Optimization of oral isavuconazole dose for population in special physiological or pathological state: a physiologically based pharmacokinetics model-informed precision dosing.

OBJECTIVE: To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. METHODS: Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration-time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. RESULTS: The developed PBPK model was successfully validated in different populations. Most predicted concentration-time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. CONCLUSION: The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations.

A physiologically based pharmacokinetic analysis to predict the pharmacokinetics of intravenous isavuconazole in patients with or without hepatic impairment.

Isavuconazole (ISA) is an azole antifungal used in the treatment of invasive aspergillosis and mucormycosis. Patients with mild and moderate hepatic impairment have lower clearance (CL) as compared to the healthy population. Currently, there is no data on ISA in patients with severe hepatic impairment (Child-Pugh Class C). The purpose of this study was to build a physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics (PK) of intravenous ISA, and to predict changes in ISA disposition in different patient populations and in patients with hepatic impairment to guide personalized dosing. By incorporating the systemic and drug specific parameters of ISA, the model was initially developed in healthy population and validated with 10 independent PK profiles obtained from healthy subjects and from patients with normal liver function. The results showed a satisfactory predictive capacity, with most of the relative predictive errors being between ±30% for area under the curve (AUC) and Cmax The observed plasma concentration-time profiles of ISA were well described by the model predicted profiles. The model adequately predicted the reduced CL of ISA in patients with mild and moderate hepatic impairment. Furthermore, the model predicted a decrease in CL of about 60% in patients with severe hepatic impairment. Therefore, we recommend reducing the dose by 50% in patients with severe hepatic impairment. The model also predicted differences in the PK of ISA between Caucasian and Asian population, with the CL ratio of 0.67 in Chinese vs Caucasian population. The developed PBPK model of ISA provides a reasonable approach for optimizing the dosage regimen in different ethnic populations and in patients with severe hepatic impairment.

Impact assessment of urbanization on vegetation net primary productivity: A case study of the core development area in central plains urban agglomeration, China.

Rapid urbanization process has a negative or positive impact on vegetation growth. Net primary productivity (NPP) is an effective indicator to characterize vegetation growth status. Taking the core development area of the Central Plains urban agglomeration as the study area, we estimated the NPP and its change trend in the past four decades using the Carnegie-Ames-Stanford Approach (CASA) model and statistical analysis based on meteorological and multi-source remote sensing data. Meanwhile, combined with the urbanization impact framework, we further analyzed urbanization's direct and indirect impact on NPP. The results showed that the urban area increased by 2688 km2 during a high-speed urbanization process from 1983 to 2019. As a result of the intense urbanization process, a continuous NPP decrease (direct impact) can be seen, which aggravated along with the acceleration of the urban expansion, and the mean value of direct impact was 130.84 g C·m-2·a-1. Meanwhile, urbanization also had a positive impact on NPP (indirect impact). The indirect impact showed an increasing trend during urbanization with a mean value of 10.91 g C·m-2·a-1. The indirect impact was mainly related to temperature in climatic factors. The indirect impact has a seasonal heterogeneity, and high-temperature environments of urban areas are more effective in promoting vegetation growth in autumn and winter than in summer. Among different cities, high-speed development cities have higher indirect impact values than medium's and low's because of better ecological construction. This study is of great significance for understanding the impact of urbanization on vegetation growth in the Central Plains urban agglomeration area, supporting urban greening plans, and building sustainable and resilient urban agglomerations.

A Glove-Wearing Detection Algorithm Based on Improved YOLOv8.

Wearing gloves during machinery operation in workshops is essential for preventing accidental injuries, such as mechanical damage and burns. Ensuring that workers are wearing gloves is a key strategy for accident prevention. Consequently, this study proposes a glove detection algorithm called YOLOv8-AFPN-M-C2f based on YOLOv8, offering swifter detection speeds, lower computational demands, and enhanced accuracy for workshop scenarios. This research innovates by substituting the head of YOLOv8 with the AFPN-M-C2f network, amplifying the pathways for feature vector propagation, and mitigating semantic discrepancies between non-adjacent feature layers. Additionally, the introduction of a superficial feature layer enriches surface feature information, augmenting the model's sensitivity to smaller objects. To assess the performance of the YOLOv8-AFPN-M-C2f model, this study conducted multiple experiments using a factory glove detection dataset compiled for this study. The results indicate that the enhanced YOLOv8 model surpasses other network models. Compared to the baseline YOLOv8 model, the refined version shows a 2.6% increase in mAP@50%, a 63.8% rise in FPS, and a 13% reduction in the number of parameters. This research contributes an effective solution for the detection of glove adherence.

