Stroke Evaluation in the Interventional Suite Using Dual-Layer Detector Cone-Beam CT: a First-in-human Prospective Cohort Study (the Next Generation X-ray Imaging System Trial).

PURPOSE: Cone-beam CT in the interventional suite could be an alternative to CT to shorten door-to-thrombectomy time. However, image quality in cone-beam CT is limited by artifacts and poor differentiation between gray and white matter. This study compared non-contrast brain dual-layer cone-beam CT in the interventional suite to reference standard CT in stroke patients. METHODS: A prospective single-center study enrolled consecutive participants with ischemic or hemorrhagic stroke. The hemorrhage detection accuracy, per-region ASPECTS accuracy and subjective image quality (Likert scales for gray-white matter differentiation, structure perception and artifacts) were assessed by three neuroradiologists blinded to clinical data on dual-layer cone-beam CT 75 keV monoenergetic images compared to CT. Objective image quality was assessed by region-of-interest metrics. Non-inferiority for hemorrhage detection and ASPECTS accuracy was determined by the exact binomial test with a one-sided lower performance boundary prospectively set to 80% (98.75% CI). RESULTS: 27 participants were included (74 years ± 9; 19 female) in the hyperacute or acute stroke phase. One reader missed a small bleeding, but all hemorrhages were detected in the majority analysis (100% accuracy, CI lower boundary 86%, p = 0.002). ASPECTS majority analysis showed 90% accuracy (CI lower boundary 85%, p < 0.001). Sensitivity was 66% (individual readers 67%, 69%, and 76%), specificity was 97% (97%, 96%, 89%). Subjective and objective image quality were inferior to CT. CONCLUSION: In a small single-center cohort, dual-layer cone-beam CT showed non-inferior hemorrhage detection and ASPECTS accuracy to CT. Despite inferior image quality, the technique may be useful for stroke evaluation in the interventional suite. TRIAL REGISTRATION NUMBER: NCT04571099 (clinicaltrials.gov). Prospectively registered 2020-09-04.

The butterfly effect: improving brain cone-beam CT image artifacts for stroke assessment using a novel dual-axis trajectory.

BACKGROUND: Cone-beam computed tomography (CBCT) imaging of the brain can be performed in the angiography suite to support various neurovascular procedures. Relying on CBCT brain imaging solely, however, still lacks full diagnostic confidence due to the inferior image quality compared with CT and various imaging artifacts that persist even with modern CBCT. OBJECTIVE: To perform a detailed evaluation of image artifact improvement using a new CBCT protocol which implements a novel dual-axis 'butterfly' trajectory. METHODS: Our study included 94 scans from 47 patients who received CBCT imaging for assessment of either ischemia or hemorrhage during a neurovascular procedure. Both a traditional uni-axis 'circular' and novel dual-axis 'butterfly' protocol were performed on each patient (same-patient control). Each brain scan was divided into six regions and scored out of 3 based on six artifacts originating from various physics-based and patient-based sources. RESULTS: The dual-axis trajectory produces CBCT images with significantly fewer image artifacts than the traditional circular scan (whole brain average artifact score, AS: 0.20 vs 0.33), with the greatest improvement in bone beam hardening (AS: 0.13 vs 0.78) and cone-beam artifacts (AS: 0.04 vs 0.55). CONCLUSIONS: Recent developments in CBCT imaging protocols have significantly improved image artifacts, which has improved diagnostic confidence for stroke and supports a direct-to-angiography suite transfer approach for patients with acute ischemic stroke.

Motion artifact correction for cone beam CT stroke imaging: a prospective series.

