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ScienceDirect Journal of Electrocardiology 47 (2014) 155 – 157 www.jecgonline.com
Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study Gopi Krishna Panicker, BHMS, PGDCR,⁎ Vaibhav Salvi, MBBS, PGDCR, Dilip R. Karnad, MD, FACP, FRCP (Glasg), Saikat Chakraborty, MSc, Deepak Manohar, MSc, Yash Lokhandwala, MD, DM, FACC, Snehal Kothari, MD, DM, FACC, FESC Quintiles Cardiac Safety Services, Mumbai, India
Abstract
Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebosubtracted change from baseline in QTc corrected by Fridericia's method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies. © 2014 Elsevier Inc. All rights reserved.
Keywords:
Cardiac repolarization; Gender differences; Pharmacodynamics; Assay sensitivity
Introduction In clinical pharmacology studies assessing drug-induced repolarization changes, such as thorough QT (TQT) studies, the QT interval is conventionally measured in a single ECG lead (commonly lead II) by the threshold or the tangent method though, in recent times superimposition of median beats (SMB) constructed from the 12 leads is also being increasingly used [1]. Moxifloxacin, which produces modest degrees of QT prolongation, has been extensively used as a positive control to demonstrate assay sensitivity in thorough QT studies. Assay sensitivity is demonstrated when the lower 90% two-sided confidence limit of mean QTc prolongation with moxifloxacin exceeds 5 ms at one or more time points close to the time of maximum concentration level (Cmax) is achieved by moxifloxacin, which ranges from 0.75 hours to 3.5 hours. [2,3]. The selection of lead II for QT measurement in most clinical studies was based on the assumption that the vectors of repolarization in lead II ⁎ Corresponding author. Quintiles Cardiac Safety Services, Research and Reports, 502 A, Leela Business Park, M.V. Road, Andheri (East), Mumbai, Maharashtra 400059, India. E-mail address: [email protected] 0022-0736/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jelectrocard.2013.11.004
usually result in a long single wave rather than discrete T and U waves and the presence of U wave or notched T wave confound the accurate measurement of QT interval [4,5]. Some authors suggest that lead II most frequently contains the longest QT interval although recent evaluation has shown that maximum QT interval occurs very frequently in other leads [5]. This raises the question what if QT interval is measured in any of the other 11 leads in all ECGs in a thorough QT study? We studied moxifloxacin-induced QT prolongation in each of the 12 leads in healthy subjects in a TQT study.
Subject and methods ECG data Triplicate ECGs were recorded at pre-dose baseline and 4 post-dose time points (1, 1.5, 2, and 4 hours) close to the Cmax of moxifloxacin from a TQT study conducted in 97 healthy subjects (54 males and 43 females) after administration of moxifloxacin (400-mg single oral dose) or placebo in an open-label, cross-over design on Day 1 or Day 3 (49 subjects received moxifloxacin on Day 1 and
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G.K. Panicker et al. / Journal of Electrocardiology 47 (2014) 155–157
placebo on Day 3, while 48 subjects received placebo on Day 1 and moxifloxacin on Day 3). The age distributions of the male (age 20–54 years; mean age 34 ± 10 years) and female subjects in the study (age 19–56 years; mean age 34 ± 12 years) were comparable. Subjects were in a supine position and at rest for 10 minutes prior to the recording of ECGs at each time point. Digital ECGs were acquired at 1000 Hz. (Eli 250, Mortara Instruments) and manually analyzed in a core ECG laboratory using CalECG 3.0 (AMPS LLC) computer software by a team of four physicians who had undergone training in on-screen measurement of digital ECGs. The readers were blinded to subject demographics, treatment group and time points. The ECGs were allocated to each reader such that all ECGs of a single subject were read by the same reader. QT interval was manually measured by threshold method in temporally aligned five complexes in each of the 12 leads and averaged for each lead. RR intervals were measured in the preceding complexes in lead II. T-wave amplitudes in each of the 12 leads were also measured in the complexes selected for QT measurement. QT interval was corrected for the effect of heart rate using the Fridericia's formula (QTcF). QT interval values were excluded for those leads with flat T waves, i.e., T-wave amplitude between − 0.1 and 0.1 mV [4,6]. For complexes with upright, inverted, biphasic or notched T waves, point of return of the terminal limb of T wave to the isoelectric baseline was considered as the end of T wave. Statistical analysis Data were analyzed using SAS (version 9.2). The placebosubtracted “change from baseline” values (ΔΔQTcF) for the post-dose time points in the moxifloxacin arm were calculated from the QT measurements for each of the 12 leads using a linear mixed-effects ANCOVA model with baseline QTcF as a covariate and gender, time (categorical), treatment, treatment-by-time interaction as fixed effects and subject as a random effect. The number and percent of ECGs with flat T waves (− 0.1 to 0.1 mV) in each of the 12 leads was noted.
