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Objective The aim of this study was to determine whether negative pressure wound therapy (NPWT) applied to primarily closed incisions decreases surgical site infections (SSIs) following open abdominal surgery. Background SSIs are a common cause of morbidity following open abdominal surgery. Prophylactic NPWT has shown promise for SSI reduction. However, the results of randomized controlled trials (RCTs) conducted among patients undergoing laparotomy have been inconsistent. Methods We performed a meta-analysis of English language RCTs comparing the use of prophylactic NPWT to standard dressings on primarily closed laparotomy incisions following open abdominal surgery. Medline, EMBASE, Cochrane Library, and CINAHL databases were searched from inception to December 31, 2018, for relevant studies. A random-effects model was used for statistical analysis. Results Five RCTs totaling 792 patients were included in our meta-analysis after application of our exclusion and inclusion criteria. There was no significant difference in the risk of SSIs identified among those patients who had NPWT compared to standard dressings; relative risk (RR) 0.56 (95% confidence interval 0.30-1.03, P = 0.064). There was significant statistical heterogeneity across studies (I = 67.4%; P = 0.015). Conclusion The adoption of NPWT for routine SSI prophylaxis following laparotomy is currently not supported and should be used primarily in the context of a clinical trial.

OBJECTIVES The objectives of this study were to (1) create a technical and nontechnical performance standard for the laparoscopic cholecystectomy, (2) assess the classification accuracy and (3) credibility of these standards, (4) determine a trainees' ability to meet both standards concurrently, and (5) delineate factors that predict standard acquisition. BACKGROUND Scores on performance assessments are difficult to interpret in the absence of established standards. METHODS Trained raters observed General Surgery residents performing laparoscopic cholecystectomies using the Objective Structured Assessment of Technical Skill (OSATS) and the Objective Structured Assessment of Non-Technical Skills (OSANTS) instruments, while as also providing a global competent/noncompetent decision for each performance. The global decision was used to divide the trainees into 2 contrasting groups and the OSATS or OSANTS scores were graphed per group to determine the performance standard. Parametric statistics were used to determine classification accuracy and concurrent standard acquisition, receiver operator characteristic (ROC) curves were used to delineate predictive factors. RESULTS Thirty-six trainees were observed 101 times. The technical standard was an OSATS of 21.04/35.00 and the nontechnical standard an OSANTS of 22.49/35.00. Applying these standards, competent/noncompetent trainees could be discriminated in 94% of technical and 95% of nontechnical performances (P < 0.001). A 21% discordance between technically and nontechnically competent trainees was identified (P < 0.001). ROC analysis demonstrated case experience and trainee level were both able to predict achieving the standards with an area under the curve (AUC) between 0.83 and 0.96 (P < 0.001). CONCLUSIONS The present study presents defensible standards for technical and nontechnical performance. Such standards are imperative to implementing summative assessments into surgical training.

International audience; Liver-based metabolic diseases account for a substantial burden of childhood diseases. In most patients, treatment is often limited to supportive measures and liver transplantation is ultimately required. Even despite the excellent long-term outcome of liver transplantation, the procedure is associated with a significant morbidity and mortality. Gene therapy, in contrast, has great potential to save lives, improve the quality of life, and offer few risks and adverse effects compared with present therapies including liver transplantation. The most promising results to date in liver gene transfer have been achieved with adeno-associated virus. Although safety issues, such as immunogenicity of vector and/or transgene product, remain an important concern, gene therapy is ready for clinical trials in adults and adolescents. Developing and testing safe approaches for efficient and long-term stable applications in newborns and small children, such as targeted integration and gene correction, is one of the remaining future challenges.

Objective:The purpose of this study was to create a technical skills assessment toolbox for 35 basic and advanced skills/procedures that comprise the American College of Surgeons (ACS)/Association of Program Directors in Surgery (APDS) surgical skills curriculum and to provide a critical appraisal o

