Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

Deciphering the molecular mechanism of Bu Yang Huan Wu Decoction in interference with diabetic pulmonary fibrosis via regulating oxidative stress and lipid metabolism disorder.

BACKGROUND: Diabetes mellitus type 2 and pulmonary fibrosis have been found to be closely related in clinical practice. Diabetic pulmonary fibrosis (DPF) is a complication of diabetes mellitus, but its treatment has yet to be thoroughly investigated. Bu Yang Huan Wu Decoction (BYHWD) is a well-known traditional Chinese prescription that has shown great efficacy in treating pulmonary fibrosis with hypoglycemic and hypolipidemic effects. METHODS: The active ingredients of BYHWD and the corresponding targets were retrieved from the Traditional Chinese Medicine Systematic Pharmacology Database (TCMSP) and SymMap2. Disease-related targets were obtained from the GeneCard, OMIM and CTD databases. GO enrichment and KEGG pathway enrichment were carried out using the DAVID database. AutoDock Vina software was employed to perform molecular docking. Molecular dynamics simulations of proteinligand complexes were conducted by Gromacs. Animal experiments were further performed to validate the effects of BYHWD on the selected core targets, markers of oxidative stress, serum lipids, blood glucose and pulmonary fibrosis. RESULTS: A total of 84 active ingredients and 830 target genes were screened in BYHWD, among which 56 target genes intersected with DPF-related targets. Network pharmacological analysis revealed that the active ingredients can regulate target genes such as IL-6, TNF-α, VEGFA and CASP3, mainly through AGE-RAGE signaling pathway, HIF-1 signaling pathway and TNF signaling pathway. Molecular docking and molecular dynamics simulations suggested that IL6-astragaloside IV, IL6-baicalein, TNFα-astragaloside IV, and TNFα-baicalein docking complexes could bind stably. Animal experiments showed that BYHWD could reduce the expression of core targets such as VEGFA, CASP3, IL-6 and TNF-α. In addition, BYHWD could reduce blood glucose, lipid, and MDA levels in DPF while increasing the activities of SOD, CAT and GSH-Px. BYHWD attenuated the expression of HYP and collagen I, mitigating pathological damage and collagen deposition within lung tissue. CONCLUSIONS: BYHWD modulates lipid metabolism disorders and oxidative stress by targeting the core targets of IL6, TNF-α, VEGFA and CASP3 through the AGE-RAGE signaling pathway, making it a potential therapy for DPF.

Elucidating shared biomarkers in gastroesophageal reflux disease and idiopathic pulmonary fibrosis: insights into novel therapeutic targets and the role of angelicae sinensis radix.

Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.

Causal linkage between type 2 diabetes mellitus and inflammatory bowel disease: an integrated Mendelian randomization study and bioinformatics analysis.

Background: Observational studies have indicated associations between type 2 diabetes mellitus (T2DM) and both colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, the underlying causality and biological mechanisms between these associations remains unclear. Methods: We conducted a bidirectional Mendelian randomization (MR) analysis employing summary statistics from genome-wide association studies involving European individuals. The inverse variance weighting (IVW) method was the primary method used to assess causality. Additionally, we applied MR Egger, Weighted median, Simple mode, and Weighted mode to evaluate the robustness of the results. Outliers were identified and eliminated using the MR-PRESSO, while the MR-Egger intercept was used to assess the horizontal pleiotropic effects of single nucleotide polymorphisms (SNPs). The heterogeneity was evaluated using the Cochrane Q test, and sensitivity analysis was performed using leave-one-out method. The F statistic was calculated to evaluate weak instrumental variable bias. Finally, a pilot bioinformatics analysis was conducted to explore the underlying biological mechanisms between T2DM and IBD/UC. Results: The IVW results demonstrated that T2DM significantly reduced risks of IBD (OR=0.885, 95% CI: 0.818-0.958, P=0.002) and ulcerative colitis (UC) (OR=0.887, 95% CI: 0.812-0.968, P=0.007). Although the 95% CIs of MR Egger, Weighted median, Simple mode, and Weighted mode were broad, the majority of their estimates were consistent with the direction of IVW. Despite significant heterogeneity among SNPs, no horizontal pleiotropy was observed. The leave-one-out analysis showed that the causality remained consistent after each SNP was removed, underscoring the reliability of the results. Reverse MR analysis indicated that genetic susceptibility to both CRC and IBD had no significant effect on the relative risk of T2DM. Ten hub genes were identified, which mainly enriched in pathways including maturity onset diabetes of the young, thyroid cancer, gastric acid secretion, longevity regulating pathway, melanogenesis, and pancreatic secretion. Conclusion: The presence of T2DM does not increase the risk of CRC or IBD. Moreover, T2DM might reduce risk of IBD, including UC. Conversely, the occurrence of CRC or IBD does not influence the risk of T2DM. The association between T2DM and IBD/UC may be related to the changes in multiple metabolic pathways and CTLA-4-mediated immune response.

