www.elsevier.es/ai
Allergologia et immunopathologia
SociedadEspa˜nola deInmunolog´ıaCl´ınica, Alergolog´ıayAsmaPedi´atrica
ORIGINAL ARTICLE
Atopic dermatitis incidence and risk factors in young adults in Castellon (Spain): A prospective cohort study
A. Arnedo-Pena
a,b,c,∗, J. Puig-Barberà
d, A. Artero-Civera
e, M.A. Romeu-Garcia
a, N. Meseguer-Ferrer
a, C. Fenollosa-Amposta
f, A. Vizcaino-Batllés
f, E.
Silvestre-Silvester
f, M.R. Pac-Sa
g,1, L. Segura-Navas
h, M.A. Dubón
f, J. Fabregat-Puerto
i, J.B. Bellido-Blasco
a,c,jaEpidemiologyDivision,PublicHealthCenter,CastellódelaPlana,Spain
bDepartmentHealthSciences,PublicUniversityNavarra,Pamplona,Spain
cCIBERSaludPúblicaEpidemiología(CIBERESP),Barcelona,Spain
dVaccinesResearchArea,FISABIO,Valencia,Spain
eHealthCenter,Benicassim,Castellón,Spain
fPublicHealthCenter,CastellódelaPlana,Spain
gInternationalHealth,SanidadExterior,CastellódelaPlana,Spain
hHealthCenter,Burriana,Castellón,Spain
iHospitalGeneralUniversitary,CastellódelaPlana,Spain
jDepartmentHealthSciences,UniversitatJaumeI,CastellódelaPlana,Spain
Received26December2019;accepted29January2020 Availableonline10May2020
KEYWORDS Atopicdermatitis;
Cohort;
Incidence;
Youngadults;
Riskfactors
Abstract
Introduction:Therearefewatopicdermatitis(AD)incidencecohortstudiesinyoungadults,the etiologyofthisdiseaseremainsobscure,andADriskfactorsinadultsarenotwellunderstood.
TheobjectiveofthisstudywastoestimateADten-yearincidenceandprevalenceinacohortof adolescentaged14---16atinceptioninCastellonprovinceinValenciaRegion,Spainanddescribe relatedriskfactors.
Materialandmethods: From2002to2012,apopulation-basedprospectivecohortstudy was carriedout.QuestionnairesfromtheInternationalStudyofAsthmaandAllergiesinChildhood (ISAAC)wereusedwithanadditionalquestionnaireforrelatedfactorscompletedbyparticipants andtheirparents,respectively,in2002.In2012thesamequestionnaireswerecompletedby theparticipants’throughatelephoneinterview,andincidenceandprevalenceofADwereesti- mated.Directedacyclicgraphs,Poissonregressionandinverseprobabilityweightedregression adjustmentwereused.
Results:Theparticipationratewas79.5%(1435/1805)withADlifetimeprevalenceof34.9%and ADincidenceof13.5per1000personyears.Femalespresentedhigherprevalenceandincidence
∗Correspondingauthor.
E-mailaddress:[email protected](A.Arnedo-Pena).
1Retired.
https://doi.org/10.1016/j.aller.2020.01.004
0301-0546/©2020SEICAP.PublishedbyElsevierEspa˜na,S.L.U.Allrightsreserved.
than males.After adjustmentsignificant risk factorswere being female, historyofasthma orallergicrhinitis,familyhistoryofAD,historyofrespiratoryinfections,historyofbronchitis, historyofpneumonia,historyofsinusitis,andbirthplaceoutsideCastellonprovince.Thehighest ADpopulationattributableriskswerefemale,30.3%,andhistoryofrespiratoryinfections15.3%.
DifferenceswithADchildhoodriskfactorswerefound.
Conclusions: ADincidenceinourcohortwashighandseveralrisksfactorswererelatedtoAD.
©2020SEICAP.PublishedbyElsevierEspa˜na,S.L.U.Allrightsreserved.
