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Obesity is a highly prevalent disease and providers are expected to offer or refer patients for weight management yet increasingly fewer clinical visits address obesity. Challenges to offering care are known but less is known about referrals and how specialists who treat obesity-related comorbidities address care and referrals. This study explored perceptions of primary care providers (PCPs) and specialty providers regarding care and referrals for weight management, specifically referrals to programs in the community setting. A qualitative design was used to interview 33 PCPs (mean age 54 years) and 31 specialists (cardiology, gynecology, endocrinology, and orthopedics [mean age 62 years]) in the USA during 2019. Each interview was conducted by telephone, audio-recorded, and transcribed verbatim. Inductive analysis was used and followed the constant comparative method. Four themes emerged from the data including (a) Clinical guidelines and provider discretion influence obesity care; (b) Facilitators and barriers to discussing weight and small step strategies; (c) Informal referrals are made for weight management in community settings; and (d) Opportunities and challenges for integrating clinical and community services for weight management. Facilitating referrals to effective programs, ideally with a feedback loop could coordinate care and enhance accountability, but education, compliance, and cost issues need addressed. Care may be offered but not be well-aligned with clinical guidelines. Knowledge gaps regarding community programs’ offerings and efficacy were evident. Referrals could be systematically promoted, facilitated, and tracked to advance weight management objectives.

This study examined the associations between overall diet quality and the risk of dementia in a rural cohort among the oldest old. Included in this prospective cohort study were 2232 participants aged ≥ 80 years and dementia-free at the baseline according to the Geisinger Rural Aging Study (GRAS), a longitudinal cohort in rural Pennsylvania. In 2009, diet quality was assessed by a validated dietary screening tool (DST). Incident cases of dementia during 2009–2021 were identified using diagnosis codes. This approach was validated by a review of electronic health records. Associations between diet quality scores and the incidence of dementia were estimated using the Cox proportional hazards models, adjusted for potential confounders. Across a mean of 6.90 years of follow-up, we identified 408 incident cases of all-cause dementia. Having a higher diet quality was not significantly associated with a lower risk for incidents of all-cause dementia (adjusted HR for the highest compared with the lowest tertile: 1.01, 95% CI: 0.79, 1.29, P-trend = 0.95). Similarly, we did not observe a significant association between diet quality and altered risks of Alzheimer’s disease and other forms of dementia. Overall, having a higher diet quality was not significantly associated with a lower risk of dementia among the oldest old during the full follow-up.

Obesity increases the risk of developing type 2 diabetes, hypertension, and hyperlipidemia. We sought to determine the impact of obesity maintenance, weight regain, weight loss maintenance, and magnitudes of weight loss on future risk and time to developing these cardiometabolic conditions. This was a retrospective cohort study of adults receiving primary care at Geisinger Health System between 2001 and 2017. Using electronic health records, patients with ≥3-weight measurements over a 2-year index period were identified and categorized. Obesity maintainers (OM) had obesity (body mass index ≥30 kg/m²) and maintained their weight within ±3% from baseline (reference group). Both weight loss rebounders (WLR) and weight loss maintainers (WLM) had obesity at baseline and lost5% body weight in year 1; WLR regained ≥20% of weight loss by end of year 2 and WLM maintained ≥80% of weight loss. Incident type 2 diabetes, hypertension, and hyperlipidemia, and time-to-outcome were determined for each study group and by weight loss category for WLM. Of the 63,567 patients included, 67% were OM, 19% were WLR, and 14% were WLM. The mean duration of follow-up was 6.6 years (SD, 3.9). Time until the development of electronic health record-documented type 2 diabetes, hypertension, and hyperlipidemia was longest for WLM and shortest for OM (log-rank test p0.0001). WLM had the lowest incident type 2 diabetes (adjusted hazard ratio [HR] 0.676 [95% confidence interval [CI] 0.617 to 0.740]; p0.0001), hypertension (adjusted HR 0.723 [95% CI 0.655 to 0.799]; p0.0001), and hyperlipidemia (adjusted HR 0.864 [95% CI 0.803 to 0.929]; p0.0001). WLM with the greatest weight loss (15%) had a longer time to develop any of the outcomes compared with those with the least amount of weight loss (7%) (p0.0001). In an integrated delivery network population, sustained weight loss was associated with a delayed onset of cardiometabolic diseases, particularly with a greater magnitude of weight loss.

