UOJM May 2013_PDF version.pdf

V O L U M E 3M a y 2 0 1 3

FEATURING • A debate on MSK injuries• Ethics of stem cell research• Bacteriaascancerfightingagents• Thestudentmentorshipprogram• An interview with Dr. Lauralyn McIntyre on the

world’sfirstin-humanstemcelltrialfor septicshock

uojm.ca

U n i v e r s i t y o f O t t a w aJOURNAL of MEDICINE

J o u r n a l M é d i c a l d e l ’u n i v e r s i t é d ’o t t a w a

P a g e 3 | U O J M V o l u m e 3 | M a y 2 0 1 3

FACULTY ADVISORSDr.MelissaForgie,Dr.PhilWells

EDITORIAL TEAMEditor-in-Chief: André Martel

Managing Editors: ColinSuen,LorettaCheung

Treasurer:

VP Promotion:VP Technology:VP Education:

Senior Advisor:

NischalRanganath

Jonathan KeowMichaelWangHenryZhang

Tyler Kaster

Associate Editors: GhadiAntoun,SylvainLanouette,HariMaganti,AndrewMicieli,MatthewPurser,Abi Vijenthira

Sectional Editors: KendraBarrick,WeiweiBeckerleg,AlinaBeliavsky,RamiDarwich,FrancoDattilo, JasonFishman,FrançoisGagnon,PatrickGalange,Alain-PhilipGendron, MarianaGomez-Smith,StevenGravelle,LindenHead,AmjedKadhim-Saleh, Marie-ClaudeLaplante,JoanneLau,KevinLee,PhilipLee,ZiHymnMach,BriannaRyman, EllenSnyder,MohamadTaha,JacquelineTokarew,TerriWaller,MadeleineZiss

Copy Editors:

Layout Editors:

AlinaBeliavsky,StevenGravelle,Marie-ClaudeLaplante,KevinLee,AndréMartel, NischalRanganath,BriannaRyman,EllenSnyder,JacquelineTokarew,TerriWaller, Madeleine Ziss

AndréMartel,ColinSuen,JohnBehbahani

Translation: BureaudesAffairesFrancophones(BAF)

SPONSORS TheOttawaHospital:DepartmentofMedicineFacultyofMedicine,UniversityofOttawaOfficeofVice-PresidentofResearch,UniversityofOttawa

J o u r n a l S ta f f

AlleditorialmatterinUOJMrepresentstheopinionsoftheauthorsandnotnecessarilythoseoftheeditors,theFacultyofMedicine,oranyorga-nizationsaffiliatedwithUOJM.UOJMassumesnoresponsibilityorliabilityfordamagesarisingfromanyerrororomissionorfromtheuseofanyinformationoradvicecontainedinUOJM.

COVER ART:ThecoverfeaturesanoriginalpaintingcontributedbyBhavikaPatel.


Ta b l e o f C o nte nt s

6 Preface / PréfaceAndré B. Martel

FEATURED INTERVIEW

8 The world’s first in-human stem cell trial for septic shock: A bench-to-bedside journey in critical care research from the perspective of Dr. Lauralyn McIntyreColin Suen and Loretta Cheung

COMMENTARIES

11 Examining the usefulness of the evidence-based medicine model for decision-making in clinical and research settings Amjed Kadhim-Saleh, Melanie TC Cheung and Kendra Barrick

14 The Facuty of Medicine Student Mentorship Program: A new initiativeNatasha Larocque and Nischal Ranganath

17 The unsung value of local peer-reviewed publicationsKevln F.H. Lee

19 Mentee vs. mentor: A debate on the use and efficacy of platelet-rich protein injections for the treatment of soft tissue musculoskeletal injuriesNicholas Paterson and Subhan Sediqi

21 Warning: Don’t let the fast-track slow you downKevin F.H. Lee

23 Ethics and stem cell research: The knotty businessTarunpreet Dhaliwal

UOJM JMUOUNIVERSITY OF OTTAWA

JOURNAL OF MEDICINE JOURNAL MÉDICAL DE L’UNIVERSITÉ D’OTTAWA


Ta b l e o f C o nte nt s

UOJM JMUOUNIVERSITY OF OTTAWA

JOURNAL OF MEDICINE JOURNAL MÉDICAL DE L’UNIVERSITÉ D’OTTAWA

REVIEW

26 Genetically engineered bacteria as cancer fighting agentsAlexandra Bunting

34 Pulmonary Hypertension: Difficult diagnosis, challenging prognosis, poor outcomeMohamad Taha

38 Fasciotomy wound closure following compartment syndromeAnthony Vo

ORIGINAL RESEARCH

42 Associations between neighbourhood walkability, active school transport and physical activity levels in primary and secondary school students: A pilot-studyRichard Larouche, Guy Faulkner and Mark Tremblay

GLOBAL HEALTH

47 Un aperçu des stratégies utilisées chez les pays en voie de développement pour réduire les temps d’attente pour une chirurgie de la cataracte: Y a-t-il quelque chose à apprendre?David Michael Stitt


Onbehalfoftheentireeditorialteam,weareextremelyexcited topresent youwith the third issueof theUniversityofOttawaJournalofMedicine(UOJM).Sinceitsre-launchin2011,two very impressive issues have been published. The UOJM is a student-run,peer-reviewedjournalthatisdedicatedtoshowcas-ingtheopinionsandscholarlyaccomplishmentsoftheFacultyofMedicinestudents,withbothscientificandnon-scientificpieces.Not only arewe the only bilingual student-runmedical journalinCanada,butwearealsotheonlyjournaltoactivelyintegrategraduatestudentswithintheeditorialteam.Furtheringlastyear’seffortstounitegraduateandmedicalstudents,thisyear’sedito-rialteamiscomposedof37editors–withequalrepresentationofmedicalandgraduatestudents. Thisyear,we implementedchangestonotonlyensuresustainabilityofthejournalintheyearstocome,butalsotomaxi-mizeeveryeditor’sexperience.Thefirstgoalwastore-structuretheeditorialteamtoincreaseefficiencyandworkflow.Manynewpositionshavebeencreated,suchasVPPromotion,VPTechnol-ogy,VPEducation,Treasurer,andmore. Implementingthisnewstructureincreasedtheefficiencyofvariouskeyaspects,includ-ingbudgetplanning,networking,websitemaintenance,andpro-motingthejournalthroughoutthefaculty.Thesecondimportantgoalwastomodifythetrainingofeditors.Sincefirst-lineeditingissuchanessentialpartofthejournal,wedecidedtocreateedit-ingtrainingworkshops,whereeditorsreceivedmoreexposuretothepeer-reviewprocessandpracticedhowtocriticallyappraisearticles. Itisimportanttonotethatallthisworkwouldnothavebeenpossiblewithoutthehelpandcollaborationofmanypeople.Wewouldliketorecognizeandthankthemanagingeditors,Co-linSuenandLorettaCheung,fortheirtirelesseffortsanddedica-tiontomanagingthereviewprocessandhelpingwiththeeditingtrainingworkshops.Wewouldalsoliketothanktheentirepeer-review team,whichwas comprised of 24 sectional editors and6associateeditors.Theyhaveallshowncontinuousenthusiasmthroughouttheyear-longreviewprocess. Implementedthisyear,theUOJMhascreatedtheOut-standingEditorAwardtorecognizeamemberofthereviewteamwhodemonstratedcommitmenttotheirroleaseditor.Selectingtherecipientoftheawardwasextremelydifficult,asmanyeditorshaveshownaveryhighlevelofdedication.TheUOJMisproudtopresenttheOutstandingEditorAwardtoEllenSnyder,sectionaleditor,whodistinguishedherselfwithactiveparticipationatthetrainingworkshops,alwaysgivinghigh-qualityconstructivefeed-back, assistingwith copy editing and volunteering to help pro-

motethejournaltostudentsandfacultymembers.WewouldalsoliketocongratulateBhavikaPatelforwinningthecovercontest.Wereceivedmanyimpressivesubmissionsthisyearandweareveryhappytoshowcaseherbeautifulartworkonthecoverofthethird issue. We are very grateful toDr.Melissa Forgie andDr. PhilWells,whocontinuouslysupportedusthroughtheirrolesasmen-tors.Wewouldliketothankourwonderfulsponsorsfortheirgen-erousfunding–withoutthemthis issuewouldnotbepossible.WewouldalsoliketothanktheBureauofFrancophoneAffairsfortheireffortstranslatingalltheabstracts,andfulfillingourcommit-menttobeingabilingualjournal. Weareveryimpressedwiththehighqualityandvarietyofsubmissionsthisyear.This issuecontains12excitingarticles,coveringawiderangeofsubjectsfrombacteriaascancerfightingagents,tofasciotomywoundclosures,toamenteeversusmen-tordebateonmusculoskeletalinjuries.AlsofeaturedinthisissueisaninterviewwithDr.LauralynMcIntyre,aclinicianscientistincriticalcaremedicineattheOttawaHospital.Wewerefortunateenoughtohaveachatwithherabouthercareerasanintensiv-istand,morerecently,herinvolvementinstartingupthefirstin-humanstemcellclinicaltrialforsepticshock(CISSTrial).Herworkservesasagreatexampleofhow innovationsat thebenchcanbetranslatedtothebedside,andshouldserveas inspirationtoalltrainees–whethertheyareinvolvedinbasicscience,transla-tionalresearchorclinicalpractice. TheeditorialteamhasworkedveryhardallyeartomakethisissueasuccessandIfeelveryfortunatetohaveworkedwithsuch a dedicated group of individuals.We hope you enjoy theMay2013issueasmuchasweenjoyedputtingittogether! André B. MartelEditor-in-Chief

F ro m t h e Ed i to rs

UOJM: Preface


F ro m t h e Ed i to rs

JMUO: Préface

Toutel’équipederédactionesttrèsexcitéedeprésenterlatroisièmeéditionduJournalmédicalde l’Universitéd’Ottawa(JMUO).Depuisquelapublicationaétérelancéeen2011,deuxnumérosexceptionnelsontétépubliés.LeJMUOestunepublica-tionaveccomitéderévisionquiestdirigéeparlesétudiantsetquiapourbutdeservirdevitrineauxpointsdevueetperspectivesdes étudiants de la Faculté de médecine tant sur des sujets scien-tifiquesquenonscientifiques.Nonseulementproduisons-nouslaseulepublicationmédicalecanadiennebilinguequisoitgéréepardesétudiants,maisnoussommeségalement laseulequi invitelesétudiantsgraduésàparticiperactivementdansl’équipederé-daction.Afinde continuer leseffortsdéployés l’annéedernièrepourréunir lesétudiantsgraduéset lesétudiantsenmédecine,cetteannée,l’équipederédactionestcomposéede37rédacteursrépartiségalemententrelesétudiantsdepremiercycleenméde-cineetlesétudiantsgradués. Cetteannée,nousavonsapportédenombreuxchange-ments,nonseulementdanslebutd’assurerlaviabilitédelapub-lication, mais aussi pour optimiser l’expérience de chacun desrédacteurs. Le premier objectif était de réorganiser l’équipe derédactionpouraugmenterl’efficacitéetlefluxdetravail.Denom-breux nouveaux postes ont été créés, tels que vice-présidencepromotion, vice-présidence technologie, vice-présidence péda-gogie,trésorieretbiend’autres.Lasolidificationdelastructureapermisd’améliorerl’efficacitédebiend’autresaspectsimportantstelscommelaplanificationbudgétaire,leréseautage,lemaintiendusiteinternetetlapromotiondelapublicationdansl’ensembledelafaculté.Ledeuxièmeobjectifimportantaétédemodifierlaformationen rédaction.Comme la rédactiondepremière lignejoueunrôletellementimportantdanslapublicationdenotrere-vue,nousavonsdécidédecréerdesateliersdeformationoùlesrédacteursontétéexposésauprocessusderédactionetsesontpratiquésàfairel’évaluationcritiqued’articles. Ilest importantànoterquetoutcetravailn’auraitpasétépossiblesansl’aideetlacollaborationdeplusieursgens.Nousaimerionsplusparticulièrementremercierlesgestionnairesédito-riaux,ColinSuenetLorettaCheung,pourleurseffortsinlassablesetleurdévouementdanslagestionduprocessusderévision,etpour avoir donné un coup de pouce avec les ateliers de forma-tionàlarédaction.Nousaimerionségalementremerciertouslesmembresducomitéderévisionquiestforméde24rédacteursdesectionetde6rédacteursadjoints.Ilsonttousfaitpreuved’ungranddévouementetonttravailléinlassablementtoutaulongduprocessusderédaction. Cetteannée,leJMUOacrééleprixduRédacteurexcep-tionnelafindesaluerletravaild’unmembredel’équipederédac-tionayantdémontréunengagementàleurrôlederédacteur.Ila

ététrèsdifficiledechoisirlerécipiendaire,cardenombreuxcan-didatsontfaitpreuved’unniveautrèsélevédedévouementetd’engagement.LeJMUOestfierdeprésenterleprixduRédacteurexceptionnel à Ellen Snyder, rédactrice de section qui s’est dé-marquéeenparticipantactivementauxateliersdeformation,endonnantdelarétroactionconstructivedehautequalité,enaid-antaveclestadedepublicationetenseportantvolontairelorsdesactivitéspour faire lapromotiondu JMUO.NousaimerionségalementféliciterBhavikaPatelquiaremporté leconcoursdelapagecouverture.Nousavonsreçuplusieurstrèsbellessoumis-sionscetteannée.Noussommesfiersdemontrerl’œuvreexcep-tionnelledecetteétudianteenpagecouverturede latroisièmeédition. NoussommesreconnaissantsenversDreMelissaForgieetDrPhilWellsquinousonttoujourssoutenusenendossantlerôledementors.Nousaimerionsremerciernosmerveilleuxcom-manditaires pour leur soutien généreux. Sans eux, il aurait étéimpossible de publier ce numéro. Nous aimerions aussi remer-cierleBureaudesaffairesfrancophonespourleseffortsdéployéspourtraduiretouslesrésumés,accomplissantnotreengagementàêtreunjournalbilingue. Noussommestrèsimpressionnésdelagrandequalitéetdelavariétédesarticlessoumiscetteannée.Cenumérocontient12articlesintéressants,couvranttouteunegammedesujets,al-lantdel’utilisationdesbactériesdanslaluttecontrelecancer,àlafermeturedeplaiesuiteàunefasciotomie,ainsiqu’undébatentreunmentoretunmentorésurlesblessuresmusculosquelet-tiques. Dans ce numéro, vous pourrez aussi lire une entrevueavec Dre Lauralyn McIntyre, chercheure clinique en soins auxmaladesenphasecritiqueàl’Hôpitald’Ottawa.Nousavonseuleprivilègedepouvoirdiscuteravecelledesacarrièred’intensivisteet,plusrécemment,desaparticipationaulancementdelatoutepremièreétudecliniquesurl’utilisationdecellulessouchespourtraiterlechocseptiquechezleshumains(essaiCISS).Sontravailest unmerveilleux exemple de la façon que les innovations enlaboratoire peuvent être appliquées au chevet des patients. Ildevraitinspirertouslesstagiaires,qu’ilssoientdumilieudessci-ences fondamentales, de la recherche translationnelle oude lapratiqueclinique. L’équipe de rédaction a travaillé très fort tout au longdel’annéepourassurerlesuccèsdecenuméro.Jemesenstrèsprivilégiéd’avoirputravailleravecungroupeaussidévoué.Nousespéronsquevousaimerezl’éditiondemai2013autantquenousavonsprisplaisiràlacréer!

André B. MartelRédacteur en chef


Fe at u re d I nte r v i e w

How did you become interested in medicine? EversinceIwasyoung,Ialwayswantedtohelppeople.Ingrade7Ididalotofvolunteeringwithspinalcordinjurypa-tients.Ingrade8,Ididalotofvolunteerworkwithkidswhohadtroubleswith their speech, so Iworkedwith an audiologist tohelpthekidsgetridoftheirlisps.

Can you tell us about your education background and how you started working on your research? I did an Honours Bachelor of Science Degree with aBiomedical Science Minor at the University of Guelph. I actually wasn’t readytogo intomedicineaftermyundergradso I tooka break andwas a ski instructor inWhistler for a year. Then ImoveddowntoVancouverandworkedforacoupleofyears.Af-terwards,IwenttoMcMasterUniversityformedicalschoolandthen I came to Ottawa formy residency in InternalMedicine.Iwent back out toVancouver formy critical care training andthat’swheremyresearchintereststartedtokickin.WhenIdidmy InternalMedicine training inOttawa, IdidanelectivewithDr.Hebertandhegotmestartedinmyresearchinterest.ThenIcontinuedthisoutwestinVancouverandworkedinalabfor6monthswithDr.KeithWalleyandIguessIhadalotofmentor-ship.ThemoreIdidresearch,themoreIwantedtodoitbecauseitwasreallyfun.SowhenIfinishedmyclinicalfellowshipIcamebackheretoworkwithDr.PaulHebertandDr.DeanFerguson.And the two of them mentored me for my Master’s in Epidemiol-ogyinOttawa.ThenIstartedworkingclinicallyasanintensivistanddevelopedaprogramofresearchinresuscitationandthat’s

whereitreallygotstartedformeanditstill isoneofmymaininterests:fluidresuscitationandsepticshock. All along the way, I’ve been blessed with incrediblepeoplearoundme.Whendoing research, it is so important tohave that infrastructure and people to care for and help you. It’s alwaysimportanttohaveideagenerationandtobechallengedinresearch.Incriticalcare,wehaveanationalresearchnetworkcalledtheCanadianCriticalCareTrialsgroupandtheCanadianCriticalCareTranslationalBiologygroup.Thisgroupofinvestiga-torsfromacrossCanadaisincredible.Wecometogetherandtalkaboutresearchprotocols,howtogetthatresearchfunded,andwemeet3or4timesayear.Sowealldomulti-centerclinicalre-searchtogether.Afewyearsago,Dr.DuncanStewartapproachedmeandaskedme if Iwanted tobe involvedwith septicshockresearch.

How did you become interested in this field? Well, it’sadynamicenvironment.ThingschangereallyquicklyintheICU.Peoplegetreallysickreallyquickly,buttheycanalsogetbetterreallyquickly.We’retalkingaboutweeksrath-er thanyears kindof thing. I lovehumanphysiology. I’ll neverforget [myprofessor],hewasamajormentor inuniversity forme.Hisname isDrBerkeleyfromGuelph.Anotherbigthing istheteamwork;[workingintheICU]isverycollaborativeandverymultidisciplinary.YouhaveyourICUstaffandthenyouhavetheresidents,fellows,amedicalstudent,andthenyou’vegotyournurses,researchcoordinators,nutritionists,physiotherapists,oc-cupational therapists, respiratory therapists, the socialworker,

The world’s first in-human stem cell trial for septic shock: A bench-to-bedside journey in critical care from the perspective of Dr. Lauralyn McIntyre

ColinSuen,BMSc1,2,LorettaCheung,BSc1

1FacultyofMedicine,UniversityofOttawa2SprottCentreforRegenerativeMedicine,OttawaHospitalResearchInstitute

InthisissueoftheUOJM,wesitdownwithDr.LauralynMcIntyrewhoisacriticalcarephysician,professorattheUniversityofOttawa,andscientistattheOttawaHospitalResearchInstitute(OHRI).Dr.McIntyrehasimpresseduswithherresearchonfluidresuscitationinthecriticallyilland,morespecifically,insepticshock.Recently,shehastakenontheroleastheleadinvestigatorontheCISStrial(CellularImmunotherapyforSepticShock)attheOHRI.Thisisthefirstin-humanclinicaltrialevaluatingthesafetyandefficacyofmesenchymalstemcelltherapyforsepticshockpatients.WehadtheincredibleopportunityofspeakingwithDr.McIntyreaboutherexcitingcareerasaclinician-scientist,theCISStrialandtheimportanceofcollaborationinclinicalandtranslationalresearch.Thefollowingareexcerptsfromthisinterview.

DanscetteéditionduJMUO,nousfaisonsuneentrevueapprofondieavecDreLauralynMcIntyre.Elleestintensiviste,profes-seureàl’Universitéd’Ottawaetunescientifiqueaffiliéeàl’Institutderecherchedel’Hôpitald’Ottawa(IRHO).Nousavonsétéimpres-sionnésparlarechercheduDreMcIntyreensoinsauxmaladesenphasecritique,etplusparticulièrementdansletraitementduchocseptique.Récemment,elleaendossélerôledechercheureprincipaledansl’essaicliniqueCISS(CellularImmunotherapyforSepticSchock)àl’IRHO.Ils’agitdelatoutepremièreétudechezdeshumainspourévaluerlasécuritéetl’efficacitédutraitementduchocseptiqueàl’aidedecellulessouchesmésenchymateuses.NousavonsététrèschanceuxdepouvoirparleravecDreMcIntyredesastimulantecarrièredeclinicienne-scientifique.Vouspourrezlireci-aprèsdesextraitsdel’entrevue.



thespiritualcareworkerandourwardclerks.Andmostofusarerounding.ThearmyisgoingthroughtheICU,roundingtotryandhelppatients.SoIabsolutelyadoreworkingwitheverybody.It’sjustsogreat.That’swhyIworkintheICU.

Can you tell us more about septic shock? Septic shock is sneaky and unpredictable. It is a syn-dromefroma[pathogen]thatentersyourbodyandyourespondtothat[pathogen]andtrytoeradicateit.Theinflammationandcoagulationresponsesgetrampedup,butthewaysepticshockhappens is that the inflammation responsegetsoutof controlandwethinkit’sthoseprocessesthatleadtothedevelopmentoforganfailureandthehighdeathratethatweseeinsepticshock.Theaveragebaselinedeathrateforsepticshockis30-40%andthemoreorgansthatfail,thehigherthedeathrate. Itisnotselective;youngpeopleandoldpeopleareallaffected.Patientswithcomorbiditiesandthosewhoareimmu-nosuppressedaremorepredisposedtoit,butweseepeopleatayoungagecomingtotheICUwithsepticshock.Wecanoftengetridoftheinfection,butitistheinflammatoryresponsethatcauses the problem. It is one of the most common reasons that people come to the ICU; about 20%of cases are septic shockrelated.Whensomeonecomesinwithsepticshock,thewholeteamisincluded:doctors,nurses,socialworkers,pharmacists–itisverymultidisciplinary.

Tell us about the management of septic shock. Septic shock is very perplexing; we’ve have decadesofresearchtoexplorethetreatmentandmedicaltherapiesforitandwe’vetrulymadelittleheadwayformedicaltherapies intermsof themhelping reduce thedeath rate.Themainstayoftherapyistomakethediagnosisasitisverysneakyandunpre-dictable.Ifwecanmakethediagnosis,wecantreatthepatientearlier,resuscitatethemwithenoughfluids,givethemantibiot-icsasquickaswecan,andmonitorthemsotheydonotdeterio-rate.Wealsohelpwiththeirbreathing,treattheircomas,takeaway their pain, use intravenous medication to support theirbloodpressure,andputthemonthekidneymachineiftheirkid-neysarefailing.Wereallyneedalotofsupportivemeasurestohelppatientsnotonlysurvivebutsurvivewell.LeavingtheICUis just thefirst step; this condition isassociatedwith immenselong-termmorbidity,sowearetalkingaboutweekstomonthsofrehabilitation.Evenwhentheygohome,studieshaveshownthatpatientsarephysicallydeconditionedandareleftwithemo-tional issuesandpost-traumaticstressandthatcanimpactthewaytheyintegratetheirlifebackintosociety.

What do you think needs to be changed in the management? Theprimarypreventionpartisthateverybodygetsvac-cinatedsothatyoudonotget infected.Otherthanthat,mostaresecondarypreventionmeaningthatyoualreadyhavesepsisandyouneedtopreventitfromgettingworse.Weneedtodiag-nosis[patients]earlyenoughbecauseifwediagnoseittoolate,itishardtocontrol.Wearetalkingabouthourstodiagnoseandcontroltheircondition.

Where do you think stem cells fit in? Stemcellshaveaprofoundeffectontheinflammatoryresponseandcoagulationcascade.Weknowthatsepsis’ initialphaseisentirelypro-inflammatoryandweknowthatstemcellsseemtomodulatemanyprocessesininflammation.Itwasdem-onstratedthatover3000genesaremodulatedbythese[stem]cellsinanexperimentwithsepsis[1].That’swhat’sreallyexcit-ing;it’snotjustmodulatingonesmallprocessbecausesepsisisverycomplicated.Thesecellsseemtogoinandcalmthe“house”downandputitbackinorder.Thereisalsodatatosuggestthattheyenhancetheclearanceofbugsandenhancerepairofinjuredorgansthroughmessagingwithothercells.Itisparticularlyinter-estingforsepsisbecauseithappensinsuchashorttimeframe,soyouwantsomethingthatactsquickly–inandout–asyoudon’twantlong-termeffectsfromthecells.Theyseemtohaveanim-pactoncellleak.Theliningofthebloodvesselshaveendothelialcellsandinthesettingofsepsisyougetprofoundleakofproteinsandwhitebloodcellstotheinterstitiumandthatdrawsfluidwithit.Sowheneveryouresuscitatethesepatients,thefollowingdaytheyarelikepincushionsbecauseyouhavegiventhem10-14Loffluidasitdoesn’tstayintheintravascularspace.Thestemcellsseemtorestoretheendothelialfunction,whichisverycool[2].Itrulythinkthatthesecellshaveastrongpotentialtohelpthesepatients.

What about safety? Ourteamdidasafetysystematicreviewtotallyallad-verseeventsinhumanclinicaltrialswithMSCs[3].Wetriedtofindallofthosetrialsandthenwegroupedtheadverseeventsindifferentcategoriesandwelookedforsignals.Overall,itseemsthatthecellsareverysafe indifferentpatientpopulationsandtherewerefewadverseevents,sothatgaveusmorecredibilityto move forward with our clinical trial.

When evaluating the evidence, why is a systematic review so important? Asystematicreviewisreallycriticalbecauseitisatrans-parentandunbiasedsystematicsearchoftheliteraturethatpro-videsyouwiththetotalityofevidence,bothgoodandbad.Yousynthesize it and describe it in such as way that you understand thestrengthoftheevidence-basethat’soutthere.It’sacriticalpiece forall researchers tobeapartof:both clinical andpre-clinical researchers.Now,preclinical researchersarestartingtodothesamearestartingtodothismore.Here,inOttawa,thisisthefourthorfifthone[systematicreview]…becauseifyoudon’tdoit,howdoyoureallyknoweverythingthat’soutthere?Asaresearcher,youwanttoknowthegood,andthebad.

