Hypoplastic Left Heart Syndrome with Mitral Stenosis and Aortic Atresia-Echocardiographic Findings and Early Outcomes.

BACKGROUND: Mitral stenosis/aortic atresia (MS/AA) has been reported as a high-risk variant of hypoplastic left heart syndrome (HLHS), potentially related to ventriculocoronary connections (VCCs) or endocardial fibroelastosis (EFE) and myocardial hypoperfusion. We aimed to identify echocardiographic and clinical factors associated with early death or transplant in this group. METHODS: Patients with HLHS MS/AA treated at our center between 2000 and 2020 were included. Pre-stage I palliation echocardiograms were reviewed. Certain imaging factors, such as determination of VCC, EFE, and measurement of tricuspid annular plane systolic excursion were measured from retrospective review of preoperative images; others were derived from clinical reports. Groups were compared according to primary outcome of death or transplant prior to stage II palliation. RESULTS: Of 141 patients included, 39 (27.7%) experienced a primary outcome. Ventriculocoronary connections were identified in 103 (73.0%) patients and EFE in 95 (67.4%) patients. Among imaging variables, smaller ascending aorta size (median, 2.2 [interquartile range (IQR) 1.7-2.8] vs 2.6 [2.2-3.4] mm, P = .01) was associated with primary outcome. There was similar frequency of VCC (74.4% vs 72.5%, P = .83), EFE (59.0% vs 72.5%, P = .19), moderate or greater tricuspid regurgitation (5.1% vs 5.9%, P = 1.00), and similar right ventricular systolic function (indexed tricuspid annular plane systolic excursion 32.5 ± 7.3 vs 31.4 ± 7.2 mm/m2, P = .47) in the primary outcome group compared to other patients. Clinical factors associated with primary outcome included lower birth weight (mean, 2.8 ± SD 0.8 vs 3.3 ± 0.5 kg, P = .0003), gestational age <37 weeks (31.6% vs 4.9%, P < .0001), longer cardiopulmonary bypass time (median, 112 [IQR, 93-162] vs 82 [71-119] minutes, P = .001), longer intensive care unit length of stay (median, 19 [IQR, 10-30] vs 10 [7-15] days, P = .001), and extracorporeal membrane oxygenation following stage I palliation (43.6% vs 8.8%, P < .0001). Presence of VCCs and EFE was not associated with death or transplant after controlling for birth weight and era of stage I palliation. CONCLUSIONS: In one of the largest reported single-center cohorts of HLHS MS/AA, there were few pre-stage I palliation imaging characteristics associated with primary outcome. Imaging findings evaluated in this study, including the presence of VCC and/or EFE as determined using highly sensitive echocardiogram criteria, should not preclude intervention, although impact on long-term outcomes requires further evaluation.

The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.

Real-Time Strain-Encoding Cardiovascular MRI for Assessment of Regional Heart Function in Tetralogy of Fallot Patients.

BACKGROUND: Tetralogy of Fallot (ToF) is the most common form of cyanotic congenital heart disease, where right ventricular (RV) function is an important determinant of subsequent intervention. OBJECTIVE: In this study, we evaluate the feasibility of fast strain-encoding (fastSENC; a one-heartbeat sequence) magnetic resonance imaging (MRI) for assessing regional cardiac function in ToF. METHOD: FastSENC was implemented to characterize regional circumferential (Ecc) and longitudinal (Ell) strains in the left ventricle (LV) and RV in post-repair ToF. Data analysis was conducted to compare strain measurements in the RV to those in the LV, as well as to those generated by the MRI Tissue-Tracking (MRI-TT) technique, and to assess the relationship between strain and ejection fraction (EF). RESULTS: Despite normal LVEF (55±8.5%), RVEF was borderline (46±6.4%), but significantly lower than LVEF. RV strains (RV-Ell=-20.2±2.9%, RV-Ecc=-15.7±6.4%) were less than LV strains (LV-Ell=-21.7±3.7%, LV-Ecc=-18.3±4.7%), and Ell was the dominant strain component. Strain differences between fastSENC and MRI-TT were less significant in RV than in LV. There existed moderate and weak correlations for RV-Ecc and RV-Ell, respectively, against RVEF. Compared to LV strain, RV strain showed regional heterogeneity with a trend for reduced strain from the inferior to anterior regions. Inter-ventricular strain delay was larger for Ell (64±47ms) compared to Ecc (36±40ms), reflecting a trend for contraction dyssynchrony. CONCLUSION: FastSENC allows for characterizing subclinical regional RV dysfunction in ToF. Due to its sensitivity for evaluating regional myocardial contractility patterns and real-time imaging capability without the need for breath-holding, fastSENC makes it more suitable for evaluating RV function in ToF.

