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Background: Intrasaccular flow diversion using the woven endobridge device (WEB; MicroVention, Aliso Viejo, CA, USA) for the treatment of intracranial aneurysms has demonstrated large scale safety and efficacy. However, limitations arise from its structural configuration, restricting its application to specific aneurysm sizes and shapes., Technique Overview: We introduce the CUPCAKE technique, a combination of conventional coiling followed by WEB intrasaccular flow disruption in select cases of atypical aneurysms with technically challenging morphology not typically treatable by WEB alone., Materials and Methods: A retrospective analysis of a prospectively-maintained dataset from three Australian neurovascular tertiary referral centers, identifying patients treated with the CUPCAKE technique between April 2018 and September 2023. Evaluation of patient and aneurysm characteristics, procedure parameters, complications, radiological and clinical outcomes at follow-up was performed., Results: The CUPCAKE technique was used for the treatment of 22 intracranial aneurysms of total 169 treated with WEB. Overall successful immediate flow stagnation was observed in 95.5% ( n  = 21) of aneurysms with no cases of perforation or intraoperative hemorrhage. Imaging confirmed thromboembolic complications occurred in two patients, one patient had persistent flow requiring re-treatment during initial admission. Follow-up imaging demonstrated 88.2% complete aneurysm conclusion with no delayed aneurysm expansion or rupture., Conclusion: Synergistic use of conventional coiling with WEB intrasaccular flow disruption presents a viable solution for technically difficult aneurysm treatment. In our series, 13% of all patients treated with WEB received CUPCAKE treatment, resulting in high technical success and no increase in thromboembolic complications with the union of two methods., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Efflux pumps are well known to be an important mechanism for removing noxious substances such as antibiotics from bacteria. Given that many antibiotics function by accumulating inside bacteria, efflux pumps contribute to resistance. Efflux pump inactivation is a potential strategy to combat antimicrobial resistance, as bacteria would not be able to pump out antibiotics. We recently discovered that the impact of loss of efflux function is only apparent in actively growing cells. We demonstrated that the global transcriptome of Salmonella Typhimurium is drastically altered during slower growth leading to stationary-phase cells having a remodeled, less permeable envelope that prevents antibiotics entering the cell. Here, we investigated the effects of deleting the major efflux pump of Salmonella Typhimurium, AcrB, on global gene transcription across growth. We revealed that an acrB knockout entered stationary phase later than the wild-type strain SL1344 and displayed increased and prolonged expression of genes responsible for anaerobic energy metabolism. We devised a model linking efflux and membrane potential, whereby deactivation of AcrB prevents influx of protons across the inner membrane and thereby hyperpolarization. Knockout or deactivation of AcrB was demonstrated to increase membrane potential. We propose that the global transcription regulator ArcBA senses changes to the redox state of the quinol pool (linked to the membrane potential of the bacterium) and coordinates the shift from exponential to stationary phase via the key master regulators RpoS, Rsd, and Rmf. Inactivation of efflux pumps therefore influences the fundamental physiology of Salmonella , with likely impacts on multiple phenotypes.IMPORTANCEWe demonstrate for the first time that deactivation of efflux pumps brings about changes to gross bacterial physiology and metabolism. Rather than simply being a response to noxious substances, efflux pumps appear to play a key role in maintenance of membrane potential and thereby energy metabolism. This discovery suggests that efflux pump inhibition or inactivation might have unforeseen positive consequences on antibiotic activity. Given that stationary-phase bacteria are more resistant to antibiotic uptake, late entry into stationary phase would prolong antibiotic accumulation by bacteria. Furthermore, membrane hyperpolarization could result in increased generation of reactive species proposed to be important for the activity of some antibiotics. Finally, changes in gross physiology could also explain the decreased virulence of efflux mutants., Competing Interests: The authors declare no conflict of interest.

