Author Correction: γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows:Ayano C. Kohlgruber1,2, Shani T. Gal-Oz3, Nelson M. LaMarche1,2, Moto Shimazaki1, Danielle Duquette4, Hui-Fern Koay5,6, Hung N. Nguyen1, Amir I. Mina4, Tyler Paras1, Ali Tavakkoli7, Ulrich von Andrian2,8, Adam P. Uldrich5,6, Dale I. Godfrey5,6, Alexander S. Banks4, Tal Shay3, Michael B. Brenner1,10* and Lydia Lynch1,4,9,10*1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. 2Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. 3Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 5Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia. 6ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia. 7Department of General and Gastrointestinal Surgery, Brigham and Women's Hospital, Boston, MA, USA. 8Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. 9School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. 10These authors jointly supervised this work: Michael B. Brenner, Lydia Lynch. *e-mail: mbrenner@research.bwh.harvard.edu; llynch@bwh.harvard.eduAcknowledgementsWe thank A.T. Chicoine, flow cytometry core manager at the Human Immunology Center at BWH, for flow cytometry sorting. We thank D. Sant'Angelo (Rutgers Cancer Institute) for providing Zbtb16-/- mice and R. O'Brien (National Jewish Health) for providing Vg4/6-/- mice. Supported by NIH grant R01 AI11304603 (to M.B.B.), ERC Starting Grant 679173 (to L.L.), the National Health and Medical Research Council of Australia (1013667), an Australian Research Council Future Fellowship (FT140100278 for A.P.U.) and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship (1117766 for D.I.G.).Author contributionsA.C.K., L.L., and M.B.B. conceived and designed the experiments, and wrote the manuscript. A.C.K., N.M.L., L.L., H.N.N., M.S., T.P., and D.D. performed the experiments. S.T.G.-O. and T.S. performed the RNA-seq analysis. A.S.B. and A.I.M. provided advice and performed the CLAMS experiments. A.T. provided human bariatric patient samples. Parabiosis experiments were performed in the laboratory of U.v.A. H.-F.K., A.P.U. and D.I.G provided critical insight into the TCR chain usage of PLZF+ γδ T cells. M.B.B., N.M.L., and L.L. critically reviewed the manuscript.The errors have been corrected in the HTML and PDF version of the article.Correction to: Nature Immunology doi:10.1038/s41590-018-0094-2 (2018), published online 18 April 2018.

Metabolic reprogramming of natural killer cells in obesity limits antitumor responses.

Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete 'paralysis' of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell-tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (Treg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF+ γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα+ and Pdpn+ stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2+ Treg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity.

Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease.

National trends in utilization and safety of gastric bypass, sleeve gastrectomy and conversion surgery in patients with GERD.

BACKGROUND: While some studies have reported improvement in gastro-esophageal reflux disease (GERD) symptoms after sleeve gastrectomy (SG), others have reported higher incidence of de-novo GERD, worsening of prior GERD symptoms and erosive esophagitis post SG. Furthermore, GERD unresponsive to medical management is one of the most common indications for conversion of SG to Roux-en-Y gastric bypass (RYGB). Real-world data on safety of primary SG, primary RYGB and SG to RYGB conversion for obese patients with GERD would be helpful for informing surgeons and patient procedure selection. We sought to evaluate the trends in utilization and safety of primary RYGB and primary SG for patients with GERD requiring medications, and compare the peri-operative outcomes between primary RYGB and conversion surgery from SG to RYGB for GERD using the MBSAQIP database. METHODS: A comparative analysis of post-operative outcomes within 30 days was performed for primary RYGB and primary SG after 1:1 nearest neighbor propensity score matching for patient demographics and preoperative comorbidities using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) registry from 2015 to 2021. This was followed by comparison of peri-operative outcomes between conversion surgery from SG to RYGB for GERD and primary RYGB using MBSAQIP 2020-2021 data. RESULTS: Utilization of primary RYGB increased from 38% in 2015 to 45% in 2021, while primary SG decreased from 62% in 2015 to 55% in 2021 for bariatric patients with GERD. Post-operative outcomes including reoperation, reintervention, readmission, major complications, and death within 30 days were significantly higher for patients undergoing primary RYGB compared to primary SG. Increased readmissions and ED visits were seen with conversion surgery. However, there was no difference in rates of reoperation, reintervention, major complications, or death between primary RYGB and SG conversion to RYGB cohorts. CONCLUSIONS: This data suggests that a strategy of performing a primary SG and subsequent SG-RYGB conversion for those with recalcitrant GERD symptoms is not riskier than a primary RYGB. Thus, it may be reasonable to perform SG in patients who are well informed of the risk of worsening GERD requiring additional surgical interventions. However, the impact of such staged approach (SG followed by conversion to RYGB) on long-term outcomes remains unknown.

Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects.

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

BODY-Q eating-related symptoms following sleeve gastrectomy.

BACKGROUND: Recent data describing gastrointestinal (GI) symptoms experienced by patients after bariatric surgery is lacking, and previous studies in sleeve gastrectomy patients have been limited in scope of follow-up time or extent of GI symptoms examined. We sought to characterize the prevalence and time course of patient-reported eating-related symptoms in sleeve gastrectomy patients. METHODS: From July 2020 to July 2021, sleeve gastrectomy patients seen at three Boston area hospitals received electronic surveys and prospectively reported GI symptoms using the BODY-Q eating-related symptoms scale. Descriptive analyses were performed for patient demographics and symptom prevalence. Chi-square tests were used to compare prevalence of eating-related symptoms between follow-up time intervals. RESULTS: 491 sleeve gastrectomy patients completed postoperative surveys with mean follow-up time of 1.9 years. Mean age was 46.6 years, and 81.3% were female. The most reported GI symptoms overall included constipation (56.6%), bloating (54.0%), heartburn when standing (41.5%), and heartburn when lying down (39.9%) while the least commonly reported symptoms were palpitations (16.3%), low blood sugar (15.7%), and emesis (15.1%). At greater than 12 months, the most reported symptoms similarly included bloating (60.3%), constipation (53.2%), and heartburn while standing (46.0%). When comparing prevalence of eating-related symptoms across follow-up time intervals from < 1 to > 12 months, patients reported a significant decrease in constipation, abdominal pain, and nausea over time (p = 0.012, p < .0001, p = 0.03, respectively). CONCLUSION: Patients experience both upper and lower GI symptoms following sleeve gastrectomy, and symptoms, including bloating, constipation, and heartburn may persist through long-term follow-up. These patient-centered measures add value by guiding preoperative counseling, informing postoperative expectations, and providing real-time clinical feedback for bariatric surgery patients.

Impact of the COVID-19 Pandemic on Inpatient and Outpatient Utilization of Bariatric Surgery.

BACKGROUND: During the COVID-19 pandemic, deferral of inpatient elective surgical procedures served as a primary mechanism to increase surge inpatient capacity. Given the benefit of bariatric surgery on treating obesity and associated comorbidities, decreased access to bariatric surgery may have long-term public health consequences. Understanding the extent of the disruption of the COVID-19 pandemic to bariatric surgery will help health systems plan for appropriate access. MATERIALS AND METHODS: This is an observational cohort study using the PINC AI Healthcare Database from 1/1/2019-6/31/2021. A Poisson regression model with patient characteristics and hospital-fixed effects was used to assess the relative monthly within-hospital reduction in surgical encounters, variations by race and ethnicity, and shift from inpatient to outpatient procedures. A multivariate linear probability model was used to assess the change in 30-day readmissions from 2020 and 2021 compared to 2019. RESULTS: Among 309 hospitals, there were 46,539 bariatric procedures conducted in 2019 with a 14.8% reduction in volume to 39,641 procedures in 2020. There were 22,642 bariatric procedures observed from January to June of 2021. The most pronounced decrease in volume occurred in April with an 89.7% relative reduction from 2019. Black and Hispanic patients were more likely to receive bariatric surgery after the height of the pandemic compared to white patients. A clinically significant shift from inpatient to outpatient bariatric surgical procedures was not observed. Relative to 2019, there were no significant differences in bariatric surgical readmission rates. CONCLUSION: During the pandemic there was a sizable decrease in bariatric surgical volume. There did not appear to be disparities in access to bariatric surgery for minority patients. We did not observe a meaningful shift toward outpatient bariatric surgical procedures. Post-pandemic, monitoring is needed to assess if hospitals have been able to meet the demand for bariatric surgical procedures.

