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Many single ventricle patients palliated with the Fontan operation suffer from Fontan failure and progressive liver disease. Combined heart-liver transplantation is a rarely utilized and complex transplant strategy available for select Fontan patients. At the Hospital of the University of Pennsylvania, all Fontan patients deemed eligible for a heart transplantation undergo a combined sequential dual organ transplantation with same-donor organs. This article describes the techniques utilized as well as current results.

Implementing enhanced recovery after surgery (ERAS) protocols for major abdominal surgery has been shown to decrease length of stay (LOS) and postoperative complications, including mortality and readmission. Little is known to guide which patients undergoing pancreaticoduodenectomy (PD) should be eligible for ERAS protocols.A retrospective chart review of all PD performed from 2010 to 2018 within an integrated healthcare system was conducted. A predictive score that ranges from 0 to 4 was developed, with one point assigned to each of the following: obesity (BMI 30), operating time 400 min, estimated blood loss (EBL) 400 mL, low- or high-risk pancreatic remnant (based on the presence of soft gland or small duct). Chi-squared tests and ANOVA were used to assess the relationship between this score and LOS, discharge before postoperative day 7, readmission, mortality, delayed gastric emptying (DGE), and pancreatic leak/fistula.291 patients were identified. Mean length of stay was 8.5 days in those patients who scored 0 compared to 16.2 days for those who scored 4 (p = 0.001). 30% of patients who scored 0 were discharged before postoperative day 7 compared to 0% of those who scored 4 (p = 0.019). Readmission rates for patients who scored 0 and 4 were 12% and 33%, respectively (p = 0.017). Similarly, postoperative pancreatic fistula occurred in 2% versus 25% in these groups (p = 0.007).A simple scoring system using BMI, operating time, EBL, and pancreatic remnant quality can help risk-stratify postoperative PD patients. Those with lower scores could potentially be managed via an ERAS protocol. Patients with higher scores required longer hospitalizations, and adjunctive therapy such as medication and surgical technique to decrease risk of delayed gastric emptying and pancreatic fistula could be considered.

Erythrocyte-derived microparticles (MPs) are sub-micrometer, biologically active vesicles shed by red blood cells as part of the biochemical changes that occur during storage. We hypothesized that MPs from stored red blood cells would activate endothelial cells. MPs from aged murine packed red blood cells (pRBCs) were isolated and used to treat confluent layers of cultured endothelial cells. Endothelial expression of leukocyte adhesion molecules, endothelial-leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1(ICAM-1), and inflammatory mediator, interleukin-6 (IL-6), was evaluated at 0.5, 6, 12, and 24 h of treatment. Healthy C57BL/6 mice were transfused with a MP suspension and lung sections were analyzed for adhesion molecules and sequestered interstitial leukocytes. Increased levels of ELAM-1 and ICAM-1 were found on cultured endothelial cells 6 h after MP stimulation (6.91 vs. 4.07 relative fluorescent intensity [RFI], P < 0.01, and 5.85 vs. 3.55 RFI, P = 0.01, respectively). IL-6 in cell culture supernatants was increased after 12 h of MP stimulation compared with controls (1.24 vs. 0.73 ng/mL, P = 0.03). In vivo experiments demonstrated that MP injection increased ELAM-1 and ICAM-1 expression at 1 h (18.56 vs. 7.08 RFI, P < 0.01, and 23.66 vs. 6.87 RFI, P < 0.01, respectively) and caused increased density of pulmonary interstitial leukocytes by 4 h of treatment (69.25 vs. 29.25 cells/high powered field, P < 0.01). This series of experiments supports our hypothesis that erythrocyte-derived MPs are able to activate pulmonary endothelium, leading to the pulmonary sequestration of leukocytes following the transfusion of stored pRBCs.

