The influence of motion-compensated reconstruction on coronary artery analysis for a dual-layer detector CT system: a dynamic phantom study.

OBJECTIVES: Cardiac motion artifacts hinder the assessment of coronary arteries in coronary computed tomography angiography (CCTA). We investigated the impact of motion compensation reconstruction (MCR) on motion artifacts in CCTA at various heart rates (HR) using a dynamic phantom. MATERIALS AND METHODS: An artificial hollow coronary artery (5-mm diameter lumen) filled with iodinated contrast agent (400 HU at 120 kVp), positioned centrally in an anthropomorphic chest phantom, was scanned using a dual-layer spectral detector CT. The artery was translated at constant horizontal velocities (0-80 mm/s, increment of 10 mm/s). For each velocity, five CCTA scans were repeated using a clinical protocol. Motion artifacts were quantified using the in-plane motion area. Regression analysis was performed to calculate the reduction in motion artifacts provided by MCR, by division of the slopes of non-MCR and MCR fitted lines. RESULTS: Reference mean (95% confidence interval) motion artifact area was 24.9 mm2 (23.8, 26.0). Without MCR, motion artifact areas for velocities exceeding 20 mm/s were significantly larger (up to 57.2 mm2 (40.1, 74.2)) than the reference. With MCR, no significant differences compared to the reference were shown for all velocities, except for 70 mm/s (29.0 mm2 (27.0, 31.0)). The slopes of the fitted data were 0.44 and 0.04 for standard and MCR reconstructions, respectively, resulting in an 11-time motion artifact reduction. CONCLUSION: MCR may improve CCTA assessment in patients by reducing coronary artery motion artifacts, especially in those with elevated HR who cannot receive beta blockers or do not attain the targeted HR. CLINICAL RELEVANCE STATEMENT: This vendor-specific motion compensation reconstruction may improve coronary computed tomography angiography assessment in patients by reduction of coronary artery motion artifacts, especially in those with elevated various heart rates (HR) who cannot receive beta blockers or do not attain the targeted HR. KEY POINTS: • Motion artifacts are known to hinder the assessment of coronary arteries on coronary CT angiography (CCTA), leading to more non-diagnostic scans. • This dynamic phantom study shows that motion compensation reconstruction (MCR) reduces motion artifacts at various velocities, which may help to decrease the number of non-diagnostic scans. • MCR in this study showed to reduce motion artifacts 11-fold.

A prospective multicenter validation study for a novel angiography-derived physiological assessment software: Rationale and design of the radiographic imaging validation and evaluation for Angio-iFR (ReVEAL iFR) study.

Angiography-derived physiological assessment of coronary lesions has emerged as an alternative to wire-based assessment aiming at less-invasiveness and shorter procedural time as well as cost effectiveness in physiology-guided decision making. However, current available image-derived physiology software have limitations including the requirement of multiple projections and are time consuming. METHODS/DESIGN: The ReVEAL iFR (Radiographic imaging Validation and EvALuation for Angio-iFR) trial is a multicenter, multicontinental, validation study which aims to validate the diagnostic accuracy of the Angio-iFR medical software device (Philips, San Diego, US) in patients undergoing angiography for Chronic Coronary Syndrome (CCS). The Angio-iFR will enable operators to predict both the iFR and FFR value within a few seconds from a single projection of cine angiography by using a lumped parameter fluid dynamics model. Approximately 440 patients with at least one de-novo 40% to 90% stenosis by visual angiographic assessment will be enrolled in the study. The primary endpoint is the sensitivity and specificity of the iFR and FFR for a given lesion compared to the corresponding invasive measures. The enrollment started in August 2019, and was completed in March 2021. SUMMARY: The Angio-iFR system has the potential of simplifying physiological evaluation of coronary stenosis compared with available systems, providing estimates of both FFR and iFR. The ReVEAL iFR study will investigate the predictive performance of the novel Angio-iFR software in CCS patients. Ultimately, based on its unique characteristics, the Angio-iFR system may contribute to improve adoption of functional coronary assessment and the workflow in the catheter laboratory.

Smart chest X-ray worklist prioritization using artificial intelligence: a clinical workflow simulation.

