Factors impeding physical activity in older hospitalised patients: A qualitative meta-synthesis.

BACKGROUND: Older hospitalised patients have low levels of physical activity and multiple impairing factors. AIMS: To systematically evaluate the perceived barriers to physical activity among older patients during hospitalisation, and provide reference for future intervention programs. DESIGN: Following ENTREQ, do a systematic evaluation and synthesis of qualitative investigations. METHODS: An exhaustive exploration was conducted across the CNKI, Wanfang Database, VIP Database, China Biomedical Literature Database, PubMed, Embase, Cochrane Library and Web of Science from their inception until August, 2023 to identify qualitative research on obstacles to physical activity among older hospital patients. The quality of the literature was evaluated using the Joanna Briggs Institute's critical appraisal tool for qualitative research. Meta-synthesis method was used to integrate the results. RESULTS: In total, 8 literatures were included, 43 themes were extracted, and analogous research results were amalgamated to generate 10 categories and 3 syntheses: individual level, interpersonal influencing factors and hospital environment and resources level. CONCLUSION: Older inpatients are faced with multiple barriers to physical activity. Medical staff should pay attention to changes in physical activity during hospitalisation, identify barriers to physical activity in older inpatients and provide references for promoting physical activity programs for the older. NO PATIENT OR PUBLIC CONTRIBUTION: This study is a meta-synthesis and does not require relevant contributions from patients or the public. WHAT IS ALREADY KNOWN: Older patients are at low physical activity levels during hospitalisation. Older inpatients are faced with multiple barriers to physical activity. WHAT THIS PAPER ADDS: Factors of physical activity impairment in hospitalised older patients should be considered in the context of health status, psychological factors, motivation and social support. Disease-induced psychological fallout has a greater impact on physical activity in the older.

Risk Factors and Patient-Reported Outcomes in Chinese Women with Postpartum Diastasis Recti Abdominis: An Observational Study.

Purpose: Diastasis recti abdominis (DRA) is a condition in which the linea alba is stretched and widened, and the abdominal muscles are separated from each other. DRA typically occurs in pregnant and postpartum women. We aimed to determine the risk factors and patient-reported outcomes (PROs) of DRA in Chinese postpartum women. Methods: This observational study was conducted in Hangzhou Hospital of Traditional Chinese Medicine, and involved 534 women who filled out the following risk-factor and PRO questionnaires: SF-MPQ-2, SF-ICIQ, LDQ, EPDS, MBIS, HerQles, and SF-36 (all Chinese versions). The inter-recti distance was measured by palpation. Statistical analyses were performed using SPSS v25.0 software and the Mann-Whitney U-test, chi-square test, binary logistic regression analysis (for risk factors of DRA), and the Kendall and Spearman tests (for correlation analysis). Results: After childbirth, 78.1% (417/534) of the enrolled women had DRA. Abdominal surgery (P = 0.002), number of pregnancies (P = 0.035), parity (P = 0.012), number of births (P = 0.02), fetal birth weight (P = 0.014), and waist-to-hip ratio in the supine position (P = 0.045) significantly differed between the DRA and non-DRA groups. Caesarean delivery was an independent risk factor for DRA. The PROs were significantly worse in the DRA group than in the non-DRA group. Conclusion: Caesarean delivery was an independent risk factor for DRA. Women with DRA are more likely to have limited physical activity or function after childbirth, lower self-confidence, and a decreased quality of life.

Broadband short-wave near-infrared-emitting phosphor MgNb2O6:Cr3+ for pc-LED applications.