BACKGROUND: Imaging assessment for acute ischemic stroke (AIS) patients in the angiosuite using cone beam CT (CBCT) has created increased interest since endovascular treatment became the first line therapy for proximal vessel occlusions. One of the main challenges of CBCT imaging in AIS patients is degraded image quality due to motion artifacts. This study aims to evaluate the prevalence of motion artifacts in CBCT stroke imaging and the effectiveness of a novel motion artifact correction algorithm for image quality improvement. METHODS: Patients presenting with acute stroke symptoms and considered for endovascular treatment were included in the study. CBCT scans were performed using the angiosuite X-ray system. All CBCT scans were post-processed using a motion artifact correction algorithm. Motion artifacts were scored before and after processing using a 4-point scale. RESULTS: We prospectively included 310 CBCT scans from acute stroke patients. 51% (n=159/310) of scans had motion artifacts, with 24% being moderate to severe. The post-processing algorithm improved motion artifacts in 91% of scans with motion (n=144/159), restoring clinical diagnostic capability in 34%. Overall, 76% of the scans were sufficient for clinical decision-making before correction, which improved to 93% (n=289/310) after post-processing with our algorithm. CONCLUSIONS: Our results demonstrate that CBCT motion artifacts are significantly reduced using a novel post-processing algorithm, which improved brain CBCT image quality and diagnostic assessment for stroke. This is an important step on the road towards a direct-to-angio approach for endovascular thrombectomy (EVT) treatment.

Performance characterization of a prototype dual-layer cone-beam computed tomography system.

PURPOSE: Conventional cone-beam computed tomography CT (CBCT) provides limited discrimination between low-contrast tissues. Furthermore, it is limited to full-spectrum energy integration. A dual-energy CBCT system could be used to separate photon energy spectra with the potential to increase the visibility of clinically relevant features and acquire additional information relevant in a multitude of clinical imaging applications. In this work, the performance of a novel dual-layer dual-energy CBCT (DL-DE-CBCT) C-arm system is characterized for the first time. METHODS: A prototype dual-layer detector was fitted into a commercial interventional C-arm CBCT system to enable DL-DE-CBCT acquisitions. DL-DE reconstructions were derived from material-decomposed Compton scatter and photoelectric base functions. The modulation transfer function (MTF) of the prototype DL-DE-CBCT was compared to that of a commercial CBCT. Noise and uniformity characteristics were evaluated using a cylindrical water phantom. Effective atomic numbers and electron densities were estimated in clinically relevant tissue substitutes. Iodine quantification was performed (for 0.5-15 mg/ml concentrations) and virtual noncontrast (VNC) images were evaluated. Finally, contrast-to-noise ratios (CNR) and CT number accuracies were estimated. RESULTS: The prototype and commercial CBCT showed similar spatial resolution, with a mean 10% MTF of 5.98 cycles/cm and 6.28 cycles/cm, respectively, using a commercial standard reconstruction. The lowest noise was seen in the 80 keV virtual monoenergetic images (VMI) (7.40 HU) and the most uniform images were seen at VMI 60 keV (4.74 HU) or VMI 80 keV (1.98 HU), depending on the uniformity measure used. For all the tissue substitutes measured, the mean accuracy in effective atomic number was 98.2% (SD 1.2%) and the mean accuracy in electron density was 100.3% (SD 0.9%). Iodine quantification images showed a mean difference of -0.1 (SD 0.5) mg/ml compared to the true iodine concentration for all blood and iodine-containing objects. For VNC images, all blood substitutes containing iodine averaged a CT number of 43.2 HU, whereas a blood-only substitute measured 44.8 HU. All water-containing iodine substitutes measured a mean CT number of 2.6 in the VNC images. A noise-suppressed dataset showed a CNR peak at VMI 40 keV and low at VMI 120 keV. In the same dataset without noise suppression applied, a peak in CNR was obtained at VMI 70 keV and a low at VMI 120 keV. The estimated CT numbers of various clinically relevant objects were generally very close to the calculated CT number. CONCLUSIONS: The performance of a prototype dual-layer dual-energy C-arm CBCT system was characterized. Spatial resolution and noise were comparable with a commercially available C-arm CBCT system, while offering dual-energy capability. Iodine quantifications, effective atomic numbers, and electron densities were in good agreement with expected values, indicating that the system can be used to reliably evaluate the material composition of clinically relevant tissues. The VNC and monoenergetic images indicate a consistent ability to separate clinically relevant tissues. The results presented indicate that the system could find utility in diagnostic, interventional, and radiotherapy planning settings.

Novel flat-panel cone-beam CT compared to multi-detector CT for assessment of acute ischemic stroke: A prospective study.

