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.).

Ultra-sensitive and resilient compliant strain gauges for soft machines.

Soft machines are a promising design paradigm for human-centric devices1,2 and systems required to interact gently with their environment3,4. To enable soft machines to respond intelligently to their surroundings, compliant sensory feedback mechanisms are needed. Specifically, soft alternatives to strain gauges-with high resolution at low strain (less than 5 per cent)-could unlock promising new capabilities in soft systems. However, currently available sensing mechanisms typically possess either high strain sensitivity or high mechanical resilience, but not both. The scarcity of resilient and compliant ultra-sensitive sensing mechanisms has confined their operation to laboratory settings, inhibiting their widespread deployment. Here we present a versatile and compliant transduction mechanism for high-sensitivity strain detection with high mechanical resilience, based on strain-mediated contact in anisotropically resistive structures (SCARS). The mechanism relies upon changes in Ohmic contact between stiff, micro-structured, anisotropically conductive meanders encapsulated by stretchable films. The mechanism achieves high sensitivity, with gauge factors greater than 85,000, while being adaptable for use with high-strength conductors, thus producing sensors resilient to adverse loading conditions. The sensing mechanism also exhibits high linearity, as well as insensitivity to bending and twisting deformations-features that are important for soft device applications. To demonstrate the potential impact of our technology, we construct a sensor-integrated, lightweight, textile-based arm sleeve that can recognize gestures without encumbering the hand. We demonstrate predictive tracking and classification of discrete gestures and continuous hand motions via detection of small muscle movements in the arm. The sleeve demonstration shows the potential of the SCARS technology for the development of unobtrusive, wearable biomechanical feedback systems and human-computer interfaces.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Untethered flight of an insect-sized flapping-wing microscale aerial vehicle.

Heavier-than-air flight at any scale is energetically expensive. This is greatly exacerbated at small scales and has so far presented an insurmountable obstacle for untethered flight in insect-sized (mass less than 500 milligrams and wingspan less than 5 centimetres) robots. These vehicles1-4 thus need to fly tethered to an offboard power supply and signal generator owing to the challenges associated with integrating onboard electronics within a limited payload capacity. Here we address these challenges to demonstrate sustained untethered flight of an insect-sized flapping-wing microscale aerial vehicle. The 90-milligram vehicle uses four wings driven by two alumina-reinforced piezoelectric actuators to increase aerodynamic efficiency (by up to 29 per cent relative to similar two-wing vehicles5) and achieve a peak lift-to-weight ratio of 4.1 to 1, demonstrating greater thrust per muscle mass than typical biological counterparts6. The integrated system of the vehicle together with the electronics required for untethered flight (a photovoltaic array and a signal generator) weighs 259 milligrams, with an additional payload capacity allowing for additional onboard devices. Consuming only 110-120 milliwatts of power, the system matches the thrust efficiency of similarly sized insects such as bees7. This insect-scale aerial vehicle is the lightest thus far to achieve sustained untethered flight (as opposed to impulsive jumping8 or liftoff9).

Controlled flight of a microrobot powered by soft artificial muscles.

Flying insects capable of navigating in highly cluttered natural environments can withstand in-flight collisions because of the combination of their low inertia1 and the resilience of their wings2, exoskeletons1 and muscles. Current insect-scale (less than ten centimetres long and weighing less than five grams) aerial robots3-6 use rigid microscale actuators, which are typically fragile under external impact. Biomimetic artificial muscles7-10 that are capable of large deformation offer a promising alternative for actuation because they can endure the stresses caused by such impacts. However, existing soft actuators11-13 have not yet demonstrated sufficient power density to achieve lift-off, and their actuation nonlinearity and limited bandwidth create further challenges for achieving closed-loop (driven by an input control signal that is adjusted based on sensory feedback) flight control. Here we develop heavier-than-air aerial robots powered by soft artificial muscles that demonstrate open-loop (driven by a predetermined signal without feedback), passively stable (upright during flight) ascending flight as well as closed-loop, hovering flight. The robots are driven by multi-layered dielectric elastomer actuators that weigh 100 milligrams each and have a resonance frequency of 500 hertz and power density of 600 watts per kilogram. To increase the mechanical power output of the actuator and to demonstrate flight control, we present ways to overcome challenges unique to soft actuators, such as nonlinear transduction and dynamic buckling. These robots can sense and withstand collisions with surrounding obstacles and can recover from in-flight collisions by exploiting material robustness and vehicle passive stability. We also fly two micro-aerial vehicles simultaneously in a cluttered environment. They collide with the wall and each other without suffering damage. These robots rely on offboard amplifiers and an external motion-capture system to provide power to the dielectric elastomer actuators and to control their flight. Our work demonstrates how soft actuators can achieve sufficient power density and bandwidth to enable controlled flight, illustrating the potential of developing next-generation agile soft robots.