Introduction
Atopicdermatitis(AD)isachronicinflammatoryskindisease withahighprevalenceinchildren,adolescentsandfrequent inadults.Alaboratorymeasuretoconfirmthediagnosticis lackingandADclinicalpictureofadultshassomediagnostic difficultiesandmaybelaborioustodistinguishfromother skindiseases.1,2
Several studies of AD prevalence have indicated an increase in European countries with a stability of AD incidence.3 However,there are few cohort studies of AD incidence inadolescents andyoung adults.4---7 AD etiology remainsobscure,itisconsideredamultifactorialdisease,8,9 butADadultriskfactorsarenotwellestablished.10,11
TheobjectiveofthisstudywastoestimateADincidence and prevalence in a cohort of adolescents aged14---16 at inceptionfolloweduntiltheywere24---26yearsoldinCastel- lonprovinceanddescriberelatedriskfactorsrelatedtonew cases.
Material and methods
PhaseIoftheInternational AsthmaandAllergiesinChild- hood(ISAAC)firstsurveywascarriedoutduringwinterand springin1994,withtheparticipationofschoolchildrenaged 6---7 and14---15. In 2002,Phase III ofISAAC, a second sur- vey,wascarriedoutinCastellonwiththesamegroups. In 2012,theformerparticipants,nowaged24---26yearscom- pletedasurveyimplementedbytelephone;moredetailsof thiscohortstudyhavebeenreportedbySeguraetal.12The threesurveyswerecarriedoutbystaffoftheepidemiology divisionofthepublichealthcenter,andotherhealthcenters inCastellon,Spain.
The ISAAC questionnairewasusedtoestimate ADwith anadditionalriskfactorsquestionnaire;parentsofthe6---7 yearsoldgroupcompletedthetwoquestionnairesin1994 andanextensiveadditionalquestionnairein2002.Thesame cohort of schoolchildren who participated in the survey in 1994 wasfollowed upto2012, and a population-based prospectivecohortstudywasimplementedconsideringthe period2002---2012,from14---16to24---26yearsold.Thethree surveyswerecarriedoutinthesameseasonsoftheyear.AD incidencewasestimated including onlythose participants freeofADatthebeginningofthefirstandsecondsurveys.
The questions used to estimate the AD incident cases wereapositiveanswertoatleastoneofthesetwoquestions inthe2002and2012surveys,respectively:Haveyouever hadeczemaoratopicdermatitis?Doyoutake anymedica- tionfor atopicdermatitis?TheADlifetimeprevalencewas
estimatedbyapositiveanswertothefirstquestioninthe 1994survey,andapositiveanswertoatleastoneofthetwo questionsinthe2002and2012surveys.
Riskfactors for ADincidence wereestimated fromthe second tothird survey withan extended additional ques- tionnaire. These risk factors were family history of AD, historyofasthma or/andallergicrhinitis,history ofrespi- ratoryinfections (bronchitis,pneumonia, sinusitis,otitis), exposureofsmokingat home,animalsathome (dog,cat, others),history ofbreastfeeding,historyof daycare, fre- quencyof trucktraffic in homestreet, birthplaceoutside ofCastellonprovince,ageofmotheratparticipant’sbirth, presenceofoldersiblings,occupationalsocialclassbaseon parents’occupation,townofresidencewith50,000inhabi- tantsormore,andpresenceofceramicindustryinthetown ofresidence.
Statisticalanalysis
Person years were calculated to estimate AD incidence during eight years from 1994 to 2002 and 10 years from 2002 to2012; AD newcases were divided by the popula- tionfreeofADin1994and2002,respectively. ADlifetime prevalence was estimated with the accumulation of AD casesofthethreedescribedsurveys.Chi2andFisherexact tests were used for comparison of categorical variables, andKruskal---Wallistestforcontinuousvariables.Univariate Poisson regression analysis was used toestimate associa- tionsbetweenADincidenceandindependentvariablesfrom 2002to2012.DAGittyversion3.013 wasusedtoimplement theDirected Acyclic Graphs(DAGs)14 approachwhich was employedtostudy therelationship between ADincidence (outcome)andpotentialconfounders.Multivariate inverse probabilityweighted regression adjustment(IPWRA)15 was usedtomodelADincidenceandpotentialriskfactorsadjust- ingforconfoundersandADincidence.Ageandgenderwere included in allmodels. Populationattributable riskswere estimatedfollowingRokchilletal.16Statisticalanalysiswas performedusingStata®14program.
TheEthicCommitteeoftheHospitalGeneraldeCastellon approvedthestudyandinformedconsentwasobtainedfrom eachparticipantortheirparents.
