Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10-9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10-16 and CPA3; p = 2.39 × 10-14) and wound healing (FN1; p = 7.63 × 10-9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora.

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. OBJECTIVE: To determine if nasal allergen challenge (NAC) responses to cockroach allergen would improve following one year of SCIT. METHODS: Urban children with asthma, that were cockroach-sensitized and reactive on NAC, participated in a yearlong randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean total nasal symptoms scores (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test (SPT) 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=0.63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum specific IgE (sIgE) decreased to a similar extent in both groups, while decreased cockroach SPT wheal size was greater among SCIT participants (p=0.04). A 200-fold increase in cockroach sIgG4 was observed among subjects receiving SCIT (p<0.001) but was unchanged in the placebo group. T-cell interleukin-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (p=0.002), while no effect was observed for interleukin-10 or interferon-gamma. CONCLUSION: 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 sIgG4 production and down-modulation of allergen stimulated T-cell responses.

The Child Opportunity Index 2.0 and exacerbation-prone asthma in a cohort of urban children.

RATIONALE: Social determinants of health underlie disparities in asthma. However, the effects of individual determinants likely interact, so a summary metric may better capture their impact. The Child Opportunity Index 2.0 (COI) is one such tool, yet its association with exacerbation-prone (EP) asthma is unknown. OBJECTIVE: To investigate the association between the COI and EP asthma and clinical measures of asthma severity in children. METHODS: We analyzed data from two prospective observational pediatric asthma cohorts (n = 193). Children were classified as EP (≥1 exacerbation in the past 12 months) or exacerbation-null (no exacerbations in the past 5 years). Spirometry, exhaled nitric oxide, IgE, and Composite Asthma Severity Index (CASI) were obtained. The association between COI and EP status was assessed with logistic regression. We fit linear and logistic regression models to test the association between COI and each clinical measure. RESULTS: A 20-point COI decrease conferred 40% higher odds of EP asthma (OR 1.4; 95%CI 1.1-1.76). The effect was similar when adjusted for age and sex (OR 1.38, 95%CI 1.1-1.75) but was attenuated with additional adjustment for race and ethnicity (OR 1.19, 95%CI 0.92-1.54). A similar effect was seen for the Social/Economic and Education COI domains but not the Health/Environment Domain. A 20-point COI decrease was associated with an increase in CASI of 0.34. COI was not associated with other clinical measures. CONCLUSIONS: Lower COI was associated with greater odds of EP asthma. This highlights the potential use of the COI to understand neighborhood-level risk and identify community targets to reduce asthma disparities.

Extreme genome scrambling in marine planktonic Oikopleura dioica cryptic species.

Genome structural variations within species are rare. How selective constraints preserve gene order and chromosome structure is a central question in evolutionary biology that remains unsolved. Our sequencing of several genomes of the appendicularian tunicate Oikopleura dioica around the globe reveals extreme genome scrambling caused by thousands of chromosomal rearrangements, although showing no obvious morphological differences between these animals. The breakpoint accumulation rate is an order of magnitude higher than in ascidian tunicates, nematodes, Drosophila, or mammals. Chromosome arms and sex-specific regions appear to be the primary unit of macrosynteny conservation. At the microsyntenic level, scrambling did not preserve operon structures, suggesting an absence of selective pressure to maintain them. The uncoupling of the genome scrambling with morphological conservation in O. dioica suggests the presence of previously unnoticed cryptic species and provides a new biological system that challenges our previous vision of speciation in which similar animals always share similar genome structures.

Scaling between cell cycle duration and wing growth is regulated by Fat-Dachsous signaling in Drosophila.

The atypical cadherins Fat and Dachsous (Ds) signal through the Hippo pathway to regulate growth of numerous organs, including the Drosophila wing. Here, we find that Ds-Fat signaling tunes a unique feature of cell proliferation found to control the rate of wing growth during the third instar larval phase. The duration of the cell cycle increases in direct proportion to the size of the wing, leading to linear-like growth during the third instar. Ds-Fat signaling enhances the rate at which the cell cycle lengthens with wing size, thus diminishing the rate of wing growth. We show that this results in a complex but stereotyped relative scaling of wing growth with body growth in Drosophila. Finally, we examine the dynamics of Fat and Ds protein distribution in the wing, observing graded distributions that change during growth. However, the significance of these dynamics is unclear since perturbations in expression have negligible impact on wing growth.

Public perceptions of synthetic cooling agents in electronic cigarettes on Twitter.

