An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis
Abstract
This work was supported by the Research Committee from Hospital Universitario de Galdakao. IR-L is supported by a research grant from Gobierno Vasco – Eusko Jaurlaritza (grant number 2020111061) and Biobizkaia (BCB/I/LIB/22/008). The apheresis column and Promonitor kit were kindly provided by Adacyte and Progenika Biopharma, neither of them were involved on study design nor interpretation of the results.
Full text
Gas oen e ología
y
Hepa ología
47
(2024)
347---351
www.else ie .es/gas oen e ologia
Gas oen e ología
y
Hepa ología
ORIGINAL
ARTICLE
An
in
i o
analysis
o
he
in e ac ion
be ween
infliximab
and
g anulocy e---monocy e
aphe esis
Iago
Rod íguez-Lagoa,∗,
Le icia
Abeciab,c,
I a xe
Seoaneb,c,
Juan
Angui ab,d,
José
Luis
Cab iadaa
aGas oen e ology
Depa men ,
Hospi al
Uni e si a io
de
Galdakao,
Bioc uces
Bizkaia
HRI,
Galdakao,
Spain
bCIC
bioGUNE,
Basque
Resea ch
and
Technology
Alliance
(BRTA),
Bizkaia
Science
and
Technology
Pa k,
De io,
Spain
cImmunology,
Mic obiology
and
Pa asi ology
Depa men ,
Facul y
o
Medicine
and
Nu se y
School,
Uni e si y
o
he
Basque
Coun y,
UPV/EHU,
Bilbao,
Spain
dIke basque,
Basque
Founda ion
o
Science,
Bilbao,
Spain
Recei ed
11
Ap il
2023;
accep ed
3
July
2023
A ailable
online
6
July
2023
KEYWORDS
Infliximab;
G anulocy e---monocy e
aphe esis;
Inflamma o y
bowel
disease
Abs ac
Objec i e:
P ima y
non- esponse
and
seconda y
loss
o
esponse
o
an i-TNF
agen s
a e
common
in
inflamma o y
bowel
disease.
Inc easing
d ug
concen a ions
a e
co ela ed
o
be e
clinical
esponse
and
emission
a es.
Combina ion
o
g anulocy e---monocy e
aphe esis
(GMA)
wi h
an i-
umo
nec osis
ac o
(TNF)
agen s
could
be
an
op ion
in
hese
pa ien s.
The
objec i e
o
ou
s udy
was
o
pe o m
an
in
i o
assay
o
de e mine
i
he
GMA
de ice
can
lead
o
infliximab
(IFX)
adso p ion.
Pa ien s
and
me hods: A
blood
sample
was
ob ained
om
a
heal hy
con ol.
I
was
incuba ed
wi h
h ee
concen a ions
o
IFX
(3,
6,
and
9
g/ml)
a
oom
empe a u e
o
10
min.
A
ha
ime,
1
ml
was
collec ed
o
de e mine
he
IFX
concen a ion.
Then,
10
ml
o
each
d ug
concen a ion
was
incuba ed
wi h
5
ml
o
cellulose
ace a e
(CA)
beads
om
he
GMA
de ice
a
200
pm
o
1
h
a
37◦C
o
simula e
physiological
human
condi ions.
A
second
sample
o
each
concen a ion
was
collec ed
and
IFX
le els
we e
de e mined.
Resul s:
No
s a is ically
significan
di e ences
we e
obse ed
in
he
IFX
le els
in
he
blood
sam-
ples
be o e
and
a e
incuba ion
wi h
he
CA
beads
(p
=
0.41)
and
a e
epea ed
measu emen s
(p
=
0.31).
Mean
change
was
3.8
g/ml.
Conclusions:
The
in
i o
combina ion
o
GMA
and
IFX
did
no
change
he
ci cula ing
le els
o
IFX
a
he
h ee
concen a ions
es ed,
sugges ing
ha
he e
is
no
in e ac ion
be ween
he
d ug
and
he
aphe esis
de ice
in
i o
and
ha
hey
migh
be
sa ely
combined
wi h
each
o he .
©
2023
The
Au ho s.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
∗Co esponding
au ho .
E-mail
add ess:
iago. [email p o ec ed]
(I.
