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Objective To examine the risk factors of developing functional decline and make probabilistic predictions by using a tree-based method that allows higher order polynomials and interactions of the risk factors. Methods The conditional inference tree analysis, a data mining approach, was used to construct a risk stratification algorithm for developing functional limitation based on BMI and other potential risk factors for disability in 1,951 older adults without functional limitations at baseline (baseline age 73.1 ± 4.2 y). We also analyzed the data with multivariate stepwise logistic regression and compared the two approaches (e.g., cross-validation). Over a mean of 9.2 ± 1.7 years of follow-up, 221 individuals developed functional limitation. Results Higher BMI, age, and comorbidity were consistently identified as significant risk factors for functional decline using both methods. Based on these factors, individuals were stratified into four risk groups via the conditional inference tree analysis. Compared to the low-risk group, all other groups had a significantly higher risk of developing functional limitation. The odds ratio comparing two extreme categories was 9.09 (95% confidence interval: 4.68, 17.6). Conclusions Higher BMI, age, and comorbid disease were consistently identified as significant risk factors for functional decline among older individuals across all approaches and analyses.

The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. CONCLUSIONS These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542).

Objective: The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society, American Society of Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists. Methods: Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts. Results: New or updated topics in this CPG include: contextualization in an adiposity-based chronic disease complications-centric model, nuance-based and algorithm/checklist-assisted clinical decision-making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health-care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest). Conclusion: Bariatric procedures remain a safe and effective intervention for higher-risk patients with obesity. Clinical decision-making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues. A1C = hemoglobin A1c; AACE = American Association of Clinical Endocrinologists; ABCD = adiposity-based chronic disease; ACE = American College of Endocrinology; ADA = American Diabetes Association; AHI = Apnea-Hypopnea Index; ASA = American Society of Anesthesiologists; ASMBS = American Society of Metabolic and Bariatric Surgery; BMI = body mass index; BPD = biliopancreatic diversion; BPD/DS = biliopancreatic diversion with duodenal switch; CI = confidence interval; CPAP = continuous positive airway pressure; CPG = clinical practice guideline; CRP = C-reactive protein; CT = computed tomography; CVD = cardiovascular disease; DBCD = dysglycemia-based chronic disease; DS = duodenal switch; DVT = deep venous thrombosis; DXA = dual-energy X-ray absorptiometry; EFA = essential fatty acid; EL = evidence level; EN = enteral nutrition; ERABS = enhanced recovery after bariatric surgery; FDA = U.S. Food and Drug Administration; G4G = Guidelines for Guidelines; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HCP = health-care professional(s); HTN = hypertension; ICU = intensive care unit; IGB = intragastric balloon(s); IV = intravenous; LAGB = laparoscopic adjustable gastric band; LAGBP = laparoscopic adjustable gastric banded plication; LGP = laparoscopic greater curvature (gastric) plication; LRYGB = laparoscopic Roux-en-Y gastric bypass; LSG = laparoscopic sleeve gastrectomy; MetS = metabolic syndrome; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; OAGB = one-anastomosis gastric bypass; OMA = Obesity Medicine Association; OR = odds ratio; ORC = obesity-related complication(s); OSA = obstructive sleep apnea; PE = pulmonary embolism; PN = parenteral nutrition; PRM = pulmonary recruitment maneuver; RCT = randomized controlled trial; RD = registered dietician; RDA = recommended daily allowance; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; SIBO = small intestinal bacterial overgrowth; TOS = The Obesity Society; TSH = thyroid-stimulating hormone; T1D = type 1 diabetes; T2D = type 2 diabetes; VTE = venous thromboembolism; WE = Wernicke encephalopathy; WHO = World Health Organization.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) improves after bariatric surgery. The aim of this study was to determine whether peripheral blood mononuclear cell albumin gene expression was related to NAFLD and whether albumin (ALB) and alpha fetoprotein (AFP) expression could be detected in whole blood and visceral adipose tissue. METHODS: Using a retrospective case control study design, RNA isolated from peripheral blood mononuclear cells from patients prior to undergoing bariatric surgery was used for pooled microarray analysis. Quantitative polymerase chain reaction (QPCR) was used to analyze whole blood and visceral adipose tissue. Liver histology was obtained via intra-operative biopsy and clinical data extracted from the electronic health record. RESULTS: The albumin (ALB) gene was the second most up-regulated found in microarray analysis of peripheral blood mononuclear cell RNA from patients with hepatic lobular inflammation versus normal liver histology. Transcript levels of ALB were significantly different across those with normal (n = 50), steatosis (n = 50), lobular inflammation (n = 50), and peri-sinusoidal fibrosis (n = 50) liver histologies, with lobular inflammation 3.9 times higher than those with normal histology (p < 0.017). Albumin expression levels decreased in 11/13 patients in paired samples obtained prior to and at 1 year after Roux-en-Y gastric bypass surgery. ALB expression could be detected in 23 visceral adipose tissue samples obtained intra-operatively and in 18/19 available paired whole blood samples. No significant correlation was found between ALB expression in visceral adipose tissue and whole blood RNA samples. Alpha fetoprotein expression as a marker of early hepatocytic differentiation was detected in 17/17 available VAT RNA samples, but in only 2/17 whole blood RNA samples. CONCLUSION: Albumin RNA expression from blood cells may serve as a biomarker of NAFLD. Albumin and alpha fetoprotein appear to be ubiquitously expressed in visceral adipose tissue in patients with extreme obesity.