Results
TheflowchartofparticipantsofCastellon’scohortisshown in Fig. 1. In 1994, the first survey included 3607 partici- pants and the second survey 1807 participants (50%). In thethirdsurvey,in2012,theparticipationratewas79.5%
First Survey 1994 n=3607
•
• Second Survey 2002 n=1805 n=1802 lost in foll-upow
•
•
• Third Survey 2012 n=1435 n=370 lost in foll-upow Figure1 Flowchartofparticipants(n)ofCastellon’scohort.
(1435/1807).Characteristicsof thethreesurveysarepre- sented in Table 1. No differences in gender, size of the residencetownandsocialclasswereobservedinthethree surveys,although the percentages of participants born in Castellonhaddecreased.
LifetimeprevalenceofADinthethreesurveyswas15.5%, 25.7%,and34.9%,respectively(Table2).Femalespresented significanthigherprevalencethanmalesin2002and2012, andthis differenceincreased withage. In 2002, 182 new casesofADwerefoundwithanincidenceof15.9per1000 personyears,1.4%peryear(182/1520x8).In2012,135new casesofADwerefoundwithanincidenceof13.5per1000 personyears,and1.3%peryear(135/1069x10).Adecrease rateratioof0.85(95%CI0.68---1.06)wasobservedbetween 2002and2012.Femaleshadsignificantlyhigherincidences thanmales in thetwo surveys,21.1 versus 11.0 and18.1 versus9.2per1000personyears.
DAGs approach is presented in Fig. 2, and univariate and multivariate analysis of variables related to AD inci- dence are shown in Table 3. In the period 2002---2012, AD incidence rate in females was 16.6% (87/525) and 8.8% (48/544) in males (p=0.000). The mean age was 24.9±0.5 in cases and 24.9±0.6 in no-cases (p=0.307).
In the Poisson analysis, the significant risk factors were:
beingfemale,historyofasthmaand/orrhinitis,familyhis- toryofatopicdermatitis,historyofrespiratoryinfections, history of bronchitis, and birthplace outside of Castellon province.IntheIPWRAanalysis,significantriskfactorswere:
female (RR=1.89; 95% CI 1.36---2.64), history of asthma
and/or allergicrhinitis (RR=1.61;95%CI1.04---2.51),fam- ily history of AD (RR=2.78; 95% CI 1.77---4.37), history of respiratoryinfections (RR=1.55;95% CI1.04---2.31),his- tory ofbronchitis(RR=1.79; 95%CI1.17---2.75),history of pneumonia (RR=1.74;95% CI1.05---2.88), history of sinusi- tis (RR=1.82;95% CI 1.01---3.27) and birthplace outside of Castellonprovince(RR=2.02;95%CI1.30---3.14).
PopulationattributableriskofADrelatedfactorsinthe adjusted analysisareshown inTable4. Beingfemalerep- resents a30.1%ADrisk, followedbyhistoryof respiratory infections 15.3%, and history of bronchitis 9.3%. Fewer effectswereobservedwithhistoryofasthmaand/oraller- gicrhinitis,historyofpneumonia,historyofsinusitis,family historyofAD,andbirthplaceoutsideofCastellonprovince.
Discussion
In this cohort of young adults,AD incidence and lifetime prevalencewereestimated.RiskfactorsrangedbetweenRR of1.55(respiratoryinfections)andRRof2.78(familyhistory ofAD)whichindicatemoderateassociationswithADandthis variabilitysuggestsmultifactorialgenesis.Someoftheserisk factorsmaybemodifiable,suchasasthma,allergicrhinitis, andrespiratoryinfections.
ADincidences of ourstudy were15.9 (1994---2002) and 13.5 per 1000 person years (2002---2012), lower than AD cumulativeincidenceinDanishadolescents,21.5per1000 personyears,7buthigherthananothercohortfollowedfrom age9---11 to16---20in Germany.4However,ourcasedefini- tionwasdifferent.Petersetal.4includedonly12monthsAD symptoms,withADincidence1.7%;thisincidenceishigher thantheADincidenceannualrateinourstudy,1.3%.Also, ourADincidencewashigherthantheincidencefoundina Danishcohortage14to29years5withmedicalexamination andquestionnaires,8.9per1000personyears;incontrast, the ADlifetimeprevalence inour studywas34.9%, which wassimilartothe34.1%intheDanishstudy.5InanIcelander
Table1 CharacteristicsofCastellon’scohortinthethreesurveys1994,2002,2012.