Survival After Adrenalectomy for Metastatic Lung Cancer.

BACKGROUND: Adrenal metastasectomy is associated with increased survival in non-small cell lung cancer (NSCLC) with isolated adrenal metastases. Although clinical use of adrenal metastasectomy has expanded, indications remain poorly defined. The aim of this study was to evaluate the clinical benefit of adrenal metastasectomy for all lung cancer subtypes. PATIENTS AND METHODS: We performed a retrospective cohort study of patients who underwent adrenal metastasectomy for metastatic lung cancer at six institutions between 2001 and 2015. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Cox proportional hazards regressions and Kaplan-Meier survival analysis were performed. RESULTS: For 122 patients, the mean age was 60.5 years and 49.2% were female. Median time to detection of the metastasis was 11 months, and 41.8% were ipsilateral to the primary lung cancer. Median DFS was 40 months (1 year: 64.8%; 5 year: 42.9%). Factors associated with longer DFS included primary tumor resection [hazard ratio (HR): 0.001; p = 0.005], longer time to adrenal metastasis (HR: 0.94; p = 0.005), and ipsilateral metastases (HR: 0.13; p = 0.004). Shorter DFS corresponded with older age (HR: 1.11; p = 0.01), R1 resection (HR: 8.94; p = 0.01), adjuvant radiation (HR: 9.45; p = 0.02), and open adrenal metastasectomy (HR: 10.0; p = 0.03). Median OS was 47 months (1 year: 80.2%; 5 year: 35.2%). Longer OS was associated with ipsilateral metastasis (HR: 0.55; p = 0.02) and adjuvant chemotherapy (HR: 0.35; p = 0.02). Shorter OS was associated with extra-adrenal metastases at adrenalectomy (HR: 3.52; p = 0.007), small cell histology (HR: 15.0; p = 0.04), and lung radiation (HR: 3.37; p = 0.002). DISCUSSION: Durable survival was observed in patients undergoing adrenal metastasectomy and should be considered for isolated adrenal metastases of NSCLC. Small cell histology and extra-adrenal metastases are relative contraindications to adrenal metastasectomy.

Fellowship training influences learning curves for laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most commonly performed bariatric surgical procedure. Little is known about how surgeon training background influences the learning curve of this procedure. We examined operating times (OT), weight loss outcomes, and 30-day complications between surgeons with and without fellowship training in LSG. We hypothesize that post-residency training specific to LSG influences learning curves. METHODS: Surgeons from a single institution were split into two groups: those who had not completed fellowship training in LSG (NF, n = 3), and those who had completed LSG specific training in fellowship (SGF, n = 3). OTs, BMI changes at 1 year, and 30-day readmissions, reoperations, and complications were extracted for the first 100 LSG cases of each surgeon. Data were analyzed in bins of 20 cases. Comparisons were made between cohorts within a bin and between adjacent bins of the same surgeon cohort. Logistic regression analyses were performed of OT and weight loss outcomes. RESULTS: SGF surgeons showed no difference in OTs over their first 100 cases. NF surgeons had statistically significant increased OTs compared to SGF surgeons during their first 60 cases and progressively shortened OTs during that interval (109 min to 78 min, p < 0.001 for NF surgeons vs. 73 min to 69 min, SGF surgeons). NF surgeons had a significantly steeper slope for improvement in OT over case number. There was no correlation between case number and weight loss outcomes in either group, and no differences in 30-day outcomes between groups. CONCLUSION: Surgeons who trained to perform LSG in fellowship demonstrate faster and consistent OR times on their initial independent LSG cases compared to surgeons who did not, with no correlation between case number and weight loss outcomes or safety profiles for either group. This suggests that learning curves for LSG are achieved during formal case-specific fellowship training.

Adrenalectomy for Secondary Malignancy: Patients, Outcomes, and Indications.

