PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo. Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM (PLAU and KRT80) also supported this conclusion.

Gaps in patient care practices to prevent hospital-acquired delirium.

OBJECTIVE: To evaluate the current patient care practices that address the predisposing and precipitating factors contributing to the prevention of hospital-acquired delirium in the elderly. DESIGN: Prospective cohort (observational) study. PARTICIPANTS: Patients 65 years of age and older who were admitted to medical teaching units at the University of Alberta Hospital in Edmonton over a period of 7 months and who were at risk of delirium. SETTING: Medical teaching units at the University of Alberta. MAIN OUTCOME MEASURES: Demographic data and information on predisposing factors for hospital-acquired delirium were obtained for all patients. Documented clinical practices that likely prevent common precipitants of delirium were also recorded. RESULTS: Of the 132 patients enrolled, 20 (15.2%) developed hospital-acquired delirium. At the time of admission several predisposing factors were not documented (eg, possible cognitive impairment 16 [12%], visual impairment 52 [39.4%], and functional status of activities of daily living 99 [75.0%]). Recorded precipitating factors included catheter use, screening for dehydration, and medications. Catheters were used in 35 (26.5%) patients, and fluid intake-and-output charting assessed dehydration in 57 (43.2%) patients. At the time of admission there was no documentation of hearing status in 69 (52.3%) patients and aspiration risk in 104 (78.8%) patients. After admission, reorientation measures were documented in only 16 (12.1%) patients. Although all patients had brief mental status evaluations performed once daily, this was not noted to occur twice daily (which would provide important information about fluctuation of mental status) and there was no formal attention span testing. In this study, hospital-acquired delirium was also associated with increased mortality (P < .004), increased length of stay (P < .007), and increased institutionalization (P < .027). CONCLUSION: Gaps were noted in patient care practices that might contribute to hospital-acquired delirium and also in measures to identify the development of delirium at an earlier stage. Effort should be made to educate health professionals to identify the predisposing and precipitating factors, and to screen for delirium. This might improve the prevention of delirium.

Clinical Practice Recommendations on the Routine Use of Eversense, the First Long-Term Implantable Continuous Glucose Monitoring System.

Background: The use of real-time continuous glucose monitoring (rtCGM) systems has proved to positively impact the management of type 1 diabetes with the potential to lower HbA1c, reduce frequency and time spent in hypoglycemia, and lower glycemic variability. Nevertheless, the acceptance of rtCGM remains below expectations and the dropout rate within the first year has been reported to be 27%. Besides financial reasons due to limited reimbursement, reasons include the need for frequent sensor replacement, the discomfort of wearing a sensor, the presence of adverse skin reactions, or privacy. Thus, novel approaches to rtCGM are desired to overcome these barriers. The first long-term implantable rtCGM system diversifies the field of glucose monitoring further. However, due to its novelty, there are no published clinical practice guidelines available. Aims: The aim of this article is to set the foundation for a best clinical practice for the everyday clinical care using a long-term implantable CGM system. Methods: An international expert panel for the long-term implantable CGM system developed this best practice guidance. All participants were certified and experienced in the use of the Eversense® long-term implantable CGM system. The workflows from the respective clinics were presented, discussed and are summarized in an ideal care workflow outlined in these practice recommendations. Results: The participants agreed on the following aspects: definition of the patient population that will benefit from a long-term implantable CGM device; real-world experience on safety and accuracy of a long-term CGM; definition of the ideal sensor position; description of the optimal process for sensor insertion, removal, and replacement.

Impact of a triage liaison physician on emergency department overcrowding and throughput: a randomized controlled trial.

BACKGROUND: Triage liaison physicians (TLPs) have been employed in overcrowded emergency departments (EDs); however, their effectiveness remains unclear. OBJECTIVES: To evaluate the implementation of TLP shifts at an academic tertiary care adult ED using comprehensive outcome reporting. METHODS: A six-week TLP clinical research project was conducted between December 9, 2005, and February 9, 2006. A TLP was deployed for nine hours (11 AM to 8 PM) daily to initiate patient management, assist triage nurses, answer all medical consult or transfer calls, and manage ED administrative matters. The study was divided into three two-week blocks; within each block, seven days were randomized to TLP shifts and the other seven to control shifts. Outcomes included patient length of stay, proportion of patients who left without complete assessment, staff satisfaction, and episodes of ambulance diversion. RESULTS: TLPs assessed a median of 14 patients per shift (interquartile range, 13-17), received 15 telephone calls per shift (interquartile range, 14-20), and spent 17-81 minutes per shift consulting on the telephone. The number of patients and their age, gender, and triage score during the TLP and control shifts were similar. Overall, length of stay was decreased by 36 minutes compared with control days (4:21 vs. 4:57; p = 0.001). Left without complete assessment cases decreased from 6.6% to 5.4% (a 20% relative decrease) during the TLP coverage. The ambulance wait time and number of episodes of ambulance diversion were similar on TLP and control days. CONCLUSIONS: A TLP improved important outcomes in an overcrowded ED and could improve delivery of emergency medical care in similar tertiary care EDs.