European Journal of Pediatrics

https://doi.org/10.1007/s00431-021-04140-w

REVIEW

Association between neonatal hyperglycemia and retinopathy

of prematurity: a meta-analysis
Chunyan Lei 1,2 & Jianan Duan 1,2 & Ge Ge 1,2 & Meixia Zhang 1,2,3,4

Received: 26 April 2021 / Revised: 27 May 2021 / Accepted: 31 May 2021

# The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Through a meta-analysis, we aimed to investigate whether neonatal hyperglycemia was associated with an increased risk of
retinopathy of prematurity (ROP) by summarizing all available observational evidence. We searched online databases for studies
published prior to December 2020; 26745 neonates with 3227 cases of ROP in 11 case–control studies and 997 neonates with 496
cases of hyperglycemia in 5 cohort studies were included. The results showed that the association between hyperglycemia and the
occurrence of ROP was statistically significant in case–control studies (OR 3.93, 95% CI 2.36–6.53) and cohort studies (OR 1.70,
95% CI 1.11–2.60). Besides, the borderline significant association between the duration of hyperglycemia and ROP was observed in
case–control studies (MD = 1.96, 95% CI 0.90–3.03; adjusted OR = 1.08, 95% CI 1.01–1.15). Furthermore, we found that the mean
blood glucose level is higher in the ROP group than the non-ROP group in case–control studies (MD = 14.86, 95% CI 5.06–24.66)
and the mean blood glucose level is higher in the hyperglycemia group than in the non-hyperglycemia group (MD = 86.54, 95% CI
11.03–162.05). However, after adjusting other confounders, the association between the mean blood glucose level and ROP varied
in cohort studies (OR 1.96, 95% CI 1.23–3.13) and case–control studies (OR 1.02, 95% CI 1.00–1.05).
Conclusion: This meta-analysis demonstrates that preterm infants with hyperglycemia have a tendency to increase the risk of
ROP. Further studies will be required to achieve a firm conclusion for hyperglycemia and ROP and promote a better under-
standing of the prevention of ROP.
Trial registration: CRD42021228733

What is Known:
• Hyperglycemia including the duration and daily mean blood glucose concentration has been associated with the risk of developing ROP in some
clinical studies. Current evidence cannot reach a consensus on whether neonatal hyperglycemia is a risk factor for ROP.
What is New:
• This meta-analysis demonstrates that preterm infants with hyperglycemia have a tendency to increase the risk of ROP.
• While the association between the mean blood glucose level and ROP remains inconclusive.

Chunyan Lei and Jianan Duan contributed equally to this work.

Communicated by Peter de Winter

* Meixia Zhang 1
Department of Ophthalmology, West China Hospital, Sichuan
zhangmeixia@scu.edu.cn University, Chengdu 610041, China
2
Chunyan Lei Research Laboratory of Macular Disease, West China Hospital,
lei_chunyan@foxmail.com Sichuan University, Chengdu 610041, China
3
National Clinical Research Center for Geriatrics, West China
Jianan Duan Hospital, Sichuan University, Chengdu 610041, China
duan_jianan@foxmail.com
4
Department of Ophthalmology and Research Laboratory of Macular
Ge Ge Disease, West China Hospital, Sichuan University,
gegescu@foxmail.com Chengdu 610041, Sichuan, China

