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To evaluate the prognostic value of fully automatic lung quantification based on spectral computed tomography (CT) and laboratory parameters for combined outcome prediction in COVID-19 pneumonia. CT images of 53 hospitalized COVID-19 patients including virtual monochromatic reconstructions at 40-140keV were analyzed using a fully automated software system. Quantitative CT (QCT) parameters including mean and percentiles of lung density, fibrosis index (FIBI.sub.-700, defined as the percentage of segmented lung voxels [greater than or equal to]-700 HU), quantification of ground-glass opacities and well-aerated lung areas were analyzed. QCT parameters were correlated to laboratory and patient outcome parameters (hospitalization, days on intensive care unit, invasive and non-invasive ventilation). Best correlations were found for laboratory parameters LDH (r = 0.54), CRP (r = 0.49), Procalcitonin (r = 0.37) and partial pressure of oxygen (r = 0.35) with the QCT parameter 75.sup.th percentile of lung density. LDH, Procalcitonin, 75.sup.th percentile of lung density and FIBI-.sub.700 were the strongest independent predictors of patients' outcome in terms of days of invasive ventilation. The combination of LDH and Procalcitonin with either 75.sup.th percentile of lung density or FIBI.sub.-700 achieved a r.sup.2 of 0.84 and 1.0 as well as an area under the receiver operating characteristic curve (AUC) of 0.99 and 1.0 for the prediction of the need of invasive ventilation. QCT parameters in combination with laboratory parameters could deliver a feasible prognostic tool for the prediction of invasive ventilation in patients with COVID-19 pneumonia.

Surgical or bronchoscopic lung volume reduction (BLVR) techniques can be beneficial for heterogeneous emphysema. Post-processing software tools for lobar emphysema quantification are useful for patient and target lobe selection, treatment planning and post-interventional follow-up. We aimed to evaluate the inter-software variability of emphysema quantification using fully automated lobar segmentation prototypes. 66 patients with moderate to severe COPD who underwent CT for planning of BLVR were included. Emphysema quantification was performed using 2 modified versions of in-house software (without and with prototype advanced lung vessel segmentation; programs 1 [YACTA v.2.3.0.2] and 2 [YACTA v.2.4.3.1]), as well as 1 commercial program 3 [Pulmo3D VA30A_HF2] and 1 pre-commercial prototype 4 [CT COPD ISP ver7.0]). The following parameters were computed for each segmented anatomical lung lobe and the whole lung: lobar volume (LV), mean lobar density (MLD), 15th percentile of lobar density (15th), emphysema volume (EV) and emphysema index (EI). Bland-Altman analysis (limits of agreement, LoA) and linear random effects models were used for comparison between the software. Segmentation using programs 1, 3 and 4 was unsuccessful in 1 (1%), 7 (10%) and 5 (7%) patients, respectively. Program 2 could analyze all datasets. The 53 patients with successful segmentation by all 4 programs were included for further analysis. For LV, program 1 and 4 showed the largest mean difference of 72 ml and the widest LoA of [-356, 499 ml] (p<0.05). Program 3 and 4 showed the largest mean difference of 4% and the widest LoA of [-7, 14%] for EI (p<0.001). Only a single software program was able to successfully analyze all scheduled data-sets. Although mean bias of LV and EV were relatively low in lobar quantification, ranges of disagreement were substantial in both of them. For longitudinal emphysema monitoring, not only scanning protocol but also quantification software needs to be kept constant.