PURPOSE: Cone beam CT (CBCT) imaging assessment of acute ischemic stroke (AIS) patients with large-vessel occlusion (LVO) in the angiosuite may improve stroke workflow and decrease time to recanalization. In order for this workflow to gain widespread acceptance, current CBCT imaging needs further development to improve image quality. Our study aimed to compare the image quality of a new CBCT protocol performed directly in the angiosuite with imaging from multidetector CT as a gold standard. METHODS: AIS patients with an LVO who were candidates for endovascular treatment were prospectively included in this study. Following conventional multidetector CT (MDCT), patients underwent unenhanced cone beam CT (XperCT, Philips) imaging in the angiosuite, using two different protocols: a standard 20.8 s XperCT and/or an improved 10.4 s XperCT protocol. Images were evaluated using both qualitative and quantitative methods. RESULTS: We included 65 patients in the study. Patients received CBCT imaging prior to endovascular treatment; 18 patients were assessed with a standard 20.8 s protocol scans and 47 with a newer 10.4 s scan. The quantitative analysis showed that the mean contrast-to-noise ratio (CNR) was significantly higher for the newer 10.4 s protocol compared with the 20.8 s protocol (2.08 +/- 0.64 vs. 1.15 +/- 0.27, p < 0.004) and the mean image noise was significantly lower for the 10.4 s XperCTs when compared with the 20.8 s XperCTs (6.30 +/- 1.34 vs. 7.82 +/- 2.03, p=<0.003). Qualitative analysis, including 6 measures of image quality, demonstrated that 74.1 % of the 10.4 s XperCT scans were ranked as 'Acceptable' for assessing parenchymal imaging in AIS patients(scoring 3-5 points on a 5-point Likert-scale), compared with 32.4 % of the standard 20.8 s XperCT and 100 % of the MDCT scans. Compared to the MDCT studies, 83 % of the 10.4 s XperCT scans were deemed sufficient image quality for a direct-to-angiosuite selection, compared to only 11 % for the standard 20.8 s scans. The largest image quality improvements included grey/white matter differentiation (59 % improvement), and reduction of image noise and artefacts (63 % & 50 % improvement, respectively). CONCLUSIONS: Continued advances in cone-beam CT allow marked improvements in image quality for the assessment of brain parenchyma, which supports a direct-to-angiosuite approach for AIS patients eligible for thrombectomy treatment.

The role of phagocytic cells in enhanced susceptibility of broilers to colibacillosis after Infectious Bronchitis Virus infection.

Colibacillosis results from infection with avian pathogenic Escherichia coli bacteria. Healthy broilers are resistant to inhaled E. coli, but previous infection with vaccine or virulent strains of Infectious Bronchitis Virus (IBV) predisposes birds for severe colibacillosis. We investigated whether IBV affects recruitment and function of phagocytic cells and examined NO production, phagocytic and bactericidal activity, and kinetics of peripheral blood mononuclear cells (PBMC) and splenocytes. Moreover, we measured cytokine mRNA expression in lung and spleen samples. Broilers were inoculated with IBV H120 vaccine or virulent M41 and challenged 5 days later with E. coli 506. A PBS control and E. coli group without previous virus inoculation were also included. Birds were sacrificed at various time points after inoculation (h/dpi). Inoculation with IBV induced extended and more severe colibacillosis than with E. coli alone. At 4dpi, the number of KUL-01(+) PBMC in all E. coli-inoculated groups was significantly higher than in PBS-inoculated birds, which correlated with lesion scores. From 1 to 4dpi, NO production by PBMC from all E. coli-inoculated animals was elevated compared to PBS birds. Bactericidal activity of PBMC in IBV-inoculated animals at 7dpi was lower than in PBS- and E. coli-inoculated birds, but phagocytic capacity and recruitment were not severely impaired. In spleen samples of IBV-infected animals reduced expression of IL-1beta, IL-6, IL-8, IL-10, IL-18 and IFN-gamma mRNA was found 1dpi. Our results suggest that enhanced colibacillosis after IBV infection or vaccination is caused at least by altered innate immunity and less by impairment of phagocytic cell function.

Differential lung NK cell responses in avian influenza virus infected chickens correlate with pathogenicity.