Results The frequency of ECGs with flat T waves (− 0.1 to 0.1 mV) for male and female subjects is shown in Table 1. Of the 12 ECG leads, flat T waves were seen in leads aVL, III and V1 in the maximum number of ECGs, which were excluded from calculation of ΔΔQTcF. Lead II showed the typical pattern of moxifloxacininduced QT prolongation with maximum prolongation seen between 1.5 and 4 hours. The lower 90% two-sided confidence bound for the mean change in QTcF exceeded 5 ms at all four post-dose time points (Fig. 1). It also exceeded 5 ms at one or more time points in all the other leads in men and women except in leads III, aVL, and V1 in men due to wide confidence limits. In female subjects, the 90% two-sided lower confidence bound of ΔΔQTcF exceeded 5 ms in one or more time points in these leads as well, despite wide confidence limits because of a greater degree of mean ΔΔQTcF.
Table 1 Frequency (%) of ECGs with flat T waves (− 100 to 100 μV) for each of the 12 leads in the study. Lead
I II III aVR aVL aVF V1 V2 V3 V4 V5 V6
Number (%) of ECGs with flat T waves
P values versus lead II
Male
Female
Male
Female
42 (2.7%) 24 (1.5%) 672 (43.2%) 28 (1.8%) 823 (52.9%) 114 (7.3%) 610 (39.2%) 12 (0.8%) 0 (0.0%) 11 (0.7%) 29 (1.9%) 78 (5.0%)
39 (3%) 34 (2.6%) 610 (47.4%) 32 (2.5%) 911 (70.8%) 132 (10.3%) 569 (44.3%) 135 (10.5%) 160 (12.4%) 94 (7.3%) 89 (6.9%) 108 (8.4%)
0.0345 NA b 0.0001 0.6749 b 0.0001 b 0.0001 b 0.0001 0.0652 b 0.0001 0.0414 0.5796 b 0.0001
0.6348 NA b0.0001 0.9008 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
Discussion Assay sensitivity in detecting moxifloxacin-induced QT prolongation was demonstrated in all ECG leads except leads III, aVL and V1 in men due to wide confidence limits in ΔΔQTcF. The confidence limits were wide in women too, but the lower confidence bound exceeded 5 ms at one or more time points because of greater mean ΔΔQTcF in women possibly due to greater sensitivity of women to druginduced QT prolongation [7]. In most thorough QT studies, QT interval is not measured in leads with a flat T wave as there is a large variability in identifying the end of the T wave when T-wave amplitude ranges between − 0.1 and 0.1 mV [3,5]. The proportion of ECGs with flat T waves was highest in leads III, aVL and V1. As a result, 60% of ECGs in aVL, 45% in lead III and 42% in V1 had to be excluded from statistical analysis. This may be one of the reasons for the wide confidence limits for the ΔΔQTcF in these leads. The high proportion of flat T waves in lead III, aVL and V1 is unlikely to affect QT measurements by the superimposed median beat method since the limitation of the indistinct T end will be overcome by overlapping complexes from leads with more prominent T waves, making it relatively easy to identify the latest offset of the T wave. On the other hand, it would severely compromise QT measurement by the tangent method [1]. Clinical implications This study confirms the validity of lead II as the preferred lead for measurement of the QT interval in serial ECGs in clinical pharmacology studies and in clinical practice. Leads III, aVL and V1 did not demonstrate assay sensitivity for ΔΔQTcF. Leads I, aVR, V5, aVF, V6 and V4 (in order of preference) showed mean estimates, width of 90% confidence intervals as well as the time course of the moxifloxacin effect that were similar to that in lead II, across all time points and could be considered as alternatives for QT measurement in serial ECGs, when it cannot be measured in lead II.
