Gallbladder carcinosarcoma with a poor prognosis: A case report.

BACKGROUND: Carcinosarcoma of the gallbladder is a rare malignant tumor with a very poor prognosis. To date, only approximately 100 patients have been reported in the English literature. The prognosis of this tumor type is poor, the preoperative diagnosis is difficult, and there is a possibility of a misdiagnosis. We present an unsuccessful case of carcinosarcoma of the gallbladder with a preoperative misdiagnosis and rapid early postoperative recurrence. Therefore, we have a deeper understanding of the poor prognosis of gallbladder carcinosarcoma (GBC) patients. CASE SUMMARY: The patient is a 65-year-old male. He was admitted to the hospital because of right upper abdomen distending pain and discomfort for half a month. Abdominal magnetic resonance imaging revealed a polycystic mass in the right lobe of the liver and the fossa of the gallbladder. After admission, the patient was diagnosed with a liver abscess, which was treated by abscess puncture drainage. Obviously, this treatment was unsuccessful. Hepatectomy and cholecystectomy were performed one month after the puncture. Postoperative pathologic examination revealed carcinosarcoma of the gallbladder, and the resected specimen contained two tumor components. One month after surgery, the patient's tumor recurred in situ and started to compress the duodenum, resulting in duodenal obstruction and bleeding. The treatment was not effective. The patient died of gastrointestinal hemorrhage and hypovolemic shock. CONCLUSION: Carcinosarcoma of the gallbladder is a rare malignant tumor that is easily misdiagnosed preoperatively and has a poor prognosis.

Diagnostic value of one-step nucleic acid amplification for sentinel lymph node metastasis in cytokeratin 19-positive tumors: evidence from bioinformatics and meta-analysis.

Background: The status of the sentinel lymph nodes (SLNs) was an important prognostic factor in varies cancers. A one-step nucleic acid amplification (OSNA) assay, a molecular-based whole-node analysis method based on CK19 mRNA copy number, was developed to diagnose lymph node metastases. We aimed to evaluate the value of OSNA for the diagnosis of sentinel lymph node metastasis in CK19 positive cancers. CK19 mRNA and protein expression for pan-caner analysis were obtained from TCGA and the Human protein atlas database. Methods: Two researchers independently searched the PubMed, Cochrane Library and Web of Science databases for qualified articles published before December 1, 2023. A meta-analysis was performed using MetaDisc and STATA. Risk bias and quality assessments of the included studies were evaluated, and a subgroup analysis was performed. Ten cancer types were found to be CK19 positively expressed and 7 of 10 had been reported to use OSNA for SLN detection. Results: After literature review, there were 61 articles included in the meta-analysis, which consisted of 7115 patients with 18007 sentinel lymph nodes. The pooled sensitivity and specificity of OSNA were 0.87 and 0.95 in overall patients. Moreover, we found the background CK19 expression in normal tissue affected the diagnostic accuracy of OSNA. In breast cancer, we performed subgroup analysis. OSNA exhibited to be a stable method across different population groups and various medical centers. In addition, when 250 copies/µl was chosen as the cutoff point of CK19 mRNA, there were a relatively higher sensitivity and AUC in detecting SLN micro-metastasis than 5000 copies/µl. Discussion: OSNA can predict the occurrence of SLN metastasis accurately in CK19 positive cancers, especially in breast cancer, colorectal cancer, lung cancer, gastric cancer and endometrial cancer. Our study warrants future studies investigating the clinical application of OSNA in pancreatic, ovarian and bladder cancers.

Barriers and facilitators to guideline for the management of pediatric off-label use of drugs in China: a qualitative descriptive study.

BACKGROUND: Despite being a global public health concern, there is a research gap in analyzing implementation strategies for managing off-label drug use in children. This study aims to understand professional health managers' perspectives on implementing the Guideline in hospitals and determine the Guideline's implementation facilitators and barriers. METHODS: Pediatric directors, pharmacy directors, and medical department directors from secondary and tertiary hospitals across the country were recruited for online interviews. The interviews were performed between June 27 and August 25, 2022. The Consolidated Framework for Implementation Research (CFIR) was adopted for data collection, data analysis, and findings interpretation to implement interventions across healthcare settings. RESULTS: Individual interviews were conducted with 28 healthcare professionals from all over the Chinese mainland. Key stakeholders in implementing the Guideline for the Management of Pediatric Off-Label Use of Drugs in China (2021) were interviewed to identify 57 influencing factors, including 27 facilitators, 29 barriers, and one neutral factor, based on the CFIR framework. The study revealed the complexity of the factors influencing managing children's off-label medication use. A lack of policy incentives was the key obstacle in external settings. The communication barrier between pharmacists and physicians was the most critical internal barrier. CONCLUSION: To our knowledge, this study significantly reduces the implementation gap in managing children's off-label drug use. We provided a reference for the standardized management of children's off-label use of drugs.

