1 00:00:05,680 --> 00:00:10,000 I'M RICHARD DAVEY THE DEPUTY 2 00:00:10,000 --> 00:00:17,040 CLINICAL DIRECTOR OF NIAID AND 3 00:00:17,040 --> 00:00:21,120 I'M HERE TO INTRODUCE 4 00:00:21,120 --> 00:00:24,600 DR. CHERTOW THE HEAD OF THE 5 00:00:24,600 --> 00:00:26,800 EMERGING PATHOGEN SECTION IN THE 6 00:00:26,800 --> 00:00:28,360 CLINICAL CENTERS CLINICAL CARE 7 00:00:28,360 --> 00:00:31,120 DEPARTMENT AND TENURE-TRACK 8 00:00:31,120 --> 00:00:32,680 INVESTIGATOR IN THE NIAID'S 9 00:00:32,680 --> 00:00:34,400 LABORATORY OF REGULATION. 10 00:00:34,400 --> 00:00:36,720 MANY OF YOU KNOW DAN BUT BY WAY 11 00:00:36,720 --> 00:00:39,600 OF BRIEF BACKGROUND, DAN DID HIS 12 00:00:39,600 --> 00:00:41,760 UNDERGRADUATE WORK AT BOSTON 13 00:00:41,760 --> 00:00:43,800 COLLEGE FOLLOWED BY MEDICAL 14 00:00:43,800 --> 00:00:44,880 SCHOOL AT NORTHWESTERN DURING 15 00:00:44,880 --> 00:00:50,840 WHICH TIME HE ALSO OBTAINED AN 16 00:00:50,840 --> 00:00:58,920 M.P.H. FROM U.C. BERKELEY AND 17 00:00:58,920 --> 00:01:01,600 DID TRAINING AT U.C. SAN DIEGO 18 00:01:01,600 --> 00:01:02,920 AND WAS AT THE INTELLIGENCE 19 00:01:02,920 --> 00:01:05,160 SERVICE AND SPENT TIME WITH THE 20 00:01:05,160 --> 00:01:06,040 FLORIDA STATE DEPARTMENT DEALING 21 00:01:06,040 --> 00:01:08,120 WITH OUTBREAK AND CONTROL IN 22 00:01:08,120 --> 00:01:10,280 THAT STATE. 23 00:01:10,280 --> 00:01:15,200 HE CAME TO NIH IN 2007 FOR HIS 24 00:01:15,200 --> 00:01:17,200 CRITICAL CARE MEDICINE 25 00:01:17,200 --> 00:01:18,760 FELLOWSHIP FOLLOWING WHICH HE 26 00:01:18,760 --> 00:01:20,720 DID INFECTIOUS DISEASE 27 00:01:20,720 --> 00:01:22,040 FELLOWSHIP AT JOHNS HOPKINS. 28 00:01:22,040 --> 00:01:27,000 ONCE HE HAD COMPLETED THOSE 29 00:01:27,000 --> 00:01:32,240 TRAININGS, DAD -- DAN EMBARKED 30 00:01:32,240 --> 00:01:34,240 IN AN EXCITING CAREER BASICALLY 31 00:01:34,240 --> 00:01:37,120 FOCUSSING ON EMERGING PATHOGENS 32 00:01:37,120 --> 00:01:38,320 OF MAJOR PUBLIC HEALTH 33 00:01:38,320 --> 00:01:40,400 IMPORTANCE AND OVER THE TIME 34 00:01:40,400 --> 00:01:46,320 HE'S BEEN HERE THAT'S INCLUDED 35 00:01:46,320 --> 00:01:48,800 WORK ON SEASONAL INFLUENZA AND 36 00:01:48,800 --> 00:01:51,880 RECENTLY ON OTHER MAJOR 37 00:01:51,880 --> 00:01:53,040 PATHOGENS OF CONCERN YOU MAY 38 00:01:53,040 --> 00:01:59,000 KNOW DAN MOSTLY FROM HIS WORK ON 39 00:01:59,000 --> 00:02:01,120 TWO MORE RECENT PATHOGENS EBOLA 40 00:02:01,120 --> 00:02:03,000 AND COVID-19. 41 00:02:03,000 --> 00:02:07,320 IN TERMS OF HIS WORK WITH EBOLA 42 00:02:07,320 --> 00:02:12,600 DAN SPENT TIME OVER IN MONROVIA, 43 00:02:12,600 --> 00:02:14,400 LIBERIA UNDER THE AUSPICES OF 44 00:02:14,400 --> 00:02:15,760 DOCTORS WITHOUT BORDERS. 45 00:02:15,760 --> 00:02:21,160 UPON HIS RETURN HE WAS A SENIOR 46 00:02:21,160 --> 00:02:23,640 A MEMBER OF THE CRITICAL CARE 47 00:02:23,640 --> 00:02:25,000 MEDICINE DEPARTMENT WHO WORKED 48 00:02:25,000 --> 00:02:26,600 WITH NIAID IN CARING FOR THE 49 00:02:26,600 --> 00:02:29,640 FOUR INDIVIDUALS WE WERE 50 00:02:29,640 --> 00:02:31,680 PRIVILEGED TO MEDICALLY EVACUATE 51 00:02:31,680 --> 00:02:32,800 TO PROVIDE CARE FOR. 52 00:02:32,800 --> 00:02:39,000 ONE PATIENT WAS PARTICULARLY ILL 53 00:02:39,000 --> 00:02:49,360 AND IN -- DAD IS A 54 00:02:50,960 --> 00:02:52,240 TRANSCRIPTIONAL ANALYSIS TO 55 00:02:52,240 --> 00:02:55,000 EBOLA INFECTION OVER THAT TIME 56 00:02:55,000 --> 00:02:57,240 PUBLISHED IN SCIENCE 57 00:02:57,240 --> 00:02:57,760 TRANSLATIONAL MEDICINE. 58 00:02:57,760 --> 00:03:00,040 DAN HAS BEEN INVOLVED IN CARING 59 00:03:00,040 --> 00:03:02,560 FOR AND RESEARCHING PATIENTS 60 00:03:02,560 --> 00:03:03,920 WITH COVID-19 INFECTION. 61 00:03:03,920 --> 00:03:05,240 HE WAS AMONGST THE SENIOR TEAM 62 00:03:05,240 --> 00:03:10,360 IN CCMD WHO WORKED WITH US AT 63 00:03:10,360 --> 00:03:11,880 NIAID TO BRING THE FIRST 64 00:03:11,880 --> 00:03:16,440 PATIENTS WITH SARS COV2 TO THE 65 00:03:16,440 --> 00:03:18,000 CLINICAL CENTER AND PROVIDE CARE 66 00:03:18,000 --> 00:03:21,040 FOR THEM AND WAS INSTRUMENTAL IN 67 00:03:21,040 --> 00:03:23,960 THE FIRST RESEARCH PROTOCOLS 68 00:03:23,960 --> 00:03:26,880 INCLUDING THE ACT-T PROTOCOLS 69 00:03:26,880 --> 00:03:29,800 THAT ULTIMATELY RESULTED IN THE 70 00:03:29,800 --> 00:03:32,600 LICENSURE OF REMDESIVIR FOR 71 00:03:32,600 --> 00:03:34,400 TREATMENT OF COVID-19 INFECTION. 72 00:03:34,400 --> 00:03:38,080 TODAY'S TOPIC'S GOING TO BE 73 00:03:38,080 --> 00:03:39,160 FOCUSSED ON ONE OF HIS MOST 74 00:03:39,160 --> 00:03:42,640 IMPORTANT BODY OF WORK IN THIS 75 00:03:42,640 --> 00:03:46,400 AREA WHICH WAS INSTRUMENTAL IN 76 00:03:46,400 --> 00:03:53,000 ORGANIZING A CONSORTIUM OF LOCAL 77 00:03:53,000 --> 00:03:55,000 INVESTIGATORS TO CONDUCT A STUDY 78 00:03:55,000 --> 00:04:00,840 OF INDIVIDUALS WHO SUCCUMBED TO 79 00:04:00,840 --> 00:04:03,440 COVID-19 AND FAMILIES AGREED TO 80 00:04:03,440 --> 00:04:07,000 HAVE THEIR BODIES SENT FOR 81 00:04:07,000 --> 00:04:08,600 AUTOPSY AND NUMEROUS TISSUE 82 00:04:08,600 --> 00:04:11,040 SAMPLES WERE OBTAINED LOOKING AT 83 00:04:11,040 --> 00:04:12,360 THE PRESENCE OF VIRUS THROUGHOUT 84 00:04:12,360 --> 00:04:14,400 THE BODY AND THAT'S THE TOPIC OF 85 00:04:14,400 --> 00:04:17,280 DAN'S TALK ENTITLED SARS COV2 86 00:04:17,280 --> 00:04:20,080 INFECTION AND PERSISTENCE 87 00:04:20,080 --> 00:04:21,280 THROUGH THE HUMAN BODY AND 88 00:04:21,280 --> 00:04:22,560 BRAIN. 89 00:04:22,560 --> 00:04:25,680 LET ME TURN THINGS OVER TO DAN 90 00:04:25,680 --> 00:04:29,080 FOR THIS I THINK WILL BE AN 91 00:04:29,080 --> 00:04:39,360 EXCITING LECTURE. 92 00:04:40,560 --> 00:04:41,160 >> I APPRECIATE THE INTEREST 93 00:04:41,160 --> 00:04:42,160 GROUP'S INVITATION FOR THE 94 00:04:42,160 --> 00:04:45,560 OPPORTUNITY TO GIVE THE LECTURE. 95 00:04:45,560 --> 00:04:50,960 I'LL BE DISCUSSING A 96 00:04:50,960 --> 00:04:53,400 RESEARCH WITH SARS COV2 AN 97 00:04:53,400 --> 00:04:57,280 PERSISTENCE AMONG THE HUMAN BODY 98 00:04:57,280 --> 00:05:00,040 AND BRAIN AMONG FATAL AUTOPSY 99 00:05:00,040 --> 00:05:01,600 I HAVE NO DISCLOSURES. 100 00:05:01,600 --> 00:05:06,080 WE HAD OBJECTIVES TO DESCRIBE 101 00:05:06,080 --> 00:05:07,960 THE BURDEN OF SARS COV2 102 00:05:07,960 --> 00:05:11,080 INFECTION WITHIN VERSUS OUTSIDE 103 00:05:11,080 --> 00:05:14,040 THE RESPIRATORY TRACT TO DEFINE 104 00:05:14,040 --> 00:05:17,760 SARS COV2 CELLULAR TROPISM AMONG 105 00:05:17,760 --> 00:05:20,680 THE BODY AND BRAIN AND IF IT 106 00:05:20,680 --> 00:05:22,640 PERSISTS IN TISSUES AND IF SO 107 00:05:22,640 --> 00:05:27,640 OVER WHAT INTERVAL AND TO 108 00:05:27,640 --> 00:05:30,280 DETERMINE IF SARS COV2 EVOLVES 109 00:05:30,280 --> 00:05:31,960 IN DIFFERENT ANATOMIC 110 00:05:31,960 --> 00:05:36,480 COMPARTMENTS OF THE BODY. 111 00:05:36,480 --> 00:05:39,400 I'LL START BY DESCRIBING OUR 112 00:05:39,400 --> 00:05:40,000 STUDY DESIGN. 113 00:05:40,000 --> 00:05:42,360 WE COLLABORATED WITH THE 114 00:05:42,360 --> 00:05:44,800 UNIVERSITY OF MEDICINE IN THE 115 00:05:44,800 --> 00:05:48,400 CENTRAL CAPITAL AND EASTERN 116 00:05:48,400 --> 00:05:50,000 SHORE REGIONS STUDY RECRUITMENT 117 00:05:50,000 --> 00:05:55,760 WAS INITIATED BY DEDICATED 118 00:05:55,760 --> 00:05:57,640 UPSTREAM CLINICAL PARTNERS OFTEN 119 00:05:57,640 --> 00:06:01,160 WITH SURGING NUMBERS ALERTED US 120 00:06:01,160 --> 00:06:01,760 WITH COVID-19 DEATHS WITH 121 00:06:01,760 --> 00:06:03,280 POTENTIAL PARTICIPATION IN THE 122 00:06:03,280 --> 00:06:06,320 STUDY. 123 00:06:06,320 --> 00:06:07,400 SPECIFICALLY CRITICAL CARE 124 00:06:07,400 --> 00:06:08,360 PROVIDERS ALERTED US FROM 125 00:06:08,360 --> 00:06:11,480 PATIENTS WHO DIED AND NEXT OF 126 00:06:11,480 --> 00:06:12,840 KIN WHO EXPRESSED INTEREST IN 127 00:06:12,840 --> 00:06:13,560 STUDY PARTICIPATION. 128 00:06:13,560 --> 00:06:15,320 THE NEXT OF KIN WERE CONSENTED 129 00:06:15,320 --> 00:06:18,480 BY MYSELF AND THE REMAINS WERE 130 00:06:18,480 --> 00:06:19,400 TRANSFERRED TO THE NIH CLINICAL 131 00:06:19,400 --> 00:06:20,720 CENTER WHICH WAS COORDINATED 132 00:06:20,720 --> 00:06:25,240 THROUGH OUR TRULY AMAZING CLINIC 133 00:06:25,240 --> 00:06:27,680 CENTER ADMISSIONS DEPARTMENT AND 134 00:06:27,680 --> 00:06:35,440 THE TISSUE PROCUREMENT WAS 135 00:06:35,440 --> 00:06:37,560 PERFORMED BY THE NATIONAL 136 00:06:37,560 --> 00:06:39,400 INSTITUTE PATHOLOGY TEAM TO KEEP 137 00:06:39,400 --> 00:06:41,920 THE POSTMOREM INTERVALS OF OUR 138 00:06:41,920 --> 00:06:43,760 STUDIES WITHIN THE FOLLOWING 139 00:06:43,760 --> 00:06:44,160 MORN. 140 00:06:44,160 --> 00:06:47,080 WE PERFORMED A TOTAL OF 44 141 00:06:47,080 --> 00:06:50,800 AUTOPSIES BETWEEN MARCH 2020 AND 142 00:06:50,800 --> 00:06:54,000 MARCH 2021. 143 00:06:54,000 --> 00:06:57,400 EACH AUTOPSY EACH IS DENOTED AS 144 00:06:57,400 --> 00:06:57,920 SHOWN HERE. 145 00:06:57,920 --> 00:07:00,400 YOU CAN SEE OUR CASES WERE WELL 146 00:07:00,400 --> 00:07:02,840 DISTRIBUTED OVER THE FIRST YEAR 147 00:07:02,840 --> 00:07:04,120 OF THE PANDEMIC. 