Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Implementing a Clinical Decision Support Tool to Increase Early Peanut Introduction Guidance.

BACKGROUND: General pediatric providers are the frontline for early peanut introduction discussions, but many feel ill-equipped to handle such discussions as guidelines have quickly changed. OBJECTIVE: We hypothesized that a clinical decision support (CDS) tool could improve peanut introduction discussions. METHODS: CDS tools were designed by stakeholders, improved through usability testing, and integrated into the current note templates. Based on queries of electronic health record (EHR), we did a pre-post performance evaluation of peanut introduction conversations, barriers for introduction, and percentage of 12-month WCC visits that had successfully introduced peanut. Providers completed surveys before and after intervention to assess awareness of early peanut introduction and comfort using CDS. RESULTS: Providers' awareness of early peanut introduction guidelines increased from 17.8% to 66.7% after the CDS tool was implemented. 79.1% were comfortable using the tool. The CDS tool improved peanut introduction conversations at the 4-month well-child (WCC) care visit from 2.4% to 81.2%, at the 6-month WCC visit from 3.0% to 84.2%, and at the 12-month WCC visit from 2.7% to 82.9%. 56.6% of families had a plan to introduce peanut at the 4-month WCC visit. Of those who did not have a plan, the most common barrier was family's unawareness of the benefits of early peanut introduction. At the 12-month visit, 62.8% of families had introduced peanut without concerns. CONCLUSION: A point-of-care CDS tool encouraged more discussions by general pediatric providers on early peanut introduction to all patients. CDS tools should be considered in quality improvement projects as an implementation method for the most up-to-date guidelines.

Evaluation and Modification of a Shared Decision-Making Tool for Peanut Allergy Management.

PURPOSE OF REVIEW: Based on shared decision-making (SDM) principles, a decision aid was previously developed to help patients, their caregivers, and physicians decide which peanut allergy management approach best suits them. This study refined the decision aid's content to better reflect patients' and caregivers' lived experience. RECENT FINDINGS: Current standard of care for peanut allergy is avoidance, although peanut oral immunotherapy has been approved by the Food and Drug Administration for use in patients 4-17 years old. An advisory board of allergy therapy experts (n = 3) and patient advocates (n = 3) informed modifications to the decision aid. The revised tool underwent cognitive debriefing interviews (CDIs) among adolescents (12-17 years old) with peanut allergy and caregivers of patients 4-17 years old with peanut allergy to evaluate its relevance, understandability, and usefulness. The 20 CDI participants understood the information presented in the SDM tool and reported it was important and relevant. Some revisions were made based on participant feedback. Results support content validity of the Peanut Allergy Treatment SDM Tool.

Current and future treatments for peanut allergy.

Peanut allergy (PA) is a common, burdensome childhood disease that in most patients continues into adulthood and has historically been untreatable. However, peanut oral immunotherapy (POIT) is increasingly being incorporated into allergy practices, using both the first FDA-approved product, PTAH (previously AR101; Palforzia™, Aimmune Therapeutics), as well as store-bought peanut products. POIT in preschoolers continues to gain more acceptance as evidence accrues that it is a safe and feasible approach that may have distinct advantages. There are many new therapeutic interventions currently under study with a variety of different approaches and potential mechanisms. With respect to other forms of immunotherapy, none are currently approved, but the epicutaneous approach is the most well-studied and others are being actively investigated, including sublingual, subcutaneous, and intralymphatic. Biologics are gaining evidence both as adjunctive treatments to POIT and as monotherapy. Omalizumab is the most widely studied biologic for PA but others also have potential. Looking ahead to a future therapeutic landscape of choice, allergists will need to understand each patient's goal of treatment through shared decision-making and fully evaluate the risks, benefits, and alternatives of each new therapy.

Social determinants of health influence preschool and caregiver experiences during symptoms and exacerbations of wheezing.