Rod íguez-Lago).
h ps://doi.o g/10.1016/j.gas ohep.2023.07.001
0210-5705/©
2023
The
Au ho s.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://
c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
I.
Rod íguez-Lago,
L.
Abecia,
I.
Seoane
e
al.
PALABRAS
CLAVE
Infliximab;
G anuloci o-monoci o
a é esis;
En e medad
inflama o ia
in es inal
Análisis
in
i o
de
la
in e acción
en e
infliximab
y
la
a é esis
de
g anuloci os
y
monoci os
Resumen
Obje i o:
La
al a
de
espues a
p ima ia
y
la
pé dida
de
espues a
secunda ia
a
los
agen es
an i ac o
de
nec osis
umo al
(TNF)
son
comunes
en
la
en e medad
inflama o ia
in es inal.
El
aumen o
de
los
ni eles
de
á maco
se
co elaciona
con
una
mejo
espues a
clínica
y
de
las
asas
de
emisión.
La
combinación
de
la
a é esis
selec i a
de
g anuloci os
y
monoci os
(GMA)
con
agen es
an i-TNF
pod ía
se
una
opción
en
es os
pacien es.
El
obje i o
de
nues o
es udio
ue
ealiza
un
ensayo
in
i o
pa a
de e mina
si
el
disposi i o
de
GMA
puede
in e acciona
con
infliximab
(IFX).
Pacien es
y
mé odos: Se
ob u o
una
mues a
de
sang e
de
un
con ol
sano.
Se
incubó
con
3
concen aciones
de
IFX
(3,
6
y
9
g/ml)
a
empe a u a
ambien e
du an e
10
minu os.
En
ese
momen o,
se
ecogió
1
ml
pa a
de e mina
la
concen ación
de
IFX.
Luego,
se
incuba on
10
ml
de
cada
concen ación
de
á maco
con
5
ml
de
cuen as
de
ace a o
de
celulosa
del
disposi i o
GMA
a
200
pm
du an e
una
ho a
a
37◦C
pa a
simula
las
condiciones
fisiológicas
humanas.
Se
ecogió
una
segunda
mues a
de
cada
concen ación
y
se
de e mina on
los
ni eles
de
IFX.
Resul ados:
No
se
obse a on
di e encias
es adís icamen e
significa i as
en
los
ni eles
de
IFX
en
las
mues as
de
sang e
an es
y
después
de
la
incubación
con
las
cuen as
de
ace a o
de
celulosa
(p
=
0,41)
ni
as
mediciones
epe idas
(p
=
0,31).
La
media
de
cambio
ue
de
3,8
g/ml.
Conclusiones:
La
combinación
in
i o
de
IFX
y
GMA
no
modificó
los
ni eles
ci culan es
del
á maco
en
las
3
concen aciones
p obadas,
lo
que
indica
que
no
exis e
in e acción
en e
el
á maco
y
el
disposi i o
de
a é esis
in
i o
y
que
pod ían
combina se
de
o ma
segu a.
©
2023
Los
Au o es.
Publicado
po
Else ie
Espa˜
na,
S.L.U.
Es e
es
un
a ´
ıculo
Open
Access
bajo
la
licencia
CC
BY-NC-ND
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
In oduc ion
An i-TNF
monoclonal
an ibodies
as
infliximab
(IFX)
a e
e ec i e
ea men s
o
pa ien s
wi h
inflamma o y
bowel
disease
(IBD)
e ac o y
o
con en ional
he apies.
Success-
ul
ea men
leads
o
mucosal
healing,
less
hospi alisa ions
and
su ge ies,
and
imp o emen
in
quali y
o
li e.1 --- 3 Ne -
e heless,
p ima y
non- esponse
o
an i-TNF
ea men
is
common4,5;
24---46%
o
pa ien s
can
de elop
seconda y
loss
o
esponse
(LOR)
du ing
he
fi s
yea ,6and
app oxima ely
10%
show
in ole ance.7
In
he
la ges
p ospec i e
s udy
o
an i-TNF
he apy
in
IBD
o
da e,
Kennedy
e
al.
