1
00:00:09,142 --> 00:00:11,277
WELCOME TO THE CLINICAL
CENTER GRAND ROUNDS,

2
00:00:11,344 --> 00:00:15,081
A WEEKLY SERIES OF EDUCATIONAL
LECTURES FOR PHYSICIANS AND

3
00:00:15,148 --> 00:00:17,717
HEALTH CARE PROFESSIONALS
BROADCAST FROM THE CLINICAL

4
00:00:17,784 --> 00:00:20,687
CENTER AT THE NATIONAL
INSTITUTES OF HEALTH IN

5
00:00:20,754 --> 00:00:22,489
BETHESDA, MD.

6
00:00:22,555 --> 00:00:26,025
THE NIH CLINICAL CENTER IS THE
WORLD'S LARGEST HOSPITAL TOTALLY

7
00:00:26,092 --> 00:00:29,729
DEDICATED TO INVESTIGATIONAL
RESEARCH AND LEADS THE GLOBAL

8
00:00:29,796 --> 00:00:32,665
EFFORT IN TRAINING TODAY'S
INVESTIGATORS AND DISCOVERING

9
00:00:32,732 --> 00:00:34,834
TOMORROW'S CURES.

10
00:00:34,901 --> 00:00:43,843
LEARN MORE BY VISITING US ONLINE
AT HTTP://CLINICALCENTER.NIH.GOV

11
00:00:43,910 --> 00:00:47,080
>> GOOD AFTERNOON AND WELCOME TO

12
00:00:47,147 --> 00:00:49,182
TODAY'S CLINICAL CENTER GRAND

13
00:00:49,249 --> 00:00:49,949
ROUNDS.

14
00:00:50,016 --> 00:00:52,752
THE HOPKINS CME ACTIVITY CODE IS

15
00:00:52,819 --> 00:00:53,086
50557.

16
00:00:53,153 --> 00:00:55,021
PLEASE TEXT THIS CODE TO THE

17
00:00:55,088 --> 00:00:56,890
JOHNS HOPKINS CME CODE TO

18
00:00:56,956 --> 00:00:59,259
RECEIVE CREDIT FOR THIS LECTURE,

19
00:00:59,325 --> 00:01:00,660
WE KINDLY ASK THAT YOU PROVIDE

20
00:01:00,727 --> 00:01:02,295
FEEDBACK ON TODAY'S LECTURE BY

21
00:01:02,362 --> 00:01:04,798
SCANNING THE QR CODE SHOWNOT CME

22
00:01:04,864 --> 00:01:05,498
SLIDE.

23
00:01:05,565 --> 00:01:07,033
FOR THOSE APPLYING FOR CME, YOU

24
00:01:07,100 --> 00:01:09,269
WILL RECEIVE A FEEDBACK SURVEY

25
00:01:09,335 --> 00:01:09,869
LINK VIA E-MAIL.

26
00:01:09,936 --> 00:01:12,605
IT WILL BE USED BY US FOR

27
00:01:12,672 --> 00:01:13,940
IMPORTANT FEEDBACK ABOUT THIS

28
00:01:14,007 --> 00:01:16,676
PRESENTATION AND ALLOWS TO YOU

29
00:01:16,743 --> 00:01:18,812
SUBMIT ANY FUTURE SUGGESTIONS

30
00:01:18,878 --> 00:01:21,981
FOR GRAND ROUND TOPICS,

31
00:01:22,048 --> 00:01:23,082
FOLLOWING THE SPEAKER, QUESTIONS

32
00:01:23,149 --> 00:01:26,186
WILL BE TAKEN BY MICROPHONES IN

33
00:01:26,252 --> 00:01:27,854
THE AIFULS ADDITIONALLY, VIEWERS

34
00:01:27,921 --> 00:01:29,823
MAY SCROLL DOWN AND CLICK THE

35
00:01:29,889 --> 00:01:31,591
LIVE FEEDBACK BUTTON LOCATED ON

36
00:01:31,658 --> 00:01:32,792
THE VIDEOCAST WEBSITE.

37
00:01:32,859 --> 00:01:34,561
QUESTIONS WILL BE SORRIED AS

38
00:01:34,627 --> 00:01:36,196
TIME PERMITS AT THE CONCLUSION

39
00:01:36,262 --> 00:01:36,896
OF THE PRESENTATION.

40
00:01:36,963 --> 00:01:40,500
TODAY WE ARE HONOR TO HAVE OUR

41
00:01:40,567 --> 00:01:42,402
SPEAKER DR. DAVID GOLDMAN,

42
00:01:42,469 --> 00:01:43,770
CLINICAL DIRECTOR OF THE

43
00:01:43,837 --> 00:01:45,738
NATIONAL INSTITUTE ON ALCOHOL

44
00:01:45,805 --> 00:01:47,173
ABUSE AND ALCOHOLISM AND CHIEF

45
00:01:47,240 --> 00:01:50,643
OF THE LABORATORY OF

46
00:01:50,710 --> 00:01:51,244
NEUROGENETICS.

47
00:01:51,311 --> 00:01:52,412
DR. GOLDMAN EARNED HIS BACHELOR

48
00:01:52,479 --> 00:01:54,948
OF SCIENCE FROM YALE, MEDICAL

49
00:01:55,014 --> 00:02:00,119
DEGREE FROM THE UNIVERSITY OF

50
00:02:00,186 --> 00:02:05,291
TEXAS GALVESTON BRANCH

51
00:02:05,358 --> 00:02:08,328
GRADUATING SUMMA CUM LAUDE, AND

52
00:02:08,394 --> 00:02:09,662
COMPLETED INTERNSHIPS AT THE

53
00:02:09,729 --> 00:02:10,330
NIH.

54
00:02:10,396 --> 00:02:13,600
A YEAR LATER DR. GOLDMAN JOINED

55
00:02:13,666 --> 00:02:14,934
THE NIH AS A RESEARCH FELLOW AND

56
00:02:15,001 --> 00:02:17,504
HAS BEEN PART OF THE NIH EVER

57
00:02:17,570 --> 00:02:21,307
SINCE, BOTH AT NIAARK, AND NIMH,

58
00:02:21,374 --> 00:02:22,642
AN INSTITUTION WITHIN AN

59
00:02:22,709 --> 00:02:22,942
INSTITUTION.

60
00:02:23,009 --> 00:02:25,144
THANK YOU.

61
00:02:25,211 --> 00:02:27,046
A DISTINGUISHED INVESTIGATOR

62
00:02:27,113 --> 00:02:29,949
DR. GOLDMAN HAS BEEN 1 OF THE

63
00:02:30,016 --> 00:02:32,685
MOST CITED DOCTORS IN GENETICS.

64
00:02:32,752 --> 00:02:35,021
HE IDENTIFIED GENES THAT

65
00:02:35,088 --> 00:02:37,090
INCREASE GENES TO VULNERABILITY

66
00:02:37,156 --> 00:02:39,092
TO ALCOHOLIC DISORDER AND

67
00:02:39,158 --> 00:02:40,393
PSYCHIATRIC DECS INCLUDING IN

68
00:02:40,460 --> 00:02:41,561
FOUNDER POPULATIONS SUCH AS

69
00:02:41,628 --> 00:02:43,429
NATIVE AMERICAN TRIBES AND

70
00:02:43,496 --> 00:02:44,564
FINLAND.

71
00:02:44,631 --> 00:02:46,900
HIS LABORATORY USED THE

72
00:02:46,966 --> 00:02:49,102
COMBINATION OF PHENOTYPE AND

73
00:02:49,168 --> 00:02:51,104
GENETIC METHODS TO IDENTIFY

74
00:02:51,170 --> 00:02:53,673
CAUSAL INFLUENCE VULNERABILITY

75
00:02:53,740 --> 00:02:55,074
TO PSYCHIATRIC DISORDERS.

76
00:02:55,141 --> 00:03:02,916
DR. GOLD MAN HAS AUTHORED OVER

77
00:03:02,982 --> 00:03:05,251
500 PAPERS INCLUDING IMAGING

78
00:03:05,318 --> 00:03:07,820
STUDIES, DR. GOLDMAN AND HIS

79
00:03:07,887 --> 00:03:10,723
GROUP DISCOVERED INHERITED GENE

80
00:03:10,790 --> 00:03:11,858
VARIATIONS THAT INFLUENCE

81
00:03:11,925 --> 00:03:13,059
VULNERABILITY AND TRACER

82
00:03:13,126 --> 00:03:15,161
MUTATIONS THROUGH COMPLEX

83
00:03:15,228 --> 00:03:16,229
BEHAVIORS, BOTH IN HUMAN

84
00:03:16,296 --> 00:03:17,964
RESEARCH STUDIES AND MODEL

85
00:03:18,031 --> 00:03:18,298
ORGANISMS.

86
00:03:18,364 --> 00:03:21,901
AMONG HIS MANY AWARDS,

87
00:03:21,968 --> 00:03:23,536
DR. GOLDMAN HAS BEEN HONORED

88
00:03:23,603 --> 00:03:24,971
WITH HIS MENTORING AWARDS, FOR

89
00:03:25,038 --> 00:03:26,839
THE RESEARCH SOCIETY ON

90
00:03:26,906 --> 00:03:28,441
ALCOHOLISM, THE OUTSTANDING

91
00:03:28,508 --> 00:03:29,509
RESEARCHER JAMES ISAAC SON

92
00:03:29,576 --> 00:03:31,177
RESEARCH AWARD OF THE

93
00:03:31,244 --> 00:03:32,312
INTERNATIONAL SOCIETY FOR

94
00:03:32,378 --> 00:03:33,513
BIOLOGICAL RESEARCH ON

95
00:03:33,580 --> 00:03:35,782
ALCOHOLISM AND MULTIPLE NIH

96
00:03:35,848 --> 00:03:37,083
DIRECTORS AWARDS.

97
00:03:37,150 --> 00:03:38,851
HE HAS SERVED ON EDITORIAL

98
00:03:38,918 --> 00:03:41,287
BOARDS OF MANY LEADING JOURNALS

99
00:03:41,354 --> 00:03:43,289
AND AUTHOR OF SEVERAL BOOKS,

100
00:03:43,356 --> 00:03:45,825
INCLUDING OUR GENES, OUR CHOICES

101
00:03:45,892 --> 00:03:47,894
WHICH WON THE BRITISH MEDICAL

102
00:03:47,961 --> 00:03:49,195
ASSOCIATION TOP PRIZE.

103
00:03:49,262 --> 00:03:50,263
HIS LATEST BOOK IMMORAL IS ABOUT

104
00:03:50,330 --> 00:03:51,431
THE NATURE OF LIFE.

105
00:03:51,497 --> 00:03:54,133
THE TITLE OF HIS TALK TODAY IS

106
00:03:54,200 --> 00:03:56,269
GENETICS AND EPIGENETICS OF

107
00:03:56,336 --> 00:03:56,936
ALCOHOL USE DISORDER.

108
00:03:57,003 --> 00:03:58,938
NOW PLEASE JOIN ME IN WELCOMING

109
00:03:59,005 --> 00:04:08,748
TODAY'S SPEAKER DR. GOLDMAN.

110
00:04:08,815 --> 00:04:09,215
[ APPLAUSE ]

111
00:04:09,282 --> 00:04:09,682
>> THANK YOU.

112
00:04:09,749 --> 00:04:12,919
FIRST I WOULD LIKE TO THANK TOM

113
00:04:12,986 --> 00:04:14,187
BURKLOW FOR THAT GENEROUS

114
00:04:14,253 --> 00:04:15,989
INTRODUCTION AND ALSO RITA

115
00:04:16,055 --> 00:04:18,191
STEPHENS FOR HELPING ORGANIZE

116
00:04:18,257 --> 00:04:20,560
THIS AND TO SAY THAT IT'S GOOD

117
00:04:20,627 --> 00:04:23,429
TO SEE SOME OF YOU WHO I KNOW

118
00:04:23,496 --> 00:04:25,298
WELL IN THE AUDIENCE AND THOSE

119
00:04:25,365 --> 00:04:27,133
WHO HAVE JOINED ONLINE, ALSO,

120
00:04:27,200 --> 00:04:29,302
THANK YOU.

121
00:04:29,369 --> 00:04:31,270
AND SO, THIS TALK TITLE COULD

122
00:04:31,337 --> 00:04:33,139
HAVE BEEN GENOMICS AND

123
00:04:33,206 --> 00:04:35,108
EPIGENERATED NOAMICS OF ALCOHOL

124
00:04:35,174 --> 00:04:36,943
USE DISORDER BECAUSE OF WHERE

125
00:04:37,010 --> 00:04:39,579
THE FIELD HAS REALLY MOVED.

126
00:04:39,646 --> 00:04:43,583
ALCOHOL USE DISORDER IS A GENE

127
00:04:43,650 --> 00:04:45,018
BY ENVIRONMENT INTERACTION

128
00:04:45,084 --> 00:04:46,519
WITHOUT ALCOHOL, THERE'S NO

129
00:04:46,586 --> 00:04:51,024
ALCOHOL USE DISORDER, SO THIS IS

130
00:04:51,090 --> 00:04:53,860
ONLY A SOCIOLOGICAL CULTURAL

131
00:04:53,926 --> 00:04:55,995
CONTEXT OF AUD IS DISCUSSED BUT

132
00:04:56,062 --> 00:04:58,197
THERE ARE ALSO GENE BY

133
00:04:58,264 --> 00:05:00,066
ENVIRONMENT CORRELATIONS BECAUSE

134
00:05:00,133 --> 00:05:02,502
HUMANS UNIQUELY AMONGST SPECIES

135
00:05:02,568 --> 00:05:04,037
HAVE AN ABILITY TO CHOOSE AND

136
00:05:04,103 --> 00:05:05,104
SHAPE THEIR ENVIRONMENT.

137
00:05:05,171 --> 00:05:09,609
AND THESE GENE BY ENVIRONMENT

138
00:05:09,676 --> 00:05:10,677
INTERACT CORRELATIONS INCLUDE

139
00:05:10,743 --> 00:05:12,879
PASSIVE 1S, WE NEED TO CHOOSE

140
00:05:12,945 --> 00:05:14,047
OUR PARENTS WISELY BECAUSE

141
00:05:14,113 --> 00:05:15,314
THEY'RE GOING TO TRANSMIT GENES

142
00:05:15,381 --> 00:05:16,883
TO US AND THEY'RE ALSO GOING TO

143
00:05:16,949 --> 00:05:21,254
SUBJECT US TO BEHAVIORS THAT WE

144
00:05:21,320 --> 00:05:22,522
CAN'T REALLY CONTROL.

145
00:05:22,588 --> 00:05:24,490
EVOCATIVE WHAT WE TRIGGER, AND

146
00:05:24,557 --> 00:05:25,992
THEN ACTIVE, WHAT WE CHOOSE AND

147
00:05:26,059 --> 00:05:28,861
CREATE AND IT'S GOING TO BE

148
00:05:28,928 --> 00:05:29,929
RECOGNIZED THAT ALCOHOL USE

149
00:05:29,996 --> 00:05:33,299
DISORDER AS THE OTHER SUBSTANCE

150
00:05:33,366 --> 00:05:36,536
USE DISORDERS INVOLVES

151
00:05:36,602 --> 00:05:37,937
EVOLUTIONAL COMPONENT.

152
00:05:38,004 --> 00:05:38,538
NEVERTHELESS THE VULNERABILITY

153
00:05:38,604 --> 00:05:42,375
IS SO HIGH IN THE GENERAL

154
00:05:42,442 --> 00:05:45,144
POPULATION THAT 29.1% OF PEOPLE

155
00:05:45,211 --> 00:05:47,947
ON A LIFETIME BASIS HAVE ALCOHOL

156
00:05:48,014 --> 00:05:48,381
USE DISORDER.

157
00:05:48,448 --> 00:05:53,119
SO WE CAN SEE THAT MANY OF US

158
00:05:53,186 --> 00:05:55,421
ARE VULNERABLE.

159
00:05:55,488 --> 00:05:59,859
THIS CAPTURES THE EFFECT OF A

160
00:05:59,926 --> 00:06:01,461
CULTURES COMSUMPTION OF ALCOHOL

161
00:06:01,527 --> 00:06:04,230
ON ALCOHOL USE DISORDER BY

162
00:06:04,297 --> 00:06:05,732
LOOKING AT CIRRHOSIS DEATHS AND

163
00:06:05,798 --> 00:06:12,004
YOU SEE PLOTTED HERE IS PER

164
00:06:12,071 --> 00:06:13,172
CAPITA ALCOHOL COMSUMPTION IN

165
00:06:13,239 --> 00:06:14,674
LITERS PER YEAR, IN THE UNITED

166
00:06:14,741 --> 00:06:17,610
STATES IT'S NOW ABOUT MIDWAY IN

167
00:06:17,677 --> 00:06:18,644
PERCAPITTA COMSUMPTION AND IT'S

168
00:06:18,711 --> 00:06:20,646
ALSO ABOUT MIDWAY IN CIRRHOSIS

169
00:06:20,713 --> 00:06:21,314
DEATHS PER YEAR.

170
00:06:21,380 --> 00:06:26,953
NOW THIS IS EXPANDING DUE TO

171
00:06:27,019 --> 00:06:27,987
METABOLIC ASSOCIATED DATA

172
00:06:28,054 --> 00:06:30,523
HEPATITIS AND OF COURSE THERE

173
00:06:30,590 --> 00:06:32,091
ARE OTHER FACTORS, BUT JUST ON A

174
00:06:32,158 --> 00:06:34,360
CRUDE BASIS, YOU CAN SEE THAT

175
00:06:34,427 --> 00:06:37,930
WHERE YOU LIVE STRONGLY

176
00:06:37,997 --> 00:06:39,398
INFLUENCES, YOUR VULNERABILITY

177
00:06:39,465 --> 00:06:41,167
AND I REALIZED I MANAGED TO HIT

178
00:06:41,234 --> 00:06:44,470
THE WRONG BUTTON ALREADY.

179
00:06:44,537 --> 00:06:47,240
THIS IS THE TEMPORAL VARIATION

180
00:06:47,306 --> 00:06:51,344
IN CIRRHOSIS WITHIN 1 COUNTRY,

181
00:06:51,410 --> 00:06:51,778
THE UNITED STATES.

