EMS Administration of Systemic Corticosteroids to Pediatric Asthma Patients: An Analysis by Severity and Transport Interval.

INTRODUCTION: Pediatric asthma exacerbations are a common cause of emergency medical services (EMS) encounters. Bronchodilators and systemic corticosteroids are mainstays of asthma exacerbation therapy, yet data on the efficacy of EMS administration of systemic corticosteroids are mixed. This study's objective was to assess the association between EMS administration of systemic corticosteroids to pediatric asthma patients on hospital admission rates based on asthma exacerbation severity and EMS transport intervals. METHODS: This is a sub-analysis of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI AS ODT). EASI AS ODT is a non-randomized, stepped wedge, observational study examining outcomes one year before and one year after seven EMS agencies incorporated an oral systemic corticosteroid option into their protocols for the treatment of pediatric asthma exacerbations. We included EMS encounters for patients ages 2-18 years confirmed by manual chart review to have asthma exacerbations. We compared hospital admission rates across asthma exacerbation severities and EMS transport intervals using univariate analyses. We geocoded patients and created maps to visualize the general trends of patient characteristics. RESULTS: A total of 841 pediatric asthma patients met inclusion criteria. While most patients were administered inhaled bronchodilators by EMS (82.3%), only 21% received systemic corticosteroids, and only 19% received both inhaled bronchodilators and systemic corticosteroids. Overall, there was no significant difference in hospitalization rates between patients who did and did not receive systemic corticosteroids from EMS (33% vs. 32%, p = 0.78). However, although not statistically significant, for patients who received systemic corticosteroids from EMS, there was an 11% decrease in hospitalizations for mild exacerbation patients and a 16% decrease in hospitalizations for patients with EMS transport intervals greater than 40 min. CONCLUSION: In this study, systemic corticosteroids were not associated with a decrease in hospitalizations of pediatric patients with asthma overall. However, while limited by small sample size and lack of statistical significance, our results suggest there may be a benefit in certain subgroups, particularly patients with mild exacerbations and those with transport intervals longer than 40 min. Given the heterogeneity of EMS agencies, EMS agencies should consider local operational and pediatric patient characteristics when developing standard operating protocols for pediatric asthma.

Thymic involution and rising disease incidence with age.

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

A Statewide Analysis of EMS' Pediatric Transport Destination Decisions.

Introduction: Deciding where to transport a patient is a key decision made by emergency medical services (EMS), particularly for children because pediatric hospital resources are regionalized. Since evidence-based guidelines for pediatric transport destinations are being developed, the purpose of this study was to use a large statewide EMS database to describe current patterns of EMS providers' transport destination decisions for pediatric patients.Methods: This is a retrospective study of pediatric transports from 2011-2016 in EMS Tracking and Reporting System (EMSTARS), Florida's statewide EMS database. We included patients greater than 1 day and less than or equal to 18 years who were primary EMS scene transports. Our primary outcome variable was 'reason for choosing destination.' We performed descriptive and comparative analysis between closest facility and all other 'reason for choosing destination' choices. We used geospatial analysis to examine destination choice in urban and rural counties.Results: Our final study sample was 446,274, and 48.2% of patients had closest facility as their 'reason for choosing destination.' The next largest category was patient/family choice (154,035 patients, 35.7%). Closest facility patients were older (median age 12 versus 10 years, p < 0.0001) and had shorter median EMS transport times (11.3 versus 15 minutes, p < 0.0001) compared to all other destination decisions. Notably, 60% of respiratory distress patients' and 44% of seizure patients' reason for choosing destination was something other than closest facility. Geospatial analysis revealed that fewer rural patients were documented as closest facility compared to urban (43.9% versus 47%, p < 0.0001). Correspondingly, more rural patients' destination decision was patient/family choice than urban patients (36.3% versus 34.3%, p < 0.0001).Conclusions: This large, statewide study describes EMS' reason for choosing destination for pediatric patients. We found that just under half of patients were documented as closest facility, and over one-third as patient/family choice. Significant differences in destination reasons were noted for rural versus urban counties. This study can help those currently developing pediatric EMS destination guidelines by revealing a high proportion of patient/family choice and identifying conditions with high proportions of destination reasons other than closest facility.

A Geospatial Analysis of Distances to Hospitals that Admit Pediatric Asthma Patients.

