Eric S. Wise

Women in Academic Surgery: The Pipeline Is Busted

PURPOSE This investigation examined the trends for gender-based advancement in academic surgery by performing a comparative analysis of the rate of change in the percentage of medical students, surgery residents, and full professors of surgery who are women. METHODS All available Women in Medicine Annual Reports were obtained from the American Association of Medical Colleges (AAMC). The gender compositions of medical graduates, surgery residents, and full professors were plotted. Binomial and linear trendlines were calculated to estimate the year when 50% of surgery full professors would be women. Additionally, the percentage distribution of men and women at each professorial rank was determined from 1995 to 2009 using these reports to demonstrate the rate of academic advancement of each gender. RESULTS The slope of the line of increase for women full professors is significantly less than for female medical students and for female general surgery residents (0.36, compared with 0.75 and 0.99, respectively). This predicts that the earliest time that females will account for 50% of full professors in surgery is the year 2096. When comparing women and men in academic ranks, we find that women are much less likely than men to be full professors. CONCLUSIONS The percentage of full professors in surgery who are women is increasing at a rate disproportionately slower than the increases in female medical students and surgery residents. The rates of increase in female medical students and surgery residents are similar. The disproportionately slow rate of increase in the number of female full professors suggests that multiple factors may be responsible for this discrepancy.

Preservation solution impacts physiologic function and cellular viability of human saphenous vein graft

INTRODUCTION Recent clinical data suggest intraoperative preservation of human saphenous vein (HSV) in normal saline is associated with vein graft failure. We evaluated the influence of several preservation media on acute physiologic function and cellular viability of HSV conduit. METHODS Unprepared (UP) HSV obtained from coronary artery bypass graft patients was characterized on a muscle bath after 2-hour storage in 6 solutions: Plasma-Lyte A, 0.9% NaCl (normal saline), University of Wisconsin solution, Celsior solution, autologous whole blood, or glutathione-ascorbic acid L-arginine (GALA) solution. Vascular smooth muscle contractility was assessed after exposure to depolarizing KCl and phenylephrine. The relaxation of phenylephrine-precontracted HSV to sodium nitroprusside and carbachol (endothelial-independent and -dependent relaxation, respectively) was also assessed. Cellular viability was determined via the methyl thiazolyl tetrazolium (MTT) assay. Rat aortae were used to assess the effect of pH during graft preservation on endothelial-dependent relaxation. RESULTS Preservation of HSV in normal saline and autologous whole blood impaired contractile responses to KCl relative to UP tissues, whereas preservation in University of Wisconsin solution and Celsior solution enhanced contractile responses (P < .05). Relative to UP tissues, responses to phenylephrine were decreased with preservation in normal saline, whereas preservation in University of Wisconsin solution, Celsior solution, and GALA all potentiated these responses (P < .05). Only preservation in normal saline impaired endothelial-independent relaxation (P = .005). Preservation in Plasma-Lyte A (P = .02), normal saline (P = .002), and University of Wisconsin solution (P = .02) impaired endothelial-dependent relaxation. Normal saline preservation decreased MTT viability index relative to UP tissues (0.02 ± 0.002 mg(-1)0.5 mL(-1) vs 0.033 ± 0.005 mg(-1)0.5 mL(-1); P = .03). Endothelial function was impaired by acidic pH in rat aorta. CONCLUSION Preservation of HSV in normal saline causes graft injury leading to impaired physiologic function and decreased viability of the HSV. This harm is mitigated by the use of buffered salt solutions as preservation media.

Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction

A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.

Prediction of in-hospital mortality after ruptured abdominal aortic aneurysm repair using an artificial neural network

