Clinical Rehabilitation 2006; 20: 67-78

Health problems and health-related quality of life inpeople with multiple sclerosisAngus Forbes, Alison While, Lucia Mathes and Peter Griffiths Primary and Intermediate Care Section, The FlorenceNightingale School of Nursing & Midwifery, King's College London, UK

Received 16th October 2004; returned for revisions 3rd December 2004; revised manuscript accepted 16th January 2005.

Objective: To explore the interrelationship between a number of common multiplesclerosis-related problems and health-related quality of life independent of the effectof physical disease impact.Design: A cross-sectional postal survey.Setting: The study was conducted in seven treatment centres within England.Subjects: Nine hundred and twenty-nine people with multiple sclerosis.Measures: The severity of the multiple sclerosis problems (fatigue, pain, urinaryincontinence, bowel, depression, pressure ulcers, sexual and employment problems)was assessed using 5-point self-report ordinal scales. Disease impact was measuredusing the Multiple Sclerosis Impact Scale-29. Health-related quality of life wasmeasured using the 36-Item Short Form Health Survey, version 2 (SF-36). Therelationship between the problems, disease impact and health-related quality of lifewas determined using multivariate analysis of covariance.Results: Seventy four per cent of the sample experienced four or more of theselected problems. The extent and severity of problems increased with the level ofdisease impact (P< 0.001). Fatigue, pain, employment, depression and relationshipproblems were all found to have negative effect on the SF-36 scales independent tothe effect of disease impact. SF-36 scores were most compromised in patientsexperiencing multiple problems. The data suggest an interdependent relationshipbetween depression, fatigue and pain.Conclusion: The data suggest that many multiple sclerosis complications negativelyaffect health-related quality of life, independent of the effect of overall diseaseimpact.

Introduction

Multiple sclerosis is heterogeneous progressiveneurological disorder that can result in a broadrange of physical, psychological and social pro-blems. The problems experienced vary depending

Address for correspondence: Angus Forbes, King's CollegeLondon, The Florence Nightingale School of Nursing &Midwifery, Research in Primary and Intermediate Care Section,James Clerk Maxwell Building, Waterloo Road, London SEI8WA, UK. e-mail: angus.forbes(kcl.ac.uk

2006 Edward Arnold (Publishers) Ltd

on the type, duration and extent of the disease andare often complex, interdependent and difficult tomanage. '

Health-related quality of life is a multidimen-sional concept related to an individual's percep-tion of their general well-being and level of rolefulfilment across a range of different physical,psychosocial and symptom-related phenomena.2The negative impact of multiple sclerosis onhealth-related quality of life is well documented.3While physical disability contributes much to this

10.1 191/0269215506cr880oa

68 A Forbes et al.

negative impact, psychosocial factors have alsobeen found to be important.4 There is a growinginterest in how the many specific problems asso-ciated with multiple sclerosis, such as fatigue anddepression, impact on different dimensions ofhealth-related quality of life independent of thecontribution of physical disability.F7

This paper explores the interrelationships be-tween a number of common problems associatedwith multiple sclerosis, disease impact and health-related quality of life. The multiple sclerosisproblems explored were related to specific impair-ments (fatigue, pain, urinary incontinence, bowelproblems, depression and pressure ulcers), activ-ities (sexual and relationship problems) and parti-cipation (employment problems).

Methods

The data used for this analysis were derived from alarge data set (n = 929) collected to evaluate anational programme of multiple sclerosis nursespecialists.8 Data were collected by postal surveyusing a piloted questionnaire containing validatedmeasures of disease impact and health-relatedquality of life. Data were collected at baselineprior to the appointment of any multiple sclerosisnurses. The study was approved by a multicentreresearch ethics committee.

Aim and objectivesThe analysis aimed to explore the interrela-

tionships between the identified problems andhealth-related quality of life. The objectives were:

1) to describe the frequency and severity of theselected multiple sclerosis-related problems;

2) to identify any differences in the severity ofthe problems in relation to the level of diseaseimpact;

3) to examine the effect of the problems onhealth-related quality of life (after adjustingfor the effect of physical disease impact); and

4) to explore whether there were any additiveeffects of the problems in combination onhealth-related quality of life.

