The impact of CYP3A5*3 on oral quetiapine: A population pharmacokinetic model in Chinese bipolar disorder patients.

BACKGROUND: There is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. METHODS: Patients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3, CYP2D6*10, and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. RESULTS: A total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. LIMITATIONS: Only trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. CONCLUSIONS: The currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response.

Circulating T-cell subsets discrepancy between bipolar disorder and major depressive disorder during mood episodes: A naturalistic, retrospective study of 1015 cases.

AIMS: We aimed to investigate whether peripheral T-cell subsets could be a biomarker to distinguish major depressive disorder (MDD) and bipolar disorder (BD). METHODS: Medical records of hospitalized patients in the Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2015 to September 2020 with a discharge diagnosis of MDD or BD were reviewed. Patients who underwent peripheral blood examination of T-cell subtype proportions, including CD3+, CD4+, CD8+ T-cell, and natural killer (NK) cells, were enrolled. The Chi-square test, t-test, or one-way analysis of variance were used to analyze group differences. Demographic profiles and T-cell data were used to construct a random forest classifier-based diagnostic model. RESULTS: Totally, 98 cases of BD mania, 459 cases of BD depression (BD-D), and 458 cases of MDD were included. There were significant differences in the proportions of CD3+, CD4+, CD8+ T-cell, and NK cells among the three groups. Compared with MDD, the BD-D group showed higher CD8+ but lower CD4+ T-cell and a significantly lower ratio of CD4+ and CD8+ proportions. The random forest model achieved an area under the curve of 0.77 (95% confidence interval: 0.71-0.83) to distinguish BD-D from MDD patients. CONCLUSION: These findings imply that BD and MDD patients may harbor different T-cell inflammatory patterns, which could be a potential diagnostic biomarker for mood disorders.

CsPM5.2, a phosphate transporter protein-like gene, promotes powdery mildew resistance in cucumber.

Powdery mildew (PM) is one of the most serious fungal diseases affecting cucumbers (Cucumis sativus L.). The mechanism of PM resistance in cucumber is intricate and remains fragmentary as it is controlled by several genes. In this study, we detected the major-effect Quantitative Trait Locus (QTL), PM5.2, involved in PM resistance by QTL mapping. Through fine mapping, the dominant PM resistance gene, CsPM5.2, was cloned and its function was confirmed by transgenic complementation and natural variation identification. In cultivar 9930, a dysfunctional CsPM5.2 mutant resulted from a single nucleotide polymorphism in the coding region and endowed susceptibility to PM. CsPM5.2 encodes a phosphate transporter-like protein PHO1; H3. The expression of CsPM5.2 is ubiquitous and induced by the PM pathogen. In cucumber, both CsPM5.2 and Cspm5.1 (Csmlo1) are required for PM resistance. Transcriptome analysis suggested that the salicylic acid (SA) pathway may play an important role in CsPM5.2-mediated PM resistance. Our findings help parse the mechanisms of PM resistance and provide strategies for breeding PM-resistant cucumber cultivars.

A Bayesian approach to pilot-pivotal trials for bioequivalence assessment.

BACKGROUND: To demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial. METHODS: We consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics. RESULTS: Compared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent. CONCLUSIONS: The proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.

The Influence of Diagnosis Intervention Packet Policy Intervention on Medication Structure and Drug Cost of Elderly Hypertensive Inpatients in China: A Multicenter Interrupted Time-Series Analysis.

Background: DIP is a new medical insurance payment system developed in China which was implemented in Guangzhou in January 2018, but few studies have focused on its intervention effect on the drug burden of elderly hypertensive patients. Methods: Nine medical institutions in Guangzhou, China, were selected, among which, daily full medical orders of elderly hypertensive inpatients from 2016 to 2020 were randomly collected. To assess the impact of DIP policy intervention on patient drug burden, we took the data after policy implementation in January 2018, as the intervention data, and applied a segmented regression model with interrupted time series to analyze the trend and changes in average daily drug costs per month and medication structure, stratified by age, sex, and inpatient department. Results: A total of 34,276 elderly hypertensive patients' daily full medical orders were obtained. The immediate level change of drug costs after intervention was -23.884 RMB/month (P = 0.652), and the trend change was statistically significant (-15.642 RMB/month, P = 0.002). The relative cumulative effect at the end of the study was -78.860% (95% CI: -86.087% to -69.076%), and the intervention effect was more significant in surgical and male patients. The analysis of drug structure changes showed that after the implementation of the DIP policy intervention, the proportion of anti-infective drugs, anti-tumor drugs, and biological products all showed a significant downward trend (P < 0.05), while nutritional drugs showed a significant upward trend (P = 0.011), but no immediate horizontal change in slope was observed. Conclusion: The typical practice in China showed that DIP policy intervention can improve the drug burden of elderly hypertensive hospitalized patients and has a stable long-term effect, and the intervention effect is not consistent across different clinical department and populations with different characteristics, and it would also cause changes in the medication structure.

