Background: Current evidence shows that uric acid is a potent antioxidant whose serum concentration increases rapidly after acute ischemic stroke (AIS). Nevertheless, the relationship between serum uric acid (SUA) levels and AIS outcome remains debatable. We aimed to describe the prognostic significance of SUA in AIS. Methods: We studied 463 patients (52% men, mean age 68 years, 13% with glomerular filtration rate <60 />2) at 30 days, or with any outcome measure at 3, 6 or 12 months poststroke. After adjustment for age, gender, stroke type and severity (NIHSS <9),><24 h. Conclusions: A low SUA concentration is modestly associated with a very good short-term outcome. Our findings support the hypothesis that SUA is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome.

1. Original Paper
Received: July 10, 2012
Accepted: December 18, 2012
Published online: February 22, 2013
Cerebrovasc Dis 2013;35:168–174
DOI: 10.1159/000346603
Serum Uric Acid and Outcome after
Acute Ischemic Stroke: PREMIER Study
Erwin Chiquete a José L. Ruiz-Sandoval b Luis M. Murillo-Bonilla c Antonio Arauz d
Diego R. Orozco-Valera b Ana Ochoa-Guzmán b Jorge Villarreal-Careaga e
Carolina León-Jiménez f Fernando Barinagarrementeria g Alma Ramos-Moreno h
Carlos Cantú-Brito a
a
Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Médicas y Nutrición ‘Salvador Zubirán’,
Mexico City, b Department of Neurology, Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’, Guadalajara,
c
Department of Neurology, Universidad Autónoma de Guadalajara, Zapopan, d Stroke Clinic, Instituto Nacional
de Neurología y Neurocirugía, Mexico City, e Department of Neurology, Hospital General de Culiacán, Culiacán,
f
Department of Neurology, Hospital Regional ‘Dr. Valentín Gómez Farías’, ISSSTE, Zapopan, g Department of Neurology,
Hospital Ángeles de Querétaro, Querétaro, h Medical Research Area, Sanofi-Aventis, Mexico City, Mexico
Key Words
Chronic renal disease · Creatinine · Small-vessel disease,
Mexico · Stroke · Urate · Uric acid
Abstract
Background: Current evidence shows that uric acid is a potent antioxidant whose serum concentration increases rapidly after acute ischemic stroke (AIS). Nevertheless, the relationship between serum uric acid (SUA) levels and AIS
outcome remains debatable. We aimed to describe the
prognostic significance of SUA in AIS. Methods: We studied
463 patients (52% men, mean age 68 years, 13% with glomerular filtration rate <60 ml/min at hospital arrival) with
AIS pertaining to the multicenter registry PREMIER, who had
SUA measurements at hospital presentation. Multivariate
models were constructed to analyze the association of SUA
with functional outcome as assessed by the modified Rankin
scale (mRS) at 30-day, 3-, 6- and 12-month follow-up. A mRS
0–1 was regarded as a very good outcome. Results: Mean
SUA concentration at hospital arrival was 6.1 ± 3.7 mg/dl
© 2013 S. Karger AG, Basel
1015–9770/13/0352–0168$38.00/0
E-Mail karger@karger.com
www.karger.com/ced
(362.8 ± 220.0 μmol/l). Compared with cases with higher
SUA levels at hospital admission, patients with ≤4.5 mg/dl
(≤267.7 μmol/l; the lowest tertile of the sample) had more
cases of a very good 30-day outcome (30.5 vs. 18.9%, respectively; p = 0.004). SUA was not associated with mortality or functional dependence (mRS >2) at 30 days, or with
any outcome measure at 3, 6 or 12 months poststroke. After
adjustment for age, gender, stroke type and severity (NIHSS
<9), time since event onset, serum creatinine, hypertension,
diabetes and smoking, a SUA ≤4.5 mg/dl (≤267.7 μmol/l)
was positively associated with a very good short-term outcome (odds ratio: 1.76, 95% confidence interval: 1.05–2.95;
negative predictive value: 81.1%), but not at 3, 6 or 12
months of follow-up. When NIHSS was entered in the multivariate model as a continuous variable, the independent
association of SUA with outcome was lost. Compared with
cases with higher levels, patients with SUA ≤4.5 mg/dl
(≤267.7 μmol/l) were more frequently younger than 55
years, women, with mild strokes, with normal serum creatinine and fewer had hypertension. The time since event onset to hospital arrival was not significantly associated with
Carlos Cantú-Brito
Department of Neurology and Psychiatry, INCMNSZ
Vasco de Quiroga 15
Tlalpan, Mexico City 14000 (Mexico)
E-Mail carloscantu_brito@hotmail.com

2. AIS severity or SUA levels; nevertheless, a nonsignificant
tendency was observed for patients with severe strokes and
high SUA levels arriving in <24 h. Conclusions: A low SUA
concentration is modestly associated with a very good
short-term outcome. Our findings support the hypothesis
that SUA is more a marker of the magnitude of the cerebral
infarction than an independent predictor of stroke outcome.
