Hypoxia-Inducible Factor 1α Stabilization Restores Epigenetic Control of Nitric Oxide Synthase 1 Expression and Reverses Gastroparesis in Female Diabetic Mice.

BACKGROUND & AIMS: Although depletion of neuronal nitric oxide synthase (NOS1)-expressing neurons contributes to gastroparesis, stimulating nitrergic signaling is not an effective therapy. We investigated whether hypoxia-inducible factor 1α (HIF1A), which is activated by high O2 consumption in central neurons, is a Nos1 transcription factor in enteric neurons and whether stabilizing HIF1A reverses gastroparesis. METHODS: Mice with streptozotocin-induced diabetes, human and mouse tissues, NOS1+ mouse neuroblastoma cells, and isolated nitrergic neurons were studied. Gastric emptying of solids and volumes were determined by breath test and single-photon emission computed tomography, respectively. Gene expression was analyzed by RNA-sequencing, microarrays, immunoblotting, and immunofluorescence. Epigenetic assays included chromatin immunoprecipitation sequencing (13 targets), chromosome conformation capture sequencing, and reporter assays. Mechanistic studies used Cre-mediated recombination, RNA interference, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated epigenome editing. RESULTS: HIF1A signaling from physiological intracellular hypoxia was active in mouse and human NOS1+ myenteric neurons but reduced in diabetes. Deleting Hif1a in Nos1-expressing neurons reduced NOS1 protein by 50% to 92% and delayed gastric emptying of solids in female but not male mice. Stabilizing HIF1A with roxadustat (FG-4592), which is approved for human use, restored NOS1 and reversed gastroparesis in female diabetic mice. In nitrergic neurons, HIF1A up-regulated Nos1 transcription by binding and activating proximal and distal cis-regulatory elements, including newly discovered super-enhancers, facilitating RNA polymerase loading and pause-release, and by recruiting cohesin to loop anchors to alter chromosome topology. CONCLUSIONS: Pharmacologic HIF1A stabilization is a novel, translatable approach to restoring nitrergic signaling and treating diabetic gastroparesis. The newly recognized effects of HIF1A on chromosome topology may provide insights into physioxia- and ischemia-related organ function.

Lumen-apposing metal stents for the treatment of benign gastrointestinal tract strictures: a single-center experience and proposed treatment algorithm.

BACKGROUND: Lumen-apposing metal stents (LAMS) are an alternative therapeutic option for benign gastrointestinal (GI) tract strictures. Our study aimed to evaluate the safety and efficacy of LAMS for the management of benign GI strictures. METHODS: Consecutive patients who underwent a LAMS placement for benign luminal GI strictures at a tertiary care center between January 2014 and July 2021 were reviewed. Primary outcomes included technical success, early clinical success, and adverse events (AEs). Other outcomes included rates of stent migration and re-intervention after LAMS removal. RESULTS: One hundred and nine patients who underwent 128 LAMS placements (67.9% female, mean age of 54.3 ± 14.2 years) were included, and 70.6% of the patients had failed prior endoscopic treatments. The majority of strictures (83.5%) were anastomotic, and the most common stricture site was the gastrojejunal anastomosis (65.9%). Technical success was achieved in 100% of procedures, while early clinical success was achieved in 98.4%. The overall stent-related AE rate was 25%. The migration rate was 27.3% (35/128). Of these, five stents were successfully repositioned endoscopically. The median stent dwell time was 119 days [interquartile range (IQR) 68-189 days], and the median follow-up duration was 668.5 days [IQR: 285.5-1441.5 days]. The re-intervention rate after LAMS removal was 58.3%. CONCLUSIONS: LAMS is an effective therapeutic option for benign GI strictures, offering high technical and early clinical success. However, the re-intervention rate after LAMS removal was high. In select cases, using LAMS placement as destination therapy with close surveillance is a reasonable option.

Ten year comparative analysis of sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch in patients with BMI ≥ 50 kg/m2.