SampleThe sample was drawn from the populations of

people with multiple sclerosis known to sevenneurology treatment centres located in five Englishregions: the South East (n = 2); East Anglia (n =1); the South West (n = 1); the Midlands (n = 1);and the North (n = 2). Everyone with multiplesclerosis (aged over 16 years) known to eachtreatment centre was invited to participate (n =1849). It was estimated (based on 1:1000 popula-tion) that this sample represented about half of thetotal population of people with multiple sclerosis(n = 3680) served by these treatment centres.

Data collectionThe questionnaires were mailed in the spring

and summer of 2000 to addresses held on thepatient records. Two reminder questionnaires weresent at three-weekly intervals to improve response.The questionnaire was reviewed by an expert panelwhich included: a neurologist; multiple sclerosisnurse specialists; people with multiple sclerosis;representatives of the UK Multiple Sclerosis So-ciety and Multiple Sclerosis Trust; and a neuro-physiotherapist. The questionnaire was piloted'face to face' with people with multiple sclerosis(n = 10) with varying levels of disability and as apostal instrument (n = 23). A full copy of the studyinstrument can be found at http://www.kcl.ac.uk/nursing/question. doc.Demographic and disease-related data were

collected. Participants were asked to categorizetheir multiple sclerosis as either relapsing/remit-ting, progressive or other. They were asked to statein years and months time since the onset ofsymptoms and their diagnosis and how theygenerally got around: 'walked unaided', 'with astick' or 'wheelchair'. They were also asked to ratetheir multiple sclerosis-related symptoms overall asmild, moderate or severe.The multiple sclerosis-related problems (fatigue,

pain, urinary incontinence, bowel problems, de-pression, pressure ulcers, relationship problems,and employment) were assessed using single itemsin the questionnaire. The items directed partici-pants to identify whether they experienced theproblem (yes or no) and to indicate the severity ofthe problem using 5-point ordinal scales (1 = 'not

Health problems in multiple sclerosis 69

at all', 5 ='very'). These problems were selectedwith reference to the expert panel.The questionnaire also contained validated in-

struments to assess the level of disease impact (theMultiple Sclerosis Impact Scale 29, MSIS-29)9 andhealth-related quality of life (SF-36 Short FormHealth Survey version 2).10The MSIS-29 provides two scales measuring

physical and psychological disease impact andhas reported satisfactory internal consistency,reliability and validity." The scale scores from 0to 100; the lower the score the lower the diseaseimpact. The MSIS-29 physical scale has beenfound to be highly correlated to the Barthel Index(r = 0.71)9 and the Expanded Disability StatusScale (EDSS) (r = 0.69),12 and although weakercorrelations were found in patients with moreadvanced disability the authors suggested thatthis was largely due to the limited variabilityinherent to the EDDS scale. The MSIS-29 wasalso highly correlated with the perceived level ofmultiple sclerosis severity (r = 0.71) and mobilityrating (r = 0.71) of the participants in the study.The physical scale of the MSIS-29 was used todetermine four groups of participants indicatingthe level of disease impact. These four groups weredefined as: minimal (score < 25), mild (score =25-49), moderate (score = 50-74) and severe(score > 74).The SF-36 provides a subjective measure of

health status across eight scales: physical function-ing, social functioning, role limitations due tophysical problems, role limitation due to emotionalproblems, mental health, energy/vitality, bodilypain and general health perception. The scalescores from 0 to 100; the lower the score the lowerthe health-related quality of life. A number ofvalidation studies of the SF-36 with people whohave multiple sclerosis have been undertaken.'3"14Overall these studies have reported acceptable dataon the internal consistency of the scales.

Data analysisAll analyses were performed in SPSS version 11

for Windows.

Objective ]The dichotomous variables and short ordinal

scales were used to group patients into fourcategories: those who did not experience the

problem (no problem); those who had someexperience of the problem, points 1-2 on theordinal scales; those who experienced it moder-ately, point 3; and those who experienced it moreseverely (points 4-5). Descriptive statistics werethen generated for each of the identified problemsin these groups. Data on employment problemswere only reported for participants who were inemployment and data on relationship problemswere only reported on those in an identifiedrelationship (specifically those who were marriedor were living with a partner). While it could beargued that relationship issues may exist outside ofthe participant's marital status, this exclusionfocused the analysis on the conjugal domain.

