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Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.

The recommended therapeutic target for vancomycin for serious methicillin‐resistant S. aureus infections is an area under the concentration–time curve (AUC) over 24 h to a minimum inhibitory concentration (MIC) ratio of ≥ 400. Its applicability to coagulase‐negative staphylococcal (CoNS) bloodstream infections is unclear. Our review aims to determine the pharmacodynamic target of vancomycin for CoNS bloodstream infections. In January 2025, MEDLINE, Embase, and PubMed were searched to identify manuscripts reporting the relationship between vancomycin drug exposure (AUC) and bactericidal activity or clinical response for CoNS. Studies of alternative drug delivery systems/formulations, combination therapy, prophylaxis, other infections, and static in vitro studies were excluded. Overall, six articles were included. One in vivo study in young infants found that an AUC0‐24 ≥ 300 mg/L·h and AUC24 ≥ 424 mg/L·h were associated with a 7.8‐fold and 7.3‐fold increased likelihood of bacteriological cure, respectively. Two studies in adults showed that an AUC24/MIC ratio ≥ 373 resulted in improved treatment success and microbiological eradication. An in vitro model demonstrated that a vancomycin AUC24/MIC ratio ≥ 665 achieved maximal bacterial killing, while a rabbit model linked an AUC24/MIC ≥ 520 to an 80% reduction in C‐reactive protein. Early treatment within 24 h was associated with the greatest chance of bacteriological cure. Two studies of biofilm‐embedded CoNS demonstrated inadequate bacterial killing at AUC24/MIC ratios of 260 and 354. Overall, or CoNS bloodstream infections, an AUC24 ≥ 424 mg/L·h (median MIC 1 mg/L) or AUC24/MIC ≥ 373 improves clinical outcomes. This review highlights the need for early effective vancomycin treatment. Alternative antibiotic therapy should be considered for biofilm‐embedded CoNS infections. PRISMA flow chart for literature search.

The pediatric population receives the majority of vaccines globally, yet there is a paucity of studies on the transcriptional response induced by immunization in this special population. In this study, we performed a systems-level analysis of immune responses to the trivalent inactivated influenza vaccine adjuvanted with MF-59 in children (15–24 months old) and in young, healthy adults. We analyzed transcriptional responses elicited by vaccination in peripheral blood, as well as cellular and antibody responses following primary and booster vaccinations. Our analysis revealed that primary vaccination induced a persistent transcriptional signature of innate immunity; booster vaccination induced a transcriptional signature of an enhanced memory-like innate response, which was consistent with enhanced activation of myeloid cells assessed by flow cytometry. Furthermore, we identified a transcriptional signature of type 1 interferon response post-booster vaccination and at baseline that was correlated with the local reactogenicity to vaccination and defined an early signature that correlated with the hemagglutinin antibody titers. These results highlight an adaptive behavior of the innate immune system in evoking a memory-like response to secondary vaccination and define molecular correlates of reactogenicity and immunogenicity in infants.

ObjectiveBeta-lactam antibiotic allergies are reported in 5%–10% of children; however, up to 90% do not have any reaction at oral challenge test (OCT). This study aimed to determine the frequency and identify predictors of positive in-hospital graded beta-lactam OCTs in children with a beta-lactam antibiotic allergy label (AAL).DesignThis is a retrospective study conducted over 7 years, including children aged 0–19 years who underwent a beta-lactam OCT. The OCT comprised an in-hospital graded challenge followed by a 5-day outpatient antibiotic course. Univariate and multivariate logistic regression analyses were performed to identify predictors of a positive in-hospital graded OCT.ResultsOverall, 1259 beta-lactam OCTs were included: median age at time of OCT was 6.3 years (range 8.8 months to 19.2 years). Of these, 18 (1.4%) in-hospital graded OCTs were positive and 10 (0.8%) were equivocal, with only 4 children (0.3%) having an immediate, severe reaction to their in-hospital graded OCT. Factors associated with a positive in-hospital graded OCT on univariate analysis were: history of other drug allergy (OR 2.7, 95% CI 1.0 to 7.2; p 0.05), an index reaction which was severe (OR 2.9, 95% CI 1.1 to 7.6; p 0.035), immediate and severe (OR 5.85, 95% CI 1.7 to 20.0; p 0.005) or that required epinephrine (OR 9.65, 95% CI 1.7 to 53.6; p 0.01).ConclusionOf the children referred with a beta-lactam AAL, only 1.4% had a positive in-hospital graded OCT. Risk factors for a positive in-hospital graded OCT were history of other drug allergy, an index reaction which was severe, immediate and severe or required epinephrine.

I'm a black female, married with two kids. I'm writing regarding the March 27 article \"Monroeville, Mt. Lebanon Are Entering Fray Over Public Housing.\" I am completely overwhelmed by a decision to incorporate public housing families into Pittsburgh's suburban communities.

A workshop entitled “Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate” (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF, (c) discuss opportunities for pharmacological mitigation, intervention and modulation of specific molecular pathways, (d) consider the design of optimal clinical trials for mitigation and treatment and (e) outline key regulatory nonprescriptive frameworks for approval.

Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.

The koala, the only extant species of the marsupial family Phascolarctidae, is classified as ‘vulnerable’ due to habitat loss and widespread disease. We sequenced the koala genome, producing a complete and contiguous marsupial reference genome, including centromeres. We reveal that the koala’s ability to detoxify eucalypt foliage may be due to expansions within a cytochrome P450 gene family, and its ability to smell, taste and moderate ingestion of plant secondary metabolites may be due to expansions in the vomeronasal and taste receptors. We characterized novel lactation proteins that protect young in the pouch and annotated immune genes important for response to chlamydial disease. Historical demography showed a substantial population crash coincident with the decline of Australian megafauna, while contemporary populations had biogeographic boundaries and increased inbreeding in populations affected by historic translocations. We identified genetically diverse populations that require habitat corridors and instituting of translocation programs to aid the koala’s survival in the wild. The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

BackgroundEosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive.DesignPrompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. ConclusionMitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.