Amid a potential menthol ban, electronic cigarette (e-cigarette) companies are incorporating synthetic cooling agents like WS-3 and WS-23 to replicate menthol/mint sensations. This study examines public views on synthetic cooling agents in e-cigarettes via Twitter data. From May 2021 to March 2023, we used Twitter Streaming Application Programming Interface (API), to collect tweets related to synthetic cooling agents with keywords such as 'WS-23,' 'ice,' and 'frozen.' The deep learning RoBERTa (Robustly Optimized BERT-Pretraining Approach) model that can be optimized for contextual language understanding was used to classify attitudes expressed in tweets about synthetic cooling agents and identify e-cigarette users. The BERTopic (a topic modeling technique that leverages Bidirectional Encoder Representations from Transformers) deep-learning model, specializing in extracting and clustering topics from large texts, identified major topics of positive and negative tweets. Two proportion Z-tests were used to compare the proportions of positive and negative attitudes between e-cigarette users (vapers) and non-e-cigarette-users (non-vapers). Of 6,940,065 e-cigarettes-related tweets, 5,788 were non-commercial tweets related to synthetic cooling agents. The longitudinal trend analysis showed a clear upward trend in discussions. Vapers posted most of the tweets (73.05%, 4,228/5,788). Nearly half (47.87%, 2,771/5,788) held a positive attitude toward synthetic cooling agents, which is significantly higher than those with a negative attitude (19.92%,1,153/5,788) with a P-value < 0.0001. The likelihood of vapers expressing positive attitudes (60.17%, 2,544/4,228) was significantly higher (P < 0.0001) than that of non-vapers (14.55%, 227/1,560). Conversely, negative attitudes from non-vapers (30%, 468/1,560) were significantly (P < 0.0001) higher than vapers (16.2%, 685/4,228). Prevalent topics from positive tweets included "enjoyment of specific vape flavors," "preference for lush ice vapes," and "liking of minty/icy feelings." Major topics from negative tweets included "disliking certain vape flavors" and "dislike of others vaping around them." On Twitter, vapers are more likely to have a positive attitude toward synthetic cooling agents than non-vapers. Our study provides important insights into how the public perceives synthetic cooling agents in e-cigarettes. These insights are crucial for shaping future U.S. Food and Drug Administration (FDA) regulations aimed at safeguarding public health.

Activated sputum eosinophils associated with exacerbations in children on mepolizumab.

BACKGROUND: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. OBJECTIVE: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. METHODS: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. RESULTS: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). CONCLUSIONS: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.

Patient Engagement With and Perspectives on a Mobile Health Home Spirometry Intervention: Mixed Methods Study.

BACKGROUND: Patient engagement attrition in mobile health (mHealth) remote patient monitoring (RPM) programs decreases program benefits. Systemic disparities lead to inequities in RPM adoption and use. There is an urgent need to understand patients' experiences with RPM in the real world, especially for patients who have stopped using the programs, as addressing issues faced by patients can increase the value of mHealth for patients and subsequently decrease attrition. OBJECTIVE: This study sought to understand patient engagement and experiences in an RPM mHealth intervention in lung transplant recipients. METHODS: Between May 4, 2020, and November 1, 2022, a total of 601 lung transplant recipients were enrolled in an mHealth RPM intervention to monitor lung function. The predictors of patient engagement were evaluated using multivariable logistic and linear regression. Semistructured interviews were conducted with 6 of 39 patients who had engaged in the first month but stopped using the program, and common themes were identified. RESULTS: Patients who underwent transplant more than 1 year before enrollment in the program had 84% lower odds of engaging (odds ratio [OR] 0.16, 95% CI 0.07-0.35), 82% lower odds of submitting pulmonary function measurements (OR 0.18, 95% CI 0.09-0.33), and 78% lower odds of completing symptom checklists (OR 0.22, 95% CI 0.10-0.43). Patients whose primary language was not English had 78% lower odds of engaging compared to English speakers (OR 0.22, 95% CI 0.07-0.67). Interviews revealed 4 prominent themes: challenges with devices, communication breakdowns, a desire for more personal interactions and specific feedback with the care team about their results, understanding the purpose of the chat, and understanding how their data are used. CONCLUSIONS: Care delivery and patient experiences with RPM in lung transplant mHealth can be improved and made more equitable by tailoring outreach and enhancements toward non-English speakers and patients with a longer time between transplant and enrollment. Attention to designing programs to provide personalization through supplementary provider contact, education, and information transparency may decrease attrition rates.

An Electronic Health Record-Based Automated Self-Rescheduling Tool to Improve Patient Access: Retrospective Cohort Study.

