The Pharmacogenetic Variability Associated With the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Healthy Chinese Subjects: A National Multicenter Exploratory Study.

PURPOSE: This study aimed to explore the pharmacogenetic variability associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy Chinese subjects. METHODS: This was a multicenter study that included 304 healthy adults aged 18 to 45 years with unknown genotypes. All participants were administered a single dose of rivaroxaban at 10 mg, 15 mg, or 20 mg. PK and PD parameters were measured, and exome-wide association analysis was conducted. FINDINGS: Sixteen SNPs located on 11 genes influenced the AUC0-t. Among these, the 3 most influential genes were MiR516A2, PARP14, and MIR618. Thirty-six SNPs from 28 genes were associated with the PD of rivaroxaban. The 3 most influential genes were PKNOX2, BRD3, and APOL4 for anti-Xa activity, and GRIP2, PLCE1, and MLX for diluted prothrombin time (dPT). Among them, BRD3 played an important role in both the PK and PD of rivaroxaban. Anti-Xa activity (ng/mL) differed significantly among subjects with BRD3 rs467387: 145.1 ± 55.5 versus 139.9 ± 65.1 versus 164.0 ± 68.6 for GG, GA, and AA carriers, respectively (P = 0.0002). IMPLICATIONS: This study found that that the regulation of the BRD3 gene might affect the PK and PD of rivaroxaban, suggesting that it should be studied as a new pharmacologic target. The correlation between this gene locus and clinical outcomes has yet to be verified in patients undergoing clinical treatment.

Projected decline in the strength of vegetation carbon sequestration under climate change in India.

Tropical vegetation plays a critical role in terrestrial carbon budget and supply many ecological functions such as carbon sequestration. In recent decades, India has witnessed an increase in net primary productivity (NPP), an important measure of carbon sequestration. However, uncertainties persist regarding the sustainability of these land carbon sinks in the face of climate change. The enhanced NPP is driven by the strong CO2 fertilization effect (CFE), but the temporal patterns of this feedback remain unclear. Using the carbon flux data from the Earth System Models (ESMs), an increasing trend in NPP was observed, with projections of NPP to 2.00 ± 0.12 PgCyr-1 (25 % increase) during 2021-2049, 2.36 ± 0.12 PgCyr-1 (18 % increase) during 2050-2079, and 2.67 ± 0.07 PgCyr-1 (13 % increase) during 2080-2099 in Indian vegetation under SSP585 scenario. This suggests a significant decline in the NPP growth rate. To understand the feedback mechanisms driving NPP, the relative effects of CFE and warming were analyzed. Comparing simulations from the biogeochemically coupled model (BGC) with the fully coupled model, the BGC model projected a 74.7 % increase in NPP, significantly higher than the 55.9 % increase projected by the fully coupled model by the end of the century. This indicates that the consistent increase in NPP was associated with CO2 fertilization. More importantly, results reveal that the decrease in the NPP growth rate was due to the declining contribution of CFE at a rate of -0.62 % per 100 ppm CO2 increase. This decline could be attributed to factors such as nutrient limitations and high temperatures. Additionally, significant shifts in the strength of carbon sinks in offsetting the CO2 emissions were identified, decreasing at a rate of -1.15 % per decade. This decline in the strength of vegetation carbon sequestration may increase the societal dependence on mitigation measures to address climate change.

Population pharmacokinetics of mycophenolic acid and dose optimisation in adult Chinese kidney transplant recipients.

1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients.2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen.3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.

Gene polymorphisms affect postoperative imatinib plasma levels and edema in adults with gastrointestinal stromal tumor.

Aim: To assess the role of genetic polymorphisms in postoperative imatinib concentrations and edema in patients with gastrointestinal stromal tumor. Methods: The relationships between genetic polymorphisms, imatinib concentrations and edema were explored. Results: Carriers of the rs683369 G-allele and rs2231142 T-allele had significantly higher imatinib concentrations. Grade ≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted odds ratio of 2.85, two T-alleles in rs1867351 with an adjusted odds ratio of 3.42 and two A-alleles in rs11636419 with an adjusted odds ratio of 3.15. Conclusion: rs683369 and rs2231142 affect the metabolism of imatinib; rs2072454, rs1867351 and rs11636419 are related to grade ≥2 periorbital edemas.

Comparison of modified U-shaped and inverted L-shaped medial capsulorrhaphy in hallux valgus surgery: a prospective, randomized controlled trial of 75 patients.