OBJECTIVE: The aim is to evaluate whether smart worklist prioritization by artificial intelligence (AI) can optimize the radiology workflow and reduce report turnaround times (RTATs) for critical findings in chest radiographs (CXRs). Furthermore, we investigate a method to counteract the effect of false negative predictions by AI-resulting in an extremely and dangerously long RTAT, as CXRs are sorted to the end of the worklist. METHODS: We developed a simulation framework that models the current workflow at a university hospital by incorporating hospital-specific CXR generation rates and reporting rates and pathology distribution. Using this, we simulated the standard worklist processing "first-in, first-out" (FIFO) and compared it with a worklist prioritization based on urgency. Examination prioritization was performed by the AI, classifying eight different pathological findings ranked in descending order of urgency: pneumothorax, pleural effusion, infiltrate, congestion, atelectasis, cardiomegaly, mass, and foreign object. Furthermore, we introduced an upper limit for the maximum waiting time, after which the highest urgency is assigned to the examination. RESULTS: The average RTAT for all critical findings was significantly reduced in all prioritization simulations compared to the FIFO simulation (e.g., pneumothorax: 35.6 min vs. 80.1 min; p < 0.0001), while the maximum RTAT for most findings increased at the same time (e.g., pneumothorax: 1293 min vs 890 min; p < 0.0001). Our "upper limit" substantially reduced the maximum RTAT in all classes (e.g., pneumothorax: 979 min vs. 1293 min/1178 min; p < 0.0001). CONCLUSION: Our simulations demonstrate that smart worklist prioritization by AI can reduce the average RTAT for critical findings in CXRs while maintaining a small maximum RTAT as FIFO. KEY POINTS: • Development of a realistic clinical workflow simulator based on empirical data from a hospital allowed precise assessment of smart worklist prioritization using artificial intelligence. • Employing a smart worklist prioritization without a threshold for maximum waiting time runs the risk of false negative predictions of the artificial intelligence greatly increasing the report turnaround time. • Use of a state-of-the-art convolution neural network can reduce the average report turnaround time almost to the upper limit of a perfect classification algorithm (e.g., pneumothorax: 35.6 min vs. 30.4 min).

Practical Approach to Modeling the Impact of Amorphous Drug Nanoparticles on the Oral Absorption of Poorly Soluble Drugs.

Recently published studies have proposed that amorphous drug nanoparticles in gastrointestinal fluids may be beneficial for the absorption of poorly soluble compounds. Nanosized drug particles are known to provide rapid dissolution rates and, in some instances, a slight increase in solubility. However, in recent studies, the differences observed in vivo could not be explained solely by these attributes. Given the high dose and very low aqueous solubility of the study compounds, rapid equilibration to the drug-saturated solubility in gastrointestinal fluid would occur independent of the presence of nanoparticles. Alternatively, it has been proposed that drug nanoparticles (ca. ≤ 200 to 300 nm) may provide a "shuttle" for drug across the unstirred water layer (UWL) adjacent to the intestinal epithelium, particularly for low solubility/lipophilic compounds where absorption may be largely UWL-limited. This transport mechanism would result in a higher unbound drug concentration at the surface of the epithelium for absorption. This study evaluates this mechanism using a simple modification of the effective permeability to account for the effect of drug nanoparticles diffusing across the UWL. The modification can be made using inputs for solubility and nanoparticle size. The permeability modification was evaluated using three published case studies for amorphous formulations of itraconazole, anacetrapib, and enzalutamide, where the formation of amorphous drug nanoparticles upon dissolution resulted in improved drug absorption. Absorption modeling was performed using GastroPlus to assess the impact of the nanomodified permeability method on the accuracy of model prediction compared to in vivo data. Simulation results were compared to those for baseline simulations using an unmodified effective permeability. The results show good agreement using the nanomodified permeability, which described the data better than the standard baseline predictions. The nanomodified permeability method can be a suitable, fit-for-purpose in silico approach for evaluating or predicting oral absorption of poorly soluble, UWL-limited drugs from formulations that produce a significant number of amorphous drug nanoparticles.

