Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
1The screen versions of these slides have full details of copyright and acknowledgements
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACSProfessor of Surgery
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and BiochemistryBrody School of MedicineEast Carolina University
East Carolina
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University
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Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
2The screen versions of these slides have full details of copyright and acknowledgements
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Obesity trends* among U.S. adultsBRFSS, 2005
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
5No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
Eastern North CarolinaUSA
Regions: percent obese (body mass index: x ≥ 30.0)
nt
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Perc
en
Regions
US (2002) NC (2002) ENC41 (2001-2005)
Piedmont(2001-2005)
Western(2001-2005)
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
3The screen versions of these slides have full details of copyright and acknowledgements
North Carolina 2001 to 2005: total population age-adjusted mortality
due to diabetes mellitus
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Regional convergence of social issues
5.2 to 8.2%8.2 to 11.6%11.6 to 15.7%>15.7%
Poverty rate
Percent of the population without health insurance
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Data for 1999Center for Health Services Research and DevelopmentEast Carolina University
Premature mortality
Low
High
11.8 - 1616.1 - 1818.1 - 2020.1 - 23.1
Percent uninsured
1977: 1.2 million people; the nearest medical center 2½ hours away
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The site of the new medical school
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
4The screen versions of these slides have full details of copyright and acknowledgements
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Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
5The screen versions of these slides have full details of copyright and acknowledgements
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Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
6The screen versions of these slides have full details of copyright and acknowledgements
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1978 East Carolina University
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“Let’s researchtogether”
Obesity?
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Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
7The screen versions of these slides have full details of copyright and acknowledgements
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• Obesity is the most prevalent, fatal, chronic diseaseof the 21st century, increasing at a rate seen before only in infectious disease
• 64 5% of adult Americans are overweight or obese
Yes, obesity…
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• 64.5% of adult Americans are overweight or obese, even more in minorities
It’s not just about weight!The co-morbidities are even worse
Diabetes
Sleep apnea
Pulmonary failure
Heart disease
Stroke
Hernias
21
y
Asthma
Hypertension
Infertility
Depression
Arthritis
Pseudotumor cerebri
Immune suppression
Reflux
Stress incontinence
Pulmonary embolism
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
8The screen versions of these slides have full details of copyright and acknowledgements
The intestinal bypass
12 motions/day
Hypo-proteinemia
Liver failure
1950’s
22
Kidney stones
Mineral loss
Not a great answer
1978 - 80
23Mason gastric bypass Greenville gastric
bypass
1960’s
The platinum rules of clinical research
• Standardize: do not change the protocol
• Total integrity
f
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• Follow forever
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
9The screen versions of these slides have full details of copyright and acknowledgements
The Greenville gastric bypass
10 - 20 ml gastric pouch8 - 10 mm anastomosis40 - 60 cm alimentary loop
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Total group 1980-1998 = 83116 year cohort = 147
Weight loss after bariatric surgery@ 16 years (95% followup)
Mean weightMean % XS weight loss
Mean BMI
Preop 317 0 51
1 year 199 67 32
262003 Schauer U Pitt – 104 lb106 lb
2 years 194 69 32
5 years 209 57 34
10 years 217 51 35
16 years 211 55 37
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The Greenville gastric bypass produces durable and safe weight loss
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
10The screen versions of these slides have full details of copyright and acknowledgements
28
A morbidly obese woman who could not conceive…
250
300
LB
The weight loss is sustained
290 1 2 5 10 16
150
200
LB
Years
Mean % weight change over 15 years Swedish obesity study
in w
eigh
t (%
)
Vertical banded gastroplasty
Banding
Control
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Sjostrom: NEJM 2007;357:741-52
Years
Cha
nge
Gastric bypass
Vertical-banded gastroplasty
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
11The screen versions of these slides have full details of copyright and acknowledgements
1980: the first diabetic patients
1. Normal glucose level after surgery?
2. Normal glucose level after surgery?
3. Normal glucose level after surgery?
31
You don’t know how to work up patients!
4. Normal glucose level after surgery?
Why isn’t the lab giving us reliable values?
