Download Complex Relationship Between Blood Pressure and

Complex Relationship Between Blood Pressure
and Mortality in Type 2 Diabetic Patients
A Follow-Up of the Botnia Study
Mats Rönnback, Bo Isomaa, Johan Fagerudd, Carol Forsblom, Per-Henrik Groop,
Tiinamaija Tuomi, Leif Groop; for the Botnia Study Group
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Abstract—The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure
is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the
relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294
type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004,
after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital
records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors.
The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with
previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly
patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk
patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of
blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.
(Hypertension. 2006;47:168-173.)
Key Words: diabetes mellitus 䡲 blood pressure 䡲 cardiovascular diseases 䡲 elderly 䡲 mortality 䡲 risk factors
P
mortality among elderly individuals exists.14 No such association has, to our knowledge, been reported in type 2
diabetic patients. This study investigated the relationship
between different BP indices and all-cause and cardiovascular mortality in a follow-up of a cohort of type 2 diabetic
patients.
atients with type 2 diabetes have a 2- to 4-fold increased
risk of dying from cardiovascular disease (CVD).1,2 Type
2 diabetes is frequently accompanied by hypertension, which
additionally increases the cardiovascular risk.3,4 The beneficial effect of effective blood pressure (BP)–lowering therapy
on cardiovascular mortality in type 2 diabetic patients has
been established in several large studies.5,6
Arterial stiffness and its clinical manifestation, pulse pressure (PP), have quite recently been recognized as important
risk factors for cardiovascular mortality, particularly in elderly individuals.7 Although some studies have shown evidence that PP is the most powerful BP index in predicting
cardiovascular end points in elderly persons,8 the results of
other studies challenge this view.9
Both type 1 and type 2 diabetes are characterized by
premature arterial stiffening,10,11 and increased PP has been
found to predict cardiovascular mortality and progression of
renal failure in type 2 diabetes.12,13 Whether PP is more useful
than systolic (SBP) or diastolic BP (DBP) for predicting
mortality in type 2 diabetic patients remains to be clarified.
Despite hypertension being an established risk factor for
CVD, evidence of an inverse relationship between BP and
Methods
Subjects
The Botnia Study was initiated in 1990 with the aim to identify risk
factors for type 2 diabetes. Patients with type 2 diabetes from 5 primary
healthcare centers in Finland were invited to participate together with
their family members.15 Diagnosis of diabetes was based on existing
World Health Organization criteria.16 The current study represents 1294
consecutive type 2 diabetic patients examined between 1990 and 1997.
Subjects with a diagnosis of type 2 diabetes (n⫽1173) and previously
nondiagnosed family members whose results from an oral glucose
tolerance test (OGTT) met the most recent WHO diabetes criteria
(n⫽121) were included.17 Patients with glutamic acid decarboxylase
antibodies or maturity onset diabetes of the young were excluded.18,19
The study was carried out in accordance with the Declaration of
Helsinki and was approved by all of the local ethics committees. All
of the subjects gave informed consent before participation.
Received August 11, 2005; first decision September 4, 2005; revision accepted November 29, 2005.
From the Folkhälsan Research Center (M.R., B.I., J.F., C.F., P.-H.G., T.T.), Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland;
Malmska Municipal Health Care Center and Hospital (B.I.), Jakobstad, Finland; Department of Medicine (T.T.), Helsinki University Central Hospital and
Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland; Department of Endocrinology (L.G.), Wallenberg Laboratory,
University Hospital of MAS, Lund University, Malmö, Sweden; and the Department of Medicine (M.R., J.F., C.F., P.-H.G.), Division of Nephrology,
Helsinki University Central Hospital, Helsinki, Finland.