OBJECTIVE: The goal of this study was to examine a multi-institutional experience with adrenal metastases to describe survival outcomes and identify subpopulations who benefit from adrenal metastasectomy. BACKGROUND: Adrenalectomy for metastatic disease is well-described, although indications and outcomes are incompletely defined. METHODS: A retrospective cohort study was performed of patients undergoing adrenalectomy for secondary malignancy (2002-2015) at 6 institutions. The primary outcomes were disease free survival (DFS) and overall survival (OS). Analysis methods included Kaplan-Meier and Cox proportional hazards. RESULTS: Of 269 patients, mean age was 60.1 years; 50% were male. The most common primary malignancies were lung (n = 125, 47%), renal cell (n = 38, 14%), melanoma (n = 33, 12%), sarcoma (n = 18, 7%), and colorectal (n = 12, 5%). The median time to detection of adrenal metastasis after initial diagnosis of the primary tumor was 17 months (interquartile range: 6-41). Post-adrenalectomy, the median DFS was 18 months (1-year DFS: 54%, 5-year DFS: 31%). On multivariable analysis, lung primary was associated with longer DFS [hazard ratio (HR): 0.49, P = 0.008). Extra-adrenal oligometastatic disease at initial presentation (HR: 1.84, P = 0.016), larger tumor size (HR: 1.07, P = 0.013), chemotherapy as treatment of the primary tumor (HR: 2.07 P = 0.027) and adjuvant chemotherapy (HR: 1.95, P = 0.009) were associated with shorter DFS. Median OS was 53 months (1-year OS: 83%, 5-year OS: 43%). On multivariable analysis, extra-adrenal oligometastatic disease at adrenalectomy (HR: 1.74, P = 0.031), and incomplete resection of adrenal metastasis (R1 margins; HR: 1.62, P = 0.034; R2 margins; HR: 5.45, P = 0.002) were associated with shorter OS. CONCLUSIONS: Durable survival is observed in patients undergoing adrenal metastasectomy and should be considered for subjects with isolated adrenal metastases.

BODY-Q patient-reported outcomes measure (PROM) to assess sleeve gastrectomy vs. Roux-en-Y gastric bypass: eating behavior, eating-related distress, and eating-related symptoms.

BACKGROUND: Post-operative changes in eating behavior, eating-related distress and eating-related symptoms play an important role in the lives of bariatric surgery patients. However, there are no studies that assess these outcomes using a specifically designed patient-reported outcome measure (PROM) for patients undergoing bariatric surgery. We use our newly developed and validated scales as part of the well-established BODY-Q PROMs to compare laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass patients (LRYGB). METHODS: We analyzed data from an international multi-center prospective cohort study of patients over 18 who underwent bariatric surgery. We used multivariable linear regression models to assess the difference between LRYGB and LSG for the new BODY-Q scales, which include eating behavior, eating-related distress and eating-related symptoms. All analyses were corrected for significant confounding variables. RESULTS: Out of 1420 patients, 920 underwent LRYGB and 500 underwent LSG. The LRYGB group had a higher percentage total weight loss (p < 0.001). There was no significant difference in eating behavior (e.g., stop eating before feeling full, avoiding unhealthy snacks, etc.) or eating-related distress (e.g., feeling ashamed or out of control after eating). Patients who underwent LSG scored significantly better on the post-prandial eating-related symptoms scale (e.g., vomiting, reflux; p < 0.001). Symptoms more prevalent in the LRYGB patients were related to dumping syndrome whereas symptoms more prevalent in LSG patients were related to reflux. CONCLUSION: Patients who underwent LRYGB had a significantly better weight loss after surgery, but they scored worse on post-prandial symptoms in comparison to LSG patients. This information may be relevant for patients in the pre-operative counseling setting, as it may influence their decision for surgical procedure selection.

Sleeve gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss.

