This article details how to perform in vivo (using surface and needle electrode arrays) and ex vivo (using a dielectric cell) electrical impedance myography on the rodent gastrocnemius muscle. It will demonstrate the technique in both mice and rats and detail the modifications available, (i.e., obese animals, pups).
Electrical impedance myography (EIM) is a convenient technique that can be used in preclinical and clinical studies to assess muscle tissue health and disease. EIM is obtained by applying a low-intensity, directionally focused, electrical current to a muscle of interest across a range of frequencies (i.e., from 1 kHz to 10 MHz) and recording the resulting voltages. From these, several standard impedance components, including the reactance, resistance, and phase, are obtained. When performing ex vivo measurements on excised muscle, the inherent passive electrical properties of the tissue, namely the conductivity and relative permittivity, can also be calculated. EIM has been used extensively in animals and humans to diagnose and track muscle alterations in a variety of diseases, in relation to simple disuse atrophy, or as a measure of therapeutic intervention. Clinically, EIM offers the potential to track disease progression over time and to assess the impact of therapeutic interventions, thus offering the opportunity to shorten the clinical trial duration and reduce sample size requirements. Because it can be performed noninvasively or minimally invasively in living animal models as well as humans, EIM offers the potential to serve as a novel translational tool enabling both preclinical and clinical development. This article provides step-by-step instructions on how to perform in vivo and ex vivo EIM measurements in mice and rats, including approaches to adapt the techniques to specific conditions, such as for use in pups or obese animals.
Electrical impedance myography (EIM) provides a powerful method to assess muscle condition, potentially enabling the diagnosis of neuromuscular disorders, tracking of disease progression, and assessment of response to therapy1,2,3. It can be applied analogously to animal disease models and humans, allowing for relatively seamless translation from preclinical to clinical studies. EIM measurements are easily obtained using four linearly-placed electrodes, with the two outer ones applying a painless, weak electrical current across a range of frequencies (generally between 1 kHz and approximately 2 MHz), and the two inner ones recording the resulting voltages1. From these voltages, the impedance characteristics of the tissue can be obtained, including the resistance (R), a measure of how difficult it is for current to pass through the tissue, and the reactance (X) or "chargeability" of the tissue, a measure related to the tissue's ability to store charge (capacitance). From the reactance and resistance, the phase angle (θ) is calculated via the following equation: , providing a single summative impedance measure. Such measurements can be obtained using any multifrequency bioimpedance device. As myofibers are essentially long cylinders, muscle tissue is also highly anisotropic, with current flowing more easily along fibers than across them4,5. Thus, EIM is often performed in two directions: with the array placed along the fibers such that current runs parallel to them, and across the muscle such that the current flows perpendicular to them. Additionally, in ex vivo measurements, where a known volume of tissue is measured in an impedance measuring cell, the inherent electrical properties of the muscle (i.e. the conductivity and relative permittivity), can be derived6.
The term "neuromuscular disorders" defines a wide range of primary and secondary diseases that lead to structural muscle alteration and dysfunction. This includes amyotrophic lateral sclerosis and various forms of muscular dystrophy, as well as simpler changes related to aging (e.g., sarcopenia), disuse atrophy (e.g., due to prolonged bedrest or microgravity) or even injury7. While the causes are plentiful and can originate from the motor neuron, nerves, neuromuscular junctions, or the muscle itself, EIM can be used to detect early alterations in muscle due to many of these processes and to track progression or response to therapy. For example, in patients with Duchenne muscular dystrophy (DMD), EIM has been shown to detect disease progression and response to corticosteroids8. Recent work has also shown EIM to be sensitive to varying disuse states, including fractional gravity9, as would be experienced on the Moon or Mars, and the effects of aging10,11. Finally, by applying predictive and machine learning algorithms to the data set obtained with each measurement (multifrequency and directionally dependent data), it becomes possible to infer histological aspects of the tissue, including myofiber size12,13, inflammatory changes and edema14, and connective tissue and fat content15,16.
