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Citation: Nit
,escu, G.V.; Ulmeanu,
C.E.; Cr˘aciun, M.-D.; Ciuc˘a, A.M.;
Ulici, A.; Ghira, I.; Lonati, D.
Neurotoxicity and Other Clinical
Manifestations of a Common
European Adder (Vipera berus) Bite in
Romania. Toxins 2022,14, 500.
https://doi.org/10.3390/
toxins14070500
Received: 17 June 2022
Accepted: 13 July 2022
Published: 18 July 2022
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4.0/).
toxins
Case Report
Neurotoxicity and Other Clinical Manifestations of a Common
European Adder (Vipera berus) Bite in Romania
Gabriela Viorela Nit
,escu 1, 2, *, Coriolan Emil Ulmeanu 1,2, Maria-Dorina Crăciun 2,3 , Alina Maria Ciucă2,
Alexandru Ulici 2,4 , Ioan Ghira 5and Davide Lonati 6
1
Department of Pediatrics, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania;
coriolan.ulmeanu@umfcd.ro
2Emergency Clinical Hospital for Children “Grigore Alexandrescu”, 011743 Bucharest, Romania;
maria.craciun@umfcd.ro (M.-D.C.); alina-maria.ciuca@rez.umfcd.ro (A.M.C.);
alexandru.ulici@umfcd.ro (A.U.)
3Department of Epidemiology, University of Medicine and Pharmacy “Carol Davila”,
020021 Bucharest, Romania
4Department of Pediatric Surgery and Orthopedics, University of Medicine and Pharmacy “Carol Davila”,
020021 Bucharest, Romania
5Romanian Association of Herpetology, 400006 Cluj-Napoca, Romania; ioan.ghira@ubbcluj.ro
6Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, IRCCS,
Maugeri Foundation, 27100 Pavia, Italy; davide.lonati@icsmaugeri.it
*Correspondence: viorela.nitescu@umfcd.ro; Tel.: +40-744-389-869
Abstract:
Most cases of envenomation by common European vipers (Vipera berus) have not been
reported to have neurotoxic manifestations. However, these manifestations have been demonstrated
in some cases of envenomation by subspecies of V. berus, found in the Carpathian Basin region of
south-eastern Europe. Here, we report the case of a 5-year-old girl from the south of Romania who
presented symptoms of neurotoxicity, as well as other systemic and local symptoms, after being bitten
by an adder of the V. berus subspecies. Treatment consisted of monovalent antivenom, a corticosteroid,
and prophylactic enoxaparin. Neurotoxic manifestations of envenomation as well as other local and
systemic symptoms improved within 5 days of treatment. The presented case shows that venom
from V. berus subspecies found in the Carpathian Basin can have neurotoxic effects. This case also
confirmed the efficacy of monospecific antivenom treatment in bringing about rapid and complete
remission, following envenomation.
Keywords:
neurotoxicity; Berus Viper; common European viper; child; monospecific antivenom;
south Romania
Key Contribution:
V. berus subspecies from the Carpathian Basin can have neurotoxic effects. Treat-
ment with antivenom serum proved to be efficient with complete remission after use.
1. Introduction
According to the Romanian Society of Herpetology, the only venomous snakes in
Romania are adders (also known as vipers). These can be classified under three species,
namely, Vipera berus,Vipera ammodytes, and Vipera ursinii [
1
]. Clinical manifestations of
envenomation by these adders vary and may be local or systemic. Systemic manifestations
of envenomation may present as gastrointestinal, cardiac, neurological, and/or respiratory
symptoms, and may also include anaphylactic reactions and coagulopathy [
2
–
6
]. Neu-
rotoxic manifestations are considered unusual; in most cases published in Europe, these
manifestations were attributed to V. aspis [
4
,
6
], and not to V. berus. Nevertheless, clini-
cal symptoms of neurotoxicity in V. berus bites were observed as far back as 2008, when
Malina et al.
reported a previously healthy 27-year-old man bitten by a V. berus in eastern
Hungary [
7
] Later, in 2017, the same author also showed the possibility of neurotoxic
Toxins 2022,14, 500. https://doi.org/10.3390/toxins14070500 https://www.mdpi.com/journal/toxins
Toxins 2022,14, 500 2 of 8
manifestations of V. berus envenomation during an experimental study of V. berus venom
of adders from the same region. [
8
]. In this case report, we document the presence of
symptoms of neurotoxicity and the development of these symptoms, as well as other
associated clinical manifestations of envenomation, in a 5-year-old girl from south Roma-
nia, who was bitten by a common European viper (V. berus). The study was conducted
according to the provisions of the “EU Guidelines for the Promotion and Protection of the
Rights of the Child” and was approved by the Ethics Committee of the hospital (Protocol
Code 15351/02.06.2022).