So can you briefly describe the CISS trial? The CISS trial is the first in-human [septic shock trial]with stem cells. Themain objective of the trial is to establishsafetyandpatient-tolerabilityofthecells.Theotherobjectiveistofindthebestdoseofcellstogive.[Ifinthe]PhaseItrial,wedeemthatthecellsappearsafeandwefindoutwhatthebestdoseis,theaimwillbetogotoaPhaseIItrialthatwillbeaimed

P a g e 1 0 | U O J M V o l u m e 3 | M a y 2 0 1 3


atlookingatloosesurrogatesofefficacyforpatientswithsepticshock.Rightnow,therearetwoarmsofthetrial.Thefirstarmisanobservationalarm,sothesepatientsmeetallCISSeligibilitycriteriabuttheydon’treceivethecells.Wejustfollowthemfor-ward and we do serial blood and urine measurements of acute inflammatorymarkersandacutephaseproteinstocomparethattothegroupofpatientswhoreceivethecells.Theotherpurposeofthisobservationalarmistodocumentfrequencyandseverityofadverseeventsthatoccurinthispatientpopulation.Adverseevents related to thediseaseoccureveryday,muchmore fre-quentlythanyouwouldseeinchronicdisease.That’swhyit’sre-allyimportantthatweunderstandanddocumentthefrequencyandseverityoftheseadverseeventsbeforewegotowhatwecallthe“doseescalation”interventionarmofthetrial. We’ve recruited4patients into theobservationalarmandwehopetohavetheinterventionarmofthetrialupandrun-ningbeforetheendof2013.Fortheinterventionarm,therearethreedifferentdosesplannedforthestemcells.Foreachdose,wewillenrollthreepatients.Westartwiththelowdoseandafterthe3patientsareenrolled,wehaveasafetyanddatamonitoringboardthatwillbelooking[toassess]theoccurrenceofthead-verseevents,howtheprotocolwasadheredto,andhowthepa-tientstoleratedthecells.Iftheydeemthateverythingwentwell,wegotothemiddosearmandthenwelookatthehighdosearmuntilit’sfinished.Andifthepatientsdevelop–inanyoneofthosearms–aseriousadverseeventthat’sdefinitelythoughttoberelatedtothecells,thenthetrial’sover. Ifwedeemthistrialtobesafe,thenwewillbemovingtoaPhaseIItrialveryquickly.Wewanttoenrollalotmorepa-tientsanditwillprobablybeatrialthat’snotjustconductedatonesiteorcenter,butatmultiplecentersinCanada.(seenewsarticle:Ottawaresearcherstoleadworld-firstclinicaltrialofstemcell therapy for septic shock. http://www.ohri.ca/newsroom/newsstory.asp?ID=306[4])

What advice would you give to students who want to pursue this kind of career? Theadviceistokeepyourmindopen,pursuetheoppor-tunities,andexplorethepotentialtodoresearch.Justbecauseyoutakeonaresearchprojectasastudentdoesn’tmeanyouarecommittedtobecomingabigresearcher.Itcouldjustbescien-tificexplorationandlearninghowtothinkindifferentwaysthatyou canbenefit from.Orhaving theopportunity toworkwithsomeone you respect that could be a major mentor in your life. Evenifyoudon’tbecomearesearcher,theycanstillhelpguideyou.SoIjustthink[it’simportant]totryandpursuetheopportu-nities.Keepyourmindopenanddon’tgettoooverwhelmed.It’seasytosaybecauseIwastheretoo–Irememberthat!IstillwishthatIcouldhavegotteninvolvedearlier. I justthink itenrichesyour life to be a part of it early in your medical career.

Can you just describe what your weekly schedule is like? ClinicallyIwork12-14weeksintheICU.Alloftheotherweeksareresearch.Andtheresearchisanywherefrommypro-

gramtootherpeople’sprogramslocally,nationallyandinterna-tionally.Anotherfunthingaboutresearchwhenyou’redoingitatthislevelisthatyougettocollaboratewithincrediblepeoplearoundCanadaandtheworldontheirprojects;yougettolearnmuchmore.Also,Ichairresearchcommitteesandthere’salotofadministrativeresearchdutiesbuilt-in.Andthen,mentoringtheyoung,that’stheotherthing. It’sveryfulfilling.Sometimesit’ssobusy.You’realwaystrying tomanageyourtimeandbeing realisticabout it. That’salwaysachallengebecauseI’vegotadaughter.I’vegotasix-yearoldbehindmydoorandshe’smypriority.Nothingcomesaboveher,doesn’tmatterwhat it is.Butbalancingeverythingcanbechallenging.

How do you balance family life and work life? Reevaluate. Reevaluate regularly where you’re at. Tryto be organized. Justmaking sure that you carve out time foryourself. Andthenthelastthingistonotconstantlysay“yes”,although,we’reallkindofbadforthat.Beingabletosay“no”tosomestuff[isimportant]becauseitcanbecomeoverwhelming.So, knowwhat your limitations are. Reach out and have goodmentorsaroundyouthatcanhelpyoukeepyourselfinmind.Be-causeifyousayyesto25differentthings,there’snowayyoucangetgoodresearchdone.Soit’sgottobeabalance.

It’s good to hear that from you. It sounds like you really like what you do and that’s really inspiring. That’stheotherthing.Howdoyoumanageyourtime?Youlovewhatyoudo.Whateveryouchoosetodo,haveapas-sion about it. Don’t just do it because you’re supposed to or be-causeyouthinkyouracademicdepartmentwantsyouto.Takesomethingonbecauseyouloveit.Becauseyouaregoingtobereallybusywhateveritisyoutakeon,beiteducation,research,administration,qualityofcareinitiatives.Takeitonwithapas-sionandthenyouwillbesofulfilledbywhatyoudo. REFERENCES1. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, LilesWC,

StewartDJ.Mesenchymalstemcellsreduceinflammationwhileenhancingbacterial clearance and improving survival in sepsis. American journal ofrespiratoryandcriticalcaremedicine.2010;182:1047-57

2. LeeJW,FangX,GuptaN,SerikovV,MatthayMA.Allogeneichumanmes-enchymalstemcellsfortreatmentofe.Coliendotoxin-inducedacutelunginjury in the ex vivo perfused human lung. Proceedings of the NationalAcademyofSciencesoftheUnitedStatesofAmerica.2009;106:16357-62

3. LaluMM,McIntyre L,PuglieseC, FergussonD,WinstonBW,Marshall JC,GrantonJ,StewartDJ.Safetyofcelltherapywithmesenchymalstromalcells(safecell):Asystematicreviewandmeta-analysisofclinicaltrials.PloSone.2012;7:e47559

4. Ottawaresearcherstoleadworld-firstclinicaltrialofstemcelltherapyforseptic shock. 2012;2013 URL: http://www.ohri.ca/newsroom/newsstory.asp?ID=306


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Evidence-basedmedicine (EBM), one of several disci-plinesthathaveevolvedfromclinicalepidemiology,entailsusingthebestcurrentevidenceinmakingdecisionsrelatedtopatientcare[1].Thepracticeofthisdisciplineinvolvestheintegrationof:(i)bestavailableevidencefromresearch,(ii)clinicians’expertise,and (iii) patients’ beliefs and values (Figure 1). The best avail-able evidence refers to clinically relevant research that must be consideredwhenexaminingtheaccuracyofdiagnostictests,thepowerofprognosticmarkers,andtheeffectivenessoftherapeu-ticregimens.Expertisereferstotheproficiencyandjudgementthatcliniciansacquirethroughmedicalpractice.Patients’beliefsandvaluesrefertotheuniqueconcernsandexpectationsofeachpatientthatmustbeintegratedintoclinicaldecisions.

When making a clinical decision, health care teamsshould consider all three components. Using two recent con-troversialnewsarticles, theobjectiveof this commentary is toexamine the usefulness of EBM in decision-making related to:(i) individual-levelpatientcareand(ii)population-levelmedicalcare. Thefirst articleexaminesHassanRasouli’s case toassesstheevidenceusedtodetermineend-of-lifedecisions.Thesecondarticleassessestheevidenceusedinobtainingapprovaltocon-ductaclinicaltrialofMultipleSclerosisLiberationTherapy.

ARTICLE 1: MR. RASOULI Hassan Rasouli, a recently immigrated 60-year-old re-tired engineer, underwent surgery at Toronto’s SunnybrookHealthSciencesCentretoremoveabenignbraintumour.Mr.Ra-soulisufferedpost-operativebraindamagethatlefthiminaveg-etativestate[3,4].Thisstateisdefinedbyanabsenceofpatientawarenessduetowidespreadbraindamage.Thesepatientsareabletomaintainbloodpressureandcardiopulmonaryfunction,but lack cognitiveawareness.When this condition lasts longerthanonemonth,thepatientisconsideredtobeinapersistentvegetativestate(PVS)[5]. Recently,Mr.Rasouli’sphysicianshaveupdatedhissta-tustoaminimallyconsciousstate(MCS).PatientsinaMCSareknowntopreservesomeawarenessofthemselvesandtheirsur-roundings[5].AlthoughthereappearstobeanimprovementinMr.Rasouli’sstate,hisconditionstillrequireshimtobeonaven-tilator,aswellasfeedingandhydrationtreatment[3,4].

Clinical Evidence CurrentevidenceindicatesthatmostpatientsinaPVSdiewithin sixmonths. However, patients inMCSmay recoversome limited awareness and tend to have a better prognosiscomparedtopatientsinPVS[5].ThetreatmentforPVSandMCSpatients is similar and ismainly supportive.Unfortunately, thechance of significant functional recovery diminishes over time[6]. Measuringqualityoflife(QOL)forthesepatientsischal-lengingduetothelackofreliablecommunication.Thisdifficultyis substantiatedbya lackofevidenceonstudies thatmeasureQOLinthispatientpopulation.Severalstudieshaveusedfunc-tionalimagingmodalitiestoassesssubjectivephenomenasuchaspainperception[7].Thesestudiesarevaluable;however,cur-rentscientificunderstandingofareasassociatedwithpainpro-cessinginthebrainhasyettobefullyrealized.Itisarguedthatalthoughfunctionalimagingisinsightful,itcannotsubstitutebe-haviouralorclinicalassessment[8].

Clinicians’ expertise Althoughtheevidenceisclearonprognosis,thereisdi-agnostic uncertainty. Diagnosis is typically a clinical process todistinguishbetweenPVS,MCS,andothersevereconditions. Inadditiontomeetingclinicalcriteria, functional imagingmodali-tiessuchasPositronEmissionTomographyhavebeenused[5].Themisdiagnosis in this patient population is highlighted by astudy that demonstrated 19% of patients who were believed

Examining the usefulness of the evidence-based medicine model for decision-making in clinical and research settings

AmjedKadhim-Saleh,BHSc,MSc1,MelanieTCCheung,BSc2,KendraBarrick,BSc1

1FacultyofMedicine,UniversityofOttawa2DepartmentofCommunityHealth&Epidemiology,Queen’sUniversity

Figure 1: Evidence-BasedMedicineTriad[2]


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tobevegetativeshowedsignsofawarenessthroughElectroen-cephalography[9]. In fact,Mr.Rasouliwasfirstdiagnosedaspersistentlyvegetativeforayear.Followingfurthertesting,hisclinicalstatuswasupdatedtobeinaMCS[3,4].ItisunclearwhetherMr.Ra-souliwasmisdiagnosedorwhetherheregainedsomedegreeofconsciousness over the past year.

Patient’s beliefs and values ThelegalbattlebetweenDr.Rasouli’sphysiciansandhiswifehighlightsthisconflict.ThephysiciansbelievethatMr.Ra-soulishouldbetransferredtoapalliativecareprogram,whereashiswifedisagrees.Thephysiciansarguethattheyhavetherighttostopmedicaltreatmentwhenfutile.However,thefamilyar-gues thatMr. Rasouli displays signs of consciousness and thathasteningdeathcontradictshisreligiousbeliefs[3,4].ThiscaseiscurrentlybeforetheSupremeCourtofCanadaandjudgementispending.

Summary Thiscasehighlightstheuncertaintythatisencounteredinassessingconsciousnessandend-of-lifedecision-making.Theevidencehighlightstheclinicians’limitedunderstandingofthesepatients, includingmisdiagnosisandinabilitytoconfidentlyob-tain information on QOL. Furthermore, limitations of currentstudiessuchastherelianceonfunctional imagingtoobtainin-sightsintoMCSawarenessunderminesourconfidenceindeter-miningwhat isbest forthepatient.However,evidence isclearwhenitcomestoprognosis;thesepatientsareunlikelytorecov-erorgainfunctionalability.AnadditionalkeypointtohighlightisthatMr.Rasouli’swidespreadbraindamagepreventshimfrombreathingonhisown.ThisstatesuggestsableakprognosisforMr.RasouliduetomoresignificantbraindamagecomparedtootherMCSpatients.Despitetheprognosis,somefamiliesholdtotheirreligiousbeliefsdemandingcontinuationoftreatment.Thisconflictbetweenpatients’wishes,physicians’expertiseandevi-dencehighlightsthedifficultyinimplementingEBMineverydaypractice. ResolvingtheEBMconflictisfurthercomplicatedwhenconsideringresourceallocation.Inthiscase,theuseofintensivecareresourcescouldbeviewedasunfairwhencriticalpatientsaredeprivedofsuchaccess.Theuseoffiniteresources,whenfu-tile,isdifficulttojustifyespeciallywhendeathisimminent.ThisargumentistheessenceofthelegalbattleraisedbyMr.Rasouli’sphysicians.Therulingonthisissuewillhaveimportantimplica-tionsonend-of-lifecare,especiallyconsideringtheagingCanadi-anpopulationaswellasthecontinuousadvancementofmedicaltechnology.

ARTICLE 2: CLINICAL TRIAL OF MULTIPLE SCLEROSIS LIBERA-TION THERAPY Multiplesclerosis(MS)isaninflammatory,demyelinat-ingdiseasethatmainlyaffectsthecentralnervoussystem(CNS).InMS,thebody’simmunesystemattacksagainstmyelinandoli-

godendrocytes(cellsthatmakemyelin)intheCNS,resultinginaprogressivelossofneurons.Thisneurodegenerationcausesirre-versibleneurologicaldisabilityincludingmuscleweakness,visualdisturbances,coordinationissues,anddecreasedsensation[10].Additionally,MScanpresentasacuteorchronicattacksofdemy-elination,thelatterbeingamoreprogressivedevelopmentwithlowunderlyinglevelsofinflammation. Themostwidely accepted theory suggests thatMS isanautoimmunedisorder.However,newtheorieshavebeenpro-posed leading to thedevelopmentofnewMS therapies. Zam-boniandcolleaguesproposedthatMSiscausedbyabnormalityof cerebralvenousflow leading to irondeposition in thebrain[11], whichwould elicit an autoimmune response causing de-myelination[10].Zambonidevelopedaradicalapproachcalled“LiberationTherapy”,whichconsistsofaballoonangioplastyandinsertionofastentthatopensuptheveinstoimprovecerebralvenousflowandpreventirondepositsinthebrain[11].

Clinical Evidence SincetheimplementationofliberationtherapyinNorthAmerica, studies have highlighted several safety concerns in-cluding incidents of intracerebral hemorrhage, stent thrombo-sis,stentmigration,andcranialnerveinjury.Thesesafetyissueshavedelayedacceptancetoconduct liberationtherapytrials inCanada[12]. Inaddition to safety concerns, there is a lackofqual-itystudiesthatassesstheefficacyofliberationtherapy.BothoftheseconcernsinfluencewhetherclinicaltrialsofMSLiberationTherapyshouldbeconductedatall.Inasystematicreview,Bha-tiaetal.failedtoobserveanassociationbetweenchronicvenousinsufficiencyandMS[12].Also,studiesconductedbyBagertetal.concludedthatmethodologicalproblemsexistwithcasere-portsofliberationtherapyinEuropeandthatmoreevidenceisrequiredbefore theprocedurecanbeconsidered safe [13,14].Therefore, conducting invasive treatment studies of liberationtherapyshouldbeapproachedwithcautionuntiltherelationshipofMSandchronicvenousinsufficiencyisbetterestablished.

Patients’ beliefs and values Case reportsdemonstrate thatpatients choose toun-dergo liberation therapy formany reasons; themost commonbeingalackofavailableandeffectivetreatments[14].Inrecog-nizing the limited number of treatments available to patients,asurveybyateamofresearchers inBritishColombiafollowed80Canadianswho travelled abroad to receive liberation treat-ment.Thesepatientswerenotrespondingtoothertreatmentsandoptedtoundergoliberationtherapy.Halfofthepatientsfeltimprovementsaftersurgery,whereashalfnoticednochangeorworseningofsymptoms[15].Onepatientreportedastrokeandanother reported a heart attack post-surgery. Other commoncomplications includedbleedingandanaesthetic-related issues[15].


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Patient advocacy groups Many patient advocacy groups exist and are coordi-nated through the MS Society of Canada [9,16]. Patient-leadadvocacygroupshavebeeninfluentialinchangingtheoutlooksofgovernmentofficialsconcerningthefundingforMSpatientstoundergoliberationtherapyandforconductionofclinicaltri-als.One example is PremierDavidAlward,who in his politicalcampaignoutlinedtheplantoestablishafundforMSpatientsinNewBrunswicktopursueliberationtherapyabroad[17].Morerecently,patientadvocacygroupshaveinfluencedotherCanadi-anprovincesincludingSaskatchewan,ManitobaandNewfound-landtocommittofundingstudiesthatinvestigatetheefficacyofliberationtherapy.

Summary The MS case highlights the conflict between medicalevidenceandpatients’demands.Themainrequirementstocon-ductlargeclinicaltrialsareevidenceofsomebenefitanddem-onstrationofnoserioussafetyconcerns.Despitefailuretomeetboth of these requirements, advocacy groups have succeededingaining funding toconductclinical trials.The implicationsofthisdevelopmentarefarreachinganddangerous.First,thiscasedemonstrateshowpoliticalpressurecanaffectthescientificpro-cess, which should instead be objective. Secondly, conductingclinical trialswithsignificantconcernsoversubjects’ safetyareunethicalbecausetheysubjectpatientstounnecessaryrisks.Fi-nally, clinical equipoise indicates that there shouldbe genuineuncertaintyoftheefficacyoftreatments.InthecaseofMS,lib-erationtherapyappearstobeinferiorcomparedtootherproventherapies,suchas interferons [18].Therefore, it isunethical toassignasubjecttotheinferiorarm(i.e.liberationtherapy)asalackofequipoiseexistsforsuchatrial. The EBM model demonstrates the various forces that influence decision-making. In this case, the evidence suggeststhata largeclinical trialof liberationtherapyforMS isunjusti-fied.Physiciansandresearchersshouldusetheirknowledgetoempowerpolicymakersandsolidifythescientificprocesstoen-sureitsobjectivity.

CONCLUSION The cases presented here demonstrate that conflictsarisebetweenevidence,clinician’sexpertise,andpatient’sval-ues.Howshouldmedicaldecisionsbemadewhenconflictsarise?Thebestapproachistoensurethereiseffectivecommunicationbetweenpatients,theirfamiliesandtheclinicianforshareddeci-sion-making. Shareddecision-makingisacollaborativeprocesswherethepatient,theirfamily,andthephysicianworktogethertoar-riveatthebestmedicalchoices.Inordertoputshareddecision-making into practice, a number of recommendations include:(i) establish a conducive atmosphere, (ii) determine patient’spreferences,(iii)identifyoptions,(iv)discussandunderstandpa-tient’sbeliefsandvalues(v)explainmedicalinformationanden-sureunderstanding, (vi) sharepersonal recommendationswith

thepatient,and(vii)makeornegotiateadecisioninpartnershipwiththepatient[19]. One of the strengths of EBM is its usefulness in ap-proaching decisions related to individual and population-levelmedical care. In Rasouli’s case, applying the EBMmodel helpsanalyzethecomponentsaffectingdecision-makingatthepatientlevel.IntheMScase,theEBMmodelassessesthecomponentsinfluencingtheestablishmentofalargetrial. It is important to emphasize that the EBM model should beusedindecision-makingrelatedtoclinicalandresearchset-tings;however,thatisnotnecessarilywhathappensinpractice.TheMS case demonstrates the danger of not following EBM,suchas influencingtheobjectivityof thescientificprocessandsubjectingpatients tounnecessaryrisks.Therefore, it iscrucialtoalertstakeholders(i.e.,clinicians,patients,policymakers,etc.)ofup-to-dateinformation,aswellasensuringaccessibilityofthisevidence. Most importantly, stakeholders will need to under-standandevaluatethisevidencetomakeappropriatedecisionsinclinicalpracticeandresearch.

REFERENCES1. SackettDL.Evidence-basedmedicine.SeminPerinatol.1997;21(1):3.2. Adaptedfrom:SackettDL,RosenbergMC,GrayJA,HaynesRB,Richardson

WS.Evidencebasedmedicine:whatitisandwhatitisn’t.BMJ.1996;312:71-72.

3. TheCanadianPress.SupremeCourthearsOntarioend-of-lifecarecase[In-ternet].CBCNews;2012Dec10[updated2012Dec10;cited2013Jan20].Available from: http://www.cbc.ca/news/canada/story/2012/12/10/can-supreme-court-end-of-life-case.html.

4. CBC News. ‘Thumbs-up’ fromman on life-support revives family’s hope[Internet]. CBC News; 2012 Apr 25 [updated 2012 Apr 25; cited 2013Jan 20]. Available from: http://www.cbc.ca/news/canada/toronto/sto-ry/2012/04/25/vegetative-patient-gets-new-diagnosis.html.

5. MaieseK.VegetativeStateandMinimallyConsciousState[Internet].NewJersey (U.S.A):WhitehouseStation;2012[updated2012Sept;cited2013Jan20].Availablefrom:http://www.merckmanuals.com/professional/neu-rologic_disorders/coma_and_impaired_consciousness/vegetative_state_and_minimally_conscious_state.html.

6. GiacinoJT,AshwalS,ChildsN,etal.Theminimallyconsciousstate:defini-tionanddiagnosticcriteria.Neurology.2002;58:349e53.

7. BolyM,FaymonvilleME,SchnakersC,etal.Perceptionofpaininthemini-mally conscious statewithPETactivation:anobservational study. LancetNeurol.2008;7(11):1013-1020.

8. Eisenberg JB. Schiavo on the cutting edge: functional brain imagingand its impact on surrogate end-of-life decision-making. Neuroethics.2008;1:75e83.

9. CruseD,ChennuS,ChatelleC,etal.Bedsidedetectionofawarenessinthevegetativestate:acohortstudy.Lancet.2011;378(9809):2088-2094.

10. JournalBM.MultipleSclerosis.[Internet]:BMJPublishingGroupLtd.;2012[cited 2012 December 5]; Available from: http://bestpractice.bmj.com/best-practice/monograph/140/basics/pathophysiology.html.

11. LaupacisA,LillieE,DueckA,etal.Associationbetweenchroniccerebrospi-nalvenousinsufficiencyandmultiplesclerosis:ameta-analysis.CMAJ.[Me-ta-AnalysisResearchSupport,Non-U.S.Gov’tReview].2011;183(16):E1203-12.

12. BhatiaR,Abhishek,PrasadK.ChroniccerebrospinalvenousinsufficiencyinMultipleSclerosis:Anoteforcaution.AnnIndianAcadNeurol.2012;15(1):2-5.

13. MarderE,GuptaP,GreenbergBM,etal.Nocerebralorcervicalvenousin-sufficiencyinUSveteranswithmultiplesclerosis.ArchNeurol.[Compara-tiveStudy].2011;68(12):1521-5.

14. BagertBA,MarderE,StuveO.Chroniccerebrospinalvenous insufficiencyandmultiplesclerosis.ArchNeurol.[Review].2011;68(11):1379-84.

15. CTVNews.caStaff.CanadiastudytracksMSpatientsafter‘liberationtreat-ment’[Internet].CTVNews;2012Oct9[updated2012Oct16;cited2013Feb 4]. Available from: http://www.ctvnews.ca/health/canadian-study-tracks-ms-patients-after-liberation-treatment-1.989440.

16. MultipleSclerosisSocietyofCanada.MSSocietyofCanada[Internet].Mul-tipleSclerosisSocietyofCanada;2013[cited2013Feb4].Availablefrom:http://mssociety.ca/en/help/services.htm.

17. BissettK.MSpatientscallonCanada,provincestosupportliberationther-apy[Internet].TheGlobeandMail;2012[updated2012Aug24;cited2013Feb 4]. Available from: http://m.theglobeandmail.com/life/health-and-fit-ness/ms-patients-call-on-canada-provinces-to-support-liberation-therapy/article4262321/?service=mobile.

18. Barnes CJ, Caon C, Foley JF, et al. Intramuscular Interferon Beta-1a andEvolvingTreatmentOptionsandOutomcesMeasurementforMS:Consider-ationsforManagedCare.JMCP.2013;19(1SupplA):S1-S53.

19. LeeSJ,BackAL,BlackSD,StewartSK.EnhancingPhysician-PatientCommu-nication.Hematology.2002;464-483.


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BACKGROUND The Faculty ofMedicine StudentMentorship ProgramisanovelinitiativethatwasintroducedinSeptember2012withthevisionofcreatinganopenforumtopromoteself-reflection,studenthealthandwellbeing,aswell aspersonalandprofes-sional competencies within the medical student community.

Rationale Asprospectivemedicalprofessionals,wearechallengedeachdaywiththebalancingactofjugglingpersonalambitions,social life,andprofessionalresponsibilities.Forincomingmedi-cal students, the rapid transition into medicine, the need forprioritization and timemanagement, and the capacity to bal-ancepersonalhabitswithprofessionalobligationscanbequiteoverwhelming.TheStudentMentorshipProgramwasdesignedto create a safe and open space for medical students to discuss theseconcerns, learnfromoneanother’sexperiences,andde-velop an individualizedplan of action. The ideaofmentorshipwasbuiltupon the rationaleofempoweringstudentswith theabilityto:1. Developaself-reflectivefoundationthatallowsthem

torecognizeandgethelpearly2. Discuss and develop a healthy and balanced approach

topsychosocialandphysicalhealththroughoutmedi-cal school

3. Createastrongsocialnetworkofinterpersonalrela-tionshipsamongcolleagues

FORMATMentoring Centre TheMentoringCentre isoneof two initiativesstartedbytheStudentMentorshipProgram.ThecentreislocatedintheRogerGuindonLibrary,andisopeneveryMondayandWednes-dayfrom1pmuntil4pm.Studentsareabletocomeby(withorwithoutanappointment)andchatwithmentors.Twomen-torsarealwayspresentattheMentoringCentre,andaneffortismadetoensureonebilingualmentorisavailableonanygivenday.Mentors typicallyprovideadviceon study strategies,timemanagement,exampreparation,stressmanagement,andcareerpreparation.Allstudentsarereassuredthatvisitsareconfiden-tial. TheMentoringCentreprovidesone-on-oneservicestostudentswhohavequestionsregardingbothpersonalandpro-fessionaldevelopment.Inthefirstsemester(October-December,2012),therewere40totalvisitstotheMentoringCentreby25differentstudents.Thedataregardingthetotalnumberofvisits

inthecurrentsemester(January-May,2013)isunavailableatthepresenttime,butwillbeanalyzedfurtherinthefuture.

Tutoring centre Itwasidentifiedbythementorsthatnumerousstudentscame to the StudentMentoring Centre for inquires related toacademicconceptscoveredinthepreviousweeks.Tobetterad-dressthisneed,wesuccessfullydesignedandimplementedtheTutoringCentreinJanuary2013.TheTutoringCentrerunseveryMonday from1pmuntil3pm.During thattime, twomentorsrunatutorialbasedupontheacademicconceptslearnedbyfirstyearmedicalstudentsinthepreviousweek.Forinstance,onetu-torialwasbasedupondiscussingthebasicsonhowtoapproachanelectrocardiogram (ECG), and its applications toCardiology.ThepurposeoftheTutoringCentreisnottoundertakedidacticteaching,butrathertoprovidemedicalstudentswithaspacetodiscussandlearnfromoneanother,aswellasunderstandstrate-giesemployedby thementors in theirexperiencesof thesub-jectmatter.Dependingon the tutors’preferences, the styleofthetutorialoftenvariesfromweektoweek.Forexample,sometutorswillframethetutorialbasedonapre-determinedsetofobjectives,whileothertutorsprefertoworkfromaPowerPointpresentation.

TUTORS To ensure sustainability of the Student Mentorship Pro-gram,thekeywastocreateacentredirectedbythestudentsandfor the students. The idea was to reinforce an environment of reciprocityandsharingofpersonalexperiencesamongmedicalstudents.Consequently,thetutors in2012 includedagroupof8secondyearmedicalstudentswhowereselectedforthepro-grambasedonexperiencesandpassionformentorship,asdem-onstratedboththroughtheirapplicationsandinterviews.More-over,activeeffortsweremadetoensurethatabilingualgroupofmentorswererecruitedtobothreflectthediversityofthemedi-calstudentcommunity,aswellastheuniqueapproachestoad-dressingthearrayofstudent-specificconcerns.