Objective: Pediatric care is now concentrated in urban specialty centers ("regionalization"), even for common conditions such as asthma. At the same time, rural emergency medical services (EMS) faces challenges related to adequate workforce staffing and financing. This statewide study describes how regionalization of pediatric inpatient care for asthma exacerbations affects EMS operations, particularly for rural agencies. Methods: This is a statewide cross-sectional study of EMS encounters for pediatric asthma in patients aged 2-18 years from 2011 to 2016 using Florida's EMS Tracking and Reporting System (EMSTARS) database. EMSTARS encounters were deterministically linked to Florida's Agency for Healthcare Administration (AHCA) database. We categorized AHCA hospital facilities that received included patients by whether they did or did not admit pediatric asthma patients during the study period ("admitting facility"). We used geospatial analysis to map the EMS agency's home county and the admitting facilities addresses. For each county in Florida, we calculated the average estimated EMS travel distance to the nearest admitting facility using a dasymetric mapping approach. Results: The study included a total of 11,226 EMS pediatric asthma encounters, of which 11,153 (99%) matched to an EMS home county. AHCA data was available for 3,812 (34%) patients. Most counties with distances to admitting facilities less than or equal to 15 miles were urban (31 of 39). For distances of 31-45 miles to an admitting facility, 7 of 8 of counties were rural, and for distances greater than 46 miles, all 4 counties were rural. Conclusions: In this statewide study in Florida, we found long average estimated EMS travel distances to admitting facilities for Florida's pediatric population in rural counties for pediatric asthma exacerbations. Those long distances have great implications for rural EMS operations, including pediatric destination decisions, transport times, and availability for others who call 9-1-1. Further research on bypass and secondary transport rates, and outcomes for asthma and other pediatric conditions are required to further characterize pediatric regionalization's impact on rural EMS.

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells.

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells' RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes.

Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis.

During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC-fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells.

Examination of disparities in prehospital encounters for pediatric asthma exacerbations.

Introduction: There are disparities in multiple aspects of pediatric asthma care; however, prehospital care disparities are largely undescribed. This study's objective was to examine racial and geographic disparities in emergency medical services (EMS) medication administration to pediatric patients with asthma. Methods: This is a substudy of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial, which includes data from pediatric asthma patients ages 2-18 years. We examined rates of EMS administration of systemic corticosteroids and inhaled bronchodilators by patient race. We geocoded EMS scene addresses, characterized the locations' neighborhood-based conditions and resources relevant to children using the Child Opportunity Index (COI) 2.0, and analyzed associations between EMS scene address COI with medications administered by EMS. Results: A total of 765 patients had available racial data and 825 had scene addresses that were geocoded to a COI. EMS administered at least 1 bronchodilator to 84.7% (n = 492) of non-White patients and 83.2% of White patients (n = 153), P = 0.6. EMS administered a systemic corticosteroid to 19.4% (n = 113) of non-White patients and 20.1% (n = 37) of White patients, P = 0.8. There was a significant difference in bronchodilator administration between COI categories of low/very low versus moderate/high/very high (85.0%, n = 485 vs. 75.9%, n = 192, respectively, P = 0.003). Conclusions: There were no racial differences in EMS administration of medications to pediatric asthma patients. However, there were significantly higher rates of EMS bronchodilator administration for encounters in low/very low COIs. That latter finding may reflect inequities in asthma exacerbation severity for patients living in disadvantaged areas.

Occam's razor gets a new edge: the use of symmetries in model selection.

We demonstrate the power of using symmetries for model selection in the context of mechanistic modelling. We analyse two different models called the power law model (PLM) and the immunological model (IM) describing the increase in cancer risk with age, due to mutation accumulation or immunosenescence, respectively. The IM fits several cancer types better than the PLM implying that it would be selected based on minimizing residuals. However, recently a symmetry-based method for model selection has been developed, which has been successfully used in an in silico setting to find the correct model when traditional model fitting has failed. Here, we apply this method in a real-world setting to investigate the mechanisms of carcinogenesis. First, we derive distinct symmetry transformations of the two models and then we select the model which not only fits the original data but is also invariant under transformations by its symmetry. Contrary to the initial conclusion, we conclude that the PLM realistically describes the mechanism underlying the colon cancer dataset. These conclusions agree with experimental knowledge, and this work demonstrates how a model selection criterion based on biological properties can be implemented using symmetries.

