Global distribution and genomic characteristics analysis of avian-derived mcr-1-positive Escherichia coli.

The prevalence of avian-derived Escherichia coli (E. coli) carrying mcr-1 poses a significant threat to the development of the poultry industry and public health safety. Despite ongoing in-depth epidemiological research worldwide, a comprehensive macroscopic study based on genomics is still lacking. In response, this study collected 1104 genomic sequences of avian-derived mcr-1-positive E. coli (MCRPEC) from the NCBI public database, covering 31 countries. The majority of sequences originated from China (48.82 %), followed by the Netherlands (10.41 %). In terms of avian hosts, chicken accounted for the largest proportion (44.11 %), followed by gallus (24.09 %). Avian-derived MCRPEC also serves as a reservoir for other antibiotic resistance genes (ARGs), with 179 ARGs coexisting with mcr-1 identified. A total of 206 virulence-associated genes were also identified, revealing the pathogenic risks of MCRPEC. Pan-genome analysis revealed that avian-derived MCRPEC from different hosts, countries of origin, and serotypes exhibit minor SNP differences, indicating a high risk of cross-regional and cross-host transmission. The ST types of MCRPRC are diverse, with ST10 being the most prevalent (n=70). Spearman analysis showed a significant correlation between the number of ARGs and the insertion sequences (ISs) as well as plasmid replicon in ST10 strains. Furthermore, ST10 strains share a similar genetic basis with human-derived MCRPEC, suggesting the possibility of clonal dissemination. Pan-genome-wide association studies (pan-GWAS) indicated that the differential genes of MCRPEC from different countries and host sources are significantly different, mainly related to genes encoding type IV secretion systems and mobile genetic elements (MGEs). Plasmid mapping of showed that the prevalent plasmid types vary by country and host, with IncI2 and IncX4 being the main mcr-1-positive plasmids. Among the 12 identified mcr-1 genetic contexts with ISs, the Tn6330 transposon was the predominant carrier of mcr-1. In summary, the potential threat of avian-derived MCRPEC cannot be ignored, and long-term and comprehensive monitoring are essential.

The role of JNK signaling pathway in organ fibrosis.

BACKGROUND: Fibrosis is a tissue damage repair response caused by multiple pathogenic factors which could occur in almost every apparatus and leading to the tissue structure damage, physiological abnormality, and even organ failure until death. Up to now, there is still no specific drugs or strategies can effectively block or changeover tissue fibrosis. JNKs, a subset of mitogen-activated protein kinases (MAPK), have been reported that participates in various biological processes, such as genetic expression, DNA damage, and cell activation/proliferation/death pathways. Increasing studies indicated that abnormal regulation of JNK signal pathway has strongly associated with tissue fibrosis. AIM OF REVIEW: This review designed to sum up the molecular mechanism progresses in the role of JNK signal pathway in organ fibrosis, hoping to provide a novel therapy strategy to tackle tissue fibrosis. KEY SCIENTIFIC CONCEPTS OF REVIEW: Recent evidence shows that JNK signaling pathway could modulates inflammation, immunoreaction, oxidative stress and Multiple cell biological functions in organ fibrosis. Therefore, targeting the JNK pathway may be a useful strategy in cure fibrosis.

Protective effect of MP-40 mitigates BDL-induced hepatic fibrosis by inhibiting the NLRP3-mediated pyroptosis.

