Implantable Cardiac Defibrillator Deactivation During End-of-Life Care in the COVID-19 Pandemic.

People with implantable cardiac defibrillators (ICDs) who are nearing the end of life are at risk for arrhythmias, which activate the ICD and may cause unnecessary shocks and suffering. Because ICDs have enabled more patients to live longer, they often succumb to noncardiac diseases and may be cared for by primary care physicians. Despite published recommendations 10 years ago regarding the management of ICDs during the end of life, over half of patients with ICDs who are dying still have not been offered the choice of deactivation. The Coronavirus disease 2019 (COVID-19) pandemic has complicated this issue and the need to discuss it because of practices that separate patients from loved ones and that modify the usual interactions of patients with doctors and nurses. We offer the following recommendations: (1) the management of ICDs at the end-of-life needs to be understood by all physicians who care for patients with ICDs; (2) discussions about deactivating the ICD should occur while patients have decision-making capacity and are clinically stable, beginning at the time of ICD implantation, then periodically at follow-up appointments, and certainly when a change in the patient's clinical status warrants a reconsideration of the goals of care; and (3) clinicians should compensate for the impediments to communication with patients and families associated with the COVID-19 pandemic, which includes patient isolation and restrictive visitor policies, by using devices that permit visual communication to reexamine goals of care, including defibrillator deactivation, in patients with ICDs who are expected to die.

Diabetes SPECIAL (Students Providing Education on Chronic Illness and Lifestyle): a novel preclinical medical student elective.

BACKGROUND: Traditional medical student curricula limit substantial clinical experiences until the third and fourth years of medical school. This delay in valuable experiences hinders the ability of some medical students to choose a specialty to pursue, delays the formation of meaningful longitudinal mentorship relationships, and limits the development of important clinical acumen. Furthermore, the use of medical students in preclinical years may help to improve patient care and outcomes. APPROACH: The novel preclinical Diabetes SPECIAL (Students Providing Education on Chronic Illness and Lifestyle) elective was designed to introduce first year medical students to the field of endocrinology, promote the development of a professional identity, improve medical student communication skills, and raise awareness of the complexities of managing patients living with diabetes mellitus. Furthermore, and novel to this experience, was to measure the impact of this elective on patient outcomes. EVALUATION: Students attended patient appointments, communicated with their assigned patients regularly, relayed important health information to the attending endocrinologist, and attended monthly didactic sessions. The elective outcomes were evaluated via completed surveys by patients, students, and attending physicians as well as medical record review for pre- and post-elective hemoglobin A1C levels. REFLECTION: Students, faculty, and patients who participated in this elective generally reported having a positive experience. Seven out of 10 patients had a reduction in their hemoglobin A1C levels. The outcomes from the pilot of this novel preclinical elective support the importance of early clinical exposure in medical student training and highlight potential positive impacts on both medical student education and patient outcomes.

Validation of potential therapeutic targets in alveolar soft part sarcoma: an immunohistochemical study utilizing tissue microarray.

AIMS: The molecular signature of alveolar soft part sarcoma (ASPS) is a specific der(17)t(X;17)(p11.2;q25) translocation, resulting in a chimeric transcription factor (ASPSCR1-TFE3). When this disease is no longer amenable to surgical curative intervention, uniformly efficacious therapies are lacking. The aim of this study was to evaluate the expression of potential molecular therapeutic targets in a cohort of ASPS tumour samples. METHODS AND RESULTS: Immunohistochemical analysis for hepatocyte growth factor, c-Met, phosphorylated c-Met, phosphorylated AKT, phosphorylated MEK, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53 and vimentin was performed on an ASPS tissue microarray, yielding complete data from 26 tumours. Activation of c-Met and its downstream effectors was noted, whereas only limited EGFR expression was seen. VEGF was expressed to varying degrees. Only one sample exhibited strong nuclear p53 expression, while 10 expressed low levels. Vimentin expression was negative in the vast majority of samples (96%). CONCLUSIONS: There is a crucial need for better anti-ASPS therapies. Activated c-Met and the phosphorylation of its downstream effectors validate an intact signalling cascade probably induced by the ASPSCR1-TFE3 chimeric transcription factor. The angiogenic phenotype of these tumours is supported by increased angiogenic factor expression. Combination therapies targeting both tumour cells and angiogenesis merit further investigation.

The 19S proteasome ATPase Sug1 plays a critical role in regulating MHC class II transcription.

Emerging evidence in yeast suggests roles for ATPases of the 19S proteasome as mediators of transcriptional systems through their association with actively transcribed promoters, facilitation of clearance of paused elongation complexes and recruitment of coactivators. Although 19S subunits also regulate mammalian transcription, their role in recruiting transcription factors remains unclear. Here, we demonstrate for the first time a role for the 19S proteasome ATPase Sug1 in regulating transcription of the critical adaptive immune gene, MHC class II. Sug1 associates with the class II transactivator, CIITA, and with the MHC class II proximal promoter. In the absence of Sug1, HLA-DR promoter activity and MHC class II transcription are decreased. Critically, CIITA association with the MHC II promoter is dramatically decreased when Sug1 expression is reduced, even under conditions of proteasome inhibition. In contrast to the rapid promoter association of the 19S subunit, a 20S proteasome subunit associates with the MHC class II proximal promoter following prolonged cytokine stimulation and its association corresponds with pronounced promoter disassociation of CIITA. Taken together, these data demonstrate that both 19S and 20S subunits of the 26S proteasome play specific and critical roles in regulating CIITA activity and MHC class II transcription.