182
00:06:51,844 --> 00:06:54,981
THE UNITED STATES IS UNIQUE IN

183
00:06:55,047 --> 00:06:55,948
HAVING 2 CONSTITUTIONAL

184
00:06:56,015 --> 00:06:58,317
AMENDMENTS THAT WERE ACTUALLY

185
00:06:58,384 --> 00:07:01,120
DEVOTED TO 1 SUBSTANCE, ALCOHOL

186
00:07:01,187 --> 00:07:06,159
AND THERE WAS A DROP IN

187
00:07:06,225 --> 00:07:08,561
CIRRHOSIS RELATED DEATHS BOTH

188
00:07:08,628 --> 00:07:09,629
SEEN PREPROHIBITION AND THEN

189
00:07:09,695 --> 00:07:11,831
AFTERWARDS AND THEN THE SOLDIERS

190
00:07:11,898 --> 00:07:16,536
RETURNING FROM OVERSEAS AFTER

191
00:07:16,602 --> 00:07:19,405
WORLD WAR II WERE MORE PRONE TO

192
00:07:19,472 --> 00:07:22,375
DRINK HEAVILY AND DEVELOP A. U.

193
00:07:22,441 --> 00:07:22,508
D.

194
00:07:22,575 --> 00:07:24,610
SO DESPITE THIS TOTAL DEPENDENCE

195
00:07:24,677 --> 00:07:25,812
ON EXPOSURE, ALCOHOL USE

196
00:07:25,878 --> 00:07:28,481
DISORDER AND OTHER SUBSTANCE USE

197
00:07:28,548 --> 00:07:30,416
DISORDERS ARE HERITABLE.

198
00:07:30,483 --> 00:07:33,319
HERE YOU SEE THAT A. U. D. IS

199
00:07:33,386 --> 00:07:34,720
ABOUT MIDWAY INHERITABILITY AND

200
00:07:34,787 --> 00:07:39,058
THE HERITABILITY IS ABOUT 50%,

201
00:07:39,125 --> 00:07:41,260
THAT'S THE COMPONENT OF

202
00:07:41,327 --> 00:07:42,328
VARIABILITY THAT IS DIRECTLY

203
00:07:42,395 --> 00:07:46,165
CAPTURED BY TWIN STUDIES.

204
00:07:46,232 --> 00:07:48,935
AND ON THE OTHER HAND WE HAVE

205
00:07:49,001 --> 00:07:50,736
CROSS TRANSMISSION OF THE

206
00:07:50,803 --> 00:07:51,871
SUBSTANCE USE DISORDERS.

207
00:07:51,938 --> 00:07:56,209
THERE'S NOT A UNIQUE GENETIC

208
00:07:56,275 --> 00:07:57,777
FACTOR THAT GOVERNS 1 SUBSTANCE

209
00:07:57,844 --> 00:07:59,779
USE DISORDER AND IT'S NOT SHARED

210
00:07:59,846 --> 00:08:00,446
WITH OTHERS.

211
00:08:00,513 --> 00:08:02,114
WELL, THERE MAY BE A FEW IN

212
00:08:02,181 --> 00:08:04,784
TERMS OF THE METABOLIC GENE

213
00:08:04,851 --> 00:08:06,419
POLYMORPHISMS THAT I WILL TALK

214
00:08:06,485 --> 00:08:08,955
ABOUT LATER, BUT MUCH OF THE

215
00:08:09,021 --> 00:08:11,824
VULNERABILITY IS A GENERAL

216
00:08:11,891 --> 00:08:16,262
VULNERABILITY TO ADDICTION, THIS

217
00:08:16,329 --> 00:08:19,932
IS FROM THE NESARC III STUDY,

218
00:08:19,999 --> 00:08:22,468
WHERE IN COLLABORATION WITH

219
00:08:22,535 --> 00:08:28,474
PATRICIA CHOU AND HAITAO ZHANG,

220
00:08:28,541 --> 00:08:30,109
WE LOOKEDDA THE TRANSMISSION OF

221
00:08:30,176 --> 00:08:31,978
AUDs IN THE LARGE HOUSEHOLD

222
00:08:32,044 --> 00:08:34,881
SURVEY SAMPLE THAT HAS BEEN

223
00:08:34,947 --> 00:08:38,050
COLLECTED BY NIAAA.

224
00:08:38,117 --> 00:08:43,256
IN USING THE NP MARKERS, THE

225
00:08:43,322 --> 00:08:43,956
SINGLE NUCLEOTIDE POLYMORPHISMS,

226
00:08:44,023 --> 00:08:46,092
WERE ABLE TO ESTIMATE A

227
00:08:46,158 --> 00:08:47,627
POLYGENIC SCORE FOR RISK OF

228
00:08:47,693 --> 00:08:50,029
THESE SUBSTANCE USE DISORDERS

229
00:08:50,096 --> 00:08:52,298
AND SO THE ALCOHOL POLYGENIC

230
00:08:52,365 --> 00:08:55,902
SCORE IS HERE PREDICTIVE OF

231
00:08:55,968 --> 00:08:57,270
NICOTINE USE DISORDER RISK AND

232
00:08:57,336 --> 00:09:00,873
ON THE OTHER HAND, THE NICOTINE

233
00:09:00,940 --> 00:09:03,643
USE DISORDER POLYGENIC SCORE

234
00:09:03,709 --> 00:09:05,544
PREDICTS ALCOHOL USE DISORDER.

235
00:09:05,611 --> 00:09:07,346
AND SO THIS CROSS TRANSMISSION

236
00:09:07,413 --> 00:09:08,981
HAS BEEN REPEATEDLY OBSERVED

237
00:09:09,048 --> 00:09:11,851
ANDEN THIS OF COURSE, AS I SAID

238
00:09:11,918 --> 00:09:12,919
THERE ARE ALSO SUBSTANCE

239
00:09:12,985 --> 00:09:17,723
SPECIFIC YEENS WHICH MIGHT BE

240
00:09:17,790 --> 00:09:19,425
THE GATEWAY MOLECULE IT IS OF

241
00:09:19,492 --> 00:09:19,992
THIS PARTICULAR SUBSTANCE.

242
00:09:20,059 --> 00:09:21,994
I WILL GET THE HANG OF THIS, I

243
00:09:22,061 --> 00:09:22,228
PROMISE.

244
00:09:22,295 --> 00:09:24,397
SO WHEN WE THINK ABOUT THE

245
00:09:24,463 --> 00:09:25,264
GENERAL COMPONENT OF

246
00:09:25,331 --> 00:09:27,433
VULMERRABILITY, WHAT MIGHT BE

247
00:09:27,500 --> 00:09:33,039
INHERITED AND THIS IS THE

248
00:09:33,105 --> 00:09:33,739
ADDICTIONS NEUROCLINICAL

249
00:09:33,806 --> 00:09:37,476
ASSESSMENT IN 2 PAPERS WHICH ARE

250
00:09:37,543 --> 00:09:41,948
SHOWN HERE AT THE BOTTOM AND

251
00:09:42,014 --> 00:09:46,185
THEN ACTUALLY A NEW PAPER

252
00:09:46,252 --> 00:09:47,153
SUBMITTED BY TOMMY

253
00:09:47,219 --> 00:09:48,054
[INDISCERNIBLE] WHO'S IN THE

254
00:09:48,120 --> 00:09:49,755
AUDIENCE, WE'VE BEEN ABLE TO

255
00:09:49,822 --> 00:09:54,160
DERIVE THESE 3 MAJOR FACTORS OR

256
00:09:54,226 --> 00:09:58,197
DOMAINS OF VULNERABILITY AND

257
00:09:58,264 --> 00:10:01,200
PROGRESSION OF A. U. D.

258
00:10:01,267 --> 00:10:06,138
PREOCCUPATION AND ANTICIPATION

259
00:10:06,205 --> 00:10:09,108
BEING THE LAST 1, EXEC TEF

260
00:10:09,175 --> 00:10:10,609
TOCKSICATION AND THEN

261
00:10:10,676 --> 00:10:12,745
WITHDRAWAL, NEGATIVE AFFECT HERE

262
00:10:12,812 --> 00:10:15,147
SOMEWHERE IN THE MIDDLE.

263
00:10:15,214 --> 00:10:16,449
HOWEVER, THIS WORK WHICH IS AS

264
00:10:16,515 --> 00:10:20,720
YOU SEE LED BY LAURA KWAKO ALSO

265
00:10:20,786 --> 00:10:23,456
DOESN'T FULLY CAPTURE THE FACT

266
00:10:23,522 --> 00:10:26,525
THAT PEOPLE WITH ALCOHOL USE

267
00:10:26,592 --> 00:10:28,027
DISORDERS MAY BE ALREADY

268
00:10:28,094 --> 00:10:29,462
VULNERABLE IN THESE DIFFERENT

269
00:10:29,528 --> 00:10:29,695
DOMAINS.

270
00:10:29,762 --> 00:10:32,531
THEY MAY ALREADY HAVE NEGATIVE

271
00:10:32,598 --> 00:10:33,499
AFFECT BEFORE THEY'RE EVER

272
00:10:33,566 --> 00:10:35,668
EXPOSED TO THE DRUG.

273
00:10:35,735 --> 00:10:37,970
THEY MAY ALREADY HAVE DIMINISHED

274
00:10:38,037 --> 00:10:40,606
EXECUTIVE FUNCTION BEFORE AN

275
00:10:40,673 --> 00:10:40,873
EXPOSURE.

276
00:10:40,940 --> 00:10:43,743
SO BOTH AS A CONSEQUENCE OF

277
00:10:43,809 --> 00:10:47,613
EXPOSURE, THESE DOMAINS ARE

278
00:10:47,680 --> 00:10:49,782
AFFECTED AND AS IS COMMON TO

279
00:10:49,849 --> 00:10:51,751
PROBABLY MOST PEOPLE WITH

280
00:10:51,817 --> 00:10:53,719
ALCOHOL USE DISORDER, BUT ALSO

281
00:10:53,786 --> 00:10:57,056
AS A PRECURSOR TO ALCOHOL USE

282
00:10:57,123 --> 00:10:58,324
DISORDER, THIS ALREADY

283
00:10:58,391 --> 00:11:01,594
PREEXISTING VULNERABILITY IN

284
00:11:01,660 --> 00:11:01,827
MANY.

285
00:11:01,894 --> 00:11:05,898
ARE THEN, THE GENE BY

286
00:11:05,965 --> 00:11:06,832
ENVIRONMENT AND INTERMEDIATE

287
00:11:06,899 --> 00:11:08,434
PHENOTYPE STUDIES THE WAY

288
00:11:08,501 --> 00:11:08,667
FORWARD.

289
00:11:08,734 --> 00:11:11,337
SHOULD WE BE DOING GENETIC

290
00:11:11,404 --> 00:11:13,939
STUDIES ON THESE ADDICTIONS

291
00:11:14,006 --> 00:11:15,174
NEUROCLINICAL ASSESSMENT DOMAINS

292
00:11:15,241 --> 00:11:18,778
AND OTHER SORTS OF INTERMEDIATE

293
00:11:18,844 --> 00:11:21,280
PHENOTYPE, SORTS OF PHENOTYPES.

294
00:11:21,347 --> 00:11:23,349
INSTEAD OF ALCOHOL USE DISORDER,

295
00:11:23,416 --> 00:11:26,419
WHICH IS ITSELF SO COMMON AND SO

296
00:11:26,485 --> 00:11:27,453
MULTICAUSAL AND FACTORIAL, WELL,

297
00:11:27,520 --> 00:11:29,889
WE USED TO THINK SO.

298
00:11:29,955 --> 00:11:33,659
WE USED TO THINK THAT--AND MUCH

299
00:11:33,726 --> 00:11:35,628
OF THE ACTIVITY AT MY LAB WAS

300
00:11:35,694 --> 00:11:37,163
DEVOTED TO THAT COMSUMPTION THAT

301
00:11:37,229 --> 00:11:40,800
THE WAY FORWARD WAS THESE SORTS

302
00:11:40,866 --> 00:11:43,402
OF GX E INTERMEDIATE PHENOTYPE

303
00:11:43,469 --> 00:11:45,004
TODAYS BUT AS I WILL SHOW YOU AS

304
00:11:45,071 --> 00:11:47,106
MATTERS AND IT TURNS OUT THAT IN

305
00:11:47,173 --> 00:11:49,241
THE VERY LARGE STUDIES, THE

306
00:11:49,308 --> 00:11:50,676
LARGEST STUDIES, THE GWAS

307
00:11:50,743 --> 00:11:52,778
STUDIES THESE PHENOTYPES ARE NOT

308
00:11:52,845 --> 00:11:54,380
REALLY WHAT IS COLLECTED AND

309
00:11:54,447 --> 00:11:57,483
TREMENDOUS PROGRESS HAS BEEN

310
00:11:57,550 --> 00:11:57,817
MADE.

311
00:11:57,883 --> 00:12:00,820
SO HERE FIRST OF ALL THOUGH, IS

312
00:12:00,886 --> 00:12:02,088
THE CONCEPT THAT CONTEXT

313
00:12:02,154 --> 00:12:02,521
MATTERS.

314
00:12:02,588 --> 00:12:05,524
THIS IS A SERIES OF FUNCTIONAL

315
00:12:05,591 --> 00:12:12,832
WELL, OCI ON THE LEFT WHICH ARE

316
00:12:12,898 --> 00:12:17,136
AT NEUROGENETIC CANDIDATE GENES

317
00:12:17,203 --> 00:12:20,039
AND THE INFORMATION THAT 2 OF

318
00:12:20,106 --> 00:12:23,109
THESE FUNCTIONAL LOCI PRODUCE

319
00:12:23,175 --> 00:12:25,911
SYMPTOMS IN THE CONTEXT OF EARLY

320
00:12:25,978 --> 00:12:30,382
LIFE TRAUMA, SO THE SEROTONIN

321
00:12:30,449 --> 00:12:31,884
TRANSPORTER POLYMORPHISM IS--HAS

322
00:12:31,951 --> 00:12:34,153
A CONSEQUENCE OF SELF-REPORTED

323
00:12:34,220 --> 00:12:36,889
DEPRESSIVE SYMPTOMS BUT ONLY IN

324
00:12:36,956 --> 00:12:40,860
THE INDIVIDUALS WHO HAVE HAD 3

325
00:12:40,926 --> 00:12:44,697
OR 4 OF THESE STRESSFUL EVENTS

326
00:12:44,763 --> 00:12:47,032
IN EARLY LIFE AND SIMILARLY, WE

327
00:12:47,099 --> 00:12:49,568
DON'T HAVE THE WAXES LABELS HERE

328
00:12:49,635 --> 00:12:53,806
BUT THIS IS CONTROLLED BEHAVIOR,

329
00:12:53,873 --> 00:12:54,840
THE DISCONTROL IS OBSERVED IN

330
00:12:54,907 --> 00:12:58,310
PEOPLE WHO HAD THE LOW MAOA

331
00:12:58,377 --> 00:13:01,013
ACTIVITY POLYMORPHISM BUT HAD

332
00:13:01,080 --> 00:13:07,253
UNDERGONE SEVERE EARLY TRAUMA.

333
00:13:07,319 --> 00:13:08,554
I PROMISE THAT I WOULD GET THE

334
00:13:08,621 --> 00:13:10,189
HANG OF THIS AND I HAVE NOT YET.

335
00:13:10,256 --> 00:13:12,191
THIS IS A FURTHER EXAMPLE OF

336
00:13:12,258 --> 00:13:12,858
INTERACTION.

337
00:13:12,925 --> 00:13:16,462
HAD IS AGAIN THE MONOMEANOX DACE

338
00:13:16,529 --> 00:13:17,429
A POLYMORPHISM, AND ON THE LEFT

339
00:13:17,496 --> 00:13:25,905
YOU SEE THAT IN THE CONTEXT OF

340
00:13:25,971 --> 00:13:28,641
HIGH TESTOSTERONE LEVEL THAT

341
00:13:28,707 --> 00:13:31,277
THERE IS A HIGHER LIFETIME

342
00:13:31,343 --> 00:13:32,111
AGGRESSION SCORE BUT THAT IS

343
00:13:32,178 --> 00:13:35,281
ONLY IN THE INDIVIDUALS WHO

344
00:13:35,347 --> 00:13:38,184
CARRY THE LOW ACTIVITY MAOA

345
00:13:38,250 --> 00:13:40,452
POLYMORPHISM, NOT IN THOSE WHO

346
00:13:40,519 --> 00:13:48,227
CARRY THE HIGH MAOA ACTIVITY

347
00:13:48,294 --> 00:13:48,794
ALLELE.

348
00:13:48,861 --> 00:13:52,498
ASK MORE ON INTERMEDIATE

349
00:13:52,565 --> 00:13:52,798
PHENOTYPES.

350
00:13:52,865 --> 00:13:57,369
THIS IS--THERE IS A FUNCTIONAL

351
00:13:57,436 --> 00:14:02,374
POLYMORPHISM IN THE NEUROPEPTIDE

352
00:14:02,441 --> 00:14:05,511
MPY GENE AND THAT FUNCTIONAL

353
00:14:05,578 --> 00:14:07,146
POLYMORPHISM PREDICTS VERY

354
00:14:07,213 --> 00:14:09,582
STRONGLY BRAIN IMAGING RESPONSES

355
00:14:09,648 --> 00:14:11,417
TO EMOTIONAL STIMULI AND YOUEE

356
00:14:11,483 --> 00:14:17,556
THAT HERE FOR PEOPLE WITH A LOW

357
00:14:17,623 --> 00:14:19,091
ACTIVITY, MPY GENO TYPE OR DIP

358
00:14:19,158 --> 00:14:21,560
LO TYPE HAD THE STRONGEST

359
00:14:21,627 --> 00:14:23,195
ACTIVATIONS OF THE HYPOCAMPUS

360
00:14:23,262 --> 00:14:25,531
AND AMYGDALA IN RESPONSE TO THAT

361
00:14:25,598 --> 00:14:26,365
EMOTIONAL CHALLENGE.

362
00:14:26,432 --> 00:14:32,905
PEOPLE WITH THE HIGH ACTIVITY,

363
00:14:32,972 --> 00:14:33,339
FORM, DO NOT.

