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Background When surgery resumed following outbreak of the COVID-19 pandemic, guidelines recommended the prioritization of patients with greater obesity-related comorbidity and/or higher Body Mass Index (BMI). Objectives The aim of this study was to record the effect of the pandemic on total number, patient demographic and peri-operative outcomes of elective bariatric surgery in the United Kingdom. Setting and Method The United Kingdom National Bariatric Surgical Registry was used to identify patients that underwent elective bariatric surgery during the pandemic (one year from 1st April 2020). Characteristics of this group were compared with a pre-pandemic cohort. Primary outcomes were case volume, case-mix and provider. National Health Service (NHS) cases were analyzed for baseline health status and peri-operative outcomes. Chi-square, Fisher’s exact or Student’s t-test were used as appropriate. Results Total number of cases reduced to one third of pre-pandemic volume (8615 to 2930). Operating volume reduction varied, with thirty-six (45%) hospitals experiencing a 75-100% reduction. Cases performed in the NHS fell from 74% to 53% (p

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60min after ingestion of UDCA (12-16mg/kg), CDCA (13-16mg/ kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.

Objective To determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels. Methods We determined the effects of experimental cholesterol depletion and loading on glucagon-mediated cAMP production, ligand internalisation and glucose production in human hepatoma cells, mouse and human hepatocytes. GCGR interactions with lipid bilayers were explored using coarse-grained molecular dynamic simulations. Glucagon responsiveness was measured in mice fed a high cholesterol diet with or without simvastatin to modulate hepatocyte cholesterol content. Results GCGR cAMP signalling was reduced by higher cholesterol levels across different cellular models. Ex vivo glucagon-induced glucose output from mouse hepatocytes was enhanced by simvastatin treatment. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Simulations identified likely membrane-exposed cholesterol binding sites on the GCGR, including a site where cholesterol is a putative negative allosteric modulator. Conclusions Our results indicate that cellular cholesterol content influences glucagon sensitivity and indicate a potential molecular basis for this phenomenon. This could be relevant to the pathogenesis of non-alcoholic fatty liver disease, which is associated with both hepatic cholesterol accumulation and glucagon resistance.

To prospectively evaluate the feasibility of single-stage bariatric surgery in patients with super-super obesity and compare their outcomes with patients undergoing intra-gastric balloon insertion as a bridging device prior to definitive surgery. Data from 42 patients with BMI 60–75 kg/m2 who underwent either intra-gastric balloon insertion followed by sleeve gastrectomy (two-stage group); or attempted bariatric surgery as a single-stage procedure were compared. All patients in the single-stage group underwent successful bariatric surgery. Length of hospital stay after definitive bariatric surgery (3.3 ± 1.9 vs 2.2 ± 0.6 days, p = 0.005) and overall complication rates were significantly higher in the two-stage group. Routine use of an intra-gastric balloon in super-super obese patients is not required and may be associated with poorer peri-operative outcomes and delayed weight loss.

Objective: To determine the cost-effectiveness/utility of a superabsorbent wound dressing (Zetuvit Plus Silicone) versus the current standard of care (SoC) dressings, from the NHS perspective in England, in patients with moderate-to-high exudating leg ulcers. Method: A model-based economic evaluation was conducted to analyse the cost-effectiveness/utility of a new intervention. We used a microsimulation state-transition model with a time horizon of six months and a cycle length of one week. The model uses a combination of incidence base and risk prediction approach to inform transition probabilities. All clinical efficiency, health-related quality of life (HRQoL), cost and resource use inputs were informed by conducting a systematic review of UK specific literature. Results: Treatment with the superabsorbent dressing leads to a total expected cost per patient for a six month period of £2887, associated with 15.933 expected quality adjusted life weeks and 10.9% healing rate. When treated with SoC, the total expected cost per patient for a six month period is £3109, 15.852 expected quality adjusted life weeks and 8% healing rate. Therefore, the superabsorbent dressing leads to an increase in quality-adjusted life weeks, an increase in healing rate by 2.9% and a cost-saving of £222 per single average patient over six months. Results of several scenario analyses, one-way deterministic sensitivity analysis, and probabilistic sensitivity analysis confirmed the robustness of base-case results. The probabilistic analysis confirmed that, in any combination of variable values, the superabsorbent dressing leads to cost saving results. Conclusion: According to the model prediction, the superabsorbent dressing leads to an increase in health benefits and a decrease in associated costs of treatment.