Infection of chickens with low pathogenicity avian influenza (LPAI) virus results in mild clinical signs while infection with highly pathogenic avian influenza (HPAI) viruses causes death of the birds within 36-48 hours. Since natural killer (NK) cells have been shown to play an important role in influenza-specific immunity, we hypothesise that NK cells are involved in this difference in pathogenicity. To investigate this, the role of chicken NK-cells in LPAI virus infection was studied. Next activation of lung NK cells upon HPAI virus infection was analysed. Infection with a H9N2 LPAI virus resulted in the presence of viral RNA in the lungs which coincided with enhanced activation of lung NK cells. The presence of H5N1 viruses, measured by detection of viral RNA, did not induce activation of lung NK cells. This suggests that decreased NK-cell activation may be one of the mechanisms associated with the enhanced pathogenicity of H5N1 viruses.

FBP and BPF reconstruction methods for circular X-ray tomography with off-center detector.

PURPOSE: Circular scanning with an off-center planar detector is an acquisition scheme that allows to save detector area while keeping a large field of view (FOV). Several filtered back-projection (FBP) algorithms have been proposed earlier. The purpose of this work is to present two newly developed back-projection filtration (BPF) variants and evaluate the image quality of these methods compared to the existing state-of-the-art FBP methods. METHODS: The first new BPF algorithm applies redundancy weighting of overlapping opposite projections before differentiation in a single projection. The second one uses the Katsevich-type differentiation involving two neighboring projections followed by redundancy weighting and back-projection. An averaging scheme is presented to mitigate streak artifacts inherent to circular BPF algorithms along the Hilbert filter lines in the off-center transaxial slices of the reconstructions. The image quality is assessed visually on reconstructed slices of simulated and clinical data. Quantitative evaluation studies are performed with the Forbild head phantom by calculating root-mean-squared-deviations (RMSDs) to the voxelized phantom for different detector overlap settings and by investigating the noise resolution trade-off with a wire phantom in the full detector and off-center scenario. RESULTS: The noise-resolution behavior of all off-center reconstruction methods corresponds to their full detector performance with the best resolution for the FDK based methods with the given imaging geometry. With respect to RMSD and visual inspection, the proposed BPF with Katsevich-type differentiation outperforms all other methods for the smallest chosen detector overlap of about 15 mm. The best FBP method is the algorithm that is also based on the Katsevich-type differentiation and subsequent redundancy weighting. For wider overlap of about 40-50 mm, these two algorithms produce similar results outperforming the other three methods. The clinical case with a detector overlap of about 17 mm confirms these results. CONCLUSIONS: The BPF-type reconstructions with Katsevich differentiation are widely independent of the size of the detector overlap and give the best results with respect to RMSD and visual inspection for minimal detector overlap. The increased homogeneity will improve correct assessment of lesions in the entire field of view.

Validation of 3D multimodality roadmapping in interventional neuroradiology.

Three-dimensional multimodality roadmapping is entering clinical routine utilization for neuro-vascular treatment. Its purpose is to navigate intra-arterial and intra-venous endovascular devices through complex vascular anatomy by fusing pre-operative computed tomography (CT) or magnetic resonance (MR) with the live fluoroscopy image. The fused image presents the real-time position of the intra-vascular devices together with the patient's 3D vascular morphology and its soft-tissue context. This paper investigates the effectiveness, accuracy, robustness and computation times of the described methods in order to assess their suitability for the intended clinical purpose: accurate interventional navigation. The mutual information-based 3D-3D registration proved to be of sub-voxel accuracy and yielded an average registration error of 0.515 mm and the live machine-based 2D-3D registration delivered an average error of less than 0.2 mm. The capture range of the image-based 3D-3D registration was investigated to characterize its robustness, and yielded an extent of 35 mm and 25° for >80% of the datasets for registration of 3D rotational angiography (3DRA) with CT, and 15 mm and 20° for >80% of the datasets for registration of 3DRA with MR data. The image-based 3D-3D registration could be computed within 8 s, while applying the machine-based 2D-3D registration only took 1.5 µs, which makes them very suitable for interventional use.

Early host responses to avian influenza A virus are prolonged and enhanced at transcriptional level depending on maturation of the immune system.