Training At the startof the term,everymentorparticipated inadayofmentorshiptrainingprovidedbytheStudentAcademicSuccessServicesattheUniversityofOttawa.Intandem,allmen-torsalsoreceivedfourtrainingsessionsduringthecourseoftheyear intopics identifiedasbeingespeciallyrelevanttomedicalstudentsincluding:stressmanagementandhealthybehaviours,timemanagementandprocrastination,learningstyles,andfacili-

The Faculty of Medicine Student Mentorship Program: A new initiative

NatashaLarocque,BHSc1,NischalRanganath,BHSc1

1FacultyofMedicine,UniversityofOttawa


C o m m e nta r y

tationofacademicstudygroupsessionsdiscussedbelow.

Role The primary role of student mentors is to act as a facili-tator,activelylisteningtostudentconcernsorinquiries,identify-ingpotentialproblem-solvingstrategies,anddevelopingaplanofactionwiththestudent.Uniquetothisreciprocalrelationshipisthesharingofprofessionalexperiencesandinformationtoallowforstudentstolearnfromoneanother.Inparallel,mentorsalsoplayacriticalroleinidentifyinganddisseminatingresourcesben-eficialforstudentspecificconcerns.Forexample,afrequentcon-cernthatstudentsraiseistheirpersonalinterestinundertakingmedicalresearch,butalackofknowledgeregardingtheprocess.Insuchascenario,thementorscanveryeffectivelyintegratenotonlytheirpersonalexperiencesasmedicalstudentresearchers,but also asmentorswho are trained to help students identifyresearch-related resources offeredby the Faculty ofMedicine.Lastly,anintegralpartofthejobofmentorsistounderstandthescopeoftheMentoringCentreandknowwhen,where,andhowtoreferstudentsforadditionalhelpifneeded.

STUDENT COMMENTS Mentors always hear positive feedback from the stu-dentswhovisittheStudentMentorshipProgram.Thefollowingarequotesfromstudentswhohaveparticipatedintheprogram,andaretestamentstothebeneficialimpactsthisprogramhasonthefirstyearstudents.

“The Mentoring Centre is a wonderful resource to have available, especially in first year where it is dif-ficult enough trying to adjust to a new school, a new program, and a new set of academic and professional obligations. Knowing that I could bring my questions and concerns to upper year students anytime, not only helped me with the stress of adapting to the curricu-lum, but also provided me with fellow colleagues to talk to about any concerns I had as a medical student. The mentors were consistently willing to go above and beyond to make sure all my questions were answered, and took the time to help me through any difficulties I was having. The support I received from the mentors has been invaluable to me in so many ways, and has been a major contributor to my successful adjustment to the medical program at the University of Ottawa.” –FirstYearMedicalStudent

“Having support from upper year students through the Student Mentoring Centre is invaluable as they are able to relate to the concerns we have. I’ve found it particularly useful in helping me determine what study strategies might work best for me, how to man-age stress, and learning about what summer opportu-nities are available for medical students. The mentors are very approachable and are always happy to pro-

vide support and advice.”–FirstYearMedicalStudent

Members of the Faculty of Medicine administrationteamhavenoticedtheinfluenceofthisnewinitiative.Dr.LouiseLaramée,AssistantDeanStudentAffairs, strongly supports theStudentMentorshipProgram,andencouragesstudents topar-ticipate.OthermembersoftheStudentAffairsOfficehavealsoheardgreatfeedbackfromstudents.

“The services provided by the mentors have helped students modify and develop new study skills needed to succeed in medical school. We have noticed that several students frequent the Centre on a regular ba-sis, which indicates that they find the services benefi-cial. Nearly half of first year students have attended either a one-on-one session with a mentor or have at-tended a study group. At the Student Affairs Office, we often hear the positive impact that the Centre has had on students’ lives. Since frequenting the Centre, a stu-dent has told me that they were better able to adapt and transition through their first-year in medicine.” – MelissaBarton,LeadCouncilor,StudentAffairsOffice

WHAT ARE OTHER FACULTIES DOING? TheUniversity ofOttawahas a total of 19MentoringCentres. Each centre provides their own initiatives which arelargelydictatedonthenatureofstudiespursued.Forinstance,theFacultyofArtsoffersworkshopsonwritingstyle,andtutoringservicesforavarietyoftopicssuchasphilosophy,whereastheFacultyofLawdeliversexampreparationsessions,andresourcesfor mature students. The Faculty of Science has also developed a ScienceBuddiesprogramwhereseniorstudentsmeetwithnewstudentsandcananswerquestionsone-on-one.Anotheruniqueprogram,heldbytheHealthSciencesMentoringCentre,offerssupportandresourcesthroughonlinediscussionforums. Movingforward, theother initiativesheldbydifferentMentoringCentrescouldhelpshapetheservicesofferedbytheFacultyofMedicineStudentMentorshipProgramtobettermeettheneedsofthestudents.However,amoreformalevaluationofsuchneedsisrequiredbeforenovelinitiativesareimplemented,giventhesuccessofwhatisalreadyinplace.

CHALLENGES TheStudentMentorshipProgramfacedrelativelyminorobstaclesduringitsfirstyearofimplementation.Oneofthepri-marychallengesidentifiedwaspromotingstudentattendanceastheyearprogressed.Thementorspresumedthistrendwasdueto students becoming more comfortable with the curriculum,andthedemandsofmedicalschoolwithtime,therebydecreas-ingtheneedtoutilizetheservicesofferedbytheStudentMen-torshipProgram.Moreover,basedonpersonalcommunicationswithanumberoffirstyearstudentswhovisittheMentoringCen-tre,itwasidentifiedthatmanystudentscontinuetobeunawareofthevarietyofservicesoffered.Forexample,whenonementor


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postedon theFacebookgroup thatmentorscouldprovidead-viceonhowtosecuresummerresearchpositions,approximatelyfivestudentscameforwardrequestingmoreinformationonthesubject.Evidently,thesestudentswerelookingforadviceregard-ingcareerdevelopment,butwereunawarethatmentorscouldprovidetoolsandresourcestosupportjobsearching. In order to increase attendance, one recently imple-mented strategy that seems tobeeffective is tohave thefirstyearclasspresidentsofboththeAnglophoneandFrancophonestreams make announcements as to the services offered. Forexample, thementors currently send aweekly announcementto the presidents to advertise theweekly tutorial. To increaseawareness of the services offered by the StudentMentorshipProgram,weplanondevelopingahand-outoutliningthisinfor-mationwhichwillbedistributedtotheincomingfirstyearstu-dentsduringtheirOrientationWeek.Furthermore,thementorsplanonpreparingbriefdocumentsthatwillbeavailableonlinethrough theFacultyofMedicineMentorshipwebsite, address-ingcommonconcernsfacedbystudentssuchas“HowtoOrga-nizeElectives,”and“WhatisaMedicalStudentPerformanceRe-cord?”

FUTURE DIRECTIONS The StudentMentorship Program has been a successthusfarbecauseofthesupportoftheFacultyofMedicine,thededicationdemonstratedbythestudentmentors,aswellastheinterestandgratitudeoftheparticipatingstudents.Movingfor-ward,weplanonusing feedback formsto further identifystu-dentconcerns,andservicesofferedbytheprogramthatrequireimprovement.Indoingso,wecannotonlybetterequipthemen-torswiththenecessarytrainingandteachingtools,butwecanalsodevelopresourcessuchasbrochures,pamphlets,modules,and themedworkshops toaddress commonstudent concerns.Given the passion and interest demonstrated by the medical stu-dentbody,weintendtofurtherexpandtheStudentMentorshipProgram through accruement of funding, as well as increasedpromotionandaccessibilityoftheservicesoffered. ThegoaloftheStudentMentorshipProgramistofos-ter an environment that enhances the personal and professional well being of the student community. This initiative has beenhighlysuccessfulinitsfirstyearofimplementation,andwelookforwardtocontinuingthisprogramintheyearstocome.


Students, facultyandstaffat theUniversityofOttawamay be familiar with the locally-produced and independently-runstudentnewspapersTheFulcrum(publishedinEnglish)andLaRotonde(publishedinFrench).TheseregularpublicationsarefreeofcosttotheUniversityreadership,andarewidelydistrib-uted fixtures on newsstands across campus. The Fulcrum andLa Rotonde are not only important outlets for voicing studentopinions andpublicizing campusevents, but arealsoexcellentavenues for showcasing vibrant student culture and creativitythrough art and poetry. However, the unsung academic valueof localstudent-runpublicationsresides intheundercurrentofworkthattakesplaceduringthesubmission,reviewandeditingphasesthatprecedepublicationandprint.Inthisbriefcommen-tary,IfocusontherecentrevivaloftheUniversityofOttawaJour-nalofMedicine(UOJM)andassertthatUOJMoffersthestudentsoftheFacultyofMedicineanunrivalledopportunityforhoningwriting andediting skills. Indeed, I believe that this enterprisecanhelptocompensatefortheprogressivelyatrophyingformaleducationinwritingwithinpost-secondarycurricula. AcommonweaknessofmanyundergraduateprogramsinscienceacrossCanadaistheunderrepresentationofscientificwritingintheacademiccurricula.Frommypersonalexperiencesandthroughdiscussionswithmypeers,itisclearthatoverthecourseofafour-yearBachelorofScienceprogram,studentspro-ducelittlemorethanahandfulofwrittenresearchassignments.Furthermore,studentsareoftengradedwithminimalfeedbackontheirwrittenwork,thereforeminimizingtheformaldevelop-mentof theirwritingskills.Arguably, these limitationsaredueto growing class sizes and thetime-consuming logistical night-mare of grading hundreds of multi-page writing assignments.Herein lies an important disconnect between the content of post-secondaryeducationandthe ‘real-world’ requirementsofmanycareersinscience.Fortunately,forstudentsoftheFacultyofMedicineattheUniversityofOttawa,theUOJMoffersarichopportunitytofillthisvoid. TheUOJMwasoriginallyaquarterlypublicationfound-edinthe1960’s,andmetitsdemiseinthe1970’sduetorecedinginterest in the journal [1].Aftera40yearabsence,UOJMwasresurrectedin2011andhassinceproducedtwohigh-qualityis-suescontainingawiderangeofarticlesuniquelygearedtowardthereadershipoftheFacultyofMedicine.UnbeknownsttomanystudentsandfacultyoftheUniversityofOttawamedicalcampus,theprocessesleadingtothepublicationofeachissueofUOJMoffers a highly valuable resource for the development of stu-dents’skillsinscientificwritingandalsoprovidesstudentswithagentleimmersionintothepeer-reviewprocess.

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Thisyear,theUOJMeditorialteamiscomprisedofover30dedicated studenteditorswhoaredivided intomultipleed-iting groups. Every article submission received at UOJM is ren-dered anonymous and independently dissected by three to four editors,whoeachgenerateasystematicreportdocumentingthestrengths andweaknesses of themanuscript. Ultimately, thesereportsareamalgamatedintoasingledocumentthatisreturnedtothesubmittingauthor.Thedocumentreceivedbytheauthorcontainsdetaileddiscussionsregardingthestrengthsandweak-nessesofthemanuscript,constructivecriticisms,andsuggestionsforhowto improve themanuscript forpublication.Thesecom-mentsarewide-rangingandcanincludesuggestionsforgenerat-inganimproved‘flow’andnarrativethroughthereorganizationofthoughts,highlightsoflogicalerrors,andmayevenextendintothe minutiae of sentence structure, word-selection and verb-tense. Frommyexperience,manuscript reviews from larger in-ternationaljournals,orevenfeedbackonwritingassignmentsinadvancedgraduate-levelcourses,willrarelydelveintosuchdetailregardingthe‘writing’perse.Therefore,individualswhotaketheinitiativetosubmitamanuscripttoUOJMarerewardedwithun-paralleledfeedbackontheirwritingandauniqueopportunitytolocallyhonetheirwritingskills–completelyfreeofcharge.Thefruits of their labor are further sweetened by the prospect of im-mortalizingtheirwork inthe journalof their futurealmamater–somethingtosurelytakepridein. In a manner that complements the development of writ-ingskillsofstudentsintheFacultyofMedicine,UOJMalsoaffordsstudentswiththeuniqueandhighlyvaluableopportunitytotakeoneditorialresponsibilitiesandparticipateinthecriticalreviewandappraisalofsubmittedmanuscripts.AsanewSectionalEditoratUOJM,Ihavewitnessedthesepositiveexperiencesfirst-hand.TheUOJMeditors are guided througha step-wise trainingpro-cessthatprovidesthemwiththeinsighttobetterunderstandtheroleofareviewerinapeer-reviewedpublication.Theeditorsareexposedtohighlydiversewritingstylesandgainadeepapprecia-tionfortherangeofwritingskillswithintheiracademiccommu-nity.As such, inaddition topromoting thedevelopmentof thewriting skills of their peers (as described above),UOJMeditorsalsopersonallybenefitfromtheenlighteningexerciseofcompil-ingdetailedandobjectivereviewsofsubmittedmanuscripts.Thesimpleprocessofcriticallyassessingamanuscriptcangreatlycon-solidateanindividual’sownperspectivesontheartofwriting,andcanthereforeserveasaneducationinwritinginitself.Thus,thereisconsiderableeducationalworthinthe‘extracurricular’activitiessurroundingUOJMthatislargelyoverlooked.IassertthatfacultymembersshouldencouragestudentstosubmitarticlestoUOJM

The unsung value of local peer-reviewed publications

KevinF.H.Lee,BSc1

1Dept.ofCellularandMolecularMedicine,FacultyofMedicine,UniversityofOttawa


orapplytobecomeamemberoftheUOJMeditorialteamtotakeadvantageofthisbeneficialacademicsupportsystem.

In closing, the UOJM provides a unique resource forstudentstodeveloptheirwritingskillsandalsooffersanoppor-tunity to independently participate in the peer-reviewprocessatanearlystageintheirscientificcareers.AuthorswhosubmittheirmanuscripttoUOJMreceivedetailedandconstructivecriti-calfeedbackfromtheUOJMeditorialteamthatisunlikelytobefoundelsewhereduring theirpost-secondaryeducation. Inad-dition,UOJMeditorsareexposedtotheprocessofpeer-revieweditingwhichcan indirectlybenefit the individual’sowndevel-opmentasawriter.AlthoughcontributorstoUOJMmaynotre-ceive the sameprestigeor accolades as publishing in large in-ternationaljournals,IbelievethattheUOJMenterpriseisfertilegroundsfortheacademicdevelopmentofstudentsattheFacultyofMedicineandforthe localpromotionofscientificliteracy ingeneral.Onlytimewilldemonstratewhetherthisunsungvaluecanacquirebroaderacclaim,orwhethertheUOJMwillrecedeintothedepthsofliteraryhibernationasitdidinthe1970’s.

REFERENCES1. CheungC, SebaltA,WellsP, ForgieM.Address fromEditorsandFaculty.

UniversityofOttawaJournalofMedicine2011;5(1):4-5

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Mentee vs. mentor: A debate on the use and efficacy of platelet-rich protein injections for the treatment of soft tissue musculoskeletal injuries

TheAltitudeMentoringProgramwasestablishedtoempowerundergraduatestudentsfromunderrepresentedpopulationstopursuecareersinhealthcare.Thisisachievedbynurturinghighqualityrelationshipswithmedicalstudentmentorswhohelpthesestudentsrealizetheirpotentialasfuturehealthcareprofessionals.Thementorsworkwiththefirstyearstudentstotheskillsandcom-petenciesnecessarytoexcelinafuturehealthcarecareer.Mymentee–Subhan–andIdecidedtofocusonaprojectthatwouldequiphimwithanarsenalofresearchskillsincluding:literaturereview,evaluatingevidence,scientificwritingandusingreferencingsoftware.Thegoalwastosethimupwithhisfirstpublicationsuchthathemightbeacompetitiveapplicantforsummerresearchopportunities.

Aftermakingashortlistofareasinmedicinethatinterestedtheundergraduatestudent,wesoughtoutcontroversialtopicswithinthesedisciplines.Eventually,wesettledontheuseandefficacyofplateletrichprotein(PRP)injectionsforthetreatmentofsofttissuemusculoskeletalinjuries.SubhanarguedfortheuseofthistherapyandIarguedagainst.PRPisbloodplasmaenrichedbyplateletsthatcontaincytokinesandgrowthfactorstostimulatehealingofboneandsofttissue.TigerWoods,TroyPolamalu,KobeBryantandRafaelNadalarejustafewexamplesofprofessionalathleteswhohavemadeheadlinesusingthiscontroversialtreatment;weareabouttoexaminewhetherornotitismerited.

NicholasPaterson,BScH1,SubhanSediqi1FacultyofMedicine,UniversityofOttawa

Subhan SediqiFirst year health sciences

Nicholas PatersonFirst year medicine

FOR PRP INJECTIONS - Subhan Sediqi AGAINST PRP INJECTIONS - Nicholas Paterson

SAFETYPatientsafetyisaprimaryconcernwhendetermininganychoiceoftherapy.PRPinjectionsareautologous,meaningtheyarecre-ated fromthepatient’sown fractionedblood [1].Due to theirorigin, these injections have beenconsistently shown to be safe and to yieldnoadverse sideeffects [2].Furthermore, in two recent studiesPRP injections have trumped thegoldstandardofcorticosteroidinjec-tions in termsof reducingpainandincreasingarticular function insoft-tissue tendon inflammation [3, 4].Given the risk factors and adversesideeffectsassociatedwithcortico-steroids,PRPinjectionsarebecominganincreasinglyviableop-tion.

EFFICACY Arecentdoubleblindstudy,inwhichpatientssufferingfromOsteoarthritis(OA)wereinjectedwitheitherPRPorasa-lineplacebo,determinedthatthePRPgroupexhibitedagreateramountofsymptomaticrelief (includingasignificantreductioninpain)comparedtotheplacebogroup[5].Additionally,recentliteraturehassupportedthebeneficialeffectthatPRPinjectionscanhaveondecreasingpatient-reportedsymptomsofpainandqualityof life inOA [6,7].Anotheralternative,hyaluronicacid

SAFETYPRPinjectionsarebeingportrayedasa‘‘wonderdrug’’withoutsufficient evidence supporting their application in the clinicalscenarios inwhich theyarebeingused.PRP injectionsaread-ministered for a variety of condi-tions including: lateral epicondy-litits, osteoarthritis, knee ligamenttears, plantar fasciitis, and rotatorcuffinjury[1].Fromasafetystand-point,thepotentialadverseeffectsfromtheinjectionsthemselvesarefairly benign (pain, nerve injury,infection), but the long-term re-percussions from the therapy are unknown [14]. There has been asignificant amountof publicity regardingPRP injections thankstoeliteathletesoptingforthesenoveltreatments.Thisbegsthequestionastowhetherthistherapyisbeingdrivenbyresearchor,perhapsmorelikely,themarket.

EFFICACY Considering the importanceof “evidence-basedmedi-cine”inclinicalpractice,itissurprisinghowlittlesubstantiationthere is to supportPRPefficacy.The literaturealmost contain-smorereviewsthanclinicalstudies.Existingstudiesconsistpri-marilyofanecdotalreportsorcasestudies,andmanyofthere-centpublicationsareeitherpoorlydesigned,retrospective,havesmallsamplesizesordonotuseplacebocontrols[5].Afewcon-trolled,higher-levelstudiesexist,butmuchoftheevidencehas


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(HA),isapopularviscosupplementusedinOAtreatmentbuthasbeenassociatedwithasmall,clinicallyirrelevantbenefitandanincreasedriskofseriousadverseevents[8].PRPinjectionshaveyielded significantly higher patient satisfaction scores than HAinjections for the treatmentofOA [9,10].PRP injectionshavealsobeenshowntobeeffective insofttissuemusculo-skeletalinjuriessuchasepicondylitis,wherethePRPgrouphadagreaterimpactonfunctionandrepairafter6weekswhencomparedwithautologouswholeblood(control)[11].PlantarfasciitisisanotherdisablingconditionwherePRPinjectionsdemonstratedsuperiorresults over the standard corticosteroid injection[12]. Finally,supraspinatuspartial-tear injuries in the rotator cuff thatweretreatedwithultrasound-guidedPRP injectionswere favourableto dry-needling (similar to acupuncture) in both reducing painanddisability[13].

CONCLUSION Intheory,apatientcoulddelayinvasiveandcostlysur-geriesorexperiencelesspaininthetimeleadinguptoasched-uledsurgerybyundergoingPRPinjectiontherapy.Furthermore,ifapatientis inoperable,orhasfailedaftersurgery,thisthera-pycouldbeofgreatvalueonceappropriatedosageandtimingschedulesarebetterdeveloped.ThereisalargebodyofevidenceinsupportoftheabilityforPRPinjectionstosignificantlyreducepain,increasefunction,andimprovequalityoflife.AsPRPinjec-tionprotocolsarebetterrefined, Iexpecttheseresults tocon-tinue.Theseearlypositiveclinicalresultscombinedwiththefea-sibilityofthetherapy,whichcanbedeliveredinanout-patientsetting, suggest there is great potential for this treatment andIanticipate future researchendeavours tocontinuetodemon-strate this.

not supported the use of PRP in varioussoft-tissue conditions.One studydemonstratedno clinicalorultrasonic advantageofPRPoverplaceboinchronicAchillestendinopathyat1year[15].PRPinjectionsusedconcurrentlywithanteriorcruciateligamentsurgeryallograftsshowednodiscernibleclinicalorbiomechani-calbenefitat2years[16].Furthermore,usingPRPinameshma-trixapplied to the siteof the tendon-bone interface in rotatorcuffsurgicalrepairrevealednoeffectonbiologicalrepair,func-tionorclinicalratingsscales-itmayhaveevenbeendeleterious[17].Finally,treatmentofAchillestendonrupturesusingPRPin-jectionshadworseclinicalscoresthanthecontrolat1year[18].

CONCLUSION It is important to note that PRP injections are beingused formanyconditions thathavebeen largelyproven to re-solve with rest and/or conventional anti-inflammatory or icetherapy [1]. Furthermore,many studies focuse onminimal re-ductioninhealingtimesconferredbythistherapy,which,whilepotentiallyapplicabletotheeliteathlete,maynotbeasrelevanttotheweekendwarriorgiventheunknownlong-termrisks.Theadditional cost relative to the alternatives and lack ofmedicalcoveragefurtherdecreasestheaccessibilityofthistherapy.Forthesereasonsandtheoverwhelminglackofevidenceforitsuse,IcannotrecommendPRPinjectionsforsoft-tissueinjuries.

REFERENCES1. NguyenRT,Borg-SteinJ,McInnisK.Applicationsofplatelet-richplasmain

musculoskeletalandsportsmedicine:anevidence-basedapproach.PMR.2011Mar;3(3):226–50.

2. Andia I, SánchezM,Maffulli N. Platelet rich plasma therapies for sportsmuscleinjuries:anyevidencebehindclinicalpractice?ExpertOpinBiolTher.2011Apr;11(4):509–18.

3. PeerboomsJC,SluimerJ,BruijnDJ,GosensT.Positiveeffectofanautolo-gousplateletconcentrateinlateralepicondylitisinadouble-blindrandom-ized controlled trial: platelet-rich plasma versus corticosteroid injectionwitha1-yearfollow-up.AmJSportsMed.2010Feb;38(2):255–62.

4. Gosens T, Peerbooms JC, Van LaarW,DenOudstenBL.Ongoing positiveeffectofplatelet-richplasmaversuscorticosteroid injection in lateralepi-condylitis:adouble-blindrandomizedcontrolledtrialwith2-yearfollow-up.AmJSportsMed.2011Jun;39(6):1200–8.

5. PatelS,DhillonMS,AggarwalS,MarwahaN,JainA.Treatmentwithplatelet-richplasma ismoreeffectivethanplaceboforkneeosteoarthritis:apro-spective,double-blind,randomizedtrial.AmJSportsMed.2013Jan8;356–64.

6. FilardoG,KonE,PereiraRuizMT,VaccaroF,GuitaldiR,DiMartinoA,etal.Platelet-richplasmaintra-articularinjectionsforcartilagedegenerationandosteoarthritis: single- versusdouble-spinningapproach.KneeSurgSportsTraumatolArthrosc.2012Oct;20(10):2082–91.

7. GobbiA,KarnatzikosG,MahajanV,MalchiraS.Platelet-richplasmatreat-mentinsymptomaticpatientswithkneeosteoarthritis:preliminaryresultsinagroupofactivepatients.SportsHealth.2012Mar;4(2):162–72.

8. RutjesAWS,JüniP,DaCostaBR,TrelleS,NüeschE,ReichenbachS.Visco-supplementation for osteoarthritis of the knee: a systematic review andmeta-analysis.AnnInternMed.2012Aug7;157(3):180–91.

9. KonE,MandelbaumB,BudaR,FilardoG,DelcoglianoM,TimonciniA,etal.Platelet-richplasmaintra-articularinjectionversushyaluronicacidvisco-supplementationastreatmentsforcartilagepathology:fromearlydegen-

erationtoosteoarthritis.Arthroscopy.2011Nov;27(11):1490–501.10. Mei-DanO,CarmontMR,LaverL,MannG,MaffulliN,NyskaM.Platelet-rich

plasmaorhyaluronateinthemanagementofosteochondrallesionsofthetalus.AmJSportsMed.2012Mar;40(3):534–41.

11. ThanasasC,PapadimitriouG,CharalambidisC,Paraskevopoulos I,Papan-ikolaouA.Platelet-richplasmaversusautologouswholebloodforthetreat-mentofchroniclateralelbowepicondylitis:arandomizedcontrolledclinicaltrial.AmJSportsMed.2011Oct;39(10):2130–4.

12. Omar AS, IbrahimME, Ahmed AS, SaidM. Local injection of autologousplatelet richplasmaandcorticosteroid in treatmentof lateralepicondyli-tisandplantarfasciitis:Randomizedclinicaltrial.EgyptianRheumatologist.2012Apr;34(2):43–9.

13. RhaD-W,ParkG-Y,KimY-K,KimMT,LeeSC.Comparisonofthetherapeuticeffectsofultrasound-guidedplatelet-richplasmainjectionanddryneedlingin rotator cuff disease: a randomized controlled trial. Clin Rehabil. 2013Feb;27(2):113–2

14. SánchezM, Albillos J, Angulo F, Santisteban J, Andia I. Platelet-rich plas-ma inmuscle and tendonhealing.Oper TechOrthop. Elsevier Inc.; 2012Mar;22(1):16–24.

15. deJongeS,deVosRJ,WeirA,vanSchieHTM,Bierma-ZeinstraSM,VerhaarJN,etal.One-year follow-upofplatelet-richplasmatreatment inchronicAchillestendinopathy:adouble-blindrandomizedplacebo-controlledtrial.AmJSportsMed.2011Aug;39(8):1623–9.

16. NinJRV,GasqueGM,AzcárateAV,BeolaJDA,GonzalezMH.Hasplatelet-richplasmaanyroleinanteriorcruciateligamentallografthealing?Arthroscopy.ElsevierInc.;2009Nov;25(11):1206–13.

17. Rodeo S,DelosD,WilliamsRJ,AdlerRS, PearleA,WarrenRF. Theeffectofplatelet-richfibrinmatrixonrotatorcufftendonhealing:aprospective,randomizedclinicalstudy.AmJSportsMed.2012Jun;40(6):1234–41.