Phase I, Single-Dose Study to Assess the Pharmacokinetics and Safety of Suramin in Healthy Chinese Volunteers.

Purpose: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer. Methods: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. Results: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28-105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity. Conclusion: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.

A Randomized, Double-Blind, Parallel-Controlled Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of SCT510 to Bevacizumab (Avastin®) in Healthy Chinese Males.

BACKGROUND: SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes. OBJECTIVE: This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin®) in healthy Chinese males. METHODS: This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC0-t), and the maximum observed concentration (Cmax). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes. RESULTS: A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC0-∞, AUC0-t, and Cmax were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC0-∞, AUC0-t, and Cmax were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit. CONCLUSION: This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males. CLINICAL TRIALS REGISTRATION: NCT05113511.

Clinical characteristics and outcomes of patients with mental illnesses who attempted suicide by drug overdose: A retrospective analysis of 109 cases.

OBJECTIVE: Individuals with mental illnesses are exposed to an increased risk of suicide. In this study, we aimed to investigate the clinical characteristics and outcome of psychiatric patients who attempted suicide by drug overdose and required emergency care. METHODS: A retrospective study was carried out in the Department of Emergency, the First Affiliated Hospital, Zhejiang University School of Medicine. Electronic medical records of psychiatric patients who were hospitalized due to suicide attempts from March 2019 to February 2022, with a discharge diagnosis of drug overdose were reviewed. Suicide-related data of patients were collected, including suicide month, time from suicide to admission, type of drugs, the number of tablets taken, as well as demographic and clinical profiles (e.g., gender, age, marital status, profession, physical comorbidities, and diagnosis of mental illness). RESULTS: In the results, half of the patients were young people, female patients accounted for a higher proportion (72.5%), and the incidence of suicide was higher in winter than other seasons. Among the 109 psychiatric patients, 60 patients (55.0%) had a history of major depressive disorder, and 86 patients (78.9%) committed suicide with various psychotropic drugs, among which anxiolytics were the most commonly used drugs. Thirty-seven patients (33.9%) experienced severe physical complications caused by drug overdose, with lung infections being the most common. The clinical outcome of most patients was favorable following emergent treatment, while 2 patients (1.8%) older than 80 failed to survive. CONCLUSION: A better understanding of psychiatric patients referred to emergency care due to suicide by drug overdose helps to improve the clinical management and prognosis of patients.

Mapping and identification of CsSF4, a gene encoding a UDP-N-acetyl glucosamine-peptide N-acetylglucosaminyltransferase required for fruit elongation in cucumber (Cucumis sativus L.).

KEY MESSAGE: The short fruit length phenotype in sf4 is caused by a SNP in Csa1G665390, which encodes an O-linked N-acetylglucosamine (GlcNAc) transferase in cucumber. Cucumber fruit is an excellent resource for studying fruit morphology due to its fast growth rate and naturally abundant morphological variations. The regulatory mechanisms underlying plant organ size and shape are important and fundamental biological questions. In this study, a short-fruit length mutant, sf4, was identified from an ethyl methanesulfonate (EMS) mutagenesis population derived from the North China-type cucumber inbred line WD1. Genetic analysis indicated that the short fruit length phenotype of sf4 was controlled by a recessive nuclear gene. The SF4 locus was located in a 116.7-kb genomic region between the SNP markers GCSNP75 and GCSNP82 on chromosome 1. Genomic and cDNA sequences analysis indicated that a single G to A transition at the last nucleotide of Csa1G665390 intron 21 in sf4 changed the splice site from GT-AG to GT-AA, resulting in a 42-bp deletion in exon 22. Csa1G665390 is presumed to be a candidate gene, CsSF4 that encodes an O-linked N-acetylglucosamine (GlcNAc) transferase (OGT). CsSF4 was highly expressed in the leaves and male flowers of wild-type cucumbers. Transcriptome analysis indicated that sf4 had alterations in expression of many genes involved in hormone response pathways, cell cycle regulation, DNA replication, and cell division, suggesting that cell proliferation-associated gene networks regulate fruit development in cucumber. Identification of CsSF4 will contribute to elucidating the function of OGT in cell proliferation and to understanding fruit elongation mechanisms in cucumber.