Introduction: The purpose of this study is to evaluate the patient selection methods, treatment outcomes, complications, clinical and radiological follow-up after renal angiomyolipoma (AML) treatment with selective arterial embolization (SAE) in an Australian metropolitan tertiary centre., Methods: This study presents a retrospective single-centre review of patients' medical records who underwent SAE for renal AML during the period of 1st January 2012 and 1st January 2023., Results: A total of 32 SAE procedures for renal AML occurred during the study period. Three episodes were classified as emergency cases [9.38%] and the remaining 29 were treated electively. Mean AML size pre-treatment was 69.45 mm (range = 33-177; SD = 31.69). All AMLs demonstrated hyper-vascularity on contrast-enhanced cross-sectional imaging (arterial-phase enhancement characteristics and/or prominent tortuous feeding vessels) [n = 32; 100%] or an intralesional aneurysm or pseudoaneurysm [n = 12; 42.85%]. Periprocedural complications [n = 3; 9.38%] included: one intralesional haemorrhage after embolization, one vascular access site complication, and one lipiduria-associated urinary tract infection. No patients suffered a life-threatening complication, non-target embolization, deterioration in renal function or death following SAE. Re-treatment with SAE was performed in only three patients [10.71%]. Hospital mean length of stay was 1.58 days. Median durations of clinical and radiological follow-up post-treatment were 493 days (range = 104-1645) and 501 days (range = 35-1774), respectively. Follow-up imaging revealed AML total size reduction in all cases [mean = -17.17 mm; -26.51%] and 50% had obliteration of lesion hyper-vascularity after one episode of SAE. Outpatient clinical follow-up signifies that none of the patients included in the study have re-presented with lesion haemorrhage after successful SAE., Conclusion: In this study, renal AMLs were treated safely with a high degree of success by using SAE, and there were very low rates of periprocedural complications. Follow-up of patients after SAE treatment of renal AML should include both radiological (assessment for reduction in lesion vascularity and size) and clinical review in an outpatient clinic setting (either by an interventional radiologist or urologist)., (© 2024 Royal Australian and New Zealand College of Radiologists.)

Background: The Woven EndoBridge (WEB) is a device used for intrasaccular flow diversion, designed for the elimination of wide-necked bifurcation aneurysms from the circulation. In this study, we aim to assess the safety and efficacy of the WEB and its uses in treating aneurysms of different morphologies and locations., Methods: In a retrospective analysis, we compiled a comprehensive dataset from patients treated with the WEB device across three major Australian neurovascular centers from May 2017 to September 2023. The case series encompassed a spectrum of aneurysm types, including wide-necked bifurcation, sidewall, and irregularly shaped aneurysms, as well as cases previously managed with alternative therapeutic strategies. This study additionally encompasses cases where aneurysms were managed using the WEB device in combination with supplementary endovascular devices., Results: The study included 169 aneurysms in 161 patients. The rate of satisfactory aneurysm occlusion was 85.6%, with 86.7% of patients maintaining good functional status at their most recent follow-up. The procedure exhibited a low mortality rate of 0.6% and a thromboembolic complication rate of 7.1% (n = 12/161). There were no instances of postoperative re-rupture and the procedure-related hemorrhage rate was low (1.2%, n = 2/169), aligning with the literature regarding the safety and efficacy of the WEB device., Conclusions: Our multicenter trial reinforces the WEB device's role as an effective and safe modality for intracranial aneurysm management, supporting its expanded application beyond wide-necked bifurcation aneurysms. Further prospective studies are required to delineate its evolving role fully., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Escherichia coli is a facultative anaerobe found in a wide range of environments. Commonly described as the laboratory workhorse, E. coli is one of the best characterized bacterial species to date, however much of our understanding comes from studies involving the laboratory strain E. coli K-12. Resistance-nodulation-division efflux pumps are found in Gram-negative bacteria and can export a diverse range of substrates, including antibiotics. E. coli K-12 has six RND pumps; AcrB, AcrD, AcrF, CusA, MdtBC and MdtF, and it is frequently reported that all E. coli strains possess these six pumps. However, this is not true of E. coli ST11, a lineage of E. coli , which is primarily composed of the highly virulent important human pathogen, E. coli O157:H7. Here we show that acrF is absent from the pangenome of ST11 and that this lineage of E. coli has a highly conserved insertion within the acrF gene, which when translated encodes 13 amino acids and two stop codons. This insertion was found to be present in 97.59 % of 1787 ST11 genome assemblies. Non-function of AcrF in ST11 was confirmed in the laboratory as complementation with acrF from ST11 was unable to restore AcrF function in E. coli K-12 substr. MG1655 Δ acrB Δ acrF . This shows that the complement of RND efflux pumps present in laboratory bacterial strains may not reflect the situation in virulent strains of bacterial pathogens.