18. SchepullT,KvistJ,NorrmanH,TrinksM,BerlinG,AspenbergP.Autologousplateletshavenoeffectonthehealingofhumanachillestendonruptures:arandomizedsingle-blindstudy.AmJSportsMed.2011Jan;39(1):38–47.


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Warning: Don’t let the fast-track slow you downKevinF.H.Lee,BSc1

1Dept.ofCellularandMolecularMedicine,FacultyofMedicine,UniversityofOttawa

Every autumn in Canada, thousands of graduate stu-dentsinthesciencesapplytofederally-fundedscholarshipsfromtheCanadianInstitutesofHealthResearch(CIHR)ortheNaturalSciencesandEngineeringResearchCouncilofCanada (NSERC).Theseprestigiousandhighlycompetitivescholarshipsareaward-edtograduatestudentswhohavedemonstratedexcellentaca-demic achievement in their undergraduate studies and exhibithighresearchpotentialthroughauthorshipsonscientificpublica-tions.Aftertheeconomicdownturnof2008,federalfundshavethinnedand,asaconsequence,theintensityofcompetitionforgraduatescholarshipshasamplifiedsignificantly.Forexample,inthe2008-2009fundingcycle,373CanadaGraduateScholarship(CGS)doctoralresearchawardsweregrantednationwidebyCIHRwithabudgetof$36,589,584[1].By2011-2012,thebudgetwasnearlyhalved (to$19,748,751)andonly197doctoral studentswereawardedCGSfundingacrossCanada.Beyondthisfundingdrop,studenteligibilityforfederalfundingcanalsobeunjustlycompromised.Inthisarticle,Iexaminethe‘fast-track’programattheFacultyofMedicine,whichenablesM.Sc.studentstotransferdirectlyintothePh.D.stream,andhowthetimingofthisprocesscaninadvertentlytruncatestudenteligibilityforCIHRandNSERCfunding.Interestinthefast-trackprogramissteadilyincreasingandpresently,fast-trackstudentscompriseover50%ofallPh.D.studentsattheFacultyofMedicine(Figure1)[2].Thus,Irecom-mendthattheadministrativebodieswithintheFacultyofMedi-cinecloselyexaminethesedetailsastheycarryseriousimplica-tionsforindividualstudents,facultymembersandtheacademicinstitutionalike. InSeptember2009, Ienrolledat theUniversityofOt-tawaintheM.Sc.programinneuroscience.Iquicklydevelopedapassion formyworkanddecided topursuedoctoral studiesthrough the fast-trackmechanism. Sincemy supervisor was anewfacultymemberatthetime,wewerebothlargelyoblivioustothedetailsofthefast-trackprogram–wesimplyagreedthatitwasagoodidea.Afterearningfacultyapprovalformytransfer

and the necessary paperwork and administrative details werecomplete,IwasenrolledinthePh.D.programinSeptember2010–exactly12monthsafterstartingintheM.Sc.program.Itwasastreamlined process and I was pleased with my decision. Alongsidemyfellowpeers,Ispentagreatdealoftimecraftingandsubmittingapplications toNSERCandCIHRduringthe subsequent autumn seasons. Persevering through annualrejectionletters,Idiligentlyworkedonmyresearchproject,pre-sentedmyfindingsatscientificconferences,andcontributedtoamodestnumberofpeer-reviewedpapers.Byautumnof2012,IwasconfidentthatIhadachievedsufficientacademicandsci-entificmerittoassembleatrulycompetitivescholarshipapplica-tion.However,itwastomybittersurprisetodiscoverthatIwasnolongereligibleforfederalfundingduetoaperversetechnical-itydirectlyrelatedtomyfast-tracktransfer. Both CIHR and NSERC have set scholarship eligibilityguidelinesbasedonthedurationthatastudenthasspentintheM.Sc. programprior to transferring to thePh.D. stream.Here,I will illustrate the circumstances that personally I faced in the 2012applicationyear.CIHRguidelinesindicatethatif:

“The candidate has completed 12 months or more in a Master’s degree program prior to transferring to or starting a Ph.D. program...then the maximum amount of time he/she can be registered as a full-time student in a Ph.D. program [to be eligible for funding], as of the application deadline, is 22 months.” (Figure 2; Students A & B) [3].

At thetimeof application inOctober2012, I had justcompleted24months in thePh.D.programandwas thereforeineligible(Figure2;StudentB).Worseyet,if:

“The candidate has completed less than 12 months in a Master’s degree program prior to transferring to or starting a Ph.D. program...then the maximum amount of time he/she can be registered as a full-time student in a Ph.D. program [to be eligible for funding], as of the application deadline, is 30 months.” (Figure 2; Student C) [3].

Inshort,thesepoliciesindicatethatifIhadtransferredtothePh.D.streamonesemesterearlieroronesemesterlater,Iwouldhavebeenfullyeligibleforsubmittingascholarshipappli-cationin2012(Figure2).AsimilarrulealsonegatedmyeligibilityforanNSERCscholarship[4].Indisbelief,ImadethenecessarytelephonecallstopleadmycasewithofficialsatCIHRandNSERConlytoreceiveapologeticconfirmationsofmyineligibility.Simi-

Figure 1: Distribution Ph.D. students at the Faculty ofMedicine. Fast-trackPh.D.students(shownbydepartment)comprise56.5%ofallPh.D.studentscomparedto43.5%whohavepreviouslycompletedaMaster’sdegree(alldepartments).IllustrationbytheAuthor.


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lar appeals were made with administrators at the Faculty of Med-icine,butalsotonoavail.Thisultimatelyrenderedmyglowingscholarshipapplication,ofwhichIwasquiteproud,completelyandutterlyuseless.Ifeltcheated.Afterall,itwasonlypaperworkhinderingmyscholarshipeligibility. Afterspeakingtoothergraduatestudentsaboutmyex-perience, Iwasdisturbed todiscover that thiswasa recurrentproblem. Poor timing of fast-track transfers at the Faculty ofMedicinehadafflictedseveralstudentsbeforemeand,withlittledoubt,othersinprecedingyears.Assuch,manywell-deservingstudentshavebeenbarredfromapplyingtoscholarshipsatthetimewhentheiracademicdossiersarearguablyattheirpinnacle.Unfortunately,thesestudentsandtheirlaboratoriesquietlyab-sorbedtheirfrustrations,ultimatelyleavingsuccessivestudentssusceptible to this technical trap. Thiswas clear evidenceout-lining thedamaged linesof communicationbetween students,facultymembersandadministration. Federally-funded graduate scholarships not only be-stowprestigeupontheawardedstudent,buttheyalsobenefitthelaboratoriesandtheacademicinstitutionsinwhichtheyareheld.To illustrate this, consider thebenchmarkCIHRorNSERCdoctoral research scholarship worth $21,000/year for up to 3years [3, 4]. These awards are sufficient tofinance the annualstipendofadoctoral student thatwouldhavebeenotherwisededucted from the operating grants of the host laboratory. Ifone considers that a typical laboratoryoften includesmultiplegraduatestudents,thesumofmultiplestudentstipendscanbeasubstantialfinancialburdenonthesustainabilityandproductiv-ityof anygiven laboratory.With thehelpof externally-fundedgraduatescholarships,laboratoriescandirectgreaterresourcestoward thematerials necessary to execute important research

projects.Inturn,theacademicinstitutionstandstobenefitfromincreasedresearchproductivity.Thesearelaudableadvantagesforallmembersoftheacademicinstitutionatlarge. Studentsworkextremelyhard to compile competitivescholarship applications. To support these efforts, and for thegreaterbenefitofitsacademiccommunity,theFacultyofMedi-cinemustrevisethecurrentexecutionoffast-tracktransferstomaximizethedurationofscholarshipeligibilityfor itsstudents.Itisnecessarytoemphasizethatthespecificsemesterinwhicha student transfers to the Ph.D. program is unlikely to impacttheireducationoracademicachievements(asdepictedinFigure2).Onemightalsoappreciatethatafirst-yeargraduatestudentpreparingforatransferwillrarelycarrytheforesighttoconsidertheir future fundingeligibility.Withasimplechangeofadmin-istrativepractices,futurefast-trackedPh.D.students–someoftheFacultyofMedicine’sbestandbrightest–willneverneedtoexperiencethedeepdisappointmentofbeingunjustlyexcludedfromnationalcompetitionswhenatthepeakoftheircompeti-tiveedge.

REFERENCES 1. Canadian InstitutesofHealthResearchDoctoralResearchAwardFunding

Decisions[internet;updated2013-01-31].Availablefrom:http://www.cihr-irsc.gc.ca/e/46292.html

2. Personalcommunication,FacultyofMedicineAcademicAdministrationOf-ficers.ProportionofcurrentPh.D.inthefast-trackprogrambydepartment:Biochemistry (32/54), CMM (29/78),Microbiology (13/28),Neuroscience26/43;March2013.

3. CanadianInstitutesofHealthResearchDoctoralResearchAward[internet;updated 2013-02-21]. Available from: https://www.researchnet-recherch-enet.ca/rnr16/srch.do>>DoctoralResearchAward

4. NaturalSciencesandEngineeringResearchCouncilofCanada[internet;up-dated2012-09-06].Availablefrom:http://www.nserc-crsng.gc.ca/students-etudiants/pg-cs/bellandpostgrad-belletsuperieures_eng.asp

Figure 2. Thetimingoffast-tracktransfertoPh.D.streamcansignificantlyaffectstudenteligibilityforCIHRDoctoralResearchScholarships[3].Five-yearstudytrajectoriesofthreetypicalfast-trackstudents(A,B,C)aredepicted.EachstudentbeginsgraduatestudiesattheFacultyofMedi-cineinSeptemberofYear1andtransferstothePh.D.streamatthebeginningofdifferentsemesters(January,September,May,respectively;yellowbars).StudentsA&Bspend12monthsormoreintheM.Sc.program(grey)beforetransferringtothePh.D.program;thesestudentsareeligible(blue)toapplyforfederalfunding(redarrowsanddashedlines)upto22monthsoffull-timeregistrationinthePh.D.program.StudentCspendslessthan12monthsintheM.Sc.programbeforetransferringtothePh.D.streamandiseligibletoapplyforfederalfundingupto30monthsofregisteredfull-timePh.D.studies.Theasterisk(*)highlightsthediscordancebetweenthenumberofapplicationopportunitiesStu-dentBiseligibleforcomparedtoStudentsA&C,despiteidenticaldurationsspentinagraduateprogrambetweenallthreestudents.NSERCguidelinessubjectStudentBtoasimilardisadvantage[4].IllustrationbytheAuthor.


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RESEARCH ETHICS: AN INTRODUCTION Ethics is an important part of biomedical as well as clini-cal research.Prior to theFirstWorldWar, therewerenoFoodand Drug Administration (FDA) or Institutional Review Boards(IRBs)andhence,nosetrulesregardingtheuseofhumansub-jectsinresearch.ThefirstsignificantsetsofregulationswerenotputforthuntiltheendoftheSecondWorldWar.In1946,aUSmilitary tribunalopenedproceedingsagainstahandfulofGer-manphysicians for conducting crimesagainsthumanityduringtheHolocaust[1].Twoyearslater,theNurembergCodewases-tablished,makingvoluntaryconsentofhumanparticipantsman-datory, aswell asdeclaring that thebenefitsof researchmustexceeditsinherentrisks[1].In1964,theDeclarationofHelsinkifollowedsuitanddictatedthat,inadditiontovoluntaryconsent,laboratoryandanimalexperimentationmustalwaysprecedere-searchonhumansubjects.Eversinceitsconception,thedeclara-tionisrevisedonaregularbasis[2]. Another scandalous case of human experimentationoccurredintheUnitedStatesbetween1932and1972[3].TheTuskegeeSyphilisStudy,quotedas“arguablythemostinfamousbiomedical research study in thehistoryof theUnitedStates”,wasaclinicalprojectconductedonlow-incomeAfrican-Americanmales,ofwhommostwereinfectedwithsyphilis[4].Theissuewith the trial was that many of the subjects were denied peni-cillin treatment thathadbecomeavailable in the1950s.Manyparticipantslatersuccumbedtothedisease.Tothegovernment’sembarrassment,thestudywasfinallyterminatedin1973bytheUSDepartmentofHealth,Education,andWelfareafterthestorywentpublic[3].Despitebeingknownforitslackofethicalcon-duct,thisstudyplayedanimportantroleintheformulationofanewsetofguidelines,outlinedintheBelmontreport,whichgov-ernresearchonhumansubjectsintheUnitedStates.Draftedin1979,thisreportincludesthreemainprinciples—(1)Respectforpersons,(2)Beneficence,i.e.maximizingbenefitsandminimizingrisks,and (3) Justice, i.e.equaland fairdistributionofbenefitsandrisksofresearch[5]. WiththeestablishmentofFDA,IRBs,andanumberofdocumentsthatprotectandrespectthestatusofhumanpartici-pantsinresearch,itwasalmostimpossibletoimagineanythingthat would penetrate the stout walls of ethical guidelines. In1998, the veryfirst humanembryonic stemcells (hESCs)werederivedfromanembryoandculturedinalaboratorysetting[6].Withtheadventofanentirelynewfieldofresearch,bioethicistsaround the world had to reconsider the current bioresearch guidelines,notonlyregardingresearchinvolvingadulthumans,butalsointermsofdefiningthemoralstatusofahumanembryo.

Asaresult,theethicsreviewboardsunderwentanoverhaultoaccommodateforrulesandregulationsregardingexperimenta-tioninthisnovelfieldofresearch.Fifteenyearslater,theuseofhESCsinresearchisstillahottopicdebatedglobally. Thefieldofstemcellresearchholdsenormouspotentialforunderstandinghumanbiologyandfordevelopingnewtreat-mentsforincurablediseases.However,thereareafewthingstoconsider froman ethical standpoint. In this article, the ethicalissues involved in hESC research are succinctly discussed both fromascientificandareligious/spiritualperspective.Abriefdis-cussionofiPSCsasaprobablesolutionandalternativesofhESCresearch is also included.

A SCIENTIST’S PERSPECTIVE Almost15yearshavepassedsincethederivationofthefirsthESCline.Thisfieldofresearchhasmadeimmensestridesandiscontinuingtodosoalbeitataslowpace.Thesestemcellsarederivedfromtheinnercellmass(ICM)oftheblastocyst,ap-proximatelyfivedayspost-fertilization.Fromascientificresearchstandpoint,hESCsofferthegreatestpotentialintermsofcellulardifferentiation—thepointoforigin,sotospeak,ofallthefuturecelllineages.Thislimitlesspotentialisalsotermedthepropertyofpluripotency.Duetothisproperty,theyareoneoftheprimaryregenerative tool candidates for the treatment of a variety ofdegenerativediseasesinvolvingdiverseorgansystemsincludingbone, cartilage, nervousor immuneandmayevenbeused totreatdiversediseasessuchasType1diabetes[7]. The non-scientific community often tends to wronglyassociate hESCs with cloning. The mere mention of the word‘cloning’inanysocialsettingisenoughtosetoffaheateddebatebetween the proponents and opponents of stem cell research. Infact,cloningsimplydescribesproducingidenticalcopiesofasingleunit.Forexample,makingidenticalcellsfromasinglecell,something thehumanbodydoeson a regular basis. Addition-ally,peopletendtoforgetthatstemcellsarebeingusedtotreatleukemiapatients on a daily basis. This treatment,whichusesspecificblood-derivedhematopoieticstemcells,hasbeeninuseforalmosthalfacentury[8].Thescientificcommunitybelievesthatthepublicneedstobebettereducatedaboutthescienceofstemcellresearchandthepotentialitholdsforthetreatmentofdiseases [9].Realizing thetherapeuticpotential thatstemcellsholdrequireslargeinvestmentinresearch.IntheUnitedStates,amajorityof the funding is obtained through the federal gov-ernment[9].Thecommitmentoffundsnotonlyhelpstofurtherdevelopthefieldinadirectway,butalsostrengthenspubliccon-fidenceandapproval.Inaddition,publicfundingensuressound

Ethics and stem cell research: The Knotty Business

TarunpreetDhaliwal,MSc1

1SprottCentreforStemCellResearch,RegenerativeMedicineProgram,OttawaHospitalResearchInstitute,Ottawa,Canada.


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socialpolicybyencouragingstemcellresearchtopicsthatreflectsocialpriorities,whichmightnotbeconsiderediftheresearchisfundedbytheprivatesectoralone[9]. ScientistsbelievethathESCsaremorallyequivalenttoany other cell type in the body since they are obtained from the embryo,otherwiseknownasacollectionofcells[10].InCanadaandtheUnitedStates,hESCsusedinresearchareobtainedfrompre-implantationembryos.Thesearereproductivelyunviableby-products of in-vitro fertilization, or so-called “spare embryos”,that are used for research once informed consent and approval are received from the donor. This is a far cry from fears of assault onhuman life.However, forthecommunitieswhoconsideranembryonicstemcelltobealifeform,thisargumentisredundant. Oneof themajor sources of confusion,which causedthebanofhESCresearchduringtheBushadministration,wasthedifficultyindifferentiatingbetweenreproductiveandtherapeuticcloning.Theformerprocess,whichresultedinDollythesheep,isunacceptableinhumans.However,inthelatter,noinuteroim-plantationisperformed,andthereforeno‘clonedhumanbeing’isexpected[11].Aspreviouslymentioned,thebiggestadvantageof the pluripotent cells obtained from this embryo is their use in research.In2009,theObamaadministrationgaveagreenlighttothefieldofstemcellresearchbyallowinggenerationofnewhESClines,inadditiontothepreexistingones,forthesolepur-pose of research.

RELIGIOUS/SPIRITUAL PERSPECTIVE In2001,theheadoftheRomanCatholicChurch,PopeJohnPaulII,toldtheformerUSPresidentGeorgeW.BushthathESCresearchisanevilpracticeakintoinfanticide,euthanasia,andabortion[12]. In2005,JamesDobson,formerChairmanofAmericanorganizationcalled “Focuson theFamily”, comparedscientistsundertakinghESCresearchtoNazis.HementionedthatthediscoveriesmadeduringhumanexperimentationintheHolo-caustmighthavebenefittedmankind,butwasundoubtedlynottherightapproachtodoso[13].Anotherinstanceworthquot-ingcomesfromanonlinereligiousorganizationcalled“OntarioConsultantsonReligiousTolerance”,based inOntario,Canada.Thewebsitestatesthatifahumanembryo,twoweeksaftercon-ception,isconsideredaperson,thenhESCresearchconstitutesfirst-degreemurder.However,ifitisnotaperson,itismorallyac-ceptable[14].Thisstatementandaplethoraofstatementsmadebyanumberof religious and culturalorganizations leavea lotof looseendsandevenmoreunansweredquestions.Themainquestion is:Atwhatpointpost-conception isahumanembryoreallyconsideredahumanbeing? Manyreligiouscommunitiesbelievethat lifebeginsatconception.Theyagreethatanembryoorafetus,initself,isge-netically humanandpossesses thepotential todevelop into acompletehumanbeing[15].Aquestionthatismostconcerningis whether it is even morally appropriate to manipulate or de-stroy a human embryo for the purposes of research and therapy. However,sometraditionsdobelievethat,althoughanembryorepresentsahumanlife,sacrificingonelifeinordertosaveand

preserveotherlivesisacceptable[16].DespitethedifferenceinopinionsregardinghESCresearch,thenon-scientificcommunityingeneralbelievesthatadultstemcellresearchisapotentialso-lutionsinceitdoesnotinvolvedestructionormanipulationofahumanembryoandbecauseitmakesuseofanindividual’sresi-dentstemcellpopulationstorepairandregeneratedamagedtis-sue.

iPSCS: THE SOLUTION? Somatic cell nuclear transfer (SCNT) is a therapeuticcloning procedure that involves isolation of nuclear materialfromasomaticcellandtransferringitintoanenucleatedoocyte,therebygeneratinga“non-traditional”embryo[17].Whiletheseembryos are strictly prohibited for in utero transfers, the verynature of SCNT research involved is rife with ethical concerns and isenough to setoffadebate regardinghumancloning. In2006, however, the regenerative medicine community aroundtheworldwas leftawestruckwhen Japanese clinician-scientistDr.ShinyaYamanakaandcolleaguessuccessfullyreprogrammedmouseskinfibroblastsbacktotheirpluripotentstemcellstate(termedinducedpluripotentstemcellsoriPSCs)usingacocktailofgenes [18].Thiswassubsequentlyreproducedthe followingyear inadulthumanskinfibroblasts.These iPSCswere initiallythought tobean “ethical dilemma-free replica”of ESCs and itwas assumed that iPSCs could replace hESCs. Unfortunately,the substitution of hESCs to iPSCs does not appear to be thatstraightforward.Althoughbothcelltypesarepluripotentinna-ture,theydoexhibitdifferencesattheepigeneticlevel(geneex-pressionchangesthatdonotinvolveachangeinthesequenceof DNA). Dr. GeorgeO’Daley, a senior clinician-scientist at theHarvardStemCellInstituteinBoston,believesmoreresearchoniPSCsisrequiredinorderforthesecellstobelabeledasasafereplacementforhESCsinresearchandtherapy[19]. Some researchersdo,however,believe that iPSCswillreplacetheneedtousehESCs.Yamanakahowever,believesthattoeveryproinresearch,thereexistsacon.“Now,wecanavoidusinghumanembryos.So that isverygood,”hementioned totheTorontoStarinOctober2009[20].“But,atthesametime,wecanmakegermcells—spermoregg,fromiPSCs.Sopotentially,wecanmakenewlifefromskin.Thatisthebiggestethicalissue”[20].Inaddition,thelowcostofgeneratingiPSCsandtheeaseofaccessibilitytosomaticcellswouldpropoundtheneedtogener-ategametesinthefuture[21].

EXTINGUISHING THE FIRE: THE SEARCH FOR NON-EMBRYONIC ALTERNATIVES Anumberof scientistsaround theworldare trying toquench thefierydebate involvinghESCsbymovingaway frommethodsthatinvolvethedestructionofhumanembryos.Dr.MickBhatia, a scientist atMcMasterUniversity’s StemCellandCancerResearchInstitute,publishedastudyinwhichtheybypassed the embryonic stage altogether by reprogrammingadultskincellstoprogenitorbloodcelltypes.Thesecellswouldbeusedtoreplenishthebloodsupplyofcancerpatientsfollow-


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ing chemotherapy [22]. Another Canadian scientist, Dr. FredaMiller,hopestofindnewwaysofactivatingandmobilizingthebody’s own resident stem cell populations to repair damagedtissue [23]. She proposed using neural stem cells to stimulategrowthof neurons in hopes of replacing neurons damagedbystroke and other neurodegenerative diseases [23]. Anothersourceofstemcellsbeingconsideredfortherapeuticuseisam-nioticfluidorumbilicalcord[24,25].Thisfield,althoughinitsin-fancy,ispromisingmainlybecausethecellscouldbeharvestedatanearlydevelopmentalstage[24,25].However,moreresearchisrequiredinordertoconfirmthepotencyofstemcellsderivedfrom these sources.

CONCLUSION A vastmajorityof Canadians andAmericans (approxi-mately60%)agreethatthehumanembryodeservesmoral re-spectandaspecialstatus[8].However,theyalsobelievethatifappropriatemeasuresare inplace, thebenefitsofusinghESCssupersede[8]. As it stands, it is safe to assume that thepotentialofhESCs in treatment of various diseases is unparalleled. Despite the introductionof iPSCs andother non-embryonic sources ofstem cells, hESCs are the only pluripotent cell type that havebeenapprovedforclinicaltrials,andthereforeremainthe‘goldstandard’ of human stem cell research. If hESC research can be properly regulated, approval of such research by the generalpublicmaybe increased.Unfortunately,asreligionandculturecoexistinoursociety,havingaconsensusondifficultethical is-suessuchastheuseofhESCsis,astheysay,aHerculeantask.

REFERENCES1. TrialsofWarCriminalsbeforetheNurembergMilitaryTribunalsunderCon-

trolCouncilLaw.1949;10(2):181-182.WashingtonD.C.:U.S.GovernmentPrintingOffice.

2. TyebkhanG.DeclarationofHelsinki:Theethicalcornerstoneofhumanclini-calresearch.ResearchMethodology.2003;69(3):245-47.

3. TuskegeeStudy–Timeline.CentresforDiseaseControlandPrevention,At-lanta,GA,USA.AccessedonFeb21,2013.

4. KatzRV.,KegelesSS.,KressinNR.,etal.TheTuskegeeLegacyProject:Will-ingness of monitories to participate in biomedical research. Journal ofHealthCareforthePoorandUnderserved.2006;17(4):698-715.

5. SimsJM.AbriefreviewoftheBelmontReport.DimensionsofCriticalCare

Nursing.2010.4:173-174.6. ThomsonJA.,Itskovitz-EldorJ.,ShapiroSSetal.Embryonicstemcell lines

derivedfromhumanblastocysts.Science.1998;282(5391):1145-47.7. Carvalho AS., and Ramalho-Santos J. 2012. How can ethics relate to sci-

ence?Thecaseofstemcellresearch.EuropeanJournalofHumanGenetics.2012.pp.1-5.

8. SornbergerJ.DreamsandDueDiligence:TillandMcCulloch’sStemCellDis-coveryandLegacy.UniversityofTorontoPress.2011,Toronto,Canada.

9. ChapmanAR.,FrankelMS.,andGarfinkelMS.StemCellResearchandAp-plications:MonitoringtheFrontiersofbiomedicalresearch.AmericanAs-sociationfortheAdvancementofScience.1999.

10. HumanStemCellResearch:OpportunitiesforHealthandEthicalPerspec-tives:ADiscussionPaper.CIHR.May2001,Ottawa,Canada.

11. Philipkoski K. March 2004. Canada closes door on cloning. Wired. Ac-cessed Feb 24, 2013. http://www.wired.com/medtech/health/news/2004/03/62695.

12. CNN,‘Transcript:PopeJohnPaulII,’AccessedonFeb20,2013.http://tran-scripts.cnn.com/2001/WORLD/europe/07/23/bush.pope.

13. DobsonlikenedembryonicstemcellresearchtoNaziexperiments.August2005.MediaMattersforAmerica.AccessedonFeb13,2013.http://media-matters.org/mmtv/200508030007.

14. OntarioConsultantsonReligiousTolerance, ‘StemCellResearch:allview-points,’AccessedonFeb17,2013.http://religioustolerance.org/res_stem.htm.

15. Grisez, G. Destructive Stem-Cell Research on Human Embryos. Origins.1999;28:769-73.

16. Robertson,J.SymbolicIssuesinEmbryoResearch.HastingsCenterReport.1995.25(1):37-38.

17. BernierL.,andGregoireD.Reproductiveandtherapeuticcloning,germlinetherapy, andpurchaseof gametesandembryos: commentsonCanadianlegislationgoverningreproductiontechnologies.JournalofMedicalEthics,2004;(70):527-32.

18. Takahashi K. and Yamanaka S. Induction of Pluripotent Stem Cells fromMouseEmbryonicandAdult FibroblastCulturesbyDefinedFactors.Cell.2006;126:4(663-676).

19. Scientistsrevealhowinducedpluripotentstemcellsdifferfromembryonicstem cells and tissue of derivation. April 2009. John Hopkins Medicine:Newsandpublications.AccessedonFeb27,2013.

20. OgilvieM.October2009.Stemcellbreakthrough:Toosimple.TorontoStarGT3.AccessedonFeb27,2013.http://www.thestar.com/life/health_well-ness/news_research/2009/10/30/stem_cell_breakthrough_too_simple.html

21. LehrmanS.UndifferentiatedEthics:WhyStemCellsfromAdultSkinareasMorallyFraughtasEmbryonicStemCells.ScientificAmerican,USA.2010.

