A First-in-Human Trial of a New Aqueous Ionic Liquid Embolic Material in Distal Embolization Applications.

PURPOSE: A prospective, single-arm, open-label, multicenter, first-in-human, early feasibility study was completed to evaluate the safety and performance of the GPX Embolic Device (Fluidx, Salt Lake City, Utah), a novel liquid embolic agent, for use in the peripheral vasculature when deep distal embolization is desired. MATERIALS AND METHODS: The early feasibility study evaluated the use of the device in the peripheral vasculature. Enrollment consisted of 17 patients with diverse embolization needs requiring deep distal vessel/vessel bed occlusion. Technical success, freedom from adverse events (AEs), and handling/performance characteristics were assessed with follow-up at 30 days. RESULTS: The trial enrolled 17 patients requiring distal vascular penetration of the embolic agent, including 7 with renal angiomyolipomas, 4 with renal cell carcinomas (primary and secondary), 4 with portal veins needing embolization, 1 with pelvic sarcoma, and 1 with polycystic kidney. In all cases (100%), technical success was achieved with target regions fully occluded on the first angiogram (taken immediately after delivery). Furthermore, the material received high usability ratings, as measured by a postprocedural investigator questionnaire. Most patients (15/17, 88.2%) were free from device-related severe AEs, and there were no unanticipated AEs during the study. Each patient completed a 30-day follow-up evaluation, and sites remained fully occluded in each case where imaging was available (6 [35.3%] of 17 patients had follow-up imaging where all sites were deemed occluded [100%] with a mean of 30.2 days after the procedure). CONCLUSIONS: The results of this first-in-human, early feasibility study demonstrate that the GPX Embolic Device may provide safe and effective embolization for arterial or venous applications where deep distal penetration is desired.

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.

BACKGROUND: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood. RESULTS: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate. CONCLUSIONS: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3.

Computational Re-Entry Vulnerability Index Mapping to Guide Ablation in Patients With Postmyocardial Infarction Ventricular Tachycardia.

BACKGROUND: Ventricular tachycardias (VTs) in patients with myocardial infarction (MI) are often treated with catheter ablation. However, the VT induction during this procedure does not always identify all of the relevant activation pathways or may not be possible or tolerated. The re-entry vulnerability index (RVI) quantifies regional activation-repolarization differences and can detect multiple regions susceptible to re-entry without the need to induce the arrhythmia. OBJECTIVES: This study aimed to further develop and validate the RVI mapping in patient-specific computational models of post-MI VTs. METHODS: Cardiac magnetic resonance imaging data from 4 patients with post-MI VTs were used to induce VTs in a computational electrophysiological model by pacing. The RVI map of a premature beat in each patient model was used to guide virtual ablations. We compared our results with those of clinical ablation in the same patients. RESULTS: Single-site virtual RVI-guided ablation prevented VT induction in 3 of 9 cases. Multisite virtual ablations guided by RVI mapping successfully prevented re-entry in all cases (9 of 9). Overall, virtual ablation required 15-fold fewer ablation sites (235.5 ± 97.4 vs 17.0 ± 6.8) and 2-fold less ablation volume (5.34 ± 1.79 mL vs 2.11 ± 0.65 mL) than the clinical ablation. CONCLUSIONS: RVI mapping allows localization of multiple regions susceptible to re-entry and may help guide VT ablation. RVI mapping does not require the induction of arrhythmia and may result in less ablated myocardial volumes with fewer ablation sites.

