Emergence and ongoing outbreak of ST80 vancomycin-resistant Enterococcus faecium in Guangdong province, China from 2021 to 2023: a multicenter, time-series and genomic epidemiological study.

BACKGROUND: Surveillance systems revealed that the prevalence of vancomycin-resistant Enterococcus faecium (VREfm) has increased. We aim to investigate the epidemiological and genomic characteristics of VREfm in China. METHODS: We collected 20,747 non-redundant E. faecium isolates from inpatients across 19 hospitals in six provinces between January 2018 and June 2023. VREfm was confirmed by antimicrobial susceptibility testing. The prevalence was analyzed using changepoint package in R. Genomic characteristics were explored by whole-genome sequencing. RESULTS: 5.59% (1159/20,747) of E. faecium isolates were resistant to vancomycin. The prevalence of VREfm increased in Guangdong province from 5% before 2021 to 20-50% in 2023 (p < 0.0001), but not in the other five provinces. Two predominant clones before 2021, ST17 and ST78, were substituted by an emerging clone, ST80, from 2021 to 2023 (88.63%, 195/220). All ST80 VREfm from Guangdong formed a single lineage (SC11) and were genetically distant from the ST80 VREfm from other countries, suggesting a regional outbreak. All ST80 VREfm in SC11 carried a new type of plasmid harbouring a vanA cassette, which was embedded in a Tn1546-like structure flanked by IS1678 and ISL3. However, no conjugation-related gene was detected and no transconjugant was obtained in conjugation experiment, indicating that the outbreak of ST80 VREfm could be attributed to clonal transmission. CONCLUSIONS: We revealed an ongoing outbreak of ST80 VREfm with a new vanA-harbouring plasmid in Guangdong, China. This clone has also been identified in other provinces and countries, foreboding a risk of wider spreading shortly. Continuous surveillance is needed to inform public health interventions.

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats.

Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.

Molecular epidemiology and genomic dynamics of Pseudomonas aeruginosa isolates causing relapse infections.

Pseudomonas aeruginosa (P. aeruginosa) is one of the leading causes of chronic infections, including reinfection, relapse, and persistent infection, especially in cystic fibrosis patients. Relapse P. aeruginosa infections are more harmful because of repeated hospitalization and undertreatment of antimicrobials. However, relapse P. aeruginosa infection in China remains largely unknown. Herein, we performed a 3-year retrospective study from 2019 to 2022 in a tertiary hospital, which included 442 P. aeruginosa isolates from 196 patients. Relapse infection was identified by screening clinical records and whole-genome sequencing (WGS). We found that 31.6% (62/196) of patients had relapsed infections. The relapse incidence of carbapenem-resistant P. aeruginosa infection (51.4%) is significantly higher than that of carbapenem-susceptible P. aeruginosa infection (20.2%, P < 0.0001). These isolates were assigned to 50 distinct sequence types and sporadically distributed in phylogeny, indicating that relapsed infections were not caused by certain lineages. Fast adaptation and evolution of P. aeruginosa isolates were reflected by dynamic changes of antimicrobial resistance, gene loss and acquisition, and single-nucleotide polymorphisms during relapse episodes. Remarkably, a convergent non-synonymous mutation that occurs in a pyochelin-associated virulence gene fptA (T1056C, M252T) could be a considerable target for the diagnosis and treatment of relapse P. aeruginosa infection. These findings suggest that integrated utilization of WGS and medical records provides opportunities for improved diagnostics of relapsed infections. Continued surveillance of the genomic dynamics of relapse P. aeruginosa infection will generate further knowledge for optimizing treatment and prevention in the future.IMPORTANCEPseudomonas aeruginosa is a predominant pathogen that causes various chronic infections. Relapse infections promote the adaptation and evolution of antimicrobial resistance and virulence of P. aeruginosa, which obscure evolutionary trends and complicate infection management. We observed a high incidence of relapse P. aeruginosa infection in this study. Whole-genome sequencing (WGS) revealed that relapse infections were not caused by certain lineages of P. aeruginosa isolates. Genomic dynamics of relapse P. aeruginosa among early and later stages reflected a plasticity scattered through the entire genome and fast adaptation and genomic evolution in different ways. Remarkably, a convergent evolution was found in a significant virulence gene fptA, which could be a considerable target for diagnosis and treatment. Taken together, our findings highlight the importance of longitudinal surveillance of relapse P. aeruginosa infection in China since cystic fibrosis is rare in Chinese. Integrated utilization of WGS and medical records provides opportunities for improved diagnostics of relapse infections.

