High-Frame-Rate Volumetric Porcine Renal Vasculature Imaging.

OBJECTIVE: The aim of this study was to assess the feasibility and imaging options of contrast-enhanced volumetric ultrasound kidney vasculature imaging in a porcine model using a prototype sparse spiral array. METHODS: Transcutaneous freehand in vivo imaging of two healthy porcine kidneys was performed according to three protocols with different microbubble concentrations and transmission sequences. Combining high-frame-rate transmission sequences with our previously described spatial coherence beamformer, we determined the ability to produce detailed volumetric images of the vasculature. We also determined power, color and spectral Doppler, as well as super-resolved microvasculature in a volume. The results were compared against a clinical 2-D ultrasound machine. RESULTS: Three-dimensional visualization of the kidney vasculature structure and blood flow was possible with our method. Good structural agreement was found between the visualized vasculature structure and the 2-D reference. Microvasculature patterns in the kidney cortex were visible with super-resolution processing. Blood flow velocity estimations were within a physiological range and pattern, also in agreement with the 2-D reference results. CONCLUSION: Volumetric imaging of the kidney vasculature was possible using a prototype sparse spiral array. Reliable structural and temporal information could be extracted from these imaging results.

Sparse 2-D PZT-on-PCB Arrays With Density Tapering.

Two-dimensional (2-D) arrays offer volumetric imaging capabilities without the need for probe translation or rotation. A sparse array with elements seeded in a tapering spiral pattern enables one-to-one connection to an ultrasound machine, thus allowing flexible transmission and reception strategies. To test the concept of sparse spiral array imaging, we have designed, realized, and characterized two prototype probes designed at 2.5-MHz low-frequency (LF) and 5-MHz high-frequency (HF) center frequencies. Both probes share the same electronic design, based on piezoelectric ceramics and rapid prototyping with printed circuit board substrates to wire the elements to external connectors. Different center frequencies were achieved by adjusting the piezoelectric layer thickness. The LF and HF prototype probes had 88% and 95% of working elements, producing peak pressures of 21 and 96 kPa/V when focused at 5 and 3 cm, respectively. The one-way -3-dB bandwidths were 26% and 32%. These results, together with experimental tests on tissue-mimicking phantoms, show that the probes are viable for volumetric imaging.

Unfocused Field Analysis of a Density-Tapered Spiral Array for High-Volume-Rate 3-D Ultrasound Imaging.

Spiral array transducers with a sparse 2-D aperture have demonstrated their potential in realizing 3-D ultrasound imaging with reduced data rates. Nevertheless, their feasibility in high-volume-rate imaging based on unfocused transmissions has yet to be established. From a metrology standpoint, it is essential to characterize the acoustic field of unfocused transmissions from spiral arrays not only to assess their safety but also to identify the root cause of imaging irregularities due to the array's sparse aperture. Here, we present a field profile analysis of unfocused transmissions from a density-tapered spiral array transducer (256 hexagonal elements, 220- [Formula: see text] element diameter, and 1-cm aperture diameter) through both simulations and hydrophone measurements. We investigated plane- and diverging-wave transmissions (five-cycle, 7.5-MHz pulses) from 0° to 10° steering for their beam intensity characteristics and wavefront arrival time profiles. Unfocused firings were also tested for B-mode imaging performance (ten compounded angles, -5° to 5° span). The array was found to produce unfocused transmissions with a peak negative pressure of 93.9 kPa at 2 cm depth. All transmissions steered up to 5° were free of secondary lobes within 12 dB of the main beam peak intensity. All wavefront arrival time profiles were found to closely match the expected profiles with maximum root-mean-squared errors of [Formula: see text] for plane wave (PW) and [Formula: see text] for diverging wave. The B-mode images showed good spatial resolution with a penetration depth of 22 mm in PW imaging. Overall, these results demonstrate that the density-tapered spiral array can facilitate unfocused transmissions below regulatory limits (mechanical index: 0.034; spatial-peak, pulse-average intensity: 0.298 W/cm2) and with suppressed secondary lobes while maintaining smooth wavefronts.

Design, Implementation, and Medical Applications of 2-D Ultrasound Sparse Arrays.

