Evidence Report: Risk of Adverse Health Outcomes and ...

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EvidenceReport:

RiskofAdverseHealthOutcomesandDecrementsinPerformanceduetoIn-FlightMedicalConditionsHumanResearchProgramExplorationMedicalCapabilitiesElementApprovedforPublicRelease:May8,2017NationalAeronauticsandSpaceAdministrationLyndonB.JohnsonSpaceCenterHouston,Texas

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CURRENTCONTRIBUTINGAUTHORSErikAntonsen BaylorCollegeofMedicine,Houston,TXTinaBayuse KBRwyle,HoustonTXRebeccaBlue UniversityofTexasMedicalBranch,Galveston,TXVernieDaniels KBRwyle,Houston,TXMelindaHailey KBRwyle,HoustonTXSamHussey NASAGlennResearchCenter,Cleveland,OHEricKerstman UniversityofTexasMedicalBranch,Galveston,TXMikeKrihak UniversitiesSpaceResearchAssociation,MoffettField,CAKaraLatorella NASALangleyResearchCenter,Hampton,VAJenniferMindock KBRwyle,Houston,TXJerryMyers NASAGlennResearchCenter,Cleveland,OHRobertMulcahy UniversityofTexasMedicalBranch,Galveston,TXRebekahReed NASAJohnsonSpaceCenter,Houston,TXDavidReyes UniversityofTexasMedicalBranch,Galveston,TXMichelleUrbina MEITechnologies,Houston,TXMarleiWalton KBRwyle,HoustonTXPREVIOUSCONTRIBUTINGAUTHORSRossArchibald WyleScienceTechnology&Engineering,Houston,TXMichaelBarratt NASAJohnsonSpaceCenter,HoustonTXLaurenAmeen NASAGlennResearchCenter,Cleveland,OHGrandinBickham WyleScienceTechnology&Engineering,Houston,TXDougButler WyleScienceTechnology&Engineering,Houston,TXLisaScottCarnell NASAJohnsonSpaceCenter,HoustonTXJohnCharles NASAJohnsonSpaceCenter,HoustonTXDuaneChin KBRwyle,Houston,TXKatherineDaues NASAJohnsonSpaceCenter,HoustonTXVictorHurst WyleScienceTechnology&Engineering,Houston,TXAricKatterhagen NASAAmesResearchCenter,MoffettField,CAKevinKelleher WyleScienceTechnology&Engineering,Houston,TXCraigKundrot NASAJohnsonSpaceCenter,HoustonTXJancyMcPhee UniversitySpaceResearchAssociation,Houston,TXJohnMcQuillen NASAGlennResearchCenter,Cleveland,OHSandraOlson NASAGlennResearchCenter,Cleveland,OHJackRasbury KBRwyle,Houston,TXDavidRubin KBRwyle,Houston,TXLynnSaile KBRwyle,Houston,TXRickSenter NASAJohnsonSpaceCenter,HoustonTXRonakShah NASAJohnsonSpaceCenter,HoustonTXSusanSteinberg KBRwyle,Houston,TXBillThompson NASAGlennResearchCenter,Cleveland,OHPaulVargas WyleScienceTechnology&Engineering,Houston,TXSharmilaWatkins NASAJohnsonSpaceCenter,HoustonTXAaronWeaver NASAGlennResearchCenter,Cleveland,OHJohnZoldak ZinTechnologies,Cleveland,OH

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TableofContentsI. PRDRiskTitle:RiskofAdverseHealthOutcomesandDecrementsinPerformanceduetoIn-FlightMedicalConditions.................................................................5II. ExecutiveSummary......................................................................................................................5III. Introduction...................................................................................................................................7IV. Evidence.........................................................................................................................................7V. RiskinContextofExplorationMissionOperationalScenarios...........................10A. ConstraintsforExplorationMissions..........................................................................101. HabitatDesignConstraints..........................................................................................102. Communication,Telemetry,andDataConstraints...........................................113. EvacuationCapabilityConstraints...........................................................................11

B. AdditionalStressorsforExplorationMissions........................................................12VI. ConceptofOperationsandMissionDesign...................................................................12A.DevelopmentofaConceptofOperationsforaTransitMissiontoMars.........12B.EthicalConsiderations...........................................................................................................14

VII. ExplorationMissionMedicalSystems............................................................................16A. ModelingandPredictingRisk.........................................................................................16

• TheExplorationMedicalConditionsListandtheIntegratedMedicalModel.........................................................................................................................................18• TheMedicalOptimizationNetworkforSpaceTelemedicineResourcesProject.......................................................................................................................................19• AutonomousRiskAssessmentandDynamicProbabilisticRiskAnalysis.20

B. MedicalMissionComponents.........................................................................................201.Consumables.........................................................................................................................20• OnboardPharmaceuticals.........................................................................................20• ConsumableTracking..................................................................................................25• PersonalizedMedicine.................................................................................................27

2.SystemCapabilities.............................................................................................................29• Rehabilitation.................................................................................................................29• DecisionSupportandOnboardKnowledgeResources...................................32

C. MedicalMissionConsiderations....................................................................................341. RiskMitigation..................................................................................................................34• SelectionofthePhysicianAstronautandPre-missionMedicalTraining34• ContinuingEducationandJust-In-TimeTraining............................................35

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2. IdentifiedThreatsandFocusedMitigation..........................................................37• BoneFracture.................................................................................................................38• DustExposure.................................................................................................................40• RenalStoneFormation...............................................................................................41

3. TechnologicalInnovationandDesign.....................................................................44• In-FlightDataUtilization...........................................................................................44• MultipurposeDesignandTechnologyDevelopmentandSourcing...........46

VIII.Gaps................................................................................................................................................51IX. Conclusions.................................................................................................................................52X. References...................................................................................................................................53XI.Team................................................................................................................................................75XII. ListofAcronyms.......................................................................................................................76XIII.Appendix......................................................................................................................................77

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I. PRDRiskTitle:RiskofAdverseHealthOutcomesandDecrementsinPerformanceduetoIn-FlightMedicalConditions Description:Giventhatmedicalconditions/eventsmayoccurduringhumanspaceflightmissions,thereisthepossibilityofadversehealthoutcomesanddecrementsinperformance.II. ExecutiveSummaryThedrivetoundertakelong-durationspaceexplorationmissionsatgreaterdistancesfromEarthgivesrisetomanychallengesconcerninghumanperformanceunderextremeconditions.AtNASA,theHumanResearchProgram(HRP)hasbeenestablishedtoinvestigatethespecificriskstoastronauthealthandperformancepresentedbyspaceexploration,inadditiontodevelopingnecessarycountermeasuresandtechnologytoreduceriskandfacilitatesafer,moreproductivemissionsinspace(NASAHumanResearchProgram2009).TheHRPisdividedintofivesubsections,coveringbehavioralhealth,spaceradiation,habitability,andotherareasofinterest.WithinthisstructureistheExMCElement,whoseresearchcontributestotheoveralldevelopmentofnewtechnologiestoovercomethechallengesofexpandinghumanexplorationandhabitationofspace.TheriskstatementprovidedbytheHRPtotheExMCElementstates:“Giventhatmedicalconditions/eventswilloccurduringhumanspaceflightmissions,thereisapossibilityofadversehealthoutcomesanddecrementsinperformanceinmissionandforlongtermhealth”(NASAHumanResearchProgram2016).Withinthisriskcontext,theExplorationMedicalCapabilities(ExMC)Elementisspecificallyconcernedwithestablishingevidenced-basedmethodsofmonitoringandmaintainingastronauthealth.Essentialtocompletingthistaskistheadvancementintechniquesthatidentify,prevent,andtreatanyhealththreatsthatmayoccurduringspacemissions.Establishingcapabilitiestoprovidelong-termpreventiveandautonomoushealthcarebecomesparticularlyimportantasfuturemissions,suchasthosetoanear-Earthasteroid,theMoon,andMars,arelongerandmoreisolatedfromtheEarth.Intheeventofamedicalemergencyduringthesemissions,thepossibilityofreturningtoEarthorconsultingvialongdistancecommunicationsmaybechallengingorimpractical.Therearemanyfactorsassociatedwithlong-durationspacemissionsthatmaketheprovisionofautonomousmedicalcareparticularlyproblematic,includinglimitationsonavailablemedicalequipmentandsuppliesowingtomassandvolumeconstraints,alackofcomprehensivelytrainedmedicalpersonnelinthemissioncrew,andthepotentialforencounteringunfamiliarmedicalconditionsandhazardsparticulartothespaceenvironment.Proposedsolutionstotheseproblemsincludediagnostictechnologies,medicalrecord-keepingsystems,andguidedtreatmentmethodologies.ThesesolutionsarethefocusofcurrentExMCElementresearchactivities.TheultimategoaloftheExMCElementistodevelopanddemonstrateapathwayformedicalsystemintegrationintovehicleandmissiondesigntomitigatetheriskof

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medicalissues.Integraltothiseffortisinclusionofanevidence-basedmedicalanddatahandlingsystemappropriateforlong-duration,exploration-classmissions.ThisrequiresaclearConceptofOperations,quantitativeriskmetricsorothertoolstoaddresschangingriskthroughoutamission,andsystemscopingandsystemengineering.Becauseofthenovelnatureoftherisksinvolvedinexplorationmissions,newandcomplexethicalchallengesarelikelytobeencountered.Thisdocumentdescribestherelevantbackgroundandevidencethatinformsthedevelopmentofanexplorationmedicalsystem.

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III. IntroductionAhumanmissiontoMarsisachallengeoutsideoftheboundsofhumanexperience,butwithinthegraspofourtechnologyandimagination.Itiscriticaltobothdrawlessonsfrompriorspaceflightexperienceandtorecognizethelimitsofthatexperience.Relyingtooheavilyonpriorspaceflightexperiencecreatesariskofnotchallengingassumptionsinapplicabletoplanetaryexploration.Eachmedicalsystemdesignedforearlierhumanspaceflightwasdevelopedforaclose-proximityEarth-centeredmissionthatenjoyedtheadvantagesofreal-timetelemedicalsupport,consumableresupply,andmedicalevacuationwhennecessary.OperatingoutsidelowEarthorbit,withouttheseadvantages,requiresacloseralignmentbetweenvehicleengineeringandmedicalsystemdevelopment.Inarealsense,successinahumanMarsmissionwilldependonacomprehensiveandmission-enablingastronauthealthcaresystemaswellasanunderstandingofhowsuchasystemwillbeintegratedandimplementedwithinanexplorationmission.Allotherdesign,requirements,andresearchwithinexplorationmedicinewillbedrivenbythesetwogoals;thus,thesegoalsformtheconceptualcornerstonethatdefinesthemedicalsystemdesignandthesupportingresearchpathway.Usingthisframework,theExMCElementworkstoenvisionthemedicalneedsforahumanMarsmission,identifyoperationalbarrierstomeetingthoseneeds,andimplementaresearchpathwayinthesupportofagencyrequirementsandstakeholderinterests.ThemedicalchallengesexpectedinahumanMarsmissionareunlikeanypriormannedspaceflightexperience.Asaresult,provisionofmedicalcarewithinthelimitationsofsuchamissionrequiresaparadigmshiftintheunderstandingandacceptanceofrisk,theethicalframeworkofexperimentalflight,andthetradingofmedicalcapabilitiesagainstothervehiclecomponentswithinavehiclearchitecturelimitedbymass,volume,power,telemetry,andmanyotherfactorsuniquetodistantandinterplanetarytravel.Mannedspaceflighthasreachedacriticalmomentwherethetransitiontoahuman-centricmissionarchitecturemustbecomerealityifexplorationmissionsaretosucceed.Medicalsystemrequirementsandvehicledesignmustsharedependencetominimizetheriskstocrews,andflexibleandminimizedtechnologiesmustfactorheavilyinsystemdesigntoelevateamedicalcapabilitywithoutsacrificingothersystemscomponentsdesignedtokeepourcrewssafe.Itisimperativethatthemedicalsystembeoptimizedwithintheseconstraintstoensurethatcrewhealthandperformanceismaintainedandmissionrisksareminimized.IV. EvidenceTheNASACategoriesofEvidenceareusedtohelpcharacterizethetypeofevidenceprovidedinthisreport.Thecategoriesareadaptedfrom,andarecomparableto,morefamiliarversionsofLevelsofEvidencescales(SilagyandHaines2001).ThefourcategoriesofevidenceidentifiedatNASAinclude:

- CategoryIdata:basedonatleastonerandomizedcontrolledtrial

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- CategoryIIdata:basedonatleastonecontrolledstudywithoutrandomization,includingcohort,case-control,orsubjectoperatingasowncontrol

- CategoryIIIdata:non-experimentalobservationsorcomparative,correlation,andcase(orcase-series)studies

- CategoryIVdata:expertcommitteereportsoropinionsofrespectedauthoritiesthatarebasedonclinicalexperiences,benchresearch,or“firstprinciples”

Whileideallyallscientificpracticespursuedinmannedspaceflightwouldbebaseduponthehighestlevelofterrestrialandspaceflightevidence,realisticallythisisnotalwaysfeasible.Inparticular,anElementdedicatedtothescienceofexplorationmissions,thosemissionsthathaveyettobeachievedandwhoserisksareyetundefined,mustoftenrelyonbest-practicedecisionsmadeonthebasisofhistoricalevidenceandexpertopinion.Evenmoreso,thispracticemustoftenbeappliedtoparametersoutsideoftheoriginalintentoftheresearch,evidence,oropinion,inanefforttoprovideanysourceofreasonableknowledgebasetoinformdecision-making.Eventhemostrobustdatabecometheoreticalorbaseduponexpertopinionwhenappliedtointerplanetaryspaceflight.Inmanyofthecasespresentedinthisdocument,theevidencecategoriespresentedabovedonotdirectlyapplybecauseoftheselimitations;asaresult,thisdocumentwillpresentevidencewithadescriptionofsourceandpurpose,butwillnotattempttoforcetheevidenceintoartificialcategoriesthatarenotapplicabletotheexplorationparadigm.Determiningtheriskofunacceptablehealthandmissionoutcomesduetolimitationsofin-flightmedicalcapabilitiesfirstrequiresconsiderationofwhichmedicalscenariosaremostlikelytoariseduringamissionaswellasthosepresentingthehighestrisk.Further,itisimportanttoidentifyavailablecapabilitiesthatcanmostefficientlysupportcrewmedicalneeds,whilesimultaneouslyminimizingthemedicalsystemfootprint.Forexplorationmedicine,theevidencebaseisdrawnfromvarioussources,includingdatafrompreviousspaceflightmissions,ground-basedstudiesin‘analog’environments,generalpopulation-basedstudiesofdiseaseandhealthcareincidences,andcomputer-basedsimulations.Studiesofastronauthealthpre-flight,in-flight,andpost-flightallowtheincidencesofmedicalconditionsduringspacemissionstobeestablishedwherepossible,highlighting,whereknown,thecommonandhigh-riskconditionsthatcouldrequiremedicalattentionduringlong-durationexplorationmissions.Whileoftenlimitedinapplicabilitytotheexplorationenvironment,andsimultaneouslylimitedbyasmallpopulationsizethatprecludesstatisticalanalysisforclinicalsignificance,thesedatacanhelptoprovidecontextforexplorationscienceorinformedprobabilisticriskmodeling.TheNASALifetimeSurveillanceofAstronautHealth(LSAH)projectcollectsdataonastronautmedicalcareandworkplaceexposures,includingthoseoccurringinthetrainingandspaceflightenvironments,andconductsoccupationalsurveillancetomonitorfortrendsinexposureandhealthoutcomes.NASA’sLifeSciencesDataArchivealsoincludesdatafromhumansubjectsderivedfromboth

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pastandcurrentspaceflightaswellasdatafromanalogstudies.Severalpublicationsprovideanoverviewofin-flightmedicalconditionincidences(Davis1999;Summersetal.2005;Stewartetal.2007).Tables1and2providedintheAppendixdemonstratetheoccurrencesofmedicalconditionsthathaveariseninNASAastronautsduringpreviousspacemissions.Severaloftheseconditionsarenothigh-riskoremergentinnature,requiringarelativelylowleveloftreatmentresourcessuchasmedicationandbasicmedicalofficerinput.Non-emergentconditionsthathaveoccurredduringspacemissionsincludedermatological,musculoskeletal,cardiovascular,andmildpsychiatricconditions,aswellasminortraumaandburns.Ofgreaterconcern,particularlyforlongerandmoreremoteexplorationmissions,isthepotentialformoreseriousorlife-threateningmedicalconditionsduringaspaceflightmission.Bothbenignandmoreseriouscardiacdysrhythmias(supraventricularandventriculartachycardia)havebeenreportedduringpreviousMir,Skylab,andApollomissions(Fritsch-Yelleetal.1998);onecaseofdysrhythmiarequiredthatcrewmembersbebroughtbacktoEarth(Summersetal.2005).Additionally,dental(Berry1974)andurologicalemergencies(Cockett1964;Stepaniaketal.2007)havebeendocumentedamongastronauts.Furtherevidenceaddressingthepotentialoccurrenceofmedicalconditionsduringexplorationmissionsisdrawnfromstudiesinharshenvironmentsthatmaybeconsideredanalogsofthespaceenvironment,suchassubmarineandAntarcticresearchexpeditions.Arangeofmedicalconditionshasbeenreportedinthesesettings;mostofthesewerenon-emergentinnaturethoughsomerequiredimmediateevacuation(BallandEvans2001).Thoughtheseanalogenvironmentsdifferfromthoseencounteredbyastronauts,therearesomeveryimportantsimilaritiesthatmustbenoted.Thefirstisthat,inbothcases,crewsarehighlyscreenedandmustmeetspecifichealthcriteriatoparticipateinamission.Bothenvironmentsarealsolimitedintheircapacitytodiagnoseandtreatmedicalconditionsbylackofmedicalcapabilityandresources.Therearealsooccasionalgapsinmedicalstaffknowledgeinbothsettingsthatrequirecommunicationwithoutsidespecialiststohelpinitiateandguidetreatment.Forlongerexplorationmissions,estimationsoftheexpectedrateofasignificantmedicaleventhavebeenmadebasedontheanalysisofdatafromsubmarines,Antarcticexpeditions,militaryaviation,andU.S.andRussianspacemissions(Billicaetal.1996).Riskestimationsmadeusinganalogpopulationdataarelimitedinhowtheymaybeextrapolatedforuseinexplorationmissionriskassessments,astheydonotaccountfortheuniqueproblemsassociatedwiththespaceenvironmentsuchasradiationeffectsorphysiologicalproblemsassociatedwithmicrogravity.Generalpopulation-basedstudiesarehelpfulwhereabasisforcomparisonwithastronauthealthdataisrequiredorwhenconcerningthegoldstandardtreatmentoptionswithinamedicalsystem.Particularlywhenconsideringthedevelopmentofmedicaltechnologiesorsystem-widedataarchitecture,anunderstandingofthe

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currentstateofmedicalpracticeasawholeprovidesgreatinsightregardingavailabletechnologiesorcapabilitiesthatcouldbeincorporatedintoexplorationmedicalsystemdesign.V. RiskinContextofExplorationMissionOperationalScenarios

A. ConstraintsforExplorationMissionsExplorationmissiondesignissignificantlydifferentfrompreviousspaceflightmissions,withlimitationsinhabitatvolume,mass,andpower,communicationanddatatelemetry,andalterationstoimportanthumanfactors,includingisolationandconfinementformuchlongertimeframesandovergreaterdistancesfromtheEarththananymissiontodate.Thissectionwillattempttoidentifyandbrieflyoutlinesuchconstraintstoprovideaclearunderstandingoftheenvironmentwithinwhichanexplorationmedicalsystemmustperform.

