Background Mutations in potassium-channel genes KCNQ1 (LQT1locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A(LQT3 locus) are the most common causes of the long-QT syndrome.We stratified risk according to the genotype, in conjunctionwith other clinical variables such as sex and the length ofthe QT interval.
Methods We evaluated 647 patients (386 with a mutation at theLQT1 locus, 206 with a mutation at the LQT2 locus, and 55 witha mutation at the LQT3 locus) from 193 consecutively genotypedfamilies with the long-QT syndrome. The cumulative probabilityof a first cardiac event, defined as the occurrence of syncope,cardiac arrest, or sudden death before the age of 40 years andbefore the initiation of therapy, was determined according togenotype, sex, and the QT interval corrected for heart rate(QTc). Within each genotype we also assessed risk in the fourcategories derived from the combination of sex and QTc (<500msec or 500 msec).
Results The incidence of a first cardiac event before the ageof 40 years and before the initiation of therapy was lower amongpatients with a mutation at the LQT1 locus (30 percent) thanamong those with a mutation at the LQT2 locus (46 percent) orthose with a mutation at the LQT3 locus (42 percent) (P<0.001by Fisher's exact test). Multivariate analysis showed that thegenetic locus and the QTc, but not sex, were independent predictorsof risk. The QTc was an independent predictor of risk amongpatients with a mutation at the LQT1 locus and those with amutation at the LQT2 locus but not among those with a mutationat the LQT3 locus, whereas sex was an independent predictorof events only among those with a mutation at the LQT3 locus.
Conclusions The locus of the causative mutation affects theclinical course of the long-QT syndrome and modulates the effectsof the QTc and sex on clinical manifestations. We propose anapproach to risk stratification based on these variables.
The Romano–Ward variant of the long-QT syndrome is a geneticallytransmitted disorder characterized by prolonged ventricularrepolarization that predisposes carriers to life-threateningarrhythmias.1 Almost 40 years after its initial description,2,3the natural history of the syndrome remains incompletely characterizedand approaches to risk stratification are not well defined.These gaps in knowledge are largely due to the fact that thelong-QT syndrome is uncommon, cardiac events may be separatedby long periods without symptoms, and the initial manifestationmay occur late in life. Five genes have been linked to the long-QTsyndrome,4,5 and studies of the genotype and phenotype haveidentified clinical profiles that distinguish each genetic subgroup.6,7,8,9,10However, information on the occurrence of events in each geneticsubgroup is limited and thus insufficient for risk stratification.Such information would be useful in making decisions about treatment,particularly for patients who are asymptomatic. The objectivesof this study were to define the cumulative probability of afirst cardiac event (defined as syncope, cardiac arrest, orsudden death) before therapy (i.e., the natural history of thedisease) and to analyze the complex interplay among the geneticlocus, sex, and the duration of repolarization, which determinesthe probability of cardiac events in the long-QT syndrome. Inaddition, we examined whether the available data might provideinsights into risk stratification.
Methods
Study Population
We report data from 193 consecutively genotyped families withthe long-QT syndrome owing to mutations at the LQT1 locus ofthe KCNQ1 potassium-channel gene in 104 families, the LQT2 locusof the KCNH2 potassium-channel gene in 68 families, and theLQT3 locus of the SCN5A sodium-channel gene in 21 families.We examined a total of 647 patients, of whom 580 were genotypedin our laboratories and 67 died suddenly and unexpectedly beforethe age of 40 years and were categorized as affected by thelong-QT syndrome.
Data on natural history were collected from the overall populationof 647 patients, and the cumulative probability of cardiac eventswas calculated from data from the 580 patients with an availableelectrocardiogram. Cardiac events were defined as syncope, cardiacarrest, and sudden death. All probands and family members ortheir guardians provided written informed consent for clinicaland genetic evaluation. Protocols were approved by the institutionalreview board of the Fondazione Salvatore Maugeri.
Clinical Phenotype
We either evaluated patients at our center or examined medicalrecords (including electrocardiograms) submitted by referringphysicians. The QT interval corrected for heart rate (QTc) wasmeasured in lead II (or lead I or III if it could not be measuredin lead II)8 from 12-lead electrocardiograms with the use ofBazett's formula. Quartiles of QTc were determined in the overallpopulation and in each genetic subgroup. Clinical data wereprospectively collected at follow-up visits or by telephonecontacts and included demographic data, personal and familyhistory, symptoms, and therapy. Data were stored in a computerizeddata base custom-made at the Fondazione Salvatore Maugeri.
