Pharmacokinetic/Pharmacodynamic Correlation of Cefquinome Against Experimental Catheter-Associated Biofilm Infection Due to Staphylococcus aureus.

Biofilm formations play an important role in Staphylococcus aureus pathogenesis and contribute to antibiotic treatment failures in biofilm-associated infections. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of cefquinome against an experimental catheter-related biofilm model due to S. aureus, including three clinical isolates and one non-clinical isolate. The minimal inhibitory concentration (MIC), minimal biofilm inhibitory concentration (MBIC), biofilm bactericidal concentration (BBC), minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) and in vitro time-kill curves of cefquinome were studied in both planktonic and biofilm cells of study S. aureus strains. The in vivo post-antibiotic effects (PAEs), PK profiles and efficacy of cefquinome were performed in the catheter-related biofilm infection model in murine. A sigmoid E max model was utilized to determine the PK/PD index that best described the dose-response profiles in the model. The MICs and MBICs of cefquinome for the four S. aureus strains were 0.5 and 16 μg/mL, respectively. The BBCs (32-64 μg/mL) and MBECs (64-256 μg/mL) of these study strains were much higher than their corresponding BPC values (1-2 μg/mL). Cefquinome showed time-dependent killing both on planktonic and biofilm cells, but produced much shorter PAEs in biofilm infections. The best-correlated PK/PD parameters of cefquinome for planktonic and biofilm cells were the duration of time that the free drug level exceeded the MIC (fT > MIC, R (2) = 96.2%) and the MBIC (fT > MBIC, R (2) = 94.7%), respectively. In addition, the AUC24h/MBIC of cefquinome also significantly correlated with the anti-biofilm outcome in this model (R (2) = 93.1%). The values of AUC24h/MBIC for biofilm-static and 1-log10-unit biofilm-cidal activity were 22.8 and 35.6 h; respectively. These results indicate that the PK/PD profiles of cefquinome could be used as valuable guidance for effective dosing regimens treating S. aureus biofilm-related infections

Linezolid and Rifampicin Combination to Combat cfr-Positive Multidrug-Resistant MRSA in Murine Models of Bacteremia and Skin and Skin Structure Infection.

Linezolid resistance mediated by the cfr gene in MRSA represents a global concern. We investigated relevant phenotype differences between cfr-positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group, cfr-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (P < 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in cfr-positive vs. -negative MRSA. In vitro phenotypes of cfr-positive MRSA translated into poor outcomes of linezolid monotherapy in vivo in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC50 of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against cfr-positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by cfr-positive multidrug resistant MRSA

BEV-Locator: An End-to-end Visual Semantic Localization Network Using Multi-View Images

Accurate localization ability is fundamental in autonomous driving. Traditional visual localization frameworks approach the semantic map-matching problem with geometric models, which rely on complex parameter tuning and thus hinder large-scale deployment. In this paper, we propose BEV-Locator: an end-to-end visual semantic localization neural network using multi-view camera images. Specifically, a visual BEV (Birds-Eye-View) encoder extracts and flattens the multi-view images into BEV space. While the semantic map features are structurally embedded as map queries sequence. Then a cross-model transformer associates the BEV features and semantic map queries. The localization information of ego-car is recursively queried out by cross-attention modules. Finally, the ego pose can be inferred by decoding the transformer outputs. We evaluate the proposed method in large-scale nuScenes and Qcraft datasets. The experimental results show that the BEV-locator is capable to estimate the vehicle poses under versatile scenarios, which effectively associates the cross-model information from multi-view images and global semantic maps. The experiments report satisfactory accuracy with mean absolute errors of 0.052m, 0.135m and 0.251$^\circ$ in lateral, longitudinal translation and heading angle degree

