in Children With Multisystem Inflammatory Syndrome Audrey Dionne, MD,a,b Douglas Y. Mah, MD,a,b Mary Beth F. Son, MD,b,c Pui Y. Lee, MD, PhD,b,c Lauren Henderson, MD, MMSc,b,c Annette L. Baker, MSC, PNP,a,b Sarah D. de Ferranti, MD,a,b David R. Fulton, MD,a,b Jane W. Newburger, MD, MPH,a,b Kevin G. Friedman, MDa,b

BACKGROUND: Children are at risk for multisystem inflammatory syndrome in children (MIS-C) abstract after infection with severe acute respiratory syndrome coronavirus 2. Cardiovascular complications, including ventricular dysfunction and coronary dilation, are frequent, but there are limited data on arrhythmic complications. METHODS: Retrospective cohort study of children and young adults aged #21 years admitted with MIS-C. Demographic characteristics, electrocardiogram (ECG) and echocardiogram findings, and hospital course were described. RESULTS: Among 25 patients admitted with MIS-C (60% male; median age 9.7 [interquartile range 2.7–15.0] years), ECG anomalies were found in 14 (56%). First-degree atrioventricular block (AVB) was seen in 5 (20%) patients a median of 6 (interquartile range 5–8) days after onset of fever and progressed to second- or third-degree AVB in 4 patients. No patient required intervention for AVB. All patients with AVB were admitted to the ICU (before onset of AVB) and had ventricular dysfunction on echocardiograms. All patients with second- or third- degree AVB had elevated brain natriuretic peptide levels, whereas the patient with first- degree AVB had a normal brain natriuretic peptide level. No patient with AVB had an elevated troponin level. QTc prolongation was seen in 7 patients (28%), and nonspecific ST segment changes were seen in 14 patients (56%). Ectopic atrial was observed in 1 patient, and none developed ventricular . CONCLUSIONS: Children with MIS-C are at risk for atrioventricular conduction disease, especially those who require ICU admission and have ventricular dysfunction. ECGs should be monitored for evidence of PR prolongation. Continuous telemetry may be required in patients with evidence of first-degree AVB because of risk of progression to high-grade AVB.

’ cDivision of Immunology and aDepartment of , Boston Children’s Hospital, Boston, Massachusetts; and WHAT S KNOWN ON THIS SUBJECT: Children with bDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, Massachusetts multisystem inflammatory syndrome are at risk for cardiovascular complication, including ventricular Dr Dionne conceptualized and designed the study, collected the data, interpreted the data, drafted dysfunction and coronary artery dilation. the initial manuscript, and reviewed and revised the manuscript; Drs Mah, Son, Lee, and Henderson, Ms Baker, and Drs de Ferranti, Fulton, and Newburger were responsible for acquisition and WHAT THIS STUDY ADDS: Patients with multisystem interpretation of the data and critically reviewed the manuscript for important intellectual content; inflammatory syndrome are also at risk for Dr Friedman conceptualized and designed the study, interpreted the data, and critically reviewed atrioventricular conduction disease, especially those who the manuscript for important intellectual content; and all authors approved the final manuscript as present with or shock and ventricular submitted. dysfunction. PR prolongation on the electrocardiogram DOI: https://doi.org/10.1542/peds.2020-009704 may be used to identify patients at risk for progression to high-grade atrioventricular block. Accepted for publication Aug 21, 2020 ’ Address correspondence to Audrey Dionne, MD, Department of Cardiology, Boston Childrens To cite: Dionne A, Mah DY, Son MBF, et al. Atrioventricular Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected] Block in Children With Multisystem Inflammatory Syndrome. Pediatrics. 2020;146(5):e2020009704