BACKGROUND: In many large health centers, patients face long appointment wait times and difficulties accessing care. Last-minute cancellations and patient no-shows leave unfilled slots in a clinician's schedule, exacerbating delays in care from poor access. The mismatch between the supply of outpatient appointments and patient demand has led health systems to adopt many tools and strategies to minimize appointment no-show rates and fill open slots left by patient cancellations. OBJECTIVE: We evaluated an electronic health record (EHR)-based self-scheduling tool, Fast Pass, at a large academic medical center to understand the impacts of the tool on the ability to fill cancelled appointment slots, patient access to earlier appointments, and clinical revenue from visits that may otherwise have gone unscheduled. METHODS: In this retrospective cohort study, we extracted Fast Pass appointment offers and scheduling data, including patient demographics, from the EHR between June 18, 2022, and March 9, 2023. We analyzed the outcomes of Fast Pass offers (accepted, declined, expired, and unavailable) and the outcomes of scheduled appointments resulting from accepted Fast Pass offers (completed, canceled, and no-show). We stratified outcomes based on appointment specialty. For each specialty, the patient service revenue from appointments filled by Fast Pass was calculated using the visit slots filled, the payer mix of the appointments, and the contribution margin by payer. RESULTS: From June 18 to March 9, 2023, there were a total of 60,660 Fast Pass offers sent to patients for 21,978 available appointments. Of these offers, 6603 (11%) were accepted across all departments, and 5399 (8.9%) visits were completed. Patients were seen a median (IQR) of 14 (4-33) days sooner for their appointments. In a multivariate logistic regression model with primary outcome Fast Pass offer acceptance, patients who were aged 65 years or older (vs 20-40 years; P=.005 odds ratio [OR] 0.86, 95% CI 0.78-0.96), other ethnicity (vs White; P<.001, OR 0.84, 95% CI 0.77-0.91), primarily Chinese speakers (P<.001; OR 0.62, 95% CI 0.49-0.79), and other language speakers (vs English speakers; P=.001; OR 0.71, 95% CI 0.57-0.87) were less likely to accept an offer. Fast Pass added 2576 patient service hours to the clinical schedule, with a median (IQR) of 251 (216-322) hours per month. The estimated value of physician fees from these visits scheduled through 9 months of Fast Pass scheduling in professional fees at our institution was US $3 million. CONCLUSIONS: Self-scheduling tools that provide patients with an opportunity to schedule into cancelled or unfilled appointment slots have the potential to improve patient access and efficiently capture additional revenue from filling unfilled slots. The demographics of the patients accepting these offers suggest that such digital tools may exacerbate inequities in access.

Evaluation of Enterococcus faecium NRRL B-2354 as a surrogate for Listeria monocytogenes during chlorine and peroxyacetic acid interventions in simulated apple dump tank water.

Sanitizers are widely incorporated in commercial apple dump tank systems to mitigate the cross-contamination of foodborne pathogens. This study validated the suitability of Enterococcus faecium NRRL B-2354 as a surrogate for Listeria monocytogenes during sanitizer interventions in dump tank water systems. E. faecium NRRL B-2354 inoculated on apples exhibited statistically equivalent susceptibility to L. monocytogenes when exposed to chlorine-based sanitizers (25-100 ppm free chlorine (FC)) and peroxyacetic acid (PAA, 20-80 ppm) in simulated dump tank water (SDTW) with 1000 ppm chemical oxygen demand (COD), resulting in 0.2-0.9 and 1.1-1.7 log CFU/apple reduction, respectively. Increasing the contact time did not affect sanitizer efficacies against E. faecium NRRL B-2354 and L. monocytogenes on apples. Chlorine and PAA interventions demonstrated statistically similar efficacies against both bacteria inoculated in SDTW. Chlorine at 25 and 100 ppm FC for 0.5-5 min contact yielded ~37.68-78.25 % and > 99.85 % inactivation, respectively, in water with 1000-4000 ppm COD, while ~51.55-99.86 % and > 99.97 % inactivation was observed for PAA at 20 and 80 ppm, respectively. No statistically significant difference was observed between the transference of E. faecium NRRL B-2354 and L. monocytogenes from inoculated apples to uninoculated apples and water, and from water to uninoculated apples during chlorine- or PAA-treated SDTW exposure. The data suggest E. faecium NRRL B-2354 is a viable surrogate for L. monocytogenes in dump tank washing systems, which could be used to predict the anti-Listeria efficacy of chlorine and PAA interventions during commercial apple processing. Further investigations are recommended to assess the suitability of E. faecium NRRL B-2354 as a surrogate for L. monocytogenes, when using different sanitizers and different types of produce to ensure reliable and comprehensive results.

Emergency management and asthma risk in young Medicaid-enrolled children with recurrent wheeze.