22. HallJ.November2010.McMasterbreakthroughraisestransfusionhopes.TorontoStarA3.AccessedonFeb27,2013.http://www.thestar.com/life/health_wellness/news_research/2010/11/07/mcmaster_researchers_beat_world_in_blood_race.html

23. StemCellNetwork:Canadianinnovationsinstemcelltherapeutics.North-ernLights.Summer2009,13.

24. PresidentCouncilonBioethics:WhitePaper.2005.AlternativeSourcesofPluripotentStemCells.ThePresident’sCouncilonBioethics.http://bioeth-ics.georgetown.edu/pcbe/reports/white_paper/.

25. KossackN,Meneses J,ShefiSetal. Isolationandcharacterizationofplu-ripotenthumanspermatogonial stemcell-derivedcells.StemCells.2009;(27):138–149


INTRODUCTION Cancer is the most prominent cause of death in de-velopedcountries,withover12millionpeopleworldwidebe-ingdiagnosedeachyear.Currentconventionalcancer thera-piessuchaschemotherapy,radiation,andsurgery,havemanynegativesideeffects,andpatientswilloftenrelapse[1,2].Newcancertreatmentsarebeingdevelopedinordertomorespe-cificallyandeffectively targetcanceroustissue,whichwouldreducesideeffectsandhelptocompletelyeradicatetumours.Onesuchmethodistheuseoflive,attenuated,geneticallyen-gineeredbacterial strains tovisualize, selectively target,andactasanticanceragentsinvivo.Theideaofusingbacteriaasacancertherapystartedin1890,whenAmericansurgeonWilliamColeytreatedcancerpatientswith“Coley’sToxin”,comprisedof heat-killed Streptococcal organisms and Serratiamarces-cens, and observed tumour regression [1, 3, 4]. Since then,scientistshavediscoveredthatengineeredanaerobicorfacul-tativeanaerobicbacteriacanselectivelytargettumoursduetothehypoxicandnecroticenvironmentswithinthem,whicharenecessary for the survival of these bacteria[1-5].Geneticallyengineeredbacterialocalizeandgrowexclusivelyincanceroustissue.Thismeansthattheycanbeusedtovisualizetumoursusingbioluminescence or diagnostic imaging technologies.Theycanalsobeusedtotreattumoursthroughdirectcellkill-

Genetically engineered bacteria as cancer fighting agents

AlexandraBunting,BSc1 1FacultyofMedicine,UniversityofOttawa

Theobjectivesofthispaperaretoreviewrecentdevelopmentsinusingbacteriaascancerfightingagents.Thisnewandexcit-ingfieldofresearchhasshownpromisingresults.Themostadvancedandwell-studiedgeneticallyengineeredbacteriaarediscussedhere.Thesebacteriahaveeffectivelybeenusedtovisualizetumoursusingbioluminescenceordiagnosticimagingtechnologies,andtotreattumoursthroughdirectcellkilling,bactofection,andalternativegenetherapy.Becauseofthepositiveoutcomesseeninvitroandinanimalmodels,manyofthesegeneticallymodifiedbacteriaarecurrentlybeingtakentoclinicaltrials.Overall,usinggeneticallyengineeredbacteriatocombatcancerisapromisingandgrowingareaofresearch,andwillhopefullyleadtonewandbettertreat-mentsforcancerpatientsinthenearfuture.

Lebutduprésentarticleconsisteàfaireunerevuedesplusrécentsprogrèsdansl’utilisationdebactériescommeagentdeluttecontrelecancer.Cenouveaudomainecaptivantderechercheamontrédesrésultatsprometteurs.Cetarticleportesurlesbac-tériesgénétiquementmodifiéeslespluspousséesetlesmieuxétudiées.Cesbactériesontétéutiliséesavecsuccèspourvisualiserdestumeursgrâceàlabioluminescenceoulestechniquesd’imageriediagnostique.Ellesontaussiétéutiliséespourtraiterdestumeursparl’entremisedeladestructiondirectedecellules,labactofectionetlathérapiegénique.Grâceauxrésultatspositifsobtenuslorsdesessaisinvitroetavecdesmodèlesanimaux,plusieursdecesbactériesgénétiquementmodifiéesfontmaintenantl’objetd’essaiscliniques.Dansl’ensemble,l’utilisationdesbactériesgénétiquementmodifiéesdanslaluttecontrelecancerestprometteuseetcon-stitueunvoletderechercheenpleineprogression.Ilestespéréquecetterecherchemènerabientôtàdenouveauxetmeilleurstraite-mentspourlespatientsatteintsdecancer.

ing,alternativegenetherapyandamechanismcalledbacto-fection,inwhichbacteriaareusedasavectortodelivergenes.

METHODS Atotalofsixdatabases:PubMed,Medline/OVID,Bio-logicalAbstracts,Scopus,WebofScience,andGoogleScholar-wereusedtosearchforarticlesrelatingtothetopic.ArticleswereselectedforiftheywerewritteninEnglishandpublishedin January 2010 or later.Reviewing thetitle and abstract ofeach paper was the preliminary method for consideration,whichthenledtoselectedarticlesbeingthoroughlyanalyzed.Thisresultedinsomeinitialpapersbeingexcludediftheirtopicwascoveredinamorerecentwithadditionalinformationtooffer.Inafewinstances,paperswereexcludedduetouncer-taintiesfoundwhilereadingthroughthemethods,results,ordiscussion.For the purpose of composing this review paperadditional background information was derived from someoldersourcespublishedasearlyas1997.Samplesearchtermsinclude “bacteria AND cancer therapy”, “imaging AND bac-teria AND cancer”.Of the approximately 80 original articlesreviewed,54were included inthis review,andthereforethispaperreflectsaqualitativereviewoftheevidence-based lit-erature.

A B S T R A C T

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R É S U M É


SHORTCOMINGS OF CONVENTIONAL CANCER THERAPY Twomajorshortcomingsofcurrentconventionalcan-cer therapies are hypoxia-related resistance, and toxicity tohealthytissue.Thesedifferencesintumourscancauseprob-lemsforcertaincancertherapiesandoneexampleofthis ishowhypoxialeadstotreatmentresistanceformanyanticancerdrugsandradiotherapy.Manysystemictreatmentscurrentlyused,suchaschemotherapy, immunetherapy,viral therapy,andtargetedtherapy,aretoxictobothhealthytissueandcan-ceroustissue[6].Often,patientsarenotabletoreceivesys-temic therapybecause theyare toounwellfor treatment,asclassifiedbytheECOGperformancestatus(seeAppendixforexplanation of scoring). An ECOG performance score of 0-2deems the patientwell enough toundergo systemic chemo-therapy,whereasascoreof3+meanssystemictherapyisnotrecommendedasthereisahighchancethatthetreatmentwilldomoreharmthangood.

IMAGING OF TUMOURS Variousimagingtechniqueshavebeenusedtomoreeffectively visualize cancerous tumors. Currently, MagneticResonance Imaging (MRI) and Computed Tomography (CT)scansprovide thebestcontrastand resolution,butareveryexpensive.Thecontrastdyeisoftentoxictothekidneysandmakespatients feelunwell. Improvements in imagingwouldnot only make patient more comfortable, but would alsohelp improve contrast, resolution, and potentially decreasetheamountofmalignancies thatareoverlooked.Bonescansareusedincancerpatientstodetermineifthetumourhasme-tastasizedtothebone.Becausethesetechniquesareexpen-sive,patientsareusually screenedorobservedona routinebasisusingultrasoundtechnology.Ultrasounds,however,are

not as useful since they can only observe structures close to thesurfaceofthebody.Moreover,theaccuracyofthefindingsdepends on the availability ofspecially-trained individuals toadequatelyandaccuratelyanalyzethelowresolutionimages(Figure1).

SELECTIVE REPLICATION Theexactprocessofhowseveralbacterialspeciesse-lectively infiltrate and replicatewithin tumours is unknown.The vasculature in tumours tends to be leaky, leaving largegapsbetweentheendothelialcellsofthevesselwalls.Thesegapsare largeenoughforbacteriatoaccessthetumourbothpassivelyandactivelyusingchemotaxis.Bacterialinfectionin-duces theproductionof inflammatory cytokines such as tu-mour-necrosisfactoralpha(TNF-α)withinthetumour,whichincreasevascularpermeability[5,7].Theimmune-suppressedmicro-environment of the tumour provides protection fromthehost’simmunesystemwhich,incombinationwiththean-aerobicandnutrient-richnecroticenvironment,leadstobac-terialcolonizationofthetumour.However,thesegeneticallyengineered bacterial strains tend to only colonize the innerhypoxicandnecroticareaswithinthetumour,astheouterrimreceives adequate blood supply [5, 7-10]. Bacteria that arefound in other parts of the body tend to be cleared by the im-munesystem.Forexample,onestrainofSalmonellahasarep-licationratioof1000:1-tumourtohealthytissue[1].Damagetohealthytissuebythesebacteriaisthereforelimited,andifthebacteriacolonizeundesiredareas,antibioticscanbeusedto successfully clear them from the body.

BACTERIA FOR TUMOUR VISUALIZATION Many bacterial strains have been tested for their use

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Figure 1:Akidneytumourdepictedinbothimages,ontheleftisaCTscanandontherightisanultrasound,adaptedfromC.C.Min,2013.ItcanbeobservedthattheCTscanprovidesanimagewithahighercontrastandresolutioncomparedtotheultrasound.


in visualizing tumours through bioluminescence,with greenfluorescentprotein(GFP)andthebacterialluxsystem,aswellaswithmagneticresonanceimaging(MRI)usingmagnetotac-ticbacteria.Bioluminescentimaging(BLI)isapowerfulvisual-izationtoolthatusesaplasmidtoexpressluminescentgenessuchasGFPor lux. The LuxCDABEoperonproduces light atawavelengthof490nmanddoesnotrequiretheadditionofa substrate inorder todo so [11]. In earlier studies, patho-genic strains of Salmonella typhimurium containing the luxoperonwereused,but thesebacteria localized in theabdo-menandneck in addition to the tumour. Itwas later foundthatnon-pathogenicstrainsarelesslikelytocolonizehealthytissue,whichmaybedue to their inability toeffectivelyad-heretoorinfecthostcells[11].Forexample,non-pathogenicstrainsofEscherichiacoliK-12,Bifidobacteriumbreve,andS.Typhimurium that were transfected with a plasmid contain-ing the luxoperonwerefoundtoonly localizewithin thetu-mour[12]. Hayashi et al. in 2009 labeled multiple bacterialstrainswithGFPandobservedsimilartumour-targetingabili-tiesinvivo[13].FireflyluciferaseisanothercommonBLIgenebeingstudiedatthistimeandthisproteincatalyzesreducedluciferin to create yellow-green light of wavelength 562nmamongotherproducts[11]. TheuseofMagnetotacticbacteriasuchasMagneto-spirillummagneticum AMB-1 allow for tumour visualizationusingMRIduetotheirmagnetosome,anorganellethatstoresiron [14]. The magnetosome significantly affects transverserelaxationofMRI, thusproducingahighly contrasted imageof the tumour. Studies done in mice show an increased con-trast inMRI imagesusingAMB-1and this is currentlybeingconsideredasapotentialtoolforlocatingandtrackingcancerprogression[14].Similarly,overexpressionofbacterialferritin-likestorageproteinssuchasthebfrgeneproductscanelicitthe sameeffect.Thebioluminescentand iron-storagegeneshaveinduciblepromotersthatcanbeinducedbyexogenousligandssuchasL-arabinose,allowingforexternalcontrolovertheirexpression[11,15]. Both of thesemethods are non-invasive, but biolu-minescencetechnology,beingmoreaffordableandaccessiblethanMRI,mayhavemorepotentialasawidespreaddiagnostictool in cancer.ThequalityofBLI imagesare limitedby lightscatteringandabsorptionbythetissuesaswellasbeingtwo-dimensional, therefore lacking depth and spatial resolution.Theluxsystemdoesnothavetheissueswithlightscatteringandabsorption,butisnowbeingcombinedwithCTscanningto obtain a 3Dhigh contrast image [11]. ThemagnetotacticMRI imageshavemore contrast and spatial resolution com-paredtonormalMRItumourimaging.Bothofthesemethodsto obtain bacterial distribution and cell numbers overcometheexvivoanalyticalmethodswhicharebothtimeconsumingandexpensive.

Figure 2. Imageof aBLI scanon a rat adopted fromBabanet al.2010. The rat was injected with Bifidobacteriumbreve expressingtheluxADCBEsystem.Thisbacteriaisshowntospecificallycolonizealungcarcinomathatwasinjectedintomicesubcutaneously.

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TREATMENT: DIRECT CELL KILLING Directcellkillinginvolveslivereplicationcompetentbacteria suchasClostridiumandSalmonella,whichmainlyrelyontheirnaturaloncolyticactivitytoeliminatetumours[2, 8].Many of these strains release toxins that either killcells directly through lysis or protein synthesis inhibition,orinterferewiththecellcycleinhibitingitsprogression.Forexample,ClostridiumperfringenstypeAstrainproducesanenterotoxin (CPE),which has been shown to exert a cyto-toxiceffectonpancreatic tumourcells, leading tonecrosisandinhibitionoftumourgrowth[16].Patyaretal.speculatethatplasmidsmaybeintroducedintothesestrains,contain-ingadditionalgenesthatencodetoxinsfoundinadifferentspecies,inordertoenhancetheirlethaleffect.Despitetheirtreatmentpotentialthesebacteriacanalsoharmnormaltis-sues and thus amore efficaciousmethod being studied isBactofection.

TREATMENT OF TUMOURS: BACTOFECTION Bactofectionusesnon-invasivebacteria as a vectortodelivertherapeuticcytotoxicgeneslocalizedonplasmidsinto cancer cells to induce cell death. This delivery process eitherrequiresbacteriatodirectlyenterthecancercell,ortheuseofaconjugationalapparatus.Idealtherapeuticpro-teins for conjugation consist of anti-angiogenicmolecules,


TREATMENT: ALTERNATIVE GENE THERAPYAlternative gene therapy (AGT) uses genetically engineeredbacteriathataretransfectedwithplasmidscontaininggenesencoding desirable therapeutic proteins, cytotoxic peptides,anticanceragents,andpro-drugconvertingenzymes[1,2,16,17].Unlikebactofection,AGTusesbacteriathatproducethetherapeuticpolypeptide in situ stimulatedby lowmolecularweightinductors,andthusoffersmorecontroloverthetreat-ment[20].Anumberofanticancergeneshavebeensuccess-fully cloned into Bifidobacteriumand Salmonella plasmids.Oneofthemostinfluentialgenesbeinganapoptosis-inducercalled tumour-necrosis factor-related apoptosis-inducing li-gand(TRAIL)[1,2].TheresultsofonestudyusingaplasmidcontainingthegeneforTRAILtransfectedintoBifidobacterium

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apoptosis-inducinggenes,andtoxins[2,16,17].Forexample,S.choleraseuistransfectedwithaplasmidcontainingtheend-ostatingene,anendogenousangiogenesisinhibitor,inhibitedtumourgrowthby40-70%bydecreasingtumourvasculatureandexpressionof vascularendothelial growth factor (VEGF)[17].Salmonellastrainsarethemostwidelyusedinbactofec-tionstudies,andhavebeeneffectivelyused inexperimentalmodels consisting of plasmids carrying cytokine interleu-kin genes [18]. These genes induce tumour cells to expressand release largeamountsof cytokines thathelp stimulatean immune response against them. In another study, non-pathogenic Escherichia coli strain BL21(DE3) expressing theanti-HER2affibodyonitssurfaceallowsselectiveinternaliza-tionintoHER2positivecancerouscells.ThisE.colistrainalsocontainsthephageϕX174 lysingene,whichtriggerstheau-tolysissystemofthetumourcelluponthermalshock,andtheeukaryoticGFPtoallowforvisualization[19].

Figure 3. Imagedepictingbactofectionadopted fromBabanetal.2010. a): the bacterium invades the cell. b) Bacterial vectors es-capefromphagosomeandreplicateinthebacterialcell.c)LysisofthebacteriafacilitatesreleaseoftherapeuticDNAintohostcell.d)TherapeuticDNAplasmidmayberandomlymake itsway intothenucleus where it can be transcribed.

A similar method of cancer treatment uses viral vec-torstotransporttherapeuticgenesdirectlyintothenucleusoftumourcellsforintegrationintotheDNA.Inbactofection,plas-midtraffickingintothenucleusisconsideredtherate-limitingstep. To compensate,somebacteria cantranscribe the thera-peuticgenesintomRNAcontainingeukaryotictransgenes,andreleaseitintothehostcell’scytoplasmfortranslation[2,16].Viralvectorscaninsert8-10kB,whereasplasmidscancontain

Figure 4. The figure above, adopted from Palffy et al. 2006 [20],showshowalternativegenetherapyworks.a)Thebacteria istrans-formedwithplasmidscontainingthetherapeutictransgene.b)Trans-geneexpressionoccurswithinthebacteriumonceitpenetratesthecancercell. c)Transgeneexpressionoccurs in thebacteriumand isexocytosedintotheinterstitialspace.

Table 1: Comparison of viral and bacterial vectors in cancer therapy.Adapted from Palffy et al. 2006 [20]. Viral Vectors Bacterial VectorsSafety + +Efficiency +++ +Inexpensive + +++Ease of production + +++Ease of delivery ++ +++

up to 15kB. Bacterial artificial chromosomes (BAC) can con-tainupto150kBinsertsandmaybeusedinthefuturetoallowtheexpressionofmoretherapeuticgenes[20].However,theamount of DNA that can currently be recombined into a plas-midisalimitationofbothviralandbacterialvectors.Further-moreindirectcontrasttoviralvectors,bacteriacanreadilybeterminatedfromthehumanbodybyantibioticsmakingthemasafertreatmentoptionforcancerpatients.


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resultedintumourvolumereductionby82.6%[21].Manyoth-ertherapeuticproteinsusedinAGTtendtotargetapoptosis,angiogenesis,cytokines,andpathwaysinhibitingthecellcycle.Theprodrugtherapystrategyusesplasmidsexpressinganen-zymethatcanconvertanon-toxicprodrugintoatoxiccancer-killingdrug.Sincetumour-targetingbacterialstrainsareonlyfoundwithinthetumouritself,theprodrugcanonlybeacti-vatedwithinthetumourandthus,beneficially,eliminatestox-iceffectstohealthytissuesnormallyseenwithasystemicallyadministereddrug[2,17].AnotherpromisingexampleofAGTisdescribedinMinton’sreviewarticleusingclostridiumtrans-formedwith the cytidine deaminase (CD) gene, which con-verts5-fluorocytosine(5FC)to5-fluorouracil(5FU)[22,23]. TheuseofbacteriainAGTrequiresitspersistenceinthetargettissuetoelicitanticancereffects.Amajorissueas-sociatedwith this is the toxicityof therequireddose foref-fective therapeutic results.A keyaspectofAGTis theabilitytocontrolexpressionofthetherapeuticproteinsthroughin-ducible promoters. This ensures the bacteria do not act in any othertissueswithinthefirstfewhourswhenthebacteriaarenotyet localizedto thetarget tumour.Despite theability tocontroltransgeneexpression,Stritzkeretal.foundthatbac-tofectionproved to bemore efficient thanAGTwhenusingListeriamonocytogenes[24].Thismaybeduetothefactthatbactofectionusesmorevirulentstrainstoallowforbetterbac-terialinvasion,whichresultsinasuperiorlong-termeffectun-likeAGT,wherebacteriamustpersistinthetumourthrough-outtherapytobeeffective.

CLINICAL STUDIES Manybacteriaineachofthesetherapeuticapproach-eshavebeentakentoclinicaltrials(Table2,3)andsomeofthesignificantclinicaltrialsaredescribedbelow.

The live attenuated S. typhimurium strain VNP200009hascompletedPhaseIclinicaltrials.Itusesdirectcellkillingtoelicittumoricidaleffectsandhasbeensuccessfulintreatingadvancedormetastaticsolidtumours[36].Otherliveattenuated bacteria like Clostridia and Bifidobacterium willlikelyundergohumanclinicaltrialssoon.Newstrainsstartingpreclinicalresearchastumoricidaldirectcellkillingagentsare

Table 2: Genera of bacteria well studied in each therapeutic ap-proach, adapted from Palffy et al. 2006. [20]

Therapeutic Approach Suitable Species References

Direct Cell Killing Clostridium, Salmonella [25-28]Bactofection Salmonella, Listeria, [29-31] E. coli, Clostridium [32-33]Alternative Gene Therapy Bifidobacterium [18, 34, 35]

Salmonellacholeraesuis,Vibriocholerae,andListeriamono-cytogenes[23]. TheClostridiumNovyi-NTstrainiscurrentlyinPhaseI clinical trials for treatment of chondromas. It is incapable of producing itsexotoxin,whichprotects thepatient,andhasbeen shown to destroy hypoxic tumours and force certaintypes of cancer, namely chondromas, into complete remis-sion.Itwasshowninpreclinicaltrialphasethat30%ofmicewerecompletelycured,andallhadasignificantresponsetothebacteria[37].Thebacterialinfectioniscontainedtothesiteofthetumorandtheinflammatoryresponsecontributestothedestructionoftumourcellsviatheproductionofre-activeoxygenspecies,proteases,andotherdegradativeen-zymes[38]. Bactofection has been used successfully in studieswithmicetotreatmelanoma,coloncarcinoma,andlungcar-cinoma. Oneexample isthestrainSalmonellacholeraesuisused to target melanoma by targeted gene delivery usingthrombospondin-1. This approach significantly reduced tu-mourgrowthinthemelanomamodel[39,40].S.typhimuriumproducingCDiscurrentlyinphaseIIclinicaltrialsandsignifi-cantly improved colorectal cancerpatients and induced re-mission[41,42]. Salmonella strains combined with either nitroreduc-tase(NR)orCDareundergoingphaseIclinicaltrialsincancerpatientswithsuccessobservedinvivo.TAPET(TumourAmpli-fiedProteinExpressionTherapy)usesVNP20009,discussedabove,inadditiontoexpressinganE.coliCD,whichprefer-entially delivers CD andother anticancer drugs to tumours(43).VNP20009,whichselectivelycolonizescolon tumours,can express the prodrug-converting enzymeHSV-thymidinekinase(TK).Also,expressionofHSV-TKenhancesantitumoractivitywhen its correspondingprodrug, ganciclovir, is alsointroduced[44,45]. Bacterialproteinsandtoxinsarenowbeingexperi-mentedwithtointerferewithcancercellgrowth.OnesuchproteincalledATP-01hasshowntoinducetumourregressioninbreastcancerpatientsandhasbeenproventohaveanti-HIVcharacteristics.Anotherprotein,azurinp28isinphaseIclinicaltrialsandhasshownsignificantbenefitswithlittletox-icitytothepatient.Inmanyinstances,p28hasbeenshowntocausepartialorcompleteregressionofmetastaticsolidtu-moursinstageIVcancerpatientswhohavetriedotherthera-pieswithoutanysuccess[46]. ProteintoxinssuchasdiphtheriaandPseudomonasexotoxinarepotent cell killingagentsand so theymustbetargetedforuseincancertherapytoavoidharmofhealthycells.Sofar,theyhavebeenconjugatedtocell-bindingpro-teinssuchasgrowthfactorsandmonoclonalantibodies,thusbindingandkillingcancerouscellswhilesparinghealthy,nor-malcells[47].AphaseIclinicaltrialfortreatmentofmalig-nantastrocytomausingarecombinantinterleukin-4-Pseudo-monasexotoxin(IL4-PE)isunderway,aftersignificantresults


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werefoundinmicewithglioblastoma[48].Someotherimpor-tantPEconjugatescurrentlyinclinicaltrialsincludeIL-13andamonoclonalantibodythatrecognizesacarbohydrateantigenonmetastaticadenocarcinomacells[49].Lastly,twodiphthe-riatoxinconjugatesarealsoofsignificanceandinclinicaltrialstageIfortreatmentofbraintumoursandmetastaticcarcino-mas[50].

FUTURE DIRECTION OF BACTERIAL USE IN CANCER THERAPY Tumour-targeting bacteria are being developed toovercome the limitations of conventional cancer therapy.Thenecessaryand specificadvancementsof cancer therapyinclude improving gene delivery through novel vectors, im-provingspecificity in thetargetingof tumours,andreducingtreatment toxicity to thepatient to thus improve the thera-peuticindexofthesenoveltreatments.Bacterialcancerthera-piesarenotintendedtoreplaceconventionaltherapybuttocreatenewtreatmentstrategiesincorporatingtheiruse[51].Increasingthenumberandvarietyofavailabletreatmentop-tionsfordifferentcancersmayfacilitatemorepatient-focusedtherapy, allowing for improved remission and survival rates.Thesenovel therapies can also provide an alternativewhencurrentmethods fail to provide an adequate anti-cancer ef-fectinthepatient.Techniquesinvolvingbacteriaarealsomoreeconomicalthanviralvectors,andarea low-costalternativeto many therapies currently employed for use in cancer treat-ment. Tumourimagingismovingtowardscombinedmodal-ity use to increase the amount of detail obtained. As current technology improves, becomes more available and cost ef-fective,itisbeingcomplementedbynewimagingtechniquessuchasBLIandtheuseofmagnetotacticbacteriainMRI.SincenocurrentdiagnosticimagingsuchasCT,MRI,orPETgiveacomprehensive picture of a tumour, BLI and magnetotacticbacteriacanbeusedtohelpgainadditionalvitalinformation.BLI alonehas its limitations,which include two-dimensionalimaging lacking depth, poor spatial resolution, light scatter-ing, andabsorptionby thetissues.However, combining thismethodwithCTscanninghelpstoobtaina3Dhighcontrast

image,butmoreresearchintothistechnologyiswarrantedinthefuture[11].Foranimalmodels,combinedPET/CTandBLI/CTscanshavebeenobservedtoobtainmoreinformationfromasinglescanonasinglesubject,providingamorecom-prehensivepicture,whilealsobeingmoreefficientandcosteffective[52]. Animportantissuetoaddressregardingthesenewbacterialcancertreatmentsisthepotentialforthesethera-peutic bacterial strains to acquire antibiotic resistance, inwhichcasetheymaynolongerbeapprovedforuseasacan-certherapy.Shouldthepatientdevelopan infectionbacte-rial strainscanbeeasilyeradicatedwithantibiotics,makingthemsaferthanothertransportvectorslikeviruses.Howev-er,somesideeffectshavebeennotedduetotheinteractionbetweenthe immunesystemandthetherapeuticbacterialstrains;further investigation and testing in this area is re-quiredtoimprovethesafetyofthesenoveltherapies.Futurestudiesmayfocusonunderstandingtheunderlyingmecha-nismoftheantitumoreffectsmediatedbybacteriainvolvingpatientimmuneresponses,inadditiontoevaluatingtheiref-fectiveness[6]. Lastly,manyofthesenewbacterialtherapiesdonotcompletely eradicate tumours. Therefore, the combinationoftherapywithchemotherapeutictreatmentsisstillneces-saryatthistime.Bacterialtherapiescanhaveeitheradverseor beneficial effectswhen used in combinationwith otheranti-cancer therapies. For example, some of the bacteriathataffectangiogenesishavebeenshowntoreducetheef-ficacyofotheranti-cancerdrugs[54].Therehasbeensomeproofofthe“bystandereffect”whenusingbacterialtherapyandcertainchemotherapeuticagentswhichprovideanex-traanti-cancereffecttothetumour[6].Alastmajorconcernis thepotentialof theengineeredbacteria toacquireDNAmutationsintheirtherapeuticgenes.Ifthesemutationscre-ateanylossoffunctionalitytheymayleadtoawidevarietyofproblemssuchastherapyfailure,infection,andotherun-wantednegativeeffects[23].

