Estimation of perfusion and arterial transit time in myocardium using free‐breathing myocardial arterial spin labeling with navigator‐echo

Arterial spin labeling (ASL) provides noninvasive measurement of tissue blood flow, but sensitivity to motion has limited its application to imaging of myocardial blood flow. Although different cardiac phases can be synchronized using electrocardiography triggering, breath holding is generally required to minimize effects of respiratory motion during ASL scanning, which may be challenging in clinical populations. Here a free‐breathing myocardial ASL technique with the potential for reliable clinical application is presented, by combining ASL with a navigator‐gated, electrocardiography‐triggered TrueFISP readout sequence. Dynamic myocardial perfusion signals were measured at multiple delay times that allowed simultaneous fitting of myocardial blood flow and arterial transit time. With the assist of a nonrigid motion correction program, the estimated mean myocardial blood flow was 1.00 ± 0.55 mL/g/min with a mean transit time of ∼400 msec. The intraclass correlation coefficient of repeated scans was 0.89 with a mean within subject coefficient of variation of 22%. Perfusion response during mild to moderate stress was further measured. The capability for noninvasive, free‐breathing assessment of myocardial blood flow using ASL may offer an alternative approach to first‐pass perfusion MRI for clinical evaluation of patients with coronary artery disease. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Quantification of myocardial perfusion using free‐breathing MRI and prospective slice tracking

Quantification of myocardial perfusion using first‐pass magnetic resonance imaging (MRI) is hampered by respiratory motion of the heart. Prospective slice tracking (PST) potentially overcomes this problem, and may provide an attractive alternative or supplement to current breath‐hold techniques. This study demonstrates the feasibility of patient‐adapted 3D PST on a 3.0 Tesla MR system. Eight patients underwent free‐breathing studies of myocardial perfusion, simultaneously collecting data with and without PST. On average, PST reduced residual in‐plane motion by a factor of 2, compared to the noncorrected images, resulting in a fourfold improvement of perfusion measurements. In addition, a comparison of perfusion measurements performed with and without PST showed that through‐plane motion can contaminate measurements of myocardial perfusion. However, the quality of the navigator echoes on this field strength constituted a major source of error and needs further improvement to increase the accuracy and robustness of the method. Magn Reson Med, 2009. © 2008 Wiley‐Liss, Inc.     

Free‐breathing myocardial perfusion MRI using SW‐CG‐HYPR and motion correction

First‐pass perfusion MRI is a promising technique to detect ischemic heart disease. Sliding window (SW) conjugate‐gradient (CG) highly constrained back‐projection reconstruction (HYPR) (SW‐CG‐HYPR) has been proposed to increase spatial coverage, spatial resolution, and SNR. However, this method is sensitive to respiratory motion and thus requires breath‐hold. This work presents a non‐model‐based motion correction method combined with SW‐CG‐HYPR to perform free‐breathing myocardial MR imaging. Simulation studies were first performed to show the effectiveness of the proposed motion correction method and its independence from the pattern of the respiratory motion. After that, in vivo studies were performed in six healthy volunteers. From all of the volunteer studies, the image quality score of free breathing perfusion images with motion correction (3.11 ± 0.34) is improved compared with that of images without motion correction (2.27 ± 0.32), and is comparable with that of successful breath‐hold images (3.12 ± 0.38). This result was further validated by a quantitative sharpness analysis. The left ventricle and myocardium signal changes in motion corrected free‐breathing perfusion images were closely correlated to those observed in breath‐hold images. The correlation coefficient is 0.9764 for myocardial signals. Bland–Altman analysis confirmed the agreement between the free‐breathing SW‐CG‐HYPR method with motion correction and the breath‐hold SW‐CG‐HYPR. This technique may allow myocardial perfusion MRI during free breathing. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Improved renal perfusion measurement with a dual navigator‐gated Q2TIPS fair technique

