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1
Impact of Body Mass Index in Liver Transplantation for Nonalcoholic Fatty Liver
Disease and Alcoholic Liver Disease
Running title
Impact of Body Mass Index in Liver Transplantation
Authors
Stephen O'Neill; Transplant Surgery Registrar1
Sara Napetti, Consultant Hepatobiliary Surgeon1
Sorina Cornateanu, Consultant Transplant Surgeon1
Andrew I Sutherland; Consultant Transplant Surgeon1
Stephen Wigmore; Professor of Transplantation Surgery and Honorary Consultant Surgeon1
Gabriel C Oniscu; Consultant Transplant Surgeon and Honorary Clinical Senior Lecturer1
Anya Adair; Consultant Transplant and Hepatobiliary Surgeon and Honorary Clinical Senior
Lecturer1
Institutions
1Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK, Royal
Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA
Corresponding author
Anya Adair, Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK,
Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA
Tel.0044-7968711417
2
E-mail: [email protected]
Sources of financial support
None
Type of article for submission
Original article
Conflicts of interest
None
Word count text
2655
Word count abstract
200
Author contribution
Each author has made a substantial contribution to the conception, design, drafting and
critical revision of this article for important intellectual content; and has given final approval
of the version to be published. Specific roles are summarised below:
SON – analysis, writing of manuscript
SN - data extraction, analysis, drafting of manuscript
SC - data extraction, drafting of manuscript
AIS – data extraction, analysis, drafting of manuscript
GO – conception, design, analysis, drafting of manuscript
AA - conception, design, analysis, drafting of manuscript
3
Abstract
Background: This study evaluates long-term outcomes and body mass index (BMI)
following liver transplantation (LT) for non-alcoholic fatty liver disease (NAFLD) in
comparison with alcoholic liver disease (ALD).
Methods: Patient and graft survival were compared using Kaplan Meier curves and log rank
test. Multivariable analysis of recipient and donor characteristics was performed as
determinants of patient survival. BMI at listing was compared with BMI post-LT.
Results: Patient survival at 1-, 3-, 5- and 10 years post-LT was similar in the ALD group
(n=195) compared with the NAFLD group (n=84) (93% vs. 93%, 91% vs. 89%, 86% vs.
77%, 64% vs. 66% respectively, p=0.21). One patient in the NAFLD group was re-
transplanted and none in the ALD group therefore graft survival was also similar (p=0.20).
Multivariable analysis didn’t identify any significant predictors of reduced survival. In
comparison with the ALD group, BMI was significantly higher in the NAFLD group at
listing (31 vs. 27, p<0.001), 3-months post-LT (28 vs. 26, p<0.05) and 6-months post-LT (29
vs. 27, p<0.05) but was equivalent by 5-years post-LT (29 vs. 30, p=0.80).
Conclusions: NAFLD patients had similar patient and graft survival post-LT compared to
ALD. NAFLD patients returned to listing BMI by one-year post-LT but by 5-years post-LT
there was no difference in BMI between the groups.
Key words
Liver Transplantation, Nonalcoholic Fatty Liver Disease
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Introduction
Due to the obesity epidemic non-alcoholic fatty liver disease (NAFLD) is increasing in
prevalence worldwide and is now the second leading cause of liver transplantation (LT) in the
United States (1). In the United Kingdom, 12% of patients placed on the LT waiting list are
categorised as having NAFLD (2). Currently 25% of LTs performed per year in the Scottish
Liver transplant Unit are for NAFLD and it is now the second most common indication for
LT in Scotland. Due to the increasing prevalence of obesity and diabetes worldwide it is
likely that in the future NAFLD will become the leading indication for LT both in Europe and
in United States (3). The increase in NAFLD related LTs is anticipated to have a significant
impact on liver transplantation workload, and raises difficult questions regarding the optimal
allocation of scarce organ resources.
