Breakthrough magazine, Autumn 2022

breakthrough

Breakthrough magazineispublishedbyMEResearchUK,a ScottishCharitableIncorporatedOrganisationwiththeprin‐cipalaimofcommissioningandfundinghigh-qualityscientific (biomedical)investigationintothecauses,consequencesand treatmentofMyalgicEncephalomyelitis/ChronicFatigue Syndrome(ME/CFS).Weinfluence,informandinvestinME researchgloballybyidentifyingpotentiallyimportantareasfor futurebiomedicalresearch,andbyproducinghighqualitypro‐fessionalreviewsandreports. Breakthrough isanopen-access publicationand,apartfromimagesandillustrations,thecon‐tentmaybereproducedfreeofcharge,subjecttotheterms andconditionsfoundatmeres.uk/bt-terms. ©MEResearchUK,2022–SCIOCharityNo.SC036942

TheGateway,NorthMethvenStreet, Perth,PH15PP,UK Tel:01738451234,Email:contact@meresearch.org.uk

Inthespotlight

What’shappeningintheworldofMEresearchandfunding

Editorial

“TheTimesTheyArea-Chan‐gin’”.BobDylanmayhavewrit‐tenthissongnearlysixtyyears ago,butthelastsixmonthshave certainlyseenalotofchange.

Despitetheturmoil,were‐mainhopefulthattheinitiative startedbySajidJavidwillcon‐tinuetofruition,andweplanto remainactivelyengagedinthe developmentofaresearch strategytoinformacross-gov‐ernmentdeliveryplanforME. Manychallengeslieahead,but wearecommittedtodoingour utmosttoeffectpositivechange. There’smoreonpages4and5.

Wearedelightedtowelcome DrKeithGeraghtytoourteam, andpage7givesalittleofhis backgroundandhisnewrole withus.Oneofhisfirsttaskswas toattendthe2022IACFS/ME conference,andhisreportonthis largeeventisonpage6.

NunoSepúlvedahasnow publishedinterestingresultsfrom hisstudylookingforEBVbio‐markers,andplansafollow-up. Fulldetailsareonpage9.We werealsodelightedtoannounce oursecondPhDgrant(jointly fundedwithActionforME)at King’sCollegeLondon,whichis focusedonthegeneticbasisfor

ME.Page11givesmoredetails.

Ourlatestcallforgrantap‐plicationsgeneratedsignificant interestfromresearchersglobally, andwenowhaveover£1mil‐lionofpotentialresearchgoing throughourreviewprocess.

CortJohnson’slatest‘postcard fromNevada’isonpage13,and providesafascinatinginsightinto threeareasofresearchthatwar‐rantfurtherexploration.

Onpage16youcanreada round-upofrecentlypublished research,acommonthemebeing thecontinuingneedtoseefol‐low-upstudiestoreplicatefind‐ingsandprovidethespurfor large-scaleresearchprojects.

Ofcourseeverythingwedois onlypossibleasaresultofyour support.Thisissue,inparticular, highlightssomewonderfulex‐amplesofthefundraisingactivit‐iesthathelpuscontinueour workonyourbehalf.

Onafinalnote,Christmasis justaroundthecorner(!)andour Christmascardcollectionisnow availableforpurchase.

Thankyouforyourcontinued supportandenjoytheissue.

JonathanDavies Chair,BoardofTrustees

Christmas Cards2022

OurChristmascardsare nowavailabletoorder (forresidentsofGB,the IsleofManandthe ChannelIslandsonly). There’sagreatselection tochoosefrom,andyou canalsoorderonlineat shop.meresearch.org.uk. Asalways,theproceeds gotohelpsupportour work. Ifyouwouldprefernot tosendaphysicalcard, dontsendmeacard.com hasagoodselectionof digitalcardsandallows youtomakeadonation tous.

TheBigGive

TheBigGiveChristmas ChallengeistheUK’s largestmatched-funding campaign,andMEResearchUKistakingpart againthisyear.

Supportershavealready pledged£7,000,sothe first£7,000ofdonations madeontheBigGive’s websitefrommiddayon29 Novemberuntilmiddayon 6December2021willbe matchedbythepledgers. Eachdonationisdoubled.

Wemayalsobechosenfor CharityChampionfunding, whichwouldaddafurther £7,000tothepledgepot.

Informationonhowto makeadonationwillbeon ourwebsiteandsocialmediaduringthecampaign. Asalways,allfundswe raisewillbeinvestedinME researchglobally.

Rollercoastersummer

UKGovernmentcommitstoMEresearch

MEAwarenessDay,on12May 2022,kickedoffanexciting coupleofmonthsashopeswere raisedofaneweraforME/CFS researchfunding,andUKGov‐ernmentcommitmenttolisten andbelievethoseaffected.

Itstartedwiththepublication oftheresultsoftheME/CFS PrioritySettingPartnership (PSP),whichaimedto“identify andprioritiseevidenceuncer‐taintiesinparticularareasof healthandcarethatcouldbe answeredbyresearch”.

