Evaluation of post-COVID symptoms of the SARS-CoV-2 Delta and Omicron variants in children: a prospective study

Abstract

The post-COVID-19 syndrome is a new syndrome defined in patients with a history of probable or confirmed SARS-CoV-2 infection, usually within three months of the onset of COVID-19, with symptoms and effects lasting at least 2 months. This study is aimed at comprehensively comparing symptoms of the post-COVID-19 syndrome in children with Delta and Omicron variants. This prospective study included children with COVID-19 followed in hospitalized or outpatient clinics in a tertiary hospital. We used a special questionnaire to ask about the presence of persistent symptoms more than 12 weeks after the initial diagnosis. Patients with positive SARS-CoV-2 PCR were selected randomly and grouped according to the dominant variants in our country at that time as follows: Omicron group (after December 16, 2021); Delta (B.1.617.2) group (August 15, 2021, and December 15, 2021). This study included 200 children, 71 of whom were in the Delta group and 129 of whom were in the Omicron group. Weakness (8.5% vs. 1.6%; p = 0.017), the impact of physical efforts (5.6% vs. 3.9%; p = 0.020), fatigue (22.5% vs. 8.5%; p = 0.009), anxiety disorder (12.7% vs. 0.8%; p = 0.001), and gastrointestinal changes (12.7% vs. 4.7%, p = 0.050) were statistically significantly higher in patients with the Delta variant compared to patients with the Omicron variant. There were no differences between the groups regarding anorexia, anosmia/ageusia, arthralgia, influenza-like symptoms, sleeping disorders, decreased physical activity daily, headache, need for analgesia, concentration and memory disorder, and weight loss (p > 0.05).
Conclusion: This study showed that weakness, the impact of physical efforts, fatigue, anxiety disorder, and gastrointestinal changes were more frequent in the Delta group compared to the Omicron group. The incidence of post-COVID-19 syndrome is high in children as well as adults and affects several systems; therefore, it should be kept in mind that children should be followed for post-COVID-19 syndrome.What is Known:
• Despite the milder severity of acute COVID-19 in children, post-COVID-19 symptoms may occur. The post-COVID-19 condition is complex and novel, especially in the pediatric population.
What is New:
• Post-COVID-19 symptoms in children differ depending on the viral variant. Post-COVID-19 syndrome has a great impact on the social life of children which may have serious and long-term effects.

Full text

Vol.:(0123456789)
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European Journal of Pediatrics
https://doi.org/10.1007/s00431-023-05134-6
RESEARCH
Evaluation ofpost‑COVID symptoms oftheSARS‑CoV‑2 Delta
andOmicron variants inchildren: aprospective study
SemaYildirimArslan1· GulhadiyeAvcu1· ZumrutSahbudakBal1· AsliArslan1· FeristahFerdaOzkinay1·
ZaferKurugol1
Received: 6 February 2023 / Revised: 20 July 2023 / Accepted: 23 July 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
The post-COVID-19 syndrome is a new syndrome defined in patients with a history of probable or confirmed SARS-CoV-2
infection, usually within three months of the onset of COVID-19, with symptoms and effects lasting at least 2 months.
This study is aimed at comprehensively comparing symptoms of the post-COVID-19 syndrome in children with Delta and
Omicron variants. This prospective study included children with COVID-19 followed in hospitalized or outpatient clinics
in a tertiary hospital. We used a special questionnaire to ask about the presence of persistent symptoms more than 12 weeks
after the initial diagnosis. Patients with positive SARS-CoV-2 PCR were selected randomly and grouped according to the
dominant variants in our country at that time as follows: Omicron group (after December 16, 2021); Delta (B.1.617.2) group
(August 15, 2021, and December 15, 2021). This study included 200 children, 71 of whom were in the Delta group and 129
of whom were in the Omicron group. Weakness (8.5% vs. 1.6%; p = 0.017), the impact of physical efforts (5.6% vs. 3.9%;
p = 0.020), fatigue (22.5% vs. 8.5%; p = 0.009), anxiety disorder (12.7% vs. 0.8%; p = 0.001), and gastrointestinal changes
(12.7% vs. 4.7%, p = 0.050) were statistically significantly higher in patients with the Delta variant compared to patients
with the Omicron variant. There were no differences between the groups regarding anorexia, anosmia/ageusia, arthralgia,
influenza-like symptoms, sleeping disorders, decreased physical activity daily, headache, need for analgesia, concentration
and memory disorder, and weight loss (p > 0.05).