Introduction Sarcopenic obesity and its association with nonalcoholic fatty liver disease (NAFLD) is under‐recognized by many healthcare providers in Western medicine due to the lack of awareness and diagnostic guidelines. The result is delayed recognition and treatment, which leads to further health deterioration and increased healthcare costs. Sarcopenic obesity is characterized by the presence of increased fat mass in combination with muscle catabolism related to chronic inflammation and/or inactivity. Previous research has recommended evaluating body composition and physical function performance to adequately diagnose sarcopenic obesity. Body composition analysis can be performed by imaging applications through magnetic resonance imaging, computed tomography, and dual‐energy x‐ray absorptiometry. Due to the cost of each device and radiation exposure for patients as evidenced in all three modalities, bioelectrical impedance analysis offers a noninvasive approach capable of providing quick and reliable estimates of lean body and fat mass. Methods and Results This review analyzes the current evidence‐based literature, indicating a lower skeletal muscle mass and increased visceral adipose tissue correlation to the advancement of fibrosis in fatty liver disease. Conclusion Given the substantial promising research conducted in predominantly Asian populations regarding body tissue distribution and NAFLD, additional prospective research is needed to extend these findings in Western populations.

The presence of chronic low-grade inflammation, commonly identified in patients with severe obesity, alters iron homeostasis and indicators of iron status, fostering the development of updated guidelines for the diagnosis of iron deficiency (ID). Current recommended diagnostic thresholds for ID in obesity derived from expert opinion include a ferritin level of30 ng/mL and/or transferrin saturation (TSAT)20%. Earlier studies of ID among candidates for metabolic surgery using low levels of ferritin or iron as diagnostic thresholds demonstrated a prevalence of 5%-20%.Using the current recommended diagnostic thresholds for ID, this study measures the prevalence of ID in a large cohort of surgical candidates and its relationship to surgical outcomes.Geisinger Medical Center, Danville, Pennsylvania.The study cohort included 3,723 patients who underwent pre- operative nutritional assessment which included markers of iron nutrition over the period 2004-2018.The cohort included 2,988 women (80.3%) and 735 men (19.7%); body mass index: 49.4 ± 9 kg/mThe prevalence of ID among surgical candidates (45.4%) is more than twice that identified as ID in earlier studies. ID was commonly identified in the absence of anemia. The most severe ID was found in those with a serum ferritin level30 ng/mL and TSAT20%. ID in the presence of inflammation is often unrecognized and has implications regarding surgical outcomes after metabolic surgery.

Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants inRare germline mutations in

Low patient recruitment into diabetes prevention programs is a challenge. The primary aim of this study was to demonstrate that an increased recruitment rate can be achieved by communicating personalized risk of progression to type 2 diabetes, estimating risk reduction with weight loss, and offering program choice. Secondary aims included program participation rate, weight loss, and short-term decreased diabetes risk.In this single-arm study, persons with prediabetes from 3 primary care sites received a letter that communicated their personalized risk of progression to diabetes within 3-years, estimated risk reduction with 5, 10, 15 % weight loss, reported in pounds, and offered a choice of 5 free, 6-month, programs. A one-sided test was used to compare the recruitment rate against the maximum expected rate of (10 %).Recruitment response rate was 25.3 % (81/328, 95 % CI=[20.0 %, 29.4 %]) which was significantly higher than expected (p0.0001). Overall, 65 % of participants completed75 % of contacts. BMI, HbA1c, and diabetes risk (all p0.0001) improved at 6 months; BMI (p0.0001) and HbA1c (p0.05) improved at 12 months.Recruitment response rate was better than expected.Communicating personalized risk and reduction estimates with a choice of programs resulted in favorable outcomes, sustained at 1-year.

