Behavioural adaptations of mosquito vectors to insecticide control

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Behavioural adaptations of mosquito vectors to

insecticide control

David Carrasco, Thierry Lefèvre, Nicolas Moiroux, Cédric Pennetier, Fabrice

Chandre, Anna Cohuet

To cite this version:

David Carrasco, Thierry Lefèvre, Nicolas Moiroux, Cédric Pennetier, Fabrice Chandre, et al..

Be-havioural adaptations of mosquito vectors to insecticide control. Current Opinion in Insect Science,

Elsevier, 2019, 34, pp.48-54. �10.1016/j.cois.2019.03.005�. �hal-02411126�

Behavioural

adaptations

of

mosquito

vectors

to

insecticide

control

David

Carrasco

,

Thierry

Lefe`vre

,

Nicolas

Moiroux

,

Ce´dric

Pennetier

,

Fabrice

Chandre

and

Anna

Cohuet

Behaviouralresistancetoinsecticidesmaybeanimportant factorrestrainingtheefficacyofvectorcontrolagainst mosquito-transmitteddiseases.However,ourunderstanding ofthemechanismsunderlyingsuchbehaviouralresistance remainssparse.Inthisreview,wefocusonthebehavioural adaptationsofmosquitovectorsinresponsetotheuseof insecticidesandprovideageneralframeworkforguidingfuture investigations.Wepresentourreviewofvectorbehaviourinthe fieldandaconceptualclassificationofbehaviouraladaptations toinsecticides.Weemphasisethatbehaviouraladaptations canresultfromconstitutiveorinduced(i.e.phenotypically plastic)traits.Lastly,weidentifygapsinknowledgelimitinga betterunderstandingofhowmosquitobehaviouraladaptations mayaffectthefightagainstvector-bornediseases.

Addresses 1

MIVEGEC,IRD,CNRS,UniversityofMontpellier,Montpellier,France 2_{InstitutdeRechercheenSciencesdelaSante´ (IRSS),Bobo-Dioulasso,} BurkinaFaso

3_{InstitutPierreRichet,Bouake´,Coted’Ivoire}

Correspondingauthor:Cohuet,Anna(anna.cohuet@ird.fr)

CurrentOpinioninInsectScience2019,34:48–54

ThisreviewcomesfromathemedissueonVectorsandmedicaland veterinaryentomology

EditedbyClaudioRLazzariandAnnaCohuet ForacompleteoverviewseetheIssueandtheEditorial Availableonline28thMarch2019

https://doi.org/10.1016/j.cois.2019.03.005

2214-5745/ã2019TheAuthors.PublishedbyElsevierInc.Thisisan openaccessarticleundertheCCBY-NC-NDlicense (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Introduction

Controlofmosquito-bornediseases mainlyreliesonthe useofinsecticide-basedtools.Theincreasedcoveragein theuseofinsecticide-treatednets(ITNs)insub-Saharan Africasincetheyear2000isanexampleofamassiveand efficient intervention against malaria [1]. Arboviruses outbreaks can also be controlled through insecticide use [2]. However, using such vector control methods reduces mosquito fitness, and in response, mosquitoes have evolved resistance mechanisms threatening the continuedefficacyof insecticide-basedstrategies. Understandingthemechanismsofinsecticideresistance iskeyto predictinghow resistancemayemerge, spread

andhindercontrolinterventions.Todate,several physi-ologicalresistancemechanismstoinsecticides,including biochemical(e.g.targetsitemodificationsandmetabolic resistance) and morphological (e.g. cuticular thickness) have been described, discoveries aiding the design of resistancemanagementstrategies[3,4].Behavioural resis-tanceisalsoemergingasanimportanttopicofresearch[5,6] duetoitspotentiallydetrimentaleffectontheefficacyof insecticidesin vectorcontrol[7–9,10]and theresulting increaseinresidualtransmissionitwouldinduce[5]. Inthisreview,wefocusonthebehaviouraladaptationsof mosquitoesin responseto insecticide-basedvector con-troltools.Wefirstproposeaframeworkfororganisingand investigatingsuchbehavioursandreviewthesupporting evidence. Secondly, we highlight that resistance beha-viours may be constitutive or phenotypically plastic inducible changes in behaviour, and identify clues for distinguishing between them. Finally, we discuss research perspectives to decipher among behavioural defencesin mosquitovectors.

