 BELIEVE ALL THIS IS DECONDIT 9196 05:40:43,623 --> 05:40:46,092 DECONDITIONING FOR A MOMENT. 9197 05:40:46,159 --> 05:40:47,660 THERE ARE SOME DATA TO SUGGEST 9198 05:40:47,727 --> 05:40:50,563 IF YOU PUT NORMAL INDIVIDUALS OR 9199 05:40:50,630 --> 05:40:52,732 ATHLETES TO BED, THAT THEY DE 9200 05:40:52,799 --> 05:40:54,934 FACTO DEVELOP HYPOVOLEMIA. 9201 05:40:55,001 --> 05:40:57,203 AND THE MECHANISMS ARE PROBABLY 9202 05:40:57,270 --> 05:40:58,738 ABOVE MY PAY GRADE. 9203 05:40:58,805 --> 05:41:02,008 DON'T KNOW. 9204 05:41:02,074 --> 05:41:05,711 HAVING SAID THAT, A CANADIAN 9205 05:41:05,778 --> 05:41:07,513 NAMED DR. STRICKLAND BACK IN THE 9206 05:41:07,580 --> 05:41:10,950 DAY DID INVASIVE CARDIOPULMONARY 9207 05:41:11,017 --> 05:41:12,351 EXERCISE TESTING AND COMPARED 9208 05:41:12,418 --> 05:41:14,220 DECONDITIONED PATIENTS, NO M.E., 9209 05:41:14,287 --> 05:41:16,989 NO LONG COVID, LONG BEFORE THAT, 9210 05:41:17,056 --> 05:41:19,025 TO NORMAL INDIVIDUALS AND SHOWED 9211 05:41:19,091 --> 05:41:21,627 THAT THE FILLING PRESSURES WITH 9212 05:41:21,694 --> 05:41:23,496 DECONDITIONING DURING UPRIGHT 9213 05:41:23,563 --> 05:41:27,533 CYCLING ARE HIGHER, NOT LOWER, 9214 05:41:27,600 --> 05:41:29,602 IN THE DOUGH TRAINED OR 9215 05:41:29,669 --> 05:41:30,236 DECONDITIONED INDIVIDUALS. 9216 05:41:30,303 --> 05:41:32,672 SO I THINK WE'VE GOT THE 9217 05:41:32,738 --> 05:41:34,440 OPPOSITE END OF THE SPECTRUM AND 9218 05:41:34,507 --> 05:41:36,642 RELATE NOT JUST WHAT YOU ASKED, 9219 05:41:36,709 --> 05:41:38,744 NANCY, BUT AN OXYGEN EXTRACTION 9220 05:41:38,811 --> 05:41:40,847 STORY IS NOT A FEATURE OF SIMPLE 9221 05:41:40,913 --> 05:41:41,414 DECONDITIONING, AND THAT'S 9222 05:41:41,480 --> 05:41:43,182 REALLY BEEN PUT TO BED BY 9223 05:41:43,249 --> 05:41:45,618 MULTIPLE PEOPLE, PETER WAGNER ON 9224 05:41:45,685 --> 05:41:49,188 THE WEST COAST, AND THE FOLKS 9225 05:41:49,255 --> 05:41:50,523 WAY BACK IN THE DAY WITH THE 9226 05:41:50,590 --> 05:41:53,559 BEDREST STUDY. 9227 05:41:53,626 --> 05:41:55,161 THE EXTRACTION PROBLEM IS NOT A 9228 05:41:55,228 --> 05:41:56,529 FEATURE OF DECONDITIONING. 9229 05:41:56,596 --> 05:41:59,465 >> THANK YOU. 9230 05:41:59,532 --> 05:42:01,534 >> COULD I FOLLOW UP QUICKLY ON 9231 05:42:01,601 --> 05:42:03,369 THAT VOLUME, SO THERE IS 9232 05:42:03,436 --> 05:42:05,872 EVIDENCE THAT THERE'S HYPER 9233 05:42:05,938 --> 05:42:07,740 VOLEMIA IN ME/CFS, OR -- YOU 9234 05:42:07,807 --> 05:42:09,308 MENTIONED THE PRELOAD FAILURE, 9235 05:42:09,375 --> 05:42:10,176 RIGHT, AND THAT COULD BE BECAUSE 9236 05:42:10,243 --> 05:42:11,711 OF VOLUME OR IT COULD BE BECAUSE 9237 05:42:11,777 --> 05:42:14,680 YOU HAVE OVERLY COMPLIANT RIGHT 9238 05:42:14,747 --> 05:42:15,081 SIDE -- 9239 05:42:15,147 --> 05:42:17,083 >> AND FAILURE TO VENOCONSTRICT, 9240 05:42:17,149 --> 05:42:17,350 OR BOTH. 9241 05:42:17,416 --> 05:42:18,351 >> OR BOTH. 9242 05:42:18,417 --> 05:42:20,286 >> NO, THERE ARE DATA, AND UP 9243 05:42:20,353 --> 05:42:22,588 FORTUNATELY TO GET AT THAT 9244 05:42:22,655 --> 05:42:24,790 SCIENTIFICALLY, YOU NEED TO DO A 9245 05:42:24,857 --> 05:42:26,259 RADIOACTIVE TRACER TO LOOK AT 9246 05:42:26,325 --> 05:42:27,159 PLASMA VOLUME. 9247 05:42:27,226 --> 05:42:29,996 THERE ARE DATA, OLDER DATA ON 9248 05:42:30,062 --> 05:42:32,164 M.E. THAT SUGGEST A SUBSET OF 9249 05:42:32,231 --> 05:42:34,133 PATIENTS MAY BE HYPOVOLY MIBG. 9250 05:42:34,200 --> 05:42:36,869 SO IN THAT CASE, I WOULD HAVE TO 9251 05:42:36,936 --> 05:42:39,605 INVOKE OVERCOMING THAT WITH THE 9252 05:42:39,672 --> 05:42:41,340 PYRIDSTIGMINE, WHICH IS 9253 05:42:41,407 --> 05:42:41,641 NEUROACTIVE. 9254 05:42:41,707 --> 05:42:42,074 >> OKAY. 9255 05:42:42,141 --> 05:42:46,145 OKAY. 9256 05:42:46,212 --> 05:42:49,382 SO THERE'S A SMALL FIBER -- 9257 05:42:49,448 --> 05:42:51,684 THERE IS EVIDENCE OF SMALL FIBER 9258 05:42:51,751 --> 05:42:51,984 DYSFUNCTION? 9259 05:42:52,051 --> 05:42:52,985 >> OH, YEAH. 9260 05:42:53,052 --> 05:42:53,386 VERY MUCH SO. 9261 05:42:53,452 --> 05:42:54,954 >> I WAS WONDERING WHETHER -- 9262 05:42:55,021 --> 05:42:57,990 YOU KNOW, I'M VERY INTERESTED IN 9263 05:42:58,057 --> 05:43:00,426 OXYGEN HOMEOSTASIS, AND THE 9264 05:43:00,493 --> 05:43:02,695 OXYGEN BEING HIGH IN THE MIXED 9265 05:43:02,762 --> 05:43:03,796 VENOUS SATURATION, WHETHER THAT 9266 05:43:03,863 --> 05:43:05,631 COULD HAVE SOME EFFECT, FOR 9267 05:43:05,698 --> 05:43:09,568 EXAMPLE, IN THE OXYGEN SENSORS 9268 05:43:09,635 --> 05:43:13,539 IN THE CAROTID DO BEE BODY ANDD 9269 05:43:13,606 --> 05:43:15,441 THAT FEEDBACK TO YOUR PRELOAD 9270 05:43:15,508 --> 05:43:15,675 SYSTEM. 9271 05:43:15,741 --> 05:43:17,543 >> IT'S FASCINATING TO THINK 9272 05:43:17,610 --> 05:43:20,079 ABOUT THE CAROTID BODY'S SENSORS 9273 05:43:20,146 --> 05:43:23,582 ARE THE MITOCHONDRIA. 9274 05:43:23,649 --> 05:43:27,954 AND WHEN HIF1 ALPHA IS 9275 05:43:28,020 --> 05:43:28,955 ACTIVATED, THAT COULD DRIVE A 9276 05:43:29,021 --> 05:43:30,289 LOT OF THINGS, MAYBE EVEN 9277 05:43:30,356 --> 05:43:31,490 INCLUDING THE HYPERVENTILATION 9278 05:43:31,557 --> 05:43:33,859 THAT IS SEEN IN SOME OF THESE 9279 05:43:33,926 --> 05:43:34,293 FOLKS. 9280 05:43:34,360 --> 05:43:35,962 MAYBE A LITTLE MORE COMMON IN 9281 05:43:36,028 --> 05:43:37,630 LONG COVID THAN M.E., BUT 9282 05:43:37,697 --> 05:43:40,266 PROBABLY IN BOTH DISEASES. 9283 05:43:40,333 --> 05:43:50,343 YEAH. 9284 05:43:50,409 --> 05:43:53,279 >> FINALLY I GET TO THE MIC, 9285 05:43:53,346 --> 05:43:53,813 JOE. 9286 05:43:53,879 --> 05:43:54,246 CAN YOU HEAR? 9287 05:43:54,313 --> 05:43:54,814 >> BARELY. 9288 05:43:54,880 --> 05:43:55,548 >> BARELY? 9289 05:43:55,614 --> 05:43:56,115 OKAY. 9290 05:43:56,182 --> 05:43:57,950 I'LL TRY TO SPEAK -- IF I SPEAK 9291 05:43:58,017 --> 05:43:58,484 LOUDER, DOES THAT HELP? 9292 05:43:58,551 --> 05:43:59,118 >> A LITTLE BIT. 9293 05:43:59,185 --> 05:44:00,353 >> ONLY A LITTLE BIT. 9294 05:44:00,419 --> 05:44:01,454 OKAY. 9295 05:44:01,520 --> 05:44:06,459 SO MY FOUR MENTORS, PAUL, PETER, 9296 05:44:06,525 --> 05:44:08,361 JERRY, AND JIM WOULD BE ALL 9297 05:44:08,427 --> 05:44:12,465 UPSET IF I DIDN'T BRING UP FOUR 9298 05:44:12,531 --> 05:44:14,900 THINGS THAT NEED BE CONNECTED 9299 05:44:14,967 --> 05:44:15,201 HERE. 9300 05:44:15,267 --> 05:44:16,402 I'LL GO IN THE ORDER WE'VE 9301 05:44:16,469 --> 05:44:17,703 DISCUSSED THEM TODAY. 9302 05:44:17,770 --> 05:44:23,042 AND THE FIRST IS INFLAMMATORY 9303 05:44:23,109 --> 05:44:25,711 RESPONSE IN GUT LEAKINESS. 9304 05:44:25,778 --> 05:44:26,679 BECAUSE ONE OF THE PROBLEMS THAT 9305 05:44:26,746 --> 05:44:28,647 WE MIGHT BE SEEING IS THAT THE 9306 05:44:28,714 --> 05:44:32,218 LOW BLOOD VOLUME, NOT REALLY LOW 9307 05:44:32,284 --> 05:44:34,620 BLOOD VOLUME WHICH IS WHY IT'S 9308 05:44:34,687 --> 05:44:39,759 EPO NORMAL, HEMATOCRIT NORMAL, 9309 05:44:39,825 --> 05:44:40,760 DECREASING EFFECTIVE BLOOD 9310 05:44:40,826 --> 05:44:44,030 VOLUME AND REDUCING VENOUS 9311 05:44:44,096 --> 05:44:44,997 RETURN. 9312 05:44:45,064 --> 05:44:49,001 SECOND THING IS THAT DR. HWANG 9313 05:44:49,068 --> 05:44:53,973 WOULD BE GREAT TO LOOK AT 9314 05:44:54,040 --> 05:44:57,043 DIFFERENTIAL FIO2s, IN OTHER 9315 05:44:57,109 --> 05:44:59,879 WORDS, WHEN YOU'RE DOING YOUR 9316 05:44:59,945 --> 05:45:02,415 PNMR SPECTROSCOPY TO ALTER THE 9317 05:45:02,481 --> 05:45:05,885 FI02s VERY MUCH LIKE PETER 9318 05:45:05,951 --> 05:45:06,585 DID, BECAUSE THE SPECTRA 9319 05:45:06,652 --> 05:45:09,855 THAT YOU HAD ARE VERY COMPELLING 9320 05:45:09,922 --> 05:45:14,193 THAT O2 ENERGETICS CAPABILITIES 9321 05:45:14,260 --> 05:45:16,896 ARE DEPRESSED IN THE S1 -- 9322 05:45:16,962 --> 05:45:19,432 PARDON ME -- THE S2 PATIENT, I 9323 05:45:19,498 --> 05:45:20,766 THINK IT WAS, BUT YOU NEED TO 9324 05:45:20,833 --> 05:45:24,503 SHOW THAT THAT'S INDEPENDENT OF 9325 05:45:24,570 --> 05:45:25,337 O2 DELIVERY, AND THE WAY TO DO 9326 05:45:25,404 --> 05:45:26,639 THAT, PETER NICELY SHOWED THAT 9327 05:45:26,705 --> 05:45:28,707 THE WAY TO DO THAT IS ALTERING 9328 05:45:28,774 --> 05:45:31,777 THE FI02, SO THAT YOU CAN SHOW 9329 05:45:31,844 --> 05:45:34,313 THAT IT'S INDEPENDENT OF 9330 05:45:34,380 --> 05:45:35,281 O2 DELIVERY BECAUSE WE NEED TO 9331 05:45:35,347 --> 05:45:43,889 KNOW THAT IT'S NOT AS DR. CY IS 9332 05:45:43,956 --> 05:45:45,758 ARGUING, THAT IT'S NOT BOTH THE 9333 05:45:45,825 --> 05:45:48,160 SUPPLY AND TISSUE DEMAND AND 9334 05:45:48,227 --> 05:45:49,628 DIFFUSIVE INABILITY TO GET 9335 05:45:49,695 --> 05:45:52,565 OXYGEN INTO THE TISSUES. 9336 05:45:52,631 --> 05:45:55,201 SO THOSE ARE THE THINGS -- AND I 9337 05:45:55,267 --> 05:45:56,268 HAVE SAID THAT ONE OF THE 9338 05:45:56,335 --> 05:46:00,005 PROBLEMS WE HAVE, SINCE THE 9339 05:46:00,072 --> 05:46:00,973 MONTREAL CONFERENCE, AND HERE 9340 05:46:01,040 --> 05:46:03,642 WHEN I FIRST STARTED COMING, WE 9341 05:46:03,709 --> 05:46:05,811 NEED TO DETERMINE IF CIRCULATION 9342 05:46:05,878 --> 05:46:09,415 IS DRIVING ALL OF THIS BECAUSE 9343 05:46:09,482 --> 05:46:12,451 IF THERE'S -- IF THE BLOOD 9344 05:46:12,518 --> 05:46:14,620 VOLUME EFFECTIVE CIRCULATION IS 9345 05:46:14,687 --> 05:46:17,690 LOW, YOU CAN'T PERFUSE TISSUES 9346 05:46:17,756 --> 05:46:19,458 NORMALLY AND THE INFLAMMATORY 9347 05:46:19,525 --> 05:46:23,696 RESPONSE RELATED TO THE GUT MAY 9348 05:46:23,762 --> 05:46:24,697 BE THE DRIVING IT ALL. 9349 05:46:24,763 --> 05:46:26,899 SO THE ONE THING WE'VE GOT TO DO 9350 05:46:26,966 --> 05:46:29,702 IS NORMALIZE FOR O2 SUPPLY AND 9351 05:46:29,768 --> 05:46:33,105 SEE THEN IF THERE'S STILL 9352 05:46:33,172 --> 05:46:35,708 MYOPATHIC LIMITATIONS OR IF 9353 05:46:35,774 --> 05:46:36,208 THERE'S OTHER PROBLEMS. 