External evaluation of population pharmacokinetic models for voriconazole in Chinese adult patients with hematological malignancy.

OBJECTIVES: Patients with hematological malignancies are prone to invasive fungal disease due to long-term chemotherapy or radiotherapy. Voriconazole is a second-generation triazole broad-spectrum antibiotic used to prevent or treat invasive fungal infections. Many population pharmacokinetic (pop PK) models have been published for voriconazole, and various diagnostic methods are available to validate the performance of these pop PK models. However, most of the published models have not been strictly evaluated externally. The purpose of this study is to evaluate these models externally and assess their predictive capabilities. METHODS: The external dataset consists of adults receiving voriconazole treatment at Fujian Medical University Union Hospital. We re-established the published models based on their final estimated values in the literature and used our external dataset for initial screening. Each model was evaluated based on the following outcomes: prediction-based diagnostics, prediction- and variability-corrected visual predictive check (pvcVPC), normalized prediction distribution errors (NPDE), and Bayesian simulation results with one to two prior observations. RESULTS: A total of 237 samples from 166 patients were collected as an external dataset. After screening, six candidate models suitable for the external dataset were finally obtained for comparison. Among the models, none demonstrated excellent predictive performance. Bayesian simulation shows that all models' prediction precision and accuracy were significantly improved when one or two prior concentrations were given. CONCLUSIONS: The published pop PK models of voriconazole have significant differences in prediction performance, and none of the models could perfectly predict the concentrations of voriconazole for our data. Therefore, extensive evaluation should precede the adoption of any model in clinical practice.

Effect of posaconazole on the concentration of intravenous and oral cyclosporine in patients undergoing hematopoietic stem cell transplantation.

PURPOSE: This study aimed to investigate the interactions between posaconazole (POS) and intravenously/orally administered cyclosporine A (CsA) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS: We included 118 allogeneic HSCT patients who received CsA and POS simultaneously between January 2017 and June 2020 in this study. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) before and after POS initiation was compared. RESULTS: After the initiation of POS, the level of CsA increased 1 to 2 times in 66% (78/118) of patients compared to those without POS. However, the CsA C/D ratio increased by more than threefold in 6% (7/118) of patients after POS initiation, with an increase of more than fourfold in two patients. The median C/D ratio of CsA increased from 0.89 to 1.23 (P < 0.001) and 0.78 to 1.22 (P < 0.001) after POS initiation when CsA was administered intravenously and orally, respectively. In patients who received POS at the time of transition from intravenous to oral CsA, the value increased from 1.01 to 1.38 (P = 0.001). The route of administration had no significant effect on the change in the CsA C/D ratio (P = 0.615). Additionally, we observed the time required for the C/D ratio to reach a plateau after POS initiation was similar on days 13, 8, and 15 under various scenarios. CONCLUSION: POS treatment increased blood CsA levels. A large variability was found in the fold-change in the CsA C/D ratio. Therefore, CsA doses should be adjusted by closely monitoring the blood levels of CsA after POS initiation.

ZEB1 modulates endometrial receptivity through epithelial-mesenchymal transition in endometrial epithelial cells in vitro.

Zinc finger E-box binding homeobox 1 (ZEB1) promotes epithelial-mesenchymal transition (EMT) in carcinogenesis, but its role in embryo implantation has not yet been identified. The present study sought to verify if ZEB1 plays a role in endometrial receptivity through regulation of EMT during embryo implantation. Endometrial epithelium from sixty patients in phase of the menstrual cycle (including proliferative and secretory phases) were collected for assessment of mRNA/protein expression. In human endometrial adenocarcinoma cell line RL95-2, ZEB1 expression was suppressed by using shRNA, and the cell function and mRNA/protein expression were evaluated. RL95-2 cells and human choriocarcinoma cell line JAR were co-cultured to establish embryo implantation model in vitro. The results showed that, ZEB1 was highly expressed at both mRNA and protein levels in human endometrium during mid-secretory phase of the menstrual cycle. Knockdown of ZEB1 expression in RL95-2 cells attenuated cell growth, migration, DNA replication, and altered expression of E-cadherin and vimentin at both mRNA and protein levels. Interestingly, knockdown of ZEB1 expression in RL95-2 cells potently suppressed JAR spheroid attachment in vitro (P < 0.01). Additionally, the. Conclusively, knockdown of ZEB1 suppressed embryo implantation in vitro, paralleled with alteration of EMT markers. ZEB1 is likely to modulate endometrial receptivity through promotion of EMT, that could be crucial for embryo implantation process.