An ultrasound sparse array consists of a sparse distribution of elements over a 2-D aperture. Such an array is typically characterized by a limited number of elements, which in most cases is compatible with the channel number of the available scanners. Sparse arrays represent an attractive alternative to full 2-D arrays that may require the control of thousands of elements through expensive application-specific integrated circuits (ASICs). However, their massive use is hindered by two main drawbacks: the possible beam profile deterioration, which may worsen the image contrast, and the limited signal-to-noise ratio (SNR), which may result too low for some applications. This article reviews the work done for three decades on 2-D ultrasound sparse arrays for medical applications. First, random, optimized, and deterministic design methods are reviewed together with their main influencing factors. Then, experimental 2-D sparse array implementations based on piezoelectric and capacitive micromachined ultrasonic transducer (CMUT) technologies are presented. Sample applications to 3-D (Doppler) imaging, super-resolution imaging, photo-acoustic imaging, and therapy are reported. The final sections discuss the main shortcomings associated with the use of sparse arrays, the related countermeasures, and the next steps envisaged in the development of innovative arrays.

High Frame Rate Volumetric Imaging of Microbubbles Using a Sparse Array and Spatial Coherence Beamforming.

Volumetric ultrasound imaging of blood flow with microbubbles enables a more complete visualization of the microvasculature. Sparse arrays are ideal candidates to perform volumetric imaging at reduced manufacturing complexity and cable count. However, due to the small number of transducer elements, sparse arrays often come with high clutter levels, especially when wide beams are transmitted to increase the frame rate. In this study, we demonstrate with a prototype sparse array probe and a diverging wave transmission strategy, that a uniform transmission field can be achieved. With the implementation of a spatial coherence beamformer, the background clutter signal can be effectively suppressed, leading to a signal to background ratio improvement of 25 dB. With this approach, we demonstrate the volumetric visualization of single microbubbles in a tissue-mimicking phantom as well as vasculature mapping in a live chicken embryo chorioallantoic membrane.

Architecture for an Ultrasound Advanced Open Platform With an Arbitrary Number of Independent Channels.

Ultrasound open platforms are programmable and flexible tools for the development and test of novel methods. In most cases, they embed the electronics for the independent control of (maximum) 256 probe elements. However, a higher number of channels is needed for the control of 2-D array probes. This paper presents a system architecture that, through the hardware and software synchronization of multiple ULA-OP 256 scanners, may implement advanced open platforms with an arbitrary number of channels. The proposed solution needs a single personal computer, maintains real-time features, and preserves portability. A prototype demonstrator, composed of two ULA-OP 256 scanners connected to 512 elements of a matrix array, was implemented and tested according to different channel configurations. Experiments performed under MATLAB control confirmed that by doubling the number of elements (from 256 to 512) the signal-to-noise and contrast ratios improve by 9 dB and 3 dB, respectively. Furthermore, as a full 512-channel scanner, the demonstrator can produce real-time B-mode images at 18 Hz, high enough for probe positioning during acquisitions. Also, the demonstrator permitted the implementation of a new high frame rate, bi-plane, triplex modality. All probe elements are excited to simultaneously produce two planar, perpendicular diverging waves. Each scanner independently processes the echoes received by the 256 connected elements to beamform 1300 frames per second. For each insonified plane, good quality morphological (B-mode), qualitative (color flow-), and quantitative (spectral-) Doppler images are finally shown in real-time by a dedicated interface.

Real-Time 3-D Spectral Doppler Analysis With a Sparse Spiral Array.

2-D sparse arrays may push the development of low-cost 3-D systems, not needing to control thousands of elements by expensive application-specific integrated circuits (ASICs). However, there is still some concern about their suitability in applications, such as Doppler investigation, which inherently involve poor signal-to-noise ratios (SNRs). In this article, a novel real-time 3-D pulsed-wave (PW) Doppler system, based on a 256-element 2-D spiral array, is presented. Coded transmission (TX) and matched filtering were implemented to improve the system SNR. Standard sonograms as well as multigate spectral Doppler (MSD) profiles, along lines that can be arbitrarily located in different planes, are presented. The performance of the system was assessed quantitatively on experimental data obtained from a straight tube flow phantom. An SNR increase of 11.4 dB was measured by transmitting linear chirps instead of standard sinusoidal bursts. For a qualitative assessment of the system performance in more realistic conditions, an anthropomorphic phantom of the carotid arteries was used. Finally, real-time B-mode and MSD images were obtained from healthy volunteers.