PURPOSE: The purpose of this study was to report a modified U-shaped medial capsulorrhaphy and compare its clinical and radiological differences with an inverted L-shaped capsulorrhaphy in hallux valgus (HV) surgery. METHODS: A prospective study of 78 patients was performed between January 2018 and October 2021. All patients underwent chevron osteotomy and soft tissue procedures for HV, and the patients were randomly separated into 2 groups according to the medial capsule closing techniques: a modified U-shaped capsulorrhaphy (group U) and an L-shaped capsulorrhaphy (group L). All patients were followed for at least a year. The preoperative and follow-up data were collected for each patient and included patient demographics, weight-bearing radiographs of the foot, the active range of motion (ROM) of the first metatarsophalangeal (MTP) joint and the American Orthopedic Foot and Ankle Society (AOFAS) forefoot score. Mann-Whitney U test was used for the comparison of the postoperative measures between the groups. RESULTS: In total, 75 patients with 80 affected feet met the inclusion criteria, with 38 patients (41 feet) in group U and 37 patients (39 feet) in group L. One year after surgery, the mean hallux valgus angle (HVA), intermetatarsal angle (IMA), and AOFAS score in group U improved from 29.5 to 7.1, from 13.4 to 7.1, and from 53.4 to 85.5, respectively. The mean HVA, IMA, and AOFAS score in group L improved from 31.2 to 9.6, from 13.5 to 7.9, and from 52.3 to 86.6, respectively. Comparing the 1-year postoperative measures between the 2 groups, a significant difference was found in HVA (P = 0.02), but not found in IMA and AOFAS score (P = 0.25 and P = 0.24, respectively). The mean ROM of the first MTP joint was 66.3 degrees preoperatively and 53.3 degrees at the 1-year follow-up in group U, while 63.3 and 47.5 in group L. The degrees of ROM after 1 year in group U were better than those in group L (P = 0.04). CONCLUSION: Compared to the inverted L-shaped capsulorrhaphy, the modified U-shaped capsulorrhaphy provided a better ROM of the first MTP joint; at 1 year following surgery, the modified U-shaped capsulorrhaphy maintained the normal HVA better.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Purpose: Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Circulating miR-320a-3p and miR-483-5p level associated with pharmacokinetic-pharmacodynamic profiles of rivaroxaban.

BACKGROUND: Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic-pharmacodynamic (PK-PD) profiles of rivaroxaban. METHODS: This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration-time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein-protein interaction network was established by STRING and visualized by Cytoscape. RESULTS: A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. CONCLUSIONS: MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms.

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.

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis.

PURPOSE: Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST. METHODS: Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202. RESULTS: A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017). CONCLUSIONS: Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.

Association Between Fresh Embryo Transfers and Frozen-Thawed Embryo Transfers Regarding Live Birth Rates Among Women Undergoing Long Gonadotropin-Releasing Hormone Antagonist Protocols.

Background: The availability and use of frozen-thawed embryos after controlled ovarian hyperstimulation for assisted reproduction have increased with improvements in vitrification techniques and the rise of gonadotropin-releasing hormone (GnRH) antagonist protocols. Although evidence has shown that frozen-thawed embryo transfers (FETs) result in higher live birth rates than fresh embryo transfers, it is uncertain whether this association exists in cycles employing the GnRH antagonist protocol. Objective: To test the hypothesis that FETs are more likely to result in a live birth than fresh embryo transfers in a GnRH antagonist protocol cycle and to investigate whether frozen blastocyst transfer increases live birth rates compared to fresh blastocyst transfer. Design: A retrospective historical cohort study was conducted using data collected from the Department of Reproductive Medicine of Liuzhou Maternity and Child Healthcare Hospital for 1,437 patients who underwent the GnRH antagonist protocol between 1 January 2015, and 31 December 2020. The primary outcome was the live birth rate, which was compared between fresh embryo transfer and FET, and the secondary outcomes were clinical pregnancy rate and miscarriage rate, which were compared between the two groups. Analyses were adjusted to account for the age of the patient, number of embryo transfers, day of embryo transfer, and type of infertility. Results: Fresh embryo transfers accounted for 1,026 (71.4%) of the 1,437 patients who underwent the GnRH antagonist protocol in our analysis, while FETs accounted for 411 (28.6%). Patients with fresh and frozen-thawed embryos had comparable median body mass index (body mass index; 22.3 [IQR, 24.6-20.0] vs. 22.0 [IQR, 24.5-19.9]). There was a significant difference in the median age of the fresh embryo transfer group (34.0 [IQR, 39.0-30.0]) and the Frozen-thawed embryo transfer group (32.0 [IQR, 37.0-29.0]). Blastocysts were transferred in 14.6% of the fresh embryo transfer cycles and 45.5% of the FET cycles, whereas they account for 10.4% and 13.0% of all patients, respectively. The mean number of embryos transferred was 2 (IQR, 2.0-1.0) for the fresh embryo transfer group and 1 (IQR, 2.0-1.0) for the FET group, with a significant difference in the mean number of embryos transferred. The live birth rate after fresh embryo transfer vs. FET was 28.7% vs. 34.5% (absolute difference, 5.9%; adjusted relative risk [aRR], 1.15 [95% CI, 0.88-1.51]). The clinical pregnancy rates were 39.9% vs. 46.0%, respectively (absolute difference, 6.1%; aRR, 1.10 [95% CI, 0.85-1.43]). The miscarriage rates were 22.5% vs. 23.8%, respectively (absolute difference, 1.3%; aRR, 1.13 [95% CI, 0.75-1.70]). Conclusion: In this retrospective study of women who underwent assisted reproduction using GnRH antagonists, FETs resulted in a higher live birth rates and clinical pregnancy rates than fresh embryo transfers, which parts of these differences were attributable to embryo stage. However, the interpretation of the findings is limited by the possibility of selection and confounding biases.