COVID-19 hospitalization rates rise exponentially with age, inversely proportional to thymic T-cell production.

Here, we report that COVID-19 hospitalization rates follow an exponential relationship with age, doubling for every 16 years of age or equivalently increasing by 4.5% per year of life (R2 = 0.98). This mirrors the well-studied exponential decline of both thymus volume and T-cell production, which halve every 16 years. COVID-19 can therefore be added to the list of other diseases with this property, including those caused by methicillin-resistant Staphylococcus aureus, MERS-CoV, West Nile virus, Streptococcus pneumoniae and certain cancers, such as chronic myeloid leukaemia and brain cancers. In addition, the incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. Since these properties are shared with some non-contagious diseases, we hypothesized that the age dependence does not come from social-mixing patterns, i.e. that the probability of hospitalization given infection rises exponentially, doubling every 16 years. A Bayesian analysis of daily hospitalizations, incorporating contact matrices, found that this relationship holds for every age group except for the under 20s. While older adults have fewer contacts than young adults, our analysis suggests that there is an approximate cancellation between the effects of fewer contacts for the elderly and higher infectiousness due to a higher probability of developing severe disease. Our model fitting suggests under 20s have 49-75% additional immune protection beyond that predicted by strong thymus function alone, consistent with increased juvenile cross-immunity from other viruses. We found no evidence for differences between age groups in susceptibility to infection or infectiousness to others (given disease state), i.e. the only important factor in the age dependence of hospitalization rates is the probability of hospitalization given infection. These findings suggest the existence of a T-cell exhaustion threshold, proportional to thymic output and that clonal expansion of peripheral T-cells does not affect disease risk. The strikingly simple inverse relationship between risk and thymic T-cell output adds to the evidence that thymic involution is an important factor in the decline of the immune system with age and may also be an important clue in understanding disease progression, not just for COVID-19 but other diseases as well.

Clinical, Operational, and Socioeconomic Analysis of EMS Bypass of the Closest Facility for Pediatric Asthma Patients.

INTRODUCTION: Pediatric hospital care is becoming increasingly regionalized, with fewer facilities providing inpatient care for common conditions such as asthma. That trend has major implications for emergency medical services (EMS) medical care and operations because EMS historically transports patients to the closest facility. This study describes EMS transport patterns of pediatric asthma patients in greater depth, including an analysis of facility bypass rates and the association of bypass with demographics and clinical outcomes. METHODS: This was a retrospective study of pediatric asthma patients ages 2-18 years transported by Lee County, FL EMS between March 1, 2018 - December 31, 2019. A priori, we defined bypass as greater than five minutes extra transport time. We performed geospatial analysis and mapping of EMS pediatric asthma encounters. We used the Pediatric Destination Tree (PDTree) project's tiered approach to characterize receiving hospital facility pediatric capability. We analyzed incidence and characteristics of bypass, and bypass and non-bypass patient characteristics including demographics, emergency department (ED) clinical outcomes, and socioeconomic disadvantage (SED). RESULTS: From the study period, there were a total of 262 encounters meeting inclusion criteria, 254 (96.9%) of which could be geocoded to EMS incident and destination locations. Most encounters (72.8%) bypassed at least one facility, and the average number of facilities bypassed per encounter was 1.52. For all 185 bypass encounters, there was a median additional travel time of 13.5 minutes (interquartile range 7.5 - 17.5). Using the PDTree's classification of pediatric capability of destination facilities, 172 of the 185 bypasses (93%) went to a Level I facility. Bypass incidence varied significantly by age, but not by minority status, asthma severity, or by the area deprivation index of the patient's home address. Overall, the highest concentrations of EMS incidents tended to occur in areas of greater SED. With regard to ED outcomes, ED length of stay did not vary between bypass and non-bypass patients (P = 0.54), and neither did hospitalization (P = 0.80). CONCLUSION: We found high rates of bypass for pediatric EMS encounters for asthma exacerbations, and that bypass frequency was significantly higher in younger age groups. With national trends pointing toward increasing pediatric healthcare regionalization, bypass has significant implications for EMS operations.

Early administration of steroids in the ambulance setting: Protocol for a type I hybrid effectiveness-implementation trial with a stepped wedge design.

BACKGROUND: Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes. PURPOSE: To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework. METHODS: The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data. CONCLUSION: This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients.