Compensating unknown speed of sound in learned fast 3D limited-view photoacoustic tomography.

Real-time applications in three-dimensional photoacoustic tomography from planar sensors rely on fast reconstruction algorithms that assume the speed of sound (SoS) in the tissue is homogeneous. Moreover, the reconstruction quality depends on the correct choice for the constant SoS. In this study, we discuss the possibility of ameliorating the problem of unknown or heterogeneous SoS distributions by using learned reconstruction methods. This can be done by modelling the uncertainties in the training data. In addition, a correction term can be included in the learned reconstruction method. We investigate the influence of both and while a learned correction component can improve reconstruction quality further, we show that a careful choice of uncertainties in the training data is the primary factor to overcome unknown SoS. We support our findings with simulated and in vivo measurements in 3D.

Outcomes of re-referrals of patients with alcohol-associated liver disease, who were previously declined for liver transplantation.

Since 2018, our program has utilized specific psychosocial criteria and a multidisciplinary approach to assess patients for liver transplant due to alcohol-associated liver disease (ALD), rather than the 6-month abstinence rule alone. If declined based on these criteria, specific recommendations are provided to patients and their providers regarding goals for re-referral to increase the potential for future transplant candidacy. Recommendations include engagement in treatment for alcohol use disorder, serial negative biomarker testing, and maintenance of abstinence from alcohol. In our current study, we evaluate the outcomes of patients with ALD, who were initially declined upon assessment and re-referred to our program. This is a retrospective cohort study that includes 98 patients with ALD, who were previously declined for liver transplantation and were subsequently re-referred for liver transplant assessment between May 1, 2018, and December 31, 2021. We assess the outcomes of patients who were re-referred including acceptance for transplantation following a second assessment. Of the 98 patients who were re-referred, 46 (46.9%) fulfilled the recommendations made and proceeded to further medical evaluation. Nine were eventually transplanted; others are listed and are waiting for transplant. The presence of a partner was independently associated with a higher rate of acceptance (OR 0.16, 95% CI: 0.03-0.97, p = 0.05). Most of the patients who did not proceed further (n = 52) were declined again due to ALD contraindications (n = 33, 63.4%), including ongoing drinking and lack of engagement in recommended addiction treatment. Others had medical contraindications (11.2%), clinically improved (6.1%), had adherence issues (5.1%), or lack of adequate support (2%). Patients with ALD previously declined for a liver transplant can be re-referred and successfully accepted for transplantation by fulfilling the recommendations made by the multidisciplinary team. Important factors including ongoing abstinence, engagement in addiction treatment, and social support are key for successful acceptance.

Quantitative photoacoustic tomography: modeling and inverse problems.

Significance: Quantitative photoacoustic tomography (QPAT) exploits the photoacoustic effect with the aim of estimating images of clinically relevant quantities related to the tissue's optical absorption. The technique has two aspects: an acoustic part, where the initial acoustic pressure distribution is estimated from measured photoacoustic time-series, and an optical part, where the distributions of the optical parameters are estimated from the initial pressure. Aim: Our study is focused on the optical part. In particular, computational modeling of light propagation (forward problem) and numerical solution methodologies of the image reconstruction (inverse problem) are discussed. Approach: The commonly used mathematical models of how light and sound propagate in biological tissue are reviewed. A short overview of how the acoustic inverse problem is usually treated is given. The optical inverse problem and methods for its solution are reviewed. In addition, some limitations of real-life measurements and their effect on the inverse problems are discussed. Results: An overview of QPAT with a focus on the optical part was given. Computational modeling and inverse problems of QPAT were addressed, and some key challenges were discussed. Furthermore, the developments for tackling these problems were reviewed. Although modeling of light transport is well-understood and there is a well-developed framework of inverse mathematics for approaching the inverse problem of QPAT, there are still challenges in taking these methodologies to practice. Conclusions: Modeling and inverse problems of QPAT together were discussed. The scope was limited to the optical part, and the acoustic aspects were discussed only to the extent that they relate to the optical aspect.

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption.

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.

open-UST: An Open-Source Ultrasound Tomography Transducer Array System.

