Original
Article
Is
there
a
treatment
protocol
in
which
platelet-rich
plasma
is
effective?
Ibrahim
Yilmaz
a,*
,
Semih
Akkaya
b,
Mehmet
Isyar
c,
Ahmet
Gu¨ray
Batmaz
d,
Olcay
Guler
d,
Kadir
Oznam
d,
Akin
Ugras
d,
Mahir
Mahirog˘ullari
ea
RepublicofTurkeyMinistryofHealth,StateHospital,DepartmentofPharmacovigilance,MateriovigilanceandRationalUseofDrugs,59100Tekirdag, Turkey
b
PamukkaleUniversitySchoolofMedicine,DepartmentofOrthopaedicandTraumatology,20070Denizli,Turkey
cCentralHospitalHealthGroup,DepartmentofOrthopaedicandTraumatology,34742Istanbul,Turkey
dIstanbulMedipolUniversitySchoolofMedicine,DepartmentofOrthopaedicandTraumatology,34214Istanbul,Turkey eMemorialHealthGroup,DepartmentofOrthopaedicandTraumatology,34384Istanbul,Turkey
1. Introduction
Health-relatedqualityoflifeisdecreasingyearbyyearinthe worldduetomuscleandmusculoskeletalinjuries.1Astherehave
not been promising results in the present studies regarding treatmentoftheseinjuries,clinicalandsocialproblemscomeup. Scientiststurntowardsrepairofdamagedtissuesusingbiological methodsintheirstudies.2
Asthenumberofstudiesregardingthegrowthfactorsinwound healing and their interaction increases, it paves the way for personal and cell-based biological treatments, which can be appliedasself-executingandcombined.Whiletreatingdamaged tissues, treatments that can provide rapid tissue repair and functionalhealing,andtreatmentmodalitiesthatare biological-orientedaretargeted.Inthisrespect,PRPconstitutesanimportant step.3
PRPhasgainedpopularity,whichallowsnon-pharmaceuticand biologicrepair-orientedrecoveryprocessbyreleasinglocalgrowth factorsintheenvironment.Besides,ithasfunctionsofhomeostasis and coagulation. It involves PLT, which abundantly contains cytokineandgrowthfactorsthatareimportantintissuerepairand bone mineralization.4 Furthermore, it contains lots of growth factors–inproteinandpeptidestructure–whichplaykeyrolesin synthesisoftissuematrix.5
As a result, in literature, PRP is reported toaffect not only resorption of necrotic tissues but also macrophages which acceleratetissuehealing,mesenchymalstemcellsandosteoblasts. Itisalsoreportedtocausereleaseofbioactiveproteins.6Forthis
very reason, it is applied in all fields of medicine including orthopaedicsurgeryintissuedamagetreatments.7,8
PRP’susehasbeenincreasinginmanycasessuchasprimarily osteoarthritis,9 proximal hamstring,10Achilles,11 patellar
tendi-nopathies,12 talar osteochondral lesions,13 rotator cuff damage
repair,14lateralepicondylitistreatment,15relievingpains
follow-ing arthroplasty8 and contributing to bone healing of tibia in distractionosteogenesis.8
However,astherearecontradictoryresultsreportedinsome cases in literature where PRP was applied, there are some questions regarding the efficiencyof PRP treatment.16–18 Some
ARTICLE INFO
Articlehistory: Received15June2016 Accepted27June2016 Availableonline2July2016
Keywords:
Painfollowingarthroplasty Tendinopathy
Epicondylitis Platelet-richplasma Proximalhamstring Rotatorcuffdamage
ABSTRACT
Aim:Weaimedtorevealwhetherthereareprospectivesuggestionsforeffectiveandstandard platelet-richplasmaapplications.
Methods:Wesearchedforclinicaltrialsandtracedallthereferencesofincorporateddocuments. Results:Inliterature,therewasnostudyindicatingwhichdiseaseistreatedbywhichmechanismof action,howmuchdoseandcontentarepreparedandapplied,whenthetreatmentisappliedandhow manycuresareapplied.
Conclusion:GuidesintroducingwhichconcentrationsofPRPareusedforwhichdiseasesare tobe prepared immediately by a committee which is comprised of primarily orthopedists, clinical pharmacologistsandtoxicologists.
