Ancestry- and sex-specific effects underlying inguinal hernia susceptibility identified in a multiethnic genome-wide association study meta-analysis.

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however, it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5 × 10-8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity.

The extracellular matrix (ECM) plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accommodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weight-matched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECM-related factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship.

Socio-Demographic and Preoperative Clinical Factors Associated With 5-Year Weight Trajectories After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

Objective: To determine whether socio-demographic and preoperative clinical factors contribute to the percent total body weight loss (%TBWL) after bariatric surgery (BS). Background: BS is the most effective long-term treatment for medically complicated obesity. More information is needed about the factors that contribute to postoperative %TBWL in large and ethnically diverse cohorts. Methods: This retrospective study conducted in the Kaiser Permanente Northern California region included 7698 patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between January 2009 and March 2015. Trajectory analyses were conducted from 5-year follow-up data to assign patients to "low," "average," or "high" postoperative %TBWL groups. We then evaluated whether age, sex, race/ethnicity, neighborhood deprivation index and preoperative body mass index (BMI)/weight loss, diabetes, hypertension, and sleep apnea contributed to postoperative %TBWL using logistic regression models. Results: Of 7698 patients (83.2% women), 48.6% underwent a RYGB and 51.4% underwent a SG. Postoperative %TBWL trajectories over 5 years were obtained in 6229 (81%) of 7698 eligible patients. About 27.8% and 29.3% of patients followed the "low" postoperative %TBWL trajectory, for RYGB and SG, respectively. Men, older patients, and Asian, Black, and Hispanic/Latino patients were more likely to be classified in the low postoperative %TBWL group. Patients showing lower postoperative %TBWL had a lower preoperative BMI (but lost less weight before surgery) and were more likely to have preoperative comorbidities. Conclusions: This study confirms and extends prior findings of the effects of several demographic and preoperative clinical factors on postoperative weight loss. Findings could improve the support of patients to achieve desired surgical outcomes.

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity.

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

Bariatric surgery and the changing current scope of general surgery practice: implications for general surgery residency training.

IMPORTANCE: The scope of general surgery practice has evolved tremendously in the last 20 years. However, clinical experience in general surgery residency training has undergone relatively little change. OBJECTIVE: To evaluate the current scope of academic general surgery and its implications on surgical residency. DESIGN, SETTING, AND PARTICIPANTS: The University HealthSystem Consortium and Association of American Medical Colleges established the Faculty Practice Solution Center (FPSC) to characterize physician productivity. The FPSC is a benchmarking tool for academic medical centers created from revenue data collected from more than 90,000 physicians who practice at 95 institutions across the United States. MAIN OUTCOMES AND MEASURES: The FPSC database was queried to evaluate the annual mean procedure frequency per surgeon (PFS) in each calendar year from 2006 through 2011. The associated work relative value units (wRVUs) were also examined to measure physician effort and skill. RESULTS: During the 6-year period, 146 distinct Current Procedural Terminology codes were among the top 100 procedures, and 16 of these procedures ranked in the top 10 procedures in at least 1 year. The top 10 procedures accounted for more than half (range, 52.5%-57.2%) of the total 100 PFS evaluated for each year. Laparoscopic Roux-en-Y gastric bypass was consistently among the top 10 procedures in each year (PFS, 18.2-24.6). The other most frequently performed procedures included laparoscopic cholecystectomy (PFS, 30.3-43.5), upper gastrointestinal tract endoscopy (PFS, 26.5-34.3), mastectomy (PFS, 16.5-35.0), inguinal hernia repair (PFS, 15.5-22.1), and abdominal wall hernia repair (PFS, 21.6-26.1). In all years, laparoscopic Roux-en-Y gastric bypass generated the highest number of wRVUs (wRVUs, 491.0-618.2), and laparoscopic cholecystectomy was regularly the next highest (wRVUs, 335.8-498.7). CONCLUSIONS AND RELEVANCE: A significant proportion of academic general surgery is composed of bariatric surgery, yet surgical training does not sufficiently emphasize the necessary exposure to technical expertise and clinical management of the patient undergoing bariatric surgery. As the scope of general surgery practice continues to evolve, general surgery residency training will need to better integrate the exposure to bariatric surgery.