Several other noninvasive or minimally invasive methods are also used to evaluate muscle health in humans and animals, including needle electromyography17 and imaging technologies such as magnetic resonance imaging, computerized tomography, and ultrasound18,19. However, EIM demonstrates distinct benefits compared with these technologies. For example, electromyography records only the active electrical properties of the myofiber membranes and not the passive properties, and thus cannot provide a true assessment of muscle composition or structure. In a certain respect, imaging methods are more closely related to EIM, as they too provide information about the structure and composition of tissue. But in some sense, they provide too much data, requiring detailed image segmentation and expert analysis rather than just providing a quantitative output. Moreover, given their complexities, imaging techniques are also greatly impacted by the specifics of both the hardware and software being used, ideally requiring the use of identical systems so that data sets can be compared. In contrast, the fact that EIM is much simpler means that it is less impacted by these technical issues and does not require any form of image processing or expert analysis.
The following protocol demonstrates how to perform in vivo EIM in rats and mice, using both noninvasive (surface array) and minimally invasive (subdermal needle array) techniques, as well as ex vivo EIM on freshly excised muscle.
All methods described here have been approved by the Institutional Animal Care and Use Committee of Beth Israel Deaconess Medical Center under protocol numbers (031-2019; 025-2019). Wear proper PPE equipment to handle animals and adhere to IACUC guidelines for all animal work.
1. In vivo surface EIM
- Place the animal in an anesthesia box to induce anesthesia.
NOTE: For rats, 1.5%-3.5% isoflurane and 2 O2 L·min-1 were used, and for mice, 2% isoflurane and 1 O2 L·min-1 were used.
- Once fully anesthetized, as indicated by the absence of response after pinching the foot of the animal, place the mouse on the bench in a prone position and use the nose cone to maintain anesthesia using 1.5% isoflurane and an oxygen flow of 1 L·min-1.
- Place the animal's leg to be analyzed at a 45° angle with the hip joint (knee extended) and secure the foot with medical tape.
- Use a hair clipper to trim the fur overlaying the gastrocnemius muscle.
- Apply a thick layer of depilatory cream over the animal's skin and let it sit for 1 min. Then, use saline-saturated gauze to remove the depilatory agent. Repeat this process up to three times until all the fur overlaying the gastrocnemius muscle is removed.
NOTE: Place a gauze pad soaked in saline over the skin when measurements are not being acquired to prevent skin dehydration.
- Connect the surface array (Figure 1) to the EIM device and let the electrodes rest on a piece of gauze soaked in saline solution.
- Place the surface array directly on the skin over the gastrocnemius muscle, oriented longitudinally to the muscle fibers.
- After checking for appropriate contact, which is indicated by all bars appearing green on the software showing the stability of the 50 kHz resistance, reactance, and phase values, acquire the EIM measurements.
NOTE: Curves should be checked in real time to ensure proper data acquisition.
- Rotate the surface array by 90° and reposition it on the skin over the gastrocnemius to obtain the transverse measurements (check for green bars indicating the stability).
- Repeat steps 1.7, 1.8, and 1.9 to get a total of four measurements per muscle: two longitudinal and two transverse.
NOTE: Do not use a depilatory agent more than once (i.e., up to three applications in the same instance) every two weeks to prevent excessive skin irritation and injury. It is important to perform the measurements within about 5-10 min of removing the depilatory cream since the development of localized skin edema induced by the depilatory agent may impact the collected impedance data. Animal recovery is immediate after stopping isoflurane anesthesia and the procedure does not require analgesic treatment.
2. In vivo needle array EIM
- Anesthetize the animal and prepare the leg using the same procedure as described in steps 1.1-1.4. However, it is not necessary to use a depilatory agent when performing in vivo EIM using a needle array.
- Connect the needle array (Figure 2A-F) to the EIM device and let it rest in a weighing boat containing saline solution. Check for connectivity and signal stability (indicated by green bars).
- Place the needle array in a longitudinal position compared to the myofibers and press it firmly into the skin until all the needles penetrate the skin and the underlying muscle up to the plastic guard on the array. Acquire data.
- Gently remove the array and reinsert it through the skin and into the muscle at a 90° angle relative to the first measurement, in the transverse direction. Acquire data.
NOTE: When using needle arrays, measurements should only be acquired once in each direction to reduce the impact of the needle electrodes on the skin and muscle tissue. If bleeding occurs, gently wipe the blood away before performing the second measurement. Animal recovery is immediate after stopping isoflurane anesthesia and the procedure does not require analgesic treatment.