1. HabitatDesignConstraintsRestrictionsinavailablemass,power,andvolumewithinaspacevehiclelimitthemedicalequipment,consumables,and,consequently,theconditionsthatmaybeaddressedwithinamedicalsystemarchitecture.Currently,habitatdesignsareinformedbymissionrequirementsthroughtheuseofparametricsizingmodels,suchasEXAMINE(Komaretal.2008).Thisapproachprovidesthecapabilityforrapidquantificationoftradeconsiderationsinmissionandhabitatdesign.Atthearchitecturallevel,habitablevolumeanddimensionsarespecified,buttypicallytheallocationofthesetospecificspacesthatcanbeassignedtovarioussystemsneedsisaprocessdefinedlateintheprocessofvehicledevelopment.HumanFactorsandBehavioralPerformancepersonnelconducthabitabilityinvestigationsofcurrentcrewandenvironmentfitandmodelposturesofspecifictasks,particularlythosethatareenvisionedtoscopethelargestvolumeforadedicatedsubspacewithinahabitat.Atpresentthereisnodirectlinkagebetweenthearchitecture(habitat,mission)designeffortandmedicalsystemrequirements.Thislinkageisnecessarytoensurethatmedicalitemsandenvironmentalcharacteristicsareassessedandinterpretedbyhabitatdesignerstosupporthealthmaintenanceandcareforthecrew.SizingtoolsarealsousedinthedevelopmentofanintegratedMassEquipmentList(MEL),alistofalltheequipmentandsuppliesrequiredtosupportaplannedmissioninconsiderationofthemissionobjectives,duration,andcrewnumberandneeds.MELsgenerallyprovidemass,power,andvolumeofrequiredequipmentandsupplies.Atthearchitecturallevel,itistypicalfor“CrewHealthcare”tobeasinglelineiteminahabitatMEL.Forexample,anotionaldeep-spacehabitatdesignreferencemissionfor380daysindurationwithfourcrewmemberswasestimatedtorequire250kgofdrymass(Toupsetal.2012).Whiletheseestimatesarebasedonhistoricaldata,specificationsatthislevelrarelydifferentiateequipmentandsuppliesortheirrelativemassandvolumerequirements.Further,otherlineitemsinhabitat(non-healthcare)MELscanincludeitemsthatcouldbeconsideredwithintherealmofmedicalcapabilitysupport.Forexample,linesassociatedwithCrew

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Accommodations,MiscellaneousProvisions,WasteCollectionandPersonalHygiene,OperationalSupplies,andMaintenanceEquipmentandSparescouldallincludemedicalsystem-dedicatedresources(Toupsetal.2012).Thegeneralapproachtoaddressthesedisconnectsistodevelop,withintheExMCElementeffort,thetoolsandguidancethatpermitsmorewell-defineddescriptionoftherequirementsformedicalcapabilitysupport.Further,thesetoolsandguidancemustsupporttherequirementsoftheiterativenatureofhabitatandmissiondesignbyprovidingaMedicalMELaswellaslayoutandvolumetricguidance.Thisguidancemustbecapableofscalingwithmissioncharacteristics,includingduration,crewtypeandsize,operationaltasksanddurationofsurfaceoperations,andthelike.Further,medicalguidelinesmustbeabletosupportreconsiderationasnewcapabilitiesbecomeavailabletosupportcrewhealthmaintenance.Successfulintegrationofamedicalsystemintoavehiclearchitectureisenabledbyearlyandconsistentintegrationwithengineeringanddesignteams.Inthepast,NASAhastypicallynotbroughtmedicalsystemsengineeringeffortsintothelargervehicledesignormissionarchitecture.

2. Communication,Telemetry,andDataConstraintsCurrentmedicaloperationsontheInternationalSpaceStation(ISS)areactivelysupportedbyregularcommunicationwithgroundsupportteams,includingflightsurgeons,biomedicalengineers,andnumerousconsultantsavailableasneededforspecificmedicalconcerns.However,inalong-durationexplorationmissionoutsideoflowEarthorbit,communicationwiththegroundwillbelimitedinthebestofcircumstancesbylatencysecondarytodistance,withdelaysofupto50minutesforroundtripcommunicationsnearMars(Hamiltonetal.2008;Baisdenetal.2008).Further,availablebandwidthfordeep-spacecommunicationsislikelytobeseverelylimited,restrictingavailabletimeforcrew-to-groundconsultationpossiblytoaslittleasonehourina24hourperiod.Asidefromverbalcommunication,therewilllikelybesignificantconstraintsondatapackagetelemetry,limitingtheabilityofgroundcrewstomonitorvehicleandcrewdata,includinghealthparameters,andrestrictingtheabilitytoupdateonboardresourcessuchassoftware-basedmedicalknowledgesupportsystems.Theselimitationsleadtoaneedforahighlyrobust,autonomous,andself-supportedmedicalsystem,includingbothonboardresourcesaswellashigh-level,internalizedcrewmedicalknowledge(BridgeandWatkins2011).

3. EvacuationCapabilityConstraintsWhileevacuationandreturn-to-EarthduringevenalowEarthorbitmissionwouldrequiresignificantcostandresources,suchacapabilityispossibleandprovidesforadefinitiveoptionforthetreatmentofmedicaleventsduringspaceflight.InanexplorationmissiontoMars,crewswillbeunableduringmostoftheflighttoabandonthemissionandsimplyreturntoEarth,givenlimitationsoffuelanddistanceaswellasrelativeorbitalmechanics.Asaresult,thevehiclemustprovideascompleteamedicalsystemaspossibleallowingforrobustcareforavarietyofmedicalconcerns(Baisdenetal.2008).Further,forconditionsthatcannotbe

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managedbythelimitedresourcesavailableinanexplorationvehicle,apalliativecapabilitymustbeavailable(Hamiltonetal.2008).

B. AdditionalStressorsforExplorationMissionsHistorically,illnessandinjuryarethemostcommoncausesofmissiondelayorfailure(Baisdenetal.2008).Explorationmissionswillincludegreaterphysiological,psychological,andenvironmentalstressorsthanpreviouslyexperiencedinanyspaceflighttodate,increasingthepotentialforillnessorinjurywithresultantmissionimpact.Asidefromthehabitat,communication,anddistancelimitationsasdescribedabove,itisimportanttoconsiderthespecifichealththreatstoadeep-spacemissionasindependentfactorsthatcansignificantlyimpacthumanhealthduringsuchamission.Forexample,thedeepspaceradiationenvironmentcarriessignificantlyhigherriskthanthatoflowEarthorbit,withanincreasedpotentialforexposure-inducedillnessesincrew(Cucinottaetal.2013;Cucinotta2015).Additionally,theisolationandconfinementofadeepspacemissionraisesconcernregardingpsychologicalimpact,groupdynamics,andsimilarchallengestomentalhealthduringlong-durationmissions(Manzey2004;Basneretal.2014).Thenewchallengesposedbytheuniqueenvironmentofadeep-spacemissionmustbeconsideredwithintheconstraintsofsuchamission,andarobustmedicalsystemmustbeversatileenoughtomanagetheseconcernswhilestilladheringtothelimitationsimposedbymass,volume,andpowerdescribedabove.VI. ConceptofOperationsandMissionDesign

A.DevelopmentofaConceptofOperationsforaTransitMissiontoMarsPertheNASAProceduralRequirementsdocumentforNASASystemsEngineeringProcessesandRequirements(NPR7123.1B),aConceptofOperations(ConOps)isdevelopedintheearlyphaseofasystemsengineeringdevelopmentprocesstodescribethe“overallhigh-levelconceptofhowthesystemwillbeusedtomeetstakeholderexpectations…andhelpfacilitateanunderstandingofthesystemgoals”(NASASystemsEngineeringProcessesandRequirements2013).Currently,thereisnooverarchingandvalidatedConOpsforaTransitMissiontoMars;thelackofsuchaguidancedocumentcreatesuncertaintyregardingthemissioncomponents,capabilities,andconstraintstobeconsideredinmedicalsystemdevelopmentforsuchamission.ConOpsareregularlyusedthroughoutU.S.governmentalagencies.Forexample,theAirForcePolicyDirective63-1,amongotherdocuments,establishestheneedforaConOpsasdiscussedbytheSystemsEngineeringsectoroftheOfficeoftheDeputyAssistantSecretaryofDefense(DepartmentofDefense2011;UnitedStatesAirForce2016).ManyprivatesectorindustriesrelyupontheConOpsdesigntoestablishhigh-levelguidanceforproductionandoperations.Forexample,theInternationalCounselofSystemsEngineeringrecommendssystemsengineeringprocessesforguidanceonprojectdevelopments,providingConOps-leveldirection(INCOSE2016).WithinNASA,multiplehistoricalConOpsandsimilarandrelated

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guidancedocumentshavebeendevelopedtoidentify,guide,andsatisfymissionrequirementsforvariousaspectsofmannedspaceflight.In2009,theSpaceMedicineExplorationMedicalConditionList(EMCL,JSC-65722),wasdevelopedtopresentmedicalconditionsthatareofconcerntohumanhealthanperformanceinfutureflightsandshouldbeconsideredwithregardstoexplorationmedicalcapabilities(Watkins2010;NASASpaceMedicineDivision2012;Saileetal.2014).ThislistformsthebasisfortheIntegratedMedicalModel(IMM).TheIMMispredictivemodelthatprovidesanestimationofrisktohelpidentifyascaleofclinicalpriorityformitigationoftheEMCLmedicalconditionsthroughadequateonboardresourceswithinagivenmissiondesign(Saileetal.2014).WhiletheEMCLhasbeenusefulforpreviousworkundertheumbrellaoftheexplorationmissionarchitectureandiscertainlyapplicabletointerplanetarymissions,MarsTransitmissions(andthepotentialmedicalrisksspecifictosuchmissions)arenotspecificallyaddressedbythislistortheworkthathasfollowed.TheExplorationMedicalConditionsConceptofOperations(JSC-65973)wasbaselinedin2010anddocumentstheoperationalconceptandrationalefortheprevention,diagnosis,andtreatmentofmedicalconcernsforvariousexplorationmissions,includinglunarsortiesandoutposts.Withinthisdocument,anumberofmedicalstrategiesforexplorationmissionsupportwereidentifiedandpursued.TheExplorationMedicalCapability(ExMC)ConOps(HRP-48002)wasbaselinedin2013andmostrecentlyupdatedin2014(ExplorationMedicalCapabilityElement2013).TheExMCConOpsfocusedondesignsolutionstospecificproblemsidentifiedbytheExMCElement,outliningtasksdesignedtoaddressknowledgegapsandmanagementofspecificmedicalconcernswithregardstothedevelopmentofanexplorationmedicalarchitectureforfuturemissions.Similarly,aTelemedicineOperationalConceptsforHumanExplorationMissionstoNearEarthAsteroidswascompletedin2014anddocumentsthevisionoftheNASAspacemedicinecommunityfortelemedicine,servingasaroadmapforfutureresearchandtechnologydevelopmentintheareaoftelemedicineforlongerdurationandmoredistantmissions(Barstenetal.2014).Itpresentstheoperationalconceptsforanend-to-endtelemedicinesystemspecifictoaNearEarthAsteroidexploration-classmission;manyofthemedicalcapabilitiesdescribedwithinareapplicabletootherinterplanetaryorlong-durationexplorationmissions.ThesedocumentscouldbeassessedforapplicabilitytoaMarsTransitConOpsbutintheircurrentformdonotaddresssuchmissionarchitecture.Despitetheseprecedents,thereisaneedforclarificationofaConOpsforMarsTransitanddedicatedtothedevelopmentofarobustandcomprehensivemedicalsystem,specifictotheneedsoftheMarsTransitmissionarchitecture.CurrentspaceflightoperationsarebasedonlowEarthorbitinavehiclethatenablesreal-timegroundbasedsupportandanexpeditedreturntoahigherlevelofmedicalcareifneeded.Futureexplorationmissionswillrequiregreaterautonomy,especiallyinthecontextofhealthcare,duetoextendedmissionduration,limitedabilityto

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resupplyorupdateonboardresources,andinabilitytoevacuatetodefinitivemedicalcare.AdedicatedConOps,specifictoaMarsexplorationmission,willprovideacommonvisionofmedicalcarefordevelopingamedicalsupportsystemforsuchamission,documentinggoalsexpectedofamedicalsystemandprovidingexamplesofthetypesofactivitiesthatthesystemwillbeusedinsupportofthisgoal.ThisConOpswillultimatelyinformtheengineeringefforttodefinethetechnicalneedstobemetbythemissionmedicalsystem,whichwillsubsequentlydevelopfunctionalrequirements,systemarchitectures,interfaces,andverificationandvalidationapproachesforthemedicalsystem.Aspreviousrequirementsforstandardofmedicalcarehavebeenvague,fundamentaltothiseffortwillbetheidentificationofthelevelandtypesofmedicalcareneededinagivenmissionarchitecturesothatanappropriatemedicalsystemcanbedesignedandintegratedintotheoverallvehicleandmissionsubsystem(NASA2014).Thedevelopmentofrequirementsfor,andprioritizationof,medicaloperationsdesign,medicalprocedures,trainingplans,andthecorrespondinghardwareandsoftwareisessentialtoreducetheriskofadversehealthoutcomesanddecrementsinperformanceduetoin-flightmedicalconditions.

B.EthicalConsiderationsAtafundamentallevel,thefirstastronautsthatembarkuponexplorationmissionsbeyondlowEarthorbitareparticipatinginexperimentalactivities,justasthevehiclesonwhichwetransportthemarefundamentallyexperimental.ThespaceenvironmentbeyondlowEarthorbitisnotfullydefined,operationalconceptsareuntested,andthelong-termimpactofthespaceenvironmentonthehumanexplorersisnotfullyunderstood(BallandEvans2001;Cucinottaetal.2013).Explorerswillbeacceptingahighlevelofmissionriskindependentofthehealthconsequencesoftheirexposuretothespaceenvironment(BallandEvans2001).Insomeinstances,duetolimitedmass,volume,andsystemscapabilityonexplorationvehicles,ourabilitytoprotectthecrewagainsthealthimpactsmaybetradedagainstourabilitytoreduceoverallmissionandvehiclerisks.Ethicaldecisionsconcerningcrewhealthandmedicalcapabilitiesmustbebalancedwiththecontributionofcountermeasurestooverallmissionsuccess.Forexample,whenconsideredinisolation,afullsurgicalsuitewouldappearpotentiallyveryusefulonaplanetarymission,wouldbuydownmedicalrisk,andwouldappeartobeanethicallysounddecision.However,providingthatcapabilitywouldmeanthattheweight-limitedvehiclewouldbeunabletotransportsufficientfuelandredundantsystemstocompleteitstransittoMarssuccessfully,andthecrewwouldrequiresignificanttraininginvestmenttorealizeasurgicalcapability,drawingprecioustrainingtimefromothermissionneeds.Ultimately,theremaybeinstanceswhereprotectingthehealthofonecrewmembercouldmeanincreasingtheriskofharmtotheothercrewduetoresourcesacrifices.Asaresult,anethicalframeworkforexplorationmedicalcarewillhavetoincludenotonlyclinicalethicsdirectedatthecareofeachindividual,butalsotheimplicationsofdecisionsonthewell-beingoftheentirecrew.Finally,becausethesemissionscarrysignificantvalueforthenationandforhumanitydespitetheirhighrisk(BallandEvans2001;Instituteof

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Medicine2014a),theremaybeinstanceswheremissionsuccessoutweighsindividualinterests.BaseduponstandardsestablishedbytheBelmontReport,NASAhasprovidedpolicydefinitionsoftheethicalprinciplesitwilluseinmakingdecisionsthataffectthehealthofcrewmemberstoincludeavoidingharm,beneficence,favorablebalanceofriskandbenefit,respectforautonomy,fairness,andfidelity(TheNationalCommissionfortheProtectionofHumanSubjectsofBiomedicalandBehavioralResearch1979;InstituteofMedicine2014b;OfficeoftheChiefHealth&MedicalOfficer2016).Currently,NASAreviewstheethicalimplicationsofagivenmissionarchitectureatseverallevels(InstituteofMedicine2014b).First,withregardstomissionplanning,thereisanethicalneedtounderstandtheoverallriskoflossofcrewandthepotentialenvironmentalexposureswithinagivenmissiondesign,includingtheriskstothecrewthemselvesaswellasthegreaterrisktosocietyinthecaseofmissionloss.Second,withregardstocrewselection,thereareclearethicalguidelinesbasedonhistoricalprecedentinmannedspaceflightregardingtheethicalselectionofcrewforparticularlydangerousmissions(ReedandAntonsen2017).Establishedethicalprinciplesrequirethat“burdensandbenefits[ofmissionassignment]bedistributedfairly,andthatfairprocessesbecreatedandfollowed”(InstituteofMedicine2014b).NASAstrivestoensurethat,totheextentpracticable,crewareinformedofthehealthrisksoftheirparticipationinthemission.Further,NASAattemptstoensurethatthecrewselectedarethosebestsuitedtosuccessfullycompleteamissionwithoutunacceptablelong-termhealthconsequenceswhilealsoensuringequalityofopportunity(InstituteofMedicine2014b).Thisisoneofthemostethicallychallengingareasofexplorationmedicine,becauseitbalancesissuesofpaternalismandautonomyagainsttheobligationsforbeneficenceandtominimizeharm.Ataminimum,acontinuedstandardoffairpracticeinselectionandhonestandthoroughpresentationofmissionrisksfortrueinformedconsenthasguidedcrewselectioninthepastandshouldcontinuetobepracticedinexplorationmissions.Withaninabilitytopredictexactlywhatresourceswillbeneededinmission,understandingoftheimpactsofinclusionandexclusionofmedicalcapabilityarenecessaryfortheagencytomakeinformeddecisionsregardingmedicalriskandtocommunicatethatrisktocrewforappropriateinformedconsent.Ultimately,NASAwillneedtorefineandexerciseitsprocessesfortheidentificationandreviewoftheethicalimplicationsofexplorationmission,vehicle,andsystemdesign;forevaluatingcrewselectionandassignmentcriteria;andforclinicaldecision-makingduringexplorationmissionswithlimitedreal-timecommunicationsandonboardcapabilities.

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VII.ExplorationMissionMedicalSystems

A. ModelingandPredictingRiskInordertoscopeanexplorationmedicalsystem,aprecursorabilitytomodelandpredictriskisrequired.Thebestevidencemustbeusedtoaddressthefollowingquestions:

1. Whatmedicalissuesdowethinkwilloccur?2. Howmanytimesdowethinkthosemedicalissueswilloccur?3. Whatmedicalcapabilitieswouldweliketoprovideinordertoidentifyandaddress

thoseissues?4. Whatsubsetofourdesiredcapabilityisrealisticgiventhemissionmass,volume,

power,data,andethicalconstraints?

Thissectionwillreviewtheevidencedevelopedtothispointtosupportriskanalysisinthecontextofmedicalsystemscoping.NASA’sapproachtoriskpredictionhasvariedoverthehistoryofmannedspaceflight.Priorto1986,NASAandothertechnology-drivenorganizationsdependedonfailuremodeandeffectsanalysis(FMEA)andhazardanalysisastheirprimarymeanstoassessmissionrisk(StamatelatosandDezfuli2011).Similartoamultidisciplinaryrootcauseanalysis,FMEAreliesuponthecalculationofariskprioritynumberonascaleofseverity,occurrence,anddetectability,andthenprovidesariskassessmentbasedontheanalysisofmultidisciplinaryteamsattargetinstitutions.Thisriskanalysis,whenappliedtohealthcare,isapproachedinaprospectiveratherthanretrospectivemanner(MarxandSlonim2003).However,suchanalysisfocusesonlocalinstitutionalassessmentofriskandthereforelackstheabilitytoidentifycomplexsystemandmultifactorialeffects,reducingitsefficiencywhenappliedtonewtechnologydevelopmentorlarge,system-widehealtharchitecture.Qualitativeriskanalysisapproaches,suchasFMEA,haveprovensuccessfulinimprovinghealthcarepractices.Suchactivitieshavealsoimprovedacceptanceofquantitativehealthcareriskassessmentprocesses,suchasthosebasedonfaulttreeandprobabilisticriskanalysis(PRA)approaches.PRAtechniqueshavebeendesignedwithafocusontheoutcomesofinterestassociatedwitheventtreesandfaulttreesthatcanleadtotherelatedoutcomes.Bypopulatingtheseeventtreeswithassociatedlikelihoodprobabilitiesanduncertaintiesofthecriticalandfaultevents,aquantitativeassessmentoftheriskofthedefinedoutcomescanbeassessedthroughMarkov-ChainMonteCarlotypeapproaches(StamatelatosandDezfuli2011).Asearlyasthe1980s,thenuclearpowerindustryrefinedandregularlyimplementedPRAtechniquesasaquantitativemeansofassessingcomplextechnologicalrisk.In1986,followingtheChallengerSpaceShuttlemishap,NASAbeganutilizingPRAasanalternativeapproachtoriskprediction.By1994,theNationalResearchCouncilrecommendedtheuseofPRAmethodstoquantitativelyaddressuncertainty,variabilityandcomplexityofriskincomplexsystemtechnologiesthatimpactpublicsafety.Technology-drivenindustries,such

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asfoodsafetyandenvironmentalprotection,adoptedtheregularuseofsuchtechniquestoprospectivelyevaluateexistingrisksandthecost-benefitofnewtechnologies,processes,andtheoptimizationofresources(Thompson2002).

