Can Nonalcoholic Steatohepatitis Be Surgically Cured?: Liver Histologic Comparison After Metabolic Surgery Versus Usual Care.

OBJECTIVE: To compare histologic outcomes in patients with fibrotic nonalcoholic steatohepatitis (NASH) and obesity after metabolic surgery versus nonsurgical care. BACKGROUND: There are no published data comparing the effects of metabolic surgery versus nonsurgical care on histologic progression of NASH. METHODS: Repeat liver biopsies were performed in patients with body mass index >30 kg/m 2 at a US health system whose baseline liver biopsy between 2004 and 2016 confirmed a histologic diagnosis of NASH including the presence of liver fibrosis, but without cirrhosis. Baseline characteristics of liver histology for patients who underwent simultaneous liver biopsy at the time of metabolic surgery were balanced with a nonsurgical control group using overlap weighting methods. The primary composite endpoint required both resolution of NASH and improvement of at least 1 fibrosis stage in the repeat liver biopsy. RESULTS: A total of 133 patients (42 metabolic surgery and 91 nonsurgical controls) had a repeat liver biopsy with a median interval of 2 years. Overlap weighting provided balance for baseline histologic disease activity, fibrosis stage, and time interval between liver biopsies. In overlap-weighted patients, 50.1% in the surgical and 12.1% in the nonsurgical group met the primary endpoint (odds ratio=7.3; 95% CI, 2.8-19.2, P <0.001). NASH resolution and fibrosis improvement occurred in 68.5% and 64.1% of surgical patients, respectively. Surgical and nonsurgical patients who met the primary endpoint lost more weight than their counterparts who did not meet the primary endpoint [mean weight loss difference in the surgical group: 12.2% (95% CI, 7.3%-17.2%) and in the nonsurgical group: 11.6% (95% CI, 6.2%-16.9%)]. CONCLUSIONS: Among patients with fibrotic noncirrhotic NASH, metabolic surgery resulted in simultaneous NASH resolution and fibrosis improvement in half of patients.

Renoprotective Effects of Metabolic Surgery Versus GLP1 Receptor Agonists on Progression of Kidney Impairment in Patients with Established Kidney Disease.

OBJECTIVE: To examine the renoprotective effects of metabolic surgery in patients with established chronic kidney disease (CKD). BACKGROUND: The impact of metabolic surgery compared with glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with established CKD has not been fully characterized. METHODS: Patients with obesity (body mass index ≥30 kg/m 2 ), type 2 diabetes, and baseline estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m² who underwent metabolic bariatric surgery at a large US health system (2010-2017) were compared with nonsurgical patients who continuously received GLP-1RA. The primary end point was CKD progression, defined as a decline of eGFR by ≥50% or to <15 mL/min/1.73 m 2 , initiation of dialysis, or kidney transplant. The secondary end point was the incident kidney failure (eGFR <15 mL/min/1.73 m 2 , dialysis, or kidney transplant) or all-cause mortality. RESULTS: 425 patients, including 183 patients in the metabolic surgery group and 242 patients in the GLP-1RA group, with a median follow-up of 5.8 years (IQR, 4.4-7.6), were analyzed. The cumulative incidence of the primary end point at 8 years was 21.7% (95% CI: 12.2-30.6) in the surgical group and 45.1% (95% CI: 27.7 to 58.4) in the nonsurgical group, with an adjusted hazard ratio of 0.40 (95% CI: 0.21 to 0.76), P =0.006. The cumulative incidence of the secondary composite end point at 8 years was 24.0% (95% CI: 14.1 to 33.2) in the surgical group and 43.8% (95% CI: 28.1 to 56.1) in the nonsurgical group, with an adjusted HR of 0.56 (95% CI: 0.31 to 0.99), P =0.048. CONCLUSIONS: Among patients with type 2 diabetes, obesity, and established CKD, metabolic surgery, compared with GLP-1RA, was significantly associated with a 60% lower risk of progression of kidney impairment and a 44% lower risk of kidney failure or death. Metabolic surgery should be considered as a therapeutic option for patients with CKD and obesity.