3. Ex vivo EIM
- Prepare the ex vivo dielectric cell (Figure 2G,H), add saline solution to the chamber, and connect the cell to the EIM device to obtain the reference values.
NOTE: The phase and reactance values of saline should remain constant at or near zero and the resistance values of saline should remain constant at approximately 100 ± 25 Ω over the frequency range from 1 kHz to 1 MHz.
- Euthanize the animal according to respective IACUC guidelines.
- Using a pair of scissors, cut the skin near the Achilles tendon. Using tweezers, pull the skin in an upward motion to reveal the underlying muscles and fascia. Gently dissect out the biceps femoris overlaying the gastrocnemius muscle and section the sciatic nerve.
- Cut the Achilles tendon to free the distal end of the gastrocnemius and soleus muscles and gently pull the tendon upwards while using scissors to remove any attachments. Once all attachments are removed, use scissors to cut the rostral end of the soleus muscle and remove it.
- Use scissors to dissect the heads of the gastrocnemius muscle around the patella.
NOTE: After removal of the gastrocnemius muscle, it is important to remember the original orientation of the myofibers.
- Place the gastrocnemius muscle on a sheet of dental wax and section it using a razor blade and a ruler to obtain a 10 mm x 10 mm section from the center of the gastrocnemius muscle.
NOTE: The dielectric cell size can be customized. For rats, a 10 mm x 10 mm cell was used and for mice, a 5 mm x 5 mm cell was used.
- Using tweezers, gently place the gastrocnemius in the dielectric cells, making sure the fibers are oriented longitudinally (i.e., caudal, and rostral extremities should be touching the electrodes). Make sure that the muscle is fully in contact with the metal electrodes.
- Attach the top part of the dielectric cell and insert two monopolar needles (26 G) into the two holes. Connect the wires from the EIM device to the ex vivo cell in the following order: (1: I+, 2: V+, 3: V-, 4: I-, where I represents the current electrodes and V represents the voltage electrodes). Acquire the longitudinal measurement.
- Open the dielectric cell and reorient the muscle in the transverse direction by rotating it 90°. Reattach the top of the dielectric cell. Acquire the transverse measurement.
EIM can be obtained in many conditions, including surface in vivo arrays (Figure 1), needle in vivo arrays (Figure 2A-F), and ex vivo dielectric cells (Figure 2G,H).
EIM provides a near-instantaneous snapshot of the muscle condition based on the measured impedance values. Measurements are acquired swiftly and result in a simple output data file that does not require any special software (Figure 3A). Indeed, any multifrequency impedance device providing data for individual frequencies will be able to produce a standard .csv output that can be opened independently. The system described in this protocol also provides the name and conditions of the experiment, with values of phase, reactance, and resistance for each trial at each frequency measured, within the output file. To ensure reproducibility, two trials of longitudinal (trials 1 and 3) and transverse (trials 2 and 4) values are generally obtained and averaged, and used for all subsequent analyses.
When displayed as a function of frequency, EIM values result in standard curves that can be analyzed to detect spurious or artifact-contaminated data. Such irregularities are usually related to contact issues on surface measurements, resulting in extreme values observed at low frequencies (typically large positive or negative values). Representative curves are displayed for phase (Figure 3B), reactance (Figure 3C), and resistance (Figure 3D) for longitudinal (blue circles) and transverse (grey squares) measurements. A graph showing the reactance as a function of resistance (Cole-Cole plot) in both longitudinal and transverse directions is also displayed (Figure 3E). This step is critical as it is part of the data-checking, allowing for the straightforward detection of spurious or artifact-contaminated data. If excessive artifact (usually due to poor contact between the surface array and the skin) is detected, then several procedures can be followed to improve the contact. These include applying an additional application of depilatory cream, moistening the skin for about 1 min with a saline soaked-gauze pad, or applying gentle pressure to the electrode array. Generally, the simple process of repeating the measurement several times will also help resolve this.
EIM measurements reflect the response of the muscle tissue to electrical current across a wide range of frequencies, each targeting different structures. For example, low frequencies (i.e., 5 kHz) do not penetrate the myofiber membrane, thus providing an analysis of the extracellular features that can be used to detect inflammation and neutrophil infiltration14. In contrast, high frequencies (>1 MHz) can penetrate cell membranes and therefore interrogate both intracellular as well as extracellular spaces and have been used to differentiate muscle fiber type1.
