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Metab Brain Dis

DOI 10.1007/s11011-014-9519-2

RESEARCH ARTICLE

The nature of the control of blood glucose in those with poorer


glucose tolerance influences mood and cognition
Hayley Young & David Benton

Received: 29 August 2013 / Accepted: 12 February 2014


# Springer Science+Business Media New York 2014

Abstract The ability to control the levels of blood glucose


was related to mood and cognition. 155 adults, aged 45
85 years, without a diagnosis of diabetes, were given an oral
glucose tolerance test and cognitive tests. Participants were
classified according to age (4160/6185 years), whether they
had better or poorer glucose tolerance and whether blood
glucose did or did not fall below baseline values. There were
two main findings. Those with poorer glucose tolerance forgot
more words and had slower decision times, but only if 61 years
or older. Secondly as there are reports in animal studies that
inducing low levels of blood glucose values benefited cognitive performance, for the first time in humans, individual
differences in the tendency to develop low levels of blood
glucose were considered. In those with poor glucose tolerance
a tendency for blood glucose to fall below baseline values was
associated with better mood and faster working memory.
Keywords Glucose intolerance . Hypoglycemia . Memory .
Mild cognitive impairment . Mood
Abbreviations
LBG Low blood glucose
GT
Glucose tolerance

Introduction
As glucose is the primary fuel of the brain a continuous supply
is required to maintain cognitive functioning; both poorer
glucose tolerance (Lamport et al. 2009) and low levels of
H. Young : D. Benton (*)
Department of Psychology, Swansea University, Swansea SA2
8PP, Wales, UK
e-mail: d.benton@swansea.ac.uk

blood glucose (Warren and Frier 2005) are disruptive. The


aim was to relate, in a healthy older sample, individual differences in glucoregulation, mood and cognitive functioning.
In those without diabetes a reduced ability to regulate blood
glucose is associated with poorer attention (Donohoe and
Benton. 2000), slower reaction times (Yaffe et al. 2012) and
poorer memory (Yaffe et al. 2012). Although the mechanisms
behind the disruption of cognition in glucose intolerant individuals are unclear, one suggestion is that they reflect a
reduced ability to transport glucose into the brain (Convit
2005). There is evidence that the rate of peripheral glucose
change during cognitive testing is related to performance in
both healthy participants (De Feo et al. 1988; Benton et al.
1996; Donohoe and Benton 2000; Scholey et al. 2001) and
those with diabetes (Perlmuter et al. 2009). It is possible that a
higher rate of decline in peripheral blood glucose reflects
greater glucose uptake by the brain, facilitating cognition.
Therefore, in conditions that hinder glucose uptake, such as
poorer glucose tolerance, the brain may be deprived of the fuel
it requires. This view is consistent with reductions in cerebral
glucose metabolism in those at risk of dementia (Mosconi
et al. 2007).
Despite much research on the cognitive effects of chronically raised plasma glucose levels, there has been little research on the impact of frequent low levels of blood glucose.
Individuals in the early stage of glucose intolerance often
experience hyperinsulinemic compensation (Polonsky 2000);
that is increased levels of plasma insulin. However, if too
much insulin is produced blood glucose levels may fall to
low levels, resulting in substantial fluctuations in blood glucose levels and the possibility of developing mild hypoglycemia (Brun et al. 2000; <3.3 mmol/L). During frank hypoglycemia (<3.0 mmol/L) cognition and mood suffer
(McCrimmon et al. 1997), however, there are large individual
differences in the threshold at which cognitive symptoms
occur (Vea et al. 1992). A possible explanation for these