SARS-CoV-2 Mpro Protease Variants of Concern Display Altered Viral Substrate and Cell Host Target Galectin-8 Processing but Retain Sensitivity toward Antivirals.

The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in Mpro may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 Mpro mutants provided structural insight into their altered functionality. Additionally, we show Mpro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting Mpro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.

Effects of Mitral Valve Prolapse on Quantification of Mitral Regurgitation and Ejection Fraction Using Cardiac MRI.

Purpose: To determine the impact of prolapsed volume on regurgitant volume (RegV), regurgitant fraction (RF), and left ventricular ejection fraction (LVEF) in patients with mitral valve prolapse (MVP) using cardiac MRI. Materials and Methods: Patients with MVP and mitral regurgitation who underwent cardiac MRI from 2005 to 2020 were identified retrospectively from the electronic record. RegV is the difference between left ventricular stroke volume (LVSV) and aortic flow. Left ventricular end-systolic volume (LVESV) and LVSV were obtained from volumetric cine images, with prolapsed volume inclusion (LVESVp, LVSVp) and exclusion (LVESVa, LVSVa) providing two estimates of RegV (RegVp, RegVa), RF (RFp, RFa), and LVEF (LVEFa, LVEFp). Interobserver agreement for LVESVp was assessed using intraclass correlation coefficient (ICC). RegV was also calculated independently using measurements from mitral inflow and aortic net flow phase-contrast imaging as the reference standard (RegVg). Results: The study included 19 patients (mean age, 28 years ± 16 [SD]; 10 male patients). Interobserver agreement for LVESVp was high (ICC, 0.98; 95% CI: 0.96, 0.99). Prolapsed volume inclusion resulted in higher LVESV (LVESVp: 95.4 mL ± 34.7 vs LVESVa: 82.4 mL ± 33.8; P < .001), lower LVSV (LVSVp: 100.5 mL ± 33.8 vs LVSVa: 113.5 mL ± 35.9; P < .001), and lower LVEF (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001). RegV was larger in magnitude when prolapsed volume was excluded (RegVa: 39.4 mL ± 21.0 vs RegVg: 25.8 mL ± 22.8; P = .02), with no evidence of a difference when including prolapsed volume (RegVp: 26.4 mL ± 16.4 vs RegVg: 25.8 mL ± 22.8; P > .99). Conclusion: Measurements that included prolapsed volume most closely reflected mitral regurgitation severity, but inclusion of this volume resulted in a lower LVEF.Keywords: Cardiac, MRI© RSNA, 2023See also commentary by Lee and Markl in this issue.

Recommendations for Cardiac Point-of-Care Ultrasound in Children: A Report from the American Society of Echocardiography.