Figure 1: 3D printed surface array. Photographs of a surface array that was 3D printed to obtain surface impedance measurements (both longitudinal and transverse) in mice in vivo. (A) A photograph showing the surface array connected to the acquisition device. (B) A close-up of the surface array showing the wheel used to turn the array to 90° to obtain both longitudinal and transverse measurements. (C) A close-up of the surface electrodes. The surface electrodes have the following characteristics: electrodes width = 0.5 mm, outer electrodes length = 4 mm, inner electrodes length = 3 mm, and spacing between electrodes = 1 mm. Please click here to view a larger version of this figure.
Figure 2: Other arrays that can be used to accommodate specific experimental designs. Photographs of: (A) a needle array used for rats and coated (using nonmetallic nail lacquer) to diminish the contribution of subcutaneous fat (2 mm space, 4 mm deep, 2 mm coating); (B) a needle array with 2 mm spacing and 4 mm depth; (C) a needle array with 2 mm spacing and 3 mm depth; (D) a needle array with 2 mm spacing and 2 mm depth; (E) a needle array for smaller animals and pups with 1 mm spacing and 2 mm depth; (F) a needle array with 1 mm spacing and 1 mm depth; (G) an ex vivo dielectric cell tailored for adult mouse muscles (5 mm x 5 mm); and (H) an ex vivo dielectric cell tailored for rat muscles (10 mm x 10 mm). Modifications (results not presented here) to acquire measurements on obese animals (i.e., ob/ob or db/db mice) can be performed by increasing needle length, adding nonconductive coating, and increasing/decreasing needle spacing. Please click here to view a larger version of this figure.
Figure 3: Data output and representative curves obtained in mice with in vivo surface EIM in the longitudinal (blue) and transverse (grey) directions. (A) Output file in .csv format obtained following the acquisition of two longitudinal (measurements 1 and 3, colored in blue) and two transverse (measurements 2 and 4, colored in grey) EIM measurements in vivo. The values are indicated for each frequency (column A). Analyses are performed subsequently using the average value of the longitudinal and transverse measurements, respectively. Information found in cells A1:B4 is populated automatically by the software, according to the labels chosen during EIM acquisition. Representative curves for both longitudinal (blue circles) and transverse (grey squares) values of phase (B), reactance (C), and resistance (D) as a function of frequency. Consistent with standard practices in the impedance field, the x-axis is indicated using a logarithmic scale. (E) Representative curves of reactance as a function of resistance for both longitudinal and transverse measurements. LP: longitudinal phase; TP: transverse phase; LX: longitudinal reactance; TX: transverse reactance; LR: longitudinal resistance; and TR: transverse resistance. Please click here to view a larger version of this figure.
This article provides the basic methods for performing EIM in rodents, both in vivo and ex vivo. To acquire reliable measurements, it is critical to perform a series of steps. First, one needs to properly identify the muscle of interest, as each muscle will have different responses to diseases, treatment, and pathology. One must be mindful that the data acquired on one muscle (e.g., gastrocnemius) will not provide the same information as on another muscle (e.g., tibialis anterior). Second, one needs to carefully choose the best electrode array to perform the impedance measurements. While each array type comes with both advantages and disadvantages, it is important to choose an array that will fit the experimental design while taking into account disease progression and the effect on anatomy (e.g., severe atrophy). Lastly, EIM allows investigators to collect an incredible amount of data in a few seconds, but quality control needs to be performed properly to ensure the absence of artifacts.
The EIM system is highly customizable at several levels. While the system used here has been designed for clinical and preclinical data collection, any multifrequency impedance measuring system can be used for this purpose, as long as it provides individual frequency data. Generally, impedance systems provide a standard .csv file as output. Similarly, additional modifications can be made regarding the arrays, as all that is truly required are four electrodes placed in a line. For example, in this protocol, a variety of custom-made electrodes have been used to fulfill requirements, but arrays can be tailored to individual needs using simple (e.g., epoxy glue, subdermal needles) or complex (e.g., 3D printers) tools. Alternatively, the four electrodes can be combined into a single needle, as previously described20. In our laboratory, arrays have been developed for pups by decreasing the spacing between electrodes to ensure that small muscles could be measured in both the longitudinal and transverse directions. When working with obese animals, which have a significantly greater layer of subcutaneous fat, the use of partially coated needle electrodes is recommended. This enables a greater contribution of the muscle tissue to the impedance measurement while decreasing the contribution of the adipose tissue21.