Prevalence of undiagnosed and inadequately treated type 2 diabetes mellitus, hypertension, and dyslipidemia in morbidly obese patients who present for bariatric surgery.

BACKGROUND: Pharmacotherapy is considered the primary treatment modality for diabetes mellitus (DM), hypertension (HTN), and dyslipidemia (DYS). We sought to investigate the status of DM, HTN, and DYS in patients who seek bariatric surgery. METHODS: Demographic and comorbidity history were prospectively collected on 1,508 patients referred for bariatric consultation at a single institution from February 2008 to March 2012. We utilized published consensus guidelines (GL) to benchmark the efficacy of standard pharmacotherapy for these metabolic diseases, and 881 patients met the study design criteria. RESULTS: Most patients exhibited at least one form of metabolic dysregulation (pre-DM or DM, 75.8%; pre-HTN or HTN, 91.1%; pre-DYS or DYS, 84.0%; metabolic syndrome, 76.0%). The majority of patients either did not meet GL treatment goals (DM, 45.7%; HTN, 39.5%; DYS, 22.3%) or were previously undiagnosed (DM, 15.8%; HTN, 13.7%; DYS, 41.7%). Non-GL pharmacotherapy was significantly less effective than GL pharmacotherapy at achieving treatment goals for DM (31.8 vs. 53.2%, p < 0.001) and HTN (43.6 vs. 63.2%, p = 0.007). Patients with concurrent DM, HTN, and DYS (35.5%) were less likely than patients with only one or two of these metabolic diseases to achieve GL treatment goals for HTN (38.1 vs. 72.6%, p < 0.001) and DYS (55.7 vs. 73.8%, p = 0.002). Only 8.0% of these patients achieved treatment goals for all three metabolic comorbidities. CONCLUSIONS: In this patient group, DM, HTN, and DYS were poorly compensated, even when pharmacotherapy was consistent with published GL. This may be due to disease burden in bariatric surgery candidates or to inadequate medical management prior to presentation.

Laparoscopic liver resection: Current role and limitations.

Laparoscopic liver resection (LLR) for the treatment of benign and malignant liver lesions is often performed at specialized centers. Technological advances, such as laparoscopic ultrasonography and electrosurgical tools, have afforded surgeons simultaneous improvements in surgical technique. The utilization of minimally invasive techniques for liver resection has been reported to reduce operative time, decrease blood loss, and shorten length of hospital stay with equivalent postoperative mortality and morbidity rates compared to open liver resection (OLR). Non-anatomic liver resection and left lateral sectionectomy are now routinely performed laparoscopically at many institutions. Furthermore, major hepatic resections are performed by pure laparoscopy, hand-assisted technique, and the hybrid method. In addition, robotic surgery and single port surgery are revealing early promising results. The consensus recommendation for the treatment of benign liver disease and malignant lesions remains unchanged when considering a laparoscopic approach, except when comorbidities and anatomic limitations of the liver lesion preclude this technique. Disease free and survival rates after LLR for hepatocellular carcinoma and metastatic colon cancer correspond to OLR. Patient selection is a significant factor for these favorable outcomes. The limitations include LLR of superior and posterior liver lesions; however, adjustments in technique may now consider a laparoscopic approach as a viable option. As growing data continue to reveal the feasibility and efficacy of laparoscopic liver surgery, this skill is increasingly being adopted by hepatobiliary surgeons. Although the full scope of laparoscopic liver surgery remains infrequently used by many general surgeons, this technique will become a standard in the treatment of liver diseases as studies continue to show favorable outcomes.