Mitigating the Sign Problem through Basis Rotations.

Quantum Monte Carlo simulations of quantum many-body systems are plagued by the Fermion sign problem. The computational complexity of simulating Fermions scales exponentially in the projection time ß and system size. The sign problem is basis dependent and an improved basis, for fixed errors, leads to exponentially quicker simulations. We show how to use sign-free quantum Monte Carlo simulations to optimize over the choice of basis on large two-dimensional systems. We numerically illustrate these techniques decreasing the "badness" of the sign problem by optimizing over single-particle basis rotations on one- and two-dimensional Hubbard systems. We find a generic rotation which improves the average sign of the Hubbard model for a wide range of U and densities for L×4 systems. In one example improvement, the average sign (and hence simulation cost at fixed accuracy) for the 16×4 Hubbard model at U/t=4 and n=0.75 increases by exp[8.64(6)ß]. For typical projection times of ß⪆100, this accelerates such simulation by many orders of magnitude.

The role of school-based health centers in providing long-active reversible contraceptive care to adolescents in New York City.

Long-acting reversible contraceptives (LARCs) are effective contraceptive methods for adolescents. This study describes the initiation and continuation of LARC care to adolescents at school-based health centers (SBHCs) during the COVID-19 pandemic. Participants received contraceptive care in New York City SBHCs from April 2021-June 2022. LARC initiation, LARC discontinuation, and total contraceptive visits were measured monthly. During the study period, the SBHCs provided 1,303 contraceptive visits, including 77 LARC initiations. Among LARC initiations, six-month continuation probability was 79.3 % (95 %CI: 69.0-91.1). SBHCs play an important role in providing adolescents contraceptive services, particularly LARC care, when other health care systems are disrupted.

Comparison of robotic-assisted minimally invasive esophagectomy versus minimally invasive esophagectomy: A propensity-matched study from a single high-volume institution.

OBJECTIVE: Robotic-assisted minimally invasive esophagectomy accounts for a growing proportion of esophagectomies, potentially due to improved technical capabilities simplifying the challenging aspects of standard minimally invasive esophagectomy. However, there is limited evidence directly comparing both operations. The objective is to evaluate the short-term and long-term outcomes of robotic-assisted minimally invasive esophagectomy in comparison with the minimally invasive esophagectomy approach for patients with esophageal cancer over a 7-year period at a high-volume center. The primary end points of this study were overall survival and disease-free survival. Secondary end points included operation-specific morbidity, lymph node yield, readmission status, and in-hospital, 30-day, and 90-day mortality. METHODS: Patients who underwent robotic-assisted minimally invasive esophagectomy or standard minimally invasive esophagectomy over a 7-year period were identified from a prospectively maintained database. Inclusion criteria were patients with stage I to III disease, operations performed past the learning curve, and no evidence of scleroderma or cirrhosis. A 1:3 propensity match (robotic-assisted minimally invasive esophagectomy:minimally invasive esophagectomy) for multiple clinical covariates was performed to identify the final study cohort. Perioperative outcomes were compared between the 2 operations. RESULTS: A total of 734 patients undergoing minimally invasive esophagectomy (n = 630) or robotic-assisted minimally invasive esophagectomy (n = 104) for esophageal cancer were identified. After exclusions and matching, a total cohort of 246 patients undergoing robotic-assisted minimally invasive esophagectomy (n = 65) or minimally invasive esophagectomy (n = 181) were identified. There was no difference in overall survival (P = .69) or disease-free survival (P = .70). There were no significant differences in rates of major morbidity: pneumonia (17% vs 17%, P = .34), chylothorax (8% vs 9%, P = .95), recurrent laryngeal nerve injury (0% vs 1.5%, P = 1), anastomotic leak (5% vs 4%, P = .49), intraoperative complications (9% vs 8%, P = .73), or complete resection rates (99% vs 96%, P = .68). There was no difference in in-hospital (P = .89), 30-day (P = .66) or 90-day mortality (P = .73) between both cohorts. The robotic-assisted minimally invasive esophagectomy cohort yielded a higher median lymph node harvest in comparison with the minimally invasive esophagectomy cohort (32 vs 29, P = .02). CONCLUSIONS: Robotic-assisted minimally invasive esophagectomy may improve lymphadenectomy in patients undergoing esophagectomy for cancer. Minimally invasive esophagectomy and robotic-assisted minimally invasive esophagectomy are otherwise associated with similar mortality, morbidity, and perioperative outcomes. Further prospective study is required to investigate whether improved lymph node resection may translate to improved oncologic outcomes.

