Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown in vitro potency and in vivo efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the Cmax ranged from 3.94 to 25.82 mg/L, and the AUC0-inf ranged from 12.42 to 101.67 h·mg/L. The plasma exposure displayed a linear relationship with the dose administered. After administration of 75 and 100 mg of EVER206 every 8 hours (q8 hour), a steady state was achieved on Day 2. The accumulation ratios of Cmax and AUC from Day 1 to Day 7 were in the range of 1.12 to 1.3. The elimination half-lives ranged from 2.86 to 4.32 hours in the single-ascending-dose (SAD) study and 4.71 to 6.18 hours in the multiple-ascending-dose (MAD) study. The urinary excretion of unchanged EVER206 increased with the dose, with the mean cumulative fraction ranging from 23.70% to 47.10%. EVER206 was safe and well-tolerated in Chinese healthy subjects. No severe treatment emerging adverse events (TEAEs), serious adverse events, or TEAEs leading to discontinuation were reported. The results of the present study demonstrated a similar safety profile of EVER206 with data reported in an earlier study on SPR206-101. The exposure of EVER206 in Chinese healthy subjects was higher than that in Australian healthy subjects. These results could enable further clinical development of EVER206 in Chinese patients with severe MDR Gram-negative pathogen infections.CLINICAL TRIALSThis study was registered at the Chinese Clinical Trial Registry under identifier ChiCTR2200056692.

Diversin upregulates the proliferative ability of colorectal cancer by inducing cell cycle proteins.

Colorectal cancer (CRC) is a common gastrointestinal tumour with increasing incidence worldwide. However, the underlying molecular mechanism of CRC proliferation is not completely clear. Diversin，as an ankyrin repeat-containing protein, is upregulated in various solid tumours and accelerates cancer progression by promoting cell proliferation and increasing S phase fraction of cells. In this study, 71 CRC samples and corresponding adjacent tissue samples were included. The expression of diversin in tissues was verified via immunohistochemical analysis. The MTS assay and flow cytometry (FCM) was used to measure cell proliferation and cell cycle. Results of immunohistochemical analysis revealed that diversin was highly expressed in human CRC tissues and was significantly associated with tumour differentiation, clinical stage and lymph node metastasis. The analysis based on the CRC data from The Cancer Genome Atlas (TCGA) database showed that a high expression of diversin correlated with the poor prognosis of CRC. Results of the MTS assay indicated that the overexpression of diversin promoted the proliferation of CRC cells, while its downregulation had an inhibitory effect on CRC cell proliferation. FCM analysises presented that diversin increased the flux of the CRC cell cycle from G1 to S and regulated cycle-related proteins, namely, P21, P27, cyclin E, CDK2, cyclin D and CDK4. The results suggest that diversin contributes to CRC proliferation that involves the distribution of the cell cycle. In CRC tissues, the expression of diversin has closely related to the prognosis. The higher the expression levels of diversin, the worse the prognosis. In vitro, diversin could increase the proliferative ability of CRC cells through the G1-S checkpoint and JNK signalling pathway, confirming that diversin contributes to CRC development.

A Phase I Study to Evaluate the Safety and Pharmacokinetics of SHR0302 Base Ointment in Healthy Adult Volunteers.