Fast imaging methods are needed to promote clinical adoption of ultrasound tomography (UST), and more widely available UST hardware could support the experimental validation of new measurement configurations. In this work, an open-source 256-element transducer ring array was developed (morganjroberts.github. io/open-UST) and manufactured using rapid prototyping, for only £2k. Novel manufacturing techniques were used, resulting in a 1.17° mean beam axis skew angle, a [Formula: see text] mean element position error, and a [Formula: see text] deviation in matching layer thickness. The nominal acoustic performance was measured using hydrophone scans and watershot data, and the 61.2 dB signal-to-noise ratio (SNR), 55.4° opening angle, 10.2 mm beamwidth, and 54% transmit-receive bandwidth (-12 dB) were found to be similar to existing systems and compatible with state-of-the-art full-waveform-inversion image reconstruction methods. The interelement variation in acoustic performance was typically < 10% without using normalization, meaning that the elements can be modeled identically during image reconstruction, removing the need for individual source definitions based on hydrophone measurements. Finally, data from a phantom experiment were successfully reconstructed. These results demonstrate that the open-UST system is accessible for users and is suitable for UST imaging research.

The effect of source backing materials and excitation pulse durations on laser-generated ultrasound waveforms.

In this article, it is shown experimentally that a planar laser-generated ultrasound source with a hard reflective backing will generate higher acoustic pressures than a comparable source with an acoustically matched backing when the stress confinement condition is not met. Furthermore, while the source with an acoustically matched backing will have a broader bandwidth when the laser pulse is short enough to ensure stress confinement, the bandwidths of both source types will converge as the laser pulse duration increases beyond stress confinement. The explanation of the results is supported by numerical simulations.

A learned Born series for highly-scattering media.

A new method for solving the wave equation is presented, called the learned Born series (LBS), which is derived from a convergent Born series but its components are found through training. The LBS is shown to be significantly more accurate than the convergent Born series for the same number of iterations, in the presence of high contrast scatterers, while maintaining a comparable computational complexity. The LBS is able to generate a reasonable prediction of the global pressure field with a small number of iterations, and the errors decrease with the number of learned iterations.

Mitigating the Limited View Problem in Photoacoustic Tomography for a Planar Detection Geometry by Regularized Iterative Reconstruction.

The use of a planar detection geometry in photoacoustic tomography results in the so- called limited-view problem due to the finite extent of the acoustic detection aperture. When images are reconstructed using one-step reconstruction algorithms, image quality is compromised by the presence of streaking artefacts, reduced contrast, image distortion and reduced signal-to-noise ratio. To mitigate this, model-based iterative reconstruction approaches based on least squares minimisation with and without total variation regularization were evaluated using in-silico, experimental phantom, ex vivo and in vivo data. Compared to one-step reconstruction methods, it has been shown that iterative methods provide better image quality in terms of enhanced signal-to-artefact ratio, signal-to-noise ratio, amplitude accuracy and spatial fidelity. For the total variation approaches, the impact of the regularization parameter on image feature scale and amplitude distribution was evaluated. In addition, the extent to which the use of Bregman iterations can compensate for the systematic amplitude bias introduced by total variation was studied. This investigation is expected to inform the practical application of model-based iterative image reconstruction approaches for improving photoacoustic image quality when using finite aperture planar detection geometries.

Differentiation trajectories of the Hydra nervous system reveal transcriptional regulators of neuronal fate.

The small freshwater cnidarian polyp Hydra vulgaris uses adult stem cells (interstitial stem cells) to continually replace neurons throughout its life. This feature, combined with the ability to image the entire nervous system (Badhiwala et al., 2021; Dupre & Yuste, 2017) and availability of gene knockdown techniques (Juliano, Reich, et al., 2014; Lohmann et al., 1999; Vogg et al., 2022), makes Hydra a tractable model for studying nervous system development and regeneration at the whole-organism level. In this study, we use single-cell RNA sequencing and trajectory inference to provide a comprehensive molecular description of the adult nervous system. This includes the most detailed transcriptional characterization of the adult Hydra nervous system to date. We identified eleven unique neuron subtypes together with the transcriptional changes that occur as the interstitial stem cells differentiate into each subtype. Towards the goal of building gene regulatory networks to describe Hydra neuron differentiation, we identified 48 transcription factors expressed specifically in the Hydra nervous system, including many that are conserved regulators of neurogenesis in bilaterians. We also performed ATAC-seq on sorted neurons to uncover previously unidentified putative regulatory regions near neuron-specific genes. Finally, we provide evidence to support the existence of transdifferentiation between mature neuron subtypes and we identify previously unknown transition states in these pathways. All together, we provide a comprehensive transcriptional description of an entire adult nervous system, including differentiation and transdifferentiation pathways, which provides a significant advance towards understanding mechanisms that underlie nervous system regeneration.