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 5, November 2020:e2020009704 ARTICLE The severe acute respiratory 2020. Patients with previously chain reaction (RT-PCR), serology syndrome coronavirus 2 (SARS-CoV- diagnosed atrioventricular test, or antigen test; or exposed to 2) is the cause of the current conduction disease were excluded COVID-19 within the 4 weeks worldwide coronavirus disease 2019 from analysis. This included 1 patient before the onset of symptoms.5 (COVID-19) pandemic, with .5 with cardiac surgery complicated by million confirmed cases in the United complete block the week before Hypotension or shock was defined as States. Children were initially thought MIS-C diagnosis. Because most of the requirement for fluid resuscitation to be largely spared from severe cardiac and ECG findings described in (.20 mL/kg) or inotropic support. disease.1,2 In April 2020, initial this series were not applicable to this An elevated troponin T level was reports emerged from the United patient in the immediate defined as a troponin value Kingdom of patients presenting with postoperative period, he was .0.09 ng/mL. An elevated brain Kawasaki disease–like features and excluded from analysis. This study natriuretic peptide (BNP) level was a severe inflammatory syndrome. was approved under exemption from defined as a value .100 pg/mL. Most cases occurred in children informed consent by the Institutional Echocardiograms were reviewed testing positive for current or recent Review Board at Boston Children’s during hospital admission and follow- infection with SARS-CoV-2. Children Hospital. up after discharge for ventricular presented with fever, hypotension, function, valvar function, , and coronary artery multiorgan involvement, and Data Collection and Definitions markedly elevated inflammatory dimensions. Ventricular dysfunction markers. Gastrointestinal and Data elements, including was defined as a left ventricular myocardial involvement was demographic characteristics, ECG and ejection fraction ,55%. Coronary fi frequently observed, whereas echocardiogram ndings, and artery z scores were calculated for respiratory symptoms were rarely hospital course, were collected from the left main coronary artery, seen.3 Additional cases were reported the electronic medical record. The proximal right coronary artery, and fi throughout Europe4 and America, following criteria were used to de ne proximal left anterior descending 7 leading to a health advisory from the individuals with MIS-C on the basis of artery by using the Boston formula. US Centers for Disease Control and the Centers for Disease Control and Coronary artery dilation was defined fi Prevention in May 2020 for Prevention case de nition: as a coronary artery z score $2 but multisystem inflammatory syndrome • aged ,21 years; ,2.5. On the basis of the American Heart Association guidelines, in children (MIS-C) associated with • presenting with fever ($38.0°C for 5 coronary artery aneurysm was COVID-19. $24 hours); defined as a coronary artery z score • Cardiovascular complications, presenting with laboratory $2.5 and classified as small if the z fl including shock, decreased left evidence of in ammation score was $2.5 to ,5, medium if the $ ventricular systolic function, coronary (including, but not limited to, 1of z score was $5to,10, and large or artery dilation, and aneurysms, were the following: elevated values for giant if the z score was $10 or reported in a high proportion of C-reactive protein, the erythrocyte $8 mm absolute measurement in patients in the initial European sedimentation rate, fibrinogen, 8 3,6 diameter. On the basis of normal reports. In our institutional procalcitonin, d-dimer, ferritin, values for age, first-degree experience, we also observed lactic acid dehydrogenase, or atrioventricular block (AVB) was arrhythmias and electrocardiogram interleukin 6; an elevated defined as delayed conduction (ECG) changes in children with MIS-C. neutrophil count; a reduced (prolonged PR interval) from the In this single-center series, we lymphocyte count; and a low to the without characterize the incidence of albumin level); interruption in atrial to ventricular arrhythmias and ECG changes in • presenting with evidence of conduction.9 Second-degree AVB was patients with MIS-C. clinically severe illness requiring defined as intermittent atrial hospitalization, with multisystem conduction to the ventricle and METHODS ($2) organ involvement (cardiac, further classified as Mobitz type I renal, respiratory, hematologic, (with progressive PR prolongation Population gastrointestinal, dermatologic, or before the dropped beat) or Mobitz II We completed a retrospective cohort neurologic), and no alternative (without progressive PR prolongation study of children and young adults plausible diagnosis; before the dropped beat). Third- aged 0 to 21 years who were • testing positive for current or degree AVB was defined as no atrial admitted with a diagnosis of MIS-C recent SARS-CoV-2 infection by conduction to the ventricle. between March 1, 2020, and May 30, reverse transcription polymerase Prolonged QTc interval was defined