A dual navigator‐gated, flow‐sensitive alternating inversion recovery (FAIR) true fast imaging with steady precession (True‐FISP) sequence has been developed for accurate quantification of renal perfusion. FAIR methods typically overestimate renal perfusion when respiratory motion causes the inversion slice to move away from the imaging slice, which then incorporates unlabeled spins from static tissue. To overcome this issue, the dual navigator scheme was introduced to track inversion and imaging slices, and thus to ensure the same position for both slices. Accuracy was further improved by a well‐defined bolus length, which was achieved by a modification version of Q2TIPS (quantitative imaging of perfusion using a single subtraction, second version with interleaved thin‐slice TI₁ periodic saturation): a series of saturation pulses was applied to both sides of the imaging slice at a certain time after the inversion. The dual navigator‐gated technique was tested in eight volunteers. The measured renal cortex perfusion rates were between 191 and 378 mL/100 g/min in the renal cortex with a mean of 376 mL/100 g/min. The proposed technique may prove most beneficial for noncontrast‐based renal perfusion quantification in young children and patients who may have difficulty holding their breath for prolonged periods or are sedated/anesthetized. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Myocardial T2 mapping with respiratory navigator and automatic nonrigid motion correction

Quantitative T₂ mapping was recently shown to be superior to T₂‐weighted imaging in detecting T₂ changes across myocardium. Pixel‐wise T₂ mapping is sensitive to misregistration between the images used to generate the parameter map. In this study, utility of two motion‐compensation strategies—(i) navigator gating with prospective slice correction and (ii) nonrigid registration—was investigated for myocardial T₂ mapping in short axis and horizontal long axis views. Navigator gating provides respiratory motion compensation, whereas registration corrects for residual cardiac and respiratory motion between images; thus, the two strategies provided complementary functions. When these were combined, respiratory‐motion‐induced T₂ variability, as measured by both standard deviation and interquartile range, was comparable to that in breath‐hold T₂ maps. In normal subjects, this combined motion‐compensation strategy increased the percentage of myocardium with T₂ measured to be within normal range from 60.1% to 92.2% in short axis and 62.3% to 92.7% in horizontal long axis. The new motion‐compensated T₂ mapping technique, which combines navigator gating, prospective slice correction, and nonrigid registration to provide through‐plane and in‐plane motion correction, enables a method for fully automatic and robust free‐breathing T₂ mapping. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.     

Analysis of residual coronary artery motion for breath hold and navigator approaches using real-time coronary MRI.

Coronary artery MRI methods utilize breath holds, or diaphragmatic navigators, to compensate for respiratory motion. To increase image quality and navigator (NAV) gating efficiency, slice tracking is used, with more sophisticated affine motion models recently introduced. This study assesses the extent of remaining coronary artery motion in free breathing NAV and single and multi breath hold coronary artery MRI. Additionally, the effect of the NAV gating window size was examined. To visualize and measure the respiratory induced motion, an image containing a coronary artery cross section was acquired at each heartbeat. The amount of residual coronary artery displacement was used as a direct measure for the performance of the respiratory motion correction method. Free breathing studies with motion compensation (slice tracking with 5 mm gating window) had a similar amount of residual motion (0.76+/-0.17 mm) as a single breath hold (0.52+/-0.20 mm) and were superior to multiple breath holds (1.22+/-0.60 mm). Affine NAV methods allowed for larger gating windows ( approximately 10 mm windows) with similar residual motion (0.74+/-0.17 mm). In this healthy adult cohort (N=10), free-breathing NAV methods offered respiratory motion suppression similar to a single breath hold.     

3D radial sampling and 3D affine transform‐based respiratory motion correction technique for free‐breathing whole‐heart coronary MRA with 100% imaging efficiency

The navigator gating and slice tracking approach currently used for respiratory motion compensation during free‐breathing coronary magnetic resonance angiography (MRA) has low imaging efficiency (typically 30–50%), resulting in long imaging times. In this work, a novel respiratory motion correction technique with 100% scan efficiency was developed for free‐breathing whole‐heart coronary MRA. The navigator signal was used as a reference respiratory signal to segment the data into six bins. 3D projection reconstruction k‐space sampling was used for data acquisition and enabled reconstruction of low resolution images within each respiratory bin. The motion between bins was estimated by image registration with a 3D affine transform. The data from the different respiratory bins was retrospectively combined after motion correction to produce the final image. The proposed method was compared with a traditional navigator gating approach in nine healthy subjects. The proposed technique acquired whole‐heart coronary MRA with 1.0 mm³ isotropic spatial resolution in a scan time of 6.8 ± 0.9 min, compared with 16.2 ± 2.8 min for the navigator gating approach. The image quality scores, and length, diameter and sharpness of the right coronary artery (RCA), left anterior descending coronary artery (LAD), and left circumflex coronary artery (LCX) were similar for both approaches (P > 0.05 for all), but the proposed technique reduced scan time by a factor of 2.5. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Perfusion phantom: An efficient and reproducible method to simulate myocardial first‐pass perfusion measurements with cardiovascular magnetic resonance