ß2016Prof.PKSurendranMemorialEducationFoundation.PublishedbyElsevier,adivisionofReed ElsevierIndia,Pvt.Ltd.Allrightsreserved.
* Correspondingauthor.Tel.:+905327012858;fax:+902822625355. E-mailaddresses:ibrahimyilmaz77@yahoo.com(I.Yilmaz),
semihakkaya@yahoo.com(S.Akkaya),misyar2003@yahoo.com(M.Isyar),
guraybatmaz@hotmail.com(A.G. Batmaz), olcayguler77@gmail.com (O. Guler),
drkadiroznam@hotmail.com(K.Oznam),akinugras@gmail.com(A.Ugras),
mahirogullari@yahoo.com(M.Mahirog˘ullari).
ContentslistsavailableatScienceDirect
Journal
of
Orthopaedics
j ou rna l hom e pa ge : w w w. e l s e v i e r. co m/ l o ca t e / j or
http://dx.doi.org/10.1016/j.jor.2016.06.027
manuscripts indicated that PRPs with different contents are superiorinclinicaltreatment.19Therewasnowell-provenstudy inwhichPLTandleucocyte(WBC)rateswereseparatelydiscussed in PLT concentrations in PRP content. There was not enough evidenceregardinghowmuchWBSisresponsiblefromcurativeor negativeeffectinclinics.20,21
Recently,theuseofPRPhasgainedpopularityandhasbecomea treatmentoptionallby itself.22Therearesomequestionstobe
answeredsuchastowhom,when,howandbywhichmechanismit istobeapplied.Itisimportantthatastandardizationbeprocessed in consequence of basic and clinical studies as using different commercialkitsmightresultindifferentresults,whichleadssome issuesconcerningtheevaluationofclinicstudies.
Thepurposeofthepresentstudyistodeterminethedifferent applicationsofPRPinclinicsafterreviewingtheliteratureandset forthwhethertherearesuggestionsforefficientandstandardPRP application.
2. Materialsandmethods 2.1. Searchstrategy
ThedatabasesoftheUSNationalLibraryofMedicineNational InstitutesofHealth,Embase,OVIDandtheCochraneLibrary,as wellasthereferenceswithintheretrievedarticlesweresearched tofindallrelevantorthopaedicinjuryandPRPclinicaltrialstudies from1954toJune4,2016,withoutanylanguagerestrictions.The following keywords were used in the search: ‘‘platelet-rich plasma’’,‘‘PRP’’, ‘‘OA’’, ‘‘proximal hamstring’’, ‘‘achilles tendino-pathy’’, ‘‘patellar tendinopathy’’, ‘‘talar osteochondral lesions’’, ‘‘rotatorcuff’’,‘‘lateralepicondylitis’’and/orPRP.
Thepercentage distributionofarticlesbyyearwasrecorded, and the evidence level was determined according to Lijmer etal.23,24Bibliographiesthoughttobemissedduringthedatabase
research were examined again. Unpublished grey literature, includingarticles,comments,letters,editorials,protocols,guides, meta-analysesandcollectionswerenotincluded.Themosthighly
cited articles weredefined and re-examined in order to avoid doubleentries.
2.2. Eligibilitycriteria
Double-blindplacebo-controlledrandomizedclinicaltrialsor researchesoflevelIwereincludedtoourstudy.Allstudiesnot containing the above information were excluded. The study inclusionprocessissummarizedinFig.1.
2.3. Datacollectionandevaluation
Theauthorsselectedtheincludedstudiesindependentlyand,in ordertominimizeselectionbias,thestudieswererevisedbyall authors.Intheeventofconflictingresults,thefinaldecisionwas taken by authors, who have greater experience regarding PRP preparationsdesign.Finally,theseniorauthorswereconsultedand thetopicswererevised,ifnecessary.
2.4. Statisticalanalysis
Itwasfoundthattheobtaineddataarenotbaseduponthefact that theywere collectedfrom thesources that had probability distributionfunction.Therefore,non-pragmaticstatistical meth-odswereused.Nonetheless,giventhelackofcommonfindings, statistical analysescouldnotbeperformed andcomplementary statistical methodswereappliedinstead.MicrosoftOffice Excel (2010)wasusedandtheresultswereshownasmeanstandard deviationorfrequency(%).
