Quantitative analysis

1. General recommendations

   • i) In patients with severe arrhythmias, the end-systolic volumes tend to be overestimated and ejection fraction underestimated. In case of significant artifacts this should be denoted in the report.
   • ii) Calculated parameters: LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, cardiac output, LV mass, and body-surface area indexed values of all except ejection fraction. The parameters quantified may vary depending on the clinical need.
   • iii) Evaluation of the stack of short axis images with computer-aided analysis packages.
   • iv) Contours of endocardial and epicardial borders at end-diastole and end-systole (Fig. 1).
     

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     Fig. 1

     Left ventricular (LV) chamber quantification. For LV chamber quantification, the endocardial (blue) and epicardial (yellow) contours are delineated in diastole (left) and systole (right) in a stack of short axis slices that cover the whole left ventricle. a and b illustrate the approach with inclusion of the papillary muscles as part of the LV volume. c and d show the approach with exclusion of the papillary muscles from the LV volume

   • v) Epicardial borders should be drawn on the middle of the chemical shift artifact line (when present).
   • vi) The LV end-diastolic image should be chosen as the image with the largest LV blood volume. For its identification, the full image stack should be be evaluated and one phase has to be identified as end-diastole for all the short axis locations. In addition, closure of the mitral valve or the phase immediately before opening of the aortic valve may be used for orientation.
   • vii) The LV end-systolic image should be chosen as the image with the smallest LV blood volume. For its identification, the full image stack has to be evaluated and one phase has to be identified as end-systole for all the short axis locations.
   • viii) Deviations may occur and extra care should be taken in the setting of LV dyssynchrony.
   • ix) Automatic contour delineation algorithms must be checked for appropriateness by the reader.

2. LV volumes

   • i)

     Papillary muscles and trabecular tissue are myocardial tissue and thus ideally should be included with the myocardium as part of LV mass. As there is still discussion on the exact delineation of papillary muscles (e.g. versus trabeculation) and not all evaluation tools allow for their inclusion without manual drawing of contours, they are often included in the blood pool volume in clinical practice, which is acceptable. Reference ranges that use the same approach both on the acquisition and post-processing side must be used. (Fig. 1) [8–10].

   • ii)

     Outflow tract: The LV outflow tract is included as part of the LV blood volume. When aortic valve cusps are identified on the basal slice(s) the contour is drawn to include the outflow tract to the level of the aortic valve cusps.

   • iii)

     Basal descent: As a result of systolic motion of the mitral valve toward the apex (basal descent), care must be taken with the one or two most basal slices by using a standardized consistent approach. A slice that contains LV blood volume at end-diastole may include only left atrium (LA) without LV blood volume at end-systole. The LA can be identified by tracking wall thickening (if there is thickening - then it is in the LV cavity) and cavity (shrinking in systole, when in the cavity). Alternatively, the basal slice may be defined by at least 50% of the blood volume surrounded by myocardium. Currently however, there is no expert consensus on which method to use. Some software packages automatically adjust for systolic atrioventricular ring descent using cross-referencing from long axis locations.

3. LV mass

   • i)

     Calculation: difference between the total epicardial volume (sum of epicardial cross-sectional areas multiplied by the sum of the slice thickness and interslice gap) minus the total endocardial volume (sum of endocardial cross-sectional areas multiplied by the sum of the slice thickness and interslice gap), which is then multiplied by the specific density of myocardium (1.05g/ml).

   • ii)

     Papillary muscles: Papillary muscles and trabecular tissue are myocardial tissue and thus ideally should be included with the myocardium as part of LV mass, and this is particularly relevant in diseases with LV hypertrophy [6]. However, readers may decide to exclude trabecular tissue and papillary muscles from the myocardial mass. Reference ranges that use the same approach must be used (Fig. 1) [8–10].

   • iii)

     Basal descent and apex: When the most basal slice contains only a small crescent of basal lateral myocardium and no discernable ventricular blood pool, an epicardial contour for the visible myocardium is included for LV mass only. Similarly, when the most apical slice contains only a circle of myocardium without cavitary blood pool, an epicardial contour without an endocardial contour should be drawn for LV mass calculations.