showed
ha
he
main
modifi-
able
ac o s
associa ed
o
a
educed
ea men
e ec i eness
we e
low
d ug
concen a ions
and
immunogenici y.8I
has
been
epo ed
ha
highe
se um
d ug
concen a ions
a e
associa ed
wi h
be e
he apeu ic
ou comes
ega ding
bo h
main enance
and
induc ion
he apy,
when
he
inflamma o y
bu den
and
d ug
clea ance
a e
high.9---13
G anulocy e---monocy e
aphe esis
(GMA)
can
selec i ely
deple e
monocy es/mac ophages
by
adso p ion
and
has
been
associa ed
wi h
significan
clinical
e ficacy
in
pa ien s
wi h
IBD.14,15 The
GMA
de ice
consis s
o
a
column
o
cel-
lulose
ace a e
(CA)
beads
imme sed
in
physiological
saline
solu ion.16 I s
mechanism
o
ac ion
is
based
on
he
in e ac-
ion
be ween
cellula
and
humo al
blood
componen s
and
CA
beads.
Blood
passes
h ough
he
de ice
and
is
u he
ein used
o
he
pa ien .
The
ecommended
in usion
a e
is
30
ml/min
and
he
du a ion
o
he
sessions
is
60
min,17,18
hough
a
du a ion
o
90
min
is
also
common.19,20
The
mechanism
o
ac ion
o
GMA
appea s
o
be
mo e
han
adso p ion
o
excess
neu ophils
and
TNF-
p oducing
CD14+
CD16+
monocy es.
Adso bed
mono-
cy es/mac ophages
elease
in e leukin
(IL)-1
ecep o
an agonis ,
hepa ocy e
g ow h
ac o
and
soluble
TNF
ecep o s,
which
a e
an i-inflamma o y.21 Addi ionally,
a
sus ained
inc ease
in
lymphocy es
including
he
egula o y
CD4+
CD25+
T
cells
is
obse ed
a e
GMA.17
The
objec i e
o
ou
s udy
was
o
pe o m
an
in
i o
assay
o
de e mine
i
he
GMA
de ice
can
lead
o
adso p ion
o
an i-TNF
agen s
as
IFX
when
used
in
combina ion,
hus
p ese ing
he
he apeu ic
e ec s
o
he
d ug.
Pa ien s
and
me hods
S udy
design
Blood
sample
was
ob ained
om
a
heal hy
con ol
(43-yea -
old
woman;
non-smoke ;
o al
leukocy e
coun
6.35
×
109/L)
a
Hospi al
Uni e si a io
de
Galdakao,
Spain.
Sample
con-
ained
450
ml
o
unp ocessed
ull
blood.
The
dono
signed
an
in o med
consen
be o e
any
s udy
p ocedu e.
The
IFX
biosimila
used
(Inflec a®,
Pfize ,
B ussels)
is
a
chime ic
IgG1
monoclonal
an ibody
ha
binds
wi h
high
a fini y
o
bo h
he
soluble
and
ansmemb ane
o ms
o
TNF.23 Blood
sample
(30
ml)
was
incuba ed
wi h
h ee
concen a ions
o
IFX
(3,
6,
and
9
g/ml)
a
oom
empe -
a u e
o
10
min.
We
decided
o
use
p og essi e
dilu ions
ha
would
be
ep esen a i e
o
h ee
clinical
scena -
ios
o
h ough
le els
in
clinical
p ac ice.
A
ha
ime,
348
Gas oen e ología
y
Hepa ología
47
(2024)
347---351
Figu e
1
Infliximab
(IFX)
le els
de e mined
be o e
and
a e
incuba ion
wi h
cellulose
ace a e
beads
om
he
GMA
de ice.
The
blood
sample
was
incuba ed
wi h
h ee
di e en
concen-
a ions
o
IFX
(3,
6,
and
9
g/ml).
1
ml
was
collec ed
o
de e mine
he
IFX
concen a ion
(p e-incuba ion
sample).
Then,
10
ml
o
each
d ug
concen-
a ion
was
incuba ed
wi h
5
ml
o
CA
beads
om
he
GMA
de ice
(Adacolumn®,
JIMRO,
Takasaki,
Japan)
a
200
pm
o
1
h
a
37◦C
o
simula e
physiological
human
condi ions.
A e
incuba ion,
he
second
sample
o
each
concen a-
ion
was
collec ed
(pos -incuba ion
sample).