3. Results
A total of 13,248 studies were found to have potential for inclusion.Thenumberofarticlespublishedperyearisshownin
Fig.2.Followingrevisionofthefulltext,10articleswerefinally included (Table 1), all ofwhich werecomparative, randomized controlledclinicaltrials.8–14,25–27
Priortotheapplication,doseresponsecurvesofWBC/PLTin PRPweremade.Whentheliteratureisreviewed,nostudyhas been found purporting the effective dose to be used in treatments. Besides, we observed whether PRP content was testedbypharmaco-molecularanalyses.Inliterature,therewas no study indicating which disease is treated by which mechanismofaction,howmuchdoseandcontentareprepared andapplied,whenthetreatmentisappliedandhowmanycures areapplied.
4. Discussion
Uponreviewingtheliterature,wecouldnotfindastandardized production monograph as different companies use different commercial kits.In addition,there was no precise information regardingin whichcircumstances PRPwasobtained and maxi-mum or minimum revolutions per minute/centrifugal force/ capacity of the centrifuges which were used. Consensus that wasreachedinthesestudiesonobtainingPRPwasthenumber, speedandtimeofcentrifuge.Lastbutnottheleast,anotherthing thatwasagreedwasthethicknessofneedletobeusedduring bloodintakefromdonorsandafterobtainingPRP.Thereasonfor thiswasasdiameterofneedlesdecreases,growthfactorsinPLT mightaffectthereleasetime.ItwasreportedthatPLTmightleadto prematureactivation,so21-gaugeinjectornozzlesshouldbeused duringautologousbloodintakeandPRPapplication.28,29
Apart from thesethere was no well-proven study in which activationofPRPwasmentionedandwhetheritwasactivatedor not.There weresomepreclinical30andclinical31,32 studies,but
therewasnoconsensusonaprotocol.
Inliterature,itwasreportedthatearlyimmatureactivationand growthfactorsreleaseduringthepreparationofPRPposeother problems.Itwasemphasizedthatwhenadoublespincentrifuge methodwasused,PLT concentration rate was10% ofthe total bloodtakenfromcases.However,morebloodintakewasneeded whenasinglespincentrifugemethodwasused.33Furthermore,it was found that PRPs obtained from autologous plasma were directly used without considering their content, from which diseaseandatwhatdosetheywereobtained.7–22,34
However,asitisknown,growthfactorsinPRParevarious.34It is also known that transforming growthfactor beta-1 induces chondrogenic activity2 and fibroblastic growth factor; bone
morphogeneticprotein-2,-4,-6inducesosteoblasticstimulation and osteogenesis,2,35 bone morphogenetic protein-12 induces
tenogenicactivity.36Nonetheless,withoutknowingthe
concen-trationofgrowthfactorsinPRPcontentandcompound,theyare applied. Although bone morphogenetic proteins are highly concentrated,theycanbeappliedincartilagedamages.Similarly, thoughtransformergrowthfactorinPRPhashighincidence,itcan beusedinbonehealing.
Recent well-proved studies have reported that half-life of growthfactorsismaximum 2min.37–40Itwasemphasizedthat
whengrowthfactors–withproteinandpeptidestructure–inPRP obtainedfromhumanwereappliedafterthatperiod,bioactivity decreasedandevenvanished.37–40
WhenthestudiesinwhichPRPwasobtainedfromautologous bloodinclinicswereconsidered,itwasfoundthatitwasprepared from10to20min.7–21Nevertheless,it takestime toapplyitto
cases,whichmakesitsbioactiveandeffectivetreatmentresults controversy.