4. Rapid quantitative analysis

   • i)

     A rapid quantitative analysis, known as the area-length method, can be performed using biplanar (e.g. 2- and 4-chamber views) or rotational multiple long axis views. In cases without expected significant regional variation of wall motion, this technique allows for faster evaluation and is not limited by problems related to basal descent. However, the 4-chamber view is strongly influenced by breath-hold position. The accuracy is not similar to short axis coverage, but allows a fast analysis often more similar to transthoracic echocardiography results. When the area-length method is used, with either a single long-axis view or a biplane approach, specific mention of the analysis technique should be made in the report.

   • ii)

     Calculation [11–13]:

     • Single long-axis equation: LV volume=0.85×(LV-area)²/ LV-length. This is typically performed using a 4-chamber view with calculations of LV volume obtained on both end-diastolic and end-systolic phases. LV area is the planimetered area of the LV cavity from an endocardial contour with the base drawn as a straight line through the medial and lateral aspects of the mitral annulus. LV length is the linear dimension from the midpoint of the mitral annular line to the apical tip of the endocardial contour.

     • Biplane equation: LV volume=0.85×(LV-area1 x LV-area2) / LV length. Here, both 4-chamber (LV-area1) and 2-chamber [or vertical] (LV-area2) long-axis views are used to calculate both end-diastolic and end-systolic volumes, similar to the single long-axis equation.

     • Multi-plane long axis: A series of long-axis views rotating around the central longitudinal axis of the LV is used to calculate volumes. Six views provide results that do not differ from short-axis stacks [14].

5. Cavity diameter and LV wall thickness can be obtained similar to echocardiography using two CMR approaches [12, 15]:

   • i)

     Basal short-axis slice: immediately basal to the tips of the papillary muscles.

   • ii)

     3-chamber view: in the LV minor axis plane at the mitral chordae level basal to the tips of the papillary muscles.

   • iii)

     Both approaches have good reproducibility. The 3-chamber view is most comparable to data obtained with echocardiography.

   • iv)

     For maximal LV wall thickness, the measurement should be made perpendicular to the LV wall to ensure accurate measurements. At the apex, short-axis images are oblique to the axis of the wall and will be inaccurate. In this location in particular, long-axis views should be used.

6. Research:

   • i)

     Real-time cine acquisitions become increasingly available and might be beneficial in patients with arrhythmia or limited breathholding capacity. 3D cine acquisitions are also evolving to accelerate examination time. Post-processing of real-time images and 3D cine acquisitions is still technically evolving. The Task Force chooses to refrain from making a dedicated statement at this time.

   • ii)

     Quantitative evaluation of LV myocardial dynamics (e.g., strain, rotation, time-to-peak velocity) is feasible by several imaging techniques (e.g., tagging, DENSE, SENC, tissue phase mapping, feature tracking) and requires specific post-processing software. As research applications are evolving and consensus evidence is being accumulated, the Task Force chooses to refrain from making a dedicated statement at this time.

Quantitative analysis

1. General recommendations

   • i) Calculated parameters: RV end-diastolic volume, RV end-systolic volume, RV ejection fraction, RV stroke volume, cardiac output, and body-surface area indexed values of all except ejection fraction. Similar to the LV, the parameters quantified may vary depending on the clinical need [16].
   • ii) The contiguous stack of short-axis images or axial cine images is evaluated with computer-aided analysis packages (Fig. 2) [17, 18]. Automatically generated contours have to be carefully reviewed.
     

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     Fig. 2

     Right ventricular (RV) chamber quantification. For RV volume quantification, the endocardial (red) contours are delineated in diastole (a) and systole (b) in a stack of transaxial slices covering the whole RV (top). Alternatively, a stack of short axis slices can be used (c, d). Here, the yellow contours indicate the RV in diastole (c) and systole (d); the RV is contoured following the LV analysis (in c and d, red / green contours indicate endocardial / epicardial borders of the LV) and with reference to the LV

   • iii) An axial stack of cines covering the RV provides the best identification of the tricuspid valve plane. A short-axis stack of cines is best for delineating the inferior wall.
   • iv) Endocardial borders are contoured at end-diastole and end-systole (Fig. 2).
   • v) The RV end-diastolic image should be chosen as the image with the largest RV blood volume. For its identification, the full image stack has to be evaluated and one phase has to be identified as end-diastole for all locations.
   • vi) RV end-systolic image should be chosen as the image with the smallest RV blood volume. For its identification, the full image stack has to be evaluated and one phase has to be identified as end-systole for all slices.
   • vii) As for the LV, it may be necessary to review all image slices in the stack to define end-systole.
   • viii) The pulmonary valve may be visualized, and contours are included just up to, but not superior to this level.