INTRODUCTION: SHR0302 is a highly selective JAK1 inhibitor. This study aimed to investigate the safety, tolerability, and pharmacokinetics of single and multiple-dose topical skin application of SHR0302 base ointment in healthy adult subjects. METHODS: This phase I clinical trial (registration number: CTR20192188) consisted of two parts. Part 1 was a single-dose ascending study with four dose levels in 32 healthy Australian adults (8 subjects in each dose group). All Australian subjects were randomized 3:1 to a single-dose topical skin application of SHR0302 base ointment or placebo. The dose escalated from 1% SHR0302 base ointment on 3% of body surface area (BSA) to 2% SHR0302 base ointment on 20% of BSA. Part 2 combined single and multiple-dose ascension studies with two dose levels in 20 healthy Chinese adults (10 subjects in each dose group). All Chinese subjects were randomized 4:1 to a combination of single and multiple doses for consecutive 10 days of topical application of 1% SHR0302 base ointment on 20% BSA or 2% SHR0302 base ointment on 20% BSA. The safety and pharmacokinetics of the SHR0302 base ointment were evaluated. RESULTS: The incidence of treatment-emergent adverse events (TEAEs) in both parts was comparable between the SHR0302 base ointment group and the vehicle group (part 1: 33.3% vs. 37.5%; part 2: 56.3% vs. 75.0%). All TEAEs were transient, recovered, and equally well-tolerated in the two racial groups. The overall absorption of the SHR0302 base ointment was slow after topical application, with Tmax>10 h. After a single dose of the SHR0302 base ointment, drug exposure in healthy Australian and Chinese subjects increased nonlinearly with the increase in the administration area and drug content. Drug exposure increased in a less-than-dose-proportional manner within the dose range tested. Due to differences in the clinical practice of topical application, the Tmax of the drug in Australian subjects was earlier than in Chinese subjects, but the overall extent of absorption seemed comparable in Australian and Chinese subjects (with comparable AUC0-t). CONCLUSION: The SHR0302 base ointment (either single or multiple doses) was well tolerated and safe, with no racial disparity. KEY MESSAGE: The SHR0302 base ointment (either single or multiples doses) was well tolerated and safe.

Traction Machine State Recognition Method Based on DPCA Algorithm and Convolution Neural Network.

It is important to improve the identification accuracy of the operating status of elevator traction machines. The distribution difference of the time-frequency signals utilized to identify operating circumstances is modest, making it difficult to extract features from the vibration signals of traction machines under various operating conditions, leading to low recognition accuracy. A novel method for identifying the operating status of traction machines based on signal demodulation method and convolutional neural network (CNN) is proposed. The original vibration time-frequency signals are demodulated by the demodulation method based on time-frequency analysis and principal component analysis (DPCA). Firstly, the signal demodulation method based on principal component analysis is used to extract the modulation features of the experimentally measured vibration signals. Then, The CNN is used for feature vector extraction, and the training model is obtained through multiple iterations to achieve automatic recognition of the running state. The experimental results show that the proposed method can effectively extract feature parameters under different states. The diagnostic accuracy is up to 96.94%, which is about 16.61% higher than conventional methods. It provides a feasible solution for identifying the operating status of elevator traction machines.

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).

A Verticillium dahliae Extracellular Cutinase Modulates Plant Immune Responses.

Cutinases have been implicated as important enzymes during the process of fungal infection of aerial plant organs. The function of cutinases in the disease cycle of fungal pathogens that invade plants through the roots has been less studied. Here, functional analysis of 13 cutinase (carbohydrate esterase family 5 domain-containing) genes (VdCUTs) in the highly virulent vascular wilt pathogen Verticillium dahliae Vd991 was performed. Significant sequence divergence in cutinase family members was observed in the genome of V. dahliae Vd991. Functional analyses demonstrated that only VdCUT11, as purified protein, induced cell death and triggered defense responses in Nicotiana benthamiana, cotton, and tomato plants. Virus-induced gene silencing showed that VdCUT11 induces plant defense responses in Nicotiana benthamania in a BAK1 and SOBIR-dependent manner. Furthermore, coinfiltration assays revealed that the carbohydrate-binding module family 1 protein (VdCBM1) suppressed VdCUT11-induced cell death and other defense responses in N. benthamiana. Targeted deletion of VdCUT11 in V. dahliae significantly compromised virulence on cotton plants. The cutinase VdCUT11 is an important secreted enzyme and virulence factor that elicits plant defense responses in the absence of VdCBM1.

Comparative genomics reveals cotton-specific virulence factors in flexible genomic regions in Verticillium dahliae and evidence of horizontal gene transfer from Fusarium.