Ina study,treatmentsofPRPandhyaluronicacid(HA)were comparedin caseswithcartilagedefectand osteochondropathy (n=109)withthepurposeofevaluatingtheeffectivenessofPRP, which contains highincidence ofgrowthfactor. 55 cases were applied HA whereas 54 were applied PRP and followed for 12 months. Clinical evaluations were made by means of International Knee Documentation Committee (IKDC), EuroQol (EQ)–VisualAnalogueScale(VAS),TegnerLysholmKneeScoring Scale(TLKS),andKnee injuryand OsteoarthritisOutcomeScore (KOOS), circumference measurement of knee and goniometric measurementofthekneerange.Asaresult,itwasobservedthat cases inboth groups had recovery, but cases withPRPapplied early-stagedefectshadbetterrecovery.Ontheotherhand,itwas emphasizedthattherecoveryinmidlifeearly-stageosteoarthritis was not superior to the HA applied cases contrary to the literature.25
Dragoo et al. injected PRP to cases (n=23) with patellar tendinopathy by means of ultrasonography. Whereas 10 cases
wereinjectedPRP,13caseswereapplieddryneedling.During3rd, 6th,9thand12thweeks,theycarriedoutclinicalevaluationusing VictorianInstituteofSportsAssessment(VISA)scoring.Inaddition, during12thand26thweeks,theyobtainedsecondarydatausing VAS,TLKSandShortForm(SF-12)questionnaire.After12weeks, theyreportedthattheyobservedanincreaseby5.2indryneedling applicationinVISAscoring.Nevertheless,theyreportedthatthe increasewasby25.4inPRPappliedgroup.Following26thweek, theyobserved that the increase in dry needlinggroup wasby 33.2whereasitwasby28.9inPRPgroup.Ontheotherhand,they emphasizedthatalthoughtherewasnotanincreaseinPRPgroup
inthe12thweek,therewasnotasignificantdifferencebetween thegroupsinthe26thweek.12
DohanEhrenfestetal.,intheirmanuscript,informedthatPLT concentrations–throughtopicalandinfiltratingroutes–gained popularityprimarilyinsportsmedicineandorthopaedicsurgery. Nonetheless,althoughtheypresentedtreatmentperspective,they reported that the studies in literature were confusing. They classifiedPRPproductsinto4maingroupsinordertobenefitfrom them in advanced stage researches; pure platelet-rich plasma (P-PRP), such as the PRGF-Endoret technique; leukocyte- and platelet-rich plasma (LPRP), such as Biomet GPS system; pure
Table1
Characteristicsoftheincludedstudies.
AreWBC/PLTvalues inPRPcontentformed followingdose responsecurve? IsPRPcontent testedata molecularlevel?
Arethereany explanations aboutwhich diseasesare treatedbywhich mechanismofaction?
Arethereany explanationsabout whatdosageis preparedinwhat content,whenand howmanycures areused? FilardoGetal.25
(2012) Platelet-richplasmavs hyaluronicacidtotreatknee degenerativepathology:study designandpreliminaryresultsof arandomizedcontrolledtrial.
– – – –
DragooJLetal.12
(2014) Platelet-richplasmaasa treatmentforpatellar tendinopathy:adouble-blind, randomizedcontrolledtrial.
– – – –
MalavoltaEAetal.14
(2014) Platelet-richplasmainrotator cuffrepair:aprospective randomizedstudy.
– – – –
FilardoGetal.11
(2014) Platelet-richplasmainjections forthetreatmentofrefractory Achillestendinopathy:resultsat 4years.
– – – –
DuifCetal.8
(2015) Doesintraoperativeapplication ofleukocyte-poorplatelet-rich plasmaduringarthroscopyfor kneedegenerationaffect postoperativepain,functionand qualityoflife?A12-month randomizedcontrolled double-blindtrial.
– – – –
GobbiAetal.9
(2015) Theeffectsofrepeated intra-articularPRPinjectionson clinicaloutcomesofearly osteoarthritisoftheknee.
– – – –
DavenportKLetal.10(2015) Ultrasound-guided
intratendinousinjectionswith platelet-richplasmaor autologouswholebloodfor treatmentofproximalhamstring tendinopathy:adouble-blind randomizedcontrolledtrial.
– – – –
FilardoGetal.26(2015) Platelet-richplasma
intra-articularkneeinjections shownosuperiorityvs viscosupplementation:a randomizedcontrolledtrial.
– – – –
Go¨rmeliGetal.13
(2015) Clinicaleffectsofplatelet-rich plasmaandhyaluronicacidasan additionaltherapyfortalar osteochondrallesionstreated withmicrofracturesurgery:a prospectiverandomizedclinical trial
– – – –
MontalvanBetal.27
(2016) Inefficacyofultrasound-guided localinjectionsofautologous conditionedplasmafor recentepicondylitis:resultsofa double-blindplacebo-controlled randomizedclinicaltrialwith one-yearfollow-up.