364
00:14:33,405 --> 00:14:36,942
AND HERE YOU SEE THE OVERALL

365
00:14:37,009 --> 00:14:38,444
AFFECT OF THIS POLYMORPHISM ON

366
00:14:38,510 --> 00:14:42,615
BEHAVIOR WHERE IF YOU MOVE FROM

367
00:14:42,681 --> 00:14:44,450
THE LEVEL OF HOLDING COMPANY

368
00:14:44,516 --> 00:14:46,051
KIEWL AND THEN THROUGH BRAIN,

369
00:14:46,118 --> 00:14:47,786
AND THEN FINALLY TO BEHAVIOR,

370
00:14:47,853 --> 00:14:53,092
THE AFFECT OF THE POLYMORPHISM

371
00:14:53,158 --> 00:14:56,328
IS PROGRESSIVELY DILUTED.

372
00:14:56,395 --> 00:14:59,064
STRONG EFFECTS ON MRNA

373
00:14:59,131 --> 00:15:01,700
EXPRESSION AND PLASMA

374
00:15:01,767 --> 00:15:05,337
NEUROPEPTIDE Y LEVELS BUT WEAK

375
00:15:05,404 --> 00:15:07,406
EFFECTSOT EMERGENT BEHAVIOR OF

376
00:15:07,473 --> 00:15:08,240
TRADE ANXIETY OR PAIN THRESH

377
00:15:08,307 --> 00:15:08,474
OLD.

378
00:15:08,540 --> 00:15:09,808
SO WE HAVE A PROBLEM THAT THE

379
00:15:09,875 --> 00:15:11,477
WHICH IS THAT THE CLINICAL

380
00:15:11,543 --> 00:15:14,313
RELEVANCE IS STRONGEST DOWN HERE

381
00:15:14,380 --> 00:15:19,451
BUT ON THE OTHER HAND, THE GENE

382
00:15:19,518 --> 00:15:24,857
EFFECTS ARE STRONGEST UP HERE SO

383
00:15:24,923 --> 00:15:26,959
WHAT HAS HAPPENED THEN--OH, 1

384
00:15:27,026 --> 00:15:29,495
MORE CANDIDATE GENE IF YOU WILL.

385
00:15:29,561 --> 00:15:30,829
THIS WAS ACTUALLY FOUND AS A

386
00:15:30,896 --> 00:15:35,401
RESULT OF A SEQUENCING STUDY, WE

387
00:15:35,467 --> 00:15:39,538
FOUND A STOP CODON IN 1 OF THE

388
00:15:39,605 --> 00:15:40,406
SEROTONIN RECEPTORS HCR2 B AND

389
00:15:40,472 --> 00:15:42,374
YOU SEE THE LOCATION OF THIS

390
00:15:42,441 --> 00:15:44,777
STOP CODON HERE AND IT

391
00:15:44,843 --> 00:15:47,279
TRUNCATING THIS PROTEIN, SO

392
00:15:47,346 --> 00:15:49,715
THERE'S A LACK OF THE PROTEIN IN

393
00:15:49,782 --> 00:15:54,186
PEOPLE WHO HAVE THE STOP CODON,

394
00:15:54,253 --> 00:15:55,587
IT'S LIKE A YEEN KNOCK OUT.

395
00:15:55,654 --> 00:16:01,460
IT'S COMMON IN FINNS, IT'S LIKE

396
00:16:01,527 --> 00:16:04,763
1 AND HALF% FREQUENCY IN ALLELES

397
00:16:04,830 --> 00:16:07,733
IN FINMS, AND IT IS ALSO

398
00:16:07,800 --> 00:16:09,335
ASSOCIATED WITH MULTIPLE

399
00:16:09,401 --> 00:16:10,402
PERSONALITY DISORDER AND ALCOHOL

400
00:16:10,469 --> 00:16:12,137
USE DISORDER AND LINKED TO

401
00:16:12,204 --> 00:16:14,973
FAMILIES IN THESE BEHAVIORS AND

402
00:16:15,040 --> 00:16:15,908
THEN THERE'S PREDICTIVE VALIDITY

403
00:16:15,974 --> 00:16:17,276
WHERE WE SHOW, WE KNOCKED OUT

404
00:16:17,343 --> 00:16:19,078
THIS YEEN IN THE MOUSE AND THIS

405
00:16:19,144 --> 00:16:20,512
MICE THAT HAVE IT KNOCKED OUT,

406
00:16:20,579 --> 00:16:25,851
YOU SEE THAT THEY HAVE

407
00:16:25,918 --> 00:16:27,319
IMPAIRMENTS AND DELAYED

408
00:16:27,386 --> 00:16:27,786
DISCOUNTING.

409
00:16:27,853 --> 00:16:29,221
THEY HAVE MORE LOCOMOTION AND

410
00:16:29,288 --> 00:16:33,726
RESPONSE TO A NOVEL ENVIRONMENT.

411
00:16:33,792 --> 00:16:36,528
THEY ARE LIKELY TO TOUCH NOVEL

412
00:16:36,595 --> 00:16:39,198
OBLIGATIONS YECTS THAT THEY'RE

413
00:16:39,264 --> 00:16:41,600
PRESENTED, LET'S SEE WHERE THE

414
00:16:41,667 --> 00:16:44,069
NEXT SLIDE IS.

415
00:16:44,136 --> 00:16:48,974
AH, AND HERE'S THE CUTE FIGURE

416
00:16:49,041 --> 00:16:49,675
THAT LUKE [INDISCERNIBLE]

417
00:16:49,742 --> 00:16:51,176
DEVISED WHICH SHOWS THAT THE 2 B

418
00:16:51,243 --> 00:16:56,014
MOUSE THAT HAS THE HCRG2 B

419
00:16:56,081 --> 00:16:56,815
RECEPTOR WHICH PATIENTLY--BUT

420
00:16:56,882 --> 00:16:58,484
ALSO ON THE OTHER HAND THE MOUSE

421
00:16:58,550 --> 00:16:59,985
WITH THIS GENE KNOCKED DOWN IF

422
00:17:00,052 --> 00:17:01,754
YOU PUT IT IN A CLOSURE WHERE

423
00:17:01,820 --> 00:17:05,224
THERE'S FOOD IN THE MIDDLE, IT

424
00:17:05,290 --> 00:17:09,328
KNOWS THAT, IT WILL VENTURE TO

425
00:17:09,395 --> 00:17:11,730
THE DANGEROUS MIDDLE WHERE AS A

426
00:17:11,797 --> 00:17:14,700
HAWK MIGHT SWOOP DOWN OR A CAT

427
00:17:14,767 --> 00:17:16,468
MIGHT POUNCE ON IT IN ORDER TO

428
00:17:16,535 --> 00:17:19,571
GET THAT PELLET OF FOOD.

429
00:17:19,638 --> 00:17:21,440
SO NOW LET'S MOVE TO WHERE THE

430
00:17:21,507 --> 00:17:22,608
FIELD WENT AND WHERE THE FIELD

431
00:17:22,674 --> 00:17:24,777
WENT WAS TO GENOME STUDIES.

432
00:17:24,843 --> 00:17:28,647
AND SO WHAT IS A GENOME WIDE

433
00:17:28,714 --> 00:17:29,782
ASSOCIATION STUDY?

434
00:17:29,848 --> 00:17:32,785
WELL IT IS ABASED LINKAGE

435
00:17:32,851 --> 00:17:34,553
INSTEAD OF FAMILY BASED LINKAGE

436
00:17:34,620 --> 00:17:36,722
WHICH IS LOCUST BASED LINKAGE,

437
00:17:36,789 --> 00:17:37,723
IT'S DISASSOCIATION STUDY WITH

438
00:17:37,790 --> 00:17:40,159
HUNDREDS OF THOUSANDS OF

439
00:17:40,225 --> 00:17:41,226
MARKERS, USUALLY THE SNPs,

440
00:17:41,293 --> 00:17:43,262
BECAUSE THEY CAN BE EFFICIENTLY

441
00:17:43,328 --> 00:17:46,064
AND CHEAPLY GENO TYPED ON ARRAY

442
00:17:46,131 --> 00:17:48,167
AND THEN MILLIONS OF ARK

443
00:17:48,233 --> 00:17:50,202
DITIONAL SNPs, MAY BE

444
00:17:50,269 --> 00:17:51,470
INFORMATICLY IMPUTED AND WHAT

445
00:17:51,537 --> 00:17:54,006
THAT YIELDS IS THE PLOT LIKE

446
00:17:54,072 --> 00:17:56,008
THIS WITH A LEVEL OF GENOME WIDE

447
00:17:56,074 --> 00:17:58,310
SIGNIFICANCE AND THEN ACROSS THE

448
00:17:58,377 --> 00:18:00,179
CHROMOSOMES, YOU LOOK FOR THE

449
00:18:00,245 --> 00:18:01,814
SIGNALS, EACH DOT REPRESENTING

450
00:18:01,880 --> 00:18:04,616
THE SNP AND THERE'S CERTAIN

451
00:18:04,683 --> 00:18:05,451
PLACES WHERE THESE SIGNALS RISE

452
00:18:05,517 --> 00:18:08,220
TO THE LEVEL OF SIGNIFICANCE, SO

453
00:18:08,287 --> 00:18:10,889
THEY LOOK LIKE, RATHER LIKE A

454
00:18:10,956 --> 00:18:15,894
SKYSCRAPER IN MANNA HAT AN AND

455
00:18:15,961 --> 00:18:17,663
THIS LOOKS LIKE A, WHAT DO YOU

456
00:18:17,729 --> 00:18:20,999
CALL IT, A SKY LINE, SO IT'S A

457
00:18:21,066 --> 00:18:22,401
MANHATTAN PLOT AND FOR THOSE WHO

458
00:18:22,468 --> 00:18:27,339
ARE INTERESTED, YOU CAN DOWNLOAD

459
00:18:27,406 --> 00:18:29,074
FROM THE INTERNET THISART WORK

460
00:18:29,141 --> 00:18:30,976
BY A FORMER PRESIDENT SHOWING

461
00:18:31,043 --> 00:18:33,145
THE MANHATTAN CHI LINE WHICH AS

462
00:18:33,212 --> 00:18:35,113
YOU OBSERVATION LOOKS EXACTLY

463
00:18:35,180 --> 00:18:36,482
LIKE A MANHATTAN PLOT.

464
00:18:36,548 --> 00:18:39,485
THIS ISN'T TO SAY THAT THIS IS

465
00:18:39,551 --> 00:18:41,186
AN ESPECIALLY VALUABLE PIECE OF

466
00:18:41,253 --> 00:18:44,056
ART BUT IT'S READILY OBTAINED

467
00:18:44,122 --> 00:18:46,125
AND YOU SEE HIS NAME THERE WHICH

468
00:18:46,191 --> 00:18:48,026
MAY NOT BE READABLE BUT HE'S

469
00:18:48,093 --> 00:18:54,700
CURRENTLY ON TRIAL IN MANHATTAN.

470
00:18:54,766 --> 00:18:57,135
LET'S SEE, YES, ARE AND SO, THIS

471
00:18:57,202 --> 00:19:01,540
METHOD THEN WAS USED TO DO

472
00:19:01,607 --> 00:19:02,174
GENOME WIDE ASSOCIATION STUDIES

473
00:19:02,241 --> 00:19:06,812
AND YOU SEE THE RESULT OF 1

474
00:19:06,879 --> 00:19:09,414
LARGEST OF THESE GENOME WIDE

475
00:19:09,481 --> 00:19:11,049
ASSOCIATIONS, THIS IS SEVERAL

476
00:19:11,116 --> 00:19:12,751
YEARS AGO WHERE THERE ARE QUITE

477
00:19:12,818 --> 00:19:16,655
A NUMBER OF LOCI THAT RISE TO

478
00:19:16,722 --> 00:19:20,092
THE LEVEL OF SIGNIFICANCE, BUT

479
00:19:20,158 --> 00:19:21,593
ALSO THE POLYGENIC SCORE FROM

480
00:19:21,660 --> 00:19:23,128
THESE GWAS HAVE BEEN USED TO

481
00:19:23,195 --> 00:19:24,796
LOOK AT WHAT IS CROSS

482
00:19:24,863 --> 00:19:26,431
TRANSMITTED, WHAT IS CROSS

483
00:19:26,498 --> 00:19:30,869
TRANSMITTED AND ALSO WHAT IS

484
00:19:30,936 --> 00:19:32,137
ANTITRANSMITTED WITH THE

485
00:19:32,204 --> 00:19:33,639
VULNERABILITY TO A. U. D.?

486
00:19:33,705 --> 00:19:36,141
SO SHARED WITH THE VULNERABILITY

487
00:19:36,208 --> 00:19:39,745
TO A. U. D. IS LIFETIME CANNABIS

488
00:19:39,811 --> 00:19:43,482
USE, WHETHER 1 IS A SMOKER AND

489
00:19:43,549 --> 00:19:45,417
THEN NEGATIVELY CORRELATED ARE

490
00:19:45,484 --> 00:19:48,086
THINGS SUCH AS THE AGE AT FIRST

491
00:19:48,153 --> 00:19:49,221
BIRTH, THE EDUCATIONAL

492
00:19:49,288 --> 00:19:52,858
ATTAINMENT OF THE INDIVIDUAL, IN

493
00:19:52,925 --> 00:19:54,026
THE COGNITIVE PERFORMANCE OF THE

494
00:19:54,092 --> 00:19:56,228
INDIVIDUAL, SO YOU CAN SEE THAT

495
00:19:56,295 --> 00:19:58,430
SOME OF THESE PREEXISTING

496
00:19:58,497 --> 00:20:02,067
VULNERABILITY FACTORS ARE ALSO

497
00:20:02,134 --> 00:20:08,540
PREDICTED BY POLYGENIC CORE FOR

498
00:20:08,607 --> 00:20:09,675
A. U. D.

499
00:20:09,741 --> 00:20:11,710
I SEEM TO LINK THE ORDER OF THIS

500
00:20:11,777 --> 00:20:13,211
BECAUSE USUALLY BIGGER COMES

501
00:20:13,278 --> 00:20:15,614
AFTER BIG INSTEAD OF THE OTHER

502
00:20:15,681 --> 00:20:18,817
WAY AROUND BUT HERE YOU SEE THE

503
00:20:18,884 --> 00:20:21,219
BIG GWAS OF A. U. D., ON THE

504
00:20:21,286 --> 00:20:22,554
SLIDE IT'S NICE BECAUSE YOU CAN

505
00:20:22,621 --> 00:20:23,755
SEE A MAJOR CLUSTER OF HITS

506
00:20:23,822 --> 00:20:26,925
WHICH ARE RIGHT AT THE ALCOHOL

507
00:20:26,992 --> 00:20:31,063
DEHODGE NAS CLUSTER 4, THAT'S

508
00:20:31,129 --> 00:20:32,064
THIS CLUSTER HERE.

509
00:20:32,130 --> 00:20:33,932
SO WHAT DID WE FIND?

510
00:20:33,999 --> 00:20:36,368
WHAT WE FOUND WITH THE GWAS

511
00:20:36,435 --> 00:20:40,606
STUDIES WELL, THERE ARE 281 GWAS

512
00:20:40,672 --> 00:20:42,941
LISTINGS FOR A. U. D. CURRENTLY

513
00:20:43,008 --> 00:20:44,676
IN THE GWAS CATALOG, AND THERE

514
00:20:44,743 --> 00:20:46,578
ARE OVER A THOUSAND LISTINGS FOR

515
00:20:46,645 --> 00:20:48,447
DRINKING AND WE FIND SOME OLD

516
00:20:48,513 --> 00:20:53,719
FRIENDS, WE FIND YEENS LIKE ALD

517
00:20:53,785 --> 00:20:54,920
HIDE DEHYDROGENASE 1 B WHICH

518
00:20:54,987 --> 00:20:58,523
WERE WELL KNOWN TO BE RISK LOCI

519
00:20:58,590 --> 00:20:59,224
FOR ALCOHOL USE DISORDER AND I

520
00:20:59,291 --> 00:21:01,360
WILL SHOW YOU WHY IN A MOMENT.

521
00:21:01,426 --> 00:21:03,895
WE ALSO FIND OLD FRIENDS LIKE

522
00:21:03,962 --> 00:21:09,167
THE DRD2 DOPAMINE RECEPTOR, THIS

523
00:21:09,234 --> 00:21:10,335
DOPAMINE RECEPTOR OF COURSE

524
00:21:10,402 --> 00:21:12,738
CRITICAL IN REWARD BUT ALSO MOST

525
00:21:12,804 --> 00:21:14,039
IMPORTANTLY WE FIND NEW GENES

526
00:21:14,106 --> 00:21:16,174
AND NEW PATHWAYS AND SO SOME OF

527
00:21:16,241 --> 00:21:19,411
THESE ARE LISTED HERE, A METAL

528
00:21:19,478 --> 00:21:22,180
ION TRANSPORTER, AN FGP

529
00:21:22,247 --> 00:21:24,483
KORESEPTORSOR, A GLUE KINASE

530
00:21:24,549 --> 00:21:26,585
REGULATOR AND A CYTOPLASM

531
00:21:26,652 --> 00:21:27,619
NUCLEAR PROTEIN FOR TRANSPORT,

532
00:21:27,686 --> 00:21:29,888
BY AND LARGE THE FUNCTIONAL LOCI

533
00:21:29,955 --> 00:21:34,526
HAD NOT BEEN IDENTIFIED AT THIS

534
00:21:34,593 --> 00:21:39,097
GENES AND SO THEY'RE NOT IN THE

535
00:21:39,164 --> 00:21:42,701
STATUS OF ALPHA DEHYDROGENASE 2

536
00:21:42,768 --> 00:21:44,369
OR DRD2, AND THOSE ARE RS

537
00:21:44,436 --> 00:21:45,437
NUMBERS FOR THEM, BUT THE

538
00:21:45,504 --> 00:21:46,805
IMPORTANCE IS THAT THEY HAVE

539
00:21:46,872 --> 00:21:50,175
SHOWN US NEW PATHWAYS TO A. U.

540
00:21:50,242 --> 00:21:50,509
D.