Background Prolonged storage of packed red blood cells (pRBCs) induces a series of harmful biochemical and metabolic changes known as the RBC storage lesion. RBCs are currently stored in an acidic storage solution, but the effect of pH on the RBC storage lesion is unknown. We investigated the effect of modulation of storage pH on the RBC storage lesion and on erythrocyte survival after transfusion. Methods Murine pRBCs were stored in Additive Solution-3 (AS3) under standard conditions (pH, 5.8), acidic AS3 (pH, 4.5), or alkalinized AS3 (pH, 8.5). pRBC units were analyzed at the end of the storage period. Several components of the storage lesion were measured, including cell-free hemoglobin, microparticle production, phosphatidylserine externalization, lactate accumulation, and byproducts of lipid peroxidation. Carboxyfluorescein-labeled erythrocytes were transfused into healthy mice to determine cell survival. Results Compared with pRBCs stored in standard AS3, those stored in alkaline solution exhibited decreased hemolysis, phosphatidylserine externalization, microparticle production, and lipid peroxidation. Lactate levels were greater after storage in alkaline conditions, suggesting that these pRBCs remained more metabolically viable. Storage in acidic AS3 accelerated erythrocyte deterioration. Compared with standard AS3 storage, circulating half-life of cells was increased by alkaline storage but decreased in acidic conditions. Conclusions Storage pH significantly affects the quality of stored RBCs and cell survival after transfusion. Current erythrocyte storage solutions may benefit from refinements in pH levels.

We aimed to quantify and predict variability that exists in resource utilization after pancreaticoduodenectomy and determine how such variability impacts postoperative outcomes.The University HealthSystems Consortium database was queried for all pancreaticoduodenectomies performed between 2011-2013 (n = 9,737). A composite resource utilization score was created using z-scores of 8 clinically significant postoperative care delivery variables including number of laboratory tests, imaging tests, computed tomographic scans, days on antibiotics, anticoagulation, antiemetics, promotility agents, and total number of blood products transfused per patient. Logistic, Poisson, and gamma regression models were used to determine predictors of increased variability in care between patients.Having a high (versus low) resource utilization score after pancreaticoduodenectomy correlated with increased duration of stay; (odds ratio 2.28), cost (odds ratio 1.89), readmission rate (odds ratio 1.46), and mortality (odds ratio 7.54). Patient-specific factors were the strongest predictors and included extreme severity of illness (odds ratio 114), major comorbidities/complications (odds ratio 5.99), and admission prior to procedure (odds ratio 2.72; all P .01). Surgeon and center volume were not associated with resource utilization.Public reporting of patient outcomes and resource utilization, invariably tied to reimbursement in the near future, should consider that much of the postoperative variability after complex pancreatic operation is related to patient-specific risk factors.

A growing number of renal transplant recipients have a body mass index ≥40. While previous studies have shown that patient and graft survival are significantly decreased in renal transplant recipients with body mass indexes ≥40, less is known about perioperative outcomes and resource utilization in morbidly obese patients. We aimed to analyze the effects of morbid obesity on these parameters in renal transplant.Using a linkage between the Scientific Registry of Transplant Recipients and the databases of the University HealthSystem Consortium, we identified 29,728 adult renal transplant recipients and divided them into 2 cohorts based on body mass index (40 vs ≥40 kg/mBody mass index ≥40 recipients incurred greater direct costs ($84,075 vs $79,580, P .01), index admission costs ($91,169 vs $86,141, P .01), readmission costs ($5,306 vs $4,596, P = .01), and combined costs ($99,590 vs $93,939, P .001). Thirty-day readmission rates were also greater among body mass index ≥40 recipients (33.92% vs 26.9%, P .01). Morbid obesity was not predictive of stay (odds ratio 1.01, P = .75).Morbidly obese renal transplant recipients incur greater costs and readmission rates compared with nonobese patients. Recognition of increased resource utilization should be accompanied by appropriate, risk-adjustment reimbursement.

BACKGROUND During storage, packed red blood cells (pRBCs) undergo a number of biochemical, metabolic, and morphologic changes, collectively known as the "storage lesion." We aimed to determine the effect of cryopreservation on the red blood cell storage lesion compared with traditional 4°C storage. METHODS Previously cryopreserved human pRBCs were compared with age-matched never-frozen pRBCs obtained from the local blood bank. The development of the red cell storage lesion was evaluated after 7, 14, 21, 28, and 42 days of storage at 4°C in AS-3 storage medium. We measured physiological parameters including cell counts, lactic acid, and potassium concentrations as well as signs of eryptosis including loss of phosphatidylserine (PS) asymmetry, microparticle production, and osmotic fragility in hypotonic saline. RESULTS Compared with controls, previously cryopreserved pRBC at 7 days of storage in AS-3 showed lower red cell counts (3.7 vs. 5.3 × 10 cells/μL, P