Broadband short-wave near-infrared (NIR) phosphor-converted light-emitting diodes (pc-LEDs) have been attracting keen interest for miniature NIR spectroscopy, while still lacking sufficient novel broadband NIR-emitting phosphors. Herein, we report a novel MgNb2O6:Cr3+ polycrystalline phosphor with a broad NIR emission band centered at 970 nm and a large full-width at half-maximum of approximately 155 nm under excitation of bluish-green light at around 515 nm. The optimized phosphor MgNb2O6:1%Cr3+ features a high internal quantum efficiency (IQE) of ∼85.5% and a moderate external QE of 25.2%. The fluorescence properties determined by two distorted hexa-coordination octahedral sites (i.e. [MgO6] and [NbO6]), low crystal field strength (Dq/B ∼ 1.65), and Cr3+-doping concentration were systematically investigated for comprehensive understanding of photophysical mechanisms. Besides, this broadband NIR phosphor MgNb2O6:Cr3+ exhibits a moderate thermal quenching of 21.4%@373 K for pc-LED application. An NIR pc-LED self-built by combining the optimal phosphor with a commercial cyan of ∼515 nm exhibits an NIR output power increase from 3.19 to 11.38 mW as the drive current is varied from 40 to 220 mA. With the help of this prototype pc-LED device, multiple applications were successfully performed to clearly recognize blood vessel distributions in the human finger, penetrate a plastic cap, and distinguish multi-color text. Undoubtedly, further development of such broadband short-wave NIR-emitting phosphors will make novel pc-LED devices for significant applications in biomedical imaging, nondestructive safety detection, intelligent identification, etc.

Chicken feedlot revisited: Co-dispersal of antibiotic and metal resistome under banning in-feed veterinary antibiotics.

Intensive livestock farming has been implicated as a notorious hotspot for antibiotic resistance genes (ARGs) due to the excessive or inappropriate use of in-feed antibiotics over the past few decades. Since China implemented a ban on the use of antibiotics in animal feed since 2020, the dissemination of ARGs in the vicinity of feedlots has remained unclear. This study presents a case study that aims to investigate the dispersal of antibiotics and ARGs from a chicken feedlot (established in 2020) to the adjacent aquatic and soil environments. Comparing the sample collected from upstream area, the water and sediment samples from midstream and downstream areas showed an increase in total antibiotic residues and metal content (Cu and Zn) by 4.2-5.3 fold and 1.3-22.6 fold, respectively. The downstream water samples exhibited a 2.49-2.93-fold increase in the abundance of ARGs and a 1.48-1.75-fold increase in the abundance of metal resistance genes (MRGs). The results of Pearson correlation and metagenome-assembled genome revealed a tendency for the co-occurrence of ARGs and MRGs. The dissemination of ARGs and MRGs is primarily driven by tetracycline, tylosin, Cu, and, Mn, with mobile genetic elements playing a more significant role than bacterial communities. These findings shed light on the overlooked co-dispersal pattern of ARGs and MRGs in the environment surrounding feedlots, particularly in the context of banning in-feed veterinary antibiotics.

Hypertension and hyperglycaemia are positively correlated with local invasion of early cervical cancer.

Background: Metabolic disorders are involved in the development of numerous cancers, but their association with the progression of cervical cancer is unclear. This study aims to investigate the association between metabolic disorders and the pathological risk factors and survival in patients with early cervical cancer. Methods: Patients with FIGO IB1 (2009) primary cervical cancer who underwent radical hysterectomy and systematic pelvic lymph node dissection at our institution from October 2014 to December 2017 were included retrospectively. Clinical data regarding the metabolic syndrome and surgical pathology of the patient were collected. The correlations between metabolic disorders (hypertension, hyperglycemia, and obesity) and clinicopathological characteristics as well as survival after surgery were analyzed. Results: The study included 246 patients with clinical IB1 cervical cancer, 111 (45.1%) of whom had at least one of the comorbidities of hypertension, obesity, or hyperglycemia. Hypertension was positively correlated with parametrial invasion and poorly differentiated histology; hyperglycemia was positively correlated with stromal invasion; obesity was negatively associated with lymph node metastasis; but arbitrary disorder did not show any correlation with pathologic features. Hypertension was an independent risk factor for parametrial invasion (OR=6.54, 95% CI: 1.60-26.69); hyperglycemia was an independent risk factor for stromal invasion (OR=2.05, 95% CI: 1.07-3.95); and obesity was an independent protective factor for lymph node metastasis (OR=0.07, 95% CI: 0.01-0.60). Moreover, the patients with hypertension had a significantly lower 5-year OS rate (70.0% vs. 95.3%, P<0.0001) and a significantly lower 5-year PFS rate than those without hypertension (70.0% vs. 91.2%, P=0.010). Conclusion: Hypertension and hyperglycemia are positively associated with local invasion of early cervical cancer, which need to be verified in multi-center, large scale studies.

