Triggering of stroke by by ambient temperature variation: A case-crossover study in Maputo, Mozambique

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ContentslistsavailableatScienceDirect

Clinical

Neurology

and

Neurosurgery

j ou rn a l h o m e pa g e :w w w . e l s e v i e r . c o m / l oc a t e / c l i n e u r o

Triggering

of

stroke

by

ambient

temperature

variation:

A

case-crossover

study

in

Maputo,

Mozambique

Joana

Gomes

a,b,∗

_,

_Albertino

_Damasceno

a,c,2

_,

_Carla

_Carrilho

c,2

_,

_Vitória

_Lobo

c,2

_,

Hélder

Lopes

c,2

_,

_Tavares

_Madede

c,2

_,

_Pius

_Pravinrai

c,2

_,

_Carla

_Silva-Matos

c,2

_,

Domingos

Diogo

c,2

_,

_Ana

_Azevedo

a,b,1

_,

_Nuno

_Lunet

a,b,1

a_Department_of_Clinical_{Epidemiology,}_Predictive_Medicine_and_Public_Health,_University_of_Porto_Medical_School,_Porto,_Portugal b_Institute_of_Public_Health,_University_of_Porto_(ISPUP),_Porto,_Portugal

c_Faculty_of_Medicine,_Eduardo_Mondlane_University,_Maputo,_Mozambique

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received3August2014

Receivedinrevisedform8December2014 Accepted9December2014

Availableonline17December2014 Keywords: Stroke Ambienttemperature Trigger Case-crossover Mozambique

a

b

s

t

r

a

c

t

Objectives:Theeffectofambienttemperatureasastroketriggerislikelytodifferbytypeofstrokeand todependonnon-transientexposuresthatinﬂuencetheriskofthisoutcome.Weaimedtoquantifythe associationbetweenambienttemperaturevariationandstroke,accordingtoclinicalcharacteristicsof theevents,andotherriskfactorsforstroke.

Methods:Weconductedacase-crossoverstudybasedona1-yearregistryofthehospitaladmissions duetonewlyoccurringischemicandhemorrhagicstrokeeventsinMaputo,Mozambique’scapitalcity (N=593).Thecase-periodwasdefinedasthe7daysbeforethestrokeevent,whichwascomparedtotwo controlperiods(14–21daysand21–28daysbeforetheevent).Wecomputedhumidity-and precipitation-adjustedoddsratios(OR)and95%confidenceintervals(95%CI)usingconditionallogisticregression. Results:Anassociationbetweenminimumtemperaturedeclineshigherthan2.4◦Cinanytwo consecu-tivedaysinthepreviousweekandtheoccurrenceofstrokewasobservedonlyforfirstevents(OR=1.43, 95%CI:1.15–1.76).Strongerandstatisticallysignificantassociationswereobservedforhemorrhagic stroke(OR=1.50,95%CI:1.07–2.09)andamongsubjectsnotexposedtoriskfactors,including smok-ing,highserumcholesteroloratrialfibrillation.Nodifferencesintheeffectoftemperaturewerefound accordingtothepatients’vitalstatus28daysaftertheevent.

Conclusions:Firststrokeevents,especiallyofthehemorrhagictype,weretriggeredbydeclinesinthe minimumtemperaturebetweenconsecutivedaysoftheprecedingweek.

1. Introduction

Moststrokeeventsareattributabletoarelativelysmallnumber ofwellidentiﬁedriskfactors,correspondingtoexposuresthatare essentiallystablethroughouttime,whichcontributetoahigher backgroundriskofstrokeandtoitsoverallburden[1,2];however,

∗ Correspondingauthorat:DepartamentodeEpidemiologiaClínica,Medicina PreditivaeSaúdePública,FaculdadedeMedicinadaUniversidadedoPorto,Al.Prof. HernâniMonteiro,4200-319Porto,Portugal.Tel.:+351225513652;

fax:+351225513653.

E-mailaddress:joanacostabgomes@hotmail.com(J.Gomes).

1 _Address:_Faculdade_de_Medicina_da_Universidade_do_Porto,_Al._Prof._Hernâni

Monteiro,4200-319Porto,Portugal.

2 _Address:_Hospital_Central_de_Maputo,_Avenida_Eduardo_Mondlane,_Maputo,

Mozambique.

thesedonotexplainwhyaneventoccurstoacertainindividualat aspeciﬁctime[3,4].