Effect of Tacrolimus Time in Therapeutic Range on Postoperative Recurrence in Patients Undergoing Liver Transplantation for Liver Cancer.

BACKGROUND AND OBJECTIVE: Liver cancer is the second highest cause of cancer-related deaths worldwide. It is commonly treated with liver transplantation, where tacrolimus is typically used as an antirejection immunosuppressant. The purpose of this study was to evaluate the effect of tacrolimus time in therapeutic range (TTR) on liver cancer recurrence in liver transplant recipients and to compare the performance of TTRs calculated according to the target ranges recommended in published guidelines. METHODS: A total of 84 patients who underwent liver transplantation for liver cancer were retrospectively included. Tacrolimus TTR was calculated using linear interpolation from the date of transplantation until recurrence or the last follow-up according to target ranges recommended in the Chinese guideline and international expert consensus. RESULT: Twenty-four recipients developed liver cancer recurrence after liver transplantation. The CTTR (TTR calculated according to the Chinese guideline) for the recurrence group was significantly lower than that of the nonrecurrence group (26.39% vs. 50.27%, P < 0.001), whereas the ITTR (TTR calculated according to the international consensus) was not significantly different between the two groups (47.81% vs. 56.37%, P = 0.165). Multivariate survival analysis revealed that age, microvascular invasion, hepatocellular carcinoma, CTTR, and mean tacrolimus trough concentration were independent predictors of liver cancer recurrence after liver transplantation. CONCLUSIONS: TTR predicts liver cancer recurrence in liver transplant recipients. The range of tacrolimus concentrations recommended in the Chinese guideline was more beneficial than that recommended in the international consensus for Chinese patients undergoing liver transplantation for liver cancer.

COMPARISON BETWEEN ACTIVE ABDOMINAL COMPRESSION-DECOMPRESSION CARDIOPULMONARY RESUSCITATION AND STANDARD CARDIOPULMONARY RESUSCITATION IN ASPHYCTIC CARDIAC ARREST RATS WITH MULTIPLE RIB FRACTURES.

ABSTRACT: Background: Active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR) is potentially more effective for cardiac arrest (CA) with multiple rib fractures. However, its effect on survival rates and neurological outcomes remains unknown. This study aimed to assess if AACD-CPR improves survival rates and neurological outcomes in a rat model of asphyctic CA with multiple rib fractures. Methods: Adult male Sprague-Dawley rats were randomized into three groups-AACD group (n = 15), standard cardiopulmonary resuscitation (STD-CPR) group (n = 15), and sham group (n = 10)-after bilateral rib fractures were surgically created and endotracheal intubation was performed. AACD-CPR and STD-CPR groups underwent 8 min of asphyxia followed by different CPR techniques. The sham group had venous catheterization only. Physiological variables and arterial blood gases were recorded at baseline and during a 4-h monitoring period. Neurological deficit scores (NDSs) and cumulative survival rates were assessed at 24, 48, and 72 h. NDS, serum biomarkers, and hippocampal neuron analysis were used to evaluate neurological outcomes. Results: No statistical differences were observed in the return of spontaneous circulation (ROSC), 24-, 48-, and 72-h survival rates between the AACD-CPR and STD-CPR groups. AACD-CPR rats had lower serum levels of neuron-specific enolase and S100B at 72 h post-ROSC, and higher NDS at 72 h post-ROSC compared with STD-CPR animals. Cellular morphology analysis, hematoxylin and eosin staining, and TUNEL/DAPI assays showed more viable neurons and fewer apoptotic neurons in the AACD-CPR group than in the STD-CPR group. Conclusions: AACD-CPR can achieve similar survival rates and better neurological outcome after asphyxial CA in rats with multiple rib fractures when compared with STD-CPR.

Virtual Standardized Patients Versus Traditional Academic Training for Improving Clinical Competence Among Traditional Chinese Medicine Students: Prospective Randomized Controlled Trial.