Therapeutic utility of human umbilical cord-derived mesenchymal stem cells-based approaches in pulmonary diseases: Recent advancements and prospects.

Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide. For diverse disease conditions, the currently available approaches are focused on alleviating clinical symptoms and delaying disease progression but have not shown significant therapeutic effects in patients with lung diseases. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) isolated from the human UC have the capacity for self-renewal and multilineage differentiation. Moreover, in recent years, these cells have been demonstrated to have unique advantages in the treatment of lung diseases. We searched the Public Clinical Trial Database and found 55 clinical trials involving UC-MSC therapy for pulmonary diseases, including coronavirus disease 2019, acute respiratory distress syndrome, bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. In this review, we summarize the characteristics of these registered clinical trials and relevant published results and explore in depth the challenges and opportunitiesfaced in clinical application. Moreover, the underlying molecular mechanisms involved in UC-MSC-based therapy for pulmonary diseases are also analyzed in depth. In brief, this comprehensive review and detailed analysis of these clinical trials can be expected to provide a scientific reference for future large-scale clinical application.

Apatinib weakens proliferation, migration, invasion, and angiogenesis of thyroid cancer cells through downregulating pyruvate kinase M2.

Thyroid cancer (TC) is the most frequent malignancy of the endocrine system. Apatinib, as an anti-angiogenic agent, has been applied in the therapy of several cancers. However, the function and mechanism of Apatinib in TC have not been clearly elucidated. After processing with Apatinib alone or combined PKM2 overexpression plasmids, cell proliferation, migration, and invasion were analyzed by EdU staining, CCK-8, wound healing, and Transwell. Meanwhile. HUVECs were incubated with the conditioned medium prepared from cell culture medium, and tube formation and VEGFR2 expression in HUVECs were examined using tube formation and immunofluorescence (IF) assays. Besides, we established a nude mouse xenograft model by lentivirus-mediated PKM2 shRNAs, and tested the growth of tumors; the pathological structure was analyzed with H&E staining. And the expressions of N-cadherin, Vimentin, E-cadherin, PKM2, VEGFA, VEGFR2, and Ki67 were determined by immunohistochemistry or Western blot. Apatinib could prominently suppress proliferation, migration, invasion, and HUVEC tube formation in SW579 and TPC-1 cells. Besides, we discovered that Apatinib had a significant inhibitory role on the expression of pyruvate kinase M2 (PKM2) in TC cells. And PKM2 overexpression also could notably reverse Apatinib-mediated inhibition of TC progression. Moreover, PKM2 shRNAs were applied to TC xenografts, resulting in significant reduction in tumor volume and suppression of angiogenesis-related protein expression. In summary, Apatinib has a regulatory role in TC progression, and Apatinib can block cancer cell angiogenesis by downregulating PKM2. This will provide a theoretical basis for therapy of TC.

A novel ratiometric fluorescence probe based on the FRET-ICT mechanism for detecting fluoride ions and viscosity.

Fluoride ion is not only important for dental health, but also a contributing factor in a variety of diseases. At the same time, fluoride ions and cell viscosity are both important to the physiological environment of mitochondria. We developed a dual-response ratiometric fluorescent probe BDF based on Förster resonance energy transfer (FRET) and intramolecular charge transfer (ICT) mechanism for the detection of F- and viscosity. BDF has an outstanding intramolecular energy transfer efficiency of 97.7% and shows excellent performance for fluorine ion detection. In addition, when the system viscosity increases, the fluorescence emission intensity of BDF is greatly heightened, indicating the possibility of viscosity detection. Finally, based on the fluorescence properties of BDF, we used the probe to detect F- in the toothpaste sample and image exogenous fluoride ions in HeLa cells.