ThehealthcareindustryhassimilarlybegunutilizingvariousaspectsofPRAtechniquesinriskprediction.Inparticular,therelativelyrecenthealthcarefocusoninformeddecision-makinghasbenefittedfromquantitativeriskmodelingbyimprovingtheevidencesupportingdesignandfundingcapturefordevelopmentofnewhealthcaretechnologies(Briggsetal.2004).Resourceallocationintheplanningfornaturaldisasterresponseanddiseaseoutbreaksbenefittedfromsuchevidencemodelingsupport(Sobierajetal.2007;ZolfaghariandPeyghaleh2015).PRA-derivedtechniques,suchasSociotechnicalPRA(ST-PRA),haveproventobeimportantriskvs.costvs.outcomesutilityestimatetoolsformedicalstaff,hospitaladministrators,andgovernmentdecision-makerswhencomparedtoqualitativetechniques(MarxandSlonim2003;Comdenetal.2005;Garsideetal.2007).HospitaladmittancepracticesandresourceplanninghaveutilizedPRA-typemethods,suchasprobabilisticmortalitymodels,toimproveotherrisk-scoringadmittancetechniquesandasameanstostratifytreatmentresourceallocations(Iezzonietal.1996;GandjourandWeyler2006;Kansagaraetal.2011;Hippisley-CoxandCoupland2013;Lichetal.2014).Furtherapplicationintheseareashasledtoimplementationofoptimizationtechniquestorefineresourceallocationandplacementingeneralhealthcareanddisastersettings(Parkeretal.1998;Mooreetal.2012;ZolfaghariandPeyghaleh2015).Markovprobabilisticmodelsrelatedtotheriskofspecificapplicationsortreatmentprocesseshavebecomerelativelyprevalentincurrentrisk-predictionliterature.Predictingfalls,caries,strokeoutcomes,hospitalre-admittanceaftercardiacevents,anddiabetestreatmentimpactsarejustasamplingofthemyriadapplicationstowhichprobabilistictechniqueshavebeenusedtoevaluatehealthcaretreatmentandtechnology(MossandZero1995;Selkeretal.1997;Singhetal.2004;Oostenbrinketal.2005;Rutten-vanMölkenetal.2007;Pageetal.2011;Palmeretal.2013).NASAhasadoptedPRAtechniquesintheassessmentofmedicalconditionsrelatedtotheuniqueaspectsofspaceflight,particularlythoselackinginsightsecondarytoalackofobservableeventssuchasbonefracture(Nelsonetal.2009;Sulkowskietal.2011),headinjury(Weaveretal.2013),anddecompressionsickness(Conkinetal.1996).ModelsandrelationaldatabasesarebeingdevelopedtoallowcomputationalanalysisofmultiplefactorsandenableNASAmedicalandengineeringcommunitiestocommunicate.Theapproachutilizesprobabilisticandstatisticalmodels,incombinationwithrelationaldatabases,inanapproachsimilartoengineeringandtoothertechnicalorganizations.Thesimilarityisintendedtoprovidemedicalinformationinafamiliarriskcharacterizationthatenablesquantitativediscussionswithvehicledesignersandengineeringteams.Specificapplicationsofthisapproachforexploration-classmissionsincludetheEMCL,theIMMproject,andtheMedicalOptimizationNetworkforSpaceTelemedicineResources(MONSTR)project.

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• TheExplorationMedicalConditionsListandtheIntegratedMedicalModelAsdescribedabove(seesectionVI.A),theEMCLconsistsofalistof100medicalconditionsthathaveeitheroccurredorareofsignificantconcernforaffectingcrewsurvivalorthreateningmissionobjectivesintheeventthattheydooccurinfuturemissions(Watkins2010;Antonsenetal.2016;Cangaetal.2016).ThisListprovidesaminimumsetofcriteriathatmustbeaddressedbythespacemedicalsystem;specifically,anyoperationalsystemmustprovidein-flightcapabilitiesneededforscreening,diagnosis,andtreatmentoftheconditionsthatcomprisetheEMCL(Watkins2010;Saileetal.2014).Initiallydevelopedin2009,theEMCLhasbeenusedtodevelopaframeworkofmedicalconcernsthathashelpedtoprovidecontextforfurtherexploration-classdevelopmentswithinExMC.DevelopedinparallelwiththeEMCL,theIMMisaMonteCarlosimulationapproachtospaceflightmissionsthatexplorestheeventspaceformedicalconcernsduringagivenreferencemission.TheIMMwasdesignedtobeaprobabilisticmodelsystemanddatabaseofsupportingmedicalconditionsusedtoprovidetherelativerisk,includinglikelihoodandseverityofoutcomes,forthelistofmedicalconditions.TheIMMusesamedicalevidencebasefrombothspaceflightandterrestrialliteratureaswellasadatabaseofavailabletreatmentcapabilitiesderivedfromtheISSmedicalkit,withmassandvolumeforallcomponentsandassignmentofresourcesneededfortreatment.ThequantitativeoutputsprovidedbytheIMMincludemedicalconditionprobabilityofoccurrence,eventdistribution,likelihoodofmedicalevacuationcriteriabeingmet,likelihoodoflossofcrewlife,andcrewhealthindex.TheapplicablerangeofIMMislimitedbyanumberofnecessaryassumptions,suchastheframeworkthatalltreatmentandoutcomesextendfromreferencesourcesassociatedwithhowmedicineistobepracticedontheISS;asaresult,resourcelimitationsandalterationstostandardofcarecanchangeoutcomeparametersfromtheIMM.Asmentionedabove,theIMMhasbeenpreviouslyutilizedforspecificriskapplications,particularlywherespecificmedicaleventsorconditionshavenotoccurredinpriorspaceflightexperience.Forexample,theBoneFractureRiskModule,acomputationalmodelsubsetoftheIMM,wasconstructedtocalculatetheriskofbonefracturegivenspecificflightconditions,withskeletalloading,alteredactivity,sex,bodymass,alteredbonestrengthdependentonmissionlengthandtype,andsimilarfactorsallconsideredbythemodel(Nelsonetal.2009).ThemodelwasabletoprovideapredictionofriskofbonefractureduringreferencemissionstothemoonandMars,demonstratinghigherriskonMarsduetocompromisedboneintegrityfromlong-durationflight,andevendemonstratedtheabilitytopredictriskbaseduponboneloadorientationandsubjectflexibility(Nelsonetal.2009).Resultsofthemodel’spredictivecapabilitieswerereportedintheNASAHumanResearchProgramEvidenceBook(McPheeandCharles2009).In2011,Sulkowskietalpublisheddataregardingpredictionoftheriskofastronautbonefracturerelatedtoextravehicularactivity(EVA)utilizingthemodelingcapabilitiesoftheIMM(Sulkowskietal.2011).Themodelprovidedaconservativeriskassessmentthatwasdeemedtobemorerealisticthanpriorriskpredictionapproaches,giventhe

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highfidelityoftheEVAsuitanalogandboneanalogsusedinthedevelopmentofthemodel(Sulkowskietal.2011).Similarly,aHeadInjuryModelwasdevelopedasafurthersubsetoftheIMMtooltoprovidepredictivecapabilitiesregardingtheriskofheadinjuryaboardtheISS(Weaveretal.2013).HeadinjuryisamongtheEMCLconditionsthatdonothaveadequateobservationaldataregardingpriorheadinjuryeventsinobit,noraretheremanyanalogsavailableforrepresentativestudyontheground(Weaveretal.2013).TheIMMHeadInjuryModelprovidedameanstoassessthisriskwithoutsignificantsupportingdata,insteadrelyinguponheadaccelerationresponsemodelsmodifiedforuseinthemicrogravityenvironment(Weaveretal.2013).Themodelwasdemonstratedtobevalidandreliableandprovidedaneededriskassessmentregardingamedicalconditionwithfortunatelyfewactualhistoricalevents(Weaveretal.2013).

• TheMedicalOptimizationNetworkforSpaceTelemedicineResourcesProjectTosupplementthepredictivepoweroftheIMM,theMONSTRprojectwasdesignedtoexplorethephysiciancallspaceacrossthemedicalconditionsofinterestusingaterrestrialstandardofcaretoidentify,percondition,whatcapabilities,actions,andresourcesarerequiredordesiredtoimplementthecomponentsofmedicalcarethatareindicatedbytheEMCL.TheinformationcontainedintheMONSTRdatabasehasbeenobtainedfromthegeneralmedicalcommunitywithanefforttocapturethebesttechnologicalapproachesforbestoutcomeinthetreatmentofEMCLmedicalconditionsduringlong-durationflight.Initsinception,MONSTRwasdesignedtohelpidentifyhigh-yieldresearchinvestmentsincapabilitiesthatwillmitigatemedicalriskthroughmaximizingflexiblemedicalcapability.Thecurrentversion(MONSTR2.0)allowsforphysicianrankingofactionsandresources,aswellasprobabilityofoccurrenceforagivenmedicalcondition,utilizingtheIMMmodelingpowertoprioritizemedicalcapabilitiesofinterestforresearchinvestment.Currently,MONSTRexistsasapilotprojectdesignedtodemonstratewhetherornotsuchadatabaseprovidesvaluableinputformissionplannerswithregardstothemedicalcapabilitiestradespace.Providingareferenceforaterrestrialstandardofcareallowsmissionplannerstoidentifyresourcesrequiredtoaddressallmedicalconcerns,thenweighstherisksandbenefitsofeliminatinganyofthoseresourcestosavemassorspaceinfuturevehicleandsystemdesign(Antonsenetal.2016;Cangaetal.2016).Deconstructionofmedicalresourcesinthismannerallowsforthedevelopmentofrelativeweightingbybothcriticalityandbyprobabilityofoccurrence,aspredictedbytheIMM,allowingforareasonablecomparisonoftherelativeutilityofvariousmedicalresources,andfurtherfacilitatingtradesinmedicalresourcemassandvolume(Minardetal.2011;Antonsenetal.2016;Cangaetal.2016).WithEMCL,IMM,andMONSTRcapabilities,predictionofmedicalriskandweightedriskofinclusionorexclusionofvariousmedicalresourcescanevaluatedwithgreaterfidelity,allowingforearlierandmoreaccurateinputintotheevidence-baseddevelopmentofamorerobustmedicalsystemforfutureexploration-classmissions.

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• AutonomousRiskAssessmentandDynamicProbabilisticRiskAnalysisCurrentmodelingtechniques,includingtheIMM,provideprobabilitiesbasedupontheresourcesonboardtheISS.Giventhatmedicalsystemparametersforafutureexplorationmission,includingMarsTransit,haveyettobedefined,itiscurrentlynotpossibletodevelopamodelbasedupontheseundefinedsystemparameters.However,theidealPRAmodelwouldbeonethataccountsforallonboardresourcesthroughoutaspecificexplorationmission,butfurtherfactorsinanychangeinmissionparameters,includingtimeremainingbeforereturntoEarthaswellastheresourcesalreadyexhaustedinearliermedicalevents,toprovideadynamic,changing,probabilisticanalysisthroughoutthemission.Monitoringthedepletionofresourcescouldprovidesignificantinsightintoanadjustingriskpredictionandcouldprovidecrewmembersandgroundsupportwithnecessaryinformationtofacilitatedecision-makingregardinganynecessaryalterationsoradjustmentstomissionparameters,goals,oroperations.DynamicPRAsarecurrentlyofinterestinthemedicalcommunity,particularlywithregardstoeconomicmodelinganduseofresourcesacrossalargermedicalsystemorhospitalunit.Predictivemodelingtoolsarebeingdevelopedtoaddressoptimizationofmultifacetedpopulationhealthsystems,addressing,forexample,deficienciesintechnologicalfactors,accessibilityconcerns,workflowoptimization,andresourceutilizationtoaugmentahealthsystemasasingleentity(Johnsonetal.2015).Similarly,dynamicmodelingisappliedtolocal-andstate-levelemergencypreparedness,providingriskpredictionforvariousdisastercapabilitiesthatisresponsivetochangingresourcesandcurrentmedicalburdens(Rosenfeldetal.2009).Whileeventhosewhoareactivelymakinguseofthesemodelsrecognizetheirlimitations,dynamicmodelsarealreadybeingrecognizedfortheirenhancementofsystemunderstanding,particularlyinprovidingearlyidentificationofsystemvulnerabilitiesandinguidingadjustmentofappropriateresponsestoresourcelimitations(Rosenfeldetal.2009).Developmentofsuchamodelforexplorationmissions,oradjustmentofcurrentmodelsinuseinotherhealthapplicationstomakethesemodelsusefulintheaerospaceenvironment,wouldbedependentuponfirstdevelopingthemedicalsystemtobeincludedinanexplorationvehicle,andthereforemustwaituntilthemedicalsystemisrealized.However,suchdynamicpredictivecapabilitieswouldultimatelyprovideimportantinsightforcrewandgroundalike,andassuchwouldbehighlydesirableasanonboardresourceforanexploration-classmission.

B. MedicalMissionComponents

1.Consumables

• OnboardPharmaceuticalsAcomprehensivemedicationformularyideallyisdesignedtoaccommodatethesizeandspacelimitationsofthespacecraftwhileaddressingtheindividualmedicationneedsandpreferencesofthecrew.Challengesintheprovisionofsuchapharmacy

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forexplorationclassmissionsinclude:thenegativeoutcomeofadegradinginventoryovertime,theinabilitytoresupplybeforeexpirationdates,andtheneedtoproperlyforecastthebestpossiblemedicationcandidatestotreatconditionsthatwilloccurinthefuture.CurrentprovisionofapharmacyfortheISSisheavilydependentontheabilitytoresupplymedicationsthathavebeenused.Inaplanetarymissionexpectedtohaveadurationof2.5-3yearsandincludeexposuretoapreviouslyunexperiencedradiationenvironment,thestabilityofpre-suppliedmedicationsissuspect.UsingFDAstandards,only16%ofthe107medicationsinthecurrentISSformularywouldlast2.5yearsbyexpirationdatewhenaccountingfororderingandpackingtimestypicalofpre-missionlaunchphases(Bayuse2016).Littleispublicallyknownaboutmostmedicationsstabilitybeyondexpirationdates,andinformationisoftenchallengingtogatherduetopharmaceuticalcompanyproprietaryconcerns.Existingrecordsofmedicationusageduringpriorhumanspaceflightareinsufficienttodrawconclusionsonanappropriateprioritizationofmedicationsforexplorationclassmissions.Facedwiththeobstacleofaccesstoin-flightmedicalcare,andlimitationsofvehiclespace,time,andcommunications,itisnecessarytoprioritizewhatmedicalconsumablesaremanifestedfortheflightandwhichmedicalconditionsareaddressed.Studiesofastronauthealthestablishtheincidenceofcommonandhigh-riskmedicalconditionsthatrequiremedicalinterventionduringlong-durationexplorationmissions.In2000,theInstituteofMedicineconvenedacommitteeofexperts,CommitteeonCreatingaVisionforSpaceMedicineduringTravelbeyondEarthOrbit,toexaminetheissuessurroundingastronauthealthandsafetyforlong-durationspacemissions.Twothemesrunthroughoutthecommittee’sfinalreport:first,thatnotenoughisknownabouttheriskstohumanhealthduringlong-durationmissionsbeyondEarth’sorbitoraboutwhatcaneffectivelymitigatethoseriskstoenablehumanstotravelandworksafelyintheenvironmentofdeepspace,andsecond,thateverythingreasonableshouldbedonetogainthenecessaryinformationbeforehumansaresentonmissionsofspaceexploration(BallandEvans2001).Althoughseveralspaceflight-focusedpharmaceuticalresearchstudieshavebeenconducted,fewhaveprovidedsufficientdataregardingmedicationusageorpotencychangesduringspaceflight.TheDupharmaceuticalstabilitystudyassessedmedicationsflownonSpaceShuttlestoandfromtheISSfrom2006until2008;theirstudyfoundthatsomemedicationswerestillviablebeyondtheirexpirationdates(Duetal.2011).However,aswithmanyspaceflightstudies,thesmallsamplesizeassociatedwiththisstudylimitstheabilitytodrawstrongconclusions.Otherrecentstudieshaveprovidedinformationregardingmedicationusage,indications,andefficacygleanedfromspaceflightrecords(Bargeretal.2014;BasnerandDinges2014;Wotring2015,2016).Althoughsomeconclusionscanbedrawnfromthesestudies,theinabilitytofullyquantifymedicationusage,indications,sideeffects,and

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effectivenesslimitsinsightastowhichmedicationsshouldbeprioritizedforfurtherresearch.

TheFoodandDrugAdministration(FDA)conductedaterrestrialstudytoevaluatepharmaceuticalsthatwerestoredbeyondtheiroriginalexpirationdatebasedonacomprehensivetestingprogramTheFederalShelfLifeExtensionProgram(SLEP)Programwasestablishedin1986,andadministeredbytheU.S.DepartmentofDefenseincooperationwiththeFDA,todeferreplacementcostsofstockpiledmedicationsandmaterialsbyextendingtheirexpirationdates.TheFDAconductedallqualitytestingandmedicationevaluationsfortheSLEPProgram.Potencywasevaluatedforallproductsbyconductingactiveingredientassays,andregressionanalysesofreal-timeassaydatadeterminedifshelflifeextensionsweregranted.Resultsindicatedthattheactualshelflifeofproductstestedmaybelongerthantheirlabeledexpirationdates,dependingontheirstorageconditions(Lyonetal.2006).Thestudysummarizedthelong-termstabilityof122medicationsstoredinoriginalpackagingfrom3005differentlotstestedusingU.S.pharmacopeiaandFDAstabilitytestingstandardstodetermineshelflifeextensiondata.Overall,2650(88%)ofthe3005lotstestedwereextendedpasttheiroriginalexpirationdates,withanaverageextensionof66months(Lyonetal.2006).However,only7pharmaceuticalcompoundstestedintheSLEPprogramarerepresentedinthecurrentISSoperationalflightformulary(includingamoxicillin,atropine,ceftriaxone,clindamycin,diphenhydramine,doxycycline,epinephrine,diazepam,lidocaine,methylprednisolone,phenytoin,andpromethazine).Cantrelletal.conductedastudyevaluatingeightlong-expiredmedicationswith15differentactiveingredientsthatwerediscoveredinaretailpharmacyinoriginal,unopenedcontainers(Cantrelletal.2012).Themedicationshadallexpired28to40yearspriortoanalysis.Threedosageunitsofeachmedicationwereanalyzed,andeachsampletested3times.Twelveofthe14drugcompoundstested(86%)werepresentinconcentrationsatleast90%ofthelabeledamounts,thegenerallyrecognizedminimum-acceptablepotency.Threeofthesecompoundswerepresentatgreaterthan110%ofthelabeledcontent.Twocompounds,aspirinandamphetamine,werepresentinamountsoflessthan90%oflabeledcontent.Onecompound,phenacetin,bannedbytheFDAin1983foruseintheU.S.,waspresentatgreaterthan90%oflabeledamountsfromonemedicationsampletested,butlessthan90%inothermedicationsamplesofthatcompound.Inthisstudy,12of14medicationsretainedfullpotencyforatleast336months,and8oftheseforatleast480months.Theresultsofthisstudyprovidesadditionalevidencethatmanymedicationsretaintheirfullchemicalpotencyfordecadesbeyondtheirmanufacturerlabeledexpirationdates(Cantrelletal.2012).Du,etal.,conductedaninvestigationinto33pharmaceuticalproducts,22solids,7semisolid,and4liquidformulations,packagedinpayloadmedicationkitsthatwereflownto,andreturnedfrom,theISSviatheSpaceShuttle(Duetal.2011).Groundcontrolsstoredinanenvironmentalchamberwereavailableforcomparison.Fourpayloadswerereturnedafteranon-orbitdurationrangingfrom13to880days.

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Cumulativeradiationdoseduringthe880dayswasobservedtobelinearovertime.ThestudyfoundthatthenumberofformulationsthatdidnotmeetcontentrequirementofActivePharmaceuticalIngredient(API)washigherinflightkits,ascomparedtothecorrespondingcontrolkitsfromallfourpayloads(Duetal.2011).Additionally,itwasnotedthatthenumberofunstableformulationsbetweenflightandcontrolincreasedasafunctionofstoragetimeinspace.However,althoughdegradationwasfoundtobefasterinspacethanonthegroundformostoftheAPIs,lossofAPIcontentwasgenerallylessthan20%oflabelclaim(Duetal.2011).

Dr.VirginiaWotringoftheBaylorCollegeofMedicine’sCenterforSpaceMedicineconductedanopportunistic,observational,pilot-scaleinvestigationtotestthehypothesisthatISS-agingdoesnotcauseunusualdegradation(Wotring2016).Ninemedicationswereanalyzedforactivepharmaceuticalingredient(API)contentanddegradantamounts;resultswerecomparedto2012U.S.Pharmacopeia(USP)requirements.Themedicationsweretwosleepaids,twoantihistamines/decongestants,threepainrelievers,anantidiarrheal,andanalertnessmedication.Becausethesampleswereobtainedopportunisticallyfromunusedpharmacysupplies,eachmedicationwasavailableatonlyonetimepointandnocontrolsamples(samplesagedforasimilarperiodonEarth)wereavailable.Onemedication(acetaminophen)metUSPrequirements5monthsafteritsexpirationdate.Fouroftheninemedicationstested(44%,includingloratadine,pseudoephedrine,zolpidem,andaspirin)metUSPrequirements8monthspost-expiration.Anotherthreemedications(33%,includingloperamide,modafinil,andibuprofen)metUSPguidelines2–3monthsbeforeexpiration.Onecompound,adietarysupplementusedasasleepaid(melatonin),failedtomeetUSPrequirementsat11monthspost-expiration.Nounusualdegradationproductswereidentified(Wotring2016).Theseresultsagreewiththoseofotherstudiesofmedicationpotency.