Transitory exposures,such as day-to-day variation in ambi-enttemperature,havebeenshown totriggertheoccurrenceof stroke events [4–9], possibly by inﬂuencing, either directly or indirectly, biological factors that lead to an acute event (e.g., bloodpressureandheartrate;serumconcentrationoflipidsand vasoactivepeptides;plateletaggregation) [10,11].Nevertheless, themechanismsunderlyingthistriggeringeffectremainpoorly understood,namelyregardingthepotentialinteractionwith con-ventionalriskfactorsforstrokeanddifferencesaccordingtostroke subtype.

Inan earlierstudywe showedthatsuddendecreasesinthe minimumtemperatureswereassociatedwithanincreaseinthe incidence rates of stroke in Maputowithin 5–10 days [12]. In the present study we further addressed this topic by quanti-fying the association between ambient temperature variation

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onstrokeoccurrence,accordingtoclinicalcharacteristicsofthe eventsand otherriskfactorsforstroke,usinga case-crossover methodology.

2. Patientsandmethods

We conducted a case-crossover studybased ona 12-month registryofthehospitaladmissionsduetonewlyoccurringstroke eventsinMaputo,thecapitalcityofMozambique.

2.1. Identiﬁcationofstrokeeventsanddatacollection

BetweenAugust1,2005andJuly31,2006,weprospectively evaluatedallpatientsadmittedtoanygovernmentalorprivate hos-pitalinMaputo(theMaputoCentralHospital,threegeneralpublic hospitals,theMilitaryHospital,andsixprivateclinics),livingin townfor>12months,andsuspectedofhavinganincidentstroke. TheinvestigationfollowedtheSTEPSStrokeprotocol,Step1 (reg-istrationofhospitalizedpatients)accordingtotheSTEPSStroke ManualVersion2.0[13]aspreviouslydescribed[14].

StrokewasdeﬁnedaccordingtotheWorldHealthOrganization clinicaldeﬁnition:“afocal(orattimesglobal)neurological impair-mentofsuddenonset,andlastingmorethan24h(orleadingto death),andofpresumedvascularorigin[15]”.During thestudy periodtrainedinterviewerswerepermanentlyattheMaputo Cen-tralHospitalEmergencyDepartmentfordatacollection.Atother medicalfacilities atrained nursein eachshiftwasincharge of gatheringinformationregardingpatientswithsuspectedstroke.

Duringthestudyperiod651strokeeventswereregistered;CT scanorautopsywereperformedin601(92.3%),fromwhich351 (58.4%)wereclassiﬁedasischemic, 242(40.3%) ashemorrhagic and8(1.3%)assubarachnoidhemorrhages.Forthisinvestigation, subarachnoidhemorrhages(n=8)andstrokeeventswithno classi-ﬁcationregardingsubtype(n=50)wereexcludedleavingatotalof 593ischemicorhemorrhagicstrokeeventsfordataanalysis.The dateofsymptomonset,asreportedbythepatientora next-of-kin,wasrecordedandconsideredthedayoftheevent(indexdate), regardlessoftheadmissiondate.

Hypertension and diabetes were considered present when reportedbythepatientsortheirnextofkinorwhen pharmaco-logicaltreatmentwasprescribedonaninpatientorpost-discharge basis. Information on socio-demographic characteristics, high serumcholesterolandcurrentsmokingwasgatheredusinga stan-dardizedquestionnaire,basedonself-report.Atrialﬁbrillationwas assessedthroughanelectrocardiogram (EKG)performedto416 patientsatbaselineorduringthein-hospitalstay.Glasgowscore atadmissionwasrecordedand patientswerefollowedupuntil the28thdaypost-event(eitherthroughapre-scheduledmedical appointmentorbytelephone)toassesstheirvitalstatus.

DataonthetemperatureinMaputo(maximum,minimumand meantemperaturesforeachday)wereobtainedfromthe Meteo-rologicalInstituteofMozambique,fortheperiodbetweenJuly1, 2005andJuly31,2006,alongwithmeanrelativedailyhumidity (%)andtotaldailyprecipitation(mm3₎_data.