2. Case Report
A previously healthy 5-year-old girl was bitten on her right leg by a viper near her
house, in south Romania. Twelve hours later, she was presented to our clinic, after being
transferred from a local hospital.
On admission, the girl presented with a mildly altered general status. Examination
revealed local signs of a snake bite on her right leg, including local pain and heat, swelling,
infiltration, erythema surrounded by cyanosis and functional impairment. The snake bite
mark is shown in Figure 1a. Systemic manifestations were also present, and include mild
gastrointestinal and neurological symptoms. Gastrointestinal symptoms consisted of dif-
fuse abdominal pain and nausea. Neurological manifestations included severe somnolence
and axial hypotonia. Moreover, bilateral ophthalmologic disturbances (shown in Figure 1b)
were noted, including palpebral ptosis and ophthalmoplegia. Diplopia was also confirmed.
Toxins 2022, 14, x FOR PEER REVIEW 3 of 8
The patient’s progress was clinically monitored after the initiation of the treatment.
The laboratory results and symptoms over time are presented below (see Tables 1 and 3).
Thirty minutes after administration of the antivenom, ocular movements reappeared and
blood pressure increased to 98/66 mmHg. Somnolence, diplopia, and gastrointestinal
manifestations withdrew on Day 2, while palpebral ptosis disappeared on Day 4. Local
signs, after initially worsening progressively, improved and completely disappeared by
Day 5.
The child was discharged on Day 6 without any clinical signs or symptoms. The
laboratory test results were within normal ranges (see Table 1). No immediate or delayed
adverse reactions were reported after antivenom administration, apart from a slight in-
crease in IgE level, without clinical expression.
(a) (b)
Figure 1. (a) Local signs of viper bite including swelling, erythema (lower calf and ankle); (b) image
showing inferior displacement of the upper eyelid with associated narrowing of the vertical pal-
pebral fissure (bilateral palpebral ptosis).
Table 1. Laboratory results on days 1, 2, and 6.
Laboratory Test Normal Values Changes by Day:
Day 1 (admission) Day 2 Day 6 (discharge)
Hemoglobin (g/dL) 12–16 11.8 13.2
Leucocytes (mmc) 4000–12,000 9100 5200
Thrombocytes
(mmc) 150,000–400,000 321,000 293,000
ESR (mm/h) 7–12 7
Fibrinogen
(mg/dL) 150–400 243.9 253
C reactive protein
(mg/dL) 0–0.5 0.29
ALT (IU/L) 0–35 24 21 27
AST (IU/L) 0–35 50 42 45
GGT (IU/L) 15–132 10 13
LDH (IU/L) 110–295 311 224 252
Amylase (IU/L) 22–80 39
Direct bilirubin
(mg/dL) 0–0.2 0.06
Indirect bilirubin
(mg/dL) 0–1 0.26
Total bilirubin 0.3–1.2 0.32
Figure 1.
(
a
) Local signs of viper bite including swelling, erythema (lower calf and ankle); (
b
) image
showing inferior displacement of the upper eyelid with associated narrowing of the vertical palpebral
fissure (bilateral palpebral ptosis).
The initial cardiovascular assessment did not show any abnormalities; blood pressure
and heart rate were within the normal ranges according to age (102/55 mmHg and 110 bpm,
respectively). The results of laboratory tests were normal (see Table 1). Electrocardiogram
and cardiac echography showed no abnormalities, and Doppler echography of the right
lower limb showed normal results.
One hour after admission, local signs and general symptoms worsened and swelling
and pain spread to the middle of the right calf, somnolence and palpebral ptosis became
pronounced and blood pressure started to decrease gradually (to 80/67 mmHg, 1 h post-
admission). Based on the above clinical presentation, the severity of the case was graded as
2b (regional oedema and moderate general symptoms as mild hypotension and neurotoxic
signs), according to the Audebert–Boels classification, adapted to children by Marano et al.