ObjectiveOne-third of American adults are estimated to have prediabetes but the vast majority are unaware. Accordingly, persons with prediabetes are equally unaware of their personal susceptibility of developing type 2 diabetes and the impact of weight loss on reducing the risk of progression. The primary aim of this study was to demonstrate that raising awareness of present risk, risk reduction, and offering available, accessible preventive interventions would result in fewer incidences of type 2 diabetes at 1- and 3-year follow-up periods. Secondary aims included clinician use of a novel diabetes risk calculator in primary care indicated by the proportion of patients being offered a preventive intervention.MethodsIn this single-arm study, persons with prediabetes from three primary care sites received a letter that communicated their personalized risk of progression to diabetes within three years; estimated risk reduction with 5, 10, 15% weight loss, reported in pounds, representing data illustrated in the diabetes risk calculator; and offered a choice of five free, 6-month, programs. Progression to type 2 diabetes was evaluated at 1- and 3-year follow-up periods using electronic health record data. Comparisons are made between the active participants and the non-respondent group. The diabetes risk calculator was implemented in 53 primary clinics in July 2020 and viewable in the electronic health record of persons with prediabetes without the need for clinician action. Electronic health record data were used to evaluate the rate of clinicians offering or referring persons with prediabetes to a preventive intervention—these rates of referral were compared between two phases (pre-implementation: 8/2019-2/2020; early implementation: 8/2020-2/2021).ResultsPersons with prediabetes (N=328) received letters and n=83 responded to the invitation to choose a preventive intervention (treatment). Follow-up data were available for n=55 treatment and n=169 non-respondents at 1- and 3-years. At 1-year follow-up, 2% of treatment and 20% of non-respondents developed type 2 diabetes (pConclusionProgression to type 2 diabetes was halted at 1- and 3-year follow-up for a significantly higher proportion of persons who received diabetes risk calculator results and initiated a preventive intervention compared to those who did not. In the early implementation phase, clinicians referred a higher proportion of persons with prediabetes to preventive intervention when presented with diabetes risk calculator results as compared the pre-implementation period.

Background: With the increasing focus of metabolomic methods on obesityrelated diseases, it is important to consider how sample handling may need to be adapted for the high compositions of lipids that can occur in such subjects. Introduction: High-lipid (cloudy, milky appearances; a.k.a. lipemic) biofluids are common in very high BMI subjects. Organic extractions of biofluids are useful for removing protein backgrounds, inactivating capsid viruses, and yielding relatively stable samples with excellent spectroscopic characteristics. This work considered how acetonitrile extractions, which are widely used, perform on lipemic sera. Results: In this technical note, we report the observation and remediation of a liquid-liquid phase separation in acetonitrile extractions of many lipemic sera. This unexpected behavior can be challenging to identify, especially if working with small volumes. The liquid-liquid separation shows a high miscibility of proteins in both liquid phases that impairs NMR data quality. We also report a simple temperature-based adaption of the acetonitrile extraction procedure that consistently results in a single aqueous phase and eliminates unwanted constituents. Conclusion: A robust approach to achieving reproducible, high quality samples of aqueous metabolites from lipemic sera from very high BMI subjects should be of utility in expanding metabolomics applications to lipemic biofluids.

Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.

Taste-signaling proteins, which are expressed throughout the digestive tract, are involved in regulating metabolism and immunity. This study aimed to determine if these genes are expressed and altered in jejunal tissues from patients with extreme obesity who received bariatric surgery. Reverse transcription polymerase chain reaction revealed that phospholipase C beta 2 and transient receptor potential channel M5 expression was downregulated in the jejunum of patients with a body mass index above 50, whereas gustducin expression remained unchanged. Our data suggest that taste-signaling dysregulation might contribute to obesity.

