Study of the mass balance, biotransformation and safety of [14C]SHR8554, a novel μ-opioid receptor injection, in healthy Chinese subjects

Background: SHR8554 is a novel μ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects.Methods: A single 1 mg/41.3 μCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatography-tandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection.Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed.Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/, identifier CTR2022045

A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects.Methods: In this phase 1 trial, 36 healthy subjects aged ≥18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated.Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5–5 mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5–1.5 h, and the apparent terminal t1/2z ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46–1927 were observed in multiple-dose group.Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia.Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR2020197

A new mathematical mixed effect model was used for analysing the influencing factors of hypoglycaemia of newborns from women with gestational diabetes mellitus

A mathematical mixed effect model was established to analyse the factors of neonatal hypoglycaemia of gestational diabetes mellitus (GDM). 229 cases of GDM patients were enrolled in this study. The data were analysed by logarithmic transformation of non-normal distribution. Furthermore, the mathematical model was used to analyse influencing factors of hypoglycaemia of neonatal from women with GDM. The results showed that the blood glucose distribution level had a trend of increasing with time, which indicates that it is necessary to strengthen blood glucose intervention of newborns from GDM maternal and provides a data for the timely detection of hypoglycaemia in GDM newborns. Furthermore, we successfully established the GDM newborn blood glucose level mixed mathematical model. From this model, we calculated the GDM newborn blood glucose normal confidence interval based on mixed factors. The results indicate that the minimum value of blood glucose level in GDM newborns did not exceed the risk level 2.2 mmol/L. We concluded that the mathematical mixed effect model is successfully established, from which the change discipline of blood glucose level of newborn from GDM parturient are found. Impact statement What is already known on this subject? The morbidity of gestational diabetes mellitus (GDM) in China has been increased. However, the clinical data is difficult to be collected and the data that is used for statistics is not enough, which makes it difficult to understand the neonatal hypoglycaemia of GDM more clearly. What do the results of this study add? In this study, we successfully established a mathematical mixed effect model of neonatal hypoglycaemia of women with GDM, which can investigate the influence factor of hypoglycaemia of newborn from women with GDM to find the discipline of blood glucose level of newborn from GDM parturient via mathematical model. What are the implications of these findings for clinical practice and/or further research? Our research helps to better understand and improve the health problem of pregnant women with GDM and their newborn babies

Zonotope-based quantification of the impact of renewable power generation on hybrid AC/DC distribution system

Hybrid AC/DC distribution network has developed rapidly owing to its convenience for renewable energy integration, thus the authors are interested in quantifying the impact of uncertainty from renewable power on system static performance. This paper proposes a zonotope-based set-theoretic method for quantifying the impact of renewable power fluctuations on system-state variables in hybrid AC/DC distribution network, both for the assessment of the capabilities for integrating renewable resources by hybrid AC/DC system, and for the appropriate selection of operating method in hybrid power systems. The authors bound the uncertain variations of generation by a zonotope and propagate it through a linearised power flow to get another zonotope, which captures all possible values of the system state variables. The zonotope-based method is computationally tractable and takes less computation than probabilistic methods especially when considering the generation uncertainty of multiple renewable energy resources. The proposed method is applied to a hybrid AC/DC test system with different control strategies of converters. The results show that hybrid AC/DC system with proper control mode may help reduce the impact of generation uncertainty

An Improved U-Net for Watermark Removal

Convolutional neural networks (CNNs) with different layers have performed with excellent results in watermark removal. However, how to extract robust and effective features via CNNs of black box in watermark removal is very important. In this paper, we propose an improved watermark removal U-net (IWRU-net). Taking the robustness of obtained information into account, a serial architecture is designed to facilitate useful information for guaranteeing performance in watermark removal. Taking the problem of long-term dependency into account, U-nets based simple components are integrated into the serial architecture to extract more salient hierarchical information for addressing watermark removal problems. To increase the adaptability of IWRU-net to the real world, we use randomly distributed blind watermarks to implement a blind watermark removal model. The experiment results illustrate that the proposed method is superior to other popular watermark removal methods in terms of quantitative and qualitative evaluations

Fresh versus frozen embryo transfer for full-term singleton birth: a retrospective cohort study

