Severe Cavitary Pneumonia Caused by Legionella pneumophila: a Case Report.

BACKGROUND: Pulmonary cavities caused by Legionella occur mainly in immunocompromised patients, and clinical information in patients with normal immune function is therefore limited. METHODS: We report a 64-year-old female who developed a Legionella pulmonary cavity without any immunological abnormality. RESULTS: She suffered severe pneumonia complicated by acute respiratory failure and acute renal insufficiency. Despite long-term antibiotic therapy, she showed signs of a life-threatening infection and a progressive pulmonary cavity. CONCLUSIONS: Our case report provided clinical data regarding the diagnosis and therapy of patients who develop Legionella pulmonary cavities without any underlying disease.

Predicting the presence and mechanism of busulfan drug-drug interactions in hematopoietic stem cell transplantation using pharmacokinetic interaction network-based molecular structure similarity and network pharmacology.

PURPOSE: This study aimed to predict the presence and mechanism of busulfan drug-drug interactions (DDIs) in hematopoietic stem cell transplantation (HSCT) using pharmacokinetic interaction (PKI) network-based molecular structure similarity and network pharmacology. METHODS: Logistic function models were established to predict busulfan DDIs based on the assumption that an approved drug tends to interact with the drug used in HSCT (DH) if structurally similar to the drugs in the PKI network of the DH. The PKI network of the DH represented the association between drugs and the proteins related to the PK of the DH. The most appropriate model was applied to predict busulfan DDIs in HSCT. Candidate targets for busulfan DDIs and their interacting were identified by network pharmacology. RESULTS: Six of the top ten predicted busulfan DDIs were clinically relevant and involved voriconazole, fludarabine, itraconazole, cyclophosphamide, metronidazole, and melphalan. Candidate targets for these DDIs were CYP450s (3A4, 2B6, 2C9, and 2C19), GSTs (GSTA1, GSTP1, GSTT1, and GSTM1), and ABC transporters (ABCB1, ABCC1, ABCC2, and ABCC3), in the targets of drug-induced liver injury (DILI). The networks of interacting proteins and candidate targets indicated the regulatory potential of pregnane X receptor (PXR), as a nuclear receptor. Enrichment analysis showed the metabolism of drugs and xenobiotics, glutathione metabolism, and bile secretion associated with busulfan DDIs and DILI. CONCLUSIONS: This study has successfully predicted busulfan DDIs in HSCT through PKI-based molecular structure similarity. The mechanism of busulfan DDI and DILI was attributed mostly to CYP450s, GSTs, and ABC transporters, and PXR was identified as a potential target.

The pharmacokinetics of vancomycin in patients with severe acute pancreatitis.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics of vancomycin in patients with severe acute pancreatitis (SAP). METHODS: Sixty-seven patients with SAP were included. The FPIA method was used to measure vancomycin serum trough concentrations, and the pharmacokinetic parameters were calculated using the Bayesian estimator. Comparisons of mean values were analyzed using SPSS 11.0. RESULTS: The average daily dose of vancomycin was 15.0 ± 3.7 mg/kg (q 12 h). Sixty-seven trough concentrations were collected. Compared with the recommended standard vancomycin trough concentration (15 mg/L), SAP patients had significantly lower vancomycin trough concentrations (6.1 ± 3.0 mg/L; p < 0.0001) while the volume of distribution (Vd) and clearance (CL) of vancomycin were significantly increased. Multiple regression analysis revealed that vancomycin trough concentration was strongly correlated not only with age and albumin but also with the duration from SAP onset to vancomycin therapy (p < 0.0001). Stepwise regression analysis revealed that the duration was the most important variable for vancomycin trough concentration (r (2) = 0.456). The relationships between vancomycin trough concentrations and the duration were further evaluated after the 67 patients were stratified into two groups according to the duration from SAP onset to vancomycin therapeutic drug monitoring (TDM) within or over 4 weeks. Early group had much lower trough concentrations compared to late group, and the CL was also significantly increased in the early group. Of these 67 patients, 24 patients made vancomycin dosage adjustment (increased to 18.5 ± 3.9 mg/kg, q 12 h) and the average trough concentrations increased to 12.6 ± 3.8 mg/L. CONCLUSIONS: The serum trough concentration of vancomycin was significantly reduced in SAP patients. Higher dosage regimens are needed to ensure the clinical effect.

