Applications of Electronic-Nose Technologies for Noninvasive Early Detection of Plant, Animal and Human Diseases


previous item | next item

Citation
Applications of Electronic-Nose Technologies for Noninvasive Early Detection of Plant, Animal and Human Diseases

Material Information

Title:
Applications of Electronic-Nose Technologies for Noninvasive Early Detection of Plant, Animal and Human Diseases
Series Title:
Chemosensors
Creator:
Wilson, Alphus Dan
Publisher:
MDPI AG
Publication Date:
Language:
English

Subjects

Subjects / Keywords:
Bat White-Nose Syndrome ( local )
Diagnostic Pathology ( local )
Disease Biomarker Metabolites ( local )
Electronic Aroma Detection ( local )
E-Nose ( local )
Early Disease Diagnosis ( local )
Human Diseases ( local )
Genre:
serial ( sobekcm )

Notes

Abstract:
The development of electronic-nose (e-nose) technologies for disease diagnostics was initiated in the biomedical field for detection of biotic (microbial) causes of human diseases during the mid-1980s. The use of e-nose devices for disease-diagnostic applications subsequently was extended to plant and animal hosts through the invention of new gas-sensing instrument types and disease-detection methods with sensor arrays developed and adapted for additional host types and chemical classes of volatile organic compounds (VOCs) closely associated with individual diseases. Considerable progress in animal disease detection using e-noses in combination with metabolomics has been accomplished in the field of veterinary medicine with new important discoveries of biomarker metabolites and aroma profiles for major infectious diseases of livestock, wildlife, and fish from both terrestrial and aquaculture pathology research. Progress in the discovery of new e-nose technologies developed for biomedical applications has exploded with new information and methods for diagnostic sampling and disease detection, identification of key chemical disease biomarkers, improvements in sensor designs, algorithms for discriminant analysis, and greater, more widespread testing of efficacy in clinical trials. This review summarizes progressive advancements in utilizing these specialized gas-sensing devices for numerous diagnostic applications involving noninvasive early detections of plant, animal, and human diseases.
Original Version:
Chemosensors, Vol. 6, no. 4 (2018-10-04).

Record Information

Source Institution:
University of South Florida Library
Holding Location:
University of South Florida
Rights Management:
This item is licensed with the Creative Commons Attribution License. This license lets others distribute, remix, tweak, and build upon this work, even commercially, as long as they credit the author for the original creation.
Resource Identifier:
K26-05169 ( USFLDC: LOCAL DOI )
k26.5169 ( USFLDC: LOCAL Handle )

USFLDC Membership

Aggregations:
University of South Florida
Karst Information Portal

Postcard Information

Format:
serial

Downloads

This item is only available as the following downloads:


Full Text

PAGE 1

Review ApplicationsofElectronic-NoseTechnologiesfor NoninvasiveEarlyDetectionofPlant,Animaland HumanDiseases AlphusDanWilson SouthernHardwoodsLaboratory,PathologyDepartment,CenterforBottomlandHardwoodsResearch, SouthernResearchStation,USDAForestService,432StonevilleRoad,Stoneville,MS38776,USA; dwilson02@fs.fed.us;Tel.:+1-662-336-4809 Received:27August2018;Accepted:26September2018;Published:4October2018 Abstract:Thedevelopmentofelectronic-nosee-nosetechnologiesfordiseasediagnosticswasinitiatedinthebiomedicaleldfordetectionofbioticmicrobialcausesofhumandiseasesduringthemid-1980s.Theuseofe-nosedevicesfordisease-diagnosticapplicationssubsequentlywasextendedtoplantandanimalhoststhroughtheinventionofnewgas-sensinginstrumenttypesanddisease-detectionmethodswithsensorarraysdevelopedandadaptedforadditionalhosttypesandchemicalclassesofvolatileorganiccompoundsVOCscloselyassociatedwithindividualdiseases.Considerableprogressinanimaldiseasedetectionusinge-nosesincombinationwithmetabolomicshasbeenaccomplishedintheeldofveterinarymedicinewithnewimportantdiscoveriesofbiomarkermetabolitesandaromaprolesformajorinfectiousdiseasesoflivestock,wildlife,andshfrombothterrestrialandaquaculturepathologyresearch.Progressinthediscoveryofnewe-nosetechnologiesdevelopedforbiomedicalapplicationshasexplodedwithnewinformationandmethodsfordiagnosticsamplinganddiseasedetection,identicationofkeychemicaldiseasebiomarkers,improvementsinsensordesigns,algorithmsfordiscriminantanalysis,andgreater,morewidespreadtestingofefcacyinclinicaltrials.Thisreviewsummarizesprogressiveadvancementsinutilizingthesespecializedgas-sensingdevicesfornumerousdiagnosticapplicationsinvolvingnoninvasiveearlydetectionsofplant,animal,andhumandiseases. Keywords:batwhite-nosesyndrome;diagnosticpathology;diseasebiomarkermetabolites;electronicaromadetection;e-nose;earlydiseasediagnosis;humandiseases 1.IntroductionThedevelopmentofelectronic-nosee-nosetechnologiesanddevicesfordiseasediagnosticapplicationshasacceleratedrapidlyoverthepastdecade.Theimpressiverateofprogressine-nosetechnologicaldevelopments,specicallyfordisease-detectionapplications,hasbeenachievedlargelythroughdiscoveriesofnewelectronicmethodsandassociatedoperationalmechanismsforchemicaldetectionofcomplexgaseousmixtures,primarilyconsistingofvolatileorganiccompoundsVOCs.Improvementsinsensortechnologiesandarrays,machine-learningmethodssuchasarticialneuralnetworksANN,disease-specicreferencelibrariesanddatabases,data-analysissoftware,andidenticationofdiseasebiomarkersalsohavecontributedtoadvancementsine-nosediagnosticmethods[1–8].Thesekeyadvanceshaveresultedinnumerousnewapplicationsofe-nosetechnologiesusefulforthedetectionandidenticationofdiseaseswithmanydifferentcausesbiotic,abiotic,andgeneticwhichoccurinvariousformsoflivingorganismsincludingplants,animals,andhumans[7,9,10].Applicationsofe-nosedevicesforidenticationofbioticcausesofdiseaseprimarilyinvolvedetectionofmicrobialpathogensonorwithindiseasedorganisms[11–13]. Chemosensors 2018 , 6 ,45;doi:10.3390/chemosensors6040045www.mdpi.com/journal/chemosensors

PAGE 2

Chemosensors 2018 , 6 ,45 2of36Electronic-nosedeviceshavebeenusedextensivelysincethe1980sbyawiderangeofgovernmentalagenciesandcommercialindustriesfromaerospace[14–17],agriculturalandforestry[10,13,18,19],biomedicalforpoint-of-caretestingPOCT[8,12,20,21],cosmetics,drugandpharmaceutical[5],environmentalprotection[18,22–24],foodscienceandtechnologies[12,25,26],tomanyotherspecializedusesforbiosecurity,disasteroperationsandrecovery,forensics,militaryoperations,regulatory,lawenforcement,transportationsafety,andforscienticresearch[5,27].Oneofthemostimportante-noseapplicationscommonamongvariousindustrialuseshasbeenforqualityassuranceandqualitycontrolQA/QC.E-nosedevicesareusedtocontinuallyevaluatemanufacturingprocessesandmethodstomeasureandmaintainthequalityofcommercialproductsandtoensurethatproductsandservicesconsistentlymeetconsumerexpectations.Assessmentsofqualitycontrolsinmanufacturingprocessesareessentialformaintainingproductuniformityandconsistencyforbrandrecognitionandconsumersatisfaction[13].Inthebiomedicalandrelateddrugindustries,applicationsofe-nosedeviceshaveincreaseddramaticallyoverthepastdecadeduetotheneedfornew,simplerandeasytousetechnologieswiththecapabilitiesofprovidingrapid,noninvasiveaccuratediagnoseswithminimalcosts[20].Electronic-nosedevicesalsoarepotentiallyusefulforconrmingpatientidentityanddeterminingthenecessityfornonreversible,criticalmedicalprocedurese.g.,biopsies,correctivesurgeries,organandlimbremovals,orimplantationsofdevicesorprostheticsappliedtospeciclocationsorpartsofthehumanbody[28,29].Thegreaterease-of-useofe-nosedevicesbydoctorsandclinicaltechnicianshasmadee-noseclinicaltrialsandinstrument-trainingoperationssimpler,allowingshorterstartuptimesforthedevelopmentandinitiationofelectronicnose-baseddiagnosticclinicalapplicationsandprocedures.Chemicalstudiesofdiseasemetabolomicshaveprovidedcriticalinformationexplainingtheeffectsofdisease-developmentalprocessespathogenesis,mechanismsofdisease,andeffectsonhostmetabolicprocessesandpathwaysonhostpathophysiologywhichhaveprovidedeffectivechemicalcluesintotheidentitieschemicalclassesofdisease-associatedtargetmoleculeschemicalbiomarkersofdiseasemostindicativeofandstronglycorrelatedwiththepresenceofdiseasewithinlivingorganisms[1,6,7,30–32].Thewidelyvaryingchemicalcompositionofdifferentlivingorganismsaffectedbydiseaseprocesseswhetherplant,animal,orhumanhosttypes,haspresenteduniqueanddifferentchallengestodiagnosticiansinusinge-nosedevicesfordiseasedetection.Mostkeyadvancesinthedevelopmentofe-noseinstrumentsandapplicationsfordiseasediagnosticspredominantlyhavebeenrelatedtoimprovementsinreninge-nosesensorarrays,developmentanduseofnewsensortypeswithnoveloperationalmechanisms,patternrecognitionalgorithmsandanalysissoftware,application-specicreferencedatabases,andmoreeffectivedata-analysesprocedures.Arecentemergingtrendinnext-generationdiseasediagnosticshasbeentheuseofe-nosedevicesforinitialpreliminarydiagnoses,followedbyconrmationsifnecessarythroughdetectionandidenticationofkeychemicaldiseasebiomarkersmostcorrelatedwithorestablishedaschemicalindicatorsofspecicdiseasestatesfoundwithinahostbody.Theareaofmetabolic-chemistrydiagnosticsknownasmetabolomicsinvolvestheidenticationandquanticationofmetabolitesfoundinclinicalsamples.Thisareaofstudyislargelyresponsibleforidentifyingdiseasebiomarkers.Specicchemicalbiomarkershavebeendeterminedformanytypesofdiseases.Ashortlistofdiseasebiomarkersdiscoveredforspecicdiseasesofplant,animal,andhumanhostsaresummarizedwithparticularexamplesforeachdisease-typecategoryandbiomarkerchemicalclassinTable1.MoredetailsonbiomarkerswillbecoveredinSection2onBiomarkerMetaboliteE-noseSignatures.Volatilechemicalbiomarkersofdiseaseoccurinawiderangeofchemicalclassesthatgenerallyprovidecluestothetypesofhostmetabolicpathwaysaffectedbyindividualdiseases[7].Studiesinphysiopathologyattempttodeterminethepathwaysaffectedbydiseaseinordertounderstandtheprecisemechanismsbywhichuniquediagnosticbiomarkersareproduced.

PAGE 3

Chemosensors 2018 , 6 ,45 3of36 Table1.ChemicalclassesandmolecularstructuresofrepresentativevolatileorganiccompoundsVOCsbiomarkermetabolitesassociatedwithspecicplant,animal,andhumandiseases. Disease 1 Pathogen Host 2 LocationBiomarkersChemicalClassMolecularStructureReferences Fireblight Erwiniaamylovora AppleLeaves Phenylethyl alcohol Benzenealcohol [33,34] Graymold Botrytiscinerea TomatoLeaves -CopaeneTricyclicsesquiterpene [35] Powderymildew Oidiumneolycopersici TomatoLeaves1-FluorododecaneFluoro-aliphaticHC [36] Bovine tuberculosis Mycobacteriumbovis CattleLungs 1,3-Dimethylbutyl cycloalkane Cycloalkane [37] Infective endocarditis Staphylococcus spp.HumanHeartMethanethiolOrganosulfur [38–41] COPD,CF Abiotic, noninfectious HumanLungsNitrotyrosineTyrosinederiv. [42] 1Diseasenameabbreviations:CF=cysticbrosis;COPD=chronicobstructivepulmonarydisease;2Planthostscienticnames:AppleMalusdomestica;TomatoLycopersiconesculentum.

PAGE 4

Chemosensors 2018 , 6 ,45 4of36Animportantcontroversyindiseasediagnostics,debatedamongpathologists,diagnosticians,physiciansandotherhealthcareexperts,involvesdeterminingwhichtechnologiesaremostusefulforfacilitatingthedevelopmentofmoreefcient,rapid,andreliableclinicaldiagnosticproceduresforthefuture.Choicesinselectingimproveddiagnostictechnologiesmusttakeintoaccountthetrendtowardnewermedicalgoalsofachievingmorerapiddiagnosticresultsandeffectivediseasetreatmentsolutionsthroughacceleratedclinicalprocedures,butwithcheapertotalhealthcarecosts.Amongthetwomajorcategoriesofnoninvasivediagnostictechnologiesbeingmostdebatedaretheuseof:sophisticatedchemical-analysisinstrumentsandsimplersensor-arraytypedevicessuchase-nosesthatdonotidentifyspecicchemicalcomponentsindiagnosticsamples.Thesalientfactsanddetailsofviewpointsandargumentssurroundingthisdebatewillbeconsideredherebasedonnewresearchndings.Theultimateaimfordeterminingwhichnewtechnologiesarelikelytoimproveondiseasediagnosticmethodsandproceduresistoascertainwhichapproachesaremostlikelytomeettheneedsandprogressivegoalsofmodernmedicalservices.Thedevelopmentofdisease-detectionmethodologiesutilizinge-nosedevicesrequiresathoroughunderstandingofhostphysiologyandmetabolicpathwaysaffectedbydiseaseprocesses,differentmechanismsofdiseasecausedbybioticandabioticcausalagents,andchemicalclassesofabnormalVOCsreleasedduetoeffectsofpathogenesisonhostmetabolisms.Theseuniquecharacteristicsofhost-pathogenchemicalinteractionsareconsideredandexploredforeachtypeoflivinghostplants,animals,andhumanstoprovidedetailsandexamplesofhowe-nosedeviceshavebeenmodiedanddevelopedspecicallyasdiagnostictoolsfordifferenthost-diseasesystems.Thisapproachtakesintoaccounttheparticularchemicalnatureofdiseaseinteractionsinlivingorganismsthatvarydependingontheuniquebiochemicalcharacteristicsofthehostandthoseofdiseaseetiologicalcausalagents.KnowledgeofspecicgaseousmixturesofVOCsproducedinassociationwithindividualhostsinresponsetodifferentdiseasetypesandprocessesprovidesessentialinformationabouttargetcompoundsoftenreferredtoaschemicaldiseasebiomarkersneededfordevelopingthemosteffectiveapproachesfore-nosediseasedetection.Thisreviewprovidesadetailedsummaryofrecentelectronic-nosetechnologiesdevelopedoverthepastdecadeforspecicapplicationsindetectinganddiagnosingdiseasesfoundinplant,animal,andhumanlivinghosts.Theliteraturesearchstrategyadoptedforthisreviewwasbasedonselectioncriteriathataredifferentfromthosespeciedbypreferredreportingitemsforsystematicreviewsandmeta-analysesPRISMAorqualityofreportingofmeta-analysisQUOROMguidelines.Theuseoftheseparticularguidelines,relevanttoreviewsofdiagnosticpractices,aredesignedtoprovideinformationforevaluatingthesafety,risks,benets,efcacy,andpotentialharmoradverseeffectsassociatedwiththeuseofmedicalprocedures,diagnosticmethods,resultsorconclusionsdrawnfromresearchstudies.Reportingsuchinformationisbeyondthescopeandobjectivesofthisreviewbecauseofthepotentialforintroducingbiasinimpliedjudgmentsofthesignicanceorpotentialusefulnessofdiscoveriesandinrecognizingtheinherentvalueofscienticcontributions.Forthesereasons,theauthorhasselectedpapersforinclusionandreportedinformationbasedonobjectivecriteriaindicativeoftheabsolutescienticvalueofpresentedinformation,includingusefulnessofindividualpapersin:providingnewinformationrelatingtothefull-rangeofe-nosedetectionmethodsandtechniquesavailable,offeringnewconceptsassociatedwithdiseasediagnosticsandtheoryrelatingtodiseasedetection,indicatingpotentialimprovementsonexistingdiagnosticmethods,andsummarizingnewrecentpotentialapplicationsforclinicaldiagnosisofdiseases,particularlythosenotpreviouslytreatedorcoveredintheliterature. 2.BiomarkerMetaboliteElectronic-NoseSignaturesMostformsofhumancancers,andotherterminalillnesses,oftenaredetectedinadvancedstagesofthedisease,resultinginpoorpatientsurvivalrates.Consequently,thereisanimminentneedforthedevelopmentofprophylacticdisease-screeningproceduresthatprovidemeansfordetectingmajorlife-threateningdiseasesatearlystagesofdiseasedevelopment[8,21].Thereisagrowingtrendoverthe

PAGE 5

Chemosensors 2018 , 6 ,45 5of36pastdecadetodevelopdualapproachestodiseasediagnosticsthatutilizemorerapiddisease-screeningmethodse.g.,electronicchemicalsensorsorsensorarraysincombinationwithproceduresbasedonthedetectionofdisease-specicchemicalbiomarkerstoconrmdiagnoses[7,43,44].Diagnosticclinicalproceduresallowingefcient,noninvasive,painless,andaffordabledisease-screeningswithhighspecicityandsensitivityareessentialforachievingeffectivediseaseprevention.Inorderforearlydisease-detectionsystemstobepossible,specicandeffectivechemicalbiomarkers,mosthighlycorrelatedwithdiseaseincidence,musttobeidentiedforindividualdiseasesanddetectedatearlypresymptomaticstagesofpathogenesiswithincomplexheadspacevolatilesVOC-metabolitemixturesderivedfromdiagnosticsamplesobtainedfromdiseasedindividuals.ArecentstudyofurinaryVOCheadspacemetabolitesassociatedwithheadandneckcancerHNCpatientswasperformedusingheadspacesolidphasemicroextractionSPMEcoupledtogaschromatographymassspectrometryGC–MStoidentifyandcharacterizeurinaryVOCalterationsspecictoHNC[45].Univariateandmultivariatestatisticalanalysesrevealed28metaboliteswithhighestcontributiontowardsdiscriminationofHNCpatientsfromhealthycontrols.Furthermore,fourVOCmetabolitesintheurineheadspacevolatileprole,including2,6-dimethyl-7-octen-2-ol,1-butanol,p-xyleneand4-methyl-2-heptanone,wereidentiedaspossiblechemicalbiomarkermetaboliteswithhighestsensitivityandspecicitytoHNC.ThisinformationprovidedbiochemicalcluestoseveraldysregulatedmetabolicpathwaysinHNCpatientswhichcouldpotentiallyhelpunravelnovelmechanisticinsightsintoHNC-diseasepathophysiologybyimprovingunderstandingofHNCdiseasemechanismstofacilitatenon-invasivebiomarker-basedapproachestoHNCdiagnosis.Thedevelopmentofrapidanalyticalstrategiesfordetectingandidentifyingurineandotherdiseasebiomarkers,includingdetermininglimitsofdetectionandlimitsofquanticationofpotentialbiomarkers,haveplayedavitalroleinresearch,discoveryandconrmationofbiomarkermetabolitesmostassociatedwithspecicdiseases[46].Theidenticationoftumor-specicVOCemissionsignaturesfromclinicalsamplesofdiseasedpatientshasincreasedsignicantlyinrecentyearsduetostudiesfocusingonthedevelopmentofacancer-characteristic“odorngerprints”.Thisworkhasbeenconductedthroughapplicationofsensorialorsenso-instrumentalanalysesthatchemicallycharacterizeassociatedcomplexheadspaceVOCmixturesofbiologicaluids,suchastoidentifyprostatecancerPCa-specicbiomarkersinurine,toimproveontraditionaldiagnosticprocedures.[47].Thesearchforimproved,morerapidandeffectivemethodsforaccuratediseasediagnoseshaveledmanyresearchers,physicians,anddiagnosticianstowardtwonewerapproachestodiseasediagnosticsforclinicalPOCTthatdifferconsiderablyfromconventionaldiagnosticmethodsthatutilizeexpensivetime-consuminglaboratorytests[7,8].Thesetwomajorapproachesinvolvetheuseofelectronic-nosedevicesandmetabolomicanalyses.Recentreviewssummarizedtheadvantagesanddisadvantagesofe-nosevs.metabolomicsapproachestodiseasediagnostics[7,44].Metabolomics,relativetodiseasediagnostics,involvesthestudyofchangesinthecompositionandconcentrationsofcellularvolatileandnonvolatile,primaryandsecondarymetabolitesproducedasaresultofdiseaseprocessespathogenesis.Metabolomicmethods,suchasprotonandcarbonnuclearmagneticresonanceNMRspectroscopy,areusedtodeterminetheprecisechemicalcompositionandquantitationofcomponentspresentindiagnosticclinicalsamples,includingidentifyingdisease-specicchemicalVOC-biomarkers.StudiesofanimalandhumanpulmonarydiseaseshaveidentiedpotentialbiomarkersfromanalysesofVOCprolesinexhaledbreathwhichmaybeusedtodeterminethecauseofspecicdiseasesandimprovetheaccuracyofdiseasediagnosticprocessesforpneumoniaandotherrespiratorydiseases[48].AsummaryofmetabolomicdatacollectedfromseveralstudiesonpneumoniashowedthesameconsistentVOCswithchangesinconcentrationsofhealthyvs.diseasedpatientsbasedonVOCprolesbasedonbreathomics.Thestudyof`breathomics'involvestheanalysisofVOCsinexhaledbreaththatresultfromcellularmetabolism.Analysesoftheexhaledbreathofpneumoniavs.healthypatientsindicatedconsistentincreasesordecreasesintwenty-veVOCsderivedfromelevenchemicalclasses[49–52].AlthoughtheoccurrenceofchangesinlevelsorconcentrationsofVOCswereconsistent,thedirectionofchangewasnotalwaysconsistent.Somevolatilemetabolitesincreasedor