Date Glucose Insulin given
16 Nov ‘80 PREOP/OP 495 90
17 Nov 281 818 Nov 308 16
Insulin requirementspre & post gastricb pass
Pt. LT
Remission of diabetes after gastric bypass
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19 Nov 240 820 Nov 210 421 Nov 230 822 Nov 216 428 Nov 193 030 Nov 153 014 Dec 155 0
bypass
608 morbidly obese
165 Type 2Diabetics
165 IGT“impaired”
146 long enoughfollowup
152 long enoughfollowup
33
121/146 (83%)euglycemic
150/152 (99%)euglycemic
Schauer:1,160 pts.83% remission
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
12The screen versions of these slides have full details of copyright and acknowledgements
78
232 morbidly obese diabetics
154
Gastric BypassOperation refused
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Gastric Bypassfor personal or insurance reasons
22/78 (28%)/6.2 yrs14/154 (9%)/ 9 yrs
P<0.0003
Mortality
1%/yr 4.5%/yr
Long-term survival CanadaChristou et al., Ann Surg 2004; 240: 416-424
Rel. Risk = 0.11 (.04-.27)
89% reduction in risk of death over 5 years
6.17
6
7
35
of death over 5 years
0.68
0
1
2
3
4
5
% M
orta
lity
Control Bariatric
Unadjusted cumulative mortalitySwedish obesity study
36Sjostrom: NEJM 2007; 357: 741-52
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
13The screen versions of these slides have full details of copyright and acknowledgements
Morbid obesityOperative changes in abdominal pressure
37Sugerman et al.
P<0.0001
Surgically induced weight loss effects on urinary diary parameters
38Sugerman et al.
Before surgery After surgery
39
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
14The screen versions of these slides have full details of copyright and acknowledgements
40
Pulmonary artery pressure before and after surgically induced weight loss
for morbid obesity
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PaO2 and PaCO2 before and after surgically weight loss for morbid obesity
42
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
15The screen versions of these slides have full details of copyright and acknowledgements
43
Preoperative
After weight loss
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Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
16The screen versions of these slides have full details of copyright and acknowledgements
Health problems associated with morbid obesity
Diabetes
Sleep apnea
Pulmonary failure
Congestive heart failure
Stroke ?
Hernias
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Asthma
Hypertension
Infertility
Depression ?
Arthritis
Pseudotumor cerebri
Immune suppression ?
Reflux
Stress incontinence
Pulmonary embolism
Five year comorbidity comparison
*
*
*
Musculoskeletal
Infectious
Cancer
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*
*p<0.001Christou et al., Ann Surg 2004; 240: 416-424
0 5 10 15 20 25 30 35 40%
Cardiovascular
Endocrinological
MusculoskeletalControlBariatric
*
What’s going on here?
Let’s go ask a medical student: “What is Diabetes Mellitus?”
48
g
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
17The screen versions of these slides have full details of copyright and acknowledgements
Type 2 diabetes:“Patients don’t make enough insulin…”
Insulin resistance
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Insulin resistance
Look, type 2 diabetes is due to failure of the islets!
50
Oral glucose tolerance test
Are the islets the problem?
51No; the islets may be sick, but they work;
in fact, Type 2 diabetics are hyper-insulinemic
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
18The screen versions of these slides have full details of copyright and acknowledgements
52Type 2 diabetes: an islet of Langerhans demonstrates amorphous pink deposition of amyloid
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Type 1 diabetes: an islet of Langerhans demonstrates insulitis with lymphocytic infiltrates in a patient developing type I diabetes mellitus
54
What if insulin resistance is a protective mechanism of the cell against the overproduction of insulin?
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
19The screen versions of these slides have full details of copyright and acknowledgements
If the gut is overstimulating the islets,
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Then bypassing the gutshould make the insulin levels fall
Response of insulin levels to the GGB
in (μ
U/m
l)
100
60
40
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Pla
sma
Insu
l
Months postop
-12 0 12 24 36 48 60 72
80
20
0
Too much
Too muchgluconeogenesis
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insulin
Overwhelmedmitochondria
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
20The screen versions of these slides have full details of copyright and acknowledgements
CHO
Incretins Hormonesfrom fat
So, it’s not just a matter of glucose levels…
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from fat
CCK GhrelinoleylethanolamideGLIP-1 GLIP-2GIP apo A-IVPPY LeptinPYY etc.
LeptinAdiponectinResistinInflammatory cytokinesetc.Muscle
Neuro-endocrine
Genetic leptin deficiency causes obesity in ob/ob mice
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From Michael Swart
Leptin receptor mutation causes obesity in db/db mice
60db/db mouse+/+ mouse
From Michael Swart
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
21The screen versions of these slides have full details of copyright and acknowledgements
CHO
Incretins Hormonesf f t
Leptin insulinMC3R, PPARyMC4R. PYY, Neuropeptide YAgouti-related protCiliary neutrophic factors, etc.
