Esketamine vs Midazolam in Boosting the Efficacy of Oral Antidepressants for Major Depressive Disorder: A Pilot Randomized Clinical Trial.

Importance: Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive disorder (MDD); therefore, there is a need to develop novel effective treatment strategies. Objective: To assess the efficacy and safety of a single subanesthetic dose of esketamine in boosting the efficacy of oral antidepressants for treating fluctuating antidepressant response in MDD. Design, Setting, and Participants: This single-center, double-blind, midazolam-controlled pilot randomized clinical trial was conducted at Beijing Anding Hospital, Capital Medical University in China. The study enrolled participants aged 18 years and older with fluctuating antidepressant response, defined as patients with MDD experiencing fluctuating symptoms after symptom relief and stabilization. Patient recruitment was conducted from August 2021 to January 2022, and participants were followed-up for 6 weeks. Data were analyzed as intention-to-treat from July to September 2022. Interventions: All participants in the esketamine-treated group received intravenous esketamine at 0.2 mg/kg in 40 minutes. Participants in the midazolam control group received intravenous midazolam at 0.045 mg/kg in 40 minutes. Main Outcomes and Measures: The primary outcome was the response rate at 2 weeks, defined as a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included response rate at 6 weeks, remission rates at 2 and 6 weeks, and change in MADRS and Clinical Global Impression-Severity score from baseline to 6 weeks; remission was defined by a MADRS score of 10 or lower. Results: A total of 30 patients (median [IQR] age, 28.0 [24.0-40.0] years; 17 [56.7%] female) were randomized, including 15 patients randomized to midazolam and 15 patients randomized to esketamine; 29 patients completed the study. Response rates at 2 weeks were significantly higher in the esketamine-treated group than in the midazolam control group (10 patients [66.7%] vs 1 patient [6.7%]; P < .001). Participants treated with esketamine experienced significantly greater reduction in MADRS score from baseline to 2 weeks compared with those treated with midazolam (mean [SD] reduction, 15.7 [1.5] vs 3.1 [1.3]; P < .001). No serious adverse events were observed in this trial, and no psychotogenic effects and clinically significant manic symptoms were reported. Conclusions and Relevance: This pilot randomized clinical trial found that a single subanesthetic dose of esketamine could boost the efficacy of oral antidepressants in treating fluctuating antidepressant response, with a good safety profile. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100050335.

Purification, Identification, and Mechanistic Investigation of Novel Selenium-Enriched Antioxidant Peptides from Moringa oleifera Seeds.

In this study, five novel Se-enriched antioxidant peptides (FLSeML, LSeMAAL, LASeMMVL, SeMLLAA, and LSeMAL) were purified and identified from Se-enriched Moringa oleifera (M. oleifera) seed protein hydrolysate. The five peptides showed excellent cellular antioxidant activity, with respective EC50 values of 0.291, 0.383, 0.662, 0.1, and 0.123 µg/mL. The five peptides (0.025 mg/mL) increased the cell viability from 78.72 to 90.71, 89.16, 93.92, 83.68, and 98.29%, respectively, effectively reducing reactive oxygen species accumulation and significantly increasing superoxide dismutase and catalase activities in damaged cells. Molecular docking results revealed that the five novel Se-enriched peptides interacted with the key amino acid of Keap1, thus directly blocking the interaction of Keap1-Nrf2 and activating the antioxidant stress response to enhance the ability of scavenging free radicals in vitro. In conclusion, Se-enriched M. oleifera seed peptides exhibited significant antioxidant activity and can be expected to find widespread use as a highly active natural functional food additive and ingredient.

Measure on innovation efficiency of China's pharmaceutical manufacturing industry.

Pharmaceutical manufacturing industry is an important industry to ensure human life safety. The innovation efficiency is a significant factor to stimulate the development of pharmaceutical manufacturing industry. At present, there are few studies on the innovation efficiency of pharmaceutical manufacturing industry. To fill this gap, this paper estimates the innovation efficiency of China's pharmaceutical manufacturing industry in 23 provinces of China from 2010 to 2020 based on the super-network SBM model and Global-Malmquist index. The results show that: (1) From the perspective of efficiency of research and development stage (ERDS), the ERDS of China shows an increasing trend, with the most prominent growth in the western region. (2) From the perspective of efficiency of economic transformation stage (EETS), although there are fluctuations in the EETS, the overall development is good. The EETS of the central region and western region is better than that of the eastern region. (3) By comparing the efficiency of the two stages, it is found that the change direction of the efficiency of the two stages is not necessarily the same in some provinces.

Protective Mechanism of a Layer-by-Layer-Assembled Artificial Cell Wall on Probiotics.

Constructing an artificial cell wall (AFCW) based on the layer-by-layer assembly of polymer films to protect probiotics in harsh conditions is highly desirable. Early findings showed that encapsulating yeast cells by an AFCW improved the cell viability by 50% in antibiotic solution. However, the detailed molecular interaction mechanism remains unclear by experiments. Herein, two ciprofloxacin (CPFX) permeation models, including models 1 and 2 that were, respectively, composed of just the yeast cell membrane and the AFCW coating cell membrane, were investigated by molecular dynamics simulations. The free energy profiles delineating the permeation process of CPFX reveal that the permeation of CPFX through the cell membrane of model 2 is more difficult than through that of model 1. The analysis results show that the AFCW leads to two sharp increases in free energy barriers, amounting to 8.9 and 6.2 kcal/mol, thereby reducing the penetrating rate of CPFX into the cell membrane. Moreover, decomposition of the potentials of mean force into free energy components suggested that the electrostatic interactions of CPFX with the AFCW predominantly contributed to the high free energy barriers. The current results provide a good understanding of the protective mechanism of the self-assembled cell walls against CPFX and help to design other AFCWs.