PAGE 6

Chemosensors 2018 , 6 ,45 6of36decreasedinconcentrationwithinthebreathofpneumoniapatientscomparedtohealthypatients,buttheinvolvementofthesameVOCsindicatedeffectsoncertainmetabolicpathways.Differenttypesofchemicalbiomarkersareproducedthatmayserveasindicatorsorevidenceofspecicdisease.Diseasebiomarkershavebeenclassiedbydifferentclassicationsystemsthatgenerallybasethechemicalbiomarkertypeontheoriginofthechemicalspeciesbeingdetected.Thehighesthierarchicalcategoriesofchemicalbiomarkersaredividedintotwoprimarygroups.Theendogenousbiomarkersincludethosethatoriginatefromwithinthebodyandareformedfromeithernormalphysiologicalprocessesorfromabnormalmetabolicprocessescausedbydisease.Exogenousbiomarkersoriginatefromsourcesoutsideofthebodyandenterthebodythroughinhalation,ingestion,absorptionthroughtheskin,orbysomeothermeans[7,8].Endogenousbiomarkersmaybesubdividedintoadditionalcategoriesincludingdisease-predispositionbiomarkers,diseasebiomarkers,pathogenbiomarkers,andgut-microbiomemicroorabiomarkers[7].Exogenousbiomarkersgenerallyarenotconsidereddirectindicatorsofinfectiousdiseases,butmaypotentiallyserveaspredispositionindicatorsofdisease[53,54].Arecentanalysisofchemicalbiomarkersproducedbythesixmostfrequentpathogenicbacteriacausinghumansepsis,includingStaphylococcusaureus,Streptococcuspneumoniae,Enterococcusfaecalis,Pseudomonasaeruginosa,Klebsiellapneumoniae,andEscherichiacoli,indicatedthatspecicVOCscouldbeusedaspotentialbiologicalmarkerstodiagnosesepsisincriticallyillpatients[1].AsystematicreviewrevealedthatallsixbacteriaproducedspecicVOCsincommonsuchasisopentanol,formaldehyde,methylmercaptan,andtrimethylamine.AlthoughhumansdonotproducetheseVOCs,theyareofmicrobialoriginpathogenbiomarkersandserveassepsis-indicativechemicalmarkersforthesesixbacterialpathogens.Otherdifferenttypesofvolatilebiomarkerswerefoundtobeusefulforidentifyinganddiscriminatingbetweeneachbacterialspecies:isovalericacidand2-methylbutanalforStaphylococcusaureus;1-undecene,2,4-dimethyl-1-heptane,2-butanone,4-methylquinazoline,hydrogencyanide,andmethylthiocyanideforPseudomonasaeruginosa;andmethanol,pentanol,ethylacetate,andindolefor Escherichiacoli . 3.Electronic-NoseDetectionofBioticDiseasesMostelectronic-nosedevicesdonothavethecapabilityofidentifyingorquantifyingindividualVOCspresentincomplexgaseousmixtures[9].Nevertheless,e-nosedeviceshavebeenusedtoidentifyindividualVOCsinsimplemixturesandprovidemanyadvantagesovercomplexanalyticalinstrumentsbecausetheyareeasilyoperatedatrelativelylowcosts,haverapidlyrespondingsensorarrayswithfastrecoveriesafteranalysis,goodprecision,andtheexibilityofdetectingaverylargevarietyofVOCsfrommanydifferentchemicalclasses.Alargenumberofe-noseinstrumentshavebeendevelopedbasedonawiderangeofoperatingVOCsensor-detectionprinciples[5,6].Sensorresponsesfromane-nosesensorarrayaredigitallytranslatedbyatransducertogenerateacharacteristicresponsepatternforallVOCspresentinsampleheadspacethatindicatesthesourceofthevolatilechemicalemissionswhencomparedtoreferencedatabasesofresponsepatternsfromknownsampletypes[5,10,55].Thus,differencesinVOCscompositionsareindicatedbyuniquee-noseproles,whichmaybecomparedtotheoverallvariationofapoolofreferencegassamples.Electronic-nosetechnologiespreviouslyhavebeendevelopedfornumerousapplicationsinawiderangeoffields,includinghumanandanimaldiagnostics,foodquality,andenvironmentalsafety[5,26,56,57].Morerecentusesofe-noseinstrumentsinagriculture,botany,forestryandrelatedplantscienceshaveincludedplantandcultivaridentication,woodidentication,anddetectionofpesticideresidualsonthefoliageofcropplants[13,19,22–24,58].Additionally,e-noseshavebeentestedfordiagnosticapplicationsonawidevarietyofplantpathosystemswithexcellentperformancescomparabletoGC-MSintermsofefcacywhilerequiringloweranalyticalandpost-analysistimeandwithloweroperatingcosts[9].Thee-nosemethodsdevelopedandusedfordiagnosisofdiseasesinplanthostsvarysignificantlyfromthemethodsusedfordetectionofhumanandanimaldiseases.Forexample,methodsofsamplepreparationandanalysisrequiredfore-nosedetectionofplantdiseasesaresignificantlydifferentduetostructuralandchemicaldifferencesinplantcellcomponentswithinplanttissuesamples.

PAGE 7

Chemosensors 2018 , 6 ,45 7of36 3.1.PlantDiseaseDetectionConventionalmethodsusedfordiseasediagnosisinplantshavebeenbasedonhostsymptomology,pathogenmorphologydirectmicroscopicidentification,serologicaltests,anddisease-associatedmetabolicassays[59–61].Theseapproachesarenotsufcientorusefulfordiseasedetectionandidenticationwhendisease-associatedsymptomsoccurinlatephasesofinfectionpathogenesis,pathogenidenticationisdifcult,orwhencurativedisease-controltreatmentsarelargelyineffective[62,63].Moleculartechniquesfordirectdetectionofpathogensbytheirintra-orextra-genomicDNA-sequences,suchaspolymerasechainreactionPCRforDNA-amplificationfollowedbysequencing,havebeenwidelyadoptedinternationallytoachieveearlydiagnosisfromplantmaterialsindependentlyofhostsymptomology.Polymerasechainreactionhasbeenrecognizeduniversallyasawell-established,oftenrstmethodofchoiceforrelativelyquickdiagnosesofnumerousplantandanimaldiseaseslargelybecauseoftheverylargenumberofknownDNAsequencesnowavailablefromGenBankattheNationalCenterforBiotechnologyInformationNCBI,andothergeneticsequencedatabases,foridenticationofspecicpathogensassociatedwithknownbioticdiseases.Pathogen-specicdetectionbyPCRandDNAsequencingispossibleduetothehighspecicityofthemethod,highsensitivityachievableduetopathogenDNA-amplication,andlowoperationalcostsnowpossibleduetorobotics,highthroughputDNA-sequencingapparatiavailable,andassociatedautomatization[59].However,thereareanumberofdrawbackstoPCRsuchas:requirementsforthedesignandvalidationofPCR-primersfortargetedDNAsequencesofspecicphytopathogens,theunavailabilityofreferenceDNAsequencesforcertainpathogens,insufcientpathogentemplateDNAavailableatearlystagesofinfectionrequiringhighhosttissue-samplingrates,devisingeffectivepathogenDNA-extractionmethodsforisolationfromhosttissue,involvesdestructivesamplingofhosttissuewithpotentialassociatedeconomiclossesimpactsoncropsalability,particularlyifforpost-harvestproductscrops,DNA-detectionespeciallywithquantitative,qPCRdoesnotnecessarilyindicatethatthepathogenisalivewithinahostitisanon-viabilitytestofpathogenDNApresence,andmanystepsinPCRcanpotentiallyfailtoamplifypathogenDNAprecludingtheyieldofaproductforsequencing,andthealwaysubiquitousandnumerousopportunitiesforcontaminationofdiagnosticsamplesfrommanysourcespriortoPCRmayinvalidatetheresults;allofwhichcanprecludeeffectivediagnosis.Theselimitationshavepromptedpathologistsanddiagnosticianstolookforotherdiagnostictoolsandmethodswithdifferent,non-DNA-dependentapproachestodiseasedetectionthatarenoninvasivedonotrequiredestructivesampling.Newalternativemethodsforearlydiagnosisofplantdiseases,besidestheoftencumbersometraditionalmoleculartechniques,havebeendevelopedtoimprove,simplify,increaseeffectivenessofearlydetection,andminimizedamagetosampledplantmaterial.Manyalternativemethodsofdiseasedetectionhavebeenreviewedpreviously[59,64,65].Electronic-nosedevisesareparticularlywellsuitedfornoninvasiveearlydiseasedetectionduetotheirlowcost,highprecision,andsensitivitytoprecisecomplexmixturesofVOCs[6,44].E-nosedetectionofgaseousemissions,containingabnormalVOCsreleasedfromdiseasedhosttissuesinsampledheadspace,provideopportunitiesforeffectivenoninvasivedetectionofspecicdiseasesthathavebeenpreviouslycorrelatedandcloselyassociatedwiththeproductionofparticularcombinationsofvolatilemetabolites.Aromasignaturedatabasesofdifferentplantsampletypeshealthyvs.diseased,containedwithinreferencelibrariesofe-noseinstruments,aregeneratedfromprioranalysisofknownclinicalsamplesofspecichostplantsusuallyfromparticularhealthyordiseasedplantparts—i.e.,fromroots,stems,leaves,owerorotherreproductivepartsusingneuralnetorsimilartrainingalgorithms.ThesesignatureVOC-proledatabasesconsistofdiagnosticpatternsproducedfromthecollectivemultisensoryarrayoutputsassembledtogethertoformasignaturesmellprintpatternwiththeoutputsofeachsensortypeusuallyrepresentedbyabargraph[10].Thestrengthorintensityofeachsensorresponsefromthesensorarray,representedbythesmellprintpattern,isdeterminedbythecollectiveeffectsofallVOCcomponentswithinthesampledheadspace.Validationofe-nosetrainingdatabasesofknownsample

PAGE 8

Chemosensors 2018 , 6 ,45 8of36typesinreferencelibraries,usingsamplesnotusedfortraining,isrequiredtoassurethatclassicationalgorithmsprovideeffectivesamplediscriminations[66,67].Themainadvantagesofusinge-noseinstrumentsandmethodsforearlydiseasedetectionsarethattheseallowfor:noninvasivenondestructivediagnosticsampling,diseasedetectioninbulkhostsamples,capabilitiesofdetectingmultiplediseases,levelsofdetectioncanbeadjustedthroughtrainingandspecicationofdiscriminationlevels,sensorarrayselectionfortargetingspecicclassesofdisease-associatedVOCsbeingdetected,andmultipleclassesofpathogensmaybedetectedusingdifferentreferencedatabaseswiththesamee-noseinstrument[9].Thekeycharacteristicsofe-nosedeviceswhichmakethemadvantageoustodisease-diagnosticapplicationsareportability,affordability,easeofusewithrelativelyminimaltraining,andeffectivenessindetecting,identifyingandclassifyingthetypesanddigitalsignaturepatternsofcomplexVOCmixturesreleasedfromtissuesofspeciclivingorganicsourceswithoutidentifyingindividualchemicalspeciesindiagnosticsample[10,44].InitialinvestigationstoassessbiochemicalchangesinplantphysiologyassociatedwithdiseasehaveinvolvedstudyingchangesinVOC-emissionsoffruitandvegetablecropplantsusingGC-MS[34,62,68–76].Thesestudiesweredonewithmetabolomicsanalysestoassessbothqualitativeandquantitativechangesinspecicvolatilemetabolitesofdiseasedplantscomparedwithhealthyplants.Thisworkalsoincludedsearchesforspecicchemicalbiomarkerscompoundsthatmaybeindicativeofspecicdiseases.ResearchinvestigatingchangesinplantVOC-emissionsassociatedwithplantdiseaseseventuallyledtoanewapproachofcollective-VOCanalysisofallvolatilemetabolitesreleasedfromdiseasedplantpartsusingsensorarraysinelectronic-nosedevices.Therstpioneeringworktodemonstrateapplicationsofe-nosedevicesandmethodsfordetectionofplantdiseaseswasdonebasedonresearchofrootandbole-rotfungithatcausediseasesanddecaysofforestandlandscapetreesandotherwoodyplants[10,77].PartofthisinitialworkrequireddevelopingthecapabilitiesofdiscriminatingbetweenvolatilesfromdifferentspeciesofplanthostsbecausehostvolatilesareessentialbackgroundVOCcomponentspresentinadditiontoabnormalVOCsproducefrompathogensthemselvesandhost-inducedplantvolatilesproducedasaresultofdisease[19].TheimportanceofmaintaininglowrelativehumidityRHinsamplingairwasfoundtobeakeyrequirementforeffectivee-nosedetectionanddiscriminationsofheadspaceVOCsfromdifferentsampletypes.Thisworkeventuallyledtoinvestigationsofe-noseplantdiseasedetectioninwoody,smallfruitandvineplantsblueberries,kiwis,grapes,herbaceousfruitsstrawberries,pineberry,vegetablespotatoes,onions,carrots,andeldcropplantscorn,wheat,barley,cotton.Anabbreviatedlistofawidevarietyofplantdiseasetypesdetectedusinge-nosedevicesinvariousplanthostsaresummarizedinTable2.Thee-noseapplicationsdevelopedfordetectionofindividualdiseasesareorganizedbasedonanalphabeticallistingofplanthostsbycommonname.Someadditionalinformationprovidedincludestheplantpartorlocationwherethediseaseoccursonthehost,thenameofthedisease,thepathogenorpestknowntocausethedisease,thee-nosemodelalongwithtypeandnumberofsensorswithinthesensorarrayusedfordiseasedetection,individualreferencesdocumentingtheseresults.Anumberofvariablefactorsmayaffecttheperformanceandeffectivenessofe-nosediscriminationsinplantdiseasediagnoses.SomeofthemostimportantsourcesofvariabilityinVOCprolesincludeRHofsamplingair,typeofbackgroundVOCsthatmayenterintosamplingair,levelofdiseaseseverity,ageofplantanddiseasetissuessampled,plantphysiologicalstates,environmentalfactorsaffectingVOCemissionslight,temperature,humidity,photoperiod,andoccurrenceofsecondaryopportunisticmicrobesandinfections.TheVOCprolesofbiologicalsampleschangeandconstantlyevolveovertimeasaresultofnaturalageingprocesses,planthormonelevels,andplantphysiologicalactivities[9].Thesimplest,naturalplanthormoneethylene,whichregulatesmanyplantphysiologicalactivities,controlsthereleaseofmanyplantVOCemissionsassociatedwithfruitripening,senescence,abscission,andhost-defensemetabolicpathways[26,78,79].Factorsthataffectleafstomatalclosurealsomayaffecttheplant'sVOCsprole[80].

PAGE 9

Chemosensors 2018 , 6 ,45 9of36 Table2. Applicationsofelectronic-nosedevicestodetectplantdiseasesassociatedwithspecichost-pathogenandpestcombinations. PlantHosts 1 Plant Part/Location DiseaseTypePathogens/PestsE-noseModel E-noseType/SensorNo. 2 References AppleFruitPost-harvestrotUnspeciedFOX4000MOS18[81] Leaves;shootsFireblight,Bacterialblast Erwiniaamylovora , Pseudomonassyringae EOS-507C/PEN3MOS6,MOS10[34] LeavesFireblight Erwiniaamylovora EOS-835MOS6[74] BarleyGrainToxigenicinfestation Aspergillusochraceus , Aspergilluscarbonarius , Penicilliumverrucosum , Fusarium.graminearum , Fusariumculmorum VCM422 MOSFET10,MOS6, GascardCO 2 1 [82] BasswoodWoodBacterialwetwoodAnaerobicbacteriaAromascanA32SCP32[83] Beech,BlackcherryWoodBacterialwetwoodAnaerobicbacteriaAromascanA32SCP32[84] BlueberryFruitFruitrotBotrytiscinerea,Colletotrichumgloeosporioides,Alternaria species Cyranose320CBPC32[85] FruitQualityratingunspeciedTGS822MOS2[86] CornGrainAatoxins Aspergillusavus PEN2MOS10[87,88] Toxigenicinfestation Fusariumverticillioides EOS835MOS6[89] CottonBollsWounding Anthonomusgrandis Cyranose320CBPC32[90] CottonwoodWoodBacterialwetwood Clostridium spp.AromascanA32SCP32[10] CucumberLeavesSpidermiteUnidentiedBloodhoundST214CP14[66] ElmWoodBacterialwetwoodAnaerobicbacteriaAromascanA32SCP32[83] GrapeRootRootgalls Agrobacteriumvitis PEN3MOS10[91,92] KiwiFruitBacterialcanker Pseudomonassyringae pv. actinidiae EOS-507C/PEN3MOS6,MOS10[76] Fruitrot Botrytiscinerea , Sclerotiniasclerotiorum EOS835MOS6[93] OaksSapwoodOakwilt Ceratocystisfagacearum AromascanA32SCP32[10,94] RootsRootrots Armillariamellea , Ganodermalucidum , Heterobasidionannosum PEN3MOS10[95] BoleWooddecayManywooddecayfungi AromascanA32S, LibraNose2.1,PEN3 CP32,QMB8,MOS10[10,77]

PAGE 10

Chemosensors 2018 , 6 ,45 10of36 Table2. Cont. PlantHosts 1 Plant Part/Location DiseaseTypePathogens/PestsE-noseModel E-noseType/SensorNo. 2 References OilpalmLowerboleBasalstemrot Ganodermaboninense Cyranose320CBPC32[62] OnionBulbsSourskin Burkholderiacepacia OwlstoneFAIMS[96] OrangeFruitCitrusgreening Liberibacterasiaticus Agilent6890GCMS1[97] Fruitrot Penicillium spp.LibraNose2.1QMB8[98] Ornamentalpalm Crown,trunk, leaves Wounding Rhynchophorusferrugineous PEN3MOS10[63] PearFruitPost-harvestrotUnspeciedFOX4000MOS18[81] PepperPlantsWoundingUnidentiedBloodhoundST214CP14[66] PineWoodinserviceWooddecay Serpulalacrymans PrototypeCP10[99] PotatoTubersStoragesoftrot Ralstoniasolanacearum , Clavibactermichiganensis spp. sepedonicus , Pectobacterium species PrototypeMOS8[100] Ralstoniasolanacearum , Clavibacter michiganensis spp. sepedonicus PEN3MOS10[101] Pectobacteriumcarotovorum WOLF4.1EC9,NDIR2[102] RiceStalksWilting Nilaparvatalugens PEN2MOS10[103,104] StrawberryFruitFruitrot Botrytis , Fusarium ,and Penicillium spp.PEN3MOS10[105] TomatoLeavesPowderymildew Oidiumneolycopersici BloodhoundST214CP14[66] SeedlingGraymold Botrytiscinerea PEN2MOS10[106] WheatGrainDecay Penicilliumchrysogenum , Fusariumverticillioides LibraNose2.1QMB8[107] Fusarium spp.PrototypeQMB8[108] Rhyzoperthadominica PEN2MOS10[109] 1Planthostscienticnames:AppleMalusdomestica,BarleyHordeumvulgare,BasswoodTiliaamericana,BeechFagusgrandifolia,BlackcherryPrunusserotina,BlueberryVacciniumspp.,CornZeamays,CottonGossypiumhirsutum,CottonwoodPopulusdeltoides,CucumberCucumissativus,ElmUlmusamericana,GrapeVitisvinifera,KiwiActinidiadeliciosa,OaksQuercusspp.,OilpalmElaeisguineensis,OnionAlliumcepa;OrangeCitrussinensis,OrnamentalpalmPhoenixcanariensis,PearPrunuscommunis,PepperCapsicumannuum,PinePinusspp.,PotatoSolanumtuberosum,RiceSecalecereale,StrawberryFragariaananassa,TomatoLycopersiconesculentum,WheatTriticumaestivum;2Electronicnosee-nosesensortypesandnumbersinsensorarray:CBPC=carbonblackpolymercomposite;CO2=carbondioxide;CP=conductingpolymer;EC=electrochemical;FAIMS=eldasymmetricionmobilityspectroscopy;GC-FID=gaschromatographyusingameionizationdetector;GNP=goldnanoparticle;MOS=metaloxidesemiconductor;MOSFET=membrane-oxidesemiconductoreld-effecttransistor;MS=massspectroscopy;NDIR=nondispersiveinfrared;QMB=quartzcrystalmicrobalance.