Background & AimsA common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.MethodsWe performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.ResultsData from 1,047,265 participants (8,303 with liver biopsies) across 42 studies was included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05]) and diagnosis of NAFLD (OR 1.22 [95% CI 1.08 - 1.39]) in Caucasian adults. The variant was also positively associated with presence of severe steatosis, NASH, and advanced fibrosis (OR: 1.32 [95% CI: 1.06 - 1.63]) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (Pz=0.002) and lower serum triglycerides (Pz=1.5×10−4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.ConclusionOur study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Background Formal psychosocial support programs after weight-loss surgery are limited in scope and availability. Objective This randomized pilot study evaluated the feasibility of a postoperative behavioral intervention program. Materials and methods Postoperative weight-loss surgery patients (N = 50) were recruited from February 2017–July 2017 and randomized to a four-month behavioral program or usual care wait-list. Outcomes evaluated in addition to feasibility included health-related quality of life (Short Form -36), psychosocial functioning and adherence. Secondary outcomes included within-group changes for each outcome. Results Out of eight possible sessions, intervention participants attended a mean of 4.2 sessions. Intervention group participants experienced greater improvements in the social functioning domain of health-related quality of life compared to usual care. Self-reported dietary adherence in the intervention group remained stable, while usual care group dietary adherence declined. Within the intervention group, participants also reported gains in the physical function, pain and general health aspects of quality life from baseline to post-treatment. No differences in weight, mood or other eating behaviors (e.g., loss of control, emotional eating) were evident between groups. Conclusion Though participation in a postoperative behavioral intervention varied, the program helped participants to maintain aspects of quality of life and self-reported adherence to dietary recommendations. Trial registration ClinicalTrials.gov NCT03092479

OBJECTIVE: We sought to validate an algorithm designed to identify patients with post-gastric bypass hypoglycemia (PGBH) using clinician chart review. METHODS: We conducted a chart review study of nondiabetic patients who underwent Roux-en-Y gastric bypass (RYGB) at our institution from 2004 to 2013. The EMR algorithm was based on any post-operative glucose

OBJECTIVES: Little is known regarding dietary patterns and diet composition for the oldest old (defined as adults ≥ 80 years old) who usually have compromised diet quality due to age-related decline. We examined overall dietary patterns and further related the patterns to consumption of selected nutrients as well as perceived physical and mental fatigue. We hypothesized that those that had a healthy dietary pattern would have better nutrient intake profiles and reduced perceived fatigue. METHODS: We studied a cross-section of the Geisinger Rural Aging Study (GRAS) longitudinal cohort in rural Pennsylvania that included 122 participants (56 men and 66 women) aged from 82 to 97 years old. Average daily nutrient and food group intake were calculated from the average of three dietary recalls (1 weekend and 2 weekdays) by telephone. Dietary patterns were characterized using cluster analysis of 34 food groups. Mean nutrient intake and standard errors across dietary patterns were calculated after adjusting for age, sex, and energy consumption. Mean Pittsburgh fatigability questionnaire score examining physical and mental fatigue were calculated after adjusting for age, sex, and body mass index. RESULTS: Two dietary patterns were defined: one pattern (n = 53) characterized by its higher consumption of fruits, vegetables, seafood, and whole grains, and another pattern (n = 69), with higher intake of fats and oil, refined grains, and cheese. After adjusting for potential confounders, participants in the healthier pattern had significantly higher consumption of carbohydrate, protein, fiber, vitamin A, E, K, C, B6, B12, iron, zinc, and potassium with lower intakes of fat and sodium compared with those in the less healthy pattern (P

OBJECTIVE To characterize the status of cardiometabolic risk factors after late relapse of type 2 diabetes mellitus (T2DM) and to identify factors predicting relapse after initial diabetes remission following bariatric surgery to construct prediction models for clinical practice. RESEARCH DESIGN AND METHODS Outcomes of 736 patients with T2DM who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at an academic center (2004–2012) and had ≥5 years’ glycemic follow-up were assessed. Of 736 patients, 425 (58%) experienced diabetes remission (HbA1c RESULTS In 136 (32%) patients who experienced late relapse, a statistically significant improvement in glycemic control, number of diabetes medications including insulin use, blood pressure, and lipid profile was still observed at long-term. Independent baseline predictors of late relapse were preoperative number of diabetes medications, duration of T2DM before surgery, and SG versus RYGB. Furthermore, patients who relapsed lost less weight during the 1st year after surgery and regained more weight afterward. Prediction models were constructed and externally validated. CONCLUSIONS While late relapse of T2DM is a real phenomenon (one-third of our cohort), it should not be considered a failure, as the trajectory of the disease and its related cardiometabolic risk factors is changed favorably after bariatric surgery. Earlier surgical intervention, RYGB (compared with SG) and more weight loss (less late weight regain) are associated with less diabetes relapse in the long-term.

We previously reported dysregulated expression of liver-derived messenger RNA (mRNA) and long noncoding RNA (lncRNA) in patients with advanced fibrosis resulting from nonalcoholic fatty liver disease (NAFLD). Here we sought to identify changes in mRNA and lncRNA levels associated with activation of hepatic stellate cells (HSCs), the predominant source of extracellular matrix production in the liver and key to NAFLD-related fibrogenesis. We performed expression profiling of mRNA and lncRNA from LX-2 cells, an immortalized human HSC cell line, treated to induce phenotypes resembling quiescent and myofibroblastic states. We identified 1964 mRNAs (1377 upregulated and 587 downregulated) and 1460 lncRNAs (665 upregulated and 795 downregulated) showing statistically significant evidence (FDR ≤0.05) for differential expression (fold change ≥|2|) between quiescent and activated states. Pathway analysis of differentially expressed genes showed enrichment for hepatic fibrosis (FDR = 1.35E-16), osteoarthritis (FDR = 1.47E-14), and axonal guidance signaling (FDR = 1.09E-09). We observed 127 lncRNAs/nearby mRNA pairs showing differential expression, the majority of which were dysregulated in the same direction. A comparison of differentially expressed transcripts in LX-2 cells with RNA-sequencing results from NAFLD patients with or without liver fibrosis revealed 1047 mRNAs and 91 lncRNAs shared between the two datasets, suggesting that some of the expression changes occurring during HSC activation can be observed in biopsied human tissue. These results identify lncRNA and mRNA expression patterns associated with activated human HSCs that appear to recapitulate human NAFLD fibrosis., Highlights • Molecular mechanisms underlying HSC activation in the development of NASH fibrosis remain incompletely understood. • 1964 mRNAs and 1460 lncRNAs were differentially expressed between quiescent and activated states. • Pathway analysis of differentially expressed RNAs associated with HSC activation showed enrichment for hepatic fibrosis. • Changes in expression of many RNAs that accompany HSC activation are mirrored in advanced fibrosis in NASH patients.

