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Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular related death, particularly in those with hepatic fibrosis. We determined the prevalence of predicted fibrosis based on non-invasive fibrosis markers and the association of hepatic fibrosis with cardiovascular risk factors. Cross-sectional study of 575 Framingham Heart Study participants with NAFLD based on computed tomography. We determined the prevalence of predicted fibrosis based on the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), the Fibrosis-4 score (FIB4), and the NAFLD Fibrosis Score (NFS). Using multivariable logistic regression models, we examined the association between low, indeterminate, or high risk for fibrosis according to the NFS and various cardiometabolic risk factors. The predicted risk of fibrosis was 12%, 4%, 5%, and 32% for the NFS, FIB4, APRI, and AST/ALT ratio, respectively. In multivariable models, participants with a high risk for advanced fibrosis by the NFS had a wider pulse pressure (adjusted mean difference = 6.87 mm Hg; p = 0.0002) and an increased odds of hypertension (OR 2.92; p = 0.007) compared to those with low risk of fibrosis. There were no statistically significant differences between other cardiovascular risk factors for those with a high versus low risk of fibrosis. The AST/ALT ratio, APRI, and NFS give widely disparate predictions of liver fibrosis. Participants with a high risk for fibrosis based on NFS had wider pulse pressure and increased odds of hypertension. Whether modifying these risk factors impacts cardiovascular endpoints in NAFLD patients remains unknown.

The proportion of women editorial board members and authors of editorials in major gastroenterology journals is not known. We determined the sex of editorial board members (n = 2,282) and authors of editorials (n = 1,705) across 6 journals from 1985 to 2020 at 5-year intervals. The proportion of women editorial board members increased from 2.9% in 1985 to 19.8% in 2020 (P < 0.0001) and women authors of editorials increased from 0% in 1985 to 22.2% in 2020 (P < 0.0001). The proportion of women represented over time has improved, but opportunities likely exist to improve further.

Unbiased, \"nontargeted\" metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

Abstract Context Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. Objective We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. Methods In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. Results Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: −5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of −8.9% (95% CI, −14.5 to −3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. Conclusion GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.

Long and Fox present a Timeline of milestones from the first 67 years of the Framingham Heart Study, considering many important contributions to our understanding of the epidemiology of metabolic disease, and discussing what the future holds for this ground-breaking study. The Framingham Heart Study (FHS), initiated in 1948, is the longest running prospective cohort study in the USA. Through >65 years of discovery, the FHS has contributed to our understanding of obesity, type 2 diabetes mellitus and prediabetes mellitus, the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and to how these conditions relate to our overall and cardiovascular-related mortality. This Timeline gives an overview of the substantial role the FHS has played in advancing the understanding of obesity, diabetes mellitus and NAFLD, and considers the direction the FHS will take in the years to come.

Safety-net hospitals provide care for racially/ethnically diverse and disadvantaged urban populations. Their hospitalized patients with cirrhosis are relatively understudied and may be vulnerable to poor outcomes and racial/ethnic disparities. To examine the outcomes of patients with cirrhosis hospitalized at regionally diverse safety-net hospitals and the impact of race/ethnicity. A study of patients with cirrhosis hospitalized at 4 safety-net hospitals in 2012 was conducted. Demographic, clinical factors, and outcomes were compared between centers and racial/ethnic groups. Study endpoints included mortality and 30-day readmission. In 2012, 733 of 1,212 patients with cirrhosis were hospitalized for liver-related indications (median age 55 years, 65% male). The cohort was racially diverse (43% White, 25% black, 22% Hispanic, 3% Asian) with cirrhosis related to alcohol and viral hepatitis in 635 (87%) patients. Patients were hospitalized mainly for ascites (35%), hepatic encephalopathy (20%) and gastrointestinal bleeding (GIB) (17%). Fifty-four (7%) patients died during hospitalization and 145 (21%) survivors were readmitted within 30 days. Mortality rates ranged from 4 to 15% by center (p = .007) and from 3 to 10% by race/ethnicity (p = .03), but 30-day readmission rates were similar. Mortality was associated with Model for End-stage Liver Disease (MELD), acute-on-chronic liver failure, hepatocellular carcinoma, sodium and white blood cell count. Thirty-day readmission was associated with MELD and Charlson Comorbidity Index >4, with lower risk for GIB. We did not observe geographic or racial/ethnic differences in hospital outcomes in the risk-adjusted analysis. Hospital mortality and 30-day readmission in patients with cirrhosis at safety-net hospitals are associated with disease severity and comorbidities, with lower readmissions in patients admitted for GIB. Despite geographic and racial/ethnic differences in hospital mortality, these factors were not independently associated with mortality.

