Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. Key Messages: - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. Capsule summary: This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Influence of social media on psychological health of youth during COVID-19 pandemic.

Context: Medical undergraduates, being away from their institutes due to the lockdown, are at a greater risk of being affected by the negative news, which may easily instill fear and panic among them. Therefore, the present study was planned with the objective to study the effects of media exposure on the psychological health of undergraduate medical students at a tertiary health institute. Aim: To assess the psychological effects of social media/media use and coping mechanisms adopted during the COVID-19 pandemic. Settings and Design: Tertiary care teaching Institute and Cross-sectional study. Material and Methods: It is a cross-sectional observational study performed among (under graduate) UG students, which was assessed using a pre-tested questionnaire including the pre-validated DASS-21 scale. Statistical Analysis: Data collected was entered in MS Excel. Descriptive statistics and correlation of the study variables were analyzed while controlling for demographics using Epi-info software version 7.2.2. Results: It was observed that around one-fifth of the participants have moderate depression, followed by mild 10.97%; one-fifth of the participants have moderate levels of anxiety 20.41% followed by extremely severe anxiety 13.27% and about two-thirds of the study participants having no stress 64.29% followed by mild stress 14.80% and moderate stress 9.69%. Conclusion: There was a significant psychological impact of the use of social media among young populations, particularly anxiety, stress, and depression with exposure to negative news and reports on social media platforms.

Evaluating the Impact of Training Teachers to Identify Learning Disabilities: A Pre-experimental Study on Knowledge Enhancement.

Introduction Learning disability (LD) affects many school-going children and is seldom recognized or treated. As teachers spend time with students, they can easily recognize LD by observing academic activities and behaviors. In this context, the present study was conducted to assess the knowledge and practices of teachers regarding LD and evaluate the impact of an educational intervention on teachers' knowledge regarding LD and its screening and referral. Methods A pre-experimental study, including pre-post interventional assessments of teachers, was conducted from June 2018 to December 2019. A universal sample of 150 teachers from 10 schools teaching primary (first to fifth grade) and upper primary (sixth to eight grade) grades was included. Their knowledge about LD was assessed using the Dyslexia Assessment for the Languages of India (DALI), and an educational intervention for assessing, screening, and identifying LD was implemented. Data was analyzed using SPSS version 24.0 (IBM Inc., Armonk, New York). Using descriptive statistics (mean, median, and standard deviation). The pre-post test results were compared using the McNemar test. Results Overall knowledge about LD was 24.7% at baseline, and improved to 76% post-intervention (p<0.001). The knowledge for most of the components showed improvement. Teachers with a good level of knowledge increased from 21% to 84%. Post-intervention screening of students increased from 0.53% to 13.37%. The suspicion rate for LD increased from 0.04% to 1.94% post-intervention. Conclusion Knowledge about LD was poor among the school teachers. However, the overall knowledge about LD, its specific domains, screening as well as actual LD screening significantly improved after the intervention (p<0.001). This emphasizes the need of training primary and post-primary school teachers about LD and the services available for children with LD.

Management of Food Allergies and Food-Related Anaphylaxis.

Importance: An estimated 7.6% of children and 10.8% of adults have IgE-mediated food-protein allergies in the US. IgE-mediated food allergies may cause anaphylaxis and death. A delayed, IgE-mediated allergic response to the food-carbohydrate galactose-α-1,3-galactose (alpha-gal) in mammalian meat affects an estimated 96 000 to 450 000 individuals in the US and is currently a leading cause of food-related anaphylaxis in adults. Observations: In the US, 9 foods account for more than 90% of IgE-mediated food allergies-crustacean shellfish, dairy, peanut, tree nuts, fin fish, egg, wheat, soy, and sesame. Peanut is the leading food-related cause of fatal and near-fatal anaphylaxis in the US, followed by tree nuts and shellfish. The fatality rate from anaphylaxis due to food in the US is estimated to be 0.04 per million per year. Alpha-gal syndrome, which is associated with tick bites, is a rising cause of IgE-mediated food anaphylaxis. The seroprevalence of sensitization to alpha-gal ranges from 20% to 31% in the southeastern US. Self-injectable epinephrine is the first-line treatment for food-related anaphylaxis. The cornerstone of IgE-food allergy management is avoidance of the culprit food allergen. There are emerging immunotherapies to desensitize to one or more foods, with one current US Food and Drug Administration-approved oral immunotherapy product for treatment of peanut allergy. Conclusions and Relevance: IgE-mediated food allergies, including delayed IgE-mediated allergic responses to red meat in alpha-gal syndrome, are common in the US, and may cause anaphylaxis and rarely, death. IgE-mediated anaphylaxis to food requires prompt treatment with epinephrine injection. Both food-protein allergy and alpha-gal syndrome management require avoiding allergenic foods, whereas alpha-gal syndrome also requires avoiding tick bites.