2.2. Case-crossoverstudydesign

Foreachstrokeevent,aperiodof7daysbeforetheindexdate wasdefinedasthecase period,which wascompared withtwo distincteventfreeperiods,namelybetweenday14 andday21 beforetheevent(D14–D21)andbetweenday21andday28before theevent(D21–D28)(Fig.1).Todefinethemaximumdaily vari-ationintheminimumtemperatureineach7-daycaseorcontrol periods,wecomputedthedifferencebetweentheminimum tem-peratureineachdayandthedaybefore,andselectedthefigure correspondingtothehighestdecreaseinanyconsecutivedays.A

7-daycase-periodwasselectedbecauseitcorrespondstothe mid-pointofthe5–10-dayperiodwithinwhichwepreviouslyobserved ahigherincidenceofstrokeaftersuddentemperaturedeclines[12], andtofacilitatethematchingbydayoftheweek,sinceitmayalso beassociatedwithtransitoryexposures.Twocontrolperiodswere selectedtoimprovethestatisticalpowerofthestudy.

We computed the decrease in the minimum temperature betweeneverytwoconsecutivedays,inthecaseperiod(D0–D7) andineachofthecontrolperiods(D14–D21andD21–D28)[12], andthehighestdecreaseinminimumtemperatureineachperiod wasselectedtodeﬁnetheexposuretotemperaturevariationin caseandcontrolperiods.Inthepresentreportweconsideredonly theminimumtemperaturedecreasesasourpreviousanalysisof incidenceofstrokeaccordingtotemperatureinthissetting iden-tiﬁedthedeclineinminimumtemperatureasthemostimportant trigger[12].

2.3. Statisticalanalyses

We computedoddsratios(OR)and 95%conﬁdenceintervals (95%CI),crudeandadjustedformeanrelativedailyhumidity(%) andtotaldailyprecipitation(mm3₎_in_the_case_and_control_periods,

as applicable,for the associationbetween thedecline in mini-mumtemperatureandstrokeoccurrence,usingconditionallogistic regression;themedianofthedistributionofthemaximum day-to-daydecreaseintheminimumtemperatureinthecaseperiod wasusedasthecutofftodefinetheexposuretohigherdeclines. Analyseswerestratifiedbystrokesubtype(firstorrecurrentand ischemic,hemorrhagic)age(≤44;45–64or≥65years),sex,andthe presenceofseveralstrokeriskfactors(hypertension,current smok-ing,highserumcholesterol,diabetesandatrialfibrillation),stroke severity(basedonpatients’Glasgowscoreatadmission)andvital statusassessedatthe28-daypost-event(aliveordead).For strati-fiedanalysestheORestimateswerecomputedusingallparticipants withavailableinformationforeachvariable.

AllanalyseswereconductedusingSTATA,Version11.0(Stata Corporation,CollegeStation,TX,USA).

2.4. Ethics

ThestudyprotocolwasapprovedbytheNationalMozambican EthicsCommitteeandwritteninformedconsentwasobtainedfor allparticipants.

3. Results

Nearlyhalf thepatientswerewomen and aged between45 and64 years.Atotalof86.2%ofthepatientshad hypertension, 9.5%werecurrentsmokers,12.6%hadhighserumcholesteroland 13.4% had diabetes. Atrial ﬁbrillation was present in just over 5% of the patients, mostly among those with ischemic stroke (Table1).

Duringthe12-monthstudyperiod,themedianminimum tem-peratureswerehighestinFebruary(22.8◦C)and lowestinJune (14.2◦C). Themonthlymedian ofthehighest decreasein mini-mumtemperaturebetweenevery2consecutivedaysineach7-day periodrangedfrom1.3◦C inJulyto4.2◦C inDecember(Fig.2). Whenconsideringthecasesamongwhomthehighestdeclinein minimumtemperaturewashigherforthecasethanforthecontrol periods,themeanofthedifferencesbetweeneachcaseperiodand thecorrespondingcontrolperiodsD14–D21andD21–D28were 1.53◦Cand1.42◦C,respectively.

Minimum temperature declines higher than 2.4◦C in any consecutive days in the previous week were associated with the occurrence of stroke (crude OR=1.23, 95%CI: 1.02–1.49; adjusted OR=1.28, 95%CI: 1.05–1.56). However, no signiﬁcant

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Fig.1.Case(grayrectangle)andcontrol-periods(whiterectangles)usedforthecase-crossoveranalysis.