Metabolite identification and quantitation of RBD1016 siRNA: a direct comparison of hybridization-based LC-FD and LC-HRAM assays.

Aim: RBD1016 is an N-acetylgalactosamine-conjugated siRNA drug currently in a phase II trial for treatment of chronic hepatitis B virus. To evaluate its absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic/pharmacodynamic (PK/PD) properties, two LC-based bioanalytical methods, LC-high-resolution/accuracy MS and LC-fluorescence detection, were developed and qualified. Materials & methods: The LC-high-resolution/accuracy MS method was used for metabolite identification and simultaneous quantitation of the antisense and sense strands as well as their respective metabolites. The LC-fluorescence detection assay was primarily used for analyzing the antisense strand and its metabolites in low-concentration plasma samples. The two methods were successfully bridged by analyzing the same sets of study samples. Results & conclusion: Both methods were found to have excellent accuracy/precision, specificity and reproducibility to support ADME and PK/PD studies of RBD1016 siRNA.

Meet the Editorial Board - an interview with Min Meng and transitions from small regional labs to global CRO.

Min Meng received her PhD in biomedicinal chemistry from the School of Pharmacy, University of Maryland, in 1996. From 1996 to 1998, Meng was a postdoctoral fellow at the American Health Foundation, focusing on the carcinogenic toxicity of tobacco smoke using various chromatographic technologies such as LC-UV, GC-MS/MS and LC-MS/MS. From 1998 to 2017, Meng worked for Tandem Labs/LabCorp/Covance, a bioanalytical contract research organization (CRO), holding various positions from scientist to lab director and technical director. In 2017, Meng moved back to her hometown and set up a bioanalytical CRO, Denali Medpharma, Chongqing, China. In October 2023, Denali was acquired by Resolian Bioanalytics, a global bioanalytical CRO. Currently, Dr Meng is the chief scientific officer and president of the Asia Pacific region for Resolian Bioanalytics.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B.

BACKGROUND: Bitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances. Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo. METHODS: To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues, multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique. A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes. Then, T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds. Perception to taste substance was also studied using two-bottle preference tests. RESULTS: We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique. Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice. But qRT-PCR results revealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice. With two-bottle preference tests, these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105. In addition, these mutant mice showed a loss of taste perception to quinine dihydrochloride, denatonium benzoate, and cucurbitacin B (CuB). Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception. CONCLUSIONS: These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

Lack of incremental value of three-dimensional measurement in assessing invasiveness for lung cancer.

OBJECTIVES: The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS: A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS: A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P = 0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P < 0.000 vs P < 0.000) and overall survival (P = 0.003 vs P = 0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P = 0.189). CONCLUSIONS: Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional.

Microwave ablation versus laparoscopic resection for hepatocellular carcinoma in patients with clinically significant portal hypertension: a propensity score-matched study of postoperative liver decompensation.

OBJECTIVES: The study of postoperative liver decompensation after microwave ablation (MWA) for hepatocellular carcinoma (HCC) in patients with clinically significant portal hypertension (CSPH) is still lacking. The purpose of the present study was to compare the postoperative liver decompensation after MWA and laparoscopic resection (LR) for HCC in patients with CSPH. METHODS: The present retrospective study enrolled 222 HCC patients with CSPH who underwent MWA (n = 67) or LR (n = 155). Postoperative liver decompensation, complications, postoperative hospital stays, and overall survival were analyzed. Factors associated with postoperative liver decompensation were identified. RESULTS: After propensity score matching, the postoperative liver decompensation rate was significantly lower in the MWA group than that in the LR group (15.5% versus 32.8%, p = 0.030). The multivariable regression analysis identified that type of treatment (MWA vs. LR, odds ratio [OR] 0.44; 95% confidence interval [CI], 0.21-0.91; p = 0.026) and Child-Pugh B (OR, 2.86; 95% CI, 1.24-6.61; p = 0.014) were independent predictors for postoperative liver decompensation. The rate of complications for patients in the MWA group was significantly lower than that in the LR group (p < 0.001). And MWA showed shorter postoperative hospital stays than LR (3 days vs. 6 days, p < 0.001). Overall survival rate between the two groups was not significantly different (p = 0.163). CONCLUSION: Compared with laparoscopic resection, microwave ablation has a lower rate of postoperative liver decompensation and might be a better option for HCC patients with CSPH. CLINICAL RELEVANCE STATEMENT: Microwave ablation exhibited a lower incidence of postoperative liver decompensation in comparison to laparoscopic resection, thereby conferring greater advantages to hepatocellular carcinoma patients with clinically significant portal hypertension. KEY POINTS: •Postoperative liver decompensation rate after microwave ablation was lower than that of laparoscopic resection for hepatocellular carcinoma in patients with clinically significant portal hypertension. •Microwave ablation showed shorter postoperative hospital stays than laparoscopic resection. •Microwave ablation had fewer complications than laparoscopic resection.