(see Table 2) [6].
Toxins 2022,14, 500 3 of 8
Table 1. Laboratory results on days 1, 2, and 6.
Laboratory Test Normal Values Changes by Day:
Day 1
(admission) Day 2 Day 6
(discharge)
Hemoglobin (g/dL) 12–16 11.8 13.2
Leucocytes (mmc) 4000–12,000 9100 5200
Thrombocytes (mmc) 150,000–400,000 321,000 293,000
ESR (mm/h) 7–12 7
Fibrinogen (mg/dL) 150–400 243.9 253
C reactive protein (mg/dL) 0–0.5 0.29
ALT (IU/L) 0–35 24 21 27
AST (IU/L) 0–35 50 42 45
GGT (IU/L) 15–132 10 13
LDH (IU/L) 110–295 311 224 252
Amylase (IU/L) 22–80 39
Direct bilirubin (mg/dL) 0–0.2 0.06
Indirect bilirubin (mg/dL) 0–1 0.26
Total bilirubin (mg/dL) 0.3–1.2 0.32
Iron (µg/dL) 40–100 44
Chloride (mmol/L) 101–109 105 103 102
Sodium (mmol/L) 132–142 134 136 135
Potassium (mmol/L) 3.5–5.1 4.1 3.37 4.71
Urea (mg/dL) 10.8–38.4 28 28 23
Creatinine (mg/dL) 0.26–0.77 0.45 0.41 0.42
CK (IU/L) 0–145 120 106 135
CK-MB (ng/mL) <5 <5 <1 <1
Myoglobin (ng/mL) <50 <50 <50 <50
Troponin (ng/mL) <1 <1 <0.05 <0.05
D-dimers (ng/mL) <500 <100 <100
BNP (pg/mL) <100 15.4 <5
IgA (g/L) 0.41–2.97 0.71
IgG (g/L) 5–13 10
IgM (g/L) 0.4–1.8 0.63
IgE (IU/mL) <100 89.53 233
C3 fraction (g/L) 0.9–1.8 1.27
C4 fraction (g/L) 0.1–0.4 0.32
CIC (IU/mL) <10 2
Quick Time (s) 11–14 14.1 13.1
INR 0.8–1.3 1.28 1.17
Prothrombin activity (%) 70–140 77.9 84.8
APTT (s) 24.4–36.4 25.1 21.6
ESR–erythrocyte sedimentation rate, ALT–alanine aminotransferase, AST–aspartate aminotransferase,
GGT–gamma-glutamyl transferase
, LDH–lactate dehydrogenase, CK–creatine kinase, CK-MB–creatine
kinase–myocardial
band, BNP–B-type natriuretic peptide, IgA–immunoglobulin A; IgG–immunoglobulin
G,
IgM–immunoglobulin
M, IgE–immunoglobulin E, C3–complement C3 fraction, C4–complement C4
fraction,
CIC–circulating
immune complexes, INR–international normalized ratio, APTT–activated partial
thromboplastin time.
Toxins 2022,14, 500 4 of 8
Table 2. Audebert–Boels Classification modified by Marano et al. adapted from [6].
Grade Description Signs and Symptoms Treatment
0No envenoming (“dry
bite”)
Fang marks
No oedema
No local reaction
- 6 h surveillance in the emergency
room
1 Minimal envenoming Local oedema around the bite area
No systemic symptoms
- clinical observation up to evident
reduction of edema
- supportive care, including
hydration and pain relief
2
Moderate envenoming
Grade 2a
One or both of the following:
-
Regional edema with progression
to most of the limb
- Haematoma or adenopathy
Grade 2b
- Grade 2a + moderate general
symptoms (mild hypotension,
vomiting, diarrhea, neurotoxic
signs), and/or biological criteria
for severity:
- Leukocytes > 11,000/L
- Neutrophils > 65%
- INR > 1.15
- Clinical observation up to the
evident reduction of edema
(evaluate district perfusion and
saturation)
- Supportive care, including
hydration and pain relief
- Doppler-ultrasound of affected
limb’s blood vessels
- Administration of antivenom
- Evaluate antibiotic therapy *
- Administer LMWH **
3 Severe envenoming
Other or both of the following:
- Edema spreading to the trunk
- Signs of hemodynamic instability
(prolonged hypotension, shock,
bleeding)
- Same intervention as in Grade 2
- Admission to PICU
* Only if clinical or laboratory signs of bacterial contamination are evident, ** Only if direct evidence of throm-
bophlebitis is available or in cases of extensive edema; dehydration; decreased mobility; prolonged decubitus;
admission to PICU; anticipated hospitalization longer than 48 h. Do not administer in the case of overt hemorrhage
or a bleeding disorder.
