The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

Neonatal PMN (polymorphonuclear neutrophils) exhibit altered inflammatory responsiveness and greater longevity compared with adult PMN; however, the involved mechanisms are incompletely defined. Receptors containing immunoreceptor tyrosine-based inhibitory motif (ITIM) domains promote apoptosis by activating inhibitory phosphatases, such as Src homology domain 2-containing tyrosine phosphatase-1 (SHP-1), that block survival signals. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9, an immune inhibitory receptor with an ITIM domain, has been shown to induce cell death in adult PMN in association with SHP-1. To test our hypothesis that neonatal PMN inflammatory function may be modulated by unique Siglec-9 and SHP-1 interactions, we compared expression of these proteins in adult and neonatal PMN. Neonatal PMN exhibited diminished cellular expression of Siglec-9, which was phosphorylated in the basal state. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment decreased Siglec-9 phosphorylation levels in neonatal PMN but promoted its phosphorylation in adult PMN, observations associated with altered survival signaling. Although SHP-1 expression was also diminished in neonatal PMN, GM-CSF treatment had minimal effect on phosphorylation status. Further analysis revealed that Siglec-9 and SHP-1 physically interact, as has been observed in other immune cells. Our data suggest that age-specific interactions between Siglec-9 and SHP-1 may influence the altered inflammatory responsiveness and longevity of neonatal PMN. invasion and contribute to the clearance of pathogens. During resolution of the inflammatory process, neutrophils undergo apoptosis and are removed through ingestion by resident macrophages (1,2). However, a delay in the clearance of activated neutrophils promotes their persistence in tissues, a contributing factor in the pathogenesis of a variety of chronic inflammatory conditions (3). We reported a prolonged survival of neonatal neutrophils with enhanced inflammatory and cytotoxic activity (4,5). Altered inflammatory responses and delayed apoptosis may contribute to a variety of chronic inflammatory disorders in neonates, including bronchopulmonary dysplasia (6 -8). Understanding the mechanisms modulating neonatal neutrophil responses to inflammation is therefore paramount in designing targeted therapeutic approaches.Neonatal neutrophils have an intrinsic resistance to spontaneous and Fas-mediated apoptosis associated with decreased expression of proapoptotic proteins (4,9,10); however, the underlying mechanisms remain unclear. Compromise of this neutrophil function in neonates suggests a dysregulation of mechanisms important to inflammation and its resolution. Normally, the initiation and termination of inflammatory processes are tightly regulated through a combination of activating and inhibitory signals (11). An imbalance in this regulation could result in prolongation of processes that induce tissue damage and neutrophil reactivation, setting the stage for chronic infla...

Objectives:The number of psychiatric encounters is steadily increasing across all pediatric emergency departments. Based on this growing national crisis, we hypothesized there is a lack of robust education in behavioral/mental health emergencies during pediatric emergency medicine (PEM) fellowship.Methods: This was a cross-sectional survey of PEM fellowship directors.

ObjectivesThe frequency of lumbar punctures (LPs) has declined across US children's hospitals over the past decade, potentially decreasing procedural learning opportunities for pediatric resident trainees. Our study sought to determine whether the proportion of successful LPs performed by our pediatric residents has significantly changed over time.MethodsThis study is a single-center retrospective study to evaluate our pediatric resident LP success. We evaluated our primary outcome, proportion of overall LP success over time, using linear regression. We similarly used linear regression for proportion of successful resident-associated LPs over time. We calculated the median number of LPs of all pediatric residents during the study period.ResultsWe analyzed 3143 LPs from April 2012 to December 2019. Both the overall number of LPs performed and the proportion of LPs that were successful have not significantly changed over an 8-year period (P > 0.05, P > 0.05). Similarly, the number of our resident-associated LPs and the proportion of successful resident-associated LPs have not changed over the study period (P > 0.05, P > 0.05). Our pediatric residents performed a median of 3 LPs (interquartile range: 2–4) in the pediatric emergency department (PED) over residency.ConclusionsDespite national trends showing decreased LP rates at pediatric hospitals, we demonstrated stable proportions of LPs and success by our pediatric residents. Pediatric residents perform a relatively low number of LPs in the PED setting alone. Future research is needed to demonstrate whether these overall low numbers in the PED translate to procedural competency after residency graduation.

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