Virtual Real-Time for High PRF Multiline Vector Doppler on ULA-OP 256.

The recent development of high-frame-rate (HFR) imaging/Doppler methods based on the transmission of plane or diverging waves has proposed new challenges to echographic data management and display. Due to the huge amount of data that need to be processed at very high speed, the pulse repetition frequency (PRF) is typically limited to hundreds hertz or few kilohertz. In Doppler applications, a PRF limitation may result unacceptable since it inherently translates to a corresponding limitation in the maximum detectable velocity. In this article, the ULA-OP 256 implementation of a novel ultrasound modality, called virtual real-time (VRT), is described. First, for a given HFR RT modality, the scanner displays the processed results while saving channel data into an internal buffer. Then, ULA-OP 256 switches to VRT mode, according to which the raw data stored in the buffer are immediately reprocessed by the same hardware used in RT. In the two phases, the ULA-OP 256 calculation power can be differently distributed to increase the acquisition frame rate or the quality of processing results. VRT was here used to extend the PRF limit in a multiline vector Doppler (MLVD) application. In RT, the PRF was maximized at the expense of the display quality; in VRT, data were reprocessed at a lower rate in a high-quality display format, which provides more detailed flow information. Experiments are reported in which the MLVD technique is shown capable of working at 16-kHz PRF, so that flow jet velocities higher up to 3 m/s can be detected.

3-D Super-Resolution Ultrasound Imaging With a 2-D Sparse Array.

High-frame-rate 3-D ultrasound imaging technology combined with super-resolution processing method can visualize 3-D microvascular structures by overcoming the diffraction-limited resolution in every spatial direction. However, 3-D super-resolution ultrasound imaging using a full 2-D array requires a system with a large number of independent channels, the design of which might be impractical due to the high cost, complexity, and volume of data produced. In this study, a 2-D sparse array was designed and fabricated with 512 elements chosen from a density-tapered 2-D spiral layout. High-frame-rate volumetric imaging was performed using two synchronized ULA-OP 256 research scanners. Volumetric images were constructed by coherently compounding nine-angle plane waves acquired at a pulse repetition frequency of 4500 Hz. Localization-based 3-D super-resolution images of two touching subwavelength tubes were generated from 6000 volumes acquired in 12 s. Finally, this work demonstrates the feasibility of 3-D super-resolution imaging and super-resolved velocity mapping using a customized 2-D sparse array transducer.

High-Frame-Rate Tri-Plane Echocardiography With Spiral Arrays: From Simulation to Real-Time Implementation.

Major cardiovascular diseases (CVDs) are associated with (regional) dysfunction of the left ventricle. Despite the 3-D nature of the heart and its dynamics, the assessment of myocardial function is still largely based on 2-D ultrasound imaging, thereby making diagnosis heavily susceptible to the operator's expertise. Unfortunately, to date, 3-D echocardiography cannot provide adequate spatiotemporal resolution in real-time. Hence, tri-plane imaging has been introduced as a compromise between 2-D and true volumetric ultrasound imaging. However, tri-plane imaging typically requires high-end ultrasound systems equipped with fully populated matrix array probes embedded with expensive and little flexible electronics for two-stage beamforming. This article presents an advanced ultrasound system for real-time, high frame rate (HFR), and tri-plane echocardiography based on low element count sparse arrays, i.e., the so-called spiral arrays. The system was simulated, experimentally validated, and implemented for real-time operation on the ULA-OP 256 system. Five different array configurations were tested together with four different scan sequences, including multi-line and planar diverging wave transmission. In particular, the former can be exploited to achieve, in tri-plane imaging, the same temporal resolution currently used in clinical 2-D echocardiography, at the expenses of contrast (-3.5 dB) and signal-to-noise ratio (SNR) (-8.7 dB). On the other hand, the transmission of planar diverging waves boosts the frame rate up to 250 Hz, but further compromises contrast (-10.5 dB), SNR (-9.7 dB), and lateral resolution (+46%). In conclusion, despite an unavoidable loss in image quality and sensitivity due to the limited number of elements, HFR tri-plane imaging with spiral arrays is shown to be feasible in real-time and may enable real-time functional analysis of all left ventricular segments of the heart.

