R E S E A R C H A R T I C L E Open Access
Effect of folic acid supplementation on
homocysteine concentration and association with
training in handball players
, José M Molina
, Luís J Chirosa
, Daniela I Florea
, Laura Sáez
and Elena Planells
Background: Strenuous physical activity can alter the status of folic acid, a vitamin directly associated with
homocysteine (Hcy); alterations in this nutrient are a risk factor for cardiovascular disease. Handball players are a
population at risk for nutrient deficiency because of poor dietary habits.
Objective: The aims of this study were to evaluate nutritional status for macronutrients and folic acid in members
of a high-performance handball team, and determine the effect of a nutritional intervention with folic acid
supplementation and education.
Design: A total of 14 high-performance handball players were monitored by recording training time, training
intensity (according to three levels of residual heart rate (RHR): <60%, 60%–80% and >80%), and subjective
perceived exertion (RPE) during a 4-month training period. Nutritional, laboratory and physical activity variables
were recorded at baseline (Week 0), after 2 months of dietary supplementation with 200 μg folic acid (50% of the
recommended daily allowance) (Week 8) and after 2 months without supplementation (Week 16). We compared
training load and analyzed changes in plasma concentrations of Hcy before and after the intervention.
Results: Bivariate analysis showed a significant negative correlation (P< 0.01) between Hcy and folic acid
concentrations (r=−0.84) at Week 8, reflecting a significant change in Hcy concentration (P< 0.05) as a result of
hyperhomocysteinemia following the accumulation of high training loads. At Week 16 we observed a significant
negative correlation (P< 0.01) between Hcy concentration and training time with an RHR <60%, indicating that
aerobic exercise avoided abrupt changes in Hcy and may thus reduce the risk of cardiovascular accidents in high-
Conclusion: Integral monitoring and education are needed for practitioners of handball sports to record their folic
acid status, a factor that directly affects Hcy metabolism. Folic acid supplementation may protect athletes against
alterations that can lead to cardiovascular events related to exertion during competition.
Keywords: Nutritional status, Sport, Folic acid, Supplementation, Homocysteine
Folic acid is a vitamin needed by a number of enzymes
essential for DNA synthesis and amino acid metabolism
. This nutrient is an important co-factor in the me-
thionine pathway, the most important source of methyl
groups in the human organism . Low folic acid intake
is known to contribute to increased levels of homocyst-
eine (Hcy) as a result of its interrelation with methionine
metabolism [2-6]. Inadequate intake of folic acid has
been described in athletes who practice different sports
, and athletes are often deficient in their intake of
total calories, carbohydrate, protein, and micronutrients
. Some authors consider supplementation with folic
acid as an efficient way to reduce elevated Hcy levels
[8,9], and it has been suggested that in certain cases,
folic acid supplementation should be used for preventive
purposes . Earlier findings have suggested that doses
* Correspondence: email@example.com
Department of Physiology, Institute of Nutrition and Food Technology,
University of Granada, Granada 18071, Spain
Full list of author information is available at the end of the article
© 2013 Molina-López et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10
of 0.2 to 0.4 mg/d can achieve maximal reductions in
Hcy in healthy young populations, whereas doses up to
0.8 mg/d are needed to reduce Hcy in individuals with
coronary heart disease .
Regular physical activity (PA) can alter the requirements
for some micronutrients . This makes it important
to choose foods carefully, taking into account the
quality and quantity of macronutrient intakes, since
requirements can vary depending on the type of exer-
cise performed .
Elevated plasma levels of Hcy are considered a risk
factor for cardiovascular disease (CVD) . Regular
physical activity is now well established as a key compo-
nent in the maintenance of good health and disease pre-
vention, and has been specifically recognized to reduce
the risk of appearance of CVD by reducing chronic in-
flammation, which plays a key role in the atherogenic
process, blood pressure, body composition, insulin sensi-
tivity and psychological behavior [14,15].
