Efficacy, Safety, and Cost-effectiveness Analysis of Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with higher non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). But the preferred drug for preventing cytomegalovirus infection is still controversial. We evaluate the efficacy, safety, and cost-effectiveness of antiviral agents based on the most recent studies. METHODS: A pairwise and network meta-analysis was conducted to obtain direct and indirect evidence of antivirals. The cost of allo-HSCT recipients in a teaching hospital was collected, and a cost-effectiveness analysis using a decision tree combined with Markov model was completed from the perspective of allo-HSCT recipients over a lifetime horizon. RESULTS: A total of 19 RCTs involving 3565 patients (8 antivirals) were included. In the network meta-analysis, relative to placebo, letermovir, valacyclovir, and ganciclovir significantly reduced CMV infection incidence; ganciclovir significantly reduced CMV disease incidence; ganciclovir significantly increased the incidence of serious adverse event; none of antivirals significantly reduced all-cause mortality. Based on meta-analysis and Chinese medical data, the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) saved for maribavir, acyclovir, valacyclovir, ganciclovir, and letermovir relative to placebo corresponded to US$216 635.70, US$11 590.20, US$11 816.40, US$13 049.90, and US$12 189.40, respectively. One-way sensitivity analysis showed the most influential parameter was discount rate. The probabilistic sensitivity analysis indicated a 53.0% probability of letermovir producing an ICER below the willingness-to-pay threshold of US$38 824.23/QALY. The scenario analysis demonstrated prophylaxis with letermovir is considered cost-effective in the United States. CONCLUSIONS: Currently, letermovir is an effective and well-tolerated treatment for preventing CMV infection, and it might be a cost-effective choice in allo-HSCT recipients in China.

Six Transmembrane Epithelial Antigen 1 as a Prognostic Biomarker in Carcinomas: A Meta-Analysis.

BACKGROUND: Six transmembrane epithelial antigen 1 (STEAP1) is aberrantly expressed in cancers and could therefore be a potential biomarker. This study examined the connection between STEAP1 expression and clinical features/prognosis in cancer patients. METHODS: Several databases were comprehensively searched for related published studies. The combination of hazard ratios (HRs), odd ratios (ORs), and 95% confidence intervals (95% CIs) was used to assess the role of STEAP1. The Cancer Genome Atlas (TCGA) dataset was used to estimate the prognostic value of STEAP1 in multiple cancer types, and several biological behaviors related to STEAP1 were evaluated by CancerSEA. RESULTS: Searches of electronic databases revealed 7 relevant trials with 765 patients. A significant connection was found between high STEAP1 expression and worse overall survival amongst cancer patients (HR = 1.87, 95% CI: 1.49-2.34, p < 0.001). In addition, a strong correlation was found between high STEAP1 expression and the occurrence of lymph node metastases (OR = 3.19, 95% CI: 1.26-8.09, p < 0.001). Analysis of TCGA datasets verified that a higher level of STEAP1 expression is linked with reduced survival in many kinds of cancer. At the single cell level, STEAP1 expression was correlated with some tumor biological behaviors, such as angiogenesis, quiescence, and stemness. CONCLUSIONS: STEAP1 could regulate various biological functions in tumors and predict prognosis as a novel biomarker in a number of cancer types.

Metallo-ß-lactamases immobilized by magnetic zeolitic imidazolate frameworks-8 for degradation of ß-lactam antibiotics in an aqueous environment.

Residual antibiotics in nature are an important cause of antimicrobial drug resistance, and how to deal with residual ß-lactam antibiotics in aqueous environments has become an urgent issue. In this work, magnetic zeolitic imidazolate frameworks-8 (ZIF-8) for immobilizing metallo-ß-lactamases (MBLs), or Fe3O4@ZIF-8@MBLs, were successfully synthesized using the one-pot method in aqueous solution. The morphology and chemical structure of Fe3O4@ZIF-8@MBLs were characterized by scanning electron microscopy, energy dispersive spectra, X-ray diffraction, infrared spectra, physical adsorption, and zeta potential. Further, the degradation performance of Fe3O4@ZIF-8@MBLs for ß-lactam antibiotics (penicillin G, cefoperazone, meropenem) in an aqueous environment was investigated by UV-visible absorption spectrophotometry. The results indicated that Fe3O4@ZIF-8@MBLs, compared to control ZIF-8, exhibited superior degradation ability, excellent reusability, and better stability under several harsh conditions. The strategy of combining ZIF-8 and MBLs to form magnetic porous polymers may be suitable for removing ß-lactam antibiotics from an aqueous environment. This work provided an original insight into future studies on the degradation of ß-lactam antibiotics employing MBLs immobilized by magnetic metal-organic frameworks.

A novel strategy for therapeutic drug monitoring: application of biosensors to quantify antimicrobials in biological matrices.