Classification

of

behavioural

adaptations

to

insecticides

Thereisawiderangeofbehavioursthatmosquitoscould adopttopreventorreducethenegativeconsequencesof insecticides. We propose a conceptual classification of thesebehaviouraladaptations inspired bythe classifica-tionofinsectresponsestonaturalenemies[11](Box1). Thefirstlineofdefenceisqualitativebehaviouralresistance wherebymosquitoesavoid(eithertemporally,spatiallyor trophically)contactwithinsecticides.Inareaswith exten-sive use of ITNs or indoor residual spraying (IRS), selection may favour foraging earlier in the evening or laterinthemorning,timeswhenthehumanhostsarenot protectedbybednetsorindoortreatments[7].Increased outdoorhost-seekingand/orzoophagyarealsoconsistent withmosquitobehaviouraladaptationtotheuseofITNs andIRS.

Behavioural observations in the field following imple-mentationof ITNsand IRShave provided support for theexistenceofsuchbehaviouralmodifications[5]. Tem-poralavoidance in theform of abehavioural shift from night to evening aggressiveness has been observed in AnophelesfarautiontheSolomonIslands[12]andPapua NewGuinea[13],AnophelesfunestusinTanzania[14],and bothAn.funestusandAnophelesarabiensisinKenya[15].In

Benin,peakbitingtimeinAn.funestuswasdelayedtothe earlymorning[16].Examplesofspatial avoidancecome from Anopheles gambiae s.l. in Bioko Island [17] and An. funestusin Tanzania[14],whichdisplayedincreased out-door host-seeking followingimplementation of IRS and ITNsrespectively.Finally,trophicavoidancewithashift towards increased zoophilic behaviours was reported in Culexquinquefasciatus, An.funestus[18]andinAn.gambiae

s.s.inareasofhighbednetcoverageinKenya[18,19]andin AnophelesfluviatilisandAnophelesculicifaciesinIndiawhere IRShadbeenimplemented[20].

Asinsecticides becomemore widelyimplemented, it is likelythatmosquitoesmaynotbeabletoavoidcontact. Inthisscenario,ifmosquitoesarenotimmediatelykilled after insecticide exposure (e.g. sublethal doses or

BehaviouralresistancesinmosquitovectorsCarrascoetal. 49

Box1Expandingthefieldofmosquitoinsecticideresistance

Evolution of resistance / tolerance mechanisms Costs BEHAVIOURAL MORPHOLOGICAL

e.g. cuticular resistance

BIOCHEMICAL e.g. target-site, metabolic resistance Mosquito population Selection on mosquitoes Insecticides

Temporal avoidance:mosquitoes can reduce their risk of exposure by changing their activity to mismatch the timing of insecticide use. For example, in areas of extensive ITN coverage, early or late mosquito biters can be favoured over night mosquito biters.

Spatial avoidance: mosquitoes can reduce their risk of exposure

by avoiding habitats where insecticides are predictably found. For example, in areas of extensive indoor insecticide use, outdoor-feeding mosquitoes can be favoured over indoor-outdoor-feeding counteparts. Spatial avoidance could also occur through increased dispersion to untreated areas.

Trophic avoidance: mosquitoes can decerase the probability of

contact with the insecticide by avoiding feeding on hosts in close association with insecticide use. For example, in areas of extensive human protection (IRS, ITNs), more zoophagic mosquitoes can be favoured over anthropophagic counterparts.

Escaping: Once exposed, could mosquitoes limit their contact

time with the insecticide contacted by quickly escaping, and thus reduce the contacted dose?

Behavioural thermoregulation: Once exposed, could mosquitoes

limit or reduce insecticide activity by behaviourally changing their body temperature?

Curative self-medication: Once exposed, could mosquitoes

consume food or other compounds to reduce insecticide activity?

Fecundity compensation: Could mosquitoes increase their

current reproductive effort when insecticide exposure decreases their chances of future reproduction?

Tolerance thermoregulation: Once exposed, could mosquitoes

behaviourally change their body temperature to increase tolerance to the insecticide? (Tolerance, here and below, is defences that reduce fitness loss not by limiting insecticide activity, but by compensating for the fitness reductions).

Tolerance self-medication: Could mosquitoes use food or

compounds to increase tolerance to insecticide?