Utility evaluation of HLA-B*13:01 screening in preventing trichloroethylene-induced hypersensitivity syndrome in a prospective cohort study.

OBJECTIVES: Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. METHODS: The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. RESULTS: Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. CONCLUSIONS: Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.

A multi-center study on the risk factors of infection caused by multi-drug resistant Acinetobacter baumannii.

BACKGROUND: Acinetobacter baumannii (AB) is critical for healthcare-associated infections (HAI) with significant regional differences in the resistance rate, but its risk factors and infection trends has not been well studied. We aimed to explore the risk factors, epidemiological characteristics and resistance of multidrug-resistant Acinetobacter baumannii (MDR-AB) in intensive care unit inpatients. METHODS: Data of patients with MDR-AB (195 cases), and with antibiotic-sensitive AB infection (294 cases, control) during January to December, 2015 in three medical centers in Xiamen, China were conducted and analyzed in the present retrospective study. RESULTS: Lower respiratory tract infection with AB accounted for 68.71%. MDR-AB was detected in 39.88% of all cases. Univariate analysis suggested that mechanical ventilation, indwelling catheter, cancer patients, length of hospitalization in intensive care unit (ICU) ≥15 d, Acute Physiology and Chronic Health Evaluation (APACHE) II score, combined using antibiotic before isolation of AB and use of third-lines cephalosporins were associated with the development of MDR-AB healthcare-associated infections. Dose-response relationship analysis suggested that the age and the days of mechanical ventilation were associated with increased infection with MDR-AB. Logistic regression analysis suggested that, mechanical ventilation, combined using antibiotic before isolation of AB, and indwelling catheter, were associated with MDR-AB infection, with odds ratios (OR) and 95% confidence intervals (CI) of 3.93 (1.52-10.14), 4.11 (1.58-10.73), and 4.15 (1.32-12.99), respectively. CONCLUSIONS: MDR-AB infection was associated with mechanical ventilation, combined using antibiotic before isolation of AB, and indwelling catheter. Furthermore, the age and the days of mechanical ventilation were associated with increased infection with MDR-AB.

Characterisation of dissolved organic matter in stormwater using high-performance size exclusion chromatography.

Understanding the complexity of dissolved organic matter (DOM) in stormwater has drawn a lot of interest, since DOM from stormwater causes not only environmental impacts, but also worsens downstream aquatic quality associated with water supply and treatability. This study introduced and employed high-performance size exclusion chromatography (HPSEC) coupled with an ultraviolet-visible (UV-vis) diode array detector to assess changes in stormwater-associated DOM characteristics. Stormwater DOM was also analysed in relation to storm event characteristics, water quality and spectroscopic analysis. Statistical tools were used to determine the correlations within DOM and water quality measurements. Results showed that dissolved organic carbon (DOC) and UV absorbance at 254 nm (UV254) as conventional DOM parameters were found to be correlated well to the changes in stormwater quality during each of the three storm events studied. Both detector wavelengths (210 and 254 nm) and their ratio (A210/A254) were found to provide additional information on the physiochemical properties of stormwater-associated DOM. This study indicated that A210/A254 is an important parameter which could be used to estimate the DOM proportions of functional groups and conjugated carbon species. This study provided also an understanding of stormwater quality constituents through assessing variability and sensitivity for various parameters, and the additional information of rainfall characteristics on runoff quality data for a better understanding of parameter correlations and influences.

High-performance size exclusion chromatography with a multi-wavelength absorbance detector study on dissolved organic matter characterisation along a water distribution system.