Background: Hepatic fibrosis and its associated consequences continue to pose a substantial global health challenge. Developing novel approaches to hepatic fibrosis management and prevention is critically necessary. Radix Paeoniae Alba (RPA) is widely used in Traditional Chinese Medicine (TCM) to treat various diseases. Our earlier research found that a bioactive component of RPA had a dose-dependent effect on anti-allergic asthma. RPA reduces allergic asthma by slowing the hepatic wind, according to "Treatise on Febrile Diseases". However, this bioactive fraction's pharmacological effects and mechanisms on the liver are unknown. Aim: This study examined the bioactive fraction MP-40, the methanol extract of RPA (MRPA), on bile duct ligation (BDL) for its anti-hepatic fibrosis activity and potential mechanisms. Methods: First, the effectiveness of MP-40 in treating BDL-induced hepatic fibrosis in mice and rats was evaluated through survival rates, ALT, AST HYP, and pathological changes. Molecular assays were performed using in vitro cultures of HSC-T6 activation. The expression of α-SMA and Collagen I evaluated fibro-tropic factors with HSC activation. Furthermore, the levels of pyroptosis were assessed by examining the expression of the pyroptosis-related proteins, including NLRP3, Cleaved Caspase-1, GSDMD-N, and 1L-1ß. Additionally, the effective constituents of MP-40 were identified by extraction, separation, and identification. Finally, PF and TGG, as the delegate compounds of MP-40, were tested to confirm their inhibition effects on HSC-T6 activation. Results: The findings demonstrated that MP-40 and MRPA could lower ALT, AST, and HYP levels, boost survival rates, and reduce liver damage in BDL mice and rats. Furthermore, MP-40 outperforms MRPA. MP-40 was proven to drastically diminish fibrotic α-SMA and Collagen I. The expression of pyroptosis-related proteins NLRP3, Cleaved Caspase-1, TGF-ß1, GSDMD-N, and 1L-1ß decreased. MP-40 inhibited the synthesis of pyroptosis-related proteins more effectively than MCC950 (an NLRP3-specific inhibitor). Monoterpene glycosides and tannins were shown to be the most potent MP-40 components. Finally, the delegate compounds MP-40, PF, and TGG were shown to have substantial inhibitory effects on HSC-T6 activation. Conclusion: The results proved that MP-40 alleviates BDL-induced cholestatic hepatic fibrosis by inhibiting NLRP3-mediated pyroptosis. PF and TGG play a role in treating BDL-induced cholestatic hepatic fibrosis in MP-40.

Vector competence of Culex quinquefasciatus for Tembusu virus and viral factors for virus transmission by mosquitoes.

The ongoing epidemic of flaviviruses worldwide has underscored the importance of studying flavivirus vector competence, considering their close association with mosquito vectors. Tembusu virus is an avian-related mosquito-borne flavivirus that has been an epidemic in China and Southeast Asia since 2010. However, the reason for the outbreak of Tembusu virus in 2010 remains unclear, and it is unknown whether changes in vector transmission played an essential role in this process. To address these questions, we conducted a study using Culex quinquefasciatus as a model for Tembusu virus infection, employing both oral infection and microinjection methods. Our findings confirmed that both vertical and venereal transmission collectively contribute to the cycle of Tembusu virus within the mosquito population, with persistent infections observed. Importantly, our data revealed that the prototypical Tembusu virus MM_1775 strain exhibited significantly greater infectivity and transmission rates in mosquitoes than did the duck Tembusu virus (CQW1 strain). Furthermore, we revealed that the viral E protein and 3' untranslated region are key elements responsible for these differences. In conclusion, our study sheds light on mosquito transmission of Tembusu virus and provides valuable insights into the factors influencing its infectivity and transmission rates. These findings contribute to a better understanding of Tembusu virus epidemiology and can potentially aid in the development of strategies to control its spread.

N-myc and STAT interactor degrades interferon regulatory factor 7 mediated type I interferon signaling to promote duck Tembusu virus replication.

N-myc and STAT interactor (NMI) is an interferon-induced protein, which plays a variety of biological functions by participating in signal transduction and transcriptional activation, it has been reported to regulate antiviral response of different viruses in many species. However, the role of NMI in ducks during Duck Tembusu Virus (DTMUV) infection is completely unknown. In order to reveal whether duck NMI (duNMI) is involved in the antiviral response in the process of DTMUV infection and its role, we cloned and identified duNMI gene, and conducted sequence analysis of duNMI, the open reading frame region of duNMI gene is 1,137 bp, encoding 378 amino acid residues (aa), including 3 domains, Coiled-coil domain (22-126aa), NMI/IFP 35 domain 1 (NID1) domain (174-261aa) and NMI/IFP 35 domain 2 (NID2) domain (272-360aa). Analysis of tissue distribution of duNMI in 7-day-old ducks shows that the expression of duNMI is the highest in harderian gland, followed by small intestine and pancreas. Subsequently, we found that mRNA level of duNMI increases significantly after DTMUV stimulation, and overexpression of duNMI inhibits DTMUV replication in a dose-dependent manner. Besides, duNMI inhibits the transcriptional activity of IFN-I related cytokines. Specifically, we confirmed that duNMI interacts with duck regulatory factor 7 (duIRF7) through NID1 and NID2 domains and inhibit its expression and activated-IFN-ß. These results support that duNMI is an inhibitor of antiviral innate immune response in the process of DTMUV infection, which will provide a theoretical basis for the prevention of DTMUV infection.

