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Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1 , are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.

Researchers consistently report that children from low socioeconomic status (SES) families have, on average, smaller vocabularies as assessed by measures of existing vocabulary knowledge than children from higher SES families. Yet, few studies have examined the word-learning process of children from low SES families. The present study was an examination of fast mapping by preschoolers from low SES families. The study also examined the relation between measures of existing vocabulary and performance on the fast mapping task. Forty-six preschoolers (mean age: 4;6, range: 3;11-5;3) from low SES families completed a part-term fast mapping task and two measures of existing vocabulary knowledge. On the fast mapping task, children demonstrated the use of three sources of information (familiar whole objects, possessive syntax and whole-part juxtaposition). Measures of existing vocabulary did not correlate with performance on the fast mapping task. Findings suggest that children from low SES families use multiple sources of information in linguistic input to learn words.

Purpose: Educators rely on sufficient knowledge and skill to provide effective phonemic awareness instruction, an important component of early literacy instruction, particularly for children who experience difficulty learning to read. The purpose of this study was to evaluate and compare the phonemic awareness skill of several groups of educators, including speech-language pathologists (SLPs; n = 160), kindergarten teachers (n = 109), first-grade teachers (n = 112), reading teachers (n = 100), and special education teachers (n = 60)., Method: Participants completed a paper-pencil measure of phonemic awareness skill that included 3 tasks. The measure was designed to assess sophisticated explicit phonemic awareness skill within a print context, representing an advanced skill level that has been deemed critical to teaching., Results: SLPs demonstrated superior performance on the measure of phonemic awareness skill when compared to other educators (d = 1.54). The performance of reading and special education teachers was comparable to that of kindergarten and first-grade teachers. Orthographic knowledge had an adverse impact on the performance of all groups. However, SLPs were far more proficient than other educators at segmenting words that had a complex relationship between speech and print (e.g., box, use)., Clinical Implications: SLPs have relative expertise in phonemic awareness, yet their performance may not be proficient. Three recommendations are discussed: (a) Increase the phonemic awareness skill of all educators, (b) revise instructional materials to enhance educators' efforts to provide accurate and effective phonemic awareness instruction, and (c) include SLPs as members of the team responsible for phonemic awareness instruction and intervention.

The purpose of this article is to summarize the literacy outcomes for children with specific language impairment and to consider principles and approaches for literacy intervention with preschool and early school-age children with language impairments. Initially, specific language impairment is defined and differentiated from nonspecific language impairment. In addressing intervention considerations, we first consider the application of best practice principles and then specifically focus on intervention with preschool children and intervention with early school-age children. Consideration of evidence-based treatment approaches is guided by the developmental literature and by the intervention literature.