Abstract Background Improvements in vitrification and frozen embryo transfer (FET) technologies have rapidly increased, and some evidence suggests that FET may increase pregnancy rates and lead to more favourable perinatal outcomes. However, the outcome of interest should be offspring safety. Therefore, the primary objective of our study was to investigate whether FET was preferable to fresh embryo transfer (ET) in terms of full-term neonatal birthweight and congenital malformations. Methods This was a retrospective cohort study of patients with no pregnancy-related complications who underwent first fresh ETs (n = 2059) or FETs (n = 2053), resulting in full-term singletons births. Outcome measures were neonatal birthweight, low birthweight (LBW), small-for-gestational age (SGA), large-for-gestational age (LGA), macrosomia and congenital malformations. Additionally, we used logistic regression to adjust for baseline characteristics (age, BMI, No. of embryos transferred and embryo stage) between the two groups. Results The mean neonatal birthweight was higher for singletons born after FET than for singletons born after fresh ET (3468.7 ± 475.3 vs. 3386.7 ± 448.1; p < 0.001). The frequencies of full-term singleton LBW and SGA after FET were significantly lower than those after fresh ET (1.7% vs. 3.0 and 4.4% vs. 6.7%, respectively), with adjusted rate ratios of 0.59 (95% CI, 0.37 to 0.98; p = 0.026) and 0.73 (95% CI, 0.55 to 0.99; p = 0.041), respectively. FET resulted in higher frequencies of macrosomia and LGA (15.1% vs 10.2 and 22.8% vs. 17.5%, respectively) than fresh ET, with adjusted rate ratios of 1.43 (95% CI, 1.16 to 1.75; p = 0.001) and 1.26 (95% CI, 1.07 to 1.49; p = 0.007), respectively. Furthermore, the incidence of congenital malformations was not different between the two groups (1.2% vs. 0.9%), with a rate ratio of 0.288. Conclusions After the cycles with pregnancy-related complications were excluded and after adjustments for baseline characteristics, women undergoing FET were associated with a higher neonatal birthweight than women undergoing fresh ET cycles. Additionally, the FET protocol was associated with lower rates of LBW and SGA and higher rates of macrosomia and LGA than the fresh ET protocol. Meanwhile, no difference in the congenital malformation rate was evident between the two groups

Construction and application of enhanced recovery after surgery‐optimized management system with nurse‐led multidisciplinary cooperation

Abstract Aim To evaluate the effect of enhanced recovery after surgery (ERAS)‐optimized management system with nurse‐led multidisciplinary cooperation. Design A quasi‐experimental design. Methods Nursing department cooperated with medical and clinical department to establish an ERAS‐optimized management system. After the system was developed, it was applied in surgical departments of the hospital. Using convenience sampling, 220 selective surgical patients, 82 nurses and 98 doctors from January 1st, 2021 to July 31st, 2021 were selected as the trial group. 220 selective surgical patients, 82 nurses and 98 doctors were selected as the control group from January 1st, 2020 to July 31st, 2020. ERAS observation indicators were compared between the two groups before and 6 months after implementation. The nurse professional identity scores and satisfaction of medical cooperation scores of the two groups at different time points were analysed by repeated analysis of variance. Results After the implementation, ERAS observation indicators in the trial group were better than the control group (p < 0.05). There were significant differences in the group main effect, time main effect and interaction effect of nurse professional identity scores, satisfaction of medical cooperation scores and scores in all dimensions between the two groups (p < 0.05). The scores of the experimental group at 3 months and 6 months after implementation were better than those of the control group (p < 0.05). Conclusions Enhanced recovery after surgery‐optimized management system with nurse‐led multidisciplinary cooperation was an effective working method. It could promote patients recovery and enhance nurse professional identity

Circular RNAs as Potential Theranostics in the Cardiovascular System

Cardiovascular diseases (CVDs) represent the largest contributor to mortality worldwide. Identification of novel therapeutic targets and biomarkers for CVDs is urgently needed. Circular RNAs (circRNAs) are endogenous, abundant, and stable non-coding RNAs formed by back-splicing events. Their role as regulators of gene expression has been increasingly reported. Notably, circRNAs mediate essential physiological and pathological processes in the cardiovascular system. Our first aim, therefore, is to summarize recent advances in the role of circRNAs in cardiac development as well as in pathogenesis of various CVDs. Because circRNAs are stable in circulation and their dynamic changes may reflect different disease stages, they are considered ideal biomarkers. Therefore, our second aim is to review studies that have identified circulating circRNAs as biomarkers for CVDs. Finally, we discuss the shortage of functional studies and the limitations of available clinical studies and provide future perspectives