Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and 150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery

Inhaled Epoprostenol Compared with Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery

Background: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. Methods: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. Results: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, –6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. Conclusions: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03081052

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable preclinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2 and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four TCGA subtypes: 8 classical, 8 mesenchymal, and 4 proneural; none neural. Amplification of EGFR gene was observed in 9 out of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n=5) and low (n=15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent preclinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR

Toward a General Theory of Standards of Proof

Which standard of proof is best for a particular type of case This deceptively simple question has been much discussed but the current state of understanding is unsatisfactory Statisticians posed a general answer philosophers and others launched an assault on that answer practically oriented scholars draw on both strains unsystematically and courts generally offer little or no reasoning for their decisions The goal of this article is to outline a systematic and complete justification for selecting one probabilistic standard of proof over another By training a microscope on one small corner of the law incapacity will contests this article demonstrates the relevance of old factors identifies several new factors and integrates the factors into an approach that will hopefully guide future inquiry One important implication is that the choice of proof standard will almost necessarily be tentative too much is unknown or unknowabl

Screening extremely obese pregnant women for obstructive sleep apnea

BackgroundObesity is prevalent among pregnant women in the United States; obstructive sleep apnea is highly comorbid with obesity and is associated with adverse pregnancy outcomes. Screening for obstructive sleep apnea in pregnant women has remained a challenge because of a lack of validated screening tools.ObjectiveThe purpose of this study was to evaluate established obstructive sleep apnea screening tools, a sleepiness scale, and individual component items in a cohort of pregnant women with extreme obesity in mid pregnancy with the use of objective testing to determine obstructive sleep apnea status and to describe the prevalence of obstructive sleep apnea among women with extreme obesity.Study designAdult pregnant subjects, between 24 and 35 weeks gestation, with a body mass index ≥40 kg/m2 at the time of enrollment completed obstructive sleep apnea screening tools (Berlin Questionnaire, American Society of Anesthesiologists checklist, and STOP-BANG questionnaire) and the Epworth Sleepiness Scale; they also underwent physical examination of the neck, mouth, and airway. The published obstructive sleep apnea in pregnancy prediction score was calculated for each subject. Obstructive sleep apnea status for each subject was determined by the results of an overnight, unattended type III home sleep apnea test.ResultsTwenty-four percent of pregnant women with extreme obesity had obstructive sleep apnea on home sleep apnea testing in mid pregnancy (Apnea-Hypopnea Index, ≥5 events per hour]. Established obstructive sleep apnea screening tools performed very poorly to screen for obstructive sleep apnea in this cohort. Age, body mass index, neck circumference, frequently witnessed apneas, and highly likely to fall asleep while driving were associated most strongly with obstructive sleep apnea status in this cohort.ConclusionWe found that 24% of pregnant women with body mass index ≥40 kg/m2 between 24 and 35 weeks gestation have obstructive sleep apnea, defined as Apnea-Hypopnea Index ≥5 events per hour on an overnight type III home sleep apnea test. We found the Berlin Questionnaire, American Society of Anesthesiologists checklist, STOP-BANG, obstructive sleep apnea in pregnancy score by Facco et al, and the Epworth Sleepiness Scale were not useful screening tools for obstructive sleep apnea in a cohort of obese pregnant women. However, age, body mass index, neck circumference, frequently witnessed apneas, and likely to fall asleep while driving were associated with obstructive sleep apnea in this cohort. Further studies are needed to adjust the criteria and thresholds within the available screening tools to better predict obstructive sleep apnea in pregnant women with obesity

Associations between ASA Physical Status and postoperative mortality at 48 h: a contemporary dataset analysis compared to a historical cohort

Abstract Background In this study, we examined the association between American Society of Anesthesiologists Physical Status (ASA PS) designation and 48-h mortality for both elective and emergent procedures in a large contemporary dataset (patient encounters between 2009 and 2014) and compared this association with data from a landmark study published by Vacanti et al. in 1970. Methods Patient history, hospital characteristics, anesthetic approach, surgical procedure, efficiency and quality indicators, and patient outcomes were prospectively collected for 732,704 consecutive patient encounters between January 1, 2009, and December 31, 2014, at 233 anesthetizing locations across 19 facilities in two US states and stored in the Quantum™ Clinical Navigation System (QCNS) database. The outcome (death within 48 h of procedure) was tabulated against ASA PS designations separately for patients with and without “E” status labels. To maintain consistency with the historical cohort from the landmark study performed by Vacanti et al. on adult men at US naval hospitals in 1970, we then created a comparison cohort in the contemporary dataset that consisted of 242,103 adult male patients (with/without E designations) undergoing elective and emergent procedures. Differences in the relationship between ASA PS and 48-h mortality in the historical and contemporary cohorts were assessed for patients undergoing elective and emergent procedures. Results As reported nearly five decades ago, we found a significant trend toward increased mortality with increasing ASA PS for patients undergoing both elective and emergent procedures in a large contemporary cohort (p < 0.0001). Additionally, the overall mortality rate at 48 h was significantly higher among patients undergoing emergent compared to elective procedures in the large contemporary cohort (1.27 versus 0.03 %, p < 0.0001). In the comparative analysis with the historical cohort that focused on adult males, we found the overall 48-h mortality rate was significantly lower among patients undergoing elective procedures in the contemporary cohort (0.05 % now versus 0.24 % in 1970, p < 0.0001) but not significantly lower among those undergoing emergent procedures (1.88 % now versus 1.22 % in 1970, p < 0.0001). Conclusions The association between increasing ASA PS designation (1–5) and mortality within 48 h of surgery is significant for patients undergoing both elective and emergent procedures in a contemporary dataset consisting of over 700,000 patient encounters. Emergency surgery was associated with a higher risk of patient death within 48 h of surgery in this contemporary dataset. These data trends are similar to those observed nearly five decades ago in a landmark study evaluating the association between ASA PS and 48-h surgical mortality on adult men at US naval hospitals. When a comparison cohort was created from the contemporary dataset and compared to this landmark historical cohort, the absolute 48-h mortality rate was significantly lower in the contemporary cohort for elective procedures but not significantly lower for emergency procedures. The underlying implications of these findings remain to be determined