Outcomes after minimally invasive esophagectomy: review of over 1000 patients.

BACKGROUND: Esophagectomy is a complex operation and is associated with significant morbidity and mortality. In an attempt to lower morbidity, we have adopted a minimally invasive approach to esophagectomy. OBJECTIVES: Our primary objective was to evaluate the outcomes of minimally invasive esophagectomy (MIE) in a large group of patients. Our secondary objective was to compare the modified McKeown minimally invasive approach (videothoracoscopic surgery, laparoscopy, neck anastomosis [MIE-neck]) with our current approach, a modified Ivor Lewis approach (laparoscopy, videothoracoscopic surgery, chest anastomosis [MIE-chest]). METHODS: We reviewed 1033 consecutive patients undergoing MIE. Elective operation was performed on 1011 patients; 22 patients with nonelective operations were excluded. Patients were stratified by surgical approach and perioperative outcomes analyzed. The primary endpoint studied was 30-day mortality. RESULTS: The MIE-neck was performed in 481 (48%) and MIE-Ivor Lewis in 530 (52%). Patients undergoing MIE-Ivor Lewis were operated in the current era. The median number of lymph nodes resected was 21. The operative mortality was 1.68%. Median length of stay (8 days) and ICU stay (2 days) were similar between the 2 approaches. Mortality rate was 0.9%, and recurrent nerve injury was less frequent in the Ivor Lewis MIE group (P < 0.001). CONCLUSIONS: MIE in our center resulted in acceptable lymph node resection, postoperative outcomes, and low mortality using either an MIE-neck or an MIE-chest approach. The MIE Ivor Lewis approach was associated with reduced recurrent laryngeal nerve injury and mortality of 0.9% and is now our preferred approach. Minimally invasive esophagectomy can be performed safely, with good results in an experienced center.

Activity-Based Cost Analysis of Robotic Anatomic Lung Resection During Program Implementation.

BACKGROUND: While robotic-assisted lung resection has seen a significant rise in adoption, concerns remain regarding initial programmatic outcomes and potential increased costs. We present our initial outcomes and cost analysis since initiation of a robotic lung resection program. METHODS: Patients undergoing either video-assisted thoracoscopic lobectomy or segmentectomy (VATS) or robotic-assisted lobectomy or segmentectomy (RALS) between August of 2014 and January of 2017 underwent retrospective review. Patients underwent 1:1 propensity matching based on preoperative characteristics. Perioperative and 30-day outcomes were compared between groups. Detailed activity-based costing analysis was performed on individual patient encounters taking into effect direct and indirect controllable costs, including robotic operative supplies. RESULTS: There were no differences in 30-day mortality between RALS (n = 74) and VATS (n = 74) groups (0% vs 1.4%; P = 1). RALS patients had a decreased median length of stay (4 days vs 7 days; P < .001) and decreased median chest tube duration (3 days vs 5 days, P < .001). Total direct costs, including direct supply costs, were not significantly different between RALS and VATS ($6621 vs $6483; P = .784). Median total operating costs and total unit support costs, which are closely correlated to length of stay, were lower in the RALS group. Overall median controllable costs were significantly different between RALS and VATS ($16,352 vs $21,154; P = .025). CONCLUSIONS: A potentially cost-advantageous robotic-assisted pulmonary resection program can be initiated within the context of an existing minimally invasive thoracic surgery program while maintaining good clinical outcomes when compared with traditional VATS. Process-of-care changes associated with RALS may account for decreased costs in this setting.

Transoral endoscopic repair of Zenker diverticulum by a thoracic surgical service.