Background Obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome. Bariatric surgery is an effective available treatment for OSA; however, limited research predicts which patients undergoing bariatric surgery will undergo OSA resolution. Objectives To determine perioperative predictors for OSA resolution following bariatric surgery using a national database. Setting United Kingdom national bariatric surgery database. Methods The UK National Bariatric Surgery Registry (NBSR) was interrogated to identify all patients with OSA that underwent primary bariatric surgery between January 2009 and June 2017. Those with at least 1 follow-up recording postoperative OSA status were selected for further analysis. Demographic, pre- and postoperative outcomes were collected and analyzed. Poisson multivariate regression was conducted to identify predictors of OSA remission. Results A total of 4015 bariatric cases were eligible for inclusion: 2482 (61.8%) patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB), 1196 (29.8%) sleeve gastrectomy (LSG), and 337 (8.4%) adjustable gastric banding (LAGB). Overall, the mean excess weight loss (EWL) % for the whole group was 61.2 (SD ± 27.2). OSA resolution was recorded in 2377 (59.2%) patients. Following Poisson regression, LRYGB (risk ratio [RR], 1.49 confidence interval [CI] 1.25–1.78) and LSG (RR, 1.46 [CI 1.22–1.75] were associated with approximately 50% increased likelihood of OSA remission compared with LAGB. Greater weight loss following intervention was associated with greater likelihood of OSA remission, while both greater age and greater preoperative body mass index (BMI) were associated with reduced likelihood of OSA remission (P Conclusion This study demonstrated that metabolic surgery results in OSA remission in the majority of patients with obesity. Younger age, lower BMI preprocedure, greater %EWL and the use of LSG or LRYGB positively predicted OSA remission.

Summary Background Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Methods In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. Findings Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of −13·3 mmol/mol (−1·22%, 95% CI −19·7 to −7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. Interpretation These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Funding JP Moulton Foundation.

This chapter introduces the concept of the open abdomen and describes the various aetiologies of this complex condition, including the rationale for elective laparostomy in damage control surgery and as a treatment for abdominal compartment syndrome. The significance of the open abdomen is described in terms of its local and systemic complications, which form the basis of the established classification. Important considerations in the acute systemic management of patients with this condition are outlined, and methods of temporary abdominal closure are described. Advantages and disadvantages of these alternatives, including the use of negative-pressure wound therapy, are discussed.

Background Bariatric and metabolic surgery (BMS) is an established safe, effective, and durable treatment for obesity and its complications. However, there is still a paucity of evidence on surgery outcomes in patients suffering from extreme obesity. Objectives This study aimed to evaluate outcomes of BMS in weight loss and the resolution of co-morbidities in patients with a body mass index (BMI) ≥70kg/m2. Setting National Health Service and private hospitals in the United Kingdom. Methods This cohort study analyzed prospectively collected records from the UK National Bariatric Surgery Registry of patients with a BMI ≥70 kg/m2 undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric band (AGB) between January 2009 and June 2014. Results There were 230 patients (64% female) eligible for inclusion in the study: 22 underwent AGB; 102 underwent SG, and 106 underwent RYGB. Preoperative weight and BMI values were comparable (76 ± 7 kg/m2 for AGB; 75 ± 5 kg/m2 for SG; 74 ± 5 kg/m2 for RYGB). The median postoperative follow-up was 13 months for AGB (10–22 mo), 18 for SG (6–28 mo), and 15 for RYGB (6–24 mo). Patients undergoing RYGB and SG exhibited the greatest postoperative total body weight loss (35 ± 13% and 31 ± 15%, respectively; P = .14), which led to postoperative BMIs of 48 ± 10 kg/m2 and 51 ± 11 kg/m2, respectively (P = .14). All procedures conferred a reduction in the incidence of co-morbidities, including type 2 diabetes, and led to improved functional statuses. The overall complication rate was 7%, with 3 deaths (1%) within 30 days of surgery. Conclusion This study found that primary BMS in patients with a BMI >70kg/m2 has an acceptable safety profile and is associated with good medium-term clinical outcomes. RYGB and SG are associated with better weight loss and great improvements in co-morbidities than AGB. Given the noninferiority of SG outcomes and SG’s potential for further conversion to other BMS procedures if required, SG may be the best choice for primary BMS in patients with extreme obesity.