Genetic Analysis
Patients were consecutively genotyped at the molecular cardiologylaboratories of the Maugeri Foundation between June 1996 andDecember 2001 and classified as carriers of a single mutationon KCNQ1, KCNH2, or SCN5A. DNA was extracted from peripheral-bloodlymphocytes according to standard procedures. Primer pairs forKCNQ1, KCNH2, and SCN5A amplification were used.11,12 Single-strandconformational polymorphism analysis, denaturing high-performanceliquid chromatography (Wave Transgenomics), or both were performedwith amplified genomic DNA. For samples with abnormal patterns,both strands were sequenced with use of an automated DNA analyzer(ABI Prism 310, ABI). A panel of results from 400 healthy personswas used as the control; a mutation was defined as a DNA changethat modified the encoded protein and that was not present inany control.
Statistical Analysis
The clinical features and end points of the analysis were assessedwith the use of the SPSS software (version 10.0): analysis ofvariance, paired and unpaired t-tests, and cross-tabulationswith Fisher's exact test were used as appropriate. The cumulativeprobability of a first cardiac arrest or sudden death beforethe age of 40 years and before therapy and the cumulative probabilityof a first cardiac event (syncope, cardiac arrest, or suddendeath) before the age of 40 years and before therapy were determinedin the entire population and in each genetic subgroup with theuse of the life-table method of Kaplan and Meier, and the resultswere compared with use of the log-rank test with Bonferroni'scorrection for multiplicity. Cox multivariate survivorship analyseswere performed to evaluate the statistical significance andindependence of predictors of a first cardiac arrest or suddendeath and of a first cardiac event alone.
Results
The population under study included 647 patients from 193 familieswith the long-QT syndrome: 386 with a mutation at the LQT1 locus,206 with a mutation at the LQT2 locus, and 55 with a mutationat the LQT3 locus.
Natural History
Over a mean observation period of 28 years, 87 patients (13percent) had cardiac arrest or died suddenly before the ageof 40 years and before the initiation of any treatment relatedto the long-QT syndrome (Table 1). The mean (±SD) observationperiod was similar among the genetic subgroups (29±20years in the group with a mutation at the LQT1 locus, 28±18years in the group with a mutation at the LQT2 locus, and 25±18years in the group with a mutation at the LQT3 locus). The cumulativeincidence of cardiac arrest or sudden death was similar betweenthe sexes: 14 percent among women (53 of 372) and 12 percentamong men (34 of 275, P=0.56). The incidence of cardiac arrestor sudden death was 20 percent among patients with a mutationat the LQT2 locus (41 of 206), 16.4 percent among patients witha mutation at the LQT3 locus (9 of 55), and 10 percent amongpatients with a mutation at the LQT1 locus (37 of 386). Kaplan–Meieranalysis showed that the cumulative rate of survival withoutcardiac arrest or sudden death differed among the subgroups(P=0.002 by the log-rank test). Specifically, the cumulativesurvival rate was lower among patients with a mutation at theLQT2 locus than among those with a mutation at the LQT1 locus(P<0.001 by the log-rank test), and there was a trend towarda lower cumulative survival rate among those with a mutationat the LQT3 locus than among those with a mutation at the LQT1locus (P=0.07 by the log-rank test).
Table 1. Incidence of a First Cardiac Arrest or Sudden Death before the Age of 40 Years and before Therapy among Patients with the Long-QT Syndrome, According to the Genetic Locus of the Mutation.
The same pattern was observed when the analysis included allfirst cardiac events — syncope, cardiac arrest, and suddendeath — since there was no significant sex-related difference,but there was a significant difference related to the geneticlocus (P=0.002 by the log-rank test) in the overall population.Pairwise analysis showed a significantly higher number of eventsamong patients with a mutation at the LQT2 locus than amongthose with a mutation at the LQT1 locus (P<0.001 by the log-ranktest), and there was a trend toward more events among patientswith a mutation at the LQT3 locus than among those with a mutationat the LQT1 locus (P=0.05 by the log-rank test) (Table 2).