Background: Overweight and obesity are predisposing conditions for the development of prediabetes and type 2 diabetes. Insulin resistance caused by excess adiposity is a key factor in this process. Methods: The effect of Gelesis100, a novel hydrogel, was assessed in patients who were overweight or had obesity, without antidiabetic medications, and who completed the Gelesis Loss Of Weight (GLOW; NCT02307279) study. GLOW was a multicenter, double-blind, placebo-controlled pivotal study with patients randomized to 2.25 g of Gelesis100 or placebo in capsules taken with 500 mL of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. Insulin resistance was measured by homeostasis model assessment-insulin resistance (HOMA-IR). Data were analyzed using analysis of covariance and Logit models comparing Gelesis100 to placebo arms in 2 subgroups of patients based on baseline HOMA-IR (subgroup 1, HOMA-IR ≥ 3.0, subgroup 2, HOMA-IR < 3.0). Results: The overall population included 290 patients (132 males, 158 females, 91 in subgroup 1, 199 in subgroup 2, 155 on Gelesis100, 135 on placebo), who were normoglycemic, had prediabetes, or had untreated type 2 diabetes. Statistically significant difference in reduction of HOMA-IR was observed in subgroup 1 (mean baseline HOMA-IR = 5.0) but not in subgroup 2 (mean baseline HOMA-IR = 1.8). Indeed, placebo-subtracted HOMA-IR changes (mean, SE) were -22.3 ± 9.5% (P = 0.0212) and -9.0 ± 9.5% (P = 0.3432) in subgroup 1 and subgroup 2, respectively. Furthermore, in subgroup 1, patients who lost < 5% body weight (n = 44, mean body weight loss = 1.3%) had a statistically significant placebo-subtracted HOMA-IR change of -27.6 ± 13.2% (P = 0.0435), while patients who lost ≥ 5% body weight (n = 47, mean body weight loss = 9.7%) had no statistically significant placebo-subtracted HOMA-IR change (-15.6 ± 13.6%, P = 0.2584). The effect on HOMA-IR decrease was driven by significant reduction in fasting serum insulin. Safety and tolerability of Gelesis100 demonstrated no increased risk compared to placebo. Conclusion: Treatment with Gelesis100 results in a significantly higher reduction in insulin resistance compared to placebo as assessed by HOMA-IR in patients who are overweight or have obesity with elevated baseline HOMA-IR. The results also suggest a potential weight-independent effect of Gelesis100 in the reduction of insulin resistance. If these findings are confirmed in future studies with larger subgroups, Gelesis100 could become a potential new treatment for insulin-resistant clinical conditions associated with overweight and obesity.

Background: In a previous pilot weight-loss study, an association was observed between baseline fasting plasma glucose (FPG) levels and the effectiveness of the Gelesis100 treatment. The aim of this subanalysis of the Gelesis Loss Of Weight (GLOW; NCT02307279) study is to further assess the association between FPG and body weight (BW) responders in subjects with overweight or obesity treated with Gelesis100, a non-systemic hydrogel. Methods: This subanalysis was conducted in subjects who were overweight or had obesity and who completed the GLOW study. GLOW was a multicenter, double-blind, placebo-controlled pivotal study with subjects randomized to 2.25 g of Gelesis100 or placebo in capsules taken with 500 mL of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. BW responders at 5% and 10% (super-responders) were analyzed using Logit model comparing Gelesis100 to placebo arms in 2 subgroups of subjects defined by their initial FPG (two consecutive consistent values). Subgroup 1 had normoglycemia (FPG < 100 mg/dL) and subgroup 2 had prediabetes (PD) (FPG ≥ 100 mg/dL and < 126 mg/dL) or untreated type 2 diabetes (T2D) (FPG ≥ 126 mg/dL). Results: The population included 206 subjects (94 males, 112 females, 138 in subgroup 1, 68 in subgroup 2, 105 on Gelesis100, 101 on placebo). In subgroup 1 (mean baseline FPG = 91 mg/dL), BW responders at 5% and 10% in Gelesis100 arm were 60% (placebo arm = 34%, adjusted odds ratio (OR) = 3.1, P = 0.0022) and 22% (placebo arm = 15%, OR = 1.5, P = 0.4254), respectively. In subgroup 2 (mean baseline FPG = 113 mg/dL), BW responders at 5% and 10% in Gelesis100 arm were 72% (placebo arm = 56%, OR = 2.2, P = 0.1509) and 44% (placebo arm = 14%, OR = 6.1, P = 0.0071), respectively. In the overall population, baseline FPG was inversely correlated with BW percent change in the Gelesis100 arm (r = -0.24, P = 0.0144). The safety and tolerability of Gelesis100 demonstrated no increased risk compared to placebo. No serious adverse events were observed in any arm. Conclusion: Gelesis100 offers a compelling new approach in the management of overweight and obesity. Notably, in Gelesis100-treated subjects with PD or untreated T2D, the odds of being super-responders are 6 times higher compared to placebo. This finding may be used as a tool for identifying subjects who are both at higher clinical risk and more likely to achieve greater levels of BW loss when treated with Gelesis100. The mechanisms underlying this finding require further investigations. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

OBJECTIVES Diet quality has been associated with health outcomes and quality of life. However, the association between diet quality and mortality in older people, those aged 80 years and older, is understudied. Therefore, we conducted a prospective study to examine whether better diet quality, assessed by a validated dietary screening tool (DST), was associated with lower mortality in those aged 80 years and older. METHODS Our study included 1990 participants (812 men and 1178 women), with a mean age of 84.1 years at baseline (ranging from 80 to 102 years old), from the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Baseline descriptive information was obtained in 2009, and the DST was administered via mailed survey. The DST is composed of 25 food- and behavior-specific questions associated with dietary intake that generate a diet quality score ranging from 0 (lowest) to 100 (highest). Death was identified using electronic medical record and the Social Security Death Index data. Hazard ratios (HRs) and 95% confidence intervals (CIs) across three diet quality categories were calculated by using Cox proportional hazards models after adjusting for potential confounders. RESULTS Over 8 years of follow-up (October 2009-February 2018), 931 deaths were documented. Higher diet quality was associated with lower mortality risk (P-trend = .04). Participants with high diet quality (defined as DST scores >75) had significantly lower risk of mortality compared with those with low diet quality (defined as DST scores

Objective The epidemiology of post-gastric bypass surgery hypoglycemia (PGBH) is incompletely understood. This study aimed to evaluate the risk of PGBH among nondiabetic patients and associated factors. Methods A cohort study of nondiabetic patients who underwent Roux-en-Y gastric bypass (RYGB) was conducted. PGBH was defined by any postoperative record of glucose