Thetoptenpluspriorities theyarrivedataresummarised intheboxopposite.

Atthesametime,theRtHon. SajidJavid,thenSecretaryof StateforHealthandSocialCare, issuedaverywelcomestatement pledgingtheGovernment’ssup‐portofthesepriorities,andan‐

nouncingacross-Government deliveryplanforME/CFS.

Thenextstagewasameeting co-chairedbyMrJavidandthe ChiefScientificAdviser,Pro‐fessorLucyChappell.

Thiswasattendedbyfunders, researchers,charitiesandpeople withME/CFS,andMERe‐searchUKwasrepresentedby ourChair,JonathanDavies.

Underdiscussionwerethere‐searchprioritiesidentifiedbythe PrioritySettingPartnership,the overlapswithlongCOVID,the needtoencouragenewresearch‐ersintoME/CFS,andhowre‐searchfundingcanbeimproved.

Thenewlyformedsubcom‐mitteeonMEresearch(under theguidanceoftheUKClinical ResearchCollaboration)then haditsfirstmeetingon30June.

Unfortunately,theseexciting

developmentswereputinto questionwiththeresignationof MrJavidon5July.

Theflurryofactivityinthe precedingcoupleofmonths meantthatmeetingsbetweenre‐searchers,charities,patientrep‐resentativesandtheHealth Departmenthavealreadytaken place,coveringpatientexperi‐ence,educationandtraining, andresearch.

Furthermore,astructurewith ataskandfinishgroupandthree sub-committeeshasalreadybeen established,andanumberof constructivemeetingsheld.ME ResearchUKattendstheME/ CFSResearchWorkingGroup. Itisenvisagedthattheprocess willculminateinthepublication ofawide-rangingdeliveryplan onME/CFSwithintwoyears.

Whatevertheoutcome,ME ResearchUKremainscommit‐tedtoinvestingintheverybest ME/CFSresearch.

Top10(or11)ME/CFS researchprioritiesofthePSP

1.Whatisthebiologicalmechanismthatcausespost-exertionalmalaise(symptomscausedormadeworseby physical,mentaloremotionaleffort,whichcanbe delayed)inpeoplewithME/CFS?Howisthisbest treatedandmanaged?

2.Whichexistingdrugsusedtotreatotherconditions mightbeusefulfortreatingME/CFS,suchaslowdose naltrexone,ordrugsusedtotreatPosturalOrthostatic TachycardiaSyndrome(POTS)?

3.HowcananaccurateandreliablediagnostictestbedevelopedforME/CFS?

4.IsME/CFScausedbyafaultyimmunesystem?IsME/ CFSanautoimmunecondition?

5.AretheredifferenttypesofME/CFSlinkedtodifferent causesand/orhowsevereitbecomes?Dodifferent typesofME/CFSneeddifferenttreatmentsand/orhave differentchancesofrecovery?

6.WhydosomepeopledevelopME/CFSfollowinganinfection?IstherealinkwithlongCOVID?

7.Whatcausesthecentralandperipheralnervoussystems (brain,spinalcordandnervesinthebody)tomalfunctioninpeoplewithME/CFS?Couldthisunderstanding leadtonewtreatments?

8.IsthereageneticlinktoME/CFS?Ifyes,howdoesthis affecttheriskofME/CFSinfamilies?Couldthisleadto newtreatments?

9.WhatcausesME/CFStobecomesevere?

10.Howaremitochondria,responsibleforthebody’senergyproduction,affectedinME/CFS?Couldthisunderstandingleadtonewtreatments?

10+.Doespoordeliveryoruseofoxygenwithinthebody causeME/CFSsymptoms?Ifso,howisthisbesttreated?

Atimeforoptimism

Keythemesfromthe2022IACFS/MEconference

Theannualconferenceofthe IACFS/MEtookplaceinJuly, andDrKeithGeraghty,ournew ScienceandResearchLead,at‐tendedonbehalfofMERe‐searchUK.

TakingonanewlookpostCOVID,theconferencewashos‐tedinavirtualauditoriumforat‐tendeestomingleandpresent theirlatestresearchfindings. Therewere58speakers,20 posterentrantsandalmost300 attendees,includingmanyearlystageresearchers.Thisgrowthin numbersreflectsincreasingin‐terestinME/CFSamongscient‐istsandhealthprofessionals internationally.

LongCOVID

Themoststrikingdifference frompreviousconferenceswas theinclusionoflongCOVID, withmultipletalksonfatiguefol‐lowingacuteCOVID-19.One peculiarupsideofthepandemic isthatithasreinvigoratedthe scientificcommunitytorecon‐

siderandinvestigatepost-viralfa‐tigue,withobviousbenefitsfor ME/CFSresearch.

Prof.AkikoIwasakifromYale MedicalSchoolprovidedanes‐peciallyinsightfultalkonthebio‐chemicalsignaturesoflong COVID,andpresentedresults showinghowshewasableto identifyanddifferentiatelong COVIDpatientsbasedonblood analysisofimmunemarkers,an‐tibodiesandhormones.