Clinical outcomes of bariatric surgery in patients with obesity and idiopathic intracranial hypertension.

INTRODUCTION: Obesity is a major risk factor for idiopathic intracranial hypertension (IIH). Effective therapeutics for preventing disease progression and alleviating symptoms are limited. This study aims to examine the effects of bariatric surgery on clinical outcomes of IIH. METHODS: We retrospectively collected data from the medical record of 97 patients with obesity and an existing diagnosis of IIH who underwent primary bariatric surgery at the Cleveland Clinic health system in the USA between 2005 and 2023. Pre- and postoperative data on presence of symptoms and clinical markers of IIH (headaches, visual field defects, papilledema, visual symptoms), intracranial pressure, and usage of IIH medications were compared. RESULTS: A total of 97 patients (98% female, median age 46.7 years, median BMI 48.3 kg/m2) with IIH who underwent bariatric surgery including Roux-en-Y gastric bypass (n = 66, 68%), sleeve gastrectomy (n = 27, 27.8%), and gastric banding (n = 4, 4.1%) were analyzed. In a median follow-up time of 3.0 years, the median total weight loss was 24% (interquartile range, 13-33%). There was a significant improvement in headache, papilledema, visual field deficits, and visual symptoms after bariatric surgery. The mean lumbar opening pressure before and after bariatric surgery was 34.8 ± 8.2 cm CSF and 24.2 ± 7.6 cm CSF, respectively, with a mean reduction of 10.7 cm CSF (95% confidence interval, 4.7 to 16.6), p = 0.003. The dosage of acetazolamide and topiramate, as well as the number of medications taken for IIH, decreased significantly after bariatric surgery (p < 0.001). CONCLUSION: For patients who have obesity, bariatric surgery is a viable treatment modality for alleviation or improvement of symptoms of IIH.

Association between geospatial disparities in food security with weight loss and nutritional outcomes of metabolic surgery.

BACKGROUND: Food insecurity has been linked to higher rates of obesity. It has also been shown to diminish the effectiveness of weight loss strategies, including intensive lifestyle interventions. One essential component of food insecurity is having a geospatial disadvantage in access to healthy, affordable food, such as living within a food desert. This study aims to determine if food insecurity also impacts weight loss and nutritional outcomes in patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). METHODS: Clinical outcomes of patients who underwent RYGB or SG at Cleveland Clinic or affiliate regional hospitals in the United States from 2010 to 2018 were collected. Modified Retail Food Environmental Index (mRFEI) data was collected from the Center for Disease Control and merged with patient census tract data, allowing the patient cohort to be divided into those living in areas identified as food secure (mRFEI > 10%), food swamps (mRFEI = 1-10%), or food deserts (mRFEI = 0). Postoperative weight change was evaluated with quadratic growth mixture models and stratified by surgery type. RESULTS: A total of 5097 patients were included in this study cohort, including 3424 patients who underwent RYGB and 1673 who underwent SG. The median duration of follow-up was 2.3 years (IQR 0.89-3.6 years). Food security status was not associated with postoperative weight change (RYGB p = 0.73, SG p = 0.60), weight loss nadir (RYGB p = 0.60, SG p = 0.79), or weight regain (RYGB p = 0.93, SG p = 0.85). Deficiencies in nutritional markers at 1-2 years after surgery were also not significantly different between food security groups. CONCLUSION: Despite the established relationship between food insecurity and obesity, food insecurity does not negatively impact weight loss or nutritional outcomes following RYGB or SG, demonstrating metabolic surgery as a powerful and equitable tool for treating obesity. LEVEL OF EVIDENCE: IV.

Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity.

