The first international Delphi consensus statement on Laparoscopic Gastrointestinal surgery.

BACKGROUND: Laparoscopic surgery has almost replaced open surgery in many areas of Gastro-Intestinal (GI) surgery. There is currently no published expert consensus statement on the principles of laparoscopic GI surgery. This may have affected the training of new surgeons. This exercise aimed to achieve an expert consensus on important principles of laparoscopic GI surgery. METHODS: A committee of 38 international experts in laparoscopic GI surgery proposed and voted on 149 statements in two rounds following a strict modified Delphi protocol. RESULTS: A consensus was achieved on 133 statements after two rounds of voting. All experts agreed on tailoring the first port site to the patient, whereas 84.2% advised avoiding the umbilical area for pneumoperitoneum in patients who had a prior midline laparotomy. Moreover, 86.8% agreed on closing all 15 mm ports irrespective of the patient's body mass index. There was a 100% consensus on using cartridges of appropriate height for stapling, checking the doughnuts after using circular staplers, and keeping the vibrating blade of the ultrasonic energy device in view and away from vascular structures. An 84.2% advised avoiding drain insertion through a ≥10 mm port site as it increases the risk of port-site hernia. There was 94.7% consensus on adding laparoscopic retrieval bags to the operating count and ensuring any surgical specimen left inside for later removal is added to the operating count. CONCLUSION: Thirty-eight experts achieved a consensus on 133 statements concerning various aspects of laparoscopic GI Surgery. Increased awareness of these could facilitate training and improve patient outcomes.

Bariatric surgery during COVID-19 in the UK: a British Obesity and Metabolic Surgery Society (BOMSS) survey.

BACKGROUND: After the declaration of COVID-19 as a pandemic last March 2020, several adjustments in surgical services were implemented. Plans are now being formulated for restarting bariatric surgery. The aim of this survey is to capture the practice during the pandemic and the readiness to restart to provide a framework to deal with the backlog of bariatric cases. METHOD: A survey was delivered to consultant surgeon members of the British Obesity and Metabolic Surgery Society and non-bariatric surgery consultant members of the Association of Upper GI Surgeons. RESULTS: The survey elicited a response rate of 40% (n = 66) among bariatric surgeons and 15.5% (n = 34) between non-bariatric surgeons. The average question response rate was 93% (88-100%). Most of the elective bariatric surgeries and clinics were cancelled early after declaration of the pandemic. Remote technologies for patient education evolved and were used heavily during the pandemic. The average cancelled elective bariatric surgery operations per week was 9. Nearly a quarter of responders reported performing emergency bariatric surgery during the pandemic. Most of the bariatric surgeons reported being ready to restart the service within 1-2 months. Responders recommended using private sector beds to increase NHS capacity and using the link between obesity and poor COVID-19 outcomes to push for prioritisation of bariatric patients. CONCLUSION: This survey is an attempt to understand the impact of COVID-19 on UK bariatric service and the preparedness to restart. It expressed the bariatric surgery consultants' view of prioritisation of bariatric patients on clinical basis rather than the first-come-first-served basis.

Food Intake Following Gastric Bypass Surgery: Patients Eat Less but Do Not Eat Differently.

BACKGROUND: Lack of robust research methodology for assessing ingestive behavior has impeded clarification of the mediators of food intake following gastric bypass (GBP) surgery. OBJECTIVES: To evaluate changes in directly measured 24-h energy intake (EI), energy density (ED) (primary outcomes), eating patterns, and food preferences (secondary outcomes) in patients and time-matched weight-stable comparator participants. METHODS: Patients [n = 31, 77% female, BMI (in kg/m2) 45.5 ± 1.3] and comparators (n = 32, 47% female, BMI 27.2 ± 0.8) were assessed for 36 h under fully residential conditions at baseline (1 mo presurgery) and at 3 and 12 mo postsurgery. Participants had ad libitum access to a personalized menu (n = 54 foods) based on a 6-macronutrient mix paradigm. Food preferences were assessed by the Leeds Food Preference Questionnaire. Body composition was measured by whole-body DXA. RESULTS: In the comparator group, there was an increase in relative fat intake at 3 mo postsurgery; otherwise, no changes were observed in food intake or body composition. At 12 mo postsurgery, patients lost 27.7 ± 1.6% of initial body weight (P < 0.001). The decline in EI at 3 mo postsurgery (-44% from baseline, P < 0.001) was followed by a partial rebound at 12 mo (-18% from baseline), but at both times, dietary ED and relative macronutrient intake remained constant. The decline in EI was due to eating the same foods as consumed presurgery and by decreasing the size (g, MJ), but not the number, of eating occasions. In patients, reduction in explicit liking at 3 mo (-11.56 ± 4.67, P = 0.007) and implicit wanting at 3 (-15.75 ± 7.76, P = 0.01) and 12 mo (-15.18 ± 6.52, P = 0.022) for sweet foods were not matched by reduced intake of these foods. Patients with the greatest reduction in ED postsurgery reduced both EI and preference for sweet foods. CONCLUSIONS: After GBP, patients continue to eat the same foods but in smaller amounts. These findings challenge prevailing views about the dynamics of food intake following GBP surgery. This trial was registered as clinicaltrials.gov as NCT03113305.

Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells.

Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1-/- mouse studies, we know relatively little of the role of NFKB1 in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of NFKB1-/- human macrophages. Transcriptomic analysis reveals that activated NFKB1-/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF, IL6, and IL1B, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70, CD83 and CD209. NFKB1-/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology.

The first modified Delphi consensus statement on sleeve gastrectomy.

INTRODUCTION: Sleeve gastrectomy (SG) is the commonest bariatric procedure worldwide. Yet there is significant variation in practice concerning its various aspects. This paper report results from the first modified Delphi consensus-building exercise on SG. METHODS: We established a committee of 54 globally recognized opinion makers in this field. The committee agreed to vote on several statements concerning SG. An agreement or disagreement amongst ≥ 70.0% experts was construed as a consensus. RESULTS: The committee achieved a consensus of agreement (n = 71) or disagreement (n = 7) for 78 out of 97 proposed statements after two rounds of voting. The committee agreed with 96.3% consensus that the characterization of SG as a purely restrictive procedure was inaccurate and there was 88.7% consensus that SG was not a suitable standalone, primary, surgical weight loss option for patients with Barrett's esophagus (BE) without dysplasia. There was an overwhelming consensus of 92.5% that the sleeve should be fashioned over an orogastric tube of 36-40 Fr and a 90.7% consensus that surgeons should stay at least 1 cm away from the angle of His. Remarkably, the committee agreed with 81.1% consensus that SG patients should undergo a screening endoscopy every 5 years after surgery to screen for BE. CONCLUSION: A multinational team of experts achieved consensus on several aspects of SG. The findings of this exercise should help improve the outcomes of SG, the commonest bariatric procedure worldwide, and guide future research on this topic.

The First Modified Delphi Consensus Statement for Resuming Bariatric and Metabolic Surgery in the COVID-19 Times.

The purpose of this study was to achieve consensus amongst a global panel of expert bariatric surgeons on various aspects of resuming Bariatric and Metabolic Surgery (BMS) during the Coronavirus Disease-2019 (COVID-19) pandemic. A modified Delphi consensus-building protocol was used to build consensus amongst 44 globally recognised bariatric surgeons. The experts were asked to either agree or disagree with 111 statements they collectively proposed over two separate rounds. An agreement amongst ≥ 70.0% of experts was construed as consensus as per the predetermined methodology. We present here 38 of our key recommendations. This first global consensus statement on the resumption of BMS can provide a framework for multidisciplinary BMS teams planning to resume local services as well as guide future research in this area.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

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.

The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast.

It is widely believed that infection with the SARS-CoV-2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1ß, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense 'cytokine storm' is postulated as the mechanism behind the extreme immune response seen in severe COVID-19. It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV-2 infection; they also have a higher prevalence of central obesity and its metabolic complications. In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19. Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1ß and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus's main protease enzyme which is needed for virus RNA synthesis and replication. Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. HYPOTHESIS: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV-2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.

The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence, Bcl3-/- macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3-mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3-mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation.

The regulation of sequence specific NF-κB DNA binding and transcription by IKKß phosphorylation of NF-κB p50 at serine 80.

Phosphorylation of the NF-κB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-κB, and IKKß as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNFα inducible expression of a subset of NF-κB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-κB binding (κB) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at κB sites with an adenine at the -1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF-κB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific κB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses.

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver.

BACKGROUND: Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown. METHODS: In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses. RESULTS: In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1). CONCLUSIONS: Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.

