Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke.

Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and cerebrovascular endothelium from ischemic injury. A recombinant APC, drotrecogin alfa (activated) (DrotAA) (Xigris®), was approved by the Food and Drug Administration for the treatment of sepsis; however, serious bleeding was a dose-limiting side effect. A modified APC, containing 405 amino acid residues, 3K3A-APC, was designed to possess significantly reduced anticoagulant activity ( < 10 %) while maintaining full cytoprotective properties. The preclinical safety assessment of 3K3A-APC was conducted to support initiation of ischemic stroke clinical trials.The safety and toxicokinetics of 3K3A-APC were studied in CD-1 mice and cynomolgus monkeys. Multiple-dose (14-day), intravenous GLP toxicology assessed toxicity, histopathology, immunogenicity, and toxicokinetics.Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T(1/2) in monkeys was 1 hour. 3K3A-APC was well tolerated in mice and monkeys, and no signs of 3K3A-APC toxicity were identified in mice or monkeys at any time. Additionally,wild-type APC (DrotAA) was studied to obtain comparative anticoagulant data using clotting assays. Anticoagulant activity of 3K3A-APC was observed in monkeys at doses of 1 and 5 mg/kg/day .In contrast, DrotAA showed prolongation of clotting assays in monkeys at doses 1/10(th) of those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APC-induced bleeding in clinical trials of 3K3A-APC is greatly reduced relative to wild type APC which makes this new drug a feasible therapy for ischemic stroke patients.

Experiential leadership training for pediatric chief residents: impact on individuals and organizations.

BACKGROUND: The past decade has seen a proliferation of leadership training programs for physicians that teach skills outside the graduate medical education curriculum. OBJECTIVE: To determine the perceived value and impact of an experiential leadership training program for pediatric chief residents on the chief residents and on their programs and institutions. METHODS: The authors conducted a retrospective study. Surveys were sent to chief residents who completed the Chief Resident Training Program (CRTP) between 1988 and 2003 and to their program directors and department chairs asking about the value of the program, its impact on leadership capabilities, as well as the effect of chief resident training on programs and institutions. RESULTS: Ninety-four percent of the chief residents and 94% of program directors and department chairs reported that the CRTP was "very" or "somewhat" relevant, and 92% of the chief residents indicated CRTP had a positive impact on their year as chief resident; and 75% responded it had a positive impact beyond residency. Areas of greatest positive impact included awareness of personality characteristics, ability to manage conflict, giving and receiving feedback, and relationships with others. Fifty-six percent of chief residents reported having held a formal leadership position since chief residency, yet only 28% reported having received additional leadership training. CONCLUSION: The study demonstrates a perceived positive impact on CRTP participants and their programs and institutions in the short and long term.

An assessment of user acceptance and satisfaction with the tobacco use cessation automated clinical practice guideline.

OBJECTIVE: To describe user acceptance of and satisfaction with the Tobacco Use Cessation (TUC) Automated Clinical Practice Guideline (ACPG) at the Henry Ford Health System. STUDY DESIGN: A previous investigation assessed compliance with the 5 As (ask, advise, assess, assist, and arrange) of the TUC ACPG across 3 study arms. This article describes user satisfaction with the TUC ACPG after implementation. METHODS: In all study arms, providers completed a survey before participating in a focus group. RESULTS: All providers in the TUC arm indicated that they "almost always" asked their patients about tobacco use. Providers in the TUC arm were generally satisfied with the features of the TUC ACPG, particularly the ease of electronically referring a patient to the Smoking Intervention Program. Barriers to use included time constraints, lack of staff, and the desire to "opt out" of the program for patients in specific situations (eg, patients with terminal illnesses). CONCLUSION: Because ACPGs are incorporated into electronic medical records, it is important to obtain provider input before implementation, to supply technology that is user friendly and fits into the work flow of the clinic, and to afford physicians the autonomy to opt out of the guideline in specific clinical circumstances.

Implementation of an obstetrics EMR module: overcoming user dissatisfaction.

To improve quality and efficiency, Henry Ford Health System developed and implemented a new obstetrics application that displays pertinent clinical practice guideline information and standardizes documentation. The initial application included an overview of the patient's vital sign history, a structured note appropriate for each visit and patient educational materials. Despite involvement by clinician subject-matter experts in its design, many clinicians were dissatisfied with the initial application, noting both performance and functionality issues. In response, the health system suspended mandatory use of the application, created a previously unplanned pilot period, made modifications, intensified training and fostered user support. These efforts culminated with clinicians formally voting to accept the application for mandatory use. Understanding the lessons learned from this implementation may help other organizations that are rolling out new information systems.

Effects of the tobacco use cessation automated clinical practice guideline.

OBJECTIVE: To evaluate the effects of the Tobacco Use Cessation (TUC) Automated Clinical Practice Guideline (ACPG) (a variation of the US Department of Health and Human Services Clinical Practice Guideline on Treating Tobacco Use and Dependence) on guideline adherence in a multisite health system. STUDY DESIGN: The study used a pre-post cross-sectional design. Paneled patients were enrolled from 6 clinics, including 2 control clinics (arm 1), 2 control clinics that received a check-in screen only (the check-in screen provided a simplified method for entering patient vital signs into the electronic medical record) (arm 2), and 2 clinics that received the TUC intervention (arm 3). METHODS: Baseline data on physician compliance with the 5 As (ask, assess, advise, assist, and arrange) at the last office visit were collected via telephone surveys from patients in the 3 study arms. The TUC-ACPG was then introduced in the TUC intervention clinics as part of the existing electronic medical record. Approximately 2 weeks after the TUC intervention, postimplementation data were collected via telephone survey. RESULTS: In the TUC intervention arm, postimplementation adherence rates increased relative to baseline for all 5 points of the guideline, with the largest increases seen in the assess and arrange guideline points. Controlling for factors such as age, race, and relevant comorbidities, logistic regression analysis indicated that the time (preimplementation vs postimplementation)-x-TUC intervention arm interaction demonstrated a statistically significant increase in the assess guideline point. CONCLUSION: Although baseline adherence rates were already high, the introduction of the TUC-ACPG led to further increases in guideline adherence.