Importance: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk. Objective: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity. Design, Setting, and Participants: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021. Exposures: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265). Main Outcomes and Measures: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality. Results: The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01). Conclusions and Relevance: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.

Metabolic surgery: A clinical update.

Metabolic and bariatric surgery has grown beyond 'experimental' weight-loss surgery. As techniques have advanced over the last few decades, so has the growing body of research and evidence, proving that both weight-loss and metabolic health improvement are induced. Metabolic surgery has become the more appropriate term for weight-loss surgery because of the altered gastrointestinal anatomy and subsequent beneficial metabolic effects. Although the tool of metabolic surgery has been well refined, a large portion of the global population does not have adequate access to it. This clinical update aims to (a) inform healthcare providers from all disciplines about the myriad of benefits of metabolic surgery and (b) equip them with the necessary knowledge to bridge the gap between patients in need of metabolic treatment and the therapies in metabolic surgery available to them.

Metabolic effects of duodenojejunal bypass surgery in a rat model of type 1 diabetes.

BACKGROUND: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. METHODS: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n = 15) or sham (n = 15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. RESULTS: Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g, P = 0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham, P = 0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin-positive cells in the pancreas. DJB rats needed 1.3 ± 0.4 insulin implants vs 1.9 ± 0.5 in sham rats (P = 0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases in Akkermansia and Ruminococcus, while the changes were minimal in sham rats. CONCLUSION: DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome.

Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.

IMPORTANCE: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH). OBJECTIVE: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021. EXPOSURES: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care. MAIN OUTCOMES AND MEASURES: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework. RESULTS: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2). CONCLUSIONS AND RELEVANCE: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE.

Increased survivability of ischemic skin flap tissue in Flk-1+/- mice by Pellino-1 intervention.

OBJECTIVE: Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia. METHODS: Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/- mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis. RESULTS: Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/- mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis. CONCLUSION: Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.

Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice.

BACKGROUND: Sepsis is a leading cause of mortality among patients in intensive care units across the USA. Thioredoxin-1 (Trx-1) is an essential 12 kDa cytosolic protein that, apart from maintaining the cellular redox state, possesses multifunctional properties. In this study, we explored the possibility of controlling adverse myocardial depression by overexpression of Trx-1 in a mouse model of severe sepsis. METHODS: Adult C57BL/6J and Trx-1Tg/+ mice were divided into wild-type sham (WTS), wild-type cecal ligation and puncture (WTCLP), Trx-1Tg/+sham (Trx-1Tg/+S), and Trx-1Tg/+CLP groups. Cardiac function was evaluated before surgery, 6 and 24 hours after CLP surgery. Immunohistochemical and Western blot analysis were performed after 24 hours in heart tissue sections. RESULTS: Echocardiography analysis showed preserved cardiac function in the Trx-1Tg/+ CLP group compared with the WTCLP group. Similarly, Western blot analysis revealed increased expression of Trx-1, heme oxygenase-1 (HO-1), survivin (an inhibitor of apoptosis [IAP] protein family), and decreased expression of thioredoxin-interacting protein (TXNIP), caspase-3, and 3- nitrotyrosine in the Trx-1Tg/+CLP group compared with the WTCLP group. Immunohistochemical analysis showed reduced 4-hydroxynonenal, apoptosis, and vascular leakage in the cardiac tissue of Trx-1Tg/+CLP mice compared with mice in the WTCLP group. CONCLUSIONS: Our results indicate that overexpression of Trx-1 attenuates cardiac dysfunction during CLP. The mechanism of action may involve reduction of oxidative stress, apoptosis, and vascular permeability through activation of Trx-1/HO-1 and anti-apoptotic protein survivin.

Reactive oxygen species-caspase-3 relationship in mediating blood-brain barrier endothelial cell hyperpermeability following oxygen-glucose deprivation and reoxygenation.