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 DIONNE et al as a QTc interval in the .98th TABLE 1 Baseline Characteristics of Patients With MIS-C Based on Presence or Absence of Second- or percentile for age and sex.9 All ECGs Third-Degree AVB were reviewed by the investigator All Patients AVB (n = 5) No AVB (n = 20) (A.D.) blinded to patients’ clinical (N = 25) course. Age, y, median (IQR) 9.7 (2.7–15.0) 12.1 7.2 (2.2–13.7) (10.3–16.2) Statistical Analysis Male sex, n (%) 15 (60) 2 (40) 13 (65) Past medical history, n (%) 10 (40) 1 (20) 9 (45) Descriptive statistics were obtained Hospital course for all study variables. Quantitative Duration of fever, d, median (IQR) 6 (4–8) 7 (6–9) 5 (4–6) variables were summarized as Hospital length of stay, d, median (IQR) 7 (3–11) 11 (9–12) 6 (3–9) medians and interquartile ranges ICU admission, n (%) 14 (56) 5 (100) 9 (45) – – – (IQRs), and categorical variables were ICU length of stay, d, median (IQR) 7 (4 11) 6 (3 14) 7 (4 10) Inotropic support, n (%) 7 (28) 4 (80) 3 (15) summarized as frequencies and Noninvasive positive pressure ventilation, n 6 (24) 1 (20) 4 (20) percentages. Because of the small (%) sample size, no statistical tests were Intubation, n (%) 1 (4) 1 (20) 1 (5) used to compare differences between Treatments received, n (%) groups. IVIg 16 (64) 5 (100) 11 (55)) Steroids 13 (52) 5 (100) 9 (45) Anakinra 4 (16) 2 (40) 2 (10) RESULTS Aspirin 14 (56) 4 (80) 10 (50) Enoxaparin 14 (56) 4 (80) 10 (50) Patient Characteristics Remdesivir 9 (36) 3 (60) 6 (30) SARS-CoV-2 testing, n (%) During the study period, 25 patients PCR 15 (60) 3 (60) 12 (60) were admitted for management of Antibodies 13 (52) 2 (40) 11 (55) MIS-C, of whom 15 (60%) were male, IVIg, intravenous immunoglobulin; PCR, polymerase chain reaction. and the median age was 9.7 (IQR 2.7–15.0) years (Table 1). Forty ICU admission for monitoring and Echocardiographic Anomalies percent of patients (n = 10) had treatment was required in 14 patients significant previous morbidities, All patients with a diagnosis of MIS-C (56%) for a median of 7 (IQR 4–11) including asthma (n = 3; 15%), had an echocardiogram performed days. Inotropic support was obesity (n = 3; 15%), a previous during hospital admission, and 23 administered in 7 patients (28%), episode of Kawasaki disease (n =2; patients (92%) had at least 1 follow- noninvasive positive pressure 8%), sickle cell anemia (n = 1), up echocardiogram. ventilation was administered in 6 mitochondrial disease (n = 1), and patients (24%); and mechanical triploidy with prematurity and Left ventricular systolic dysfunction ventilation was administered in 1 chronic respiratory failure status post (left ventricular ejection fraction patient (4%). The only patient , tracheostomy (n = 1). 55%) was found in 15 patients requiring mechanical ventilation had (60%) at a median of 5 (IQR 3–8) Fever was present in all patients, a past medical history of chronic lung days after onset of fever (Table 2). followed in frequency by disease and had a previous The majority of patients had mild gastrointestinal symptoms (n = 18; tracheostomy. ventricular dysfunction, whereas 2 72%), dermatologic manifestations Treatment received included patients (8%) had moderate (n = 14; 56%), respiratory symptoms intravenous immunoglobulin in 16 ventricular dysfunction or greater (n = 11; 44%), hypotension or shock patients (64%), steroids in 13 (left ventricular ejection fraction (n = 11; 44%), hematologic anomalies , patients (50%), anakinra in 4 patients 40%). Of those with ventricular (n = 7; 28%), acute renal failure (n = (15%), and remdesivir in 9 patients systolic dysfunction during the acute 2; 8%), and neurologic symptoms (35%). A majority of patients were phase of illness, function normalized (n = 1; 4%). All patients had treated with aspirin (14 patients; in 13 of 15 patients (87%) at documented SARS-CoV-2 infection – 56%) and/or enoxaparin (14 a median of 5 (3 8) days after onset (RT-PCR in 15 patients [60%], patients; 56%). of dysfunction, with persistent mild serology tests in 13 patients [52%]). ventricular dysfunction in 2 of 15 Four patients had positive RT-PCR At the time of publication, patients patients (13%). test results 2 to 8 days before MIS-C had a median follow-up of 51 (IQR diagnosis, whereas the remainder had 38–64) days after onset of illness, and New coronary artery enlargement positive results at the time of hospital all patients were discharged from the was diagnosed in 5 patients (20%) at admission and MIS-C diagnosis. hospital. a median of 5 (IQR 2–5) days after