AreportbyKimandPlantein2015assessedthepotentialeffectsofradiationonfoodandpharmaceuticalstorageduringa3yearspaceflightjourneyoutsidetheprotectionofthegeomagnetosphere(KimandPlante2015).Investigatorscalculatedthemeannumberofchargedparticlehitsandtheradiolyticyieldsinthetargetmaterialsoffreeze-driedfood,intermediatemoisturefood,andliquidformulationpharmaceuticals.Forthisassessment,theexteriorbackgroundradiationenvironmentatdeepsolarminimumwasassumedtobeuniform,isotropic,andconstantthroughouttheentireround-tripjourneytoMars.Thisstudypredictedanunlikelihoodofbackgroundradiationtocausearapidchangeoffunctionalpropertiesinpharmaceuticalsstoredinsidethevehicle,butrathersuggestedthatprogressivefunctionaldefectswouldoccurovertime.Thesefunctionaldefectswoulddependonenergydeposition,yieldsofradiolyticspecies,bond-dissociationfrequency,oranyotherbreak-typechemistryphenomena.Thestudyalsoproposedthattheradiationdosereceivedduringa3yearmissiontoMarswouldbeseveralordersofmagnitudelowerthanthatreceivedduringmanufacturersterilizationorpreservationprocedures,andthattheprobabilityofspaceradiationhittingtheindividualmoleculescomprisingconsumablesisvery

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low.Thesummaryfurthersuggeststhatradiolyticspeciesmaynotbegeneratedinsoliddosageformsduetowaterremovalduringmanufacturing.Therefore,theauthorsconcludedthatspaceradiationisnotaconcernforlong-termpreservationpharmaceuticals(KimandPlante2015).

AssuggestedbytheKimandPlantereport,gammairradiationhasbeenusedasamethodofmicrobialsterilizationinthefoodandmedicaldevicesindustries,buttoalesserextentinthepharmaceuticalindustries.Contrarytothissummary,however,theuseofgammairradiationonpharmaceuticalproductscanresultinalossofAPIpotency,thecreationofradiolysisbyproducts,andareductionofthemolecularweightofpolymerexcipients,andcaninfluencedrugreleasefromthefinalproduct(Garciaetal.2004).Despitetheserisks,useofgammasterilizationhascontinuedtoincreaseanddemonstratestrongapplicabilitytoawiderangeofpharmaceuticalproducts.Forexample,waterdissociatesasaresultofexposuretoradiationandisamajorsourceoffreeradicals;thosefreeradicalscancausechemicalcompromise.Therefore,drugswithhigherwatercontenttendtorespondpoorlytoirradiation(Garciaetal.2004).

Arecentliteraturereviewarticle(Hasanainetal.2014)discussedhowpotentiallyharmfulhighionizationenergyfromgammairradiationcouldbeharnessedandoptimizedbyformulationchanges,suchastheadditionofradioprotectants,orbyvaryingtheirradiationconditions,includingtemperature,productstate,oxygenenvironment,dose,anddoserate.Theadvancementsmadeingammasterilizationresearchmayhavefurtherapplicationforpharmaceuticalproductsusedduringanexplorationspaceflightmission.However,thepotentialdamageandsubsequentsolutionsfortheseproductswhentheyareexposedtoformsofionizingradiationfoundindeepspace(i.e.galacticcosmicrays,solarenergeticparticles)maybeconsiderablydifferentfromdamageresultingfromgammasterilizationandsolutionstopreventorcounteractsuchdamage.Ideally,stabilitystudieswouldbecapableofcharacterizingquality,chemicalintegrity,andsafetyofmedicationsexposedtothedeepspaceenvironment.However,intheabsenceofobtainingthosecharacterizationsfromdeepspaceexposure,acloseenvironmentalanalogsuchastheISSortargetedradiationexposurecouldrevealadditionalinsightthatcouldbringusclosertothatsafeandeffectiveexplorationmissionmedicationformulary.

GlennResearchCenterreleasedaNASATechnicalReport,“PharmaceuticalsExposedtotheSpaceEnvironment:ProblemsandProspects”(JaworskeandMyers2016).ThisreportreviewedseveralNASAandexternalreportsevaluatingpharmaceuticalstabilityandshelflifeextension.ThereportacknowledgedthatpreviousstudiesandNASAEvidenceReportshaveillustratedthatselectedpharmaceuticalsontheISSmayhaveashortershelflifeinspacethanonEarth,andoffersacompellingargumentforcontinuingopportunisticretrievalofmedicationsreturnedfromallspaceflightopportunities,includingmedicationsretrievedfromtheISS,aswellaspassivepayloadsmissionsreturnedfromoutsideofEarth’smagneticfield.Thereportfurthersuggeststhatdataobtainedfromtheanalysesof

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thesemedicationsamplesreturnedfromspaceflightwouldenhancestatisticaldatabasesforprobabilisticriskassessmentsandpredictivemodeling.

Anotheroptiontoaddressradiation-relatedpharmaceuticaldegradationisstorageatcryogenictemperatures.AstudyconductedbyMeentsetal.illustratedthatwhencubicinsulincrystalswerestoredat50K,radiationdamagetodisulfidebridgestructureswerereducedbyafactorof4whencomparedtoanalogousobservationsat100K(Meentsetal.2010),suggestingthatcryogenicstoragemaybeaviableoptiontoreducedamagefromtheradiationenvironment.Similarly,Garciaetal.suggestedthatperformingirradiationondrugproductsinafrozenstatecouldmitigateirradiationeffects(Garciaetal.2004).Whilepromising,thismethodisdependentupontheabilityoftheproducttobesafelyfrozenandthawed.Thatsaid,freezingadrugtrapsfreeradicalsintheicecrystals,therebyreducingtheirfreedomtomoveabout;thismayinducethemoleculestorecombinewitheachother,ratherthancausedisruptioninthecompound.Thisprocesscouldpossiblyimprovedrugstabilityandsimultaneouslyimpartresistancetodegradationduetoirradiation.Garciaandcolleaguesalsorecommendedotheroptionssuchasfreeze-dryingandusingfree-radicalscavengerstoalleviatedegradationeffectsresultingfromirradiation(Garciaetal.2004).

TheelectronicMedicinesCompendium(eMC)containsup-to-dateinformationaboutmedicineslicensedforuseintheUnitedKingdom(UK).AllinformationontheeMCwebsitecomesdirectlyfromthe200pharmaceuticalcompaniesthatsubscribetotheeMC;manyofthesehavecorporateheadquartersintheUnitedStates.PharmaceuticalcompaniessubmitandupdatetheSummariesofProductCharacteristics(SPCs)providedbytheeMC.ReviewoftheeMCSPCsrevealedthatthemaximumshelflife,ormaximumamountoftimethemedicationmeetsregulatorystandardsforpotencybasedondrugstabilitytesting,isreportedasgreaterthan3yearsformostmedicationsintheeMC(eMC2017).SPCshelflifeinformationwasidentifiedfor40ofthe63medicationsonNASA’sprioritizedmedicationformularylist,with63%reportedashaving3ormoreyearsofshelflife.Itisclearthatpharmaceuticalinterventionisanessentialcomponentofriskmanagementplanningforastronauthealthcareduringexplorationmissions.However,thechallengestillremainsofhowtoassembleaformularythatiscomprehensiveenoughtopreventortreatanticipatedmedicaleventsandisalsochemicallystable,safe,androbustenoughtohavesufficientpotencytolastforthedurationofanexplorationspacemission.Incaseswhereapharmaceuticalagentwillnothavesufficientpotencyforafullmission,addressingthiscapabilitygapmayrequireexplorationofnoveldrugdevelopmenttechniques,dosageforms,anddosagedeliveryplatformsthatenhancechemicalstabilityaswellastherapeuticeffectiveness.

• ConsumableTrackingInadditiontodecisionsregardingwhichpharmaceuticalstoincludeinanexplorationmission,therearequestionsregardinghowmuchmedicationwillbe

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neededandhowtoensurethatsuchmedicationresourcesaremanagedtoensureavailabilitywhentheyareneeded,evenlateinamissiontimeline.Inclusionofanadequatepharmacydesignedtoaddressallpotentialneedsofalong-duration,exploration-classcrewraisesconcernsregardingmassandresourceutilization.OntheISS,currentonboardpharmaceuticalsareminimized,giventheoptionofevacuationandreturntoEarthforanysignificantmedicalcondition.Inaninterplanetarymission,earlymissionterminationandevacuationisunlikelytobeafeasibleoption,increasingtheneedforalargerandmorecomprehensivepharmacy.Currentpharmaceuticaluseduringspaceflightisnotcomprehensivelymonitoredduetothebalancebetweencrewtimedemandsandadecreasedneedforusagerateinformationinasettingwhereresupplyispossible(Wotring2015).Asaresult,ourunderstandingofthefrequencyofmedicationuses,aswellasanunderstandingofthequantityofmedicationsneededoveragivenmissionduration,couldbeimproved.Inordertobetterunderstandthevolumeandmassofpharmaceuticalsneededforalong-duration,explorationclassmission,avalidandrobustmeansofmedicationtrackingisneeded.SuchsystemsalreadyexistaboardtheISSfornon-pharmaceuticalpurposes.Forexample,nutritionalrequirementsarecloselymonitored,utilizingarobustdietaryintaketrackingmethodtoensureadequatecaloricandnutritionalintakeandidentifyingvolumetricfoodrequirementsforfuturemissions.Astronautstracktheirfoodintake,aswellaspreferencesanddislikes,utilizingtrackingtechnologydevelopedforefficiencyandaccuracy.TheISSFoodIntakeTrackerallowsforiteminputbywayofselectionfromalist,photographicfooditems,barcodescanning,voicerecording,ormanualkeypadinput(NASAMissionPages2013;Smithetal.2014).Thistrackingsystemhasgreatlyimprovedtheawarenessofthevolume,type,andnutritionalcontentofthefoodsconsumedduringagivenmission,andhasprovidedimportantinsightregardingthevolumeandmassoffoodsnecessaryforlongerormoredistantmissions.Earlyprototypesofasimilarsystemforpharmaceuticalmonitoringareindevelopment,withexperimentsaboardtheISSongoing.Forexample,theMedicalConsumablesTrackingprojectusesradio-frequencyidentificationcodestotrackmedicationsandmedicalsuppliesontheISS,allowinggroundsupporttotrackwhichmedicalresourcesareusedandwhenreplenishmentwouldberequired(NASA2017a).Similarly,theDoseTrackerprojectwasdesignedtotrackcrewmedicationuses,associatedsymptomsorrelief,andanyadverseeffectstoidentifywhethermedicationsactdifferentlyonhumansinspacecomparedtoterrestrialnorms(NASAMissionPages2017).Ifsuccessful,suchcapabilitiescouldprovidemuch-neededawarenessregardingtheseparametersforpharmaceuticals.Ground-basedsystemsareincommonuseinmosthealthcarefacilities.Automatedmedicationstorageanddistributionsystemshavebecomethegold-standardinhospitalwards,providingeasyandrapidaccesstosingle-dosemedicationswithaccuratetrackingofmedicationsadministered,timeofdosage,andthepatientreceivingthemedications(CanadianAgencyforDrugsandTechnologiesinHealth

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(CADTH)2010).Mostsystemsutilizeidentifiersincludingbarcodescanning,personnelidentificationnumbers,andpatientidentifierstoensurethattherightpatientreceivestherightmedication,asordered(andoftenpre-approved)throughanelectronicmedicalsystem.Implementationofsuchtechnologyhasbeenbotheconomicallyandorganizationallypraised.Economically,automateddistributionsystemsallowforimprovedbilling,reducetheneedforunnecessarystockingofminimally-usedmedications,andreducetheriskofmedicalerrorandthecostsassociatedwithsuch(Khenieneetal.2008;CanadianAgencyforDrugsandTechnologiesinHealth(CADTH)2010).Withregardstosafetyandorganizationalimpacts,thesesystemshavebeendemonstratedtoreducemedicalerror,improvetime-to-first-treatment,improveidentificationofexpiredmedications,improvetimelystockingandensureappropriateavailabilityofhighlyutilizedmedications,andtoreduceoveralltimespentonpharmaceutical-relatedpaperwork,freeingupsignificanttimeforhospitalpersonnel(Leeetal.1992;Khenieneetal.2008;CanadianAgencyforDrugsandTechnologiesinHealth(CADTH)2010;Bourcieretal.2016).Installationofafullyautomateddispensingcabinetwillmostlikelyrequiremassandvolumethatisincompatiblewithexplorationmission-classvehicles.However,utilizationofsimilartechnologicalapplicationsislikelyfeasible.Alterationofthefoodtrackingsystemtoincludepharmaceuticaltracking,orfurtherdevelopmentofaparallelmedicationtrackingsystem,isoneoptionforfuturemissions.Developmentofsimilartrackingdevices,suchasbarcodescannersorlistidentifiersofmedicationsdispensed,wouldimproveuponpharmaceuticaltrackingcapabilities,whetherornotafullycontrolleddispensingcabinetisincluded.Developmentofsuchonboardcapabilitiesinthenear-term,withnear-Earthmissionimplementation,wouldprovidemuch-neededinformationregardingmedicationusagehabits,futuremissionneeds,andthelike,andthetechnologiesdevelopedwouldundoubtedlybeusefulforresourcemanagementduringalongerexplorationmissioninthefuture.

• PersonalizedMedicinePersonalizedmedicinewillbeanimportantelementofexplorationmedicalcapabilities.Inparticular,providinginterventionstailoredtoindividualcrewmembersthroughpharmacogeneticsandpharmacogenomicswillimproveoutcomesandminimizemassrequirementsoftheonboardpharmacybyoptimizingthedrugselectionforthecrewcomplement.Overtime,enhancedinsightintothegenomicsandphenotypesofindividualcrewwillhelpNASAtodevelopmoreeffectivecountermeasuresandinterventionstoaddresstheeffectsofspaceflightonthehuman.Personalizedmedicineisnotnovelinspaceflight.InboththeSpaceShuttleandISSPrograms,NASAusedpersonalizedmedicine,intheformofindividualizeddrugtolerancetesting,topersonalizesleepandalertnessinterventionsforcrew(Johnstonetal.2015).OntheISStoday,personalizedpharmaceuticalprescriptionsarepairedwithcomplementarybehavioralandenvironmentalinterventionssuchas

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sleepschedulesandsmartlighting(Brainardetal.2013;ScheuringandJohnston2015;Flynn-Evansetal.2016).Recentresearchhasdemonstratedsignificantgeneticvariabilityamongindividualsthataffectsneedforsleepandthecognitiveeffectsofsleepdeprivation(GoelandDinges2012).Workisunderwaytodevelopgeneticmarkersthatwillinformpersonalizedcountermeasurestocognitiveoroperationallimitationsduetosleeploss,optimizationofsleepscheduling,anddeterminationofacrewmember’sneedforonboardpharmaceuticalinterventions(GoelandDinges2012).Sleepwilllikelyremainafocusofpersonalizedmedicineinexplorationmedicine.Terrestrialpharmacogeneticsismakingsignificantstridesthatwillsupportexplorationmedicineinthefuture.Ground-basedpharmaceuticalstudieshavedemonstratedsignificantgenetic-andpopulation-baseddifferencesinresponsetovariousdrugs.Forexample,responsetomedicationcanbesignificantlyalteredbyage,possiblysecondarytoDNAmethylationorsimilarage-relateddegradationoralterationofgeneexpression(FitzpatrickandWilson2003).Pharmaceuticalresponsecanbevariedbysex,asdemonstratedbydifferencesbetweenmaleandfemaleresponsestocardiovascularpharmacotherapy(Jochmannetal.2005).Raceandethnicitycanalsoaffectdrugresponse;examplesinclude:cardiovascularmedicationsonlyeffectiveinpersonsofAfricandescent(Tayloretal.2002);alteredmetabolismofsedativemedicationinpersonsofEastAsiandescent(Tangetal.1983);anddifferencesinthemetabolismofantihypertensivesinpersonsofAfricanandChineseheritagewhencomparedtothoseofEuropeandescent(Kalow2001).Thesourceofthesedifferencesmaybeduetovariedexpressionofspecificgenes.Cytochromaticexpression,forexample,hasbeenidentifiedinnumerousstudiestobethebasisofsignificantalterationsindrugmetabolismandresponse,includingcytochromeCYP2D6andresponsetometoprolol(SchwartzandTurner2004)andcytochromeCYP2C9andresponsetowarfarin(Hermanetal.2005).Similarly,thepresenceofN-acetyltransferaseactivitypreventsmanyoftheunpleasantsideeffectsassociatedwiththeadministrationofisoniazid(BonickeandReif1953).Researcharelookingatsimilarenzyme-drivenresponseaboardtheISS.EarlyresultssuggestthatasmanyasathirdofthedrugsavailableontheISSareregulatedbyenzymaticresponse(suchasthecytochromesystem)potentiallyleadingtosignificantresponsevarianceamongindividuals(Stingletal.2015).Personalizedmedicineasafieldisinitsinfancy.Interrestrialmedicineotherfederalagenciesareworkingtorealizethepotentialofthisfieldinthelargermedicalarena(HamburgandCollins2010).ForNASA,additionalresearchongeneticandgenomicinformationtoinformpersonalizedmedicineposesbothlogisticalandregulatorychallenges.Therearefewastronautswhohaveexperiencedextendedstaysinspace,andfewanalogstoidentifyspaceflight-inducedgeneticchanges.Terrestrialmedicalresearchisexploringdifferenttechniquesinclinicalmedicinethatincludetrackingtheindividualratherthanaverageresponsestotherapies(Schork2015)thatmaybemoreapplicabletothechallengesNASAfaceswithsmallcrewsandlongdurationmissions.Instudyingour

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currentastronauts,NASAisboundbyFederallawthatlimitsthecollectionanduseofgeneticinformation.Forinstance,NASAmayusegeneticinformationforoccupationalsurveillanceandcountermeasuredevelopment,butnotforcrewselectionandassignmentdecisions(ReedandAntonsen2017).Evenworkingwithintheseconstraints,thereismuchNASAcanaccomplishtoimprovetheabilitytodeploypersonalizedmedicineonexplorationmissions,particularlybybuildingonadvancesinterrestrialpersonalizedmedicine.

2.SystemCapabilitiesProlongedmicrogravityexposureisknowntocausesignificantdeconditioningofthemusculoskeletalsystem,placingcrewatriskofinjurywhentheyreturntoanormalgravitationalenvironment.Similarly,crewarrivingtotheMarssurfacewillfaceanincreasedriskofinjuryifmusculoskeletalhealthisnotmaintained,andsustainedplanetaryactivitieswillcontributefurthertophysiologicalstressors.Inaddition,anyillnessexperiencedduringtheflightbetweentheEarthandMarscouldresultinsignificantcardiovascularormusculoskeletaldeconditioning.MuchlikeonEarth,whereprolongedbedrestisassociatedwithdecreasedstrengthandcardiovascularreserve,illnessinspaceflightcouldsimilarlyreducethephysicalcapabilitiesofafflictedcrewmembers.Asaresult,anonboardmedicalsystemmusthavethecapabilitytoproviderehabilitationtechniquestomitigatesuchrisk.Further,asystemknowledgeresourcethatcouldprovideguidancetoanonboardmedicalofficer,directingdecision-makingwithregardstorehabilitationregimesorspecificinterventions,couldoffermuch-neededsupportintheabsenceofregularcommunicationorinterventionbygroundsupport.Theseconsiderationswillbediscussedatlengthbelow.