Keywords Retinopathy of prematurity . Hyperglycemia . Blood glucose . Meta-analysis . Review
Introduction
Retinopathy of prematurity (ROP), initially called retrolental
fibroplasia, is an ischemic neovascularization disease in pre-
term infants. It has become a leading cause of visual impair-
ment and vision loss in childhood worldwide [1]. Until now,
the pathogenesis of ROP has not been fully understood, while
the levels of vascular endothelial growth factor (VEGF) and
insulin-like growth factor-1 (IGF-1) have been discovered to
involve in the development of ROP. Low birth weight and
prematurity have been shown to be important risk factors for
ROP [2]. Besides, many relevant factors have been confirmed
in the pathophysiology of ROP development, including nutri-
tional factors, maternal factors, exposure to oxygen, and so on
[3]. Reducing the identified risk factors on the early stage of
retinal vascularization of ROP may have benefits over the
treatment of neovascularization at the late stage [4].
Therefore, studies aimed at risk factors are extremely impor-
tant for the prevention of ROP.
Neonatal hyperglycemia is a common problem and the
incidence of hyperglycemia ranges from 20 to 86% in ex-
tremely preterm neonates [5]. Many studies have demonstrat-
ed that hyperglycemia may be correlated with an increased
risk of morbidity of ROP in premature infants [6–11]. As a
potentially modifiable risk factor of ROP, hyperglycemia has
been confirmed to impair retinal neovascularization during
retinal development in animal models of retinopathy [12,
13]. Furthermore, hyperglycemia including the duration and
daily mean blood glucose concentration has been associated
with the risk of developing ROP in clinical studies [7, 8, 10,
11, 14]. However, current evidence cannot reach a consensus
among clinicians whether hyperglycemia is a risk factor for
ROP. To resolve the discrepancy across these studies, this
meta-analysis was conducted to integrate all available studies
measuring the association between hyperglycemia and ROP.
Methods
This meta-analysis was performed by following the recom-
mendations of the PRISMA statement. Online registration is
available at http://www.crd.york.ac.uk/PROSPERO/
(registration number: CRD42021228733).
Searching strategy
All relevant studies published prior to December 2020 were
searched on PubMed, EMBASE, Cochrane Library, and Web
of Science databases. The searching strategy was previously
Eur J Pediatr
described [15]. The following keywords were retrieved as free
words and also as MeSH terms: [“retrolental fibroplasia” OR
“retinopathy of prematurity” OR “ROP”] AND [“blood glu-
cose” OR “blood sugar” OR “glycemia” OR “glycaemia” OR
“hyperglycaemia” OR “hyperglycemia” OR “diabetes
mellitus” OR “gestational diabetes” OR “DM” OR “GDM”].
Study selection
The inclusion criteria were (i) original observational studies
(case–control or cohort studies) evaluating the association be-
tween hyperglycemia and ROP; (ii) hyperglycemia defined as
blood glucose level ≥ 150 mg/dL or 8.3 mmol/L; and (iii) raw
data provided for calculation or odds ratios (OR) and relative
risks (RR) were recorded with 95% confidence interval (CI).
The exclusion criteria were (i) animal studies, reviews, ed-
itorials, commentaries, case reports, abstracts, and letters; (ii)
the studies were written in non-English language; and (iii)
studies with insufficient data or outcomes for analysis.
Data extraction
Two investigators (Chunyan Lei and Jianan Duan) extracted
data from the retrieved records independently with standard-
ized data sheets and discrepancies were resolved by consensus
with a third investigator.
Data were recorded as follows: first author, year of publi-
cation, country of study, sample size, gestational age, birth
weight, the definition of hyperglycemia, definition, and grad-
ing of ROP, percentage of male, duration of average glucose
level (days), the mean blood glucose level in both ROP group
and non-ROP group or both hyperglycemia group and non-
hyperglycemia group, mean duration of hyperglycemia in
both ROP group and non-ROP group or both hyperglycemia
group and non-hyperglycemia group, the number of hypergly-
cemic patients in both ROP group and non-ROP group, the
number of ROP patients in both hyperglycemia group and
non-hyperglycemia group, and adjusted OR and 95% CI of
mean blood glucose level and duration of hyperglycemia.
The unit of blood glucose varies in different studies. To
unify the unit, 1 mmol/L was converted to 18 mg/dL. To
combine the adjusted ORs for analysis, the ORs and 95%
CIs with the unit of 1 ml/dL was converted as previously
described [15].
Risk of bias and quality assessment
The Newcastle-Ottawa Scale (NOS) was used to assess the
methodological qualities of the included studies [16].
Eur J Pediatr
Disagreements would be resolved through consultation with a
third reviewer. Each study was assessed as following: partic-