Given the relatively recent increase in the proportion of LTs performed for NAFLD, there is
very little evidence of long-term outcomes following LT including 10-year graft and patient
survival. Indeed, there have been recent calls for comprehensive follow-up studies to be
conducted in NAFLD patients following LT to better understand long-term outcomes and
disease recurrence in this group (3). Alcoholic liver disease (ALD) is an established
indication for LT, and similar to NAFLD, lifestyle choices play an important role in the
pathogenesis of ALD. Therefore to better appreciate the long-term outcomes of LT in
NAFLD patients, the ALD population is a rational comparator group (4).
A recent systematic review and meta-analysis that examined 9 studies and 717 patients after
LT for NAFLD found similar 1-, 3-, and 5-year survival between NAFLD and other causes of
liver failure (5). In a review of the United Network for Organ Sharing a superior survival of
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patients undergoing LT for NAFLD was identified when compared with patients undergoing
LT for ALD (6). In a single centre study, however, a non-significant trend toward lower
survival post-LT was identified in the NAFLD group when compared with ALD patients (4).
In a further single centre analysis, obese and overweight patients did not have reduced patient
or graft survival following LT but had increased morbidity with longer lengths of intensive
care and hospitalisation (7). A body mass index (BMI) of >35 kg/m2 was identified as a
significant risk factor for mortality following LT (8), whilst patients with a BMI > 40 kg/m2
had significantly worse 5-year graft and patient survival (9). In a further study patients with
BMI of 35.1-40 kg/m2 also had lower patient and graft survival (10). A recent meta-analysis
has found that BMI does not reduce patient survival overall post-LT but that obese patients
have reduced survival when compared with non-obese patients with similar causes of liver
disease (11).
This study aims to evaluate long-term outcomes including patient and graft survival and BMI
changes following LT for NAFLD, and compare these outcomes with patients undergoing a
LT for ALD.
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Methods
This study retrospectively reviewed a prospectively collected database of patients undergoing
LT in the Scottish Liver transplant Unit between November 2002 and May 2015. The
demographics of patients and outcome measures including patient and graft survival, and
body mass index (BMI) throughout the post-LT period were compared between patients
undergoing LT for a primary indication of NAFLD and patients undergoing LT for a primary
indication of ALD. Graft survival was defined as death or re-transplantation and BMI as
weight (kg)/height (meters)2. In the Scottish Liver Transplant Unit there is no upper limit of
BMI beyond which patients are not considered for LT. Patients were also not excluded if they
had evidence of ascites or sarcopenia. Histologically proven recurrences of NAFLD on liver
biopsy are described in patients that had selective liver biopsies performed.
In this study, parametric data are presented as mean +/- standard deviation and non-
parametric data as median and range. Statistical comparisons of continuous parametric data
and non-parametric data were performed using student’s t-test and Mann-Whitney-U test
respectively. Statistical comparisons of categorical data were performed using Pearson’s Chi-
square test. Kaplan-Meier curves were constructed to evaluate patient survival probabilities
with differences compared using the log-rank test. Survival percentages are given with 95%
confidence intervals in parentheses. Multivariable survival analysis was performed using a
Cox proportional hazard regression model. All comparisons were performed on R v3.1.3 (R
Foundation for Statistical Computing) with p<0.05 considered statistically significant.
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Results
During the study period 866 LTs were undertaken. As the study progressed the number of
LTs performed for ALD and NAFLD increased year on year, but the most marked increase
occurred in the NAFLD group after 2011 (Figure 1). In total 84 patients who had a LT for
NAFLD and 195 for ALD were identified. In the NAFLD group 22 patients had a history of
alcohol use but none of the patients in the ALD group had a history of NAFLD. The NAFLD
group was significantly older and had a significantly higher BMI at listing but was otherwise
non-significantly different to the ALD group in terms of sex distribution, incidence of
hepatocellular carcinoma (HCC), model for end stage liver disease (MELD) score, follow up,
resource utilisation and donor characteristics including age, sex and graft type (Table 1).