Objectives Receptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were to investigate the effects of RAMP2 on GCGR trafficking and signalling in the liver, where glucagon (GCG) is important for carbohydrate and lipid metabolism. Methods Subcellular localisation of GCGR in the presence and absence of RAMP2 was investigated using confocal microscopy, trafficking and radioligand binding assays in human embryonic kidney (HEK293T) and human hepatoma (Huh7) cells. Mouse embryonic fibroblasts (MEFs) lacking the Wiskott-Aldrich Syndrome protein and scar homologue (WASH) complex and the trafficking inhibitor monensin were used to investigate the effect of halted recycling of internalised proteins on GCGR subcellular localisation and signalling in the absence of RAMP2. NanoBiT complementation and cyclic AMP assays were used to study the functional effect of RAMP2 on the recruitment and activation of GCGR signalling mediators. Response to hepatic RAMP2 upregulation in lean and obese adult mice using a bespoke adeno-associated viral vector was also studied. Results GCGR is predominantly localised at the plasma membrane in the absence of RAMP2 and exhibits remarkably slow internalisation in response to agonist stimulation. Rapid intracellular accumulation of GCG-stimulated GCGR in cells lacking the WASH complex or in the presence of monensin indicates that activated GCGR undergoes continuous cycles of internalisation and recycling, despite apparent GCGR plasma membrane localisation up to 40 min post-stimulation. Co-expression of RAMP2 induces GCGR internalisation both basally and in response to agonist stimulation. The intracellular retention of GCGR in the presence of RAMP2 confers a bias away from β-arrestin-2 recruitment coupled with increased activation of Gαs proteins at endosomes. This is associated with increased short-term efficacy for glucagon-stimulated cAMP production, although long-term signalling is dampened by increased receptor lysosomal targeting for degradation. Despite these signalling effects, only a minor disturbance of carbohydrate metabolism was observed in mice with upregulated hepatic RAMP2. Conclusions By retaining GCGR intracellularly, RAMP2 alters the spatiotemporal pattern of GCGR signalling. Further exploration of the effects of RAMP2 on GCGR in vivo is warranted., Graphical abstract Image 1, Highlights • The glucagon receptor rapidly recycles to the cell membrane in the absence of RAMP2. • RAMP2 promotes internalisation of the glucagon receptor basally and after agonist stimulation. • RAMP2 confers signalling bias to the glucagon receptor with a reduction in β-arrestin-2 recruitment. • A novel NanoBiT bystander assay demonstrates increased endosomal activation of Gαs with RAMP2. • RAMP2 has time-dependent effects on glucagon-stimulated cAMP accumulation.

ObjectiveGlucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein activation and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation.MethodsDipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss.ResultsLigand-specific reductions in β-arrestin-2 recruitment led to reduced GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured.ConclusionsDiminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

Bariatric and metabolic surgery (BMS) is an established safe, effective, and durable treatment for obesity and its complications. However, there is still a paucity of evidence on surgery outcomes in patients suffering from extreme obesity.This study aimed to evaluate outcomes of BMS in weight loss and the resolution of co-morbidities in patients with a body mass index (BMI) ≥70kg/mNational Health Service and private hospitals in the United Kingdom.This cohort study analyzed prospectively collected records from the UK National Bariatric Surgery Registry of patients with a BMI ≥70 kg/mThere were 230 patients (64% female) eligible for inclusion in the study: 22 underwent AGB; 102 underwent SG, and 106 underwent RYGB. Preoperative weight and BMI values were comparable (76 ± 7 kg/mThis study found that primary BMS in patients with a BMI70kg/m

Background Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). Methods and findings Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86–0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34–0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90–1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40–0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. Conclusions In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon., Emma Rose McGlone and colleagues report the clinical and cost- effectiveness of bariatric surgery for patients with Type 2 diabetes., Author summary Why was this study done? Bariatric or weight loss surgery can dramatically improve type 2 diabetes mellitus (T2DM) in patients with obesity, allowing many patients to stop medicines for T2DM completely. Unfortunately, there are limited resources for performing bariatric surgery. Patients with severe T2DM, who require daily insulin injections, are at risk of being considered lower priority than those with T2DM managed by tablet medications. This is because some small studies have suggested that T2DM requiring insulin (T2DM-Ins) is too advanced to be reversed by surgery. The aims of this study were to see how effective bariatric surgery is in patients with obesity and T2DM-Ins, as well as to determine if performing surgery in this group is cost-effective over a 5-year period. What did the researchers do and find? We used data from a nationwide registry of patients undergoing bariatric surgery in the UK to examine the effect of surgery on patients that require insulin for T2DM. We found that certain types of procedure (Roux en Y gastric bypass (RYGB) and sleeve gastrectomy (SG)) were associated with excellent rates of stopping insulin (approximately two-thirds of patients). We then devised an economic model to compare the costs of this type of surgery with the costs of treating patients using optimal medicines for T2DM. We found that performing surgery was less costly and more effective for the national healthcare provider (National Health Service (NHS)), over a 5-year timeline. What do these findings mean? These findings are important because they suggest that patients with obesity and T2DM-Ins are good candidates for bariatric surgery. Offering bariatric surgery to such patients could improve their health and provide cost savings to national healthcare payers.

