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Objective. In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a first in vivo proof-of-concept of this technology. Approach. First, the in vitro biocompatibility of radiation-sensitive poly(vinyl alcohol) perfluorobutane nanodroplets was investigated using several colorimetric assays. Then, in vivo ultrasound contrast was characterized using acoustic droplet vaporization (ADV) and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of the in vivo biocompatibility was performed using ADV and a combination of physiology monitoring and histology. Main results. Nanodroplets were non-toxic over a wide concentration range (<1 mM). In healthy rats, intravenously injected nanodroplets primarily accumulated in the organs of the reticuloendothelial system, where the lifetime of the generated ultrasound contrast (<30 min) was compatible with a typical radiotherapy fraction (<5 min). Spontaneous droplet vaporization did not result in significant background signals. Online ultrasound imaging of the liver of droplet-injected rats demonstrated an energy-dependent proton response, which can be tuned by varying the nanodroplet concentration. However, caution is warranted when deciding on the exact nanodroplet dose regimen as a mild physiological response (drop in cardiac rate, granuloma formation) was observed after ADV. Significance. These findings underline the potential of phase-change ultrasound contrast agents for in vivo proton range verification and provide the next step towards eventual clinical applications., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Aims: By combining temporal changes in left ventricular (LV) global longitudinal strain (GLS) with LV volume, LV strain-volume loops can assess cardiac function across the cardiac cycle. This study compared LV strain-volume loops between bicuspid aortic valve (BAV) patients and controls, and investigated the loop's prognostic value for clinical events., Methods and Results: From a prospective cohort of congenital heart disease patients, BAV patients were selected and compared with healthy volunteers, who were matched for age and sex at group level. GLS analysis from apical views was used to construct strain-volume loops. Associations with clinical events, i.e. a composite of all-cause mortality, heart failure, arrhythmias, and aortic valve replacement, were assessed by Cox regression. A total of 113 BAV patients were included (median age 32 years, 40% female). BAV patients demonstrated lower Sslope (0.21%/mL, [Q1-Q3: 0.17-0.28] vs. 0.27%/mL [0.24-0.34], P < 0.001) and ESslope (0.19%/mL [0.12-0.25] vs. 0.29%/mL [0.21-0.43], P < 0.001) compared with controls, but also greater uncoupling during early (0.48 ± 1.29 vs. 0.05 ± 1.21, P = 0.04) and late diastole (0.66 ± 1.02 vs. -0.07 ± 1.07, P < 0.001). Median follow-up duration was 9.9 [9.3-10.4] years. Peak aortic jet velocity (HR 1.22, P = 0.03), enlarged left atrium (HR 3.16, P = 0.003), E/e' ratio (HR 1.17, P = 0.002), GLS (HR 1.16, P = 0.008), and ESslope (HR 0.66, P = 0.04) were associated with the occurrence of clinical events., Conclusion: Greater uncoupling and lower systolic and diastolic slopes were observed in BAV patients compared with healthy controls, suggesting presence of altered LV cardiomechanics. Moreover, lower ESslope was associated with clinical events, highlighting the strain-volume loop's potential as prognostic marker., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective . An elevated interstitial fluid pressure (IFP) can lead to strain-induced stiffening of poroelastic biological tissues. As shear wave elastography (SWE) measures functional tissue stiffness based on the propagation speed of acoustically induced shear waves, the shear wave velocity (SWV) can be used as an indirect measurement of the IFP. The underlying biomechanical principle for this stiffening behavior with pressurization is however not well understood, and we therefore studied how IFP affects SWV through SWE experiments and numerical modeling. Approach . For model set-up and verification, SWE experiments were performed while dynamically modulating IFP in a chicken breast. To identify the confounding factors of the SWV-IFP relationship, we manipulated the material model (linear poroelastic versus porohyperelastic), deformation assumptions (geometric linearity versus nonlinearity), and boundary conditions (constrained versus unconstrained) in a finite element model mimicking the SWE experiments. Main results . The experiments demonstrated a statistically significant positive correlation between the SWV and IFP. The model was able to reproduce a similar SWV-IFP relationship by considering an unconstrained porohyperelastic tissue. Material nonlinearity was identified as the primary factor contributing to this relationship, whereas geometric nonlinearity played a smaller role. The experiments also highlighted the importance of the dynamic nature of the pressurization procedure, as indicated by a different observed SWV-IFP for pressure buildup and relaxation, but its clinical relevance needs to be further investigated. Significance . The developed model provides an adaptable framework for SWE of poroelastic tissues and paves the way towards non-invasive measurements of IFP., (© 2024 Institute of Physics and Engineering in Medicine.)