Key taxa and mobilome-mediated responses co-reshape the soil antibiotic resistome under dazomet fumigation stress.

Agrochemicals are emergingly being implicated in the widespread dissemination of antibiotic resistance genes (ARGs) in agroecosystems. However, minimal research exists on the disturbance of fumigant on soil ARGs. Focusing on a typical fumigant dazomet in a simulated soil microcosm, we characterized the dazomet-triggered timely response and longstanding dynamic of ARGs at one-fold and two-fold field recommended doses using metagenome and quantitative PCR. Dazomet treatments reduced 13.17%-69.98% of absolute abundance of 16S rRNA gene and targeted ARGs, but, awfully, boosted diversity and relative abundance of ARGs up to 1.33-1.60 and 1.62-1.90 folds, respectively. Approximately 77.28% of changes in relative abundance of ARGs could be explained by bacterial community and mobile genetic elements (MGEs). Mechanistically, primary hosts of ARGs shifted from Proteobacteria (control) to Firmicutes and Actinobacteria (treatments) accompanied with corresponding changes in their abundance by combining community analysis, host tracking analysis and antibiotic resistant bacteria assay. Meanwhile, dazomet exposure significantly increased the incidence of MGEs and stimulated the conjugation of antibiotic-resistant plasmid. In addition, absolute abundance of targeted ARGs gradually recovered in the post-fumigation stage. Collectively, our results elucidate the dazomet-triggered emergence and spread of soil ARGs and highlight the importance of navigating toward rational use of fumigant in agricultural fields.

UVB upconversion of LiYO2:Ho3+,Gd3+ for application in luminescence thermometry.

Development of novel ultraviolet (UV) upconversion materials has been emerging as a hot research topic for application in tunable UV lasers, photocatalysis, sterilization, tagging, and most recently luminescence thermometry. We readily synthesized a series of Ho3+/Gd3+ co-doped LiYO2 upconversion phosphors by a traditional high-temperature reaction. Under excitation from a blue ∼445 nm laser, LiYO2:Ho3+,Gd3+ polycrystalline powders yield intense sharp ultraviolet B (UVB) upconversion luminescence from Gd3+ 6Pj (j = 7/2, 5/2, 3/2) excited states. By means of steady and dynamic photoluminescence spectra, we systematically investigated the involved two-photon absorption upconversion as well as the accompanying energy transfer processes between Ho3+ and Gd3+ ions in the LiYO2 host lattice. Interestingly, the distinguishable UVB luminescence constituents from Gd3+ 6Pj excited states exhibit sensitive temperature dependence in a 353-673 K range. Shedding light on thermal equilibria between Gd3+ 6Pj UV-emitting levels, their luminescence intensity ratios follow Boltzmann statistics for the application of new luminescence thermometry. For the scheme of 6P7/2-6P3/2 thermally coupled levels, it works over a temperature range of 373-673 K with a maximum relative sensitivity (Sr) of about 1.07% K-1 at 373 K, and its 6P7/2-6P5/2 counterpart works over 353-533 K with a maximum Sr of about 0.83% K-1 at 353 K. Overall, our study provides a new pathway to develop UV upconversion materials, and promotes the application of Gd3+-related UV luminescence constituents in sensitive temperature sensing over a wide temperature range.

Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies.

Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment.

Pharmacokinetic bioequivalence, safety, and immunogenicity of GB222, a bevacizumab biosimilar candidate, and bevacizumab in Chinese healthy males: a randomized clinical trial.

BACKGROUND: This study was conducted to compare the similarity of the pharmacokinetics (PKs), safety, and immunogenicity of GB222, a potential bevacizumab biosimilar, to that of reference bevacizumab in Chinese healthy males. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, single-dose, parallel-group clinical trial performed in 84 Chinese healthy males, who were randomly assigned to receive a single infusion dose of 1 mg/kg GB222 or bevacizumab with an 84-days follow-up. The primary endpoint was the area under the plasma concentration-time curve (AUC) from zero to the last quantifiable concentration at time t (AUC0-t). The second endpoints were the safety and immunogenicity evaluation. The PK bioequivalence was verified by the 90% confidence intervals (CIs) of the geometrical mean (GM) ratio for AUC0-t falling within the bioequivalence margin, 80-125%. RESULTS: The PK profiles of GB222 and bevacizumab were comparable. The 90% CIs of GM ratio of GB222 to bevacizumab for AUC0-t was within the pre-specified bioequivalence margin. The most common treatment-related adverse event was sinus bradycardia. Seventeen subjects (20.2%) tested positive for anti-drug antibodies (ADAs). CONCLUSION: GB222 was found to be comparable to bevacizumab in terms of PKs, safety, and immunogenicity for Chinese healthy males. TRIAL REGISTRATION: ChiCTR-IIR-17,011,143.

