Notes

Molecular investigation from the tandem Tudor site along with seed homeodomain histone binding internet domain names with the epigenetic regulator UHRF2.
Heart failure (HF) with reduced contractile function is a common and lethal syndrome in which the heart cannot pump blood to adequately meet bodily demands, resulting in high mortality despite the current standard of care. In modern societies, the most common drivers of HF are ischemic heart disease and hypertension. However, in a substantial subset of cases, patients present with dilated and poorly contracting hearts without evidence of common inciting stressors, a syndrome called dilated cardiomyopathy (DCM). Genome sequencing has identified a host of deleterious germline variants in key cardiomyocyte genes as causes of heritable DCM, including mutations in LMNA, which encodes the nuclear lamina-associated protein lamin A/C. In this issue of the JCI, Auguste et al. generate a mouse model of DCM in which they delete Lmna in cardiomyocytes and discover that bromodomain and extraterminal (BET) protein activation is a druggable epigenetic mechanism of disease pathogenesis in this heritable HF syndrome.Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically.The COVID-19 pandemic that struck New York City in the spring of 2020 was a natural experiment for the clinical ethics services of NewYork-Presbyterian (NYP). Two distinct teams at NYP's flagship academic medical centers-at NYP/Columbia University Medical Center (Columbia) and NYP/Weill Cornell Medical Center (Weill Cornell)-were faced with the same pandemic and operated under the same institutional rules. Each campus used time as an heuristic to analyze our collective response. The Columbia team compares consults during the pandemic with the same period during the year prior. read more The Weill Cornell service describes the phases of the pandemic to depict its temporal evolution and subsequent ethical challenges. Both sites report that the predominant ethical challenges centered around end-of-life decision making, setting goals of care, and medical futility, all complicated by resource allocation questions and the ambiguity of state law under crisis standards of care. The Columbia campus saw a statistically significant increase in ethics consultations provided to Hispanic patients, perhaps reflective of the disproportionate burden of COVID-19 suffered by this demographic. While Weill Cornell and Columbia saw a surge in clinical ethics consultations, the two services assumed a more expansive role than one normally played in institutional life. Serving as intermediaries between frontline clinicians and senior hospital administrators, consultants provided critical intelligence to hospital leadership about the evolution of the pandemic, disseminated information to clinicians, and attended to the moral distress of colleagues who were asked to provide care under truly extraordinary circumstances. The COVID-19 surge in New York City revealed latent capabilities in ethics consultation that may prove useful to the broader clinical ethics community as it responds to the current pandemic and reconceptualizes its potential for future service.When the COVID-19 surge hit New York City hospitals, the Division of Medical Ethics at Weill Cornell Medical College, and our affiliated ethics consultation services, faced waves of ethical issues sweeping forward with intensity and urgency. In this article, we describe our experience over an eight-week period (16 March through 10 May 2020), and describe three types of services clinical ethics consultation (CEC); service practice communications/interventions (SPCI); and organizational ethics advisement (OEA). We tell this narrative through the prism of time, describing the evolution of ethical issues and trends as the pandemic unfolded. We delineate three phases anticipation and preparation, crisis management, and reflection and adjustment. The first phase focused predominantly on ways to address impending resource shortages and to plan for remote ethics consultation, and CECs focused on code status discussions with surrogates. The second phase was characterized by the dramatic convergence of a rapid increaseled the many enduring ways that ethics consultation services can more robustly contribute to the ethical life of their institutions moving forward.The COVID-19 pandemic swept through New York City swiftly and with devastating effect. The crisis put enormous pressure on all hospital services, including the clinical ethics consultation team. This report describes the recent experience of the ethics consultants and Columbia University Irving Medical Center during the COVID-19 surge and compares the case load and characteristics to the corresponding period in 2019. By reporting this experience, we hope to supplement the growing body of COVID-19 scientific literature and provide details of the human toll the virus took on our hospitals and communities. We also aim to highlight the role of the clinical ethics consultant as well as areas of policy and law that may need to be addressed in order to be better prepared for a future public health crisis.
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