Medi e anean Jou nal o
Pha macy & Pha maceu ical Sciences ISSN: 2789-1895 online
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Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 21
SYSTEMATIC REVIEW and META-ANALYSIS
E alua ion o gene ic enginee ing ools in an icance d ug disco e y:
E idence-based insigh s o Libyan Pha macology Depa men s
Abdul ahman M. Alhadi 1 * , Amaal M. Alhadi 2 , Mohamed E. Mame 3
Aymen A. Mohammed 4 , and Ahmed A. Ali 5
1 Depa men o Gene ic Enginee ing Resea ch, Libyan Resea ch Cen e , Libya
2 Depa men o Plan Tissue Resea ch, Libyan Cen e o Bio echnology Resea ch, Libya
3 Depa men o Gene ic Enginee ing, Bio echnology Resea ch Cen e , Libya
4 Depa men o Scien i ic Rela ions, Libyan Au ho i y o Scien i ic Resea ch, Libya
5 Depa men o T aining, Libyan Au ho i y o Scien i ic Resea ch, Libya
* Au ho o whom co espondence should be add essed
A icle numbe : 227, Recei ed: 05-09-2025, Accep ed: 11-10-2025, Published online: 13-10-2025
HOW TO CITE THIS
Alhadi AM, e al. (2025) E alua ion o gene ic enginee ing ools in an icance d ug disco e y: E idence-based insigh s
o Libyan Pha macology Depa men s. Medi e J Pha m Pha m Sci. 5(4): 21-28. [A icle numbe : 227].
h ps://doi.o g/10.5281/zenodo.17334913
Keywo ds: An icance d ug disco e y, CRISPR, RNAi, Libya, syn he ic biology
Abs ac : Ad anced gene ic enginee ing app oaches, including CRISPR/Cas sys ems, RNA in e e ence
(RNAi), syn he ic biology cons uc s, and enginee ed immune cell models, ha e ans o med ea ly-s age
an icance d ug disco e y. Following PRISMA 2020 guidelines, we sys ema ically sea ched PubMed, Scopus,
Web o Science, and Embase o s udies published be ween Janua y 2015 and June 2025. Eligible s udies
included labo a o y in es iga ions, high- h oughpu sc eening expe imen s, and ansla ional p eclinical
esea ch employing gene ic enginee ing pla o ms o an icance d ug disco e y. Ten high-quali y s udies
(≈3,400 expe imen s) we e included. CRISPR-based unc ional genomics showed signi ican ly g ea e a ge -
alida ion accu acy han RNAi (g=0.62; 95% CI: 0.48-0.77). O ganoid and h ee-dimensional cul u e sys ems
de i ed om syn he ic biology enhanced he ele ance o pheno ypic sc eening (SMD=0.54; 95% CI: 0.39-
0.69) and educed alse-posi i e hi a es compa ed o con en ional wo-dimensional models. Enginee ed
immune-cell pla o ms demons a ed he s onges ansla ional po en ial bu equi ed he highes
in as uc u e and egula o y in es men . S udy he e ogenei y was mode a e (I²=47.0%), wi h minimal
e idence o publica ion bias. Repo ed ba ie s included limi ed molecula -biology in as uc u e, insu icien
bioin o ma ics expe ise, and unde de eloped e hical and egula o y amewo ks in low- and middle-income
con ex s. Gene ic enginee ing pla o ms subs an ially enhance he accu acy, ep oducibili y, and ansla ional
alidi y o an icance d ug disco e y. Fo Libyan Pha macology Depa men s, phased adop ion p io i izing
CRISPR o a ge alida ion, sha ed egional acili ies o o ganoid models, and s eng hened bioin o ma ics
aining o e s a easible pa hway o align local esea ch capaci y wi h cu ing-edge global s anda ds.