Verticillium dahliae isolates are most virulent on the host from which they were originally isolated. Mechanisms underlying these dominant host adaptations are currently unknown. We sequenced the genome of V. dahliae Vd991, which is highly virulent on its original host, cotton, and performed comparisons with the reference genomes of JR2 (from tomato) and VdLs.17 (from lettuce). Pathogenicity-related factor prediction, orthology and multigene family classification, transcriptome analyses, phylogenetic analyses, and pathogenicity experiments were performed. The Vd991 genome harbored several exclusive, lineage-specific (LS) genes within LS regions (LSRs). Deletion mutants of the seven genes within one LSR (G-LSR2) in Vd991 were less virulent only on cotton. Integration of G-LSR2 genes individually into JR2 and VdLs.17 resulted in significantly enhanced virulence on cotton but did not affect virulence on tomato or lettuce. Transcription levels of the seven LS genes in Vd991 were higher during the early stages of cotton infection, as compared with other hosts. Phylogenetic analyses suggested that G-LSR2 was acquired from Fusarium oxysporum f. sp. vasinfectum through horizontal gene transfer. Our results provide evidence that horizontal gene transfer from Fusarium to Vd991 contributed significantly to its adaptation to cotton and may represent a significant mechanism in the evolution of an asexual plant pathogen.

Music for reducing the anxiety and pain of patients undergoing a biopsy: A meta-analysis.

AIM: This study aimed to evaluate the efficacy of music therapy for reducing the anxiety and pain of patients who underwent a biopsy. BACKGROUND: Music can affect human anxiety and pain by triggering a neuroendocrine effect. Clinical study results indicated that music can influence the anxiety and pain caused by invasive procedures. There is no effective solution for anxiety and pain arising from a biopsy. Although researchers in this field have different views, music still holds promise in reducing the anxiety and pain in patients undergoing the biopsy. DESIGN: Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: Systematic searches were conducted in PubMed, Embase, Medline and Cochrane databases for studies reported in the English language. The review period covered 2000 - December 2016. The outcome measure of interest was anxiety and pain. METHODS: This review followed Cochrane methods. Studies were selected according to the PICOS framework. The methodological quality of studies was assessed with the Cochrane risk of bias tool. A systematic review of effectiveness was conducted by using GRADE approach. RESULTS: Nine randomized controlled trials with a total of 326 participants in the music intervention group and 323 controls met the inclusion criteria. Music had a tendency towards decreasing systolic blood pressure before the biopsy, State-Trait Anxiety Inventory scores after the biopsy, diastolic blood pressure after the biopsy and heart rate after the biopsy. Similarly, music also tended to be more effective for controlling pain after the biopsy. There was moderate quality evidence for the outcome: State-Trait Anxiety Inventory scores after the biopsy; and low- or very low-quality evidence for other outcomes. CONCLUSION: Music can be used for patients before and during the biopsy procedure. This approach may be performed by nurses to promote the recovery of patients after the biopsy.

Verticillium dahliae manipulates plant immunity by glycoside hydrolase 12 proteins in conjunction with carbohydrate-binding module 1.

Glycoside hydrolase 12 (GH12) proteins act as virulence factors and pathogen-associated molecular patterns (PAMPs) in oomycetes. However, the pathogenic mechanisms of fungal GH12 proteins have not been characterized. In this study, we demonstrated that two of the six GH12 proteins produced by the fungus Verticillium dahliae Vd991, VdEG1 and VdEG3 acted as PAMPs to trigger cell death and PAMP-triggered immunity (PTI) independent of their enzymatic activity in Nicotiana benthamiana. A 63-amino-acid peptide of VdEG3 was sufficient for cell death-inducing activity, but this was not the case for the corresponding peptide of VdEG1. Further study indicated that VdEG1 and VdEG3 trigger PTI in different ways: BAK1 is required for VdEG1- and VdEG3-triggered immunity, while SOBIR1 is specifically required for VdEG1-triggered immunity in N. benthamiana. Unlike oomycetes, which employ RXLR effectors to suppress host immunity, a carbohydrate-binding module family 1 (CBM1) protein domain suppressed GH12 protein-induced cell death. Furthermore, during infection of N. benthamiana and cotton, VdEG1 and VdEG3 acted as PAMPs and virulence factors, respectively indicative of host-dependent molecular functions. These results suggest that VdEG1 and VdEG3 associate differently with BAK1 and SOBIR1 receptor-like kinases to trigger immunity in N. benthamiana, and together with CBM1-containing proteins manipulate plant immunity.