BACKGROUND: Social determinants of health have been inadequately studied in preschool children with wheezing and their caregivers but may influence the care received. OBJECTIVE: To evaluate the symptom and exacerbation experiences of wheezing preschool children and their caregivers, stratified by risk of social vulnerability, over 1 year of longitudinal follow-up. METHODS: A total of 79 caregivers and their preschool children with recurrent wheezing and at least 1 exacerbation in the previous year were stratified by a composite measure of social vulnerability into "low" (N = 19), "intermediate" (N = 27), and "high" (N = 33) risk groups. Outcome measures at the follow-up visits included child respiratory symptom scores, asthma control, caregiver-reported outcome measures of mental and social health, exacerbations, and health care utilization. The severity of exacerbations reflected by symptom scores and albuterol use and exacerbation-related caregiver quality of life were also assessed. RESULTS: Preschool children at high risk of social vulnerability had greater day-to-day symptom severity and more severe symptoms during acute exacerbations. High-risk caregivers were also distinguished by lower general life satisfaction at all visits and lower global and emotional quality of life during acute exacerbations which did not improve with exacerbation resolution. Rates of exacerbation or emergency department visits did not differ, but intermediate- and high-risk families were significantly less likely to seek unscheduled outpatient care. CONCLUSION: Social determinants of health influence wheezing outcomes in preschool children and their caregivers. These findings argue for routine assessment of social determinants of health during medical encounters and tailored interventions in high-risk families to promote health equity and improve respiratory outcomes.

The nasal microbiome in asthma.

BACKGROUND: Nasal microbiota may influence asthma pathobiology. OBJECTIVE: We sought to characterize the nasal microbiome of subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls to identify nasal microbiota associated with asthma activity. METHODS: We performed 16S ribosomal RNA sequencing on nasal swabs obtained from 72 primarily adult subjects with exacerbated asthma (n = 20), nonexacerbated asthma (n = 31), and healthy controls (n = 21). Analyses were performed using Quantitative Insights into Microbial (QIIME); linear discriminant analysis effect size (LEfSe); Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; and Statistical Analysis of Metagenomic Profiles (PICRUSt); and Statistical Analysis of Metagenomic Profiles (STAMP). Species found to be associated with asthma activity were validated using quantitative PCR. Metabolic pathways associated with differentially abundant nasal taxa were inferred through metagenomic functional prediction. RESULTS: Nasal bacterial composition significantly differed among subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls (permutational multivariate ANOVA, P = 2.2 × 10-2). Relative to controls, the nasal microbiota of subjects with asthma were enriched with taxa from Bacteroidetes (Wilcoxon-Mann-Whitney, r = 0.33, P = 5.1 × 10-3) and Proteobacteria (r = 0.29, P = 1.4 × 10-2). Four species were differentially abundant based on asthma status after correction for multiple comparisons: Prevotella buccalis, Padj = 1.0 × 10-2; Dialister invisus, Padj = 9.1 × 10-3; Gardnerella vaginalis, Padj = 2.8 × 10-3; Alkanindiges hongkongensis, Padj = 2.6 × 10-3. These phyla and species were also differentially abundant based on asthma activity (exacerbated asthma vs nonexacerbated asthma vs controls). Quantitative PCR confirmed species overrepresentation in asthma relative to controls for Prevotella buccalis (fold change = 130, P = 2.1 × 10-4) and Gardnerella vaginalis (fold change = 160, P = 6.8 × 10-4). Metagenomic inference revealed differential glycerolipid metabolism (Kruskal-Wallis, P = 1.9 × 10-4) based on asthma activity. CONCLUSIONS: Nasal microbiome composition differs in subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls. The identified nasal taxa could be further investigated for potential mechanistic roles in asthma and as possible biomarkers of asthma activity.

Altered Symptom Perception in Children With Asthma Is Associated With Poor Childhood Opportunity and Adverse Outcomes.

BACKGROUND: Effective asthma self-management requires that children recognize their asthma symptoms when they occur. However, some children have altered symptom perception, which impairs their ability to respond to their asthma symptoms in a timely manner. OBJECTIVE: To characterize the prevalence and features of altered symptom perception in children aged 5 to 18 years. We hypothesized that children with altered symptom perception would have more features of uncontrolled asthma, more health inequity, and poorer longitudinal asthma outcomes over 12 months. METHODS: Children (N = 371) completed an outpatient research visit for clinical characterization. Altered symptom perception was defined by discordance between child responses on the 6-item Asthma Control Questionnaire and medical provider-elicited symptoms. Electronic medical records were reviewed for 12 months for the occurrence of an asthma exacerbation treated with systemic corticosteroids and an asthma exacerbation prompting an emergency department visit. RESULTS: Approximately 15% of children had altered symptom perception and their asthma features were similar to those of children with uncontrolled asthma. Children with altered symptom perception were uniquely distinguished by non-White race and more severe prior exacerbations. These children also resided in ZIP codes with the poorest childhood opportunity (ie, poorest education, health and environmental features, and socioeconomic features). Outcomes of children with altered symptom perception were equally disparate with approximately 2-fold higher odds of a future exacerbation and approximately 3-fold higher odds of an emergency department visit for asthma. CONCLUSIONS: Altered symptom perception is present in a small but significant number of children with asthma and is related to poorer childhood opportunity and other health inequities that require additional intervention.