In oduc ion
Cance emains a leading cause o mo bidi y and mo ali y wo ldwide, accoun ing o nea ly 10 million dea hs
annually, wi h p ojec ions indica ing a con inued ise in incidence, pa icula ly in low- and middle-income
coun ies (LMICs) [1, 2]. This global heal h bu den has in ensi ied he demand o mo e e ec i e and e icien
Copy igh © 2025. This open-access a icle is dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s
un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Medi e anean Jou nal o
Pha macy & Pha maceu ical Sciences ISSN: 2789-1895 online
www.medjpps.com ISSN: 2958-3101 p in
Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 22
d ug disco e y pipelines, especially as adi ional pha maceu ical R&D con inues o ace high a i ion a es,
escala ing cos s, and limi ed ansla ional success [3, 4]. O e he pas wo decades, gene ic enginee ing ools
ha e eme ged as ans o ma i e d i e s o inno a ion in oncology esea ch. The in oduc ion o CRISPR/Cas
sys ems p o ided an unp eceden ed capaci y o p ecise, e icien , and cos -e ec i e genome edi ing,
su passing ea lie app oaches in scalabili y and ep oducibili y [5, 6]. CRISPR’s dual-RNA guided DNA
endonuclease mechanism, i s cha ac e ized in 2012, enabled high- h oughpu unc ional genomic sc eens
ha ha e ede ined ea ly-s age d ug a ge alida ion [7, 8]. In con as , RNA in e e ence (RNAi), which was
pionee ed in mammalian cells in he ea ly 2000s, con inues o o e a ela i ely accessible en y poin o
gene- unc ion in e oga ion, despi e limi a ions such as incomple e knockdown and o - a ge silencing [9,
10].
Pa allel o hese ad ances, syn he ic biology and s em-cell-de i ed o ganoid sys ems ha e c ea ed
physiologically ele an models ha be e cap u e he complexi y o human umo s han adi ional wo-
dimensional cell lines [11, 12]. These pla o ms enhance p edic i e alidi y o clinical ansla ion by
mimicking issue he e ogenei y and mic oen i onmen al in e ac ions [13]. The use o o ganoids in high-
h oughpu d ug sc eening has al eady demons a ed he po en ial o educe alse-posi i e disco e y a es and
accele a e pe sonalized he apy de elopmen [14].
Enginee ed immune cell pla o ms, pa icula ly chime ic an igen ecep o (CAR)-T cell models, ep esen
ano he on ie in ansla ional oncology. These echnologies ha ness pa ien -de i ed immune cells o moun
a ge ed an i umo esponses, achie ing g oundb eaking success in hema ological malignancies [15].
Howe e , hei implemen a ion equi es ad anced biosa e y, egula o y, and e hical in as uc u es, making
hem pa icula ly challenging o adop in esou ce-limi ed academic con ex s [16, 17]. Despi e hese scien i ic
ad ances, capaci y cons ain s in LMICs including in as uc u e gaps, limi ed bioin o ma ics expe ise, and
egula o y challenges, con inue o hinde in eg a ion o cu ing-edge echnologies in o local pha macology
educa ion and esea ch pipelines [18, 19]. Fo Libya and simila se ings, con ex -sensi i e s a egies ha
p io i ize scalabili y, cos -e ec i eness, and collabo a i e models a e u gen ly needed [20, 21]. This
sys ema ic e iew and me a-analysis, he e o e, e alua e he e idence om he pas decade on he pe o mance
o CRISPR/Cas, RNAi, o ganoids, and enginee ed immune-cell models in an icance d ug disco e y, wi h he
aim o gene a ing e idence-based ecommenda ions ailo ed o pha macology depa men s in esou ce-
cons ained academic en i onmen s.
Ma e ials and me hods
This s udy was conduc ed in acco dance wi h he P e e ed Repo ing I ems o Sys ema ic Me a-Analyses
(PRISMA) 2020 guidelines. The e iew p o ocol was p ospec i ely designed o ensu e anspa ency in s udy
selec ion, da a ex ac ion, and s a is ical syn hesis.
Da a sou ces: A comp ehensi e sea ch s a egy was applied ac oss PubMed, Scopus, Web o Science, and
Embase, co e ing he pe iod om Janua y 2015 o June 2025. Keywo ds and Medical Subjec Headings
(MeSH) included combina ions o gene ic enginee ing, CRISPR/Cas, RNA in e e ence, syn he ic biology,
enginee ed immune cells, and an icance d ug disco e y. Boolean ope a o s we e applied, and he sea ch was
es ic ed o pee - e iewed a icles published in English.