Cardiac point-of-care ultrasound has the potential to improve patient care, but its application to children requires consideration of anatomic and physiologic differences from adult populations, and corresponding technical aspects of performance. This document is the product of an American Society of Echocardiography task force composed of representatives from pediatric cardiology, pediatric critical care medicine, pediatric emergency medicine, pediatric anesthesiology, and others, assembled to provide expert guidance. This diverse group aimed to identify common considerations across disciplines to guide evolution of indications, and to identify common requirements and infrastructure necessary for optimal performance, training, and quality assurance in the practice of cardiac point-of-care ultrasound in children. The recommendations presented are intended to facilitate collaboration among subspecialties and with pediatric echocardiography laboratories by identifying key considerations regarding (1) indications, (2) imaging recommendations, (3) training and competency assessment, and (4) quality assurance.

Data-driven computational models of ventricular-arterial hemodynamics in pediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a complex disease involving increased resistance in the pulmonary arteries and subsequent right ventricular (RV) remodeling. Ventricular-arterial interactions are fundamental to PAH pathophysiology but are rarely captured in computational models. It is important to identify metrics that capture and quantify these interactions to inform our understanding of this disease as well as potentially facilitate patient stratification. Towards this end, we developed and calibrated two multi-scale high-resolution closed-loop computational models using open-source software: a high-resolution arterial model implemented using CRIMSON, and a high-resolution ventricular model implemented using FEniCS. Models were constructed with clinical data including non-invasive imaging and invasive hemodynamic measurements from a cohort of pediatric PAH patients. A contribution of this work is the discussion of inconsistencies in anatomical and hemodynamic data routinely acquired in PAH patients. We proposed and implemented strategies to mitigate these inconsistencies, and subsequently use this data to inform and calibrate computational models of the ventricles and large arteries. Computational models based on adjusted clinical data were calibrated until the simulated results for the high-resolution arterial models matched within 10% of adjusted data consisting of pressure and flow, whereas the high-resolution ventricular models were calibrated until simulation results matched adjusted data of volume and pressure waveforms within 10%. A statistical analysis was performed to correlate numerous data-derived and model-derived metrics with clinically assessed disease severity. Several model-derived metrics were strongly correlated with clinically assessed disease severity, suggesting that computational models may aid in assessing PAH severity.

Cardiac Magnetic Resonance to Predict Coronary Artery Compression in Transcatheter Pulmonary Valve Implantation Into Conduits.

OBJECTIVES: The aim of this study was to evaluate the accuracy of cardiac magnetic resonance (CMR) in predicting coronary artery (CA) compression during transcatheter pulmonary valve implantation (TPVi). BACKGROUND: TPVi is a widely available option to treat dysfunctional right ventricle (RV)-to-pulmonary artery (PA) conduits, but CA compression is an absolute contraindication. CMR can evaluate coronary anatomy, but its utility in predicting CA compression is not well established. METHODS: After Institutional Review Board approval was obtained, all patients at 9 centers with attempted TPVi in RV-PA conduits and recent CMR (≤12 months) were analyzed. A core laboratory reviewed all CMR studies for the shortest orthogonal distance from a CA to the conduit, the shortest distance from a CA to the most stenotic area of the conduit, and subjective assessment of CA compression risk. RESULTS: Among 231 patients, TPVi was successful in 198 (86%); in 24 (10%), balloon testing precluded implantation (documented CA compression or high risk). Distance to the RV-PA conduit ≤2.1 mm (area under the curve [AUC]: 0.70) and distance to most stenotic area ≤13.1 mm (AUC: 0.69) predicted CA compression. Subjective assessment had the highest AUC (0.78), with 96% negative predictive value. Both distances and qualitative assessment remained independently associated with CA compression when controlling for abnormal coronary anatomy or degree of conduit calcification. CONCLUSIONS: CMR can help predict the risk for CA compression during TPVi in RV-PA conduits but cannot completely exclude CA compression. CMR may assist in patient selection and counseling families prior to TPVi, although balloon testing remains essential.

Crystallization of Feline Coronavirus Mpro With GC376 Reveals Mechanism of Inhibition.

Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host via the same mechanism. The coronavirus main protease (Mpro, also called 3CLpro), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An Mpro inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 Mpro and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) Mpro with the feline drugs have been published so far. Here, we present crystal structures of FIPV Mpro-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 Mpro. Additionally, GC376 has a higher affinity for FIPV Mpro with lower nanomolar Ki values compared to SARS-CoV and SARS-CoV-2 Mpro. We also show that improved derivatives of GC376 have higher potency for FIPV Mpro. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV Mpro with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.

Non-invasive detection and complementary diagnosis of liver metastases via chemokine receptor 4 imaging.

Noninvasive detection of early-stage liver metastases from different primary cancers is a pressing unmet medical need. The lack of both molecular biomarkers and the sensitive imaging methodology makes the detection challenging. In this study, we observed the elevated expression of chemokine receptor 4 (CXCR4) in uveal melanoma (UM) patient liver tissues, and high CXCR4 expression in liver metastases of UM murine models, regardless of the expression levels in the primary tumors. Based on these findings, we identified CXCR4 as an imaging biomarker and exploited a CXCR4-targeted MRI contrast agent ProCA32.CXCR4 for molecular MRI imaging. ProCA32.CXCR4 has strong CXCR4 binding affinity, high metal selectivity, and r1 and r2 relaxivities, which enables the sensitive detection of liver micrometastases. The MRI imaging capacity for detecting liver metastases was demonstrated in three UM models and one ovarian cancer model. The imaging results were validated by histological and immunohistochemical analysis. ProCA32.CXCR4 has strong potential clinical application for non-invasive diagnosis of liver metastases.

Kommerell Diverticulum: Distinctions Between Arch Side and Evaluation of Morphology, Size, And Risk.

BACKGROUND: Kommerell diverticulum (KD) is a dilated proximal aberrant right or left subclavian artery associated with either right or left aortic arches (RAA-ARSA or LAA-ALSA). Although case series suggest that KD may be a liability for vascular complications, the risk, pattern of dilation throughout the life span, and differences between arch sides are not known. METHODS: This study was a single-center retrospective review of patients of all ages with KD on cross-sectional imaging. Maximal short-axis diameter of KD (KDmax), absolute and indexed to descending aortic diameter (DAo), was correlated with age. Comparisons were made between arch sides. Patients with vascular complications were described. RESULTS: A total of 104 patients with KD were included: 68 (65%) with RAA-ALSA, 36 (35%) with LAA-ARSA, 43 (41%) asymptomatic. Although KDmax was correlated with age (RAA-ALSA r = 0.84; [P< .0001]; LAA-ARSA r = 0.51 [P = .001]), KDmax indexed to DAo was not (RAA-ALSA r = 0.14 [P = .27]; LAA-ARSA r = -0.22 [P = .21]). Patients with RAA-ALSA had larger KDmax indexed to DAo (1.02 ± 0.20 mm/mm vs 0.89 ± 0.18 mm/mm; P = .002) and more symptoms (75% vs 28%; P < .0001), and they were younger (median, 9.5 years vs 61.7 years; P < .0001). Six patients (58 to 80 years of age) had vascular complications, and all 6 had LAA-ARSA and risk factors for acquired aneurysms. CONCLUSIONS: In older patients, KDmax indexed to DAo was not larger, thus arguing against isolated KD dilation with age. Diverticula from RAA-ALSA and LAA-ARSA demonstrated different phenotypes, a finding suggesting different disease processes and likely different risk. The incidence of vascular complications was lower than in previous reports, and these complications occurred exclusively in patients with LAA-ARSA and aneurysm risk factors. This finding suggests that conservative management of asymptomatic KD is often reasonable, especially in patients with RAA-ALSA.

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

Ventricular Function in Physiologically Repaired and Unrepaired Congenitally Corrected Transposition of the Great Arteries.

