Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models.

WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.

Quantitative Characterization of Respiratory Patterns on Dynamic Higher Temporal Resolution MRI to Stratify Postacute Covid-19 Patients by Cardiopulmonary Symptom Burden.

BACKGROUND: Postacute Covid-19 patients commonly present with respiratory symptoms; however, a noninvasive imaging method for quantitative characterization of respiratory patterns is lacking. PURPOSE: To evaluate if quantitative characterization of respiratory pattern on free-breathing higher temporal resolution MRI stratifies patients by cardiopulmonary symptom burden. STUDY TYPE: Prospective analysis of retrospectively acquired data. SUBJECTS: A total of 37 postacute Covid-19 patients (25 male; median [interquartile range (IQR)] age: 58 [42-64] years; median [IQR] days from acute infection: 335 [186-449]). FIELD STRENGTH/SEQUENCE: 0.55 T/two-dimensional coronal true fast imaging with steady-state free precession (trueFISP) at higher temporal resolution. ASSESSMENT: Patients were stratified into three groups based on presence of no (N = 11), 1 (N = 14), or ≥2 (N = 14) cardiopulmonary symptoms, assessed using a standardized symptom inventory within 1 month of MRI. An automated lung postprocessing workflow segmented each lung in each trueFISP image (temporal resolution 0.2 seconds) and respiratory curves were generated. Quantitative parameters were derived including tidal lung area, rates of inspiration and expiration, lung area coefficient of variability (CV), and respiratory incoherence (departure from sinusoidal pattern) were. Pulmonary function tests were recorded if within 1 month of MRI. Qualitative assessment of respiratory pattern and lung opacity was performed by three independent readers with 6, 9, and 23 years of experience. STATISTICAL TESTS: Analysis of variance to assess differences in demographic, clinical, and quantitative MRI parameters among groups; univariable analysis and multinomial logistic regression modeling to determine features predictive of patient symptom status; Akaike information criterion to compare the quality of regression models; Cohen and Fleiss kappa (κ) to quantify inter-reader reliability. Two-sided 5% significance level was used. RESULTS: Tidal area and lung area CV were significantly higher in patients with two or more symptoms than in those with one or no symptoms (area: 15.4 cm2 vs. 12.9 cm2 vs. 12.8 cm2 ; CV: 0.072, 0.067, and 0.058). Respiratory incoherence was significantly higher in patients with two or more symptoms than in those with one or no symptoms (0.05 vs. 0.043 vs. 0.033). There were no significant differences in patient age (P = 0.19), sex (P = 0.88), lung opacity severity (P = 0.48), or pulmonary function tests (P = 0.35-0.97) among groups. Qualitative reader assessment did not distinguish between groups and showed slight inter-reader agreement (κ = 0.05-0.11). DATA CONCLUSION: Quantitative respiratory pattern measures derived from dynamic higher-temporal resolution MRI have potential to stratify patients by symptom burden in a postacute Covid-19 cohort. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Block copolymer self-assembly derived mesoporous magnetic materials with three-dimensionally (3D) co-continuous gyroid nanostructure.

Magnetic nanomaterials are gaining interest for their many applications in technological areas from information science and computing to next-generation quantum energy materials. While magnetic materials have historically been nanostructured through techniques such as lithography and molecular beam epitaxy, there has recently been growing interest in using soft matter self-assembly. In this work, a triblock terpolymer, poly(isoprene-block-styrene-block-ethylene oxide) (ISO), is used as a structure directing agent for aluminosilicate sol nanoparticles and magnetic material precursors to generate organic-inorganic bulk hybrid films with co-continuous morphology. After thermal processing into mesoporous materials, results from a combination of small angle X-ray scattering (SAXS) and scanning electron microscopy (SEM) are consistent with the double gyroid morphology. Nitrogen sorption measurements reveal a type IV isotherm with H1 hysteresis, and yield a specific surface area of around 200 m2 g-1 and an average pore size of 23 nm. The magnetization of the mesostructured material as a function of applied field shows magnetic hysteresis and coercivity at 300 K and 10 K. Comparison of magnetic measurements between the mesoporous gyroid and an unstructured bulk magnetic material, derived from the identical inorganic precursors, reveals the structured material exhibits a coercivity of 250 Oe, opposed to 148 Oe for the unstructured at 10 K, and presence of remnant magnetic moment not conventionally found in bulk hematite; both of these properties are attributed to the mesostructure. This scalable route to mesoporous magnetic materials with co-continuous morphologies from block copolymer self-assembly may provide a pathway to advanced magnetic nanomaterials with a range of potential applications.