How Does Green Training Boost Employee Green Creativity? A Sequential Mediation Process Model.

Despite accumulated evidence from previous studies that green creativity is highly emphasized in various industries, limited research has been conducted in the context of public sectors. Drawing on the dynamic componential model of creativity and innovation in organizations, this paper aims to propose and sequentially test the relationship between green training and employees' green creativity through green values and green intrinsic motivation. Based on the data collected in Chinese public sectors (N = 464) at two different time points, the results indicate that green training is positively related to green creativity. Moreover, this relationship is sequentially mediated by green values and green intrinsic motivation. The results in our study advance the emergent literature on green human resource management in the public sector for the practical applications of training and creativity in terms of green management.

Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions.

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N6-methyladenosine (m6A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m6A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m6A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m6A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m6A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

Comparative efficacy and safety of 8 GLP-1RAs in patients with type 2 diabetes: A network meta-analysis.

AIMS: To inform clinical practice by comparing and ranking the lowing blood glucose and weight-loss abilities of 8 glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes (T2D). METHODS: We searched PubMed, EMBASE, and CENTRAL from database inception to April 13, 2021. The outcomes were Δ HbA1c, Δ weight, adverse events [AE] withdrawals, and incidence of hypoglycemia. We estimated standardized mean differences [SMD] and summary odds ratios (ORs) using frequentist network meta-analysis with random effects. RESULTS: Retrieved trials included 11,126 patients, the overall mean age was 56.7 ± 10.36 years old. In terms of efficacy, all GLP-1RAs were more effective than the placebo except albiglutide-30 mg QW (Δ weight: SMD -0.26 kg [95 %CI: -1.10, 0.59 kg). When it came to safety, oral semaglutide-14mgQD, semaglutide-1mgQW, Liraglutide-1.8mgQD, and Exenatide-2ugBID were associated with an increased risk of AE withdrawals. And GLP-1RAs were associated with a higher incidence of hypoglycemia than placebo except albiglutide-30mgQW and orally administered semaglutide-14mgQD. CONCLUSION: Overall GLP-1RAs were more efficacious than placebo in patients with T2D on efficacy. Unfortunately, differences between GLP1-RAs regarding safety were mostly not significant. We may realize the individualized GLP-1RAs administration based on blood glucose level and obesity degree.

A Systematic Review and Meta-Analysis: Safety and Efficacy of Mesenchymal Stem Cells Therapy for Heart Failure.