Abdominoperineal resection is a procedure associated with high rates of perineal surgical site infections, causing distress to the patient, costs to the hospital system, and delays in further treatment.The aim of this study was to investigate the role of incisional negative pressure wound therapy in decreasing the rates of perineal surgical site infection.This retrospective cohort study had a historical, consecutively sampled control group.This study was conducted at a single-institution tertiary care academic institution.All patients undergoing an abdominoperineal resection between 2008 and 2012 were assessed.Perineal incisional negative pressure wound therapy was applied to all patients following an abdominoperineal resection between 2010 and 2012 at 125 mmHg continuous suction for 5 days postoperatively.The development of a perineal surgical site infection within the first 30 days postoperatively was the primary outcome measured.Fifty-nine patients were included: 27 in the incisional negative pressure wound therapy group and 32 in the control group. A statistically lower proportion of perineal surgical site infections were detected in the incisional negative pressure wound therapy group than in the standard dressing group (15% vs 41%; p = 0.02). Both populations were similar in perioperative risk factors, with the exception of increased levels of blood urea nitrogen, a higher proportion of hypertensive patients, and a longer mean operative time in the incisional negative pressure wound therapy group. Additionally, an increased length of stay was observed in the incisional negative pressure wound therapy group (11 vs 8 days; p = 0.03). After adjusting for confounders, including the type of perineal dissection, incisional negative pressure wound therapy was found to be an independent predictor of not developing an surgical site infection (adjusted OR, 0.11; 95% CI, 0.04-0.66; p = 0.01).The study's retrospective nature limits the results because of the risk of interpreter bias, although this was addressed in part by reviewing data in duplicate. We controlled for the potential for selection bias with our consecutive sampling model.Our study demonstrates a role for incisional negative pressure wound therapy in decreasing rates of perineal surgical site infection following abdominoperineal resection. Prospective randomized trials will be required to further investigate this intervention.

A Mixed Presentation of Serotonin Syndrome Versus Neuroleptic Malignant Syndrome in a 12-Year-Old Boy

Purpose In clinical settings, uncertainty is part of everyday practice. However, a lack of insight into how experts approach uncertainty limits the ability to explicitly teach and assess it in training. This study explored how experienced surgeons perceived and handled uncertainty during challenging intraoperative situations, to develop a theoretical language supporting both education and research. Method This constructivist qualitative study included observations and interviews during 26 surgical cases. The cases, drawn from seven staff surgeons from various specialties at a medical school, were purposively sampled after being preidentified by the surgeon as "likely challenging." The authors combined template and inductive analyses. In template analysis, an existing theory was used to identify instances of uncertainty in the dataset. Inductive analysis was used to elaborate and refine the concepts. Results Template analysis confirmed that existing theoretical concepts are relevant to surgery. However, inductive analysis revealed additional concepts and positioned existing concepts within new relationships. Two new theoretical themes were recognizing uncertainty and responding to uncertainty, each with corresponding subthemes. Factors such as the novelty of the situation, difficulty in predicting the outcome, and difficulty deciding the course of action mainly characterize an uncertain situation in surgery according to the participants. Conclusions The results offer a refined language for conceptualizing uncertainty in surgery. Although further research could elaborate and test the explanatory power of this language, the authors anticipate that it has implications both for current discussions of surgical safety and for future development of explicit training for effective management of surgical uncertainty.

Lentiviral (LV) vectors are promising tools for long-term genetic correction of hereditary diseases. In hematopoietic stem cell gene therapies adverse events in patients due to vector integration-associated genotoxicity have been observed. Only a few studies have explored the potential risks of LV gene therapy targeting the liver. To analyze hepatic genotoxicity in vivo, we transferred the fumarylacetoacetate hydrolase (FAH) gene by LV vectors into FAH(-/-) mice (n = 97) and performed serial hepatocyte transplantations (four generations). The integration profile (4,349 mapped insertions) of the LV vectors was assessed by ligation-mediated polymerase chain reaction and deep sequencing. We tested whether the polyclonality of vector insertions was maintained in serially transplanted mice, linked the integration sites to global hepatocyte gene expression, and investigated the effects of LV liver gene therapy on the survival of the animals. The lifespan of in vivo gene-corrected mice was increased compared to 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) control animals and unchanged in serially transplanted animals. The integration profile (4,349 mapped insertions) remained polyclonal through all mouse generations with only mild clonal expansion. Genes close to the integration sites of expanding clones may be associated with enhanced hepatocyte proliferation capacity. Conclusion: We did not find evidence for vector-induced tumors. LV hepatic gene therapy showed a favorable risk profile for stable and long-term therapeutic gene expression. Polyclonality of hepatocyte regeneration was maintained even in an environment of enforced proliferation. (HEPATOLOGY 2013)

The tightly controlled replication of hepatocytes in liver regeneration and uncontrolled proliferation of tumor cells in hepatocellular carcinoma (HCC) are often modulated by common regulatory pathways. Several microRNAs (miRNAs) are involved in HCC progression by modulating posttranscriptional expression of multiple target genes. miR-221, which is frequently up-regulated in HCCs, delays fulminant liver failure in mice by inhibiting apoptosis, indicating a pleiotropic role of miR-221 in hepatocytes. Here, we hypothesize that modulation of miR-221 targets in primary hepatocytes enhances proliferation, providing novel clues for enhanced liver regeneration. We demonstrate that miR-221 enhances proliferation of in vitro cultivated primary hepatocytes. Furthermore, applying two-thirds partial hepatectomy as a surgically induced liver regeneration model we show that adeno-associated virus-mediated overexpression of miR-221 in the mouse liver also accelerates hepatocyte proliferation in vivo. miR-221 overexpression leads to rapid S-phase entry of hepatocytes during liver regeneration. In addition to the known targets p27 and p57, we identify Aryl hydrocarbon nuclear translocator (Arnt) messenger RNA (mRNA) as a novel target of miR-221, which contributes to the pro-proliferative activity of miR-221. Conclusion: miR-221 overexpression accelerates hepatocyte proliferation. Pharmacological intervention targeting miR-221 may thus be therapeutically beneficial in liver failure by preventing apoptosis and by inducing liver regeneration. (HEPATOLOGY 2013;)

Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein α (SIRPα) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPα polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-ΔRAG/γ(c) -uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. (HEPATOLOGY 2012).

Death receptor-mediated apoptosis of hepatocytes contributes to hepatitis and fulminant liver failure. MicroRNAs (miRNAs), 19-25 nucleotide-long noncoding RNAs, have been implicated in the posttranscriptional regulation of the various apoptotic pathways. Here we report that global loss of miRNAs in hepatic cells leads to increased cell death in a model of FAS/CD95 receptor-induced apoptosis. miRNA profiling of murine liver identified 11 conserved miRNAs, which were up-regulated in response to FAS-induced fulminant liver failure. We show that ectopic expression of miR-221, one of the highly up-regulated miRNAs in response to apoptosis, protects primary hepatocytes and hepatoma cells from apoptosis. Importantly, in vivo overexpression of miR-221 by adeno-associated virus serotype 8 (AAV8) delays FAS-induced fulminant liver failure in mice. We additionally demonstrate that miR-221 regulates hepatic expression of p53 up-regulated modulator of apoptosis (Puma), a well-known proapoptotic member of the Bcl2 protein family. Conclusion: We identified miR-221 as a potent posttranscriptional regulator of FAS-induced apoptosis. miR-221 may serve as a potential therapeutic target for the treatment of hepatitis and liver failure. (HEPATOLOGY 2011;)

Background Urea cycle disorders (UCD) have a poor prognosis despite dietary and pharmacologic therapy, especially if the onset of the disease is within the neonatal period. They are promising target diseases for liver cell transplantation (LCT), which may be a less invasive alternative or supplementation to orthotopic liver transplantation. Methods Cryopreserved hepatocytes were isolated under good manufacturing practice conditions. Four children with severe neonatal UCD (age 1 day-3 years) received multiple intraportal infusions of cryopreserved hepatocytes from that same donor, a 9-day old neonate. Portal vein access was achieved surgically in two children, whereas the umbilical vein was suitable for interventional catheter placement in two neonates. Cell applications were carefully monitored by means of Doppler ultrasound and portal vein pressure. Results LCT was feasible in all children. No signs of portal vein thrombosis or extrahepatic shunting were observed. All children showed metabolic stabilization during observation periods of 4 to 13 months. One child with prenatally diagnosed ornithine transcarbamylase deficiency died after 4 months from a fatal metabolic decompensation. Conclusions Given the poor prognosis of UCD with conservative therapy, LCT caused considerable beneficial effects. Periods of hyperammonemia and clinically relevant crises could be reduced during an observation period of up to 13 months. Though cell therapy is not a permanent therapeutic option, bridging to liver transplantation may be substantially improved.

Hepatocyte transplantation has been proposed as an attractive therapeutic approach to a variety of liver diseases. Progress, however, in several areas is needed, before this form of therapy is broadly accepted and applied to patients with liver disease. The purpose of the review is to provide the reader with the latest scientific developments relevant for future liver cell therapies.Clinical application of hepatocyte transplantation is limited by good quality donor livers for the isolation of cells. Recent publications thus focus on stem cells as suitable sources for hepatocytes and liver repopulation strategies that could reduce the number of transplanted cells. How to overcome host immune responses against allogeneic cells can potentially be learned from a new tolerance protocol. Recently discovered technologies for reprogramming of postnatal cells into pluripotent stem cells may pave the way towards the generation of patient-specific autologous cells.The current focus of research aims to reduce the shortage of transplantable cells by the application of stem cell sources or by the conditioning of recipient livers. Therapies for severe chronic liver diseases based on adult (stem) cells are already beginning to move into clinical trials. However, many questions about safety and efficacy need to be answered, before fetal liver progenitor cells, embryonic stem cells and induced pluripotent stem cells can be applied in humans.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.)