In mosquitoes with effective defences against insecticides, the costs of exposure are reduced and recognition of insecticide uses could even become exploited to the benefit of the mosquito if it is reliably associated with the presence of hosts (e.g. blood meal proxy). For example, indirect evidence suggest that some washed ITNs can become attractive compared to control untreated bednets.

T o lerance Behavioural exploitation Quantitative Resistance Qualitative Resistance

Insecticidesreducemosquitofitness,andinresponse,selectionhasfavouredgenotypeswitheffectivedefencemechanisms,includingboth resistanceandtolerancetoinsecticides.Muchworkhasfocusedonunderstandingphysiological(biochemicalandmorphological)defences,but mosquitoescanalsoexpressbehavioursthatprotectagainstinsecticides.These‘anti-insecticide’behaviourscanbecategorisedintothree possiblemechanisms:(1)qualitativeresistancewhichpreventsorlimitstheprobabilityofcontactwiththeinsecticide;(2)quantitativeresistance, whichstops,limitsorreducesinsecticideactiononcecontacthasoccurred;and(3)tolerance,whichdoesnotprevent_persetheinsecticide exposureorlimititsaction,butinsteadalleviatesfitnessreductionscausedbytheinsecticide.Afourthcategoryofadaptivebehaviouralresponse toinsecticideuse,coined‘behaviouralexploitation,’isproposed.Thisisnotadefencemechanism.Instead,behaviouralexploitationisenvisioned asasecondarybehaviouraladaptationfollowingtheevolutionofphysiological(i.e.biochemicalandmorphological)resistance(greydashedlines) wherebymosquitoesexploitrecognitionoftheinsecticidetotheirbenefit.Thisschematicrepresentationalsohighlightsthatthecostsofresistance mechanisms(definedasthenegativefitnesseffectofresistanceintheabsenceoftheinsecticide)shouldnotonlyfocusonbiochemicalresistance butshouldalsoincludeotherdefencemechanisms,suchasmorphologicalandbehaviouraldefences.Thecostsqualitativebehaviouralresistance, forinstance,remaincurrentlyunquantified.Finally,bluearrowsshowpossibleassociationsbetweenphenotypicdefences.Forexample,ifdefence iscostly,trade-offsbetweenphysiologicalandbehaviouraldefencesareexpected.Forexample,individualswithhighlyefficientbehavioural defencesmaynotneedphysiologicalresistance,andviceversa.‘’indicatestheexistenceoffieldstudiesprovidingsome,moreorless convincing,supporttothesehypotheses;whereas‘?’indicatesundescribedcases.

physiologically resistant genotypes), then they could theoretically evolve quantitative behavioural resistance (Box1).Asshownindiverseinsectspecies,behavioural quantitativeresistancemayincludeescapereactionsthat reduce contactduration withthe insecticide [21], resis-tance-promoting behavioural thermoregulation [22,23], and/or curative self-medication [24,25] (Box 1). Similar to biochemical metabolic resistance, which lowers the amount of insecticidereaching targetsites, these beha-viourscouldlimittheinsecticide’sdirectadverseeffects followingnon-lethalexposures.

If mosquitoes cannot avoid exposure (qualitative resis-tance)orreducethedirecteffectsoftheinsecticidewhen exposuredoesoccur(quantitativeresistance),thenthey could still limit their fitness loss through behavioural tolerance(Box1).Thiscouldoccurbyalteringbehaviours associated with offspring production that increase their currentreproductiveeffort,suchasi)maximisingnutrient intakequality(e.g.bloodfeedingchoice),ii)minimising energyexpenditure(e.g.feedingratesandrestingtimes), or iii) adjusting egg production and allocation patterns [26].Similartoquantitativebehaviouralresistance, toler-ancecouldalsooccurthroughbehavioural thermoregula-tion if mosquitoes rest at some specific temperatures [22,23]or byself-medicationifmosquitoesfeedon spe-cificdiets(e.g.nectars)[24,25]thatallowthemto main-tainhealthdespiteinsecticide exposure.

Whilewefullyconcedethatthetwopost-exposurelines of defence (i.e. quantitative behavioural resistance and tolerance to insecticides) have yet to be observed in mosquitoes,theyfullydeservetobeconsideredassome evidence has been found in other insect species [11,24,25].