Sleeve gastrectomy (SG) induces weight loss-independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements. Nonobese C57BL/6J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-fluorodeoxyglucose (18-FDG) PET/computed tomography, and RNA sequencing was used for gene-expression analysis. In this model, SG induced durable improvements in glucose tolerance in the absence of changes in weight, body composition, or food intake. Indirect calorimetry revealed that SG increased the average respiratory exchange ratio toward 1.0, indicating a weight-independent, systemic shift to carbohydrate utilization. Following SG, orally administered 18-FDG preferentially localized to white adipose depots, showing tissue-specific increases in glucose utilization induced by surgery. Transcriptional analysis with RNA sequencing demonstrated that increased glucose uptake in the visceral adipose tissue was associated with upregulation in transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation. SG induces a rapid, weight loss-independent shift toward glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue. Continued study of this early post-SG physiology may lead to a better understanding of the anti-diabetic mechanisms of bariatric surgery.

Predicting venous thrombosis in patients undergoing elective splenectomy.

BACKGROUND: Venous thrombosis (VT) is an ongoing problem for patients undergoing elective splenectomy. There is limited data evaluating risk factors for VTs. An increase in platelet counts is commonly seen after splenectomy; however, there is a paucity of literature evaluating post-operative platelet counts as a risk factor for VTs in this patient cohort. The objective of this study was to determine the incidence of VT events and to use the platelet count as a predictor for VT development. METHODS: A retrospective review was undertaken at Brigham Women's Hospital, evaluating elective splenectomy patients between 1997 and 2018. Descriptive statistics were utilized to determine the incidence of VTs. Receiver operator characteristic (ROC) curves were utilized to identify platelet counts that could predict VTs. RESULTS: Five hundred and twenty splenectomies were included in the study of which 344 were completed in an open manner and 176 were done laparoscopically. The overall incidence of VT events was 6.7% (35/520), 6.1% (21/344) for open, and 8.0% (14/176) for laparoscopic approaches (p = 0.43). ROC curves demonstrated platelet counts to be a good predictor for the development of VTs with an area under the curve (AUC) of 0.77 (95% CI 0.69-0.86; p < 0.001) for all splenectomy patients, 0.70 (95% CI 0.59-0.81; p < 0.001) for those completed in an open manner, and 0.88 (95% CI 0.77-0.99; p < 0.001) for those done laparoscopically. The optimal platelet cutoff was found to be 545 for the overall splenectomy cohort, 457 for the open, and 659 for the laparoscopic cohorts. These platelet counts had a diagnostic accuracy that ranged from 61 to 86% and a negative predictive value (NPV) that ranged from 97 to 99%. CONCLUSION: These results suggest platelet cutoffs that predict VTs. This information can be used to individualize prophylactic strategies.

Portal milieu and the interplay of multiple antidiabetic effects after gastric bypass surgery.

Diabetes is a worldwide health problem. Roux-en-Y gastric bypass (RYGB) leads to rapid resolution of type 2 diabetes (T2D). Decreased hepatic insulin resistance is key, but underlying mechanisms are poorly understood. We hypothesized that changes in intestinal function and subsequent changes in portal venous milieu drive some of these postoperative benefits. We therefore aimed to evaluate postoperative changes in portal milieu. Two rat strains, healthy [Sprague-Dawley (SD)] and obese diabetic [Zucker diabetic fatty (ZDF)] rats, underwent RYGB or control surgery. After 4 wk, portal and systemic blood was sampled before and during an intestinal glucose bolus to investigate changes in intestinal glucose absorption (Gabsorp) and utilization (Gutil), and intestinal secretion of incretins and glucagon-like peptide-2 (GLP-2). Hepatic activity of dipeptidyl peptidase-4 (DPP4), which degrades incretins, was also measured. RYGB decreased Gabsorp in both rat strains. Gutil increased in SD rats and decreased in ZDF rats. In both strains, there was increased expression of intestinal hexokinase and gluconeogenesis enzymes. Systemic incretin and GLP-2 levels also increased after RYGB. This occurred without an increase in secretion. Hepatic DPP4 activity and expression were unchanged. RYGB perturbs multiple intestinal pathways, leading to decreased intestinal glucose absorption and increased incretin levels in both healthy and diabetic animals. In diabetic rats, intestinal glucose balance shifts toward glucose release. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to rapid changes in hepatic glucose and hormone handling. This fresh insight into the surgical physiology of RYGB raises the hope of less invasive alternatives. NEW & NOTEWORTHY Portal milieu after gastric bypass surgery is an underinvestigated area. Roux-en-Y gastric bypass perturbs multiple intestinal pathways, reducing intestinal glucose absorption and increasing incretin levels. In diabetic rats, the intestine becomes a net releaser of glucose, increasing portal glucose levels. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to changes in hepatic glucose handling. This fresh insight raises the hope of less invasive alternatives.

