Glial-derived neurotrophic factor in human airway smooth muscle.

Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain-derived neurotrophic factor (BDNF). The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca2+ ]i . Serum-deprived ASM cells from non-asthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura-2 loaded cells, acute GDNF or NRTN alone induced [Ca2+ ]i responses, and further enhanced responses to 1 µM ACh or 10 µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1-Fc (1 µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca2+ ]i response to histamine. Furthermore, conditioned media of nonasthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRα1-Fc chelator markedly decreased [Ca2+ ]i response compared with vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine-induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca2+ ]i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness.

A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.

Impact of single-incision laparoscopic cholecystectomy (SILC) versus conventional laparoscopic cholecystectomy (CLC) procedures on surgeon stress and workload: a randomized controlled trial.

INTRODUCTION: Single-incision laparoscopic cholecystectomy (SILC) may lead to higher patient satisfaction; however, SILC may expose the surgeon to increased workload. The goal of this study was to compare surgeon stress and workload between SILC and conventional laparoscopic cholecystectomy (CLC). METHODS: During a double-blind randomized controlled trial comparing patient outcomes for SILC versus CLC (NCT0148943), surgeon workload was assessed by four measures: surgery task load index questionnaire (Surg-TLX), maximum heart rate, salivary cortisol level, and instruments usability survey. The maximum heart rate and salivary cortisol levels were sampled from the surgeon before the random assignment of the surgical procedure, intraoperatively after the cystic duct was clipped, and at skin closure. After each procedure, the surgeon completed the Surg-TLX and an instrument usability survey. Student's t tests, Wilcoxon rank sum test, and Kruskal-Wallis nonparametric ANOVAs on the dependent variables by the technique (SILC vs. CLC) were performed with α = 0.05. RESULTS: Twenty-three SILC and 25 CLC procedures were included in the intent-to-treat analysis. No significant differences were observed between SILC and CLC for patient demographics and procedure duration. SILC had significantly higher post-surgery surgeon maximum heart rates than CLC (p < 0.05). SILC also had significantly higher mean change in the maximum heart rate between during and post-procedure (p < 0.05) than CLC. Salivary cortisol level was significantly higher during SILC than CLC (p < 0.01). Awkward manipulation of the instruments and limited fine motions were reported significantly more frequently with SILC than CLC (p < 0.01). In the surgeon-reported Surg-TLX, subscale of physical demand was significantly more demanding for SILC than CLC (p < 0.05). CONCLUSIONS: Surgeon heart rate, salivary cortisol level, instrument usability, and Surg-TLX ratings indicate that SILC is significantly more stressful and physically demanding than the CLC. Surgeon stress and workload may impact patients' outcomes; thus, ergonomic improvement on SILC is necessary.

Success of elective cholecystectomy treatment plans after emergency department visit.

BACKGROUND: Differentiation between patients with acute cholecystitis and patients with severe biliary colic can be challenging. Patients with undiagnosed acute cholecystitis can incur repeat emergency department (ED) visits, which is resource intensive. METHODS: Billing records from 2000-2013 of all adults who visited the ED in the 30 d preceding their cholecystectomy were analyzed. Patients who were discharged from the ED and underwent elective cholecystectomy were compared with those who were discharged and returned to the ED within 30 d. T-tests, chi-square tests, and multivariable analysis were used as appropriate. RESULTS: From 2000-2013, 3138 patients (34%) presented to the ED within 30 d before surgery, 63% were women, mean age 51 y, and of those 1625 were directly admitted from the ED for cholecystectomy, whereas 1513 patients left the ED to return for an elective cholecystectomy. Patients who were discharged were younger (mean age 49 versus 54 y, P < 0.001) and had shorter ED stays (5.9 versus 7.2 h, P < 0.001) than the patients admitted immediately. Of the discharged patients, 303 (20%) returned to the ED within 30 d to undergo urgent cholecystectomy. Compared with patients with successful elective cholecystectomy after the ED visit, those who failed the pathway were more likely to have an American Society of Anesthesiologists score ≥3 and were <40 or ≥60 compared with the successful group. CONCLUSIONS: One in five patients failed the elective cholecystectomy pathway after ED discharge, leading to additional patient distress and use of resources. Further risk factor assessment may help design efficient care pathways.

Methodological differences account for inconsistencies in reported free VEGF concentrations in pregnant rats.