In contrast, acute intense exercise has been shown to
increase plasma Hcy concentrations . Several factors
have been reported to be associated with increases in
Hcy, such as endothelial cell injury, which stimulates
vascular smooth muscle cell growth, increases platelet
adhesiveness, enhances LDL cholesterol oxidation and
deposition in the arterial wall, and directly activates the
coagulation cascade . Some research has concluded
that Hcy levels may be influenced by the duration, inten-
sity and type of exercise [6,14,17,18], whereas other
studies have identified lifestyle factors such as smoking,
eating habits and alcohol consumption [6,19,20], as well
as age, elevated blood pressure, renal failure [17,21] and
genetic factors , as factors that contribute to
increased plasma concentrations of Hcy. In addition, nu-
tritional factors such as reduced folic acid intake have
been implicated [3,13].
Several authors [4,13,22,23] have established a direct
relationship between regular physical exercise (PA) and
a reduction in CVD risk, although the data regarding
the effect of PA on plasma Hcy concentrations remain
controversial because of methodological differences
among different studies. Murakami et al.  noted that
these discrepancies may reflect differences in the
methods used to evaluate PA, the lack quantitative infor-
mation on training intensity or training time, and in
some cases the lack of adjustment for folate intake status
. However, Venta et al.  suggested three possible
mechanisms that may explain the increase in Hcy with
increasing exercise intensity: increased free radical pro-
duction , increases in methylated forms such as cre-
atine and acetylcholine, and increases in the amino acid
pool as a result of protein catabolism. The need for re-
search in athletes who take part in different sports has
been suggested to be important in order to account for
the high prevalence of hyperchromocysteinemia . To
date, however, there have been no studies that evaluated
plasma Hcy levels while taking into account nutrient
intakes, training intensity and training time, and rate of
perceived exertion (RPE). Moreover, the relationship be-
tween PA and Hcy has not been studied in team sports
such as handball, in which intermittent activity
alternates with periods of intense aerobic activity .
In the present study our aims were to evaluate macronu-
trient and folic acid nutritional status in high-performance
athletes (handball players), and to determine the effect
on these parameters of training and a nutritional inter-
vention based on dietary supplementation with folic acid.
We analyzed the data in the light of training load and
plasma Hcy concentrations.
The study was done during the February to June 2010
sports season and all participants were members of the
handball team (n = 14) sponsored by the Club Deportivo
Puente Genil de Balonmano (Granada, Spain), in the
Honor B Division of the Spanish professional handball
league. The sample comprised 14 men (mean age 22.9 ±
2.7 years) who trained for a mean of 4 days per week in
addition to competing in matches on weekends.
Participation in the study was voluntary. None of the
participants had evidence of CVD, diabetes or hyperten-
sion. All participants provided their informed consent in
writing, and were given detailed information at the be-
ginning and end of the study regarding the aims and
procedures involved. The study was approved by the Re-
search Ethics Committee of the University of Granada.
Anthropometric and biochemical measures
Body weight, body mass index and body fat percentage in
all participants were determined with a Tanita TBF-300WA
Body Composition Analyzer. Height was measured on a
scale to within the nearest 0.01 cm.
Blood samples for laboratory analyses were obtained
after a 12-h fast after the last training session in each
time period. Venous blood was drawn, centrifuged to
separate plasma and red blood cells, and stored at
−80C. Folic acid concentration was measured with an
electrochemical luminescence immunoassay (ECLIA, Elecsys
2010 and Modular Analytics E 170, Roche Diagnostics,
Mannheim, Germany) with a reference value of 3 pg/l
. Plasma concentrations of Hcy were measured with
a fluorescence polarization immunoassay (IM
Laboratories, Abbott Park, IL, USA) . Laboratory
values were determined for transferrin, prealbumin,
high-density lipoprotein, low-density lipoprotein and
total cholesterol to verify adequate nutritional status in
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10 Page 2 of 8
all participants and rule out the possibility of nutri-
tional alterations that might have affected the findings.