Millisecond Self-Assembly of Stable Nanodispersed Drug Formulations.

We report the development of a new spray-drying and nanoparticle assembly process (SNAP) that enables the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline particles within a high Tg glassy matrix. SNAP expands the class of drugs that spray-dried dispersion (SDD) processing can address to encompass highly crystalline, but modestly hydrophobic, drugs that are difficult to process by conventional SDD. The process integrates rapid precipitation and spray-drying within a custom designed nozzle to produce high supersaturations and precipitation of the drug and high Tg glassy polymer. Keeping the time between precipitation and drying to tens of milliseconds allows for kinetic trapping of drug nanocrystals in the polymer matrix. Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows that adding an amphiphilic block copolymer (BCP) to the solvent gives essentially complete crystallization of the active pharmaceutical ingredient (API) with sub-200 nm domains. In contrast, the absence of the block copolymer results in the API being partially dispersed in the matrix as an amorphous phase, which can be sensitive to changes in bioavailability over time. Quantification of the API-excipient interactions by 2D 13C-1H NMR correlation spectroscopy shows that the mechanism of enhanced nanocrystal formation is not due to interactions between the drug and the BCP, but rather the BCP masks interactions between the drug and hydrophobic regions of the matrix polymers. BCP-facilitated SNAP samples show improved stability during aging studies and rapid dissolution and release of API in vitro.

Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations.

Bioavailability-enhancing formulations are often used to overcome challenges of poor gastrointestinal solubility for drug substances developed for oral administration. Conventional in vitro dissolution tests often do not properly compare such formulations due to the many different drug species that may exist in solution. To overcome these limitations, we have designed a practical in vitro membrane flux test, that requires minimal active pharmaceutical ingredient (API) and is capable of rapidly screening many drug product intermediates. This test can be used to quickly compare performance of bioavailability-enhancing formulations with fundamental knowledge of the rate-limiting step(s) to membrane flux. Using this system, we demonstrate that the flux of amorphous itraconazole (logD = 5.7) is limited by aqueous boundary layer (ABL) diffusion and can be increased by adding drug-solubilizing micelles or drug-rich colloids. Conversely, the flux of crystalline ketoconazole at pH 5 (logD = 2.2) is membrane-limited, and adding solubilizing micelles does not increase flux. Under certain circumstances, the flux of ketoconazole may also be limited by dissolution rate. These cases highlight how a well-designed in vitro assay can provide critical insight for oral formulation development. Knowing whether flux is limited by membrane diffusion, ABL diffusion, or dissolution rate can help drive formulation development decisions. It may also be useful in predicting in vivo performance, dose linearity, food effects, and regional-dependent flux along the length of the gastrointestinal tract.

Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux in Vitro and Oral Bioavailability in Rats.

Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux in vitro. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on in vitro flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank-ordered with membrane flux in vitro. The relative maximum absorption rate in vivo correlated well with the in vitro flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. In vitro it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug-containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability.

Multimodality Imaging of Ethiodized Oil-loaded Radiopaque Microspheres during Transarterial Embolization of Rabbits with VX2 Liver Tumors.

Purpose To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70-150-µm radiopaque microspheres in saline (radiopaque microsphere group), 70-150-µm radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70-150-µm radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P < .05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P < .05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. (©) RSNA, 2015.

Automatic bone removal for 3D TACE planning with C-arm CBCT: Evaluation of technical feasibility.