CONCLUSION Inrecentyears,manyadvanceshavebeenmadeus-

Table 3: Relevant clinical trials, the phase and status listed below with the various cancers being treated. Adapted from Patyar et al. 2010 [23].

Therapeutic Strain Clinical Trial Phase Status Disease Conditions

VNP20009- S. typhimurium Phase I Completed Advanced or metastatic solid tumours [36]Clostridium Novyi-NT Phase I Ongoing Chondroma [37]TAPET – CD: VNP200009 expressing E. coli CD Phase I Completed Head, neck, and esophagus cancer [36]Tf-CRM 107: transferrin-diptheria toxin conjugate Phase I Ongoing Brainentral nervous system tumours [47]IL4-PE: interleukin-4-Pseudomonas exotoxin Phase I Ongoing Brain entral nervous system tumours [48]IL 12-PE: Interleukin-13-Pseudomonas exotoxin Phase I Ongoing Malignant glioma, glioblastomamultiforme, anaplastic astrocytoma, anaplastic oligoden droglioma, mixed oligoastrocytoma [49]


inggeneticallyengineeredbacteriaforcancertherapy.Certainstrainscanelicitanti-cancereffectsthroughdirectcellkilling,bactofection,andalternativegenetherapyasdescribedinthisreviewarticle.However,thesuccessinmanystudiesisjustbe-ginning to be translated into human clinical trials. Althoughmuchofthepreclinicalresearchispromising,furtherinvestiga-tionanddevelopmentofbacterialcancertherapyisnecessarytoovercome its limitations, improvesafetyandefficacy,andreach its full potential. In the future, genetically engineeredbacteriawilllikelybeusedforcancertherapyincombinationwithcurrenttherapiestoachievethedesiredsynergisticanti-cancereffectsandthusimprovecancersurvivalandremissionrates.

STRENGTHS AND LIMITATIONS OF THIS REVIEW Amajorstrengthofthispaperisthatithighlightsthemostrelevantandpromisingresearchonwell-studiedbacteriaforuseincancerdiagnosisandtherapy.Itexplainsandsum-marizes the variousbacterial techniques used to image andtreatcancer,andgivessuggestionsforfutureresearch.Alimi-tationofthisreviewisthatnotallrelevantstudiesandpaperswereincludedandnostudiesthatmayhavenegativeevidencetowardsbacteriaascancer-fightingagentswereincluded.Themore reliable and relevant studies in medicine are those that havebeenbroughtintoclinicaltrialsanddemonstratesignifi-canteffectsobservedinhumancancerpatients.Somestudiesdiscussedwerenewandneedmorework.Asthisisarapidlygrowingareaofresearch,manyoftheitemsinthisreviewarebeing improvedupon inongoingstudies.Should this reviewpromptyoutoseekmorecurrentinformation,furtherliteraryinquiriesarerecommended.

APPENDIX ECOG(EasternCooperativeOncologyGroup)Perfor-mance Status is used by physicians to measure a cancer pa-tients’well-beingandactivitiesofdailyliving,inordertomakedecisionsaboutfurthertreatmentandpalliativecare.

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Grade ECOG

0 Fully active, able to carry on all pre-disease per formance without restriction.1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours.3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.5 Dead.

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Pulmonary Hypertension: Difficult diagnosis, challenging prognosis, poor outcome

MohamadTaha,BSc1


A B S T R A C T

“Weallletherdie”isthetitleofaTorontoStarnewsarticlepublishedinApril2006.ThisnewsarticledescribedthestoryofBrookeDiBernardo,a14-year-oldthatpassedawayfromadvancedstagepulmonaryhypertensionafterbeingmisdiagnosedforfouryears.Inlightofthisstory,thefollowingmanuscriptwilldiscusspulmonaryhypertensionintermsofitssymptoms,diagnosis,causes,incidence,classification,pathology,aswellascurrentandfuturetreatments.

“WE ALL LET HER DIE!” Acompetitiveswimmerandahorseenthusiast,Brookewasanexcellentathlete[1].However,attheageof10,Brookestartedtoexperienceshortnessofbreathandfatigueafteronlya short ride. After being admitted to the hospital, the doctorswereabletoruleoutafewofthecommonpossibilitiesforhersymptoms,includingasthma,allergiesandhormonalimbalance,butfailedtogiveadefinitivediagnosis.Unfortunately,Brooke’ssymptomscontinuedtoworsenandshestartedexperiencingep-isodesofflushingfromdoingsimplechores,followedbyturningpale,andeventuallyfainting.Severalmoretripstothehospitalresultedinyetmorenegativetests,includinganechocardiogram(ECHO) that revealed no cardiac abnormalities. At this point,Brookewas referred to a psychiatrist for evaluation, and theysuggestedthathersymptomsweremerelyapleaforattention.Brookecontinuedtosufferthroughtwomoreyearsofshortnessofbreathandexhaustionuntil,afteroneofherworstepisodes,she was transferred to Sick Kids hospital in Toronto. An X-rayandECHOanalysiswereconductedandrevealedthatherrightventriclewasenlargedandherleftwasfailing.ThedoctorswereabletodiagnoseBrookewithaveryraredisease:advancedstagepulmonaryhypertension(PH).Atthispoint,thephysicianscon-sideredalungtransplantforBrooke.Unfortunately,shepassedawayfromheartfailurewithin24hoursofherdiagnosis[1].

WHAT IS PULMONARY HYPERTENSION? Although technology-enhanced simulation has beenusedinmComparedtothesystemiccirculation,thepulmonarycirculationhaslowresistancebutcanaccommodateahighflow[2,3].Moreover,thesmallerarterioleshaveaverydelicatestruc-ture, composed only of a thin single layer of endothelial cells

(ECs)[3].Theseuniquepropertiesallowforgasexchangeandre-oxygenationofbloodinthelungs[3].Consequently,disruptionofthisdelicatebalancecanleadtoseveralpossiblediseasestates,PHincluded.PHisasyndromethatresultsfromrestrictedflowthroughthepulmonarycirculation,thusleadingtoincreasedpul-monaryvascularresistance[4].PHischaracterizedbydegrada-tionofthesmallerpulmonaryvessels,remodellingandocclusionofthelargerpulmonaryvasculature,endothelialcelldysfunctionandvasoconstriction [2,5]. In response to the increasedafter-load, the right ventricle (fromwhichoriginates thepulmonarycirculation)undergoescompensatorychangessuchashypertro-phyandremodelling[5].Eventually,therightventricleenlargesto thepointwhere thehypertrophy ismaladaptive, leading todecompensationandfailure.

PH: SYMPTOMS AND DIAGNOSIS Thenon-specificandgeneralnatureofsymptomspre-sentedplaysa large role inmisdiagnosing theearlier stagesofPH. At these early stages, patients merely experience unex-plained dyspnea and decreased exercise tolerance [3] . There-fore, the low incidence rate and absenceof significant cardiacabnormalitiesattheearlierstagesexplainwhyPHismorelikelytobemissed.Asthediseaseprogresses,patientscansufferfromsyncopeandperipheraledema,making itmorelikelyforPHtobediagnosedsuccessfully,howeveritbecomesmorechallengingtotreat[3,6].ToconfirmaPHdiagnosis,thepulmonaryarterypressure(PAP)isdirectlymeasuredbyrightheartcatheterization(RHC), inwhichaballoon-tipped catheter is advanced throughthejugularveinandintothepulmonaryartery[3].PHisdefinedthefollowingmeasurements:ameanPAP≥25mmHgatrest,re-ducedcardiacoutputandpulmonaryvascularresistancegreater

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«Weallletherdie»(Nousl’avonstouslaissémourir)estletitred’unarticleparudansleTorontoStarenavril2006.Cetarticledepressedécrivaitl’histoiredeBrookeDiBernando,unejeunefemmede14ansdécédéedessuitesd’unehypertensionpulmonaireàunstadeavancéaprèsavoirfaitl’objetd’undiagnosticerronépendantquatreans.Àlalumièredecetarticle,leprésentmanuscritdiscuteradel’hypertensionartériellepulmonaireenfonctiondessymptômes,dudiagnostic,descauses,del’incidence,delaclassifica-tion,delapathologieetdestraitementsactuelsetfuturs.


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than3WoodUnits combinedwith pulmonary capillarywedgepressure≥15mmHg[4,7].ARHCisrequiredtoconfirmthediag-nosis,classificationandassessmentofseverityofPH[7].OthermethodsofPHassessmentincludeECHOandchestradiography.However,unlessitisinthelaterstages,itisverydifficulttode-tectPHusingthesemethods.ThusRHCremainsthegoldstan-dardforPHdiagnosis[3,7].

PH: CAUSES, CLASSIFICATION, INCIDENCE AND PREVALENCE Since its discovery nearly a century ago, significantprogresshasbeenmadeintermsofclassifyingPH.AccordingtothemostrecentandupdatedclassificationoftheWorldHealthOrganization,PHisdividedintoseveralcategoriesbasedonthepathologicandgeneticoriginsofthedisease,aswellasthetypeof the associated disease (Table 1) [8]. The first PH group de-scribesPulmonaryArterialHypertension(PAH),whichisassoci-atedwithstructuralabnormalitiestothepre-capillarypulmonaryarteriolarmicrovessels[3,8].TheprevalenceofPAHisabout6.6-15casespermillionadultswhileitsincidencerateis1.1-2.4casespermillionperyearaccordingtothemostrecentepidemiologystudiesinEurope[9,10].PAHcanbefurthersub-classifiedintoidiopathicPAH(IPAH),whenthecauseofthediseaseisunknownand the hypertension occurs as a primary disease process [8].IPAHaccountsforalmost46%ofPAHcasesintheUnitedStatesaccordingtotheREVEALregistry,thelargestPAHregistrytodate[11]. IPAH ismost likely the typeof diseaseBrookeDi Bernar-dowasexhibitingsince itusuallyoccurs inyounger individualswithoutshowinganypatternofinheritanceorfamilyhistory.Ontheotherhand,PAHcanbehereditaryandhasbeen reportedtohaveanautosomaldominantpatternof inheritance,mainlylinkedtomutationsintheBoneMorphogeneticReceptorTypeII(BMPR2)gene[8].PAHisclassifiedunderthethirdsubtypewhenitisdrugortoxininduced[4,8].Examplesofsuchdrugsincludeanorexigens,whichareappetitesuppressantdrugsthatcontrib-utedtoaPAHepidemicinEuropeinthe1960s[4].PAHcanalsooccur in associationwithotherdiseases, such asHIV infectionorcongenitalheartdisease,andhasahigherprevalenceinpa-tientswithconnectivetissuediseases[8,11].WhenPAHoccursasasecondarydiseaseprocess,itisclassifiedasassociatedPAH[8].PHcanappearinassociationwithleftheartdisease,inwhichcase itwould be classified under the second group [8]. In thethirdgroup,PHappearsasaresultoflungdiseasesuchaschronicobstructivepulmonary disease (COPD), emphysemaor chronicexposuretohighaltitude[8].PHcanalsooccurafterapulmo-nary embolism, in which case it is classified under the fourthgroup,chronicthromboembolicpulmonaryhypertension(CTPH)[8].ThefifthandlastgroupofPHconsistsofseveralformsofPHwhere the etiology is unclear ormultifactorial [8]. A summaryofPHclassification,includingincidenceandprevalenceofeachmajorgroup,isincludedinTable1.

PH: PATHOLOGY OurknowledgeandunderstandingaboutPHpathologyhas evolved over the last one hundred years since its research be-

gan.SomeofthehistologicalfeaturesassociatedwithPHincludearterial remodelling causing increased thicknessof the arterialvessel layers(intima,mediaandadventitia)and leadingtopul-monaryarteriolarnarrowingandevenocclusion [5,12].Theseabnormalitiesarecombinedwithabroadimbalanceinthevaso-dilative/vasoconstrictivemediatorswithinthepulmonaryvascu-lature[4].Thisimbalancepresentsitselfasadecreaseinvasodi-lators(e.g.NitricOxide(NO)andprostacyclins)andanincreaseinvasoconstrictors(e.g.endothelin-1andthromboxaneA2)re-sultinginanoverallvasoconstrictivepulmonaryenvironment[4].Complexplexiformlesionscanalsoappearinthelaterstagesofthedisease.Theselesionsareoftenreferredtoasthehallmarkof humanPH and are composedof dysregulated, hyper-prolif-erative and apoptosis-resistant vascular cells [5, 12, 13].Morerecently, inflammation andmetabolic imbalance are becomingincreasinglyrecognizedaskeymodulatorsofPHasinflammatorycells are strongly associatedwith pathological lesions fromPHpatients[13,14].Also,ashiftfromnormalmetabolicpathways

Figure 1:SummaryofthepathologicaleventsobservedinPH.Anormalpulmonary arteriole (top) is composed of the following three layers:the internal layer (intima) composed of endothelial cells (ECs), themiddle layer (media) composed of smooth muscle cells (SMCs) andtheoutermost layer (adventitia), composedof connectivetissue. Theinternalandexternalelasticlaminasseparatethesethreelayers.InPH,thereisevidenceforanincreaseinSMCproliferationwhich,combinedwith inflammatory cells infiltrates, lead to thickening of the media.Thisisalsoaccompaniedbyendothelialcellapoptosisandselectionofapoptosis resistanthyper-proliferativeECs thatobstruct the lumenofthebloodvessel.DysregulationofECsisalsoobservedwithincreasedproduction of vasoconstrictor factors and decreased production ofvasodilators.


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hasbeennoted in thevascularcells inPHpatientsandanimalmodels,andhasbeenproposedtocontributetothehyper-pro-liferativephenotypeobserved[14].AsummaryofsomeofthesepathologicalpathwaysisincludedinFigure1. Insomecases,asinthecaseofPHowingtoleftheartdisease,thecauseofPHisknown,however,theprecisemecha-nismsofcauseofsomeoftheothergroupsofPHarelargelyun-known.Forexample,thereareseveralhypothesesthatattempttoexplain themechanismof group1, PAH,development.Cur-rently,several linesofevidencearepointingtoendothelialcell(EC) injury as part of the initiatingmechanism leading to PAH[5].ApoptosisinECsmayleadtodegenerationofthefragilelungmicrovesselsandinduceareactiveprocess.Thisprocessinturncausessubsequentinflammation,aswellasECandsmoothmus-clecellproliferation,ultimatelyresulting inthePAHphenotype[5].Still,ECapoptosisalonedoesnotseemsufficienttoexplainallofthechangesthatoccurinthepulmonaryvasculatureinPAHpatients.Thus,moreresearchisnecessarytoaddressalternativepathwaysthatmightbeinvolved.

PH: TREATMENT InmostformsofPH,theincreasedvascularresistanceiscoupledwithabroadimbalanceinvasodilative/vasoconstrictivemediators [4]. Thus, current PH treatments attempt to restorethisbalanceinthepulmonaryvasculature(vasodilatortherapies–table1)[4].CurrentPHtherapiesincludeendothelin-1receptorantagonists(e.g.bosentan),prostacyclinderivatives(eg.trepro-stenil)aswellasphosphodiesterasetype5(PDE5)inhibitors(e.g.sildenafil)which potentiate the nitric oxide-dependent vasodi-latorypathways[4].Whilethesedrugssucceedinreducingthevascularresistanceandpulmonaryarterypressure,aswellasde-laytheprogressionofthediseaseinsomepatients,theystilllacktheabilitytoreverseremodelingwithinthe lungsandthusfailtocurethedisease[4].DatafromsixdifferentregistriesindicateaPAHmortalityrateof44%(totalof4,525patients)withinthefirstfiveyearsofenrolment,regardlessoftreatmentoptions[6].SincealungtransplantistheonlycurrenttreatmentoptionforPAHthatispossiblycurative,itisclearthatnewtherapeuticop-tionsarenecessarytoimproveprognosis.

PH: THE HORIZON Several alternative therapies are currently being ex-plored.Imatinibisatyrosinekinaseinhibitorthatiscurrentlybe-ingconsideredasatherapeuticoptionforPH[15].Imatinibfunc-tions to inhibit signalling through the platelet-derived growthfactor(PDGF)receptorwhich,inPH,leadstosmoothmusclecellproliferation[15].Arandomizeddouble-blindplacebo-controlledphase-IIclinicaltrialdemonstratedapromisingdecreaseinpul-monary vascular resistance and an increase in cardiac output in PAH patients treatedwith Imatinib. Further investigations in aphaseIIIclinicaltrialarebeingconductedinordertodetermineif Imatinib can be used for treating PH [15]. Another interest-ing therapeutic option for patients with PH is targetingmeta-bolic dysregulationusingDichloroacetate (DCA) [16].Ahuman

clinicaltrialiscurrentlytestingtheabilityofDCAtoreversethehyper-proliferativephenotypeobservedinvascularcells inPAH(NCT01083524–PhaseI). StillanotherpotentialfieldofPHtherapeuticsisexplor-ing theuseofcell therapyorcombinedgeneandcell therapy,where a stem or progenitor cell’s therapeutic potential is en-hancedbytransfectionwithatargetgene[5].Resultsfromthefirst clinical trials using endothelial progenitor cells (stem cellprecursorsofendothelialcells)inPAHpatientsshowedimprove-mentinpulmonarycapacityandabsenceofadverseeffects[17].Anotherhumanclinical trialbeingconducted is thePulmonaryHypertension: Assessment of Cell Therapy (NCT00469027 –PhaseI)orPHACeTclinicaltrial,whichisusingEPCstransfectedwith eNOS to enhance their therapeutic potential. The resultsfromtheseclinicaltrialswillpavetheroadforestablishingnewinnovativetherapiesforPH. CONCLUSION Pulmonary hypertension is a devastating pulmonarycardiovasculardiseasethatischallengingtobothdiagnoseandtreat.Itisararediseaseandusuallypresentswithnon-specificsymptomsinthepatients.ThestoryofBrookeDiBernardoillus-trateshowPHcanbemisdiagnosedasamorecommondisease.IncasesofsuccessfulPHdiagnosis,currenttreatmentscanonlyslowitsprogression,withnosuccessinreversalofthevascularremodeling.Thus,effectivenoveltherapiesareurgentlyneeded.

REFERENCES1. LeederJ.‘Weallletherdie’;brookedibernardo’sheartsimplyworeout.

herparentswonderwhy,infouryearsofshuttlinghertodoctors,noonesawitcoming.TorontoStar.Apr22,2006.

2. TabimaDM,FrizzellS,GladwinMT.Reactiveoxygenandnitrogenspeciesinpulmonaryhypertension.Freeradicalbiology&medicine.2012;52(9):1970-86.Epub2012/03/10.

3. LanglebenD,ArcherS,GrantonJ,HirschAM,LevyRD,MehtaS,etal.Cana-dianCardiovascularSocietyandCanadianThoracicSocietypositionstate-ment on pulmonary arterial hypertension. The Canadian journal of cardiol-ogy.2005;21(11):909-14.Epub2005/10/22.

4. McLaughlinVV,ArcherSL,BadeschDB,BarstRJ,FarberHW,LindnerJR,etal.ACCF/AHA2009expert consensusdocumentonpulmonaryhyperten-sion:areportoftheAmericanCollegeofCardiologyFoundationTaskForceonExpertConsensusDocumentsandtheAmericanHeartAssociation:de-veloped in collaboration with the American College of Chest Physicians,AmericanThoracicSociety,Inc.,andthePulmonaryHypertensionAssocia-tion.Circulation.2009;119(16):2250-94.Epub2009/04/01.

5. JuraszP,CourtmanD,BabaieS,StewartDJ.Roleofapoptosisinpulmonaryhypertension:fromexperimentalmodelstoclinicaltrials.PharmacolTher.2010;126(1):1-8.Epub2010/02/02.

6. ThenappanT,RyanJJ,ArcherSL.Evolvingepidemiologyofpulmonaryarteri-alhypertension.Americanjournalofrespiratoryandcriticalcaremedicine.2012;186(8):707-9.Epub2012/10/17.

7. Saggar R, Sitbon O. Hemodynamics in pulmonary arterial hypertension:current and future perspectives. The American journal of cardiology.2012;110(6Suppl):9S-15S.Epub2012/09/07.

8. SimonneauG,RobbinsIM,BeghettiM,ChannickRN,DelcroixM,DentonCP,etal.Updatedclinicalclassificationofpulmonaryhypertension.JAmCollCardiol.2009;54(1Suppl):S43-54.Epub2009/07/09.

9. HumbertM,SitbonO,ChaouatA,BertocchiM,HabibG,GressinV,etal.PulmonaryarterialhypertensioninFrance:resultsfromanationalregistry.AmJRespirCritCareMed.2006;173(9):1023-30.Epub2006/02/04.

10. PeacockAJ,MurphyNF,McMurrayJJ,CaballeroL,StewartS.Anepidemio-logicalstudyofpulmonaryarterialhypertension.TheEuropeanrespiratoryjournal : official journal of the European Society for Clinical RespiratoryPhysiology.2007;30(1):104-9.Epub2007/03/16.

11. BadeschDB,RaskobGE,ElliottCG,KrichmanAM,FarberHW,FrostAE,etal.Pulmonaryarterialhypertension:baselinecharacteristicsfromtheREVEALRegistry.Chest.2010;137(2):376-87.Epub2009/10/20.

12. FarberHW,LoscalzoJ.Pulmonaryarterialhypertension.TheNewEngland


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Table 1: ClassificationofPulmonaryHypertensionaccordingtotheDanapointWHOclassification[8]aswellasincidence,prevalenceandtreatmentoptions.

journalofmedicine.2004;351(16):1655-65.Epub2004/10/16.13. SakaoS,TatsumiK,VoelkelNF.Reversibleorirreversibleremodelinginpul-

monary arterial hypertension. American journal of respiratory cell and mo-lecularbiology.2010;43(6):629-34.Epub2009/12/17.

14. BonnetS,MichelakisED,PorterCJ,Andrade-NavarroMA,ThebaudB,Ha-romyA,etal.Anabnormalmitochondrial-hypoxiainduciblefactor-1alpha-Kvchannelpathwaydisruptsoxygensensingandtriggerspulmonaryarterialhypertensioninfawnhoodedrats:similaritiestohumanpulmonaryarterialhypertension.Circulation.2006;113(22):2630-41.Epub2006/06/01.

15. GhofraniHA,MorrellNW,HoeperMM,OlschewskiH,PeacockAJ,BarstRJ,etal.Imatinibinpulmonaryarterialhypertensionpatientswithinadequateresponsetoestablishedtherapy.Americanjournalofrespiratoryandcriticalcaremedicine.2010;182(9):1171-7.Epub2010/06/29.

16. MichelakisED,McMurtryMS,WuXC,DyckJR,MoudgilR,HopkinsTA,etal.Dichloroacetate,ametabolicmodulator,preventsandreverseschronichypoxicpulmonaryhypertensioninrats:roleof increasedexpressionand

activityofvoltage-gatedpotassiumchannels.Circulation.2002;105(2):244-50.Epub2002/01/16.

17. WangXX,ZhangFR,ShangYP,ZhuJH,XieXD,TaoQM,etal.Transplantationofautologousendothelialprogenitorcellsmaybebeneficialinpatientswithidiopathicpulmonaryarterialhypertension:apilotrandomizedcontrolledtrial.JAmCollCardiol.2007;49(14):1566-71.Epub2007/04/10.

18. Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, GheorghiadeM, But-ler J. Left ventricular dysfunction with pulmonary hypertension: part 1:epidemiology, pathophysiology, and definitions. Circulation Heart failure.2013;6(2):344-54.Epub2013/03/21.

19. RuggieroRM,BartolomeS,TorresF.Pulmonaryhypertensioninparenchy-mallungdisease.Heartfailureclinics.2012;8(3):461-74.Epub2012/07/04.

20. Haythe J. Chronic thromboembolic pulmonary hypertension: a review ofcurrent practice. Progress in cardiovascular diseases. 2012;55(2):134-43.Epub2012/09/27.

Sub-group Treatment Options Incidence Prevalence

Group I - Pulmonary Arterial Hypertension (PAH)

-IdiopathicPAH-HeritablePAH-Inducedbydrugsandtoxins-AssociatedPAH-Persistentpulmonaryhypertensionofthenewborn-PAHsecondarytoveno-occlusivediseaseand/orpulmo-narycapillaryhemangiomatosis

Vasodilatortherapy:Sub-group/Casespecific[4]

1.1-2.4cpm/yr[9,10] 6.6-15cpm[9,10]

Group II - PH owing to Left Heart Disease (LHD)

-Systolicdysfunction-Diastolicdysfunction-Valvulardisease

Surgical[18] -- 8.6-83%(ofpatientswithLHD)[18]

Group III - PH owing to lung disease and/or hypoxia

-Chronicobstructivepulmonarydisease-Interstitiallungdisease-Otherpulmonarydiseaseswithmixedrestrictiveandobstructivepattern-Sleep-disorderedbreathing-Alveolarhypoventilationdisorders-Chronicexposuretohighaltitude-Developmentalabnormalities

Vasodilatortherapy:Sub-group/Casespecific[19]

12.9-23.9%(ofpatientswithlungdisease)[19]

--

Group IV - Chronic thromboembolic PH

-Surgicalremovalofemboli-Vasodilatortherapy[20]

0.5-3.8%(afteracutePE)10%(afterrecurrentPE)[20]

--

Group V - PH with unclear multifactorial mechanisms

-Hematologicdisorders-Systemicdisorders-Metabolicdisorders-Others:Tumoralobstruction,fibrosingmediastinitis,chronic renal failure on dialysis

Sub-group/Casespecific -- --

Abbreviations:cpm=casespermillionadults;PE=PulmonaryEmbolism


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Closing the fasciotomy wound following compartment syndromeAnthony Vo1


INTRODUCTION During compartment syndrome, there is an increaseinthe interstitialpressurewithinclosedandunforgivingosteo-fascial spaces. It is causedbynumerous injuries including frac-tures,crushinjuriesandburns[1].Thecompressionofvascularstructures within these spaces leads to muscle and nerve isch-emia.Ifischemiaremainsfortwohours,nervedamageandtis-suenecrosisoccur[2].Inastudyof108patientsadmittedtothehospitalwithlegproblems,14%ofpatientswithlegpainand9%ofpatientswithlegfractureswerediagnosedwithcompartmentsyndrome[3].Todate,fasciotomyisthemosteffectivetreatmentforpatientswithcompartmentsyndrome.However,thefasciot-omywoundoftenpresentsaproblemforphysiciansperformingprimaryclosureduetothepersistenttissueedemaandskincon-tracture[4].Furthermore,fasciotomywoundsareoftenaestheti-callyunappealingandthiscanbedebilitatingforthepatients.Inastudyof60patientsfollowingfasciotomywoundclosure,23%wereupsetbytheappearanceofthewoundanddidnotexposeit,28%changedhobbiesand12%changedoccupation[5]. Currently, therearenumeroustechniques in literaturethatattempttooptimizeclosure.However,eachtechniquehasitsownadvantagesanddisadvantages thatmustbe taken intoconsideration.Toaidclinicaldecision-making,thispaperwillpro-videadiscussionofpertinent featuresofeach technique.Thispaperreviewsliteraturefrom1990to2012thatdescribeswound

closuretechniques.Relevantinformationextractedinclude:• Timetowoundclosure:Thetimetakenfromimplemen-

tationofthetechniquetothetimeofwoundclosure• Cost:Thecostassociatedwithusingaparticularclosing

technique• Advantages/Disadvantages compared to other tech-

niques• Outcomes: Complications, revisions, loss of sensation,

andmanagementrequirements• Total number of patients and fasciotomy wounds for

eachtechnique

RESULTS Split-thickness skin grafting Split-thicknessskingraftingisthemostcommonproce-duretoclosefasciotomywounds[6].Itusesaskingraftfromadonorsitetoreducetheappositionrequiredforskinclosure.Asaresult,thistechniqueisoftentensionfree.However,thistech-niquerequiresanotheroperativeprocedure,results inanotherwound,complicateswoundcare,extendshospitalstaybyrough-ly3-5days,andrequiresimmobilizationofthewound.Thereisalsochancethatthegraftmayfail.Thefinalresultisathin,aes-theticallyunappealingscarwithoutsensation[4,7,8](seeTable1).