Newly hatched chickens are more susceptible to infectious diseases than older birds because of an immature immune system. The aim of this study was to determine to what extent host responses to avian influenza virus (AIV) inoculation are affected by age. Therefore, 1- and 4-week (wk) old birds were inoculated with H9N2 AIV or saline. The trachea and lung were sampled at 0, 8, 16 and 24h post-inoculation (h.p.i.) and gene expression profiles determined using microarray analysis. Firstly, saline controls of both groups were compared to analyse the changes in gene profiles related to development. In 1-wk-old birds, higher expression of genes related to development of the respiratory immune system and innate responses were found, whereas in 4-wk-old birds genes were up regulated that relate to the presence of higher numbers of leukocytes in the respiratory tract. After inoculation with H9N2, gene expression was most affected at 16 h.p.i. in 1-wk-old birds and at 16 and 24h.p.i. in 4-wk-old birds in the trachea and especially in the lung. In 1-wk-old birds less immune related genes including innate related genes were induced which might be due to age-dependent reduced functionality of antigen presenting cells (APC), T cells and NK cells. In contrast cytokine and chemokines gene expression was related to viral load in 1-wk-old birds and less in 4-wk-old birds. Expression of cellular host factors that block virus replication by interacting with viral factors was independent of age or tissue for most host factors. These data show that differences in development are reflected in gene expression and suggest that the strength of host responses at transcriptional level may be a key factor in age-dependent susceptibility to infection, and the cellular host factors involved in virus replication are not.

Reduced immune reaction prevents immunopathology after challenge with avian influenza virus: a transcriptomics analysis of adjuvanted vaccines.

To gain more insight in underlying mechanisms correlating to protection against avian influenza virus (AIV) infection, we investigated correlates of protection after AIV H9N2 infection and studied the contribution of different adjuvants to a protective response at host transcriptional level. One-day-old chickens were immunised with inactivated H9N2 supplemented with w/o, Al(OH)(3), CpG or without adjuvant. Two weeks later, birds were homologously challenged and at 1-4 days post challenge (d.p.c.) trachea and lung were collected. Birds immunised with H9N2+w/o or H9N2+Al(OH)(3) were protected against challenge infection and had lower viral RNA expression, less immune related genes induced after challenge, a lower amplitude of change of gene expression and smaller cellular influxes compared to the higher and prolonged gene expression in unprotected birds. We show that a limited number of differentially expressed genes correlates with reduced immune activation and subsequently reduced immunopathology after challenge with AIV.

Identification of new populations of chicken natural killer (NK) cells.

Natural killer (NK) cell activity is conserved throughout vertebrate development, but characterization of non-mammalian NK-cells has been hampered by the absence of specific mAbs for these cells. Monoclonal antibodies were generated against in vitro IL-2 expanded sorted CD3-CD8alpha+ peripheral blood lymphocytes, previously described to contain chicken NK-cells. Screening of embryonic and adult splenocytes with hybridoma supernatants resulted in five candidate NK markers. Activation of chicken NK-cells with PMA/Ionomycin or with the NK target cell-line LSCC-RP9 resulted in increased expression of CD107 (LAMP-1) and a newly developed flow cytometry based cytotoxicity assay showed that NK-cells were able to kill target cells. Combining NK markers with functional assays indicated that marker positive cells showed NK-cell function. In conclusion, we generated new monoclonal antibodies and developed two functional assays which will enhance our understanding of the role of NK-cells in healthy and diseased chickens.

Infectious Bronchitis Virus induces acute interferon-gamma production through polyclonal stimulation of chicken leukocytes.

Infectious Bronchitis Virus, a member of the Coronaviridae, is a respiratory pathogen in poultry. We found that in vitro stimulation with IBV resulted in ChIFN-gamma production in splenocytes of both infected birds and uninfected birds. The non-specific stimulation did not occur when other avian viruses or other coronaviruses were used or when mammalian cells were stimulated with IBV. Inactivation of IBV reduced ChIFN-gamma production, but ChIFN-gamma remained elevated compared to unstimulated cells. An increase in ChIFN-gamma mRNA was detected in splenocytes from IBV-infected and uninfected chickens as early as 1 h after stimulation with IBV. These results indicate that IBV acts as a polyclonal stimulus, inducing a rapid production of IFN-gamma even without previous exposure to the virus.