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Background The vast majority of coronavirus disease 2019 (COVID-19) disease occurs in outpatients where treatment is limited to antivirals for high-risk subgroups. Acebilustat, a leukotriene B4 inhibitor, has potential to reduce inflammation and symptom duration. Methods In a single-center trial spanning Delta and Omicron variants, outpatients were randomized to 100 mg/d of oral acebilustat or placebo for 28 days. Patients reported daily symptoms via electronic query through day 28 with phone follow-up on day 120 and collected nasal swab samples on days 1–10. The primary outcome was sustained symptom resolution to day 28. Secondary 28-day outcomes included time to first symptom resolution, area under the curve (AUC) for longitudinal daily symptom scores, duration of viral shedding through day 10, and symptoms on day 120. Results Sixty participants were randomized to each study arm. At enrollment, the median duration was 4 days (interquartile range, 3–5 days), and the median number of symptoms was 9 (7–11). Most patients (90%) were vaccinated, with 73% having neutralizing antibodies. A minority of participants (44%; 35% in the acebilustat arm and 53% in placebo) had sustained symptom resolution at day 28 (hazard ratio, 0.6 [95% confidence interval,.34–1.04]; P =.07 favoring placebo). There was no difference in the mean AUC for symptom scores over 28 days (difference in mean AUC, 9.4 [95% confidence interval, −42.1 to 60.9]; P =.72). Acebilustat did not affect viral shedding or symptoms at day 120. Conclusions Sustained symptoms through day 28 were common in this low-risk population. Despite this, leukotriene B4 antagonism with acebilustat did not shorten symptom duration in outpatients with COVID-19. Clinical Trials Registration. NCT04662060. [ABSTRACT FROM AUTHOR]

Background Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. Methods We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2–10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. Results We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI},.48–1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI,.54–1.29]; sustained: HR, 0.87 [95% CI,.52–1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. Conclusions Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. Clinical Trials Registration NCT04346628. [ABSTRACT FROM AUTHOR]

Background: Multifood oral immunotherapy (mOIT) with adjunctive anti‐IgE (omalizumab, XOLAIR®) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated. Methods: Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high‐dimensional mass cytometry, component‐resolved diagnostics, the indirect basophil activation test, and Luminex. Results: We found (i) decreased frequency of IL‐4+ peanut‐reactive CD4+ T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8+ T‐cell subsets at week 8 during the initial, omalizumab‐alone induction phase; (ii) significant upregulation of the skin‐homing receptor CCR4 in peanut‐reactive CD4+ T and Th2 effector memory (EM) cells and of cutaneous lymphocyte‐associated antigen (CLA) in peanut‐reactive CD8+ T and CD8+ EM cells; (iii) downregulation of CD86 expression among antigen‐presenting cell subsets; and (iv) reduction in pro‐inflammatory cytokines, notably IL‐17, at week 36 post‐OIT. We also observed significant attenuation of the Th2 phenotype post‐OIT, defined by downregulation of IL‐4 peanut‐reactive T cells and OX40 in Th2EM cells, increased allergen component‐specific IgG4/IgE ratio, and decreased allergen‐driven activation of indirectly sensitized basophils. Conclusions: This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab‐facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT. [ABSTRACT FROM AUTHOR]

The evaluation of double‐blind, placebo‐controlled food challenges (DBPCFC) generally focuses on a participant passing a challenge at a predetermined dose, and does not consider the dose of reaction for those who fail or are censored due to study discontinuation. Further, a number of food allergy trials have incorporated multiple DBPCFCs throughout the duration of the study in order to evaluate changes in reaction over time including sustained unresponsiveness from treatment. Outcomes arising from these trials are commonly modeled using Chi‐squared or Fisher's exact tests at each time point. We propose applying time‐to‐event methodology to food allergy trials in order to exploit the inherent granularity of challenge outcomes that additionally accommodates repeated DBPCFCs. Specifically, we consider dose‐to‐failure for each study challenge and extend the cumulative tolerated dose across challenges to result in a dose‐time axis. A discrete time‐to‐event framework is applied to the dose‐time outcome to assess the efficacy of treatment across the entire study period. We illustrate ideas with data from the Peanut Oral Immunotherapy Study: Safety, Efficacy and Discovery (POISED) trial, conducted at Stanford University, which evaluated the efficacy of oral immunotherapy on desensitization and sustained unresponsiveness in peanut allergic children and adults. We demonstrate the advantages of time‐to‐event approaches for assessing the efficacy of treatment over time and incorporating information for those who failed or were lost to follow up. Further, we introduce a dose‐time outcome that is interpretable to clinicians and allows for examination of such outcomes over time. [ABSTRACT FROM AUTHOR]