PAGE 11

Chemosensors 2018 , 6 ,45 11of36SomekeyVOCsinducedinplantsduetomicrobialexposuretoplantgrowth-promotingfungiPGPFandplantpathogensmayresultintheinductionofsystemicresistancetospecicplantdiseasesandcorrespondingconcomitantchangesinthephysiologyoftheentireplant.PreviousstudieshaveshownthatVOCmixturesemittedfromAmpelomycessp.andCladosporiumsp.potentialfungalbiocontrolagentssignicantlyreduceddiseaseseverityinArabidopsisplantsagainstthebacterialplantpathogenPseudomonassyringaepv.tomato[110].TwoVOCs,m-cresolandmethylbenzoate,wereidentiedasmajoractiveVOCsofAmpelomycessp.andCladosporiumsp.,respectively,thatelicitedinductionofsystemicresistanceagainstthepathogen.Systemicresistance-induceddefense-associatedVOCssignicantlyaffecttheVOCsignatureofdiseasedplantscomparedwithdiseasedplantsthatlackthesystemicPGPF-inducedresistanceresponse.Volatileplantdefenseandprotectivecompoundsincludeterpenoids,essentialoils,planthormones,secondarymetabolitesaswellasothermetabolicbyproducts,andcompoundsassociatedwithcelldamage[68,111–113]. 3.2.AnimalDiseaseDetectionThevolatilomeisdenedastheentiresetofVOCsproducedbyanorganism,includinganimalsandhighervertebrateswithcomplexmetabolicprocessesthatoccurinvariouscomplexorgansandtissuesystems[114].Theuniquemetabolicstateofanorganism,whetheritishealthyordiseased,isconstantlychanging,butisalwaysreectedbythecurrentaccumulationofVOC-metabolitespresentinsideandcontinuallyreleasedfromthebodytotheoutsidethroughvariousexcretoryprocesses.Scientistsaredevelopinge-nosetechnologiestonon-invasivelydetectVOCspresentinclinicalsamplesforpurposesofmedicaldiagnoses,diseasemonitoring,patienttherapeuticrecovery,diseaseoutbreakcontainment,anddiseaseprevention.Thus,theanalysisofvolatilomicomissionsfromanimals,usinggas-sensorarrayswithine-noseinstruments,providesaneffectivemeansofdetectingdiseasestatesinanimalsjustaseffectivelyasinhighermammalsandhumans.MeasureddifferencesinconcentrationsofseveralspecicVOC-metabolitespreviouslyhavebeenusedinmetabolomicstudieswithcomplexstatisticalmodelstodiscriminatebetweenhealthyanddiseasedstateswithinindividuals.Theadvantagesanddisadvantagesofusinge-nosesvs.metabolomicsindiseasedetectionhavebeenreviewedpreviously[44].Animportantrelevantinquiryregardingtheuseofe-nosedevicesforthispurpose,ratherthanmetabolomicsinstruments,iswhethere-nosedevicescanbedevelopedwithsensorarrayscapableofsensingdifferencesorchangesinconcentrationsofonlyoneorafewspecicVOCs,particularlyprincipalcomponentsofcomplexheadspacevolatilemixtureswhichmightserveaspotentialdiseasebiomarkers.Traditionally-denede-nosedevicesprovideonlysemi-quantitativeindicationsoftotalcollectiveVOCconcentrationvariationsbyproportionalchangesinsensor-outputintensityresponsesfromsensorarraystoallVOCspresentinsampleanalytes.IfsomesensorsinthearrayareparticularlysensitivetooneormoreindividualVOCspresentinthesample,thentheoutputpatternfromthesensorarraycanvarysubstantially.E-nosedesignerscantakeadvantageofthisfactbyselectingsensorsforthesensorarrayfromalargelibraryofavailablesensorsthataremostsensitivetoknownhealthyordisease-specicVOC-biomarkersfromveryspecicchemicalclasses.Consequently,e-nosesensorarrayscanbemadecapableofdetectingchangesinconcentrationsofspecictypesofVOCsduetorecordablechangesinthemolarratiosandconcentrationsofVOCconstituentsinthegassampleanalyzed[10].CumulativeorcollectivedifferencesinseveralmajorcomponentVOCsandsignicantbiomarkersofdiseasevs.healthystatesareaccordinglymeasurableinVOCprolesandsmellprintpatternsofconventionale-noseinstrumentoutputs.Otherstrategiesareavailablefordevelopingandusinge-noseinstrumentshavinggreatercapabilitiesofmeasuringchangesordifferencesinVOCconcentrationsbetweensampletypes,similartometabolomicinstruments.E-noseinstrumentsmaybeusedintandemwithmetabolomicinstrumentstargetedtodetectspecicknownVOC-biomarkersaswasrecentlyproposed[44].Newergeneratione-noseinstruments,havingamuchsmallnumberofsensors,ratherthanasensorarray,arenowavailableforidentifyingandquantifyingindividualpotentialbiomarkersfordiseasediagnoses.

PAGE 12

Chemosensors 2018 , 6 ,45 12of36TheseinstrumenttypesaredescribedinSection3.3.Combination-technologyanddual-technologye-nosedevicesthatprovidesimilarchemical-identicationdataarecoveredinmoredetailinSection4.Futuree-nosetechnologiesforimproveddiseasediagnostics.Therecentuseofe-nosetechnologiesanddevicesinveterinarymedicineforthedetectionofanimaldiseaseshasaidedinthediagnosisofdiseasesofgreatimportanceandsignicanceinbothdomesticatedanimalsandwildlife,particularlybecausemanyanimaldiseasesarecausedbyverysimilaroridenticalpathogenstothosethatcauserelatedhumandiseasesandthereforethemethodsusefulforearlydiseasedetectionarequitesimilartocomparablediseasesinhumans.Electronic-nosedeviceshavebeenusedtodetectdifferenttypesofdiseasesinawidediversityofanimalspeciesincludingtuberculosisTBinbadgersandcattle,white-nosesyndromeWNSinbats,andcutaneousmyiasisCMinsheepaspresentedinTable3.Tuberculosisisanexampleofanexceptionallyimportantdiseasethatoccursworldwideandaffectsawidevarietyofwildanimalspeciessuchasbadgers,birds,deer,possums,rodents,reptiles,variouswildcarnivoresfoxesandcoyotesandomnivorescommonbrushtailpossum,mustelidsandrodents[115–117].PreviousattemptsateradicatingbovineTBcausedbyMycobacteriumbovisinNewZealandcattleanddeerherdswasrelativelysuccessful,buteradicationtreatmentsintheGreatBritainhavebeenonlymarginallysuccessful[118–120].TuberculosiswaswidespreadintheU.S.amongcaptiveelephantsin2015duetopurportedtransmissionfromhumansbyreversezoonosis.BecauseTBmicrobescanbetransmittedthroughtheairtoinfectbothhumansandanimals,thereispublichealthconcernforhigh-hazardzonesforTBinfectionsincircusesandzoos[121,122].BovineTBalsocausesachronicinfectiousdiseaseinseveraldomesticatedmammalianhosts,includingcattle,pigs,andhousecats,butrarelyaffectsequidshorses,donkeys,andzebrasorsheep[123,124].Besidestransmissionbydirectcontactwithexcretaofaninfectedanimal,TBpathogensalsomaybetransmittedinwaterdropletsfromexhaledair,sputum,urine,fecesandpusthroughinhalationofaerosols.TuberculosisisaninfectiousdiseasecausedbyMycobacteriaMycobacteriumspecieswhichareclassifiedasmycoplasmas,characterizedasprokaryotesthatdonothavecellwallsandarethereforenotsusceptibletocellwall-actingantibioticssuchasBetalactamse.g.,penicillin,cephalosporinsetc.withmodesofactionthatinhibitbacterialcellwallbiosynthesis.Consequently,TBgenerallyisconsideredaconsumptivediseaseduetoitspersistenceanddifcultyofcontrolwithtraditionalantibiotics.Theterm“consumptive”referstothecommonlossofbodyweightintheinfectedhostovertimeasthediseaserunsitscourseandcontinuestocausedamagetoaffectedtissues,eventuallyleadingtotheshutdownoforgansinthebodyifnotcontrolledbyaneffectivetreatment[123].Tuberculosisinfectionsusuallywarrantpre-symptomatictreatmentwhendetectedearlybye-nosedevicesorotherdiagnosticmethods.AntibioticsthathavebeenusedspecicallyforcontrolofTBthroughinhibitionofgrowthcausingdeathofmycobacterialpathogens.Streptomycin,themosteffectivesecondarymetaboliteantibioticderivedfromanActinobacteriaspeciesStreptomycesgriseus,wasrstusedasacureforTBin1946.Streptomycinisoftengiventogetherwithisoniazid,rifampicin,andpyrazinamideformoreeffectiveTBcontrol[125].

PAGE 13

Chemosensors 2018 , 6 ,45 13of36 Table3. Applicationsofelectronic-nosedevicesusedinveterinarydiagnosticpathologytodetectanimaldiseases. Animal 1 Disease 2 VOCSampleTypePathogens/Pests/DisorderE-noseModel E-noseType,SensorNo. 3 References BadgersEurasianBovineTBBloodserum Mycobacteriumbovis BloodhoundBH-114CP14[126] Batscave-dwellingWhite-nosesyndromeWNS Purecultureofpathogen isolatedfrombatskin Pseudogymnoascusdestructans HeraclesIIGC-FID1,MOS100s[127,128] CatshFleshoff-avorFilletedmeat Geosmin-producingaquatic Actinomycetes AromascanA32SCP32[129] Chicken Salmonella contaminationSC Meatproduct Salmonellatyphimurium SpreetaSPRB[130] CowscattleBRDBloodserum Mannheimiahaemolytica BloodhoundST-214CP13[131] BovineTBBloodserum Mycobacteriumbovis BloodhoundBH-114CP14[126] Exhaledbreath Mycobacteriumbovis NA-NOSEGNP6[37] HyperketonaemiaExhaledbreath,milkMetabolicdisorderMetabolomicsMS[132] RatsALFExhaledbreathLivercellnecrosis,ischemiaeNoseMOS8[133] SheepCMSkin Luciliacuprina ylarvaePrototypeMOS6[134] 1Animalhostscienticnames:BadgersMelesmeles;BatsEptesicusspp.,Myotisspp.,Perimyotisspp.,CatshIctaluruspunctatus;ChickenGallusgallussubsp.domesticus;CowsBostaurus;RatsRattusnorvegicus;SheepOvisaries;2Diseasenameabbreviations:ALF=acuteliverfailure;BRD=bovinerespiratorydisease;CM=cutaneousmyiasis;SC=Salmonellacontaminationandinfection;TB=tuberculosis;WNS=white-nosesyndrome;3Electronic-nosesensortypesandnumbersinsensorarray:CP=conductingpolymer;GC-FID=gaschromatographyusingameionizationdetector;GNP=goldnanoparticle;MOS=metaloxidesemiconductor;MS=massspectroscopy;SPRB=surfaceplasmonresonancebiosensor;ModelNA-NOSE=NanoArticialNOSE.

PAGE 14

Chemosensors 2018 , 6 ,45 14of36TheMycobacteriumtuberculosiscomplexMTBCofspeciesincludesfourotherTB-causingmycobacteriainadditiontoM.tuberculosisinhumansincludingM.africanum,M.bovis,M.canetti,andM.microti[135].MycobacteriumafricanumisasignicantcauseofTBonlyincertainregionsofAfrica[136,137].Mycobacteriumtuberculosisrarelyoccursinwildanimals[138].MycobacteriumboviswaspreviouslyaverycommonandmajorcauseofTBindevelopedcountries,butthishealthproblemwasalmostcompletelyeliminated,exceptindevelopingcountries,withtheintroductionofpasteurizedmilk,precludingbovinetohumantransmissionviaconsumptionofM.bovis-contaminatedmilk[139,140].MycobacteriumcanettirarelycausesTBwithinthelimitedsoutherngeographicalregionoftheHornofAfrica,althoughsomecasesalsooccurinAfricanemigrants[141,142].MycobacteriummicrotialsorarelycausesTBanditprimarilyoccursonlyinimmunodecientpeople,especiallythosewithhumanimmunodeciencyvirusinfectionandacquiredimmunedeciencysyndromeHIV/AIDS,althoughitsprevalencemaybesignicantlyunderestimated[143].ThehighestriskfactorsofTBinhumansaremalnutrition,highpopulationdensities,andHIV.OtherknownpathogenicmycobacteriaincludeM.leprae,M.avium,andM.kansasii.Mycobacteriumlepraecausesleprosywhereasthelattertwospeciesareclassifiedas“nontuberculousmycobacteria”NTMthatneithercauseTBnorleprosy,buttheyarecapableofcausinglungdiseasesthatresembleTB[144].Attemptsatdiagnosingactivetuberculosisbasedonsignsandsymptomsaloneorinpatientswhohaveaweakenedimmunesystemisdifcult[145–147].InitialevaluationsofpotentialTBinfectionsinindividualswithsignsorsymptomsoflungdiseaseusuallyinvolveachestX-rayandmultiplesputumculturesforacid-fastbacilliwithadenitivediagnosisindicatedbyidentifyingM.tuberculosisinaclinicalsamplee.g.,sputum,pus,oratissuebiopsy,althoughtheculturingprocessisslowandmaytake2-6weeks[146,148].Consequently,treatmentisnormallybegunbeforeculturesareconrmedtoavoidunnecessaryrisksofnotreatment[149].Polymerasechainreactionandadenosinedeaminasetesting,althoughnotroutinelyrecommended,mayallowrapidTBdiagnosis,butthesetestsrarelyalterhowapatientistreated[145,149].DetectionofTB-antibodyproductionusingbloodtestsusuallyarenotrecommended[150].OthertestssuchasInterferon-releaseassaysandtuberculinskintestsareoflimiteduseinthedevelopingworld[147,151,152].AllofthesemethodsofTB-detectionhaveconsiderablelimitationsduetothelongtimerequirementsfordeterminationsandconrmationsofdiagnosis.Theneedforearly,morerapiddetectionmethodsbecameobviousandtheearlydevelopmentsofnoninvasivee-nosedevisesarrivedfortuitouslyattherighttime.E-noseinstruments,utilizedhithertoforearlydiagnosisofTB,causedbyM.bovis,inbadgersandcattlecontainedsensorarrays,consistedofaconductingpolymerCPandgoldnanoparticleGNPsensorarrays,respectively[37,126,131].Inbothcases,theinstrumentsdetecteduniquemixturesofVOC-metabolitescharacteristicofthediseaseindifferentanimalspecies.BloodserumempiricallywasfoundtobemostusefulfordetectingTBdetectioninbadgersandcattleusingtheBloodhoundBH-114e-nosewith14CPsensors.Bycontrast,VOCsinexhaledbreathsampleswerethepreferredsampletypesusedinthediagnosisofTBincattleusingtheNanoArticialNOSENA-NOSEwithsixgoldnanoparticleGNPsensors.OtherwildlifediseasessuchasWNSinbats,ALSinrats,andCMinsheepwerepreferentiallydetectedinheadspacevolatilesfromeitherculture,breath,orskinVOCsamples,respectively,usinge-noseswithmetaloxidesemiconductorMOSsensorarrays[127,128,133,134].Theclinicalsampletypesbestsuitablefore-nosedetectionofdiseaserelatedvolatilesdependonthenatureofthepathogen,theclassesandvolatilityoforganiccompoundsproduced,thehostmetabolicpathwaysaffected,andtheeasewithwhichdisease-associatedVOCsaretranslocatedandconcentratedindifferentpartsofthebody.Thediscoveryofdiseasebiomarkersinveterinaryandaquaculturescienceshasfacilitateddiagnosisofanimaldiseasesandprovidedcluestotheidentityofpossiblebiomarkersofsimilardiseasesinhumans[44].ResearchintheeldofveterinarymedicinehasbeencreditedwiththeidenticationofnewpotentialdiseasebiomarkersofbovineTBdisease.Peledetal.[37]analyzedVOCsinbreathsamplesofhealthyTB-negativeandM.bovis-infectedTB-positivecattlebasedonGC-MSande-nosesignaturepatterns.Theyutilizedananotechnology-basedonane-nosesensor

PAGE 15

Chemosensors 2018 , 6 ,45 15of36array,anarticialolfactorysystemcalledtheNA-NOSE,tailoredfordetectionofTBdiseasefromexhaledbreath.TheNA-NOSEcorrectlyidentiedanddiscriminatedbetweencattlenaturallyinfectedwithM.bovisand79%ofTB-negativeanimals.ThreepotentialVOC-biomarkersforbovineTBwereidentiedbyGC-MS,including2,2-dimethylundecane,octadecanoicacid,andhexadecanoicacid[37].Inaddition,nonanalappearedtobeastrong,relativelyabundantVOC-metaboliteproducedbyuninfectedcattle,indicativeofahealthymetabolism.ProleanalysisofheadspaceVOCsfromcattleserumsamplespreviouslywasusedtodistinguishbetweendiseasedcattleinfectedwithBrucella,MAP,andM.bovisusingane-nose[126,153].TuberculosisalsohasbeendetectedinhumansbybreathanalysisofVOCswithsomesuccess[154,155].AstudybyduPreezandLoots[156]providedevidencethatTB-detectioncouldbeaccomplishedbasedondetectionoftentativeVOC-biomarkersinfourchemicalclassesincludingaminosugars,monosaccharides,sugaralcohols,andglycosidederivatives.Bruinsetal.[157]detectedTBinhumansbyanalysisofexhaledbreathwithaDiagNosee-nosethatcontainedasensorarraywith12MOSsensors.Diseasebiomarkersidentiedforcatsh,livestock,andseveralwildlifediseasesmayfacilitatee-noseearlydiseasedetectionsinaquaticandterrestrialenvironments[37,126–131,134].Thediscoveryofgeosmin,10-trans-dimethyl-trans--decanoland2-methylisoborneolMIB,VOC-biomarkersecondarymetabolitesassociatedwithsystemicinfectionoflivecatshbyaquaticActinobacteria,weredeterminedtobethemainVOCspresentorabsentintheheadspaceofrawskinlesscatshesh[158,159].TheseeffectiveVOC-biomarkerdetectionswerefoundtoberesponsiblefortheeffectivee-nosediscriminationsbetween“off-avor”and“good-avor”catshmeatllets[129]. 3.3.HumanDiseaseDetectionAvarietyofe-nosetechnologytypeshavebeenusedfordetectionofawiderangeofhumandiseaseswhicharesummarizedinTable4.Thee-noseinstrumenttypesmostfrequentlytestedfordiagnosticapplicationsindetectinghumandiseasesincludedeviceswithcarbonblackpolymercompositeCBPC,CP,electrochemicalsensorEC,MOS,GNP,andquartzcrystalmicrobalanceQMBsensorarrays.Somenon-traditionalnewertechnologytypesinvestigatedforusedinhumandiseasediagnoseshaveincludedeldasymmetricionmobilityspectroscopyFAIMS;ionmoleculereaction-massspectrometryIMR-MS,ionmobilityspectrometryIMS,non-dispersiveinfra-redNDIRandphoto-ionizationdetectorPIDinstrumentsthatdonotcontainmultisensoryarrays.TheCyranose320C320e-noseSensigent,BaldwinPark,CA,USAhasbeentestedforefcacyindetectingmorehumandiseasesthanprobablyanyotherportableelectronicaromadetectionEADdevice.Over100biomedicalandrelatedjournalarticleshavebeenpublishedusingthisdevice.Itcontainsasensorarraywith32CBPCsensorsthataresensitivetoawiderangeofVOCs.ThisinstrumentinsomewhatuniqueinthattheCBPCsensorsarenothighlyresponsivetomoistureandthereforehaveanadvantageinbeingabletodiscriminatebetweenVOCsingassampleswithhighmoisturecontent.Thisfeatureenhancesthecapabilitiesandoptionsofusingtheinstrumentforanalysisofdiagnosticsamplescontaininghighrelativehumidity,suchasforbreathandliquidexcretorysamples.Consequently,theC320instrumentmaybeusedtodiagnoseawiderangeofdiseasesthataredetectablefromVOCprolingandanalysisofairexpelledfromthelungs.DiagnosisofinvasivepulmonaryaspergillosisIPAinpatients,particularlythosewithprolongedchemotherapy-inducedneutropeniaPCIN,remainsadifcultchallengeduetononspecicsignsandsymptoms[160–165].HighpatientmortalityoftenoccurswhenIPA-diagnosesaredelayed[163,166,167].Theacquisitionofbronchoalveolarlavage-uidclinicalsamplesforthePlateliagalactomannanassay,theonlytestwithsufcientsensitivityandspecicitytoruleoutIA,isinvasiveandhighlyuncomfortabletopatients[168–173].

