Natalie Yip

Direct Interaction of Jak1 and v-Abl Is Required for v-Abl-Induced Activation of STATs and Proliferation

ABSTRACT In Abelson murine leukemia virus (A-MuLV)-transformed cells, members of the Janus kinase (Jak) family of non-receptor tyrosine kinases and the signal transducers and activators of transcription (STAT) family of signaling proteins are constitutively activated. In these cells, the v-Abl oncoprotein and the Jak proteins physically associate. To define the molecular mechanism of constitutive Jak-STAT signaling in these cells, the functional significance of the v-Abl–Jak association was examined. Mapping the Jak1 interaction domain in v-Abl demonstrates that amino acids 858 to 1080 within the carboxyl-terminal region of v-Abl bind Jak1 through a direct interaction. A mutant of v-Abl lacking this region exhibits a significant defect in Jak1 binding in vivo, fails to activate Jak1 and STAT proteins, and does not support either the proliferation or the survival of BAF/3 cells in the absence of cytokine. Cells expressing this v-Abl mutant show extended latency and decreased frequency in generating tumors in nude mice. In addition, inducible expression of a kinase-inactive mutant of Jak1 protein inhibits the ability of v-Abl to activate STATs and to induce cytokine-independent proliferation, indicating that an active Jak1 is required for these v-Abl-induced signaling pathways in vivo. We propose that Jak1 is a mediator of v-Abl-induced STAT activation and v-Abl induced proliferation in BAF/3 cells, and may be important for efficient transformation of immature B cells by the v-abloncogene.

Analysis of Hospitalizations for COPD Exacerbation: Opportunities for Improving Care

ABSTRACT Background: Little is known about the actual treatment of patients with chronic obstructive pulmonary disease (COPD), either in the inpatient or outpatient settings. We hypothesized that there are substantial opportunities for improvement in adherence with current guidelines and recommendations. Methods: We reviewed the medical records of all patients hospitalized with acute exacerbation of COPD between January 2005 and December 2006 at 5 New York City hospitals. Results: There were 1285 unique patients with 1653 hospitalizations. Of these 1653, 83% were for patients with a prior history of COPD and 368 (22%) represented repeat admissions during our study period. The majority were treated during their hospitalization with a combination of systemic steroids (85%), bronchodilators (94%) and antibiotics (80%). There were 59 deaths (3.6%). Smoking cessation counseling was offered to 48% of active smokers. Influenza and pneumococcal vaccines were administered to half of eligible patients. On discharge, only 46.0% were prescribed maintenance bronchodilators and 24% were not prescribed any inhaled therapy. Even in the 226 unique patients (17.6%) readmitted at least once during course of the study, on discharge only 44.7% were prescribed maintenance bronchodilators and 23% were not prescribed any regular inhaled therapy. Conclusions: Patients hospitalized with acute exacerbation of COPD generally receive adequate hospital care, but there may be opportunities to improve care pharmacologically and with smoking cessation counseling and vaccination during and after hospitalization.

The implementation of an early rehabilitation program is associated with reduced length of stay: A multi-ICU study

Introduction Survivors of critical illness face many potential long-term sequelae. Prior studies showed that early rehabilitation in the intensive care unit (ICU) reduces physical impairment and decreases ICU and hospital length of stay (LOS). However, these studies are based on a single ICU or were conducted with a small subset of all ICU patients. We examined the effect of an early rehabilitation program concurrently implemented in multiple ICUs on ICU and hospital LOS. Methods An early rehabilitation program was systematically implemented in five ICUs at the sites of two affiliated academic institutions. We retrospectively compared ICU and hospital LOS in the year before (1/2011–12/2011) and after (1/2012–12/2012) implementation. Results In the pre- and post-implementation periods, respectively, there were a total of 3945 and 4200 ICU admissions among the five ICUs. After implementation, there was a significant increase in the proportion of patients who received more rehabilitation treatments during their ICU stay (p < 0.001). The mean number of rehabilitation treatments per ICU patient-day increased from 0.16 to 0.72 (p < 0.001). In the post-implementation period, four of the five ICUs had a statistically significant decrease in mean ICU LOS among all patients. The overall decrease in mean ICU LOS across all five ICUs was 0.4 days (6.9%) (5.8 versus 5.4 days, p < 0.001). Across all five ICUs, there were 255 (6.5%) more admissions in the post-implementation period. The mean hospital LOS for patients from the five ICUs also decreased by 5.4% (14.7 vs. 13.9 days, p < 0.001). Conclusions A multi-ICU, coordinated implementation of an early rehabilitation program markedly increased rehabilitation treatments in the ICU and was associated with reduced ICU and hospital LOS as well as increased ICU admissions.

