Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: A 24-week, randomized, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Bexagliflozin and dapagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors. No direct comparison of SGLT2 inhibitors in a randomized controlled trial has been reported to date. METHODS: This was a multicenter, randomized, double-blind, active-controlled trial comparing bexagliflozin to dapagliflozin for the treatment of type 2 diabetes mellitus in adults with disease inadequately controlled by metformin. Subjects (n = 406) were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin. The primary endpoint was noninferiority of bexagliflozin to dapagliflozin for the change in glycated hemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included intergroup differences in fasting plasma glucose (FPG), 2-h-postprandial glucose (PPG), body weight, and systolic blood pressure (SBP) from baseline to week 24. The trial also evaluated the safety profiles. RESULTS: The model-adjusted mean change from baseline to week 24 HbA1c was -1.08% for bexagliflozin and -1.10% for dapagliflozin. The intergroup difference of 0.03% (95% confidence interval [CI] -0.14% to 0.19%) was below the prespecified margin of 0.4%, confirming the noninferiority of bexagliflozin. The changes from baseline in FPG, PPG, body weight, and SBP were -1.95 mmol/L, -3.24 mmol/L, -2.52 kg, and -6.4 mm Hg in the bexagliflozin arm and -1.87 mmol/L, -3.07 mmol/L, -2.22 kg, and -6.3 mm Hg in the dapagliflozin arm. Adverse events were experienced in 62.6% and 65.0% and serious adverse events affected 4.4% and 3.5% of subjects in the bexagliflozin and dapagliflozin arm, respectively. CONCLUSIONS: Bexagliflozin showed nearly identical effects and a similar safety profile to dapagliflozin when used in Chinese patients on metformin.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

Impact of Ocean Acidification on the Gut Histopathology and Intestinal Microflora of Exopalaemon carinicauda.

Marine crustaceans are severely threatened by environmental factors such as ocean acidification, but, despite the latter's negative impact on growth, molting, and immunity, its effects on intestinal microflora remain poorly understood. This work studied the gut morphology and intestinal microflora of Exopalaemon carinicauda, grown in seawater of different pH levels: 8.1 (control group), 7.4 (AC74 group), and 7.0 (AC70 group). Ocean acidification was found to cause intestinal damage, while significantly altering the microflora's composition. However, the α-diversity did not differ significantly between the groups. At the phylum level, the relative abundance of Proteobacteria decreased in the acidification groups, while at the genus level, the relative abundance of Sphingomonas decreased. Babeliales was a prominent discriminative biomarker in the AC74 group, with Actinobacteriota, Micrococcales, Beijerinckiaceae, Methylobacterium, and Flavobacteriales being the main ones in the AC70 group. The function prediction results also indicated an enrichment of pathways related to metabolism for the acidification groups. At the same time, those related to xenobiotics' biodegradation and metabolism were inhibited in AC74 but enhanced in AC70. This is the first study examining the impact of ocean acidification on the intestinal microflora of crustaceans. The results are expected to provide a better understanding of the interactions between shrimp and their microflora in response to environmental stressors.

Tafolecimab in Chinese Patients With Hypercholesterolemia (CREDIT-4): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial.

Background: Tafolecimab is a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, developed for the treatment of hypercholesterolemia. Objectives: The purpose of this study was to assess the efficacy and safety of tafolecimab in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. Methods: Patients with diagnoses of heterozygous familial hypercholesterolemia (HeFH) by the Simon Broome criteria or at high or very high cardiovascular risk with nonfamilial hypercholesterolemia, with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L, were randomized 2:1 to receive tafolecimab or placebo 450 mg every 4 weeks (Q4W) in the 12-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Results: A total of 303 patients were enrolled and received at least 1 dose of tafolecimab (n = 205) or placebo (n = 98). The least squares mean percent change in LDL-C level from baseline to week 12 was -68.9% (SE 1.4%) in the tafolecimab group and -5.8% (1.8%) in the placebo group (difference: -63.0%; [95% CI: -66.5% to -59.6%]; P < 0.0001). More patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C <1.8 mmol/L, and LDL-C <1.4 mmol/L at week 12 than did those in the placebo group (all P < 0.0001). Furthermore, tafolecimab markedly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. During the double-blind treatment period, the most commonly reported adverse events included urinary tract infection (5.9% with tafolecimab vs 4.1% with placebo) and hyperuricemia (3.4% vs 4.1%). Conclusions: Tafolecimab was safe and showed robust lipid-lowering efficacy in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. (A Study of IBI306 in Participants With Hypercholesterolemia; NCT04709536).