Metab Brain Dis

differences is that recurrent episodes of low blood glucose


lead to subsequent brain adaptation, so that if hypoglycemia
re-occurs cognition is preserved. For example, animals exposed to recurrent hypoglycemia (2.53.0 mmol/L or 45
54 mg/dl) have increased hippocampal glucose concentrations
once glycemia is restored (McNay et al. 2006). In humans,
Fruehwald-Schultes et al. (2000) using a hypoglycemic
clamp, found that a single episode of antecedent hypoglycemia (3.1 mmol/L) preserved cognition during subsequent
hypoglycemia.
Previous studies have tended to artificially lower blood
glucose to levels that will rarely be found in everyday life.
As the levels of blood glucose needed to induce adaptation are
unclear one aim was to see if comparable effects occur in those
whose physiology predisposes to the development of moderately low levels of blood glucose. A glucose profile often
observed in adults in the early stages of glucose intolerance
is the tendency for blood glucose to drop to low levels 2 to 3 h
after an OGTT (Brun et al. 2000; <3.3 mmol/L), the result of
hyperinsulinemia (Stuart et al. 2013; 2.33.4 mmol/L) or
defective counter-regulatory responses (Ahmadpour and
Kabadi 1997; 2.7 mmol/L). The present study therefore examined, in older adults with better or poorer glucose tolerance,
the association between mood and memory, and the tendency
for blood glucose to fall to low levels.

using an enzymic method, coupled with microelectronic measurement that has been shown to be accurate (Matthews et al.
1987). In addition to the oral glucose tolerance test (OGTT)
participants completed a 30 min cognitive test battery in the
following order; immediate episodic recall, working memory,
reaction times, delayed episodic recall. Participants also completed the General health questionnaire (GHQ-30). Based on a
factor analysis by Chan (1985) the GHQ was also divided into
subscales representing depression and anxiety.
In studies of blood glucose and cognition inevitably the
food that has been eaten, and how recently, are confounding
factors. The test battery was therefore started 10 min after the
consumption of the OGTT to ensure that all participants were
comparably nourished and were tested at a time when blood
glucose levels were similar and individual differences in
physiology had little time to be influential (Fig. 1). Evidence
suggests that the consumption of glucose may reduce the
differences in cognition that are observed between those with
better or poorer glucose tolerance (Awad et al. 2002; Kaplan
et al. 2000), thus it was considered that this approach would
bias against rather than in favor of detecting differences. The
procedure was identical for all participants.
Test battery
Episodic memory

Methods
Subjects
One hundred and fifty five adults (58 males; 97 females) aged
45 to 85 years (average age 56 (SD 12.3)), were recruited.
Anyone diagnosed with type 1 or type 2 diabetes, liver disease, gastrointestinal problems that may interfere with absorption, a current diagnosis of a mood disorder, dementia or other
mental disorder that may affect cognition were excluded.
Eyesight and hearing was normal or corrected to normal.
Of the subjects 16.1 % were taking drugs to control blood
pressure, 3.8 % thyroxine, 3.2 % statins and 2.7 % asthma
(Table 1). The raw National Adult Reading Test raw scores
averaged 42.2 (7.5) that corresponded to an IQ of 117.0 (6.2).
Procedure
The procedure was followed with the approval of the Swansea
University ethics committee (reference: 0825/2009/1) and
only after the participants had given written informed consent.
After abstaining for at least 12 h from all food and drink
except water, 1.75 g of glucose per kilogram of body weight
was consumed, to a maximum of 75 g. Every 30 min for
150 min blood glucose was monitored from finger pricks
using an ExacTech sensor (Medisense Britain Limited) that

Episodic memory was measured by recalling a word list.


Using the MRC Psycholinguistic Database a list of 30 words
was matched for the number of syllables, image-ability and
the frequency with which they occur in English. Using a
recorder words were presented one every 2 s. Immediately
after the presentation as many words as possible were written
down (immediate recall). Approximately 20 min later, after
completion of the other tasks, subjects again recalled the
words (delayed recall).
Working memory
Working memory was assessed with a computerized version
of the serial sevens task. A series of numbers between 800 and
999 was given and the subject indicated whether a second
number was seven less than the previously observed number.
The responses to 28 sequences were recorded and the number
of errors made, and the time to respond to the second number
reported.
Reaction times
On a panel eight lamps were arranged in a semicircle, each
5.5 in. from a central button (the home key). The index finger
was placed on the home key. Within 1 to 2 s an auditory
warning signal sounded and after a random interval of 1 to 4 s

Metab Brain Dis


Table 1 Demographic and blood glucose data for the four glucoregulatory groups

BMI
Male
Female
Age
Thyroxine
Asthma medication
Statins
Blood pressure medication
Baseline glucose

Poorer GT LBG
above baseline

Poorer GT LBG
below baseline

Better GT LBG
above baseline

Better GT LBG
below baseline

Probability

28.1 (0.8)
20
47
58 (11.4)*
**
5/67
5/67
8/67
17/67

29.5 (1.6)
17
26
56.2 (9.6)