ipant selection (0–4 points), comparability (0–2 points), and
outcome/exposure (0–3 points). A score of 5 or above is con-
sidered as satisfactory quality [17].
Data analysis
The Review Manager software (RevMan, version 5.4; the
Nordic Cochrane Center, Copenhagen, Denmark) was used
for the meta-analysis. The included case–control studies and
cohort studies were analyzed separately. Continuous data were
summarized as mean difference (MD) and standard deviation
(SD) from the published articles. The pooled adjusted ORs and
unadjusted ORs were calculated separately. The heterogeneity
of the included studies was evaluated by the chi-square test and
I2 statistics. When the P value was greater than 0.100 and I2 <
50%, no heterogeneity was found and we used the fixed-effect
model; otherwise, we applied the random-effect model.
Sensitivity analyses were conducted to determine the source
of heterogeneity by excluding one study at a time to see if the
results were changed. Begg’s test was done to assess publica-
tion bias of experimental events using the STATA statistical
software (version 16.0; Stata Corp, College Station, TX,
USA), in which P < 0.1 indicated a statistically significant
difference.
Results
Search results and quality assessments
Initial screening yielded 1109 potentially relevant studies.
After removing 264 duplicate articles, 845 publications were
left; 799 articles were removed after reviewing the title and
abstract because their topics and results did not meet our re-
quirements, leaving 46 studies included for full-length article
review. The reasons for further exclusion include conference
abstract (n = 13), insufficient data (n = 11), unclear definition
of hyperglycemia (n = 4), editorial (n = 1), and non-English
article (n = 1). Finally, 26,745 neonates with 3227 cases of
ROP in 11 case–control studies [6, 8, 10, 14, 18–24] and 997
neonates with 496 cases of hyperglycemia in 5 cohort studies
[7, 9, 25–27] were identified in our meta-analysis (Fig. 1). The
detailed characteristics of 16 selected clinical studies are
shown in Table 1 and Supplemental Table 1.
Meta-analysis results
Hyperglycemia and the occurrence of ROP
Eight case–control studies and four cohort studies reported
numerical counts for analysis and were analyzed separately.
We found that there was a statistically significant association
between hyperglycemia and the occurrence of ROP in case–
control studies (OR 3.93, 95% CI 2.36–6.53, I2 = 80%, P <
0.00001; Fig. 2A) and cohort studies (OR 1.70, 95% CI 1.11–
2.60, I2 = 48%, P = 0.12; Fig. 2B).
Duration of hyperglycemia and the development of ROP
The duration of hyperglycemia (days as the unit) was provid-
ed in five case–control studies and three out of five case–
control studies provided the adjusted ORs and 95% CIs for
analysis. The combined data displayed that the duration of
hyperglycemia was significantly longer in the ROP group
compared with the non-ROP group (MD = 1.96, 95% CI
0.90–3.03, I2 = 95%, P < 0.00001; Fig. 3A). Pooling up all
these adjusted ORs, the duration of hyperglycemia had a little
but statistically significant association with ROP (adjusted OR
= 1.08, 95% CI 1.01–1.15, I2 = 49%, P = 0.14; Fig. 3B).
Mean blood glucose level and the development of ROP
The mean blood glucose level (mg/dL as the unit) was pro-
vided for analysis in five case–control studies and three cohort
studies. Pooling up the data from the case–control studies, we
found that the mean blood glucose level is higher in the ROP
group than in the non-ROP group (MD = 14.86, 95% CI 5.06–
24.66, I2 = 83%, P < 0.0001; Fig. 4A). The combined data
from cohort studies showed that the mean blood glucose level
is higher in the hyperglycemia group than in the non-
hyperglycemia group (MD = 86.54, 95% CI 11.03–162.05,
I2 = 99%, P < 0.00001; Fig. 4A). Besides, the five case–
control studies and two cohort studies provided the adjusted
ORs and 95% CI. After pooling the data together separately,
we found that the mean blood glucose level was associated
with ROP in cohort studies (adjusted OR 1.96, 95% CI 1.23–
3.13, I2 = 36%, P = 0.21; Fig. 4C). In case–control studies, we
found that there was no association between the mean blood
glucose level and ROP (adjusted OR 1.02, 95% CI 1.00–1.05,
I2 = 69%, P = 0.01; Fig. 4C).
Publication bias and heterogeneity analysis
No obvious publication bias of experimental events was iden-
tified by Begg’s test (Z = 1.51, P = 0.574). Significant hetero-
geneity was observed in some analyses. When we excluded
Mohamed et al., the adjusted OR of the duration of hypergly-
cemia was unrelated to ROP (OR 1.46, 95% CI 0.82–2.61, I2
= 65%, P = 0.09) with an increased heterogeneity. In other
analyses, when we conducted the sensitivity analysis, the het-
erogeneities were reduced (excluding Ertl 2006, Bozdag
2011, Garg 2003, Mohsen 2014, Ahmadpour-Kacho 2014
separately), but all of the other results remained consistent.
Table 1 Main characteristics of the included studies