Free vascular endothelial growth factor (VEGF) is undetectable in plasma during human pregnancy. However, studies examining pregnant rats have reported both low (8-29 pg/ml) and high (527-1,030 pg/ml) free VEGF. These discrepancies cast uncertainty over the use of rat models to study angiogenic factors in pregnancy and preeclampsia. This study investigates methodological factors that may explain these discrepancies. Plasma VEGF in nonpregnant, day 7 pregnant, and day 19 pregnant rats was measured using rat and mouse ELISAs (R&D Systems). The rat ELISA detected VEGF in plasma from nonpregnant rats but not in plasma from day 19 pregnant rats. The mouse ELISA detected higher VEGF concentrations than the rat ELISA in every sample tested. This discrepancy was greater in day 19 pregnant rats (median: 2,273 vs. 0 pg/ml) than in nonpregnant (97 vs. 20 pg/ml) and day 7 pregnant (66 vs. 2 pg/ml) rats. Recovery of recombinant rat VEGF (rrVEGF) spiked into plasma from nonpregnant and day 7 pregnant rats was high for the rat ELISA (82-105%) but low for the mouse ELISA (17-22%). The rat ELISA did not recover rrVEGF in plasma from day 19 pregnant rats, suggesting that this ELISA measures free VEGF. The use of the rat versus mouse ELISA likely explains the differences in reported VEGF concentrations in pregnant rats. While the rat ELISA appears to measure free VEGF, plasma concentrations in nonpregnant and pregnant rats are below the assay sensitivity limit. As most previous studies of pregnant rats used the mouse VEGF ELISA, these data should be interpreted cautiously.

Qualitative and quantitative analysis of women's perceptions of transvaginal surgery.

BACKGROUND: Prior surveys evaluating women's perceptions of transvaginal surgery both support and refute the acceptability of transvaginal access. Most surveys employed mainly quantitative analysis, limiting the insight into the women's perspective. In this mixed-methods study, we include qualitative and quantitative methodology to assess women's perceptions of transvaginal procedures. METHODS: Women seen at the outpatient clinics of a tertiary-care center were asked to complete a survey. Demographics and preferences for appendectomy, cholecystectomy, and tubal ligation were elicited, along with open-ended questions about concerns or benefits of transvaginal access. Multivariate logistic regression models were constructed to examine the impact of age, education, parity, and prior transvaginal procedures on preferences. For the qualitative evaluation, content analysis by independent investigators identified themes, issues, and concerns raised in the comments. RESULTS: The completed survey tool was returned by 409 women (grouped mean age 53 years, mean number of 2 children, 82% ≥ some college education, and 56% with previous transvaginal procedure). The transvaginal approach was acceptable for tubal ligation to 59%, for appendectomy to 43%, and for cholecystectomy to 41% of the women. The most frequently mentioned factors that would make women prefer a vaginal approach were decreased invasiveness (14.4%), recovery time (13.9%), scarring (13.7%), pain (6%), and surgical entry location relative to organ removed (4.4%). The most frequently mentioned concerns about the vaginal approach were the possibility of complications/safety (14.7%), pain (9%), infection (5.6%), and recovery time (4.9%). A number of women voiced technical concerns about the vaginal approach. CONCLUSIONS: As in prior studies, scarring and pain were important issues to be considered, but recovery time and increased invasiveness were also in the "top five" list. The surveyed women appeared to actively participate in evaluating the technical components of the procedures.

Natural orifice transluminal endoscopic surgery for patients with perforated peptic ulcer.

BACKGROUND: Perforation accounts for 70% of deaths attributed to peptic ulcers. Laparoscopic repair is effective but infrequently used. Our aim was to assess how many patients with perforated peptic ulcer could be candidates for a transluminal endoscopic omental patch closure. METHODS: This retrospective study reviewed patients with perforated peptic ulcer from 2005 to 2010. Demographics, ulcer characteristics, operative procedure, and outcomes were recorded. Candidates for endoscopic transluminal repair were defined as those having undergone omental patch closure of an ulcer of appropriate size and no contraindications to laparoscopy or endoscopy. RESULTS: In the retrospective review, a total of 104 patients were identified; 62% female, mean age = 68 years, mean ASA of 3, and 63% medication-related ulcers. Fifty-nine (63%) had an omental patch (80% open), and 35 (37%) had other procedures. Ten patients had nonoperative management. Thirty-day mortality was 14% and 1 year mortality was 35%. Forty-nine patients (52%) were considered potential candidates for transluminal repair. CONCLUSION: Sixty-three percent of our patients sustained a medication-related perforation with 1 year mortality of 35%. The majority of patients were treated using open omental patch repair. Transluminal endoscopic repair may provide an additional situation for a minimally invasive approach for a number of these patients.

Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition.

Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of "fast food" (high saturated fats, cholesterol, and fructose). Mice (n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.

In utero cell transfer between porcine littermates.

Trafficking of cells between mother and fetus during the course of normal pregnancy is well documented. Similarly, cells are known to travel between twins that share either a placenta (i.e. monozygotic) or associated chorion (i.e. monochorionic). Transferred cells are thought to be channelled via the vessels of the placenta or vascular connections established via the chorion and the long-term presence of these cells (i.e. microchimerism) can have important consequences for immune system function and reparative capacity of the host. Whether cells can be transferred between twins with separate placentas and separate chorions (i.e. no vascular connections between placentas) has not been investigated nor have the biological consequences of such a transfer. In the present study, we tested the possibility of this type of cell transfer by injecting human cord blood-derived cells into a portion of the littermates of swine and probing for human cells in the blood and tissues of unmanipulated littermates. Human cells were detected in the blood of 78% of unmanipulated littermates. Human cells were also detected in various tissues of the unmanipulated littermates, including kidney (56%), spleen (33%), thymus (11%) and heart (22%). Human cells were maintained in the blood until the piglets were sacrificed (8 months after birth), suggesting the establishment of long-term microchimerism. Our findings show that the transfer of cells between fetuses with separate placentas and separate chorions is significant and thus such twins may be subject to the same consequences of microchimerism as monozygotic or monochorionic counterparts.

Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs.

Objective: Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig­an animal model with vagus anatomy similar to human­using the bipolar helical lead deployed clinically. Approach: Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Main results: Contraction of the cricoarytenoid muscle occurred at low amplitudes (~0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (~1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. Significance: Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 µA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation.

OBJECTIVE: Given current clinical interest in vagus nerve stimulation (VNS), there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the pig, whose vagus nerve organization and size approximates the human vagus nerve. APPROACH: Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans. MAIN RESULTS: In a swine model we quantified the nerve diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for VNS with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the vagus nerve. This often leads to a distinct bimodal organization, or 'vagotopy'. This vagotopy was supported by immunohistochemistry where approximately half of the fascicles were immunoreactive for choline acetyltransferase, and reactive fascicles were generally grouped in one half of the nerve. SIGNIFICANCE: The vagotopy observed via histology may be advantageous to exploit in design of electrodes/stimulation paradigms. We also placed our data in context of historic and recent histology spanning multiple models, thus providing a comprehensive resource to understand similarities and differences across species.

Surgical team workload comparison for 4-port and single-port laparoscopic cholecystectomy procedures.

Advanced minimally invasive procedures may cause postural constraints and increased workload and stress for providers. This study compared workload and stress across surgical team roles for 48 laparoscopic cholecystectomies (4-port vs single-port) using a task load index (NASA-TLX), a procedural difficulty question, and salivary stress hormones. Statistical analyses were performed based on the presence intra-cluster correlation within team roles, at α=0.05. The single-port technique resulted in an 89% increase in physical workload for the surgeon and 63% increase for the assistant (both p<0.05). The surgeon had significantly higher salivary stress hormones during single-port surgeries. The degree of procedural difficulty was positively correlated between the surgeon and most roles: resident (r=0.67), assistant (r=0.81), and technician (r=0.81). There was a statistically significant positive correlation between the surgeon and assistant for all selfreported workload measures (p<0.05). The single-port technique requires further improvement to balance surgical team workload for optimal patient safety and satisfaction.

An Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite.

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone-metal-particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost-effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.

A Double-Blinded Randomized Trial to Compare the Effectiveness of Minimally Invasive Procedures Using Patient-Reported Outcomes.