INTRODUCTION: Bariatric surgery is the most effective modality to stably reduce weight and related comorbidities in patients suffering from class II and III obesity. Data comparing long-term safety and efficacy of the three most effective bariatric operations are limited in patients with BMI ≥ 50 kg/m2, which complicate shared surgeon-patient decision making regarding optimal procedure selection. METHODS: A retrospective analysis was performed on all patients with BMI ≥ 50 kg/m2 who underwent biliopancreatic diversion with duodenal switch (BPD/DS), Roux-en-Y gastric bypass (RYGB), or sleeve gastrectomy (SG) at our institution between 2009 and 2019. Data collected from patients' electronic medical records included operative details as well as BMI and presence and resolution of obesity-related comorbidities at 0, 6, 12, 24, 48, and 60 months post-operatively. RESULTS: Among 537 patients with BMI ≥ 50 kg/m2 who had a primary bariatric procedure, 93 patients underwent BPD/DS (17.3%), 341 patients underwent RYGB (63.5%), and 103 patients underwent SG (19.2%). BMI decreased by 23.7 kg/m2 in BPD/DS, 14.7 kg/m2 in RYGB, and 13.6 kg/m2 in SG cohorts at 60 months post-operatively (p < 0.0001). The greatest %TWL occurred in BPD/DS cohort (38.4%) followed by the RYGB (26.3%) and SG (23.6%) cohorts (p < 0.0001). The thirty-day complication rate was 12.9% for BPD/DS, 4.7% for RYGB, and 8.7% for SG (p = 0.015). CONCLUSIONS: Our study demonstrated that the BPD/DS is the most effective operation at long-term reduction of BMI and achieved highest %TWL while SG and RYGB had similar results at 60 months post-op. BPD/DS is associated with increased early and late surgical complications compared to RYGB and SG.

The Role of Three-Dimensional Magnetic Resonance Elastography in the Diagnosis of Nonalcoholic Steatohepatitis in Obese Patients Undergoing Bariatric Surgery.

The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three-dimensional magnetic resonance elastography (3D-MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D-MRE (mf3D-MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI-PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D-MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D-MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI-PDFF correlated with steatosis (P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross-validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross-validated AUROC = 0.82. Conclusion: The mf3D-MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.

Endoscopic management of refractory leaks and fistulas after bariatric surgery with long-term follow-up.

BACKGROUND: In selected cases of post-bariatric leaks and fistulas, endoscopy is an initial treatment modality. Management can be complex and require multiple endoscopic sessions with varying degrees of success. Our aim was to describe our tertiary care experience on endoscopy management of refractory post-bariatric leaks and fistulas. METHODS: Patients with post-bariatric leaks and/or fistulas who failed an initial endoscopic intervention were included. Endoscopic treatments were classified into four strategies: (1) closure management, (2) active drainage, (3) passive drainage, and (4) plugging. Clinical success and adverse events were assessed. RESULTS: A total of 25 patients (mean age = 45.3 ± 11.8 years and 56% female) were included. Clinical success was achieved in 20 patients (80%) with a mean of 3.0 ± 1.5 procedures and a median time to healing of 114.5 (53-210.3) days. Closure and plugging were the main successful strategies used for early and acute leaks/fistulas, while drainage was for late and chronic leaks/fistulas. Adverse events were observed in 13 patients (52%) with one serious adverse event. Patients with fistulas had a lower success rate (72.2% vs. 100%, P = 0.052). Of those with clinical failure (n = 5), four underwent reconstructive surgery, eventually led to success in 3 patients. The other one died of septic shock related to a complicated fistula. CONCLUSIONS: Complex multi-modality endoscopic management ultimately achieved clinical success in most cases of refractory leaks/fistulas post-bariatric with an acceptable safety profile. However, a close follow-up to detect the development of long-term failure is warranted. These patients should be referred to a specialized bariatric center with expertise in bariatric endoscopy and surgery.

Endoscopic management of dumping syndrome after Roux-en-Y gastric bypass: a large international series and proposed management strategy.