POTS

Posturaltachycardiasyndrome (POTS)–anabnormalincrease inheartrateaftersittingupor standing–wasperhapsthecent‐ralthemeoftheconference.For example,LaurenStilesof StonybrookUniversityspoke aboutthehighprevalenceof POTSinbothME/CFSand longCOVID,highlightingthe manyteststhatcouldbeper‐formedtoidentifyPOTS,and thetreatmentsavailabletotreat thecondition.

Inflammationupregulated

Inflammationofthebrainand centralnervoussystemwasan‐othermajortheme,andDrGun‐narGottschalkoftheSimmaron ResearchCentrespokeaboutthe roleofATG13,aproteinin‐volvedincausingdamagedorin‐fectedcellstodieoff.ATG13is stronglyupregulatedintheblood ofME/CFSpatients,indicating impairmentinthisprocess.

PEM

Anotherhighlightwasanillu‐minatingtalkbyDrDavidSys‐tromfromBrighamand Women’sHospital.Hespoke aboutthepathophysiologyof post-exterionalmalaise(PEM), andhowitcanbeprovokedand investigatedbyastresstest.He believesPOTSandPEMarere‐lated,andtheprimarycausemay lieinthemitochondria.

YoucanreadKeith’sfullreports fromthisyear’sconferenceon ourwebsite.

DrKeithGeraghty

Meetournewcolleague

Wearedelightedtowelcome Keithontotheteamasthenew ScienceandResearchLeadfor MEResearchUK.

Hisfirstworkforthecharity hasbeentoestablishasteady streamofarticlesonourwebsite andsocialmedia,keepingsup‐portersup-to-dateonnewME/ CFSresearchnews.

Keithisalreadywellknown andrespectedintheME/CFS field.Heisanexperiencedhealth researcherwhohaspublished morethanthirtypapersandart‐icles.Buthealsobringstheper‐spectiveofapersonwithME/ CFS,havingbeendiagnosed withtheillnessseveralyearsago.

HegrewupinIreland,and movedtoWalestostudyat CardiffUniversity(partlydueto itsproximitytotheBrecon Beaconsandopportunitiesfor hillwalking).

Aftergraduating,hegothis PhDandstartedapostdoctoral

career,butthenmovedintoclin‐icalmedicineashewantedtodo moredirectlywithpatients.

DuringhistrainingKeithcon‐tractedanunexplainedviralill‐ness,leavinghimveryunwell andincapacitatedforseveral years.Hisdoctorswereper‐plexedbyhissymptomsanddia‐gnosedpost-viralfatigueand chronicfatiguesyndrome.

Herecallshowsuchanillness hadhardlyeverbeenmentioned atmedicalschool,meaninghe hadlittleunderstandingofhis ownprognosis.

Havingabackgroundinre‐search,Keithfeltcompelledto lookforanswersforhimself.He startedresearchingME/CFSby speakingtoexpertsandreading theliterature,andthenreturned toacademiaasaresearchfellow attheUniversityofManchester.

Hisworkhasincludedwriting aboutthelackofevidenceand potentialharmsofCBTand

Christmas shopping

Whenyoushoponlinefor Christmasthisyear,you couldalsoberaisingfunds forMEResearchUK,atno extracosttoyou.

Visitsmile.amazon.co.uk andselectMEResearchUK asyourchosencharity,or useeasyfundraising.org.uk whichhostssomeofthe UK’sbestonlinestores. Notonlywillyoubeaccessingsomegreatdeals, butyouwillalsoberaising fundsforMEResearchUK withoutcostingyouanextrapenny.

GET,aswellashighlightingthe methodologicalflawsinthe PACEstudy.Headvocatedfora newapproachtoME/CFS–one thatrecognisesthebiologicalfea‐turesoftheillnessandtheir pathophysiologicbasis.Hewas alsocommissionedbyNICEto presentevidenceontheviewsof peoplelivingwithsevereME/ CFSduringtheirguidelinere‐view.

SoKeithhasconsiderable knowledgeofME/CFS,and bringsawealthofexperienceto hisnewroleinMEResearch UK,andweverymuchlookfor‐wardtoworkingwithhim.

Signature style

Theemergenceof longCOVIDhas highlightedthepo‐tentiallong-term consequencesofaviralinfection, leadingtosymptomssuchasfa‐tigue,musclepainandbrainfog thatcanlastforweeksormonths.

Thesesymptomsareshared bypeoplewithME/CFS,many ofwhomalsoreportaviraltrig‐gerfortheirillness.Butwhich virusesareassociatedwithME/ CFS,andhowmightthisinform‐

ationhelpinitsdiagnosis?

OnecandidateisEpsteinBarrvirus(EBV),longsuggested asatriggerforME/CFS.Inhis recentwork,fundedbyMERe‐searchUKwiththesupportof theFredandJoanDaviesBe‐quest,DrNunoSepúlvedafrom theLondonSchoolofHygiene &TropicalMedicinehasbeen takinganotherlookatthisim‐portantpathogen.