Monitoring of regional lung function in interventional COPD trials requires alternative endpoints beyond global parameters such as FEV1. T1 relaxation times of the lung might allow to draw conclusions on tissue composition, blood volume and oxygen fraction. The aim of this study was to evaluate the potential value of lung Magnetic resonance imaging (MRI) with native and oxygen-enhanced T1 mapping for the assessment of COPD patients in comparison with contrast enhanced perfusion MRI. 20 COPD patients (GOLD I-IV) underwent a coronal 2-dimensional inversion recovery snapshot flash sequence (8 slices/lung) at room air and during inhalation of pure oxygen, as well as dynamic contrast-enhanced first-pass perfusion imaging. Regional distribution of T1 at room air (T1), oxygen-induced T1 shortening (ΔT1) and peak enhancement were rated by 2 chest radiologists in consensus using a semi-quantitative 3-point scale in a zone-based approach. Abnormal T1 and ΔT1 were highly prevalent in the patient cohort. T1 and ΔT1 correlated positively with perfusion abnormalities (r = 0.81 and r = 0.80; p&0.001), and with each other (r = 0.80; p<0.001). In GOLD stages I and II ΔT1 was normal in 16/29 lung zones with mildly abnormal perfusion (15/16 with abnormal T1). The extent of T1 (r = 0.45; p<0.05), ΔT1 (r = 0.52; p<0.05) and perfusion abnormalities (r = 0.52; p<0.05) showed a moderate correlation with GOLD stage. Native and oxygen-enhanced T1 mapping correlated with lung perfusion deficits and severity of COPD. Under the assumption that T1 at room air correlates with the regional pulmonary blood pool and that oxygen-enhanced T1 reflects lung ventilation, both techniques in combination are principally suitable to characterize ventilation-perfusion imbalance. This appears valuable for the assessment of regional lung characteristics in COPD trials without administration of i.v. contrast.

Mucus plugging is a hallmark of muco-obstructive lung diseases; however, the spatiotemporal dynamics of plug formation remain poorly understood. We used a multimodal high-resolution imaging approach to study mucus plugging in newborn (0–1 days), juvenile (13–16 days), and adult (49–59 days) βENaC-transgenic mice (βENaC-tg, n  = 24), a model of muco-obstructive lung disease, in comparison to age-matched wild-type mice ( n  = 28). Micro-computed tomography (µCT) enabled whole lung mucus scoring on a scale from 0 (no obstruction) to 2 (> 50% obstruction) using an extended murine airway tree nomenclature. A subset of βENaC-tg lungs (5 juvenile, 5 adult) underwent localised synchrotron radiation-based computed tomography (SRCT) for segmentation-based calculation of mucus area and contact ratios as indicators of luminal obstruction and airway wall adherence. µCT-guided scanning electron microscopy (SEM) provided nanoscale visualisation of mucus plugs on selected βENaC-tg lung samples (3 juvenile). µCT revealed age-dependent, heterogeneous mucus plug formation, with significantly increased mucus scores in juvenile (0.45 ± 0.26) and adult (0.30 ± 0.17) βENaC-tg compared to wild-type mice (0.01 ± 0.02 with P <  0.01, and 0.01 ± 0.02 with P  < 0.05, respectively). SRCT analysis showed a strong positive correlation between mucus area and contact ratios ( r  ≥ 0.80), while SEM revealed the mucus plug ultrastructure. This multimodal imaging approach highlights the spatiotemporal heterogeneity of mucus plugging, forming a basis for future research on targeted therapeutic strategies for muco-obstructive lung diseases.

In children with pneumonia, chest x-ray (CXR) is typically the first imaging modality used for diagnostic work-up. Repeated CXR or computed tomography (CT) are often necessary if complications such as abscesses or empyema arise, thus increasing radiation exposure. The aim of this retrospective study was to evaluate the potential of radiation-free chest magnetic resonance imaging (MRI) to detect complications at baseline and follow-up, compared to CXR with and without additional lung ultrasound (LUS). Paired MRI and CXR scans were retrospectively reviewed by two blinded readers for presence and severity of pulmonary abscess, consolidation, bronchial wall thickening, mucus plugging and pleural effusion/empyema using a chest MRI scoring system. The scores for MRI and CXR were compared at baseline and follow-up. Furthermore, the MRI scores at baseline with and without contrast media were evaluated. 33 pediatric patients (6.3±4.6 years), who had 33 paired MRI and CXR scans at baseline and 12 at follow-up were included. MRI detected significantly more lung abscess formations with a prevalence of 72.7% compared to 27.3% by CXR at baseline (p = 0.001), whereas CXR+LUS was nearly as good as MRI. MRI also showed a higher sensitivity in detecting empyema (p = 0.003). At follow-up, MRI also showed a slightly better sensitivity regarding residual abscesses. The overall severity of disease was rated higher on MRI. Contrast material did not improve detection of abscesses or empyema by MRI. CXR and LUS seem to be sufficient in most cases. In cases where LUS cannot be realized or the combination of CXR+LUS might be not sufficient, MRI, as a radiation free modality, should be preferred to CT. Furthermore, the admission of contrast media is not mandatory in this context.