Development and validation of the AF score for diagnosis of adult-onset Still's disease in fever of unknown origin.

Objective: To develop and validate a diagnostic score to identify adult-onset Still's disease (AOSD) in fever of unknown origin (FUO). Methods: A single center, retrospective case-control study of inpatients with FUO from January 2018 to December 2021. Using clinical and laboratory data from 178 cases with AOSD and 486 cases with FUO, we developed an AOSD/FUO (AF) score with a Bayesian Model Averaging approach. AF score and Yamaguchi's criteria were evaluated by sensitivity, specificity, accuracy, and positive/negative predictive value for diagnosis of AOSD in developmental and validation samples. Results: Persistent pruritic eruptions (PPEs) in patients with rashes was higher in AOSD group than FUO group (52.3% vs 7.4%; P < 0.01). PPEs yielded a specificity of 97.5% and a sensitivity of 44.9%. AF score = PPEs × 3.795+Evanescent rash × 2.774+Serum ferritin × 1.678+Myalgia × 0.958+Neutrophil count × 0.185+Platelet count × 0.004. A cut-off value ≥ 5.245 revealed the maximizing sensitivity of 88.7% and specificity of 95.8% in discriminating AOSD from FUO in the validation group. And AF score improved the accuracy from 82.6% to 93.3% compared with Yamaguchi's criteria. Conclusions: We developed and validated a new score which can identify AOSD in FUO with higher classification accuracy than Yamaguchi's criteria. Future multi-centric prospective studies need to be designed to confirm the diagnosis value of AF score.

Comparative Transcriptome Analysis of Hard and Tender Fruit Spines of Cucumber to Identify Genes Involved in the Morphological Development of Fruit Spines.

The spines of cucumber fruit not only have important commercial value but are also a classical tissue to study cell division and differentiation modes of multicellular trichomes. It has been reported that CsTs (C-type Lectin receptor-like kinase) can influence the development of fruit spines. In this study, we took a pair of cucumber materials defined as hard (Ts, wild type) and tender spines (ts, mutant) and defined the developmental process of fruit spines as consisting of four stages (stage I to stage IV) by continuously observing by microscope and SEM. Comparisons of transcriptome profiles at different development stages of wild-type spines showed that 803 and 722 genes were upregulated in the stalk (stage II and stage III) and base (stage IV) development stages of fruit spines, respectively. The function analysis of DEGs showed that genes related to auxin polar transport and HD-ZIP transcription factor are significantly upregulated during the development of the stalk. bHLH transcription factors and cytoskeleton-related genes were significantly upregulated during the development of the base. In addition, stage III is the key point for the difference between wild-type and mutant spines. We detected 628 DEGs between wild type and mutant at stage III. These DEGs are mainly involved in the calcium signaling of the cytoskeleton and auxin polar transport. Coincidentally, we found that CsVTI11, a factor involved in auxin signal transmission, can interact with CsTs in vivo, but this interaction does not occur between CsVTI11 and Csts, further suggesting that CsTs may regulate the development of fruit spines by influencing cell polarity. These results provide useful tools to study the molecular networks associated with cucumber fruit spine development and elucidate the biological pathways that C-type Lectin receptor-like kinase plays in regulating the development of fruit spines.

Pharmacokinetics, Safety, and Tolerability of Ravidasvir, with and without Danoprevir/Ritonavir, in Healthy Subjects.