Real-Time High-Frame-Rate Cardiac B-Mode and Tissue Doppler Imaging Based on Multiline Transmission and Multiline Acquisition.

Cardiovascular diseases, the leading cause of death in the world, are often associated with the dysfunction of the left ventricle. Even if, in clinical practice, the myocardial function is often assessed through visual wall motion scoring on B-mode images, quantitative techniques have been introduced, e.g., ultrasound tissue Doppler imaging (TDI). However, this technique suffers from the limited frame rate of currently available imaging techniques that needs to be balanced with the field of view. High-frame-rate (HFR) cardiac imaging has been recently tested off-line by simultaneously transmitting multiple focused beams into different directions and acquiring raw channel data into a PC. Several image lines were then reconstructed from the echoes of each transmission (TX) event. The same approach has been used to increase the TDI frame rate without restricting the field of view. This paper demonstrates the real-time feasibility of multiline TX and acquisition methods for both HFR cardiac B-mode and TDI. These approaches have been implemented on the ULA-OP 256 research scanner, by taking care that the related resources were optimally exploited for these new applications. The obtainable performance in terms of image quality and frame rate has also been investigated. Experiments performed with a 128-element phased array probe show, for the first time, that real-time B-mode imaging is feasible at up to 1150 Hz without significant reduction in image quality or field of view. The implementation of a real-time TDI algorithm allowed obtaining TDI images with a frame rate of 288 Hz for a 90°-wide field of view. Finally, in vivo examples demonstrate the feasibility and the suitability of the method in clinical studies.

Ultrasound Open Platforms for Next-Generation Imaging Technique Development.

Open platform (OP) ultrasound systems are aimed primarily at the research community. They have been at the forefront of the development of synthetic aperture, plane wave, shear wave elastography, and vector flow imaging. Such platforms are driven by a need for broad flexibility of parameters that are normally preset or fixed within clinical scanners. OP ultrasound scanners are defined to have three key features including customization of the transmit waveform, access to the prebeamformed receive data, and the ability to implement real-time imaging. In this paper, a formative discussion is given on the development of OPs from both the research community and the commercial sector. Both software- and hardware-based architectures are considered, and their specifications are compared in terms of resources and programmability. Software-based platforms capable of real-time beamforming generally make use of scalable graphics processing unit architectures, whereas a common feature of hardware-based platforms is the use of field-programmable gate array and digital signal processor devices to provide additional on-board processing capacity. OPs with extended number of channels (>256) are also discussed in relation to their role in supporting 3-D imaging technique development. With the increasing maturity of OP ultrasound scanners, the pace of advancement in ultrasound imaging algorithms is poised to be accelerated.

Real-Time Blood Velocity Vector Measurement Over a 2-D Region.

Quantitative blood velocity measurements, as currently implemented in commercial ultrasound scanners, are based on pulsed-wave (PW) spectral Doppler and are limited to detect the axial component of the velocity in a single sample volume. On the other hand, vector Doppler methods produce angle-independent estimates by, e.g., combining the frequency shifts measured from different directions. Moreover, thanks to the transmission of plane waves, the investigation of a 2-D region is possible with high temporal resolution, but, unfortunately, the clinical use of these methods is hampered by the massive calculation power required for their real-time execution. In this paper, we present a novel approach based on the transmission of plane waves and the simultaneous reception of echoes from 16 distinct subapertures of a linear array probe, which produces eight lines distributed over a 2-D region. The method was implemented on the ULAO-OP 256 research scanner and tested both in phantom and in vivo. A continuous real-time refresh rate of 36 Hz was achieved in duplex combination with a standard B-mode at pulse repetition frequency of 8 kHz. Accuracies of -11% on velocity and of 2°on angle measurements have been obtained in phantom experiments. Accompanying movies show how the method improves the quantitative measurements of blood velocities and details the flow configurations in the carotid artery of a volunteer.