Copyright © 2013 S. Karger AG, Basel
Introduction
Raised serum uric acid (SUA) is a modest risk factor
for stroke and cardiovascular disease, especially among
patients with hypertension or diabetes mellitus [1–5].
Uric acid is a potent endogenous antioxidant whose serum concentrations increases within the first hours after
acute ischemic stroke (AIS), showing a decrease to basal
levels in the following days after the event [6]. Basic and
clinical evidence points to a function of uric acid as an
antioxidant that acts chronically during inflammation
and long-standing ischemia [6–8], as well as acutely in
tissue infarction [9–14]. However, the relationship between SUA and stroke outcome remains controversial
[15–19], and it is not clear whether this association is either causal or circumstantial. As a consequence, some investigators suggest that anti-hyperuricemic therapy may
be beneficial [16, 20–22], while others currently investigate the pharmacological administration of uric acid as a
free-radical scavenger in AIS treatment, particularly as an
adjuvant to thrombolysis [15, 23–25]. We sought to examine the role of SUA at hospital admission as a prognostic marker of functional outcome in patients with AIS.
Our hypothesis was that SUA levels are independently
associated with stroke severity and outcome. This study
supports the notion that SUA elevation is proportional to
the magnitude of the cerebral infarction, but at the other
extreme of the phenomenon, that low SUA levels are associated with better outcomes.
Methods
We analyzed data of patients with AIS, for whom SUA was
measured at hospital admittance, from different geographic regions of Mexico, included in the PREMIER (Primer Registro Mexicano de Isquemia Cerebral) study [26–28]. Briefly, PREMIER was
a prospective, hospital-based multicenter registry of consecutive
patients with AIS or transient ischemic attack (TIA) in Mexico,
performed in 59 urban hospitals by 77 physicians [26, 27]. A cen-
Serum Uric Acid and Stroke Outcome
tral Institutional Review Board and the local Committee of Ethics
of each participating center approved the protocol. Signed informed consent was required for all patients or their legal proxies.
Consecutive patients with AIS or TIA aged ≥18 years were registered. All patients received medical care within 7 days of stroke
onset. Data collection was prospectively performed during one
year (in 6 different medical visits) by using a standardized structured questionnaire (clinical research format, CRF) outlined in a
manual of definitions and procedures. All participating physicians
were formally instructed on current stroke guidelines, stroke classification, evaluation, treatment and prevention. Stroke subtypes
were registered according to the Trial of ORG 10172 in Acute
Stroke (TOAST) classification. AIS severity was assessed by the
National Institutes of Health Stroke Scale (NIHSS) at baseline, and
the modified Rankin scale (mRS) was used to evaluate the functional outcome at hospital discharge, and at 1, 3, 6, 12 and 18
months after AIS. Demographic, clinical, laboratory, anthropometric and neuroimaging variables were systematically registered
in a standardized format. Other variables registered were about
management of comorbidities, preventive measures, hospitalizations, vascular events and stroke recurrences during follow-up and
functional outcome at each visit. Information of the CRF was saved
on independent electronic files in data capture software developed
and revised periodically by a contract research organization (CRO;
INNOVAL Co.). Members of the CRO analyzed information on
every patient for completeness and plausibility. Missing or implausible variables were referred to the investigators for clarification.
Data quality was ascertained by periodic statistical reports and onsite visits by CRO monitors [26, 27].