Active entanglement enables stochastic, topological grasping.

Grasping, in both biological and engineered mechanisms, can be highly sensitive to the gripper and object morphology, as well as perception and motion planning. Here, we circumvent the need for feedback or precise planning by using an array of fluidically actuated slender hollow elastomeric filaments to actively entangle with objects that vary in geometric and topological complexity. The resulting stochastic interactions enable a unique soft and conformable grasping strategy across a range of target objects that vary in size, weight, and shape. We experimentally evaluate the grasping performance of our strategy and use a computational framework for the collective mechanics of flexible filaments in contact with complex objects to explain our findings. Overall, our study highlights how active collective entanglement of a filament array via an uncontrolled, spatially distributed scheme provides options for soft, adaptable grasping.

Relationships between lung function, allergy, and wheezing in urban children.

BACKGROUND: Allergic sensitization and low lung function in early childhood are risk factors for subsequent wheezing and asthma. However, it is unclear how allergic sensitization affects lung function over time. OBJECTIVE: We sought to test whether allergy influences lung function and whether these factors synergistically increase the risk of continued wheezing in childhood. METHODS: We analyzed longitudinal measurements of lung function (spirometry and impulse oscillometry) and allergic sensitization (aeroallergen skin tests and serum allergen-specific IgE) throughout early childhood in the Urban Environmental and Childhood Asthma study, which included high-risk urban children living in disadvantaged neighborhoods. Intraclass correlation coefficients were calculated to assess lung function stability. Cluster analysis identified low, medium, and high allergy trajectories, which were compared with lung function and wheezing episodes in linear regression models. A variable selection model assessed predictors at age 5 years for continued wheezing through age 12 years. RESULTS: Lung function adjusted for growth was stable (intraclass correlation coefficient, 0.5-0.7) from age 5 to 12 years and unrelated to allergy trajectory. Lung function and allergic sensitization were associated with wheezing episodes in an additive fashion. In children with asthma, measuring lung function at age 5 years added little to the medical history for predicting future wheezing episodes through age 12 years. CONCLUSIONS: In high-risk urban children, age-related trajectories of allergic sensitization were not associated with lung function development; however, both indicators were related to continued wheezing. These results underscore the importance of understanding early-life factors that negatively affect lung development and suggest that treating allergic sensitization may not alter lung function development in early to mid-childhood.

Early-life nasal microbiota dynamics relate to longitudinal respiratory phenotypes in urban children.

BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization. and pulmonary function measured in urban children from ages from 0 to 7 years have previously been described. OBJECTIVE: Our aim was to determine whether distinct respiratory phenotypes are associated with early-life upper respiratory microbiota development and environmental microbial exposures. METHODS: Microbiota profiling was performed using 16S ribosomal RNA-based sequencing of nasal samples collected at age 12 months (n = 120) or age 36 months (n = 142) and paired house dust samples collected at 3 months (12-month, n = 73; 36-month, n = 90) from all 4 centers in the Urban Environment and Childhood Asthma (URECA) cohort. RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between ages 12 and 36 months (ß = 2.04; P = .006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (interaction P = .0007), increasing most in the transient wheeze group. At age 12 months, respiratory illness (R2 = 0.055; P = .0001) and dominant bacterial genus (R2 = 0.59; P = .0001) explained variance in nasal microbiota composition, and enrichment of Moraxella and Haemophilus members was associated with both transient and high-wheeze respiratory phenotypes. By age 36 months, nasal microbiota was significantly associated with respiratory phenotypes (R2 = 0.019; P = .0376), and Moraxella-dominated microbiota was associated specifically with atopy-associated phenotypes. Analysis of paired house dust and nasal samples indicated that 12 month olds with low wheeze and atopy incidence exhibited the largest number of shared bacterial taxa with their environment. CONCLUSION: Nasal microbiota development over the course of early childhood and composition at age 3 years are associated with longitudinal respiratory phenotypes. These data provide evidence supporting an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associates with wheeze- and atopy-associated respiratory phenotypes through age 7 years.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Viral and non-viral episodes of wheezing in early life and the development of asthma and respiratory phenotypes among urban children.