OBJECTIVES: To describe clinical characteristics of young children presenting to the emergency department (ED) for early recurrent wheeze, and determine factors associated with subsequent persistent wheeze and risk for early childhood asthma. METHODS: Retrospective cohort study of Medicaid-enrolled children 0-3 years old with an index ED visit for wheeze (e.g. bronchiolitis, reactive airway disease) from 2009 to 2013, and at least one prior documented episode of wheeze at an ED or primary care visit. The primary outcome was persistent wheeze between 4 and 6 years of age. Demographics and clinical characteristics were collected from the index ED visit. Logistic regression was used to estimate the association between potential risk factors and subsequent persistent wheeze. RESULTS: During the study period, 41,710 children presented to the ED for recurrent wheeze. Mean age was 1.3 years; 59% were male, 42% Black, and 6% Hispanic. At index ED visits, the most common diagnosis was acute bronchiolitis (40%); 77% of children received an oral corticosteroid prescription. Between 4 and 6 years of age, 11,708 (28%) children had persistent wheeze. A greater number of wheezing episodes was associated with an increased odds of ED treatment with asthma medications. Subsequent persistent wheeze was associated with male sex, Black race, atopy, prescription for bronchodilators or corticosteroids, and greater number of visits for wheeze. CONCLUSIONS: Young children with persistent wheeze are at risk for childhood asthma. Thus, identification of risk factors associated with persistent wheeze in young children with recurrent wheeze might aid in early detection of asthma and initiation of preventative therapies.

Lifelong Chronic Sleep Disruption in a Mouse Model of Traumatic Brain Injury.

Chronic sleep/wake disturbances (SWDs) are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong SWDs. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in 4-month-old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. Sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at 3 months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Further, TBI mice showed extensive brain tissue loss and increased glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 levels in the hypothalamus and vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes post-TBI early in life.

Investigating navigation strategies in the Morris Water Maze through deep reinforcement learning.

Navigation is a complex skill with a long history of research in animals and humans. In this work, we simulate the Morris Water Maze in 2D to train deep reinforcement learning agents. We perform automatic classification of navigation strategies, analyze the distribution of strategies used by artificial agents, and compare them with experimental data to show similar learning dynamics as those seen in humans and rodents. We develop environment-specific auxiliary tasks and examine factors affecting their usefulness. We suggest that the most beneficial tasks are potentially more biologically feasible for real agents to use. Lastly, we explore the development of internal representations in the activations of artificial agent neural networks. These representations resemble place cells and head-direction cells found in mouse brains, and their presence has correlation to the navigation strategies that artificial agents employ.

Prehospital Naloxone Administration Patterns during the Era of Synthetic Opioids.

Background: The opioid epidemic is an ongoing public health emergency, exacerbated in recent years by the introduction and rising prevalence of synthetic opioids. The National EMS Scope of Practice Model was changed in 2017 to recommend allowing basic life support (BLS) clinicians to administer intranasal (IN) naloxone. This study examines local IN naloxone administration rates for 4 years after the new recommendation, and Glasgow Coma Scale (GCS) scores and respiratory rates before and after naloxone administration.Methods: This retrospective cohort study evaluated naloxone administrations between April 1st 2017 and March 31st 2021 in a mixed urban-suburban EMS system. Naloxone dosages, routes of administration, and frequency of administrations were captured along with demographic information. Analysis of change in the ratio of IN to intravenous (IV) naloxone administrations per patient was performed, with the intention of capturing administration patterns in the area. Analyses were performed for change over time of IN naloxone rates of administration, change in respiratory rates, and change in GCS scores after antidote administration. ALS and BLS clinician certification levels were also identified. Bootstrapping procedures were used to estimate 95% confidence intervals for correlation coefficients.Results: Two thousand and ninety patients were analyzed. There was no statistically significant change in the IN/parenteral ratio over time (p = 0.79). Repeat dosing increased over time from 1.2 ± 0.4 administrations per patient to 1.3 ± 0.5 administrations per patient (r = 0.078, 95% CI: 0.036 - 0.120; p = 0.036). Mean respiratory rates before (mean = 12.6 - 12.6, r = -0.04, 95% CI: -0.09 - 0.01; p = 0.1) and after (mean = 15.2 - 14.9, r = -0.03, 95% CI: -0.08 - 0.01; p = 0.172) naloxone administration have not changed. While initial GCS scores have become significantly lower, GCS scores after administration of naloxone have not changed (initial median GCS 10 - 6, p < 0.001; final median GCS 15 - 15, p = 0.23).Conclusions: Current dosing protocols of naloxone appear effective in the era of synthetic opioids in our region, although patients may be marginally more likely to require repeat naloxone doses.