9354 05:46:36,275 --> 05:46:37,676 AND THOSE ARE THE DOTS THAT NEED 9355 05:46:37,743 --> 05:46:41,647 TO BE CONNECTED. 9356 05:46:41,714 --> 05:46:43,883 >> AMEN. 9357 05:46:43,949 --> 05:46:50,823 [LAUGHTER] 9358 05:46:50,890 --> 05:46:53,626 >> PAUL, HAVE YOU CHECKED 9359 05:46:53,692 --> 05:46:54,960 WASF3 LEVELS IN OTHER TISSUES 9360 05:46:55,027 --> 05:46:57,696 BESIDES SKELETAL MUSCLE? 9361 05:46:57,763 --> 05:46:59,665 >> IN PATIENTS? 9362 05:46:59,732 --> 05:47:00,099 IS THAT -- 9363 05:47:00,166 --> 05:47:00,399 >> YEAH. 9364 05:47:00,466 --> 05:47:01,734 >> WE ACTUALLY DON'T HAVE ANY 9365 05:47:01,800 --> 05:47:05,771 OTHER TISSUES OTHER THAN IN THAT 9366 05:47:05,838 --> 05:47:07,072 SINGLE -- THE FIRST PATIENT WHO 9367 05:47:07,139 --> 05:47:09,708 WAS JUST A SKIN BIOPSY, SO IT'S 9368 05:47:09,775 --> 05:47:10,910 FIBROBLASTS, THAT'S WHERE WE SAW 9369 05:47:10,976 --> 05:47:13,145 THE WASF INDUCED. 9370 05:47:13,212 --> 05:47:15,514 AND THEN IT WAS THE SKELETAL 9371 05:47:15,581 --> 05:47:17,816 MUSCLE NEEDLE BIOPSIES FROM THE 9372 05:47:17,883 --> 05:47:19,852 ME/CFS PATIENTS THAT HAD BEEN 9373 05:47:19,919 --> 05:47:20,419 STORED. 9374 05:47:20,486 --> 05:47:22,154 BUT THOSE ARE USUALLY THE TWO -- 9375 05:47:22,221 --> 05:47:24,323 WELL, I'M SURE THERE ARE OTHER 9376 05:47:24,390 --> 05:47:24,790 SAMPLES. 9377 05:47:24,857 --> 05:47:27,927 BLOOD CELLS, OBVIOUS THING. 9378 05:47:27,993 --> 05:47:31,997 WE'VE NOT SEEN -- WE DON'T SEE 9379 05:47:32,064 --> 05:47:33,966 WASF3 AT LEAST WITH USING OUR 9380 05:47:34,033 --> 05:47:36,035 ANTIBODIES IN MONO NUCLEAR CELLS 9381 05:47:36,101 --> 05:47:36,802 OR BLOOD CELLS. 9382 05:47:36,869 --> 05:47:38,470 WE DON'T SEE THAT. 9383 05:47:38,537 --> 05:47:42,274 AT LEAST ON A NORMAL BASAL 9384 05:47:42,341 --> 05:47:42,575 CONDITIONS. 9385 05:47:42,641 --> 05:47:45,311 >> SO CAN YOU GUESS WHY THERE'S 9386 05:47:45,377 --> 05:47:47,646 INCREASED ER STRESS, WHICH SEEMS 9387 05:47:47,713 --> 05:47:50,583 TO BE INCREASING WASF3? 9388 05:47:50,649 --> 05:47:51,917 >> SO THERE'S SOMETHING -- I 9389 05:47:51,984 --> 05:47:54,386 MEAN, THOSE FIBROBLASTS FROM THE 9390 05:47:54,453 --> 05:47:56,689 FIRST PATIENT S1, YOU KNOW, 9391 05:47:56,755 --> 05:47:59,992 THOSE ARE NORMAL HEALTHY GROWING 9392 05:48:00,059 --> 05:48:02,595 FIBROBLASTS IN TISSUE CULTURE 9393 05:48:02,661 --> 05:48:03,896 FAR, FAR REMOVED FROM THE 9394 05:48:03,963 --> 05:48:06,532 PATIENT'S BLOOD AND PLASMA AND 9395 05:48:06,599 --> 05:48:07,199 CYTOKINES, WHATEVER HAVE BEEN IN 9396 05:48:07,266 --> 05:48:10,236 THERE, BUT WE SEE THE ER STRESS 9397 05:48:10,302 --> 05:48:11,670 IS ACTIVATED. 9398 05:48:11,737 --> 05:48:14,540 SO IT'S SOMETHING -- IT COULD BE 9399 05:48:14,607 --> 05:48:16,108 A GENETIC -- I MEAN, IT'S 9400 05:48:16,175 --> 05:48:18,744 INTRINSIC TO THE FIBROBLASTS. 9401 05:48:18,811 --> 05:48:20,813 COMPARED TO THE BROTHER'S 9402 05:48:20,879 --> 05:48:21,247 FIBROBLASTS. 9403 05:48:21,313 --> 05:48:22,348 SO WE DON'T KNOW. 9404 05:48:22,414 --> 05:48:24,550 WE DON'T KNOW. 9405 05:48:24,617 --> 05:48:26,418 I SAID THAT WE DIDN'T THINK IT 9406 05:48:26,485 --> 05:48:28,621 WAS RELATED TO THE P53 MUTATION 9407 05:48:28,687 --> 05:48:31,523 STATUS BECAUSE, AGAIN, BOTH 9408 05:48:31,590 --> 05:48:35,461 SIBLINGS HAD THE SAME MUTATION. 9409 05:48:35,527 --> 05:48:37,096 BUT THEY COULD BE SOMETHING, 9410 05:48:37,162 --> 05:48:38,998 SOME INDIRECT WAY IN THE GENETIC 9411 05:48:39,064 --> 05:48:42,034 BACKGROUND, OBVIOUSLY THEY SHARE 9412 05:48:42,101 --> 05:48:44,036 50% OF THE GENOME, BUT THERE 9413 05:48:44,103 --> 05:48:46,405 COULD BE OTHER DIFFERENCES THAT 9414 05:48:46,472 --> 05:48:48,474 COULD MAKE HER CELLS SENSITIVE 9415 05:48:48,540 --> 05:48:50,342 TO THE P53 MUTATION BUT WE DON'T 9416 05:48:50,409 --> 05:48:56,482 KNOW. 9417 05:48:56,548 --> 05:48:57,683 >> HELLO. 9418 05:48:57,750 --> 05:48:59,118 I'VE BEEN GRAPPLING, LIKE 9419 05:48:59,184 --> 05:49:01,654 STRUGGLING TO UNDERSTAND HOW 9420 05:49:01,720 --> 05:49:03,922 THIS METABOLIC DYSFUNCTION OR 9421 05:49:03,989 --> 05:49:05,124 CARDIOVASCULAR DYSREGULATION 9422 05:49:05,190 --> 05:49:09,595 WOULD APPLY TO POST EXERTIONAL 9423 05:49:09,662 --> 05:49:11,664 MALAISE IN THE CONTEXT OF 9424 05:49:11,730 --> 05:49:14,066 MAXIMAL EXERTIONS, BECAUSE IN 9425 05:49:14,133 --> 05:49:16,168 THE C BETs, WE SEE THAT THE 9426 05:49:16,235 --> 05:49:18,971 MAIN DIFFERENCES OCCUR AT PEAK 9427 05:49:19,038 --> 05:49:22,174 EXERCISE. 9428 05:49:22,241 --> 05:49:25,110 YET PATIENTS CONTINUOUSLY 9429 05:49:25,177 --> 05:49:26,312 REPORT -- AFTER ACTIVITIES OF 9430 05:49:26,378 --> 05:49:26,979 DAILY LIVING. 9431 05:49:27,046 --> 05:49:28,914 SO COULD YOU ALL BRAINSTORM ON 9432 05:49:28,981 --> 05:49:29,782 HOW THESE TWO THINGS ARE 9433 05:49:29,848 --> 05:49:34,853 CONNECTED? 9434 05:49:34,920 --> 05:49:39,325 >> I HEARD PARTLY AT LEAST. 9435 05:49:39,391 --> 05:49:40,759 AGAIN, THE COMMENT TO SOME OF 9436 05:49:40,826 --> 05:49:43,362 IT, AND THEN YOU CAN REPEAT THE 9437 05:49:43,429 --> 05:49:43,629 QUESTION. 9438 05:49:43,696 --> 05:49:51,670 >> SO YOUR QUESTION WAS, HOW CAN 9439 05:49:51,737 --> 05:49:55,874 OXYGEN LIMITATION AND METABOLIC 9440 05:49:55,941 --> 05:49:56,508 EFFECTS OCCUR AT THE SAME TIME 9441 05:49:56,575 --> 05:49:57,276 UNDER EXERCISE? 9442 05:49:57,343 --> 05:49:57,710 >> NO, NO. 9443 05:49:57,776 --> 05:49:59,878 THE BIGGEST DIFFERENCES ARE 9444 05:49:59,945 --> 05:50:02,281 OCCURRING AT PEAK EXERCISE. 9445 05:50:02,348 --> 05:50:05,451 BUT POST EXERTIONAL MALAISE 9446 05:50:05,517 --> 05:50:06,485 OCCURS AFTER ACTIVITIES OF DAY 9447 05:50:06,552 --> 05:50:07,319 LEA LIVING. 9448 05:50:07,386 --> 05:50:09,188 >> OKAY. 9449 05:50:09,254 --> 05:50:09,388 SO -- 9450 05:50:09,455 --> 05:50:11,357 >> I CAN TAKE A WHACK AT IT. 9451 05:50:11,423 --> 05:50:11,924 NO, IT'S A GOOD QUESTION. 9452 05:50:11,990 --> 05:50:14,893 I THINK BROADLY SPEAKING, IF WE 9453 05:50:14,960 --> 05:50:16,729 GOT IT RIGHT UP HERE, PEAK 9454 05:50:16,795 --> 05:50:20,132 EXERCISE IS KIND OF THE STRATUS 9455 05:50:20,199 --> 05:50:25,504 FEASTRATOSPHERE, IT IS NOT WHERE 9456 05:50:25,571 --> 05:50:26,805 MOST PATIENTS SPEND A MAJORITY 9457 05:50:26,872 --> 05:50:28,540 OF THEIR TIME YET THEY HAVE 9458 05:50:28,607 --> 05:50:31,276 SYMPTOMS AT REST AND AT OTHER 9459 05:50:31,343 --> 05:50:34,680 TIMES, AND POST EXERTIONAL 9460 05:50:34,747 --> 05:50:36,982 MALAISE IS OF MAJOR INTEREST. 9461 05:50:37,049 --> 05:50:38,083 SO WE WONDERED IF WE HAD -- 9462 05:50:38,150 --> 05:50:39,051 THERE ARE OTHER LINES OF 9463 05:50:39,118 --> 05:50:39,918 EVIDENCE AND I'LL DEFER TO 9464 05:50:39,985 --> 05:50:41,220 OTHERS, BUT WE WONDERED IF WE 9465 05:50:41,286 --> 05:50:44,423 HAD A LITTLE BIT OF A SIGNAL IN 9466 05:50:44,490 --> 05:50:47,359 THE ACUTE PYRIDSTIGMINE 9467 05:50:47,426 --> 05:50:48,427 RANDOMIZED CONTROL STUDY OF 9468 05:50:48,494 --> 05:50:50,496 EARLY PEM, AND THAT ALL OF THE 9469 05:50:50,562 --> 05:50:53,799 NUMBERS THAT WE MEASURED AT PEAK 9470 05:50:53,866 --> 05:50:54,867 EXERCISE WERE WORSE ONE HOUR 9471 05:50:54,933 --> 05:50:56,735 AFTER THE PRIOR EXERCISE. 9472 05:50:56,802 --> 05:50:59,571 MAYBE THAT WAS THE BEGINNING. 9473 05:50:59,638 --> 05:51:03,308 AND MAYBE -- NOT SHOWN THERE, WE 9474 05:51:03,375 --> 05:51:05,043 ACTUALLY HAD EVIDENCE THAT 9475 05:51:05,110 --> 05:51:09,415 RESTING VO2 READ METABOLISM WAS 9476 05:51:09,481 --> 05:51:11,483 ELEVATED WHEN PATIENTS RECEIVED 9477 05:51:11,550 --> 05:51:11,750 PLACEBO. 9478 05:51:11,817 --> 05:51:15,020 SO WE DON'T HAVE ALL THE 9479 05:51:15,087 --> 05:51:16,021 CYTOKINE MEASUREMENTS TO GO WITH 9480 05:51:16,088 --> 05:51:17,423 THAT IN THAT PARTICULAR STUDY, 9481 05:51:17,489 --> 05:51:21,093 OR OTHER BIOMARKERS, BUT OUR 9482 05:51:21,160 --> 05:51:22,895 SPECULATION WAS THAT THE ACUTE 9483 05:51:22,961 --> 05:51:26,298 EXERCISE MIGHT HAVE ELICITED 9484 05:51:26,365 --> 05:51:28,600 INFLAMMATION AND THE BEGINNINGS 9485 05:51:28,667 --> 05:51:30,469 OF PEM EVEN ONE HOUR OUT, AND 9486 05:51:30,536 --> 05:51:32,704 THAT THAT MIGHT BE A CONNECTION. 9487 05:51:32,771 --> 05:51:33,806 BUT I THINK I'LL DEFER TO 9488 05:51:33,872 --> 05:51:35,007 OTHERS, BUT I THINK PRIME 9489 05:51:35,073 --> 05:51:41,814 MINISTERPEM IS WAYMORE COMPLICAE 9490 05:51:41,880 --> 05:51:43,248 YA, IT'S INFLAMMATION THAT'S 9491 05:51:43,315 --> 05:51:44,116 ONGOING AND ALL THE BAD THINGS 9492 05:51:44,183 --> 05:51:45,083 THAT GO WITH IT. 9493 05:51:45,150 --> 05:51:46,785 >> AGAIN, CAN YOU COMMENT A 9494 05:51:46,852 --> 05:51:48,086 LITTLE BIT ON THE METABOLIC 9495 05:51:48,153 --> 05:51:51,757 SIDE, BECAUSE IF IT IS TRUE THAT 9496 05:51:51,824 --> 05:51:55,160 THERE IS UNDERLYING STRESS, ON 9497 05:51:55,227 --> 05:51:56,528 ONE SIDE IT MEANS THE PROTECTION 9498 05:51:56,595 --> 05:51:57,996 SYSTEM IS ACTIVATED ALL THE TIME 9499 05:51:58,063 --> 05:51:58,363 IN THE PATIENT. 