BACKGROUND: Viral wheezing is an important risk factor for asthma, which comprises several respiratory phenotypes. We sought to understand if the etiology of early-life wheezing illnesses relates to childhood respiratory and asthma phenotypes. METHODS: Data were collected prospectively on 429 children in the Urban Environment and Childhood Asthma (URECA) birth cohort study through age 10 years. We identified wheezing illnesses and the corresponding viral etiology (PCR testing of nasal mucus) during the first 3 years of life. Six phenotypes of respiratory health were identified at 10 years of age based on trajectories of wheezing, allergic sensitization, and lung function. We compared the etiology of early wheezing illnesses to these wheezing respiratory phenotypes and the development of asthma. RESULTS: In the first 3 years of life, at least one virus was detected in 324 (67%) of the 483 wheezing episodes documented in the study cohort. Using hierarchical partitioning we found that non-viral wheezing episodes accounted for the greatest variance in asthma diagnosed at both 7 and 10 years of age (8.0% and 5.8% respectively). Rhinovirus wheezing illnesses explained the most variance in respiratory phenotype outcome followed by non-viral wheezing episodes (4.9% and 3.9% respectively) at 10 years of age. CONCLUSION AND RELEVANCE: Within this high-risk urban-residing cohort in early life, non-viral wheezing episodes were frequently identified and associated with asthma development. Though rhinovirus wheezing illnesses had the greatest association with phenotype outcome, the specific etiology of wheezing episodes in early life provided limited information about subsequent wheezing phenotypes.

A dynamic electrically driven soft valve for control of soft hydraulic actuators.

Regulation systems for fluid-driven soft robots predominantly consist of inflexible and bulky components. These rigid structures considerably limit the adaptability and mobility of these robots. Soft valves in various forms for fluidic actuators have been developed, primarily fluidically or electrically driven. However, fluidic soft valves require external pressure sources that limit robot locomotion. State-of-the-art electrostatic valves are unable to modulate pressure beyond 3.5 kPa with a sufficient flow rate (>6 mL⋅min-1). In this work, we present an electrically powered soft valve for hydraulic actuators with mesoscale channels based on a different class of ultrahigh-power density dynamic dielectric elastomer actuators. The dynamic dielectric elastomer actuators (DEAs) are actuated at 500 Hz or above. These DEAs generate 300% higher blocked force compared with the dynamic DEAs in previous works and their loaded power density reaches 290 W⋅kg-1 at operating conditions. The soft valves are developed with compact (7 mm tall) and lightweight (0.35 g) dynamic DEAs, and they allow effective control of up to 51 kPa of pressure and a 40 mL⋅min-1 flow rate with a response time less than 0.1 s. The valves can also tune flow rates based on their driving voltages. Using the DEA soft valves, we demonstrate control of hydraulic actuators of different volumes and achieve independent control of multiple actuators powered by a single pressure source. This compact and lightweight DEA valve is capable of unprecedented electrical control of hydraulic actuators, showing the potential for future onboard motion control of soft fluid-driven robots.

A physical model of mantis shrimp for exploring the dynamics of ultrafast systems.

Efficient and effective generation of high-acceleration movement in biology requires a process to control energy flow and amplify mechanical power from power density-limited muscle. Until recently, this ability was exclusive to ultrafast, small organisms, and this process was largely ascribed to the high mechanical power density of small elastic recoil mechanisms. In several ultrafast organisms, linkages suddenly initiate rotation when they overcenter and reverse torque; this process mediates the release of stored elastic energy and enhances the mechanical power output of extremely fast, spring-actuated systems. Here we report the discovery of linkage dynamics and geometric latching that reveals how organisms and synthetic systems generate extremely high-acceleration, short-duration movements. Through synergistic analyses of mantis shrimp strikes, a synthetic mantis shrimp robot, and a dynamic mathematical model, we discover that linkages can exhibit distinct dynamic phases that control energy transfer from stored elastic energy to ultrafast movement. These design principles are embodied in a 1.5-g mantis shrimp scale mechanism capable of striking velocities over 26 m [Formula: see text] in air and 5 m [Formula: see text] in water. The physical, mathematical, and biological datasets establish latching mechanics with four temporal phases and identify a nondimensional performance metric to analyze potential energy transfer. These temporal phases enable control of an extreme cascade of mechanical power amplification. Linkage dynamics and temporal phase characteristics are easily adjusted through linkage design in robotic and mathematical systems and provide a framework to understand the function of linkages and latches in biological systems.

Treatment for food allergy: Current status and unmet needs.

The treatment of food allergy has traditionally relied on avoidance of the offending food(s) and use of emergency medications in the event of accidental exposures. However, this long-standing paradigm is beginning to shift, as a variety of treatment approaches have been and are being developed. This report provides an overview of the past, present, and future landscape of interventional clinical trials for the treatment of food allergy. It focuses on specific issues related to participant characteristics, protocol design, and study end points in the key clinical trials in the literature and examine how differences between studies may impact the clinical significance of the study results. Recommendations are provided for the optimization of future trial designs and focus on specific unmet needs in this rapidly evolving field.

Longitudinal dynamics of the gut microbiome and metabolome in peanut allergy development.

BACKGROUND: Rising rates of peanut allergy (PA) motivate investigations of its development to inform prevention and therapy. Microbiota and the metabolites they produce shape food allergy risk. OBJECTIVE: We sought to gain insight into gut microbiome and metabolome dynamics in the development of PA. METHODS: We performed a longitudinal, integrative study of the gut microbiome and metabolome of infants with allergy risk factors but no PA from a multicenter cohort followed through mid-childhood. We performed 16S rRNA sequencing, short chain fatty acid measurements, and global metabolome profiling of fecal samples at infancy and at mid-childhood. RESULTS: In this longitudinal, multicenter sample (n = 122), 28.7% of infants developed PA by mid-childhood (mean age 9 years). Lower infant gut microbiome diversity was associated with PA development (P = .014). Temporal changes in the relative abundance of specific microbiota and gut metabolite levels significantly differed in children who developed PA. PA-bound children had different abundance trajectories of Clostridium sensu stricto 1 sp (false discovery rate (FDR) = 0.015) and Bifidobacterium sp (FDR = 0.033), with butyrate (FDR = 0.045) and isovalerate (FDR = 0.036) decreasing over time. Metabolites associated with PA development clustered within the histidine metabolism pathway. Positive correlations between microbiota, butyrate, and isovalerate and negative correlations with histamine marked the PA-free network. CONCLUSION: The temporal dynamics of the gut microbiome and metabolome in early childhood are distinct for children who develop PA. These findings inform our thinking on the mechanisms underlying and strategies for potentially preventing PA.

Identification of cow milk epitopes to characterize and quantify disease-specific T cells in allergic children.

