Hybrid ultrasound and single wavelength optoacoustic imaging reveals muscle degeneration in peripheral artery disease.

Peripheral arterial disease (PAD) leads to chronic vascular occlusion and results in end organ damage in critically perfused limbs. There are currently no clinical methods available to determine the muscular damage induced by chronic mal-perfusion. This monocentric prospective cross-sectional study investigated n = 193 adults, healthy to severe PAD, in order to quantify the degree of calf muscle degeneration caused by PAD using a non-invasive hybrid ultrasound and single wavelength optoacoustic imaging (US/SWL-OAI) approach. While US provides morphologic information, SWL-OAI visualizes the absorption of pulsed laser light and the resulting sound waves from molecules undergoing thermoelastic expansion. US/SWL-OAI was compared to multispectral data, clinical disease severity, angiographic findings, phantom experiments, and histological examinations from calf muscle biopsies. We were able to show that synergistic use of US/SWL-OAI is most likely to map clinical degeneration of the muscle and progressive PAD.

Artificial intelligence for the classification of focal liver lesions in ultrasound - a systematic review.

Focal liver lesions are detected in about 15% of abdominal ultrasound examinations. The diagnosis of frequent benign lesions can be determined reliably based on the characteristic B-mode appearance of cysts, hemangiomas, or typical focal fatty changes. In the case of focal liver lesions which remain unclear on B-mode ultrasound, contrast-enhanced ultrasound (CEUS) increases diagnostic accuracy for the distinction between benign and malignant liver lesions. Artificial intelligence describes applications that try to emulate human intelligence, at least in subfields such as the classification of images. Since ultrasound is considered to be a particularly examiner-dependent technique, the application of artificial intelligence could be an interesting approach for an objective and accurate diagnosis. In this systematic review we analyzed how artificial intelligence can be used to classify the benign or malignant nature and entity of focal liver lesions on the basis of B-mode or CEUS data. In a structured search on Scopus, Web of Science, PubMed, and IEEE, we found 52 studies that met the inclusion criteria. Studies showed good diagnostic performance for both the classification as benign or malignant and the differentiation of individual tumor entities. The results could be improved by inclusion of clinical parameters and were comparable to those of experienced investigators in terms of diagnostic accuracy. However, due to the limited spectrum of lesions included in the studies and a lack of independent validation cohorts, the transfer of the results into clinical practice is limited.

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.

BACKGROUND: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor-ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. METHODS: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. RESULTS: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). CONCLUSIONS: ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.

Hybrid reflected-ultrasound computed tomography versus B-mode-ultrasound for muscle scoring in spinal muscular atrophy.

BACKGROUND AND PURPOSE: Novel light- and sound-based technologies like multispectral optoacoustic tomography (MSOT) with co-registered reflected-ultrasound computed tomography (RUCT) could add additional value to conventional ultrasound (US) for disease phenotyping in pediatric spinal muscular atrophy (SMA). The aim of this study was to investigate the quality of RUCT compared to US for qualitative and quantitative assessment of imaging neuromuscular disorders. METHODS: Subanalyzing the MSOT SMA study, 288 RUCT and 276 US images from 10 SMA patients (mean age 9.0 ± 3.7) and 10 gender- and age-matched healthy volunteers (HV; mean age 8.7 ± 4.3) were analyzed for quantitative (grayscale levels [GSLs]) and qualitative (echogenicity, distribution pattern, Heckmatt scale, and muscle texture) muscle changes. RUCT and US measures were further correlated with clinical standard motor outcomes. RESULTS: Quantitative agreement using GSLs revealed significantly higher GSLs in muscles of SMA patients compared to healthy muscles in both techniques (US mean GSL [SD] SMA vs. HV: 110.70 [27.8] vs. 68.85 [19.2], p < .0001; RUCT mean GSL [SD] SMA vs. HV: 91.81 [21.8] vs. 59.86 [8.2], p < .0001) with good correlation with motor outcome tests, respectively. Qualitative agreement between methods for muscle composition was excellent for differentiation of pathological versus healthy muscles, echogenicity, and distribution pattern, moderate for Heckmatt scale, and poor for muscle texture. CONCLUSIONS: The data suggest that RUCT may allow the assessment of basic qualitative and quantitative measures for muscular diseases with comparable results to conventional US.

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography.

OBJECTIVE: To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. METHODS: We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. RESULTS: We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. CONCLUSION: MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.

Multispectral optoacoustic tomography for the non-invasive identification of patients with severe anemia in vivo.