148 00:07:04,120 --> 00:07:05,120 IT'S IMPORTANT TO EMPHASIZE UP 149 00:07:05,120 --> 00:07:07,400 FRONT THAT NONE OF THESE 150 00:07:07,400 --> 00:07:08,840 INDIVIDUALS WERE VACCINATE AND 151 00:07:08,840 --> 00:07:12,080 ALL WERE INFECTED BEFORE 152 00:07:12,080 --> 00:07:12,920 VARIANTS OF CONCERN WERE WIDELY 153 00:07:12,920 --> 00:07:13,480 CIRCULATING IN THE UNITED 154 00:07:13,480 --> 00:07:23,600 STATES. 155 00:07:26,080 --> 00:07:29,520 AND WE PRESERVED MORE THAN 156 00:07:29,520 --> 00:07:32,520 10,000 SPECIMENS FOR DOWNSTREAM 157 00:07:32,520 --> 00:07:33,840 ANALYSES ACROSS 85 DISTINCT 158 00:07:33,840 --> 00:07:36,640 ANATOMIC SITES AND BODY FLUIDS. 159 00:07:36,640 --> 00:07:38,280 PERTAINING TO THE RESULTS I'LL 160 00:07:38,280 --> 00:07:40,280 SHOW ON THE SUBSEQUENT SLIDES 161 00:07:40,280 --> 00:07:43,440 FRESH TISSUE AND BODY FLUIDS 162 00:07:43,440 --> 00:07:46,360 WERE PRESERVED FOR DOWN STREAM 163 00:07:46,360 --> 00:07:50,800 ANALYSIS BY OUR DROPLET PCR 164 00:07:50,800 --> 00:07:54,080 ASSAY FOR SARS COV2 AND FOR SUB 165 00:07:54,080 --> 00:07:56,320 GENOMIC RNA THOUGHT TO BE A 166 00:07:56,320 --> 00:08:00,680 MARKER OF RECENT REPLICATION AND 167 00:08:00,680 --> 00:08:03,400 HIGH THROUGHPUT AMPLIFICATION 168 00:08:03,400 --> 00:08:05,520 SEQUENCING TO COMPARE THE SARS 169 00:08:05,520 --> 00:08:07,400 COV2 SPIKE GENE WITHIN AND 170 00:08:07,400 --> 00:08:11,400 ACROSS ANATOMIC COMPARTMENTS. 171 00:08:11,400 --> 00:08:14,440 ADDITIONALLY FLASH FLUIDS AND 172 00:08:14,440 --> 00:08:20,840 TISSUES WERE FROZEN TO LOOK FOR 173 00:08:20,840 --> 00:08:30,360 VIRUS AND HISTO LOGIC 174 00:08:30,360 --> 00:08:34,600 EXAMINATION AND SARS COV2 175 00:08:34,600 --> 00:08:35,160 TROPISM. 176 00:08:35,160 --> 00:08:36,560 I'LL NOW PROVIDE THE CLINICAL 177 00:08:36,560 --> 00:08:38,880 FEATURES OF OUR COHORT. 178 00:08:38,880 --> 00:08:42,040 IT WAS DIVERSE WITH A MEDIAN AGE 179 00:08:42,040 --> 00:08:49,520 OF 62.4 YEARS, 29.5% WERE FEMALE 180 00:08:49,520 --> 00:08:54,840 AND 41% BLACK AND 15% HISPANIC 181 00:08:54,840 --> 00:08:55,320 OR LATINO. 182 00:08:55,320 --> 00:08:59,040 PRE EXISTING CONTINUES WERE 183 00:08:59,040 --> 00:09:01,400 PREVALENT WITH 77% OF OUR 184 00:09:01,400 --> 00:09:05,720 PATIENTS HAVE TWO OR MORE 185 00:09:05,720 --> 00:09:08,120 COMORBID CONDITIONS, 186 00:09:08,120 --> 00:09:11,200 CARDIOVASCULAR DISEASE, CHRONIC 187 00:09:11,200 --> 00:09:14,520 RESPIRATORY DISEASE AND 188 00:09:14,520 --> 00:09:15,080 DIABETES, HYPERTENSION AND 189 00:09:15,080 --> 00:09:18,000 OBESITY WERE MOST PREVALENT. 190 00:09:18,000 --> 00:09:19,600 THE MEDIAN INTERVAL FROM SYMPTOM 191 00:09:19,600 --> 00:09:23,400 ONSET TO DEATH WAS 18.5 DAYS AND 192 00:09:23,400 --> 00:09:25,440 THE MEDIAN POSTMORTEM INTERVAL 193 00:09:25,440 --> 00:09:28,120 WAS 22.2 HOURS. 194 00:09:28,120 --> 00:09:31,160 MOST OF THE COHORT WERE 195 00:09:31,160 --> 00:09:33,960 ADMINISTERED VASO PRESSERS, 196 00:09:33,960 --> 00:09:39,400 ANTIBODIES AND ANTICOAGULATION 197 00:09:39,400 --> 00:09:40,800 PRE-MORTEM. 198 00:09:40,800 --> 00:09:42,800 77% RECEIVED INVASIVE MECHANICAL 199 00:09:42,800 --> 00:09:44,840 VENTILATION AND 41% RECEIVED 200 00:09:44,840 --> 00:09:45,520 RENAL REPLACEMENT THERAPY PRIOR 201 00:09:45,520 --> 00:09:51,280 TO DEATH. 202 00:09:51,280 --> 00:09:56,080 THIS SECTION WILL FOCUS ON OUR 203 00:09:56,080 --> 00:09:58,000 CHARACTERIZATION OF SARS COV2 204 00:09:58,000 --> 00:09:59,400 TISSUE DISTRIBUTION AND 205 00:09:59,400 --> 00:09:59,720 PERSISTENCE. 206 00:09:59,720 --> 00:10:02,000 WE DEFINE PERSISTENCE AS 207 00:10:02,000 --> 00:10:04,960 DETECTION OF ALL RNA IN TISSUES 208 00:10:04,960 --> 00:10:08,120 GREATER THAN OR EQUAL TO 31 DAYS 209 00:10:08,120 --> 00:10:08,880 AFTER INITIAL COVID-19 SYMPTOM 210 00:10:08,880 --> 00:10:11,400 ONSET. 211 00:10:11,400 --> 00:10:14,560 FOR EASE OF PRESENTATION, I'M 212 00:10:14,560 --> 00:10:15,800 GOING TO SHOW A HEAT MAP 213 00:10:15,800 --> 00:10:20,160 DEPICTING OUR SARS COV2 RNA 214 00:10:20,160 --> 00:10:23,120 RESULTS LIMITED ONLY TO THE 11 215 00:10:23,120 --> 00:10:24,120 PATIENTS FROM WHICH WE COLLECTED 216 00:10:24,120 --> 00:10:26,840 BOTH BODY AND BRAIN TISSUES. 217 00:10:26,840 --> 00:10:29,320 TO ORIENT YOU ON THE LEFT SIDE 218 00:10:29,320 --> 00:10:30,920 ARE THE TISSUES SAMPLED 219 00:10:30,920 --> 00:10:32,720 ORGANIZED BY TISSUE GROUPS. 220 00:10:32,720 --> 00:10:35,520 THESE GROUPS INCLUDED 221 00:10:35,520 --> 00:10:38,600 RESPIRATORY, CARDIOVASCULAR, 222 00:10:38,600 --> 00:10:43,280 LYMPHOID AND GENERAL URINARY AND 223 00:10:43,280 --> 00:10:44,960 SKELETAL MUSCLE AND TISSUES AND 224 00:10:44,960 --> 00:10:46,240 EACH COLUMN REPRESENTS A PATIENT 225 00:10:46,240 --> 00:10:47,800 WITH THEIR I.D. NUMBER AT THE 226 00:10:47,800 --> 00:10:50,400 TOP AND DENOTED AT THE BOTTOM IS 227 00:10:50,400 --> 00:10:53,280 THEIR DURATION OF ILLNESS PRIOR 228 00:10:53,280 --> 00:10:54,440 TO DEATH. 229 00:10:54,440 --> 00:10:56,680 ILLNESS DURATION IS GROUPED INTO 230 00:10:56,680 --> 00:10:59,400 EARLY, MID AND LATE CASES 231 00:10:59,400 --> 00:11:03,280 DEFINED BY DEATH WITHIN 14 DAYS 232 00:11:03,280 --> 00:11:05,920 BETWEEN 15 TO 30 DAYS OR GREATER 233 00:11:05,920 --> 00:11:08,840 OR EQUAL TO 31 DAYS FOLLOWING 234 00:11:08,840 --> 00:11:14,280 SYMPTOM ONSET RESPECTIVELY. 235 00:11:14,280 --> 00:11:15,640 DARK RED REPRESENTS HIGH NUMBERS 236 00:11:15,640 --> 00:11:18,920 OF SARS COV2 NUCLEOTIDES AND 237 00:11:18,920 --> 00:11:23,040 DARK BLUE REPRESENTS LOW COPY 238 00:11:23,040 --> 00:11:25,320 NUMBERS BY RDPRR ASSAY. 239 00:11:25,320 --> 00:11:29,480 AS YOU CAN SEE WE'VE TAKEN SARS 240 00:11:29,480 --> 00:11:30,240 COV2 RNA ACROSS ALL TISSUE 241 00:11:30,240 --> 00:11:34,400 GROUPS WITH THE HIGHEST LEVELS 242 00:11:34,400 --> 00:11:36,360 DETECTS IN RESPIRATORY AND 243 00:11:36,360 --> 00:11:37,080 CARDIOVASCULAR TISSUES AMONG THE 244 00:11:37,080 --> 00:11:38,840 EARLY GROUP. 245 00:11:38,840 --> 00:11:41,080 ADDITIONALLY, WE OBSERVED 246 00:11:41,080 --> 00:11:44,400 RELATIVELY HIGH LEVELS OF SARS 247 00:11:44,400 --> 00:11:46,680 COV2 RNA IN P33 OR PATIENT 33 IN 248 00:11:46,680 --> 00:11:50,840 THE LATE GROUP AT 76 DAYS AFTER 249 00:11:50,840 --> 00:11:54,040 ILLNESS ONSET AND NOTABLY 250 00:11:54,040 --> 00:11:56,880 DETECTED SARS COV2 RNA IN 251 00:11:56,880 --> 00:11:58,920 MULTIPLE TISSUES IN P42 SHOWN 252 00:11:58,920 --> 00:12:02,040 ALL THE WAY TO THE RIGHT WHO 253 00:12:02,040 --> 00:12:03,000 DIED APPROXIMATELY EIGHT MONTHS 254 00:12:03,000 --> 00:12:06,400 AFTER COVID-19 ILLNESS ONSET. 255 00:12:06,400 --> 00:12:08,880 IN THIS PARTICULAR CASE THE 256 00:12:08,880 --> 00:12:12,600 PATIENT REPORTED ONLY MILD 257 00:12:12,600 --> 00:12:15,880 COVID-19 ILLNESS RECOVERING AND 258 00:12:15,880 --> 00:12:19,640 THEN CONTRACTED HEPATITIS A 259 00:12:19,640 --> 00:12:22,120 ANDLET LED TO LIVER TRANSPLANT 260 00:12:22,120 --> 00:12:23,400 AND ULTIMATELY DEATH. 261 00:12:23,400 --> 00:12:27,400 DISPLAYED ARE THE PDCCR RESULTS 262 00:12:27,400 --> 00:12:31,040 FOR THE SAME PATIENTS ACROSS 10 263 00:12:31,040 --> 00:12:33,000 DISTINCT ANATOMIC SITES ACROSS 264 00:12:33,000 --> 00:12:34,680 THE NERVOUS SYSTEM AND DETECTED 265 00:12:34,680 --> 00:12:38,320 RNA IN ALL REGIONS TESTED AND 266 00:12:38,320 --> 00:12:40,800 DETECTED RESIDUAL RNA IN ALL 267 00:12:40,800 --> 00:12:42,120 LATE CASES BOXED IN RED 268 00:12:42,120 --> 00:12:43,080 INCLUDING ACROSS MULTIPLE 269 00:12:43,080 --> 00:12:45,640 REGIONS OF THE BRAIN AND P42 ALL 270 00:12:45,640 --> 00:12:47,200 THE WAY TO THE RIGHT AT 230 DAYS 271 00:12:47,200 --> 00:12:53,080 AFTER INITIAL INFECTION. 272 00:12:53,080 --> 00:12:56,320 IN ORDER TO MORE FULLY 273 00:12:56,320 --> 00:12:57,880 CHARACTERIZE CRENS AND RNA 274 00:12:57,880 --> 00:13:01,040 BURDEN WITHIN VERSUS OUTSIDE THE 275 00:13:01,040 --> 00:13:03,400 RESPIRATORY TRACT, WE FORMED A 276 00:13:03,400 --> 00:13:05,840 LINEAR REGRESSION OF RNA LEVELS 277 00:13:05,840 --> 00:13:07,400 IN RESPIRATORY VERSUS 278 00:13:07,400 --> 00:13:09,520 NON-RESPIRATORY TISSUES BY 279 00:13:09,520 --> 00:13:10,920 ILLNESS DAY. 280 00:13:10,920 --> 00:13:14,600 ON THIS FIGURE LOG TRANSFORMED 281 00:13:14,600 --> 00:13:17,640 RNA LEVELS ARE SHOWN ON THE Y 282 00:13:17,640 --> 00:13:21,480 AXIS AND DAY OF ILLNESS ON THE X 283 00:13:21,480 --> 00:13:23,800 AND RNA LEVELS WERE 284 00:13:23,800 --> 00:13:24,960 SIGNIFICANTLY HIGHER IN THE 285 00:13:24,960 --> 00:13:26,320 RESPIRATORY TISSUES INDICATED BY 286 00:13:26,320 --> 00:13:29,200 THE RED COLOR COMPARED TO 287 00:13:29,200 --> 00:13:31,240 NON-RESPIRATORY TISSUES SHOWN IN 288 00:13:31,240 --> 00:13:31,920 BLUE FOR MONTHS FOLLOWING 289 00:13:31,920 --> 00:13:33,720 ILLNESS ONSET. 290 00:13:33,720 --> 00:13:36,960 A SIGNIFICANTLY STEEPER RATE OF 291 00:13:36,960 --> 00:13:38,840 DECLINE IN RNA LEVELS OR 292 00:13:38,840 --> 00:13:40,920 NEGATIVE SLOPE WAS OBSERVED IN 293 00:13:40,920 --> 00:13:43,440 RESPIRATORY COMPARED TO 294 00:13:43,440 --> 00:13:46,400 NON-RESPIRATORY TISSUES. 