541
00:21:50,575 --> 00:21:53,545
WE ALSO KNOW THAT ONLY A PORTION

542
00:21:53,612 --> 00:21:55,881
OF RISK OF THE A. U. D. IS

543
00:21:55,947 --> 00:21:57,983
CAPTURED SO FAR, BUT EVEN WITH

544
00:21:58,050 --> 00:22:00,052
THAT PORTION OF RISK BEING

545
00:22:00,118 --> 00:22:00,852
CAPTURED, WERE ABLE TO

546
00:22:00,919 --> 00:22:03,722
UNDERSTAND THAT THERE ARE

547
00:22:03,789 --> 00:22:07,492
PATHWAYS TO JUST METAL ION

548
00:22:07,559 --> 00:22:10,462
TRANSPORT OR FGF OR GLUE O

549
00:22:10,529 --> 00:22:12,064
KINASE WHICH MAY BE IMPORTANT IN

550
00:22:12,130 --> 00:22:17,436
A. U. D. RISK AND SO AS PROMISED

551
00:22:17,502 --> 00:22:22,941
HE HEARS THE--HERE'S THE

552
00:22:23,008 --> 00:22:25,143
POLYMORPHISMS OF ALD H1 AND

553
00:22:25,210 --> 00:22:26,778
ADHWORKS BEFORE ACCIDENT AND

554
00:22:26,845 --> 00:22:28,046
THERE ARE MOW SUBTUITIONS,

555
00:22:28,113 --> 00:22:31,950
THEY'RE COMMON IN POPULATIONS

556
00:22:32,017 --> 00:22:33,919
ESPECIALLY IN SOUTHEAST ASIA

557
00:22:33,985 --> 00:22:36,054
WHERE THERE ARE MORE THAN HALF A

558
00:22:36,121 --> 00:22:37,322
BILLION PEOPLE WHO ACTUALLY CARE

559
00:22:37,389 --> 00:22:45,764
THEM, AS A RESULT THESE

560
00:22:45,831 --> 00:22:47,466
INDIVIDUALS WILL ACCUMULATE ALD

561
00:22:47,532 --> 00:22:49,000
HIDE LEADING TO THE FLUSHING

562
00:22:49,067 --> 00:22:51,770
ACTION, AND HOWEVER, EVEN THOUGH

563
00:22:51,837 --> 00:22:52,738
THEY'RE RELATIVELY PROTECTED

564
00:22:52,804 --> 00:22:54,873
AGAINST A. U. D., THEY ARE A

565
00:22:54,940 --> 00:22:56,141
HIGHER UPPER GI AND BREAST

566
00:22:56,208 --> 00:23:00,579
CANCER RISK AS A RESULT.

567
00:23:00,645 --> 00:23:05,150
HERE'S WHAT THAT FLUSHING

568
00:23:05,217 --> 00:23:06,051
REACTION LOOKS LIKE.

569
00:23:06,118 --> 00:23:08,253
A MAJOR PROBLEM TODAY IS THAT

570
00:23:08,320 --> 00:23:10,655
PEOPLE ARE BLOCKING THE FLUSHING

571
00:23:10,722 --> 00:23:15,694
REACTION WITHIN ANTIHISTAMINE

572
00:23:15,761 --> 00:23:16,895
DRUGS AND THOSE ANTIHISTAMINE

573
00:23:16,962 --> 00:23:20,031
DRUGS DO NOTHING TO ELIMINATE

574
00:23:20,098 --> 00:23:22,200
THE GENO TOXICITY OF ALCOHOL

575
00:23:22,267 --> 00:23:25,637
WHICH IS SO MUCH GREATER IN

576
00:23:25,704 --> 00:23:29,307
PEOPLE WHO CARRY THESE VARIANTS

577
00:23:29,374 --> 00:23:31,576
INCRUCKING ALDA HIDE LEVELS.

578
00:23:31,643 --> 00:23:33,879
SO THEN WHAT IS CONSEQUENT TO

579
00:23:33,945 --> 00:23:35,647
ALCOHOL EXPOSURE OTHER THAN

580
00:23:35,714 --> 00:23:36,915
FLUSHING, WELL, THERE'S A BROAD

581
00:23:36,982 --> 00:23:42,454
IMPACT ON THE GENOME.

582
00:23:42,521 --> 00:23:44,422
AND INVESTIGATOR AT NIAAA WITH

583
00:23:44,489 --> 00:23:47,626
MY HELP HAS BEEN STUDYING THIS,

584
00:23:47,692 --> 00:23:48,827
THIS IS [INDISCERNIBLE] WHO YOU

585
00:23:48,894 --> 00:23:51,163
SEE HERE, THIS IS

586
00:23:51,229 --> 00:23:51,997
[INDISCERNIBLE] WHOSE FIRST

587
00:23:52,063 --> 00:23:52,964
AUTHOR ON THIS RECENT PAPER AND

588
00:23:53,031 --> 00:23:56,034
WHAT YOU ARE SEEING IS THAT

589
00:23:56,101 --> 00:24:00,172
PEOPLE WHO DRINK HEAVILY HAVE AN

590
00:24:00,238 --> 00:24:02,808
EPIGENETIC AGE ACCELERATION OF

591
00:24:02,874 --> 00:24:04,075
ABOUT 2 YEARS AND FURTHER MORE,

592
00:24:04,142 --> 00:24:06,077
IF THEY HAVE HAD THE EARLY LIFE

593
00:24:06,144 --> 00:24:08,513
TRAUMA, THEY HAVE AN EPIGENETIC

594
00:24:08,580 --> 00:24:10,715
AGE ACCELERATION OF ABOUT 2

595
00:24:10,782 --> 00:24:13,084
YEARS AND THESE EFFECTS ARE

596
00:24:13,151 --> 00:24:13,585
ROUGHLY ADDITIVE.

597
00:24:13,652 --> 00:24:15,787
HOW DO WE DO THIS WORK?

598
00:24:15,854 --> 00:24:20,258
WELL WE RUN AN ARRAY WITH

599
00:24:20,325 --> 00:24:21,560
850,000 FEATURES, CPG CITES ON

600
00:24:21,626 --> 00:24:27,032
IT AND MEASURE THE METHYLATION

601
00:24:27,098 --> 00:24:29,301
AT THESE SITES, MANY OF WHICH

602
00:24:29,367 --> 00:24:38,844
ARE ONLY NEARBY GENES.

603
00:24:38,910 --> 00:24:41,079
SO WHY ARE WE CONCERNED AS

604
00:24:41,146 --> 00:24:43,615
PHYSICIANS ABOUT A. U. D. AND

605
00:24:43,682 --> 00:24:44,349
HEAVY DRINKING, WELL, CONCERN

606
00:24:44,416 --> 00:24:46,184
BECAUSE AS YOU SEE THE 1 YEAR

607
00:24:46,251 --> 00:24:48,720
PREVALENCE OF A. U. D. IS HIGH,

608
00:24:48,787 --> 00:24:53,491
IT'S 13 PBT 9% BY THE

609
00:24:53,558 --> 00:24:54,192
NESEA HOUSEHOLD SURVEY EMPLOY

610
00:24:54,259 --> 00:24:55,393
WHEN WE LOOK AT MEDICAL

611
00:24:55,460 --> 00:24:58,230
PATIENTS, JUST LESS THAN HALF OF

612
00:24:58,296 --> 00:24:59,664
THEM MEET CRITERIA, ALCOHOL'S

613
00:24:59,731 --> 00:25:02,000
DIVERSE EFFECTS ON ORGANS, IT

614
00:25:02,067 --> 00:25:03,468
INTERACTS WITH THE MEDICATIONS

615
00:25:03,535 --> 00:25:04,703
ISSUES AVAILABILITY OF

616
00:25:04,769 --> 00:25:06,571
TREATMENT, LOW STAFF AND PATIENT

617
00:25:06,638 --> 00:25:08,974
BURDEN OF ASSESSING IT AND IN

618
00:25:09,040 --> 00:25:09,975
FACT, ON THE KREEN WHICH I WILL

619
00:25:10,041 --> 00:25:13,311
SHOW YOU IN A MOMENT, IS NOW

620
00:25:13,378 --> 00:25:14,946
ROUTINE AT MOST HEALTH

621
00:25:15,013 --> 00:25:18,016
MAINTENANCE ORGANIZATIONS IN THE

622
00:25:18,083 --> 00:25:20,886
VA BUT UNTIL A YEAR AGO, WE

623
00:25:20,952 --> 00:25:26,391
DIDN'T ACTUALLY HAVE A FORM AT

624
00:25:26,458 --> 00:25:27,826
SCREENING FOR AUD AND HEAVY

625
00:25:27,893 --> 00:25:29,027
DRINKING AT THE CLINICAL CENTER,

626
00:25:29,094 --> 00:25:34,165
SO A GROUP OF US ORGANIZED AND

627
00:25:34,232 --> 00:25:36,234
LED BY JENNY [INDISCERNIBLE] GOT

628
00:25:36,301 --> 00:25:37,936
TOGETHER TO IMPLEMENT THIS AND

629
00:25:38,003 --> 00:25:41,106
SO HERE IS THE AUDIT C AND YOU

630
00:25:41,172 --> 00:25:43,208
SEE THAT JUST THESE 3 SIMPLE

631
00:25:43,275 --> 00:25:45,043
QUESTIONS WHICH SOMEBODY

632
00:25:45,110 --> 00:25:46,745
NEEDS--WHICH A PERSON NEEDS TO

633
00:25:46,811 --> 00:25:49,414
ANSWER AND THEY'RE GIVEN THIS

634
00:25:49,481 --> 00:25:50,215
QUESTIONNAIRE AT ADMISSION AND

635
00:25:50,282 --> 00:25:51,850
THEY'RE SHOWN WHAT A STANDARD

636
00:25:51,917 --> 00:25:54,953
DRINK IS WITH THIS LITTLE CHART

637
00:25:55,020 --> 00:25:56,421
HERE ON THE RIGHT.

638
00:25:56,488 --> 00:25:59,424
THIS IS THE AREA UNDERTHE CURVE

639
00:25:59,491 --> 00:26:02,460
FOR THE SENSITIVITY AND

640
00:26:02,527 --> 00:26:06,464
SPECIFICITY OF THE SCREENING FOR

641
00:26:06,531 --> 00:26:10,101
ALCOHOL USE DISORDER, BY THE

642
00:26:10,168 --> 00:26:13,672
AUC, THIS IS OUR INTRAMURAL

643
00:26:13,738 --> 00:26:14,539
CLINICAL SAMPLE WHICH IS QUITE

644
00:26:14,606 --> 00:26:16,041
POWERFUL FOR ARK ASSESSING THE

645
00:26:16,107 --> 00:26:21,413
VALIDITY AND POWER OF THE AUDIT

646
00:26:21,479 --> 00:26:23,715
C, IF THE PERSON HAS AN AUDIT C

647
00:26:23,782 --> 00:26:25,583
SCORE OF GREATER THAN 5, THE

648
00:26:25,650 --> 00:26:27,886
AREA OF THE CURVE IS ABOUT .97

649
00:26:27,953 --> 00:26:32,290
WHICH MEANS THAT WE REALLY, FOR

650
00:26:32,357 --> 00:26:35,060
MOST PEOPLE DON'T NEED A TEST

651
00:26:35,126 --> 00:26:35,994
FOR ALCOHOL USE DISORDER.

652
00:26:36,061 --> 00:26:39,197
WE COULD JUST ASK THEM.

653
00:26:39,264 --> 00:26:40,532
THESE 3 SIMPLE QUESTIONS SO NOW

654
00:26:40,598 --> 00:26:45,704
WE'RE DOING THAT AND THIS IS THE

655
00:26:45,770 --> 00:26:47,806
1 YEAR EXPERIENCE, WE JUST

656
00:26:47,872 --> 00:26:49,307
ABOUT--WE HAVE MORE THAN DOUBLED

657
00:26:49,374 --> 00:26:51,409
THE CLINICAL TRUSTEES ADDICTIONS

658
00:26:51,476 --> 00:26:57,716
CONSULTS WHICH IS VERY GOOD

659
00:26:57,782 --> 00:26:58,149
CONSEQUENCE.

660
00:26:58,216 --> 00:26:59,217
[INDISCERNIBLE] WHO DID MEDICAL

661
00:26:59,284 --> 00:27:06,024
EDOCCASION OF THE NURSES FOR

662
00:27:06,091 --> 00:27:08,259
THIS AND SURVEYED 620 CLINICAL

663
00:27:08,326 --> 00:27:09,461
CENTER NURSES, 554 OF WHOM

664
00:27:09,527 --> 00:27:13,264
ACTUALLY RESPONDED TO THE SURVEY

665
00:27:13,331 --> 00:27:14,799
AND YOU SEE THEY'RE RESPONDING

666
00:27:14,866 --> 00:27:17,469
ON THE LACK ARD SCALE WHETHER

667
00:27:17,535 --> 00:27:18,737
THEY STRONGLY DISAGREE OR

668
00:27:18,803 --> 00:27:21,506
STRONGLY AGREE, AND I THINK THE

669
00:27:21,573 --> 00:27:23,541
IMPORTANT TAKE HOME MESSAGE HERE

670
00:27:23,608 --> 00:27:26,344
IS THAT THE SCALE HERE ONLY GOES

671
00:27:26,411 --> 00:27:29,381
FROM 4.1 TO 5.

672
00:27:29,447 --> 00:27:33,018
SO, THAT TELLS YOU WHAT THE

673
00:27:33,084 --> 00:27:35,420
LEVEL OF ACCEPTANCE OF THE AUDIT

674
00:27:35,487 --> 00:27:39,924
C SURVEY AS BEEN BY CLINICAL

675
00:27:39,991 --> 00:27:40,425
CENTER NURSING.

676
00:27:40,492 --> 00:27:42,360
AND HERE I PUT IN THE RED BOX IT

677
00:27:42,427 --> 00:27:45,130
DOES NOT INTERFERE WITH THE WORK

678
00:27:45,196 --> 00:27:47,198
LOAD ON ADMISSION AND THAT ALL

679
00:27:47,265 --> 00:27:50,201
PATIENTS SHOULD BE SCREENED FOR

680
00:27:50,268 --> 00:27:54,172
ALCOHOL USE DISORDER WHERE

681
00:27:54,239 --> 00:27:55,840
THERE'S REALLY UNANIMITY FOR

682
00:27:55,907 --> 00:27:56,508
BOTH OF THOSE.

683
00:27:56,574 --> 00:28:00,545
MEAN WHILE WITHIN THE NIAA UNIT,

684
00:28:00,612 --> 00:28:02,280
WE HAVE A BONA FIDE COLLECTION

685
00:28:02,347 --> 00:28:03,581
OF PHENOTYPE AND GENO TYPE WHICH

686
00:28:03,648 --> 00:28:05,350
IS GOING TO BE IMPORTANT FOR

687
00:28:05,417 --> 00:28:07,285
STUDIES THAT I'M GOING TO SHOW

688
00:28:07,352 --> 00:28:09,487
YOU NEXT AND SO THIS IS DONE VIA

689
00:28:09,554 --> 00:28:12,924
A NATURAL HISTORY PROTOCOL WHICH

690
00:28:12,991 --> 00:28:15,727
NANCY DIAZ [INDISCERNIBLE] IS A

691
00:28:15,794 --> 00:28:16,861
PI ON.

692
00:28:16,928 --> 00:28:26,004
AND THE GENOMICS WHICH IS EXOME

693
00:28:26,071 --> 00:28:28,006
SNPs, A RAY ARE ALL IN MY LABS

694
00:28:28,073 --> 00:28:33,511
AND THEN SAVED AND SHARED IN

695
00:28:33,578 --> 00:28:36,915
MANY WAYS INCLUDING AMONGST THE

696
00:28:36,981 --> 00:28:40,085
NIAAA PIs AND ALSO INTO THE

697
00:28:40,151 --> 00:28:40,885
CONSORTIA NIAAA DATA ARCHIVE.

698
00:28:40,952 --> 00:28:45,857
SO WITH THE LONG RUN A VERY

699
00:28:45,924 --> 00:28:47,158
DEEPLY GENO TYPED AND ALSO

700
00:28:47,225 --> 00:28:50,428
GENOMIC DATA SET IS CREATED.

701
00:28:50,495 --> 00:28:53,264
SO HERE'S 1 OF THE WAYS THAT

702
00:28:53,331 --> 00:28:53,865
WE'VE USED THAT.

703
00:28:53,932 --> 00:28:56,634
WE USED THAT TO EXPLORE HOW IT

704
00:28:56,701 --> 00:28:59,938
IS THAT ONLY SOME DRINKERS

705
00:29:00,004 --> 00:29:01,239
DEVELOP ALCOHOL USE DISORDER AND

706
00:29:01,306 --> 00:29:03,875
ONLY SOME HEAVY DRINKERS DEVELOP

707
00:29:03,942 --> 00:29:05,844
LIVER DISEASE, SO JUST ABOUT ALL

708
00:29:05,910 --> 00:29:08,813
PEOPLE WITH A. U. D. WILL

709
00:29:08,880 --> 00:29:09,380
DEVELOP ALCOHOL FATTY LIVER

710
00:29:09,447 --> 00:29:13,151
DISEASE AND YOU SEE THE

711
00:29:13,218 --> 00:29:15,086
HISTOLOGY THERE WITH THE--OF THE

712
00:29:15,153 --> 00:29:18,556
LIVER, BUT THEN ONLY 10-35%

713
00:29:18,623 --> 00:29:25,697
PROGRESS TO ALCOHOL ASSOCIATED

714
00:29:25,763 --> 00:29:26,064
ASSOCIATED

715
00:29:26,131 --> 00:29:28,099
HEPATITIS AND ONLY 20% TO

716
00:29:28,166 --> 00:29:31,336
ALCOHOL RELATED CIRRHOSIS.

717
00:29:31,402 --> 00:29:36,407
SO GWAS OF WHOLE CIRRHOSIS WAS

718
00:29:36,474 --> 00:29:41,212
DONE BY US AND THIS ALCOHOL

719
00:29:41,279 --> 00:29:43,982
CIRRHOSIS GWAS, THE INTRAMURAL

720
00:29:44,048 --> 00:29:46,317
AUD PEASHTS WITHOUT CIRRHOSIS

721
00:29:46,384 --> 00:29:47,852
WERE ESPECIALLY VALUABLE.