Objective Obstructive sleep apnea (OSA) is common among candidates for bariatric surgery. OSA and its associated intermittent hypoxia have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. A large cohort of bariatric surgery patients was studied in an effort to explore the relationship between OSA severity, hypoxia, metabolic syndrome, and the severity of NAFLD. Methods Bariatric surgery candidates who underwent both polysomnography and liver biopsy were studied. The severity of OSA as determined by the apnea-hypopnea index (AHI) and parameters of hypoxia was studied in relation to extent of abnormalities of liver histology as measured by the presence of hepatic steatosis, inflammation, and fibrosis. Results The study cohort included 362 patients with a mean age of 46.2 years and BMI of 49.9 kg/m(2) . On the basis of AHI, 26% of the cohort had no OSA, 32% mild OSA, 22% moderate OSA, and 20% severe OSA. For the study subjects without metabolic syndrome, positive correlations were found between OSA severity, as measured by AHI, and parameters of hypoxia, with the severity of NAFLD. Conclusions OSA severity and its accompanying hypoxia are associated with the severity of NAFLD.

Increased inflammation and oxidative stress associated with obesity can accelerate aging. Telomere length (TL) has the capacity to serve as an aging indicator at the cellular level. Obesity has a known association with shorter TL. This study evaluated TL of immune cells in a population of obese individuals who underwent gastric bypass surgery. Pre- and post-operative DNA samples were available for 50 subjects who had gastric bypass surgery. DNA was analyzed via quantitative polymerase chain reaction to determine TL. Changes in TL were evaluated by comparing TL at baseline to TL at 3-5 years post gastric bypass surgery. Sixty percent of the individuals in the study observed an increase in TL. Significant lengthening was observed for those with the shortest baseline TL (P=0.0011), but not for those with intermediate baseline TL (P=0.411) or longest baseline TL (P=0.207). Change in TL was negatively correlated with age and triglycerides but not correlated with weight loss induced by bariatric surgery. This study confirms that TL lengthening is observed post bariatric surgery and is the first to detect TL lengthening 3-5 years after surgery.

BACKGROUND: History of abuse may impact weight loss (WL) following bariatric surgery. Some investigations have indicated slower WL rates among patients reporting abuse; however, among studies with multiple assessments, significant differences in WL are not evidenced at later measurement. Few investigations have extended follow-up beyond 18 months, limiting understanding of the impact of abuse on weight trajectory over time. Furthermore, existing research has insufficiently accounted for forms of interpersonal trauma beyond sexual abuse (i.e., emotional, physical) that may impact WL and other health outcomes. OBJECTIVES: To determine whether post-surgical percent total WL (%TWL) and specific clinical outcomes are differentially impacted by history of interpersonal abuse. SETTING: Large, comprehensive medical center. METHODS: Retrospective data was collected from patients who underwent bariatric surgery at a single center (N = 433). Based on pre-surgical interview, patients were grouped according to reported history of interpersonal abuse (Y/N). Nonlinear repeated measures regression examined impact of abuse history on %TWL, and clinical selequae. RESULTS: Differences in %TWL at 6, 12, 18, 24 and 36 months post-surgically did not differ significantly. Further, %TWL did not differ across time, according to group. A significantly greater number of those with history of interpersonal abuse had a clinical diagnosis of depression as compared with those not reporting interpersonal abuse (38% vs. 22% respectively), p < .001. CONCLUSIONS: Interpersonal abuse history does not negatively impact %TWL post-surgically but is associated with diagnosis of depression, indicating depressive symptoms may be a viable clinical intervention target for surgery patients with interpersonal trauma history.

Background DiaRem is a validated tool for predicting the likelihood of type 2 diabetes (T2D) remission after Roux-en-Y gastric bypass (RYGB) surgery. Objectives The objective of this study was to determine if the addition of duration of T2D to DiaRem improves its ability to discriminate between patients with or without T2D remission and/or to reclassify presurgery patients into accurate risk groups. Setting Academic Medical Center. Methods This study included patients consented into a prospective registry of Roux-en-Y gastric bypass between July 2009 and November 2015 with known duration of T2D (n = 307). Electronic health record–derived duration of T2D was compared with patient reported duration of T2D in a subset of patients (n = 48). DiaRem2 was created using clinical variables from DiaRem and duration of T2D. Area under the curve and the net reclassification index were used to assess increased performance of DiaRem2. Results Self-reported duration of T2D was highly concordant with electronic health record–derived T2D duration (96% agreement). Early T2D remission occurred in 44% of patients. DiaRem2 included age, hemoglobin A1C, insulin medication use, and duration of T2D. DiaRem2 had a higher area under the curve than DiaRem (.876 versus .850, P = .026), reduced the number of remission risk groups from 5 down to 3, and reclassified patients from intermediate to either high or low remission groups (net reclassification index, P Conclusions DiaRem2 simplifies and improves the accuracy of assessing probability of T2M remission after Roux-en-Y gastric bypass. Self-reported duration of T2D is an acceptable surrogate for T2D duration derived from clinical data.

Iron deficiency and anaemia after metabolic surgery, potentially modifiable nutritional complications, are becoming an increasing cause for concern as prevalence increases with time and there is limited evidence supporting the effectiveness of the current guidelines for prophylactic oral iron supplementation and treatment for deficiency. Abnormalities in iron nutrition predisposing to deficiency are common in severely obese patients, and the low-grade systemic inflammation, also common to these patients, reduces the effectiveness of oral iron supplementation. The surgical procedures result in alterations of foregut anatomy and physiology, which limit iron absorptive capacity and daily food intake. These alterations and the limited effects of oral iron supplementation explain the high prevalence of postoperative iron deficiency and anaemia. This review outlines current mechanisms concerning the pathogenesis of disordered iron nutrition in patients with severe obesity, current gaps in knowledge, and opportunities for quality improvement.

