Simulation in Perioperative Liver Transplant Anesthesia: A Systematic Review.

Due to the complexity of liver transplant patients and the variability in exposure to transplantation by anesthesia trainees, simulation is often required as an adjunct to clinical experience. This systematic review identifies current simulation models in the literature that pertain to perioperative liver transplant anesthesia. Data were collected by performing an electronic search of the PubMed and Scopus databases for articles describing simulation in transplant anesthesia. Abstracts were screened using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Three reviewers analyzed 16 abstracts found in the search and agreed upon articles that met the inclusion criteria for the systematic review. A total of five publications met the inclusion criteria; they could be grouped as cognitive skills and technical skills simulators. Cognitive skills simulators utilized high-fidelity mannequins and animal models combined with traditional educational material to enhance pattern recognition of critical complications during liver transplantation. One manuscript focused on a technical skills acquisition by utilizing transesophageal echocardiography (TEE) to identify intraoperative pathologies. There is a heterogeneity in the exposure to liver transplant care during anesthesia training. Simulation provides low-stakes exposure to the high-stakes skills required in the operating room. Hence, it can be used as an adjunct to improve both cognitive and technical skill acquisition for perioperative transplant anesthesia. The goal of these simulation programs is to improve patient outcomes and produce more capable anesthesiologists.

Cross-Sectional Study of Osteopathic General Surgeons in University-Based General Surgery Departments.

INTRODUCTION: Discrepancy between osteopathic (DO) and allopathic (MD) graduates in general surgery spans across all levels of training. In this cross-sectional study, we characterized DO surgeons who serve as faculty at university-based general surgery departments. METHODS: Overall, 106 university-based surgery departments were reviewed. DO and MD surgeons from the same institutions were identified, and demographic data were tabulated. MD surgeons were the control group. Univariate analysis and multivariate regression models were used to compare total publications, h-index, and citations. RESULTS: A total of 70 DO surgeons from 34 institutions were identified: 53 assistant professors, 16 associate professors, and one full professor. Of the DO surgeons, 35.7% completed residency at a university-based program, and 92.9% completed a fellowship, with surgical critical care and trauma being the most common. They were compared to 1,307 MD surgeons from the same institutions. Univariate analysis showed that MD faculty graduated medical school earlier (mean years (standard deviation (SD)): 14.8 (6.0) versus 23.3 (10.6); p<0.0001), had more total publications (median (interquartile range (IQR)): 5 (2.0-18.3) versus 35 (15.0-79.0); p<0.0001), had higher number of citations (median (IQR): 61.0 (14.0-265.0) versus 655.0 (155.0-2267.0); p<0.001), and had a higher h-index (median (IQR): 3 (1.0-8.0) versus 12 (6.0-24.0); p<0.001). Negative binomial regression models accounting for years since graduation, gender, and degree were performed. At the assistant professor rank, MD surgeons had more total publications (exponential coefficient (CI): 2.24 (1.67-3.02); p<0.001), more citations (3.10 (2.20-4.11); p<0.001), and a higher h-index (1.93 (1.36-2.73); p<0.001). Similar trends were noted at the associate professor level with MD surgeons having more total publication (1.67 (1.00-2.79); p=0.049), more citations (3.63 (2.13-6.18); p<0.001), and higher h-index (1.93 (1.10-3.39); p=0.022). CONCLUSIONS: To address this discrepancy between DO and MD faculty surgeons, action must begin at the medical school and continue through residency. DO trainees need better access to mentorship and research support to foster an academic career.

Assessment of genetic determinants of the association of γ' fibrinogen in relation to cardiovascular disease.

OBJECTIVE: γ' fibrinogen is a newly emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of γ' fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3042 participants from the Framingham Heart Study Offspring Cohort. METHODS AND RESULTS: A genome-wide association study with 2.5 million single-nucleotide polymorphisms (SNPs) was carried out for γ' fibrinogen levels from the cycle 7 examination. Fifty-four SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance (P<5.0×10(-8)) for association with γ' fibrinogen levels. The top-signal SNP was rs7681423 (P=9.97×10(-110)) in the fibrinogen gene locus near FGG, which encodes the γ chain. Conditional on the top SNP, the only other SNP that remained genome-wide significant was rs1049636. Associations between SNPs, γ' fibrinogen levels, and prevalent CVD events were examined using multiple logistic regression. γ' fibrinogen levels were associated with prevalent CVD (P=0.02), although the top 2 SNPs associated with γ' fibrinogen levels were not associated with CVD. These findings contrast those for total fibrinogen levels, which are associated with different genetic loci, particularly FGB, which encodes the Bß chain. CONCLUSIONS: γ' fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus.

Gamma' fibrinogen: evaluation of a new assay for study of associations with cardiovascular disease.

BACKGROUND: Studies of disease associations with gamma' fibrinogen, a newly emerging risk factor for cardiovascular disease, have been hampered by the lack of a standardized and well-characterized assay. METHODS: We developed an immunometric technique to measure gamma' fibrinogen concentrations in plasma and studied the clinical utility of this test in samples from healthy individuals enrolled in the Framingham Offspring Study and in a separate case/control study of coronary artery disease (CAD). Monoclonal antibody 2.G2.H9, specific for the unique carboxyl terminal peptide of the fibrinogen gamma' chain, was used as capture antibody. Sheep antihuman fibrinogen/horseradish peroxidase conjugate was used for detection, with 3,3',5,5'-tetramethylbenzidine as substrate. We evaluated the linearity, imprecision, analytical specificity, and lower limit of quantification of the assay. We determined the reference interval for gamma' fibrinogen in healthy individuals from the Framingham Offspring Study (n = 2879) and quantified associations between gamma' fibrinogen and cardiovascular disease risk factors. The sensitivity and specificity of gamma' fibrinogen in evaluating CAD patients (n = 133) was determined with ROC curve analysis. RESULTS: The gamma' fibrinogen ELISA had within-run CVs of 13.4% at 0.127 g/L and 4.8% at 0.416 g/L. The limit of quantification at an imprecision of 20% was 0.10 g/L. The reference interval for healthy individuals was 0.088-0.551 g/L. ROC curve analysis of results from patients with CAD yielded an area under the curve of 0.76, with a diagnostic accuracy of 0.78 at a decision threshold of 0.30 g/L. CONCLUSIONS: gamma' Fibrinogen shows excellent utility for cardiovascular risk analysis.