• RehabilitationExperienceinlowEarthorbithasdemonstratedthatmanyinjuriesoccurringduringflightaremusculoskeletalinnature(Scheuringetal.2009).Inaddition,therearenumerousstudiesregardingthesignificantatrophyofskeletalmuscleandboneduringlong-durationspaceflightsecondarytotheunloadingofaxialstressinthemicrogravityenvironment(Ploutz-Snyderetal.2015).Todate,mostmedicaleventsthathaveoccurredin-missionhavebeenself-limiting,minor,oreasilytreatedwithexistingvehiclemedicalcapabilities(Scheuringetal.2009).Formoreseriousconditions,evacuationtodefinitivemedicalcareisavailableandthereisnoneedforprolongedin-missionrehabilitationcapability.Withouttheabilitytoevacuateaninjuredcrewmember,in-missionrehabilitationcapabilitiesmayberequired.LongerstaysinEarthorbithavenecessitatedthedevelopmentofcountermeasurestoprevent,oratleastlimit,theatrophiceffectofmicrogravity,prepareastronautsforthereturntoEarthanditsgravitationalenvironment,andtopreventinjurysecondarytomuscleorboneatrophyduringflight,andservethebasisofevidenceforpotentialcountermeasuresforfutureexplorationmissions(Hawkey2003;Orwolletal.2013;Ploutz-Snyderetal.2015).Whilecountermeasurecapabilitiesareaimedtowardspreventionofdeconditioning,thereisaclosecorrelationbetweensuchpreventiveeffortsandexplorationmissioninjuryandrehabilitation

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concerns.AsfutureexplorationmissionsincreasetimeanddistancefromEarth,thereisthepossibilitythatmedicaleventswilloccurthatresultinsignificantcrewfunctionalimpairmentrequiringin-missionrehabilitation(Hamiltonetal.2008).Inparticular,theneedforimmediatephysicalperformanceandoperationalcapabilitiesuponarrivaltoadistantplanetarysurfacelikeMarscouldplacedeconditionedcrewatincreasedriskforinjury.Asinterrestrialrehabilitationefforts,useofexerciseequipmentwilllikelyformalargepartofthepreventiveandrecuperativerehabilitativecapabilitiesonboardanexplorationvehicle.Giventhecorrelationbetweendeconditioningcountermeasures,injuryrisk,andrehabilitationneeds,abriefintroductiontocountermeasuresisprovidedbelowforcontext.MultiplecountermeasuredeviceshavebeenutilizedaboardtheISSandotherhistoricalspacecraft.CurrentdevicesinuseaboardtheISSincludethecycleergometerwithvibrationisolationandstabilization(CEVIS),treadmillwithvibrationisolationandstabilizationsystem(secondgeneration,calledT2),andtheAdvancedResistiveExerciseDevice(ARED),whichreplacedtheinterimResistiveExerciseDevice(iRED)in2010(Ploutz-Snyderetal.2015).TheCEVISandT2providecardiovascularconditioningthroughrunningorcycling,allowingformaintenanceofcardiovascularreserve,preventingorthostasis,hypotension,andcardiovascularstressuponreturntoagravitationalenvironmentafterlanding(Ploutz-Snyderetal.2015;Petersenetal.2016).Thesedevicesarenotoriousforonboardfailuresleadingtoreducedavailability;particularlyduringearlyISSmissions,itwasrarethatallexercisedeviceswereworking,makingitdifficultforcrewtomaintaincardiovascularconditioningduringlong-durationmissions(Ploutz-Snyderetal.2015).TheiREDisanelastomer-basedresistancehardwaredevice,utilizedduringlong-durationmissionsuntiltheintroductionoftheAREDin2010.Instudiesregardingspaceflight-relatedmusculoskeletalalterations,datademonstratedsuccessfulmuscularactivationandstrengthtrainingusingiREDwithmuscleresponsessimilartothatseenwithground-baseduseoffreeweights(Schneideretal.2003).However,iREDfailedtostimulateboneandpreventatrophyduringflight,demonstratinganeedforimprovedcountermeasurestrategiesforlong-durationmissionstopreventmicrogravitydeconditioning(Schneideretal.2003;Ploutz-Snyderetal.2015).TheadditionoftheAREDallowedforvariedandimprovedresistantexerciseregimes.TheAREDusesvacuumcanisterstoprovideupto600poundsofresistance,mimickinginertialloadsgeneratedbytheuseoffreeweightsonEarth(Ploutz-Snyderetal.2015).Ground-basedstudiesdemonstratedprotectionofbothmusclemassandbonemineraldensitywithuseoftheARED(Loehretal.2011).AboardtheISS,crewmembersshowimprovedprotectionandevengainofmusclemassaswellasprotectionofbonedensityduringflightthroughAREDuse(Smithetal.2012;Ploutz-Snyderetal.2015).Despitetheseadvances,rehabilitationcapabilitiesforexploration-classmissionsarestilllacking.WhiletheAREDhassignificantlyimproveduponexercise-relatedrehabilitationandmitigationofmicrogravity-inducedmusculoskeletaldetriments,

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themassandvolumerequiredforasystemliketheAREDareprohibitivelylargewhenconsideringthelimitationsofaninterplanetarymission.Smallerdevices,suchastheiRED,havebeenlesssuccessfulandarelikelyinsufficientforsuccessfulmitigationofatrophyduringamulti-yearmission.Further,whileexercisehasbeentheprimarycountermeasurefordeconditioningduringprolongedmicrogravityexposureandmitigatingnegativephysiologicalchange,theyhavebeenassociatedwithnumerousmusculoskeletalinjuriesinthepast(Scheuringetal.2009).Thereisaneedforeffectivebutvolume-reducedrehabilitationcountermeasuresthatprovideeffectivemitigationatminimalrisktothecrewforexploration-classmissions.Newdevicesareunderinvestigationforexercise-relatedcountermeasureandrehabilitationefforts.Forexample,theResistiveOverloadCombinedwithKineticYo-YoDevice(ROCKY)wasdevelopedbyZinTechnologies,Ohio,toprovidearobustexercisecapabilityatanexponentialdeclineinmassandvolumerequirements(Garcia2016;ZinTechnologies2016).Alternativestoexercise-mitigationofmicrogravitydeconditioningarealsoofinterest.Forexample,lower-bodynegativepressure(LBNP)deviceshavedemonstratedsomesuccessinmitigatingpost-flightorthostaticintolerance;thesedevicesareoftenrelativelycompact,requiringlessmassandvolumethanmanyofthehistoricandcurrentexercisedevicesdescribedabove(Murthyetal.1994;Trappeetal.2007).However,theeffectsofLBNPtendtobebestobtainedwhenthecapabilityisusedinconjunctionwithcardiovascularexercise(Murthyetal.1994;Trappeetal.2007).Further,LBNPdoesnotprovideeffectivemitigationofmusculoskeletalatrophyinlong-durationexposuretomicrogravity.Anonboardmedicalcapabilitymustbeabletopreventinjury,includingpreventionofdeconditioningthatwillleadtoincreasedphysicalrisk.Itislikelythat,intheabsenceofgroundinstruction,thecrewwilllooktoanonboardmedicalofficertoguiderehabilitationandtrainingregimes,tailoringthemtospecificinjuriesandweaknessesortodecliningfunctionalperformancecapabilitiesthatfollowprolongedillnessorconvalescence.Oneconsiderationforfuturelong-durationmissionsistheinclusionofguidedrehabilitationregimeswithuseoftelerehabilitationtotailorspecificexercisecountermeasurestoagivencrewmember,addressinganyknownlimitations,injuries,orsimilarfactors.OnEarth,rehabilitationtechniquestypicallyinvolveanextensivecomplementofmedicalexpertiseandequipment,includingphysicians,nurses,therapists,andspecializedequipmentthatarespecificallytailoredtoagivenpatient’sneeds(Frontera2013).Toaddressout-of-hospitalneeds,telerehabilitationiscurrentlybeingdevelopedforpatientsinremoteterrestriallocations(Schmeleretal.2009).Astelerehabilitationoftenrequiresalessextensivearrayofon-sitemedicalpersonnelandmakesuseofoftenlimitedequipment,telerehabilitationcapabilitiescouldbeimportantcomponentsofanin-flightrehabilitationcapabilityinasimilarlylimitedresourceenvironmentofanexplorationmission(KumarandCohn2013;Papali2016).

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Whiletechniquesorequipmenthaveyettobedevelopedtomeetthespecificneedsofexplorationorinterplanetaryspaceflight,theriskofinjuryordeconditioningduringlongermissionsisquitereal,andposesasignificantthreattocrewsthatmustbecapableofphysicalperformanceuponreachingtheirdestination.Developmentofappropriatetechnologyortelerehabilitationtechniquestomitigatespecificinjuryoratrophythatmeetmassandvolumeconstraintsforlong-duration,exploration-classmissionswillbeanimportantcomponentoffuturemissiondesign.

• DecisionSupportandOnboardKnowledgeResourcesCurrentmissionsaboardtheISSrelyheavilyupongroundsupportandtelemedicalcapabilitiesinthewayofliveremoteguidance,monitoring,andcoveragetoassistinthediagnosis,treatment,andothermanagementofacutemedicalissuesandneedsduringflight(Hamiltonetal.2008;BridgeandWatkins2011;Blueetal.2014).Inanexploration-classmission,immediateterrestrialsupportmaybeunavailable;inemergentsituations,communicationdelaysorblackoutsmaylimittheabilityforground-basedsupporttoassistcrewdecision-making.Ashiftinthecurrenttelemedicineparadigmisneededtosupportreal-timeclinicaldecision-makinginaremoteenvironment.Moreautonomousdatasystemsmustbedevelopedthatarerobustenoughtoallowthecrewtoindependentlyandrapidlydiagnoseillnessandassessthebestavailabletreatments,evaluatethelikelihoodofsuccessoftreatment,anddeterminetheimplicationsfortherestofthecrewandthemissionregardingtheuseoftheresourcesrequiredtotreataninjuredcrewmember.Withregardstospecificonboardresources,thereareanumberofguidanceprogramsavailabletoassistindiagnosticexaminationaswellasinterpretationoftestresults.Forexample,multipleguidedimagingprogramsexistfortheassistanceofsonographictechniques.Toimproveuponoperatorskillinultrasound,developershavedesignedroboticimagingtechnologythatprovidespoint-of-careguidanceonprobeplacement,imageacquisition,andtelemedicalinterfaces(Monfaredietal.2015).SimilartechnologieshavebeendevelopedforuseontheISS,includingtheAdvancedDiagnosticUltrasoundinMicrogravity(ADUM)project.TheADUMsystemusesremoteguidance,telemedicalinterfaces,andjust-in-timeinstructiontechniquestoguideminimallytrainedcrewmembersinacquisitionofadequateimagingthatcouldbeusedfordiagnosticpurposes(Foaleetal.2005;Hamiltonetal.2011;NASAMissionPages2016a).Follow-onstudiesaimtoexpanduponthistechnology,allowingformorecomputer-basedguidanceandrelyinglessupontelemedicalsupportfromgroundcrews.Forexample,the“ClinicalOutcomeMetricsforOptimizationofRobustTraining”(COMFORT)studyaimstodevelopclinicaloutcomemetricsandguidedtrainingtoolsforphysicianandnon-physiciancrewmedicalofficersforuseinexplorationmedicine(Ebert2017).Interrestrialmedicine,similartechniquesarebeingdevelopedforothermedicalapplications,suchasroboticguidanceforinvasiveproceduressuchaspercutaneousneedleguidance(Clearyetal.2006;KettenbachandKronreif2015).Roboticassistancefortelemedicineisoccasionallyusedforremotephysicianpresenceinunderservedregions;whilemanyoftheseresourcesfocusprimarilyonvideo

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conferencing,someincorporateothertoolsincludingremotebedsidemonitoringandmedicaldecision-makingalgorithmsforassisteddecisionsupport(Ackermanetal.2010).Itisimportanttorememberthatthebenefitsofthesetechnologicaladvancesmustbeweighedagainsttheassociatedmassandvolumerequirementsofflyingequipmentneededtosupportthetechnology.However,roboticguidanceforproceduralsupportorassisteddecision-makinghasthepotentialtogreatlyamplifyautonomouscrewmedicalcapabilities,allowingforpoint-of-careguidanceforinterventionsinwhichthecrewreceivesminimaltrainingorproceduresthatareoutsideoftheexpertiseoftheonboardPhysicianAstronaut.Atthemoment,thesetechnologiesareearly,andapplicabilitytothechallengesofspaceflightiscurrentlyoutsideofthescopeofthesetechnologies.Further,anytechnologyincludedinanexplorationmedicalsystemmustbenearautonomousandrobustenoughtobereliableforthedurationofthemission;this,too,isnotachievablewithtoday’stechnologies. Inadditiontoproceduralassistance,onboardknowledgesupporttechnologieswillbenecessarytoenhancemedicalcapabilitiesonalong-durationmission.Ataverybasiclevel,theonboardPhysicianAstronautwilllikelyhaveneedforeducationalresourcesandrefreshermaterials,suchascomputerizedclinicalknowledgesystemslikeUpToDate®,eMedicineTM,WheelessOnline,andotheronlineresourcesavailableinmosthospitals(Medscape2017;UpToDate2017;Wheeless2017).Retrospectiveandnon-blindedcomparativestudieshavedemonstratedimprovementinpatientoutcome,decreasedlengthofstay,andreducedresourceutilizationinhospitalsystemsthatallowphysicianstodirectlyaccesssuchknowledgesupplementsduringclinicalactivities(Bonisetal.2008;Isaacetal.2012).Knowledgeresourcesareideallyrapidlyaccessed,withdirectedinformationindexedbysimplesearchterminologysuchasdiagnosticcriteria,symptomatology,andclinicalsigns,andprovidespecificinformationregardingtreatmentoptions,prognosis,andthelike.Suchresourceswouldundoubtedlyprovidemuch-neededknowledgeresourcesinthecaseofanin-missionmedicalevent.WhileabasicsearchabletextofknowledgewouldcertainlycomplementthePhysicianAstronautcapabilities,amorerobustsystemcouldprovidehigher-leveldecisionsupporttechnologies.Forexample,artificialintelligencetechnologieshavebeendevelopedthatapplyalgorithmstomedicaldiagnosticcriteria,providingdecisionsupportregardingbesttreatmentoptions,idealmedicationanddosinginformation,andsimilar.Suchsystemshavebeenusedinclinicaldiagnosisprotocols,imageanalysis,andcomplexdatainterpretation,andtheapplicationofthesetechnologiesisbeingexploredinmultiplefieldsofmedicine(Hensonetal.1997;Pesonenetal.1998;Rameshetal.2004;deBruijne2016).Ifthesesystemswereadjustedforaerospacemedicalconsiderations,protocolguidanceandassisteddecision-makingtechnologiescouldprovidesupportformedicalresponseinanexplorationmissionwherecommunicationwithgroundsupportandtelemedicalcapabilitiesarelimited.Whilepromising,thereisaneedforsignificantdevelopmentofthesetechnologicaladvancesbeforesuchtechniquesareclinicallyrobustenoughforincorporationintoanexplorationmedicalsystem,andtheExMCElement

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continuestoassessthelikelymaturityofthesesystemsinanticipationofaMarsmission.

C. MedicalMissionConsiderations

1. RiskMitigation

• SelectionofthePhysicianAstronautandPre-missionMedicalTrainingCurrentpre-missionmedicaltrainingforISSmissionsisbaseduponthepresentparadigmofanassignedcrewmedicalofficer.Presently,amission’screwmedicalofficerisanyindividualchosentoberesponsibleforacutemedicalcareaboardtheISS;thisindividualmayormaynothavehadanypriormedicaltrainingorexperience(BridgeandWatkins2011).ISSstandardsincludedesignationofonemedicalofficerpereverythree-personcrew(Hamiltonetal.2008).Priortolaunch,thismedicalofficerreceivesapproximately40hoursofinstructionintheuseofonboardresourcesandabasiceducationregardingthepresentationofcommonmedicalconditionsandrelatedsuperficialtreatmentoptions(BridgeandWatkins2011).Thisincludesapproximately4hoursoflectureonmedicaldiagnostics,5hoursontherapeuticinterventions,and10hoursofbasiclifesupport(BLS)andadvancedcardiaclifesupport(ACLS)algorithmtrainingtoAmericanHeartAssociationstandards(BridgeandWatkins2011).ISScrewmedicalofficersmaychoosetofurthershadowmedicalprovidersinvariousclinicalscenarios,includinganemergencyortraumacenterorpre-hospitalcaresettings(BridgeandWatkins2011;Blueetal.2014).Finally,allcrewmedicalofficersareprovidedguidanceregardingclinicalindicationstoinvolvetelemedicalinterventionandgroundmedicalsupport(BridgeandWatkins2011;Blueetal.2014).NASAstandardsrequireadesignatedmedicalofficer,trainedtothelevelofaphysician,aspartoftheonboardastronautskillmixforplanetarymissionslongerthat210daysgiventheincreasedduration,uncertaintyandcomplexitysurroundingmedicalcareinthisenvironment(NationalAeronauticsandSpaceAdministration2016).Thus,futuremissionplanningtomitigatemedicalandhumanperformanceriskforplanetarymissionswillneedtoconsiderwhattypeofpriortraining(i.e.whattypeofphysiciantrainingorbackgroundismostsuitedtothemissionneeds)aswellasprovidingredundancyforthephysician-trainedmedicalofficer,referredtohereasPhysicianAstronaut(BridgeandWatkins2011).PhysicianAstronautssupportingplanetarymissionsmusthavesufficienteducationandtechnicalcompetencytoprovidemedicaldecision-makingandprovisionoftreatmentforanynumberofvariedmedicaleventsthatcouldoccurduringflight.Physician-levelmedicaltrainingtypicallytakesatleastsevendedicatedyearsofmedicalschoolandresidencytrainingtoachievethecapabilitytopracticeindependentlyintheUnitedStates.Thisleveloftrainingisunrealistictoduplicatewithintheastronauttrainingregime;thus,anindividualwithanappropriateskillsetmustbeselected,withtrainingpathwaysdesignedformaintenanceofskillspriortoamission,andtrainingneedsidentifiedforin-missionknowledgeandskillsmaintenance(Blueetal.2014).

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Inthecontextofamoredistantexploration-classmission,pre-flighttrainingforthePhysicianAstronautwouldneedtofocusonfamiliarizationwithcommonailmentsorinjuries,aswellasonboardcapabilitiesandresources(Blueetal.2014).NASAhasassessedtheneedsforexplorationmissionsandfoundcommonmedicalcapabilitiesandmanagementstrategiesthatshouldbeemphasizedforPhysicianAstronauttraining,includingdentalprocedures,behavioralhealthissues,andmusculoskeletalinjury.Allofthesehavebeenidentifiedaspotentiallyfrequentand/orincapacitatingwithouteffectiveintervention(Scheuringetal.2009;Blueetal.2014).Onboardmedicalequipment,particularlyhardwareandpharmaceuticals,shouldbefamiliarenoughthatPhysicianAstronautscanrapidlyaccessassetsincaseofemergency(Blueetal.2014).Specializedtrainingintheclassicandevennon-conventionalcapabilitiesofonboardresources,suchasexpandedsonographictechniquesifanultrasoundisincludedwithinthemedicalsystem,couldensurethatthePhysicianAstronautcanmakefulluseofsuchresourcesandevenpotentiallyimproviseanalternativesolutioninthecaseofaninjurythatisoutsidetheclassicindicationsofonboardresources(Finckeetal.2005;Sargsyanetal.2006;Kwonetal.2007;Kirkpatricketal.2007;Jonesetal.2009a;Sireketal.2014).Furtherpre-flighttrainingmaybeneededforspecificillnessesorinjuriesanticipatedinagivenmissionthatfalloutsideaPhysicianAstronaut’sfieldofknowledgeorpersonalexperience(Blueetal.2014).GiventhataPhysicianAstronautwilllikelybemanyyearsremovedfromtheiroriginalmedicaltraining,pre-fightrefreshertrainingmayberequiredinareasofpracticethatrequiremanualskill,complexthinking,orrapidandcriticaldecision-making.Inaddition,thePhysicianAstronautwouldneedtobefamiliarwiththeeffectsoflong-durationflightonthehumanbody,particularlywithregardstomusculoskeletalandcardiovasculardeconditioning,neurovestibularalterations,immunesuppression,effectsofchronicradiationexposure,behavioralhealthimplications,andeffectsonmetabolismandendocrineactivity(Grigorievetal.2002;PoolandDavis2007;Baisdenetal.2008;BridgeandWatkins2011).Theabilitytorecognizesignsorsymptomsofsignificantdeconditioningandtoimplementcountermeasuresmaybecriticalinthecaseofinterplanetaryflight,wherecrewmemberswouldrequirephysicalagilityandstrengthimmediatelyafterlandingforlikelymission-criticalactivities(BridgeandWatkins2011).Awarenessandtraininginin-flightrehabilitationandcountermeasureresources,asdescribedabove,wouldhelpthePhysicianAstronautrecognizedeconditioningandmakefulluseofonboardresourcestocounteractsuchtrends.Apre-flightawarenessandunderstandingofaerospacephysiologywouldprovidesignificantinsightregardingrisksandpotentialopportunitiesforinterventionduringanexplorationmission.