Assessment of macronutrient and folic acid intake
To evaluate dietary intakes we used a food consumption
questionnaire  consistent with a 72-h recall system
during 3 consecutive days (2 working days and 1 non-
working day). During the educational intervention the
participants were instructed to abstain from consuming
caffeine or alcohol. Three time points were used during
a 4-month period: baseline (Week 0), followed by 2
months of dietary supplementation (Week 8), followed
by 2 months without supplementation (Week 16). Food
intakes were recorded with the help of a manual
containing photographs of standard amounts of different
foods and prepared dishes. To record portion sizes and
the amounts of different foods as accurately as possible,
the participants were asked to identify the foods
consumed and describe the size of the portions. Food
intakes were analyzed with Nutriber
software  to
convert them into data for absolute nutrient intakes and
percentage values of adequate intakes according to indi-
Macronutrient intakes (carbohydrates, protein, and fat
and folic acid) were compared to reference intakes .
Percentage macronutrient intakes referred to total en-
ergy intake were compared with recommended dietary
allowances (RDA) .
Nutritional supplementation and education intervention
Dietary supplementation consisted of folic acid at 200
μg/d, starting on day 1 in Week 0 and ending on the
final day of this 2-month period in Week 8. For the
following 2 months no dietary supplementation was
used; this period lasted from Week 8 to Week 16, when
the study period ended.
The educational intervention was designed ad hoc for
this type of study population by a team of nutrition
specialists. The intervention consisted of three phases.
First, the nutrition team explained aspects related with
nutrition in general, with emphasis on the different types
of nutrients and their importance for maintaining good
health in basically healthy persons. This was followed by
education focusing more specifically on nutrition and
PA. In this second phase the emphasis was on specific
nutritional requirements in persons who perform con-
tinuous PA, since nutrition in this population is often
not well balanced, and supplements are often used to in-
crease performance . In the third phase, team members
responded to the questions participants raised at any
time throughout the study period to provide additional
information and clarification.
To record training parameters we used three variables
that define training load: training time, intensity and
RPE. All participants trained for a mean of 4 days per
week in addition to participating in competition matches
Training time was recorded during a 4-month period
covering the professional handball competition season,
divided into four 1-month mesocycles. In each training
session we recorded the number of minutes spent on
each type of exercise until the desired training time was
reached. The first 2 months (mesocycles 1 and 2)
comprised the period of training when supplementation
was used (STp), and the following 2 months (mesocycles
3 and 4) comprised the period of training without diet-
ary intervention (NSTp). Total training time in each
mesocycle was calculated as the sum for all training
sessions and competition match times.
Training intensity was recorded with Polar S610
and Polar Team pulse meters (Polar Electro Ibérica,
Barcelona, Spain) once per training week, for a total of
22 final recorded training sessions (11 for each training
period). To calculate maximum heart rate (HR
used the course navette test of maximum aerobic power.
We also recorded baseline heart rate during 7 days to
obtain an accurate mean value. Heart rate reserve or re-
sidual heart rate (RHR) was calculated as HR
basal heart rate to establish the level of intensity and
the time each athlete spent in each level . We used
three ranges of intensity: <60%, between 60% and 80%,
and >80% RHR.
The RPE was used to determine whether the amount
of exertion each participant perceived was consistent
with actual intensity of exertion once per training week,
for a total of 22 final recorded training sessions (11 for
each training period). The participants indicated one of
the three levels of perceived exertion at the end of each
training session. We calculated RPE as the mean ±
standard deviation (SD) (n= 14) to evaluate perceived
load in each mesocycle or month of training.
Training sessions were monitored and standardized by
using the same exercises in the same order and with the
same duration across sessions. The results were
compared as the mean ± SD (n= 14) for each of the
three study periods.
The data are reported with descriptive statistics. For nu-
merical variables we used the arithmetic mean, SD and
standard error of the mean. The results for categorical
variables are reported as percentage frequencies. To de-
termine whether the data fitted a parametric model, the
Kolmogorov-Smirnov test was used to verify normal dis-
tribution. To check the homoscedasticity of the
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10 Page 3 of 8
variables, the Levene test was used. Between-group
comparisons were made with the chi-squared test and
single-factor analysis of variance. Linear regression ana-
lysis was used to identify correlations by calculating
Pearson’s bivariate correlation coefficient. All statistical
analyses were done with SPSS v. 16.0 for Windows.
The general characteristics of the participants are shown
in Table 1, and these characteristics did not change sig-
nificantly during any of the three study periods.