OBJECTIVE: Zenker diverticulum (ZD), a pulsion diverticulum of the esophagus, has been traditionally managed with an open surgical approach, but endoscopic transoral stapling has been reported with increasing frequency. The objective of this study was to evaluate the results of endoscopic repair of ZD by a thoracic surgery service. METHODS: We conducted a retrospective review of patients who underwent transoral stapling repair of ZD at our institution by the thoracic surgery service. We evaluated perioperative outcomes including dysphagia (1, no dysphagia to 5, unable to swallow saliva) and failure of repair requiring surgical intervention. RESULTS: A total of 151 patients (median age, 78 years; 75 men, 76 women) underwent evaluation for endoscopic repair of ZD. Endoscopic stapled repair of the ZD was completed in 135. Sixteen patients underwent conversion to open repair. The perioperative mortality was 0.6% (1 patient). The median hospital stay was 2 days (range, 0-18 days). Complications occurred in 5 patients who underwent endoscopic repair. The mean preoperative dysphagia score was 2.8 and improved to 1.2 during follow-up (median, 16 months; P < .001). During further follow-up (median, 52 months), 8 patients (5.3%) had failure of the endoscopic repair requiring open surgery (n = 5) or redo transoral stapling (n = 3). CONCLUSIONS: Endoscopic stapling repair of ZD can be performed safely with good results in experienced centers by thoracic surgeons with significant esophageal experience. Long-term follow-up is required to evaluate the durability of endoscopic repair of ZD.

Transcriptomic response of murine liver to severe injury and hemorrhagic shock: a dual-platform microarray analysis.

Trauma-hemorrhagic shock (HS/T) is a complex process that elicits numerous molecular pathways. We hypothesized that a dual-platform microarray analysis of the liver, an organ that integrates immunology and metabolism, would reveal key pathways engaged following HS/T. C57BL/6 mice were divided into five groups (n = 4/group), anesthetized, and surgically treated to simulate a time course and trauma severity model: 1) nonmanipulated animals, 2) minor trauma, 3) 1.5 h of hemorrhagic shock and severe trauma (HS/T), 4) 1.5 h HS/T followed by 1 h resuscitation (HS/T+1.0R), 5) 1.5 h HS/T followed by 4.5 h resuscitation (HS/T+4.5R). Liver RNA was hybridized to CodeLink and Affymetrix mouse whole genome microarray chips. Common genes with a cross-platform correlation >0.6 (2,353 genes in total) were clustered using k-means clustering, and clusters were analyzed using Ingenuity Pathways Analysis. Genes involved in the stress response and immunoregulation were upregulated early and remained upregulated throughout the course of the experiment. Genes involved in cell death and inflammatory pathways were upregulated in a linear fashion with elapsed time and in severe injury compared with minor trauma. Three of the six clusters contained genes involved in metabolic function; these were downregulated with elapsed time. Transcripts involved in amino acid metabolism as well as signaling pathways associated with glucocorticoid receptors, IL-6, IL-10, and the acute phase response were elevated in a severity-dependent manner. This is the first study to examine the postinjury response using dual-platform microarray analysis, revealing responses that may enable novel therapies or diagnostics.

DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma.

Intestinal mucosal injury occurs after remote trauma although the mechanisms that sense remote injury and lead to intestinal epithelial disruption remain incompletely understood. We now hypothesize that Toll-like receptor 4 (TLR4) signaling on enterocytes after remote injury, potentially through the endogenous TLR4 ligand high-mobility group box-1 (HMGB1), could lead to intestinal dysfunction and bacterial translocation and that activation of TLR9 with DNA could reverse these effects. In support of this hypothesis, exposure of TLR4-expressing mice to bilateral femur fracture and systemic hypotension resulted in increased TLR4 expression and signaling and disruption of the ileal mucosa, leading to bacterial translocation, which was not observed in TLR4-mutant mice. TLR4 signaling in enterocytes, not immune cells, was required for this effect, as adenoviral-mediated inhibition of TLR4 in enterocytes prevented these findings. In seeking to identify the endogenous TLR4 ligands involved, the expression of HMGB1 was increased in the intestinal mucosa after injury in wild-type, but not TLR4-mutant, mice, and administration of anti-HMGB1 antibodies reduced both intestinal mucosal TLR4 signaling and bacterial translocation after remote trauma. Strikingly, mucosal injury was significantly increased in TLR9-mutant mice, whereas administration of exogenous DNA reduced the extent of TLR4-mediated enterocyte apoptosis, restored mucosal healing, and maintained the histological integrity of the intestinal barrier after remote injury. Taken together, these findings identify a novel link between remote injury and enterocyte TLR4 signaling leading to barrier injury, potentially through HMGB1 as a ligand, and demonstrate the reversal of these adverse effects through activation of TLR9.

Laparoscopic repair of giant paraesophageal hernia.

Video 1Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 2Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 3Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 4Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 5Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 6Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 7Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 8Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 9Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 10Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.Video 11Video available at: https://www.jtcvs.org/article/S2666-2507(21)00514-9/fulltext.