Patients in the NAFLD group were followed up for a median of 4 years (range 0 – 13) during
which time 17 patients died. The cause of death was known for 14 of these patients and
included pneumonia (n=2), HCC recurrence (n=2), NAFLD recurrence (n=1), myocardial
infarction (n=1), sepsis (n=1), chronic obstructive pulmonary disease (n=1), colon cancer
(n=1), lung cancer (n=1), intra-abdominal haemorrhage (n=1), liver failure secondary to acute
rejection (n=1) and pulmonary fibrosis (n=1). One patient in the NAFLD group had normal
liver function tests at the time of death. The overall patient survival at 1-, 3-, 5- and 10 years
was 93% (88 - 99), 89% (82 - 96), 77% (67 – 90) and 66% (50 – 87) respectively. There was
one patient re-transplanted in the NAFLD group for primary-non-function therefore the
overall graft survival at 1-, 3-, 5- and 10 years was 93% (87 - 99), 89% (83 - 96), 77% (66 –
90) and 66% (50 – 87) respectively.
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Patients in the ALD group were followed up for a median of 5 years (range 0 – 14) during
which time 40 patients died. The cause of death was known for 34 of these patients and
included chronic obstructive pulmonary disease (n=5), cerebrovascular accident (n=4), liver
failure (n=4), pneumonia (n=4), sepsis (n=4), malignancy (n=4), haemorrhage (n=2), accident
(n=1), elevated pulmonary vascular resistance (n=1), myocardial infarction (n=1), pulmonary
embolus (n=1), recurrent HCC (n=1), respiratory failure (n=1) and sclerosing peritoneal
disease (n=1). Three patients in the ALD group had normal liver function tests at the time of
death. This gave an overall patient survival at 1-, 3-, 5- and 10 years of 93% (90 - 97), 91%
(87 - 95), 86% (81 – 91) and 64% (53 – 77). None of the ALD group was re-transplanted
therefore patient and graft survival was identical in the ALD group. Overall the patient
survival (Figure 2) and graft survival (Figure 3) was similar in the ALD group compared with
the NAFLD group. Multivariable survival analysis of recipient (age, sex, presence of
hepatocellular carcinoma, MELD) and donor characteristics (age, donor type) did not identify
any significant predictors of patient survival (Table 2).
In the NAFLD group there was a significant decrease in BMI at three and six months post-LT
(31 +/- 5 vs. 28 +/- 4, p<0.001 and 30 +/- 5 vs. 29 +/- 4, p<0.05 respectively) compared with
BMI at listing, but BMI returned to pre-transplant levels by the end of the first year following
LT (Figure 4). In the ALD group there was no significant decrease in BMI, but by 2 years
after LT there was a significant increase in BMI compared with the time of adding to the
waiting list (27 +/- 5 vs. 29 +/- 5, p<0.01), which was sustained up to 5 years after LT (27 +/-
5 vs. 30 +/- 6, p<0.05) (Figure 4). In comparison with the ALD group, BMI was significantly
higher in the NAFLD group at listing (31 +/- 5 vs. 27 +/- 5, p<0.001), 3 months post-LT (28
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+/- 4 vs. 26 +/- 4, p<0.05), 6 months post-LT (29 +/- 4 vs. 27 +/- 4, p<0.05) and 3 years
post-LT (32 +/- 6 vs. 29 +/- 5, p<0.05) but not at the other time points including 2 years, 4
years and 5 years post-LT (Table 1, Figure 4). None of the patients included in this study
underwent bariatric surgery at any time point.
Twenty patients in the NAFLD group underwent a selective liver biopsy for persistently
deranged liver function tests during follow up and disease recurrence of NAFLD was
histologically identified in four patients.