PAGE 16

Chemosensors 2018 , 6 ,45 16of36 Table4. Clinicalapplicationsofelectronic-nosedevicesfordetectionofhumandiseasesinPoint-Of-CarePOCtesting. DiseaseName 1 Location 2 VOCSampleType Pathogen/Disorder 2 e-NoseModel e-NoseType,SensorNo. 3 References ABILungExhaled-aircultures Pseudomonasaeruginosa , Haemophilusinuenza , Streptococcuspneumoniae , Moraxellacatarrhalis , Staphylococcusaureus Cyranose320CBPC32[174,175] ALSMusclesExhaledbreathNeurodegenerativemusculardiseaseCyranose320CBPC32[176] ARDSLungExhaledbreathLunginammationCyranose320CBPC32[177] ArthritisJointsExhaledbreathJointinammationCyranose320CBPC32[178] AsthmaLungExhaledbreathBronchialinammation&obstructionCyranose320CBPC32[179] LungExhaledbreathBronchialinammation&obstructionPrototype,NIOXQMB8,NOS1[180] BacteriuriaUrinarytractUrine Escherichiacoli , Klebsiellapneumoniae , Proteusmirabilis , Staphylococcusaureus ,Staphylococcussaprophyticus,EnterococcusfaecalisOsmetechMicrobial Analyzer CP4[181] BADBowelUrineBileacidmalabsorptionFox4000MOS18[182] BVVagina Intravaginalswab culture Neisseriagonorrhoeae , Chlamydiatrachomatis , Trichomonasvaginalis OsmetechMicrobial Analyzer CP4[183] CancerLungExhaledbreathAbnormalcellgrowthPrototypeQMB8[184] CFLungExhaledbreathGeneticdiseaseofthemucusandsweatglandsCyranose320CBPC32[185] COPDLung Lungbacterial cultures Hemophilusinuenzae , Streptococcuspneumoniae , Moraxellacatarrhalis ,gramnegative-bacilli, Pseudomonasaeruginosa , Staphylococcusaureus , Streptococcusviridans , Candidaspecies , Corynebacterium spp., Staphylococcusepidermidis Cyranose320CBPC32[174] CKDKidneyExhaledbreathMultiplecausesPrototypeMOS6[186] CRCColonUrineAbnormalcellgrowthWOLFEC8,NDIR2,PID1[187] ColonFecalAbnormalcellgrowthCyranose320CBPC32[188] ColonBreathAbnormalcellgrowthPrototypeGNP14[189] DFIFoot Woundbacterial cultures Staphylococcusaureus , Pseudomonasaeruginosa , Escherichiacoli Cyranose320CBPC32[190] DMSystemicExhaledbreathInsufcientinsulinproductionPrototypeMOS6[186]

PAGE 17

Chemosensors 2018 , 6 ,45 17of36 Table4. Cont. DiseaseName 1 Location 2 VOCSampleType Pathogen/Disorder 2 e-NoseModel e-NoseType,SensorNo. 3 References EIEye Eyeswabbroth cultures Staphylococcusaureus , Haemophilusinuenzae , Streptococcuspneumoniae , Escherichiacoli , Pseudomonasaeruginosa , Moraxellacatarrhalis Cyranose320CBPC32[191] ENT Ear,nose,& throat Sputumswab cultures Staphylococcusaureus , Staphylococcusepidermis ,Streptococcuspneumoniae,PseudomonasaeruginosaCyranose320CBPC32[191] HNCHead,neckBreathCancerNA-NOSEGNP5[192] IBDIntestineUrineUnknowncauseOwlstoneFAIMS[193] ColonFecalUnknowncauseCyranose320CBPC32[194] ColonUrineUnknowncauseWOLFEC8,NDIR2,PID1[186] IBSColonFecalGastrointestinaldisorderPrototypeGC-MOS1[195] ColonAveolarbreathGastrointestinaldisorderV&FAirsenseIMR-MS[196] IDColonFecalGastroenteritisPrototypeGC-MOS1[197] IECHeartOralcavityairBacterialinammationoftheendocardiumPrototypeMOS6[198] ILDLungExhaledbreathUnknowncauseNIOXNOS1[199] IPALungsExhaledbreath Aspergillus speciesCyranose320CBPC32[160,200] IRCTeethRootcanalculture Prevotella , Porphyromonas , Fusobacterium , and Bacteroides species ShimadzuFF-1MOS10[201] LOSSystemicFecalBacteremiaCyranose320CBPC32[202] MPMLungExhaledbreath Cancerofpleuratissuecausedbyinhalationof asbestosbers Cyranose320CBPC32[177,203] NECColonFecalUnknowncauseCyranose320CBPC32[204] PAJointsExhaledbreathInammatoryjointdiseaseCyranose320CBPC32[178] PDSystemicExhaledbreathNeurodegenerativediseasePrototypeGNP,CNT40[205] PneumoconiosisLungExhaledbreath Occupationalinhalationofdustcausing inammation Cyranose320CBPC32[206] Pneumonia bacterial LungExhaledbreathBacteriallunginfectionCyranose320CBPC32[207] LungExhaledbreathBacteriallunginfectionPrototypeBS[208]

PAGE 18

Chemosensors 2018 , 6 ,45 18of36 Table4. Cont. DiseaseName 1 Location 2 VOCSampleType Pathogen/Disorder 2 e-NoseModel e-NoseType,SensorNo. 3 References PSLungExhaledbreathSystemicgranulomatousdiseaseCyranose320CBPC32[209] RAJointsExhaledbreathInammatoryjointdiseaseCyranose320CBPC32[178] SISkin,othersSkinswabculture Staphylococcusaureus Cyranose320CBPC32[210] TBLungExhaledair Mycobacteriumtuberculosis DiagNoseMOS12[157] UlcerStomachExhaledbreath Helicobacterpylori PrototypeNH 4 [211] URTI Upper respiratorytract ExhaledbreathBacterialpathogensCyranose320CBPC32[212] UTIUrinarytractUrine Staphylococcussaprophyticus , Escherichiacoli , Enterococcusfaecalis , Klebsiella species ChemPro100iIMS8,MOS6[213] VAPLungExhaledairBacterialpathogensCyranose320CBPC32[207,214] LungExhaledbreathBacterialpathogensDiagNoseMOS3[215] WISkinSkinwoundcultures Staphylococcusaureus , Staphylococcusepidermis , Streptococcuspyogenes , Acinetobacterbaumannii , Escherichiacoli , Klebsiellapneumoniae , Pseudomonasaeruginosa PrototypeMOS6,EC1[216] SkinSkinwoundcultures Staphylococcusaureus MSSA, methicillin-resistant Staphylococcusaureus MRSA, Streptococcuspyogenes , Escherichiacoli , Pseudomonasaeruginosa , Clostridiumperfringens ChemPro100iIMS8,MOS6[217] 1Diseasenameabbreviations:ABI=Airwaybacterialinfection;ALS=amyotrophiclateralsclerosis;ARDS=acuterespiratorydistresssyndrome;BAD=Bileaciddiarrhea;BV=bacterialvaginosis;CF=cysticbrosis;CKD=chronickidneydisease;COPD=chronicobstructivepulmonarydisease;CRC=colorectalcancer;DFI=diabeticfootinfection;DM=diabetesmellitus;EI=eyeinfections;ENT=ear,noseandthroatinfections;HNC=headandneckcancer;IBD=inammatoryboweldisease;IBS=irritablebowelsyndrome;ID=Infectiousdiarrhea;IEC=infectiveendocarditis;ILD=inammatorylungdisease;IPA=invasivepulmonaryaspergillosis;IRC=infectedrootcanal;LOS=late-onsetsepsis;MPM=malignantpleuralmesothelioma;NEC=Necrotizingenterocolitis;PA=psoriaticarthritis;PD=Parkinson'sdisease;PS=pulmonarysarcoidosis;RA=rheumatoidarthritis;SI=Staphylococcusinfection;TB=tuberculosisactive;URTI=upperrespiratorytractinfection;UTI=urinarytractinfections;VAP=Ventilator-associatedpneumonia;WI=woundinfection;2Pathogen/Disorderindicatesthebioticcausalagentmicrobeofinfectiousdiseasesorabioticdisordersandtheirdiseasemechanismorcategory;3Electronic-nosegassensortypesymbolabbreviations:BS=biosensor;CBPC=carbonblackpolymercomposite;CNT=carbonnanotubes;CP=conductingpolymer;EC=electrochemicalsensor;FAIM=eldasymmetricionmobilityspectroscopy;GNP=goldnanoparticles;IMR-MS=IonMoleculeReaction-MassSpectrometry;IMS=ionmobilityspectrometry;MOS=metaloxidesemiconductor,NH4=ammoniasensor;NDIR=Non-DispersiveInfra-redopticaldevices;NOS=nitricoxidesensor,PID=Photo-IonizationDetector;QMB=quartzcrystalmicrobalance.

PAGE 19

Chemosensors 2018 , 6 ,45 19of36RecentanalysesofexhaledbreathVOC-prolesbreathprintsofIApatientsusingtheC320e-noseshowedthattheyhaveadistinctaromasignatureprolethatcanbediscriminatedfromnon-IPApatientswithinminutes[160].Inthisstudy,Aspergillusfumigatus-colonizationwasdetectedusingthee-noseon27cysticbrosisCFpatients.E-nosedatawereclassiedusingcanonicaldiscriminantanalysisafterprincipalcomponentreduction.Cross-validatedaccuracyofe-nosedeterminations,denedasthepercentageofcorrectlyclassiedsubjectsusingtheleave-one-outmethod,wereconductedwithculturesofsputumsamples.ResultsshowedthatonlythreesubjectsweremisclassiedasIPApositive,resultinginacross-validatedaccuracyfortheC320detectingIAof89%p<0.004;sensitivity,78%;specicity,94%.ReceiveroperatingcharacteristicROCcurveanalysisshowedanareaunderthecurveAUCof0.89.TheseresultsindicatedthatA.fumigatuscolonizationproducedadistinctivebreathprintinCFpatientsthatcouldbedetectednoninvasivelyforthersttimeusingaCyranoseC320e-noseSensigent,BaldwinPark,CA,USA.Lungdiseasesarerankedasthethirdmostcommoncauseofdeathworldwide[218].Approximately15%oflungdiseasesareattributedtopneumoconiosis,alungdiseaseattributedtooccupationalexposuretovarioustypesofdust,asbestos,orsmoke[219,220].Diagnosisofearly-stagepneumoconiosisisdifcultinclinicalpracticeusingconventionalmethods[221].Yangetal.[206]analyzedtheexhaledbreathVOCsof34subjectswithpneumoconiosisand64healthypatientsusingaC320e-nose.Performanceofthee-noseusingapredictionmodelbasedonlineardiscriminantanalysisLDAindicatedthatC320-discriminationsofsampletypeshadhighspecicity.0%,acceptablesensitivity.9%,andgoodaccuracy.8%inthetrainingset.Inthetestset,sensitivitywas66.7%,specicitywas71.4%,andaccuracywas70.0%byLDAsuggestingthatC320e-nose-basedbreathtestsmayhavegoodpotentialasascreeningtoolforpneumoconiosis.Brekelmanetal.[178]investigatedtheC320e-noseasapotentialdiagnostictoolforinammatoryarthritisIAtodifferentiatebetweeninammatoryjointdiseasesandhealthycontrols.Theyanalyzedandcomparedtheexhaledbreathof21rheumatoidarthritisRA,18psoriaticarthritisPsApatientswithactivediseaseand21healthycontrolsusingprincipalcomponentanalysis,discriminantanalysis,andareaundercurveAUCofreceiveroperatingcharacteristicsROCcurves.VOCswereidentiedbyGC-MSandtherelationshipsbetweenbreathprintsandpotentialbiomarkersofdiseaseactivitywereexplored.BreathprintsofRApatientsweredistinguishedfromcontrolswithanaccuracyof71%,sensitivityof76%andspecicityof67%.Similarly,breathprintsfromPsApatientswereseparatedfromcontrolswith69%accuracy,sensitivityof72%andspecicityof71%.DistinctionbetweenexhaledbreathofRAandPsApatientsexhibitedanaccuracyof69%,sensitivity71%andspecicityof72%.TherewasapositivecorrelationbetweenRApatientsofexhaledbreathprintswithdiseaseactivityscoreDAS28andnumberofpainfuljoints.SevenkeypotentialVOC-biomarkercompoundswereidentiedwithGC-MSwhichsignicantlydifferedbetweenthesampletypesoftestgroups.TheseVOCsincludedfouraliphaticalcohols-propanol,2-propanol,2,2-dimethylpropanol,n-hexanol,andasinglealiphaticketone-pentanone.Arecentreviewprovidedathoroughsummaryofhumandiseasesthatmaybedetectedbye-noseanalysisofurinesamples[222].Urothelialcancercarcinomaofthebladder,knownastransitionalcellcarcinomaTCC,isbyfarthemostcommontypeofbladdercancerwhichmaybedetectedfromurineanalysis.Aurinarypathologypilotstudywasinitiatedin2015toexaminethepotentialfornoninvasiveearlydetectionofbladdercancerBCthroughVOCanalysisofurineheadspacebyaromaorolfactorydistinctionusinganexperimentalMOSe-nose[223].Urinesampleswerecollectedfrom15patientswithclinicalsuspicionofprimaryorrecurrentbladdercancerandfrom21controlpatientswithoutBC,buthavingbenignurologicalconditionse.g.,benignprostatichyperplasiaBPH,inammatorydiseasewererandomlyselectedandevaluatedforthepresenceofBCbyMOSe-noseanalysis.Inaddition,patientswithclinicalsuspicionofBCunderwenttransurethralresectionTURBforhistopathologicalverication.Histopathologyofresectedbladderspecimensrevealed53%ofpatientshadurothelialcancer.Ofthese,63%hadpTa,2T1and1Cisonly.Inaddition,63%ofpatientshadlowgradetumorsand38%hadhighgradetumors.Histopathologyndingsrevealednocancer

PAGE 20

Chemosensors 2018 , 6 ,45 20of36in47%ofpatients.Amongthecontrols,13hadBPH,fourinammatorydisease,onenephrolithiasisandthreeotherbenigndiseases.Theelectronicnosecorrectlydetectedcancerin75%ofBCpatients,butmissedtwopTatumors,resultingin75%sensitivity.ForpatientswithoutBC,86%ofpatientswithnegativeTURBwerecorrectlydiagnosedwithaspecicityof86%.Falsepositivetestswerefoundinfourpatientsofwhomallfourhadurocystitisbasedonhistopathology.ConsideringonlytheBC-controlgroupallpatientswerecorrectlyclassiedwithaspecicityof100%.TheresultssuggestedthehighpotentialoftheexperimentalMOSe-noseindetectionofBCwithanoverallsensitivityof75%andspecicityof86%.Saidietal.[185]evaluatedanexperimentalMOSe-noseasanexhaledbreathVOC-analysistoolfordetectionofchronickidneydiseaseCKDdiabetesmellitusDMcomparedwithhealthysubjects.Theyalsousedgaschromatographyquadrupoletime-of-ightmassspectrometryGC/Q-TOF-MStoidentifyindividualbreathvolatiles.UrinesamplesalsowerecollectedtomeasurecreatininelevelsbyUV–visspectrophotometryasareferencemethod.E-nosedatafrom44testsubjectswereanalyzedusingprincipalcomponentanalysisPCA,supportvectormachinesSVMs,hierarchicalclusteranalysisHCAandpartialleastsquares-regressionsPLSR.ThePLSRmodelrevealedapositiverelationshipbetweenbreathandurinarycreatininelevels.Theresultsindicatedthate-nosedataincombinationwithpatternrecognitionalgorithmsprovidedaninexpensivebasisfornon-invasivediagnosisanddistinguishingbetweenexhaledbreathofCKDandDMpatientsaswellashealthycontrolsbasedonbreathVOC-analysis.InammatoryboweldiseasesIBDareagroupofautoimmunediseasesthathavebeenincreasinginworldwideincidence,prevalenceandseverityparticularlyinchildren[43,44].ThediseasecomplexofIBDincludesCrohn'sdiseaseCD,ulcerativecolitisUC,andmicroscopiccolitisincludingbothcollagenouscolitisandlymphocyticcolitisforms.IndividualssufferingfromthesediseasesareprofoundlyaffectedintermsofqualityoflifeandfrequentlyunpleasantGI-relatedsymptoms.ThecreationofmodelsbasedonVOCsproles,preciseinstrumentationandadvancedstatisticalmethodshavebeenusedtodevelopnewrelativelyinexpensivediagnostictoolsforIBDdiagnoseswithhighsensitivityandspecicity.StudiesinvolvingVOC-prolemodeldevelopmentareprovidingcriticalinformationtowardsbetterunderstandingtheetiologyofIBDthroughanalysisofspecicVOCsproducedasaresultofdisease-modicationsofhostmetabolicprocesses.AnalysisofVOCpatternsinalveolarairofpediatricpatientswithIBDwasinvestigatedinarecentstudyofyoungCDandUCpatientscomparedtocontrolswithandwithoutgastrointestinalsymptomatology[196].AlveolarbreathwasanalyzedbyionmoleculereactionmassspectrometryIMR-MS.FourseparatemolecularmodelswerebuiltforIBDanalysesbasedondifferentnumbersofspecicVOCsincludedfromalistof81totalmoleculesplustheageofsubjectsasindependentvariables,adoptingapenalizingLASSOlogisticregressionapproach.Thefourmodelsincluded:IBDsvs.controls,basedon18VOCssensitivity=95%,specicity=69%,AUC=0.925,CDvs.UCbasedon13VOCssensitivity=94%,specicity=76%,AUC=0.934,IBDsvs.gastroenterologicalcontrolsbasedon15VOCssensitivity=94%,specicity=65%,AUC=0.918,andIBDsvs.controls,initiallybasedon21molecules,butnallyon12VOCssensitivity=94%,specicity=71%,AUC=0.888.TheVOCsidentiedbythemodelsascontributingmosttoIBDeffectswerestudiedrelativetoconcernedoutcomes.Themicrobialcauseofsofttissuewoundinfections,includingpost-operativewoundinfections,areconventionallybasedonidenticationofbacterialorfungalpathogensbyswabcultures,microscopicexaminations,laboratorytestsandPCRassayswhichrequireseveralhourstodaystoobtainadiagnosis[217].Consequently,broad-spectrumantibiotictreatmentgenerallyisadministeredearlyasaprecautionarymeasurebeforeaspecicdiagnosis.Thiscommonpracticeoftenresultsintheinappropriateandoveruseofantibiotics,basedpurelyoneducatedguess-workthatmaybeineffectiveintreatingtheparticularstrainofmicrobesinvolvedinsoft-tissueinfections.Theneedforreal-time,rapidandaccuratediagnoses,allowingformoreeffectiveearlytargetedpathogen-specictreatments,requirethedevelopmentanduseofmethodsforidentifyingpathogensmuchearlier

PAGE 21

Chemosensors 2018 , 6 ,45 21of36basedonchemicalsurveillancemethodsthatdetecttheuniquemicrobialmetabolitesignaturesVOC-prolesproducedbyindividualmicrobialspeciesduetotheirparticularuseofspeciccombinationsofmetabolicpathways[10].Saviauketal.[217]recentlytestedahandheldionmobilityspectrometryIMS-typee-nosedeviceforPOCTtorapidlydifferentiatebetweenthemostcommonSSTIandlife-threateningpathogenscausinggasgangreneinfections.TheyexaminedthemostrelevantbacteriacausingwoundinfectionsbyanalyzinggaseousheadspaceVOCsofclinicalbacterialbloodculturesonstandardizedculturemedia.TheIMS-e-nosesystemwascapableofdistinguishingbetweenmethicillin-sensitiveStaphylococcusaureusMSSA,Streptococcuspyogenes,Escherichiacoli,Pseudomonasaeruginosa,andClostridiumperfringenswithanaccuracyof78%,sensitivityof83%,andspecicityof100%withinminuteswithoutpriorsamplepreparation.Withanoverallaccuracyof91%,theyconcludedthatthisIMS-e-nosemethodologycouldbeusedfortherapiddetectionandidenticationofmostbacteriacausingwoundinfections. VolatileOrganicCompound-BiomarkersofHumanDiseasesResearchinvolvingthediscoveryofnewpotentialVOC-biomarkersofspecichumanandanimaldiseaseshasacceleratedoverthepastdecadeasnovelmetabolomic-typeinstrumentshavebeeninventedtoassistintheidenticationofvolatilemetabolites.Summariesofmanyputativevolatilebiomarkersassociatedwithspecicdiseases,includingmanygastrointestinaldiseases,areavailableinrecentreviews[7,44].Additionalreviewsprovideextensiveinformationonspecice-nosedevicesthathavebeenusedfordetectionofcomplexmixturesofVOC-biomarkers,basedonuniquesmellprintsignaturesVOCproles,foundinexhaledbreathandheadspacegasesderivedfromclinicalsamples[12,27,32,43,44].Theuseofdual-technologye-nosesortraditionale-nosesincombinationwithtargetedknownbiomarkerdetectionwithmetabolomicinstrumentswasrecentlyproposedtoimprovetheaccuracyandeffectivenessofnoninvasiveearlydiseasediagnoses[44].ProgressinthediscoveryofreliableVOC-biomarkersofdiseasehasbeenslowduetodifcultiesinidentifyingsinglecompoundsstronglycorrelatedwithdiseaseandmetabolomicchangesinpathophysiologicaldisease-associatedmetabolicpathwaysthatareclearlyindicativeofspecicmechanismsofdisease.Isolatingtheeffectsandpossiblerolesofsinglebiomarkercompoundsinpathogenesisisamajorchallengeparticularlywhenthemechanismsofdiseasearenotfullyunderstood.Nevertheless,someprogressinidentifyingunique,relativelywell-establisheddiseasebiomarkershasbeenachievedthroughmetabolomicstudiesofhumandiseases[7,32].Otherindicationsofpossibledisease-associatedVOC-biomarkersaretentativeandrequireadditionalresearchforconrmation.TheincreaseinnitricoxideNOproductionthroughoutthebodyasahealingresponsetoghtinammationhasbeenwellestablished[224,225].Asaconsequence,manyhumandiseasescausinginammationpotentiallyaredetectablebyelectronicmeasurementsofNOlevelsinthehumanbreathorbloodserum,particularlywhenusedincombinationwithotherdisease-specicVOC-biomarkers.PortableNO-sensitivee-noseseNOdevicesarealreadyroutinelyusedintheU.S.todetectasthmaseverityinclinicalpatients.SimilarelevatedexhaledNOlevelshavebeenreportedtobeassociatedwithmanyotherpulmonarydiseasesbesidesasthma.HypoxiaassociatedwithacutemountainsicknessAMSmaybeagoodcandidatediseaseforpotentialdetectionbyeNOmeasurementsinexhaledbreath.EvidenceoflunginammationinAMSpatients,mostlikelymediatedbyhigh-altitudehypoxiaandassociatedconcomitantincreaseinNOproduction,hasbeensuggestedasthemostplausiblephysiologicalmechanismexplainingobserveddifferencesine-nosederivedVOCprolesbetweenAMS-resistantandAMS-susceptibleindividuals[226].InammationassociatedwithhigherNOproductionalsohasbeenobservedforotherhumandiseasesincludinghypertension[227,228],arthritis[229,230],lungdiseasessuchasacuterespiratorydistresssyndromeARDS,bronchiectasis,andcysticbrosis[231],andinammatoryboweldiseaseIBDinthecolonandsmallintestine[232].AwiderangeofstatisticalmethodsdevelopedforpatternrecognitionareincreasinglybeingusedfordataanalysisinVOC-emissionstudiesinvolvingdetectionofdisease-relatedVOCprofiles.UnivariatemethodsarenotsuitablefortheinvestigationofVOCprolesbecausetheyconsiderpossibledisease