Assessment of macronutrient and folic acid intake
Energy, macronutrient and folic acid intakes are
summarized in Table 2, and are referred to RDAs for
athletes [28,29]. The main finding was a significantly
higher (P< 0.01) folic acid intake in Week 8 compared
to Week 0 and Week 16, as a result of supplementation.
When folic acid intake was adjusted for energy intake in
Week 8 regardless of supplementation, the difference be-
Macronutrient intakes were significantly higher (P< 0.05)
in Week 0 compared to Week 8 and Week 16 for
carbohydrates. Fat intake was significantly higher in
Week 0 and Week 8, and protein intake was significantly
higher in Week 0 and Week 16.
Table 3 shows the percentages of participants whose
macronutrient and folic acid intakes were within each
tercile of the RDA, or were above the RDA, in each of
the three study periods. The results show that folic acid
intake was above 100% the RDA in Week 8. In Week 0
and Week 16, intake was below 2/3 of the RDA in 42.9%
of the participants . Mean carbohydrate intake was
below the RDA  at all time points, whereas fat and
protein intakes were above 100% of the RDA .
The results in Figure 1 show the training loads recorded
during the study period. Training load is reported here
as training time, RPE and distribution among three
levels of intensity during the intervention (STp) and
post-intervention periods (NSTp). There were no
statistically significant differences in training time be-
tween STp and NSTp.
Overall RPE during STp was significantly lower (P<0.05)
than during NSTp. With regard to the durations of diffe-
rent RHR levels (training intensity), a significant diffe-
rence (P< 0.05) was found for the 60%–80% range,
which accounted for 30.35% of the total training time
during STp, and for 35.87% of the training time du-
ring the NSTp. There were no significant differences for
training intensity levels in the <60% range or the >80%
Bivariate analysis to calculate Pearson’s correlation
coefficient detected statistically significant correlations
(P< 0.01) between overall RPE and training intensity levels
of 60%–80% RHR (r= 0.64) and >80% RHR (r=0.76).
The results of biochemical analyses are shown in Table 4.
There were no significant changes in plasma folic acid at
any time point, and all values were within the normal
range for the healthy population. However, plasma
concentrations of Hcy increased significantly (P< 0.05)
to above the normal range of values during the Week 8
and Week 16 periods compared to baseline values in
Week 0. Regarding the relationship between plasma
concentrations of Hcy and folic acid and training inten-
sity, we found that both plasma concentrations showed a
significant negative correlation (r=−0.75) (P< 0.01) with
the level of intensity of <60% RHR. Bivariate analysis
disclosed a significant negative correlation (P< 0.01) be-
tween Hcy and folic acid concentrations (r=−0.84) in
The other nutritional parameters studied here (albu-
min and prealbumin) showed no statistically significant
changes at any time point. Among the lipid parameters
we measured, HDL, LDL and total cholesterol were sig-
nificantly higher (P< 0.05) in Week 0 compared to Week
16, and HDL and LDL were significantly higher in Week
8 compared to Week 16.
The results of the present study suggest that after the
dietary and educational intervention, there were no sig-
nificant changes in plasma concentrations of folic acid.
However, we did note changes in plasma Hcy levels, des-
pite the significant inverse correlation between the two
values. Folic acid supplementation may have reduced
cardiovascular risk during the NSTp in the handball
players we studied.
In the present study, increased food intake as a result
of nutritional education may have contributed to weight
maintenance throughout the experimental period, which
Table 1 Characteristics of the participants at three time
Measurement Mean SD
Age (years) 22.9 2.7
Height (m) 1.87 0.06
Week 0 Week 8 Week 16
Mean SD Mean SD Mean SD
Weight (kg) 86.72 5.36 86.47 5.59 86.38 4.81
Body mass index (kg/m
) 24.72 1.12 24.61 1.30 24.62 1.14
Body fat (%) 11.58 2.53 11.60 2.45 11.57 2.34
SD, standard deviation.
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10 Page 4 of 8
would avoid possible alterations in body weight as a re-
sult of poor dietary habits . Regular PA is known to
alter the requirements for certain micronutrients .