2. RV volumes

   • i)

     Total volumes are taken as the sum of volumes from individual 2D slices, accounting for any interslice gap and slice thickness. RV trabeculae and papillary muscles are typically included in RV volumes.

3. RV mass is usually not quantified in routine assessment. In selected patients, quantification of RV mass may be considered (e.g., in pulmonary hypertension).

4. Confirmation of results

   • i)

     If no shunts or valvular regurgitation is present, the RV and LV stroke volumes should be nearly equal (small differences are seen as a result of bronchial artery supply and papillary muscle inclusions in the measurements). Since the LV stroke volume is more reliably determined than the RV stroke volume, the LV data can be used to validate RV data.

Quantitative analysis

1. A quantitative analysis of the SI change in myocardial perfusion CMR studies can be performed. Several methods have been described for this purpose. In clinical practice, these are rarely required, but they may supplement visual analysis for example in suspected multi-vessel disease or suspected inadequate response to vasodilator stress. Fully automated methods for quantitative perfusion analysis are becoming available and may soon become more widely used. Quantitative analysis is also frequently used in research studies.

2. Requirements:

   • i)

     Validation and definition of a normal range with the specific pulse sequence and contrast regime used for data acquisition. If only a comparison between regions of the same study is made, establishing a normal range is less relevant.

   • ii)

     A temporal resolution of one RR interval is recommended.

   • iii)

     Consideration of potential saturation effects (higher contrast agent doses are more likely to lead to saturation effects).

3. Semi-quantitative analysis:

   • i)

     Analysis methods that describe characteristics of the SI profile of myocardial perfusion CMR studies without estimating myocardial blood flow are typically referred to as “semi-quantitative analysis methods”.

   • ii)

     Workflow:

     • Select an image from the dynamic series with good contrast between all cardiac compartments (some post-processing tools generate an average image of the series).

     • Outline LV endocardial and epicardial contours on this image (manual or automated) (Fig. 3c).

     • Propagate contours to all other dynamic images.

     • Correct contour position for in-plane motion (some analysis packages register images prior to contours being outlined).

     • Depending on the type of analysis to be performed, place a separate ROI in the LV blood pool. Preferably, the basal slice is used. Exclude papillary muscles and flow artifacts from the ROI.

     • Select a reference point in the LV myocardium for segmentation (usually one of the RV insertion points) [5].

     • Segment LV myocardium according to AHA classification [5]

     • Generate SI / time profiles for myocardial segments +/− LV blood pool.

     • Consider generating division into endocardial and epicardial layers and repeat analysis [20].

   • iii)

     Frequently used semi-quantitative analysis methods (see [29] for detailed review):

     • Maximal upslope of the myocardial SI profile, may be normalized to LV upslope [30].

     • Time to peak SI of the myocardial SI profile [31, 32].

     • Ratio of stress/rest values for the above (often referred to as “myocardial perfusion reserve index”) [33, 34].

     • The upslope integral (area under the signal intensity-time curve) [35].

   • iv)

     Limitations of semi-quantitative analysis methods:

     • SI may vary according to distance from coil. This can be partially corrected by using a pre-contrast proton density image or other coil sensitivity correction tools.

     • No absolute measurement of myocardial blood flow given.

4. Quantitative analysis

   • i)

     Analysis methods that process the SI profile of myocardial perfusion CMR studies to derive estimates of myocardial blood flow are typically referred to as “quantitative analysis methods” [29, 36, 37].

   • ii)

     Requirements:

     • It is a prerequisite for reliable quantification that data acquisition used an appropriate pulse sequence and contrast regime.

     • The requirements for the acquisition method depend on the analysis method. Currently, this typically requires at least a proton density image, the generation of an input function which is not saturated by using dual bolus [38] or dual contrast [39].

     • Motion correction to correct for respiratory motion is preferable.

   • iii)

     Workflow:

     • Manual analysis methods require contour placement as described above for semi-quantitative analysis. Dynamic SI data are then typically exported to off-line workstations for further processing.