PAGE 22

Chemosensors 2018 , 6 ,45 22of36biomarkercompoundsseparatelyandarenotabletodiscoverVOCpatterns.Acontrolled-animalstudyonparatuberculosisrecentlycomparedthepattern-recognitionapproach,usingtherandomforestclassicationmethod,toadisease-predictionapproachbasedonsinglebiomarkercompounds[233].Acomparisonofbothstrategies,basedonVOCdatausingcross-validationprocedures,revealedthatrandomforestsachievedhighersensitivitiesandspecicitiesthanpredictionsbasedonsinglecompounds.Theyconcludedthatthepattern-recognitionapproachismorelikelytobefruitfulfordiseasepredictionthansinglebiomarkersforthisdisease.InsituationswhereaverylargenumberofVOCsarepresentinclinicalsamples,suchasanalysisofexhaledbreath,VOCprolesgenerallyaremoreusefulfordiseasedetectionunlesswell-establisheddiseasebiomarkershavebeenclearlyidentiedandconsistentlydemonstrated.Durn-Acevedoetal.[234]recentlyreportedonthedevelopmentofanewchip-basedgoldnanoparticleAuNPe-nosesensortechnology,amenableforearlydiseasescreening,whichcorrectlypredictedgastriccancerGCwith97%accuracy.TheyidentiedsixnewGCVOC-biomarkersusingGC-MSanalyses,indicatingthatconcentrationsofthesebiomarkersinthebreathofpatientsdiagnosedwithGCwerestatisticallydifferentfromthoseofacontrolgroupofpatientsdiagnosedwithothergastricdiseases.FourofthebiomarkersincreasedinconcentrationwithintheexhaledbreathofGCpatients,whiletheothertwobiomarkersdecreasedinconcentrationcomparedwithcontrols.TheputativeidentitiesoftheseGCbiomarkers,foundinColombianpatients,includedtrans-2,2-dimethyl-3-decene,octadecane,m-xylene,hexadecane,1-cyclohexyl-2-cyclohexylmethylpentane,andeicosane.TheGC-biomarkercompoundsfoundinthebreathofLatinAmericanpatientsweredifferentfromthoseidentiedpreviouslyinindividualsfromseparatepopulationswithhighincidenceofGCfromChinaeasternAsiaregionandLatviaaBalticState[235,236].ThedifferencesinbreathGCbiomarkersfromdifferentregionsoftheworldwereattributedtogeographicalvariationsinculture,lifestyle,diet,andgeneticsdifferences. 4.FutureElectronic-NoseTechnologiesforImprovedDiseaseDiagnosticsAffordableandportable,electronic-nosedeviceswithmultisensoryarraysgenerallydonothavethecapabilityofprovidinganalyticalqualitativeidenticationsofindividualVOCsincomplexgasmixtures,butaremostusefulfortherecognitionanddiscriminationofdifferencesinVOC-compositionofheadspacevolatilegasmixturesfromparticularsampletypes,providinginformationabouttheorigin,chemicalcharacteristicsandaromaclassicationofthesample[5,6].Eache-nosetype,regardlessofoperatingprinciple,simultaneouslyrecordssensorresponsesfromallsensorswithinthearraytoallVOCspresentinsampleanalytestoformacollectiveVOCsampleproleorsmellprint.E-nosetechnologiesalsodonotusuallyprovidesuitableinformationforquantitativedeterminations[9].Theusefulnessofhavingbothanalyticalandquantitativechemicaldatafordiseasediagnoseshascometolightinnumerousmetabolomicsstudiesthathaveelucidateddocumentedchangesinhostmetabolicpathwaysthatoccurasaconsequenceofdisease.ThesechangesresultintheproductionandreleaseofdifferentquantitiesandtypesofVOCsfromdiseasedtissues,resultingfromdiseasealterationsinhostmetabolicprocesses,whicharedetectableinclinicalsamples[7,27].Commercialcombination-technologye-noseinstruments,capableofsensoryoutputsthatprovidebothVOCaromasignaturesandchemicalanalysisdata,recentlyarebecomingmoreavailableasnew-generatione-nosesaredesignedwithgreaterchemical-identicationcapabilities.Thesenewere-noseinstrumentshavebeendevelopedtofullltheneedforsomechemicalanalysesassociatedwithVOCproles.Thecombined-technologye-noseslikelywillnottotallyeliminatetheneedforanalyticalmetabolomic-typeinstruments,duetotheimportantfunctionofmetabolomicsinidentifyingchemicaldiseasebiomarkersanddisease-associatedchangesinmetaboliteconcentrations,butthesenewere-noseinstrumentsmayservearoleaspossibleeffectiveandcheaperoptionsinprophylacticscreeningsfornoninvasiveearlydiseasedetections.Onecombination-technologyinstrument,theHeraclesIIGC/Electronic-nosesystemAlphaMOS,Toulouse,France,composedofadual-columngaschromatographwithaverylargemetal-oxideMOSe-nosesensorarray

PAGE 23

Chemosensors 2018 , 6 ,45 23of36andanextensive>83,000organiccompoundssearchableKovatsIndexchemicalreferencelibrarydatabasethatmaybeusedincombinationwithanalyticalstandards,providesameansforthetentativeidenticationofVOCmetabolitesandchemicalbiomarkersassociatedwithdiseaseaswellassmellprintsignaturesofVOCprolesthatmaybecomparedusingPCAandotherstatisticalmethods.Otherdual-technologye-nosesystemshavebeendescribedpreviously[5].Someadvantagesofcombiningane-noseinstrumentcombinedwithGCcapabilitiesisthepotentialfordeterminingnotonlyhowmanyVOCsarepresentintheclinicalsampleanalyte,theirrelativemolecularweightsandamountsproduced,butalsotentativecompoundidentities,gaschromatogramsforpeak-patterncomparisonsofsampletypes,andsimilare-nosearomasignaturepatternsVOCprolesofheadspaceanalytecomposition.Thedevelopmentofsmaller,lightweightandmoreportableelectronic-nosedevicesprovidemoreeffectivemeansofachievingearlydiseasediagnosesineldsituationswhereaccesstohospitalsisdifcultingeographicallyisolatedlocations.Thecontinueddevelopmentofimprovedportablee-nosesalsoincreasesthepotentialforusinganalyticaltoolsthathelptosimplifyandacceleratePOCTclinicaldiagnosticprocessesthatfacilitatemorerapidnoninvasiveearlydiseasedetection.Theresultofusinganacceleratedapproachtodiseasediagnosticsistoachieveamoreefcienthealthcaresystemwithgreaterpotentialforadministeringearliermoreeffectiveandtargeteddisease-controltreatmentsthatimprovediseaseprognosesandsignicantlyshortenpatientrecoverytimesfollowingdiseasetreatments. 5.ConclusionsElectronicnosesareEADdeviceswiththecapabilityofhigh-throughputanalysisofcomplexgaseousVOCmixturesascompositemetaboliteproles[21,22].Theseinstrumentsareinnovativediagnostictoolswithgreatpotentialfornon-invasiveearlierdetectionofnumeroustypesofplant,animalandhumandiseasesbasedonanalysisofheadspaceVOC-metabolitesderivedfromclinicalsamples.Theyareaffordable,havelowoperationandmaintenancecostsandprovidereal-timemeasurementcapabilities[44].Theneedforsimplerandportablee-nosedevicestoproviderapid,accuratediagnosticresultsandreplaceconventionalcumbersomeandtime-consumingclinicalandlaboratorymethodshaveresultedfromthegrowingdemandforimprovedhealthcareinstrumentsandproceduresthatarenoninvasiveandspeedupPOCT,allowingfastertreatmentsfordiseases,improvedprognoses,shorterhospitalstays,morerapiddiseaserecoveryandreducedhealthcarecosts[6,8].ContinuedadvancesandPOCTofnewe-nosetechnologiesalongwithdevelopmentofstandardizeddiagnosticmethodologieswillcontinuetohelpbringtheseinstrumentsintoroutineclinicalpractice[44].Asignicantportionofcitedpapers,reportingtestresultsofdiagnosticmethodsprimarilyfordiseasedetectioninthisreview,areproof-of-conceptpilotstudiesutilizingdiagnosticmodelsbasedonrelativelyfewasmallsubsetofthetotalVOCsderivedfromclinicalsamples.ItshouldbenotedthatexternalvalidationstudiesmustuseidenticalVOC-modelswhenevaluatingthesemethodsbyefcacytestsinclinicaltrials.Suchevaluationsusuallyrequirethatscientistsorclinicianstestingthemethodsconsulttheadviceofthepaper'sauthorstoassurepreciseduplicationofdiagnosticmodelsandmethodsusedinexternalvalidationtests.Acquisitionofmodel-inputandstatisticaldataaswellastestresultsfromtheoriginalmodel-developmentstudiesalsoisrecommendedbecausethisinformationisparticularlyusefulinfacilitatingduplicationofidenticaltestmethods.Electronic-nosedevicesareattractingincreasinglymoreinterestfromhealthcareprovidersduetothemanyadvantagesandversatilitytheseinstrumentsprovideforawiderangeofclinicalapplications.Overtime,improvementsinthedesignsofe-nosesystemsforspecicbiomedicalapplicationshaveadvancedtheaccuracy,reliabilityandeffectivenessoftheseinstrumentsasdiagnostictools[8,12].ImportantissuesneedtobeaddressedbeforeVOCanalysiswithe-noseinstrumentscanachievetheirfullpotentialaseffectivediseasedetectionandmonitoringtoolsforclinicaldiagnoses.Additionalpriorityresearchshouldfocusondevelopinguniversalstandardizationofe-noseinstruments,

PAGE 24

Chemosensors 2018 , 6 ,45 24of36samplingprotocols,sampletransportandstorageconditionsandanalyticalmethodologiestoallowinter-studydatacomparisons[237,238].Thefuturedevelopmentofspecicdisease-associatede-nosedatabaseswithworldwideaccessibilitybyhealthcareprofessionalsandresearchersbasedonspecicstandardizeddiagnosticmethodsandinstrumenttypes[239],theidenticationofadditionaleffectiveVOC-biomarkersofspecicdiseasesforconrmingdiagnoses,thedevelopmentofnewpotentialclinicale-noseapplicationsfordetectingadditionaldiseasese.g.,epilepsy[240],andimprovementsinelectronicsminiaturization,ergonomicsanddiagnosticsoftwareshouldpermite-noseinstrumentsandmethodstobefullyacceptedandintegratedintoclinicalprocedures. Funding:Thisliteraturereviewandassociatedresearchprojectwasnotfundedbyanexternalfundingsource.AllfundingwasprovidedbyspecialWhite-noseSyndromeWNSdedicatedfunds,anationalstrategicpriorityresearchtopic,fromtheUSDAForestService,SouthernResearchStation,forresearchinvolvinganimalpathologyandassociatedearly,noninvasivedisease-diagnosticsresearch.TheauthorhasreceivedallocatedresearchfundsfromtheUSDAForestService,availablefortechnologytransferofnewdiseasedetectionanddiagnostictechnologies,andtocoverthecostsofpublishinginopenaccessjournals. Acknowledgments:TheauthorappreciatestheassistanceofLisaB.Forseforcollectingreferences,performingtechnicalworktasks,andproofreadingthemanuscript. ConictsofInterest: Theauthordeclaresnoconictofinterest. References 1.Bos,L.D.;Sterk,P.J.;Schultz,M.J.Volatilemetabolitesofpathogens:Asystematicreview.PLoSPathog.2013,9 ,e1003311.[CrossRef][PubMed] 2.Santini,G.;Mores,N.;Penas,A.;Capuano,R.;Mondino,C.;Trov,A.;Macagno,F.;Zini,G.;Cattani,P.;Martinelli,E.;etal.ElectronicnoseandexhaledbreathNMR-basedmetabolomicsapplicationsinairwaysdisease. Curr.Top.Med.Chem. 2016 , 16 ,1610.[CrossRef][PubMed] 3.Spanel,P.;Smith,D.ProgressinSIFT-MS:Breathanalysisandotherapplications.MassSpectrom.Rev.2011,30 ,236.[CrossRef][PubMed] 4.Wang,C.;Sahay,P.Breathanalysisusinglaserspectroscopictechniques:Breathbiomarkers,spectralngerprints,anddetectionlimits. Sensors 2009 , 9 ,8230.[CrossRef][PubMed] 5.Wilson,A.D.;Baietto,M.Applicationsandadvancesinelectronic-nosetechnologies.Sensors2009,9,5099.[CrossRef][PubMed] 6.Wilson,A.D.Recentprogressinthedesignandclinicaldevelopmentofelectronic-nosetechnologies.Nanobiosens.Dis.Diagn. 2016 , 5 ,15.[CrossRef] 7.Wilson,A.D.Biomarkermetabolitesignaturespavethewayforelectronic-noseapplicationsinearlyclinicaldiseasediagnoses. Curr.Metabolomics 2017 , 5 ,90.[CrossRef] 8.Wilson,A.D.Electronic-nosedevices—Potentialfornoninvasiveearlydisease-detectionapplications.Ann.Clin.CaseRep.2017,2,1401.Availableonline:http://www.anncaserep.com/full-text/accr-v2-id1401.phpaccessedon14July2017. 9.Cellini,A.;Blasioli,S.;Biondi,E.;Bertaccini,A.;Braschi,I.;Spinelli,F.Potentialapplicationsandlimitationsofelectronicnosedevicesforplantdiseasediagnosis. Sensors 2017 , 17 ,2596.[CrossRef][PubMed] 10.Wilson,A.D.;Lester,D.G.;Oberle,C.S.Developmentofconductivepolymeranalysisfortherapiddetectionandidenticationofphytopathogenicmicrobes. Phytopathology 2004 , 94 ,419.[CrossRef][PubMed] 11.Casalinuovo,I.A.;DiPierro,D.;Coletta,M.;DiFrancesco,P.Applicationofelectronicnosesfordiseasediagnosisandfoodspoilagedetection. Sensors 2006 , 6 ,1428.[CrossRef] 12.Wilson,A.D.;Baietto,M.Advancesinelectronic-nosetechnologiesdevelopedforbiomedicalapplications.Sensors 2011 , 11 ,1105.[CrossRef][PubMed] 13.Wilson,A.D.Diverseapplicationsofelectronicnosetechnologiesinagricultureandforestry.Sensors2013,13 ,2295.[CrossRef][PubMed] 14.Ryan,M.A.;Shevade,A.V.;Taylor,C.J.;Homer,M.L.;Jewell,A.D.;Kisor,A.;Manatt,K.S.;Yen,S.P.S.;Blanco,M.;Goddard,W.A.ExpandingtheCapabilitiesoftheJPLElectronicNoseforanInternationalSpaceStationTechnologyDemonstration;SAETechnicalPaper2006-01-2179;JetPropulsionLaboratory,NationalAeronauticsandSpaceAdministration:Pasadena,CA,USA,2006.

PAGE 25

Chemosensors 2018 , 6 ,45 25of36 15.Shevade,A.V.;Homer,M.L.;Zhou,H.;Jewell,A.D.;Kisor,A.K.;Manatt,K.S.;Torres,J.;Soler,J.;Yen,S.P.S.;Ryan,M.A.;etal.DevelopmentoftheThirdGenerationJPLElectronicNoseforInternationalSpaceStationTechnologyDemonstration;SAETechnicalPaper2007-01-3149;JetPropulsionLaboratory,CaliforniaInstituteofTechnology:Pasadena,CA,USA,2007. 16.Ryan,M.A.;Manatt,K.S.;Gluck,S.E.;Shevade,A.V.;Kisor,A.K.;Zhou,H.;Lara,L.M.;Homer,M.L.OperationofThirdGenerationJPLElectronicNoseontheInternationalSpaceStation;SAETechnicalPaper2009-01-2522;JetPropulsionLaboratory,CaliforniaInstituteofTechnology:Pasadena,CA,USA,2009. 17.Kateb,B.;Ryan,M.A.;Homer,M.L.;Lara,L.M.;Yin,Y.;Higa,K.;Chen,M.Y.SnifngoutcancerusingtheJPLelectronicnose:Apilotstudyofanovelapproachtodetectionanddifferentiationofbraincancer.NeuroImage2009 , 47 ,T5–T9.[CrossRef][PubMed] 18.Wilson,A.D.Reviewofelectronic-nosetechnologiesandalgorithmstodetecthazardouschemicalsintheenvironment. ProcediaTechnol. 2012 , 1 ,453.[CrossRef] 19.Wilson,A.D.;Lester,D.G.;Oberle,C.S.Applicationofconductivepolymeranalysisforwoodandwoodyplantidentications. For.Ecol.Manag. 2005 , 209 ,207.[CrossRef] 20.Wilson,A.D.Futureapplicationsofelectronic-nosetechnologiesinhealthcareandbiomedicine.InWideSpectraofQualityControl ;Akyar,I.,Ed.;InTechPublishing:Rijeka,Croatia,2011;ISBN978-953-307-683-6. 21.Wilson,A.D.FindingAromaCluesintheHumanBreathtoDiagnoseDiseases.AtlasofScience29February2016.Availableonline:http://atlasofscience.org/nding-aroma-clues-in-the-human-breath-to-diagnose-diseasesaccessedon20August2018. 22.Wilson,A.D.Identicationofinsecticideresidueswithaconducting-polymerelectronicnose.Chem.Sens.2014 , 4 ,1. 23.Wilson,A.D.Fungicideresidueidenticationanddiscriminationusingaconductingpolymerelectronic-nose.InProceedingsoftheIVInternationalConferenceonSensorDeviceTechnologiesandApplications,Barcelona,Spain,25August2013;Yurish,S.,Chilibon,I.,Carvalho,V.,Gervais-Ducouret,S.,Eds.;XpertPublishingServices:Wilmington,DE,USA,2013;pp.116. 24.Wilson,A.D.Identicationanddiscriminationofherbicideresiduesusingaconductingpolymerelectronicnose.InProceedingsoftheVIIInternationalConferenceonSensorDeviceTechnologiesandApplications,Nice,France,24July2016;InternationalAcademy,Research,andIndustryAssociationIARIA:Wilmington,DE,USA,2016;pp.4. 25.Baldwin,E.A.;Bai,J.;Plotto,A.;Dea,S.Electronicnosesandtongues:Applicationforthefoodandpharmaceuticalindustries. Sensors 2011 , 11 ,4744.[CrossRef][PubMed] 26.Baietto,M.;Wilson,A.D.Electronic-noseapplicationsforfruitidentication,ripenessandqualitygrading.Sensors 2015 , 15 ,899.[CrossRef][PubMed] 27.Wilson,A.D.Electronic-noseapplicationsinforensicscienceandforanalysisofvolatilebiomarkersinthehumanbreath. J.ForensicSci.Criminol. 2014 , 1 ,S103.[CrossRef] 28.Wilson,A.D.Theoreticalandpracticalconsiderationsforteachingdiagnosticelectronic-nosetechnologiestoclinicallaboratorytechnicians. Proc.Soc.Behav.Sci. 2012 , 31 ,262.[CrossRef] 29.Wilson,A.D.Advancedmethodsforteachingelectronic-nosetechnologiestodiagnosticiansandclinicallaboratorytechnicians. Proc.Soc.Behav.Sci. 2012 , 46 ,4544.[CrossRef] 30.Li,H.;Tang,H.;Wang,Y.Advancesinmetabonomicsoninfectiousdiseases.Curr.Metabolomics2013,1,318.[CrossRef] 31.Emwas,A.M.;Salek,R.M.NMR-basedmetabolomicsinhumandiseasediagnosis:Applications,limitations,andrecommendations. Metabolomics 2013 , 9 ,1048.[CrossRef] 32.Wilson,A.D.Advancesinelectronic-nosetechnologiesforthedetectionofvolatilebiomarkermetabolitesinthehumanbreath. Metabolites 2015 , 5 ,140.[CrossRef][PubMed] 33.Spinelli,F.;Cellini,A.;Vanneste,J.L.;Rodriguez-Estrada,M.T.;Costa,G.;Savioli,S.;Harren,F.J.M.;Cristescu,S.M.EmissionofvolatilecompoundsbyErwiniaamylovorabiologicalactivityinvitroandpossibleexploitationforbacterialidentication. Trees 2012 , 26 ,141.[CrossRef] 34.Cellini,A.;Biondi,E.;Blasioli,S.;Rocchi,L.;Farneti,B.;Braschi,I.;Savioli,S.;Rodriguez-Estrada,M.T.;Biasioli,F.;Spinelli,F.Earlydetectionofbacterialdiseasesinappleplantsbyanalysisofvolatileorganiccompoundsprolesanduseofelectronicnose. Ann.Appl.Biol. 2016 , 168 ,409.[CrossRef]