Therapeutic luminal coating of the intestine.

The gastrointestinal tract is the site of most drug delivery and therapeutic interventions for the management and treatment of numerous diseases. However, selective access to its mucosa, especially in the small bowel, is challenging. Here we develop an orally administered gut-coating formulation that provides a transient coating of the bowel. Through a materials screening campaign, we identified a sucrose octasulfate aluminium complex and further engineered the pH-dependent material into a complex coacervate formulation linked via pH-independent electrostatic interaction, which allowed an effective transient physical coating on the gastrointestinal mucosa, independent of gastric acid exposure. We tested the therapeutic values of this technology in two settings. Oral administration of this gut-coating formulation modulated the nutrient contact with bowel mucosa, which lowered the glucose responses in rodent models indicating a potential therapeutic utility in diabetes. Furthermore, the formulation protected biological agents from gastric acid exposure and degradation, which enabled oral delivery to the small bowel mucosa.

Laparoscopic versus open splenectomy for splenomegaly: the verdict is unclear.

BACKGROUND: The benefits of laparoscopic splenectomy (LS) over open splenectomy (OS) for normal-sized spleens have been well documented. However, the role of laparoscopy for moderate and massive splenomegaly is debated. METHODS: A retrospective review of patients undergoing elective splenectomy at one institution from 1997 to 2017 was conducted. Moderate and massive splenomegaly was defined as splenic weight of 500-1000 g and greater than 1000 g, respectively. We performed a 1:2 matching of laparoscopic to open splenectomy to control for differences in splenic weight. Differences in perioperative morbidity (infection, thromboembolism, reoperation, readmission), intraoperative factors (blood loss, operative time), length of stay, and mortality were examined. RESULTS: A total of 491 elective splenectomies were identified. 268 cases were for splenic weights greater than 500 g. After a 1:2 matching of LS:OS, we identified 22 LS and 44 matched OS for moderate splenomegaly. The LS group had longer mean operative times (178 vs. 107 min, p < 0.01), with similar length of stay and blood loss. For massive splenomegaly, 26 LS were identified and matched to 52 OS. LS had longer mean operative times (171 vs. 112 min, p < 0.01) and higher readmission rates (27% vs. 6%, p < 0.05). Other factors and outcomes did not differ between LS and OS for moderate or massive splenomegaly. The conversion rate for LS was higher for massive versus moderate splenomegaly, but was not statistically significant (35% vs. 14%, p = 0.09). CONCLUSIONS: LS for moderate and massive splenomegaly is associated with longer operative times. Other perioperative outcomes were comparable to OS, with no demonstrated benefits for LS. Although LS may be a feasible approach to moderate and massive splenomegaly, its benefits require further clarification in this patient population.

The Impact of Bariatric Surgery on Pelvic Floor Dysfunction: A Systematic Review.