9500 05:51:58,430 --> 05:52:02,935 SO THIS CAN ACTUALLY HELP TO 9501 05:52:03,001 --> 05:52:04,770 KEEP A HEALTHY TYPE OF 9502 05:52:04,837 --> 05:52:06,205 METABOLISM EVEN IN REST, BUT THE 9503 05:52:06,271 --> 05:52:07,206 DOWNSIDE IS, OF COURSE, THAT 9504 05:52:07,272 --> 05:52:09,708 THIS IS AN ELEVATED ENERGY 9505 05:52:09,775 --> 05:52:13,779 LEVEL, SO IT MAY LEAD TO 9506 05:52:13,846 --> 05:52:14,680 OVERCHARGING THE SYSTEM MORE 9507 05:52:14,746 --> 05:52:15,581 EASILY. 9508 05:52:15,647 --> 05:52:18,450 SO -- AND ALSO WHEN IT COMES TO 9509 05:52:18,517 --> 05:52:22,521 EXERCISE, THERE IS ALSO 9510 05:52:22,588 --> 05:52:24,823 SOMETHING CALLED OXYGEN DEPTH 9511 05:52:24,890 --> 05:52:28,193 THAT YOU ACTUALLY OVERUSE SOME 9512 05:52:28,260 --> 05:52:29,962 OF THE OXYGEN IN THE WAY THAT 9513 05:52:30,028 --> 05:52:31,163 YOU CAN TELL MORE ABOUT THAT, 9514 05:52:31,230 --> 05:52:36,201 BUT THAT CAN ALSO TELL SOME 9515 05:52:36,268 --> 05:52:43,408 ELEMENTS OF THE EFFECT OF THE 9516 05:52:43,475 --> 05:52:47,446 EXERCISE IMMEDIATELY AFTER THE 9517 05:52:47,513 --> 05:52:48,647 PEAK EXERCISE. 9518 05:52:48,714 --> 05:52:50,516 AND MAYBE IT'S ALSO SO THAT DUE 9519 05:52:50,582 --> 05:52:53,685 TO METABOLIC OVERCHARGE, THE 9520 05:52:53,752 --> 05:52:55,654 PATIENTS ARE NOT ABLE TO REALLY 9521 05:52:55,721 --> 05:52:59,958 GET BACK TO THE RECOVER TYPE OF 9522 05:53:00,025 --> 05:53:00,926 METABOLISM SO THEY ARE ALWAYS IN 9523 05:53:00,993 --> 05:53:05,163 KIND OF AN ELEVATED STATE. 9524 05:53:05,230 --> 05:53:09,101 >> HI, MY NAME IS LOU, I'M WITH 9525 05:53:09,167 --> 05:53:09,668 VASSER. 9526 05:53:09,735 --> 05:53:12,638 I HAVE BEEN SORT OF THINKING 9527 05:53:12,704 --> 05:53:14,473 ABOUT THE EARLIEST SORT OF 9528 05:53:14,540 --> 05:53:15,674 PHASES OF METABOLISM. 9529 05:53:15,741 --> 05:53:16,775 I FEEL LIKE WE'RE KIND OF 9530 05:53:16,842 --> 05:53:18,076 LOOKING AT SORT OF LIKE FURTHER 9531 05:53:18,143 --> 05:53:20,145 DOWN IN THE PATHWAY, FURTHER 9532 05:53:20,212 --> 05:53:24,650 DOWN IN THE SIGNALING, AND I'M 9533 05:53:24,716 --> 05:53:26,385 CURIOUS IF THE COLLECTIVE WE 9534 05:53:26,451 --> 05:53:27,920 FEEL VERY STRONGLY THAT THIS IS 9535 05:53:27,986 --> 05:53:31,156 NOT AN OXYGEN FIXATION ISSUE OR 9536 05:53:31,223 --> 05:53:32,190 WHETHER OR NOT THERE'S SOME SORT 9537 05:53:32,257 --> 05:53:33,859 OF -- AND THIS MAY BE MORE OF A 9538 05:53:33,926 --> 05:53:35,294 QUESTION FOR SOME OF THE MORE 9539 05:53:35,360 --> 05:53:36,461 GENETIC CENTERED TALKS WE'RE 9540 05:53:36,528 --> 05:53:37,563 GOING TO HEAR TOMORROW, BUT 9541 05:53:37,629 --> 05:53:39,097 SINCE WE'RE ALL LOOKING AT SOME 9542 05:53:39,164 --> 05:53:41,600 VERY SPECIFIC TISSUES, I'M SORT 9543 05:53:41,667 --> 05:53:43,168 OF THINKING ABOUT -- I WOULD 9544 05:53:43,235 --> 05:53:46,672 LOVE TO HEAR YOUR THOUGHTS ON 9545 05:53:46,738 --> 05:53:47,739 WHETHER OR NOT THERE COULD 9546 05:53:47,806 --> 05:53:50,475 POTENTIALLY BE SOME SORT OF GENE 9547 05:53:50,542 --> 05:53:52,344 THAT'S BEING EXPRESSED FOLLOWING 9548 05:53:52,411 --> 05:53:55,847 A VIRAL INFECTION THAT MIGHT BE 9549 05:53:55,914 --> 05:53:57,816 INTERFERING WITH OXYGEN FIXATION 9550 05:53:57,883 --> 05:54:01,653 OR PERHAPS FURTHER DOWN THE 9551 05:54:01,720 --> 05:54:03,288 POTENTIAL PERFUSION OF OXYGEN 9552 05:54:03,355 --> 05:54:05,757 INTO TISSUES, WHETHER OR NOT IT 9553 05:54:05,824 --> 05:54:06,925 IS ACTUALLY BEING FIXED IN THE 9554 05:54:06,992 --> 05:54:08,460 CORRECT PLACES IN THE LUNGS AND 9555 05:54:08,527 --> 05:54:10,963 THEN BEING DISTRIBUTED AND 9556 05:54:11,029 --> 05:54:14,066 SOMEHOW HAVING AN ISSUE SORT OF 9557 05:54:14,132 --> 05:54:16,368 ACCESSING THE PROPER RECEPTORS 9558 05:54:16,435 --> 05:54:18,403 AND ACCESSING ATP, AND THEN SORT 9559 05:54:18,470 --> 05:54:20,339 OF A FOLLOW-UP QUESTION TO THAT. 9560 05:54:20,405 --> 05:54:21,873 THIS MIGHT BE OBVIOUS AND IT 9561 05:54:21,940 --> 05:54:23,609 MIGHT BE A LITTLE RIDICULOUS, 9562 05:54:23,675 --> 05:54:27,446 BUT I WAS WONDERING IF WE HAD 9563 05:54:27,512 --> 05:54:30,749 TAKEN A LOOK AT A RESIDUAL ADP 9564 05:54:30,816 --> 05:54:32,618 IN TISSUES, AND WHETHER OR NOT 9565 05:54:32,684 --> 05:54:36,121 THERE WAS JUST AN ISSUE OF 9566 05:54:36,188 --> 05:54:38,724 PHOSPHORYLATING ADP. 9567 05:54:38,790 --> 05:54:40,025 JUST SORT OF THINKING AS EARLY 9568 05:54:40,092 --> 05:54:46,498 AS POSSIBLE. 9569 05:54:46,565 --> 05:54:52,304 >> SO THE LAST QUESTION WAS 9570 05:54:52,371 --> 05:54:57,776 ABOUT THE -- IF THE LEVEL OF ADP 9571 05:54:57,843 --> 05:55:00,078 WAS CHANGED IN PATIENTS. 9572 05:55:00,145 --> 05:55:01,947 AND THE FIRST JUST AS I RECALL 9573 05:55:02,014 --> 05:55:05,450 WERE IF THERE WERE ANY SPECIFIC 9574 05:55:05,517 --> 05:55:08,620 GENES ASSOCIATED WITH THE OXYGEN 9575 05:55:08,687 --> 05:55:11,456 FIXATION THAT HAS BEEN FOUND. 9576 05:55:11,523 --> 05:55:13,725 I DON'T KNOW ANYTHING ABOUT THE 9577 05:55:13,792 --> 05:55:16,061 FIRST QUESTION, THE GENES. 9578 05:55:16,128 --> 05:55:18,530 DOES ANYONE KNOW? 9579 05:55:18,597 --> 05:55:18,697 NO. 9580 05:55:18,764 --> 05:55:24,903 WHEN IT COMES TO AD P AND ATP, I 9581 05:55:24,970 --> 05:55:29,508 THINK THAT HAS PROBABLY NOT BEEN 9582 05:55:29,574 --> 05:55:31,576 MENTIONED, AND I'M ALSO A LITTLE 9583 05:55:31,643 --> 05:55:33,445 BIT SKEPTIC ABOUT THOSE KINDS OF 9584 05:55:33,512 --> 05:55:34,279 MEASUREMENTS IN TISSUES IN 9585 05:55:34,346 --> 05:55:36,815 PATIENTS BECAUSE THIS IS SO 9586 05:55:36,882 --> 05:55:37,949 DIFFICULT MEASUREMENTS FROM 9587 05:55:38,016 --> 05:55:40,886 TAKING THE BIOPSY TO DOING THE 9588 05:55:40,952 --> 05:55:43,388 MEASUREMENTS AND REALLY MAKE -- 9589 05:55:43,455 --> 05:55:45,624 IT DEPENDS ON SO MANY FACTORS. 9590 05:55:45,691 --> 05:55:50,095 I THINK THIS IS THE MOST VITAL 9591 05:55:50,162 --> 05:55:52,064 SYSTEM IN THE CELLS AND IN THE 9592 05:55:52,130 --> 05:55:54,032 TISSUES TO KEEP AND MAINTAIN A 9593 05:55:54,099 --> 05:55:55,567 STABLE ATP LEVEL, SO THE BODY 9594 05:55:55,634 --> 05:55:58,637 WILL DO WHATEVER IT CAN TO 9595 05:55:58,704 --> 05:56:00,072 REALLY MAINTAIN THOSE LEVELS AND 9596 05:56:00,138 --> 05:56:03,775 INCREASE THEM IF NECESSAR NECES. 9597 05:56:03,842 --> 05:56:12,851 THERE HAS BEEN FOUND SOME -- SO 9598 05:56:12,918 --> 05:56:16,154 I THINK TRYING TO SUPPORT THE 9599 05:56:16,221 --> 05:56:17,355 ENERGY PRODUCTION SYSTEM SEEMS 9600 05:56:17,422 --> 05:56:18,990 TO WORK FOR SOME PATIENT BY 9601 05:56:19,057 --> 05:56:20,425 TAKING SUPPLEMENTS AND THINGS 9602 05:56:20,492 --> 05:56:22,394 LIKE THAT AND EVEN ADJUST THEIR 9603 05:56:22,461 --> 05:56:24,463 DIET, AND THIS IS TYPICALLY TO 9604 05:56:24,529 --> 05:56:26,531 ACTIVATE SPECIFIC PART OF THE 9605 05:56:26,598 --> 05:56:30,168 ADAPTATION OF PROGRAMS. 9606 05:56:30,235 --> 05:56:33,238 BUT DIRECT RELATION TO THE 9607 05:56:33,305 --> 05:56:34,539 ACTUAL ATP LEVEL, I INK THIS 9608 05:56:34,606 --> 05:56:37,175 THAT'S A DIFFICULT ONE. 9609 05:56:37,242 --> 05:56:40,245 JUST TO REMEMBER ONE GENE THAT 9610 05:56:40,312 --> 05:56:43,081 WAS NOT ASSOCIATED WITH THE -- 9611 05:56:43,148 --> 05:56:45,484 WITH ENERGY PRODUCTION OR OXYGEN 9612 05:56:45,550 --> 05:56:48,286 FIXATION, BUT WE DO KNOW THAT IN 9613 05:56:48,353 --> 05:56:51,723 ONE OF THE CLINICAL TRIALS IN 9614 05:56:51,790 --> 05:56:58,930 BERGEN, THEY FOUND A SPECIFIC -- 9615 05:56:58,997 --> 05:57:04,536 WITH HLA MUTATION, OR GENE 9616 05:57:04,603 --> 05:57:06,104 VARIANT, AND IT SEEMS TO BE 9617 05:57:06,171 --> 05:57:08,273 ASSOCIATED ALSO WITH A 9618 05:57:08,340 --> 05:57:08,974 THERAPEUTIC EFFECT. 9619 05:57:09,040 --> 05:57:10,475 AND THESE VARIANTS, THEY ARE 9620 05:57:10,542 --> 05:57:16,281 FOUND TO BE MORE FREQUENT IN 9621 05:57:16,348 --> 05:57:17,816 M.E. POPULATION IN BIGGER 9622 05:57:17,883 --> 05:57:18,383 STUDIES. 9623 05:57:18,450 --> 05:57:19,484 SO THERE ARE SOME GENES THAT ARE 9624 05:57:19,551 --> 05:57:20,986 ASSOCIATED BUT NOT DIRECTLY WITH 9625 05:57:21,052 --> 05:57:21,987 THE OXYGEN FIXATION. 9626 05:57:22,053 --> 05:57:24,823 THIS WAS MORE WITH THE POSSIBLE 9627 05:57:24,890 --> 05:57:26,491 UNDERLYING AUTOIMMUNE MECHANISM. 9628 05:57:26,558 --> 05:57:30,428 >> I HAVE TO BRING US TO A CLOSE 9629 05:57:30,495 --> 05:57:30,695 ACTUALLY. 9630 05:57:30,762 --> 05:57:32,531 >> CAN I ASK ONE IMPORTANT 9631 05:57:32,597 --> 05:57:33,098 QUESTION? 9632 05:57:33,165 --> 05:57:36,234 >> ACTUALLY WE HAVE TO -- SORRY. 9633 05:57:36,301 --> 05:57:38,904 IF YOU HAVE ANY FINAL COMMENTS? 9634 05:57:38,970 --> 05:57:40,305 , THAT WOULD BE GREAT. 9635 05:57:40,372 --> 05:57:42,040 OTHERWISE I'D LIKE TO THANK OUR 9636 05:57:42,107 --> 05:57:43,141 PANELISTS FOR ANSWERING 9637 05:57:43,208 --> 05:57:44,676 ADDITIONAL QUESTIONS IN THEIR 9638 05:57:44,743 --> 05:57:45,544 TIME TODAY. 9639 05:57:45,610 --> 05:57:47,412 >> THANKS, JOE. 9640 05:57:47,479 --> 05:57:48,079 >. 9641 05:57:48,146 --> 05:57:58,323 [APPLAUSE] 9642 05:58:45,871 --> 05:58:47,472 >> THANKS FOR HARNGING IN THERE. 