The viper was identified as belonging to the species V. berus based on the morpholog-
ical description of the viper provided by the girl’s mother and the information obtained
from the Romanian Association of Herpetology. The mother who accompanied the child at
the moment of the incident described a completely black snake without a zigzag pattern
and about 50 cm long. The last mapping of the distribution of vipers in Romania shows the
presence of V. berus and V. ammodytes in the geographical location of the incident reported as
the Subcarpathian area of south Romania, specifically Vâlcea county [
1
]. According to the
mapping, the herpetologist stated that the viper belongs to the V. berus species, because V.
ammodytes does not have any melanic gene and thus cannot be entirely black. Even though
some authors have reported the presence of a certain subspecies of vipers, namely, Vipera
berus nikolskii in Vâlcea [
9
], it is rather difficult to establish the viper in question belonging
to this subspecies whose presence here has not been certified by DNA identification.
Twenty hours after the viper bite, treatment was initiated with Viper Venom Antitoxin
(Immunoserum contra venena viperarum europaearum) manufactured by Biomed, Poland. The
patient was administered 500 AU (one vial) as a bolus dose in 250 mL normal saline over
3 h. The patient was also treated with intravenous fluid therapy containing glucose and
electrolytes, intravenous methylprednisolone, and subcutaneous enoxaparin (prophylactic
dosage of 2000 UI/day) for 5 days.
The patient’s progress was clinically monitored after the initiation of the treatment.
The laboratory results and symptoms over time are presented below (see Tables 1and 3).
Thirty minutes after administration of the antivenom, ocular movements reappeared and
Toxins 2022,14, 500 5 of 8
blood pressure increased to 98/66 mmHg. Somnolence, diplopia, and gastrointestinal man-
ifestations withdrew on Day 2, while palpebral ptosis disappeared on Day 4. Local signs,
after initially worsening progressively, improved and completely disappeared by Day 5.
Table 3. Changes in the clinical profile of the patient over time.
Day Clinical Features
Day 1: at the time of treatment initiation
Somnolence, palpebral ptosis, ophthalmoplegia, and bilateral diplopia.
Mild gastrointestinal symptoms (nausea and diffuse abdominal pain).
Local manifestations (swelling, erythema surrounded by cyanosis, local heat,
induration, and pain in lower half of right calf).
BP = 80/67 mmHg, HR = 116 beats/min
Day 1: 30 min after treatment initiation Return of ocular movements.
BP = 98/58 mmHg, HR = 118 beats/min
Day 2: 12 h after treatment initiation
No somnolence, no diplopia, and no gastrointestinal symptoms present.
Persistence of palpebral ptosis.
Local inflammation reduced.
BP = 103/55 mmHg; HR = 80 beats/min
Day 3 Palpebral ptosis in remission, local signs improved (decreased swelling, no
local heat, modest pain); BP = 90/66 mmHg; HR = 89 beats/min
Day 4 No palpebral ptosis noted.
BP = 101/61 mmHg; HR = 105 beats/min
Day 5 No local signs or symptoms.
BP = 107/67 mmHg; HR = 100 beats/min
Day 6 Complete remission was noted, and patient was discharged from our clinic.
BP = blood pressure; HR = heart rate.
The child was discharged on Day 6 without any clinical signs or symptoms. The
laboratory test results were within normal ranges (see Table 1). No immediate or delayed
adverse reactions were reported after antivenom administration, apart from a slight increase
in IgE level, without clinical expression.
Daily lab testing was conducted using bedside assessment.