Samples
we e
s o ed
a
−80◦C.
IFX
le els
we e
de e mined
using
he
P omoni o ®ki
(P ogenika
Biopha ma,
De io,
Vizcaya).
Two
addi ional
sepa a e
measu emen s
and
wi h
he
same
ech-
nique
and
unde
he
same
condi ions
we e
pe o med.
Resul s
ob ained
om
he
blood
sample
we e
compa ed
using
a
Wilcoxon
es
o
con inuous
a iables
and
by
one-
way
ANOVA.
Resul s
IFX
le els
p e-
and
pos -incuba ion
a e
p esen ed
in
Fig.
1.
No
s a is ically
significan
di e ences
we e
obse ed
in
he
IFX
le els
de e mined
in
he
blood
samples
be o e
incu-
ba ion
and
a e
con ac ing
he
CA
beads
(p
=
0.41).
Mean
change
was
3.8
g/ml.
Mean
infliximab
concen a ions
a
baseline
we e
10.39,
7.8
and
5.20
g/ml,
a
each
o
he
p especified
a ge
le els.
In
he
second
measu emen ,
al-
ues
we e
7.75,
7.21
and
5.95
g/ml,
espec i ely.
Repea ed
measu emen s
showed
no
s a is ically
significan
di e -
ences
be ween
bo h
ime
poin s
(p
=
0.31;
Supplemen a y
Fig.
1).
Discussion
Ou
s udy
shows
ha
he
in
i o
combina ion
o
GMA
and
IFX
does
no
change
he
ci cula ing
le els
o
IFX
a
he
h ee
con-
cen a ions
es ed,
sugges ing
ha
he e
is
no
in e ac ion
be ween
he
d ug
and
he
aphe esis
de ice.
An i-TNF
agen s
a e
e ec i e
o
he
managemen
o
IBD
bu
p ima y
non- esponse
and
seconda y
loss
o
esponse
a e
common.
Inc easing
d ug
concen a ions
a e
co ela ed
o
be e
clinical
esponse
and
emission
a es,
highe
endo-
scopic
healing
a es
and
lowe
C- eac i e
p o ein
and
ecal
calp o ec in
le els.
This
co ela ion
be ween
exposu e
and
esponse
has
been
demons a ed
ac oss
se e al
an i-TNF
agen s
app o ed
o
he
ea men
o
ulce a i e
coli is
(UC).9---13
Combina ion
o
GMA
wi h
an i-TNF
agen s
could
be
an
op ion
in
pa ien s
who
do
no
espond
adequa ely
o
lose
esponse
o
biologics.22---25 In
a
case
epo
o
a
emale
wi h
C ohn’s
disease
who
los
esponse
while
being
on
main e-
nance
wi h
IFX,
he
pa ien
emained
in
s able
clinical
and
endoscopic
emission
a e
5
GMA
cou ses
wi hou
expe i-
encing
any
se ious
side
e ec s.23 In
2017,
we
desc ibed
ou
expe ience
wi h
his
combined
he apy
in
UC
pa ien s
a e
loss
o
esponse
o
an i-TNF
ea men .
GMA
was
indica ed
in
4
pa ien s
wi h
le -sided
o
ex ensi e
coli is
because
o
pa ial
esponse
o
biological
he apy
o
seconda y
LOR
o
i .
A
dec ease
in
he
Mayo
sco e
was
obse ed.
The
o e -
all
esponse
a e
was
50%
wi h
one
pa ien
demons a ing
sus ained
esponse.24 La e ,
we
desc ibed
a
e ospec i e
s udy
on
42
UC
pa ien s
(23
ecei ing
IFX),
whe e
GMA
was
combined
a e
a
p ima y
non- esponse
o
seconda y
LOR
o
an i-TNF
he apy.
Fi een
pa ien s
(32%)
esponded
o
he
combina ion
he apy
wi hou
an i-TNF
in ensifica ion,
swi ch,
swap
o
colec omy.25 Fu he mo e,
GMA
seems
o
be
well
ole a ed
by
he
pa ien s,
wi h
accep ance
a es
as
high
as
82%
ega dless
o
he
esponse
o
he
ea men .26
GMA
has
been
shown
o
ha e
clinical
e ficacy
oge he
wi h
immunomodula o y
e ec s
in
IBD
pa ien s.