9643 05:58:47,539 --> 05:58:48,807 WE'RE GOING TO TALK ABOUT THE 9644 05:58:48,874 --> 05:58:51,009 PROCESS WE'VE BEEN UNDERGOING 9645 05:58:51,076 --> 05:58:53,078 FOR THE ME/CFS RESEARCH ROAD 9646 05:58:53,144 --> 05:58:54,713 MAP. 9647 05:58:54,779 --> 05:58:57,415 IN 2019, 2018 TO 2019, THERE WAS 9648 05:58:57,482 --> 05:59:00,452 A WORKING GROUP OF NINDS 9649 05:59:00,518 --> 05:59:02,854 ADVISORY COUNCIL THAT TOOK A 9650 05:59:02,921 --> 05:59:05,857 LOOK AT WHAT WAS HAPPENING 9651 05:59:05,924 --> 05:59:08,326 ACROSS THE LANDSCAPE OF RESEARCH 9652 05:59:08,393 --> 05:59:09,527 ON ME/CFS. 9653 05:59:09,594 --> 05:59:12,964 THE REPORT THAT CAME FROM THAT 9654 05:59:13,031 --> 05:59:15,800 WORKING GROUP OF COUNCIL MADE 9655 05:59:15,867 --> 05:59:18,069 NUMEROUS RECOMMENDATIONS, 9656 05:59:18,136 --> 05:59:19,104 PRIMARILY AROUND INFRASTRUCTURE, 9657 05:59:19,170 --> 05:59:22,340 WORKFORCE DEVELOPMENT, THE NEED 9658 05:59:22,407 --> 05:59:23,942 FOR ADDITIONAL CLINICIANS IN THE 9659 05:59:24,009 --> 05:59:25,777 FIELD, AND ONE OF THE 9660 05:59:25,844 --> 05:59:28,813 RECOMMENDATIONS THAT WAS MADE 9661 05:59:28,880 --> 05:59:30,782 WAS TO DO A STRATEGIC PLANNING 9662 05:59:30,849 --> 05:59:34,552 PROCESS FOR RESEARCH ON ME/CFS. 9663 05:59:34,619 --> 05:59:37,289 SO THAT REPORT WAS DELIVERED IN 9664 05:59:37,355 --> 05:59:38,023 SEPTEMBER 2019. 9665 05:59:38,089 --> 05:59:41,126 WE BEGAN WORKING TO DEVELOP A 9666 05:59:41,192 --> 05:59:43,862 PLAN TO START AND INITIATE THE 9667 05:59:43,929 --> 05:59:48,033 RESEARCH ROAD MAP PROCESS, AND 9668 05:59:48,099 --> 05:59:50,302 THEN SARS-COV-2 CAME ALONG. 9669 05:59:50,368 --> 05:59:53,171 AND WE TALKED TO MANY PEOPLE IN 9670 05:59:53,238 --> 05:59:54,906 THE FIELD, CLINICIANS WERE 9671 05:59:54,973 --> 05:59:56,241 ABSOLUTELY SWAMPED IN THE 9672 05:59:56,308 --> 05:59:57,442 HOSPITALS, RESEARCHERS WERE 9673 05:59:57,509 --> 05:59:59,311 TRYING TO FIGURE OUT HOW TO KEEP 9674 05:59:59,377 --> 06:00:00,745 THINGS GOING IN THEIR LAB. 9675 06:00:00,812 --> 06:00:02,714 IT JUST WAS NOT THE TIME TO 9676 06:00:02,781 --> 06:00:06,017 START A PROCESS LIKE THIS. 9677 06:00:06,084 --> 06:00:07,786 SO WE PUT IT ON HOLD AND 9678 06:00:07,852 --> 06:00:08,954 RESTARTED THE PROCESS IN THE 9679 06:00:09,020 --> 06:00:12,991 FALL OF '22 AND LAUNCHED -- 9680 06:00:13,058 --> 06:00:14,693 ACTUALLY LAUNCHED THE WHOLE 9681 06:00:14,759 --> 06:00:17,796 PROCESS IN FEBRUARY OF '23. 9682 06:00:17,862 --> 06:00:19,464 SO THE CHARGE TO THE WORKING 9683 06:00:19,531 --> 06:00:21,466 GROUP OF COUNCIL IS TO DEVELOP A 9684 06:00:21,533 --> 06:00:23,535 RESEARCH ROAD MAP TO PROVIDE 9685 06:00:23,601 --> 06:00:26,471 SCIENTIFIC GUIDANCE TO THE NINDS 9686 06:00:26,538 --> 06:00:28,473 COUNCIL ON HOW TO BEST ADVANCE 9687 06:00:28,540 --> 06:00:30,775 RESEARCH ON ME/CFS. 9688 06:00:30,842 --> 06:00:32,410 CONSISTENT WITH THE CHARGE, THE 9689 06:00:32,477 --> 06:00:33,945 WORKING GROUP WILL ASSESS 9690 06:00:34,012 --> 06:00:35,814 CURRENT ME/CFS RESEARCH 9691 06:00:35,880 --> 06:00:37,115 ACTIVITIES AND IDENTIFY 9692 06:00:37,182 --> 06:00:39,751 OPPORTUNITIES AND GAPS IN ME/CFS 9693 06:00:39,818 --> 06:00:41,486 RESEARCH TO IDENTIFY TARGETS FOR 9694 06:00:41,553 --> 06:00:44,022 THE DEVELOPMENT OF TREATMENTS. 9695 06:00:44,089 --> 06:00:46,124 SO THAT'S REALLY KEY HERE IN 9696 06:00:46,191 --> 06:00:47,759 WHAT ALL OF THE WORK THAT WE'VE 9697 06:00:47,826 --> 06:00:50,829 BEEN DOING IS TO REALLY, NUMBER 9698 06:00:50,895 --> 06:00:52,797 ONE, ASSESS THE FIELD BUT NUMBER 9699 06:00:52,864 --> 06:00:54,899 TWO, THINK FORWARD AS TO HOW CAN 9700 06:00:54,966 --> 06:00:57,168 WE ACCELERATE THE RESEARCH TO 9701 06:00:57,235 --> 06:00:59,270 REALLY MOVE TOWARD TREATMENT 9702 06:00:59,337 --> 06:01:00,905 TRIALS AND DEVELOPMENT OF 9703 06:01:00,972 --> 06:01:02,440 TREATMENTS FOR ME/CFS. 9704 06:01:02,507 --> 06:01:04,542 SO YOU SAW A VERSION OF THIS 9705 06:01:04,609 --> 06:01:07,512 SLIDE THIS MORNING, WHEN 9706 06:01:07,579 --> 06:01:08,613 DR. KOROSHETZ SPOKE, WE HAVE 9707 06:01:08,680 --> 06:01:10,582 ACTUALLY ADDED AN EIGHTH 9708 06:01:10,648 --> 06:01:10,815 WEBINAR. 9709 06:01:10,882 --> 06:01:14,519 SO THE PROCESS HERE IS THAT WE 9710 06:01:14,586 --> 06:01:16,921 IDENTIFIED INDIVIDUALS TO SERVE 9711 06:01:16,988 --> 06:01:18,356 ON THE ME/CFS WORKING GROUP OF 9712 06:01:18,423 --> 06:01:19,991 COUNCIL, AND I'LL SHOW YOU 9713 06:01:20,058 --> 06:01:21,259 THAT -- HOW HA COMMITTEE IS 9714 06:01:21,326 --> 06:01:24,396 COMPOSED IN A MOMENT. 9715 06:01:24,462 --> 06:01:26,031 WE THEN DECIDED WE WOULD LIKE TO 9716 06:01:26,097 --> 06:01:27,766 INCLUDE ADDITIONAL INDIVIDUALS 9717 06:01:27,832 --> 06:01:31,369 WITH LIVED EXPERIENCE, SO WE PUT 9718 06:01:31,436 --> 06:01:33,071 OUT A CALL FOR NOMINATIONS AND 9719 06:01:33,138 --> 06:01:34,372 RECEIVED ALMOST A HUNDRED 9720 06:01:34,439 --> 06:01:35,673 NOMINATIONS, SELF-NOMINATIONS 9721 06:01:35,740 --> 06:01:38,309 FROM INDIVIDUALS WHO WANTED TO 9722 06:01:38,376 --> 06:01:39,978 PARTICIPATE IN THIS PROCESS. 9723 06:01:40,045 --> 06:01:42,747 WE SELECTED 21 INDIVIDUALS WITH 9724 06:01:42,814 --> 06:01:45,350 LIVED EXPERIENCE, WHO ARE NOW 9725 06:01:45,417 --> 06:01:46,451 PARTICIPATING, WE SPREAD THEM 9726 06:01:46,518 --> 06:01:49,120 OUT ACROSS ALL OF THE WEBINAR 9727 06:01:49,187 --> 06:01:52,257 PLANNING GROUPS AND HAVE BEEN 9728 06:01:52,323 --> 06:01:52,857 PARTICIPATING IN THIS PROCESS 9729 06:01:52,924 --> 06:01:54,793 WITH US, AND OF COURSE NIH STAFF 9730 06:01:54,859 --> 06:02:00,698 TO SUPPORT THE ERT. 9731 06:02:00,765 --> 06:02:01,132 THE EFFORT. 9732 06:02:01,199 --> 06:02:02,434 SO WE'VE ALREADY HAD SIX OF THE 9733 06:02:02,500 --> 06:02:04,969 WEBINARS ON THE SYSTEMS YOU CAN 9734 06:02:05,036 --> 06:02:06,171 SEE HERE. 9735 06:02:06,237 --> 06:02:07,705 WE HAVE TWO LEFT, AND THANKS, 9736 06:02:07,772 --> 06:02:08,807 DAVID, FOR THE ADVERTISEMENT FOR 9737 06:02:08,873 --> 06:02:10,442 THE CIRCULATION ONE, AND THEN 9738 06:02:10,508 --> 06:02:12,110 THERE'S ONE LESSER STUDY 9739 06:02:12,177 --> 06:02:13,845 PATHOLOGY THAT WILL TAKE PLACE 9740 06:02:13,912 --> 06:02:15,480 ON JANUARY 5TH. 9741 06:02:15,547 --> 06:02:17,449 SO THE END RESULT OF THIS IS 9742 06:02:17,515 --> 06:02:18,983 THAT THE RESEARCH PRIORITIES 9743 06:02:19,050 --> 06:02:24,689 THAT COME FROM ALL OF THESE 9744 06:02:24,756 --> 06:02:26,458 WEBINAR GROUPS, WHAT WE HEAR AT 9745 06:02:26,524 --> 06:02:27,659 THE WEBINARS AND WEBINAR 9746 06:02:27,725 --> 06:02:28,927 PLANNING GROUPS ARE RESEARCH 9747 06:02:28,993 --> 06:02:29,527 PRIORITIES THAT WILL COME 9748 06:02:29,594 --> 06:02:31,830 TOGETHER AGAIN INTO A REPORT 9749 06:02:31,896 --> 06:02:33,164 WHICH WE'LL PUT OUT FOR PUBLIC 9750 06:02:33,231 --> 06:02:34,265 FEEDBACK AND THEN EVENTUALLY 9751 06:02:34,332 --> 06:02:38,770 THAT REPORT WILL GO TO THE NINDS 9752 06:02:38,837 --> 06:02:40,505 ADVISORY COUNCIL AND NINDS 9753 06:02:40,572 --> 06:02:42,140 LEADERSHIP AND NIH LEADERSHIP 9754 06:02:42,207 --> 06:02:45,443 OVERALL. 9755 06:02:45,510 --> 06:02:47,679 SO THE WORKING GROUP CONSISTS OF 9756 06:02:47,745 --> 06:02:49,180 INDIVIDUALS THAT CROSS THE 9757 06:02:49,247 --> 06:02:52,717 PATIENT ADVOCACY GROUPS, AS I 9758 06:02:52,784 --> 06:02:53,718 SAID SOME INDIVIDUAL WITH LIVED 9759 06:02:53,785 --> 06:02:55,553 EXPERIENCE, SOME OF OUR FEDERAL 9760 06:02:55,620 --> 06:02:58,723 PARTNERS, CLINICIANS, AND 9761 06:02:58,790 --> 06:02:59,524 INVESTIGATORS, AND THE CO-CHAIRS 9762 06:02:59,591 --> 06:03:01,593 OF THIS WORKING GROUP ARE CINDY 9763 06:03:01,659 --> 06:03:03,461 BATEMAN FROM BATEMAN HORNE 9764 06:03:03,528 --> 06:03:05,230 CENTER, AND MAUREEN HANSON, WHO 9765 06:03:05,296 --> 06:03:06,731 YOU'LL HEAR -- FROM CORNELL WHO 9766 06:03:06,798 --> 06:03:12,770 YOU'LL HEAR FROM IN A MOMENT. 9767 06:03:12,837 --> 06:03:15,540 I'D LIKE TO ACKNOWLEDGE ALL OF 9768 06:03:15,607 --> 06:03:16,407 THE INDIVIDUALS WITH LIVED 9769 06:03:16,474 --> 06:03:17,408 EXPERIENCE WHO HAVE REALLY 9770 06:03:17,475 --> 06:03:19,711 PROVIDED REALLY SIGNIFICANT AND 9771 06:03:19,777 --> 06:03:21,346 IMPORTANT INPUT INTO THE 9772 06:03:21,412 --> 06:03:24,315 PERSPECTIVE OF RESEARCH AND INTO 9773 06:03:24,382 --> 06:03:26,818 THE -- AND THEIR PERSPECTIVE ON 9774 06:03:26,885 --> 06:03:29,053 LIVING WITH THE DISEASE OR 9775 06:03:29,120 --> 06:03:29,787 CARING, SOME OF THEM ARE 9776 06:03:29,854 --> 06:03:32,690 CAREGIVERS, FOR ONE OR MORE 9777 06:03:32,757 --> 06:03:39,197 INDIVIDUALS WITH ME/CFS. 9778 06:03:39,264 --> 06:03:41,199 SO WITH THAT, I'M GOING TO TURN 9779 06:03:41,266 --> 06:03:42,300 IT OVER TO CINDY, BUT JUST 9780 06:03:42,367 --> 06:03:43,501 BEFORE I DO THAT, WHAT YOU SEE 9781 06:03:43,568 --> 06:03:44,435 NEXT ARE SLIDES THAT REPRESENT 9782 06:03:44,502 --> 06:03:46,504 THE RESEARCH PRIORITIES FOR THE 9783 06:03:46,571 --> 06:03:47,472 FIRST FOUR WEBINARS. 9784 06:03:47,539 --> 06:03:51,643 THE FIRST IS THE NERVOUS SYSTEM. 9785 06:03:51,709 --> 06:03:51,910 WEBINAR. 9786 06:03:51,976 --> 06:03:54,579 THERE WAS A VERY LONG AND 9787 06:03:54,646 --> 06:03:57,015 EX-TENSE SEXTENSIVE LIST OF PRIS 9788 06:03:57,081 --> 06:03:58,583 THAT THIS PLANNING GROUP HAS 9789 06:03:58,650 --> 06:04:00,218 CONDENSED INTO THE RESEARCH 9790 06:04:00,285 --> 06:04:03,388 PRIORITIES THAT YOU'LL SEE HERE. 9791 06:04:03,454 --> 06:04:04,389 THE OTHER THREE THAT YOU WILL 9792 06:04:04,455 --> 06:04:05,957 SEE ARE SORT OF LONGER LISTS 9793 06:04:06,024 --> 06:04:08,893 THAT HAVEN'T YET KIND OF COME TO 9794 06:04:08,960 --> 06:04:11,629 CONSENSUS, AND WE WILL BE, 9795 06:04:11,696 --> 06:04:13,998 AGAIN, ESTABLISHING THESE 9796 06:04:14,065 --> 06:04:18,203 SIMILAR TYPE RESEARCH PRIORITIES 9797 06:04:18,269 --> 06:04:19,537 FOR THE ADDITIONAL FOUR 9798 06:04:19,604 --> 06:04:19,971 WEBINARS. 