BACKGROUND AND AIMS: Roux-en-Y gastric bypass (RYGB) is refractory to lifestyle and pharmacotherapy measures, requiring reversal of the patient's bariatric surgery. Reversal can lead to weight regain and recrudescence of their comorbidities. Our aim was to report a multicenter experience on the endoscopic management of refractory dumping syndrome with endoscopic transoral outlet reduction (TORe). METHODS: A multicenter international series of consecutive patients who underwent TORe with a full-thickness endoscopic suturing device was analyzed for technical success, improvement in Sigstad scores, and weight trajectories after the procedure. Failure was defined as needing an enteral feeding tube, surgical reversal, or repeat TORe. RESULTS: One hundred fifteen patients across 2 large academic centers in Germany and the United States underwent TORe for dumping syndrome. Patient age was mean 8.9 ± 1.1 years from their initial RYGB with an average percent total body weight loss of 31% ± 10.6% at the time of endoscopy. Three months postprocedure, the Sigstad score improved from a mean of 17 ± 6.1 to 2.6 ± 1.9 (paired t test P = .0001) with only 2% of patients (n = 2) experiencing weight gain. Mean weight loss and percentage of total body weight loss 3 months post-TORe were 9.47 ± 3.6 kg and 9.47% ± 2.5%, respectively. Six patients (5%) failed initial endoscopic therapy, with 50% (n = 3) successfully treated with a repeat TORe. Three patients underwent surgical reversal, indicating an overall 97% endoscopic success rate. CONCLUSIONS: TORe as an adjunct to lifestyle and pharmacologic therapy for refractory dumping syndrome is safe and effective at improving dumping syndrome and reducing rates of surgical revision.

Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10-9; IG FDR = 6.3 × 10-12]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long-term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long-term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow-up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre-LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow-up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow-up. CONCLUSION: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow-up. (Hepatology 2018).

Transoral outlet reduction with full thickness endoscopic suturing for weight regain after gastric bypass: a large multicenter international experience and meta-analysis.

BACKGROUND AND AIMS: Many patients who undergo bariatric surgery will experience weight regain and effective strategies are needed to help these patients. A dilated gastrojejunal anastomosis (GJA) has been associated with weight recidivism after Roux-en-Y gastric bypass surgery (RYGB). Endoscopic transoral outlet reduction (TORe) with a full thickness endoscopic suturing device (Overstitch, Apollo Endosurgery, Austin, TX) is a minimally invasive therapeutic option. The primary aim of this project was to examine the safety and long-term efficacy data from three bariatric surgery centers and to conduct a systematic review and meta-analysis of the existing literature. METHODS: Patients who underwent TORe with the Overstitch device from Jan 2013 to Nov 2016 at 3 participating bariatric surgery centers were included in the multicenter analysis. For the systematic review and meta-analysis, a comprehensive search of multiple English databases was conducted. Random effects model was used. RESULTS: 130 consecutive patients across three centers underwent TORe with an endolumenal suturing device. These patients (mean age 47; mean BMI 36.8) had experienced 24.6% weight regain from nadir weight after RYGB. Average weight lost at 6, 12, and 18 months after TORe was 9.31 ± 6.7 kg (N = 84), 7.75 ± 8.4  kg (N = 70), 8 ± 8.8 kg (N = 46) (p < 0.01 for all three time points), respectively. The meta-analysis included 330 patients. The pooled weight lost at 12 months was 8.4 kg (95% CI 6.5-10.3) with no significant heterogeneity across included studies (p = 0.07). Overall, 14% of patients experienced nausea, 18% had pain and 8% required a repeat EGD. No serious adverse events reported. CONCLUSION: When implemented as part of a multidisciplinary intervention, TORe using endolumenal suturing is safe, reproducible, and effective approach to manage weight recidivism after RYGB and should be utilized early in the management algorithm of these patients.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated under-nutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC, gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg i.p. BID for 3 weeks). Gastric ICC were analyzed by western blotting (WB) and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

Type-2 diabetes mellitus remission prediction models after Roux-En-Y gastric bypass and sleeve gastrectomy based on disease severity scores.