Hypothalamus
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from fatCCK GhrelinoleylethanolamideGLIP-1 GLIP-2GIP apo A-IVPPY LeptinPYY etc.
LeptinAdiponectinResistinInflammatory cytokinesetc.Muscle
Neuro-endocrine
Insulin
S SSS S
S
IRS-1/2
NEFA
Fatty acyl-CoA
Glucose
CO2Ser
Ser P
P
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GLUT4
PI3K
PDK
Akt/PKB
aPKCζP
P
PKC (q or b) DAG
TAG
Dohm, GL et al.
Insulin sensitivity in non-diabetic gastric bypass patients (post-surgery)
and non-surgery control subjects
4
5
6
7
8
sitiv
ity In
dex
*
*
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0
1
2
3
4
Lean Weight-matched Morbidly obese Post-surgery
BMI <25 BMI = 25-35 BMI >35 BMI = 28.5
Insu
lin S
ens
†
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
22The screen versions of these slides have full details of copyright and acknowledgements
Muscle IRS1 serine phosphorylation in non-diabetic gastric bypass patients (post-
surgery) and non-surgery control subjects
11.21.41.61.8
ho-S
er31
2/IR
S1
ry u
nits
)
†
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00.20.40.60.8
Lean Weight-matched
Morbidly obese Post-surgery
BMI <25 BMI = 25-35 BMI >35 BMI = 29.9
IRS1
-Pho
sph
(arb
itra *
Obese
0
100
200
300
400
500
600
0 30 60 90 120 150 180 210 240 270 300Time (min)
Insu
lin (p
M) Before surgery
Surgery week3 month
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Diabetic
0
100
200
300
400
500
600
0 30 60 90 120 150 180 210 240 270 300
Time (min)
Insu
lin (p
M)
Before surgerySurgery week3 month
All patients – HOMA
3
4
5
6
7
*#O
MA
66
Pre 1 Wkpost
3 Mopost
0
1
2
3
*#
* p < 0.05# p < 0.05
(n = 6)
H
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
23The screen versions of these slides have full details of copyright and acknowledgements
Obese
0102030405060708090
0 30 60 90 120 150 180 210 240 270 300
Time (min)
GLP
1 (p
M) Before surgery
Surgery week3 month
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Diabetic
0102030405060708090
0 30 60 90 120 150 180 210 240 270 300
Time (min)
GLP
1 (p
M) Before surgery
Surgery week3 month
50
60
70
80
90
100
M
GLP-1 in response to a meal in non-diabetics
MID DOSE
680
10
20
30
40
50p
Time in minutes
HeadquartersSuppliers
Receiving
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Jobbers
Warehouse Customers
Insulin Inc.
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
24The screen versions of these slides have full details of copyright and acknowledgements
Restrictive Malabsorptive
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Gastric bypass
Adjustablegastric band
Verticalbandedgastroplasty
Duodenalswitch
BandingGastric bypass
Duodenal switch
Excess weight
Comparison of bariatric operations: the resolution of diabetes is “dose related”
n = 22,094 patients; 2738 citations 1990-2002
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Excess weight loss
47.5% 61.6% 70.1%
Operative mortality
0.1% 0.5% 1.1%
Resolution of diabetes
47.8% 83.6% 97.9%
Buchwald, Avidor, Braunwald, Jensen, Pories, Farbach, SchoellesJAMA 2004; 292: 1724-1737
Diabetologists maintain that the remission
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is due to weight loss alone; is that true?
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
25The screen versions of these slides have full details of copyright and acknowledgements
Rubino: Goto-Kakizaki Rat (GK)
Animal model of type 2 diabetes
• The most-widely used lean model in type 2 diabetes research
(Nature Genet 1996)
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– Non-obese
– Normolipidemic
– Hyperinsulinism
– Insulin resistance
Rubino: duodenal-jejunal bypass (DJB) in the GK rat
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Rubino: duodenal exclusion in the diabetic non-obese rat
OGTT
300350400450
Diet
Bypass
75P<0.001
050
100150200250
Baseline 10 min 30 min 60 min 120 min 180 min
Bypass
Sham
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
26The screen versions of these slides have full details of copyright and acknowledgements
Rubino: OGTT after duodenal exclusion
69000
OGTTAUC
Duodenal Pass.Duod. Exclus
76Annals of Surgery 2006
P<0.0544000
49000
54000
59000
64000
Duodenal Pass. Duod. Exclus
Rubino, F: Annals of Surgery, Nov 2006
Diabetic lean rats
77Duodenal silastic
tube; Diabetes clears
With perforations, the Diabetes returns
Insulin sensitivity in non-diabetic gastric bypass patients (>12 mo.)