Table1

Distributionofsocio-demographiccharacteristicsandriskfactorsforallpatientsandbyﬁrstandrecurrenteventsaccordingtosubtype.

Alleventsa_n₌₅₉₃ _First_eventsa _Recurrent_eventsa

Ischemicn=264 Hemorrhagic (intracerebral)n=217 Ischemicn=87 Hemorrhagic (intracerebral)n=25 Sex[n(%)] Women 282(47.5) 124(47.0) 96(44.2) 47(57.0) 15(60.0) Men 311(52.5) 140(53.0) 121(55.8) 40(46.0) 10(40.0)

Age(years),[mean(SD)] 58.8(13.1) 60.5(13.8) 54.7(11.5) 63.9(11.8) 57.2(11.8)

Age(years),[n(%)] 25–44 77(13.1) 33(12.5) 38(17.5) 4(4.6) 2(8.0) 45–64 317(53.4) 128(48.5) 133(61.3) 39(44.8) 17(68.0) ≥65 199(33.6) 103(39.2) 46(21.2) 44(50.6) 6(24.0) Riskfactors,[n(%)]b Hypertensionb ₅₁₃_(86.5) ₂₁₃_(80.7) ₁₉₆_(90.3) ₈₀_(92.0) ₂₄_(96.0) Currentsmokingc ₅₂_(8.8) ₂₇_(10.2) ₁₈_(8.3) ₄_(4.6) ₃_(12.0)

Highserumcholesterold ₇₅_(12.6) ₃₇_(14.0) ₂₃_(10.6) ₁₁_(12.6) ₄_(16.0)

Diabetese ₇₉_(13.3) ₄₀_(15.2) ₂₀_(9.2) ₁₆_(18.4) ₃_(12.0)

Atrialﬁbrillationf ₃₃_(5.6) ₁₆_(6.1) ₃_(1.4) ₁₃_(14.9) ₁_(4.0)

SD,standarddeviation.

a_Including₅₉₃_cases_with_available_information_regarding_the_stroke_subtype_and_after_the_exclusion_of_eight_subarachnoid_hemorrhages. b _Data_are_missing_from₃₆_subjects.

c _Data_are_missing_from₁₇_subjects. d _Data_are_missing_from₇₇_subjects. e_Data_are_missing_from₃₄_subjects. f _Data_are_missing_from₃₂_subjects.

effectwasobservedforrecurrentevents(adjustedOR=0.96,95%CI: 0.61–1.50)andanincreasedriskwasobservedonlyforﬁrstevents (adjustedOR=1.39,95%CI:1.11–1.74).Amongthelatter(Table2), therewerenomeaningfuldifferencesbetweenmenandwomen, butstrongerandstatisticallysigniﬁcantassociationswereobserved for hemorrhagic stroke (adjusted OR=1.50, 95%CI: 1.07–2.09), hypertensiveindividuals (adjusted OR=1.37, 95%CI:1.08–1.75), non-smokers(adjustedOR=1.42,95%CI:1.12–1.80)andsubjects withlowerserum cholesterol levels(adjusted OR=1.53, 95%CI: 1.20–1.96).Nodifferenceswerefoundregardingstrokeseverityor vitalstatus28daysaftertheevent(Table2).

Forpatientsarrivingtothehospitallessthan24hafterstroke onsetadjustedORwas1.24(95%CI:0.92–1.67)andforthose arriv-ingtothehospitalmorethan24hafterstrokeonsetadjustedOR was1.62(95%CI:1.15–2.27).Consideringthedifferencebetween thedaybeforetheeventandtheindexdateasthecaseperiodand tocorrespondingcontrolperiods(D8–D7andD15–D14),the over-alladjustedORfordecreaseshigherthan2.4◦Cwas1.06(95%CI: 0.82–1.37).

4. Discussion

Thisstudyconfirmsthatstrokeeventsmaybetriggeredbydrops intheminimumtemperature, ina setting witha tropical,high humidityclimate.It addstoourpreviousfindingsevidencethat thisassociationonlyappliestofirstevents,mainlyhemorrhagic, andthattherewasnorelationwiththe28-dayvitalstatusofthese patients.

