A Small-Molecule Inhibitor of trans-Translation Synergistically Interacts with Cathelicidin Antimicrobial Peptides To Impair Survival of Staphylococcus aureus.

Staphylococcus aureus is a leading cause of infection in the United States, and due to the rapid development of resistance, new antibiotics are constantly needed. trans-Translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical for bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small-molecule inhibitor of trans-translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of S. aureus KKL-40 is also effective against Gram-positive pathogens, including a vancomycin-resistant strain of Enterococcus faecalis, Bacillus subtilis, and Streptococcus pyogenes, although its performance with Gram-negative pathogens is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit S. aureus but not other antibiotics tested, including daptomycin, kanamycin, or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold higher than the effective MIC. We also find that S. aureus develops minimal resistance to KKL-40 even after multiday passage at sublethal concentrations. Therefore, trans-translation inhibitors could be a particularly promising drug target against S. aureus, not only because of their ability to inhibit bacterial growth but also because of their potential to simultaneously render S. aureus more susceptible to host antimicrobial peptides.

Female Victims of Firearm Intimate Partner Violence: Characterization and Lethality Predictors.

Objective: To characterize the sociological risk factors for firearm intimate partner violence (IPV) among women in Texas, with a focus on lethal predictors to aid in screening and intervention guidelines. Methods: A retrospective medical and forensic chart review was conducted and supplemented by news sources, public police reports, and court records on firearm cases in Houston, TX, from 2018 to 2020. IPV was defined as a cis-gendered female victim of firearm violence from a current or ex-intimate partner. Non-IPV was defined as cis-gendered female victims of firearm violence from strangers, friends/acquaintances, gang, client, or similar relationships. Numeric variables were compared using the Wilcoxon rank-sum test and reported as median [Q1, Q3]. Categorical variables were compared using Fisher's exact test and reported as count (%). Results: A total of 102 cases of IPV were identified. Nonspousal IPV was more prevalent than spousal (65.7% versus 34.3%). Lethal injuries, older age, home location, and head injuries were more prevalent in the IPV cohort. Older age, spousal perpetrator, home shooting location, and history of prior domestic abuse were associated with lethal IPV. There were 31 cases of murder-suicide. During the COVID-19 pandemic, IPV cases increased by 91.3%, with lethal cases increasing by 57.6%. Conclusion: Risk factors for overall IPV and lethal IPV are not the same; therefore, it is imperative that all women, irrespective of race, age, or relationship status, be screened for IPV and prior domestic violence to allow intervention and prevention of lethal IPV. Patients should also be screened for personal or partner access to firearms as firearm IPV is a highly lethal form of violence.

"I'd rather see action": Application and recruitment experiences of underrepresented in emergency medicine trainees.

Objectives: The emergency medicine (EM) physician workforce is largely composed of white men. Despite recruitment efforts over the past decade, there has not been a significant increase of trainees with underrepresented racial and ethnic identities in EM (URM). Prior studies have focused on institutional strategies to improve diversity, equity, and inclusion (DEI) in EM residency recruitment but have been limited in describing URM trainees' perspectives. We sought to assess URM trainees' perspectives on DEI in the EM residency application and selection process. Methods: This study was conducted at an urban academic medical center in the United States from November 2021 to March 2022. Junior residents were invited to participate in individual semistructured interviews. We used a combined deductive-inductive approach to categorize responses in predetermined areas of interest then elicit dominant themes within each category through consensus discussions. Thematic saturation was reached after eight interviews, indicating adequate sample size. Results: Ten residents participated in semistructured interviews. All identified as racial or ethnic minorities. Three dominant themes emerged relating to authenticity, representation, and being treated as a learner first. Participants assessed the authenticity of a program's DEI efforts by evaluating the time frame and scope of DEI efforts. Participants reported a desire for representation of other URM colleagues in a residency program and training environment. While participants wanted their lived experience as URM trainees acknowledged, they were wary of being viewed solely through the lens of future DEI leaders rather than as learners first. Conclusions: URM residents value multifaceted commitment to DEI efforts, representation, and being seen as learners first when assessing residency programs. Programs seeking to recruit URM residents should develop a department-wide, multipronged, comprehensive DEI plan and showcase how their program will contribute to an applicant's professional development.

Case report: Spindle cell neoplasm presenting as a spontaneous intestinal perforation in a term infant.

Spontaneous intestinal perforations in the neonatal population are mostly associated with low birth weight, prematurity, and necrotizing enterocolitis. Spontaneous intestinal perforation in the absence of these risk factors is extremely rare and should raise clinical concern for an underlying bowel pathology. Here we present a unique case of a normal-weight, full-term girl with spontaneous intestinal perforation due to a spindle cell neoplasm with a novel BRAF mutation and infantile fibrosarcoma-like morphology. Though rare, malignancy should be considered in the differential diagnosis for bowel perforation in an otherwise healthy, term infant as complete surgical excision can be curative.

CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT.

Type 3 Secretion System (T3SS) is a highly conserved virulence structure that plays an essential role in the pathogenesis of many Gram-negative pathogenic bacteria, including Pseudomonas aeruginosa. Exotoxin T (ExoT) is the only T3SS effector protein that is expressed in all T3SS-expressing P. aeruginosa strains. Here we show that T3SS recognition leads to a rapid phosphorylation cascade involving Abl / PKCδ / NLRC4, which results in NLRC4 inflammasome activation, culminating in inflammatory responses that limit P. aeruginosa infection in wounds. We further show that ExoT functions as the main anti-inflammatory agent for P. aeruginosa in that it blocks the phosphorylation cascade through Abl / PKCδ / NLRC4 by targeting CrkII, which we further demonstrate to be important for Abl transactivation and NLRC4 inflammasome activation in response to T3SS and P. aeruginosa infection.

Total synthesis of (+)-spiroindimicin A and congeners unveils their antiparasitic activity.

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3'/C-5''-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key Pd-catalyzed asymmetric spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.