9799 06:04:20,038 --> 06:04:23,341 THE TWO THAT HAVE BEEN HELD 9800 06:04:23,408 --> 06:04:24,442 ALREADY, THOSE ARE IN THE WORKS, 9801 06:04:24,509 --> 06:04:26,311 AND THEN THE TWO WILL BE HELD IN 9802 06:04:26,377 --> 06:04:27,412 JANUARY, WE'LL COME UP WITH 9803 06:04:27,478 --> 06:04:28,680 SIMILAR RESEARCH PRIORITIES. 9804 06:04:28,746 --> 06:04:33,785 AND THERE ARE SOME SIMILARITIES, 9805 06:04:33,851 --> 06:04:35,420 CROSS AND OVERLAPPING PRIORITIES 9806 06:04:35,486 --> 06:04:36,888 THAT AGAIN WILL ALL COME 9807 06:04:36,955 --> 06:04:37,789 TOGETHER IN THE REPORT THAT WILL 9808 06:04:37,855 --> 06:04:38,656 GO TO THE NINDS COUNCIL. 9809 06:04:38,723 --> 06:04:41,059 SO WITH THAT, I'LL INTRODUCE 9810 06:04:41,125 --> 06:04:42,827 CINDY BATEMAN FROM BATEMAN HORNE 9811 06:04:42,894 --> 06:04:49,400 CENTER WHO WILL TAKE OVER HERE. 9812 06:04:49,467 --> 06:04:49,667 [APPLAUSE] 9813 06:04:49,734 --> 06:04:50,001 >> THANK YOU. 9814 06:04:50,068 --> 06:04:51,169 THIS HAS BEEN A REALLY 9815 06:04:51,236 --> 06:04:52,637 INCREDIBLE EFFORT, AND IT'S BEEN 9816 06:04:52,704 --> 06:04:57,408 AN HONOR TO PARTICIPATE IN THIS 9817 06:04:57,475 --> 06:04:58,610 EFFORT AS A CLINICIAN. 9818 06:04:58,676 --> 06:05:00,745 SO MAUREEN AND I ARE CHAIRING 9819 06:05:00,812 --> 06:05:02,180 THIS, AND PARTNERING WITH VICKY, 9820 06:05:02,247 --> 06:05:05,416 BUT WE'VE HAD THE OPPORTUNITY TO 9821 06:05:05,483 --> 06:05:06,884 BE WITH MANY, MANY PEOPLE AND 9822 06:05:06,951 --> 06:05:09,854 LEARN FROM THEM. 9823 06:05:09,921 --> 06:05:12,056 SO I'M GOING TO PRESENT TO YOU 9824 06:05:12,123 --> 06:05:15,193 SOME OF WHAT THE NERVOUS SYSTEM 9825 06:05:15,260 --> 06:05:16,160 PRIORITIES ARE AT THIS POINT AND 9826 06:05:16,227 --> 06:05:17,495 THE IMMUNE SYSTEM PRIORITIES, 9827 06:05:17,562 --> 06:05:18,663 AND THEN MAUREEN WILL TAKE IT 9828 06:05:18,730 --> 06:05:22,767 OVER FROM THERE. 9829 06:05:22,834 --> 06:05:24,535 SO AS YOU CAN IMAGINE, THESE 9830 06:05:24,602 --> 06:05:25,503 WEBINARS WERE ABOUT FOUR HOURS 9831 06:05:25,570 --> 06:05:26,638 LONG WITH EXCELLENT 9832 06:05:26,704 --> 06:05:27,605 PRESENTATIONS, AND THEN THE 9833 06:05:27,672 --> 06:05:31,442 COMMITTEES MET AFTERWARDS TO 9834 06:05:31,509 --> 06:05:32,543 SORT OF REVIEW EACH OF THE 9835 06:05:32,610 --> 06:05:33,578 SPEAKERS' RESEARCH PRIORITIES 9836 06:05:33,645 --> 06:05:36,481 AND GIVE INPUT AND THEN AS VICKY 9837 06:05:36,547 --> 06:05:38,416 SAID, SOME OF THEM ARE MORE 9838 06:05:38,483 --> 06:05:39,684 ORGANIZED AND HONED DOWN AND 9839 06:05:39,751 --> 06:05:40,785 LESS REPETITIVE THAN OTHERS 9840 06:05:40,852 --> 06:05:42,220 BECAUSE THEY'RE ALL IN STAGES OF 9841 06:05:42,287 --> 06:05:44,422 DEVELOP M. 9842 06:05:44,489 --> 06:05:44,756 MENT. 9843 06:05:44,822 --> 06:05:46,090 SO THESE ARE THE SUBCATEGORIES 9844 06:05:46,157 --> 06:05:48,092 IN THE NERVOUS SYSTEM RESEARCH 9845 06:05:48,159 --> 06:05:48,726 PRIORITIES. 9846 06:05:48,793 --> 06:05:52,897 NOT NECESSARILY IN ANY ORDER. 9847 06:05:52,964 --> 06:05:54,532 AND WE PUT RED PRINT IN THERE TO 9848 06:05:54,599 --> 06:05:55,833 MAYBE PICK OUT SOME TO 9849 06:05:55,900 --> 06:05:56,868 EMPHASIZE, BUT THERE ISN'T 9850 06:05:56,934 --> 06:05:58,636 ANYTHING MORE REAL SIGNIFICANT 9851 06:05:58,703 --> 06:06:01,105 ABOUT THAT PRINT. 9852 06:06:01,172 --> 06:06:02,240 SO COGNITION WAS A VERY 9853 06:06:02,307 --> 06:06:03,908 IMPORTANT AREA. 9854 06:06:03,975 --> 06:06:05,643 AND WE ALL SENSE THAT IT'S 9855 06:06:05,710 --> 06:06:07,612 IMPORTANT TO DEVELOP AND 9856 06:06:07,679 --> 06:06:09,013 VALIDATE TOOLS, OBJECTIVE TOOLS 9857 06:06:09,080 --> 06:06:12,350 FOR COGNITIVE ASSESSMENT AND 9858 06:06:12,417 --> 06:06:13,685 SPECIFICALLY FOR REMOTE 9859 06:06:13,751 --> 06:06:14,285 ASSESSMENT. 9860 06:06:14,352 --> 06:06:17,255 AND COGNITIVE BATTERIES THAT ARE 9861 06:06:17,322 --> 06:06:19,590 SPECIFICALLY FOR USE IN ME/CFS 9862 06:06:19,657 --> 06:06:20,458 STUDIES EASILY ADMINISTERED, ET 9863 06:06:20,525 --> 06:06:22,894 CETERA. 9864 06:06:22,960 --> 06:06:25,163 THE NEXT CATEGORY IS THAT OF 9865 06:06:25,229 --> 06:06:26,831 DYSAUTONOMIA. 9866 06:06:26,898 --> 06:06:28,333 AND SOME OF THE TOP PRIORITIES 9867 06:06:28,399 --> 06:06:29,834 WERE TO REALLY TRY TO UNDERSTAND 9868 06:06:29,901 --> 06:06:34,272 THE IMPACT OF OR T ORTHOSTATIC S 9869 06:06:34,339 --> 06:06:36,207 AND HOW IT HELPS OR REVEALS 9870 06:06:36,274 --> 06:06:39,811 ME/CFS PATHOLOGY SYMPTOM AND 9871 06:06:39,877 --> 06:06:41,646 DISEASE SEVERITY, AND REALLY 9872 06:06:41,713 --> 06:06:43,514 INVESTIGATE CIRCULATORY 9873 06:06:43,581 --> 06:06:45,983 DYSFUNCTION IN ME/CFS NEURAL, 9874 06:06:46,050 --> 06:06:47,418 IMMUNE AND AUTO NO MIBG 9875 06:06:47,485 --> 06:06:49,354 SYMPTOMS. 9876 06:06:49,420 --> 06:06:50,288 KNOW MIBG 9877 06:06:50,355 --> 06:06:50,555 SYMPTOMS. 9878 06:06:50,621 --> 06:06:51,222 ALSO I'M GOING TO ADD THERE THAT 9879 06:06:51,289 --> 06:06:52,857 IT WOULD BE GOOD TO UNDERSTAND 9880 06:06:52,924 --> 06:06:55,360 THE IMPACT, THE RELATIONSHIP OF 9881 06:06:55,426 --> 06:06:57,495 MAST CELL ACTIVATION ON 9882 06:06:57,562 --> 06:06:58,796 ORTHOSTATIC INTOLERANCE AS WELL. 9883 06:06:58,863 --> 06:07:01,232 THE SUBCATEGORY OF 9884 06:07:01,299 --> 06:07:01,799 NEUROINFLAMMATION EMPHASIZED 9885 06:07:01,866 --> 06:07:04,068 THAT WE NEED TO STUDY MORE 9886 06:07:04,135 --> 06:07:06,471 CEREBROSPINAL FLUID TO REVEAL 9887 06:07:06,537 --> 06:07:07,805 IMMUNOLOGICAL AND 9888 06:07:07,872 --> 06:07:09,640 NEUROINFLAMMATORY ABNORMALITIES, 9889 06:07:09,707 --> 06:07:13,244 AND MAYBE TO USE MEDICATIONS 9890 06:07:13,311 --> 06:07:14,445 THAT CROSS THE BLOOD BRAIN 9891 06:07:14,512 --> 06:07:16,013 BARRIER TO UNDERSTAND SOME OF 9892 06:07:16,080 --> 06:07:17,482 THESE MECHANISMS OF 9893 06:07:17,548 --> 06:07:23,187 NEUROINFLAMMATION. 9894 06:07:23,254 --> 06:07:26,457 SO ANOTHER SUBCATEGORY WAS 9895 06:07:26,524 --> 06:07:28,960 NEUROIMAGING, AND WE REALLY NEED 9896 06:07:29,026 --> 06:07:31,396 TO UNDERSTAND MORE ABOUT 9897 06:07:31,462 --> 06:07:32,697 NEUROIMAGING USING MRI, PET 9898 06:07:32,764 --> 06:07:35,633 SCANS AND EEG. 9899 06:07:35,700 --> 06:07:37,802 AND COMPARE ACROSS STUDIES AND 9900 06:07:37,869 --> 06:07:39,637 AMONG PATIENTS TO UNCOVER BRAIN 9901 06:07:39,704 --> 06:07:40,838 ABNORMALITIES, BUT ALSO TO 9902 06:07:40,905 --> 06:07:43,207 UNDERSTAND THE EFFECTS OF 9903 06:07:43,274 --> 06:07:44,409 PATIENT TRAVEL AND UNDERSTAND 9904 06:07:44,475 --> 06:07:45,710 ALL THE DIFFERENT THINGS THAT 9905 06:07:45,777 --> 06:07:47,345 COULD IMPACT THESE OUTCOMES OF 9906 06:07:47,412 --> 06:07:48,346 THESE SCANS. 9907 06:07:48,413 --> 06:07:50,715 AND TO TRY TO GET AS MANY 9908 06:07:50,782 --> 06:07:52,283 NEUROIMAGING SCANS IN CLINICAL 9909 06:07:52,350 --> 06:07:55,052 TRIALS AS POSSIBLE. 9910 06:07:55,119 --> 06:07:56,721 THE NEXT SUBCATEGORY IN NERVOUS 9911 06:07:56,788 --> 06:07:59,157 SYSTEM RESEARCH PRIORITIES WAS 9912 06:07:59,223 --> 06:08:00,458 DISORDERED SLEEP, AND WE 9913 06:08:00,525 --> 06:08:02,627 REALLY -- WE HAVE A LOT TO DO ON 9914 06:08:02,693 --> 06:08:05,663 WHY SLEEP IS DISORDERED AND 9915 06:08:05,730 --> 06:08:07,498 UNREFRESHING AND NEED TO DEVELOP 9916 06:08:07,565 --> 06:08:08,566 AND VALIDATE BIOMARKERS TO 9917 06:08:08,633 --> 06:08:10,201 UNDERSTAND MORE ABOUT THIS 9918 06:08:10,268 --> 06:08:13,037 NON-RESTORATIVE SLEEP, MAYBE 9919 06:08:13,104 --> 06:08:14,739 LEARNING MORE ABOUT EEG 9920 06:08:14,806 --> 06:08:16,040 CORRELATES, SUBGROUPS, 9921 06:08:16,107 --> 06:08:21,612 INDIVIDUAL SLEEP PATTERNS, AND 9922 06:08:21,679 --> 06:08:25,216 UNDERSTANDING WHY SLEEP PHASE 9923 06:08:25,283 --> 06:08:30,087 REVERSAL HAPPENS IN ME/CFS. 9924 06:08:30,154 --> 06:08:31,856 SMALL FIBER NEUROPATHY AND HOW 9925 06:08:31,923 --> 06:08:37,128 IT DRIVES ME/CFS, ORTHOSTATIC 9926 06:08:37,195 --> 06:08:41,699 INTOLERANCE, CEREBROPIE CEREBRON 9927 06:08:41,766 --> 06:08:42,834 AND POTS, WHAT ARE THE 9928 06:08:42,900 --> 06:08:44,635 CHARACTERISTICS OF ORTHOSTATIC 9929 06:08:44,702 --> 06:08:45,837 INTOLERANCE WITH AND WITHOUT 9930 06:08:45,903 --> 06:08:47,271 ME/CFS, AND I WOULD SAY WE NEED 9931 06:08:47,338 --> 06:08:51,576 TO UNDERSTAND POTs THAT OCCURS 9932 06:08:51,642 --> 06:08:52,810 WITHOUT ME/CFS, AND ME/CFS THAT 9933 06:08:52,877 --> 06:08:54,946 DOESN'T HAVE POTs, AND TRY TO 9934 06:08:55,012 --> 06:08:56,781 UNDERSTAND THESE OVERLAPS. 9935 06:08:56,848 --> 06:09:00,051 THERE WERE SOME OVERARCHING 9936 06:09:00,117 --> 06:09:01,853 COMMENTS THAT MAYBE A LITTLE BIT 9937 06:09:01,919 --> 06:09:03,988 LESS DISTINCT BUT REALLY TO 9938 06:09:04,055 --> 06:09:05,389 UNDERSTAND HOW -- AND THIS IS 9939 06:09:05,456 --> 06:09:06,791 RELATED ALSO TO THE COMMENT 9940 06:09:06,858 --> 06:09:11,362 ABOUT IMAGING, HOW -- WHAT IS 9941 06:09:11,429 --> 06:09:12,964 THE IMPACT OF GOING TO THE 9942 06:09:13,030 --> 06:09:13,931 CLINIC, GOING TO THE LABORATORY 9943 06:09:13,998 --> 06:09:17,435 TO GET VARIABLES OR GOING TO THE 9944 06:09:17,502 --> 06:09:18,736 RESEARCH LAB AND REALLY TRY TO 9945 06:09:18,803 --> 06:09:19,570 UNDERSTAND HOW SOME OF THESE 9946 06:09:19,637 --> 06:09:23,941 MEASURES CAN BE DONE AT HOME IF 9947 06:09:24,008 --> 06:09:26,511 POSSIBLE AND ALSO PRIORITIZING 9948 06:09:26,577 --> 06:09:28,246 SEX DIFFERENCES, AND UNCOVER 9949 06:09:28,312 --> 06:09:29,280 PROVOCATION STRESS TASKS OR 9950 06:09:29,347 --> 06:09:31,282 CREATE THEM, THAT CAN UNCOVER 9951 06:09:31,349 --> 06:09:32,149 PATHOLOGY WHILE MINIMIZING 9952 06:09:32,216 --> 06:09:33,985 BURDENS ON PARTICIPANTS TO THE 9953 06:09:34,051 --> 06:09:36,420 EXTENT THAT ARE POSSIBLE. 