Background Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. Results Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p –8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. Conclusion These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.

BACKGROUND: The extent to which obesity and genetics determine post-operative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990-2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records & Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score (GRS) was constructed from 97 obesity-risk single nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk for obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m(2)) had increased risk for incisional hernia (Odds ratio [OR] 1.7-5.5, p

The oldest old (aged ≥80 years) are often the population subgroup at high nutritional risk due to age-related metabolic changes. We performed a validation analysis of a dietary screening tool (DST) which was developed for older adults among the oldest old. We examined dietary intakes using three 24-hour dietary recalls and the DST among 122 participants (aged 82-97) of the Geisinger Rural Aging Study. DST scores were compared with the Health Eating Index (HEI)-2015 scores, which were calculated based on three-day dietary recalls. Pearson correlations were used to characterize concurrent validity and Bland-Altman plots were used to identify potential bias. DST scores were significantly correlated with HEI scores (adjusted r = 0.68; p 0.001) in an age- and sex-adjusted model. Those within the not-at-risk DST group had significantly higher HEI scores (adjusted means = 79.6 ± 3.68) compared with those who were in the at-risk (adjusted means = 51.2 ± 1.56) and the possibly-at-risk (adjusted means = 66.3 ± 1.79) groups (p-trend0.001). The DST appears to be a valid measure of diet quality in the oldest old when compared with the HEI and may be a potential tool to assess overall diet quality in this population.

The worldwide increase in the prevalence of obesity and adiposity-related comorbidities has required a novel approach to cardiometabolic risk mitigation focused on the key mechanistic drivers of disease. The current manuscript presents the case of a 74-year-old male with obesity complicated by coronary artery disease, hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and type 2 diabetes. Expert panelists discuss optimal diagnostic and treatment strategies focused on lifestyle modifications including dietary interventions such as the Mediterranean dietary pattern, medications that target multiple drivers of disease, as well as procedural options.

More perceived physical fatigability and poor diet quality are associated with impairments in physical function in older adults. However, the degree to which more perceived fatigability explains the association between poor diet quality and low physical function is unknown. We examined this relationship in 122 (66F, 56M) of the oldest-old participants from the Geisinger Rural Aging Study (GRAS). We used 24-h dietary recalls to assess the Healthy Eating Index (HEI), the Pittsburgh Fatigability Scale (PFS, 0–50) to assess perceived physical fatigability, and the PROMIS Physical Function 20a* to assess physical function. We grouped participants into three age categories: 80–84 (n = 51), 85–89 (n = 51), and 90+ (n = 20) years. Multiple linear regression revealed that a lower HEI was associated with higher PFS Physical score after adjusting for age group, sex, body mass index, and the number of medical conditions (p = 0.001). Several macro- and micro-nutrient intakes were also lower in those reporting more (≥15) compared to less (&lt, 15) perceived physical fatigability. Mediation analysis revealed that PFS Physical scores explained ~65% (p = 0.001) of the association between HEI total score and PROMIS19 Physical Function score. Poor diet quality may contribute to more perceived physical fatigability, which could exacerbate impairments in the oldest-old’s physical function.