Epifriedelanol enhances adriamycin-induced cytotoxicity towards K562/ADM cells by down regulating of P-gp and MRP2.

1. Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Epifriedelanol (Epi) is the effective compounds from the Root Bark of Ulmus davidiana. This study aims to investigate the effect of Epi on MDR and its potential mechanism in the adriamycin (Adr)-resistant K562/ADM cells.2. The effect of Epi on MDR, P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) were investigated in the adriamycin (Adr)-resistant K562/ADM cells. In addition, the alterations of nuclear receptor pregnane X receptor (PXR) and constitutive androstane receptor (CAR) mRNA expression levels in K562/ADM cells after Epi treatment were also examined.3. Epi significantly enhanced Adr-induced cytotoxicity towards K562/ADM cells. Combination of Epi and Adr can significantly reduce the 50% inhibitory concentration (IC50) of K562/ADM cells to Adr. The reversal fold was 1.83 and 3.64 after treated with Epi at 10 and 20 µM, respectively. The intracellular accumulation of Adr was significant increased after exposure to Epi at 5-20 µM compared with the control group. Furthermore, Epi treatment significantly decreased the mRNA and protein expression of P-gp and MRP2 in K562/ADM cells.4. The present study demonstrated that Epi could enhance Adr-induced cytotoxicity towards K562/ADM cells accompanied by the down-regulation of P-gp and MRP2.

Nature-based framework for sustainable afforestation in global drylands under changing climate.

Drylands cover more than 40% of Earth's land surface and occur at the margin of forest distributions due to the limited availability of water for tree growth. Recent elevated temperature and low precipitation have driven greater forest declines and pulses of tree mortality on dryland sites compared to humid sites, particularly in temperate Eurasia and North America. Afforestation of dryland areas has been widely implemented and is expected to increase in many drylands globally to enhance carbon sequestration and benefits to the human environment, but the interplay of sometimes conflicting afforestation outcomes has not been formally evaluated yet. Most previous studies point to conflicts between additional forest area and water consumption, in particular water yield and soil conservation/desalinization in drylands, but were generally confined to local and regional scales. Our global synthesis demonstrates that additional tree cover can amplify water consumption through a nonlinear increase in evapotranspiration-depending on tree species, age, and structure-which will be further intensified by future climate change. In this review we identify substantial knowledge gaps in addressing the dryland afforestation dilemma, where there are trade-offs with planted forests between increased availability of some resources and benefits to human habitats versus the depletion of other resources that are required for sustainable development of drylands. Here we propose a method of addressing comprehensive vegetation carrying capacity, based on regulating the distribution and structure of forest plantations to better deal with these trade-offs in forest multifunctionality. We also recommend new priority research topics for dryland afforestation, including: responses and feedbacks of dryland forests to climate change; shifts in the ratio of ecosystem ET to tree cover; assessing the role of scale of afforestation in influencing the trade-offs of dryland afforestation; and comprehensive modeling of the multifunctionality of dryland forests, including both ecophysiological and socioeconomic aspects, under a changing climate.