9954 06:09:36,487 --> 06:09:37,788 I THINK THAT'S IN PART A 9955 06:09:37,855 --> 06:09:39,590 REFERENCE TO CARDIOPULMONARY 9956 06:09:39,657 --> 06:09:40,591 EXERCISE TESTING, FOR EXAMPLE, 9957 06:09:40,658 --> 06:09:42,393 AND HOW HARD THAT CAN BE ON 9958 06:09:42,460 --> 06:09:43,194 PATIENTS AND THE SACRIFICE THEY 9959 06:09:43,261 --> 06:09:46,264 MAKE TO HELP GET THAT IMPORTANT 9960 06:09:46,330 --> 06:09:49,033 DATA. 9961 06:09:49,100 --> 06:09:50,902 WE NEED TO COMPARE AND CONTRAST 9962 06:09:50,968 --> 06:09:53,070 ME/CFS FOLLOWING COVID-19 9963 06:09:53,137 --> 06:09:54,171 INFECTION, TO ME/CFS OCCURRING 9964 06:09:54,238 --> 06:09:55,706 INDEPENDENTLY OF COVID, AND 9965 06:09:55,773 --> 06:09:58,910 REALLY TRY TO UNDERSTAND 9966 06:09:58,976 --> 06:09:59,677 SUBGROUPS BASED ON AGE, DURATION 9967 06:09:59,744 --> 06:10:01,445 OF ILLNESS, NON-RESTORATIVE 9968 06:10:01,512 --> 06:10:05,583 SLEEP AND OTHERS. 9969 06:10:05,650 --> 06:10:07,118 OKAY, ON TO THE IMMUNE SYSTEM 9970 06:10:07,184 --> 06:10:07,852 RESEARCH PRIORITIES. 9971 06:10:07,919 --> 06:10:10,655 REMEMBER, THESE ARE STILL SOME 9972 06:10:10,721 --> 06:10:12,189 OVERLAPPING CATEGORIES THAT NEED 9973 06:10:12,256 --> 06:10:13,891 TO BE DEVELOPED AND NEED INPUT. 9974 06:10:13,958 --> 06:10:16,627 UNDER THE CLINICAL IMMUNOLOGY 9975 06:10:16,694 --> 06:10:20,298 SUBGROUP, I PRIORITIZE, IDENTIFY 9976 06:10:20,364 --> 06:10:23,134 AND CHARACTERIZE DYINGS NO TICK 9977 06:10:23,200 --> 06:10:24,468 IMMUNOLOGIC INDICATORS AND 9978 06:10:24,535 --> 06:10:25,603 MEDIATORS OF ME/CFS. 9979 06:10:25,670 --> 06:10:27,338 A LOT OF SIGH NENS THERE, BUT WE 9980 06:10:27,405 --> 06:10:28,539 NEED TO PULL IT TOGETHER AND 9981 06:10:28,606 --> 06:10:29,640 UNDERSTAND MORE ABOUT HOW THESE 9982 06:10:29,707 --> 06:10:35,379 THINGS CAN BE USED IN THE CLI 9983 06:10:35,446 --> 06:10:35,613 CLINIC. 9984 06:10:35,680 --> 06:10:37,882 PULL TOGETHER PUBLISHED REPORTS 9985 06:10:37,949 --> 06:10:40,785 AND DEVELOP MORE ROBUST SAMPLE 9986 06:10:40,851 --> 06:10:41,986 REPOSITORIES AND DATA SHARING 9987 06:10:42,053 --> 06:10:43,955 PLATFORMS AND MAYBE BRING IN 9988 06:10:44,021 --> 06:10:45,156 INPUT FROM CLINICAL PROVIDERS 9989 06:10:45,222 --> 06:10:46,958 BECAUSE THEY ORDER A LOT OF 9990 06:10:47,024 --> 06:10:47,725 THESE DIFFERENT LABS, AND SEE IF 9991 06:10:47,792 --> 06:10:49,260 WE CAN LEARN MORE FROM THAT. 9992 06:10:49,327 --> 06:10:50,795 AND THEN AGAIN PRIORITIZE 9993 06:10:50,861 --> 06:10:52,597 STUDIES THAT FOCUS ON 9994 06:10:52,663 --> 06:10:54,365 DIFFERENCES IN GENDER, AGE, 9995 06:10:54,432 --> 06:10:56,200 STAGE OF ILLNESS, CO-MORBID 9996 06:10:56,267 --> 06:10:56,968 CONDITIONS. 9997 06:10:57,034 --> 06:10:59,170 AND ENSURE RESEARCH HAS 9998 06:10:59,236 --> 06:10:59,971 REPRESENTATIVE DEMOGRAPHICS AS 9999 06:11:00,037 --> 06:11:04,075 WELL. 10000 06:11:04,141 --> 06:11:06,077 THE SUBCATEGORY OF AUTOIMMUNITY, 10001 06:11:06,143 --> 06:11:08,779 ONE OF THE BIG FOCUSES OF 10002 06:11:08,846 --> 06:11:12,917 DISCUSSION WAS ON D PROTEIN 10003 06:11:12,984 --> 06:11:14,452 RECEPTOR COUPLED ANTIBODIES AND 10004 06:11:14,518 --> 06:11:15,953 WHETHER THESE TESTS CAN BE 10005 06:11:16,020 --> 06:11:18,756 REPLICATED AND WHETHER OTHER 10006 06:11:18,823 --> 06:11:19,690 AUTOANTIBODIES CAN BE ASSOCIATED 10007 06:11:19,757 --> 06:11:20,558 WITH ME/CFS. 10008 06:11:20,625 --> 06:11:21,993 INVESTIGATE THE ROLE OF B CELL 10009 06:11:22,059 --> 06:11:25,196 AND B CELL RECEPTOR SIGNALING 10010 06:11:25,262 --> 06:11:25,896 CONTRIBUTING, AND EVERYBODY 10011 06:11:25,963 --> 06:11:27,798 WOULD LOVE TO HAVE A RELIABLE 10012 06:11:27,865 --> 06:11:31,736 CONSISTENT ANIMAL MODEL FOR MANY 10013 06:11:31,802 --> 06:11:33,337 OF THE THINGS WE DO INCLUDING 10014 06:11:33,404 --> 06:11:37,475 SERUM TRANSFER ASSAYS. 10015 06:11:37,541 --> 06:11:39,443 IMMUNE CELL TYPES WAS A 10016 06:11:39,510 --> 06:11:39,844 SUBCATEGORY. 10017 06:11:39,910 --> 06:11:41,579 WE NEED TO INVESTIGATE THE 10018 06:11:41,646 --> 06:11:43,414 SIGNALING PATHWAYS RESPONSIBLE 10019 06:11:43,481 --> 06:11:46,450 FOR DRIVING DYSREGULATION. 10020 06:11:46,517 --> 06:11:49,520 AND DETERMINE MORE ABOUT THESE 10021 06:11:49,587 --> 06:11:50,955 EXHAUSTED T CELLS AND WHETHER 10022 06:11:51,022 --> 06:11:51,822 THEY'RE CHARACTERISTIC OF 10023 06:11:51,889 --> 06:11:52,256 ME/CFS. 10024 06:11:52,323 --> 06:11:53,658 BUT WE NEED TO LOOK AT OTHER 10025 06:11:53,724 --> 06:11:58,429 CELL TYPES. 10026 06:11:58,496 --> 06:11:59,964 AND REALLY CLARIFY WHETHER 10027 06:12:00,031 --> 06:12:01,599 IMMUNE CELLS ARE FUNCTIONING 10028 06:12:01,666 --> 06:12:03,701 NORMAL IN TISSUES AND IN ORGANS 10029 06:12:03,768 --> 06:12:04,802 AS OPPOSED TO JUST IN THE 10030 06:12:04,869 --> 06:12:07,204 BLOODSTREAM. 10031 06:12:07,271 --> 06:12:10,007 IMMUNE PERTURBATION SUBCATEGORY 10032 06:12:10,074 --> 06:12:12,777 AGAIN HAS SOME OVERLAP, BUT TO 10033 06:12:12,843 --> 06:12:15,446 IDENTIFY ACTIONABLE METABOLIC OR 10034 06:12:15,513 --> 06:12:18,349 MICROBIOTA TARGETS THAT ARE 10035 06:12:18,416 --> 06:12:19,550 DISRUPTED, TO DEVELOP SENSITIVE 10036 06:12:19,617 --> 06:12:22,386 AND SPECIFIC BIOMARKERS BASE ON 10037 06:12:22,453 --> 06:12:25,489 IMMUNE AND METABALOME DATA FOR 10038 06:12:25,556 --> 06:12:26,857 ACCURATE ME/CFS DIAGNOSIS. 10039 06:12:26,924 --> 06:12:29,794 AND REALLY MAYBE CONDUCT SMALL 10040 06:12:29,860 --> 06:12:30,995 INTERVENTION TRIALS BASED ON 10041 06:12:31,062 --> 06:12:32,463 AVAILABLE TARGETS THAT WE KNOW 10042 06:12:32,530 --> 06:12:35,199 NOW TO EVALUATE CHANGES IN 10043 06:12:35,266 --> 06:12:37,501 IMMUNE RESPONSE METABOLIC 10044 06:12:37,568 --> 06:12:40,271 PATHWAYS IN MICROBIOME IN WAYS 10045 06:12:40,337 --> 06:12:41,806 THAT MIGHT LEAD US FORWARD TO 10046 06:12:41,872 --> 06:12:42,707 UNDERSTAND THE SIGNIFICANCE 10047 06:12:42,773 --> 06:12:43,107 BETTER. 10048 06:12:43,174 --> 06:12:45,810 THE GUT IMMUNE METABOLIC 10049 06:12:45,876 --> 06:12:47,211 INTERPLAY HAS BEEN REFERRED TO, 10050 06:12:47,278 --> 06:12:49,080 BUT WE FEEL LIKE IT'S REALLY 10051 06:12:49,146 --> 06:12:51,082 IMPORTANT TO ELUCIDATE THE 10052 06:12:51,148 --> 06:12:52,516 DISTINCT MECHANISMS UNDERLYING 10053 06:12:52,583 --> 06:12:54,685 THE GUT IMMUNE METABOLIC 10054 06:12:54,752 --> 06:12:56,787 INTERPLAY AS WELL AS BIOMARKER 10055 06:12:56,854 --> 06:12:59,356 PROFILES OF INDIVIDUALS WITH 10056 06:12:59,423 --> 06:13:01,425 ME/CFS TO REALLY UNDERSTAND THE 10057 06:13:01,492 --> 06:13:02,960 CONNECTIONS BETWEEN THEM AND 10058 06:13:03,027 --> 06:13:04,695 DEVELOP BIOMARKERS TO STRATIFY 10059 06:13:04,762 --> 06:13:07,031 THEM BASED ON DISEASE ETIOLOGY 10060 06:13:07,098 --> 06:13:11,535 AND UNDERLYING MECHANISMS. 10061 06:13:11,602 --> 06:13:13,471 THERE IS THE POTENTIAL TO DESIGN 10062 06:13:13,537 --> 06:13:14,572 POSITION THERAPIES TAILORED TO 10063 06:13:14,638 --> 06:13:16,307 SPECIFIC SUBSETS OF INDIVIDUALS 10064 06:13:16,373 --> 06:13:18,075 WITH ME/CFS IF WE CAN DO SOME OF 10065 06:13:18,142 --> 06:13:19,744 THESE THINGS. 10066 06:13:19,810 --> 06:13:21,412 SO THIS GROUP MADE SPECIFIC 10067 06:13:21,479 --> 06:13:23,147 RECOMMENDATIONS FOR ME/CFS 10068 06:13:23,214 --> 06:13:26,083 CLINICAL TRIALS. 10069 06:13:26,150 --> 06:13:29,386 THIS CAME A LOT FROM THE LIVED 10070 06:13:29,453 --> 06:13:30,755 EXPERIENCE PEOPLE TO INVOLVE 10071 06:13:30,821 --> 06:13:32,089 MORE INDIVIDUALS WITH LIVED 10072 06:13:32,156 --> 06:13:33,924 EXPERIENCE IN CLINICAL TRIALS, 10073 06:13:33,991 --> 06:13:36,026 WHILE BALANCING THE POTENTIAL 10074 06:13:36,093 --> 06:13:37,361 ASSOCIATED HEALTH RISKS. 10075 06:13:37,428 --> 06:13:39,230 IN OTHER WORDS, CONSIDER TAKING 10076 06:13:39,296 --> 06:13:42,433 MORE RISKY ACTIONS IN CLINICAL 10077 06:13:42,500 --> 06:13:44,969 TRIALS TO ASSERTIVELY TACKLE 10078 06:13:45,035 --> 06:13:45,202 ME/CFS. 10079 06:13:45,269 --> 06:13:48,172 THE WAY WE DO WITH LETHAL 10080 06:13:48,239 --> 06:13:49,607 DISEASES AND LETHAL CANCER IN 10081 06:13:49,673 --> 06:13:56,881 ORDER TO MOVE MORE QUICKLY. 10082 06:13:56,947 --> 06:13:58,149 IT IS IMPORTANT TO IDENTIFY AND 10083 06:13:58,215 --> 06:14:00,017 ESTABLISH A CLINICAL TRIALS 10084 06:14:00,084 --> 06:14:02,553 CONSORTIUM MAYBE USING THE 10085 06:14:02,620 --> 06:14:05,322 EXISTING NINDS NEURONEX NETWORK 10086 06:14:05,389 --> 06:14:06,423 TO SUPPORT AN INFRASTRUCTURE TO 10087 06:14:06,490 --> 06:14:08,492 ROLL OUT CLINICAL TRIALS WITH 10088 06:14:08,559 --> 06:14:11,228 THE INCLUSION OF SITES WITH 10089 06:14:11,295 --> 06:14:13,397 EXPERTISE IN ME/CFS TO ASSIST 10090 06:14:13,464 --> 06:14:14,565 THIS GRANT FUNDING MECHANISM. 10091 06:14:14,632 --> 06:14:16,634 WE NEED TO PROVIDE SUPPORT AND 10092 06:14:16,700 --> 06:14:18,335 GUIDANCE FOR THE USE OF IMMUNE 10093 06:14:18,402 --> 06:14:20,838 MEASURES IN CLINICAL PRACTICE, 10094 06:14:20,905 --> 06:14:22,940 AND EDUCATE CLINICIAN -- REALLY 10095 06:14:23,007 --> 06:14:25,409 ENHANCE THE EDUCATION OF 10096 06:14:25,476 --> 06:14:27,545 CLINICIANS AND PHYSICIANS ABOUT 10097 06:14:27,611 --> 06:14:31,081 ME/CFS IN ORDER TO DIAGNOSE AND 10098 06:14:31,148 --> 06:14:31,916 CHARACTERIZE CASES MORE 10099 06:14:31,982 --> 06:14:34,051 ACTIVELY, WHICH IS A REALLY 10100 06:14:34,118 --> 06:14:34,718 OVERARCHING PROBLEM IN OUR 10101 06:14:34,785 --> 06:14:35,152 FIELD. 