Liver Transplant Recipients Speak Out on Public Awareness and Education Surrounding Alcohol-Related Health Effects: A Survey Study.

BACKGROUND: Compared to other recreational substances in Canada, alcohol consumption incurs the highest healthcare costs. Liver transplant recipients are unique stakeholders as members of the general public with lived experiences of liver disease. We sought to explore their perspectives on the current state of public education on alcohol-related health effects. METHODS: The most recent 400 liver transplant recipients at Vancouver General Hospital, Canada, were invited to participate in an anonymous online survey on alcohol-related health effects by mail, email, and phone. RESULTS: Of 372 contacted patients, 212 (57%) completed the survey. Most patients were between 60-79 years, 63% were male, and 69% were Caucasian. The most common liver conditions leading to transplant were viral hepatitis (33%), alcohol-related liver disease (16%), autoimmune liver disease (14%), and non-alcoholic fatty liver disease (15%). Most patients knew that alcohol leads to liver failure (85%), but fewer knew about alcohol leading to cancer (54%), heart disease (50%), and damage to other organs (58%). Most common sources of information included public media (61%), family and friends (52%), and physicians (49%), with narrative comments about learning of alcohol-related health effects after liver diagnosis. Most patients believed that public health education at a middle/high school level would have long-term efficacy (72%) compared to health warning labels (33%) and safety messaging in commercials (39%). Current public education was felt to be adequate by only 20% of patients and 73% of patients supported health warning labels. CONCLUSIONS: Liver transplant patients reported a high, but not universal, awareness of alcohol-related health effects. A majority thought that current public health efforts were inadequate; it is critical to implement public health interventions to ensure consumers are able to make an informed decision on alcohol consumption.

Elevated serum ferritin in non-alcoholic fatty liver disease is not predictive of fibrosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common with widely ranging severity. Non-invasive risk scores for risk stratification are recommended but misclassify a significant proportion of patients. In situations where non-invasive risk scores do not provide guidance, referral is typically made to a Hepatologist for transient elastography or liver biopsy. Serum ferritin is elevated in many patients with NAFLD related to dysmetabolic and inflammatory hyperferritinemia. Ferritin is widely available and part of a standard workup for chronic liver disease. METHODS: To explore the association of ferritin and risk of fibrosis in NAFLD, we reviewed patients diagnosed with NAFLD at the hepatology clinic of the Vancouver General Hospital between the years of 2015 and 2018. We collected data on 317 patients retrospectively assessing for a relationship between serum ferritin and elastography score. RESULTS: Two hundred twenty-four patients were included in the final analysis. Median ferritin was 145 µg/L (IQR 62-311). Median liver stiffness was 5.2 kPa with 14.3% of patients having liver stiffness ≥8.7 kPa and 17.4% ≥ 8.0 kPa. ROC curve analysis using a liver stiffness ≥8.0 kPa as a cutoff for F2 fibrosis showed an AUROC of 0.54 for serum ferritin levels. At a cut-off of both 300 µg/L; and 450 µg/L median liver stiffness did not differ significantly in those with ferritin above the cutoff (ferritin ≥300 µg/L; p = 0.099, ferritin ≥450 µg/L; p = 0.12). Ferritin was significantly higher in male patients (198 versus 91 µg/L; p = 0.0001). There was a weak linear association between AST and ferritin levels. CONCLUSION: In this cohort of 224 patients with NAFLD, serum ferritin was not predictive of significant liver fibrosis.

The IPASC data format: A consensus data format for photoacoustic imaging.

Photoacoustic imaging (PAI) is an emerging modality that has shown promise for improving patient management in a range of applications. Unfortunately, the current lack of uniformity in PAI data formats compromises inter-user data exchange and comparison, which impedes: technological progress; effective research collaboration; and efforts to deliver multi-centre clinical trials. To overcome this challenge, the International Photoacoustic Standardisation Consortium (IPASC) has established a data format with a defined consensus metadata structure and developed an open-source software application programming interface (API) to enable conversion from proprietary file formats into the IPASC format. The format is based on Hierarchical Data Format 5 (HDF5) and designed to store photoacoustic raw time series data. Internal quality control mechanisms are included to ensure completeness and consistency of the converted data. By unifying the variety of proprietary data and metadata definitions into a consensus format, IPASC hopes to facilitate the exchange and comparison of PAI data.

