Association of inappropriate outpatient pediatric antibiotic prescriptions with adverse drug events and health care expenditures

Importance: Nonguideline antibiotic prescribing for the treatment of pediatric infections is common, but the consequences of inappropriate antibiotics are not well described. Objective: To evaluate the comparative safety and health care expenditures of inappropriate vs appropriate oral antibiotic prescriptions for common outpatient pediatric infections. Design, Setting, and Participants: This cohort study included children aged 6 months to 17 years diagnosed with a bacterial infection (suppurative otitis media [OM], pharyngitis, sinusitis) or viral infection (influenza, viral upper respiratory infection [URI], bronchiolitis, bronchitis, nonsuppurative OM) as an outpatient from April 1, 2016, to September 30, 2018, in the IBM MarketScan Commercial Database. Data were analyzed from August to November 2021. Exposures: Inappropriate (ie, non-guideline-recommended) vs appropriate (ie, guideline-recommended) oral antibiotic agents dispensed from an outpatient pharmacy on the date of infection. Main Outcomes and Measures: Propensity score-weighted Cox proportional hazards models were used to estimate hazards ratios (HRs) and 95% CIs for the association between inappropriate antibiotic prescriptions and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable health care expenditures by infection type. National-level annual attributable expenditures were calculated by scaling attributable expenditures in the study cohort to the national employer-sponsored insurance population. Results: The cohort included 2 804 245 eligible children (52% male; median [IQR] age, 8 [4-12] years). Overall, 31% to 36% received inappropriate antibiotics for bacterial infections and 4% to 70% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and severe allergic reaction among children treated with a nonrecommended antibiotic agent for a bacterial infection (among patients with suppurative OM, C. difficile infection: HR, 6.23; 95% CI, 2.24-17.32; allergic reaction: HR, 4.14; 95% CI, 2.48-6.92). Thirty-day attributable health care expenditures were generally higher among children who received inappropriate antibiotics, ranging from $21 to$56 for bacterial infections and from -$96 to$97 for viral infections. National annual attributable expenditure estimates were highest for suppurative OM ($25.3 million), pharyngitis ($21.3 million), and viral URI ($19.1 million). Conclusions and Relevance: In this cohort study of children with common infections treated in an outpatient setting, inappropriate antibiotic prescriptions were common and associated with increased risks of adverse drug events and higher attributable health care expenditures. These findings highlight the individual- and national-level consequences of inappropriate antibiotic prescribing and further support implementation of outpatient antibiotic stewardship programs

A Liposome-Based Mycobacterial Vaccine Induces Potent Adult and Neonatal Multifunctional T Cells through the Exquisite Targeting of Dendritic Cells

BACKGROUND: In the search for more potent and safer tuberculosis vaccines, CAF01 was identified as a remarkable formulation. Based on cationic liposomes and including a synthetic mycobacterial glycolipid as TLR-independent immunomodulator, it induces strong and protective T helper-1 and T helper-17 adult murine responses to Ag85B-ESAT-6, a major mycobacterial fusion protein. Here, we assessed whether these properties extend to early life and how CAF01 mediates its adjuvant properties in vivo. METHODS/FINDINGS: Following adult or neonatal murine immunization, Ag85B-ESAT-6/CAF01 similarly reduced the post-challenge bacterial growth of M. bovis BCG, whereas no protection was observed using Alum as control. This protection was mediated by the induction of similarly strong Th1 and Th17 responses in both age groups. Multifunctional Th1 cells were already elicited after a single vaccine dose and persisted at high levels for at least 6 months even after neonatal priming. Unexpectedly, this potent adjuvanticity was not mediated by a massive targeting/activation of dendritic cells: in contrast, very few DCs in the draining lymph nodes were bearing the labeled antigen/adjuvant. The increased expression of the CD40 and CD86 activation markers was restricted to the minute portion of adjuvant-bearing DCs. However, vaccine-associated activated DCs were recovered several days after immunization. CONCLUSION: The potent adult and neonatal adjuvanticity of CAF01 is associated in vivo with an exquisite but prolonged DC uptake and activation, fulfilling the preclinical requirements for novel tuberculosis vaccines to be used in early life