Nearlyallofusareinfected withEBVatsometimeinour

lives,andinmostcasesourim‐munesystemcanfightitoff.But thevirusisknowntocausesev‐eraldiseases(includingautoim‐muneconditions),andpeople withME/CFSareoftenfoundto haveactiveEBVinfectionsoran‐tibodyreactivityagainstEBV.

Antibodysignatures

Inpreviousexperiments–using datafromProf.Carmen

Scheibenbogen’sgroupatChar‐itéUniversitätmedizinBerlin–

NunoSepúlvedaandcolleagueshave publishedresultsfromtheirstudylooking for EBVbiomarkersinME/CFS

DrSepúlvedaidentifiedanum‐berofEBV-derivedproteins(an‐tigens)thatwereincreasedor decreasedinME/CFSpatients comparedwithcontrolsubjects.

Hehasnowextendedthis workbylookingspecificallyfor antibodysignaturesthatcould serveasbiomarkersforME/ CFS,andfocusingonpatients withaninfectioustriggerattheir diseaseonset.

Theresearchwasconducted incollaborationwithanumber ofotherresearchers,including Prof.ScheibenbogeninBerlin, andDrElianaLacerdaatthe LondonSchoolofHygiene& TropicalMedicine.

Thegroupanalysedantibody responsesagainst3,054EBV-de‐

rivedantigensin92patientswith ME/CFSandin50healthycon‐trolsubjects.Fifty-fourofthepa‐tientsreportedanacuteinfection atthetimetheirdiseasebegan.

Thefirstroundofanalyses didnotfindanyantibodiesasso‐ciatedwithME/CFS,butthis changedwhenthepatientswere dividedintosubgroupsbasedon theirdiseaseonset.

Infectioustrigger

Whiletherewerestillnoassoci‐ationsamongthosewithanoninfectiousorunknowndisease trigger,inME/CFSpatientswith aninfectionatdiseaseonsettwo antibodyresponseswerestronger thanseeninhealthycontrols.

Furtheranalysesshowedthat

thesetworesponsescoulddistin‐guishthissubgroupfromcontrols withahighsensitivityandspe‐cificity,andmaythereforehave potentialinthediagnosisof theseME/CFSpatientswithan infectioustrigger,specifically thoseaffectedbyEBV.

Theresearchersplantocon‐firmthesefindingsinotherco‐hortsofpatientsfromtheUK ME/CFSBiobank.Theyalso suggestthattheEBV-derivedan‐tigensidentifiedmayprovide someevidenceofhowthereact‐ivationofEBVplaysarolein thedevelopmentofME/CFS.

AsCortJohnsonpointedout onourwebsitelastyear,viruses haven’tgoneawayinME/CFS, they’vejustgotmoreinteresting.

DrElianaLacerda

DrNunoSepúlveda

Prof.CarmenScheibenbogen

Anewclass

NewPhD-levelresearchlookingat the involvementofRIPsinME/CFS

InJuneofthisyear,ME ResearchUKandAc‐tionforMEwerede‐lightedtoannounce jointfundingforaPhD-levelre‐searchprojectatKing’sCollege London.

ThisisoursecondPhD-level researchproject,andourfirst suchfundingcollaborationwith ActionforME.

Thenewprojectisbeingcon‐ductedbyPhDstudentLuke Marney,underthesupervisionof DrAlfredoIacoangeli,andisfo‐cusedonthegeneticbasisof ME/CFS.

Thebiologicalabnormalities leadingtothedevelopmentof ME/CFSarenotwellunder‐stood,butgeneticsarethoughtto playanimportantpart.Thisnew projectwilllookataspecifictype ofgeneticvariationcalledan RIP(retrotransposoninsertion polymorphism).

Retrotransposonsarepieces ofDNAoftenreferredtoas

jumpinggenesbecausetheycan movearoundwithinthegenome ofacell,potentiallycausing mutations(RIPs)thatcanchange thefunctionofthatcell.

RIPshavebeenimplicatedin thedevelopmentandprogression ofdisorderssuchasmotorneur‐onediseaseandParkinson’sdis‐ease,andthisprojectaimstouse genetic-sequencingdatafromthe UKBiobanktodetermineifa

specificRIPorsetofRIPsisalso involvedinME/CFS.

Aswellascontributingtoa betterunderstandingofME/ CFS,thisresearchmayhelp identifynewdirectionsfortreat‐ingthedisease.

Bothcharitiesareexcitedby theopportunitytoworktogether, andtohelpsupportthisimport‐antnewresearchandaPhDstu‐dentatthestartofhiscareer.

Callforapplications

Inthe22yearssinceourformation,MEResearchUKhas funded60researchprojectsatatotalcostofnearly£3 million.Butwearecertainlynotstoppingthere.

InJuly,weannouncedanewcallforapplicationsforour researchgrants,andthesearecurrentlyprogressing throughourrigorousreviewprocess.

SowehopetobeabletoannouncemorenewME/CFS researchinthemonthsahead–moreprogressinunderstandingthediseasebetterandinfindingacure.