COVID-19 infection immediately post-transplant in an unvaccinated patient: Clinical observations and ethical implications.

We report the case of a 28-year-old woman who presented with acute liver failure from suspected drug-induced liver injury. She was not vaccinated against COVID-19 and expressed considerable reluctance to become vaccinated, prompting discussions within the transplant group regarding her candidacy. She received a liver transplant and acquired COVID-19 immediately post-operatively that was treated with sotrovimab. She recovered well and was discharged shortly following her transplant. This case suggests that unwillingness to receive COVID-19 vaccination pre-transplant should not represent an absolute contraindication to a life-saving liver transplantation.

Measurement of the ultrasound attenuation and dispersion in 3D-printed photopolymer materials from 1 to 3.5 MHz.

Over the past decade, the range of applications in biomedical ultrasound exploiting 3D printing has rapidly expanded. For wavefront shaping specifically, 3D printing has enabled a diverse range of new, low-cost approaches for controlling acoustic fields. These methods rely on accurate knowledge of the bulk acoustic properties of the materials; however, to date, robust knowledge of these parameters is lacking for many materials that are commonly used. In this work, the acoustic properties of eight 3D-printed photopolymer materials were characterised over a frequency range from 1 to 3.5 MHz. The properties measured were the frequency-dependent phase velocity and attenuation, group velocity, signal velocity, and mass density. The materials were fabricated using two separate techniques [PolyJet and stereolithograph (SLA)], and included Agilus30, FLXA9960, FLXA9995, Formlabs Clear, RGDA8625, RGDA8630, VeroClear, and VeroWhite. The range of measured density values across all eight materials was 1120-1180 kg · m-3, while the sound speed values were between 2020 to 2630 m · s-1, and attenuation values typically in the range 3-9 dB · MHz-1· cm-1.

Modelling laser ultrasound waveforms: The effect of varying pulse duration and material properties.

Optical generation of ultrasound using nanosecond duration laser pulses has generated great interest both in industrial and biomedical applications. The availability of portable laser devices using semiconductor technology and optical fibres, as well as numerous source material types based on nanocomposites, has proliferated the applications of laser ultrasound. The nanocomposites can be deposited on the tip of optical fibres as well as planar hard and soft backing materials using various fabrication techniques, making devices suitable for a variety of applications. The ability to choose the acoustic material properties and the laser pulse duration gives considerable control over the ultrasound output. Here, an analytical time-domain solution is derived for the acoustic pressure waveform generated by a planar optical ultrasound source consisting of an optically absorbing layer on a backing. It is shown that by varying the optical attenuation coefficient, the thickness of the absorbing layer, the acoustic properties of the materials, and the laser pulse duration, a wide variety of pulse shapes and trains can be generated. It is shown that a source with a reflecting backing can generate pulses with higher amplitude than a source with an acoustically-matched backing in the same circumstances when stress-confinement has not been satisfied.

Control of osteoblast regeneration by a train of Erk activity waves.

Regeneration is a complex chain of events that restores a tissue to its original size and shape. The tissue-wide coordination of cellular dynamics that is needed for proper morphogenesis is challenged by the large dimensions of regenerating body parts. Feedback mechanisms in biochemical pathways can provide effective communication across great distances1-5, but how they might regulate growth during tissue regeneration is unresolved6,7. Here we report that rhythmic travelling waves of Erk activity control the growth of bone in time and space in regenerating zebrafish scales, millimetre-sized discs of protective body armour. We find that waves of Erk activity travel across the osteoblast population as expanding concentric rings that are broadcast from a central source, inducing ring-like patterns of tissue growth. Using a combination of theoretical and experimental analyses, we show that Erk activity propagates as excitable trigger waves that are able to traverse the entire scale in approximately two days and that the frequency of wave generation controls the rate of scale regeneration. Furthermore, the periodic induction of synchronous, tissue-wide activation of Erk in place of travelling waves impairs tissue growth, which indicates that wave-distributed Erk activation is key to regeneration. Our findings reveal trigger waves as a regulatory strategy to coordinate cell behaviour and instruct tissue form during regeneration.

Comparing the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score with transient elastography scores of people with non-alcoholic fatty liver disease.