Genome-wide association study discovered candidate genes of Verticillium wilt resistance in upland cotton (Gossypium hirsutum L.).

Verticillium wilt (VW), caused by infection by Verticillium dahliae, is considered one of the most yield-limiting diseases in cotton. To examine the genetic architecture of cotton VW resistance, we performed a genome-wide association study (GWAS) using a panel of 299 accessions and 85 630 single nucleotide polymorphisms (SNPs) detected using the specific-locus amplified fragment sequencing (SLAF-seq) approach. Trait-SNP association analysis detected a total of 17 significant SNPs at P < 1.17 × 10-5 (P = 1/85 630, -log10 P = 4.93); the peaks of SNPs associated with VW resistance on A10 were continuous and common in three environments (RDIG2015, RDIF2015 and RDIF2016). Haplotype block structure analysis predicted 22 candidate genes for VW resistance based on A10_99672586 with a minimum P-value (-log10 P = 6.21). One of these genes (CG02) was near the significant SNP A10_99672586 (0.26 Mb), located in a 372-kb haplotype block, and its Arabidopsis AT3G25510 homologues contain TIR-NBS-LRR domains that may be involved in disease resistance response. Real-time quantitative PCR and virus-induced gene silencing (VIGS) analysis showed that CG02 was specific to up-regulation in the resistant (R) genotype Zhongzhimian2 (ZZM2) and that silenced plants were more susceptible to V. dahliae. These results indicate that CG02 is likely the candidate gene for resistance against V. dahliae in cotton. The identified locus or gene may serve as a promising target for genetic engineering and selection for improving resistance to VW in cotton.

[Antimicrobial susceptibility of community-acquired respiratory tract pathogens isolated from class B hospitals in China during 2013 and 2014].

OBJECTIVE: To investigate the drug-resistance rate of community-acquired respiratory tract pathogens isolated from class B hospitals in China during 2013 and 2014. METHODS: A total of 860 strains (S.pneumoniae 299, K. pneumoniae 221, H. influenzae 185, S. aureus 116, and M. catarrhalis 39) of non-duplicated community-acquired respiratory tract pathogens were isolated from 10 class B hospitals in 9 cities. The minimal inhibitory concentration (MIC) of antibacterial agents was determined by the broth microdilution method. The sensitive rates and MIC range of the antibiotics were analyzed by the WHONET-5.6 software. RESULTS: Only 19.7%(59/299) S. pneumoniae was sensitive to oral penicillin. The sensitive rates of S. pneumoniae to second-generation cephalosporins(cefuroxime and cefaclor), amoxicillin with clavulanic acid, ceftriaxone, and macrolides (erythromycin, azithromycin and clarithromycin) were 25.6% (77/299), 33.4% (100/299), 63.5% (190/299), and 4.4% (13/299), respectively. About 93.5% (280/299)and 98.0% (293/299)of S. pneumoniae isolates were sensitive to levofloxacin and moxifloxacin.All of the K. pneumoniae isolates were sensitive to ertapenem and imipenem. The sensitive rates of K. pneumoniae to ceftriaxone, cefotaxime, ceftazidime, cefepime, and cefoxitin were about 85.0%, 93.2% (206/221), and 90.3% (200/221)of K. pneumoniae isolates were sensitive to levofloxacin and moxifloxacin.The mean prevalence of ESBL-producing K. pneumoniae was 8.1% (18/221). No S. aureus isolates resistant to vancomycin were detected in this study.The sensitive rates of S. aureus to levofloxacin, moxifloxacin, trimethoprim/sulfamethoxazole, and rifampin were 83.5% (97/116), 82.8% (96/116), 89.6% (104/116) and 83.5% (97/116), respectively. 37.4% (43/116) and 34.8% (40/116)of S. aureus isolates were sensitive to erythromycin and chloramphenicol.All of the H. influenzae and M. catarrhalis isolates were sensitive to amoxicillin with clavulanic acid, ceftriaxone, levofloxacin and moxifloxacin. The sensitive rates of H. influenza and M. catarrhalis to ampicillin, cefuroxime, cefaclor, erythromycin, azithromycin, and clarithromycin were from 80% to 100%. CONCLUSIONS: Penicillins, second-generation cephalosporins (cefuroxime and cefaclor) and amoxicillin with clavulanic acid showed low antimicrobial activity to S. pneumoniae, but a higher sensitive rate to ceftriaxone. The macrolides exhibited a high activity against H. influenza and M. catarrhalis, but low antimicrobial activity against S. pneumoniae and S. aureus. The antimicrobial activity of fluoroquinolones such as levofloxacin and moxifloxacin against most of the respiratory pathogens was high.