This study examined the associations between dissolved organic matter (DOM) characteristics and potential nitrification occurrence in the presence of chloramine along a drinking water distribution system. High-performance size exclusion chromatography (HPSEC) coupled with a multiple wavelength detector (200-280nm) was employed to characterise DOM by molecular weight distribution, bacterial activity was analysed using flow cytometry, and a package of simple analytical tools, such as dissolved organic carbon, absorbance at 254nm, nitrate, nitrite, ammonia and total disinfectant residual were also applied and their applicability to indicate water quality changes in distribution systems were also evaluated. Results showed that multi-wavelength HPSEC analysis was useful to provide information about DOM character while changes in molecule weight profiles at wavelengths less than 230nm were also able to be related to other water quality parameters. Correct selection of the UV wavelengths can be an important factor for providing appropriate indicators associated with different DOM compositions. DOM molecular weight in the range of 0.2-0.5kDa measured at 210nm correlated positively with oxidised nitrogen concentration (r=0.99), and the concentrations of active bacterial cells in the distribution system (r=0.85). Our study also showed that the changes of DOM character and bacterial cells were significant in those sampling points that had decreases in total disinfectant residual. HPSEC-UV measured at 210nm and flow cytometry can detect the changes of low molecular weight of DOM and bacterial levels, respectively, when nitrification occurred within the chloraminated distribution system.

[Association of CYP2C19 gene polymorphisms with long-term recurrent risk of ischemic stroke among ethnic Han Chinese from Fujian].

OBJECTIVE: To assess the association of genetic polymorphisms of CYP2C19*2,*3,*17 with the recurrence risk of ischemic stroke during clopidogrel prevention in ethnic Han Chinese from Fujian Province. METHODS: Clinical data of 985 patients with acute ischemic stroke was collected. After 1 year postdischarge follow-up evaluations, only 114 patients with persistence of clopidogrel were enrolled. CYP2C19 genetic polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)and direct sequencing ,then we analysis the correlation between polymorphisms and the recurrence of stroke. RESULTS: Among the 114 patients, 23 had a second onset whilst receiving clopidogrel treatment. During the antiplatelet therapy with clopidogrel, carriers of CYP2C19 poor metabolizer (CYP2C19*2/*2 or *2/*3) had a higher rate of recurrent stroke compared with extensive metabolizers (CYP2C19*1/*1) (OR=4.71, 95%CI: 1.18-18.80, P<0.05). Carriers of CYP2C19 *2 mutant allele had increased recurrence compared with those carrying none loss-of-function allele (OR=2.31, 95%CI: 1.20-4.46, P<0.05). The rate of recurrent stroke in those carrying homozygous mutant *2 allele (CYP2C19*2/*2) was 6.14 times greater than the rate of wild-type homozygotes (CYP2C19*1/*1) (95%CI: 1.54-24.54, P<0.05). Patients with previous stroke history had increased risk of recurrence (OR= 4.146, 95%CI: 1.259-13.655, P<0.05). However, CYP2C19*17 was not detected in the group. CONCLUSION: For ethnic Han Chinese patients receiving clopidogrel treatment, carriers of poor metabolizer or homozygous mutant *2 allele (CYP2C19*2/*2) have a higher risk of recurrent stroke. The CYP2C19 *2 allele is an independent risk factor for recurrent stroke. Those with previous history of stroke are more prone to the recurrence.

Hepatic infarction occurred after 125I particle stent treatment for hepatocellular carcinoma with portal vein tumor thrombus: A case report.

BACKGROUND: Hepatic infarction is a rare liver condition. The purpose of this study is to report a case of hepatic infarction caused by thrombus formation following portal vein stent implantation in a patient with hepatocellular carcinoma and portal vein tumor thrombus, and to explore the underlying causes. CASE REPORT: The patient in this study was a 52-year-old male admitted with diffuse hepatocellular carcinoma involving the right lobe and portal vein tumor thrombus. After undergoing portal vein stent implantation and 125I particle strand implantation treatment, the portal vein was patent, and the pressure decreased. However, multiple instances of hepatic artery chemoembolization combined with targeted immunotherapy resulted in gradual reduction in the diameter of the hepatic artery and affecting hepatic arterial blood flow. Two months post-stent implantation, thrombus formation within the stent was noted, and the patient's condition did not improve with anticoagulant therapy, as evidenced by follow-up CT scans showing an increase in thrombi. Six months later, the patient suffered from gastrointestinal bleeding and, despite emergency esophagogastric variceal ligation and hemostatic treatment, developed hepatic parenchymal infarction and liver function failure. CONCLUSIONS: We reveal the underlying cause is that (1) thrombus formation within the portal vein stent, leading to portal vein embolism and obstructed blood flow due to exacerbate portal hypertension after various treatments; and (2) the effect of hepatic artery chemoembolization, immunotherapy, and targeted therapy on tumor angiogenesis, causing reduced hepatic artery diameter and impaired arterial blood flow. These factors disrupt the liver's dual blood supply system, ultimately contributing to hepatic infarction. To our knowledge, this is the first report of hepatic infarction as a complication following portal vein stent implantation for hepatocellular carcinoma with portal vein tumor thrombus, and it holds significant reference value for guiding the treatment of hepatocellular carcinoma with concurrent portal vein tumor thrombus in a clinical setting.