Background: With the rate of non-alcoholic fatty liver disease (NAFLD) on the rise, the necessity of identifying patients at risk of cirrhosis and its complications is becoming ever more important. Liver biopsy remains the gold standard for assessing fibrosis, although costs, risks, and availability prohibit its widespread use with at-risk patients. Transient elastography has proven to be a non-invasive and accurate way of assessing fibrosis, although the availability of this modality is often limited in primary care settings. The Fibrosis-4 (FIB-4) and Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS) are scoring systems that incorporate commonly measured lab parameters and BMI to predict fibrosis. Method: In this study, we compared FIB-4 and NFS scores with transient elastography scores to assess the accuracy of these inexpensive and readily available scoring systems in detecting fibrosis. Results: Using an NFS score cut-off of -1.455 and a FibroScan score cut-off of ≥8.7 kPa, the NFS score had a negative predictive value of 94.1%. Using a FibroScan score cut-off of ≥8.7 kPa, the FIB-4 score had a negative predictive value of 91.6%. Conclusion: The NFS and FIB-4 are non-invasive, inexpensive scoring systems that have high negative predictive value for fibrosis compared with transient elastography scores. These findings suggest that the NFS and FIB-4 can provide adequate reassurance to rule out fibrosis in patients with NAFLD and can be used with select patients to circumvent the need for transient elastography or liver biopsy.

Broadband All-Optical Plane-Wave Ultrasound Imaging System Based on a Fabry-Perot Scanner.

A broadband all-optical plane-wave ultrasound imaging system for high-resolution 3-D imaging of biological tissues is presented. The system is based on a planar Fabry-Perot (FP) scanner for ultrasound detection and the photoacoustic generation of ultrasound in a carbon-nanotube-polydimethylsiloxane (CNT-PDMS) composite film. The FP sensor head was coated with the CNT-PDMS film which acts as an ultrasound transmitting layer for pulse-echo imaging. Exciting the CNT-PDMS coating with nanosecond laser pulses generated monopolar plane-wave ultrasound pulses with MPa-range peak pressures and a -6-dB bandwidth of 22 MHz, which were transmitted into the target. The resulting scattered acoustic field was detected across a 15 mm ×15 mm scan area with a step size of 100 [Formula: see text] and an optically defined element size of [Formula: see text]. The -3-dB bandwidth of the sensor was 30 MHz. A 3-D image of the scatterer distribution was then recovered using a k -space reconstruction algorithm. To obtain a measure of spatial resolution, the instrument line-spread function (LSF) was measured as a function of position. At the center of the scan area, the depth-dependent lateral LSF ranged from 46 to 65 [Formula: see text] for depths between 1 and 12 mm. The vertical LSF was independent of position and measured to be [Formula: see text] over the entire field of view. To demonstrate the ability of the system to provide high-resolution 3-D images, phantoms with well-defined scattering structures of arbitrary geometry were imaged. To demonstrate its suitability for imaging biological tissues, phantoms with similar impedance mismatches, sound speed and scattering properties to those present in the tissue, and ex vivo tissue samples were imaged. Compared with conventional piezoelectric-based ultrasound scanners, this approach offers the potential for improved image quality and higher resolution for superficial tissue imaging. Since the FP scanner is capable of high-resolution 3-D photoacoustic imaging of in vivo biological tissues, the system could ultimately be developed into an instrument for dual-mode all-optical ultrasound and photoacoustic imaging.

Toward accurate quantitative photoacoustic imaging: learning vascular blood oxygen saturation in three dimensions.

SIGNIFICANCE: Two-dimensional (2-D) fully convolutional neural networks have been shown capable of producing maps of sO2 from 2-D simulated images of simple tissue models. However, their potential to produce accurate estimates in vivo is uncertain as they are limited by the 2-D nature of the training data when the problem is inherently three-dimensional (3-D), and they have not been tested with realistic images. AIM: To demonstrate the capability of deep neural networks to process whole 3-D images and output 3-D maps of vascular sO2 from realistic tissue models/images. APPROACH: Two separate fully convolutional neural networks were trained to produce 3-D maps of vascular blood oxygen saturation and vessel positions from multiwavelength simulated images of tissue models. RESULTS: The mean of the absolute difference between the true mean vessel sO2 and the network output for 40 examples was 4.4% and the standard deviation was 4.5%. CONCLUSIONS: 3-D fully convolutional networks were shown capable of producing accurate sO2 maps using the full extent of spatial information contained within 3-D images generated under conditions mimicking real imaging scenarios. We demonstrate that networks can cope with some of the confounding effects present in real images such as limited-view artifacts and have the potential to produce accurate estimates in vivo.