Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. METHODS: Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. RESULTS: Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. CONCLUSIONS: PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. LAY SUMMARY: Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.

BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial.

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75-4.5 mg), B (14 days on, 7 days off; 2.0-3.0 mg), and C (7 days on, 14 days off; 2.0-4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1-4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

Modeling performance of sample collection sites using whole exome sequencing metrics.

Although next-generation sequencing assays are routinely carried out using samples from cancer trials, the sequencing data are not always of the required quality. There is a need to evaluate the performance of tissue collection sites and provide feedback about the quality of next-generation sequencing data. This study used a modeling approach based on whole exome sequencing quality control (QC) metrics to evaluate the relative performance of sites participating in the Bristol Myers Squibb Immuno-Oncology clinical trials sample collection. We identified several events for the sample swap. Overall, most sites performed well and few showed poor performance. These findings can increase awareness of sample failure and improve the quality of samples.

Diastolic velocity half time is associated with aortic coarctation gradient at catheterization independent of echocardiographic and clinical blood pressure gradients.

OBJECTIVE: The most accurate noninvasive parameter to predict whether a patient with aortic coarctation will meet interventional criteria at catheterization remains elusive. We aim to determine the best independent echocardiographic predictors of a coarctation peak-to-peak pressure gradient ≥20 mm Hg at catheterization, the accepted threshold for intervention. DESIGN: Retrospective query of our catheterization database from 1/2007 to 7/2016 for the diagnostic code of aortic coarctation was performed. Multiple echocardiographic measurements and blood pressure gradients prior to cardiac catheterization were collected. Univariate correlation of variables with the continuous catheterization peak were calculated using Spearman's rho. Univariate association with peak-to-peak gradient at catheterization ≥20 mm Hg was tested using Mann-Whitney U test and the Pearson chi-square test or Fisher's exact test. Multivariable logistic regression assessed the independent association of the clinically relevant metrics with gradient at catheterization ≥20 mm Hg. RESULTS: Sixty-eight patients met study criteria (median age 9.25 years), of whom 84% underwent intervention at catheterization. Echocardiographic peak and mean coarctation velocity, indexed systolic and diastolic velocity half times (SVHTi, DVHTi), and blood pressure gradient all had moderate correlation (Spearman's rho = 0.529-0.617, P < .001) with the continuous catheterization gradient and were significantly associated with the binary outcome of catheterization peak ≥20 mm Hg (P < .001). Logistic regression found echocardiographic mean systolic gradient (OR 1.213 [95% CI 1.041-1.414]) and DVHTi (OR 1.039 [95% CI 1.004-1.074]) independently associate with catheterization peak ≥20 mm Hg after controlling for blood pressure gradient (OR 1.066 [0.987-1.150]). CONCLUSIONS: Most echocardiographic estimates show moderate correlation with arch gradient at catheterization. Noninvasive four extremity blood pressure gradient is significantly associated with peak-to-peak gradient ≥20 mm Hg. DVHTi may provide a unique independently associated echocardiographic estimate of coarctation severity. Further study of these variables with larger cohorts may allow for development of predictive models to direct catheterization.

An Inexpensive, Point-of-Care Urine Test for Bladder Cancer in Patients Undergoing Hematuria Evaluation.

Although hematuria (blood in urine) is the most common symptom of bladder cancer, 70-98% of hematuria cases are benign. These hematuria patients unnecessarily undergo costly, invasive, and expensive evaluation for bladder cancer. Therefore, there remains a need for noninvasive office-based tests that can rapidly and reliably rule out bladder cancer in patients undergoing hematuria evaluation. Herein, a clinical assay for matrix metalloproteinases ("Ammps") is presented, which generates a visual signal based on the collagenase activity (in urine of patients) on the Ammps substrates. Ammps substrates are generated by crosslinking gelatin with Fe(II) chelated alginate nanoparticles, which precipitate in urine samples. The cleavage of gelatin-conjugated alginate (Fe(II)) nanoparticles by collagenases generates free-floating alginate (Fe(II)) nanoparticles that participate in Fenton's reaction to generate a visual signal. In a pilot study of 88 patients, Ammps had 100% sensitivity, 85% specificity, and a negative predictive value (NPV) of 100% for diagnosing bladder cancer. This high NPV can be useful in ruling out bladder cancer in patients referred for hematuria evaluation.

A first look at the Accreditation Council for Graduate Medical Education anesthesiology milestones: implementation of self-evaluation in a large residency program.

STUDY OBJECTIVE: The objective was to determine if there is a correlation between resident postgraduate year (PGY) of training and self-evaluation of performance using the Accreditation Council for Graduate Medical Education milestones. DESIGN: Survey. SETTING: Residency program at a large academic center. PATIENTS: Residents and Faculty Clinical Competency Committee (CCC). INTERVENTIONS: None. MEASUREMENTS: Resident and CCC milestone scores. MAIN RESULTS: Correlation coefficients for average score for each milestone vs PGY level ranged from 0.80 for receiving and giving feedback to 0.95 for anesthetic choice and conduct. All milestones showed a relatively linear relationship with PGY of training, and none were found to be consistently reached very late or very early in training. When examining variation across the scores for the individual residents, the distributions for PGY-2 and -3 appeared to be wider than those for PGY-1 and -4. The intraclass correlation coefficients ranged from 0.718 to 0.928. CONCLUSIONS: There was a remarkable degree of consistency in the relationship between level of training and resident self-assessment score for every milestone, as well as strong agreement between the resident and CCC faculty scores. Examination of the variance in the scores, when interpreted in light of our particular training program's characteristics, suggests that the milestones accurately reflect the progression in skill across the residency. In addition, given the concordance between the self-evaluation scores and the CCC faculty scores, self-evaluation may be a reasonable starting point as programs begin the daunting task of determining scores for each of the 25 milestones as part of the biannual evaluation process.