PURPOSE: The objective of this descriptive study was to identify clinical characteristics of Roux-en-Y Gastric Bypass (RYGB) patients who died from intentional self-harm or accidental overdose postoperatively. MATERIALS AND METHODS: This retrospective, descriptive study included RYGB patients from a large rural medical center that completed surgery between January 2004 and December 2014 and died from intentional self-harm or accidental overdose through December 2015. Specific causes of death were obtained from the National Death Index and clinical data from electronic health records. Clinical characteristics explored were age, sex, time to surgery, weight loss expectations, postoperative weight loss, medication, diagnoses, psychiatric histories (diagnoses, self-harm, suicidal ideation and behaviors, medications, substance use, preoperative Beck Depression Inventory-II scores), pain, social support and reported life stressors. RESULTS: Overall, twenty-two patients of 146 total deceased patients died from intention self-harm (n = 6) or accidental overdose (n = 16) over the study period (77.3% female, mean age at time of surgery = 38.4±9.1 years). Younger age (< 40 years), history of self-harm or depression, preoperative pain and use of opioids at the time of surgery emerged as common characteristics in weight-loss surgery patients who died from intentional self-harm or accidental overdose. No trends regarding social support, life stressors, or actual or expected weight loss were identified. CONCLUSION: Certain weight-loss surgery patients may be at risk for death from self-harm or overdose and may benefit from greater surveillance postoperatively.

Numerous studies have shown that bariatric surgery in older patients is safe and effective. However, both the Agency for Healthcare Research and Quality (AHRQ) and a Medicare Evidence Advisory Committee (MEDCAC) have cited gaps in the evidence for outcomes in Medicare patients undergoing bariatric surgery. These gaps are predominantly in the safety and outcomes evidence in Medicare patients younger than 65 years old (Centers for Medicare and Medicaid Services [CMS]65).The aim of our study was to review both the safety and efficacy of gastric bypass (RYGB) and sleeve gastrectomy (SG) in Medicare patients compared with other payers.A single academic medical center.A prospectively maintained database of 3300 patients who underwent bariatric surgery between January 2007 and December 2017 was utilized. The outcomes of Medicare patients undergoing RYGB and SG were analyzed and compared to those of similar patients covered by Medicaid or Commercial insurers.There were too few patients with commercial insurance older than 65 to compare to those with Medicare (CMS ≥ 65). Mortality at 90 days for CMS ≥ 65 was 1.3% and the overall complication rate was 20.1% (minor 15.6%; major 7.1%). Total weight loss (TWL) at 6 months and 1, 2, and 3 years was 25.3%, 30.0%, 29.9%, and 29.4% respectively. For any time after surgery, 23% of CMS ≥ 65 had complete remission of diabetes and 45% had partial remission. Demographic analysis of CMS65 found Medicare patients were significantly older with more diabetes, hypertension and hyperlipidemia than those with commercial payers. Mortality at 90 days for CMS65 was 0.6% and the overall complication rate was 18.3% (minor 14.3%; major 4.7%). Mortality was not significantly different between payers. After adjustment for baseline differences and comparing to the Medicare group, the commercial group was less likely to have minor complications (P = .019), any complications (P = .007), and extended length of stay (P.001). The TWL for the entire cohort age65 at 6 months and 1, 2, and 3 years was 28.1%, 34.1%, 34.1%, and 31.8% respectively. After adjusting for differences, there was no significant difference in TWL between payers. For any time after surgery, complete remission of diabetes was 45% in CMS65 patients and partial remission was 59%. The comparison of remission between groups was then adjusted for DiaRem score and surgery type. CMS65 patients had significantly less partial remission of diabetes than commercial patients (P = .034) but no difference in complete remission.RYGB and SG are both safe and effective in Medicare patients of all ages. CMS ≥ 65 have acceptable mortality and complication rates with TWL and diabetes remission similar to younger patients. CMS65 patients are older than those with commercial insurance with more comorbid disease. While they have longer hospital stays after bariatric surgery, their weight loss and complete remission of diabetes are no different than patients with Medicaid or commercial insurance. This study helps fill an important evidence gap in bariatric surgical patients raised by both Agency for Healthcare Research and Quality, and a Medicare Evidence Advisory Committee.

Nonalcoholic steatohepatitis (NASH) is strongly associated with obesity and type 2 diabetes. The molecular factors underlying the development of inflammation and severe fibrosis in NASH remain largely unknown. The purpose of this study was to identify gene expression patterns related to obesity-related NASH inflammation and fibrosis. We performed sequencing-based mRNA profiling analysis of liver samples from individuals with normal histology (n = 24), lobular inflammation (n = 53), or bridging fibrosis, incomplete cirrhosis, or cirrhosis (n = 65). Hepatic expression of a subset of mRNAs was validated using an orthogonal method, analyzed in a hepatic stellate cell line, and used to identify transcriptional patterns shared by other forms of cirrhosis. We observed evidence for differential levels of 3820 and 2980 transcripts in lobular inflammation and advanced fibrosis, respectively, compared with normal histology (false discovery rate ≤0.05), including 176 genes specific to fibrosis. Functional enrichment analysis of these genes revealed participation in pathways involving cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix-receptor interaction. We identified 34 differentially expressed transcripts in comparisons of lobular inflammation and fibrosis, a proportion of which were also upregulated during activation of hepatic stellate cells. A set of 16 genes from a previous independent study of NASH bridging fibrosis/cirrhosis were replicated, several of which have also been associated with advanced fibrosis/cirrhosis due to hepatitis viruses or alcohol in human patients. Dysregulated mRNA expression is associated with inflammation and fibrosis in NASH. Advanced NASH fibrosis is characterized by distinct set of molecular changes that are shared with other causes of cirrhosis., RNA-sequencing of liver biopsy tissue was used to define a fibrosis-specific gene expression profile in obese individuals with nonalcoholic steatohepatitis (NASH).

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was found to be associated with reduced levels of ALT (P=4.20×10(−12)) and AST (P=6.2×10(−10)). Among DiscovEHR study participants, this variant was found to be associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 is associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.)

Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent complication of extreme obesity. Loading of the liver with fat can progress to inflammation and fibrosis including cirrhosis. The molecular factors involved in the progression from simple steatosis to fibrosis remain poorly understood. Methods Gene expression profiling using microarray, PCR array, and RNA sequencing was performed on RNA from liver biopsy tissue from patients with extreme obesity. Patients were grouped based on histological findings including normal liver histology with no steatosis, lobular inflammation, or fibrosis, and grades 1, 2, 3, and 4 fibrosis with coexistent steatosis and lobular inflammation. Validation of expression was conducted using quantitative PCR. Serum analysis was performed using ELISA. Expression analysis of hepatocytes and hepatic stellate cells in response to lipid loading were conducted in vitro using quantitative PCR and ELISA. Results Three orthogonal methods to profile human liver biopsy RNA each identified the chemokine CCL20 (CC chemokine ligand 20 or MIP-3 alpha) gene as one of the most up-regulated transcripts in NAFLD fibrosis relative to normal histology, validated in a replication group. CCL20 protein levels in serum measured in 224 NAFLD patients were increased in severe fibrosis (p

Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.