• ContinuingEducationandJust-In-TimeTrainingContinuingeducationthatincludesrepeatpatientexposureiscriticalformaintenanceofcompetencyforanyclinician(ACGME2016).Thecontent,frequency,andamountofthatexposuretomaintainminimumlevelsofcompetencyisnotclearlydefinedoutsideofregulatorybodyrequirementsforlicensingandlikelyvariescliniciantoclinician.CurrentISSastronautscanhavedelaysofmany

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yearsbetweenselectionandmissionassignment,andduringthistimeperiodtheyarecross-trainedinmultipleprofessionalfieldsinpreparationforfuturemissionassignments(BarshiandDempsey2016).Itiscriticaltoensurethatcoreclinicalskillsandcompetenciesaremaintainedduringthistimeframebetweenhireandmissionassignmentwhilemanagingcompetingprioritiesforworktime.Further,asallpotentiallynecessarymedicalproceduralskillsarenotlikelytobetrainedpriortoamission,anevidencebasedapproachtojust-in-timelearningstrategiesneededfromanexplorationmedicalsystemmustbescoped,researched,andeventuallytested(Blueetal.2014).ClinicallycompetentPhysicianAstronautsandthosedesignatedasbackupswillalsorequirespaceflight-specificmedicaltrainingduringthistimeperiodtofamiliarizethemwiththemedicaloperationalenvironmentoftheirspacecraftandhabitat.Currently,ISScrewmedicalofficersareabletoreferenceknowledgeresources,includingtutorialsandstudymaterials,forpoint-of-caretrainingforvariousmedicalscenariosorresourceusage(Foaleetal.2005;Blueetal.2014).Further,ground-basedmedicalsupportisavailableforconference,assisteddecision-making,andprovisionofadditionalresourcesasneeded(Blueetal.2014).Fortherareandgenerallyminorinjuriesormedicaleventsthathaveoccurredtodate,thiscapabilityhasbeensufficienttoensurethatthenecessarymedicalcareisavailableinlowEarthorbit.However,exploration-classmissionsoutsideoflowEarthorbitareunlikelytobeabletoemergentlyutilizeground-basedassetsgivencommunicationlimitationsimposedbydistanceandtechnologyorbandwidthrestrictions.Physicianastronautsandbackupmedicalofficersneedonboardresourcestoassistinthecaseofamedicaleventoutsidetheirareaofmedicalexpertisetoprovidepoint-of-careorjust-in-timetraining(Blueetal.2014).Onetrainingmodalitythathasbeendemonstratedtobeeffectiveinevencriticaloperationsistheuseofintegratedsimulation(Blueetal.2014).Simulationshavebeendemonstratedeffectiveinimprovingcrewresourcemanagement,leadership,teamintegration,communication,mission-specifictraining,andcriticalperformancemetrics(Davidsonetal.2012;Blueetal.2014).Medicalsimulationinparticularhasbeendemonstratedtobemoreeffectivethanlecturesorsimilarlyformatteddiscussionswhentrainingforskillperformance(Cooketal.2011,2012).Ithasbeenfurtherdemonstratedtoimproveskillretentionandprovideeffectivere-traininginpreviouslylearnedtechniques(Gaba2004;Anderetal.2009;Didwaniaetal.2011).Currently,ISSastronautsutilizesimulationtopracticecardiopulmonaryresuscitationandsimilarbasiclifesupportskillsneededformedicalemergency(BarshiandDempsey2016).Incorporationoffurthersimulation-basedtrainingmaybeaneffectivemeansofmaintainingclinicalskillsinlonger-durationmissions.Just-in-timetrainingisusedaboardtheISSforotherskills,includingacquisitionorrefreshmentofskillsrelatedtoonboardexperimentsandplannedproceduresforextravehicularactivities(EVAs)(BarshiandDempsey2016).Suchtrainingprogramshavebeenreceivedwithvaryingdegreesofsuccess,andastronautshavecommentedoninconsistencyinimplementationorvaryingefficacyofavailable

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trainingresources(BarshiandDempsey2016).Ingeneral,themoreinteractiveandhigh-fidelitythetrainingmodality,thehigherthelikelihoodthatitwillbefoundusefulbycrewmembers.Evenso,currentjust-in-timetrainingmodalitiesgenerallyworkfromtheassumptionthattrainingcrewshavethesupportofground-basedassets,includingtrainers,experimentalleads,andothersupportstafftoensureadequateunderstandingoftheonboardmaterials.Transitiontoafullyautonomoustrainingsystemforexplorationmissionswillbeachallengeinfuturemissiondevelopment.Inadditiontoidentifyingsuccessfultrainingtechniques,thereisaneedforeffectivetoolstoidentifycompetencyinmedicalskillsduringflight.Suchevaluationscouldprovideevidenceofbothpre-flightmasteryofrequiredskillsandjust-in-timedemonstrationofretentionofneededcriticalcapabilitiesinthecaseofmedicalemergency(Blueetal.2014).Therearenumerousstudiesdemonstratingvariousoptionsforvalidationofeffectivetraining,includingwrittenexaminations,mini-clinicalevaluations,directobservationbysubjectmatterexperts,case-baseddiscussionorsimulation,andobjective-structuredclinicalexaminations(OSCEs)(Blueetal.2014).Foruseinanin-flightenvironment,OSCEandsimulation-basedexaminationsaremostlikelytobeuseful(Blueetal.2014).Theseexaminationsarebaseduponsimulatedclinicalscenarios,wheretraineesarerequiredtomeetstandardizedandpre-establishedchecklistcriteriaorskills(Sloanetal.1995;Durningetal.2002;KreiterandBergus2009).Failuretomeetobjectives,orotherevidenceofwaningperformance,couldpromptincreasedtrainingthroughonboardsimulationorresourceutilizationtoensuremaintenanceofskillsthroughoutthedurationofthemission(Blueetal.2014).However,suchsimulationsmustworkwithintheconstraintthattheycannotimpactconsumablesthatareneededforoperationalcapabilitiesorfuturemedicalresponse.Therefore,alternativetechnologiesthatutilizevirtualrealityorsimulatedprocedureswithoutrequiringconsumableequipmentmayprovetobebetteralternativesforonboardtraining(McWilliamsandMalecha2017).

2. IdentifiedThreatsandFocusedMitigationNASA’sHumanSystemsRiskBoardhasidentifiedspecificmedicalconditionsthataredeemedhighrisktoexploration-classmissions;subsequently,thededicatedefforttomitigatesuchriskhasbeenmadeapriorityforexplorationscience(NASAHumanResearchProgram2009).Themitigationoftheserisksrequiresafundamentalunderstandingoftheseproblemswithinthespaceflightenvironment,challengesinthedevelopmentofpreventivecountermeasures,incorporationofsuchmodalitiesintoanexplorationmedicalsystem,andtheneedfordevelopmentofcapabilityinrelevantcomponentsofmedicalcarethatwillaidindiagnosisandtreatmentoptionsfortheseconditions.Anumberoftheserisksrequiremedicalawarenessandresponsecapability.Thespecificmedicalrisksconsideredhereincludebonefracture,planetarydustexposure,andrenalstoneformation.Giventhespecificityoftheserisksandtheevidencepresentedhere,wewillprovidecase-by-caseevidencecategorizationforclarityofstrengthofevidence;evidencepresentedinthissectionisCategoryIIIexceptwhereotherwiseindicated.

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• BoneFractureBoneminerallossoccursinmicrogravityduetounloadingoftheskeletalsystem,withaveragelossratesofapproximately1%permonth(LeBlancetal.2000).Itisunclearwhetherbonemineraldensitywillstabilizeatalowerlevelorcontinuetodiminishwithlongermicrogravityexposure.Itisalsounknowniffractionalgravity,presentonthemoonandMars,wouldmitigatesomeoralloftheloss.ThislevelofbonelossdoesnotcreateanunacceptableriskoffracturesforISSmissions,butcouldposeagreaterriskduringfuturelongerormoredistantmissions.Thedefinitiveindexforafractureriskduetospaceflightisanincreasedincidenceoffracturesinlong-durationcrewmembersrelativetoacomparable,non-flyingpopulation.Theastronautcohort,however,isstatisticallyunderpoweredtosubstantiateanincreasedfractureriskbyepidemiologyinareasonabletimeperiod.Specifically,therearedataregardingonlyaround70crewmemberstodatewithlong-durationspaceflights;theaverageageoflong-durationcrewmembersis47years(range36-58years),andthereareonlyaroundtenlong-durationastronautscurrentlyinthisdatabasebetweentheagesof60-75.Currently,NASAusesmeasuredarealbonemineraldensity(aBMD),bydual-energyx-rayabsorptiometry(DXA),asasurrogateforfracturerisk,buttheclinicalassessmenttodatesuggeststhatlong-durationastronautsdonothaveanincreasedrelativeriskforfragilityfractures(i.e.fracturesduetoage-relatedosteoporosis)(Sibongaetal.2015).However,therelianceonthisassessmentforfractureriskislikelyinsufficientforunderstandingtheriskintheastronautcohortwithitsnovelskeletalinsultsecondarytodeconditioning(NIHConsensusDevelopmentPanelonOsteoporosisPreventionetal.2001;Orwolletal.2013).Further,populationstudieshaverevealeddeclinesinthespecificityandsensitivityofaBMDforpredictingthosepersonswhofractureintheagingpopulation(Schuitetal.2004;Wainwrightetal.2005;Sornay-Renduetal.2005).In2010,subject-matterexpertsinosteoporosisandbonedensitometryreviewedtheaccumulatingclinicalandresearchdatafromlong-durationastronautstoassisttheNASADirectoratewithassessingskeletalhealthandfracturerisk[CategoryIVevidence](Orwolletal.2013).TheseexpertsexpressedthatclinicaltestingbyDXAtechnologyandbiochemicalassayswasnotsufficienttocaptureandunderstandtheuniqueeffectsofspaceflightbecausemanyofthesechangesareunlikeskeletalchangesobservedincomparableterrestrialpopulationsorwithclinically-relevantage-relatedboneloss[CategoryIIIandIVevidence](NASAConferenceProceedings2010;Orwolletal.2013).

OnereasonwhyDXAmeasurementofaBMDwouldbeconsideredinsufficientasatestforastronautsisthatitaveragestotalbonemineralcontentinatwodimensionalarealprojectionofbone;subsequently,DXAfailstocapturechangesduetospaceflightorcountermeasuresinbonesize,geometry,orinthethreedimensionaldistributionofmassbetweencorticalandtrabecularbonesub-regions.Incontrast,researchdataacquiredbyquantitativecomputedtomography(QCT)havecharacterizedthree-dimensionalchangesintrabecularandcorticalhipbonesub-regionsduringspaceflightandrecovery(Langetal.2004,2006;DanaCarpenteretal.2010).TheseconventionalQCThipindices,includingtrabecularvolumetric

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BMD,minimumcross-sectionaldiameteroffemoralneck,andpercentcorticalbonevolume,donotout-performDXAaBMDasapredictorofage-relatedfragilityfractures,butdoprovideadditionalmeasurementstounderstandhowspaceflightmightinfluencehipfractureprobabilityortounderstandtheetiologyofhipfractures(Blacketal.2008;Boussonetal.2011).Thisexpandedevaluationisnecessarybecausespaceflightchangesareunlikeclinically-assessedterrestrialchangestobone(NASAConferenceProceedings2010;Orwolletal.2013).Moreover,finiteelementmodelsweregeneratedfromthoseQCTdataand,uponanalysis,indicatedasignificantreductioninhipbonestrengthduringspaceflight[CategoryIIevidence](Keyaketal.2009).Consequently,clinicalexpertsassertedthatthesystematicuseofQCTimagingcouldenhancetheoverallmanagementofskeletalhealthinastronauts,butwouldbenecessarytodetectanappropriateclinicaltriggerforpossibleintervention(Orwolletal.2013).Inapilotstudytomonitorfortheclinicaltrigger,suchasalackofrecoveryinareasonablepost-flighttimeframetobaselineBMD,theadditionofQCTtoDXAintenastronautsrevealedthatQCT,butnotDXA,coulddetectspace-induceddeficitsinhiptrabecularvolumetricBMD(vBMD)afterspaceflightandalackofrecoveryattwoyearsafterreturn(Sibonga2017).Inaddition,biochemicalassaysofboneturnoverfromin-flightspecimensconsistentlycharacterizedsignificantboneresorptionduringspaceflight,eveninthecontextofstimulatedboneformationinresponsetohigh-fidelityresistiveexercise(Smithetal.2012,2015).Baseduponthreeseparatereviewsofbiomedicaldataoflong-durationastronautsaccumulatedsince2010,theclinicalpanelofexpertsrecommendedthatbisphosphonatetreatmentbeconsideredforallastronautsservingonspaceflightsgreaterthan6months.Researchinthisdomaincontinues.

QCTdataforanalysisoffiniteelementmodelcarriessomeadditionalradiationburdenforacrew(GriffithandGenant2008).TheExMCElementhasaninterestinexploringalternativemethodologiesfortrabecularstructureinterrogationthatdonotrelyontheincreasedradiationloadandmayprovideanalternativeorevenpoint-of-caremeansofassessingthelikelihoodoffractureinexplorationcrewsthatwillalreadybeexposedtoahighradiationenvironment.TheNationalSpaceBiomedicalResearchInstitute(NSBRI)haspreviouslysupportedDr.Yi-XianQinfromtheStateUniversityofNewYorkatSunnybrookinthedevelopmentofultrasoundcapabilitytocharacterizebonetrabecularstructureaswellasmethodsforusingultrasoundtoacceleratebonehealinginthecaseoffracture[CategoryIIevidence](LamandQin2008;QinandLam2009;Qinetal.2010;Lametal.2011).OneadvantageoftheseapproachesisthatquantitativediagnosisandtherapeuticultrasoundtechniquesarebeingdesignedtointegratewithflexibleultrasoundcapabilitiesintendedforimplementationaboardtheISSandfuturevehicles,potentiallyallowingsuchtechniquestobeavailableforpoint-of-careuseinfutureflight.Inaddition,researcheffortsincollaborationwiththeIMMpredictivecapabilityhavedevelopedtheBoneFractureRiskModel,describedabove(seesectionVII.A)(Nelsonetal.2009).Advancesintheseareasofprognosticriskandmitigationtechniquesareimportantforfutureexplorationmedicalcapabilitiesaddressingthespecificriskofbonefractureduringlong-durationspaceflight.

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• DustExposureDustexposurefromnon-terrestrialsourceswillposeseveralchallengestocrewhealthonfutureexplorationmissionstothemoonandMars.Planetarysurfacesarelargelycoveredbyahard,abrasivedustandlooserockknownasregolith,thecompositionofwhichhasbeenstudiedextensively(Colwelletal.2007;Parketal.2008;Cooperetal.2010;Tayloretal.2010;LiuandTaylor2011;McKayetal.2015).Boththediagnosticandtherapeuticapproachtothemanagementofpulmonaryorsystemicconditionsresultingfromexposuretonon-terrestrialdustwillbechallengingduringaspacemissionduetolimitedonboardresources.Apollomissionstothelunarsurfaceprovidedsignificantexperiencewithdustexposureandrelatedconcerns.AftercrewmembersperformEVAsonaplanetarysurface,theymayintroducedustintothehabitatfromdepositsthathavecollectedontheirspacesuits.CleaningofthesuitsbetweenEVAsandchangingoftheEnvironmentalControlLifeSupportSystemfilterscouldsimilarlyresultindirectexposuretocelestialdusts.Inaddition,ifthespacesuitsusedinexplorationmissionsabradetheskin,ascurrentEVAsuitshave,contactwiththesewoundswouldprovideasourceoftransdermalexposure.Further,ifcelestialdustsgainaccesstoasuit’sinterior,aswasthecaseduringtheApollomissions,thedustcouldserveasanadditionalsourceofabrasionsorenhancesuitinducedinjuries[CategoryIIIandIVevidence](Armstrongetal.1969;Conradetal.1969;Center1971;Shepardetal.1971;Youngetal.1972;Cernanetal.1973).Whenacrewleavesthesurfaceofacelestialbodyandreturnstomicrogravity,thedustthatisintroducedintothereturnvehiclewill“float,”thusincreasingtheopportunityforocularandrespiratoryexposureandsubsequentinjury[CategoryII-IVevidence](Wagner2006;Scheuringetal.2008;Meyersetal.2012;Theriotetal.2014).

NASAhasconductedseveralstudiesutilizinglunardustsimulantsandauthenticlunardusttodeterminetheuniquepropertiesoflunardustthataffectphysiology,assessthedermalandocularirritancyofthedust,andestablishapermissibleexposurelimit(PEL)forepisodicexposuretoairbornelunardustduringmissionsthatwouldinvolvenomorethan6monthsstayonthelunarsurface(Jonesetal.2009b).Studieswithauthenticlunarsoilsfrombothhighland(Apollo16)andmare(Apollo17)regionsdemonstratedthatthelunarsoilishighlyabrasivetoahigh-fidelitymodelofhumanskin(Jonesetal.2009b);anecdotally,thissupportsreportsmadebyApolloastronautsaftertheirownmissions(Armstrongetal.1969;Conradetal.1969;Center1971;Shepardetal.1971;Youngetal.1972;Cernanetal.1973).StudiesoflunardustreturnedduringtheApollo14missionfromanareaofthemooninwhichthesoilswerecomprisedofmineralconstituentsfrombothhighlandsandmaresdemonstratedonlyminimalocularirritancyandpulmonarytoxicitythatwaslessthanthehighlytoxicterrestrialcrystallinesilica(PEL0.05mg/m3),thoughmoretoxicthanthenuisancedusttitaniumdioxide[CategoryIIandIIIevidence](TiO2,PEL5.0mg/m3)(Meyersetal.2012;Jamesetal.2013;Lametal.2013).APELforepisodicexposuretoairbornelunardustduringasixmonthstayonthelunarsurfacewasestablishedat0.3mg/m3inconsultationwithan

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independent,extramuralpanelofexpertpulmonarytoxicologists(Jamesetal.2014).

ThePELprovidedforlunardustislimitedtotheconditionsandexposurespecified;additionalresearchisneededtofurtheraddressotherfactorsofdustexposure,theeffectsofmoreuniquelunarorMartiangeology(Glotchetal.2010;Greenhagenetal.2010),thepotentialtoxicologicaleffectsofinhaledoringesteddustuponnon-pulmonaryorgansystemsincludingcardiovascular(Brooketal.2010;Richetal.2010)andnervoussystems(Nakane2012),theeffectsofacuteexposuretomassivedosesofdustsuchasmayoccurduringoff-nominalsituations,andtherisksassociatedwiththeprolongedexposuresthatcouldoccurduringexplorationmissions.WorktosupporttheestablishmentofPELsforMartiandustanddustsofasteroidshasyettobeaccomplished.

AspartofexplorationmissionplanningforaMarstransitmission,therehasbeensomelevelofdiscussionaboutuniquehealthchallengesassociatedwithasteroidsorMartiandustexposuresincludingtheeffectsofenvironmentalfactors,suchaswindstormsorothersourcesofincreasedexposure,anduniquechemicalcomponentsofMars-specificexposures(Schuergeretal.2012;Davilaetal.2013).Asspecificmissiondestinationsandtimelinesarenotyetestablished,NASAhassoughtapragmaticresearchstrategytocontinuetoprepareforfuturemissionsinaflexiblemannerwhilenotembarkingonlarge-scaleinvestigationswhichmaynotbeappropriateatthistime.Thisstrategyhasseveraldimensionsandisrisk-drivenandcollaborative.Muchofthestrategyiscenteredonanattempttoappropriatelyrelatethebodyofscientificevidencegeneratedforlunardusttoothercelestiallocations.ThelunarduststandardstatesthattheexistingPELisspecificallyrelevanttoalunarmission,andthatitsdirectapplicabilitytoothermissiondestinationsshouldnotbepresumed(Jamesetal.2014).However,ifMarsorothercelestialdestinationscanberelatedtolunardustthroughgeologicalorchemicalsimilarities,itislikelythatlunardustfindingscanbeatleastpartiallyleveragedtotheassessmentofriskforfuturemissions.Recentresearcheffortshavebeendedicatedtotheseefforts.In2015,Dr.ChiuWingLamproducedawhitepaperonMartianDustChemicalRiskAssessment.Inthispaper,Dr.LamaddressedthechemicalcomponentsofMartiandusttohelpidentifyriskcontributorsandtohelpidentifytheirpotentialimpacttocrewhealth(Lam2015).In2016,theNASAHRPhelpedtodesignacallforcollaborativeresearchinregardtocelestialdustandriskassessmenttechniques,issuedintheCelestialDustDataMiningSolarSystemExplorationResearchVirtualInstituteCooperativeAgreementNotice(NASA2016).Thatsameyear,aMarsDustTechnicalInformationExchangemeetingwasheldtocoordinateknowledgesharingbetweenhealthscientists,EnvironmentControlandLifeSupportSystemsexperts,andoperationalplanners,focusingonthechallengesofMartiandustexposure(McCoy2016).Researchinalloftheseimportantareasisongoing.