Folic acid intake in the athletes studied here (Table 2)
was below the RDA except during Week 8, and was simi-
lar to the values reported by Rousseau et al. . In this
connection, a meta-analysis by Woolf and Manore 
concluded that most studies which had analyzed folic
acid intake based on a 3-day (72-h) recall period obtained
values similar to those found in the present study. Sup-
plementation with folic acid was implemented after an
initial evaluation which showed the intake of this nutri-
ent to be inadequate. The amount used in the dietary
supplement was consistent with the theoretical basis
described by McNully et al. , who suggested that
doses of 0.2 to 0.4 mg folic acid per day may achieve
maximal reductions in Hcy in healthy young people,
whereas doses up to 0.8 mg folic acid per day would be
needed to reduce Hcy in individuals with coronary artery
disease. However, in the present study plasma Hcy con-
centration did not change despite the significant increase
in folic acid intake.
Regular PA is known to reduce the risk of CVD [6,12].
Handball, like other team sports such as soccer and field
hockey, is considered an intermittent intensity sport on
the basis of the aerobic energy pathways involved .
When we analyzed training load, we found a significant
negative correlation between exercise training time at an
intensity range of <60% RHR and plasma Hcy level
(Figure 2). Rousseau et al.  reported that athletes
who performed aerobic exercise had lower levels of Hcy.
This finding is consistent with our results; moreover, our
direct method for quantifying training load provided
data that can be considered accurate and reliable. How-
ever, a potential limitation that should be taken into ac-
count is that the present study was done under actual
Table 2 Energy, macronutrient and folic acid intakes at three time points
N = 14 RDA Week 0 Week 8 Week 16
Mean SD Mean SD Mean SD
Energy (kcal/kg/day) 44* 34.45 3.56 38.91
Protein 104 –147* 133.43 14.32 146.64 35.64 147.04
Carbohydrate 519 –865* 360.91 27.64 421.50
Fat 78 –95* 118.57 22.52 132.22
17.75 129.57 21.79
Protein 1.2 - 1.7* 1.54 0.22 1.70 0.44 1.70
Carbohydrate 6 –10* 4.17 0.41 4.88
Fat 0.9 –1.1* 1.37 0.28 1.53
0.19 1.49 0.21
Macronutrients (% energy intake)
Protein 12 –15%* 17.97 1.83 17.47 3.73 17.65 2.54
Carbohydrate 45 –65%* 48.66 4.10 50.21 2.54 50.20 3.62
Fat 20 –35%* 35.71 4.88 35.51 3.81 34.92 4.01
Folic acid 400* 301.97 89.05 516.11
RDA, recommended daily allowance. SD, standard deviation.
* Values used for comparison were from previous publications [28,29].
Statistically significant differences (P< 0.05) between Week 0 vs. Week 8 and Week 16.
Statistically significant differences (P< 0.05) between Week 8 vs. Week 16.
Table 3 Recommended daily allowance covered for
energy, macronutrients and folic acid at three time
Nutrient ≤2/3 RDA > 2/3 RDA ≤RDA > RDA
Protein Week 0 - - 100
Week 8 - - 100
Week 16 - - 100
Carbohydrate Week 0 35.7 64.3 -
Week 8 - 92.9 7.1
Week 16 - 100 -
Fat Week 0 - - 100
Week 8 - - 100
Week 16 - - 100
Folic acid Week 0 42.9 42.9 14.3
Week 8 - - 100
Week 16 42.9 50.0 7.1
RDA, recommended daily allowance.
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10 Page 5 of 8
training conditions, although it seems that a better study
design would have been to (prospectively) control the
volume and intensity of PA to keep them equal among
Other authors reported different values for Hcy levels
after exercise; the variations among different studies
may reflect the use of indirect methods to quantify PA,
the lack of nutritional studies and differences between
studies in mean age of the participants [4,31,32].