Metabolic surgery has emerged as the preferred sustainable treatment for the disease of obesity and its formidable health comorbidities. This evolution has resulted from major advances in surgical quality care including minimally invasive techniques and the introduction of accredited multidisciplinary centers of excellence. Multidisciplinary care including obesity medicine specialists, certified bariatric nurses, dietitians, and behavioral medicine professionals has improved perioperative care and helped to identify many early and late metabolic as well as nutritional complications of these procedures.

Background Obesity and its association with reduced life expectancy are well established, with cardiovascular disease as one of the major causes of fatality. Metabolic surgery is a powerful intervention for severe obesity, resulting in improvement in comorbid diseases and in cardiovascular risk factors. This study investigates the relationship between metabolic surgery and long‐term cardiovascular events. Methods and Results A cohort of Roux‐en‐Y gastric bypass surgery ( RYGB ) patients was tightly matched by age, body mass index, sex, Framingham Risk Score, smoking history, use of antihypertension medication, diabetes mellitus status, and calendar year with a concurrent cohort of nonoperated control patients. The primary study end points of major cardiovascular events (myocardial infarction, stroke, and congestive heart failure) were evaluated using Cox regression. Secondary end points of longitudinal cardiovascular risk factors were evaluated using repeated‐measures regression. The RYGB and matched controls (N=1724 in each cohort) were followed for up to 12 years after surgery (overall median of 6.3 years). Kaplan–Meier analysis revealed a statistically significant reduction in incident major composite cardiovascular events ( P =0.017) and congestive heart failure (0.0077) for the RYGB cohort. Adjusted Cox regression models confirmed the reductions in severe composite cardiovascular events in the RYGB cohort (hazard ratio=0.58, 95% CI =0.42–0.82). Improvements of cardiovascular risk factors (eg, 10‐year cardiovascular risk score, total cholesterol, high‐density lipoprotein, systolic blood pressure, and diabetes mellitus) were observed within the RYGB cohort after surgery. Conclusions Gastric bypass is associated with a reduced risk of major cardiovascular events and the development of congestive heart failure.

Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters. In contrast, loss of Mll3/4 proteins leads to strong depletion of enhancer Pol II occupancy and eRNA synthesis, concomitant with downregulation of target genes. Interestingly, downregulated genes exhibit reduced polymerase levels in gene bodies, but not at promoters, suggestive of pause-release defects. Altogether, our results suggest that enhancer H3K4me1 provides only a minor contribution to the long-range coactivator function of Mll3/4.

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan® proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs738409 single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L1-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs738409 genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain.

To examine the risk factors of developing functional decline and make probabilistic predictions by using a tree-based method that allows higher order polynomials and interactions of the risk factors.The conditional inference tree analysis, a data mining approach, was used to construct a risk stratification algorithm for developing functional limitation based on BMI and other potential risk factors for disability in 1,951 older adults without functional limitations at baseline (baseline age 73.1 ± 4.2 y). We also analyzed the data with multivariate stepwise logistic regression and compared the two approaches (e.g., cross-validation). Over a mean of 9.2 ± 1.7 years of follow-up, 221 individuals developed functional limitation.Higher BMI, age, and comorbidity were consistently identified as significant risk factors for functional decline using both methods. Based on these factors, individuals were stratified into four risk groups via the conditional inference tree analysis. Compared to the low-risk group, all other groups had a significantly higher risk of developing functional limitation. The odds ratio comparing two extreme categories was 9.09 (95% confidence interval: 4.68, 17.6).Higher BMI, age, and comorbid disease were consistently identified as significant risk factors for functional decline among older individuals across all approaches and analyses.

Health care resource consumption is a growing concern. The aim of this study was to examine the associations between diet quality and body mass index with health care resource use (HRU) in a cohort of advanced age. Participants in the Geisinger Rural Aging Study (n=5,993) were mailed demographic and dietary questionnaires in 2009. Of those eligible, 2,995 (50%; 1,267 male, 1,728 female; mean age 81.4±4.4 years) provided completed surveys. Multivariate negative binomial models were used to estimate relative risk and 95% CI of HRU outcomes with diet quality as assessed by the Dietary Screening Tool score and body mass index determined from self-reported height and weight. Poor diet quality was associated with a 20% increased risk for emergency room (ER) visits. Fruit and vegetable consumption was grouped into quintiles of intake, with the highest quintile serving as the reference group in analyses. The three lowest fruit and vegetable quintiles were associated with increased risk for ER visits (23% to 31%); the lowest quintile increased risk for inpatient visits (27%). Obesity increased risk of outpatient visits; however, individuals with class I obesity were less likely than normal-weight individuals to have ER visits (relative risk=0.84; 95% CI 0.70 to 0.99). Diets of greater quality, particularly with greater fruit and vegetable intake, are associated with favorable effects on HRU outcomes among older adults. Overweight and obesity are associated with increased outpatient HRU and, among obese individuals, with decreased ER visits. These findings suggest that BMI and diet quality beyond age 74 years continue to affect HRU measures.

Objective To evaluate the impact of adult bariatric surgery on the body mass index (BMI) of children living in the same household. Methods A retrospective case-control study. Case dyads (n = 128) were composed of one adult who had bariatric surgery and one child at the same address. Control dyads (n = 384) were composed of an adult with obesity but no bariatric surgery and a child at the same address. Two-sample t-test was used to determine whether the differences between actual and expected BMI at follow-up (post-surgery) differed between children in the case and control dyads. Results Among boys who were overweight, boys who lived with a surgery patient had a lower than expected BMI post-surgery, while boys who did not live with a surgery patient had a higher than expected BMI at follow-up (P = 0.045). Differences between actual and expected BMIs of children were not significantly different between cases and controls in girls or in children in other weight classes. Conclusions Overweight boys who lived with an adult bariatric surgery patient had a lower than expected BMI after surgery as compared to controls. Future studies may be warranted to determine the mechanisms by which these children experience collateral weight loss.