Objective 2The four problem groups (no problem, some,

moderate, severe) were cross-tabulated with thefour disease-impact groups (identified using theMSIS-29) to examine the relationship between theproblems and the level of disease-impact. Chi-squared analyses were undertaken to establishwhether there were any differences between thefour disease-impact groups.

Objective 3The relationship between the health problems

experienced, disease impact and the SF-36 scaleswas assessed using multivariate analysis of covar-iance within the general linear model. The analysistested the null hypothesis that there were nodifferences in SF-36 scale scores between the fourproblem groups (no problem, some, moderate,severe) independent of the effect of the underlyingdisability. If the main effect was significant, con-sideration was then given to the between-subjecteffects indicating which of the SF-36 subscalesshowed a significant difference between the groups.Confidence intervals were examined to determinewhich of the four groups contributed most to theobserved effects. Groups were considered distinctwhen there was no overlap between the confidenceintervals.The comparisons for fatigue and pressure ulcers

were restricted to moderate versus severe and noproblem versus problem (combining the moderateand severe groups) respectively, because of the verysmall group numbers in the other categories.

70 A Forbes et al.

Age (in years) and the MSIS-29 physical scalewere used as covariates to control for the con-founding effects of (physical) disease impact andage (age is also highly correlated with diseaseduration, r = 0.53), within the multivariate analysismodels. Correlation analysis between the depen-dent variables (the SF-36) and the covariatesrevealed multicollinearity (r > 0.5) between theMSIS-29 physical and the physical functioningand role physical scales of the SF-36. The physicalfunctioning scale was, therefore, dropped from theanalysis models and the role physical scale exam-ined with caution.

It is important to recognize the underlyingrelationship between some of the studied pro-blems and the scales within the SF-36: fatigueand the 'energy and vitality'; pain and the'bodily pain'; and depression and the 'mentalhealth'. Therefore, the relationship between thesevariables was not viewed causally but as a meansof validating the reported severity of the pro-blem from the single item self-report ordinalscales.To determine whether there were any additive

effects of the problems on the SF-36 scales, theproblems in which significant effects were observedwere subject to a hierarchical cluster analysis toidentify distinct groups of participants experien-cing particular combinations of problems. Thecluster analysis was performed using the 5-pointproblem severity scales. The resulting clusters werethen used as a factor in a general linear model(controlling for age and disease impact) with theSF-36 as the dependent variable. Relationship andwork problems were excluded from this analysisbecause they were not applicable to all partici-pants.The study was powered to detect small differ-

ences (equivalent to 0.11 effect size) between theproblem groups (n = 4) on the SF-36 scales, with85% power and 5% significance, using G*Powerfor ANOVA (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower).

Results

Sample characteristicsCompleted questionnaires were received from

929 patients (a 50% response rate). The demo-

Table 1 Sample characteristics

GenderFemaleMale

Age (years)MeanRangeSD

LivingAloneWith others

EmploymentEmployedUnemployedRetired due to multiple sclerosisRetired other

Type of multiple sclerosisRelapsing/remittingProgressiveOther

Disease duration (years)MeanRangeSD

MobilityWalk unaidedWalk with stickWheelchair

Perceived level of disabilityMildModerateSevere

Disease impactMild MSIS-29 physical < 25Intermediate MSIS-29 physical 26-50Moderate MSIS-29 physical 51 -75Severe MSIS-29 physical 76-100

aExcept where indicated otherwise.MS, multiple sclerosis; MSIS-29, MultipleScale 29.

640 69287 31

4817-8111.4

143757

2569347677

277511141

16< 1 -6610.4

284351294

182504243

166211297255

1882

28105210

305515

303832

265420

18233227

Sclerosis Impact

graphic and disease characteristics of participantsare summarized in Table 1.The observed scores on both the MSIS-29 and

SF-36 were found to be within the range of scoresreported in previous studies. The scores of peoplewith multiple sclerosis were lower on all SF-36scales when compared with the normative data forthe general population (Table 2).