First author Year Study design Experimental Control Adjusted OR Adjusted Adjusted OR Adjusted NOS
of duration factors of glucose factors score
Total No. of ROP/ Duration Glucose Total No. of ROP/ Duration Glucose (per day) level (per mg/
hyperglycemia (days) level hyperglycemia (days) level dL)
(mg/dL) (mg/dL)

Garg, R. 2003 Retrospective 16 NA 8.4 ± 1.1 117 ± 18 31 NA 5.3 ± 0.8 104 ± 14 NA NA 1.1 (1–1.22) a 9
case–-
control
Blanco, C. L. 2006 Retrospective 150 NA NA 248 ± 83 19 NA NA 128 ± 16 NA NA 4.6 (1.1–18.9) b 7
cohort
Ertl, T. 2006 Retrospective 71 30 NA NA 130 9 NA NA NA NA NA NA 8
case–-
control
Heimann, K. 2007 Retrospective 170 4 NA NA 82 3 NA NA NA NA NA NA 6
cohort
Bozdag, S. 2011 Prospective 124 78 3.05 ± 92.29 ± 43 16 1.69 ± 85.63 ± 3.26 c NA NA 9
case–- 2.37 17.46 1.14 14.79 (1.09–9.8)
control
Chavez-Valdez, R. 2011 Retrospective 17 15 NA NA 97 75 NA NA NA NA NA NA 5
case–-
control
Kaempf, J. W. 2011 Retrospective 132 51 NA 121 ± 21 240 62 NA 112 ± 19 NA NA 1.01 (1–1.03) d 9
case–-
control
Mohamed, S. 2013 Retrospective 170 NA 7.1 ± 6.6 NA 412 NA 2.3 ± 3.2 NA 1.073 e NA NA 8
case–- (1.004–1.-
control 146)
van der Merwe, S. 2013 Retrospective 15 11 NA NA 329 145 NA NA NA NA NA NA 7
K. case–-
control
Ahmadpour-Kacho, 2014 Retrospective 70 38 2.32 ± 147.53 ± 85 5 1.33 ± 93.8 ± 1.07 f 1.03 g 9
M. case–- 2.37 71.14 0.87 37.37 (0.54–2.1- (1.01–1.05)
control 2)
Mohsen, L. 2014 Prospective 31 14 NA 311 ± 80 34 5 NA 194 ± 59 NA NA 1.77 h 9
cohort (1.08–2.86)
Sabzehei, M. K. 2014 Retrospective 88 22 NA NA 312 47 NA NA NA NA NA NA 7
cohort
Nicolaeva, G. V. 2015 Prospective 50 50 3.1 ± 133.2 ± 14 14 1.6 ± 0.9 133.74 ± NA NA NA NA 8
case–- 1.79 48.42 46.8
control
Lee, J. H. 2016 Retrospective 2547 1102 NA NA 22,001 5764 NA NA NA NA 0.88 i 8
case–- (0.66–1.17)
control
Mutangana, F. 2019 Prospective 15 8 NA NA 136 20 NA NA NA NA 3.5 (1–12.4) j 8
case–-
control
Eur J Pediatr
Eur J Pediatr

score
Adjusted NOS
Discussion

8
This is the latest meta-analysis to integrate all relevant re-

h: Days on oxygen, days on respiratory support, maternal age (years), maternal hypertension, premature rupture of membranes, GA, BW, respiratory distress, phototherapy, use of breast milk
factors
searches and investigate the association between hyperglyce-

NA
mia and the development of ROP in premature infants. All
level (per mg/

included studies achieved a score of 5 or above on assessment

Adjusted Adjusted OR
of glucose

of the methodological quality using the NOS. In this study, we

found that the ORs of developing ROP were significantly
NA
dL)

higher in infants with hyperglycemia from unadjusted data

extracted from cohort and case–control studies. We can see
factors

a borderline significant relationship between the duration of

NA

hyperglycemia and ROP in case–control studies in unadjusted

i: GA, gender, small for GA status, Apgar score, percent oxygen days, percent mechanical ventilation days, steroid use, bacteremia, left and discharge year
OR or adjusted OR. Although the unadjusted ORs give sup-
Adjusted OR

port for the association between the mean blood glucose level
of duration
Duration Glucose (per day)

and ROP in all studies, for the adjusted OR, there is no asso-
NA

ciation between mean blood glucose level and ROP in case–

control studies, and a relationship between the mean blood
(mg/dL)

94 ± 11

glucose level and ROP was found in cohort studies. In con-

level

clusion, this meta-analysis demonstrates that preterm infants

with hyperglycemia have a tendency to increase the risk of
ROP, but we cannot draw a firm conclusion on the relation-
hyperglycemia (days)

NA

ship between neonatal hyperglycemia and ROP.