722
00:29:47,919 --> 00:29:51,656
AND FROM THAT GWAS, 3 OF THE TOP

723
00:29:51,723 --> 00:29:53,158
GENES THAT WERE IMPLICATED WERE

724
00:29:53,224 --> 00:29:56,694
ACTUALLY 1S THAT WERE INVOLVED

725
00:29:56,761 --> 00:29:58,429
IN LIPID DROPLET FORMATION AND

726
00:29:58,496 --> 00:30:04,936
THERE IS THE PI OF THIS--OF THIS

727
00:30:05,003 --> 00:30:06,471
GENOME OUT CONSORTIUM AND I WILL

728
00:30:06,538 --> 00:30:07,772
JUST EMPHASIZE 1 THING THAT THE

729
00:30:07,839 --> 00:30:11,209
JEEPS THAT HAVE BEEN FOUND SO

730
00:30:11,276 --> 00:30:13,511
FAR FOR CIRRHOSIS ARE 1S OF VERY

731
00:30:13,578 --> 00:30:14,012
LARGE EFFECT.

732
00:30:14,078 --> 00:30:16,681
YOU SEE THESE ODDS RATIOS SUCH

733
00:30:16,748 --> 00:30:19,584
AS 2 OR .78 OR .79, THESE ARE

734
00:30:19,651 --> 00:30:21,786
MUCH LARGER THAN THE TYPICAL

735
00:30:21,853 --> 00:30:23,755
ODDS RATIOS THAT ARE SEEN WITH

736
00:30:23,821 --> 00:30:25,089
GWAS STUDIES.

737
00:30:25,156 --> 00:30:26,925
NOW, GWAS STUDIES REQUIRING

738
00:30:26,991 --> 00:30:29,894
HUNDREDS OF THOUSANDS OF

739
00:30:29,961 --> 00:30:31,229
INDIVIDUALS WITHIN DETECT LOCI,

740
00:30:31,296 --> 00:30:34,532
BUT THE LOCI THAT REQUIRE SUCH

741
00:30:34,599 --> 00:30:36,267
LARGE SAMPLE SIZES ARE 1S THAT

742
00:30:36,334 --> 00:30:40,138
VERY SMALL EFFECT, NOT 1'S LIKE

743
00:30:40,205 --> 00:30:40,371
THIS.

744
00:30:40,438 --> 00:30:42,907
WHICH ARE LARGE AND WHICH EMERGE

745
00:30:42,974 --> 00:30:45,476
FROM EVEN SMALLER GWAS STUDIES,

746
00:30:45,543 --> 00:30:48,813
WE KNOW THAT AS THE STUDIES GET

747
00:30:48,880 --> 00:30:50,014
LARGER THAT ADDITIONAL GENES

748
00:30:50,081 --> 00:30:51,883
WILL BE REVEALED BUT IT'S VERY

749
00:30:51,950 --> 00:30:56,354
INTERESTING OF  THE GENES THAT E

750
00:30:56,421 --> 00:31:00,191
HAVE SO FAR THAT THEY OF LARGE

751
00:31:00,258 --> 00:31:00,425
EFFECT.

752
00:31:00,491 --> 00:31:05,296
SO WE'VE ALWAYS STUDIED ALCOHOL

753
00:31:05,363 --> 00:31:07,532
HEPA TITIS, THIS IS DONE WITH A

754
00:31:07,599 --> 00:31:11,669
DIFFERENT CONSORTIUM LED BY

755
00:31:11,736 --> 00:31:16,808
LAUREN NAGEY, SO ALCOHOL PEP A

756
00:31:16,874 --> 00:31:19,244
TITIS, IS UNLIKE CIRRHOSIS IS

757
00:31:19,310 --> 00:31:20,545
ALSO MARKED BY INFILTRATION OF

758
00:31:20,612 --> 00:31:23,815
CELLS AND OTHER CELLS AND

759
00:31:23,881 --> 00:31:27,051
DELIVER CUTE PHASE REACTANTS AND

760
00:31:27,118 --> 00:31:34,158
ACUTE SYMPTOMS INCLUDE ABDOMINAL

761
00:31:34,225 --> 00:31:36,194
PAIN, NAUSEA, [INDISCERNIBLE]

762
00:31:36,261 --> 00:31:37,996
AND JAUNDICE, SO WE SEQUENCED

763
00:31:38,062 --> 00:31:42,000
ALCOHOL AS PART OF THIS

764
00:31:42,066 --> 00:31:42,300
CONSORTIUM.

765
00:31:42,367 --> 00:31:44,402
THERE WAS A LARGE NUMBER OF

766
00:31:44,469 --> 00:31:45,870
HEAVY DRINKERS.

767
00:31:45,937 --> 00:31:48,973
THE HEAVY DRINKERS WITHOUT

768
00:31:49,040 --> 00:31:51,609
CIRRHOSIS--SORRY WITHOUT ALCOHOL

769
00:31:51,676 --> 00:31:52,777
HEPATITIS PREDOMINANTLY BEING

770
00:31:52,844 --> 00:32:00,752
FROM OUR INTRAMURAL PROGRAM AND

771
00:32:00,818 --> 00:32:02,954
THIS' A 58 MEGABASE GENOME

772
00:32:03,021 --> 00:32:04,122
TARGET AND ACCURACY AND

773
00:32:04,188 --> 00:32:06,891
COMPLETENESS AND YOU SEE THAT

774
00:32:06,958 --> 00:32:08,826
THEY'RE ARE 45 OR 50,000

775
00:32:08,893 --> 00:32:11,229
SEQUENCE VARIANTS WITHIN THIS

776
00:32:11,296 --> 00:32:12,664
EXOME TARGET PER INDIVIDUAL.

777
00:32:12,730 --> 00:32:15,033
AND DEPENDING UPON THE

778
00:32:15,099 --> 00:32:16,968
POPULATION OF ORIGIN, AFRICANS

779
00:32:17,035 --> 00:32:18,803
HAVING MORE VARIATION, I WOULD

780
00:32:18,870 --> 00:32:25,543
JUST LIKE TO DRAW ATTENTION TO

781
00:32:25,610 --> 00:32:27,679
QIAOPING YUAN, FROM OUR LAB WHO

782
00:32:27,745 --> 00:32:34,485
WAS THE FIRST AUTHOR ON THIS

783
00:32:34,552 --> 00:32:35,553
PAPER SUBMITTED.

784
00:32:35,620 --> 00:32:40,058
SO WE FOUND EXOME WIDE SNPs,

785
00:32:40,124 --> 00:32:42,160
INCLUDING MRS. BIG IN THIS FIELD

786
00:32:42,226 --> 00:32:44,095
OR MRS. BIG IN THIS FIELD,

787
00:32:44,162 --> 00:32:46,664
PASMMENT 3 WHICH IS A GENE

788
00:32:46,731 --> 00:32:47,965
INVOLVED IN LIPID DROPLET

789
00:32:48,032 --> 00:32:49,033
FORMATION, THESE ARE ALL ABOVE

790
00:32:49,100 --> 00:32:51,602
THE RED LINE AND THEN THESE 2

791
00:32:51,669 --> 00:32:53,371
ADDITIONAL GENES, THESE 2

792
00:32:53,438 --> 00:32:57,575
ADDITIONAL GENES BEING INVOLVED

793
00:32:57,642 --> 00:32:58,009
IN INFLAMMATION.

794
00:32:58,076 --> 00:32:59,577
SO YOU HAVE THE FINDINGS

795
00:32:59,644 --> 00:33:03,114
SUMMARIZED HERE AND I WON'T GO

796
00:33:03,181 --> 00:33:04,582
INTO REALLY GREAT DETAIL EXCEPT

797
00:33:04,649 --> 00:33:07,785
AGAIN TO SAY THAT THE ODDS RATIO

798
00:33:07,852 --> 00:33:12,657
EFFECTS OF THESE ARE LARGE AND

799
00:33:12,724 --> 00:33:14,392
RECENTLY FOR ALCOHOL CIRRHOSIS,

800
00:33:14,459 --> 00:33:16,060
THE YEENS HAVE BEEN PUT TOGETHER

801
00:33:16,127 --> 00:33:18,930
TO MAKE A POLYGENIC SCORE, THE

802
00:33:18,996 --> 00:33:20,098
POLYGENIC SCORE FOR ALCOHOL

803
00:33:20,164 --> 00:33:23,568
CIRRHOSIS AND A PAPER THAT JUST

804
00:33:23,634 --> 00:33:27,338
CAME OUT 2 DAYS AGO FROM OUR

805
00:33:27,405 --> 00:33:29,073
GENOME OUT CONSORTIUM, THAT

806
00:33:29,140 --> 00:33:31,642
POLYGENIC CORE IS BASED UPON 20

807
00:33:31,709 --> 00:33:33,978
GENES AND THERE'S A RISK OF

808
00:33:34,045 --> 00:33:36,180
ABOUT--JUST AN ODDS RATIO EFFECT

809
00:33:36,247 --> 00:33:40,084
OF ABOUT 3 DEPENDING UPON

810
00:33:40,151 --> 00:33:42,053
WHAT--DEPENDING UPON YOUR GENO

811
00:33:42,120 --> 00:33:44,589
TYPE AT THESE 20 GENES, SO IT'S

812
00:33:44,655 --> 00:33:46,290
STILL VERY PRECLINICAL, IT'S

813
00:33:46,357 --> 00:33:47,125
VERY PRECLINICAL BUT IT'S

814
00:33:47,191 --> 00:33:48,893
GETTING THERE FOR PREDICTIVE

815
00:33:48,960 --> 00:33:49,127
POWER.

816
00:33:49,193 --> 00:33:51,763
WE MIGHT ANTICIPATE THAT FOR

817
00:33:51,829 --> 00:33:53,064
ALCOHOL HEPATITIS THERE WILL BE

818
00:33:53,131 --> 00:33:55,199
SIMILARLY, THERE WILL BE EFFORTS

819
00:33:55,266 --> 00:33:59,570
TO CONSTRUCT POLYGENIC SCORES

820
00:33:59,637 --> 00:33:59,837
FOR IT.

821
00:33:59,904 --> 00:34:03,541
AND SO WHAT ABOUT THAT POLYGENIC

822
00:34:03,608 --> 00:34:04,509
CONTRIBUTION TO ALCOHOL

823
00:34:04,575 --> 00:34:06,310
HEPATITIS, THESE VARIANTS THAT

824
00:34:06,377 --> 00:34:08,379
ARE NOT GENOME WIDE SIGNIFICANT

825
00:34:08,446 --> 00:34:10,681
BUT THAT ARE RESPONSIBLE IN AN

826
00:34:10,748 --> 00:34:15,219
ACUTE PLOT FOR THE SLIGHT LAMDA

827
00:34:15,286 --> 00:34:16,387
VALUE INFLATION TAKEN--THEY WE

828
00:34:16,454 --> 00:34:18,656
OBSERVED, SO YOU HAVE EXPECTED

829
00:34:18,723 --> 00:34:20,725
P-VALUES AND OBSERVED P-VALUES

830
00:34:20,792 --> 00:34:22,493
AND THERE'S SLIGHT EXCESS DUE TO

831
00:34:22,560 --> 00:34:23,895
POLYGENIC CONTRIBUTION OF GENES

832
00:34:23,961 --> 00:34:25,329
THAT ARE STILL SUBTHRESHOLD IN A

833
00:34:25,396 --> 00:34:33,504
GWAS, SO WE LOOKED AT THAT

834
00:34:33,571 --> 00:34:34,405
POLYGENIC CONTRIBUTION AND PING

835
00:34:34,472 --> 00:34:37,141
DID IT IN A CLEVER WAY WHICH WAS

836
00:34:37,208 --> 00:34:39,477
TO TAKE ALL THE GENES AND RANK

837
00:34:39,544 --> 00:34:40,945
ORDER THEM AND THEN COMPARE THEM

838
00:34:41,012 --> 00:34:46,884
TO THE RANK ORDER OF PRECOMPILED

839
00:34:46,951 --> 00:34:48,052
LISTS, PRECURATED LISTS OF GENES

840
00:34:48,119 --> 00:34:51,823
SO FOR EXAMPLE, ALL THESE WIKI

841
00:34:51,889 --> 00:34:53,424
PATHWAYS, PRECOMPILED LISTS OR A

842
00:34:53,491 --> 00:34:55,493
LIST THAT MIGHT BE COMPOSED OF

843
00:34:55,560 --> 00:34:57,462
THE TOP GENES IN THE GWAS

844
00:34:57,528 --> 00:34:59,764
CATALOG AND YOU LOOK FOR

845
00:34:59,831 --> 00:35:04,001
ENRICHMENT AT THE EXTREMES OF

846
00:35:04,068 --> 00:35:06,404
THE P-VALUES AND SO WHAT WE

847
00:35:06,471 --> 00:35:09,640
OBSERVED WAS THIS THAT FIRST OF

848
00:35:09,707 --> 00:35:11,976
ALL THERE ARE GLYCEROL LIPID

849
00:35:12,043 --> 00:35:13,644
GENES WHICH ARE SIGNIFICANTLY

850
00:35:13,711 --> 00:35:15,780
IMPLICATED AND THIS WHOLE

851
00:35:15,847 --> 00:35:18,015
PATHWAY, THE 69 GENE WICKY

852
00:35:18,082 --> 00:35:21,152
PATHWAY THAT IS A MASTER

853
00:35:21,219 --> 00:35:23,588
REGULATOR OF FATTY ACID

854
00:35:23,654 --> 00:35:27,024
BIOSYNTHESIS IS IMPLICATED BUT

855
00:35:27,091 --> 00:35:28,759
FURTHER MORE, THERE'S THEN

856
00:35:28,826 --> 00:35:30,294
THIS--THERE ARE THEN THESE

857
00:35:30,361 --> 00:35:31,796
INFLAMMATORY GENES WHICH

858
00:35:31,863 --> 00:35:34,365
BASICALLY DO NOT PLAY SUCH A

859
00:35:34,432 --> 00:35:35,900
ROLE IN CIRRHOSIS.

860
00:35:35,967 --> 00:35:39,971
THESE INFLAMMATORY GENES

861
00:35:40,037 --> 00:35:42,707
INCLUDING THIS VITAMIN D

862
00:35:42,773 --> 00:35:44,308
SENSITIVE CALCIUM SIGNALING AND

863
00:35:44,375 --> 00:35:45,443
THIS BEING VERY IMPORTANT, IT'S

864
00:35:45,510 --> 00:35:47,278
BEEN KNOWN FOR A LONG TIME THAT

865
00:35:47,345 --> 00:35:48,713
VITAMIN D WAS CONNECTED TO

866
00:35:48,779 --> 00:35:51,983
INFLAMMATION AND THIS IS

867
00:35:52,049 --> 00:35:53,084
DRUGGABLE OF COURSE, AND THEN

868
00:35:53,150 --> 00:35:54,852
ALSO LOOKING AT THE GWAS CATALOG

869
00:35:54,919 --> 00:35:57,755
AT THE GENES THAT ARE SIMPLY

870
00:35:57,822 --> 00:35:58,556
LABELED INFLAMMATION GENES.

871
00:35:58,623 --> 00:36:01,225
AND SO YOU SEE THIS ENRICHMENT

872
00:36:01,292 --> 00:36:07,498
WHICH GOES UP TO 40% FOR THE

873
00:36:07,565 --> 00:36:09,267
VITAMIN D SENSITIVE CALCIUM

874
00:36:09,333 --> 00:36:09,934
SIGNALING YEENS.

875
00:36:10,001 --> 00:36:11,502
NOW ON THE OTHER HAND ISSUES

876
00:36:11,569 --> 00:36:12,336
WA'S NEGATIVE, WELL, WE DON'T

877
00:36:12,403 --> 00:36:14,138
HAVE TOO MUCH OF A ROLE FOR

878
00:36:14,205 --> 00:36:18,309
GENES THAT ARE INVOLVED IN

879
00:36:18,376 --> 00:36:21,979
ALCOHOL USE DISORDER OR

880
00:36:22,046 --> 00:36:22,780
DRINKING, EITHER NOT SIGNIFICANT

881
00:36:22,847 --> 00:36:24,682
IN THE CASE OF ALCOHOL

882
00:36:24,749 --> 00:36:27,051
DEPENDENCE GENES OR VERY--IT'S

883
00:36:27,118 --> 00:36:29,754
OVER HERE ON TOP OF IT ABOUT

884
00:36:29,820 --> 00:36:30,922
VERY MARGINALLY SIGNIFICANT AND

885
00:36:30,988 --> 00:36:33,357
THAT'S BECAUSE OUR CONTROLS WERE

886
00:36:33,424 --> 00:36:34,859
ALSO HEAVY DRINKERS, SO WE'VE

887
00:36:34,926 --> 00:36:37,028
ALREADY CONTROLLED FOR DRINKING.

888
00:36:37,094 --> 00:36:44,001
BUT SO FAR, THE GWAS THAT HAVE

889
00:36:44,068 --> 00:36:45,570
BEEN   PERFORMED ON ALCOHOL

890
00:36:45,636 --> 00:36:48,306
CIRRHOSIS AND RELATED PHENOTYPES

891
00:36:48,372 --> 00:36:50,074
HAVE NOT REVEALED THOSE ALCOHOL

892
00:36:50,141 --> 00:36:57,815
RELATED GENES, THAT'S PROBABLY

893
00:36:57,882 --> 00:36:59,250
COMING WITH LARGER GWAS.

894
00:36:59,317 --> 00:37:00,418
NOW FOLLOWING UP ON THIS FINDING

895
00:37:00,484 --> 00:37:05,690
ON A NUMBER OF GENES THAT ARE

896
00:37:05,756 --> 00:37:07,525
INVOLVED IN ALCOHOL CIRRHOSIS,

897
00:37:07,592 --> 00:37:09,427
ARE THE 1S THAT WOULD BE

898
00:37:09,493 --> 00:37:10,828
INTRINSIC TO THE HEPATOCYTES

899
00:37:10,895 --> 00:37:13,397
BECAUSE THEY'RE INVOLVED IN

900
00:37:13,464 --> 00:37:15,199
LIPID FORMATION FIRST.

901
00:37:15,266 --> 00:37:18,636
WE THEN MADE INDUCED HEPATOCYTE

902
00:37:18,703 --> 00:37:20,871
TYPE LIKE CELLS FROM THE

903
00:37:20,938 --> 00:37:22,373
SAME--FROM THE VERY PATIENT WHO

904
00:37:22,440 --> 00:37:24,208
IS HAVE ALCOHOL CIRRHOSIS AND

905
00:37:24,275 --> 00:37:27,979
WHO WOULD HAVE THE COMPLETE

906
00:37:28,045 --> 00:37:29,013
POLYGENIC CONTRIBUTION TO

907
00:37:29,080 --> 00:37:30,214
ALCOHOL CIRRHOSIS.