Giventhe widespread occurrence of physiological resis-tancein mosquito populations,thestudy of behavioural defencesshouldnotbeconsideredindependently.Inthis context,afourthcategoryofbehaviouraladaptationcanbe introduced:behaviouralexploitation(Box1),whereby physi-ologicallyresistantmosquitoesmayusetherecognitionof insecticide-basedcontroltoolsasaproxyforhostpresence. Some experiments and field observations are consistent withsuchbehaviouralexploitationofITNsby physiologi-callyresistantmosquitos.Inalaboratorystudy, physiologi-callyresistantmosquitoeswerepreferentiallyattractedto hosts under permethrin-treated nets compared to those under untreated nets [27]. Additionally, a retrospective analysisofexperimentalhuttrialstudiesfoundevidence thattwoWHO-recommendedITNsareattractivetowild An.gambiaes.l.aftermultiplewashings[28].Similarly,a review on the efficacy of ITNs reported 55 deterrence values(definedasthereductionofentryintoexperimental hutsinthepresenceofanITNrelativetocontrolhutswith untreated nets) from 17 articles. Thirteen (24%) of the deterrence values (from seven articles) were negative,

suggestingthepossibilityofattractiveness[29].Negative deterrencevalues havebeenreported morerecently [30,31] suggestingthatbehaviouralexploitationmaybeassociated withdifferenttypesofITNs.

Constitutive

versus

inducible

behavioural

resistance

traits

to

insecticide

Providedthereissufficientgeneticvariationinconstitutive behavioural resistance traits and/or inducible behavioural resistance traits, they can adaptively evolve in response to selection pressures imposed by insecticide tool use. Constitutiveresistancetraitsoccurwhengeneticvariants spreadthroughthepopulationovergenerations,whereas inducedresistancetraits(akaplastictraits)occurwithina generation. Phenotypic plasticity, theability of agiven genotypetoproducedifferentphenotypesinresponseto different environmental conditions, can indeed allow organismsto quicklyrespond to environmentalchanges by producing better matching phenotypes. Theoretical andexperimentalstudiessuggestthatwhen environmen-talconditionsarevariable(e.g.theriskofcontactingthe insecticideisunpredictableorvariable,perhapsbecause of heterogeneous ITNcoverage, etc.),the evolution of phenotypic plasticity (here inducible behavioural resis-tance)is expected;whereas in constantconditions (e.g. high overall risk of contact with an insecticide, wide-spreadITNcoverage,etc.),constitutivetraits(here con-stitutivebehaviouralresistance)willbefavoured[32,33]. Nonetheless, constitutive and induced resistance traits arenotmutuallyexclusive;they canco-existin agiven population.Inotherwords,attheindividuallevel,some behaviouralresistancetraitscanbefixed(e.g.earlybiting) whileothersplastic(e.g.zoophagy);andatthepopulation level, some individuals may display constitutive resis-tancetraitswhileothersdisplayplasticresistancetraits. Thepotentialbehaviouralresponsespresentedabovefor qualitativeandquantitativeresistance,behavioural toler-anceand exploitation canresultfromthe expression of eitherconstitutiveorinducedbehaviouraltraits.In Fig-ure1weillustratetheconstitutiveversusinducednature ofthesebehaviouraltraitsinthepresenceof insecticide-basedvectorcontrolmeasuresimplementedinthefield (Figure1).Mostofthebehaviouralresistancephenotypes thus far observed in the field fall into the category of qualitative behavioural resistance (shiftsin biting time/ site, shiftsof bitten hosts), althoughsome observations areconsistentwithpotentialbehaviouralexploitationof insecticides (cases of negative deterrence of ITNs). Whilesomestudiesaredirectlyorindirectlyinformative aboutthepotentialconstitutiveorinduciblenatureofthe resistance traits (see below), in many cases it remains difficultto distinguish theoriginof theobserved beha-viouralphenotypes.

Behaviouralshiftsobservedinthefieldcanbegroupedin relationtoi)changesinspatiotemporalbitingbehaviour,

ii)changesinhostpreference,andiii)thesensory detec-tionof thecontroltoolsimplemented.

