ww w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Original
article
Prediction
of
brain
atrophy
using
three
drug
scores
in
neuroasymptomatic
HIV-infected
patients
with
controlled
viremia
Marko
Novakovic
a,b,∗,
Vesna
Turkulov
a,c,
Daniela
Maric
a,c,
Dusko
Kozic
c,d,
Uros
Rajkovic
e,
Mladen
Bjelan
c,d,
Milos
Lucic
c,d,
Snezana
Brkic
a,caInfectiousDiseasesClinic–HIV/AIDSCentre,ClinicalCentreofVojvodina,NoviSad,Serbia bFacultyofMedicine,UniversityofLjubljana,Ljubljana,Slovenia
cFacultyofMedicine,UniversityofNoviSad,NoviSad,Serbia
dDiagnosticImagingCentre,OncologyInstituteofVojvodina,SremskaKamenica,Serbia eFacultyofOrganizationalSciences,UniversityofMaribor,Kranj,Slovenia
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received27March2015 Accepted6July2015
Availableonline19August2015
Keywords: CPE
Monocyteefficacyscore Brainatrophy
HAART HIV
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s
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t
Background:Despitepotentantiretroviraltherapy,HIVstillcausesbraindamage.Better pen-etrationintotheCNSandefficienteliminationofmonocyte/macrophagesreservoirsaretwo maincharacteristicsofanantiretroviraldrugthatcouldpreventbraindamage.Theaimof ourstudywastoassessefficacyofthreeantiretroviraldrugscorestopredictbrainatrophy inHIV-infectedpatients.
Methods:A cross sectionalstudy consisting of56 HIV-infected patientswith controlled viremia,whohadnoclinicallyevidentneurocognitiveimpairment.AllpatientshadMRI ofthehead.AtypicalT2transversalslicewasanalyzedandventricles–brainratio(VBr)as anoverallbrainatrophyindexwascalculated.Threeantiretroviraldrugscoreswereused andcorrelatedwithVBr:2008and2010CNSpenetrationeffectivenessscores(CPE2008and CPE2010)andtherecentlyestablishedmonocyteefficacy(ME)score.Ap-value<0.05was consideredsignificant.
Results:CPE2010 was significantly associated with VBr in both univariate (r=−0.285, p=0.033)andmultivariate(ˇ=−0.299,p=0.016)regressionmodels,whileCPE2008wasnot (r=−0.141,p=0.300andˇ=−0.156,p=0.214).MEwasassociatedwithVBrinmultivariate modelonly(r=−0.297,p=0.111andˇ=−0.406,p=0.029).AgeandreporteddurationofHIV infectionwerealsosignificantpredictorsofoverallbrainatrophyinmultivariateregression models.
Conclusions: Althoughbasedonsimilartypeofresearch,CPE2010isasuperiordrugscore comparedtoCPE2008.MEisanefficientdrugscoreindeterminingbraindamage.Both CPE2010andMEscoresshouldbetakenintoaccountinpreventivestrategiesofbrain atrophyandneurocognitiveimpairmentinHIV-infectedpatients.
©2015ElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthorat:ClinicalCentreofVojvodina–InfectiousDiseasesClinic,HajdukVeljkova1,21000NoviSad,Serbia. E-mailaddress:markonovakovic@rocketmail.com(M.Novakovic).
http://dx.doi.org/10.1016/j.bjid.2015.07.002
Introduction
Different neuropathological and neuroradiological studies have shown that HIV-infected patients have significant reduction ofthe brain parenchyma of both cortical1,2 and
subcorticalbrainregions.3,4DespiteeffectiveHIVtreatment,
brain tissue remains susceptible to the virus1 as there is
stilldetectable viralloadincerebrospinalfluid(CSF),5 brain volume loss6–8 and neurocognitive(NC) impairment.9,10 As
shownineuroSIDAstudy,antiretroviraltherapysignificantly reducedtheincidenceofNCdisorders causedbyHIV,11 but
itsprevalenceisstillhigh(15–40%).12Duetotheblood–brain
andtheblood–CSFbarriers,drugentryintotheCNSislimited, whichresultsinincompleteviralsuppressionintheCNS.That might bethe reasonwhy CNS actsas areservoir forviral persistence and evolution ofdrugresistance, inwhich the virusacquireuniqueproperties.13,14Differentpenetration
lev-elsofantiretroviraldrugsintotheCNShavebeenquantified byCNS-penetrationeffectivenessscore(CPE),establishedby Letendreetal.15Thescorehas2008(CPE
2008)and2010(CPE2010)
versions.15,16HigherCPEmeansnotonlyabetterpenetration
efficacyintotheCNS,butalsoadeclineofnewCNSevents andevenadeclineinmortalityrates.17Incontrast,astudyby
McManusetal.18hasnotreachedthesameconclusion.