908
00:37:30,281 --> 00:37:40,791
THIS WAS DONE COLLABORATIVELY

909
00:37:41,626 --> 00:37:42,460
WITH KUNOS SANYALL, AND WHAT WE

910
00:37:42,526 --> 00:37:48,099
WERE ABLE TO SHOW IS THAT THE

911
00:37:48,165 --> 00:37:48,899
IHLCs SPONTANEOUSLY ACCUMULATE

912
00:37:48,966 --> 00:37:51,502
FAT AND THEY SHOW METABOLIC

913
00:37:51,569 --> 00:37:53,437
TRANSCREPT ORDER OF MICRONSIC

914
00:37:53,504 --> 00:37:55,706
ANDOXIDATIVE STRESS DIFFERENCES

915
00:37:55,773 --> 00:38:00,177
AS WAS--AS WE PUBLISHED ABOUT 2

916
00:38:00,244 --> 00:38:05,583
WEEKS AGO IN NATURE

917
00:38:05,650 --> 00:38:05,950
COMMUNICATIONS.

918
00:38:06,017 --> 00:38:12,790
SO HERE'S THE PROCESS BY WHICH

919
00:38:12,857 --> 00:38:13,891
THE IHLCs, HEPATOCYTE LIKE

920
00:38:13,958 --> 00:38:15,359
CELLS ARE MADE.

921
00:38:15,426 --> 00:38:17,762
WE START WITH PERIPHERAL BLOOD,

922
00:38:17,828 --> 00:38:22,900
WE PURIFY THE CD4 POSITIVE

923
00:38:22,967 --> 00:38:26,070
T-CELLS, THOSE T-CELLS ARE

924
00:38:26,137 --> 00:38:32,843
TRANSFECTED WITH THE 4 PRO

925
00:38:32,910 --> 00:38:34,679
POTENCY GENES THAT

926
00:38:34,745 --> 00:38:35,413
[INDISCERNIBLE] DISCOVERED AND

927
00:38:35,479 --> 00:38:38,482
THEN THAT TAKES ABOUT A MONTH,

928
00:38:38,549 --> 00:38:41,852
OUT TO ABOUT HERE, YOU HAVE

929
00:38:41,919 --> 00:38:44,255
IPSCs AND THEN OVER ABOUT 2

930
00:38:44,321 --> 00:38:48,259
MONTHS THEY'RE FORMED INTO

931
00:38:48,325 --> 00:38:56,200
IHLCs USING A DIFFERENTIATION

932
00:38:56,267 --> 00:38:56,901
METHOD OF ACADA.

933
00:38:56,967 --> 00:38:58,769
YOU CAN SEE IT HERE WHERE THEY

934
00:38:58,836 --> 00:39:00,304
START OFF WITH CLUMPS OF CELLS,

935
00:39:00,371 --> 00:39:02,773
YOU END UP WITH A BETTER

936
00:39:02,840 --> 00:39:03,974
MICROGRAPH OF THIS, BUT IT

937
00:39:04,041 --> 00:39:06,243
WOULDN'T SHOW IN THIS ROOM,

938
00:39:06,310 --> 00:39:09,714
ANYWAY, YOU WIND UP WITH NICE

939
00:39:09,780 --> 00:39:12,349
CUBOIDAL LIKE CELLS,LES LOOK FOR

940
00:39:12,416 --> 00:39:13,884
MUCH LEAK A PEP AT O SIGHT AND

941
00:39:13,951 --> 00:39:15,953
THESE ARE CELLS WHICH NO LONGER

942
00:39:16,020 --> 00:39:20,091
EXPRESS THE FLUR O POTENCY

943
00:39:20,157 --> 00:39:22,326
MARKER, SESA4 WHICH THE IPSCs

944
00:39:22,393 --> 00:39:25,463
DO, BUT THE MATURE, THESE MATURE

945
00:39:25,529 --> 00:39:30,468
CELLS ARE SEMIMATURE CELLS

946
00:39:30,534 --> 00:39:31,502
EXPRESS HEPATOCYTE

947
00:39:31,569 --> 00:39:34,805
CHARACTERISTIC GENES SUCH AS

948
00:39:34,872 --> 00:39:36,173
HNF4 AND ALBUT MIN.

949
00:39:36,240 --> 00:39:39,977
AND IT DOESN'T MATTER IF THEY

950
00:39:40,044 --> 00:39:42,780
ARE HEALTHY IHLCsS OR CONTROL

951
00:39:42,847 --> 00:39:44,415
IHLCs, WHEN THEY'RE MATURE,

952
00:39:44,482 --> 00:39:49,320
THEY EXPRESS SIMILAR LEVELS OF

953
00:39:49,386 --> 00:39:57,895
THE HNF 4 OR THE ALBUMIN.

954
00:39:57,962 --> 00:40:01,899
I'M KIND OF CONDITIONED TO HIT

955
00:40:01,966 --> 00:40:03,200
THIS KEYBOARD, INTERESTING, NOT

956
00:40:03,267 --> 00:40:05,169
VERY INTERESTING TO YOU, BUT TO

957
00:40:05,236 --> 00:40:06,303
ME.

958
00:40:06,370 --> 00:40:06,570
[LAUGHTER]

959
00:40:06,637 --> 00:40:13,644
SO HERE'S THE FAC THAT THE

960
00:40:13,711 --> 00:40:14,545
AC-IHLC SPONTANEOUSLY ACCUMULATE

961
00:40:14,612 --> 00:40:14,812
FAT.

962
00:40:14,879 --> 00:40:16,013
AND YOU CAN'T SEE THE

963
00:40:16,080 --> 00:40:18,082
MICROGRAPHS BUT WE'RE USING HERE

964
00:40:18,149 --> 00:40:28,692
3 DIFFERENT LIPID STAINS IN THE

965
00:40:29,493 --> 00:40:30,895
ALCOHOL CIRRHOSIS IHLCs

966
00:40:30,961 --> 00:40:32,730
ARE--WITH WE QUANTITATE IT ARE

967
00:40:32,797 --> 00:40:34,265
ACCUMULATING WAY MORE OF THESE

968
00:40:34,331 --> 00:40:37,501
LIPID TAINS THAN ARE THE HEALTHY

969
00:40:37,568 --> 00:40:37,701
IHLCs.

970
00:40:37,768 --> 00:40:42,606
AND HERE YOU SEE THAT THE

971
00:40:42,673 --> 00:40:43,908
MITOCHONDRIA RESPIRATION OF

972
00:40:43,974 --> 00:40:44,909
THESE CELLS WERE DISRUPPED.

973
00:40:44,975 --> 00:40:46,710
WE WERE ANAL TO TAKE THESE

974
00:40:46,777 --> 00:40:48,646
CELLS, PUT THEM IN AN INSTRUMENT

975
00:40:48,712 --> 00:40:51,182
CALLED THE SEA HORSE WHICH

976
00:40:51,248 --> 00:40:52,116
MEASURES OXYGEN COMSUMPTION

977
00:40:52,183 --> 00:40:54,518
RIGHT, USE THESE SPECIFIC

978
00:40:54,585 --> 00:40:57,588
INHIBITORS THAT LET US ACCESS

979
00:40:57,655 --> 00:41:00,858
DIFFERENT PARTS OF THEOXIDATIVE

980
00:41:00,925 --> 00:41:02,092
RESPIRATORY CHAIN, THESE

981
00:41:02,159 --> 00:41:07,932
DIFFERENT INHIBITORS, YOU CAN

982
00:41:07,998 --> 00:41:10,301
SEE THEM THERE, ANAMICEIN A AND

983
00:41:10,367 --> 00:41:11,802
FCCP, AND ESTIMATE ALL THESE

984
00:41:11,869 --> 00:41:12,870
DIFFERENT PARAMETERS AND THE

985
00:41:12,937 --> 00:41:14,972
IMPORTANT THING IS THAT EXCEPT

986
00:41:15,039 --> 00:41:18,976
FOR BASE--EXCEPT FOR THE

987
00:41:19,043 --> 00:41:19,710
NONMITOCHONDRIA RESPIRRAATION

988
00:41:19,777 --> 00:41:20,644
WHICH IS NOT MUCH DIFFERENT THAN

989
00:41:20,711 --> 00:41:21,946
THE CASES AND CONTROLS THAT

990
00:41:22,012 --> 00:41:24,281
THESE CELLS WHICH HAVE BEEN

991
00:41:24,348 --> 00:41:28,319
GROWING INVITRO, AND OUTSIDE THE

992
00:41:28,385 --> 00:41:31,522
BODY FOR ALL THESE MONTHS THAT

993
00:41:31,589 --> 00:41:40,698
THESE CELLS ARE ALREADY AT BASE

994
00:41:40,764 --> 00:41:42,666
LINE, DIFFERENT IN THE ZONE, YOU

995
00:41:42,733 --> 00:41:45,536
CAN LOOK AT MAXIMAL RESPIRATION

996
00:41:45,603 --> 00:41:46,303
OR SPARE CAPACITY OR WHATEVER

997
00:41:46,370 --> 00:41:49,006
AND SEE THAT THE BLUE LINES ARE

998
00:41:49,073 --> 00:41:54,144
ABOVE THE RED LINES AND FURTHER

999
00:41:54,211 --> 00:41:57,214
MORE THE AC RESULTS ARE NOT ABLE

1000
00:41:57,281 --> 00:41:59,717
TO UTILIZE FATTY ACIDS AND

1001
00:41:59,783 --> 00:42:01,919
GLUTAMATE AND GLUTAMINE AS WELL,

1002
00:42:01,986 --> 00:42:09,526
AND FOR THIS THE IRREVERSIBLE

1003
00:42:09,593 --> 00:42:10,294
TRANSPORT INHIBITOR ANAMOCKSIER

1004
00:42:10,361 --> 00:42:14,265
ARE USED FOR FATTY ACIDS AND

1005
00:42:14,331 --> 00:42:21,038
THEN [INDISCERNIBLE] IS USED TO

1006
00:42:21,105 --> 00:42:24,241
ESTIMATE THE METABOLISM OF

1007
00:42:24,308 --> 00:42:24,508
GLUTAMATE.

1008
00:42:24,575 --> 00:42:32,483
AND WHAT WE SEE AGAIN IS THAT

1009
00:42:32,549 --> 00:42:35,953
THE DEPENDENCE OF THESE

1010
00:42:36,020 --> 00:42:37,688
AC AHLCs ON THE SUBSTRATES IS

1011
00:42:37,755 --> 00:42:45,095
MUCH LOWER THAN NORM AT IHLCs.

1012
00:42:45,162 --> 00:42:50,267
SO THEN 1 CAN FOLLOW THIS UP BY

1013
00:42:50,334 --> 00:42:53,270
THE YEERN LEVEL BY

1014
00:42:53,337 --> 00:42:54,638
TRANSCRIPTOMICS AND SO WHAT'S

1015
00:42:54,705 --> 00:42:57,708
DONE HERE IS TO DO SO CALLED RNA

1016
00:42:57,775 --> 00:43:03,447
SEQ, ON THE RNA FROM THE CELLS,

1017
00:43:03,514 --> 00:43:09,186
JUST BULK RNA SEQUENCING, THAT

1018
00:43:09,253 --> 00:43:13,657
LETS YOU MEASURE ABOUT  16,000

1019
00:43:13,724 --> 00:43:16,994
GENES AND TO LOOK AT THE

1020
00:43:17,061 --> 00:43:21,832
DIFFERENTIALLY EXPRESSED YEENS

1021
00:43:21,899 --> 00:43:24,902
BETWEEN CONTROL AND AND ALCOHOL

1022
00:43:24,969 --> 00:43:25,836
CIRRHOSIS, IHLCs AND WHAT YOU

1023
00:43:25,903 --> 00:43:30,240
SEE IS DOWN REGULATION IN THE ON

1024
00:43:30,307 --> 00:43:32,009
THE IHLCs ON A NUMBER OF

1025
00:43:32,076 --> 00:43:36,413
PATHWAYS INCLUDING IT, C CYCLE,

1026
00:43:36,480 --> 00:43:38,882
GLYCOLYSIS AND

1027
00:43:38,949 --> 00:43:41,151
GLUCONEOGENESIS,OXIDATIVE

1028
00:43:41,218 --> 00:43:41,752
PHOSPHORYLATION AND ELECTRON

1029
00:43:41,819 --> 00:43:48,258
TRANSPORT CHAIN AND VERY LARGE

1030
00:43:48,325 --> 00:43:52,863
OF THESE GENES IN THESE FORMERLY

1031
00:43:52,930 --> 00:43:53,731
PREDEFINED WIKIPATHWAYS.

1032
00:43:53,797 --> 00:43:59,269
AND THENOT OTHER HAND

1033
00:43:59,336 --> 00:44:02,906
UPREGULATED ARE APOPTOSIS AND

1034
00:44:02,973 --> 00:44:04,775
DNA DAMAGE AND ADIPOSE GENESIS,

1035
00:44:04,842 --> 00:44:09,380
AND SO IT REFLECTS WHAT YOU SEE

1036
00:44:09,446 --> 00:44:10,280
THROUGH A MICROSCOPE.

1037
00:44:10,347 --> 00:44:12,549
THE SICKENING OF CELLS AND THE

1038
00:44:12,616 --> 00:44:13,517
ACCUMULATION OF DROPLETS AND

1039
00:44:13,584 --> 00:44:15,019
FINALLY IT'S A POTENTIAL

1040
00:44:15,085 --> 00:44:16,920
PLATFORM FOR TESTING

1041
00:44:16,987 --> 00:44:17,254
THERAPEUTICS.

1042
00:44:17,321 --> 00:44:20,891
THIS IS A THERAPEUTIC RAM CALL

1043
00:44:20,958 --> 00:44:23,761
THAT'S ALREADY IN A PHASE 2 B

1044
00:44:23,827 --> 00:44:27,231
TRIAL, AND SHOWING POSITIVE

1045
00:44:27,297 --> 00:44:31,902
RESULTS IN METABOLIC ASSOCIATED

1046
00:44:31,969 --> 00:44:38,008
HEPATITIS, WHICH USE TO BE

1047
00:44:38,075 --> 00:44:45,916
CALLED SNASH AND FACTORED IN TO

1048
00:44:45,983 --> 00:44:47,851
SEE ARAMCHOL HAS A POETIC

1049
00:44:47,918 --> 00:44:48,685
TEBTIAL BENEFIT IN THESE

1050
00:44:48,752 --> 00:44:53,057
PATIENTS WHEN YOU GO FROM 5%

1051
00:44:53,123 --> 00:44:59,830
MASH RESOLVED TO 16.7% MASH

1052
00:44:59,897 --> 00:45:00,097
RESOLVED.

1053
00:45:00,164 --> 00:45:03,567
SO WE THEN TOOK THAT ARAMCHOL

1054
00:45:03,634 --> 00:45:06,236
AND USED IT IN THE IHLCs AND

1055
00:45:06,303 --> 00:45:08,772
SAW THAT IT IMPROVED THE

1056
00:45:08,839 --> 00:45:09,673
MITOCHONDRIA PERFORMANCE IN A

1057
00:45:09,740 --> 00:45:10,107
POWERFUL WAY.

1058
00:45:10,174 --> 00:45:13,177
AND YOU CAN JUST SEE THE

1059
00:45:13,243 --> 00:45:15,345
DIFFERENCE BETWEEN THE RED BAR

1060
00:45:15,412 --> 00:45:18,315
AND THE GREEN BAR FOR THESE

1061
00:45:18,382 --> 00:45:22,519
DIFFERENT PARAMETERS FOR THE

1062
00:45:22,586 --> 00:45:24,221
MITOCHONDRIA FUNCTIONAL

1063
00:45:24,288 --> 00:45:28,158
RESPIRATION, ATP PRODUCTION,

1064
00:45:28,225 --> 00:45:36,166
SPARE RESPIRATORY CAPACITY AND

1065
00:45:36,233 --> 00:45:38,102
FACIAL RESTORATION, AND COULD

1066
00:45:38,168 --> 00:45:40,204
PROVE IN THE HEPATOCYTE AND

1067
00:45:40,270 --> 00:45:41,705
POTENTIALLY MIGHT HELP PATIENTS

1068
00:45:41,772 --> 00:45:44,741
AND HELP MORE PATIENTS BY THESE

1069
00:45:44,808 --> 00:45:45,375
DRUGS THAN OTHERS.

1070
00:45:45,442 --> 00:45:53,117
SO I WOULD LIKE TO CONCLUDE TO

1071
00:45:53,183 --> 00:45:56,553
SAY THAT ALCOHOL USE HAS USE

1072
00:45:56,620 --> 00:45:58,355
DISORDERS AND PSYCHIATRIC

1073
00:45:58,422 --> 00:46:00,591
DISEASES AND NEVERTHELESS, IT'S

1074
00:46:00,657 --> 00:46:05,462
A CLASSIC THEME BY ENVIRONMENT

1075
00:46:05,529 --> 00:46:06,563
INTERACTION DISORDER, AND THE

1076
00:46:06,630 --> 00:46:07,798
GENE EFFECTS ARE STRONGER IN

1077
00:46:07,865 --> 00:46:09,333
MEDICAL KIEWLS AND ISHT MEDIATE

1078
00:46:09,399 --> 00:46:12,169
PROCESSES BUT WE'VE LEARNED THAT

1079
00:46:12,236 --> 00:46:14,304
LARGE GWAS ON CRUDE PHENOTYPES

1080
00:46:14,371 --> 00:46:15,606
CAN DETECT UNKNOWN GENES AND

1081
00:46:15,672 --> 00:46:17,407
MANY MORE GENES OF SMALL EFFECT

1082
00:46:17,474 --> 00:46:22,312
AND THAT ARE LARGELY UNKNOWN.

1083
00:46:22,379 --> 00:46:23,947
ALCOHOL HAS POWERFUL EPIGENETIC

1084
00:46:24,014 --> 00:46:27,117
EFFECTS AS YOU WOULD EXPECT BUT

1085
00:46:27,184 --> 00:46:28,852
IT'S WONDERFUL TO SEE THIS

1086
00:46:28,919 --> 00:46:30,854
MAPPED OUT NOW WITH OUR POWERFUL

1087
00:46:30,921 --> 00:46:32,322
TECHNOLOGIES AND TO REALIZE THAT

1088
00:46:32,389 --> 00:46:34,758
THE AFFECTS ARE STRONGER IN SOME

1089
00:46:34,825 --> 00:46:36,393
PEOPLE THAN THIS OTHERS AND

1090
00:46:36,460 --> 00:46:39,062
NOBODY WANTS TO ACCELERATE THEIR

1091
00:46:39,129 --> 00:46:42,065
EPIGENETIC AGE BY 2 YEARS.