10102 06:14:35,219 --> 06:14:38,889 I'LL ALSO BACK UP AND SAY WE 10103 06:14:38,956 --> 06:14:41,058 REALLY NEED TO HAVE GUIDELINES 10104 06:14:41,125 --> 06:14:42,359 FOR CLINICIANS ABOUT HOW TO 10105 06:14:42,426 --> 06:14:47,832 TREATY MTREAT IMMUNE DYSFUNCTIOE 10106 06:14:47,898 --> 06:14:48,732 WE'RE WAITING FOR INSIGHTS FROM 10107 06:14:48,799 --> 06:14:49,767 LATE STAGE TRIALS. 10108 06:14:49,834 --> 06:14:51,268 AND I THINK I'M GOING TO TURN IT 10109 06:14:51,335 --> 06:14:54,638 OVER TO MAUREEN TO CONTINUE WITH 10110 06:14:54,705 --> 06:15:01,946 THE NEXT WEBINAR. 10111 06:15:02,012 --> 06:15:02,479 PRIORITIES. 10112 06:15:02,546 --> 06:15:03,247 MAUREEN HANSON. 10113 06:15:03,314 --> 06:15:04,882 THINK WE ALL KNOW HER. 10114 06:15:04,949 --> 06:15:09,820 [APPLAUSE] 10115 06:15:09,887 --> 06:15:11,655 >> THANKS. 10116 06:15:11,722 --> 06:15:15,860 SO THE NEXT TWO WEBINARS HAVE 10117 06:15:15,926 --> 06:15:19,864 UNDERGONE LESS DISCUSSION AND 10118 06:15:19,930 --> 06:15:23,000 POLISHING, SO ACTUALLY I PUT THE 10119 06:15:23,067 --> 06:15:26,103 RED THERE TO REMIND MYSELF WHAT 10120 06:15:26,170 --> 06:15:27,404 I CAN TALK ABOUT IN THE SHORT 10121 06:15:27,471 --> 06:15:28,439 TIME THAT WE HAVE. 10122 06:15:28,505 --> 06:15:30,274 SO I SELECTED THINGS THAT I KNOW 10123 06:15:30,341 --> 06:15:32,943 SOMETHING ABOUT, OR THAT I AGREE 10124 06:15:33,010 --> 06:15:34,411 WITH. 10125 06:15:34,478 --> 06:15:37,648 [LAUGHTER] 10126 06:15:37,715 --> 06:15:43,487 SO THE FIRST ONE IS RESEARCH 10127 06:15:43,554 --> 06:15:45,155 INTO TRANSCRIPTOMIC DATA BULK 10128 06:15:45,222 --> 06:15:47,224 AND SINGLE CELL RNA SEQ. 10129 06:15:47,291 --> 06:15:48,392 TOMORROW YOU'RE GOING TO HEAR AN 10130 06:15:48,459 --> 06:15:49,360 EXAMPLE OF A STUDY LIKE THAT, 10131 06:15:49,426 --> 06:15:51,028 BUT I THINK WE NEED MORE 10132 06:15:51,095 --> 06:15:51,428 STUDIES. 10133 06:15:51,495 --> 06:15:55,099 YOU'LL HEAR IT FROM ANDREW 10134 06:15:55,165 --> 06:16:00,004 GRIMSON. 10135 06:16:00,070 --> 06:16:01,205 MORE NEEDS TO BE DONE IN THAT 10136 06:16:01,272 --> 06:16:03,540 AREA TOO. 10137 06:16:03,607 --> 06:16:05,743 I ALSO AGREE THAT WE NEED TO 10138 06:16:05,809 --> 06:16:09,813 EXPAND THE ME/CFS BIOREPOSITORY, 10139 06:16:09,880 --> 06:16:10,981 BECAUSE WHEN I STARTED GETTING 10140 06:16:11,048 --> 06:16:12,683 IN THE FIELD, THE THING THAT WAS 10141 06:16:12,750 --> 06:16:16,320 MOST DAUNTING TO ME WAS WHERE 10142 06:16:16,387 --> 06:16:19,623 ARE THE SAMPLES, WHERE AM I 10143 06:16:19,690 --> 06:16:21,091 GOING TO GET THEM. 10144 06:16:21,158 --> 06:16:21,859 BUT ALSO IT'S IMPORTANT TO THINK 10145 06:16:21,926 --> 06:16:26,964 ABOUT HAVING A BIOREPOSITORY 10146 06:16:27,031 --> 06:16:28,299 FROM CLINICAL TRIALS IN WHICH 10147 06:16:28,365 --> 06:16:29,566 PEOPLE EITHER GET BETTER OR 10148 06:16:29,633 --> 06:16:30,434 WORSE AS A RESULT OF THE 10149 06:16:30,501 --> 06:16:30,801 CLINICAL TRIAL. 10150 06:16:30,868 --> 06:16:32,836 WE KNOW HOW TO MAKE PEOPLE WORSE 10151 06:16:32,903 --> 06:16:34,371 IF THEY HAVE ME/CFS. 10152 06:16:34,438 --> 06:16:35,873 WE DON'T KNOW HOW TO MAKE THEM 10153 06:16:35,940 --> 06:16:36,607 BETTER. 10154 06:16:36,674 --> 06:16:38,142 SO IF A CLINICAL TRIAL MAKES 10155 06:16:38,208 --> 06:16:40,010 SOMEONE BETTER, HAVING SAMPLES 10156 06:16:40,077 --> 06:16:41,178 OF SOMEONE WHEN THEY WERE WORSE 10157 06:16:41,245 --> 06:16:42,513 AND SOMEONE WHEN THEY'RE BETTER 10158 06:16:42,579 --> 06:16:46,350 WOULD BE EXTREMELY VALUABLE. 10159 06:16:46,417 --> 06:16:50,154 SO YOU HEARD -- THIS IS AN 10160 06:16:50,220 --> 06:16:51,522 EXAMPLE OF -- ANOTHER EXAMPLE OF 10161 06:16:51,588 --> 06:16:54,725 THE OVERLAP BETWEEN METABOLISM 10162 06:16:54,792 --> 06:16:57,661 AND IMMUNOLOGY IN THAT YOU HEARD 10163 06:16:57,728 --> 06:17:00,331 A TALK FROM JESSICA MAYA ABOUT 10164 06:17:00,397 --> 06:17:04,201 IT. ABOUTIT. CELL EXHAUSTION. 10165 06:17:04,268 --> 06:17:05,903 THIS NEEDS TO BE EXPLORED TO 10166 06:17:05,970 --> 06:17:08,072 FIND OUT IF IT IS REALLY T-CELL 10167 06:17:08,138 --> 06:17:09,206 EXHAUSTION GOING ON AND IF IT IS 10168 06:17:09,273 --> 06:17:11,976 GOING ON, WHY IS IT HAPPENING. 10169 06:17:12,042 --> 06:17:15,512 I WAS ALSO VERY IMPRESSED BY THE 10170 06:17:15,579 --> 06:17:19,516 WEBINAR ON -- THE TALK AT THE 10171 06:17:19,583 --> 06:17:22,753 WEBINAR ON RAMON SPECTROSCOPY. 10172 06:17:22,820 --> 06:17:24,054 THIS SEEMS LIKE A VERY PROMISING 10173 06:17:24,121 --> 06:17:25,489 METHOD THAT WE MIGHT BE ABLE TO 10174 06:17:25,556 --> 06:17:27,057 USE IN CLINICAL TRIALS AND ALSO 10175 06:17:27,124 --> 06:17:32,096 TO USE MORE TO FIND OUT WHAT'S 10176 06:17:32,162 --> 06:17:34,698 HAPPENING IN ME/CFS. 10177 06:17:34,765 --> 06:17:37,334 SO THEN WITH REGARD TO 10178 06:17:37,401 --> 06:17:41,105 COMPUTATION, A LOT OF THE 10179 06:17:41,171 --> 06:17:44,508 STUDIES ON METABOLISM ARE ON THE 10180 06:17:44,575 --> 06:17:47,144 EASIEST TO ACQUIRE CELL, WHICH 10181 06:17:47,211 --> 06:17:48,946 ARE IMMUNE CELLS, BUT IT WOULD 10182 06:17:49,013 --> 06:17:52,316 BE IMPORTANT TO LOOK AT TISSUE 10183 06:17:52,383 --> 06:17:54,184 METABOLISM IN MUSCLES AND IN THE 10184 06:17:54,251 --> 06:17:56,120 CENTRAL NERVOUS SYSTEM AS WELL, 10185 06:17:56,186 --> 06:17:59,156 ACCORDING TO THE RESEARCH 10186 06:17:59,223 --> 06:18:00,691 PRIORITIES PRESENTED IN THIS 10187 06:18:00,758 --> 06:18:03,460 METABOLISM WEBINAR. 10188 06:18:03,527 --> 06:18:06,997 I ALSO WANTED TO HIGHLIGHT THAT 10189 06:18:07,064 --> 06:18:10,968 WE SHOULD BE LOOKING OBJECTIVELY 10190 06:18:11,035 --> 06:18:13,303 AT METABOLITE MARKERS DOING 10191 06:18:13,370 --> 06:18:13,971 UNBIASED ANALYSIS. 10192 06:18:14,038 --> 06:18:16,140 WE STILL NEED TO DO UNBIASED 10193 06:18:16,206 --> 06:18:22,346 ANALYSES TO FIND METABOLIC 10194 06:18:22,413 --> 06:18:22,579 MARKERS. 10195 06:18:22,646 --> 06:18:23,881 ONE THING THIS GROUP SUGGESTED 10196 06:18:23,947 --> 06:18:26,183 WAS TO ESTABLISH CONNECTIONS 10197 06:18:26,250 --> 06:18:30,921 BETWEEN THE METABALOME WITH 10198 06:18:30,988 --> 06:18:31,455 PHYSICAL -- PHYSIOLOGICAL 10199 06:18:31,522 --> 06:18:32,156 MEASURES AND FUNCTION, AND I 10200 06:18:32,222 --> 06:18:33,991 WOULD ADD TO THAT, WITH CLINICAL 10201 06:18:34,058 --> 06:18:36,393 DATA, BECAUSE IT'S EXTREMELY 10202 06:18:36,460 --> 06:18:39,830 POWERFUL TO CORRELATE YOUR ASSAY 10203 06:18:39,897 --> 06:18:42,800 WITH CLINICAL DATA IF IT 10204 06:18:42,866 --> 06:18:44,701 CORRELATES WITH SEVERITY, FOR 10205 06:18:44,768 --> 06:18:46,036 EXAMPLE, THEN IT REALLY 10206 06:18:46,103 --> 06:18:47,337 REASSURES YOU THAT WHAT YOU'RE 10207 06:18:47,404 --> 06:18:48,872 MEASURING MIGHT HAVE SOME 10208 06:18:48,939 --> 06:18:56,046 RELEVANCE TO THE DISEASE. 10209 06:18:56,113 --> 06:18:57,181 THERE ARE A LOT OF 10210 06:18:57,247 --> 06:18:58,182 RECOMMENDATIONS FOR CLINICAL 10211 06:18:58,248 --> 06:19:00,250 TRIALS HERE, NOT FOR WHICH DRUGS 10212 06:19:00,317 --> 06:19:02,352 TO TRY BUT HOW TO PERFORM THEM. 10213 06:19:02,419 --> 06:19:05,456 AND ONE THING THAT I DECIDED TO 10214 06:19:05,522 --> 06:19:07,858 HIHIGHLIGHT HERE WAS, WE DO HAVE 10215 06:19:07,925 --> 06:19:09,993 THIS PROBLEM OF METABOLOMICS 10216 06:19:10,060 --> 06:19:11,095 HETEROGENEITY AMONG INDIVIDUALS, 10217 06:19:11,161 --> 06:19:12,396 AND ONE OF THE PROBLEMS IS IT'S 10218 06:19:12,463 --> 06:19:14,765 SO DIFFICULT TO CONTROL PEOPLE'S 10219 06:19:14,832 --> 06:19:16,934 DIETS AND WHAT DRUGS THEY MIGHT 10220 06:19:17,000 --> 06:19:19,136 BE TAKING AND EVERYTHING ELSE, 10221 06:19:19,203 --> 06:19:21,538 SO THAT'S ALWAYS A CONFOUNDING 10222 06:19:21,605 --> 06:19:24,775 ASPECT OF ANY SORT OF 10223 06:19:24,842 --> 06:19:30,814 METABOLOMICS STUDY. 10224 06:19:30,881 --> 06:19:31,915 SO THE LAST ONE I'M GOING TO 10225 06:19:31,982 --> 06:19:34,551 MENTION IS THE GENOMICS WEBINAR, 10226 06:19:34,618 --> 06:19:35,586 WHICH WAS QUITE FASCINATING, I 10227 06:19:35,652 --> 06:19:37,121 THOUGHT, BECAUSE IT HAD A HIGH 10228 06:19:37,187 --> 06:19:38,355 PERCENTAGE OF UNPUSH LISHED 10229 06:19:38,422 --> 06:19:40,057 DATA. 10230 06:19:40,124 --> 06:19:41,225 OF I THINK THERE'S GOING TO BE A 10231 06:19:41,291 --> 06:19:43,327 LOT OF INTERESTING INFORMATION 10232 06:19:43,393 --> 06:19:45,162 COMING OUT OF THE LARGE GWAS 10233 06:19:45,229 --> 06:19:47,197 STUDY IN THE U.K., AND WE HEARD 10234 06:19:47,264 --> 06:19:48,665 THIS MORNING FROM IAN LIPKIN 10235 06:19:48,732 --> 06:19:51,368 THAT HE'S INTERESTED IN 10236 06:19:51,435 --> 06:19:54,838 COLLABORATING WITH THE UK AND 10237 06:19:54,905 --> 06:19:56,573 WORKING WITH THE COHORT TO DO 10238 06:19:56,640 --> 06:19:59,109 GENETIC STUDIES. 10239 06:19:59,176 --> 06:20:00,944 I THINK IT WILL BE IMPORTANT TO 10240 06:20:01,011 --> 06:20:02,579 FIND COMMON DNA VARIANTS THAT 10241 06:20:02,646 --> 06:20:04,348 MIGHT BE CORRELATED WITH ME/CFS 10242 06:20:04,414 --> 06:20:05,949 IN ORDER TO UNDERSTAND THEIR 10243 06:20:06,016 --> 06:20:08,418 ROLE IN DISEASES, NOT JUST RARE 10244 06:20:08,485 --> 06:20:14,324 VARIANTS. 