A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis.

BACKGROUND AND AIMS: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm. APPROACH AND RESULTS: Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P < 0.001). The ML HVPG score differentiated patients with normal (0-5 mm Hg) and elevated (5.5-9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P < 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML-HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML-HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML-HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement. CONCLUSIONS: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis.

Innovative virtual screening of PD-L1 inhibitors: the synergy of molecular similarity, neural networks and GNINA docking.

Aims: Immune checkpoint inhibitors targeting PD-L1 are crucial in cancer research for preventing cancer cells from evading the immune system.Materials & methods: This study developed a screening model combining ANN, molecular similarity, and GNINA 1.0 docking to target PD-L1. A database of 2044 substances was compiled from patents.Results: For molecular similarity, the AVALON emerged as the most effective fingerprint, demonstrating an AUC-ROC of 0.963. The ANN model outperformed the Random Forest and Support Vector Classifier in cross-validation and external validation, achieving an average precision of 0.851 and an F1 score of 0.790. GNINA 1.0 was validated through redocking and retrospective control, achieving an AUC of 0.975.Conclusions: From 15235 DrugBank compounds, 22 candidates were shortlisted. Among which (3S)-1-(4-acetylphenyl)-5-oxopyrrolidine-3-carboxylic acid emerged as the most promising.

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THz Thin Film Varactor Based on Integrated Ferroelectric HfZrO2.

In this paper, we present a broadband microwave characterization of ferroelectric hafnium zirconium oxide (Hf0.5Zr0.5O2) metal-ferroelectric-metal (MFM) thin film varactor from 1 kHz up to 0.11 THz. The varactor is integrated into the back-end-of-line (BEoL) of 180 nm CMOS technology as a shunting capacitor for the coplanar waveguide (CPW) transmission line. At low frequencies, the varactor shows a slight imprint behavior, with a maximum tunability of 15% after the wake-up. In the radio- and mmWave frequency range, the varactor's maximum tunability decreases slightly from 13% at 30 MHz to 10% at 110 GHz. Ferroelectric varactors were known for their frequency-independent, linear tunability as well as low loss. However, this potential was never fully realized due to limitations in integration. Here, we show that ferroelectric HfO2 thin films with good back-end-of-line compatibility support very large scale integration. This opens up a broad range of possible applications in the mmWave and THz frequency range such as 6G communications, imaging radar, or THz imaging.

Single column plate plus other column lag screw fixation vs. both column plate fixation for anterior column with posterior hemitransverse acetabular fractures - a biomechanical analysis using different loading protocols.

OBJECTIVES: Open reduction and internal fixation of both columns is considered the treatment of choice for displaced anterior column with posterior hemitransverse (ACPHT) fractures in non-geriatric patients. Plate fixation of one column combined with lag screw fixation of the other column allows to decrease operative time and approach-related morbidity compared to conventional both column plating. The aim of this biomechanical study was to evaluate whether single column plate plus other column lag screw fixation confers similar stability to both column plate fixation. Physiological loads were simulated using both the single-leg stance (SLS) as well as the sit-to-stand (STS) loading protocols. METHODS: A clinically relevant ACPHT fracture model was created using fourth-generation composite hemipelves. Fractures were stabilized with three different fixation constructs: (1) anterior column plate plus posterior column screw fixation (AP+PCS), posterior column plate plus anterior column screw fixation (PP+ACS) and anterior column plate plus posterior column plate fixation (AP+PP). Specimens were loaded from 50 to 750 N with a ramp of 100 N/s. Fracture gap motion (FGM) and relative interfragmentary rotation (RIFR) between the three main fracture fragments were assessed under loads of 750 N using an optical 3D measurement system. RESULTS: STS loading generally resulted in higher mean FGM and RIFR than STS loading in the AP+PCS and AP+PP groups, while no significant differences were found in the PP+ACS group. Compared to conventional both column plate fixation (AP+PP), PP+ACS displayed significantly higher FGM and RIFR between the iliac wing and the posterior column during SLS loading. No significant differences in FGM and RIFR were identified between the AP+PCS and the AP+PP group. CONCLUSION: Overall, single column plate plus other column lag screw fixation conferred similar stability to conventional both column plate fixation. From a clinical point of view, AP+PCS appears to be the most attractive alternative to conventional AP+PP for internal fixation of ACPHT fractures.

Biomechanical comparison of fixation techniques for transverse acetabular fractures - Single-leg stance vs. sit-to-stand loading.

OBJECTIVES: To biomechanically compare five different fixation techniques for transverse acetabular fractures using both the single-leg stance (SLS) and the sit-to-stand (STS) loading protocols and to directly compare fracture gap motion (FGM) and relative interfragmentary rotation (RIFR). METHODS: Transtectal transverse acetabular fractures were created on fourth-generation composite hemipelves in a reproducible manner. Five different fixation techniques were biomechanically assessed using both an SLS and STS loading protocol: anterior plate (AP) only, posterior plate (PP) only, anterior plate plus posterior column screw (AP+PCS), posterior plate plus anterior column screw (PP+ACS) and anterior plus posterior plate (AP+PP). After preconditioning, the specimens were loaded from 50 to 750 N with a ramp of 100 N/s. FGM and RIFR under loads of 750 N were measured using an optical 3D measurement system. RESULTS: In the three groups of fixation techniques addressing both columns, STS loading resulted in higher mean FGM and in RIFR than SLS loading. No construct failure was observed. In the single plate groups (AP only and PP only), STS loading resulted in failure of all specimens before reaching loads of 750 N, while no failure occurred after SLS loading. No significant differences in FGM and RIFR were found between the double plate (AP+PP) and the single plate plus column screw (AP+PCS and PP+ACS) techniques. CONCLUSION: SLS loading appeared to overestimate the strength of acetabular fracture fixation constructs and STS loading may be more appropriate to provide clinically relevant biomechanical data. Internal fixation of a single column might not provide adequate stability for transverse fractures, while strength of single plate plus column screw fixation and double plate fixation was comparable.

Glycoxidized HDL, HDL enriched with oxidized phospholipids and HDL from diabetic patients inhibit platelet function.

CONTEXT: High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). OBJECTIVE: The objective of our study was to investigate the effects of in vitro glycoxidized HDL and HDL from patients with T2D on platelet aggregation and arachidonic acid signaling cascade. At the same time, the contents of hydroxylated fatty acids were assessed in HDL. RESULTS: Compared with control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15-hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively, especially hydroxy derivatives esterified in phospholipids. Glycoxidized HDL dose-dependently decreased collagen-induced platelet aggregation by binding to scavenger receptor BI (SR-BI). Glycoxidized HDL prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. HDL enriched with oxidized phosphatidylcholine (PC), namely PC(16:0/13-HODE) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE, and 15-HETE in phospholipids (2.1-, 2.1-, and 2.4-fold increase, respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation via SR-BI. CONCLUSIONS: Our results suggest that in vitro glycoxidized HDL as well as HDL from patients with T2D inhibit platelet aggregation, and suggest that oxidized LA-containing phospholipids may contribute to the anti-aggregatory effects of glycoxidized HDL and HDL from patients with T2D.