Objective: Post-operative brain injury in neonates may result from disturbed cerebral perfusion, but accurate peri-operative monitoring is lacking. High-frame-rate (HFR) cerebral ultrasound could visualize and quantify flow in all detectable vessels using spectral Doppler; however, automated quantification in small vessels is challenging because of low signal amplitude. We have developed an automatic envelope detection algorithm for HFR pulsed wave spectral Doppler signals, enabling neonatal brain quantitative parameter maps during and after surgery., Methods: HFR ultrasound data from high-risk neonatal surgeries were recorded with a custom HFR mode (frame rate = 1000 Hz) on a Zonare ZS3 system. A pulsed wave Doppler spectrogram was calculated for each pixel containing blood flow in the image, and spectral peak velocity was tracked using a max-likelihood estimation algorithm of signal and noise regions in the spectrogram, where the most likely cross-over point marks the blood flow velocity. The resulting peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistivity index (RI) were compared with other detection schemes, manual tracking and RIs from regular pulsed wave Doppler measurements in 10 neonates., Results: Envelope detection was successful in both high- and low-quality arterial and venous flow spectrograms. Our technique had the lowest root mean square error for EDV, PSV and RI (0.46 cm/s, 0.53 cm/s and 0.15, respectively) when compared with manual tracking. There was good agreement between the clinical pulsed wave Doppler RI and HFR measurement with a mean difference of 0.07., Conclusion: The max-likelihood algorithm is a promising approach to accurate, automated cerebral blood flow monitoring with HFR imaging in neonates., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The advent of high-frame rate imaging in ultrasound allowed the development of shear wave elastography as a noninvasive alternative for myocardial stiffness assessment. It measures mechanical waves propagating along the cardiac wall with speeds that are related to stiffness. The use of cardiac shear wave elastography in clinical studies is increasing, but a proper understanding of the different factors that affect wave propagation is required to correctly interpret results because of the heart's thin-walled geometry and intricate material properties. The aims of this review are to give an overview of the general concepts in cardiac shear wave elastography and to discuss in depth the effects of age, hemodynamic loading, cardiac morphology, fiber architecture, contractility, viscoelasticity, and system-dependent factors on the measurements, with a focus on clinical application. It also describes how these factors should be considered during acquisition, analysis, and reporting to ensure an accurate, robust, and reproducible measurement of the shear wave., Competing Interests: Funding Support and Author Disclosures This work was supported by the Research Foundation Flanders under grants 1211620N and 12B3124N to Dr Caenen and grant G092318N to Dr Bézy. Dr Voigt holds a personal research mandate of the Research Foundation Flanders (1832922N). Dr Nightingale has intellectual property related to radiation force-based imaging technologies that has been licensed to Siemens, Samsung, and MicroElastic Ultrasound Systems. Dr Pernot has intellectual property related to SWE that has been licensed to eMyoSound. Dr Vos has an ongoing research collaboration with Mindray Ultrasound. Drs Voigt and Jan D’hooge have an ongoing research collaboration with GE Vingmed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Described here is the development of an ultrasound matrix transducer prototype for high-frame-rate 3-D intra-cardiac echocardiography., Methods: The matrix array consists of 16 × 18 lead zirconate titanate elements with a pitch of 160 µm × 160 µm built on top of an application-specific integrated circuit that generates transmission signals and digitizes the received signals. To reduce the number of cables in the catheter to a feasible number, we implement subarray beamforming and digitization in receive and use a combination of time-division multiplexing and pulse amplitude modulation data transmission, achieving an 18-fold reduction. The proposed imaging scheme employs seven fan-shaped diverging transmit beams operating at a pulse repetition frequency of 7.7 kHz to obtain a high frame rate. The performance of the prototype is characterized, and its functionality is fully verified., Results: The transducer exhibits a transmit efficiency of 28 Pa/V at 5 cm per element and a bandwidth of 60% in transmission. In receive, a dynamic range of 80 dB is measured with a minimum detectable pressure of 10 Pa per element. The element yield of the prototype is 98%, indicating the efficacy of the manufacturing process. The transducer is capable of imaging at a frame rate of up to 1000 volumes/s and is intended to cover a volume of 70° × 70° × 10 cm., Conclusion: These advanced imaging capabilities have the potential to support complex interventional procedures and enable full-volumetric flow, tissue, and electromechanical wave tracking in the heart., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ultrafast cerebral Doppler ultrasound enables simultaneous quantification and visualization of cerebral blood flow velocity. The aim of this study is to compare the use of conventional and ultrafast spectral Doppler during anesthesia and their potential to show the effect of anesthesiologic procedures on cerebral blood flow velocities, in relation to blood pressure and cerebral oxygenation in infants undergoing inguinal hernia repair., Methods: A single-center prospective observational cohort study in infants up to six months of age. We evaluated conventional and ultrafast spectral Doppler cerebral ultrasound measurements in terms of number of successful measurements during the induction of anesthesia, after sevoflurane induction, administration of caudal analgesia, a fluid bolus and emergence of anesthesia. Cerebral blood flow velocity was quantified in pial arteries using conventional spectral Doppler and in the cerebral cortex using ultrafast Doppler by peak systolic velocity, end diastolic velocity and resistivity index., Results: Twenty infants were included with useable conventional spectral Doppler images in 72/100 measurements and ultrafast Doppler images in 51/100 measurements. Intraoperatively, the success rates were 53/60 (88.3%) and 41/60 (68.3%), respectively. Cerebral blood flow velocity increased after emergence for both conventional (end diastolic velocity, from 2.01 to 2.75 cm/s, p < 0.001) and ultrafast spectral Doppler (end diastolic velocity, from 0.59 to 0.94 cm/s), whereas cerebral oxygenation showed a reverse pattern with a decrease after the emergence of the infant (85% to 68%, p < 0.001)., Conclusion: It is possible to quantify cortical blood flow velocity during general anesthesia using conventional and ultrafast spectral Doppler cerebral ultrasound. Cerebral blood flow velocity and blood pressure decreased, while regional cerebral oxygenation increased during general anesthesia. Ultrafast spectral Doppler ultrasound offers novel insights into perfusion within the cerebral cortex, unattainable through conventional spectral ultrasound. Yet, ultrafast Doppler is curtailed by a lower success rate and a more rigorous learning curve compared to conventional method., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023. Published by Elsevier Inc.)