Background Several dietary components have been shown to be neuroprotective against risk of neurodegeneration. However, limited observational studies have examined the role of overall diet quality on risk of Parkinson's disease. Objectives We examined the associations between diet quality and risk of Parkinson's disease in a prospective cohort study and meta-analysis. Methods Included in the cohort study were 3,653 participants (1,519 men and 2,134 women; mean age: 81.5 years) in the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Diet quality was assessed using a validated dietary screening tool containing 25 food- and behavior-specific questions in 2009. Potential Parkinson's cases were identified using electronic health records based on ICD9 (332.*), ICD10 (G20), and Parkinson-related treatments. Hazard ratios (HRs) and 95% confidence intervals (CIs) across diet quality tertiles were calculated using Cox proportional hazards models after adjusting for potential confounders. We further performed a meta-analysis by pooling our study with four published papers on this topic. Random-effects model was utilized to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results During a mean of 6.94 years of follow-up, 47 incident Parkinson's cases were documented. Having high diet quality at baseline was associated with lower Parkinson's disease risk (adjusted HR for the highest vs the lowest diet quality tertile = 0.39; 95% CI: 0.17, 0.89; p-trend = 0.02). The meta-analysis including 140,617 individuals also showed that adherence to high diet quality or a healthy dietary pattern was associated with lower risk of Parkinson's disease (pooled risk ratio = 0.64; 95% CI: 0.49, 0.83). Conclusion Having high diet quality or a healthy dietary pattern was associated with lower future risk of Parkinson's disease.

The near universal presence of chronic low-grade systemic inflammation among patients with severe obesity disrupts iron homeostasis and underlies the association between obesity and iron deficiency. Immune activation and inflammation results in a reduction in circulating iron and diminished iron bioavailability for erythropoiesis. Inflammation also alters blood levels of commonly measured markers of iron nutrition status, which makes the diagnosis of iron deficiency difficult and has led to new recommendations regarding laboratory markers for the diagnosis. Recent evidence utilizing these newly recommended laboratory markers which include levels of ferritin, C Reactive Protein, and Transferrin Saturation suggests that the actual prevalence of iron deficiency among candidates for metabolic surgery may be double or triple the prevalence identified by low levels of ferritin alone. Thus, large numbers of surgical candidates have iron deficiency which has been heretofore largely unrecognized and inadequately treated. The assessment of iron status utilizing the currently recommended markers in the presence of chronic inflammatory diseases, and repletion of depleted stores for surgical candidates with deficiency during the pre-operative period presents an important opportunity for mitigating this condition in post-operative patients.

Bile acids have been implicated in the mechanism by which Roux-en-Y gastric bypass (RYGB) can induce remission of type 2 diabetes (T2D). Our goal was to identify circulating proteins whose levels changed after RYGB when dysglycemic parameters normalized.This was a retrospective study of 26 participants who underwent RYGB. Blood proteins were identified using two-dimensional electrophoresis and mass spectroscopy. Complement proteins were measured using immunoassays and bile acids measured using ultra-high-performance liquid chromatography and mass spectroscopy.A total of 7/452 blood proteins were found to change 2 days after RYGB. Complement component 3 (C3) was selected because of its regulation by bile acids and the glucoregulatory function of its proteolytically processed product C3adesArg or acylation-stimulating protein (ASP). The median (inter-quartile range/IQR) C3 level was 47.4 (34.5, 65.9) mg/dL before surgery decreasing to 40.9 (13.4, 64.1) mg/dL within 2 days after surgery (p = 0.0292). The median (IQR) ASP level increased from 2.8 (0.9, 7.3) nM before surgery to 8.0 (5.3, 14.1) nM within 2 days after surgery (p = 0.0016). ASP levels increased in 14/17 (82%) with T2D remission and in 6/6 with normoglycemia but decreased in 3/3 with persistent T2D. Of ten bile acids measured, the levels of ursodeoxycholic acid (UDCA) were significantly decreased after RYGB and the levels of taurodeoxycholic acid (TDCA) were significantly decreased with T2D remission.These data further support an association of C3 with glucose metabolism and implicate bile acids and ASP in the early remittive effects of RYGB on T2D.