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 5, November 2020 3 TABLE 2 Cardiac Complications in Patients With MIS-C Based on Presence or Absence of Second- or degree AVB resolved in 4 of 5 patients Third-Degree AVB between 10 and 14 days after onset of All Patients AVB No AVB fever; 1 patient had persistent first- (N = 25) (n =5) (n = 20) degree AVB on the latest outpatient Ventricular dysfunction, n (%) follow-up (75 days after onset of EF ,55% 15 (60) 5 (100) 10 (50) fever). EF ,40% 2 (8) 1 (20) 1 (5) Coronary artery dilation, n (%) All patients with AVB had ventricular Dilation (z score $2 but ,2.5) 3 (12) 1 (25) 2 (10) dysfunction on the echocardiogram Aneurysm (z score $2.5) 3 (12) 0 (0) 3 (15) (mild in 4 patients, moderate in 1 ECG changes, n (%) patient). All were admitted to the ICU First-degree AVB 5 (20) 5 (100) 0 (0) Second-degree AVB, Mobitz 1 2 (8) 2 (40) 0 (0) (unrelated to AVB), and 4 of 5 Second-degree AVB, Mobitz 2 1 (4) 1 (20) 0 (0) patients required inotropic support Third-degree AVB 1 (4) 1 (20) 0 (0) for hypotension or shock at the time QTc prolongation 7 (28) 4 (80) 3 (15) of initial presentation. One patient QTc prolongation .500 ms 1 (4) 1 (25) 0 (0) was intubated because of cardiogenic Nonspecific ST segment changes 14 (56) 5 (100) 9 (45) Laboratory testing, n (%) shock, and another required positive Elevated troponin level 2 (8) 0 (0) 2 (10) pressure ventilation for COVID-19 Elevated BNP level 11 (44) 4 (80) 8 (40) pneumonia. Although second- and EF, ejection fraction. third-degree AVB occurred during the initial ICU admission in 2 of 4 patients, it occurred later in the onset of fever (excluding patient with subsequently developed AVB, and 1 course of the disease in the other 2 a previous history of Kawasaki of 5 had first-degree AVB on the patients, requiring transfer back to disease and coronary aneurysm). Of admission ECG. AVB progressed to the ICU or to a cardiology floor for those, 3 patients had coronary artery the second or third degree in 4 of 5 closer monitoring. All patients who dilation (z score $2 but ,2.5) and 2 patients during the hospital developed second- or third-degree patients had small coronary artery admission (Mobitz type I in 2 AVB presented with hypotension or aneurysms (z score $2.5 but ,5). patients, Mobitz type II in 1 patient shock, gastrointestinal symptoms, One of the patients with coronary [without QRS widening], and third- and dermatologic manifestations. The artery aneurysms had a previous degree AVB in 1 patient) within 0 to other patient with first-degree AVB diagnosis of Kawasaki disease and no 3 days after onset of first-degree AVB. presented with COVID-19 pneumonia significant change in coronary artery No patient required acute and hypotension responsive to fluid dimension after MIS-C diagnosis. resuscitation, pacing, or medication to resuscitation but did not have improve atrioventricular conduction Troponin levels were elevated in 2 gastrointestinal or dermatologic or increase the escape rate. Second- patients (13%), both of whom had manifestations, as opposed to those and third-degree AVB resolved in all ventricular dysfunction. BNP levels who progressed to higher-grade AVB. patients within 1 to 6 days. First- were elevated in 10 of 15 patients None of the patients with AVB had (67%) with ventricular dysfunction elevated troponin levels. All patients (median 395 [IQR 105–1008] pg/mL) with second- or third-degree AVB had and in only 1 of 10 patients (10%) elevated BNP levels (median 1407 with normal biventricular systolic [IQR 1127–1776] pg/mL), whereas function (median 35 [IQR 16–79] pg/ the patient with first-degree AVB had mL). a normal BNP level. QTc