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) have been shown to improve metabolic comorbidities as well as quality of life (QoL) in the obese population. The vast majority of previous studies have investigated the metabolic effects of bariatric surgery and there is a dearth of studies examining long-term QoL outcomes post bariatric surgery. The outcomes of 43 patients who underwent bariatric surgery were prospectively assessed, using BAROS questionnaires to quantify QoL and metabolic status pre-operatively, at 1 year and at 8 years. Total weight loss and comorbidity resolution were similar between RYGB and SG. The RYGB cohort experienced greater QoL improvement from baseline and had higher BAROS scores at 8 years. RYGB may provide more substantial and durable long-term benefits as compared to SG.

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Recently described GLP-1 receptor agonists showing signal bias in favour of cyclic AMP over β-arrestin-2 recruitment have delivered promising results in preclinical studies. Here we first sought to establish the role of β-arrestins in the control of intracellular signalling and trafficking responses at the closely related GLP-1, GIP and GCG receptors, through studies performed in cells depleted of both β-arrestin isoforms. We also generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion from INS-1 832/3 clonal beta cells, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release, or glucose output in hepatocytes.

Background For patients in whom laparoscopic adjustable gastric band has failed, conversion to Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy are both options for further surgical treatment. There are limited data comparing these 2 procedures. The National Bariatric Surgery Registry is a comprehensive United Kingdom–wide database of bariatric procedures, in which preoperative demographic characteristics and clinical outcomes are prospectively recorded. Objectives To compare perioperative complication rate and short-term outcomes of patients undergoing single-stage conversion of gastric band to Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy. Setting United Kingdom national bariatric surgery database. Methods From the National Bariatric Surgical Registry data set, we identified 141 patients undergoing single-stage conversion from gastric band to either gastric bypass (113) or sleeve gastrectomy (28) between 2009 and 2014, and analyzed their clinical outcomes. Results With respect to perioperative outcomes gastric bypass was associated with a higher incidence of readmission or reintervention postoperatively (16 versus 0; P = .04). There was no difference in percentage excess weight loss between sleeve gastrectomy and gastric bypass at final follow-up at 1 year (52.1% versus 57.1% respectively; P = .4). Conclusions Conversion from band to sleeve or bypass give comparable good early excess weight loss; however, conversion to sleeve is associated with a better perioperative safety profile.

Complete and reliable neuromuscular reversal is important to successful anaesthetic recovery in the morbidly obese patient undergoing laparoscopic surgery. Our goal was to determine whether sugammadex, a selective reversal agent is associated with better respiratory recovery than neostigmine following the reversal of anaesthesia-associated neuromuscular blockade by rocuronium in the morbidly obese. Peak Expiratory Flow Rate a surrogate marker for respiratory function, was the primary outcome measured and secondary outcome measures included post-operative nausea and vomiting, pain and head lifting. We found that patients reversed with sugammadex had a significantly higher post-operative PEFR as compared to those reversed with neostigmine and glycopyrrolate group. Keywords: Sugammadex, Laparoscopic surgery, Neuromuscular blockade, Morbidly obese

A Best Evidence Topic was undertaken to systematically review the evidence regarding the use of NSAIDS in breast cancer patients. The search strategy generated 149 titles, of which six were best placed to answer the clinical question. These included three prospective cohort studies, two retrospective cohort studies and one case control study, examining a total of 18,415 breast cancer patients. The study methodologies were highly variable and all relied on approximate measures of NSAID consumption. There is limited evidence that use of aspirin and non-aspirin NSAIDs may be associated with decreased breast cancer mortality and all-cause mortality in patients diagnosed with breast cancer. Optimum type and dosage of NSAID for this purpose remains unclear. There is a need for large-scale randomised controlled trials to further clarify.

