Mechanisms of acquisition of the vanA operon among vancomycin-resistant Staphylococcus aureus genomes: The tip of the iceberg?

BACKGROUND: Vancomycin is frequently used as a last line of defence against infections due to multidrug-resistant Staphylococcus aureus (S. aureus). A recent finding described the acquisition of vancomycin-resistant S. aureus strains by the integration of an enterococcal plasmid containing the vanA operon into the S. aureus chromosome via homologous recombination involving a specific integration site called locus L2. METHODS: To characterise all mechanisms of acquisition of vanA, this study analysed the 15 706 S. aureus genomes to look for vanA and described its genetic environment. RESULTS: A complete vanA operon was found in 25 S. aureus strains isolated from 12 patients, including nine co-isolated with vancomycin-resistant Enterococcus strains. VanA was found within transposon Tn1546-like elements on 17 plasmids and eight chromosomes. VanA might be acquired through conjugation of enterococcal and staphylococcal plasmids, transposition of Tn1546 carrying vanA and plasmid integration into the chromosome. Further, L2 was detected in 2087 genomes (13.3%) of S. aureus strains across different continents. Six potential chromosomal hotspots for integration of the entire vanA-containing enterococcal plasmid were identified by homologous recombination via L2. CONCLUSIONS: These findings suggest that the recently described scenario in a New York patient could be reproduced anywhere. Surveillance of this possibility is mandatory, especially in patients with vancomycin-resistant Enterococcus infection or colonisation.

Anaphylaxis management in a French pediatric emergency department: Lessons from the ANA-PED study.

BACKGROUND: Anaphylaxis is a serious systemic hypersensitivity reaction that requires immediate recognition and prompt administration of epinephrine/adrenaline. The present study aimed to assess the appropriateness of epinephrine/adrenaline use in children identified as allergic by physicians in the emergency department (ED) at the time of the reaction, and to identify factors that are possibly associated with epinephrine/adrenaline administration, auto-injector prescription, and further referral to an allergist. METHODS: We performed a retrospective cross-sectional study at the pediatric ED of the University Hospital of Montpellier, France. We included all consecutive children who attended the ED between 2016 and 2020 with an allergy-related diagnosis at discharge. RESULTS: We included 1056 allergy-related visits, including 224 (21.2%) with a diagnosis of anaphylaxis at discharge; only 17.0% of them received an epinephrine/adrenaline injection, and 57.1% consulted an allergist after the acute episode. An auto-injector was prescribed to 63 (28.1%) patients at discharge from the ED. Besides the severity of the clinical presentation, factors associated with a guidelines-based management of the anaphylactic reaction and with an increased administration rate of epinephrine/adrenaline included presence of asthma symptoms and presence of extended skin reactions. CONCLUSIONS: Our study underlines persistent gaps in the management of pediatric anaphylaxis in ED, focusing on hereby identified levers. By disseminating current knowledge and guidelines on anaphylaxis and allergies, specialists could work together with emergency physicians to establish effective management algorithms and improve anaphylaxis management and care pathways for children experiencing allergic reactions, especially anaphylaxis. TRAIL REGISTRATION: Clinical Trials, number NCT05112367.

Hypersensitivity reactions to iodinated radiocontrast media: Cluster analysis reveals distinct clinical phenotypes.

Background: Drug hypersensitivity reaction (DHR) to iodinated radiocontrast media (iRCM) is reported in 1%-3% of injections. Risk assessment of patients with suspicion of DHR to iRCM relies solely on clinical phenotyping and drug allergy workup. Using a novel unsupervised TwoStep cluster analysis, we aimed to identify prototypic patterns within a large cohort of patients evaluated for a potential iRCM DHR. Methods: A retrospective study was conducted using data from the Drug Allergy and Hypersensitivity Database of the Allergy Unit, University Hospital of Montpellier, Montpellier, France. All referred patients during February 2001 to December 2019 with suspicion of iRCM DHR with either confirmed positive or confirmed negative skin tests were included in the analysis. Results: A total of 1439 patients were evaluated. The chronology of the index reaction was immediate and nonimmediate in 77.1% and 22.4%, respectively. Cluster analysis categorized the total study population in 5 clusters. Cluster 1 compiled all nonimmediate and cluster 2-5 almost all immediate reactors. Cluster 1 and 2 had recent reactions (<1 y) with mostly known iRCMs and the highest iRCM allergy prevalence (16-17%). In the other clusters, more remote reactions, unknown iRCMs and a lower allergy prevalence (3-8%) was observed. Chronology and semiology of the index reaction were the factors most strongly differentiated among clusters. History of anaphylactic shock and chronology of immediate hypersensitivity reactions were shown to be independent predictors of allergy with adjusted OR (aOR) of 4.68 (95%CI: 3.01-7.27, p < 0.001) and 2.51 (95%CI: 1.67-3.78, p < 0.001), respectively. Conclusions: Unsupervised cluster analysis identified 5 prototypic patterns within patients with a suspected DHR to iRCMs. Well-phenotyped patients cluster together in 2 groups in which the prevalence of allergy is approximately 1 in 6. However, this value decreases for patients with reactions dating back to more than a decade.

Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors.

Export of lactic acid from glycolytic cancer cells to the extracellular tumor milieu has been reported to enhance tumor growth and suppress antitumor immunity. In this study, a pH-activatable nanodrug is reported for tumor-targeted inhibition of monocarboxylate transporter-1 (MCT1) that reverses lactic acid-induced tumor immunosuppression. The nanodrug is composed of an MCT1 inhibitor (AZD3965) loaded inside the ultra-pH-sensitive nanoparticles (AZD-UPS NPs). AZD-UPS NP is produced by a microfluidics method with improved drug loading efficiency and optimal nanoparticle size over sonication methods. The nanodrug remains as intact micelles at pH 7.4 but rapidly disassembles and releases payload upon exposure to acidic pH. When combined with anti-PD-1 therapy, AZD-UPS NP leads to potent tumor growth inhibition and increases survival in two tumor models over oral administration of AZD3965 at dramatically reduced dose (>200-fold). Safety evaluations demonstrate reduced drug distribution in heart and liver tissues with decrease in toxic biomarkers such as cardiac troponin by the nanodrug. Increased T-cell infiltration and reduced exhaustive PD1+ Tim3+ T cells are found in tumors. These data illustrate that tumor-targeted inhibition of MCT1 can reverse the immune suppressive microenvironment of solid tumors for increased safety and antitumor efficacy of cancer immunotherapy.

Development of a Spatial Decision Support System for Real-Time Flood Early Warning in the Vu Gia-Thu Bon River Basin, Quang Nam Province, Vietnam.

Vu Gia-Thu Bon (VGTB) river basin is an area where flash flood and heavy flood events occur frequently, negatively impacting the local community and socio-economic development of Quang Nam Province. In recent years, structural and non-structural solutions have been implemented to mitigate damages due to floods. However, under the impact of climate change, natural disasters continue to happen unpredictably day by day. It is, therefore, necessary to develop a spatial decision support system for real-time flood warnings in the VGTB river basin, which will support in ensuring the area's socio-economic development. The main purpose of this study is to develop an online flood warning system in real-time based on Internet-of-Things (IoT) technologies, GIS, telecommunications, and modeling (Soil and Water Assessment Tool (SWAT) and Hydrologic Engineering Center's River Analysis System (HEC-RAS)) in order to support the local community in the vulnerable downstream areas in the event of heavy rainfall upstream. The structure of the designed system consists of these following components: (1) real-time hydro-meteorological monitoring network, (2) IoT communication infrastructure (Global System for Mobile Communications (GSM), General Packet Radio Service (GPRS), wireless networks), (3) database management system (bio-physical, socio-economic, hydro-meteorological, and inundation), (4) simulating and predicting model (SWAT, HEC-RAS), (5) automated simulating and predicting module, (6) flood warning module via short message service (SMS), (7) WebGIS, application for providing and managing hydro-meteorological and inundation data, and (8) users (citizens and government officers). The entire operating processes of the flood warning system (i.e., hydro-meteorological data collecting, transferring, updating, processing, running SWAT and HEC-RAS, visualizing) are automated. A complete flood warning system for the VGTB river basin has been developed as an outcome of this study, which enables the prediction of flood events 5 h in advance and with high accuracy of 80%.

Language Consideration and Methodological Transparency in "Systematic" Reviews of Animal Toxicity Studies.

This study evaluated the use of non-English literature (NEL) in systematic reviews (SRs) or meta-analyses (MAs) of animal-based toxicity or communicable disease (CD) studies. A secondary goal was to assess how grant funding, country of primary authorship, or study quality reporting influenced the use of NEL in these reviews. Inclusion criteria and data extraction forms were based on a pilot evaluation of a 10% random sample of reviews that were identified from a PubMed search (2006 to May 2017). This search yielded 111 animal toxicity and 69 CD reviews. Reviews (33 animal toxicity and 32 CD studies) were included when the authors identified their work as an SR or MA, described a literature search strategy, and provided defined inclusion criteria. Extracted data included PubMed indexing of publication type, author affiliations, and grant funding. Language use was mentioned in the methods in 55% of the toxicity SRs and 69% of CD SRs, of which 44% (n = 8) and 41% (n = 9) were limited to English, respectively. Neither the study type, grant funding, nor first author country of affiliation was associated with an increased consideration of NEL. Study quality reporting was more common in SRs that considered multiple languages. Despite guidelines that encourage the use of NEL in SRs and translation tools, SR/MA authors often fail to report language inclusion or focus on English publications. Librarian involvement in SR can promote awareness of relevant NEL and collaborative and technological strategies to improve their incorporation into the SR process.