As viral reservoirs, circulating monocytes are consid-ered to be responsible for chronic HIV infection in the brain.Activatedmonocytes traffictothebrain, wherethey becomemacrophagesandproduceinflammatorymolecules. Increasedinflammatorymilieuresultsindamageofthebrain tissueandeventuallyleadstoNCimpairment.19–23 Autopsy
studies have shown increased number of macrophages in braindespiteantiretroviraltreatment.24Therefore,
antiretro-viral drugs that are effective in destroying viral reservoirs (monocytesandbrainmacrophages)shouldslowdownbrain atrophyandNCdeteriorationcausedbyHIV.Collectinginvitro dataabouteffectivenessofantiretroviraldrugsagainst acti-vated monocytes/macrophages, Shikuma et al. established monocyteefficacy(ME)scoreofdrugsandproveditsefficacy inpredictingNCimpairment.25
Toourknowledge,thereisonlyonestudyinwhichthese threedrugsscoreswerecomparedandNCparameterswere usedasoutcome.25Thereisnoneuroimagingstudyinwhich
ME score was validated and compared with CPE scores in assessingbrainatrophyinHIV-infectedpatients.
Theaimofourstudywastocomparerecentlyestablished MEscorewithtwoCPEscoresintermsofefficacyin predict-ingbrainatrophyinHIV-infectedpatients. Wealsowanted toinvestigateotherpotentialdeterminantsofbrainatrophy, suchasage,nadirandcurrentCD4+T-cellcountanddurations
ofHIVinfectionandHAART.
Materials
and
methods
Studydesignandsubjects
Thiscross-sectionalstudyconsistedofHIV-infectedpatients receiving care at the HIV/AIDS Center, Infectious Diseases Clinic,ClinicalCenterofVojvodinainNoviSad,Serbia.There were81patients,whohadundergoneMRIofthebrain,which
isaroundone-thirdofallregisteredpatients.AllMRIswere performedattheDiagnosticImagingCenter,Oncology Insti-tuteinSremskaKamenica,SerbiafromJuly2011toJuly2014. Out ofthe 81patients,63 wereonHAARTand hadplasma HIVRNA<50copies/mLforatleastthreemonths.Exclusion criteriawerepresenceoffocalbrainchangesonMRI,clinically evidentNCimpairment,co-infectionwithhepatitisCvirus, andintravenousdruguse.Inatotalof56patientswhometall theabovecriteria(Suppl.1)theInternationalHIVDementia Scale(IHDS)wasappliedasaneuropsychologicalscreening test,establishedbySacktoretal.26inwhich0istheworstand
12 isthe bestscore.Thestudyisapartofalargerproject, whichhasbeenapprovedbythelocalethicscommitteeand informedconsentwasobtainedfromeachpatient.
Morphometry
For everyincluded patienttypicalT2transversal MRIslices were obtainedin which lateral ventricles are mostvisible. Ventricular–brainratio(VBr)wascalculatedbymeasuring lat-eralventriclesareaanddividingbythebrainareaatthesame level.Thisisamarkerofoverallbrainatrophyandhasalready been used in studies on brain atrophy related to diseases includingHIV.27,28
Antiretroviraldrugsanddrugscoringsystems
All patients were on highly active antiretroviral therapy (HAART)thatconsistedoftwonucleosidereverse transcrip-tase inhibitors (NRTI) plus a protease inhibitor (PI) and/or non-nucleosidereversetranscriptaseinhibitor(NNRTI).Three antiretroviraldrug-scoringsystemswereused:2008and2010 (CPE2008andCPE2010)CPEscoreversions,15,16andMEscore.25
All scores forantiretroviral regimens were calculated as a sum oftheindividual gradesfrom the score.There are no publisheddataonMEscoreoflopinavir/ritonavir(lpv/r)and darunavir.Therefore,for26(46.4%)patients,whowereonlpv/r ordarunavir,itwasnotpossibletocalculateMEvalues.