BACKGROUND: The Institute of Medicine has included the comparison of minimally invasive surgical techniques in its research agenda. This study seeks to evaluate a model for the comparison of minimally invasive procedures using patient-reported outcomes. STUDY DESIGN: A double-blinded randomized controlled trial (NCT01489436) was conducted. Baseline data were obtained, standardized anesthesia was induced, and patients were randomized to single-port (SP) or 4-port (FP) laparoscopic cholecystectomy. Perioperative care was standardized. The outcomes were pain (Visual Analog Scale) on postoperative day 1 (primary) and quality of life (Patient-Reported Outcomes Measures Information System and Linear Analog Self-Assessment), serum cytokines, and heart rate variability (secondary). Analysis was intention to treat. Using identical occlusive dressings, patients and the outcomes assessor remained blinded until postoperative day 2. RESULTS: Fifty-five patients were randomized to each arm. There was no difference in demographics. Visual Analog Scale pain score on postoperative day 1 was significantly different from baseline in each group (SP: 1.6 ± 1.9 to 4.2 ± 2.4 vs FP: 1.8 ± 2.3 to 4.2 ± 2.2), but not different from each other (p = 0.83). Patients in the FP arm reported significantly less fatigue on postoperative day 7 than patients in the SP group (3.1 ± 2.1 vs 4.2 ± 2.2; p = 0.009). Fewer patients in the FP group required postoperative oral narcotics before discharge (40% vs 60%; p = 0.056). Cytokines levels and heart rate variability were similar between arms. In patients followed for >1 year, no difference in umbilical hernia rates was noted. CONCLUSIONS: Early postoperative quality of life data captured differences in fatigue, indicating improved recovery after FP within a controlled trial. Physiologic measures were similar, suggesting that the differences between SP and FP are minimal.

PROMIS for Laparoscopy.

INTRODUCTION: We tested the responsiveness of the National Institutes of Health-sponsored Patient-Reported Outcomes Measures Information System (PROMIS) global health short form and a linear analog self-assessment for laparoscopy. METHODS: From May 2011 through December 2013, patients undergoing laparoscopy responded to patient reported outcome questionnaires perioperatively. Composite and single item scores were compared. RESULTS: One hundred fifteen patients, mean age 55 years, 58 % female, were enrolled. Visual analog pain scores differed significantly from baseline (mean 1.7 ± 2.3) to postoperative day 1 (mean 4.8 ± 2.6) and 7 (mean 2.5 ± 2.1) (p<0.0001). PROMIS physical subscale and total physical component subscore differed significantly from baseline (14.4 ± 3.0/47.4 ± 8.3) to postoperative day 1 (12.7 ± 3.2/42.1 ± 8.8) (p=0.0007/0.0003), due to everyday physical activities (p=0.0001). Linear analog self-assessment scores differed from baseline for pain frequency (p<0.0001), pain severity (p<0.0001), and social activity (p=0.0052); 40 % of subjects reported worsening in PROMIS physical T-score to postoperative day 1 and 25 % to postoperative day 7. Linear analog self-assessment mental well-being scores were worse in 32 % of patients at postoperative day 7, emotional well-being in 28 %, social activity in 24 %, and fatigue in 20 % of patients. CONCLUSION: Single items and change from baseline are responsive perioperative quality of life assessments for laparoscopy.

Natural orifice translumenal endoscopic surgery used for perforated viscus repair is feasible using lower peritoneal pressures than laparoscopy in a porcine model.

BACKGROUND: Procedure-related complications contribute to 1-year mortality in patients with perforated ulcers. Natural orifice translumenal endoscopic surgery (NOTES) might offer a new repair approach. STUDY DESIGN: Swine were randomized to laparoscopic or NOTES repair. Laparoscopic gastrotomy creation (1 cm) was followed by 4 hours soilage time. After peritoneal cavity irrigation (per group assignment), repair proceeded with a laparoscopic or NOTES approach. For NOTES repair, omentum was endoscopically grasped, pulled into the gastric lumen, and fixed with metallic clips. Feasibility; time to complete procedures; pneumoperitoneal pressures; and clinical parameters, including necropsy and peritoneal culture at 2 weeks, were recorded. RESULTS: NOTES repair failed in 1 animal (technical); repair was completed laparoscopically, and data were analyzed as intention to treat. Specific NOTES repair time (minutes) was comparable with laparoscopy (36 versus 46; p = 0.2). Mean abdominal pressure (mmHg) required to complete NOTES repair was lower than in laparoscopy (4 versus 12; p < 0.001). Nineteen of 23 animals thrived until necropsy at 2 weeks. Three animals succumbed to airway compromise in recovery; 1 NOTES animal failed to thrive on postoperative day 7. No intra-abdominal cause for these deaths was found. At necropsy all repairs were intact, and peritoneal cultures revealed a small and equivalent amount of colony-forming units in each group. CONCLUSIONS: Endoscopic ulcer repair appears technically feasible with similar clinical and infectious outcomes to laparoscopy. The lower required pneumoperitoneal pressures used in these NOTES techniques are recognizable different outcomes from laparoscopy and can be advantageous in critically ill patients.