Hi aishi
e
al.
in es iga ed
in
2003
he
mechanisms
unde lying
he
adhesion
o
g anulocy e
and
monocy e
o
CA
beads
ol-
lowing
exposu e
o
human
blood
o
he
ca ie s
a
37◦C
o
up
o
60
min
unde
con olled
condi ions.
Beads
selec-
i ely
adso bed
g anulocy es,
monocy es,
CD19+
(B
cells)
and
CD56+
(NK
cells).
The
g anulocy e
and
monocy e
adso p-
ion
was
inhibi ed
by
hea -inac i a ed
plasma
and
EDTA,
sugges ing
ha
he
adso p ion
was
plasma
p o ein
and
cal-
cium
dependen .
The
esul s
showed
ha
IgG
and
ac i e
complemen
agmen s
media ed
leukocy e
adhesion
o
CA
beads
ia
he
FcR
and/o
leukocy e
complemen
ecep o s
like
CR3.
Addi ionally,
CA
beads
induced
loss
o
exp ession
o
TNF
ecep o s
on
CD16+
g anulocy es
and
CD14+
monocy es,
bu
no
on
CD3+
lymphocy es.27
The
aim
o
he
combina ion
o
GMA
and
an i-TNF
agen s
is
o
ob ain
a
syne gis ic
e ec
o
bo h
mechanisms
o
ac ion
o
block
he
mig a ion
o
leukocy es
o
inflamed
issue.
How-
e e ,
bo h
can
con ibu e
o
he
inc ease
in
some
pe iphe al
lymphocy e
subpopula ions
(especially
T eg)
obse ed
in
he
fi s
weeks
o
ea men ,28 and
he
changes
induced
by
GMA
in
he
p ofile
o
cy okines
exp essed
in
he
colonic
mucosa
can
inc ease
he
e ec
o
an i-TNF
d ugs.25
Po en ial
in e ac ion
be ween
bo h
ea men s
has
also
been
pos ula ed,
ei he
by
inc easing
he
blood
ough
le -
els
o
by
educing
an i-d ug
an ibodies,29,30 al hough
he e
is
no
di ec
e idence.
Yokoyama
e
al.
fi s
epo ed
an
imp o emen
in
an i-TNF
biologic
d ug
le els
wi h
his
combina ion.29 As
desc ibed,
he
p esence
o
an ibodies- o-
IFX
(ATI)
in
IBD
pa ien s
is
esponsible
o
LOR
and
in usion
eac ions
(IR)
o
IFX.
This
g oup
measu ed
ATI
in
pa ien s
ecei ing
IFX
(56
wi h
sus ained
esponse,
76
wi h
LOR
and
6
wi h
IR).
Fou een
pa ien s
wi h
LOR
(6
wi h
C ohn’s
dis-
ease
and
7
wi h
UC),
showed
significan ly
imp o ed
clinical
ac i i y,
and
dec eased
ATI
and
IL-6
a
week
8
ollowing
ini ia ion
o
GMA
plus
IFX.
Nine
pa ien s
achie ed
emis-
sion,
which
was
main ained
a
week
24
wi h
IFX
alone.
P e-
and
pos -IFX
in usion
ATI
le els
we e
simila .
Pa ien s
wi h
ATI
>
0.153
g/ml
(cu -o
alue)
we e
likely
o
expe ience
LOR.
The
au ho s
concluded
ha
pa ien s
who
ecei ed
GMA
349
I.
Rod íguez-Lago,
L.
Abecia,
I.
Seoane
e
al.
in
addi ion
o
IFX
appea ed
o
egain
clinical
esponse
o
IFX
by
a
dec ease
in
ATI
le el,
and
he
concen a ion
o
IFX
was
associa ed
wi h
clinical
esponse.30
Ou
s udy
has
also
some
limi a ions
ha
should
be
consid-
e ed.
The
use
o
blood
ob ained
om
a
single
dono
could
be
a
majo
conce n.
Also,
samples
om
indi iduals
wi hou
IBD
may
no
be
ep esen a i e
o
he
ac ual
immunological
and
p o-inflamma o y
en i onmen
expec ed
in
pa ien s
wi h
ac i e
disease.