OBJECTIVE: Microvascular hyperpermeability that occurs due to breakdown of the BBB is a major contributor of brain vasogenic edema, following IR injury. In microvascular endothelial cells, increased ROS formation leads to caspase-3 activation following IR injury. The specific mechanisms, by which ROS mediates microvascular hyperpermeability following IR, are not clearly known. We utilized an OGD-R in vitro model of IR injury to study this. METHODS: RBMEC were subjected to OGD-R in presence of a caspase-3 inhibitor Z-DEVD, caspase-3 siRNA or an ROS inhibitor L-AA. Cytochrome c levels were measured by ELISA and caspase-3 activity was measured fluorometrically. TJ integrity and cytoskeletal assembly were studied using ZO-1 immunofluorescence and rhodamine phalloidin staining for f-actin, respectively. RESULTS: OGD-R significantly increased monolayer permeability, ROS formation, cytochrome c levels, and caspase-3 activity (p < 0.05) and induced TJ disruption and actin stress fiber formation. Z-DEVD, L-AA and caspase-3 siRNA significantly attenuated OGD-R-induced hyperpermeability (p < 0.05) while only L-AA decreased cytochrome c levels. Z-DEVD and L-AA protected TJ integrity and actin cytoskeletal assembly. CONCLUSIONS: These results suggest that OGD-R-induced hyperpermeability is ROS and caspase-3 dependent and can be regulated by their inhibitors.

Adverse Cardiovascular Outcomes in Patients With Obstructive Sleep Apnea and Obesity: Metabolic Surgery vs Usual Care.

BACKGROUND: No therapy has been shown to reduce the risk of major adverse cardiovascular events (MACE) and death in patients with obstructive sleep apnea (OSA). OBJECTIVES: The authors sought to investigate the long-term relationship between metabolic surgery and incident MACE in patients with OSA and obesity. METHODS: Adult patients with a body mass index 35 to 70 kg/m2 and moderate-to-severe OSA at a U.S. health system (2004-2018) were identified. Baseline characteristics of patients who underwent metabolic surgery were balanced with a nonsurgical control group using overlap-weighting methods. Multivariable Cox regression analysis estimated time-to-incident MACE. Follow-up ended in September 2022. RESULTS: A total of 13,657 patients (7,496 [54.9%] men; mean age 52.0 ± 12.4 years; median body mass index 41.0 kg/m2 [Q1-Q3: 37.6-46.2 kg/m2]), including 970 patients in the metabolic surgery group and 12,687 patients in the nonsurgical group, with a median follow-up of 5.3 years (Q1-Q3: 3.1-8.4 years) were analyzed. The mean between-group difference in body weight at 10 years was 26.6 kg (95% CI: 25.6-27.6 kg) or 19.3% (95% CI: 18.6%-19.9%). The 10-year cumulative incidence of MACE was 27.0% (95% CI: 21.6%-32.0%) in the metabolic surgery group and 35.6% (95% CI: 33.8%-37.4%) in the nonsurgical group (adjusted HR: 0.58 [95% CI: 0.48-0.71]; P < 0.001). The 10-year cumulative incidence of all-cause mortality was 9.1% (95% CI: 5.7%-12.4%) in the metabolic surgery group and 12.5% (95% CI: 11.2%-13.8%) in the nonsurgical group (adjusted HR: 0.63 [95% CI: 0.45-0.89]; P = 0.009). CONCLUSIONS: Among patients with moderate-to-severe OSA and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MACE and death.

Impact of Bariatric Surgery on Left Ventricular Structure and Function.