Perplexing EPR Signals from 5f36d1 U(II) Complexes.

Metal complexes with unpaired electrons in orbitals of different angular momentum quantum numbers (e.g., f and d orbitals) are unusual and opportunities to study the interactions among these electrons are rare. X-band electron paramagnetic resonance (EPR) data were collected at <10 and 77 K on 10 U(II) complexes with 5f36d1 electron configurations and on some analogous Ce(II), Pr(II), and Nd(II) complexes with 4fn5d1 electron configurations. The U(II) compounds unexpectedly display similar two-line axial signals with g|| = 2.04 and g⊥ = 2.00 at 77 K. In contrast, U(II) complexes with 5f4 configurations are EPR-silent. Unlike U(II), the congenic 4f35d1 Nd(II) complex is EPR-silent. The Ce(II) complex with a 4f15d1 configuration is also EPR-silent, but a signal is observed for the Pr(II) complex, which has a 4f25d1 configuration. Whether or not an EPR signal is expected for these complexes depends on the coupling between f and d electrons. Since the coupling in U(II) systems is expected to be sufficiently strong to preclude an EPR signal from compounds with a 5f36d1 configuration, the results are viewed as unexplained phenomena. However, they do show that 5f36d1 U(II) samples can be differentiated from 5f4 U(II) complexes by EPR spectroscopy.

The Perfect Cup? Coffee-Derived Polyphenols and Their Roles in Mitigating Factors Affecting Type 2 Diabetes Pathogenesis.

Type 2 diabetes (T2D) is a growing health concern with an estimated 462 million people having been diagnosed worldwide. T2D is characterized by chronically elevated blood glucose and insulin resistance, which culminate in a diminished function of the ß-cell mass in its later stages. This can be perpetuated by and result in inflammation, excess reactive oxygen species production, obesity, and the dysregulation of multiple cellular pathways. Many naturally occurring small molecules have been investigated in terms of their roles in modulating glucose homeostasis and ß-cell function. Many of these compounds can be found in commonly used sources of food and drink. Interestingly, a correlation has been observed between coffee consumption and T2D incidence. However, the specific compounds responsible for this correlation and their mechanisms are still somewhat undetermined. This paper reviews recent research findings on the effects of several polyphenols that are either found in coffee or are metabolites of compounds found in coffee (enterodiol, enterolactone, matairesinol, secoisolariciresinol, kaempferol, quercetin, and chlorogenic acid) on glucose homeostasis and health complications associated with glucose dysregulation, with a special emphasis on their potential anti-diabetic effects. The factors that affect polyphenol content in coffee are also addressed.

OME-Zarr: a cloud-optimized bioimaging file format with international community support.

A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the cloud-optimized format itself-OME-Zarr-along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process. The current momentum offers an opportunity to unify a key component of the bioimaging domain-the file format that underlies so many personal, institutional, and global data management and analysis tasks.

Finding the sentinel lymph node in early cervical cancer: When is unusual not uncommon?