BACKGROUND: Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating Heart Failure (HF). However, the effects of stem cell therapy in patients with heart failure is an ongoing debate and the safety and efficacy of MSCs therapy are not well-known. We conducted a systematic review of clinical trials that evaluated the safety and efficacy of MSCs for HF. This study aimed to assess the safety and efficacy of MSCs therapy compared to the placebo in heart failure patients. METHODS: We searched PubMed, Embase, Cochrane library systematically, with no language restrictions. Randomized Controlled Trials (RCTs) assessing the influence of MSCs treatment function controlled with placebo in heart failure were included in this analysis. We included RCTs with data on safety and efficacy in patients with heart failure after mesenchymal stem cell transplantation. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Pooled data was performed using the fixed-effect model or random-effect model by the use of Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was safely assessed by death and rehospitalization and the secondary outcome was efficacy, which was assessed by six-minute walk distance and Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-systolic Volume (LVESV), Left Ventricular End-diastolic Volume (LVEDV) and Brain Natriuretic Peptide (BNP). RESULTS: A total of twelve studies were included, involving 823 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 27% (RR [CI]=0.73 [0.49, 1.09], p=0.12) in the MSCs treatment group. The incidence of rehospitalization was reduced by 47% (RR [CI]=0.53[0.38, 0.75], p=0.0004). The patients in the MSCs treatment group realised an average of 117.01m (MD [95% CI]=117.01m [94.87, 139.14], p<0.00001) improvement in 6MWT. MSCs transplantation significantly improved Left Ventricular Ejection Fraction (LVEF) by 5.66 % (MD [95% CI]=5.66 [4.39, 6.92], p<0.00001), decreased Left Ventricular End-Systolic Volume (LVESV) by 14.75 ml (MD [95% CI]=-14.75 [-16.18, - 12.83], p<0.00001) and Left Ventricular End-Diastolic Volume (LVEDV) by 5.78 ml (MD [95% CI]=- 5.78[-12.00, 0.43], p=0.07), in the MSCs group, BNP was decreased by 133.51 pg/ml MD [95% CI]= - 133.51 [-228.17,-38.85], p=0.54, I2= 0.0%) than did in the placebo group. CONCLUSION: Our results suggested that mesenchymal stem cells as a regenerative therapeutic approach for heart failure are safe and effective by virtue of their self-renewal potential, vast differentiation capacity and immune modulating properties. Allogenic MSCs have superior therapeutic effects and intracoronary injection is the optimum delivery approach. In the tissue origin, patients who received treatment with umbilical cord MSCs seem more effective than bone marrow MSCs. As to dosage injected, (1-10)*10^8 cells were of better effect.

Farnesoid X Receptor as a Promising Therapeutic Target for Nonalcoholic Fatty Liver Disease (NAFLD) and the Current Development of Its Agonists.

Nonalcoholic fatty liver disease (NAFLD) comprises a group of clinical syndromes characterized by excessive fat deposition in liver cells. Owing to its increasing incidence, NAFLD has becomea pertinent global health problem as well as an important contributor to the fatality rate of liver and metabolic diseases. Farnesoid X receptor (FXR) has emerged as a new target in the treatment of NAFLD, and related drugs are being reported. This review provides an overview of the structure and function of FXR, along with its important regulatory roles in bile acid metabolism and lipid metabolism. The review also highlights the clinical application of FXR and the progress on basic research related to FXR modulators in NAFLD treatment. Identifying potent FXR modulators, structure-based virtual screening strategy, and the development of new drugs to regulate the allosteric pathway of FXR activity have become effective approaches for the study of novel ligand, which can expand the therapeutic applications of novel FXR agonists. Identification of potential FXR modulators may help elucidate the physiological effects of FXR and provide new opportunities for targeting FXR for metabolic diseases.

Randomised, double-blind, multicentre, phase â /â ¡ dose escalation and expansion trial of GR1501 in patients with plaque psoriasis: study protocol.

INTRODUCTION: Psoriasis is a life-long, immune-mediated disease that greatly reduces the quality of life of patients. Plaque psoriasis is the most common form of psoriasis. Treatment options for plaque psoriasis with good tolerance and sufficient response remain profoundly limited. Based on mechanistic findings that suggest the key pathogenic role of interleukin (IL)-17 in plaque psoriasis, we hypothesise that GR1501, a new monoclonal antibody (IL-17A targeted), will be an efficacious treatment for plaque psoriasis. This phase I/II trial aims to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and preliminary efficacy of GR1501. METHODS AND ANALYSIS: A multicentre, randomised, double-blind, phase I/II dose escalation and expansion trial will be conducted at four hospitals in China. In total, 226 patients with plaque psoriasis will be enrolled in the study, with 46 cases in the dose-escalation stage and 180 cases randomised to GR1501 or the placebo in a 3:1 ratio in the expansion cohort. The primary outcomes are safety and tolerability; the secondary outcomes include pharmacokinetics, immunogenicity and efficacy. ETHICS AND DISSEMINATION: The study is in accordance with the Declaration of Helsinki, and the ethics approvals of the protocol have been obtained from the ethics committees of all participating centres, including Peking University People's Hospital, Chinese PLA General Hospital, The First Affiliated Hospital, College of Medicine, Zhejiang University and the Second Xiangya Hospital of Central South University. The findings of the study will be presented in published journals or at scientific conferences or meetings. TRIAL REGISTRATION NUMBER: ChiCTR1800017956.