3. Discussion
From the venom composition, it is thought that neurotoxic effects of venom from
common European adders are caused by neurotoxins with phospholipase A2 (PLA2)
enzymatic activity [
10
,
11
]. A study published by Zanetti et al. in 2018 regarding the
effects of V. aspis and V. berus venoms in mice showed that both types of venom have
phospholipase A2 enzymes, but only V. aspis venom is neurotoxic. Clinical observations
from various regions of France and Italy support this finding, attributing neurological
manifestations exclusively to envenomation by V. aspis [
4
,
6
,
12
–
14
]. Nevertheless, studies
and clinical observations [
8
,
10
] have shown that the venom of some V. berus subspecies
from Eastern Europe can have neurotoxic effects, not only in animal experimental models
but also in humans. Neurotoxic manifestations following V. berus envenomation have been
sporadically communicated in the literature, with all incidents reported in the Carpathian
Basin of Hungary, Romania, and Bulgaria [
8
,
15
]. Three cases out of the seven reported
cases involved children aged 14, 12, and 9 years, respectively [16–18].
In our case, the incident took place in the Subcarpathian area of the south of Romania,
which is in the geographical region of Oltenia (see Figure 2). Symptoms of neurotoxicity
appeared 30 min after envenomation and included somnolence, palpebral ptosis, ophthal-
moplegia, and bilateral diplopia. These symptoms are similar to symptoms previously
described in the literature in cases of V. berus bites in the Carpathian Basin region [
8
]. An-
tivenom indication was established after classifying the case severity as grade 2b, using the
Audebert–Boels classification adapted to children by Marano et al. as shown in Table 2[
6
].
Toxins 2022,14, 500 6 of 8
Toxins 2022, 14, x FOR PEER REVIEW 6 of 8
In our case, the incident took place in the Subcarpathian area of the south of Roma-
nia, which is in the geographical region of Oltenia (see Figure 2). Symptoms of neuro-
toxicity appeared 30 min after envenomation and included somnolence, palpebral ptosis,
ophthalmoplegia, and bilateral diplopia. These symptoms are similar to symptoms pre-
viously described in the literature in cases of V. berus bites in the Carpathian Basin region
[8]. Antivenom indication was established after classifying the case severity as grade 2b,
using the Audebert–Boels classification adapted to children by Marano et al. as shown in
Table 2 [6].
Figure 2. V. berus distribution in Romania [1]. Red dots: new records of V. berus after 1990; blue
dots: records of V. berus before 1990.
Using other classification systems published in the literature, regarding severity of
viper envenomation, we can classify our case as Stage 2 according to the Clinical Grada-
tion of European Viper Envenomation system [12], and Stage 1 (ocular and mild gastro-
intestinal symptoms present) according to the Modified Grading Severity Score (GSS)
system for peripheral neurotoxic effects, after Italian viper bites [4]. Both stages in the
above classification systems are stages in which antivenom treatment is indicated.
In our case, viper Venom Antitoxin serum (Biomed, Poland) was administered. Vi-
per Venom Antitoxin serum is a monovalent antivenom containing Fab specific equine
immunoglobulins that bind the venom of V. berus.
Enoxaparin was administered prophylactically to prevent secondary venous
thrombosis due to prolonged immobilization of the affected leg [12]. We excluded the
need for antibiotic therapy since there were no local or general signs of infection. As
stated in the literature, antibiotics in snakebite cases should only be administered if there
is a positive history of infection, or clinical or biological signs of infection. [6,19].
Although the use of corticosteroids is controversial [6,19], the decision was made to
administer intravenous methylprednisolone as a symptomatic treatment for its
well-known anti-inflammatory effects. The outcome of methylprednisolone was fa-
vourable. Progressive amelioration of neurological symptoms was noted as follows: 30
min after immunotherapy administration, ocular movements reappeared; after 12 h,
somnolence and diplopia withdrew; and on the fourth day, palpebral ptosis was com-
pletely absent. We believe that the complete resolution of symptoms of neurotoxicity af-
ter treatment with the monospecific antivenom could be an argument that the snake re-
sponsible for envenomation was a viper of the V. berus subspecies. Moreover, other sys-
temic manifestations rapidly resolved, and local symptoms progressively improved, un-
til complete remission was achieved on the fifth day. No adverse reactions were observed
after antivenom serum administration. This is consistent with the literature [2,4,6]. In our
case, however, a slight increase in the IgE level, without clinical symptoms, was noted.