User-Centered Design and Evaluation of Clinical Decision Support to Improve Early Peanut Introduction: Formative Study.

BACKGROUND: Peanut allergy has recently become more prevalent. Peanut introduction recommendations have evolved from suggesting peanut avoidance until the age of 3 years to more recent guidelines encouraging early peanut introduction after the Learning Early about Peanut Allergy (LEAP) study in 2015. Guideline adherence is poor, leading to missed care opportunities. OBJECTIVE: In this study, we aimed to develop a user-centered clinical decision support (CDS) tool to improve implementation of the most recent early peanut introduction guidelines in the primary care clinic setting. METHODS: We edited the note template of the well-child check (WCC) visits at ages 4 and 6 months with CDS prompts and point-of-care education. Formative and summative usability testing were completed with pediatric residents in a simulated electronic health record (EHR). We estimated task completion rates and perceived usefulness of the CDS in summative testing, comparing a test EHR with and without the CDS. RESULTS: Formative usability testing with the residents provided qualitative data that led to improvements in the build for both the 4-month and 6-month WCC note templates. During summative usability testing, the CDS tool significantly improved discussion of early peanut introduction at the 4-month WCC visit compared to scenarios without the CDS tool (9/15, 60% with CDS and 0/15, 0% without CDS). All providers except one at the 4-month WCC scenario gave at least an adequate score for the ease of use of the CDS tool for the history of present illness and assessment and plan sections. During the summative usability testing with the 6-month WCC new build note template, providers more commonly provided comprehensive care once obtaining a patient history concerning for an immunoglobulin E-mediated peanut reaction by placing a referral to allergy/immunology (P=.48), prescribing an epinephrine auto-injector (P=.07), instructing on how to avoid peanut products (P<.001), and providing an emergency treatment plan (P=.003) with CDS guidance. All providers gave at least an adequate score for ease of use of the CDS tool in the after-visit summary. CONCLUSIONS: User-centered CDS improved application of early peanut introduction recommendations and comprehensive care for patients who have symptoms concerning for peanut allergy in a simulation.

A practical focus on peanut oral immunotherapy.

A new era of active treatment for food allergy has arrived because patients with peanut allergy are increasingly able to access options for oral immunotherapy (OIT). This milestone is a culmination of years of clinical research and represents a major inflection point for the field because it will have dramatic impacts on allergy practice. In this review, we provide a brief review of the literature as well as practical guidance with concern for the use of U.S. Food and Drug Administration approved peanut OIT as well as shelf-bought products.

The verbal Oxford Knee Score is not clinically different from the written score when assessed before or after total knee arthroplasty.

BACKGROUND: The aim of this study was to assess the reliability of the Oxford Knee Score (OKS) collected verbally compared with the validated written score, using a population of patients who underwent total knee arthroplasty (TKR). METHODS: Ninety patients (mean age 70.6; (43-92), 56.7% female) undergoing TKR were prospectively assessed. One group (n = 45) completed written (standard) and verbal (over the telephone) OKS preoperatively, half (n = 23) performed the written questionnaire first followed by the verbal questionnaire, and the other half (n = 22) performed this in reverse. A separate group (n = 45) completed the same regime one year postoperatively. RESULTS: A mean difference of 0.63 (95% CI -0.985-2.23) points between verbal and written OKS was observed preoperatively, and of 1.36 (95% CI -0.942-3.65) points was observed at one year postoperatively. Excellent reliability was observed using 'average measures' intra-class coefficient for the OKS preoperatively (r = 0.848) and at one year postoperatively (r = 0.970) in both groups who had written scores performed first, and those who had verbal scores performed first (preoperative r = 0.780, one year r = 892). Bland and Altman plots demonstrated consistent correlation between patients reporting their preoperative score and one-year postoperative score verbally and written. There was no significant variation between groups who had written scores performed prior to verbal, compared with those who reported verbal scores prior to written. CONCLUSIONS: Prospective written collection of OKS remains the benchmark. However, verbal recording of OKS is not clinically different to written score, and may be a useful alternative to OKS in patients who are unable to attend or complete written questionnaires.