Problem frequenciesSeventy-four per cent (n = 686) of participants

had experienced four or more of the selectedproblems in the previous 12 months. Fatigue was

Health problems in multiple sclerosis 71

Table 2 Disease impact and quality of life scores (MSIS-29, SF-36)

Outcome scales Total sample (n = 927)Mean (SD)

Range of normative data multiplesclerosis populationa Mean (SD)

Normative datageneral populationb

SF-36 (0-100)Role emotionalRole physicalBodily painEnergy and vitalityGeneral healthSocial functioningPhysical functioningMental health

MSIS-29 (0-100)Physical impactPsychological impact

aFrom refs 9, 13, 15-17.bData from the 1996 Health Survey for England, n = 20.328.16SF-36 higher scores = better health, MSIS-29 higher scores = greater impact.SF-36, 36-Item Short Form Health Survey, version 2; MSIS-29, Multiple Sclerosis Impact Scale-29;

the most frequent problem, affecting 93% (n = 863)of participants, followed by depression (75%, n =

698), urinary incontinence (74%, n = 686) and pain(73%, n = 676). Employment and relationshipproblems were experienced by 60% (n = 153) and52% (n = 350) of participants respectively (exclu-sions as described). The least frequently experi-enced problem was pressure ulcers (19%, n = 176).The majority of participants reported problemswith fatigue, urinary incontinence and depressionperceived those problems as severe. Table 3 pro-vides full details of the frequencies of the problemsand their perceived severity.

The problems and disease impactAn incremental increase in the number of people

experiencing the problems and their severity wasobserved with greater levels of disease impact, withsignificant linear trend (P < 0.001) (see Table 3).The only exception to this pattern was fatigue,which was equally prevalent in all the diseaseimpact groups, although severity increased withdisease impact.

The impact of problem severity on the SF-36 scalesUrinary incontinence (F= 0.7, df = 21, P = 0.8),

bowel (F= 1.2, df= 21, P = 0.3) and pressure sores(F= 1.7, df= 7, P = 0.1) did not have any effect on

NA, not applicable.

the SF-36 scores independent of disease impact(the MSIS-29 physical). Fatigue (F= 8.8, df= 14,P <0.001), pain (F=40.7, df=21, P <0.001),employment (F= 3.0, df = 21, P < 0.001), depres-sion (F=17.5, df=21, P<0.001) and sexual!

relationship (F=3.1, df=21, P<0.001) were

related to SF-36 scores, independently of diseaseimpact. The between-subject effects and confi-dence interval comparisons showed that the ex-

perience of these problems resulted in a globalreduction in SF-36 scale scores with the greatestdifferences being between the no-problem andsevere groups. The adjusted means with 95%confidence intervals for each of the significantSF-36 scales from these models are presented inTable 4.

Additive effectsPain, fatigue and depression were entered into

the hierarchical cluster analysis. The analysisidentified four problem groups:

1) Fatigue (n = 165) - this group exhibitedmoderate fatigue (mean 2.5) with mean de-pression and pain scores < 1.

2) Pain plus fatigue (n = 169) - this group hadhigh levels of fatigue (mean 4) and pain (mean3.9) with minimal depression (mean 1.1).

63.8 (33.4)39.7 (29.9)55.9 (26.0)34.7 (22.2)46.1 (23.9)56.5 (30.3)29.2 (29.7)65.9 (19.8)

55.7 (43.0)-29.1 (35.8)-50.5 (25.5)-37.8 (21.7)-41.9 (30.4)-49.7 (26.6)-27.9 (28.1)-61.8 (20.3)-

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57.2 (27.2)46.2 (25.0)

84 (31.6)80 (35.5)77 (26.7)63 (18.1)69 (15.8)85 (24.1)81 (26.6)75 (17.8)

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74 A Forbes et al.

3) Depression plus fatigue (n = 388) - this grouphad high levels of fatigue (mean 4) anddepression(mean 3.5) with minimal pain(mean < 1).

4) Global (n= 149) - this group had high levelsof severity for fatigue (mean 4.9), depression(mean 4.2) and pain (mean 3.5).

The main effect for the four problem groupsidentified through the cluster analysis on the SF-36 scores was significant in the multivariate model(F= 32.5, df = 21, P < 0.001). The between-subjecteffects and confidence interval comparisonsshowed that multiple problem combinations withhigher severity had an additive effect, with the SF-36 scores being significantly lower in the globalcluster compared with the fatigue-only cluster(after adjusting for disease impact). The depressionplus fatigue cluster showed greater negative effectson the psychological scales whereas the pain plusfatigue cluster showed greater negative effects onthe bodily pain and general health perceptionscales (Table 5).