Conclusion: This study showed that weakness, the impact of physical efforts, fatigue, anxiety disorder, and gastrointestinal
changes were more frequent in the Delta group compared to the Omicron group. The incidence of post-COVID-19 syndrome
is high in children as well as adults and affects several systems; therefore, it should be kept in mind that children should be
followed for post-COVID-19 syndrome.
What is Known:
•Despite the milder severity of acute COVID-19 in children, post-COVID-19 symptoms may occur. The post-COVID-19 condition is complex
and novel, especially in the pediatric population.
What is New:
• Post-COVID-19 symptoms in children differ depending on the viral variant. Post-COVID-19 syndrome has a great impact on the social life of
children which may have serious and long-term effects.
Keywords Post-COVID· Delta· Omicron· Children
Communicated by Tobias Tenenbaum
* Zumrut Sahbudak Bal
z.sahbudak@gmail.com
Sema Yildirim Arslan
semayildirimarslan@gmail.com
Gulhadiye Avcu
gul_akbas@yahoo.com.tr
Asli Arslan
asly_k@hotmail.com
Feristah Ferda Ozkinay
ferdafo@yahoo.com
Zafer Kurugol
zafer.kurugol@ege.edu.tr
1 Division ofInfectious Disease, Department ofPediatrics,
Medical School ofEge University, Izmir, Turkey

European Journal of Pediatrics
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Introduction
Post-COVID-19 condition is defined as a disease occurring
in persons with a history of SARS-CoV-2 infection; within
12 weeks of the onset of COVID-19, with symptoms and
effects lasting at least 2 months, and alternative diagnoses
should be excluded [1]. The most common symptoms of
the post-COVID-19 condition include fatigue, shortness of
breath or difficulty in breathing, memory, concentration or
sleep problems, persistent cough, chest pain, trouble speak-
ing, muscle aches, loss of smell or taste, depression or anxi-
ety, and fever. People with the post-COVID-19 syndrome,
frequently known as the “long COVID,” may have difficulty
in daily activities. Their condition may affect their ability
to perform daily work or housework. The pathophysiology
of post-viral syndromes is thought to be a complex interac-
tion between viral load and humoral and cellular immune
responses that may elicit both direct non-immunological
and indirect immune effects [2, 3]. Information regard-
ing the pathophysiology of the post-COVID-19 syndrome
is still insufficient and controversial [4–7]. Recent studies
from Italy and the UK determined that post-COVID-19
syndrome also occurs in children [8, 9]. Ludvigssonet al.
[10] reported that children have post-COVID-19 symptoms
similar to adults, such as persistent fatigue, headache, and
difficulty concentrating. However, the risk factors of the
long-term effects of COVID-19 on children could not be
clarified [8, 11, 12]. Meanwhile, the differences between
variants of SARS-CoV-2 regarding post-COVID-19 syn-
drome have not been determined. Therefore, this study is
aimed at comprehensively comparing the symptoms of the
post-COVID-19 syndrome in children infected with Delta
and Omicron variants.
Materials andmethods
A single-center prospective study was conducted at a tertiary-
level university hospital (Turkey, Izmir). All consecutive chil-
dren in and outpatients (4–18 years) attending the pediatric
infectious disease department diagnosed with COVID-19
from September 2021 to January 2022 were included. We ran-
domly selected the children aged 4 years and older (so they
were able to communicate their problems with their parents
clearly). Children under 4 years of age were excluded due to
their inability to describe the symptoms. Every other patient
in our database was randomly chosen (sorted by their phone
numbers). If no one responded, we chose the next patient
on the list. We compared patients’ data before and after the
Omicron variant was dominant. The Delta variant could be
detected by PCR in our hospital after August 15, 2021. The
first group included patients admitted between August 15 and
December 15, 2021. The second group was identified as the
Omicron group, which included patients between Decem-
ber 16, 2021, and January 2022. A total of 200 patients were
included in the study; 71 patients were infected with the Delta
variant, and 129 were infected with the Omicron variant. The
diagnosis of COVID-19 was microbiologically confirmed in
all children (PCR analysis on oropharyngeal and nasopharyn-
geal swabs). We confirmed the infections caused by the Delta
variant by testing. However, we could not perform the analy-
sis of the Omicron variant due unavailability of these tests in
our hospital during this study. This study included children
who recovered from COVID-19 but had persistent symptoms
after COVID-19. Patients who volunteered to participate
were included, and we used a standardized form to collect
the demographic and clinical data. Three months after dis-
ease onset (December 2021 and April 2022), patients were
interviewed via telephone by a trained doctor about persistent
symptoms potentially associated with COVID-19 and filled
out a questionnaire form. The answers to the questions were
reported by the children who could express themselves and
their families. We used the term “self-reported symptoms.”