Statisticalanalyses
Data were evaluated and statistically processed using the softwarepackageIBMSPSSStatisticsver.21.T-testfor inde-pendent sampleswas usedto assess differencesin means ofbrainatrophyindexbetweentwogroups.Pearson’s coef-ficient was used for estimating correlation between brain atrophyindexandparameters,suchasage,nadirandcurrent CD4+ T-cellcount,duration ofHIV,duration ofHAART, and
drugscores.Multivariatelinearregressionanalyseswere per-formedforassessingpredictorsofbraindamage.Alltestswere two-tailed.Ap<0.05wasconsideredstatisticallysignificant.
Results
Meanage ofpatients inthe studywas 41 years,89% were males. Demographic and virologic characteristics of the patientsareshowninTable1.
Lamivudine was taken by 94.6%, abacavir by 67.9%, lpv/r by 44.6%, efavirenz by 42.9%, zidovudine by 30.4%,
1.8% 10.7% 44.6% 3.6% 42.9% 5.4% 30.4% 67.9% 94.6% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Darunavir Saquinavir/ritonavir Lopinavir/ritonavir Nevirapine Efavirenz Didanozine Zidovudine Abacavir Lamivudine PI NN R TI NR TI
Fig.1–Antiretroviraldrugsonusebystudyparticipants.
saquinavir/ritonavirby10.7%,didanosineby5.4%,nevirapine by3.6%,anddarunavirby1.8%ofpatients(Fig.1).Basedonthe presenceofefavirenzintheregimenthepatientswere cate-gorizedintotwogroups.Therewerenosignificantdifferences inVBr(p=0.926)andIHDS(p=0.501)valuesbetweenthesetwo groups.
Mean values, SD, medians, IQR, minimal and maximal valuesofCPE2008, CPE2010,and MEscoresare shownin
Table2.MEsignificantlycorrelatedwithCPE2010(r=0.546,
p=0.002),whiletheassociationbetweenMEand CPE2008
wasnotsignificant(r=0.097,p=0.609).Correlation between twotheCPEversions(CPE2008andCPE2010)washighly
sig-nificant(r=0.644,p<0.001).
Alinearregressionmodelwasbuiltincludingeachofthe threedrugscoringsystems.Theindependentvariablesage, nadirandcurrentCD4+ T-cellcount,durationofHIVstatus
andHAARTtherapywereincludedineachofthethree regres-sionmodels.ThedependentvariableinallmodelswasVBr, ameasureofbrainatrophy.Resultsoftheselinearregression
Table1–Characteristicsofpatients.Dataareshownas meanvalue(SD)orpercentage.
Total(n=56)
Demographics
Age,years 41.1(9.6)
Malegender 89%
Virologyandtherapy
NadirCD4+T-cellcount,cells/mm3 186.0(112.5)
CurrentCD4+T-cellcount,cells/mm3 472.5(254.1)
HIV-positivestatus,months 69.9(52.6) Durationoftherapy,months 39.4(35.4)
Neuropsychologicalscreening
IHDS,points 10.9(1.0)
Brainmorphometry
VBr,×1000 84.2(16.2)
IHDS,InternationalHIVDementiaScale;VBr,ventricles–brainratio.
modelsarepresentedinTable3.Inunivariateanalysesage (r=0.283, p=0.035) and CPE2010 (r=−0.285, p=0.033)were
foundtobesignificantlyassociatedwithbrainatrophy. How-ever,inmultivariateanalyses,bothCPE2010andMEwere
significantpredictorsofbrainatrophy(ˇ=−0.299,p=0.016and ˇ=−0.406,p=0.029,respectively). CPE2008 wasneither
sig-nificantlyassociatedinunivariate(r=−0.141,p=0.300)norin multivariate(ˇ=−0.156,p=0.214)regressionmodels.Ageand duration ofHIV-positive statuswere parameters thatwere significantlyassociatedwithbrainatrophyinallthree mul-tivariatemodels(Table3).