Most previous studies aiming to evaluate the relationship betweentemperatureandstrokeoccurrencefoundstroketobe associatedwithlowertemperatures[16–19].Alargestudy con-ductedin17countries,includingthreefromAfrica(Kenya,Zambia andZimbabwe)showedthathospitalizationsduetostrokewere associatedwithlowerenvironmentalairtemperatureandthatthis effect wasveriﬁed for lags betweendrops in temperature and strokeoccurrencenotlargerthan1month[20],whichis compat-iblewithourdata.Thecase-crossovermethodologyallowsforan efﬁcientcontroloftime-invariantconfounders,suchas socioecono-micstatusandothersocio-demographiccharacteristicsandfactors associatedwiththedayoftheweek(e.g.,patternsofpredominant alcoholdrinkingintheweekends),contributingtothevalidityof theriskestimates[21,22].Thefactthatthecontrolperiodsprecede thecase periodonlyby2–3weeksalsoaccountsforapotential effectofseasonalvariation.

However,toourknowledgeonlyafewstudieshaveshownthe associationbetweenambienttemperatureandstrokeoccurrence usingthisstudydesign [6,7,23].Oneinvestigationconductedin SouthKoreashowedthatstrokeriskwasassociatedwithdecreases inambienttemperatureof5◦Cforariskperiodof1day(adjusted OR=1.4,95%CI:1.1–1.6)[6].AstudyconductedinGermanyfound norelevantassociationsbetweentemperatureandstrokealthough therewasatendencyforhigherriskwithchangesinmaximum temperature(eitherdownwardsorupwards)greaterthan5◦C(one daylag-time);however,theauthorsalsoanalyzedminimumand meantemperaturesobtainingsimilarresults[7].Morerecently,a case-crossoverconductedinTheUnitedStatesshowedthattherisk

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Fig.2. Minimumtemperature(monthlymedian)andmaximumdeclineinminimumtemperaturebetweeneverytwoconsecutivedaysineach7-dayperiod(monthly median),betweenAugust1,2005andJuly31,2006.

ofischemicstrokewashigherfollowinga5◦Cdecrementinaverage apparenttemperatureoverthe2daysprecedingsymptomonset. Theriskdidnotvaryacrossstrataofstrokeriskfactorsnamelysex, age(<65vs.≥65),smokinghistory(current,former, never), his-toryof diabetesmellitus,hypertensionor atrialﬁbrillation;this study,however,didnotinclude hemorrhagicstrokeeventsand wasconductedinapopulationwithdifferentbaseline character-istics(mostlywhite,youngerpatients,withlowerprevalenceof hypertension)[23].

Thedifferentlag-timesandmagnitudeoftemperaturevariation usedinthepreviousstudiesmayreflecttheclimaticdifferences betweencountries,sinceMozambiqueisacountrywithfairlyhigh temperaturesthroughouttheyearandsmallday-to-dayvariations, whichmayhaveagreaterimpactonthebiologicalmechanisms involveddue toamore difficultadaptation[24,25].Also, asour findings show a stronger association with hemorrhagic stroke events,theeffectofambienttemperatureinsettingswithlower proportionofthissubtypecouldbelesspronounced.These het-erogeneousfindingsreinforcetheneedforlocale-specificdatafor furtherunderstandingtheeffectsoftemperatureontheoccurrence ofstroke.Itwaspreviouslyshownthatmeansystolicanddiastolic bloodpressuretendtobehigherduringcoldermonthsandthatcold exposurecanexacerbatehypertensioninhypertensiveindividuals

[10];thismayreﬂectincreasingsystemicvascularresistanceand oxygendemand,potentiallyleadingtoischemia,aswellasthefact thatindividualswithhypertensionarelesseffectiveincold adap-tationduetoautonomicnervoussystemdysregulation[26].The

lattermayalsoapplytodiabeticsubjects[27],buttherewasno signiﬁcantlyhigherriskinthesepatients.

Thefact thattheeffectoftemperatureonstrokeoccurrence wasnotimmediateandwasverifiedforarelativelysmall temper-aturedropwhencomparedtopreviousevidence[28],supportsthe theorythatalthoughhypertensionislikelytobeinvolvedinthe relationshipbetweenambienttemperatureandstroke,the mech-anisms underlining this associationgo furtherthan theinstant influenceonbloodpressurelevelsandcouldbemediatedbythe pro-inflammatorystateandhypertension-associated dysautono-mia or to be influenced by other variables such as infections, changesinvasoactivepeptidesserumconcentration, hypercoagu-labilityandothers[10,29].Furtherclarificationofthemechanisms throughwhichtemperaturecanelicitstrokeonanhypertensive individualisnecessary.