The post-COVID-19 condition was defined by the Delphi con-
sensus [13]. Children with symptoms compatible with another
diagnosis, with underlying liver, renal, pulmonary, neurode-
velopmental, and cardiovascular disease, or without a positive
SARS-CoV-2 PCR result were excluded. None of the children
included in the study had received a SARS-CoV-2 vaccine.
The post-COVID-19 syndrome was defined as symptoms
that developed during or after COVID-19, persisted for ≥ 12
weeks, and were not explained by an alternative diagnosis.
All patients were evaluated at least 3 months (range 90–100
days) after being positive for SARS-CoV-2 PCR, and post-
COVID-19 symptoms persisted for three months.
Microbiological analyses
In a viral transport medium containing VNat, combined
nasopharyngeal and oropharyngeal swab specimens were
obtained (Bioeksen, Turkey). The Bio-speedy® SARS-
CoV-2 Double Gene Real-Time Quantitative Reverse
Transcription PCR was used to examine all samples in
our Molecular Virology laboratories (Bioeksen, Turkey).
This assay amplifies and detects the virus’s two targets
(ORF1ab and N), with a detection limit of 200 genomes
per mL. For internal control, the human gene target RNAse
P (RP) was evaluated in each sample. The Rotor-Gene was
used to do reverse transcription-polymerase chain reac-
tion (RT-PCR) (Qiagen, Luxemburg). If the signal was
observed (Ct35) for the RP, ORF1ab, and N genes, the
results were considered positive.

European Journal of Pediatrics
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Statistical analyses
The SPSS statistics software was used to perform the sta-
tistical analysis (version 25 for Windows). Mean (stand-
ard deviation (SD)) and median (interquartile range (IQR))
for continuous variables and percentages for categorical
variables were calculated. Categorical variables were com-
pared using the chi-squared test or Fisher’s exact test, while
continuous variables were compared using Student’s t-test
or Mann–Whitney U test for two groups. Statistical sig-
nificance of differences and correlations were defined p
value of < 0.05.
Results
Two hundred children were included, 71 (35.5%) were
infected with the Delta variant, and 129 (64.5%) were
infected with the Omicron variant. The mean age was 12.1
± 3.9 years in the Delta group, 11.4 ± 3.6 years in the Omi-
cron group, and 39 (54.9%) were male in the Delta group,
61 (47.3%) were male in the Omicron group. There was no
difference in age and gender between the two groups (p =
0.375, p = 0.154). Hospitalized children (49.3% vs. 1.6%;
p < 0.001) and children admitted to the pediatric inten-
sive care unit (PICU) (22.5% vs. 1.6%; p < 0.001) were
more common in the Delta group; p < 0.001. The length
of hospital stays and the length of stay in the PICU did not
show significant differences between the groups. When the
acute symptoms of COVID-19 were evaluated, cough (31%
vs. 14.7%; p = 0.01) and dyspnea (15.5% vs. 11.6%; p <
0.001) were higher in the Delta group than in the Omicron
group. Baseline demographic and clinical characteristics are
summarized in Table1.
Weakness (8.5% vs. 1.6%; p = 0.017), the impact of phys-
ical efforts (12.7% vs. 3.9%; p = 0.020), fatigue (22.5% vs.
8.5%; p = 0.009), anxiety disorder (12.7% vs. 0.8%; p <
0.001), and changes in the gastrointestinal system (4.2% vs.