Machine learning-based method for tacrolimus dose predictions in Chinese kidney transplant perioperative patients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC), a first-line immunosuppressant in solid-organ transplant, has a narrow therapeutic window and large inter-individual variability, which affects its use in clinical practice. Successful predictions using machine learning algorithms have been reported in several fields. However, a comparison of 10 machine learning model-based TAC pharmacogenetic and pharmacokinetic dosing algorithms for kidney transplant perioperative patients of Chinese descent has not been reported. The objective of this study was to screen and establish an appropriate machine learning method to predict the individualized dosages of TAC for perioperative kidney transplant patients. METHODS: The records of 2551 patients were collected from three transplant centres, 80% of which were randomly selected as a 'derivation cohort' to develop the dose prediction algorithm, while the remaining 20% constituted a 'validation cohort' to validate the final algorithm selected. Important features were screened according to our previously established population pharmacokinetic model of tacrolimus. The performances of the algorithms were evaluated and compared using R-squared and the mean percentage in the remaining 20% of patients. RESULTS AND DISCUSSION: This study identified several factors influencing TAC dosage, including CYP3A5 rs776746, CYP3A4 rs4646437, haematocrit, Wuzhi capsules, TAC daily dose, age, height, weight, post-operative time, nifedipine and the medication history of the patient. According to our results, among the 10 machine learning models, the extra trees regressor (ETR) algorithm showed the best performance in the training set (R-squared: 1, mean percentage within 20%: 100%) and test set (R-squared: 0.85, mean percentage within 20%: 92.77%) of the derivation cohort. The ETR model successfully predicted the ideal TAC dosage in 97.73% of patients, especially in the intermediate dosage range (>5 mg/day to <8 mg/day), whereby the ideal TAC dosage could be successfully predicted in 99% of the patients. WHAT IS NEW AND CONCLUSION: The results indicated that the ETR algorithm, which was chosen to establish the dose prediction model, performed better than the other nine machine learning models. This study is the first to establish ETR algorithms to predict TAC dosage. This study will further promote the individualized medication of TAC in kidney transplant patients in the future, which has great significance in ensuring the safety and effectiveness of drug use.

The role of biodiversity in mitigating the effects of nutrient limitation and short-term rotations in plantations of subtropical China.

Species diversity plays an essential role in enhancing ecosystem functions (EF) in both natural and plantation forests. However, we do not fully understand whether species diversity could maintain the sustainability of EFs in multiple-rotation plantations. Here, we hypothesized that tree species mixtures could mitigate declines in EFs along successive rotations, but could not maintain ecosystem multifunctionality. To test our hypothesis, we examined the effects of species diversity on four EFs, i.e., aboveground biomass (AGB), soil available nitrogen (SAN) and phosphorus (SAP), and soil organic matter (SOM), based on pure model simulation in plantations of subtropical China. The model fusion framework was set up by the integration of the process-based FORECAST and Multivariate Diversity-Interactions models. In the simulation, four local typical plantation tree species (two conifers, one evergreen broadleaf, and one deciduous N-fixing broadleaf) were selected and combined to form four monoculture and 11 mixture stands, and for each stand, the simulation was made for four 25-year rotations. The results showed that all the four EFs declined with the progress of rotations in both monoculture and mixtures, and the declining range was larger in monoculture than in mixtures in each rotation. Particularly, SAP significantly decreased while AGB, SAN, and SOM increased with diversity evenness from 0 (monoculture) to 1 (four species being equal abundant in the mixture). Overall, SAP and AGB displayed higher sensitivity to the disturbance of successive rotations compared with SAN and SOM. These results suggest that mixing species could not maintain EFs along with successive rotations because it could not alleviate SAP deficiencies in the soils resulted from the disturbances of silvicultural measures.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Dramatic increase in water use efficiency with cumulative forest disturbance at the large forested watershed scale.

BACKGROUND: Forest disturbance induced changes in the coupling of forest carbon and water have important implications for ecosystem functioning and sustainable forest management. However, this is rarely investigated at the large watershed scale with cumulative forest disturbance. We used a combination of techniques including modeling, statistical analysis, and machine learning to investigate the effects of cumulative forest disturbance on water use efficiency (WUE, a proxy for carbon and water coupling) in the 19,200 km2 Chilcotin watershed situated in the central interior of British Columbia, Canada. Harvesting, wildfire, and a severe Mountain Pine Beetle (MPB) infestation have gradually cumulated over the 45-year study period, and the watershed reached a cumulative equivalent clear-cut area of 10% in 1999 and then 40% in 2016. RESULTS: Surprisingly, with the dramatic forest disturbance increase from 2000 to 2016 which was mainly due to MPB, watershed-level carbon stocks and sequestration showed an insignificant reduction. This resilience was mainly due to landscape-level carbon dynamics that saw a balance between a variety of disturbance rates and types, an accumulation of older stand types, and fast growing young regenerated forests. Watershed-level carbon sequestration capacity was sustained, measured by Net Primary Production (NPP). A concurrent significant decrease in annual evapotranspiration (ET), led to a 19% increase in WUE (defined as the ratio of NPP to ET), which is contrary to common findings after disturbance at the forest stand-level. During this period of high disturbance, ET was the dominant driver of the WUE increase. CONCLUSIONS: We conclude that disturbance-driven forest dynamics and the appropriate scale must be considered when investigating carbon and water relationship. In contrast to the stand-level trade-off relationship between carbon and water, forested watersheds may be managed to maintain timber, carbon and water resources across large landscapes.