25.0 (1.4)
10
15
53.0 (10.7)*

26.8 (1.0)
11
8
54.2 (10.8)**

ns
ns

2/43
4/43
1/43
2/43

4/25
0/25
1/25
3/25

2/19
0/19
1/19
3/19

5.5 (0.6)*

4.9 (0.5)**
***
5.9 (0.7)
0.9 (0.7)

5.3 (0.5)**

5.6 (1.1)*
***
7.7 (2.3)*
2.0 (1.6)

Glucose 150 min


Drop below baseline

4.2 (0.6)*
1.2 (0.8)*

4.1 (0.5)*
1.2 (0.6)*

*p<0.01
**p<0.005
ns
ns
ns
p=0.06.
*p<0.001
**p<0.003
***p<0.005
All comparisons p<0.0001 except
All comparisons p<0.0001 except

Blood glucose in mmol/L (SD)

one of the lamps illuminated. The subject then extinguished


the light by depressing a button directly below the lamp, using
the finger initially on the home key. Simple reaction times
were measured for 20 trials using one lamp. Choice reaction
times were then measured over three sets of 20 trials when one
of 2, 4 or 8 lamps could potentially illuminate. Decision times,
the time taken to lift the finger from the home key, were
analyzed.
12.8

TEST BATTERY

Blood glucose (mmol/L)

11.8

National adult reading test


The National Adult Reading Test (NART; Nelson 1982) is
widely used to retrospectively estimate the level of premorbid
intellectual functioning, as unlike other aspects of cognition
the ability to recognize words is relatively preserved with age
(Bright et al. 2002). The test involves reading aloud of 50
phonetically irregular words that occur progressively less
frequently in English. Essentially it is a measure of vocabulary
that correlates with measures of overall intelligence.
Statistical analysis

10.8
9.8
8.8
7.8
6.8
5.8
4.8
3.8
0

30

60
90
Time (minutes)

120

150

Fig. 1 Oral glucose tolerance profiles of four groups of subjects. The


data are mean blood glucose values as mmol/dl for four groups defined in
terms of poorer and better glucose tolerance (above and below 7 mmol/dl
at 120 min) and either staying above or falling below baseline values.
Poorer glucose toleranceAbove baseline N=67.
Poorer glucose toleranceBelow baseline N=43.
Better glucose toleranceBelow baseline N=19.
Better glucose toleranceAbove baseline N=25

Subjects were divided into two groups according to their


blood glucose level after 2 h of the OGTT. To allow sufficient
sample sizes as near a median split as possible was made. If
their blood glucose was 7.0 mmol/L or higher they were
described as having poorer glucose tolerance (GT), if their
blood glucose was less than 7 mmol/L they were described as
having better GT. The World Health Organisation (WHO)
defines glucose intolerance as blood glucose>7.8 mmol/L at
2 h OGTT, although this definition does not reflect any
measure of cognitive functioning. According to this definition
32 % of the samples (n=49) were glucose intolerant.
Individuals were also divided into two groups depending
on the tendency for blood glucose to remain above or fall
below fasting values. This cut-off was chosen as a convenient,
albeit arbitrary, indication of the tendency of blood glucose
levels to fall. However, falling below the baseline value does
not necessary result in problems as there are individual differences in the response to low levels of blood glucose. Those
whose levels fell below baseline at the end of the test
(150 min) all had glucose levels at this time <5.0 mmol/L.