Toxicology of ZnO and TiO2 nanoparticles on hepatocytes: impact on metabolism and bioenergetics.

BACKGROUND AND AIM: Zinc oxide (ZnO) and titanium dioxide (TiO2) nanomaterials (NMs) are used in many consumer products, including foodstuffs. Ingested and inhaled NM can reach the liver. Whilst their effects on inflammation, cytotoxicity, genotoxicity and mitochondrial function have been explored, no work has been reported on their impact on liver intermediary metabolism. Our aim was to assess the effects of sub-lethal doses of these materials on hepatocyte intermediary metabolism. MATERIAL AND METHODS: After characterisation, ZnO and TiO2 NM were used to treat C3A cells for 4 hours at concentrations ranging between 0 and 10 µg/cm(2), well below their EC50, before the assessment of (i) glucose production and glycolysis from endogenous glycogen and (ii) gluconeogenesis and glycolysis from lactate and pyruvate (LP). Mitochondrial membrane potential was assessed using JC-10 after 0-40 µg/cm(2) ZnO. qRT-PCR was used to assess phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression. Dihydroethidium (DHE) staining and FACS were used to assess intracellular reactive oxygen species (ROS) concentration. RESULTS: Treatment of cells with ZnO, but not TiO2, depressed mitochondrial membrane potential, leading to a dose-dependent increase in glycogen breakdown by up to 430%, with an increase of both glycolysis and glucose release. Interestingly, gluconeogenesis from LP was also increased, up to 10-fold and correlated with a 420% increase in the PEPCK mRNA expression, the enzyme controlling gluconeogenesis from LP. An intracellular increase of ROS production after ZnO treatment could explain these effects. CONCLUSION: At sub-lethal concentrations, ZnO nanoparticles dramatically increased both gluconeogenesis and glycogenolysis, which warrants further in vivo studies.

Broncholithiasis From Histoplasmosis in a Pediatric Patient: Case Reports and Review of Literature.

Broncholithiasis is a calcification in the airway. Though broncholiths are not common, it is even more unusual in a pediatric patient. We present a 15-year-old immunocompetent pediatric patient who had a broncholith that was found and removed by bronchoscopy.

Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane.

BACKGROUND: Mesenchymal stem cell (MSC) was previously shown to secrete lipid vesicles that when purified by high performance liquid chromatography as a population of homogenously sized particles with a hydrodynamic radius of 55-65 nm reduce infarct size in a mouse model of myocardial ischemia/reperfusion injury. As these vesicles exhibit many biophysical and biochemical properties of exosomes, they were identified as exosomes. Here we investigated if these lipid vesicles were indeed exosomes that have an endosomal biogenesis. METHOD: In most cells, endocytosis is thought to occur at specialized microdomains known as lipid rafts. To demonstrate an endosomal origin for MSC exosomes, MSCs were pulsed with ligands e.g. transferrin (Tfs) and Cholera Toxin B (CTB) that bind receptors in lipid rafts. The endocytosed ligands were then chased to determine if they were incorporated into the exosomes. RESULTS: A fraction of exogenous Tfs was found to recycle into MSC exosomes. When MSCs were pulsed with labelled Tfs in the presence of chlorpromazine, an inhibitor of clathrin-mediated endocytosis, Tf incorporation in CD81-immunoprecipitate was reduced during the chase. CTB which binds GM1 gangliosides that are enriched in lipid rafts extracted exosome-associated proteins, CD81, CD9, Alix and Tsg101 from MSC-conditioned medium. Exogenous CTBs were pulse-chased into secreted vesicles. Extraction of Tf- or CTB-binding vesicles in an exosome preparation mutually depleted each other. Inhibition of sphingomyelinases reduced CTB-binding vesicles. CONCLUSION: Together, our data demonstrated that MSC exosomes are derived from endocytosed lipid rafts and that their protein cargo includes exosome-associated proteins CD81, CD9, Alix and Tsg101.