Systematic Review and Pharmacological Considerations for Chloroquine and Its Analogs in the Treatment for COVID-19.

COVID-19 has been announced pandemic by WHO and over 17,000,000 people infected (Till April 21st 2020). The disease is currently under control in China, with a curative rate of 86.8%. Chloroquine (CQ) is an old anti-malarial drug with good tolerability, which had proved to be effective in previous SARS-coronavirus, which spread and disappeared between 2002-2003. In vitro studies demonstrated the efficacy of CQ in curing COVID-19. Consequently, via analytical PBPK modeling, a further preliminary clinical trial has proved the efficacy and safety of CQ in China., and multiple clinical trials were registered and approved to investigate the activity of other analogs of CQ against COVID-19. We have listed all the clinical trials and made a meta-analysis of published data of hydroxychloroquine (HCQ). HCQ could increase the CT improvement and adverse reactions (ADRs) significantly though there was considerable heterogeneity among current researches. Actually, CQ and its analogs have unique pharmacokinetic characteristics, which would induce severe side effects in some circumstances. We have then summarized pharmacological considerations for these drugs so as to provide to the busy clinicians to avoid potential side effects when administered CQ or its analogs to COVID-19 patients, especially in the elderly, pediatrics, and pregnancies.

Responses of forest carbon and water coupling to thinning treatments from leaf to stand scales in a young montane pine forest.

BACKGROUND: Water-use efficiency (WUE) represents the coupling of forest carbon and water. Little is known about the responses of WUE to thinning at multiple spatial scales. The objective of this research was to use field measurements to understand short-term effects of two thinning treatments (T1: 4500 stems ha-1; and T2: 1100 stems ha-1) and the control (NT: 27,000 stems ha-1) on WUE at the three spatial scales (leaf level: the ratio of leaf photosynthesis to leaf transpiration; tree-level: tree growth to tree transpiration; and stand level: net primary production (NPP) to stand transpiration) and intrinsic WUEi (the ratio of leaf photosynthesis to stomatal conductance at leaf-level; and NPP to canopy conductance at stand-level) in a 16-year old natural lodgepole pine forest. Leaf-level measurements were conducted in 2017, while tree- and stand-level measurements were conducted in both 2016 (the normal precipitation year) and 2017 (the drought year). RESULTS: The thinning treatments did not significantly affect the tree- and stand-level WUE in the normal year of 2016. However, the thinning significantly affected WUE in the drought year of 2017: T2 exhibited significantly higher tree-level WUE (0.49 mm2 kg-1) than NT (0.08 mm2 kg-1), and compared to NT, the stand-level WUE values in the thinned stands (T1 and T2) were significantly higher, with means of 0.31, 0.56 and 0.70 kg m-3, respectively. However, the leaf-level and stand-level WUEi in the thinned stands in the drought year were significantly lower than those in the unthinned stands. No significant differences in the leaf-level WUE were found among the treatments in 2017. In addition, the thinning did not significantly change the WUE-VPD relationships at any studied spatial scale. CONCLUSIONS: The thinning treatments did not cause significant changes in all studied WUE metrics in a normal year. However, their effects were significantly promoted under the drought conditions probably due to the decrease in soil water availability, demonstrating that thinning can improve WUE and consequently support forests to cope with the drought effects. The inconsistent results on the effects of the thinning on forest carbon and water coupling at the spatial scales and the lack of the consistent WUE metrics constraint across-scale comparison and transferring of WUE.

Pharmacotherapics Advice in Guidelines for COVID-19.

Since December 2019 to May 2020, coronavirus disease 2019 (COVID-19) has infected over 6 million people worldwide. Due to its sudden and rapid outbreak, effective treatment for COVID-19 is scarce. Based on national clinical trials of novel treatments, China, Italy, Germany, and other countries and organizations have published multiple guidelines for COVID-19 and advised many medicines, such as chloroquine and tocilizumab. In this paper, we summarize the pharmacotherapy for COVID-19 according to those guidelines, highlight updates of the pharmacotherapy guidelines, and review the efficacy and safety of the indicated anti-COVID-19 drugs.