A B S T R A C T

Compartmentsyndromeisacommonandseveremedicalconditionthatcanleadtoischemiaandultimatelytissueloss.Fas-ciotomyisthemosteffectivetreatmentforpatientswithcompartmentsyndrome.However,closingthefasciotomywoundoftenpres-entsaproblembecauseofedemaandskinretraction.Asaresult,numeroustechniqueshavebeendevisedtooptimizewoundclosure.Eachtechniqueachievesclosuredifferentlyandhasitsownadvantagesanddisadvantages.Inthisreviewoftheliteraturefrom1990to2012,commontechniqueswillbediscussedalongwiththeirimportantfindingspertainingtowoundclosure.Adecision-makingalgorithmhasbeendevisedtoassistintheappropriateselectionoftechniquetooptimizefasciotomywoundclosure.

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Lesyndromeducompartimentestuntroublemédicalcourant,maisgravequipeutentraînerl’ischémieet,ultérieurement,lapertedetissus.Lafasciotomieestletraitementleplusefficacepourlespatientsprésentantunsyndromeducompartiment.Parcon-tre,lafermeturedelaplaieaprèsunetelleinterventionpeuts’avérerdifficileàcausedel’œdèmeetdelarétractioncutanée.Encon-séquence,denombreusestechniquesontétéconçuespouroptimiserlafermeturedelaplaie.Chaquetechniquepermetdefermerlaplaiedefaçondifférente,etcomportesesavantagesetsesdésavantages.Cetterevue,quiaétépubliésurlesujetentre1990et2012,abordelestechniquescourantes,demêmequelesconstatationsimportantesrelativementàlafermeturedelaplaie.Unalgorithmedécisionnelaétéconçupouraideràchoisirlabonnetechniqueenvued’optimiserlafermeturedelaplaieaprèsunefasciotomie.


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Table 1 : Adetailedstudyevaluatingthesplit-thicknessskingrafttech-niqueforfasciotomywoundclosure.

Author Medina,C.etal.9

Year ofpublication

2007

Number of patients

6

Average closuretime

9.2days

Complications in patients

3reportedscarpain,5reportednumbnessofextremity,5unsatisfiedwithresult

Management Dailydressingchanges

Secondary intention Secondary intentionusesonlyskincontractiontohealthefasciotomywound.Thistechnique isasimpleandpracticalapproachforpatientswhoareabletomanagetheirwoundswith-outdirectsupervision.Itreducesadditionalscarsfromskingraft-ing,reduceshospitalstayincomparisontoothertechniquesandtheneed fora secondprocedure,which reducesmanagementcosts[10](seeTable2).Dressingsarechanged1to3timesadayandcanbeusedinconjunctionwithotherclosingtechniques,ifneeded.Thedisadvantageisthatcompletehealingtakesanav-erageof3to4monthsdependingonthesizeofthewoundandnormalizationofthescarcontourtakesroughly4years[10].

Vacuum-assisted closure (VAC) VACusesnegativepressuretoexploittheelasticproper-tiesoftheskin.Thiscausesstretchingoftheskin,reducesede-ma,promotesbloodflow,lowersbacterialcountsandincreasesthetissuegranulationratetoultimatelycreateawoundthatismoreconducivetoclosure[11].However,thistechniquerequires

dressingchangesroughlyevery3daysandisveryexpensivetouse. Furthermore,VAC itselfmay fail toprovideadequate skinedge approximation for final closure and as a result, anotherclosingtechniquewouldberequired[12](seeTable3).

Table 2 : Adetailedstudyevaluatingfasciotomywoundclosure-usinghealingbysecondaryintention.

Author Boxer,L.etal.10

Year ofpublication

2003

Number of patients

2

Average closuretime

9.2days


3reportedscarpain,5reportednumbnessofextremity,5unsatisfiedwithresult

Management Dressingschanged1-3/day

Dermal apposition Dermalappositiontakesadvantageoftheelasticprop-ertiesof the skin. Essentially, a constant load is placedon thewoundmarginresultinginagradualincreaseinskinlengthandreductioninforcerequiredtomaintainthatlength.Withcyclesofre-loadingthewoundmargin,primaryclosureispossible[16].Intheliterature,thereisaplethoraoftechniquesandvariationsthat takeadvantageofdermal apposition, including the vesselloop shoelace, sub-cuticular suture, Ty-Raps, Sure-Closure, Dy-namicWoundClosure,STARandSilverBulletWoundClosureDe-vice(SBWCD). Theshoelacetechniqueusesstaplesandvesselloopstograduallyapposethewoundmargins.Thistechniquecanreadily

Table 3 : Detailedresearchstudiesfrom1990to2012evaluatingthevacuum-assistedclosuretechniqueforfasciotomywounds.Studiesthatdidnotprovidetheinformationarelistedwitha“-”.

Author Yang,C.etal.13 Zannis,J.etal.6 Saziye,K.etal.12 Kakagia,D.etal.14

Year of publication 2006 2009 2011 2012

Number of patients 34 370 7 25

Average length of wound - - 27cmx9.4cm -

Number of fasciotomy wounds

68 - - 42

Average closure time 6.7days 5.2days 11 days -

Complications in patients None 25patientsrequiredasecond procedure

2requiredasecondprocedure to close

5requiredasecondprocedure to close

Limitations noted - - - Expensiveandrequiressecond procedure

Management Dressingschangedevery3 days

Dressingschangedevery2-3days

Dressingschangedevery2-4days

Dressingschangedevery3 days

Cost - - - $176.09/day


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DISCUSSION Currently,therearenumeroustechniquesdescribedinthe literature pertaining to the optimization ofwound closurefollowing fasciotomy. Once the advantages and disadvantagesofeachtechniqueareunderstood,acliniciancandecidewhichtechnique to use to optimize fasciotomy wound closure for aparticularpatient.Apotential algorithm to assist thedecision-makingprocess includes taking intoconsideration thefinancialinvestmentforawoundclosure,thepatient’spreferenceandthepatient’s current medical conditions. The clinician should firstconsider the financial restraints andwhether or not the fasci-otomywoundrequiresasignificantfinancialinvestment.Thisisespeciallyimportantinhealthcaresettingswithlimitedresourc-es. Thenextquestion iswhich approach is best, given thepa-tient’spreferenceandthepatient’scurrentmedicalconditions.Patientsmaypreferonetechniquetoanotherorthestateofthepatient’shealthmaydictatetheuseofonetechniqueoveran-other.AsdescribedintheResultssection,eachtechniquehasitsownnicheandwillbestfitaparticulartypeofpatient.

LIMITATIONS Articlesweresearchedfrom1990to2012andassuch,techniques thatweremadepopularand studiedprior to1990(skingrafting)werenotfoundinthisliteraturesearch.Fromthe38 articles identified from the literature search, only 20 were

beperformedwithmaterialsfoundinanoperatingroom.Com-pared to the VAC technique, the shoelace approach takes lesstimeforclosure,isconsiderablylessexpensive,anddoesnotre-quireasecondprocedureforclosure[14]. The sub-cuticular suture techniqueuses sutures toap-pose thewound edges, taking roughly 7 to 11 days forwoundclosure[13].Thistechnique,liketheshoelace,usesreadilyavail-able materials and has a lower cost in comparison to commer-cialdermalappositiondevices.Disadvantagesincludeinflamma-tionaround suturesand suturebreaking requiring replacement[17,18]. Commercial devices such as Sure-Closure, DynamicWoundClosure,STARandtheSilverBulletWoundClosureDevicemayresultinwoundclosureinonly4days[13].However,theyareexpensivetopurchaseandtheymustbemadeavailablebefore-hand.Forexample,theSureClosuredevicecostsbetween$300and$500[15]. Withalldermalappositiontechniques, thebiggestdis-advantageisthattheycannotbeapplieduntiltheedemasettles,which often requires 3 to 5 days postoperatively. They also re-quirethewoundtobeimmobilizedduringtreatment.Oncethetechniqueisapplied,theconstanttensionfromthedevicescancauseskinnecrosisandrecurrenceofcompartmentsyndrome.Assuch,closemonitoringofthelimbduringclosureisoftenrequired[17].

Table 4 : Detailedresearchstudiesfrom1990to2012evaluatingvariousdermalappositiondevicesforfasciotomywoundclosure.Studiesthatdidnotprovidetheinformationarelistedwitha“-”.

Author McKenney,M.et al.4

Taylor,R.etal.17 Zorrila,P.etal.20 Medina,C.etal.9 Geertruida,A.etal.16

Kakagia,D.etal.14

Year of publication 1997 2003 2005 2007 2010 2012

Technique STAR Skinanchors Shoelace SBWCD Ty-raps Shoelace

Number of patients 13 5 20 8 13 25

Average dimensions of wound

7.6cm 28cmx8.5cm - - - -

Number of fasciotomy wounds

- 6 - - 23 40

Average closure time 2.9days 11.5days(range6-14days)

8.8days 7.4days 6.3days -


1withsuperficialinfection

None 1 with scar contracture

2 with scar tender-ness,2withnumb-nessofextremity,3unsatifsfiedwith

results

1requiredasecond procedure

6requiredreplacement of

device

Limitations reported - Excessiveskintension

Tighteningwasdone in the

operatingroom

- Small wound dehiscence

occurred once device removed

-

Management Dailytightening Tightenevery1-3days

Tighteningevery48hours

Dailytightening Tightenevery24-48hours

Dailytightening

Cost - - - $575/device $23.73fora30 cm wound

$18.26/day


foundtocontainpertinentinformation.Furthermore,notallde-tailedstudiesfoundinthetablesincludedpertinentinformation,suchasthecosts,thenumberoffasciotomywoundsandthefas-ciotomywounddimensions.Thismakesitdifficulttoaccuratelycomparestudiesusingthesametechnique.

CONCLUSION Compartmentsyndromeisacommonandoftensevereconditionthat ismanagedwithfasciotomy.Therearecurrentlynumeroustechniquesdescribedintheliteraturetocloseafasci-otomy wound. It is important to be aware of the numerous tech-niquesandtohaveanapproachtochooseonetechniqueoveranotherforaparticularpatient.Whendecidingwhichtechniquetoapply,financialrestraints,thepatient’spreferenceandthepa-tient’scurrentmedicalconditionswillbeimportanttoconsider.Havingtheknowledgeandasimplealgorithmwillhelpoptimizewoundclosurepromptlywithaslittlecomplicationsandcostsaspossibletobothparties.

REFERENCES1.TiwariA,HaqAL,MyintF,HamiltonG.Acutecompartmentsyndrome.BritishJournalofSurgery.2002;89:397-412.2.MatsenFA3rd,WinquistRA,KrugmireRB Jr.Diagnosisandmanagementofcompartmentalsyndromes.JBoneJointSurgAm.1980;62(2):286-91.3.QvarfordtP,ChristensonJT,EklofB,etal.Intramuscularpressure,musclebloodflow,andskeletalmusclemetabolisminchronicanteriortibialcompartmentsyn-drome.ClinOrthop.1983;(179):284-90.4.McKenneyM,NirI,FeeT,MartinL,LentzK.Asimpledeviceforclosureoffasci-otomywounds.TheAmericanJournalofSurgery1996;172:275-277.

5.FitzgeraldAM,GastonP,WilsonY,QuabaAMcQueenMM.Long-termsequelaeoffasciotomywounds.BritishJofPlastSurg2000;53:690-693.6.ZannisJ,AngobaldoJ,MarksM,etal.Comparisonoffasciotomywoundclo-suresusingtraditionaldressingchangesandthevacuum-assistedclosuredevice.AnnPlastSurg2009;62(4):407-409.7.HarrisI.Gradualclosureoffasciotomywoundsusingavessel loopshoelace.Injury1993;24(8):565-6.8.SinghN,BlumanE,StarnesB,AndersenC.Dynamicwoundclosurefordecom-pressivelegfasciotomywounds.AmSurg.2008;74(3):217-20.9.MedinaC,SpearsJ,MitraA.Theuseofaninnovativedeviceforwoundclosureafterupperextremityfasciotomy.Hand(NY)2008;3(2):146-151.10. Boxer LK, Buchman SR. An Alternative method for closure of fasciotomywounds:healingbysecondaryintention.TheInternetJ.ofPlastSurg.2003;1(2).11.ZannisJ,AngobaldoJ,MarksM,etal.Comparisonoffasciotomywoundclo-suresusingtraditionaldressingchangesandthevacuum-assistedclosuredevices.AnnPlastSurg.2009;62:407-409.12. Saziye K,Mustafa C, IlkerU, Afksendyios K. Comparison of vacuum-assistedclosuredeviceandconservativetreatmentforfasciotomywoundhealinginisch-aemia-reperfusionsyndrome:preliminaryresults.IntWoundJ.2011;8(3):229-236.14. KakgaiaD, Karadimas E, DrososG, Ververidis A, Trypsiannis G, VerettasD.Woundclosureoflegfasciotomy:comparisonofvacuum-assistedclosureversusshoelacetechnique.Arandomizedstudy.Injury2012;[Epubaheadofprint].15.YangCC,ChangDS,WebbLX.Vacuum-assistedclosureforfasciotomywoundsfollowingcompartmentsyndromeoftheleg.JSurgOrthopAdv.2006;15(1):19-23.16.GeertruidaAM,GovaertG,vanHeldenS.Ty-RapsinTrauma:anovelclosingtechniqueofextremityfasciotomywounds.JTrauma.2010;69(4):972-5.17. Taylor RC, Reitsma BJ, Sarazin S, Bell MG. Early results using a dynamicmethodfordelayedprimaryclosureoffasciotomywounds.JAmCollSurg.2003;197(5):872-8.18.JanzingHM,BroosPL.Dermatotraction:aneffectivetechniquefortheclosureoffasciotomywounds:apreliminaryreportoffifteenpatients.JOrthopTrauma.2004;15(6):438-41.19.ChivertonN,ReddenJF.Anewtechniquefordelayedprimaryclosureoffasci-otomywounds.Injury.2000;31(1):21-41.20.ZorillaP,MarinA,GomezLA,SalidJA.Shoelacetechniqueforgradualclosureoffasciotomywounds.JTrauma.2005;59(6):1515-7.

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Or i g ina l Research

Associations between neighbourhood walkability, active school transport and physical activity levels in primary and secondary school students: A pilot-study

RichardLarouche,MSc1,2,GuyFaulkner,PhD3,MarkTremblay,PhD1,2,4

1HealthyActiveLivingandObesityResearchGroup,Children’sHospitalofEasternOntarioResearchInstitute2SchoolofHumanKineticsattheUniversityofOttawa3FacultyofKinesiologyandPhysicalEducationattheUniversityofToronto

4DepartmentofPediatricsattheUniversityofOttawa

A B S T R A C T

Objectives:Thislongitudinalpilot-studyexaminedtheassociationsofneighbourhoodwalkabilitywithactiveschooltransport(AST)andpedometer-determinedphysicalactivity(PA)immediatelybeforeandafterthetransitionfromprimarytosecondaryschool.Methods:Fifty-fivegrade6studentswererecruitedfrom4primaryschoolsinOttawainMay/June2012.Theywereaskedtocompleteadiaryindicatingtheirmodeoftransportto/fromschoolfor1weekandwearaSC-StepMXpedometerfor8consecutivedays.48studypackageswerereturnedatbaselineand29atfollow-up(September/October2012).TheWalkScore®applicationwasusedasaproxyforwalkabilityaroundthehomeandaroundtheschool.TheassociationsofwalkabilitywithASTandaveragedailystepcountsatbothtimepointswererespectivelyexaminedwithbinarylogisticregressionandlinearregressionmodelsadjustedforgender.Results:Atbaseline,onlywalkabilityaroundtheschoolwaspositivelyassociatedwithAST(OR=1.04).Atfollow-up,higherWalkScoreratingsaroundthehomeandtheschoolwerebothassociatedwithgreateroddsofAST(OR=1.12and1.29respectively).Furthermore,walkabilityaroundthehomewasassociatedwithhigherstepcountswithalargeeffectsize(η2=0.19).Conclusions:Therewasanegativeassociationbetweenhavingaregularmedicaldoctorandhighself-perceivedhealth,modifiedbyage.Thefindingssuggestthatindividualaccesstocaredoesnotpredicthealthinthesamewayasphysiciandensity.

INTRODUCTION Recentsurveyfindingsindicatethatthemajorityofchil-drenandyouthdonotmeetcurrentphysicalactivity(PA)guide-lines, which recommend 60 minutes of moderate-to-vigorousphysicalactivityperday[1,2].Eveninthepediatricpopulation,insufficientPAlevelsareassociatedwithdetrimentalhealthpa-rameterssuchascardiovasculardiseaseriskfactors[3,4],under-

scoringtheneedfor interventionsthatpromotePA.Sincechil-drenandyouthmusttraveltoandfromschoolonaregularbasis,active school transport (AST; e.g. using non-motorized travelmodes suchaswalkingandcycling to travel to/fromschool) isregardedasapromisingstrategytoincreasePAatthepopulationlevel[5,6]. Duringthelasttwodecades,therehasbeenarapidin

R É S U M É

Objectifs:Cetteétudepilotelongitudinalevérifiaitl’associationentrelesquartiersfavorablesàlamarche,letransportactifscolaire(TAS)etleniveaud’activitéphysique(AP)déterminéàl’aided’unpodomètre,immédiatementavantetaprèslatransitiondel’écoleprimaireàl’écolesecondaire.Méthodes:Enmaietjuin2012,55élèvesdelasixièmeannéeontétérecrutésdans4écolesprimairesd’Ottawa.Onleurademandéderemplirquotidiennementunjournaldeborddanslequelilsdevaientindiquerleurmodedetransportpourserendreàl’écoleetenrevenirdurantunesemaine.IlsdevaientégalementporterunpodomètreSC-StepMXduranthuitjoursconsécutifs.Àlapremièreétape,48troussesd’étudeontétéretournéesàlapremièreétapeet29lorsdusuivienseptembreetoctobre2012.L’applicationWalkScore®aétéutiliséecommetémoinpourdéterminersilemilieuenvironnantledomicileetl’écoleétaitfavorableàlamarche.L’associationentrelesquartiersfavorablesàlamarche,leTASetlenombremoyendepasfaitsdansunejournéeaétéexaminéerespectivementauxdeuxétapesdel’étudeàl’aided’unerégressionlogistiquebinaireetd’unmodèlederégressionlinéaireajustéselonlesexe.Résultats:Àl’étapeinitiale,seulunmilieufavorableàlamarcheautourdel’écoleétaitassociépositivementauTAS(RC=1,04).Lorsdusuivi,unindiceWalkScoreélevéauxalentoursdelamaisonetdel’écoleétaitassociéàuneprobabilitésupérieuredeTAS(RC=1,12et1,29respectivement).Deplus,unquartierfavorableàlamarcheautourdudomicileétaitassociéàunnombreplusélevédepasavecunetailled’effetélevée(η2=0,19).Conclusion:Cesobservationspréliminairessuggèrentqu’ilpeuts’avérerplusimportantpourlesétudiantsdel’écolesecondairequeleurmilieusoitfavorableàlamarche.Puisqu’aucuneautreétudelongitudinalen’aétémenéepourévaluersil’associationentrelesquartiersfavorablesàlamarche,leTASetleniveaud’APvarieaufildutemps,ilseraitjustifiédeprocéderàdegrandesétudesprospectives.



creaseinthenumberofscientificstudiesassessingtheassocia-tionbetweencharacteristicsofthebuiltenvironment(i.e.densi-ty,landusemix,streetconnectivity,availabilityofsidewalksandcyclepaths,etc.)andindividuals’activetransportandPAlevels[7].Researchershavedevelopedcompositemeasuresofneigh-bourhoodcharacteristicsthatfavour“walkability”,whichreferstothepotentialforindividualstowalktolocaldestinations[8,9].Measuresofneighbourhoodwalkabilityhaveconsistentlybeenshowntobeassociatedwithadults’travelmodeandPA[10,11].However,theevidenceregardingtheassociationbetweenchar-acteristics of the built environment and children’s AST and PAremains inconsistent [12,13]. In their systematic review of 14studies that used objective measures of environmental char-acteristics,Wongetal.foundthatdistancebetweenhomeandschoolwastheonlyconsistentcorrelateofAST[13]. Giles-Cortietal.[14]hypothesizedthattheinfluenceofthebuiltenvironmentonASTandPAmaybestrongerinadoles-centsthaninchildrenbecausetheformergenerallyhavegreaterindependentmobility.Thisconceptreferstothedegreeoffree-dom of children and youth to move around in public spaces with-outadultsupervision[15].Todate,moststudiesthatexaminedthe association between the built environment and AST haveonlyconsideredassociationswithindividualcharacteristicsrath-er than compositemeasures ofwalkability [13].OneUS studyfoundthatcharacteristicsofthebuiltenvironmenthadastron-gerassociationwithwalkinginyouthaged12-15yearsoldcom-paredtoyoungerparticipants[16];howeverthecross-sectionaldesignisanimportantlimitationofthisstudy. Therefore,theobjectiveofthepresentpilot-studywastoexaminetheassociationsofneighbourhoodwalkabilitywithASTandPAattheendofprimaryschool(grade6)andthebegin-ningofsecondaryschool(grade7)amongthesameparticipants.TheschooltransitionisamajorlifeeventthatcoincideswithalargedecreaseinPA[17].Itwashypothesizedthattheassocia-tions of neighbourhoodwalkabilitywithAST and PAwould bestrongerinsecondaryschool.

METHODSParticipants and setting Fifty-five grade 6 students were recruited from fourprimary schools in Ottawa (Canada) inMay/June 2012 (33.3%responserate).Ofthesefourschools,twowerelocatedincen-sustractswithhighpopulationdensity(3531-4100inhabitants/km2),accordingtothe2006Canadiancensusdata[18].Thetwoschoolswere located in lowerdensityareas (988-2159 inhabit-ants/km2), thereby providing variability in built environmentcharacteristics.Parentsindicatedtheirchild’sprospectiveschoolforgrade7andeithertheirphonenumberore-mailaddressforfollow-uppurposes.48children(24girlsand24boys)returnedtheirstudypackageatbaselineand29(16girlsand13boys)atfollow-up (September/October2012). Ethical approvalwasob-tainedfrominstitutionalResearchEthicsBoardsandfromthe2participatingschoolboards.

Measures Atbothtimepoints,participantswereaskedto:1)com-plete a travel diary indicating theirmodeof transport to/fromschoolforeachdayduring1week;2)wearaSC-StepMXpedom-eter(Stepscount,DeepRiver,ON)ontherighthipfor8consecu-tivedays;and3)completealogrecordingtheirdailystepcountsandthetimethepedometerwaswornduringwakinghours.Thispedometerhasbeenshowntobevalidandreliable[19].Parentsofeachparticipantindicatedtheirpostalcode,whichallowedfortheestimationofneighbourhoodwalkability.

Data treatment Participantswereclassifiedasactivetravelersiftheyre-portedusingactivetravelmodesforatleast50%ofschooltrips.Thisclassificationmethodshowedveryhightest-retestreliabilityover two consecutiveweeks ofmeasurement [20]. Pedometrydatawere screenedbasedon established criteria including: 1)between1,000and30,000steps/day[21];2)≥10hoursofdata/day[22]and3)≥3daysofvaliddata(e.g.meetingthedailywearthresholdvalues)[23].Applicationofthesethresholdsledtotheexclusionofpedometerdatafrom2participantsatbaselineandnoneatfollow-up.Thepostalcodesprovidedbytheparentwereusedasaproxyforresidentialaddress,basedonevidencethatCanadianpostalcodesareasuitableproxyinurbanareas[24,25].TheWalk Score®application (http://www.walkscore.com/)wasused as an estimate of neighbourhoodwalkability around theparticipants’ residence (using postal codes) and around theirschool(usingthestreetaddress)atbothtimepoints.TheWalkScore is a composite measure of accessibility to a variety of des-tinations including schools, parks, shops, and public transit bywalking.Amenitieslocatedwithina1.6kmlinearbuffercontrib-utetoa location’sWalkScore,butamenitieswithina400me-tersbufferreceivehigherpointsthanthosewithin800meters,1.2kmand1.6kmbuffers.WalkScoreratingsrangefrom0to100withhighervaluesindicatinggreaterwalkability.AvalidationstudyhasfoundstrongcorrelationsbetweenWalkScoreratingsandobjectivemeasuresofthebuiltenvironment(i.e.residentialdensity,intersectiondensity,streetdensity,averageblocklengthandaccesstopublictransit)[26].

Analyses First,Pearsoncorrelationsassessedtheassociationbe-tweenWalkScoreratingsaroundthehomeandaroundtheschoolatbothtimepoints.Second,theassociationsofneighbourhoodwalkabilitywithASTandaveragedailystepcountsatbothtimepointswereexaminedwithbinarylogisticregressionandlinearregressionmodelsrespectively,andadjustedforgender.Theη2statisticwasusedasameasureoftheindependenteffectsizeofneighbourhoodwalkabilitywithintheregressionmodels.Analy-ses were performed with IBM SPSS 20 and the probability of type Ierrorwassetat5%.



Variable Categories Healthy Baseline

Gender(n)Girls 24 16

Boys 24 13

Travel mode

Active 27(14G,13B) 13(8G,5B)

Inactive 19(9G,10B) 15(7G,8B)

Missing 2(1G,1B) 1(1G)

Distance(km) N/A 2.3±2.4 3.9±3.4

WalkScore†around the home

N/A 62.4±17.8 62.0±19.3

WalkScorearound the school

N/A 62.0±20.2 61.5±27.8

Averagesteps/day

Overall 16,805±3,744* 14,071±3,680*

Girls 15,235±2,973 12,728±3,301

Boys 18,447±3,820 15,415±3,662BaselinedatawascollectedinMay/June2012andfollow-updatawascollectedinSeptember/October2012.G=girls;B=boys.†WalkScoreratingsrangefrom0to100withhigherscoresindicatinggreaterwalk-ability.WalkScoreratings,distanceandsteps/dayarepresentedasmean±SD.*denotesstatisticallysignificantdifferencesbetweenboysandgirls(p<0.05).Twoparticipantsprovidedinsufficientinformationtoallowforthedeterminationoftheirprimarytravelmodeatbaselineandoneatfollow-up

Table 1. Descriptivecharacteristicsofthesampleatbaselineandfollow-up.

