High-dose methotrexate pharmacokinetics and its impact on prognosis of paediatric acute lymphoblastic leukaemia patients: A population pharmacokinetic study.

This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 µmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range.

Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

OBJECTIVES: To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. PATIENTS AND METHODS: We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. RESULTS: We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. CONCLUSIONS: We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

Forms of nitrogen inputs regulate the intensity of soil acidification.

Soil acidification induced by reactive nitrogen (N) inputs can alter the structure and function of terrestrial ecosystems. Because different N-transformation processes contribute to the production and consumption of H+ , the magnitude of acidification likely depends on the relative amounts of organic N (ON) and inorganic N (IN) inputs. However, few studies have explicitly measured the effects of N composition on soil acidification. In this study, we first conducted a meta-analysis to test the effects of ON or IN inputs on soil acidification across 53 studies in grasslands. We then compared soil acidification across five different ON:IN ratios and two input rates based on long-term field N addition experiments. The meta-analysis showed that ON had weaker effects on soil acidification than IN when the N addition rate was above 20 g N m-2 year-1 . The field experiment confirmed the findings from meta-analysis: N addition with proportions of ON ≥ 20% caused less soil acidification, especially at a high input rate (30 g N m-2 year-1 ). Structural equation model analysis showed that this result was largely due to a relatively low rate of H+ production from ON as NH3 volatilization and uptake of ON and NH4 + by the dominant grass species Leymus chinensis (which are both lower net contributors to H+ production) result in less NH4 + available for nitrification (which is a higher net contributor to H+ production). These results indicate that the evaluation of soil acidification induced by N inputs should consider N forms and manipulations of relative composition of N inputs may provide an effective approach to alleviate the N-induced soil acidification.

Lensless computationally defined confocal incoherent imaging with a Fresnel zone plane as coded aperture.

We present a Fresnel zone plate (FZP) mask-based system for single-shot lensless confocal imaging. The system uses an FZP as coded aperture, which allows each point source to cast a unique pattern onto the sensor, representing their horizontal and axial positions. This results in a 2D sensor measurement comprising a series of FZP patterns, which records the spatial intensity distribution of the incoherent illuminant. The reconstruction process is facilitated by an algorithm based on compress sensing (CS) theory and the use of the nuclear norm of gradient scanning and hologram segmentation technology for autofocusing. The simulative and experimental results of this study align well with the expectation that every layered scene can be accurately recovered at the corresponding depth, without undesirable signals from other layers. Additionally, we analyze the deviation of the reconstruction results in the experiment, which emphasizes the need to consider the thickness of the FZP for a precise forward propagation model.

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer.

AIM: Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. METHODS: First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. RESULTS: The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 µg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). CONCLUSIONS: Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

A preliminary clinical trial comparing wet silver dressings versus wet-to-dry povidone-iodine dressings for wound healing in pemphigus vulgaris patients.

There is insufficient evidence concerning the efficacy of wet silver-containing dressings for wound healing in pemphigus vulgaris (PV). In this randomized, controlled clinical trial, 58 patients with PV skin erosions (10%-70% body surface area) were assigned to receive either wet silver-containing dressings (n = 28) or wet to dry povidone-iodine dressings as a control (n = 30). The patients in the treatment group demonstrated a significant improvement in the number of dressing changes, wound healing time, and duration of hospital stay compared with the control group. Patients treated with wet silver dressings had significantly lower NRS pain scores and reported better subjective satisfaction compared with the control group. The only adverse reactions were an occasional abnormal discharge or infection, but there was no difference between the two groups. In our study the wet silver-containing dressings were safe and effective for the treatment of wound healing in PV patients.

The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase.