We have previously shown that inferior outcomes at safety-net hospitals are largely dependent on hospital factors. We hypothesized that hospitals providing "high value" care (low cost and better outcomes) would have advantages in human and financial resources.The University HealthSystems Consortium Clinical Database and the American Hospital Association Annual Survey were used to examine hospitals performing eight complex surgical procedures from 2009 to 2013. Hospitals in the lowest quartiles of both mortality rate and cost were characterized as high value (n = 45), whereas those in the highest quartiles of both cost and mortality were low value (n = 45). Hospital size, staffing, and financial characteristics were compared between these two groups.On average, high-value hospitals had lower proportions of Medicaid patient days (17% versus 30%; P 0.01), higher proportions of outpatient surgery (63% versus 53%; P 0.01), and spent more on capital expenditures per bed ($155,710 versus $62,434; P 0.05). Also, high-value hospitals employed more hospitalists (0.08 versus 0.04 per bed; P 0.01), had more privileged physicians (2.04 versus 1.25 per bed; P 0.01), and had more full-time equivalent personnel (8.48 versus 6.79 per bed; all P 0.05). As a result, these hospitals appeared to be more efficient; high-value hospitals had more total admissions per bed (46 versus 38; P 0.01), fewer days per admission (5.20 versus 5.77; P 0.01), and more inpatient surgeries per bed (15.7 versus 12.6; all P 0.05).Hospitals that invest in more human resources and demonstrate increased throughput perform complex surgery at higher "value" (i.e., lower costs and mortality). Value-based purchasing initiatives that link hospital reimbursement to unadjusted surgical outcomes may exacerbate, rather than improve, disparities in surgical care that currently exist.

Background and Objectives Pasireotide decreases leak rates after pancreatic resection, though significant drug cost may be prohibitive. We conducted a cost-effectiveness analysis to determine whether prophylactic pasireotide possesses a reasonable cost profile. Methods A cost-effectiveness model compared pasireotide administration after pancreatic resection versus usual care, populated by probabilities of clinical outcomes from a randomized trial and hospital costs (2013 US$) from a university pancreatic disease center. Sensitivity analyses were performed to identify influential clinical components of the model. Results With the cost of pasireotide included, per patient costs of pancreatectomy, including those for readmission, were lower in the intervention arm (41,769 versus 42,159$; net savings of 390$, or 1%). This was associated with a 56% reduction in pancreatic fistula/pancreatic leak/abscess (PF/PL/A; 21.9–9.2%). Pasireotide cost would need to increase by over 15.4% to make the intervention strategy more costly than usual care. Sensitivity analyses exploring variability of key model inputs demonstrated that the three strongest drivers of cost were (i) cost of pasireotide; (ii) probability of readmission; and (iii) probability of PF/PL/A. Conclusions Prophylactic pasireotide administration following pancreatectomy is cost savings, reducing expensive post-operative sequealae (major complications and readmissions). Pasireotide should be utilized as a cost-saving measure in pancreatic resection. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Background The rate and consequences of reoperation after liver transplantation (LT) are unknown in the United States. Study Design Adult patients (n = 10,295; 45% of all LT) undergoing LT from 2009 through 2012 were examined using a linkage of the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases providing recipient, donor, center, hospitalization, and survival details. Median follow-up was 2 years. Reoperations were identified within 90 days after LT. Results Overall 90-day reoperation rate after LT was 29.3%. Risk factors for 90-day reoperation included recipients with a history of hemodialysis, severely ill functional status, government insurance, increasing Model for End-Stage Liver Disease score, and increasing donor risk index. Reoperation within 90 days was found to be an independent predictor of adjusted 1-year mortality (odds ratio = 1.8; 95% CI, 1.5–2.1), as was government-provided insurance and increasing donor risk index. Additionally, patients undergoing delayed reoperative intervention (after 30 days) were found to have increased risk of 1-year mortality compared with those undergoing early reoperative intervention (odds ratio = 1.96; 95% CI, 1.4–2.7; p Conclusions This is the first national study reporting that nearly one-third of transplant recipients undergo reoperation within 90 days of LT. Although necessary at times, reoperation is associated with increased risk of death at 1 year; however, it appears that the timing of these interventions can be critical, due to the type of intervention required. Early reoperative intervention does not appear to influence long-term outcomes, and delayed intervention (after 30 days) is strongly associated with decreased survival.