platelet-rich fibrin (P-PRF), such as Fibrinet; leukocyte- and platelet-richfibrin(L-PRF),suchasIntra-SpinL-PRF.They under-lined the fact that this classification should be improved and reported that there are discussions on cell content, storage conditionsand/oractivation.20
Malavoltaetal.studiedeffectivenessofPRPinjectionsusedin rotatorcuffrepair.Theyincluded54casesanddividedtheminto twogroups.Completesupraspinatustearswithretractionofless than3cmweresubjectedtoarthroscopicsingle-rowrepair;atthe endofthesurgicalprocedure,liquid PRPpreparedbyapheresis was given to the patients in the PRP group with autologous thrombin.In clinicalevaluations,University ofCalifornia atLos Angeles(UCLA)andConstantscales,VASandmagneticresonance imagingwereusedduringthe3rd,6th,12thand24thmonthsafter thesurgery.Theyindicatedthatwhentheycomparedthecasesin twogroupsintermsof24-monthfollow-up,UCLAscoreincreased from13.63 in the PRPgroup while it increased from 13.93 to 32.44.Inaddition,theystatedthatConstantscoreincreasedfrom 47.37to 85.12in the control groupwhereas it increasedfrom 46.96to84.78.AsforVASscore,itdecreasedfrom7to1.15inthe controlgroupwhereasitdecreasedfrom6.67to0.96.Theyalso reportedthat1casehadrecurrentcompletetearand4caseshad partialtearinthecontrolgroup,whereas2caseshadpartialtearin thePRPgroup.14
In anotherstudy,PRPapplicationresults, whichincludehigh leucocytewereresearchedincaseswithchronicachilles tendino-pathy(n=27),which resultedfromdecreasing physical perfor-mance.Inthisstudy,caseswereappliedPRP3timeseveryother 2weeksconsequently.Blazina,VISA,EQ-VASandTLKSwereused toevaluatecasesbefore andduringthe2nd,6thand54-month follow-up. As a result, they concluded that the results of PRP injection were promising and stabilized when they had been evaluatedinthemidphase.11
Duifetal.usedleukocyte-poorplatelet-richplasma(LP-PRP)to evaluateeffectsthatoccurredduringthearthroscopictreatmentof knee lesions, which have detrimental effects concerning pain, functionandqualityoflife.Tothisend,theyappliedrandomized anddoubleblindstudyincaseswithkneearthroscopy(n=58).The controlgroupwascomprisedof34caseswhereastheworkgroup wascomprisedof24cases.TheyinjectedLP-PRPintra-articularto casesinworkgroupduringarthroscopyprocess. Thefunction of kneewasevaluatedduringthefirstapplication,6thand12thweeks intermsofqualityoflife.Attheendof12thmonth,theyreported that91%ofthecasesinthegroupwhereLP-PRPwasappliedduring the6thmonthhadlesspain,yettherewasnosignificantdifference acrossthegroupsatendofthe12thmonthintermsofqualityoflife. Theyconcludedthat during6–12monthspost-op period, intra-operativeLP-PRPappliedgroupwassuperiortoothergroupsasfar aspainreliefandfunctionalityofkneewasconcerned.8
Gobbi et al. investigated tofind out whether intra-articular appliedPRPatcyclicdosetocaseswithearlystageosteoarthritis would affect treatment results, so they followed 113 knees of 93casesforapproximately2years.TheyappliedPRPattheendof thefirstyear.Thecasesbeforetheinjectionandduringthe12th, 18thand24thmonthsaftertheinjectionwereassessedbyKOOS, VAS,TegnerandMarxactivityscalessystems.Theyinformedthat allscoredshowthattherewasasignificantimprovementwhen compared to the pre-treatment. On the other hand, they emphasizedthatinthegroupwherePRPwasappliedduringthe 18th month as the second cycle, there was a significant improvementin otherparameters exceptfor KOOS and Tegner scores.Theyconcludedthataregressionoccurredattheendofthe 2ndyear;still,itwasnotstatisticallysignificant.9
Go¨rmelietal.comparedHAandPRPapplicantsin osteochon-dralankleinjuries,whichaffecttalusdomeandleadtoathletic disability, so they included arthroscopic micro-fracture cases