OBJECTIVE Ruptured abdominal aortic aneurysm (rAAA) carries a high mortality rate, even with prompt transfer to a medical center. An artificial neural network (ANN) is a computational model that improves predictive ability through pattern recognition while continually adapting to new input data. The goal of this study was to effectively use ANN modeling to provide vascular surgeons a discriminant adjunct to assess the likelihood of in-hospital mortality on a pending rAAA admission using easily obtainable patient information from the field. METHODS Of 332 total patients from a single institution from 1998 to 2013 who had attempted rAAA repair, 125 were reviewed for preoperative factors associated with in-hospital mortality; 108 patients received an open operation, and 17 patients received endovascular repair. Five variables were found significant on multivariate analysis (P < .05), and four of these five (preoperative shock, loss of consciousness, cardiac arrest, and age) were modeled by multiple logistic regression and an ANN. These predictive models were compared against the Glasgow Aneurysm Score. All models were assessed by generation of receiver operating characteristic curves and actual vs predicted outcomes plots, with area under the curve and Pearson r(2) value as the primary measures of discriminant ability. RESULTS Of the 125 patients, 53 (42%) did not survive to discharge. Five preoperative factors were significant (P < .05) independent predictors of in-hospital mortality in multivariate analysis: advanced age, renal disease, loss of consciousness, cardiac arrest, and shock, although renal disease was excluded from the models. The sequential accumulation of zero to four of these risk factors progressively increased overall mortality rate, from 11% to 16% to 44% to 76% to 89% (age ≥ 70 years considered a risk factor). Algorithms derived from multiple logistic regression, ANN, and Glasgow Aneurysm Score models generated area under the curve values of 0.85 ± 0.04, 0.88 ± 0.04 (training set), and 0.77 ± 0.06 and Pearson r(2) values of .36, .52 and .17, respectively. The ANN model represented the most discriminant of the three. CONCLUSIONS An ANN-based predictive model may represent a simple, useful, and highly discriminant adjunct to the vascular surgeon in accurately identifying those patients who may carry a high mortality risk from attempted repair of rAAA, using only easily definable preoperative variables. Although still requiring external validation, our model is available for demonstration at https://redcap.vanderbilt.edu/surveys/?s=NN97NM7DTK.

Traditional graft preparation decreases physiologic responses, diminishes viscoelasticity, and reduces cellular viability of the conduit: A porcine saphenous vein model

Traditional methods of intraoperative human saphenous vein preparation for use as bypass grafts can be deleterious to the conduit. The purpose of this study was to characterize acute graft preparation injury, and to mitigate this harm via an improved preparation technique. Porcine saphenous veins were surgically harvested (unprepared controls, UnP) and prepared using traditional (TraP) and improved preparations (ImP). The TraP used unregulated radial distension, marking with a surgical skin marker and preservation in heparinized normal saline. ImP used pressure-regulated distension, brilliant blue FCF-based pen marking and preservation in heparinized Plasma-Lyte A. Rings from each preparation were suspended in a muscle bath for characterization of physiologic responses to vasoactive agents and viscoelasticity. Cellular viability was assessed using the methyl thiazolyl tetrazolium (MTT) assay and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay for apoptosis. Contractile responses to potassium chloride (110 mM) and phenylephrine (10 µM), and endothelial-dependent and independent vasodilatory responses to carbachol (0.5 µM) and sodium nitroprusside (1 µM), respectively, were decreased in TraP tissues compared to both UnP and ImP tissues (p ⩽ 0.05). TraP tissues demonstrated diminished viscoelasticity relative to UnP and ImP tissues (p ⩽ 0.05), and reduced cellular viability relative to UnP control (p ⩽ 0.01) by the MTT assay. On the TUNEL assay, TraP tissues demonstrated a greater degree of apoptosis relative to UnP and ImP tissues (p ⩽ 0.01). In conclusion, an improved preparation technique prevents vascular graft smooth muscle and endothelial injury observed in tissues prepared using a traditional approach.

Race as a predictor of delay from diagnosis to endarterectomy in clinically significant carotid stenosis