Absorption-based clinical computed tomography (CT) is the current imaging method of choice in the diagnosis of lung diseases. Many pulmonary diseases are affecting microscopic structures of the lung, such as terminal bronchi, alveolar spaces, sublobular blood vessels or the pulmonary interstitial tissue. As spatial resolution in CT is limited by the clinically acceptable applied X-ray dose, a comprehensive diagnosis of conditions such as interstitial lung disease, idiopathic pulmonary fibrosis or the characterization of small pulmonary nodules is limited and may require additional validation by invasive lung biopsies. Propagation-based imaging (PBI) is a phase sensitive X-ray imaging technique capable of reaching high spatial resolutions at relatively low applied radiation dose levels. In this publication, we present technical refinements of PBI for the characterization of different artificial lung pathologies, mimicking clinically relevant patterns in ventilated fresh porcine lungs in a human-scale chest phantom. The combination of a very large propagation distance of 10.7 m and a photon counting detector with 100 μ m pixel size enabled high resolution PBI CT with significantly improved dose efficiency, measured by thermoluminescence detectors. Image quality was directly compared with state-of-the-art clinical CT. PBI with increased propagation distance was found to provide improved image quality at the same or even lower X-ray dose levels than clinical CT. By combining PBI with iodine k-edge subtraction imaging we further demonstrate that, the high quality of the calculated iodine concentration maps might be a potential tool for the analysis of lung perfusion in great detail. Our results indicate PBI to be of great value for accurate diagnosis of lung disease in patients as it allows to depict pathological lesions non-invasively at high resolution in 3D. This will especially benefit patients at high risk of complications from invasive lung biopsies such as in the setting of suspected idiopathic pulmonary fibrosis (IPF).

The mesothelium is a dynamic and specialized tissue layer that covers the somatic cavities (pleural, peritoneal, and pericardial) as well as the surface of the visceral organs such as the lung, heart, liver, bowel and tunica vaginalis testis. The potential therapeutic manipulation of visceral organs has been complicated by the carbohydrate surface layer-here, called the mesopolysaccharide (MPS)-that coats the outer layer of the mesothelium. The traditional understanding of MPS structure has relied upon fixation techniques known to degrade carbohydrates. The recent development of carbohydrate-preserving fixation for high resolution imaging techniques has provided an opportunity to re-examine the structure of both the MPS and the visceral mesothelium. In this report, we used high pressure freezing (HPF) as well as serial section transmission electron microscopy to redefine the structure of the MPS expressed on the murine lung, heart and liver surface. Tissue preserved by HPF and examined by transmission electron microscopy demonstrated a pleural MPS layer 13.01±1.1 um deep-a 100-fold increase in depth compared to previously reported data obtained with conventional fixation techniques. At the base of the MPS were microvilli 1.1±0.35 um long and 42±5 nm in diameter. Morphological evidence suggested that the MPS was anchored to the mesothelium by microvilli. In addition, membrane pits 97±17 nm in diameter were observed in the apical mesothelial membrane. The spatial proximity and surface density (29±4.5%) of the pits suggested an active process linked to the structural maintenance of the MPS. The striking magnitude and complex structure of the MPS indicates that it is an important consideration in studies of the visceral mesothelium.

To systematically evaluate the influence of acquisition settings in conjunction with raw-data based iterative image reconstruction (IR) on lung densitometry based on multi-row detector computed tomography (CT) in an anthropomorphic chest phantom. Ten porcine heart-lung explants were mounted in an ex vivo chest phantom shell, six with highly and four with low attenuating chest wall. CT (Somatom Definition Flash, Siemens Healthineers) was performed at 120kV.sub.p and 80kV.sub.p, each combined with current-time products of 120, 60, 30, and 12mAs, and was reconstructed with filtered back projection (FBP) and IR (Safire, Siemens Healthineers). Mean lung density (LD), air density (AD) and noise were measured by semi-automated region-of interest (ROI) analysis, with 120kV.sub.p /120 mAs serving as the standard of reference. Using IR, noise in lung parenchyma was reduced by ~ 31% at high attenuating chest wall and by ~ 22% at low attenuating chest wall compared to FBP, respectively (p<0.05). IR induced changes in the order of ±1 HU to mean absolute LD and AD compared to corresponding FBP reconstructions which were statistically significant (p<0.05). Densitometry is influenced by acquisition parameters and reconstruction algorithms to a degree that may be clinically negligible. However, in longitudinal studies and clinical research identical protocols and potentially other measures for calibration may be required.

Classical histopathology of formalin fixed and paraffin embedded (FFPE) tissue using light microscopy (LM) remains the undisputed gold standard in biomedical microstructural lung tissue analysis. To extend this method, we developed an integrative imaging and processing pipeline which adds 3D context and screening capabilities by microCT (µCT) imaging of the entire paraffin block and adds ultrastructural information by correlative same-slide scanning electron microscopy (SEM). The different modalities are integrated by elastic registration to provide hybrid image datasets. Without compromising standard light microscopic readout, we overcome the limitations of conventional histology by combining and integrating several imaging modalities. The biochemical information contained in histological and immunohistological tissue staining is embedded into the 3D tissue configuration and is amplified by adding ultrastructural visualization of features of interest. By combining µCT and conventional histological processing, specimens can be screened, and specifically preselected areas of interest can be targeted in the subsequent sectioning process. While most of the µCT data shown in the manuscript was acquired at a Synchrotron, we further demonstrate that our workflow can also be applied using X-ray microscopy.

Quantitative analysis of multi-detector computed tomography (MDCT) plays an increasingly important role in assessing airway disease. Depending on the algorithms used, airway dimensions may be over- or underestimated, primarily if contrast material was used. Therefore, we tested a modified integral-based method (IBM) to address this problem. Temporally resolved cine-MDCT was performed in seven ventilated pigs in breath-hold during iodinated contrast material (CM) infusion over 60s. Identical slices in non-enhanced (NE), pulmonary-arterial (PA), systemic-arterial (SA), and venous phase (VE) were subjected to an in-house software using a standard and a modified IBM. Total diameter (TD), lumen area (LA), wall area (WA), and wall thickness (WT) were measured for ten extra- and six intrapulmonary airways. The modified IBM significantly reduced TD by 7.6%, LA by 12.7%, WA by 9.7%, and WT by 3.9% compared to standard IBM on non-enhanced CT (p<0.05). Using standard IBM, CM led to a decrease of all airway parameters compared to NE. For example, LA decreased from 80.85±49.26mm.sup.2 at NE, to 75.14±47.96mm.sup.2 (-7.1%) at PA (p<0.001), 74.96±48.55mm.sup.2 (-7.3%) at SA (p<0.001), and to 78.95±48.94mm.sup.2 (-2.4%) at VE (p = 0.200). Using modified IBM, the differences were reduced to -3.1% at PA, -2.9% at SA and -0.7% at VE (p<0.001; p<0.001; p = 1.000). The modified IBM can optimize airway wall segmentation and reduce the influence of CM on quantitative CT. This allows a more precise measurement as well as potentially the comparison of enhanced with non-enhanced scans in inflammatory airway disease.