10245 06:20:14,391 --> 06:20:15,659 IT IS IMPORTANT TO KNOW HOW 10246 06:20:15,726 --> 06:20:19,029 THESE GENETIC VARIATIONS CAN BE 10247 06:20:19,096 --> 06:20:22,833 CONTRIBUTING AND WE ALWAYS THINK 10248 06:20:22,900 --> 06:20:24,568 ABOUT WHAT'S CAUSING THEM TO GET 10249 06:20:24,635 --> 06:20:25,669 ME/CFS BUT I THOUGHT IT WAS 10250 06:20:25,736 --> 06:20:27,204 INTERESTING THAT THIS GROUP CAME 10251 06:20:27,271 --> 06:20:28,939 UP WITH THIS POINT THAT WE 10252 06:20:29,006 --> 06:20:32,309 SHOULD FIND OUT WHAT MIGHT BE 10253 06:20:32,376 --> 06:20:34,811 PROTECTIVE OF WHAT VARIANTS 10254 06:20:34,878 --> 06:20:35,946 MIGHT PROTECT YOU FROM GETTING 10255 06:20:36,013 --> 06:20:45,389 ME/CFS. 10256 06:20:45,455 --> 06:20:47,090 SO THEN WITH REGARD TO MORE ON 10257 06:20:47,157 --> 06:20:48,992 THE GENETIC SUSCEPTIBILITY, I 10258 06:20:49,059 --> 06:20:52,029 THINK USING POPULATION-LEVEL 10259 06:20:52,095 --> 06:20:53,297 DATA FOR, AGAIN, UNBIASED 10260 06:20:53,363 --> 06:20:57,201 SCREENS FOR GENETIC VARIANTS, 10261 06:20:57,267 --> 06:20:57,935 ASSOCIATED WITH ME/CFS IS GOING 10262 06:20:58,001 --> 06:21:01,838 TO BE QUITE IMPORTANT, AND 10263 06:21:01,905 --> 06:21:04,241 LOOKING AT WHAT FUNCTION THESE 10264 06:21:04,308 --> 06:21:08,378 VARIANTS MIGHT HAVE IN THE 10265 06:21:08,445 --> 06:21:10,480 DISEASE IS ALSO REALLY 10266 06:21:10,547 --> 06:21:13,884 ESSENTIAL. 10267 06:21:13,951 --> 06:21:16,887 AS YOU CAN SEE, THIS IS QUITE A 10268 06:21:16,954 --> 06:21:17,454 LONG LIST. 10269 06:21:17,521 --> 06:21:18,522 WITH REGARD TO CASE CONTROL AND 10270 06:21:18,589 --> 06:21:21,058 FAMILY STUDIES, THE SUGGESTION 10271 06:21:21,124 --> 06:21:23,227 IS TO COMBINE FAMILY AND 10272 06:21:23,293 --> 06:21:24,394 POPULATION-BASED STUDIES, 10273 06:21:24,461 --> 06:21:25,495 BECAUSE FAMILY STUDIES CAN BE 10274 06:21:25,562 --> 06:21:30,100 QUITE INFORMATIVE. 10275 06:21:30,167 --> 06:21:34,471 AND THEN AGAIN, EPIGENETICS, SO 10276 06:21:34,538 --> 06:21:36,773 WE HEARD IN THE YOUNG 10277 06:21:36,840 --> 06:21:39,509 INVESTIGATOR TALKS ABOUT AN 10278 06:21:39,576 --> 06:21:42,246 EPIGENETIC ASPECT OF MEFERS AND 10279 06:21:42,312 --> 06:21:46,516 ME/CFS ANWE REALLY NEED TO UNDEE 10280 06:21:46,583 --> 06:21:47,351 GENETIC FACTORS INVOLVED IN THE 10281 06:21:47,417 --> 06:21:49,653 CONDITION. 10282 06:21:49,720 --> 06:21:51,655 SO WITH REGARD TO ME/CFS 10283 06:21:51,722 --> 06:21:54,524 CLINICAL TRIALS, THE SUGGESTION 10284 06:21:54,591 --> 06:21:57,628 IS TO PRIORITIZE INTEGRATION OF 10285 06:21:57,694 --> 06:21:58,895 GENETIC INFORMATION WITH OTHER 10286 06:21:58,962 --> 06:22:02,966 RESEARCH FINDINGS, AND WE HEARD 10287 06:22:03,033 --> 06:22:05,002 ABOUT MULTI-OMICS TODAY ALSO, 10288 06:22:05,068 --> 06:22:07,938 AND I THINK MULTI-OMICS IS ALSO 10289 06:22:08,005 --> 06:22:08,605 VERY CRITICAL. 10290 06:22:08,672 --> 06:22:10,474 GETTING A LOT OF DATA ON THE 10291 06:22:10,540 --> 06:22:13,510 SAME POPULATION, IT WILL BE VERY 10292 06:22:13,577 --> 06:22:18,849 INFORMATIVE. 10293 06:22:18,915 --> 06:22:20,284 SO DO YOU WANT TO TAKE OVER? 10294 06:22:20,350 --> 06:22:24,988 [APPLAUSE] 10295 06:22:25,055 --> 06:22:26,556 >> SO THANK YOU, MAUREEN AND 10296 06:22:26,623 --> 06:22:27,124 CINDY. 10297 06:22:27,190 --> 06:22:30,794 SO AGAIN, WE HAVE TWO WEBINARS 10298 06:22:30,861 --> 06:22:32,929 COMING UP ON JANUARY 5TH AND THE 10299 06:22:32,996 --> 06:22:35,966 11TH, SO YOU CAN GO TO THE NINDS 10300 06:22:36,033 --> 06:22:38,168 WEBSITE, IF YOU GO TO THAT 10301 06:22:38,235 --> 06:22:40,037 WEBSITE, RATHER THAN TAKING DOWN 10302 06:22:40,103 --> 06:22:41,505 THIS URL, IF YOU GO TO THE 10303 06:22:41,571 --> 06:22:44,474 WEBSITE AND JUST TYPE IN ME/CFS 10304 06:22:44,541 --> 06:22:45,909 RESEARCH ROAD MAP, IT WILL TAKE 10305 06:22:45,976 --> 06:22:47,811 YOU TO THE PAGE. 10306 06:22:47,878 --> 06:22:49,846 AND THAT WILL ALSO TAKE YOU TO 10307 06:22:49,913 --> 06:22:54,184 THE PAGE FROM OUR CONTRACTOR, 10308 06:22:54,251 --> 06:23:02,326 ROSAROSELI ASSOCIATES, RECORDINS 10309 06:23:02,392 --> 06:23:04,227 FROM MOST OF THE WEBINARS AND 10310 06:23:04,294 --> 06:23:05,529 TRANSCRIPTS ARE POSTED AND THEY 10311 06:23:05,595 --> 06:23:06,697 WILL ALL EVENTUALLY BE POSTED AT 10312 06:23:06,763 --> 06:23:10,534 THIS SITE. 10313 06:23:10,600 --> 06:23:12,736 IF YOU WANT TO PROVIDE FEEDBACK, 10314 06:23:12,803 --> 06:23:15,739 YOU CAN GO TO THIS -- OR SEND AN 10315 06:23:15,806 --> 06:23:17,974 EMAIL TO ME/CFS RESEARCH ROAD 10316 06:23:18,041 --> 06:23:20,977 MAP AT NINDS.NIH.GOV. 10317 06:23:21,044 --> 06:23:23,714 THE BEST WAY TO GET UPDATES 10318 06:23:23,780 --> 06:23:25,248 ABOUT WHAT'S HAPPENING WITH THIS 10319 06:23:25,315 --> 06:23:27,651 INITIATIVE AND OTHER ACTIVITIES 10320 06:23:27,718 --> 06:23:30,253 AT NIH IS TO SIGN UP FOR THE NIH 10321 06:23:30,320 --> 06:23:34,291 ME/CFS LISTSERV AT THIS WEBSITE 10322 06:23:34,358 --> 06:23:40,297 IF YOU GO TO NIH.GO.GOV/ME/CFS, 10323 06:23:40,364 --> 06:23:42,232 THAT'S THE WEBSITE FOR ME/CFS 10324 06:23:42,299 --> 06:23:43,333 AND THE TRANS ME/CFS WORKING 10325 06:23:43,400 --> 06:23:45,402 GROUP AND WHERE CAN YOU FIND 10326 06:23:45,469 --> 06:23:46,403 ADDITIONAL INFORMATION. 10327 06:23:46,470 --> 06:23:48,305 AND AS I SAID, WE'LL SOLICIT 10328 06:23:48,372 --> 06:23:49,439 INFORMATION AND FEEDBACK FROM 10329 06:23:49,506 --> 06:23:51,174 THE COMMUNITY ON THE RESEARCH 10330 06:23:51,241 --> 06:23:53,243 PRIORITIES IDENTIFIED, AND THIS 10331 06:23:53,310 --> 06:23:55,145 IS COMING SOON, SO WE'RE GOING 10332 06:23:55,212 --> 06:23:58,148 TO ROLL OUT PART OF IT AS WE'RE 10333 06:23:58,215 --> 06:24:00,650 COMPLETING THE OTHER FOUR 10334 06:24:00,717 --> 06:24:01,651 WEBINARS. 10335 06:24:01,718 --> 06:24:03,954 AND JUST ONE LAST PLUG BEFORE I 10336 06:24:04,020 --> 06:24:06,223 CALL CINDY AND MAUREEN BACK UP, 10337 06:24:06,289 --> 06:24:09,893 WE DO HAVE AN EXISTING BIO 10338 06:24:09,960 --> 06:24:10,394 REPOSITORY. 10339 06:24:10,460 --> 06:24:12,229 SO NINDS HAS BEEN -- NIH HAS 10340 06:24:12,295 --> 06:24:13,663 BEEN SUPPORTING A DATA 10341 06:24:13,730 --> 06:24:15,298 MANAGEMENT COORDINATING CENTER 10342 06:24:15,365 --> 06:24:17,334 AT RTI FOR FIVE YEARS, WHICH WAS 10343 06:24:17,401 --> 06:24:19,202 JUST RENEWED FOR ANOTHER FIVE 10344 06:24:19,269 --> 06:24:22,005 YEARS, AND THEY HAVE DEVELOPED, 10345 06:24:22,072 --> 06:24:25,776 TOGETHER WITH THE NINDS 10346 06:24:25,842 --> 06:24:27,844 CONTRACTED BIOREPOSITORY AT 10347 06:24:27,911 --> 06:24:29,913 INDIANA UNIVERSITY CALLED 10348 06:24:29,980 --> 06:24:31,515 BIOSEND, THE DATA COORDINATING 10349 06:24:31,581 --> 06:24:34,351 CENTER DEVELOPED A TOOL CALLED 10350 06:24:34,418 --> 06:24:36,186 SEARCH ME/CFS, WHERE YOU CAN GO 10351 06:24:36,253 --> 06:24:38,588 ONLINE AND SEARCH FOR WHAT 10352 06:24:38,655 --> 06:24:41,024 BIOSPECIMENS ARE AVAILABLE, AND 10353 06:24:41,091 --> 06:24:43,393 THERE'S CLINICAL DATA THAT 10354 06:24:43,460 --> 06:24:45,162 CORRELATES AND GOES ALONG WITH 10355 06:24:45,228 --> 06:24:47,130 THOSE BIOSPECIMENS. 10356 06:24:47,197 --> 06:24:48,632 WHAT'S THERE CURRENTLY IS FROM 10357 06:24:48,698 --> 06:24:50,801 THE CFI STUDY THAT WAS DONE 10358 06:24:50,867 --> 06:24:53,437 SEVERAL YEARS AGO, WHICH WAS A 10359 06:24:53,503 --> 06:24:55,839 MULTISITE STUDY, AND WE'VE JUST 10360 06:24:55,906 --> 06:24:56,573 GOTTEN PERMISSION TO AND WE'RE 10361 06:24:56,640 --> 06:24:59,509 WORKING WITH THE CDC TO INCLUDE 10362 06:24:59,576 --> 06:25:03,914 LOTS MORE BIOSPECIMENS FROM THE 10363 06:25:03,980 --> 06:25:06,149 MCAM STUDY THAT WAS DONE, AGAIN, 10364 06:25:06,216 --> 06:25:07,784 ANOTHER MULTISITE STUDY WITH 10365 06:25:07,851 --> 06:25:09,119 EXTENSIVE CLINICAL DATA, SO 10366 06:25:09,186 --> 06:25:12,055 WE'RE WORKING WITH THE CDC 10367 06:25:12,122 --> 06:25:13,690 TOGETHER WITH OUR DATA 10368 06:25:13,757 --> 06:25:15,025 COORDINATING CENTER. 10369 06:25:15,091 --> 06:25:17,494 SO QUINN BARNETT AND MEGAN 10370 06:25:17,561 --> 06:25:20,230 CARNES ARE HERE FROM RTI, THEY 10371 06:25:20,297 --> 06:25:21,631 HAD A TABLE UP WHERE WE WERE ON 10372 06:25:21,698 --> 06:25:23,400 THE TERRACE, SO STOP BY AND SEE 10373 06:25:23,467 --> 06:25:24,835 THEM IF YOU HAVE ANY QUESTIONS 10374 06:25:24,901 --> 06:25:27,571 OR NEED INFORMATION ABOUT EITHER 10375 06:25:27,637 --> 06:25:29,940 SEARCH ME/CFS OR MAP ME/CFS. 10376 06:25:30,006 --> 06:25:37,147 SO WITH THAT, IT'S ALMOST 5:00. 10377 06:25:37,214 --> 06:25:43,820 SO A COUPLE OF QUICK QUESTIONS? 10378 06:25:43,887 --> 06:25:45,355 JEFF. 10379 06:25:45,422 --> 06:25:46,656 NO, HE DOESN'T HAVE A QUESTION. 10380 06:25:46,723 --> 06:25:48,825 ANY QUICK QUESTIONS? 10381 06:25:48,892 --> 06:25:51,027 BECAUSE WE'RE TWO SECONDS AWAY 10382 06:25:51,094 --> 06:25:54,664 FROM 5:00. 10383 06:25:54,731 --> 06:25:54,865 OKAY. 10384 06:25:54,931 --> 06:25:57,133 IF NOT, THANK YOU. 10385 06:25:57,200 --> 06:25:59,002 AND WE'LL BE AROUND, SO IF YOU 10386 06:25:59,069 --> 06:25:59,736 HAVE QUESTIONS ABOUT THE ROAD 10387 06:25:59,803 --> 06:26:03,039 MAP PROCESS, JUST CHECK US OUT. 10388 06:26:03,106 --> 06:26:03,874 THANK YOU. 10389 06:26:03,940 --> 06:26:05,675 SO WE'LL START AT 9:00 TOMORROW, 10390 06:26:05,742 --> 06:26:06,943 SO HAVE A GOOD EVENING AND WE 10391 06:26:07,010 --> 06:26:07,844 LOOK FORWARD TO SEEING YOU 10392 06:26:07,911 TOMORROW.