Advanced cardiovascular life support algorithm for the management of the hospitalized unresponsive patient on continuous flow left ventricular assist device support outside the intensive care unit

Over the past decade, continuous flow left ventricular assist devices (CF-LVADs) have become the mainstay of therapy for end stage heart failure. While the number of patients on support is exponentially growing, at present there are no American Heart Association or European Society of Cardiology Advanced Cardiovascular Life Support guidelines for the management of this unique patient population. We propose an algorithm for the hospitalized unresponsive CF-LVAD patient outside of the intensive care unit setting. Key elements of this algorithm are: creation of a dedicated LVAD code pager and LVAD code team; early assessment and correction of LVAD malfunction; early determination of blood flow using Doppler technique in carotid and femoral arteries; prompt administration of external chest compressions in the absence of Doppler flow; bedside veno-arterial extracorporeal membranous oxygenation support if no response to resuscitation measures; and early consideration for stroke.

983: LONG-TERM EFFECTS OF A SEDATION GUIDELINE IN MICUS MANAGED BY NURSE PRACTITIONERS VERSUS RESIDENTS

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Sedation protocols, daily interruption of sedation, early mobilization (EM), and analgesia-first sedation have been associated with decreased time of invasive mechanical ventilation and decreased length of stay. In 2011 we implemented a sedation guideline which promoted an analgesia-first strategy and encouraged intermittent, as-needed dosing before infusions in two identical medical intensive care units (MICUs) differing only in the presence of acute care nurse practitioners (ACNPs) or residents. Long-term effects of this guideline on opioid and sedative prescribing were assessed in MICU patients cared for by ACNPs (MICU-NP) and medical residents (MICU-R). Methods: Patients who were admitted to MICU-R or MICUNP between January through June in 2011, 2012, and 2016, and received at least one dose of a sedative were evaluated. Patients managed with ECMO were excluded. Numbers of patients who received each drug and quantities received were collected and compared. Fisher’s exact test was used for categorical data. A p < 0.05 was considered significant. Results: Patients admitted to MICU-R and MICU-NP numbered 174 and 169 in 2011; 211 and 179 in 2012; and 169 and 115 in 2016, respectively. From 2011 to 2012, opioid drips were reduced from 50% to 37% in MICU-R and from 43% to 29% in MICUNP. Similarly, benzodiazepine drips were reduced from 46% to 27% in MICU-R and from 39% to 22% in MICU-NP. In 2016, patients in MICU-R received more opioid drips as compared to MICU-NP (69% vs 50%, p = 0.002) as well as benzodiazepine drips (37% vs 21%, p = 0.006) and were less likely to be managed by only intermittent dosing of opioids (27% vs 42%, p = 0.01) or benzodiazepines (34% vs 46%, p = 0.049). In 2016 use of propofol and dexmedetomidine increased compared to prior years but did not differ between units. A logistic regression model examining interactions did not find a significant difference between units across the three time points for any opioid or sedative. Conclusions: A sedation guideline reduced opioids and benzodiazepines in both an ACNP unit and resident unit, but these decreases were better sustained in the ACNP unit.