OBJECTIVE: To report our institutional experience with sentinel lymph node (SLN) detection using indocyanine green for cervical cancer, in terms of detection rates, detection of SLN at unusual locations, and factors associated with unusual SLN locations. In addition, we performed a systematic review of the literature to identify factors associated with unusual SLN localizations. METHODS: This is a retrospective cohort study of women with early-stage cervical cancer undergoing sentinel lymph node mapping between 2015 and 2019. Outcome measures were SLN detection rates, detection rates of unusual locations for SLN and risk factors for aberrant lymphatic drainage pathways. In addition, studies evaluating factors associated with unusual SLN locations in cervical cancer were assessed in a systematic review. RESULTS: A total of 100 patients were included. The unilateral SLN detection rate was 88%, whereas the bilateral detection rate was 75%. In 37% of all patients, SLN were found in unusual locations, and in 10% of patients SLN were solely found in unusual locations. Body mass index (BMI) was associated with finding SLN in unusual locations, with unusual nodes detected in 52% of patients with BMI <25 kg/m2 and in 28% of patients with BMI ≥25 kg/m2. The systematic review identified three studies, identifying lower BMI, nulliparity and tumor size of >20 mm as factors associated with finding SLN at unusual locations. CONCLUSION: Aberrant drainage sites represent a significant proportion of SLN detected in cervical cancer. Factors associated with increased rates of unusual nodal locations are a lower BMI, with a possible association with nulliparity and tumor size of >20 mm.

Pulmonary Cryoablation Outcomes in Octogenarians and Nonagenarians with Primary Lung Cancer.

PURPOSE: To characterize the effectiveness, safety, and length of stay (LOS) associated with pulmonary cryoablation for management of primary lung malignancies in patients aged ≥80 years. MATERIALS AND METHODS: A retrospective single-center database was compiled of all consecutive patients aged ≥80 years who underwent percutaneous computed tomography-guided cryoablation using modified triple-freeze protocol (1-3 ablation probes) for Stage IA-IIB primary lung malignancies between March 2017 and March 2020 (n = 19; 53% women; mean age, 85 years ± 3.5; range, 80-94 years). Follow-up imaging was assessed for local recurrence. Adverse events and LOS were recorded from chart review. Kaplan-Meier analysis was performed to assess both overall and local recurrence-free survival. RESULTS: Mean patient follow-up period was 21.6 months ± 10.8, and mean imaging follow-up period was 19.2 months ± 9.6. Overall survival at 3 years was 94% (95% CI, 81%-100%). Local recurrence-free survival was 100% throughout the imaging follow-up period. Intraprocedural pneumothorax occurred in 37% (7 of 19) of patients; pneumothorax risk was significantly associated with increased tumor distance from pleura (odds ratio, 1.2; P = .018). Sixty-three percent (12 of 19) of patients were discharged on the day of the procedure, with a mean LOS of 7.7 hours ± 1.6, whereas 37% of patients required overnight observation (2 of 19) or admission (5 of 19), with a mean LOS of 48.1 hours ± 19.4. Overall LOS for all patients was 22.6 hours ± 22.9. CONCLUSIONS: Percutaneous cryoablation of primary pulmonary malignancies can be performed in select octogenarians and nonagenarians with high 3-year overall and recurrence-free survival. Despite nonnegligible risk of pneumothorax, most patients are discharged on the day of the procedure.

Reductive C-O Cleavage of Ethereal Solvents and 18-Crown-6 in Ln(NR2)3/KC8 Reactions (R = SiMe3).