OBJECTIVE: To determine the effect of bariatric surgery (BS) on the prevalence of pelvic floor dysfunctions (PFD), specifically on urinary incontinence (UI), pelvic organ prolapse (POP), and fecal incontinence (FI). DATA SOURCES: A systematic review (PROSPERO registration no. CRD42017068452) with a literature search was performed using the PubMed, Scopus, and SciELO databases for all publications related to BS and PFD, with no language restrictions, from inception to September 2018. METHODS OF STUDY SELECTION: Two authors screened for study eligibility and extracted data. Only prospective cohorts assessing women with morbid obesity and the prevalence of PFD before and after BS in multiple academic and private centers were included. UI, POP, and FI were defined according to the International Urogynecological Association/International Continence Society joint consensus, and diagnosis was made based on self-report or questionnaires. TABULATION, INTEGRATION, AND RESULTS: Our search strategy retrieved 957 results. Of those, 28 studies were included for full analysis, and 20 studies (n = 3684 patients) were selected for final analysis. The main reasons for exclusion were missing data before and after BS (n = 7) and combined data of men and women who underwent BS (n = 1). Laparoscopic Roux-en-Y gastric bypass was the most common surgical technique. Pooled analysis (16 studies) showed that women had a mean body mass index reduction of 12.90 kg/m2 after treatment (95% confidence interval [CI], -14.82 to -10.97; p < .0001). The relative risk reduction was 67% (n = 19; odds ratio [OR], 0.33; 95% CI, 0.26-0.41; p < .0001) for UI, 52% (n = 5; OR, 0.48; 95% CI, 0.22-1.07; p = .07) for POP, and 20% (n = 9; OR, 0.80; 95% CI, 0.53-1.21; p = .29) for FI. Funnel plots for UI and FI did not suggest any publication bias. With regard to the standardized questionnaires for PFD, the International Consultation on Incontinence-Short Form, Pelvic Floor Impact Questionnaire-7 and its subscale Colorectal-Anal Impact Questionnaire-7, Pelvic Floor Distress Inventory-20, and its subscale Urinary Distress Inventory-6 showed statistically significantly lower scores. Sexual function, represented by the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12, showed no statistically significant improvement after surgery. CONCLUSION: BS has a significant impact on reducing UI, but FI and POP, in obese women.

The impact of lipomatous tumors on type 2 diabetes: are adipose-derived tumors metabolically active?

BACKGROUND: The metabolic and immunologic properties of adipose tissue are linked to the pathogenesis of type 2 diabetes mellitus. Lipomatous tumors, such as liposarcomas, are rare but can reach significant size. We hypothesized that some lipomatous tumors are metabolically active and can alter systemic glucose homeostasis. METHODS: We performed a retrospective study of patients who underwent resection of a lipomatous tumor at a tertiary cancer referral center (2004-2015). We divided patients into nondiabetics, well-controlled diabetics (hemoglobin A1c [HbA1c] < 7), and poorly controlled diabetics (HbA1c ≥ 7). We compared patient demographics, tumor characteristics, and measures of glycemic control among these groups before and after tumor resection. RESULTS: We reviewed 217 operations for lipomatous tumors. No differences were observed in tumor characteristics in patients with and without diabetes. However, tumor characteristics differed significantly between the well-controlled and poorly controlled diabetics groups. Patients with poorly controlled diabetes had larger tumors that were more likely to be malignant, retroperitoneal, and well-differentiated. Tumor resection had no detectable impact on diabetes, as assessed by HbA1c, and requirement for diabetic medications. CONCLUSIONS: Poorly controlled diabetes was linked to the presence of large, malignant, and retroperitoneal lipomatous tumors. However, in limited follow-up, no detectable impact of tumor resection was apparent on glycemic control. These data suggest that most lipomatous tumors do not exert a clinically relevant impact on glucose homeostasis.

The myrtus communis L. solution versus ketoconazole shampoo in treatment of dandruff: A double blinded randomized clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of myrtus communis L. solution in the treatment of dandruff and to compare it with ketoconazole. METHODS: This double-blind randomised clinical trial was conducted at Shiraz University of Medical Sciences, Shiraz, Iran, from December 2015 to August 2016, and comprised patients with dandruff aged 18-60 years visiting the dermatology out-patient clinic. The subjects were randomised into two equal groups. The treatment group received myrtus communis L. solution and a placebo shampoo, while the control group received ketoconazole shampoo and a placebo solution. The total duration of the study for each subject was one month and subjects in both groups used their respective interventions 8 times during that period. The parameters studied were pruritus, erythema, severity of scaling, and the extent of scalp involvement. All subjects underwent scalp scaling tests at the beginning, after 10 days and at the end of the 30th day. SPSS 21 was used for data analysis. RESULTS: Of the 90 individuals, there were 45(50%) in each of the two groups. However, 74(82%) subjects completed the third visit and, of them, there were 37(50%) in each group. Both groups showed significant improvement in all outcome measures (p<0.001). There were no significant differences between the groups in terms of efficacy, satisfaction rate and side effects (p>0.05 for each outcome). CONCLUSIONS: Myrtus solution was found to be effective in the treatment of dandruff.