Desensitization and remission after peanut sublingual immunotherapy in 1- to 4-year-old peanut-allergic children: A randomized, placebo-controlled trial.

BACKGROUND: Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age at treatment initiation. OBJECTIVE: We studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. METHODS: Peanut-allergic 1- to 4-year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36 months of treatment. Participants desensitized to at least 443 mg peanut protein discontinued therapy for 3 months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment. RESULTS: Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across 2 sites. The primary end point of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg vs 143 mg), higher likelihood of passing the month 36 DBPCFC (60% vs 0), and higher likelihood of demonstrating remission (48% vs 0). The highest rate of desensitization and remission was seen in 1- to 2-year-olds, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between treatment groups. CONCLUSION: Peanut SLIT safely induces desensitization and remission in 1- to 4-year-old children, with improved outcomes seen with younger age at initiation.

Factors influencing age of common allergen introduction in early childhood.

Objectives: We evaluated factors influencing the timing of allergen introduction in the U.S., including updated peanut introduction guidelines. Study design: The Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) study is a prospective observational cohort in suburban Massachusetts. Infants' caregivers enrolled between 2014 and 2017, and they reported when they introduced common allergens to their child. Multivariable linear and survival regression analyses were used to examine factors influencing time of introduction of allergens. Results: By 9 months, children old enough to be potentially affected by NIAID's 2017 peanut introduction guidelines were more often introduced to peanut than children enrolled well before guidelines publication [54% vs. 42%, OR: 1.63, CI: (1.03, 2.57), P = 0.03]. At any given time, Black children were 73% [HR: 0.27, CI: (0.11, 0.69), P = 0.006] less likely to be introduced to peanut as early as White children. Asian children were, respectively, 36% [HR: 0.64, CI: (0.47, 0.86), P = 0.003] and 26% [HR: 0.74, CI: (0.55, 0.97), P = 0.03] less likely to be introduced to peanut and egg as early as White children. A first child was 27% [HR: 1.27, CI: (1.04, 1.56), P = 0.02] more likely to have been introduced to peanut earlier than a non-first child. There was no association between age of introduction and sex, gestational age, family history of food allergy, or other allergic comorbidities. Conclusion: Updated introduction guidelines, race, and birth order all influenced earlier introduction of peanut. Further studies to evaluate current practices for allergen introduction with a focus on potential disparities are needed.

Environmental effects and interaction of nanoparticles on beneficial soil and aquatic microorganisms.

A steadily increasing production volume of nanoparticles reflects their numerous industrial and domestic applications. These economic successes come with the potential adverse effects on natural systems that are associated with their presence in the environment. Biological activities and effects of nanoparticles are affected by their entry method together with their specificities like their size, shape, charge, area, and chemical composition. Particles can be classified as safe or dangerous depending on their specific properties. As both aquatic and terrestrial systems suffer from organic and inorganic contamination, nanoparticles remain a sink for these contaminants. Researching the sources, synthesis, fate, and toxicity of nanoparticles has advanced significantly during the last ten years. We summarise nanoparticle pathways throughout the ecosystem and their interactions with beneficial microorganisms in this research. The prevalence of nanoparticles in the ecosystem causes beneficial microorganisms to become hazardous to their cells, which prevents the synthesis of bioactive molecules from undergoing molecular modifications and diminishes the microbe population. Recently, observed concentrations in the field could support predictions of ambient concentrations based on modeling methodologies. The aim is to illustrate the beneficial and negative effects that nanoparticles have on aqueous and terrestrial ecosystems, as well as the methods utilized to reduce their toxicity.