G.K. Panicker et al. / Journal of Electrocardiology 47 (2014) 155–157
157
A Lead I
Lead II
Lead III
Lead aVR
Lead aVL
Lead aVF
Lead V1
Lead V2
Lead V3
Lead V4
Lead V5
Lead V6
B
Fig. 1. Mean placebo-adjusted change from baseline in QTcF (ΔΔQTcF) and its 90% two-sided confidence limits obtained in each of the 12 leads in 97 healthy subjects (54 males and 43 females) after administration of 400 mg moxifloxacin. Mean ΔΔQTcF and its 90% confidence limits are shown in red (dark) in men and blue (light) in women. Panel A shows limb leads and Panel B shows precordial leads. Color illustration online.
Conclusions Moxifloxacin-induced QT prolongation is not satisfactorily demonstrated when QT intervals are measured in leads III, aVL and V1. These leads should be avoided when measuring QT interval in thorough QT studies.
[3]
References
[5]
[1] Salvi V, Karnad DR, Panicker GK, et al. Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers. J Electrocardiol 2011;44(2):96–104. [2] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: E14. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005. http://www.ich.org/fi-
[4]
[6]
[7]
leadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_ Guideline.pdf. Accessed December 18, 2013. Rodvold KA, Neuhauser M. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy 2001;21(10 Pt 2): 233S–52S. Shetty S, Khan M, Salvi S, et al. Do ECG characteristics predict variability in QT measurements in clinical trials? Indian Heart J 2005;57:302. Salvi V, Karnad DR, Kerkar V, et al. Choice of an alternative lead for QT interval measurement in serial ECGs when lead II is not suitable for analysis. Indian Heart J 2012;64(6):535–40. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009;53(11):982–91. Darpo B, Karnad DR, Badilini F, et al. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modeling in a phase 1 study with oral rac-sotalol. Br J Clin Pharmacol 2013, http://dx.doi.org/10.1111/bcp.12201 [Epub ahead of print].
ScienceDirect Journal of Electrocardiology 47 (2014) 155 – 157 www.jecgonline.com
Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study Gopi Krishna Panicker, BHMS, PGDCR,⁎ Vaibhav Salvi, MBBS, PGDCR, Dilip R. Karnad, MD, FACP, FRCP (Glasg), Saikat Chakraborty, MSc, Deepak Manohar, MSc, Yash Lokhandwala, MD, DM, FACC, Snehal Kothari, MD, DM, FACC, FESC Quintiles Cardiac Safety Services, Mumbai, India
Abstract
Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebosubtracted change from baseline in QTc corrected by Fridericia's method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies. © 2014 Elsevier Inc. All rights reserved.
Keywords:
Cardiac repolarization; Gender differences; Pharmacodynamics; Assay sensitivity
Introduction In clinical pharmacology studies assessing drug-induced repolarization changes, such as thorough QT (TQT) studies, the QT interval is conventionally measured in a single ECG lead (commonly lead II) by the threshold or the tangent method though, in recent times superimposition of median beats (SMB) constructed from the 12 leads is also being increasingly used [1]. Moxifloxacin, which produces modest degrees of QT prolongation, has been extensively used as a positive control to demonstrate assay sensitivity in thorough QT studies. Assay sensitivity is demonstrated when the lower 90% two-sided confidence limit of mean QTc prolongation with moxifloxacin exceeds 5 ms at one or more time points close to the time of maximum concentration level (Cmax) is achieved by moxifloxacin, which ranges from 0.75 hours to 3.5 hours. [2,3]. The selection of lead II for QT measurement in most clinical studies was based on the assumption that the vectors of repolarization in lead II ⁎ Corresponding author. Quintiles Cardiac Safety Services, Research and Reports, 502 A, Leela Business Park, M.V. Road, Andheri (East), Mumbai, Maharashtra 400059, India. E-mail address: [email protected] 0022-0736/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jelectrocard.2013.11.004
usually result in a long single wave rather than discrete T and U waves and the presence of U wave or notched T wave confound the accurate measurement of QT interval [4,5]. Some authors suggest that lead II most frequently contains the longest QT interval although recent evaluation has shown that maximum QT interval occurs very frequently in other leads [5]. This raises the question what if QT interval is measured in any of the other 11 leads in all ECGs in a thorough QT study? We studied moxifloxacin-induced QT prolongation in each of the 12 leads in healthy subjects in a TQT study.