BACKGROUND: Obesity leads to an increased risk of cardiovascular disease morbidity and death, including heart failure. Bariatric surgery has been proven to be the most effective long-term weight management treatment. This study investigated the changes in cardiac structure and function after bariatric surgery, including left ventricular global longitudinal strain. METHODS AND RESULTS: There were 398 consecutive patients who underwent bariatric surgery with pre- and postoperative transthoracic echocardiographic imaging at a US health system between 2004 and 2019. We compared cardiovascular risk factors and echocardiographic parameters between baseline and follow-up at least 6 months postoperatively. Along with decreases in weight postoperatively, there were significant improvements in cardiovascular risk factors, including reduction in systolic blood pressure levels from 132 mm Hg (25th-75th percentile: 120-148 mm Hg) to 127 mm Hg (115-140 mm Hg; P=0.003), glycated hemoglobin levels from 6.5% (5.9%-7.6%) to 5.7% (5.4%-6.3%; P<0.001), and low-density lipoprotein levels from 97 mg/dL (74-121 mg/dL) to 86 mg/dL (63-106 mg/dL; P<0.001). Left ventricular mass decreased from 205 g (165-261 g) to 190 g (151-236 g; P<0.001), left ventricular ejection fraction increased from 58% (55%-61%) to 60% (55%-64%; P<0.001), and left ventricular global longitudinal strain improved from -15.7% (-14.3% to -17.5%) to -18.6% (-16.0% to -20.3%; P<0.001) postoperatively. CONCLUSIONS: This study has shown the long-term impact of bariatric surgery on cardiac structure and function, with reductions in left ventricular mass and improvement in left ventricular global longitudinal strain. These findings support the cardiovascular benefits of bariatric surgery.

Regulation of tumor necrosis factor-α-induced microvascular endothelial cell hyperpermeability by recombinant B-cell lymphoma-extra large.

BACKGROUND: Tumor necrosis factor-α (TNF-α), a cytotoxic cytokine, induces endothelial cell barrier dysfunction and microvascular hyperpermeability, leading to tissue edema, a hallmark of traumatic injuries. The objective of the present study was to determine whether B-cell lymphoma-extra large (Bcl-xL), an antiapoptotic protein, would regulate and protect against TNF-α-mediated endothelial cell barrier dysfunction and microvascular hyperpermeability. METHODS: Rat lung microvascular endothelial cells were grown as monolayers on Transwell membranes, and fluorescein isothiocyanate-bovine albumin flux (5 mg/mL) across the monolayer was measured fluorometrically to indicate changes in monolayer permeability. The rat lung microvascular endothelial cell adherens junctional integrity and actin cytoskeleton was studied using ß-catenin immunofluorescence and rhodamine phalloidin dye, respectively. Pretreatment of caspase-8 inhibitor (Z-IETD-FMK, 100 µM) for 1 hour and transfection of Bcl-2-homology domain 3-interacting domain death agonist small interfering RNA (10 µM) for 48 hours were performed to study their respective effects on TNF-α-induced (10 ng/mL; 1-hour treatment) monolayer permeability. Recombinant Bcl-xL protein (2.5 µg/ml) was transfected in rat lung microvascular endothelial cells for 1 hour, and its effect on permeability was demonstrated using a permeability assay. Caspase-3 activity was assayed fluorometrically. RESULTS: Z-IETD-FMK pretreatment protected the adherens junctions and decreased TNF-α-induced monolayer hyperpermeability. Bcl-2-homology domain 3-interacting domain death agonist small interfering RNA transfection attenuated the TNF-α-induced increase in monolayer permeability. Recombinant Bcl-xL protein showed protection against TNF-α-induced actin stress fiber formation, an increase in caspase-3 activity, and monolayer hyperpermeability. CONCLUSIONS: Our results have demonstrated the protective effects of recombinant Bcl-xL protein against TNF-α-induced endothelial cell adherens junction damage and microvascular endothelial cell hyperpermeability. These findings support the potential for Bcl-xL-based drug development against microvascular hyperpermeability and tissue edema.

Obesity-associated cancer risk reduction after metabolic surgery: insights from the SPLENDID study and the path forward.