Efficacy and safety of macrolides in the treatment of children with bronchiectasis: a meta-analysis.

BACKGROUND: This study summarized the available randomized controlled trials (RCTs) to assess the efficacy and safety of macrolides on pathogens, lung function, laboratory parameters, and safety in children with bronchiectasis. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for available papers published up to June 2021. The outcomes were the pathogens, adverse events (AEs), and the forced expiratory volume in one second (FEV1%) predicted. RESULTS: Seven RCTs (633 participants) were included. The long-term use of macrolides reduced the risk of the presence of Moraxella catarrhalis (RR = 0.67, 95% CI: 0.30-1.50, P = 0.001; I2 = 0.0%, Pheterogeneity = 0.433), but not Haemophilus influenza (RR = 0.19, 95% CI: 0.08-0.49, P = 0.333; I2 = 57.0%, Pheterogeneity = 0.040), Streptococcus pneumonia (RR = 0.91, 95% CI: 0.61-1.35, P = 0.635; I2 = 0.0%, Pheterogeneity = 0.515), Staphylococcus aureus (RR = 1.01, 95% CI: 0.36-2.84, P = 0.986; I2 = 61.9%, Pheterogeneity = 0.033), and any pathogens present (RR = 0.61, 95% CI: 0.29-1.29, P = 0.195; I2 = 80.3%, Pheterogeneity = 0.006). Long-term macrolides had no effect on FEV1% predicted (WMD = 2.61, 95% CI: -1.31, 6.53, P = 0.192; I2 = 0.0%, Pheterogeneity = 0.896). Long-term macrolides did not increase the risk of AEs or serious AEs. CONCLUSION: Macrolides do not significantly reduce the risk of pathogens present (except for Moraxella catarrhalis) or increase FEV1% predicted among children with bronchiectasis. Moreover, macrolides were not associated with AEs. Considering the limitations of the meta-analysis, further larger-scale RCTs are needed to confirm the findings. IMPACT: Macrolides do not significantly reduce the risk of pathogens present (except for Moraxella catarrhalis) among children with bronchiectasis. Macrolides do not significantly increase FEV1% predicted among children with bronchiectasis. This meta-analysis reports on the efficacy and safety of macrolides in the treatment of children with bronchiectasis, providing evidence for the management of children with bronchiectasis. This meta-analysis does not support the use of macrolides in the management of children with bronchiectasis unless the presence of Moraxella catarrhalis is provenor suspected.

Effect of Panax ginseng and Fructus Mume on Intestinal Barrier and Gut Microbiota in Rats with Diarrhea.

Panax ginseng and Fructus mume (Renshen Wumei in Chinese, RW) are natural medicines with high nutritional and pharmacological value. They have been widely used together in China to treat gastrointestinal diseases, especially persistent diarrhea, but the potential mechanisms remain elusive. In this study, a diarrhea model was established in rats using a 30% aqueous extract of senna. The therapeutic effects of RW were evaluated by recording the prevalence of loose stools, the diarrhea index, and histopathological changes in colon tissue. The levels of mucins, tight junction (TJ) proteins, inflammatory cytokines, and phosphoinositide 3-kinase/Akt/nuclear factor-κB (PI3K/Akt/NF-κB) signaling pathway proteins were measured. Metagenomic sequencing was used to analyze the gut microbiota. Treatment with RW alleviated injury to the intestinal barrier in rats with diarrhea and also upregulated levels of Muc2 and TJ proteins, such as occludin, zonula occludens-1, and claudin-1. Administration of RW regulated the structure of the gut microbiota in diarrheal rats. Furthermore, RW suppressed levels of interleukin (IL), tumor necrosis factor (TNF)-α, IL-1, PI3K, Akt, and p-NF-κB p65 and also increased IL-4 levels. Our study indicates that P. ginseng and Fructus mume help improve the symptoms of diarrhea, possibly by alleviating the intestinal barrier injury, regulating intestinal flora composition, and inhibiting the PI3K/Akt/NF-κB signaling pathway.