Limited Sampling Strategy for the Estimation of Tacrolimus Area Under the Concentration-Time Curve in Chinese Adult Liver Transplant Patients.

OBJECTIVES: Limited sampling strategies (LSS) have been proposed as an alternative method for estimating area under concentration-time curve (AUC) of immunosuppressive agent tacrolimus (TAC). In this study, we aimed to develop the LSS models for predicting AUC of TAC in Chinese liver transplant patients. METHODS: Twenty-eight adult liver transplant patients receiving immunosuppressive regimen including TAC were enrolled. A total of 47 pharmacokinetic profiles were obtained after 1 or 3 weeks therapy. TAC concentrations were determined before dose (0 h) and at 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after dosing by LC-MS/MS assay. Optimal subset regression analysis was used to establish the models for estimating TAC AUC0-12. Prediction error (PE) and absolute PE were calculated. The agreement between predicted and measured AUC0-12 was investigated by Bland-Altman analysis. The obtained models were validated by bootstrap analysis. The prediction performance among various CYP3A5 and ABCB1 genotypes was compared. The models selected from previous published studies were also validated using our data. RESULTS: Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r2 = 0.653-0.979). The best model for prediction of TAC AUC0-12 was 0.81 + 1.73C1 + 1.32C2 + 3.87C4 + 3.75C8 (r2 = 0.979). Forty profiles (85.1%) had estimated TAC AUC0-12 within ±15% of observed TAC AUC0-12. Model with C0-C2 (r2 = 0.880) can be used for outpatients who need monitoring to be carried out in a short period. We also found that ABCB1 genotype may be a reason of variation in the prediction performance. There was good correlation between predicted and measured AUC0-12 (r2 = 0.880-0.928) by using models from previous studies with sample collected within 4 h post dose. CONCLUSION: The LSS is an effective approach for estimation of full TAC AUC0-12 in Chinese liver transplant patients.

Pre-Treatment Serum C-Reactive Protein Level Is An Independent Risk Factor for Development of Nephrotoxicity in Patients Receiving High-Dose Vancomycin.

High-dose vancomycin treatment increases the likelihood of vancomycin-related nephrotoxicity. C-reactive protein (CRP) is a sensitive marker of systemic inflammation. In this study, we evaluated the pre-treatment serum CRP level as a risk factor of the development of nephrotoxicity in patients receiving high total daily doses (>2.5 g) of vancomycin. Data extracted from medical records for 174 patients who received total daily doses of >2.5 g of intravenous vancomycin for a minimum of 48 h and had their serum CRP level and erythrocyte sedimentation rate tested within 24 h before vancomycin treatment were subject to final analyses. Univariate analyses showed that patients who developed nephrotoxicity during vancomycin treatment had significantly higher median vancomycin serum concentration, duration of vancomycin treatment, and the serum CRP level within 24 h before vancomycin treatment than the non-nephrotoxicity group. Multivariate logistic regression analysis showed that after adjustment for potential confounders, median vancomycin serum concentration, duration of treatment, serum CRP level within 24 h before vancomycin treatment, and nephrotoxic medication were found significantly associated with the development of nephrotoxicity. This was confirmed by multivariate hazard ratio analysis after adjustment for potential confounders. In conclusion, this study provides the first evidence supporting the fact that the serum CRP level within 24 h before vancomycin treatment is an independent risk factor for the development of nephrotoxicity in patients receiving total daily doses of >2.5 g of vancomycin. Therefore, the serum CRP level within 24 h before vancomycin treatment could be a potential biomarker or prognostic factor for the development of vancomycin nephrotoxicity.

Nod2-Rip2 Signaling Contributes to Intestinal Injury Induced by Muramyl Dipeptide Via Oligopeptide Transporter in Rats.