Spatial distribution of antibiotics and antibiotic resistance genes in tidal flat reclamation areas in China.

Tidal flat areas are important resources for land development and are becoming antibiotic resistance receivers that trigger major health concerns. The spatial distributions of forty-nine antibiotics, nine antibiotic resistance genes (ARGs), one mobile gene element (MGE) gene, and nine available metals in the soils and sediments along the coastlines of the Yellow Sea in China were quantified. Hierarchical linear model analysis was used to explore relationships between the antibiotics and ARGs across multiple effects resulting from human activities and environmental factors. Fish farm sediments and farmland soils showed high levels of quinolones (QNs) (maximum 637 ng·g-1), sulfonamides (SAs) (maximum 221 ng·g-1), and corresponding ARGs. Significant positive correlations (P from 5.47 × 10-14 to 0.0487) were observed between the antibiotics (QNs, SAs, and chlortetracycline) and their corresponding ARGs (qnrA, qnrD, aac(6')-Ib-cr, dfrA, sul2, and tetA), indicating the selective pressure from antibiotics in soils and sediments. Nine available metals had positive correlations with at least one ARG, indicating heavy metal pollution could enhance the ARGs. Sheep and poultry husbandry and marine aquaculture contribute the most to the antibiotic resistance in the coastlines. In conclusion, antibiotic pollutions have promoting effects at sub-inhibitory concentrations and more attention should be given to inhibit the enrichment of ARGs during tidal flat reclamation processes. The study also suggests the induction effects from metal pollutions, MGE spread, and the antibiotic pollutions from the usage in livestock and aquaculture.

Metabolic pathway of tebuconazole by soil fungus Cunninghamella elegans ATCC36112.

Tebuconazole is the most widely used fungicide in agriculture. Due to its long half-life, tebuconazole residues can be found in the environment media such as in soil and water bodies. Here, the metabolic pathway of tebuconazole was studied in Cunninghamella elegans (C. elegans). Approximately 98% of tebuconazole was degraded within 7 days, accompanied by the accumulation of five metabolites. The structures of the metabolites were completely or tentatively identified by gas chromatography-mass spectrometry (GC-MS) and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). To identify representative oxidative enzymes that may be involved in the metabolic process, treatment with piperonyl butoxide (PB) and methimazole (MZ) was performed. PB had a strong inhibitory effect on the metabolic reactions, while MZ had a weak inhibitory effect. The results suggest that cytochrome P450 (CYP) and flavin-dependent monooxygenase are involved in the metabolism of tebuconazole. Based on the results, we propose a metabolic pathway for the fungal metabolism of tebuconazole. Data are of interest to gain insight into the toxicological effects of tebuconazole and for tebuconazole bioremediation.

Spatial downregulation of CD74 signatures may drive invasive component development in part-solid lung adenocarcinoma.

Pulmonary nodules with part-solid imaging features manifest during the progression from preinvasive to invasive lung adenocarcinoma. To define the spatial composition and evolutionary trajectories of early-stage lung adenocarcinoma, we combined spatial transcriptomics (ST) and pathological annotations from 20 part-solid nodules (PSNs), four of which were matched with single-cell RNA sequencing. Two malignant cell populations (MC1 and MC2) were identified, and a linear evolutionary relationship was observed. Compared to MC2, the pre-existing malignant MC1 exhibited a lower metastatic signature, corresponding to the preinvasive component (lepidic) on pathology and the ground glass component on PSN imaging. Higher immune infiltration was observed among MC1 regions in ST profiles, and further analysis revealed that macrophages may be involved in this process through the CD74 axis. This work provides deeper insights into the evolutionary process and spatial immune cell composition behind PSNs and highlights the mechanisms of immune escape behind this adenocarcinoma trajectory.