     • Fully automated methods are becoming available, which generate pixel-wise maps of myocardial perfusion without user input.

   • iv)

     Several analysis methods have been described, including:

     • Model-based methods [40, 41].

     • Model-independent methods [42, 43].

Research tools / quantitative analysis

1. Quantification of LGE extent:

   • i)

     Manual planimetry:

     • Outline endocardial and epicardial borders.

     • Manual planimetry of LGE regions in each slice.

     • Summation of LGE areas.

     • Multiplication of total LGE area with slice thickness plus interslice gap as well as specific gravity of myocardium provides the approximate LGE mass, which can be used to calculate the ratio of LGE to total myocardial mass.

     • Considered subjective.

     • Adjustment for regions with intermediate signal intensities (grey zones) caused by partial volume can improve reproducibility of measurements [54].

   • ii)

     The n-SD technique:

     • Manual outlining of endocardial and epicardial borders for the myocardial ROI.

     • Manual selection of a normal “remote” (dark) region ROI within the myocardium to define the reference SI (mean and standard deviation, SD). This subjective approach can affect measurements.

     • It is susceptible to spatial variations in surface coil sensitivity.

     • Selection of a threshold between normal myocardium and LGE. The relative SNR of scar tissue versus normal myocardium can vary dependent on contrast agent type, dose and time after injection, field strength, type of sequence and other variables including the underlying injury itself. As such, there is no cutoff value which works for all situations and usually manual tracing is performed as the standard of truth. But (semi-) automated thresholding may improve reproducibility after adequate standardization. As a starting point for semiautomatic thresholding we recommend 5-SD for infarction. There is currently not enough evidence to provide a cut-off for non-ischemic LGE.

     • The presence of LGE within the myocardium is then determined automatically.

     • Requires manual corrections to include no-reflow zones and to exclude artifacts and LV blood pool (errors in the endocardial contour).

   • iii)

     FWHM technique:

     • Manual outlining of endocardial and epicardial borders for the myocardial ROI.

     • Uses the full width of the myocardial ROI SI histogram at half the maximal signal within the scar as the threshold between normal myocardium and LGE.

     • Visual determination whether LGE is present or not, and, if LGE is present, manual selection of a ROI that includes the region of “maximum” signal. This subjective selection can affect measurements.

     • Is also susceptible to spatial variations in surface coil sensitivity, albeit perhaps less so than the n-SD technique [51].

     • Considered more reproducible than the n-SD technique [53].

     • Since the technique assumes a bright LGE core, it may be less accurate than the n-SD technique if LGE is patchy or grey [56].

     • Requires manual corrections to include no-reflow zones and to exclude artifacts and LV blood pool (errors in the endocardial contour).

2. Peri-infarct zone:

   • Multiple methods for quantifying the extent of the peri-infarct or grey zones are reported [57, 58].

   • The Task Force does not endorse any specific evaluation technique due to the strong impact of partial volume effects.

3. Dark-blood/grey blood LGE

   • Multiple techniques are described in the literature but one that is “flow-independent”, (i.e., does not rely on blood flow to suppress blood-pool signal) is preferable [59–61].

   • As the research application(s) are evolving and consensus evidence is being accumulated, the writing group chooses to refrain from making a dedicated statement at this time regarding the optimal method for quantitative assessment of dark-blood/grey blood LGE images.

4. LGE in other chambers than LV

There is increasing evidence about LGE imaging of the RV, which is usually captured with standard LGE protocols imaging the LV. Imaging the thin LA wall is difficult and requires specialized sequences. As the applications are evolving and consensus evidence is being accumulated, the writing group chooses to refrain from making a dedicated statement at this time regarding the post-processing assessment of LGE in chambers other than the LV.

Quantitative analysis

1. For global assessment and diffuse disease, a single ROI should be drawn conservatively in the septum on mid-cavity short-axis maps to reduce the impact of susceptibility artifacts from adjacent tissues.

2. In case of artifacts or inconclusive results obtained from mid-cavity ROIs, basal ROIs can be used for validation.

3. For focal disease, additional ROIs might be drawn in areas of abnormal appearance on visual inspection. A very small ROI (<20 pixels) should be avoided.