The immediate diagnosis of severe anemia is crucial for patient outcome. However, reliable non-invasive point-of-care diagnostic tools for e.g., ICU monitoring are currently lacking. Using an advanced Multispectral Optoacoustic Tomography (MSOT) research device, we first substantiated a strong positive correlation of MSOT-signal and absolute hemoglobin concentration ex vivo in blood samples. In a clinical exploratory proof-of-concept study, we then evaluated 19 patients with different severities of anemia and controls by non-invasive in vivo measurement of hemoglobin in the radial artery. Our approach proved excellent in identifying patients with severe anemia triggering RBC transfusion based on a strong positive correlation of MSOT-signal intensity and hemoglobin concentration for 700 nm single wavelength and HbR unmixed MSOT-parameter analysis. In conclusion, our study lays the foundation to further develop MSOT-based real-time quantitative perfusion analyses in follow-up preclinical and clinical imaging studies and as a promising diagnostic tool to improve patient care in the future. DRKS00021442.

Neutralizing monoclonal antibodies against SARS-CoV-2 for COVID-19 pneumonia in a rituximab treated patient with systemic sclerosis-A case report and literature review.

Patients with immune-mediated diseases (IMID) such as systemic sclerosis (SSc), who are treated with B cell depleting treatments, are at risk for developing severe COVID-19 due to inadequate humoral immune response. During B cell depletion, therapeutic substitution of neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein (mAbs) might be helpful to prevent severe COVID-19. It has been shown, that in non-IMID patients mABs reduce SARS-CoV-2 viral load and lower the risk of COVID-19 associated hospitalization or death. However, there are limited data on the effect of mAbs in IMID patients after exposure, especially in patients treated with B cell depleting agents. Herein, we report a case of a rituximab treated SSc patient who developed COVID-19 and was successfully treated with a combination of mAbs (casirivimab/imdevimab). With this case we show that IMID patients may benefit from post-exposure administration of mAbs. In our case treatment with neutralizing autoantibodies was safe and a possible contributor in protecting the patient from mechanical ventilation and eventually death. We frame this case within the current evidence from the literature and provide a perspective on the future potential role of mAbs for treating IMID patients suffering from COVID-19.

Free-Breathing Low-Field MRI of the Lungs Detects Functional Alterations Associated With Persistent Symptoms After COVID-19 Infection.

OBJECTIVES: With the COVID-19 pandemic, repetitive lung examinations have become necessary to follow-up symptoms and associated alterations. Low-field MRI, benefiting from reduced susceptibility effects, is a promising alternative for lung imaging to limit radiations absorbed by patients during CT examinations, which also have limited capability to assess functional alterations. The aim of this investigative study was to explore the functional abnormalities that free-breathing 0.55 T MRI in combination with the phase-resolved functional lung (PREFUL) analysis could identify in patients with persistent symptoms after COVID-19 infection. MATERIALS AND METHODS: Seventy-four COVID-19 patients and 8 healthy volunteers were prospectively scanned in free-breathing with a balanced steady-state free-precession sequence optimized at 0.55 T, 5 months postinfection on average. Normalized perfusion (Q), fractional ventilation (FV), and flow-volume loop correlation (FVLc) maps were extracted with the PREFUL technique. Q, FV, and FVLc defects as well as defect overlaps between these metrics were quantified. Morphological turbo-spin-echo images were also acquired, and the extent of abnormalities was scored by a board-certified radiologist. To investigate the functional correlates of persistent symptoms, a recursive feature elimination algorithm was applied to find the most informative variables to detect the presence of persistent symptoms with a logistic regression model and a cross-validation strategy. All MRI metrics, sex, age, body mass index, and the presence of preexisting lung conditions were included. RESULTS: The most informative variables to detect persistent symptoms were the percentage of concurrent Q and FVLc defects and of areas free of those defects. A detection accuracy of 71.4% was obtained with these 2 variables when fitting the model on the entire dataset. Although none of the single variables differed between patients with and without persistent symptoms ( P > 0.05), the combined score of these 2 variables did ( P < 0.02). This score also showed a consistent increase from healthy volunteers (7.7) to patients without persistent symptoms (8.2) and with persistent symptoms (8.6). The morphological abnormality score showed poor correlation with the functional parameters. CONCLUSIONS: Functional pulmonary examinations using free-breathing 0.55 T MRI with PREFUL analysis revealed potential quantitative markers of impaired lung function in patients with persistent symptoms after COVID-19 infection, potentially complementing morphologic imaging. Future work is needed to explore the translational relevance and clinical implication of these findings.

Shear Wave Dispersion Imaging for the Characterization of Focal Liver Lesions - A Pilot study.