The high reactivity accessible from the reduction of the tris(amide) complexes Ln(NR2)3 (R = SiMe3) with potassium graphite in the presence of a variety of ethers is demonstrated by crystal structures of six different types of products of C-O bond cleavage reactions with Ln = Y, Ho, Er, and Lu. Specifically, 1,2-dimethoxyethane (DME) can be cleaved in Ln(NR2)3/KC8 reactions as shown by three different types of crystals: [K (crypt)][(R2N)3Y(OCH2CH2OCH3)], 1-Y, [(R2N)2Y(µ-OCH2CH2OCH3-κO,κO')]2, 2-Y, and [K2(18-c-6)3]{[(R2N)3Lu]2[(µ-OCH2CH2O)]}, 3-Lu (18-c-6 = 18-crown-6; crypt = 2.2.2-cryptand). THF can be ring opened by the Y(NR2)3/KC8 reaction system, as shown by crystals of the butoxide, [K(crypt)][(R2N)3Y(OCH2CH2CH2CH3)], 4-Y. The cyclic ether, oxetane, OC3H6, ring opens in Ln(NR2)3/KC8 reactions to form crystals of the propoxide, [K(18-c-6)(OC3H6)][(R2N)3Ln(OCH2CH2CH3)], 5-Ln, for Ln = Ho and Er. In Et2O, the Y(NR2)3/KC8 reactions do not attack the solvent, but C-O cleavage of 18-c-6 is observed to form {[(R2N)2]Y[µ-η1:η1-O2(C10H20O4)K]}2, 6-Y. These Ln(NR2)3/KC8 C-O cleavage reactions are typically accompanied by C-H bond activation reactions, which form cyclometalates such as [K(crypt)]{(R2N)2Ln[N(SiMe3)(SiMe2CH2)-κC,κN]}, 7-Ln (Ln = Y, Ho, Er), and [K(18-c-6)]{(R2N)2Y[N(SiMe3)(SiMe2CH2)-κC,κN]}, 8-Y, which are common decomposition products of Ln(NR2)3 reactions. In addition, in this study, the hydride complex, [K(18-c-6)][(R2N)3YH], 9-Y, was isolated. NMR analysis indicates that the yttrium reactions form mixtures that consistently contain the yttrium cyclometalates 7-Y and 8-Y as major components. These results show the diversity of available reaction pathways for the Ln(NR2)3/KC8 system and highlight the inherent difficulties in isolating Ln(II) complexes containing the [Ln(NR2)3]1- anion.

Prevalence of Adenopathy at Chest Computed Tomography After Vaccination for Severe Acute Respiratory Syndrome Coronavirus 2.

OBJECTIVE: This study aimed to determine the prevalence of axillary and subpectoral (SP) lymph nodes after ipsilateral COVID-19 vaccine administration on chest computed tomography (CT). METHODS: Subjects with chest CTs between 2 and 25 days after a first or second vaccine dose, December 15, 2020, to February 12, 2021, were included. Orthogonal measures of the largest axillary and SP nodes were recorded by 2 readers blinded to vaccine administration and clinical details. A mean nodal diameter discrepancy of ≥6 mm between contralateral stations was considered positive for asymmetry. Correlation with the side of vaccination, using a Spearman rank correlation, was performed on the full cohort and after excluding patients with diseases associated with adenopathy. RESULTS: Of the 138 subjects (81 women, 57 men; mean [SD] age, 74.4 ± 11.7 years), 48 (35%) had asymmetrically enlarged axillary and/or SP lymph nodes, 42 (30%) had ipsilateral, and 6 (4%) had contralateral to vaccination ( P = 0.003). Exclusion of 29 subjects with conditions associated with adenopathy showed almost identical correlation, with asymmetric nodes in 32 of 109 (29%) ipsilateral and in 5 of 109 (5%) contralateral to vaccination ( P = 0.002). CONCLUSIONS: Axillary and/or SP lymph nodes ipsilateral to vaccine administration represents a clinical conundrum. Asymmetric nodes were detected at CT in 30% of subjects overall and 29% of subjects without conditions associated with adenopathy, approximately double the prevalence rate reported to the Centers for Disease Control and Prevention by vaccine manufacturers. When interpreting examinations correlation with vaccine administration timing and site is important for pragmatic management.

Deep Learning Denoising of Low-Dose Computed Tomography Chest Images: A Quantitative and Qualitative Image Analysis.

