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ImportanceIbrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown.ObjectiveTo assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity.Design, Setting, and ParticipantsThis cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry.ExposuresIbrutinib treatment for cancer control.Main Outcomes and MeasuresThe primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk–matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE.ResultsOverall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P P = .01, and P 2SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE.Conclusions and RelevanceIn this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Contemporary therapies improve breast cancer (BC) outcomes. Yet, many of these therapies have been increasingly linked with serious cardiotoxicity, including reports of profound hypertension. Yet, the incidence, predictors, and impacts of these events are largely unknown.Leveraging two large U.S.-based registries, the National Inpatient Sample (NIS) and the Food and Drug Administration Adverse Event Reporting System (FAERS) databases, we assessed the incidence, factors, and outcomes of hypertensive events among BC patients from 2007 to 2015. Differences in baseline characteristics, hypertension-related discharges, and complications were examined over time. Further, we performed a disproportionality analysis using reporting-odds-ratios (ROR) to determine the association between individual BC drugs and hypertensive events. Utilizing an ROR cutoff of1.0, we quantified associations by drug-class, and individual drugs with the likelihood of excess hypertension.Overall, there were 5,464,401 BC-admissions, of which 46,989 (0.8%) presented with hypertension. Hypertensive BC patients were older, and saw initially increased in-hospital mortality, which equilibrated over time. The mean incidence of hypertension-related admissions was 732 per 100,000 among BC patients, versus 96 per 100,000 among non-cancer patients (RR 7.71, p 0.001). Moreover, in FAERS, those with hypertension versus other BC-treatment side-effects were more frequently hospitalized (40.1% vs. 36.7%, p 0.001), and were most commonly associated with chemotherapy (45.9%). Outside of Eribulin (ROR 3.36; 95% CI 1.37-8.22), no specific drug was associated with a higher reporting of hypertension; however, collectively BC drugs were associated with a higher odds of hypertension (ROR 1.66; 95% CI 1.09-2.53).BC therapies are associated with a substantial increase in limiting hypertension.

Introduction Frequent right AQ4ventricular pacing (≥40%) with a transvenous pacemaker (TVP) is associated with the risk of pacing‐induced cardiomyopathy (PICM). Leadless pacemakers (LPs) have distinct physical and mechanical differences from TVP. The risk of PICM with LP is not known. To identify incidence, predictors, and long‐term outcomes of PICM in LP and TVP patients. Methods The study comprised all pacemaker‐dependent patients with LP or TVP who had left ventricular ejection fraction (LVEF) of ≥50 from 2014 to 2019. The incidence of PICM (≥10% LVEF drop) was assessed with an echocardiogram. Predictors for PICM were identified using multivariate analysis. Long‐term outcomes after cardiac resynchronization (CRT) were assessed in both groups. Results A total of 131 patients with TVP and 67 with LP comprised the study. All patients in the TVP group and the majority in the LP group underwent atrioventricular node ablation. The mean follow‐up duration in TVP and LP groups was 592 ± 549 and 817 ± 600 days, respectively. A total of 18 (13.7%) patients in TVP and 2 (3%) in LP developed PICM after a median duration of 254 (interquartile range: 470) days. The incidence of PICM was significantly higher with TVP compared with LP (p = .02). TVP as pacing modality was a positive (odds ratio [OR]: 1.07) while age was negative (OR: 0.94) predictor for PICM on multivariable analysis. Both patients in LP and all except two in the TVP group responded to CRT. Conclusion Incidence of PICM is significantly lower with LP compared with TVP in pacemaker‐dependent patients. Age and TVP as pacing modality were predictors for PICM.