OBJECTIVE Gastric bypass surgery is an effective therapy for extreme obesity. However, substantial variability in weight loss outcomes exists that remains largely unexplained. Our objective was to determine whether any commonly collected pre-operative clinical variables were associated with weight loss following Roux-en-Y gastric bypass surgery. DESIGN The analysis was based on a prospectively recruited observational cohort of 2365 patients who underwent Roux-en-Y gastric bypass surgery from 2004-2009. Weight loss was stratified into three major phases, early (0-6 months), nadir, and long-term (>36 months). Multivariate regression models were constructed using a database of over 350 variables. RESULTS A total of 12-14 pre-operative variables were independently associated (p50 years, and the presence of fibrosis on liver biopsy. CONCLUSIONS Several variables previously associated with poorer weight loss after RYGB surgery including age, baseline BMI, and type 2 diabetes were replicated. Several others suggest possible clinical interventions for post-operative management of RYGB patients to improve weight loss outcomes.

CCL20 (CC chemokine ligand 20) is emerging as an important regulatory molecule in a pathway common to virus infection, alcoholic hepatitis, and non-alcoholic fatty liver disease (NAFLD) leading to the development of hepatic fibrosis. We previously observed upregulation of CCL20 in patients with NAFLD fibrosis and human hepatic stellate cells (LX-2 cells) in response to lipid loading. To date, the mechanisms mediating the relationship between CCL20 and hepatic fibrogenesis remain unknown. In this study, we sought to characterize the molecular mechanisms by which CCL20 may contribute to fibrogenesis in NAFLD. We observed that CCL20 levels increased with worsening severity of liver histology in NAFLD patients (normal < steatosis

Factors governing the development of liver fibrosis in nonalcoholic steatohepatitis (NASH) are only partially understood. We recently identified adipocyte enhancer binding protein 1 (AEBP1) as a member of a core set of dysregulated fibrosis-specific genes in human NASH. Here we sought to investigate the relationship between AEBP1 and hepatic fibrosis. We confirmed that hepatic AEBP1 expression is elevated in fibrosis compared to lobular inflammation, steatosis, and normal liver, and increases with worsening fibrosis in NASH patients. AEBP1 expression was upregulated 5.8-fold in activated hepatic stellate cells and downregulated during chemical and contact induction of biological quiescence. In LX-2 and HepG2 cells treated with high glucose (25 mM), AEBP1 expression increased over 7-fold compared to normal glucose conditions. In response to treatment with either fructose or palmitate, AEBP1 expression in primary human hepatocytes increased 2.4-fold or 9.6-fold, but was upregulated 55.8-fold in the presence of fructose and palmitate together. AEBP1 knockdown resulted in decreased expression of nine genes previously identified to be part of a predicted AEBP1-associated NASH co-regulatory network and confirmed to be upregulated in fibrotic tissue. We identified binding sites for two miRNAs known to be downregulated in NASH fibrosis, miR-372-3p and miR-373-3p in the AEBP1 3’ untranslated region. Both miRNAs functionally interacted with AEBP1 to regulate its expression. These findings indicate a novel AEBP1-mediated pathway in the pathogenesis of hepatic fibrosis in NASH.

Summary Background About 60% of patients with type 2 diabetes achieve remission after Roux-en-Y gastric bypass (RYGB) surgery. No accurate method is available to preoperatively predict the probability of remission. Our goal was to develop a way to predict probability of diabetes remission after RYGB surgery on the basis of preoperative clinical criteria. Methods In a retrospective cohort study, we identified individuals with type 2 diabetes for whom electronic medical records were available from a primary cohort of 2300 patients who underwent RYGB surgery at the Geisinger Health System (Danville, PA, USA) between Jan 1, 2004, and Feb 15, 2011. Partial and complete remission were defined according to the American Diabetes Association criteria. We examined 259 clinical variables for our algorithm and used multiple logistic regression models to identify independent predictors of early remission (beginning within first 2 months after surgery and lasting at least 12 months) or late remission (beginning more than 2 months after surgery and lasting at least 12 months). We assessed a final Cox regression model with a consistent subset of variables that predicted remission, and used the resulting hazard ratios (HRs) to guide creation of a weighting system to produce a score (DiaRem) to predict probability of diabetes remission within 5 years. We assessed the validity of the DiaRem score with data from two additional cohorts. Findings Electronic medical records were available for 690 patients in the primary cohort, of whom 463 (63%) had achieved partial or complete remission. Four preoperative clinical variables were included in the final Cox regression model: insulin use, age, HbA 1c concentration, and type of antidiabetic drugs. We developed a DiaRem score that ranges from 0 to 22, with the greatest weight given to insulin use before surgery (adding ten to the score; HR 5·90, 95% CI 4·41–7·90; p Interpretation The DiaRem score is a novel preoperative method to predict the probability of remission of type 2 diabetes after RYGB surgery. Funding Geisinger Health System and the US National Institutes of Health.

We sought to identify the major risk factors associated with mortality in Roux-en-Y gastric bypass (RYGB) surgery.Bariatric surgery has become an established treatment for extreme obesity. Bariatric surgery mortality has steadily declined with current rates of less than 0.5%. However, significant variation in the mortality rates has been reported for specific patient cohorts and among bariatric centers.Clinical outcome data from 185,315 bariatric surgery patients from the Bariatric Outcome Longitudinal Database were reviewed. Of these, 157,559 patients had either documented 30 or more day follow-up data, including mortality. Multiple demographic, socioeconomic, and clinical factors were analyzed by univariate analysis for their association with 30-day mortality after gastric bypass. Variables found to be significant were entered into a multiple logistic regression model to identify factors independently associated with 30-day mortality. On the basis of these results, a RYGB mortality risk score was developed.The overall 30-day mortality rate for the entire bariatric surgery cohort was 0.1%. Of the 81,751 RYGB patients, the mortality rate was 0.15%. Factors significantly associated with 30-day gastric bypass mortality included increasing body mass index (BMI) (P0.0001), increasing age (P0.005), male gender (P0.001), pulmonary hypertension (P0.0001), congestive heart failure (P=0.0008), and liver disease (P=0.038). When the RYGB risk score was applied, a significant trend (P0.0001) between increasing risk score and mortality rate is found.Increasing BMI, increasing age, male gender, pulmonary hypertension, congestive heart failure, and liver disease are risk factors for 30-day mortality after RYGB. The RYGB risk score can be used to determine patients at greater risk for mortality after RYGB surgery.