Variables Firststudyyear1994 Secondstudyyear2002 Thirdstudyyear2012 p-Value
N(%) N(%) N(%)
Participants 3607 1805 1435
Female 1787(49.5) 905(50.1) 743(51.8) 0.601
Age(years)
6y:1580 14y:1150 24y:341
7y:2027 15y:634 25y:953
16y:21 26y:141
Agemean±SD 6.3±0.5 14.4±0.5 24.9±0.6 0.00
Citywith≥50,000inhabitants 2784(77.2) 1426(79.3) 1113(77.9) 0.21
BirthinCastellon
Yes 3193(88.5) 1657(91.8) 1324(92.3) 0.00
No 396(11.5) 148(8.2) 111(7.7)
Socialclass N=3183 n=1726 N=1371
I---II 732(23.0) 356(20.6) 284(20.7) 0.13
III---VI 2451(77.0) 1370(79.4) 1087(79.3)
Social class: I=professional, II=managerial and technical, III=skilled non-manual, IV=skilled manual, V---VI=partially skilled and unskilled.
Table2 Atopicdermatitislifetimeprevalenceandincidenceratesfrom1994to2002andfrom2002to2012forCastellon’s cohort.
Variables Firststudyyear1994 Secondstudyyear2002 Thirdstudyyear2012
Cases/Sample(%) Cases/Sample(%) Cases/Sample(%) Lifetimeprevalence
Female 271/178715.2 269/90329.8 305/74341.1
Male 271/182014.9 193/89721.5 196/69228.3
Total 542/360715.0 462/180525.6 501/143534.9
Prevalenceratio95%Confidenceinterval 1.02(0.86---1.21) 1.38(1.15---1.67) 1.41(1.21---1.73)
p-Value 0.83 0.00 0.00
Cases/Sample/PYRate* Cases/Sample/PYRate*
Incidencerate ---
Female 117/751/554021.1 87/525/481518.1
Male 65/769/589211.0 48/544/52009.2
Total 182/1520/1143215.9 135/1069/1001513.5
Rate/ratio95%Confidenceinterval 1.91(1.41---2.59) 1.96(1.38---2.78)
p-Value 0.00 0.00
* Rateper1000personyearsPY=personyears.
cohortfrombirthto21 yearsage,ADlifetimeprevalence was45%.17IntwoBritishcohortsof1958and1970,ADlife- time prevalence was inferior, 18% and 28%, suggesting a constantincreaseofAD.18
Someriskfactorsinourstudy,suchashistoryofasthma orallergicrhinitis,andfamilyhistoryofADareinlinewith theresultsofothercohortstudies.4,6Theriskfactorofbirth- placeoutsideofCastellonwasobservedinthefirstsurvey,19 andADprevalenceinthegroupage6---7yearswaslowerthan otherzones;somestudiesfoundmoreADprevalenceinthe migrantpopulationthanthenative populationconsidering theageofmigration.20 Ingeneral,femaleshavehigherAD incidencethanmales,althoughthisisnotconsistentinall studies.18,21
Other childhood AD risk factors were not related to ADincidence,includingbreastfeeding,pets,daycare,sib- lings, and dog exposure in early life.21,22 In fact, some studies suggest thatAD in children is associatedwithlow rates of infection, absence of older siblings, and antibi- otics exposure.23,24 Our results are opposed, considering
that history of respiratory infections, history of bronchi- tis,pneumonia andsinusitiswereriskfactors.It hasbeen suggested that some infections may protect against AD while others increase the risk of AD. Previous studies support our results, reporting AD increase with prenatal infections,25 earlyinfections,26 enterovirusandother virus infections,27,28 Staphylococcus aureus colonization before ADonset,29whereasoldersiblingsincreasedADriskintwo Germanbirthcohortstudies.30Inaddition,ADpatientssuf- ferfrequentinfections,31suggestingahighsusceptibilityto infection.Itisplausiblethatrespiratoryinfectionsmaybe contributingcomponentstoAD.Ontheotherhand,ADrisk factorsmaybedifferingfromchildhoodtoadulthood.32
Other risk factors such as social class, passive smok- ing,truck trafficexposure,andhard-waterexposurewere notrelatedtoAD incidence.Highsocial classandpassive smoking have been identified as risk factors in a cohort ofAD incidencefromadolescence toyoung adults.4 How- ever,lowersocialclasshasbeenassociatedwithADlifetime prevalenceinadults.18 SmokingwasassociatedwithADin
Figure2 DirectedAcyclicGraphsfortheassociationbetweenriskfactors(exposure)andatopicdermatitis(outcome).Example:
Infections(exposure) andredcolorindicateancestors ofexposure andoutcomeandbluecolorancestorsofoutcome.DAGitty version3.0.