BACKGROUND AND AIMS: Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, though parallel changes in body weight and other confounding variables limits this interpretation. METHODS: Global G protein-coupled bile acid receptor-1 null (Tgr5(−/−)) and intestinal-specific farnesoid X receptor null (Fxr(Δ/E)) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r(−/−)) mice on chow diet were characterized following bile diversion to the ileum (GB-IL). RESULTS: GB-IL induced weight loss and improved oral glucose tolerance in HFD-fed Tgr5(−/−), but not Fxr(Δ/E) mice, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with Ex-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole body Glp-1r(−/−) mice. CONCLUSIONS: Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.

BACKGROUND: An excessively long-blind end of the alimentary limb following a Roux-en-Y gastric bypass (RYGB), known as a 'candy cane' (CC), may cause symptoms including abdominal pain, regurgitation and vomiting. Very few studies have examined the efficacy of surgical resection of the CC. OBJECTIVES: The aim of this study was to assess sensitivity of preoperative diagnostic tools for CC, as well as perioperative outcomes and symptom resolution after CC revision surgery. SETTING: High volume bariatric centre of excellence, United Kingdom. METHODS: Observational study of CC revisions from 2010 to 2017. RESULTS: Twenty-eight CC revision cases were identified (mean age 45 ± 9 years, female preponderance 9:1). Presenting symptoms were abdominal pain (86%), regurgitation/vomiting (43%), suboptimal weight loss (36%) and acid reflux (21%). Preoperative tests provided correct diagnosis in 63% of barium contrast swallows, 50% of upper gastrointestinal endoscopies and 29% computed tomographies. Patients presenting with pain had significantly higher CC size as compared with pain-free group (4.2 vs. 2 cm, p = 0.001). Perioperative complications occurred in 25% of cases. Complete or partial symptom resolution was documented in 73% of patients undergoing CC revision. Highest success rates were recorded in the regurgitation/vomiting group (67%). CONCLUSION: Surgical revision of CC is associated with good symptom resolution in the majority of patients, especially those presenting with regurgitation/vomiting. However, it carries certain risk of complications. CC diagnosis may frequently be missed; hence more than one diagnostic tool should be considered when investigating symptomatic patients after RYGB.

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes and obesity, is known to undergo palmitoylation by covalent ligation of an acyl chain to cysteine 438 in its carboxyl-terminal tail. Work with other GPCRs indicates that palmitoylation can be dynamically regulated to allow receptors to partition into plasma membrane nanodomains that act as signaling hotspots. Here, we demonstrate that the palmitoylated state of the GLP-1R is increased by agonist binding, leading to its segregation and clustering into plasma membrane signaling nanodomains before undergoing internalization in a clathrin-dependent manner. Both GLP-1R signaling and trafficking are modulated by strategies targeting nanodomain segregation and cluster formation, including depletion of cholesterol or expression of a palmitoylation-defective GLP-1R mutant. Differences in receptor binding affinity exhibited by biased GLP-1R agonists, and modulation of binding kinetics with the positive allosteric modulator BETP, influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.

In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al. (2018) demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes.

Although the prevalence of obese elderly patients is increasing, the outcomes of bariatric surgery in this potentially high-risk cohort remain poorly understood, especially those relating to quality of life. Furthermore, there is no data on the efficacy of bariatric surgery in the super-obese elderly. We identified 50 consecutive patients undergoing bariatric surgery aged 60 years or over, and compared the outcomes of the super-obese (BMI ≥ 50; n = 26) with those of BMI < 50. Mean follow-up was 33 months. There were no significant differences between the groups in terms of comorbidities, operation-type and peri-operative complications. Mean percentage excess weight loss was comparable between the groups (56.7 vs. 58.8 %; p = 0.81), as was resolution of comorbidities and post-operative quality of life (mean Bariatric Analysis and Reporting Outcome System (BAROS) 3.5 vs. 3.1; p = 0.64).