PAGE 26

Chemosensors 2018 , 6 ,45 26of36 35.Thelen,J.;Harbinson,J.;Jansen,R.;VanStraten,G.;Posthumus,M.A.;Woltering,E.J.;Bouwmeester,H.J.Thesesquiterpene-copaeneisinducedintomatoleavesinfectedbyBotrytiscinerea.J.PlantInteract.2005,1,163.[CrossRef] 36.Laothawornkitkul,J.;Moore,J.P.;Taylor,J.E.;Possell,M.;Gibson,T.D.;Hewett,C.N.;Paul,N.D.Discriminationofplantvolatilesignaturesbyanelectronicnose:Apotentialtechnologyforplantpestand diseasemonitoring. Environ.Sci.Technol. 2008 , 42 ,8433.[CrossRef][PubMed] 37.Peled,N.;Koslow,M.;Ryan,J.;Haick,H.Detectionofvolatileorganiccompoundsincattlenaturallyinfectedwith Mycobacteriumbovis . Sens.ActuatorsB 2012 , 171 ,588.[CrossRef] 38.VandenVelde,S.;vanSteenberghe,D.;vanHee,P.;Quirynen,M.Detectionofodorouscompoundsinbreath.J.Dent.Res. 2009 , 88 ,285.[CrossRef][PubMed] 39.Okell,C.C.;Elliott,S.D.Bacteraemiaandoralsepsiswithspecialreferencetotheaetiologyofsubacuteendocarditis. Lancet 1935 , 2 ,869.[CrossRef] 40.Drangsholt,M.T.Anewcausalmodelofdentaldiseasesassociatedwithendocarditis.Ann.Periodontol.1998,3 ,184.[CrossRef][PubMed] 41.Lacassin,F.;Hoen,B.;Leport,C.;Selton-Suty,C.;Delahaye,F.;Goulet,V.;Etienne,J.;Brianon,S.Proceduresassociatedwithinfectiveendocarditisinadults:Acase-controlstudy.Eur.HeartJ.1995,16,1968.[CrossRef][PubMed] 42.Balint,B.;Kharitonov,S.A.;Hanazawa,T.;Donnelly,L.E.;Shah,P.L.;Hodson,M.E.;Barnes,P.J.Increasednitrotyrosineinexhaledbreathcondensateincysticbrosis.Eur.Respir.J.2001,17,1201.[CrossRef][PubMed] 43.Wilson,A.D.Recentapplicationsofelectronic-nosetechnologiesforthenoninvasiveearlydiagnosisofgastrointestinaldiseases. Proceedings 2018 , 2 ,147.[CrossRef] 44.Wilson,A.D.Applicationofelectronic-nosetechnologiesandVOC-biomarkersforthenoninvasiveearlydiagnosisofgastrointestinaldiseases. Sensors 2018 , 18 ,2613.[CrossRef][PubMed] 45.Taware,R.;Taunk,K.;Pereira,JA.;Dhakne,R.;Kannan,N.;Soneji,D.;Cmara,J.;Nagara,H.A.;Rapole,S.Investigationofurinaryvolatomicalterationsinheadandneckcancer:Anon-invasiveapproachtowardsdiagnosisandprognosis. Metabolomics 2017 , 13 ,111.[CrossRef] 46.Paredes,R.M.G.;Pinto,C.G.;Pavn,J.L.P.;Cordero,B.M.Headspace-gaschromatography-massspectrometryfortherapiddeterminationofpossiblebiomarkersinurinesamples.Anal.Methods2017,9,5784.[CrossRef] 47.Bax,C.;Taverna,G.;Eusebio,L.;Sironi,S.;Grizzi,F.;Guazzoni,G.;Capelli,L.Innovativediagnosticmethodsforearlyprostatecancerdetectionthroughurineanalysis:Areview.Cancers2018,10,123.[CrossRef][PubMed] 48.VanOort,P.;Povoa,P.;Schnabel,R.;Dark,P.M.;Artigas,A.;Bergmans,D.C.J.-J.;Felton,T.W.;Coelho,L.;Schultz,M.J.;Fowler,S.J.;etal.Thepotentialroleofexhaledbreathanalysisinthediagnosticprocessofpneumonia—Asystematicreview. J.BreathRes. 2018 , 12 ,024001.[CrossRef][PubMed] 49.Bos,L.D.;Sterk,P.J.;Fowler,S.J.Breathomicsinthesettingofasthmaandchronicobstructivepulmonarydisease. J.AllergyClin.Immunol. 2016 , 138 ,970.[CrossRef][PubMed] 50.Schnabel,R.;Fijten,R.;Smolinska,A.;Dallinga,J.;Boumans,M.-L.;Stobberingh,E.;Boots,A.;Roekaerts,P.;Bergmans,D.;vanSchooten,F.J.Analysisofvolatileorganiccompoundsinexhaledbreathtodiagnoseventilator-associatedpneumonia. Sci.Rep. 2015 , 5 ,17179.[CrossRef][PubMed] 51.Fowler,S.J.;Basanta-Sanchez,M.;Xu,Y.;Goodacre,R.;Dark,P.M.Surveillanceforlowerairwaypathogensinmechanicallyventilatedpatientsbymetabolomicanalysisofexhaledbreath:Acase-controlstudy.Thorax2015 , 70 ,320.[CrossRef][PubMed] 52.VanOort,P.M.P.;DeBruin,S.;Weda,H.;Knobel,H.H.;Schultz,M.J.;Bos,L.D.Exhaledbreathmetabolomicsforthediagnosisofpneumoniainintubatedandmechanically-ventilatedintensivecareunitICU-patients.Int.J.Mol.Sci. 2017 , 18 ,449.[CrossRef][PubMed] 53.Nicholson,J.K.;Lindon,J.C.;Holmes,E.`Metabonomics':UnderstandingthemetabolicresponsesoflivingsystemstopathophysiologicalstimuliviamultivariatestatisticalanalysisofbiologicalNMRspectroscopicdata. Xenobiotica 1999 , 29 ,1181.[CrossRef][PubMed] 54.Tang,H.R.;Wang,Y.L.Metabonomics:Arevolutioninprogress. Prog.Biochem.Biophys. 2006 , 33 ,401. 55.Pardo,M.;Sberveglieri,G.Electronicolfactorysystemsbasedonmetaloxidesemiconductorsensorarrays.MRSBull. 2004 , 29 ,703.[CrossRef]

PAGE 27

Chemosensors 2018 , 6 ,45 27of36 56.Lout,A.;Coradeschi,S.;Mani,G.K.;Shankar,P.;Rayappan,J.B.B.Electronicnosesforfoodquality:Areview.J.FoodEng. 2015 , 144 ,103.[CrossRef] 57.Peris,M.;Escuder-Gilabert,L.A21stcenturytechniqueforfoodcontrol:Electronicnoses.Anal.Chim.Acta2009 , 638 ,1.[CrossRef][PubMed] 58.Wilson,A.D.Applicationofaconductivepolymerelectronic-nosedevicetoidentifyagedwoodysamples.InProceedingsofthe3rdInternationalIARIAConferenceonSensorDeviceTechnologiesandApplications,Rome,Italy,19August2012;XpertPublishingServices:Wilmington,DE,USA,2012;pp.77,ISBN978-1-61208-208-0. 59.Martinelli,F.;Scalenghe,R.;Davino,S.;Panno,S.;Scuderi,G.;Ruisi,P.;Villa,P.;Stroppiana,D.;Boschetti,M.;Goulart,L.R.;etal.Advancedmethodsofplantdiseasedetection.Areview.Agron.Sustain.Dev.2015,35 ,1.[CrossRef] 60.Sankaran,S.;Mishra,A.;Ehsani,R.;Davis,C.Areviewofadvancedtechniquesfordetectingplantdiseases.Comput.Electron.Agric. 2010 , 72 ,1.[CrossRef] 61.Ray,M.;Ray,A.;Dash,S.;Mishra,A.;Achary,K.G.;Nayak,S.;Singh,S.Fungaldiseasedetectioninplants:Traditionalassays,noveldiagnostictechniquesandbiosensors.Biosens.Bioelectron.2017,87,708.[CrossRef][PubMed] 62.Markom,M.A.;Shakaff,A.Y.M.;Adom,A.H.;Ahmad,M.N.;Hidayat,W.;Abdullah,A.H.;Fikri,N.A.Intelligentelectronicnosesystemforbasalstemrotdiseasedetection.Comput.Electron.Agric.2009,66,140.[CrossRef] 63.Rizzolo,A.;Bianchi,G.;Lucido,P.;Cangelosi,B.;Pozzi,L.;Villa,G.;Clematis,F.;Pasini,C.;Curir,P.ElectronicnosefortheearlydetectionofredpalmweevilRhynchophorusferrugineousOlivierinfestationinpalms:Preliminaryresults. ActaHortic. 2015 , 1099 ,347.[CrossRef] 64.Fang,Y.;Ramasamy,R.P.Currentandprospectivemethodsforplantdiseasedetection.Biosensors2015,4 ,537.[CrossRef][PubMed] 65.Mahlein,A.-K.Plantdiseasedetectionbyimagingsensors—Parallelsandspecicdemandsforprecisionagricultureandplantphenotyping. PlantDis. 2016 , 100 ,241.[CrossRef] 66.Ghaffari,R.;Laothawornkitkul,J.;Zhang,F.;Iliescu,D.;Hines,E.;Leeson,M.;Napier,R.;Moore,J.P.;Paul,N.D.;Hewitt,C.N.;etal.Plantpestanddiseasediagnosis:Electronicnoseandsupportvectormachineapproach. J.PlantDis.Protect. 2012 , 119 ,200.[CrossRef] 67.Li,G.;Fu,J.;Zhang,J.;Zheng,J.Progressinbionicinformationprocessingtechniquesforanelectronicnosebasedonolfactorymodels. Chin.Sci.Bull. 2009 , 54 ,521.[CrossRef] 68.Dudareva,N.;Negre,F.;Nagegowda,D.A.;Orlova,I.Plantvolatiles:Recentadvancesandfutureperspectives. Crit.Rev.PlantSci. 2006 , 25 ,417.[CrossRef] 69.DeLacyCostello,B.P.J.;Evans,P.;Ewen,R.J.;Gunson,H.E.;Jones,P.R.H.;Ratcliffe,N.M.;Spencer-Phillips,P.T.N.Gaschromatography-massspectrometryanalysesofvolatileorganiccompoundsfrompotatotubersinoculatedwith Phytophthorainfestans or Fusariumcoeruleum . PlantPathol. 2001 , 50 ,489–496.[CrossRef] 70.Kushalappa,A.C.;Lui,L.H.;Chen,C.R.;Lee,B.VolatilengerprintingSPME-GCFIDtodetectanddiscriminatediseasesofpotatotubers. PlantDis. 2002 , 86 ,131.[CrossRef] 71.Blasioli,S.;Biondi,E.;Samudrala,D.;Spinelli,F.;Cellini,A.;Bertaccini,A.;Cristescu,S.M.;Braschi,I.IdentificationofvolatilemarkersinpotatobrownrotandringrotbycombinedGC-MSandPTR-MStechniques:Studyoninvitroandinvivosamples. J.Agric.FoodChem. 2014 , 62 ,337–347.[CrossRef][PubMed] 72.Vikram,A.;Prithiviraj,B.;Hamzehzarghani,H.;Kushalappa,A.C.VolatilemetaboliteprolingtodiscriminatediseasesofMcIntoshappleinoculatedwithfungalpathogens.J.Sci.FoodAgric.2004,84,1333.[CrossRef] 73.Prithiviraj,B.;Vikram,A.;Kushalappa,A.C.;Yaylayan,V.VolatilemetaboliteprolingforthediscriminationofonionbulbsinfectedbyErwiniacarotovorassp.carotovora,FusariumoxysporumandBotrytisallii.Eur.J.PlantPathol. 2004 , 110 ,371.[CrossRef] 74.Spinelli,F.;Noferini,M.;Costa,G.NearinfraredspectroscopyNIRS:Perspectiveofreblightdetectioninasymptomaticplantmaterial. ActaHortic. 2006 , 704 ,87.[CrossRef] 75.Spinelli,F.;Costa,G.;Rondelli,E.;Vanneste,J.L.;RodriguezEstrada,M.T.;Busi,S.;Savioli,S.;Cristescu,S.VolatilecompoundsproducedbyErwiniaamylovoraandtheirpotentialexploitationforbacterialidentication.ActaHortic. 2011 , 896 ,77.[CrossRef]

PAGE 28

Chemosensors 2018 , 6 ,45 28of36 76.Cellini,A.;Biondi,E.;Buriani,G.;Farneti,B.;Rodriguez-Estrada,M.T.;Braschi,I.;Savioli,S.;Blasioli,S.;Rocchi,L.;Biasioli,F.;etal.CharacterizationofvolatileorganiccompoundsemittedbykiwifruitplantsinfectedwithPseudomonassyringaepv.actinidiaeandtheireffectsonhostdefenses.Trees2016,30,795.[CrossRef] 77.Baietto,M.;Wilson,A.D.;Bassi,D.;Ferrini,F.Evaluationofthreeelectronicnosesfordetectingincipientwooddecay. Sensors 2010 , 10 ,1062.[CrossRef][PubMed] 78.Iqbal,N.;Khan,N.A.;Ferrante,A.;Trivellini,A.;Francini,A.;Khan,M.I.R.Ethyleneroleinplantgrowth,developmentandsenescence:Interactionwithotherphytohormones.Front.PlantSci.2017,8,475.[CrossRef][PubMed] 79.VonDahl,C.C.;Baldwin,I.T.Decipheringtheroleofethyleneinplant–herbivoreinteractions.J.PlantGrowthRegul. 2007 , 26 ,201.[CrossRef] 80.Niinemets,U.;Loreto,F.;Reichstein,M.Physiologicalandphysicochemicalcontrolsonfoliarvolatileorganiccompoundemissions. TrendsPlantSci. 2004 , 9 ,180.[CrossRef][PubMed] 81.Bai,J.;Baldwin,E.A.;Fortuny,R.C.S.;Mattheis,J.P.;Stanley,R.;Perera,C.;Brecht,J.K.Effectofpretreatmentofintact`Gala'applewithethanolvapor,hear,or1-methylcyclopropeneonqualityandshelflifeoffresh-cutslices. J.Am.Soc.Hortic.Sci. 2004 , 129 ,583. 82.Olsson,J.;Borjesson,T.;Lundstedt,T.;Schnurer,J.DetectionandquanticationofochratoxinAanddeoxynivalenolinbarleygrainsbyGC–MSandelectronicnose.Int.J.Food.Microbiol.2002,72,203.[CrossRef] 83.Wilson,A.D.DetectionanddiagnosisofbacterialwetwoodinTiliaamericanaandUlmusamericanasapwoodusingaCPelectronic-nose.InIndustrial,MedicalandEnvironmentalApplicationsofMicroorganisms:CurrentStatusandTrends;Mndez-Vilas,A.,Ed.;WageningenAcademicPublishers:Wageningen,TheNetherlands,2014;pp.209.ISBN978-90-8686-243-6. 84.Wilson,A.D.BacterialwetwooddetectioninFagusgrandifoliaandPrunusserotinasapwoodusingaconductingpolymerelectronic-nosedevice.InProceedingsoftheVInternationalConferenceonSensorDeviceTechnologiesandApplications,Lisbon,Portugal,16November2014;InternationalAcademy,Research,andIndustryAssociationIARIA:Wilmington,DE,USA,2014;pp.109. 85.Li,C.;Krewer,G.W.;Ji,P.;Scherm,H.;Kays,S.J.Gassensorarrayforblueberryfruitdiseasedetectionandclassication. PostharvestBiol.Technol. 2010 , 55 ,144.[CrossRef] 86.Simon,J.E.;Hetzroni,A.;Bordelon,B.;Miles,G.E.;Charles,D.J.Electronicsensingofaromaticvolatilesforqualitysortingofblueberries. J.FoodSci. 1996 , 61 ,967.[CrossRef] 87.Cheli,F.;Campagnoli,A.;Pinotti,L.;Savoini,G.;Dell'Orto,V.Electronicnosefordeterminationofaatoxinsinmaize. Biotechnol.Agron.Soc.Environ. 2009 , 13 ,39. 88.Campagnoli,A.;Cheli,F.;Savoini,G.;Crotti,A.;Pastori,A.G.M.;Dell'Orto,V.Applicationofanelectronicnosetodetectionofaatoxinsincorn. Vet.Res.Commun. 2009 , 33 ,S273–S275.[CrossRef][PubMed] 89.Falasconi,M.;Gobbi,E.;Pardo,M.;DellaTorre,M.;Bresciani,A.;Sberveglieri,G.DetectionoftoxigenicstrainsofFusariumverticillioidesincornbyelectronicolfactorysystem.Sens.ActuatorsB2005,108,250.[CrossRef] 90.Henderson,W.G.;Khalilian,A.;Han,Y.J.;Greene,J.K.;Degenhardt,D.C.Detectingstinkbugs/damageincottonutilizingaportableelectronicnose. Comput.Electron.Agric. 2010 , 70 ,157.[CrossRef] 91.Blasioli,S.;Biondi,E.;Braschi,I.;Mazzucchi,U.;Bazzi,C.;Gessa,C.E.Electronicnoseasaninnovativetoolforthediagnosisofgrapevinecrowngall. Anal.Chim.Acta 2010 , 672 ,20.[CrossRef][PubMed] 92.Biondi,E.;Blasioli,S.;Fantini,M.;Braschi,I.;Bertaccini,A.Grapevinecrowngalldetectionbyelectronicnose.InProceedingsofthe16thInternationalSymposiumonOlfactionandElectronicNoses,Dijon,France,28JuneJuly2015. 93.Spinelli,F.;Noferini,M.;Vanneste,J.L.;Costa,G.Potentialoftheelectronic-noseforthediagnosisofbacterialandfungaldiseasesinfruittrees. Bull.OEPP/EPPOBull. 2010 , 40 ,59.[CrossRef] 94.Wilson,A.D.;Lester,D.G.Applicationofaromascananalysistodetectanddiagnoseoakwiltinliveoaks.Phytopathology 1998 , 88 ,S97. 95.Baietto,M.;Pozzi,L.;Wilson,A.D.;Bassi,D.EvaluationofaportableMOSelectronicnosetodetectrootrotsinshadetreespecies. Comput.Electron.Agric. 2013 , 96 ,117.[CrossRef] 96.Sinha,R.;Khot,L.R.;Schroeder,B.K.FAIMSbasedsensingofBurkholderiacepaciacausedsourskininonionsunderbulkstoragecondition. FoodMeas. 2017 , 11 ,1578.[CrossRef]

PAGE 29

Chemosensors 2018 , 6 ,45 29of36 97.Baldwin,E.;Plotto,A.;Manthey,J.;McCollum,G.;Bai,J.;Irey,M.;Cameron,R.;Luzio,G.EffectofLiberibacterinfectionHuanglongbingdiseaseofcitrusonorangefruitphysiologyandfruit/fruitjuicequality:Chemicalandphysicalanalyses. J.Agric.FoodChem. 2010 , 58 ,1247.[CrossRef][PubMed] 98.Pallottino,F.;Costa,C.;Antonucci,F.;Strano,M.C.;Calandra,M.;Solaini,S.;Menesatti,P.ElectronicnoseapplicationfordeterminationofPenicilliumdigitatuminValenciaoranges.J.Sci.FoodAgric.2012,92,2008.[CrossRef][PubMed] 99.Hamilton,S.;Hepher,M.J.;Sommerville,J.DetectionofSerpulalacrymansinfestationwithapolypyrrolesensorarray. Sens.ActuatorBChem. 2006 , 113 ,989.[CrossRef] 100.Stinson,J.A.;Persaud,K.C.;Bryning,G.Genericsystemforthedetectionofstatutorypotatopathogens.Sens.ActuatorsBChem. 2006 , 116 ,100.[CrossRef] 101.Biondi,E.;Blasioli,S.;Galeone,A.;Spinelli,F.;Cellini,A.;Lucchese,C.;Braschi,I.Detectionofpotatobrownrotandringrotbyelectronicnose:Fromlaboratorytorealscale.Talanta2014,129,422.[CrossRef][PubMed] 102.Rutolo,M.F.;Clarkson,J.P.;Covington,J.A.Theuseofanelectronicnosetodetectearlysignsofsoft-rotinfectioninpotatoes. Biosyst.Eng. 2018 , 167 ,137.[CrossRef] 103.Zhou,B.;Wang,J.UseofelectronicnosetechnologyforidentifyingriceinfestationbyNilaparvatalugens.Sens.ActuatorsBChem. 2011 , 160 ,15.[CrossRef] 104.Xu,S.;Zhou,Z.;Lu,H.;Luo,X.;Lan,Y.;Zhang,Y.;Li,Y.Estimationoftheageandamountofbrownriceplanthoppersbasedonbionicelectronicnoseuse. Sensors 2014 , 14 ,18114.[CrossRef][PubMed] 105.Pan,L.;Zhang,W.;Zhu,N.;Mao,S.;Tu,K.Earlydetectionandclassicationofpathogenicfungaldiseaseinpost-harveststrawberryfruitbyelectronicnoseandgaschromatography–massspectrometry.FoodRes.Int.2014 , 62 ,162.[CrossRef] 106.Sun,Y.;Wang,J.;Cheng,S.Predictingattackedtimeoftomatoseedlingbye-nosebasedonkernelprincipalcomponentanalysis.InProceedingsoftheASABEAnnualInternationalMeeting,Orlando,FL,USA,17July2016. 107.Paolesse,R.;Alimelli,A.;Martinelli,E.;DiNatale,C.;D'Amico,A.;D'Egidio,M.G.;Aureli,G.;Ricelli,A.;Fanelli,C.Detectionoffungalcontaminationofcerealgrainsamplesbyanelectronicnose.Sens.ActuatorsBChem. 2006 , 119 ,425–430.[CrossRef] 108.Eier,J.;Martinelli,E.;Santonico,M.;Capuano,R.;Schild,D.;DiNatale,C.DifferentialdetectionofpotentiallyhazardousFusariumspeciesinwheatgrainsbyanelectronicnose.PLoSONE2011,6,e21026.[CrossRef][PubMed] 109.Zhang,H.;Wang,J.Detectionofageandinsectdamageincurredbywheat,withanelectronicnose.J.StoredProd.Res. 2007 , 43 ,489.[CrossRef] 110.Naznin,H.A.;Kiyohara,D.;Kimura,M.;Miyazawa,M.;Shimizu,M.;Hyakumachi,M.Systemicresistanceinducedbyvolatileorganiccompoundsemittedbyplantgrowth-promotingfungiinArabidopsisthaliana.PLoSONE 2014 , 9 ,e86882.[CrossRef][PubMed] 111.Jansen,R.M.;Wildt,J.;Kappers,I.F.;Bouwmeester,H.J.;Hofstee,J.W.;vanHenten,E.J.Detectionofdiseasedplantsbyanalysisofvolatileorganiccompoundemission.Annu.Rev.Phytopathol.2011,49,157.[CrossRef][PubMed] 112.Kanchiswamy,C.N.;Malnoy,M.;Maffei,M.E.Chemicaldiversityofmicrobialvolatilesandtheirpotentialforplantgrowthandproductivity. Front.PlantSci. 2015 , 6 ,151.[CrossRef][PubMed] 113.Bitas,V.;Kim,H.;Bennett,J.W.;Kang,S.Snifngonmicrobes:Diverserolesofmicrobialvolatileorganiccompoundsinplanthealth. Mol.Plant-MicrobeInteract. 2013 , 26 ,835.[CrossRef][PubMed] 114.Angle,C.;Waggoner,L.P.;Ferrando,A.;Haney,P.;Passler,T.Caninedetectionofthevolatilome:Areviewofimplicationsforpathogenanddiseasedetection. Front.Vet.Sci. 2016 , 3 ,47.[CrossRef][PubMed] 115.Zuckerman,D.;Yttri,J.Antibiotics:WhenScienceandWishfulThinkingCollide.HealthAffairsBlogg.Availableonline:http://www.center4research.org/antibiotics-science-wishful-thinking-collideaccessedon21August2018. 116.Shivaprasad,H.L.;Palmieri,C.Pathologyofmycobacteriosisinbirds.TheVeterinaryClinicsofNorthAmerica. Exot.Anim.Pract. 2012 , 15 ,41.[CrossRef][PubMed] 117.Reavill,D.R.;Schmidt,R.E.Mycobacteriallesionsinsh,amphibians,reptiles,rodents,lagomorphs,andferretswithreferencetoanimalmodels.TheVeterinaryClinicsofNorthAmerica.Exot.Anim.Pract.2012 , 15 ,25.[CrossRef][PubMed]