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug-drug interactions between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In the 1st study, healthy volunteers were administered single oral doses of 100, 200, and 300 mg of RDV and 200 mg once daily for 7 days. The 2nd study was a randomized, double-blinded, and placebo-controlled sequential design (day 1 for 200 mg of RDV alone, day 7 for 100 mg/100 mg of DNVr, day 13 for 200 mg of RDV plus 100 mg/100 mg DNVr, followed by 200 mg of RDV once daily with 100 mg/100 mg of DNVr twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Coadministration with DNVr (100 mg/100 mg, twice daily) resulted in a 2.92-fold and 1.99-fold increase in minimum plasma concentration at steady state (Cmin,ss) and area under the concentration-time curve at steady state (AUCτ) of RDV, respectively. With coadministration of RDV, maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 12 h (AUC0-12) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir's continued clinical development and treatment. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT03430830 and NCT03288636.).

A SNP of HD-ZIP I transcription factor leads to distortion of trichome morphology in cucumber (Cucumis sativus L.).

BACKGROUND: Trichomes are excellent model systems for the analysis of cell differentiation and play essential roles in plant protection. From cucumber inbred line 'WD1', we identified an EMS-induced trichome abnormally developing mutant, nps, which exhibited smaller, denser and no pyramid-shaped head trichomes. RESULTS: Using F2 and BC1 populations constructed from a cross between nps and '9930', the genetic analysis showed that the nps trait is controlled by a single recessive nuclear gene. We identified CsNps by map-based cloning with 576 individuals of the F2 population generated from the cross of nps and inbred line '9930'. The CsNps was located at a 13.4-kb genomic region on chromosome 3, which region contains three predicted genes. Sequence analysis showed that only one single nucleotide mutation (C → T) between 9930 and nps was found in the second exon of Csa3G748220, a plant-specific class I HD-Zip gene. The result of allelism test also indicated that nps is a novel allelic mutant of Mict (Micro-trichome). Thus, nps was renamed mict-L130F. By comparing the transcriptome of mict-L130F vs WD1 and 06-2 (mict) vs 06-1 (wildtype, near-isogenic line of 06-2), several potential target genes that may be related to trichome development were identified. CONCLUSIONS: Our results demonstrate that Mict-L130F is involved in the morphogenesis of trichomes. Map-based cloning of the Mict-L130F gene could promote the study of trichome development in cucumber.

Mapping and identification of CsSh5.1, a gene encoding a xyloglucan galactosyltransferase required for hypocotyl elongation in cucumber (Cucumis sativus L.).

KEY MESSAGE: CsSh5.1, which controls hypocotyl elongation under high temperature conditions in cucumber, was mapped to a 57.1 kb region on chromosome 5 containing a candidate gene encoding a xyloglucan galactosyltransferase. Hypocotyl growth is a vital process in seedling establishment. Hypocotyl elongation after germination relies more on longitudinal cell elongation than cell division. Cell elongation is largely determined by the extensibility of the cell wall. Here, we identified a spontaneous mutant in cucumber (Cucumis sativus L.), sh5.1, which exhibits a temperature-insensitive short hypocotyl phenotype. Genetic analysis showed that the phenotype of sh5.1 was controlled by a recessive nuclear gene. CsSh5.1 was mapped to a 57.1 kb interval on chromosome 5, containing eight predicted genes. Sequencing analysis revealed that the Csa5G171710 is the candidate gene of CsSh5.1, which was further confirmed via co-segregation analysis and genomic DNA sequencing in natural cucumber variations. The result indicated that hypocotyl elongation might be controlled by this gene. CsSh5.1 encodes a xyloglucan galactosyltransferase that specifically adds galactose to xyloglucan and forms galactosylated xyloglucans, which determine the strength and extensibility of the cell walls. CsSh5.1 expression in wild-type (WT) hypocotyl was significantly higher than that in sh5.1 hypocotyl under high temperature, suggesting its important role in hypocotyl cell elongation under high temperature. The identification of CsSh5.1 is helpful for elucidating the function of xyloglucan galactosyltransferase in cell wall expansion and understanding the mechanism of hypocotyl elongation in cucumber.

Effect of silibinin capsules combined with lifestyle modification on hepatic steatosis in patients with chronic hepatitis B.