Chromosome-scale reference genome of broccoli (Brassica oleracea var. italica Plenck) provides insights into glucosinolate biosynthesis.

Broccoli (Brassica oleracea var. italica Plenck) is an important vegetable crop, as it is rich in health-beneficial glucosinolates (GSLs). However, the genetic basis of the GSL diversity in Brassicaceae remains unclear. Here we report a chromosome-level genome assembly of broccoli generated using PacBio HiFi reads and Hi-C technology. The final genome assembly is 613.79 Mb in size, with a contig N50 of 14.70 Mb. The GSL profile and content analysis of different B. oleracea varieties, combined with a phylogenetic tree analysis, sequence alignment, and the construction of a 3D model of the methylthioalkylmalate synthase 1 (MAM1) protein, revealed that the gene copy number and amino acid sequence variation both contributed to the diversity of GSL biosynthesis in B. oleracea. The overexpression of BoMAM1 (BolI0108790) in broccoli resulted in high accumulation and a high ratio of C4-GSLs, demonstrating that BoMAM1 is the key enzyme in C4-GSL biosynthesis. These results provide valuable insights for future genetic studies and nutritive component applications of Brassica crops.

Spatiotemporal variation of irrigation water requirements for grain crops under climate change in Northwest China.

Clarifying the spatiotemporal variation of crop irrigation water requirement (IWR) under the background of climate change is an essential basis for water resource management, determining the irrigation quota and adjusting the planting structure. Using 61 years of climate data from 205 stations in Northwest China, this study investigated the spatiotemporal variations of climatic factors and IWR during the growth period of five main grain crops (spring wheat, winter wheat, spring maize, summer maize, and rice) and explored the dominant climatic driving factors of IWR variation. Results showed that (1) the IWR of grain crops showed distinct differences. Rice was the highest water consumption crop (mean of 753.78 mm), and summer maize was the lowest (mean of 452.90 mm). (2) The variation trends and average values of IWR of different grain crops have spatial heterogeneity across Northwest China. For most crops, high values and increasing trends of IWR were mainly located in eastern Xinjiang, western Gansu, and western Inner Mongolia. (3) Tmax (maximum temperature), Tmin (minimum temperature), and Peff (effective precipitation) showed an increasing trend during the growth period of each grain crop, while U10 (wind speed at 10 m height), SD (solar radiation), and RH (relative humidity) presented decreasing trends. (4) SD, Tmax, and U10 promoted the increase of grain crops' IWR, while Peff and RH inhibited it. The impacts of climatic factors on the grain crop IWR differed among different regions. Peff was the most influential factor to the IWR of all grain crops in most areas. Therefore, under the premise of a significant increase in T and uncertain precipitation mode in the future, it is urgent to take effective water-saving measures according to the irrigation needs of the region. To cope with the adverse impact of climate change on the sustainable development of agriculture in the northwest dry area, to ensure regional and national food security.

Spatiotemporal variations and its driving factors of NDVI in Northwest China during 2000-2021.