BACKGROUND: The practical training course of internal medicine of traditional Chinese medicine (PTC-IMTCM) is primarily based on traditional case teaching, which can be stressful for teachers. The use of virtual standardized patient (VSP) applications could be an alternative; however, there is limited evidence regarding their feasibility and effectiveness. OBJECTIVE: This study aimed to build a VSP-TCM application according to the characteristics of PTC-IMTCM and the needs of students and to compare its efficacy with that of traditional teaching in improving TCM clinical competence among students. METHODS: A prequestionnaire investigation was conducted before the course, and a VSP-TCM system was developed based on the results of the questionnaire. A randomized controlled trial was then conducted between February 26, 2020, and August 20, 2021. A total of 84 medical students were included and were divided into 2 groups: an observation group, trained with VSP-TCM (n=42, 50%), and a control group, trained with traditional academic training (n=42, 50%). Formative and summative assessments were conducted to evaluate teaching effectiveness. After completing the course, the students were administered a questionnaire to self-assess their satisfaction with the course. A questionnaire was also administered to 15 teachers to uncover their perspectives on VSP-TCM. RESULTS: All participants completed the study. In the formative assessment, the VSP-TCM group performed better in medical interviewing ability (mean 7.19, SD 0.63, vs mean 6.83, SD 0.81; P=.04), clinical judgment (mean 6.48, SD 0.98, vs mean 5.86, SD 1.04; P=.006), and comprehensive ability (mean 6.71, SD 0.59, vs mean 6.40, SD 0.58; P=.02) than the control group. Similarly, in the summative evaluation, the VSP-TCM group performed better in the online systematic knowledge test (OSKT; mean 86.62, SD 2.71, vs mean 85.38, SD 2.62; P=.046), application of TCM technology (mean 87.86, SD 3.04, vs mean 86.19, SD 3.08; P=.02), TCM syndrome differentiation and therapeutic regimen (mean 90.93, SD 2.42, vs mean 89.60, SD 2.86; P=.03), and communication skills (mean 90.67, SD 4.52, vs mean 88.24, SD 4.56; P=.02) than the control group. There was no significant difference in medical writing between both groups (mean 75.07, SD 3.61, vs mean 75.71, SD 2.86; P=.37). The postcourse feedback questionnaire indicated that VSP-TCM can better enhance students' TCM thinking ability (n=39, 93%, vs n=37, 88%; P=.002), medical history collection (n=38, 90%, vs n=30, 72; P=.001), syndrome differentiation and treatment and critical thinking (n=38, 90%, vs n=37, 88%; P=.046), comprehensive clinical application ability (n=40, 95%, vs n=36, 86%; P=.009), interpersonal communication skills (n=36, 86%, vs n=28, 67%; P=.01), and autonomous learning ability (n=37, 88%, vs n=28, 67%; P=.01) than traditional academic training. Similarly, the teachers held a positive perspective on VSP-TCM. CONCLUSIONS: VSP-TCM enhances students' TCM clinical competence and dialectical thinking and improves their ability to work autonomously. Moreover, the VSP-TCM system is feasible, practical, and cost-effective and thus merits further promotion in TCM education.

Pharmacist-Driven Dosing Services and Pharmaceutical Care Increase Probability of Teicoplanin Target Concentration Attainment and Improve Clinical and Economic Outcomes in Non-Critically Ill Patients.

INTRODUCTION: Pharmacist-driven (PD) dosing and monitoring services have been shown to improve the clinical and economic outcomes in patients treated with different antibiotics, other than teicoplanin. This study investigates the impact of PD dosing and monitoring services on the clinical and economic outcomes of non-critically ill patients receiving teicoplanin treatment. METHODS: A single-center retrospective study was conducted. Patients were divided into the PD group and the non-PD (NPD) group. Primary outcomes included the achievement of target serum concentration, and a composite endpoint of all-cause mortality, intensive care unit (ICU) admission, and sepsis or septic shock development during hospitalization or within 30 days of hospital admission. The cost of teicoplanin, overall medication cost, and total cost during hospital stay were also compared. RESULTS: A total of 163 patients from January to December 2019 were included and assessed. Seventy patients were assigned to the PD group and 93 to the NPD group. The PD group had a higher percentage of patients reaching the target trough concentration (54% versus 16%, p < 0.001). Around 26% of the patients in the PD group and 50% of the patients in the NPD group met the composite endpoint during their hospital stay (p = 0.002). The PD group exhibited a significantly lower incidence of sepsis or septic shock, shorter hospital stays, reduced drug costs, and lower total expenses. CONCLUSIONS: Our study demonstrates that pharmacist-driven teicoplanin therapy can improve the clinical and economic outcomes for non-critically ill patients. TRIAL REGISTRATION: https://www.chictr.org.cn ; identifier, ChiCTR2000033521.