3.1%, p = 0.050) were statistically significantly higher in the
Delta group than in the Omicron group. There was no differ-
ence in terms of anorexia, anosmia/ageusia, arthralgia, influ-
enza-like symptoms, sleeping disorders, decreased physical
activity daily, headache, need for analgesia, concentration,
and memory disorder, and weight loss between the groups
(p > 0.05) (Table2). Patients were evaluated at an average
of 3 months after the onset of the first COVID-19 symptoms;
only 36 (50.7%) patients in the Delta group and 64 (49.6%)
in the Omicron group were completely free of any self-
reported post-COVID-19 symptoms. 28.6% of the patients
in the Delta group with self-reported post-COVID-19 symp-
toms had one symptom, 20% had two symptoms, 22.9% had
three, and 28.6% had four or more symptoms (Table2). In
the Omicron group, 50.8% had one symptom, 29.2% had
two, 7.7% had three, and 12.3% had four or more symptoms.
Table 1 Demographic and laboratory data of patients
Delta (n: 71) Omicron (n: 129) p value OR or β (95% CI)
Sex, male (n, %) 39 (54.9) 61 (47.3) 0.375
Age, years (mean ± SD) 12.1 ± 3.9 11.4 ± 3.6 0.154
Hospitalization (n, %) 35 (49.3) 2 (1.6) < 0.001 0.16 (0.004–0.071
PICU admission (n, %) 16 (22.5) 2 (1.6) < 0.001 0.054 (0.012–0.243)
Hospitalization days, (mean ± SD) 9 ± 3.2 6.5 ± 0.7 0.563
PICU length of stay, days (median, min–max) 3 (1–39) 6 (4–8) 0.339
Total hospitalization days (mean ± SD) 16.2 ± 9.4 12.5 ± 2.1 0.363
Asymptomatic 20 (28.2) 31 (24) 0.611
Symptoms of acute COVID-19 (n, %)
 Fever 34 (47.9) 57 (44.2) 0.658
 Nausea 4 (5.6) 6 (4.7) 0.760
 Headache 8 (11.3) 14 (10.9) 1.000
 Chest pain 3 (4.2) 1 (0.8) 0.095
 Anosmia/ageusia 3 (4.2) 5 (3.9) 0.905
 Diarrhea 0 (0) 1 (0.8) 0.457
 Cough 22 (31) 19 (14.7) 0.01 0.385 (0.191–0.775)
 Dyspnea 11 (15.5) 1 (11.6) < 0.001 0.086 (0.018–0.400)
 Malaise 21 (29.6) 45 (34.9) 0.530
 Sore throat 6 (8.5) 13 (10.1) 0.805
 Dizziness 2 (2.8) 0 (0) 0.055

European Journal of Pediatrics
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Among the patients included in our study, post-COVID-19
symptoms were detected in 17 of 35 children hospitalized
with the Delta variant, and post-COVID-19 symptoms were
not detected in any patient hospitalized patients during the
Omicron-dominant period (Table2). None of the patients
had a fever or any signs or symptoms of acute illness at the
time of the evaluation.
Discussion
This study showed 49.3% of the pediatric patients during
the Delta-dominant period, and 50.4% of pediatric patients
during the Omicron-dominant variant reported at least one
symptom that persisted for 3 months. We determined that
hospitalization and PICU admission, acute COVID-19
symptoms such as cough and dyspnea, and self-reported
post-COVID-19 symptoms, including weakness, the impact
of physical efforts, fatigue, anxiety disorder, and changes in
the gastrointestinal system, were higher in the Delta group
than in the Omicron group.
The Omicron variant of SARS-CoV-2 spreads rapidly
worldwide, surpassing previous variants shortly after its first
detection in November 2021. Between December 2021 and
March 2022 (Omicron interval), the number of confirmed
cases reported in Europe surpassed all previously known
cases. The Omicron variant appears to cause less severe
acute illness than previous variants, at least in vaccinated
groups [14]. However, the possibility of experiencing the
post-COVID-19 symptoms of large numbers of patients was
a major concern.