Among 1,376 participants with AIS or TIA registered in the
PREMIER study [18], 463 AIS patients with complete clinical and
laboratory evaluations, as well as complete 12-month follow-up
information were selected for this analysis. TIA cases were not included here. A mRS = 0–1 was regarded as a very good outcome.
Clinical raters of the mRS were not blinded to SUA levels; nonetheless, they were not aware of the objective of the present report,
since the purpose of this analysis arose when the registry was terminated.
Statistical Analysis
Parametric continuous variables are expressed as geometric
means and standard deviations (SD), or minimum and maximum.
Nonparametric continuous variables are expressed as medians.
Categorical variables are expressed as percentages. To compare
quantitative variables distributed between two groups, Student’s t
test and Mann-Whitney U test were performed in distributions of
parametric and nonparametric variables, respectively. Chi-square
statistics (i.e. Pearson’s χ2 or Fisher’s exact test, as corresponded)
were used to compare nominal variables in bivariate analyses,
among two or more nominal categories. SUA was analyzed as tertiles, quartiles and quintiles to find a rational cutoff to dichotomize
SUA levels in prediction analyses, to facilitate its clinical application. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), positive likelihood ratio (LR+) and
negative likelihood ratio (LR–) was calculated for the selected SUA
cutoff that had any statistically significant association with an outcome measure. Multivariate analyses were used to assess the independent relationship of SUA levels and outcome (mRS = 0, mRS =
0–1, mRS ≥2, mRS ≥3 and mRS = 6) at 30- and 90-day, 6- and
12-month follow-up. Known factors that may influence SUA (i.e.
Cerebrovasc Dis 2013;35:168–174
DOI: 10.1159/000346603
169

3. Table 1. Main characteristics of the patients according to 30-day outcome
Baseline characteristics
30-day functional outcome
all (n = 463)
Age, years*
Male gender
Risks factors
Chronic renal failure
Hypertension*
Diabetes mellitus
BMI >30
Non-valvular atrial fibrillation*
Coronary artery disease
Previous cerebral infarction
Clinical and laboratory variables
Glucose, mg/dl*
Glucose <150 mg/dl
Creatinine, mg/dl
Creatinine <1.2 mg/dl*
Serum uric acid, mg/dl
Serum uric acid ≤4.5 mg/dl*
NIHSS*
NIHSS <9
Stroke subtypes
Large-artery disease
Lacune*
Cardioembolism*
Mixed
Other defined etiologies
Undetermined*
mRS 0–1 (n = 107)
mRS 2–5 (n = 305)
mRS 6 (n = 51)
71 (21–104)
241 (52.1)
65 (21–91)
65 (60.7)
72 (22–94)
149 (48.9)
76 (38–104)
27 (52.9)
9 (1.9)
314 (67.8)
148 (32.0)
101 (21.8)
52 (11.2)
106 (22.9)
90 (19.4)
1 (0.1)
60 (56.1)
32 (29.9)
28 (26.2)
6 (5.6)
24 (22.4)
17 (15.9)
6 (2.0)
220 (72.1)
102 (33.4)
64 (21.0)
40 (13.1)
74 (24.3)
64 (21.0)
2 (3.9)
34 (66.7)
14 (27.5)
9 (17.6)
6 (11.8)
8 (15.7)
9 (17.6)
145.2±73.5
199 (65.2)
1.43±2.02
207 (67.8)
6.17±3.71
100 (32.8)
11 (1–36)
90 (29.7)
177.1±99.1
29 (56.9)
1.59±1.55
25 (50.9)
6.16±3.33
16 (31.4)
23 (4–39)
6 (11.8)
96 (31.5)
47 (15.4)
62 (20.3)
24 (7.9)
17 (5.6)
59 (19.3)
17 (33.3)
3 (5.9)
13 (25.5)
3 (5.9)
0 (0)
15 (29.4)
144.0±73.5
308 (66.5)
1.40±1.86
312 (67.4)
6.10±3.72
167 (36.1)
11 (1–39)
172 (37.6)
124.7±50.0
80 (74.7)
1.22±1.47
80 (74.8)
5.88±3.91
51 (47.7)
5 (1–22)
76 (73.8)
144 (31.1)
84 (18.1)
83 (17.9)
34 (7.3)
27 (5.8)
91 (19.7)
31 (29.0)
34 (31.8)
8 (7.5)
7 (6.5)
10 (9.3)
17 (15.9)
Data are expressed as median (range), n (%) or mean ± standard deviation.