BACKGROUND AND AIMS: PepT1 can transport bacterial oligopeptide products and induce intestinal inflammation. Our aim was to investigate the mechanism of the small intestine injury induced by bacterial oligopeptide product muramyl dipeptide (MDP) which is transported by PepT1. METHODS: We perfused the jejunum with a solution with or without MDP, or with a solution of MDP + Gly-Gly and explored the degree of inflammation to determine the role of PepT1-Nod2 signaling pathway in small intestine mucosa. RESULTS: MDP perfusion induced inflammatory cell accumulation and intestinal damage, accompanied by an increase in mucosal Nod2 and Rip2 transcript expression. NFκB activity and inflammatory cytokine expression, including serum levels of TNF-α, IL-1ß, and IL-6, increased in the MDP group compared to the controls; these effects were reversed by perfusion of the nutritional dipeptide Gly-Gly. CONCLUSION: MDP can be transported through PepT1, causing inflammatory damage in the rat small intestine. Nod2-Rip2-NFκB signaling involved in the small intestinal inflammatory injury caused by MDP which is transported through PepT1.

[Prognostic value of Picco monitoring combined with plasma microRNA-150 detection in septic shock patients].

OBJECTIVE: To assess the prognostic value of pulse indicator continuous cardiac output (Picco) monitoring combined with plasma microRNA-150 detection in septic shock patients. METHODS: Clinical data of 48 patients with septic shock admitted in General Intensive Care Unit (GICU), Shanghai First People's Hospital Songjiang Branch Affiliated to Shanghai Jiaotong University from August 2012 to August 2014 were analyzed retrospectively. The plasma levels of microRNA-150 in 48 patients at admission were assayed by qRT-PCR; and Picco monitoring was performed to record hemodynamic changes. The correlation of microRNA-150 or Picco parameters with prognosis of patients was assessed by univariate analysis and multivariate logistic analysis. Spearman correlation test showed the relationship between microRNA-150 and Picco parameters. Finally, the clinical value of combining microRNA-150 with Picco monitoring to predict the outcome of septic shock patients was analyzed by ROC curves. RESULTS: Twenty-three patients survived and 25 died in 28 d after admission in GICU. Compared with survival patients, microRNA-150 was significantly lower in fatal patients (t=-10.32, P<0.05). Univariate analysis showed that low microRNA-150 level was a risk factor for poor prognosis(OR=2.176,95% CI:1.121-4.223, P<0.05). Compared with fatal cases, the cardiac index of survival patients was higher, while EVLWI and PVPI were lower. MicroRNA-150 level was positively correlated with cardiac index (r=0.712, P<0.05), negatively correlated with EVLWI and PVPI (r=-0.622 and-0.689, both P<0.05). ROC curves showed a satisfactory diagnostic efficiency of combining microRNA-150 with Picco monitoring. CONCLUSION: Lower microRNA-150 may indicate a poor prognosis, and Picco monitoring combined with microRNA 150 detection may improve the prognostic efficiency in septic shock patients.

ChatGPT's innovative application in blood morphology recognition.

BACKGROUND: Recently, the rapid advancement in generative artificial intelligence (AI) technology, such as ChatGPT-4, has sparked discussions, particularly in image recognition. Accurate results are critical for hematological diagnosis, particularly for blood morphology identification. Despite advanced hematology analyzers, reliance on professional hematopathologists for manual identification remains in cases of abnormal or rare conditions, a process prone to human subjectivity and potential errors. Consequently, this study aimed to investigate the potential of ChatGPT-4 to assist with blood morphology identification. METHODS: We conducted a retrospective study using blood images obtained from the American Society of Hematology (ASH). These images comprised a range of normal and abnormal morphologies. Each sample was analyzed by expert technicians (control group) and classified using ChatGPT-4 (test group). RESULTS: Preliminary results showed that ChatGPT-4 could identify normal blood cells with an accuracy of 88%, exceeding the accuracy of identifying abnormal blood cells at a rate of 54%. Regarding identifying abnormal cells, the accuracy of ChatGPT-4 was slightly higher than that of the manual method, which was 49.5%. CONCLUSION: This study shows that although generative AI shows the potential for blood type identification, it has not yet reached the point where it can replace the professional judgment of medical staff. The results showed that ChatGPT-4 is excellent for identifying red blood cell morphology, particularly inclusion bodies. It can be used as an auxiliary tool for clinical diagnosis. However, the overall recognition accuracy must be further improved. Our study produced innovative results in this field, establishing a foundation for future studies and highlighting the potential of generative AI in aiding blood morphology recognition. Future research should focus on enhancing the effectiveness of AI to improve overall standards of medical care.