PURPOSE: To evaluate the technical feasibility of automatically removing the ribs and spine from C-arm cone-beam computed tomography (CBCT) images acquired during transcatheter arterial chemoembolization (TACE). MATERIAL AND METHODS: Fifty-eight patients (45.8 ± 5.0 years) with unresectable hepatocellular carcinoma (HCC) underwent transcatheter arterial chemoembolization and had intraprocedural CBCT imaging. Automatic bone removal was performed using model-based segmentation of the ventral cavity. Two interventional radiologists independently evaluated the performance of bone removal, remaining soft tissue retention, and general usability (where both the bone is appropriately removed while retaining soft tissue) for 3D TACE planning on a four-level (complete/excellent, adequate/good, incomplete/questionable, insufficient/bad) score. The proportion of inter-reader agreement was calculated. RESULTS: For ribs and spine removal, 98.3-100% and 100% of cases showed complete or adequate performance, respectively. In 96.6% of the cases, soft tissue was at least adequately retained. 91.3-93.1% of the cases demonstrated good or excellent general usability for TACE planning. Satisfactory inter-reader agreement proportion was achieved in ribs (93.1%) and spine removal (89.7%), soft tissue retention (84.5%), and general usability for TACE planning (72.4%). CONCLUSION: Intraprocedural automatic bone removal on CBCT images is technically feasible and offers good removal of ribs and spine while preserving soft tissue. Its clinical value needs further assessment.

Nondestructive Quantification of Local Plasticizer Concentration in PVC by (1)H NMR Relaxometry.

The properties of plasticized poly(vinyl chloride) (PVC) , one of the most important polymers today, are strongly dictated by the concentration of plasticizer. Yet, it has been impossible to quantify this concentration at different positions inside a PVC product without its destruction because of a lack of suitable analytical methods. Thus, this paper introduces a simple, fast, and efficient way to determine truly nondestructively the concentration of plasticizer in PVC by single-sided nuclear magnetic resonance (NMR). With the help of correlation curves between the concentration of plasticizer inside nonaged PVC samples and the corresponding volume-averaged NMR parameters, single-sided NMR allows the quantification of the local concentration of plasticizer in aged PVC plates at different depths by spatially resolved relaxation measurements. The presented approach represents a fundamental step toward in situ characterization of plasticized PVC.

C-arm cone-beam computed tomography in interventional oncology: technical aspects and clinical applications.

C-arm cone-beam computed tomography (CBCT) is a new imaging technology integrated in modern angiographic systems. Due to its ability to obtain cross-sectional imaging and the possibility to use dedicated planning and navigation software, it provides an informed platform for interventional oncology procedures. In this paper, we highlight the technical aspects and clinical applications of CBCT imaging and navigation in the most common loco-regional oncological treatments.

Removing streak artifacts from ECG-gated reconstructions using deconvolution.

BACKGROUND: 4D cardiac computed tomography aims at reconstructing the beating heart from a series of 2D projections and the simultaneously acquired electrocardiogram. Each cardiac phase is reconstructed by exploiting the subset of projections acquired during this particular cardiac phase only. In these conditions, the Feldkamp, Davis and Kress method (FDK) generates large streak artifacts in the reconstructed volumes, hampering the medical interpretation. These artifacts can be substantially reduced by deconvolution methods. OBJECTIVE: The aim of this paper is to compare two 4D cardiac CT reconstruction methods based on deconvolution, and to evaluate their practical benefits on two applications: cardiac micro CT and human cardiac C-arm CT. METHODS: The first evaluated method builds upon inverse filtering. It has been proposed recently and demonstrated on 4D cardiac micro CT. The second one is an iterative deconvolution method, and turns out equivalent to an ECG-gated Iterative Filtered Back Projection (ECG-gated IFBP). RESULTS: Results are presented on simulated data in 2D parallel beam, 2D fan beam and 3D cone beam geometries. CONCLUSIONS: Both methods are efficient on the cardiac micro CT simulations, but insufficient to handle 4D human cardiac C-Arm CT simulations. Overall, ECG-gated IFPB largely outperforms the inverse filtering method.

Mechanistic studies of water electrolysis and hydrogen electro-oxidation on high temperature ceria-based solid oxide electrochemical cells.

Through the use of ambient pressure X-ray photoelectron spectroscopy (APXPS) and a single-sided solid oxide electrochemical cell (SOC), we have studied the mechanism of electrocatalytic splitting of water (H2O + 2e(-) → H2 + O(2-)) and electro-oxidation of hydrogen (H2 + O(2-) → H2O + 2e(-)) at ∼700 °C in 0.5 Torr of H2/H2O on ceria (CeO2-x) electrodes. The experiments reveal a transient build-up of surface intermediates (OH(-) and Ce(3+)) and show the separation of charge at the gas-solid interface exclusively in the electrochemically active region of the SOC. During water electrolysis on ceria, the increase in surface potentials of the adsorbed OH(-) and incorporated O(2-) differ by 0.25 eV in the active regions. For hydrogen electro-oxidation on ceria, the surface concentrations of OH(-) and O(2-) shift significantly from their equilibrium values. These data suggest that the same charge transfer step (H2O + Ce(3+) <-> Ce(4+) + OH(-) + H(•)) is rate limiting in both the forward (water electrolysis) and reverse (H2 electro-oxidation) reactions. This separation of potentials reflects an induced surface dipole layer on the ceria surface and represents the effective electrochemical double layer at a gas-solid interface. The in situ XPS data and DFT calculations show that the chemical origin of the OH(-)/O(2-) potential separation resides in the reduced polarization of the Ce-OH bond due to the increase of Ce(3+) on the electrode surface. These results provide a graphical illustration of the electrochemically driven surface charge transfer processes under relevant and nonultrahigh vacuum conditions.

Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy.

Weak base therapeutic agents can show reduced absorption or large pharmacokinetic variability when coadministered with pH-modifying agents, or in achlorhydria disease states, due to reduced dissolution rate and/or solubility at high gastric pH. This is often referred to as pH-effect. The goal of this study was to understand why some drugs exhibit a stronger pH-effect than others. To study this, an API-sparing, two-stage, in vitro microdissolution test was developed to generate drug dissolution, supersaturation, and precipitation kinetic data under conditions that mimic the dynamic pH changes in the gastrointestinal tract. In vitro dissolution was assessed for a chemically diverse set of compounds under high pH and low pH, analogous to elevated and normal gastric pH conditions observed in pH-modifier cotreated and untreated subjects, respectively. Represented as a ratio between the conditions, the in vitro pH-effect correlated linearly with clinical pH-effect based on the Cmax ratio and in a non-linear relationship based on AUC ratio. Additionally, several in silico approaches that use the in vitro dissolution data were found to be reasonably predictive of the clinical pH-effect. To explore the hypothesis that physicochemical properties are predictors of clinical pH-effect, statistical correlation analyses were conducted using linear sequential feature selection and partial least-squares regression. Physicochemical parameters did not show statistically significant linear correlations to clinical pH-effect for this data set, which highlights the complexity and poorly understood nature of the interplay between parameters. Finally, a strategy is proposed for implementation early in clinical development, to systematically assess the risk of clinical pH-effect for new molecular entities that integrates physicochemical analysis and in vitro, in vivo and in silico methods.

Oxidation and reduction of size-selected subnanometer Pd clusters on Al2O3 surface.

In this paper, we investigate uniformly dispersed size-selected Pd(n) clusters (n = 4, 10, and 17) on alumina supports. We study the changes of clustered Pd atoms under oxidizing and reducing (O2 and CO, respectively) conditions in situ using ambient pressure XPS. The behavior of Pd in the clusters is quite different from that of Pd foil under the same conditions. For all Pd clusters, we observe only one Pd peak. The binding energy of this Pd 3d peak is ~1-1.4 eV higher than that of metallic Pd species and changes slightly in CO and O2 environments. On the Pd foil however many different Pd species co-exist on the surface and change their oxidation states under different conditions. We find that the Pd atoms in direct contact with Al2O3 differ in oxidation state from the surface Pd atoms in a foil under reaction conditions. Compared to previous literature, we find that Pd 3d peak positions are greatly influenced by the different types of Al2O3 supports due to the combination of both initial and final state effects.

Image quality improvements in C-Arm CT (CACT) for liver oncology applications: preliminary study in rabbits.