Microwave ablation for the treatment of peripheral ground-glass nodule-like lung cancer: Long-term results from a multi-center study.

Introduction: Microwave ablation (MWA) is an effective and safe approach for the treatment of ground-glass nodule (GGN)-like lung cancer, but long-term follow-up is warranted. Therefore, this multi-center retrospective study aimed to evaluate the results of MWA for the treatment of peripheral GGN-like lung cancer with a long-term follow-up. Materials and Methods: From June 2013 to January 2018, a total of 87 patients (47 males and 40 females, mean age 64.6 ± 10.2 years) with 87 peripheral lung cancer lesions showing GGN (mean long axis diameter, 17 ± 5 mm) underwent computed tomography (CT)-guided percutaneous MWA. All GGN-like lung cancers were histologically verified. The primary endpoints were local progression-free survival (LPFS) and overall survival (OS). The secondary endpoints were cancer-specific survival (CSS) and complications. Results: During a median follow-up of 65 months, both the 3-year and 5-year LPFS rates were 96.6% and 96.6%. The OS rate was 94.3% at 3 years and 84.9% at 5 years, whereas the 3-year and 5-year CSS rates were 100% and 100%, respectively. No periprocedural deaths were observed. Complications were observed in 49 patients (51.6%). Grade 3 or higher complications included pneumothorax, pleural effusion, hemorrhage, and pulmonary infection, which were identified in ten (10.5%), two (2.1%), two (2.1%), and one (1.1%) patient, respectively. Conclusions: CT-guided percutaneous MWA is an effective, safe, and potentially curative treatment regimen for GGN-like lung cancer.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

PURPOSE: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. PATIENTS AND METHODS: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. RESULTS: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). CONCLUSIONS: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

Tracking spatio-temporal distribution and transmission of antibiotic resistance in aquatic environments by using ESBL-producing Escherichia coli as an indicator.

Wastewater treatment plants (WWTPs) play an important role in the production, and transmission of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) as a convergence for human, animal, and environmental wastewater. The aim of this study was to investigate the spatio-temporal variation and influencing factors of ARB in different functional areas of the urban WWTP and the connecting rivers for 1-year monitoring using extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-Ec) as an indicator bacteria, and to study the transmission patterns of ARB in the aquatic environment. The results showed that ESBL-Ec isolates were identified from the WWTP (n = 219), including influent (n = 53), anaerobiotic tank (n = 40), aerobiotic tank (n = 36), activated sludge tank (n = 31), sludge thickner tank (n = 30), effluent (n = 16), and mudcake storage area (n = 13). The dehydration process can significantly remove the ESBL-Ec isolates; however, ESBL-Ec was still detected in samples collected from the effluent of the WWTP (37.0%). The detection rate of ESBL-Ec was significantly different across seasons (P < 0.05), and ambient temperature was negatively correlated with the detection rate of ESBL-Ec (P < 0.05). Furthermore, a high prevalence of ESBL-Ec isolates (29/187, 15.5%) was detected in samples collected from the river system. These findings emphasize that the high majority of ESBL-Ec in aquatic environments is alarming because it poses a significant threat to public health. Clonal transmission of ESBL-Ec isolates between the WWTP and rivers based on the spatio-temporal scale was observed by pulsed-field gel electrophoresis analysis, ST38 and ST69 ESBL-Ec clone were selected as prioritized isolates for antibiotic resistance monitoring in the aquatic environment. Further phylogenetic analysis showed human-associated (feces, blood) E. coli was the main source contributing to the presence of antibiotic resistance in aquatic environments. Longitudinal and targeted monitoring of ESBL-Ec in WWTPs and the development of effective wastewater disinfection strategies before effluent discharge from WWTPs are urgently required, to prevent and control the spread of antibiotic resistance in the environment.

Association of serum uric acid with risk of stroke in US adults: A cross-sectional study from NHANES 1999-2020.