A real-time trial of a cancer blood test Cancers diagnosed early are often more responsive to treatment. Blood tests that detect molecular markers of cancer have successfully identified individuals already known to have the disease. Lennon et al. conducted an exploratory study that more closely reflects the way in which such blood tests would be used in the future. They evaluated the feasibility and safety of incorporating a multicancer blood test into the routine clinical care of 10,000 women with no history of cancer. Over a 12-month period, the blood test detected 26 cancers of different types. A combination of the blood test and positron emission tomography–computed tomography (PET-CT) imaging led to surgical removal of nine of these cancers. Use of the blood test did not result in a large number of futile follow-up procedures. Science , this issue p. eabb9601

Summary Objective The purpose of this study was to compare body composition measurements estimated by multi‐frequency bioelectrical impedance analysis (MF‐BIA) with air displacement plethysmography (ADP) in individuals with obesity. Methods Bariatric patients were recruited from Geisinger's Center for Nutrition and Weight Management Clinic in Danville, Pennsylvania. Sixty‐two participants (age = 52.4 ± 9.3 years; body mass index = 38.9 ± 8.0 kg m−2) reported for a same‐day testing visit. Body composition was measured using a common MF‐BIA analyzer (InBody 720, Biospace Co., Beverly Hills, CA) and ADP. Results Strong relationships were observed between MF‐BIA and ADP methods (r = 0.88–0.96, P

Objective: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity.Methods: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss.Results: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks.Conclusions: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.

The current popularity of metabolic surgery has led to increasing attention to long-term nutritional complications.The purpose of this retrospective study is to accurately define the long-term incidence of clinically significant anemia after Roux-en-Y gastric bypass (RYGB) and to identify factors that contribute to increased risk.The study cohort consisted of 2116 patients who underwent RYGB with necessary laboratory information available, and with longitudinal follow-up available (mean 5.3 ± 3.3 yr). A concurrent cohort of nonoperated patients matched for age, sex, body mass index, and baseline hemoglobin was identified (N = 1126). The RYGB and control cohorts were followed longitudinally to estimate the percent that develop mild, moderate, or severe anemia using Kaplan-Meier analysis. Predictors of severe anemia within the RYGB cohort were identified using Cox regression.The percent developing postRYGB mild, moderate, and severe anemia was 27%, 9%, and 2% at 1 year postRYGB and increased to 68%, 33%, and 11% at 5 years postRYGB. As compared with the nonoperated control cohort, the RYGB cohort was more likely to develop mild anemia (hazard ratio [HR] = 1.36, P.001), moderate anemia (HR = 1.75, P.001), and severe anemia (HR = 1.87, P.001). Severity of anemia was associated with an increasing percentage of microcytosis (P.0001). Clinical factors independently associated with an increased risk of severe anemia within the RYGB cohort included females and males40 years of age (HR = 2.97, 95% confidence interval [CI] = 1.14, 7.75, P = .026), preoperative anemia (HR = 1.65, 95% CI = 1.19, 2.29, P = .0029), preoperative low ferritin level (HR = 2.28, 95% CI = 1.39, 3.74, P = .0029), and a rapid 6-month weight loss trajectory (HR = 1.71, 95% CI = 1.22, 2.38, P = .0018).The long-term incidence of clinically significant anemia after RYGB is alarmingly high and warrants more detailed study.

Altered DNA methylation events contribute to the pathogenesis and progression of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Investigations of global DNA methylation patterns in liver biopsies representing severe NAFLD fibrosis have been limited. We used the HumanMethylation 450K BeadChip to analyze genome-wide methylation in patients with biopsy-proven grade 3/4 NAFLD fibrosis/cirrhosis (N = 14) and age- and sex-matched controls with normal histology (N = 15). We identified 208 CpG islands (CGIs), including 99 hypomethylated and 109 hypermethylated CGIs, showing statistically significant evidence (adjusted P value