INTRODUCTION: C-Arm CT (CACT) is a new imaging modality in liver oncology therapy that allows for the acquisition of 3D images intra-procedurally. CACT has been used to enhance intra-arterial therapies for the liver by improving lesion detection, avoiding non-target embolization, and allowing for more selective delivery of agents. However, one of the limitations of this technology is image artifacts created by respiratory motion. PURPOSE: To determine in this preliminary study improvements in image acquisition, motion compensation, and high resolution 3D reconstruction that can improve CACT image quality (IQ). MATERIAL AND METHODS: Three adult male New Zealand white rabbits were used for this study. First, a control rabbit was used to select the best x-ray acquisition imaging protocol and then two rabbits were implanted with liver tumor to further develop 3D image reconstruction and motion compensation algorithms. RESULTS: The best IQ was obtained using the low 80 kVp protocol with motion compensated reconstruction with high resolution and fast acquisition speed (60 fps, 5 s/scan, and 312 images). CONCLUSION: IQ improved by: (1) decreasing acquisition time, (2) applying motion-compensated reconstruction, and (3) high resolution 3D reconstruction. The findings of this study can be applied to future animal studies and eventually could be translated into the clinical environment.

Reversible formation of a PdC(x) phase in Pd nanoparticles upon CO and O2 exposure.

The structure and chemical composition of Pd nanoparticles exposed to pure CO and mixtures of CO and O(2) at elevated temperatures have been studied in situ by a combination of X-ray Diffraction and X-ray Photoelectron Spectroscopy in pressures ranging from ultra high vacuum to 10 mbar and from room temperature to a few hundred degrees celsius. Our investigation shows that under CO exposure, above a certain temperature, carbon dissolves into the Pd particles forming a carbide phase. Upon exposure to CO and O(2) mixtures, the carbide phase forms and disappears reversibly, switching at the stoichiometric ratio for CO oxidation. This finding opens new scenarios for the understanding of catalytic oxidation of C-based molecules.

A Critical Overview of the Biological Effects of Excipients (Part II): Scientific Considerations and Tools for Oral Product Development.

It is now recognized that a number of excipients previously considered to be "inert" have the capacity to alter drug oral bioavailability through a range of in vivo effects. The various mechanisms through which an excipient can affect in vivo gastrointestinal physiology and drug absorption characteristics were explored in "A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption." The next critical issue that needs to be discussed is how these biological effects are evaluated. Therefore, in Part 2 of this critical overview, the in vitro, in vivo, and in silico methods for evaluating excipient effects are considered. Examples are provided to illustrate how such studies employing these various procedures have been used to promote formulation understanding and optimization. Finally, a discussion of how the Center for Drug Evaluation and Research applies these tools to support biowaivers is provided.

Correction: Adam et al. Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture. Pharmaceutics 2022, 14, 555.

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Cascaded learning in intravascular ultrasound: coronary stent delineation in manual pullbacks.

Purpose: Implanting stents to re-open stenotic lesions during percutaneous coronary interventions is considered a standard treatment for acute or chronic coronary syndrome. Intravascular ultrasound (IVUS) can be used to guide and assess the technical success of these interventions. Automatically segmenting stent struts in IVUS sequences improves workflow efficiency but is non-trivial due to a challenging image appearance entailing manifold ambiguities with other structures. Manual, ungated IVUS pullbacks constitute a challenge in this context. We propose a fully data-driven strategy to first longitudinally detect and subsequently segment stent struts in IVUS frames. Approach: A cascaded deep learning approach is presented. It first trains an encoder model to classify frames as "stent," "no stent," or "no use." A segmentation model then delineates stent struts on a pixel level only in frames with a stent label. The first stage of the cascade acts as a gateway to reduce the risk for false positives in the second stage, the segmentation, which is trained on a smaller and difficult-to-annotate dataset. Training of the classification and segmentation model was based on 49,888 and 1826 frames of 74 sequences from 35 patients, respectively. Results: The longitudinal classification yielded Dice scores of 92.96%, 82.35%, and 94.03% for the classes stent, no stent, and no use, respectively. The segmentation achieved a Dice score of 65.1% on the stent ground truth (intra-observer performance: 75.5%) and 43.5% on all frames (including frames without stent, with guidewires, calcium, or without clinical use). The latter improved to 49.5% when gating the frames by the classification decision and further increased to 57.4% with a heuristic on the plausible stent strut area. Conclusions: A data-driven strategy for segmenting stents in ungated, manual pullbacks was presented-the most common and practical scenario in the time-critical clinical workflow. We demonstrated a mitigated risk for ambiguities and false positive predictions.