OBJECTIVE Prompt carotid endarterectomy (CEA) in clinically significant carotid stenosis is important in the prevention of neurologic sequelae. The greatest benefit from surgery is obtained by prompt revascularization on diagnosis. It has been demonstrated that black patients both receive CEA less frequently than white patients do and experience worse postoperative outcomes. We sought to test our hypothesis that black race is an independent risk factor for a prolonged time from sonographic diagnosis of carotid stenosis warranting surgery to the day of operation (TDO). METHODS From 1998 to 2013 at a single institution, 166 CEA patients were retrospectively reviewed using Synthetic Derivative, a de-identified electronic medical record. Factors potentially affecting TDO, including demographics, preoperative cardiac stress testing, degree of stenosis, smoking status, and comorbidities, were noted. Multivariate analysis was performed on variables that trended with prolonged TDO on univariate analysis (P < .10) to determine independent (P < .05) predictors of TDO. Subgroup analyses were further performed on the symptomatic and asymptomatic stenosis cohorts. RESULTS There were 32 black patients and 134 white patients studied; the mean TDO was 78 ± 17 days vs 33 ± 3 days, respectively (P < .001). In addition to the need for preoperative cardiac stress testing, black race was the only variable that demonstrated a trend with (P < .10) or was an independent risk factor for (P < .05) prolonged TDO among all patients (B = 42 days; P < .001) and within the symptomatic (B = 35 days; P = .08) and asymptomatic (B = 35 days; P = .003) cohorts. On Kaplan-Meier analysis, black patients in each stratum of symptomatology (all, symptomatic, and asymptomatic patients) experienced prolonged TDO (log-rank, P < .03 for all three groups). CONCLUSIONS Black race is a risk factor for a temporal delay in CEA for carotid stenosis. Awareness of this disparity may help surgeons avoid undesirable delays in operation for their black patients.

Hyperlactemia Predicts Surgical Mortality in Patients Presenting with Acute Stanford Type-A Aortic Dissection

OBJECTIVE Inspired by the limited facility of the Penn classification, the authors aimed to determine a rapid and optimal preoperative assessment tool to predict surgical mortality after acute Stanford type-A aortic dissection (AAAD) repair. DESIGN Patients who underwent an attempted surgical repair of AAAD were determined using a de-identified single institution database. The charts of 144 patients were reviewed retrospectively for preoperative demographics and surrogates for disease severity and malperfusion. Bivariate analysis was used to determine significant (p≤0.05) predictors of in-hospital and 1-year mortality, the primary endpoints. Receiver operating characteristic curve generation was used to define optimal cut-off values for continuous predictors. SETTING Single center, level 1 trauma, university teaching hospital. PARTICIPANTS The study included 144 cardiac surgical patients with acute type-A aortic dissection presenting for surgical correction. INTERVENTIONS Surgical repair of aortic dissection with preoperative laboratory samples drawn before patient transfer to the operating room or immediately after arterial catheter placement intraoperatively. MEASUREMENTS AND MAIN RESULTS The study cohort comprised 144 patients. In-hospital mortality was 9%, and the 1-year mortality rate was 17%. Variables that demonstrated a correlation with in-hospital mortality included an elevated serum lactic acid level (odds ratio [OR] 1.5 [1.3-1.9], p<0.001), a depressed ejection fraction (OR 0.91 [0.86-0.96], p = .001), effusion (OR 4.8 [1.02-22.5], p = 0.04), neurologic change (OR 5.3 [1.6-17.4], p = 0.006), severe aortic regurgitation (OR 8.2 [2.0-33.9], p = 0.006), and cardiopulmonary resuscitation (OR 6.8 [1.7-26.9], p = 0.01). Only an increased serum lactic acid level demonstrated a trend with 1-year mortality using univariate Cox regression (hazard ratio 1.1 [1.0-1.1], p = 0.006). Receiver operating characteristic analysis revealed optimal cut-off lactic acid levels of 6.0 mmol/L and 6.9 mmol/L for in-hospital and 1-year mortality, respectively. CONCLUSION Lactic acidosis, ostensibly as a surrogate for systemic malperfusion, represents a novel, accurate, and easily obtainable preoperative predictor of short-term mortality after attempted AAAD repair. These data may improve identification of patients who would not benefit from surgery.

Papaverine Prevents Vasospasm by Regulation of Myosin Light Chain Phosphorylation and Actin Polymerization in Human Saphenous Vein.