In recent centuries, an increasing understanding of the physiologic changes resulting in clinically significant portal hypertension has led to innumerable advances in the management of these patients. Highly morbid operative decompression has been largely replaced by medical therapy, endoscopic intervention, and endovascular techniques. A number of novel operations to relieve portal hypertension are still occasionally indicated due to the limited availability of liver transplantation. The high complexity of these patients requires a multidisciplinary approach with a clear understanding of both the natural history of cirrhosis and portal hypertension as well as the evolving techniques available to alter the progression of this disease.

Hemorrhagic shock is a leading cause of mortality within the trauma population, and blood transfusion is the standard of care. Leukoreduction filters remove donor leukocytes prior to transfusion of blood products. While the benefits of leukocyte depletion are well documented in scientific literature, these benefits do not translate directly to the clinical setting. This review summarizes current research regarding leukoreduction in the clinical arena, as well as studies performed exclusively in the trauma population.

Orthogonally functionalized nanopatterend surfaces presenting discrete domains of fibronectin ranging from 92 to 405 nm were implemented to investigate the influence of limiting adhesion site growth on cell migration. We demonstrate that limiting adhesion site growth to small, immature adhesions using sub-100 nm patterns induced cells to form a significantly increased number of smaller, more densely packed adhesions that displayed few interactions with actin stress fibers. Human umbilical vein endothelial cells exhibiting these traits displayed highly dynamic fluctuations in spreading and a 4.8-fold increase in speed compared to cells on nonpatterned controls. As adhesions were allowed to mature in size in cells cultured on larger nanopatterns, 222 to 405 nm, the dynamic fluctuations in spread area and migration began to slow, yet cells still displayed a 2.1-fold increase in speed compared to controls. As all restrictions on adhesion site growth were lifted using nonpatterned controls, cells formed significantly fewer, less densely packed, larger, mature adhesions that acted as terminating sites for actin stress fibers and significantly slower migration. The results revealed an exponential decay in cell speed with increased adhesion site size, indicating that preventing the formation of large mature adhesions may disrupt cell stability thereby inducing highly migratory behavior.

Hemorrhagic shock is a leading cause of mortality within the trauma population, and blood transfusion is the standard of care. Leukoreduction filters remove donor leukocytes prior to transfusion of blood products. While the benefits of leukocyte depletion are well documented in scientific literature, these benefits do not translate directly to the clinical setting. This review summarizes current research regarding leukoreduction in the clinical arena, as well as studies performed exclusively in the trauma population.

Chronic pancreatitis is a complex disease process best addressed by a multidisciplinary approach. The surgical treatment of chronic pancreatitis requires a detailed understanding of the ductal anatomy and natural history of the disease. Surgical drainage of the distal pancreatic duct via longitudinal pancreatojejunostomy can successfully alleviate ductal hypertension, relieve pain, and preserve endocrine and exocrine function. Preferred approaches, as described by several prominent surgeons of the past, include the Frey and Puestow procedures. With a growing understanding of the pathophysiology of ductal hypertension, pancreatic pain, and chronic inflammation, modern modifications of classic surgical techniques remain critical tools in successful, sustained management for patients requiring ductal decompression.