Laparoscopic and thoracoscopic esophagectomy.

Over the past decade, our technique of MIE has evolved considerably. In the incipient phase of our experience, we used a totally laparoscopic approach similar to that described in the initial reports from DePaula and colleagues and Swanstrom and Hansen. However, it was soon apparent that there were several critical disadvantages to a purely laparoscopic approach. Laparoscopic transhiatal mobilization of the esophagus offers suboptimal visualization of important periesophageal structures, including the inferior pulmonary vein and the left mainstem bronchus. Moreover, decreased visibility hindered hemostatic division of periesophageal vessels and negatively impacted the completeness of the mediastinal lymph node dissection. These problems are further exacerbated in taller patients. In light of these considerations, we soon transitioned to a laparoscopic-thoracoscopic McKeown approach (thoracoscopic mobilization of the intrathoracic esophagus, laparoscopic gastric tube creation, cervical anastomosis). To this date, the great majority of our minimally invasive esophagectomies (>500 cases) have been performed with this 3-field technique. Indeed, the procedure has been the mainstay of our experience in the past 10 years with reduced perioperative morbidity and mortality compared with many other open series. In our experience, perhaps the most significant technical concern with this operation is the cervical dissection. Recurrent laryngeal nerve injuries, perturbations in pharyngeal transit, and swallowing dysfunction even in the absence of recurrent nerve injury are not infrequent. Moreover, as described in open series using a cervical anastomosis, anastomotic stricture and leak have been shown to occur with increased frequency [35]. In short, there is a significant learning curve with the cervical dissection. Out of these concerns emerged our more recent experience with completely thoracoscopic-laparoscopic Ivor Lewis esophagectomy. However, we did first evolve through a transition phase whereby a mini-thoracotomy (hybrid approach) was performed for creation of the intrathoracic anastomosis. We believe that the experience with totally thoracoscopic-laparoscopic Ivor Lewis esophagectomy will ultimately reproduce the low morbidity and mortality we have previously published with our established MIE technique. The omission of a cervical dissection has reduced our recurrent nerve injury rate to zero. From a theoretical standpoint, one would presume that pharyngeal transit problems and oropharyngeal swallowing dysfunction should be reduced as well with a chest anastomosis. It should be emphasized that there is a steep operator learning curve associated with this approach. Indeed, thoracoscopic port placement is critical, as poorly positioned trocars can result in difficulty maneuvering instruments through the rigid chest wall. Additionally, both blood and lung can obscure visualization of the esophagus, which lies at the dependent aspect of the operative field. Prone positioning has been described as an alternative approach that may facilitate operative exposure and address such technical concerns. Low rates of anastomotic leak (3%), low mortality (1.5%), and equivalent stage-specific survival compared with open series have been shown with this thoracoscopic prone approach [36]. In conclusion, our technique of MIE has evolved such that laparoscopic-thoracoscopic Ivor Lewis esophagectomy has become our preferred approach. Although somewhat early in our experience, we are convinced that this operative technique is feasible with reproducible results. Perioperative morbidity and mortality are comparable with our previously established MIE with cervical anastomosis while essentially eliminating recurrent nerve injury, limiting the length of the gastric conduit required, and allowing a more aggressive gastric resection margin. Recent data from other publications also suggests that lymph node yields may be improved, although insufficient data exist at this time to comment on oncologic results or outcomes with this technique.

Robotic assisted minimally invasive thymectomy with simultaneous bilateral thoracoscopy and contralateral phrenic nerve visualization.

BACKGROUND: Thoracoscopic approaches to thymectomy and anterior mediastinal mass resection has become increasingly common due to the potential for decreased blood loss and hospital length of stay. However, contralateral mediastinal and phrenic nerve visualization if often difficult from these unilateral approaches, which may affect the ability to achieve a full phrenic to phrenic dissection Herein, we present our early experience of robotic assisted minimally invasive thymectomy (RAMIT) with simultaneous bilateral thoracoscopy and contralateral phrenic nerve visualization. METHODS: This was a retrospective review of all sequential patients undergoing RAMIT with simultaneous bilateral thoracoscopy from January 2015 to May 2016. This study was approved by our Institutional Review Board (PRO15080367). Individual patient consent was waived. RESULTS: Twenty-six patients [median age 58 (range, 29-76) years] were included in this study. Sixteen operations were performed for anterior mediastinal mass, 7 for non-thymomatous myasthenia gravis, and 3 for concurrent myasthenia gravis and thymoma. Median blood loss and hospital stay were 25 mL (range, 3-150 mL) and 3 days (range, 2-8 days), respectively. Twenty-one (80.8%) patients experienced an uncomplicated hospital course. The highest graded complication by Clavien Dindo Classification was a grade III due to pleural effusion requiring drainage via pleural catheter. One patient experienced asymptomatic hemidiaphram palsy postoperatively. There were no 90-day postoperative deaths. CONCLUSIONS: RAMIT with simultaneous bilateral thoracoscopy is a feasible approach that may allow for enhanced visualization and more complete thymic resection compared to existing unilateral minimally invasive operations. Comparative studies and long-term follow up are needed to adequately assess the potential benefits of RAMIT.

