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Our studies have previously shown a role for persistent TSLP production in the lungs of mice after early-life respiratory syncytial virus (RSV) infection that leads to an altered immune phenotype, including accumulation of "inflammatory" dendritic cells (DC). This study investigates the role of TSLP driving systemic trained immunity in DC in early-life RSV-infected mice. Bone marrow-derived DCs (BMDC) from early-life RSV-infected mice at 4 wk postinfection showed enhanced expression of costimulatory molecules and cytokines, including Tslp, that regulate immune cell function. The adoptive transfer of BMDC grown from early-life RSV-infected mice was sufficient to exacerbate allergic disease development. The addition of recombinant TSLP during differentiation of BMDC from naive mice induced a similar altered phenotype as BMDC grown from early-life RSV-infected mice, suggesting a role for TSLP in the phenotypic changes. To assess the role of TSLP in these changes, global transcriptomic characterization of TSLPR-/- BMDC infected with RSV was performed and showed a higher upregulation of type 1 IFN genes and concomitant downregulation of inflammatory genes. Assay for transposase-accessible chromatin using sequencing analysis demonstrated that TSLPR-/- BMDC had a parallel gain in physical chromatin accessibility near type 1 genes and loss in accessibility near genes related to RSV pathology, with IFN regulatory factor 4 (IRF4) and STAT3 predicted as top transcription factors binding within differentially accessible regions in wild-type. Importantly, these studies show that in the absence of TSLP signaling, BMDC are able to mount an appropriate type 1 IFN-associated antiviral response to RSV. In summary, RSV-induced TSLP alters chromatin structure in DC to drive trained innate immunity and activates pathogenic gene programs in mice.Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are associated with poor survival outcomes in many human cancers. MDSCs inhibit T cell-mediated tumor immunity in part because they strongly inhibit T-cell function. However, whether MDSCs inhibit early or later steps of T-cell activation is not well established. Here we show that MDSCs inhibited proliferation and induced apoptosis of CD8+ T cells even in the presence of dendritic cells (DC) presenting a high-affinity cognate peptide. Vismodegib cell line This inhibitory effect was also observed with delayed addition of MDSCs to cocultures, consistent with functional data showing that T cells expressed multiple early activation markers even in the presence of MDSCs. Single-cell RNA-sequencing analysis of CD8+ T cells demonstrated a p53 transcriptional signature in CD8+ T cells cocultured with MDSCs and DCs. Confocal microscopy showed induction of DNA damage and nuclear accumulation of activated p53 protein in a substantial fraction of these T cells. DNA damage in T cells was dependent on the iNOS enzyme and subsequent nitric oxide release by MDSCs. Small molecule-mediated inhibition of iNOS or inactivation of the Nos2 gene in MDSCs markedly diminished DNA damage in CD8+ T cells. DNA damage in CD8+ T cells was also observed in KPC pancreatic tumors but was reduced in tumors implanted into Nos2-deficient mice compared with wild-type mice. These data demonstrate that MDSCs do not block early steps of T-cell activation but rather induce DNA damage and p53 pathway activation in CD8+ T cells through an iNOS-dependent pathway.

To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea.

Cohort study.

A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019.

441 399 girls aged 11-14 years who had been vaccinated in 2017 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV.

Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV ying follow-up periods and for vaccine subtypes.

In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

Acute pain after surgery is one of the most frequent indications for opioid prescribing in children. Opioids are often not stored or disposed of safely after their use, placing children and others in the home at risk for accidental ingestion or intentional misuse. We currently lack evidence-based guidelines for post-operative pain management after common ambulatory pediatric urologic procedures. Thus, each surgeon must decide if and how much opioid to prescribe based on his/her own assumptions of perceived post-operative pain.

As part of an effort to establish opioid prescribing guidelines across two academic centers, the objectives of this study were to evaluate current variability in pediatric urologists' opioid prescribing factors and identify patients at greatest risk of being prescribed high doses of opioids after common ambulatory pediatric urologic procedures.

We retrospectively evaluated post-operative opioid prescribing patterns after common ambulatory pediatric urology procedures (circumcision, orchiopexy, and hernia/hydrocele) at two major children's hospitals.