Comparative analysis of GPT-3.5 and GPT-4.0 in Taiwan's medical technologist certification: A study in artificial intelligence advancements.

BACKGROUND: This study examines the comparative effectiveness of GPT-3.5 and GPT-4.0, in the certification of medical technologists (MT) in Taiwan, exploring their adeptness in processing complex medical language and their contributory role in the educational and communicative aspects of professional healthcare training. METHODS: This study used GPT-3.5 and GPT-4.0 to test the medical laboratory technician professional college entrance examination questions. The questions in different fields, including six subjects, such as Clinical Physiology and Pathology, Hematology, and Blood Bank, among others were answered one-on-one using two generative pretrained transformer (GPT) versions, simulating the situations during exam preparation. RESULTS: A total of 480 questions were analyzed and the results showed that both versions of the GPT met the certification standards. Version 4.0 was better than version 3.5 for all subjects, particularly in Clinical Biochemistry (score = 96.25) and Microbiology (score = 91.25). Outstanding performance compared to version 3.5, which had an average score of 65.42 and a maximum score of 77.5. Overall, version 4.0, which was significantly better than version 3.5 in both median and average scores, reflects a significant improvement in professional knowledge processing capabilities. CONCLUSION: The GPT can provide valuable support for both the upstream and downstream processes of MT certification. Future research can further explore the application of GPT in different educational and certification contexts and improve the passing rate of medical personnel in the certification process. This study provides useful information for exploring the potential applications of GPT in certifying medical examiners. Furthermore, it provides new directions for future research in medical education.

DT390-triTMTP1, a novel fusion protein of diphtheria toxin with tandem repeat TMTP1 peptide, preferentially targets metastatic tumors.

Peptide-based therapies have emerged as one of the most promising therapeutics strategy in cancer-targeted therapy. Using our laboratory newly identified peptide TMTP1 and diphtheria toxin, we developed a new fusion protein that showed remarkable ability to target highly metastatic tumors. Fusion protein toxins were generated by fusing the first 390 amino acids of diphtheria toxin [truncated diphtheria toxin (DT390)] to different repeats of peptide TMTP1 (DT390-TMTP1, DT390-biTMTP1, and DT390-triTMTP1). Efficacies of the recombinant fusion proteins on tumor growth and metastasis were evaluated in vitro and in vivo. DT390-triTMTP1 showed the most powerful toxicity against cancer, which led to tumor growth retardation or regression and prolonged survival of human prostate cancer PC-3M-1E8 subcutaneously bearing or gastric cancer MKN-45 orthotopic nude mice. Increased TUNEL and caspase-3 staining and reduced ki67 staining in tumor cells suggested that the anticancer effects of DT390-triTMTP1 were through selectively inducing apoptosis and inhibiting proliferation of cancer cells. In a murine model of human orthotopic gastric carcinoma, DT390-biTMTP1 significantly inhibited metastases to liver and spleen, while DT390-triTMTP1 not only totally suppressed metastasis but also reduced primary tumors by 66.6%. In the biodistribution test, DT390-triTMTP1 was observed to home to tumor tissue rapidly and lasted over 48 h, with only a transient appearance in liver and kidney immediately after injection. Thus, our present study provided a novel recombinant fusion protein DT390-triTMTP1 with preferential targeting and high cytotoxicity, which may be a promising strategy for the targeted therapy of cancer metastasis.