Impact of antimicrobial stewardship managed by clinical pharmacists on antibiotic use and drug resistance in a Chinese hospital, 2010-2016: a retrospective observational study.

OBJECTIVES: 'National Special Stewardship in the Clinical Use of Antibiotics' was put forward in July 2011 in China. We aimed to retrospectively evaluate the impact of antimicrobial stewardship (AMS) managed by clinical pharmacists on antibiotic utilisation, prophylaxis and antimicrobial resistance (AMR). DESIGN: This was a retrospective observational study of trends in antibiotic use and AMR in the context of AMS. SETTING: Beijing Chaoyang Hospital, a 1400-bed tertiary hospital, in China. DATA AND PARTICIPANTS: Antibiotic prescriptions from 820 doctors included all outpatients (n=17 766 637) and inpatients (n=376 627) during 2010-2016. Bacterial resistance data were from all inpatients (n=350 699) during 2011-2016. INTERVENTIONS: Multiaspect intervention measures were implemented by clinical pharmacists (13 persons), for example, formulating the activity programme and performance management, advising on antibacterial prescriptions and training. OUTCOME MEASURES: The proportion of antibiotic prescriptions among outpatients and inpatients, intensity of consumption in defined daily dose (DDD)/100 bed-days, antibiotic prophylaxis in type I incision operations and resistance rates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were retrospectively analysed. RESULTS: The proportion of antibiotic prescriptions decreased in outpatients (from 19.38% to 13.21%) and in inpatients (from 64.34% to 34.65%), the intensity of consumption dropped from 102.46 to 37.38 DDD/100 bed-days. The proportion of antibiotic prophylaxis decreased from 98.94% to 18.93%. The proportion of rational timing of initial dose increased from 71.11% to 96.74%, the proportion of rational duration rose from 2.84% to 42.63%. Time series analysis demonstrated the resistance rates of E. coli and P. aeruginosa to fluoroquinolones decreased, the incidence rate of methicillin-resistant Staphylococcus aureus also decreased, whereas the resistance rates of E. coli and K. pneumoniae to carbapenems increased. The antibiotic use was partly positively correlated with AMR. CONCLUSIONS: AMS had an important role in reducing antibiotic use and surgical antibiotic prophylaxis. The AMR was positively correlated with antibiotic consumption to some extent.

One-pot synthesis of biomimetic glutathione peroxidase with temperature responsive catalytic behaviors.

Excessive reactive oxygen free radicals (ROS) are the main cause of various oxidative diseases. It is of great significance to develop antioxidant drugs that can intelligently regulate free radical concentrations. The biomimetic simulation of glutathione peroxidase (GPx) can provide an important theoretical basis for the development of antioxidant drugs. In order to explore a simple and efficient strategy for constructing biomimetic GPx, a microgel biomimetic GPx (PNTegel) with temperature responsive catalytic activity was prepared by a one-pot synthesis method. The PNTegel, with typical enzymatic catalytic characteristics, exhibited a maximum catalytic activity at 37 °C (υ 0 = 11.51 mM min-1). The investigation of the catalytic mechanism of PNTegel suggested that the binding of different hydrophobic substrates to PNTegel was altered by the change of hydrophobicity of poly(N-isopropylacrylamide) (PNIPAM) in the microgel scaffold of PNTegel during the temperature response process. The change of hydrophobicity was the main factor for regulating the catalytic activity of PNTegel, which resulted in a temperature responsive catalytic behavior of PNTegel. This new strategy for the simple and efficient construction of biomimetic GPx by a one-pot method provides important theoretical support for exploring the preparation of highly effective antioxidant drugs.

Leapfrog/finite element method for fractional diffusion equation.

We analyze a fully discrete leapfrog/Galerkin finite element method for the numerical solution of the space fractional order (fractional for simplicity) diffusion equation. The generalized fractional derivative spaces are defined in a bounded interval. And some related properties are further discussed for the following finite element analysis. Then the fractional diffusion equation is discretized in space by the finite element method and in time by the explicit leapfrog scheme. For the resulting fully discrete, conditionally stable scheme, we prove an L (2)-error bound of finite element accuracy and of second order in time. Numerical examples are included to confirm our theoretical analysis.

[Optimization of extraction on flavonoids from leaves of Heritiera littoralis].

OBJECTIVE: To optimize the preparation procedure for extraction of flavonoids from leaves of Heritiera littoralis. METHODS: Comparing microwave extraction and ultrasonic extraction, The content of total flavonoids was measure by UV spectrophometry and the wavelength set at 510 nm. The effects of treatment time, extraction power, ethanol concentration and solid-liquid ratio were studied. The orthogonal test of four factors and three levels were studied to obtain the extraction technology of flavonoids from leaves of Heritiera littoralis. RESULTS: The optimal technical conditions were mixing leaves of Heritiera littoralis with 70% ethanol on the ratio of 1 g: 30 mL, when microwave treatment time was 8 min and micro-wave power was 400 W. Under this condition, the extraction rate reached 6.15%. CONCLUSION: This study explores a practical extraction method for flavonoids from leaves of Heritiera littoralis, and lay a good foundation for mangrove medical research in future.