The aim of this article is to describe a novel hardware perfusion phantom that simulates myocardial first‐pass perfusion allowing comparisons between different MR techniques and validation of the results against a true gold standard. MR perfusion images were acquired at different myocardial perfusion rates and variable doses of gadolinium and cardiac output. The system proved to be sensitive to controlled variations of myocardial perfusion rate, contrast agent dose, and cardiac output. It produced distinct signal intensity curves for perfusion rates ranging from 1 to 10 mL/mL/min. Quantification of myocardial blood flow by signal deconvolution techniques provided accurate measurements of perfusion. The phantom also proved to be very reproducible between different sessions and different operators. This novel hardware perfusion phantom system allows reliable, reproducible, and efficient simulation of myocardial first‐pass MR perfusion. Direct comparison between the results of image‐based quantification and reference values of flow and myocardial perfusion will allow development and validation of accurate quantification methods. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Lung imaging under free‐breathing conditions

Respiratory motion and pulsatile blood flow can generate artifacts in morphological and functional lung imaging. Total acquisition time, and thus the achievable signal to noise ratio, is limited when performing breath‐hold and/or electrocardiogram‐triggered imaging. To overcome these limitations, imaging during free respiration can be performed using respiratory gating/triggering devices or navigator echoes. However, these techniques provide only poor gating resolution and can induce saturation bands and signal fluctuations into the lung volume. In this work, acquisition schemes for nonphase encoded navigator echoes were implemented into different sequences for morphological and functional lung imaging at 1.5 Tesla (T) and 0.2T. The navigator echoes allow monitoring of respiratory motion and provide an ECG‐trigger signal for correction of the heart cycle without influencing the imaged slices. Artifact free images acquired during free respiration using a 3D GE, 2D multislice TSE or multi‐Gradient Echo sequence for oxygen‐enhanced T quantification are presented. Magn Reson Med, 2009. © 2008 Wiley‐Liss, Inc.     

Free‐breathing high‐spatial‐resolution delayed contrast‐enhanced three‐dimensional viability MR imaging of the myocardium at 3.0T: A feasibility study

Purpose

To assess the feasibility of free‐breathing high‐spatial‐resolution delayed contrast‐enhanced three‐dimensional (3D) viability magnetic resonance imaging (MRI) at 3.0T for the detection of myocardial damages.

Materials and Methods

Twenty‐five patients with myocardial diseases, including myocardial infarction and cardiomyopathies, were enrolled after informed consent was given. Free‐breathing 3D viability MRI with high spatial resolution (1.5 × 1.25 × 2.5 mm) at 3.0T, for which cardiac and navigator gating techniques were employed, was compared with breath‐hold two‐dimensional (2D) viability imaging (1.77 × 1.18 × 10 mm) for assessment of contrast‐to‐noise ratio (CNR) and myocardial damage.

Results

Free‐breathing 3D viability imaging was achieved successfully in 21 of the 25 patients. This imaging technique depicted 84.6% of hyperenhancing myocardium with a higher CNR between hyperenhancing myocardium and blood and with excellent agreement for the transmural extension of myocardial damage (k = 0.91). In particular, the 3D viability images delineated the myocardial infarction and linear hyperenhancing myocardium, comparable to the 2D viability images.

Conclusion

Free‐breathing high‐spatial‐resolution delayed contrast‐enhanced 3D viability MRI using 3.0T was feasible for the evaluation of hyperenhancing myocardium, as seen with myocardial infarction and cardiomyopathies. J. Magn. Reson. Imaging 2008;28:1361–1367. © 2008 Wiley‐Liss, Inc.     