Impaired immune response and barrier function in GSPD-1-deficient C. elegans infected with Klebsiella pneumoniae.

gspd-1-RNAi knockdown Caenorhabditis elegans was used as an immune-compromised model to investigate the role of G6PD in host-pathogen interactions. A shorted lifespan, increased bacterial burden and bacterial translocation were observed in gspd-1-knockdown C. elegans infected with Klebsiella pneumoniae (KP). RNAseq revealed that the innate immune pathway, including clc-1 and tsp-1, was affected by gspd-1 knockdown. qPCR confirmed that tight junction (zoo-1, clc-1) and immune-associated genes (tsp-1) were down-regulated in gspd-1-knockdown C. elegans and following infection with KP. The down-regulation of antimicrobial effector lysozymes, including lys-1, lys-2, lys-7, lys-8, ilys-2 and ilys-3, was found in gspd-1-knockdown C. elegans infected with KP. Deletion of clc-1, tsp-1, lys-7, and daf-2 in gspd-1-knockdown C. elegans infected with KP abolished the shorten lifespan seen in the Mock control. GSPD-1 deficiency in C. elegans resulted in bacterial accumulation and lethality, possibly due to a defective immune response. These findings indicate that GSPD-1 has a protective role in microbial defense in C. elegans by preventing bacterial colonization through bacterial clearance.

High inferior vena cava thrombosis in a 16-year-old postpartum patient: a case report.

Postpartum inferior vena cava (IVC) thrombosis is a rare, but potentially life-threatening disorder. Here we reported one case of the youngest woman to date who presented with massive IVC thrombus extending from deep veins of the right leg to the level of the 11th thoracic vertebra, associated with asymptomatic pulmonary embolism.

Investigating the Molecular Mechanism of Quercetin Protecting against Podocyte Injury to Attenuate Diabetic Nephropathy through Network Pharmacology, MicroarrayData Analysis, and Molecular Docking.

Quercetin (QUE), a health supplement, can improve renal function in diabetic nephropathy (DN) rats by ameliorating podocyte injury. Its clinical trial for renal insufficiency in advanced diabetes (NCT02848131) is currently underway. This study aimed to investigate the mechanism of QUE protecting against podocyte injury to attenuate DN through network pharmacology, microarray data analysis, and molecular docking. QUE-associated targets, genes related to both DN, and podocyte injury were obtained from different comprehensive databases and were intersected and analyzed to obtain mapping targets. Candidate targets were identified by constructing network of protein-protein interaction (PPI) of mapping targets and ranked to obtain key targets. The major pathways were obtained from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) term enrichment analysis of candidate targets via ClueGO plug-in and R project software, respectively. Potential receptor-ligand interactions between QUE and key targets were evaluated via Autodocktools-1.5.6. 41. Candidate targets, of which three key targets (TNF, VEGFA, and AKT1), and the major AGE-RAGE signaling pathway in diabetic complications were ascertained and associated with QUE against podocyte injury in DN. Molecular docking models showed that QUE could closely bind to the key targets. This study revealed that QUE could protect against podocyte injury in DN through the following mechanisms: downregulating inflammatory cytokine of TNF, reducing VEGF-induced vascular permeability, inhibiting apoptosis by stimulating AKT1 phosphorylation, and suppressing the AGE-induced oxidative stress via the AGE-RAGE signaling pathway.

Identifying Drug-Induced Liver Injury Associated With Inflammation-Drug and Drug-Drug Interactions in Pharmacologic Treatments for COVID-19 by Bioinformatics and System Biology Analyses: The Role of Pregnane X Receptor.