PURPOSE: To assess deep learning denoised (DLD) computed tomography (CT) chest images at various low doses by both quantitative and qualitative perceptual image analysis. METHODS: Simulated noise was inserted into sinogram data from 32 chest CTs acquired at 100 mAs, generating anatomically registered images at 40, 20, 10, and 5 mAs. A DLD model was developed, with 23 scans selected for training, 5 for validation, and 4 for test.Quantitative analysis of perceptual image quality was assessed with Structural SIMilarity Index (SSIM) and Fréchet Inception Distance (FID). Four thoracic radiologists graded overall diagnostic image quality, image artifact, visibility of small structures, and lesion conspicuity. Noise-simulated and denoised image series were evaluated in comparison with one another, and in comparison with standard 100 mAs acquisition at the 4 mAs levels. Statistical tests were conducted at the 2-sided 5% significance level, with multiple comparison correction. RESULTS: At the same mAs levels, SSIM and FID between noise-simulated and reconstructed DLD images indicated that images were closer to a perfect match with increasing mAs (closer to 1 for SSIM, and 0 for FID).In comparing noise-simulated and DLD images to standard-dose 100-mAs images, DLD improved SSIM and FID. Deep learning denoising improved SSIM of 40-, 20-, 10-, and 5-mAs simulations in comparison with standard-dose 100-mAs images, with change in SSIM from 0.91 to 0.94, 0.87 to 0.93, 0.67 to 0.87, and 0.54 to 0.84, respectively. Deep learning denoising improved FID of 40-, 20-, 10-, and 5-mAs simulations in comparison with standard-dose 100-mAs images, with change in FID from 20 to 13, 46 to 21, 104 to 41, and 148 to 69, respectively.Qualitative image analysis showed no significant difference in lesion conspicuity between DLD images at any mAs in comparison with 100-mAs images. Deep learning denoising images at 10 and 5 mAs were rated lower for overall diagnostic image quality ( P < 0.001), and at 5 mAs lower for overall image artifact and visibility of small structures ( P = 0.002), in comparison with 100 mAs. CONCLUSIONS: Deep learning denoising resulted in quantitative improvements in image quality. Qualitative assessment demonstrated DLD images at or less than 10 mAs to be rated inferior to standard-dose images.

Real-World Experience of Bamlanivimab for Coronavirus Disease 2019 (COVID-19): A Case-Control Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has strained healthcare systems with patient hospitalizations and deaths. Anti-spike monoclonal antibodies, including bamlanivimab, have demonstrated reduction in hospitalization rates in clinical trials, yet real-world evidence is lacking. METHODS: We conducted a retrospective case-control study across a single healthcare system of nonhospitalized patients, age 18 years or older, with documented positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, risk factors for severe COVID-19, and referrals for bamlanivimab via emergency use authorization. Cases were defined as patients who received bamlanivimab; contemporary controls had a referral order placed but did not receive bamlanivimab. The primary outcome was 30-day hospitalization rate from initial positive SARS-CoV-2 polymerase chain reaction (PCR). Descriptive statistics, including χ 2 and Mann-Whitney U test, were performed. Multivariable logistic regression was used for adjusted analysis to evaluate independent associations with 30-day hospitalization. RESULTS: Between 30 November 2020 and 19 January 2021, 218 patients received bamlanivimab (cases), and 185 were referred but did not receive drug (controls). Thirty-day hospitalization rate was significantly lower among patients who received bamlanivimab (7.3% vs 20.0%, risk ratio [RR] 0.37, 95% confidence interval [CI]: .21-.64, P < .001), and the number needed to treat was 8. On logistic regression, odds of hospitalization were increased in patients not receiving bamlanivimab and with a higher number of pre-specified comorbidities (odds ratio [OR] 4.19 ,95% CI: 1.31-2.16, P < .001; OR 1.68, 95% CI: 2.12-8.30, P < .001, respectively). CONCLUSIONS: Ambulatory patients with COVID-19 who received bamlanivimab had a lower 30-day hospitalization than control patients in real-world experience. We identified receipt of bamlanivimab and fewer comorbidities as protective factors against hospitalization.Bamlanivimab's role in preventing hospitalization associated with coronavirus disease 2019 (COVID-19) remains unclear. In a real-world, retrospective study of 403 high-risk, ambulatory patients with COVID-19, receipt of bamlanivimab compared to no monoclonal antibody therapy was associated with lower 30-day hospitalization.

Functional activation features of memory in successful agers across the adult lifespan.

