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Despite extensive research on the impact of warming and nitrogen deposition on soil organic carbon components, the response mechanisms of microbial community composition and enzyme activity to soil organic carbon remain poorly understood. This study investigated the effects of warming and nitrogen deposition on soil organic carbon components in the Tibetan Plateau alpine meadow and elucidated the regulatory mechanisms of microbial characteristics, including soil microbial community, enzyme activity, and stoichiometry, on organic carbon components. Results indicated that both warming and nitrogen deposition significantly increased soil organic carbon, readily oxidizable carbon, dissolved organic carbon, and microbial biomass carbon. The interaction between warming and nitrogen deposition influenced soil carbon components, with soil organic carbon, readily oxidizable carbon, and dissolved organic carbon reaching maximum values in the W0N32 treatment, while microbial biomass carbon peaked in the W3N32 treatment. Warming and nitrogen deposition also significantly increased soil Cellobiohydrolase, ß-1,4-N-acetylglucosaminidase, leucine aminopeptidase, and alkaline phosphatase. Warming decreased the soil enzyme C: N ratio and C:P ratio but increased the soil enzyme N:P ratio, while nitrogen deposition had the opposite effect. The bacterial Chao1 index and Shannon index increased significantly under warming conditions, particularly in the N32 treatment, whereas there were no significant changes in the fungal Chao1 index and Shannon index with warming and nitrogen addition. Structural equation modeling revealed that soil organic carbon components were directly influenced by the negative impact of warming and the positive impact of nitrogen deposition. Furthermore, warming and nitrogen deposition altered soil bacterial community composition, specifically Gemmatimonadota and Nitrospirota, resulting in a positive impact on soil enzyme activity, particularly soil alkaline phosphatase and ß-xylosidase, and enzyme stoichiometry, including N:P and C:P ratios. In summary, changes in soil organic carbon components under warming and nitrogen deposition in the alpine meadows of the Tibetan Plateau primarily depend on the composition of soil bacterial communities, soil enzyme activity, and stoichiometric characteristics.
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AIM: To explore the reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products (OIDPs). METHODS: Screening data of 1 432 healthy subjects who participated in clinical trials of OIDPs were collected. The main reasons for the screening failure, gender differences in screening failure rate and the correlation between age and screening failure rate were summarized and analyzed. RESULTS: The screening failure rate was 72.4 % and increased with age. The failure rate was slightly higher in females than in males. Besides abnormal vital signs (17.3%), abnormal laboratory test results (16.5%) and withdrawal of consent (7.6%), poor venous condition (13.9%), positive for cigarette test results (12.6%) and failure in inhalation training (7.1%) were also the other three main reasons affecting the screening success rate. Abnormal vital signs and poor venous conditions were the primary screening failure reasons for males and females, respectively. CONCLUSION: The screening success rate could be improved by informing fully and communicating effectively, selecting young subjects with strong understanding abilities, and enhancing the training skills of investigators.
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AIM: To investigate the safety of bioequivalence (BE) studies of orally inhaled drug products (OIDPs) conducted by Phase I clinical Research Center of our hospital. METHODS: The safety data were collected from 482 healthy subjects enrolled in 20 OIDPs BE studies in Wuxi People's hospital from 2017 to 2022. The difference of adverse events (AEs) between test preparation and reference preparation were compared, as well as the influence of gender, age, mechanism of drug action and device type on AE were analyzed. RESULTS: A total of 102 cases of AEs were occurred in 77 subjects (16.0%, 77/482), 87 cases of AEs were related to experimental drugs, all AEs were mild or moderate, and no serious adverse events occurred. There was no difference in the incidence of AE between test preparation and reference preparation. In addition, gender, age, mechanism of drug action and device type had no significant effects on AEs. CONCLUSION: In 20 bioequivalence studies of OIDPs, OIDPs were safe and well tolerated in healthy subjects after dosing, and safety features of generic OIDPs and original drug were basically similar.
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Chronic kidney disease （CKD） is a global health problem， and its incidence increases year by year. Studies have revealed that the progression of CKD into end-stage renal disease （ESRD） is related to its inability to effectively eliminate toxins due to decreased renal function. Additionally， intestinal microflora produces a large amount of gut-derived uremic toxins （GDUTs） during protein fermentation. The theory of gut-kidney axis holds that gut and kidney interact with each other， and CKD reduces the ability to remove uremic toxins （UTs）， resulting in the accumulation of UTs in the blood. The accumulation of UTs also accelerates the deterioration of renal function， leading to a vicious circle. This paper focused on the sources of indoxyl sulfate and p-cresol sulfate in GDUTs and their mechanisms against CKD （such as inducing renal tubular cell death， oxidative stress and endothelial injury， promoting renal fibrosis and down-regulating renal protective protein） as well as the sources of trimethylamine oxide and its mechanisms against CKD （such as promoting renal fibrosis and inflammation）. Moreover， starting from gut-kidney axis， this paper summarized the ways of diet and nutrition regulation， toxin adsorption， enhanced dialysis to increase the clearance， inhibiting the sources of gut-derived toxins and traditional Chinese medicine （TCM） therapy （TCM preparations and TCM active ingredients） to regulate intestinal microecology and reduce the generation of GDUTs， aiming to provide new therapeutic ideas for delaying the progression of CKD.
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Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs.
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Objective: To analyze the distribution and drug resistance characteristics of clinical separation germ in a hospital from 2013 to 2015 to provide reference and basis for the prevention and control of nosocomial infection and rational use of antibiotics.Methods: The microbial susceptibility of isolated strains was detected using the conventional methods, and the drug sensitivity was analyzed by BioMerieux ATB 1.22.The drug sensitivity was determined according to CLSI 2014 criteria.Results: A total of 18 421 specimens were isolated during 2013 and 2015, and a total of 3 744 strains were isolated with the total positive rate of 20.32%.The separation and identification of pathogenic bacteria at the top 5 were Escherichia coli (967 strains, 44.34%), Bauman Acinetobacter (323 strains, 14.81%), Klebsiella pneumoniae (312 strains, 14.31%), Staphylococcus aureus (297 strains 13.62%) and Pseudomonas aeruginosa (282 strains, 12.92%).Besides the natural resistance of Klebsiella pneumoniae to amoxicillin, the resistance rate of Escherichia coli to piperacillin was over 75%, while the sensitivity rate of Klebsiella pneumoniae to piperacillin and tazobactam was more than 90%.The sensitivity of Acinetobacter baumannii and Pseudomonas aeruginosa to clinical antibiotics was basically below 40%, and the overall resistance level was higher than that of Bauman.MRSA was sensitive to nitrofurantoin, minocycline, quinupristin-Dafoe and leptin glycopeptide antibiotics (such as teicoplanin and vancomycin).Conclusion: The hospital should strengthen the monitoring of bacterial resistance and track the results in a timely manner so as to provide reference for the rational drug use in clinical practice.