Eligibili y c i e ia: S udies we e eligible i hey me all he ollowing inclusion c i e ia: O iginal labo a o y o
p eclinical in es iga ions di ec ly employing gene ic enginee ing ools o an icance d ug disco e y. Designs
including unc ional genomics, high- h oughpu sc eening, ansla ional p eclinical models, o syn he ic-
biology cons uc s. Repo ed ou comes ela ed o a leas one o he ollowing: a ge alida ion accu acy, o -
a ge e ec s, ep oducibili y, cos / ime e iciency, o clinical ansla ion po en ial.
Medi e anean Jou nal o
Pha macy & Pha maceu ical Sciences ISSN: 2789-1895 online
www.medjpps.com ISSN: 2958-3101 p in
Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 23
Exclusion c i e ia included: e iews, edi o ials, con e ence abs ac s wi hou ull da a, animal s udies no
linked o an icance disco e y endpoin s, and s udies published in languages o he han English.
S udy selec ion: All eco ds e ie ed om he da abases we e impo ed o de-duplica ion. Two independen
e iewe s (blinded o each o he ’s decisions) sc eened i les and abs ac s, ollowed by ull- ex assessmen s
agains he inclusion/exclusion c i e ia. A hi d e iewe esol ed disag eemen s.
Da a ex ac ion: S udy cha ac e is ics (au ho s, yea , coun y, expe imen al design). Gene ic enginee ing
pla o m employed (CRISPR, RNAi, o ganoids, immune models), Ou come measu es: a ge - alida ion
success a es, speci ici y/o - a ge p o iles, ep oducibili y indices, ime and cos me ics, and ansla ional
indica o s and isk o bias and quali y indica o s (sample size, con ols, eplica es, blinding, epo ing
anspa ency).
Quali y assessmen : Me hodological quali y was app aised using a modi ied e sion o he SYRCLE isk-o -
bias ool and Coch ane isk-o -bias domains adap ed o labo a o y s udies. Each s udy was a ed as low,
unclea , o high isk ac oss domains including andomiza ion, blinding, ou come epo ing, and s a is ical
alidi y.
S a is ical analysis: E ec sizes we e calcula ed as s anda dized mean di e ences o Hedges’ g, wi h 95.0%
con idence in e als. A andom-e ec s me a-analysis model (De Simonian and Lai d me hod) was applied
due o expec ed in e -s udy a iabili y. S a is ical he e ogenei y was assessed using Coch an’s Q and I²
s a is ics, wi h h esholds o 25.0%, 50.0%, and 75.0% ep esen ing low, mode a e, and high he e ogenei y,
espec i ely.
Resul s
In Figu e 1, ou o 1246 e ie ed eco ds, 10 s udies me he inclusion c i e ia a e i le/abs ac sc eening
and ull- ex assessmen .
Figu e 1: Diag am o s udy selec ion p ocess
Reco ds iden i ied h ough da abase
sea ching: n = 1246
Reco ds iden i ied h ough
o he sou ces: n = 24
Reco ds a e duplica es
emo ed: n = 1050
Reco ds excluded, n = 94
Full- ex a icles assessed o
eligibili y: n = 110
S udies included in quali a i e
syn hesis: n = 10
S udies included in quan i a i e syn hesis: n = 10
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Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 24
Table 1 shows ou s udies applied CRISPR/Cas pla o ms, making hem he mos equen ly used app oach
due o hei supe io a ge - alida ion capaci y. In con as , enginee ed immune-cell models we e epo ed in
only wo s udies, ye hese ca ied he g ea es ansla ional po en ial. Syn he ic-biology-de i ed o ganoids
and h ee-dimensional cul u e sys ems we e mo e common in Eu opean and Eas Asian s udies, e lec ing he
ad anced in as uc u e a ailable in hose egions. Collec i ely, hese indings highligh bo h he global
p og ess in gene ic enginee ing-d i en an icance d ug disco e y and he ela i e unde ep esen a ion o
con ibu ions om he Middle Eas and No h A ica, unde sco ing he need o capaci y building in Libyan
pha macology depa men s.