4. The position and size of automatically generated ROIs should be validated.

5. Drawing ROIs on greyscale images rather than color maps may reduce bias.

6. For assessing diffuse disease, focal fibrosis as assessed by LGE imaging should be excluded from the ROI.

7. There is currently no specific recommended / preferred analysis software package. The image reader should be trained with the local standards and with the analysis software package of choice and be familiar with the appearance of artifacts.

8. The sensitivity of mapping techniques to confounders such as heart rate and magnetic field inhomogeneities should be considered during interpretation.

9. Extracellular volume (ECV) estimation requires T1 mapping acquisitions before contrast agent administration (native T1) and after contrast agent administration (typically >10min post-contrast to approach steady-state conditions). The proposed post-processing steps should be applied equally to both maps.

10. For calculating ECV, a ROI in the center of the blood pool in the native and in the post-contrast T1 map should be drawn excluding papillary muscles and trabeculae.

11. For calculating ECV, hematocrit of the same day should be available. If this is not available, hematocrit may be estimated from native values of blood pool T1 (“synthetic ECV”) [65].

12. ECV is given in %. The formula for calculating ECV:

• m)

  Inline ECV maps can be a useful alternative to manual ECV calculations. The raw images should be checked to verify a diagnostic image quality and processing.

• n)

  For clinical reports, the type of pulse sequence, reference range, and type/dose of gadolinium contrast agent (if applied) should be quoted.

• o)

  Mapping results should include the numerical absolute value, the Z-score (number of standard deviations by which the result differs from the local normal mean; if available), and the normal range of the CMR system.

• p)

  Local results should be benchmarked against published reported ranges, but a local reference range should be primarily used.

• q)

  Reference ranges should be generated from data sets that were acquired, processed, and analyzed in the same way as the intended application, with the upper and lower range of normal defined by the mean±2 SD of the normal data, respectively.

• r)

  Parameter values should only be compared to other parameter values if they are obtained under similar conditions. In other words, the acquisition scheme, field strength, contrast agent and processing approach should be the same, and the results should be reported along with corresponding reference ranges for the given methodology.

Semi-quantitative analysis

1. Because low SI artifacts can lead to SI distribution patterns that may mimic extensive myocardial edema, a mere visual analysis may lead to incorrect results. SI quantification with reference regions is much less sensitive to these errors and therefore is recommended.

2. Requirements:

   • i)

     Tested normal values for SI values or ratios.

3. Workflow

   • i)

     Global SI analysis:

     • Outline LV endocardial and epicardial contours.

     • For the T2 SI ratio, draw the contour for a ROI in a large area of the skeletal muscle closest to the heart and to the center of the reception field of the coil (for short axis views preferably in the M. serratus anterior [66].

   • ii)

     Regional SI analysis:

     • Draw the contour for a ROI in the affected area and divide the SI by that of the skeletal muscle.

   • iii)

     While a cut-off of 1.9 can be used for dark blood triple-inversion recovery spin echo [67], a locally established value is recommended, because SI and ratio values may vary between sequence settings (especially echo time (TE)) and CMR scanner models. For these images, a color-coded map, based on the parametric calculation and display of myocardial pixels with a SI ratio of 2 or higher, can also be used.

Quantitative analysis

1. For global assessment and diffuse disease, a single ROI should be drawn conservatively in the septum on mid-cavity short-axis maps to reduce the impact of susceptibility artifacts from adjacent tissues.

2. In case of artifacts or non-conclusive results on mid-cavity ROIs, basal ROIs can be used for validation.

3. For focal disease, additional ROIs might be drawn in areas of abnormal appearance on visual inspection. Very small ROIs (<20 pixels) should be avoided.

4. ROIs should be checked if generated automatically.

5. Drawing ROIs on greyscale instead of color maps may avoid bias.

6. Depending on the goal of the analysis, focal fibrosis as assessed by LGE imaging may be excluded from the ROI.

7. There is currently no specific preferred analysis software package. The image reader should be trained with the local standards and with the analysis software package of choice and be aware of and familiar with the appearance of artifacts.

8. Sensitivity of mapping techniques to confounders such as heart rate and magnetic field inhomogeneities should be considered during interpretation.

9. Mapping results should include the numerical absolute value, the Z-score (number of standard deviations by which the result differs from the local normal mean), and the normal reference range.