The Impact of Social Capital on Rural Residents' Medical Service Utilization in China-An Empirical Study Based on CFPS Data.

Based on CFPS data, the article analyzes the impact of social capital on the utilization of medical services by rural residents in China using binary logit and multinomial logit models. The social capital includes two dimensions: cognitive social capital and structural social capital, and the indicators of medical service utilization are "whether to seek medical treatment when sick" and "choice of medical institution". This paper concludes that: (1) among the cognitive social capital, special trust and religious beliefs have a significant positive influence on whether rural residents choose to seek medical treatment when they are sick; (2) among the structural social capital, social participation has a significant positive influence on choice of medical institution, and social network has a significant positive influence on the choice of township health center, specialty hospital, and general hospital. According to the empirical results, this paper proposes the following suggestions. The trust mechanism of rural society should be reconstructed, the positive role of religious beliefs should be given full play, the healthy development of social networks should be promoted, and the rural social organizations should be fostered and developed.

Modified Renshen Wumei Decoction Alleviates Intestinal Barrier Destruction in Rats with Diarrhea.

Modified Renshen Wumei decoction (MRWD), a famous traditional Chinese medicine, is widely used for treating persistent diarrhea. However, as the mechanism by which MRWD regulates diarrhea remains unknown, we examined the protective effects of MRWD on intestinal barrier integrity in a diarrhea model. In total, 48 male rats were randomly distributed to four treatment groups: the blank group (CK group), model group (MC group), Medilac-Vita group (MV group) and Chinese herb group (MRWD group). After a 21-day experiment, serum and colon samples were assessed. The diarrhea index, pathological examination findings and change in D-lactate and diamine oxidase (DAO) contents illustrated that the induction of diarrhea caused intestinal injury, which was ameliorated by MV and MRWD infusion. Metabolomics analysis identified several metabolites in the serum. Some critical metabolites, such as phosphoric acid, taurine, cortisone, leukotriene B4 and calcitriol, were found to be significantly elevated by MRWD infusion. Importantly, these differences correlated with mineral absorption and metabolism and peroxisome proliferator-activated receptor (PPAR) pathways. Moreover, it significantly increased the expression levels of TLR4, MyD88 and p-NF-κB p65 proteins and the contents of IL-1 and TNF-α, while the expression levels of occludin, claudin-1 and ZO-1 proteins decreased. These deleterious effects were significantly alleviated by MV and MRWD infusion. Our findings indicate that MRWD infusion helps alleviate diarrhea, possibly by maintaining electrolyte homeostasis, improving the intestinal barrier integrity, and inhibiting the TLR4/NF-κB axis.

[Progress on diagnosis and treatment of crown dens syndrome].

Crowned dens syndrome(CDS) is a major imaging manifestation of "coronary" calcified deposits around the odontoid, with pain, stiffness, fever, and even cervical cord compression in the upper head and neck. It was first described by Bouvet et al. in 1985, and the onset was generally thought to be caused by crystal deposition. The clinical manifestations of CDS are often similar to meningitis and often accompanied by an increase in inflammatory markers in the blood. As a result, it is very easy to obtain missed diagnosis and misdiagnosis, and it is clinically prone to obtain wrong or unnecessary treatment. At present, the diagnosis of CDS is based on the imaging findings in CT as a "golden standard". NASIDs drugs and corticosteroids are the main treatment. The prognosis is also generally good, and the imaging findings of the patients with the disease disappear completely within 3 months.