Background: Clinical trials, conducted efficiently and with the utmost integrity, are a key component in identifying effective vaccines, therapies, and other interventions urgently needed to solve the COVID-19 crisis. Yet launching and implementing trials with the rigor necessary to produce convincing results is a complicated and time-consuming process. Balancing rigor and efficiency involves relying on designs that employ flexible features to respond to a fast-changing landscape, measuring valid endpoints that result in translational actions and disseminating findings in a timely manner. We describe the challenges involved in creating infrastructure with potential utility for shared learning. Methods: We have established a shared infrastructure that borrows strength across multiple trials. The infrastructure includes an endpoint registry to aid in selecting appropriate endpoints, a registry to facilitate establishing a Data & Safety Monitoring Board, common data collection instruments, a COVID-19 dedicated design and analysis team, and a pragmatic platform protocol, among other elements. Results: The authors have relied on the shared infrastructure for six clinical trials for which they serve as the Data Coordinating Center and have a design and analysis team comprising 15 members who are dedicated to COVID-19. The authors established a pragmatic platform to simultaneously investigate multiple treatments for the outpatient with adaptive features to add or drop treatment arms. Conclusion: The shared infrastructure provides appealing opportunities to evaluate disease in a more robust manner with fewer resources and is especially valued during a pandemic where efficiency in time and resources is crucial. The most important element of the shared infrastructure is the pragmatic platform. While it may be the most challenging of the elements to establish, it may provide the greatest benefit to both patients and researchers. [ABSTRACT FROM AUTHOR]

To the editor, Asthma is the most prevalent chronic lung inflammatory disorder characterized by reversible airflow obstruction, affecting 358 million people worldwide,[1] with aggravating factors like obesity, attention-deficit/hyperactivity disorder, socioeconomic status like poor healthcare affordability and facility, smoking and alcohol intake.[2] RNA sequencing (RNA-seq) in atopic asthma,[3] childhood asthma[4] and adult-onset severe asthma[5] has improved our understanding of cellular and molecular pathways involved. The transcriptomic RNA-seq was done on all 16 twin pairs, and the methylomic whole-genome bisulfite sequencing was done on 8 twin pairs (3 concordant asthmatic pairs; 5 concordant nonasthmatic pairs) wherein 6 individuals were asthmatics (GINA score 1 n = 1; 2 n = 1; 3 n = 4). Twin pairs discordant for asthma would be ideal for exploration of genetic vs environmental influence on asthma. [Extracted from the article]

Peanuts in the gut: Peanut allergy affects millions of children and adults worldwide, and peripheral blood IgE+ B cells have been studied in previous peanut allergy studies. Less is known about B cells in tissues exposed to peanuts, and Hoh et al. have now characterized IgE+ B cell clones in the blood, esophagus, stomach, and duodenum in 19 peanut-allergic patients. The stomach and duodenum were enriched for IgE+ B cells with a plasma cell phenotype in allergic patients. High-throughput DNA analysis indicated that tissues were the sites of local isotype switching, and similar antibody sequences for the Ara h 2 peanut allergen were shared between patients. These data better define a role for IgE+ B cells in the gastrointestinal tract in peanut allergy. B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE+ B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE+ clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE+ cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE+ and non-IgE–expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE+ B lineage cells in food allergy. [ABSTRACT FROM AUTHOR]

To the Editor, Allergies to hen's egg and cow's milk are the most common allergies in infants and young children. GLO:1X5/01jun20:all14107-fig-0001.jpg PHOTO (COLOR): sIgE (A) and sIgG4 (B) levels to egg and 3 components (Gal d 1-3) in participants who were never egg-allergic, allergic to egg and subsequently successfully desensitized by OIT to egg, or outgrew their egg allergy. Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts. [Extracted from the article]

Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0–0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing. [ABSTRACT FROM AUTHOR]