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo We found that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found that these effects were not mediated by tubacin's inhibitory effect on HDAC6 activity, but rather were due to its ability to stabilize eNOS mRNA transcripts. Consistent with these findings, tubacin also inhibited proinflammatory cytokine-induced degradation of eNOS transcripts and impairment of endothelium-dependent relaxation in the mouse aorta. Furthermore, we found that tubacin-induced up-regulation in eNOS expression in vivo is associated with improved endothelial function in diabetic db/db mice and with a marked attenuation of ischemic brain injury in a murine stroke model. Our findings indicate that tubacin exhibits potent eNOS-inducing effects and suggest that this compound might be useful for the prevention or management of endothelial dysfunction-associated cardiovascular diseases.

Binary sinusoidal single-order multilayer gratings for tender x-ray region.

We propose and theoretically analyze a single-order diffractive optical element, termed binary sinusoidal multilayer grating (BSMG), to effectively suppress high-order diffractions while retaining high diffraction efficiency in the first order. The key idea is to integrate sinusoidal-shaped microstructures with high-reflectivity multilayer coatings. The dependence of the high-order diffraction property on the microstructure shape and multilayer coatings is investigated. Theoretical calculation reveals that the second-, third-, fourth-, and fifth-order diffraction efficiencies are as low as 0.01%. Strikingly, we show that first-order relative diffraction efficiency (the ratio between the intensity of the first diffraction order versus that of the reflected light) as high as 97.7% can be achieved. Thus, the proposed BSMG should be highly advantageous in future development and application of tender x-ray spectroscopy.

The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.

We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.

Retrospective Analysis of Vancomycin Nephrotoxicity in Elderly Chinese Patients.

This study explored nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors. This was a single-center retrospective study. The patient population included those who were ≥60 years of age, had normal baseline serum creatinine values, and received vancomycin for ≥48 h between January 1, 2013 and August 30, 2014. Nephrotoxicity occurred in 29% of 124 patients. A baseline creatinine clearance ≥63.5 ml/min was more common in the nephrotoxic group. Patients with high (≥15 mg/l) rather than low (<15 mg/l) average vancomycin troughs had elevated nephrotoxicity (47.2 vs. 27.3%, p = 0.0001). Of the comorbid conditions evaluated, there were more patients with shock (p = 0.001), hypertension (p = 0.020) and congestive heart failure (p = 0.04) in the nephrotoxic group. Drugs frequently given at the same time with vancomycin, such as angiotensin receptor blockers and furosemide, were also associated with increased nephrotoxic risk. In conclusion, nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥15 µg/ml and hypertension, shock, congestive heart failure. In addition, drugs concurrently used with vancomycin may also increase its nephrotoxicity. Therefore, renal function and vancomycin serum troughs should be closely monitored, especially in patients with other renal injury risk factors.

Neutron penumbral image reconstruction with a convolution neural network using fast Fourier transform.

In Inertial Confinement Fusion (ICF), the asymmetry of a hot spot is an important influence factor in implosion performance. Neutron penumbral imaging, which serves as an encoded-aperture imaging technique, is one of the most important diagnostic methods for detecting the shape of a hot spot. The detector image is a uniformly bright range surrounded by a penumbral area, which presents the strength distribution of hot spots. The present diagnostic modality employs an indirect imaging technique, necessitating the reconstruction process to be a pivotal aspect of the imaging protocol. The accuracy of imaging and the applicable range are significantly influenced by the reconstruction algorithm employed. We develop a neural network named Fast Fourier transform Neural Network (FFTNN) to reconstruct two-dimensional neutron emission images from the penumbral area of the detector images. The FFTNN architecture consists of 16 layers that include a FFT layer, convolution layer, fully connected layer, dropout layer, and reshape layer. Due to the limitations in experimental data, we propose a phenomenological method for describing hot spots to generate datasets for training neural networks. The reconstruction performance of the trained FFTNN is better than that of the traditional Wiener filtering and Lucy-Richardson algorithm on the simulated dataset, especially when the noise level is high as indicated by the evaluation metrics, such as mean squared error and structure similar index measure. This proposed neural network provides a new perspective, paving the way for integrating neutron imaging diagnosis into ICF.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

Background: High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. Methods: From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. Results: This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. Conclusions: To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

Analysis of bioactive components and synergistic action mechanism of ShuGan-QieZhi Capsule for treating non-alcoholic fatty liver disease.