BACKGROUND: Cow milk (CM) allergy is the most prevalent food allergy in young children in the United States and Great Britain. Current diagnostic tests are either unreliable (IgE test and skin prick test) or resource-intensive with risks (food challenges). OBJECTIVE: We sought to determine whether allergen-specific T cells in CM-allergic (CMA) patients have a distinct quality and/or quantity that could potentially be used as a diagnostic marker. METHODS: Using PBMCs from 147 food-allergic pediatric subjects, we mapped T-cell responses to a set of reactive epitopes in CM that we compiled in a peptide pool. This pool induced cytokine responses in in vitro cultured cells distinguishing subjects with CMA from subjects without CMA. We further used the pool to isolate and characterize antigen-specific CD4 memory T cells using flow cytometry and single-cell RNA/TCR sequencing assays. RESULTS: We detected significant changes in the transcriptional program and clonality of CM antigen-specific (CM+) T cells elicited by the pool in subjects with CMA versus subjects without CMA ex vivo. CM+ T cells from subjects with CMA had increased percentages of FOXP3+ cells over FOXP3- cells. FOXP3+ cells are often equated with regulatory T cells that have suppressive activity, but CM+ FOXP3+ cells from subjects with CMA showed significant expression of interferon-responsive genes and dysregulated chemokine receptor expression compared with subjects without CMA, suggesting that these are not conventional regulatory T cells. The CM+ FOXP3+ cells were also more clonally expanded than the FOXP3- population. We were further able to use surface markers (CD25, CD127, and CCR7) in combination with our peptide pool stimulation to quantify these CM+ FOXP3+ cells by a simple flow-cytometry assay. We show increased percentages of CM+ CD127-CD25+ cells from subjects with CMA in an independent cohort, which could be used for diagnostic purposes. Looking specifically for TH2 cells normally associated with allergic diseases, we found a small population of clonally expanded CM+ cells that were significantly increased in subjects with CMA and that had high expression of TH2 cytokines and pathogenic TH2/T follicular helper markers. CONCLUSIONS: Overall, these findings suggest that there are several differences in the phenotypes of CM+ T cells with CM allergy and that the increase in CM+ FOXP3+ cells is a potential diagnostic marker of an allergic state. Such markers have promising applications in monitoring natural disease outgrowth and/or the efficacy of immunotherapy that will need to be validated in future studies.

The role of biologics in pediatric food allergy and eosinophilic gastrointestinal disorders.

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.

A functional genomics pipeline to identify high-value asthma and allergy CpGs in the human methylome.

BACKGROUND: DNA methylation of cytosines at cytosine-phosphate-guanine (CpG) dinucleotides (CpGs) is a widespread epigenetic mark, but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays. OBJECTIVES: To explore this hidden portion of the epigenome, this study combined whole-genome bisulfite sequencing with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. This study focused on airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk. METHODS: This study identified differentially methylated regions from whole-genome bisulfite sequencing in nasal epithelial cell DNA from a total of 39 children with and without allergic asthma of both European and African ancestries. This study selected CpGs from differentially methylated regions, previous allergy or asthma epigenome-wide association studies (EWAS), or genome-wide association study loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. This study used both the custom and EPIC arrays to perform EWAS of allergic sensitization (AS) in nasal epithelial cell DNA from children in the URECA (Urban Environment and Childhood Asthma) birth cohort and using the custom array in the INSPIRE [Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure] birth cohort. Each CpG on the arrays was assigned to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes. RESULTS: Custom array CpGs were enriched for intermediate methylation levels compared to EPIC CpGs. Intermediate methylation CpGs were further enriched among those associated with AS and for eQTMs on both arrays. CONCLUSIONS: This study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography.

High-throughput segmentation, data visualization, and analysis of sea star skeletal networks.

The remarkably complex skeletal systems of the sea stars (Echinodermata, Asteroidea), consisting of hundreds to thousands of individual elements (ossicles), have intrigued investigators for more than 150 years. While the general features and structural diversity of isolated asteroid ossicles have been well documented in the literature, the task of mapping the spatial organization of these constituent skeletal elements in a whole-animal context represents an incredibly laborious process, and as such, has remained largely unexplored. To address this unmet need, particularly in the context of understanding structure-function relationships in these complex skeletal systems, we present an integrated approach that combines micro-computed tomography, automated ossicle segmentation, data visualization tools, and the production of additively manufactured tangible models to reveal biologically relevant structural data that can be rapidly analyzed in an intuitive manner. In the present study, we demonstrate this high-throughput workflow by segmenting and analyzing entire skeletal systems of the giant knobby star, Pisaster giganteus, at four different stages of growth. The in-depth analysis, presented herein, provides a fundamental understanding of the three-dimensional skeletal architecture of the sea star body wall, the process of skeletal maturation during growth, and the relationship between skeletal organization and morphological characteristics of individual ossicles. The widespread implementation of this approach for investigating other species, subspecies, and growth series has the potential to fundamentally improve our understanding of asteroid skeletal architecture and biodiversity in relation to mobility, feeding habits, and environmental specialization in this fascinating group of echinoderms.

Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.

BACKGROUND: For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. METHODS: We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. FINDINGS: Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. INTERPRETATION: In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. FUNDING: National Institute of Allergy and Infectious Disease, Immune Tolerance Network.