Efficacy and safety of Dachaihu Decoction for acute pancreatitis: Protocol for a systematic review and meta-analysis.

BACKGROUND: Dachaihu Decoction (DCD) is a traditional herbal formula widely used for treating acute pancreatitis (AP) in China. However, the efficacy and safety of DCD has never been validated, limiting its application. This study will assess the efficacy and safety of DCD for AP treatment. METHODS: Relevant randomized controlled trials of DCD in treating AP will be searched through Cochrane Library, PubMed, Embase, Web of Science, Scopus, CINAHL, China National Knowledge Infrastructure database, Wanfang Database, VIP Database, and Chinese Biological Medicine Literature Service System database. Only studies published between the inception of the databases and May 31, 2023 shall be considered. Searches will also be performed in the WHO International Clinical Trials Registry Platform, Chinese Clinical Trial Registry, and ClinicalTrials.gov. Preprint databases and grey literature sources such as OpenGrey, British Library Inside, ProQuest Dissertations & Theses Global, and BIOSIS preview will also be searched for relevant resources. The primary outcomes to be assessed will include mortality rate, rate of surgical intervention, proportion of patients with severe acute pancreatitis transferred to ICU, gastrointestinal symptoms, and the acute physiology and chronic health evaluation II score. Secondary outcomes will include systemic complications, local complications, the normalization period of C-reactive protein, length of stay in the hospital, TNF-α, IL-1, IL-6, IL-8, and IL-10 levels, and adverse events. Study selection, data extraction, and assessment of bias risk will be conducted independently by two reviewers using the Endnote X9 and Microsoft Office Excel 2016 software. The risk of bias of included studies will be assessed by the Cochrane "risk of bias" tool. Data analysis will be performed using the RevMan software (V.5.3). Subgroup and sensitivity analysis will be performed where necessary. RESULTS: This study will provide high-quality current evidence of DCD for treating AP. CONCLUSION: This systematic review will provide evidence of whether DCD is an effective and safe therapy for treating AP. TRIAL REGISTRATION: PROSPERO registration number CRD42021245735. The protocol for this study was registered at PROSPERO, and is available in the S1 Appendix. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021245735.

Mechanism exploration and prognosis study of Astragali Radix-Spreading hedyotis herb for the treatment of lung adenocarcinoma based on bioinformatics approaches and molecular dynamics simulation.

Background: Herb pair of Astragali Radix (AR) and Spreading Hedyotis Herb (SH) has been frequently prescribed in clinical for the treatment of lung cancer owing to its favorable efficacy. Yet, the mechanism under the therapeutic effects remained unveiled, which has limited its clinical applications, and new drug development for lung cancer. Methods: The bioactive ingredients of AR and SH were retrieved from the Traditional Chinese Medicine System Pharmacology Database, with the targets of obtained components predicted by Swiss Target Prediction. Genes related to lung adenocarcinoma (LUAD) were acquired from GeneCards, OMIM and CTD databases, with the hub genes of LUAD screened by CTD database. The intersected targets of LUAD and AR-SH were obtained by Venn, with David Database employed to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Survival analysis of the hub genes of LUAD was carried out using TCGA-LUAD dataset. Molecular docking of core proteins and active ingredients was performed by Auto-Dock Vina software, followed by molecular dynamics simulations of protein-ligand complexes with well-docked conformations. Results: 29 active ingredients were screened out with 422 corresponding targets predicted. It is revealed that AR-SH can act on various targets such as EGFR, MAPK1, and KARS by ursolic acid (UA), Astragaloside IV(ASIV), and Isomucronulatol 7,2'-di-O-glucoside (IDOG) to alleviate the symptoms of LUAD. Biological processes involved are protein phosphorylation, negative regulation of apoptotic process, and pathways involved are endocrine resistance, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt, and HIF-1 pathway. Molecular docking analysis indicated that the binding energy of most of the screened active ingredients to proteins encoded by core genes was less than -5.6 kcal/mol, with some active ingredients showing even lower binding energy to EGFR than Gefitinib. Three ligand-receptor complexes including EGFR-UA, MAPK1-ASIV, and KRAS-IDOG were found to bind relatively stable by molecular dynamics simulation, which was consistent with the results of molecule docking. Conclusion: We suggested that the herb pair of AR-SH can act on targets like EGFR, MAPK1 and KRAS by UA, ASIV and IDOG, to play a vital role in the treatment and the enhancement of prognosis of LUAD.