prolongation was seen in 7 ECG Anomalies patients (28%) at a median of 6 (IQR ECGs were performed in all patients, 2–8) days after onset of fever and 20 (80%) patients had multiple (median QTc 484 [IQR 474–493] ECGs to review. First-degree AVB was milliseconds). QTc prolongation was found in 5 (20%) patients admitted more often seen in patients with with MIS-C at a median of 6 (IQR 5–8) FIGURE 1 ventricular dysfunction (n =6) days after onset of fever (Fig 1, PR interval in patients with and without AVB by compared with those with normal days from onset of fever. Arrows reveal onset n Supplemental Table 3). Of the 5 and resolution of higher-grade AVB (second ventricular function ( = 1) and those patients with first-degree AVB, 4 of 5 and/or third degree). AVB1-5, individual with AVB (4 of 5 [80%] patients with had a normal admission ECG and patients with AVB. AVB versus 3 of 20 [15%] patients

Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 DIONNE et al without AVB). NonspecificST inflammatory response with MIS-C differs from the previous segment changes were seen in 14 syndrome.10–14 Clinical presentation experience with . In patients (56%), without a difference ranges from asymptomatic elevation non–COVID-19-related myocarditis, between those with and without of troponin levels to fulminant complete was generally ventricular dysfunction (9 of 15 vs 5 myocarditis requiring extracorporeal present at the time of initial of 10 patients, respectively). All membrane oxygenation support. presentation and frequently required patients with AVB had nonspecificST Atrial and ventricular arrhythmias interventions, including pacing and segment changes on the ECG, have been reported in 3% to 17% of extracorporeal membrane compared with only 9 (45%) patients adults hospitalized with COVID- oxygenation. In comparison, AVB without AVB. 19.15–17 Bradyarrhythmias have not developed later in the hospital course been typically seen, but there was one in patients with MIS-C, and no Two patients had atrial ectopy, and reported case of transient complete patients required pacing or another patient had sustained ectopic heart block in a critically ill 54-year- extracorporeal membrane . No ventricular old woman with COVID-19 oxygenation for AVB. However, this arrhythmias were seen. No patient pneumonia who required initial experience with MIS-C is based required antiarrhythmic medication. cardiopulmonary resuscitation for on a small number of patients, and ∼10 minutes until resumption of our understanding will likely evolve DISCUSSION normal sinus rhythm.18 as we learn more about the disease. In this series, ECG anomalies were Initial reports suggested that children In contrast, AVB seen in patients with found in 14 (56%) children with MIS- with COVID-19 have a much milder MIS-C appears more similar to the C and included PR prolongation, ST form of COVID-19 than adults.1,2 previous experience with Lyme segment changes, and QTc However, there have now been . In a surveillance study in the prolongation. First-degree AVB was multiple reports of cases of MIS-C in United States, cardiac manifestations found in 5 children (20%) during conjunction with recent SARS-CoV-2 were present in 84 of 875 patients hospital admission, with 4 of 5 infection. Published case series have (10%) with , including patients progressing to second- or revealed cardiovascular involvement conduction abnormalities in 16 21 third-degree AVB. The incidence of in a significant proportion of patients, patients (1.8%). Similarly, patients AVB was highest among patients with reports of elevated troponin with Lyme carditis presented with requiring ICU admission (4 of 14 levels, elevated BNP levels, first-degree AVB that progressed to patients; 29%). All patients with ventricular dysfunction, and coronary high-grade AVB, with the highest risk second- and third-degree AVB artery dilation and aneurysm.5,6 No of progression in patients with a PR 22–24 presented with hypotension or shock, significant tachyarrhythmias have interval .300 milliseconds. This gastrointestinal symptoms, and been reported in children, compared is similar to findings in our cohort, in dermatologic manifestations and had with adult patients (in whom a much which most patients had initially evidence of ventricular dysfunction higher