Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

Predicting the current fishable habitat distribution of Antarctic toothfish (Dissostichus mawsoni) and its shift in the future under climate change in the Southern Ocean.

Global warming continues to exert unprecedented impacts on marine habitats. Species distribution models (SDMs) are proven powerful in predicting habitat distribution for marine demersal species under climate change impacts. The Antarctic toothfish, Dissostichus mawsoni (Norman 1937), an ecologically and commercially significant species, is endemic to the Southern Ocean. Utilizing occurrence records and environmental data, we developed an ensemble model that integrates various modelling techniques. This model characterizes species-environment relationships and predicts current and future fishable habitats of D. mawsoni under four climate change scenarios. Ice thickness, depth and mean water temperature were the top three important factors in affecting the distribution of D. mawsoni. The ensemble prediction suggests an overall expansion of fishable habitats, potentially due to the limited occurrence records from fishery-dependent surveys. Future projections indicate varying degrees of fishable habitat loss in large areas of the Amery Ice Shelf's eastern and western portions. Suitable fishable habitats, including the spawning grounds in the seamounts around the northern Ross Sea and the coastal waters of the Bellingshausen Sea and Amundsen Sea, were persistent under present and future environmental conditions, highlighting the importance to protect these climate refugia from anthropogenic disturbance. Though data deficiency existed in this study, our predictions can provide valuable information for designing climate-adaptive development and conservation strategies in maintaining the sustainability of this species.

Influence of polystyrene microplastics on the growth, photosynthetic efficiency and aggregation of freshwater microalgae Chlamydomonas reinhardtii.

Microplastics are ubiquitous in aquatic ecosystems worldwide, but knowledge on their impacts on phytoplankton, especially freshwater microalgae, is still limited. To investigate this issue, microalgae Chlamydomonas reinhardtii was exposed to polystyrene (PS) microplastics with 4 concentration gradients (5, 25, 50 and 100 mg/L), and the growth, chlorophyll a fluorescence, photosynthetic activities (Fv/Fm), the contents of malondialdehydes (MDA), soluble proteins, extracellular polymeric substances (EPS) and settlement rate were accordingly measured. Results showed that the density of microalgae decreased as the increase of PS microplastics concentrations, and the highest inhibitory rate (IR) was 45.8% on the 7th day under the concentration of 100 mg/L. The high concentration (100 mg/L) of microplastics evidently inhibited the content of EPS released by microalgae into the solution. PS under all dosages tested could reduce both the chlorophyll a fluorescence yields and photosynthetic activities. The scanning electron microscope (SEM) images demonstrated that microplastic beads were wrapped on the surface of microalgae and damaged their membranes, which could suggest the reduction of photosynthetic activities and the increase of soluble proteins and MDA content. The results also showed that PS microplastics could inhibit the settlement of microalgae at the later stage, which also indicated the recovery of microalgae from the toxic environment. Our findings will contribute to understanding the effects of microplastics on freshwater microalgae, as well as evaluating the possible influences of microplastics on aquatic ecosystems.