In an aging population, potentially modifiable factors impacting mortality such as diet quality, body mass index (BMI), and health-related quality of life (HRQOL) are of interest. Surviving members of the Geisinger Rural Aging Study (GRAS) (n = 5,993; aged ?74 years) were contacted in the fall of 2009. Participants in the present study were the 2,995 (1,267 male, 1,728 female; mean age 81.4 ± 4.4 years) who completed dietary and demographic questionnaires and were enrolled in the Geisinger Health Plan over follow-up (mean = 3.1 years). Cox proportional hazards multivariate regression models were used to examine the associations between all-cause mortality and BMI, diet quality, and HRQOL. Compared to GRAS participants with BMIs in the normal range, a BMI < 18.5 was associated with increased mortality (HR 1.85 95%CI 1.09, 3.14, P = 0.02), while a BMI of 25-29.9 was associated with decreased risk of mortality (HR 0.71 95%CI 0.55, 0.91, P =0.007). Poor diet quality increased risk for mortality (HR 1.53 95%CI 1.06, 2.22, P = 0.02). Finally, favorable health-related quality of life was inversely associated with mortality (HR 0.09 95%CI 0.06, 0.13, P < 0.0001). Higher diet quality and HALex scores, and overweight status, were associated with reduced all-cause mortality in a cohort of advanced age. While underweight (BMI < 18.5) increased risk of all-cause mortality, no association was found between obesity and all-cause mortality in this aged cohort.

Bariatric surgery may increase the risk of substance use. The purpose of this study was to prospectively assess smoking and alcohol use before and after bariatric surgery, identify characteristics associated with alcohol use and smoking, and examine substance use and weight loss. Participants (N = 155, mean = 50.1 ± 11.3 y and 45.7 ± 7.0 kg/m(2)) were Roux-en-Y gastric bypass (RYGB) patients that completed surveys on substance use preoperatively and postoperatively. Alcohol use decreased significantly from the preoperative (72.3%) to the postoperative (63.2%) period. As preoperative alcohol quantity rose, the odds of consuming any alcohol postoperatively increased six-fold. Higher BMI increased the odds of high alcohol consumption. Older age decreased the odds of alcohol use and smoking. Smoking status did not differ pre- (19.4%) to post- (14.8%) surgery. Alcohol use and smoking were not associated with weight loss. After weight-loss surgery, alcohol use declined but smoking rates did not significantly change. Younger patients were more likely to use alcohol and smoke postoperatively. Patients with a higher BMI or a history of substance use may be more likely to use alcohol postoperatively.

Purpose of review Despite being one of the most prevalent chronic diseases, obesity was not recognized as such until very recently. Although linked to ubiquitous diseases like diabetes, hypertension, coronary artery disease, obstructive sleep apnea, and many others, targeted treatments are few. Diet, exercise, and behavior modification are the pillars of weight loss. When they alone do not achieve the required weight reduction, medications may be used for patients with a BMI above 30 or above 27 if obesity-related comorbidities are present. The spectrum of pharmacologic agents aimed at obesity treatment will be reviewed. Recent findings Two medications, phentermine and orlistat, have been the only agents approved many years ago and now still standing. Others have come and gone, removed from the market by the Food and Drug Administration (FDA) because of harmful side-effects. However, in the last few years, new drugs have started to emerge. Since 2012, two new medications phentermine-topiramate extended-release combination and lorcaserin have been FDA approved, while at least one more, naltrexone SR/bupropion SR combination is expected to be re-evaluated by the FDA in 2014. Summary Treating obesity is crucial as it will ultimately result in the prevention of many related chronic diseases and will decrease morbidity and mortality. Weight loss medications are a valuable part of the clinician's toolbox in the treatment of obesity and should be used when appropriate. Having a variety of medications would be a great asset to accommodate various patients' needs and pre-existing medical conditions.

Objective The goal of the present study was to identify differences in gene expression between SAT, VAT, and EAT depots in Class III severely obese individuals. Design Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT) in terms of its function and contribution to metabolism. Subjects and Methods Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT, and EAT, using microarrays validated by real time quantitative PCR. Results The three depots were found to share 1,907 genes. VAT had the greatest number of genes [66] expressed exclusively in this depot, followed by SAT [23], and then EAT [14]. Moreover, VAT shared more genes with EAT [65] than with SAT [38]. Further analyses using ratios of SAT/EAT, VAT/EAT, and SAT/VAT, identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer, and development. Targeted analysis of genes playing a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5), were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7, and FGF10, whereas, FGF19 and FGF21 were undetectable. Conclusions These data indicate that EAT has more in common with VAT suggesting similar metabolic potential. The human epigastric adipose depot could play a significant functional role in metabolic diseases and should be further investigated.

OBJECTIVE Roux-en-Y gastric bypass (RYGB) in humans can remit type 2 diabetes, but the operative mechanism is not completely understood. In mice, fibroblast growth factor (FGF) 15 (FGF19 in humans) regulates hepatic bile acid (BA) production and can also resolve diabetes. In this study, we tested the hypothesis that the FGF19–BA pathway plays a role in the remission of human diabetes after RYGB surgery. RESEARCH DESIGN AND METHODS Cohorts of diabetic and nondiabetic individuals of various body weights were used. In addition, RYGB patients without diabetes (No-Diabetes), RYGB patients with diabetes who experienced remission for at least 12 months after surgery (Diabetes-R), and RYGB patients with diabetes who did not go into remission after surgery (Diabetes-NoR) were studied. Circulating FGF19 and BA levels, hepatic glycogen content, and expression levels of genes regulating the FGF19–BA pathway were compared among these groups of patients using pre- and postoperative serum samples and intraoperative liver biopsies. RESULTS Preoperatively, patients with diabetes had lower FGF19 and higher BA levels than nondiabetic patients, irrespective of body weight. In diabetic patients undergoing RYGB, lower FGF19 levels were significantly correlated with increased hepatic expression of the cholesterol 7alpha-hydroxylase 1 (CYP7A1) gene, which modulates BA production. Following RYGB surgery, however, FGF19 and BA levels (particularly cholic and deoxycholic acids) exhibited larger increases in Diabetic-R patients compared with nondiabetic and Diabetic-NoR patients. CONCLUSIONS Taken together, the baseline and postoperative data implicate the FGF19–CYP7A1–BA pathway in the etiology and remission of type 2 diabetes following RYGB surgery.