Total Knee Arthroplasty (TKA, also known as total knee replacement) is a highly effective surgical intervention for the restoration of physical function and improving quality of life in patients with disabling knee osteoarthritis. Recent data suggest that obesity is a major risk factor in the pathogenesis and progression of knee osteoarthritis, with increases in body mass index (BMI, kg/m2) directly correlating with the prevalence of knee osteoarthritis. However, recent data also suggest that there are increased risks associated with TKAs when performed in patients with morbid obesity (BMI > 40 kg/m2). Patients with morbid obesity are routinely referred for weight management prior to surgery. Many of these patients fail to meet the recommended weight loss goals prior to TKA, potentially making them ineligible for surgery or placing them at increased risk for sub-optimal outcomes. Thus, the purpose of this study is to examine the potential therapeutic impact and long-term outcomes of surgically induced weight loss on TKA outcomes. Specifically, these outcomes will include measures of physical function, mobility, and indices of joint function at 1 and 2 years post-TKA compared between extremely obese patients who undergo TKA (Control group, n = 150) and those with TKA performed ~1 year after bariatric surgery (Test group, n = 150). An additional primary endpoint will be the percent of bariatric patients that negate or delay the need for TKA. Secondary endpoints include perioperative outcomes after TKA.

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.

AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. METHODS: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic–euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. RESULTS: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

Objective Determine the impact of long-term non-surgical weight loss maintenance on clinical relevance for osteoarthritis, cancer, opioid use, and depression/anxiety and healthcare resource utilization. Methods A cohort of adults receiving primary care within Geisinger Health System between 2001–2017 was retrospectively studied. Patients with ≥3 weight measurements in the two-year index period and obesity at baseline (BMI ≥30 kg/m2) were categorized: Obesity Maintainers (reference group) maintained weight within +/-3%; Weight Loss Rebounders lost ≥5% body weight in year one, regaining ≥20% of weight loss in year two; Weight Loss Maintainers lost ≥5% body weight in year one, maintaining ≥80% of weight loss. Association with development of osteoarthritis, cancer, opioid use, and depression/anxiety, was assessed; healthcare resource utilization was quantified. Magnitude of weight loss among maintainers was evaluated for impact on health outcomes. Results In total, 63,567 patients were analyzed including 67% Obesity Maintainers, 19% Weight Loss Rebounders, and 14% Weight Loss Maintainers; median follow-up was 9.7 years. Time until osteoarthritis onset was delayed for Weight Loss Maintainers compared to Obesity Maintainers (Logrank test p 15% weight loss was associated with the greatest decrease in incident osteoarthritis. Healthcare resource utilization was significantly higher for Weight Loss Rebounders and Maintainers compared to Obesity Maintainers. Increased weight loss among Weight Loss Maintainers trended with lower overall healthcare resource utilization, except for hospitalizations. Conclusions In people with obesity, sustained weight loss was associated with greater clinical benefits than regained short-term weight loss and obesity maintenance. Higher weight loss magnitudes were associated with delayed onset of osteoarthritis and led to decreased healthcare utilization.

IMPACT: Understanding dietary patterns and nutrient intakes of the aging population may help address concerns and dietary guidelines regarding their nutritional needs. OBJECTIVES/GOALS: The objective of this study is to test the hypothesis that a healthy dietary pattern in the oldest old (aged 80 years and older) is related to greater compliance with dietary recommendations and better nutrient intake profiles. METHODS/STUDY POPULATION: We conducted a cross-sectional study of 122 participants aged 82 to 97 years old from the Geisinger Rural Aging Study (GRAS) cohort in rural Pennsylvania (n = 56 men and 66 women). The main outcome measures of the investigation were the daily nutrient intakes and food group intakes evaluated from the average of three 24-hour dietary recalls. The dietary patterns were determined by cluster analysis from 28 food groups. Diet quality and adherence to the Dietary Guidelines for Americans was assessed by the Healthy Eating Index (HEI)-2015 and the Dietary Screening Tool (DST). Recommended intakes were determined by the Recommended Dietary Allowances (RDAs) or Adequate Intakes (AIs). RESULTS/ANTICIPATED RESULTS: Less than 50% of participants met the dietary recommended intakes for vitamins D, E, K, B6, dietary fiber, zinc, potassium, and calcium. The more-nutrient-dense cluster was characterized by higher intakes of fruits and vegetables. The less-nutrient-dense cluster was characterized by higher intakes of foods including desserts and sweets. After adjusting for age, sex, and energy intake, participants in the more-nutrient-dense dietary pattern had a higher intake of vitamins A, D, K, C, fiber, and potassium (p < 0.05 for all). After adjusting for age and sex, participants in the more-nutrient-dense pattern had better diet quality assessed by the (HEI)-2015 (p < 0.001) and DST (p = 0.006). DISCUSSION/SIGNIFICANCE OF FINDINGS: Among the oldest old, many participants were found to have nutrient intakes lower than the recommended levels for fundamental nutrients suggesting that dietary guidance in addition to a dietary pattern more aligned with dietary guidelines may be beneficial for supporting healthy aging.