Although laparoscopic sleeve gastrectomy is an established operation for severe obesity, there is controversy regarding the extent to which the antrum is excised. The objective of this systematic review was to investigate the effect on perioperative complications and medium-term outcomes of antral resecting versus antral preserving sleeve gastrectomy. MEDLINE, EMBASE, and Cochrane databases were searched from 1946 to April 2017. Eligible studies compared antral resection (staple line commencing 2-3 cm from pylorus) with antral preservation (>5 cm from pylorus) in patients undergoing primary sleeve gastrectomy for obesity. Meta-analyses were performed with a random-effects model, and risk of bias within and across studies was assessed using validated scoring systems. Eight studies (619 participants) were included: 6 randomized controlled trials and 2 cohort studies. Overall follow-up was 94% for the specified outcomes of each study. Mean percentage excess weight loss was 62% at 12 months (7 studies; 574 patients) and 67% at 24 months (4 studies; 412 patients). Antral resection was associated with significant improvement in percentage excess weight loss at 24-month follow-up (mean 70% versus 61%; standardized mean difference .95; confidence interval .35-1.58, P

Etymologically, the term ‘bariatric surgery’ means surgery to reduce weight, deriving from the Greek ‘baros’ (heavy). It is clear however that most bariatric operations have dramatic effects on type 2 diabetes mellitus and other metabolic conditions, many of which occur independently of weight loss. Weight loss may be regarded as just one of several clinical outcomes that result from the systemic changes in nutrient metabolism conferred by operations such as Roux-en-Y gastric bypass (RYGB): hence these operations can be considered examples of ‘metabolic surgery’.

The increasing subspecialisation of general surgeons in their elective work may result in problems for the provision of expert care for emergency cases. There is very little evidence of the impact of subspecialism on outcomes following emergency major upper gastrointestinal surgery. This prospective study investigated whether elective subspecialism of general surgeon is associated with a difference in outcome following major emergency gastric surgery.Between February 1994 and June 2010, the data from all emergency major gastric procedures (defined as patients who underwent laparotomy within 12 hours of referral to the surgical service for bleeding gastroduodenal ulcer and/or undergoing major gastric resection) was prospectively recorded. The sub-specialty interest of operating surgeon was noted and related to post-operative outcomes.Over the study period, a total of 63 major gastric procedures were performed of which 23 (37%) were performed by specialist upper gastrointestinal (UGI) consultants. Surgery performed by a specialist UGI surgeon was associated with a significantly lower surgical complication (4% vs. 28% of cases; p=0.04) and in-patient mortality rate (22% vs. 50%; p=0.03).Major emergency gastric surgery has significantly better clinical outcomes when performed by a specialist UGI surgeon. These results have important implications for provision of an emergency general surgical service.

Background Primary care practitioners (PCP) are the “gate-keepers” for publicly funded weight loss surgery (WLS) in the United Kingdom, but their attitude toward WLS has not been studied to date. Objective This pilot study aimed to investigate opinions and experience of PCPs regarding WLS in the United Kingdom. Setting PCPs from 3 publicly funded primary care consortiums from distinct geographic areas within the United Kingdom were surveyed. Methods A cross-sectional survey approach was used to assess PCP attitude to WLS surgery. A questionnaire was sent electronically to PCPs, designed to assess PCP demographic, experience, knowledge, and attitude regarding obesity and WLS. For the purposes of analysis, PCPs were divided into junior and senior based on duration of practice. Results Of PCPs, 35 completed and returned the questionnaire. Although PCPs stated that approximately 30% of their patients were obese, 17 (49%) had made not a single referral for WLS in the previous 12 months. PCPs overestimated early WLS mortality rate more than 10-fold and 23 (66%) did not feel confident providing care to patients post-WLS. Junior PCPs were significantly more likely to feel that WLS should not be publicly funded (P = .01). Conclusions These findings suggest a prejudice against WLS amongst PCPs in England, particularly among junior doctors.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: in patients with symptomatic gallstones and concomitant common bile duct (CBD) stones, is a single-stage surgical strategy (laparoscopic cholecystectomy (LC) with common bile duct exploration) preferable, or a two-stage procedure involving LC with pre or post-operative endoscopic retrograde cholangiography (ERCP)? Two hundred and six papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. A recent large meta-analysis concluded no significant difference in the clinical effectiveness or complication rate of either strategy. Three recent smaller studies concurred with this conclusion; however each noted improved cost-effectiveness of the single-stage approach advocating its use as the superior strategy when local resources and expertise are available. We conclude that for patients with symptomatic gallstones and concomitant choledocholithiasis, a single-stage surgical procedure is equivalent to two-stage LC and ERCP in terms of clinical outcomes, is associated with a shorter overall hospital stay and may be more cost-effective. On this basis a single-stage procedure is recommended for management of symptomatic gallstones and choledocholithiasis where local resources and expertise permit.