Improved arterial spin labeling after myocardial infarction in mice using cardiac and respiratory gated look‐locker imaging with fuzzy C‐means clustering

Experimental myocardial infarction (MI) in mice is an important disease model, in part due to the ability to study genetic manipulations. MRI has been used to assess cardiac structural and functional changes after MI in mice, but changes in myocardial perfusion after acute MI have not previously been examined. Arterial spin labeling noninvasively measures perfusion but is sensitive to respiratory motion and heart rate variability and is difficult to apply after acute MI in mice. To account for these factors, a cardiorespiratory‐gated arterial spin labeling sequence using a fuzzy C‐means algorithm to retrospectively reconstruct images was developed. Using this method, myocardial perfusion was measured in remote and infarcted regions at 1, 7, 14, and 28 days post‐MI. Baseline perfusion was 4.9 ± 0.5 mL/g·min and 1 day post‐MI decreased to 0.9 ± 0.8 mL/g·min in infarcted myocardium (P < 0.05 versus baseline) while remaining at 5.2 ± 0.8 mL/g·min in remote myocardium. During the subsequent 28 days, perfusion in the remote zone remained unchanged, while a partial recovery of perfusion in the infarct zone was seen. This technique, when applied to genetically engineered mice, will allow for the investigation of the roles of specific genes in myocardial perfusion during infarct healing. Magn Reson Med 63:648–657, 2010. © 2010 Wiley‐Liss, Inc.     

Quantitative analysis of first‐pass contrast‐enhanced myocardial perfusion MRI using a patlak plot method and blood saturation correction

The objectives of this study were to develop a method for quantifying myocardial K₁ and blood flow (MBF) with minimal operator interaction by using a Patlak plot method and to compare the MBF obtained by perfusion MRI with that from coronary sinus blood flow in the resting state. A method that can correct for the nonlinearity of the blood time–signal intensity curve on perfusion MR images was developed. Myocardial perfusion MR images were acquired with a saturation‐recovery balanced turbo field‐echo sequence in 10 patients. Coronary sinus blood flow was determined by phase‐contrast cine MRI, and the average MBF was calculated as coronary sinus blood flow divided by left ventricular (LV) mass obtained by cine MRI. Patlak plot analysis was performed using the saturation‐corrected blood time–signal intensity curve as an input function and the regional myocardial time–signal intensity curve as an output function. The mean MBF obtained by perfusion MRI was 86 ± 25 ml/min/100 g, showing good agreement with MBF calculated from coronary sinus blood flow (89 ± 30 ml/min/100 g, r = 0.74). The mean coefficient of variation for measuring regional MBF in 16 LV myocardial segments was 0.11. The current method using Patlak plot permits quantification of MBF with operator interaction limited to tracing the LV wall contours, registration, and time delays. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Estimates of systolic and diastolic myocardial blood flow by dynamic contrast‐enhanced MRI

Myocardial blood flow varies during the cardiac cycle in response to pulsatile changes in epicardial circulation and cyclical variation in myocardial tension. First‐pass assessment of myocardial perfusion by dynamic contrast‐enhanced MRI is one of the most challenging applications of MRI because of the spatial and temporal constraints imposed by the cardiac physiology and the nature of dynamic contrast‐enhanced MRI signal collection. Here, we describe a dynamic contrast‐enhanced MRI method for simultaneous assessment of systolic and diastolic myocardial blood flow. The feasibility of this method was demonstrated in a study of 17 healthy volunteers at rest and under adenosine‐induced vasodilatory stress. We found that myocardial blood flow was independent of the cardiac phase at rest. However, under adenosine‐induced hyperemia, myocardial blood flow and myocardial perfusion reserve were significantly higher in diastole than in systole. Furthermore, the transmural distribution of myocardial blood flow and myocardial perfusion reserve was cardiac phase dependent, with a reversal of the typical subendocardial to subepicardial myocardial blood flow gradient in systole, but not diastole, under stress. The observed difference between systolic and diastolic myocardial blood flow must be taken into account when assessing myocardial blood flow using dynamic contrast‐enhanced MRI. Furthermore, targeted assessment of systolic or diastolic perfusion using dynamic contrast‐enhanced MRI may provide novel insights into the pathophysiology of ischemic and microvascular heart disease. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Free‐breathing cine MRI