Genome-wide analysis of the gene families of resistance gene analogues in cotton and their response to Verticillium wilt.

BACKGROUND: Gossypium raimondii is a Verticillium wilt-resistant cotton species whose genome encodes numerous disease resistance genes that play important roles in the defence against pathogens. However, the characteristics of resistance gene analogues (RGAs) and Verticillium dahliae response loci (VdRLs) have not been investigated on a global scale. In this study, the characteristics of RGA genes were systematically analysed using bioinformatics-driven methods. Moreover, the potential VdRLs involved in the defence response to Verticillium wilt were identified by RNA-seq and correlations with known resistance QTLs. RESULTS: The G. raimondii genome encodes 1004 RGA genes, and most of these genes cluster in homology groups based on high levels of similarity. Interestingly, nearly half of the RGA genes occurred in 26 RGA-gene-rich clusters (Rgrcs). The homology analysis showed that sequence exchanges and tandem duplications frequently occurred within Rgrcs, and segmental duplications took place among the different Rgrcs. An RNA-seq analysis showed that the RGA genes play roles in cotton defence responses, forming 26 VdRLs inside in the Rgrcs after being inoculated with V. dahliae. A correlation analysis found that 12 VdRLs were adjacent to the known Verticillium wilt resistance QTLs, and that 5 were rich in NB-ARC domain-containing disease resistance genes. CONCLUSIONS: The cotton genome contains numerous RGA genes, and nearly half of them are located in clusters, which evolved by sequence exchanges, tandem duplications and segmental duplications. In the Rgrcs, 26 loci were induced by the V. dahliae inoculation, and 12 are in the vicinity of known Verticillium wilt resistance QTLs.

An alginate-based edible coating containing lactic acid bacteria extends the shelf life of fresh strawberry (Fragaria × ananassa Duch.).

Edible coatings, formulated with sodium alginate and various strains of lactic acid bacteria, were evaluated for their effectiveness in extending the shelf life and mitigating microbial risks associated with strawberries. This study specifically employed strains of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Lacticaseibacillus plantarum as antimicrobial agents. Through physicochemical property analysis, the alginate-based antimicrobial coating proved most effective in reducing the strawberry weight loss rate, decay index, and ascorbic acid degradation. Over time, all treatments exhibited increased fungal growth. However, strawberries treated with alginate and lactic acid bacteria recorded lower final colony formation counts-6.82 log CFU/g for SA + LPC, 6.04 log CFU/g for SA + LGG, and 6.26 log CFU/g for SA + LP-compared to 8.73 log CFU/g in the control group. In terms of bacterial resistance under gastrointestinal conditions, L. paracasei demonstrated the highest survival rate post-simulated gastric fluid exposure, while L. plantarum showed the greatest resilience post-simulated intestinal fluid exposure. These findings underscore the efficacy of alginate-based antimicrobial coatings in not only enhancing the storage quality of strawberries but also ensuring microbial safety and potential benefits for gut health.

Regulation of Gut Microbiota and Microbial Metabolome of Kefir Supernatant against Fusobacterium nucleatum and DSS-Coinduced Colitis.