The limitation of our study consisted of the identification modality of the snake, which
was conducted by the herpetologist based on the following arguments: the viper is the
only venomous snake in our country, the geographical mapping, and the morphological
description provided by the adult accompanying the child at the time of the incident.
Figure 2.
V. berus distribution in Romania [
1
]. Red dots: new records of V. berus after 1990; blue
dots: records of V. berus before 1990.
Using other classification systems published in the literature, regarding severity of
viper envenomation, we can classify our case as Stage 2 according to the Clinical Gradation
of European Viper Envenomation system [
12
], and Stage 1 (ocular and mild gastrointesti-
nal symptoms present) according to the Modified Grading Severity Score (GSS) system
for peripheral neurotoxic effects, after Italian viper bites [
4
]. Both stages in the above
classification systems are stages in which antivenom treatment is indicated.
In our case, viper Venom Antitoxin serum (Biomed, Poland) was administered. Viper
Venom Antitoxin serum is a monovalent antivenom containing Fab specific equine im-
munoglobulins that bind the venom of V. berus.
Enoxaparin was administered prophylactically to prevent secondary venous throm-
bosis due to prolonged immobilization of the affected leg [
12
]. We excluded the need for
antibiotic therapy since there were no local or general signs of infection. As stated in the
literature, antibiotics in snakebite cases should only be administered if there is a positive
history of infection, or clinical or biological signs of infection. [6,19].
Although the use of corticosteroids is controversial [
6
,
19
], the decision was made
to administer intravenous methylprednisolone as a symptomatic treatment for its well-
known anti-inflammatory effects. The outcome of methylprednisolone was favourable.
Progressive amelioration of neurological symptoms was noted as follows: 30 min after
immunotherapy administration, ocular movements reappeared; after 12 h, somnolence
and diplopia withdrew; and on the fourth day, palpebral ptosis was completely absent. We
believe that the complete resolution of symptoms of neurotoxicity after treatment with the
monospecific antivenom could be an argument that the snake responsible for envenomation
was a viper of the V. berus subspecies. Moreover, other systemic manifestations rapidly
resolved, and local symptoms progressively improved, until complete remission was
achieved on the fifth day. No adverse reactions were observed after antivenom serum
administration. This is consistent with the literature [
2
,
4
,
6
]. In our case, however, a slight
increase in the IgE level, without clinical symptoms, was noted. The limitation of our
study consisted of the identification modality of the snake, which was conducted by the
herpetologist based on the following arguments: the viper is the only venomous snake in
our country, the geographical mapping, and the morphological description provided by
the adult accompanying the child at the time of the incident.
4. Conclusions
We can conclude that the venom of V. berus subspecies, found in the Carpathian Basin
region, appears to have neurotoxic effects. This conclusion was reached from specialist
consultation in V. berus identification, clinical observation, and possibly because of the
complete and rapid remission of the symptoms under monospecific antivenom treatment.
Consequently, we must take into consideration V. berus when confronted with neurological
symptoms in patients bitten by snakes in the Subcarpathian Basin from Eastern Europe.
However, further studies are necessary to confirm it.
Toxins 2022,14, 500 7 of 8
Author Contributions:
Conceptualization, G.V.N., C.E.U., D.L. and I.G.; validation, C.E.U., G.V.N.,
M.-D.C. and D.L.; formal analysis, I.G.; investigation, I.G.; resources, C.E.U., G.V.N. and A.U.; data
curation, D.L.; writing—original draft preparation, G.V.N. and A.M.C.; writing—review and editing,
G.V.N., D.L. and A.M.C.; visualization, M.-D.C., A.U., D.L. and I.G.; supervision, G.V.N. and D.L. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
The case-report study was approved by the Ethics Commit-
tee of the hospital protocol code 15351/02.06.2022 (approved date 2 June 2022)
Informed Consent Statement:
Written informed consent has been obtained from the patient to
publish this paper.
Data Availability Statement: Not applicable.
Acknowledgments:
Romanian Association of Herpetology for providing scientific data during
the research.
Conflicts of Interest: The authors declare no conflict of interest.
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