Aging is intimately linked to system‐wide metabolic changes that can be captured in blood. Understanding biological processes of aging in humans could help maintain a healthy aging trajectory and promote longevity. We performed untargeted plasma metabolomics quantifying 770 metabolites on a cross‐sectional cohort of 268 healthy individuals including 125 twin pairs covering human lifespan (from 6 months to 82 years). Unsupervised clustering of metabolic profiles revealed 6 main aging trajectories throughout life that were associated with key metabolic pathways such as progestin steroids, xanthine metabolism, and long‐chain fatty acids. A random forest (RF) model was successful to predict age in adult subjects (≥16 years) using 52 metabolites (R2 =.97). Another RF model selected 54 metabolites to classify pediatric and adult participants (out‐of‐bag error = 8.58%). These RF models in combination with correlation network analysis were used to explore biological processes of healthy aging. The models highlighted established metabolites, like steroids, amino acids, and free fatty acids as well as novel metabolites and pathways. Finally, we show that metabolic profiles of twins become more dissimilar with age which provides insights into nongenetic age‐related variability in metabolic profiles in response to environmental exposure. [ABSTRACT FROM AUTHOR]

In a randomized, pre-post intervention study, we evaluated the influence of a large language model (LLM) generative AI system on accuracy of physician decision-making and bias in healthcare. 50 US-licensed physicians reviewed a video clinical vignette, featuring actors representing different demographics (a White male or a Black female) with chest pain. Participants were asked to answer clinical questions around triage, risk, and treatment based on these vignettes, then asked to reconsider after receiving advice generated by ChatGPT+ (GPT4). The primary outcome was the accuracy of clinical decisions based on pre-established evidence-based guidelines. Results showed that physicians are willing to change their initial clinical impressions given AI assistance, and that this led to a significant improvement in clinical decision-making accuracy in a chest pain evaluation scenario without introducing or exacerbating existing race or gender biases. A survey of physician participants indicates that the majority expect LLM tools to play a significant role in clinical decision making.

Introduction: Clinical trials provide the "gold standard" evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources - data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor., Methods: Three examples of real-world trials that leverage different types of data sources - wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived., Results: Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity., Conclusions: Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials., Competing Interests: BJB, HH, JDC, JOF, AG, RJ, JL, KOO, MP, KR, HS, MT, & MD have no disclosures. JHC has received research grant support from NIH/National Institute on Drug Abuse Clinical Trials Network (UG1DA015815 - CTN-0136), Stanford Artificial Intelligence in Medicine and Imaging - Human-Centered Artificial Intelligence (AIMI-HAI) Partnership Grant, Doris Duke Charitable Foundation - Covid-19 Fund to Retain Clinical Scientists (20211260), Google, Inc. Research collaboration Co-I to leverage EHR data to predict a range of clinical outcomes, and American Heart Association - Strategically Focused Research Network - Diversity in Clinical Trials. JHC discloses: Co-founder of Reaction Explorer LLC that develops and licenses organic chemistry education software & Paid consulting fees from Sutton Pierce and Younker Hyde MacFarlane PLLC as a medical expert witness. EF is supported in part by AFOSR Grant FA9550-21-1-0397, ONR Grant N00014-22-1-2110, and the Stanford Institute for Human-Centered Artificial Intelligence (HAI). EBF is a Chan Zuckerberg Biohub – San Francisco Investigator. AGo has received research funding from the National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases; and the National Institute on Aging. He has also received research grants through his institution from Novartis, Bristol Myers Squibb, Pfizer, Janssen Research & Development, CSL Behring, iRhythm Technologies, and Amarin Pharmaceuticals. RJ was partially supported by the National Science Foundation under grant 2205084, and by the Stanford Maternal and Child Health Research Institute under the Transdisciplinary Initiatives Program. DMM has had research support from the NIH, JDRF, NSF, and the Helmsley Charitable Trust and his institution has had research support from Medtronic, Dexcom, Insulet, Bigfoot Biomedical, Tandem, and Roche. Dr Maahs has consulted for Abbott, Aditxt, the Helmsley Charitable Trust, Lifescan, Mannkind, Sanofi, Novo Nordisk, Eli Lilly, Medtronic, Insulet, Dompe, Biospex, Provention Bio, and Bayer. DS discloses advising Carta Healthcare. MPT has received grants or personal fees from American Heart Association, Apple, Bayer, Bristol Myers Squibb, FDA, Gilead Sciences, Johnson & Johnson, Medtronic Inc., Myokardia, Pfizer, and Sanofi, is a shareholder of AliveCor, Connect America, Evidently, Forward, iRhythm, and PocketRN, and is an employee of iRhythm Technologies, Inc. KWM’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey., (© The Author(s) 2023.)