295 00:13:46,400 --> 00:13:49,080 THE Y SLOPE VALUES ARE BOTH 296 00:13:49,080 --> 00:13:50,840 GROUPED AND INDIVIDUAL 297 00:13:50,840 --> 00:13:53,040 RESPIRATORY AND NON-RESPIRATORY 298 00:13:53,040 --> 00:13:54,920 TISSUES ARE SUMMARIZED IN THE 299 00:13:54,920 --> 00:13:55,560 TABLE TO THE RIGHT. 300 00:13:55,560 --> 00:13:59,000 WE ALSO PERFORMED A LINEAR MIXED 301 00:13:59,000 --> 00:14:01,360 MODEL ANALYSIS OF RNA BURDEN IN 302 00:14:01,360 --> 00:14:02,840 RESPIRATORY VERSUS 303 00:14:02,840 --> 00:14:05,400 NON-RESPIRATORY TISSUES IN OUR 304 00:14:05,400 --> 00:14:07,600 PRE-DETERMINED EARLY, MID AND 305 00:14:07,600 --> 00:14:08,200 LATE GROUPS. 306 00:14:08,200 --> 00:14:10,480 AMONG THE EARLY GROUP WE 307 00:14:10,480 --> 00:14:14,560 OBSERVED APPROXIMATELY 100 FOLD 308 00:14:14,560 --> 00:14:15,840 HIGHER SARS COV2 LEVELS IN 309 00:14:15,840 --> 00:14:17,840 RESPIRATORY COMPARED TO 310 00:14:17,840 --> 00:14:19,000 NON-RESPIRATORY TISSUES. 311 00:14:19,000 --> 00:14:21,720 A 20 FOLD AND FOURFOLD 312 00:14:21,720 --> 00:14:23,400 DIFFERENCE IN THE MID AND LATE 313 00:14:23,400 --> 00:14:26,360 GROUPS RESPECTIVELY. 314 00:14:26,360 --> 00:14:28,920 HERE'S TO THE SAME HEAT MAP WE 315 00:14:28,920 --> 00:14:30,960 LOOKED AT BEFORE BUT NOW WITH 316 00:14:30,960 --> 00:14:34,240 THE RESULTS FROM THE QPCR 317 00:14:34,240 --> 00:14:38,800 EVALUATING FOR SUBGENOMIC RNA 318 00:14:38,800 --> 00:14:43,280 DENOTED BY VERTICAL HASH LINES 319 00:14:43,280 --> 00:14:44,840 OVERLYING OUR COLOR-CODED HEAT 320 00:14:44,840 --> 00:14:45,320 MAP. 321 00:14:45,320 --> 00:14:47,440 I'D LIKE TO FIRST HIGHLIGHT THE 322 00:14:47,440 --> 00:14:48,640 FOUR EARLIEST PATIENTS 323 00:14:48,640 --> 00:14:52,040 REPRESENTING A DURATION OF UP TO 324 00:14:52,040 --> 00:14:55,000 18 DAYS POST-ILLNESS ONSET ALL 325 00:14:55,000 --> 00:14:58,920 HAD SUB GENOMIC DETECTED ACROSS 326 00:14:58,920 --> 00:15:00,080 RESPIRATORY AND MANY 327 00:15:00,080 --> 00:15:01,200 NON-RESPIRATORY TISSUES 328 00:15:01,200 --> 00:15:02,480 INCLUDING THE BRAIN. 329 00:15:02,480 --> 00:15:06,840 WE ALSO DETECTED SUBGENOMIC RNA 330 00:15:06,840 --> 00:15:08,800 SPORADICALLY IN SOME LATE CASES 331 00:15:08,800 --> 00:15:10,360 INCLUDING ACROSS FOUR TISSUE 332 00:15:10,360 --> 00:15:13,080 GROUPS IN P33 AT 76 DAYS 333 00:15:13,080 --> 00:15:19,040 FOLLOWING ILLNESS ONSET. 334 00:15:19,040 --> 00:15:22,240 TO BETTER CHARACTERIZE THE 335 00:15:22,240 --> 00:15:23,400 RELATIONSHIP BETWEEN SARS COV2 336 00:15:23,400 --> 00:15:26,840 RNA LEVELS DETECTED BY OUR PDCCR 337 00:15:26,840 --> 00:15:30,320 ASSAY AND LEVELS OF SARS COV2 338 00:15:30,320 --> 00:15:35,360 SUB GENOMIC RNA DETECTED WE 339 00:15:35,360 --> 00:15:38,240 CONDUCTED CORRELATIONS. 340 00:15:38,240 --> 00:15:44,840 AMONG THE 10,025 SAMPLES THAT 341 00:15:44,840 --> 00:15:48,400 WERE EVALUATED AND FOR SUB 342 00:15:48,400 --> 00:15:50,840 GENOMIC RNA THE RNA LEVELS 343 00:15:50,840 --> 00:15:53,480 SIGNIFICANTLY CORRELATED WITH 344 00:15:53,480 --> 00:15:55,400 THE CORRELATED COEFFICIENT OF 345 00:15:55,400 --> 00:15:56,840 76. 346 00:15:56,840 --> 00:15:59,480 THIS ASSOCIATION STRENGTHENED TO 347 00:15:59,480 --> 00:16:03,960 .88 AND . 86 WHEN THE ANALYSIS 348 00:16:03,960 --> 00:16:07,400 WERE RESTRICTED TO THE 496 349 00:16:07,400 --> 00:16:10,840 SAMPLES FROM EARLY CASES OR THE 350 00:16:10,840 --> 00:16:13,960 396 SAMPLES COLLECTED FROM 351 00:16:13,960 --> 00:16:15,720 RESPIRATORY TISSUE RESPECTIVELY. 352 00:16:15,720 --> 00:16:18,000 WHEN THE ANALYSIS WAS LIMITED TO 353 00:16:18,000 --> 00:16:19,800 THE 302 SAMPLES THAT WERE 354 00:16:19,800 --> 00:16:22,760 POSITIVE FOR BOTH OF OUR ASSAYS, 355 00:16:22,760 --> 00:16:24,400 A SIGNIFICANT CORRELATION 356 00:16:24,400 --> 00:16:29,120 COEFFICIENT OF .91 WAS OBSERVED. 357 00:16:29,120 --> 00:16:32,040 FINALLY, WE FORMED A REGRESSION 358 00:16:32,040 --> 00:16:34,880 ANALYSIS USING THE QUANTITY OF 359 00:16:34,880 --> 00:16:38,640 OF DETECTED BY PCR TO PREDICT 360 00:16:38,640 --> 00:16:42,120 WHETHER A SAMPLE WOULD BE 361 00:16:42,120 --> 00:16:47,400 POSITIVE AND THE PDCCR VALUE OF 362 00:16:47,400 --> 00:16:50,760 1.47 COPIES PER NANOGRAM INTO 363 00:16:50,760 --> 00:16:54,360 THE ASSAY RESULTED IN 93% 364 00:16:54,360 --> 00:17:00,040 SENSITIVITY AND 91.6% 365 00:17:00,040 --> 00:17:03,240 SPECIFICITY WITH AN RUC UNDER 366 00:17:03,240 --> 00:17:07,080 THE CURVE OF .965 SUPPORTING THE 367 00:17:07,080 --> 00:17:07,680 STRONG PREDICTIVE CAPACITY OF 368 00:17:07,680 --> 00:17:14,840 THIS MODEL. 369 00:17:14,840 --> 00:17:17,080 AFTER DETECTING SUBGENOMIC RNA 370 00:17:17,080 --> 00:17:19,400 IN OVER 300 SAMPLES WE SOUGHT TO 371 00:17:19,400 --> 00:17:25,160 DETERMINE IF WE COULD ISOLATE 372 00:17:25,160 --> 00:17:28,240 SARS COV2 IN CULTURE AND WE 373 00:17:28,240 --> 00:17:29,760 ATTEMPTED TO ISOLATE IT FROM 374 00:17:29,760 --> 00:17:31,440 RESPIRATORY AND NON-RESPIRATORY 375 00:17:31,440 --> 00:17:35,480 TISSUES ACROSS 20 PATIENTS. 376 00:17:35,480 --> 00:17:38,680 WE SUCCESSFULLY COLLECT FROM 377 00:17:38,680 --> 00:17:40,680 NINE PATIENTS WHO DIED FROM ONE 378 00:17:40,680 --> 00:17:44,800 TO 12 DAYS OF ILLNESS ONSET AND 379 00:17:44,800 --> 00:17:49,320 IN THE TISSUES CYTOPATHIC EFFECT 380 00:17:49,320 --> 00:17:51,920 AND RELATIVE TO LEVELS IN THE 381 00:17:51,920 --> 00:17:56,840 ORIGINAL TISSUE OBSERVED 382 00:17:56,840 --> 00:17:59,440 CONFIRMING REPLICATION CONFIDENT 383 00:17:59,440 --> 00:18:00,040 VIRUS. 384 00:18:00,040 --> 00:18:02,600 WE FURTHER CHARACTERIZED THE RNA 385 00:18:02,600 --> 00:18:04,640 AND REPLICATION CONFIDENT VIRUS 386 00:18:04,640 --> 00:18:08,040 AND OBSERVED THAT 100% OF 387 00:18:08,040 --> 00:18:12,880 TISSUES WITH A SUB GENOME 388 00:18:12,880 --> 00:18:14,400 THRESHOLD BETWEEN 15 AND 20 HAD 389 00:18:14,400 --> 00:18:15,920 REPLICATION CONFIDENT VIRUS. 390 00:18:15,920 --> 00:18:18,280 THIS NUMBER DECREASED TO 64.3% 391 00:18:18,280 --> 00:18:21,440 OF TISSUES THAT HAD A CT VALUE 392 00:18:21,440 --> 00:18:23,560 BETWEEN 20 AND 25 AND FURTHER 393 00:18:23,560 --> 00:18:26,320 DECREASED TO 31.1% OF TISSUES 394 00:18:26,320 --> 00:18:29,360 THAT HAD A CT VALUE BETWEEN 25 395 00:18:29,360 --> 00:18:31,120 AND 30 AND NO REPLICATION 396 00:18:31,120 --> 00:18:36,240 COMPETENT VIRUS WAS DETECTED IN 397 00:18:36,240 --> 00:18:38,920 TISSUES ACROSS THE THRESHOLD OF 398 00:18:38,920 --> 00:18:40,240 30 OR HIGHER. 399 00:18:40,240 --> 00:18:45,760 OVERALL, WE'RE ABLE TO ISOLATE 400 00:18:45,760 --> 00:18:50,840 SARS COV2 FROM NASAL SINUS, LUNG 401 00:18:50,840 --> 00:18:52,480 AND IN THE NON-RESPIRATORY 402 00:18:52,480 --> 00:19:01,680 COMPARTMENT OF THE EYE, THE 403 00:19:01,680 --> 00:19:06,080 MEDIAL STINAL LYMPH NODE AND 404 00:19:06,080 --> 00:19:08,800 ADRENAL GLAND. 405 00:19:08,800 --> 00:19:11,240 WE ESTIMATE SARS COV2 RNA LEVELS 406 00:19:11,240 --> 00:19:14,840 STRONGLY PREDICTIVE OF 407 00:19:14,840 --> 00:19:17,200 REPLICATION CONFIDENT OF 408 00:19:17,200 --> 00:19:17,520 CULTURE. 409 00:19:17,520 --> 00:19:19,320 TO ACCOMPLISH THIS WE FORMED 410 00:19:19,320 --> 00:19:23,880 REGRESSION ANALYSIS WITH THE ROC 411 00:19:23,880 --> 00:19:27,480 CURVES AND FOUND THAT A DVPCR 412 00:19:27,480 --> 00:19:30,720 VALUE OF THE COPIES PER NANOGRAM 413 00:19:30,720 --> 00:19:32,840 PUT IN THE ASSAY PREDICTED 414 00:19:32,840 --> 00:19:35,280 REPLICATION COMPETENT VIRUS WITH 415 00:19:35,280 --> 00:19:39,200 A 76% SENSITIVITY, 90% 416 00:19:39,200 --> 00:19:45,960 SPECIFICITY AND ROCAUC OF .887. 417 00:19:45,960 --> 00:19:51,280 A SUB GENOMIC RNA VALUE OF 418 00:19:51,280 --> 00:19:55,320 25,069 COPIES PER MICROLITER OF 419 00:19:55,320 --> 00:19:57,200 RNA PREDICTED REPLICATION 420 00:19:57,200 --> 00:19:59,920 COMPETENT VIRUS WITH 72% 421 00:19:59,920 --> 00:20:05,160 SENSITIVITY AND 100% SPECIFICITY 422 00:20:05,160 --> 00:20:14,280 WITH AN AUCROC OF .915 AND 423 00:20:14,280 --> 00:20:15,400 DETERMINE IT'S LIKELY 424 00:20:15,400 --> 00:20:17,000 REPLICATION COMPETENT VIRUS 425 00:20:17,000 --> 00:20:18,880 WITHOUT HAVING TO PERFORM CELL 426 00:20:18,880 --> 00:20:23,400 CULTURE IN A BSL3 SETTING WHICH 427 00:20:23,400 --> 00:20:25,120 IS A LIMITED RESOURCE. 428 00:20:25,120 --> 00:20:28,640 NOW I'LL BRIEFLY TAKE YOU 429 00:20:28,640 --> 00:20:37,440 THROUGH THE INSITU RESULT IN OUR 430 00:20:37,440 --> 00:20:37,680 COHORT. 431 00:20:37,680 --> 00:20:43,000 USING OUR DVPCR AND SUBGENOMIC 432 00:20:43,000 --> 00:20:48,720 QPCR RESULTS AS A GUIDE, WE 433 00:20:48,720 --> 00:20:54,080 REALIZED AN INSITU WITH THE 434 00:20:54,080 --> 00:21:00,000 GENOME TO VALIDATE OUR PCR 435 00:21:00,000 --> 00:21:01,880 ASSAYS AND POSITIVE NEGATIVE 436 00:21:01,880 --> 00:21:06,240 CONTROLS FOR HUMAN HOUSEKEEPING 437 00:21:06,240 --> 00:21:07,600 GENE AND E. COLI GENE WERE USED 438 00:21:07,600 --> 00:21:08,520 TO IDENTIFY SPECIFICITY OF THE 439 00:21:08,520 --> 00:21:10,760 ASSAY. 