The coexistence of HBV infection and hepatic steatosis is a novel characteristic of liver disease. Silibinin capsules (SC) is a silybin-phospholipid complex containing silybin as the bioactive component, which exerts a remarkable biological effect on various liver diseases, including nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to investigate (1) the prevalence of hepatic steatosis in the general population and patients with chronic hepatitis B (CHB) and (2) to evaluate the effect of SC combined with therapeutic lifestyle changes (TLC) compared with TLC alone on hepatic steatosis in patients with CHB. A total of 16,451 individuals underwent transient elastography (TE) with the control attenuation parameter (CAP) measurement, among which the prevalence of hepatic steatosis was 31.1% in patients with CHB and 42.2% in the general population. The prevalence of hepatic steatosis differed between patients with CHB and the general population at an age of 40 years or older but was similar in individuals aged 39 years or younger (p < 0.05). Furthermore, in patients with CHB presenting hepatic steatosis, the post-6-month relative reduction in CAP in the SC combined with TLC group (p = 0.001) was significantly greater than in the TLC alone group (p = 0.183). The CAP distribution of different steatosis grades (S1, S2, and S3) in the SC combined with TLC group was decreased and S0 (CAP < 248 dB/m) increased significantly, but not significant in the TLC group. Thus, SC combined with TLC may effectively improve hepatic steatosis in patients with CHB.

Hepatocyte nuclear factor 4α and cancer-related cell signaling pathways: a promising insight into cancer treatment.

Hepatocyte nuclear factor 4α (HNF4α), a member of the nuclear receptor superfamily, is described as a protein that binds to the promoters of specific genes. It controls the expression of functional genes and is also involved in the regulation of numerous cellular processes. A large number of studies have demonstrated that HNF4α is involved in many human malignancies. Abnormal expression of HNF4α is emerging as a critical factor in cancer cell proliferation, apoptosis, invasion, dedifferentiation, and metastasis. In this review, we present emerging insights into the roles of HNF4α in the occurrence, progression, and treatment of cancer; reveal various mechanisms of HNF4α in cancer (e.g., the Wnt/ß-catenin, nuclear factor-κB, signal transducer and activator of transcription 3, and transforming growth factor ß signaling pathways); and highlight potential clinical uses of HNF4α as a biomarker and therapeutic target for cancer.

Genome-Wide Identification and Characterization of Lectin Receptor-Like Kinase Gene Family in Cucumber and Expression Profiling Analysis under Different Treatments.

Lectin receptor-like kinases (LecRLKs) are a class of membrane proteins found in plants that are involved in diverse functions, including plant development and stress responses. Although LecRLK families have been identified in a variety of plants, a comprehensive analysis has not yet been undertaken in cucumber (Cucumis sativus L.). In this study, 46 putative LecRLK genes were identified in the cucumber genome, including 23 G-type and 22 L-type, and one C-type LecRLK gene. They were unequally distributed on all seven chromosomes, with a clustering tendency. Most of the genes in the cucumber LecRLK (CsLecRLK) gene family lacked introns. In addition, there were many regulatory elements associated with phytohormones and stress on these genes' promoters. Transcriptome data demonstrated distinct expression patterns of CsLecRLK genes in various tissues. Furthermore, we found that each member of the CsLecRLK family had its own unique expression pattern under hormone and stress treatment by the quantitative real-time PCR (qRT-PCR) analysis. This study provides a better understanding of the character and function of the LecRLK gene family in cucumber and opens up the possibility to exploring the roles that LecRLKs might play in the life cycle of cucumber.

Derivation and Validation of a Risk Prediction Model for Vancomycin-Associated Acute Kidney Injury in Chinese Population.

BACKGROUND: Vancomycin is the standard therapy for methicillin-resistant Staphylococcus aureus (MRSA) infection; however, nephrotoxicity happened with a high incidence of 15%~40%. Weighting the risk before receiving vancomycin treatment facilitates timely prevention of nephrotoxicity, but no standardized strategy exists for this purpose. METHODS: A retrospective cohort study was performed. A total of 524 hospitalized patients treated with vancomycin were included in this study. They were divided into derivation cohort (n=341) and externally validation cohort (n=183) according to their admission time. Using univariate and multivariable logistic regression, we identified potential predictors of vancomycin-associated acute kidney injury (AKI) and developed a risk score by plotting nomogram. The predictive performance of this novel risk score was assessed and validated by discrimination and calibration. Besides, the risk score was also compared with existing prediction models according to integrated discrimination index (IDI) and net reclassification index (NRI). RESULTS: The incidence of AKI was 16.1% (55/341) in the derivation cohort and 16.4% (30/183) in the validation cohort. Three factors (vancomycin serum trough concentration, piperacillin/tazobactam and furosemide) were determined as predictors for vancomycin-associated AKI. The established three-item risk score showed a comparable discrimination in both derivation cohort (AUC=0.793, 95% CI: 0.732-0.855) and validation cohort (AUC=0.788, 95% CI: 0.698-0.877). The risk score also demonstrated a good calibration in the derivation cohort (χ 2=6.079, P=0.638>0.05) and validation cohort (χ2=5.665, P=0.686>0.05). Compared with prediction by Cmin alone, this risk score significantly improved reclassification accuracy (IDI=0.050, 95% CI: 0.024-0.076, P<0.001, NRI=0.166, 95% CI: 0.044-0.289, P=0.007). CONCLUSION: The established model in this study is a simplified three-item risk score, which provides a robust tool for the prediction of AKI after receiving vancomycin treatment.