The objective of this study was to determine whether the DiaRem, a score that predicts type 2 diabetes (T2D) remission following roux-en-y gastric bariatric surgery (RYGB), also predicts remission following laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) in white and Hispanic patients.While bariatric surgery is highly effective in reversing insulin resistance, there are patients for whom surgery will not lead to remission. To date, there is no score for predicting remission following LAGB or LSG surgery. Additionally, there is little known about how to predict whether Hispanic patients will experience remission.We conducted a retrospective cohort study of white and Hispanic patients with T2D who received bariatric surgery. There were 361 white and 130 Hispanic patients among whom 328 had RYGB surgery, 107 had LSG surgery, and 56 had LAGB surgery. We used age, diabetes treatment, and hemoglobin A1c to calculate DiaRem scores. Mann-Whitney U test was used to determine the association between DiaRem scores and remission. Area under the receiver operant curve (AUC) was used to assess the ability of the DiaRem to discriminate between patients who did and did not remit.The DiaRem was associated with partial remission in all surgery types for white and Hispanic patients (Mann-Whitney, p 0.001). The DiaRem had moderate to high discriminant ability (AUC 0.70) for all surgical and racial/ethnic groups.The DiaRem distinguishes between patients likely and unlikely to experience remission, informing expectations of patients making T2D treatment decisions.

OBJECTIVE This study assessed all-cause and specific-cause mortality after Roux-en-Y gastric bypass (RYGB) and in matched control subjects, stratified by diabetes status. RESEARCH DESIGN AND METHODS RYGB patients were matched by age, BMI, sex, and diabetes status at time of surgery to nonsurgical control subjects using data from the electronic health record. Kaplan-Meier curves and Cox regression were used to assess differences in all-cause and specific-cause mortality between RYGB patients and control subjects with and without diabetes. RESULTS Of the 3,242 eligible RYGB patients enrolled from January 2004 to December 2015, control subjects were identified for 2,428 (n = 625 with diabetes and n = 1,803 without diabetes). Median postoperative follow-up was 5.8 years for patients with diabetes and 6.7 years for patients without diabetes. All-cause mortality was reduced in RYGB patients compared with control subjects only for those with diabetes at the time of surgery (adjusted hazard ratio 0.44; P < 0.0001). Mortality was not significantly improved in RYGB patients without diabetes compared with control subjects without diabetes (adjusted hazard ratio 0.84; P = 0.37). Deaths from cardiovascular diseases (P = 0.011), respiratory conditions (P = 0.017), and diabetes P = 0.011) were more frequent in control subjects with diabetes than in RYGB patients with diabetes. RYGB patients without diabetes were less likely to die of cancer (P = 0.0038) and respiratory diseases (P = 0.046) than control subjects without diabetes but were at higher risk of death from external causes (P = 0.012), including intentional self-harm (P = 0.025), than control subjects without diabetes. CONCLUSIONS All-cause mortality benefits of RYGB are driven predominantly by patients with diabetes at the time of surgery. RYGB patients with diabetes were less likely to die of cardiovascular diseases, diabetes, and respiratory conditions than their counterparts without RYGB.

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.