Table3 Riskandprotectivefactorsofnewcasesofatopicdermatitisincidencebyunivariateanalysis(Poissonregression)and multivariateanalysis(inverseprobabilityweightedregressionadjustment)(IPWRA).Castellon’scohort2012.
Variables(*) CasesN=135 CohortN=1069 UnivariateAnalysis
RR(95%CI)
MultivariateAnalysis1 RR(95%CI)
Gender:female 87 525 1.88(1.32---2.67) 1.89(1.36---2.64)2
Age25---26versus24yearsold 110 828 1.28(0.83---1.98) 1.31(0.86---1.97)2 Historyasthmaand/orallergicrhinitis* 37 103 1.94(1.23---2.83) 1.61(1.04---2.51)3 Familyhistoryatopicdermatitis* 18 60 2.85(1.70---4.76) 2.78(1.77---4.37)2 Historyofrespiratoryinfections*16 58 407 1.47(0.98---2.22) 1.55(1.04---2.31)4
Historyofbronchitis* 28 156 1.71(1.10---2.66) 1.79(1.17---2.75)4
Historyofpneumonia* 10 56 1.59(0.82---3.07) 1.74(1.05---2.88)4
Historyofsinusitis* 13 72 1.58(0.88---2.84) 1.82(1.01---3.27)4
Historyofotitis* 40 299 1.26(0.84---1.91) 1.18(0.77---1.80)4
Familysmokeathome* 90 723 1.00(0.67---1.50) 0.94(0.63---1.40)5
Animalsathome*17 89 736 0.88(0.61---1.25) 0.97(0.63---1.51)6
Dogathome* 50 402 0.99(0.69---1.41) 1.05(0.71---1.54)6
Catathome* 23 174 1.01(0.64---1.59) 0.99(0.61---1.60)6
Socialclass:I---IIversusIII---VI* 28 196 1.16(0.76---1.76) 1.13(0.77---1.67)7 BirthplaceoutsideofCastellon 19 81 2.00(1.23---3.25) 2.02(1.30---3.14)8
Town≥50,000inhabitants* 101 830 0.89(0.60---1.33) 0.94(0.64---1.37)9
Exclusivebreastfeeding≥6months* 16 123 1.05(0.60---1.84) 1.05(0.62---1.77)10
Day-carebefore3years* 61 528 0.87(0.58---1.30) 1.03(0.69---1.56)11
Presenceofoldersiblings* 57 420 1.29(0.86---1.92) 1.53(0.99---2.37)12
Agemother
14---24years 21 157 1.00 1.007
25---29years 48 358 1.00(0.60---1.67) 1.08(0.67---1.73)
30---34years 22 320 0.75(0.41---1.36) 0.78(0.44---1.36)
≥35years 44 334 0.98(0.59---1.66) 0.94(0.66---1.73)
Constanttrucktrafficinhome’sstreet* 10 51 1.70(0.89---3.28) 1.50(0.80---2.83)13 Zonehardwater≥165mg/lCaMg* 100 751 1.18(0.80---1.73) 1.11(0.70---1.77)14
Ceramicindustry* 28 237 0.92(0.61---1.40) 0.72(0.47---1.09)15
*Variableswithlostinformationinsomeparticipants.1:IntheIPWRAanalysis,all variableswereadjustedforgenderandage.2:
Ageofmother.3:FamilyhistoryAD,familysmokeathome,ageofmother,socialclass.4:Exclusivebreastfeeding≥6months,town
≥50,000inhabitants,day-carebefore3years,familyhistoryAD,familysmokeathome,socialclass,oldersiblings,constanttrucksin home’sstreet,animalsathome.5:FamilyhistoryAD,ageofmother,socialclass.6:historyofasthmaorallergicrhinitis,town≥50,000 inhabitants,socialclass,familyhistoryAD.7:Gender,age.8.Socialclass,ageofmother9:ceramicindustry,socialclass.10.History ofasthmaorallergicrhinitis,town≥50,000inhabitants,familyhistoryAD,ageofmother,familysmokeathome,socialclass.11:town
≥50,000inhabitants,familyhistoryAD,presenceoldersiblings,socialclass,ageofmother.12:FamilyhistoryAD,socialclass,ageof mother.13:ceramicindustry,town≥50,000inhabitants,socialclass.14:FamilyhistoryAD,ageofmother,socialclass.15:Socialclass.