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Discussion
This was an exploratory study driven by the upsurge in NAFLD related disease in the LT
population in Scotland. This study has identified that patient survival is similar in NAFLD
patients compared with ALD patients after LT. In addition, after controlling for other donor
and recipient factors NAFLD was not an independent predictor of mortality post-LT. The
overall patient survival rate at 1-, 3-, and 5-years following LT for NAFLD reported in this
study (93%, 89% and 78% respectively) are comparable with other reports (3). The survival
rate reported from other single centre studies, which have diverse patient numbers (ranging
from 9 to 144) and severity of illness (mean MELD ranging from 9-33), varies from 78-90%,
73-88% and 60-85% at 1-, 3- and 5-year respectively (3). Larger database studies (n= 1840)
conducted by the Scientific Registry of Transplant Recipients (12), and United Network for
Organ Sharing (n=1810, mean MELD 21) (6) also report comparable survival rates post-LT
in NAFLD patients as observed in this study (84-88 % at 1 year, 78-82 % at 3 years and 77 %
at 5 years). The European Liver Transplant Registry reports a 63% survival at 10-years post
LT for NAFLD compared with 66% in this study.
ALD is a long-recognized indication for LT and it is well established that excellent outcomes
are possible if patients refrain from alcohol relapse (13). The reasons why the ALD
population was selected as a comparator group was because similar to NAFLD, lifestyle
choices play an important role in the pathogenesis of ALD. However, it is appreciated that
differences exist between the groups, as the NAFLD population has previously been
associated with a higher frequency of cardiovascular events and ALD patients have more
potential for malignant tumour development (3, 14). The Scottish Liver Transplant Unit
routinely conducts rigorous pre-assessment of ALD patients and carefully selects candidates
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to be listed for LT. This is reflected in the excellent outcomes reported in the ALD group
with overall patient survival at 1-, 3-, 5- and 10 years of 93%, 91%, 86% and 64%
respectively. In comparison, the European Liver Transplant Registry reports lower 1-, 5-, and
10-year patient survival rates of 86%, 73%, and 59% for ALD patients after LT (15).
NAFLD patients have previously been considered to be higher risk surgical candidates in the
short-term following LT particularly with regards cardiovascular events (3). In a study of 115
patients who underwent LT for NAFLD, it was found that they were significantly more likely
than patients with ALD (127 patients) to experience an adverse cardiac event one year after
transplant, even after risk adjustment (odds ratio 4.12; 95 % CI 1.91–8.90) (16). However, in
this study the outcomes in the NAFLD group tended to be similar in the longer term as well
as the first year post-transplant, this may reflect our policy of intensive pre-operative
cardiovascular investigation in this group.
The NAFLD population in this study, despite having a reduction in BMI early following LT,
regained their pre-transplant BMI by one year. In a review of 159 patients with a diagnosis of
HCC, higher BMI increased the risk for complications and led to a poorer oncologic outcome
following LT (17). It is unclear whether a lack of sustained BMI reduction contributed to
poorer longer-term transplant outcomes across the NAFLD group in this current study but
based on the evolution of BMI post-LT it would seem unlikely since there were no significant
differences in BMI compared to the ALD population in the longer term. However, BMI does
not take into account the fact that NAFLD is known to be associated with a six-fold increase
in sarcopenic obesity in the LT population (18). Sarcopenia, which was not assessed in this
study, strongly correlates with mortality following LT (19).
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Despite having cachexia, patients with chronic liver failure that have ascites or peripheral
oedema may have elevated BMI secondary to fluid overload rather than obesity (20). Pre-
transplant BMI can be corrected for ascites by subtracting the volume of ascites from the
patient weight (21). Corrected BMI was not utilised in this study and BMI may therefore
have been overestimated, particularly at the listing stage when ascites was more likely to be
present. However, this would have affected both the NAFLD and ALD groups.
Furthermore, BMI does not exclude the possibility of disease recurrence, which was evident
in 20% (4/20) of patients that had a post-LT biopsy. This finding could also be an
underestimation, as protocol biopsies are not routinely performed in the Scottish Liver
Transplant Unit, and are generally only considered in patients with steatosis on ultrasound
and/or persistently deranged liver function tests (22). The literature would suggest that
recurrent NAFLD varies between 25-60% following LT (3). Indeed, evaluation of recurrence
via liver biopsies in a cohort of 88 patients transplanted for NAFLD found recurrence in 39%
(23). Therefore clinicians could consider performing liver biopsies or undertake Fibroscans
for these patients at more regular intervals and aggressively seek to reduce risk factors for
recurrence including BMI (24).