Postcard from Nevada

Inhislatestpostcard, CortJohnson looksatsomeoftheroadsnot(yet) takeninME/CFSresearch

Thisispotentiallya richtimeforME/ CFSresearch.The recentlongCOVID studiespresentapictureofadis‐easethat–withissuesrelatingto lowcortisol,exercise,immune exhaustion,Epstein-Barrvirus reactivationandbloodvesselab‐normalities–looksuncannily similartoME/CFS.Itseemsas ifbroadthemesarebeginningto emerge.

That’sgoodnews,butME/ CFSisacomplexandpoorly

fundeddisease.Itsresearchhis‐tory–nowdatingbackalmost fortyyears–includessome effortsthatdidn’tpanout,some thatdid,andsomethatseemed topanoutbutforonereasonor anotherweredroppedornever fullyexplored.Let’stakealook atthreeofthoseunexplored roads.

Brainsonfire? Neuroinflammationsticksout herelikeasorethumb.The2014 Nakatomistudy–whichcon‐

tainedamerenineteenparti‐cipants–washeraldedasoneof themostpotentiallyimportant studiesinME/CFShistory. Therewasgoodreasonforthat: lowlevelsofwidespread neuroinflammationmadesense givenwhatweknowaboutthe disease.

Sincethen,neuroinflamma‐tionandactivationofmicroglia (immunecellsinthebrainand nervoussystem)havebecomehot topics.Theywerefeaturedprom‐inentlyinthreerecenthypo‐

theses.Researchersarecurrently huntingforeffectivemicroglial inhibitors,whilemodellingstud‐iessuggestthatneuroinflamma‐tionmayneedtobeaddressed firstforothertreatmentstosuc‐ceed.

Yetdespiteallthisinterest,in theeightyearssincethepublica‐tionoftheNakatomistudy,only twosmallstudieshavebeenpub‐lished–aDutchstudyand JarredYounger’sthermography study,whichproducedconflicting findings–leavingtheME/CFS fieldinthedarkaboutwhether ornotitreallyexists.

That’sashame.Thefinding ofneuroinflammationwouldpo‐tentiallyalignME/CFSwith well-fundedneurologicaldiseases suchasmultiplesclerosis,Parkin‐son’sdiseaseandAlzheimer’sdis‐ease.Researchersareactively searchingforwaysto‘quenchthe fires’intheseconditions.Docu‐mentingthatneuroinflammation existsinME/CFScouldfurther

CortJohnson

legitimiseit andultimately openupnew treatmentop‐portunities.

Neuroin‐flammation studiesare thankfullyun‐derwayinlong COVID.Per‐hapsJarred Younger’son‐going,MERe‐searchUKfundedstudy

lookingatimmunecellinfiltra‐tionofthebrainwilltakeafew morestepstowardsanswering thisquestionforME/CFS.

Theparadox

Evidencesuggeststhereisapara‐doxinbothME/CFSandpos‐turalorthostatictachycardia syndrome(POTS).

Thelowbloodvolumefound inboththeseconditionsshould triggertherenin-angiotensin-al‐dosteronesystem(RAAS)tohelp maintainbloodpressure.This systeminvolvesanincreasein renin,leadingtoproductionof angiotensinwhichthenstimu‐latesthereleaseofaldosterone.

However,reninandaldoster‐onelevelsarelowinthesecondi‐tions.And,tomakematters moreconfusing,angiotensin levelsareveryhigh.

Hencetheparadox–inthe midstoflowbloodvolumelevels, theendproductoftheRAAS system,aldosterone,which

shouldbeincreased,isactually lowerthannormal.

Thearetwoarmstothe RAASsystem.Oneturnsonan‐giotensinIIwhichtriggersa bunchofactivity(bloodvessel vasoconstriction,sympathetic nervousactivityandinflamma‐tion)weprobablydon’twant happeninginME/CFS.The other(lessactiveinME/CFS)is anti-inflammatory.Twostudies haveimplicatedaculprit:re‐ducedactivityoftheACE-2en‐zyme.

Allinall,it’saprettyimport‐antsystemtohavereceivedal‐mostnoresearchinME/CFS. Buthere’swhereitreallygetsin‐teresting.

Inabizarrecoincidence,it turnsoutthatthecoronavirus enterscellsthroughthesame ACE-2receptorthatappearsto bemalfunctioninginME/CFS andPOTS.

That’sledtothesamescen‐ariobeingsuggestedfor COVID-19,ME/CFSand POTS:reducedACE2activation andincreasedactivationofthe classicalorinflammatoryarmof theRAAS.

ThereducedACE2activa‐tioncouldberesponsibleforalot ofmischief.It’sbeenassociated withimpairedoxygenuptake,in‐creasedoxidativestress,leaky gut,problemswithlungperfu‐sion,reducedvasodilationofthe bloodvesselsandinflammation.

It’sevenbeensuggestedthat theincreasedangiotensinII couldbecausingnegativereac‐

tionstothecoronavirusvaccines. That’saninterestingpossibility giventhehighangiotensinII levelsfoundinME/CFS.