440 00:21:10,760 --> 00:21:12,800 WHAT WE FOUND POSITIVE STAINING 441 00:21:12,800 --> 00:21:15,400 IN ALL TISSUE GROUPS I HAVE A 442 00:21:15,400 --> 00:21:16,800 SMALL PANEL THAT HIGHLIGHTS 443 00:21:16,800 --> 00:21:19,400 STAINING IN BRAIN AND OTHER 444 00:21:19,400 --> 00:21:22,120 TISSUES. 445 00:21:22,120 --> 00:21:23,400 DISPLAYED IN THE FIRST ROW IN 446 00:21:23,400 --> 00:21:25,720 ORDER FROM LEFT TO RIGHT ARE 447 00:21:25,720 --> 00:21:30,840 FRONTAL LOBE OF THE LEFT AND 448 00:21:30,840 --> 00:21:32,120 CORPUS CALLOSUM AND CEREBELLUM 449 00:21:32,120 --> 00:21:33,560 OF A LATE CASE AND CERVICAL 450 00:21:33,560 --> 00:21:38,840 SPINAL CORD OF A LATE CASE D. 451 00:21:38,840 --> 00:21:44,840 SHOWN IN THE SECOND ROW ARE 452 00:21:44,840 --> 00:21:55,400 FOLLICULAR CELLS AND THE SPLEEN 453 00:21:59,800 --> 00:22:05,440 AND PANEL G AND EPITHELIUM AND 454 00:22:05,440 --> 00:22:07,080 MONONUCLEAR AND EXCUSE ME SPLEEN 455 00:22:07,080 --> 00:22:17,480 IS G AND IN H COLONIC 456 00:22:19,160 --> 00:22:26,840 EPITHELIUM AND HERE'S THE 457 00:22:26,840 --> 00:22:37,400 ADRENAL GLAND A AND THE TESTES 458 00:22:38,200 --> 00:22:42,600 IS K AND THE STROMAL CELLS OF A 459 00:22:42,600 --> 00:22:44,160 UTERUS IN L. 460 00:22:44,160 --> 00:22:48,560 WE FURTHER EVALUATED SARS COV2 461 00:22:48,560 --> 00:22:50,160 CELLULAR TROPISM WITHIN THE 462 00:22:50,160 --> 00:22:53,560 CEREBELLUM AND OTHER REGIONS OF 463 00:22:53,560 --> 00:22:58,800 THE BRAIN WITH FOCAL MICROSCOPY. 464 00:22:58,800 --> 00:23:02,200 AND THE IMAGES THE CELL NUKE LEE 465 00:23:02,200 --> 00:23:05,480 ARE BLUE AND THE NUCLEO CAPSID 466 00:23:05,480 --> 00:23:07,400 IS GREEN AND NEURONS ARE 467 00:23:07,400 --> 00:23:07,680 MAGENTA. 468 00:23:07,680 --> 00:23:12,880 THE LOCATIONS OF THE MOLECULAR 469 00:23:12,880 --> 00:23:14,560 LAYER AND GRANULAR LAYER AND 470 00:23:14,560 --> 00:23:18,320 WHITE MATTER ARE INDICATED ON 471 00:23:18,320 --> 00:23:19,040 THE SLIDE. 472 00:23:19,040 --> 00:23:22,800 PANEL A SHOWED A LOW 473 00:23:22,800 --> 00:23:25,320 MAGNIFICATION VISUALIZATION OF A 474 00:23:25,320 --> 00:23:26,520 KNOWN ANTIBODY CONTROL AND B 475 00:23:26,520 --> 00:23:31,160 SHOWS AN ADJACENT SECTION WITH 476 00:23:31,160 --> 00:23:32,840 SPECIFIC PROTEIN EXPRESSION. 477 00:23:32,840 --> 00:23:38,840 HIGHER MAG ANY FINGS -- 478 00:23:38,840 --> 00:23:40,000 MAGNIFICATIONS DEMONSTRATES 479 00:23:40,000 --> 00:23:42,120 SPECIFIC INFECTION IN C AND 480 00:23:42,120 --> 00:23:44,840 POSITIVE NEURONS ARE INDICATED 481 00:23:44,840 --> 00:23:47,400 IN THE YELLOW ARROWS. 482 00:23:47,400 --> 00:23:49,240 OTHER UNIDENTIFIED CELLS ARE 483 00:23:49,240 --> 00:23:52,000 ASSOCIATED WITH PROTEIN IN THE 484 00:23:52,000 --> 00:23:56,760 GRANULAR LAYER. 485 00:23:56,760 --> 00:24:03,560 KIDNEY CELLS ARE INEFFEFECTED AN 486 00:24:03,560 --> 00:24:04,920 E THEY WERE ASSOCIATED WITH 487 00:24:04,920 --> 00:24:14,640 VIRAL PROTEIN. 488 00:24:14,640 --> 00:24:15,360 THIS SUMMARIZES THE CELL TYPES 489 00:24:15,360 --> 00:24:20,760 ACROSS THE BODY AND BRAIN THAT 490 00:24:20,760 --> 00:24:23,360 WERE ISH POSITIVE FOR SARS COV2 491 00:24:23,360 --> 00:24:33,600 IN OUR COHORT. 492 00:24:36,280 --> 00:24:39,600 WE LOOKED AT DIFFERENT ANATOMIC 493 00:24:39,600 --> 00:24:41,160 COMPONENTS WITHIN THE PATIENT 494 00:24:41,160 --> 00:24:45,240 AND THE BOARD'S LAB PERFORMED 495 00:24:45,240 --> 00:24:48,040 HIGH THROUGHPUT SINGLE GENOME 496 00:24:48,040 --> 00:24:50,200 SEQUENCING FROM A TOTAL OF 46 497 00:24:50,200 --> 00:24:55,200 TISSUES FROM SIX INDIVIDUALS. 498 00:24:55,200 --> 00:24:57,560 AND PATIENT 18 ARE SHOWN ON THE 499 00:24:57,560 --> 00:25:01,240 LEFT WHICH WERE IDENTICAL ACROSS 500 00:25:01,240 --> 00:25:02,760 ALL ANATOMIC COMPARTMENTS 501 00:25:02,760 --> 00:25:04,040 TESTED. 502 00:25:04,040 --> 00:25:05,880 P19 ON THE RIGHT IN THIS PATIENT 503 00:25:05,880 --> 00:25:07,720 WE DETECT A SINGLE SYNONYMOUS 504 00:25:07,720 --> 00:25:10,920 MUTATION WHICH IS DENOTED IN 505 00:25:10,920 --> 00:25:13,920 BLUE HERE AND A MINOR VARIANT IN 506 00:25:13,920 --> 00:25:15,880 THE WHITE SUPERIOR LUNG LOBE. 507 00:25:15,880 --> 00:25:19,360 OVERALL THE TWO PATIENTS 508 00:25:19,360 --> 00:25:21,880 DEMONSTRATE SARS COV2 CAN INFECT 509 00:25:21,880 --> 00:25:24,920 CELLS WITHIN NON-RESPIRATORY 510 00:25:24,920 --> 00:25:25,520 TISSUES WITHOUT REQUIRING 511 00:25:25,520 --> 00:25:33,920 CHANGES IN THE SPIKE GENOME. 512 00:25:33,920 --> 00:25:36,680 AND SYNONYMOUS MUTATIONS WERE 513 00:25:36,680 --> 00:25:39,760 DETECTED WITHIN THE RESPIRATORY 514 00:25:39,760 --> 00:25:45,440 TRACT AND OUTSIDE OF IT AND THE 515 00:25:45,440 --> 00:25:52,240 MEDIAL STINAL LYMPH MODE AND 516 00:25:52,240 --> 00:25:53,480 DENOTED IN BLUE. 517 00:25:53,480 --> 00:25:55,040 WE WERE UNABLE TO GET TISSUE 518 00:25:55,040 --> 00:25:56,760 FROM THE LATE CASE THERE ARE TWO 519 00:25:56,760 --> 00:26:02,000 TWO TYPES DETECTED WITHIN THE 520 00:26:02,000 --> 00:26:03,160 THORACIC LYMPH NODE OF THIS 521 00:26:03,160 --> 00:26:05,720 INDIVIDUAL. 522 00:26:05,720 --> 00:26:07,320 FINALLY, WE'RE ABLE TO SEQUENCE 523 00:26:07,320 --> 00:26:08,760 BRAIN SAMPLES FROM TWO PATIENTS 524 00:26:08,760 --> 00:26:11,760 IN OUR COHORT WHICH ARE SHOWN 525 00:26:11,760 --> 00:26:17,600 HERE WHICH REVEALED 526 00:26:17,600 --> 00:26:19,720 NON-SYNONYMOUS MUTATIONS WITHIN 527 00:26:19,720 --> 00:26:22,760 HAPLOTYPES WITHIN THE CNS AND 528 00:26:22,760 --> 00:26:25,480 THE REST OF THE BODY 529 00:26:25,480 --> 00:26:30,640 SPECIFICALLY IN THE DURAMATTER 530 00:26:30,640 --> 00:26:34,760 FOR P36 AND THE HYPOTHALAMUS AND 531 00:26:34,760 --> 00:26:37,440 THALAMUS OF P38 SHOWN HERE. 532 00:26:37,440 --> 00:26:38,760 THESE RESULTS SHOW SARS COV2 533 00:26:38,760 --> 00:26:40,560 WITHIN THE BRAIN IS SUBJECT TO 534 00:26:40,560 --> 00:26:44,280 THE DEVELOPMENT OF GENETIC 535 00:26:44,280 --> 00:26:44,880 COMPARTMENTALIZATION AND 536 00:26:44,880 --> 00:26:47,160 EXPLORING THE MECHANISMS BEHIND 537 00:26:47,160 --> 00:26:47,720 THIS WILL BE IMPORTANT FOR 538 00:26:47,720 --> 00:26:55,760 FUTURE WORK. 539 00:26:55,760 --> 00:26:59,120 I'LL SUMMARIZE THE HISTO LOGIC 540 00:26:59,120 --> 00:27:01,640 CORRELATES IN OUR COHORT. 541 00:27:01,640 --> 00:27:03,800 OUR PATHOLOGY COLLEAGUES AT NCI 542 00:27:03,800 --> 00:27:05,920 IN ADDITION TO RUNNING ALL OF 543 00:27:05,920 --> 00:27:09,920 OUR ISH ASSAYS DETERMINED THE 544 00:27:09,920 --> 00:27:12,320 CAUSE OF DEATH AND CHARACTERIZES 545 00:27:12,320 --> 00:27:14,920 THE PATHOLOGIC FINDINGS FOR ALL 546 00:27:14,920 --> 00:27:25,040 CASES. 547 00:27:26,640 --> 00:27:28,480 THE DAMAGE WAS DETECTED IN ALL 548 00:27:28,480 --> 00:27:34,760 BUT 18% OF CASES AND A PANEL 549 00:27:34,760 --> 00:27:40,840 SHOWS THE DAMAGE WITH MEMBRANES 550 00:27:40,840 --> 00:27:44,320 AND PANEL B SHOWS THE 551 00:27:44,320 --> 00:27:47,320 PROLIFERATIVE PHASE WITH SPARSE 552 00:27:47,320 --> 00:27:51,960 INFLAMMATION IN A MILD CASE. 553 00:27:51,960 --> 00:27:53,840 EXCUSE ME, NOT MILD BUT MID 554 00:27:53,840 --> 00:27:54,760 CASE. 555 00:27:54,760 --> 00:27:58,120 ACUTE PNEUMONIA WAS PRESENT IN 556 00:27:58,120 --> 00:28:03,320 61% AND PULMONARY HEMORRHAGE IN 557 00:28:03,320 --> 00:28:06,160 32% DEMONSTRATED DIFFUSELY IN 558 00:28:06,160 --> 00:28:09,840 PANEL B AND THROMBOWLISM WAS 559 00:28:09,840 --> 00:28:12,480 DETECTED IN 23% AN EXAMPLE IN 560 00:28:12,480 --> 00:28:17,080 PANEL C IN A MEDIAN PULMONARY 561 00:28:17,080 --> 00:28:20,320 VESSEL ON THE RIGHT. 562 00:28:20,320 --> 00:28:22,840 WE WERE ABLE TO QUANTIFY THE 563 00:28:22,840 --> 00:28:24,120 PROGRESSION FROM THE EARLY PHASE 564 00:28:24,120 --> 00:28:26,400 SHOWN BY THE ORANGE STACK BARS 565 00:28:26,400 --> 00:28:29,960 DURING WEEK 1 TO 2 TO THE 566 00:28:29,960 --> 00:28:31,320 INTERMEDIATE PROLIFERATIVE PHASE 567 00:28:31,320 --> 00:28:41,840 THE GRAY STACK BARS IN THE LATE 568 00:28:44,720 --> 00:28:47,920 FIBROSING PHASE. 569 00:28:47,920 --> 00:28:52,120 IN THE HEART WE SAW INFILTRATED 570 00:28:52,120 --> 00:28:56,320 IN 9% DESPITE RNA IN 80% OF OUR 571 00:28:56,320 --> 00:28:56,600 CASES. 572 00:28:56,600 --> 00:28:59,280 PATIENT 3 SHOWN IN PANEL E IS AN 573 00:28:59,280 --> 00:29:04,000 EXAMPLE OF A SINGLE CASE THAT 574 00:29:04,000 --> 00:29:08,120 HAD ACTIVE LYMPHOCYTIC CARDITIS 575 00:29:08,120 --> 00:29:11,080 AT THE TIME OF DEATH AND 576 00:29:11,080 --> 00:29:21,520 ISCHEMIA AND MYOCARDIAL 577 00:29:24,960 --> 00:29:31,320 MYCROISIS WAS DENOTE AND LYMPH 578 00:29:31,320 --> 00:29:35,360 NODE ARCHITECTURE REMAPED INTACT 579 00:29:35,360 --> 00:29:42,440 WITHOUT LYMPHODEFLATION -- 580 00:29:42,440 --> 00:29:43,360 LYMPHODEPLETION AND THERE WAS 581 00:29:43,360 --> 00:29:49,480 WELL DEFINED FOLLICLES IN 582 00:29:49,480 --> 00:29:50,240 CYTOSIS. 583 00:29:50,240 --> 00:29:55,280 IN CONTRAST, SOME DEGREE OF 584 00:29:55,280 --> 00:29:57,960 LYMPHO DEPLETION WAS SCREENED IN 585 00:29:57,960 --> 00:30:07,520 35% OF CASES PANEL K IS LYMPHO 586 00:30:07,520 --> 00:30:17,800 DEPLETION HERE. 587 00:30:23,000 --> 00:30:25,760 WE OBSERVED NON-SPECIFIC 588 00:30:25,760 --> 00:30:28,360 FINDINGS INCLUDING FOCAL OR 589 00:30:28,360 --> 00:30:29,760 DIFFUSE HYPOXIC ISCHEMIC INJURY 590 00:30:29,760 --> 00:30:33,560 IN 45% OF CASES. 