RESULTS Descriptive characteristics of the participants at base-lineandfollow-upareprovidedinTable1.Baselinedatadidnotdiffer between participants who provided follow-up data andthosewhoprovidedonlybaselinedatawithrespecttogender,WalkScore,ASTandPA(allp>0.49).WalkScoreratingsaroundthehomeandaroundtheschoolweresignificantlycorrelatedatbaseline (r=0.70;p< .001)andfollow-up(r=0.53;p= .003);therefore,toavoidmulti-collinearity,separatemodelsweredonetoassesstheeffectofwalkabilityaroundthehomeandaroundthe school. Atbaseline,WalkScoreratingsaroundthehomedidnotdifferbetweenactiveandinactivetravelers(OR=0.99;95%CI=0.96-1.03; p = .87), but children attending schoolswithhigherratingsweremorelikelytoengageinAST(OR=1.04;95%CI=

1.01-1.07;p=.03)(Table2).Atfollow-up,higherWalkScorerat-ingsaroundthehome(OR=1.12;95%CI=1.03-1.21;p= .01)andaroundtheschool(OR=1.29;95%CI=1.00-1.66;p=.05)werebothassociatedwithgreateroddsofAST.Ofnote, theseoddsratiosrepresentthechangeintheoddsofASTassociatedwitheachunit increase inWalkScore.For instance,a10-pointincreaseinWalkScorearoundthehomeatfollow-upwouldbeassociatedwitha3-foldincrease(OR=3.02)intheoddsofAST. Table3 illustratestheassociationbetweenWalkScoreandaveragedailystepcountsatbothtimepoints.Atbaseline,WalkScoreratingsaroundthehomeandaroundtheschoolwerenotassociatedwithstepcounts(allp> .79).Atfollow-up,chil-drenlivinginmorewalkableareasweresignificantlymoreactive(F=5.21;p=.03)withalargeeffectsize(η2=0.19),butnoas-sociationwasfoundforwalkabilityaroundtheschool(F=1.97;p=.17).Inallregressionmodels,boysweremoreactivethangirls(allp≤.04);however,therewerenogenderdifferencesintravelmodesatanytimepoint(p≥.62). DISCUSSION Thepresentpilot-studyassessedtheinfluenceofneigh-bourhoodwalkabilityonASTandPAimmediatelybeforeandaf-terthetransitionfromprimarytosecondaryschool,amajorlifeevent that has been understudied with respect to AST. At base-line,walkabilitymeasureswerenotassociatedwithPA,andonlyWalkScoreratingsaroundtheschoolwereassociatedwithAST.Atfollow-up,WalkScoreratingsaroundthehomeandtheschoolwerebothstronglyassociatedwithAST.WalkabilityaroundthehomewassignificantlyassociatedtoPAwithalargeeffectsize;however,thisrelationshipwasnotfoundforwalkabilityaroundtheschool.Despitesomeinconsistencies,thesefindingsprovidepreliminaryevidencesupportingGiles-Cortiandcolleagues’[14]hypothesis that the influenceof neighbourhoodwalkability onASTandPAlevelsisstrongerinsecondaryschoolstudentsthanin primary school students. Previous systematic reviews have concluded that theevidencesupportingassociationsbetweenneighbourhoodwalk-ability(ordifferentbuiltenvironmentconstructs),ASTandPAisinconsistentandthatmostincludedstudieswerecross-sectional[12,13]. Inconsistentfindings couldbedue tomany factors in-cludingmethodologicaldifferencesintheassessmentofbuilten-vironmentcharacteristics[13,27]orPAlevels[12]andfailureto

Time point WalkScore ActiveTravellers(mean± SD) InactiveTravellers(mean± SD) OR(95%CI) p-value

BaselineHome 61.5±17.4 62.8±18.8 0.99(0.96-1.03) .87

School 68.3±18.1 54.7±19.7 1.04(1.01-1.07) .03

Follow-upHome 76.3±9.7 51.7±17.1 1.12(1.03-1.21) .01

School 79.5±1.5 45.9±31.4 1.29(1.00-1.66) .05DifferencesinWalkScoreratingsbetweenactiveandinactivetravelerswereassessedatbaseline(May/June2012)andfollow-up(September/Octo-ber)usingbinarylogisticregressionadjustedforgender.

Table 2.Associationsbetweenneighbourhoodwalkabilityandparticipant’sprimarytravelmodeatbaselineandfollow-up.



considerpotentialmoderatorssuchasage,gender,ethnicityandsocioeconomicstatus[28,29]. Inaddition,ithasbeensuggestedthattheinfluenceofbuiltenvironmentcharacteristicsmaybeadditive[7,30],sostud-iesthatexamineindividualcharacteristicsinsteadofusingacom-positemeasureofwalkabilitymayunderestimatethestrengthofobservedassociations.McDonald [31] reported that thedirectinfluenceofpopulationdensityonASTwasweak,butthathigherdensitymayleadtoshorterdistancesbetweenhomeandschool,whichisinturnstronglyassociatedwithAST.Furthermore,theremaybecomplexinteractionsbetweenbarriersandfacilitatorsofAST.Forexample,highdensityandstreetconnectivitymaybeas-sociatedwithbothshorterdistancetoschoolandheaviertrafficexposure[14]. Anotherpotentialreasonforthelackofassociationbe-tweenWalkScoreratingsandPAatbaselineisthatschooljour-neysmayaccountforalowerproportionofdailyPAinchildrenthan inadolescents [32,33].Primaryschoolchildrenmayaccu-mulateagreaterproportionoftheirPAthroughactiveplaythansecondaryschoolyouth.Therefore,lowdensityneighbourhoodswithlargerlotsandcul-de-sacsmaybemoreconducivetoactiveplaythanhighdensityneighbourhoodswithheavytrafficandas-sociatedroadsafetyconcerns.Incontrast,aschildrengetolder,activetransport(notonlyto/fromschool)maybecomeamoreimportantsourceofPA;hence,walkableneighbourhoodscouldbecomeincreasinglyimportantforfosteringPA. The school transitionmight be a good time for inter-ventionsthatpromoteASTbecausetravelhabitsarelikelytobemodifiedduetochangesinschool location.InaScottishstudy,travel habits explaineda significantproportionof the variance

instepcountsduringthetriptoschooloverandaboveplannedbehaviourconstructs (e.g.attitudes, subjectivenormsandper-ceivedbehavioural control) [34]. In addition, Panter et al. [29]suggestedthatparentalsafetyconcernsmightbecomelessinflu-entialintravelmodedecisionsaschildrenacquireindependentmobility. Themainlimitationsofthisstudyarethesmallsamplesizeandthelowresponseratesuggestingthatthesamplepopu-lationmaynotberepresentativeofthegeneralpopulation.Asaresult, theremayhavebeenaselectionbiaswithhighlyactivechildrenbeingmorelikelytoparticipateatbaseline.Furthermore,the small sample size precludes the adjustment of regressionmodels for a larger range of socio-demographic variables thatmayinfluencetravelmodechoicesandPApatterns(i.e.parentaleducationandemploymentstatus,carownership).ChildrenmayhaveincreasedtheirlevelofPAwhenwearingapedometer;how-ever,arecentreviewofpedometeruseamongchildrenreportedconflictingfindings regarding the issueofpedometer reactivity[35].Thus,itremainsunclearwhetherreactivitymayhavecon-tributedto theobservedchanges inphysicalactivity.However,theobservedchangesareconsistentwiththedeclinesinphysicalactivitycommonlyseenduringthistransitionalperiod[17].Fur-therstudiesareneededtoconfirmthepresentfindings.Manystudieshave shown that childrenaremoreactiveduring sum-mermonths,thustheobserveddifferences instepcountsmaybepartiallyexplainedbyseasonalvariations[36]. Inthisstudy,the follow-upwasdoneasearlyaspossible in theschoolyeartominimizeseasonalitybias. Interestingly,previousresearch inToronto (Canada) has shown no seasonal differences in travelmodesamong11-12yearsoldchildren [37].Theobservedde-creaseintheproportionofparticipantsengaginginASTmaybeattributabletoa50%increaseinthedistancebetweenhomeandschoolacrosstheschooltransition[20].AlthoughWalkScorerat-ingshavebeenshowntobecorrelatedwithotheraspectsofthebuiltenvironment(i.e.density,diversityanddesign),itmayfailtocapturecharacteristicsassociatedwithyoungerchildren’stravelandPApatterns. Finally, postal codeswereused as a proxyofresidentialaddressasrequiredbyResearchEthicsBoards.Nev-ertheless,previousresearchinCalgary(Canada)hasshownthat87.9%of postal code locationswerewithin 200meters of thetrueaddresslocation[24]. The main strength of the study is the assessment ofneighbourhoodwalkability,ASTandPAimmediatelybeforeandaftertheschooltransition,amajorlifeeventusuallycharacter-izedbyalargedecreaseinPAlevels.Moreover,walkabilitywasassessed both around the home and around the school. The use of an objectivemeasure of PA, rather than a questionnaire, isanother important strengthbecauseusingaquestionnaire canleadtoalargeoverestimationofchildren’sPAlevel[38].Toourknowledge,onlyoneotherstudyhasassessedtheinfluenceoftheschooltransitiononAST[39],butnoassociationsofbuilten-vironmentcharacteristicswithASTandPAwerereported.

Time point WalkScore

Variable F p η2

Baseline

Home

Corrected model 4.28 .02 .19

WalkScore 0.04 .85 <.01

Gender 8.12 <.01 .18

School


WalkScore 0.71 .79 <.01

Gender 9.38 <.01 .18

Follow-up

Home


WalkScore 5.21 .03 .19

Gender 6.83 .02 .23

School


WalkScore 1.97 .17 .08

Gender 5.02 .04 .18PhysicalactivitywasmeasuredwithSC-StepMXpedometersatbaseline(May/June2012)andfollow-up(September/October);thatisimmedi-atelybeforeandaftertheschooltransition.

Table 3.Associationsbetweenneighbourhoodwalkabilityandstepcountsatbaselineandfollow-up.



CONCLUSION Inthislongitudinalpilot-study,theassociationbetweenneighbourhoodwalkability (as assessedby theWalk Score ap-plication)andmeasuresofASTandPAwasstrongerinsecondaryschool compared to primary school. This suggests that neigh-bourhood walkability may be more important for supportingadolescents’ASTandPAlevels.However,giventhesmallsamplesize,futureprospectivestudiesareneededtoconfirmthesefind-ings.SincetheschooltransitionhasbeenshowntocoincidewithalargedecreaseinPA[17],thereisaneedforstudiestoexaminewhetherwalkableenvironmentscanattenuatethisdecline.

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G l o b a l H e a l t h

Un aperçu des stratégies utilisées par les pays en voie de développement pour réduire les temps d’attente pour une chirurgie de la cataracte: Y a-t-il quelque chose à apprendre? DavidMichaelStitt,BSc1

1Facultédemédecine,Universitéd’Ottawa

INTRODUCTION Selonuneétuderécente, lamoyenneglobaledejoursd’attentepour recevoirunechirurgiede la cataracteenOntar-ios’élèveà68,8 jourset l’âgemoyendespatientsest72,5ans[1].Deplus, les experts estiment que le taux de chirurgies dela cataracteest corrélé très faiblementau tempsd’attente [1].Cependant,selonuneautreétude, lesrisquesdechutesoudedépressionenattendantplusdesixmoisavecunecataractenon-traitéesonttrèsélevés[2].BienquelesraisonsquiexpliquentlasituationactuelleenOntario soientcomplexes, cequiestbienconnu,c’estquelefacteurderisqueprincipaldelacataracteestl’âgeavancé.Cecidevientproblématiquecarl’espérancedeviemoyenneauCanadaestenaugmentationconstante(Figure1).

D’ailleurs,c’estlacohortedesgensâgésdeplusde65ansquioccupe81%destraitementschirurgicauxdelacataracteenOntario[2-4].Pourrépondreàcebesoin,desavancéestech-niques significatives ont été développées pour le traitementchirurgicaldans lesannées1990.Cequiprenaitauparavantde2 à 3 heures par chirurgie prendmaintenant de 20 à 30min-utes.Lorsdecettetechnique,nommée laphacoémulsification,lecristallindel’oeilsefaitdésintégreràl’aided’unesondeàul-trasonsouspressionpositive.Ceciévitel’effetindésirabledecol-lapsus oculaire. Par la suite, une lentille intraoculaire (LIO) estinstallée dans la chambre postérieure de l’œil. Cette chirurgieest maintenant considérée comme l’étalon d’or du traitement de cataracte.Cependant,nousavonsatteintunplateauenmatière

d’innovationtechnologiqueet letraitementde lacataracteris-quedeperdresonefficacitéàcausedel’augmentationrapidedeslistesd’attentes.Lebutdecetarticleviseàdémontrercommentl’adoptiondedeuxdifférentesstratégiesmisesenévidencedansles pays en voie de développement peut améliorer l’efficacitédanslessoinsiciauCanada.Notamment,selondeuxophtalmol-ogistesafricains,letraitementplus«agréableauxpatients»estunebonneapproche,oubien selondesétudes faitesen Inde,l’accentdoitêtremissurlesdiscussionsderésultatspositifsdutraitementcasparcaspourvaloriserlephénomènede«boucheàoreille».

L’EFFICACITÉ ACTUELLE AU CANADA Durantmesdeuxdernièresannéesdemédecine,j’aieul’occasiondefaireplusieursstagesd’observationenophtalmolo-gieàtravers lepays.D’aprèscetteexpérience, l’étatactueldessoinsauxpatientsdiagnostiquésavecunecataracteesttrèsef-ficace.Selonuneétudecollaboratived’expertsenophtalmologiefaite auCanadaen2009, la cataracteest la causeprimairedepertedevisiondans16%decas[3].Letauxdechirurgiesdelacataracteestélevé,maiscommecetauxestfaiblementcorréléavecletempsd’attenteenOntario,ilsepeutqu’ilyaitunautrephénomèneexpliquantnostempsd’attente[1,2,5].Letableau1démontrelesdifférencesdestauxdechirurgiesdelacataracteentrel’Ontarioetlesdeuxrégionscibléesdanscecommentaire:l’Afriqueet l’Inde.Avec l’augmentationdubesoindechirurgiesdelacataracteetlacroissancerapidedeslistesd’attente,lesys-tèmecanadiendoitenvisager l’intégrationdenouvelles straté-giespourmaintenirl’efficacitédecetraitement.

Tableau 1 : TauxdechirurgiedelacataracteenOntario,enAfriqueeten Inde.

Région Taux de chirurgie de la cataracte par

année par 100 000 habitants

Pourcentage per capita

Estimation de la population

actuelle

Ontario 540,3 0,54% 13505900a

Afrique <15-150 0,015–0,15% 1,0325billionb

Inde 370 0,37% 1,2415billionc

Sourcesdesestimationsdelapopulationactuelle:a.)http://www.fin.gov.on.ca/en/economy/ecupdates/factsheet.html; b.) http://esa.un.org/wpp/; c.) http://data.worldbank.org/

Figure 1. L’espérancedevieauCanadade1921jusqu’en2005.Sources:1921à1981:NagnurD.Longévitéettablesdemortalitéchronologiques(abrégées), 1921 à 1981, Statistique Canada, Catalogue 89-506, 1986; 1986 :Duchesne,D,Nault,F,Gilmour,H,Wilkins,R.Recueildestatistiquesdel’étatcivil1996,StatistiqueCanada,Catalogue84-214,1999;1991à2005:TableauCANSIM102-0511,Espérancedevie,tabledemortalitéabrégée,à lanaissanceetà65ans,selonlesexe,Canada,provincesetterritoires,annuel.



L’ÉTAT DES LIEUX ACTUEL EN AFRIQUE Parmilesdifférentspaysdusub-saharien, ilexisteunegrandehétérogénéitédanslestauxdechirurgiesdelacataracte[6].IlestimportantànoterquelacauseprincipaledecécitéenAfriqueestdeloinlacataracte(Tableau2).Selonuneétudeen2001, la cataracteest la causeprimaired’environ50%des casdecécitéenAfrique. [7]. Deplus, leseffortspourtrouverdessolutionssontenpleinessorgrâceauxinitiativesd’expertsinter-nationauxensantépubliquequiluttentcontrelacécitétraitable.Un bon exemple est l’introduction du programme internation-alVision2020« ledroità lavue»,quiacommebutprincipalde sensibiliser les gens au concept de cécité traitable. Cepro-grammeamisunegrandeemphasesurlacataractedanslevoletd’Afrique[8,9].Deplus,Vision2020agitcommeliaisond’effortscollaboratifs évaluant et comparant les différents programmesdetraitementdansplusieursrégionsdel’Afrique.

CE QU’ON PEUT APPRENDRE DE L’AFRIQUE Leseffortspourmieuxcomprendreetquantifierlesbe-soinspourlacataracteontétéfaitsenAfriqueetlesmisesàjoursdecestravauxsontnombreuses.NousdevonsfairedemêmeauCanada.Enfait,lapremièreétudedecegenreaétéfaiteen2009[3].EnOntario,ilexisteunprogrammegouvernementalprovin-cialdetempsd’attentepourchaquehôpital,quiestmisà jourrégulièrement.Cependant,uneétudedesbesoinsenmatièredechirurgiesde la cataracten’a jamaisété faiteenOntario.Avecla réductionde10%dufinancementdes chirurgiesde la cata-racteparlegouvernementprovincial,ilexisteunrisquequeplu-sieurshôpitauxchoisissentdecesserleursservicesdecataracte[10]. Je considère l’Afrique comme une région avec beaucoup

d’expertise sur l’inaccessibilité des services, car ils étudient ceproblèmedepuislongtemps.Selonunarticleécritpardeuxoph-talmologistesafricainsetpubliéen2001parl’Organisationmon-dialedelasanté(OMS),uneapprocheautraitementdelacata-racteconsidéréeplus«agréableauxpatients»seranécessaireàl’avenir.Enautresmots,dèslapremièreconsultationjusqu’ausuivipost-opératoire,lessoinsdevraientêtrepratiquespourlespatientsetleursfamilles[11].Cecinécessiteralaparticipationac-tivedescommunautésdanslaplanificationetledéveloppementdes servicespour les yeux [11]. Lespatientset leurentouragesontdirectement touchéspar lapertedevisiondueà la cata-racte.EnAfrique,lesgensquiviventsurlesfermesperdentdeuxouvriers autrement physiquementhabiles chaque foisqu’il yaunpatientatteintd’unecataracte– lespatientseux-mêmesetlespersonness’occupantdespatients[11-13].Ils’agitdoncd’unénormeproblèmepourcesfamilles.PouréviterceproblèmeauCanada,nousdevrionsquantifierlesbesoinsdeservicesdanslesrégionsruralesettravaillerdirectementaveccescommunautéspourmieuxcomprendrecommentsensibiliserlesgensautraite-mentdelacataracte.Lapertedevisiondueàlacataracteestunproblèmedévastateur,maisfacilementtraitableauCanada.

L’ÉTAT DES LIEUX ACTUEL DANS LES RÉGIONS RURALES EN INDE L’impactsocialdelapertedevisiondueàlacataractedoitégalementêtreprisenconsidération.Commeexemple,lesrésidentsdansleszonesruralesdel’Inden’ontpasàs’inquiéterdeperdreleurpermisdeconduirecar,engénéral,ilsn’ontpasdevoiture[14].Parconséquent,cescommunautésutilisentautresmoyenspourguiderlespersonnesâgéesatteintesdecécité.Au

Tableau 2 :Aperçunon-exhaustifdestatistiquessurl’étatactuelenAfrique.

Pays Nombre de per-sonnes aveugles

Causes principales de la cécité Nombre de per-sonnes atteintes de cataracte en attente

Nombre d’ophtalmologistes

Population

Érythréea 41700(50ans+)

Cataracte(55%),glaucome(15%),DMLA(6%)

22900(50ans+)

8(4locauxet4ex-patriés)

5,2millions

Éthiopieb 1,28millionsd’aveugleset2.96millionsavec une vision basse

Cataracte(50%),trachome(11,5%),cica-trisationdelacornée(8%),erreursdelaréfraction(8%),glaucome(5%)

638720 Environ104avecunautre46chirurgiensdela cataracte

85millions

Rwandac 30 000 Cataracte(65%) N/D 11 10,9millions

Kenyad 224000 Cataracte(43%),trachomeetcicatrisationdelacornée(19%),glaucome(9%),cécitéchezl’enfant(6%)

107 000 avec une incidence annuelle de 14500cas

Environ85dont33desophtalmologistestravaillentàNairobi

41,6millions

Burundie 87000 Cataracte(50%),erreursdelaréfraction(10%),cécitéchezl’enfant(5%)

48000avecuneincidence annuelle de 9600cas

10connus(seulement2fontleschirurgiesdelacataracte)

8,6millions

Sources:a.)EritreanRapidAssessmentofAvoidableBlindness(RAAB2008);UNDPHumanDevelopmentReport2010;b.)NationalFive-YearStrategicPlanforEyeHealthinEthiopia2003-2007EC(2010/11–2014/15),GovernmentofEthiopia;UNDPHumDevelRep2010;c.)NationalPreventionofBlindnessPlan2009-2013,MinistryofHealth,Rwanda;UNDPHumDevelRep2010&2011;UNICEFStateoftheWorld’sChildrenReport2012;d.)HumDevelRep2006,ChiefOphthalmologistofKenya,KenyanNationalEyeCarePlan2005-2010;UNDPHumDevelRep2010&2011;UNICEFStateoftheWorld’sChildrenReport2012;e.)UNDPHumDevelReport2010&2011;UNICEFStateoftheWorld’sChildrenReport2012.


seinduvillage,lesenfantsguidentlesmembresâgésdelafamille par lamainetparuneattache lorsde lamarche surde longulonguesdistances(figure2).AuCanada,unetechniquesimilaireaétéadoptéepourguiderlesathlètesdehauteperformanceat-teintsdebassevision[15].Deplus,l’accèsauxressourcestech-nologiquesen Indeestcomparableàcelle retrouvéeenmilieururalcanadien.Lesgenssontdoncmieuxinformésdesoptionss’offrantàeuxenmatièredesoinsdesanté,particulièrementencasdepertedevision[16-19].

Figure 2:Cethommeaétéaveugléparlacataractependanttroisans.Alorsque sa famille travailledans les champsde riz chaque jour, sonpetit-filsdoits’absenterdel’écolepours’occuperdelui.Source:http://www.hollows.org.au/news-media/lom-lun

CE QU’ON PEUT APPRENDRE DES RÉGIONS RURALES EN INDE EnInde,leproblèmedecataractenon-traitéen’estpassimplementdûaufaitquelespatientsviventenrégionsrurales,oud’unmanquederessourcespouraccéderàuntraitement.Ils’agitdavantaged’unmanquedecommunicationde lapartdupatientaffectédecécitéavecsonentourageparlephénomènede«bouche àoreille » [16]. Ceci est devenuévident après lacréationdeplusieurscampsdedépistagedelacataracteàtrav-ers l’Indedans les années1980. Selon les critèresde l’AravindEyeCareSystem,l’accentaétémissurl’explicationdesrésultatsd’acuité visuelle, en s’assurant que lameilleure acuité visuellesoit atteinte de façon chirurgicale ainsi qu’avec des lunettescorrectricesappropriées [20].Decettefaçon, lasatisfactiondupatientsefaitpartagerlorsdesonretourdanssacommunauté[16].Ledéveloppementdecesystèmeavaitunimpactextrême-mentpositifsur laperceptionsocialedutraitementde lacata-racteenInde.BienquelescoûtsdescampagnesdedépistagedelacataractesoientélevésauCanada,commec’estlecasenInde,lesavantagesduphénomènede«boucheàoreille»envalentnettementl’investissement.

CONCLUSION ET DIRECTIONS FUTURES Enfin,lesstratégiesmisesenplaceparlespaysenvoie

dedéveloppementsontdesélémentsinestimablesd’informationpouvantêtreappliquésdansdenombreuxdomainesdessoinsde santé au Canada. Afin de comparer efficacement les tech-niqueschirurgicales,nousdevonscontinueràaidercespaysparl’entremise d’organisations à but non-lucratif, tel que l’ORBISFlyingEyeHospital [21].Danscetteorganisation,ungroupedespécialistes,encollaborationavecuneéquipeaériennemobile,visitedifférentspaysenbesoin.Encoreplusimpressionnant,touslesservicesdechirurgieoculairesontinstalléssurl’avion.Cetteinnovationcomporteplusieursavantages,notammentl’occasionde traiter les patients dès leur arrivée, utiliser des techniquesdéjàmaîtriséeset fourniruneéducationauxmédecins locaux.De plus, avec l’approche « ouvert aux patients » (Afrique) etl’emphase sur l’explication de résultats positifs (« le bouche àoreille»)(Inde),ilyaurasansdouteplusdeleçonsàretenirdespays en voie de développement.

REMERCIEMENTSJ’aimerais remercier Dre Annick Fournier, ophtalmologiste,départementd’OphtalmologieàCHEOetl’Institutdel’Oeil,Uni-versitéd’Ottawa.

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betweencataractsurgerywaittimesandratesofsurgery.CanJOpthalmol.2012;47:11-15.

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3. Lecoûtde lapertedevisionauCanada:Rapportsommaire.Étudecom-mandéeparINCAetlasociétécanadienned’ophtalmologie.2009.Consultéenlignele17avril2013.www.inca.ca/cpv

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5. Hatch,WV,Cernat,G,Singer,S,etal.A10-yearpopulation-basedcohortanal-ysisofcataractsurgeryratesinOntario.CanJOphthalmol.2007;42:552-6.

6. Lewallen,S,Williams,TD,Dray,A,etal.EstimatingIncidenceofVision-Re-ducingCataractinAfrica.ArchOphthalmol.2010;128(12):1584-1589.

7. Lewallen,S,Courtright,P.BlindnessinAfrica:presentsitationandfutureneeds.BrJOphthalmol.2001;85:897-903.

8. Vision 2020 Report onWorld Sight 2002. Consulté en ligne le 27 février2013. http://www.who.int/ncd/vision2020_actionplan/documents/Repor-tonWorldSight2002.pdf

9. VISION2020Africa.Consultéen ligne le17mars2013.http://www.iapb.org/about-iapb/regions/global-network-africa

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13. EjimaduCS,AdioAO.TheburdenoflowvisioninfarmingcommunitiesinSouth-SouthNigeria.NigerJMed.2012;21(2):218-22.

14. Ramesh,Randeep.Indiagearsupformassmotoringrevolutionwith£1,260car–ReshapingNation.TheGuardian(London).January2008.

15. American Foundation for the Blind. Tips for Runnerswith Visual Impair-ments.Consultéenlignele18avril2013.http://www.afb.org/section.aspx?SectionID=40&TopicID=219&DocumentID=2805

16. Prajna,NV,Venkataswamy,G.Cataractblindness–theIndianexerperience.BullWorldHealthOrgan.2001;79(3)259-260.

17. Venkata,G,Murthy,S,Gupta,SK,etal.Currentestimatesofblindness inIndia.BrJOphthalmol2005;89:257–260.

18. PwC,2012,TheValueofSight:aquantificationofthebenefitsassociatedwith eliminating avoidable blindness and visual impairment. Case Study:India.

19. KhannaRC,MarmamulaS,KrishnaiahS,etal.Changingtrendsinthepreva-lenceofblindnessandvisualimpairmentinaruraldistrictofIndia:System-aticobservationsoveradecade.IndianJOphthalmol2012;60:492-7

20. Aravind Eye Care System. Accessed online on February 27, 2013. http://www.aravind.org/

21. ORBISSavingsightworldwide.AccessedonlineFebruary27,2013.http://www.orbis.org/



FOUR SCIENTIFIC SECTIONS WILL BE KEYNOTED BY INTERNATIONALLY RENOWNED EXPERTS

Heart Failure: Dr.PremSoman(UniversityofPittsburgh)

Advances in Vascular Imaging: Dr.PeterLiu(UniversityofOttawaHeartInstitute)

Biomarker Development: Dr.JuhaniKnuuti(UniversityofTurku)

Imaging Guided Therapeutics: Dr.HowardLeong-Poi(UniversityofToronto)

Pa r t n e rs h i p I n i t i a t i ve

CALLFORABSTRACTSDEADLINE:May17,2013

MFI Symposium Website:

www.ottawaheart.ca/MFIsymposium

SAVE THE DATE! June 27–28, 2013

We hope to attract trainees from across the country to present their exciting research in the field of cardiovascular imaging and therapy!

“Bringing Cardiovascular imaging and therapy to life”


N o te s