AIM: Metabolic and bariatric surgery (MBS) is considered one of the most effective interventions for weight loss and associated type-2 diabetes mellitus (T2DM) remission. Multiple scores including the Individualized Metabolic Surgery (IMS), DiaRem, advanced DiaRem, and Robert et al. scores, have been developed predict T2DM remission after MBS. We aim to validate each of these scores in our cohort of patients undergoing MBS with long-term follow-up and assess their efficacy based on procedure type and preoperative BMI. METHODS: We conducted a multicenter cohort study including patients with T2DM undergoing either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Areas under the receiver operating characteristics (ROC) curve (AUC) were calculated to assess the discriminatory ability of the four models to detect T2DM remission. RESULTS: A total of 503 patients (67 % females, mean age 53.5 [11] years, BMI 46.2 [8.8] kg/m2) with T2DM were included. The majority (78 %) underwent RYGB, while the rest (28 %) had SG. All four scores predicted T2DM remission in our cohort with an ROC AUC of 0.79 for IMS, 0.78 for both DiaRem and advanced-DiaRem, and 0.75 for Robert et al. score. Specific subgroups for each of these scores demonstrated higher T2DM remission rates after RYGB compared to SG. CONCLUSION: We demonstrate the ability of the IMS, DiaRem, advanced-DiaRem and Robert et al. scores to predict T2DM remission in patients undergoing MBS. T2DM remission rates was demonstrated to decrease with more severe IMS, DiaRem and advanced-DiaRem scores and lower Robert et al. scores.

Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis.

Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from the gastric tissue of 20 subjects. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.

Mucosal and hormonal adaptations after Roux-en-Y gastric bypass.

The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.

Telemedicine Video Follow-Up for Bariatric Surgery Patients: What Do Patients Prefer? A Prepandemic Pilot Randomized Clinical Trial.

While the safety of video follow-up in bariatric surgery is established, patients' perception of telemedicine visits remained unknown. A randomized clinical trial evaluating patients' perception of video postoperative follow-up (F/U) visits was conducted in the pre COVID-19 era. 24 patients were randomized in the preoperative clinic to receive either in-person or video F/U, and then surveyed about their experience and preference. The majority reported that if they had to do it over, they would prefer a video visit. Among those who received video visits, 11/12 reported that the lack of physical contact was acceptable. 82% of the video group expressed that their visit was better or as good as an in-person visit, while 9% were not sure, and 9% reported that video was worse. This finding suggests that postoperative video follow-up visits are acceptable among bariatric surgery patients and should be offered as an alternative to traditional visits.

Impact of Chronic Immunosuppression on Short-, Mid-, and Long-Term Bariatric Surgery Outcomes.

INTRODUCTION: Bariatric surgical outcomes depend heavily on proper healing of gastrointestinal anatomy, metabolic alterations, and patient lifestyle modifications which are all negatively impacted by immunosuppression and underlying inflammatory diseases. There is a lack of literature exploring how patients with diseases requiring immunosuppression respond to bariatric surgical intervention in the long term. METHODS: A retrospective analysis of chronically immunosuppressed patients who underwent primary bariatric surgeries at Mayo Clinic was conducted (2008-2020). Data collected included patient demographics, BMI, underlying disease, and immunosuppression regimen and complications at 3, 6, 12, 24, and 60 months. RESULTS: We identified a total of 89 (RYGB = 49, SG = 34, BPD/DS = 6) patients on chronic immunosuppression who underwent bariatric surgery at our center. RYGB (N = 49), 38.2% had a SG (N = 34) and 6.7% had a BPD/DS (N = 6). Rheumatoid arthritis and renal transplantation were the most underlying condition at 20.22% each (N = 18). There were a total of 2 (2.25%) intraoperative complications. In the immediate post-operative period, there were 15 (16.5%) minor complications. In follow-up, 6.1% of RYGB patients experienced marginal ulcerations, while no gastrointestinal leaks occurred. The mean pre-surgical BMI was 48.29 kg/m2 (SD = 18.41). Percent total weight loss (%TWL) and BMI reduction were 30.89% and 14.83 kg/m2 (SD = 9.07) at 12 months and 29.48% and 14.43 kg/m2 (SD = 13.46) at 60 months, respectively. The mean follow-up time was 30.49 months. CONCLUSIONS: Bariatric surgery remains safe and effective therapy for chronically immunosuppressed patients with excellent long-term outcomes for patients with moderate to severe obesity.