Standard MRI cine exams for the study of cardiac function are segmented over several heartbeats and thus require a breath‐hold to minimize breathing motion artifacts, which is a current limitation of this approach. The purpose of this study was to develop a method for the measurement and correction of respiratory motion that is compatible with cine imaging. Real‐time images were used to measure the respiratory motion of heart, to allow translations, rotations, and shears to be measured and corrected in the k‐space domain prior to a final gated‐segmented reconstruction, using the same data for both purposes. A method for data rejection to address the effects of through‐plane motion and complex deformations is described (respiratory gating). A radial k‐space trajectory was used in this study to allow direct reconstruction of undersampled real‐time images, although the techniques presented are applicable with Cartesian k‐space trajectories. Corrected and uncorrected free‐breathing gated‐segmented images acquired over 18 sec were compared to the current standard breath‐hold Cartesian images using both quantitative sharpness profiles (mm^?1) and clinical scoring (1 to 5 scale, 3: clinically acceptable). Free‐breathing, free‐breathing corrected, and breath‐hold images had average sharpness values of 0.23 ± 0.04, 0.38 ± 0.04, and 0.44 ± 0.04 mm^?1 measured at the blood–endocardium interface, and clinical scores of 2.2 ± 0.5, 4.2 ± 0.4, and 4.7 ± 0.5, respectively. Magn Reson Med 60:709–717, 2008. © 2008 Wiley‐Liss, Inc.     

Myocardial perfusion MRI with sliding‐window conjugate‐gradient HYPR

First‐pass perfusion MRI is a promising technique for detecting ischemic heart disease. However, the diagnostic value of the method is limited by the low spatial coverage, resolution, signal‐to‐noise ratio (SNR), and cardiac motion‐related image artifacts. In this study we investigated the feasibility of using a method that combines sliding window and CG‐HYPR methods (SW‐CG‐HYPR) to reduce the acquisition window for each slice while maintaining the temporal resolution of one frame per heartbeat in myocardial perfusion MRI. This method allows an increased number of slices, reduced motion artifacts, and preserves the relatively high SNR and spatial resolution of the “composite images.” Results from eight volunteers demonstrate the feasibility of SW‐CG‐HYPR for accelerated myocardial perfusion imaging with accurate signal intensity changes of left ventricle blood pool and myocardium. Using this method the acquisition time per cardiac cycle was reduced by a factor of 4 and the number of slices was increased from 3 to 8 as compared to the conventional technique. The SNR of the myocardium at peak enhancement with SW‐CG‐HYPR (13.83 ± 2.60) was significantly higher (P < 0.05) than the conventional turbo‐FLASH protocol (8.40 ± 1.62). Also, the spatial resolution of the myocardial perfection images was significantly improved. SW‐CG‐HYPR is a promising technique for myocardial perfusion MRI. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Myocardial blood flow mapping in mice using high-resolution spin labeling magnetic resonance imaging: influence of ketamine/xylazine and isoflurane anesthesia.

Genetically modified mouse models of many human diseases reflecting cardiovascular alterations are currently available. To date, little information on absolute myocardial perfusion in mice is found in the literature. High-resolution quantitative myocardial blood flow maps (in-plane resolution 156 x 312 mum(2), slice thickness 1.5 mm) have been obtained noninvasively within 25 min at 4.7 T in 30 freely breathing C57/Bl6J mice using electrocardiogram- and respiration-gated spin labeling magnetic resonance imaging (MRI). Regional myocardial blood flow measurements were carried out, and the effects of isoflurane at two different concentrations and ketamine/xylazine anesthesia were assessed. The mean blood flow value in the left ventricular myocardium was 6.0 +/- 1.9 mL g(-1) min(-1) under ketamine/xylazine and 6.9 +/- 1.7 mL g(-1) min(-1) (group average +/- SD) under isoflurane (1.25%). Under the influence of higher isoflurane concentration (2.00%), myocardial blood flow increased dramatically to 16.9 +/- 1.8 mL g(-1)min(-1) with no significant change in heart rate. This work illustrates the feasibility of noninvasive quantitative myocardial perfusion mapping in mice using MRI. The study of the influence of anesthesia shows that myocardial blood flow is highly sensitive to isoflurane concentration. The method employed offers a noninvasive approach to longitudinal studies of murine models of cardiac disease.     