Discussion

It is acknowledged that the study has somepotential limitations. Two principal sources ofbias may place important limitations on theexternal validity of the study; selection bias andresponse bias. The selection bias relates to the factthat the patients included in this study were knownto the treatment centres and so may have had moremultiple sclerosis-related complications than thosewho were not known to the treatment centres.Thus, these data cannot be used to infer the extentof these problems in the wider multiple sclerosispopulation. The response bias relates to the factthat only half of those surveyed participated in thestudy, some may have been due to poor contactdetails. Data from the follow-up analysis in themain study indicated that characteristics such asliving alone and greater disease impact contributedto attrition, suggesting that these phenomena mayhave influenced primary response. Nevertheless,this is a very large sample from across England andrepresents a quarter of the total population ofpeople with multiple sclerosis in the study treat-ment centres. The sample demographic and disease

data also indicate that the sample conforms to theknown characteristics of the multiple sclerosispopulation. Thus, despite these potential biasesthe findings should be seen as informative,although they should be interpreted with cautionparticularly in relation to the frequency of thestudied problems.

Sample characteristicsThe proportion of female to male participants

reflected the accepted gender distribution of thedisease.'8 The sample comprised a broad profile ofpeople with multiple sclerosis in terms of diseaseduration (from under a year to more than 65years). While over half the sample (55%) describedtheir disease as progressive, this is likely to includea substantial number of patients who were in thesecondary progressive phase of the relapsing/remit-ting disease. It has been reported that around 60%of people with relapsing/remitting disease will be inthe secondary progressive phase at any one time.'9

Frequency of the problemsThe frequency of the impairment-specific pro-

blems in the sample were generally concordantwith those reported in previous studies,20-22 withthe exception of fatigue and depression which wereslightly higher."7'23 The higher frequency for theseproblems could be explained by the use of self-report rather than clinical assessments24 or vali-dated scales,25 together with the identified poten-tial selection bias. It is also important to note thatfatigue was measured as a unitary concept when ithas been shown to have distinct mental, cognitiveand physical components.26 This limitation alsoapplies to pain, which is also multidimensional innature.27 The frequency of pressure ulcers espe-cially in the severe disease impact group was high,even allowing for the effect of selection bias andthe high risk of pressure ulcers in multiple sclerosis.This would seem to be an important area for futureinquiry as no studies on that occurrence ormanagement of pressure ulcers in people withmultiple sclerosis were identified following aMEDLINE search.While acknowledging the potential bias in the

sample, these data support the observations ofothers that many people with multiple sclerosis ex-perience both sexual and relationship28 and employ-ment problems.29'30 However, it is acknowledged

Health problems in multiple sclerosis 75

lCO' ci r, that the relationship item was very broad and likely

Lc- W to reflect both sexual dysfunction and interperso-LO Mlzt m <nal issues. The majority of participants who

C: creported relationship problems were male, asdi _ M reported in previous studies.22 The high proportion

of participants in work experiencing employmentcCx problems should be read together with the high

- t proportion of participants who had retired due to-,CD CY) 4 - - their multiple sclerosis (52%).

v 6 LO'0co'' Problems and disease impactThe data show a linear relationship between the

-0>LO 14 LOstudied problems and disease impact. Furtherinquiry into the nature of these problems at

66CD CD & different points in the disease trajectory might beXi chelpful to ascertain whether there are particular

_(D a) 1 Oissues that should be addressed at different diseaser r>>tn stages. Such knowledge could help inform the

m) C00. O CDdevelopment of both assessment schedules andC treatment algorithms for these problems.