Purpose: Enrollment in Children's Oncology Group (COG) clinical trials has led to significant improvements in survival; however, disparities in survival persist, particularly among ethnic minorities, adolescents and young adults (AYAs), and the underinsured, partly due to inadequate access to cooperative group cancer clinical trials. In 2008, two COG sites University of Illinois at Chicago (UIC) and Rush University Medical Center, and a nonmember institution, John H Stroger Hospital, created a unified COG program utilizing one lead Institutional Review Board and research team. This study assesses the impact that the tri-institutional COG program had on clinical trial accrual for minority, AYA, and uninsured patients. Methods: Analysis and comparison of COG enrollment data from 2002 to 2008 (pre-merger) and 2008 to 2017 (post-merger) by age, ethnicity, insurance type, clinical trial type, oncologic diagnosis, and specialty of the enrolling physician were completed. Results: Following the merger, the total studies open to enrollment increased by 100%, enrollments increased by 446%, and, for each diagnoses, increased by more than 200%. Enrollment of ethnic minorities rose by 533%, most significantly for Hispanic patients by 925%. AYA enrollments increased by 822%. There was a 28-fold increase in enrollment of uninsured patients. Significantly more providers from various oncology specialties were engaged in enrolling patients and a consistent increase in the percentile standing of the program occurred after the merger. Conclusions: Creation of a tri-institutional COG research program was associated with significant increases in clinical trial enrollments, especially for underrepresented minorities, AYAs, and uninsured patients. The UIC/Rush/Stroger COG Program provides a novel and exemplary approach to address cancer health disparities for these vulnerable populations.

Radiation-induced cardiovascular disease, including coronary artery disease, is a well-known sequela of radiation therapy and represents a significant source of morbidity and mortality for cancer survivors. This review examines current literature and guidelines to care for this growing population of cancer survivors. The development of radiation-induced ischemic heart disease following radiation can lead even to early cardiotoxicities, inclusive of coronary artery disease, which limit cancer treatment outcomes. These coronary lesions tend to be diffuse, complex, and proximal. Early detection with multimodality imaging and targeted intervention is required to minimize these risks. Early awareness, detection, and management of radiation-induced cardiovascular disease are paramount as cancer survivorship continues to grow.

Coronavirus Disease 2019 (COVID‐19) has infected more than 3.0 million people worldwide and killed more than 200,000 as of April 27, 2020. In this White Paper, we address the cardiovascular co‐morbidities of COVID‐19 infection; the diagnosis and treatment of standard cardiovascular conditions during the pandemic; and the diagnosis and treatment of the cardiovascular consequences of COVID‐19 infection. In addition, we will also address various issues related to the safety of healthcare workers and the ethical issues related to patient care in this pandemic.

Necrotizing myopathy (NM), a type of idiopathic inflammatory myopathy (IIM), is an autoimmune disorder in which immune cells target skeletal muscle, resulting in muscle breakdown and weakness. Cardiac involvement in this disorder is rare. We highlight a case of autoantibody-negative NM complicated by myocarditis and sudden cardiac death. Case Report: A 45-year-old male with a history of hypertension, previous hepatitis B, and obesity presented with 6 months of progressive proximal lower extremity weakness. Workup revealed elevated creatinine phosphokinase, ESR and CRP, elevated troponin, and electromyography notable for a myopathic process. Age appropriate malignancy screening, infectious workup, and myositis panel were negative. The patient underwent left bicep biopsy which revealed muscle fiber necrosis and regeneration, consistent with the diagnosis of seronegative NM. Patient was discharged on mycophenolate and intravenous immunoglobulin with improvements in peripheral strength. Unfortunately, while recovering, he was readmitted with palpitations and dyspnea. Electrocardiogram showed a new trifascicular block and telemetry revealed frequent runs of non-sustained ventricular tachycardia (NSVT). A Cardiac MRI revealed evidence of myocarditis (Image 1). Endomyocardial biopsy showed fibrosis with entrapped myocytes (Image 2). He was treated with pulse dose intravenous glucocorticoids and mycophenolate was increased. EP study (EPS) was performed which did not reveal inducible VT; therefore, implantable cardiac defibrillator (ICD) was not implanted. Three months later the patient had sudden unexplained death at home. Discussion: Cardiac involvement in IIM—especially seronegative NM—is rare and not well described. Our patient had worsening cardiac involvement despite improvements in his skeletal myopathy. Despite a recent negative EPS, the patient had sudden unexplained death. Perhaps, a lower threshold for ICD implantation should be considered in this population. This case raises awareness for cardiac involvement in seronegative NM and raises the question of whether these patients are at increased risk of sudden cardiac death.