There’sabigproblem, though.Despiteitspotentialfor mischief,letaloneitspossible connectiontoCOVID-19and longCOVID,becauseonlytwo smallstudiesoftheRAASsys‐temhavebeendoneinME/ CFS,wedon’treallyknowifthe RAASisarealproblemornot. Surelythoughit’saresearcharea thatcouldusemoreexploring.

Thegenderissue

Fromtheverybeginningsofthis illness,it’sbeenclearthatit strikesmanymorewomenthan men.But,decadeslater,it’sre‐markablehowlittleweknow aboutthisphenomenon.

Hamperedbylowfunding, smallsamplesizesandthecom‐plexityofthehormonalsystem, genderhasrarelybeencon‐sidered.SomeME/CFSand

fibromyalgiaresearchhascoped withtheissuesimplybylocking menoutoftheirstudies.

Ifyou’renotamanthat’snot abadstrategyasthegenderissue inME/CFScouldbeahuge one.Studiessuggestthatmen andwomenhavealteredgutmi‐crobiomes,heartratevariability, responsestoexerciseandmicro RNApatterns–andthismay justbethetipoftheiceberg.

Therearesomecluesasto whatishappening.Anincreased incidenceofME/CFSduring timesofmajorhormonal changes(adolescence,pregnancy, perimenopause)pointsatthesex hormonesbeinginvolved.Sodo thehigherratesofgynaecolo‐gicaldisorders,pelvicpain,men‐strualabnormalitiesand surgeries(especiallyhysterectom‐ies).

Modelssuggestthatthe highertestosteronelevelsfound inmenmaybeprotective,while highoestrogenlevelsinwomen

mayincreasetheirrisk.Likewise, highprogesteroneandtestoster‐onelevelsappeartoprotect againstpaininfibromyalgia, whilelowprogesteroneandhigh cortisolpromoteit.

Withsimilargenderimbal‐ancesfoundinME/CFS,long COVID,fibromyalgia,postural orthostatictachycardiasyn‐drome,migraineandmore,it’s clearwe’llneverfullyunderstand thesediseasesuntilthegender imbalanceisexplained.

Inafieldscrappingforfunds, thegenderimbalanceproblem presentsanaddedcomplication thatmostfunderswouldunder‐standablyrathernotdealwith. Thecureforthatproblem–as withalloftheseunexploredav‐enues–isastraightforwardone: morefunding.

LongCOVIDshouldbeget‐tingthatfunding.Andifthose scientiststakethetimetocheck outME/CFSresearch,theywill findsomerichveinstomine.

Researchbites

Ourround-upofrecentresearchfromaroundtheworld

Whenthebodybreaksdownnutrientstogenerate energy (aprocesscalledmetabolism),itproduces substancesknownasmetabolites.Thestudyof thesemetabolites (metabolomics) cantellusmore abouttheactivityandstateofcellsandtissues,and hasprovedusefulinunderstandingthecausesof diseaseandidentifyingbiomarkers.

Someexamplesofitsapplicationtodateinclude advancesinknowledgeaboutischaemicstroke,hy‐pertensivenephrosclerosisandglaucoma.Andthis istheapproachusedinarecentME/CFSstudy conductedbyresearchersatColumbiaUniversity.

Theinvestigatorsfoundthatlevelsofanumber ofimportantmetaboliteswereabnormalinpa‐

tientswithME/CFScomparedwithhealthycon‐trolsubjects.Somemetaboliteswerefoundtobeat lowerthannormallevels,whileotherswerehigher thannormal.

Accordingtotheresearchers,theirresultssug‐gestthatlipidremodellingisimpairedinthesepa‐tients.Lipidsareimportantcomponentsofevery cellwallormembrane,andlipidremodellingisin‐volvedinmaintainingthecellmembranes,aswell assignallingbetweencells.

Thesefindings,ifconfirmedinotherstudies, mayultimatelyhelpusunderstandmoreaboutthe diseaseprocess,andpotentiallydevelopbiomarkers fordiagnosis.

Mitochondrialsupplement?

Cash&Kaufman,J.ofTranslat.Med.,2022

OnemetabolitepotentiallydepletedinME/CFSis oxaloacetate,andanecdotalreportssuggestthatan oxaloacetatesupplementmayimprovephysicaland mentalfatigueinsomepatients.Whenitwastested inatrialof76ME/CFSpatients,treatmentwith thesecapsulesdidappeartoreducefatigueby around25%(assessedusingaquestionnaire).How‐ever,thestudydidnothaveaplaceboarmandit wasnotrandomized–bothconsideredvitalinas‐sessingtheefficacyoftreatments.Amorerigorous trialisthereforeneededtosupportthefindings.

IsfibromyalgiasimilartoME/CFS?