We foundno associationwithtemperature dropsfor recur-rentstrokeevents.Previouslyconductedinvestigationshowedthat recurrentstrokeriskvariedaccordingtogeographicalregion, inde-pendentlyofthepresenceofstrokeriskfactors[30].Thoughnot fullyunderstood,differencesmightberelatedtofactorssuchas geneticvariation,environmentalfactors,healthcare accessibility andinfectiousdiseaseexposure,whichcanalsoexplainourresults. Mostpreviousstudiesshowedhighersusceptibilityto temper-aturechangesintheelderly,duetolesseffectivecoldadaptation

[6,31].Inourstudy,nosignificantvariationwasobservedacross age-groups, which may reflect the specificities of this setting regardingthemeanandday-to-dayvariationintemperature,as

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Table2

Associationbetweenthemaximumdecreaseinminimumtemperatureand inci-denceofaﬁrststrokeevent,using0–7daysbeforetheeventsascaseperiod(D0–D7) and14–21and21–28daysbeforetheeventasthecontrolperiods(D14–D21and D21–D28,respectively)(N=593).

AdjustedOR(95%CI)a_for_≥2.4◦_C_vs.

<2.4◦_Cb_decrease_in_minimum temperature Allparticipants 1.39(1.11–1.74) Sex Women 1.38(1.00–1.93) Men 1.40(1.04–1.89) Age 25–44years 1.52(0.83–2.77) 45–64years 1.51(1.12–2.05) ≥65years 1.16(0.78–1.74) Strokesubtype Ischemic 1.32(0.98–1.78) Hemorrhagic 1.50(1.07–2.09) Hypertension Yes 1.37(1.08–1.75) No 1.40(0.65–3.04) Currentsmoking Yes 0.98(0.47–2.04) No 1.42(1.12–1.80)

Highserumcholesterol

Yes 0.79(0.42–1.47) No 1.53(1.20–1.96) Diabetes Yes 1.42(0.77–2.64) No 1.31(1.02–1.67) Atrialﬁbrillationc Yes 1.05(0.27–4.02) No 1.33(0.97–1.81)

Glasgowscoreatadmission

≤10 0.94(0.58–1.91)

11–15 1.45(0.93–2.26)

Vitalstatusat28-daypost-event

Alive 1.38(1.05–1.81)

Dead 1.49(1.00–2.11)

a_OR_adjusted_for_mean_relative_daily_humidity_(%)_and_mean_{precipitation}_(mm3₎

ineachcase/controlperiod.

b _2.4◦_C_corresponds_to_the_median_value_of_the_distribution_of_the_maximum

day-to-daydecreaseintheminimumtemperatureinthecaseperiod.

c _Analysis_conducted_only_for_ischemic_events.

wellasmoredifﬁcultiesintheaccesstohealthcareservicesby olderpeople.

Thepresentstudyprovidesrelevantinformationfor abetter understandingofthetriggeringofstrokebysuddentemperature changes,fromasettingwhereresearchonthistopicisscarce,and usingarobuststudydesign.Thereare,however,somelimitations thatneedtobeaddressed.Thisunidirectionalcase-crossover anal-ysisdoesnotallowforcontrollingoftime-variantconfounders(e.g.: levelofairpollutants;adherencetoantihypertensivetherapy)that couldnotbetakenintoaccount.Previousinvestigationshowthat higherpollution levels areassociated withan increasedrisk of stroke[32],anditwouldbeinterestingtostudyitsinfluenceinthe Mozambicancontext;nevertheless,Maputodoesnothaveheavy industryandroadtraffichasincreasedmostlyinthemorerecent years.Ourresultsarealsolimitedbythefactthatthedefinition ofthedayofthesymptomsonsetmaynotbeaccurate,asmany patientsarrivedinthehospitalseveraldaysaftertheindexdate, thusincreasingthepossibilityofmemorybiasandconsequently, themisclassification of thecase-period [14]. Althoughwe may hypothesizethatbadweathermaycontributetoamoredifficult accesstohealthservices,misclassificationmaybelesspronounced

whenconsideringtheday-to-dayvariationintheminimum tem-peratureacrossa7-dayperiod.Despitetheexposuretoambient temperatureisinﬂuencedbyhousingconditions,typeofworkand leisureactivities,intheMozambicancontext,wheremostofthe populationlivesinhouseswithpoorthermalinsulation,anhigh correlationbetweenindoorand outdoortemperaturestowhich mostoftheparticipantswereexposedmaybeexpected[33].