ROP is a multifactorial disease associated with microvas-
No. of ROP/

cular degeneration, which is characterized by an arrest in

physiological retinal angiogenesis [1]. The mechanism of
how hyperglycemia affects ROP is still inconclusive.
a: Average inspiratory oxygen concentration, FiO2, birth weight (BW), and vitamin E supplementation
40

Experimental studies have shown that ROP-like changes—

Control

j: GA, low birth weight (g), sepsis, supplemental oxygen, total days on any supplemental oxygen

neuronal loss and delayed retinal angiogenesis—are observed

Duration Glucose Total

119 ± 16 54

in newborn rodents with early hyperglycemic exposure in

g: GA, BW, glucose infusion rate (mg/kg/min), duration of hyperglycemia, PO2, transfusion
c: BW, Gram (+), sepsis, IVH (≥ grade 3), respiratory distress syndrome, NCPAP, oxygen

ranges [12, 13]. VEGF is known to be primarily involved in

(mg/dL)

neoangiogenesis and increased endothelial permeability,

level

f: GA, BW, glucose infusion rate (mg/kg/min), mean blood sugar, PO2, transfusion

which plays a very important role in the pathogenesis and

development of ROP. With the support of rat studies [28,
hyperglycemia (days)

29] showing expression of VEGF protein increases in higher

NA

glucose concentration on retinal Müller and mesangial cell,

VEGF was considered to be the link between hyperglycemia
Total No. of ROP/

and ROP. Besides, hyperglycemia in preterm infants has also

b: Gestational age (GA), BW, and postnatal steroid exposure

d: Postmenstrual age, gender, weight O/E, mean weight gain

e: GA, ventilator days, sepsis, IVH, PDA, neonatal steroids

a relationship with low IGF-1 levels [30]. IGF-1 is essential

Experimental

and critical for prenatal and postnatal development, which is

43

considered to counteract insulin resistance. The level of IGF-1

57

is decreased after preterm birth. The most recent study [31]

has found that high early postnatal plasma glucose levels and
Year Study design

signs of insulin insensitivity have an association with lower

2020 Cohort

IGF-1 levels and increased ROP severity in extremely preterm

infants. Furthermore, they found that low serum IGF-1 level
facilitated retinal pathological neovascularization in a hyper-
glycemia retinopathy rodent model. Taken together, whether
Table 1 (continued)

hyperglycemia is just a clinical presentation of low IGF-1 or a

real cause of ROP remains unclear.
More recently, three large cohorts [32] suggested that high
First author

Leung, M.

blood glucose concentration is considered to be an indepen-

dent risk factor for severe ROP. Furthermore, compared with a
single high glucose value, overall average exposure and
 Eur J Pediatr

Articles identified from Articles identified from Articles identified from Articles identified from
PubMed (n=188) EMBASE (n=470) Cochrane Library (n=151) Web of Science (n=300)

Articles after removing replicates (n=845)

Articles for title and abstract screening (n=845)

Articles excluded (n=799)

Full text articles assessed for eligibility (n=46)

Articles were exluded (n=30)

·Conference abstract (n=13)
·Insufficient data (n=11)
·Unclear definition of
hyperglycemia (n=4)
·Editorial (n=1)
·Non-English article (n=1)

Studies included in meta-analysis (n=16)

Fig. 1 The flow diagram of the study selection process

duration of hyperglycemia matter more when determining the glucose level and ROP. Even so, whether hyperglycemia has a
risk of retinopathy, which explains to a certain extent why it is causal relationship to ROP or just a reflection of illness sever-
not easy to observe the statistical difference between the mean ity is still inconclusive.