Functions of the UL51 protein during the herpesvirus life cycle.

The herpesvirus UL51 protein is a multifunctional tegument protein involved in the regulation of multiple aspects of the viral life cycle. This article reviews the biological characteristics of the UL51 protein and its functions in herpesviruses, including participating in the maintenance of the viral assembly complex (cVAC) during viral assembly, affecting the production of mature viral particles and promoting primary and secondary envelopment, as well as its positive impact on viral cell-to-cell spread (CCS) through interactions with multiple viral proteins and its key role in the proliferation and pathogenicity of the virus in the later stage of infection. This paper discusses how the UL51 protein participates in the life cycle of herpesviruses and provides new ideas for further research on UL51 protein function.

Host miRNA and mRNA profiles during in DEF and duck after DHAV-1 infection.

DHAV-1 is a highly infectious pathogen that can cause acute hepatitis in ducklings. MicroRNA (miRNA) plays an essential regulatory role in virus response. We characterized and compared miRNA and mRNA expression profiles in duck embryonic fibroblasts (DEF) and the liver of ducklings infected with DHAV-1. DHAV-1 infected DEF was divided into infection group (D group) and blank group (M group), and DHAV-1 infected duckling group was divided into infection group (H group) and blank group (N group). D vs. M have 130 differentially expressed (DE) miRNA (DEM) and 2204 differentially expressed (DE) mRNA (DEG), H vs. N have 72 DEM and 1976 DEG. By the intersection of D vs. M and H vs. N comparisons, 15 upregulated DEM, 5 downregulated DEM, 340 upregulated DEG and 50 downregulated DEG were found with both in vivo and in vitro DHAV-1 infection. In particular, we identified the same DE miRNA target genes and functional annotations of DE mRNA. We enriched with multiple gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may have important roles in viral virulence, host immunity, and metabolism. We selected miR-155, which is co-upregulated, and found that miR-155 targets SOCS1 to inhibit DHVA-1 replication.

Duck enteritis virus LORF4 gene is a late gene and nonessential for virus replication in vitro.

Duck enteritis virus (DEV) is an avian alpha-herpesvirus that primarily causes an acute and highly contagious infectious disease of ducks. The LORF4 gene is one of the specific genes of DEV, with limited reports on its biological characteristics and functions. This study investigates the basic biological properties of LORF4 protein (pLORF4). The results show that DEV LORF4 is a late gene mainly localized in the cytoplasm of DEV-infected DEF. To explore the role of pLORF4 in the DEV replication life cycle, a recombinant virus lacking pLORF4 expression was constructed. The results showed that pLORF4 is not essential for virus replication and does not affect virus adsorption, assembly and release, it plays a positive role in virus invasion and DNA replication. In summary, this study provides a foundation for further research on the function of the LORF4 gene.

Duck hepatitis A virus utilizes PCBP2 to facilitate viral translation and replication.