Metab Brain Dis

Importantly, 50 % of these final values fell below 4.0 mmol/L


and 30 % were <3.6 mmol; this variable was labelled Lowest
Blood Glucose (LBG). The average fall below baseline was
1.5 mmol/l with a range of 0.6 mmol/l to 3.8 mmol/l. Figure 1
illustrates the blood glucose profiles for the four experimental
groups.
The possibility was considered that in those with poorer
glucose tolerance, it might be more likely that blood glucose
fell below baseline simply because the baseline glucose level
were higher than in those with better glucose tolerance. Blood
glucose at baseline, after 150 min and the average drops in
blood glucose are shown in Table 1. When those whose levels
fell below baseline were considered, the profiles of those with
poorer and better glucose tolerance were similar; there were
no significant differences in blood glucose after 150 min or in
the average drop below baseline. As would be expected the
profile of those whose values stayed above baseline differed
significantly as it was differences in the profile that defined
poorer and better GT (Table 1).
The baseline value in those with better glucose tolerance
(4.9 mmol/L), with a final difference of only +0.9 mmol/L,
suggested the possibility that blood glucose values below
baseline, in those with poorer GT, might actually have been
higher than those in the better GT/above baseline group. In
fact an examination of values at 150 min found relatively little
overlap in blood glucose values, reflecting a highly significant
difference between these two groups (4.2 mmol/L (0.6) vs
5.9(0.7); p<0.0001). Of the 43 subjects in the poorer GT/fell
below baseline group, only five had blood glucose values at
150 min above 4.9 mmol/L (baseline value for those with
better GT/stayed above baseline). Repeating the analysis with
these five subjected excluded made no difference to the final
results.
Table 1 shows the demographic data for the participants in
each glucoregulatory group. There were no significant differences in BMI between any of the glucoregulatory groups
(F(3,152)=1.736, ns). Similarly, BMI was not related to any
measure of cognition and mood so was not considered further.
Gender did not determine glucoregulatory status (2(3)
=5.177, p=0.158). Gender significantly predicted memory
(F(1,154)=4.118, p<0.05); females has better memory than
males (Males 9.4(0.4) Females 10.6(0.3)). However, there
were no interactions between gender and glucoregulatory
profile and thus gender was not further considered. The number of participants taking thyroxine, statins or asthma medication did not differ depending on the glucoregulatory group;
however, there was a trend for more adults with poorer
GT and LBG above baseline to be taking medication to
control blood pressure, an effect that approached significance (2(6)=11.746, p=0.06). Adults with better GT
and LBG above baseline were significantly younger than
those with poorer GT and LBG above baseline (p<0.01).
Similarly, adults with better GT and LBG below baseline

were significantly younger than those with poorer GT and


LBG above baseline (p<0.01).
As gluco-regulatory capability tends to decrease with age it
was considered a potentially important moderator: it was
possibility that poor glucose tolerance was simply a marker
for other age-related problems. Age was considered by
distinguishing those 60 years and below from 61 years and
above. This was chosen as the cut off because it had been
argued that there may be a critical period, which begins at
around 60 years, during which glucose intolerance has the
greatest impact on cognition (Biessels et al. 2008). Table 2
shows cell frequencies and plasma blood glucose levels 2 h
after OGTT for each level of each of the four groups included
in the analysis. Age did not influence the 2 h plasma glucose
levels in any of the four groups suggesting that our attempt to
control for this confound was successful. Given the resulting
uneven sample sizes, sum of squares type III were used that
uses an un-weighted mean: in this context it deals robustly
with the effects of uneven sample sizes.
The effects of GT and LBG were considered using analysis
of variance: typically they took the form of GT (Better/poorer)
X LBG (Above/below baseline) X Age (under 61/61 years
and over). Where appropriate additional factors were added to
the analysis, for example, with memory the immediate and
delayed scores were entered as a repeated measures factor to
test for effects on forgetting. Interactions were probed using
appropriate post hoc tests. Where Levenes test for equality of
variances was significant adjusted p values were reported.

Results
Episodic memory
The interaction GT (Better/Poorer) X Age (under 61/61 years
and over) X Immediate/delayed recall reached significance
(F(1,146)=7.02, p<0.009) and is illustrated in Fig. 2. Post
hoc tests revealed that older subjects with poorer GT forgot
more words (difference between immediate and delayed recall) than both older subjects with better GT (p<0.02) and
younger subjects with poorer GT (p<0.01). GT did not influence forgetting in younger subjects and LBG did not affect
memory.
Working memory
With the response times of the serial sevens test the interaction
GT X LBG reached significance (F(1,139)=5.57, p<0.02;
Fig. 3). Post hoc tests found that those with better GT responses did not differ depending on LBG. However, with
poorer GT, if LBG fell below baseline mental arithmetic was
performed more quickly (p<0.02). No other post hoc tests
reached significance. When the number of correct responses