Food allergies are a leading cause of anaphylaxis, and cellular mechanisms involving antigen presentation likely play key roles in their pathogenesis. However, little is known about the response of specific antigen-presenting cell (APC) subsets to food allergens in the setting of food allergies. Here, we show that in peanut-allergic humans, peanut allergen drives the differentiation of CD209+ monocyte-derived dendritic cells (DCs) and CD23+ (FcєRII) myeloid dendritic cells through the action of allergen-specific CD4+ T cells. CD209+ DCs act reciprocally on the same peanut-specific CD4+ T cell population to reinforce Th2 cytokine expression in a positive feedback loop, which may explain the persistence of established food allergy. In support of this novel model, we show clinically that the initiation of oral immunotherapy (OIT) in peanut-allergic patients is associated with a decrease in CD209+ DCs, suggesting that breaking the cycle of positive feedback is associated with therapeutic effect., Competing Interests: Disclosures: E.D. Mellins reported grants from Glaxo-Smith-Kline and Novartis outside the submitted work. K.C. Nadeau reported grants from the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Environmental Health Sciences, and Food Allergy Research and Education; "other" from World Allergy Organization, Cour Pharma, Before Brands, Alladapt, Latitude, IgGenix, Immune Tolerance Network, and the National Institutes of Health clinical research centers outside the submitted work. In addition, K.C. Nadeau had a patent to "inhibition of allergic reaction to peanut allergen using an IL-33 inhibitor" (US patent no. 62/647,389, filed 3/23/2018), a patent to "special oral formula for decreasing food allergy risk and treatment for food allergy (US patent no. 62/119,014, filed 2/20/15, issued 8/15/17) issued, a patent to "basophil activation-based diagnostic allergy test" (US application no. S10-392, filed 10/1/2010), a patent to "granulocyte-based methods for detecting and monitoring immune system disorders" (US application no. 12/686,121, filed 1/12/2010), a patent to "methods and assays for detecting and quantifying pure subpopulations of white blood cells in immune system disorders" (US patent no. 12/610,940, filed 11/2/2009, issued 8/12/2018), a patent to "mixed allergen compositions and methods for using the same" (US patent no. 10/064,936, issued 9/4/2018), and a patent to "microfluidic device and diagnostic methods for allergy testing based on detection of basophil activation" (US patent no. 62/767,444, filed 11/14/2018). No other disclosures were reported., (© 2021 Zhou et al.)

DNA methylation (DNAm) has been shown to play a role in mediating food allergy; however, the mechanism by which it does so is poorly understood. In this study, we used targeted next-generation bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) versus nonallergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 potentially novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity), as well as DNAm signature combinations with superior diagnostic potential compared with serum peanut-specific IgE for PA versus NA. Furthermore, we found that, following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared with NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than those in randomly paired genetically unrelated individuals, suggesting that PA-related DNAm signatures may be associated with genetic factors.

B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE + B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE + clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE + cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE + and non-IgE-expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE + B lineage cells in food allergy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Asthma and rhinitis are complex, heterogeneous diseases characterized by chronic inflammation of the upper and lower airways. While genome-wide association studies (GWAS) have identified a number of susceptible loci and candidate genes associated with the pathogenesis of asthma and allergic rhinitis (AR), the risk-associated alleles account for only a very small percent of the genetic risk. In allergic airway and other complex diseases, it is thought that epigenetic modifications, including DNA methylation, histone modifications, and non-coding microRNAs, caused by complex interactions between the underlying genome and the environment may account for some of this "missing heritability" and may explain the high degree of plasticity in immune responses. In this chapter, we will focus on the current knowledge of classical epigenetic modifications, DNA methylation and histone modifications, and their potential role in asthma and AR. In particular, we will review epigenetic variations associated with maternal airway disease, demographics, environment, and non-specific associations. The role of specific genetic haplotypes in environmentally induced epigenetic changes are also discussed. A major limitation of many of the current studies of asthma epigenetics is that they evaluate epigenetic modifications in both allergic and non-allergic asthma, making it difficult to distinguish those epigenetic modifications that mediate allergic asthma from those that mediate non-allergic asthma. Additionally, most DNA methylation studies in asthma use peripheral or cord blood due to poor accessibility of airway cells or tissue. Unlike DNA sequences, epigenetic alterations are quite cell- and tissue-specific, and epigenetic changes found in airway tissue or cells may be discordant from that of circulating blood. These two confounding factors should be considered when reviewing epigenetic studies in allergic airway disease.