A Novel BCC-Structure Zr-Nb-Ti Medium-Entropy Alloys (MEAs) with Excellent Structure and Irradiation Resistance.

Medium-entropy alloys (MEAs) are prospective structural materials for emerging advanced nuclear systems because of their outstanding mechanical properties and irradiation resistance. In this study, the microstructure and mechanical properties of three new single-phase body-centered cubic (BCC) structured MEAs (Zr40Nb35Ti25, Zr50Nb35Ti15, and Zr60Nb35Ti5) before and after irradiation were investigated. It is shown that the yield strength and elongation after fracture at room temperature are greater than 900 MPa and 10%, respectively. Three MEAs were irradiated with 3 MeV Fe11+ ions to 8 × 1015 and 2.5 × 1016 ions/cm2 at temperatures of 300 and 500 °C, to investigate the irradiation-induced hardening and microstructure changes. Compared with most conventional alloys, the three MEAs showed only negligible irradiation hardening and even softening in some cases. After irradiation, they exhibit somewhat surprising lattice constant reduction, and the microstructure contains small dislocation loops. Neither cavities nor precipitates were observed. This indicates that the MEAs have better irradiation resistance than traditional alloys, which can be attributed to the high-entropy and lattice distortion effect of MEAs.

Effect of solid-solution and aging treatment on corrosion behavior of orthogonal designed and vacuum melted Mg-Zn-Ca-Mn alloys.

Fast degradation rate and inhomogeneous corrosion are obstacles for magnesium alloy bio-corrosion properties. In this paper, a quaternary Mg-Zn-Ca-Mn alloy was designed by an orthogonal method and prepared by vacuum induction melting to investigate its bio-corrosion. Microstructure, corrosion morphology, and bio-corrosion properties of as-cast alloys 1 to 5 with good corrosion resistance were characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction with immersion and electrochemical tests in simulated body fluid (SBF), respectively. Both the orthogonal method and in vitro degradation experiments demonstrated that alloy 3 exhibited the lowest degradation rate among the tested quaternary Mg-Zn-Ca-Mn alloys. Then, as-cast alloy 3 was treated by solid-solution and solid-solution aging. In vitro experimental results indicated that as-cast alloy 3 showed better corrosion resistance than heat-treated specimens and the average corrosion rate was approximately 0.15 mm/y. Heat-treated alloy 3 exhibited more uniform corrosion than as-cast alloy specimens. These results suggest that alloy 3 has the potential to become a biodegradable candidate material.

Biocompatibility of bioabsorbable Mg-Ca alloys with rare earth elements addition.

The objectives were to investigate the mechanical strength and biocompatibility of Mg2Ca2Gd and Mg1Ca2Nd (wt%) alloys developed for biomedical application as implantable bioabsorbable devices. Samples were implanted in New-Zealand rabbits tibia for 3, 6 and 8 weeks and compatibility analysis involved whole blood test, biochemistry, histopathology, histology, and radiographs. Refinement in grains were observed in Mg2Ca2Gd alloy; and Mg5Gd, Mg41Nd5, α-Mg and Mg2Ca phases were identified. Polarization curves revealed easier oxidation of Mg2Ca2Gd alloy, smaller values of corrosion rate and a higher polarization resistance of Mg1Ca2Nd. Adequate compatibility of both alloys was identified with pre-osteoblast stem cells. Red and white cells stayed compatible with reference ranges. Enzymes from liver and kidneys stayed at regular values and samples from kidneys and liver tissues presented similar organization to control animals. Histological displays from implantation sites disclosed well-structured tissues with evidences of bone cells activities compatible with the new bone tissues observed. Radiographs from tibias did not revealed relevant gas pockets. Mg2Ca2Gd alloy demonstrated faster degradation. Adequate biocompatibility was observed in Mg-Ca alloys with RE addition, being potential candidates for development of metallic implantable bioabsorbable devices.

Study of the Dynamic Recrystallization Process of the Inconel625 Alloy at a High Strain Rate.

