Ethan Y. Brovman

Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells ☆

Scutellaria baicalensis (SB) and SB-derived polyphenols possess anti-proliferative activities in several cancers, including pancreatic cancer (PaCa). However, the precise molecular mechanisms have not been fully defined. SB extract and SB-derived polyphenols (wogonin, baicalin, and baicalein) were used to determine their anti-proliferative mechanisms. Baicalein significantly inhibited the proliferation of PaCa cell lines in a dose-dependent manner, whereas wogonin and baicalin exhibited a much less robust effect. Treatment with baicalein induced apoptosis with release of cytochrome c from mitochondria, and activation of caspase-3 and -7 and PARP. The general caspase inhibitor zVAD-fmk reversed baicalein-induced apoptosis, indicating a caspase-dependent mechanism. Baicalein decreased expression of Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, presumably through a transcriptional mechanism. Genetic knockdown of Mcl-1 resulted in marked induction of apoptosis. The effect of baicalein on apoptosis was significantly attenuated by Mcl-1 over-expression, suggesting a critical role of Mcl-1 in this process. Our results provide evidence that baicalein induces apoptosis in pancreatic cancer cells through down-regulation of the anti-apoptotic Mcl-1 protein.

Mapping of Interdomain Interfaces Required for the Functional Architecture of Yor1p, a Eukaryotic ATP-binding Cassette (ABC) Transporter

ATP-binding cassette (ABC) transporters are a large superfamily of proteins that mediate substrate translocation across biological membranes. Our goal was to define the intramolecular interactions that contribute to quaternary assembly of a eukaryotic ABC transporter and determine how the architecture of this protein influences its biogenesis within the secretory pathway. We used chemical cross-linking approaches to map interdomain interactions in the yeast ABC transporter, Yor1p, which functions as a pleiotropic drug pump at the plasma membrane. We have defined interactions between the two nucleotide-binding domains (NBDs) and between the NBDs and specific intracellular loops (ICLs) that are consistent with current structural models of bacterial ABC exporters. Furthermore, we detected relatively weak NBD-NBD and ICL-ICL interactions that may correspond to transient sites of cross-talk between domains required for coupling of ATP hydrolysis with substrate translocation. Mutation of a key residue in ICL2 caused misassembly of the altered protein, leading to increased sensitivity to the mitochondrial poison, oligomycin. We identified intragenic suppressing mutations that rescued the oligomycin resistance associated with this aberrant protein and demonstrated that the suppressing mutations restored multiple interdomain interfaces. Together, our biochemical and genetic approaches contribute to a greater understanding of the architecture of this important class of proteins and provide insight into the quality control surveillance that regulates their biogenesis and deployment within the eukaryotic cell.

Pulmonary Artery Catheter Use During Cardiac Surgery in the United States, 2010 to 2014

OBJECTIVES To examine patterns of use of pulmonary artery catheters in a large cohort of patients undergoing cardiac surgery. DESIGN A retrospective study with univariate and multivariate logistic regression to identify independent predictors for the utilization of pulmonary artery catheters. SETTING University, small, medium and large community hospitals participating in the National Anesthesia Clinical Outcomes Registry. PARTICIPANTS A total of 116,333 patients undergoing pulmonary artery catheter placement during cardiac surgery in the National Anesthesia Clinical Outcomes Registry from the Anesthesia Quality Institute. MEASUREMENTS AND MAIN RESULTS Age older than 50 years, American Society of Anesthesiologists classification of 3 or higher, case duration of longer than 6 hours, and presence of a resident physician or certified nurse anesthetist were associated with increased likelihood of pulmonary artery catheter (PAC) placement. Age<18 years, or presence of a board-certified anesthesiologist, were associated with a decreased likelihood of catheter placement. The use of PACs has increased from 2010 to 2014. The presence of a PAC did not alter the risk of cardiac arrest intraoperatively. A nonsignificant decrease in mortality was associated with catheter placement. Transfusion was 75% less likely in the PAC cohort than in the control group. CONCLUSIONS Pulmonary artery catheter use remains a mainstay of cardiac anesthesia practice. No significant change in the incidence of intraoperative death was noted, but patients with a PAC were less likely to have blood transfused.