Duck hepatitis A virus type 1 (DHAV-1) is an important member of the Picornaviridae family that causes highly fatal hepatitis in ducklings. Since picornaviruses have small genomes with limited coding capacity, they must utilize host proteins for viral cap-independent translation and RNA replication. Here, we report the role of duck poly(rC)-binding protein 2 (PCBP2) in regulating the replication and translation of DHAV-1. During DHAV-1 infection, PCBP2 expression was upregulated. A biotinylated RNA pull-down assay revealed that PCBP2 positively regulates DHAV-1 translation through specific interactions with structural domains II and III of the DHAV-1 internal ribosome entry site (IRES). Further studies revealed that PCBP2 promotes DHAV-1 replication via an interaction of its KH1 domain (aa 1-92) with DHAV-1 3Dpol. Thus, our studies demonstrated the specific role of PCBP2 in regulating DHAV-1 translation and replication, revealing a novel mechanism by which host‒virus interactions regulate viral translation and replication. These findings contribute to further understanding of the pathogenesis of picornavirus infections.

The greasy finger region of DTMUV NS1 plays an essential role in NS1 secretion and viral proliferation.

Duck Tembusu virus (DTMUV) of the Orthoflavivirus genus poses a significant threat to waterfowl aquaculture. Nonstructural protein 1 (NS1), a multifunctional glycoprotein, exists in various oligomeric forms and performs diverse functions. The greasy finger (GF) region within NS1 of other flaviviruses has been shown to be a crucial component of the hydrophobic protrusion aiding in anchoring NS1 to the endoplasmic reticulum (ER). However, detailed studies on the role of the GF region in viral proliferation in vitro and the biological properties of NS1 remain scarce. A series of recombinant DTMUV (rDTMUV) with mutations in the GF region, including NS1-F158A, G159A, F160A, G161A, V162A, L163A, F160R, multipoint mutations (GF-4M), or regional deletions (ΔGF), were rescued using a DNA-based reverse genetics system. Only 5 rDTMUV variants (G159A, F160A, G161A, V162A, and L163A) could be rescued successfully, and these mutations were found to impair replication, reduce virulence, and decrease plaque size, as shown by growth kinetics, duck embryo virulence, and plaque assays, respectively. Upon examining NS1 expression by western blot, we discovered that secreted NS1 (sNS1) presented in large quantities in the supernatant of cells infected with rDTMUV-NS1-G159A, whereas intracellular NS1 was less abundant. These mutations also impacted the primary forms and secretion rates of NS1 in cases of overexpression by western blot and indirect ELISA. Exception for F160A and G161A, which showed decreased secretion rates, all other mutations increased sNS1 expression, with the most pronounced increase observed in F158A and ΔGF, and rDTMUV with these mutations can't be rescued. Co-localization studies of NS1 with the ER demonstrated that the ΔGF mutation attenuated NS1 anchoring to the ER, thereby inhibiting its intracellular residence and promoting secretion. Although these effects vary between flaviviruses, our data reveal that the GF region of NS1 is crucial for viral proliferation and NS1 secretion.

Chemokine Receptor 4-Targeted PET/CT with [68Ga]pentixather in Newly Diagnosed Multiple Myeloma: a Comparative Study with [68Ga]pentixafor PET/CT.

PURPOSE: This study aimed to compare the detection rate of [68Ga]pentixather PET/CT and [68Ga]pentixafor PET/CT in newly diagnosed multiple myeloma (NDMM) patients, and to explore the value of [68Ga]pentixather PET/CT for tumor load assessment. METHODS: Nineteen NDMM Patients were prospectively recruited and underwent both [68Ga]pentixather PET/CT and [68Ga]pentixafor PET/CT. A positive PET scan was defined as the presence of PET-positive focal bone lesions, paraskeletal disease, extramedullary plasmacytoma, or diffuse bone marrow uptake. Lesion numbers, SUVmax and PET-related tumor burden values were compared. The correlations between PET-related tumor burden and clinical risk stratification were analyzed. RESULTS: [68Ga]pentixather PET/CT showed a tendency of higher positive rate compared with [68Ga]pentixafor PET/CT [94.7% (18/19) vs. 78.9% (15/19), p > 0.05]. Among 14 patients with 151 matched focal bone lesions, [68Ga]pentixather PET detected more or equal number of lesions in 13 patients, and demonstrated higher uptake value than 68 Ga-pentixafor PET [SUVmax, 16.8 (9.0, 23.8) vs. 13.4 (6.5, 20.4), p < 0.001]. For PET related-tumor burden, positive correlations of total bone marrow uptake (TBmU) (r = 0.9540, p < 0.0001) and SUVmean of total bone marrow (r = 0.9632, p < 0.0001) in two PET scans were observed. Higher TBmU [7864.9 (5549.2, 11,616.2) vs. 5383.4(4102.7, 11,041.8), p < 0.001], SUVmean of total bone marrow [1.4 (1.1, 2.2) vs. 1.1 (0.7, 2.1), p < 0.001] were demonstrated on [68Ga]pentixather PET than [68Ga]pentixafor PET. And the level of TBmU in [68Ga]pentixather PET and [68Ga]pentixafor PET were both elevated in Durie-Salmon Staging (DSS) III than DSS I (p < 0.01). CONCLUSIONS: [68Ga]pentixather PET/CT performed a non-inferior capability for tumor detection compared to [68Ga]pentixafor PET/CT in NDMM patients. [68Ga]pentixather PET/CT can assess tumor load in MM patients and depict a significantly higher PET-related total tumor burden than [68Ga]pentixafor PET/CT.