It is worth noting that folic acid levels in plasma
were near the lower limit of normality. Other authors
found that a 5-mmol/l increase in plasma Hcy levels
(>10 mmol/l) was associated with a 60% increase in the
risk of coronary artery disease in men [8,33]. McCully
 noted that if the concentration of Hcy is between 8
and 12 mmol/l, improvements in the quality of the diet
are needed to provide adequate vitamin intakes able to
maintain Hcy at concentrations that can reduce the risk
of coronary disease in adults. As described in the Results
section, there was a significant negative correlation be-
tween plasma Hcy levels and plasma folic acid levels in
Week 8. However, Hcy concentration increased despite
dietary folic acid supplementation. This finding suggests
that in contrast to the expected increase in plasma folic
acid concentrations and decrease in Hcy, the opposite ef-
fect was likely attributable to training. In most
participants in the present study, plasma levels of folic
acid were near the lower limit of the reference values
(4.2–19.l ng/ml), and after the intervention there was no
significant change at the end of the supplementation
period or at the end of the post-supplementation period.
König et al.  showed that the increase in Hcy was
dependent on the initial plasma level of folic acid as well
as on training time. These authors attributed the increase
in Hcy to increased methionine catabolism, which
induced a greater influx of molecules with methyl groups
as a result of high-intensity PA . A study by Borrione
et al.  analyzed team sports similar to handball but
did not use dietary supplementation. They found Hcy
levels that were much higher than those we found, and
folic acid levels similar to those in the athletes we
Our experimental approach was designed to evaluate
training load, nutritional and biochemical indicators in
an integrated manner to obtain accurate data in profes-
sional athletes during the sports season. Our method
emphasized accurate data capture for both training load
and dietary intakes. Variations in either of these factors
Figure 1 Comparison of training variables throughout the experimental trial.
Statistically significant difference (P < 0.05) STp vs NSTp.
Table 4 Biochemical values of clinical and nutritional parameters at three time points
N=14 Study period
Biochemical parameters Reference value Week 0 Week 8 Week 16
Mean SD Mean SD Mean SD
Transferrin (mg/dl) 200 –360 261.21 27.82 261.71 33.00 265.50 28.67
Prealbumin (mg/dl) 20 –40 26.76 3.53 27.19 3.12 26.76 2.77
HDL (mg/dl) 40 –60 58.29 13.58 57.29 12.28 61.00
LDL (mg/dl) 70 –150 74.00 22.89 71.35 20.84 83.07
Total cholesterol (mg/dl) 110 –200 147.86 26.74 149.71 27.68 154.57
Folic acid (ng/ml) 4.2 –19.9 8.14 1.17 7.73 2.57 7.62 2.36
Homocysteine (μmol/l) 5 –12 11.64 2.65 13.92
HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.
Statistically significant differences (P< 0.05) Week 0 vs. Week 8 and Week 16.
Statistically significant differences (P< 0.05) Week 8 vs. Week 16.
Molina-López et al. Journal of the International Society of Sports Nutrition 2013, 10:10 Page 6 of 8
can affect plasma levels of Hcy and folic acid, so it was
important to avoid alterations that might compromise
the data this study was designed to seek.
Our study appears to be the first to use careful controls
for participants’training load and nutritional and bio-
chemical status before, during and after the professional
sports season. Our results suggest that high-performance
athletes such as handball players may require preventive
dietary supplementation with folic acid to curtail the
effects of a sharp increase in blood Hcy concentrations.
This increase may be associated with a sudden increase in
the risk of CVD as a result of the high training load
accumulated in successive training sessions during the
professional competition season.
Hcy: Homocysteine; PA: Physical activity; RDA: Recommended daily
allowance; RHR: Residual heart rate; RPE: Rate of perceived exertion;
SD: Standard deviation.
The authors declare no conflicts of interest.
All the authors contributed to and approved the final manuscript.
This work was supported by the Spanish Ministry of Education (grant
number AP2009- 3701) and by FIS Project PI07/1228 form the Carlos III
Health Institute. The authors thank K. Shashok for translating the manuscript
into English and for advice on technical editing.
Department of Physiology, Institute of Nutrition and Food Technology,
University of Granada, Granada 18071, Spain.
Department of Physical
Education and Sports, Faculty of Sports Sciences, University of Granada,
Granada 18071, Spain.
Received: 11 January 2012 Accepted: 31 December 2012
Published: 21 February 2013
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Cite this article as: Molina-López et al.:Effect of folic acid
supplementation on homocysteine concentration and association with
training in handball players. Journal of the International Society of Sports
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