Architecture of an Ultrasound System for Continuous Real-Time High Frame Rate Imaging.

High frame rate (HFR) imaging methods based on the transmission of defocused or plane waves rather than focused beams are increasingly popular. However, the production of HFR images poses severe requirements both in the transmission and the reception sections of ultrasound scanners. In particular, major technical difficulties arise if the images must be continuously produced in real-time, i.e., without any acquisition interruption nor loss of data. This paper presents the implementation of the real-time HFR-compounded imaging application in the ULA-OP 256 research platform. The beamformer sustains an average output sample rate of 470 MSPS. This allows continuously producing coherently compounded images, each of 64 lines by 1280 depths (here corresponding to 15.7 mm width and 45 mm depth, respectively), at frame rates up to 5.3 kHz. Imaging tests addressed to evaluate the achievable speed and quality performance were conducted on phantom. Results obtained by real-time compounding frames obtained with different numbers of steering angles between +7.5° and -7.5° are presented.

Coded Spectral Doppler Imaging: From Simulation to Real-Time Processing.

Transmission of coded pulses and matched receive filtering can improve the ultrasound imaging penetration depth while preserving the axial resolution. This paper shows that the pulse compression technique may be integrated in a low-cost scanner to be profitably used also in spectral Doppler investigations. By operating on beamformed, demodulated, and down-sampled data in the frequency domain, a single digital signal processor is proved sufficient to perform both pulse compression and multigate spectral Doppler algorithms in real time. Simulations, phantom, and in vivo experiments demonstrate that the transmission of (2.5 or [Formula: see text] long) linear frequency-modulated chirps with bandwidths over the range 1.6-5.4 MHz, rather than of corresponding sine-burst pulses, provides signal-to-noise ratio (SNR) improvements very close to theory. Even in the presence of selective tissue attenuation, SNR gains up to 11 and 13.3 dB have been obtained for the short and the longer chirp, respectively. This may be important in clinical Doppler applications where the needed penetration depth is not achieved with sufficient SNR unless very long bursts are transmitted.

ULA-OP 256: A 256-Channel Open Scanner for Development and Real-Time Implementation of New Ultrasound Methods.

Open scanners offer an increasing support to the ultrasound researchers who are involved in the experimental test of novel methods. Each system presents specific performance in terms of number of channels, flexibility, processing power, data storage capability, and overall dimensions. This paper reports the design criteria and hardware/software implementation details of a new 256-channel ultrasound advanced open platform. This system is organized in a modular architecture, including multiple front-end boards, interconnected by a high-speed (80 Gb/s) ring, capable of finely controlling all transmit (TX) and receive (RX) signals. High flexibility and processing power (equivalent to 2500 GFLOP) are guaranteed by the possibility of individually programming multiple digital signal processors and field programmable gate arrays. Eighty GB of on-board memory are available for the storage of prebeamforming, postbeamforming, and baseband data. The use of latest generation devices allowed to integrate all needed electronics in a small size ( 34 cm ×30 cm ×26 cm). The system implements a multiline beamformer that allows obtaining images of 96 lines by 2048 depths at a frame rate of 720 Hz (expandable to 3000 Hz). The multiline beamforming capability is also exploited to implement a real-time vector Doppler scheme in which a single TX and two independent RX apertures are simultaneously used to maintain the analysis over a full pulse repetition frequency range.

Density-tapered spiral arrays for ultrasound 3-D imaging.