PAGE 30

Chemosensors 2018 , 6 ,45 30of36 118.Wobeser,G.A.EssentialsofDiseaseinWildAnimals,1sted.;BlackwellPublishing:Ames,IA,USA,2006;p.170.ISBN978-0-8138-0589-4. 119.Ryan,T.J.;Livingstone,P.G.;Ramsey,D.S.;deLisle,G.W.;Nugent,G.;Collins,D.M.;Buddle,B.M.Advancesinunderstandingdiseaseepidemiologyandimplicationsforcontrolanderadicationoftuberculosisinlivestock:TheexperiencefromNewZealand. Vet.Microbiol. 2006 , 112 ,211.[CrossRef][PubMed] 120.White,P.C.;Bhm,M.;Marion,G.;Hutchings,M.R.ControlofbovinetuberculosisinBritishlivestock:Thereisno`silverbullet'. TrendsMicrobiol. 2008 , 16 ,420.[CrossRef][PubMed] 121.Ward,A.I.;Judge,J.;Delahay,R.J.Farmhusbandryandbadgerbehaviour:OpportunitiestomanagebadgertocattletransmissionofMycobacteriumbovis? Prev.Vet.Med. 2010 , 93 ,2.[CrossRef][PubMed] 122.Holt,N.TheInfectedElephantintheRoom.Slate'sAnimalBlog.Availableonline:http://www.slate.com/blogs/wild_things/2015/03/24/elephant_tuberculosis_epidemic_zoo_and_circus_animals_passing_tb_to_humans.htmlaccessedon24August2018. 123.Schwarz,C.M.TheChambersDictionary;AlliedChambersIndiaLtd.:Edinburg,UK,1998;p.352.ISBN978-81-86062-25-8. 124.Mandell,G.;Bennett,J.;Dolin,R.Mandell,Douglas,andBennett'sPrinciplesandPracticeofInfectiousDiseases,7thed.;ChurchillLivingstone;Elsevier:Philadelphia,PA,USA,2010;Chapter250;ISBN978-0-443-06839-3.125.WHOModelFormulary.Availableonline:http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdfaccessedon21August2018. 126.Fend,R.;Geddes,R.;Lesellier,S.;Vordermeier,H.-M.;Corner,L.A.L.;Gormley,E.;Costello,E.;Hewinson,R.G.;Marlin,D.J.;Woodman,A.C.;etal.UseofanelectronicnosetodiagnoseMycobacteriumbovisinfectioninbadgersandcattle. J.Clin.Microbiol. 2005 , 43 ,1745.[CrossRef][PubMed] 127.Wilson,A.D.;Forse,L.B.DiscriminationbetweenPseudogymnoascusdestructans,otherdermatophytesofcave-dwellingbats,andrelatedinnocuouskeratinophilicfungibasedonelectronic-nose/GCsignaturesofVOC-metabolitesproducedinculture.InProceedingsoftheVIIIInternationalConferenceonSensorDeviceTechnologiesandApplications,Rome,Italy,10September2017;InternationalAcademy,Research,andIndustryAssociationIARIA:Wilmington,DE,USA,2017;pp.5. 128.Wilson,A.D.;Forse,L.B.DifferencesinVOC-metaboliteprolesofPseudogymnoascusdestructansandrelatedfungibyelectronic-nose/GCanalysesofheadspacevolatilesderivedfromaxeniccultures.Sens.Transducers2018 , 220 ,9. 129.Wilson,A.D.;Oberle,C.S.;Oberle,D.F.Detectionofoff-avorincatshusingaconductingpolymerelectronic-nosetechnology. Sensors 2013 , 13 ,15968.[CrossRef][PubMed] 130.Lan,Y.B.;Wang,S.Z.;Yin,Y.G.;Hoffmann,W.C.;Zheng,X.Z.Usingasurfaceplasmonresonancebiosensorforrapiddetectionof Salmonellatyphimurium inchickencarcass. J.BionicEng. 2008 , 5 ,239.[CrossRef] 131.Knobloch,H.;Schroedl,W.;Turner,C.;Chambers,M.;Reinhold,P.Electronicnoseresponsesandacutephaseproteinscorrelateinbloodusingabovinemodelofrespiratoryinfection.Sens.ActuatorsB2010,144,81.[CrossRef] 132.Mottram,T.T.;Dobbelaar,P.;Schukken,Y.H.;Hobbs,P.J.;Bartlett,P.N.Anexperimenttodeterminethefeasibilityofautomaticallydetectinghyperketonaemiaindairycows. Livest.Prod.Sci. 1999 , 61 ,7–11.[CrossRef] 133.Wlodzimirow,K.A.;Abu-Hanna,A.;Schultz,M.J.;Maas,M.A.;Bos,L.D.;Sterk,P.J.;Knobel,H.H.;Soers,R.J.;Chamuleau,R.A.Exhaledbreathanalysiswithelectronicnosetechnologyfordetectionofacuteliverfailureinrats. Biosens.Bioelectron. 2014 , 53 ,129.[CrossRef][PubMed] 134.Cramp,A.P.;Sohn,J.H.;James,P.J.Detectionofcutaneousmyiasisinsheepusingan`electronicnose'.Vet.Parasitol. 2009 , 166 ,293.[CrossRef][PubMed] 135.VanSoolingen,D.;Hoogenboezem,T.;deHaas,P.E.;Hermans,P.W.;Koedam,M.A.;Teppema,K.S.;Brennan,P.J.;Besra,G.S.;Portaels,F.;Top,J.;etal.AnovelpathogenictaxonoftheMycobacteriumtuberculosiscomplex,Canetti:CharacterizationofanexceptionalisolatefromAfrica.Int.J.Syst.Bacteriol.1997 , 47 ,1236.[CrossRef][PubMed] 136.Niemann,S.;Rsch-Gerdes,S.;Joloba,M.L.;Whalen,C.C.;Guwatudde,D.;Ellner,J.J.;Eisenach,K.;Fumokong,N.;Johnson,J.L.;Aisu,T.;etal.MycobacteriumafricanumsubtypeIIisassociatedwithtwodistinctgenotypesandisamajorcauseofhumantuberculosisinKampala,Uganda.J.Clin.Microbiol.2002 , 40 ,3398.[CrossRef][PubMed]

PAGE 31

Chemosensors 2018 , 6 ,45 31of36 137.Niobe-Eyangoh,S.N.;Kuaban,C.;Sorlin,P.;Cunin,P.;Thonnon,J.;Sola,C.;Rastogi,N.;Vincent,V.;Gutierrez,M.C.GeneticbiodiversityofMycobacteriumtuberculosiscomplexstrainsfrompatientswithpulmonarytuberculosisinCameroon. J.Clin.Microbiol. 2003 , 41 ,2547.[CrossRef][PubMed] 138.Mitchell,M.A.Mycobacterialinfectionsinreptiles.Vet.Clin.Exot.Anim.2012,15,101.[CrossRef][PubMed] 139.Kumar,V.;Abbas,A.K.;Fausto,N.;Mitchell,R.N.RobbinsBasicPathology,8thed.;Saunders;Elsevier:Philadelphia,PA,USA,2007;pp.516.ISBN978-1-4160-2973-1. 140.Thoen,C.;Lobue,P.;deKantor,I.TheimportanceofMycobacteriumbovisasazoonosis.Vet.Microbiol.2006 , 112 ,339.[CrossRef][PubMed] 141.Acton,Q.A.MycobacteriumInfections:NewInsightsfortheHealthcareProfessional;ScholarlyEditions:Atlanta,GA,USA,2011;p.1968.ISBN978-1-4649-0122-5. 142.Pfyffer,G.E.;Auckenthaler,R.;vanEmbden,J.D.;vanSoolingen,D.Mycobacteriumcanettii,thesmoothvariantofM.tuberculosis,isolatedfromaSwisspatientexposedinAfrica.Emerg.Infect.Dis.1998,4,631.[CrossRef][PubMed] 143.Panteix,G.;Gutierrez,M.C.;Boschiroli,M.L.;Rouviere,M.;Plaidy,A.;Pressac,D.;Porcheret,H.;Chyderiotis,G.;Ponsada,M.;VanOortegem,K.;etal.PulmonarytuberculosisduetoMycobacteriummicroti :AstudyofsixrecentcasesinFrance. J.Med.Microbiol. 2010 , 59 ,984.[CrossRef][PubMed] 144.Anonymous.Diagnosisandtreatmentofdiseasecausedbynontuberculousmycobacteria.AmericanThoracicSociety,MedicalSectionoftheAmericanLungAssociation.Am.J.Respir.Crit.CareMed.1997,156,S1–S25.[CrossRef][PubMed] 145.Bento,J.;Silva,A.S.;Rodrigues,F.;Duarte,R.Diagnostictoolsintuberculosis.ActaMed.Port.2011,24,145.[PubMed] 146.Escalante,P.Intheclinic.Tuberculosis.Ann.Intern.Med.2009,150,ITC61-614,quizITV616.[CrossRef][PubMed] 147.Chen,J.;Zhang,R.;Wang,J.;Liu,L.;Zheng,Y.;Shen,Y.;Qi,T.;Lu,H.Interferon-gammareleaseassaysforthediagnosisofactivetuberculosisinHIV-infectedpatients:Asystematicreviewandmeta-analysis.PLoSONE 2011 , 6 ,e26827.[CrossRef][PubMed] 148.FoundationforInnovativeNewDiagnostics.DiagnosticsforTuberculosis:GlobalDemandandMarketPotential;SpecialProgrammeforResearchandTraininginTropicalDiseases;WorldHealthOrganization:Geneva,Switzerland,2006;pp.36.ISBN978-92-4-156330-7. 149.NationalCollaboratingCentreforChronicConditionsUK.Tuberculosis:ClinicalDiagnosisandManagementofTuberculosis,andMeasuresforItsPreventionandControl;TBClinicalGuideline117;NationalInstituteforHealthandClinicalExcellence:London,UK,2011;pp.42.ISBN978-1-84936-537-6. 150.Steingart,K.R.;Flores,L.L.;Dendukuri,N.;Schiller,I.;Laal,S.;Ramsay,A.;Hopewell,P.C.;Pai,M.Commercialserologicaltestsforthediagnosisofactivepulmonaryandextrapulmonarytuberculosis:Anupdatedsystematicreviewandmeta-analysis. PLoSMed. 2011 , 8 ,e1001062.[CrossRef][PubMed] 151.Metcalfe,J.Z.;Everett,C.K.;Steingart,K.R.;Cattamanchi,A.;Huang,L.;Hopewell,P.C.;Pai,M.Interferon-releaseassaysforactivepulmonarytuberculosisdiagnosisinadultsinlow-andmiddle-incomecountries:Systematicreviewandmeta-analysis.J.Infect.Dis.2011,204Suppl.4,S1120–S1129.[CrossRef][PubMed]152.Sester,M.;Sotgiu,G.;Lange,C.;Giehl,C.;Girardi,E.;Migliori,G.B.;Bossink,A.;Dheda,K.;Diel,R.;Dominguez,J.;etal.Interferon-releaseassaysforthediagnosisofactivetuberculosis:Asystematicreviewandmeta-analysis. Eur.Respir.J. 2011 , 37 ,100.[CrossRef][PubMed] 153.Knobloch,H.;Khler,N.;Reinhold,P.;Turner,C.;Chambers,M.VolatileorganiccompoundVOCanalysisfordiseasedetection:Proofofprincipleforeldstudiesdetectingparatuberculosisandbrucellosis.AIPConf.Proc. 2009 , 1137 ,195.[CrossRef] 154.Phillips,M.;Cataneo,R.N.;Condos,R.;RingErickson,G.A.;Greenberg,J.;LaBombardi,V.;Munawar,M.I.;Tietje,O.Volatilebiomarkersofpulmonarytuberculosisinthebreath.Tuberculosis2007,87,44.[CrossRef][PubMed] 155.Phillips,M.;Basa-Dalay,V.;Bothamley,G.;Cataneo,R.N.;Lam,P.K.;Natividad,M.P.;Schmitt,P.;Wai,J.Breathbiomarkersofactivepulmonarytuberculosis. Tuberculosis 2010 , 90 ,145.[CrossRef][PubMed] 156.DuPreez,I.;Loots,D.T.NewsputummetabolitemarkersimplicatingadaptationsofthehosttoMycobacteriumtuberculosis,andviceversa. Tuberculosis 2013 , 93 ,330.[CrossRef][PubMed]

PAGE 32

Chemosensors 2018 , 6 ,45 32of36 157.Bruins,M.;Rahim,Z.;Bos,A.;vandeSande,W.W.J.;Endtz,H.P.;vanBelkum,A.Diagnosisofactivetuberculosisbye-noseanalysisofexhaledair. Tuberculosis 2013 , 93 ,232.[CrossRef][PubMed] 158.Gerber,N.N.;Lechevalier,H.A.Geosmin,anearthy-smellingcompoundisolatedfromactinomycetes.Appl.Microbiol. 1965 , 13 ,935.[PubMed] 159.Grimm,C.C.;Lloyd,S.W.;Batista,R.;Zimba,P.V.Usingmicrowavedistillation-solid-phase-microextraction-gaschromatography-massspectrometryforanalyzingfishtissue.J.Chromatogr.Sci.2000,38,289–296.[CrossRef][PubMed] 160.deHeer,K.;Kok,M.G.M.;Fens,N.;Weersink,E.J.M.;Zwinderman,A.H.;vanderSchee,M.P.C.;Visser,C.E.;vanOers,M.H.J.;Sterk,P.J.DetectionofairwaycolonizationbyAspergillusfumigatusbyuseofelectronicnosetechnologyinpatientswithcysticbrosis. J.Clin.Microbiol. 2016 , 54 ,569.[CrossRef][PubMed] 161.Dettenkofer,M.;Wenzler-Rttele,S.;Babikir,R.;Bertz,H.;Ebner,W.;Meyer,E.;Rden,H.;Gastmeier,P.;Daschner,F.D.Surveillanceofnosocomialsepsisandpneumoniainpatientswithabonemarroworperipheralbloodstemcelltransplant:Amulticenterproject.Clin.Infect.Dis.2005,40,926.[CrossRef][PubMed] 162.Cornillet,A.;Camus,C.;Nimubona,S.;Gandemer,V.;Tattevin,P.;Belleguic,C.;Chevrier,S.;Meunier,C.;Lebert,C.;Aupe,M.;etal.Comparisonofepidemiological,clinical,andbiologicalfeaturesofinvasiveaspergillosisinneutropenicandnonneutropenicpatients:A6-yearsurvey.Clin.Infect.Dis.2006,43,577.[CrossRef][PubMed] 163.Robenshtok,E.;Gafter-Gvili,A.;Goldberg,E.;Weinberger,M.;Yeshurun,M.;Leibovici,L.;Paul,M.Antifungalprophylaxisincancerpatientsafterchemotherapyorhematopoieticstem-celltransplantation:Systematicreviewandmeta-analysis. J.Clin.Oncol. 2007 , 25 ,5471.[CrossRef][PubMed] 164.Barth,P.J.;Rossberg,C.;Koch,S.;Ramaswamy,A.Pulmonaryaspergillosisinanunselectedautopsyseries.Pathol.Res.Pract. 2000 , 196 ,73.[CrossRef] 165.Groll,A.H.;Shah,P.M.;Mentzel,C.;Schneider,M.;Just-Nuebling,G.;Huebner,K.Trendsinthepostmortemepidemiologyofinvasivefungalinfectionsatauniversityhospital. J.Infect. 1996 , 33 ,23.[CrossRef] 166.Aisner,J.;Wiernik,P.H.;Schimpff,S.C.Treatmentofinvasiveaspergillosis:Relationofearlydiagnosisandtreatmenttoresponse. Ann.Intern.Med. 1977 , 86 ,539.[CrossRef][PubMed] 167.vonEiff,M.;Roos,N.;Schulten,R.;Hesse,M.;Zuhlsdorf,M.;vandeLoo,J.Pulmonaryaspergillosis:Earlydiagnosisimprovessurvival. Respiration 1995 , 62 ,341.[CrossRef][PubMed] 168.Guo,Y.L.;Chen,Y.Q.;Wang,K.;Qin,S.M.;Wu,C.;Kong,J.L.AccuracyofBALgalactomannanindiagnosinginvasiveaspergillosis:Abivariatemetaanalysisandsystematicreview.Chest2010,138,817.[CrossRef][PubMed] 169.Tukey,M.H.;Wiener,R.S.Population-basedestimatesoftransbronchiallungbiopsyutilizationandcomplications. Respir.Med. 2012 , 106 ,1559.[CrossRef][PubMed] 170.Carr,I.M.;Koegelenberg,C.F.N.;vonGroote-Bidlingmaier,F.;Mowlana,A.;Silos,K.;Haverman,T.;Diacon,A.H.;Bolliger,C.T.Bloodlossduringexiblebronchoscopy:Aprospectiveobservationalstudy.Respiration 2012 , 84 ,312.[CrossRef][PubMed] 171.Facciolongo,N.;Patelli,M.;Gasparini,S.;Lazzari,A.L.;Salio,M.;Simonassi,C.;DelPrato,B.;Zanoni,P.Incidenceofcomplicationsinbronchoscopy:Multicentreprospectivestudyof20,986bronchoscopies.MonaldiArch.ChestDis. 2009 , 71 ,8.[CrossRef][PubMed] 172.Jin,F.;Mu,D.;Chu,D.;Fu,E.;Xie,Y.;Liu,T.Severecomplicationsofbronchoscopy.Respiration2008,76,429.[CrossRef][PubMed] 173.Pue,C.A.;Pacht,E.R.Complicationsofberopticbronchoscopyatauniversityhospital.Chest1995,107,430.[CrossRef][PubMed] 174.Sibila,O.;Garcia-Bellmunt,L.;Giner,J.;Merino,J.L.;Suarez-Cuartin,G.;Torrego,A.;Solanes,I.;Castillo,D.;Valera,J.L.;Cosio,B.G.;etal.Identicationofairwaybacterialcolonizationbyanelectronicnoseinchronicobstructivepulmonarydisease. Respir.Med. 2014 , 108 ,1608.[CrossRef][PubMed] 175.Shaek,H.;Fiorentino,F.;Merino,J.L.;Lpez,C.;Oliver,A.;Segura,J.;dePaul,I.;Sibila,O.;Agust,A.;Coso,B.G.UsingtheelectronicnosetoidentifyairwayinfectionduringCOPDexacerbations.PLoSONE2015 , 10 ,e0135199.[CrossRef][PubMed] 176.Dragonieri,S.;Quaranta,V.N.;Carratu,P.;Ranieri,T.;Marra,L.;D'Alba,G.;Resta,O.Anelectronicnosemaysniffoutamyotrophiclateralsclerosis. Resp.Physiol.Neurobiol. 2016 , 232 ,22.[CrossRef][PubMed]

