John D. Mellinger

GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon.

Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein-coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-kappaB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.

Surgical simulation: a current review

BackgroundSimulation tools offer the opportunity for the acquisition of surgical skill in the preclinical setting. Potential educational, safety, cost, and outcome benefits have brought increasing attention to this area in recent years. Utility in ongoing assessment and documentation of surgical skill, and in documenting proficiency and competency by standardized metrics, is another potential application of this technology. Significant work is yet to be done in validating simulation tools in the teaching of endoscopic, laparoscopic, and other surgical skills. Early data suggest face and construct validity, and the potential for clinical benefit, from simulation-based preclinical skills development. The purpose of this review is to highlight the status of simulation in surgical education, including available simulator options, and to briefly discuss the future impact of these modalities on surgical training.

Colonic Gene Expression in Conventional and Germ-Free Mice with a Focus on the Butyrate Receptor GPR109A and the Butyrate Transporter SLC5A8

IntroductionButyrate is a bacterial fermentation product that produces its beneficial effects on colon through GPR109A, a butyrate receptor, and SLC5A8, a butyrate transporter. In this study, we compared the expression of GPR109A and SLC5A8 between conventional mice and germ-free mice to test the hypothesis that the expression of these two proteins will be decreased in germ-free mice compared to conventional mice because of the absence of bacterial fermentation products and that colonization of germ-free mouse colon with conventional bacteria will reverse these changes.MethodsRNA was prepared from the ileum and colon of conventional mice and germ-free mice and used for RT-PCR to determine mRNA levels. Tissue sections were used for immunohistochemical analysis to monitor the expression of GPR109A and SLC5A8 at the protein level. cDNA microarray was used to determine the differential expression of the genes in the colon between conventional mice and germ-free mice.ResultsIn conventional mice with normal bacterial colonization of the intestinal tract, GPR109A and SLC5A8 are expressed on the apical membrane of epithelial cells lining the ileum and colon. In germ-free mice, the expression of GPR109A and SLC5A8 is reduced markedly in the ileum and colon. The expression returns to normal levels when the intestinal tract of germ-free mice is colonized with bacteria. The expression of the Na+-coupled glucose transporter, SGLT1, follows a similar pattern. Microarray analysis identifies ∼700 genes whose expression is altered more than twofold in germ-free mice compared to conventional mice. Among these genes are the chloride/bicarbonate exchanger SLC26A3 and the water channel aquaporin 4. The expression of SLC26A3 and AQP4 in ileum and colon is reduced in germ-free mice, but the levels return to normal upon bacterial colonization.ConclusionGut bacteria play an active role in the control of gene expression in the host intestinal tract, promoting the expression of the genes that are obligatory for the biological actions of the bacterial fermentation product butyrate and also the genes that are related to electrolyte and water absorption.

Endoluminal and transluminal surgery: Current status and future possibilities

The field of minimally invasive surgery has seen tremendous growth since the first laparoscopic cholecystectomy was performed in 1987. The key question is not how successful these techniques are currently, but rather where may they lead in the future? New technologies promise to usher in an era of even less invasive procedures. The terms being coined in the literature include “incisionless,” “endoluminal,” “transluminal,” and “natural orifice” transluminal endoscopic surgery. These techniques certainly have the potential to become the next wave of minimally invasive procedures. A recent editorial in Surgical Endoscopy by Macfadyen and Cuschieri highlighted the ongoing developments in endoscopic surgery and stressed the critical importance of surgeons being involved in future applications and permutations of these techniques [1]. There are early signs of such involvement. The work of numerous investigators in the field was presented recently at the 2005 Digestive Disease Week. The American Society for Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), in collaboration with the American College of Surgeons, recently organized a postgraduate course in endoluminal therapy at the spring 2005 meeting held in Hollywood, Florida. The course is being offered again at the 2006 SAGES annual meeting. Similar courses are being offered at other regional and national meetings. This review attempts to highlight some of the available and evolving endoluminal therapies reviewed at that forum, including techniques for the management of gastroesophageal reflux disease, endoscopic mucosal resection, endoluminal bariatric surgery, transanal endoscopic microsurgery, and transgastric endoscopic surgery, as well as new technologies and possible future directions in luminal access surgery.

Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer.

IntroductionSLC5A8, expressed predominantly in the colon, is a Na+-coupled transporter for short-chain fatty acids. In this paper, we report on the characterization of butyrate transport by SLC5A8 and the relevance of SLC5A8-mediated butyrate transport to colon cancer.ResultsSLC5A8 transports butyrate via a Na+-dependent electrogenic process. Na+ activation of the transport process exhibits sigmoidal kinetics, indicating involvement of more than one Na+ in the activation process. SLC5A8 is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of SLC5A8 involves DNA methylation by DNA methyltransferase 1. Reexpression of SLC5A8 in colon cancer cells leads to apoptosis but only in the presence of butyrate. SLC5A8-mediated entry of butyrate into cancer cells is associated with inhibition of histone deacetylation. The changes in gene expression in SLC5A8/butyrate-induced apoptosis include upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes. In addition, the expression of phosphatidylinositol-3-kinase subunits is affected differentially, with downregulation of p85α and upregulation of p55α and p50α.ConclusionThese studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.

Perceptions of Graduating General Surgery Chief Residents: Are They Confident in Their Training?

BACKGROUND Debate exists within the surgical education community about whether 5 years is sufficient time to train a general surgeon, whether graduating chief residents are confident in their skills, why residents choose to do fellowships, and the scope of general surgery practice today. STUDY DESIGN In May 2013, a 16-question online survey was sent to every general surgery program director in the United States for dissemination to each graduating chief resident (CR). RESULTS Of the 297 surveys returned, 76% of CRs trained at university programs, 81% trained at 5-year programs, and 28% were going directly into general surgery practice. The 77% of CRs who had done >950 cases were significantly more comfortable than those who had done less (p < 0.0001). Only a few CRs were uncomfortable performing a laparoscopic colectomy (7%) or a colonoscopy (6%), and 80% were comfortable being on call at a Level I trauma center. Compared with other procedures, CRs were most uncomfortable with open common bile duct explorations (27%), pancreaticoduodenectomies (38%), hepatic lobectomies (48%), and esophagectomies (60%) (p < 0.00001). Of those going into fellowships, 67% said they truly had an interest in that specialty and only 7% said it was because they were not confident in their surgical skills. CONCLUSIONS Current graduates of general surgery residencies appear to be confident in their skills, including care of the trauma patient. Fellowships are being chosen primarily because of an interest in the subspecialty. General surgery residency no longer provides adequate training in esophageal or hepatopancreatobiliary surgery.

Duty-hour restrictions and the work of surgical faculty: results of a multi-institutional study.

Purpose To examine whether duty-hour restrictions have been consequential for various aspects of the work of surgical faculty and if those consequences differ for faculty in academic and nonacademic general surgery residency programs. Method Questionnaires were distributed in 2004 to 233 faculty members in five academic and four nonacademic U.S. residency programs in general surgery. Participation was restricted to those who had been faculty for at least one year. Ten items on the questionnaire probed faculty work experiences. Results include means, percentages, and t-tests on mean differences. Of the 146 faculty members (63%) who completed the questionnaire, 101 volunteered to be interviewed. Of these, 28 were randomly chosen for follow-up interviews that probed experiences and rationales underlying items on the questionnaire. Interview transcripts (187 single-spaced pages) were analyzed for main themes. Results Questionnaire respondents and interviewees associated duty-hour restrictions with lowered faculty expectations and standards for residents, little change in the supervision of residents, a loss of time for teaching, increased work and stress, and less satisfaction. No significant differences in these perceptions (p ≪ .05) were found for faculty in academic and nonacademic programs. Main themes from the interviews included a shift of routine work from residents to faculty, a transfer of responsibility to faculty, more frequent skill gaps at night, a loss of time for research, and the challenges of controlling residents’ hours. Conclusions Duty-hour restrictions have been consequential for the work of surgical faculty. Faculty should not be overlooked in future studies of duty-hour restrictions.