591 00:30:33,560 --> 00:30:35,320 VASCULAR CONGESTION WAS OBSERVED 592 00:30:35,320 --> 00:30:38,720 IN 45% OF CASES AND MICROSCOPIC 593 00:30:38,720 --> 00:30:44,760 HEMORRHAGE IN 18% OF CASES. 594 00:30:44,760 --> 00:30:47,840 IN SUMMARY, WE OBSERVED THAT 595 00:30:47,840 --> 00:30:50,480 SARS COV2 IS WIDELY DISSEMINATED 596 00:30:50,480 --> 00:30:54,960 ACROSS THE HUMAN BODY AND BRAIN 597 00:30:54,960 --> 00:30:57,760 EARLY IN INFECTION AND SARS COV2 598 00:30:57,760 --> 00:31:00,920 RNA CAN PERSIST IN MULTIPLE 599 00:31:00,920 --> 00:31:02,720 ANATOMIC COMPARTMENTS FOR OVER 600 00:31:02,720 --> 00:31:06,880 SEVEN MONTHS AND OBSERVED THE 601 00:31:06,880 --> 00:31:15,400 APAUCITY -- APOSITY OF 602 00:31:15,400 --> 00:31:18,080 INFLAMMATION AND I'LL MAKE MANY 603 00:31:18,080 --> 00:31:19,200 IMPORTANT ACKNOWLEDGEMENTS. 604 00:31:19,200 --> 00:31:21,560 I'D LIKE TO START WITH THE MANY 605 00:31:21,560 --> 00:31:25,040 HEALTH CARE PROVIDERS AT OUR 606 00:31:25,040 --> 00:31:26,240 CONSORTIUM HOSPITALS LISTED 607 00:31:26,240 --> 00:31:26,440 HERE. 608 00:31:26,440 --> 00:31:29,520 I'D LIKE TO SPECIFICALLY 609 00:31:29,520 --> 00:31:33,040 ACKNOWLEDGE DR. ALISON GRAZIOLI 610 00:31:33,040 --> 00:31:36,720 WHO SPEARHEADED THE PATIENT 611 00:31:36,720 --> 00:31:39,520 ENROLLMENT AT ALL OF OUR 612 00:31:39,520 --> 00:31:41,520 CONSORTIUM HOSPITALS AND TO 613 00:31:41,520 --> 00:31:46,720 ACKNOWLEDGES DR. SAHARIA AND 614 00:31:46,720 --> 00:31:47,320 DR. RABIN INVOLVED IN THIS 615 00:31:47,320 --> 00:31:55,040 COHORT. 616 00:31:55,040 --> 00:31:58,200 THIS WORK WOULD NOT HAVE BEEN 617 00:31:58,200 --> 00:32:00,920 POSSIBLE WITHOUT THE 618 00:32:00,920 --> 00:32:02,720 ENTHUSIASTIC LEADERSHIP AND 619 00:32:02,720 --> 00:32:13,280 SUPPORT BY DR. HEWITT AND MANY 620 00:32:14,720 --> 00:32:17,920 IN THE LABORATORY MEMBER 621 00:32:17,920 --> 00:32:18,600 SUPPORTING THE CULTURE WORK I 622 00:32:18,600 --> 00:32:25,320 SHOWED AND DOCTORS PETERSON AND 623 00:32:25,320 --> 00:32:27,560 CLAYTON WINKLER WHO LED THE WORK 624 00:32:27,560 --> 00:32:28,000 IN THE BRAIN. 625 00:32:28,000 --> 00:32:32,760 DR. BORITZ GROUP PERFORM THE 626 00:32:32,760 --> 00:32:38,320 SPIKE SEQUENCING AND I RECOGNIZE 627 00:32:38,320 --> 00:32:39,320 DR. HOLLAND FOR ENCOURAGEMENT 628 00:32:39,320 --> 00:32:41,480 AND FUNDING TO SUPPORT THE 629 00:32:41,480 --> 00:32:42,800 STUDIES EARLY ON AND CONTINUALLY 630 00:32:42,800 --> 00:32:47,960 THROUGH THIS PANDEMIC. 631 00:32:47,960 --> 00:32:50,720 MANY MEMBERS OF THE MEDICINE 632 00:32:50,720 --> 00:32:51,920 DEPARTMENT CONTRIBUTED TO THIS 633 00:32:51,920 --> 00:32:53,560 WORK DIRECTLY OR INDIRECTLY. 634 00:32:53,560 --> 00:32:56,360 I'D LIKE TO SPECIFICALLY 635 00:32:56,360 --> 00:32:59,800 ACKNOWLEDGE DR. STEIN THE FIRST 636 00:32:59,800 --> 00:33:05,280 AUTHOR OF THIS WORK AND SABRINA 637 00:33:05,280 --> 00:33:08,720 ROMELI WHO WORKED THE PDCCR ON 638 00:33:08,720 --> 00:33:10,560 THOUSANDS OF SPECIMENS AND LIKED 639 00:33:10,560 --> 00:33:15,280 TO THANK OUR STATISTICS SUPPORT 640 00:33:15,280 --> 00:33:18,280 WHO PERFORMED OUR REGRESSION 641 00:33:18,280 --> 00:33:18,520 ANALYSES. 642 00:33:18,520 --> 00:33:19,720 I'D LIKE TO ACKNOWLEDGE AND 643 00:33:19,720 --> 00:33:22,920 THANK TRACY LEWIS AND ALL 644 00:33:22,920 --> 00:33:24,160 MEMBERS OF THE NIH CLINICAL 645 00:33:24,160 --> 00:33:25,320 CENTER MISSION DEPARTMENT STAFF 646 00:33:25,320 --> 00:33:28,000 FOR THEIR AGILITY AND 647 00:33:28,000 --> 00:33:31,760 ADAPTABILITY IN SUPPORTING OUR 648 00:33:31,760 --> 00:33:34,440 REQUESTS FOR TRANSFERS OF NEXT 649 00:33:34,440 --> 00:33:37,720 OF KIN OR DECEASED OFTEN IN THE 650 00:33:37,720 --> 00:33:38,760 EARLY HOURS OF THE MORNING 651 00:33:38,760 --> 00:33:40,920 DURING THIS ONE-YEAR INTERVAL 652 00:33:40,920 --> 00:33:43,240 OVER AND OVER AGAIN. 653 00:33:43,240 --> 00:33:45,200 AND WITH THAT, I WILL THANK YOU 654 00:33:45,200 --> 00:33:53,360 AND CLOSE AND TAKE QUESTIONS. 655 00:33:53,360 --> 00:33:56,840 >> THANK YOU VERY MUCH FOR A 656 00:33:56,840 --> 00:33:58,480 VERY INTERESTING TALK. 657 00:33:58,480 --> 00:33:59,440 WE HAVE A LOT OF QUESTIONS BUT 658 00:33:59,440 --> 00:34:01,560 BEFORE I START WITH THEM I WANT 659 00:34:01,560 --> 00:34:04,560 TO REITERATE THE CME CODE NUMBER 660 00:34:04,560 --> 00:34:07,680 FOR THOSE TAKING THE CREDIT. 661 00:34:07,680 --> 00:34:16,080 IT'S 37971. 662 00:34:16,080 --> 00:34:16,720 37971. 663 00:34:16,720 --> 00:34:20,120 I'LL START WITH A QUESTION FROM 664 00:34:20,120 --> 00:34:20,680 JIM BORIS. 665 00:34:20,680 --> 00:34:24,840 DO POSTMORTEM ANALYSIS OF PEOPLE 666 00:34:24,840 --> 00:34:26,720 WHO HAVE HAD MILD COVID-19 AND 667 00:34:26,720 --> 00:34:31,320 RECOVERED FROM IT AND DIED OF 668 00:34:31,320 --> 00:34:33,520 SOMETHING ELSE AFTER DO THEY 669 00:34:33,520 --> 00:34:36,080 SHOW THE SAME CELLULAR TROPISM 670 00:34:36,080 --> 00:34:42,400 AND PERSISTENCE OF SARS COV2? 671 00:34:42,400 --> 00:34:44,560 >> EXCELLENT QUESTION, JIM. 672 00:34:44,560 --> 00:34:46,760 WE'RE VERY CAUTIOUS AND OPENLY 673 00:34:46,760 --> 00:34:48,680 ACKNOWLEDGE THAT OUR COHORT WAS 674 00:34:48,680 --> 00:34:53,880 LARGELY LIMITED TO OLDER 675 00:34:53,880 --> 00:34:57,400 INDIVIDUALS WITH A NUMBER OF 676 00:34:57,400 --> 00:34:58,360 COMORBID CONDITIONS THAT 677 00:34:58,360 --> 00:35:00,280 DEVELOPED SEVERE AND ULTIMATELY 678 00:35:00,280 --> 00:35:03,840 FATAL COVID SO WE'RE CAUTIOUS 679 00:35:03,840 --> 00:35:06,840 ABOUT GENERALIZING OUR 680 00:35:06,840 --> 00:35:11,280 OBSERVATIONS TO A YOUNGER, 681 00:35:11,280 --> 00:35:12,680 HEALTHIER POPULATION OR 682 00:35:12,680 --> 00:35:13,000 VACCINATED. 683 00:35:13,000 --> 00:35:15,280 THOSE ARE ALL LIMITATIONS. 684 00:35:15,280 --> 00:35:16,960 HAVING SAID THAT, THERE ARE A 685 00:35:16,960 --> 00:35:19,560 NUMBER OF INDIVIDUALS IN OUR 686 00:35:19,560 --> 00:35:21,320 COHORT THAT WERE YOUNG. 687 00:35:21,320 --> 00:35:25,960 WE HAD A 6-YEAR-OLD WHO 688 00:35:25,960 --> 00:35:27,720 PRESENTED TO THE HOSPITAL FOR A 689 00:35:27,720 --> 00:35:28,960 COMPLICATION OF A SEIZURE 690 00:35:28,960 --> 00:35:32,480 DISORDER UNRELATED TO COVID AND 691 00:35:32,480 --> 00:35:33,800 INCIDENTALLY FOUND TO HAVE COVID 692 00:35:33,800 --> 00:35:35,520 WHERE WE FOUND THE SAME 693 00:35:35,520 --> 00:35:36,520 DISTRIBUTION OF VIRUS ACROSS 694 00:35:36,520 --> 00:35:39,320 THAT INDIVIDUAL'S BODY AND OF 695 00:35:39,320 --> 00:35:42,400 COURSE I MENTIONED THE ONE CASE 696 00:35:42,400 --> 00:35:46,120 THAT WAS IN AN ADULT WHERE THIS 697 00:35:46,120 --> 00:35:48,680 PERSON HAD REPORTED MILD 698 00:35:48,680 --> 00:35:50,400 RESPIRATORY SYMPTOMS AND EIGHT 699 00:35:50,400 --> 00:35:53,840 MONTHS LATER UNRELATED TO COVID, 700 00:35:53,840 --> 00:35:56,040 AS FAR AS WE KNOW, DEVELOPED 701 00:35:56,040 --> 00:36:02,560 HEPATITIS A IN FUNCTION THROUGH 702 00:36:02,560 --> 00:36:04,680 FOODBORNE ILLNESS AND DIED OF A 703 00:36:04,680 --> 00:36:07,520 COMPLICATION 230 DAYS AFTER 704 00:36:07,520 --> 00:36:10,160 THEIR INITIAL ILLNESS WE 705 00:36:10,160 --> 00:36:11,360 OBVIOUSLY FOUND PERSISTENCE OF 706 00:36:11,360 --> 00:36:14,960 RNA IN MANY COMPARTMENTS. 707 00:36:14,960 --> 00:36:18,040 THE SHORT ANSWER IS WE'RE 708 00:36:18,040 --> 00:36:19,120 CAREFUL ABOUT GENERALIZING OUR 709 00:36:19,120 --> 00:36:19,760 OBSERVATION TO A DIFFERENT 710 00:36:19,760 --> 00:36:23,080 POPULATION AND DO THINK THE 711 00:36:23,080 --> 00:36:31,080 STUDIES NEED TO BE DONE. 712 00:36:31,080 --> 00:36:34,800 >> HE'S ASKING WHETHER THE 713 00:36:34,800 --> 00:36:37,560 HISTO PATH ARE MINIMAL OR LOWER 714 00:36:37,560 --> 00:36:40,440 IN THE LATE CASES WHAT'S THE 715 00:36:40,440 --> 00:36:43,120 CAUSE OF DEATH IN THE LATE 716 00:36:43,120 --> 00:36:44,760 CASES. 717 00:36:44,760 --> 00:36:49,880 >> IN THE SHORT ANSWER IS WE 718 00:36:49,880 --> 00:36:54,480 HAVE A TABLE THAT SUMMARIZES 719 00:36:54,480 --> 00:36:55,600 INDIVIDUAL-LEVEL PATIENT DATA 720 00:36:55,600 --> 00:36:57,600 THAT WILL SPECIFICALLY OUTLINE 721 00:36:57,600 --> 00:37:03,080 THE CAUSE OF DEATH FOR EACH 722 00:37:03,080 --> 00:37:08,200 PATIENT BUT IN GENERAL THOSE ARE 723 00:37:08,200 --> 00:37:11,080 OLDER AND HAD MORE COMORBIDITIES 724 00:37:11,080 --> 00:37:14,160 MORE OFTEN THAN NOT WERE 725 00:37:14,160 --> 00:37:15,520 ADMITTED TO THE HOSPITAL, REMAIN 726 00:37:15,520 --> 00:37:18,000 IN THE HOSPITAL FOR AN EXTENDED 727 00:37:18,000 --> 00:37:20,560 PERIOD OF TIME WITH PROVIDED 728 00:37:20,560 --> 00:37:23,120 LIFE SUPPORT AND DIED DUE TO 729 00:37:23,120 --> 00:37:24,760 COVID COMPLICATIONS TYPICALLY 730 00:37:24,760 --> 00:37:25,400 RESPIRATORY FAILURE. 731 00:37:25,400 --> 00:37:30,920 IN THAT GROUP WE OBVIOUSLY HAVE 732 00:37:30,920 --> 00:37:32,560 A NICE TIME LINE OF WHEN 733 00:37:32,560 --> 00:37:33,840 SYMPTOMS STARTED AND WERE 734 00:37:33,840 --> 00:37:34,840 OBSERVED IN THE HOSPITAL FOR AN 735 00:37:34,840 --> 00:37:35,920 EXTENDED PERIOD OF TIME AND HAVE 736 00:37:35,920 --> 00:37:36,960 AN INTERVAL AT THE TIME OF 737 00:37:36,960 --> 00:37:43,480 DEATH. 