BACKGROUND: ShuGan-QieZhi capsule (SGQZC) is a traditional Chinese preparation used to treat hyperlipidemia and obesity, even non-alcoholic fatty liver disease (NAFLD). However, its therapeutic effects, main bioactive ingredients, as well as potential mechanisms for NAFLD are still unclear. PURPOSE: To investigate the pharmacological effect, main active ingredients, and mechanisms of SGQZC against high-fat diet (HFD)-induced NAFLD in mice. METHODS: NAFLD models were established by feeding C57BL/6 J mice an HFD for 24 weeks. From the 12th week, HFD-fed mice received daily gavage of either SGQZC or silibinin for 12 weeks. Hepatic hypertrophy parameters, along with hepatic and systemic lipid metabolism changes in NAFLD mice, were assessed. Oil red O and histopathological staining techniques determined lipid accumulation and liver injury severity. qRT-PCR analysis measured the expression of genes tied to liver lipid metabolism and inflammation. HPLC-MS/MS identified the primary components of SGQZC in the serum. Human normal hepatocytes (LO2) and hepatic stellate cells (LX-2) were used to screen SGQZC's bioactive ingredients. Network pharmacological analysis, transcriptomics, and western blotting delved into SGQZC's synergistic mechanisms against NAFLD. RESULTS: SGQZC ameliorated abnormal lipid metabolism and liver hypertrophy in mice with HFD-induced NAFLD, consequently reducing hepatic lipid accumulation, inflammatory cell infiltration, and liver impairment. Eight crucial components of SGQZC were detected in serum using HPLC-MS/MS and were found to effectively attenuate lipid accumulation and inflammation in liver cells. Further investigation indicated that SGQZC modulates MAPK pathway and AKT/NF-κB pathway, subsequently improving lipid metabolism and inflammation. CONCLUSION: SGQZC alleviates NAFLD by synergistically modulating the MAPK-mediated lipid metabolism and inhibiting AKT/NF-κB pathways-mediated inflammation. Our findings reveal the enormous potential of SGQZC for the treatment of NAFLD, providing a possible new clinical therapeutic strategy.

Efficacy and Safety Factors Related to Plasma Concentration-Optimized Polymyxin B Therapy in Treating Carbapenem-Resistant Gram-Negative Bacterial Infections in China.

Background: Polymyxin B (PMB)-based combination therapies are used to treat severe carbapenem-resistant gram-negative bacterial (CR-GNB) infections. This observational study investigated the relationship between clinical factors, including PMB concentration, and clinical efficacy and safety. Patients and Methods: Polymyxin B regimens were optimized through therapeutic drug monitoring (TDM) and area under the concentration-time curve (AUC). In all, 382 samples were tested from 130 patients. Logistic regression was used to analyze the relationships between variables with clinical efficacy and 30-day mortality factors were analyzed by Cox regression. The sensitivity and specificity of Cmin and AUC for the occurrence of acute kidney injury (AKI) were determined by ROC curve analysis. Results: The clinical effectiveness of PMB was 65.4%. Multivariate logistic regression analysis revealed that lung infection, continuous renal replacement therapy, and C-reactive protein were independent factors significantly associated with efficacy. AKI occurred in 14.6% of the patients during treatment; age > 73 years (OR: 3.63; 95% CI: 1.035-12.727; P = 0.044), Cmin greater than 2.3 µg/mL (OR: 7.37; 95% CI: 1.571-34.580; P = 0.011), combined vancomycin (OR: 9.47; 95% CI: 1.732-51.731; P = 0.009), and combined piperacillin-tazobactam (OR: 21.87; 95% CI: 3.139-152.324; P = 0.002) were independent risk factors. The identified PMB cut-offs for predicting AKI were Cmin = 2.3 µg/mL and AUC = 82.0 mg h/L. Conclusion: Polymyxin B-based combination regimens are effective in treating CR-GNB infections, particularly bloodstream infections, but have shown unsatisfactory for lung infections. Cmin ≥ 2.3 µg /mL and AUC ≥ 82.0 mg h/L may increase PMB-associated AKI incidence. PMB dose should be adjusted based on TDM to ensure efficacy.