How should we establish the clinical case numbers required to achieve proficiency in flexible endoscopy

BACKGROUND Recommended procedure numbers for upper endoscopy (UE) and colonoscopy (C) are 35 and 50 for surgical residents, and 130 and 140 for gastroenterology fellows, respectively. The purpose of this study was to challenge the methods used to determine proficiency in flexible endoscopy. METHODS Global assessment of gastrointestinal endoscopic skills (GAGES) was used to evaluate 139 procedures. Scores for UE were compared using self-reported case numbers and grouped according to requirements for each discipline. C scores were compared using the requirements to define novice and experienced endoscopists. Procedure volumes were plotted against GAGES scores. RESULTS Three groups were compared for UE based on case volumes: fewer than 35 cases (group 1), 35 to 130 cases (group 2), and more than 130 cases (group 3). There was no difference between group 2 (17.8 +/- 1.8) and group 3 (19.1 +/- 1.1), but both scored higher than group 1 (14.4 +/- 3.7; P < .05). For C, the scores were 11.8 +/- 3.8 (novices) and 18.8 +/- 1.34 (experienced; P < .001) at a 50-case minimum and 12.4 +/- 4.2 and 18.8 +/- 1.3 (P < .001) for a 140-case proficiency cut-off level, respectively. The curve of procedures versus GAGES plateaued at 50 (UE) and 75 (C). CONCLUSIONS The surgical and gastroenterology case recommendations may not represent the experience needed to achieve proficiency. GAGES scores could help define proficiency in basic endoscopy.

Teaching operating room conflict management to surgeons: clarifying the optimal approach

Medical Education 2011:45: 939–945

Development of the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial Protocol: A National Cluster-Randomized Trial of Resident Duty Hour Policies

IMPORTANCE Debate continues regarding whether to further restrict resident duty hour policies, but little high-level evidence is available to guide policy changes. OBJECTIVE To inform decision making regarding duty hour policies, the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial is being conducted to evaluate whether changing resident duty hour policies to permit greater flexibility in work hours affects patient postoperative outcomes, resident education, and resident well-being. DESIGN, SETTING, AND PARTICIPANTS Pragmatic noninferiority cluster-randomized trial of general surgery residency programs with 2 study arms. Participating in the study are Accreditation Council for Graduate Medical Education (ACGME)-approved US general surgery residency programs (n = 118), their affiliated hospitals (n = 154), surgical residents and program directors, and general surgery patients from July 1, 2014, to June 30, 2015, with additional patient safety outcomes collected through June 30, 2016. The data collection platform for patient outcomes is the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), thus only hospitals participating in the ACS NSQIP were included. INTERVENTIONS In the usual care arm, programs adhered to current ACGME resident duty hour standards. In the intervention arm, programs were allowed to deviate from current standards regarding maximum shift lengths and minimum time off between shifts through an ACGME waiver. MAIN OUTCOMES AND MEASURES Death or serious morbidity within 30 days of surgery measured through ACS NSQIP, as well as resident satisfaction and well-being measured through a survey delivered at the time of the 2015 American Board of Surgery in Training Examination (ABSITE). RESULTS A total of 118 general surgery residency programs and 154 hospitals were enrolled in the FIRST Trial and randomized. Fifty-nine programs (73 hospitals) were randomized to the usual care arm and 59 programs (81 hospitals) were randomized to the intervention arm. Intent-to-treat analysis will be used to estimate the effectiveness of assignment to the intervention arm on patient outcomes, resident education, and resident well-being compared with the usual care arm. Several sensitivity analyses will be performed to determine whether there were differential effects when examining only inpatients, high-risk patients, and emergent/urgent cases. CONCLUSIONS AND RELEVANCE To our knowledge, the FIRST Trial is the first national randomized clinical trial of duty hour policies. Results of this study may be informative to policymakers and other stakeholders engaged in restructuring graduate medical training to enhance the quality of patient care and resident education. TRIAL REGISTRATION clinicaltrials.org Identifier: NCT02050789.