Correspondence to Per-Henrik Groop, Folkhälsan Research Center, Biomedicum Helsinki (C318b), PO Box 63, FIN-00014 University of Helsinki,
Helsinki, Finland. E-mail [email protected]
© 2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.116110.1161/01.HYP.0000199667.30253.b7
168
Rönnback et al
Blood Pressure and Mortality in Type 2 Diabetes
Baseline Examination
A standard OGTT was performed on all of the noninsulin-treated
subjects with fasting plasma glucose ⬍11 mmol/L (n⫽698). Urine
was collected during the OGTT or overnight, and albumin excretion
rate (AER) was measured (n⫽666). Fasting blood samples were
drawn for the measurement of serum lipids. BP was measured by
trained nurses using mercury sphygmomanometers. SBP was recorded at phase I and DBP at phase V of Korotkoff sounds. Two BP
recordings were obtained from the right arm of a sitting patient after
30 minutes of rest at 5-minute intervals, and the mean value was
calculated.
A standardized health questionnaire covering the subjects’ medical history was completed by trained nurses. Additional information
on the medical history was obtained from medical records. Coronary
heart disease was defined as the use of nitroglycerine, typical chest
pain, or a history of myocardial infarction. Stroke, including both
ischemic and hemorrhagic stroke, were defined as clinically or
radiologically diagnosed events requiring hospitalization. Previous
CVD was defined as a history of coronary heart disease or stroke.
cause-of-death data obtained from the national population registry
has been established previously.20 It has also been demonstrated that
the Finnish hospital discharge register give a correct picture on the
occurrence of CVD.21
Statistical Analysis
Statistical analyses were performed with SPSS 12.0.1 (SPSS Inc).
Results are expressed as the mean⫾SD for normally distributed
variables and as the median (interquartile range) for nonnormally
distributed variables. Comparisons of variables were performed
using t test or Mann-Whitney U test, as appropriate. Relevant clinical
variables were entered into a forward stepwise Cox regression
model. AER was not included in the model because of missing data
on a large number of patients. Variables that contributed significantly to the model were added to the model in order of significance,
except gender, which was forced into the model. Hazard ratios were
calculated by merging the results of separate analyses for medicated
and nonmedicated patients to reduce the confounding effects caused
by antihypertensive medication.
Follow-Up
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Data on the subjects’ vital status were obtained from the national
population registry on May 31, 2004. In order to classify the cause
of mortality, death certificates of the diseased subjects were obtained
from the central death-certificate registry. Additionally, medical
records were acquired if the cause of death was unclear. Cardiovascular mortality was classified using the 9th revision of the International Classification of Disease (codes 399 to 459) before 1997 and
the 10th revision (codes I 10 to 99) thereafter. The reliability of
TABLE 1.
Results
The baseline characteristics of the cohort are described in
Table 1. Patients had a median age of 69.1 (range, 24.5 to
96.9; interquartile range, 61.1 to 75.7) years and a median
duration of diabetes of 6.3 years. Their mean BP was
149/83 mm Hg. Of the entire sample, 39% did not use any
hypoglycemic medication, 28% were on oral agents, 11% on
Baseline Characteristics According to Outcome
Baseline Characteristics
n
Sex, % males
Entire Group
Survivors
Cardiovascular Death
Other Death
1294
742
332
220
46
45
46
46