Discussion
Numerous studies emphasized basal ganglia as the main regioninwhichpathologicaleffectsofHIVtakeplaceinthe CNS.4,6Otherstudiesshowedthatnumerouscorticalpartsof
thebrainaredamagedaswell.29,30 Therefore,wehaveused
VBrinourstudy,asanindexofoverallbrainatrophy. Ourhypothesiswasthatthelevelofanantiretroviraldrug intheCNSaffectsallstepsintheneuropathogenesischain. The first step includes inflammatory changes and neuro-logical injury. It can be diagnosed with CSF markers and magnetic resonance spectroscopy. Atrophic changes occur
Table2–Mean,medianandmeasuresofdispersionfor threedrugscoresofpatientsinthestudy.
Mean SD Median IQR Range CPE2008 2.16 0.45 2 2.0–2.5 1–3
CPE2010 8.18 0.81 8 8–9 6–10
ME 152.80 35.52 153 153–170 73–200 CPE2010,CNS-penetrationeffectivenessscore(version2010)ofthe
HAARTregimen.
CPE2008,CNS-penetrationeffectivenessscore(version2008)ofthe
HAARTregimen.
Table3–Linearregressionmodelsofthreedrugscoringsystemswithbrainatrophyindex(VBr)asadependantvariable.
Regressionmodel Independentvariables Univariate Multivariate Correlation coefficientr p Regression coefficientˇ p Model significance CPE2010 Age 0.283 0.035 0.390 0.003 p=0.001 NadirCD4+count −0.113 0.406 CurrentCD4+count −0.112 0.413 DurationofHIV 0.235 0.082 0.291 0.022 DurationofHAART 0.238 0.078 CPE2010 −0.285 0.033 −0.299 0.016 CPE2008 Age 0.283 0.035 0.365 0.006 p=0.008 NadirCD4+count −0.113 0.406 CurrentCD4+count −0.112 0.413 DurationofHIV 0.235 0.082 0.322 0.015 DurationofHAART 0.238 0.078 CPE2008 −0.141 0.300 −0.156 0.214 ME Age 0.283 0.035 0.348 0.045 p=0.022 NadirCD4+count −0.113 0.406 CurrentCD4+count −0.112 0.413 DurationofHIV 0.235 0.082 0.377 0.043 DurationofHAART 0.238 0.078 ME −0.297 0.111 −0.406 0.029
CPE2010,CNS-penetrationeffectivenessscore(version2010)oftheHAARTregimen.
CPE2008,CNS-penetrationeffectivenessscore(version2008)oftheHAARTregimen.
ME,monocyteefficacyscoreoftheHAARTregimen.
inthe second step,which can be evaluated withdifferent
neuroimagingmethods.Structuraldamagefurtherresultsin
functional changes, the hallmark of the third step. These
functionalchangesareobservedasNCimpairmentandcan
bediagnosedusingdifferentneuropsychologicaltests. This integralapproachhasbeenprovedwithcorrelationsbetween structuralandfunctionalvariablesinnumerousstudies,3,31–35
althoughtherearealsostudiesinwhichcorrelationswerenot shown.2,6
Oneof the aimsofour study was to compare two CPE scoringsystems. Theoriginal CPE2008 scoringsystemwas
basedonclinical,pharmacologicalandchemicalreportson antiretroviraldrugs.Inliteratureitwasmostlyindicatedas apredictorofdecreasingviralloadinCSF15,36;in
neuropsy-chologicalstudiestheresultsarecontroversial.37–40 Imaging
studies failed to prove CPE2008 as a predictor of brain
atrophy.4,7,8Ourresultsareinlinewithpublishedreportsas
wefoundnosignificantassociationbetweenCPE2008andVBr.
Althoughsuchanoutcome wasexpectedduetosimilar resultspreviouslyreported, we hypothesizedthat CPE2008
couldbeusedtopredict brainatrophyasit strongly corre-lateswithCPE2010.Therearesomepossiblereasonswhythe
associationisnotshown:
– Sumofscorevaluesrangeistoonarrowtoshowsmall dif-ferences.
– CPEscaleclassifiesdrugsintoonlythreecategories, mask-ingthedifferencesamongdrugsinthesamecategory.