Thefirstgroup(i)referstochangesinbitingrhythmsand thedegreeofexophagyorendophagy.These spatiotem-poral shifts in biting behaviour are generally observed togetherbecauseoftheconfoundingeffectthathumans are usually outdoorsin evenings and morningswhereas theyareindoors atnight,makingdifficulttodistinguish theunderlyingcauseof thebehaviouralshift.Circadian

activityinmosquitovectorsisknowntobeundergenetic regulation[34–36]witholfactoryfunctions,essentialfor host seeking, being adjusted by daily rhythms [37,38]. Thesefactsprovideaplausiblescenarioforthepossible selection of constitutive behavioural resistance traits relatedtobiting-time.However,specificvariants associ-ated withbiting timehavenotyetbeenidentified [39], and a potential biting time shift resulting from beha-vioural plasticity (induced resistance) cannot be excluded.The geneticdeterminantspossibly regulating

BehaviouralresistancesinmosquitovectorsCarrascoetal. 51

Figure1

Current Opinion in Insect Science

Genotypic variability

within a population Genotype Phenotype

No resistance

Physiological resistance

Constitutive behavioural resistance Induced behavioural resistance

(2) (5) (4a) (4b) (4c) (3a) (3b) (3c) (1)

Schematicrepresentationoftheobservedmosquitophenotypicresponsesagainstinsecticidesinthefield.

Givenageneticallyvariablemosquitopopulation,host-seekingindividualsmayexpressdifferentphenotypeswhenfacinginsecticides(redhalo) dependingontheirgeneticbackgroundandtheirbehaviouralplasticity.(1)Mosquitoessensitivetotheinsecticidewillbekilledafterexposure/ contact.(2)Physiologicallyresistantmosquitoeswillencounterinsecticides,buttheirbehaviourwillberelativelyunaffected,beingeventuallyable tobloodfeed(reddrop).(3)Constitutivebehaviouralresistancemechanismswillfavourindividualswithgeneticallydeterminedbehavioursthat reduceoreliminatecontactwithcontroltools.Forinstance,ashiftinbitingtime(3a;clock),exophagy(3b;sun/cloud)orpreferentialzoophagy(3c; cow).(4)Individualswithinducedbehaviouralresistancemechanismsmustfirstrecognize(!!)controltools,triggeringadeterrencereaction,which isfollowedbyadaptivebehaviouralmodification,forexamplebymodulationofbitingtime(4a;clock),increasedexophagy(4b;sun/cloud)or increasedzoophagy(4c;cow).Whenmosquitospossessphysiologicalresistancetotheinsecticide,recognitioncouldtriggeranattractiveeffect, (5)ifmosquitoslearn(hat)thepresenceoftheinsecticidetoolisareliableindicatorofhostpresence.

shiftsfromendophagytoexophagyareevenless under-stoodandasisthepotentialroleofphenotypicplasticity inspatialbehaviourin mosquitoes[40].

Thesecondgroupofresponsesexpectedtobefavoured byinsecticides(ii)referstotheshiftsinhostpreference. Mosquito species are often described as being either generalistsorspecialistsdependingonthefidelityoftheir hostpreference[41].Thepreferenceofmosquitosforone particularhost over another mayberegulatedby genes involved in the chemosensory detection of hosts [40,42,43]. Thus, between-species differences in host preferencearegeneticallybased.However,thepresence ofwithin-populationgeneticvariationisrequiredforthe evolutionofpotentialhostshiftsfollowingthe implemen-tationofinsecticidesascontrolmeasures.Itisreasonable toexpectthathighlyspecialisedanthropophilic individ-ualswillbemoreexposedtoinsecticidesthanindividuals searching for animals outdoors. Genetic selection of anthropophilic preference [44] and identification of geneticvariantsforhostpreferences[45]providesupport fortheideathatselectioninthecontextofvectorcontrol throughinsecticidescouldcausetheevolutionofa beha-viouralshiftforpreferenceofalternativehostsinnatural mosquitopopulations(i.e.constitutivebehavioural resis-tance). In contrast, there are also studies showing host preferencemodulationduetochangesinenvironmental conditions (e.g. host availability) [46] and past experi-ences[47].Theformationofmemoryasaconsequenceof pastexperiencesmaycreateamoredurable shiftinthe individual as long as the behaviour is reinforced [48]. Indeed, it hasbeenshown that mosquitoes canmodify theirbehaviouralresponsestovisualandolfactorystimuli thankstobothappetitiveandaversiveassociative learn-ing[49–51,52,53].Ifso,associative learning, aformof phenotypic plasticity, could play an important role in restructuringhostchoicepreferencesinresponseto insec-ticideexposure.