A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic.

Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small-molecule library for inhibitors of UT-facilitated urea transport. A novel class of thienoquinolin UT-B inhibitors were identified, of which PU-14 had potent inhibition activity on human, rabbit, rat, and mouse UT-B. The half-maximal inhibitory concentration of PU-14 on rat UT-B-mediated urea transport was ∼0.8 µmol/l, and it did not affect urea transport in mouse erythrocytes lacking UT-B but inhibited UT-A-type urea transporters, with 36% inhibition at 4 µmol/l. PU-14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 µmol/l. Subcutaneous delivery of PU-14 (at 12.5, 50, and 100 mg/kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU-14 has a diuretic effect by urea-selective diuresis. Thus, PU-14 or its analogs might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance. PU-14 may establish 'chemical knockout' animal models to study the physiological functions of UTs.

Decoupling of nutrient stoichiometry in Suaeda glauca (Bunge) senesced leaves under salt treatment.

The stoichiometry of senesced leaves is pivotal in nutrient cycling and can be significantly influenced by soil salinization, a rising global issue threatening the functionality of ecosystems. However, the impacts of soil salinization on senesced leaf stoichiometry are not fully understood. In this study, we conducted a pot experiment with varying soil salt concentrations to examine their influence on the concentrations and stoichiometric ratios of nitrogen (N), phosphorus (P), sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), and zinc (Zn) in the senesced leaves of Suaeda glauca (Bunge). Compared to the control group, salt treatments significantly enhanced Na concentration while diminishing the concentrations of K, Ca, Mg, Zn, N, and P. Interestingly, as salinity levels escalated, N concentration maintained stability, whereas P concentration exhibited an increasing trend. Moreover, K, Ca, and Mg significantly declined as salt levels rose. Salt treatments brought about significant changes in stoichiometric ratios, with the N:P, K:Na, N:Na, N:Mg, and Ca : Mg ratios dropping and the N:Ca and N:K ratios rising, illustrating the varying nutrient coupling cycles under different salt conditions. These findings shed light on the plasticity of stoichiometric traits in S. glauca senesced leaves in response to soil salinization shifts, which could potentially offer insights into nutrient cycling reactions to soil salinization.

A LC-MS/MS Method for Quantifying the Schisandrin B and Exploring Its Intracellular Exposure Correlating Antitumor Effect.

Schisandrin B (Sch.B) shows antineoplastic activity in colorectal cancer, but the mechanism is still obscure. The intracellular spatial distribution may be helpful in elucidating the mechanism. To investigate the intracellular drug distribution of Sch.B in cancer cells, a simple, rapid, and sensitive ultra-highperformance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was established for the determination of Sch.B in colorectal cancer cells. Warfarin was utilized as an internal standard. The sample pretreatment was carried out with protein precipitation using methanol. The analyte was separated on an Atlantis T3-C18 column (3 µm, 2.1∗100 mm) using gradient elution with a mobile phase comprised of methanol and 0.2% formic acid in water. The flow rate was 0.4 mL/min. The linear range of Sch.B was 20.0-1000.0 ng/mL with a correlation coefficient (R) more than 0.99. The matrix effect and recovery ranged from 88.01% to 94.59% and from 85.25% to 91.71%; the interday and intraday precision and accuracy, stability, specificity, carryover, matrix effect, and recovery all conformed to the requirements of pharmacopoeia. Cell viability and apoptosis assays demonstrated that Sch.B has an inhibitory effect in a dose-dependent way on HCT116 proliferation and achieved significant suppression at 75 µM (IC50). It was found that in HCT116 cell, nucleus, and mitochondria, exposure levels of Sch.B peaked at 36 h and then decreased, and mitochondria possessed more Sch.B than nucleus. These results may help to elucidate the antitumor effect of Sch.B.