Onthecontrary,arevisedCPE2010wasshowntobeagood
predictorofbrainatrophyinbothunivariateandmultivariate regressionmodels.Accordingtoourresults,itisexpectedthat HAARTregimensconsistingofdrugswithhigherCPE2010score
haveaprotectiveeffectonthebraintissue.Thestudyby Cic-carellietal.,usingNCperformanceastheoutcomeofinterest, foundresultsregardingCPE2008andCPE2010similartoour
study.IntheirstudyCPE2010wasemphasizedasanimproved
predictingtoolandastepforwardcomparedtoCPE2008.41
There are very few neuroimaging studies that have examined CPE2010.Raginet al.conductedaneuroimaging
study that showed association betweenbrain atrophy and CPE2010.29 On thecontrary,thereare numerousstudiesin
whichNCperformancewasusedasanoutcome.Somestudies haveshownsignificantpositiveassociation,whereas others havenotshownanyassociation;furthermore,otherstudies havefoundevenworseNCperformanceinpatientswhowere onhigherCPEdrugregimens.31,41–43Possiblereasonsforsuch
discrepancy mightbeheterogonous cohortsregarding viro-logical status and NC performance, HCV co-infection, and intravenousdrug useamongexaminedpatients. Therefore, our cohort consisted only of neuroasymptomatic patients with HIV RNA<50copies/mL for at least three months. In order to reduce possible biases,44,45 we excluded HCV-HIV
co-infectedpatientsandintravenousdrugusers.Thus,a rel-atively homogenoussamplewas gatheredrepresenting the majority ofour HIV-infected patients. Further longitudinal studies areneededtoprovidemoredataaboutexact influ-encesofdifferentvariablesonbraindamageinthesepatients. Possibleneurotoxiceffectsofdrugswithbetter penetra-tionmentionedinseveralstudies38,39,43werenotidentifiedin
ourstudy.Efavirenzisthemostoftenemphasizeddrugforits potentialneurotoxicity.46However,inourstudythe
relation-shipbetweentheuseofefavirenzandbraindamagewasnot found.
ReporteddurationofHIVinfectionwassignificantly asso-ciated with brain atrophy. Results suggest that chronic
infectionoftheCNSpermanentlydamagesbraintissueand causes brain atrophy, which has been documented in the literature.4,30,34Hiddenbehindblood–brainbarrier,relatively
isolated environment increases the magnitude of damage. Thisfindingsuggeststhatpatientsshouldbealwaysaskedto provide,ifpossible,approximatedateofinfectionwithHIV,as thisinformationmightbeimportanttoestimatetheextent ofbrainatrophy.Theobvious problemofthisparameter is itssubjectivenature.Oftenitisnotpossibletoestablishthe approximatetimeofinfectionduetolargenumberof part-nersandrarityoftesting.AslifeexpectancyofHIV-infected patientscontinuouslyincreases,durationofHIVpositive sta-tusalsoincreases.Accordingtoourresults,higherCPE2010
mightdecreaseeffectsofHIVdurationintermsofbrain atro-phy.