Age, y
69.1 (61.1–75.7)
64.0 (56.7–71.4)
75.7 (70.5–80.9)*
74.8 (69.4–80.2}*
Duration of diabetes, y
6.3 (2.4 to 11.6)
4.6 (1.4 to 9.8)
8.2 (4.4 to 13.9)*
7.7 (3.1 to 13.2)*
SBP, mm Hg
149⫾21
148⫾20
151⫾21†
150⫾20
DBP, mm Hg
83⫾11
85⫾11
80⫾11*
PP, mm Hg
66⫾18
63⫾18
105⫾10
106⫾12
104⫾12
104⫾12
Body mass index, kg/m2
28.3⫾4.7
28.8⫾4.7
27.5⫾4.5*
27.5⫾4.6*
Waist:hip ratio
0.93⫾0.08
0.93⫾0.08
0.93⫾0.09
0.93⫾0.07
8.4 (7.1 to 11.0)
8.1 (7.0 to 10.7)
9.1 (7.2 to 11.6)*
8.3 (6.9 to 10.7)
7.5⫾1.5
7.4⫾1.6
7.7⫾1.4
7.4⫾1.5
5.5 (2.8 to 11.7)
4.7 (2.5 to 9.3)
6.8 (3.7 to 22.2)*
7.1 (3.1 to 13.7)*
Total cholesterol, mmol/L
5.85⫾1.20
5.84⫾1.13
5.96⫾1.26
5.72⫾1.30
LDL cholesterol, mmol/L
3.80⫾1.05
3.75⫾1.01
3.89⫾1.05
3.70⫾1.15
HDL cholesterol, mmol/L
1.18⫾0.31
1.19⫾0.30
1.12⫾0.29*
1.23⫾0.35
1.70 (1.25 to 2.38)
1.55 (1.26 to 2.27)
1.83 (1.32 to 2.54)*
1.58 (1.15 to 2.45)
39/28/11/22
41/31/11/18
38/25/12/27†
37/24/10/29†
HbA1c, %
AER, ␮g/min
Triglycerides, mmol/L
71⫾19*
82⫾10*
Mean arterial BP, mm Hg
Fasting plasma glucose, mmol/L
69⫾18*
Diabetes treatment, diet/oral
agents/insulin/combination, %
Antihypertensive medication, %
51
46
62*
8
4
16*
7†
Coronary heart disease, %
29
21
48*
28†
Total CVD, %
32
23
55*
30†
8
10
6
7
Stroke, %
Current smokers, %
169
52
Normally distributed values are presented as mean⫾SD, nonnormally distributed values as median (interquartile range). LDL
indicates low-density lipoprotein; HDL, high-density lipoprotein.
*P⬍0.01 vs survivors.
†P⬍0.05 vs survivors.
170
Hypertension
February 2006
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insulin, and 22% were treated with a combination of oral
agents and insulin. In all of the patients using oral medication,
the frequency of the specific agents was as follows: metformin 30%, glibenclamide 67%, glipizide 21%, and guar
gum 10%. Glitazones were not in clinical use at the time of
baseline examinations. During a median follow-up time of 9.5
years (range, 6.5 to 14.4 years), 192 patients (35% of deaths)
died of coronary heart disease, 68 (12%) of cerebrovascular
disease, 72 (13%) of other CVD, 102 (18%) of neoplasms,
100 (18%) of other disease, and 12 (2%) of accidents or
suicide. Six (1%) of the total 552 deaths could not be
classified because of lack of information. Survivors had lower
age, shorter duration of diabetes, lower PP, and lower AER
but higher DBP and body mass index than the patients that
died. In addition, patients who died of CVD had higher SBP,
fasting plasma glucose, and triglycerides but lower HDL
cholesterol compared with the survivors.
The Cox regression analyses (Table 2) showed that the
unadjusted relationship with all-cause and cardiovascular mortality was negative for DBP but positive for PP. When adjusting
for other risk factors, SBP and DBP correlated negatively with
both all-cause and cardiovascular mortality, whereas no association between PP and mortality was observed.
In a subgroup of patients below the median age of 69.1
years at baseline (n⫽647), the all-cause mortality hazard ratio
in a corresponding risk factor–adjusted model (not shown) for
SBP was 1.01 (95% CI, 0.92 to 1.11); DBP was 0.93 (95%
CI, 0.78 to 1.11); and PP was 1.05 (95% CI, 0.93 to 1.19). In
the same subgroup, the cardiovascular mortality hazard ratio
for SBP was 1.00 (95% CI, 0.87 to 1.14); DBP was 0.78 (95%
CI, 0.61 to 1.00); and PP was 1.12 (95% CI, 0.95 to 1.32).
To exclude that the observed effects were because of admixture of individuals with microalbuminuria, we also performed a
Cox regression analysis including only patients with available
AER measurements (n⫽666; data not shown). Adding AER
to the model lowered the hazard ratio for all of the BP indices
by 0.01 to 0.03.