Obesity incidence continues to rise globally along with obesity-associated conditions, which heavily burden individuals' quality of life and healthcare systems. Evidence regarding the power of metabolic and bariatric surgery to treat obesity has, fortunately, brought to light how substantial and sustained weight loss can mitigate adverse clinical outcomes of obesity and metabolic disease. Obesity-associated cancer has been an important focus of studies in recent decades to further elucidate what impact metabolic surgery could have on incidence of cancer and cancer-related mortality. The SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) study is one of the recent large cohort studies that highlights the power of substantial weight loss and the long-term benefits to patients with obesity in preventing cancer. This review of SPLENDID aims to highlight both consistency of results with prior studies and new findings unexplored previously.

How much narcotics are really needed after bariatric surgery: results of a prospective study.

BACKGROUND: To mitigate the opioid crisis, physicians are reevaluating opioid prescribing patterns. OBJECTIVES: To evaluate outcomes of maximal opioid reduction on top of an existing Enhanced Recovery after Surgery (ERAS) pathway in our The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited bariatric surgery program. SETTING: Academic tertiary care hospital, United States. METHODS: Patients undergoing primary bariatric operation were studied from July 2017 to April 2019, (standard ERAS cohort), and compared to patients from April 2019 to February 2021 (standard ERAS with Sparing Opioid Use Postoperatively protocol) (SOUP cohort). The primary endpoint was reduction of perioperative opioid use. RESULTS: Of 367 patients, 212 (57.8%) and 155 (42.2%) were in the ERAS and SOUP cohorts, respectively. Roux-en-Y gastric bypass was 48.6% (n = 103) versus 54.2% (n = 84) and sleeve gastrectomy was 51.4% (n = 109) versus 45.8% (n = 71) for ERAS versus SOUP, respectively (P = .29). The SOUP cohort of patients required a low median inpatient morphine equivalent dose of 4 mg [0-6.2]. The ERAS cohort was discharged on a higher morphine equivalent dose than the SOUP cohort at 186.7 mg ± 92.9 versus 37.6 ± 32.3 (P < .05), and median consumption of the standard 5 mg oxycodone tablet was 1.5 tablets [0-4]. The SOUP cohort patients rated their pain satisfaction score on a scale of 1 to 10 at 9.1 points (standard deviation ± 1.8). The SOUP cohort had a shorter length of stay (P < .05), with comparable readmission rates. CONCLUSIONS: An opioid-sparing protocol can be implemented after bariatric surgery with high overall satisfaction with pain control.

Role of Pellino-1 in Inflammation and Cardioprotection following Severe Sepsis: A Novel Mechanism in a Murine Severe Sepsis Model †.

OBJECTIVES: Intra-abdominal sepsis is commonly diagnosed in the surgical population and remains the second most common cause of sepsis overall. Sepsis-related mortality remains a significant burden in the intensive care unit despite advances in critical care. Nearly a quarter of the deaths in people with heart failure are caused by sepsis. We have observed that overexpression of mammalian Pellino-1 (Peli1), an E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Given these manifold applications, we investigated the role of Peli1 in sepsis using transgenic and knockout mouse models specific to this protein. Therefore, we aimed to explore further the myocardial dysfunction seen in sepsis through its relation to the Peli 1 protein by using the loss of function and gain-of-function strategy. METHODS: A series of genetic animals were created to understand the role of Peli1 in sepsis and the preservation of heart function. Wild-type, global Peli1 knock out (Peli1-/-), cardiomyocyte-specific Peli1 deletion (CP1KO), and cardiomyocyte-specific Peli1 overexpressing (alpha MHC (αMHC) Peli1; AMPEL1Tg/+) animals were divided into sham and cecal ligation and puncture (CLP) surgical procedure groups. Cardiac function was determined by two-dimensional echocardiography pre-surgery and at 6- and 24-h post-surgery. Serum IL-6 and TNF-alpha levels (ELISA) (6 h), cardiac apoptosis (TUNEL assay), and Bax expression (24 h) post-surgery were measured. Results are expressed as mean ± S.E.M. RESULTS: AMPEL1Tg/+ prevents sepsis-induced cardiac dysfunction assessed by echocardiographic analysis, whereas global and cardiomyocyte-specific deletion of Peli1 shows significant deterioration of cardiac functions. Cardiac function was similar across the sham groups in all three genetically modified mice. ELISA assay displayed how Peli 1 overexpression decreased cardo-suppressive circulating inflammatory cytokines (TNF-alpha, IL-6) compared to both the knockout groups. The proportion of TUNEL-positive cells varied according to Peli1 expression, with overexpression (AMPEL1Tg/+) leading to a significant reduction and Peli1 gene knockout (Peli1-/- and CP1KO) leading to a significant increase in their presence. A similar trend was also observed with Bax protein expression. The improved cellular survival associated with Peli1 overexpression was again shown with the reduction of oxidative stress marker 4-Hydroxy-2-Nonenal (4-HNE). CONCLUSION: Our results indicate that overexpression of Peli1 is a novel approach that not only preserved cardiac function but reduced inflammatory markers and apoptosis following severe sepsis in a murine genetic model.

Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and ß-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery. RESEARCH DESIGN AND METHODS: A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin <6.5% [48 mmol/mol] off medications). RESULTS: Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04-3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. CONCLUSIONS: This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity: Comparison of Gastric Bypass, Sleeve Gastrectomy, and Usual Care.

OBJECTIVE: To determine which one of the two most common metabolic surgical procedures is associated with greater reduction in risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and obesity. RESEARCH DESIGN AND METHODS: A total of 13,490 patients including 1,362 Roux-en-Y gastric bypass (RYGB), 693 sleeve gastrectomy (SG), and 11,435 matched nonsurgical patients with T2DM and obesity who received their care at the Cleveland Clinic (1998-2017) were analyzed, with follow-up through December 2018. With multivariable Cox regression analysis we estimated time to incident extended MACE, defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality. RESULTS: The cumulative incidence of the primary end point at 5 years was 13.7% (95% CI 11.4-15.9) in the RYGB groups and 24.7% (95% CI 19.0-30.0) in the SG group, with an adjusted hazard ratio (HR) of 0.77 (95% CI 0.60-0.98, P = 0.04). Of the six individual end points, RYGB was associated with a significantly lower cumulative incidence of nephropathy at 5 years compared with SG (2.8% vs. 8.3%, respectively; HR 0.47 [95% CI 0.28-0.79], P = 0.005). Furthermore, RYGB was associated with a greater reduction in body weight, glycated hemoglobin, and use of medications to treat diabetes and cardiovascular diseases. Five years after RYGB, patients required more upper endoscopy (45.8% vs. 35.6%, P < 0.001) and abdominal surgical procedures (10.8% vs. 5.4%, P = 0.001) compared with SG. CONCLUSIONS: In patients with obesity and T2DM, RYGB may be associated with greater weight loss, better diabetes control, and lower risk of MACE and nephropathy compared with SG.

A Structured Approach for Safely Reintroducing Bariatric Surgery in a COVID-19 Environment.

Due to the profound effect of novel coronavirus disease 2019 (COVID-19) on healthcare systems, surgical programs across the country have paused surgical operations and have been utilizing virtual visits to help maintain public safety. For those who treat obesity, the importance of bariatric surgery has never been more clear. Emerging studies continue to identify obesity and several other obesity-related comorbid conditions as major risk factors for a more severe COVID-19 disease course. However, this also suggests that patients seeking bariatric surgery are inherently at risk of suffering severe complications if they were to contract COVID-19 in the perioperative period. The aim of this protocol is to utilize careful analysis of existing risk stratification for bariatric patients, novel COVID-19-related data, and consensus opinion from multiple academic bariatric centers within our organization to help guide the reanimation of our programs when appropriate and to use this template to prospectively study this risk-stratified population in real time. The core principles of this protocol can be applied to any surgical specialty.