Introduction: Pasireotide was recently shown to decrease leak rates after pancreatic resection, though the significant cost of the drug may be prohibitive. We conducted a cost-effectiveness analysis to determine whether prophylactic pasireotide possesses a reasonable cost profile by improving outcomes. Methods: A cost-effectiveness model was constructed to compare pasireotide administration after pancreatic resection versus usual care, populated by probabilities of clinical outcomes from a recent randomized trial and hospital costs (2013 US$) from a university pancreatic disease center. Sensitivity analyses were performed to identify the most influential clinical components of the model. Results: Without considering pasireotide cost, prophylactic use of the drug saved an average of $8,109 per patient. However, when the cost of pasireotide was included, per patient costs increased from $42,159 to $77,202. This was associated with a 56% reduction in pancreatic fistula/pancreatic leak/abscess (PF/PL/A) (21.9% to 9.2%). The resultant cost per PF/PL/A avoided was $301,628. Threshold analysis demonstrated that for this intervention to be cost neutral, either the purchase price of pasireotide ($43,172) must be reduced by 92.3% (to $3324) or drug reimbursement must be $39,848. Sensitivity analyses exploring variable perioperative mortality, rate of PF/PL/A, and readmission rates did not significantly alter model outcomes. Conclusions: Our analyses demonstrate that when prophylactic pasireotide is administered, the cost per PF/PL/A avoided is approximately $300,000. Aggressive pricing negotiation, payer reimbursement for the drug, high-volume use, and consensus among the public, payers, and surgical community regarding the value of reducing morbidity will ultimately determine the utility of widespread pasireotide application in pancreatic resection.

Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.

Urgent colectomy is a common procedure with a high mortality rate that is performed by a variety of surgeons and hospitals. We investigated patient, surgeon, and hospital characteristics that predicted mortality after urgent colectomy.The University HealthSystem Consortium was queried for adults undergoing urgent or emergent colectomy between 2009 and 2013 (n = 50,707). Hospitals were grouped into quartiles according to risk-adjusted observed-to-expected (O/E) mortality ratios and compared using the 2013 American Hospital Association Annual Survey. Multiple logistic regression was used to determine patient and provider characteristics associated with in-hospital mortality.The overall mortality rate after urgent colectomy was 9 %. Mortality rates were higher for patients with extreme severity of illness (27.6 %), lowest socioeconomic status (10.6 %), weekend admissions (10.7 %), and open (10.5 %) and total (15.8 %) colectomies. Hospitals with the lowest O/E ratios were smaller and had lower volume and less teaching intensity, but there were no significant trends with regard to financial (expenses, payroll, capital expenditures per bed) or personnel characteristics (physicians, nurses, technicians per bed). On multivariate analysis, mortality was associated with patient age (10 years: OR 1.31, p 0.01), severity of illness (extreme: OR 34.68, p 0.01), insurance status (Medicaid: OR 1.24, p 0.01; uninsured: OR 1.40, p 0.01), and weekend admission (OR 1.09, p = 0.04). Surgeon volume was associated with reduced mortality (per 10 cases: OR 0.99, p 0.01), but hospital volume was not (per case: OR 1.00, p = 0.84).Mortality is common after urgent colectomy and is associated with patient characteristics. Surgeon volume and practice patterns predicted differences in mortality, whereas hospital factors did not. These data suggest that policies focusing solely on hospital volume ignore other more important predictors of patient outcomes.

Efforts to regionalize surgery based on thresholds in procedure volume may have consequences on the cost of health care delivery. This study aims to delineate the relationship between hospital volume, case mix, and variability in the cost of operative intervention using colectomy as the model.All patients undergoing colectomy (n = 90,583) at 183 academic hospitals from 2009-2012 in The University HealthSystems Consortium Database were studied. Patient and procedure details were used to generate a case mix-adjusted predictive model of total direct costs. Observed to expected costs for each center were evaluated between centers based on overall procedure volume.Patient and procedure characteristics were significantly different between volume tertiles. Observed costs at high-volume centers were less than at middle- and low-volume centers. According to our predictive model, high-volume centers cared for a less expensive case mix than middle- and low-volume centers ($12,786 vs $13,236 and $14,497, P .01). Our predictive model accounted for 44% of the variation in costs. Overall efficiency (standardized observed to expected costs) was greatest at high-volume centers compared to middle- and low-volume tertiles (z score -0.16 vs 0.02 and -0.07, P .01).Hospital costs and cost efficiency after an elective colectomy varies significantly between centers and may be attributed partially to the patient differences at those centers. These data demonstrate that a significant proportion of the cost variation is due to a distinct case mix at low-volume centers, which may lead to perceived poor performance at these centers.