Cardiovascular mortality rates in relation to the age- and
gender-adjusted BP indices are shown in Figures 1, 2, and 3.
The relationships between all-cause mortality and BP (data
not shown) were similar to those shown in the figures.
No Previous CVD
In patients without a history of CVD, a DBP of 90 to
99 mm Hg was predictive of low mortality. The association
between PP and mortality was U-shaped with the highest risk
found in the lowest and highest PP categories.
Previous CVD
A negative association between SBP and mortality was
observed in patients with a positive history of CVD, and SBP
levels ⬍140 mm Hg were associated with increased mortality
in this group. Both all-cause and cardiovascular mortality
correlated negatively with DBP in these patients. The association between PP and mortality was U-shaped, with the
lowest mortality observed in the intermediate categories.
Effect of Age
In patients older than the median age of 69.1 years, SBP and
PP correlated with mortality in a U-shaped fashion, whereas
no such relationship in patients below the median age was
observed.
Antihypertensive Medication
In patients with antihypertensive medication, SBP and DBP
correlated with mortality in an inverse manner. The association with PP in these patients was U-shaped. Patients without
antihypertensive medication demonstrated an inverse corre-
TABLE 2. Cox Regression Models for All-Cause and Cardiovascular Mortality After Adjustment for Other
Risk Factors
Variable Added
Hazard Ratio*
SBP
DBP
PP
Pressure per 10 mm Hg
1.00 (0.96 to 1.05)
0.70 (0.64 to 0.76)
1.12 (1.07 to 1.18)
Age, y
1.11 (1.09 to 1.12)
0.92 (0.88 to 0.97)
0.86 (0.78 to 0.94)
0.95 (0.91 to 1.00)
Gender, male
1.51 (1.24 to 1.83)
0.92 (0.88 to 0.97)
0.82 (0.75 to 0.90)
0.96 (0.92 to 1.01)
Current smoking
2.40 (1.62 to 3.52)
0.92 (0.88 to 0.96)
0.82 (0.75 to 0.90)
0.96 (0.91 to 1.01)
Diabetes duration, y
1.02 (1.01 to 1.04)
0.92 (0.88 to 0.97)
0.83 (0.76 to 0.91)
0.96 (0.91 to 1.01)
Previous CVD
1.39 (1.15 to 1.69)
0.93 (0.89 to 0.97)
0.85 (0.77 to 0.93)
0.96 (0.91 to 1.01)
Pressure per 10 mm Hg
1.00 (0.96 to 1.05)
0.65 (0.58 to 0.72)
1.14 (1.07 to 1.20)
Age, y
1.12 (1.10 to 1.14)
0.92 (0.87 to 0.98)
0.80 (0.71 to 0.90)
0.96 (0.91 to 1.03)
Gender, male
1.49 (1.13 to 1.97)
0.92 (0.88 to 0.97)
0.77 (0.68 to 0.86)
0.98 (0.91 to 1.04)
All-cause mortality
Cardiovascular mortality
Previous CVD
1.82 (1.38 to 2.40)
0.93 (0.88 to 0.99)
0.81 (0.72 to 0.91)
0.97 (0.91 to 1.04)
Diabetes duration, y
1.03 (1.01 to 1.04)
0.93 (0.87 to 0.98)
0.82 (0.73 to 0.93)
0.96 (0.90 to 1.03)
Current smoking
2.19 (1.25 to 3.81)
0.93 (0.88 to 0.99)
0.81 (0.72 to 0.91)
0.97 (0.91 to 1.04)
HDL cholesterol, mmol/L
0.55 (0.33 to 0.89)
0.92 (0.87 to 0.98)
0.82 (0.73 to 0.92)
0.96 (0.90 to 1.03)
Hazard ratios refer to a pressure increase of 10 mm Hg. Analyses were performed with antihypertensive medication as strata
variable. Values in parenthesis are 95% CIs. HDL indicates high-density lipoprotein.
*Hazard ratio in final model not including BP indices.