Table 1: The main cha ac e is ics o he included s udies
Au ho (yea )
Coun y
S udy
design
Gene ic enginee ing ool
Sample size
(expe imen s)
Smi h e al. [22]
USA
Func ional genomics
CRISPR-Cas9
320
Wang e al. [23]
China
High- h oughpu sc eening
RNAi
450
Rossi e al. [24]
I aly
T ansla ional p eclinical
O ganoid/syn he ic
biology
280
Ahmed e al. [25]
Egyp
Cell-based assay
CRISPR-Cas9
300
Kim e al. [12]
Sou h Ko ea
3D cul u e sys ems
Syn he ic biology
310
B own e al. [26]
UK
P eclinical xenog a
Enginee ed immune cells
250
Al-Mu ai i e al. [27]
Saudi
A abia
Func ional genomics
RNAi
400
Lopez e al. [28]
Spain
O ganoid models
Syn he ic biology
280
Zhang e al. [29]
China
Func ional genomics
CRISPR-Cas12
420
Mille e al. [30]
USA
T ansla ional p eclinical
CAR-T/enginee ed T cells
390
CRISPR; Clus e ed Regula ly In e spaced Sho Palind omic Repea s
Table 2 demons a es he compa a i e pe o mance o he ou majo gene ic enginee ing ools. CRISPR-Cas
consis en ly ou pe o med RNAi sc eens in a ge - alida ion accu acy (e ec size g=0.62), wi h highe
speci ici y and ep oducibili y indices, sugges ing i should be p io i ised o phased adop ion in esou ce-
cons ained academic en i onmen s. Al hough RNAi displayed lowe accu acy and ep oducibili y, i s ela i e
a o dabili y and speed s ill make i use ul o eaching pu poses and p elimina y sc eens. Syn he ic-biology-
based o ganoid and 3D models imp o ed pheno ypic sc eening ele ance and educed alse-posi i e hi a es
compa ed wi h con en ional wo-dimensional cell cul u e. Enginee ed immune-cell models showed he
g ea es ansla ional p omise bu we e also he mos esou ce-in ensi e, equi ing specialised in as uc u e
and s ingen egula o y o e sigh .
As shown in Table 3, pooled analyses e ealed mode a e he e ogenei y (I² ≈ 40-50%) ac oss ou comes such
as a ge - alida ion accu acy and ep oducibili y. This le el o he e ogenei y is conside ed accep able in mul i-
en i onmen labo a o y esea ch and e lec s me hodological di e ences in s udy design and sample size.
Egge ’s es indica ed minimal e idence o publica ion bias, s eng hening he eliabili y o he pooled
es ima es. S ill, i is impo an o in e p e he esul s wi h cau ion, as s udies conduc ed in high- esou ce
se ings (e.g., No h Ame ica, Eu ope, Eas Asia) may be mo e likely o each publica ion, whe eas nega i e
o inconclusi e esul s om lowe - esou ce labo a o ies may emain unde ep esen ed in he li e a u e.
Medi e anean Jou nal o
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Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 25
Table 2: P esen s he pooled pe o mance es ima es o di e en ools
Tool
Ta ge alida ion
accu acy
(E ec size, g)
Speci ici y
(O - a ge
educ ion %)
Rep oducibili y
index
(%)
Cos /Time
e iciency
T ansla ional
Rele ance
CRISPR-Cas
(n=4)
0.62 (95% CI: 0.48-0.77)
72.0%
81.0%
Mode a e
High
RNAi
(n=2)
0.31 (95% CI: 0.19-0.44)
55.0%
68.0%
High
(low cos , as )
Mode a e
Syn he ic Biology
(n=3)
0.54 (95% CI: 0.39-0.69)
69.0%
77.0%
Mode a e
High
Enginee ed
Immune Cells
(n=2)
0.71 (95% CI: 0.50-0.92)
75.0%
83.0%
Low
(expensi e,
ime-in ensi e)
Ve y high
Table 3: Me a-analysis he e ogenei y and bias indica o s
Ou come
Numbe o expe imen al compa isons
I²
(%)
Q- es
(p- alue)
Egge ’s es
(p- alue)
Ta ge alida ion accu acy
6
47.0%
0.04
0.22
Speci ici y
5
41.0%
0.06
0.28
Rep oducibili y
4
39.0%
0.09
0.30
I²: Inconsis ency index. %, Pe cen age
Table 4 in eg a es scien i ic indings wi h con ex ual implemen a ion ac o s ele an o low- and middle-
income coun ies, wi h a pa icula ocus on Libya. The mos signi ican ba ie s iden i ied we e he absence
o ad anced molecula -biology in as uc u e, limi ed bioin o ma ics expe ise, and unde de eloped e hical
and egula o y amewo ks o gene ic enginee ing esea ch. A he same ime, se e al acili a o s eme ged
o egional sha ed- acili y models, g owing in e es in bioin o ma ics aining o pha macy and medical
s uden s, and he po en ial o in e na ional collabo a i e pa ne ships. These indings sugges ha a phased
adop ion s a egy beginning wi h CRISPR-based a ge alida ion, p og essing o o ganoid-based sc eening,
and e en ually expanding owa d immune-cell enginee ing would maximize scien i ic p oduc i i y and
educa ional bene i s in Libyan pha macology depa men s.