Arrhythmia in hypertrophic cardiomyopathy: Risk prediction using contrast enhanced MRI, T1 mapping, and personalized virtual heart technology.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), a disease with myocardial fibrosis manifestation, is a common cause of sudden cardiac death (SCD) due to ventricular arrhythmias (VA). Current clinical risk stratification criteria are inadequate in identifying patients who are at risk for VA and in need of an implantable cardioverter defibrillator (ICD) for primary prevention. OBJECTIVE: We aimed to develop a risk prediction approach based on imaging biomarkers from the combination of late gadolinium contrast-enhanced (LGE) MRI and T1 mapping. We then aimed to compare the prediction to a virtual heart computational risk assessment approach based on LGE-T1 virtual heart models. METHODS: The methodology involved combining short-axis LGE-MRI with post-contrast T1 maps to define personalized thresholds for diffuse and dense fibrosis. The combined LGE-T1 maps were used to evaluate imaging biomarkers for VA risk prediction. The risk prediction capability of the biomarkers was compared with that of the LGE-T1 virtual heart arrhythmia inducibility simulation. VA risk prediction performance from both approaches was compared to clinical outcome (presence of clinical VA). RESULTS: Image-based biomarkers, including hypertrophy, signal intensity heterogeneity, and fibrotic border complexity, could not discriminate high vs low VA risk. LGE-T1 virtual heart technology outperformed all the image-based biomarker metrics and was statistically significant in predicting VA risk in HCM. CONCLUSIONS: We combined two MR imaging techniques to analyze imaging biomarkers in HCM. Raw and processed image-based biomarkers cannot discriminate patients with VA from those without VA. Hybrid LGE-T1 virtual heart models could correctly predict VA risk for this cohort and may improve SCD risk stratification to better identify HCM patients for primary preventative ICD implantation.

Survival and Toxicities after 90Y Transarterial Radioembolization of Metastatic Colorectal Cancer in the RESIN Registry.

Background Patients with unresectable, chemorefractory hepatic metastases from colorectal cancer have considerable mortality. The role of transarterial radioembolization (TARE) with yttrium 90 (90Y) microspheres is not defined because most reports are from a single center with limited patient numbers. Purpose To report outcomes in participants with colorectal cancer metastases treated with resin 90Y microspheres from a prospective multicenter observational registry. Materials and Methods This study treated enrolled adult participants with TARE using resin microspheres for liver-dominant metastatic colorectal cancer at 42 centers, with enrollment from July 2015 through August 2020. TARE was used as the first-, second-, or third-line therapy or beyond. Overall survival (OS), progression-free survival (PFS), and toxicity outcomes were assessed by line of therapy by using Kaplan-Meier analysis for OS and PFS and Common Terminology Criteria for Adverse Events, version 5, for toxicities. Results A total of 498 participants (median age, 60 years [IQR, 52-69 years]; 298 men [60%]) were treated. TARE was used in first-line therapy in 74 of 442 participants (17%), second-line therapy in 180 participants (41%), and third-line therapy or beyond in 188 participants (43%). The median OS of the entire cohort was 15.0 months (95% CI: 13.3, 16.9). The median OS by line of therapy was 13.9 months for first-line therapy, 17.4 months for second-line therapy, and 12.5 months for third-line therapy (χ2 = 9.7; P = .002). Whole-group PFS was 7.4 months (95% CI: 6.4, 9.5). The median PFS by line of therapy was 7.9 months for first-line therapy, 10.0 months for second-line therapy, and 5.9 months for third-line therapy (χ2 = 8.3; P = .004). TARE-attributable grade 3 or 4 hepatic toxicities were 8.4% for bilirubin (29 of 347 participants) and 3.7% for albumin (13 of 347). Grade 3 and higher toxicities were greater with third-line therapy for bilirubin (P = .01) and albumin (P = .008). Conclusion Median overall survival (OS) after transarterial radioembolization (TARE) with yttrium 90 microspheres for liver-dominant metastatic colorectal cancer was 15.0 months. The longest OS was achieved when TARE was part of second-line therapy. Grade 3 or greater hepatic function toxicity rates were less than 10%. Clinical trial registration no. NCT02685631 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Treating patients with acute COPD in the ED: Are 5 days of azithromycin enough?

ABSTRACT: ED clinicians typically discharge patients on 5-day regimens of azithromycin and corticosteroids after an acute COPD exacerbation. This article discusses various studies that evaluated chronic azithromycin therapy to prevent exacerbations in patients with COPD. Although ED clinicians typically do not prescribe chronic medications, they can provide patient-centered care and determine a patient's follow-up to see if chronic azithromycin is needed.

Long-term outcomes following 90Y Radioembolization of neuroendocrine liver metastases: evaluation of the radiation-emitting SIR-spheres in non-resectable liver tumor (RESiN) registry.