Weight gain is common after LT and 30%–70% of patients become overweight or obese (3).
In a study of BMI following LT in 597 patients, by 1 and 3 years post LT, 24% and 31% of
LT patients had a BMI >30 kg/m2 with weight gain significantly greater in patients aged >50
years and those transplanted for chronic liver disease compared to fulminant liver failure
(25). It has been suggested that chronic fatigue and the metabolic effects of
immunosuppression make sustained reduction of weight difficult leading to progressively
increasing BMIs after LT (22). Current guidance makes no specific recommendation for the
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prevention or treatment of NAFLD in LT recipients other than the correction and
optimisation of individual components of the metabolic syndrome and cardiovascular risk
factors (2, 26). However, it seems sensible that longer-term nutritional programs could be
advantageous, especially for NAFLD patients (3). Minimising dietary cholesterol intake,
consumption of 2 or more cups of coffee per day and a Mediterranean diet, including
approximately 60 mL/d of olive oil have all been advocated in a recent review (22).
Medically supervised weight loss alone can be relatively ineffectual in the general
population, and this is also true in the transplant clinic where patients are found to regain
weight, acquire diabetes, and develop recurrent steatosis (27). This could also be a
component of steroid and calcineurin induction of diabetes and not just obesity. In a recent
randomised controlled trial, evorolimus with reduced exposure to tacrolimus showed reduced
post liver transplantation weight gain at 1 and 2 years post-transplant in comparison to a
standard tacrolimus immunosuppression regimen (28).
More radical approaches to weight management such as bariatric surgery could be considered
in the NAFLD population but the optimal timing of such intervention needs clarified. In an
analysis of the United States Nationwide Inpatient Sample patients with decompensated liver
disease had a higher risk of mortality following bariatric surgery (16.3%) compared to those
with compensated liver disease (0.9%) or no liver disease (0.3%) (28). In a systematic review
22 cases of bariatric surgery following LT were reported with a complication rate following
the procedure of 32% and an overall mortality rate of 13.6% (29). A recent study from the
Mayo Clinic reported sustained weight loss (from a mean BMI of 48 kg/m2 to a mean BMI of
29 kg/m2) and no mortality following seven combined LT and sleeve gastrectomy procedures
(27). Therefore combined LT with bariatric surgery may represent the most acceptable of
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these options in terms of timing but larger studies are required to confirm the safety and
efficacy of this approach.
The strengths of this current study include the current importance of NAFLD along with the
long-term follow up of patients. Weaknesses include the retrospective nature of the study and
disease overlap with 22 patients in the NAFLD group having a history of alcohol use. The
NAFLD group was also mainly transplanted later in the study period and the study does not
take into account NAFLD patients listed but not transplanted. Future research in this area
could focus on metabolic profiling and identifying strategies to sustain reduction in BMI in
the NAFLD population after LT, in order to assess whether this impacts upon outcomes in the
longer term. There are currently no Food and Drug Administration–approved therapies for
NAFLD but it has been suggested that vitamin E could be considered in all patients with
histologically proven recurrence of NAFLD, with Pioglitazone considered in patients with
recurrence of NAFLD in the presence of type 2 diabetes mellitus (22). Increased average
steroid dose at 6 months post-LT has been correlated with increased NAFLD recurrence (23)
as has cumulative steroid use (29). Therefore tapering steroid dose earlier in the NAFLD
population could represent an attractive strategy if the immunosuppressive status of the
patient permits. It is our practice to discontinue steroids 3 months post-LT and continue with
Tacrolimus and Mycophenolate Mofetil in the longer term.