The aim of this study was to investigate the intervention effect of kefir supernatant (KS) on the initiation and progression of an ulcerative colitis (UC) murine model. We established an UC murine model by orally administrating with 109 CFUs of Fusobacterium nucleatum for 3 weeks and 3% dextran sulfate sodium (DSS) treatment in the third week. KS was used to intervene in this colitis model. Our results showed that KS supplementation ameliorated the symptoms, restrained the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-17F), promoted the release of anti-inflammatory cytokines (IL-4 and IL-10), and ameliorated oxidative stress. Furthermore, the increased number of goblet cells and upregulated expression of MUC2, occludin and claudin-1 indicated that the colon barrier was protected by KS. Additionally, KS supplementation mitigated gut microbiota dysbiosis in the UC murine model, leading to an increase in the abundance of Blautia and Akkermansia and a decrease in the level of Bacteroides. The altered gut microbiota also affected colon metabolism, with differential metabolites mainly associated with the biosynthesis of the l-arginine pathway. This study revealed that KS supplementation restored the community structure of gut microbiota, altered the biosynthesis of l-arginine, and thereby modulated the process of colonic inflammation.

Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

Diagnostic value of human fecal SDC2 gene in colorectal cancer.

OBJECTIVE: To explore the clinical value of human fecal Syndecan-2 (SDC2) gene methylation in colorectal cancer screening. METHODS: There were 30 patients with colorectal cancer receiving treatment in Zhangjiakou First Hospital from January 2019 to December 2019 collected as the tumor group. There were 30 healthy people determined by a physical examination in 2019 collected as the normal group. The methylation level of fecal SDC2 gene and the level of serum tumor markers including carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9) were analyzed. The diagnostic effects of fecal SDC2 methylation and serum tumor markers on colorectal cancer were compared. The area under curve (AUC) of different methods for colorectal cancer diagnosis were evaluated based on the receiver operating characteristic (ROC) curve. RESULTS: There was no distinction between the tumor group and the normal group in clinical basic data, including gender, age, and body mass index (P > 0.05), revealing the comparability between the two groups. The level of fecal SDC2 methylation in the tumor group was lower than that in the normal group (P < 0.05). CEA and CA19-9 in the tumor group were higher than those in the normal group (P < 0.05). Among the 30 colorectal cancers, 28 (93.33%) were positive for SDC2 gene methylation, 18 (60%) were positive for serum CEA, and 19 (63.33%) were positive for serum CA19-9. This indicated that the true positive rate of SDC2 gene methylation was higher than that of serum tumor markers (P < 0.05). The AUC of fecal SDC2 gene methylation was 0.981. These were higher than that of serum tumor markers (P < 0.05). CONCLUSIONS: Fecal SDC2 gene detection has a high sensitivity and specificity for colorectal cancer. It has a very ideal detection effect in detecting colorectal cancer patients in the population.

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection.

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment. Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented. Results: In the treatment process, ceftazidime-avibactam (CAZ-AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ-AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L. Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

Safety and pharmacokinetics of IBI112, an IL-23 monoclonal antibody, in Chinese healthy volunteers: a first-in-human phase 1 study.

BACKGROUND: Interleukin (IL) 23p19 monoclonal antibodies were efficacious and safe in the treatment of psoriasis. A first-in-human (FIH) study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of IBI112, a novel IL-23p19 monoclonal antibody. METHODS: In this FIH, randomized, double-blind, placebo-controlled, single-ascending-dose study, a subcutaneous (SC, 5-600 mg) or intravenous (IV, 100 and 600 mg) or placebo was administered to eligible healthy subjects. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Furthermore, non-compartment analysis and population PK modeling were conducted to characterize PK, and model-based simulation was applied to justify dose selection for psoriasis patients. RESULTS: A total of 46 subjects were enrolled, with 35 receiving IBI112 and 11 receiving placebo. No serious adverse events (SAEs) and no clinically significant adverse events were identified. After a single SC of IBI112, the median Tmax was 4-10.5 days, and the half-life (t1/2) ranged from 21.8 to 35.8 days. IBI112 exposures (Cmax and AUCinf) approached dose proportionality across 5-300 mg range. CONCLUSION: IBI112 was well tolerated and safe at SC or IV dose up to 600 mg and showed a linear PK characteristics at SC dose from 5 to 300 mg. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT04511624.