Background Partial correction of metabolic liver disease by hepatocyte transplantation requires infusion of a large number of cells into the portal vein. Uncontrolled infusion of cells leads to extrahepatic shunting. Obstruction of the sinusoidal space may result in hemodynamic changes and impairment of liver function. Methods. Catheters connected to a port were placed into the caudal mesenteric vein of rabbits. After injection of 99m technetium-macroaggregated albumin ( 99m Tc-MAA) surrogates or 99m Tc-MAA/hepatocyte (Hc) mixtures (1:125), shunting into the lung was scintigraphically monitored. Volume flow (mL/min) and maximum velocity of the portal vein were recorded by color-coded Doppler ultrasound during intraportal application of 2.5×10 7 MAA particles, 2.5×10 7 isolated hepatocytes, and saline solution without particles or cells. Results. 99m Tc-MAA particles (2.5 x 10 7 ) or equivalent MAA/Hc mixtures were completely retained in the liver. With additional application of 2.5×10 7 particles, shunting into the lung was observed in two animals of the MAA group. All animals in the hepatocyte group have received 5×10 7 MAA/Hc mixtures, and three of these received 10 8 mixtures without shunting. Maximum velocity and volume flow increased with saline infusion. Hepatocyte suspended in the same volume blunted the increase observed in the control group, but parameters remained normal. Liver enzymes increased after hepatocyte application but returned to normal values within 5 days. Conclusions. Sinusoidal uptake capacity for hepatocyte or MAA particles varies at a wide range in normal rabbits. Scintigraphic monitoring of transplanted cells allows efficient monitoring of cell translocation into the lungs. No significant impairments of portal hemodynamics and liver function were detected.

Exposure to wild-type adenoviruses is common in humans and results in immune response against adenoviruses. The pre-existing antibodies and a strong secondary humoral and cellular immune response would interfere with gene transfer using recombinant adenoviral vectors. To test whether the secondary immune response can be abrogated by oral tolerization to adenoviral antigens, we immunized bilirubin-UDP-glucuronosyltransferase (BUGT)-deficient jaundiced Gunn rats with a recombinant adenovirus (5 x 10(9) pfu/rat) expressing the human UDP-glucouronosyltransferase (BUGT1) gene (Ad-hBUGT). Transgene expression was shown by reduction of mean serum bilirubin levels from 7.0 mg/dL to 2.3 mg/dL in 14 days, which then increased gradually to pretreatment levels in 6 weeks. All recipients developed antibodies (1:2[10]) and cytotoxic lymphocytes against the adenovirus. For oral tolerization, we administered to the immunized rats protein extracts of a recombinant adenovirus type 5 (1-1.5 mg/day) via duodenostomy tubes 10 to 40 days after the initial virus injection; control rats received bovine serum albumin. In rats fed adenoviral proteins and the BSA-fed controls, the antibody titers decreased to 1:2(7) and 1:2(9), respectively, in 70 days. Lymphocytes from the tolerized rats expressed TGF-beta1 upon exposure to antigen-presenting cells primed with adenoviral antigens, whereas IFN-gamma expression was undetectable. In contrast, lymphocytes from the BSA-treated control rats expressed IFN-gamma but not transforming growth factor beta1 (TGF-beta1). Seventy days after the first injection in the orally tolerized rats, but not in the controls, a second Ad-hBUGT injection caused human BUGT1 expression again, reducing serum bilirubin levels to those observed after the first injection. In the tolerized rats, serum antibody titers and anti-adenoviral cytotoxic lymphocyte activities continued to decline despite the second injection, whereas the antibody levels were boosted in the non-tolerized group. This results show that by preventing the secondary booster response, oral tolerization permits repeated adenovirus-directed gene transfer despite the presence of a residual antibody titer from a previous adenoviral exposure.

Introduction Work hour restrictions have had a profound impact on surgical education. However, little is known of how they may affect the future practices of current surgical residents. The purpose of this study is to compare the anticipated career practice patterns of surgical residents with that of current faculty. Methods An electronic survey was sent to all surgery residents and faculty at a university affiliated medical center. The survey consisted of questions regarding expected (residents) or current (faculty) practice patterns. Results A total of 73 residents and 57 faculty completed the survey (50.3% & 52.3% response rates respectively). There was a greater proportion of males in the faculty cohort than in the resident group (89.5% vs 61.6%, p=0.0003). More faculty, than residents, felt that work hour restrictions have a negative effect on residency education (42.1% vs 23.3%, p=0.003) and preparation for a surgical career (63.2% vs 26%, p Conclusions Current surgical residents plan to adopt resident work hour guidelines into their surgical practices upon completion of residency. These practice patterns will have surgical work force implications requiring larger surgical groups and reconsideration of resource allocation.

The expression of the CD40 receptor in different tumours suggests that it might be involved in tumour development and proliferation. In this article, we discuss recent findings on CD40 expression in hepatocellular carcinoma, its possible biological role for tumour development, and different experimental therapeutic strategies such as gene therapy and immunotherapy protocols.