Much neuroimaging research has explored the neural mechanisms underlying successful cognitive aging. Two different patterns of functional activation, maintenance of youth-like activity and compensatory novel recruitment, have been proposed to represent different brain functional features underlying individual differences in cognitive aging. In this study, we investigated the functional features in individuals across the adult lifespan who appeared to resist age-related cognitive decline, in comparison to those with typical age-related declines, over the course of four years. We first implemented latent mixture modeling, a data-driven approach, to classify participants as successful and average agers in middle-aged, young-old, and very old groups, based on their baseline and longitudinal cognitive performance. Then, using fMRI with a subsequent memory paradigm at the follow-up visit, brain activation specifically related to successful encoding (i.e., subsequent memory effect: subsequently remembered with high confidence > subsequently forgotten) was compared between people who established successful cognitive aging versus average aging in the three age groups. Several differences in the subsequent memory effect were revealed. First, across core task-related regions commonly used during successful encoding, successful agers exhibited high subsequent memory effect, at a level comparable to the young control group, until very old age; in contrast, average agers showed reduced subsequent memory effect, compared to successful agers, beginning in young-old age when memory performance also reduced in average agers, compared to successful agers. Second, additional recruitment in prefrontal clusters, distant from the core task-related regions, were identified in the left superior frontal and right orbitofrontal cortices in successful agers of young-old age, possibly reflecting functional compensation in successful aging. In summary, successful agers demonstrate a pattern of youth-like activation spanning from middle age to young-old age, as well as novel frontal recruitment in young-old age. Overall, our study demonstrated evidence of two neural patterns related to successful cognitive aging, offering an integrated view of functional features underlying successful aging, and suggests the importance of studying individuals across the lifespan to understand brain changes occurring in mid and early-late life.

Computed Tomography Evaluation of In Vivo Pulmonary Cryoablation Zone Sizes.

PURPOSE: To evaluate ablation zone sizes in patients undergoing pulmonary tumor cryoablation with 14-gauge cryoablation probes. MATERIALS AND METHODS: A single-center retrospective analysis of all consecutive patients who underwent cryoablation of pulmonary tumors with 1 or more 14-gauge probes (August 2017 to June 2020) was performed. Intraprocedural and 1-2-month postprocedural chest computed tomography (CT) scans were evaluated to characterize pulmonary lesions, ice balls, and ablation zones. Single-probe 14-gauge ablation zone volumes were compared with manufacturer reference isotherms and single- and 2-probe ablation zones from a prior investigation of 17-gauge probes. Overall survival and local recurrence-free survival were calculated to 3 years. RESULTS: Forty-seven pulmonary malignancies in 42 patients (women, 50%; mean age, 75.2 years ± 11.5) underwent cryoablation with 1 (n = 35), 2 (n = 10), or 3 (n = 2) cryoablation probes. One- to 2-month follow-up CT images were available for 30 of the 42 patients. The mean cryoablation zone volumes at 1-2 months when 1 (n = 21), 2 (n = 8), and 3 (n = 1) probes were used were 5.0 cm3 ± 2.3, 37.5 cm3 ± 20.5, and 28.4 cm3, respectively. The mean single-probe follow-up ablation zone volume was larger than that previously reported for 17-gauge probes (3.0 cm3 ± 0.3) (P < .001) but smaller than manufacturer-reported isotherms (11.6 cm3 for -40 °C isotherm) and the 2-probe ablation zone volume with 17-gauge devices (12.9 cm3 ± 2.4) (for all, P < 001). The 3-year overall survival and local recurrence-free survival were 69% (95% confidence interval [CI], 53%-89%) and 87% (95% CI, 74%-100%), respectively. CONCLUSIONS: Fourteen-gauge probes generate larger ablation volumes than those generated by 17-gauge probes. Manufacturer-reported isotherms are significantly larger than actual cryoablation zones. Cryoablation can attain low rates of local recurrence.

Reduction of Rare-Earth Metal Complexes Induced by γ Irradiation.