PURPOSE: Shear wave dispersion imaging is a novel ultrasound-based technique, which analyzes the speed of different shear wave components depending on their frequency. The dispersion of shear wave speed correlates with the viscosity of the liver parenchyma. The aim of this prospective study was to evaluate the use of shear wave dispersion imaging in focal liver lesions in the non-cirrhotic liver. METHODS: Patients with unclear focal liver lesions in B-mode ultrasound were prospectively assigned to shear wave dispersion imaging (m/s/kHz). Measurements were conducted within the lesion and in the liver parenchyma of the right liver lobe using an intercostal window. Histology and contrast-enhanced ultrasound served as the reference for the characterization of the lesions. RESULTS: Out of 46 patients included in this study, 24 had liver metastases and 22 had benign liver lesions. Benign lesions consisted mostly of hemangiomas (n=12) and focal nodular hyperplasia (n=8). Malignant lesions showed significantly lower shear wave dispersion (13.0±2.45 m/s/kHz) compared to benign tumors (15.2±2.74 m/s/kHz, p<0.01). In further subgroup analysis, the difference was significant for hemangiomas (15.32±2.42 m/s/kHz, p=0.04) but not for FNHs (14.98±3.36 m/s/kHz, p=0.38). The dispersion of reference liver parenchyma did not differ significantly between the groups (p=0.54). CONCLUSION: The quantification of viscosity by shear wave dispersion is a new parameter for the characterization of focal liver lesions with higher dispersion values in hemangiomas and lower dispersion values in metastases. However, it cannot differentiate reliably between benign and malignant lesions.

Multispectral optoacoustic tomography for non-invasive disease phenotyping in pediatric spinal muscular atrophy patients.

Proximal spinal muscular atrophy (SMA) is a rare progressive, life limiting genetic motor neuron disease. While promising causal therapies are available, meaningful prognostic biomarkers for therapeutic monitoring are missing. We demonstrate handheld Multispectral Optoacoustic Tomography (MSOT) as a novel non-invasive imaging approach to visualize and quantify muscle wasting in pediatric SMA. While MSOT signals were distributed homogeneously in muscles of healthy volunteers (HVs), SMA patients showed moth-eaten optoacoustic signal patterns. Further signal quantification revealed greatest differences between groups at the isosbestic point for hemoglobin (SWL 800 nm). The SWL 800 nm signal intensities further correlated with clinical phenotype tested by standard motor outcome measures. Therefore, handheld MSOT could enable non-invasive assessment of disease burden in SMA patients.

Precision of handheld multispectral optoacoustic tomography for muscle imaging.

Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm-1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82-0.92; MSOT-parameter: 0.72-0.92) and interrater reproducibility (SWL: 0.79-0.87; MSOT-parameter: 0.78-0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.

Ultrasound-Based Attenuation Imaging for the Non-Invasive Quantification of Liver Fat - A Pilot Study on Feasibility and Inter-Observer Variability.

Attenuation imaging is a novel, ultrasound-based technique to objectively detect and quantify liver steatosis. In this study, we evaluated the performance and inter-observer variability of attenuation imaging and compared it to a known quantification method of liver fat, the hepatorenal index (HRI). Two observers measured attenuation coefficients (AC) in an attenuation phantom, 20 healthy volunteers and 27 patients scheduled for biopsy for suspected diffuse liver disease. Results were compared with the HRI and histological findings. Both observers were blinded to the results of the biopsy and the measurements of the other observer. Our results showed that patients with moderate (S2, 33-66%) and severe fatty infiltration of the liver (S3, >66%) showed significantly higher ACs in comparison to patients with a liver fat fraction of less than 33% (S0/1). There was no significant difference in AC-values of patients with fatty infiltration of less than 5% (S0) and 5-32% (S1). In the Receiver Operating Characteristic (ROC)-analysis, the area under the curve (AUC)-values for the detection of moderate and severe steatosis were excellent at 0.98. Cut-off values were 0.64 dB/cm/MHz for the detection of S2- and 0.68 dB/cm/MHz for the detection of S3-steatosis. The inter-observer agreement of attenuation imaging was very good with an intraclass correlation coefficient (ICC) of 0.92 in patient and 0.96 in phantom measurements. The ICC decreased with depth in the phantom measurements. In summary, attenuation imaging showed very good inter-observer agreement and is a promising tool for the detection and quantification of moderate and severe hepatic steatosis.

Quantitative contrast-enhanced ultrasound for monitoring vedolizumab therapy in inflammatory bowel disease patients: a pilot study.

Background Microvascularization of the bowel wall can be visualized and quantified non-invasively by software-assisted analysis of derived time-intensity curves. Purpose To perform software-based quantification of bowel wall perfusion using quantitative contrast-enhanced ultrasound (CEUS) according to clinical response in patients with inflammatory bowel disease treated with vedolizumab. Material and Methods In a prospective study, in 18 out of 34 patients, high-frequency ultrasound of bowel wall thickness using color Doppler flow combined with CEUS was performed at baseline and after 14 weeks of treatment with vedolizumab. Clinical activity scores at week 14 were used to differentiate between responders and non-responders. CEUS parameters were calculated by software analysis of the video loops. Results Nine of 18 patients (11 with Crohn's disease and seven with ulcerative colitis) showed response to treatment with vedolizumab. Overall, the responder group showed a significant decrease in the semi-quantitative color Doppler vascularization score. Amplitude-derived CEUS parameters of mural microvascularization such as peak enhancement or wash-in rate decreased in responders, in contrast with non-responders. Time-derived parameters remained stable or increased during treatment in all patients. Conclusion Analysis of bowel microvascularization by CEUS shows statistically significant changes in the wash-in-rate related to response of vedolizumab therapy.