Safety, tolerability, pharmacokinetics, and immunogenicity of an anti-SARS-CoV-2 monoclonal antibody HFB30132A after single dose intravenous administration in healthy Chinese subjects: a phase 1, randomized, double-blind, placebo-controlled study.

Objective: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) still protracts worldwide. HFB30132A is an anti- SARS-CoV-2 monoclonal antibody purposely engineered for an extended half-life with neutralizing activity against majority of the virus variants identified so far. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of HFB30132A in healthy Chinese subjects. Methods: A phase 1, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. Twenty subjects were enrolled to Cohort 1 (1,000 mg dose level, 10 subjects) or Cohort 2 (2,000 mg dose level, 10 subjects). Subjects in each cohort were assigned randomly to receive a single intravenous (IV) dose of HFB30132A or placebo at a ratio of 8:2. Safety was assessed in terms of treatment emergent adverse events (TEAEs), vital signs, physical examination, laboratory tests, and ECG findings. PK parameters were measured and calculated appropriately. Anti-drug antibody (ADA) test was performed to detect anti-HFB30132A antibodies. Results: All subjects completed the study. Overall, 13 (65%) of the 20 subjects experienced TEAEs. The most common TEAEs were laboratory abnormalities (12 subjects [60%]), gastrointestinal disorders (6 subjects [30%]), and dizziness (4 subjects [20%]). All TEAEs were Grade 1 or Grade 2 in severity based on the criteria of Common Terminology Criteria for Adverse Events (CTCAE). Serum exposure (Cmax, AUC0-t, AUC0-∞) of HFB30132A increased with ascending dose. After single dose of 1,000 mg and 2000 mg HFB30132A, the mean Cmax was 570.18 µg/mL and 898.65 µg/mL, the mean AUC0-t value was 644,749.42 h*µg/mL and 1,046,209.06 h*µg/mL, and the mean AUC0-∞ value was 806,127.47 h*µg/mL and 1,299,190.74 h*µg/mL, respectively. HFB30132A showed low clearance ranging from 1.38 to 1.59 mL/h, and a long terminal elimination half-life (t½) of 89-107 days. ADA test did not detect any anti-HFB30132A antibodies Conclusion: HFB30132A was safe and generally well-tolerated after single IV dose of 1,000 mg or 2000 mg in healthy Chinese adults. HFB30132A did not induce immunogenic response in this study. Our data support further clinical development of HFB30132A. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT05275660.

Comparative efficacy of vancomycin in treating ST5 and ST764 methicillin-resistant Staphylococcus aureus infections in adult patients.

IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to multiple drugs and can cause serious infections. In recent years, one of the most widespread strains of MRSA worldwide has been the clonal complex 5 (CC5) type. Sequence type 5 (ST5) and ST764 are two prevalent CC5 strains. Although ST5 and ST764 are genotypically identical, ST764 is classified as a hybrid variant of ST5 with characteristics of community-associated MRSA (CA-MRSA). In contrast to ST5, ST764 lacks the tst and sec genes but carries the staphylococcal enterotoxin B (seb) gene. Vancomycin is commonly used as the first-line treatment for MRSA infections. However, it is currently unclear whether the genetic differences between the ST5 and ST764 strains have any impact on the efficacy of vancomycin in treating MRSA infections. We conducted a prospective observational study comparing the efficacy of vancomycin against ST5-MRSA and ST764-MRSA in five hospitals in China. There were significant differences in bacteriological efficacy between the two groups, with virulence genes, such as the tst gene, being a risk factor for bacterial persistence (adjusted odds ratio, 4.509; 95% confidence interval, 1.216 to 16.724; P = 0.024). In the future, it may be necessary to consider personalized vancomycin treatment strategies based on the genetic characteristics of MRSA isolates.