Background Metabolic syndrome is increasing among patients undergoing liver transplantation. Nonalcoholic steatohepatitis is a manifestation of metabolic syndrome and is an increasingly common cause of end-stage liver disease necessitating orthotopic liver transplantation. We sought to determine the effect of preoperative risk factors on the development of post-transplant metabolic syndrome, complications, readmissions, and mortality. Methods We conducted a review of 114 orthotopic liver transplantations at our institution from May 2012 to April 2014. Results Patients with (n = 19) and without (n = 95) metabolic syndrome were similar with regard to age, race, and model for end-stage liver disease at time of transplant. Donor and operative factors also were similar between the groups. Preoperative diabetes was found to be associated with an increased rate of readmission (odds ratio 3.45, P = .03). While preoperative metabolic syndrome itself was not a significant predictor of worse outcomes, postoperative metabolic syndrome was associated with significantly greater readmissions in the first year. Major predictors of new onset metabolic syndrome after orthotopic liver transplantation included preoperative diabetes and obesity (odds ratio 8.54 and odds ratio 5.49, P Conclusion Efforts to decrease the incidence of postoperative metabolic syndrome after orthotopic liver transplantation may decrease readmissions and improve outcomes, along with decreasing resource utilization.

With the increasing complexity of modern medical therapies, it is becoming imperative to recognize the marginal cost and gains of increasingly sophisticated (and expensive) interventions. By understanding the incremental cost of a given intervention, investigators must help answer questions about healthcare resource utilization that are not answered by randomized clinical trials. The continued funding of biomedical research and pharmaceuticals will require more objective study of the return on investment for any given treatment modality, and cost-effectiveness analyses will be instrumental in providing solutions to the inequalities in healthcare delivery.

BACKGROUND For nearly a decade, our center performed thromboelastograms (TEGs) to analyze coagulation profiles, allowing rapid data-driven blood component therapy. After consensus recommendations for massive transfusion protocols (MTPs), we implemented an MTP in October 2009 with 1:1:1 ratio of blood (red blood cells [RBC]), plasma (fresh-frozen plasma [FFP]), and platelets. We hypothesized that TEG-directed resuscitation is equivalent to MTP resuscitation. METHODS All patients receiving 6 units (U) or more of RBC in the first 24 hours for 21 months before and after MTP initiation in an urban Level I trauma center were examined. Demographics, mechanism of injury (MOI), Injury Severity Score (ISS), 24-hour volume of RBC, FFP, platelets, crystalloid, and 30-day mortality were compared, excluding patients with traumatic brain injuries. Variables were analyzed using Student's t-test and χ2 or Fisher's exact test. RESULTS For the preMTP group, there were 165 patients. In the MTP group, there were 124 patients. There were no significant differences in ISS, age, or sex. PreMTP patients with 6U or more RBC had significantly more penetrating MOI (p = 0.017), whereas preMTP patients with 10U or more RBC had similar MOIs. All patients received less crystalloid after MTP adoption (p < 0.001). There was no difference in volume of blood products or mortality in patients receiving 6U or more RBC. Blunt trauma MTP patients who received 10U or more RBC received more FFP (p = 0.02), with no change in mortality. Penetrating trauma patients who received 10U or more RBC received a similar volume of FFP; however, mortality increased from 54.1% for MTP versus 33.3% preMTP (p = 0.04). CONCLUSION TEG-directed resuscitation is equivalent to standardized MTP for patients receiving 6U or more RBC and for blunt MOI patients receiving 10U or more RBC. MTP therapy worsened mortality in penetrating MOI patients receiving 10U or more RBC, indicating a continued need for TEG-directed therapy. A 1:1:1 strategy may not be adequate in all patients. LEVEL OF EVIDENCE Therapeutic study, level IV.