Table 2. Incidence of a First Cardiac Event before the Age of 40 Years and before Therapy in Patients with the Long-QT Syndrome, According to the Genetic Locus of the Mutation.
The mean age at the time of the first cardiac event (beforethe age of 40 years) was not significantly different among thethree subgroups: 13±9 years in the LQT1 subgroup, 18±10years in the LQT2 subgroup, and 16±10 years in the LQT3subgroup. The age at the time of the first cardiac event wasyounger in male patients than in female patients (13±9vs. 20±14 years, P<0.001). Specifically, it was 11±9years among male patients with a mutation at the LQT1 locusand 18±15 years among female patients (P=0.006), 13±10years among male patients with a mutation at the LQT2 locusand 22±12 years among female patients (P=0.003), and16±12 years among male patients with a mutation at theLQT3 locus and 23±18 years among female patients (P=0.24).
Risk Stratification
We considered the association of genetic locus, sex, and QTcwith the risk of a first cardiac event before the age of 40years and before therapy in the 580 patients entered in therisk-stratification analysis: 355 patients with a mutation atthe LQT1 locus, 176 with a mutation at the LQT2 locus, and 49with a mutation at the LQT3 locus. Kaplan–Meier analysisshowed a differential cumulative event-free survival among thethree genetic subgroups (P=0.007 by the log-rank test) (Figure 1).Kaplan–Meier analysis showed that in the entire population,sex-related differences were not statistically significant (P=0.06by the log-rank test). When the analysis was repeated for eachsubgroup, sex had no influence among patients with a mutationat the LQT1 locus (P=0.18), whereas female patients with a mutationat the LQT2 locus had a higher risk than male patients (P=0.02by the log-rank test), and there was a trend toward a higherrisk among male patients with a mutation at the LQT3 locus thanamong female patients (P=0.048 by the log-rank test). This findingsupports the observation that the annual incidence of a firstcardiac arrest or sudden death was highest among female patientswith a mutation at the LQT2 locus (0.82 per year) and male patientswith a mutation at the LQT3 locus (0.96 per year) (Table 1).Thus, the role of sex varies according to the genetic locus.
Figure 1. Kaplan–Meier Estimates of Survival Free of Cardiac Events among the 580 Patients with the Long-QT Syndrome in the Risk-Stratification Analysis, According to the Genetic Locus of the Mutation.
The difference among the groups was significant (P=0.007 by the log-rank test).
When QTc was examined, significant differences were observedamong the three subgroups. The mean QTc was 466±44 msecamong patients with a mutation at the LQT1 locus, 490±49msec among those with a mutation at the LQT2 locus, and 496±49msec among those with a mutation at the LQT3 locus (P<0.001for the comparisons of the LQT1 group with the LQT2 group andthe LQT1 group with the LQT3 group, and P=0.22 for the comparisonof the LQT2 group with the LQT3 group). In each subgroup theQTc of patients who had cardiac events was significantly longerthan that of asymptomatic patients (488±47 msec vs. 459±40msec in the LQT1 group, P<0.001; 519±55 msec vs. 472±35msec in the LQT2 group, P<0.001; and 523±55 msec vs.481±38 msec in the LQT3 subgroup, P=0.003). The percentageof genetically affected patients with a normal QTc (silent mutationcarriers) was significantly higher (P<0.001) in the LQT1group (36 percent) than in the LQT2 group (19 percent) or theLQT3 group (10 percent).
When the cumulative event-free survival was analyzed in the580 patients in the risk-stratification analysis according tothe quartile of QTc, there was a progressive decrease in survivalat longer QTc values (Figure 2). Since the QTc differed amongthe three subgroups, we performed the analysis using both quartilesof QTc derived from the entire population under study and thequartiles in each subgroup (locus-specific quartiles). Bothanalyses demonstrated an increased probability of a first cardiacevent before the age of 40 years and before therapy among patientswith a QTc in the upper quartiles (P<0.001 by the log-ranktest). Kaplan–Meier analysis showed that the cumulativeprobability of a first cardiac event was higher among patientswith a longer QTc in the LQT1 group and the LQT2 group (P<0.001for both comparisons), but not among those in the LQT3 group(P=0.23).