Surprisingly,otherHIV-relatedparameters,nadirand cur-rentCD4+ T-cellcount,werenotassociatedwithVBrinour
study.AsfornadirCD4+T-cellcount,resultssuggestthatbrain
atrophyisaffectedmorebythedurationofimmune compro-misethanits“depth”.Afailuretoprovesignificantassociation betweenbrainatrophyand currentCD4+ T-cellcountcould
beexplainedbyindividualizedpatternoftheimmunological recoveryinpatientswithundetectableviralload.Therefore itseffectontheCNSisunpredictable.Inliterature,resultsin regardtoeffectsofnadirand currentCD4+ T-cellcounton
braindamageextent/NCimpairmentarecontroversial.1,6,29,47
DurationofHAARTwassignificantlyassociatedwithVBr inunivariateanalyses,similartodurationofHIV.Durationof HAARTanddurationofHIVarehighlycorrelatedwitheach other.Forthisreasonitwasnecessarytoselectoneofthese twovariablesformultivariateanalyses.AsdurationofHAART dependsonthedurationofHIV,wehaveincludeddurationof HIVinmultivariateanalyses.Asimilarreasoningwasusedin thestudybyKuperetal.8
Asitwasalreadymentioned,thisisthefirstneuroimaging study,toourknowledge,inwhichassociationbetweena neu-roimagingparameterandMEscoreisinvestigated.MEscore isbasedonthehypothesisthatsuppressionofHIVintheCNS actuallymeanseliminationofmonocyte/macrophage reser-voirs.OurresultsshowedthatMEisnegativelyassociated withbraindamage,suggestingthatdrugsthatareeffective ineliminatingmonocyte/macrophagereservoirs might pro-tectbraintissuefrominjury.Similar resultswere shownin thestudybyShikumaetal.,inwhichMEscorewasassociated withNCperformance.25
Effective ME drug regimens provide a completely new insightinpreventionandtreatmentoftheneurocognitive dis-orderscausedbyHIV.Eliminationofreservoirscanstarteven beforeactivatedmonocytescrosstheblood–brainbarrierand continuesasbrainmacrophagesenterinto theCNS.Inthat sense,theoreticallytheidealantiretroviraldrugwouldbeone thateffectivelydestroysmonocyte/macrophagereservoirs(in theperipheryandintheCNS)andpenetrates wellintothe CNS.So,combiningbothCPEandMEdrugscoresand integrat-ingbothqualitiesofadrugwouldbeastepforwardtoabetter understandingofpathologicaleffectsofHIVintheCNSand effectsofHAARTontocounteractingthem.For establishing suchascoringsystem,largercohortsandfurther investiga-tiononpharmacokineticsandpharmacologyofthedrugsare needed.
Inthatsense,HAARTregimenswithhighMEvaluescould bemoreeffectiveinclearinglatentreservoirsnotonlyinthe CNS,butalsothroughoutthewholebody,assystemicclearing viralreservoirswouldleadtoeradicationoftheHIV.48Toprove
this,longitudinalstudiesareneeded.
Themain limitation ofME scoreislack ofknown ME values fordarunavir, atazanavir, and mostimportantly for lpv/r, althoughit iswell knownthatthisdrugaccumulates inmonocytes.49Furtherinvitroanalysesareneededto
deter-mineacuteinfectionEC50valuesofthesedrugsandcalculate
theirMEvalues.
Conclusions
Althoughthesamplesizemightseemsmallandafollow-up wouldbealogicalnextstep,theexpensiveandsophisticated imagingmethodsusedinthisstudyarenotdoneroutinely. Previoussimilarneuroimagingstudiesweredoneona sim-ilar or evensmaller sample. Although the markerused in thisstudywasusedinotherstudiesonbrainatrophy,there arenowmoreaccuratetechniquestodefinebrainvolumes. Despite theselimitations,our resultssuggesta few impor-tantconclusions.Firstly,CPE2010isasuperiordrug-scoring
systemcomparedtoCPE2008.Secondly,MEisaneffective
drug-scoringsystem indeterminingbraindamage.Thirdly, bothCPE2010andMEscoresshouldbetakenintoaccount
inpreventingstrategiesofbrainatrophyandNCimpairment inHIV-infectedpatients.
Controversialresultsinliteratureconcerningdrug-scoring systemsunderscoretheneedforanewscoringsystem.Oneof thepossibilitiesistobuildamathematicalmodelcombining CPE2010andMEscores,inwhichbothimportantqualitiesof
adrug(penetrationintheCNSandeliminationofreservoirs) would bepresented.Thiswould requirelargerlongitudinal studies.TheuseofMEscoringsystemislimiteddueto miss-ingvaluesforsomecommonHIVdrugs,suchasdarunavir, atazanavir,andlpv/r.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
Wethankallthepatientsfortheirinvolvementinthestudy. Wealsothankthe nursing staffatthe HIV/AIDS Centerof InfectiousDiseasesClinicinNoviSadandattheDiagnostic ImagingCenterofOncologyInstituteinSremskaKamenica.
ThisstudywassupportedbytheProvincialSecretariatfor ScienceandTechnologicalDevelopment,Governmentofthe AutonomousProvinceofVojvodina,Serbia(project 114-451-2255/2011-01).
Appendix
A.
Supplementary
data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bjid.2015.07.002.
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