• RenalStoneFormationRenalstoneformationintheuniquespaceflightenvironmenthasbeenidentifiedbyNASAasaspecificconditionriskrequiringmitigation.Theformationofrenalstones

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posesanin-flighthealthriskofhighseverity,notonlybecauseoftheimpactofrenalcoliconhumanperformance,butbecauseofcomplicationsthatcouldpossiblyrequirecrewevacuationsuchashematuria,infection,orhydronephrosis(Jonesetal.2008).Anuntreatedkidneystoneonalong-duration,exploration-classmissioncanresultinseverepain,dysuria,hematuria,nausea,andvomiting(Jonesetal.2008).Generally,stonesgreaterthan5mmindiameterarelesslikelytobepassedspontaneously(Jonesetal.2008).Whentreatmentordefinitivemedicalmanagementisunavailable,andparticularlywhenstoneprogressionoccurswithgrowthtogreaterthan5mm,nephrolithimpactionmayleadtoureteralobstructioncausinghydronephrosis,acuterenalfailure,infection,orsepsis(Jonesetal.2008).Consequently,kidneystoneformationandpassagehasthepotentialtogreatlyimpactcrewmemberhealthforlong-durationmissionsand,subsequently,threatenmissionsuccess.Giventhehigherprobabilityofkidneystoneformationincrewmembersduringlong-durationmissions(Gilkeyetal.2012;Myers2015),capabilitiesforin-flightscreening,prevention,diagnosis,andtreatmentarehighlydesirable.

Evidenceforriskfactorscomesfromurineanalysesofcrewmembersdocumentingchangestotheurinaryenvironmentthatareconducivetoincreasedsaturationofstone-formingsalts,whicharethedrivingforcefornucleationandgrowthofastonenidus(Whitsonetal.1993,1999;Pietrzyketal.2007).Giventheseverityoftheriskforrenalstoneformation,itisimportanttocharacterizethespaceflightconditionsthatpromotenephrolithiasisinordertotakeappropriatestepstomitigatetherisk.Oneoftheprimaryriskfactorsforrenalstoneformationinspaceistheincreasedexcretionofcalciumduetotheresorptionofbone(Jonesetal.2008).Othercontributingriskfactorsincludedehydration,diet(highsodium,highanimalproteins),lowurinarycitrate,pathological(Randall’splaques),genetics,andenvironmentalderangementssuchasalterationofambienttemperature.Thesefactorscancontributetourinarysupersaturationofsalts,highurineacidity,andreducedurinevolumes,allofwhichcreatefavorableconditionsforcrystallization(Jonesetal.2008).

Therehasbeenonereportedcaseofasymptomaticrenalstoneinspaceflight,whereinacosmonautexperiencedseverelowerabdominalpainthatspontaneouslyresolved.However,thecosmonaut’ssymptomsweresevereenoughtopromptinitialplanningforanemergencyde-orbit;whileresolutionofhissymptomspreventedmissiontermination,thiscasehighlightedthepotentialmissionriskofnephrolithiasis(Lebedev1990).AsofJuly2015,NASAastronautshavehad37symptomatickidneystonesin23crewmembers(beforeorafterflight),butnoreportedin-flightevents.

ThecurrentevidencebaseofdatainlowEarthorbitdoesnotallowustopredictwhatwillhappenwhencrewmembersareexposedtothespaceflightenvironmentforlongerexplorationmissions.Asaresult,developmentofapplicablemodelsprovidesthebestmethodsforpredictionofthelikelihoodofarenalstoneevent.AmodeldevelopedbyKassemiandThompsonusesrenalbiochemicalprofilesofa

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subjectasinputandpredictsthesteady-statedistributionofnucleating,growing,andagglomeratingcalciumoxalatecrystalsduringtransitthroughthekidney(KassemiandThompson2016a).TheKassemimodelindicatesthatthepredictedrenalcalculisizedistributionforamicrogravityastronautisclosertothatofarecurrentstoneformeronEarthratherthantoanormalsubjectinnormalgravity(KassemiandThompson2016a).Themodelalsoindicatesthatanincreaseincitratelevelsbeyondaverageground-basedurinaryvaluescanbebeneficialinthepreventionofnephrolithformation,butonlytoalimitedextent(KassemiandThompson2016b).However,anydeclineinthecitratelevelsduringspacetravelbelowitsnormalurinaryvaluesonEarthcaneasilymovetheastronautintothestone-formingriskcategory(KassemiandThompson2016b).Furtherworkonthismodelwillprovideabetterunderstandingandriskpredictionofrenalstoneeventsinmicrogravity.

Preventionstrategiesareinplacetominimizetheriskofstoneformation.Allastronautsarescreenedbyultrasoundpre-flightforthepresenceofrenalstones,andallreceiveaurinarybiochemicalassessmentthroughmeasurementofstoneriskparameterssuchasurinarypH,volume,andsupersaturationofcalciumoxalate,calciumphosphate,anduricacid(Reyes2016).In2016,post-flightrenalultrasoundswereaddedtoassessthepotentialcontributionofmicrogravityexposuretothedevelopmentofstone(Reyes2016).Ifevidenceofincreasednephrolithriskisidentified,pharmacologicaltreatmentisavailableandmaybeusedtoreducethepotentialforstoneformation.Forexample,potassiumcitrateisusedclinicallytominimizethedevelopmentofcrystalsandthegrowthofrenalstonesbyincreasingurinarycitrateconcentrationandurinepH(Whitsonetal.2009).Thecitratecomplexeswithcalcium,decreasingionactivity,and,subsequently,reducingurinarysupersaturationandcrystallizationofcalciumoxalateandbrushite.Administrationofbisphosphonatesincombinationwitharesistiveexerciseregimenappearstoimprovebonehealthanddecreaseurinarycalciumexcretion,andthusmayreducetheriskofstoneformationduringandpossiblyafterlong-durationspaceflight(LeBlancetal.2013).Allastronautsareeducatedintheinthebenefitsofincreasedhydrationduringflight,asincreasingfluidintake(therebyincreasingurinevolume)canprovidefavorablechangesintheurinarysupersaturationofthestone-formingsalts(Whitsonetal.2001).

Recently,theresearchcommunityhasprovidedevidencedemonstratingthecapabilityofultrasoundtodiagnoseandmonitorstoneformation.Clinicalevidencehassupportedtheabilitytoimagerenalstonesandstudiesconductedduringspaceflighthaveshowntheuseofultrasoundcanbeusedtolocalizeandmeasureureteralstonesize,ordetectthepresenceofobstructionoralternativediagnoses[CategoryIIandIIIevidence](Sargsyanetal.2005;Jonesetal.2009a;Smith-Bindmanetal.2014).Aflexibleultrasoundcapabilityiscurrentlybeingdevelopedtotargettherapeuticsonography,withpossibleinterventionsincludingtranscutaneousrepositioningofastoneorstimulationofureteralperistalsistoenhanceureteralstoneexpulsion(Sorensenetal.2013;Harperetal.2016).Theadditionofthiscapabilitytoexistingimagingtechnologywouldprovideatreatment

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armtothecurrentcapabilityofmonitoringanddiagnosinganin-flightrenalstone,potentiallyreducingtheneedforfurtherintervention.Additionally,researchintousingthesametechnologytofragmentstoneswithultrasound,providinganeffectivetranscutaneouslithotripsycapability,isconsideredhigh-valuefutureresearch(Maxwelletal.2015).

3. TechnologicalInnovationandDesign

• In-FlightDataUtilizationHandlingofmedicalinformationrequiresafundamentalunderstandinghowmedicaldataaregathered,used,stored,andrecalled.Somekeycapabilitiesinonboardmedicalcapabilitiesduringagivenmissionincludecaptureofrelevantmedicalhistoryandexamsinanelectronicmedicalrecord,controlofavailablemedicaldiagnosticsandrelateddevices,streamingandprocessingdatainreal-time,storageandretrievalofdiagnosticimagingandlaboratoryresults,samplingofenvironmentaldatafromavehicle,providingaknowledgebaseofmedicalreferencematerials,andtheprovisionofvideo,audio,andaugmentedrealityassistanceandtrainingondemand.Toreducecrewtimeformedicaldatahandingduringexplorationmissionsandtoensuredataisseamlesslyandaccuratelyrecordedandtransferredtomedicalsupportstaffandarchivaldatabases,itisessentialthatdatatransferbecomesmuchmoreautonomous.Intheterrestrialsetting,electronicmedicalrecord(EMR)systemsarecentraltothemedicaldataarchitecturethatperformsthesefunctions.ManylargeEMRsystems,suchasEpicCareorCentricity,areserver-basedsystemsthatcanspanalargemedicalenterprise,acrosslargedistances,servingallspecialtiesandaspectsofmedicalcare(Mehtaetal.2016;EpicCare2017;GEHealthcare2017).Terrestrialmedicalsystemstypicallyemploylarge-scaledataarchitecturetargetedatthehealthcareindustry.Thesesystemsoftencontroldataforhundredsofthousandsofpatients,andincludeinsuranceandotherancillaryinformationinadditiontopatientcarerecords.Theadditionalcomplexityofhighpatientvolume,billingandinsurancecapabilities,andhigh-leveladministrativefunctionalityisnotrequiredinthespaceflightsetting.AlthoughtheCentricityEMRfromGeneralElectric(GEHealthcare2017)isusedattheNASAFlightMedicineClinictotrackastronauthealthcarerecords,andoccasionallyemployedtomanuallyrecordsomein-flightmedicaleventsrelayedtotheground,thissystemisnotcurrentlyusedin-flight.FurtherflightandhealthdataarerecordedintheLSAHrepositoryorinaMissionMedicalRepositorydatabaseandmaynotberecordedintheEMR(Johnson-Throop2016).AnonboardEMRsystemthatservesasahubofmedicaldatacollection,recordkeeping,andtrainingsuitableforexplorationmissionsdoesnotcurrentlyexist.ThefederalgovernmentdrivestheadoptionofEMRsthroughtheHealthInformationTechnologyforEconomicandClinicalHealthActof2009,whichprovidedincentivesforhealthcareprovidersandorganizationstoadoptEMRs(NationalCenterforHealthStatistics2016).TheCentersforMedicareandMedicaid

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ServicesalsodrivesuniversalEMRadoptionbythedevelopmentofEMRuseandreportingstandards(CentersforMedicaidandMedicareServices2017).ThewidespreadadoptionofEMRsintheU.S.isrelativelyrecent,andnearlyallEMRsandmedicaldevicesuseproprietaryformsofdataexchange.AsdifferentEMRplatformsarenotstandardized,interoperabilitybetweensystemsanddevicesrequirethatuniqueapplicationinterfacesbewrittenforeachnewdevicetoautomatetheinputofdataintoanygivenEMRorforEMRstotransferdatabetweendifferingsystemsandvendors(duPontetal.2009).Datacommunicationstandardsformedicaldeviceshavebeendevelopedandarejustnowbeingadoptedbyindustry(IEEEStandardsAssociation2013).Asaresult,itisnotpossibletopredictwhichmedicaltechnologiesanddataprotocolswillbeinuseatthetimeofanexplorationvehicledesignfreeze.Thus,thedesignoffuturemedicaldataarchitecturemustfocusonthedevelopmentofaconceptualmodelthatisagnostictothefinaltechnologyanddatacommunicationstandardsemployed.Currently,medicaldatamanagementaboardtheISSisnotdesignedforefficientclinicalcare,requiringexcessivecrewtimetocollect,store,andtransmitdataregardinganymedicalevent,datacollection,orevenroutineexamination.WhilesomehealthandmedicaldevicesontheISShavetheabilitytotransmitdatadirectlyviaISSnetworkresources,othersrequirethemanualtransferofdatabycrewmembersfromthesedevicestootherISScomputersforeventualtransfertotheground.Crew-generateddataisoftenmanuallyenteredintovariousdatacollectionapplicationsortransmittedverballythroughvoicecommunicationstothegroundsupportteams.Forexample,crewaudiologyexamdatafromtheISShavebeendownloadasaMatLabfile,withsubsequentpost-processingandmanualentryintotheEMRformedicalcross-referencing(Dicken2012).HealthandmedicaldatathusexistinavarietyofformatsandinnumerouslocationswithintheISSenvironment,andcurrentrecord-keepingoptionsarelessthanideal.SeveralopensourceEMRsystemsexistthatmaybesuitableormodifiedfordeep-spaceuseandimproveddatamanagement(FreeMedSoftwareFoundation2016;OpenEMR2016;OpenMRS2016).However,challengespersistinintegrationanddatamanagementsecondarytothediversityofthesedatasources(Mezghanietal.2015),astherearecurrentlynostandarddataprotocolsformedicaldatasysteminteroperability(Fentonetal.2013).Additionalchallengesinthespaceenvironmentincludedatarateconstraintssecondarytotelemetrybandwidthlimitationsthathinderthesynchronizationofmedicalinformationbetweenthevehicleandtheground.Further,themedicalsystemforthespacevehiclemayneedadditionalfunctionsnottypicallyseeninterrestrialEMRs,suchasmedicalreferences,medicaltrainingprograms,andvehicleenvironmentaldataintegration.Thus,asinglecommercialsolutionwillnotbesuitableforspaceexplorationmissions,andamorerobustsolutionremainstobefound.In2015,theExplorationMedicalSystemDemonstration(EMSD)projectwasundertakentoshowthatseveralmedicaltechnologiesneededforanexplorationmission,includingmedicalinformaticstoolsformanagingevidenceanddecision-

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making,canbeintegratedintoasinglesystemandusedbyanexplorationcrewinanefficientandmeaningfulmanner(RubinandWatkins2014).TheESMDsystemwassuccessfullydemonstratedduringaHumanExplorationResearchAnalog(HERA)missionatNASAJohnsonSpaceCenterandwasfurtherdiscussedwithinternationalpartnersattheCanadianSpaceAgencytofacilitateinteragencycollaborationforanintegratedmedicaldatamanagementandclinicaldecisionsupportsystemforfuturemissions(RubinandWatkins2014).Similarly,theSpaceMEDprojectundertheNSBRI(NSBRI2016)demonstratedanintegratedmedicalsystemcapabilitytoautomaticallycollectdatafromavarietyofsources.Aimsofthisprojectincludedthedevelopmentofaprototypeplatformforfuturemedicalcapabilitiesintegrationandvalidationfortheintegrationoftelemetrically-gatheredphysiologicaldatafromvarieddevicesforpoint-of-caredecision-makingassistance.Theseprototypeprojectshavedemonstratedthefeasibilityofanall-encompassingmedicaldatasupportsystemandpromptedExMCtoinvestinthedevelopmentofamorerobustmedicaldataarchitecture.Anoperationallysoundsystemhasyettobecompleted,andaholisticdataarchitectureapproachtomanagedatasourceheterogeneityandscalabilityisstillneeded.

• MultipurposeDesignandTechnologyDevelopmentandSourcingMedicalcapabilitiesthatarecapableofaddressingmultipleneedsareessentialtocreateanefficientandeffectivemedicalsystem.Idealmedicalcapabilitiescutacrossmultipleapplications,meetingdiverseoperationalneedswhileminimizingmass,volume,andtheneedforcrewtraining.Whilecurrentmedicaltechnologiesattempttoaddressthisissuebyexpandingtraditionaluseofavailablemodalitiestoincludeoff-labelornon-conventionaltechniques,thereisaneedforimprovedtechnologicalapplications,orimprovedtechnologicaldesign,toadvancetheefficiencyandminimizethedesignimpactsofexploration-classmedicalresourceswhileensuringrobustsystemcapabilities.Threeareasidentifiedinwhichdevelopmentofmultipurposedesignsornon-conventionalexpansionofoff-the-shelftechnologywouldbeofparticularuseinexplorationmissionsareimagingmodalities,laboratoryanalyzers,andbiomonitoringdevices.ImagingOneexampleofamultipurposemedicaltechnologyisseeninthecurrentuseofultrasoundimaginginlowEarthorbit.UltrasoundimaginghasbeenusedtoaddressconditionsidentifiedintheEMCLfordiagnosisorpreventivemonitoring,andultrasoundapplicationshavebeencontinuouslyexpandedsincetheintroductionofultrasoundtechnologyaboardtheISSin2002.Initialultrasoundindicationswerelimitedtoretroperitonealandpelvicexamination(NASAMissionPages2016b);however,anonboardexercisein2002demonstratedtheutilityofultrasoundinmicrogravityforaFocusedAssessmentinSonographicTechnique(FAST)exam,arapidultrasoundexaminationtoruleoutinternalbleedinginthecaseoftraumaticabdominalinjury(Sargsyanetal.2005).Ofnote,thisexamwasperformedbyminimallytrainedcrewmembersthroughremoteguidance;despiteground-to-ISScommunicationlatency,clinicalresultsandspeedofimagingweredeemedbetterthanadequateforeffectiveFASTevaluation(Sargsyanetal.2005).In2005,

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ultrasoundimagingwasagainusedinademonstrationofarapidocularevaluationfortrauma-relatedinjury,withminimallytrainedcrewagainsuccessfulinobtainingadequatediagnosticimagingthroughremoteguidance(Chiaoetal.2005).Sincethattime,ultrasoundtechnologyhasbeenutilizedasanimagingmodalityforthemonitoringanddiagnosisofocularchangesrelatedtothespaceflightenvironment(Martinetal.2012)aswellasmanyotherbroadapplicationsoftheimagingmodalityforvariedmedicalconditionsandconcerns(Finckeetal.2005;Sargsyanetal.2006;Kwonetal.2007;Kirkpatricketal.2007;Jonesetal.2009a;Sireketal.2014).Whileultrasoundimagingisusedfrequently,oftensecondarytoitsavailabilityinlieuofanyotherimagingtechnologiesinorbitaswellasitssmallphysicalfootprintandpowerrequirements,thereareproblemswithrelyingoncurrentultrasoundtechnologyforallimagingneeds.Whilemanystudiesinboththespaceenvironment(Sargsyanetal.2005;Finckeetal.2005;Chiaoetal.2005)andinanalogterrestrialenvironments(Shahetal.2009,2016)demonstratethatmotivatedpersonscanbereadilytrainedineffectiveuseofultrasoundformedicaldiagnosis,ultrasoundisoftencritiquedforitsnon-intuitiveimages,longlearningcurve,anddependenceonoperatorskill(KijowskiandDeSmet2006;Lewetal.2007),anditcanbedifficultforminimallytrainedoperatorstogethighdiagnosticqualityimageswithoutsomeformalizedtraining.Evenwithappropriatetraining,someanatomicalstructures,likethecraniumorlungs,arepoorlyimagedusingultrasound,whereanalternativemodalitysuchasradiographywouldgreatlycomplementultrasoundimaging.Advancedultrasoundisbeingdevelopedfordiagnosingortreatingcertainconditions;however,integratingnewtechnologiesintotraditionalultrasoundcapabilitiescanbeachallenging,thoughnotinsurmountable,process.Advancedclinicalmodalitiessuchastherapeuticultrasoundandthree-dimensionalocularscanningoftenrequiredevelopmentofspecialsoftwareortheuseofcustomhardware.TypicalFDA-approvedclinicalscannersdonotreadilyaccommodatethesespecialsoftwareandhardwarecomponents.Asmentionedabove(SeeVI.C.2),aflexibleultrasoundcapabilityiscurrentlybeingdevelopedtotargettherapeuticsonography,withpossibleinterventionsincludingtranscutaneousrepositioningofastoneorstimulationofureteralperistalsistoenhanceureteralstoneexpulsion(Sorensenetal.2013;Harperetal.2016).Additionally,researchintousingthesametechnologytofragmentstoneswithultrasound,providinganeffectivetranscutaneouslithotripsycapability,isconsideredhigh-valuefutureresearch(Maxwelletal.2015).Otherresearchfocusesonthedevelopmentofultrasoundcapabilitytocharacterizebonetrabecularstructureaswellasmethodsforusingultrasoundtoacceleratebonehealinginthecaseoffracture(LamandQin2008;QinandLam2009;Qinetal.2010;Lametal.2011).Theadditionofthesecapabilitiestoexistingimagingtechnologywouldprovideatreatmentarmtomonitoringanddiagnosingin-flightmedicalissues.Similarly,technologythatcanautonomouslyguideultrasoundscanningbyminimally-trainedcrewmembersishighlydesirable.Virtualguidanceisanareawhereaflightprecedenthasbeenestablished(Martinet