Phenotypic Expression of ADAMTS13 in Glomerular Endothelial Cells

Background: ADAMTS13 is the physiological von Willebrand factor (VWF)-cleaving protease. The aim of this study was to examine ADAMTS13 expression in kidneys from ADAMTS13 wild-type (Adamts13+/+) and deficient (Adamts13-/-) mice and to investigate the expression pattern and bioactivity in human glomerular endothelial cells. Methodology/Principal Findings: Immunohistochemistry was performed on kidney sections from ADAMTS13 wild-type and ADAMTS13-deficient mice. Phenotypic differences were examined by ultramorphology. ADAMTS13 expression in human glomerular endothelial cells and dermal microvascular endothelial cells was investigated by real-time PCR, flow cytometry, immunofluorescence and immunoblotting. VWF cleavage was demonstrated by multimer structure analysis and immunoblotting. ADAMTS13 was demonstrated in glomerular endothelial cells in Adamts13+/+ mice but no staining was visible in tissue from Adamts13-/- mice. Thickening of glomerular capillaries with platelet deposition on the vessel wall was detected in Adamts13-/- mice. ADAMTS13 mRNA and protein were detected in both human endothelial cells and the protease was secreted. ADAMTS13 activity was demonstrated in glomerular endothelial cells as cleavage of VWF. Conclusions/Significance: Glomerular endothelial cells express and secrete ADAMTS13. The proteolytic activity could have a protective effect preventing deposition of platelets along capillary lumina under the conditions of high shear stress present in glomerular capillaries. © 2011 Tati et al.published_or_final_versio

DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%–80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4+ and CD8+ cells using Illumina's HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4+ cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease

Genome editing in food and feed production – implications for risk assessment. Scientific Opinion of the Scientific Steering Committee of the Norwegian Scientific Committee for Food and Environment

The Norwegian Scientific Committee for Food and Environment (VKM) initiated this work to examine the extent to which organisms developed by genome-editing technologies pose new challenges in terms of risk assessment. This report considers whether the risk assessment guidance on genetically modified organisms, developed by the European Food Safety Authority (EFSA), can be applied to evaluate potential risks of organisms developed by genome editing. Background Gene technology has allowed for the transfer of genes between organisms and species, and thereby to design altered genotypes with novel traits, i.e. GMOs. A new paradigm started in the early 2000s with the development of genome-editing techniques. Unlike traditional genetic modification techniques resulting in insertion of foreign DNA fragments at random locations in the genome, the new genome-editing techniques additionally open for a few single nucleotide edits or short insertions/deletions at a targeted site in an organism’s genome. These new techniques can be applied to most types of organisms, including plants, animals and microorganisms of commercial interest. An important question is how the novel, genome-edited organisms should be evaluated with respect to risks to health and the environment. The European Court of Justice decided in 2018 to include genome-edited organisms in the GMO definition and hence in the regulatory system already in place. This implies that all products developed by genome-editing techniques must be risk-assessed within the existing regulatory framework for GMOs. The European and Norwegian regulatory frameworks regulate the production, import and placing on the market of food and feed containing, consisting of or produced from GMOs, as well as the release of GMOs into the environment. The assessment draws on guidance documents originally developed by EFSA for risk assessment of GMOs, which were drawn up mainly to address risks regarding insertion of transgenes. The new genome-editing techniques, however, provide a new continuum of organisms ranging from those only containing a minor genetic alteration to organisms containing insertion or deletion of larger genomic regions. Risk assessment of organisms developed by genome editing The present discourse on how new genome-editing techniques should be regulated lacks an analysis of whether risk assessment methodologies for GMOs are adequate for risk assessment of organisms developed through the use of the new genome-editing techniques. Therefore, this report describes the use of genome-editing techniques in food and feed production and discusses challenges in risk assessment with the regulatory framework. Specifically, this report poses the question as to whether the EFSA guidance documents are sufficient for evaluating risks to health and environment posed by genome-edited plants, animals and microorganisms. To address these questions, the report makes use of case examples relevant for Norway. These examples, intended for food and feed, include oilseed rape with a modified fatty acid profile, herbicide-tolerant and pest-resistant crops, sterile salmon, virus-resistant pigs and hornless cattle. The report considers all aspects of the stepwise approach as described in the EFSA guidance documents. Conclusions The inherent flexibility of the EFSA guidance makes it suitable to cover health and environmental risk assessments of a wide range of organisms with various traits and intended uses. Combined with the embedded case-by-case approach the guidance is applicable to genome-edited organisms. The evaluation of the guidance demonstrates that the parts of the health and environmental risk assessment concerned with novel traits (i.e. the phenotype of the organism) may be fully applied to all categories of genome-edited organisms. ............publishedVersio