1092
00:46:42,132 --> 00:46:43,667
THE YEENS AFFAIRS TEAM

1093
00:46:43,734 --> 00:46:48,438
LEADERRERRING RISK OF AUD,

1094
00:46:48,505 --> 00:46:49,606
ALCOHOL CIRRHOSIS AND HEPATITIS

1095
00:46:49,673 --> 00:46:51,775
ARE OVERLAPPING BUT THEY ARE

1096
00:46:51,842 --> 00:46:53,443
DISTINCT OF THE THE HEPATITIS

1097
00:46:53,510 --> 00:46:55,579
GENES ARE MUCH MORE INVOLVED IN

1098
00:46:55,646 --> 00:46:58,081
INFLAMMATION BUT TILL METABOLIC

1099
00:46:58,148 --> 00:47:00,918
GENES ARE ALSO INVOFFED IN

1100
00:47:00,984 --> 00:47:02,653
ALCOHOL ASSOCIATED HEPATITIS.

1101
00:47:02,719 --> 00:47:06,123
INVITRO, THE INTRINSIC METABOLIC

1102
00:47:06,190 --> 00:47:07,758
VULNERABILITY IF HEPATOCYTES,

1103
00:47:07,824 --> 00:47:12,262
THE IHLCs THAT IS, DERIVED THE

1104
00:47:12,329 --> 00:47:14,031
PATIENTS OH IPSCs APPEARS TO

1105
00:47:14,097 --> 00:47:15,866
BE CONSERVED, I WILL JUST

1106
00:47:15,933 --> 00:47:18,735
CONCLUDE BY THANKING YOU ALL FOR

1107
00:47:18,802 --> 00:47:21,104
YOUR ATTENTION AND SPECIAL

1108
00:47:21,171 --> 00:47:28,312
THANKS TO THE ALCOHOL CIRRHOSIS

1109
00:47:28,378 --> 00:47:29,880
CONSORTIUM, MY 2 PIs FOR THAT,

1110
00:47:29,947 --> 00:47:34,218
AND THEN OUR NEW DATA ON ALCOHOL

1111
00:47:34,284 --> 00:47:36,520
HEPATITIS THAT STUDY REALLY

1112
00:47:36,587 --> 00:47:43,427
INVOLVING A NUMBER OF OUR STAFF

1113
00:47:43,493 --> 00:47:51,802
NANCY DIAZ, MEL SCHWANDT, AND

1114
00:47:51,868 --> 00:47:53,437
BONNIE MOVED TO [INDISCERNIBLE]

1115
00:47:53,503 --> 00:47:57,241
AND THE LAB IS LEADING IT.

1116
00:47:57,307 --> 00:48:00,110
OUR EPIGENETIC STUDIES ARE WITH

1117
00:48:00,177 --> 00:48:01,545
FALK, AND HIS GROUP AND MANY

1118
00:48:01,612 --> 00:48:03,747
OTHERS AND FINALLY THIS WORK ON

1119
00:48:03,814 --> 00:48:07,784
THE AUDIT C, A SPECIAL SHOUT OUT

1120
00:48:07,851 --> 00:48:11,021
TO GEIN, NY, MBAMALU AND THE

1121
00:48:11,088 --> 00:48:14,958
REST OF THE CENTER AT THE

1122
00:48:15,025 --> 00:48:15,459
CKRSHES AUGHTIT C TEAM.

1123
00:48:15,525 --> 00:48:17,194
THANK YOU VERY MUCH.

1124
00:48:17,261 --> 00:48:23,634
[ APPLAUSE ]

1125
00:48:23,700 --> 00:48:24,434
TOM?

1126
00:48:24,501 --> 00:48:27,537
>> WELL WE DID HAVE A FEW

1127
00:48:27,604 --> 00:48:28,005
VIDEOCAST QUESTIONS.

1128
00:48:28,071 --> 00:48:30,107
WE DO HAVE A FEW

1129
00:48:30,173 --> 00:48:31,308
VIDEOCAST--FIEVER FIRST I WANT

1130
00:48:31,375 --> 00:48:32,843
TO SAY THANK YOU VERY MUCH FOR

1131
00:48:32,909 --> 00:48:38,615
THAT VERY THOUGHT PROVOKING AND

1132
00:48:38,682 --> 00:48:40,684
PRESENTATION ON GENOMICS AND

1133
00:48:40,751 --> 00:48:41,718
CELLULAR TOXICITIES ASSOCIATE

1134
00:48:41,785 --> 00:48:45,789
WIDE ALCOHOL USE, WHICH IS IF I

1135
00:48:45,856 --> 00:48:46,590
WILL SOBERING, ANYWAY.

1136
00:48:46,657 --> 00:48:48,225
SORRY ABOUT THAT, I'M HERE EVERY

1137
00:48:48,292 --> 00:48:48,492
THURSDAY.

1138
00:48:48,558 --> 00:48:50,093
WE DO HAVE A FEW QUESTIONS COME

1139
00:48:50,160 --> 00:48:50,260
IN.

1140
00:48:50,327 --> 00:48:52,529
ONE QUESTION IS AND I SHOWED

1141
00:48:52,596 --> 00:48:54,364
THIS TO YOU BEFORE HAND IS WHY

1142
00:48:54,431 --> 00:49:02,639
IS ALCOHOL NOT ILLEGAL?

1143
00:49:02,706 --> 00:49:03,974
>> WELL THE SIMPLE ANSWER IS WE

1144
00:49:04,041 --> 00:49:07,878
TRIED THAT AND THERE WERE 2

1145
00:49:07,944 --> 00:49:08,879
CONSTITUTIONAL AMENDMENTS

1146
00:49:08,945 --> 00:49:12,883
DEVOTED TO THE LEGALITY OF

1147
00:49:12,949 --> 00:49:13,350
ALCOHOLISM.

1148
00:49:13,417 --> 00:49:20,090
THE TEMPERANCE MOVEMENT WHICH

1149
00:49:20,157 --> 00:49:20,691
PRECEDED THE PROHIBITION

1150
00:49:20,757 --> 00:49:23,727
ACTUALLY HAD A LONG HISTORY MORE

1151
00:49:23,794 --> 00:49:24,661
THAN A CENTURY HISTORY IN THE

1152
00:49:24,728 --> 00:49:27,064
UNITED STATES AND YOU KNOW, IT

1153
00:49:27,130 --> 00:49:28,465
WAS MARKED BY ACTIVISTS,

1154
00:49:28,532 --> 00:49:33,270
MARCHING IN THE TREATS AND

1155
00:49:33,337 --> 00:49:35,305
ACTUALLY INNOVATING BARS AND

1156
00:49:35,372 --> 00:49:37,808
SMASHING ALCOHOL.

1157
00:49:37,874 --> 00:49:41,778
THERE ARE MANY DRY AREAS STILL

1158
00:49:41,845 --> 00:49:42,746
OF THE UNITED STATES.

1159
00:49:42,813 --> 00:49:47,317
MY HOME STATE OF TEXAS HAS

1160
00:49:47,384 --> 00:49:49,419
COUNTIES LIKE DEAF-SMITH COUNTY

1161
00:49:49,486 --> 00:49:51,388
WHERE 1 CANNOT BUY ALCOHOL AND

1162
00:49:51,455 --> 00:49:52,723
EVEN IN PLACES WHERE YOU CAN

1163
00:49:52,789 --> 00:49:53,890
PURCHASE ALCOHOL, YOU MAY NOT BE

1164
00:49:53,957 --> 00:49:58,095
ABLE TO DO SO ON A SUNDAY.

1165
00:49:58,161 --> 00:50:01,932
WE KNOW THAT SHORT OF MAKING

1166
00:50:01,998 --> 00:50:03,367
ALCOHOL ILLEGAL THAT JUST MAKING

1167
00:50:03,433 --> 00:50:07,404
IT MORE EXPENSIVE OR MORE

1168
00:50:07,471 --> 00:50:08,839
TYPICAL TO OBTAIN HAS ENORMOUS

1169
00:50:08,905 --> 00:50:11,475
EFFECTS SO I THINK THAT IT'S A

1170
00:50:11,541 --> 00:50:14,778
LOGICAL QUESTION TO ASK, BUT

1171
00:50:14,845 --> 00:50:16,713
THEN THE REALITY OF PROHIBITION

1172
00:50:16,780 --> 00:50:19,716
WAS THAT THERE WAS A COUNTER

1173
00:50:19,783 --> 00:50:20,917
MOVEMENT AND THAT COUNTER

1174
00:50:20,984 --> 00:50:24,988
MOVEMENT WAS VERY POWERFUL AND

1175
00:50:25,055 --> 00:50:25,922
IT WAS POWERFUL BECAUSE ALCOHOL

1176
00:50:25,989 --> 00:50:29,259
IS SUCH A WIDELY ENJOYED

1177
00:50:29,326 --> 00:50:34,431
SUBSTANCE BECAUSE THERE'S SUCH A

1178
00:50:34,498 --> 00:50:37,501
CULTURE OF ASSOCIATED WITH

1179
00:50:37,567 --> 00:50:39,002
ALCOHOL WHERE, YOU KNOW WHERE

1180
00:50:39,069 --> 00:50:42,839
WINE AND WHISKEY AND EVEN BEER,

1181
00:50:42,906 --> 00:50:45,609
EVEN BEER PLAY VERY IMPORTANT

1182
00:50:45,675 --> 00:50:47,210
PARTS IN PEOPLE'S LIVES AND

1183
00:50:47,277 --> 00:50:47,511
TRADITIONS.

1184
00:50:47,577 --> 00:50:50,647
AND SO IT'S A DIFFICULT THING TO

1185
00:50:50,714 --> 00:50:51,915
STAMP OUT.

1186
00:50:51,982 --> 00:50:53,683
AND WE NEVER WILL AND PROBABLY

1187
00:50:53,750 --> 00:50:55,852
WITHIN THE NEXT WEEK OR 2, I

1188
00:50:55,919 --> 00:51:00,891
WILL HAVE A GLASS OF WINE,

1189
00:51:00,957 --> 00:51:01,124
MYSELF.

1190
00:51:01,191 --> 00:51:04,995
BUT I LOVE THE QUESTION AND IT'S

1191
00:51:05,061 --> 00:51:06,329
CERTAINLY A VERY RELEVANT

1192
00:51:06,396 --> 00:51:09,199
QUESTION, ALSO IN TERMS OF THE

1193
00:51:09,266 --> 00:51:12,369
HARM REDUCTION MOVEMENT AND THE

1194
00:51:12,436 --> 00:51:15,238
TENDENCY TO LEGALIZE OTHER DRUGS

1195
00:51:15,305 --> 00:51:18,074
AND YOU KNOW WE'RE CERTAINLY

1196
00:51:18,141 --> 00:51:18,909
SEEN THAT CONVERSATION PLAY OUT

1197
00:51:18,975 --> 00:51:22,779
AND WE TALK ABOUT WHETHER THAT

1198
00:51:22,846 --> 00:51:24,981
CANNABIS SHOULD BE SCHEDULE 1,

1199
00:51:25,048 --> 00:51:27,884
SCHEDULE 3 OR COMPLETELY LEGAL

1200
00:51:27,951 --> 00:51:32,255
AS IT IS IN 26 STATES PRESENTLY.

1201
00:51:32,322 --> 00:51:34,191
SO WE'VE SEEN THAT, WE'RE SEEING

1202
00:51:34,257 --> 00:51:36,159
THAT WITH CANNABIS, WE'RE SEEING

1203
00:51:36,226 --> 00:51:40,430
IT WITH PSYCHEDELIC DRUGS, WHERE

1204
00:51:40,497 --> 00:51:41,631
THEY'VE BEEN MADE LEGAL IN A

1205
00:51:41,698 --> 00:51:47,137
COUPLE OF STATES AND WE'RE

1206
00:51:47,204 --> 00:51:50,507
LIKELY TO SEE THIS EXPERIMENT

1207
00:51:50,574 --> 00:51:52,843
PLAY OUT OVER THE NEXT FEW YEARS

1208
00:51:52,909 --> 00:51:56,179
AND AS THE EXPERIMENT PLAYS OUT,

1209
00:51:56,246 --> 00:51:57,681
IT'S VERY PREDICTABLE THAT A

1210
00:51:57,747 --> 00:51:59,182
CONSEQUENCE MAY BE THAT PEOPLE

1211
00:51:59,249 --> 00:52:04,154
WILL ENJOY THESE DRUGS BUT THAT

1212
00:52:04,221 --> 00:52:07,157
MANY PEOPLE WILL BECOME VICTIMS

1213
00:52:07,224 --> 00:52:08,158
OF THESE DRUGS.

1214
00:52:08,225 --> 00:52:10,160
SO I WOULD LOVE THE QUESTION, I

1215
00:52:10,227 --> 00:52:12,963
LOVE WHAT'S BEHIND IT.

1216
00:52:13,029 --> 00:52:13,463
>> THANK YOU.

1217
00:52:13,530 --> 00:52:15,365
I HAVE ANOTHER QUESTION, DOES

1218
00:52:15,432 --> 00:52:16,466
ANYBODY HAVE ANY QUESTIONS, WE

1219
00:52:16,533 --> 00:52:18,201
WILL TAKE THEM FROM THE AUDIENCE

1220
00:52:18,268 --> 00:52:20,270
OTHERWISE I WILL KEEP GOING

1221
00:52:20,337 --> 00:52:20,770
HERE.

1222
00:52:20,837 --> 00:52:26,409
ANOTHER VIEWER WRITES IN, PLEASE

1223
00:52:26,476 --> 00:52:30,247
DISCUSS THE GUT MICROBI OTA AND

1224
00:52:30,313 --> 00:52:32,516
THE EFFECTS OF THE ENVIRONMENT

1225
00:52:32,582 --> 00:52:34,985
AND WITH THE STUDY.

1226
00:52:35,051 --> 00:52:35,652
>> GREAT QUESTION.

1227
00:52:35,719 --> 00:52:37,654
SO THE CLINICAL CENTER, AND

1228
00:52:37,721 --> 00:52:40,490
COLLABORATIVELY WITH CLINICAL

1229
00:52:40,557 --> 00:52:41,091
TRUSTEES PERSONNEL INCLUDING

1230
00:52:41,157 --> 00:52:42,192
NANCY [INDISCERNIBLE] WHO IS

1231
00:52:42,259 --> 00:52:45,195
RETIRED NOW, WE DID A

1232
00:52:45,262 --> 00:52:48,465
LONGITUDINAL MICROBIOME STUDY IN

1233
00:52:48,532 --> 00:52:52,369
AUD, AND THIS IS A DNA

1234
00:52:52,435 --> 00:52:54,271
SEQUENCING, LOOKING AT THE

1235
00:52:54,337 --> 00:52:55,338
MICROBIOME OF AUD PATIENTS ON

1236
00:52:55,405 --> 00:52:56,973
ADMISSION AND THEN FOLLOWING

1237
00:52:57,040 --> 00:52:59,009
THEM ACROSS TIME WHEN THEY COME

1238
00:52:59,075 --> 00:53:03,346
INTO THE HOSPITAL, THEY'RE VERY

1239
00:53:03,413 --> 00:53:08,018
DISBIOTIC, THE SO CALLED

1240
00:53:08,084 --> 00:53:09,486
DIVERSITY INDEX, THE DIVERSITY

1241
00:53:09,553 --> 00:53:12,222
OF ORGANISMS THAT ARE IN THE

1242
00:53:12,289 --> 00:53:14,958
MICROBIOME ARE VASTLY PRODUCED

1243
00:53:15,025 --> 00:53:17,594
TO WHAT WILL HAPPEN OVER JUST A

1244
00:53:17,661 --> 00:53:19,329
COUPLE OF WEEKS OF ABSTINENCE

1245
00:53:19,396 --> 00:53:24,000
AND RESUSMGZ OF NORMAL NUTRITION

1246
00:53:24,067 --> 00:53:27,671
AND IT'S KNOWN THAT THE GUT

1247
00:53:27,737 --> 00:53:29,739
MICROBIOME PLAYS A CRITICAL ROLE

1248
00:53:29,806 --> 00:53:32,976
IN SOME OF THE ALCOHOL

1249
00:53:33,043 --> 00:53:34,244
ASSOCIATED DECS, ESPECIALLY

1250
00:53:34,311 --> 00:53:36,913
LIVER DISEASE, RON THURM AN

1251
00:53:36,980 --> 00:53:38,448
DECADES AGO SHOWED IF YOU

1252
00:53:38,515 --> 00:53:39,983
ACTUALLY ELIMINATE THE GUT

1253
00:53:40,050 --> 00:53:41,484
MICROBIOME YOU CAN LARGELY

1254
00:53:41,551 --> 00:53:44,888
PREDICT, YOU CAN LARGELY PREVENT

1255
00:53:44,955 --> 00:53:47,357
LIVER DISEASE IN LIFE, SO,

1256
00:53:47,424 --> 00:53:50,126
THE--WHEN YOU LOOK AT WHAT COMES

1257
00:53:50,193 --> 00:53:53,263
FROM THE GUT, FACTORS LIKE TUMOR

1258
00:53:53,330 --> 00:53:57,100
NECROSIS FACTOR AND OTHERS, YOU

1259
00:53:57,167 --> 00:54:01,071
REALIZE THAT AND REALIZE THE

1260
00:54:01,137 --> 00:54:02,839
IMPORTANT ROLE OF INFLAMMATION,

1261
00:54:02,906 --> 00:54:04,140
THE GUT MICROBIOME IS PLAYING A

1262
00:54:04,207 --> 00:54:08,812
CRITICAL ROLE IN THAT AND

1263
00:54:08,878 --> 00:54:11,281
ALCOHOL STRONGLY PERTURBS IN THE

1264
00:54:11,348 --> 00:54:12,015
GUT MICROBIOME.

1265
00:54:12,082 --> 00:54:12,415
>> THANK YOU.