(n=40)intheirstudy.TheyinjectedPRPto13cases,HAto14cases and the rest of the cases were injected saline. All cases were evaluated by American Orthopedics Foot and Ankle Society (AOFAS) functional scale and VAS scores before and after 15.3months(in average)theapplication. Theyunderlinedthat allcasesshowedanincreaseinAOFASscores,andadecreaseinVAS scores.Theyalsomaintained thatAOFASscorewassignificantly higherinPRPthansalineandHAgroups.TheystatedthatAOFAS scorewashigherinHAgroupthansalinegroup.AsforVASscoring, theymaintainedthattherewasasignificantdecreaseinPRPgroup thansalineandHAgroups.TheyconcludedthatPRPshouldbeused primarilyin talar osteochondral damages as theresultsof PRP groupwasbetter.13
Davenportetal.comparedPRPandtotalbloodapplicationsin caseswithchronichamstringtendinopathy.Beforetheapplication and during the 2nd, 6th, 12th week and the 6th month, they measuredpainandfunctionoutcomesviatheModifiedHarrisHip Score(MHHS), HipOutcome Scores foractivitiesof dailyliving (ADL)andsport-specificfunction,andInternationalHipOutcome Tool33(IHOT-33)scoring.Theyreportedthatbefore12thweek, totalbloodresultswerebetterthanPRPapplicationswherePRP applicationresultswerebetterattheend ofthe6thweek. The casesinPRPgroupshowedsignificantincreaseinADLandIHOT-33 scoringduring6thmonthwhencomparedtopre-injection,yetit wasnotthecaseintotalbloodapplications.10
In another manuscript, PRP and HA injected groups were comparedin caseswith osteoarthritis (n=192). Thecaseswere injected PRP and HA for the purpose of delay of surgery.They includedcaseswhohadunilateralkneepainforatleastfourmonths andwith Kellgren-Lawrencescoreof 0–3at radiographsor MRI evidenceofdegenerativechondropathy.ThecaseswereappliedPRP andHAinjectionseveryotherweekand3timesintotal.Theyused IKDCsubjectivescore,KOOS,EQ-VASandTLKSwhileevaluatingthe cases.FollowingPRPapplication,theyreportedthatswellingand painoccurredintheinjectionarea.TheyreportedthatIKDCscore increasedfrom52to66inPRPgroupwhereasitincreasedfrom 49to64inHAgroup.TheyemphasizedthatPRPandHAgroupsdid notgainanadvantageovereachother.26
Montalvanetal.studiedintratendinouseffectofPRPincases whohadepicondylitisforlessthan3months.Theyincludedcases who had PRPand salineinjectionswhich wasaccompanied by ultrasonographyfourweeksapart.Caseswereevaluatedbyblind study criteria. Following theisometric spasm of extensorcarpi radialisandextensordigitorumcommunismuscles,thecaseswere assessedbyVASandRolesMandsleyscoringduring1st,3rd,6th and12thmonths.Asaresult,twogroupshadpromisingresults; still,therewasnodifferencebetweentwogroupsafter6months.27 Given thelow numberof studiesand theconflicting results between these, performing a meta-analysis of the results and decidingwhichoftheseresultsshouldbedisregardedorincluded isadifficulttask.Nevertheless,itisimportantforsuchdatatobe compiledandcompared.24
The studies included in the presentreview did not provide commondataand thereforehomogeneityorheterogeneity tests couldnotbeperformed.Asaresultofthisstudy,itcanbeconcluded thatthehypothesisthatthereisonlyonerealunderlyingeffectthat tobepredictedcannotbejustifiedstatistically.Forthisreason,the graphdrawingofthedataregardingsamplequantityorvariation reciprocalcouldnotberealized.Inthepresentstudy,allthearticles were retrospectivelydesignedand mosthad smallsamplesizes subjecttosystematicandrandombias.
5. Conclusion
Thereisaneedtoestablishworldwidemulticentrestudyset-ups inwhichvolunteersfromallracestakepart.Theseset-upsinclude
doseresponsecurvesofWBCratioinPRPcontent.Afterwards,they shouldbetestedaspre-clinicand clinicat molecularlevel.Itis importanttoclarifywhichtreatmentisreceived,whichmechanism of action is usedand which disease is treated. Some questions concerningapplication of treatmenton which cases, amount of doses,durationandnumberofcuresaretobeanswered.Through theresultsofthesestudies,guidesintroducingwhich concentra-tions of PRP are used for which diseases are to be prepared immediately by a committee which is comprised of primarily orthopaedists,clinicalpharmacologistsandtoxicologists.
Conflictsofinterest
Theauthorshavenonetodeclare. Funding
This research received no specific grant from any funding agencyinthepublic,commercialornot-for-profitsectors. References
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