To convert uric acid concentration to μmol/l multiply by the factor 59.48. To convert creatinine concentration to μmol/l multiply by
the factor 88.4. To convert glucose concentration to mmol/l multiply by the factor 0.0555.
* p < 0.05 for univariate comparison of mRS = 0–1 vs. mRS = 2–5.
gender, renal function, time since stroke onset, stroke severity,
type of stroke) were taken into account. Multivariate analyses were
constructed by forward stepwise binary logistic regression. Input
variables were those that resulted significantly associated with AIS
outcome in bivariate analyses. Adjusted odds ratios (OR) with 95%
confidence intervals (CI) are provided. The fitness of the models
was evaluated by using the Hosmer-Lemeshow goodness-of-fit
test, which was considered as reliable if p > 0.2. All p values are
two-sided and considered significant when p < 0.05. SPSS v 17.0
software was used for all statistical calculations.
Results
A total of 463 patients were analyzed (52% men, mean
age 68 years; range 21–104 years) (table 1); 61 (13%) patients had glomerular filtration rate <60 ml/min at hospital arrival. Mean SUA at hospital admittance was 6.1 ± 3.7
170
Cerebrovasc Dis 2013;35:168–174
DOI: 10.1159/000346603
mg/dl (362.8 ± 220.0 μmol/l), higher in men than in women [6.6 ± 3.9 vs. 5.5 ± 3.5 mg/dl (392.6 ± 232.0 vs. 327.1 ±
208.2 μmol/l); p = 0.002] (fig. 1).
At 30 days after AIS, a very good outcome occurred
more frequently in patients with SUA ≤4.5 mg/dl (≤267.7
μmol/l; the lowest tertile of the sample) than in those
with higher levels (30.5 vs. 18.9%, respectively; p = 0.004;
univariate Mantel-Haenszel OR: 1.88, 95% CI: 1.21–2.92).
Neither low nor high SUA levels were associated with
stroke mortality or functional dependence (mRS >2, or
mRS >3) at 30-day follow-up. Moreover, we could not
find any significant association between SUA and any
outcome at 3-, 6-, or 12-month follow-up, either in univariate or in multivariate analyses.
In a multivariate analysis adjusted for relevant cofactors (table 2), SUA ≤4.5 mg/dl (≤267.7 μmol/l) was associated with 30-day very good outcome (mRS = 0–1). HowChiquete et al.

4. Men
<
100
Frequency (%)
80
60
40
less, a nonsignificant tendency was observed for patients
with severe strokes and high SUA levels arriving earlier
(fig. 2). Low SUA levels did not occur more frequently
among patients with NIHSS <9 points (fig. 3), but milder
strokes (i.e. NIHSS <5 points) occurred more commonly
among cases with SUA ≤4.5 mg/dl (≤267.7 μmol/l) (fig. 3).
Furthermore, variables significantly associated with low
SUA levels were: female gender, young age, normal serum
creatinine and (inversely) hypertension (table 3).
20
0
SUA first tertile
(
Discussion
(
(
Fig. 1. SUA tertiles as a function of gender.
Table 2. Factors positively associated with a very good outcome
(modified Rankin scale 0–1) at 30-day follow-up: a multivariate
logistic regression model*
Variable
Multivariate odds
ratios (95% CI)
p value
NIHSS <9 points
Age <55 years
Cardioembolic stroke
SUA ≤4.5 mg/dl (≤268 μmol/l)
6.99 (4.14–11.79)
2.10 (1.18–3.74)
0.41 (0.19–0.88)
1.76 (1.05–2.95)
<0.001
<0.012
<0.023
<0.031
* Hosmer-Lemeshow test for goodness of fit in final step of the
regression model: χ2 = 1.85, 6 d.f., p = 0.933. Only variables significantly associated with mortality are shown. Model adjusted for
gender, chronic renal failure, diabetes, hypertension, dyslipidemia,
atrial fibrillation, lacunar stroke, undetermined stroke, admission
blood glucose <150 mg/dl (<8.3 mmol/l), admission serum creatinine <1.2 mg/dl (<106 μmol/l), hospital arrival <24 h since stroke
onset, previous cerebral infarction and body mass index >30. Only
variables significantly associated with a score of 0 to 1 in the modified Rankin scale are shown in this table. SUA association with
short-term outcome showed significance only when dichotomised
NIHSS was considered instead of a continuous variable.