Longitudinal assessment of early growth in children with IgE- and non-IgE-mediated food allergy in a healthy infant cohort.

BACKGROUND: There are conflicting associations reported between food allergies (FAs) and poor growth, with some indication that children with multiple FAs are at highest risk. OBJECTIVE: We analyzed longitudinal weight-for-length (WFL) trajectories from our healthy cohort to evaluate growth in children with IgE-mediated FAs and food protein-induced allergic proctocolitis (FPIAP), a non-IgE-mediated FA. METHODS: Our observational cohort of 903 healthy newborn infants was prospectively enrolled to evaluate the development of FAs. Longitudinal mixed effects modeling was used to compare differences in WFL among children with IgE-FA and FPIAP, compared with unaffected children, through age 2. RESULTS: Among the 804 participants who met inclusion criteria, FPIAP cases had significantly lower WFL than unaffected controls during active disease, which resolved by 1 year of age. In contrast, children with IgE-FA had significantly lower WFL than unaffected controls after 1 year. We also found that children with IgE-FA to cow's milk had significantly lower WFL over the first 2 years of age. Children with multiple IgE-FAs had markedly lower WFL over the first 2 years of age. CONCLUSION: Children with FPIAP have impaired growth during active disease in the first year of age which resolves, whereas children with IgE-FA, particularly those with multiple IgE-FA, have impaired growth more prominently after the first year of age. It may be appropriate to focus nutritional assessment and interventions accordingly during these higher risk periods in these patient populations.

Metabolic capacity to alter polycyclic aromatic hydrocarbons and its microbe-mediated remediation.

The elimination of contaminants caused by anthropogenic activities and rapid industrialization can be accomplished using the widely used technology of bioremediation. Recent years have seen significant advancement in our understanding of the bioremediation of coupled polycyclic aromatic hydrocarbon contamination caused by microbial communities including bacteria, algae, fungi, yeast, etc. One of the newest techniques is microbial-based bioremediation because of its greater productivity, high efficiency, and non-toxic approach. Microbes are appealing candidates for bioremediation because they have amazing metabolic capacity to alter most types of organic material and can endure harsh environmental conditions. Microbes have been characterized as extremophiles that can survive in a variety of environmental circumstances, making them the treasure troves for environmental cleanup and the recovery of contaminated soil. In this study, the mechanisms underlying the bioremediation process as well as the current situation of microbial bioremediation of polycyclic aromatic hydrocarbon are briefly described.

Food Allergy Management Practices Utilizing Individual Patient Thresholds: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee.

The paradigm for food allergy management has been strict avoidance of the food allergen. There is literature supporting a "high-threshold" phenotype, those who tolerate a small-to-modest amount of allergen but react to larger amounts. There is no consensus for best practice for these "high-threshold" individuals. We sought to understand management practices of "high-threshold" reactors using a survey that was distributed to a random sample of fellows and members of the American Academy of Allergy, Asthma, and Immunology. There were 89 respondents from the United States and Canada (11% response rate), with 64 (72%) answering all questions. Participants worked in private (52%) and academic practice (38%) and saw a median of 30 food allergic patients monthly. Eighty-one percent of respondents reported management strategies other than strict avoidance. When threshold was known, strategies ranged from allowing ingestion up to a specified amount (57%), proactively advising ingestion to a certain amount (56%), or oral immunotherapy (47%). Participants were more likely to choose a permissive approach for a mild reaction in a high-threshold milk-allergic patient compared with a peanut-allergic patient (83% vs 71%, p=.01). Important factors that influenced the approach included severity of reaction (52%), comfort with family/patient using emergency medications (42%), and family/patient preferences (41%). These survey results suggest that food allergy management recommendations are no longer binary in nature, with clinicians solely recommending avoidance for those who are allergic and ingestion for those who may not be.

Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children.