Magnetic resonance imaging (MRI) is known to have high predictive accuracy for circumferential resection margin (CRM) involvement of pre-treatment rectal tumours. This study aims to assess predictive accuracy of MRI for CRM involvement in rectal cancers post-long-course chemoradiotherapy (CRT) and in particular to understand how this information can influence surgical planning. Forty-seven rectal cancers treated with CRT followed by bowel resection in one hospital since 2005 were reviewed for clinical, radiological and pathological characteristics. Using a validated pro forma, a radiologist blinded to final histology and original MRI report predicted CRM status from post-CRT MRI images. Results were compared to histological CRM status of final specimen, and differential analysis by type of surgical operation was performed. Overall accuracy of MRI for CRM involvement post-CRT was 72 % with a negative predictive value of 92 %. Abdominoperineal excision (APE) post-CRT was associated with non-significantly higher rates of histologically involved CRM than anterior resection (AR; 41 vs. 21 %) as were mucinous adenocarcinomas when compared to non-mucinous (56 vs. 21 %). Overall accuracy and positive predictive value were non-significantly higher for cancer treated with a standard APE than AR, and negative predictive value was high for both groups. MRI post-CRT has high negative predictive value for CRM status. Such information is of particular clinical relevance in low rectal cancers treated with APE as it can indicate when a standard surgical approach is likely to be sufficient.

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable., Nanodomain segregation and clustering of the glucagon-like peptide-1 receptor, a key target for type 2 diabetes therapy, is regulated by agonist binding, leading to compartmentalization of downstream signaling and clathrin-dependent internalization and impacting pancreatic beta cell responses.

Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and β-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of β-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities., A combination of competition binding, functional assays assessing the Gαs and Gq pathways and β-arrestin recruitment, and siRNA knockdown was used to examine the effect of RAMP2 on the GCGR.

Studies showing a volume-outcome relationship in vascular surgery have led to a drive towards centralisation of vascular surgical services. This has led to these services being transferred from the district general hospital (DGH) to a central ‘network’ hospital. An unintended consequence of this is that the tariff funding stays with the operating hospital. Patients who are transferred back to the DGH for rehabilitation following treatment at the network hospital do not receive funding to cover their inpatient stay. We present data showing that since centralisation there has been a drop in overall income in a DGH along with sicker patients being repatriated. These patients also stay longer. This has implications for funding of rehabilitation tariffs and for the viability of district general vascular services.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was whether patients who have undergone chemoradiotherapy (CRT) for locally advanced squamous cell carcinoma of the oesophagus benefit from surgical resection. 505 papers were found using the reported search, of which 5 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. Of these five studies, two were randomised controlled trials. These demonstrated that there was no survival benefit in adding surgery to patients who have undergone CRT for oesophageal cancer. The remaining three observational studies suggest that surgery may have a prognostic benefit for patients who show a partial, but not complete response to CRT. We conclude that for patients who are complete responders to induction CRT, surgery adds no survival benefit. With regard to partial responders there is weak evidence suggesting that there may be some benefit in surgery after CRT, but further trials are needed to clarify the survival benefit (if any) of adding oesophagectomy to CRT for this sub-group.

A best evidence topic was written according to a structured protocol. The question addressed whether laparoscopic approach confers a difference in functional outcome compared to conventional open resectional surgery for rectal cancer. 246 papers were found using the reported search, of which five represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and key results of these papers are tabulated. Of these five studies, none showed any difference in post-operative urinary function between patients undergoing laparoscopic or open surgery. The two randomised studies reported either a trend or a significant difference in favour of open surgery for sexual outcome in men. Three more recent, case–control studies showed differences in favour of laparoscopic surgery for sexual function in men. We conclude that there is no evidence to suggest that laparoscopic approach makes any difference to post-operative urinary function. The data relating to sexual function in men is contradictory, and as none of the studies available have generated high level evidence and further trials are required to clarify whether laparoscopic approach confers an advantage or disadvantage in terms of sexual function for men post-operatively. In terms of sexual function in women, the available data is far too scarce to satisfactorily determine whether laparoscopy is superior to open surgery.