Sex-specific effects of prenatal stress on glucose homoeostasis and peripheral metabolism in rats.

Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically relevant maternal stress is less clear, yet of physiological importance. Here, we investigated in rats the short- and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose-insulin homoeostasis and peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action. Prenatal stress (PNS) was associated with reduced birth weight in female, but not male, offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months; however, at 6 months, PNS females were hyperinsulinaemic following an oral glucose load. In PNS males, plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor α (Pparα (Ppara)) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1α (Ppargc1a)) and Pparγ (Pparg) expression, whereas only Pgc1α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ßhsd1), phosphoenolpyruvate carboxykinase (Pepck (Pck1)), adipose triglyceride lipase (Atgl) and diglyceride acyltransferase 2 (Dgat2) in females, but only Pepck mRNA expression was reduced in PNS males. Thus, prenatal social stress differentially programmes glucose homoeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.

Lassoing of the small bowel mesentery and abdominal pain caused by band tubing after "band on bypass".

Weight regain after laparoscopic gastric bypass can be difficult to manage. A common finding is an enlarged gastrojejunal complex (dilated gastric pouch and/or jejunum, dilated gastrojejunal anastomosis). Revision of the gastrojejunal complex can be accomplished by surgical resection, endoscopic plication techniques, or more recently, placement of an adjustable band around the dilated gastric pouch ("band on bypass," BoB). We present an unusual complication of the BoB procedure, in which the band tubing looped around the small bowel causing severe abdominal pain.

Obstructive sleep apnea can be safely managed in a level 2 critical care setting after laparoscopic bariatric surgery.

BACKGROUND: In the United Kingdom, demand for intensive care beds (level 3 critical care) often outstrips supply, leading to frequent and frustrating cancellation of complex elective surgery. It has been suggested that patients with obstructive sleep apnea who undergo bariatric surgery should be admitted to a level 3 facility for routine postoperative management. We have questioned the validity of this dogma in the era of laparoscopic bariatric surgery by using a simple easily applicable algorithm. OBJECTIVES: The aim of this study was to investigate the clinical outcome of patients with obstructive sleep apnea (OSA) without admission to the intensive care unit after laparoscopic bariatric surgery. METHODS: For the first 24 hours after surgery, all patients were admitted to a level 2 (high-dependency) area on a general surgical ward with experience of bariatric surgery. They received supplemental oxygen, continuous pulse oximetry, and judicious analgesic administration using a combination of small boluses of i.v. morphine together with i.v. paracetamol. Perioperative continuous positive airway pressure support was not routinely given, unless patients with OSA had oxygen saturation below their recorded preoperative level on 2 consecutive readings. RESULTS: A total of 1623 patients underwent laparoscopic bariatric surgery over a 12-year period. Of those, 192 had OSA with a median operative body mass index of 52 kg/m(2) (range 34-78 kg/m(2)). The incidence of respiratory complications and the median length of stay (3 nights) were identical in patients with OSA and those without OSA. Four patients self-administered perioperative continuous positive airway pressure, but none required transfer to intensive care or mechanical ventilation. There were no in-hospital deaths. CONCLUSION: Laparoscopic bariatric surgery in patients with OSA is well tolerated and does not require the routine use of level 3 critical care facilities.

Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects.

Exposure to an adverse early life environment is associated with increased cardio-metabolic disease risk, a phenomenon termed "programming." The effects of this are not limited to the exposed first (F1) generation but can be transmissible to a second generation (F2) through male and female lines. Using a three generation animal model of programming by initial prenatal glucocorticoid overexposure we have identified effects on fetal and placental weight in both the F1 and F2 offspring. However, the expression of candidate imprinted genes in the fetus and placenta differed between the F1 and F2, with marked parent-of-origin effects in F2. Since DNA methylation at imprinted genes is maintained at fertilization, they are potential templates for the transmission of programming effects across generations. Although we detected alterations in DNA methylation at differentially methylated regions (DMRs) of the key prenatal growth factor Igf2 in F1 and F2 fetal liver, the changes in DNA methylation at these DMRs do not appear to underlie the transmission of effects on Igf2 expression through sperm. Thus, multigenerational programming effects on birth weight and disease risk is associated with different processes in F1 and F2. These findings have implications for the pathogenesis and future attempts to stratify therapies for the "developmental component" of cardiometabolic disease.