Figure 2. Kaplan–Meier Estimates of Cumulative Survival Free of Cardiac Events among the 580 Patients with the Long-QT Syndrome in the Risk-Stratification Analysis, According to the Quartile of the QT Interval Corrected for Heart Rate (QTc).
The four quartiles of QTc were as follows: first, 446 msec or less; second, 447 to 468 msec; third, 469 to 498 msec; and fourth, more than 498 msec. The difference among the quartiles was significant (P<0.001).
To assess the significance and independence of the predictorsof the occurrence of a first cardiac event before the age of40 years and before therapy, we entered the genetic locus, sex,and QTc in a Cox regression model. The analysis showed thatboth QTc (P<0.001) and genetic locus (P=0.005), but not sex,were independent predictors of a first cardiac event.
Patients with a mutation at the LQT1 locus were at the lowestrisk for a first cardiac event before the age of 40 years andbefore therapy; thus, a substantial proportion of such patientsremain asymptomatic. As compared with patients with a mutationat the LQT1 locus, patients with a mutation at the LQT2 locushad a relative risk of a first cardiac event of 1.61 (95 percentconfidence interval, 1.16 to 2.25) and those with a mutationat the LQT3 locus had a relative risk of 1.80 (95 percent confidenceinterval, 1.07 to 3.04). Among patients with a mutation at theLQT1 locus and patients with a mutation at the LQT2 locus, thosewith a QTc in the third quartile (469 to 498 msec) had a riskof cardiac events that was increased by a factor of 5.34 (95percent confidence interval, 2.82 to 10.13) and those with aQTc in the highest quartile (more than 498 msec) had a riskthat was increased by a factor of 8.36 (95 percent confidenceinterval, 2.53 to 27.21), as compared with those with a QTcin the lowest quartile (446 msec or less; these patients weresilent mutation carriers). By contrast, among patients witha mutation at the LQT3 locus, the QTc did not differentiaterisk between the first and fourth quartiles, whereas male sexwas associated with a significantly greater risk of such eventsthan was female sex (relative risk, 2.76; 95 percent confidenceinterval, 1.01 to 7.51).
For a more detailed characterization of risk according to genotypeamong patients with the long-QT syndrome, we created 12 categoriesincluding, for each genetic locus, the four combinations ofsex (male and female) and QTc (less than 500 msec and 500 msecor more). The cumulative rate of survival free of a first cardiacevent before the age of 40 years and before therapy differedsignificantly among these categories, thus making possible theidentification of a differential risk (Figure 3). A QTc of 500msec or more, present in 24 percent of this patient population,had the single most important role in predicting events; however,this factor was modulated by sex and genetic locus. Among patientswith a mutation at the LQT1 locus and a QTc of 500 msec or more,the risk of a first event was not affected by increasing ageamong female patients, whereas for male patients the risk wasextremely high during the first 10 years of life, when symptomsdeveloped in 70 percent, but subsequently declined. Among patientswith a mutation at the LQT2 locus, female sex carried an especiallyhigh risk, since even female patients with a QTc of less than500 msec had a probability of becoming symptomatic that wasfour times as high as that of male patients with a similar QTc.Among patients with a mutation at the LQT3 locus, male patientsbecame symptomatic much earlier than female patients even whentheir QTc was below 500 msec (however, caution is required indrawing conclusions from this group given its relatively smallsize). Ranking the cumulative probability of a first cardiacevent before the age of 40 years and before therapy yieldeda risk-stratification scheme that may guide therapeutic strategiesin patients with the long-QT syndrome whose genotypes had beendetermined (Figure 4).
Figure 3. Kaplan–Meier Estimates of Cumulative Survival Free of Cardiac Events among the 580 Patients with the Long-QT Syndrome in the Risk-Stratification Analysis, According to Sex and the QT Interval Corrected for Heart Rate (QTc), in the Group with a Mutation at the LQT1 Locus (Panel A), the Group with a Mutation at the LQT2 Locus (Panel B), and the Group with a Mutation at the LQT3 Locus (Panel C).
P values were calculated with use of the log-rank test.
Figure 4. Proposed Scheme for Risk Stratification among Patients with the Long-QT Syndrome According to Genotype and Sex.