Of the patients infected with coronavirus disease 2019 (COVID-19), approximately 14-53% developed liver injury resulting in poor outcomes. Drug-induced liver injury (DILI) is the primary cause of liver injury in COVID-19 patients. In this study, we elucidated liver injury mechanism induced by drugs of pharmacologic treatments against SARS-CoV-2 (DPTS) using bioinformatics and systems biology. Totally, 1209 genes directly related to 216 DPTS (DPTSGs) were genes encoding pharmacokinetics and therapeutic targets of DPTS and enriched in the pathways related to drug metabolism of CYP450s, pregnane X receptor (PXR), and COVID-19 adverse outcome. A network, constructed by 110 candidate targets which were the shared part of DPTSGs and 445 DILI targets, identified 49 key targets and four Molecular Complex Detection clusters. Enrichment results revealed that the 4 clusters were related to inflammatory responses, CYP450s regulated by PXR, NRF2-regualted oxidative stress, and HLA-related adaptive immunity respectively. In cluster 1, IL6, IL1B, TNF, and CCL2 of the top ten key targets were enriched in COVID-19 adverse outcomes pathway, indicating the exacerbation of COVID-19 inflammation on DILI. PXR-CYP3A4 expression of cluster 2 caused DILI through inflammation-drug interaction and drug-drug interactions among pharmaco-immunomodulatory agents, including tocilizumab, glucocorticoids (dexamethasone, methylprednisolone, and hydrocortisone), and ritonavir. NRF2 of cluster 3 and HLA targets of cluster four promoted DILI, being related to ritonavir/glucocorticoids and clavulanate/vancomycin. This study showed the pivotal role of PXR associated with inflammation-drug and drug-drug interactions on DILI and highlighted the cautious clinical decision-making for pharmacotherapy to avoid DILI in the treatment of COVID-19 patients.

A Clinical Practice Guideline for the Emergency Management of Anaphylaxis (2020).

Background: For anaphylaxis, a life-threatening allergic reaction, the incidence rate was presented to have increased from the beginning of the 21st century. Underdiagnosis and undertreatment of anaphylaxis are public health concerns. Objective: This guideline aimed to provide high-quality and evidence-based recommendations for the emergency management of anaphylaxis. Method: The panel of health professionals from fifteen medical areas selected twenty-five clinical questions and formulated the recommendations with the supervision of four methodologists. We collected evidence by conducting systematic literature retrieval and using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: This guideline made twenty-five recommendations that covered the diagnosis, preparation, emergency treatment, and post-emergency management of anaphylaxis. We recommended the use of a set of adapted diagnostic criteria from the American National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network (NIAID/FAAN), and developed a severity grading system that classified anaphylaxis into four grades. We recommended epinephrine as the first-line treatment, with specific doses and routes of administration for different severity of anaphylaxis or different conditions. Proper dosage is critical in the administration of epinephrine, and the monitor is important in the IV administration. Though there was only very low or low-quality evidence supported the use of glucocorticoids and H1 antagonists, we still weakly recommended them as second-line medications. We could not make a well-directed recommendation regarding premedication for preventing anaphylaxis since it is difficult to weigh the concerns and potential effects. Conclusion: For the emergency management of anaphylaxis we conclude that: • NIAID/FAAN diagnostic criteria and the four-tier grading system should be used for the diagnosis • Prompt and proper administration of epinephrine is critical.

Evaluation of SLOG/TCI-III pediatric system on target control infusion of propofol.

BACKGROUND: The target-controlled infusion-III (SLOG/TCI-III) system was derived from a model set up by the local pediatric population for target control infusion of propofol. METHODS: The current study aimed at evaluating the difference between target concentrations of propofol and performance, which was measured using the SLOG/TCI-III system in children. Thirty children fulfilling the I-II criteria according to American Society of Anesthesiology were enrolled in the study. The target plasma concentration of propofol was fed into the SLOG/TCI-III system and compared with the measured concentrations of propofol. Blood samples were collected and analyzed by high performance liquid chromatography with fluorescence detector. The performance error (PE) was determined for each measured blood propofol concentration. The performances of the TCI-III system were determined by the median performance error (MDPE), the median absolute performance error (MDAPE), and Wobble (the median absolute deviation of each PE from the MDPE), respectively. RESULTS: Concentration against target concentration showed good linear correlation: concentration = 1.3428 target concentration - 0.2633 (r = 0.8667). The MDPE and MDAPE of the pediatric system were 10 and 22%, respectively, and the median value for Wobble was 24%. MDPE and MDAPE were less than 15 and 30%, respectively. CONCLUSIONS: The performance of TCI-III system seems to be in the accepted limits for clinical practice in children.