Enhanced phytoremediation of cadmium-contaminated soil using chelating agents and plant growth regulators: effect and mechanism.

The heavy metal cadmium (Cd) is a major threat to food safety and human health. Phytoremediation is the most widely used remediation technology, and how to improve the remediation efficiency of phytoremediation has become a key issue. In this study, we constructed an intensive phytoremediation technology for remediation of Cd-contaminated soil with biodegradable chelating agent and plant growth regulator combined with maize and investigated the mechanism of this technology. The results showed that the best remediation effect was achieved in the treatment with 10-6 mol l-1 gibberellic acid (GA3) and 6 mmol kg-1 aspartate diethoxysuccinic acid (AES) combined with maize. In this treatment, the total biomass and extraction efficiency of maize were 3.6 and 8.67 times higher than those of the control, respectively, and the antioxidant enzyme activities of maize were also increased. The soil was enriched with dominant bacterial genera that promote plant growth and metabolism and tolerance to heavy metal stress, which in turn promoted maize growth and Cd accumulation. Structural equation modelling results indicated a large effect of plant Cd concentration and plant antioxidant enzyme activity on plant Cd extraction. The enhanced phytoremediation technology showed good potential for safe use of Cd-contaminated soil.

Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis.

Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing a major public health challenge worldwide. The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear, and effective treatments are still lacking. Renal tubular epithelial cells (RTECs) maintain kidney function, and their dysfunction has emerged as a critical contributor to renal fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system (UPS), autophagy, mitochondrial homeostasis (mitophagy and mitochondrial metabolism), endoplasmic reticulum (ER, unfolded protein response), and lysosomes. Failures in the cellular quality control of RTECs, including DNA, protein, and organelle damage, exert profibrotic functions by leading to senescence, defective autophagy, ER stress, mitochondrial and lysosomal dysfunction, apoptosis, fibroblast activation, and immune cell recruitment. In this review, we summarize recent advances in understanding the role of quality control components and intercellular crosstalk networks in RTECs, within the context of renal fibrosis.

Dynamics of sediment-associated nitrogen export from intermittent streams in subtropical forests of southeast China.

The significance of intermittent streams in nutrient loss within forest ecosystems is becoming increasingly critical due to changes in precipitation patterns associated with global climate change. However, few studies have focused on nutrient export from intermittent streams. We conducted continuous sediment collection from intermittent streams from March 2022 to February 2023 to investigate the export pattern and mechanism of sediment-associated nitrogen (N) from intermittent streams of different forest types (composed forest of Castanopsis carlesii (Cas. carlesii) and Cunninghamia lanceolata (C. lanceolata) forests, compared to Cas. carlesii forests). We measured the N concentrations and calculated the export amounts of four common forms of N associated with sediments: total N (TN), dissolved N (DN), nitrate, and ammonia. Our results showed that (1) the annual average exports of TN, DN, nitrate, and ammonia associated with sediments from intermittent streams from both forest types were 273, 1.62, 0.26, and 0.84 kg ha-1, respectively; (2) N export was significantly higher in composite forests of Cas. carlesii and C. lanceolata, compared to Cas. carlesii forests; (3) stream sediment export amount positively affected N export both in composite forests and Cas. carlesii forests; and (4) N export was also controlled by rainfall amount and stream characteristics. Our study quantified sediment-associated N export from intermittent streams among different subtropical forest types, which will enhance our understanding of N dynamics associated with stream hydrological processes in subtropical forests.