While needle methods and surface methods can be used in both rats and mice, as described and demonstrated, it is generally recommended to use the needle measurements in rats, as these are faster since they do not require effort to prepare the skin. In addition, their larger size means that the needle electrodes only minimally injure the muscle. In mice, given their small size, surface measurements are recommended to avoid muscle injury and given that the skin preparation is relatively simple and fast.
Each EIM technique comes with its own set of limitations. A key limitation is that electrode arrays are not readily available through vendors, and instead require customized generation in the laboratory. To assist new investigators, this protocol includes measurements for several arrays (both handmade and 3D printed), and the authors will provide custom arrays or make the related CAD files available upon request. As previously mentioned, data quality is critical, and additional issues can interfere with data quality for each of the measurement types (e.g., surface, needle, and ex vivo). For good surface data, it is necessary to remove the hair completely, and likely the stratum corneum of the skin as well, to get the best results with minimal contact artifact. However, the use of the depilatory agent also means that the skin will slowly become edematous over time, so it is necessary to rapidly complete the impedance measurements following hair removal. Waiting 10 min or longer may yield significantly different values compared to performing the measurements within a minute or two of hair removal. Needle array measurements in either rats or mice will typically induce at least a small amount of bleeding, which could impact the readings if it turns into a larger hematoma around the inserted needles. Finally, ex vivo measurements require special care to ensure that the muscle fibers within the dielectric cell are aligned accurately with respect to the metal plates. Finally, in small or diseased mice, it may be impossible to obtain transverse measurements, given the small size of the muscles. But, as noted above, it remains possible to design custom 4-electrode arrays that could be sufficiently small to take longitudinal measurements within even the smallest of muscles.
Data analysis can be kept quite simple - for example, by measuring a single output (e.g., phase) at a single frequency (e.g., 50 kHz) in a single direction (e.g., longitudinal) - or quite complex, by incorporating all impedance parameters across the entire frequency spectrum in both longitudinal and transverse directions. When single frequency impedance values are used, they are typically in the range of 30-100 kHz, since muscle tends to be most reactive (i.e., it is most "chargeable") in this frequency range. However, condensed or collapsed parameters, which attempt to capture the shape of the frequency spectrum, have also been utilized. These values have included slopes of linear fits of the resistance, reactance, and phase data22 and 2-frequency ratios23. Alternatively, Cole-Cole parameters can be calculated from fits of the impedance data, including the R0 (determination of the resistance at zero frequency), Rinf (determination of the resistance at infinity frequency), and fc (center frequency)24,25,26,27. Finally, machine learning can be used to analyze all the data at once and improve predictive models, both for regression12,13,15,16, and classification.
Despite these limitations, EIM is a powerful and relatively simple tool to assess multiple aspects of muscle health. While the focus of this manuscript is on a single muscle (gastrocnemius), there is nothing precluding the use of EIM on other superficial muscles (e.g., quadriceps or biceps brachii) using surface electrodes or deeper muscles using the needle electrode array. Indeed, in humans, the technique has been used in a wide variety of muscles, including both upper and lower extremity muscles8,28, as well axial muscles (e.g. paraspinal muscles and abdominal muscles)29,30.
It has been shown that EIM provides reliable measures regarding disease progression, remission of atrophy, and treatment over time. Single-frequency data may be entirely sufficient to assess disease status over time31; nevertheless, the value of multifrequency data is that it can still help assess the quality of the measurement, as described above. Single-frequency data in isolation could be substantially contaminated by contact artifacts, and this would not be apparent without reviewing the entire impedance spectrum. In clinical studies, surface EIM can be used frequently to obtain painless measurements making it a simple tool to apply32. This abundance of data can be critical to more sensitively tracking disease progression. Moreover, the addition of EIM to clinical protocols can significantly reduce the number of participants required during a clinical trial28,31.