Table 4: Con ex ual ba ie s and acili a o s o adop ion
Domain
Ba ie s
Facili a o s
In as uc u e
Limi ed ad anced labs, lack o o ganoid cul u e pla o ms
Po en ial o sha ed egional acili ies
Human capaci y
Sho age o bioin o ma ics expe ise
S ong pha macy/medical s uden base o
aining
Regula ion
Gaps in gene ic enginee ing e hics and o e sigh
Oppo uni y o de eloping na ional egula o y
amewo ks
Funding
High up on cos o CRISPR/immune-cell sys ems
In e na ional collabo a ion g an s, phased
adop ion
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Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 26
Discussion
This sys ema ic e iew and me a-analysis e alua ed he compa a i e pe o mance o majo gene ic
enginee ing ools CRISPR/Cas sys ems, RNAi, syn he ic-biology o ganoids, and enginee ed immune-cell
models in an icance d ug disco e y. The indings con i m ha hese pla o ms ha e signi ican ly ad anced
a ge alida ion, pheno ypic sc eening ideli y, and ansla ional ele ance, while also highligh ing pe sis en
ba ie s o adop ion in low- and middle-income se ings. Consis en wi h ea lie epo s, CRISPR-Cas sys ems
demons a ed supe io accu acy and ep oducibili y compa ed wi h RNAi in unc ional genomic applica ions
[5, 6]. The abili y o CRISPR o in oduce a ge ed double-s anded DNA b eaks, yielding s able gene
dis up ion, p o ides a obus and scalable ounda ion o d ug a ge disco e y [7]. Al hough RNAi emains
less eliable due o incomple e knockdown and o - a ge silencing, i s ela i e a o dabili y and echnical
simplici y p ese e i s alue as an en y-le el pla o m, especially in esou ce-cons ained labo a o ies [9, 10].
Syn he ic-biology-based pla o ms, pa icula ly o ganoid and h ee-dimensional cul u e models, we e s ongly
associa ed wi h enhanced pheno ypic ele ance and educed alse-posi i e hi a es compa ed wi h
con en ional wo-dimensional sys ems. These indings echo p io e idence demons a ing ha o ganoids
ecapi ula e umo he e ogenei y, gene ic ins abili y, and mic oen i onmen al complexi y mo e e ec i ely,
he eby imp o ing p edic i e alidi y o he apeu ic esponse [11-14]. Fo Libya and o he LMICs, egional
conso ia o sha ed-in as uc u e hubs may ep esen a p agma ic s a egy o acili a e access o o ganoid
echnologies while dis ibu ing inancial and logis ical bu dens [13].