BACKGROUND: The goal of this study was to evaluate efficacy and safety of 90Y radioembolization for neuroendocrine liver metastases (NELM) in a multicenter registry. METHODS: One hundred-seventy patients with NELM were enrolled in the registry (NCT02685631). Prior treatments included hepatic resection (n = 23, 14%), arterial therapy (n = 62, 36%), octreotide (n = 119, 83%), cytotoxic chemotherapy (n = 58, 41%), biologic therapy (n = 49, 33%) and immunotherapy (n = 10, 6%). Seventy-seven (45%) patients had extrahepatic disease. Seventy-eight (48%), 61 (37%), and 25 (15%) patients were Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or ≥ 2. Tumor grade was known in 81 (48%) patients: 57 (70%) were well-, 12 (15%) moderate-, and 12 (15%) poorly-differentiated. Kaplan-Meier analysis and log rank tests were performed to compare overall and progression-free survival (OS/PFS) by tumor location and grade. Toxicities were reported using Common Terminology Criteria for Adverse Events v.5. Cox Proportional Hazards were calculated for pancreatic primary, performance status, extrahepatic disease at treatment, unilobar treatment, baseline ascites, and > 25% tumor burden. RESULTS: One, 2, and 3-year OS rates were 75, 62 and 46%, respectively. Median OS was 33 months [(95% CI: 25-not reached (NR)]. The longest median OS was in patients with pancreatic (42 months, 95% CI: 33-NR) and hindgut 41 months, 95% CI: 12-NR) primaries. The shortest OS was in foregut primaries (26 months; 95% CI: 23-NR; X2 = 7, p = 0.1). Median OS of well-differentiated tumors was 36 months (95% CI: 10-NR), compared to 44 (95% CI: 7-NR) and 25 (95% CI: 3-NR) months for moderate and poorly differentiated tumors. Median progression-free survival (PFS) was 25 months with 1, 2, and 3-year PFS rates of 70, 54, and 35%, respectively. Thirteen patients (7.6%) developed grade 3 hepatic toxicity, most commonly new ascites (n = 8, 5%) at a median of 5.5 months. Performance status of ≥2 (HR 2.7, p = 0.01) and baseline ascites (HR 2.8, P = 0.049) predicted shorter OS. DISCUSSION: In a population with a high incidence of extrahepatic disease, 90Y was effective and safe in treatment of NELM, with median OS of 41 months for well differentiated tumors. Grade 3 or greater hepatic toxicity was developed in 7.6% of patients. TRIAL REGISTRATION: NCT02685631 .

The Do-It-Yourself Electrocardiogram.

Hands-on labs are a critical component of biomedical engineering undergraduate education. Due to both the pandemic and the growing interest in online education, we developed a Do-it-yourself Electrocardiogram (DIY EKG) project. The Arduino-based DIY EKG kit instructed students how to build a circuit to obtain their own EKG and then analyze their EKG data using Matlab. Despite the obstacles of virtually trouble-shooting, 85.4% of students (n = 103) were able to obtain their own EKG at home. We have provided the labelled circuit drawings, step-by-step instructions, Matlab files, and results in this paper. Survey results indicate that 89% of students felt the DIY EKG project was a "challenging yet fulfilling experience." Supplementary Information: The online version of this article contains supplementary material available 10.1007/s43683-021-00061-0.

Personalized computational heart models with T1-mapped fibrotic remodeling predict sudden death risk in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VAs) arising from the proliferation of fibrosis in the heart. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic resonance imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients.

ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress.

ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

Presence of Left Atrial Fibrosis May Contribute to Aberrant Hemodynamics and Increased Risk of Stroke in Atrial Fibrillation Patients.