In patients with congenitally corrected transposition of the great arteries (ccTGA) and hemodynamically significant concomitant lesions, physiologic repair may be undertaken, in which the circulation is septated but the morphologic right ventricle (RV) remains the systemic ventricle. Patients without significant concomitant lesions may be observed without surgery, with a similar physiologic result. We compared cardiovascular magnetic resonance measures of ventricular size and function in patients with physiologically repaired and unrepaired ccTGA. Patients with ccTGA who underwent cardiovascular magnetic resonance at our center between September 2007 and July 2019 were analyzed. In 38 patients identified (12, physiologically repaired; 26, unrepaired; mean age 34.5 [18.7 to 52.0] years), there was a higher proportion of RV ejection fraction ≤45% in physiologically repaired (75% vs unrepaired 35%, p = 0.02). Physiologically repaired patients had worse left ventricle global longitudinal strain (-14.9% ± 5.0% vs unrepaired patients -18.4% ± 2.7%, p = 0.04). The difference in tricuspid regurgitant fraction between groups did not achieve statistical significance (physiologically repaired 27.4 ± 11.1% vs unrepaired patients 19.2 ± 13.0%, p = 0.08). Evaluation for late gadolinium enhancement was more commonly undertaken in physiologically repaired patients (8 of 12 vs unrepaired 7 of 26, p = 0.03) and present more frequently in the left ventricle in physiologically repaired patients in patients evaluated (6 of 8 vs unrepaired 0 of 7, p = 0.01). In conclusion, ventricular function is decreased in patients with ccTGA undergoing physiologic repair compared with those without previous surgery. These cohorts should be considered separately when using ventricular function as an outcome. RV dysfunction is concerning for long-term outcomes following physiologic repair.

Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors.

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitro SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.

Interventional Planning for Endovascular Revision of a Lateral Tunnel Fontan: A Patient-Specific Computational Analysis.

INTRODUCTION: A 2-year-old female with hypoplastic left heart syndrome (HLHS)-variant, a complex congenital heart defect (CHD) characterized by the underdevelopment of the left ventricle, presented with complications following single ventricle palliation. Diagnostic work-up revealed elevated Fontan pathway pressures, as well as significant dilation of the inferior Fontan pathway with inefficient swirling flow and hepatic venous reflux. Due to the frail condition of the patient, the clinical team considered an endovascular revision of the Fontan pathway. In this work, we performed a computational fluid dynamics (CFD) analysis informed by data on anatomy, flow, and pressure to investigate the hemodynamic effect of the endovascular Fontan revision. METHODS: A patient-specific anatomical model of the Fontan pathway was constructed from magnetic resonance imaging (MRI) data using the cardiovascular modeling software CardiovasculaR Integrated Modeling and SimulatiON (CRIMSON). We first created and calibrated a pre-intervention 3D-0D multi-scale model of the patient's circulation using fluid-structure interaction (FSI) analyses and custom lumped parameter models (LPMs), including the Fontan pathway, the single ventricle, arterial and venous systemic, and pulmonary circulations. Model parameters were iteratively tuned until simulation results matched clinical data on flow and pressure. Following calibration of the pre-intervention model, a custom bifurcated endograft was introduced into the anatomical model to virtually assess post-intervention hemodynamics. RESULTS: The pre-intervention model successfully reproduced the clinical hemodynamic data on regional flow splits, pressures, and hepatic venous reflux. The proposed endovascular repair model revealed increases of mean and pulse pressure at the inferior vena cava (IVC) of 6 and 29%, respectively. Inflows at the superior vena cava (SVC) and IVC were each reduced by 5%, whereas outflows at the left pulmonary artery (LPA) and right pulmonary artery (RPA) increased by 4%. Hepatic venous reflux increased by 6%. CONCLUSION: Our computational analysis indicated that the proposed endovascular revision would lead to unfavorable hemodynamic conditions. For these reasons, the clinical team decided to forgo the proposed endovascular repair and to reassess the management of this patient. This study confirms the relevance of CFD modeling as a beneficial tool in surgical planning for single ventricle CHD patients.