IntroductionOn June 3, 2005 in a United States federal courtroom in Nashville, Tennessee, seven words disrupted the age-old, natural cycle of musical development: "Get a license or do not sample."1 At the heart of the case was a sample2 of a common, three-note guitar riff3 from the introduction to the George Clinton funk song Get Off Your Ass and Jam. The sampled portion was sonically altered and repeated five times in the background of the song 100 Miles and Runnin ' by the hip-hop group N.W.A. 100 Miles was also featured on the soundtrack to the film I Got the Hook Up. In this pivotal case, the Sixth Circuit Court reversed a lower court ruling that the use of the sample was de minimis4 and established a bright-line rule5 for digital sampling. The three-judge panel concluded, "We do not see this as stifling creativity in any significant way."6 This article intends to show that while the court was technically correct in its assessment of the Copyright Act in relation to Sound Recordings,7 the decision exposed a flaw in the Act itself. Namely, as currently defined, Sound Recordings are fundamentally different from other categories of works8 in that they do not, and in fact cannot, meet the same minimal creativity requirement9 for copyright. The "idea/expression dichotomy"10 is not relevant to Sound Recordings because unlike every other category of works, they are not the result of an expression of ideas fixed in tangible form. They are strictly the result of fixation regardless of the nature, quality, and originality (or lack thereof) of the sounds embodied therein. Authorship of Sound Recordings is problematic since they are not the result of any individual's expression and thus cannot be infringed upon save by the physical duplication of a material object. Therefore in contrast to all other categories of copyrightable works, ideas cannot be freely extracted from them to be used as the building blocks for new, independent creations. The historical record shows that Sound Recordings were afforded copyright protection for a singular economic reason: to combat record piracy. Owners exercise a complete monopoly over any reproduction and derivative of Sound Recordings for the full term of copyright. While enormously effective in battling record piracy, this broad statutory stranglehold continues to impact the naturally transformative cycle of musical development in regards to sample-based music. The court was legally right: sampling requires copying.11 But the court was musically wrong: transformational copying is the heart of musical innovation and development. Creativity has been significantly stifled.A Brief History of Copyright in Sound Recordings in the United States: 1900-1970Law typically follows innovation; an axiom exemplified throughout the history of recorded music. By the turn of the twentieth century, emerging audio recording technology had already made an indelible mark on the music industry. Three major labels (Edison, Victor, and Columbia) were selling three million records per year in the United States by 1900.12 Yet federal copyright protection was not made available to producers of recordings until 1972. Why? Lawmakers in the U.S. were reluctant to define recordings, then known as phonograms, as "writings." The U.S. Constitution states that "Congress shall have the power...To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries."13 The Copyright Act of 1909 specified in Section 4, "...the works for which copyright may be secured under this Act shall include all the writings of an author"14 (emphasis added). In 1908 the Supreme Court in the landmark case White-Smith Co. v. Apollo Co. concluded that because the pattern of perforations on piano rolls15 were not visually perceivable as music, the objects were not copies of musical works (i.e., not writings),16 authors could not control their use. …

e18000Background: Access to COG clinical trials has led to significant improvements in overall survival rates; however, disparities persist, particularly among Black and Hispanic patients, AYAs, an...

Sialic acids such as N-acetylneuraminic acid have been found at the surfaces of various cells. They may play an important role in intercellular adhesion and hence in animal morphogenesis. This work demonstrates sialic acid at the surfaces of seven-day chick embryo neural retinal cells and its regeneration after enzymatic removal. Neural retinas were excised and dissociated with trypsin. The cells were incubated in a solution of Vibrio cholerae neuraminidase. The enzymatic treat ment released sialic acid which was assayed by thg thiobarbituric acid method of Warren. The enzymatic treatment also reduced the cellular electrophoretic mobility from 1.1 to 0.4 × 10−4 cm/sec/volt/cm measured in 0.067 molar phos phate buffer at pH 7.5. Cells which had been treated with neuraminidase were cultured in a modified Eagle's minimum essential medium for up to 24 hours. During the period of culture, the replacement of surface material was observed in two ways. First was the progressive return of electrophoretic mobility to the pre-neuraminidase level. Second was the progressive return of sialic acid at the cell surface to the original level. The latter was shown by second neuraminidase treatments and determinations of sialic acid released. Effects of neuraminidase upon the reaggregation of cells cultured on a gyratory shaker in Eagle's medium were investigated. Neuraminidase was not effective for dissociation of neural retina.