Duck hepatitis A virus 1-encoded 2B protein disturbs ion and organelle homeostasis to promote NF-κB/NLRP3-mediated inflammatory response.

Previous studies by our group and others have highlighted the critical role of hyperinflammation in the pathogenicity of duck hepatitis A virus 1 (DHAV-1), an avian picornavirus that has caused significant devastation in the duck industry worldwide for decades. However, the precise mechanisms by which DHAV-1 infection regulates the inflammatory responses, particularly the production of IL-1ß, remain poorly understood. In this study, we demonstrate that DHAV-1 infection triggers NF-κB- and NLRP3 inflammasome-mediated IL-1ß production. Mechanistically, DHAV-1 infection, particularly its replication and translation, disrupts cellular homeostasis of Ca2+, K+, ROS and cathepsin, which act cooperatively as assembly signals for NLRP3 inflammasome activation. By screening DHAV-1-encoded proteins, we identified that the viroporin 2B dominates NF-κB as well as NLRP3 inflammasome activation. Mutation analysis revealed that I43 within the 2B protein is the key amino acid for Ca2+ mobilization and subsequent activation of NF-κB transcriptional activity and NLRP3 inflammasome. Moreover, DHAV-1 infection and the 2B protein activate the MAVS- and MyD88-NF-κB pathways by relay, providing the necessary priming signals for NLRP3 inflammasome activation. In summary, our findings elucidate a mechanism through which DHAV-1 triggers inflammatory responses via NF-κB/NLRP3 inflammasome activation, offering new perspectives on DHAV-1 pathogenesis and informing the development of targeted anti-DHAV-1 treatments.

Effect of Corynebacterium glutamicum Fermentation on the Volatile Flavors of the Enzymatic Hydrolysate of Soybean Protein Isolate.

This study focused on improving the flavor quality of seasonings, and enzymatic hydrolysis of soybean protein isolate (SPI) seasoning via traditional technology may lead to undesirable flavors. Herein, we aimed to develop a new type of SPI seasoning through microbial fermentation to improve its flavor quality. The effect of Corynebacterium glutamicum fermentation on the flavoring compounds of seasonings in SPI enzymatic hydrolysate was examined. Sensory evaluation showed that the SPI seasoning had mainly aromatic and roasted flavor, and the response signals of S18 (aromatic compounds), S24 (alcohols and aldehydes), and S25 (esters and ketones) sensors of the electronic nose differed significantly. Overall, 91 volatile compounds were identified via gas chromatography-mass spectrometry. SPI seasonings contained a higher number of alcohols, ketones, aromatics, and heterocyclic compounds than traditional seasonings, which had stronger cheese, fatty, and roasted aromas. According to the relative odor activity value (ROAV) analysis, n-pentylpyrzine, 2,6-dimethylpyrazine, and tetramethylpyrazine are the key flavoring compounds (ROAV ≥ 1) of SPI seasoning, which may impart a unique roasted and meaty aroma. Therefore, the fermentation of SPI enzymatic hydrolysate with C. glutamicum may improve the flavor quality of its products, providing a new method for the development and production of new seasoning products.

Duck plague virus-encoded microRNA dev-miR-D28-3p inhibits viral replication via targeting UL27.