Obesity is common amongst patients with renal transplants (RT). It is associated not only with generic obesity-related complications including diabetes, but also with higher rates of graft rejection and loss. A Best Evidence Topic in surgery was written according to a structured protocol: this is a systematic review of the literature, suitable when the quality of available evidence is low. The question addressed was: is weight-loss surgery (WLS) safe and effective in patients that have had a previous renal transplant? Three prospective case series and one multicentre retrospective study were identified, together reporting on a total of 112 patients who underwent WLS after RT. Eighty-seven patients underwent open WLS and 25 patients underwent laparoscopic operations of which 11 had sleeve gastrectomy and 14 RYGB. Percentage excess weight loss was highly variable between the studies, ranging from an average of 30.8%-75% at 12 months. One graft rejection occurred within 30 days of surgery. All studies were limited by lack of suitable comparison group, short follow-up and heterogeneity in type of bariatric procedure and approach. To date, there is limited evidence to suggest that bariatric surgery is safe and has good short-term outcomes for selected obese patients post-renal transplant.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: which is the best regimen of enoxaparin thromboprophylaxis for patients undergoing bariatric surgery? One hundred and twenty-five papers were identified using the reported literature search, of which four represented the best evidence to answer the clinical question. The authors, country and date of publication, patient groups, relevant outcomes and results of these papers were tabulated. All four studies are non-randomized cohort studies examining venous thromboembolism rates and major postoperative bleeding following varying regimens of Enoxaparin thromboprophylaxis. There is no level 1 evidence which significantly favors any particular thromboprophylaxis regimen. There is some evidence that extended duration of treatment of ten days after discharge significantly reduces the incidence of VTE compared to in-hospital treatment only, and that a higher incidence of post-operative bleeding occurs with a regimen that includes a pre-operative dose of Enoxaparin. With regard to dosage, for in-hospital treatment the higher dosage of 40 mg twice daily as opposed to 30 mg seems to significantly reduce the incidence of VTE without significantly affecting bleeding rate.

Background Bariatric surgery is associated with late and procedure-specific acute surgical complications. There is very little evidence available regarding the volume, nature, and outcomes of acute surgical admissions directly stemming from bariatric surgery. Centralization of bariatric elective services in the United Kingdom may have an adverse impact on the ability of local services to manage such unpredictable complications. To address this potential problem, we set up a comprehensive and specialist emergency bariatric service. Objectives The aim of this study was to quantify and characterize the workload of a specialist emergency surgical bariatric service. Setting University National Health Service hospital. Methods Over 2 years, we prospectively collected data on demographic characteristics, management, and outcomes of all acute surgical admissions related directly to previous bariatric surgery. Results Between December 2011 and November 2013, 69 patients had 71 emergency admissions due to a surgical emergency directly related to previous bariatric surgery. Thirty-seven (54%) had undergone primary bariatric surgery at our institution, 13 (19%) at a different National Health Service hospital, 16 (23%) at private U.K. hospitals, and 3 (4%) at private overseas hospitals. Forty-four endoscopic or surgical interventions were required, of which 17 (39%) were performed on nights or weekends and within 12 hours of admission. Of 27 operations, 25 (93%) were completed laparoscopically. Median length of stay was 2 days, there were no mortalities, and there was 1 readmission within 30 days. Conclusions There is a significant volume of late bariatric surgical emergencies, many requiring urgent intervention. These may be effectively managed by a specialist bariatric service.

Background Evidence-based interventions may reduce mortality in surgical patients. This study documented the prevalence of sepsis, adherence to guidelines in its management, and timing of source control in general surgical patients presenting as an emergency. Methods Patients aged 16 years or more presenting with emergency general surgery problems were identified over a 7-day period and then screened for sepsis compliance (using the Sepsis Six standards, devised for severe sepsis) and the timing of source control (whether radiological or surgical). Exploratory analyses examined associations between the mode (emergency department or general practitioner) and time of admission, adherence to the sepsis guidelines, and outcomes (complications or death within 30 days). Results Of a total of 5067 patients from 97 hospitals across the UK, 911 (18·0 per cent) fulfilled the criteria for sepsis, 165 (3·3 per cent) for severe sepsis and 24 (0·5 per cent) for septic shock. Timely delivery of all Sepsis Six guidelines for patients with severe sepsis was achieved in four patients. For patients with severe sepsis, 17·6–94·5 per cent of individual guidelines within the Sepsis Six were delivered. Oxygen was the criterion most likely to be missed, followed by blood cultures in all sepsis severity categories. Surgery for source control occurred a median of 19·8 (i.q.r. 10·0–35·4) h after diagnosis. Omission of Sepsis Six parameters did not appear to be associated with an increase in morbidity or mortality. Conclusion Although sepsis was common in general surgical patients presenting as an emergency, adherence to severe sepsis guidelines was incomplete in the majority. Despite this, no evidence of harm was apparent.