10. Parameter values should only be compared to other parameter values if they are obtained under similar conditions. In other words, the acquisition scheme, field strength and processing approach should be the same, and the results should be reported along with corresponding reference ranges for the given methodology.

Quantitative analysis

1. Evaluation of T2* always requires a quantitative analysis using software with regulatory approval for T2* evaluation in patients.

2. Full thickness ROI located in the ventricular septum

   • i)

     Septal ROI is drawn on mid-LV short-axis image.

   • ii)

     Take care to avoid blood pool and proximal blood vessels.

   • iii)

     A septal ROI avoids susceptibility artifact from tissue interfaces.

3. Mean myocardial SI from the ROI is plotted against TE (Fig. 7)

   • i)

     SI falls with increasing TE.

   • ii)

     Curve fitting should apply a validated algorithm.

   • iii)

     The time for the decay of SI falls (shorter T2*) with increasing iron burden.

   • iv)

     In heavily iron overloaded patients, SI for higher TEs may fall below background noise causing the curve to plateau and underestimating T2*.

   • v)

     This can be compensated for by:

     • Truncating the curve by removing later echo times (Fig. 7e) [68, 69].

     • This issue is not significant when using the double inversion recovery (black blood) sequence [70].

   

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   Fig. 7

   T2* imaging to assess myocardial iron overload. a T2* scan of a normal heart showing slow signal loss with increasing TE. b Decay curve for normal heart. T2*=33.3ms. c Heavily iron overloaded heart. Note there is substantial signal loss at TE=9.09. d Decay curve for heavily iron overloaded heart showing rapid signal loss with increasing TE. The curve plateaus as myocardial SI falls below background noise. e Values for higher TEs are removed (truncation method) resulting in a better curve fit and a lower T2* value

4. Cut-off values at 1.5 Tesla:

   • i)

     Normal cardiac T2* is 40ms [71]

   • ii)

     T2* <20ms indicates cardiac iron overload [72]

   • iii)

     T2* <10ms indicates increased risk of development of heart failure [73]

5. CMR assessment of T2* at 3T for assessment of iron overload cardiomyopathy cannot be recommended at this time. T2* shortens with increasing field strength making assessment of severe iron overload more problematic, and there is a lack of clinical verification.

Research tools

1. Real time velocity mapping: The utility and post-processing algorithm best applied to this approach is the subject of ongoing research.

Quantitative analysis

1. Aorta:

   • i)

     Diameters of the aorta are measured on double oblique MPR of source images perpendicular to the vessel centerline at standardized levels (Fig. 10) [87]. In oval shaped vessels the longest diameter and its perpendicular diameter shall be reported. Both, inner (lumen) or outer (external vessel wall) diameter may be measured. This should be included in the report, as well as the type of angiography (with or without contrast-enhancement). Measurement of outer contour is recommended in dilation such as in aneurysms, while the inner contour is recommended in the setting of stenosis, such as in coarctation.

     

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     Fig. 10

     Anatomic landmarks for standardized reporting of diameters of the aorta at the level of sinuses of Valsalva (1), sinotubular junction (2), mid-ascending aorta (3), proximal to brachiocephalic trunk (4), between left common carotid and left subclavian arteries (5), distal to left subclavian artery (6), mid-descending aorta (7), diaphragm (8), abdominal aorta above celiac trunk (9). (Adapted from [87])

   • ii)

     In the presence of wall thickening (e.g. thrombus or intramural hematoma) inner and outer diameter including vessel wall thickness should be reported.

   • iii)

     Aortic root measurements require ECG-gated images. Diameter of the sinus portion should be recorded as the maximum sinus to sinus measurement perpendicular to the vessel centerline. For more details and normal values refer to [82].

   • iv)

     Standardized structured reports with tables of diameters are helpful for reporting follow-up examinations.

2. Pulmonary artery:

   • i)

     Diameters are measured on double oblique images perpendicular to the centerlines of the pulmonary trunk as well as right and left pulmonary arteries. It should be reported whether the inner or outer contour was measured. In oval shaped vessels the longest diameter and its perpendicular diameter shall be reported, with measurement during systole recommended. Alternatively, cross-sectional area may be measured. For normal values refer to [84].

3. Pulmonary veins:

   • i)

     Double oblique MPR of pulmonary veins perpendicular to centerline for diameter measurements. For a more comprehensive assessment including flow measurements refer to [85].