Children have a low risk of developing a severe condition
due to COVID-19, and low rates of hospitalization (< 2%)
and mortality (< 0.03%) were reported [15, 16]. However,
it is unclear whether people in this age group infected with
SARS-CoV-2 will experience persistent symptoms, and the
characteristics of “post-COVID-19” are not well understood.
Acute COVID-19 in children has a low risk in the short
term, but the long-term development of MIS-C and the
post-COVID-19 syndrome are more concerning. Data on
the post-COVID-19 syndrome in children are limited. The
prevalence of post-COVID-19 symptoms ranged from 4 to
66% in different studies [1, 8, 11, 17–26]. Miller etal. [23]
reported that 4.6% of children with a history of COVID-19
had persistent symptoms for 3 months. Antonelli etal. [14]
reported that 4.5% of Omicron cases and 10.8% of Delta
cases in adults had post-COVID-19 symptoms. We deter-
mined children showed post-COVID-19 symptoms in 50.4%
of the Omicron group and 49.3% of the Delta group, whereas
post-COVID-19 symptoms were similar in both groups. Two
or more doses of the vaccination given before infection with
the SARS-CoV-2 virus were shown to significantly lower
the rates of prolonged COVID-19 in the systemic review
by Byambasuren etal. [27]. Data from the UK’s COVID-
19 Surveillance Study have also shown that vaccination
may reduce the prevalence of post-COVID-19 symptoms
Table 2 Comparison of post-
COVID-19 symptoms in Delta
and Omicron cases
Delta (n:71) Omicron
(n: 129) p-value OR or β (95% CI)
Symptoms of Post-COVID-19 syndrome (n,%)
 Anorexia 7 (9.9) 13 (10.1) 1.000
 Weakness
Impact after physical efforts
Fatigue
Anxiety disorder
Anosmia/Ageusia
Arthralgia
Influenza-like symptoms
Sleeping disorders
Decreased physical activity daily
Headache
Need analgesia
Concentration and memory disorder
6 (8.5)
9 (12.7)
16 (22.5)
9 (12.7)
2 (2.8)
8 (11.3)
4 (5.6)
12 (16.9)
4 (5.6)
9 (12.7)
0 (0)
12 (16.9)
2 (1.6)
5 (3.9)
11 (8.5)
1 (0.8)
0 (0)
15 (11.6)
10 (7.8)
15 (11.6)
5 (3.9)
11 (8.5)
3 (2.3)
23 (17.8)
0.017
0.020
0.009
<0.001
0.055
1.000
0.574
1.000
0.566
0.460
0.195
1.000
0.171 (0.033-0.869)
0.278 (0.089-0.864)
0.320 (0.139-0.736)
0.054 (0.007-0.434)
Changes in gastrointestinal system
Weight loss 9 (12.7)
3 (4.2) 6 (4.7)
4 (3.1) 0.050
0.679 0.336 (0.114-0.987)
post-COVID-19 symptom (n,%) 35 (49.3) 65 (50.4) 0.813
1 symptom
2 symptoms 10 (28.6)
7 (20) 33 (50.8)
19 (29.2) 0.032
0.315 2.578 (1.069-6.125)
3 symptoms
≥4 symptoms
Previous hospitalization due to COVID-
19
8 (22.9)
10 (28.6)
17/35
5 (7.7)
8 (12.3)
0/65
0.031
0.043
<0.001
0.281 (0.084-0.940)
0.351 (0.124-0.995)
0.217 (0.144-0.326)

European Journal of Pediatrics
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to less than 5% [28]. We reported higher self-reported post-
COVID-19 symptoms than the previous report in adults [14].
We think that self-reported post-COVID-19 symptoms may
have been high in our study because most of the adults were
vaccinated, and the children in our study were not vacci-
nated. Because the vaccine may have a protective benefit
from post-COVID-19 symptoms as well as acute illness.
Pediatric studies evaluated post-COVID-19 syndrome
are limited, and the findings of studies are heterogeneous
[8, 10, 12, 16–21, 26, 29]. Borch etal. [29] reported that
the most common symptoms were fatigue, loss of smell,
and loss of taste, headache, and concentration difficulties.