Ramírez-Moralesetal.,Autoimmun.Rev.,2022

Thereismuchdebateaboutwhetherfibromyalgia (FM)andME/CFSaresimilarillnesses.Whilethey sharecommonsymptomssuchaspainandfatigue, therearedifferencesintheirapparentcausesand presentation.Ananalysispoolingtheresultsof21 studiesfoundawell-definedclinicaloverlap betweenthetwoconditions–almosthalfofFM patientsmetdiagnosticcriteriaforME/CFS.The authorssaythismightreflectasimilarunderlying cause,suchasahistoryofviralinfectionleadingto autonomicdysfunctionandchronicinflammation.

PredictingsevereME/CFS

Jasonetal.,JournalofRehabilitationTherapy,2022

Around10%ofindividualswithinfectiousmono‐nucleosis(mono)meetdiagnosticcriteriaforME/ CFSsixmonthslater.Toinvestigatewhetherthey couldpredictthis,researcherslookedatseveral factorsincollegestudentswhohaddevelopedME/ CFSfollowingmono.Patientswithgastrointestinal symptoms,anirritablebowelandabnormallylow immunemarkersatthetimeofmonohadanal‐most80%chanceofdevelopingsevereME/CFS sixmonthslater.Thesefindingssupporttheim‐portanceofthesefactorsinthedevelopmentof ME/CFS.

Transmissionelectronmicroscopy

Jahanbanietal.,PloSOne,2022

Transmissionelectronmicroscopy(TEM)repres‐entsastepupfromtraditionallightmicroscopybe‐causethebeamofelectronsusedcanprovidemuch higherresolutionimagesandsocapturemuchfiner details.Butwhatcanthetechniquetellusabout ME/CFS?ResearchersatStanfordUniversityused TEMtolookatimmunecellsfrompeoplewiththe illness,andtheirfindingssuggestthatanincreased numberofthesecellsaredyingduetoapoptosis (programmedcelldeath)ornecrosis(causedby damage).Theyalsofoundabnormalitiesinthemi‐tochondria(whichgenerateenergyinthecell).

Changesinthehippocampus

Thapaliyaetal.,J.ofNeuroscienceRes.,2021

RecentresearchfromAustraliasuggeststhatsymptomsofME/CFS suchasfatigue,painandsleepdisturbancemaybelinkedtostructural changesinapartofthebraincalledthehippocampus.Thisregionis involvedincognition,memoryandregulationofthehypothalamus. Usingatechniquecalledmagneticresonanceimaging,theresearchers foundthatvolumesofspecificareasofthehippocampusweregreater inME/CFSpatientswhometthestrictInternationalConsensusCri‐teria(ICC)thantheywereinhealthycontrolsubjects.Thiswasnot thecaseinpatientswhometonlythemoregeneralFukudadiagnostic criteriaforME/CFS.

Furthermore,increasesordecreasesinthesizeofdifferent areasofthehippocampuswereassociatedwithsymptomsincluding fatigue,pain,sleepdisturbanceandphysicalfunction,andtheselinks werestrongerinICCpatients.Theresearcherssuggestthattheirfind‐ingsindicatethehippocampusmaybeinvolvedinsomeofthesymp‐tomsofME/CFS,includingbrainfog,memoryproblemsandthe abilitytodocomplextasks.However,theresultsneedtobereplicated onalargerscaletoconfirmthis.

Orthostaticintolerance

Vernonetal.,FrontiersinMedicine,2022

ME/CFSandlongCOVIDmaybothbeassoci‐atedwithorthostaticintolerance–abnormaldizzi‐nessorfaintingafterstanding.Inthisstudyof patientswitheitherillness,symptomsandother measureswereassessedfollowingaNASALean Testinvolvingperiodsofsittingup,lyingdownand standingup.Thetestworsenedsymptomsinboth patientgroups(butnotincontrols),andcaused narrowingofthepulsepressureandworsecognit‐ivereactiontimes.Theresearchersthereforere‐commendanorthostaticstresstestforallpatients withME/CFSorlongCOVID.

Measuringsleep

Yangetal.,QualityofLifeResearch,2022

Sleepdisturbancesareasignificantbutperhapsun‐der-researchedsymptomofME/CFS,soitisim‐portanttobeabletomeasuresleepqualityandits impactonqualityoflifeinpeoplewiththeillness. Thepatient-reportedoutcomemeasurementin‐formationsystem(PROMIS)hasbeendesignedto assesssleepdisturbance,sleep-relatedimpairment, paininterferenceandpainbehaviour.Thisstudy fromtheUSAshowsthatthesystemperformswell inpatientswithME/CFSforallfourofthese measures,andtheauthorssuggestitcouldbeused bothinresearchandinclinicalpractice.

“hippocampus maybe involvedin someofthe symptomsof ME/CFS”

Immunefunctioninadolescents

Jasonetal.,ChronicIllness,2022

Thereissomeevidenceofimmunedysfunctionin adolescentswithME/CFS,althoughthisisvaried. Toinvestigatethequestionmoreclosely,research‐ersinChicagotookbloodsamplesfromyouths aged5to17yearswithME/CFS,includinga groupwithseveredisease.Ananalysisofthecy‐tokinesintheblood(whichareinvolvedinregulat‐ingtheimmunesystem)identifiedapattern suggestingactiveinflammatoryresponses,andthis wasparticularlystronginthosewithseveredisease. Theresearcherssuggestthismayhelpinidentifying abiomarkerforpaediatricME/CFS.