1266
00:54:12,482 --> 00:54:14,250
I ACTUALLY HAVE A QUESTION ABOUT

1267
00:54:14,317 --> 00:54:17,020
THE AUDIT C PROJECT WHICH IS

1268
00:54:17,087 --> 00:54:18,455
OBVIOUSLY VERY POWERFUL AND

1269
00:54:18,521 --> 00:54:20,256
SENSITIVE TO IDENTIFYING THOSE

1270
00:54:20,323 --> 00:54:20,857
AT RISK.

1271
00:54:20,924 --> 00:54:22,158
I THINK 1 OF THE QUESTIONS AND

1272
00:54:22,225 --> 00:54:25,161
THIS S UP A LOT IS THE KREENING

1273
00:54:25,228 --> 00:54:26,830
THAT WE DO IS LIKE WHAT DO YOU

1274
00:54:26,896 --> 00:54:27,998
DO WITH THE RESULTS,

1275
00:54:28,064 --> 00:54:29,666
SPECIFICALLY FOR THE PATIENT.

1276
00:54:29,733 --> 00:54:31,501
I SUPPOSE A PATIENT WHO SCORES A

1277
00:54:31,568 --> 00:54:33,103
12 PROBABLY HAS ENOUGH INSIGHT

1278
00:54:33,169 --> 00:54:35,071
TO REALIZE HE OR SHE HAS ISSUES

1279
00:54:35,138 --> 00:54:36,373
WITH ALCOHOL USE BEFORE BUT FOR

1280
00:54:36,439 --> 00:54:38,508
THE 1S THAT CAME UP WITH, WERE

1281
00:54:38,575 --> 00:54:39,809
MORE LIKE TOWARD THE 5 AND 6

1282
00:54:39,876 --> 00:54:42,012
RANGE AND HOW DO YOU COUNSEL

1283
00:54:42,078 --> 00:54:43,079
THOSE PATIENTS ON OUR SYSTEMS

1284
00:54:43,146 --> 00:54:44,814
AND PROGRAMS IN PLACE FOR THAT,

1285
00:54:44,881 --> 00:54:47,050
FOR THOSE TYPE PATIENTS.

1286
00:54:47,117 --> 00:54:49,219
NYEAH, EXCELLENT QUESTION, TOM,

1287
00:54:49,285 --> 00:54:50,420
YOU KNOW I THINK THAT THE

1288
00:54:50,487 --> 00:54:56,860
INFORMATION IS REALLY FOR THE

1289
00:54:56,926 --> 00:54:57,527
PRIMARY CARE TEAM.

1290
00:54:57,594 --> 00:54:59,963
THE PHYSICIAN MAY BE WELL AWARE

1291
00:55:00,030 --> 00:55:01,131
ALREADY OF PATIENT'S HEAVY

1292
00:55:01,197 --> 00:55:02,565
DRINKING OR ALCOHOL USE

1293
00:55:02,632 --> 00:55:04,167
DISORDER, THE PATIENT MAY HAVE

1294
00:55:04,234 --> 00:55:07,971
EVEN ALREADY BEEN TREATED FOR

1295
00:55:08,038 --> 00:55:10,407
ALCOHOL USE DISORDER.

1296
00:55:10,473 --> 00:55:12,575
THE PATIENT THEMSELVES MAY NOT

1297
00:55:12,642 --> 00:55:16,012
HAVE THE FULL INSIGHT INTO THE

1298
00:55:16,079 --> 00:55:17,280
INTERACTIONS BETWEEN THE ALCOHOL

1299
00:55:17,347 --> 00:55:19,249
AND DRUGS THAT THEY MAY BE

1300
00:55:19,315 --> 00:55:21,751
TAKING OR WHY IT IS THAT THEY

1301
00:55:21,818 --> 00:55:24,521
HAVE SYMPTOMS LIKE ANXIETY,

1302
00:55:24,587 --> 00:55:26,056
DEPRESSION, OR WHY THEIR SEIZURE

1303
00:55:26,122 --> 00:55:28,024
THRESHOLD MIGHT BE LOWERED,

1304
00:55:28,091 --> 00:55:31,528
THERE ARE MANY INSIGHTS THAT THE

1305
00:55:31,594 --> 00:55:33,296
PHYSICIAN MIGHT HAVE, THE

1306
00:55:33,363 --> 00:55:35,365
PATIENT MIGHT NOT, MANY PATIENTS

1307
00:55:35,432 --> 00:55:37,901
DON'T KNOW THAT THERE'S A

1308
00:55:37,967 --> 00:55:38,935
DANGEROUS INTERACTION FOR

1309
00:55:39,002 --> 00:55:41,671
EXAMPLE BETWEEN TYLENOL AND

1310
00:55:41,738 --> 00:55:43,540
ALCOHOL AND THEY SHOULD, AND A

1311
00:55:43,606 --> 00:55:46,576
PHYSICIAN SHOULD BE ASKING ABOUT

1312
00:55:46,643 --> 00:55:48,812
THAT BECAUSE TYLENOL IS A DRUG

1313
00:55:48,878 --> 00:55:53,016
THAT IS PROBABLY SOLD IN

1314
00:55:53,083 --> 00:55:56,553
HUNDREDS OF MILLIONS IF NOT

1315
00:55:56,619 --> 00:55:59,522
BILLIONS OF DOSES IN THIS

1316
00:55:59,589 --> 00:56:03,827
COUNTRY AND IF YOU JUST LOOK AT

1317
00:56:03,893 --> 00:56:06,830
THE RESULTS FROM LAB CHEMISTRIES

1318
00:56:06,896 --> 00:56:08,765
OR HEMEATOLOGY REPORTS THAT MAY

1319
00:56:08,832 --> 00:56:11,468
COME BACK ON TO THE CHART, VERY

1320
00:56:11,534 --> 00:56:14,437
OFTEN TIMES TO INTERPRET THESE

1321
00:56:14,504 --> 00:56:15,538
RESULTS CORRECTLY AND CAREFULLY,

1322
00:56:15,605 --> 00:56:18,408
YOU MEDE TO KNOW ABOUT THE HEAVY

1323
00:56:18,475 --> 00:56:19,909
DRINKING OF A PERSON.

1324
00:56:19,976 --> 00:56:24,514
I MEAN THERE'S A REASON WHY THE

1325
00:56:24,581 --> 00:56:25,882
C-REACTIVE PROTEIN LEVEL, MAY BE

1326
00:56:25,949 --> 00:56:26,116
HIGH.

1327
00:56:26,182 --> 00:56:28,451
IT'S NOT JUST RANDOM, THEYA MAY

1328
00:56:28,518 --> 00:56:31,588
NOT HAVE AN AUTOIMMUNE DISORDER,

1329
00:56:31,654 --> 00:56:32,889
IT MAY BE THAT THEY ARE A PERSON

1330
00:56:32,956 --> 00:56:38,328
WHO HAS A LOT OF ALCOHOL

1331
00:56:38,394 --> 00:56:39,129
ASSOCIATED INFLAMMATION AND

1332
00:56:39,195 --> 00:56:42,198
THERE'S ALSO A GREAT NEED FOR

1333
00:56:42,265 --> 00:56:44,634
MANY PEOPLE WHO HAVE BEEN

1334
00:56:44,701 --> 00:56:47,270
DRINKING HEAV AND WHO ARE

1335
00:56:47,337 --> 00:56:49,806
NUTRITIONALLY DEFICIENT TO HAVE

1336
00:56:49,873 --> 00:56:51,174
VITAMIN SUPPLEMENTATION

1337
00:56:51,241 --> 00:56:55,645
INCLUDING THYMA MIN SO THEY DO

1338
00:56:55,712 --> 00:57:00,917
NOT DEVELOP [INDISCERNIBLE]

1339
00:57:00,984 --> 00:57:01,818
COUGH SYNDROME.

1340
00:57:01,885 --> 00:57:03,086
SO THERE'S A VARIETY OF REASONS

1341
00:57:03,153 --> 00:57:05,789
THAT THE AUDIT C SHOULD EVEN BE

1342
00:57:05,855 --> 00:57:06,956
THE SO CALLED FIFTH VITAL SIGN.

1343
00:57:07,023 --> 00:57:08,191
I DON'T KNOW IF I WOULD GO THAT

1344
00:57:08,258 --> 00:57:12,362
FAR BUT I THINK THAT EVERY

1345
00:57:12,428 --> 00:57:14,631
PHYSICIAN, EVERY HEALTH SYSTEM

1346
00:57:14,697 --> 00:57:16,366
SHOULD BE INQUIRING ABOUT

1347
00:57:16,432 --> 00:57:19,169
ALCOHOL IN THE SAME WAY THAT

1348
00:57:19,235 --> 00:57:22,872
THEY INQUIRE ABOUT PAIN OR THAT

1349
00:57:22,939 --> 00:57:24,808
THEY INQUIRE--THEY WANT TO KNOW

1350
00:57:24,874 --> 00:57:25,975
WHAT BLOOD PRESSURE AND A PULSE

1351
00:57:26,042 --> 00:57:27,110
AND A PULSE AND A TEMPERATURE

1352
00:57:27,177 --> 00:57:27,911
ARE IN A PERSON.

1353
00:57:27,977 --> 00:57:29,846
THIS IS NOT SOMETHING THAT YOU

1354
00:57:29,913 --> 00:57:35,919
NEED TO REPEAT OVER AND OVER,

1355
00:57:35,985 --> 00:57:37,220
BUT MISSION TO HAVE THAT

1356
00:57:37,287 --> 00:57:38,755
INFORMATION IS EXTREMELY

1357
00:57:38,822 --> 00:57:39,522
POWERFUL.

1358
00:57:39,589 --> 00:57:40,123
I THINK.

1359
00:57:40,190 --> 00:57:40,723
NIT'S POWER EMPLOY THANK YOU

1360
00:57:40,790 --> 00:57:40,990
VERY MUCH.

1361
00:57:41,057 --> 00:57:42,859
I THINK WE HAVE TIME FOR 1 MORE

1362
00:57:42,926 --> 00:57:43,126
QUESTION.

1363
00:57:43,193 --> 00:57:45,795
LET'S SEE, WHAT IS THE--WHAT ARE

1364
00:57:45,862 --> 00:57:47,864
THE NEXT STEPS IN AUD GENETICS

1365
00:57:47,931 --> 00:57:49,833
RESEARCH AND DO YOU THINK

1366
00:57:49,899 --> 00:57:53,636
POLYGENIC RISK FACTORS ARE

1367
00:57:53,703 --> 00:57:54,971
OFFERING PROMISING CONCLUSIONS?

1368
00:57:55,038 --> 00:57:57,173
>> CAN YOU REPEAT THAT?

1369
00:57:57,240 --> 00:57:57,440
>> YEAH.

1370
00:57:57,507 --> 00:58:01,778
WHAT ARE THE NEXT STEPS IN AUD

1371
00:58:01,845 --> 00:58:04,080
GENETICS RESEARCH AND DO YOU

1372
00:58:04,147 --> 00:58:07,383
THINK POLYGENIC RISK SCORES ARE

1373
00:58:07,450 --> 00:58:08,184
OFFERING PROMISING CONCLUSIONS?

1374
00:58:08,251 --> 00:58:08,518
>> YES.

1375
00:58:08,585 --> 00:58:10,286
OF COURSE THE NEXT STEP MIGHT BE

1376
00:58:10,353 --> 00:58:12,388
TO GET RID OF ME, BUT LET'S NOT

1377
00:58:12,455 --> 00:58:16,593
GO THERE.

1378
00:58:16,659 --> 00:58:17,794
I THINK THAT THEY'RE VERY USEFUL

1379
00:58:17,861 --> 00:58:18,995
IN A COUPLE WAYS.

1380
00:58:19,062 --> 00:58:20,864
ONE THING IS TO LOOK AT THE

1381
00:58:20,930 --> 00:58:21,965
INTERACTION OF EXPOSURES WITH

1382
00:58:22,031 --> 00:58:24,033
VULNERABILITY, SO IN THE OLD

1383
00:58:24,100 --> 00:58:27,036
DAYS, WE WOULD GET A FAMILY

1384
00:58:27,103 --> 00:58:31,007
HISTORY OR WE WOULD GET A FAMILY

1385
00:58:31,074 --> 00:58:33,409
HISTORY SCORE, AND SO NOW IS THE

1386
00:58:33,476 --> 00:58:34,344
POLYGENIC SCORE THAT'S BECOMING

1387
00:58:34,410 --> 00:58:37,747
MORE AND MORE POWERFUL, YOU KNOW

1388
00:58:37,814 --> 00:58:42,886
NOT JUST THE PERSON IS THE SON

1389
00:58:42,952 --> 00:58:45,288
OR DAUGHTER OF SOMEONE WHO MAY

1390
00:58:45,355 --> 00:58:46,823
HAVE ALCOHOL USE DISORDER OR

1391
00:58:46,890 --> 00:58:48,324
SOME OTHER VULNERABLE, BUT YOU

1392
00:58:48,391 --> 00:58:50,460
HAVE THE INFORMATION ON THE

1393
00:58:50,526 --> 00:58:53,796
GENES THAT THEY CARRY AND THAT'S

1394
00:58:53,863 --> 00:58:55,565
AS THE POLYGENIC SCORES GET MORE

1395
00:58:55,632 --> 00:58:57,300
POWERFUL, THEY'RE NOT YET VERY

1396
00:58:57,367 --> 00:59:02,171
POWERFUL AND SO, THAT'S CLEARLY

1397
00:59:02,238 --> 00:59:03,840
1 USE.

1398
00:59:03,907 --> 00:59:06,009
ANOTHER USE MIGHT BE COUNSELING

1399
00:59:06,075 --> 00:59:08,344
USE, YOU MIGHT USE THE POLYGENIC

1400
00:59:08,411 --> 00:59:10,079
CORE SCORES TO COUNCIL PEOPLE AS

1401
00:59:10,146 --> 00:59:11,147
TO THEIR VULNERABLE, A LOT OF

1402
00:59:11,214 --> 00:59:13,383
PEOPLE WHO COME FROM A FAMILY,

1403
00:59:13,449 --> 00:59:15,685
WHERE THERE MAY BE A LOT OF

1404
00:59:15,752 --> 00:59:17,587
ALCOHOL USE DISORDER OR ARE WELL

1405
00:59:17,654 --> 00:59:20,757
AWARE THAT THEY HAVE A

1406
00:59:20,823 --> 00:59:24,661
VULNERABILITY AND IT CAN ALSO BE

1407
00:59:24,727 --> 00:59:27,630
USED TO--FOR MEN DEALIAN

1408
00:59:27,697 --> 00:59:28,698
RANDOMIZATION TO STRATIFY PEOPLE

1409
00:59:28,765 --> 00:59:29,165
IN OUR STUDIES.

1410
00:59:29,232 --> 00:59:35,071
SO IF YOU HAVE A STUDY WHICH IS

1411
00:59:35,138 --> 00:59:36,339
A--WE'RE INVESTIGATE A TREATMENT

1412
00:59:36,406 --> 00:59:39,108
MODALITY TO KNOW THAT OVER HERE,

1413
00:59:39,175 --> 00:59:41,644
YOU HAVE PATIENTS WHO HAVE A

1414
00:59:41,711 --> 00:59:43,613
STRONG VULNERABILITY TO AUD AND

1415
00:59:43,680 --> 00:59:46,049
OVER THERE, THAT YOU HAVE SOME

1416
00:59:46,115 --> 00:59:47,450
PATIENTS WHO HAVE AUD BECAUSE

1417
00:59:47,517 --> 00:59:50,653
THEY JUST DECIDED TO START

1418
00:59:50,720 --> 00:59:52,655
DRINKING NOT THAT THEY HAD THE

1419
00:59:52,722 --> 00:59:53,690
STRONG VULNERABILITY, THE NUANCE

1420
00:59:53,756 --> 00:59:57,360
THERE IS THAT IT'S NOT JUST A

1421
00:59:57,427 --> 00:59:59,696
POLYGENIC SCORE FOR AUD, THAT 1

1422
00:59:59,762 --> 01:00:01,431
WOULD HAVE, 1 WOULD HAVE A

1423
01:00:01,497 --> 01:00:04,033
POLYGENIC CORE FOR RISK TAKING,

1424
01:00:04,100 --> 01:00:05,335
FOR NEGATIVE EMOTIONALITY, FOR

1425
01:00:05,401 --> 01:00:07,203
MANY OTHER PHENOTYPES THAT ARE

1426
01:00:07,270 --> 01:00:13,309
RELATED TO AUD AND SO YOU CAN

1427
01:00:13,376 --> 01:00:16,045
BEGIN TO ACTUALLY PARSE

1428
01:00:16,112 --> 01:00:20,216
INDIVIDUALITY IN NEW WAYS AND WE

1429
01:00:20,283 --> 01:00:21,718
WANT AS MUCH INFORMATION AS WE

1430
01:00:21,784 --> 01:00:23,019
CAN IN GENERAL IN MEDICINE, WE

1431
01:00:23,086 --> 01:00:24,787
WANT TO KNOW IF THE PERSON IS

1432
01:00:24,854 --> 01:00:26,422
MALE OR FEMALE, WE WANT TO KNOW

1433
01:00:26,489 --> 01:00:28,057
IF THEY'RE YOUNG OR OLD, SO

1434
01:00:28,124 --> 01:00:29,225
HERE'S ANOTHER PIECE OF

1435
01:00:29,292 --> 01:00:32,128
INFORMATION THAT WE CAN GIVE TO

1436
01:00:32,195 --> 01:00:35,231
CLINICIANS AND ALSO TO

1437
01:00:35,298 --> 01:00:35,765
INVESTIGATORS.

1438
01:00:35,832 --> 01:00:36,366
>> THANK YOU VERY MUCH.

1439
01:00:36,432 --> 01:00:37,900
AND THAT SORT OF TAKES US RIGHT

1440
01:00:37,967 --> 01:00:41,337
UP TO THE HOUR.

1441
01:00:41,404 --> 01:00:43,973
DR. GOLDMAN, THANK YOU FOR YOUR

1442
01:00:44,040 --> 01:00:45,008
OUTSTANDING PRESENTATIONS AND

1443
01:00:45,074 --> 01:00:46,709
YOUR EXTRAORDINARY BODY OF WORK

1444
01:00:46,776 --> 01:00:47,777
APPRECIATE IT.

1445
01:00:47,844
[ APPLAUSE ]