Insulin-Like Growth Factor1 Preserves Gastric Pacemaker Cells and Motor Function in Aging via ERK1/2 Activation.

BACKGROUND & AIMS: Impaired gastric motor function in the elderly causes reduced food intake leading to frailty and sarcopenia. We previously found that aging-related impaired gastric compliance was mainly owing to depletion of interstitial cells of Cajal (ICC), pacemaker cells, and neuromodulator cells. These changes were associated with reduced food intake. Transformation-related protein 53-induced suppression of extracellular signal-regulated protein kinase (ERK)1/2 in ICC stem cell (ICC-SC) cell-cycle arrest is a key process for ICC depletion and gastric dysfunction during aging. Here, we investigated whether insulin-like growth factor 1 (IGF1), which can activate ERK in gastric smooth muscles and invariably is reduced with age, could mitigate ICC-SC/ICC loss and gastric dysfunction in klotho mice, a model of accelerated aging. METHODS: Klotho mice were treated with the stable IGF1 analog LONG R3 recombinant human (rh) IGF1 (150 µg/kg intraperitoneally twice daily for 3 weeks). Gastric ICC/ICC-SC and signaling pathways were studied by flow cytometry, Western blot, and immunohistochemistry. Gastric compliance was assessed in ex vivo systems. Transformation-related protein 53 was induced with nutlin 3a and ERK1/2 signaling was activated by rhIGF-1 in the ICC-SC line. RESULTS: LONG R3 rhIGF1 treatment prevented reduced ERK1/2 phosphorylation and gastric ICC/ICC-SC decrease. LONG R3 rhIGF1 also mitigated the reduced food intake and impaired body weight gain. Improved gastric function by LONG R3 rhIGF1 was verified by in vivo systems. In ICC-SC cultures, rhIGF1 mitigated nutlin 3a-induced reduced ERK1/2 phosphorylation and cell growth arrest. CONCLUSIONS: IGF1 can mitigate age-related ICC/ICC-SC loss by activating ERK1/2 signaling, leading to improved gastric compliance and increased food intake in klotho mice.

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Transoral Outlet Reduction After Roux-en-Y Gastric Bypass: A Case-Control Study and Review of Literature.

BACKGROUND: Transoral outlet reduction (TORe) is a safe and effective technique for management of weight regain (WR) after Roux-en-Y Gastric Bypass (RYGB). Carriers of a heterozygous variant in the leptin melanocortin pathway (LMP) have been shown to be at high risk for WR in the mid- and long-term after RYGB. Our case series includes four patients with heterozygous LMP variants and presents novel data on their weight loss after TORe. METHODS: We performed a retrospective study of the Mayo Clinic Biobank and identified adult participants who had been genotyped and found to have or do not have a heterozygous variant in the LMP ("carriers" vs "non-carriers", respectively) and had undergone a TORe procedure. TBWL% at 1, 3, 6, 9, and 12 months ± 15 days were calculated based on baseline weight at TORe procedure. RESULTS: A total of 14 patients were included in the analysis: four patients (mean age 51.0 [5.2] years, 100% females, body mass index [BMI] 40.5 [8.7] kg/m2) with LMP variant and 10 non-carriers (age 55.4 [15.3] years, 90% females, BMI 37.3 [7.7] kg/m2). There were no baseline differences between carriers and non-carriers at time of TORe procedure. After TORE, carriers lost less weight when compared to non-carriers at 3, 6, 9, and 12 months. The difference at 12 months was statistically significant (1.6 vs 12.3%; p = 0.03). CONCLUSIONS: Patients with a LMP variant and that underwent RYGB showed decreased weight loss after undergoing TORe. Further and larger studies are needed to comprehend the effect of TORe on patients with LMP variants.

Positive Predictive Value for Multitarget Stool DNA After Bariatric and Metabolic Surgery.