Anastomotic complications after esophagectomy: Influence of omentoplasty in propensity-weighted cohorts.

OBJECTIVE: A recent meta-analysis of 3 randomized controlled trials reported reduced incidence and severity of postesophagectomy anastomotic dehiscence with anastomotic omentoplasty. Unfortunately, these trials excluded neoadjuvant patients who received chemoradiation. We aimed to determine whether anastomotic omentoplasty was associated with differential postesophagectomy anastomotic complications after neoadjuvant chemoradiotherapy. METHODS: Data for patients who underwent minimally invasive esophagectomy following neoadjuvant chemoradiotherapy were abstracted (n = 245; 2001-2016; omentoplasty = 147 [60%]). Propensity for omentoplasty was estimated on 21 pretreatment variables, using augmented inverse probability of treatment weights, and used to determine the adjusted proportion of adverse anastomotic outcomes, major morbidity, and 30-day/in-hospital mortality. RESULTS: Overall, anastomotic leak rate was 15%; leak-associated mortality was 13% (n = 5 out of 37). Leak rates (omentoplasty n = 24 [16%] vs no omentoplasty n = 13 [13%]; P = .512) and incidence of any major complications (48% vs 48%; P = .958) were similar. Leaks requiring surgical intervention occurred in 12 patients (5% vs 5%; P = .904). Propensity weighting achieved excellent balance across all 21 pretreatment variables (before weighting, standardized differences ranged from -0.23 to 0.35; postweighting standardized differences ranged from -0.09 to 0.07). In propensity-weighted data, omentoplasty was not associated with differential adjusted risk of anastomotic leak (13.2% vs 14.3%; P = .83), major morbidity (27.9% vs 32.6%; P = .44), or mortality (6.7% vs 4.8%; P = .61). CONCLUSIONS: Within the limits of our sample size and statistical approach, our study failed to find evidence that anastomotic omentoplasty during esophagectomy after neoadjuvant chemoradiation reduced anastomotic leak rate or need for leak-related reoperation.

The association of robotic lobectomy volume and nodal upstaging in non-small cell lung cancer.

Robotic lung resection for lung cancer has gained popularity over the last 10 years. As with many surgical techniques, there are improvements in outcomes associated with increased operative volume. We sought to investigate lymph-node harvest and upstaging rates for robotic lobectomies performed at hospitals with varying robotic experience. The National Cancer Data Base was queried for patients with early stage non-small cell lung cancer who received lobectomy between 2010 and 2015. Hospitals were stratified into volume categories based on the number of robotic resections performed, as a proxy for robotic experience: low at ≤ 12, low-middle 13-26, middle-high 27-52, and high volume at greater than or equal to 53. Lymph-node counts and nodal upstaging were compared among these volume categories. 8360 robotic lobectomies were performed. Mean lymph-node counts were for low, low-middle, middle-high, and high-volume robotic lobectomies were 9.8, 11.4, 12.9, and 12.6, respectively (P < 0.001), while nodal-upstaging rates were 10.3%, 10.2%, 12.8%, and 13.4%, respectively (P < 0.001). Compared to low-volume hospitals, on multivariable analysis, high-volume robotic centers had increased nodal harvest (P < 0.001) and nodal-upstaging rates (P < 0.001). Robotic lobectomies performed at high-volume hospitals have greater lymph-node harvest and upstaging than low-volume hospitals.

Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells.