A Randomized Study on the Bioequivalence of Desloratadine in Healthy Chinese Subjects and the Association of Different Metabolic Phenotypes With UGT2B10 and CYP2C8 Genotypes.

BACKGROUND: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. OBJECTIVE: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. METHODS: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. RESULTS: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. CONCLUSION: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.

SKF83959, an agonist of phosphatidylinositol-linked dopamine receptors, prevents renewal of extinguished conditioned fear and facilitates extinction.

Fear-related anxiety disorders, such as social phobia and post-traumatic stress disorder, are partly explained by an uncontrollable state of fear. An emerging literature suggests dopamine receptor-1 (D1 receptor) in the amygdala is involved in the regulation of fear memory. An early study has reported that amygdaloid D1 receptor (D1R) is not coupled to the classic cAMP-dependent signal transduction. Here, we investigated whether SKF83959, a typical D1R agonist that mainly activates a D1-like receptor-dependent phosphatidylinositol (PI) signal pathway, facilitates fear extinction and reduces the return of extinguished fear. Interestingly, long-term loss of fearful memories can be induced through a combination of SKF83959 (1 mg/kg/day, i.p., once daily for one week) pharmacotherapy and extinction training. Furthermore, sub-chronic administration of SKF83959 after fear conditioning reduced fear renewal and reinstatement in the mice. We found that the activation D1R and PI signaling in the amygdala was responsible for the effect of SKF83959 on fear extinction. Additionally, SKF83959 significantly promoted the elevation of brain-derived neurotrophic factor (BDNF) expression, possibly by the cAMP response element binding protein (CREB) -directed gene transcription. Given the beneficial effects on extinction, SKF83959 may emerge as a candidate pharmacological approach for improving cognitive-behavioral therapy on fear-related anxiety disorders.

A randomized phase I clinical trial comparing the pharmacokinetic, safety, and immunogenicity of potential biosimilar recombinant human HER2 monoclonal antibody for injection and trastuzumab in healthy Chinese adults.

OBJECTIVES: Recombinant human HER2 monoclonal antibody for injection (AK-HER2) is a potential biosimilar of trastuzumab (Herceptin®). This phase Ⅰ study aimed to demonstrate the pharmacokinetic (PK) equivalence between AK-HER2 and trastuzumab in healthy volunteers. Besides, safety and immunogenicity were investigated. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind phase Ⅰ trial in 96 healthy adults who received a single intravenous infusion of AK-HER2 or trastuzumab at 6 mg/kg. The primary PK endpoints were area under the serum concentration curve (AUC) from time 0 to the last time point (AUC0-t) and peak concentration in serum (Cmax). The PK bioequivalence was confirmed using the standard equivalence margins of 80%-125%. RESULTS: The PK profiles of AK-HER2 and trastuzumab displayed high similarity. The geometric mean ratios (90% confidence intervals) of primary PK endpoints were within 80%-125%. The C max and AUC 0-t of female subjects in the AK-HER2 group were greater than those of male subjects (P <0.05). No infusion-related reactions (IRRs) or anti-drug antibody-positivity was observed after dosing. CONCLUSIONS: AK-HER2 was demonstrated to have highly similar PK to trastuzumab in healthy Chinese adults. Both drugs showed comparable safety and immunogenicity using dexamethasone as premedication to prevent IRRs..

Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants. METHODS: The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model. RESULTS: Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway. CONCLUSIONS: Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.

The long-term efficacy of cytokine-induced killer cellular therapy for hepatocellular carcinoma: a meta-analysis.

Aim: The long-term efficacy of cytokine-induced killer cellular therapy for hepatocellular carcinoma patients after curative treatments remains controversial. Methods: A meta-analysis was conducted, and the outcomes were the recurrence rate and overall survival. Results: Eight randomized clinical trials with 1038 participants were included. Compared with the control group, cytokine-induced killer cellular therapy group could reduce 1-year, 3-year recurrence rates, as well as improve 1-5 years overall survival for hepatocellular carcinoma patients (p < 0.05). However, it failed to affect the 5-year recurrence rate and 6-year overall survival (p > 0.05). Conclusion: Cytokine-induced killer cellular adjuvant therapy exerted a favorable role in improving early and long-term efficacy for hepatocellular carcinoma patients.