Safety-net hospitals care for vulnerable patients, providing complex surgery at increased costs. These hospitals are at risk due to changing health care reimbursement policies and demand for better value in surgical care.To model different techniques for reducing the cost of complex surgery performed at safety-net hospitals.Hospitals performing pancreaticoduodenectomy (PD) were queried from the University HealthSystem Consortium database (January 1, 2009, to December 31, 2013) and grouped according to safety-net burden. A decision analytic model was constructed and populated with clinical and cost data. Sensitivity analyses were then conducted to determine how changes in the management or redistribution of patients between hospital groups affected cost.Overall cost per patient after PD.During the 5 years of the study, 15 090 patients underwent PD. Among safety-net hospitals, low-burden hospitals (LBHs), medium-burden hospitals (MBHs), and high-burden hospitals (HBHs) treated 4220 (28.0%), 9505 (63.0%), and 1365 (9.0%) patients, respectively. High-burden hospitals had higher rates of complications or comorbidities and more patients with increased severity of illness. Perioperative mortality was twice as high at HBHs (3.7%) than at LBHs (1.6%) and MBHs (1.7%) (P .001). In the base case, when all clinical and cost data were considered, PD at HBHs cost $35 303 per patient, 30.1% and 36.2% higher than at MBHs ($27 130) and LBHs ($25 916), respectively. Reducing perioperative complications or comorbidities by 50% resulted in a cost reduction of up to $4607 for HBH patients, while reducing mortality rates had a negligible effect. However, redistribution of HBH patients to LBHs and MBHs resulted in significantly more cost savings of $9155 per HBH patient, or $699 per patient overall.Safety-net hospitals performing PD have inferior outcomes and higher costs, and improving perioperative outcomes may have a nominal effect on reducing these costs. Redirecting patients away from safety-net hospitals for complex surgery may represent the best option for reducing costs, but the implementation of such a policy will undoubtedly meet significant challenges.

Transforming growth factor-beta-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor alpha (TNFalpha)- and interleukin-1beta (IL-1beta)-induced IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFalpha and IL-1beta induce Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFalpha and IL-1beta-mediated IKK/NF-kappaB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys(63)-linked polyubiquitination of TAK1 at Lys(158) is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFalpha and IL-1beta stimulation.

We studied the molecular basis of familial Type I hyperlipoproteinemia in two brothers of Turkish descent who had normal plasma apolipoprotein C-II levels and undetectable plasma post-heparin lipoprotein lipase (LPL) activity. We cloned the cDNAs of LPL mRNA from adipose tissue biopsies obtained from these individuals by the polymerase chain reaction and directional cloning into M13 vectors. Direct sequencing of pools of greater than 2000 cDNA clones indicates that their LPL mRNA contains two mutations: a missense mutation changing codon 156 from GAU to GGU predicting an Asp156----Gly substitution and a nonsense mutation changing the codon for Ser447 from UCA to UGA, a stop codon, predicting a truncated LPL protein that contains 446 instead of 448 amino acid residues. Both patients were homozygous for both mutations. Analysis of genomic DNAs of the patients and their family members by the polymerase chain reaction, restriction enzyme digestion (the GAT----GGT mutation abolishes a TaqI restriction site), and allele-specific oligonucleotide hybridization confirms that the patients were homozygous for these mutations at the chromosomal level, and the clinically unaffected parents and sibling were true obligate heterozygotes for both mutations. In order to examine the functional significance of the mutations in this family, we expressed wild type and mutant LPLs in vitro using a eukaryotic expression vector. Five types of LPL proteins were produced in COS cells by transient transfection: (i) wild type LPL, (ii) Asp156----Gly mutant, (iii) Ser447----Ter mutant, (iv) Gly448----Ter mutant, and (v) Asp156----Gly/Ser447----Ter double mutant. Both LPL immunoreactive mass and enzyme activity were determined in the culture media and intracellularly. Immunoreactive LPLs were produced in all cases. The mutant LPLs, Asp156----Gly and Asp156----Gly/Ser447----Ter, were devoid of enzyme activity, indicating that the Asp156----Gly mutation is the underlying defect for the LPL deficiency in the two patients. The two mutant LPLs missing a single residue (Gly448) or a dipeptide (Ser447-Gly448) from its carboxyl terminus had normal enzyme activity. Thus, despite its conservation among all mammalian LPLs examined to date, the carboxyl terminus of LPL is not essential for enzyme activity. We further screened 224 unrelated normal Caucasians for the Ser447----Ter mutation and found 36 individuals who were heterozygous and one individual who was homozygous for this mutation, indicating that it is a sequence polymorphism of no functional significance. Human LPL shows high homology to hepatic triglyceride lipase and pancreatic lipase.(ABSTRACT TRUNCATED AT 400 WORDS)