Unplanned Reintubation Following Cardiac Surgery: Incidence, Timing, Risk Factors, and Outcomes

OBJECTIVES To determine the incidence, timing, risk factors for, and outcomes after unplanned reintubation following cardiac surgery in adults. DESIGN Retrospective analysis of admission data from the American College of Surgeons National Surgical Quality Improvement Project Database, 2007-2013, inclusive. Univariate and multivariate analyses of risk factors and outcomes. PARTICIPANTS A total of 18,571 patients, over 18 years of age, undergoing cardiac surgery. INTERVENTIONS Not applicable. MEASUREMENTS AND MAIN RESULTS Reintubation incidence was 4.0%. Risk factors included older age, preoperative partial or total dependence, dyspnea at rest or on exertion, chronic kidney disease, chronic obstructive pulmonary disease, previous cardiac surgery, congestive heart failure, emergency surgery, longer duration of surgery, and mitral and tricuspid valve surgery. Patients requiring reintubation after surgery had 7.5 times higher mortality (21.9% v 2.9%), longer hospital admissions (22.2 v 7.8 days), and were less likely to be discharged home within 30 days (35% v 80%). Multivariate analysis demonstrated increased risk of failure to wean from the ventilator, pneumonia, sepsis, pulmonary embolism, deep vein thrombosis, and discharge to skilled care, rehabilitation, or other care. CONCLUSIONS Patients reintubated after cardiac surgery had significantly higher mortality, complication rates, and length of stay. Novel risk factors identified could be used to tailor extubation timing and strategy appropriately. Compared to noncardiac surgery, some risk factors for reintubation differed and risk continued beyond the immediate postoperative period to a greater degree.

Rate of Major Anesthetic-Related Outcomes in the Intraoperative and Immediate Postoperative Period After Cardiac Surgery

OBJECTIVES To examine anesthesia-centered outcomes in a large cohort of patients undergoing coronary artery bypass grafting (CABG) or valvular heart surgery. DESIGN A retrospective study with univariate and multivariate logistic regression to identify independent predictors for mortality. SETTING Diverse setting including university, small, medium, and large community hospitals. PARTICIPANTS All patients undergoing CABG or valve surgery in the National Anesthesia Clinical Outcomes Registry (NACOR) from the Anesthesia Quality Institute. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Common anesthesia-centered outcomes including arrhythmia, cardiac arrest, death, hemodynamic instability, hypotension, inadequate pain control, nausea/vomiting, seizure, stroke, reintubation and transfusion were reported. All outcomes, consistent with NACOR data entry, were defined as occurring intraoperatively or during phase I or II recovery in the PACU. Death occurred in 0.15% of CABGs and 0.23% of valve surgeries. Age less than 18, American Society of Anesthesiologists physical status (ASA PS) classification of 5, and mean case duration greater than 6 hours were associated with increased mortality (p<0.05). The presence of a board-certified anesthesiologist was associated with decreased odds for mortality. CONCLUSIONS Death was a rare outcome in this cohort, reflecting the infrequent occurrence of intraoperative or immediate postoperative death. The presence of a board-certified anesthesiologist represented a modifiable risk factor for reducing mortality risk.

Comparison of Postoperative Outcomes in Elderly Patients With a Do-Not-Resuscitate Order Undergoing Elective and Nonelective Hip Surgery:

Purpose: Emergency hip surgery generally has worse outcomes than elective hip surgery, even when adjusted for patient and surgical factors. Do-not-resuscitate (DNR) status patients are typically at higher perioperative risk and undergo a narrow range of surgical procedures. We aimed to compare the outcomes after hip surgery of differing degrees of urgency in this cohort. Materials and Methods: Using National Surgical Quality Improvement Program (NSQIP) data, we conducted univariate and multivariate analyses comparing outcomes of DNR status patients after emergency and nonemergency hip surgery (2007-2013). We conducted a subanalysis of mortality in elective versus nonelective cases (elective variable introduced from 2011). Results: Of 668 hip surgery cases in DNR status patients, 210 (31.4%) were emergency and 458 (68.8%) were nonemergency. There were no significant associations between emergency and nonemergency surgery regarding patient demographics, comorbidities, functional capacity, anesthesia type, or operative duration. There was no significant difference in the 30-day postoperative mortality between emergency (21.4%) and nonemergency (16.4%) or between elective (19.6%) and nonelective (18.3%) hip fracture surgeries performed in patients with preexisting DNR status. Morbidity patterns in emergency vs nonemergency cases demonstrated no significant differences, with the commonest 3 complications being transfusion (21.0% and 21.4%, respectively), urinary tract infection (9.5% and 7.9%, respectively), and pneumonia (both at 5.2%). The 30-day home discharge rates were low at 4.7% and 5.6%, respectively. Multivariate analysis demonstrated no significant associations between emergency and nonemergency surgery for mortality, discharge destination, length of stay or complications, except perioperative myocardial infarction (3.7% vs 1.3%, P < .04). Conclusion: For patients with DNR status, both emergent and non-emergent hip surgery carries high mortality, greatly exceeding rates predicted for that patient by American College of Surgeons NSQIP risk calculators. Morbidity rates and patterns for patients with DNR status are also similar in emergency and nonemergency groups. These data may be useful in discussing risk and obtaining adequately informed consent in DNR patients undergoing hip surgery.

A Contemporary Medicolegal Analysis of Outpatient Medication Management in Chronic Pain

BACKGROUND: Opioids are frequently used in chronic pain management but are associated with significant morbidity and mortality in some patient populations. An important avenue for identifying complications—including serious or rare complications—is the study of closed malpractice claims. The present study is intended to complement the existing closed claims literature by drawing on claims from a more recent timeframe through a partnership with a large malpractice carrier, the Controlled Risk Insurance Company (CRICO). The goal of this study was to identify patient medical comorbidities and aberrant drug behaviors, as well as prescriber practices associated with patient injury and malpractice claims. Another objective was to identify claims most likely to result in payments and use this information to propose a strategy for reducing medicolegal risk. METHODS: The CRICO Strategies Comparative Benchmarking System is a database of claims drawing from >350,000 malpractice claims from Harvard-affiliated institutions and >400 other academic and community institutions across the United States. This database was queried for closed claims from January 1, 2009, to December 31, 2013, and identified 37 cases concerning noninterventional, outpatient chronic pain management. Each file consisted of a narrative summary, including expert witness testimony, as well as coded fields for patient demographics, medical comorbidities, the alleged damaging event, the alleged injurious outcome, the total financial amount incurred, and more. We performed an analysis using these claim files. RESULTS: The mean patient age was 43.5 years, with men representing 59.5% of cases. Payments were made in 27% of cases, with a median payment of

Factors associated with an increased risk of perioperative cardiac arrest in emergent and elective craniotomy and spine surgery

72,500 and a range of

A medicolegal analysis of malpractice claims involving anesthesiologists in the gastrointestinal endoscopy suite (2007–2016)

7500–

Analysis of adverse outcomes in the post-anesthesia care unit based on anesthesia liability data

687,500. The majority of cases related to degenerative joint disease of the spine and failed back surgery syndrome; no patients in this series received treatment of malignant pain. Approximately half (49%) of cases involved a patient death. The use of long-acting opioids and medical conditions affecting the cardiac and pulmonary systems were more closely associated with death than with other outcomes. The nonpain medical conditions present in this analysis included obesity, obstructive sleep apnea, chronic obstructive pulmonary disease, hypertension, and coronary artery disease. Other claims ranged from alleged addiction to opioids from improper prescribing to alleged abandonment with withdrawal of care. The CRICO analysis suggested that patient behavior contributed to over half of these claims, whereas deficits in clinical judgment contributed to approximately 40% of the claims filed. CONCLUSIONS: Claims related to outpatient medication management in pain medicine are multifactorial, stemming from deficits in clinical judgment by physicians, noncooperation in care by patients, and poor clinical documentation. Minimization of both legal risk and patient harm can be achieved by carefully selecting patients for chronic opioid therapy and documenting compliance and improvement with the treatment plan. Medical comorbidities such as obstructive sleep apnea and the use of long-acting opioids may be particularly dangerous. Continuing physician education on the safest and most effective approaches to manage these medications in everyday practice will lead to both improved legal security and patient safety.