Subject and methods ECG data Triplicate ECGs were recorded at pre-dose baseline and 4 post-dose time points (1, 1.5, 2, and 4 hours) close to the Cmax of moxifloxacin from a TQT study conducted in 97 healthy subjects (54 males and 43 females) after administration of moxifloxacin (400-mg single oral dose) or placebo in an open-label, cross-over design on Day 1 or Day 3 (49 subjects received moxifloxacin on Day 1 and
156
G.K. Panicker et al. / Journal of Electrocardiology 47 (2014) 155–157
placebo on Day 3, while 48 subjects received placebo on Day 1 and moxifloxacin on Day 3). The age distributions of the male (age 20–54 years; mean age 34 ± 10 years) and female subjects in the study (age 19–56 years; mean age 34 ± 12 years) were comparable. Subjects were in a supine position and at rest for 10 minutes prior to the recording of ECGs at each time point. Digital ECGs were acquired at 1000 Hz. (Eli 250, Mortara Instruments) and manually analyzed in a core ECG laboratory using CalECG 3.0 (AMPS LLC) computer software by a team of four physicians who had undergone training in on-screen measurement of digital ECGs. The readers were blinded to subject demographics, treatment group and time points. The ECGs were allocated to each reader such that all ECGs of a single subject were read by the same reader. QT interval was manually measured by threshold method in temporally aligned five complexes in each of the 12 leads and averaged for each lead. RR intervals were measured in the preceding complexes in lead II. T-wave amplitudes in each of the 12 leads were also measured in the complexes selected for QT measurement. QT interval was corrected for the effect of heart rate using the Fridericia's formula (QTcF). QT interval values were excluded for those leads with flat T waves, i.e., T-wave amplitude between − 0.1 and 0.1 mV [4,6]. For complexes with upright, inverted, biphasic or notched T waves, point of return of the terminal limb of T wave to the isoelectric baseline was considered as the end of T wave. Statistical analysis Data were analyzed using SAS (version 9.2). The placebosubtracted “change from baseline” values (ΔΔQTcF) for the post-dose time points in the moxifloxacin arm were calculated from the QT measurements for each of the 12 leads using a linear mixed-effects ANCOVA model with baseline QTcF as a covariate and gender, time (categorical), treatment, treatment-by-time interaction as fixed effects and subject as a random effect. The number and percent of ECGs with flat T waves (− 0.1 to 0.1 mV) in each of the 12 leads was noted.
Results The frequency of ECGs with flat T waves (− 0.1 to 0.1 mV) for male and female subjects is shown in Table 1. Of the 12 ECG leads, flat T waves were seen in leads aVL, III and V1 in the maximum number of ECGs, which were excluded from calculation of ΔΔQTcF. Lead II showed the typical pattern of moxifloxacininduced QT prolongation with maximum prolongation seen between 1.5 and 4 hours. The lower 90% two-sided confidence bound for the mean change in QTcF exceeded 5 ms at all four post-dose time points (Fig. 1). It also exceeded 5 ms at one or more time points in all the other leads in men and women except in leads III, aVL, and V1 in men due to wide confidence limits. In female subjects, the 90% two-sided lower confidence bound of ΔΔQTcF exceeded 5 ms in one or more time points in these leads as well, despite wide confidence limits because of a greater degree of mean ΔΔQTcF.