BACKGROUND AND AIMS: The validity of high uric acid levels as an independent cause of stroke remains controversial, and the association between its low concentration and stroke is unclear. This study determines how different serum uric acid (SUA) levels are associated with stroke risk. METHODS: This cross-sectional study used continuous National Health and Nutrition Examination Survey data in the United States during 1999-2020. The SUA levels of 6.0, 6.8, and 9.0 mg/dL were all considered as cut-off points. Restricted cubic spline interpolation and logistic regression models were used to evaluate the different associations. Subgroup analyses and sensitivity analyses were conducted to evaluate the influence of multiple factors on the outcomes. RESULTS: The study included 23,413 participants aged ≥ 20 years. A J-shaped curve existed between SUA and stroke risk, and the risk of stroke was positively correlated with SUA levels in the overall population. Subgroup analysis of all adults in the SUA 6.8-9.0 mg/dL group showed that stroke risk for non-Hispanic white, obese, ex-smoker, and heavy drinking groups was increased, but for the other Hispanic group was reduced. In the SUA < 6.0 mg/dL group, stroke risk for ex-smoker, heavy drinkers, and no chronic kidney disease groups was increased. CONCLUSION: Our findings indicate a J-shaped relationship between SUA levels and stroke risk. Low and high SUA levels increased stroke risk for different populations, except in the other Hispanic population. Early SUA management is highly significant for stroke prevention in high-risk populations.

Persistent transmission of carbapenem-resistant, hypervirulent Klebsiella pneumoniae between a hospital and urban aquatic environments.

The increasing prevalence of infections caused by carbapenem-resistant hypervirulent Klebsiella pneumoniae strains (CR-hvKP) prompts the question of whether these strains also circulate outside of clinical settings. However, the environmental occurrence and dissemination of CR-hvKP are poorly studied. In the current study, we investigated the epidemiological characteristics, and dissemination dynamics of carbapenem-resistant K. pneumoniae (CRKP) isolated from a hospital, an urban wastewater treatment plant (WWTP), and adjacent rivers in Eastern China during one year of monitoring. A total of 101 CRKP were isolated, 54 were determined to be CR-hvKP harboring pLVPK-like virulence plasmids, which were isolated from the hospital (29 out of 51), WWTP (23 out of 46), and rivers (2 out of 4), respectively. The period with lowest detection rate of CR-hvKP in the WWTP, August, corresponded with the lowest detection rate at the hospital. Comparing the inlet and outlet of the WWTP, no significant reduction of the detection of CR-hvKP and relative abundance of carbapenem resistance genes was observed. The detection rate of CR-hvKP and the relative abundance of carbapenemase genes were significantly higher in the WWTP in colder months compared to warmer months. Clonal dissemination of CR-hvKP clones of ST11-KL64 between the hospital and the aquatic environment, as well as the horizontal spread of IncFII-IncR and IncC plasmids carrying carbapenemase genes, was observed. Furthermore, phylogenetic analysis showed that the ST11-KL64 CR-hvKP strain has spread nationally by interregional transmission. These results indicated transmission of CR-hvKP clones between hospital and urban aquatic environments, prompting the need for improved wastewater disinfection and epidemiological models to predict the public health hazard from prevalence data of CR-hvKP.

Metabolism of an insecticide fipronil by soil fungus Cunninghamella elegans ATCC36112.

In this study, the metabolic pathway of the phenylpyrazole insecticide fipronil in Cunninghamella elegans (C. elegans) was investigated. Approximately 92% of fipronil was removed within 5 days, and seven metabolites were accumulated simultaneously. The structures of the metabolites were completely or tentatively identified by GC-MS and 1H, 13C NMR. To determine the oxidative enzymes involved in metabolism, piperonyl butoxide (PB) and methimazole (MZ) were used, and the kinetic responses of fipronil and its metabolites were determined. PB strongly inhibited fipronil metabolism, while MZ weakly inhibited its metabolism. The results suggest that cytochrome P450 (CYP) and flavin-dependent monooxygenase (FMO) may participate in fipronil metabolism. Integrated metabolic pathways can be inferred from the control and inhibitor experiments. Several novel products from the fungal transformation of fipronil were identified, and similarities between C. elegans transformation and mammalian metabolism of fipronil were compared. Therefore, these results will help to gain insight into the fungal degradation of fipronil and potential applications in fipronil bioremediation. At present, microbial degradation of fipronil is the most promising approach and maintains environmental sustainability. In addition, the ability of C. elegans to mimic mammalian metabolism will assist in illustrating the metabolic fate of fipronil in mammalian hepatocytes and assess its toxicity and potential adverse effects.