Herpesviruses-encoded microRNAs (miRNAs) have been discovered to be essential regulators in viral life cycle, participating in viral replication, latent or lytic infection, and immunological escape. However, the roles of miRNAs encoded by duck plague virus (DPV) are still unknown. Dev-miR-D28-3p is a miRNA uniquely encoded by DPV CHv strain. The aim of this study was to explore the effect of dev-miR-D28-3p on DPV replication and explore the potential mechanisms involved. Our findings demonstrated that transfection of dev-miR-D28-3p mimic into duck embryo fibroblasts (DEFs) effectively suppressed viral copies, viral titers and viral protein expressions during DPV infection, while the results above were reversed after transfection with dev-miR-D28-3p inhibitor. Subsequently, we further discovered that dev-miR-D28-3p specifically bound to DPV-encoded UL27 and inhibited its expression, suggesting that UL27 was the target gene of dev-miR-D28-3p. Finally, we investigated the role of UL27 in DPV replication and found the overexpression of UL27 increased viral copies, viral titers, and viral protein expressions; whereas the opposite results appear when knockdown of UL27. Our findings illustrated a novel mechanism that DPV regulated itself replication via dev-miR-D28-3p, paving the way for exploring the role of DPV-encoded miRNAs.

Effectiveness and Safety of Qishen Yiqi Dripping Pill in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: 3-Year Results from a Multicentre Cohort Study.

OBJECTIVES: To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ). RESULTS: A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517-602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41-0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53-1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46-0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05). CONCLUSION: In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ (Registration No. ChiCTR-OOC-14005552).

Clinical Application of Different Doses of Hydromorphone Slow-Release Analgesia in Lumbar Fusion in Elderly Patients.

INTRODUCTION: The aim of this study is to examine the analgesic efficacy of varying doses of hydromorphone hydrochloride in conjunction with absorbable gelatin sponge for postoperative pain management in elderly individuals undergoing lumbar fusion surgery. Additionally, the study aims to assess the sustained release analgesic properties of this combination and to determine the optimal dosage of hydromorphone hydrochloride for effective pain relief. METHODS: A total of 113 elderly patients (aged ≥ 65 years old) meeting the criteria for 1-2-level posterior lumbar fusion surgery at Ganzhou City People's Hospital between July 2022 and August 2023 were randomly assigned to four groups: group A (0.2 mg hydromorphone hydrochloride 1 ml), group B (0.3 mg hydromorphone hydrochloride 1.5 ml), group C (0.4 mg hydromorphone hydrochloride 2 ml), and group D (0.9% normal saline 2 ml) for standard anesthesia induction and maintenance. Prior to suturing the incision, gelfoam was utilized to administer epidural analgesia to each group. Following the surgical procedure, an intravenous analgesia pump was utilized for pain management. The baseline infusion rate was set at 0.5 ml/h. Patient-controlled analgesia (PCA) was administered at a dose of 2 ml, with a lockout interval of 20 min, allowing the patient to self-administer as needed. Pain relief was assessed using the visual analogue scale (VAS) prior to surgery, as well as at 1 day and 3 days post-operation. The frequency of PCA requests within the initial 48-h postoperative period, the remedial analgesia with dezocine, postoperative adverse reactions, and duration of hospitalization were documented for analysis. RESULTS: The VAS scores of groups B and C were found to be significantly lower than those of group D 1 day after the operation. Additionally, VAS scores at 3 days post-operation, remedial rate of dezocine and PCA follow-up times at 48 h in groups A, B, and C were significantly lower compared to group D (P < 0.001). There was no statistically significant difference between group B and group C in VAS scores at 1 day and 3 days post-operation, as well as PCA follow-up times at 48 h post-operation (P < 0.001). Furthermore, the VAS scores of groups B and C were lower than those of group A at 1 day and 3 days post-operation (P < 0.05). The PCA frequency of group C was also lower than that of group A at 48 h post-operation (P < 0.05). CONCLUSION: The combination of hydromorphone hydrochloride and absorbable gelatin sponge epidural analgesia has been shown to enhance postoperative pain management. A dosage of 0.4 mg of hydromorphone hydrochloride may be considered an appropriate analgesic dose, as it can provide effective pain relief without eliciting adverse reactions. TRIAL REGISTRATION: ChiCTR.org.cn(ChiCTR2200064863). Registered on October 20, 2022.

Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation. Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method. Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed. Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.