Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: current status and future directions.

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics.

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Control of Postprandial Hyperglycemia in Type 1 Diabetes by 24-Hour Fixed-Dose Coadministration of Pramlintide and Regular Human Insulin: A Randomized, Two-Way Crossover Study.

OBJECTIVE: Healthy pancreatic ß-cells secrete the hormones insulin and amylin in a fixed ratio. Both hormones are lacking in type 1 diabetes, and postprandial glucose control using insulin therapy alone is difficult. This study tested the pharmacodynamic effects of the amylin analog pramlintide and insulin delivered in a fixed ratio over a 24-h period. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes were stabilized on insulin pump therapy with insulin lispro before a randomized, single-masked, two-way crossover, 24-h inpatient study in which regular human insulin was administered with pramlintide or placebo using separate infusion pumps in a fixed ratio (9 µg/unit). Meal content and timing and patient-specific insulin doses were the same with each treatment. The primary outcome measure was change in mean glucose by continuous glucose monitoring (CGM). Profiles of laboratory-measured glucose, insulin, glucagon, and triglycerides were also compared. RESULTS: Mean 24-h glucose measured by CGM was lower with pramlintide versus placebo (8.5 vs. 9.7 mmol/L, respectively; P = 0.012) due to a marked reduction of postprandial increments. Glycemic variability was reduced, and postprandial glucagon and triglycerides were also lower with pramlintide versus placebo. Gastrointestinal side effects were more frequent during use of pramlintide; no major hypoglycemic events occurred with pramlintide or placebo. CONCLUSIONS: Coadministration of fixed-ratio pramlintide and regular human insulin for 24 h improved postprandial hyperglycemia and glycemic variability in patients with type 1 diabetes. Longer studies including dose titration under daily conditions are needed to determine whether this regimen could provide long-term improvement of glycemic control.

Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin.

We compared intrasubject variability of insulin and glucose profiles after a standardized meal between insulin inhaled via the AERx insulin Diabetes Management System (AERx iDMS, Aradigm Corp., Hayward, CA) and given as a subcutaneous injection. In this single-center, parallel, randomized, open-labeled trial, 17 male, non-smoking patients with type 1 diabetes (mean age, 27.7 years; body mass index, 23.4 kg/m(2)) received a fixed, individualized dose of human insulin, on four treatment days followed by an individualized breakfast, administered either by inhalation via AERx iDMS (n = 9) or by subcutaneous injection. Serum insulin and serum glucose levels were determined at regular intervals for 6 h postdose. Intrasubject variability was expressed as coefficient of variation. No statistically significant differences in intrasubject variability were observed between the treatments for the areas under the insulin curves for 0-6 h [27% vs. 19% (inhaled insulin vs. subcutaneous)] and areas under the glucose curves 0-6 h (30% vs. 23%). Intrasubject variability values for insulin half-life, terminal elimination rate constant, and mean residence time were significantly less in the inhaled insulin group compared with the subcutaneous insulin group (P = 0.01-0.02). Only one potentially trial product-related adverse event (an audible wheeze) was reported, and no clinically relevant changes in pulmonary function were detected. The intrasubject variability was comparable between patients receiving inhaled insulin and subcutaneous insulin, thereby confirming the reproducibility of administering insulin via AERx iDMS. Inhaled insulin was well tolerated and is a feasible alternative to subcutaneous insulin in patients with type 1 diabetes.