Ano he
impo an
me hodological
aspec
could
be
he
absence
o
in o ma ion
on
TNF
concen a ions
in
hese
samples.
Despi e
hese
ele an
conside a ions,
i
should
be
no ed
ha
ou
aim
was
o
ex apola e
how
IFX
and
GMA
may
in e ac
in
i o
om
da a
ob ained
a
ideal
labo-
a o y
condi ions.
Howe e ,
explo ing
his
aspec
in
pa ien s
wi h
IBD
is
ad isable
in
o de
o
p o ide
e en
mo e
app o-
p ia e
da a
o
ou
clinical
p ac ice.
The
da a
epo ed
in
ou
s udy
show
ha
he
in
i o
combina ion
o
GMA
wi h
IFX
does
no
modi y
he
ci cula -
ing
le els
o
he
biologic
a
he
h ee
concen a ions
es ed,
sugges ing
ha
he e
is
no
in e ac ion
be ween
he
d ug
and
he
aphe esis
de ice
and
ha
hey
migh
be
sa ely
combined
and
wi hou
isk
o
in e ac ion
wi h
each
o he .
I
could
be
hypo hesized
ha ,
by
eco e ing
clinical
esponse
wi hou
modi ying
he
d ug
le els,
he
combina ion
wi h
GMA
migh
educe
he
inflamma o y
bu den
hus
es o ing
an i-TNF
e fi-
cacy.
Au ho s’
con ibu ions
IR-L,
LA
and
JLC:
s udy
design,
da a
analysis
and
d a ing
he
manusc ip .
LA,
IS
and
JA:
pe o med
he
in
i o
analysis.
JA
and
JLC:
e ised
he
manusc ip
o
impo an
in el-
lec ual
con en .
E hical
conside a ions
This
s udy
was
conduc ed
unde
he
Decla a ion
o
Helsinki.
The
s udy
p o ocol
was
app o ed
by
he
local
E hics
Com-
mi ee
( e e ence
24/18).
Da a
a ailabili y
s a emen
The
da a
ha
suppo
he
findings
o
his
s udy
a e
a ailable
om
he
co esponding
au ho
upon
easonable
eques .
Funding
This
wo k
was
suppo ed
by
he
Resea ch
Commi ee
om
Hospi al
Uni e si a io
de
Galdakao.
IR-L
is
sup-
po ed
by
a
esea ch
g an
om
Gobie no
Vasco
---
Eusko
Jau la i za
(g an
numbe
2020111061)
and
Biobizkaia
(BCB/I/LIB/22/008).
The
aphe esis
column
and
P omoni o
ki
we e
kindly
p o ided
by
Adacy e
and
P ogenika
Bio-
pha ma,
nei he
o
hem
we e
in ol ed
on
s udy
design
no
in e p e a ion
o
he
esul s.
Conflic s
o
in e es
IR-L
has
ecei ed
financial
suppo
o
a eling
and
edu-
ca ional
ac i i ies
om
o
has
se ed
as
an
ad iso y
boa d
membe
o
Abb ie,
Adacy e,
Cell ion,
Chiesi,
Danone,
Fe -
ing,
Faes
Fa ma,
Janssen,
Galapagos,
MSD,
Pfize ,
Roche,
Takeda,
and
Tillo s
Pha ma.
Financial
suppo
o
esea ch:
Tillo s
Pha ma.
JLC
has
ecei ed
financial
suppo
o
a eling
and
edu-
ca ional
ac i i ies
om
o
has
se ed
as
an
ad iso y
boa d
membe
o
Abb ie,
Adacy e,
Chiesi,
Fe ing,
Janssen,
MSD,
Pfize ,
Takeda,
and
Tillo s
Pha ma.
The
emaining
au ho s
ha e
no
conflic s
o
in e es
o
decla e.
Acknowledgmen s
We
hank
Miguel
Ángel
Pascual-I oiz
o
his
echnical
sup-
po .
Appendix
A.
Supplemen a y
da a
Supplemen a y
da a
associa ed
wi h
his
a icle
can
be
ound,
in
he
online
e sion,
a
doi:10.1016/j.
gas ohep.2023.07.001.
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