BACKGROUND AND AIMS: Bariatric and metabolic surgery (BMS) may adversely affect noninvasive stool tests for colorectal cancer (CRC) screening through several mechanisms. Multitarget stool DNA (mt-sDNA) is approved for CRC screening; however, performance in post-BMS patients is unknown. As the rates of BMS are anticipated to increase with rising incidence of obesity, it is important to evaluate mt-sDNA test performance among these patients. METHODS: In a multisite academic and community-based practice, we obtained mt-sDNA results from 10/2014 to 12/2019 through electronic records and an institutional BMS registry. Average CRC risk patients with BMS prior to a positive mt-sDNA underwent a detailed chart review. Follow-up colonoscopy findings were compared to those among BMS patients screened with colonoscopy alone and a historical cohort of patients without BMS, screened by mt-sDNA. The primary study endpoint was the positive predictive value (PPV) for advanced colorectal neoplasia. RESULTS: Among 336 average-risk patients who had mt-sDNA after BMS, mt-sDNA was positive in 49 (14.6%), 47/49 (96%) underwent follow-up colonoscopy, and the PPV for advanced neoplasia was 12/47 (25.5%). This is similar to the PPV for advanced colorectal neoplasia (425/1542, 28%) in a historical cohort of persons without prior BMS, screened by mt-sDNA at our center (P = .86). Among those who had prior BMS, the rate of advanced neoplasia was higher after mt-sDNA compared to screening colonoscopy alone. CONCLUSION: Despite anatomic and physiologic mechanisms that could alter blood or DNA content in stool, BMS does not appear to adversely affect the PPV of mt-sDNA.

Human Obesity Attenuates Cardioprotection Conferred by Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells.

To explore the impact of obesity on reparative potency of adipose tissue-derived mesenchymal stromal/stem cells (A-MSC) in hypertensive cardiomyopathy, A-MSC were harvested from subcutaneous fat of obese and age-matched non-obese human subjects during bariatric or kidney donation surgeries, and then injected into mice 2 weeks after inducing renovascular hypertension (RVH) or sham surgery. Two weeks later, left ventricular (LV) function and deformation were estimated in vivo by micro-magnetic resonance imaging and myocardial damage ex vivo. Blood pressure and myocardial wall thickening were elevated in RVH + Vehicle and normalized only by lean-A-MSC. Both A-MSC types reduced LV mass and normalized the reduced LV peak strain radial in RVH, yet obese-A-MSC also impaired LV systolic function. A-MSC alleviated myocardial tissue damage in RVH, but lean-A-MSC decreased oxidative stress more effectively. Obese-A-MSC also showed increased cellular inflammation in vitro. Therefore, obese-A-MSC are less effective than lean-A-MSC in blunting hypertensive cardiomyopathy in mice with RVH.

Bariatric surgery outcomes in patients with bipolar or schizoaffective disorders.

BACKGROUND: Obesity is associated with many co-morbidities and can cause harm to physical and mental well-being. While much has been studied in the general population about the outcomes of bariatric surgery, its implications in patients with bipolar/schizoaffective disorder (BSD) are less well understood. OBJECTIVE: We aimed to describe outcomes of bariatric surgery in patients with BSD. SETTING: Referral center for bariatric surgery. METHODS: We conducted a retrospective chart review analysis of bariatric surgical procedures in patients with BSD between 2008 and 2021 at Mayo Clinic. Patients with BSD (cases) were matched via propensity score matching (1:2) with non-BSD controls based on surgical procedure, age, sex, body mass index, and type 2 diabetes. Hierarchical logistic regression model was performed using SAS software. RESULTS: We matched 71 patients with BSD with 142 controls in a 1:2 ratio. After adjusting for baseline preoperative weight, patients with BSD had a 3.4% greater total weight loss compared with controls over 24 months (P = .02 [95% CI, .65-6.08]). Remission in obesity-related diseases, such as diabetes, hypertension, dyslipidemia, and sleep apnea, was similar in both groups. Perioperative complication rates were similar other than deep venous thrombosis, which showed a higher rate in patients with BSD (P = .04). Patients with long-term BSD were at increased risk of alcohol use compared with controls. CONCLUSIONS: When compared with the general bariatric population, weight loss was similar to slightly improved, with a comparable risk and complication profile. Patients with BSD have increased alcohol use after bariatric surgery, highlighting the need for psychological care before and after surgery in this population.