BACKGROUND: Studies on the efficacy of peanut sublingual immunotherapy (SLIT) are limited. The durability of desensitization after SLIT has not been well described. OBJECTIVE: We sought to evaluate the efficacy and safety of 4-mg peanut SLIT and persistence of desensitization after SLIT discontinuation. METHODS: Challenge-proven peanut-allergic 1- to 11-year-old children were treated with open-label 4-mg peanut SLIT for 48 months. Desensitization after peanut SLIT was assessed by a 5000-mg double-blind, placebo-controlled food challenge (DBPCFC). A novel randomly assigned avoidance period of 1 to 17 weeks was followed by the DBPCFC. Skin prick test results immunoglobulin levels, basophil activation test results, TH1, TH2, and IL-10 cytokines were measured longitudinally. Safety was assessed through patient-reported home diaries. RESULTS: Fifty-four participants were enrolled and 47 (87%) completed peanut SLIT and the 48-month DBPCFC per protocol. The mean successfully consumed dose (SCD) during the DBPCFC increased from 48 to 2723 mg of peanut protein after SLIT (P < .0001), with 70% achieving clinically significant desensitization (SCD > 800 mg) and 36% achieving full desensitization (SCD = 5000 mg). Modeled median time to loss of clinically significant desensitization was 22 weeks. Peanut skin prick test; peanut-specific IgE, IgG4, and IgG4/IgE ratio; and peanut-stimulated basophil activation test, IL-4, IL-5, IL-13, IFN-γ, and IL-10 changed significantly compared with baseline, with changes seen as early as 6 months. Median rate of reaction per dose was 0.5%, with transient oropharyngeal itching being the most common, and there were no dosing symptoms requiring epinephrine. CONCLUSIONS: In this open-label, prospective study, peanut SLIT was safe and induced clinically significant desensitization in most of the children, lasting more than 17 weeks after discontinuation of therapy.

Early infancy dysbiosis in food protein-induced enterocolitis syndrome: A prospective cohort study.

BACKGROUND: The microbiome associations of food protein-induced enterocolitis syndrome (FPIES) are understudied. We sought to prospectively define the clinical features of FPIES in a birth cohort, and investigate for the evidence of gut dysbiosis. METHODS: We identified children diagnosed with FPIES in the Gastrointestinal Microbiome and Allergic Proctocolitis Study, a healthy infant cohort. Children were assessed and stools were collected at each well child visit. The clinical features of the children with FPIES were summarized. Stool microbiome was analyzed using 16S rRNA sequencing comparing children with and without FPIES. RESULTS: Of the 874 children followed up for 3 years, 8 FPIES cases (4 male) were identified, yielding a cumulative incidence of 0.92%. The most common triggers were oat and rice (n = 3, each) followed by milk (n = 2). The children with FPIES were more likely to have family history of food allergy (50% vs. 15.9% among unaffected, p = .03). The average age of disease presentation was 6 months old. During the first 6 months of life, stool from children with FPIES contained significantly less Bifidobacterium adolescentis, but more pathobionts, including Bacteroides spp. (especially Bacteroides fragilis), Holdemania spp., Lachnobacterium spp., and Acinetobacter lwoffii. The short-chain fatty acid (SCFA)-producing Bifidobacterium shunt was expressed significantly less in the stool from FPIES children. CONCLUSIONS: In this cohort, the cumulative incidence over the 3-year study period was 0.92%. During the first 6 months of life, children with FPIES had evidence of dysbiosis and SCFA production pathway was expressed less in their stool, which may play an important role in the pathogenesis of FPIES.

Longitudinal disease-associated gut microbiome differences in infants with food protein-induced allergic proctocolitis.

BACKGROUND: Complex interactions between the gut microbiome and immune cells in infancy are thought to be part of the pathogenesis for the marked rise in pediatric allergic diseases, particularly food allergies. Food protein-induced allergic proctocolitis (FPIAP) is commonly the earliest recognized non-immunoglobulin E (IgE)-mediated food allergy in infancy and is associated with atopic dermatitis and subsequent IgE-mediated food allergy later in childhood. Yet, a large prospective longitudinal study of the microbiome of infants with FPIAP, including samples prior to symptom onset, has not been done. RESULTS: Here, we analyzed 954 longitudinal samples from 160 infants in a nested case-control study (81 who developed FPIAP and 79 matched controls) from 1 week to 1 year of age by 16S rRNA ribosomal gene sequencing as part of the Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) study. We found key differences in the microbiome of infants with FPIAP, most strongly a higher abundance of a genus of Enterobacteriaceae and a lower abundance of a family of Clostridiales during the symptomatic period. We saw some of these significant taxonomic differences even prior to symptom onset. There were no consistent longitudinal differences in richness or stability diversity metrics between infants with FPIAP and healthy controls. CONCLUSIONS: This study is the first to identify differences in the infant gut microbiome in children who develop FPIAP, some even before they develop symptoms, and provides a foundation for more mechanistic investigation into the pathogenesis of FPIAP and subsequent food allergic diseases in childhood. Video abstract.