The associations of blood pressure parameters with all-cause and cardiovascular mortality in peritoneal dialysis patients: a cohort study in China.

BACKGROUND: It remains controversial to claim blood pressure (BP) as a leading risk factor for high risk of death in peritoneal dialysis patients, and less is known about the relationship between BP and mortality in Chinese peritoneal dialysis patients. METHODS: From Zhejiang Renal Data System in China, we collected data on patients treated and followed up at 98 peritoneal dialysis centres from 2008 to 2016. The associations of BP parameters [SBP, DBP, mean arterial pressure (MAP) and pulse pressure (PP)] with all-cause and cardiovascular mortality were examined. We fitted Cox models for mortality with penalized splines using nonparametric smoothers. Several sensitivity analyses were performed to confirm the robustness of our primary findings. RESULTS: A total of 7335 Chinese peritoneal dialysis patients were included. During a median follow-up of 35.8 months, 1281 (17.5%) patients died. SBP, DBP, MAP follow a U-shaped pattern of both all-cause and cardiovascular mortality. PP presents a reverse L-shaped association with all-cause mortality. Either a higher (SBP >141, DBP >85 or MAP >102 mmHg) or lower (SBP <119, DBP <67 or MAP <88 mmHg) BP tends to have a significantly higher all-cause and cardiovascular mortality risk. Higher PP (>60 mmHg) is related to a higher risk of all-cause mortality, but not cardiovascular mortality. These associations remain the same in our competing risk analysis and subgroup analyses. CONCLUSION: These data indicate U-shaped associations of SBP, DBP and MAP with all-cause mortality and cardiovascular mortality, respectively, and a reverse L-shaped association of PP with all-cause mortality. Further studies are needed to reliably establish the optimal BP targets for better hypertension control in peritoneal dialysis patients.

Seasonal variation and correlation analysis of vitamin D and parathyroid hormone in Hangzhou, Southeast China.

This study aimed to describe the 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) status of Southeast Chinese individuals influenced by season. The secondary aim was to determine the cutoff for sufficient 25(OH)D in a four-season region. From January 2011 to June 2014, a total of 17 646 individuals were evaluated in our study. The serum levels of PTH were detected simultaneously in 5579 cases. A total of 25(OH)D and intact PTH were measured by the electrochemiluminescent immunoassay. The distribution of the concentration, prevalence and seasonal variability of 25(OH)D and PTH were studied. The mean 25(OH)D concentration in our study was 43.00(30.40) nmol/L. The prevalence of insufficiency (25(OH)D < 50 nmol/L) was 62.87% and that of deficiency (<30 nmol/L) was 28.54%. Mean serum 25(OH)D levels revealed a limited sinusoidal profile throughout the year and were significantly higher in Autumn. On the other hand, PTH levels showed an opposite response to seasonal effects relative to 25(OH)D. Age, BMI and daylight were not significantly correlated with 25(OH)D and serum PTH reached a plateau at higher values of serum 25(OH)D of 42.86 nmol/L. This study demonstrated that Vitamin D insufficiency is highly prevalent in Southeast China. The concentration of 25(OH)D in the male group was generally higher than that in the female group. Seasonal variation was an important aspect of 25(OH)D and PTH concentration. This study revealed that the optimal serum threshold of 25(OH)D for bone health should be between 40 and 50 nmol/L for Southeast Chinese individuals.