The current high interest in 3-D ultrasound imaging is pushing the development of 2-D probes with a challenging number of active elements. The most popular approach to limit this number is the sparse array technique, which designs the array layout by means of complex optimization algorithms. These algorithms are typically constrained by a few steering conditions, and, as such, cannot guarantee uniform side-lobe performance at all angles. The performance may be improved by the ungridded extensions of the sparse array technique, but this result is achieved at the expense of a further complication of the optimization process. In this paper, a method to design the layout of large circular arrays with a limited number of elements according to Fermat's spiral seeds and spatial density modulation is proposed and shown to be suitable for application to 3-D ultrasound imaging. This deterministic, aperiodic, and balanced positioning procedure attempts to guarantee uniform performance over a wide range of steering angles. The capabilities of the method are demonstrated by simulating and comparing the performance of spiral and dense arrays. A good trade-off for small vessel imaging is found, e.g., in the 60λ spiral array with 1.0λ elements and Blackman density tapering window. Here, the grating lobe level is -16 dB, the lateral resolution is lower than 6λ the depth of field is 120λ and, the average contrast is 10.3 dB, while the sensitivity remains in a 5 dB range for a wide selection of steering angles. The simulation results may represent a reference guide to the design of spiral sparse array probes for different application fields.

Supervised exercise training reduces oxidative stress and cardiometabolic risk in adults with type 2 diabetes: a randomized controlled trial.

To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting, and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O2max (+14.4%), gas exchange threshold (+23.4%), waist circumference (-1.4%), total cholesterol (-14.6%), LDL cholesterol (-20.2%), fasting insulinemia (-48.5%), HOMA-IR (-52.5%), plasma POVPC (-27.9%) and PGPC (-31.6%). After 12 months, the control group presented a V'O2max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM.

High-frame-rate 2-D vector blood flow imaging in the frequency domain.

Conventional ultrasound Doppler techniques estimate the blood velocity exclusively in the axial direction to produce the sonograms and color flow maps needed for diagnosis of cardiovascular diseases. In this paper, a novel method to produce bi-dimensional maps of 2-D velocity vectors is proposed. The region of interest (ROI) is illuminated by plane waves transmitted at the pulse repetition frequency (PRF) in a fixed direction. For each transmitted plane wave, the backscattered echoes are recombined offline to produce the radio-frequency image of the ROI. The local 2-D phase shifts between consecutive speckle images are efficiently estimated in the frequency domain, to produce vector maps up to 15 kHz PRF. Simulations and in vitro steady-flow experiments with different setup conditions have been conducted to thoroughly evaluate the method's performance. Bias is proved to be lower than 10% in most simulations and lower than 20% in experiments. Further simulations and in vivo experiments have been made to test the approach's feasibility in pulsatile flow conditions. It has been estimated that the computation of the frequency domain algorithm is more than 50 times faster than the computation of the reference 2-D cross-correlation algorithm.

Tidal expiratory flow limitation at rest as a functional marker of pulmonary emphysema in moderate-to-severe COPD.

BACKGROUND: Tidal expiratory flow limitation (EFL) is a step of paramount importance in the functional decline in COPD. Among mechanisms contributing to EFL, loss of airway-parenchymal interdependence could mostly be involved. AIM: To assess if EFL is a functional marker more frequently linked to prevalent pulmonary emphysema rather than to prevalent chronic bronchiolitis in COPD patients with moderate-to-severe airflow obstruction. METHODS: Forty consecutive stable COPD patients with FEV1 between 59 and 30% of predicted were functionally evaluated by measuring spirometry, maximal flow-volume curve and lung diffusion capacity (DLCO) and coefficient of diffusion (KCO). EFL was assessed by the negative expiratory pressure (NEP) method both in sitting and supine position. Chronic dyspnea was also scored by modified Medical Research Council (mMRC) scale. RESULTS: In sitting position 13 patients (33%) were flow limited (FL) and 27 were non-flow limited (NFL). Only FEV1/FVC, FEV1 and MEF25-75% were different between FL and NFL patients (p < 0.01). In supine position, however, among NFL patients in sitting position those who developed EFL, had significantly lower values of DLCO and KCO (p < 0.05) and higher mMRC score (p < 0.01), but similar values of FEV1 as compared to those who did not have EFL. CONCLUSIONS: In COPD EFL in sitting position is highly dependent by the severity of airflow obstruction. In contrast, the occurrence of EFL in supine position is associated with worse DLCO and KCO and greater chronic dyspnea, reflecting a prevalent emphysematous phenotype in moderate-to-severe COPD patients.