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al.2012)andwilllikelycontinuetoproducebeneficialresultsasthesetechnologiesadvance. LaboratoryAnalysisSimilartoimagingchallenges,therearelimitationstocurrenttechnologiesforlaboratoryanalysisofhumanbiomedicalsamplesduringspaceflight.Atpresent,ISScrewsfreezeurineandbloodsamplesforanalysisuponeventualreturntoEarth.Thisstrategyhasprovenadequateforresearch-orientedanalysis;however,terrestrialexperimentsdeterminedthatsomebloodanalytesdegradewithin24hoursafterphlebotomywhenplacedincontrolledstorage,renderingsamplesinadequateformoredetailedorsensitiveanalysis(Zwartetal.2009).Asanalysisofbloodandotherbodilyfluidsisanessentialcomponentofmedicaldiagnosis,long-durationflightandautonomouscapabilitiescallforbloodanalysistosatisfytimelyclinicaldiagnosticandresearchneeds.Portablepoint-of-carebloodanalyzersholdenormouspotentialforrevolutionizingterrestrialmedicinebyprovidingreal-timediagnosticdatainclinics,emergencyrooms,surgeries,andausterelocations.However,researchonsuchpoint-of-carebiomedicaldeviceshaslargelyfocusedondevelopmentofdevicecomponents,suchassamplepretreatment,reagentmixing,andfiltration,ratherthanthedevelopmentofarobustgeneralanalyzer(Nelson2011;Chinetal.2012;Sharmaetal.2015).NASAhasevaluatedcommercialpoint-of-caredevicesforon-orbitbloodanalysis,suchasAbbottLaboratories’i-STATTManalyzer(Jacobsetal.1993).However,useofsuchdevicesinspaceflightcarriespotentiallimitations,includinganyeffectsofmicrogravityondeviceoperation,theneedforanextremelylongshelflife,minimally-trainedpersonnelrequiringautomated,easy-to-useprotocols,andthelackofrefrigeratedstorageconstraints(Nelson2011).Otheraspectsofthespacecraftenvironment,suchastheimpactofradiation,mayplayaroleinthedegradationofreagentsandothersupplies(Duetal.2011;JaworskeandMyers2016),althoughevidenceislackinginthisarea.Further,spacecraftareclosedenvironments,andassuchextremecautionisnecessaryinmaterialsselectionanddevicedesignsecondarytoconcernsofoff-gassingandtoxicityinaclosedenvironment.Finally,spaceflight-specificlaboratoryneedsmaybesignificantlyremovedfromnormaloff-the-shelfapplications.Forexample,effectivediagnosticsforboneloss,muscleatrophy,andotherspaceflight-specificmedicalissuesrequiremeasurementsofanalytesthatmaybeoutsideoftherangeofnormal,terrestrialclinicalpractice(Smithetal.2005;Zwartetal.2009).Finally,resourceconstraintswillrequiremultipurposedevicesthatcananalyzemanymeasurementsfromasinglebloodorotherbodilyfluidsample.Forexample,oneofthemajorconstraintsinspace-basedbloodanalysisforlong-durationflightistheneedforlongreagentshelflife,potentiallylasting3yearsormore.Thei-STATTMtestcartridgesforclinicalchemistrycanmaintainstabilityforuptooneyear,whichisbeyondthemanufacturerspecifications(Smithetal.2004),butothercrucialbloodassaysdegradefaster.Incontrast,urinalysisteststripsmaintainthereagentsinadryconditionbeforeuse,whichismoreconducivetolong

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shelflife.Forexample,RocheDiagnosticsChemstripsTMhavebeenusedsuccessfullyontheISS(Smithetal.2004)andareratedbythemanufactureruptoitslabeledexpirationdataortwoyearsafteropeningitssealedcontainer(RocheDiagnosticsCorporation2001).NASAhascloselyfollowstheexplosionofresearchanddevelopmentinpoint-of-caredevicesthroughmarketsurveysandassessmentofcommercialandnearlycommercialplatformsinindustryandacademia(NelsonandChait2010;Krihaketal.2011).Onesignificantchallengefordevelopersisthatthemarketforpoint-of-carebloodanalysishasbeendominatedbylargeindustryproviders,leavingsmallcompanieswithnewtechnologiesstrugglingtofindorcreateanicheforcommercialviability(Nelson2011).Inordertopromotedevelopmentofaflightworthybloodanalyzerfromevenasmallorunknowndeveloper,NASAhasengagedpromisingplatformdevelopersintechnologydevelopment.TwodeveloperswerefundedbyNASAandtheNSBRItodevelopplatformsforanalysisofwhitebloodcellsanddifferentials:Prof.Yu-ChongTai,CaliforniaInstituteofTechnology,Pasadena,CA,andDr.EugeneChan,DNAMedicineInstitute,Cambridge,MA.Bothdeveloperscreatedbenchtopflowcytometers,althoughneitherreachedthestandardofautomationthatwasdesired.AlaterprototypeoftheDNAMedicineInstitute’srHEALTHdesignfunctionedappropriatelyinthereducedgravityofparabolicflight(NASASmallBusinessInnovationResearch2016).NASAcontinuestofundandmonitorongoingresearchanddevelopmenteffortsofportablebloodanalyzersforexplorationmedicaluse.BiomonitoringBiomonitoringisanareaofgreatinterestforfutureexploration-classmissions.Theabilitytomonitoranastronaut’svitalsignsandresponsetostrenuousactivitysuchasexercise,eitherintermittentlyorinreal-time,isapplicabletobothclinicalandresearchneedsinspaceflight.Thecurrentmonitoringsystemisadequateforbasicmonitoringonanas-neededbasisaboardtheISS.U.S.capabilitiesincluderhythmmonitoringvia12-leadwiredelectrocardiogram(ECG),semi-automatedbloodpressureassessment,andnon-invasivebloodoximetryviafingerprobethatmeasuresoxygensaturation,carbonmonoxide,methemoglobin,andperfusionindex(BarrattandPool2008).Russiancapabilitiesaresimilarwithregardstobasicbiomedicalmonitoringcapabilities(BarrattandPool2008).However,thissystemistimeconsumingtouse;theECGrequiresshavingforapplicationofadhesiveelectrodesandrequiressoftwareinitiationandsignalchecks;thebloodpressuredeviceissensitivetooperatorerrorandcuffsizeselection,patientmovement,andnoise.Theoximeterdisplayisnotuser-friendlyevenfortrainedmedicalprofessionals.Alldevicesrequiremanualdataentryandfiletransfertoinformationsystemsandgroundmonitors,furtherconsumingcrewtime.Finally,alldevicesshowsignificantwear-and-tearaftermultipleusesandextensivecleaning,especiallyasdevicesareoftenusedduringexercise.Amoreefficientsystemisneededtosavecrewtimeandreducethevolumeandmassofconsumablecomponents,particularlyforexplorationmissions.Someadvancedcapabilities,suchasautomatedbloodpressuredevices,havebeenflownforresearchintent,but

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haveyettobeincorporatedintotheonboardmedicalsystemarchitecture.Theintegrationofsmall,easy-to-use,preferablywirelessbiomedicalsensorsthatwillhavetheabilitytomeasure,store,andtransmitphysiologicalparameterswouldprovideawealthofdataforthemedicalandresearchcommunities.Devicesthatmeasurephysiologicalparametersinspacehaveslightlydifferentrequirementsthanthoseusedterrestrially.Forexample,mostECGmachinesusedonEartharelargeandbulkywithnumerousleadsandelectrodes,andinterpretationofECGsrequirestrainingandmedicalknowledge.Inordertoensureanoperationthatwasneithercomplexnorinvasive,thereisinterestindryclothelectrodesandpatchesthatcouldwirelesslytransmitECGdata(Chenetal.2013;Daietal.2016).Built-insoftwarethatprovidesreal-timeanalysisofdataoutputhasbeendevelopedforoff-the-shelfproducts,includingfitnessmonitoringandsleeppatterns,andcouldpotentiallyprovidereal-timefeedbacktocrewmembersduringamissionregardingadherencetoacountermeasureandfitnessregimen,successofapersonalizedsleepschedule,andthelike(Markwaldetal.2016;Jonesetal.2016;Jee2017;Grigsby-Toussaintetal.2017).Withregardstobloodpressuremonitoring,itispreferabletoobtainreal-time,continuous,andnon-invasivemeasurementsformoreaccurateandusefulmonitoring;therefore,thereisinterestinautomaticwirelesscuffsormethodsthatdonotrequireacuffatall(SmulyanandSafar2011;Gauravetal.2016).Evenso,useofreal-time,wireless,noninvasivebiomonitoringraisesnewchallengesrelatedtopatientprivacyandautonomywhenmeasuredinthecontextofaworkenvironment.Researchisongoingineachoftheseareas,andasofyetthereisnoidealdevicethatprovidesnon-invasive,accuratemeasurementsthatmeettheneedsoftheboththemedicalandscientificinterestsofexplorationmissions.However,therapidpaceofmarkettechnologicaldevelopmentwilllikelyoutpaceNASA-fundedordirectedresearchefforts;asaresult,continuedeffortdedicatedtomonitoringmarketandcommercialdevicesthatcanmeettheseneedsislikelytobemoresuccessfulthananattempttodevelopnoveldevicesthataimtofillthisgap.

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VIII.GapsAtthetimeofwriting,theExMCElementhasidentified13researchknowledgegapsdirectlyrelatedtotheriskofadversehealthoutcomesanddecrementsinperformanceduetoin-flightmedicalconditions.Theseare:

• Med01:Wedonothaveaconceptofoperationsformedicalcareduringexplorationmissions.

• Med02:Wedonothavethecapabilitytoprovideasafeandeffectivepharmacyforexplorationmissions.

• Med03:Wedonotknowhowtoapplypersonalizedmedicineeffectivelytoreducehealthriskforaselectedcrew.

• Med04:Wedonothaveadefinedrehabilitationcapabilityforinjuredordeconditionedcrewmembersduringexplorationmissions.

• Med05:Wedonotknowhowtodefinemedicalplanningoroperationalneedsforethicalissuesthatmayariseduringexplorationmissions.

• Med07:Wedonothavethecapabilitytocomprehensivelyprocessmedicallyrelevantinformationtosupportmedicaloperationsduringexplorationmissions.

• Med08:Wedonothavequantifiedknowledgebasesandmodelingtoestimatemedicalriskincurredonexplorationmissions.

• Med09:Wedonothavethecapabilitytopredictestimatedmedicalriskpostureduringexplorationmissionsbasedoncurrentcrewhealthandresources.

• Med10:Wedonothavethecapabilitytoprovidecomputedmedicaldecisionsupportduringexplorationmissions.

• Med11:Wedonothavethecapabilitytominimizemedicalsystemresourceutilizationduringexplorationmissions.

• Med12:Wedonothavethecapabilitytomitigateselectmedicalconditions.• Med13:Wedonothavethecapabilitytoimplementmedicalresourcesthat

enhanceoperationalinnovationformedicalneeds.

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IX.ConclusionsEvidencegatheredfromspaceflight,computersimulation,andgroundanalogs,includinglong-durationisolationinremoteandaustereenvironments,demonstratesthatsudden,incapacitatingmedicaleventscanrapidlycompromisethesuccessofamission.Theabilityofarobustmedicalsystemtoaddresssuchevents,orthelimitationsofsuchasystemwithinthemissionarchitecture,willdeterminetheriskofunacceptablehealthandmissionoutcomes.Limitationsarisefromvehicularconstraintsinmass,power,andvolume,aswellasgapsincurrentmedicalknowledgeandtechnologiesavailabletoadequatelyscreenfor,diagnose,andtreatarangeofmedicalconditions.TheExMCElementhasestablishedspecificknowledgeandsystemgapsthat,ifaddressed,couldsignificantlyimproveupononboardmedicalcapabilitieswhileminimizingtheoverallfootprintandburden,withregardstofinancialexpenseandthecostofcrewtrainingtime,ofanexplorationmedicalsystem.Whilespecificmedicalconcernswillvarydependingonthefeaturesofanexplorationmission,effortsthatstrivetowardscreationofarobustandcomprehensivemedicalcapabilitywillenhancethepotentialformissionsuccess,nomatterthedestination.Thisreviewofevidencerevealsthatmuchworkhasbeendoneinanefforttoachievethesegoals;however,asmannedspaceflightcontinuestoventureeverfurthertowardsmoredistantandchallengingdestinations,therewillcontinuetobeaneedfordedicatedeffortsinprovidingthemostcapablemedicalsupportsystemtoprotectandprovideforourcrews.TheExMCElementwillcontinuetoworktowardsachievingthismission,addressingthegapsdefinedabove,toprovideeffectivecountermeasures,capableresourcesformedicalresponse,andever-improvingtechnologiestoenablemankindtoleavelowEarthorbitandcontinueitsexplorationofspace.

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XI. TeamItisimpossibletoacknowledgebynameallthoseinvolvedinthetesting,analysis,andtheorywithinthedocumentationofworkthatistheExMCElement.Thecoreteamthatisprimarilyresponsiblefortheworkmentionedhereinasofthetimeofwritingofthisreportincludesthefollowingindividuals:NASAJohnsonSpaceCenterErikAntonsen,MD,PhDEricKerstman,MD,MPHDavidReyes,MD,MPHMelindaHailey,RNTinaBayuse,PharmDVernieDaniels,M.S.,R.Ph.MarleiWalton,PhDMikeCangaRonakShah,DO,MPHRobertMulcahy,MD,MPHMichelleUrbina,M.S.RebekahReed,JD,PhDJenniferMindock,PhDDavidRubin,M.S.KerryMcGuire,PhDNASAGlennResearchCenterJerryMyers,PhDKellyGilkeyEmilyNelson,PhDJohnZoldakWilliamThompsonNASAAmesResearchCenterMichaelKrihak,PhDWilliamB.Toscano,PhDNASALangleyResearchCenterKaraLatorella,PhDMatthewSimon,PhD

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XII. ListofAcronymsaBMD:arealbonemineraldensityADUM:AdvancedDiagnosticUltrasoundinMicrogravityAPI:activepharmaceuticalingredientARED:advancedresistiveexercisedeviceBMD:bonemineraldensityCEVIS:cycleergometerwithvibrationisolationandstabilizationConOps:ConceptofOperationsCT:ComputedtomographyDXA:dual-energyx-rayabsorptiometryECG:electrocardiogrameMC:electronicMedicinesCompendiumEMCL:ExplorationMedicalConditionListEMR:ElectronicMedicalRecordEMSD:ExplorationMedicalSystemDemonstrationEVA:ExtravehicularActivityExMC:ExplorationMedicalCapabilityFAST:FocusedAssessmentinSonographicTechniqueFDA:FoodandDrugAdministrationFMEA:FailureModeandEffectsAnalysisHERA:HumanExplorationResearchAnalogHRP:HumanResearchProgramIMM:IntegratedMedicalModeliRED:interimresistiveexercisedeviceISS:InternationalSpaceStationLBNP:LowerbodynegativepressureLSAH:LifetimeSurveillanceofAstronautHealthMEL:MassEquipmentListMONSTR:MedicalOptimizationNetworkforSpaceTelemedicineResourcesNIH:NationalInstituteofHealthNSBRI:NationalSpaceBiomedicalResearchInstituteOSCE:objective-structuredclinicalexaminationsPEL:permissibleexposurelimitPRA:ProbabilisticriskanalysisQCT:quantitativecomputedtomographySLEP:ShelfLifeExtensionProgramSPC:SummariesofProductCharacteristicsT2:secondgenerationtreadmillwithvibrationisolationandstabilizationUSP:UnitedStatesPharmacopeiavBMD:volumetricbonemineraldensity

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XIII.Appendix Table1:MedicaleventsandsymptomsoccurringduringISSmissions(throughISSExpedition40).Numberofevents,person-yearincidence,andnumberofeventsattributedtoextravehicularactivity(EVA)areprovided.(NB:DataareascomprehensiveaspossiblethroughISSExpedition40.Someexpeditionshadmorereportsandinformationthanothers,sodatamaybeheavilyinfluencedbycertainmissionsorcrewmembers.)LSAHDataRequestID:#10912.

Category Complaint N Person-Year Incidence EVA Attributed Orthopedics Arm 2 0.14 2

General 1 0.07 1 Groin 2 0.14 1 Hamstring 5 0.34 Hip 6 0.41 Knee 9 0.62 Leg 3 0.21 Neck 2 0.14 Shoulder 8 0.55 2 Unknown 2 0.14 Wrist 3 0.21 Total 43 2.96 6

Skin Abrasion 9 0.62 3 Dry Skin 4 0.28 Irritation 10 0.69 2 Itch 3 0.21 Laceration 1 0.07 Rash 10 0.69 Total 37 2.55 5

Headache 33 2.27 Total 33 2.27

Nasal Congestion 28 1.93 1 Dry 1 0.07 Irritation 1 0.07 Nose Bleed 2 0.14 Total 32 2.20 1

Back Pain 29 1.99 2 Total 29 1.99 2

Eye Abnormality 9 0.62 Debris 4 0.28 Dry Eyes 4 0.28 Irritation 5 0.34 Puffy 1 0.07

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Watery 4 0.28 Total 27 1.86

GI Constipation 9 0.62 1 Diarrhea 2 0.14 Hemorrhoid 1 0.07 Indigestion 8 0.55 Nausea 1 0.07 Stomach 1 0.07 Total 22 1.51 1

Sleep 1 0.07 Disruption 1 0.07 Hypersomnia 1 0.07 Insomnia 19 1.31 Total 22 1.51

Systemic Fatigue 21 1.44 5 Total 21 1.44 5

SMS 16 1.10 Total 16 1.10

VIIP 14 0.96 Total 14 0.96

Urinary 1 0.07 Decreased Urination

2 0.14

Dysuria 2 0.14 Hematuria 1 0.07 Incontinence 1 0.07 Increased Urination

2 0.14

Nocturia 1 0.07 Retention 1 0.07 1 Urine Reflux 1 0.07 Total 12 0.83 1

Hand 9 0.62 7 Total 9 0.62 7

Psych 9 0.62 Total 9 0.62

Elbow Pain 6 0.41 1 Total 6 0.41 1

Mouth Ulcer 6 0.41 Total 6 0.41

Vestibular 6 0.41 Total 6 0.41

Bruising Due to Blood Draw

Arm 5 0.34 Total 5 0.34

Ear Congestion 5 0.34 1

79

Total 5 0.34 1

Neurologic Loss of Feeling 5 0.34 2 Total 5 0.34 2

ENT Sneezing 2 0.14 Sore Throat 2 0.14 Total 4 0.28

Fingernail Delamination 1 0.07 1 Pain 3 0.21 3 Total 4 0.28 4

Fluid Shift Composition Change

1 0.07

Facial Fullness 3 0.21 Total 4 0.28

Thermal Comfort 1 0.07 1 Feet 1 0.07 1 Hands 2 0.14 2 Total 4 0.28 4

Bruise Arm 1 0.07 1 Hand 1 0.07 1 Shoulder 1 0.07 1 Total 3 0.21 3

Dehydration 2 0.14 Total 2 0.14

Respiratory Bronchitis 1 0.07 Total 1 0.07

Grand Total 381 26.21 43

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Table2.NumberofoccurrencesofmedicalconditionsthathaveaffectedNASAastronautsduringpreviousspacemissions(NASA2017b).DataareobtainedfromLSAHrecordsformedicalconditionsthatoccurredamongUSastronautsduringtheSpaceShuttleProgram,Mir,andISS(throughExpedition13in2006)missions.EVA:extravehicularactivityMedical Condition Events Medical Condition Events Allergic reaction (mild to

moderate) 11

Mouth ulcer 9

Ankle sprain/strain 11 Nasal congestion (space adaptation) 389

Back injury 31 Neck injury 9

Back pain (space adaptation) 382 Nose bleed (space adaptation) 6

Barotrauma (ear/sinus block) 31 Otitis externa 3

Choking/obstructed airway 3 Otitis media 3

Constipation (space

adaptation) 113

Paresthesias 26

Diarrhea 33 Pharyngitis 11

Elbow sprain/strain 12 Respiratory infection 33

Eye abrasion (foreign body) 70 Shoulder sprain/strain 22

Eye chemical burn 6 Sinusitis 6

Eye infection 5 Skin abrasion 94

Finger dislocation 1 Skin infection 13

Fingernail delamination (EVA) 16 Skin laceration 1

Gastroenteritis 4 Skin rash 94

Headache (CO2 induced) 20 Smoke inhalation 3

Headache (late) 49 Space motion sickness (space adaptation) 325

Headache (space adaptation) 233 Urinary incontinence (space adaptation) 5

Hemorrhoids 2

Urinary retention (space adaptation) –

female 5

Herpes Zoster reactivation

(shingles) 1

Urinary retention (space adaptation) – male 4

Indigestion 6 Urinary tract infection – female 5

Influenza 1 Urinary tract infection – male 4

Insomnia (space adaptation 299

Visual impairment/increased intracranial

pressure (space adaptation) 15

Insomnia (late) 133 Wrist sprain/strain 5

Knee sprain/strain 7

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