Cystatin C and/or creatinine-based estimated glomerular filtration rate for prediction of vancomycin clearance in long-stay critically ill patients with persistent inflammation, immunosuppression and catabolism syndrome (PICS): a population pharmacokinetics analysis.

Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill patients are associated with unreliable creatinine (Cr)-based estimated glomerular filtration rate (eGFR) and alteration in vancomycin clearance (CL) due to ongoing muscle wasting and renal dysfunction (RD). Currently, cystatin C (Cys) is of great interest for eGFR due to its muscle independence. Patients receiving intravenous vancomycin with trough concentration monitoring after intensive care unit stay ≥ 14 days were retrospectively enrolled. Those with C-reactive protein > 30.0 mg/L, lymphocytes count < 0.80 × 109, albumin < 30 mg/L and weight loss > 10% were diagnosed with PICS. Impact of PICS on vancomycin trough achievement was analyzed. Plasma Cys and Cr levels with their eGFRs in RD were compared in patients with and without PICS. Furthermore, the performance of eGFRs in predicting vancomycin CL was quantificationally evaluated by population pharmacokinetics (PPK) analysis using the Phoenix NLME software. Of 69 enrolled patients, 32 (46.4%) were PICS. PICS was predictive of Cr-guided vancomycin supratherapeutic trough concentrations (OR = 5.26, P = 0.013). Significant elevation of Cys, not of Cr, was observed in patients with PICS suffering from RD (P = 0.022), causing substantial differences among eGFRs. Fifty-two and 17 patients were enrolled for the modeling group and validation group, respectively. A one-compartment PPK model with first-order elimination adequately described the data of 126 Ctrough. Prediction of vancomycin CL with Cys and Cr-based eGFR (CKD-EPIcys-cr) significantly reduced the interindividual variability of CL (from 75.6 to 28.5%). External validation with 34 Ctrough showed the robustness and accuracy of this model. This study showed the negative impact of PICS on Cr-guided vancomycin trough achievement. PPK model with CKD-EPIcys-cr can be used to optimize vancomycin dosage in patients with PICS.

Investigation into molecular mechanisms and high-frequency core TCM for pulmonary fibrosis secondary to COVID-19 based on network pharmacology and data mining.

BACKGROUND: The complication, pulmonary fibrosis (PF) secondary to COVID-19, may have a second wave of late mortality, given the huge number of individuals infected by COVID-19. However, the molecular mechanisms of PF secondary to COVID-19 haven't been fully elucidated, making the identification of novel strategies for targeted therapy challenging. This study aimed to systematically identify the molecular mechanisms and high-frequency core traditional Chinese medicine (TCM) targeting PF secondary to COVID-19 through network pharmacology and data mining. METHODS: The molecular mechanisms of PF secondary to COVID-19 were identified by mapping the COVID-19 differentially expressed gene and known targets associated with PF, protein-protein interactions network analysis, and enrichment pathway analysis; then the high-frequency core TCM targeting PF secondary to COVID-19 were identified by data mining and "Key targets related to PF secondary to COVID-19 - Ingredients" and "Key ingredients-key herbs" network analysis; and last we validated the interaction between the key ingredients and key targets by molecular docking. RESULTS: The molecular mechanisms of PF secondary to COVID-19 were mainly related to tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interaction pathway, and NF-κB signaling pathway. Among these, cytokines interleukin 6 (IL-6), TNF, and IL-1ß were identified as the key targets associated with PF secondary to COVID-19. The high-frequency core TCM targeting these key targets were identified, including ingredients of quercetin, epigallocatechin-3-gallate, emodin, triptolide, resveratrol, and herb of Polygonum cuspidatum. Finally, our results were validated by quercetin and resveratrol both well docked to IL-6, TNF, and IL-1ß protein, with the estimated docking energy <0 kcal/mol. CONCLUSIONS: This study identified the cytokines-related molecular mechanisms of PF secondary to COVID-19, and the high-frequency core TCM against PF by targeting IL-6, TNF, and IL-1ß. Which provides new ideas for the discovery of small molecular compounds with potential therapeutic effects on PF secondary to COVID-19.