Metab Brain Dis


Table 2 Plasma blood glucose after 2 h of OGTT
LBG below baseline
Better GT

LBG above baseline


Poorer GT

Better GT

Poorer GT

Younger

Older

Younger

Older

Younger

Older

Younger

Older

5.0 (0.9)
n=12

5.5 (0.9)
n=9

7.6 (1.5)
n=25

7.9 (1.5)
n=16

6.0 (0.7)
n=18

6.0 (0.6)
n=7

8.4 (1.5)
n=32

9.4 (3.0)
n=35

The data are mmol/L (SD). There were no differences in 2 h plasma glucose levels, between younger and older adults, in any of the four glucoregulatory
groups
GT glucose tolerance, LBG lowest blood glucose

were examined the GT X LBG X Age interaction was nonsignificant (F(1,139)=0.33 n.s.).
Reaction times
With decision times the GT X Age interaction was significant
(F(3,432)=2.84, p<0.03; Fig. 4). There were no differences
when those aged 60 or under were examined (F(3,171)=0.17,
n.s.). However, in older individuals there was a main effect of
GT (F(1,57)=12.90, p<0.001); the responses of those with
poorer GT were slower (1266.9 ms (84.6) vs 843.8(81.9)).
LBG did not influence decision times (1019.1(92.2) vs
991.7(73.22), n.s.).
Depression and anxiety

Discussion

With the depression sub-scale of the GHQ there was a significant GT X LBG interaction (F(1,146) =7.04, p < 0.009;
Fig. 5). When a LBG that fell below baseline was combined
with a poorer GT, depression was lower than when it was
combined with better GT (p<0.02). However, when those
with LBG above baseline were considered, those with poorer
as opposed to better GT were more depressed (p<0.01). When
those with poorer GT were selected, those with LBG below

The present study examined, in older adults with better or


poorer glucose tolerance, the association between the tendency for blood glucose to fall to low levels, mood and aspects of
cognition. Noteworthy were the findings with poorer GT, that
having blood glucose that subsequently fell below baseline
values, was associated with improved working memory
(Fig. 3) and decreased depression (Fig. 5). Although the brain
p<0.02

3300

p<0.02
Reaction Times (ms)

p<0.01

the baseline had a less a depressed mood than those without


that tendency (p<0.007). When those with better GT were
selected, those with a LBG below as opposed to above the
baseline had a more depressed mood (p<0.04). Thus, a LBG
below baseline was associated with less depression in those
with poor GT, whereas it increased the depression of those
with better GT.
With the anxiety subscale the interaction GT X LBG was
non-significant (F(1,146)=0.29, n.s.), although the main effect of GT reached significance (F(1,146)=4.67, p<0.03).
Those with poorer rather than better GT were more anxious
(22.2(0.53) vs 20.7(0.51)).

3100
2900
2700

Below baseline

2500

Above baseline

2300
2100
1900
Better GT

Fig. 2 The association between age, glucose tolerance and forgetting.


The data are mean (SE) number of words forgotten

Poorer GT

Fig. 3 The association between glucose tolerance and reaction times in


the working memory task. Data are the mean (S.E.) response times in
milliseconds (ms). A lower score indicates a faster reaction time

Metab Brain Dis


p<0.001

Fig. 4 The relation between age, glucose tolerance and decision times.
The data are decision times (S.E.) in milli-seconds where a higher score
reflects a poorer performance

adaptation to low levels of blood glucose has been little


considered in healthy subjects, similar phenomena have been
described in diabetics (Lobmann et al. 2000) and animals
(McNay et al. 2006; McNay and Sherwin 2004). In animals,
low blood sugar levels (2.53.0 mmol/l) have been reported to
induce brain adaptation such that cognitive functioning improved. For example, a single episode of low blood glucose
increased hippocampal interstitial glucose concentrations
(McNay et al. 2006; McNay and Sherwin 2004). You can
speculate that this increase in brain glucose levels enhanced
subsequent cognitive performance by providing a greater
supply of glucose. For example, maze learning by rats, a task
that is associated with a drop in hippocampal interstitial glucose levels (McNay et al. 2000), was performed better after
3 days of exposure to hypoglycemia (McNay and Sherwin
2004): there were smaller falls in interstitial glucose when
animals had been exposed to hypoglycemia. Although the
mechanisms underlying these findings remain unclear,
GLUT 1 at the endothelium (Boado and Pardridge 1993)
and the neuronal glucose transporter GLUT 3 (Uehara et al.
1997) are both up regulated following hypoglycemia. It is
interesting that localized drops in brain interstitial glucose
p<0.01
p<0.02