Objective Papaverine is used to prevent vasospasm in human saphenous veins (HSV) during vein graft preparation prior to implantation as a bypass conduit. Papaverine is a nonspecific inhibitor of phosphodiesterases, leading to increases in both intracellular cGMP and cAMP. We hypothesized that papaverine reduces force by decreasing intracellular calcium concentrations ([Ca2+]i) and myosin light chain phosphorylation, and increasing actin depolymerization via regulation of actin regulatory protein phosphorylation. Approach and Results HSV was equilibrated in a muscle bath, pre-treated with 1 mM papaverine followed by 5 μM norepinephrine, and force along with [Ca2+]i levels were concurrently measured. Filamentous actin (F-actin) level was measured by an in vitro actin assay. Tissue was snap frozen to measure myosin light chain and actin regulatory protein phosphorylation. Pre-treatment with papaverine completely inhibited norepinephrine-induced force generation, blocked increases in [Ca2+]i and led to a decrease in the phosphorylation of myosin light chain. Papaverine pre-treatment also led to increased phosphorylation of the heat shock-related protein 20 (HSPB6) and the vasodilator stimulated phosphoprotein (VASP), as well as decreased filamentous actin (F-actin) levels suggesting depolymerization of actin. Conclusions These results suggest that papaverine-induced force inhibition of HSV involves [Ca2+]i-mediated inhibition of myosin light chain phosphorylation and actin regulatory protein phosphorylation-mediated actin depolymerization. Thus, papaverine induces sustained inhibition of contraction of HSV by the modulation of both myosin cross-bridge formation and actin cytoskeletal dynamics and is a pharmacological alternative to high pressure distention to prevent vasospasm.

Limiting Injury During Saphenous Vein Graft Preparation For Coronary Arterial Bypass Prevents Metabolic Decompensation

Standard harvest and preparation of human saphenous vein (HSV) for autologous coronary and peripheral arterial bypass procedures is associated with injury and increased oxidative stress that negatively affect graft performance. In this study we investigated the global metabolomic profiles of HSV before (unprepared; UP) and after standard vein graft preparation (AP). AP-HSV showed impaired vasomotor function that was associated with increased oxidative stress, phospholipid hydrolysis and energy depletion that are characteristic of mechanical and chemical injury. A porcine model (PSV) was utilized to validate these metabolomic changes in HSV and to determine the efficacy of an improved preparation technique (OP) using pressure-regulated distension, a non-toxic vein marker, and graft storage in buffered PlasmaLyte solution in limiting metabolic decompensation due to graft preparation. Deficits in vasomotor function and metabolic signature observed in AP-PSV could be largely mitigated with the OP procedure. These findings suggest that simple strategies aimed at reducing injury during graft harvest and preparation represents a straightforward and viable strategy to preserve conduit function and possibly improve graft patency.

Postoperative bleeding after laparoscopic Roux en Y gastric bypass: predictors and consequences

BackgroundLaparoscopic Roux-en-Y gastric bypass (LRYGB) is a common, safe and effective bariatric procedure. Bleeding is a significant source of postoperative morbidity. We aimed to determine the incidence, outcomes, and predictors of postoperative bleeding after LRYGB.MethodsLRYGB patients included in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) 2015 dataset were identified. Preoperative and intraoperative factors were tested for associations with bleeding using univariable and multivariable logistic regression analysis. Outcomes of length of stay, in-hospital mortality, 30-day mortality, discharge disposition, and 30-day complications among patients with and without clinically significant postoperative bleeding were compared using multivariable regression.ResultsIn the 43,280 LRYGB patients included in this analysis, postoperative bleeding occurred in 652 (1.51%) patients. Of these, 165 (25.3%) underwent a re-operation and 97 (14.9%) underwent an unplanned endoscopy for ‘bleeding’. Postoperative bleeding was associated with a longer median postoperative length of stay (4 vs. 2 days), higher in-hospital mortality (1.23 vs. 0.04%), higher 30-day mortality (1.38 vs. 0.15%), discharge to an extended-care facility (3.88 vs. 0.6%), and higher rates of major complications (all P < 0.05). Independent predictors of postoperative bleeding included; a history of renal insufficiency (OR 2.55, 95% CI 1.43–4.52), preoperative therapeutic anticoagulation (OR 2.44, 95% CI 1.69–3.53), and revisional surgery (OR 1.45, 95% CI 1.06–1.97). Intraoperative associated factors included conversions (OR 3.37, 95% CI 1.42–7.97), and drain placement (OR 1.40, 95% CI 1.18–1.67). Robotic approaches resulted in independently lower postoperative bleeding rates (OR 0.50, 95% CI 0.32–0.77).ConclusionsPostoperative bleeding occurs in 1.5% of patients undergoing a LRYGB and is associated with significantly increased morbidity and mortality. We have identified patient and operative factors that are independently associated with postoperative bleeding.