ever, the significance of this association was lost when NIHSS was entered as a continuous variable. SUA ≤4.5 mg/
dl (≤267.7 μmol/l) had a sensitivity, specificity, PPV,
NPV, LR+ and LR– for predicting a very good 30-day outcome, of 47.7% (95% CI: 38.4–57.0), 67.4% (95% CI: 62.4–
72.1), 30.5% (95% CI: 24.1–37.9), 81.1% (95% CI: 76.2–
85.1), 1.46 (95% CI: 1.14–1.87) and 0.78 (95% CI: 0.64–
0.94), respectively. The time since AIS onset to hospital
arrival was not significantly associated with AIS severity
(scoring of the NIHSS), or SUA levels (fig. 2); nevertheSerum Uric Acid and Stroke Outcome
In this study we found that a low SUA at hospital admission is modestly associated with a very good shortterm outcome. However, we could not demonstrate the
opposite, that severe strokes or adverse outcomes are associated with higher concentrations of SUA. Our results
may contrast with some previous findings [9, 17, 20, 21,
29, 30], but are in line with the report of Nardi and Milia
[31] showing that a low SUA is associated with an excellent functional state after AIS. Moreover, the factors that
we found as associated with SUA concentrations have
also been described in similar settings [31]. Nonetheless,
although from a different perspective, our findings support the concept that SUA elevation is proportional to
the magnitude of the brain ischemia [12, 13, 18], with low
SUA levels indicating a good outcome possibly through
mild strokes. The present results offer relevant information on the factors that may confound and partially explain the variation of SUA among AIS cohorts.
The time of blood sampling appears to be a crucial issue
that may explain much of the variation of results among
publications [9, 12, 13]. If SUA is a consumptive and rapidly changing marker of the antioxidant response elicit by
the brain ischemia, then higher SUA levels should be observed during certain moments in larger strokes to offer a
metabolic response for scavenging oxygen free radicals excessively produced during blood deprivation. Patients failing to mount such a reaction may have a bad outcome. In
the end, large strokes may originate in part the SUA response, but may also be the consequence of a failing antioxidant reaction. This subject needs more exploration in
basic and clinical studies. The considerable debate on the
significance of SUA as a marker of AIS outcome may be due
to different interpretations of the same phenomenon [19].
Cells and tissue preparations exposed to hypoxia/ischemia exhibit an increased expression of xanthine oxidase,
the rate-limiting enzyme in the conversion of hypoxanthine to xanthine and xanthine to uric acid [32]. Xanthine
Cerebrovasc Dis 2013;35:168–174
DOI: 10.1159/000346603
171

5. p for trend = 0.74
60
36.8
63.2
80
32.0
34.9
65.1
Frequency (%)
Frequency (%)
80
68.0
40
20
0
a
p for trend = 0.19
100
100
NIHSS
<9 points
NIHSS
9–18 points
Hospital arrival in <24 h
60
40
50.3
b
Hospital arrival in ≥24 h
60.3
56.6
20
0
NIHSS
>18 points
39.7
43.4
49.7
SUA first
tertile
(≤4.5 mg/dl)
SUA second
tertile
(4.6–6 mg/dl)
SUA third
tertile
(>6 mg/dl)
Fig. 2. Hospital arrival according to stroke severity by the NIHSS (a), and SUA tertiles (b).
p for trend = 0.41
80
60
40
20
0
a
50
62.2
66.8
37.8
63.4
33.2
36.6
NIHSS
9–18 points
Frequency (%)
Frequency (%)
100
40
p = 0.02 *
30
29.3
26.1
20
NIHSS
>18 points
38.1
44.6
32.5
36.5
29.4
33.3
32.5
30.1
34.9
10
SUA >6 mg/dl
0
NIHSS
<9 points
SUA ≤
SUA >
SUA 4.6–6 mg/dl
NIHSS <5
points
b
32.5
NIHSS
5–10
points
NIHSS
11–20
points
SUA ≤4.5 mg/dl
NIHSS >20
points
Fig. 3. Stroke severity by the NIHSS as a function of SUA tertiles, dividing the NIHSS distribution with wider (a) and closer (b) score
ranges.