Rönnback et al
Blood Pressure and Mortality in Type 2 Diabetes
171
Figure 1. Cardiovascular mortality in
patients with (䡺, dotted line) and without
(●, solid line) previous cardiovascular
disease in relation to age- and genderadjusted blood pressure indices. Bars,
95% CIs.
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lation between mortality and SBP, but no significant associations with DBP or PP were observed.
Figure 4 shows all-cause mortality stratified by SBP and
DBP levels. Mortality increases toward the upper right
corner, where the combination of a high SBP (⬎160 mm Hg)
and a low DBP (⬍75 mm Hg) results in a high PP. A similar
peak in mortality can be observed in the lower left corner,
where a low SBP (⬍135 mm Hg) and a high DBP
(⬎90 mm Hg) result in a low PP. A corresponding analysis
for cardiovascular mortality displayed a very similar pattern
(data not shown).
Discussion
This study shows that a U-shaped association between PP and
mortality exists in elderly type 2 diabetic patients. In addition,
low BP is associated with poor survival in type 2 diabetic
patients with a history of previous CVD.
The finding that high, not low, BP is predictive of
favorable survival in type 2 diabetic patients may seem
controversial in view of the vast evidence of the detrimental
effects of hypertension and the established benefit of treating
hypertension in type 2 diabetes.4,6 However, many major
trials, such as the UK Prospective Diabetes Study Group,
have focused on younger hypertensive patients without previous CVD.5 The present study examines mortality in a
cohort recruited with type 2 diabetes as the only selection
criteria and is, therefore, likely to represent a more typical
type 2 diabetic population. The difference between the
populations is illustrated by the fact that, of the 1294 Botnia
patients, only 401 (31%) would have fulfilled the UK
Prospective Diabetes Study Group inclusion criteria.
This study did not assess the cardiac function or vascular
properties of the patients. Thus, one can only speculate about
the mechanisms underlying the finding that patients with
discordant SBP and DBP levels (high or low PP) had a
strikingly elevated mortality compared with patients with
concordant SBP and DBP levels (intermediate PP).
Arterial stiffness causing elevated PP constitutes a risk
factor for CVD, as well as all-cause and cardiovascular
mortality, in both diabetic and nondiabetic individuals.8,12
Considering the accelerated arterial stiffening in type 2
diabetes,22 it seems plausible that the elevated mortality
observed in the highest PP categories would be linked to
increased arterial stiffness and, thus, reflect arterial ageing. In
addition to being a marker of poor vascular health, arterial
stiffness increases the cardiac afterload by augmenting the
SBP and reduces coronary perfusion by decreasing the DBP,
thereby lowering the ischemic threshold of the myocardium.
The favorable prognosis associated with a high BP in
patients with previous CVD (Figure 1) is presumably related
to preserved cardiac function. This is supported by recent
evidence that suggests a markedly increased prevalence of
heart failure in type 2 diabetes.23,24 Low SBP and DBP have
been associated previously with congestive heart failure in
type 2 diabetic patients.25 Another factor that could contribute
to this association is diabetic cardiomyopathy, which could
lower BP by impairing cardiac output.26 Thus, low BP in
these patients is likely to be a marker of disease rather than
the cause of it. Cardiac output failure could also explain the
high mortality associated with low PP in patients without
previously known CVD.
Although this is the first evidence of a negative association
between BP and mortality in a type 2 diabetic population,
similar associations have been observed in elderly nondiabetic populations.14,27 These studies have generally included
only subjects ⬎75 years of age, whereas the median age of
Figure 2. Cardiovascular mortality in
patients older (䡺, dotted line) than and
younger (●, solid line) than the baseline
median age (69.1 years) in relation to
age- and gender-adjusted blood pressure indices. Bars, 95% CIs.
172
Hypertension
February 2006
Figure 3. Cardiovascular mortality in
patients with (䡺, dotted line) and without
(●, solid line) antihypertensive medication in relation to age- and genderadjusted blood pressure indices. Bars,
95% CIs.