U)LL0tO-+ zProblems and health-related quality of life

LoC'0C6 a))' 0n Fatigue, depression and pain had significantnegative effects on all of the SF-36 scales, suggest-

CO xi r- ing a global effect on health-related quality of lifeCO | t E 2(as measured). Overall this impact showed incre-

CD '-U 00 mental deterioration between the no-problem,E Q C some, moderate and severe problem groups,z :5 a)t >c x although the confidence intervals suggest that the

most consistent difference is between the no-CD

l n > n >problem (or some groups) and the severe group.r_ X

l- w LO sRelationship and employment problems showed. 2 _a U)< L effects on five of the seven SF-36 scales. Sexual and

EE relationship problems showed a strong effect on0 ) C:

-5 4 a)C-S6 the psychological scales (role emotional and men-> Ir ->O (D L3 tal health), suggesting that relationship problems

0NN 0) CD may compromise psychological well-being or that-l °<y < psychological morbidity contributes to the rela-O tionship problem. The effect of employment pro-

O blems was strongest on role physical and socialo) CD CD O - functioning scales, suggesting that the factors that

4CO> < m cn 00contribute to employment problems (in addition tothe effects of the underlying neurological disabil-

a) ity) also affect the person's ability to perform theirCO X daily activities more generally and their level of

D -:) social interaction. An indication of the nature ofV) n nthose factors is evidenced in the strong effects onLna both the bodily pain and energy and vitality scales,

F. | a C1 o |suggesting that pain and fatigue may play a role inF U*.La- 0the experience of employment problems.

76 A Forbes et al.

Pressure ulcers, urinary and bowel problemsshowed no independent effect additional to diseaseseverity on the SF-36 scales, suggesting that theinfluence of these problems is bound within thephysical disabilities experienced by people withmultiple sclerosis. However, this does not meanthat these problems do not contribute to psycho-logical or social well-being.31

In assessing the observed effects, considerationwas given to the size of those effects. It has beensuggested that a 10-point difference betweengroups on the SF-36 scales indicates a clinicallyimportant difference.32 The differences betweenthe no problem and severe problem groups were> 10 points for most of the SF-36 scales forwhich a statistically significant effect was de-tected. The scale showing the lowest effect wasthe role physical scale (with the exception ofemployment problems). The reduced effect on

this scale was explained by the use of the MSIS-29 as a covariate which removed much of theeffect.

Problem interactionsThe findings suggest that many of these pro-

blems are interactive, with that interaction beingreflected in the SF-36 scores. The strongest inter-action observed was between fatigue, depressionand pain, with each problem showing reciprocaleffects on the SF-36 scales related to the otherproblems (e.g. depression affects the bodily painand energy and vitality scales).

While it is not possible to conclude that therelationship between these problems is causative, itis suggested that each contributes something to theother. Karlein et al.33 in a more focused examina-

tion of the relationship between fatigue anddepression (controlling for disability) distinguishedbetween mental and physical fatigue and showedthat when viewed cross-sectionally mentalfatigue was associated with depression. Longitud-inally (12-month follow-up) they found that thepresence of physical fatigue and depression atbaseline were predictive of increased disability atfollow-up.The relationship between these problems is,

therefore, complex and at present poorly under-stood. Flachenecker et al. 3 suggested that theassociation between fatigue and depression may beexplained either by a common mechanism (possi-bly patho-physiological) driving both depressionand fatigue (covariance) or interdependence withone feeding the other (cause and effect). Furtherexploration of the relationship between theseproblems is needed to inform multilevelled ini-tiatives for problem management in multiplesclerosis.The need to address the interactive nature of

multiple sclerosis-related problems is reinforced bythe findings of the cluster group analysis whichindicted that multiple problems of greater severitywere associated with an even greater negative effecton the SF-36 scales. This finding suggests theimportance of both considering the overall burdenof symptoms together with their individual andcumulative impact.

In conclusion, the findings suggest that whilethere is a relationship between the studiedproblems and disease impact, many of the pro-blems also exhibited an effect on the SF-36 scalesindependent of the physical impact of the disease.This relationship may suggest that improve-ments in health-related quality of life (indepen-dent of disease status) are attainable throughbetter management of these multiple sclerosisproblems.

AcknowledgementsThe research team is grateful to all the people

with multiple sclerosis who completed a ques-tionnaire, the sites which supported the study,the Multiple Sclerosis Society for Great Britainwhich funded the research and Dr JeremyHobart for permission and support in using theMSIS-29.

Clinical messages

* More effective management of problemsmay improve health-related quality of life.

* Multiple problem exposure is likely to beassociated to a greater reduction in health-related quality of life.

* The interrelationships between problemssuch as depression, pain and fatigue mightbe important in some patients.

Health problems in multiple sclerosis 77

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