Another pediatric study reported that the most common
symptoms included insomnia (18.6%), respiratory symp-
toms (including pain and chest tightness) (14.7%), nasal
congestion (12.4%), fatigue (10.8%), muscle (10.1%), joint
pain (6.9%), and concentration difficulties (10.1%) [8].
Radtke etal. [24] reported that the most common symp-
toms were fatigue, dyspnea, and concentration difficulties
at 87%, 55%, and 45%, respectively. Ashkenazi-Hoffnung
etal. [19] reported that 51% of children with COVID-19
had significant tiredness complaints, loss of taste/smell, and
headache until 1–3 months after the onset of symptoms. In a
single-center study from Italy by Buonsenso etal. [8], per-
sistent symptoms were reported in 42.6% of children for
120 days. Among seropositive children in one study, the
most frequently reported symptoms lasting longer than 12
weeks were fatigue (3%), difficulty concentrating (2%), and
increased need for sleep (2%) [17]. Another pediatric study
reported persistent symptoms > 4 weeks from diagnosis,
including sleep disturbances (33.3%), chest pain (31.1%),
paresthesia (28.9%), and headache (28.9%) [22]. We deter-
mined that the most common symptoms were fatigue, con-
centration and memory disorders, and sleeping disorders.
The heterogeneity in the age range of the participants, the
inclusion criteria, the severity of the disease, the evaluation
time, the data collection method, and the follow-up period
may explain these differences.
Borch etal. [29] showed that 1323 children (34.7%)
reported one symptom; 1095 children (28.7%) had two
symptoms; 1395 children (36.6%) ≥ 3 symptoms. A study
reported 87.4% persistence of at least one symptom for a
mean of 60.3 (SD, 13.6) days [7]. Several studies in adults
have shown that women are at greater risk for long-term
COVID-19; however, no difference was found in our study
[6, 30, 31].
In a systematic review by Fernández-de-Las-Peñas etal.
[32], it has been reported that people infected with the
Omicron variant have the lowest long-term prevalence of
COVID-19 and the highest rate of fatigue in all variants.
The impact of physical effort and fatigue were higher in
the Delta group than in the Omicron group in our study.
The impact of physical effort and fatigue may have been
detected more frequently in the Delta variant period due to
several epidemic-related factors; fear or uncertainty about
the prognosis in the early pandemic and physical inactivity
are more common throughout the Delta variant period due
to limitations.
The single-center design with a relatively small sample
size and reliance on self- or parent-reported symptoms with-
out clinical evaluation is the limitation of our study. There
could be a problem with information bias because the par-
ents responded to the questions on behalf of their children.
Another limitation was the lack of a control group and the
lack of confirmation of the Omicron variant due unavailabil-
ity of the test in our hospital. However, the Turkish Ministry
of Health declared that over 90% of COVID-19 cases were
caused by the Omicron variant during this period.
In conclusion, despite the milder severity of acute
COVID-19 in children, self-reported post-COVID-19
symptoms such as concentration and memory impair-
ment, sleep disorders, and fatigue persisted for at least 3
months. We showed that weakness, the impact of physical
effort, and fatigue were higher in the Delta group than in
the Omicron group. Children have often been overlooked
during this pandemic; however, childhood is a critical,
sensitive, and fundamental period of life for the acquisi-
tion of social, behavioral, and educational development.
Evidence that COVID-19 can have long-term effects on
children raises the issue of taking measures to reduce the
impact of the pandemic on children’s health. Furthermore,
prospective studies are needed to clarify the burden of
long-term effects of COVID-19 in children, not only based
on questionnaires but also involving healthy controls with
an objective clinical assessment.
Author contributions SYA, GA, and ZSB wrote the research protocol.
FO, AA, and ZK accessed and verified all data. SYA and AA wrote the
first draft of the manuscript. All authors contributed to the writing and
approved the final version.
Data availability The corresponding author can provide the data sup-
porting this study upon reasonable request, providing patientdata pri-
vacy is not violated.
Declarations
Ethics approval and consent to participate The Research Ethics Com-
mittee of the Medical School of Ege University and the Ministry of
Health approved the study (ethical decision no. 22-3T/30). Written
informed consent was obtained from all participants. Our research was
carried out in line in accordance with the standards.
Competing interests The authors declare no competing interests.

European Journal of Pediatrics
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