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Conclusion
In the experience of the Scottish Liver Transplant Unit, NAFLD patients had similar long-
term patient and graft survival after LT compared with ALD patients. After controlling for
other donor and recipient factors NAFLD was not an independent predictor of mortality after
LT. In NAFLD patients post transplant BMI dropped initially but returned to pre-transplant
levels within one year of transplant. However, there was no difference in long-term BMI at 4
and 5-years following LT in the NAFLD and ALD groups.
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Figure legends
Figure 1: LTs for NAFLD per year (2003 – 2014). Note the study period was November 2002
to May 2015. Therefore this graph excludes one ALD case from 2002, seven ALD cases from
2015 and one NAFLD case from 2015.
Figure 2: Kaplan-Meier curve to evaluate patient survival probabilities in patients receiving
LTs for NAFLD and ALD.
Figure 3: Kaplan-Meier curve to evaluate graft survival probabilities in patients receiving
LTs for NAFLD and ALD.
Figure 4: BMI of patients receiving a LT for NAFLD and ALD at time of listing and on
follow up.
Table legends
Table 1: Characteristics of recipients receiving LT for NAFLD and ALD as well as donor
characteristics. Results are expressed as overall count with percentage in parentheses, as
mean +/- standard deviation or median with range in parentheses.
*Data missing for 4 donors
**Normothermic regional perfusion used in 1 donor
***Normothermic regional perfusion used in 2 donors
Table 2: Cox regression analysis of recipient (age, sex, presence of hepatocellular carcinoma,
MELD) and donor characteristics (age, sex, donor type) as determinants of patient survival.
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Abbreviations: NAFLD = Non-alcoholic fatty liver disease, ALD = alcoholic liver disease,
HCC = hepatocellular carcinoma, MELD = model for end stage liver disease, DBD =
donation after brain death, DCD = donation after circulatory death, BMI = body mass index
Table 1 |
Recipient characteristics NAFLD (n=84) ALD (n=195) P value
Recipient male: female 52: 32
(62%: 38%)
147: 48
(75%: 25%)
0.03
Recipient age 62 (27-73) 58 (27-72) <0.001
HCC 26 (31%) 50 (26%) 0.44
MELD 17 (7-30) 19 (6-34) 0.12
Follow up 4 (0-13) 5 (0-14) 0.16
Donor characteristics
Donor age 53 (16-75) 50 (16-80) 0.47
Donor male: female 45: 39
(54%: 46%)
106: 85
(55%: 45%)*
0.87
Graft type
DBD 75 (89%) 180 (92%) 0.55
DCD 9 (11%)** 15 (8%)*** 0.55
Split LT 3 (4%) 18 (9%) 0.16
Resources
Operating time (minutes) 375 (200-570) 377 (179-900) 0.97
Packed red cells (units) 2 (0-22) 3 (0-49) 0.05
Fresh frozen plasma (units) 3 (0-20) 4 (0-24) 0.09
Platelets (units) 2 (0-6) 1 (0-9) 0.99
Cryoprecipitate (units) 0 (0-14) 0 (0-8) 0.09
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Length of stay (days) 18 (10-71) 16 (5-144) 0.38
BMI
At listing 31 (5) 27 (5) <0.001
3 months post-LT 28 (4) 26 (4) 0.01
6 months post-LT 29 (4) 27 (5) 0.01
1 year post-LT 29 (5) 28 (5) 0.12
2 years post-LT 30 (5) 29 (5) 0.13
3 years post-LT 32 (6) 29 (5) 0.02
4 years post-LT 31 (4) 29 (5) 0.22
5 years post-LT 29 (6) 30 (6) 0.78
Table 2 |
Factor Hazard ratio Lower 95% CI Upper 95% CI P value
NAFLD 1.85 0.89 3.86 0.10
Recipient age 1.02 0.98 1.07 0.36
Recipient sex
(male)
1.21 0.56 2.62 0.63
HCC 0.87 0.39 1.96 0.74
MELD 0.99 0.93 1.05 0.74
Donor age 1.00 0.98 1.02 0.75
Graft (DCD) 0.29 0.03 2.22 0.24
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