Endogenous damage-associated molecular pattern (DAMP) molecules are released from cells during traumatic injury, allowing them to interact with pattern recognition receptors such as the toll-like receptors (TLRs) on other cells and subsequently, to stimulate inflammatory signaling. TLR4, in particular, plays a key role in systemic and remote organ responses to hemorrhagic shock (HS) and peripheral tissue injury in the form of bilateral femur fracture. TLR4 chimeric mice were generated to investigate the cell lineage in which functional TLR4 is needed to initiate the injury response to trauma. Chimeric mice were generated by adoptive bone marrow (BM) transfer, whereby donor marrow was given to an irradiated host using reciprocal combinations of TLR4 wild-type (WT; C3H/HeOuJ) and TLR4 mutant (Mu; C3H/HeJ) mice. After a period of engraftment, chimeric mice were then subjected to HS or bilateral femur fracture. Control groups, including TLR4-WT mice receiving WT BM and TLR4-Mu mice receiving Mu BM, responded to injury in a similar pattern to unaltered HeOuJ and HeJ mice, and protection was afforded to those mice lacking functional TLR4. In contrast, TLR4-WT mice receiving Mu BM and TLR4-Mu mice receiving WT BM demonstrated intermediate inflammatory and cellular damage profiles. These data demonstrate that functional TLR4 is required in BM-derived cells and parenchymal cells for an optimal inflammatory response to trauma.

Laparoscopic Approach to Paraesophageal Hernia Repair.

The introduction of minimally invasive techniques to the field of foregut surgery has revolutionized the surgical approach to giant paraesophageal hernia repair. Laparoscopy has become the standard approach in patients with giant paraesophageal hernia because it has been shown to be safe and is associated with lower morbidity and mortality when compared with various open approaches. Specifically, it has been associated with decreased intraoperative blood loss, decreased complications, and reduced hospital length of stay. This is despite a rise in comorbid conditions associated with this patient population. This article describes our operative approach to laparoscopic giant paraesophageal hernia repair.

Pulmonary pathologic alterations associated with biopsy inserted hydrogel plugs.

The prevention of pneumothorax after percutaneous lung biopsy is a major patient safety concern. The insertion of hydrogel plugs into biopsy sites to mitigate this complication is a new intervention. The histology of the plug has not been previously reported, and in this study the histologic reaction is reported in 13 cases. The hydrogel plug forms a spherical basophilic matrix pool with an adjacent foreign body giant cell reaction and patchy eosinophilia. No extension to the pleural surface is present. The potential diagnostic errors related to the presence of the plug are discussed.

Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes.

The earliest events after the induction of hemorrhagic shock (HS) are complex and poorly understood. We have recently demonstrated that decreased tissue perfusion and hypoxia during HS lead to an increased phosphorylation of c-Jun N-terminal kinase (JNK) in vivo. The purpose of these investigations was to test the hypothesis that hypoxia activates JNK via Rac1-dependent reactive oxygen species (ROS) signaling. Mice subjected to HS and resuscitated with Ringer's ethyl pyruvate solution (REPS) or N-acetylcysteine (NAC), two scavengers of ROS, demonstrated decreased levels of phosphorylated JNK. Exposure of primary mouse hepatocytes in culture to 1% oxygen led to increased production of ROS and phosphorylation of JNK. The duration of hypoxia correlated with the level of generation of ROS and JNK activation. The phosphorylation of JNK was attenuated in the presence of ROS scavengers or the nicotinamide adenosine dinucleotide phosphate [NDA(P)H] oxidase inhibitor, diphenyleneiodonium (DPI). In addition, hypoxia increased activation of Rac1. Inhibition of Rac1 activation by adenoviral gene transfer of dominant-negative Rac1 (AdRac1) attenuated both ROS formation and JNK activation. Together, these data suggest that ROS generation during hypoxia in the liver directly leads to JNK activation in a Rac1-dependent process.

Early growth response 1 mediates the systemic and hepatic inflammatory response initiated by hemorrhagic shock.