Dyonic Born-Infeld black hole in four-dimensional Horndeski gravity

The action of four-dimensional Horndeski gravity coupled to Born-Infeld electromagnetic fields is given via the Kaluza-Klein process. Dyonic black hole solution of the theory is constructed. The metric is devoid of singularity at the origin independent of the parameter selections, this property is different from the one of Einstein-Born-Infeld black holes. Thermodynamics of the black hole is studied, thermodynamic quantities are calculated and the first law is checked to be satisfied. Thermodynamic phase transitions of the black holes are studied in extended phase space.Comment: 13 pages, 2 figures. Phys.Lett.B 819 (2021) 13642

High-fidelity quantitative differential phase contrast deconvolution using dark-field sparse prior

Differential phase contrast (DPC) imaging plays an important role in the family of quantitative phase measurement. However, the reconstruction algorithm for quantitative DPC (qDPC) imaging is not yet optimized, as it does not incorporate the inborn properties of qDPC imaging. In this research, we propose a simple but effective image prior, the dark-field sparse prior (DSP), to facilitate the phase reconstruction quality for all DPC-based phase reconstruction algorithms. The DSP is based on the key observation that most pixel values for an idea differential phase contrast image are zeros since the subtraction of two images under anti-symmetric illumination cancels all background components. With this DSP prior, we formed a new cost function in which L0-norm was used to represent the DSP. Further, we developed the algorithm based on the Half Quadratic Splitting to solve this NP-hard L0-norm problem. We tested our new model on both simulated and experimental data and compare it against state-of-The-Art (SOTA) methods including L2-norm and total variation regularizations. Results show that our proposed model is superior in terms of phase reconstruction quality and implementation efficiency, which significantly increases the experimental robustness, while maintaining the data fidelity. In general, the DSP supports high-fidelity qDPC reconstruction without any modification of the optical system, which simplifies the system complexity and benefit all qDPC applications

TASA: Deceiving Question Answering Models by Twin Answer Sentences Attack

We present Twin Answer Sentences Attack (TASA), an adversarial attack method for question answering (QA) models that produces fluent and grammatical adversarial contexts while maintaining gold answers. Despite phenomenal progress on general adversarial attacks, few works have investigated the vulnerability and attack specifically for QA models. In this work, we first explore the biases in the existing models and discover that they mainly rely on keyword matching between the question and context, and ignore the relevant contextual relations for answer prediction. Based on two biases above, TASA attacks the target model in two folds: (1) lowering the model's confidence on the gold answer with a perturbed answer sentence; (2) misguiding the model towards a wrong answer with a distracting answer sentence. Equipped with designed beam search and filtering methods, TASA can generate more effective attacks than existing textual attack methods while sustaining the quality of contexts, in extensive experiments on five QA datasets and human evaluations.Comment: Accepted by EMNLP 2022 (long), 9 pages main + 2 pages references + 7 pages appendi

Colchicine protects against acute pancreatitis via downregulation of cytokine levels

Purpose: To investigate the effect of colchicine on acute pancreatitis (AP) in a rat model, and the molecular mechanism involved. Methods: Acute pancreatitis (AP) was induced in rats by injection with 5 % sodium taurocholate. Changes in histology of pancreatic tissues were determined following treatment with colchicine. Serum amylase activity was measured using Automated Biochemistry Analyser. Results: Hematoxylin and eosin (H & E) staining showed that colchicine prevented histopathological changes such as infiltration of interstitial leukocytes and erythrocytes, cell necrosis, oedema formation and vacuolization in the rat pancreas. Treatment of AP rats with colchicine significantly and dosedependently decreased ascite volume in the abdominal cavity. Serum amylase activity was significantly suppressed in AP rats on treatment with 100 mg/kg colchicine. Furthermore, treatment of the AP rats with colchicine caused marked decrease in the expressions of interleukin 6 and tumor necrosis factor α, and upregulated expressions of IL 10 in serum. Colchicine treatment of AP rats also caused significant increase in CGRP level in the plasma. Conclusion: Colchicine prevents pancreatic tissue damage induced by AP by down-regulating proinflammatory cytokines, upregulation of anti-inflammatory cytokines, and enhancing CGRP release. Therefore, colchicine may be useful for the treatment of acute pancreatitis