The utility of γ irradiation for generating unstable, low oxidation state molecular species containing rare-earth metal ions in frozen solution has been examined. The method was evaluated by irradiating Ln(III) precursors (Ln = Sc, Y, and La) in a solid matrix of 2-methyltetrahydrofuran at 77 K with a 700 keV 137Cs source to generate free electrons capable of reducing the Ln(III) species. These experiments yielded EPR and UV-visible spectroscopic data that matched those of the known Ln(II) species [(C5H4SiMe3)3YII]1-, [(C5H4SiMe3)3LaII]1-, and {ScII[N(SiMe3)2]3}1-. Irradiation of the La(III) complex LaIII[N(SiMe3)2]3 by this method gave EPR and UV-visible absorption spectra consistent with {LaII[N(SiMe3)2]3}1-, a species that had previously eluded preparation by chemical reduction. Specifically, the irradiation product exhibited an axial EPR spectrum split into eight lines by the I = 7/2 139La nucleus (g⊥ = 1.98, g|| = 2.06, Aave = 519.1 G). The UV-visible absorption spectrum contains broad bands centered at 390 and 670 nm that are consistent with a La(II) ion in a trigonal ligand environment based on time-dependent density functional theory which qualitatively reproduces the observed spectrum. Additionally, the rate of formation of the [(C5H4SiMe3)3YII]1- species during the irradiation of (C5H4SiMe3)3YIII was monitored by measuring the concentration via UV-visible spectroscopy over time to provide data on the rate at which a molecular species is reduced in a glass via γ irradiation.

Association of distal hyperintense vessel sign and recurrent stroke in patients with symptomatic intracranial stenosis.

OBJECTIVE: The distal hyperintense vessel sign (DHV) on fluid-attenuated inversion recovery magnetic resonance image (MRI) is an imaging biomarker of slow leptomeningeal collateral flow in the presence of large artery stenosis or occlusion reflecting impaired cerebral hemodynamics. In this study, we aim to investigate the significance of the DHV sign in patients with symptomatic ≥ 70% intracranial atherosclerotic stenosis. METHODS: We retrospectively reviewed patients with ischemic stroke or transient ischemic attack admitted to a single center from January 2010 to December 2017. Patients were included if they had symptomatic ≥ 70% atherosclerotic stenosis of the intracranial internal carotid artery or middle cerebral artery. The presence of the DHV sign was evaluated by blinded neuroradiologist and vascular neurologists. Recurrent ischemic stroke in the vascular territory of symptomatic intracranial artery was defined as new neurological deficits with associated neuroimaging findings during the follow up period. RESULTS: A total of 109 patients were included in the study, of which 55 had DHV sign. Average duration of follow up was 297 ± 326 days. Four patients were lost during follow up. Patients with the DHV sign had a higher rate of recurrent ischemic stroke (38%), compared to patients without the DHV sign (17%; p=0.018). In multivariate regression analysis, the presence of DHV sign was an independent predictor of recurrent ischemic stroke. A DHV score of ≥ 2 had a 63% sensitivity and 69% specificity for recurrent ischemic stroke. INTERPRETATION: In patients with severe symptomatic intracranial atherosclerotic stenosis, those with a DHV sign on MRI are at higher risk of recurrent ischemic stroke.

Percutaneous Dilational Tracheostomy for Coronavirus Disease 2019 Patients Requiring Mechanical Ventilation.

OBJECTIVES: To assess the impact of percutaneous dilational tracheostomy in coronavirus disease 2019 patients requiring mechanical ventilation and the risk for healthcare providers. DESIGN: Prospective cohort study; patients were enrolled between March 11, and April 29, 2020. The date of final follow-up was July 30, 2020. We used a propensity score matching approach to compare outcomes. Study outcomes were formulated before data collection and analysis. SETTING: Critical care units at two large metropolitan hospitals in New York City. PATIENTS: Five-hundred forty-one patients with confirmed severe coronavirus disease 2019 respiratory failure requiring mechanical ventilation. INTERVENTIONS: Bedside percutaneous dilational tracheostomy with modified visualization and ventilation. MEASUREMENTS AND MAIN RESULTS: Required time for discontinuation off mechanical ventilation, total length of hospitalization, and overall patient survival. Of the 541 patients, 394 patients were eligible for a tracheostomy. One-hundred sixteen were early percutaneous dilational tracheostomies with median time of 9 days after initiation of mechanical ventilation (interquartile range, 7-12 d), whereas 89 were late percutaneous dilational tracheostomies with a median time of 19 days after initiation of mechanical ventilation (interquartile range, 16-24 d). Compared with patients with no tracheostomy, patients with an early percutaneous dilational tracheostomy had a higher probability of discontinuation from mechanical ventilation (absolute difference, 30%; p < 0.001; hazard ratio for successful discontinuation, 2.8; 95% CI, 1.34-5.84; p = 0.006) and a lower mortality (absolute difference, 34%, p < 0.001; hazard ratio for death, 0.11; 95% CI, 0.06-0.22; p < 0.001). Compared with patients with late percutaneous dilational tracheostomy, patients with early percutaneous dilational tracheostomy had higher discontinuation rates from mechanical ventilation (absolute difference 7%; p < 0.35; hazard ratio for successful discontinuation, 1.53; 95% CI, 1.01-2.3; p = 0.04) and had a shorter median duration of mechanical ventilation in survivors (absolute difference, -15 d; p < 0.001). None of the healthcare providers who performed all the percutaneous dilational tracheostomies procedures had clinical symptoms or any positive laboratory test for severe acute respiratory syndrome coronavirus 2 infection. CONCLUSIONS: In coronavirus disease 2019 patients on mechanical ventilation, an early modified percutaneous dilational tracheostomy was safe for patients and healthcare providers and associated with improved clinical outcomes.

Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.

Chest CT Angiography for Acute Aortic Pathologic Conditions: Pearls and Pitfalls.

Chest CT angiography (CTA) is essential in the diagnosis of acute aortic syndromes. Chest CTA quality can be optimized with attention to technical parameters pertaining to noncontrast imaging, timing of contrast-enhanced imaging, contrast material volume, kilovolt potential, tube-current modulation, and decisions regarding electrocardiographic-gating and ultra-fast imaging, which may affect the accurate diagnosis of acute aortic syndromes. An understanding of methods to apply to address suboptimal image quality is useful, as the accurate identification of acute aortic syndromes is essential for appropriate patient management. Acute aortic syndromes have high morbidity and mortality, particularly when involving the ascending aorta, and include classic aortic dissection, penetrating atherosclerotic ulcer, and acute intramural hematoma. An understanding of the pathogenesis and distinguishing imaging features of acute aortic syndromes and aortic rupture and some less common manifestations is helpful when interpreting imaging examinations. Related entities, such as ulcerated plaque, ulcerlike projections, and intramural blood pools, and mimics, such as vasculitis and aortic thrombus, are important to recognize; knowledge of these is important to avoid interpretive pitfalls. In addition, an awareness of postsurgical aortic changes can be useful when interpreting CTA examinations when patient history is incomplete. The authors review technical considerations when performing CTA, discuss acute aortic syndromes, and highlight diagnostic challenges encountered when interpreting aortic CTA examinations. ©RSNA, 2021.

Imaging Course of Lung Transplantation: From Patient Selection to Postoperative Complications.

Lung transplant is increasingly performed for the treatment of end-stage lung disease. As the number of lung transplants and transplant centers continues to rise, radiologists will more frequently participate in the care of patients undergoing lung transplant, both before and after transplant. Potential donors and recipients undergo chest radiography and CT as part of their pretransplant assessment to evaluate for contraindications to transplant and to aid in surgical planning. After transplant, recipients undergo imaging during the postoperative hospitalization and also in the long-term outpatient setting. Radiologists encounter a wide variety of conditions leading to end-stage lung disease and a myriad of posttransplant complications, some of which are unique to lung transplantation. Familiarity with these pathologic conditions, including their imaging findings and their temporal relationship to the transplant, is crucial to accurate radiologic interpretation. Knowledge of the surgical techniques and expected postoperative appearance prevents confusing normal posttransplant imaging findings with complications. A basic understanding of the indications, contraindications, and surgical considerations of lung transplant aids in imaging interpretation and protocoling and also facilitates communication between radiologists and transplant physicians. Despite medical and surgical advances over the past several decades, lung transplant recipients currently have an average posttransplant life expectancy of only 6.7 years. As members of the transplant team, radiologists can help maximize patient survival and hopefully increase posttransplant life expectancy and quality of life in the coming decades. ©RSNA, 2021 An invited commentary by Bierhals is available online. Online supplemental material is available for this article.