Over the past few years, therapeutic drug monitoring (TDM) has gained practical significance in antimicrobial precision therapy. Yet two categories of mainstream TDM techniques (chromatographic analysis and immunoassays) that are widely adopted nowadays retain certain inherent limitations. The use of biosensors, an innovative strategy for rapid evaluation of antimicrobial concentrations in biological samples, enables the implementation of point-of-care testing (POCT) and continuous monitoring, which may circumvent the constraints of conventional TDM and provide strong technological support for individualized antimicrobial treatment. This comprehensive review summarizes the investigations that have harnessed biosensors to detect antimicrobial drugs in biological matrices, provides insights into the performance and characteristics of each sensing form, and explores the feasibility of translating them into clinical practice. Furthermore, the future trends and obstacles to achieving POCT and continuous monitoring are discussed. More efforts are necessary to address the four key 'appropriateness' challenges to deploy biosensors in clinical practice, paving the way for personalized antimicrobial stewardship.

Lessons learned from COVID-19 vaccination implementation: How psychological antecedents of vaccinations mediate the relationship between vaccine literacy and vaccine hesitancy.

BACKGROUND: Enhancing the public's vaccine literacy is critical for curbing vaccine hesitancy and enhancing society's pandemic preparedness, particularly in an era of infodemic. Evidence on vaccine literacy as an influencing factor of hesitancy is scarce. Lessons could be learned from COVID-19 vaccination implementation. Taking the COVID-19 vaccines as an example, the current study aimed to examine the relationship between vaccine literacy and hesitancy and the mediating role of psychological antecedents of vaccination on the relationship. METHODS: A baseline online questionnaire survey among the general public in China based on quota sampling was conducted in April 2021 to measure participants' vaccine literacy, psychological antecedents of vaccination, COVID-19 vaccination status, and vaccine hesitancy. A follow-up online survey tracked the updated COVID-19 vaccination status among those who hadn't taken COVID-19 vaccines at the baseline survey. Structural equation modeling has been applied to examine the direct and indirect effect of vaccine literacy on vaccine hesitancy. Time-to-event analysis was used to explore the effect of vaccine hesitancy on vaccination behavior. RESULTS: Lower vaccine hesitancy was associated with higher vaccine literacy. The "3Cs" psychological antecedents were important mediators between vaccine literacy and vaccine hesitancy. The pathway between critical/interactive vaccine literacy and vaccine hesitancy through the "3Cs" psychological antecedents played a more important role. Time-to-event analysis showed participants with a higher vaccine hesitancy were prone to have a longer delay in vaccination. CONCLUSIONS: Improving the public's ability to obtain and evaluate vaccination information can fix the public's psychological determinants of vaccination, reducing vaccine hesitancy and promoting vaccination. Governments need to put more effort into guiding and regulating the media to disseminate evidence-based information, rectifying misinformation, and improving the public's vaccine literacy through education, especially the public's capability to critically discern mixed information.

Dexmedetomidine Combined with Low-Dose Norepinephrine Continuous Pumping to Prevent Hypotension after Cesaresan Section: A Randomized Controlled Trial.

Objective: The aim of the study is to explore the clinical effect of dexmedetomidine combined with low-dose norepinephrine (NE) continuous pumping in preventing supine hypotension. Methods: A total of 160 puerperaes who underwent elective cesarean section were selected. The puerperaes were equally divided into S group (saline), D group (dexmedetomidine), N group (norepinephrine), and DN group (dexmedetomidine combined with norepinephrine) by a random number table method. Apgar scores and umbilical cord venous blood gas values were recorded at 1 and 5 minutes. Results: There were no statistically significant differences in the age, gestational age, body mass index, bleeding volume, fluid supplement volume, Apgar scores of new borns at the 1st and 5th minute, the blood gas values of umbilical cord arterial and venous in the four groups (P > 0.05). Compared with the S group, the incidence of supine hypotension, the number of NE supplements, the supplementary doses of NE, and the incidence of adverse reactions were significantly reduced in the D, N, and DN groups after spinal anesthesia (P < 0.05). Compared with group D, the incidence of supine hypotension, the number of additional NE, additional dose of NE, and the incidence of adverse reactions in the DN group after spinal anesthesia were significantly reduced (P < 0.05). Compared with the N group, the incidence of supine hypotension, the number of additional NE, the additional dose of NE, and the incidence of adverse reactions in the DN group after spinal anesthesia were significantly reduced (P < 0.05). Conclusion: Dexmedetomidine combined with continuous pumping of low-dose norepinephrine can effectively prevent the occurrence of supine hypotension, reduce the occurrence of other adverse reactions, and have no obvious adverse effects on neonates. Registration. Chinese Clinical Trial Registry (https://www.chictr.org.cn/enIndex.aspx; ChiCTR2000040979).

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study.

OBJECTIVES: To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS: This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS: Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION: Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.

Optimizing Antimicrobial Dosing for Critically Ill Patients with MRSA Infections: A New Paradigm for Improving Efficacy during Continuous Renal Replacement Therapy.

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30-35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6-8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8-10 mg/kg every 24 h was optimal under 30-35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.