Hemorrhagic shock (HS) is a major cause of morbidity and mortality in trauma patients. The early growth response 1 (Egr-1) transcription factor is induced by a variety of cellular stresses, including hypoxia, and may function as a master switch to trigger the expression of numerous key inflammatory mediators. We hypothesized that HS would induce hepatic expression of Egr-1 and that Egr-1 upregulates the inflammatory response after HS. The Egr-1 mice and wild-type (WT) controls (n>or=5 for all groups) were subjected to HS alone or HS followed by resuscitation (HS/R). Other mice were subjected to a sham procedure which included general anesthesia and vessel cannulation but no shock (sham). After the HS, HS/R, or sham procedures, mice were euthanized for determination of serum concentrations of interleukin (IL) 6, IL-10, and alanine aminotransferase. Northern blot analysis was performed to evaluate Egr-1 messenger RNA (mRNA) expression. Liver whole cell lysates were evaluated for Egr-1 protein expression by Western blot analysis. Hepatic expression of IL-6, granulocyte colony-stimulating factor, and intracellular adhesion molecule 1 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The Egr-1 DNA binding was assessed using the electrophoretic mobility shift assay. Hemorrhagic shock results in a rapid and transient hepatic expression of Egr-1 mRNA in WT mice by 1 h, whereas protein and DNA binding activity was evident by 2.5 h. The Egr-1 mRNA expression diminished after 4 h of resuscitation, whereas Egr-1 protein expression and DNA binding activity persisted through resuscitation. The Egr-1 mice exhibited decreased levels of hepatic inflammatory mediators compared with WT controls with a decrease in hepatic mRNA levels of IL-6 by 42%, granulocyte colony-stimulating factor by 39%, and intracellular adhesion molecule 1 by 43%. Similarly, Egr-1 mice demonstrated a decreased systemic inflammatory response and hepatic injury after HS/R compared with their WT counterparts. Early growth response 1 is rapidly upregulated in the liver during and after resuscitation from HS. Our results showing a blunted inflammatory response in Egr-1 mice provides evidence that Egr-1 functions as a proximal signal transduction mechanism responding to shock by amplifying the systemic inflammatory response.

Mesh cruroplasty in laparoscopic repair of paraesophageal hernias is not associated with better long-term outcomes compared to primary repair.

BACKGROUND: Equipoise still exists regarding routine mesh cruroplasty during laparoscopic paraesophageal hernia (PEH). We aimed to determine whether selective mesh cruroplasty is associated with differences in recurrence and patient-reported outcomes. METHODS: We compared symptom outcomes (n = 688) and radiographic recurrences (n = 101; at least 10% [or 2 cm] of stomach above hiatus) for 795 non-emergent PEH repair with fundoplication (n = 106 with mesh). RESULTS: Heartburn, regurgitation, epigastric pain, and anti-reflux medication use decreased significantly in both groups while postoperative dysphagia (mesh; p = 0.14), and bloating (non-mesh; p = 0.32), were unchanged. Radiographic recurrence rates were similar (15 mesh [22%] versus 86 non-mesh [17%]; p = 0.32; median 27 [IQR 14, 53] months), but was associated with surgical dissatisfaction (13% vs 4%; p = 0.007). CONCLUSIONS: Selective mesh cruroplasty was not associated with differences in symptom outcomes or radiographic recurrence rates during laparoscopic PEH repair. Radiographic recurrence was associated with dissatisfaction, emphasizing the need for continued focus on reducing recurrences.

Non-Elective Paraesophageal Hernia Repair Portends Worse Outcomes in Comparable Patients: a Propensity-Adjusted Analysis.

INTRODUCTION: Patients undergoing non-elective paraesophageal hernia repair (PEHR) have worse perioperative outcomes. Because they are usually older and sicker, however, these patients may be more prone to adverse events, independent of surgical urgency. Our study aimed to determine whether non-elective PEHR is associated with differential postoperative outcome compared to elective repair, using propensity-score weighting. METHODS: We abstracted data for patients undergoing PEHR (n = 924; non-elective n = 171 (19 %); 1997-2010). Using boosted regression, we generated a propensity-weighted dataset. Odds of 30-day/in-hospital mortality and major complications after non-elective surgery were determined. RESULTS: Patients undergoing non-elective repair were significantly older, had more adverse prognostic factors, and significantly more major complications (38 versus 18 %; p < 0.001) and death (8 versus 1 %; p < 0.001). After propensity weighting, median absolute percentage bias across 28 propensity-score variables improved from 19 % (significant imbalance) to 5.6 % (well-balanced). After adjusting propensity-weighted data for age and comorbidity score, odds of major complications were still nearly two times greater (OR 1.67, CI 1.07-2.61) and mortality nearly three times greater (OR 2.74, CI 0.93-8.1) than for elective repair. CONCLUSIONS: Even after balancing significant differences in baseline characteristics, non-elective PEHR was associated with worse outcomes than elective repair. Symptomatic patients should be referred for elective repair by experienced surgeons.