Identification of antigen-specific TCR sequences based on biological and statistical enrichment in unselected individuals.

Recent advances in high-throughput T cell receptor (TCR) sequencing have allowed for new insights into the human TCR repertoire. However, methods for capturing antigen-specific repertoires remain an area of development. Here, we describe a potentially novel approach that utilizes both a biological and statistical enrichment to define putatively antigen-specific complementarity-determining region 3 (CDR3) repertoires in unselected individuals. The biological enrichment entailed FACS of in vitro antigen-activated memory CD4+ T cells, followed by TCRß sequencing. The resulting TCRß sequences were then filtered by selecting those that are statistically enriched when compared with their frequency in the autologous resting T cell compartment. Applying this method to define putatively peanut protein-specific repertoires in 27 peanut-allergic individuals resulted in a library of 7345 unique CDR3ß amino acid sequences that had similar characteristics to other validated antigen-specific repertoires in terms of homology and diversity. In-depth analysis of these CDR3ßs revealed 36 public sequences that demonstrated high levels of convergent recombination. In a network analysis, the public CDR3ßs were shown to be core sequences with more edges than their private counterparts. This method has the potential to be applied to a wide range of T cell-mediated disorders and to yield new biomarkers and biological insights.

Rates and risk factors for preterm birth and low birthweight in the global network sites in six low- and low middle-income countries.

BACKGROUND: Preterm birth continues to be a major public health problem contributing to 75% of the neonatal mortality worldwide. Low birth weight (LBW) is an important but imperfect surrogate for prematurity when accurate assessment of gestational age is not possible. While there is overlap between preterm birth and LBW newborns, those that are both premature and LBW are at the highest risk of adverse neonatal outcomes. Understanding the epidemiology of preterm birth and LBW is important for prevention and improved care for at risk newborns, but in many countries, data are sparse and incomplete. METHODS: We conducted data analyses using the Global Network's (GN) population-based registry of pregnant women and their babies in rural communities in six low- and middle-income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India and Pakistan). We analyzed data from January 2014 to December 2018. Trained study staff enrolled all pregnant women in the study catchment area as early as possible during pregnancy and conducted follow-up visits shortly after delivery and at 42 days after delivery. We analyzed the rates of preterm birth, LBW and the combination of preterm birth and LBW and studied risk factors associated with these outcomes across the GN sites. RESULTS: A total of 272,192 live births were included in the analysis. The overall preterm birth rate was 12.6% (ranging from 8.6% in Belagavi, India to 21.8% in the Pakistani site). The overall LBW rate was 13.6% (ranging from 2.7% in the Kenyan site to 21.4% in the Pakistani site). The overall rate of both preterm birth and LBW was 5.5% (ranging from 1.2% in the Kenyan site to 11.0% in the Pakistani site). Risk factors associated with preterm birth, LBW and the combination were similar across sites and included nulliparity [RR - 1.27 (95% CI 1.21-1.33)], maternal age under 20 [RR 1.41 (95% CI 1.32-1.49)] years, severe antenatal hemorrhage [RR 5.18 95% CI 4.44-6.04)], hypertensive disorders [RR 2.74 (95% CI - 1.21-1.33], and 1-3 antenatal visits versus four or more [RR 1.68 (95% CI 1.55-1.83)]. CONCLUSIONS: Preterm birth, LBW and their combination continue to be common public health problems at some of the GN sites, particularly among young, nulliparous women who have received limited antenatal care services. Trial registration The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475. TRIAL REGISTRATION: The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.