Atrial fibrillation (AF) patients are at high risk of stroke, with the left atrial appendage (LAA) found to be the most common site of clot formation. Presence of left atrial (LA) fibrosis has also been associated with higher stroke risk. However, the mechanisms for increased stroke risk in patients with atrial fibrotic remodeling are poorly understood. We sought to explore these mechanisms using fluid dynamic analysis and to test the hypothesis that the presence of LA fibrosis leads to aberrant hemodynamics in the LA, contributing to increased stroke risk in AF patients. We retrospectively collected late-gadolinium-enhanced MRI (LGE-MRI) images of eight AF patients (four persistent and four paroxysmal) and reconstructed their 3D LA surfaces. Personalized computational fluid dynamic simulations were performed, and hemodynamics at the LA wall were quantified by wall shear stress (WSS, friction of blood), oscillatory shear index (OSI, temporal directional change of WSS), endothelial cell activation potential (ECAP, ratio of OSI and WSS), and relative residence time (RRT, residence time of blood near the LA wall). For each case, these hemodynamic metrics were compared between fibrotic and non-fibrotic portions of the wall. Our results showed that WSS was lower, and OSI, ECAP, and RRT was higher in the fibrotic region as compared to the non-fibrotic region, with ECAP (p = 0.001) and RRT (p = 0.002) having significant differences. Case-wise analysis showed that these differences in hemodynamics were statistically significant for seven cases. Furthermore, patients with higher fibrotic burden were exposed to larger regions of high ECAP, which represents regions of low WSS and high OSI. Consistently, high ECAP in the vicinity of the fibrotic wall suggest that local blood flow was slow and oscillating that represents aberrant hemodynamic conditions, thus enabling prothrombotic conditions for circulating blood. AF patients with high LA fibrotic burden had more prothrombotic regions, providing more sites for potential clot formation, thus increasing their risk of stroke.

Incidence and risk factors for sustained hepatic function toxicity 6 months after radioembolization: analysis of the radiation-emitting sir-spheres in non-resectable liver tumor (RESIN) registry.

BACKGROUND: To quantify rates and risk factors for toxicity after hepatic radioembolization using resin yttrium-90 microspheres. METHODS: Radiation-Emitting SIR-Spheres in Non-resectable liver tumor (RESIN) registry enrollees were reviewed with 614 patients included. Mean patient age was 63.1±12.5 years. The majority of patients were male (n=375, 61%) and white (n=490, 80%). Common tumor types were hepatocellular (n=197, 32%), colorectal (n=187, 30%) and neuroendocrine (n=56, 9%). Hepatotoxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE v 5). Potential risk factors for hepatotoxicity were tested using the Kruskal-Wallis or Pearson Chi-squared tests, and multivariate linear regressions. RESULTS: At 6 months, 115 patients (18.7%) died (n=91, 14.8%), entered hospice (n=20, 3.3%) or sought treatment elsewhere (n=4, 4%). Seven (1.1%) deaths were from liver decompensation. Grade 3 toxicity rates were: bilirubin (n=85, 13.8%), albumin (n=28, 4.6%), ALT (n=26, 4.2%) and AST (n=37, 6.0%). For each of these liver function test components, baseline abnormal labs predicted Grade 3 toxicity at follow-up by Kruskal-Wallis test (P<0.001) and linear regression (all P<0.03). Other significant factors predicting toxicity at regression included elevated Body-Mass Index (albumin P=0.0056), whole liver treatment (bilirubin P=0.046), and lower tumor volume (ALT and INR, P<0.035 for both). CONCLUSIONS: Baseline liver function abnormalities prior to radioembolization is the strongest predictor of post-treatment Grade 3 toxicity with rates as high as 13.8%. Toxicity rates for specific lab values are affected by large volume treatments especially with low tumor volumes.

Extracellular Matrix Enterocutaneous Fistula Plugs Show Promise for Low-Flow Colocutaneous and Enterocutaneous Fistulae.

PURPOSE: To evaluate extracellular matrix enterocutaneous fistula plugs (ECMFPs) in treatment of enteric fistulae at a single institution. MATERIALS AND METHODS: The study included 18 patients who had an ECMFP placed between 2012 and 2018 with treatment follow-up through July 2020. Median patient age was 52.5 years (interquartile range, 11.5 y). There were 28 ECMFP procedures performed on 19 separate fistulae. Fistulae locations were gastrocutaneous (n = 4), enterocutaneous (n = 9), and colocutaneous (n = 6). Descriptive statistics were used to define closure rates, recurrence rates, and complications. RESULTS: Fistula closure was achieved in 1 of 4 gastrocutaneous (25%), 4 of 9 enterocutaneous (44%), and 3 of 6 colocutaneous (50%) locations. The median time from procedure to fistula tract closure was 29 days interquartile range 25 days. The median time from ECMFP placement to fistula recurrence was 28 days (interquartile range 27 days). Of the fistulae that eventually closed, 6 of 8 closed after the first attempt (75%), and 2 closed after the second attempt (25%). Of the procedures that resulted in complete closure, 7 of 8 were categorized as low flow, and 1 of 8 was categorized as high flow. Complications were seen in 4 patients (23%), with major complications in 3 patients (17%). CONCLUSIONS: Low-flow fistulae originating from the small bowel are most likely to have complete closure. High-flow and/or gastrocutaneous fistulae are less likely to benefit from this intervention. In patients who are not surgical candidates or who have failed surgical management, ECMFPs may provide a solution.

Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution.

Mitochondria are involved in a number of diverse cellular functions, including energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, and motility, as well as free radical generation. Mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner. mtDNA copy number also varies during aging and disease progression and therefore might be considered as a biomarker that mirrors alterations within the human body. Here, we present a new quantitative, highly sensitive droplet digital PCR (ddPCR) method, droplet digital mitochondrial DNA measurement (ddMDM), to measure mtDNA copy number not only from cell populations but also from single cells. Our developed assay can generate data in as little as 3 h, is optimized for 96-well plates, and also allows the direct use of cell lysates without the need for DNA purification or nuclear reference genes. We show that ddMDM is able to detect differences between samples whose mtDNA copy number was close enough as to be indistinguishable by other commonly used mtDNA quantitation methods. By utilizing ddMDM, we show quantitative changes in mtDNA content per cell across a wide variety of physiological contexts including cancer progression, cell cycle progression, human T cell activation, and human aging.

Renal hilar block predicts long-term success of renal auto-transplantation for loin pain hematuria syndrome.

PURPOSE: In patients with loin pain hematuria syndrome (LPHS), a response to percutaneous renal hilar blockade (RHB) and a multidisciplinary team (MDT) evaluation predicts patient's potential renal auto-transplantation (RAT) success. METHODS: A pain assessment was performed using a 0-10 numeric pain rating scale prior to a percutaneous RHB under CT guidance. If the pain score was reduced > 50% immediately after the RHB, patients were evaluated for RAT by a MDT. Pre-operative and 1-year post-operative quality-of-life surveys were administered to each RAT patient. RESULTS: 43 LPHS patients were referred for RHB. Of the 38 patients who received a RHB, 31 had > 50% reduction in pain scores. Pre- and post-RHB mean pain scores were 6/10 and 0.7/10, respectively, in patients who had > 50% reduction in pain. 22 of the patients who responded favorably then proceeded to RAT. Twelve patients had at least 1-year follow-up after RAT. All patients had a meaningful decrease in their pain. Mean pain score at 1 year was 0.8/10 for an 85% overall reduction in pain. 92% of patients experienced a ≥ 50% reduction in pain at 1 year. Mean Beck Depression Inventory (BDI) score (0-66) 1 year after RAT decreased from 25.2 pre-op (moderate depression) to 12.8 post-op (minimal depression). CONCLUSIONS: A MDT approach utilizing a RHB should be considered as a tool to select appropriate LPHS patients for RAT to achieve long-term success in reducing chronic pain and depression while increasing quality of life.

Are gestures worth a thousand words? Verbal and nonverbal communication during robot-assisted surgery.

Communication breakdowns in the operating room (OR) have been linked to errors during surgery. Robot-assisted surgery (RAS), a new surgical technology, can lead to new challenges in communication owing to the remote location of the surgeon away from the patient and bedside assistants. Nevertheless, few studies have studied communication strategies during RAS. In this study, 11 robot-assisted radical prostatectomies were recorded and the interaction events between the surgeon and two bedside surgical team members were categorized by modality (verbal/nonverbal), topic, and pair (sender and receiver). Both verbal and nonverbal modalities were used by all pairs. The percentage of nonverbal interactions differed significantly by pair: 66% for the Surgeon-Physician Assistant, 50% for the Physician Assistant-Scrub Nurse, and 25% for the Surgeon-Scrub Nurse, indicating different communication strategies across pairs. In addition, there was a significant dependence between topic and the percentages of verbal and nonverbal events for all pairs. Strategies to improve team communication during RAS should take into account the use of verbal and nonverbal communication means and the variation in interaction strategies based on the topic of communication.