Introduction: Antimicrobial peptides (AMPs) play an important role in defending against the attack of pathogenic microorganisms. Among them, the proline-rich antibacterial peptides (PrAMPs) have been attracting close attention due to their simple structure, strong antibacterial activity, and low cell toxicity. OaBac5mini is an active fragment of the sheep-derived OaBac5 belonging to the PrAMPs family., Methods: In this study, the antibacterial activity of OaBac5mini was investigated by testing the MICs against different stains of E. coli and S. aureus as well as the time-kill curve. The bactericidal mechanism was explored by determining the effect of OaBac5mini on the cell membrane. The stability and biosafety were also evaluated., Results: The susceptibility test demonstrated that OaBac5mini showed potent antibacterial activity against the multidrug-resistant (MDR) E. coli isolates. It is noticeable that the absence of inner membrane protein SbmA in E. coli ATCC 25922 caused the MIC of OaBac5mini to increase 4-fold, implying OaBac5mini can enter into the cytoplasm via SbmA and plays its antibacterial activity. Moreover, the antibacterial activity of OaBac5mini against E. coli ATCC 25922 was not remarkably affected by the serum salts except for CaCl 2 at a physiological concentration, pH, temperature, repeated freeze-thawing and proteases (trypsin < 20 μg/mL, pepsin or proteinase K). Time-kill curve analysis showed OaBac5mini at the concentration of 200 μg/mL (8 × MICs) could effectively kill E. coli ATCC 25922 after co-incubation for 12 h. In addition, OaBac5mini was not hemolytic against rabbit red blood cells and also was not cytotoxic to porcine small intestinal epithelial cells (IPEC-J2). Bioinformatic analysis indicated that OaBac5mini is a linear peptide with 8 net positive charges. Furthermore, OaBac5mini significantly increased the outer membrane permeability and impaired the inner membrane integrity and ultrastructure of E. coli ATCC25922., Conclusion: OaBac5mini is a stable and potent PrAMP that kills E. coli by two different modes of action - inhibiting intracellular target(s) and damaging cell membrane., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shen, Sun, Ren, Blair, Siasat, Fan, Hu and He.)

Background: Resistance nodulation division (RND) family efflux pumps, including the major pump AcrAB-TolC, are important mediators of intrinsic and evolved antibiotic resistance. Expression of these pumps is carefully controlled by a network of regulators that respond to different environmental cues. EnvR is a TetR family transcriptional regulator encoded upstream of the RND efflux pump acrEF., Methods: Binding of EnvR protein upstream of acrAB was determined by electrophoretic mobility shift assays and the phenotypic consequence of envR overexpression on antimicrobial susceptibility, biofilm motility and invasion of eukaryotic cells in vitro was measured. Additionally, the global transcriptome of clinical Salmonella isolates overexpressing envR was determined by RNA-Seq., Results: EnvR bound to the promoter region upstream of the genes coding for the major efflux pump AcrAB in Salmonella, inhibiting transcription and preventing production of AcrAB protein. The phenotype conferred by overexpression of envR mimicked deletion of acrB as it conferred multidrug susceptibility, decreased motility and decreased invasion into intestinal cells in vitro. Importantly, we demonstrate the clinical relevance of this regulatory mechanism because RNA-Seq revealed that a drug-susceptible clinical isolate of Salmonella had low acrB expression even though expression of its major regulator RamA was very high; this was caused by very high EnvR expression., Conclusions: In summary, we show that EnvR is a potent repressor of acrAB transcription in Salmonella, and can override binding by RamA so preventing MDR to clinically useful drugs. Finding novel tools to increase EnvR expression may form the basis of a new way to prevent or treat MDR infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)