Northwest China (WTL) is an essential ecological barrier zone of China, an important node of the "Silk Road Economic Belt," and a crucial bearing area for China's execution of the "One Road and One Belt" and "Going Global" strategies. However, its ecology is exceedingly fragile and particularly vulnerable to climate change and human interference. This study explored the spatiotemporal evolution characteristics of vegetation in WTL using NDVI data and investigated its drive mechanisms by geodetector, partial correlation analysis, and residual trend analysis methods. As well as forecasting the trend for vegetation changes. The findings demonstrated that (1) the change in NDVI manifested an overall improvement trend and the distribution in space of NDVI rose from the center to the periphery. 57.07% of the area had a sparse cover of vegetation (NDVI between 0 and 0.2). In addition, about 49% of regions had deterioration tendencies, which were mainly aggregated in HX, QCXDB, QCXDN, and the eastern of QCXQN and QCXXB. (2) The NDVI's shifting trend was unsustainability, and the region of uncertain future accounted for 57.45% of the total, with apparent unsustainability features. (3) The key parameters influencing NDVI spatial distribution were Pre (precipitation), vegetation type, land use type, and soil type. The interaction between two factors enhanced the influence of any single element, which appeared as bivariate and nonlinear enhancements. (4) Both climate variations and human activities have been recognized as key variables affecting NDVI growth. NDVI variance in 73.02% of areas was influenced by the combined effects of climate variations and human activities. However, human activities were the most influential element in NDVI growth, with the relative contributions of 80.28% (19.72% of which was caused by climate variations). These results can be conducive to deepening insights into the local vegetation status, identifying the mechanisms driving vegetation change, and providing scientific recommendations for WTL's ecosystem restoration measures based on actual situations.

Predicting busulfan exposure in patients undergoing hematopoietic stem cell transplantation using machine learning techniques.

PURPOSE: This study aimed to establish an optimal model to predict the busulfan (BU) area under the curve at steady state (AUCss) by using machine learning (ML). PATIENTS AND METHODS: Seventy-nine adult patients (age ≥18 years) who received BU intravenously and underwent therapeutic drug monitoring from 2013 to 2021 at Fujian Medical University Union Hospital were enrolled in this retrospective study. The whole dataset was divided into a training group and test group at the ratio of 8:2. BU AUCss were considered as the target variable. Nine different ML algorithms and one population pharmacokinetic (pop PK) model were developed and validated, and their predictive performance was compared. RESULTS: All ML models were superior to the pop PK model (R2 = 0.751, MSE = 0.722, 14 and RMSE = 0.830) in model fitting and had better predictive accuracy. The ML model of BU AUCss established through support vector regression (SVR) and gradient boosted regression trees (GBRT) had the best predictive ability (R2 = 0.953 and 0.953, MSE = 0.323 and 0.326, and RMSE = 0.423 and 0.425). CONCLUSION: All the ML models can potentially be used to estimate BU AUCss with the aim of facilitating rational use of BU on the individualized level, especially models built by SVR and GBRT algorithms.

Population Pharmacokinetic Modeling Using Polymyxin B Free Plasma Concentrations From Published Reports and Evaluation of Dosage Regimens Based on Monte Carlo Simulation in Critically Ill Patients.

A population pharmacokinetic (pop PK) model of polymyxin B was developed using nonlinear mixed-effects (NONMEM) modeling based on free plasma concentrations to determine whether dose adjustment is required in critically ill patients. One thousand pharmacokinetic profiles for virtual patients with a body weight of 70 kg were simulated using Monte Carlo simulation at different dose scenarios, and area under the concentration-time curve of free drug (fAUC) was computed. The probability of target attainment (PTA) at each minimum inhibitory concentration (MIC) was calculated using fAUC/MIC as a pharmacokinetic/pharmacodynamic (PK/PD) index. The final population PK model was a 2-compartment model. PTA showed that 3.5 mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MIC of 1 mg/L or less (PTA,  90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2 mg/L or greater (PTA, 56.9% or less). For Klebsiella pneumoniae, the fAUC/MIC target of 17.4 (one log10 kill) was achieved in more than 90.4% of cases for MIC of 0.5 mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1 mg/L (PTA, 56.1% or less). The polymyxin B dosage regimen of 3.5 mg/kg/day and 3 mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1 mg/L or less and K. pneumoniae infections with an MIC of 0.5 mg/L or less, respectively. The current recommended dose (1.5-3 mg/kg/day) of polymyxin B appears inadequate to attain the PK/PD target for therapeutic efficacy against infections caused by P. aeruginosa and K. pneumoniae isolates when MIC is above the values.

Interactive effect between sleep and exercise on depressive symptoms in Chinese adolescents.

