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.

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.

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.

Type 2 diabetes remission after Roux-en-Y gastric bypass: a multicentered experience with long-term follow-up.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is associated with short- and mid-term type 2 diabetes (T2D) remission. Long-term outcomes and predictive parameters associated with remission following RYGB have not been well elucidated. OBJECTIVE: Determining the overall long-term T2D remission rates following RYGB and identifying predictive variables associated with remission. SETTING: Multicentered study including patients who underwent RYGB at 3 tertiary referral centers for bariatric surgery. METHODS: We performed a retrospective cohort study between 2008-2017 to allow a minimum of 5 years of follow-up. We evaluated long-term T2D remission rates and annual T2D clinical and metabolic parameters up to 14 years after surgery. Predictors of remission were assessed using multivariate logistic regression. Patients were divided into 4 groups based on quartiles of total body weight loss percentage (%TBWL) to compare remission rates between groups. RESULTS: A total of 815 patients were included (68.9% female, age 52.1 ± 11.5 yr; body mass index 45.1 ± 7.7 kg/m2) with a follow-up of 7.3 ± 3.8 years. Remission was demonstrated in 51% of patients. Predictors of remission included pre-operative duration of diabetes, baseline HbA1C, insulin use prior to surgery, number of antidiabetic medications and %TBWL (all P < .01). Remission rates were proportionally associated with %TBWL quartile (Q1, 40.9%; Q2, 52.7%; Q3, 53.1%; Q4, 56.1%) (P = .02). CONCLUSIONS: Longer duration and higher severity of T2D were negatively associated with remission while higher %TBWL had a positive association. A significant proportion of patients in all quartiles experienced long-term remission after RYGB with a greater likelihood of remission correlated with greater weight loss.

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.

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.

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.

Feasibility and Outcomes of Simultaneous Gastric Bypass with Paraesophageal Hernia Repair in Elderly Patients.

BACKGROUND: Paraesophageal hernias (PEH) have a higher incidence in patients with obesity. Roux-en-Y gastric bypass (RYGB) with concomitant PEH repair is established as a valid surgical option for PEH management in patients with obesity. The safety and feasibility of this approach in the elderly population are not well elucidated. METHODS: We performed a multicenter retrospective cohort study of patients aged 65 years and older who underwent simultaneous PEH repair and RYGB from 2008 to 2022. Patient demographics, hernia characteristics, postoperative complications, and weight loss data were collected. Obesity-related medical conditions' resolution rates were evaluated at the last follow-up. A matched paired t-test and Pearson's test were used to assess continuous and categorical parameters, respectively. RESULTS: A total of 40 patients (82.5% female; age, 69.2 ± 3.6 years; BMI, 39.4 ± 4.7 kg/m2) with a mean follow-up of 32.3 months were included. The average hernia size was 5.8 cm. Most cases did not require mesh use during surgery (92.5%) with only 3 (7.5%) hernial recurrences. Postoperative complications (17.5%) and mortality rates (2.5%), as well as readmission (2.5%), reoperation (2.5%), and reintervention (0%) rates at 30-day follow-up were reported. There was a statistically significant resolution in gastroesophageal reflux disease (p < 0.001), hypertension (p = 0.019), and sleep apnea (p = 0.014). CONCLUSIONS: The safety and effectiveness of simultaneous PEH repair and RYGB are adequate for the elderly population. Patient selection is crucial to reduce postoperative complications. Further studies with larger cohorts are needed to fully assess the impact of this surgery on elderly patients with 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.

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.

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.

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.

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.

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.

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study.

INTRODUCTION: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. METHODS: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB. RESULTS: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m2, and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8). CONCLUSIONS: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.

Bariatric Surgery in Patients with Existing Ostomy: A Preliminary Feasibility Study.

Background: Bariatric surgery is the most effective treatment for weight loss and obesity-related comorbidity resolution. However, bariatric surgery is not readily offered in specific populations due to the lack of data assessing its feasibility. This study intends to evaluate bariatric surgery in patients with an existing ostomy. Methods: We conducted a retrospective case series to assess the safety of Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in patients with an end ileostomy or colostomy. Patient demographics, including obesity-related comorbidities, overall health status (American Society of Anesthesiologists score), and short-term complications (up to 30 days postoperatively), were analyzed. Results: Six patients were included. The mean age was 58 years, and the mean preoperative body mass index was 41.6. Three patients had a colostomy, and three had an ileostomy. The mean time of ostomy before surgery was 11 years. Two ostomies were due to trauma, two due to inflammatory bowel disease, one due to cancer, and one due to scleroderma. Mean postoperative follow-up was 23 months. No patient had increased ostomy output or infusion center visit. One patient had an ED visit, one had a short-term complication, and one had SG conversion to RYGB. Conclusions: Bariatric surgery is technically feasible in selected patients with ileostomy/colostomy with a reasonable short-term safety profile.

Does BMI Matter? A 10-Year Single Institutional Experience on 571 Bariatric Surgery Patients With BMI >50 kg/m 2.

INTRODUCTION: Patients undergoing bariatric surgery with body mass index (BMI) >50 kg/m 2 are at a higher risk of surgical morbidity when compared with less obese patients, however, there is limited data correlating surgical risk and efficacy with increasing BMI in patients with severe obesity. We hypothesize that regardless of the degree above 50 kg/m 2 their BMI, patients with severe obesity respond similarly to bariatric surgery. MATERIALS AND METHODS: We performed a retrospective analysis of patients with BMI >50 kg/m 2 who underwent biliopancreatic diversion with duodenal switch, Roux-en-Y gastric bypass, or sleeve gastrectomy at a single institution. Outcomes were compared in patients with a BMI between 50 and 60 kg/m 2 to patients with a BMI >60 kg/m 2 and included percent total weight loss as well as early and late complications. Statistical analyses were performed using logistic regression, univariate, and multivariate models. RESULTS: There were 571 patients with BMI >50 kg/m 2 who underwent bariatric surgery at our center, 170 (29.8%) had a BMI >60 kg/m 2 . Percent total weight loss was statistically significant between the BMI 50 and 60 kg/m 2 and BMI >60 kg/m 2 groups at 24 months ( P =0.047) but not at 60 months ( P =0.54). No significant difference was found in the incidence of early complications in a univariate ( P =0.46) or a multivariate ( P =0.06) analysis. The BMI >60 subgroup was associated with a higher rate of late complications in univariate analysis (heart rate=2.37; 1.03-5.47, P =0.04), but not in multivariate analysis ( P =0.78). CONCLUSIONS: Efficacy and complication rates of bariatric surgeries are similar in patients with BMI 50 to 60 kg/m 2 and >60 kg/m 2 , providing evidence supporting similar management of patients despite specific subgroups.

The Outcomes of Laparoscopic Biliopancreatic Diversion with Duodenal Switch on Gastro-esophageal Reflux Disease: the Mayo Clinic Experience.

PURPOSE: The outcomes of laparoscopic biliopancreatic diversion with duodenal switch (BPD-DS) on gastro-esophageal reflux disease (GERD) are not well elucidated. MATERIAL/METHODS: This retrospective review included patients undergoing laparoscopic primary BPD-DS at Mayo Clinic from 2009 to 2019. GERD parameters analyzed included subjective symptom report/anti-reflux medication intake and/or endoscopic findings. GERD-HRQL questionnaire was also utilized post-operatively. Three subgroups were employed to stratify patients depending on GERD outcomes: the "No-effect" subgroup included patients where surgery did not affect either positively (GERD resolution) or negatively (de novo GERD) GERD outcome, "De novo GERD" subgroup, and "GERD-resolved" subgroup. Multinomial logistic modeling was used to examine associations with the 3-level GERD subgroup (p<0.05). RESULTS: Seventy-six patients were included in the analysis. Thirty-four (44.7%) patients were found to be in the "GERD-resolved" subgroup, 28 (36.8%) patients in the "No-effect" subgroup, and 14 (18.4%) patients in the "De novo GERD" subgroup. Multinomial logistic modeling showed that patients with pre-surgery diabetes mellitus (DM) had lesser odds (OR= 0.248, (95% CI: 0.085-0.724, p=0.0108)) of GERD resolution than patients without pre-surgery DM. An association was also established between %TWL at 6 and 12 months following the procedure and GERD outcome (p=0.017 and 0.008, respectively). Finally, the mean (SD) post-operative GERD-HRQL score was 8.7 (8.1) points, and 69 (91%) patients were currently satisfied with their post-operative condition. CONCLUSION: Laparoscopic BPD-DS appears to have a satisfactory GERD outcome in most patients undergoing the operation. There appears to be an association between pre-operative DM, %TWL at 6 and 12 months, and GERD prognosis in this population.

Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair.

Mesenchymal stem/stromal cells (MSCs) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 participants with DKD and 16 control subjects were assessed for cell surface markers, trilineage differentiation, RNA sequencing (RNA-seq), in vitro function (coculture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD-MSC versus Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved, but migration was reduced. DKD-MSC with and without interferon-γ priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase 1 and prostaglandin-E2) and prorepair factors (hepatocyte growth factor and stromal cell-derived factor 1) but lower IL-6 versus control-MSC medium. DKD-MSC medium protected high glucose plus transforming growth factor-ß-exposed HK-2 cells by reducing apoptotic, fibrotic, and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics, including age, sex, BMI, hemoglobin A1c, kidney function, and urine albumin excretion. However, senescence-associated ß-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while DKD altered the transcriptome and migratory function of culture-expanded MSCs, DKD-MSC functionality, trophic factor secretion, and immunomodulatory activities contributing to repair remained intact. These observations support testing of patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.