The risk groups have been defined on the basis of the probability of a first cardiac event (syncope, cardiac arrest, or sudden death) before the age of 40 years and before therapy. A probability of 50 percent or higher defines the high-risk group, a risk of 30 to 49 percent the intermediate-risk group, and a risk below 30 percent the low-risk group.
Discussion
This study provides two main insights relevant for the managementof the long-QT syndrome. By investigating our large data baseof unselected, consecutively genotyped patients and by analyzingthe incidence of cardiac events before the initiation of therapy,we were able to characterize the natural history of the syndromeaccording to the genetic locus. By using two clinical features(sex and QTc) in addition to the genetic locus, we developeda tool for gene-specific risk stratification with possible implicationsfor disease management.
The efforts of the International Registry for Long QT Syndrome13have proved the most successful to date in defining the naturalhistory of the syndrome and identifying risk factors. In 1985,Moss et al. suggested an association between phenotypic anddemographic features (congenital deafness, female sex, and ahistory of syncope or ventricular tachyarrhythmias) and cardiacevents by analyzing data from 196 patients, of whom only 25percent had a history of syncope.14 In 1991, Moss et al. usedrecords from 328 families of unknown genotype to demonstratethe link between QTc and the risk of cardiac events.15 Zarebaet al. subsequently examined the influence of genotype on theclinical course of the long-QT syndrome and found that the riskof cardiac events was higher among patients with a mutationat the LQT1 locus and those with a mutation at the LQT2 locusthan among those with a mutation at the LQT3 locus, whereasthe percentage of lethal cardiac events was highest among patientswith a mutation at the LQT3 locus.8 However, this study waspotentially biased, since it included only 38 families (selectedbecause they were large enough to permit linkage analysis).We have further analyzed risk in patients with the long-QT syndromeby studying a large number of patients of known genotype fromconsecutive and unselected families.
The high potential of the long-QT syndrome to cause lethal eventsis demonstrated by the 13 percent incidence of cardiac arrestor sudden death among untreated patients. At variance with earlierobservations,8 we found that the incidence of life-threateningevents was lowest among patients with a mutation at the LQT1locus. Sex affected the probability of a first cardiac event:the risk of becoming symptomatic before the age of 40 yearsand before therapy was higher among female than male patientswith a mutation at the LQT2 locus and among male than femalepatients with a mutation at the LQT3 locus, whereas there wasno significant difference between the sexes among patients witha mutation at the LQT1 locus. Interestingly, cardiac eventsoccurred earlier in male patients with a mutation at the LQT1locus or with a mutation at the LQT2 locus than in female patients,whereas we found no sex-based difference in the age at onsetof symptoms among patients with a mutation at the LQT3 locus.However, caution is required in interpreting data in the LQT3subgroup because of its small size.
We found that the QT interval is influenced by the genetic locusand correlates significantly with the likelihood of cardiacevents. The robustness of the latter finding relied on the useof QTc quartiles derived from both the entire population andthe specific genetic variants. The prevalence of silent mutationcarriers (carriers with a normal QTc) varied according to thegenetic locus and was the highest among patients with a mutationat the LQT1 locus (36 percent). Therefore, it could be hazardousto assume that a member of a family with a mutation at the LQT1locus who has a normal QTc is not affected.12 By contrast, thisrisk is small in a member of a family with a mutation at theLQT3 locus, since only few carriers (10 percent) in this grouphave a normal QTc.
We developed a risk-stratification model in order to quantify,for each genetic variant, the risk of symptoms before the ageof 40 years and before therapy on the basis of two simple clinicalcharacteristics: sex and QTc. Analysis of QTc revealed thatonly the highest quartile (QTc more than 498 msec) was associatedwith a markedly increased probability of cardiac events. Therefore,we used 500 msec as the cutoff point for categorical risk stratification.To quantify the probability of a first cardiac event beforethe age of 40 years, we categorized patients according to thegenetic locus, and within each genetic variant, we identifiedfour groups: male patients with a QTc of less than 500 msec,female patients with a QTc of less than 500 msec, male patientswith a QTc of 500 msec or more, and female patients with a QTcof 500 msec or more.