Improving MR Image Quality in Patients with Metallic Implants.

The number of implanted devices such as orthopedic hardware and cardiac implantable devices continues to increase with an increase in the age of the patient population, as well as an increase in the number of indications for specific devices. Many patients with these devices have or will develop clinical conditions that are best depicted at MRI. However, implanted devices containing paramagnetic or ferromagnetic substances can cause significant artifact, which could limit the diagnostic capability of this modality. Performing imaging with MRI when an implant is present may be challenging, and there are numerous techniques the radiologist and technologist can use to help minimize artifacts related to implants. First, knowledge of the presence of an implant before patient arrival is critical to ensure safety of the patient when the device is subjected to a strong magnetic field. Once safety is ensured, the examination should be performed with the MRI system that is expected to provide the best image quality. The selection of the MRI system includes multiple considerations such as the effects of field strength and availability of specific sequences, which can reduce metal artifact. Appropriate patient positioning, attention to MRI parameters (including bandwidth, voxel size, and echo), and appropriate selection of sequences (those with less metal artifact and advanced metal reduction sequences) are critical to improve image quality. Patients with implants can be successfully imaged with MRI with appropriate planning and understanding of how to minimize artifacts. This improves image quality and the diagnostic confidence of the radiologist. ©RSNA, 2021.

Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies.

Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (Mpro) to cleave viral proteins. Consequently, Mpro is a target for antiviral agents. We and others previously demonstrated that GC376, a bisulfite prodrug with efficacy as an anti-coronaviral agent in animals, is an effective inhibitor of Mpro in SARS-CoV-2. Here, we report structure-activity studies of improved GC376 derivatives with nanomolar affinities and therapeutic indices >200. Crystallographic structures of inhibitor-Mpro complexes reveal that an alternative binding pocket in Mpro, S4, accommodates the P3 position. Alternative binding is induced by polar P3 groups or a nearby methyl. NMR and solubility studies with GC376 show that it exists as a mixture of stereoisomers and forms colloids in aqueous media at higher concentrations, a property not previously reported. Replacement of its Na+ counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for Mpro inhibitor design.

Characterization of Post-Operative Hemodynamics Following the Norwood Procedure Using Population Data and Multi-Scale Modeling.

Children with hypoplastic left heart syndrome (HLHS) must undergo multiple surgical stages to reconstruct the anatomy to a sustainable single ventricle system. Stage I palliation, or the Norwood procedure, provides circulation to both pulmonary and systemic vasculature. The aorta is reconstructed and attached to the right ventricle and a fraction of systemic flow is redirected to the pulmonary arteries (PAs) through a systemic-to-PA shunt. Despite abundant hemodynamic data available 4-5 months after Norwood palliation, data is very scarce immediately following stage I. This data is critical in determining post-operative success. In this work, we combined population data and computational fluid dynamics (CFD) to characterize hemodynamics immediately following stage I (post-stage I) and prior to stage II palliation (pre-stage II). A patient-specific model was constructed as a baseline geometry, which was then scaled to reflect population-based morphological data at both time-points. Population-based hemodynamic data was then used to calibrate each model to reproduce blood flow representative of HLHS patients. The post-stage I simulation produced a PA pressure of 22 mmHg and high-frequency oscillations within the flow field indicating highly disturbed hemodynamics. Despite PA mean pressure dropping to 14 mmHg, the pre-stage II model also produced high-frequency flow components and PA wall shear stress increases. These suboptimal conditions may be necessary to ensure adequate PA flow throughout the pre-stage II period, as the shunt becomes relatively smaller compared to the patient's somatic growth. In the future, CFD can be used to optimize shunt design and minimize these suboptimal conditions.

N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 Mpro Dimer.

The main protease (Mpro, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar Ki values with the Mpro from both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro. The comparison of a new X-ray crystal structure of Mpro from SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro, which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.