15

Depression

14

p<0.007
p<0.04

13
Below baseline

12

Above baseline

11
10
9
Better GT

Poorer GT

Fig. 5 The association between glucose tolerance and rating of depression. Data are the mean (S.E.) of ratings of depression where a higher
score indicates feeling more depressed

during activation have been reported to be greater, and to last


longer, in aged rather than young animals (McNay and Gold
2001) and that exposure to hypoglycemic episodes modified
the effects of aging on cognitive decline (McNay 2005).
Whilst in adults with poorer GT the tendency for blood
glucose to fall was beneficial, this was not the case for those
with better GT. It is possible that the beneficial effects associated with LBG are more easily demonstrated in those with
poorer GT because performance had already deteriorated; a
reflection of lower levels of brain glucose (Convit 2005). In
addition, it may be hypothesised that if LBG leads to an
adaptive response that increases cerebral interstitial glucose,
then this may offset the negative repercussions of reduced
cerebral glucose uptake associated with poorer GT, thus facilitating cognition.
A critical question is why did the blood glucose levels of
some with poor GT remained high while in others there was a
sharp decline after 120 and 150 min (Fig. 1): it was this fall in
blood glucose that was beneficial (Figs. 3 and 5). Although
levels were not measured it is probable that this effect reflected
a late increase in insulin secretion in those with the tendency
for blood glucose to fall below baseline levels. The usual
response to insulin resistance is compensatory
hyperinsulinemia (Polonsky 2000), therefore hyperglycemia
and glucose intolerance do not occur until insulin secretion is
impaired (Triplitt 2012). Thus it is possible that adults with
poorer GT, whose blood glucose values subsequently fell,
may have developed hyperinsulinemia to compensate for
insulin resistance. This consideration of the role played by
insulin in controlling blood glucose in those with poor GT
raises the question whether it directly played a part in improving the cognitive functioning of those with poorer GT whose
levels fell below baseline values. Although the current consensus is that glucose transport into the brain is not dependent
on insulin, the hormone crosses the blood brain barrier and is
thought to modulate memory (Zhao et al. 2004). As such, a
higher rate of insulin secretion could be the mechanism that
produces both falling blood glucose levels and enhanced
cognitive functioning.
The beneficial effect of a tendency of blood glucose to fall
in those with poorer GT is an intriguing finding, although it
raises questions. Is this glucose response a stage between
glucose intolerance and later diabetes? In time would those
whose glucose levels fell sharply turn into the group whose
levels remained high: a sample needs to be considered over
time? The question also arises as to whether cognitive decline
may be influenced by a prolonged dietary intervention based
on the glycemic response to meals?
Also noteworthy was that the negative effects of poor GT
were more pronounced in those over 61 years; in older rather
than younger individuals poorer GT was associated with
slower decision times and forgetting more words. Although
previously when considering GT and cognition a stronger

Metab Brain Dis

association has been found in older (Messier et al. 2003) rather


than young adults (Lamport et al. 2009), this is the first study
to directly compare younger and older adults with a similar
level of impaired GT (Table 2). Although the exact mechanism is to be determined, there was a negative interaction
between age and the metabolic consequences of impaired GT.
A recent study found that raised blood glucose levels, that
as defined by the WHO were still in the normal range, were
associated with lower grey/white matter volumes in otherwise
cognitively healthy older adults (Mortby et al. 2013). This is a
potentially important observation as white matter plays an
important role in allowing messages to be sent quickly in the
brain and damage in white matter is frequently observed in
people with dementia. There is clear relationship between
damage to white matter and cognitive impairment. It seems
reasonable to suggest that in part at least that damage to white
matter might reflect problems with the ability of blood vessels
to supply glucose.
In conclusion, older rather than younger adults with poorer
GT had poorer cognitive performance. In addition, the tendency to develop LBG was associated with better cognitive
performance and mood in those with poorer glucose tolerance.
Further research is required to establish the level at which
raised blood glucose becomes detrimental.
Acknowledgments The authors declare that they have no conflict of
interest and that the work was not externally funded. We are grateful to
the Swansea University for supplying the necessary facilities.

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