prevalence has been seen). normal ECGs and developed first- on the echocardiogram. ECGs should degree AVB before higher-grade AVB be monitored for evidence of PR There has been one recent report of (although the progression occurred prolongation throughout admission in transient complete heart block in the same day in some cases). In MIS- 19 patients with MIS-C. Patients who a child after SARS-CoV-2 infection. C, patients with a prolonged PR develop first-degree AVB may benefit The etiology of the AVB remains interval for age were at high risk of from continuous telemetry because of unclear but may result from progression of AVB, even with only the risk of progression to high- inflammation and edema of the mild PR prolongation (ie, ,300 grade AVB. conduction tissue as part of a more milliseconds; Fig 1). diffuse process of myocardial injury. Evidence of myocardial injury is The course of AVB remains unclear in common among adults hospitalized Authors of an earlier single-center patients with MIS-C. Although higher- with COVID-19. Possible causes of series of children with non–COVID- grade AVB resolved within ∼1 week myocardial injury in patients with 19-related acute myocarditis reported in this series, some patient still had COVID-19 include myocarditis, a high incidence of arrhythmias, persistent first-degree AVB at the hypoxic injury, stress (takotsubo) occurring in 38 patients (45%) and time of discharge. Antibiotic , ischemic injury including supraventricular treatment has been shown to caused by cardiac microvascular tachycardia in 9 patients, ventricular decrease the duration of cardiac damage or , in 30 patients, and manifestations in Lyme carditis.25 right heart strain (acute cor complete heart block in 11 patients.20 Antiinflammatory treatment of pulmonale), and systemic The clinical course of AVB in patients patients with MIS-C with intravenous

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 5, November 2020 5 immunoglobulin, steroids, or institution. Moreover, there was no better understand the anakinra may help decrease the systematic protocol for ECG testing, pathophysiology, clinical incidence of AVB in MIS-C; however, and some patients without a follow- presentation, and impact of treatment we were unable to assess the impact up ECG study or telemetry may have on atrioventricular conduction of therapy because of the empirical been missed. The limited follow-up disease in MIS-C. treatment of the most severe cases. on patients at the time of publication Ongoing outpatient follow-up of limits our ability to comment on long- patients with MIS-C will help us term outcomes. ABBREVIATIONS better understand the trajectory of AVB: atrioventricular block AVB in patients with MIS-C. Until we BNP: brain natriuretic peptide know more about AVB in MIS-C, CONCLUSIONS COVID-19: coronavirus disease children should have frequent ECGs In this series, MIS-C was associated 2019 during admission to monitor for PR with a high incidence of ECG: electrocardiogram prolongation and have long-term atrioventricular conduction disease in IQR: interquartile range follow-up after discharge. A 24-hour children, particularly in patients MIS-C: multisystem inflammatory should be considered presenting with hypotension or shock syndrome in children in patients with persistent first- and ventricular dysfunction. This RT-PCR: reverse transcription degree AVB during outpatient follow- experience highlights the importance polymerase chain up. of ECG monitoring throughout reaction This study should be interpreted in admission to identify patients with SARS-CoV-2: severe acute respira- light of its limitations. This is PR prolongation at risk for tory syndrome a retrospective series of only a small progression to high-grade AVB. Large coronavirus 2 number of patients from a single multicenter studies are required to

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Atrioventricular Block in Children With Multisystem Inflammatory Syndrome Audrey Dionne, Douglas Y. Mah, Mary Beth F. Son, Pui Y. Lee, Lauren Henderson, Annette L. Baker, Sarah D. de Ferranti, David R. Fulton, Jane W. Newburger and Kevin G. Friedman Pediatrics originally published online August 27, 2020; originally published online August 27, 2020;

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