The risk of events among patients with a mutation at the LQT1locus was strongly dependent on the duration of QTc: male patientswith a QTc of 500 msec or more were at high risk for a firstcardiac event during childhood, whereas the risk of a firstevent among female patients with a mutation at the LQT1 locuswho had a QTc of 500 msec or more was unchanged over time. Patientsof either sex with a mutation at the LQT1 locus who had a QTcof less than 500 msec had a risk of a first cardiac event beforethe age of 40 years of less than 30 percent. Female patientswith a mutation at the LQT2 locus had a more severe prognosisirrespective of the duration of the QTc, whereas in patientswith a mutation at the LQT3 locus, the prognosis was mainlyinfluenced by sex: male patients had a higher probability ofbecoming symptomatic by the age of 40 years than did femalepatients.
Our data make possible a revision of previous recommendationsfor risk stratification16 and the management of asymptomaticlong-QT syndrome whenever information on genotype is available.Although an assessment of the efficacy of prophylactic therapywith beta-blockers17 is clearly beyond the scope of our presentstudy, it is reasonable to assume, on the basis of our findings,that prophylactic treatment is warranted in male and femalepatients with a mutation at the LQT1 locus who have a QTc of500 msec or more, male patients with a mutation at the LQT2locus who have a QTc of 500 msec or more, all female patientswith a mutation at the LQT2 locus irrespective of the QTc, andall patients with a mutation at the LQT3 locus. By contrast,the decision to institute therapy in patients at lower riskof becoming symptomatic before the age of 40 years should beindividualized. Our risk-stratification scheme will help physiciansassess the risk–benefit ratio of long-term therapy intheir asymptomatic patients.
Our study was based on the assumption that patients with thelong-QT syndrome who have mutations at the same locus have asimilar risk of cardiac events. Should preliminary evidencethat specific mutations are more malignant than others18,19be confirmed, it might become possible to develop locus-specificrisk-stratification schemes based either on specific mutationsor on their functional effects.
Supported in part by the Leducq Foundation, a BIOMED grant (BMH4-CT98-3872),a Telethon grant (P0227/01), a Ricerca Finalizzata grant (DG-RSVE-RF2001-1862),and a grant from the Cariplo Foundation (2001.3009/10.9079).
We are indebted to the following physicians: Maria Grazia Bettuzzi(Lancisi Hospital, Ancona, Italy), Giuliano Bosi (Civil Hospital,Ferrara, Italy), Giuseppe Calcaterra (Aiuto Materno Hospital,Palermo, Italy), Alfredo Condò (Sport Medicine Center,San Donà del Piave, Italy), Maria Rosa Conte (RivoliHospital, Rivoli, Italy), Maria J. Correia (UTIC Intensive CareUnit A Cordero, Lisbon, Portugal), Luciano De Simone (MeierPediatric Hospital, Florence, Italy), Fabrizio Drago (BambinGesù Hospital, Rome), Paolo Liistro (Ambrosiano MedicalCenter, Milan, Italy), Peter Luckac (Slovak Institute of CardiovascularDiseases, Bratislava, Slovakia), Jay W. Mason (University ofKentucky, Lexington), Pascal McKeown (Royal Hospital, Belfast,Northern Ireland), Alessio Micchi (Civil Hospital, Bussolengo,Italy), Pasquale Palazzolo and Salvatore Pipitone (Casa delSole Hospital, Palermo, Italy), Wataru Shimizu (National CardiovascularCenter, Osaka, Japan), Velio Sperandeo (Casa del Sole Hospital,Palermo, Italy), Marco Stramba Badiale (Istituto di Ricoveroe Cura a Carattere Scientifico, Auxologico Institute, Milan,Italy), and Victoria Vetter (Philadelphia Children's Hospital,Philadelphia); to all the patients and the families who participatedin this study; and to Dr. Elena Scotti for editorial assistance.
Source Information
From the Department of Molecular Cardiology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione S. Maugeri (S.G.P., C.N., R.B., E.R., M.G., A.V., J.N., G.B., R.F., D.C.); the Department of Cardiology, Istituto di Ricovero e Cura a Carattere Policlinico San Matteo (P.J.S., C.S.); and the University of Pavia (S.G.P., P.J.S.) — all in Pavia, Italy.
Address reprint requests to Dr. Priori at Molecular Cardiology, Maugeri Foundation, University of Pavia, Via Ferrata 8, 27100 Pavia, Italy, or at spriori{at}fsm.it.
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500 msec). 
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