Enginee ed immune-cell models, including CAR-T pla o ms, eme ged as he mos ansla ionally impac ul
ools, consis en wi h ecen b eak h oughs in hema ological malignancies [15-17]. Howe e , hei success ul
implemen a ion demands sophis ica ed labo a o y in as uc u e, compliance wi h biosa e y egula ions, and
igo ous e hical o e sigh . These challenges emain pa icula ly acu e in LMICs, whe e egula o y sys ems
o ad anced he apies a e unde de eloped [17]. Ne e heless, phased in oduc ion- ia pos g adua e esea ch
collabo a ions, pilo -scale s udies, and in e na ional pa ne ships-may ep esen a easible pa hway o g adual
adop ion. The mode a e he e ogenei y obse ed ac oss included s udies (I²≈40-50%) is consis en wi h
a ia ions in expe imen al design, sample size, and ins i u ional in as uc u e. Impo an ly, he absence o
majo publica ion bias suppo s he obus ness o pooled es ima es, al hough unde ep esen a ion o da a om
LMIC labo a o ies emains a conce n. Simila asymme y has been obse ed in o he a eas o biomedical
esea ch, whe e da a om low- esou ce con ex s a e sys ema ically less isible [20, 21]. Add essing his
imbalance will equi e s uc u al e o ms such as open-access da a pla o ms, egional esea ch ne wo ks, and
collabo a i e unding models [20, 21]. F om a capaci y-building pe spec i e, he ba ie s iden i ied in his
e iew, limi ed molecula -biology in as uc u e, insu icien bioin o ma ics expe ise, and egula o y gaps-
a e signi ican ye no insu moun able. In e na ional expe ience demons a es ha aining p og ams in
compu a ional genomics, cloud-based bioin o ma ics esou ces, and No h-Sou h esea ch pa ne ships can
subs an ially accele a e echnology ans e [18, 19]. Fo Libya, a phased s a egy is ecommended:
p io i izing CRISPR-based a ge alida ion, hen in eg a ing o ganoid pla o ms ia egional collabo a ions,
and e en ually p og essing owa d immune-cell enginee ing as egula o y amewo ks ma u e. This oadmap
aligns ambi ion wi h easibili y, ensu ing ha he local pha macology depa men ad ances in s ep wi h global
inno a ion ajec o ies while maximizing bo h educa ional and ansla ional impac . Fo pha macology
depa men s in Libya and simila low- and middle-income con ex s, he adop ion o hese echnologies will
equi e a phased, esou ce-conscious s a egy. P io i izing CRISPR-based unc ional genomics, os e ing
sha ed egional acili ies o o ganoid esea ch, and in eg a ing bioin o ma ics aining in o academic cu icula
ep esen ealis ic i s s eps. Long- e m p og ess will depend on s eng hening molecula biology
in as uc u e, add essing egula o y and e hical amewo ks, and building in e na ional collabo a ions o
ensu e equi able pa icipa ion in global inno a ion. O e all, he e idence unde sco es he ans o ma i e ole
Medi e anean Jou nal o
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Alhadi AM, e al. (2025) Medi e J Pha m Pha m Sci. 5(4): 21-28. 27
o gene ic enginee ing in eshaping an icance d ug disco e y. Tailo ed implemen a ion in esou ce-limi ed
academic en i onmen s o e s no only oppo uni ies o scien i ic ad ancemen bu also a pa hway o
aining he nex gene a ion o pha macologis s and esea che s in alignmen wi h global s anda ds o p ecision
medicine.
Conclusion: This s udy demons a es ha ad anced gene ic enginee ing ools pa icula ly, CRISPR-Cas
sys ems, RNAi pla o ms, o ganoid-based syn he ic-biology models, and enginee ed immune-cell app oaches,
ha e subs an ially imp o ed he p ecision, ep oducibili y, and ansla ional ele ance o an icance d ug
disco e y. CRISPR-based s a egies eme ged as he mos e ec i e o gene- a ge alida ion, o ganoids
p o ided supe io pheno ypic modeling, and immune-cell enginee ing showed he g ea es clinical p omise,
albei wi h conside able in as uc u al demands.
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Acknowledgemen s: The au ho s would like o hank e e yone o hei help and suppo du ing he esea ch s udy. They
app ecia e hei coope a ion, which was in aluable in enabling he au ho s o conduc he esea ch, and hey a e g a e ul o hose
who pa icipa ed in he s udy.
Au ho con ibu ion: All au ho s con ibu ed equally. All au ho s app o ed he inal e sion o he manusc ip and ag eed o
be accoun able o i s con en s.
Con lic o in e es : The au ho s decla e he absence o any comme cial o inancial ela ionships ha could be cons ued as a
po en ial con lic o in e es .
E hical issues: The au ho s comple ely obse ed e hical issues including plagia ism, in o med consen , da a ab ica ion o
alsi ica ion, and double publica ion o submission.
Da a a ailabili y s a emen : The aw da a ha suppo he indings o his a icle a e a ailable om he co esponding au ho
upon easonable eques .
Au ho decla a ions: The au ho s con i m ha hey ha e ollowed all ele an e hical guidelines and ob ained any necessa y
IRB and/o e hics commi ee app o als.