738 00:37:43,480 --> 00:37:44,920 AS A MENTIONED, AN INTERESTING 739 00:37:44,920 --> 00:37:47,040 FINDING WE'RE FOCUSSED ON AND 740 00:37:47,040 --> 00:37:49,000 NEEDS TO BE FOCUSSED ON IS WHY 741 00:37:49,000 --> 00:37:53,120 IS IT THAT THE VIRUS GETS TO 742 00:37:53,120 --> 00:37:57,760 REMAIN IN PLAIN SIGHT IN ALL 743 00:37:57,760 --> 00:38:04,880 THESE EXTRA PULMONARY SITES WITH 744 00:38:04,880 --> 00:38:06,080 INJURY AND/OR INFLAMMATION. 745 00:38:06,080 --> 00:38:10,960 HOW IS IT THE VIRUS LEADS THE 746 00:38:10,960 --> 00:38:14,680 IMMUNE RESPONSE IN THE EXTRA 747 00:38:14,680 --> 00:38:17,080 RESPIRATORY SITES. 748 00:38:17,080 --> 00:38:18,800 >> QUICK QUESTION FROM ME BEFORE 749 00:38:18,800 --> 00:38:20,560 I GET TO THE NEXT ONE. 750 00:38:20,560 --> 00:38:28,960 THE PATIENTS WHERE YOU SAW BRAIN 751 00:38:28,960 --> 00:38:29,680 INFILTRATION, WHERE FOR INSTANCE 752 00:38:29,680 --> 00:38:32,560 THE CELLS WERE STAINING IT 753 00:38:32,560 --> 00:38:35,720 WASN'T CLEAR TO ME, WAS A 754 00:38:35,720 --> 00:38:36,800 STRUCTURAL STAINING OF THE 755 00:38:36,800 --> 00:38:39,040 PROTEIN OF THE VIRUS OR 756 00:38:39,040 --> 00:38:39,840 INDICATING LOW LEVEL REPLICATION 757 00:38:39,840 --> 00:38:41,400 OF THE CELLS? 758 00:38:41,400 --> 00:38:45,280 >> SO THE TARGET FOR OUR 759 00:38:45,280 --> 00:38:51,080 IMMUNOHISTIC CHEMISTRY WAS NUKE 760 00:38:51,080 --> 00:39:01,800 LEO CAP -- NUKE L-- NUCLEOCAPSI 761 00:39:04,240 --> 00:39:05,680 AND WE APPROACHED THE BRAIN 762 00:39:05,680 --> 00:39:07,880 BECAUSE THERE'S MAJOR 763 00:39:07,880 --> 00:39:09,520 IMPLICATIONS ABOUT FINDING VIRUS 764 00:39:09,520 --> 00:39:11,920 IN MULTIPLE REGIONS OF BRAIN AND 765 00:39:11,920 --> 00:39:13,240 SPECIFIC CELL TYPES. 766 00:39:13,240 --> 00:39:15,600 SO WE'RE QUITE CAUTIOUS ABOUT 767 00:39:15,600 --> 00:39:18,600 THOSE OBSERVES AND HAVE TAKEN A 768 00:39:18,600 --> 00:39:23,080 NUMBER OF ASSAYS TO SUPPORT OR 769 00:39:23,080 --> 00:39:27,440 CONFIRM CELL TYPE SPECIFICITY. 770 00:39:27,440 --> 00:39:30,560 AS FAR AS REPLICATION IN THE 771 00:39:30,560 --> 00:39:36,480 BRAIN WE HAVE RIGHT NOW INDIRECT 772 00:39:36,480 --> 00:39:38,680 AND PURSUING DIRECT EVIDENCE OF 773 00:39:38,680 --> 00:39:40,400 REPLICATION COMPETENT VIRUS IN 774 00:39:40,400 --> 00:39:41,280 THE BRAIN. 775 00:39:41,280 --> 00:39:44,000 THE INDIRECT EVIDENCE IS THAT 776 00:39:44,000 --> 00:39:50,960 THE SEQUENCING RESULTS I SHOWED 777 00:39:50,960 --> 00:39:54,440 YOU, SHOW EVIDENCE IN THE BRAIN. 778 00:39:54,440 --> 00:39:56,080 THEY'RE NEARING EQUAL 779 00:39:56,080 --> 00:39:57,920 DISTRIBUTION OF VARIANCE WITH 780 00:39:57,920 --> 00:39:59,640 NON-SYNONYMOUS MUTATIONS WE 781 00:39:59,640 --> 00:40:02,400 DETECTED IN THE BRAIN THAT WE 782 00:40:02,400 --> 00:40:04,760 DID NOT DETECT IN THE 783 00:40:04,760 --> 00:40:06,600 RESPIRATORY TISSUE SUGGESTING 784 00:40:06,600 --> 00:40:07,800 THAT ONGOING VIRAL REPLICATION 785 00:40:07,800 --> 00:40:09,360 DOES TAKE PLACE IN THE BRAIN AND 786 00:40:09,360 --> 00:40:11,120 THEY'RE ACTUALLY IS SOME 787 00:40:11,120 --> 00:40:14,040 EVOLUTION OF THE VIRUS IN THE 788 00:40:14,040 --> 00:40:14,560 BRAIN. 789 00:40:14,560 --> 00:40:16,840 WE HAVE TRIED TO GROW THE VIRUS 790 00:40:16,840 --> 00:40:19,040 FROM THE BRAIN BUT WE'RE NOT 791 00:40:19,040 --> 00:40:19,240 DONE. 792 00:40:19,240 --> 00:40:24,360 WE'RE GOING TO PERSIST. 793 00:40:24,360 --> 00:40:26,560 SO FAR WE HAVE NOT DEFINITIVELY 794 00:40:26,560 --> 00:40:27,280 ACCOMPLISHED THAT BUT SOMETHING 795 00:40:27,280 --> 00:40:29,720 WE CONTINUE TO PURSUE. 796 00:40:29,720 --> 00:40:32,440 >> AND YOUR ANSWER IS RELATED TO 797 00:40:32,440 --> 00:40:35,160 TWO QUESTIONS SO LET ME ASK. 798 00:40:35,160 --> 00:40:38,240 ONE IS FROM ROLAND OWENS, DOES 799 00:40:38,240 --> 00:40:39,800 YOUR VIRUS DISTRIBUTION STUDY 800 00:40:39,800 --> 00:40:42,400 SUGGEST ANY NOVEL RECEPTORS FOR 801 00:40:42,400 --> 00:40:44,000 INSTANCE IN THE BRAIN WHAT'S THE 802 00:40:44,000 --> 00:40:47,800 DISTRIBUTION OF THE CLASSICAL 803 00:40:47,800 --> 00:40:50,120 RECEPTORS SERVICE WHAT MIGHT BE 804 00:40:50,120 --> 00:40:51,600 NOVEL AND SECOND QUESTION IS 805 00:40:51,600 --> 00:40:54,240 FROM CAROLYN OBARU, THANK YOU 806 00:40:54,240 --> 00:40:56,560 FOR THE SEMINAR, CAN YOU PLEASE 807 00:40:56,560 --> 00:41:00,920 BRIEFLY ELABORATE ON THE GENETIC 808 00:41:00,920 --> 00:41:02,560 COMPARTMENTALIZATION YOU SEE IN 809 00:41:02,560 --> 00:41:03,920 THE INFECTED BRAIN TISSUES. 810 00:41:03,920 --> 00:41:05,680 WHAT DOES THAT MEAN? 811 00:41:05,680 --> 00:41:08,000 YOU ALLUDED TO THAT SO MAYBE YOU 812 00:41:08,000 --> 00:41:08,320 CAN REITERATE. 813 00:41:08,320 --> 00:41:11,400 >> THAT'S PERFECT. 814 00:41:11,400 --> 00:41:15,800 DR. OWENS, THANK YOU FOR YOUR 815 00:41:15,800 --> 00:41:19,120 QUESTION AND ALSO FOR THE SECOND 816 00:41:19,120 --> 00:41:24,520 QUESTION AS WELL. 817 00:41:24,520 --> 00:41:29,160 SPECIFICALLY, WE DID NOT OR HAVE 818 00:41:29,160 --> 00:41:31,840 NOT YET QUERY THE ASSOCIATION 819 00:41:31,840 --> 00:41:35,120 WITH THE KNOWN SARS COV2 820 00:41:35,120 --> 00:41:38,480 RECEPTORS AND CO-RECEPTORS IN 821 00:41:38,480 --> 00:41:43,160 TISSUES AND CO-LOCALIZATION OR 822 00:41:43,160 --> 00:41:45,320 PRESENCE OF VIRUS. 823 00:41:45,320 --> 00:41:48,000 THAT WAS BY OUR ASSAYS. 824 00:41:48,000 --> 00:41:53,080 LARGELY BECAUSE OTHERS HAVE 825 00:41:53,080 --> 00:41:57,960 FOCUSSED ON THE PROTEOME MAP OF 826 00:41:57,960 --> 00:41:59,480 THE HUMAN BODY OR PRESENCE OR 827 00:41:59,480 --> 00:42:02,560 ABSENCE OF THESE RECEPTORS IN 828 00:42:02,560 --> 00:42:04,320 DIFFERENT TISSUES AND SO WE 829 00:42:04,320 --> 00:42:05,200 DIDN'T PURSUE THAT. 830 00:42:05,200 --> 00:42:10,160 OBVIOUSLY, THAT IS SOMETHING 831 00:42:10,160 --> 00:42:14,560 THAT WE COULD PURSUE WE CANNOT 832 00:42:14,560 --> 00:42:16,720 DIRECTLY ANSWER THAT QUESTION 833 00:42:16,720 --> 00:42:20,560 BUT THERE ARE CELL TYPES THAT 834 00:42:20,560 --> 00:42:26,440 ARE NOT KNOWN TO HAVE ACE 2 835 00:42:26,440 --> 00:42:33,600 RECEPTORS, MONOSIGHTSS -- 836 00:42:33,600 --> 00:42:36,160 MONOCYTES HAVE PRESENT AND IT'S 837 00:42:36,160 --> 00:42:39,560 BEEN PUBLISHED IN NATURE THERE'S 838 00:42:39,560 --> 00:42:41,880 EVIDENCE THOSE CELLS ARE EITHER 839 00:42:41,880 --> 00:42:51,240 INFECTED OR PERHAPS TAKE UP 840 00:42:51,240 --> 00:42:52,960 OPSENIZED VIRUS FOR THE ORIGINAL 841 00:42:52,960 --> 00:42:55,600 SARS COV2 RECEPTORS AND THAT'S 842 00:42:55,600 --> 00:42:56,680 WORK WE CAN PURSUE AND 843 00:42:56,680 --> 00:42:58,560 ADDITIONAL WORK THAT LIKELY 844 00:42:58,560 --> 00:43:02,280 NEEDS TO BE ACCOMPLISHED. 845 00:43:02,280 --> 00:43:04,400 AS FAR AS THE 846 00:43:04,400 --> 00:43:07,080 COMPARTMENTALIZATION OF THE 847 00:43:07,080 --> 00:43:17,600 VIRUS, I SHOWED SIX CASES IN 848 00:43:27,040 --> 00:43:31,440 THOSE TWO CASES, THE IMPORTANT 849 00:43:31,440 --> 00:43:33,800 OBSERVATION AND THIS IS 850 00:43:33,800 --> 00:43:35,440 SOMETHING THAT NEEDS TO BE 851 00:43:35,440 --> 00:43:36,720 FOLLOWED UP WITH LARGER COHORTS 852 00:43:36,720 --> 00:43:40,640 AND COHORTS THAT EMULATE OUR 853 00:43:40,640 --> 00:43:43,080 STUDY DESIGN THAT OPTIMIZE 854 00:43:43,080 --> 00:43:49,120 TISSUE PRESERVATION AND SHORT 855 00:43:49,120 --> 00:43:51,800 POST MORTEM OBSERVATIONS WE HAD 856 00:43:51,800 --> 00:43:55,600 BUT THE OBSERVATION IS THERE 857 00:43:55,600 --> 00:43:58,160 WERE VIRAL VARIANTS IN THE 858 00:43:58,160 --> 00:43:58,400 BRAIN. 859 00:43:58,400 --> 00:43:59,360 POPULATIONS OF VIRAL VARIANTS IN 860 00:43:59,360 --> 00:44:02,560 THE BRAIN NOT DETECTED IN THE 861 00:44:02,560 --> 00:44:03,960 RESPIRATORY TRACT SUGGESTING 862 00:44:03,960 --> 00:44:06,600 THAT THERE'S SEEDING OF VIRUS IN 863 00:44:06,600 --> 00:44:10,880 THE BRAIN, THERE'S ONGOING 864 00:44:10,880 --> 00:44:14,560 REPLICATION IN THE BRAIN AND AS 865 00:44:14,560 --> 00:44:16,320 IT REPLICATES THERE'S A VARYING 866 00:44:16,320 --> 00:44:17,360 POPULATIONS PRODUCED AND THROUGH 867 00:44:17,360 --> 00:44:19,680 THE VERY SENSITIVE SEQUENCING 868 00:44:19,680 --> 00:44:23,080 TECHNIQUE OUT OF THE LAB WE'RE 869 00:44:23,080 --> 00:44:26,520 ABLE TO DETECT VARIANTS IN THE 870 00:44:26,520 --> 00:44:29,120 BRAIN SUGGESTING THAT THERE IS 871 00:44:29,120 --> 00:44:30,440 REPLICATION THERE AND PERHAPS 872 00:44:30,440 --> 00:44:32,720 THERE'S A PARTICULAR IMMUNE 873 00:44:32,720 --> 00:44:35,160 ENVIRONMENT THERE AND THIS IS 874 00:44:35,160 --> 00:44:36,280 SPECULATIVE. 875 00:44:36,280 --> 00:44:39,120 OBVIOUSLY, IT'S AN IMMUNE 876 00:44:39,120 --> 00:44:42,760 PROTECT SITE THAT WILL ALLOW FOR 877 00:44:42,760 --> 00:44:43,640 VIRAL REPLICATION AND EVOLUTION 878 00:44:43,640 --> 00:44:44,000 OF THE VIRUS. 879 00:44:44,000 --> 00:44:46,080 >> RELATED TO THAT AGAIN THERE'S 880 00:44:46,080 --> 00:44:47,200 A LOT OF QUESTIONS ABOUT THE 881 00:44:47,200 --> 00:44:57,360 BRAIN ACTUALLY. 