PAGE 33

Chemosensors 2018 , 6 ,45 33of36 177.Chapman,E.A.;Thomas,P.S.;Stone,E.;Lewis,C.;Yates,D.H.Abreathtestformalignantmesotheliomausinganelectronicnose. Eur.Respir.J. 2012 , 40 ,448.[CrossRef][PubMed] 178.Brekelmans,M.P.;Fens,N.;Brinkman,P.;Bos,L.D.;Sterk,P.J.;Tak,P.P.;Gerlag,D.M.SmellingtheDiagnosis:TheElectronicNoseasDiagnosticToolinInammatoryArthritis.ACase-ReferenceStudy.PLoSONE2016,11 ,e0151715.[CrossRef][PubMed] 179.Dragonieri,S.;Schot,R.;Mertens,B.J.;LeCessie,S.;Gauw,S.A.;Spanevello,A.;Resta,O.;Willard,N.P.;Vink,T.J.;Rabe,K.F.;etal.Anelectronicnoseinthediscriminationofpatientswithasthmaandcontrols.J.AllergyClin.Immunol. 2007 , 120 ,856.[CrossRef][PubMed] 180.Montuschi,P.;Santonico,M.;Mondino,C.;Pennazza,G.;Mantini,G.;Martinelli,E.;Capuano,R.;Ciabattoni,G.;Paolesse,R.;DiNatale,C.;etal.Diagnoseperformanceofanelectronicnose,fractionalexhalednitricoxideandlungfunctiontestinginasthma. Chest 2010 , 137 ,790.[CrossRef][PubMed] 181.Aathithan,S.;Plant,J.C.;Chaudry,A.N.;French,G.L.Diagnosisofbacteriuriabydetectionofvolatileorganiccompoundsinurineusinganautomatedheadspaceanalyzerwithmultipleconductingpolymersensors.J.Clin.Microbiol. 2001 , 39 ,2590.[CrossRef][PubMed] 182.Covington,J.A.;Westenbrink,E.W.;Ouaret,N.;Harbord,R.;Bailey,C.;O'Connell,N.;Cullis,J.;Williams,N.;Nwokolo,C.U.;Bardhan,K.D.;etal.Applicationofanoveltoolfordiagnosingbileaciddiarrhoea.Sensors2013 , 13 ,11899.[CrossRef][PubMed] 183.Hay,P.;Tummon,A.;Ogunle,M.;Adebiyi,A.;Adefowora,A.Evaluationofanoveldiagnostictestforbacterialvaginosis:Theelectronicnose. Int.J.STDAIDS 2003 , 14 ,114.[CrossRef][PubMed] 184.D'Amico,A.;Pennazza,G.;Santonico,M.;Martinelli,E.;Roscioni,C.;Galluccio,G.;Paolesse,R.;DiNatale,C.Aninvestigationonelectronicnosediagnosisoflungcancer.LungCancer2010,68,170.[CrossRef][PubMed] 185.Joensen,O.;Paff,T.;Haarman,E.G.;Skovgaard,I.M.;Jensen,P..;Bjarnsholt,T.;Nielsen,K.G.Exhaledbreathanalysisusingelectronicnoseincysticbrosisandprimaryciliarydyskinesiapatientswithchronicpulmonaryinfections. PLoSONE 2014 , 9 ,e115584.[CrossRef][PubMed] 186.Saidi,T.;Zaima,O.;Mouda,M.;ElBarib,N.;Ionescuc,R.;Bouchikhi,B.Exhaledbreathanalysisusingelectronicnoseandgaschromatography–massspectrometryfornon-invasivediagnosisofchronickidneydisease,diabetesmellitusandhealthysubjects. Sens.ActuatorsB 2018 , 257 ,178.[CrossRef] 187.Westenbrink,E.;Arasaradnam,R.P.;O'Connell,N.O.;Bailey,C.;Nwokolo,C.;Bardhan,K.D.;Covington,J.A.Developmentandapplicationofanewelectronicnoseinstrumentforthedetectionofcolorectalcancer.Biosens.Bioelectron. 2015 , 67 ,733.[CrossRef][PubMed] 188.DeMeij,T.G.;Larbi,I.B.;vanderSchee,M.P.;Lentferink,Y.E.;Paff,T.;TerhaarSiveDroste,J.S.;Mulder,C.J.;vanBodegraven,A.A.;deBoer,N.K.Electronicnosecandiscriminatecolorectalcarcinomaandadvancedadenomasbyfecalvolatilebiomarkeranalysis:Proofofprinciplestudy.Int.J.Cancer2014,134,1132.[CrossRef][PubMed] 189.Peng,G.;Hakim,M.;Broza,Y.Y.;Billan,S.;Abdah-Bortnyak,R.;Kuten,A.;Tisch,U.;Haick,H.Detectionoflung,breast,colorectal,andprostatecancersfromexhaledbreathusingasinglearrayofnanosensors.Br.J.Cancer 2010 , 103 ,542.[CrossRef][PubMed] 190.Yusuf,N.;Zakaria,A.;Omar,M.I.;Shakaff,A.Y.;Masnan,M.J.;Kamarudin,L.M.;Rahim,N.A.;Zakaria,N.Z.I.;Abdullah,A.A.;Othman,A.;etal.In-vitrodiagnosisofsingleandpolymicrobialspeciestargetedfordiabeticfootinfectionusinge-nosetechnology. BMCBioinform. 2015 , 16 ,158.[CrossRef][PubMed] 191.Boilot,P.;Hines,E.;Gardner,J.;Pitt,R.;John,S.;Mitchell,J.;Morgan,D.W.ClassicationofbacteriaresponsibleforENTandeyeinfectionsusingtheCyranosesystem.IEEESens.J.2002,2,247.[CrossRef]192.Hakim,M.;Billan,S.;Tisch,U.;Peng,G.;Dvrokind,I.;Marom,O.;Abdah-Bortnya,R.;Kuten,A.;Haick,H.Diagnosisofhead-and-neckcancerfromexhaledbreath.Br.J.Cancer2011,104,1649–1655.[CrossRef][PubMed]193.Covington,J.;Harbord,R.;Westenbrink,E.W.;Bailey,C.;O'Connell,N.;Dhaliwal,A.;Nwokolo,C.;Foley,A.;Marya,N.B.;Baptista,V.;etal.Detectionofurinaryvolatileorganiccompoundsinpatientswithinammatoryboweldiseaseandcontrolsbyanelectronicnose—Atransatlanticstudy.Gastroenterology2014 , 146 ,S795–S796.[CrossRef] 194.DeMeij,T.G.J.;deBoer,N.K.H.;Benninga,M.A.;Lentferink,Y.E.;deGroot,E.F.J.;vandeVelde,M.E.;vanBodegraven,A.A.;vanderScheea,M.P.Faecalgasanalysisbyelectronicnoseasanovel,non-invasivemethodforassessmentofactiveandquiescentpaediatricinammatoryboweldisease:Proofofprinciplestudy. J.Crohn'sColitis 2014 , 8 ,91.[CrossRef]

PAGE 34

Chemosensors 2018 , 6 ,45 34of36 195.Shepherd,S.F.;McGuire,N.D.;deLacyCostello,B.P.;Ewen,R.J.;Jayasena,D.H.;Vaughan,K.;Ahmed,I.;Probert,C.S.;Ratcliffe,N.M.Theuseofagaschromatographcoupledtoametaloxidesensorforrapidassessmentofstoolsamplesfromirritablebowelsyndromeandinammatoryboweldiseasepatients.J.BreathRes. 2014 , 8 ,026001.[CrossRef][PubMed] 196.Monasta,L.;Pierobon,C.;Princivalle,A.;Martelossi,S.;Marcuzzi,A.;Pasini,F.;Perbellini,L.Inammatoryboweldiseaseandpatternsofvolatileorganiccompoundsintheexhaledbreathofchildren:Acase-controlstudyusingIonMoleculeReaction-MassSpectrometry.PLoSONE2017,12,e0184118.[CrossRef][PubMed]197.McGuire,N.D.;Ewen,R.J.;Costello,C.D.;Garner,C.E.;Probert,C.S.J.;Vaughan,K.;Ratcliffe,N.M.TowardspointofcaretestingforC.difcileinfectionbyvolatileproling,usingthecombinationofashortmulti-capillarygaschromatographycolumnwithmetaloxidedetection.Meas.Sci.Technol.2014,25,065108.[CrossRef][PubMed] 198.Tanaka,M.;Anguri,H.;Nonaka,A.;Kataoka,K.;Nagata,H.;Kita,J.;Shizukuishi,S.Clinicalassessmentoforalmalodorbytheelectronicnosesystem. J.Dent.Res. 2004 , 83 ,317.[CrossRef][PubMed] 199.Kharitonov,S.Exhaledmarkersofinammatorylungdisease,readyforroutinemonitoring.SwissMed.Wkly.2004 , 134 ,175.[PubMed] 200.DeHeer,K.;vanderSchee,M.P.;Zwinderman,K.;vandenBerk,I.A.;Visser,C.E.;vanOers,R.;Sterk,P.J.Invasivepulmonaryaspergillosisinprolongedchemotherapy-inducedneutropenia:Aproof-of-principlestudy. J.Clin.Microbiol. 2013 , 51 ,1490.[CrossRef][PubMed] 201.Yamada,Y.;Takahashi,Y.;Konishi,K.;Katsuumi,I.Associationofodorfrominfectedrootcanalanalyzedbyanelectronicnosewithisolatedbacteria. J.Endod. 2007 , 33 ,1106.[CrossRef][PubMed] 202.Berkhout,D.J.C.;Niemark,H.J.;Buijck,M.;vanWeissenbruch,M.M.;Brinkman,P.;Benninga,M.A.;vanKaam,A.H.;Kramer,B.W.;Andriessen,P.;deBoer,N.K.H.;etal.Detectionofsepsisinpreterminfantsbyfecalvolatileorganiccompoundsanalysis:Aproofofprinciplestudy.J.Pediatr.Gastroenterol.Nutr.2017,65,e47–e52.[CrossRef][PubMed] 203.DeGennaro,G.;Dragonieri,S.;Longobardi,F.;Musti,M.;Stallone,G.;Trizio,L.;Tutino,M.Chemicalcharacterizationofexhaledbreathtodifferentiatebetweenpatientswithmalignantpleuralmesotheliomafromsubjectswithsimilarprofessionalasbestosexposure.Anal.Bioanal.Chem.2010,398,3043.[CrossRef][PubMed] 204.DeMeij,T.G.;vanderSchee,M.P.;Berkhout,D.J.;vandeVelde,M.E.;Jansen,A.E.;Kramer,B.W.;vanWeissenbruch,M.M.;vanKaam,A.H.;Andriessen,P.;vanGoudoever,J.B.;etal.Earlydetectionofnecrotizingenterocolitisbyfecalvolatileorganiccompoundsanalysis.J.Pediatr.2015,167,562.[CrossRef][PubMed]205.Finberg,J.P.M.;Schwartz,M.;Jeries,R.;Badarny,S.;Nakhleh,M.K.;AbuDaoud,E.;Ayubkhanov,Y.;Aboud-Hawa,M.;Broza,Y.Y.;Haick,H.SensorarrayfordetectionofearlystageParkinson'sdiseasebeforemedication. ACSChem.Neurosci. 2018 ,inpress.[CrossRef][PubMed] 206.Yang,H.-Y.;Peng,H.-Y.;Chang,C.-J.;Chen,P.-C.Diagnosticaccuracyofbreathtestsforpneumoconiosisusinganelectronicnose. J.BreathRes. 2017 , 12 ,016001.[CrossRef][PubMed] 207.Hockstein,N.G.;Thaler,E.R.;Torigian,D.;Miller,W.T.,Jr.;Deffenderfer,O.;Hanson,C.W.Diagnosisofpneumoniawithanelectronicnose:Correlationofvaporsignaturewithchestcomputedtomographyscanndings. Laryngoscope 2004 , 114 ,1701.[CrossRef][PubMed] 208.Hanson,C.W.,III;Thaler,E.R.Electronicnosepredictionofaclinicalpneumoniascore:Biosensorsandmicrobes. Anesthesiology 2005 , 102 ,63.[CrossRef][PubMed] 209.Dragonieri,S.;Brinkman,P.;Mouw,E.;Zwinderman,A.H.;Carratu,P.;Resta,O.;Sterk,P.J.;Jonkers,R.E.Anelectronicnosediscriminatesexhaledbreathofpatientswithuntreatedpulmonarysarcoidosisfromcontrols. Respir.Med. 2013 , 107 ,1073.[CrossRef][PubMed] 210.Dutta,R.;Morgan,D.;Baker,N.;Gardner,J.W.;Hines,E.L.IdenticationofStaphylococcusaureusinfectionsinhospitalenvironment:Electronicnosebasedapproach. Sens.ActuatorsB 2005 , 109 ,335.[CrossRef] 211.Vaira,D.;Holton,J.;Ricci,C.;Basset,C.;Gatta,L.;Perna,F.;Tampieri,A.;Miglioli,M.Helicobacterpyloriinfectionfrompathogenesistotreatment:Acriticalreappraisal.Aliment.Pharm.Ther.2002,16,105.[CrossRef] 212.Lai,S.Y.;Deffenderfer,O.F.;Hanson,W.;Phillips,M.P.;Thaler,E.R.Identicationofupperrespiratorybacterialpathogenswiththeelectronicnose. Laryngoscope 2002 , 112 ,975.[CrossRef][PubMed]

PAGE 35

Chemosensors 2018 , 6 ,45 35of36 213.Roine,A.;Saviauk,T.;Kumpulainen,P.;Karjalainen,M.;Tuokko,A.;Aittoniemi,J.;Vuento,R.;Lekkala,J.;Lehtima,T.;Tammela,T.L.;etal.RapidandaccuratedetectionofurinarypathogensbymobileIMS-basedelectronicnose:AProof-of-principlestudy. PLoSONE 2014 , 9 ,e114279.[CrossRef][PubMed] 214.Hockstein,N.G.;Thaler,E.R.;Lin,Y.;Lee,D.D.;Hanson,C.W.Correlationofpneumoniascorewithelectronicnosesignature:Aprospectivestudy. Ann.Otol.Rhinol.Laryngol. 2005 , 114 ,504.[CrossRef][PubMed] 215.Schnabel,R.M.;Boumans,M.L.L.;Smolinska,A.;Stobberingh,E.E.;Kaufmann,R.;Roekaerts,P.M.H.J.;Bergmans,D.C.J.J.Electronicnoseanalysisofexhaledbreathtodiagnoseventilatorassociatedpneumonia.Respir.Med. 2015 , 109 ,1454.[CrossRef][PubMed] 216.Tian,F.;Xu,X.;Shen,Y.;Yan,J.;He,Q.;Ma,J.;Liu,T.Detectionofwoundpathogenbyanintelligentelectronicnose. Sens.Mater. 2009 , 21 ,155. 217.Saviauk,T.;Kiiski,J.P.;Nieminen,M.K.;Tamminen,N.N.;Roine,A.N.;Kumpulainen,P.S.;Hokkinen,L.J.;Karjalainen,M.T.;Vuento,R.E.;Aittoniemi,J.J.;etal.Electronicnoseinthedetectionofwoundinfectionbacteriafrombacterialcultures:Aproof-of-principlestudy. Eur.Surg.Res. 2018 , 59 ,1–11.[CrossRef][PubMed] 218.WorldHealthOrganization.GlobalSurveillance,PreventionandControlofChronicRespiratoryDiseases:AComprehensiveApproach.Availableonline:http://www.who.int/respiratory/publications/global_surveillance/enaccessedon27August2018. 219.Balmes,J.;Becklakem,M.;Blanc,P.;Henneberger,P.;Kreiss,K.;Mapp,C.;Milton,D.;Schwartz,D.;Toren,K.;Viegi,G.AmericanThoracicSocietystatement:Occupationalcontributiontotheburdenofairwaydisease.Am.J.Respir.Crit.CareMed. 2003 , 167 ,787.[CrossRef] 220.Cohen,R.A.Resurgentcoalminedustlungdisease:Waveofthefutureorarelicofthepast?Occup.Environ.Med.2016 , 73 ,715.[CrossRef][PubMed] 221.Joshi,T.K.;Gupta,R.K.Asbestosindevelopingcountries:Magnitudeofriskanditspracticalimplications.Int.J.Occup.Med.Environ.Health 2004 , 17 ,179.[CrossRef] 222.Capelli,L.;Taverna,G.;Bellini,A.;Eusebio,L.;Buf,N.;Lazzeri,M.;Guazzoni,G.;Bozzini,G.;Seveso,M.;Mandressi,A.;etal.Applicationandusesofelectronicnosesforclinicaldiagnosisonurinesamples:Areview. Sensors 2016 , 16 ,1708.[CrossRef][PubMed] 223.Horstmann,M.;Steinbach,D.;Fischer,C.;Enkelmann,A.;Grimm,M.;Voss,A.Anelectronicnosesystemdetectsbladdercancerinurinespecimen:Firstresultsofapilotstudy.J.Urol.2015,193,560.[CrossRef]224.Pendharkar,S.;Mehta,S.Theclinicalsignicanceofexhalednitricoxideinasthma.Can.Respir.J.2008,15,99.[CrossRef][PubMed] 225.Prado,C.M.;Martins,M.A.;Tibrio,I.F.Nitricoxideinasthmaphysiopathology.ISRNAllergy2011,19 ,832560.[CrossRef][PubMed] 226.Lacey,J.N.;Kidel,C.;vanderKaaij,J.M.;Brinkman,P.;Gilbert-Kawai,E.T.;Grocott,M.P.W.;Mythen,M.G.;Martin,D.S.TheSmellofHypoxia:Usinganelectronicnoseataltitudeandproofofconceptofitsroleinthepredictionanddiagnosisofacutemountainsickness. Physiol.Rep. 2018 , 6 ,e13854.[CrossRef][PubMed] 227.Lscher,T.F.;Barton,M.Biologyoftheendothelium. Clin.Cardiol. 1997 , 20 ,3. 228.Ma,F.X.;Zhou,B.;Chen,Z.;Ren,Q.;Lu,S.H.;Sawamura,T.;Han,Z.C.Oxidizedlowdensitylipoproteinimpairsendothelialprogenitorcellsbyregulationofendothelialnitricoxidesynthase.J.LipidRes.2006,47,1227.[CrossRef][PubMed] 229.Abramson,S.B.Nitricoxideininammationandpainassociatedwithosteoarthritis.ArthritisRes.Ther.2008,10 ,S2.[CrossRef][PubMed] 230.Maki-Petaja,K.M.;Cheriyan,J.;Booth,A.D.;Hall,F.C.;Brown,J.;Wallace,S.M.;Ashby,M.J.;McEniery,C.M.;Wilkinson,I.B.Induciblenitricoxidesynthaseactivityisincreasedinpatientswithrheumatoidarthritisandcontributestoendothelialdysfunction. Int.J.Cardiol. 2008 , 129 ,399.[CrossRef][PubMed] 231.VanderVliet,A.;Eiserich,J.P.;Cross,C.E.Nitricoxide:Apro-inammatorymediatorinlungdisease?Respir.Res. 2000 , 1 ,67.[CrossRef][PubMed] 232.Dhillon,S.S.;Mastropaolo,L.A.;Murchie,R.;Griffiths,C.;Thni,C.;Elkadri,A.;Xu,W.;Mack,A.;Walters,T.;Guo,C.;etal.Higheractivityoftheinduciblenitricoxidesynthasecontributestoveryearlyonsetinflammatoryboweldisease. Clin.Transl.Gastroenterol. 2014 , 5 ,e46.[CrossRef][PubMed] 233.Kasbohm,E.;Fischer,S.;Kntzel,A.;Oertel,P.;Bergmann,A.;Trefz,P.;Miekisch,W.;Schubert,J.K.;Reinhold,P.;Ziller,M.;etal.Strategiesfortheidenticationofdisease-relatedpatternsofvolatileorganiccompounds:Predictionofparatuberculosisinananimalmodelusingrandomforests.J.BreathRes.2017,11 ,047105.[CrossRef][PubMed]

PAGE 36

Chemosensors 2018 , 6 ,45 36of36 234.Durn-Acevedo,C.M.;Jaimes-Mogolln,A.L.;Gualdrn-Guerrero,O.E.;Welearegay,T.G.;Martinez-Marn,J.D.;Caceres-Tarazona,J.M.;Snchez-Acevedo,Z.C.;Beleo-Saenz,K.J.;Cindemir,U.;sterlund,L.;etal.ExhaledbreathanalysisforgastriccancerdiagnosisinColombianpatients.Oncotarget2018,9,28805–28817.[CrossRef][PubMed] 235.Xu,Z.Q.;Broza,Y.Y.;Ionsecu,R.;Tisch,U.;Ding,L.;Liu,H.;Song,Q.;Pan,Y.Y.;Xiong,F.X.;Gu,K.S.;etal.Ananomaterial-basedbreathtestfordistinguishinggastriccancerfrombenigngastricconditions.Br.J.Cancer2013 , 108 ,941.[CrossRef][PubMed] 236.Amal,H.;Leja,M.;Broza,Y.Y.;Tisch,U.;Funka,K.;Liepniece-Karele,I.;Skapars,R.;Xu,Z.Q.;Liu,H.;Haick,H.Geographicalvariationintheexhaledvolatileorganiccompounds.J.BreathRes.2013,7,047102.[CrossRef][PubMed] 237.ElManouniElHassani,S.;Berkhout,D.J.C.;Bosch,S.;Benninga,M.A.;deBoer,N.K.H.;deMeij,T.G.J.Applicationoffecalvolatileorganiccompoundanalysisinclinicalpractice:Currentstateandfutureperspectives. Chemosensors 2018 , 6 ,29.[CrossRef] 238.Bosch,S.;ElManouniElHassani,S.;Covington,J.A.;Wicaksono,A.N.;Bomers,M.K.;Benninga,M.A.;Mulder,C.J.J.;deBoer,N.K.H.;deMeij,T.G.J.Optimizedsamplingconditionsforfecalvolatileorganiccompoundanalysisbymeansofeldasymmetricionmobilityspectrometry.Anal.Chem.2018,90,7972.[CrossRef][PubMed] 239.Kou,L.;Zhang,D.;Liu,D.Anovelmedicale-nosesignalanalysissystem. Sensors 2017 , 17 ,402.[CrossRef] [PubMed] 240.Electronic`Nose'OffersRapidEpilepsyDiagnosis.Availableonline:https://www.medscape.com/viewarticle/889666accessedon24August2018. 2018bytheauthor.LicenseeMDPI,Basel,Switzerland.ThisarticleisanopenaccessarticledistributedunderthetermsandconditionsoftheCreativeCommonsAttributionCCBYlicensehttp://creativecommons.org/licenses/by/4.0/.


printinsert_linkshareget_appmore_horiz

Download Options

close


  • info Info

    There are only PDFs associated with this resource.

  • link PDF(s)



Cite this item close

APA

Cras ut cursus ante, a fringilla nunc. Mauris lorem nunc, cursus sit amet enim ac, vehicula vestibulum mi. Mauris viverra nisl vel enim faucibus porta. Praesent sit amet ornare diam, non finibus nulla.

MLA

Cras efficitur magna et sapien varius, luctus ullamcorper dolor convallis. Orci varius natoque penatibus et magnis dis parturient montes, nascetur ridiculus mus. Fusce sit amet justo ut erat laoreet congue sed a ante.

CHICAGO

Phasellus ornare in augue eu imperdiet. Donec malesuada sapien ante, at vehicula orci tempor molestie. Proin vitae urna elit. Pellentesque vitae nisi et diam euismod malesuada aliquet non erat.

WIKIPEDIA

Nunc fringilla dolor ut dictum placerat. Proin ac neque rutrum, consectetur ligula id, laoreet ligula. Nulla lorem massa, consectetur vitae consequat in, lobortis at dolor. Nunc sed leo odio.