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.

Assessing the contributions of phylogenetic and environmental determinants of allergic cosensitization to fungi in humans.

BACKGROUND: Understanding how allergies to 1 environmental fungus can lead to cosensitization to related fungi is important for the clinical management of allergies. Cosensitization can be caused by monosensitization combined with antibody cross-reactivity, or by coexposures driving independent sensitizations. A pioneering study showed that patterns of IgE cosensitization among 17 fungal species mirror fungal phylogeny. This could reflect either epitope or habitat similarity. Thanks to an improved understanding of fungal phylogeny, larger serologic testing datasets, and environmental data on household fungi, we can now characterize the relationship between cosensitization, species similarity, and likely coexposure with greater precision. OBJECTIVE: To assess the degree to which IgE cosensitization in a group of 17 fungi can be attributed to species similarity or environmental coexposure. METHODS: Cosensitization patterns among 17 fungal species were estimated from a dataset of approximately 8 million serologic tests on 1.6 million patients. Linear regression of cosensitization on phylogenetic distance and imputed coexposure was performed. In addition, branch lengths for the phylogenetic tree were re-estimated on the basis of cosensitization and compared with corresponding phylogenetic branch lengths. RESULTS: Phylogenetic distance explains much of the observed cosensitization (adjusted r2 = .68, p < .001). Imputed environmental coexposures and test co-ordering patterns do not significantly predict cosensitization. Branch length comparisons between the cosensitization and phylogenetic trees identified several species as less cosensitizing than phylogenetic distance predicts. CONCLUSION: Combined evidence from clinical IgE testing data on fungi, along with phylogenetic and environmental exposure data, supports the hypothesis that cosensitization is caused primarily by monosensitization plus cross-reactivity, rather than multisensitization. A serologic test result should be interpreted as pointing to a group of related species that include the sensitizing agent rather than as uniquely identifying the agent. The identified patterns of cross-reactivity may help optimize test panel design.

A Wireless Wearable Patch for Remote Monitoring of Respiratory and Cardiac Rhythm in Children.

Remote patient monitoring (RPM) is an innovative strategy to promote health and improve patient management and care. Recent advances in healthcare technologies have seen the emergence of wearable sensors allowing longitudinal physiological measurements in any environment. This paper introduces a wireless wearable patch 'Leo' for continuous remote monitoring of physiological data at home and healthcare settings. This includes single lead ECG, chest impedance, heart rate (HR), respiration rate (RR) and body posture. To test Leo's ability to capture longitudinal physiological data at home, 15 children experiencing acute severe asthma exacerbations were recruited during their emergency department (ED) visits. Participants wore the Leo device for 7 (+/-2) days post-hospital discharge. Nocturnal RR and HR and variability were higher during the first half of the night on Day1 compared to Day7 (p<0.005). Participants also completed a usability questionnaire and reported the patch wear to be comfortable (average score of 3.3 out of 5) and easy to wear during the night (average score of 3.5 out of 5) with 5/15 (33%) reported very slight barely perceptible skin irritation/redness and 2 (13%) reported well defined skin irritation and redness.Clinical Relevance- These results highlight the potential use of the Leo device in clinical practice for continuous un-obstructive monitoring of diseased populations, such as asthma.

Effectiveness of caffeine and blue-enriched light on cognitive performance and electroencephalography correlates of alertness in a spaceflight robotics simulation.

Human cognitive impairment associated with sleep loss, circadian misalignment and work overload is a major concern in any high stress occupation but has potentially catastrophic consequences during spaceflight human robotic interactions. Two safe, wake-promoting countermeasures, caffeine and blue-enriched white light have been studied on Earth and are available on the International Space Station. We therefore conducted a randomized, placebo-controlled, cross-over trial examining the impact of regularly timed low-dose caffeine (0.3 mg per kg per h) and moderate illuminance blue-enriched white light (~90 lux, ~88 melEDI lux, 6300 K) as countermeasures, separately and combined, in a multi-night simulation of sleep-wake shifts experienced during spaceflight among 16 participants (7 F, ages 26-55). We find that chronic administration of low-dose caffeine improves subjective and objective correlates of alertness and performance during an overnight work schedule involving chronic sleep loss and circadian misalignment, although we also find that caffeine disrupts subsequent sleep. We further find that 90 lux of blue-enriched light moderately reduces electroencephalogram (EEG) power in the theta and delta regions, which are associated with sleepiness. These findings support the use of low-dose caffeine and potentially blue-enriched white light to enhance alertness and performance among astronauts and shiftworking populations.