gammaA/gamma' fibrinogen inhibits thrombin-induced platelet aggregation.

The minor gammaA/gamma' fibrinogen isoform contains a high affinity binding site for thrombin exosite II that is lacking in the major gammaA/gammaA fibrinogen isoform. We therefore investigated the biological consequences of the gamma' chain binding to thrombin. Thrombin-induced platelet aggregation was inhibited by gammaA/gamma' fibrinogen. Carboxyl terminal peptide fragment gamma'410-427 from the gamma' chain was also inhibitory, with an IC(50) of approximately 200 microM in whole plasma. Deletion of the peptide from either the amino or carboxyl end significantly decreased inhibition. In contrast to thrombin-induced platelet aggregation, aggregation induced by epinephrine, ADP, arachidonic acid, or SFLLRN peptide showed little inhibition by the gamma' peptide. The inhibition of thrombin-induced platelet aggregation was not due to direct inhibition of the thrombin active site, since cleavage of a small peptidyl substrate was 91% of normal even in the presence of 1 mM gamma'410-427. The gamma'410-427 peptide blocked platelet adhesion to immobilized thrombin under both static and flow conditions, blocked soluble thrombin binding to platelet GPIbalpha, and inhibited PAR1 cleavage by thrombin. These results suggest that the gamma' chain of fibrinogen inhibits thrombin-induced platelet aggregation by binding to thrombin exosite II. Thrombin that is bound to the gamma' chain is thereby prevented from activating platelets, while retaining its amidolytic activity.

Fibrinogen Hershey IV: a novel dysfibrinogen with a gammaV411I mutation in the integrin alpha(IIb)beta(3) binding site.

The carboxyl terminal segment of the fibrinogen gamma chain from gamma408-411 plays a crucial role in platelet aggregation via interactions with the platelet receptor alpha(IIb)beta(3). We describe here the first naturally-occurring fibrinogen point mutation affecting this region and demonstrate its effects on platelet interactions. DNA sequencing was used to sequence the proband DNA, and platelet aggregation and direct binding assays were used to quantitate the biological effects of fibrinogen Hershey IV. The Hershey IV proband was found to be heterozygous for two mutations, gammaV411I and gammaR275C. Little difference in aggregation was seen when fibrinogen Hershey IV was compared to normal fibrinogen. However, less aggregation inhibition was observed using a competing synthetic dodecapeptide containing the V411I mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet alpha(IIb)beta(3) with a lower affinity than wild-type fibrinogen. These findings show that the gammaV411I mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available wild-type fibrinogen appears to be sufficient to support normal platelet aggregation.

Fibrinogen gamma' chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway.

The minor gammaA/gamma' isoform of fibrinogen contains a high affinity binding site for thrombin exosite II that is lacking in the major fibrinogen isoform, gammaA/gammaA fibrinogen. The biological consequences of gamma' chain binding to thrombin were therefore investigated. Coagulation assays, thrombin activity assays, and a primate thrombosis model were used to characterize the biological effects of the gamma' 410-427 peptide. The gamma' peptide had little effect on thrombin cleavage of the small peptidyl substrate tosyl-glycyl-prolyl-arginine-4-nitranilide acetate. However, in vitro assays demonstrated that the gamma' peptide inhibited thrombin cleavage of larger proteinaceous substrates, including fibrinogen and factor VIII. The gamma' peptide inhibited the activated partial thromboplastin time in plasma and showed greater inhibition of activated partial thromboplastin time assays than prothrombin time assays, consistent with the inhibition of factor VIII cleavage. Studies in a baboon thrombosis model showed that the gamma' 410-427 peptide inhibited fibrin-rich thrombus formation (typical of venous thrombi) and, to a lesser extent, platelet-rich thrombus formation (typical of arterial thrombi). These results indicate that binding of thrombin exosite II by the gamma' peptide has selective effects on the intrinsic pathway.

Association of gammaA/gamma' fibrinogen levels and coronary artery disease.

GammaA/gamma' fibrinogen is a fibrinogen isoform that constitutes about 15% of total plasma fibrinogen. This isoform contains an additional binding site for zymogen factor XIII and for active thrombin, and forms fibrin clots that are resistant to fibrinolysis in vitro. Little is known about the variability of gammaA/gamma' fibrinogen levels in human populations, whereas total fibrinogen levels are known to increase with age and are higher in women than in men. In this report, evidence is presented that, in contrast to total fibrinogen levels, gammaA/gamma' fibrinogen levels showed no significant association with age or gender in a population of normal blood donors. A study of gammaA/gamma' fibrinogen levels in patients undergoing coronary angiography also showed that gammaA/gamma' fibrinogen levels were higher on average in coronary artery disease patients than in patients without coronary artery disease, and that this association was independent of total fibrinogen levels.