882 00:44:57,360 --> 00:45:00,240 WERE YOU ABLE TO QUANTIFY IN THE 883 00:45:00,240 --> 00:45:00,440 CSF? 884 00:45:00,440 --> 00:45:02,120 >> THE SHORT ANSWER IS I DON'T 885 00:45:02,120 --> 00:45:04,520 KNOW I NEED TO PHONE A FRIEND 886 00:45:04,520 --> 00:45:06,360 FROM DR. STEIN. 887 00:45:06,360 --> 00:45:09,240 I KNOW AS TO WHETHER OR NOT WE 888 00:45:09,240 --> 00:45:13,520 COLLECTED CSF. 889 00:45:13,520 --> 00:45:15,280 IF WE COLLECTED CSF IT WAS ON A 890 00:45:15,280 --> 00:45:16,160 LIMITED NUMBER OF INDIVIDUALS 891 00:45:16,160 --> 00:45:20,560 AND WHETHER OR NOT WE DETECTED 892 00:45:20,560 --> 00:45:23,480 RNA OR SUB GENOMIC RNA I CANNOT 893 00:45:23,480 --> 00:45:24,240 RECALL. 894 00:45:24,240 --> 00:45:26,160 I'D HAVE TO PHONE A FRIEND AND 895 00:45:26,160 --> 00:45:29,120 CHECK THE PRE PRINT. 896 00:45:29,120 --> 00:45:34,560 I DO KNOW WE DIDN'T PURSUE 897 00:45:34,560 --> 00:45:36,040 VACCINATION OF ANTIBODY 898 00:45:36,040 --> 00:45:37,560 RESPONSES OR FOR EXAMPLE SOLUBLE 899 00:45:37,560 --> 00:45:39,320 MEDIATOR RESPONSES OR OTHERWISE 900 00:45:39,320 --> 00:45:40,560 IN CSF. 901 00:45:40,560 --> 00:45:44,320 I'D HAVE TO GO BACK TO REVIEW 902 00:45:44,320 --> 00:45:46,000 THE INVENTORY TO DETERMINE WHAT 903 00:45:46,000 --> 00:45:46,920 EXISTS THAT MIGHT BE 904 00:45:46,920 --> 00:45:47,520 ACCOMPLISHED WITH THAT SAMPLE 905 00:45:47,520 --> 00:45:53,080 TYPE. 906 00:45:53,080 --> 00:45:56,240 >> HAVE YOU SEEN THE PRESENCE OF 907 00:45:56,240 --> 00:46:02,560 VIRAL PARTICLES IN EYE TISSUES? 908 00:46:02,560 --> 00:46:06,720 THANK YOU FOR THE QUESTION. 909 00:46:06,720 --> 00:46:08,960 WE DID QUERY EYE TISSUE AND 910 00:46:08,960 --> 00:46:11,800 FOUND PRESENCE OF RNA IN EYE 911 00:46:11,800 --> 00:46:14,560 TISSUE SUMMARIZED AND 912 00:46:14,560 --> 00:46:17,400 CATEGORIZED IN THE PRE PRINT. 913 00:46:17,400 --> 00:46:22,480 WHAT'S NOT IN THE PRE PRINT ARE 914 00:46:22,480 --> 00:46:27,560 CONFIRM TRY IMMUNO ISH CELL 915 00:46:27,560 --> 00:46:29,200 TYPES IN THE EYES AND THAT MAY 916 00:46:29,200 --> 00:46:31,320 OR MAY NOT BE FORTHCOMING IN A 917 00:46:31,320 --> 00:46:38,280 SEPARATE BODY OF WORK. 918 00:46:38,280 --> 00:46:43,120 >> THIS IS A QUESTION IS THERE 919 00:46:43,120 --> 00:46:46,640 ANY INDICATION -- THIS IS VERY 920 00:46:46,640 --> 00:46:47,440 SPECULATIVE RESIDUAL COV2 IN THE 921 00:46:47,440 --> 00:46:50,560 BRAIN OR OTHER TISSUES CAN 922 00:46:50,560 --> 00:46:52,680 BECOME RE-ACTIVATED TO PRODUCE A 923 00:46:52,680 --> 00:46:53,440 DISEASE CONDITION IN THE FUTURE. 924 00:46:53,440 --> 00:46:55,360 IT'S EARLY TO SAY, RIGHT? 925 00:46:55,360 --> 00:47:00,040 WE'RE AT THE BEGINNING OF THIS. 926 00:47:00,040 --> 00:47:02,000 >> YOU'RE CORRECT, YOU'RE ANSWER 927 00:47:02,000 --> 00:47:03,040 IS THE CORRECT ANSWER. 928 00:47:03,040 --> 00:47:04,400 WE CAN'T ANSWER THAT BASED ON 929 00:47:04,400 --> 00:47:05,680 THE STUDY WE DID. 930 00:47:05,680 --> 00:47:08,320 IT WASN'T DESIGNED AS SUCH BUT 931 00:47:08,320 --> 00:47:11,880 FOR CERTAIN THOSE ARE THE TYPES 932 00:47:11,880 --> 00:47:14,160 OF QUESTIONS THAT NEED TO BE 933 00:47:14,160 --> 00:47:18,840 PURSUED IN THE FUTURE AND 934 00:47:18,840 --> 00:47:20,360 OBVIOUSLY THERE ARE CONCERNS OR 935 00:47:20,360 --> 00:47:24,160 QUESTIONS ABOUT, WELL, WHAT IS 936 00:47:24,160 --> 00:47:26,600 THE RELATIONSHIP BETWEEN POST 937 00:47:26,600 --> 00:47:32,440 ACUTE SEQUELAE AND OUR 938 00:47:32,440 --> 00:47:35,160 OBSERVATION OF mRNA IN ANATOMIC 939 00:47:35,160 --> 00:47:36,560 SITES AND ACKNOWLEDGING THE 940 00:47:36,560 --> 00:47:41,120 LIMITATION OF OUR STUDY, WE 941 00:47:41,120 --> 00:47:43,080 DIDN'T QUERY THE PAST 942 00:47:43,080 --> 00:47:45,680 POPULATION. 943 00:47:45,680 --> 00:47:48,720 WE'RE CURRENCY ABOUT MAKING 944 00:47:48,720 --> 00:47:52,720 ABOUT OVER STATEMENTS HOW OUR 945 00:47:52,720 --> 00:47:55,960 FINDINGS RELATES TO PAST BUT IN 946 00:47:55,960 --> 00:47:57,840 THE PATIENT POPULATION THERE 947 00:47:57,840 --> 00:47:59,320 SHOULD BE STUDIES DESIGNED TO 948 00:47:59,320 --> 00:48:01,440 SPECIFICALLY EVALUATE WHETHER OR 949 00:48:01,440 --> 00:48:05,480 NOT THERE IS PERSISTENCE OF mRNA 950 00:48:05,480 --> 00:48:07,320 IN DIFFERENT ANATOMIC SITES AND 951 00:48:07,320 --> 00:48:11,920 TO WHAT DEGREE THAT PERSISTENCE 952 00:48:11,920 --> 00:48:14,360 IS ASSOCIATED WITH THE CLINICAL 953 00:48:14,360 --> 00:48:18,000 MANIFESTATIONS OF PSAC. 954 00:48:18,000 --> 00:48:19,640 -- PASC. 955 00:48:19,640 --> 00:48:25,720 >> HOW LIKELY IS IT OTHER 956 00:48:25,720 --> 00:48:26,920 RESPIRATORY VIRUSES LIKE COMMON 957 00:48:26,920 --> 00:48:29,160 COLD HAVE WIDESPREAD TROPISM AND 958 00:48:29,160 --> 00:48:32,320 PERSISTENCE IN NON-RESPIRATORY 959 00:48:32,320 --> 00:48:34,800 TISSUES OR HAS IT GONE 960 00:48:34,800 --> 00:48:36,000 UNDETECTED BUT THERE? 961 00:48:36,000 --> 00:48:41,440 >> THAT'S A GREAT QUESTION AND 962 00:48:41,440 --> 00:48:45,120 ONE WE HAVE HAD ENJOYABLE 963 00:48:45,120 --> 00:48:46,040 CONVERSATIONS AND DEBATES AROUND 964 00:48:46,040 --> 00:48:50,560 AND THE IMPLICATIONS ARE SHOULD 965 00:48:50,560 --> 00:48:53,440 WE EXTEND THE APPROACH TO FILL 966 00:48:53,440 --> 00:48:57,000 IN THE BLANK X, Y AND Z 967 00:48:57,000 --> 00:48:59,120 RESPIRATORY OR OTHER VIRAL 968 00:48:59,120 --> 00:49:01,840 ILLNESSES THAT ARE ASSOCIATED 969 00:49:01,840 --> 00:49:03,800 WITH HUMAN SEVERE ILLNESS. 970 00:49:03,800 --> 00:49:07,080 WHAT I'LL SAY IS THIS, THAT PART 971 00:49:07,080 --> 00:49:11,440 OF OUR APPROACH FOR COV2 WAS 972 00:49:11,440 --> 00:49:14,560 INFORMED BY THE HISTORIC 973 00:49:14,560 --> 00:49:20,400 LITERATURE OF THE RECEPTOR MERS 974 00:49:20,400 --> 00:49:22,400 DIFFERENT DIFFERENT RECEPTOR AND 975 00:49:22,400 --> 00:49:24,040 SMALLER BODY OF LITERATURE BUT A 976 00:49:24,040 --> 00:49:26,280 LITERATURE THAT FAIRLY DEFINES 977 00:49:26,280 --> 00:49:28,800 THE CORONAVIRUSES AT LEAST THE 978 00:49:28,800 --> 00:49:31,120 SEVERE HUMAN CORONAVIRUSES MAKE 979 00:49:31,120 --> 00:49:33,280 THEIR WAY OUTSIDE THEIR 980 00:49:33,280 --> 00:49:35,040 RESPIRATORY TRACT AND INFECT 981 00:49:35,040 --> 00:49:35,680 TISSUES ELSEWHERE. 982 00:49:35,680 --> 00:49:38,440 BASED ON THAT LITERATURE AND OUR 983 00:49:38,440 --> 00:49:40,120 UNDERSTANDING, WE PURSUED THIS 984 00:49:40,120 --> 00:49:41,480 QUOTE, UNQUOTE, AGGRESSIVE 985 00:49:41,480 --> 00:49:42,720 APPROACH TO BETTER UNDERSTAND 986 00:49:42,720 --> 00:49:43,080 COV2. 987 00:49:43,080 --> 00:49:50,480 IF YOU LOOK AT THE LITERATURE 988 00:49:50,480 --> 00:49:52,320 FOR EXAMPLE, INFLUENZA, I DON'T 989 00:49:52,320 --> 00:49:53,920 THINK PEOPLE HAVE TAKEN THE 990 00:49:53,920 --> 00:49:55,320 APPROACH WE HAVE TO LOOK AT 991 00:49:55,320 --> 00:49:59,040 DISTRIBUTION ACROSS THE BODY AND 992 00:49:59,040 --> 00:50:01,040 BRAIN BUT HAVING SAID THAT, 993 00:50:01,040 --> 00:50:01,720 PEOPLE HAVE BEEN STUDYING 994 00:50:01,720 --> 00:50:04,520 INFLUENZA FOR A LONG TIME AND 995 00:50:04,520 --> 00:50:05,960 HAVE DONE A LOT OF CAREFUL 996 00:50:05,960 --> 00:50:08,560 STUDIES AND THOSE STUDIES DO 997 00:50:08,560 --> 00:50:11,080 SUGGEST THE PREVAILING KNOWLEDGE 998 00:50:11,080 --> 00:50:18,040 AND DOGMA IS THE VIRUSES ABSENT 999 00:50:18,040 --> 00:50:19,080 THE HIGH PATH INFLUENZA VIRUSES 1000 00:50:19,080 --> 00:50:23,080 WITH A CLEAVAGE SITE THAT ALLOW 1001 00:50:23,080 --> 00:50:26,160 THEM TO GET OUTSIDE THE 1002 00:50:26,160 --> 00:50:36,720 RESPIRATORY TRACT DON'T DO THIS 1003 00:50:40,600 --> 00:50:43,120 AND WE'RE DISCUSSING THOSE AMONG 1004 00:50:43,120 --> 00:50:44,520 OURSELVES. 1005 00:50:44,520 --> 00:50:49,000 >> AND THERE'S NONE OF THE 1006 00:50:49,000 --> 00:50:51,080 ANECDOTAL CLINICAL NEUROLOGICAL 1007 00:50:51,080 --> 00:50:55,080 EVIDENCE PEOPLE SAY THEY HAVE 1008 00:50:55,080 --> 00:50:57,520 WITH EVEN HAVING EXPERIENCE 1009 00:50:57,520 --> 00:50:59,080 COVID PERSONALLY THE BRAIN FOG, 1010 00:50:59,080 --> 00:51:02,280 THE VERTIGO, THESE THINGS 1011 00:51:02,280 --> 00:51:07,680 PERSISTED FOR MONTHS AFTER I 1012 00:51:07,680 --> 00:51:11,760 TESTED NEGATIVE FOR THE VIRUS 1013 00:51:11,760 --> 00:51:15,120 AND THIS YOU DON'T HEAR FROM THE 1014 00:51:15,120 --> 00:51:19,080 FLU OR COMMON COLD. 1015 00:51:19,080 --> 00:51:22,000 >> IT'S REALLY TOUGH. 1016 00:51:22,000 --> 00:51:22,840 SUPER TOUGH. 1017 00:51:22,840 --> 00:51:24,080 THERE'S LITERATURE OUT THERE IN 1018 00:51:24,080 --> 00:51:27,120 THE NON-RESPIRATORY 1019 00:51:27,120 --> 00:51:29,360 COMPLICATIONS OF FLU BUT MOST OF 1020 00:51:29,360 --> 00:51:35,680 THEM APPEAR TO BE NOT DUE TO 1021 00:51:35,680 --> 00:51:40,240 ORGANS BUT INDIRECT EFFECTS BUT 1022 00:51:40,240 --> 00:51:45,320 THE PASC IS A MAJOR ISSUE AND 1023 00:51:45,320 --> 00:51:46,360 NOW THERE'S STRONG DATA 1024 00:51:46,360 --> 00:51:47,600 SUPPORTING THAT THIS IS NOT JUST 1025 00:51:47,600 --> 00:51:52,120 A BIG CONSTELLATION OF THINGS. 