Table 1 Frequency (%) of ECGs with flat T waves (− 100 to 100 μV) for each of the 12 leads in the study. Lead
I II III aVR aVL aVF V1 V2 V3 V4 V5 V6
Number (%) of ECGs with flat T waves
P values versus lead II
Male
Female
Male
Female
42 (2.7%) 24 (1.5%) 672 (43.2%) 28 (1.8%) 823 (52.9%) 114 (7.3%) 610 (39.2%) 12 (0.8%) 0 (0.0%) 11 (0.7%) 29 (1.9%) 78 (5.0%)
39 (3%) 34 (2.6%) 610 (47.4%) 32 (2.5%) 911 (70.8%) 132 (10.3%) 569 (44.3%) 135 (10.5%) 160 (12.4%) 94 (7.3%) 89 (6.9%) 108 (8.4%)
0.0345 NA b 0.0001 0.6749 b 0.0001 b 0.0001 b 0.0001 0.0652 b 0.0001 0.0414 0.5796 b 0.0001
0.6348 NA b0.0001 0.9008 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
Discussion Assay sensitivity in detecting moxifloxacin-induced QT prolongation was demonstrated in all ECG leads except leads III, aVL and V1 in men due to wide confidence limits in ΔΔQTcF. The confidence limits were wide in women too, but the lower confidence bound exceeded 5 ms at one or more time points because of greater mean ΔΔQTcF in women possibly due to greater sensitivity of women to druginduced QT prolongation [7]. In most thorough QT studies, QT interval is not measured in leads with a flat T wave as there is a large variability in identifying the end of the T wave when T-wave amplitude ranges between − 0.1 and 0.1 mV [3,5]. The proportion of ECGs with flat T waves was highest in leads III, aVL and V1. As a result, 60% of ECGs in aVL, 45% in lead III and 42% in V1 had to be excluded from statistical analysis. This may be one of the reasons for the wide confidence limits for the ΔΔQTcF in these leads. The high proportion of flat T waves in lead III, aVL and V1 is unlikely to affect QT measurements by the superimposed median beat method since the limitation of the indistinct T end will be overcome by overlapping complexes from leads with more prominent T waves, making it relatively easy to identify the latest offset of the T wave. On the other hand, it would severely compromise QT measurement by the tangent method [1]. Clinical implications This study confirms the validity of lead II as the preferred lead for measurement of the QT interval in serial ECGs in clinical pharmacology studies and in clinical practice. Leads III, aVL and V1 did not demonstrate assay sensitivity for ΔΔQTcF. Leads I, aVR, V5, aVF, V6 and V4 (in order of preference) showed mean estimates, width of 90% confidence intervals as well as the time course of the moxifloxacin effect that were similar to that in lead II, across all time points and could be considered as alternatives for QT measurement in serial ECGs, when it cannot be measured in lead II.
G.K. Panicker et al. / Journal of Electrocardiology 47 (2014) 155–157
157
A Lead I
Lead II
Lead III
Lead aVR
Lead aVL
Lead aVF
Lead V1
Lead V2
Lead V3
Lead V4
Lead V5
Lead V6
B
Fig. 1. Mean placebo-adjusted change from baseline in QTcF (ΔΔQTcF) and its 90% two-sided confidence limits obtained in each of the 12 leads in 97 healthy subjects (54 males and 43 females) after administration of 400 mg moxifloxacin. Mean ΔΔQTcF and its 90% confidence limits are shown in red (dark) in men and blue (light) in women. Panel A shows limb leads and Panel B shows precordial leads. Color illustration online.
Conclusions Moxifloxacin-induced QT prolongation is not satisfactorily demonstrated when QT intervals are measured in leads III, aVL and V1. These leads should be avoided when measuring QT interval in thorough QT studies.
[3]
References
[5]
[1] Salvi V, Karnad DR, Panicker GK, et al. Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers. J Electrocardiol 2011;44(2):96–104. [2] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: E14. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005. http://www.ich.org/fi-
[4]
[6]
[7]
leadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_ Guideline.pdf. Accessed December 18, 2013. Rodvold KA, Neuhauser M. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy 2001;21(10 Pt 2): 233S–52S. Shetty S, Khan M, Salvi S, et al. Do ECG characteristics predict variability in QT measurements in clinical trials? Indian Heart J 2005;57:302. Salvi V, Karnad DR, Kerkar V, et al. Choice of an alternative lead for QT interval measurement in serial ECGs when lead II is not suitable for analysis. Indian Heart J 2012;64(6):535–40. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009;53(11):982–91. Darpo B, Karnad DR, Badilini F, et al. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modeling in a phase 1 study with oral rac-sotalol. Br J Clin Pharmacol 2013, http://dx.doi.org/10.1111/bcp.12201 [Epub ahead of print].