Ionchannelfunction

Sassoetal.,MolecularMedicine,2022

TRPM3isanionchannelresponsiblefortrans‐portingionssuchascalciumbetweencells–apro‐cesswhichiscrucialfortheirnormalfunction.The findingofimpairedTRPM3activityinimmune cellsfrompatientswithME/CFSsuggeststhatthis maybeanimportantfeatureoftheillness,and couldpotentiallybetreatedusingadrugtorestore theinfluxofcalciumintothecell.Now,research fromAustraliahasfoundsimilarlyimpaired TRPM3ionchannelactivityincellsfrompatients withlongCOVID–moreevidenceofthesimilarit‐iesbetweenME/CFSandlongCOVID.

Fundraisingstories

Recentfundraisingactivitiesbyoursupporters. TosupportMEResearchUK,pleasevisitourwebsiteforideas.

VikingCoastalTrail

Watchingoutforlongboatson thehorizonthisAugustwere GraceMitchellandhermum Tracey,whowalkedtheeightmileVikingCoastalTrailtoraise fundsforMEResearchUK.The TrailbeginsnearRamsgate, followingclifftoppathstolink numerousbaysthroughMargate andalongtheseawallto Westgate-on-Sea,untilitreaches ReculverCountryPark.Thank yousomuchtoGraceand Traceyandtheirsupportersfor

fundraisingforus,andfor keepingthecoastofKentsafe frommarauders.

100milesdone

TerrySmithandhisdaughter Poppycontinuetheiradventure crossingthecountryfrom LiverpooltoGoolebycanoe. Takingitsectionbysection,asof writingtheyhadcompletedmore than100milesofthe162-mile trip.Terry’sbloghaskept supportersuptodatewiththeir progressandsightsalongthe

way,includinglotsofbirdlife suchasducks,geese,heronsand swans.KeepgoingTerryand Poppy!Youcansupportthem here:bit.ly/3odEvg9.

WakeboardingforME

Congratulationsandmany thankstoFinlayScottwho completedhischallengeto wakeboard50kminonedayto raiseawarenessandmoneyfor researchintoME/CFS,which hashadadevastatingimpacton hisyoungersister.

MontBlanc

KathrynAveyardhassetherself themonumentaltaskofclimbing MontBlancinaidofME ResearchUK.Thismulti-day hikeisasignificantchallenge requiringtheuseofspecialised equipmentsuchascrampons andiceaxes.“Ihavebeen trainingtotryandimprovemy enduranceandlungefficiency. Supposedly,duetothealtitude,

thesummitdayismore challengingthanrunninga marathon.”Thankyouandgood luck,Kathryn.Youcansupport herhere:bit.ly/3zDvvrA.

24-hourwarriors From9a.m.onFriday27May, aspartofTeam24Hour SportathonWarriors,Chrissy Nazifcompleteda24-hour sportathontoraisemoneyfor

MEResearchUKandTheLink Foundation(whichsupportslocal childrenandfamiliesin Maidenhead).Overthecourse ofthisperiod,theteamtookpart inmorethan24differentsports –“adreamcometrueforsome, anightmareforothers!”Thank yousomuchtoChrissyandthe restofthewarriorsfortheir efforts,whichraisedaterrific totalforthecharities.

MegaMayMiles

Maywasahugemonthfor fundraisingastheMegaMay MilesforMEteamwalked,ran, swamandcycledatotalofmore than1,000milesoverthecourse ofthemonth,inaidoftwoME researchcharitiesincludingME ResearchUK.Congratulations andthankyoutoeveryonewho tookpart.

SwimmingtheLakes

JoeWelton,WillMcCausland andTomGilbertsonhave

recentlycompletedtheir challengetoswimthefulllength ofeveryswimmablelakeinthe LakeDistrictoverthecourseof oneweek–atotaldistanceof 66kmacrossthirteenlakes.The threefriendsjoinonlyahandful ofpeopletohavemanagedthis feat.Whatafantastic achievement–wearesograteful fortheirfundraisingefforts.

Anautumnofreading Herearesomesuggestionsif you’relookingforyournextread.

01 Joe,Tom andWill headinginfor theirlastdayof swimming 02 Whatwill youreadnext?

03 Rackingup themilesthis May

Theauthorsarealldonating someoralloftheirroyaltiesto ourwork.RobertMcMullen’s StrangerandStranger tellsofan encounterinthelifeofaman withME(amzn.to/XDVnyK).

InJackCroxall’sacclaimed TethersTrilogy,KarlandEsther discoverananonymousjournal filledwithbizarrescribblings (amzn.to/1oqY9N2).Merryn Fergusson’s WhatisWrongwith ME isastoryofMEthroughthe experiencesofhersonChrisand hisfamily(amzn.to/X1Hw5w).

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