1026 00:51:52,120 --> 00:51:55,000 IT IS RELATED TO PRIOR INFECTION 1027 00:51:55,000 --> 00:51:59,080 AND SO BEGINNING TO UNRAVEL THE 1028 00:51:59,080 --> 00:52:02,280 PATHOGENESIS OF THAT I THINK IS 1029 00:52:02,280 --> 00:52:03,640 AND OBVIOUSLY THE NIH I THINK 1030 00:52:03,640 --> 00:52:05,400 HAS DEVOTED OVER A BILLION 1031 00:52:05,400 --> 00:52:06,280 DOLLARS IN RESEARCH FUNDING TO 1032 00:52:06,280 --> 00:52:08,080 THAT PARTICULAR QUESTION. 1033 00:52:08,080 --> 00:52:11,160 >> AND CAN YOU COMMENT ON THE 1034 00:52:11,160 --> 00:52:13,280 RECENT STUDY IN NATURE WHERE 1035 00:52:13,280 --> 00:52:16,840 THEY FOLLOWED PATIENTS WITH F 1036 00:52:16,840 --> 00:52:18,520 MRI AND HAVE SEEN SHRINKAGE OF 1037 00:52:18,520 --> 00:52:19,120 GRAY MATTER? 1038 00:52:19,120 --> 00:52:22,760 >> I LOVE THAT STUDY. 1039 00:52:22,760 --> 00:52:27,400 THAT STUDY'S FASCINATING. 1040 00:52:27,400 --> 00:52:30,160 STRONGLY SUGGESTIVE, RIGHT? 1041 00:52:30,160 --> 00:52:34,000 IT'S REALLY THAT STUDY FROM THE 1042 00:52:34,000 --> 00:52:39,080 U.K. TOOK ADVANTAGE OF THESE 1043 00:52:39,080 --> 00:52:40,640 INDIVIDUALS SYSTEMATICALLY 1044 00:52:40,640 --> 00:52:44,920 FOLLOWED BY MRI PRE-COVID AND 1045 00:52:44,920 --> 00:52:47,680 WERE ABLE TO FOLLOW THE SAME 1046 00:52:47,680 --> 00:52:50,320 PEOPLE POST-INFECTION AND LOOK 1047 00:52:50,320 --> 00:52:53,040 AT FUNCTIONAL REGIONS AND THEY 1048 00:52:53,040 --> 00:52:55,600 FOUND A STRONG SIGNAL THAT 1049 00:52:55,600 --> 00:52:57,520 SOMETHING'S NOT RIGHT. 1050 00:52:57,520 --> 00:53:02,600 AND WHETHER THAT SOMETHING IS 1051 00:53:02,600 --> 00:53:08,840 NOT RIGHT PERSISTENCE OF mRNA 1052 00:53:08,840 --> 00:53:09,640 IN THE BRAIN IS IMPORTANT TO 1053 00:53:09,640 --> 00:53:11,080 FIGURE OUT. 1054 00:53:11,080 --> 00:53:12,240 >> SO IMPORTANT. 1055 00:53:12,240 --> 00:53:14,600 THERE'S A QUESTION ABOUT THE 1056 00:53:14,600 --> 00:53:16,480 SENSITIVITY OF YOUR ASSAYS WHEN 1057 00:53:16,480 --> 00:53:17,600 YOU HARVESTED THE VIRUS. 1058 00:53:17,600 --> 00:53:20,320 COULD IT BE YOUR MISSING OUT ON 1059 00:53:20,320 --> 00:53:26,440 VIRUS LEVELS BECAUSE YOUR 1060 00:53:26,440 --> 00:53:28,640 SENSITIVITY'S NOT THERE IN THE 1061 00:53:28,640 --> 00:53:29,680 EX VIVO ASSAYS? 1062 00:53:29,680 --> 00:53:31,320 >> THE ANSWER IS ABSOLUTELY YES. 1063 00:53:31,320 --> 00:53:34,000 THOUGH IT'S A SIMPLE ANSWER, 1064 00:53:34,000 --> 00:53:36,720 IT'S A HARD MESSAGE TO TRANSLATE 1065 00:53:36,720 --> 00:53:47,080 TO THE AVERAGE LISTENER. 1066 00:53:47,080 --> 00:53:49,480 WE K 1067 00:53:49,480 --> 00:53:52,120 WE KNOW CELL CULTURE THE GOLD 1068 00:53:52,120 --> 00:53:53,960 STANDARD WAY BUT THE WAY TO GET 1069 00:53:53,960 --> 00:53:59,120 AROUND THIS OR TO TRY TO 1070 00:53:59,120 --> 00:54:01,360 INCREASE SENSITIVITY TO FIND 1071 00:54:01,360 --> 00:54:03,120 REPLICATION COMPETENT VIRUS IN 1072 00:54:03,120 --> 00:54:07,800 SAMPLES THAT DIDN'T GROW IN CELL 1073 00:54:07,800 --> 00:54:10,640 CULTURE IS YOU CAN MANIPULATE 1074 00:54:10,640 --> 00:54:13,160 YOUR CELL CULTURE AND PUT IN 1075 00:54:13,160 --> 00:54:14,080 HUMANIZED RECEPTORS AND TAKE IT 1076 00:54:14,080 --> 00:54:18,640 TO A DIFFERENT SYSTEM IN OTHER 1077 00:54:18,640 --> 00:54:23,080 VIRUSES AS YOU ALL KNOW PEOPLE 1078 00:54:23,080 --> 00:54:26,440 HAVE USED IMMUNOCOMPROMISED MICE 1079 00:54:26,440 --> 00:54:29,400 THAT ARE NEONATAL MICE THAT 1080 00:54:29,400 --> 00:54:31,320 PERHAPS ARE PARTICULARLY 1081 00:54:31,320 --> 00:54:31,880 SUSCEPTIBLE. 1082 00:54:31,880 --> 00:54:34,960 THERE'S OTHER WAYS BUT VIRAL 1083 00:54:34,960 --> 00:54:41,520 CULTURE IS AN INSENSITIVE WAY OF 1084 00:54:41,520 --> 00:54:44,520 DETECTING THIS AND IS THERE 1085 00:54:44,520 --> 00:54:45,760 LIKELY THAN MORE OBSERVING 1086 00:54:45,760 --> 00:54:46,960 PROBABLY BUT WE HAVE TO WORK 1087 00:54:46,960 --> 00:54:48,800 WITH WHAT WE HAVE. 1088 00:54:48,800 --> 00:54:51,760 >> THERE'S A QUESTION FROM JOHN 1089 00:54:51,760 --> 00:54:52,800 SINER. 1090 00:54:52,800 --> 00:54:54,440 I WONDER IF YOU LOOK AT WHAT 1091 00:54:54,440 --> 00:54:56,040 PERCENTAGE OF PEOPLE YOU LOOKED 1092 00:54:56,040 --> 00:54:58,840 AT HAD PERSISTENCE IN THE BRAIN. 1093 00:54:58,840 --> 00:55:00,840 JI WAS CAREFUL AND I'LL 1094 00:55:00,840 --> 00:55:02,000 REITERATE TO ACKNOWLEDGE A 1095 00:55:02,000 --> 00:55:04,240 LIMITATION OF OUR STUDY IS THAT 1096 00:55:04,240 --> 00:55:06,320 THIS WAS DONE DURING THE FIRST 1097 00:55:06,320 --> 00:55:10,720 YEAR OF THE PANDEMIC BEFORE 1098 00:55:10,720 --> 00:55:11,960 AVAILABILITY OF VACCINES AND 1099 00:55:11,960 --> 00:55:14,440 NONE OF OUR COHORT WERE 1100 00:55:14,440 --> 00:55:14,760 VACCINATED. 1101 00:55:14,760 --> 00:55:17,000 WE KNOW, AS I KNOW THE PERSON 1102 00:55:17,000 --> 00:55:18,240 WHO ASKED THE QUESTION KNOWS, 1103 00:55:18,240 --> 00:55:21,840 THAT VACCINES ARE REMARKABLE AS 1104 00:55:21,840 --> 00:55:22,480 FAR AS PREVENTING SEVERE DISEASE 1105 00:55:22,480 --> 00:55:26,080 AND DEATH. 1106 00:55:26,080 --> 00:55:32,560 HOW GOOD ARE THEY AT PREVENTING 1107 00:55:32,560 --> 00:55:34,600 VIRAL DISSEMINATION TO EXTRA 1108 00:55:34,600 --> 00:55:35,160 PULMONARY SITES? 1109 00:55:35,160 --> 00:55:36,680 I DON'T KNOW AND WOULD THINK 1110 00:55:36,680 --> 00:55:38,440 THEY'RE PROBABLY PRETTY GOOD BUT 1111 00:55:38,440 --> 00:55:41,080 AGAIN A QUESTION WORTH ASKING. 1112 00:55:41,080 --> 00:55:43,080 WE KNOW THAT FOR EXAMPLE AND 1113 00:55:43,080 --> 00:55:45,560 AGAIN NOT TO CONFOUND ISSUES 1114 00:55:45,560 --> 00:55:47,000 HERE BUT EVEN VACCINATED PEOPLE 1115 00:55:47,000 --> 00:55:48,840 WHO HAVE BREAKTHROUGH INFECTIONS 1116 00:55:48,840 --> 00:55:50,640 THAT GO ON TO EXPERIENCE 1117 00:55:50,640 --> 00:55:57,120 SYMPTOMS OF PASC, MILD ILLNESS 1118 00:55:57,120 --> 00:55:59,080 YOU CAN HAVE IT AND 1119 00:55:59,080 --> 00:56:00,120 POST-BREAKTHROUGH INFECTIONS YOU 1120 00:56:00,120 --> 00:56:01,280 CAN HAVE IT. 1121 00:56:01,280 --> 00:56:04,000 I'M NOT TRYING TO CONFOUND THOSE 1122 00:56:04,000 --> 00:56:04,800 QUESTIONS BUT IDENTIFYING 1123 00:56:04,800 --> 00:56:06,080 QUESTIONS THAT REMAIN TO BE 1124 00:56:06,080 --> 00:56:07,200 ANSWERED AND THAT IS A QUESTION 1125 00:56:07,200 --> 00:56:12,520 THAT REMAINS TO BE ANSWERED. 1126 00:56:12,520 --> 00:56:14,600 >> HOWARD YOUNG IS ASKING IF 1127 00:56:14,600 --> 00:56:16,720 THERE WAS AN INTERFERON 1128 00:56:16,720 --> 00:56:17,760 SIGNATURE IN THE BRAIN? 1129 00:56:17,760 --> 00:56:20,520 >> HOWARD, YOU ASK A VERY GOOD 1130 00:56:20,520 --> 00:56:21,640 QUESTION AND THE ANSWER IS WE 1131 00:56:21,640 --> 00:56:22,880 DON'T KNOW YET. 1132 00:56:22,880 --> 00:56:28,040 THAT'S ON THE LIST OF FUTURE 1133 00:56:28,040 --> 00:56:31,560 WORK AND TO BE SPECIFIC THIS 1134 00:56:31,560 --> 00:56:33,440 FIRST EFFORT WAS REALLY FOCUSSED 1135 00:56:33,440 --> 00:56:37,000 ON THE PATHOGEN, AS YOU NOTICE. 1136 00:56:37,000 --> 00:56:40,120 OUR GROUP AND OUR NUMBER OF 1137 00:56:40,120 --> 00:56:44,600 COLLABORATORS BOTH WITHIN NIAID 1138 00:56:44,600 --> 00:56:47,120 AND MANY OTHER INTRAMURAL 1139 00:56:47,120 --> 00:56:48,160 INSTITUTES ARE BEGINNING TO 1140 00:56:48,160 --> 00:56:51,000 SHIFT OUR FOCUS TO APPLY VARIOUS 1141 00:56:51,000 --> 00:56:53,600 TECHNOLOGIES TO FOCUS ON MORE ON 1142 00:56:53,600 --> 00:56:56,600 THE HOST RESPONSE BEYOND 1143 00:56:56,600 --> 00:56:58,120 HISTOPATHOLOGIC EVIDENCE OR 1144 00:56:58,120 --> 00:56:59,480 EVIDENCE OF INFLAMMATORY CELLS 1145 00:56:59,480 --> 00:57:00,640 IN TISSUES. 1146 00:57:00,640 --> 00:57:04,280 AND ONE OF THOSE STUDIES IS 1147 00:57:04,280 --> 00:57:06,000 DIRECTLY FOCUSSED ON CELLULAR 1148 00:57:06,000 --> 00:57:07,080 RESPONSES IN THE BRAIN USING 1149 00:57:07,080 --> 00:57:08,000 AVAILABLE TISSUE. 1150 00:57:08,000 --> 00:57:12,040 ONE OF THE BENEFITS OF 1151 00:57:12,040 --> 00:57:13,360 COLLECTING FLASH FROZEN 1152 00:57:13,360 --> 00:57:15,120 SPECIMENS THAT ARE IMMEDIATELY 1153 00:57:15,120 --> 00:57:19,120 ADJACENT TO SPECIMENS WHERE 1154 00:57:19,120 --> 00:57:22,360 WE'VE CHARACTERIZED IN GREAT 1155 00:57:22,360 --> 00:57:26,200 DETAIL RNA LEVELS BY DDPCR IS 1156 00:57:26,200 --> 00:57:28,440 THOSE FLASH FROZEN SAMPLES ARE 1157 00:57:28,440 --> 00:57:31,080 AMENABLE TO TECHNOLOGIES LIKE 1158 00:57:31,080 --> 00:57:35,160 SINGLE NUCLIDE SEQ AND 1159 00:57:35,160 --> 00:57:40,120 APPLICATION OF ADDITIONAL 1160 00:57:40,120 --> 00:57:40,760 TECHNOLOGIES WHERE FOR EXAMPLE 1161 00:57:40,760 --> 00:57:43,000 SPATIAL TRANSCRIPTOMICS AND 1162 00:57:43,000 --> 00:57:44,720 THOSE THINGS TO BEGIN TO ANSWER 1163 00:57:44,720 --> 00:57:48,920 THAT TYPE OF QUESTION. 1164 00:57:48,920 --> 00:57:50,120 OTHERS HAVE APPLY THOSE TOOLS IN 1165 00:57:50,120 --> 00:57:51,120 THE BRAIN AND ELSEWHERE. 1166 00:57:51,120 --> 00:57:53,120 WE DO INTEND TO PURSUE THESE 1167 00:57:53,120 --> 00:57:58,560 THINGS IN OUR COHORT. 1168 00:57:58,560 --> 00:57:59,560 >> OKAY, WELL, THANK YOU SO 1169 00:57:59,560 --> 00:58:01,120 MUCH, DAN. 1170 00:58:01,120 --> 00:58:04,560 IT'S BEEN VERY ENLIGHTENING AND 1171 00:58:04,560 --> 00:58:06,000 THIS ENDS TODAY'S SEMINAR. 1172 00:58:06,000 --> 00:00:00,000 THANK YOU.