Fig. 2 Overall ORs and 95% CIs of hyperglycemia and the occurrence of ROP in case–control studies (A) and cohort studies (B)
Eur J Pediatr

Fig. 3 MDs and 95% CIs (A) and adjusted ORs and 95% CIs (B) of the duration of hyperglycemia for ROP in case–control studies

As a potential confounding factor, insulin therapy in hyper-
glycemic preterm infants has proven to be associated with ROP
[22, 24]. Insulin treatment is usually used for controlling glyce-
mia and avoiding an unwanted restriction of caloric intake. A few
randomized controlled trials showing a beneficial effect of insulin
on glucose intake and growth in the short term [5, 33, 34].
Kaempf et al. [24] suggested that insulin therapy by itself in
premature infants might be a stronger predictor of ROP than
hyperglycemia. Lee et al. [22] in their study also observed a
possible trend between the use of insulin and severe ROP, while
they failed to find the association between hyperglycemia and
severe ROP in ELBW infants. However, a large cohort study

Fig. 4 MDs and 95% CIs and adjusted ORs and 95% CIs of the mean blood glucose level for ROP in case–control studies (A, B) and cohort studies (A,
C)

[32] demonstrated that after adjusting for important risk factors,
insulin treatment had a large but not significant protective effect
on severe ROP (OR 0.40, P = 0.106). In addition, another study
[35] demonstrated that early insulin therapy improved glycemic
control and increases IGF-1 bioactivity levels, which might be
beneficial for ROP. Therefore, the relationship between insulin
therapy and ROP is still unclear. Recently, continuous glucose
monitoring (CGM) has been applied to explore the association
between hyperglycemia and ROP in very low birth weight neo-
nates, due to its many more glycemic concentration measure-
ments [36]. The use of CGM system could increase the number
of data points available and improve the power of studies (288
measurements/day) [37, 38], which might provide a more reli-
able strategy to study the relationship between hyperglycemia,
insulin, and ROP.
There are several limitations in our study. First, compared
to randomized controlled trials, the observational studies we
included were more susceptible to have selection bias.
However, it is not possible or ethical to induce hyperglycemia
to investigate its effect on ROP. The results from well-
designed observational studies were also reliable. Second,
the major limitation in our study is the significant heterogene-
ity observed in the analysis. In our opinion, one of the impor-
tant sources of heterogeneity may be the different adjusted
factors among the studies we included, so the adjusted OR is
inappropriate to compare between different studies.
Additionally, the definition of hyperglycemia, classification
of ROP, and different lengths of study periods may be differ-
ent in different studies. Lastly, the number of studies that met
the criteria was still limited, even though we have searched for
all available studies, failing to conduct further subgroup anal-
ysis. More related observational studies were required.
Conclusions
In conclusion, this meta-analysis did not reveal an accordant
result and the conclusion remains inconclusive, especially the
relationship between the mean glucose level and ROP. Further
studies will be required to achieve a conclusion for hypergly-
cemia and ROP and promote a better understanding of the
prevention of ROP.
Abbreviations ROP, Retinopathy of prematurity; VEGF, Vascular en-
dothelial growth factor; IGF-1, Insulin-like growth factor-1; OR, Odds
ratios; RR, Relative risks; CI, Confidence interval; NOS, Newcastle-
Ottawa Scale; MD, Mean difference; SD, Standard deviation
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s00431-021-04140-w.
Data and material availability N/A.
Code availability N/A.
Eur J Pediatr
Author’s contributions C.L. conceptualized and designed the study;
conducted literature searches, study selections, and data extrac-
tions; and drafted the initial manuscript. J.D. conducted literature
searches, study selections, and data extractions and reviewed and
revised the manuscript. G.G. reviewed and revised the manuscript.
M.Z. conceptualized and designed the study and reviewed and
revised the manuscript. All authors have approved the final man-
uscript and agree to be accountable for all aspects of the work.
Funding This work was supported by 1.3.5 project for disciplines of
excellence, West China Hospital, Sichuan University (ZYJC21025) and
National Clinical Research Center for Geriatrics, West China Hospital,
Sichuan University (Z2018B22). The funders had no role in study design,
data collection, and analysis, decision to publish, or preparation of the
manuscript.
Declarations
Ethics approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Consent to participate N/A.
Consent for publication N/A.
Conflict of interest The authors declare no competing interests.
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