EIM is finding increasing application in the assessment of a variety of neuromuscular conditions in humans. Accordingly, the ability to perform the technique effectively in rodents helps to expand the potential practical value of the technology while also enhancing our understanding of the relationship between various EIM outputs and underlying histology. The technique is generally easy to use and together with the useful quantitative data it provides, deserves to be included in the standard armamentarium of tools for assessment of nerve and muscle disorders in rodent disease models.
S. B. Rutkove has equity in, and serves as a consultant and scientific advisor to, Myolex, Inc., a company that designs impedance devices for clinical and research use, and the mView system used here. He is also a member of the company's Board of Directors. The company also has an option to license patented impedance technology of which S. B. Rutkove is named as an inventor. The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
This work was supported by Charley's Fund and NIH R01NS055099.
|3D Printer||Formlabs Inc.||Form 2 Desktop||3D printer|
|3D Printer||Shenzhen Creality 3D Technology Co. LTD||Creality Ender 3 V2||3D printer|
|3M Micropore surgical tape||Fisher||19-027761 and 19-061655||models 1530-0 and 1530-1|
|3M TRANSPORE surgical tape||Fisher||18-999-380 and 18-999-381||models 1527-0 and 1527-1|
|Connector header vertical 10 POS 1 mm spacing||Digi-Key (Sullins connector solution)||S9214-ND (SMH100-LPSE-S10-ST-BK)||Plastic spacer 1 mm holes for the rat in vivo array displayed in Figure 2A|
|Depilatory agent||NAIR||NA||hair remover lotion with softening baby oil|
|Dumont #7b Forceps||Fine Science Tools||No. 11270-20||Used for dissection, Style: #7b, Tip Shape: Curved, Tips: Standard, Tip Dimensions: 0.17 mm x 0.1 mm, Alloy/Material: Inox, Length: 11 cm|
|Electronic Digital Caliper||Fisher||14-648-17||Used to measure out the dimensions of the Gastrocnemius muscle|
|Epoxy adhesive dual cartridge 4 min work life||Devcon||series 14265, model 2217||Glue used in the rat in vivo array displayed in Figure 2A|
|Ex vivo dielectric impedance cell||Custom||NA||Dielectric cells were 3D printed in the Rutkove laboratory|
|Graefe Forceps||Fine Science Tools||No. 11051-10||Used for muscle to place and adjust, Length: 10 cm, Tip Shape: Curved, Tips: Serrated, Tip Width: 0.8 mm, Tip Dimensions: 0.8 mm x 0.7 mm, Alloy/Material|
|Hair clipper||Amazon||NA||Wahl professional animal BravMini+|
|Impedance Animal Device||Myolex||EIM1103||mView system - investigational electrical impedance myography device for use in animal research|
|In vivo needle arrays||Custom||NA||Custom arrays using 27 G subdermal needles from Ambu. The construction was finalized using a 3D printer in the Rutkove laboratory|
|In vivo surface array||Custom||NA||The in vivo surface array was printed and assembled in the Rutkove laboratory|
|Isoflurane||Patterson Veterinary Supplies||07-893-8441 (NDC: 46066-755-04)||Pivetal - 250 mL bottle|
|Non-woven gauze||Fisher||22-028-559||2 x 2 inch|
|Polystyrene Weighing Dishes||Fisher||S67090A||Dimensions (L x W x H): 88.9 mm x 88.9 mm x 25.4 mm|
|Razor Blades||Fisher||12-640||Used to cut muscle to right dimensions, Single-edge carbon steel blades|
|Student Fine Scissors||Fine Science Tools||No. 91460-11||Used for dissection, Tips: Sharp-Sharp, Alloy/Material: Student Stainless Steel, Serrated: No, Tip Shape: Straight, Cutting Edge: 20 mm, Length: 11.5 cm, Feature: Student Quality|
|Subdermal needles 27 G Neuroline||Ambu||745 12-50/24||Needles used in the rat in vivo array displayed in Figure 2A|
|Surgical Scissors - Sharp||Fine Science Tools||No. 14002-13||Used to cut skin, Tips: Sharp-Sharp, Alloy/Material: Stainless Steel, Serrated: No, Tip Shape: Straight, Cutting Edge: 42 mm, Length: 13 cm|
|TECA ELITE monopolar needle electrodes||Natus||902-DMG50-S||0.46 mm diameter (26 G). Blue hub|
|Teknova 0.9% saline solution||Fisher||S5815||1000 mL sterile|
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