Free‐Breathing 3D Cardiac MRI Using Iterative Image‐Based Respiratory Motion Correction

Respiratory motion compensation using diaphragmatic navigator gating with a 5 mm gating window is conventionally used for free‐breathing cardiac MRI. Because of the narrow gating window, scan efficiency is low resulting in long scan times, especially for patients with irregular breathing patterns. In this work, a new retrospective motion compensation algorithm is presented to reduce the scan time for free‐breathing cardiac MRI that increasing the gating window to 15 mm without compromising image quality. The proposed algorithm iteratively corrects for respiratory‐induced cardiac motion by optimizing the sharpness of the heart. To evaluate this technique, two coronary MRI datasets with 1.3 mm³ resolution were acquired from 11 healthy subjects (seven females, 25 ± 9 years); one using a navigator with a 5 mm gating window acquired in 12.0 ± 2.0 min and one with a 15 mm gating window acquired in 7.1 ± 1.0 min. The images acquired with a 15 mm gating window were corrected using the proposed algorithm and compared to the uncorrected images acquired with the 5 and 15 mm gating windows. The image quality score, sharpness, and length of the three major coronary arteries were equivalent between the corrected images and the images acquired with a 5 mm gating window (P‐value > 0.05), while the scan time was reduced by a factor of 1.7. Magn Reson Med, 70:1005–1015, 2013. © 2012 Wiley Periodicals, Inc.     

Respiratory and cardiac self‐gated free‐breathing cardiac CINE imaging with multiecho 3D hybrid radial SSFP acquisition

A respiratory and cardiac self‐gated free‐breathing three‐dimensional cine steady‐state free precession imaging method using multiecho hybrid radial sampling is presented. Cartesian mapping of the k‐space center along the slice encoding direction provides intensity‐weighted position information, from which both respiratory and cardiac motions are derived. With in plan radial sampling acquired at every pulse repetition time, no extra scan time is required for sampling the k‐space center. Temporal filtering based on density compensation is used for radial reconstruction to achieve high signal‐to‐noise ratio and contrast‐to‐noise ratio. High correlation between the self‐gating signals and external gating signals is demonstrated. This respiratory and cardiac self‐gated, free‐breathing, three‐dimensional, radial cardiac cine imaging technique provides image quality comparable to that acquired with the multiple breath‐hold two‐dimensional Cartesian steady‐state free precession technique in short‐axis, four‐chamber, and two‐chamber orientations. Functional measurements from the three‐dimensional cardiac short axis cine images are found to be comparable to those obtained using the standard two‐dimensional technique. Magn Reson Med 63:1230–1237, 2010. © 2010 Wiley‐Liss, Inc.     

Motion correction using coil arrays (MOCCA) for free‐breathing cardiac cine MRI

In this study, we present a motion correction technique using coil arrays (MOCCA) and evaluate its application in free‐breathing respiratory self‐gated cine MRI. Motion correction technique using coil arrays takes advantages of the fact that motion‐induced changes in k‐space signal are modulated by individual coil sensitivity profiles. In the proposed implementation of motion correction technique using coil arrays self‐gating for free‐breathing cine MRI, the k‐space center line is acquired at the beginning of each k‐space segment for each cardiac cycle with 4 repetitions. For each k‐space segment, the k‐space center line acquired immediately before was used to select one of the 4 acquired repetitions to be included in the final self‐gated cine image by calculating the cross correlation between the k‐space center line with a reference line. The proposed method was tested on a cohort of healthy adult subjects for subjective image quality and objective blood‐myocardium border sharpness. The method was also tested on a cohort of patients to compare the left and right ventricular volumes and ejection fraction measurements with that of standard breath‐hold cine MRI. Our data indicate that the proposed motion correction technique using coil arrays method provides significantly improved image quality and sharpness compared with free‐breathing cine without respiratory self‐gating and provides similar volume measurements compared with breath‐hold cine MRI. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.