BackgroundStudies have shown the efficacy of hepatitis B (HBV) vaccination in patients with inflammatory bowel disease (IBD) is impaired, but few data exist regarding the effectiveness of revaccination strategies following primary vaccination failure. Our aim was to analyze the association between administration of additional vaccine doses and hepatitis B surface antibody (HBsAb) seroconversion.MethodsThis is a retrospective cohort study. Inclusion criteria are as follows: age ≥ 18, diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC), inadequate HBsAb < 10 IU/L following initial HBV vaccination series, subsequent administration of 1–3 additional doses of HBV vaccine with follow-up serum HBsAb measurements. Patients were stratified into groups of ≤ 2 or 3 doses received. Primary outcome was achieving HBsAb > 10 IU/L. Outcomes were stratified by age ≥ or < 40 years. We performed logistic and linear multivariable regression analyses for categorical and continuous data.ResultsThe study cohort consists of (n = 149) 54.4% women; 77.9% white; 72.6% with CD, with mean age: 46.2. Patients of all ages and age ≥ 40 years, who received 3 additional doses of vaccine, were more likely to achieve seroprotective HBsAb levels than patients who received 1 or 2 doses (OR 1.77, P = 0.01; OR 1.9, P = 0.03, respectively, after adjusting for age, sex, race, immunosuppressive medication exposure, time between vaccine/titer).ConclusionsFollowing initial HBV vaccination failure, patients with IBD of all ages are more likely to develop seroprotective levels of HBsAb following 3 additional vaccine doses, rather than 1 or 2 alone. In patients who fail primary HBV vaccination, providers should consider a more aggressive revaccination strategy with an additional 3-dose series.

Objectives To provide a standard for total abdominal muscle mass (TAM) quantification on computed tomography (CT) and investigate its association with cardiovascular risk in a primary prevention setting. Methods We included 3016 Framingham Heart Study participants free of cardiovascular disease (CVD) who underwent abdominal CT between 2002 and 2005. On a single CT slice at the level of L3/L4, we segmented (1) TAM-Area, (2) TAM-Index (= TAM-Area/height) and, (3) TAM-Fraction (= TAM-Area/total cross-sectional CT-area). We tested the association of these muscle mass measures with prevalent and incident cardiometabolic risk factors and incident CVD events during a follow-up of 11.0 ± 2.7 years. Results In this community-based sample (49% women, mean age: 50.0 ± 10.0 years), all muscle quantity measures were significantly associated with prevalent and incident cardiometabolic risk factors and CVD events. However, only TAM-Fraction remained significantly associated with key outcomes (e.g., adj. OR 0.68 [0.55, 0.84] and HR 0.73 [0.57, 0.92] for incident hypertension and CVD events, respectively) after adjustment for age, sex, body mass index, and waist circumference. Moreover, only higher TAM-Fraction was associated with a lower risk (e.g., adj. OR: 0.56 [0.36–0.89] for incident diabetes versus TAM-Area: adj. OR 1.26 [0.79–2.01] and TAM-Index: 1.09 [0.75–1.58]). Conclusion TAM-Fraction on a single CT slice at L3/L4 is a novel body composition marker of cardiometabolic risk in a primary prevention setting that has the potential to improve risk stratification beyond traditional measures of obesity. Key Points • In this analysis of the Framingham Heart Study (n = 3016), TAM-F on a single slice CT was more closely associated with prevalent and incident cardiometabolic risk factors as compared to TAM alone or TAM indexed to body surface area. • TAM-F on a single abdominal CT slice at the level of L3/L4 could serve as a standard measure of muscle mass and improve risk prediction

Baculovirus inhibitor of apoptosis repeat-containing 1 (Birc1) proteins have homology to several germline-encoded receptors of the innate immune system. However, their function in immune surveillance is not clear. Here we describe a Birc1e-dependent signaling pathway that restricted replication of the intracellular pathogen Legionella pneumophila in mouse macrophages. Translocation of bacterial products into host-cell cytosol was essential for Birc1e-mediated control of bacterial replication. Caspase-1 was required for Birc1e-dependent antibacterial responses ex vivo in macrophages and in a mouse model of Legionnaires' disease. The interleukin 1β converting enzyme–protease-activating factor was necessary for L. pneumophila growth restriction, but interleukin 1β was not required. These results establish Birc1e as a nucleotide-binding oligomerization–leucine-rich repeat protein involved in the detection and control of intracellular L. pneumophila .