Total mercury and methylmercury accumulation in wild plants grown at wastelands composed of mine tailings: Insights into potential candidates for phytoremediation.

Total mercury (THg) and methylmercury (MMHg) were investigated in 259 wild plants belonging to 49 species in 29 families that grew in heavily Hg-contaminated wastelands composed of cinnabar ore mine tailings (calcines) in the Wanshan region, southwestern China, the world's third largest Hg mining district. The bioconcentration factors (BCFs) of THg and MMHg from soil to roots ([THg]root/[THg]soil, [MMHg]root/[MMHg]soil) were evaluated. The results showed that THg and MMHg in both plants and soils varied widely, with ranges of 0.076-140 µg/g THg and 0.19-87 ng/g MMHg in roots, 0.19-106 µg/g THg and 0.06-31 ng/g MMHg in shoots, and 0.74-1440 µg/g THg and 0.41-820 ng/g MMHg in soil. Among all investigated species, Arthraxon hispidus, Eremochloa ciliaris, Clerodendrum bunge, and Ixeris sonchifolia had significantly elevated concentrations of THg in shoots and/or roots that reached 100 µg/g, whereas Chenopodium glaucum, Corydalisedulis maxim, and Rumex acetosa contained low values below 0.5 µg/g. In addition to the high THg concentrations, the fern E. ciliaris also showed high BCF values for both THg and MMHg exceeding 1.0, suggesting its capability to extract Hg from soils. Considering its dominance and the tolerance identified in the present study, E. ciliaris is suggested to be a practical candidate for phytoextraction, whereas A. hispidus is identified as a potential candidate for phytostabilization of Hg mining-contaminated soils.

Characterization of the in Vitro Metabolic Profile of Evodiamine in Human Liver Microsomes and Hepatocytes by UHPLC-Q Exactive Mass Spectrometer.

Evodiamine is an indoloquinazoline alkaloid isolated from the fruit of Evodia rutaecarpa, which has a wide range of pharmacological effects like anti-tumor and anti-inflammatory effects. This study was intended to investigate the metabolic characteristics of evodiamine in human liver microsomes and hepatocytes by ultra-high performance liquid chromatography coupled with a Q Exactive mass spectrometer. A total of 12 phase I metabolites were detected in human liver microsomes; whereas in human hepatocytes 19 metabolites, including seven phase II metabolites were detected. The structures of the metabolites were characterized based on their accurate masses, fragment ions, and chromatographic retention times. Four metabolites (M1, M2, M5, and M7) were further unambiguously confirmed by matching their retention times, accurate masses, and fragment ions with those of their reference standards. Among these metabolites, 12 metabolites are first identified (M2, M5-M8, M10-M13, and M17-M19). The current study revealed that oxygenation, N-demethylation, dehydrogenation, glucuronidation, and GSH conjugation were the major metabolic pathways for evodiamine. This study elucidated the detailed metabolite profiles of evodiamine, which is helpful in predicting in vivo metabolism of evodiamine in human and in understanding the elimination mechanism of evodiamine and in turn, the effectiveness and toxicity.

Computational analysis of spiro-oxindole inhibitors of the MDM2-p53 interaction: insights and selection of novel inhibitors.

Since MDM2 is an inhibitor of the p53 tumor suppressor, disrupting the MDM2-p53 interaction is a promising approach for cancer therapy. Here, we used molecular dynamics simulations followed by free energy decomposition analysis to study conformational changes in MDM2 induced by three known spiro-oxindole inhibitors. Analysis of individual energy terms suggests that van der Waals and electrostatic interactions explain much of the binding affinities of these inhibitors. Binding free energies calculated for the three inhibitors using the molecular mechanics-generalized Born surface area model were consistent with experimental data, suggesting the validity of this approach. Based on this structure-function analysis, several novel spiro-oxindole derivatives were selected and evaluated for their ability to block the MDM2-p53 interaction in vitro. These results suggest that combining in silico and experimental techniques can provide insights into the structure-function relationships of MDM2 inhibitors and guide the rational design of anticancer drugs targeting the MDM2-p53 interaction.