Sincenopreviousregistrieswereconducted inMozambique includingalsopatientsnot seekinghealth careduetostroke,it isdifﬁculttopredicttheextenttowhichthissample underesti-matesstrokeincidenceinMaputoduringthisperiod,andtherefore ourconclusionsapplyonlytocasesofhospitalizedstrokepatients. Meteorologicalconditionsmayhavecontributedforsomepatients nothavingreachedanhospital,andtherefore,furtherstudiesare neededtounderstandtheeffectoftemperatureonstrokeevents thatweretakencareinthecommunity.

Becausewehadnoinformationregardingtravelingintheperiod beforestroke,orinthecorrespondingcontrolperiods,the inter-pretationofourresultsrequirestheassumptionthattravelingfor regionswithdifferentpatternsoftemperaturechangesisunlikely tohaveoccurred.

Thefactthatsomepatientsarrivedtothehospitalseveraldays afterstrokeincreasesthepossibilityofrecallbias,regardingthe dayofsymptomonset.Wehaveconductedasensitivityanalysis bystratifyingpatientsaccordingtodelayonreachingthehospital (<1dayvs.≥1day)andresultstherewasaslighterhigherriskof strokeforpatientsarrivingtothehospitalmorethan1dayafter strokesymptomonset. Thisresult probablyalso reﬂects differ-encesbetweenthesegroupsregardingstrokeseverityandaccess tomedicalcare.

Misclassificationregardingriskfactorsassessmentcouldalsobe present,althoughonlytheassessmentofsmokingstatusandhigh serumcholesterolwerebasedexclusivelyonself-report.Regarding atrialfibrillation,underdiagnosesispossibleasresultswerebased onasingleEKG.Nevertheless,African-originstrokepatientshave lowerprevalenceofatrialfibrillationandpreviousevidencehas shownanatrialfibrillationprevalenceof6.8%in blackpatients, whichis notfarfromtheprevalencefoundin ourstudywhich onlyaccountsforstrokepatients[34].Nostatisticallysignificant resultswereobservedwhentestingformallyforthepresenceof effectmodification(datanotshown),mostlikelyduetothesmall sampleinmanyofthestrataanalyzed;furtherstudieswithlarger samplesareneededtoconfirmourfindings.

5. Conclusions

Thisstudyshowedtheimpactoftemperaturechangesinthe triggeringof stroke events, in Maputo.Although the triggering effectobservedwassimilarregardlessof thevitalstatus ofthe patients28daysaftertheevent,theseresultsmaybeusefulfor theplanningofhealth-careservicesinMaputo,namelybyensuring thattheresourcesneededforthediagnosisandacutemanagement ofstrokeareavailableintheseperiods,whichisrelevantinasetting herehealthresourcesarescarce.Futureresearchshouldcontinueto pursuetheclariﬁcationofthemechanismsunderlyingthecascade ofeventsthatunderlietherelationbetweentemperaturechanges andthetriggeringofstroke.

Sourcesoffunding

DatacollectionfundedbytheMozambicanMinistryofHealth andtheAfricanRegionalOfﬁceoftheWorldHealthOrganization. TheworkofA.D.and C.C.wassupportedbytheGrantNumber R24TW008908fromtheFogartyInternationalCenter.Thecontent issolelytheresponsibilityoftheauthorsanddoesnotnecessarily

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representtheofficialviewsoftheFogartyInternationalCenteror theNationalInstitutesofHealth.Thisawardissupportedbyfunds providedtotheNIHandHRSAunderthe“TomLantosandHenry HydeUnitedStatesLeadershipAgainstHIV/AIDS,Tuberculosis,and MalariaReauthorizationActof2008,”PublicLaw110-293,whichis morecommonlyknownastheU.S.PresidentsEmergencyPlanfor AIDSRelief(PEPFAR).CofundingisalsoprovidedbytheNIHOffice ofResearchonWomen’sHealthandtheOfficeofAIDSResearch.

Conﬂictsofinterest

None.

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