oxidase is the only enzyme capable of catalyzing the formation of uric acid in humans. In other mammals, urate
oxidase can metabolize uric acid to allantoin, a potent antioxidant, but this enzyme activity is lost in primates. It is
possible that uric acid production may have evolved as a
compensatory mechanism in primates that cannot produce other potent organic antioxidants [33]. As such, uric
acid production by means of xanthine oxidase activity is
possibly the most potent acute antioxidant mechanism in
response to ischemia in humans, and hence, it represents
a marker of tissue infarction [22, 32, 33]. However, a limitation of the models that examine the SUA systemic reaction to focal ischemia (i.e. AIS) is that uric acid production in situ may not be adequately measured with peripheral blood sampling.
172
Cerebrovasc Dis 2013;35:168–174
DOI: 10.1159/000346603
Here we could not demonstrate a particular pattern of
SUA concentration as a function of time from stroke onset
to hospital arrival, possibly because patients with mild
strokes tended to arrive later than patients with profound
neurologic deficits. However, although SUA levels were
measured at hospital admittance, we did not standardize
precisely the moment of blood sampling or laboratory
analyses, and no serial SUA measurements were undertaken; therefore, our data set is not adequate to evaluate the
SUA time response as a function of stroke severity. This is
a very interesting topic to be examined in future studies.
The main limitation of this study is the sample size that
might not be large enough to detect a more robust difference between SUA levels across the whole range of stroke
severity, and to find that patients with severe strokes and
Chiquete et al.

6. Table 3. Factors positively associated with a SUA ≤4.5 mg/dl (≤268 μmol/l) at hospital admittance
Variable
SUA ≤4.5 mg/dl
(≤267.7 μmol/l)
(n = 167)
SUA >4.5 mg/dl
(>267.7 μmol/l)
(n = 296)
p value
Female gender
Age <55 years
Age <65 years
NIHSS <5 points
NIHSS <9 points
Serum creatinine <1.2 mg/dl
(<106 μmol/l)
Serum creatinine <1.4 mg/dl
(<124 μmol/l)
Blood glucose <150 mg/dl
(<8.32 mmol/l)
Blood glucose <200 mg/dl
(<11.10 mmol/l)
BMI >30
Chronic renal failure
Hypertension
Diabetes mellitus
Cardioembolic stroke
Lacunar stroke
102 (61.1)
49 (29.3)
76 (45.5)
42 (25.2)
67 (40.1)
120 (40.5)
47 (15.9)
98 (33.1)
51 (17.2)
108 (36.5)
<0.001
<0.001
<0.008
<0.046
<0.462
139 (83.2)
172 (58.1)
<0.001
153 (91.6)
220 (74.3)
<0.001
109 (65.7)
197 (67.0)
<0.769
138 (83.1)
31 (18.6)
4 (2.4)
95 (56.9)
57 (34.1)
38 (22.8)
44 (26.3)
249 (84.7)
70 (23.6)
5 (1.7)
216 (74)
91 (30.7)
70 (23.6)
62 (20.9)
<0.660
<0.203
<0.597
<0.001
<0.453
<0.827
<0.184
Values are n (%).
with higher SUA levels arrive earlier than their counterparts. No volumetric analyses were performed to demonstrate that SUA is associated with the size of the cerebral
necrosis, and no serial measurements were performed to
demonstrate that SUA levels change over time, as a function of stroke volume, clinical severity, renal function, age
and gender. Also, the previous use of thiazides and other
uric acid-modifying drugs was not registered in our
study, although indeed, none of the patients was treated
with thiazides during the poststroke hospitalization.
In conclusion, these findings support the hypothesis
that SUA is more a marker of the magnitude of the cerebral infarction than a strong independent predictor of
AIS outcome. In other words, SUA is an acute indicator
of stroke severity if this response is proportional to the
infarction size. This idea should be consistently confirmed in further studies.
Acknowledgements
The PREMIER study received unrestricted financial support
from conception to execution by Sanofi, Mexico. The pharmaceutical company was involved in the design of the study, but had no
role in the selection of patients, data analysis, the preparation of
this article or the decision for submission to publication.
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