16:Respiratoryinfections:positivebronchitis,pneumonia,sinusitis,orotitis.17:Animalsathome;positivedog,cat,orotheranimalat home.
Table4 Populationattributablerisk1ofatopicdermatitisofCastellon’scohortthroughrelativerisks(RR)adjustedforcon- foundingfactorsfrominverseprobabilityweightingregressionadjusted(IPWRA).Castellon’scohort2012.
Riskfactors CasesN=135 Proportionriskfactorsin
thecases(pd)2
PopulationAttributable risk(%)(95%CI)3
Female 87 0.64 30.1(16.9---39.8)
Historyofasthmaand/orallergicrhinitis 37 0.27 10.2(1.0---16.2)
Familyhistoryofatopicdermatitis 18 0.13 8.3(5.7---10.0)
Historyofrespiratoryinfections 58 0.43 15.3(1.7---24.4)
Historyofbronchitis 28 0.21 9.3(3.1---13.4)
Historyofpneumonia 10 0.07 3.0(0.3---4.6)
Historyofsinusitis 13 0.10 4.5(0.1---6.9)
BirthplaceoutsideCastellon 19 0.14 7.1(3.2---9.5)
1:Populationattributablerisk=pd(RR-1)/RR.2:pd=caseswithariskfactor/totalofcases3:CI=Confidenceinterval.
adultsandadolescentsandtobaccoisconsideredariskfac- torofeczema.33 AirpollutionhasincreasedADprevalence inchildhoodandelderly.34 Withrespecttohardwater,its actionsmay bemore importantin childhoodthan in ado- lescentsandyoungadults.Inthesecondsurvey,hard-water exposurewasassociatedwithADin6---7yearsoldgroup,but notadolescents14---16yearsoldgroup,35 andthisassocia- tionhasbeenfound intwostudies fromGreatBritain and Denmarkininfants.36,37
Ourstudyhasaprospective design,acceptablepartici- pation,control ofpotentialconfoundersbyIPWRA, usesa validatedISAACquestionnaire,andallsurveyswereimple- mentedinthesameseasonsoftheyear.Aparallelquestion usedinourstudyhasbeenusedbyStenbergetal.38(have you hadchildhood eczema?)withsensitivity of 89.9% and specificityof 70.7%. However,Silverberg etal.39 used the question(haveyoueverbeentoldbyadoctororotherhealth professionalthatyouhadeczemaoranykindofskinallergy?) forADself-reporthistoryinadultswithlowsensitivity(43%) andhighspecificity(97%).
Thelimitationsofthisstudyincludethefollowingpoints:
first,nomedicalexaminationwascarriedouttoconfirmthe casesandsomeobservationalbiasmayhaveoccurred.Sec- ond, in thefollow-up of the cohort, the power todetect significant differences has decreased. Third, the AD inci- dent definitionpresentshigh variabilityandthereis nota generalconsensus.21 Fourth, somepotentialfactorswhich havebeenrelatedtoADincidencewerenotincludedinthe questionnairessuchas diet,foodallergy, air pollution,or vaccinations.8,9
ConsideringAD complexity,aglobalapproachhasbeen proposedtostudyitsprevention,diagnosis,andtreatment, including genetics, immune and environmental factors.40 Cohortstudiesarewellsituatedtobetterunderstandandto bringnewknowledgetothisfrequentandchronicpathology.
InconclusiontheADincidenceinourcohortwashighand severalrisksfactorswererelatedtoAD.
Conflict of interest
Theauthorshavenoconflictofinteresttodeclare.
Acknowledgement
We thankall the participants in the Castelloncohort and theirfamiliesfor theircooperationandsupportin making thisstudypossible.WeappreciatethehelpofRicardoTosca- Segura,Miriam Ortu˜no-Forcada, SaulFernández-González, FranciscoConde,andLidonMuseros-Recataláinthisstudy.
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