Objectives: The study aimed to investigate the effects of sleep and exercise, individually and jointly, on depressive symptoms in Chinese adolescents. Methods: Cluster sampling was used to conduct a cross-sectional, electronic survey among 11,563 students from five primary and high schools in Sichuan Province in Western China. The questionnaire contained custom-designed items concerning sleep and exercise, while it used the Center for Epidemiologic Studies Depression Scale to assess depressive symptoms and the Core Self-Evaluations Scale to assess core self-evaluation. Data were analyzed using descriptive statistics and multivariate linear regression. Results: A total of 10,185 valid questionnaires were collected, corresponding to an effective response rate of 88.1%. Among the respondents in the final analysis, 5,555 (54.5%) were boys and 4,630 (45.5%) were girls, and the average age was 15.20 ± 1.72 years (range, 11-18 years). Only less than half of the respondents (4,914, 48.2%) reported insufficient sleep, while the remainder (5,271, 51.8%) had adequate sleep. Nearly one-quarter (2,250, 22.1%) reported insufficient exercise, while the remainder (7,935, 77.9%) reported adequate exercise. More than half of the respondents (5,681, 55.7%) were from vocational high school, 3,368 (33.1%) were from junior high school, 945 (9.3%) were from senior high school, and 191 (1.9%) were from primary school. The prevalence of depressive symptoms among all respondents was 29.5% (95% CI 28.7%-30.4%). When other variables were controlled, the depression score did not vary significantly with gender (B = -0.244, SE = 0.127, P = 0.054), but it decreased by 0.194 points per 1-year increase in age (B = -0.194, SE = 0.037, P < 0.001). Students getting adequate sleep had depression scores 2.614 points lower than those getting insufficient sleep (B = -2.614, SE = 0.577, P < 0.001), while students who engaged in adequate exercise had depression scores 1.779 points lower than those not exercising enough (B = -1.779, SE = 0.461, P < 0.001). The depression score decreased by 0.919 points per 1-point increase in the core self-evaluation score (B = -0.919, SE = 0.008, P < 0.001). In regression controlling for gender, age, and core self-evaluation, sleep and exercise were found to be related significantly to influence depressive symptoms (B = 0.821, SE = 0.315, P = 0.009). Conclusion: Adequate sleep and adequate exercise are individually associated with milder depressive symptoms in Chinese adolescents. Our results further highlight the need for researchers and clinicians to take into account not only the individual but also the joint effects of sleep and exercise on depression in adolescents when conducting research and designing interventions. If sleep or physical exercise has substantially reduced the risk of depressive symptoms, further reductions by improving sleep and exercise become difficult and may even have opposite effects.

Impact of the Grain for Green Project on water resources and ecological water stress in the Yanhe River Basin.

The Grain for Green project (GGP), initialized by the Chinese government in 1999, has achieved substantial achievements accompanied by a decrease in surface runoff on the Loess Plateau, but the impacts of large-scale afforestation on regional water resources are uncertain. Hence, the objective of this study was to explore the impact of land use change on generalized water resources and ecological water stress using the blue and green water concepts, taking the Yanhe River Basin as the case study. The Soil and Water Assessment Tool (SWAT) was applied to quantify the green water and blue water, which are defined as generalized water resources. The ecological water requirement of vegetation (forest and grass), agricultural water footprint and virtual water flow are considered regional water requirements. The land use types of 1980 (Scenario I) and 2017 (Scenario II) were entered into the SWAT model while keeping the other parameters constant to isolate the influence of land use changes. The results show that the average annual differences in blue, green and generalized water resources were -72.08 million m3, 24.34 million m3, and -47.74 million m3, respectively, when the simulation results of Scenario II were subtracted from those of Scenario I, which shows that land use change caused by the GGP led to a decrease in blue and generalized water resources and an increase in green water resources. Surface runoff in Scenario I was more than that in Scenario II in all of the years of the study period from 1980-2017, and green water storage in Scenario I was more than that in Scenario II in all of the years of the study period except in 1998; although lateral flow in Scenario I was less than that in Scenario II except in 2000 and 2015, as was groundwater runoff in 1992, 2000 and 2015, and green water flow in 1998. Blue water flow, green water storage and green water flow in Scenario II were less than those in Scenario I in the whole basin, 12.89 percent of the basin and 99.21 percent of the basin, respectively. The total water footprint increased from 1995 to 2010 because the forest water footprint increased significantly in this period, although the agricultural water footprint and grass water footprint decreased. The ecological water stress index values had no obvious temporal change trends in either land use scenario, but the ecological water stress index in Scenario II was greater than that in Scenario I, which illustrates that the GGP led to an increase in ecological water stress from the perspective of generalized water resources.