High-temperature compression and electron backscatter diffraction (EBSD) techniques were used in a systematic investigation of the dynamic recrystallization (DRX) behavior and texture evolution of the Inconel625 alloy. The true stress⁻true strain curves and the constitutive equation of Inconel625 were obtained at temperatures ranging from 900 to 1200 °C and strain rates of 10, 1, 0.1, and 0.01 s-1. The adiabatic heating effect was observed during the hot compression process. At a high strain rate, as the temperature increased, the grains initially refined and then grew, and the proportion of high-angle grain boundaries increased. The volume fraction of the dynamic recrystallization increased. Most of the grains were randomly distributed and the proportion of recrystallized texture components first increased and then decreased. Complete dynamic recrystallization occurred at 1100 °C, where the recrystallized volume fraction and the random distribution ratios of grains reached a maximum. This study indicated that the dynamic recrystallization mechanism of the Inconel625 alloy at a high strain rate included continuous dynamic recrystallization with subgrain merging and rotation, and discontinuous dynamic recrystallization with bulging grain boundary induced by twinning. The latter mechanism was less dominant.

Multiscale designs of the chitinous nanocomposite of beetle horn towards an enhanced biomechanical functionality.

Operating mainly as a type of weapon, the beetle horn develops an impressive mechanical efficiency based on chitinous materials to maximize the injury to opponent and simultaneously minimize the damage to itself and underlying brain under stringent loading conditions. Here the cephalic horn of the beetle Allomyrina dichotoma is probed using multiscale characterization combined with finite element simulations to explore the origins of its biomechanical functionality from the perspective of materials science. The horn is revealed to be highly regulated from the macroscopic shape, geometry, and connection with the body to the meso- and microscopic architecture, moisture content, and chemical and structural characteristics. Varying kinds of gradients are integrated at all length-scales. Such designs are demonstrated to benefit the mechanical performance by mitigating stress concentrations, retarding crack propagation, and modulating local properties to better adapt to stress. Enhanced rigidity, robustness and stability are additionally generated from the constrained flexibility endowed by the nanocomposite plywood structure through the reorientation of chitin nanofibrils within the proteinaceous matrix. These findings shed light on the intriguing materials-design strategies of nature in creating synergy of offence and persistence. They may even offer inspiration for the synthesis of high-performance materials and structures, in particular beams to resist bending and torsion.

Degradation mechanism of magnesium alloy stent under simulated human micro-stress environment.

In this study, a vascular stent made of WE43 magnesium alloy was used as a research object and placed in a special physical simulation device constructed independently. This device provided a platform for the study of the degradation of the stent in a dynamic environment. The simulated body fluid of Hank's buffered salt solution flowing inside it would not only make the stent corroded but also apply cyclic shear stress to it, which get closer to the micro-stress environment in human blood vessels. In addition, by means of computer numerical simulation software, ANSYS Fluent 15.0, the fluid-structure interaction (FSI) model was established to simulate the wall shear stress (WSS) exerted by the flowing blood on stent in the blood vessel. Combined with the results of numerical simulation and physical simulation experiments, the degradation mechanism of magnesium alloy sent in an environment similar to the human blood vessels was studied.

Influence of fine-grain and solid-solution strengthening on mechanical properties and in vitro degradation of WE43 alloy.

As one of the most important potential candidate alloys for vascular stent application, Mg-Y-Zr based Mg-4.2wt%Y-2.4wt%Nd-0.6wt%Ce(La)-0.5wt%Zr (WE43) alloys were investigated in combination with the forming processes of micro-tubes with 2.0 mm diameter and 0.1 mm wall thickness. Orthogonal experimental design for alloy composition, vacuum melting ingot, heat treatment, integrated plastic deformation and micro-tube forward extrusion are included in the processing procedures. Significant improvements in both the mechanical properties and corrosion resistance in phosphate buffered saline solution for WE43 alloys were achieved through this processing sequence. The influence of the heat treatment and hot extrusion on in vitro degradation and plasticity was found to be associated with grain size reduction and the redistribution of intermetallic particles within the microstructure. As a result, the mechanical properties and the corrosion resistance of Mg alloys can be improved through fine-grain strengthening and solid-solution strengthening to some extent.