and non-surgery subjects
8
10
12ControlPost bypassLinear (control)Linear (post bypass)
78
0
2
4
6
15.00 25.00 35.00 45.00 55.00 65.00BMI
HO
MA
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
27The screen versions of these slides have full details of copyright and acknowledgements
Interesting;Have there been any studies
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Have there been any studies in non-obese diabetic patients?
Patients Follow-upFasting
Glycemia Pre-op
Fasting GlycemiaPost-op
1. RG 7m 216 98
Duodenal-jejunal lap bypass in lean diabetic patients
Ramos A, Galvao Neto M, Galvao M.
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2. CD 7m 168 110
3. MC 6m 157 79
4. MM 5m 148 82
5. RD 2m 225 94
6. JG 1m 173 92
Patients Follow-upHbA1c Pre-op
HbA1cPost-op
1. RG 7m 8,6 6,2
Ramos A, Galvao Neto M, Galvao M.
Duodenal-jejunal lap bypass in lean diabetic patients
81
2. CD 7m 7,5 6,0
3. MC 6m 8,2 5,8
4. MM 5m 7,8 6,3
5. RD 2m 8,2 7,6
6. JG 1m 8,7 7,9
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
28The screen versions of these slides have full details of copyright and acknowledgements
Dr M. Lakdawala M.S. India 6 months follow up duodeno-jejunal bypass in lean diabetic patients
Pre-surgery (N = 3) Post surgery (6 months)
BMI1. 27.52. 283. 29.5
27.52729
HbA1C1. 92. 10.4
5.16.3
82
3. 9.5 6.0
PP Insulin1. 2402. 2323. 244
59.556.550.0
FBS1. 1282. 1553. 162
959290
PPBS1. 2652. 2443. 275
104134124
Gastrectomy and diabetes
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Surgery, Gynecology & Obstetrics; February 1955
OK, you have my interest; what are the indications for bariatric
surgery today?
• BMI ≥ 40
• BMI ≥ 35 with significant co-morbidities
≥ 18 f
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• ≥ 18 years of age
• Full understanding of surgery and its consequences
• Contract for life-long follow-up
• Supportive family
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
29The screen versions of these slides have full details of copyright and acknowledgements
Which operation is best?
85
48% 84% ?51% 98% ?100%
Rates of remission of Type 2 diabetes
Adjustable gastricband
Gastricbypass
Duodenalswitch
Gastric sleeve
Duodeno-jejunal bypass
OK;but isn’t bariatric surgery dangerous?
86
SRC data: 272 hospitals, 495 surgeons>110,000 patients
Hospital mortality 76 0.14%
Operative mortality at 30 days (76 + 89 = 165) 165 0.29%
87
Operative mortality at 90 days (76+89+31 = 196) 196 0.35%
Re-admissions 1,956 4.75%
Re-operations 887 2.15%
Bariatric Surgery:Techniques and Mechanisms of Action
Walter J. Pories, MD, FACS
30The screen versions of these slides have full details of copyright and acknowledgements
TABLE 2. Mortality rates following common operations in U.S. hospitals
AorticAneur
CABG CraniotEsophagResect
HipReplac
PancPed.Heart
Surgery
Number of hospitals performing operation
2485 1036 1600 1717 3445 1302 458
National average3 9 3 5 10 7 9 1 0 3 8 3 5 4
88
mortality rate(%)3.9 3.5 10.7 9.1 0.3 8.3 5.4
Average hospital caseloads median
30 491 12 5 24 8 4
[i] Dimick JB, Welch HG, Birkmeyer JD; Surgical mortality as an indicator of hospital quality; JAMA 2004, 292, 847-851
SRC: bariatric surgery mortality 0.3% (55,567 patients)
106 hospitals reporting average case load: 312 cases/year
Conclusions
• Diabetes is no longer a hopeless disease
• Current medical therapies for diabetes are complex, expensive with little proof that the new medications are better
S f ff f
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• Surgery for diabetes is effective and safe
• Surgery must be considered a therapeutic option
• Bariatric and metabolic surgery offers new research avenues toward the understanding of diabetes
• East Carolina University is a great place; come and visit us
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