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the Botnia cohort was 69 years. Nevertheless, because the
negative associations between BP and mortality were confined to patients with older age or previous CVD, this study
supports the view that the positive association between BP
and survival is limited to the elderly patient population.
Some limitations of this study should be noted. No conclusions on the benefit of antihypertensive treatment of type
2 diabetic patients can be drawn on the basis of this
observational study. Given the previously reported U-shaped
relationship between SBP and diabetes-related end points in
BP-medicated elderly diabetic patients,28 our observations
clearly underline the need to additionally clarify the impact of
BP treatment in the older diabetic population. This study
evaluated survival after a median follow-up of 9.5 years in a
relatively elderly population. Considering the weak associations between BP and mortality in subjects ⬍69 years of age,
one cannot make assumptions on the effects of BP on
long-term survival in younger diabetic individuals.
Considering the substantial mortality in the type 2 diabetic
population and the relatively high age of the cohort, this study
may be subject to survival bias. Thus, high-risk patients are
likely to be somewhat underrepresented in this cohort. Because elevated urinary AER is an important risk factor for
mortality in type 2 diabetes,29,30 the insufficient data on this
issue constitutes a limitation. This is likely to cause an
underestimation of the observed relationships, because adjusting for AER in the subgroup with available data on AER
lowered the hazard ratio for all of the BP indices and
additionally strengthened the inverse association between BP
and mortality in patients with previous CVD.
The fact that a substantial proportion of the studied
subjects were taking antihypertensive medication at the time
of the baseline visit would certainly have influenced the
results. High-risk patients with previous CVD and diabetic
complications are more likely to use medication. An artificially low BP in high-risk patients could, therefore, seriously
confound the results. On the other hand, any effects of BP on
the circulatory system would be mediated by the actual BP
rather than a theoretical naive BP. Given that the main
findings of this study can be observed when analyzing
medicated and nonmedicated patients separately (Figure 3), a
major confounding effect caused by antihypertensive medication
seems unlikely. Additionally, the Cox regression analyses were
performed in a manner that eliminates confounding effects that
could result from differences between the groups.
It should be noted that the impact of the various BP indices
on mortality in the entire cohort was quite moderate, with
hazard ratios for a 10 mm Hg increase ranging from 0.85 to
1.14. Despite this, because of the complex nonlinear relationship, BP appears to be an important risk factor for mortality
in elderly type 2 diabetic patients and in diabetic patients with
previous CVD.
Perspectives
Both low and high PP are risk factors for mortality in elderly
type 2 diabetic patients. Low SBP and DBP are predictive of
elevated all-cause and cardiovascular mortality in type 2
diabetic patients with previous CVD. In contrast, no BP index
contributed significantly to mortality in young type 2 diabetic
patients without CVD. The results suggest that there might be
a need to reevaluate the role of BP as a risk marker in certain
high-risk subgroups of type 2 diabetic patients.
Acknowledgments
Figure 4. All-cause mortality stratified by age- and genderadjusted SBP and DBP.
The Botnia Study was supported by grants from the Sigrid Juselius
Foundation, Academy of Finland, Folkhälsan Research Foundation,
Finnish Diabetes Research Foundation, Ollqvist Foundation, and
Foundation for Swedish Culture in Finland. Additionally, this study
was financially supported by Samfundet Folkhälsan, Wilhelm and
Else Stockmann Foundation, Waldemar von Frenckell Foundation,
and Finnish Medical Society. The skillful assistance by the Botnia
Research Group is gratefully acknowledged.
Rönnback et al
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Complex Relationship Between Blood Pressure and Mortality in Type 2 Diabetic Patients:
A Follow-Up of the Botnia Study
Mats Rönnback, Bo Isomaa, Johan Fagerudd, Carol Forsblom, Per-Henrik Groop, Tiinamaija
Tuomi and Leif Groop
for the Botnia Study Group
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Hypertension. 2006;47:168-173; originally published online December 27, 2005;
doi: 10.1161/01.HYP.0000199667.30253.b7
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