The effect of Shengmai injection in patients with coronary heart disease in real world and its personalized medicine research using machine learning techniques.

Objective: Shengmai injection is a common treatment for coronary heart disease. The accurate dose regimen is important to maximize effectiveness and minimize adverse reactions. We aim to explore the effect of Shengmai injection in patients with coronary heart disease based on real-world data and establish a personalized medicine model using machine learning and deep learning techniques. Methods: 211 patients were enrolled. The length of hospital stay was used to explore the effect of Shengmai injection in a case-control study. We applied propensity score matching to reduce bias and Wilcoxon rank sum test to compare results between the experimental group and the control group. Important variables influencing the dose regimen of Shengmai injection were screened by XGBoost. A personalized medicine model of Shengmai injection was established by XGBoost selected from nine algorithm models. SHapley Additive exPlanations and confusion matrix were used to interpret the results clinically. Results: Patients using Shengmai injection had shorter length of hospital stay than those not using Shengmai injection (median 10.00 days vs. 11.00 days, p = 0.006). The personalized medicine model established via XGBoost shows accuracy = 0.81 and AUC = 0.87 in test cohort and accuracy = 0.84 and AUC = 0.84 in external verification. The important variables influencing the dose regimen of Shengmai injection include lipid-lowering drugs, platelet-lowering drugs, levels of GGT, hemoglobin, prealbumin, and cholesterol at admission. Finally, the personalized model shows precision = 75%, recall rate = 83% and F1-score = 79% for predicting 40 mg of Shengmai injection; and precision = 86%, recall rate = 79% and F1-score = 83% for predicting 60 mg of Shengmai injection. Conclusion: This study provides evidence supporting the clinical effectiveness of Shengmai injection, and established its personalized medicine model, which may help clinicians make better decisions.

Evaluation of in vivo antibacterial drug efficacy using Caenorhabditis elegans infected with carbapenem-resistant Klebsiella pneumoniae as a model host.

Objective: This study was developed to assess the in vivo antimicrobial activity of specific drugs using a model system consisting of Caenorhabditis elegans (C. elegans) infected with Carbapenem-resistant Klebsiella pneumoniae (CRKP) in an effort to identify promising drugs for CRKP-infected patient treatment. Methods: A C. elegans-CRKP liquid assay platform was developed and used to conduct limited in vivo screening for antimicrobial agents with potential activity against CRKP. Time curves for 10 different concentrations of tested antimicrobial agents were tested in this model system at 0, 2, 6, 8, and 12 h after treatment. The protective effects of these different antimicrobial agents were compared at different time points. Furthermore, ten CRKP strains samples were isolated from clinical specimens to demonstrate the applicability of the nematode model method, and two typical clinical cases are presented. Results: CRKP bacteria were sufficient to induce C. elegans death in a dose- and time-dependent fashion, while effective antimicrobial agents improved the survival of these nematodes in a dose-dependent manner. Notably, PB and TGC exhibited robust antibacterial protection within 12 h even at low tested concentrations, and clear efficacy remained evident for high doses of CAZ at this same time point as mediators of improved nematode survival. The results of C. elegans model method were well consistent with that using the Kirby-Bauer method in 10 CRKP strains samples, and two typical clinical cases showed applicability, reliability and efficacy of C. elegans model method. Conclusion: Overall, nematode models in drug sensitivity testing have shown advantages in clinical settings. Our results highlight the value of C. elegans model systems as tools for the simultaneous screening of different agents for in vivo antibacterial efficacy and are deserved further study.