Lastly(iii),theexistenceinthepopulationofvariationin theabilityofindividualsto detectandperceive insecti-cides asnoxious will determinetheirlevelof exposure. Thus,theadaptiveevolutionofneurophysiological abili-tiestodetectinsecticides,eitheruponcontactorfroma certaindistance,wouldsignificantlyreducetheimpactof insecticides through qualitative or quantitative beha-vioural resistance or even behavioural exploitation, and provideameansfortheexpressionofbothconstitutive(e. g. escaping) and induced behavioural responses (e.g. alternative host choice, etc.) (Box 1, Figure 1). It has been suggested that the olfactory system is capable of detectingsome of themost commonlyused pyrethroid insecticides used on ITNs from a distance [54–56] althoughthisassertionremains controversialbecauseof thenon-volatilityofthemoleculesandthedivergenceof results depending on the experimental design [57]. If mosquitosaretrulycapableofsmellinginsecticides,itis

possible that physiologically resistant individuals may becomeattractedto insecticideseither throughlearning [53]or throughgeneticchanges of insecticideshedonic sensoryvalence[58]becauseoftheassociationwithhost presence. In contrast, detection of insecticides upon contactiscommonlyobservedthroughmeasuresof irri-tancy[59]. Mosquitoesable to escape a treatedsurface beforeacquiringalethaldoseareexpectedtobefavoured over counterparts expressing a slower escape reaction. While there are to date no field observations of such quantitativeresistance, experimentalevolutionofquick escapers[21]suggestsitspotentialexistance.

Conclusions

and

perspectives

Thisreviewupdatesourcurrentunderstandingof beha-viouralresistancetoinsecticidesinmosquitovectors.The mechanismsunderlying theobservedbehavioural shifts and the extent of their costs remain poorly known. Because behavioural resistance in mosquito vectors mayhaveimportantandpotentiallysevere epidemiologi-cal consequences, it is worth shedding light on these phenotypes and initiating studies deciphering their underlying mechanisms and quantifying their fitness benefitsandcosts.Theproposedtheoreticalclassification ofbehaviouraladaptations offersaframeworkfor inves-tigations. For instance, we list several possible beha-vioural adaptations that maybe expressed in mosquito populations in response to insecticide pressure. While some of these behavioural resistance traits may appear speculative (e.g. quantitative resistance and tolerance), exampleshavebeendescribedinotherbiologicalsystems andhencemayrepresentpromisingfutureresearch ave-nues. Moreover, behavioural exploitation could have a potentially dramatic impact on the efficacy of vector control if mosquitoes become able to use insecticides asaproxyfor bloodmealsource,resultinginthecontrol intervention having the unintended consequence of heighteningcontactwithvectors.

Behaviouraladaptations mayresultfromconstitutive or inducible traits and their selection will depend on the constancy and intensity of insecticide use in a given mosquito population. In order to identify the genetic determinantsof thesetraits,genomic analysissearching for signatures of selection in the genomes of mosquito vectorsandtheirsiblingspeciessequencedinthelastfew years[60]maybecomevaluable.Regardingtheinterest of entomologist/epidemiologist community in beha-viouralresistance,weareoptimisticthatfutureresearch will rapidly provide meaningful insight on the beha-viouraladaptationsof mosquitoestovectorcontroltools andthattheseinsightswillhelptoadaptcontrolstrategies inthefightagainstvector-bornediseases.Finally, physi-ologicalandbehaviouralresistancemaylikelycoexistin naturalmosquitopopulationsanditwillbeimportant to study the possible trade-offs and associations between thesedifferentprotectivestrategies.

Funding

This work was supported by The French National Research Program for Environmental and Occupational Health of Anses (EST-2016/1/39), by the Languedoc-Roussillon(LR)/OccitanieregionandEU-FEDERunder the name‘Chercheur(se)s d’Avenir’, bytheANR grant ‘STORM’ 16-CE35, and by Initiative 5%—Expertise France (N 15SANIN213). The funders had norole in study design, data collection and analysis, decision to publish,or preparationof themanuscript.

Conflict

of

interest

statement

Nothing declared.

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