Shenjinhuoxue Mixture Attenuates Inflammation, Pain, and Cartilage Degeneration by Inhibiting TLR-4 and NF-κB Activation in Rats with Osteoarthritis: A Synergistic Combination of Multitarget Active Phytochemicals.

Osteoarthritis (OA), a highly prevalent chronic joint disease, involves a complex network of inflammatory mediators that not only triggers pain and cartilage degeneration but also accelerates disease progression. Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti-inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti-OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including ß-sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR-4 and NF-κB, eliciting anti-OA activity. These phytochemicals can enter the active pockets of TLR-4 and NF-κB with docking score ≤ -3.86 kcal/mol, as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR-4-binding affinity. In OA rats, oral SHM at mid and high doses (8.72 g/kg and 26.2 g/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia (P < 0.0001). Accordingly, the expression of inflammatory mediators (TLR-4, interleukin (IL-) 1 receptor-associated kinase 1 (IRAK1), NF-κB-p65, tumor necrosis factor (TNF-) α, IL-6, and IL-1ß), receptor activator of the NF-κB ligand (RANKL), and transient receptor potential vanilloid 1 (TRPV1) in the synovial and cartilage tissue of OA rats was significantly decreased (P < 0.05). Moreover, pathological observation illustrated amelioration of cartilage degeneration and joint injury. In chronic toxicity experiment of rats, SHM at 60 mg/kg demonstrated the safety. SHM had an anti-inflammatory effect through a synergistic combination of active phytochemicals to attenuate pain and cartilage degeneration by inhibiting TLR-4 and NF-κB activation. This study provided the experimental foundation for the development of SHM into a more effective dosage form or new drugs for OA treatment.

Compound XiongShao Capsule ameliorates streptozotocin-induced diabetic peripheral neuropathy in rats via inhibiting apoptosis, oxidative - nitrosative stress and advanced glycation end products.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound XiongShao Capsule (CXSC), a traditional herb formula, has been approved for using to treat diabetic peripheral neuropathy (DPN) by the Shanghai Food and Drug Administration, with significant efficacy in clinic. AIM OF THE STUDY: This study aimed to investigate the multidimensional pharmacological mechanisms and synergism of CXSC against DPN in rats. METHODS: The quality analysis of CXSC was performed by high-performance liquid chromatography (HPLC) and thin-layer chromatography. Rats with DPNinduced by streptozotocin/high-fat diet for 4 weeks were treated with CXSC at three doses (1.2 g/kg, 0.36 g/kg, and 0.12 g/kg), or epalrestat (15 mg/kg) daily for 8 weeks continuously. During the treatment period, body weight, serum glucose levels, and nerve function, including nerve conduction velocity (NCV), and mechanical and thermal hyperalgesia were tested and assessed every 4 weeks. In the 13th week, the histopathological examination in the sciatic nerve was performed using a transmission electron microscope. The expression of apoptosis-related proteins of BAX, BCL2, and caspase-3 in the sciatic nerve was examined using hematoxylin and eosin staining. The serum levels of advanced glycation end products (AGEs), oxidative-nitrosative stress biomarkers of superoxide dismutase (SOD), and nitric oxide synthase (NOS) were measured using a rat-specific ELISA kit. RESULTS: CXSC had no significant effect on body weight or serum glucose levels (P > 0.05), but it significantly improved mechanical hyperalgesia (F5,36 = 18.24, P < 0.0001), thermal hyperalgesia (F5,36 = 8.45, P < 0.0001), and NCV (motor NCV: F5,36 = 7.644, P < 0.0001, sensory NCV: F5,36 = 12.83, P < 0.0001). Besides, it maintained myelin and axonal structure integrity, downregulated the expression of apoptosis-related proteins in the sciatic nerve tissue, reduced AGEs and NOS levels, and enhanced antioxidant enzyme SOD activities in the serum. CONCLUSION: CXSC exerted neuroprotective effects against rats with DPN through multidimensional pharmacological mechanisms including antiapoptotic activity in the sciatic nerve and downregulation of the level of serum NOS, SOD and AGEs.